Cyclopropene derivatives

FIELD OF THE INVENTION
The present invention relates to novel cyclopropene derivatives, and more specifically, the present invention relates to novel cyclopropene derivatives useful as intermediates for the production of cyclopropenone derivatives having strong inhibitory activity against thiol protease such as calpain, papain, cathepsin B, cathepsin H, cathepsin L and the like, or the salts thereof.
BACKGROUND OF THE INVENTION
As the biological action of thiol protease such as calpain, papain, cathepsin B, cathepsin H, cathepsin L. etc. has been elucidated, it has been found that the abnormal increase thereof is the cause of various diseases, so that the inhibitors of thiol protease have been used as their therapeutical agents of those diseases. For example,, reports have been issued that calpain inhibitors have effects on animal models with muscular dystrophy, cataract, myocardial infarction, delayed death of neurocytes after brain infarction, and the like, while cathepsin inhibitors have effects on cancer metastasis, amyotrophy, osteoporosis and the like. However, because known inhibitors of thiol proteases, such as peptidyl aldehydes, epoxy succinate derivatives, etc., are poor in oral administration, tissue distribution, and cell membrane permeability, expectation has been toward the development of novel thiol protease inhibitors which can overcome these problems.
SUMMARY OF THE INVENTION
Thus, the present inventors have made investigations of the intermediate for the production of a thiol protease inhibitor showing excellent oral administration, tissue distribution, and cell membrane permeability. Then, the inventors have achieved the present invention.
The present invention resides in cyclopropene derivatives represented by the general formula (I): ##STR1## [In the above general formula (I), R.sup.1 represents hydrogen atom or a protective group of amino group; R.sup.2 represents hydrogen atom, a protective group of amino group or C.sub.1 -C.sub.5 alkyl group; or when R.sup.1 and R.sup.2 are taken together, they represent phthaloyl group; R.sup.4 and R.sup.6 independently represent hydrogen atom or C.sub.1 -C.sub.5 alkyl group; R.sup.3 and R.sup.5 independently represent hydrogen atom or C.sub.1 -C.sub.15 alkyl group optionally substituted with C.sub.3 -C.sub.10 cycloalkyl group or C.sub.6 -C.sub.10 aryl group; or when R.sup.5 and R.sup.6 are taken together, they represent C.sub.2 -C.sub.6 alkylene group; R.sup.7 and R.sup.8 represent --OR.sup.10 and --OR.sup.11, respectively (wherein R.sup.10 and R.sup.11 independently represent C.sub.1 -C.sub.5 alkyl group optionally substituted with phenyl group: or when R.sup.10 and R.sup.11 are taken together, they represent C.sub.2 -C.sub.6 alkylene group optionally substituted with one or more C.sub.1 -C.sub.5 alkyl groups); or when R.sup.7 and R.sup.8 are taken together, they represent .dbd.O; R.sup.9 represents hydrogen atom, C.sub.1 -C.sub.15 alkyl group, C.sub.3 -C.sub.10 cycloalkyl group, C.sub.2 -C.sub.15 alkenyl group, C.sub.6 -C.sub.10 aryl group optionally substituted with a substituent, heterocyclic group optionally substituted with a substituent, or --CR.sup.12 R.sup.13 OH (wherein R.sup.12 and R.sup.13 independently represent hydrogen atom, C.sub.1 -C.sub.15 alkyl group or C.sub.6 -C.sub.10 aryl group; or when R.sup.12 and R.sup.13 are taken together to form C.sub.3 -C.sub.10 cycloalkyl group); and n represents 0 or 1, provided that when n represents 1, R.sup.7,when taken together with R.sup.8 does not represent .dbd.O], and the salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention will now be explained in details. The compound of the present invention is cyclopropene derivatives represented by the general formula (I): ##STR2## [In the above general formula (I), R.sup.1 represents hydrogen atom or a protective group of amino group (urethane-type protective group such as methoxycarbonyl group, tert-butoxycarbonyl group, benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, 4-chlorobenzyloxycarbonyl group, 3,5-dimethoxybenzyloxycarbonyl group, 3,4,5-trimethoxybenzyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, etc.; acyl-type protective group such as formyl group, trifluoroacetyl group, p-toluene sulfonyl group, 2,4,6-trimethylbenzene sulfonyl group, benzoyl group, chloroacetyl group, etc.; alkyl-type protective group such as benzyl group, diphenylmethyl group, trityl group, etc.); R.sup.2 represents hydrogen atom, a protective group of amino group (which is as defined for R.sup.1) or C.sub.1 -C.sub.5 alkyl group (methyl group, propyl group, pentyl group, etc.); or when R.sup.1 and R.sup.2 are taken together, they represent phthaloyl group; R.sup.4 and R.sup.6 independently represent hydrogen atom or C.sub.1 -C.sub.5 alkyl group (methyl group, propyl group, pentyl group, etc.); R.sup.3 and R.sup.5 independently represent hydrogen atom or C.sub.1 -C.sub.15 alkyl group (methyl group, hexyl group, decyl group, pentadecyl group, etc.) optionally substituted with C.sub.3 -C.sub.10 cycloalkyl group (cyclopropyl group, cyclopentyl group, cyclodecyl group, etc.) or C.sub.6 -C.sub.10 aryl group (phenyl group, naphtyl group, etc.); or when R.sup.5 and R.sup.6 are taken together, they represent C.sub.2 -C.sub.6 alkylene group (ethylene group, tetramethylene group, hexamethylene group, etc.); R.sup.7 and R.sup.8 represent --OR.sup.10 and --OR.sup.11, respectively (wherein R.sup.10 and R.sup.11 independently represent C.sub.1 -C.sub.5 alkyl group (methyl group, propyl group, pentyl group, etc.) optionally substituted with phenyl group; or when R.sup.10 and R.sup.11 are taken together, they represent C.sub.2 -C.sub.6 alkylene group (ethylene group, tetramethylene group, hexamethylene group, etc.) optionally substituted with one or more C.sub.1 -C.sub.5 alkyl groups (methyl group, propyl group, pentyl group, etc.); or when R.sup.7 and R.sup.8 are taken together, they represent .dbd.O; R.sup.9 represents hydrogen atom; C.sub.1 -C.sub.15 alkyl group (methyl group, hexyl group, decyl group, pentadecyl group, etc.); C.sub.3 -C.sub.10 cycloalkyl group (cyclopropyl group, cyclopentyl group, cyclodecyl group, etc.); C.sub.2 -C.sub.15 alkenyl group (vinyl group, hexenyl group, undecenyl group, pentadecenyl group, etc.); C.sub.6 -C.sub.10 aryl group (phenyl group, naphtyl group, etc.) optionally substituted with one or more substituents selected from the group consisting of halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), C.sub.1 -C.sub.5 alkyl group (methyl group, propyl group, pentyl group, etc.), hydroxyl group and C.sub.1 -C.sub.5 alkoxy group (methoxy group, propoxy group, pentyloxy group, etc.); a heterocyclic group having one to four hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom with the total number of the atoms constituting the ring being in the range of from 5 to 10 (furane ring, thiophene ring, pyridine ring, pyridine oxide ring, pyrimidine ring, pyridazine ring, benzofurane ring, benzothiophene ring, quinoline ring, naphthyridine ring, etc.), and optionally substituted with one or more substituents selected from the group consisting of C.sub.3 -C.sub.12 trialkylsilyl group (trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, etc.), halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), C.sub.1 -C.sub.5 alkyl group (methyl group, propyl group, pentyl group, etc.), hydroxyl group and C.sub.1 -C.sub.5 alkoxy group (methoxy group, propoxy group, pentyloxy group, etc.); or --CR.sup.12 R.sup.13 OH (wherein R.sup.12 and R.sup.13 independently represent hydrogen atom, C.sub.1 -C.sub.15 alkyl group (methyl group, hexyl group, decyl group, pentadecyl group, etc.) or C.sub.6 -C.sub.10 aryl group (phenyl group, naphthyl group, etc.); or when R.sup.12 and R.sup.13 are taken to form C.sub.3 -C.sub.10 cycloalkyl group (cyclopropyl group, cyclopentyl group, cyclodecyl group, etc.); and n represents 0 or 1, provided that when n represents 1, R.sup.7, when taken together with R.sup.8 does not represent .dbd.O], and the salt thereof.
Particularly preferable is a compound of the formula (I) in which R.sup.1 represents hydrogen atom, tert-butoxycarbonyl group, benzyloxycarbonyl group, methoxycarbonyl group, 9-fluorenylmethoxycarbonyl group, p-toluene sulfonyl group, or trityl group; R.sup.2, R.sup.4 and R.sup.6 independently represent hydrogen atom or C.sub.1 -C.sub.3 alkyl group; or when R.sup.1 and R.sup.2 are taken together, they represent phthaloyl group; R.sup.3 and R.sup.5 independently represent hydrogen atom or C.sub.1 -C.sub.5 alkyl group optionally substituted with C.sub.1 -C.sub.5 cycloalkyl group, phenyl group or naphtyl group; or R.sup.5, when taken together with R.sup.6 represents C.sub.3 -C.sub.6 cycloalkyl group; R.sup.7 and R.sup.8 represent-OR.sup.10 and --OR.sup.11, respectively (wherein R.sup.10 and R.sup.11 independently represent C.sub.1 -C.sub.3 alkyl group optionally substituted with phenyl group; or R.sup.10, when taken together with R.sup.11 represents C.sub.2 -C.sub.4 alkylene group optionally substituted with one or more C.sub.1 -C.sub.3 alkyl groups; or R.sup.7,when taken together with R.sup.8 represents .dbd.O;R.sup.9 represents hydrogen atom; C.sub.1 -C.sub.6 alkyl group; C.sub.3 -C.sub.8 cycloalkyl group; C.sub.2 -C.sub.8 alkenyl group; phenyl group or naphtyl group each optionally substituted with one or more substituents selected from the group consisting of halogen atom, C.sub.1 -C.sub.5 alkyl group and C.sub.1 -C.sub.5 alkoxy group; heterocyclic group having one to four hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom with the total number of the atoms constituting the ring being in the range of from 5 to 10, and optionally substituted with one or more substituents selected from the group consisting of halogen atom, C.sub.1 -C.sub.5 alkyl group, C.sub.1 -C.sub.5 alkoxy group and C.sub.3 -C.sub.12 trialkylsilyl group; or --CR.sup.12 R.sup.13 OH (wherein R.sup.12 and R.sup.13 independently represent hydrogen atom, C.sub.1 -C.sub.3 alkyl group or phenyl group); and n represents 0 or 1, provided that when n represents 1, R.sup.7, when taken together with R.sup.8 does not represent .dbd.O.
Most preferable is a compound of the formula (I) in which R.sup.1 represents hydrogen atom, tert-butoxycarbonyl group, benzyloxycarbonyl group or methoxycarbonyl group; R.sup.2, R.sup.4 and R.sup.6 independently represent hydrogen atom or C.sub.1 -C.sub.3 alkyl group; R.sup.3 and R.sup.5 independently represent hydrogen atom or C.sub.1 -C.sub.5 alkyl group optionally substituted with phenyl group; R.sup.7 and R.sup.8 represent --OR.sup.10 and --OR.sup.11, respectively (wherein R.sup.10, when taken together with R.sup.11 represents C.sub.2 -C.sub.4 alkylene group optionally substituted with one or more substituents selected from C.sub.1 -C.sub.3 alkyl groups; or R.sup.7, when taken together with R.sup.8 represents .dbd.O; R.sup.9 represents hydrogen atom; C.sub.1 -C.sub.6 alkyl group; C.sub.2 -C.sub.8 alkenyl group; phenyl group optinally substituted with one or more substituents selected from the group consisting of halogen atom and C.sub.1 -C.sub.5 alkyl group; furyl group or thienyl group each optionally substituted with one or more C.sub.3 -C.sub.12 trialkylsilyl groups; or --CR.sup.12 R.sup.13 OH (wherein R.sup.12 and R.sup.13 independently represent hydrogen atom, C.sub.1 -C.sub.3 alkyl group or phenyl group); and n represents 0 or 1, provided that when n represents 1, R.sup.7, when taken together with R.sup.8 does not represent .dbd.O.
The asymmetric carbons present in the cyclopropene derivatives represented by the above general formula (I) independently form (R), (S) or (RS) configuration.
Specific examples of the compounds in accordance with the present invention are shown in tables. Table 1 shows the compounds wherein R.sup.7 and R.sup.8 represent --OR.sup.10 and --OR.sup.11, respectively, and n is zero; Table 2 shows the compounds wherein R.sup.7,taken together with R.sup.8 represents .dbd.O, and n is zero; Table 3 shows the compounds wherein n is one and R.sup.7 and R.sup.8 represent --OR.sup.10 and --OR.sup.11, respectively. In the Tables 1, 2 and 3, Boc represents tert-butoxycarbonyl group; Z represents benzyloxycarbonyl group; pMZ represents 4-methoxybenzyloxycarbonyl group; Moc represents methoxycarbonyl group; Fmoc represents 9-fluorenylmethoxycarbonyl group; Tfa represents trifluoroacetyl group; Tos represents p-toluene sulfonyl group; Mts represents 2,4,6-trimethylbenzene sulfonyl group; Trt represents trityl group; and Pht represents phthalyl group.
TABLE 1__________________________________________________________________________Comp.No. R.sup.1 R.sup.2 R.sup.5 R.sup.6 R.sup.10 R.sup.11 R.sup.9__________________________________________________________________________1 Boc H H H ##STR3## H2 Boc H CH.sub.3 H ##STR4## H3 Boc H CH(CH.sub.3).sub.2 H ##STR5## H4 Z H CH(CH.sub.3).sub.2 H ##STR6## H5 Boc H CH.sub.2 CH.sub.2 CH.sub.3 H ##STR7## H6 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR8## H7 Boc CH.sub.3 CH.sub.2 CH(CH.sub.3).sub.2 H ##STR9## H8 Boc H ##STR10## H ##STR11## H9 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H CH.sub.3 CH.sub.3 H10 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.3 H11 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR12## ##STR13## H12 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H CH.sub.2 CH.sub.2 H13 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H CH.sub.2 CH.sub.2 CH.sub.2 H14 Boc H CH.sub.2 CH.sub.2 CH.sub. 2 CH.sub.3 H ##STR14## H15 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR15## H16 Z H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR16## H17 pMZ H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR17## H18 Fmoc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR18## H19 Tos H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR19## H20 Mts H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR20## H21 Trt H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR21## H22 Pht CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR22## H23 Boc H ##STR23## H ##STR24## H24 Boc H ##STR25## H ##STR26## H25 Boc H ##STR27## H ##STR28## H26 Boc H ##STR29## H ##STR30## H27 Boc H CH.sub.3 CH.sub.3 ##STR31## H28 Boc H CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.3 ##STR32## H29 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 ##STR33## H30 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 ##STR34## H31 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR35## CH.sub.332 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR36## CH.sub.333 Boc H ##STR37## H ##STR38## CH.sub.334 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR39## CH.sub.2 CH.sub.335 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR40## CH.sub.2 CH.sub.336 Boc H ##STR41## H ##STR42## CH.sub.2 CH.sub.337 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR43## CH(CH.sub.3).sub.238 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR44## CH(CH.sub.3).sub.239 Boc H ##STR45## H ##STR46## CH(CH.sub.3).sub.240 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR47## CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.241 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR48## CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.242 Boc H ##STR49## H ##STR50## CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.243 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR51## ##STR52##44 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR53## ##STR54##45 Boc H ##STR55## H ##STR56## ##STR57##46 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR58## CHCH.sub.247 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR59## CHCH.sub.248 Boc H ##STR60## H ##STR61## CHCH.sub.249 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR62## CHCH(CH.sub.2).sub.3 CH.sub.3 (trans)50 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR63## CHCH(CH.sub.2).sub.3 CH.sub.3 (trans)51 Boc H ##STR64## H ##STR65## CHCH(CH.sub.2).sub.3 CH.sub.3 (trans)52 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR66## CHCH(CH.sub.2).sub.3 CH.sub.3 (cis)53 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR67## CHCH(CH.sub.2).sub.3 CH.sub.3 (cis)54 Boc H ##STR68## H ##STR69## CHCH(CH.sub.2).sub.3 CH.sub.3 (cis)55 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR70## CH.sub.2CHCH.sub.256 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR71## CH.sub.2CHCH.sub.257 Boc H ##STR72## H ##STR73## CH.sub.2CHCH.sub.258 Boc H H H ##STR74## ##STR75##59 Boc H CH.sub.3 H ##STR76## ##STR77##60 Boc H CH(CH.sub.3).sub.2 H CH.sub.3 CH.sub.3 ##STR78##61 Boc H CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.3 ##STR79##62 Boc H CH(CH.sub.3).sub.2 H ##STR80## ##STR81## ##STR82##63 Boc H CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 ##STR83##64 Boc H CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 ##STR84##65 Boc H CH(CH.sub.3).sub.2 H ##STR85## ##STR86##66 Boc H CH(CH.sub.3).sub.2 H ##STR87## ##STR88##67 Z H CH(CH.sub.3).sub.2 H ##STR89## ##STR90##68 pMZ H CH(CH.sub.3).sub.2 H ##STR91## ##STR92##69 Fmoc H CH(CH.sub.3).sub.2 H ##STR93## ##STR94##70 Tos H CH(CH.sub.3).sub.2 H ##STR95## ##STR96##71 Mts H CH(CH.sub.3).sub.2 H ##STR97## ##STR98##72 Trt H CH(CH.sub.3).sub.2 H ##STR99## ##STR100##73 Pht CH(CH.sub.3).sub.2 H ##STR101## ##STR102##74 Boc CH.sub.3 CH(CH.sub.3).sub.2 H ##STR103## ##STR104##75 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR105## ##STR106##76 Boc H CH.sub.2 CH.sub.2 CH.sub. 2 CH.sub.3 H ##STR107## ##STR108##77 Boc CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR109## ##STR110##78 Boc H ##STR111## H ##STR112## ##STR113##79 Boc H ##STR114## H ##STR115## ##STR116##80 Boc H ##STR117## H ##STR118## ##STR119##81 Boc H ##STR120## H ##STR121## ##STR122##82 Boc H CH.sub.3 CH.sub. 3 ##STR123## ##STR124##83 Boc H CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.3 ##STR125## ##STR126##84 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 ##STR127## ##STR128##85 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 ##STR129## ##STR130##86 Boc H CH(CH.sub.3).sub.2 H ##STR131## ##STR132##87 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR133## ##STR134##88 Boc H CH(CH.sub.3).sub.2 H ##STR135## ##STR136##89 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR137## ##STR138##90 Boc H CH(CH.sub.3).sub.2 H ##STR139## ##STR140##91 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR141## ##STR142##92 Boc H CH(CH.sub.3).sub.2 H ##STR143## ##STR144##93 Boc H CH.sub.2 CH.sub.2 CH.sub. 2 CH.sub.3 H ##STR145## ##STR146##94 Boc H CH(CH.sub.3).sub.2 H ##STR147## ##STR148##95 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR149## ##STR150##96 Boc H CH(CH.sub.3).sub.2 H ##STR151## ##STR152##97 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR153## ##STR154##98 Boc H CH(CH.sub.3).sub.2 H ##STR155## ##STR156##99 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR157## ##STR158##100 Boc H CH(CH.sub.3).sub.2 H ##STR159## ##STR160##101 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR161## ##STR162##102 Boc H CH(CH.sub.3).sub.2 H ##STR163## ##STR164##103 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR165## ##STR166##104 Boc H CH(CH.sub.3).sub.2 H ##STR167## ##STR168##105 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR169## ##STR170##106 Boc H CH(CH.sub.3).sub.2 H ##STR171## ##STR172##107 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR173## ##STR174##108 Boc H CH(CH.sub.3).sub.2 H ##STR175## ##STR176##109 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR177## ##STR178##110 Boc H CH.sub.3 H ##STR179## ##STR180##111 Boc H CH(CH.sub.3).sub.2 H ##STR181## ##STR182##112 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR183## ##STR184##113 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR185## ##STR186##114 Boc H CH.sub.3 H ##STR187## ##STR188##115 Boc H CH(CH.sub.3).sub.2 H ##STR189## ##STR190##116 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR191## ##STR192##117 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR193## ##STR194##118 Boc H CH(CH.sub.3).sub.2 H ##STR195## ##STR196##119 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR197## ##STR198##120 Boc H CH(CH.sub.3).sub.2 H ##STR199## ##STR200##121 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR201## ##STR202##122 Boc H CH(CH.sub.3).sub.2 H ##STR203## ##STR204##123 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR205## ##STR206##124 Boc H CH(CH.sub.3).sub.2 H ##STR207## ##STR208##125 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR209## ##STR210##126 Boc H CH(CH.sub.3).sub.2 H ##STR211## ##STR212##127 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR213## ##STR214##128 Boc H CH(CH.sub.3).sub.2 H ##STR215## ##STR216##129 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR217## ##STR218##130 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR219## ##STR220##131 Boc H CH(CH.sub.3).sub.2 H ##STR221## ##STR222##132 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR223## ##STR224##133 Boc H CH(CH.sub.3).sub.2 H ##STR225## ##STR226##134 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR227## ##STR228##135 Boc H CH(CH.sub.3).sub.2 H ##STR229## ##STR230##136 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR231## ##STR232##137 Boc H CH(CH.sub.3).sub.2 H ##STR233## ##STR234##138 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR235## ##STR236##139 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR237## ##STR238##140 Boc H CH(CH.sub.3).sub.2 H ##STR239## CH.sub.2 OH141 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR240## CH.sub.2 OH142 Boc H CH(CH.sub.3).sub.2 H ##STR241## ##STR242##143 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR243## ##STR244##144 Boc H CH(CH.sub.3).sub.2 H ##STR245## ##STR246##145 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR247## ##STR248##146 Boc H CH.sub.3 H ##STR249## ##STR250##147 Boc H CH(CH.sub.3).sub.2 H ##STR251## ##STR252##148 Z H CH(CH.sub.3).sub.2 H ##STR253## ##STR254##149 Fmoc H CH(CH.sub.3).sub.2 H ##STR255## ##STR256##150 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR257## ##STR258##151 Boc H ##STR259## H ##STR260## ##STR261##152 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR262## ##STR263##153 Boc H ##STR264## H ##STR265## ##STR266##154 Boc H ##STR267## H ##STR268## ##STR269##155 Boc H CH.sub.3 H ##STR270## ##STR271##156 Boc H CH(CH.sub.3).sub.2 H ##STR272## ##STR273##157 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR274## ##STR275##158 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR276## ##STR277##159 Boc H CH(CH.sub.3).sub.2 H ##STR278## ##STR279##160 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR280## ##STR281##161 Moc H CH(CH.sub.3).sub.2 H ##STR282## ##STR283##162 Moc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR284## ##STR285##__________________________________________________________________________
TABLE 2__________________________________________________________________________Comp.No. R.sup.1 R.sup.2 R.sup.5 R.sup.6 R.sup.9__________________________________________________________________________163 Boc H H H H164 H H H H H165 Boc H CH.sub.3 H H166 H H CH.sub.3 H H167 Boc H CH(CH.sub.3).sub.2 H H168 H H CH(CH.sub.3).sub.2 H H169 Z H CH(CH.sub.3).sub.2 H H170 Boc H CH.sub.2 CH.sub.2 CH.sub.3 H H171 H H CH.sub.2 CH.sub.2 CH.sub.3 H H172 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H H173 H H CH.sub.2 CH(CH.sub.3).sub.2 H H174 Boc CH.sub.3 CH.sub.2 CH(CH.sub.3).sub.2 H H175 H CH.sub.3 CH.sub.2 CH(CH.sub.3).sub.2 H H176 Boc H ##STR286## H H177 H H ##STR287## H H178 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H H179 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H H180 Z H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H H181 pMZ H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H H182 Fmoc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H H183 Tos H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H H184 Mts H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H H185 Trt H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H H186 Pht CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H H187 Boc H ##STR288## H H188 H H ##STR289## H H189 Boc H ##STR290## H H190 H H ##STR291## H H191 Boc H ##STR292## H H192 H H ##STR293## H H193 Boc H ##STR294## H H194 H H ##STR295## H H195 Boc H CH.sub.3 CH.sub.3 H196 H H CH.sub.3 CH.sub.3 H197 Boc H CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.3 H198 H H CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.3 H199 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 H200 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 H201 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 H202 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 H203 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.3204 H H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.3205 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H CH.sub.3206 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H CH.sub.3207 Boc H ##STR296## H CH.sub.3208 H H ##STR297## H CH.sub.3209 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.3210 H H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.3211 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H CH.sub.2 CH.sub.3212 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H CH.sub.2 CH.sub.3213 Boc H ##STR298## H CH.sub.2 CH.sub.3214 H H ##STR299## H CH.sub.2 CH.sub.3215 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2216 H H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2217 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2218 H H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2219 Boc H ##STR300## H CH(CH.sub.3).sub.2220 H H ##STR301## H CH(CH.sub.3).sub.2221 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH(CH.sub. 3).sub.2222 H H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH(CH.sub. 3).sub.2223 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H CH.sub.2 CH.sub.2 CH(CH.sub. 3).sub.2224 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H CH.sub.2 CH.sub.2 CH(CH.sub. 3).sub.2225 Boc H ##STR302## H CH.sub.2 CH.sub.2 CH(CH.sub. 3).sub.2226 H H ##STR303## H CH.sub.2 CH.sub.2 CH(CH.sub. 3).sub.2227 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR304##228 H H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR305##229 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR306##230 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR307##231 Boc H ##STR308## H ##STR309##232 H H ##STR310## H ##STR311##233 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CHCH.sub.2234 H H CH.sub.2 CH(CH.sub.3).sub.2 H CHCH.sub.2235 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H CHCH.sub.2236 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H CHCH.sub.2237 Boc H ##STR312## H CHCH.sub.2238 H H ##STR313## H CHCH.sub.2239 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR314##240 H H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR315##241 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR316##242 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR317##243 Boc H ##STR318## H ##STR319##244 H H ##STR320## H ##STR321##245 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR322##246 H H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR323##247 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR324##248 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR325##249 Boc H ##STR326## H ##STR327##250 H H ##STR328## H ##STR329##251 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CHCH.sub.2252 H H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CHCH.sub.2253 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H CH.sub.2 CHCH.sub.2254 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H CH.sub.2 CHCH.sub.2255 Boc H ##STR330## H CH.sub.2 CHCH.sub.2256 H H ##STR331## H CH.sub.2 CHCH.sub.2257 Boc H H H ##STR332##258 H H H H ##STR333##259 Boc H CH.sub.3 H ##STR334##260 H H CH.sub.3 H ##STR335##261 Boc H CH(CH.sub.3).sub.2 H ##STR336##262 H H CH(CH.sub.3).sub.2 H ##STR337##263 Z H CH(CH.sub.3).sub.2 H ##STR338##264 pMZ H CH(CH.sub.3).sub.2 H ##STR339##265 Fmoc H CH(CH.sub.3).sub.2 H ##STR340##266 Tos H CH(CH.sub.3).sub.2 H ##STR341##267 Mts H CH(CH.sub.3).sub.2 H ##STR342##268 Moc H CH(CH.sub.3).sub.2 H ##STR343##269 Trt H CH(CH.sub.3).sub.2 H ##STR344##270 Pht CH(CH.sub.3).sub.2 H ##STR345##271 Boc CH.sub.3 CH(CH.sub.3).sub.2 H ##STR346##272 H CH.sub.3 CH(CH.sub.3).sub.2 H ##STR347##273 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR348##274 H H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR349##275 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR350##276 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR351##277 Boc CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR352##278 H CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR353##279 Boc H ##STR354## H ##STR355##280 H H ##STR356## H ##STR357##281 Boc H ##STR358## H ##STR359##282 H H ##STR360## H ##STR361##283 Boc H ##STR362## H ##STR363##284 H H ##STR364## H ##STR365##285 Boc H ##STR366## H ##STR367##286 H H ##STR368## H ##STR369##287 Boc H CH.sub.3 CH.sub.3 ##STR370##288 H H CH.sub.3 CH.sub.3 ##STR371##289 Boc H CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.3 ##STR372##290 H H CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.3 ##STR373##291 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 ##STR374##292 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 ##STR375##293 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 ##STR376##294 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 ##STR377##295 Boc H CH(CH.sub.3).sub.2 H ##STR378##296 H H CH(CH.sub.3).sub.2 H ##STR379##297 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR380##298 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR381##299 Boc H CH(CH.sub.3).sub.2 H ##STR382##300 H H CH(CH.sub.3).sub.2 H ##STR383##301 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR384##302 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR385##303 Boc H CH(CH.sub.3).sub.2 H ##STR386##304 H H CH(CH.sub.3).sub.2 H ##STR387##305 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR388##306 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR389##307 Boc H CH(CH.sub.3).sub.2 H ##STR390##308 H H CH(CH.sub.3).sub.2 H ##STR391##309 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR392##310 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR393##311 Boc H CH(CH.sub.3).sub.2 H ##STR394##312 H H CH(CH.sub.3).sub.2 H ##STR395##313 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR396##314 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR397##315 Boc H CH(CH.sub.3).sub.2 H ##STR398##316 H H CH(CH.sub.3).sub.2 H ##STR399##317 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR400##318 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR401##319 Boc H CH(CH.sub.3).sub.2 H ##STR402##320 H H CH(CH.sub.3).sub.2 H ##STR403##321 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR404##322 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR405##323 Boc H CH(CH.sub.3).sub.2 H ##STR406##324 H H CH(CH.sub.3).sub.2 H ##STR407##325 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR408##326 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR409##327 Boc H CH(CH.sub.3).sub.2 H ##STR410##328 H H CH(CH.sub.3).sub.2 H ##STR411##329 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR412##330 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR413##331 Boc H CH(CH.sub.3).sub.2 H ##STR414##332 H H CH(CH.sub.3).sub.2 H ##STR415##333 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR416##334 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR417##335 Boc H CH(CH.sub.3).sub.2 H ##STR418##336 H H CH(CH.sub.3).sub.2 H ##STR419##337 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR420##338 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR421##339 Boc H CH(CH.sub.3).sub.2 H ##STR422##340 H H CH(CH.sub.3).sub.2 H ##STR423##341 Boc H CH.sub.2 CH.sub.2 CH.sub. 2 CH.sub.3 H ##STR424##342 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR425##343 Boc H CH.sub.3 H ##STR426##344 H H CH.sub.3 H ##STR427##345 Boc H CH(CH.sub.3).sub.2 H ##STR428##346 H H CH(CH.sub.3).sub.2 H ##STR429##347 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR430##348 H H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR431##349 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR432##350 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR433##351 Boc H CH.sub.3 H ##STR434##352 H H CH.sub.3 H ##STR435##353 Boc H CH(CH.sub.3).sub.2 H ##STR436##354 H H CH(CH.sub.3).sub.2 H ##STR437##355 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR438##356 H H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR439##357 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR440##358 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR441##359 Boc H CH(CH.sub.3).sub.2 H ##STR442##360 H H CH(CH.sub.3).sub.2 H ##STR443##361 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR444##362 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR445##363 Boc H CH(CH.sub.3).sub.2 H ##STR446##364 H H CH(CH.sub.3).sub.2 H ##STR447##365 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR448##366 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR449##367 Boc H CH(CH.sub.3).sub.2 H ##STR450##368 H H CH(CH.sub.3).sub.2 H ##STR451##369 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR452##370 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR453##371 Boc H CH(CH.sub.3).sub.2 H ##STR454##372 H H CH(CH.sub.3).sub.2 H ##STR455##373 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR456##374 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR457##375 Boc H CH(CH.sub.3).sub.2 H ##STR458##376 H H CH(CH.sub.3).sub.2 H ##STR459##377 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR460##378 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR461##379 Boc H CH(CH.sub.3).sub.2 H ##STR462##380 H H CH(CH.sub.3).sub.2 H ##STR463##381 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR464##382 H H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR465##383 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR466##384 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR467##385 Boc H CH(CH.sub.3).sub.2 H ##STR468##386 H H CH(CH.sub.3).sub.2 H ##STR469##387 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR470##388 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR471##389 Boc H CH(CH.sub.3).sub.2 H ##STR472##390 H H CH(CH.sub.3).sub.2 H ##STR473##391 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR474##392 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR475##393 Boc H CH(CH.sub.3).sub.2 H ##STR476##394 H H CH(CH.sub.3).sub.2 H ##STR477##395 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR478##396 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR479##397 Boc H CH(CH.sub.3).sub.2 H ##STR480##398 H H CH(CH.sub.3).sub.2 H ##STR481##399 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR482##400 H H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR483##401 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR484##402 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR485##403 Boc H CH(CH.sub.3).sub.2 H CH.sub.2 OH404 H H CH(CH.sub.3).sub.2 H CH.sub.2 OH405 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H CH.sub.2 OH406 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H CH.sub.2 OH407 Boc H CH(CH.sub.3).sub.2 H CH(CH.sub.3)OH408 H H CH(CH.sub.3).sub.2 H CH(CH.sub.3)OH409 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3)OH410 H H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3)OH411 Boc H CH(CH.sub.3).sub.2 H ##STR486##412 H H CH(CH.sub.3).sub.2 H ##STR487##413 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR488##414 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR489##415 Boc H CH.sub.3 H C(CH.sub.3).sub.2 OH416 H H CH.sub.3 H C(CH.sub.3).sub.2 OH417 Boc H CH(CH.sub.3).sub.2 H C(CH.sub.3).sub.2 OH418 H H CH(CH.sub.3).sub.2 H C(CH.sub.3).sub.2 OH419 Z H CH(CH.sub.3).sub.2 H C(CH.sub.3).sub.2 OH420 Fmoc H CH(CH.sub.3).sub.2 H C(CH.sub.3).sub.2 OH421 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H C(CH.sub.3).sub.2 OH422 H H CH.sub.2 CH(CH.sub.3).sub.2 H C(CH.sub.3).sub.2 OH423 Boc H ##STR490## H C(CH.sub.3).sub.2 OH424 H H ##STR491## H C(CH.sub.3).sub.2 OH425 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H C(CH.sub.3).sub.2 OH426 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub. H C(CH.sub.3).sub.2 OH427 Boc H ##STR492## H C(CH.sub.3).sub.2 OH428 H H ##STR493## H C(CH.sub.3).sub.2 OH429 Boc H ##STR494## H C(CH.sub.3).sub.2 OH430 H H ##STR495## H C(CH.sub.3).sub.2 OH431 Boc H CH.sub.3 H ##STR496##432 H H CH.sub.3 H ##STR497##433 Boc H CH(CH.sub.3).sub.2 H ##STR498##434 H H CH(CH.sub.3).sub.2 H ##STR499##435 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR500##436 H H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR501##437 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR502##438 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR503##439 Boc H CH(CH.sub.3).sub.2 H ##STR504##440 H H CH(CH.sub.3).sub.2 H ##STR505##441 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR506##442 H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR507##__________________________________________________________________________
TABLE 3 Comp. No. R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 R.sup.6 R.sup.10 R.sup.11 R.sup.9 443 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H ##STR508## H 444 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H CH.sub.3 CH.sub.3 H 445 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.3 H 446 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR509## ##STR510## H 447 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H CH.sub.2 CH.sub.2 H 448 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H CH.sub.2 CH.sub.2 CH.sub.2 H 449 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR511## H 450 Z H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR512## H 451 Fmoc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR513## H 452 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR514## H 453 Boc H ##STR515## H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR516## H 454 Boc H ##STR517## H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR518## H 455 Boc H CH.sub.3 H ##STR519## H ##STR520## H 456 Boc H CH(CH.sub.3).sub.2 H ##STR521## H ##STR522## H 457 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR523## H ##STR524## H 458 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR525## CH.sub.3 459 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR526## CHCH.sub.2 460 Boc H ##STR527## H CH.sub.3 H ##STR528## ##STR529## 461 Boc H CH.sub.3 H CH(CH.sub.3).sub.2 H ##STR530## ##STR531## 462 Boc H CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.3 H ##STR532## ##STR533## 463 Boc H CH.sub.2 CH(CH.sub.3 ).sub.2 H CH(CH.sub.3).sub.2 H CH.sub.3 CH.sub.3 ##STR534## 464 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 (CH.sub.3).sub.2 H CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.3 ##STR535## 465 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 (CH.sub.3).sub.2 H ##STR536## ##STR537## ##STR538## 466 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 ##STR539## 467 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 ##STR540## 468 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H ##STR541## ##STR542## 469 Boc H CH.sub.2 CH(CH.sub.3).sub.2 CH.sub.3 CH(CH.sub.3).sub.2 H ##STR543## ##STR544## 470 Boc CH.sub.3 CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H ##STR545## ##STR546## 471 Boc CH.sub.3 CH.sub.2 CH(CH.sub.3).sub.2 CH.sub.3 CH(CH.sub.3).sub.2 H ##STR547## ##STR548## 472 Z H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H ##STR549## ##STR550## 473 Fmoc H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H ##STR551## ##STR552## 474 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H ##STR553## ##STR554## 475 Boc H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H CH(CH.sub.3).sub.2 H ##STR555## ##STR556## 476 Boc H ##STR557## H CH(CH.sub.3).sub.2 H ##STR558## ##STR559## 477 Boc H ##STR560## H CH(CH.sub.3).sub.2 H ##STR561## ##STR562## 478 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H ##STR563## ##STR564## 479 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR565## ##STR566## 480 Z H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR567## ##STR568## 481 Boc H CH(CH.sub.3).sub.2 H ##STR569## H ##STR570## ##STR571## 482 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR572## H ##STR573## ##STR574## 483 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR575## ##STR576## 484 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR577## ##STR578## 485 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H ##STR579## ##STR580## 486 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H ##STR581## ##STR582## 487 Boc H CH.sub.2 CH(CH.sub.3).sub.2 H ##STR583## H ##STR584## ##STR585## 488 Boc H CH.sub.2 CH(CH.sub.3).sub. 2 H CH(CH.sub.3).sub.2 H ##STR586## ##STR587##
The process for the production of the compounds of the present invention will now be explained. The cyclopropene derivatives of the present invention may be produced, for example, by the following process:
Process 1: A process for producing a compound represented by the above general formula (I) wherein R.sup.7 and R.sup.8 represent --OR.sup.10 and --OR.sup.11, respectively: ##STR588## (In the above general formula, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.9, R.sup.10, R.sup.11 and n are those as defined above.)
Using the known process described in the reference (Tetrahedron Letters, Vol.32, pp.1339, 1991), cyclopropenone ketal derivative represented by the above general formula (II) is readily synthesized. The derivative is dissolved in an ethereal solvent such as tetrahydrofuran, diethylether, etc., followed by addition of a strong base such as n-butyl lithium, methyl lithium, lithium diisopropylamide in the presence of an additive such as tetramethylethylenediamine, hexamethylphosphoric triamide, 1,3-dimethyl-2-imidazolidone, etc. to prepare a lithiated compound thereof. Then, an aldehyde derivative represented by the above general formula (III) is added to the resulting lithiated compound to prepare the cyclopropene derivative represented by the above general formula (1-a). In the reaction, anhydrous cerium chloride suspension in a solvent such as tetrahydrofuran, diethylether, hexane and the like may further be added to the lithiated compound of the resulting compound (II) to transform the compound into the cerium salt thereof, with which the aldehyde derivative represented by the general formula (III) may be reacted.
Process 2: A process for producing a compound represented by the above general formula (I) wherein R.sup.7, taken together with R.sup.8 represents .dbd.O, and n is zero: ##STR589## (In the above general formula, R.sup.1, R.sup.2, R.sup.5, R.sup.6, R.sup.9, R.sup.10, and R.sup.11 are those as defined above.)
The cyclopropene derivative represented by the above general formula (I-a)', produced by the process of Process 1, is dissolved in acetone, diethyl ether, tetrahydrofuran, etc., followed by treatment with an ion exchange resin such as Amberlist 15 (registered trade mark) or followed by addition of a mineral acid such as dilute sulfuric acid to effect selective deprotection of ketal, whereby the cyclopropene derivative represented by the above general formula (I-b) is produced.
By the process described in Japanese Patent Application No. Hei 4-146024, the cyclopropene derivative represented by the above general formula (I) can be lead to cyclopropenone derivatives exhibiting a strong inhibitory activity against thiol protease such as calpain, papain, cathepsin B, cathepsin H, cathepsin L and the like.

The present invention will now be described in examples hereinbelow, but the invention is not limited to the examples, unless departing from the spirit and scope of the invention.
EXAMPLE 1
Preparation of 2-((2S)-2-tert-butoxycarbonylamino-1-hydroxy-3-methylbutyl)-3-phenylcyclopropenone 2,2-dimethyl-1,3-propanediyl acetal (Compound No. 65 in Table 1)
To a solution of 3.51 g of 2-phenylcyclopropenone 2,2-dimethyl-1,3-propanediyl acetal in 30 ml of tetrahydrofuran was added 3.8 g of N, N, N', N'-tetramethylethylenediamine. To the reaction solution chilled at -78.degree. C. was added a 1.55 ml/l solution of n-butyl lithium in 10.5 ml of hexane, and the mixture was stirred for 20 minutes. Then, 30 ml of tetrahydrofuran suspension of anhydrous cerium chloride prepared by drying 8.0 g of cerium chloride heptahydrate at 140.degree. C./1 mmHg for 2 hours was added to the mixture, which was stirred for 20 minutes. A solution of 1.82 g of N-tert-butoxycarbonyl-L-valinal in 20 ml of tetrahydrofuran was added, and the resultant mixture was stirred at -78.degree. C. for 2 hours. A solution of 1 ml of water in 5 ml of tetrahydrofuran was added to the reaction mixture, which was allowed to warm at room temperature and filtered through celite. The celite was washed well with ethyl acetate, and the filtrate was dried over sodium sulfate, filtered, concentrated and chromatographed on a column of silica gel, eluting with hexane containing 20% ethyl acetate as a developing solvent to give 2.71 g of the titled product.
Yield: 72% IR (KBr, cm.sup.-1): 3430, 2960, 1855, 1800, 1710, 1690 NMR (CD.sub.3 OD, .delta.): 0.95-1.60 (m, 12H), 1.38 (s, 3H), 1.42 (s, 6H), 1.95-2.15 (m, 1H), 3.60-3.75 (m, 1H), 3.75-3.95 (m, 4H), 5.0-5.10 (m, 1H), 6.03 (d, J=10 Hz, 0.33H), 6.23 (d, J=10 Hz, 0.67H), 7.40-7.65 (m, 3H), 7.70-7.90 (m, 2H)
In the same manner as in Example 1, the following compounds were produced.
EXAMPLE 2
Preparation of 2-(2-tert-butoxycarbonylamino-1-hydroxyethyl)cyclopropenone 2,2-dimethyl-l,3-propanediyl acetal (Compound No. 1 in Table 1)
NMR (CDCl.sub.3, .delta.): 0.97 (s, 3H), 1.09 (s, 3H), 1.44 (s, 9H), 3.35-3.60 (m, 2B), 3.63 (s, 4H), 4.80-4.88 (m, 1H), 5.07-5.26 (m, 1H), 5.26-5.52 (m, 1H), 7.63 (s, 1H)
EXAMPLE 3
Preparation of 2-((2S)-2-tert-butoxycarbonylamino-1-hydroxy-3-methylbutyl)cyclopropenone 2,2-dimethyl-1-1,3-propanediyl acetal (Compound No. 3 in Table 1)
IR (neat, cm.sup.-1): 3380, 1722, 1708, 1690 NMR (CDCl.sub.3, .delta.): 0.87-1.10 (m, 12H), 1.43 (s, 7.2H), 1.45 (s, 1.8H), 2.05-2.20 (m, 1H), 3.35-3.70 (m, 5H), 4.80-5.03 (m, 2H), 7.57 (s, 0.8H), 7.71 (s, 0.2H)
EXAMPLE 4
Preparation of 2-((2S)-2-tert-butoxycarbonylamino-1-hydroxy-4-methylpentyl)cyclopropenone 2,2-dimethyl-1,3-propanediyl acetal (Compound No. 6 in Table 1)
IR (neat, cm.sup.-1): 3445, 3360, 1705 NMR (CDCl.sub.3, .delta.): 0.80-0.95 (m, 9H), 1.15 is, 3B), 1.44 (s, 9H), 1.55-1.78 (m, 3H), 3.63 (s, 2H), 3.65 (s, 2H), 3.72-3.95 (m, 1H), 4.70-4.84 (m, 2H), 5.02-5.15 (m, 1H), 7.68 (s, 0.9H), 7.71 (s, 0.1H)
EXAMPLE 5
Preparation of 2-((2S)-2-tert-butoxycarbonylamino-1-hydroxyhexyl)cyclopropenone 2,2-dimethyl-1,3-propanediyl acetal (Compound No. 14 in Table 1)
IR (neat, cm.sup.-1): 3460, 3370, 1700 NMR (CDCl.sub.3, .delta.): 0.85-1.0 (m, 3H), 0.92 (s, 3H), 1.14 (s, 3H), 1.25-1.55 (m, 6H), 1.44 (s, 9H), 3.05-3.15 (m, 0.7H), 3.25-3.35 (m, 0.3H), 3.61 (s, 2H), 3.63 (s, 2H), 3.65-3.85 (m, 0.7H), 3.85-4.05 (m, 0.3H), 4.70-4.85 (m, 1H), 4.85-4.95 (m, 0.3H), 5.0-5.15 (m, 0.7H), 7.65 (s, 0.7H), 7.72 (s, 0.3H)
EXAMPLE 6
Preparation of 2-((2S)-2-benzyloxycarbonylamino-1-hydroxyhexyl)cyclopropenone 2,2-dimethyl-1,3-propanediyl acetal (Compound No. 16 in Table 1)
IR (neat, cm.sup.-1): 3360, 1723 NMR (CDCl.sub.3, .delta.): 0.75-0.98 (m, 6H), 1.08 (s, 1.5H), 1.12 (s, 1.5H), 1.18-1.60 (m, 6H), 3.04 (s, 0.5H), 3.32 (d, J=7.8 Hz, 0.5H), 3.55-3.70 (m, 4H), 3.80 (m, 0.5H), 4.01 (m, 0.5H), 4.76 (d, J=7.8 Hz, 0.5H), 4.83 (m, 0.5H), 5.11 (s, 2H), 5.13 (m, 0.5H), 5.63 (d, J=8.1 Hz, 0.5H), 7.65 (s, 0.5H), 7.73 (s, 0.5H)
EXAMPLE 7
Preparation of 2-((2S)-2-tert-butoxycarbonylamino-1-hydroxyhexyl)-3-methylcyclopropenone 2,2-dimethyl-1,3-propanediyl acetal (Compound No. 32 in Table 1)
NMR (CDCl.sub.3, .delta.): 0.84-0.96 (m, 3H), 0.95 (s, 3H), 1.08 (s, 3H), 1.28-1.55 (m, 6H), 1.43 (s, 9H), 2.17 (s, 3H), 3.53-3.80 (m, 5H), 4.63-4.74 (m, 1H), 4.88-5.07 (m, 1H)
EXAMPLE 8
Preparation of 2-((2S)-2-tert-butoxycarbonylamino-1-hydroxy-4-methylpentyl)-3-ethylcyclopropenone 2,2-dimethyl-1,3-propanediyl acetal (Compound No. 34 in Table 1)
IR (neat, cm.sup.-1): 3360, 1853, 1696, 1623 NMR (CDCl.sub.3, .delta.): 0.88-1.01 (m, 12H ), 1.32 (t, J=7.7 Hz, 3H), 1.37-1.55 (m, 2H), 1.41 (s, 9H), 1.60-1.78 (m, 1H), 2.69 (q, J=7.7 Hz, 2H), 3.55-3.70 (m, 4H), 3.79-4.02 (m, 1H), 4.67-4.78 (m, 1H), 4.80-5.03 (m, 1H), 5.16 -5.22 (m, 1H)
EXAMPLE 9
Preparation of 2-((2S)-2-tert-butoxycarbonylamino-1-hydroxyhexyl)-3-isopentylcyclopropenone 2,2-dimethyl-1,3-propanediyl acetal (Compound No. 41 in Table 1)
IR (neat, cm.sup.-1): 3360, 1816,,1715, 1698 NMR (CDCl.sub.3, .delta.): 0.78-0.98 (m, 12H), 1.11 (s, 3H), 1.18-1.77 (m, 9H), 1.43 (s, 9H), 2.53 (d, J=7.6 Hz, 2H), 3.56-3.80 (m, 5H), 4.65-4.80 (m, 1H), 4.98-5.12 (m, 1H)
EXAMPLE 10
Preparation of 2-((1S, 2S)-2-tert-butoxycarbonylamino-1-hydroxyhexyl)-3-((Z)-1-hexenyl)cyclopropenone 2,2-dimethyl-1,3-propanediyl acetal (Compound No. 53 in Table 1)
IR (neat, cm.sup.-1): 3440, 1785, 1703 NMR (CDCl.sub.3, .delta.): 0.80-0.97 (m, 9H), 1.19 (s, 3H), 1.21-1.80 (m, 10H), 1.43 (s, 9H), 2.35-2.50 (m, 2H), 2.82 (s, 1H), 3.57-3.82 (m, 5H), 4.66-4.85 (m, 2H), 5.82-6.06 (m, 2H)
EXAMPLE 11
Preparation of 2-[(2S)-2-(N-tert-butoxycarbonyl)methylamino-1-hydroxy-3-methylbutyl]-3-phenylcycloprene 2,2-dimethyl-1,3-propanediyl acetal (Compound No. 74 in Table 1)
IR (KBr, cm.sup.-1): 3430, 1798, 1688, 1672 NMR (CD.sub.3 OD, .delta.): 0.80-1.35 (m, 12H), 1.45 (s, 9H), 2.30 (m, 1H), 2.69 (s, 1.5H), 2.72 (s, 1.5H), 3.65-3.90 (m, 4H), 4.09 (m, 1H), 5.02 (m, 1H), 7.30-7.52 (m, 3H), 7.70-7.82 (m, 2H)
EXAMPLE 12
Preparation of 2-((2S)-2-tert-butoxycarbonylamino-1-hydroxyhexyl)-3-phenylcyclopropenone 2,2-dimethyl-1,3-propanediyl acetal (Compound No. 76 in Table 1)
IR (KBr, cm.sup.-1): 3310, 1800, 1720, 1792 NMR (CDCl.sub.3, .delta.): 0.80-0.98 (m, 3H), 0.99 (s, 3H), 1.21 (s, 3H), 1.15-1.90 (m, 6H), 1.39 (s, 2.7H), 1.43 (s, 6.3H), 3.58 (m, 0.7H), 3.68-4.95 (m, 4.6H), 4.95-4.10 (m, 0.7H), 4.88-5.07 (m, 1.3H), 5.24 (d, J=7.4 Hz, 0.7H), 7.28-7.45 (m, 3H), 7.69 (d, J=6.5 Hz, 2H)
EXAMPLE 13
Preparation of 2-(2-tert-butoxycarbonylamino-1-hydroxy-2-methylpropyl)-3-phenylcyclopropenone 2,2-dimethyl-1,3-propanediyl acetal (Compound No. 82 in Table 1)
IR (KBr, cm.sup.-1): 3290, 1800, 1673 NMR (CDCl.sub.3, .delta.): 0.94 (s, 3H), 1.25 (s, 3H), 1.27 (s, 9H), 1.41 (s, 3H), 1.64 (s, 3H), 3.70-3.90 (m, 4H), 4.77 (d, J=8.6 Hz, 1H), 4.93 (s, 1H), 5.57 (s, 1H), 7.28-7.46 (m, 3H), 7.75 (dd, J=8.2 Hz, 1.4 Hz, 2H )
EXAMPLE 14
Preparation of 2-((2S)-2-tert-butoxycarbonylamino-1-hydroxy-3-methylbutyl)-3-(4-fluorophenyl) cyclopropenone 2,2-dimethyl-1,3-propanediyl acetal (Compound No. 90 in Table 1 )
IR (KBr, cm.sup.-1): 3340, 1802, 1710, 1695, 1602 NMR (CD.sub.3 OD, .delta.): 0.90-1.25 (m, 12H), 1.38 (s, 6.3H), 1.42 (s, 2.7H), 2.08 (m, 1H), 3.63 (m, 1H), 3.70-3.93 (m, 4H), 5.08 (d, J=4.5 Hz, 0.3H), 5.02 (d, J=4.5 Hz, 0.7H), 6.05 (d, J=10 Hz, 0.3H), 6.19 (d, J=10 Hz, 0.7H), 7.18-7.30 (m, 2H), 7.70-7.88 (m, 2H)
EXAMPLE 15
Preparation of 2-((2S)-2-tert-butoxycarbonylamino-1-hydroxyhexyl)-3-(2-tolyl)cyclopropenone 2,2-dimethyl-1,3propanediyl acetal (Compound No. 105 in Table 1)
NMR (CDCl.sub.3, .delta.): 0.83-1.03 (m, 3H), 0.96 (s, 3H), 1.25 (s, 3H), 1.25-1.51 (m, 4H), 1.40 (s, 1.8H), 1.43 (s, 7.2H), 1.60-1.95 (m, 2H), 2.45 (s, 0.6H), 2.52 (s, 2.4H), 3.65-3.90 (m, 1H), 3.73 (s, 4H), 4.80-5.20 (m, 2H), 7.05-7.30 (m, 3H), 7.55-7.65 (m, 1H)
EXAMPLE 16
Preparation of 2-((2S)-2-tert-butoxycarbonylamino-1-hydroxyhexyl)-3-(5-trimethylsilyl-2-furyl)cyclopenone 2,2dimethyl-1,3-propandiyl acetal (Compound No. 130 in Table 1)
NMR (CDCl.sub.3, .delta.): 0.28 (s, 9H), 0.85-0.95 (m, 6H), 1.22 (s, 3H), 1.21-1.85 (m, 15H), 3.65-4.05 (m, 5H), 4.80-5.20 (m, 3H), 6.70 (d, J=3.9 Hz, 1), 6.78 (d, J=3.9 Hz, 1H)
EXAMPLE 17
Preparation of 2-((2S)-2-tert-butoxycarbonylamino-1-hydroxyhexyl)-3-(5-trimethylsilyl-2-thienyl)cyclopropenone 2,2dimethyl-1,3-propanediyl acetal (Compound No. 139 in Table 1)
NMR (CDCl.sub.3, .delta.): 0.34 (s, 9H), 0.84-0.97 (m, 6H), 1.24 (s, 3H), 1.27-1.50 (m, 13H), 1.55-1.92 (m, 2H), 3.64-4.04 (m, 5H), 4.83-5.30 (m, 2H), 7.21 (d, J=3.4 Hz, 1H), 7.38 (d, J=3.4 Hz, 1H)
EXAMPLE 18
Preparation of 2-((2S)-2-tert-butoxycarbonylamino-1-hydroxy-3-methylbutyl)-3-(1-hydroxy-1-methylbutyl)-3-(hydroxy-1-methylethyl)cyclopropenone 2,2-dimethyl-1,3-propanediyl acetal (Compound No. 147 in Table 1)
NMR (CDCl.sub.3, .delta.): 0.92-1.07 (m, 12H), 1.41-1.53 (m, 15H), 1.80-2.05 (m, 1H), 3.56-3.78 (m, 5H), 4.84-4.90 (m, 1H), 5.10 (d, J=11 Hz, 0.3H), 5.26 (d, J=11 Hz, 0.7H), 6.0 (s, 2H)
EXAMPLE 19
Preparation of 2-((2S)-2-tert-butoxycarbonylamino-1-hydroxy-3-methylbutyl)-3-[(hydroxy)(phenyl)methyl]cyclopropenone 2,2-dimethyl-1,3-propanediyl acetal (Compound No. 156 in Table 1)
NMR (CDCl.sub.3, .delta.): 0.86-1.12 (m, 12H), 1.36-1.48 (m, 9H), 1.77-2.05 (m, 1H), 3.40-3.78 (m, 5H), 4.82-4.92 (m, 1H), 5.24-5.42 (m, 1H), 5.67-5.74 (m, 2H), 5.98 (s, 1H), 7.25-7.50 (m, 5H)
EXAMPLE 20
Preparation of 2-((2S)-2-methoxycarbonylamino-3-methyl1-hydroxybutyl)-3-phenylcyclopropenone 2,2-dimethyl-1,3-diyl acetal (Compound No. 161 in Table 1)
IR (KBr, cm.sup.-1): 3436, 3378, 1858, 1792, 1703, 1626 NMR (CD.sub.3 OD, .delta.): 0.88-1.35 (m, 12H), 1.90-2.15 (m, 1H), 3.55-3.90 (m, 8H), 4.95 (d, J=5.2 Hz, 0.2H), 4.98 (d, J=5.0 Hz, 0.8H), 7.32-7.55 (m, 3H), 7.60-7.83 (m, 2H)
EXAMPLE 21
Preparation of 2-[(2S)-2-((2S)-2-benzyloxycarbonylamino-3-methylvalerylamino)-1-hydroxyhexyl)-3-(4-fluorophenyl)cyclopropenone 2,2-dimethyl-1,3-propanediyl acetal (Compound No. 490 in Table 3)
IR (KBr, cm.sup.-1): 3320, 1802, 1710, 1660, 1602 NMR (CD.sub.3 OD, .delta.): 0.70-1.18 (m, 15H), 1.18-1.95 (m, 9H), 3.66-3.90 (m, 4H), 4.02-4.30 (m, 2H), 4.95 (m, 1H), 5.02 (s, 2H), 7.10-7.40 (m, 7H), 7.40-7.60 (m, 1H), 7.70-7.83 (m, 2H)
EXAMPLE 22
Preparation of 2-((2S)-2-tert-butoxycarbonylamino-1-hydroxyhexyl) cyclopropenone (Compound No. 178 in Table 2)
To a solution of 8.80 g of 2-((2S)-2-tert-Butoxycarbonylamino-1-hydroxyhexyl) cyclopropenone 2,2-dimethyl-1.3-propanediyl acetal obtained in Example 5 in 100 ml of diethyl ether and 20 ml of tetrahydrofuran were added 0.2 ml of 2 N sulfuric acid and 1 ml of water, and the mixture was stirred for 30 minutes. After subsequent addition of 300 ml of ether, the resulting product was washed sequentially in 50 ml of an aqueous 0.01 N sodium hydroxide solution and an aqueous saturated brine. After drying over magnesium sulfate, the product was filtered and concentrated, followed by purification by silica gel column chromatography (eluent; hexane: ethyl acetate =1:2) to produce the objective product (3.15 g).
Yield: 47% IR (neat, cm.sup.-1): 3440, 1835, 1700 NMR (CDCl.sub.3, .delta.): 0.85-1.9 (m, 3H), 1.25-1.85 (m, 6H), 1.42 (s, 9H), 2.60-2.90 (m, 1H), 3.75-3.95 (m, 1H), 4.75-4.85 (m, 0.8H), 4.85-4.95 (m, 0.2H), 5.19 (d, J=9 Hz, 1H), 8.59 (s, 0.8H), 8.65 (s, 0.2H)
In the same manner as in Example 22, the following compounds were produced.
EXAMPLE 23
Preparation of 2-(2-tert-Butoxycarbonylamino-1-hydroxyethyl) cyclopropenone (Compound No. 163 in Table 2)
IR (neat, cm.sup.-1): 3350, 1840, 1718, 1700 NMR (CDCl.sub.3, .delta.): 1.44 (s, 9H), 3.43-3.70 (m, 2H), 4.84-4.97 (m, 2H), 5.15-5.70 (m, 1H), 8.63 (s, 1H)
EXAMPLE 24
Preparation of 2-((2S)-2-tert-Butoxycarbonylamino-1-hydroxy-3-methylbutyl) cyclopropenone (Compound No. 167 in Table 2)
IR (KBr, cm.sup.-1): 3330, 1838, 1820, 1712, 1690, 1678 NMR (CDCl.sub.3, .delta.): 1.02 (d, J=7.2 Hz, 2.1H), 1.05 (d, J=7.3 Hz, 2.1H), 1.08 (d, J=7.3 Hz, 0.9H), 1.11 (d, J=7.3 Hz, 0.9H), 1.41 (s, 6.3H), 1.43 (s, 2.7H), 1.90-2.05 (m, 0.3H), 2.15-2.33 (m, 0.7), 3.40 (m. 0.7H), 3.68 (m, 0.3H), 4.87-4.98 (m, 1H), 5.02-5.16 (m, 2H), 8.57 (s, 0.7H), 8.66 (s, 0.3H)
EXAMPLE 25
Preparation of 2-((2S) -2-tert-Butoxycarbonylamino-1-hydroxy-4-methylpentyl)cyclopropenone (Compound No. 172 in Table 2 )
IR (neat, cm.sup.-1): 3350, 1833, 1700 NMR (CDCl.sub.3, .delta.): 0.86-0.98 (m, 6H), 1.43 (s, 9H), 1.55-1.83 (m, 3H), 3.88-4.06 (m, 1H), 4.70-4.86 (m, 1H), 5.12-5.38 (m, 1H), 8.61 (s, 0.75H), 8.66 (s, 0.25H)
EXAMPLE 26
Preparation of 2-((2S)-2-benzyloxycarbonylamino-1hydroxyhexyl) cyclopropenone (Compound No. 190 in Table 2)
IR (neat, cm.sup.-1): 3440, 3350, 1840, 1715 NMR (CDCl.sub.3, .delta.): 0.82-0.98 (m, 3H), 1.26-1.80 (m, 6H), 3.85-4.05 (m, 1H), 4.76-4.84 (m, 1H), 4.86-4.93 (m, 0.4H), 5.02-5.16 (m, 2.6H), 5.27 (d, J=7.8 Hz, 0.4H), 5.47 (d, J=7.7 Hz, 0.6H), 8.44 (s, 0.4H), 8.49 (s, 0.6H)
EXAMPLE 27
Preparation of 2-((2S)-2-tert-Butoxycarbonylamino-1-hydroxy-3-phenylpropyl)cyclopropenone (Compound No. 199 in Table 2)
IR (KBr, cm.sup.-1): 3265, 1838, 1700 NMR (CDCl.sub.3, .delta.): 1.41 (s, 6.3H), 1.43 (s, 2.7H), 2.80-3.18 (m, 2H), 3.94-4.25 (m, 1H), 4.65-4.77 (m, 1H), 4.82-4.95 (m, 0.3H), 5.15-5.25 (m, 0.7H), 5.30-5.42 (m, 0.7H), 5.50-5.60 (m, 0.3H), 7.13-7.35 (m, 5H), 8.43 (s, 0.7H), 8.51 (s, 0.3H)
EXAMPLE 28
Preparation of 2-((2S)-2-tert-Butoxycarbonylamino-1-hydroxyhexyl)-3-methylcyclopropenone (Compound No. 215 in Table 2)
NMR (CDCl.sub.3, .delta.): 0.87-0.96 (m, 3H), 1.28-1.50 (m, 2H), 1.41 (s, 9H), 1.50-1.82 (m, 4H), 2.32 (s, 3H), 3.68-3.82 (m, 0.6H), 3.82-3.93 (m, 0.4H), 4.67-4.82 (m, 1.4H), 4.87-5.0 (m, 0.4H), 5.02-5.14 (m, 0.6H), 5.44 (d, J=6.8 Hz, 0.6H )
EXAMPLE 29
Preparation of 2-((2S)-2-tert-Butoxycarbonylamino-1-hydroxy-4-methylpentyl)-3-ethylcyclopropenone (Compound No. 219 in Table 2)
IR (neat, cm.sup.-1): 3360, 1852, 1696, 1622 NMR (CDCl.sub.3, .delta.): 0.90 (d, J=7.2 Hz, 3H), 0.94 (d, J=7.1 Hz, 3H), 1.28 (t, J=7.7 Hz, 3H), 1.42 (s, 9H), 1.40-1.58 (m, 2H), 1.60-1.78 (m, 1H), 2.63 (q, J=7.7 Hz, 2H), 3.70-3.85 (m, 1H), 4.60-4.75 (m, 1H), 4.75-4.90 (m, 1H), 5.0-5.18 (m, 1H)
EXAMPLE 30
Preparation of 2-((2S)-2-tert-Butoxycarbonylamino-1-hydroxyhexyl)-3-isopentylcyclopropenone (Compound No. 233 in Table 2)
IR (neat, cm.sup.-1): 3320, 1842, 1707, 1683, 1620 NMR (CDCl.sub.3, .delta.): 0.83-0.98 (m, 9H), 1.28-1.85 (m, 9H), 1.41 (s, 9H), 2.66 (q, J=7.2 Hz, 2H), 3.67-3.95 (m, 1H), 4.60-4.70 (m, 1H), 4.70-4.78 (m, 1H), 4.98-5.08 (m, 1H)
EXAMPLE 31
Preparation of 2-((1S, 2S ) -2-tert-Butoxycarbonylamino-1-hydroxyhexyl)-3-((Z)-1-hexenyl) cycloplopropenone (Compound No. 257 in Table 2)
IR (neat, cm.sup.-1): 3270, 1842, 1710 , 1690, 1635 NMR (CDCl.sub.3, .delta.): 0.80-0.97 (m, 6H), 1.25-1.83 (m, 10H), 1.40 (s, 9H), 2.59 (q, J=7.0 Hz, 2H), 3.75 (m, 1H), 4.70 (m, 1H), 4.79 (d, J=4.7 Hz, 1H), 5.01 (d, J=8.6 Hz, 1H), 6.26 (d, J=11 Hz, 1H), 6.40-6.55 (m, 1H)
EXAMPLE 32
Preparation of 2-((2S)-2-tert-Butoxycarbonylamino-1-hydroxyhexyl)-3-phenylcyclopropenone (Compound No. 285 in Table 2)
NMR (CDCl.sub.3, .delta.): 0.86-0.97 (m, 3H), 1.28-1.51 (m, 4H), 1.31 (s, 1.8H), 1.34 (s, 7.2H), 1.52-1.93 (m, 2H), 3.73-3.88 (m, 0.8H), 3.93-4.03 (m, 0.2H), 4.84 (d, J=6.8 Hz, 0.2H), 4.91-5.03 (m, 1H), 5.12-5.27 (m, 1.6H), 5.73 (d, J=8.1 Hz, 0.2H), 7.42-7.60 (m, 3H), 7.95-8.05 (m, 2H)
EXAMPLE 33
Preparation of 2-((2S)-2-tert,Butoxycarbonylamino-1-hydroxyhexyl)-3-(2-tolyl) cyclopropenone (Compound No. 343 in Table 2 )
NMR (CDCl.sub.3, .delta.): 0.85-0.96 (m, 3H), 1.28-1.51 (m, 13H), 1.53-1.95 (m, 2H), 2.68 (s, 3H), 3.72-3.88 (m, 0.7H), 3.94-4.05 (m, 0.3H), 4.75-5.18 (m, 2.7H), 5.59 (d, J=8.1 Hz, 0.3H), 7.25-7.34 (m, 2H), 7.38-7.47 (m, 1H), 8.07-8.16 (m, 1H)
EXAMPLE 34
Preparation of 2((2S)-2-tert-Butoxycarbonylamino-1-hydroxyhexyl)-3-(5-trimethylsilyl-2-thienyl)cyclopropenone (Compound No. 411 in Table 2)
NHR (CDCl.sub.3, .delta.): 0.34 (s, 2.7H), 0.35 (s, 6.3H), 0.86-0.97 (m, 3H), 1.25-1.52 (m, 4H), 1.32 (s. 2.7H), 1.35 (s, 6.3H), 1.53-1.92 (m, 2H), 3.68-3.82 (m, 0.7H), 3.92-4.02 (m, 0.3H), 4.65-5.09 (m, 2.7H), 5.69 (d, J=7.7 Hz, 0.3H), 7.28 (d, J=4.1 Hz, 0.3H), 7.29 (d, J=4.1 Hz, 0.7H), 7.82 (d, J=4.1 Hz, 1H)
EXAMPLE 35
Preparation of 2((2S)-2-tert-Butoxycarbonylamino-1-hydroxy-3-methylbutyl)-3-(1-hydroxy-1-methylethyl)cyclopropenone (Compound No. 427 in Table 2)
IR (neat, cm.sup.-1): 3430, 3300, 1840, 1683, 1628 NMR (CDCl.sub.3, .delta.): 0.98 (d, J=6.8 Hz, 1.8H), 1.04 (d, J=6.8 Hz, 1.8H), 1.05 (d, J=6.7 Hz, 1.2H), 1.10 (d, J=6.8 Hz, 1.2H), 1.41 (s, 5.4H), 1.43 (s, 3.6H), 1.48-1.57 (m, 6H), 1.90-2.12 (m, 1H), 3.65-3.80 (m, 1H), 4.20 (s, 0.4H), 4.76 (d, J=7.7 Hz, 0.4H), 4.85-4.17 (m, 2.8H), 5.59 (m, 0.4H)
EXAMPLE 36
Preparation of 2-((2S)-2-tert-Butoxycarbonylamino-1-hydroxy-3-methylbutyl)-3[(hydroxy)(phenyl)methyl]cyclopropenone (Compound No. 443 in Table 2)
IR (neat, cm.sup.-1): 3440, 3330, 1845, 1716, 1683, 1630 NMR (CDCl.sub.3, .delta.): 0.96-1.11 (m, 6H), 1.18 (s, 1.9H), 1.37 (s, 1.0H), 1.39 (s, 3.6H), 1.43 (s, 2.5H), 1.90-2.15 (m, 1H), 3.68-3.78 (m, 0.3H), 3.78-3.89 (m, 0.7H), 4.89-5.40 (m, 1H), 5.16 (d, J=11 Hz, 0.7H), 5.40 (d, J=11 Hz, 0.3H), 5.30-5.41 (m, 1H), 5.62 (d, J=9.2 Hz, 0.3H), 5.80 (d, J=9.2 Hz, 0.7H), 5.86 (s, 1H), 7.50-7.86 (m, 3H), 7.86-8.11 (m, 2H)
EXAMPLE 37
Preparation of 2-((2S)-2-amino-1-hydroxyhexyl) cyclopropenone p-toluene sulfonate (Compound No. 179 in Table 2)
To 5 ml of a dichloroethane solution of 150 mg of 2-((2S)-2-tert-butoxycarbonylamino-1-hydroxyhexyl) cyclopropenone obtained in Example 22 was added 106 mg of p-toluene sulfonate monohydrate. After stirring at room temperature for 5 hours, the solvent was distilled off under reduced pressure to give 250 mg of the titled product.
NMR (CD.sub.3 OD, .delta.): 0.93-1.10 (m, 3H), 1.30-1.65 (m, 4H), 1.65-2.05 (m, 2H), 2.41 (s, 3H), 3.40-3.60 (m, 0.7H), 3.60-3.75 (m, 0.3H), 4.89 (d, J=4 Hz, 0.7H), 5.15 (d, J=4 Hz, 0.3H), 7.28 (d, J=8 Hz, 2H), 7.74 (d, J=8 Hz, 2H), 9.12 (s, 0.7H), 9.18 (s, 0.3H)
EXAMPLE 38
Preparation of 2-((2S)-2-amino-l-hydroxy-3-methylbutyl)-3-phenylcyclopropenone hydrochloride (Compound No. 262 in Table 2)
To 8 ml of a dioxane solution of 3.12 g of 2-((2S)-2-tert-butoxycarbonylamino-1-hydroxy-3-methylbutyl)-3-phenylcyclopropenone 2,2-dimethyl, 1,3-propanediyl acetal obtained in Example 1 was added 24 ml of a dioxane solution containing 4 N HCl, and the mixture was stirred for 20 minutes. The resulting crystal was filtered and washed with dioxane, to give 1.87 g of the titled product.
Yield: 94% IR (KBr, cm.sup.-1): 3200, 2975, 1855, 1618, 1510, 1450, 1055, 770, 690 NMR (CD3OD, 8): 1.21 (t, J=7 Hz, 4.5H), 1.24 (t, J=7 Hz, 1.5H), 2.0-2.2 (m, 0.25H), 2.2-2.4 (m, 0.75H), 3.38 (t, J=6 Hz, 0.25H), 3.45 (t, J=6 Hz, 0.75H), 5.21 (d, J=6 Hz, 0.75H), 5.45 (d, J=6 Hz, 0.25H), 7.60-7.80 (m, 3H), 8.10-8.20 (m, 2H)
In the same manner as in Examples 37 and 38, the following compounds were produced.
EXAMPLE 39
Preparation of 2-((1S, 2S)-2-amino-1-hydroxy-4-methylpentyl)cyclopropenone p-toluene sulfonate (Compound No. 173 in Table 2)
NMR (CD.sub.3 OD, .delta.): 1.02 (d, J=6.2 Hz, 3H), 1.06 (d, J=6.3 Hz, 3H), 1.60-1.95 (m, 3H), 2.42 (s, 3H), 3.58 (m, 1H), 4.88 (d, J=4.9 Hz, 1H), 7.31 (d, J=8.2 Hz, 2H), 7.75 (d, J=8.2 Hz, 2H), 9.11 (s, 1H)
EXAMPLE 40
Preparation of 2-((2S)-2-amino-1-hydroxy-3-phenylpropyl)cyclopropenone p-toluene sulfonate (Compound No. 200 in Table 2)
NMR (CD.sub.3 OD, .delta.): 2.41 (s, 3H), 3.03-3.30 (m, 2H), 3.80-4.10 (m, 1H), 4.75-5.00 (m, 1H), 7.15 -7.45 (m, 7H), 7.75 (d, J=8.1 Hz, 2H), 8.88 (s, 0.3H), 9.04 (s, 0.7H)
EXAMPLE 41
Preparation of 2-((2S)-2-amino-1-hydroxy-4-methylpentyl)-3-ethylcyclopropenone p-toluene sulfonate (Compound No. 220 in Table 2)
NMR (CD.sub.3 OD, .delta.): 0.95-1.15 (m, 6H), 1.55-1.95 (m, 3H), 2.41 (s, 3H), 2.68-2.88 (m, 2H), 3.40-3.60 (m, 1H), 4.75-4.85 (m, 1H), 7.27 (d, J=8.0 Hz, 2H), 7.75 (d, J=8.0 Hz, 2H)
EXAMPLE 42
Preparation of 2-((1S, 2S)-2-amino-1-hydroxyhexyl-3-((E)-1-hexenyl) cyclopropenone p-toluene sulfonate (Compound No. 252 in Table 2)
IR (KBr, cm.sup.-1): 3422, 1845, 1630, 1601 NMR (CD.sub.3 OD, .delta.): 0.80-1.05 (m, 6H), 1.20-1.95 (m, 10H), 2.36 (s, 3H), 2.32-2.40 (m, 2H), 3.25-3.45 (m, 1H), 4.82 (d, J=7.3 Hz, 1H), 6.38 (d, J=16 Hz, 1H), 7.02 (dd, J=16 Hz, 7.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 2H), 7.70 (d, J=8.0 Hz, 2H)
EXAMPLE 43
Preparation of 2-((1S, 2S)-2-amino-1-hydroxyhexyl)-3-((Z)-1-hexenyl) cyclopropenone p-toluene sulfonate (Compound No. 258 in Table 2)
IR (neat, cm.sup.-1): 3260, 1845, 1633 NMR (CDCl.sub.3, .delta.): 0.73 (t, J=7.1 Hz, 3H), 0.89 (t, J=6.7 Hz, 3H), 1.08-1.95 (m, 10H), 2.35 (s, 3H), 2.40-2.65 (m, 2H), 3.33 (m, 1H), 3.92 (s, 3H), 4.88 (m, 1H), 6.21 (d, J=10 Hz, 1H), 6.40 (dd, J=10 Hz, 6.8 Hz, 1H), 7.14 (d, J=6.7 Hz, 2H), 7.71 (d, J=6.7 Hz, 2H), 7.81 (m, 1H)
EXAMPLE 44
Preparation of 2-((2S)-1-hydroxy-3-methyl-2-methylaminobutyl)-3-phenylcyclopropenone hydrochloride (Compound No. 282 in Table 2)
IR (KBr, cm.sup.-1): 3422, 1858, 1626 NMR (CD.sub.3 OD, .delta.: 0.78-0.95 (m, 6H), 2.05-2.40 (m, 1H), 2.79 (s, 3H), 3.47 (m, 1H), 5.28 (d, J=4.5 Hz, 0.5H), 5.43 (d, J=4.4 Hz, 0.5H), 7.55-7.75 (m, 3H), 7.95-8.13 (m, 2H)
EXAMPLE 45
Preparation of 2-(2-amino-1-hydroxy-2-methylpropyl)-3-phenylcyclopropenone hydrochloride (Compound No. 298 in Table 2 )
IR (KBr, cm.sup.-1): 3300, 3250, 1858, 1620 NMR (CD.sub.3 OD, .delta.): 1.42 (s, 3H), 1.57 (s, 3H), 4.98 (s, 1H), 7.55-7.78 (m, 3H), 8.07 (d, J=7.3 Hz, 2H)
EXAMPLE 46
Preparation of 2-((2S)-2-amino-1-hydroxy-3-methylbutyl)-3-(1-hydroxy-1-methylethyl) cyclopropenone hydrochloride (Compound No. 428 in Table 2)
IR (KBr, cm.sup.-1): 3420, 1846, 1615 NMR (CD.sub.3 OD, .delta.: 1.09 (d, J=6.9 Hz, 2.1H), 1.13 (d, J=6.9 Hz, 2.1H), 1.14 (s, 1.8H), 1.56 (s, 4.2H), 1.58 (s, 1.8H), 1.99 (m, 0.3H), 2.15 (m, 0.7H), 3.25 (m, 0.3H), 3.39 (m, 0.7H), 5.01 (d, J=5.5 Hz, 0.7H), 5.19 (d, J=4.5 Hz, 0.3H)
EXAMPLE 47
Preparation of 2-((2S)-2-amino-1-hydroxy-3-methylbutyl)-(4-fluorophenyl) cyclopropenone (Compound No. 314 in Table 2)
IR (KBr, cm.sup.-1): 3280, 1858, 1620, 1600 NMR (CD.sub.3 OD, .delta.): 1.05-1.33 (m, 6H), 2.07 (m, 0.2H), 2.29 (m, 0.8H), 3.38 (m, 0.2H), 3.44 (m, 0.8H), 5.20 (d, J=6.1 Hz, 0.8H), 5.41 (d, J=4.7 Hz, 0.2H), 7.38-7.52 2H), 8.15-8.32 (m, 2H)
EXAMPLE 48
Preparation of 2-((2S)-2-amino-1-hydroxy-3-methylbutyl)-3-[(hydroxy)(phenyl)methyl]cyclopropenone hydrochlorine (Compound No. 444 in Table 2)
IR (KBr, cm.sup.-1): 3430, 1846, 1626 NMR (CD.sub.3 OD, .delta.): 1.0-1.20 (m, 6H), 1.90-2.22 (m, 1H), 3.20-3.45 (m, 1H), 5.0-5.25 (m, 1H), 5.97 (s, 0.75H), 6.0 (s, 0.25H), 7.28-7.45 (m, 3H), 7.45-7.60 (m, 2H)
EXAMPLE 49
Preparation of 2-((2S)-2-methoxycarbonylamino-3-methyl-1-hydroxybutyl)-3-phenylcyclopropenone (Compound No. 278 in Table 2)
IR (neat, cm.sup.-1): 3333, 1856, 1705, 1622 NMR (CDCl.sub.3, .delta.): 0.95-1.15 (m, 6H), 1.95-2.40 (m, 1H), 3.56 (s, 2.4H), 3.63 (s, 0.6H), 3.72 (m, 0.2H), 3.80 (m, 0.8H), 5.09 (d, J=4.5 Hz, 1H), 5.72 (d, J=6.7 Hz, 1H), 7.45-7.60 (m, 3H), 7.93-8.08 (m, 2H)

Number	Date	Country
4-262473	Sep 1992	JPX
4-262474	Sep 1992	JPX
4-262475	Sep 1992	JPX

Number	Name	Date
4474800	Tamai et al.	Oct 1984
4714777	Dowd et al.	Dec 1987
5081284	Higuchi et al.	Jan 1992
5158936	Krantz et al.	Oct 1992

Cyclopropene derivatives

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