TREA

Prolineamide derivatives

Follow

Information

  • Patent Grant
  • 5744487
  • Patent Number
    5,744,487
  • Date Filed
    Thursday, January 26, 1995
    31 years ago
  • Date Issued
    Tuesday, April 28, 1998
    28 years ago
Information
Abstract
A prolineamide derivative represented by the formula (I): ##STR1## or a salt or hydrate thereof or a pharmaceutically acceptable salt thereof, which has a protease inhibition activity and is useful as an active ingredient of pharmaceutical compositions is provided.
Description

FIELD OF THE INVENTION
The present invention relates to novel proline derivatives. More particularly, it relates to proline derivatives having a protease inhibition activity or pharmaceutically acceptable salts thereof and protease inhibitors containing the same as an active ingredient.
BACKGROUND OF THE INVENTION
It has been known that various proteases are present in the living body, for example, a group of serine proteases such as thrombin, factor Xa, factor IXa, factor VIIa, trypsin, plasmin, tissue plasminogen activator, kallikrein, C3/C5 convertase in the complement system, tryptase, etc. is known. Further, it is also known that these proteases cause various diseases when they are activated abnormally by some reason. Accordingly, substances which inhibit the activity of these proteases are useful as a clinical remedy. For example, antithrombin agents, anti-factor Xa agents and anti-factor VIIa agents are useful for treating thrombosis, antitrypsin agents are useful for treating pancreatitis, antiplasmin agents are useful as hemostatics, antiallergic agents and antiinflammatory agents, antikallikrein agents are useful as a remedy for inflammation and ulcer, and anticomplementary agents are useful as a remedy for nephritis and rheumatoid arthritis. Protease inhibitors having these actions have hitherto been developed, but they are not necessarily sufficient for practical use in view of protease inhibition activity, stability in the living body and the like. For example, tripeptide derivatives consist of arginine derivatives are known as protease inhibitors. That is, D-phenylalanyl-L-prolyl-L-arginal is known as a thrombin inhibitor (e.g. Folia Haematol., 109, 22 (1982)) but is fairly unstable in the living body (J. Med. Chem., 33, 1729 (1990)). Further, arginal derivatives (Japanese Laid-open Patent Publication No. 4-89498) or amidinophenylalanine derivatives (Thromb. Res., 17, 425 (1980)) are reported as protease inhibitors but their inhibition activity is low.
Under these circumstances, the present inventors have studied to develop structurally novel drugs having enzyme inhibition activity and stability in vivo, which are sufficient for practical use. As a result, it has been found that certain prolineamide derivatives can attain the desired object, thus the present invention has been established.
SUMMARY OF THE INVENTION
That is, the present invention provides a prolineamide derivative represented by the formula (I): ##STR2## wherein A is a carbon atom or a nitrogen atom; n is an integer of 0 to 2; a broken line is absent or a single bond;
R.sup.1 is ##STR3## {wherein D and E independently indicate a single bond or an optionally branched C.sub.1 -C.sub.6 alkylene group;
R.sup.4 is a C.sub.1 -C.sub.6 alkyl group, --OR.sup.6 (R.sup.6 is a hydrogen atom, a C.sub.1 -C.sub.6 alkyl group, an optionally substituted C.sub.6 -C.sub.10 aryl group, an optionally substituted C.sub.3 -C.sub.8 cycloalkyl group or an optionally substituted C.sub.7 -C.sub.12 aralkyl group), --SR.sup.7 (R.sup.7 is a C.sub.1 -C.sub.6 alkyl group, an optionally substituted C.sub.6 -C.sub.10 aryl group, an optionally substituted C.sub.3 -C.sub.8 cycloalkyl group or an optionally substituted C.sub.7 -C.sub.12 aralkyl group), --SOR.sup.8 (R.sup.8 is an optionally substituted C.sub.6 -C.sub.10 aryl group or an optionally substituted C.sub.3 -C.sub.8 cycloalkyl group), --SO.sub.2 R.sup.9 (R.sup.9 is an optionally substituted C.sub.6 -C.sub.10 aryl group or an optionally substituted C.sub.3 -C.sub.8 cycloalkyl group), --COR.sup.10 (R.sup.10 is a hydroxyl group, a C.sub.1 -C.sub.6 alkoxy group, an optionally substituted C.sub.6 -C.sub.10 aryl group or an optionally substituted C.sub.3 -C.sub.8 cycloalkyl group), --NHR.sup.11 (R.sup.11 is a C.sub.1 -C.sub.6 alkyl group, an optionally substituted C.sub.6 -C.sub.10 aryl group, an optionally substituted C.sub.3 -C.sub.8 cycloalkyl group or an optionally substituted C.sub.7 -C.sub.12 aralkyl group), --NHCOR.sup.12 (R.sup.12 is a C.sub.1 -C.sub.6 alkoxy group, an optionally substituted C.sub.6 -C.sub.10 aryl group, an optionally substituted C.sub.3 -C.sub.8 cycloalkyl group or an optionally substituted C.sub.7 -C.sub.12 aralkyloxy group), --NHSO.sub.2 R.sup.13 (R.sup.13 is a C.sub.1 -C.sub.6 alkyl group, an optionally substituted C.sub.6 -C.sub.10 aryl group, an optionally substituted C.sub.3 -C.sub.8 cycloalkyl group, an optionally substituted C.sub.7 -C.sub.12 aralkyl group, an optionally substituted 5- to 10-membered heterocyclic group), an optionally substituted C.sub.6 -C.sub.1 aryl group, an optionally substituted C.sub.3 -C.sub.8 cycloalkyl group, an optionally substituted 5- to 10membered heterocyclic group or --SiR.sup.14 R.sup.15 R.sup.16 (R.sup.14, R.sup.15, and R.sup.16 independently indicate a C.sub.1 -C.sub.6 alkyl group);
R.sup.5 is a --OR.sup.17 (R.sup.17 is a hydrogen atom, --SiR.sup.22 R.sup.23 R.sup.24 (R.sup.22, R.sup.23, and R.sup.24 independently indicate a C.sub.1 -C.sub.6 alkyl group), a C.sub.1 -C.sub.6 alkyl group or an optionally substituted 5- to 10-membered heterocyclic group)), --OCOR.sup.18 (R.sup.18 is a hydrogen atom, a C.sub.1 -C.sub.6 alkyl group, a C.sub.1 -C.sub.6 alkoxy group, an amino group, a C.sub.1 -C.sub.6 alkylamino group, a C.sub.2 -C.sub.12 dialkylamino group or a C.sub.2 -C.sub.7 alkenylamino group), --NHR.sup.19 (R.sup.19 is a hydrogen atom, a C.sub.1 -C.sub.6 alkyl group or an optionally substituted C.sub.7 -C.sub.12 aralkyl group), --NHCOR.sup.20 (R.sup.20 is a hydrogen atom, a C.sub.1 -C.sub.6 alkyl group, a C.sub.1 -C.sub.6 haloalkyl group, a C.sub.1 -C.sub.6 alkoxy group, an optionally substituted C.sub.3 -C.sub.8 cycloalkyl group, a C.sub.2 -C.sub.7 carboxyalkyloxy group, a C.sub.2 -C.sub.7 alkenyloxy group, an optionally substituted C.sub.6 -C.sub.10 aryl group, an optionally substituted C.sub.6 -C.sub.10 aryloxy group, a C.sub.3 -C.sub.9 alkoxycarbonylalkoxy group, a C.sub.2 -C.sub.12 dialkylamino group or an optionally substituted C.sub.7 -C.sub.12 aralkyloxy group) or --NHSO.sub.2 R.sup.21 (R.sup.21 is a C.sub.1 -C.sub.6 alkyl group, a C.sub.1 -C.sub.6 haloalkyl group, a C.sub.2 -C.sub.7 carboxyalkyl group, an optionally substituted C.sub.6 -C.sub.10 aryl group, a C.sub.3 -C.sub.9 alkoxycarbonylalkyl group or an optionally substituted C.sub.7 -C.sub.12 aralkyl group); and m is 0 or 1};
R.sup.2 is a hydrogen atom or a C.sub.1 -C.sub.6 alkyl group; and R.sup.3 is --C(.dbd.NR.sup.25)NH.sub.2 (R.sup.25 is a hydrogen atom, a C.sub.1 -C.sub.6 alkyl group, a C.sub.2 -C.sub.7 acyl group, a C.sub.2 -C.sub.7 acyloxy group, a C.sub.1 -C.sub.6 alkoxy group, a C.sub.2 -C.sub.7 alkoxycarbonyl group, a C.sub.2 -C.sub.7 alkoxycarbonyloxy group, a hydroxyl group or a C.sub.2 -C.sub.7 hydroxyalkylcarbonyloxy group), --NH--C(.dbd.NR.sup.25)NH.sub.2 (R.sup.25 is as defined above) or --NHR.sup.26 (R.sup.26 is a hydrogen atom, a C.sub.1 -C.sub.6 alkyl group, a C.sub.2 -C.sub.7 acyl group, a C.sub.2 -C.sub.7 alkoxycarbonyl group or a 5-C.sub.1 -C.sub.3 alkyl-1,3-dioxol-2-on-4-ylmethyl group; provided that R.sup.3 is --C(.dbd.NR.sup.25)NH.sub.2 when A is a nitrogen atom or a salt and pharmaceutical use thereof.
DETAILED DESCRIPTION OF THE INVENTION
The prolineamide derivative of the present invention is represented by the above formula (I). Examples of the optionally branched C.sub.1 -C.sub.6 alkylene group in the above definition include --CH.sub.2 --, --(CH.sub.2).sub.2 --, --(CH.sub.2).sub.3 --, --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 --, --(CH.sub.2).sub.6 --, --CH(CH.sub.3)--, --C(CH.sub.3).sub.2 --, --CH(CH.sub.3)CH.sub.2 --, --CH.sub.2 CH(CH.sub.3)--, --C(CH.sub.3).sub.2 CH.sub.2 --, --CH.sub.2 C(CH.sub.3).sub.2 --, --CH(CH.sub.3)CH(CH.sub.3)-- and the like. Examples of the C.sub.1 -C.sub.6 alkyl group include methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, s-butyl group, i-butyl group, t-butyl group, n-pentyl group, n-hexyl group and the like. Examples of the C.sub.1 -C.sub.3 alkyl group include those having three carbon atoms or less among those illustrated above. Examples of the C.sub.1 -C.sub.6 alkoxy group include methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butyloxy group, s-butyloxy group, i-butyloxy group, t-butyloxy group, n-pentyloxy group, n-hexyloxy group and the like. Examples of the C.sub.2 -C.sub.7 alkoxycarbonyl group include methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, i-propoxycarbonyl group, n-butyloxycarbonyl group, t-butyloxycarbonyl group, n-pentyloxycarbonyl group, n-hexyloxycarbonyl group and the like. Examples of the C.sub.3 -C.sub.8 cycloalkyl group include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group and the like. Examples of the C.sub.6 -C.sub.10 aryl group include phenyl group, tolyl group, naphthyl group and the like. Examples of the C.sub.7 -C.sub.12 aralkyl group include benzyl group, phenylethyl group, phenylpropyl group, naphthylmethyl group and the like. Examples of the C.sub.6 -C.sub.10 aryloxy group include phenyloxy group, naphthyloxy group and the like. Examples of the C.sub.7 -C.sub.12 aralkyloxy group include benzyloxy group, phenylethyloxy group, phenylpropyloxy group, naphthylmethyloxy group and the like. Examples of the heterocyclic group include those contain 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and the total number of atoms constituting the ring is 5 to 10, specifically, respective residues of furan ring, tetrahydrofuran ring, pyran ring, benzofuran ring, chroman ring, thiophene ring, benzothiophene ring, pyrrole ring, imidazole ring, pyrazole ring, triazole ring, pyridine ring, piperidine ring, pyrazine ring, piperazine ring, pyrimidine ring, indole ring, benzimidazole ring, purine ring, quinoline ring, phthalazine ring, quinazoline ring, cinnoline ring, oxazole ring, thiazole ring, morpholine ring and the like. Examples of the C.sub.1 -C.sub.6 haloalkyl group include chloromethyl group, bromomethyl group, dichloromethyl group, 1-chloroethyl group, 2-chloroethyl group, 3-chloropropyl group, 4-chlorobutyl group, 5-chloropentyl group, 6-chlorohexyl group, difluoromethyl group, trifluoromethyl group and the like. Examples of the C.sub.2 -C.sub.7 carboxyalkyl group include carboxymethyl group, 2-carboxyethyl group, 3-carboxypropyl group, 4-carboxybutyl group, 5-carboxypentyl group, 6-carboxyhexyl group and the like. Examples of the C.sub.2 -C.sub.7 carboxyalkyloxy group include carboxymethoxy group, 2-carboxyethoxy group, 3-carboxypropoxy group, 4-carboxybutyloxy group, 5-carboxypentyloxy group, 6-carboxyhexyloxy group and the like. Examples of the C.sub.2 -C.sub.7 alkenyloxy group include vinyloxy group, aryloxy group, 2-propenyloxy group, isopropenyloxy group, 3-butenyloxy group, 4-pentenyloxy group, 5-hexenyloxy group and the like. Examples of the C.sub.2 -C.sub.7 alkenylamino group include vinylamino group, arylamino group, 2-propenylamino group, isopropenylamino group, 3-butenylamino group, 4-pentenylamino group, 5-hexenylamino group and the like. Examples of the C.sub.1 -C.sub.6 alkylamino group include methylamino group, ethylamino group, n-propylamino group, n-butylamino group and the like. Examples of the C.sub.2 -C.sub.12 dialkylamino group include dimethylamino group, methylethylamino group, diethylamino group, di-n-propylamino group and the like. Examples of the C.sub.2 -C.sub.7 acyl group include acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaroyl group, hexanoyl group, heptanoyl group and the like. Examples of the C.sub.2 -C.sub.7 acyloxy group include acetyloxy group, propionyloxy group, butyryloxy group, isobutyryloxy group, valeryloxy group, isovaleryloxy group, pivaroyloxy group, hexanoyloxy group, heptanoyloxy group and the like. Examples of the C.sub.2 -C.sub.7 alkokycarbonyloxy group include methoxycarbonyloxy group, ethoxycarbonyloxy group, n-propoxycarbonyloxy group, n-butyloxycarbonyloxy group, n-pentyloxycarbonyloxy group, n-hexyloxycarbonyloxy group and the like. Examples of the C.sub.2 -C.sub.7 hydroxyalkylcarbonyloxy group include hydroxymethylcarbonyloxy group, 2-hydroxyethylcarbonyloxy group, 3hydroxypropylcarbonyloxy group, 4-hydroxybutylcarbonyloxy group, 5hydroxypentylcarbonyloxy group, 6-hydroxyhexylcarbonyloxy group and the like. Examples of the C.sub.3 -C.sub.9 alkoxycarbonylalkoxy group include methoxycarbonylmethoxy group, ethoxycarbonylmethoxy group, propoxycarbonylmethoxy group, methoxycarbonylethoxy group, ethoxycarbonylethoxy group, propoxycarbonylethoxy group and the like. Examples of the C.sub.3 -C.sub.9 alkoxycarbonylalkyl group include methoxycarbonylmethyl group, ethoxycarbonylmethyl group, propoxycarbonylmethyl group, methoxycarbonylethyl group, methoxycarbonylmethyl group, propoxycarbonylethyl group and the like.
Examples of the substituent in the above definition of "optionally substituted (with substituent)" include above-described C.sub.1 -C.sub.6 alkyl group; above-described C.sub.1 -C.sub.6 haloalkyl group; above-described C.sub.1 -C.sub.6 alkoxy group; hydroxyl group; carboxyl group; above-described C.sub.2 -C.sub.7 carboxyalkyl group; above-described C.sub.2 -C.sub.7 carboxyalkyloxy group; above-described C.sub.2 -C.sub.7 acyl group; above-described C.sub.2 -C.sub.7 acyloxy group; above-described C.sub.2 -C.sub.7 alkoxycarbonyl group; above-described C.sub.2 -C.sub.7 alkoxycarbonyloxy group; C.sub.8 -C.sub.13 aralkyloxycarbonyl group such as benzyloxycarbonyl group, phenylethyloxycarbonyl group, phenylpropyloxycarbonyl group, naphthylmethyloxycarbonyl group, etc.; halogen atoms such as fluorine atom, chlorine atom, bromine atom and the like.
In the compound represented by the above formula (I), it is preferred that the 5- to 6-membered contains 1 to 4 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom and the total number of atoms constituting the ring is 5 to 10. Further, as the substituent of the respective groups, a group(s) selected from C.sub.1 -C.sub.6 alkyl group, C.sub.1 -C.sub.6 haloalkyl group, C.sub.1 -C.sub.6 alkoxy group, hydroxyl group, carboxyl group, C.sub.2 -C.sub.7 carboxyalkyl group, C.sub.2 -C.sub.7 carboxyalkyloxy group, C.sub.2 -C.sub.7 acyl group, C.sub.2 -C.sub.7 acyloxy group, C.sub.2 -C.sub.7 alkoxycarbonyl group, C.sub.2 -C.sub.7 alkoxycarbonyloxy group, C.sub.8 -C.sub.13 aralkyloxycarbonyl group, C.sub.3 -C.sub.9 alkoxycarbonylalkoxy group and halogen atoms is preferred.
In the compound represented by the above formula (I) of the present invention, a carbon atom is preferred as A.
Examples of preferred compounds of the present invention include those of the formula (I), wherein A is a carbon atom; n is 1 or 2; R.sup.1 is ##STR4## {wherein D and E independently indicate a single bond or an optionally branched C.sub.1 -C.sub.6 alkylene group;
R.sup.4 is a C.sub.1 -C.sub.6 alkyl group: --OR.sup.6 (R.sup.6 is a C.sub.1 -C.sub.6 alkyl group; a C.sub.6 -C.sub.10 aryl group which may be substituted with at least one substituent selected from the group consisting of a C.sub.1 -C.sub.6 alkyl group, a C.sub.1 -C.sub.6 alkoxy group, a halogen atom, a hydroxyl group, a carboxyl group, a C.sub.2 -C.sub.7 alkoxycarbonyl group, a C.sub.2 -C.sub.7 carboxyalkyl group, a C.sub.2 -C.sub.7 acyl group, a C.sub.2 -C.sub.7 acyloxy group, a C.sub.2 -C.sub.7 alkoxycarbonyloxy group, a C.sub.3 -C.sub.9 alkoxycarbonylalkoxy group and a benzyloxycarbonyl group; or a C.sub.7 -C.sub.12 aralkyl group which may be substituted with at least one substituent selected from the group consisting of a C.sub.1 -C.sub.6 alkyl group, a C.sub.1 -C.sub.6 alkoxy group, a halogen atom, a hydroxyl group, a carboxyl group, a C.sub.2 -C.sub.7 alkoxycarbonyl group, a C.sub.2 -C.sub.7 carboxyalkyl group, a C.sub.2 -C.sub.7 acyl group, a C.sub.2 -C.sub.7 acyloxy group, a C.sub.2 -C.sub.7 alkoxycarbonyloxy group, a C.sub.3 -C.sub.9 alkoxycarbonylalkoxy group and a benzyloxycarbonyl group): --SR.sup.7 (R.sup.7 is a C.sub.1 -C.sub.6 alkyl group, a C.sub.6 -C.sub.10 aryl group which may be substituted with at least one substituent selected from the group consisting of a C.sub.1 -C.sub.6 alkyl group, a C.sub.1 -C.sub.6 alkoxy group, a halogen atom, a hydroxyl group, a carboxyl group, a C.sub.2 -C.sub.7 alkoxycarbonyl group, a C.sub.2 -C.sub.7 carboxyalkyl group, a C.sub.2 -C.sub.7 acyl group, a C.sub.2 -C.sub.7 acyloxy group, a C.sub.2 -C.sub.7 alkoxycarbonyloxy group, a C.sub.3 -C.sub.9 alkoxycarbonylalkoxy group and a benzyloxycarbonyl group; or a C.sub.7 -C.sub.12 aralkyl group which may be substituted with at least one substituent selected from the group consisting of a C.sub.1 -C.sub.6 alkyl group, a C.sub.1 -C.sub.6 alkoxy group, a halogen atom, a hydroxyl group, a carboxyl group, a C.sub.2 -C.sub.7 alkoxycarbonyl group, a C.sub.2 -C.sub.7 carboxyalkyl group, a C.sub.2 -C.sub.7 acyl group, a C.sub.2 -C.sub.7 acyloxy group, a C.sub.2 -C.sub.7 alkoxycarbonyloxy group, a C.sub.3 -C.sub.9 alkoxycarbonylalkoxy group and a benzyloxycarbonyl group): --COOH: a C.sub.6 -C.sub.10 aryl group which may be substituted with at least one substituent selected from the group consisting of a C.sub.1 -C.sub.6 alkyl group, a C.sub.1 -C.sub.6 alkoxy group, a halogen atom, a hydroxyl group, a carboxyl group, a C.sub.2 -C.sub.7 alkoxycarbonyl group, a C.sub.2 -C.sub.7 carboxyalkyl group, a C.sub.2 -C.sub.7 acyl group, a C.sub.2 -C.sub.7 acyloxy group, a C.sub.2 -C.sub.7 alkoxycarbonyloxy group, a C.sub.3 -C.sub.9 alkoxycarbonylalkoxy group and a benzyloxycarbonyl group: a C.sub.3 -C.sub.8 cycloalkyl group: or --SiR.sup.14 R.sup.15 R.sup.16 (R.sup.14, R.sup.15, and R.sup.16 independently indicate a C.sub.1 -C.sub.6 alkyl group);
R.sup.5 is --OH, --OCOR.sup.18 (R.sup.18 is a C.sub.1 -C.sub.6 alkoxy group or a C.sub.2 -C.sub.7 alkenylamino group), --NH.sub.2, --NHCOR.sup.20 (R.sup.20 is a Cl -C.sub.6 alkoxy group, a C.sub.6 -C.sub.10 aryloxy group, a C.sub.3 -C.sub.9 alkoxycarbonylalkoxy group, a C.sub.2 -C.sub.12 dialkylamino group or a C.sub.7 -C.sub.12 aralkyloxy group) or --NHSO.sub.2 R.sup.21 (R.sup.21 is a C.sub.1 -C.sub.6 alkyl group, a C.sub.2 -C.sub.7 carboxyalkyl group, a C.sub.6 -Cl0 aryl group, a C.sub.3 -C.sub.9 alkoxycarbonylalkyl group or a C.sub.7 -C.sub.12 aralkyl group);
and m is 0 or 1};
R.sup.2 is a hydrogen atom; and
R.sup.3 is --C(.dbd.NR.sup.25)NH.sub.2 (R.sup.25 is a hydrogen atom, a C.sub.2 -C.sub.7 alkoxycarbonyl group or a hydroxyl group), --NH--C(.dbd.NR.sup.25)NH.sub.2 (R.sup.25 is as defined above) or --NHR.sup.26 (R.sup.26 is a hydrogen atom, a C.sub.2 -C.sub.7 alkoxycarbonyl group or a 5-C.sub.1 -C.sub.3 alkyl-1,3-dioxol-2-on-4-yl methyl group).
As the more preferred compound of the present invention, there is a compound of the formula (I), wherein A is a carbon atom; n is 1; R.sup.1 is ##STR5## {(wherein D and E independently indicate a single bond or an optionally branched C.sub.1 -C.sub.6 alkylene group;
R.sup.4 is a C.sub.1 -C.sub.6 alkyl group; -OR.sup.6 (R.sup.6 is a C.sub.6 -C.sub.10 aryl or C.sub.7 -C.sub.12 aralkyl group which may be substituted with at least one substituent selected from the group consisting of a C.sub.1 -C.sub.6 alkyl group, a halogen atom, a carboxyl group, a C.sub.2 -C.sub.7 carboxyalkyl group and a benzyloxycarbonyl group); --SR.sup.7 (R.sup.7 is a C.sub.1 -C.sub.6 alkyl group); a C.sub.6 -C.sub.10 aryl group which may be substituted with at least one substituent selected from the group consisting of a C.sub.1 -C.sub.6 alkyl group, a halogen atom, a carboxyl group, a C.sub.2 -C.sub.7 carboxyalkyl group and a benzyloxycarbonyl group; or a C.sub.3 -C.sub.6 cycloalkyl group;
R.sup.5 is --OH, --NH.sub.2, --NHCOR.sup.20 (R.sup.20 is a C.sub.1 -C.sub.6 alkoxy group or a C.sub.7 -C.sub.12 aralkyloxy group) or --NHSO.sub.2 R.sup.21 (R.sup.21 is a C.sub.1 -C.sub.6 alkyl group or a C.sub.6 -C.sub.10 aryl group);
and m is 1};
R.sup.2 is a hydrogen atom; and
R.sup.3 is --C(.dbd.NR.sup.25)NH.sub.2 (R.sup.25 is a hydrogen atom or a hydroxyl group) or --NH.sub.2.
As the more preferred compound of the present invention, there is a compound of the formula (I), wherein A is a carbon atom; n is 1; R.sup.1 is ##STR6## {wherein D is a single bond and E is a single bond or a C.sub.1 -C.sub.6 alkylene group;
R.sup.4 is a C.sub.1 -C.sub.6 alkyl group; --OR.sup.6 (R.sup.6 is a C.sub.6 -C.sub.10 aryl or C.sub.7 -C.sub.12 aralkyl group which may be substituted with at least one substituent selected from the group consisting of a C.sub.1 -C.sub.6 alkyl group, a halogen atom, a carboxyl group, a C.sub.2 -C.sub.7 carboxyalkyl group and a benzyloxycarbonyl group); --SR.sup.7 (R.sup.7 is a C.sub.1 -C.sub.6 alkyl group); a C.sub.6 -C.sub.10 aryl group which may be substituted with at least one substituent selected from the group consisting of a C.sub.1 -C.sub.6 alkyl group, a halogen atom, a carboxyl group, a C.sub.2 -C.sub.7 carboxyalkyl group and a benzyloxycarbonyl group; or a C.sub.3 -C.sub.6 cycloalkyl group;
R.sup.5 is --NH.sub.2, --NHCOR.sup.20 (R.sup.20 is a C.sub.1 -C.sub.6 alkoxy group or a C.sub.7 -C.sub.12 aralkyloxy group) or --NHSO.sub.2 R.sup.21 (R.sup.21 is a C.sub.1 -C.sub.6 alkyl group or a C.sub.6 -C.sub.10 aryl group);
and m is 1};
R.sup.2 is a hydrogen atom; and
R.sup.3 is --C(.dbd.NR.sup.25)NH.sub.2 (R.sup.25 is a hydrogen atom or a hydroxyl group) or --NH.sub.2.
As the still more preferred compound of the present invention, there is a compound of the formula (I), wherein A is a carbon atom; n is 1; R.sup.1 is ##STR7## {wherein D is a single bond; E is a single bond or a C.sub.1 -C.sub.3 alkylene group; R.sup.4 is a C.sub.3 -C.sub.6 alkyl group, --OR.sup.6 (R.sup.6 is a C.sub.1 -C.sub.6 alkyl group), a phenyl group or a C.sub.3 -C.sub.6 cycloalkyl group; R.sup.5 is --OH, --NHR.sup.19 (R.sup.19 is a hydrogen atom), NHCOR.sup.20 (R.sup.20 is a C.sub.1 -C.sub.6 alkoxy group) or --NHSO.sub.2 R.sup.21 (R.sup.21 is a C.sub.1 -C.sub.3 alkyl group); and m is 1};
R.sup.2 is a hydrogen atom; and
R.sup.3 is --C(.dbd.NR.sup.25)NH.sub.2 (R.sup.25 is a hydrogen atom or a hydroxyl group) or --NH.sub.2.
As the particularly preferred compound of the present invention, there is a compound of the formula (I), wherein A is a carbon atom; n is 1; R.sup.1 is ##STR8## {wherein D is a single bond; E is a single bond or a C.sub.1 -C.sub.6 alkylene group;
R.sup.4 is a C.sub.1 -C.sub.6 alkyl group; R.sup.5 is --NHCOR.sup.20 (R.sup.20 is a C.sub.1 -C.sub.6 alkoxy group); and
m is 1};
R.sup.2 is a hydrogen atom; and
R.sup.3 is --C(.dbd.NR.sup.25)NH.sub.2 (R.sup.25 is a hydrogen atom or a hydroxyl group)).
As the most preferred compound of the present invention, there is trans-4-�(S)-N-((R)-2-ethoxycarbonylamino-4,4-dimethylpentanoyl) prolyl!aminomethylcyclohexanecarboxamidoxime (compound No. 461 in Table 1 in Example 33).
The prolineamide derivatives represented by the above formula (I) can afford various stereoisomers. For example, concerning asymmetric carbon atoms, the absolute configuration may be D-configuration, L-configuration or DL configuration and all types thereof are included in the compounds of the present invention.
Examples of the salt which can be formed with the compounds of the above formula (I) of the present invention include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.; organic acid salts such as succinate, oxalate, fumarate, maleate, lactate, tartrate, citrate, acetate, glycolate, methanesulfonate, toluenesulfonate, etc. Further, the proline derivatives of the above formula (I) containing a free carboxyl group can also form a salt with a pharmaceutically acceptable base.
Examples of the salt include alkaline metal salt, alkaline earth metal salt, ammonium salt, alkyl ammonium salt and the like.
Further, the prolineamide derivatives of the above formula (I) and the salts thereof can also form a hydrate.
Hereinafter, examples of the compounds of the present invention will be described.
TABLE 1__________________________________________________________________________ ##STR9##Compound No. ##STR10## R.sup.2 R.sup.3 n A Broken__________________________________________________________________________ line ##STR11## H ##STR12## 1 C Single bond2 ##STR13## H ##STR14## 1 C Single bond3 ##STR15## H ##STR16## 1 C Single bond4 ##STR17## H ##STR18## 1 C Single bond5 ##STR19## H ##STR20## 1 C Single bond6 ##STR21## H ##STR22## 1 C Single bond7 ##STR23## H ##STR24## 1 C Single bond8 ##STR25## H ##STR26## 1 C Single bond9 ##STR27## H ##STR28## 1 C Single bond10 ##STR29## H ##STR30## 1 C Single bond11 ##STR31## H ##STR32## 1 C Single bond12 ##STR33## H ##STR34## 1 C Single bond13 ##STR35## H ##STR36## 1 C Single bond14 ##STR37## H ##STR38## 1 C Single bond15 ##STR39## H ##STR40## 1 C Single bond16 ##STR41## H ##STR42## 1 C Single bond17 ##STR43## H ##STR44## 1 C Single bond18 ##STR45## H ##STR46## 1 C Single bond19 ##STR47## H ##STR48## 1 C Single bond20 ##STR49## H ##STR50## 1 C Single bond21 ##STR51## H ##STR52## 1 C Single bond22 ##STR53## H ##STR54## 1 C Single bond23 ##STR55## H ##STR56## 1 C Single bond24 ##STR57## H ##STR58## 1 C Single bond25 ##STR59## H ##STR60## 1 C Single bond26 ##STR61## H ##STR62## 1 C Single bond27 ##STR63## H ##STR64## 1 C Single bond28 ##STR65## H ##STR66## 1 C Single bond29 ##STR67## H ##STR68## 1 C Single bond30 ##STR69## H ##STR70## 1 C Single bond31 ##STR71## H ##STR72## 1 C Single bond32 ##STR73## H ##STR74## 1 C Single bond33 ##STR75## H ##STR76## 1 C Single bond34 ##STR77## H ##STR78## 1 C Single bond35 ##STR79## H ##STR80## 1 C Single bond36 ##STR81## H ##STR82## 1 C Single bond37 ##STR83## H ##STR84## 1 C Single bond38 ##STR85## H ##STR86## 1 C Single bond39 ##STR87## H ##STR88## 1 C Single bond40 ##STR89## H ##STR90## 1 C Single bond41 CH.sub.3 H ##STR91## 1 C Single bond42 CH.sub.2 CH.sub.3 H ##STR92## 1 C Single bond43 (CH.sub.2).sub.2 CH.sub.3 H ##STR93## 1 C Single bond44 CH(CH.sub.3).sub.2 H ##STR94## 1 C Single bond45 (CH.sub.2).sub.3 CH.sub.3 H ##STR95## 1 C Single bond46 C(CH.sub.3).sub.3 H ##STR96## 1 C Single bond47 (CH.sub.2).sub.4 CH.sub.3 H ##STR97## 1 C Single bond48 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.3 H ##STR98## 1 C Single bond49 (CH.sub.2).sub.9 CH.sub.3 H ##STR99## 1 C Single bond50 CH.sub.2 Si(CH.sub.3).sub.3 H ##STR100## 1 C Single bond51 CH.sub.2 CH.sub.2 Si(CH.sub.3).sub.3 H ##STR101## 1 C Single bond52 CH.sub.2 OCH.sub.3 H ##STR102## 1 C Single bond53 ##STR103## H ##STR104## 1 C Single bond54 ##STR105## H ##STR106## 1 C Single bond55 ##STR107## H ##STR108## 1 C Single bond56 CH.sub.2 OH H ##STR109## 1 C Single bond57 CH.sub.2 SCH.sub.3 H ##STR110## 1 C Single bond58 ##STR111## H ##STR112## 1 C Single bond59 ##STR113## H ##STR114## 1 C Single bond60 ##STR115## H ##STR116## 1 C Single bond61 ##STR117## H ##STR118## 1 C Single bond62 ##STR119## H ##STR120## 1 C Single bond63 ##STR121## H ##STR122## 1 C Single bond64 ##STR123## H ##STR124## 1 C Single bond65 ##STR125## H ##STR126## 1 C Single bond66 ##STR127## H ##STR128## 1 C Single bond67 CH.sub.2 COOH H ##STR129## 1 C Single bond68 CH.sub.2 COOCH.sub.3 H ##STR130## 1 C Single bond69 CH.sub.2 NHCH.sub.3 H ##STR131## 1 C Single bond70 ##STR132## H ##STR133## 1 C Single bond71 ##STR134## H ##STR135## 1 C Single bond72 ##STR136## H ##STR137## 1 C Single bond73 CH.sub.2 NHCOOCH.sub.3 H ##STR138## 1 C Single bond74 ##STR139## H ##STR140## 1 C Single bond75 ##STR141## H ##STR142## 1 C Single bond76 ##STR143## H ##STR144## 1 C Single bond77 ##STR145## H ##STR146## 1 C Single bond78 CH.sub.2 NHSO.sub.2 CH.sub.3 H ##STR147## 1 C Single bond79 ##STR148## H ##STR149## 1 C Single bond80 ##STR150## H ##STR151## 1 C Single bond81 ##STR152## H ##STR153## 1 C Single bond82 ##STR154## H ##STR155## 1 C Single bond83 ##STR156## H ##STR157## 1 C Single bond84 ##STR158## H ##STR159## 1 C Single bond85 ##STR160## H ##STR161## 1 C Single bond86 ##STR162## H ##STR163## 1 C Single bond87 ##STR164## H ##STR165## 1 C Single bond88 ##STR166## H ##STR167## 1 C Single bond89 ##STR168## H ##STR169## 1 C Single bond90 ##STR170## H ##STR171## 1 C Single bond91 ##STR172## H ##STR173## 1 C Single bond92 ##STR174## H ##STR175## 1 C Single bond93 ##STR176## H ##STR177## 1 C Single bond94 ##STR178## H ##STR179## 1 C Single bond95 ##STR180## H ##STR181## 1 C Single bond96 ##STR182## H ##STR183## 1 C Single bond97 ##STR184## H ##STR185## 1 C Single bond98 ##STR186## H ##STR187## 1 C Single bond99 ##STR188## H ##STR189## 1 C Single bond100 ##STR190## H ##STR191## 1 C Single bond101 ##STR192## H ##STR193## 1 C Single bond102 ##STR194## H ##STR195## 1 C Single bond103 ##STR196## H ##STR197## 1 C Single bond104 ##STR198## H ##STR199## 1 C Single bond105 ##STR200## H ##STR201## 1 C Single bond106 ##STR202## H ##STR203## 1 C Single bond107 ##STR204## H ##STR205## 1 C Single bond108 ##STR206## H ##STR207## 1 C Single bond109 ##STR208## H ##STR209## 1 C Single bond110 ##STR210## H ##STR211## 1 C Single bond111 ##STR212## H ##STR213## 1 C Single bond112 ##STR214## H ##STR215## 1 C Single bond113 ##STR216## H ##STR217## 1 C Single bond114 ##STR218## H ##STR219## 1 C Single bond115 ##STR220## H ##STR221## 1 C Single bond116 ##STR222## H ##STR223## 1 C Single bond117 ##STR224## H ##STR225## 1 C Single bond118 ##STR226## H ##STR227## 1 C Single bond119 ##STR228## H ##STR229## 1 C Single bond120 ##STR230## H ##STR231## 1 C Single bond121 ##STR232## H ##STR233## 1 C Single bond122 ##STR234## H ##STR235## 1 C Single bond123 ##STR236## H ##STR237## 1 C Single bond124 ##STR238## H ##STR239## 1 C Single bond125 ##STR240## H ##STR241## 1 C Single bond126 ##STR242## H ##STR243## 1 C Single bond127 ##STR244## H ##STR245## 1 C Single bond128 ##STR246## H ##STR247## 1 C Single bond129 ##STR248## H ##STR249## 1 C Single bond130 ##STR250## H ##STR251## 1 C Single bond131 ##STR252## H ##STR253## 1 C Single bond132 ##STR254## H ##STR255## 1 C Single bond133 ##STR256## H ##STR257## 1 C Single bond134 ##STR258## H ##STR259## 1 C Single bond135 ##STR260## H ##STR261## 1 C Single bond136 ##STR262## H ##STR263## 1 C Single bond137 ##STR264## H ##STR265## 1 C Single bond138 ##STR266## H ##STR267## 1 C Single bond139 ##STR268## H ##STR269## 1 C Single bond140 ##STR270## H ##STR271## 1 C Single bond141 ##STR272## H ##STR273## 1 C Single bond142 ##STR274## H ##STR275## 1 C Single bond143 ##STR276## H ##STR277## 1 C Single bond144 ##STR278## H ##STR279## 1 C Single bond145 ##STR280## H ##STR281## 1 C Single bond146 ##STR282## H ##STR283## 1 C Single bond147 ##STR284## H ##STR285## 1 C Single bond148 ##STR286## H ##STR287## 1 C Single bond149 ##STR288## H ##STR289## 1 C Single bond150 ##STR290## H ##STR291## 1 C Single bond151 ##STR292## H ##STR293## 1 C Single bond152 ##STR294## H ##STR295## 1 C Single bond153 ##STR296## H ##STR297## 1 C Single bond154 ##STR298## H ##STR299## 1 C Single bond155 ##STR300## H ##STR301## 1 C Single bond156 ##STR302## H ##STR303## 1 C Single bond157 ##STR304## H ##STR305## 1 C Single bond158 ##STR306## H ##STR307## 1 C Single bond159 ##STR308## H ##STR309## 1 C Single bond160 ##STR310## H ##STR311## 1 C Single bond161 ##STR312## H ##STR313## 1 C Single bond162 ##STR314## H ##STR315## 1 C Single bond163 ##STR316## H ##STR317## 1 C Single bond164 ##STR318## H ##STR319## 1 C Single bond165 ##STR320## H ##STR321## 1 C Single bond166 ##STR322## H ##STR323## 1 C Single bond167 ##STR324## H ##STR325## 1 C Single bond168 ##STR326## H ##STR327## 1 C Single bond169 ##STR328## H ##STR329## 1 C Single bond170 ##STR330## H ##STR331## 1 C Single bond171 ##STR332## H ##STR333## 1 C Single bond172 ##STR334## H ##STR335## 1 C Single bond173 ##STR336## H ##STR337## 1 C Single bond174 ##STR338## H ##STR339## 1 C Single bond175 ##STR340## H ##STR341## 1 C Single bond176 ##STR342## H ##STR343## 1 C Single bond177 ##STR344## H ##STR345## 1 C Single bond178 ##STR346## H ##STR347## 1 C Single bond179 ##STR348## H ##STR349## 1 C Single bond180 ##STR350## H ##STR351## 1 C Single bond181 ##STR352## H ##STR353## 1 C Single bond182 ##STR354## H ##STR355## 1 C Single bond183 ##STR356## H ##STR357## 1 C Single bond184 ##STR358## H ##STR359## 1 C Single bond185 ##STR360## H ##STR361## 1 C Single bond186 ##STR362## H ##STR363## 1 C Single bond187 ##STR364## H ##STR365## 1 C Single bond188 ##STR366## H ##STR367## 1 C Single bond189 ##STR368## H ##STR369## 1 C Single bond190 ##STR370## H ##STR371## 1 C Single bond191 ##STR372## H ##STR373## 1 C Single bond192 ##STR374## H ##STR375## 1 C Single bond193 ##STR376## H ##STR377## 1 C Single bond194 ##STR378## H ##STR379## 1 C Single bond195 ##STR380## H ##STR381## 1 C Single bond196 ##STR382## H ##STR383## 1 C Single bond197 ##STR384## H ##STR385## 1 C Single bond198 ##STR386## H ##STR387## 1 C Single bond199 ##STR388## H ##STR389## 1 C Single bond200 ##STR390## H ##STR391## 1 C Single bond201 ##STR392## H ##STR393## 1 C --202 ##STR394## H ##STR395## 1 C --203 ##STR396## H ##STR397## 1 C --204 (CH.sub.2).sub.2 CH.sub.3 H ##STR398## 1 C --205 ##STR399## H ##STR400## 1 C --206 ##STR401## H ##STR402## 1 C --207 ##STR403## H ##STR404## 1 C --208 ##STR405## H ##STR406## 1 C --209 ##STR407## H ##STR408## 1 C --210 ##STR409## H ##STR410## 1 C --211 ##STR411## H ##STR412## 1 C --212 ##STR413## H ##STR414## 1 C --213 ##STR415## H ##STR416## 1 C --214 ##STR417## H ##STR418## 1 C --215 ##STR419## H ##STR420## 1 C --216 ##STR421## H ##STR422## 1 C --217 ##STR423## H ##STR424## 1 C --218 ##STR425## H ##STR426## 1 C --219 ##STR427## H ##STR428## 1 C --220 ##STR429## H ##STR430## 1 C --221 ##STR431## H ##STR432## 1 C --222 ##STR433## H ##STR434## 1 C --223 ##STR435## H ##STR436## 1 C --224 ##STR437## H ##STR438## 1 C --225 ##STR439## H ##STR440## 1 C --226 ##STR441## H ##STR442## 1 C --227 ##STR443## H ##STR444## 1 C --228 ##STR445## H ##STR446## 1 C --229 ##STR447## H ##STR448## 1 C --230 ##STR449## H ##STR450## 1 C --231 ##STR451## H ##STR452## 1 C --232 ##STR453## H ##STR454## 1 C --233 ##STR455## H ##STR456## 1 C --234 ##STR457## H ##STR458## 1 C --235 ##STR459## H ##STR460## 1 C --236 ##STR461## H ##STR462## 1 C --237 ##STR463## H ##STR464## 1 C --238 ##STR465## H ##STR466## 1 C --239 ##STR467## H ##STR468## 1 C --240 ##STR469## H ##STR470## 1 C --241 ##STR471## H ##STR472## 1 C --242 ##STR473## H ##STR474## 1 C --243 ##STR475## H ##STR476## 1 C --244 ##STR477## H ##STR478## 1 C --245 ##STR479## H ##STR480## 1 C --246 ##STR481## H ##STR482## 1 C --247 ##STR483## H ##STR484## 1 C --248 ##STR485## H ##STR486## 1 C --249 ##STR487## H ##STR488## 1 C --250 ##STR489## H ##STR490## 1 C --251 ##STR491## H ##STR492## 1 C --252 ##STR493## H ##STR494## 1 C --253 ##STR495## H ##STR496## 1 C --254 ##STR497## H ##STR498## 1 C --255 ##STR499## H ##STR500## 1 C --256 ##STR501## H ##STR502## 1 C --257 ##STR503## H ##STR504## 1 C --258 ##STR505## H ##STR506## 1 C --259 ##STR507## H ##STR508## 1 C --260 ##STR509## H ##STR510## 1 C --261 ##STR511## H ##STR512## 1 C --262 ##STR513## H ##STR514## 1 C --263 ##STR515## H ##STR516## 1 C --264 ##STR517## H ##STR518## 1 C --265 ##STR519## H ##STR520## 1 C --266 ##STR521## H ##STR522## 1 C --267 ##STR523## H ##STR524## 1 C --268 ##STR525## H ##STR526## 1 C --269 ##STR527## H ##STR528## 1 C --270 ##STR529## H ##STR530## 1 C --271 ##STR531## H ##STR532## 1 C --272 ##STR533## H ##STR534## 1 N --273 ##STR535## H ##STR536## 1 N --274 ##STR537## H ##STR538## 1 N --275 ##STR539## H ##STR540## 1 N --276 ##STR541## H ##STR542## 1 N --277 ##STR543## H ##STR544## 1 N --278 ##STR545## H ##STR546## 1 N --279 ##STR547## H ##STR548## 1 N --280 ##STR549## H ##STR550## 1 N --281 ##STR551## H ##STR552## 1 N --282 ##STR553## H ##STR554## 1 N --283 ##STR555## H ##STR556## 1 N --284 ##STR557## H ##STR558## 1 N --285 ##STR559## H ##STR560## 1 N --286 ##STR561## H ##STR562## 1 N --287 ##STR563## H ##STR564## 1 N --288 ##STR565## H ##STR566## 1 N --289 ##STR567## H ##STR568## 1 N --290 ##STR569## H ##STR570## 1 N --291 ##STR571## H ##STR572## 1 N --292 ##STR573## H ##STR574## 1 N --293 ##STR575## H ##STR576## 1 N --294 ##STR577## H ##STR578## 1 N --295 ##STR579## H ##STR580## 1 N --296 ##STR581## H ##STR582## 1 N --297 ##STR583## H ##STR584## 1 N --298 ##STR585## H ##STR586## 1 N --299 ##STR587## H ##STR588## 1 N --300 ##STR589## H ##STR590## 1 N --301 ##STR591## H ##STR592## 1 N --302 ##STR593## H ##STR594## 1 N --303 ##STR595## H ##STR596## 2 C Single bond304 ##STR597## H ##STR598## 2 C Single bond305 ##STR599## H ##STR600## 2 C Single bond306 ##STR601## H ##STR602## 2 C Single bond307 ##STR603## H ##STR604## 2 C Single bond308 ##STR605## H ##STR606## 2 C Single bond309 ##STR607## H ##STR608## 2 C Single bond310 ##STR609## H ##STR610## 2 C Single bond311 ##STR611## H ##STR612## 2 C Single bond312 ##STR613## H ##STR614## 2 C Single bond313 ##STR615## H ##STR616## 2 C Single bond314 ##STR617## H ##STR618## 2 C Single bond315 ##STR619## H ##STR620## 2 C Single bond316 ##STR621## H ##STR622## 2 C Single bond317 ##STR623## H ##STR624## 2 C --318 ##STR625## H ##STR626## 2 C --319 ##STR627## H ##STR628## 2 C --320 ##STR629## H ##STR630## 2 C --321 ##STR631## H ##STR632## 2 C --322 ##STR633## H ##STR634## 2 C --323 ##STR635## H ##STR636## 2 C --324 ##STR637## H ##STR638## 2 N --325 ##STR639## H ##STR640## 2 N --326 ##STR641## H ##STR642## 2 N --327 ##STR643## H ##STR644## 2 N --328 ##STR645## H ##STR646## 2 N --329 ##STR647## H ##STR648## 2 N --330 ##STR649## H ##STR650## 2 N --331 ##STR651## CH.sub.3 ##STR652## 1 C Single bond332 ##STR653## CH.sub.3 ##STR654## 1 C Single bond333 ##STR655## CH.sub.3 ##STR656## 1 C Single bond334 ##STR657## CH.sub.3 ##STR658## 1 C Single bond335 ##STR659## CH.sub.3 ##STR660## 1 C Single bond336 ##STR661## CH.sub.3 ##STR662## 1 C Single bond337 ##STR663## CH.sub.3 ##STR664## 1 C Single bond338 ##STR665## CH.sub.3 ##STR666## 1 C --339 ##STR667## CH.sub.3 ##STR668## 1 C --340 ##STR669## CH.sub.3 ##STR670## 1 C --341 ##STR671## CH.sub.3 ##STR672## 1 C --342 ##STR673## CH.sub.3 ##STR674## 1 C --343 ##STR675## CH.sub.3 ##STR676## 1 C --344 ##STR677## CH.sub.3 ##STR678## 1 C --345 ##STR679## CH.sub.3 ##STR680## 1 N --346 ##STR681## CH.sub.3 ##STR682## 1 N --347 ##STR683## CH.sub.3 ##STR684## 1 N --348 ##STR685## CH.sub.3 ##STR686## 1 N --349 ##STR687## CH.sub.3 ##STR688## 1 N --350 ##STR689## CH.sub.3 ##STR690## 1 N --351 ##STR691## CH.sub.3 ##STR692## 1 N --352 ##STR693## CH.sub.3 ##STR694## 2 C Single bond353 ##STR695## CH.sub.3 ##STR696## 2 C Single bond354 ##STR697## CH.sub.3 ##STR698## 2 C Single bond355 ##STR699## CH.sub.3 ##STR700## 2 C Single bond356 ##STR701## CH.sub.3 ##STR702## 2 C Single bond357 ##STR703## CH.sub.3 ##STR704## 2 C Single bond358 ##STR705## CH.sub.3 ##STR706## 2 C Single bond359 ##STR707## CH.sub.3 ##STR708## 2 C --360 ##STR709## CH.sub.3 ##STR710## 2 C --361 ##STR711## CH.sub.3 ##STR712## 2 C --362 ##STR713## CH.sub.3 ##STR714## 2 C --363 ##STR715## CH.sub.3 ##STR716## 2 C --364 ##STR717## CH.sub.3 ##STR718## 2 C --365 ##STR719## CH.sub.3 ##STR720## 2 C --366 ##STR721## CH.sub.3 ##STR722## 2 N --367 ##STR723## CH.sub.3 ##STR724## 2 N --368 ##STR725## CH.sub.3 ##STR726## 2 N --369 ##STR727## CH.sub.3 ##STR728## 2 N --370 ##STR729## CH.sub.3 ##STR730## 2 N --371 ##STR731## CH.sub.3 ##STR732## 2 N --372 ##STR733## CH.sub.3 ##STR734## 2 N --373 ##STR735## H ##STR736## 1 C Single bond374 ##STR737## H ##STR738## 1 C Single bond375 ##STR739## H ##STR740## 1 C Single bond376 ##STR741## H ##STR742## 1 C Single bond377 ##STR743## H ##STR744## 1 C Single bond378 ##STR745## H ##STR746## 1 C Single bond379 ##STR747## H ##STR748## 1 C Single bond380 CH.sub.2 SC.sub.2 H.sub.5 H ##STR749## 1 C Single bond381 (CH.sub.2).sub.4 COOH H ##STR750## 1 C Single bond382 ##STR751## H ##STR752## 1 C Single bond383 ##STR753## H ##STR754## 1 C Single bond384 ##STR755## H ##STR756## 1 C Single bond385 ##STR757## H ##STR758## 1 C Single bond386 ##STR759## H ##STR760## 1 C Single bond387 ##STR761## H ##STR762## 1 C Single bond388 ##STR763## H ##STR764## 1 C Single bond389 ##STR765## H ##STR766## 1 C Single bond390 ##STR767## H ##STR768## 1 C Single bond391 ##STR769## H ##STR770## 1 C Single bond392 ##STR771## H ##STR772## 1 C Single bond393 ##STR773## H ##STR774## 1 C Single bond394 ##STR775## H ##STR776## 1 C Single bond395 ##STR777## H ##STR778## 1 C Single bond396 ##STR779## H ##STR780## 1 C Single bond397 ##STR781## H ##STR782## 1 C Single bond398 ##STR783## H ##STR784## 1 C Single bond399 ##STR785## H ##STR786## 1 C Single bond400 ##STR787## H ##STR788## 1 C Single bond401 ##STR789## H ##STR790## 1 C Single bond402 ##STR791## H ##STR792## 1 C Single bond403 ##STR793## H ##STR794## 1 C Single bond404 ##STR795## H ##STR796## 1 C Single bond405 ##STR797## H ##STR798## 1 C Single bond406 ##STR799## H ##STR800## 1 C Single bond407 ##STR801## H ##STR802## 1 C Single bond408 ##STR803## H ##STR804## 1 C Single bond409 ##STR805## H ##STR806## 1 C Single bond410 ##STR807## H ##STR808## 1 C Single bond411 ##STR809## H ##STR810## 1 C Single bond412 ##STR811## H ##STR812## 1 C Single bond413 ##STR813## H ##STR814## 1 C Single bond414 ##STR815## H ##STR816## 1 C Single bond415 ##STR817## H ##STR818## 1 C Single bond416 ##STR819## H ##STR820## 1 C Single bond417 ##STR821## H ##STR822## 1 C Single bond418 ##STR823## H ##STR824## 1 C Single bond419 ##STR825## H ##STR826## 1 C Single bond420 ##STR827## H ##STR828## 1 C Single bond421 ##STR829## H ##STR830## 1 C Single bond422 ##STR831## H ##STR832## 1 C --423 ##STR833## H ##STR834## 1 C --424 ##STR835## H ##STR836## 1 C --425 ##STR837## H ##STR838## 1 C --426 ##STR839## H ##STR840## 1 C --427 ##STR841## H ##STR842## 1 C --428 ##STR843## H ##STR844## 1 C --429 ##STR845## H ##STR846## 1 C --430 ##STR847## H ##STR848## 1 C --431 ##STR849## H ##STR850## 1 C --432 ##STR851## H ##STR852## 1 C --433 ##STR853## H ##STR854## 1 C --434 ##STR855## H ##STR856## 1 C --435 ##STR857## H ##STR858## 1 C --436 ##STR859## H ##STR860## 1 C --437 ##STR861## H ##STR862## 1 C --438 ##STR863## H ##STR864## 1 C --439 ##STR865## H ##STR866## 1 C --440 ##STR867## H ##STR868## 1 C --441 ##STR869## H ##STR870## 1 C --442 ##STR871## H ##STR872## 1 C --443 ##STR873## H ##STR874## 1 C --444 ##STR875## H ##STR876## 1 C --445 ##STR877## H ##STR878## 1 C --446 ##STR879## H ##STR880## 1 C --447 ##STR881## H ##STR882## 1 C --448 ##STR883## H ##STR884## 1 C --449 ##STR885## H ##STR886## 1 C --450 ##STR887## H ##STR888## 1 C --451 ##STR889## H ##STR890## 1 C --452 ##STR891## H ##STR892## 1 C --453 ##STR893## H ##STR894## 1 C --454 ##STR895## H ##STR896## 1 C --455 ##STR897## H ##STR898## 1 C --456 ##STR899## H ##STR900## 1 C --457 ##STR901## H ##STR902## 1 C --458 ##STR903## H ##STR904## 1 C --459 ##STR905## H ##STR906## 1 C --460 ##STR907## H ##STR908## 1 C --461 ##STR909## H ##STR910## 1 C --462 ##STR911## H ##STR912## 1 C --463 ##STR913## H ##STR914## 1 C --464 ##STR915## H ##STR916## 1 C --465 ##STR917## H ##STR918## 1 C --466 ##STR919## H ##STR920## 1 C --467 ##STR921## H ##STR922## 1 C --468 ##STR923## H ##STR924## 1 C --469 ##STR925## H ##STR926## 1 C --470 ##STR927## H ##STR928## 1 C --471 ##STR929## H ##STR930## 1 C --472 ##STR931## H ##STR932## 1 C --473 ##STR933## H ##STR934## 1 C --474 ##STR935## H ##STR936## 1 C --475 ##STR937## H ##STR938## 1 C --476 ##STR939## H ##STR940## 1 C --477 ##STR941## H ##STR942## 1 C --478 ##STR943## H ##STR944## 1 C --479 ##STR945## H ##STR946## 1 C --480 ##STR947## H ##STR948## 1 C --481 ##STR949## H ##STR950## 1 C --482 ##STR951## H ##STR952## 1 C --483 ##STR953## H ##STR954## 1 C --484 ##STR955## H ##STR956## 1 C --485 ##STR957## H ##STR958## 1 C --486 ##STR959## H ##STR960## 1 C --487 ##STR961## H ##STR962## 1 C --488 ##STR963## H ##STR964## 1 C --489 ##STR965## H ##STR966## 1 C --490 ##STR967## H ##STR968## 1 C --491 ##STR969## H ##STR970## 1 C --492 ##STR971## H ##STR972## 1 C --493 ##STR973## H ##STR974## 1 C --494 ##STR975## H ##STR976## 1 C --495 ##STR977## H ##STR978## 1 C --496 ##STR979## H ##STR980## 1 C --497 ##STR981## H ##STR982## 1 C --498 ##STR983## H ##STR984## 1 C --499 ##STR985## H ##STR986## 1 C --500 ##STR987## H ##STR988## 1 C --501 ##STR989## H ##STR990## 1 C --502 ##STR991## H ##STR992## 1 C --503 ##STR993## H ##STR994## 1 C --504 ##STR995## H ##STR996## 1 C --505 ##STR997## H ##STR998## 1 N --506 ##STR999## H ##STR1000## 1 N --507 ##STR1001## H ##STR1002## 1 N --508 ##STR1003## H ##STR1004## 1 N --509 ##STR1005## H ##STR1006## 1 N --510 ##STR1007## H ##STR1008## 1 N --511 ##STR1009## CH.sub.3 ##STR1010## 2 C Single bond512 ##STR1011## CH.sub.3 ##STR1012## 2 C Single bond513 ##STR1013## CH.sub.3 ##STR1014## 2 C Single bond514 ##STR1015## CH.sub.3 ##STR1016## 2 C Single bond515 ##STR1017## H ##STR1018## 1 C Single bond516 ##STR1019## H ##STR1020## 1 C Single bond517 ##STR1021## H ##STR1022## 1 C Single bond518 ##STR1023## H ##STR1024## 1 C Single bond519 ##STR1025## H ##STR1026## 1 C Single bond520 ##STR1027## H ##STR1028## 1 C Single bond521 ##STR1029## H ##STR1030## 1 C Single bond522 ##STR1031## H ##STR1032## 1 C Single bond523 ##STR1033## H ##STR1034## 1 C Single bond524 ##STR1035## H ##STR1036## 1 C Single bond525 ##STR1037## H ##STR1038## 1 C --526 ##STR1039## H ##STR1040## 1 C --527 ##STR1041## H ##STR1042## 1 C --528 ##STR1043## H ##STR1044## 1 C --529 ##STR1045## H ##STR1046## 1 C --530 ##STR1047## H ##STR1048## 1 C --531 ##STR1049## H ##STR1050## 1 C --532 ##STR1051## H ##STR1052## 1 C --533 ##STR1053## H ##STR1054## 1 C --534 ##STR1055## H ##STR1056## 1 C --535 ##STR1057## H ##STR1058## 1 C --536 ##STR1059## H ##STR1060## 1 C --537 ##STR1061## H ##STR1062## 1 C --538 ##STR1063## H ##STR1064## 1 C --539 ##STR1065## H ##STR1066## 1 C --540 ##STR1067## H ##STR1068## 1 C --541 ##STR1069## H ##STR1070## 1 C Single bond542 ##STR1071## H ##STR1072## 1 C Single bond543 ##STR1073## H ##STR1074## 1 C Single bond544 ##STR1075## H ##STR1076## 1 C Single bond545 ##STR1077## H ##STR1078## 1 C Single bond546 ##STR1079## H ##STR1080## 1 C Single bond547 ##STR1081## H ##STR1082## 1 C Single bond548 ##STR1083## H ##STR1084## 1 C Single bond549 ##STR1085## H ##STR1086## 1 C --550 ##STR1087## H ##STR1088## 1 C --551 ##STR1089## H ##STR1090## 1 C --552 ##STR1091## H ##STR1092## 1 C --553 ##STR1093## H ##STR1094## 1 C --554 ##STR1095## H ##STR1096## 1 C --555 ##STR1097## H ##STR1098## 1 C --556 ##STR1099## H ##STR1100## 1 C --557 ##STR1101## H ##STR1102## 1 C --558 ##STR1103## H ##STR1104## 1 C --559 ##STR1105## H ##STR1106## 1 C --560 ##STR1107## H ##STR1108## 1 C --561 ##STR1109## H ##STR1110## 1 C --562 ##STR1111## H ##STR1112## 1 C --563 ##STR1113## H ##STR1114## 1 C --564 ##STR1115## H ##STR1116## 1 C --565 ##STR1117## H ##STR1118## 1 C Single bond566 ##STR1119## H ##STR1120## 1 C Single bond567 ##STR1121## H ##STR1122## 1 C Single bond568 ##STR1123## H ##STR1124## 1 C Single bond569 ##STR1125## H ##STR1126## 1 C Single bond570 ##STR1127## H ##STR1128## 1 C Single bond571 ##STR1129## H ##STR1130## 1 C --572 ##STR1131## H ##STR1132## 1 C --573 ##STR1133## H ##STR1134## 1 C --574 ##STR1135## H ##STR1136## 1 C --575 ##STR1137## H ##STR1138## 1 C --576 ##STR1139## H ##STR1140## 1 C --577 ##STR1141## H ##STR1142## 1 C Single bond578 ##STR1143## H ##STR1144## 1 C Single bond579 ##STR1145## H ##STR1146## 1 C Single bond580 ##STR1147## H ##STR1148## 1 C Single bond581 ##STR1149## H ##STR1150## 1 C Single bond582 ##STR1151## H ##STR1152## 1 C Single bond583 ##STR1153## H ##STR1154## 1 C --584 ##STR1155## H ##STR1156## 1 C --585 ##STR1157## H ##STR1158## 1 C --586 ##STR1159## H ##STR1160## 1 C --587 ##STR1161## H ##STR1162## 1 C --588 ##STR1163## H ##STR1164## 1 C --589 ##STR1165## H ##STR1166## 1 C Single bond590 ##STR1167## H ##STR1168## 1 C Single bond591 ##STR1169## H ##STR1170## 1 C Single bond592 ##STR1171## H ##STR1172## 1 C Single bond593 ##STR1173## H ##STR1174## 1 C Single bond594 ##STR1175## H ##STR1176## 1 C Single bond595 ##STR1177## H ##STR1178## 1 C --596 ##STR1179## H ##STR1180## 1 C --597 ##STR1181## H ##STR1182## 1 C --598 ##STR1183## H ##STR1184## 1 C --599 ##STR1185## H ##STR1186## 1 C --600 ##STR1187## H ##STR1188## 1 C --601 ##STR1189## H ##STR1190## 1 C Single bond602 ##STR1191## H ##STR1192## 1 C Single bond603 ##STR1193## H ##STR1194## 1 C Single bond604 ##STR1195## H ##STR1196## 1 C Single bond605 ##STR1197## H ##STR1198## 1 C Single bond606 ##STR1199## H ##STR1200## 1 C Single bond607 ##STR1201## H ##STR1202## 1 C --608 ##STR1203## H ##STR1204## 1 C --609 ##STR1205## H ##STR1206## 1 C --610 ##STR1207## H ##STR1208## 1 C --611 ##STR1209## H ##STR1210## 1 C --612 ##STR1211## H ##STR1212## 1 C --613 ##STR1213## H ##STR1214## 1 C Single bond614 ##STR1215## H ##STR1216## 1 C Single bond615 ##STR1217## H ##STR1218## 1 C Single bond616 ##STR1219## H ##STR1220## 1 C Single bond617 ##STR1221## H ##STR1222## 1 C Single bond618 ##STR1223## H ##STR1224## 1 C Single bond619 ##STR1225## H ##STR1226## 1 C --620 ##STR1227## H ##STR1228## 1 C --621 ##STR1229## H ##STR1230## 1 C --622 ##STR1231## H ##STR1232## 1 C --623 ##STR1233## H ##STR1234## 1 C --624 ##STR1235## H ##STR1236## 1 C --625 ##STR1237## H ##STR1238## 1 C Single bond626 ##STR1239## H ##STR1240## 1 C Single bond627 ##STR1241## H ##STR1242## 1 C Single bond628 ##STR1243## H ##STR1244## 1 C Single bond629 ##STR1245## H ##STR1246## 1 C Single bond630 ##STR1247## H ##STR1248## 1 C Single bond631 ##STR1249## H ##STR1250## 1 C --632 ##STR1251## H ##STR1252## 1 C --633 ##STR1253## H ##STR1254## 1 C --634 ##STR1255## H ##STR1256## 1 C --635 ##STR1257## H ##STR1258## 1 C --636 ##STR1259## H ##STR1260## 1 C --637 ##STR1261## H ##STR1262## 1 C Single bond638 ##STR1263## H ##STR1264## 1 C Single bond639 ##STR1265## H ##STR1266## 1 C Single bond640 ##STR1267## H ##STR1268## 1 C Single bond641 ##STR1269## H ##STR1270## 1 C Single bond642 ##STR1271## H ##STR1272## 1 C Single bond643 ##STR1273## H ##STR1274## 1 C --644 ##STR1275## H ##STR1276## 1 C --645 ##STR1277## H ##STR1278## 1 C --646 ##STR1279## H ##STR1280## 1 C --647 ##STR1281## H ##STR1282## 1 C --648 ##STR1283## H ##STR1284## 1 C --649 ##STR1285## H ##STR1286## 1 C Single bond650 ##STR1287## H ##STR1288## 1 C Single bond651 ##STR1289## H ##STR1290## 1 C Single bond652 ##STR1291## H ##STR1292## 1 C Single bond653 ##STR1293## H ##STR1294## 1 C Single bond654 ##STR1295## H ##STR1296## 1 C Single bond655 ##STR1297## H ##STR1298## 1 C --656 ##STR1299## H ##STR1300## 1 C --657 ##STR1301## H ##STR1302## 1 C --658 ##STR1303## H ##STR1304## 1 C --659 ##STR1305## H ##STR1306## 1 C --660 ##STR1307## H ##STR1308## 1 C --661 ##STR1309## H ##STR1310## 1 C Single bond662 ##STR1311## H ##STR1312## 1 C Single bond663 ##STR1313## H ##STR1314## 1 C Single bond664 ##STR1315## H ##STR1316## 1 C Single bond665 ##STR1317## H ##STR1318## 1 C Single bond666 ##STR1319## H ##STR1320## 1 C Single bond667 ##STR1321## H ##STR1322## 1 C --668 ##STR1323## H ##STR1324## 1 C --669 ##STR1325## H ##STR1326## 1 C --670 ##STR1327## H ##STR1328## 1 C --671 ##STR1329## H ##STR1330## 1 C --672 ##STR1331## H ##STR1332## 1 C --673 ##STR1333## H ##STR1334## 1 C Single bond674 ##STR1335## H ##STR1336## 1 C Single bond675 ##STR1337## H ##STR1338## 1 C Single bond676 ##STR1339## H ##STR1340## 1 C Single bond677 ##STR1341## H ##STR1342## 1 C Single bond678 ##STR1343## H ##STR1344## 1 C Single bond679 ##STR1345## H ##STR1346## 1 C --680 ##STR1347## H ##STR1348## 1 C --681 ##STR1349## H ##STR1350## 1 C --682 ##STR1351## H ##STR1352## 1 C --683 ##STR1353## H ##STR1354## 1 C --684 ##STR1355## H ##STR1356## 1 C --685 ##STR1357## H ##STR1358## 1 C Single bond686 ##STR1359## H ##STR1360## 1 C Single bond687 ##STR1361## H ##STR1362## 1 C Single bond688 ##STR1363## H ##STR1364## 1 C Single bond689 ##STR1365## H ##STR1366## 1 C Single bond690 ##STR1367## H ##STR1368## 1 C Single bond691 ##STR1369## H ##STR1370## 1 C --692 ##STR1371## H ##STR1372## 1 C --693 ##STR1373## H ##STR1374## 1 C --694 ##STR1375## H ##STR1376## 1 C --695 ##STR1377## H ##STR1378## 1 C --696 ##STR1379## H ##STR1380## 1 C --697 ##STR1381## H ##STR1382## 1 C Single bond698 ##STR1383## H ##STR1384## 1 C Single bond699 ##STR1385## H ##STR1386## 1 C Single bond700 ##STR1387## H ##STR1388## 1 C Single bond701 ##STR1389## H ##STR1390## 1 C Single bond702 ##STR1391## H ##STR1392## 1 C Single bond703 ##STR1393## H ##STR1394## 1 C --704 ##STR1395## H ##STR1396## 1 C --705 ##STR1397## H ##STR1398## 1 C --706 ##STR1399## H ##STR1400## 1 C --707 ##STR1401## H ##STR1402## 1 C --708 ##STR1403## H ##STR1404## 1 C --709 ##STR1405## H ##STR1406## 1 C Single bond710 ##STR1407## H ##STR1408## 1 C Single bond711 ##STR1409## H ##STR1410## 1 C Single bond712 ##STR1411## H ##STR1412## 1 C Single bond713 ##STR1413## H ##STR1414## 1 C Single bond714 ##STR1415## H ##STR1416## 1 C Single bond715 ##STR1417## H ##STR1418## 1 C --716 ##STR1419## H ##STR1420## 1 C --717 ##STR1421## H ##STR1422## 1 C --718 ##STR1423## H ##STR1424## 1 C --719 ##STR1425## H ##STR1426## 1 C --720 ##STR1427## H ##STR1428## 1 C --721 ##STR1429## H ##STR1430## 1 C Single bond722 ##STR1431## H ##STR1432## 1 C Single bond723 ##STR1433## H ##STR1434## 1 C Single bond724 ##STR1435## H ##STR1436## 1 C Single bond725 ##STR1437## H ##STR1438## 1 C Single bond726 ##STR1439## H ##STR1440## 1 C Single bond727 ##STR1441## H ##STR1442## 1 C --728 ##STR1443## H ##STR1444## 1 C --729 ##STR1445## H ##STR1446## 1 C --730 ##STR1447## H ##STR1448## 1 C --731 ##STR1449## H ##STR1450## 1 C --732 ##STR1451## H ##STR1452## 1 C --733 ##STR1453## H ##STR1454## 1 C Single bond734 ##STR1455## H ##STR1456## 1 C Single bond735 ##STR1457## H ##STR1458## 1 C Single bond736 ##STR1459## H ##STR1460## 1 C Single bond737 ##STR1461## H ##STR1462## 1 C Single bond738 ##STR1463## H ##STR1464## 1 C Single bond739 ##STR1465## H ##STR1466## 1 C --740 ##STR1467## H ##STR1468## 1 C --741 ##STR1469## H ##STR1470## 1 C --742 ##STR1471## H ##STR1472## 1 C --743 ##STR1473## H ##STR1474## 1 C --744 ##STR1475## H ##STR1476## 1 C --745 ##STR1477## H NH.sub.2 1 C Single bond746 ##STR1478## H NH.sub.2 1 C Single bond747 ##STR1479## H NH.sub.2 1 C Single bond748 ##STR1480## H NH.sub.2 1 C Single bond749 ##STR1481## H NH.sub.2 1 C Single bond750 ##STR1482## H NH.sub.2 1 C Single bond751 ##STR1483## H NH.sub.2 1 C Single bond752 ##STR1484## H NH.sub.2 1 C Single bond753 ##STR1485## H NH.sub.2 1 C Single bond754 ##STR1486## H NH.sub.2 1 C Single bond755 ##STR1487## H NH.sub.2 1 C Single bond756 ##STR1488## H NH.sub.2 1 C Single bond757 ##STR1489## H NH.sub.2 1 C Single bond758 ##STR1490## H NH.sub.2 1 C Single bond759 ##STR1491## H NH.sub.2 1 C --760 ##STR1492## H NH.sub.2 1 C --761 ##STR1493## H NH.sub.2 1 C --762 ##STR1494## H NH.sub.2 1 C --763 ##STR1495## H NH.sub.2 1 C --764 ##STR1496## H NH.sub.2 1 C --765 ##STR1497## H NH.sub.2 1 C --766 ##STR1498## H NH.sub.2 1 C --767 ##STR1499## H NH.sub.2 1 C --768 ##STR1500## H NH.sub.2 1 C --769 ##STR1501## H NH.sub.2 1 C --770 ##STR1502## H NH.sub.2 1 C --771 ##STR1503## H NH.sub.2 1 C --772 ##STR1504## H NH.sub.2 1 C --773 ##STR1505## H NH.sub.2 1 C --774 ##STR1506## H NH.sub.2 1 C --775 ##STR1507## H NH.sub.2 1 C --776 ##STR1508## H NH.sub.2 1 C --777 ##STR1509## H NH.sub.2 1 C --778 ##STR1510## H NH.sub.2 1 C --779 ##STR1511## H NH.sub.2 1 C --780 ##STR1512## H NH.sub.2 1 C --781 ##STR1513## H NH.sub.2 1 C --782 ##STR1514## H NH.sub.2 1 C --783 ##STR1515## H NH.sub.2 1 C --784 ##STR1516## H NH.sub.2 1 C --785 ##STR1517## H NH.sub.2 1 C --786 ##STR1518## H NH.sub.2 1 C --787 ##STR1519## H NH.sub.2 1 C --788 ##STR1520## H NH.sub.2 1 C --789 ##STR1521## H NH.sub.2 1 C --790 ##STR1522## H NH.sub.2 1 C --791 ##STR1523## H NH.sub.2 1 C --792 ##STR1524## H NH.sub.2 1 C --793 ##STR1525## H NH.sub.2 1 C --794 ##STR1526## H NH.sub.2 1 C --795 ##STR1527## H NH.sub.2 1 C --796 ##STR1528## H NH.sub.2 1 C --797 ##STR1529## H NH.sub.2 1 C --798 ##STR1530## H NH.sub.2 1 C --799 ##STR1531## H NH.sub.2 1 C --800 ##STR1532## H NH.sub.2 1 C --801 ##STR1533## H NH.sub.2 1 C --802 ##STR1534## H NH.sub.2 1 C --803 ##STR1535## H NH.sub.2 1 C --804 ##STR1536## H NH.sub.2 1 C --805 ##STR1537## H NH.sub.2 1 C --806 ##STR1538## H NH.sub.2 1 C --807 ##STR1539## H NH.sub.2 1 C --808 ##STR1540## H NH.sub.2 1 C --809 ##STR1541## H NH.sub.2 1 C --810 ##STR1542## H NH.sub.2 1 C --811 ##STR1543## H NH.sub.2 1 C --812 ##STR1544## H NH.sub.2 1 C --813 ##STR1545## H NH.sub.2 1 C --814 ##STR1546## H NH.sub.2 2 C Single bond815 ##STR1547## H NH.sub.2 2 C Single bond816 ##STR1548## H NH.sub.2 2 C Single bond817 ##STR1549## H NH.sub.2 2 C Single bond818 ##STR1550## H NH.sub.2 2 C Single bond819 ##STR1551## H NH.sub.2 2 C Single bond820 ##STR1552## H NH.sub.2 2 C Single bond821 ##STR1553## H NH.sub.2 2 C Single bond822 ##STR1554## H NH.sub.2 2 C Single bond823 ##STR1555## H NH.sub.2 2 C Single bond824 ##STR1556## H NH.sub.2 2 C Single bond825 ##STR1557## H NH.sub.2 2 C Single bond826 ##STR1558## H NH.sub.2 2 C Single bond827 ##STR1559## H NH.sub.2 2 C Single bond828 ##STR1560## H NH.sub.2 2 C --829 ##STR1561## H NH.sub.2 2 C --830 ##STR1562## H NH.sub.2 2 C --831 ##STR1563## H NH.sub.2 2 C --832 ##STR1564## H NH.sub.2 2 C --833 ##STR1565## H NH.sub.2 2 C --834 ##STR1566## H NH.sub.2 2 C --835 ##STR1567## H NH.sub.2 2 C --836 ##STR1568## H NH.sub.2 2 C --837 ##STR1569## H NH.sub.2 2 C --838 ##STR1570## H NH.sub.2 2 C --839 ##STR1571## H NH.sub.2 2 C --840 ##STR1572## H NH.sub.2 2 C --841 ##STR1573## H NH.sub.2 2 C --842 ##STR1574## CH.sub.3 NH.sub.2 1 C Single bond843 ##STR1575## CH.sub.3 NH.sub.2 1 C Single bond844 ##STR1576## CH.sub.3 NH.sub.2 1 C Single bond845 ##STR1577## CH.sub.3 NH.sub.2 1 C Single bond846 ##STR1578## CH.sub.3 NH.sub.2 1 C Single bond847 ##STR1579## CH.sub.3 NH.sub.2 1 C Single bond848 ##STR1580## CH.sub.3 NH.sub.2 1 C Single bond849 ##STR1581## CH.sub.3 NH.sub.2 1 C Single bond850 ##STR1582## CH.sub.3 NH.sub.2 1 C Single bond851 ##STR1583## CH.sub.3 NH.sub.2 1 C Single bond852 ##STR1584## CH.sub.3 NH.sub.2 1 C Single bond853 ##STR1585## CH.sub.3 NH.sub.2 1 C Single bond854 ##STR1586## CH.sub.3 NH.sub.2 1 C Single bond855 ##STR1587## CH.sub.3 NH.sub.2 1 C Single bond856 ##STR1588## CH.sub.3 NH.sub.2 1 C --857 ##STR1589## CH.sub.3 NH.sub.2 1 C --858 ##STR1590## CH.sub.3 NH.sub.2 1 C --859 ##STR1591## CH.sub.3 NH.sub.2 1 C --860 ##STR1592## CH.sub.3 NH.sub.2 1 C --861 ##STR1593## CH.sub.3 NH.sub.2 1 C --862 ##STR1594## CH.sub.3 NH.sub.2 1 C --863 ##STR1595## CH.sub.3 NH.sub.2 1 C --864 ##STR1596## CH.sub.3 NH.sub.2 1 C --865 ##STR1597## CH.sub.3 NH.sub.2 1 C --866 ##STR1598## CH.sub.3 NH.sub.2 1 C --867 ##STR1599## CH.sub.3 NH.sub.2 1 C --868 ##STR1600## CH.sub.3 NH.sub.2 1 C --869 ##STR1601## CH.sub.3 NH.sub.2 1 C --870 ##STR1602## CH.sub.3 NH.sub.2 2 C Single bond871 ##STR1603## CH.sub.3 NH.sub.2 2 C Single bond872 ##STR1604## CH.sub.3 NH.sub.2 2 C Single bond873 ##STR1605## CH.sub.3 NH.sub.2 2 C Single bond874 ##STR1606## CH.sub.3 NH.sub.2 2 C Single bond875 ##STR1607## CH.sub.3 NH.sub.2 2 C Single bond876 ##STR1608## CH.sub.3 NH.sub.2 2 C Single bond877 ##STR1609## CH.sub.3 NH.sub.2 2 C Single bond878 ##STR1610## CH.sub.3 NH.sub.2 2 C Single bond879 ##STR1611## CH.sub.3 NH.sub.2 2 C Single bond880 ##STR1612## CH.sub.3 NH.sub.2 2 C Single bond881 ##STR1613## CH.sub.3 NH.sub.2 2 C Single bond882 ##STR1614## CH.sub.3 NH.sub.2 2 C Single bond883 ##STR1615## CH.sub.3 NH.sub.2 2 C Single bond884 ##STR1616## CH.sub.3 NH.sub.2 2 C --885 ##STR1617## CH.sub.3 NH.sub.2 2 C --886 ##STR1618## CH.sub.3 NH.sub.2 2 C --887 ##STR1619## CH.sub.3 NH.sub.2 2 C --888 ##STR1620## CH.sub.3 NH.sub.2 2 C --889 ##STR1621## CH.sub.3 NH.sub.2 2 C --890 ##STR1622## CH.sub.3 NH.sub.2 2 C --891 ##STR1623## CH.sub.3 NH.sub.2 2 C --892 ##STR1624## CH.sub.3 NH.sub.2 2 C --893 ##STR1625## CH.sub.3 NH.sub.2 2 C --894 ##STR1626## CH.sub.3 NH.sub.2 2 C --895 ##STR1627## CH.sub.3 NH.sub.2 2 C --896 ##STR1628## CH.sub.3 NH.sub.2 2 C --897 ##STR1629## CH.sub.3 NH.sub.2 2 C --898 ##STR1630## H NHCH.sub.3 1 C Single bond899 ##STR1631## H NHCH.sub.3 1 C Single bond900 ##STR1632## H NHCH.sub.3 1 C Single bond901 ##STR1633## H NHCH.sub.3 1 C Single bond902 ##STR1634## H NHCH.sub.3 1 C Single bond903 ##STR1635## H NHCH.sub.3 1 C Single bond904 ##STR1636## H NHCH.sub.3 1 C --905 ##STR1637## H NHCH.sub.3 1 C --906 ##STR1638## H NHCH.sub.3 1 C --907 ##STR1639## H NHCH.sub.3 1 C --908 ##STR1640## H NHCH.sub.3 1 C --909 ##STR1641## H NHCH.sub.3 1 C --910 ##STR1642## H NHC.sub.2 H.sub.5 1 C Single bond911 ##STR1643## H NHC.sub.2 H.sub.5 1 C Single bond912 ##STR1644## H NHC.sub.2 H.sub.5 1 C Single bond913 ##STR1645## H NHC.sub.2 H.sub.5 1 C Single bond914 ##STR1646## H NHC.sub.2 H.sub.5 1 C Single bond915 ##STR1647## H NHC.sub.2 H.sub.5 1 C Single bond916 ##STR1648## H NHC.sub.2 H.sub.5 1 C --917 ##STR1649## H NHC.sub.2 H.sub.5 1 C --918 ##STR1650## H NHC.sub.2 H.sub.5 1 C --919 ##STR1651## H NHC.sub.2 H.sub.5 1 C --920 ##STR1652## H NHC.sub.2 H.sub.5 1 C --921 ##STR1653## H NHC.sub.2 H.sub.5 1 C --922 ##STR1654## H NHCOCH.sub.3 1 C Single bond923 ##STR1655## H NHCOCH.sub.3 1 C Single bond924 ##STR1656## H NHCOCH.sub.3 1 C Single bond925 ##STR1657## H NHCOCH.sub.3 1 C Single bond926 ##STR1658## H NHCOCH.sub.3 1 C Single bond927 ##STR1659## H NHCOCH.sub.3 1 C Single bond928 ##STR1660## H NHCOCH.sub.3 1 C --929 ##STR1661## H NHCOCH.sub.3 1 C --930 ##STR1662## H NHCOCH.sub.3 1 C --931 ##STR1663## H NHCOCH.sub.3 1 C --932 ##STR1664## H NHCOCH.sub.3 1 C --933 ##STR1665## H NHCOCH.sub.3 1 C --934 ##STR1666## H NHCOOCH.sub.3 1 C Single bond935 ##STR1667## H NHCOOCH.sub.3 1 C Single bond936 ##STR1668## H NHCOOCH.sub.3 1 C Single bond937 ##STR1669## H NHCOOCH.sub.3 1 C Single bond938 ##STR1670## H NHCOOCH.sub.3 1 C Single bond939 ##STR1671## H NHCOOCH.sub.3 1 C Single bond940 ##STR1672## H NHCOOCH.sub.3 1 C --941 ##STR1673## H NHCOOCH.sub.3 1 C --942 ##STR1674## H NHCOOCH.sub.3 1 C --943 ##STR1675## H NHCOOCH.sub.3 1 C --944 ##STR1676## H NHCOOCH.sub.3 1 C --945 ##STR1677## H NHCOOCH.sub.3 1 C --946 ##STR1678## H NHCOOC(CH.sub.3).sub.3 1 C Single bond947 ##STR1679## H NHCOOC(CH.sub.3).sub.3 1 C Single bond948 ##STR1680## H NHCOOC(CH.sub.3).sub.3 1 C Single bond949 ##STR1681## H NHCOOC(CH.sub.3).sub.3 1 C Single bond950 ##STR1682## H NHCOOC(CH.sub.3).sub.3 1 C Single bond951 ##STR1683## H NHCOOC(CH.sub.3).sub.3 1 C Single bond952 ##STR1684## H NHCOOC(CH.sub.3).sub.3 1 C --953 ##STR1685## H NHCOOC(CH.sub.3).sub.3 1 C --954 ##STR1686## H NHCOOC(CH.sub.3).sub.3 1 C --955 ##STR1687## H NHCOOC(CH.sub.3).sub.3 1 C --956 ##STR1688## H NHCOOC(CH.sub.3).sub.3 1 C --957 ##STR1689## H NHCOOC(CH.sub.3).sub.3 1 C --958 ##STR1690## H ##STR1691## 1 C Single bond959 ##STR1692## H ##STR1693## 1 C Single bond960 ##STR1694## H ##STR1695## 1 C Single bond961 ##STR1696## H ##STR1697## 1 C Single bond962 ##STR1698## H ##STR1699## 1 C Single bond963 ##STR1700## H ##STR1701## 1 C Single bond964 ##STR1702## H ##STR1703## 1 C --965 ##STR1704## H ##STR1705## 1 C --966 ##STR1706## H ##STR1707## 1 C --967 ##STR1708## H ##STR1709## 1 C --968 ##STR1710## H ##STR1711## 1 C --969 ##STR1712## H ##STR1713## 1 C --970 ##STR1714## H ##STR1715## 1 C Single bond971 ##STR1716## H ##STR1717## 1 C Single bond972 ##STR1718## H ##STR1719## 1 C Single bond973 ##STR1720## H ##STR1721## 1 C Single bond974 ##STR1722## H ##STR1723## 1 C Single bond975 ##STR1724## H ##STR1725## 1 C Single bond976 ##STR1726## H ##STR1727## 1 C Single bond977 ##STR1728## H ##STR1729## 1 C --978 ##STR1730## H ##STR1731## 1 C --979 ##STR1732## H ##STR1733## 1 C --980 ##STR1734## H ##STR1735## 1 C --981 ##STR1736## H ##STR1737## 1 C --982 ##STR1738## H ##STR1739## 1 C --983 ##STR1740## H ##STR1741## 1 C --984 ##STR1742## H ##STR1743## 1 C Single bond985 ##STR1744## H ##STR1745## 1 C Single bond986 ##STR1746## H ##STR1747## 1 C Single bond987 ##STR1748## H ##STR1749## 1 C Single bond988 ##STR1750## H ##STR1751## 1 C Single bond989 ##STR1752## H ##STR1753## 1 C Single bond990 ##STR1754## H ##STR1755## 1 C Single bond991 ##STR1756## H ##STR1757## 1 C Single bond992 ##STR1758## H ##STR1759## 1 C --993 ##STR1760## H ##STR1761## 1 C --994 ##STR1762## H ##STR1763## 1 C --995 ##STR1764## H ##STR1765## 1 C --996 ##STR1766## H ##STR1767## 1 C --997 ##STR1768## H ##STR1769## 1 C --998 ##STR1770## H ##STR1771## 1 C --999 ##STR1772## H ##STR1773## 1 C --1000 ##STR1774## H ##STR1775## 1 C Single bond1001 ##STR1776## H ##STR1777## 1 C Single bond1002 ##STR1778## H NH.sub.2 1 C --1003 ##STR1779## H NH.sub.2 1 C --1004 ##STR1780## H ##STR1781## 1 C --1005 ##STR1782## H ##STR1783## 1 C --1006 ##STR1784## H ##STR1785## 1 C --__________________________________________________________________________
Hereinafter, the production process for the compounds of the present invention will be explained.
The compounds of the present invention can be produced through any combination of reactions suitable for the objective compounds. Typical reaction schemes will be shown below, but they should not be construed to be limiting the scope of the present invention. ##STR1786## wherein R.sup.1, R.sup.2, R.sup.25, n and broken line are as defined above; Q is an amino-protecting group, such as benzyloxycarbonyl group, tertiary butyloxycarbonyl group, etc.; Z is a leaving group such as halogen atom, methanesulfonyloxy group, toluenesulfonyloxy group, trifluoromethylsulfonyloxy group, acetoxy (acetyloxy) group, etc.; R.sup.27, R.sup.28 and R.sup.29 indicate a specific substituent contained in R.sup.25 and R.sup.26 ; R.sup.27 is a C.sub.1 -C.sub.6 alkyl group, a C.sub.2 -C.sub.7 acyl group or a C.sub.2 -C.sub.7 alkoxycarbonyl group; R.sup.28 is a C.sub.1 -C.sub.6 alkyl group, a C.sub.2 -C.sub.7 acyl group, a C.sub.2 -C.sub.7 alkoxycarbonyl group or a C.sub.2 -C.sub.7 hydroxyalkylcarbonyl group; R.sup.29 is a C.sub.1 -C.sub.6 alkyl group, a C.sub.2 -C.sub.7 acyl group, a C.sub.2 -C.sub.7 alkoxycarbonyl group or 5-C.sub.1 -C.sub.3 alkyl-1,3-dioxol-2-on-4-ylmethyl group.
In the above reaction schemes, a known method for synthesizing amide can be used for synthesizing the compounds (IV), (VI), (XII), (XIV), (XIX) and (XXI). There are various conventional methods, for example, a method using dehydrating agents such as dicyclohexylcarbodiimide, 1-ethyl-3-(dimethylaminopropyl)carbodiimide, carbonyldiimidazole, etc., azido method, acid halide method, acid anhydride method, active ester method and the like.(e.g., see, "JIKKEN KAGAKU KOZA, 22, YUKI-GOSEI IV", pp. 259-(1992), ed. "JAPAN Chemical Society", 4th. edition, published by Maruzen). The reaction is conducted under cooling or heating (or at room temperature) using an inert solvent such as tetrahydrofuran, diethyl ether, dichloromethane, etc. in a conventional manner. In the above schemes, the compounds (V), (XIII), (XV) and (XX) can be synthesized by deprotection according to a method known in the peptide chemistry (e.g. see "The Principle and Experimental Procedures of Peptide Synthesis" written by Nobuo IZUMIYA et al., published by Maruzen).
Further, the compound (VII) is synthesized by reacting imidate, which is obtained by reacting the compound (VI) with alcohol and an inorganic acid such as hydrochloric acid, with ammonia or an ammonium salt; or by reacting a thioamide compound, which is obtained by reacting the compound (VI) with hydrogen sulfide in the presence of an organic base such as triethylamine, pyridine, etc., with a lower alkylhalogen compound such as methyl iodide, etc., followed by reacting the resulting thioimidate compound with ammonia or an ammonium salt. Further, the compound (IX) is synthesized by reacting the compound (VI) with hydroxylamine or acid adduct thereof in a suitable solvent such as water, alcohol, tetrahydrofuran, etc. at room temperature or under heating.
Further, the compounds (VIII), (X) and (XVII) are synthesized by reacting the compounds (VI I), (IX) and (XV) with R.sup.27 --Z, R.sup.28 --Z or R.sup.29 --Z in an inert solvent such as tetrahydrofuran, ether, dichloromethane, etc. in the presence of an organic or inorganic base under cooling or heating (or at room temperature), respectively.
Further, the compound (XVI) is synthesized by reacting the compound (XV) with a guanidizing reagent such as 2-alkylisothiourea derivative or acid adduct thereof in a suitable solvent such as water, alcohol, tetrahydrofuran, etc. at room temperature or under heating.
The respective compounds thus obtained can be isolated and purified by conventional chemical procedures such as extraction, crystallization, recrystallization, various chromatography and the like.
When the compounds of the present invention are used for clinical application, a proportion of a therapeutically active ingredient to a carrier component varies within a range of 1 to 90% by weight. For example, the compounds of the present invention may be orally administered in the dosage form such as granules, fine granules, powders, tablets, hard capsules, soft capsules, syrups, emulsions, suspensions, solutions and the like, or intravenously, intramuscularly or subcutaneously administered in the form of injections. Further, they may also be used in the form of suppositories. They may also be formed into powders which can be converted into solutions or the like for injection before use. There can be used pharmaceutical organic or inorganic solid or liquid carriers or diluents which are suitable for oral, intestinal or parenteral administration for preparing the drugs of the present invention. As the excipient used for preparing solid preparations, for example, there can be used lactose, sucrose, starch, talc, cellulose, dextrin, kaoline, calcium carbonate and the like. Liquid preparations for oral administration, i.e. emulsions, syrups, suspensions, solutions, etc. contain inert diluents which are normally used, e.g. water, vegetable oil, etc. This preparation can contain adjuvants such as humectants, suspension auxiliary agents, sweeteners, aromatics, colorants, preservatives, etc., in addition to inert diluents. The resulting liquid preparations may be contained in a capsule of an absorbable substance such as gelatin. As the solvent or suspending agent used for preparing preparations for parenteral administration, i.e. injections, suppositories, etc., for example, there can be used water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and the like. As the base used for preparing suppositories, for example, there can be used cacao butter, emulsified cacao butter, laurin tallow, witepsol and the like. Preparations may be prepared by a conventional method.
The clinical dose varies depending upon age, pathology, condition of diseases and the like. For example, in the case of administering orally to an adult patient, the compounds of the present invention are normally administered with a dairy dose of about 0.01 to 1000 mg, preferably 10 to 1000 mg. The pharmaceutical composition of the present invention may be administered 1 to 3 times per day or administered intermittently with the above dairy dose.
When using as injections, it is advantageous that the compounds of the present invention are administered continuously or intermittently to an adult patient with a single dose of 0.001 to 100 mg.
The prolineamide derivatives of the present invention or the salts thereof have a strong inhibition activity to proteases such as thrombin, trypsin and the like. The compounds of the present invention are also superior in oral absorptive action so that they are useful as oral antithrombin agents, i.e. oral anticoagulants, or oral antitrypsin agents, i.e. remedy for pancreas diseases such as pancreatitis.
The following Examples and Experimental Examples further illustrate the present invention in detail but are not to be construed to limit the scope thereof.
The conventional abbreviations used in Examples are as follows: THF:tetrahydrofuran, DMF: N,N-dimethylformamide, DMSO: dimethyl sulfoxide, CDI: carbonyldiimidazole, DPPA: diphenylphosphorylazide, Z: benzyloxycarbonyl, Boc: tertiary butyloxycarbonyl.
Further, NMR in physical properties stands for a nuclear magnetic resonance spectrum and the numeral is .sym. value in ppm, which is conventionally used for indicating the chemical shift. TMS (tetramethylsilane) was used as the internal standard. Further, the numeral shown in parenthesis following .delta. value is the number of hydrogen atoms, and the indications following the number of hydrogen atoms mean that s is singlet, d is doublet, t is triplet, q is quartet, m is multiplet, or is broad absorption peak, respectively.
IR stands for an infrared spectrum and measured as potassium bromide tablets unless otherwise stated. The numerical means the wave number in cm.sup.-1. Only main absorption peak was shown. Further, mp means the non-corrected melting point in .degree. C.





EXAMPLE 1
Synthesis of 4-amidino-�(S)-N-((R)-2-methylsulfonylamino-cyclohexylacetyl) prolyl!aminomethylbenzene (compound No. 105 of Table 1) hydrochloride
(a) N-4-cyanobenzylphthalimide
To a solution of potassium phthalimide (76 g, 410 mmol) in DMF (250 ml), a solution of 4-cyanobenzyl bromide (73 g, 373 mmol) in THF (250 ml) is added and stirred at 50.degree. C for 3 hours.
Water (500 ml) is added to then mixture and a precipitated crystal was collected. Then, the crystal is washed with water and dried to give 96 g of the titled compound (99%). mp: 189.degree.-191.degree. C.
(b) 4-Cyano-�(S)-prolyl!aminomethylbenzene hydrochloride
To a solution of the compound (39 g, 150 mmol) obtained in the item (a) in methanol (250 ml), hydrazine hydrate (9 ml) is added and refluxed for 6 hours. After the solvent is evaporated, an aqueous 40% sodium hydroxide solution (300 ml) is added to the residue and stirred.
The reaction mixture is extracted with toluene and the organic layer is washed once with water and saturated brine, successively, and then dried over sodium sulfate. The solvent is evaporated and the resulting crude product (15 g, 73%) is used for the next step.
To a solution of (S)-N-Boc-proline (23.7 g, 110 mmol) in THF (250 ml), CDI (17.8 g, 110 mmol) is added at 0.degree. C.
After the reaction solution is stirred for 2 hours, a solution of the crudeproduct obtained in the above reaction in THF (150 ml) is added. After stirring for 6 hours, the solvent is evaporated and water (300 ml) is added to the residue. The mixture is extracted with chloroform and the organic layer is washed three times with water and once with saturated brine, successively. After drying over sodium sulfate, the solvent is evaporated and the residue is purified with silica gel chromatography (hexane-ethyl acetate).
The resulting oily product is dissolved in ethyl acetate (100 ml) and a 4N-hydrochloride in ethyl acetate (69 ml) is added and the mixture is stirred at 0.degree. C. for 3 hours. The precipitated white solid is collected, washed with ethyl acetate and dried under reduced pressure to give 25.9 g of the titled compound (89%).
NMR (DMSO-d.sup.6) 1.80-1.96 (m, 3H), 2.30-2.40 (m, 1H), 3.21 (br, 2H), 4.26 (br, 1H), 4.44 (d, 2H), 7.49 (d, 2H), 7.82 (d, 2H), 8.59 (br, 1H), 9.39 (t, 1H), 10.07 (br,
(c) 4-Cyano-�(S)-N-((R)-2-t-butyloxycarbonylamino-cyclohexylacetyl) prolyl!aminomethylbenzene
To a solution of the product (21 g, 79 mmol) obtained in the item (b) and (R)-N-t-butyloxycarbonylcyclohexylglycine (20.4 g, 79 mmol) in DMF (200 ml), a solution of triethylamine (22 ml, 159 mmol) and DPPA (22 g, 79 mmol) in DMF (50 ml) is added at 0.degree. C. The mixture is allowed to stand at room temperature and then stirred for 12 hours. Water (400 ml) isadded to the reaction mixture which is extracted with toluene-ethyl acetate(1:2). The organic layer is washed three times with water and once with saturated brine, successively, and then dried over sodium sulfate. After the solvent is evaporated, the residue is purified with silica gel chromatography (chloroform-methanol) to give 26.7 g of the titled compound(72%).
NMR (CDCl.sub.3) 1.01-1.43 (m, 15H), 1.65-2.38 (m, 9H), 3.57 (q, 1H), 3.96-4.06 (m, 2H), 4.47 (dq, 2H), 4.69 (d, 1H), 5.12 (d, 1H), 7.35 (d, 2H), 7.59 (d, 2H), 7.73 (t, 1H)
(d) 4-Cyano-�(S)-N-((R)-2-methylsulfonylamino-cyclohexylacetyl)prolyl!aminomethylbenzene
To a solution of the compound (26.7 g, 57 mmol) obtained in the item (c) inchloroform (50 ml), a 4-N hydrochloride in ethyl acetate (30 ml) is added at 0.degree. C. The mixture is stirred for 3 hours and then the solvent isevaporated. The resulting residue was dissolved in dichloromethane (250 ml)and triethylamine (19 ml) is added. Then, a solution of methanesulfonyl chloride (7.9 g, 68 mmol) in dichloromethane (50 ml) is added at 0.degree.C. and the mixture is stirred for 3 hours. The organic layer is washed oncewith a saturated sodium bicarbonate solution, water and saturated brine, successively, and then dried over sodium sulfate. The resulting residue ispurified with silica gel chromatography (hexane-ethyl acetate) to give 18.6g of the titled compound (73%).
NMR (CDCl.sub.3) 0.9-1.29 (m, 5H), 1.60-1.85 (m, 5H), 2.0-2.4 (m, 5H), 2.89(s, 3H), 3.55 (q, 1H), 3.80-3.88 (m, 2H), 4.43 (d, 2H), 4.61 (d, 2H), 5.60 (d, 2H), 7.31 (t, 1H), 7.37 (d, 2H), 7.60 (d, 2H)
(e) 4-Amidino-�(S)-N-((R)-2-methylsulfonylamino-cyclohexylacetyl) prolyl!aminomethylbenzene chloride
To a solution of the compound (18.6 g, 42 mmol) obtained in the item (d) inchloroform (100 ml), a 37% hydrochloride in ethanol (100 ml) is added at 0.degree. C. The mixture is allowed to stand at 0.degree. C. for 48 hours and then the solvent is evaporated. The resulting residue is dissolved in methanol (100 ml) and ammonium carbonate (16 g, 166 mmol) is added at 0.degree. C. After stirring for 6 hours, the solvent is evaporated and theresulting residue is purified with silica gel chromatography (chloroform-methanol) to give 5.2 g of the titled compound (73%).
NMR (DMSO-d.sup.6) 9.39 (br, 4H), 8.66 (t, 1H), 7.81 (d, 2H), 7.48 (d, 2H),7.40 (m, 1H), 4.47-4.14 (m, 3H), 3.90 (m, 1H), 3.71 (m, 1H), 3.59 (m, 1H), 2.79 (s, 3H), 2.13 (m, 1H), 1.88 (m, 3H), 1.69-1.53 (m, 5H), 1.14 (m, 6H)
IR: 3366, 2930, 2855, 1636, 1541, 1489, 1451, 1152
According to the same procedures described above, the compounds shown in the following Examples were synthesized.
EXAMPLE 2
4-Amidino-�(S)-N-�(R)-2-methylsulfonylamino-4,4-dimethylpentanoyl!prolyl!aminomethylbenzene (compound No. 104 of Table 1) methanesulfonate
NMR (DMSO-d.sup.6) 9.31 (br, 2H), 9.11 (br, 2H), 8.60 (t, 1H), 7.76 (d, 2H), 7.47 (d, 2H), 7.42 (d, 2H), 4.50-4.06 (m, 4H), 3.49 (m, 1H), 3.71 (m,1H), 2.71 (s, 3H), 2.40 (s, 3H), 2.13 (m, 1H), 1.98 (m, 2H), 1.84 (m, 1H), 1.48 (d, 2H), 0.98 (s, 9H)
IR: 3274, 2957, 1640, 1208, 1150, 1049
EXAMPLE 3
4-Amidino-�(S)-N �(R)-2-methylsulfonylamino-3-cyclohexylpropionyl!prolyl!aminomethylbenzene(compound No. 106 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 9.41 (br, 2H), 9.20 (br, 2H), 8.68 (t, 1H), 7.78 (d, 2H), 7.47 (d, 2H), 7.47 (d, 2H), 4.49-4.23 (m, 3H), 4.13 (m, 1H), 3.69 (m,1H), 3.48 (m, 1H), 2.72 (s, 3H), 2.12 (m, 1H), 1.97 (m, 1H), 1.83 (m, 2H), 1.64 (m, 5H), 1.40 (m, 2H), 1.19 (m, 4H), 0.94 (m, 2H)
IR: 3366, 2924, 1640, 1543, 1489, 1449, 1422
EXAMPLE 4
4-Amidino-�(S)-N �(R)-N'-methylsulfonylphenylalanyl!prolyl!aminomethylbenzene (compound No.108 of Table 1) methanesulfonate
NMR (DMSO-d.sup.6) 9.31 (br, 2H), 9.08 (br, 2H), 8.57 (t, 1H), 7.75 (d, 2H), 7.71 (d, 1H), 7.47 (d, 2H), 7.29 (m, 5H), 4.52-4.21 (m, 3H), 3.54 (m,2H), 3.28 (m, 2H), 3.04 (m, 1H), 2.90 (m, 2H), 2.71 (s, 3H), 2.50 (s, 3H), 1.88 (m, 2H)
IR: 3375, 1663, 1630, 1454, 1327, 1225, 1154, 1046
EXAMPLE 5
4-Amidino-�(S)-N-�(R)-N'-methylsulfonylmethionyl!prolyl!aminomethylbenzene (compound No. 110 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 9.45 (br, 2H), 9.26 (br, 2H), 8.68 (t, 1H), 7.80 (d, 2H), 7.55 (d, 2H), 7.48 (d, 2H), 4.44-4.17 (m, 4H), 3.70 (m, 1H), 3.59 (m,1H), 2.87 (s, 3H), 2.56 (m, 3H), 2.13 (m, 1H), 2.08 (s, 3H), 1.97-1.63 (m, 4H)
IR: 3368, 1638, 1543, 1489, 1426, 1314, 1150
EXAMPLE 6
4-Amidino-�(S)-N-((R)-N'-formylphenylalanyl) prolyl!aminomethylbenzene (compound No. 94 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 9.56 (br, 2H), 9.36 (br, 2H), 8.97 (t, 1H), 8.70-8.60 (m, 1H), 7.86 (d, 1H), 7.83 (d, 2H), 7.46 (d, 2H), 7.37-7.17 (m, 5H), 4.36-4.16 (m, 4H), 3.60-2.70 (m, 4H), 2.40-1.20 (m, 4H)
IR: 3370, 1647, 1541, 1489, 1454, 1404, 704
EXAMPLE 7
4-Amidino-�(S)-N-((R)-2-methylsulfonylamino-hexanoyl) prolyl!aminomethylbenzene (compound No. 109 of Table 1) methanesulfonate
NMR (DMSO-d.sup.6) 9.32 (br, 2H), 9.11 (br, 2H), 8.58 (t, 1H), 7.76 (d, 2H), 7.48 (d, 2H), 7.42 (d, 1H), 4.47-4.23 (m, 2H), 4.20-3.90 (m, 3H), 3.54-3.45 (m, 1H), 3.80-3.66 (m, 1H), 2.74 (s, 3H), 2.43 (s, 3H), 2.20-0.79 (m, 13H)
IR: 3272, 1638, 1543, 1424, 1316, 1206, 1155, 1047
EXAMPLE 8
4-Amidino-�(S)-N-((R)-2-methylsulfonylamino-4-(4'-methoxy-carbonyl-phenyl) butanoyl) prolyl!aminomethylbenzene (compound No.127 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 9.35-9.23 (m, 4H), 8.59 (t, 1H), 7.90 (d, 2H), 7.77 (d, 2H), 7.61 (d, 1H ), 7.47 (d, 2H), 7.40 (d, 2H), 4.44-4.21 (m, 3H), 4.07 (m, 1H), 3.84 (s, 3H), 3.48 (m, 2H), 2.92-2.63 (m, 3H), 2.77 (s, 3H), 2.12(m, 1H), 1.84 (m, 4H)
IR: 3370, 1638, 1541, 1489, 1437, 1287, 1150
EXAMPLE 9
4-Amidino-�(S)-N-�(R)-2-methylsulfonylamino-3-(3'-carboxyphenoxy) propanoyl!prolyl!aminomethylbenzene (compound No. 130 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 9.35 (br, 4H), 8.64 (t, 1H), 7.78 (d, 2H), 7.71 (d, 1H),7.58-7.40 (m, 5H), 7.20 (m, 1H), 4.62 (m, 1H), 4.36 (m, 3H), 4.22 (m, 2H), 3.72 (m, 2H), 2.89 s, 3H), 2.12 (m, 1H), 1.94 (m, 3H)
IR: 3856, 1644, 1543, 1489, 1449, 1316, 1256, 1154
EXAMPLE 10
4-Amidino-�(S)-N-�(R)-2-methylsulfonylamino-3-(2'-benzyloxycarbonylphenoxy)propanoyl!prolyl!aminomethylbenzene (compound No. 123 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 9.24 (br, 4H), 8.60 (t, 1H), 7.77 (d, 2H), 7.71 (m, 1H),7.57 (m, 1H), 7.49-7.35 (m, 8H), 7.16 (d, 1H), 7.07 (t, 1H), 5.29 (s, 2H), 4.62 (t, 1H), 4.37 (m, 3H), 4.28 (m, 1H), 4.17 (t, 1H), 3.67 (m, 2H), 2.91(s, 3H), 2.15 (m, 1H), 1.88 (m, 3H)
IR: 3366, 1642, 1491, 1451, 1314, 1248, 1082
EXAMPLE 11
4-Amidino-�(S)-N-�(R)-2-ethoxycarbonylamino-3-methyl-3methylthiobutanoyl!prolyl!aminomethylbenzene (compound No. 98 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 8.89 (br, 2H), 8.66 (br, 2H), 7.77 (d, 2H), 7.33 (d, 2H), 6.27 (d, 1H), 4.65 (m, 1H), 4.46 (d, 1H), 4.37 (m, 2H), 3.97-3.72 (m,4H), 2.62 (m, 1H), 2.15 (br, 3H), 2.04 (s, 3H), 1.40 (s, 3H), 1.36 (s, 3H),1.05 (t, 3H)
IR: 3323, 2926, 1635, 1535, 1439, 1242, 1055
EXAMPLE 12
4-Amidino-�(S)-N-�(R)-2-carboxymethylsulfonylaminoheptanoyl!prolyl!aminomethylbenzene (compound No. 152 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 9.80 (br, 2H), 9.23 (br, 2H), 8.80 (t, 1H), 7.69 (d, 2H), 7.42 (d, 2H), 7.23 (d, 1H), 4.51-4.17 (m, 5H), 3.70 (m, H), 2.11 (m, 1H), 1.92 (m, 3H), 1.57-1.28 (m, 8H), 0.87 (m, 3H)
IR: 3366, 2957, 1636, 1543, 1489, 1416, 1318, 1136
EXAMPLE 13
4-Amidino-�(S)-N-(4-phenylbutanoyl)prolyl!aminomethylbenzene (compound No. 3 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 9.39 (br, 2H), 9.22 (br, 2H), 8.55 (t, 1H), 7.80 (d, 2H), 7.48 (d, 2H), 7.31-7.13 (m, 5H), 4.37-4.30 (m, 3H), 3.60-3.30 (m, 2H), 2.60 (t, 2H), 2.34-1.75 (m, 8H)
IR: 3264, 1618, 1541, 1491, 1451, 702
EXAMPLE 14
4-Amidino-�(S)-N-(2-benzyloxyacetyl)prolyl!aminomethylbenzene (compound No.55 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 9.41 (br, 2H), 9.23 (br, 2H), 8.66 (t, 1H), 7.80 (d, 2H), 7.49 (d, 2H), 7.42-7.27 (m, 5H), 4.61-4.08 (m, 7H), 3.56-3.40 (m, 2H), 2.20-1.78 (m, 4H)
IR: 3262, 1645, 1539, 1489, 1454, 740
EXAMPLE 15
Trans-4-amidino-�(S)-N-�(R)-2-ethoxycarbonylamino-4,4-dimethylpentanoyl!prolyl!aminomethylcyclohexane (compound No. 263 of Table 1) hydrochloride
(a) Trans-4-N-benzyloxycarbonylaminomethyl-cyclohexylnitrile
To a solution of trans-4-aminomethylcyclohexanecarboxylic acid (25 g, 159 mmol) and sodium carbonate (20 g, 191 mmol) in water (300 ml), benzyloxycarbonyl chloride (27 ml, 190 mmol) is added at 0.degree. C. After stirring for 6 hours, 1N-hydrochloric acid is added until the pH of the reaction mixture indicates 2, and the precipitated white solid is collected, washed with water and dried. The resulting white solid is dissolved in THF (300 ml) and CDI (21 g, 130 mmol) is added at 0.degree. C. After stirring for 3 hours, the reaction mixture is added dropwise to amixed solution of 33% ammonia in water (50 ml) and THF (150 ml) at 0.degree. C. After stirring for 5 hours, the solvent is evaporated and water (500 ml) is added, and the precipitated white solid is collected, washed with water and dried.
To a solution of the resulting compound in 1,2-dichloroethane (500 ml), thionyl chloride (19 ml, 260 mmol) is added and heated to an inner temperature of 70.degree. C. After stirring for 5 hours, the reaction mixture is poured into ice water and neutralized with an aqueous 1N-sodiumhydroxide solution. After extracting with chloroform, the organic layer is washed twice with water and once with saturated brine, successively, and then dried over sodium sulfate. The solvent is evaporated and the resulting crude product is recrystallized (hexane-ethyl acetate) to give 22.8 g of the titled compound (53%). mp: 90.degree.-92.degree. C.
(b) Trans-4-(S)-prolylaminomethyl-cyclohexylnitrile
The compound obtained in the item (a) is dissolved in ethanol (250 ml) and the catalytic hydrogenation is conducted at room temperature and atomospheric pressure in the presence of palladium black (1 g). After the completion of the reaction, the catalyst is filtered off and the solvent is evaporated.
To a solution of (S)-N-benzyloxycarbonylproline (20.7 g, 83 mmol) in THF (150 ml), CDI (13.5 g, 83 mmol) is added at 0.degree. C. After stirring for 3 hours, a solution of the compound obtained in the above reaction in THF (200 ml) is added at 0.degree. C. After stirring for 12 hours, the solvent is evaporated, and chloroform (400 ml) is added to the resulting residue. The organic layer is washed three times with water and once with saturated brine, successively, and then dried over sodium sulfate. The solvent is evaporated and the resulting residue is purified with silica gel chromatography (chloroform-methanol).
The resulting compound is dissolved in ethanol (250 ml) and the catalytic hydrogenation is conducted at room temperature and atomospheric pressure in the presence of palladium black (1 g). After the completion of the reaction, the catalyst is filtered off and the solvent is evaporated to give 18.8 g of the titled compound (95%).
NMR (DMSO-d.sup.6) 0.88-1.06 (m, 2H), 1.38-1.52 (m, 3H), 1.68-2.03 (m, 7H),2.20-2.40 (m, 1H), 2.52-2.67 (m, 1H), 2.80-3.20 (m, 4H), 4.03-4.10 (m, 1H),7.53 (br, 1,H), 8.65-8.70 (m, 1H)
(c) Trans-4-amidino-�(S)-N-�(R)-2-ethoxycarbonylamino-4,4-dimethylpentanoyl!prolyl!aminomethylcyclohexane hydrochloride
According to the same manner as that described in the items (c) to (e) of Example 1, the titled compound can be synthesized from the compound obtained in the item (b) and (R)-2-t-butyloxycarbonylamino-4,4-dimethylpentanoic acid.
NMR (DMSO-d.sup.6) 8.95 (br, 2H), 8.69 (br, 2H), 7.60 (br, 1H), 6.32 (br, 1H), 4.56 (m, 1H), 4.39 (m, 1H), 4.18 (q, 2H), 4.10 (m, 1H), 3.52 (m, 1H),3.19 (m, 1H), 2.89 (m, 1H), 2.69 (m, 1H), 2.14-1.59 (m, 12H), 1.26 (t, 3H),0.98 (s, 9H), 0.98-0.89 (m, 2H)
IR: 3314, 2954, 1686, 1639, 1543, 1449, 1250, 1059
According to the same procedures, the compounds shown in the following Examples were synthesized.
EXAMPLE 16
Trans-4-amidino-�(S)-N-�(R)-2-ethoxycarbonylamino-3-cyclohexylpropanoyl!prolyl!aminoethylcyclohexane (compound No. 227 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 8.93 (br, 2H), 8.81 (br, 2H), 7.53 (br, 1H), 7.38 (t, 1H), 4.50-4.15 (m, 1H), 4.10-3.90 (m, 2H), 3.73-3.17 (m, 2H), 3.05-2.80 (m, 3H), 2.39 (br, 1H), 2.00-0.68 (m, 29H)
IR: 3297, 2926, 2853, 1684, 1543, 1449, 1262, 1053
EXAMPLE 17
Trans-4-amidino-�(S)-N-�(R)-2-isopropoxycarbonylamino-4,4-dimethylpentanoyl!prolyl!aminomethylcyclohexane (compound No. 265 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 8.91 (br, 2H), 8.78 (br, 2H), 7.55 (br, 1H), 7.28 (t, 1H), 4.78-4.70 (m, 1H), 4.30-3.92 (m, 1H), 3.80-3.20 (m, 3H), 3.0-2.75 (m,2H), 2.50-1.37 (m, 14H), 1.18-1.00 (m, 6H), 1.0-0.81 (m, 1H)
IR: 3285, 2953, 2870, 1684, 1541, 1449, 1250, 1111
EXAMPLE 18
Trans-4-amidino-�(S)-N-((R)-N'-methylsulfonylphenylalanyl) prolyl!aminomethylcyclohexane (compound No. 250 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 8.88 (br, 2H), 8.75 (br, 2H), 7.85 (t, 1H), 7.65 (d, 1H), 4.27 (m, 1H), 4.16 (m, 1H), 3.51-3.41 (m, 4H), 2.99-2.70 (m, 4H), 2.78 (s, 3H), 2.38 (t, 1H), 1.90-1.40 (m, 9H), 1.08-0.87 (m, 2H)
IR: 3375, 2930, 1637, 1452, 1309, 1149, 1097, 983
EXAMPLE 19
Trans-4-amidino-�(S)-N-((R)-N'-methylsulfonylleucyl) prolyl!aminomethylcyclohexane (compound No. 269 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 8.89 (br, 2H), 8.85 (br, 2H), 6.56 (d, 1H), 4.53 (m, 1H), 4.17 (m, 1H), 3.86 (m, 1H), 3.47 (m, 1H), 3.07 (m, 2H), 2.97 (s, 3H),2.13-1.80 (m, 10H), 1.63-1.54 (m, 4H), 1.33 (m, 1H), 0.98-0.87 (m, 2H), 0.97 (d, 6H)
IR: 3261, 2932, 1639, 1450, 1313, 1143, 1087, 985
EXAMPLE 20
Trans-4-amidino-�(S)-N-((R)-2-methylsulfonylamino-3-cyclohexyl-propanoyl) prolyl!aminomethylcyclohexane (compound No. 230 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 8.95 (br, 2H), 8.53 (br, 2H), 7.27 (m, 1H), 6.51 (d, 1H), 4.51 (m, 1H), 4.19 (m, 1H), 3.83 (m, 1H), 3.66 (m, 1H), 3.41 (m, 2H),3.04 (m, 2H), 3.04 (m, 2H), 2.95 (s, 3H), 2.46 (t, 1H), 2.12-0.92 (m, 24H)
IR: 3265, 2926, 1639, 1545, 1448, 1315, 1143, 985
EXAMPLE 21
Trans-4-amidino-�(S)-N-((R)-2-isopropoxycarbonylamino-2-cyclohexylacetyl) prolyl!aminomethylcyclohexane (compound No. 228 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 8.91 (br, 2H), 8.69 (br, 2H), 7.36 (br, 1H), 5.99 (d, 1H), 4.84-4.79 (m, 1H), 4.58 (br, 2H), 4.53-4.50 (m, 2H), 4.10-3.90 (m, 2H), 3.60-3.40 (m, 1H), 2.50-0.97 (m, 30H)
IR: 3297, 2980, 2930, 2855, 1684, 1539, 1451, 1258
EXAMPLE 22
Trans-4-amidino-�(S)-N-((R)-2-ethoxycarbonylamino-4-ethyl-hexanoyl) prolyl!aminomethylcyclohexane (compound No. 264 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 8.91 (br, 2H), 8.70 (br, 2H), 7.54 (m, 1H), 6.34 (m, 1H), 4.56 (m, 1H), 4.38 (m, 1H), 4.11 (m, 3H), 3.48 (m, 1H), 3.21 (m, 1H),2.88 (m, 1H), 2.68 (m, 1H), 2.30-1.19 (m, 18H), 1.26 (t, 3H), 0.96 (m, 2H),0.86 (t, 6H)
IR: 3279, 2962, 1685, 1639, 1541, 1448, 1257, 1059, 752
EXAMPLE 23
Trans-4-amidino-�(S)-N-�(R)-2-t-butoxycarbonylamino-4,4-dimethylpentanoyl!prolyl!aminomethylcyclohexane (compound No. 266 of Table 1) glycolate
NMR (DMSO-d.sup.6) 9.54 (br, 2H), 8.72 (br, 2H), 7.54 (br, 1H), 7.01 (t, 1H), 4.60-4.00 (m, 4H), 3.40 (m, 2H), 3.10-2.75 (m, 3H), 2.35 (br, 1H), 2.00-1.20 (m, 24H), 0.91 (s, 9H)
IR: 3316, 2953, 1686, 1543, 1449, 1368, 1167
EXAMPLE 24
4-�(S)-N-�(R)-2-t-butyloxycarbonylamino-cyclohexylacetyl!prolyl!aminomethyl-benzamidoxime (compound No. 396 of Table 1)
To a solution of the compound (0.94 g, 2 mmol) obtained in the item (c) of Example 1 in ethanol (15 ml), a solution of sodium carbonate (0.17 g, 1.6 mmol) in water (3 ml) and hydroxyamine hydrochloride (0.22 g, 3.2 mmol) are added. After the reaction mixture is heated at reflux for 8 hours, thesolvent is evaporated and the resulting residue is purified with silica gelcolumn chromatography (chloroform-methanol) to give 0.84 g of the titled compound (84%).
NMR (CDCl.sub.3) 1.0-1.49 (m, 14H), 1.5-2.4 (m, 1 OH), 3.56 (br, 1H), 3.97 (br, 1H), 4.09 (t, 1H), 4.41 (dq, 2H), 4.67 (d, 1H), 4.94 (br, 2H), 5.41 (d, 1H), 7.20 (d, 2H), 7.23-7.27 (m, 1H), 7.50 (d, 2H), 7.75 (br, 1H)
IR: 3345, 2978, 2930, 2855, 1640, 1528, 1449, 1167
According to the same procedures, the compounds shown in the following Examples were synthesized.
EXAMPLE 25
4-�(S)-N-phenylacetylprolyl!aminomethyl-benzamidoxime (compound No. 374 of Table 1)
NMR (CDCl.sub.3) 8.11 (t, 1H), 7.37 (d, 2H), 7.28-7.23 (m, 5H), 7.08 (d, 2H), 4.88 (s, 2H), 4.68 (d, 1H), 4.51 (m, 1H), 4.21 (m, 1H), 3.71 (s, 2H),3.63-3.51 (m, 2H), 2.40-2.01 (m, 4H)
IR: 3315, 2968, 1637, 1543, 1244, 1155, 927, 709
EXAMPLE 26
4-�(S)-N-�(R)-N'-ethoxycarbonylphenylalanyl!prolyl!aminomethylbenzamidoxime(compound No. 387 of Table 1)
NMR (CDCl.sub.3) 7.54 (d, 2H), 7.27-7.19 (m, 7H), 6.31 (d, 1H), 5.05 (br, 2H), 4.65-4.42 (m, 3H), 4.24-4.1 0 (m, 1H), 3.80-3.40 (m, 3H), 3.10-2.95 (m, 2H), 2.60-2.50 (m, 1H), 2.14 (br, 1H), 1.95-1.50 (m, 3H), 0.99 (t, 3H)
IR: 3339, 1641, 1539, 1451, 1260, 752, 702
EXAMPLE 27
4-�(S)-N-�(R)-2-t-butyloxycarbonylamino-3-cyclohexylpropanoyl!prolyl!aminomethyl-benzamidoxime (compound No. 397 of Table 1)
NMR (CDCl.sub.3) 7.75 (br, 1H), 7.50 (d, 2H), 7.21 (d, 2H), 5.40 (d, 1H), 4.94 (br, 2H), 4.64 (br, 1H), 4.40-4.25 (m, 3H), 3.95 (br, 1H), 3.50-3.40 (m, 1H), 2.0-0.80 (m, 26H)
IR: 3337, 2978, 2924, 2851, 1642, 1536, 1449, 1167
EXAMPLE 28
4-�(S)-N-�(R)-2-ethoxycarbonylamino-3-methyl-3-methylthiobutanoyl!prolyl!aminomethyl-benzamidoxime (compound No. 419 of Table 1)
NMR (CDCl.sub.3) 7.66 (t, 1H), 7.53 (d, 2H), 7.23 (d, 2H), 5.64 (d, 1H), 4.91 (s, 2H), 4.68 (d, 1H), 4.58-4.30 (m, 3H), 3.90 (m, 1H), 3.87-3.76 (m,2H), 3.62 (m, 1H), 2.37 (m, 1H), 2.09-2.00 (m, 3H), 2.06 (s, 3H), 1.41 (s, 3H), 1.39 (s, 3H), 1.09 (t, 3H)
IR: 3339, 2978, 1641, 1535, 1439, 1249, 1057, 929, 754
EXAMPLE 29
4-�(S)-N-�(R)-phenylalanyl!prolyl!aminomethyl-benzamidoxime (compound No. 390 of Table 1) dihydrochloride
NMR (DMSO-d.sup.6) 11.24 (br, 1H), 9.02 (br, 2H), 8.91 (t, 1H), 8.80 (br, 3H), 7.66 (d, 2H), 7.44 (d, 2H), 7.35-7.22 (m, 5H), 4.30-4.16 (m, 4H), 3.57-2.95 (m, 3H), 2.45-2.30 (m, 1H), 1.90-1.20 (m, 4H)
IR: 3059, 1649, 1539, 1491, 1454
EXAMPLE 30
Trans-4-�(S)-N-((R)-2-isopropoxycarbonylamino-2-cyclohexylacetyl) prolyl!aminomethylcyclohexanecarboxamidoxime (compound No. 430 of Table 1)
NMR (CDCl.sub.3) 7.14 (br, 1H), 5.70 (d, 1H), 4.85-4.80 (m, 1H), 4.70 -4.50(m, 3H), 4.17-4.08 (m, 2H), 3.96 (br, 1H), 3.54 (q, 1H), 3.05 (t, 2H), 2.40-2.20 (m, 1H), 2.09-0.88 (m, 30H)
IR: 3342, 2978, 2928, 2855, 1653, 1449, 1256, 1111
EXAMPLE 31
Trans-4-�(S)-N-((R)-2-t-butoxycarbonylamino-3-cyclohexylpropanoyl) prolyl!aminomethylcyclohexanecarboxamidoxime (compound No. 435 of Table 1)
NMR (CDCl.sub.3) 7.14 (br, 1H), 5.40 (d, 1H), 4.60-4.33 (m, 5H), 3.88 (br, 1H), 3.43 (q, 1H), 3.20-3.11 (m, 1H), 3.0-2.96 (m, 1H), 2.40-2.30 (m, 1H),2.0-0.84 (m, 35H)
IR: 3356, 2926, 2853, 1649, 1537, 1448, 1167
EXAMPLE 32
Trans-4-�(S)-N-((R)-2-t-butoxycarbonylamino-2-cyclohexylacetyl) prolyl!aminomethylcyclohexanecarboxamidoxime (compound No. 433 of Table 1)
NMR (CDCl.sub.3) 7.15 (br, 1H), 5.28 (d, 1H), 4.58 (br, 4H), 4.09 (t, 1H), 3.92 (br, 1H), 3.53 (q, 1H), 3.20-2.90 (m, 2H), 2.40 (br, 1H), 2.10-0.91 (m, 33H)
IR: 3347, 2930, 2855, 1649, 1541, 1451, 1169
EXAMPLE 33
Trans-4-�(S)-N-�(R)-2-t-ethoxycarbonylamino-4,4-dimethylpentanoyl!prolyl!aminomethylcyclohexanecarboxamidoxime (compound No. 461 of Table 1)
NMR (CDCl.sub.3) 7.06 (t, 1H), 5.56 (d, 1H), 4.57-4.39 (m, 4H), 4.11 (q, 2H), 3.98 (m, 1 H 3.47 (m, 1H), 3.05 (m, 2H), 2.39 (m, 1H), 2.04-1.78 (m, 1OH), 1.57 (d, 2H), 1.56-1.12 (m, 2H), 1.24 (t, 3H), 0.99 (s, 9H), 0.99-0.89 (m, 2H)
IR: 3356, 2934, 1649, 1541, 1446, 1249, 1059, 927
EXAMPLE 34
Trans-4-�(S)-N-�(R)-2-methoxycarbonylamino-4,4-dimethylpentanoyl!prolyl!aminomethylcyclohexanecarboxamidoxime (compound No. 458 of Table 1)
NMR (CDCl.sub.3) 7.04 (t, 1H), 5.53 (d, 1H), 4.68 (s, 2H), 4.56 (d, 1H), 4.43 (m, 1H), 3.98 (m, 1H), 3.66 (s, 3H), 3.47 (m, 1H), 3.07 (m, 2H), 2.39(m, 1H), 2.19-1.77 (m, 8H), 1.57 (d, 2H), 1.55-1.25 (m, 4H), 0.99 (s, 9H), 0.93 (m, 2H)
IR: 3344, 2949, 1712, 1649, 1548, 1448, 1249, 1059
EXAMPLE 35
Trans-4-�(S)-N-�(R)-2-t-butoxycarbonylamino-4,4-dimethylpentanoyl!prolyl!aminomethylcyclohexanecarboxamidoxime (compound No. 467 of Table 1)
NMR (CDCl.sub.3) 7.12 (t, 1H), 5.14 (d, 1H), 4.58 (d, 1H), 4.53 (s, 2H), 4.37 (m, 1H), 3.92 (m, 1H), 3.45 (m, 1H), 3.19 (m, 1H), 2.95 (m, 1H), 2.42(m, 1H), 2.06-1.79 (m, 8H), 1.53 (d, 2H), 1.52-1.34 (m, 4H), 1.43 (s, 9H), 0.99 (s, 9H), 1.00-0.89 (m, 2H)
IR: 3358, 2930, 1649, 1535, 1448, 1367, 1249, 1168
EXAMPLE 36
Trans-4-�(S)-N-�(R)-2-benzyloxycarbonylamino-4,4-dimethylpentanoyl!prolyl!aminomethylcyclohexanecarboxamidoxime (compound No. 469 of Table 1)
NMR (CDCl.sub.3) 7.36-7.27 (m, 5H), 7.04 (t, 1H), 5.63 (d, 1H), 5.16-5.00 (m, 2H), 4.58-4.46 (m, 4H), 3.97 (m, 1H), 3.47 (m, 1H), 3.06-2.9 2 (, 2H),2.43-2.38 (m, 1H), 2.01-1.72 (m, 8H), 1.58 (d, 2H), 1.50-1.23 (m, 4H), 0.98(s, 9H), 0.98-0.88 (m, 2H)
IR: 3356, 2928, 1649, 1541, 1448, 1249, 1053 929
EXAMPLE 37
Trans-4-�(S)-N-�(R)-2-isopropoxycarbonylamino-4,4-dimethylpentanoyl!prolyl!aminomethylcyclohexanecarboxamidoxime (compound No. 464 of Table 1)
NMR (CDCl.sub.3) 7.11 (t, 1H), 5.49 (d, 1H), 4.83 (m, 1H), 4.56 (m, 3H), 4.42 (dd, 1H), 3.98 (m, 1H), 3.47 (dd, 1H), 3.04 (m, 2H), 2.40 (m, 1H), 2.01 (m, 2H), 1.92 (m, 3H), 1.80 (m, 3H), 1.57 (d, 2H), 1.39 (m, 4H), 1.21(m, 6H), 0.99 (s, 9H), 0.94 (m, 2H)
EXAMPLE 38
Trans-4-�(S)-N-�(R)-2-isopropoxycarbonylamino-2-cyclopentylacetyl!prolyl!aminomethylcyclohexanecarboxamidoxime (compound No. 464 of Table 1)
NMR (CDCl.sub.3) 7.14 (t, 1H), 5.42 (d, 1H), 4.83 (m, 1H), 4.60 (d, 1H), 4.52 (s, 2H), 4.13 (m, 1H), 3.98 (m, 1H), 3.56 (m, 1H), 3.04 (m, 2H), 2.35(m, 1H), 2.24 (m, 1H), 2.10-1.30 (m, 20H), 1.23 (dd, 6H), 1.01-0.93 (m, 2H)
IR: 3344, 2934, 1649, 1541, 1448, 1275, 1111, 754
EXAMPLE 39
Trans-4-�(S)-N-((R)-2-t-butoxycarbonylamino-2-cyclopentylacetyl) prolyl!aminomethylcyclohexanecarboxamidoxime (compound No. 432 of Table 1)
NMR (CDCl.sub.3) 7.16 (t, 1H), 5.16 (d, 1H), 4.60 (d, 1H), 4.51 (s, 2H), 4.14 (t, 1H), 3.94 (m, 1H), 3.52 (m, 1H), 3.01 (m, 2H), 2.38 (m, 1H), 2.23-1.39 (m, 21H), 1.43 (s, 9H), 1.17-0.90 (m, 2H)
IR: 3350, 2932, 1649, 1541, 1448, 1367, 1251, 1167, 929
EXAMPLE 40
Trans-4-�(S)-N-((R)-2-ethoxycarbonylamino-3-cyclohexylpropanoyl) prolyl!aminomethylcyclohexanecarboxamidoxime (compound No. 428 of Table 1)
NMR (CDCl.sub.3) 7.08 (br, 1H), 5.53 (d, 1H), 4.80-4.40 (m, 4H), 4.10-3.85 (m, 4H), 3.44 (q, 1H), 3.06 (t, 3H), 2.15-0.90 (m, 29H)
IR: 3343, 2926, 2853, 1649, 1541, 1449, 1260, 1053
EXAMPLE 41
Trans-4-�(S)-N-((R)-2-isopropoxycarbonylamino-3-cyclohexylpropanoyl) prolyl!aminomethylcyclohexanecarboxamidoxime (compound No. 431 of Table 1)
NMR (CDCl.sub.3) 7.12 (br, 1H), 5.51 (d, 1H), 4.85-4.70 (m, 1H), 4.60-4.30 (m, 4H), 4.0-3.85 (m, 1H), 3.44 (q, 1H), 3.10-2.95 (m, 3H), 2.45-2.35 (m, 1H), 2.05-0.80 (m, 32H)
IR: 3347, 2978, 2926, 2853, 1649, 1539, 1449, 1261, 1111
EXAMPLE 42
Trans-4-�(S)-N-((R)-2-isopropoxycarbonylamino-4-ethyl-hexanoyl) prolyl!aminomethylcyclohexanecarboxamidoxime (compound No. 463 of Table 1)
NMR (CDCl.sub.3) 7.11 (t, 1H), 5.41 (d, 1H), 4.83 (m, 1H), 4.56 (m, 3H), 4.39 (m, 1H), 3.94 (m, 1H), 3.46 (m, 1H), 3.02 (m, 2H), 2.39 (m, 1H), 2.10-1.20 (m, 20H), 1.22 (dd, 6H), 1.02-0.84 (m, 2H), 0.86 (t, 6H)
IR: 33346, 2962, 2930, 1653, 1541, 1448, 1271, 1113
EXAMPLE 43
Trans-4-�(S)-N-((R)-2-t-butoxycarbonylamino-4-ethyl-hexanoyl) prolyl!aminomethylcyclohexanecarboxamidoxime (compound No. 466 of Table 1)
NMR (CDCl.sub.3) 7.19 (t, 1H), 5.14 (d, 1H), 4.60 (d, 1H), 4.50 (s, 2H), 4.33 (m, 1H), 3.89 (m, 1H), 3.43 (m, 1H), 3.15 (m, 1H), 2.95 (m, 1H), 2.40(m, 1H), 2.10-1.19 (m, 20H), 1.43 (s, 9H), 1.04-0.89 (m, 2H), 0.86 (t, 6H)
IR: 3346, 2964, 2930, 1649, 1541, 1448, 1367, 1280, 1251, 1168, 929
EXAMPLE 44
Trans-4-�(S)-N-((R)-2-ethoxycarbonylamino-heptanoyl) prolyl!aminomethylcyclohexanecarboxamidoxime (compound No. 459 of Table 1)
NMR (CDCl.sub.3) 7.08 (t, 1H), 5.60 (d, 1H), 4.58 (m, 3H), 4.35 (m, 1H), 4.07 (m, 2H), 3.92 (m, 1H), 3.48 (m, 1H), 3.06 (m, 2H), 2.40 (m, 1H), 2.04-1.32 (m, 20H), 1.24 (t, 3H), 0.89 (t, 3H), 0.98 (m, 2H)
IR: 3346, 2928, 1649, 1541, 1448, 1255, 1055, 927
EXAMPLE 45
Trans-4-�(S)-N-((R)-N'-t-butoxycarbonylamino-methionyl) prolyl!aminomethylcyclohexanecarboxamidoxime (compound No. 468 of Table 1)
NMR (CDCl.sub.3) 7.07 (m, 1H), 5.31 (d, 1H), 4.55 (m, 4H), 3.56 (m, 1H), 3.10 (m, 2H), 2.57 (t, 2H), 2.37 (m, 1H), 2.11 (s, 3H), 2.06-1.29 (m, 14H), 1.43 (s, 9H), 1.00 (m, 2H)
IR: 3354, 2928, 1647, 1541, 1448, 1367, 1251, 1167
EXAMPLE 46
Trans-4-�(S)-N-((R)-2-hydroxy-4,4-dimethyl-pentanoyl) prolyl!aminomethylcyclohexanecarboxamidoxime (compound No. 454 of Table 1)
NMR (CDCl.sub.3) 7.19 (t, 1H), 4.68 (s, 2H), 4.50 (d, 1H), 4.36 (t, 1H), 3.64 (t, 1H), 3.39 (m, 1H), 3.06 (m, 2H), 2.35 (m, 2H), 2.16-1.79 (m, 9H),1.44 (d, 2H), 1.43-1.25 (m, 3H), 1.00-0.95 (m, 2H), 1.02 (s, 9H)
IR: 3337, 2944, 1653, 1620, 1566, 1448, 1386, 1248, 1087
EXAMPLE 47
Trans-4-�(S)-N-((R)-2-ethoxycarbonylamino-4-ethyl-hexanoyl) prolyl!aminomethylcyclohexanecarboxamidoxime (compound No. 460 of Table 1)
NMR (CDCl.sub.3) 7.07 (t, 1H), 5.53 (d, 1H), 4.56 (m, 3H), 4.40 (m, 1H), 4.11 (q, 2H), 3.96 (m, 1H), 3.45 (m, 1H), 3.05 (m, 2H), 2.36 (m, 1H), 2.09-1.77 (m, 10H), 1.61-1.21 (m, 8H), 1.24 (t, 3H), 1.02-0.83 (m, 2H), 0.86 (t, 6H)
IR: 3342, 2962, 2930, 1649, 1541, 1448, 1379, 1269, 1059, 929
EXAMPLE 48
Trans-4-�(S)-N-�(R)-2-ethoxycarbonylamino-4,4-dimethylpentanoyl!prolyl!aminomethylcyclohexanecarboxamide O-methoxycarbonyloxime (compound No. 531 of Table 1)
To a solution of the compound (4.2 g, 8.9 mmol) obtained in Example 33 and triethylamine (1.9 ml, 13.3 mmol) in dichloromethane (100 ml), a solution of methyl chloroformate (1.0 g, 10 mmol) in dichloromethane (10 ml) is added at 0.degree. C. After stirring for 4 hours, the organic layer is washed once with an aqueous saturated sodium bicarbonate solution, water and saturated brine, successively. After drying over sodium sulfate, the solvent is evaporated and the residue is purified with silica gel column chromatography (ethyl acetate-methanol) to give 2.9 g of the titled compound (62%).
NMR (CDCl.sub.3) 0.89-1.07 (m, 11H), 1.21-1.60 (m, 8H), 1.79-2.40 (m, 9H), 3.0-3.10 (m, 2H), 3.40-3.50 (m, 1H), 3.84 (s, 3H), 3.84-4.20 (m, 3H), 4.35-4.40 (m,1H), 4.55 (d, 1H), 4.81 (br, 2H), 5.19 (d, 1H), 7.12 (t, 1H)
IR: 3345, 2953, 1763, 1699, 1645, 1541, 1443, 1256
According to the same procedures, the compounds shown in the following Examples were synthesized.
EXAMPLE 49
4-�(S)-N-((R)-2-hydroxy-2-cyclohexylacetyl) prolyl!aminomethylbenzamide O-ethoxycarbonyloxime (compound No. 543 of Table 1)
NMR (CDCl.sub.3) 7.56 (d, 2H), 7.47 (t, 1H), 7.22 (d, 2H), 5.35 (s, 2H), 4.53 (m, 2H), 4.37 (d, 2H), 4.30 (q, 2H), 4.07 (m, 1H), 3.64 (m, 1H), 3.47(m, 1H), 3.39 (m, 1H), 2.35-1.17 (m, 15H), 1.35 (t, 3H)
IR: 3368, 2928, 1772, 1628, 1554, 1452, 1404, 1228,1087, 856
EXAMPLE 50
Trans-4-�(S)-N-((R)-2-hydroxy-4,4-dimethylpentanoyl) prolyl!aminomethylcyclohexanecarboxamide O-methoxycarbonyloxime (compound No. 534 of Table 1)
NMR (CDCl.sub.3) 7.07 (t, 1H), 4.77 (s, 2H), 4.52 (d, 1H), 4.34 (m, 1H), 3.85 (s, 3H), 3.58 (t, 1H), 3.37 (m, 1H), 3.22 (d, 1H), 3.12-3.05 (m, 2H),2.26-2.21 (m, 1H), 1.97-1.37 (m, 13H), 1.03 (s, 9H), 1.09-0.95 (m, 2H)
IR: 3346, 2953, 1763, 1643, 1442, 1257, 1089, 879
EXAMPLE 51
Trans-4-�(S)-N-((R)-2-hydroxy-4,4-dimethylpentanoyl)prolyl!aminomethylcyclohexanecarboxamide O-ethoxycarbonyloxime (compound No. 556 of Table 1)
NMR (CDCl.sub.3) 7.05 (t, 1H), 4.73 (s, 2H), 4.52 (d, 1H), 4.34 (t, 1H), 4.27 (q, 2H), 3.58 (m, 1H), 3.45 (m, 1H), 3.08 (m, 2H), 2.44 (m, 1H), 2.30-1.30 (m, 13H), 1.32 (t, 3H), 1.03 (s, 9H), 1.07-0.92 (m, 2H)
IR: 3373, 2953, 1759, 1641, 1450, 1369, 1248, 1093
EXAMPLE 52
Trans-4-amino-�(S)-N-�(R)-N'-methanesulfonylphenyalanyl!prolyl!aminomethylcyclohexane (compound No. 776 of Table 1) L-tartrate.
(a) Trans-4-t-butyloxycarbonylamino-benzyloxycarbonylamino-methylcyclohexane
To a solution of trans-4-aminomethylcyclohexanecarboxylic acid (15.7 g, 100mmol) and sodium hydroxide (4.0 g, 100 mmol) in water (30 ml), benzyloxycarbonyl chloride (15.6 ml, 110 mmol) and sodium hydroxide (4.4 g, 110 mmol) in water (30 ml) are added dropwise at 0.degree. C., simultaneously. After stirring for 4 hours, the mixture is extracted once with ether and 1N-hydrochloric acid is added to the aqueous layer until the pH of the mixture indicates 2. Then, the precipitated white solid is collected and dried.
To a solution of the resulting compound (12.8 g, 50 mmol) in t-butanol (150ml), triethylamine (8.3 ml, 60 mmol) and DPPA (13.7 g, 50 mmol) are added and heated at reflux for 8 hours. After the solvent is evaporated, water is added to the residue and the mixture is extracted with chloroform. The organic layer is washed once with an aqueous sodium carbonate (5%), once with an aqueous potassium hydrogensulfate (5%), twice with water and once with saturated brine, successively, and then dried over sodium sulfate. The solvent is evaporated and the residue is purified with silica gel column chromatography (hexane-ethyl acetate) to give 8.6 g of the titled compound (47%).
NMR (CDCl.sub.3) 0.85-1.37 (m, 14H), 1.60-1.85 (m, 4H), 2.84 (t, 1H), 3.12 (br, 1H), 5.00 (s, 2H), 6.62 (d, 1H), 7.23-7.39 (m, 6H)
(b) Trans-4-t-butyloxycarbonylamino-�(S)-N-benzyloxycarbonylprolyl!aminomethylcyclohexane
The compound (4.4 g, 12 mmol) obtained in the item (a) is dissolved in methanol (200 ml) and the catalytic hydrogenation is conducted at room temperature and under atomospheric pressure in the presence of palladium black (0.4 g). After the completion of the reaction, the catalyst is filtered off and the solvent is evaporated.
To a solution of (S)-Z-proline (3.0 g, 12 mmol) in THF (30 ml), CDl (2.0 g,12 mmol) is added at 0.degree. C. After stirring for 3 hours, a solution ofthe compound obtained in the above reaction in THF (150 ml) is added at 0.degree. C. After stirring for 6 hours, the solvent is evaporated and water (50 ml) is added to the residue. The mixture is extracted with chloroform and the organic layer is washed three times with water and oncewith saturated brine, successively. After drying over sodium sulfate, the solvent is evaporated and the residue is purified with silica gel chromatography (chloroform-methanol) to give 4.2 g of the titled compound (77%).
NMR (CDCl.sub.3) 0.85-1.06 (m, 4H), 1.44 (s, 9H), 1.60-2.35 (m, 9H), 2.94-3.20 (m, 2H), 3.20-3.55 (m, 3H), 4.31 (br, 1H), 4.47 (br, 1H), 5.14 (s, 2H), 6.90 (br, 1H), 7.15-7.40 (m, 5H)
(c) Trans-4-t-butyloxycarbonylamino-�(S)-N-�(R)-N'-benzyloxycarbonylphenylalanyl!prolyl!aminomethylcyclohexane
The compound (3.6 g, 7.9 mmol) obtained in the item (b) is dissolved in methanol (50 ml) and the catalytichydrogenation is conducted at room temperature and under atomospheric pressure in the presence of palladium black (0.3 g). After the completion of the reaction, the catalyst is filtered off and the solvent is evaporated.
To a solution of (R)-Z-phenylalanine (2.4 g, 7.9 mmol) in THF (30 ml), CDl (1.3 g, 7.9 mmol) is added at 0.degree. C. After stirring for 4 hours, a solution of the compound obtained in the above reaction in THF (60 ml) is added. After stirring for 8 hours, the solvent is evaporated and water is added to the reaction mixture. The mixture is extracted with chloroform and the organic layer is washed three times with water and once with saturated brine, successively, and then dried over sodium sulfate. The solvent is evaporated and the residue is purified with silica gel column chromatography (chloroform-methanol) to give 4.2 g of the titled compound (89%).
NMR (CDCl.sub.3) 0.85-1.06 (m, 5H), 1.33-2.0 (m, 15H), 2.10-2.22 (m, 1H), 2.50-2.60 (m, 1H), 2.94-3.01 (m, 5H), 3.30 (br, 1H), 3.57 (t, 1H), 4.32-4.59 (m, 3H), 5.08 (d, 2H), 5.69 (d, 1H), 7.02 (br, 1H), 7.18-7.37 (m, 10H)
(d) Trans-4-amino-�(S)-N-�(R)-N'-methanesulfonylphenylalanyl!prolyl!aminomethylcyclohexane L-tartrate.
The compound (2.4 g, 3.9 mmol) obtained in the item (c) is dissolved in methanol (40 ml) and the catalytic hydrogenation is conducted at room temperature and under atomospheric pressure in the presence of palladium black (0.2 g). After the completion of the reaction, the catalyst is filtered off and the solvent is evaporated. To a solution of the resultingcompound in dichloromethane (40 ml), triethylamine (0.65 ml, 4.7 mmol) is added and a solution of methanesulfonyl chloride (0.47 g, 4.1 mmol) in dichloromethane (100 ml) is further added at 0.degree. C. After stirring for 3 hours, an aqueous saturated sodium bicarbonate solution is added andthe organic layer is washed once with water and saturated brine, successively. After drying over sodium sulfate, the solvent is evaporated and the residue is purified with silica gel chromatography (chloroform-methanol).
The resulting compound is dissolved in chloroform (10 ml) and a 4N-dioxane hydrochloride in dioxane (10 ml) is added at 0.degree. C. After stirring for 2 hours, the solvent is evaporated and chloroform (10 ml) and a 1N-sodium hydroxide solution (10 ml) are added to the residue and, further, the mixture is stirred for 10 minutes. The organic layer is driedover sodium sulfate and a solution of L-tartaric acid (0.34 g, 2.26 nm) in methanol (5 ml) is added.
The solvent is evaporated and ether (20 ml) is added, and then the precipitated white solid is collected and dried to give 1.36 g of the titled compound (58%).
NMR (DMSO-d.sup.6) 7.77 (m, 4H), 7.28 (m, 5H), 4.28 (m, 1H), 4.16 (m, 1H), 3.57-3.45 (m, 8H), 2.73 (s, 3H), 1.91-1.75 (m, 9H), 1.54 (m, 1H), 1.25 (m,4H), 0.93 (m, 2H)
IR: 3324, 2934, 1734, 1638, 1545, 1453, 1308, 1148
According to the same procedures, the compounds shown in the following Examples were synthesized.
EXAMPLE 53
Trans-4-amino-�(S)-N-�(R)-2-methylsulfonylamino-2-cyclohexylacetyl!prolyl!aminomethylcyclohexane (compound No. 759 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 8.09 (br, 3H), 7.80 (t, 1H), 7.39 (d, 1H), 4.30-4.26 (m,1H), 3.87 (t, 1H), 3.80-3.45 (m, 2H), 3.0-2.80 (m, 3H), 2.85 (s, 3H), 2.10-0.80 (m, 24H)
IR: 3382, 2930, 2857, 1638, 1543, 1451, 1154
EXAMPLE 54
Trans-4-amino-�(S)-N-�(S)-N'-benzenesulfonyl-.alpha.-glutamyl!prolyl!aminomethylcyclohexane (compound No. 792 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 8.04 (br, 3H), 7.75-7.50 (m, 5H), 4.05 (q, 1H), 3.77-3.30 (m, 5H), 3.0-2.70 (m, 3H), 2.28 (t, 2H), 2.0-1.52 (m, 10H), 1.31-1.11 (m, 3H), 1.0-0.85 (m, 2H)
IR: 3400, 2937, 1637, 1449, 1161
EXAMPLE 55
Trans-4-amino-�(S)-N-((RS)-3-methylsulfonylamino-3-phenylpropanoyl) prolyl!aminomethylcyclohexane (compound No. 777 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 8.08 (m, 3H), 7.34 (m, 5H), 4.78 (m, 1H), 4.15 (m, 2H), 3.51 (m, 1H), 3.36 (m, 2H), 2.86 (m, 4H), 2.68 (s, 3H), 2.51 (m, 2H), 2.00-1.69 (m, 6H), 1.27 (m, 4H), 0.92 (m, 2H)
IR: 3409, 2936, 1638, 1453, 1314, 1148
EXAMPLE 56
Trans-4-amino-�(S)-N-((R)-2-isopropoxycarbonylamino-4,4-dimethylpentanoyl) prolyl!aminomethylcyclohexane (compound No. 797 of Table 1)
NMR (CDCl.sub.3) 7.19 (m, 1H), 5.32 (d, 1H), 4.82 (m, 1H), 4.53 (m, 2H), 4.00 (m, 1H), 3.48 (m, 1H), 3.03-2.16 (m, 6H), 2.00-1.81 (m, 6H), 1.57 (d,2H), 1.49 (m, 4H), 1.24 (m, 6H), 1.00 (s, 9H), 0.95 (m, 2H)
IR: 3326, 2949, 1640, 1541, 1449, 1248
EXAMPLE 57
Trans-4-amino-�(S)-N-((R)-N'-ethoxycarbonyl-phenylalanyl) prolyl!aminomethylcyclohexane (compound No. 780 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 7.98 (m, 3H), 7.37 (t, 1H), 7.26 (m, 5H), 4.37 (dd, 1H),4.16 (m, 1H), 4.02 (m, 2H), 3.88 (m, 1H), 3.59 (m, 1H), 3.43 (m, 1H), 2.86 (m, 5H), 1.93-1.75 (m, 7H), 1.28 (m, 4H), 1.15 (t, 3H), 0.92 (m, 2H)
IR: 3349, 2936, 1642, 1537, 1451, 1258
EXAMPLE 58
Trans-4-amino-�(S)-((R)-phenylalanyl) prolyl!aminomethylcyclohexane (compound No. 779 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 8.69 (br, 3H), 8.09 (br, 4H), 7.37-7.20 (m, 5H), 4.19 (br, 1H), 4.09-4.06 (m, 1H), 3.20-2.82 (m, 5H), 2.0-0.85 (m, 15H)
IR: 3426, 2936, 1649, 1539, 1497, 1454
EXAMPLE 59
Trans-4-amino-�(S)-N-((R)-2-ethoxycarbonyloxy-3-phenylpropanoyl) prolyl!aminomethylcyclohexane (compound No. 785 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 7.78 (m, 3H), 7.30 (m, 5H), 7.15 (d, 1H), 5.22 (t, 1H), 4.20 (m, 1H), 4.08 (m, 3H), 3.64 (m, 1H), 3.02-2.88 (m, 5H), 1.92-1.72 (m,7H), 1.20-0.94 (m, 9H)
IR: 3397, 2938, 1740, 1655, 1453, 1269
EXAMPLE 60
Trans-4-amino-�(S)-N-((R)-2-allylcarbamoyloxy-3-phenylpropanoyl) prolyl!aminomethylcyclohexane (compound No. 787 of Table 1) hydrobromide
NMR (DMSO-d.sup.6) 7.90 (m, 3H), 7.30 (m, 5H), 7.14 (m, 1H), 5.72 (m, 2H), 5.06 (m, 2H), 4.76 (m, 1H), 4.17 (m, 1H), 3.60 (m, 1H), 2.98-2.85 (m, 5H),1.87-1.70 (m, 7H), 1.23 (m, 7H), 0.90 (m, 2H)
IR: 3364, 2936, 1707, 1645, 1543, 1454, 1256
EXAMPLE 61
Trans-4-amino-�(S)-N-((R)-2-hydroxy-2-cyclohexylacetyl) prolyl!aminomethylcyclohexane (compound No. 768 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 8.21 (br, 3H), 7.95 (m, 1H), 4.53 (m, 1H), 4.18 (d, 1H),3.95 (m, 1H), 3.07 (m, 3H), 2.18-1.55 (m, 22H), 1.30-1.03 (m, 2H)
IR: 3422, 2928, 2854, 1637, 1450, 1388, 1240, 1114, 1045
EXAMPLE 62
Trans-4-amino-�(S)-N-((R)-2-hydroxy-2-phenylacetyl) prolyl!aminomethylcyclohexane (compound No. 783 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 7.98 (br, 3H), 7.37-7.28 (m, 5H), 5.48 (br, 1H), 5.23 (d, 1H), 4.23 (d, 1H), 3.70-3.35 (m, 2H), 3.0-2.80 (m, 4H), 2.0-1.60 (m, 8H), 1.40-0.90 (m, 5H)
IR: 3329, 2935, 1667, 1626, 1552, 1448
EXAMPLE 63
Trans-4-amino-�(RS)-1-((R)-N'-methylsulfonyl-phenylalanyl)-2-piperidinecarboxyl!aminomethylcyclohexane (compound No. 834 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 8.07 (m, 3H), 7.28 (m, 5H), 4.64 (m, 1H), 4.39 (m, 1H), 3.99 (m, 1H), 3.67 (m, 1H), 2.87 (m, 7H), 2.84 (s, 3H), 1.91-1.68 (m, 5H),1.33-0.92 (m, 10H)
IR: 3385, 2936, 1638, 1535, 1453, 1314, 1150
EXAMPLE 64
Trans-4-amino-�(S)-N-�(R)-2-ethoxycarbonylamino-4,4-dimethylpentanoyl!prolyl!aminomethylcyclohexane (compound No. 794 of Table 1)
NMR (CDCl.sub.3) 7.16 (m, 1H), 5.68 (d, 1H), 4.53 (d, 1H), 4.38 (m, 1H), 4.10 (q, 2H), 4.01 (m, 1H), 3.46-3.07 (m, 4H), 2.30-1.81 (m, 8H), 1.58 (m,5H), 1.26 (t, 3H), 1.00 (s, 9H), 0.95 (m, 2H)
IR: 3329, 2949, 1642, 1541, 1447, 1248, 1059
EXAMPLE 65
Trans-4-(5-methyl-1,3-dioxo-2-on-4-ylmethyl)amino-�(S)-N-�(R)-2ethoxycarbonylamino-4,4-dimethylpentanoyl!prolyl!aminomethylcyclohexane (compound No. 968 of Table 1)
To a solution of the compound (5.4 g, 11.7 mmol) obtained in Example 64 in DMF (40 ml), sodium carbonate (3.2 g, 23.4 mmol) is added, and a solution of 4-bromomethyl-5-methyl-1,3-dioxo-2-on (4.0 g, 17.6 mmol) in DMF (5 ml) is further added at O.degree. C. After stirring for 48 hours, the solvent is evaporated and water is added to the residue, which is extracted with ethyl acetate. The organic layer is washed three times with water and oncewith saturated brine, successively, and then dried over sodium sulfate. Thesolvent is evaporated and the residue is purified with silica gel column chromatography (chloroform-methanol) to give 2.8 g of the titled compound (44%).
NMR (CDCl.sub.3) 7.07 (m, 1H), 5.15 (d, 1H), 4.56 (d, 1H), 4.41 (m, 1H), 4.10 (q, 2H), 4.00 (m, 2H), 3.48 (s, 2H), 3.45 (m, 2H), 3.04 (t, 1H), 2.62(m, 1H), 2.38 (m, 1H), 2.11 (s, 3H), 2.00 (m, 3H), 1.82 (m, 2H), 1.73-1.43 (m, 4H), 1.28 (t, 3H), 1.26 (m, 3H), 1.00 (s, 9H), 0.96 (m, 2H)
IR: 3329, 2934, 2870, 1823, 1649, 1539, 1445, 1223
According to the same procedures, the compounds shown in the following Examples were synthesized.
EXAMPLE 66
Trans-4-t-butoxycarbonylamino-�(S)-N-�(R)-N'-methanesulfonylphenylalanyl!prolyl!aminomethylcyclohexane (compound No. 955 of Table 1)
NMR (CDCl.sub.3) 7.29 (m, 3H), 7.24 (m, 2H), 6.67 (t, 1H), 5.61 (d, 1H), 4.40 (m, 2H), 4.29 (dd, 1H), 3.58 (m, 1H), 3.34 (m, 1H), 2.99 (m, 4H), 2.82 (s, 3H), 2.69 (m, 1H), 2.18-1.74 (m, 9H), 1.43 (s, 9H), 1.02 (m, 4H)
IR: 3376, 2932, 1655, 1526, 1453, 1322
EXAMPLE 67
Trans-4-guanidino-�(S)-N-�(R)-N'-methanesulfonylphenylalanyl!prolyl!aminomethylcyclohexane (compound No. 646 of Table 1) sulfate
To a solution of the compound (0.45 g, 1 mmol) obtained in Example 52 in ethanol (15 ml), a solution of 2-methylisothiourea sulfate (0.14 g, 0.5 mmol) in water (5 ml) is added and heated at reflux for 6 hours. The solvent is evaporated and ether (20 ml) is added. The precipitated white solid is collected and washed with ether, and then dried under reduced pressure to give 0.44 g of the titled compound (81%).
NMR (DMSO-d.sup.6) 8.04-2.0 (m, 13H), 2.60-3.96 (m, 7H), 2.77 (s, 3H), 4.14-4.28 (m, 2H), 5.47 (br, 1H), 6.75 (br, 1H), 7.20-7.36 (m, 5H), 7.83 (br, 1H), 8.40 (br, 4H)
IR: 3322, 2932, 2193, 2153, 1644, 1545, 1451, 1319, 1150
According to the same procedure as that described in Example 1, the following compounds of Examples 68 to 78 were synthesized.
EXAMPLE 68
4-Amidino-�(S)-N-�(R)-2-hydroxy-cyclohexylacetyl!prolyl!aminomethylbenzene (compound No. 82 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 9.29 (br, 2H), 8.93 (br, 2H), 8.51 (t, 1H), 7.75 (d, 2H), 7.49 (d, 2H), 4.37 (m, 3H), 3.96 (d, 1H), 3.70 (m, 1H), 3.60-3.40 (m,2H) 2.20-1.0 (m, 14H)
IR: 3227, 2922, 1657, 1607, 1539, 1485, 1458, 1323, 1246, 1032
EXAMPLE 70
4-Amidino-�(S)-N-�(R)-2-methylsulfonylamino-3,3-dimethylbutanoyl!prolyl!aminomethylbenzene (compound No. 114 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 9.41 (br, 2H), 9.24 (br, 2H), 8.63 (t, 1H), 7.81 (d, 2H), 7.47 (d, 2H), 7.20 (d, 1H), 4.42 (dd, 1H), 4.35 (t, 2H), 3.96 (d, 1H), 3.80-3.60 (m, 2H), 2.85 (s, 3H), 2.20-1.80 (m, 4H), 0.97 (s, 9H)
IR: 3273, 2970, 2365, 1630, 1541, 1483, 1412, 1304, 1153, 715
EXAMPLE 70
4-Amidino-�(S)-N-�(R)-2-methylsulfonylamino-6-ethoxycarbonylhexanoyl!prolyl!aminomethylbenzene (compound No. 11 7 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 9.35 (br, 4H), 8.66 (t, 1H), 7.79 (d, 1H), 7.48 (d, 2H),4.35 (m, 3H), 4.65 (q, 2H), 3.69 (m, 1H), 3.55 (m, 1H), 2.75 (s, 3H), 2.29 (t, 2H), 2.13 (m, 2H), 1.94 m, 2H), 1.85 (m, 2H), 1.52 (m, 7H), 1.18 (t, 3H)
IR: 3382, 1644, 1547, 1427, 1375, 1314, 1150, 1111
EXAMPLE 71
4-Amidino-�(S)-N-�(R)-2-methylsulfonylamino-4-(3'-carboxy)-phenylbutanoyl!prolyl!aminomethylbenzene (compound No. 119 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 9.45 (s, 2H), 9.38 (s, 2H), 8.62 (t, 1H), 7.84 (m, 2H), 7.79 (d, 2H), 7.64 (d, 1H), 7.47 (d, 2H), 7.42 (m, 2H), 4.33 (m, 3H), 4.1 0 (m, 1H), 3.57-3.37 (m, 2H), 2.85 (m, 1H), 2.78 (s, 3H), 2.73 (m, 1H), 2.12 (m, 1H), 1.95-1.81 (m, 6H)
IR: 3366, 1638, 1543, 1489, 1449, 1311, 1150, 754, 527
EXAMPLE 72
4-Amidino-�(S)-N-�(R)-N'-methylsulfonyl-4-(4'-carboxyphenyl)-seryl!prolyl!aminomethylbenzene (compound No. 970 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 9.31 (s, 2H), 9.00 (s, 2H), 8.59 (t, 1H), 7.90 (d, 2H), 7.83 (d, 1H), 7.75 (d, 2H), 7.48 (d, 2H), 7.03 (d, 2H), 4.35 (m, 4H), 4.22(m, 2H), 4.12 (dd, 1H), 3.72 (m, 2H), 2.89 (s, 3H), 2.20-1.80 (m, 4H)
IR: 3376, 1647, 1607, 1424, 1318, 1252, 1154, 1119, 774, 633, 525
EXAMPLE 73
4-Amidino-�(S)-N-�(R)-N'-methylsulfonyl-O-ethoxycarbonylmethyl-tyrosyl!prolyl!aminomethylbenzene (compound No. 971 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 9.41 (br, 2H), 9.20 (br, 2H), 8.56 (t, 1H), 7.80 (d, 2H), 7.65 (d, 1H), 7.48 (d, 2H), 7.18 (dd, 2H), 6.84 (dd, 2H), 4.75 (q, 1H), 4.30 (dd, 1H), 4.30-4.25 (m, 2H), 3.70-3.42 (m, 3H), 3.47 (q, 2H), 3.18 (t, 1H), 2.83 (d, 2H), 2.72 (s, 3H), 1.89-1.60 (m, 4H), 1.14 (dt, 3H)
IR: 3370, 2365, 1742, 1636, 1541, 1512, 1445, 1308
EXAMPLE 74
4-Amidino-�(S)-N-�(R)-N'-ethoxycarbonylphenylalanyl!prolyl!aminomethylbenzene (compound No. 972 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 9.40 (br, 2H), 9.24 (br, 2H), 8.14 (t, 1H), 7.80 (d, 2H), 7.59 (t, 1H), 7.40 (d, 2H), 7.31-7.15 (m, 2H), 4.50-4.26 (m, 4H), 3.90-3.57 (m, 3H), 3.0-2.7 (m, 3H), 1.9-1.6 (m, 4H), 1.10-1.0 (m, 3H)
IR: 3279, 2364, 1637, 1539, 1491, 1450, 1255, 704
EXAMPLE 75
4-Amidino-�(S)-N-�(R)-2-methylsulfonylaminoheptanoyl!prolyl!aminomethylbenzene (compound No. 973 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 9.37 (s, 2H), 9.16 (s, 2H), 8.60 (t, 1H), 7.76 (d, 2H), 7.48 (d, 2H), 7.40 (d, 1H), 4.50-4.23 (m, 3H), 4.08 (m, 1H), 3.69 (m, 1H),3.36 (m, 1H), 2.74 (s, 3H), 2.15 (m, 1H), 2.09-1.84 (m, 3H), 1.61-1.22 (m, 8H), 0.87 (m, 3H)
IR: 3366, 2957, 1638, 1543, 1489, 1426, 1314, 1154, 718, 527
EXAMPLE 76
4-Amidino-�(S)-N-�(R)-N'-methylsulfonyl-O-(3'-carboxymethyl-phenyl)seryl!prolyl!aminomethylbenzene (compound No. 974 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 9.46 (s, 2H), 9.31 (s, 2H), 8.70 (t, 1H), 7.83 (m, 3H), 7.48 (d, 2H), 7.19 (m, 2H), 6.89 (d, 2H), 4.58 (dd, 1H), 4.37 (m, 4H), 4.14 (d, 2H), 3.70 (m, 1H), 3.60 (m, 3H), 2.89 (s, 3H), 2.11 (m, 1H), 2.01-1.82 (m, 3H)
IR: 3382, 1724, 1640, 1543, 1489, 1447, 1316, 1262, 1154, 768, 527
EXAMPLE 77
4-Amidino-�(S)-N-�(R)-N'-methylsulfonyl-O-(4'-carboxymethyl-phenyl)seryl!prolyl!aminomethylbenzene (compound No. 975 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 9.45 (s, 2H), 9.29 (s, 2H), 8.70 (t, 1H), 7.83 (d, 2H), 7.82 (d, 2H), 7.48 (d, 2H), 7.24 (d, 1H), 6.82 (d, 2H), 4.59 (dd, 1H), 4.37 (m, 4H), 4.14 (d, 2H), 3.70 (m, 1H), 3.61 (m, 3H), 2.89 (s, 3H), 2.11(m, 1H), 2.01-1.82 (m, 3H)
IR: 3383, 1640, 1545, 1514, 1437, 1312, 1242, 1152, 824, 523
EXAMPLE 78
4-Amidino-�(S)-N-�(R)-2-ethoxycarbonylmethylsulfonylamino-heptanoyl!prolyl!aminomethylbenzene (compound No. 976 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 9.36 (s, 2H), 9.15 (s, 2H), 8.49 (t, 1H), 7.81 (d, 1H), 7.77 (d, 2H), 7.47 (d, 2H), 4.35 (m, 3H), 4.21 (d, 1H), 4.15 (m, 1H), 4.06(q, 2H), 3.93 (d, 1H), 3.73 (m, 1H), 3.53 (m, 1H), 2.14 (m, 1H), 1.94 (m, 3H), 1.67-1.18 (m, 8H), 1.14 (t, 3H), 0.89 (m, 3H)
IR: 3274, 2957, 2872, 1821, 1738, 1647, 1541, 1422, 1319, 1159, 1022, 723, 628, 527
According to the same procedures as that described in Example 15, the following compounds of Examples 79 to 86 were synthesized.
EXAMPLE 79
Trans-4-amidino-�(S)-N-�(R)-N'-ethoxycarbonyl-O-t-butyloxy-seryl!prolyl!aminomethylcyclohexane (compound No. 240 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 8.88 (br, 2H), 8.71 (br, 2H), 7.72 (m, 1H), 6.39 (m, 1H), 4.59 (m, 1H), 4.52 (m, 1H), 4.11 (m, 2H), 3.86-3.71 (m, 2H), 3.58 (m,2H), 3.22 (m, 2H), 2.79-0.88 (m, 15H), 1.24 (t, 3H), 1.15 (s, 9H)
IR: 3271, 2976, 1685, 1647, 1541, 1448, 1257, 1192, 1095, 1055
EXAMPLE 80
Trans-4-amidino-�(S)-N-�(R)-N'-isopropoxycarbonyl-O-(1',1'-dimethylpropyl)-seryl!prolyl!aminomethylcyclohexane (compound No. 977 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 8.74 (br, 4H), 7.68 (m, 1H), 6.01 (m, 1H), 4.83 (m, 1H),4.57 (m, 2H), 3.74 (m, 2H), 3.50 (m, 2H), 3.14 (m, 1H), 2.97 (m, 1H), 2.5-0.9 (m, 16H), 1.24 (dd, 6H), 1.09 (s, 6H), 0.81 (t, 3H)
IR: 3314, 2978, 1693, 1641, 1543, 1450, 1375, 1261, 1111, 1059
EXAMPLE 81
Trans-4-amidino-�(S)-N-�(R)-N'-ethoxycarbonyl-O-(1',1'-dimethylpropyl)seryl!prolyl!aminomethylcyclohexane (compound No. 978 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 8.75 (br, 4H), 7.55 (m, 1H), 6.40 (m, 1H), 4.52 (m, 2H),4.13 (m, 2H), 3.88-3.70 (m, 2H), 3.55 (m, 2H), 3.28 (m, 1H), 2.87-2.70 (m, 1H), 2.20-1.20 (m, 14H), 1.27 (t, 3H), 1.09 (s, 6H), 0.81 (t, 3H), 1.10-0.90 (m, 2H)
IR: 3292, 2974, 1689, 1645, 1543, 1448, 1259, 1095, 1055
EXAMPLE 82
Trans-4-amidino-�(S)-N-�(R)-N'-isopropoxycarbonyl-O-(1'-ethyl-1'-methyl-propyl)-seryl!prolyl!aminomethylcyclohexane (compound No. 979 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 8.78 (s, 2H), 8.69 (s, 2H), 7.55 (br, 1H), 5.99 (br, 1H), 4.84 (m, 1H), 4.54 (m, 2H), 3.71 (m, 2H), 3.49 (m, 2H), 3.20-0.90 (m,1 6H), 1.64 (q, 4H), 1.23 (t, 6H), 1.03 (s, 3H), 0.78 (t, 6H)
IR: 3315, 2976, 2934, 1685, 1641, 1543, 1450, 1375, 1261, 1111
EXAMPLE 83
Trans-4-amidino-�(S)-N-�(R)-N'-ethoxycarbonyl-S-t-butyl-cystinyl!prolyl!aminomethylcyclohexane (compound No. 980 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 8.82 (br, 2H), 8.74 (br, 2H), 7.47 (m, 1H), 6.63 (m, 1H), 4.60-4.40 (m, 2H), 4.20-4.21 (m, 2H), 4.00 (m, 1H), 3.72 (m, 1H), 3.24 (m, 1H), 2.87 (m, 2H), 2.65 (m, 1H), 2.18-1.31 (m, 12H), 1.31 (s, 9H), 1.27 (t, 3H), 1.10-0.90 (m, 2H),
IR: 3298, 2932, 1693, 1641, 1541, 1448, 1304, 1257, 1161, 1047
EXAMPLE 84
Trans-4-amidino-�(S)-N-�(R)-N'-isopropoxycarbonyl-O-(1'-methylcyclopentyl)-seryl!prolyl!aminomethylcyclohexane (compound No. 981 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 8.79 (br, 4H), 7.64 (m, 1H), 5.97 (m, 1H), 4.83 (m, 1H),4.55 (m, 2H), 3.76 (m, 2H), 3.52 (m, 2H), 3.15-1.20 (m, 22H), 1.27-1.13 (m,9H), 1.13-0.95 (m, 2H)
IR: 3329, 2934, 1684, 1639, 1541, 1450, 1261, 1182, 1111, 1060, 918
EXAMPLE 85
Trans-4-amidino-�(S)-N-�(R)-N'-isopropoxycarbonyl-O-t-butyl-threonyl!prolyl!aminomethylcyclohexane (compound No.982 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 8.74 (m, 4H), 7.80 (m, 1H), 5.66 (m, 1H), 4.85 (m, 1H), 4.57 (m, 1H), 4.29 (m, 1H), 3.80-3.60 (m, 3H), 3.05 (m, 2H), 2.60 (m, 1H),2.50-1.20 (m, 11H), 1.27-1.22 (m, 1 3H), 1.15 (d, 3H), 1.10-0.90 (m, 2H)
IR: 3331, 2978, 1697, 1639, 1543, 1450, 1375, 1265, 1182, 1111
EXAMPLE 86
Trans-4-amidino-�(S)-N-�(R)-2-ethoxycarbonylamino-3-isopropylthio-3-methyl-butanoyl!prolyl!aminomethylcyclohexane (compound No. 983 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 9.13 (br, 2H), 8.46 (br, 2H), 7.30 (m, 1H), 5.85 (m, 1H), 4.55 (m, 1H), 4.36 (m, 1H), 4.15-3.85 (m, 3H), 3.69 (m, 1H), 3.02 (m,2H), 2.30 (m, 1H), 200-1.20 (m, 13H), 1.48 (s, 3H), 1.33 (s, 3H), 1.30-1.20(m, 9H), 1.05-0.85 (m, 2H)
IR: 3420, 2974, 1635, 1556, 1521, 1448, 1385, 1298, 1259, 1060
According to the same procedures as that described in Example 24, the following compounds of Examples 87 to 113were synthesized.
EXAMPLE 87
4-�(S)-N-�(R)-2-hydroxy-cyclohexylacetyl!prolyl!aminomethylbenzamidoxime (compound No. 391 of Table 1)
NMR (DMSO-d.sup.6) 9.55 (br, 1H), 8.31 (t, 1H), 7.59 (d, 2H), 7.24 (d, 2H),5.73 (br, 2H), 4.57 (m 1H), 4.26-4.32 (m, 3H), 3.91 (br, 1H), 3.40-3.60 (m,2H), 2.05-0.80 (m, 15H)
IR: 3375, 2926, 2853, 1638, 1561, 1451, 1385, 1244
EXAMPLE 88
4-�(S)-N-�(R)-N'-isopropoxycarbonyl-phenylalanyl!prolyl!aminomethylbenzamidoxime (compound No. 395 of Table 1)
NMR (CDCl.sub.3) 7.65 (br, 1H), 7.53 (d, 2H), 7.29-7.19 (m, 8H), 5.89 (d, 2H), 5.01 (br, 2H), 4.58-4.45 (m, 4H), 4.27 (dd, 1H), 3.65 (br, 1H), 3.10-2.93 (m, 2H), 2.58 (q, 1H), 2.17 (br, 1H), 1.90-1.50 (m, 2H), 1.11 (d, 4H), 0.96 (d, 2H)
IR: 3331, 2980, 2880, 2365, 1639, 1539, 1452, 126
EXAMPLE 89
4-�(S)-N-�(R)-2-ethoxycarbonylamino-phenylacetyl!prolyl!aminomethylbenzamidoxime (compound No. 403 of Table 1)
NMR (CDCl.sub.3) 7.80 (br, 1H), 7.47 (d, 2H), 7.40-7.14 (m, 8H), 6.11 (dd, 1H), 5.43 (dd, 1H), 4.98 (br, 2H), 4.70-4.54 (m, 2H), 4.50-4.20 (m, 1H), 4.15-4.00 (m, 1H), 4.00-3.80 (m, 2H), 3.25-3.19 (m, 1H), 2.30-1.80 (m, 4H), 1. 16 (dt, 3H)
IR: 3339, 2980, 2365, 1641, 1524, 1437, 1385, 1057
EXAMPLE 90
4-�(S)-N-�(R)-N'-ethoxycarbonyl-valyl!prolyl!aminomethylbenzamidoxime (compound No. 407 of Table 1)
NMR (CDCl.sub.3) 7.57 (br, 1H), 7.54 (d, 2H), 7.20 (d, 2H), 5.98 (d, 1H), 4.97 (br, 2H), 4.68-4.59(m, 2H), 4.24 (dd, 1H), 4.07 (t, 1H), 4.10-4.00 (m, 1H), 3.90-3.80 (m, 1H), 3.60-3.45 (m, 2H), 2.31 (br, 1H), 2.20-1.95 (m, 4H) 1.88 (d, 1H), 1.01 (t, 3H), 0.97 (d, 6H)
IR: 3337, 2971, 2878, 2363, 1640, 1539, 1445, 1277, 1238
EXAMPLE 91
4-�(S)-N-�(R)-2-ethoxycarbonylamino-3,3-dimethylbutanoyl!prolyl!aminomethylbenzamidoxime (compound No. 409 of Table 1)
NMR (DMSO-d.sup.6) 8.01 (br, 1H), 7.59 (d, 2H), 7.21 (d, 2H), 7.19-7.15 (m,1H), 5.73 (br, 2H), 4.36-4.24 (m, 4H), 4.0-3.60 (m, 4H), 2.10-1.80 (m, 5H),1.06 (t, 3H), 0.96 (s, 9, H)
IR: 3345, 2966, 2364, 1647, 1535, 1443, 1240
EXAMPLE 92
4-�(S)-N-�(R)-2-ethoxycarbonylamino-heptanoyl) prolyl!aminomethylbenzamidoxime (compound No. 411 of Table 1)
NMR (CDCl.sub.3) 7.63 (m, 1H), 7.51 (d, 2H), 7.20 (d, 2H), 5.85 (d, 2H), 4.99 (br, 1H), 4.67-4.58 (m, 2H), 4.35-4.28 (m, 2H), 3.99 (br, 1H), 3.86-3.80 (m, 1H), 3.58-3.50 (m, 2H), 2.31 (br, 1H), 2.07-1.90 (m, 3H), 1.80-1.50 (m, 2H), 1.40-1.10 (m, 5H), 1.03 (t, 3H), 1.01 -0.84 (q13H)
IR: 3347, 2961, 2363, 2342, 1641, 1541, 1447, 1263, 1049
EXAMPLE 93
4-�(S)-N-�(R)-2-t-butyloxycarbonylamino-heptanoyl!prolyl!aminomethylbenzamidoxime (compound No. 412 of Table 1)
NMR (CDCl.sub.3) 7.74-7.70 (m, 1H), 7.49 (d, 2H), 7.27 (t, 1H), 7.20 (d, 2H), 5.43 (d, 1H), 4.93 (br, 2H), 4.65 (d, 1H), 4.48-4.25 (m, 3H), 3.93 (br, 1H), 3.50 (q, 1H), 2.40-2.30 (m, 1H), 2.10-1.90 (m, 3H), 1.70-1.50 (m, 2H), 1.42-1.21 (m, 13H), 0.92-0.80 (m, 3H)
IR: 3337, 2961, 2934, 2363, 1641, 1535, 1449, 1368, 1165
EXAMPLE 94
4-�(S)-N-�(R)-2-ethoxycarbonylamino-4,4-dimethylpentanoyl!prolyl!aminomethylbenzamidoxime (compound No. 418 of Table 1)
NMR (CDCl.sub.3) 7.58-7.51 (m, 1H), 7.53 (d, 2H), 7.20 (d, 2H), 5.87 (d, 1H), 5.01 (br, 2H), 4.64-4.56 (m, 2H), 4.40 (q, 1H), 4.26 (dd, 1H), 4.10-4.00 (m, 1H), 3.84-3.78 (m, 1H), 3.53-3.47 (m, 2H), 2.32 (br, 1H), 2.10-1.90 (m, 3H), 1.61 (d, 2H), 1.00 (t, 3H), 0.97 (s, 9H)
IR: 3324, 2957, 2263, 2342, 1642, 1541, 1445, 1248, 1059
EXAMPLE 95
4-�(S)-N-�(R)-N'-(ethoxycarbonylmethyl)oxycarbonyl-phenylalanyl!prolyl!aminomethylbenzamidoxime (compound No. 984 of Table 1)
NMR (CDCl.sub.3) 7.54 (d, 2H), 7.4 1 (br, 1H), 7.28-7.20 (m, 8H), 6.70 (d, 1H), 5.09 (br, 2H), 4.66 (dd, 1H), 4.60-4.55 (m, 2H), 4.22-4.0 0 (m, 4H), 4.03 (q, 2H), 3.62 (br, 1H), 3.10-3.02 (m, 2H), 2.60-2.40 (m, 1H), 2.14 (br, 1H), 2.00-1.50 (m, 3H), 1.22 (t, 3H)
IR: 3356, 3063, 2980, 2364, 1717, 1641, 1539, 1451, 1213, 702
EXAMPLE 96
4-�(S)-N-�(R)-2-ethoxycarbonylamino-cyclohexylacetyl!prolyl!aminomethylbenzamidoxime (compound No. 985 of Table 1)
NMR (CDCl.sub.3) 7.52 (d, 2H), 7.54-7.50 (m, 1H), 7.20 (d, 2H), 6.03 (br, 1H), 4.97 (br, 2H), 4.68 (q, 2H), 4.22 (dd, 1H), 4.12-4.03 (m, 2H), 3.64-3.47 (m, 1H), 3.20 (s, 3H), 2.32 (br, 1H), 2.05-1.60 (m, 9H), 1.28-0.97 (m, 6H)
IR: 3343, 2928, 2853, 2365, 1639, 1541, 1449, 1260
EXAMPLE 97
4-�(S)-N-�(R)-2-ethoxycarbonylamino-2'-thienylacetyl!prolyl!aminomethylbenzamidoxime (compound No. 986 of Table 1)
NMR (CDCl.sub.3) 7.80-7.60 (m, 1H), 7.46 (dd, 2H), 7.40-6.95 (m, 5H), 6.13 (dd, 1H), 5.71 (dd, 1H), 4.99 (br, 2H), 4.75-4.20 (m, 3H), 4.00-3.80 (m, 2H), 3.70-3.50 (m, 1H), 3.40-3.30 (m, 1H), 2.40-1.80 (m, 4H), 1.16 (dt, 3H)
IR: 3337, 2978, 2364, 1641, 1524, 1443, 1240, 1057, 710
EXAMPLE 98
4-�(S)-N-�(R)-2-ethoxycarbonylamino-4'-fluorophenylacetyl!prolyl!aminomethylbenzamidoxime (compound No. 987 of Table 1)
NMR (CDCl.sub.3) 7.80 (t, 1H), 7.46-7.27 (m, 4H), 7.19-6.92 (m, 4H), 6.19-6.15 (m, 1H), 5.50 (dd, 1H), 5.02 (br, 2H), 4.70-4.20 (m, 3H), 4.10-3.70 (m, 4H), 3.22-3.15 (m, 1H), 2.25-1.80 (m, 4H), 1.16 (dt, 3H)
IR: 3345, 3073, 2980, 2363, 2344, 1641, 1510, 1143
EXAMPLE 99
4-�(S)-N-�(R)-N'-benzyloxycarbonyl-phenylalanyl!prolyl!aminomethylbenzamidoxime (compound No. 988 of Table 1)
NMR (CDCl.sub.3) 7.50 (d, 2H), 7.49-7.30 (m, 1H), 7.26-7.12 (m, 12H), 6.40-6.10 (m, 1H), 4.85 (br, 2H), 4.90-4.70 (m, 1H), 4.55-4.40 (m, 4H), 4.30-4.20 (m, 1H) 3.70-3.60 (m, 1H), 3.03-2.95 (m, 1H), 2.20-2.15 (m, 1H),2.00-1.45 (m, 3H)
EXAMPLE 100
4-�(S)-N-(R)-2-t-butyloxycarbonylamino-4,4-dimethylpentanoyl!prolyl!aminomethylbenzamidoxime (compound No. 989 of Table 1)
NMR (CDCl.sub.3) 7.67 (t, 1H), 7.53 (d, 2H), 7.22 (d, 2H), 5.34 (d, 1H), 4.91 (br, 2H), 4.65 (d, 1(H), 4.42-4.34 (m, 3H), 4.00-3.90 (m, 1H), 3.48 (q, 1H), 2.40-2.30 (m, 1H), 2.02-1.95 (m, 3H), 1.56-1.53 (m, 2H), 1.31 (s,9H), 0.98 (s, 9H)
IR: 3345, 2959, 2367, 1641, 1535, 1446, 1367, 1167
EXAMPLE 101
4-�(S)-N-�(R)-N'-dimethylcarbamoyl-phenylalanyl!prolyl!aminomethylbenzamidoxime (compound No. 990 of Table 1)
NMR (DMSO-d.sup.6) 9.56 (s, 1H), 8.11 (t, 1H), 7.56 (d, 2H), 7.18 (d, 2H), 7.29-7.16 (m, 5H 6.70 (d, 1H), 5.74 (br, 2H), 4.40-4.05 (m, 4H), 2.94 (d, 2H), 2.93-2.70 (m, 2H), 2.60 (s, 6H), 1.90-1.60 (m, 4H)
IR: 3306, 2932, 2880, 2363, 2341, 1634, 1541, 1453
EXAMPLE 102
4-�(S)-N-�(S)-N'-benzyloxycarbonyl-.beta.-t-butylaspartyl!prolyl!aminomethylbenzamidoxime (compound No. 991 of Table 1)
NMR (CDCl.sub.3) 7.63 (br, 1H), 7.51 (d, 2H), 7.33-7.26 (m, 5H), 7.18 (d, 2H), 6.07 (d, 1H), 5.08 (dd, 2H), 4.92 (br, 2H), 4.90-4.70 (m, 1H), 4.66 (d, 1H), 4.40 (d, 2H), 3.90-3.80 (m, 2H), 3.0-2.90 (m, 1H), 2.55 (dd, 1H),2.35-2.20 (m, 1H), 2.08-1.90 (m, 3H), 1.25 (s, 9H)
IR: 3364, 3063, 2978, 2363, 2343, 2343, 1717, 1641, 1539, 1450, 1369, 1253,
EXAMPLE 103
Trans-4-�(S)-N-�(R)-N'-ethoxycarbonyl-O-t-butoxy-seryl!prolyl!aminomethylcyclohexanecarboxamidoxime (compound No. 485 of Table 1)
NMR (CDCl.sub.3) 7.16 (m, 1H), 5.53 (m, 1H), 4.60-4.53 (m, 2H), 4.47 (s, 2H), 4.13-4.06 (m, 2H), 3.76 (br, 2H), 3.60-3.50 (m, 2H), 3.07 (br, 2H), 2.41 (m, 2H), 2.04-1.20 (m, 12H), 1.27 (t, 3H), 1.16 (s, 9H), 1.03-0.94 (m, 2H)
IR: 3352, 2930, 1701, 1651, 1541, 1448, 1259, 1053, 754
EXAMPLE 104
Trans-4-�(S)-N-�(R)-N'-isopropoxycarbonyl-O-t-butylseryl!prolyl!aminomethylcyclohexanecarboxamidoxime (compound No. 486 of Table 1)
NMR (CDCl.sub.3) 7.19 (m, 1H), 5.40 (d, 1H), 4.87 (m, 1H), 4.61-4.53 (m, 2H), 4.47 (br, 2H), 3.75 (m, 2H), 3.60-3.40 (m, 2H), 3.08 (t, 2H), 2.40 (m, 1H), 2.20-1.20 (m, 12H), 1.21 (dd, 6H), 1.19 (s, 9H), 1.10-0.90 (m, 2H)
IR: 3356, 2976, 1697, 1649, 1541, 1448, 1261, 1190, 1109, 1022
EXAMPLE 105
Trans-4-�(S)-N-�(R)-N'-ethoxycarbonyl-O-t-(1',1'-dimethylpropyl!seryl)prolyl!aminomethylcyclohexanecarboxamidoxime (compound No. 487 of Table 1)
NMR (CDCl.sub.3) 7.14 (m, 1H), 5.51 (d, 1H), 4.60-4.50 (m, 2H), 4.48 (br, 2H), 4.09 (m, 2H), 3.78 (m, 2H), 3.55-3.45 (m, 2H), 3.06 (m, 2H), 2.35 (m,1H), 2.20-0.90 (m, 16H), 1.24 (t, 3H), 1.10 (s, 6H), 0.82 (t, 3H)
IR: 3346, 2976, 2930, 1649, 1543, 1448, 1261, 1176, 1095, 1055
EXAMPLE 106
Trans-4-�(S)-N-�(R)-N'-isopropoxycarbonyl-O-(1',1'-dimethylpropyl)seryl!prolyl!aminomethylcyclohexanecarboxamidoxime (compound No. 488 of Table 1)
NMR (CDCl.sub.3) 7.18 (m, 1H), 5.38 (d, 1H), 4.86 (m, 1H), 4.61-4.50 (m, 2H), 4.47 (br, 2H), 3.77 (m, 2H), 3.57-3.42 (m, 2H), 3.06 (t, 2H), 2.39 (m, 1H), 2.20-0.90 (m, 16H), 1.23 (dd, 6H), 1.10 (s, 6H), 0.82 (t, 3H)
IR: 3346, 2976, 1703, 1651, 1541, 1448, 1263, 1178, 1109, 1030
EXAMPLE 107
Trans-4-�(S)-N-�(R)-N'-isopropoxycarbonyl-O-(1'-ethyl-1'-methyl-propyl)seryl!prolyl!aminomethylcyclohexanecarboxamidoxime (compound No. 490 of Table 1)
NMR (CDCl.sub.3) 7.17 (br, 1H), 5.35 (br, 1H), 4.86 (m, 1H), 4.60-4.50 (m, 2H), 4.47 (br, 2H), 3.78 (m, 2H), 3.53-3.38 (m, 2H), 3.07 (t, 2H), 2.37-1.20 (m, 17H), 1.23 (t, 6H), 1.06 (s, 3H), 1.06-0.82 (m, 2H), 0.79 (t, 6H)
IR: 3350, 2976, 2932, 1651, 1541, 1450, 1375, 1263, 1109, 1026
EXAMPLE 108
Trans-4-�(S)-N-�(R)-N'-ethoxycarbonyl-S-t-butyl-cystinyl!prolyl!aminomethylcyclohexanecarboxamidoxime (compound No. 492 of Table 1)
NMR (CDCl.sub.3) 7.27 (m, 1H), 5.81 (m, 1H), 4.60-4.40 (m, 2H), 4.88 (br, 2H), 4.11 (m, 2H), 3.87 (m, 1H), 3.68 (m, 1H), 3.06 (m, 2H), 2.90-2.70 (m,2H), 2.37 (m, 1H), 200-1.20 (m, 12H), 1.32 (s, 9H), 1.25 (t, 3H), 1.10-0.90(m, 2H)
IR: 3346, 2930, 1699, 1649, 1541, 1448, 1257, 1163, 1051, 929
EXAMPLE 109
Trans-4-�(S)-N-�(R)-2-ethoxycarbonylamino-3-isopropylthio-3-methylbutanoyl!prolyl!aminomethylcyclohexanecarboxamidoxime (compound No. 497 of Table 1)
NMR (CDCl.sub.3) 7.16 (m, 1H), 5.62 (m, 1H), 4.61 (d, 1H), 4.47 (br, 2H), 4.35 (d, 1H), 4.12 (m, 2H), 3.96 (m, 1H), 3.76 (m, 1H), 3.10 (m, 1H), 3.00(m, 2H), 2.38 (m, 1H), 2.00-1.20 (m, 12H), 1.47 (s, 3H), 1.40 (s, 3H), 1.33-1.25 (m, 9H), 1.00-0.90 (m, 2H)
IR: 3354, 2928, 1653, 1541, 1446, 1367, 1302, 1251, 1155, 1055
EXAMPLE 110
Trans-4-�(S)-N-�(S)-N'-t-butyloxycarbonyl-seryl!prolyl!aminomethylcyclohexanecarboxamidoxime (compound No. 992 of Table 1)
NMR (CDCl.sub.3) 7.76 (br, 1H), 6.10 (br, 1H), 5.40 (br, 1H), 4.60 (br, 4H), 3.96 (br, 4H), 3.16-1.21 (m, 15H), 1.40 (s, 9H), 0.99 (br, 2H)
IR: 3314, 2978, 1691, 1639, 1541, 1450, 1367, 1165, 1049
EXAMPLE 111
Trans-4-�(S)-N-�(R)-N'-isopropoxycarbonyl-O-t-butyl-threonyl!prolyl!aminomethylcyclohexanecarboxamidoxime (compound No. 993 of Table 1)
NMR (CDCl.sub.3) 7.24 (m, 1H), 5.43 (d, 1H), 4.85 (m, 1H), 4.57 (d, 1H), 4.47 (br, 2H), 4.23 (t, 1H), 3.92 (t, 1H), 3.80-3.70 (m, 2H), 3.06 (m, 2H), 2.36 (m, 1H), 2.00-1.20 (m, 12H), 1.23 (s, 9H) 1.23 (dd, 6H), 1.15 (d, 3H), 1.10-0.90 (m, 2H)
IR: 3354, 2978, 1699, 1649, 1543, 1448, 1373, 1257, 1192, 1111, 1032
EXAMPLE 112
Trans-4-�(S)-N-�(R)-2-acetoxy-cyclohexylacetyl!prolyl!aminomethylcyclohexanecarboxamidoxime (compound No. 994 of Table 1)
NMR (CDCl.sub.3) 6.80 (br, 1H), 4.61 (t, 2H), 4.49 (br, 2H), 3.90-3.84 (m, 1H), 3.51-3.40 (m, 1H), 3.10-2.85 (m, 2H), 2.38 (br, 1H), 2.11 (s, 3H), 2.06-0.80 (m, 25H)
IR: 3484, 3389, 2928, 2855, 1725, 1649, 1451, 1250
EXAMPLE 113
Trans-4-�(S)-N-�(R)-N'-isopropoxycarbonyl-O-(1'-methylcyclopentyl)seryl!prolyl!aminomethylcyclohexanecarboxamidoxime (compound No. 995 of Table 1)
NMR (CDCl.sub.3) 7.18 (m, 1H), 5.42 (m, 1H), 4.85 (m, 2H), 4.60-4.49 (m, 4H), 3.73 (m, 2H), 3.57-3.42 (m, 2H), 3.08 (m, 1H), 2.40 (m, 1H), 2.04-1.20 (m, 21H), 1.27-1.20 (m, 9H), 1.03-0.94 (m, 2H)
IR: 3356, 2932, 1695, 1653, 1541, 1448, 1263, 1111, 1030, 918
According to the same procedures as that described in Example 48, the following compounds of Examples 114 to 122 were synthesized.
EXAMPLE 114
Trans-4-�(S)-N-�(R)-2-t-butyloxycarbonylamino-4,4-dimethylpentanoyl!prolyl!aminomethylcyclohexanecarboxamide O-methoxycarbonyloxime (compound No. 533 of Table 1)
NMR (CDCl.sub.3) 7.14 (br, 1H), 5.04 (d, 1H), 4.74 (br, 1H), 4.58 (d, 1H), 4.40-4.30 (m, 1H), 4.00-3.85 (m, 1H), 3.94 (s, 3H), 3.46 (q, 1H), 3.30-3.20 (m, 1H), 2.95-2.88 (m, 1H), 2.42 (br, 1H), 2.26 (t, 1H), 2.00-1.73 (m, 11H), 1.54-1.26 (m, 4H), 1.43 (s, 9H), 1.00 (s, 9H)
IR: 3347, 2955, 2870, 1765, 1645,1539, 1443, 1254, 1169, 879
EXAMPLE 115
Trans-4-�(S)-N-�(R)-N'-isopropoxycarbonyl-leucyl!prolyl!aminomethylcyclohexanecarboxamide O-methoxycarbonyloxime (compound No. 540 of Table 1)
NMR (CDCl.sub.3) 7.11 (br, 1H), 5.18 (d, 1H), 4.90-4.70 (m, 1H), 4.77 (br, 2H), 4.56 (d, 1H), 4.40-4.30 (m, 1H), 3.95-3.86 (m, 1H), 3.85 (s, 3H), 3.46 (q, 1H), 3.20-2.95 (m, 2H), 2.40-2.30 (m, 1H), 2.30-2.10 (m, 1H), 2.00-1.20 (m, 13H), 1.23 (dd, 6H), 1.04-0.89 (m, 8H)
IR: 3354, 2957, 2932, 2872, 2363, 2341, 1763, 1643, 1541, 1443, 1260
EXAMPLE 116
Trans-4-�(S)-N-�(R)-N'-ethoxycarbonyl-O-t-butyl-seryl!prolyl!aminomethylcyclohexanecarboxamide O-methoxycarbonyloxime (compound No. 996 of Table 1)
NMR (CDCl.sub.3) 7.20 (m, 1H), 5.34 (m, 1H), 4.70 (s, 2H), 4.61 (m, 1H), 4.50 (m, 1H), 4.12-4.06 (m, 2H), 3.85 (s, 3H), 3.74 (m, 2H), 3.60-3.39 (m,2H), 3.06 (m, 2H), 2.41-1.20 (m, 13H), 1.25 (t, 3H), 1.16 (s, 9H), 1.08-0.94 (m, 2H)
IR: 3348, 2976, 1768, 1703, 1645, 1541, 1442, 1255, 1053, 879, 752
EXAMPLE 117
Trans-4-�(S)-N-�(R)-2-hydroxy-4-methyl-pentanoyl!prolyl!aminomethylcyclohexanecarboxamide O-methoxycarbonyloxime (compound No. 997 of Table 1)
NMR (CDCl.sub.3) 7.07 (m, 1H), 4.73 (br, 2H), 4.52 (d, 1H), 4.23 (m, 4H), 3.56 (m, 1H), 3.40 (m, 1H), 3.13 (m, 3H), 2.41 (m, 1H), 2.30-0.90 (m, 15H), 1.33 (t, 3H), 0.97 (dd, 6H)
IR: 3346, 2932, 1759, 1641, 1450, 1369, 1251,1078, 920, 846
EXAMPLE 118
Trans-4-�(S)-N-�(R)-N'-ethoxycarbonyl-O-t-butyl-seryl!prolyl!aminomethylcyclohexanecarboxamide O-acetyloxime (compound No. 998 of Table 1)
NMR (CDCl.sub.3) 7.20 (m, 1H), 5.33 (m, 1H), 4.69 (s, 2H), 4.60 (m, 1H), 4.51 (m, 1H), 4.17-4.07 (m, 2H), 3.77-3.65 (m, 2H), 3.60-3.46 (m, 2H), 3.09-3.08 (m, 2H), 2.40-1.00 (m, 13H), 2.15 (s, 3H), 1.25 (t, 3H), 1.16 (s, 9H), 1.14-0.94 (m, 2H) IR: 3346, 2976, 1641, 1541, 1448, 1234, 1053, 754
EXAMPLE 119
Trans-4-�(S)-N-�(R)-N'-isopropoxycarbonyl-O-t-butyl-seryl!prolyl!aminomethylcyclohexanecarboxamide O-methoxycarbonyloxime (compound No. 999 of Table 1)
NMR (CDCl.sub.3) 7.23 (t, 1H), 5.26 (d, 1H), 4.85 (m, 1H), 4.71 (m, 1H), 4.59 (d, 1H), 4.49 (m, 1H), 3.85 (s, 3H), 3.73 (m, 2H), 3.61-3.49 (m, 2H),3.06 (t, 2H), 2.36 (m, 1H), 2.26 (t, 3H), 2.10-1.20 (m, 11H), 1.21 (dd, 6H), 1.16 (s, 9H), 1.10-0.90 (m, 2H)
IR: 3348, 2978, 1768, 1703, 1649, 1541, 1444, 1259, 1192, 1109
EXAMPLE 120
4-N-ethoxycarbonyl-amidino-�(S)-N-�(R)-2-methylsulfonylamino-4,4-dimethylpentanoyl!prolyl!aminomethylbenzene (compound No. 1000 of Table 1)
NMR (CDCl.sub.3) 7.29 (d, 2H), 7.30 (d, 2H), 7.23 (t, 1H), 5.53 (br, 1H), 4.52-4.37 (m, 2H), 4.24-4.17 (m, 2H), 4.2 0 (q, 2H), 3.90-3.80 (m, 1H), 3.50-3.40 (m, 1H), 2.77 (s, 3H), 2.28-2.20 (m, 4H), 1.84 (br, 2H), 1.60-1.40 (m, 2H), 1.34 (t, 3H), 1.02 (s, 9H)
IR: 3378, 2957, 2876, 2364, 2230, 1628, 1267, 1147
EXAMPLE 121
4-N-methoxycarbonyl-amidino-�(S)-N-�(R)-2-methylsulfonylamino-cyclohexylacetyl!prolyl!aminomethylbenzene (compound No. 1001 of Table 1)
NMR (CDCl.sub.3) 7.78 (d, 2H), 7.29 (d, 2H), 7.27 (t, 1H), 5.49 (d, 1H), 4.56 (d, 1H), 4.42 (dq, 2H), 3.77 (s, 3H), 3.80-3.70 (m, 2H), 3.60-3.51 (m, 1H), 2.79 (s, 3H), 2.23-1.60 (m, 12H), 1.20-0.95 (m, 5H)
IR: 3376, 2930, 2855, 2365, 1626, 1528, 1501, 1439, 1271, 1144
EXAMPLE 122
Trans-4-N-methoxycarbonyl-amidino-�(S)-N-�(R)-2-ethoxycarbonylamino-4,4-dimethylpentanoyl!prolyl!aminomethylcyclohexane (compound No. 599 of Table 1)
NMR (CDCl.sub.3) 7.08 (br, 1H), 5.17 (d, 1H), 4.56 (d, 1H), 4.50-4.40 (m, 1H), 4.20-3.80 (m, 3H), 3.70 (s, 3H), 3.47 (q, 1H), 3.20-3.00 (m, 2H), 2.45-2.30 (m, 1H), (m, 15H), 1.24 (t, 3H), 0.99 (s, 9H), 1.10-0.89 (m, 2H)
IR: 3366, 2953, 2365, 1780, 1697, 1640, 1533, 1441, 1271, 1055
According to the same procedures as that described in Example 52, the following compounds of Examples 123 to 125 were synthesized.
EXAMPLE 123
Trans-4-amino-�(S)-N-�(R)-2-carboxymethylsulfonylamino-heptanoyl!prolyl!aminomethylcyclohexane (compound No. 791 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 7.97 (m, 2H), 7.57 (m, 1H), 4.19 (m, 2H), 4.01 (d, 1H), 3.80 (d, 1H), 3.68 (m, 1H), 3.50 (m, 1H), 2.88 (m, 3H), 2.04 (m, 1H), 1.90(m, 5H), 1.73 (m, 4H), 1.58-1.13 (m, 12H), 1.00-0.84 (m, 5H)
IR: 3387, 2934, 1726, 1637, 1553, 1452, 1325, 1159, 1090, 1046, 604
EXAMPLE 124
Trans-4-amino-�(S)-N-�(R)-N'-methylsulfonyl-O-methyltyrosyl!prolyl!aminomethylcyclohexane (compound No. 1002 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 8.10 (br, 3H), 7.77 (t, 1H), 7.67 (d, 1H), 7.17 (d, 2H),6.87 (d, 2H), 4.25-4.16 (m, 1H), 3.75 (br, 2H), 3.73 (s, 3H), 3.57-3.40 (m,1H), 3.00-2.70 (m, 5H), 2.77 (s, 3H), 2.00-1.71 (m, 8H), 1.40-1.20 (m, 3H),1.00-0.80 (m, 2H)
IR: 3385, 2936, 2363,1639, 1514, 1450, 1304, 1248, 1149
EXAMPLE 125
Trans-4-amino-�(S)-N-�(R)-N'-ethoxycarbonyl-O-t-butyloxy-seryl!prolyl!aminomethylcyclohexane (compound No. 1003 of Table 1) hydrochloride
NMR (DMSO-d.sup.6) 8.29 (s, 3H), 7.20 (s, 1H), 5.69 (d, 1H), 4.58-4.47 (m, 2H), 4.12 (m, 2H), 3.82 (m, 1H), 3.61-3.48 (m, 2H), 3.09 (m, 2H), 2.32-0.86 (m, 15H), 1.27 (t, 3H), 1.16 (s, 9H)
IR: 3358, 2974, 1645, 1541, 1448, 1257, 1192, 1053
According to the same procedures as that described in Example 67, the following compounds 126 to 130 were synthesized.
EXAMPLE 126
Trans-4-(5-methyl-1,3-dioxo-2-on-4-ylmethyl)amino-�(S)-N-�(R)-2hydroxy-cyclohexylacetyl!prolyl!aminomethylcyclohexane (compound No. 966 of Table 1)
NMR (CDCl.sub.3) 7.08 (m, 1H), 4.54 (d, 1H), 4.06 (m, 1H), 3.59 (m, 1H), 3.49 (s, 2H), 3.46 (m, 1H), 3.07 (m, 2H), 2.48 (m, 2H), 2.11 (s, 3H), 2.01(m, 2H), 1.90-1.70 (m, 10H), 1.58 (m, 3H), 1.41-0.94 (m, 10H)
IR: 3387, 2928, 2855, 1821, 1736, 1638, 1543, 1451, 1387, 1223, 1107, 999, 712
EXAMPLE 127
Trans-4-(5-methyl-1,3-dioxo-2-on-4-ylmethyl)amino-�(S)-N-�(R)-N'-methylsulfonyl-phenylalanyl!prolyl!aminomethylcyclohexane (compound No. 967 of Table 1)
NMR (CDCl.sub.3) 7.35-7.20 (m, 5H), 6.71 (t, 1H), 5.48 (d, 1H), 4.44 (m, 1H), 4.25 (m, 1H), 3.60 (m, 1H), 3.48 (s, 2H), 3.09 (m, 1H), 2.96 (m, 3H),2.78 (s, 3H), 2.77 (m, 1H), 2.50 (m, 1H), 2.20 (m, 1H), 2.11 (s, 3H), 1.88-1.56 (m, 8H), 1.42 (m, 1H), 1.24 (m, 2H), 0.96 (m, 2H)
IR: 3387, 2930, 1819, 1736, 1649, 1541, 1499, 1451, 1318, 1223, 1152, 999
EXAMPLE 128
Trans-4-(5-methyl-1,3-dioxo-2-on-4-ylmethyl)amino-�(S)-N-�(R)-2ethoxycarbonylamino-cyclohexylacetyl!prolyl!aminomethylcyclohexane (compound No. 1004 of Table 1)
NMR (CDCl.sub.3) 7.11 (m, 1H), 5.31 (m, 1H), 4.58 (d, 1H), 4.10 (t, 2H), 4.04 (m, 1H), 3.94 (m, 1H), 3.56 (m, 1H), 3.49 (s, 2H), 3.04 (m, 2H), 2.52(m, 1H), 2.36 (m, 2H), 2.12 (s, 3H), 2.00 (m, 3H), 1.92-1.62 (m, 1OH), 1.43(m, 2H), 1.25 (q, 3H), 1.22 (m, 4H), 1.06 (m, 4H)
IR: 3353, 2930, 2855, 1823, 1653, 1537, 1449, 1223, 1040, 999, 772, 627
EXAMPLE 129
Trans-4-(5-methyl-1,3-dioxo-2-on-4-ylmethyl)amino-�(S)-N-�(R)-2isopropoxyamino-4,4-dimethyl prolyl!aminomethylcyclohexane (compound No. 1005 of Table 1)
NMR (CDCl.sub.3) 7.10 (m, 1H), 5.07 (d, 1H), 4.83 (m, 1H), 4.57 (d, 1H), 4.40 (m, 1H), 3.96 (m, 1H), 3.48 (s, 2H), 3.45 (m, 2H), 3.04 (m, 2H), 2.50(m, 1H), 2.39 (m, 1H), 2.11 (s, 3H), 2.00 (m, 3H), 1.83 (m, 3H), 1.69 (m, 5H), 1.57-1.42 (m, 3H), 1.25 (d, 3H), 1.22 (d, 3H), 1.00 (s, 9H)
IR: 3349, 2934, 2872, 1823, 1653, 1537, 1445, 1225, 1047, 999, 712, 627
EXAMPLE 130
Trans-4-(5-methyl-1,3-dioxo-2-on-4-ylmethyl)amino-�(S)-N-�(R)-2methylsulfonylamino-cyclohexylacetyl!prolyl!aminomethylcyclohexane (compound No. 1006 of Table 1)
NMR (CDCl.sub.3) 6.69 (t, 1H), 5.26 (d, 1H), 3.82 (m, 2H), 3.54 (m, 2H), 3.49 (s, 2H), 3.13 (m, 1H), 3.00 (m, 1H), 2.96 (s, 3H), 2.51 (m, 1H), 2.30(m, 1H), 2.11 (s, 3H), 2.02 (m, 4H), 1.80 (m, 9H), 1.61 (m, 2H), 1.43 (m, 1H), 1.20 (m, 5H), 0.97 (m, 3H)
IR: 3376, 2930, 2855, 1642, 1536, 1451, 1352, 1154, 984, 760, 619, 517
EXPERIMENTAL EXAMPLE 1
Determination of antithrombin activity
(i) The measuring method for hydrolysis inhibition of synthetic substrate (S-2238)
S-2238 (manufactured by Kabi Co.) is dissolved in a Tris hydrochloric acid buffer solution (pH: 8.3) to prepare a S-2238-0.4M Tris hydrochloric acid solution having a concentration of 80 .mu.m. To 175 .mu.l of the solution,an aqueous solution of a compound of the present invention (515 .mu.l) is added. After incubating at 37.degree. C. for one minute, 10 .mu.l of a bovine thrombin solution (4.4 units/ml, manufactured by Mochida Co., Ltd.)is added. A hydrolysis reaction rate of the substrate is determined by measuring a change in absorbance of 405 nm at 37.degree. C.
The inhibitor concentration exhibiting an absorbance which is half as largeas that obtained in case of adding no inhibitor (compound of the present invention) was determined as I.sub.50 (.mu.m).
(ii) The measuring method for coagulation inhibition of rat plasma The compound of the present invention is dissolved in water or saline to form a solution of a total volume of 0.1 ml. To the solution, 0.1 ml of rat plasma is added and the mixture is incubated at 37.degree. C. for 30 seconds. Then, 0.1 ml of bovine thrombin (8 units/ml, Mochida Co., Ltd.) is added and the coagulation time is measured at 37.degree. C. The concentration of the inhibitor (i.e., the compound of the present invention) which doubles the coagulation time that obtained in the absenceof the inhibitor was determined as I.sub.50 (.mu.m).
(iii) The measuring method for antithrombin activity of rat plasma on oral administration
To a rat abstained from bait overnight, an aqueous solution or suspension of the present compound (inhibitor) (30 mg/kg) is orally administered using an oral sound.
After one hour, 2 ml of blood is collected from cava abdominalis and the antithrombin activity in plasma is measured using a method of the above item (ii). As a control experiment, the coagulation time of blood collected from a rat which has not been administered the inhibitor was measured. The extension effect on the coagulation time is represented by the numerical value obtained by comparing the data with those obtained in control experiment, wherein the numerical value obtained in the control experiment was assumed to be 1.
EXPERIMENTAL EXAMPLE 2
Determination of Antitrypsin activity
(i) The measuring method for hydrolysis inhibition of synthetic substrate (S-2222)
S-2222 (manufactured by Kabi Co.) is dissolved in a Tris hydrochloric acid (pH: 8.3) to prepare a S-2222-0.4M Tris hydrochloric acid solution having a concentration of 400 .mu.m. To the solution (175 .mu.l), 515 .mu.l of a solution of a compound of the present invention is added. After incubatingat 37.degree. C. for one minute, 10 .mu.l of a bovine trypsin solution (1 to 2 mg/ml, manufactured by Sigma Co.) is added. A hydrolysis reaction rate of the substrate is determined by measuring a change in absorbance of405 nm at 37.degree. C.
The inhibitor concentration exhibiting an absorbance which is half as largeas that obtained in case of adding no inhibitor (compound of the present invention) was determined as I.sub.50 (.mu.m).
The results are shown in Table 2.
TABLE 2______________________________________ ThrombinAntithrombin activity coagulationI.sub.50 (.mu.m) time extension Synthetic coefficient onExample substrate Rat plasma Antitrypsin oralNo. method method activity I.sub.50 (.mu.m) administration______________________________________ 1 0.046 5.97 2 0.030 8.75 3 0.027 4.46 4 0.0076 0.021 0.040 6.70 5 0.048 6 0.056 3.16 7 0.030 8 0.122 9 0.1110 0.1712 0.08313 0.72 0.5915 0.011 0.038 2.216 0.021 1.717 0.015 0.053 3.218 0.06019 0.03120 0.02821 0.021 1.022 0.014 0.9423 0.017 0.058 3.624 3.2825 >300 2.8226 4.1627 3.5228 4.3530 2.7531 2.7732 3.5833 3.9935 3.7236 2.8537 4.3739 2.3740 2.7041 2.9442 4.3643 3.0946 2.1647 2.3448 4.9149 7.1250 3.5051 2.8052 0.13 0.045 14 4.1053 0.081 0.059 1.454 0.2356 0.13 0.080 14 2.1057 0.08258 0.097 2.3561 0.05662 0.088 2.1864 0.13 1.2565 3.6767 0.56 0.081 20______________________________________
EXPERIMENTAL EXAMPLE 3
Acute toxicity test
Acute toxicity was determined in rat. An approximate lethal dose was mined by conducting an oral acute toxicity test using rats. The results are deter in Table 3.
TABLE 3______________________________________ Approximate lethal dose mg/kgExample No. Male Female______________________________________ 4 750 150052 Not less than 2000 Not less than 200033 Not less than 2000 Not less than 200037 Not less than 2000 Not less than 2000______________________________________
Claims
  • 1. A prolineamide derivative represented by the formula (I): ##STR1787## wherein: A is a carbon atom or a nitrogen atom;
  • n is an integer of 0 to 2;
  • a broken line indicates that adjacent carbons are connected by a double or single bond;
  • R.sup.1 is ##STR1788## wherein: D and E independently indicate a single bond or an optionally branched C.sub.1 -C.sub.6 alkylene group;
  • R.sup.4 is a C.sub.1 -C.sub.6 alkyl group;
  • --OR.sup.6,
  • R.sup.6 is a hydrogen atom, a C.sub.1 -C.sub.6 alkyl group, an optionally substituted C.sub.6 -C.sub.10 aryl group, an optionally substituted C.sub.3 -C.sub.8 cycloalkyl group or an optionally substituted C.sub.7 -C.sub.12 aralkyl group;
  • --SR.sup.7,
  • R.sup.7 is a C.sub.1 -C.sub.6 alkyl group, an optionally substituted C.sub.6 -C.sub.10 aryl group, an optionally substituted C.sub.3 -C.sub.8 cycloalkyl group or an optionally substituted C.sub.7 -C.sub.12 aralkyl group;
  • --SOR.sup.8,
  • R.sup.8 is an optionally substituted C.sub.6 -C.sub.10 aryl group or an optionally substituted C.sub.3 -C.sub.8 cycloalkyl group;
  • --SO.sub.2 R.sup.9,
  • R.sup.9 is an optionally substituted C.sub.6 -C.sub.10 aryl group or an optionally substituted C.sub.3 -C.sub.8 cycloalkyl group;
  • --COR.sup.10,
  • R.sup.10 is a hydroxyl group, a C.sub.1 -C.sub.6 alkoxy group, an optionally substituted C.sub.6 -C.sub.10 aryl group or an optionally substituted C.sub.3 -C.sub.8 cycloalkyl group;
  • --NHR.sup.11,
  • R.sup.11 is a C.sub.1 -C.sub.6 alkyl group, an optionally substituted C.sub.6 -C.sub.10 aryl group, an optionally substituted C.sub.3 -C.sub.8 cycloalkyl group or an optionally substituted C.sub.7 -C.sub.12 aralkyl group;
  • --NHCOR.sup.12,
  • R.sup.12 is a C.sub.1 -C.sub.6 alkoxy group, an optionally substituted C.sub.6 -C.sub.10 aryl group, an optionally substituted C.sub.3 -C.sub.8 cycloalkyl group or an optionally substituted C.sub.7 -C.sub.12 aralkyloxy group;
  • --NHSO.sub.2 R.sup.13,
  • R.sup.13 is a C.sub.1 -C.sub.6 alkyl group, an optionally substituted C.sub.6 -C.sub.10 aryl group, an optionally substituted C.sub.3 -C.sub.8 cycloalkyl group, an optionally substituted C.sub.7 -C.sub.12 aralkyl group, or an optionally substituted 5- to 10-membered heterocyclic group;
  • an optionally substituted C.sub.6 -C.sub.10 aryl group;
  • an optionally substituted C.sub.3 -C.sub.8 cycloalkyl group;
  • an optionally substituted 5- to 10-membered heterocyclic group; or
  • --SiR.sup.14 R.sup.15 R.sup.16,
  • R.sup.14, R.sup.15, and R.sup.16 independently indicate a C.sub.1 -C.sub.6 alkyl group;
  • R.sup.5 is a --OR .sup.17,
  • R.sup.17 is a hydrogen atom,
  • --SiR.sup.22 R.sup.23 R.sup.24,
  • R.sup.22, R.sup.23, and R.sup.24 independently indicate a C.sub.1 -C.sub.6 alkyl group,
  • a C.sub.1 -C.sub.6 alkyl group, or
  • an optionally substituted 5- to 10-membered heterocyclic group;
  • --OCOR.sup.18,
  • R.sup.18 is a hydrogen atom, a C.sub.1 -C.sub.6 alkyl group, a C.sub.1 -C.sub.6 alkoxy group, an amino group, a C.sub.1 -C.sub.6 alkylamino group, a C.sub.2 -C.sub.12 dialkylamino group or a C.sub.2 -C.sub.7 alkenylamino group;
  • --NHR.sup.19,
  • R.sup.19 is a hydrogen atom, a C.sub.1 -C.sub.6 alkyl group or an optionally substituted C.sub.7 -C.sub.12 aralkyl group;
  • --NHCOR.sup.20,
  • R.sup.20 is a hydrogen atom, a C.sub.1 -C.sub.6 alkyl group, a C.sub.1 -C.sub.6 haloalkyl group, a C.sub.1 -C.sub.6 alkoxy group, an optionally substituted C.sub.3 -C.sub.8 cycloalkyl group, a C.sub.2 -C.sub.7 carboxyalkyloxy group, a C.sub.2 -C.sub.7 alkenyloxy group, an optionally substituted C.sub.6 -C.sub.10 aryl group, an optionally substituted C.sub.6 -C.sub.10 aryloxy group, a C.sub.3 -C.sub.9 alkoxycarbonylalkoxy group, a C.sub.2 -C.sub.12 dialkylamino group or an optionally substituted C.sub.7 -C,.sub.2 aralkyloxy group; or
  • --NHSO.sub.2 R.sup.21,
  • R.sup.21 is a C.sub.1 -C.sub.6 alkyl group, a C.sub.1 -C.sub.6 haloalkyl group, a C.sub.2 -C.sub.7 carboxylalkyl group, an optionally substituted C.sub.6 -C.sub.10 aryl group, a C.sub.3 -C.sub.9 alkoxycarbonylalkyl group or an optionally substituted C.sub.7 -C.sub.12 aralkyl group; and
  • m is 0 or 1;
  • R.sup.2 is a hydrogen atom or a C.sub.1 -C.sub.6 alkyl group; and
  • R.sup.3 is --C(.dbd.NR.sup.25)NH.sub.2,
  • R.sup.25 is a hydrogen atom, a C.sub.1 -C.sub.6 alkyl group, a C.sub.2 -C.sub.7 acyl group, a C.sub.2 -C.sub.7 acyloxy group, a C.sub.1 -C.sub.6 alkoxy group, a C.sub.2 -C.sub.7 alkoxycarbonyl group, a C.sub.2 -C.sub.7 alkoxycarbonyloxy group, a hydroxyl group or a C.sub.2 -C.sub.7 hydroxyalkylcarbonyloxy group;
  • --NH--C(.dbd.NR.sup.25) NH.sub.2,
  • R.sup.25 is a defined above; or
  • --NHR.sup.26,
  • R.sup.26 is a hydrogen atom, a C.sub.1 -C.sub.6 alkyl group, a C.sub.2 -C.sub.7 acyl group, a C.sub.2 -C.sub.7 alkoxycarbonyl group or a 5-C.sub.1 -C.sub.3 alkyl-1,3-dioxol-2-on-4-ylmethyl group;
  • each of said 5- to 10-membered heterocyclic groups is selected from the group consisting of a furan ring, tetrahydrofuran ring, pyran ring, benzofuran ring, chroman ring, thiophene ring, benzothiophene ring, pyrrole ring, imidazole ring, pyrazole ring, triazole ring, pyridine ring, piperidine ring, pyrazine ring, piperazine ring, pyrimidine ring, indole ring, benzimidazole ring, purine ring, quinoline ring, phthalazine ring, guinazoline ring, cinnoline ring, oxazole ring, thiazole ring or morpholine ring;
  • each of said optional substituents being selected from the group consisting of a C.sub.1 -C.sub.6 alkyl group, a C.sub.1 -C.sub.6 haloalkyl group, a C.sub.1 -C.sub.6 alkoxy group, a hydroxyl group, a carboxyl group, a C.sub.2 -C.sub.7 carboxyalkyl group, a C.sub.2 -C.sub.7 carboxyalkyloxy group, a C.sub.2 -C.sub.7 acyl group, a C.sub.2 -C.sub.7 acyloxy group, a C.sub.2 -C.sub.7 alkoxycarbonyl group, a C.sub.2 -C.sub.7 alkoxycarbonyloxy group, a C.sub.8 -C.sub.13 aralkyloxycarbonyl group, a C.sub.3 -C.sub.9 alkoxycarboxyalkoxy group and a halogen atom;
  • provided that R.sup.3 is --C(.dbd.NR.sup.25)NH.sub.2 (R.sup.25 is a defined above) when A is a nitrogen atom, or a salt or hydrate thereof.
  • 2. The compound according to claim 1, wherein A is a carbon atom.
  • 3. The compound according to claim 1, wherein:
  • n is 1 or 2;
  • R.sup.1 is ##STR1789## wherein: D and E independently indicate a single bond or an optionally branched C.sub.1 -C.sub.6 alkylene group;
  • R.sup.4 is a C.sub.1 -C.sub.6 alkyl group;
  • --OR.sup.6,
  • R.sup.6 is a C.sub.1 -C.sub.6 alkyl group; a C.sub.6 -C.sub.10 aryl group which may be substituted with at least one substituent selected from the group consisting of a C.sub.1 -C.sub.6 alkyl group, a C.sub.1 -C.sub.6 alkoxy group, a halogen atom, a hydroxyl group, a carboxyl group, a C.sub.2 -C.sub.7 alkoxycarbonyl group, a C.sub.2 -C.sub.7 carboxyalkyl group, a C.sub.2 -C.sub.7 acyl group, a C.sub.2 -C.sub.7 acyloxy group, a C.sub.2 -C.sub.7 alkoxycarbonyloxy group, a C.sub.3 -C.sub.9 alkoxycarbonylalkoxy group and a benzyloxycarbonyl group; or a C.sub.7 -C.sub.12 aralkyl group which may be substituted with at least one substituent selected from the group consisting of a C.sub.1 -C.sub.6 alkyl group, a C.sub.1 -C.sub.6 alkoxy group, a halogen atom, a hydroxyl group, a carboxyl group, a C.sub.2 -C.sub.7 alkoxycarbonyl group, a C.sub.2 -C.sub.7 carboxyalkyl group, a C.sub.2 -C.sub.7 acyl group, a C.sub.2 -C.sub.7 acyloxy group, a C.sub.2 -C.sub.7 alkoxycarbonyloxy group, a C.sub.3 -C.sub.9 alkoxycarbonylalkoxy group and a benzyloxycarbonyl group;
  • --SR.sup.7,
  • R.sup.7 is a C.sub.1 -C.sub.6 alkyl group; a C.sub.6 -C.sub.10 aryl group which may be substituted with at least one substituent selected from the group consisting of a C.sub.1 -C.sub.6 alkyl group, a C.sub.1 -C.sub.6 alkoxy group, a halogen atom, a hydroxyl group, a carboxyl group, a C.sub.2 -C.sub.7 alkoxycarbonyl group, a C.sub.2 -C.sub.7 carboxyalkyl group, a C.sub.2 -C.sub.7 acyl group, a C.sub.2 -C.sub.7 acyloxy group, a C.sub.2 -C.sub.7 alkoxycarbonyloxy group, a C.sub.3 -C.sub.9 alkoxycarbonylalkoxy group and a benzyloxycarbonyl group; or a C.sub.7 -C.sub.12 aralkyl group which may be substituted with at least one substituent selected from the group consisting of a C.sub.1 -C.sub.6 alkyl group, a C.sub.1 -C.sub.6 alkoxy group, a halogen atom, a hydroxyl group, a carboxyl group, a C.sub.2 -C.sub.7 alkoxycarbonyl group, a C.sub.2 -C.sub.7 carboxyalkyl group, a C.sub.2 -C.sub.7 acyl group, a C.sub.2 -C.sub.7 acyloxy group, a C.sub.2 -C.sub.7 alkoxycarbonyloxy group, a C.sub.3 -C.sub.9 alkoxycarbonylalkoxy group and a benzyloxycarbonyl group;
  • --COOH;
  • a C.sub.6 -C.sub.10 aryl group which may be substituted with at least one substituent selected from the group consisting of a C.sub.1 -C.sub.6 alkyl group, a C.sub.1 -C.sub.6 alkoxy group, a halogen atom, a hydroxyl group, a carboxyl group, a C.sub.2 -C.sub.7 alkoxycarbonyl group, a C.sub.2 -C.sub.7 carboxyalkyl group, a C.sub.2 -C.sub.7 acyl group, a C.sub.2 -C.sub.7 acyloxy group, a C.sub.2 -C.sub.7 alkoxycarbonyloxy group, a C.sub.3 -C.sub.9 alkoxycarbonylalkoxy group and a benzyloxycarbonyl group;
  • a C.sub.3 -C.sub.8 cycloalkyl group; or
  • --SiR.sup.14 R.sup.15 R.sup.16,
  • R.sup.14, R.sup.15, and R.sup.16 independently indicate a C.sub.1 -C.sub.6 alkyl group;
  • R.sup.5 is --OH,
  • --OCOR.sup.18,
  • R.sup.18 is a C.sub.1 -C.sub.6 alkoxy group or a C.sub.2 -C.sub.7 alkenylamino group;
  • --N H.sub.2 ;
  • --NHCOR.sup.20,
  • R.sup.20 is a C.sub.1 -C.sub.6 alkoxy group, a C.sub.6 -C.sub.10 aryloxy group, a C.sub.3 -C.sub.9 alkoxycarbonylalkoxy group, a C.sub.2 -C.sub.12 dialkylamino group or a C.sub.7 -C.sub.12 aralkyloxy group; or
  • --NHSO.sub.2 R.sup.21,
  • R.sup.21 is a C.sub.1 -C.sub.6 alkyl group, a C.sub.2 -C.sub.7 carboxyalkyl group, a C.sub.6 -C.sub.10 aryl group, a C.sub.3 -C.sub.9 alkoxycarbonylalkyl group or a C.sub.7 -C.sub.12 aralkyl group; and
  • m is 0 or 1;
  • R.sup.2 is a hydrogen atom; and
  • R.sup.3 is --C(.dbd.NR.sup.25)NH.sub.2,
  • R.sup.25 is a hydrogen atom, a C.sub.2 -C.sub.7 alkoxycarbonyl group or a hydroxyl group;
  • --NH--C(.dbd.NR.sup.25)NH.sub.2,
  • R.sup.25 is as defined above; or
  • --NHR.sup.26,
  • R.sup.26 is a hydrogen atom, a C.sub.2 -C.sub.7 alkoxycarbonyl group or a 5-C.sub.1 -C.sub.3 alkyl-1,3-dioxol-2-on-4-ylmethyl group.
  • 4. The compound according to claim 1,
  • wherein:
  • n is 1;
  • R.sup.1 is ##STR1790## wherein D and E independently indicate a single bond or an optionally branched C.sub.1 -C.sub.6 alkylene group;
  • R.sup.4 is a C.sub.1 -C.sub.6 alkyl group;
  • --OR.sup.6,
  • R.sup.6 is a C.sub.6 -C.sub.10 aryl which may be substituted with at least one substituent selected from the group consisting of a C.sub.1 -C.sub.6 alkyl group, a halogen atom, a carboxyl group, a C.sub.2 -C.sub.7 carboxyalkyl group and a benzyloxycarbonyl group or C.sub.7 -C.sub.12 aralkyl group;
  • --SR.sup.7,
  • R.sup.7 is a C.sub.1 -C.sub.6 alkyl group;
  • a C.sub.6 -C.sub.10 aryl group which may be substituted with at least one substituent selected from the group consisting of a C.sub.1 -C.sub.6 alkyl group, a halogen atom, a carboxyl group, a C.sub.2 -C.sub.7 carboxyalkyl group and a benzyloxycarbonyl group; or a C.sub.3 -C.sub.6 cycloalkyl group;
  • R.sup.5 is --OH;
  • NH.sub.2 ;
  • --NHCOR.sup.20,
  • R.sup.20 is a C.sub.1 -C.sub.6 alkoxy group or a C.sub.7 -C.sub.12 aralkyloxy group; or
  • --NHSO.sub.2 R.sup.21,
  • R.sup.21 is a C.sub.1 -C.sub.6 alkyl group or a C.sub.6 -C.sub.10 aryl group; and
  • m is 1;
  • R.sup.2 is a hydrogen atom; and
  • R.sup.3 is --C(.dbd.NR.sup.25)NH.sub.2,
  • R.sup.25 is a hydrogen atom or a hydroxyl group; or
  • --NH.sub.2.
  • 5. The compound according to claim 1, wherein:
  • n is 1;
  • R.sup.1 is ##STR1791## wherein: D is a single bond;
  • E is a single bond or a C.sub.1 -C.sub.6 alkylene group;
  • R.sup.4 is a C.sub.1 -C.sub.6 alkyl group;
  • --OR.sup.6,
  • R.sup.6 is a C.sub.6 -C.sub.10 aryl which may be substituted with at least one substituent selected from the group consisting of a C.sub.1 -C.sub.6 alkyl group, a halogen atom, a carboxyl group, a C.sub.2 -C.sub.7 carboxyalkyl group and a benzyloxycarbonyl group or C.sub.7 -C.sub.12 aralkyl group;
  • --SR.sup.7,
  • R.sup.7 is a C.sub.1 -C.sub.6 alkyl group;
  • a C.sub.6 -C.sub.10 aryl group which may be substituted with at least one or more substituents selected from the group consisting of a C.sub.1 -C.sub.6 alkyl group, a halogen atom, a carboxyl group, a C.sub.2 -C.sub.7 carboxyalkyl group and a benzyloxycarbonyl group; or a C.sub.3 -C.sub.6 cycloalkyl group;
  • R.sup.5 is --NH.sub.2 ;
  • --NHCOR.sup.20,
  • R.sup.20 is a C.sub.1 -C.sub.6 alkoxy group or a C.sub.7 -C.sub.12 aralkyloxy group; or
  • --NHSO.sub.2 R.sup.21,
  • R.sup.21 is a C.sub.1 -C.sub.6 alkyl group or a C.sub.6 -C.sub.10 aryl group; and
  • m is 1;
  • R.sup.2 is a hydrogen atom; and
  • R.sup.3 is --C(.dbd.NR.sup.25)NH.sub.2,
  • R.sup.25 is a hydrogen atom or a hydroxyl group; or
  • --NH.sub.2.
  • 6. The compound according to claim 1, wherein:
  • A is a carbon atom;
  • n is 1;
  • R.sup.1 is ##STR1792## wherein: D is a single bond;
  • E is a single bond or a C.sub.1 -C.sub.3 alkylene group;
  • R.sup.4 is a C.sub.3 -C.sub.6 alkyl group,
  • --OR.sup.6,
  • R.sup.6 is a C.sub.1 -C.sub.6 alkyl group,
  • a phenyl group,
  • or a C.sub.3 -C.sub.6 cycloalkyl group;
  • R.sup.5 is --OH;
  • --NHR.sup.19,
  • R.sup.19 is a hydrogen atom;
  • --NHCOR.sup.20,
  • R.sup.20 is a C.sub.1 -C.sub.6 alkoxy group; or
  • --NHSO.sub.2 R.sup.21,
  • R.sup.21 is a C.sub.1 -C.sub.3 alkyl group; and
  • m is 1;
  • R.sup.2 is a hydrogen atom; and
  • R.sup.3 is --C(.dbd.NR.sup.25)NH.sub.2,
  • R.sup.25 is a hydrogen atom or a hydroxyl group; or
  • --NH.sub.2.
  • 7. The compound according to claim 1, wherein:
  • n is 1;
  • R.sup.1 is ##STR1793## wherein: D is a single bond;
  • E is a single bond or a C.sub.1 -C.sub.6 alkylene group;
  • R.sup.4 is a C.sub.1 -C.sub.6 alkyl group;
  • R.sup.5 is --NHCOR.sup.20,
  • R.sup.20 is a C.sub.1 -C.sub.6 alkoxy group; and
  • m is 1;
  • R.sup.2 is a hydrogen atom; and
  • R.sup.3 is --C(.dbd.NR.sup.25)NH.sub.2,
  • R.sup.25 is a hydrogen atom or a hydroxyl group.
  • 8. Trans-4-�(S)-N-((R)-2-ethoxycarbonylamino-4,4-dimethylpentanoyl) prolyl!aminomethylcyclohexanecarboxamidoxime or a salt or hydrate thereof.
  • 9. A pharmaceutical composition comprising a compound as claimed in claim 1 and a pharmaceutically acceptable carrier therefor.
Priority Claims (1)
Number Date Country Kind
6-007733 Jan 1994 JPX
US Referenced Citations (2)
Number Name Date Kind
5153176 Abe et al. Oct 1992
5380713 Balasubramanian Jan 1995
Foreign Referenced Citations (3)
Number Date Country
526877 Feb 1993 EPX
0601459A2 Jun 1994 EPX
WO9315756 Aug 1993 WOX
Non-Patent Literature Citations (4)
Entry
Chemical Abstracts, vol. 104, No. 7, Abstract No. 47665b (Feb. 17, 1986).
Chemical Abstract Service (CAS) Registry Handbook, 1986 Suppl. (STN DATABASE) RN99742-41-3.
Chemical Abstracts, vol. 103, No. 3, Abstract No. 18900y (Jul. 22, 1985).
Chemical Abstracts, vol. 92, No. 3, Abstract No. 17850z, (Jan. 21, 1980).