1,4-diamino-2,3-dihydroxybutanes

FIELD OF THE INVENTION
This invention relates to 1,4-diamino 2,3-dihydroxybutanes, a process to prepare these compounds, compositions comprising such compounds and a method of treating viral infection.
BACKGROUND OF THE INVENTION
Current treatments for viral diseases usually involve administration of compounds that inhibit viral DNA synthesis. Current treatments for AIDS (Dagani, Chem. Eng. News, Nov. 23, 1987 pp. 41-49) involve administration of compounds such as 2',3'-dideoxycytidine, trisodium phosphonoformate, ammonium 21-tungsto-9-antimoniate, 1-b-D-ribofuranoxyl-1,2,4-triazole-3-carboxamide, 3'-azido-3'-deoxythymidine, and adriamycin that inhibit viral DNA synthesis; compounds such as AL-721 and polymannoacetate which may prevent HIV from penetrating the host cell; and compounds which treat the opportunistic infections caused by the immunosupression resulting from HIV infection. None of the current AIDS treatments have proven to be totally effective in treating and/or reversing the disease. In addition, many of the compounds currently used to treat AIDS cause adverse side effects including low platelet count, renal toxicity and bone marrow cytopenia.
Proteases are enzymes which cleave proteins at specific peptide bonds. Many biological functions are controlled or mediated by proteases and their complementary protease inhibitors. For example, the protease renin cleaves the peptide angiotensinogen to produce the peptide angiotensin I. Angiotensin I is further cleaved by the protease angiotension converting enzyme (ACE) to form the hypotensive peptide angiotensin II. Inhibitors of renin and ACE are known to reduce high blood pressure in vivo. However, no therapeutically useful renin protease inhibitors have been developed, due to problems of oral availability and in vivo stability. The genomes of retroviruses encode a protease that is responsible for the proteolytic processing of one or more polyprotein precursors such as the pol and gag gene products. See Wellink, Arch. Virol. 98, 1 (1988). Retroviral proteases most commonly process the gag precursor into the core proteins, and also process the pol precursor into reverse transcriptase and retroviral protease.
The correct processing of the precursor polyproteins by the retroviral protease is necessary for the assembly of the infectious virions. It has been shown that in vitro mutagenesis that produces protease-defective virus leads to the production of immature core forms which lack infectivity. See Crawford, J. Virol. 53, 899 (1985); Katoh et al., Virology 145 280 (1985). Therefore, retroviral protease inhibition provides an attractive possible target for antiviral therapy. See Mitsuya, Nature 325 775 (1987).
Moore, Biochem. Biophys. Res. Commun., 159 420 (1989) discloses peptidyl inhibitors of HIV protease. Erickson, European Patent Application No. WO 89/10752 discloses derivatives of peptides which are inhibitors of HIV protease.
U.S. Pat. No. 4,652,552 discloses methyl ketone derivatives of tetrapeptides as inhibitors of viral proteases. U.S. Pat. No. 4,644,055 discloses halomethyl derivatives of peptides as inhibitors of viral proteases. European Patent Application No. WO 87/07836 discloses L-glutamic acid gamma-monohydroxamate as an antiviral agent.
The ability to inhibit a protease provides a method for blocking viral replication and therefore a treatment for diseases, and AIDS in particular, that may have fewer side effects when compared to current treatments. The topic of this patent application is 1,4-dimino-2,3-dihydroxybutanes and the development of processes for the preparation of these diols which compounds are capable of inhibiting viral protease and which compounds are believed to serve as a means of combating viral diseases such as AIDS. The diols of this invention provide significant improvements over protease inhibitors that are known in the art. A large number of compounds have been reported to be renin inhibitors, but have suffered from lack of adequate bio-availability and are thus not useful as therapeutic agents. This poor activity has been ascribed to the unusually high molecular weight of renin inhibitors, to inadequate solubility properties, and to the presence of a number of peptide bonds, which are vulnerable to cleavage by mammalian proteases. The diols described herein have a distinct advantage in this regard, in that many do not contain peptide bonds, are of low molecular weight, and can be hydrophilic yet still inhibit the viral protease enzyme.
Additionally, many compounds that inhibit renin do not inhibit HIV protease. The structure-activity requirements of renin inhibitors differ from those of HIV protease inhibitors. The diols of the invention are particularly useful as HIV protease inhibitors.
Other HIV protease inhibitors have been reported, but to date very few have shown activity against viral replication in human cells. This lack of cellular activity is probably due to the factors discussed above for renin inhibitors. Unlike other HIV protease inhibitors, diols disclosed herein show potent inhibition of viral replication in human cells.
An additional advantage of the diols disclosed herein is that some of them are symmetrical. The symmetrical diols may offer improved binding potency to the HIV protease enzyme relative to dissymmetric counterparts, and are more readily prepared from inexpensive starting materials.
The 1,2-diol unit is one of the most ubiquitous functional groups in nature, and consequently a wealth of methods leading to its synthesis have been developed. Foremost in this arsenal are the catalytic osmylation of olefins (Behrens and Sharpless, J. Org. Chem., (1985), 50, 5696), ring opening of epoxides (Wai et al., J. Am. Chem. Soc. (1989), 111, 1123), reduction or alkylation of a-hydroxy/alkoxy carbonyls (Davis et al., J. Org. Chem., (1989), 54, 2021). Common to all of these approaches is the preexistence of the central carbon-carbon bond of the diol function. Methods that lead directly to a 1,2-diol via formation of this bond are less common and include the reaction of an a-alkoxy anion (Cohen and Lin, J. Am. Chem. Soc., (1984), 106, 1130), with a carbonyl, and the reductive coupling of two carbonyls (i.e., pinacol coupling) (Pons and Santelli, Tetrahedron, (1988), 44, 4295).
Of all these methods, pinacol coupling is conceptually one of the simplest methods for the synthesis of 1,2-diols. Consequently, a number of methods have been developed which utilize this reaction for the preparation of these compounds. For example, McMurry et al., report the preparation of a 1,2-diol by pinacol coupling of a dialdehyde in the presence of TiCl.sub.3 (dimethoxyethane).sub.2 Zn-Cu in dimethoxyethane (McMurry et al., Tetrahedron Lett., (1988), 30, 1173). In a recent review article, Pons and Santelli describe many other methods leading to 1,2-diols which rely on low valent titanium complexes (Pons and Santelli, Tetrahedron, (1988), 44, 4295). Finally, Freudenberger et al., J. Am. Chem. Soc., (1989), 111, 8014-8016 disclose a method which utilizes a vanadium (II) complex, [V.sub.2 C.sub.13 (THF).sub.6 ].sub.2 [ZN.sub.2 Cl.sub.6 ] to couple aldehydes.
While these methods are generally useful for the preparation of 1,2-diols, none of these teach how amino moieties can be incorporated into the diols. Furthermore, none of the methods disclosed in the prior art teach to make four stereocenters in a selective manner.
EP 402 646 discloses retroviral protease inhibiting compounds of the formula: A-X-B where A and B are independently substituted amino, substituted carbonyl, functionalized imino, functionalized alkyl, functionalized acyl, functionalized heterocyclic or functionalized (heterocyclic) alkyl and X is a linking group.
SUMMARY OF THE INVENTION
There is provided by this invention a compound of the formula: ##STR1## wherein:
R.sup.1 through R.sup.4 and R.sup.7 through R.sup.10 are independently selected from the following groups:
hydrogen;
C.sub.1 -C.sub.8 alkyl substituted with 0-3 R.sup.11 ;
C.sub.2 -C.sub.8 alkenyl substituted with 0-3 R.sup.11 ;
C.sub.3 -C.sub.8 alkynyl substituted with 0-3 R.sup.11 ;
C.sub.3 -C.sub.8 cycloalkyl substituted with 0-3 R.sup.11 ;
C.sub.6 -C.sub.10 bicycloalkyl substituted with 0-3 R.sup.11 ; aryl substituted with 0-3 R.sup.12 ;
a C.sub.6 -C.sub.14 carbocyclic residue substituted with 0-3 R.sup.12 ;
a heterocyclic ring system substituted with 0-2 R.sup.12, composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom;
R.sup.2A through R.sup.4A and R.sup.7A through R.sup.9A are independently selected from the following groups:
hydrogen;
C.sub.1 -C.sub.4 alkyl substituted with halogen or C.sub.1 -C.sub.2 alkoxy;
benzyl substituted with halogen or C.sub.1 -C.sub.2 alkoxy;
R.sup.5 and R.sup.6 are independently selected from the following groups:
hydrogen;
C.sub.1 -C.sub.6 alkoxycarbonyl;
C.sub.1 -C.sub.6 alkylcarbonyl;
benzoyl;
phenoxycarbonyl; or
phenylaminocarbony; wherein said alkyl residues are substituted with 0-3 R.sup.11, and said aryl residues are
substituted with 0-3 R.sup.12 ; or any other group that, when administered to a mammalian subject, cleaves to form the original diol in which R.sup.5 and R.sup.6 are hydrogen;
R.sup.11 is selected from one or more of the following:
keto, halogen, cyano, --NR.sup.13 R.sup.14, --CO.sub.2 R.sup.13, --OC(.dbd.O)R.sup.13, --OR.sup.13, C.sub.2 -C.sub.6 alkoxyalkyl, --S(O).sub.m R.sup.13, --NHC(.dbd.NH)NHR.sup.13, --C(.dbd.NH)NHR.sup.13, --C(.dbd.O)NR.sup.13 R.sup.14, --NR.sup.14 C(.dbd.O)R.sup.13 --, NR.sup.14 C(.dbd.O)OR.sup.14, --OC(.dbd.O)NR.sup.13 R.sup.14, --NR.sup.13 C(.dbd.O)NR.sup.13 R.sup.14, NR.sup.14 SO.sub.2 NR.sup.13 R.sup.14, --NR.sup.14 SO.sub.2 R.sup.13, SO.sub.2 NR.sup.13 R.sup.14, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl;
a C.sub.5 -C.sub.14 carbocyclic residue substituted with 0-3 R.sup.12 ;
aryl substituted with 0-3 R.sup.12 ;
or a heterocyclic ring system substituted with 0-2 R.sup.12, composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom;
R.sup.12, when a substituent on carbon, is selected from one or more of the following:
phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl, C.sub.7 -C.sub.10 arylalkyl, alkoxy, --NR.sup.13 R.sup.14, C.sub.2 -C.sub.6 alkoxyalkyl, C.sub.1 -C.sub.4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 haloalkoxy, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl, C.sub.1 -C.sub.4 alkylcarbonylamino, --S(O).sub.m R.sup.13, --SO.sub.2 NR.sup.13 R.sup.14, --NHSO.sub.2 R.sup.14 ;
or R.sup.12 may be a 3- or 4-carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6-membered ring being optionally substituted on the aliphatic carbons with halogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, or NR.sup.13 R.sup.14 ; or, when R.sup.12 is attached to a saturated carbon atom it may be carbonyl or thiocarbonyl;
and R.sup.12, when a substituent on nitrogen, is selected from one or more of the following:
phenyl, benzyl, phenethyl, hydroxy, C.sub.1 -C.sub.4 hydroxyalkyl, C.sub.1 -C.sub.4 alkoxy, , C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl, --NR.sup.13 R.sup.14, C.sub.2 -C.sub.6 alkoxyalkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl,
R.sup.13 is H, phenyl, benzyl or C.sub.1 -C.sub.6 alkyl;
R.sup.14 is H or C.sub.1 -C.sub.4 alkyl;
or R.sup.13 R.sup.14 can join to form (CH.sub.2).sub.4, (CH.sub.2).sub.5, (CH.sub.2 CH.sub.2 N(R.sup.15)CH.sub.2 CH.sub.2), or (CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2);
R.sup.15 is H or CH.sub.3 ;
m is 0, 1 or 2;
n and n.sup.1 are independently 0 or 1;
W and W1 are independently selected from the following:
--NR.sup.16 C(.dbd.Q)NR.sup.16 --;
--C(.dbd.Q)NR.sup.16 --;
--C(.dbd.Q)O--;
--NR.sup.16 C(.dbd.Q)O--;
--OC(.dbd.Q)NR.sup.16 --;
--NR.sup.16 C(.dbd.Q)--;
--C(.dbd.Q)--;
--C(.dbd.Q)CH.sub.2 --;
--NR.sup.16 SO.sub.2 NR.sup.16 --
--NR.sup.16 SO.sub.2 --
--SO.sub.2 NR.sup.16 --
--SO.sub.2 --;
--QCH.sub.2 --;
--Q--;
--(CH.sub.2).sub.p NR.sup.16 --;
--CH.sub.2 CH.sub.2 --;
--CH.dbd.CH--;
--CH(OH)CH(OH)--;
--CH(OH)CH.sub.2 --;
--CH.sub.2 CH(OH)--;
--CH(OH)--;
--NH--NH--;
--C(.dbd.O)NH--NH--;
--C(Cl).dbd.N--;
--C(--OR.sup.16).dbd.N--; .
--C(--NR.sup.16 R.sup.17).dbd.N--;
--OP(.dbd.O)(Q.sup.1 R.sup.16)O--;
--P(.dbd.O)(Q.sup.1 R.sup.16)O--;
--SO.sub.2 NHC(.dbd.O)NH--;
X and X.sup.1 are independently selected from the following:
--C(.dbd.Q)NR.sup.16 --;
--C(.dbd.Q)O--;
--C(.dbd.Q)--;
--CH.sub.2 C(.dbd.Q)--;
--CH.sub.2 C(.dbd.Q)CH.sub.2 --;
--C(.dbd.Q)CH.sub.2 --;
--SO.sub.2 NR.sup.16 --
--SO.sub.2 --;
--CH.sub.2 QCH.sub.2 --;
--CH.sub.2 Q--;
--CH.sub.2 NR.sup.6 --;
--CH.sub.2 CH.sub.2 --;
--CH.dbd.CH--;
--CH(OH)CH(OH)--;
--CH(OH)CH.sub.2 --;
--CH.sub.2 CH(OH)--;
--CH(OH)--;
--C(.dbd.O)NH--NH--;
--C(--OR.sup.16).dbd.N--;
--C(--NR.sup.16 R.sup.17).dbd.N--;
--C(L).dbd.N--;
Y and Y.sup.1 are independently selected from the following:
--C(.dbd.Q)NR.sup.16 --;
--(CH.sub.2)PC(.dbd.Q)NR.sup.16 --;
--SO.sub.2 NR.sup.16 --;
--CH.sub.2 NR.sup.16 --;
--C(L).dbd.N--;
--C(--OR.sup.16).dbd.N--;
--C(--NR.sup.16 R.sup.17).dbd.N--;
--NR.sup.12 C(.dbd.O)NR.sup.16 --;
--(CH.sub.2).sub.p NR.sup.12 C(.dbd.O)NR.sup.16 --;
--OC(.dbd.O)NR.sup.16 --;
--(CH.sub.2).sub.p OC(.dbd.O)NR.sup.16 --;
R.sup.16 is H, benzyl or C.sub.1 -C.sub.4 alkyl;
R.sup.17 is H or C.sub.1 -C.sub.4 alkyl;
p is 1 or 2;
Q is selected from oxygen or sulfur;
Q.sup.1 is selected from oxygen, sulfur, NR.sup.14 or a direct bond;
and pharmaceutically acceptable salts and prodrugs thereof.
There is provided a process to prepare the compound of formula I comprising contacting an aldehyde of the formula: ##STR2## with an aldehyde of the formula: ##STR3## in the presence of Caulton's reagent to form the compound of Claim 1 wherein R.sup.5 and R.sup.6 are H and optionally contacting one or both of the alcohols with a derivatizing agent; wherein:
R.sup.1 through R.sup.4 and R.sup.7 through R.sup.10 are independently selected from the following groups:
hydrogen;
C.sub.1 -C.sub.8 alkyl substituted with 0-3 R.sup.11 ;
C.sub.2 -C.sub.8 alkenyl substituted with 0-3 R.sup.11 ;
C.sub.3 -C.sub.8 alkynyl substituted with 0-3 R.sup.11 ;
C.sub.3 -C.sub.8 cycloalkyl substituted with 0-3 R.sup.11 ;
C.sub.6 -C.sub.10 bicycloalkyl substituted with 0-3 R.sup.11 ;
aryl substituted with 0-3 R.sup.12 ;
a C.sub.6 -C.sub.14 carbocyclic residue substituted with 0-3 R.sup.12 ;
a heterocyclic ring system substituted with 0-2 R.sup.12, composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom;
R.sup.2A through R.sup.4A and R.sup.7A through R.sup.9A are independently selected from the following groups:
hydrogen;
C.sub.1 -C.sub.4 alkyl substituted with halogen or C.sub.1 -C.sub.2 alkoxy;
benzyl substituted with halogen or C.sub.1 -C.sub.2 alkoxy;
R.sup.5 and R.sup.6 are independently selected from the following groups:
hydrogen;
C.sub.1 -C.sub.6 alkoxycarbonyl;
C.sub.1 -C.sub.6 alkylcarbonyl;
benzoyl;
phenoxycarbonyl; or
phenylaminocarbony; wherein said alkyl residues are substituted with 0-3 R.sup.11, and said aryl residues are
substituted with 0-3 R.sup.12 ; or any other group that, when administered to a mammalian subject, cleaves to form the original diol in which R.sup.5 and R.sup.6 are hydrogen;
R.sup.11 is selected from one or more of the following:
keto, halogen, cyano, --NR.sup.13 R.sup.14, --CO.sub.2 R.sup.13, --OC(.dbd.O)R.sup.13, --OR.sup.13, C.sub.2 -C.sub.6 alkoxyalkyl, --S(O).sub.m R.sup.13, --NHC(.dbd.NH)NHR.sup.13, --C(.dbd.NH)NHR.sup.13, --C(.dbd.O)NR.sup.13 R.sup.14, --NR.sup.14 C(.dbd.O)R.sup.13 --, NR.sup.14 C(.dbd.O)OR.sup.14, --OC(.dbd.O)NR.sup.13 R.sup.14, --NR.sup.13 C(.dbd.O)NR.sup.13 R.sup.14, --NR.sup.14 SO.sub.2 NR.sup.13 R.sup.14, --NR.sup.14 SO.sub.2 R.sup.13, --SO.sub.2 NR.sup.13 R.sup.14, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl;
a C.sub.5 -C.sub.14 carbocyclic residue substituted with 0-3 R.sup.12 ;
aryl substituted with 0-3 R.sup.12 ;
or a heterocyclic ring system substituted with 0-2 R.sup.12, composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom.
R.sup.12, when a substituent on carbon, is selected from one or more of the following:
phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl,C.sub.7 -C.sub.10 arylalkyl, alkoxy, --NR.sup.13 R.sup.14, C.sub.2 -C.sub.6 alkoxyalkyl, C.sub.1 -C.sub.4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 haloalkoxy, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl, C.sub.1 -C.sub.4 alkylcarbonylamino, --S(O).sub.m R.sup.13, --SO.sub.2 NR.sup.13 R.sup.14, --NHSO.sub.2 R.sup.14 ;
or R.sup.12 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6- membered ring being optionally substituted on the aliphatic carbons with halogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, or NR.sup.13 R.sup.14 ; or, when R.sup.12 is attached to a saturated carbon atom it may be carbonyl or thiocarbonyl;
and R.sup.12, when a substituent on nitrogen, is selected from one or more of the following:
phenyl, benzyl, phenethyl, hydroxy, C.sub.1 -C.sub.4 hydroxyalkyl, C.sub.1 -C.sub.4 alkoxy, , C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl, --NR.sup.13 R.sup.14, C.sub.2 -C.sub.6 alkoxyalkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl,
R.sup.13 is H, phenyl, benzyl or C.sub.1 -C.sub.6 alkyl;
R.sup.14 is H or C.sub.1 -C.sub.4 alkyl;
or R.sup.13 R.sup.14 can join to form (CH.sub.2).sub.4, (CH.sub.2).sub.5, (CH.sub.2 CH.sub.2 N(R.sup.15)CH.sub.2 CH.sub.2), or (CH.sub.2 CH.sub.20 CH.sub.2 CH.sub.2);
R.sup.15 is H or CH.sub.3 ;
m is 0, 1 or 2;
n and n.sup.1 are independently 0 or 1;
W and W1 are independently selected from the following:
--NR.sup.16 C(.dbd.Q)NR.sup.16 --;
--C(.dbd.Q)NR.sup.16 --;
--C(.dbd.Q)O--;
--NR.sup.16 C(.dbd.Q)O--;
--OC(.dbd.Q)NR.sup.16 --;
--NR.sup.16 C(.dbd.Q)--;
--C(.dbd.Q)--;
--C(.dbd.Q)CH.sub.2 --;
--NR.sup.16 SO.sub.2 NR.sup.16 --
--NR.sup.16 SO.sub.2 --
--SO.sub.2 NR.sup.16 --
--SO.sub.2 --;
--QCH.sub.2 --;
--Q--;
--(CH.sub.2).sub.p NR.sup.16 --;
--CH.sub.2 CH.sub.2 --;
--CH.dbd.CH--;
--CH(OH)CH(OH)--;
--CH(OH)CH.sub.2 --;
--CH.sub.2 CH(OH)--;
--CH(OH)--;
--NH--NH--;
--C(.dbd.O)NH--NH--;
--C(Cl).dbd.N--;
--C(--OR.sup.16).dbd.N--;
--C(--NR.sup.16 R.sup.17).dbd.N--;
--OP(.dbd.O)(Q.sup.1 R.sup.16)O--;
--P(.dbd.O)(Q.sup.1 R.sup.16)O--;
--SO.sub.2 NHC(.dbd.O)NH--;
X and X.sup.1 are independently selected from the following:
--C(.dbd.Q)NR.sup.16 --;
--C(.dbd.Q)O--;
--C(.dbd.Q)--;
--CH.sub.2 C(.dbd.Q)--;
--CH.sub.2 C(.dbd.Q)CH.sub.2 --;
--C(.dbd.Q)CH.sub.2 --;
--SO.sub.2 NR.sup.16 --
--SO.sub.2 --;
--CH.sub.2 QCH.sub.2 --;
--CH.sub.2 Q--;
--CH.sub.2 NR.sup.16 --;
--CH.sub.2 CH.sub.2 --;
--CH.dbd.CH--;
--CH(OH)CH(OH)--;
--CH(OH)CH.sub.2 --;
--CH.sub.2 CH(OH)--;
--CH(OH)--;
--C(.dbd.O)NH--NH--;
--C(--OR.sup.16).dbd.N--;
--C(--NR.sup.16 R.sup.16).dbd.N--;
--C(L).dbd.N--.
Y and Y.sup.1 are independently selected from the following:
--C(.dbd.Q)NR.sup.16 --;
--(CH.sub.2).sub.p C(.dbd.Q)NR.sup.16 --;
--SO.sub.2 NR.sup.16 --;
--CH.sub.2 NR.sup.16 --;
--C(L).dbd.N--;
--C(--OR.sup.16).dbd.N--;
--C(--NR.sup.16 R.sup.16).dbd.N--;
--NR.sup.12 C(.dbd.O)NR.sup.16 --;
--(CH.sub.2).sub.p NR.sup.12 C(.dbd.O)NR.sup.16 --;
--OC(.dbd.O)NR.sup.16 --;
--(CH.sub.2).sub.p OC(.dbd.O)NR.sup.16 --;
R.sup.16 is H, benzyl or C.sub.1 -C.sub.4 alkyl;
R.sup.17 is H Or C.sub.1 -C.sub.4 alkyl;
p is 1 or 2;
Q is selected from oxygen or sulfur;
L is Cl or Br;
Q.sup.1 is selected from oxygen, sulfur, NR.sup.14 or a direct bond;
and pharmaceutically acceptable salts and prodrugs thereof. Suitable derivatizing agents include, but are not limited to, acyl chlorides or anhydrides, diphenyl carbonates, and isocyanates using techniques well known to those skilled in the art.
A process for preparing an intermediate compound of the formula: ##STR4## comprising: (a) reacting an organometallic derivative R.sup.18 M or R.sup.19 M in the presence of copper (I) salts and an ether-containing, aprotic solvent system with a diepoxide of the formula: ##STR5##
(b) reacting the product of step (a) of the formula: ##STR6## with R.sup.22 R.sup.23 R.sup.24 P and C.sub.1 -C.sub.6 dialkyl azodicarboxylate in the presence of an azide anion and an aprotic organic solvent generally at a temperature between -20.degree. to 100.degree. C.; wherein:
R.sup.18 and R.sup.19 are independently C.sub.2 -C.sub.8 alkyl, C.sub.3 -C.sub.8 cycloalkyl substituted with 0-3 R.sup.25, a C.sub.6 -C.sub.10 carbocyclic aromatic residue, for example phenyl or naphthyl, substituted with 0-3 R.sup.26 ;
a heterocyclic ring system substituted with 0-2 R.sup.26, composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom; for example, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl or benzimidazolyl, piperidinyl, pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl or octahydroisoquinolinyl;
R.sup.25 is selected from one or more of the following groups: keto, halogen, R.sup.27 R.sup.28 N, CO.sub.2 R.sup.27, OCO.sub.2 R.sup.27, OR.sup.27, S(O).sub.n R.sup.27, NHC(.dbd.NH)NHR.sup.27, C(.dbd.NH)NHR.sup.27, C(.dbd.O)NHR.sup.27, or cyano; C.sub.3 -C.sub.8 cycloalkyl substituted with 0-3 R.sup.25, a C.sub.6 -C.sub.10 carbocyclic aromatic residue, for example phenyl or naphthyl, substituted with 0-3 R.sup.26 ;
a heterocyclic ring system substituted with 0-2 R.sup.26, composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom; for example, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl or benzimidazolyl, piperidinyl, pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl or octahydroisoquinolinyl;
R.sup.26 is selected from one or more of the following groups: phenyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.2 -C.sub.6 alkoxyalkyl,methylenedioxy, ethylenedioxy, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 haloalkoxy, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl, alkylsulfonyl, SO.sub.2 NR.sup.27 R.sup.28, and R.sup.27 SO.sub.2 NH;
R.sup.20 and R.sup.21 are independently H, C.sub.1 -C.sub.8 alkyl, a C.sub.6 -C.sub.10 carbocyclic aromatic residue, for example phenyl or naphthyl, substituted with 0-3 R.sup.26, or C.sub.1 -C.sub.3 alkyl substituted with a C.sub.6 -C.sub.10 carbocyclic aromatic residue, for example phenyl or naphthyl, substituted with 0-3 R.sup.26 ;
M is lithium or magnesium;
R.sup.22, R.sup.23 and R.sup.24 are independently phenyl or C.sub.1 -C.sub.6 alkyl.
Also provided by this invention are the intermediates of Formula III, IV, and V.
A process for the preparation of saturated 3-7 membered nitrogen containing heterocycles, comprising, carrying out an intramolecular Mitsunobo reaction on a precursor molecule containing a protected nitrogen atom and a hydroxyl group separated by 2-6 atoms.
A process for preparing an intermediate compound of the formula: ##STR7## comprising, carrying out an intermediate Mitsunobu reaction on a compound of the formula: ##STR8## wherein: Z is COOCH.sub.2 Ph. A process for preparing a compound of formula: ##STR9## comprising:
(a) preparation of the required catalyst by mixing VCl.sub.3 (THF).sub.3 with freshly prepared zinc-copper couple under strictly anhydrous, deoxygenated conditions in an, aprotic solvent at room temperature; and
(b) reacting the product of step (a) with an aldehyde of formula (1) in an aprotic solvent at -78.degree. C. 100.degree. C. where the ratio of zinc-copper couple: VCl.sub.3 (THF).sub.3 : aldehyde is 1-3:1-3:1.
There are provided methods for treatment of viral infections which comprises administering to a host in need of such treatment a pharmaceutically effective antiviral amount of the compound of the following formula: ##STR10## wherein:
R.sup.1 through R.sup.4 and R.sup.7 through R.sup.10 are independently selected from the following groups:
hydrogen;
C.sub.1 -C.sub.8 alkyl substituted with 0-3 R.sup.11 ;
C.sub.2 -C.sub.8 alkenyl substituted with 0-3 R.sup.11 ;
C.sub.3 -C.sub.8 alkynyl substituted with 0-3 R.sup.11 ;
C.sub.3 -C.sub.8 cycloalkyl substituted with 0-3 R.sup.11 ;
C.sub.6 -C.sub.10 bicycloalkyl substituted with 0-3 R.sup.11 ;
aryl substituted with 0-3 R.sup.12 ;
a C.sub.6 -C.sub.14 carbocyclic residue substituted with 0-3 R.sup.12 ;
a heterocyclic ring system substituted with 0-2 R.sup.12, composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom;
R.sup.2A through R.sup.4A and R.sup.7A through R.sup.9A are independently selected from the following groups: hydrogen;
C.sub.1 -C.sub.4 alkyl substituted with halogen or C.sub.1 -C.sub.2 alkoxy;
benzyl substituted with halogen or C.sub.1 -C.sub.2 alkoxy;
R.sup.5 and R.sup.6 are independently selected from the following groups:
hydrogen;
C.sub.1 -C.sub.6 alkoxycarbonyl;
C.sub.1 -C.sub.6 alkylcarbonyl;
benzoyl;
phenoxycarbonyl; or
phenylaminocarbony; wherein said alkyl residues are substituted with 0-3 R.sup.11, and said aryl residues are
substituted with 0-3 R.sup.12 ; or any other group that, when administered to a mammalian subject, cleaves to form the original diol in which R.sup.5 and R.sup.6 are hydrogen;
R.sup.11 is selected from one or more of the following:
keto, halogen, cyano, --NR.sup.13 R.sup.14, --CO.sub.2 R.sup.13, --OC(.dbd.O)R.sup.13, --OR.sup.13, C.sub.2 -C.sub.6 alkoxyalkyl, --S(O).sub.m R.sup.13, --NHC(.dbd.NH)NHR.sup.13, --C(.dbd.NH)NHR.sup.13, --C(.dbd.O)NR.sup.13 R.sup.14, --NR.sup.14 C(.dbd.O)R.sup.13 --, NR.sup.14 C(.dbd.O)OR.sup.14, --OC(.dbd.O)NR.sup.13 R.sup.14, --NR.sup.13 C(.dbd.O)NR.sup.13 R.sup.14, NR.sup.14 SO.sub.2 NR.sup.13 R.sup.14, --NR.sup.14 SO.sub.2 R.sup.13, --SO.sub.2 NR.sup.13 R.sup.14, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl;
a C.sub.5 -C.sub.14 carbocyclic residue substituted with 0-3 R.sup.12 ;
aryl substituted with 0-3 R.sup.12 ;
or a heterocyclic ring system substituted with 0-2 R.sup.12, composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom;
R.sup.12, when a substituent on carbon, is selected from one or more of the following:
phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl,C.sub.7 -C.sub.10 arylalkyl, alkoxy, --NR.sup.13 R.sup.14, C.sub.2 -C.sub.6 alkoxyalkyl, C.sub.1 -C.sub.4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 haloalkoxy, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl, C.sub.1 -C.sub.4 alkylcarbonylamino, --S(O).sub.m R.sup.13, --SO.sub.2 NR.sup.13 R.sup.14, --NHSO.sub.2 R.sup.14 ;
or R.sup.12 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6-membered ring being optionally substituted on the aliphatic carbons with halogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, or NR.sup.13 R.sup.14 ; or, when R.sup.12 is attached to a saturated carbon atom it may be carbonyl or thiocarbonyl;
and R.sup.12, when a subsistent on nitrogen, is selected from one or more of the following:
phenyl, benzyl, phenethyl, hydroxy, C.sub.1 -C.sub.4 hydroxyalkyl, C.sub.1 -C.sub.4 alkoxy, , C.sub.1 -C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl, --NR.sup.13 R.sup.14, C.sub.2 -C.sub.6 alkoxyalkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl;
R.sup.13 is H, phenyl, benzyl or C.sub.1 -C.sub.6 alkyl;
R.sup.14 is H or C.sub.1 -C.sub.4 alkyl;
or R.sup.13 R.sup.14 can join to form (CH.sub.2).sub.4, (CH.sub.2).sub.5, (CH.sub.2 CH.sub.2 N(R.sup.15)CH.sub.2 CH.sub.2), or (CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2);
R.sup.15 is H or CH.sub.3 ;
m is 0, 1 or 2;
n and n.sup.1 are independently 0 or 1;
W and W1 are independently selected from the following:
--NR.sup.16 C(.dbd.Q)NR.sup.16 --;
--C(.dbd.Q)NR.sup.16 --;
--C(.dbd.Q)O--;
--NR.sup.16 C(.dbd.Q)O--;
--OC(.dbd.Q)NR.sup.16 --;
--NR.sup.16 C(.dbd.Q)--;
--C(.dbd.Q)--;
--C(.dbd.Q)CH.sub.2 --;
--NR.sup.16 SO.sub.2 NR.sup.16 --
--NR.sup.16 SO.sub.2 --
--SO.sub.2 NR.sup.16 --
--SO.sub.2 --;
--QCH.sub.2 --;
--Q--;
--(CH.sub.2).sub.p NR.sup.16 --;
--CH.sub.2 CH.sub.2 --;
--CH.dbd.CH--;
--CH(OH)CH(OH)--;
--CH(OH)CH.sub.2 --;
--CH.sub.2 CH(OH)--;
--CH(OH)--;
--NH--NH--;
--C(.dbd.O)NH--NH--;
--C(Cl).dbd.N--;
--C(--OR.sup.16).dbd.N--;
--C(--NR.sup.16 R.sup.17).dbd.N--;
--OP(.dbd.O)(Q.sup.1 R.sup.16)O--;
--P(.dbd.O)(Q.sup.1 R.sup.16)O--;
--SO.sub.2 NHC(.dbd.O)NH--;
X and X.sup.1 are independently selected from the following:
--C(.dbd.Q)NR.sup.16 --;
--C(.dbd.Q)O--;
--C(.dbd.Q)--;
--CH.sub.2 C(.dbd.Q)--;
--CH.sub.2 C(.dbd.Q)CH.sub.2 --;
--C(.dbd.Q)CH.sub.2 --;
--SO.sub.2 NR.sup.16 --
--SO.sub.2 --;
--CH.sub.2 QCH.sub.2 --;
--CH.sub.2 Q--;
--CH.sub.2 NR.sup.16 --;
--CH.sub.2 CH.sub.2 --;
--CH.dbd.CH--;
--CH(OH)CH(OH)--;
--CH(OH)CH.sub.2 --;
--CH.sub.2 CH(OH)--;
--CH(OH)--;
--C(.dbd.O)NH--NH--;
--C(--OR.sup.16).dbd.N--;
--C(--NR.sup.16 R.sup.17).dbd.N--;
--C(L).dbd.N--;
Y and Y.sup.1 are independently selected from the following:
--C(.dbd.Q)NR.sup.16 --;
--(CH.sub.2)PC(.dbd.Q)NR.sup.16 --;
--SO.sub.2 NR.sup.16 --;
--CH.sub.2 NR.sup.16 --;
--C(L).dbd.N--;
--C(--OR.sup.16).dbd.N--;
--C(--NR.sup.16 R.sup.17).dbd.N--;
--NR.sup.12 C(.dbd.O)NR.sup.16 --;
--(CH.sub.2).sub.p NR.sup.12 C(.dbd.O)NR.sup.16 --;
--OC(.dbd.O)NR.sup.16 --;
--(CH.sub.2).sub.p OC(.dbd.O)NR.sup.16 --;
R.sup.16 is H, benzyl or C.sub.1 -C.sub.4 alkyl;
R.sup.17 is H or C.sub.1 -C.sub.4 alkyl;
p is 1 or 2;
Q is selected from oxygen or sulfur;
L is Cl or Br;
Q.sup.1 is selected from oxygen, sulfur, NR.sup.14 or a direct bond; and pharmaceutically acceptable salts and prodrugs thereof.
PREFERRED EMBODIMENTS
Compounds preferred for use in the method of this invention include the following: ##STR11##
R.sup.1 and R.sup.10 are independently selected from the following:
hydrogen;
C.sub.1 -C.sub.6 alkyl substituted with 0-2 R.sup.11 ;
C.sub.3 -C.sub.6 cycloalkyl substituted with 0-2 R.sup.11 ;
C.sub.6 -C.sub.10 bicycloalkyl substituted with 0-2 R.sup.11 ;
aryl substituted with 0-3 R.sup.12 ;
a C.sub.6 -C.sub.14 carbocyclic residue substituted with 0-2 R.sup.12 ;
a heterocyclic ring system substituted with 0-2 R.sup.12, composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom;
R.sup.3 and R.sup.8 are independently selected from the following groups:
hydrogen;
C.sub.1 -C.sub.5 alkyl substituted with 0-2 R.sup.11 ;
C.sub.2 -C.sub.4 alkenyl substituted with 0-2 R.sup.11 ;
C.sub.3 -C.sub.6 cycloalkyl substituted with 0-2 R.sup.11 ;
with the proviso that the total number of non-hydrogen atoms comprising R.sup.3 is less than or equal to 6, and the total number of non-hydrogen atoms comprising R.sup.8 is less than or equal to 6;
R.sup.4 and R.sup.7 are independently selected from the following groups:
hydrogen;
C.sub.1 -C.sub.4 alkyl substituted with 0-3 R.sup.11 ;
C.sub.2 -C.sub.3 alkenyl substituted with 0-3 R.sup.11 ;
R.sup.3A, R.sup.4A, R.sup.7A and R.sup.8A are independently selected from the following groups:
hydrogen;
C.sub.1 -C.sub.2 alkyl;
R.sup.4 and R.sup.6 are independently selected from the following groups:
hydrogen, or any other group that, when administered to a mammalian subject, cleaves to form the original diol in which R.sup.5 and R.sup.6 are hydrogen;
R.sup.11 is selected from one or more of the following:
keto, halogen, cyano, --NR.sup.13 R.sup.14, --CO.sub.2 R.sup.13, --OC(.dbd.O)R.sup.13, --OR.sup.13, C.sub.2 -C.sub.6 alkoxyalkyl, --S(O).sub.m R.sup.13, --NHC(.dbd.NH)NHR.sup.13, --C(.dbd.NH)NHR.sup.13, --C(.dbd.O)NR.sup.13 R.sup.14, --NR.sup.14 C(.dbd.O)R.sup.13 --, NR.sup.14 C(.dbd.O)OR.sup.14, --OC(.dbd.O)NR.sup.13 R.sup.14, NR.sup.13 C(.dbd.O)NR.sup.13 R.sup.14, --NR.sup.14 SO.sub.2 NR.sup.13 R.sup.14, --NR.sup.14 SO.sub.2 R.sup.13, --SO.sub.2 NR.sup.13 R.sup.14, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl;
a C.sub.5 -C.sub.14 carbocyclic residue substituted with 0-3 R.sup.12 ;
aryl substituted with 0-3 R.sup.12 ;
or a heterocyclic ring system substituted with 0-2 R.sup.12, composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom;
R.sup.12, when a substituent on carbon, is selected from one or more of the following:
phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl,C.sub.7 -C.sub.10 arylalkyl, alkoxy, --NR.sup.13 R.sup.14, C.sub.2 -C.sub.6 alkoxyalkyl, C.sub.1 -C.sub.4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 haloalkoxy, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl, C.sub.1 -C.sub.4 alkylcarbonylamino, --S(O).sub.m R.sup.13, --SO.sub.2 NR.sup.13 R.sup.14, --NHSO.sub.2 R.sup.14 ;
or R.sup.12 may be a 3- or 4-carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6-membered ring being optionally substituted on the aliphatic carbons with halogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, or NR.sup.13 R.sup.14 ; or, when R.sup.12 is attached to a saturated carbon atom it may be carbonyl or thiocarbonyl; and R.sup.12, when a substituent on nitrogen, is selected from one or more of the following:
benzyl, hydroxy, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.5 hydroxyalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl,
R.sup.13 is H, benzyl or C.sub.1 -C.sub.4 alkyl;
R.sup.14 is H or C.sub.1 -C.sub.4 alkyl;
or R.sup.13 R.sup.14 can join to form (CH.sub.2).sub.4, (CH.sub.2).sub.5, (CH.sub.2 CH.sub.2 N(R.sup.15)CH.sub.2 CH.sub.2), or (CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2);
R.sup.15 is H or CH.sub.3 ;
m is 0, 1 or 2;
W and W1 are independently selected from the following:
--NR.sup.16 C(.dbd.Q)NR.sup.16 --;
--C(.dbd.Q)NR.sup.16 --;
--OC(.dbd.Q)NR.sup.16 --;
--NR.sup.16 SO.sub.2 NR.sup.16 --
--SO.sub.2 NR.sup.16 --
--(CH.sub.2).sub.p NR.sup.16 --;
--P(.dbd.O)(Q.sup.1 R.sup.16)O--;
--SO.sub.2 NHC(.dbd.O)NH--;
Y and Y.sup.1 are independently selected from the following:
--C(.dbd.Q)NR.sup.16 --;
--NR.sup.12 C(.dbd.O)NR.sup.16 --;
--OC(.dbd.O)NR.sup.16 --; or
--(CH.sub.2).sub.p NR.sup.13 --;
R.sup.16 is H or C.sub.1 -C.sub.2 alkyl;
R.sup.17 is H or C.sub.1 -C.sub.2 alkyl;
p is 1 or 2;
Q is selected from oxygen or sulfur;
Q.sup.1 is selected from oxygen, sulfur, NR.sup.14 or a direct bond;
and pharmaceutically acceptable salts and prodrugs thereof.
More preferred for greater activity and/or ease of synthesis is a compound of Formula I, wherein: ##STR12##
R.sup.1 and R.sup.10 are independently selected from the following:
hydrogen;
C.sub.1 -C.sub.6 alkyl substituted with 0-1 R.sup.18 ;
C.sub.2 -C.sub.4 alkenyl substituted with 0-1 R.sup.18 ;
aryl substituted with 0-1 R.sup.19 ;
a heterocyclic ring system, substituted with 0-1 R.sup.19, selected from pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, or decahydroisoquinolinyl;
wherein R.sup.18 is chosen from the following group:
keto, halogen, cyano, --NR.sup.13 R.sup.14, --C.sub.02 R.sup.13, --OC(.dbd.O)R.sup.13, --OR.sup.13, C.sub.2 -C.sub.6 alkoxyalkyl, --S(O).sub.m R.sup.13, --NHC(.dbd.NH)NHR.sup.13, --C(.dbd.O)NR.sup.13 R.sup.14, --NR.sup.14 C(.dbd.O)R.sup.13 --, NR.sup.14 C(.dbd.O)OR.sup.14, --OC(.dbd.O)NR.sup.13 R.sup.14, NR.sup.13 C(.dbd.O)NR.sup.13 R.sup.14, --NR.sup.14 so2NR.sup.13 R.sup.14, --NR.sup.14 SO.sub.2 R.sup.13, --SO.sub.2 NR.sup.13 R.sup.14, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, or C.sub.3 -C.sub.6 cycloalkyl;
a C.sub.5 -C.sub.14 carbocyclic residue substituted with 0-3 R.sup.19 ;
aryl substituted with 0-2 R.sup.19 ;
or a heterocyclic ring system substituted with 0-2 R.sup.19, selected from selected from pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, or decahydroisoquinolinyl;
wherein R.sup.19, when a substituent on carbon, is selected from the following:
halogen, hydroxy, nitro, cyano, methyl, methoxy, --NR.sup.13 R.sup.14, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.2 alkoxycarbonyl, C.sub.1 -C.sub.2 alkylcarbonyloxy, C.sub.1 -C.sub.2 alkylcarbonylamino, SO.sub.2 NR.sup.13 R.sup.14, or --NHSO.sub.2 R.sup.14 ;
and R.sup.19, when a substituent on nitrogen, is C.sub.1 -C.sub.4 alkyl;
R.sup.3 and R.sup.8 are independently selected from the following groups:
hydrogen;
C.sub.1 -C.sub.5 alkyl substituted with 0-3 halogen or 0-1 R.sup.20 ;
C.sub.2 -C.sub.4 alkenyl substituted with 0-3 halogen or 0-1 R.sup.20 ;
C.sub.3 -C.sub.6 - cycloalkyl substituted with 0-3 halogen or 0-1 R.sup.20 ;
wherein R.sup.20 is selected from the following groups:
keto, amino, methylamino, dimethylamino, --C(.dbd.O)NH.sub.2, C(.dbd.O)NMe2, C(.dbd.O)NHMe, or C.sub.3 -C.sub.5 cycloalkyl;
with the proviso that the total number of non-hydrogen atoms comprising R.sup.3 is less than or equal to 6, and the total number of non-hydrogen atoms comprising R.sup.8 is less than or equal to 6;
R.sup.4 and R.sup.7 are independently selected from the following groups:
C.sub.1 -C.sub.4 alkyl substituted with 0-3 halogen or 0-1 R.sup.21, wherein R.sup.21 is selected from the following groups:
keto, halogen, cyano, --NR.sup.13 R.sup.14, --CO.sub.2 R.sup.13, --OC(.dbd.O)R.sup.13, --OR.sup.13, C.sub.2 -C.sub.4 alkoxyalkyl, --S(O).sub.m R.sup.13, --C.sub.3 -C.sub.6 cycloalkyl;
a C.sub.5 -C.sub.10 carbocyclic residue substituted with 0-1 R.sup.22 ;
aryl substituted with 0-1 R.sup.22 ;
or a heterocyclic ring system, substituted with 0-1 R.sup.22, selected from pyridyl, thienyl, indolyl, piperazyl, N-methylpiperazyl, or imidazolyl;
wherein R.sup.22 is selected from one or more of the following groups:
benzyl, benzyloxy, halogen, hydroxy, nitro, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, amino, methylamino, dimethylamino, haloalkyl, haloalkoxy, --C(.dbd.O).sub.2 R.sup.14, or --OC(O.sub.2)R.sup.14 ;
R.sup.3A, R.sup.4A, R.sup.7A and R.sup.8A are hydrogen;
R.sup.5 and R.sup.6 are independently selected from the following groups: hydrogen, or any other group that, when administered to a mammalian subject, cleaves to form the original diol in which R.sup.5 and R.sup.6 are hydrogen;
R.sup.13 and R.sup.14 are independently selected from H or C.sub.1 -C.sub.2 alkyl;
m is 0, 1 or 2;
n and n.sup.1 are 0;
W and W1 are independently selected from the following:
--NR.sup.16 C(.dbd.Q)NR.sup.16 --;
--C(.dbd.O)NR.sup.16 --;
--OC(.dbd.O)NR.sup.16 --;
--(CH.sub.2).sub.p NR.sup.16 --;
Y and Y.sup.1 are independently selected from the following:
--C(.dbd.O)NR.sup.16 --;
--NR.sup.12 C(.dbd.O)NR.sup.16 --;
--OC(.dbd.O)NR.sup.16 --; or
--(CH.sub.2).sub.p NR.sup.16 --;
R.sup.16 is H or methyl;
p is 1 or 2;
Q is selected from oxygen or sulfur; and pharmaceutically acceptable salts and prodrugs thereof.
Specific examples of compounds useful in various embodiments of the invention include compounds of the formula:
a) (S,R,R,S)--N-[4-[[(1,1-dimethylethoxy)carbonyl]amino]-2,3-dihydroxy-5-(1H-pyrrol-1-yl)-1-[(1H -pyrrol-1-yl)methyl]pentyl]-N.sub.2 -formyl-L-valinamide
b) (S,R,R,S)--N-[4-[[(1,1-dimethylethoxy)carbonyl]amino]-2,3-dihydroxy-5-phenyl-1-(phenylmethyl)pentyl]-N.sub.2 -[[N-[(1H -benzimidazol-2-yl)methyl]-N-methylamino]carbonyl]-L-valinamide
c) (S,R,R,S)-N-[4-[[(1,1-dimethylethoxy)carbonyl]amino]-2,3-dihydroxy-5-(4-pyridinyl)-1-(4-pyridinylmethyl)pentyl]-N.sub.2 -formyl-L-valinamide
d) [S,R,R,S(2S*,3S*)]-(1,1-dimethylethyl) [2,3-dihydroxy-4-[(3-hydroxy-4-methoxy-2-(1-methylethyl)-1-oxobutyl]amino]-5-(4-pyridinyl)-1-(4-pyridinylmethyl)pentyl]carbamate
e) (S,R,R,S)-N-[4-[[(1,1-dimethylethoxy)carbonyl]amino]-2,3-dihydroxy5-(4-pyridinyl)-1-(4-pyridinylmethyl)pentyl]-N.sub.2 -[(phenylmethoxy)carbonyl]-L-valinamide
f) (S,R,R,S)-N.sub.2 -[[1(dimethylamino)cyclopropyl]carbonyl]-N-[4-[[(1,1-dimethyl-ethoxy)carbonyl]amino]-2,3-dihydroxy-5-phenyl-1-(phenylmethyl)pentyl]-N-L-valinamide
g) (S,R,R,S)-N-[4-[[(1,1-dimethylethoxy)carbonyl]amino]-2,3-dihydroxy1-(phenylmethyl)hexyl]-N.sub.2 -(N-methyl-L-alanyl)-L-valinamide
h) (S,R,R,S)-(1,1-dimethylethyl) [4-[[[2-[(dimethylamino)methyl]-1H -imidazol-5-yl]carbonyl]amino]-2,3-dihydroxy-5-phenyl-1-(phenylmethyl)-pentyl]carbamate
i) (S,R,R,S)-N.sub.2 -[[[2-[(dimethylamino)carbonyl]phenyl]methoxy]carbon yl]-N-[4-[[(1,1-dimethylethoxy)carbonyl]amino]-2,3-dihydroxy-5-phenyl-1-(phenylmethyl)pentyl]-L-valinamide
j) (S,R,R,S)-N,N'-[2,3-dihydroxy-1,4-bis(phenylmethyl)-1,4-butanediyl]bis[N.sub.2 -(4-aminobenzoyl)-L-valinamide]
k) (S,R,R,S)-N.sub.2 -[[[4-(dimethylamino)phenyl]methoxy]carbonyl]-N-[4-[[(1,1-dimethylethoxy)carbonyl]amino]-2,3-dihydroxy-5-phenyl-1-(phenylmethyl)pentyl]-L-valinamide
l) (S,R,R,S)-N.sub.2 -[[[4-[(dimethylamino)methyl]phenyl]methoxy]carbonyl]-N-[4-[[(1,1-dimethylethoxy)carbonyl]amino]-2,3-dihydroxy-5-phenyl-1-(phenylmethyl)pentyl]-L-valinamide.
The compounds herein described may have asymmetric centers. All chiral, diastereomeric and racemic forms are included in the present invention. Many geometric isomers of olefins, C.dbd.N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention.
When any variable (for example, R.sup.1 through R.sup.17, R.sup.2A through R.sup.9A, m, n, p, Q, W, X, Y, Z, etc.) occurs more than one time in any constituent or in formula (I), its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; "cycloalkyl" is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; and "biycloalkyl" is intended to include saturated bicyclic ring groups such as [3.3.0]bicyclooctane, [4.3.0] bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, and so forth. "Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl and the like; and "alkynyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like. "Halo" as used herein refers to fluoro, chloro, bromo and iodo; and "counterion" is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate and the like.
As used herein, "aryl" or "aromatic residue" is intended to mean phenyl or naphthyl; "carbocyclic" is intended to mean any stable 5- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic.
As used herein, the term heterocycle is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from 1 to 3 heteroatoms selected from the group consisting of N, O and S and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Examples of such heterocycles include, but are not limited to, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl or benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl or octahydroisoquinolinyl. The term "substituted", as used herein, means that an one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
By "stable compound" or "stable structure" is meant herein a compound that is sufficiently robust to survive:
isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

DETAILED DESCRIPTION OF THE INVENTION
Synthesis
Compounds of formula (I) are synthesized according to the procedures discussed below. In addition to disclosing known methods for the preparation of these compounds, the present invention provides several novel processes for their synthesis. The first of these is an improved process for the preparation of compounds of formula (I) via the reductive coupling of aldehydes. A second is the stereoselective synthesis of compounds of formula (I) via a modified coupling method. A third is the stereospecific synthesis of compounds of formula (I) from mannitol. The present invention also provides novel processes for the preparation of key intermediates used in the mannitol route.
Reductive Coupling of Aldehydes
A preferred method for the preparation of compounds of formula (I) is the reductive coupling of aldehydes. This method utilizes a catalyst which contains vanadium(II); however, other low valent metals (such as titanium and samarium) and pinacol reagents (such as magnesium) can also be used with advantage. It is based on a process disclosed by Pederson et al. for the preparation of diols. Freudenberger, J. H.; Konradi, A. W.; Pedersen, S. F., J. Am. Chem. Soc. 1989, 111, 8014; and Konradi, A. W.; Pedersen, S. F., J. Org. Chem. 1990, 55, 4506. The preferred catalyst is Caulton's Reagent, [V.sub.2 Cl.sub.3 (THF).sub.6 ].sub.2 [ZN.sub.2 Cl.sub.6 ]. Preparation of this reagent has been disclosed. Bouma et al. Inorg. Chem., 23, 2715-2718. The process is shown in Scheme I. ##STR13## In the operation of this process, an aldehyde of Formula (1) and an aldehyde of Formula (2) are reacted, in a solvent, in the presence of Caulton's Reagent to give a compound of Formula (I) where R.sup.5, R.sup.6 =H. Many of the compounds of formula (I) are available through the operation of the process of Pederson et al. on the corresponding aldehydes. However, the improved process for the reductive coupling of aldhydes, discussed below, is preferred over the method of Pederson et al. Improved Process for the Reductive Coupling of Aldehydes.
Another aspect of the present invention is an improvement of the process disclosed by Pederson et al. for the preparation of 1,4-diamino-2,3-diols. The improvement results in a process which is easier to operate than that of Pederson et al., affords reagents of higher quality and reliability than those of the method of Pederson et al., and results in a higher yield of product than that obtained by Pederson et al.
In practicing the improved reductive coupling process of the present invention, the catalyst is prepared by placing VCl.sub.3 (THF).sub.3 in a dry, oxygen-free flask. Zinc-copper couple is then added and the two solids are stirred vigorously. An organic solvent is then added and the mixture is stirred for about 10 minutes, resulting in a deep green solution and black suspension. Next, a solution of the aldehyde in the same solvent as that used for the catalyst, is added to the catalyst over 2-3 minutes. The progress of the reaction is monitored by Thin Layer Chromatography (silica gel with 50% hexane/ethyl acetate as eluent) until it is determined that the reaction is over. The reaction mixture is then subjected to an aqueous work-up and, if necessary, the product obtained is further purified.
The zinc-copper couple utilized in the improved process is prepared following a known procedure, except that filtration with schlenkware was used instead of decanting solvent. L. Fieser and M. Fieser, Reagents for Organic Synthesis, Volume I, pp. 1292-1293, Wiley, New York, 1967. The use of a glovebag or drybox instead of schlenkware would be equally satisfactory. The solvents used for the preparation of this reagent are sparged with argon for about 30 minutes before use. The zinc-copper couple obtained is in the form of a free-flowing black powder with a few clumps. The zinc-copper couple prepared in this way is superior to commercially obtained or activated zinc dust. This material reduced V(III) to V(II) in dichloromethane within 10 minutes, whereas the use of commercial zinc dust or activated zinc required several hours and frequently did not provide the color change, described above, which is characteristic of complete reduction.
The improved reductive coupling process operates over a temperature range of from -78.degree. to 100.degree. C. The preferred range is from 0.degree. to 40.degree. C. The most preferred range is from 15.degree. to 25.degree. C.
The use of a solvent is required in practicing the improved reductive coupling process. It is anticipated that any polar, aprotic solvent will be useful. Preferred solvents are hydrocarbons, halogenated hydrocarbons and ethers. Particularly preferred are halogenated hydrocarbons such as dichloromethane and dichloroethane.
The improved reductive coupling process may be run over a time period of 0.1 to 24 hours. It is usually run over the time period of 0.3 to 2 hours. However, as expressed above, in practice it is most desirable to moniter the progress of the reaction by thin layer chromatography.
In practicing the improved reductive coupling process, it is important that the glassware and reagents be dry and free of reactive gases such as oxygen and carbon dioxide. Also, moisture, oxygen and carbon dioxide should be rigorously excluded from the reaction as it is carried out. To accomplish this, it is desirable to perform the reaction under an atmosphere of argon or nitrogen. It is desirable that the aldehyde(s) utilized in the improved reductive coupling process be freshly prepared or purified prior to use.
The molar ratio of each reagent is also important. The process operates where the ratio of zinc-copper couple:VCl.sub.3 (THF).sub.3 :aldehyde is 1-3:1-3:1 respectively. The preferred ratio of reagents is 1-1.5:2-2.5:1. The most preferred ratio is 1-1.2:2-2.2:1.
The preferred reagents for the aqueous work-up step of the improved reductive coupling process is 10% disodium tartrate. If the product does not contain an acid-sensitive functionality 1N HCl may be used.
If necessary, the 1,4-diamino-2,3-dihydroxybutanes obtained from the improved reductive coupling process can be further purified by recrystallization or chromatography or any method commonly used in organic synthesis.
Stereoselective Preparation of Compounds of Formula (I)
Another aspect of the present invention is a method for the stereoselective preparation of compounds of formula (1) via modification of the method of Pederson et al. The reductive coupling of an aldehyde using the disclosed procedure of Pederson et al. can be expected to produce a number of stereo isomers. ##STR14## Thus, if an aldehyde, such as depicted in the equation above, with s configuration at the one stereo center is used as the substrate in this reaction, three stereo isomers can be expected to form: (1s,2s,3s,4s), (1s,2r,3r,4s), and (1s,2r,3s,4s). One aspect of the present discovery is the surprising observation that under certain reaction conditions, e.g., changing the reaction solvent, one of these isomers is selectively produced. In addition, the isomer selectivity can be controlled by changing the reaction conditions. This is useful because, even though it is believed all isomers have some level of activity in inhibiting viral protease, certain isomers are more effective, and this aspect of the present invention allows for the selective preparation of the more desirable isomer.
The practice of this aspect of the invention involves using a modified version of the reductive coupling method described by Pederson et al. The usual method to carry out the reductive coupling of aldehydes in the presence of Caulton's reagent is to add the reagent under inert atmosphere to a solution of the aldehyde in a nonpolar halocarbon solvent, usually dichloromethane. This procedure produces predominantly the (1s,2r,3r,4s) isomer. However, if a polar, nonprotic solvent such as dimethylformamide (DMF) is added to the aldehyde solution, before the addition of Caulton's reagent, the predominant isomer is the (1s,2s,3s,4s) isomer. Pederson et al., J. Am. Chem. Soc., 1989, 111, 8014-8016, reports the use of Caulton's reagent for reductive coupling of aldehydes.
Derivatization of Diols
Optionally, after carrying out any of the above described coupling reactions, the product diol (formula (I), R.sup.5, R.sup.6 =H) can then be converted to a derivative (R.sup.5 not equal to H, R.sup.6 =H; R.sup.6 not equal to H, R.sup.5 =H; or R.sup.5 and R.sup.6 not equal to H) by contacting the diol product with a derivatizing agent in the presence of a suitable base The monofunctionalized compounds (e.g., R.sup.5 =H, R.sup.6 not equal to H) can be prepared by employing less than or equal to one molar equivalent of derivatizing agent; and the difunctionalized compounds (R.sup.5, R.sup.6 not equal to H) can be prepared by employing more than two molar equivalents of derivatizing agent. Suitable derivatizing agents include, but are not limited to, acyl chlorides or anhydrides, diphenyl carbonates, and isocyanates using techniques well known to those skilled in the art. Suitable bases are organic and inorganic bases including, but not limited to, aliphatic amines, heterocyclic amines, metal carbonates and metal hydrides.
Preparation of Aldehydes of Formula (1) and Formula (2)
It is anticipated that all aldehydes will work equally well in the process shown in Scheme I and the process described above for the stereoselective synthesis of compounds of formula (1). The method works particularly well with aldehydes that contain an activating group 3,4 or 5 atoms distant from the aldehyde carbon, as discussed by Pederson et al. Aldehydes without activating groups can be coupled using higher temperatures and/or longer reaction times. Different aldehydes can be cross-coupled either by mixing two activated aldehydes and separating the statistical mixture of products, or by reacting an unactivated aldehyde with an activated aldehyde as discussed in the references of Pederson et al. Where the aldehyde of formula (1) has a structure identical to that of formula (2), the resultant compound of formula (I) is a symmetrical 1,4-diamino-2,3-dihydroxybutane. Where the aldehyde of formula (1) has a structure different from that of formula (2), the resultant compound of formula (I) is an unsymmetrical 1,4-diamino-2,3-dihydroxybutane.
Aldehydes of formula (1) and aldehydes of formula (2) can be obtained commercially or can be prepared in a number of ways well known to one skilled in the art of organic synthesis. Preferred methods include but are not limited to those described below for aldehydes of formula (1):
Method A ##STR15##
Compounds wherein Z is H, n is zero, and Y is --C(.dbd.Q)NR.sup.12 --, and the other variables are as described above, can be prepared by reaction of the amine (II) with a carboxylic acid or derivative (III): ##STR16## wherein P is hydrogen or optionally an alcohol protecting group, R.sup.10 is hydrogen or an aliphatic or substituted aromatic group, and the carboxylic acid or ester is activated to nucleophilic attack by methods well known in the art (Bodansky and Bodansky, The Practice of Peptide Chemistry, Springer-Verlag, Berlin, 1984, Chapter II, pp. 89-150), with the preferred method employing 1,1'-carbonyldiimidazole as the activating agent, THF as solvent, and 0.degree.-40.degree. C. as temperature, and P.dbd.H. If a protecting group is necessary, the preferred group is the 2-methoxyethoxymethyl group. Greene, Protecting Groups in Organic Chemistry, Wiley, New York, 1981. Removal of the protecting group if employed, followed by oxidation (see below), provides aldehydes of formulae (V) or (VI). ##STR17##
Method B
Thioamides of structure (VII) and (VIII) can be made from the above protected hydroxyamides (IV) followed by treatment with a thionation reagent (Bodansky and Bodansky, The Practice of Peptide Chemistry, Springer-Verlag, Berlin, 1984, Chapter II, pp. 89-150), and deprotection followed by oxidation to the aldehyde. A preferred thionation reagent is Lawesson's reagent, and a preferred protecting group is the 2-methoxyethoxymethyl group (Greene, Protecting Groups in Organic Chemistry, Wiley, New York, 1981). ##STR18##
Method C
Compounds of structure (XI) and (XII) wherein Y is --SO.sub.2 NR.sup.12 -- can be prepared by the reaction of (II) with an activated sulfonate such as (IX), obtained as described by Bodansky and Bodansky, to produce optionally protected alcohols (X): ##STR19## wherein Act is an activating group, preferably chloride, and P is, optionally, a protecting group. Removal of the protecting group if employed, followed by oxidation (see below), provides aldehydes (XI) or (XII). ##STR20##
Method D
Compounds wherein Y is --CH.sub.2 NR.sup.12 -- can be prepared by the reaction of (11) with an alkylating agent such as (XIII): ##STR21## Wherein LG is a leaving group such as halogen or OSO.sub.2 R, as is described in the art. Bodansky and Bodansky. The preferred method employs a tosylate or iodide as leaving group, and a secondary amine as the nucleophile, i.e., R.sup.2 is not hydrogen. A preferred method for the preparation of compounds wherein R.sup.12 is hydrogen is simply by LiAlH.sub.4 reduction of the amides of formula (V), if hydride-sensitive functionality is not present. A final preferred method is the reaction of amines (II) with aldehydes (XXXIII), followed by reduction of the imine by catalyic hydrogenation or by borohydride reduction of the intermediate imine. ##STR22## Removal of the protecting group, if employed, followed by oxidation (see below), provides aldehydes (XV) and (XVI) ##STR23##
Method E
E} When Y is --C(Cl).dbd.N--, --C(--OR.sup.11).dbd.N--, or --C(--NR.sup.11 R.sup.12).dbd.N-- the aldehydes of Scheme I can be advantageously prepared by reaction of secondary amides or thioamides (XVII) with halogenating agents to produce imidoyl halides (X). Bodanszky and Bodansky. The synthesis of amides and thioamides (XVII) is described above (formula II, R.sup.12 =H; see Method A). The imidoyl halides so produced can then be reacted with alcohols to produce imidates (XIX). Gautier, Miocque and Farnoux, in The Chemistry of Amidines and Imidates, Patai, Ed., Wiley, London, 1975, pp. 398-405. Alternatively, they can be reacted with amines to produce amidines (XX) as shown. Gautier, Miocque and Farnoux, in The Chemistry of Amidines and Imidates, Patai, Ed., Wiley, London, 1975, pp. 297-301. Preferred halogenating reagents include phosphorous pentachloride and phosphorous oxychloride. ##STR24## Cleavage of the protecting group and oxidation to the aldehyde as described below produces (XXI), with the indicated Y values. ##STR25##
Method F
When Y is --NR.sup.12 C(.dbd.O)NR.sup.12 --, the compounds of the invention can be prepared by reacting amine (II) with a derivatizing agent to form the isocyanate or carbamate, followed by reaction with a primary or secondary amine (XXIV), optionally in the presence of a base to produce the protected alcohol derivative (XXVI). Satchell and Satchell, Chem. Soc. Rev., 4, 231-250 (1975).
When Y is --OC(.dbd.O)NR.sup.12, the compounds of the invention can be prepared by reacting amine (II) with a derivatizing agent to form the isocyanate, followed by reaction with an alcohol (XXIII) in the presence of a base to produce the protected alcohol (XXV). ##STR26## Cleavage of the protecting group and oxidation to the aldehyde as described below produces (XXII), with the indicated Y values. ##STR27##
Method G: Oxidation of Alcohol Intermediates
The alcohols or protected alcohols discussed above and represented here by formula (XXVIII), ##STR28## can be readily transformed to aldehydes of formulae (1) or (2). The alcohols represented by formula (XXVIII) can be oxidized directly to the aldehydes of formulae (1) or (2) using methods that are well known in the art. March, Advanced Organic Chemistry, Wiley, New York, 1985, pp. 1057-1060. The protected alcohols represented formula (XXVIII) must be deprotected prior to oxidation; this is done using methods that are well known to those in the art. For a recent review, see Tidwell, Synthesis 857 (1990). Preferred methods of oxidation include pyridinium dichromate, pyridinium chlorochromate, pyridine/sulfur trioxide, and activated dimethyl sulfoxide. The most preferred method employs dimethylsulfoxide/oxalyl chloride, also known as Swern oxidation in dichloromethane or tetrahydrofuran/dichloromethane at -60.degree. C., followed by treatment with a base such as triethylamine. Tidwell, Synthesis 857 (1990).
While the most preferred method of oxidation is gentle and specific, there are functional groups within the contemplated scope that may not survive such oxidation. Examples of these are primary alcohols, amines, indoles, sulfides, thiols. If necessary, these groups can be protected prior to oxidation of the aldehyde. Alternatively, the reductive conditions described below may be used to prepare the aldehyde when oxidative conditions cause difficulties with certain functional groups.
Amine (VIII) can be reacted with any of the above electrophiles, (III, IX or XIII) to form N-methoxyamide (XXIX). It is known that (XXIX) can be reduced cleanly to aldehyde by stoichiometric lithium aluminum hydride, provided that sensitive functionality is not present. Fehrentz and Castro, Synthesis 676 (1990). ##STR29##
Finally, there are functional groups within the contemplated scope that will survive neither lithium aluminum hydride nor oxidation. In this occasion, reduction of aminoester (XXX) with one equivalent of diisobutyl aluminum hydride at low temperature, followed by quenching at low temperature, can provide an alternative to the above conditions. Kawamura et al., Chem. Pharm. Bull 17, 1902 (1969). ##STR30##
Stereospecific Synthesis of Compounds of Formula (I)
This invention also provides a process for the steriospecific synthesis of certain compounds of formula (I) from mannitol. This process is shown in Scheme II. By steriospecific is meant this process yields one diastereomer based on the stereochemistry of the starting material. The process relies on the key intermediate 1,2,5,6-diepoxy-3,4-O-(alkylidene)hexane. This intermediate is prepared from the hexitol derivative, 2,3-O-alkylidinehexitol, which is itself derived from mannitol. The intermediate may be either the D- or L-stereoisomer; the choice of stereoisomer of the starting material determines the stereochemistry of the final product. This intermediate is prepared in two steps, by conversion of the 1,6-hydroxy groups of 2,3-O-alkylidinehexitol to suitable leaving groups, followed by reaction with a base to effect epoxide formation. The intermediate, 1,2,5,6-diepoxy-3,4-O-(alkylidene)hexane, thus prepared is then used to prepare certain compounds of Formula (I). In the next step of this process, each epoxide group of the intermediate, 1,2,5,6-diepoxy-3,4-O-(alkylidene)hexane, is reacted with an organometallic reagent to give a 2,5-dihydroxy derivative. The resulting hydroxy groups or their derivatives are then converted to amino synthons, e.g., by reaction with azide ion in the presence of compounds such as triphenylphosphine and dialkylazodicarboxylate. This procedure gives a 2,5-diazido derivative. Next, the amino synthons are converted to amino groups, e.g., by catalytic hydrogenation of azide residues. Then, the amino groups are derivatized, e.g., by reaction with an electrophile as shown in Scheme II. Finally, the alkylidine protecting group is removed to yield a product which is a compound of formula (I). Optionally, the dihydroxy groups may be derivatized as discussed above. ##STR31##
Synthesis of Dihydroxy Intermediate
Another aspect of the present invention is the preparation of the dihydroxy intermediate, 2 in Scheme II, from the addition of a cuprate to the diepoxide intermediate, 1,2,5,6-diepoxy-3,4-O-(alkylidene)hexane, represented by formula 1 in Scheme II. This is a novel process which is useful for the preparation of intermediates which are themselves useful for the preparation of compounds of formula (I). In practicing this aspect of the invention, a solution of an organometallic reagent in an organic solvent is added to a solution of a copper salt in an organic solvent in a reaction vessel. The resulting mixture is then stirred forming an organocuprate. Next, a solution of the diepoxide intermediate, 1,2,5,6-diepoxy-3,4-O-(alkylidene)hexane, represented by formula 1 in Scheme II, in an organic solvent is added to the formed organocuprate to give the dihydroxy product represented by formula 2 in Scheme II. This is stirred until the reaction is complete and is then subjected to a standard aqueous work-up, which isolates the desired product in an organic solvent. Evaporation of the organic solvent affords the desired product which is represented by formula 2 in Scheme II. If necessary, the product obtained from the practice of this aspect of the invention may purified using well known techniques.
The metal of the organometallic reagent can be lithium or magnesium. The preferred metal is lithium. The copper salt may be any copper salt which provides a source of copper(I). Preferred copper salts are copper(I) bromide, copper(I) chloride, copper(I) iodide and copper(I) bromide-dimethyl sulfide complex. Most preferred is copper(I) bromide-dimethyl sulfide complex. The solvent used in this process may be any aprotic solvent. Preferred solvents are dialkyl ethers and mixtures of dialkyl ethers with tetrahydrofuran. The solvent most preferred for use in this process is diethyl ether. The use of tetrahydrofuran by itself is not desirable. Solvents which are incompatible with this process are protic solvents.
In practicing this process it is important to rigorously exclude moisture and reactive gases such as oxygen and carbon dioxide. All reagents and solvents utilized in this process should be moisture free and free of reactive gases. The reaction vessels and containers should be similarly free of moisture and reactive gases. The reaction should be performed under an atmosphere of an inert gas such as nitrogen or argon.
In practicing this aspect of the invention, the reaction may be carried at over a temperature range of -78.degree. to 25.degree. C. The preferred temperature range is -78.degree. to -20.degree. C. It is desirable to add the solution of the organometallic reagent to the solution of the copper salt at about -20.degree. C. After adding the 1,2,5,6-diepoxy-3,4-O-(alkylidene)hexane it is desirable to stir the resultant mixture at 0.degree. C. The reaction may be carried out over a time period of 5 minutes to 18 hours. The usual reaction time is between 5 minutes and 1 hour.
If necessary, the compounds provided by this aspect of the invention may be purified by any technique useful for the purification of such compounds. Preferred methods include recrystallization and chromatography.
The intermediate represented by formula 5 in Scheme II may also be prepared according to the method shown in Scheme III. In this method, 1,2,5,6-diepoxy-3,4-O-(alkylidene)hexane is reacted sequentially with lithium bis(trimethylsilyl)amide, tetrabutylammonium fluoride and N-(benzyloxycarbonyl)succinimide to give the N-protected diaminodiol intermediate represented by formula 8 in Scheme III. This intermediate is then reacted with triphenylphoshine and diethyl azodicarboxylate to give the bisaziradine intermediate, 9. Finally, reaction of 9 with an organocuprate affords intermediate, 5, which can be further elaborated to compounds of formula (I) as shown in Scheme II.
Synthesis of Aziridines
Another aspect of the present invention is a novel process for the conversion of the N-protected diamino diol, represented by formula 8 in Scheme III, to the bisaziridine intermediate, 9. The process of the present invention is analogous to the Mitsunobu reaction and may be viewed as an intramolecular Mitsunobu reaction. The Mitsunobo reaction is a known method for the conversion of a hydroxy group to another functional group, e.g., to an amino group. Mitsunobu, O., Synthesis 1981, 1. The process of the present invention is distinguished from the known Mitsunobu reaction by being an intramolecular reaction which yields an aziridine. No references were found in the literature which disclose the synthesis of an aziridine ring via an intramolecular Mitsunobu reaction in which the amino group is protected with benzyloxy carbonyl. The Benzyloxy-carbonylgroup is readily deprotected by simple hydrogenolysis. Other protecting groups such as tosylamides are removed with difficulty and need drastic conditions. ##STR32##
In addition to the utility of this process for the preparation of bisaziridine intermediate 9 of Scheme III, it is also anticipated that this process will have utility for the synthesis of any molecule containing an aziridine ring. The only requirement which must be met in using this process for the synthesis of such molecules is that there be available a suitable precurser molecule which contains at least one functional group pair. A functional group pair is defined as a hydroxy group and an amino group beta to the hydroxy group. Practicing this process on a precurser molecule containing a single functional group pair would give rise to a product containing a single aziridine group. Practicing this process on a precurser molecule containing two functional pair groups, such as formula 8 of Scheme III, gives a product containing two aziridine groups. Similarly, precurser compounds with three or four functional group pairs would give products containing three or four aziridine groups respectively.
In practicing this aspect of the invention, diethyl azodicarboxylate is added to a solution of the precurser molecule, e.g., compound 8 in Scheme III, and triphenylphoshine in an anhydrous organic solvent. The reaction is stirred and its progress is monitored by thin layer chromatography (10:1:10, ethyl acetate/ethyl alcohol/hexane) until it is complete. The reaction mixture is then concentrated to a small volume and the product is purified, if necessary.
The ratio of triphenyl phosphine:diethyl azodicarboxylate:diol utilized in this process may be 1-4:1-4:1 respectively. A preferred ratio of reagents is 1-2:1-2:1. The most preferred ratio is 1:1:1.
The process requires the use of a reaction solvent. Polar aprotic solvents may be used. Preferred solvents include tetrahydrofuran, benzene and toluene. The most preferred solvent is tetrahydrofuran. Protic solvents are incompatible with this process.
In practicing this process it is important to rigorously exclude moisture and reactive gases such as oxygen and carbon dioxide. All reagents and solvents utilized in this process should be moisture free and free of reactive gases. The reaction vessels and containers should be similarly free of moisture and reactive gases. The process should be performed under an atmosphere of an inert gas such as nitrogen or argon.
This process operates over a temperature range of 25.degree. to 85.degree. C. The preferred temperature range is 55.degree. to 85.degree. C. The most preferred temperature range is 70.degree. to 85.degree. C.
The process may be carried out over a time range of 5 minutes to 24 hours. The process is usually carried out over a time range of 5 minutes to 30 minutes.
The aziridine products provided by this aspect of the invention can be further purified, if necessary, by recrystallization or chromatography.
It is further anticipated that this process would be useful for the preparation of saturated 3-7 membered nitrogen containing heterocycles by carrying out an intramolecular Mitsunobo reaction on a precurser molecule containing a protected nitrogen atom and a hydroxyl group separated by 2-6 atoms.
Hydrogenation of Bis(N-CBZ)-diaminodiols
The compounds of formula (I) obtained by any of the above methods can be further elaborated to give other compounds of formula (I). For example, compounds of formula (I) which are bis(N-CBZ)-diaminodiols can be hydrogenated to remove the CBZ protecting group and give the corresponding diaminodiol which may then be further elaborated at the amine residues. The hydrogenation to remove the CBZ protecting group can be carried out using any of the catalysts, solvents and reaction conditions commonly employed to effect removal of this group. A preferred method is to take up the bis(N-CBZ)-diaminodiol in a minimum amount of tetrahydrofuran to permit some solubility, add one volume of ethanol, and optionally 1.degree.-100.degree. volume % acetic acid, and 0.1 weight equivalents of 10% palladium on carbon, and stir under hydrogen at ambient temperature and pressure for 24 hours, occasionally evacuating the reaction flask and refilling with hydrogen. The reaction mixture is worked-up using standard techniques and, if necessary, the diaminodiol obtained is further purified.
Coupling of Diaminodiols
The diaminodiols of formula (I) obtained as described above or from any other source can be further elaborated by reacting them with any one of the many known electrophiles. Coupling reactions of the diaminodiols with activated esters are a particularly useful method for elaborating these compounds. Many conditions and reagents are available to effect coupling. Some preferred methods are exemplified in the Example section. For example, the diaminodiols of formula (I) can be reacted with suitably protected peptides, suitably protected amino acids or carboxylic acids in the presence of dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole hydrate using procedures commonly employed in peptide synthesis to give the corresponding diamidodiol. The diaminodiols of formula (I) can be reacted with suitably protected peptides, suitably protected amino acids or carboxylic acids in the presence of Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) to give the corresponding diamidodiol. The diaminodiols of formula (I) can be coupled with carbonyldiimidazole. The diaminodiols of formula (I) can be reacted with activated esters such as N-hydroxysuccinimide esters and p-nitrophenylesters to give the corresponding diamidodiol. The diaminodiols of formula (I) can be reacted with isocyanates to give the corresponding urea. The diaminodiols of formula (I) can be reacted with epoxides to give the corresponding addition product.
Biochemistry
The compounds of formula (I) prepared were then tested as described herein to determine their ability to inhibit HIV protease activity.
It is believed the antiviral compounds of this invention can be administered as treatment for viral infections by any means that produces contact of the active agent with the agent's site of action in the body of a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
The dosage administered will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired. A daily dosage of active ingredient can be expected to be about 0.001 to 1000 milligrams per kilogram of body weight.
Dosage forms (compositions suitable for administration contain from about 1 milligram to about 100 milligrams of active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.
The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.
Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field.
Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:
Capsules
A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
Soft Gelatin Capsules
A mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil was prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules are washed and dried.
Tablets
A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.
EXAMPLES
Procedure I: Preparation of Intermediates ##STR33##
N-Carbobenzyloxyalanine (6.63 g, 29.7 mmol; Sigma Chemical Company) was dissolved in 30 mL THF in a 100 mL oven-dried flask under N.sub.2 and stirred at room temperature while adding 1,1'-carbonyl diimidazole (4.82 g, 29.7 mmol; Aldrich Chemical Company) neat. Copious bubbling occurred, indicating CO.sub.2 formation. The mixture was stirred 30 minutes and (s)-2-amino-1-phenylpropanol (4.5 g, 29.7 mmol; Sigma Chemical Company) was added neat. Stirring was continued for 18 hours. The mixture was poured into a separatory funnel and the flask rinsed with dichloromethane. 100 mL of dichloromethane was added, and 50 mL saturated aqueous disodium-L-tartaric acid. The funnel was shaken, the aqueous layer removed, the organic layer washed with saturated bicarbonate and brine, and dried with magnesium sulfate. Filtration and solvent removal yielded a white solid. Recrystallization by dissolving in hot ethyl acetate, filtering, and adding hexane until cloudy provided 6.76 g (64%) white crystals with properties consistent with alcohol (III).
Melting Point: 120.degree.-121.degree. C.
NMR (300 MHz, CDCl.sub.3); .delta., ppm: 7.1-7.5 (m, 10 H); 6.45 (broad d, 1H, NH); 5.35 (d, 1H, NH); 5.1 (broad s, 2H, OCH.sub.2 Ph); 4.1-4.2 (m, 2H, alanine a-CH); 3.6 (m, 2H, CH.sub.2 OH); 2.85 (m, 2H, phenylalaninol b-CH.sub.2); 1.2-1.4 (d, 3H, methyl).
Using the above conditions, the following a-aminoalcohols were prepared: ##STR34##
Melting Point: 158.degree.-160.degree. C.
NMR (300 MHz, CDCl.sub.3): 7.1-7.6 (m, 10 H); 6.2 (broad d,1H, NH); 5.25 (d, 1H, NH); 5.1 (broad s, 2H, OCH.sub.2 Ph); 4.2 (m, 1H, isoleucine a-CH); 3.95 (dd, 1H, isoleucine a-CH); 3.6 (m, 2H, CH.sub.20 H); 2.85 (m, 2H, phenylalaninol b-CH.sub.2); 1.85 (m, 2H, isoleucine methylene)1.3 (m, 1H, isoleucine methine); 0.8-1.1 (m, 6H, methyls). ##STR35##
Melting Point 173.degree.-180.degree. C.
NMR (300 MHz, DMSO-d6): (m, 7.65, 1H, NH); 7.2-7.-4 (11H, m, aromatic and NH); 5.05 (2H, m, OCH.sub.2); 3.9 (m, 1H, CH.sub.2 OH); 3.8 (dd, 1H, isoleucine a-CH); 3.35-3.5 (m, 2H, CH.sub.2 OH); 2.6-2.9 (m, 2H, phenylalaninol b-CH.sub.2); 1.6 (m, 2H, isoleucine methylene)1.3 (m, 1H, isoleucine methine); 0.8-1.1 (m, 6H, methyls). ##STR36##
Melting point 147.5.degree.-149.5.degree. C.
NMR (300 MHz, DMSO-d6): 7.65 (d, 1H, NH); 7.2-7.4 (6H, m, aromatic and NH); 5.05 (2H, m, OCH.sub.2); 4.7 (dd, 1H, isoleucine a-CH); 3.8 (m, 1H, methionine a-CH); 3.25-3.4 (m, 2H, CH.sub.2 OH); 2.3-2.5 (m, 2H, methione g-CH.sub.2); 1.9 (s, 3H, SCH.sub.3); and 0.7-1.9, aliphatics. ##STR37##
NMR (300 MH.sub.2, CDCl.sub.3): 7.2-7.2 (m,10H, aromatic); 6.2 (d, 1H, NH); 5.1-5.2 (m, 3H, OCH.sub.2, NH); 4.15 (m, 1H, phenylalaninol a-CH) 3.95 (dd, 1H, valine a-CH); 3.5-3.7 (m, 2H, CH.sub.2 OH); 2.8-2.9 (m, 2H, phenylalaninol .beta.-CH.sub.2); 2.1 (m, 1H, valine b-CH); 0.9 (d, 3H, methyl); 0.8 (d, 3H, methyl).
Procedure II: Synthesis of Aldehydes ##STR38##
A nitrogen-filled, oven-dried 500 mL flask was charged with 35 mL CH.sub.2 C.sub.12 and 2.90 g oxalyl chloride (25.25 mmol) under N.sub.2 and cooled to -60. Dry dimethylsulfoxide (2.42 g, 33.6 mmol) in 40 mL CH.sub.2 Cl.sub.2 was added over about 10 min. The mixture was stirred 15 min at -60, and alcohol C (6.00 g, 16.8 mmol) was added in 100 mL 1:1 THF/CH.sub.2 Cl.sub.2. After stirring 25 min at -60, triethylamine (6.8 g, 67.2 mmol) was added in 20 mL CH.sub.2 C.sub.12. Stirred 30 min at -60 and quenched with 20% aqueous KHSO.sub.4 (150 mL) at -60. A white solid formed as water froze. Added 180 mL hexane and warmed to RT. Separated aqueous layer and washed with ether. Combined organic layers, filtered off white solid (presumably unreacted, insoluble starting alcohol) and washed with sat. aq. NaHCO.sub.3, water and brine, and dried over MgSO.sub.4. Yield: 5.12 g white solid. Analytically pure sample can be obtained by recrystallization from EtOAc/hexane, but the aldehyde is very readily epimerized at the a-carbon, and a small amount of the S,R isomer is generally observed after workup or other manipulation. Additionally, variable amounts of aldehyde trimers oligermers may be observed if the aldehyde is exposed to strong acids in organic solvents.
Melting Point: 125.degree.-126.degree. C.
NMR (300 MH.sub.2, CDCl.sub.3): 9.6 (br s, 1H, CHO); 7.1-7.4 (m, 10H, aromatic); 6.5 (br, 1H, NH); 5.1-5.2 (m, 3H, NH and OCH.sub.2); 4.65 (m, 1H, phenylalaninal a-CH); 4.25 (m, 1H, alanine a-CH); 3.15 (m, 2H, phenylalaninal .beta.-CH.sub.2); 1.35 (d, 3H, CH.sub.3).
Using the above procedure, the following aminoaldehydes were prepared: ##STR39##
Melting Point 116.degree.-117.degree. C.
NMR (300 MH.sub.2, CDCl.sub.3): 9.6 (br s, 1H, CHO); 7.1-7.5 (m, 10H, aromatic); 6.45 (br d, 1H, NH); 5.1-5.2 (m, 3H, NH and OCH.sub.2); 4.65 (m, 1H, phenylalaninal a-CH); 4.1 (m, 1H, isoleucine a-CH); 3.15 (m, 2H, phenylalaninal .beta.-CH.sub.2); 1.85 (m, 2H, isoleucine methylene) 1.4 (m, 1H, isoleucine .beta.-CH.sub.2); 0.8-1.1 (m, 6H, methyls).
MS (FAB): M+H (measured) 397.21; (calculated) 397.17 ##STR40##
NMR (300 MH.sub.2, CDCl.sub.3): 9.6 (br s, 1H, CHO); 7.1-7.4 (m, 10H, aromatic); 6.4 (br d, 1H, NH); 5.1-5.2 (m, 3H, NH and OCH.sub.2); 4.75 (m, 1H, phenylalaninal a-CH); 4.0 (m, 1H, valine a-CH); 3.15 (m, 2H, phenylalaninal .beta.-CH.sub.2); 2.1 (m, 1H, valine .beta.-CH); 0.8-1.0 (m, 6H, methyls).
MS (FAB): M+H (measured) 383.13; (calculated) 383.20 ##STR41##
NMR (300 MH.sub.2, CDCl.sub.3): 9.6 (br s, 1H, CHO). ##STR42##
NMR (300 MH.sub.2, CDCl.sub.3): 9.6 (br s, 1H, CHO); 7.1-7.5 (m, 10H, aromatic); 6.45 (br d, 1H, NH); 5.1-5.2 (m, 3H, NH and OCH.sub.2); 4.7 (m, 1H, 4-chlorophenylalaninal a-CH); 4.1 (m, 1H, isoleucine a-CH); 3.1 (m, 2H, 4-chlorophenylalaninal .beta.-CH.sub.2); 1.85 (m, 2H, isoleucine methylene) 1.4 (m, 1H, isoleucine .beta.-CH.sub.2); 0.8-1.1 (m, 6H, methyls). ##STR43##
NMR (300 MH.sub.2, DMSO-d6; mixture of isomers; major isomer): 9.4 (s, 1H, CHO).
Procedure III: Preparation of Aldehydes
Method A ##STR44##
1,1-Dimethylethyl 1-formyl-2-phenylethylcarbamate
Step 1: A solution of 11.0 g (41.5 mmol) of N-tertbutoxycarbonyl-L-phenylalanine (Sigma Chemical Co., St. Louis, Mo.) in 100 mL of CHCl.sub.3 at 0.degree. C. was treated with 4.6 mL of N-methylmorpholine followed by 5.4 mL of isobutylchloroformate. After stirring for 10 minutes the reaction mixture was treated with 4.05 grams of N,O-dimethylhydroxylaminehydrochloride followed by 5.8 mL of triethylamine. Upon stirring at 0.degree. C. for 1 hour followed by 16 hours at room temperature, the reaction mixture was worked up by washing with 2.times.50 mL of 0.2N HCl, 2.times.50 mL of 0.5N NaOH and 50 mL of saturated NaCL. The organic layer was dried with MgSO.sub.4 and concentrated under reduced pressure to yield 12.4 grams of an oil which was used in the next step without further purification. This material showed NMR (CDCl.sub.3): 1.4 (s, 9H), 3.0 (m, 2H), 3.2 (s, 3H), 3.65 (s,3H), 4.95 (m, 1H), 5.2 (m, 1H), 7.2 (m,5H); MS cal 309.18 f 309.33.
Step 2: The above material was dissolved in 250 mL of ether, cooled to 0.degree. C. and treated with 9.5 grams (250 mmol) of lithium aluminum hydride. After warming to room temperature and stirring for 1 hour the reaction was quenched with a solution of 0.35 mole KHSO.sub.4 in 200 mL of water. The organic layer was separated and the aqueous layer was extracted with 200 mL of ether. The combined ether layers were washed with 2.times.100 mL 10% HCl, 100 mL NaHCO.sub.3 and dried over MgSO.sub.4. Upon concentration under reduced pressure, 9.8 g of a pale yellow oil was obtained which solidified upon standing in the refrigerator. The product showed NMR(CDCl.sub.3): 1.4 (s, 9H), 2.9 (m, 2H),7.2 (m,5H), 9.6 (s,1H).
A sample prepared in another experiment was purified by chromatography to yield a pure sample which showed the following NMR (CDCL.sub.3): 1.4(S<9H), 3.1 (d,J=10HZ,2H), 4.4 (m,1H), 5.05 (m,1H), 7.05 (m,5H), 9.6(s,1H).
Method B ##STR45##
1,1-Dimethylethyl 1-formyl-4-thia-pentylcarbamate
Step 1: A method similar to that reported in Organic Synthesis, volume 67, 69 (1988) was used. Thus, 9.75 grams of N,O-dimethyhydroxylamine hydrochloride in 60 mL of CH.sub.2 C.sub.12 was cooled below 5.degree. C. and treated with 7.35 mL of triethylamine through an addition funnel to keep the temperature below 5.degree. C. This material was maintained below 5.degree. C. and added to the reaction mixture 2 minutes after the addition of 7.73 mL of methylchloroformate to a solution at -20.degree. C. of 24.9 grams of N-tert-butoxycarbonyl-L-methionine (Sigma Chemical Co., St. Louis, Mo.) in 400 mL of CH.sub.2 C.sub.12 containing 10.97 mL of N-methylmorpholine. After the addition, the reaction mixture was warmed to room temperature and stirred for 4 hours. At the end of this period the reaction mixture was worked up as described above (Method A, Step 1) to yield 24.39 grams of an oil which was used in the next step without further purification. The product showed NMR(CDCl.sub.3): 1.4 (s,9H), 1.95 (m, 2H), 2.55 (t, J=8Hz, 2H), 2.8 (s, 6H),4.35 (m,1H).
Step 2: This material was dissolved in 80 mL of ether and added to a suspension of 4.5 grams of lithium aluminum hydride in 400 mL of ether at -45.degree. C. at such a rate that the temperature remained below -35.degree. C. Upon completion of the addition, the reaction mixture was warmed to 5.degree. C., then cooled to -35.degree. C. and treated with 24.85 grams of NaHSO.sub.4 in 65 mL of water at such a rate that temperature was below 2.degree. C. The resulting slurry was stirred for 1 hour and then filtered through a pad of celite. The celite pad was washed with 2.times.100 mL of ether and the combined ether layers were washed with 3.times.100 mL of 1N HCl, 2.times.100 mL NaHCO.sub.3 and 100 mL of saturated NaCl. The organic layer was dried over MgSO4 and concentrated under reduced pressure to yield 17.67 grams of an oil which was used without further purification. The product showed NMR (CDCl.sub.3): 1.4 (S, 9H), 1.9 (m,2H), 2.08 (s, 3H), 2.55 (t, J=10Hz, 2H), 4.25 (m, 1H), 5.2 (m, 1H).
The following aldehydes were prepared by the method of Method B:
1,1-Dimethylethyl 2-oxoethylcarbamate ##STR46##
NMR (CDCl.sub.3): 1.45 (S, 9H), 4.05 (d, J=8Hz, 2H), 5.3 (m, 1H), 9.65 (s, 1H).
1,1-Dimethylethyl 1-formylethylcarbamate: ##STR47##
NMR (CDCl.sub.3): 1.35 (d, J=10Hz, 3H), 1.45 (s, 9H), 4.2 (m, 1H), 5.15 (m, 1H), 9.55 (s, 1H).
1,1-Dimethylethyl 1-formyl-2-methylpropylcarbamate ##STR48##
NMR (CDCl.sub.3): 0.95 (d, J=7Hz, 1.5H), 1.05 (d, j=7Hz, 1.5H), 1.45 (S, 9H), 2.3 (m, 1H), 4.25 (m, 1H), 5.15 (m, 1H), 9.65 (s, 1H).
1,1-Dimethylethyl 1-formyl-3-methylbutylcarbamate ##STR49##
NMR (CDCL.sub.3): 0.95 (m, 6H), 1.4 (s, 9H), 1.6 (m, 1H), 4.2 (m, 1H), 5.0 (m, 1H) 9.55 (s, 1H).
1,1-Dimethylethyl 2-formyl-1-pyrrolidinecarbamate ##STR50##
1.48 (s, 9H), 1.72-2.20 (m, 4H), 3.23-3.72 (m, 3H)
1,1-Dimethylethyl 2-oxoethyl-1-phenylcarbamate ##STR51##
NMR (CDCL.sub.3): 1.4 (s), 7.2 (m), 9.45 (s).
Benzyl 1-formyl-2-phenylethylcarbamate ##STR52##
NMR (CDCl.sub.3): 3.15 (d, J=6Hz, 2H), 4.5 (d, j=12.6Hz, 1H), 5.1 (s, 2H), 5.35 (m, 1H), 7.1-7.4 (m, 10H), 9.6 (s, 1H).
1,1-Dimethylethyl 1-formyl-3-phenylpropylcarbamate ##STR53##
NMR (CDCL.sub.3): 1.45 (s, 9H), 1.9 (m, 2H), 2.75 (m, 2H), 4.25 (m, 1H), 5.1 (m, 1H), 7.2 (m, 5H), 9.55 (s, 1H).
1,1-Dimethylethyl 1-formyl-2-(4-fluorophenyl)ethylcarbamate ##STR54##
NMR (CDCL.sub.3): 1.45 (s, 9H), 3.1 (m, 2H), 4.4 m, 1H), 5.05 (m, 1H), 7.0 (m, 4H), 9.65 (s, 1H).
1,1-Dimethylethyl 1-formyl-2-(4-iodophenyl)ethylcalrbamate ##STR55##
NMR (CDCL.sub.3): 1.4 (s, 9H), 3.1 (m, 2H), 4.4 (s, 1H), 5.1 (m, 1H), 6.9 (d, j=8Hz, 1H), 7.2 (m, 2H), 7.6 (d, j=8Hz, 1H), 9.6 (s, 1H).
1,1-Dimethylethyl 1-formyl-2-(4-benzyloxyphenyl)ethylcarbamate ##STR56##
NMR (CDCl.sub.3): 1.45 (s,9H), 3.05 (d, J=12Hz, 2H), 4.4 (m, 1H), 5.05 (s, 2H), 6.9 (d, J=12Hz, 2H), 7.05 (d, j=12Hz, 2H), 7.3 (m, 5H),9.6 (s,1H).
Coupling of Aldehydes With Caulton's Reagent
EXAMPLE 1A AND 1B ##STR57##
Bis (1,1)-dimethylethyl) (2,3-dihydroxy-1,4-bis(2-(methylthio)ethyl)-1,4-butanediyl)biscarbamate
To a solution of 1,1-dimethylethyl 1-formyl-4-thiabutylcarbamate, from Method B, in 1 mL of CH.sub.2 Cl.sub.2, under argon, was added 5 mL of the Caultons reagent (prepared via the method reported by Bouma et al, Inorg. Chem., 23, 2715-2718 (1984)) followed by 10 drops of DMF. After stirring over night the reaction mixture was treated with 1 mL of 20% KOH, filtered through celite and the celite pad was rinsed with CH.sub.2 Cl.sub.2. The organic layer was separated from the combined filtrates, dried and concentrated under reduced pressure to afford the crude product. This material was chromatographed over silica gel using 20% EtOAc/hexane to afford a fraction containing 33.6 mg of an isomer of the desired product as a crystalline solid. A second fraction was found to contain 12 mg of another isomer of the desired product as a crystalline solid (Example 1B,). Example 1B had MS: cal 469.24 F 469.19.
EXAMPLE 2A ##STR58##
Bis(1,1-dimethylethyl) (2,3-dihydroxy-1,4-(phenylmethyl)-1,4-butanediyl)biscarbamate (1S,2S,3S,4S)
A solution of 1.06 g 1,1-dimethylethyl 1-formyl-2-phenylethylcarbamate, from Method A, in 10 mL of CH.sub.2 Cl.sub.2, was treated with 3 mL of DMF followed by 10 mL of Caulton's reagent and stirred for 16 hour. At the end of the period the reaction mixture was treated with 10 mL of 20% NaOH, stirred for 15 minutes and then diluted with 50 mL of ether. After filtering through a celite pad, the celite pad was washed with 3.times.50 mL of ether and the organic layer was separated from the filtrate. Upon washing with 2.times.20 mL of NaCl solution, drying over Na.sub.2 SO.sub.4 and concentration under reduced pressure the organic layer gave a crude product which was chromatographed over 50 grams of silica gel using 2:1 Hex:EtOAc as eluant. This afforded 0.35 g of the desired product. mp=210-213; NMR: (CDCl.sub.3) 1.4 (s,18H), 3.0 (dd,J=10 Hz,2H), 3.2 (m 4H), 4.05 (m,2H), 4.4 (m,4H), 7.2 (m,10H). Upon D.sub.2 O exchange, the multiplet at 4.4 became a doublet (d, J=10 Hz, 4H); MS Cal 501.3 F500.85; Anal Cal C: 67.18, H: 8.05, N: 5.60 F C: 66.92, H: 8.31, N: 5.64. The product of this reaction had the stereochemistry, 1S,2S,3S,4S; this was determined as described below.
The stereochemistry of each of the nitrogen bearing carbon atoms is known to be S since the starting material was the L-isomer. The stereochemistry of the hydroxy bearing carbon atoms was determined by conversion of the diol to its corresponding oxazolidinone and measuring the coupling constant between the ring protons. See J. Med. Chem. 30, 1978-83 (1987). The procedure was carried out as follows: to 100 mg of the diol, 4 mL of 4N HCl in dioxane was added and after stirring for 15 min the volatile material was evaporated by blowing nitrogen. Upon subjecting the residual product to high vacuum under KOH it was dissolved in 4 mL of CHCl.sub.3, cooled to 0.degree. C. and 0.28 mL of triethylamine was added. To this, 0.206 mL of 10% phosgene solution in toluene was added and stirred for 16 hour. At the end of this period the reaction mixture was diluted with 75 mL of EtOAc, washed with 10 mL 1N HCl, 10 mL of NaHCO.sub.3, dried and concentrated under reduced pressure to give a product which was purified by flash chromatography to give 22.3 mg of the desired oxazolidinone that crystallized to afford 15.8 mg of material. NMR (CDCl.sub.3) of this material showed a coupling of 7.5 Hz between the protons attached to the oxygen and nitrogen bearing carbon atoms. This coupling constant is consistent with each of the hydroxy bearing carbons being in the S configuration. Thus, this molecule was assigned the stereochemistry 1s,2s,3s,4s.
EXAMPLE 2B ##STR59##
Bis(1,1-dimethylethyl) (2.3-dihydroxy-1,4-(phenylmethyl)-1,4)-butanediyl)biscarbamate (1S,2R,3R,4S)
To 10 mL of Caulton's reagent, 1.06 g (4 mmol) of 1 1-formyl-2-phenylethylcarbamate, from Method A, was added and after all the aldehyde dissolved 3 mL of DMF was added. The reaction mixture was then treated in a manner similar to Example 2A to give 0.41 g of the desired compound as a solid mp 202.degree.-204.degree., NMR(CDCl.sub.3): 1.4 (s, 18H), 2.9 (m, 4H), 3.4 (s, 2H), 4.0 (s, 2H), 4.8 (d, J=10Hz, 2H), 7.2 (m, 10H). MS cal. 501.3 Found 501.05. Elemental Analysis cal C:67.18, H:8.05, N:5.60; Found C:66.94, H:8.15, N:5.60. This material was shown to have the stereochemistry 1s,2r,3r,4s by the method described in Example 2A; the oxazolidinone produced showed a coupling constant of 5.5 Hz between the protons attached to oxygen and nitrogen bearing carbon atoms.
EXAMPLE 2C ##STR60##
Bis(1,1-dimethylethyl) (2,3-dihydroxy-1,4-(phenylmethyl)-1,4-butanediyl)biscarbamate (1S,2S,3R,4S)
The 1s,2s,3r,4s isomer was prepared by adding a solution of 1.0013 grams of 1,1-Dimethylethyl 1-formyl-2-phenylethylcarbamate, from Method A, in 2 mL of dry CH.sub.2 Cl.sub.2, to 15 mL of Caulton's reagent followed by 3 mL of DMF. This was stirred for 16 h, treated with 10 mL of 20% KOH solution and stirred for 1 hour and filtered through a pad of celite. The organic layer from the filtrate was dried with Na2SO.sub.4 and concentrated under reduced pressure to give a crude product. This material was chromatographed over 80 grams of silica gel eluting with 20% EtOAc to give 0.166 g of product, mp=172.degree.-174.degree. C. MS: calcd. 501.30, found 501.66.
EXAMPLE 2D ##STR61##
Bis(1,1-dimethylethyl) (2,3-dihydroxy-1,4-(phenylmethyl)-1,4-butanediyl)biscarbamate (1S,2R,3R,4S)
To 0.997 gram (4 mmol) of 1,1-dimethylethyl 1-formyl-2-phenylethylcarbamate, from Method A, under argon, 10 mL of dry CH.sub.2 Cl.sub.2 was added and after all the aldehyde has dissolved 10 mL of Caulton's reagent was added. The reaction was then treated in a manner similar to that described in Example 16 to give 0.332 g of the desired product with NMR identical to that of Example 2B.
EXAMPLE 3 ##STR62##
Bis(1,1-dimethylethyl) (2,3-dihydroxy-1,4-butanediyl)biscarbamate
1,1-Dimethylethyl 2-oxoethylcarbamate was couple a described in Example 2B to give from 0.997 grams of the aldehyde 39 mg of the desired product. NMR (CDCl.sub.3, D.sub.2 O) 1.45 (s, 18H), 3.2-3.5 (m, 4H), 3.6 (t, J=10Hz, 4H), 5.15 (m, 2H); MS Calcd 321.20, F321.29.
EXAMPLE 4 ##STR63##
Bis(1,1-dimethylethyl) (2,3-dihydroxy-1,4-dimethyl-1,4-butanediyl)biscarbamate
1,1-Dimethylethyl 2-oxoethylcarbamate was coupled as described in Example 2B to give from 0.693 g of the aldehyde 0.342 g of the desired product. NMR (CDCl.sub.3, D.sub.2 O): 1.2 (d, J=10Hz, 6H), 1.4 (s, 18H), 3.35 (s, 2H), 3.85 (m, 2H), 4.95 (m, 2H); MS Calcd 349.23; F 349.35.
EXAMPLE 5 ##STR64##
Bis(1,1-dimethylethyl) (2,3-dihydroxy-1,4-(1-methylethyl)-1,4-butanediyl)biscarbamate
1,1-Dimethylethyl 1-formyl-2-methylpropylcarbamate was coupled as described in Example 2D to give, from 0.845 g of aldehyde, 0.160 g of the desired product, mp 156-159; NMR (CDCl.sub.3, D.sub.2 O): 1.0 (d, J=10Hz) 1,45 (s, 18H), 2.0 (m, 2H), 3.2 (t, J=10Hz, 2H), 3.65 (s, 2H),5.0 (d, J=10Hz, 2H).
EXAMPLE 6 ##STR65##
Bis(1,1-dimethylethyl) (2,3-dihydroxy-1,4-(2-methylpropyl)-1,4-butanediyl)biscarbamate
1,1-Dimethylethyl 1-formyl-3-methylbutylcarbamate was coupled as described in Example 2D to give, from 0.933 g of the aldehyde, 0.1799 g of the desired product, mp 152-153, NMR (CDCl.sub.3, D.sub.2 O): 0.95 (m,12H), 1,4 (s,18H),1.6-1.8 (m, 6H), 3.2 (s, 2H), 3.8 (m, 2H), 4.95 (m, 2H); Elemental Analysis: Cal C:61.08 H:10.25 N:6.48; Found C:60.79 H:10.31 N:6.51; Ms Cal 433.33 F 432.96.
EXAMPLE 7 ##STR66##
Bis(1,1-dimethylethyl) 2,2'-(1,2-dihydroxy-1,2-ethanediyl)-1-bis(pyrrolidinecarboxylate)
1,1-Dimethylethyl 2-formyl-1-pyrrolidinecarbamate was coupled as described in Example 2D to give, from 1.99 grams of the aldehyde, 1.14 grams of the desired product. NMR (CDCl.sub.3) 1.45 (s, 18H), 1.6-2.0 (m, 8H), 3.35 (m, 2H), 3.45 (m, 2H), 3.6 (m, 2H), 3.95 (m, 2H); MS Calc 401.27 Found 401.34.
EXAMPLE 8 ##STR67##
Bis (1,1-dimethylethyl) (2,3-dihydroxy-1,4-diphenyl-1,4-butanediyl)biscarbamate
1,1-Dimethylethyl 2-oxoethyl-1-phenylcarbamate was as described in Example 2D to give, from 1.13 grams of the aldehyde, 0.51 grams of the product which upon crystallization from EtOAc gave 0.089 g of the desired product. NMR (CDCl.sub.3, D.sub.2 O): 1.4 (s, 9H), 3.8(m, 2H), 7.2 (m, 5H); MS Calcd 473.27 Found 473.35.
EXAMPLE 9 ##STR68##
Bis(Dimethylethyl) (2,3-dihydroxy-1,4-(phenylmethyl)-1,4-butanediyl)biscarbamate
Benzyl 1-formyl-2-phenylethylcarbamate was coupled as described in Example 2D to give, from 2.02 grams of the aldehyde, 0.407 grams of the desired product, mp 201.degree.-205.degree. C.; NMR (DMSO-d.sub.6) 2.7 (m, 4H), 3.3 (s, 2H), 4.2 (m, 4H), 7.2 (m, 2OH). Material prepared in another similar experiment showed MS Cal 569.27 Found 569.31.
EXAMPLE 10 ##STR69##
Bis(1,1-dimethylethyl) (2,3-dihydroxy-1,4-(2-phenylmethyl)-1,4-butanediyl)biscarbamate
1,1-Dimethylethyl 1 -phenylpropylcarbamate was coupled as described in Example 2D to give, from 2.86 grams of the aldehyde, 0.75 grams of the desired product, mp 174.degree.-175.degree. C. NMR (CDCl.sub.3, CD.sub.3 OD): 1.35 (s,18H), 1.8 (m, 4H), 2.6 (t, J=10Hz, 4H), 3.4 (s, 2H), 3.6 (m, 2H), 7.1 (m, 10H); MS Cal 529.33 Found 529.44.
EXAMPLE 11 ##STR70##
Bis(1,1-dimethylethyl) (2,3-dihydroxy-1,4-(4-fluorophenyl)methyl)-1,4-butanediyl)biscarbamate
1,1-Dimethylethyl 1-formyl-2-(4-fluorophenyl)ethylcarbamate was coupled as described in Example 2D to give, from 2.99 grams of the aldehyde, 1.38 grams of the desired product, which upon crystallization afforded 0.172 g of a solid mp 189.degree.-91.degree. C., NMR (CDCl.sub.3, D.sub.2 O): 1.3 (2 peaks), 2.8 (m, 4H), 3.4 (m, 2H), 3.7 (m, 2H), 7.0 (m, 10H); MS calcd 537.28 Found 537.41.
EXAMPLE 12 ##STR71##
Bis(1,1-dimethylethyl) (2,3-dihydroxy-1,4-(4fluorophenyl)methyl)-1,4-butanediyl)biscarbamate
1,1-Dimethylethyl 1-formyl-2-(4-iodophenyl)ethylcarbamate was coupled as described in Example 2D to give, from 1.13 grams of aldehyde, 0.66 grams of the desired product, mp 191-194 NMR (CDCl.sub.3): 1.3 (s, 18H), 2.8 (m, 4H), 3.4 (m, 2H), 3.7(m,2H), 6.95 (d, J=10Hz, 2H), 7.2 (m, 4H), 7.55 (d, J=10Hz, 2H).
EXAMPLE 13 ##STR72##
Bis(1,1-dimethylethyl) (2,3-dihydroxy-1,4-(4-hydroxyphenyl)methyl-1,4-butaneidyl)biscarbamate
1,1-Dimethylethyl 1-formyl-2-(4-benzyloxyphenyl)ethyl carbamate was coupled as described in Example 2B to give, from 1.42 g of the aldehyde, 0.238 g of the o-benzyl protected intermediate. This material was not characterized further but was subjected to the following conditions to remove the benzyl protecting group. It was dissolved in 20 mL of MeOH:EtOAc 1:1, treated with 50 mg of 10% Pd/C and H.sub.2 gas was bubbled through for 3.5 hour. At the end of this period the reaction mixture was filtered through a celite pad and concentrated under reduced pressure to yield the crude product which was purified by chromatography over 25 grams of silica gel using 1:2 Hex:EtOAc to afford 62.3 mg of the desired product, mp 110-112; NMR (CDCl.sub.3) 1.35 (s, 18H), 2.8 (m, 4H), 3.4 (s, 2H), 3.7 (m, 2H), 6.7 d,J=15Hz, 4H), 7.0 (d, J=15Hz, 4H); MS Calcd 533.29 F 532.82.
EXAMPLE 14 ##STR73##
N,N'-((2,3-dihydroxy-1,4-(phenylmethyl)-1,4-butanediyl))bisacetamide
100 mg (0.2 mM) of bis (1,1-dimethylethyl) (2,3-dihydroxy-1,4-(phenylmethyl)-1,4-butanediyl)biscarbamate, (1S,2R,3R,4S), from Example 2D, was stirred in 2 ml of 4N HCl in dioxane. The dioxane and HCl were removed under vacuum and the residual material was taken up in 2 ml of CHCl.sub.3, and treated with 55 microliters of triethylamine and 57 microliters of acetic anhydride. The resultant mixture was stirred for one hour and was then worked up by diluting with 50 ml of ethyl acetate, washing the organic layer with IN HCl, saturated NaHCO.sub.3, and drying the organic layer over magnesium sulfate. Filtration and evaporation gave 92.7 mg of crude product. Preparative plate chromatography (with ethyl acetate as the eluant) gave 36.2 mg of product.
EXAMPLE 15 ##STR74##
2,5-Diamino-1,6-diphenyl-3,4-hexanediol dihydrochloride
20 mg of bis(1,1-dimethylethyl) (2,3-dihydroxy-1,4-(phenylmethyl)-1,4-butanediyl)biscarbamate, (1S,2S,3S,4S), from Example 2A, was treated with 2 ml of 4N HCl in dioxane. After stirring for 15 minutes, the HCl and dioxane were removed under vacuum. Thin Layer Chromatography (1:1, Hexane/Ethyl acetate) showed that all of the starting material was converted. Treatment with Ninhydrin demonstrated the presence of the amino groups. NMR showed that the Boc groups were gone.
EXAMPLE 16 ##STR75##
2,5-Diamino-1,6-diphenyl-3,4-hexanediol dihydrochloride
20 mg of Bis(1,1-dimethylethyl (2,3-dihydroxy-1,4-(phenylmethyl)-1,4-butanediyl)biscarbamate (1S,2R,3R,4S), from Example 2B, was treated as described in Example 15.
EXAMPLE 17 ##STR76##
2,5-Diamino-3,4-hexanediol dihydrochloride
20 mg of Bis(1,1-dimethylethyl) (2,3-dihydroxy-1,4-dimethyl-1,4-butanediyl)biscarbamate from Example 4 was treated as described in Example 15.
EXAMPLE 18 ##STR77##
Bis(Boc-Thr-Ala-Thr-Ala), N,N'((2,3-dihydroxy-1,4-(phenylmethyl)-1,4-butanediyl))biscarbamate
29.4 mg of Bis(1,1-dimethylethyl) (2,3-dihydroxy-1,4-(phenylmethyl)-1.4-butanediyl)biscarbamate (1S,2S,3S,4S), from Example 2C, was reacted with Boc-Thr-Ala-Thr-Ala-O-Succinamide and triethylamine in 2 ml of acetonitrile. Filtration gave 0.1083 g of product which was tested without further purification.
EXAMPLE 19 ##STR78##
Alternative Synthesis of Product of Example 2B From D-Mannitol via Cuprate Addition
Synthesis of carbamic acid, ((2,3-dihydroxy-1,4-(phenylmethyl)-1,4-butanediyl))-bis-, bis(1,1-dimethylethyl) ester, (1S,2R,3R,4S) from d-mannitol:
1,6-Di-O-(p-toluenesulfonyl)-2,3-O-isopropylidene-D-mannitol 2
A solution of 6.667 g (30 mmol) of 2,3-O-isopropylidene-D-mannitol 1 (purchased from Aldrich Chemical Co.) in 30 mL pyridine was cooled to -20.degree. C. and treated with 12.582 g (66 mmol) of p-toluenesulfonyl chloride and the stirring continued for 20 minutes at -20 C., 20 minutes at 0.degree. C. and 20 minutes at room temperature. The reaction mixture was diluted with dichloromethane and washed with 1N HCl and saturated NaHCO.sub.3. The extract after drying over anhydrous magnesium sulfate was concentrated and the residue purified (325 g, silica gel column chromatography using 2:3 EtOAc: Hexane as the eluting solvent) to provide 10.425 g (66% yield) of compound 2. This material showed NMR (CDCl.sub.3): d 1.278 (s, 6H), 2.458 (s, 6H), 3.783 (m, 4H), 4.095 (q, 2H, J.sub.AB =10.66Hz, J.sub.Ax =5.67Hz), 4.33 (q, 2H, J.sub.AB =10.6Hz, J.sub.BX =1.98), 7.35 (d, 2H, J=1.74Hz), 7.81 (d, 2H, J=1.76Hz).
1,2,5,6-Diepoxy-3,4-O-(isoproylidene)hexane 3
A solution of 10.425 g (19.65 mmol) of compound 2 in 200 mL of anhydrous methanol was cooled at 0.degree. C. and treated with 10.86 g (78.58 mmol) of K.sub.2 CO.sub.3. The ice bath was removed and the contents stirred at room temperature for 20 minutes. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and the extract was washed with water and brine. The residue after removal of the solvent was purified (200 g silica gel column using 1:5 EtOAc: Hexane as the eluting solvent) to provide 2.95 g (80% yield) of compound 3. This material showed NMR (CDCl.sub.3) d 1.45 (s, 6H), 2.4 (q, 2H, J.sub.AB =4.94Hz, J.sub.AX =2.65Hz), 2.86 (q, 2H, J.sub.AB =4.94Hz, J.sub.BX =4.2Hz), 3.13 (m, 2H), 3.85 (dd, 2H, J.sub.1 =2.3Hz, J.sub.2 =1.46)
1,6-Diphenyl-3,4-O-isopropylidene-2,5-hexanediol 4
A suspension of 9.25 g (45 mmol) of cuprous bromide-dimethyl sulfide complex in 40 mL anhydrous ether was stirred at -20.degree. C. and 1.8M 50 mL (1.8M, 90 mmol) solution of phenyllithium was added dropwise. The contents were stirred for 30 minutes at -20.degree. C. and then warmed up to 0.degree. C. A solution of 2.807 g of compound in 20 mL anhydrous ether was added to the above mixture and the contents stirred for 30 minutes at 0.degree. C. The excess reagent was quenched with saturated ammonium chloride and warmed up to room temperature. The contents were then filtered and the filtrate and the washings were washed with water and brine. The ether extract after drying over anhydrous magnesium sulfate was concentrated and the residue was purified (150 g silica gel column using 1:5 followed by 1:4 EtOAc: Hexane as the eluting solvent) to provide 4.577 g (89%) of compound 4. This material showed NMR (CDCl.sub.3): d 1.455 (s, 6H), 2.7 (q, 2H, J.sub.AB =13.8Hz, J.sub.AX =7.9Hz), 3.15 (q, 2H, J.sub.AB =13.8Hz, J.sub.BX =2.5Hz), 3.75 (m, 4H), 7.28 (m, 10H).
2,5-Diazido-1,6-diphenyl-3,4 -O-(isopropylidene)hexane 5
A solution of 900 mg (2.63 mmol) of compound 4, 2.76 g (10.52 mmol) of triphenylphosphine in 20 mL of dry tetrahydrofuran was stirred with 250 mg of molecular sieves 2A at -78.degree. C. 22.9 mL (0.46M, 10.52 mmol) solution of hydrazoic acid in xylene was added to the above mixture and stirred for 5 minutes at -78.degree. C. This was followed by the addition of 1.66 mL (10.52 mmol) of diethylazodicarboxylate. The mixture was then allowed to warm up to room temperature in the same bath and stirred for 18h. The excess reagents were quenched by the addition of 0.4 mL (10 mmol) of methanol at 0.degree. C. After stirring the mixture for 30 minutes at room temperature, it was concentrated to a small volume and purified (33 g silica gel column using hexane followed by 1:40 EtOAc: Hexane as the eluting solvent) to provide 836 mg of mixture of 5 and undesired side products. The mixture was difficult to purify at this stage and used directly in the next step.
2,5-Diazido-1,6-diphenyl-3,4-hexanediol 6
A solution of 570 mg of the mixture (as mentioned in the previous experiment) in 5 mL of ethanol and 1.67 mL of water was stirred with 1.67 g of Bio-Rad AG-50-W-X8 acid exchange resin at 70.degree. C. bath for 18 h. The contents were filtered and washed with methanol. The filtrate and the washings were combined and concentrated. The residue was extracted with dichloromethane and dried over anhydrous magnesium sulfate. The residue after removal of the solvent was purified (20 g silica gel column using 1:3 EtOAc: hexane as the eluting solvent) to provide 102 mg (11% yield from 4) of 6. This material showed NMR (CDCl.sub.3): d 2.95 (q, 2H, J.sub.AB 13.7Hz, J.sub.AX =7.9Hz), 3.06 (q, 2H, J.sub.AB =13.7Hz, J.sub.BX =6.3Hz), 3.55 (m, 2H), 3.62 (bs, 2H), 7.3 (m, 10H).
2,5-Diamino-1,6 -diphenyl-3,4-hexanediol-7
A solution of 67 mg (0.19 mmol) of 6 in 4 mL of methanol was stirred with 30 mg of 10% palladium on carbon under 1 atmospheric hydrogen pressure for 18 hours at room temperature. The mixture was filtered through a 0.45 micron Millipore filter and the residue washed with methanol. The filtrate and the washings were concentrated to provide 45 mg (79% yield) of 7. This material showed NMR (CDCl.sub.3): d 2.64 (m, 8H), 7.283 (m, 10H).
2,5-(N,N-Di-tert-butoxycarbonyl)diamino-1,6-dipheny-3,4-hexanediol 8
A solution of 45 mg (0.015 mmol) of compound 7 in 2 mL of absolute ethanol was stirred with 152 mg (0.58 mmol) of N-(tert-butoxycarbonyl)phthalimide for 18 hours at room temperature. The reaction mixture was diluted with 20 mL water and extracted with three 20 mL portions of dichloromethane. The dichloromethane extract was washed with 0.3N NaOH and brine. The residue after removal of the solvent was purified (33 g silica gel coulmn using 7% isopropanol in hexane as the eluting solvent) to provide 26 mg of pure and 12 mg of slightly contaminated 8 (total yield 51%).
This material has identical spectral data with the compound described in Example 2B.
EXAMPLE 19B
Alternative Synthesis of Product of Example 2B From D-Mannitol via Cuprate Addition
(2S,3R,4R,5S)-1,2,5,6-Diepoxy-3,4-O-(isopropylidene)hexane 1: This compound was prepared following the literature procedure (Y. L. Merrer et al, Heterocycles, 25, 541, 1987). This material showed NMR (CDCl.sub.3): d 1 45 (s, 6H), 2.4 (q, 2H, J.sub.AB =4.94Hz, J.sub.AX =2.65Hz), 2.86 (q, 2H, J.sub.AB =4.94Hz, J.sub.BX =4.2Hz), 3.13 (m, 2H), 3.85 (dd, 2H, J.sub.1 =2.3Hz, J.sub.2 =1.46)
(2S,3R,4R,5S)-1,6-Diphenyl-3,4-0-isopropylidene-2,5-hexanediol 2: A suspension of 18.5 g (90 mmol) of cuprous bromide-dimethyl sulfide complex in 80 mL anhydrous ether was stirred at -20.degree. C. and 1.8M 100 mL (1.8M, 180 mmol) solution of phenyllithium was added dropwise. The contents were stirred for 30 minutes at -20.degree. C. and then warmed up to 0.degree. C. A solution of 5.614 g of compound in 40 mL anhydrous ether was added to the above mixture and the contents stirred for 30 minutes at 0.degree. C. The excess reagent was quenched with saturated ammonium chloride and warmed up to room temperature. The contents were then filtered and the filtrate and the washings were washed with water and brine. The ether extract after drying over anhydrous magnesium sulfate was concentrated and the residue was purified (325 g silica gel column using 1:10 followed by, 1:5 followed by 1:4 EtOAc: Hexane as the eluting solvents) to provide 8.035 g (78%) of compound 2. This material showed NMR (CDCl.sub.3): d 1.455 (s, 6H), 2.7 (q, 2H, J.sub.AB =13.8Hz, J.sub.AX =7.9Hz), 3.15 (q, 2H, J.sub.AB =13.8Hz, J.sub.BX =2.5Hz), 3.75 (m, 4H), 7.28 (m, 10H).
(2S,3R,4R,5S)-2,5-Diazido-1,6-diphenyl-3,4-O-(isopropylidene)hexane 3: A solution of 16.781 g (49.00 mmol) of compound 2, 38.6 g (147 mmol) of triphenylphosphine in 300 mL of dry tetrahydrofuran was cooled in an ice bath and 23.1 ml (147 mmol) of diethylazodicarboxylate was added to the stirred mixture behind shield. 31.7 mL (147 mmol) of diphenylphosphorylazide (Caution--this reagent should be stored at 0.degree. C. and handled with care. Some azides may be explosive!) was added to the above mixture and the contents were further stirred at 0.degree. C. for 5 minutes. The mixture was then allowed to warm up to room temperature in the same bath and stirred for 1 h. TLC in 1:5 ethyl acetate/hexane indicates disappearance of compound 2 and formation of 3. The excess reagents were quenched by the addition of 6.0 mL (150 mmol) of methanol at 0.degree. C. After stirring the mixture for 30 minutes at room temperature, it was concentrated to a small volume (NOTE: do not concentrate to the extent that solids separate. Also small amount of dichloromethane is needed to keep the contents in solution while loading on silica gel column. Use of more than necessary amount of dichloromethane results inefficient separation.) and purified [800 g silica gel column using hexane (500 mL) followed by 1:40 EtOAc: Hexane (1000 mL) and finally 1:20 ethyl acetate/hexane elutes the desired compound (3000 mL)] to provide 15.523 g of mixture of 3 and undesired side products. The mixture was difficult to purify at this stage and used directly in the next step.
(2S,3R,4R,5S)-2,5-Diamino-1,6-diphenyl-3,4-O-(isopropylidene)hexane 4: The above material (15.523 g) was divided in 3 equal portions and each portion dissolved in 75 mL absolute ethanol, flushed with nitrogen and each portion stirred with 1.5 g of 10% palladium on carbon under hydrogen (hydrogen balloon) for 18h. TLC 1:10 ethyl acetate/hexane solvent indicates disappearance of starting material. (If incomplete add 0.5 g of 10% palladium on carbon and stir under fresh balloon of hydrogen). Combined yield of 12.516 g was obtained.
(2S,3R,4R,5S)-2,5-(N-(Benzyloxy)carbonyl)diamino)-1,6-diphenyl-3,4-O-(isopropylidene)hexane 5: A solution of 13.67 g (40.2 mmol) of compound 4 in 100 ml dimethylformamide was stirred in ice-bath and treated with 21.93 g (88 mmol) of benzyloxycarnonyloxysuccinimide. The ice-bath was removed and the contents were stirred for 18 hours at room temperature. The excess reagent was quenched by treatment with 0.61 ml (10 mmol). The contents were diluted with water and extracted with dichloromethane (3.times. of ethanolamine. The mixture after complete removal of solvents was purified (500 g silica gel column using 1:5 followed by 1:4 EtOAc:Hexane) to provide 20.457 g (83.6% yield) compound 5.
(2S,3R,4R,5S)-2,5-Di-(N-((Benzyloxy)carbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane 6:A solution of 20.457 g (33.61 mmol) of compound 4 in 50 ml 90% aqueous trifluoroacetic acid was stirred in ice-bath and then at room temperature. for 18h. The reaction mixture was poured with stirring in 560 ml of 1M ice-cold sodium hydroxide and then rest of the trifluoroacetic acid was quenched with sat. sodium bicarbonate. The precipitated solid was filtered dried under vacuum and crystallized from chloroform to provide 15.02 g (77% yield) of compound 6 (M. P. 209-210).
(2S,3R,4R,5S)-2,5-diamino-3,4-dihydroxy-1,6-diphenylhexane 7:A solution of 10.432 g (18.36 mmol) of compound 6 in 500 ml THF and 500 ml ethyl alcohol was stirred with 1.043 g of 10% palladium on carbon at room temperature. for 18h over 1 atmosphere hydrogen pressure. The mixture was filtered through celite pad and the filtrate was concentrated to provide 6.06 g yield) of compound 7. The oil was triturated with diethyl ether and the white solid was filtered and washed to provide pure 7 (M. P. 92-94).
EXAMPLE 19C
Alternative Synthesis of Aziridine Product of Example 2B From D-Mannitol via Biszairidine Intermediate
1,6-Di(N,-(benzyloxycarbonyl)amino)-2,5-dihydroxy-3,4-O-(isopropylidene)hexanediol 8
In a 250 mL Round Bottom Flask was placed 20 mL of 1M (20 mmol) of Lithium Bis (trimethylsilyl)amide and the contents cooled in ice bath and 1.87 g(10 mmol) of diepoxide 1 in 3 ml of THF was added to the above mixture and the contents were stirred for 18h while allowing the contents to warm up to room temperature. It was cooled back in an ice-bath and quenched with 20 ml (20 mmol) of 1M HCl in anhydrous ether. It was stirred for 5 minutes and then treated with 40 mL of 1M tetrabutylammonium fluoride in THF at 0.degree. C. and then immediately warmed-up to room temperature and stirred for additional 2 hours. It was then cooled to 0.degree. C. and then treated with 5.98 g (24 mmol) of N-(benzyloxycarbonyl)succinimide, stirred for 15 minutes, ice-bath was removed and the contents stirred at room temperature for 18h. It was concentrated and the residue dissolved in dichloromethane and the extract washed twice with water and once with brine. The residue after removal of dichloromethane was chromatographed (130 g silica gel, 2:3 followed by 1:1 ethyl acetate/hexane) to provide 2.44 g (yield 50%) of 8.
(2S,3R,4R,5S)-1,2:5,6-(N,N'-Dibenzyloxycarbonyl)diimino-3,4-O-(isopropylidene)hexanediol 9
In a 500 mL Round Bottom Flask was placed 12.147 g (24.89 g mmol) of above compound, 15.669 g (59.7 mmol) of triphenylphosphine and dissolved in 150 mL of anhydrous THF. To the above mixture was added 9.40 mL (59.7 mmol) of diethyl azodicarboxylate and refluxed for 30 minutes under nitrogen. TLC indicated completion of the reaction(10:1:10 ethyl acetate/ethyl alcohol/hexane and 1:2 ethyl acetate/hexane). It was concentrated to a small volume and chromatographed (325 g silica gel column, 1:3 followed by 1:2 ethyl acetate/hexane as the eluting solvent) to provide 7.147 g (yield, 64%) of compound 9.
(2S,3R,4R,5S)-2,5-Di(N-((benzyloxy)carbonyl)diamino)-1,6-diphenyl-3,4-O-(isopropylidene)hexane 5
In a 50 mL R. B. Flask under nitrogen and in a glove . was placed 1.37 g (6.66 mmol) of cuprous bromide-dimethylsulfide complex and suspended in 2 mL ether and cooled to -20.degree. C. and 6.66 mL (13.33 mmol) 2M solution of phenyllithium in 70:30 cyclohexane/ether was added dropwise to the mixture at -20.degree. C. The mixture stirred at -20.degree. C. for 30 minutes and then warmed to 0.degree. C. 754 mg of above bisaziridine derivative in 2 mL ether and 6 mL THF was added to to the mixture at 0.degree. C and stirred for 30 minutes at 0.degree. C. TLC in 1:3 ethyl acetate/hexane indicated disappearance of the starting material. The excess reagent was quenched with saturated ammonium chloride, the mixture filtered, diluted with 20 mL of water and extracted with 2.times.25 mL of dichloromethane. The mixture was chromatgraphed (33 g silica gel column and 1:5 ethyl acetate/hexane as the eluting solvent) to provide 475 mg (47%) of 5. This intermediate is identical to compound 5 of Example 19B from which the final compound can be prepared according to the route provided by that Example.
EXAMPLES 20 AND 21
EXAMPLE 20
Synthesis of 2,5-(N-2-Pyridylacetyl-L-Ile)diamino-1,6-diphenyl-3,4-hexanediol ##STR79##
EXAMPLE 21
Synthesis of 2,5-(N-2-Pyridyl-L-Ile,N'-2-pyridyl-D-Ile)diamino-1,6-diphenyl-3,4-hexanediol ##STR80##
Step 1: 2-Pyridylacetyl-Ile allyl ester ##STR81##
2-Pyridylacetyl-Ile allyl ester
A mixture of 1.717 g (5 mmol) pyridylacetic acid hydrochloride, 868 mg (5 mmol) of isoleucine allyl ester p-toluene sulfonate salt, molecular sieves 4.degree. A type in dimethylformamide were stirred at 0.degree. C. and 1.74 ml (10 mmol) of diisopropylethylamine was added to generate free amines. After stirring the contents at 0.degree. C. for 15 minutes it was treated with 1.23 g (6 mmol) of dicyclohexylcarbodiimide and the contents were warmed up to room temperature. The mixture was stirred for 18 h, filtered and the residue purified (130 g, silica gel column chromatography using 1:1 EtOAc:hexane as the eluting solvent) to provide 712 mg (49% yield) of 2 pyridylacetyl-Ile allyl ester. This material showed .sup.1 H NMR (CDCl.sub.3): d 0.87 (d, 3H, J=6.9Hz), 0.894 (t, 3H, J=7.4Hz), 1.15 (m, 1H), 1.42 (m, 1H), 1.92 (m, 1H), 4.6 (m, 3H), 5.2-5.7 (m, 2H), 5.85 (m, 1H), 7.25 (m, 1H), 7.668 (d.times.t, 1H, J.sub.1 =3.84, J=7 7Hz), 8.01 (bm, 1H), 8.577 (bd, 1H).
Step 2: 2-Pyridylacetyl-Ile ##STR82##
2-Pyridylacetyl-Ile
A mixture of 276 mg (0.95 mmol) of 2-pyridylacetyl 1- ester in 2 ml of 1,4-dioxane was stirred at room temperature and 1 ml of 1.0N sodium hydroxide was added in three equal portions after 15 minute intervals and the contents were stirred at room temperature for a total of 2 hours. The mixture was neutralized with addition of 1.0 ml (1 mmol) of 1N HCl. The mixture was diluted with 5 ml water and extracted with dichloromethane. The aqueous layer was saturated with solid sodium sulfate while stirring with 20 ml of chloroform. The combined organic extracts after removal of solvents provided 174 mg (74% yield) of 2-pyridylacetyl-Ile. This material showed .sup.1 H NMR (CDCl.sub.3): d 0.927 (d, 3H, J=6.8Hz), 0.927 (t, 3H, J=7.3Hz), 1.05-2.0 (bm, 3H), 3.872 (AB, 2H, JAB=13.8Hz), 4.539 (d.times.d, 1H, J.sub.1 =5.21Hz, J.sub.2 =8.22 Hz), 7.32 (d.times.d.times.d, 1H), 7.52 (bm, 1H), 7.785 (d.times.t, 1H, J.sub.1 =7.71Hz, J.sub.2 =1.8Hz), 8.53 (d.times.d.times.d, 1H).
Step 3: A solution of 101 mg (0.336 mmol) of 2,5-diamino-1,6-diphenyl-3,4-hexanediol and 168 mg (0.67 mmol) of 2-pyridylacetyl-Ile in 5 ml of dichloromethane was stirred with 25 mg of molecular sieves and 166 mg (0.8 mmol) of dicyclohexylcarbodiimide at room temperature for 18 h and filtered. The residue after removal of solvent was purified (33 silica gel column using 4%, 7% and 10% methanol in chloroform) to provide 46.5 mg (18%) of desired coupled product and 39.5 mg (15.3%) of a diastereomer to which was assigned structure 21 based on the spectral data. The compound of Example 20 had C-2 symmetry and showed .sup.13 C NMR (CDCl.sub.3): d 11.452, 15.643, 24.242, 35.975, 38.200, 44.912, 52.358, 58.680, 72.775, 122.273, 124.083, 126.171, 128.200, 129.299, 137.291, 138.056, 149.138, 149.138, 155.166, 169.740, 171.149. The compound of Example 21 had no C-2 symmetry and showed twice the number of .sup.13 C NMR resonances (CDCl.sub.3) d 11.454, 11.572, 14.380, 15.669, 24.234, 26.144, 35.891, 36.354, 38.102, 38.241, 44.837, 44.863, 52.504, 52.699, 57.485, 58.802, 72.897, 73.037, 122.197, 122.293, 124.065, 124.118, 126.140, 126.241, 128.220, 128.267, 128.381, 129.310, 137.209, 137.292, 138.121, 138.186, 149.167, 149.190, 155.205, 155.253, 169.673, 169.853, 171.319, 171.596.
EXAMPLE 23
Improved Method to Couple Aldehydes: Synthesis of Compound of Example 9
Bis(dimethylethyl) (2,3-dihydroxy-1,4-(phenylmethyl)-1,4-butanediyl)biscarbamate
Step A: Preparation of V(Cl.sub.3 (THF).sub.3
V(Cl).sub.3 (Aldrich, 25 g) was added to 400 mL argon-sparged THF and the suspension heated to reflux under air-free conditions. After 24 hours, the mixture was cooled to room temperature and filtered under rigorously air-free conditions (schlenkware, glove bag or dry box), rinsed 4 times with 50 mL pentane, transferred to a schlenk tube and evacuated at 0.1 torr for 1 hour.
The tris-THF adduct is a bright salmon color, between pink and red. If caution is taken to avoid exposure to air, this material can be kept for months in a schlenk tube. On very brief exposure to air, however, the material turns to dusty orange, then tan, and must be discarded.
Step B: Preparation of An.multidot.Cu
Zinc-copper couple was prepared following the of Fieser and Fieser.sup.3 (L. Fieser and M. Fieser, Reagents for Organic Synthesis, Volume I, pp. 1292-1293, Wiley, New York, 1967), except that filtration with schlenkware was used instead of decanting solvent. The use of a glovebag or drybox would be equally satisfactory. Also, solvents were sparged with argon for 30 minutes before use. A free-flowing black powder with few clumps was isolated. This material reduced V(III) to V(II) in dichloromethane within 10 minutes, whereas the use of commercial zinc dust or activated zinc required several hours and frequently did not provide the color change characteristic of complete reduction (see below).
Step C: Coupling Procedure
VCl.sub.3 (THF).sub.3 (1.32 g, 3.53 mmol) was weighed into an argon-filled 35 mL RBF using a schlenk tube. Zinc-copper couple (138 mg, 2.12 mmol), weighed quickly in air, was added. The flask was fitted with a dropping funnel previously filled with argon and the two solids were stirred vigorously. Dry dichloromethane (8 mL) was added via the funnel, and the mixture was stirred for 10 minutes, by which time it had turned deep green with suspended black.
1,1-Dimethylethyl 1-formyl-3-phenylpropylcarbamate (1.00 g, 3.53 mmol), freshly prepared by Swern oxidation of the requisite alcohol, was added over 2-3 minutes in 4 mL dichloromethane. Stirring at room temperature and following by TLC (50% EtOAc/hexane) indicated complete loss of aldehyde starting material after 1.5 hours.
Notes: after addition of CH.sub.2 Cl.sub.2, rigorous exclusion of air is necessary; before addition, exercise reasonable care. When exposed to even small amounts of air, the reduced material rapidly oxidizes to a deep wine-red. If this happens, discard the reaction and start over.
If the characteristic deep green color--best seen by holding a white sheet of paper behind the flask and looking at the gas-solvent interface--does not appear within 10-30 minutes, it is best to discard the reaction and re-prepare the reagents.
The reaction mixture was poured into a separatory funnel containing 50 mL dichloromethane and 100 mL 10% aqueous disodium tartrate (1N HCl can be used if acid-sensitive functionality is not present). After gentle shaking, separating, and washing the aqueous layer two times with 25 mL dichloromethane, the combined organic layers were washed with saturated sodium bicarbonate and dried with magnesium sulfate. Solvent was removed, the crude solid was taken up in minimum CHCl.sub.3, and 0.5 volumes hexane added. On sitting overnight, copious white crystals formed. Isolated 0.62 g (62%) product diol, mp 202.degree.-204.degree. C. Spectral data are consistent with the assigned structure.
EXAMPLES 24-98
Examples 24-98 were prepared by one of the methods described below. The method of preparation and physical data are shown in Table I.
Method 2C (Coupling of Aldehydes)
The improved coupling method, exemplified in Step C of Example 23, was used to prepare a number of the compounds shown in Table I.
Method 3 (Hydrogenation of Bis-N-CBZ-Diaminodiols)
The (bis-N-CBZ)-diaminodiols obtained either by vanadium coupling reaction or D-mannitol route can be hydrogenated and further elaborated at the amine residues. Table I shows examples prepared via this route.
Synthesis of Compound of Example 39
In a 200 ml R.B. Flask a suspension of 3.432 g (4.32 mmol) of the above intermediate in 25 ml ethanol and 25 ml methanol was stirred with a suspension of 343 mg 10% palladium on carbon under 1 atmospheric hydrogen pressure at room temperature for 18 hours. The suspension of starting material went into solution. The mixture was filtered through a celite pad and and the residue washed with ethanol. The filtrate and the washings were concentrated and the residue purified (130 g silica gel column using first 3% and finally 6% methanol in chloroform as the eluting solvent) to provide 1.848 g (81.3%) of 39 as a white solid.
Method 4 (Coupling of Diaminodiols)
The diamines obtained via Method 3 can be further elaborated by reaction with various electrophiles. Some preferred reaction conditions that provide active compounds are given below. Many other conditions and reagents can, of course, be employed.
4C: DICYCLOHEXYLCARBODIIMIDE (DCC) COUPLING
Dicyclohexylcarbodiimide (DCC) coupling in the presence 1-hydroxybenzotriazole hydrate was carried out according to standard procedure in peptide synthesis. A representative synthesis is described below.
Synthesis of Compound of Example 26
A solution of 101 mg (0.336 mmol) of 2,5-diamino-1,6-diphenyl-3,4-hexanediol, 108 mg (08 mmol) of 1-hydroxybenzotriazole and 168 mg (0.67 mmol) of 2-pyridylacetyl-Ile in 5 ml of dichloromethane was stirred with 25 mg of molecular sieves and 166 mg (0.8 mmol) of dicyclohexylcarbodiimide at room temperature for 18 h and filtered. The residue after removal of solvent was purified (33 g silica gel column using 4%, 7%, and 10% methanol in chloroform) to provide 86 mg (33% yield) of 26. The compound has C-2 symmetry and showed .sup.13 C NMR (CDCl3): d 11.452, 15.643, 24.242, 35.975, 38.200, 44.912, 52.358, 58.680, 72.775, 122.273, 124.083, 126.171, 128.200, 129.299, 137.291, 138.056, 149.138, 149.138, 155.166, 169.740, 171.
4B: BOP COUPLING
BOP-Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate coupling was carried out according to the procedure by B. Castro et al. (Tetrahedron Lett., 1975, 14, 1219-1222). A representative synthesis is described below.
Synthesis of Compound of Example 81
BOC-Thiozolidine-4-carboxylic acid (0.94 g; 0.40 mmol) and [NH.sub.2 CH(isopropyl)-C(O)--N--CH(OH)--]2 (0.100 g; 0.20 mmol) were dissolved in 10 ml of DMF, and BOP (0.177 g; 0.4 mmol) and triethylamine (0.056 ml; 0.40 mmol) were added in aliquots to maintain a pH of 7-8. The reaction was stirred for 18 hours. The residue after removal of solvent was purified by column chromatography on Sephadex LH-20 in methanol to provide 81 as amorphous solid (0.137 g). FAB/MS calculated for C.sub.4 6H68N6O10S2 (928.44). Found 929.64 (M+H).
4C: CARBONYLDIIMIDAZOLE COUPLING
Synthesis of Compound of Example 88
N-MSOC-isoleucine (393 mg, 2.1 equivalents) was dissolved in THF; added carbonyldiimidazole (227 mg, 2.1 equivalents) at room temperature. Stirred under TLC showed loss of starting material. The reaction mixture was diluted with chloroform and 10% aqueous disodium L-tartrate was added. The layers were separated and the aqueous layer washed 1.times. with chloroform. Washed combined organic layers with saturated aqueous sodium bicarbonate and brine, dried with magnesium sulfate, filtered and removed solvent to obtain 540 mg white solid. Recrystallized from hot chloroform/hexane to obtain 343 mg fine white crystals; NMR consistent with 88. Melting point 222.degree.-225.degree. C. (dec).
4D: N-HYDROXYSUCCINIMIDE ESTER COUPLING
N-hydroxysuccinimide esters, available from Sigma Chemical Company or Advanced ChemTech, were used.
SYNTHESIS OF COMPOUND OF EXAMPLE 89
In a 300 ml R.B. flask a solution of 6.000 g (20mmol) of diamino diol in 60 ml of dimethylformamide was cooled in an ice bath. The mixture was treated with 14.070 g (44mmol) of Z-Isoleucine succinimide ester (available from Sigma Chemical Company or Advanced ChemTech) and stirred at room temperature for 18 hours. A precipitate had formed and was dissolved by adding one liter of chloroform. The mixture was then washed with water and the organic layer separated, dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in one liter of chloroform and the hexane added to precipitate out the desired product; however, after filtration the solid was contaminated with N-Hydroxysuccinimide. It was further purified (750 g silica gel column using first 1% followed by 1.5% methanol in chloroform as the eluting solvent) to provide 9.723 g (61.2%) of 89.
4E: p-NITROPHENYLESTER COUPLING
(1) With hydroxybenzotriazole hydrate:
Synthesis of Compound of Example 92
Diaminodiol of example 63 (250 mg, 1.0 equivalent), was dissolved in 5 mL DMF and N-CBZ-asparagine-p-nitrophenylester (373 mg, 2 equivalents, Sigma Chemical Company) and 1-hydroxybenzotriazole hydrate (135 mg, 2 equivalents) were added and the mixture was stirred overnight. The reaction mixture was triturated with THF for one hour, the solid was filtered off, washed with THF and chloroform, and collected to obtain 400 mg white crystals. NMR of the material is consistent with the structure.
(2) Without hydroxybenzotriazole hydrate:
Synthesis of Compound of Example 90
Diaminodiol of example 15 (200 mg, 1.0 equivalent) was dissolved in 5 mL DMF and N-CBZ-(d)-phenylalanine-p-nitrophenylester (332 mg, 2 equivalents, Sigma Chemical Company) was added and the mixture was stirred overnight. One volume of water was added, the solid was filtered off and washed with 1:1 water/DMF, then with water and finally with ether, and collected to obtain 320 mg white crystals. NMR showed the material to be consistent with the structure.
4F: CONDENSATION WITH ISOCYANATES
Synthesis of Compound of Example 67
In a 500 ml R.B. Flask, 2.500 g (4.75mmol) of the above intermediate in 100 ml dimethylformamide was cooled in an ice bath. The mixture was treated with 1.29 ml (10.45 mmol) of benzyl isocyanate via syringe and the mixture allowed to warm to room temperature where a precipitate started forming within 5 minutes. Within 30 minutes 100 ml more dimethylformamide was added to aid stirring. After stirring the mixture at room temperature a total of 2 hours the mixture was filtered and the solid washed with first dimethylformamide and then chloroform. The solid was transferred and dried to provide 3.230 g (85.7%) of 67 as a white solid.
4G: CONDENSATION WITH EPOXIDES
Epoxides can be condensed with diaminodiols. A representative example is given below.
SYNTHESIS OF COMPOUND OF EXAMPLE 71
The corresponding epoxide was prepared from 1-adamantyl bromomethyl ketone by reduction with sodium borohydride in absolute ethanol and treatment with potassium tert-butoxide. The adamantyl ethylene oxide was reacted with [NH.sub.2 -Val-Phe[CH(OH)-]].sub.2 in methanol refluxing at 70 degrees Celsius overnight and chromatogrammed using Sephadex LH-20 column. (2 equivalents of oxide was used for every 1 equivalent of diol).
TABLE I ##STR83## MP IC.sub.50 IC.sub.90 PHYS- GAG CELLS ICAL METH- EXAMPLE R.sup.1 -W R.sup.3 R.sup.4 mg/ml mg/ml DATA OD 24 ##STR84## 2-butyl Ph 0.056 1 232-234 4A 25 ##STR85## 2-butyl Ph 0.69 >30 191- 194 4A 27 ##STR86## 2-butyl Ph 0.177 >30 207-213 4A 28 ##STR87## 2-butyl ##STR88## 0.155 2.4 (777.99) 4A 29 ##STR89## 2-propyl Ph 0.041 0.95 248-252 4A 30 ##STR90## 2-butyl Ph 0.082 2.8 (765.45) 4A 31 ##STR91## 2-butyl Ph 0.03 2.9 256-260 4A 32 ##STR92## 2-butyl Ph >9 >30 NMR 4A 33 ##STR93## 2-methyl-propane Ph >9 >30 179-182 4A 34 ##STR94## 2-butyl Ph >9 >30 (775.51) 4A 35 ##STR95## 2-butyl Ph 0.019 0.3 247-250 4F 36 ##STR96## 2-butyl Ph 0.085 0.95 NMR 4A 37 ##STR97## 2-butyl Ph 0.024 0.15 NMR 4D 38 ##STR98## 2-butyl Ph 0.055 >30 NMR 4D 39 H.sub.2 N 2-butyl Ph 0.937 10 184-190 4D;3 40 ##STR99## 2-butyl Ph 0.03 2.2 228-232 4D 41 ##STR100## 2-butyl Ph 0.21 2.8 NMR 4A 42 ##STR101## 2-propyl Ph 0.025 0.05 216-221 4D 43 ##STR102## 2-butyl Ph 0.055 0.11 263-266 4D 44 ##STR103## 2-butyl Ph 0.028 0.09 200-206 4AwithoutHOBT 45 ##STR104## 2-butyl Ph 1.24 8.9 141-144 4F 46 ##STR105## ##STR106## Ph 0.245 >30 241-244 4E 47 ##STR107## ##STR108## Ph 1.12 >30 264-267 4E 48 ##STR109## 2-propyl ##STR110## >9 >30 160-164 1B;4D 49 ##STR111## 2-propyl Ph 0.036 0.2 217-220 4A 50 ##STR112## 2-propyl Ph 0.01 0.6 194-197 4F 51 ##STR113## 2-butyl Ph 0.019 >30 257-260 4A 52 ##STR114## 2-butyl Ph 0.004 2.7 226-230 4F 53 ##STR115## ##STR116## Ph 0.2 2.6 NMR 4C 54 ##STR117## 2-butyl ##STR118## 3.4 5.0 130-134 2C 55 ##STR119## ##STR120## Ph >9 >30 >250 4C 56 ##STR121## 2-butyl Ph 0.03 2.2 228-232 4D 57 ##STR122## 2-propyl Ph 0.044 8.9 >250sintersat 220 4C 58 ##STR123## 2-propyl Ph 0.31 >30 198-199 4C 59 ##STR124## H.sub.2 CCHCH.sub.2 Ph 0.58 >30 119-123 4C 60 ##STR125## CH.sub.3 SCH.sub.2 CH.sub.2 Ph 0.82 >30 229-236 4C 61 ##STR126## 2-propyl Ph 0.04 2.9 212-216 4D;3 62 ##STR127## 2-propyl Ph 0.05 - >245 4D 63 H.sub.2 N 2-propyl Ph 215-216 2C 64 ##STR128## 2-propyl Ph >9 >30 .sup. 65.sup. ##STR129## 2-butyl Ph >10.4 >30 147-151 4A .sup. 66.sup. ##STR130## 2-propyl Ph 235-238 4A 67 ##STR131## 2-propyl Ph 288-292 4F 68 ##STR132## 2-propyl ##STR133## >9 >30 190-192 4F 69 ##STR134## 2-butyl Ph 0.065 -- 212-215 4D;3 70 ##STR135## 2-propyl Ph 4E 71 ##STR136## 2-propyl Ph >11 >30 (855.63) 4G 72 ##STR137## 2-propyl Ph >9.2 >30 (739.37) 4G 73 ##STR138## methyl Ph 1.62 >30 (1071.6) 4B 74 ##STR139## 2-propyl Ph 3.72 (937.55) 4B 75 ##STR140## 2-propyl Ph 1.22 (NMR) 4B 76 ##STR141## 2-propyl Ph 0.296 >30 (937.71) 4B 77 ##STR142## 2-propyl Ph 0.15 (737.55) 4B 78 ##STR143## 2-propyl Ph 0.061 (869.67) 4B 79 ##STR144## 2-propyl Ph 0.185 (669.60) 4B 80 ##STR145## 2-propyl Ph 13 >30 (929.64) 4B 81 ##STR146## 2-propyl Ph 0.201 >30 (729.59) 4B 82 ##STR147## 2-propyl Ph 0.625 >30 (993.81) 4B 83 ##STR148## 2-propyl Ph 0.317 >30 (725.66) 4B 84 ##STR149## CH.sub.3 Ph 0.151 >30 236-237 2C 85 ##STR150## 2-propyl Ph 0.007 >30 229-233 4D;3 86 ##STR151## 2-propyl Ph 0.3 >30 162-168sintersat 94 4D;3 87 ##STR152## 2-propyl Ph 3.3 >30 M.P.>245sinters120-130 4D;3 88 ##STR153## 2-butyl Ph 0.039 8.5 222-225 4C 89 ##STR154## 2-propyl Ph 0.04 >30 M.P.>245 4E 90 ##STR155## 2-propyl Ph 0.67 30 M.P.>245 4E 91 ##STR156## 2-propyl Ph 0.042 0.2 239-241 4E 92 ##STR157## 2-propyl Ph 0.08 >30 >245 4E 93 ##STR158## 2-propyl Ph 0.099 1.0 237-238 4D 94 ##STR159## 2-propyl ##STR160## 0.123 >30 (979.2) 2C 95 ##STR161## 2-propyl Ph 12.5 >30 209 4A 96 ##STR162## 2-propyl Ph 0.100 0.7 274 4A 97 ##STR163## 2-propyl Ph 0.250 0.9 168-170 4A 98 ##STR164## 2-propyl Ph 0.050 0.3 Physical Data indicates melting point range; parantheticals indicate parent ion of mass spec; NMR indicates compound gave satisfactory nmr. Method indicates method of preparation as described above under Examples 24-98. .sup. indicates that the diol is protected as an acetonide. .sup. indicates that this compound is a stereoisomer of the compound of Example 20.
Tables II to XVI include additional preferred embodiments of the invention. However, these embodiments are not exemplified herein.
TABLE II__________________________________________________________________________ ##STR165##EXNO. R.sup.1 R.sup.2 R.sup.3 R.sup.4__________________________________________________________________________ 99 CH.sub.3 C(O) CH.sub.3 C(O) PhCH.sub.2 PhCH.sub.2100 CH.sub.3 C(O) CH.sub.3 C(O) 4-HOC.sub.6 H.sub.4 CH.sub.2 4-HOC.sub.6 H.sub.4 CH.sub.2101 CH.sub.3 C(O) CH.sub.3 C(O) 3,4-dichloro-benzyl PhCH.sub.2102 CH.sub.3 C(O) CH.sub.3 C(O) CH.sub.3 SCH.sub.2 CH.sub.3 SCH.sub.2103 CH.sub.3 C(O) CH.sub.3 C(O) CH.sub.3 SCH.sub.2 PhCH.sub.2104 CH.sub.3 C(O) CH.sub.3 C(O) (CH.sub.3).sub.2 CHCH.sub.2 (CH.sub.3).sub.2 CHCH.sub. 2105 CH.sub.3 C(O) CH.sub.3 C(O) 3-indolyl 3-indolyl106 CH.sub.3 C(O) CH.sub.3 C(O) CH.sub.3 OC(O)(CH.sub.2).sub.5 CH.sub.3 OC(O)(CH.sub.2).sub.5107 CH.sub.3 C(O) CH.sub.3 C(O) (CH.sub.3).sub.2 N(CH.sub.2).sub.3 (CH.sub.3).sub.2 N(CH.sub.2).sub.3108 CH.sub.3 (CH.sub.2)NHC(O) CH.sub.3 (CH.sub.2)NHC(O) PhCH.sub.2 PhCH.sub.2109 PhNHC(O) PhNHC(O) PhCH.sub.2 PhCH.sub.2110 PhC(O) PhC(O) PhCH.sub.2 PhCH.sub.2111 4-ClC.sub.6 H.sub.4 C(O) 4-ClC.sub.6 H.sub.4 C(O) PhCH.sub.2 PhCH.sub.2112 3-MeC.sub.6 H.sub.4 C(O) CH.sub.3 C(O) PhCH.sub.2 PhCH.sub.2113 PhCH.sub.2 OC(O) PhCH.sub.2 OC(O) PhCH.sub.2 PhCH.sub.2__________________________________________________________________________
TABLE III__________________________________________________________________________ ##STR166##Ex.No. R.sup.7 R.sup.8 R.sup.3 R.sup.4__________________________________________________________________________114 (CH.sub.3).sub.3 C (CH.sub.3).sub.3 C PhCH.sub.2 PhCH.sub.2115 (CH.sub.3).sub.3 C (CH.sub.3).sub.3 C ##STR167## ##STR168##116 (CH.sub.3).sub.3 C (CH.sub.3).sub.3 C 4-HOC.sub.6 H.sub.4 CH.sub.2 4-HOC.sub.6 H.sub.4 CH.sub.2 1117 (CH.sub.3).sub.3 C (CH.sub.3).sub.3 C ##STR169## PhCH.sub.2118 (CH.sub.3).sub.3 C (CH.sub.3).sub. 3 C 4-cyanobenzyl 4-cyanobenzyl119 (CH.sub.3).sub.3 C (CH.sub.3).sub.3 C 2-nitrobenzyl PhCH.sub.2120 (CH.sub.3).sub.3 C (CH.sub.3).sub.3 C CF.sub.3 CH.sub.2 CF.sub.3 CH.sub.2121 (CH.sub.3).sub.3 C (CH.sub.3).sub.3 C CH.sub.3 (CH.sub.2).sub.6 CH.sub.3 (CH.sub.2).sub.6122 (CH.sub.3).sub.3 C (CH.sub.3).sub.3 C (CH.sub.3).sub.2 CCHCH.sub.2 (CH.sub.3).sub.2 CCHCH.sub.2 5123 (CH.sub.3).sub.3 C (CH.sub.3).sub.3 C CH.sub.2 CHCH.sub.2 CH.sub.2 CHCH.sub.2124 (CH.sub.3).sub.3 C (CH.sub.3).sub.3 C CH.sub.3 O.sub.2 C(CH.sub.2).sub.4 CH.sub.3 O.sub.2 C(CH.sub.2). sub.4125 (CH.sub.3).sub.3 C (CH.sub.3).sub.3 C 2-naphthyl 2-naphthyl126 122(naphthylmethyl) 123(naphthylmethyl)127 (CH.sub.3).sub.3 C (CH.sub.3).sub.3 C 1-naphthyl 1-naphthyl128 (CH.sub.3).sub.3 C (CH.sub.3).sub.3 C cyclohexylmethyl cyclohexylmethyl129 (CH.sub.3).sub.3 C (CH.sub.3).sub.3 C 1-naphthyl 3,4-dichlorobenzyl130 (CH.sub.3).sub.3 C (CH.sub.3).sub.3 C 2-(pyridylmethyl) 2-(pyridylmethyl)131 (CH.sub.3).sub.3 C (CH.sub.3).sub.3 C 3-(pyridylmethyl) 3-(pyridylmethyl)132 (CH.sub.3).sub.3 C (CH.sub.3).sub.3 C 4-(pyridylmethyl) 4-(pyridylmethyl)133 (CH.sub.3).sub.3 C (CH.sub.3).sub.3 C 4-pyridazylmethyl) 4-pyridazylmethyl)134 (CH.sub.3).sub.3 C (CH.sub.3).sub.3 C 4-(imidazolylmethyl) 4-(imidazolylmethyl)135 PhCH.sub.2 PhCH.sub.2 PhCH.sub.2 PhCH.sub.2136 PhCH.sub.2 PhCH.sub.2 4-HOC.sub.6 H.sub.4 CH.sub.2 4-HOC.sub.6 H.sub.4 CH.sub.2137 PhCH.sub.2 PhCH.sub.2 CH.sub.3 SCH.sub.2 CH.sub.3 SCH.sub.2138 PhCH.sub.2 PhCH.sub.2 2-thiophenyl 2-thiophenyl139 PhCH.sub.2 PhCH.sub.2 HS(CH.sub.2).sub.4 HS(CH.sub.2).sub.4140 PhCH.sub.2 PhCH.sub.2 4-(benzyloxy)benzyl 4-(benzyloxy)benzyl141 PhCH.sub.2 PhCH.sub.2 3-(methane-sulfonyl)benzyl 3-(methane-sulfonyl)benzyl142 PhCH.sub.2 PhCH.sub.2 3,4-methylene-dioxybenzyl 3,4-methylene-dioxybenzyl143 PhCH.sub.2 PhCH.sub.2 ##STR170## ##STR171##144 PhCH.sub.2 PhCH.sub.2 CH.sub.3 NHC(O)CH.sub.2 CH.sub.2 ##STR172##145 PhCH.sub.2 PhCH.sub. 2 cyclohexylmethyl cyclohexylmethyl146 PhCH.sub.2 PhCH.sub.2 cyclopropylmethyl cyclopropylmethyl147 PhCH.sub.2 PhCH.sub.2 ##STR173## ##STR174##148 (4-CF.sub.3)C.sub.6 H.sub.4 CH.sub.2 (4-CF.sub.3)C.sub.6 H.sub.4 CH.sub.2 PhCH.sub.2 PhCH.sub.2149 2-C.sub.5 H.sub.5 NCH.sub.2 2-C.sub.5 H.sub.5 NCH.sub.2 PhCH.sub.2 PhCH.sub.2150 4-[(CH.sub.3).sub.3 C]C.sub.6 H.sub.4 CH.sub.2 4-[(CH.sub.3).sub.3 C]C.sub.6 H.sub.4 CH.sub.2 PhCH.sub.2 PhCH.sub.2151 (CH.sub.3).sub.2 CCHCH.sub.2 (CH.sub.3).sub.2 CCHCH.sub.2 PhCH.sub.2 PhCH.sub.2152 4-[SO.sub.2 NH.sub.2 ]C.sub.6 H.sub.4 CH.sub.2 4-[SO.sub.2 NH.sub.2 ]C.sub.6 H.sub.4 CH.sub.2 PhCH.sub.2 PhCH.sub.2153 PhCH.sub.2 PhCH.sub.2 CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.2154 (CH.sub.3).sub.3 C (CH.sub.3).sub.3 C CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.2155 4-[ SO.sub.2 NH.sub.2 ]C.sub.6 H.sub.4 CH.sub.2 4-[SO.sub.2 NH.sub.2 ]C.sub.6 H.sub.4 CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.2__________________________________________________________________________
TABLE IV__________________________________________________________________________ ##STR175##EX.NO. R.sup.7 X.sup.1 R.sup.8 X.sup.2__________________________________________________________________________156 PhC(O) PhC(O)157 (CH.sub.3).sub.3 CC(O) (CH.sub.3).sub.3 CC(O)158 2-pyridylcarbonyl 2-pyridylcarbonyl159 HValVal ValValOH160 HSerAlaAla ValValOH161 BocSerAlaAla ValValOMe162 HAlaAla ValValOMe163 HValSerGlnAsn IleValOH164 AcLeuVal ValLeuOMe165 AcLysVal ValLysAc166 ValBocValVal ArgValOMe167 HArgGlyVal ValGlyArgOH168 cyclohexylcarbonyl cyclohexylcarbonyl169 PhC(O) CH.sub.3 (CO)170 PhNHC(O) PhNH(CO)171 PhCH.sub.2 NHC(O) PhCH.sub.2 NHC(O)172 4-BrC.sub.6 H.sub.4 CH(CH.sub.3)NHC(O) 4-BrC.sub.6 H.sub.4 CH(CH.sub.3)NHC(O)173 Ph(CS) Ph(C S)174 CH.sub.3 CH.sub.3175 PhSO.sub.2 PhSO.sub.2176 2-pyridylmethylaminocarbonyl 2-pyridylmethylaminocarbonyl177 2-pyridylacetyl-Asn 2-pyridylacetyl-Asn178 2-pyridylacetyl-Val 2-pyridylacetyl-Asn179 2-pyridylacetyl-Leu 2-pyridylacetyl-Leu180 2-pyridylacetyl-Gln 2-pyridylacetyl-Gln181 phenylacetyl-Ile phenylacetyl-Ile182 phenylacetyl-Asn phenylacetyl-Asn183 phenylacetyl-Gln phenylacetyl-Gln184 phenylacetyl-Val phenylacetyl-Val185 phenylacetyl-Leu phenylacetyl-Leu186 quinoline-2-carbonyl-Asn quinoline-2-carbonyl-Asn187 qunioline-2-carbonyl-Gln qunioline-2-carbonyl-Ile188 quinoline-2-carbonyl-Ile quinoline-2-carbonyl-Ile189 quinoline-2-carbonyl-Leu quinoline-2-carbonyl-Val190 2-pipecolinyl-Ile 2-pipecolinyl-Asn191 2-pipecolinyl-Asn 2-pipecolinyl-Asn192 2-pipecolinyl-Ile 2-pipecolinyl-Ile193 t-butylacetyl-Asn t-butylacetyl-Asn194 t-butylacetyl-Asn t-butylacetyl-Ile195 t-butylacetyl-Ile t-butylacetyl-Ile196 isoquinoline-3-formyl-Asn isoquinoline-3-formyl-Asn197 isoquinoline-3-formyl-Asn isoquinoline-3-formyl-Ile198 isoquinoline-3-formyl-Ile isoquinoline-3-formyl-Ile199 2-naphthoyl-Asn 2-naphthoyl-Asn200 2-naphthoyl-Gln 2-naphthoyl-Ile201 2-naphthoyl-Ile 2-naphthoyl-Ile202 2-naphthoyl-Ile 2-naphthoyl-Asn203 2-naphthoyl-Val 2-naphthoyl-Ile204 cyclohexylacetyl-Asn cyclohexylacetyl-Asn205 cyclohexylacetyl-Ile cyclohexylacetyl-Ile206 cyclohexylacetyl-Asn cyclohexylacetyl-Ile__________________________________________________________________________
TABLE V__________________________________________________________________________ ##STR176##Ex.No. R.sup.1 W R.sup.3 R.sup.4 R.sup.18__________________________________________________________________________207 2-pyridylmethyl A(O) 2-propyl benzyl H208 2-pyridylmethyl B(O) 2-butyl 4-imidazolylmethyl H209 benzyl C(O) 2-butyl cyclohexylmethyl H210 benzyl D(O) 2-propyl benzyl H211 benzyl E(O) 2-propyl benzyl CH.sub.3213 benzyl F(O) benzyl benzyl H214 n-propyl G(O) 2-propyl benzyl H215 naphthyl H(O) 2-propyl benzyl H216 phenyl I(O) 2-propyl benzyl H217 thiophenyl J(O) 2-propyl benzyl H218 trifluoromethyl K(O) 2-propyl benyzl H219 benzyl L(O)CH.sub.2 2-propyl benzyl H220 2-pyridylmethyl M(O)NH 2-butyl benzyl H221 benzyl N(O)NH 2-butyl benzyl H222 benzyl O(O)NH 2-butyl benzyl CH.sub.3223 benzyl P(O)NH 2-butyl Q(-trifluoromethylbenzyl H224 benzyl R(O)NH cyclobutyl benzyl H225 benzyl S(O)NH cyclobutylmethyl benzyl H226 methyl T(O)NH 2-butyl benzyl H227 phenylethyl U(O)NH 2-butyl benzyl H228 benzyl V(O)NHNH 2-propyl benzyl H229 benzyl W(O)O 2-propyl benzyl H230 benzyl X(S) 2-propyl benzyl H231 benzyl Y(S)NH 2-propyl benzyl H232 benzyl C(Cl)N 2-propyl benzyl H233 2-pyridylmethyl C(NHMe)N 2-propyl benzyl H234 3-methylpropyl C(NHMe)N 2-propyl benzyl H235 benzyl C(NHMe)N 2-propyl benzyl H236 benzyl C(NHMe)N 2-propyl benzyl CH.sub.3237 benzyl C(NHMe)N 2-propyl Z((HCF.sub.2 O)C.sub.6 H4CH.sub.2238 2-pyridylethyl C(OCH.sub.2 CH.sub.3)N 2-propyl benzyl H239 3-naphthylmethyl C(OCH.sub.2 CH.sub.3)N 2-propyl benzyl H240 AA(-t-butylbenzyl C(OCH.sub.2 CH.sub.3)N 2-propyl benzyl H241 benzyl C(OCH.sub.2 CH.sub.3)N 2-propyl benzyl H242 benzyl C(OCH.sub.2 CH.sub.3)N 2-propyl BB(-ytrifluoromethylbenzyl H243 benzyl C(OCH.sub.2 CH.sub.3)N 2-propyl CC(-chlorobenzyl H244 benzyl C(OCH.sub.2 CH.sub.3)N 2-propyl cyclohexylmethyl H245 benzyl C(OCH.sub.2 CH.sub.3)N cyclobutyl benzyl H246 benzyl C(OCH.sub.2 CH.sub.3)N cyclobutylmethyl benzyl H247 benzyl C(OCH.sub.2 CH.sub.3)N cyclopropyl benzyl H248 benzyl C(OCH.sub.3)N 2-propyl benzyl H249 benzyl CH.sub.2 OCH.sub.2 2-propyl benzyl H250 benzyl CH.sub.2 CH.sub.2 2-propyl benzyl H251 benzyl CH.sub.2 CHOH 2-propyl benzyl H252 benzyl CH.sub.2 O 2-propyl benzyl H253 benzyl CH.sub.2 OH 2-propyl benzyl H254 benzyl CHCH 2-propyl benzyl H255 benzyl CHOHCH.sub.2 2-propyl benzyl H256 benzyl CHOHCHOH 2-propyl benzyl H257 benzyl HNC(S)NH 2-propyl benzyl H258 benzyl HNSO.sub.2 2-butyl benzyl H259 benzyl HNSO.sub.2 NH 2-butyl benzyl H260 benzyl DD( 2-propyl benzyl H261 benzyl NHNH 2-propyl benzyl H262 (CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 ) NHC(O)NH 2-butyl benzyl H263 (CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 ) NHC(O)NH 2-butyl benzyl H264 2-hydroxy-3,3-dimethylpropyl NHC(O)NH 2-butyl benzyl H265 2-hydroxy-3,3-dimethylpropyl NHC(O)NH 2-butyl benzyl CH.sub.3266 2-hydroxyindanylmethyl NHC( O)NH 2-butyl benzyl H267 3,5-dimethoxyphenyl NHC(O)NH 2-butyl benzyl H268 3-hydroxy-n-propyl NHC(O)NH 2-butyl benzyl H269 270-nitrobenzyl NHC(O)NH 2-butyl benzyl H271 4-benzyloxyphenylmethyl NHC(O)NH 2-butyl benzyl H272 4-cyano-n-butyl NHC(O)NH 2-butyl benzyl H273 4-phenoxyphenylmethyl NHC(O)NH 2-butyl benzyl H274 4-t-butylphenylmethyl NHC(O)NH 2-butyl benzyl H275 adamantyl NHC(O)NH 2-butyl benzyl H276 benzyl NHC(O)NH 2-butyl benzyl H277 benzyl NHC(O)NH 2-butyl benzyl CH.sub.3278 benzyl NHC(O)NH 2-propyl benzyl H279 benzyl NHC(O)NH 2-propyl 2-naphthylmethyl H280 benzyl NHC(O)NH 2-propyl 3-naphthylmethyl H281 benzyl NHC(O)NH 2-propyl 1-adamantylmethul H282 benzyl NHC(O)NH 2-propyl FF(-hydroxybenzyl H283 benzyl NHC(O)NH 2-propyl 2-imidazolylethyl H284 benzyl NHC(O)NH 2-propyl 4-pyridinylmethyl H285 benzyl NHC(O)NH 2-propyl 4-bromophenyl H286 benzyl NHC(O)NH 2-propyl cycloheptylmethyl H287 benzyl NHC(O)NH 2-propyl 2-thiophenylmethyl H288 benzyl NHC(O)NH 2-propyl 3-pyrrazolylmethyl H289 benzyl NHC(O)NH 2-propyl GG((trifluoromethane- H sulfonyl)propyl290 benzyl NHC(O)NH 2-propyl HH((1- H methyl)piperidinylmethyl291 benzyl NHC(O)NH 2-thiazolylmethyl benzyl H292 benzyl NHC(O)NH benzyl benzyl H293 benzyl NHC(O)NH CH.sub.2 CF3 benzyl H294 benzyl NHC(O)NH CH.sub.2 CH.sub.2 C(O)NH2 benzyl H295 benzyl NHC(O)NH CH.sub.2 CH.sub.2 OH benzyl H296 benzyl NHC(O)NH CH.sub.2 CHOHCH.sub.3 benzyl H297 benzyl NHC(O)NH cyclobutyl benzyl H298 benzyl NHC(O)NH cyclobutyl benzyl CH.sub.3299 benzyl NHC(O)NH cyclobutylmethyl benzyl H300 benzyl NHC(O)NH cyclopentylmethyl benzyl H301 benzyl NHC(O)NH cyclopropyl benzyl H302 benzyl NHC(O)NH cyclopropylmethyl benzyl H303 cis-2-decahydronaphthylmethyl NHC(O)NH 2-butyl benzyl H304 cis-2-decahydronaphthylmethyl NHC(O)NH 2-butyl benzyl CH.sub.3305 benzyl O 2-propyl benzyl H306 (CH.sub.2 CH.sub.2 CH)CH.sub.2 CH.sub.2 OC(O)NH 2-butyl benzyl H307 1-piperidylethyl OC(O)NH 2-butyl benzyl H308 2-benzimidazolylmethyl OC(O)NH 2-butyl benzyl H309 2-naphthylmethyl OC(O)NH 2-butyl benzyl H310 2-pyridylmethyl OC(O)NH 2-butyl benzyl H311 2-quinazolinylmethyl OC(O)NH 2-butyl benzyl H312 3,4-methylene- OC(O)NH 2-butyl benzyl H dioxyphenylmethyl313 3-chlorobenzyl OC(O)NH 2-butyl benzyl H314 3-phenylpropyl OC(O)NH 2-butyl benyzl H315 II(-acetamidobenzyl OC(O)NH 2-butyl benzyl H316 4-imidazolylmethyl OC(O)NH 2-butyl benzyl H317 4-methanesulfonylbenzyl OC(O)NH 2-butyl benzyl H318 4-methoxybenzyl OC(O)NH 2-butyl benzyl H319 4-pyridylmethyl OC(O)NH 2-butyl benzyl H320 4-trifluoromethylbenzyl OC(O)NH 2-butyl benzyl H321 9-fluorenylmethyl OC(O)NH 2-butyl benzyl H322 adamantylmethyl OC(O)NH 2-butyl benzyl H323 benzyl OC(O)NH 1-methoxy-2-propyl benzyl H324 benzyl OC(O)NH 325-hydroxycyclo- benzyl H pentylmethyl326 benzyl OC(O)NH 2,2,2-tri-chloroethyl benzyl H327 benzyl OC(O)NH 2,2,2-tri-fluoroethyl benzyl H328 benzyl OC(O)NH 2-butyl benzyl H329 benzyl OC(O)NH 2-propyl benzyl H330 benzyl OC(O)NH 2-propyl benzyl CH.sub.3331 benzyl OC(O)NH 2-propyl 3-naphthylmethyl H332 benzyl OC(O)NH 2-propyl KK(-phenoxybenzyl H333 benzyl OC(O)NH 2-propyl LL(-benzyloxybenzyl H334 benzyl OC(O)NH 2-propyl MM(-(5-tetrazolyl)benzyl H335 benzyl OC(O)NH 2-propyl NN(,5'-bis(trifluore- H methyl)benzyl336 benzyl OC(O)NH 2-propyl OO(-trifluoromethylbenzyl H337 benzyl OC(O)NH 2-propyl 2-phenylethyl H338 benzyl OC(O)NH 2-propyl 2-benzimidazolylmethyl H339 benzyl OC(O)NH 2-propyl PP((4-chlorophenyl)ethyl H340 benzyl OC(O)NH 2-propyl 2-decahydronaphthylmethyl H341 benzyl OC(O)NH 2-propyl QQ((3,4-methylene- H dioxyphenyl)ethyl342 benzyl OC(O)NH RR((dimethylamino)- benzyl H 1-propyl343 benzyl OC(O)NH benzyl benzyl H344 benzyl OC(O)NH CH.sub.2 NHC(O)NHCH.sub.3 4-pyridylmethyl H345 benzyl OC(O)NH CH.sub. 2 NHSO.sub.2 CH.sub.3 benzyl H346 benzyl OC(O)NH cyclobutyl benzyl H347 benzyl OC(O)NH cyclobutylmethyl benzyl H348 benzyl OC(O)NH cyclopropyl 2-pyridylmethyl H349 benzyl OC(O)NH cyclopropylmethyl benzyl H350 benzyl OC(O)NH methyl benzyl H351 CH.sub.3 SO.sub.2 CH.sub.2 CH.sub.2 OC(O)NH 2-butyl benzyl H352 cyclopentylethyl OC(O)NH 2-butyl 2-pyridylmethyl H353 F.sub.2 HCOC.sub.6 H4CH.sub.2 OC(O)NH 2-butyl 3-pyridylmethyl H354 N,N-dimethylamino-3-propyl OC(O)NH 2-butyl benzyl H355 benzyl OCH.sub.2 2-propyl benzyl H356 benzyl OP(O)(OMe)O 2-propyl 2-pyridylmethyl H357 benzyl SO.sub.2 2-propyl benzyl H358 2,4-difluorophenyl SO.sub.2 NH 2-butyl 2-pyridylmethyl H359 SS(-methylphenyl SO.sub.2 NH 2-butyl benzyl H360 benzyl SO.sub.2 NH TT((methylamino)ethyl benzyl H361 benzyl SO.sub.2 NH 2-furanylmethyl benzyl H362 benzyl SO.sub.2 NH 2-propyl benzyl H363 benzyl SO.sub.2 NH 2-propyl benzyl Et364 benzyl SO.sub.2 NH 2-propyl UU(-trifluoromethylbenzyl H365 benzyl SO.sub.2 NH 2-propyl VV(,4'-difluorobenzyl H366 benzyl SO.sub.2 NH 2-propyl 3-phenylpropyl H367 benzyl SO.sub.2 NH 2-propyl 1-pyrrolylethyl H368 benzyl SO.sub.2 NH 2-propyl WW((4-chlorophenyl)ethyl H369 benzyl SO.sub.2 NH 2-propyl 1-phenylethyl H370 benzyl SO.sub.2 NH 3-hydroxy-1-propyl 1-phenylethyl H371 benzyl SO.sub.2 NH cyclobutyl benzyl H372 benzyl SO.sub.2 NH cyclopropyl benzyl H373 benzyl SO.sub.2 NH methylthiomethyl 1-phenylethyl H374 cyclohexylethyl SO.sub.2 NH 2-butyl 2-pyridylmethyl H375 nonafluorobutyl SO.sub.2 NH 2-butyl benzyl H376 phenyl SO.sub.2 NH 2-butyl 2-pyridylmethyl H377 trifluoromethyl SO.sub.2 NH 2-butyl benzyl H378 2,4-difluorophenyl SO.sub.2 NHC(O)NH 2-butyl benzyl H379 XX(-methylphenyl SO.sub.2 NHC(O)NH YY((dimethyl- 3-pyridylmethyl H amino)ethyl380 ZZ(-methylphenyl SO.sub.2 NHC(O)NH 2-butyl benzyl H381 AAA(-methylphenyl SO.sub.2 NHC(O)NH 2-butyl 4-pyridylmethyl H382 BBB(-methylphenyl SO.sub.2 NHC(O)NH benzyl benzyl H383 CCC(-methylphenyl SO.sub.2 NHC(O)NH CH.sub.2 CH.sub.2 OH benzyl H384 DDD(-methylphenyl SO.sub.2 NHC(O)NH cyclobutyl benzyl H385 EEE(-methylphenyl SO.sub.2 NHC(O)NH cyclohexylmethyl 4-pyridylmethyl H386 FFF(-methylphenyl SO.sub.2 NHC(O)NH cyclopropyl benzyl H387 benzyl SO.sub.2 NHC(O)NH 2-butyl benzyl H388 cyclohexylethyl SO.sub.2 NHC(O)NH 2-butyl 2-pyridylmethyl H389 methyl SO.sub.2 NHC(O)NH 2-butyl benzyl H390 nonafluorobutyl SO.sub.2 NHC(O)NH 2-butyl benzyl H391 phenyl SO.sub.2 NHC(O)NH 2-butyl 3-pyridylmethyl H392 phenyl SO.sub.2 NHC(O)NH 2-butyl benzyl H393 phenyl SO.sub.2 NHC(O)NH 2-butyl GGG(-chlorobenzyl H394 phenyl SO.sub.2 NHC(O)NH 2-butyl 3-naphthylmethyl H395 phenyl SO.sub.2 NHC(O)NH 2-butyl HHH((4-fluorophenyl)ethyl H396 phenyl SO.sub.2 NHC(O)NH 2-butyl 2-phenylethyl H397 phenyl SO.sub.2 NHC(O)NH 2-butyl III(-carbomethoxybenzyl H398 phenyl SO.sub.2 NHC(O)NH 2-butyl 2-pyridylmethyl CH.sub.3399 phenyl SO.sub.2 NHC(O)NH cyclopropyl benzyl H400 trifluoromethyl SO.sub.2 NHC(O)NH 2-butyl benzyl H401 trifluoromethyl SO.sub.2 NHC(O)NH 2-butyl benzyl H402 trifluoromethyl SO.sub.2 NHC(O)NH cyclobutyl 3-pyridylmethyl H403 trifluoromethyl SO.sub.2 NHC(O)NH cyclopropyl 4-pyridylmethyl H__________________________________________________________________________
TABLE VI__________________________________________________________________________ ##STR177##Ex.No. R.sup.1 W X R.sup.2 R.sup.3 R.sup.4 R.sup.18__________________________________________________________________________404 benzyl C(O)NH C(O)NH benzyl 2-butyl benzyl H405 benzyl C(O)NH C(O)O benzyl 2-butyl benzyl H406 benzyl C(O)NH C(O) benzyl 2-butyl 2-pyridyl- H methyl407 benzyl C(O)NH CH.sub.2 C(O) benzyl 2-butyl benzyl H408 benzyl C(O)NH CH.sub.2 C(O)CH.sub.2 benzyl 2-butyl 3-pyridyl- H methyl409 benzyl C(O)NH C(Q)CH.sub.2 benzyl 2-butyl benzyl H410 benzyl C(O)NH SO.sub.2 NH benzyl 2-butyl benzyl H411 benzyl C(O)NH SO.sub.2 benzyl 2-butyl 4-pyridyl- H methyl412 benzyl C(O)NH CH.sub.2 OCH.sub.2 benzyl 2-butyl benzyl H413 benzyl C(O)NH CH.sub.2 O benzyl 2-butyl benzyl H414 benzyl C(O)NH CH.sub.2 NCH.sub.3 benzyl 2-butyl 2-pyridyl- H methyl415 benzyl C(O)NH CH.sub.2 NH benzyl 2-butyl benzyl H416 benzyl C(O)NH CH.sub.2 CH.sub.2 benzyl 2-butyl benzyl H417 benzyl C(O)NH CHCH benzyl 2-butyl 3-pyridyl- H methyl418 benzyl C(O)NH CH(OH)CH(OH) benzyl 2-butyl benzyl H419 benzyl C(O)NH CH(OH)CH.sub.2 benzyl 2-butyl benzyl H420 benzyl C(O)NH CH.sub.2 CH(OH) benzyl 2-butyl benzyl H421 benzyl C(O)NH CH(OH) benzyl 2-butyl benzyl H422 benzyl C(O)NH C(N[Me]2)N benzyl 2-butyl benzyl H423 benzyl C(O)NH C(OEt)N benzyl 2-butyl benzyl H424 benzyl C(O)NH C(Cl)N benzyl 2-butyl 2-pyridyl- H methyl425 benzyl C(O)NH SO.sub.2 NH benzyl 2-butyl benzyl CH.sub.3426 benzyl NHC(O)NH C(O)NH benzyl 2-butyl benzyl H427 2-pyridyl- NHC(O)NH C(O)NH benzyl 2-butyl 3-pyridyl- H methyl methyl428 2-pyrimidinyl NHC(O)NH C(O)NH benzyl 2-butyl benzyl H429 benzyl NHC(O)NH C(O)NH 3-(methyl- 2-butyl benzyl H amino)propyl430 naphthyl NHC(O)NH C(O)NH benzyl cyclopropyl benzyl H431 benzyl NHC(O)NH C(O)NH benzyl cyclopropyl 4-chloro- H benzyl432 benzyl NHC(O)NH C(O)NH benzyl 2-butyl 4-pyridyl H433 benzyl NHC(O)NH C(O)NH 2-acetamido- 2-butyl benzyl H434 benzyl NHC(O)NH C(O)NH 2-(dimethyl- 2-propyl benzyl H aminoethyl)435 benzyl NHC(O)NH C(O)NH benzyl 2-butyl benzyl H436 benzyl NHC(O)NH SO.sub.2 NH benzyl 2-butyl benzyl H437 benzyl NHC(O)NH SO.sub.2 NH 3-(methyl- n-propyl benzyl H amino)propyl438 benzyl NHC(O)NH SO.sub.2 NH isobutyl 2-propyl benzyl H439 naphthyl NHC(O)NH SO.sub.2 NH benzyl 2-butyl benzyl CH.sub.3440 benzyl NHC(O)NH SO.sub.2 NH benzyl 2-butyl benzyl H441 benzyl OC(O)NH C(O)NH benzyl 2-butyl 2-pyridyl- H methyl442 2-pyridyl- OC(O)NH C(O)O benzyl 2-butyl benzyl H methyl443 benzyl OC(O)NH C(O) benzyl 2-butyl benzyl H444 benzyl OC(O)NH CH.sub.2 C(O) benzyl 2-butyl benzyl H445 benzyl OC(O)NH CH.sub.2 C(O)CH.sub.2 benzyl 2-butyl benzyl H446 benzyl OC(O)NH C(O)CH.sub.2 benzyl 2-butyl benzyl H447 benzyl OC(O)NH SO.sub.2 NH benzyl 2-butyl benzyl H__________________________________________________________________________
TABLE VII__________________________________________________________________________ ##STR178##Ex. No. R.sup.1 W R.sup.3 R.sup.4 R.sup.18__________________________________________________________________________448449 benzyl C(S) 2-propyl benzyl H450 benzyl C(S)NH 2-propyl benzyl H451 benzyl HNSO.sub.2 NH 2-butyl 2-pyridylmethyl H452 benzyl SO.sub.2 2-propyl benzyl H453 2,4-difluoro- SO.sub.2 NH 2-butyl 3-pyridylmethyl H phenyl454 4'-methylphenyl SO.sub.2 NH 2-butyl benzyl H455 benzyl SO.sub.2 NH 2-(methyl- benzyl H amino)ethyl456 benzyl SO.sub.2 NH 2-furanylmethyl 4-pyridylmethyl H457 benzyl SO.sub.2 NH 2-propyl benzyl H458 benzyl SO.sub.2 NH 2-propyl benzyl Et459 benzyl SO.sub.2 NH 2-propyl 3'-trifluoro- H methylbenzyl460 benzyl SO.sub.2 NH 2-propyl 2',4'-difluoro- H benzyl461 benzyl SO.sub.2 NH 2-propyl 3-phenylpropyl H462 benzyl SO.sub.2 NH 2-propyl 1-pyrrolylethyl H463 benzyl SO.sub.2 NH 2-propyl 2-(4-chloro- H phenyl)ethyl464 benzyl SO.sub.2 NH 2-propyl 1-phenylethyl H465 benzyl SO.sub.2 NH 3-hydroxy-1-propyl 1-phenylethyl H466 benzyl SO.sub.2 NH cyclobutyl 2-pyridylmethyl H467 benzyl SO.sub.2 NH cyclopropyl benzyl H468 benzyl SO.sub.2 NH methylthiomethyl 1-phenylethyl H469 cyclohexylethyl SO.sub.2 NH 2-butyl benzyl H470 nonafluorobutyl SO.sub.2 NH 2-butyl benzyl H471 phenyl SO.sub.2 NH 2-butyl 2-pyridylmethyl H472 trifluoromethyl SO.sub.2 NH 2-butyl benzyl H473 benzyl NHC(S)NH 2-butyl benzyl H474 benzyl NHC(S)NH 2-butyl 3-pyridylmethyl CH.sub.3475 benzyl NHC(S)NH 2-propyl benzyl H476 benzyl NHC(S)NH 2-propyl 2-naphthylmethyl H477 benzyl CH.sub.2 O 2-propyl benzyl H478 benzyl CH.sub.2 OCH.sub.2 2-propyl 2-pyridylmethyl H479 benzyl CH.sub.2 CH.sub.2 2-propyl benzyl H480 benzyl CHCH 2-propyl benzyl H__________________________________________________________________________
TABLE VIII__________________________________________________________________________ ##STR179##Ex.No. R.sup.1 W X R.sup.2 R.sup.3 R.sup.4 R.sup.18__________________________________________________________________________481482483 benzyl C(O)NH C(O)NH benzyl 2-butyl benzyl H484 benzyl C(O)NH C(O)O benzyl 2-butyl 4-chloro- H benzyl485 benzyl C(O)NH C(O) benzyl 2-butyl benzyl H486 benzyl C(O)NH CH.sub.2 C(O) benzyl 2-butyl 2-pyridyl- H methyl487 benzyl NHC(O)NH C(O)NH 2-(dimethyl- 2-propyl benzyl H aminoethyl)488 benzyl NHC(O)NH C(O)NH benzyl 2-butyl benzyl H489 benzyl NHC(O)NH SO.sub.2 NH benzyl 2-butyl benzyl H__________________________________________________________________________
TABLE IX__________________________________________________________________________ ##STR180##Ex.No. R.sup.1 W R.sup.3 R.sup.4 R.sup.18__________________________________________________________________________490491 benzyl SO.sub.2 NH 2-propyl 1-phenylethyl H492 benzyl SO.sub.2 NH 3-hydroxy-1-propyl 1-phenylethyl H493 benzyl SO.sub.2 NH methylthiomethyl 1-phenylethyl H494 phenyl SO.sub.2 NHC(O)NH 2-butyl 2-phenylethyl H495 phenyl SO.sub.2 NHC(O)NH 2-butyl 3'-carbomethoxybenzyl H496 benzyl OC(O)NH 2-propyl 3-naphthylmethyl H497 benzyl OC(O)NH 2-propyl 4'-(5-tetra- H zolyl)benzyl498 benzyl OC(O)NH 2-propyl 4'-benzyloxybenzyl H499 benzyl OC(O)NH 2-propyl 4'-phenoxybenzyl H500 benzyl C(O)NH 2-butyl 4'-trifluoro- H methylbenzyl501 2-pyridylmethyl C(O)NH 2-butyl benzyl H502 benzyl C(O)NH 2-butyl benzyl H503 benzyl C(O)NH 2-butyl 2-pyridylmethyl CH.sub.3504 benzyl C(O)NH cyclobutyl benzyl H505 benzyl C(O)NH cyclobutylmethyl benzyl H506 benzyl C(O)NH 2-butyl benzyl H507 phenylethyl C(O)NH 2-butyl 3-pyridylmethyl H508 benzyl C(O)NHNH 2-propyl benzyl H509 benzyl C(O)O 2-propyl benzyl H510 benzyl CH.sub.2 OCH.sub.2 2-propyl benzyl H511 benzyl CH.sub.2 CH.sub.2 2-propyl 4-pyridylmethyl H512 benzyl CH.sub.2 O 2-propyl benzyl H513 benzyl CHCH 2-propyl benzyl H514 benzyl HNSO.sub.2 NH 2-butyl benzyl H515 benzyl NN 2-propyl benzyl H516 benzyl NHNH 2-propyl benzyl H517 adamantyl NHC(O)NH 2-butyl 2-pyridylmethyl H518 benzyl NHC(O)NH 2-butyl benzyl H519 benzyl NHC(O)NH 2-butyl benzyl CF.sub.3520 benzyl NHC(O)NH 2-propyl benzyl H521 benzyl NHC(O)NH benzyl 3-pyridylmethyl H522 benzyl NHC(O)NH CH.sub.2 CF.sub.3 benzyl H523 benzyl NHC(O)NH CH.sub.2 CH.sub.2 C(O)NH benzyl H524 benzyl NHC(O)NH cyclobutyl benzyl H525 benzyl NHC(O)NH cyclobutyl benzyl CF.sub.3526 benzyl NHC(O)NH cyclobutylmethyl 4-pyridylmethyl H527 benzyl NHC(O)NH cyclopentylmethyl benzyl H528 benzyl NHC(O)NH cyclopropyl benzyl H529 benzyl NHC(O)NH cyclopropylmethyl benzyl H530 cis-2-deca- NHC(O)NH 2-butyl benzyl H hydronaphthylmethyl531 cis-2-deca- NHC(O)NH 2-butyl benzyl CF.sub.3 hydronaphthylmethyl532 2-hydroxy-3,3- NHC(O)NH 2-butyl benzyl H dimethylpropyl533 2-hydroxy-3,3- NHC(O)NH 2-butyl benzyl CF.sub.3 dimethylpropyl534 2-hydroxy- NHC(O)NH 2-butyl 2-pyridylmethyl H indanylmethyl535 benzyl OC(O)NH 1-methoxy-2-propyl benzyl H536 benzyl OC(O)NH 2'-hydroxy- benzyl H cyclopentylmethyl537 benzyl OC(O)NH 2,2,2-trichloroethyl 3-pyridylmethyl H538 benzyl OC(O)NH 2,2,2-trichloroethyl benzyl H539 benzyl OC(O)NH 2-butyl benzyl H540 benzyl OC(O)NH 2-propyl benzyl H541 benzyl OC(O)NH 2-propyl benzyl CF.sub.3542 2-benzimida- OC(O)NH 2-butyl benzyl H zolylmethyl543 2-naphthyl- OC(O)NH 2-butyl 4-pyridylmethyl H methyl544 2-pyridylmethyl OC(O)NH 2-butyl benzyl H545 CH.sub.3 SO.sub.2 CH.sub.2 CH.sub.2 OC(O)NH 2-butyl benzyl H546 cyclopentylethyl OC(O)NH 2-butyl benzyl H547 F.sub.2 HCOC.sub.6 H.sub.4 CH.sub.2 OC(O)NH 2-butyl benzyl H548 2,4-difluoro- SO.sub.2 NH 2-butyl benzyl H phenyl549 4'-methylphenyl SO.sub.2 NH 2-butyl benzyl H550 benzyl SO.sub.2 NH 2-(methylamino)ethyl benzyl H551 benzyl SO.sub.2 NH 2-furanylmethyl 2-pyridylmethyl H552 benzyl SO.sub.2 NH 2-propyl benzyl H553 benzyl SO.sub.2 NH cyclobutyl benzyl H554 benzyl SO.sub.2 NH cyclopropyl benzyl H555 4'-methylphenyl SO.sub.2 NHC(O)NH 2-(dimethylamino)- benzyl H ethyl556 4'-methylphenyl SO.sub.2 NHC(O)NH 2-butyl benzyl H557 4'-methylphenyl SO.sub.2 NHC(O)NH 2-butyl benzyl H558 4'-methylphenyl SO.sub.2 NHC(O)NH benzyl benzyl H559 4'-methylphenyl SO.sub.2 NHC(O)NH CH.sub.2 CH.sub.2 OH 3-pyridylmethyl H560 4'-methylphenyl SO.sub.2 NHC(O)NH cyclobutyl benzyl H561 phenyl SO.sub.2 NHC(O)NH 2-butyl 4-pyridylmethyl CF.sub.3562 phenyl SO.sub.2 NHC(O)NH cyclopropyl benzyl H563 trifluoromethyl SO.sub.2 NHC(O)NH 2-butyl benzyl H564 trifluoromethyl SO.sub.2 NHC(O)NH 2-butyl benzyl H565 trifluoromethyl SO.sub.2 NHC(O)NH cyclobutyl benzyl H566 trifluoromethyl SO.sub.2 NHC(O)NH cyclopropyl benzyl H__________________________________________________________________________
TABLE X__________________________________________________________________________ ##STR181##Ex.No. R.sup.1 W X R.sup.2 R.sup.3 R.sup.4 R.sup.12__________________________________________________________________________567568 benzyl C(O)NH C(O)NH benzyl 2-butyl benzyl H569 benzyl C(O)NH C(O)O benzyl 2-propyl benzyl H570 benzyl C(O)NH CH.sub.2 C(O)CH.sub.2 4-chlorophenyl cyclopropyl benzyl H571 benzyl C(O)NH C(O)CH.sub.2 benzyl ethyl benzyl H572 benzyl C(O)NH SO.sub.2 NH benzyl cyclobutyl benzyl H573 benzyl C(O)NH CH.sub.2 NCH.sub.3 2-(dimethyl- 2-butyl benzyl H aminoethyl)574 benzyl C(O)NH CH.sub.2 NH benzyl 2-butyl benzyl H575 benzyl C(O)NH CH.sub.2 CH.sub.2 naphthyl 2-butyl 4-fluoro- H phenyl576 benzyl C(O)NH CHCH benzyl 2-butyl benzyl H577 benzyl C(O)NH CH(OH)CH(OH) 2-acetamido 2-butyl naphthyl H578 3-trifluoro- C(O)NH CH(OH)CH.sub.2 benzyl 2-butyl benzyl H methylbenzyl579 benzyl C(O)NH CH.sub.2 CH(OH) benzyl 2-butyl 4-meth- H oxyphenyl580 benzyl C(O)NH CH(OH) 4-methanesulfonyl 2-butyl benzyl H581 benzyl C(O)NH SO.sub.2 NH benzyl 2-butyl 2,4-di- CH.sub.3 chlorophenyl582 benzyl NHC(O)NH C(O)NH benzyl 2-butyl benzyl H583 2-pyridyl- NHC(O)NH C(O)NH benzyl 2-butyl benzyl H methyl584 2,4-dimethoxy- NHC(O)NH C(O)NH benzyl 2-butyl benzyl H benzyl585 benzyl NHC(O)NH C(O)NH 3-(methyl- 2-butyl benzyl H amino)-propyl586 naphthyl NHC(O)NH C(O)NH benzyl cyclopropyl benzyl H587 benzyl NHC(O)NH C(O)NH 2-imi- cyclopropyl 4-chloro- H dazolylmethyl benzyl588 benzyl NHC(O)NH C( O)NH benzyl 2-butyl 4-pyridyl H589 benzyl NHC(O)NH C(O)NH 2-acetamido 2-butyl benzyl H590 benzyl NHC(O)NH C(O)NH 2-(dimethyl- 2-propyl benzyl H aminoethyl)591 benzyl NHC(O)NH C(O)NH benzyl 2-butyl benzyl H592 benzyl NHC(O)NH SO.sub.2 NH benzyl 2-butyl benzyl H593 benzyl NHC(O)NH SO.sub.2 NH 3-(methyl- n-propyl benzyl H amino)propyl594 benzyl NHC(O)NH SO.sub.2 NH isobutyl 2-propyl benzyl H595 naphthyl NHC(O)NH SO.sub.2 NH benzyl 2-butyl benzyl H596 benzyl NHC(O)NH SO.sub.2 NH 3-indolylmethyl 2-butyl benzyl CH.sub.3597 benzyl OC(O)NH C(O)NH benzyl 2-butyl benzyl H598 benzyl OC(O)NH C(O)O benzyl 2-propyl benzyl H599 benzyl OC(O)NH CH.sub.2 C(O)CH.sub.2 4-chlorophenyl cyclopropyl benzyl H600 adamantyl OC(O)NH C(O)CH.sub.2 benzyl ethyl benzyl H601 benzyl OC(O)NH SO.sub.2 NH benzyl cyclobutyl benzyl H602 benzyl OC(O)NH CH.sub.2 NCH.sub.3 2-(dimethyl- 2-butyl benzyl H aminoethyl)603 cyclohexylmethyl OC(O)NH CH.sub.2 NH benzyl 2-butyl benzyl H604 benzyl OC(O)NH CH.sub.2 CH.sub.2 naphthyl 2-butyl 4-fluoro- H phenyl__________________________________________________________________________
TABLE XI__________________________________________________________________________ ##STR182##Ex.No. R.sup.1 W R.sup.3 R.sup.4 R.sup.18__________________________________________________________________________605 2-pyridylmethyl C(O) 2-propyl benzyl H606 benzyl C(O) 2-butyl cyclohexylmethyl H607 benzyl C(O) 2-propyl benzyl H608 trifluoromethyl C(O) 2-propyl 2-pyridylmethyl H609 benzyl C(O)CH.sub.2 2-propyl benzyl H610 2-pyridylmethyl C(O)NH 2-butyl 3-pyridylmethyl H611 benzyl C(O)NH 2-butyl benzyl H612 benzyl C(O)NH 2-butyl benzyl CH.sub.3613 benzyl C(O)NH 2-butyl 4'-trifluoro- H methylbenzyl614 benzyl C(O)NH cyclobutyl benzyl H615 benzyl C(O)NH cyclobutylmethyl benzyl H616 methyl C(O)NH 2-butyl 3-pyridylmethyl H617 phenylethyl C(O)NH 2-butyl benzyl H618 benzyl C(O)NHNH 2-propyl benzyl H619 benzyl C(O)O 2-propyl benzyl H620 benzyl C(S) 2-propyl 4-pyridylmethyl H621 benzyl C(S)NH 2-propyl benzyl H622 benzyl C(Cl)N 2-propyl benzyl H623 2-pyridylmethyl C(NHMe)N 2-propyl benzyl H624 3-methylpropyl C(NHMe)N 2-propyl benzyl H625 benzyl C(NHMe)N 2-propyl 2-pyridylmethyl H626 benzyl C(NHMe)N 2-propyl benzyl CH.sub.3627 benzyl C(NHMe)N 2-propyl 4-(HCF.sub.2 O)C.sub.6 H.sub.4 CH.sub.2628 benzyl C(OCH.sub.2 CH.sub.3)N 2-propyl benzyl H629 benzyl C(OCH.sub.2 CH.sub.3)N 2-propyl 4'-trifluoro- H methylbenzyl630 benzyl C(OCH.sub.2 CH.sub.3)N 2-propyl 4'-chlorobenzyl H631 benzyl CH.sub.2 OCH.sub.2 2-propyl benzyl H632 benzyl CH.sub.2 CH.sub.2 2-propyl benzyl H633 benzyl CH.sub.2 CHOH 2-propyl 3-pyridylmethyl H634 benzyl CH.sub.2 O 2-propyl benzyl H635 benzyl CH.sub.2 OH 2-propyl benzyl H636 benzyl CHCH 2-propyl benzyl H637 benzyl CHOHCH.sub.2 2-propyl 4-pyridylmethyl H638 benzyl CHOHCHOH 2-propyl benzyl H639 benzyl HNC(S)NH 2-propyl benzyl H640 benzyl HNSO.sub.2 2-butyl benzyl H641 benzyl HNSO.sub.2 NH 2-butyl benzyl H642 benzyl NN 2-propyl 2-pyridylmethyl H643 benzyl NHNH 2-propyl benzyl H644 2-hydroxy-3,3- NHC(O)NH 2-butyl benzyl H dimethylpropyl645 4-t-butyl- NHC(O)NH 2-butyl benzyl H phenylmethyl646 adamantyl NHC(O)NH 2-butyl benzyl H647 benzyl NHC(O)NH 2-butyl 2-pyridylmethyl H648 benzyl NHC(O)NH 2-butyl benzyl CH.sub.3649 benzyl NHC(O)NH 2-propyl benzyl H650 benzyl NHC(O)NH 2-propyl 3-pyrrazolylmethyl H651 benzyl NHC(O)NH 2-propyl 3-(trifluoro- H methanesulfonyl)propyl652 benzyl NHC(O)NH 2-propyl 4-(1-methyl)piperi- H dinylmethyl653 benzyl NHC(O)NH 2-thiozolylmethyl benzyl H654 benzyl NHC(O)NH cyclobutyl 3-pyridylmethyl CH.sub.3655 benzyl NHC(O)NH cyclobutylmethyl benzyl H656 2-pyridylmethyl OC(O)NH 2-butyl benzyl H657 9-fluorenylmethyl OC(O)NH 2-butyl 4-pyridylmethyl H658 adamantylmethyl OC(O)NH 2-butyl benzyl H659 benzyl OC(O)NH 1-methoxy-2-propyl benzyl H660 benzyl OC(O)NH 2'-hydroxy- benzyl H cyclopentylmethyl661 benzyl OC(O)NH 2-propyl benzyl CH.sub.3662 benzyl OC(O)NH 2-propyl 3-naphthylmethyl H663 benzyl OC(O)NH 2-propyl 4'-phenoxybenzyl H664 benzyl OC(O)NH 2-propyl 4'-benzyloxybenzyl H665 benzyl OC(O)NH 2-propyl 4'-(5-tetra- H zolyl)benzyl666 benzyl OCH.sub.2 2-propyl benzyl H667 benzyl OP( O)(OMe)O 2-propyl benzyl H668 benzyl SO.sub.2 2-propyl 2-pyridylmethyl H669 2,4-difluorophenyl SO.sub.2 NH 2-butyl benzyl H670 4'-methylphenyl SO.sub.2 NH 2-butyl benzyl H671 benzyl SO.sub.2 NH 2-propyl 3-pyridylmethyl Et672 benzyl SO.sub.2 NH 2-propyl 3'-tri- H fluoromethylbenzyl673 benzyl SO.sub.2 NH 2-propyl 2',4'-difluorobenzyl H674 nonafluorobutyl SO.sub.2 NH 2-butyl benzyl H675 phenyl SO.sub.2 NH 2-butyl benzyl H676 trifluoromethyl SO.sub.2 NH 2-butyl 4-pyridylmethyl H677 2,4-difluorophenyl SO.sub.2 NHC(O)NH 2-butyl benzyl H678 4'-methylphenyl SO.sub.2 NHC(O)NH 2-(dimethyl- benzyl H amino)ethyl679 4'-methylphenyl SO.sub.2 NHC(O)NH 2-butyl benzyl H680 4'-methylphenyl SO.sub.2 NHC(O)NH CH.sub.2 CH.sub.2 OH 4-pyridylmethyl H681 4'-methylphenyl SO.sub.2 NHC(O)NH cyclobutyl benzyl H682 4'-methylphenyl SO.sub.2 NHC(O)NH cyclohexylmethyl benzyl H683 methyl SO.sub.2 NHC(O)NH 2-butyl 3-pyridylmethyl H684 phenyl SO.sub.2 NHC(O)NH 2-butyl benzyl H685 phenyl SO.sub.2 NHC(O)NH 2-butyl benzyl H686 phenyl SO.sub.2 NHC(O)NH 2-butyl 2'-chlorobenzyl H687 phenyl SO.sub.2 NHC(O)NH 2-butyl 3-naphthylmethyl H688 phenyl SO.sub.2 NHC(O)NH 2-butyl 2-(4-fluoro- H phenyl)ethyl689 phenyl SO.sub.2 NHC(O)NH 2-butyl 2-phenylethyl H690 phenyl SO.sub.2 NHC(O)NH 2-butyl 3'-carbomethoxybenzyl H691 phenyl SO.sub.2 NHC(O)NH 2-butyl benzyl CH.sub.3692 phenyl SO.sub.2 NHC(O)NH cyclopropyl 4-pyridylmethyl H693 trifluoromethyl SO.sub.2 NHC(O)NH 2-butyl benzyl H694 trifluoromethyl SO.sub.2 NHC(O)NH 2-butyl benzyl H695 trifluoromethyl SO.sub.2 NHC(O)NH cyclobutyl 2-pyridylmethyl H696 trifluoromethyl SO.sub.2 NHC(O)NH cyclopropyl benzyl H__________________________________________________________________________
TABLE XII__________________________________________________________________________ ##STR183##Ex.No. R.sup.1 W X R.sup.2 R.sup.3 R.sup.4 R.sup.18__________________________________________________________________________697 benzyl OC(O)NH C(O)NH benzyl 2-butyl benzyl H698 benzyl OC(O)NH C(O)O benzyl 2-butyl benzyl H699 benzyl OC(O)NH C(O) 2-(dimethyl- 2-butyl benzyl H amino)ethyl700 benzyl OC(O)NH CH.sub.2 C(O) benzyl 2-propyl benzyl H701 benzyl OC(O)NH CH.sub.2 C(O)CH.sub.2 benzyl 2-propyl 4-chloro- H benzyl702 benzyl OC(O)NH C(Q)CH.sub.2 benzyl 2-propyl benzyl H703 benzyl OC(O)NH SO.sub.2 NH 3-(methyl- ethyl 2-pyridyl H amino)propyl methyl704 benzyl OC(O)NH SO.sub.2 benzyl 2-thiazolyl- benzyl H methyl705 benzyl OC(O)NH CH.sub.2 OCH.sub.2 benzyl cyclobutyl benzyl H706 benzyl OC(O)NH CH.sub.2 O benzyl cyclobutyl- 3-pyridyl H methyl methyl707 benzyl OC(O)NH CH.sub.2 NCH.sub.3 cyclohexylmethyl 2-butyl benzyl CH.sub.3708 benzyl OC(O)NH CH.sub.2 NH benzyl 3-cyanopropy benzyl H709 benzyl HNC(O)NH CH.sub.2 CH.sub.2 benzyl 2-butyl 3-indolyl H710 benzyl C(O)NH CHCH benzyl 1-methoxy-2- 4-pyridyl- H propyl methyl711 2-pyridyl- OC(O)NH CH(OH)CH(OH) benzyl 2'-hydroxycyclo- benzyl H methyl pentylmethyl712 benzyl OC(O)NH CH(OH)CH.sub.2 benzyl 2-propyl 4-fluoro- H benzyl713 naphthyl OC(O)NH CH.sub.2 CH(OH) 4-pyridyl- 2-propyl benzyl H methyl714 benzyl OC(O)NH CH(OH) benzyl benzyl naphthyl H715 2,3-di- OC(O)NH C(N[Me].sub.2)N 4-imida- 2-propyl benzyl H fluorobenzyl zolylmethyl716 benzyl OC(O)NH C(OEt) N benzyl 2-propyl benzyl H717 1-cyclo- OC(O)NH C(Cl)N benzyl 2-propyl benzyl H hexenylmethyl__________________________________________________________________________
TABLE XIII__________________________________________________________________________ ##STR184##Ex.No. R.sup.1 W R.sup.3 R.sup.4 Y__________________________________________________________________________718 2-pyridylmethyl C(O) 2-propyl benzyl C(Cl)N719 benzyl C(O) 2-butyl cyclohexylmethyl C(OEt)N720 benzyl C(O)CH.sub.2 2-propyl benzyl C(OEt)N721 2-pyridylmethyl C(O)NH 2-butyl 2-pyridyl-methyl C(NMe.sub.2)N722 benzyl C(O)NH 2-butyl benzyl C(NHMe)N723 benzyl C(O)NH 2-butyl benzyl C(Cl)N724 benzyl C(O)NH 2-butyl 4'-trifluoro C(NHMe)N methylbenzyl725 benzyl C(O)NHNH 2-propyl benzyl C(NHMe)N726 benzyl C(O)O 2-propyl benzyl C(OMe)N727 benzyl C(S) 2-propyl 3-pyridyl-methyl C(NHMe.sub.2)N728 benzyl C(S)NH 2-propyl benzyl C(NHMe)N729 benzyl C(Cl)N 2-propyl benzyl C(OEt)N730 2-pyridylmethyl C(NHMe)N 2-propyl benzyl C(OEt)N731 3-methylpropyl C(NHMe)N 2-propyl benzyl C(NHMe)N732 benzyl C(NHMe)N 2-propyl benzyl C(NHMe)N733 2-pyridylethyl C(OCH.sub.2 CH.sub.3)N 2-propyl benzyl C(NHMe)N734 benzyl C(OCH.sub.3)N 2-propyl benzyl C(OEt)N735 benzyl CH.sub.2 OCH.sub.2 2-propyl benzyl C(OEt)N736 benzyl CH.sub.2 CH.sub.2 2-propyl 4-pyridyl-methyl C(NMe.sub.2)N737 benzyl CH.sub.2 CHOH 2-propyl benzyl C(NMe)N738 benzyl CH.sub.2 O 2-propyl benzyl C(OEt)N739 benzyl CH.sub.2 OH 2-propyl 2-pyridyl-methyl C(OEt)N740 benzyl CHCH 2-propyl benzyl C(NHMe)N741 benzyl CHOHCH.sub.2 2-propyl benzyl C(NHMe)N742 benzyl CHOHCHOH 2-propyl 3-pyridyl-methyl C(OEt)N743 benzyl HNC(S)NH 2-propyl benzyl C(OMe)N744 benzyl HNSO.sub.2 2-butyl benzyl C(OEt)N745 benzyl HNSO.sub.2 NH 2-butyl benzyl C(OEt)N746 benzyl NN 2-propyl 4-pyridyl-methyl C(NHMe)N747 benzyl NHNH 2-propyl benzyl C(NHMe)N748 (CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2) NHC(O)NH 2-butyl benzyl C(NHMe)N749 (CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2) NHC(O)NH 2-butyl benzyl C(OEt)N750 2-hydroxy-3,3- NHC(O)NH 2-butyl benzyl C(OMe)N dimethylpropyl751 2-hydroxy-3,3- NHC(O)NH 2-butyl benzyl C(Cl)N dimethylpropyl752 2-hydroxy- NHC(O)NH 2-butyl benzyl C(NHMe)N indanylmethyl753 adamantyl NHC(O)NH 2-butyl benzyl C(OEt)N754 benzyl NHC(O)NH 2-butyl 2-pyridyl-methyl C(OEt)N755 benzyl NHC(O)NH 2-butyl benzyl C(Cl)N756 benzyl NHC(O)NH 2-propyl benzyl C(NHMe)N757 benzyl NHC(O)NH 2-propyl 2-naphthyl C(NHMe)N methyl758 benzyl O 2-propyl benzyl C(OEt)N759 2-benzimida- OC(O)NH 2-butyl 3-pyridyl-methyl C(OEt)N zolylmethyl760 2-naphthylmethyl OC(O)NH 2-butyl benzyl C(OEt)N761 2-pyridylmethyl OC(O)NH 2-butyl benzyl C(OEt)N762 benzyl OC(O)NH 1-methoxy- benzyl C(NMe.sub.2)N 2-propyl763 benzyl OC(O)NH 2-butyl benzyl C(NHMe)N764 benzyl OC(O)NH 2-propyl 4-pyridyl-methyl C(NHMe)N765 benzyl OC(O)NH 2-propyl benzyl C(Cl)N766 benzyl OCH.sub.2 2-propyl benzyl C(OMe)N767 benzyl OP(O)(OMe)O 2-propyl benzyl C(OEt)N768 benzyl SO.sub.2 2-propyl benzyl C(NHMe)N769 2,4-di- SO.sub.2 NH 2-butyl benzyl C(NHMe)N fluorophenyl770 4'-methylphenyl SO.sub.2 NH 2-butyl benzyl C(NHMe)N771 benzyl SO.sub.2 NH 2-(methyl- benzyl C(NHMe)N amino)ethyl772 benzyl SO.sub.2 NH 2-furanyl- benzyl C(NHMe)N methyl773 benzyl SO.sub.2 NH 2-propyl 2-pyridyl-methyl C(NHMe)N774 benzyl SO.sub.2 NH 2-propyl benzyl C(Cl)N775 benzyl SO.sub.2 NHC(O)NH 2-butyl benzyl C(OEt)N776 cyclohexylethyl SO.sub.2 NHC(O)NH 2-butyl 3-pyridyl-methyl C(OEt)N777 methyl SO.sub.2 NHC(O)NH 2-butyl benzyl C(OMe)N778 nonafluorobutyl SO.sub.2 NHC(O)NH 2-butyl benzyl C(OMe)N779 phenyl SO.sub.2 NHC(O)NH 2-butyl 4-pyridyl-methyl C(NHMe)N780 phenyl SO.sub.2 NHC(O)NH 2-butyl benzyl C(NMe.sub.2)N781 trifluoromethyl SO.sub.2 NHC(O)NH cyclopropyl benzyl C(NHMe)N__________________________________________________________________________
TABLE XIV__________________________________________________________________________ ##STR185##Ex.No. R.sup.1 W X R.sup.2 R.sup.3 R.sup.4 Y__________________________________________________________________________782 2-pyridylmethyl C(O)NH C(O)NH benzyl 2-butyl benzyl C(NMe.sub.2)N783 benzyl C(O)NH C(O)NH 3-(dimethyl- cyclobutyl benzyl C(NHMe)N amino)propyl784 benzyl C(O)NH C(O)NH cyclopentylmethyl 2-butyl benzyl C(Cl)N785 benzyl C(O)NH C(O)NH benzyl cyclopropyl benzyl C(NHMe)N786 benzyl C(O)NHNH C(O)NH 4-chloro- 2-propyl benzyl C(NHMe)N benzyl787 benzyl C(O)O C(O)NH 3,3,3-triflouro- 2-propyl benzyl C(OMe)N ethyl788 benzyl C(S) C( O)NH 2-imidazol- 2-propyl benzyl C(NMe.sub.2)N ylmethyl__________________________________________________________________________
TABLE XV ##STR186## Ex. No. R.sup.1 W R.sup.3 R.sup.4 R.sup.8 R.sup.10 789 2-pyridylethyl C(O) 2-propyl benzyl 3-(dimethyl- 2,4-di- amino)-1-propyl fluorophenyl 790 2-pyridylmethylC(O) 2-butyl 4-imidazolyl - benzyl 4'-methyl- methyl phenyl 791 benzyl C(O) 2-butyl cyclohexyl methyl CH.sub.2 NHC(O)NHCH.sub.3 benzyl 792 benzyl C(O) 2-propyo benzyl CH.sub.2 NHSO.sub.2 CH.sub.3 benzyl 793 benzyl C(O) 2-propyl 2-pyridyl- cyclobutyl benzyl methyl 794 benzyl C(O) benzyl benzyl cyclobutylmeth yl benzyl 795 n-propyl C(O) 2-propyl benzyl cyclopropyl benzyl 796 naphthyl C(O) 2-propyl 3-pyridyl- cyclopropylmethyl benzyl methyl 797 phenyl C(O) 2-propyl benzyl methyl benzyl 798 thiophenyl C(O) 2-propyl benzyl 2-butyl benzyl 799 trifluoromethyl C(O) 2-propyl benzyl 2-butyl benzyl 800 benzyl C(O)CH.sub.2 2-propyl benzyl 2-butyl benzyl 801 2-pyridylmethyl C(O)NH 2-butyl 3-pyridyl- 2-propyl benzyl methyl 802 benzyl C(O)NH 2-butyl benzyl 2-propyl benzyl 803 benzyl C(O)NH 2-butyl benzyl 2-propyl benzyl 804 benzyl C(O)NH cyclobutyl 4-pyridyl- 2-butyl benzyl methyl 805 benzyl C(O)NH cyclobutyl- benzyl 2-butyl cyclohexyl- methyl ethyl 806 methyl C(O)NH 2-butyl benzyl 2-(methyl- nonafluoro- amino)ethyl butyl 807 phenylethyl C(O)NH 2-butyl benzyl 2-furanylmethyl phenyl 808 benzyl C(O)NHNH 2-propyl benzyl 2-propyl trifluoro- methyl 809 benzyl C(O)O 2-propyl benzyl 2-propyl 2,4-di- fluorophenyl 810 benzyl C(S) 2-propyl benzyl 2-propyl 4'-methyl- phenyl 811 benzyl C(S)NH 2-propyl benzyl 2-propyl 4'-methyl- phenyl 812 benzyl C(Cl)N 2-propyl benzyl 2-propyl 4'-methyl- phenyl 813 2-pyridyl- C(NHMe)N 2-propyl benzyl 2-propyl 4'-methyl- methyl phenyl 814 3-methylpropyl C(NHMe)N 2-propyl benzyl 2-propyl 4'-methyl- phenyl 815 benzyl C(NHMe)N 2-propyl benzyl 2-propyl 4'-methyl- phenyl 816 benzyl C(NHMe)N 2-propyl benzyl 3-hydroxy-1- 4'-methyl- propyl phenyl 817 2-pyridyle thyl C(OCH.sub.2 CH.sub.3)N 2-propyl benzyl cyclobutyl 4'-methyl- phenyl 818 3-naphthylmethyl C(OCH.sub.2 CH.sub.3)N 2-propyl benzyl cyclopropyl benzyl 819 4'-t-butylbenzyl C(OCH.sub.2 CH.sub.3)N 2-propyl benzyl methylthiomethyl cyclohexyl- ethyl 820 benzyl C(OCH.sub.2 CH.sub.3)N 2-propyl benzyl 2-butyl methyl 821 benzyl C(OCH.sub.2 CH.sub.3)N 2-propyl 4'-trifluoro- 2-butyl nonafluoro- methylbenzyl butyl 822 benzyl C(OCH.sub.2 CH.sub.3)N 2-propyl 4'-chloro- 2-butyl phenyl benzyl 823 benzyl C(OCH.sub.2 CH.sub.3)N 2-propyl cyclohexyl- 2-butyl phenyl methyl 824 benzyl C(OCH.sub.2 CH.sub.3)N cyclobutyl benzyl 2-butyl phenyl 825 benzyl C(OCH.sub.2 CH.sub.3)N cyclobutyl- benzyl 2-(dimethyl- phenyl methyl amino)ethyl 826 benzyl C(OCH.sub.2 CH.sub.3)N cyclopropyl benzyl 2-butyl phenyl 827 benzyl C(OCH.sub.3)N 2-propyl benzyl 2-butyl phenyl 828 benzyl CH.sub.2 OCH.sub.2 2-propyl benzyl benzyl phenyl 829 benzyl CH.sub.2 CH.sub.2 2-propyl benzyl CH.sub.2 CH.sub.2 OH phenyl 830 benzyl CH.sub.2 CHOH 2-propyl benzyl cyclobutyl phenyl 831 benzyl CH.sub.2 O 2-propyl benzyl cyclohexylmethyl trifluoromethyl 832 benzyl CH.sub.2 OH 2-propyl benzyl cyclopropyl trifluoromethyl 833 benzyl CHCH 2-propyl benzyl 2-butyl trifluoromethyl 834 benzyl CHOHCH.sub.2 2-propyl benzyl 2-butyl trifluoromethyl 835 benzyl CHOHCHOH 2-propyl benzyl 2-butyl 2-pyridyl- ethyl 836 benzyl HN(S)NH 2-propyl benzyl 2-butyl 2-pyridyl- methyl 837 benzyl HNSO.sub.2 2-butyl benzyl 2-butyl benzyl 838 benzyl HNSO.sub.2 NH 2-butyl benzyl 2-butyl benzyl 839 benzyl NN 2-propyl benzyl 2-butyl benzyl 840 benzyl NHNH 2-propyl benzyl 2-butyl benzyl 841 (CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2) NHC(O)NH 2-butyl benzyl 2-butyl n-propyl 842 (CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2) NHC(O)NH 2-butyl benzyl 2-butyl naphthyl 843 2-hydroxy- NHC(O)NH 2-butyl benzyl 2-butyl phenyl indanylmethyl 844 3,5-dimeth- NHC(O)NH 2-butyl benzyl 2-butyl thiophenyl oxyphenyl 845 3-hydroxy-n- NHC(O)NH 2-butyl benzyl cyclopropy l trifluoromethyl propyl 846 4'-nitrobenzyl NHC(O)NH 2-butyl benzyl 2-butyl benzyl 847 4-benzyloxy- NHC(O)NH 2-butyl benzyl 2-butyl 2-pyridyl - phenylmethyl methyl 848 4-cyano-n-butyl NHC(O)NH 2-butyl benzyl cyclobutyl benzyl 849 4-phenoxy- NHC(O)NH 2-butyl benzyl cyclopropyl benzyl phenylmethyl 850 4-t-butylphenyl- NHC(O)NH 2-butyl benzyl cyclobutyl benzyl methyl 851 adamantyl NHC(O)NH 2-butyl benzyl 2-propylb enzyl 852 benzyl NHC(O)NH 2-butyl benzyl 2-butyl methyl 853 benzyl NHC(O)NH 2-butyl benzyl 2-butyl phenylethyl 854 benzyl NHC(O)NH 2-propyl benzyl 2-propyl benzyl 855 benzyl NHC(O)NH 2-propyl 2-naphth- 2-propyl benzyl ylmethyl 856 benzyl NHC(O)NH 2-propyl 3-naphth- benzyl benzyl ylmethyl 857 benzyl NHC(O)NH 2-propyl 1-adamantyl- 2-propyl benzyl methyl 858 benzyl NHC(O)NH 2-propyl 4'-hydroxy- 2-propyl benzyl benzyl 859 benzyl NHC(O)NH 2-propyl 2-imidazolyl- 2-propyl 2-pyridyl- ethyl methyl 860 benzyl NHC(O)NH 2-propyl 4-pyridinyl- 2-propyl 3-methyl methyl propyl 861 benzyl NHC(O)NH 2-propyl 4-bromophenyl 2-propyl benzyl 862 benzyl NHC(O)NH 2-propyl cycloheptyl- 2-propyl benzyl methyl 863 benzyl NHC(O)NH 2-propyl 2-thiophenyl- 2-butyl 2-pyridyl- methyl ethyl 864 benzyl NHC(O)NH 2-propyl 3-pyrrazolyl- 2-butyl 3-naphth- methyl methyl 865 benzyl NHC(O)NH benzyl benzyl 2-butyl 4'-t-butyl- benzyl 866 benzyl NHC(O)NH CH.sub.2 CF.sub.3 benzyl cyclobutyl benzyl 867 benzyl NHC(O)NH CH.sub.2 CH.sub.2 C(O)NH.sub.2 benzyl cyclobutylmethyl benzyl 868 benzyl NHC(O)NH CH.sub.2 CH.sub.2 OH benzyl 2-butyl benzyl 869 benzyl NHC(O)NH CH.sub.2 CHOHCH.sub.3 benzyl 2-butyl benzyl 870 benzyl NHC(O)NH cyclobutyl benzyl 2-propyl benzyl 871 benzyl NHC(O)NH cyclobutyl benzyl 2-propyl benzyl 872 benzyl NHC(O)NH cyclobutyl- benzyl 2-propyl benzyl methyl 873 benzyl NHC(O)NH cyclopentyl- benzyl 2-propyl benzyl methyl 874 benzyl NHC(O)NH cyclopropyl benzyl 2-propyl benzyl 875 benzyl NHC(O)NH cycloprop yl- benzyl 2-propyl benzyl methyl 876 cis-2-deca- NHC(O)NH2-butyl benzyl 2-propyl benzyl hydronaphthylmethyl 877 cis-2-deca- NHC(O)NH 2-butyl benzyl 2-propyl benzyl hydronaphthylmethyl 878 benzyl O 2-propyl benzyl 2-propyl benzyl 879 (CH.sub.2 CH.sub.2 CH)CH.sub.2 CH.sub.2 OC(O)NH 2-butyl benzyl 2-propyl benzyl 880 1-piperidylethyl OC(O)NH 2-butyl benzyl 2-propyl benzyl 881 2-benzimidazolyl- OC(O)NH 2-butyl benzyl 2-propyl benzyl methyl 882 2-naphthylmethyl OC(O)NH 2-butyl benzyl 2-propyl benzyl 883 2-pyridylmethyl OC(O)NH 2-butyl benzyl 2-propyl benzyl 884 2-quinazolinyl- OC(O)NH 2-butyl benzyl 2-propyl benzyl methyl 885 3,4-methylene- OC(O)NH 2-butyl benzyl 2-propyl benzyl dioxyphenylmethyl 886 3-chlorobenzyl OC(O)NH 2-butyl benzyl cyclobutylbenzyl 887 3-phenylpropyl OC(O)NH 2-butyl benzyl cyclobutyl- (CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2) methyl 888 4'-acetamido- OC(O)NH 2-butyl benzyl cyclopropyl (CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2) benzyl 889 4-imidazolyl- OC(O)NH 2-butyl benzyl 2-propyl 2-hydroxy- methyl indanylmethyl 890 4-methane- OC(O)NH 2-butyl benzyl 2-propyl 3,5-dimethoxy- sulfonylbenzyl phenyl 891 4-methoxybenzyl OC(O)NH 2-butyl benzyl 2-propyl 3-hydroxy- n-propyl 892 4-pyridylmethyl OC(O)NH 2-butyl benzyl 2-propyl 4'-nitro- benzyl 893 4-trifluoro- OC(O)NH 2-butyl benzyl 2-propyl 4-benzyl- methylbenzyl oxyphenylmethyl 894 9-fluorenyl- OC(O)NH 2-butyl benzyl 2-propyl 4-cyano-n- methyl butyl 895 adamantylmethyl OC(O)NH 2-butyl benzyl 2-propyl 4-phenoxy- phenylmethyl 896 benzyl OC(O)NH 1-methoxy-2- benzyl 2-propyl 4-t-butyl- propyl phenylmethyl 897 benzyl OC(O)NH 2'-hydroxy- benzyl 2-propyl adamantyl cyclopentylmethyl 989 benzyl OC(O)NH 2,2,2-trichlor- benzyl 2-propyl benzyl oethyl 899 benzyl OC(O)NH 2,2,2-trifluor- benzyl 2-butyl benzyl oethyl 900 benzyl OC(O)NH 2-butyl benzyl 2-butyl benzyl 901 benzyl OC(O)NH 2-propylb enzyl 2-propyl benzyl 902 benzyl OC(O)NH 2-propylbenzyl 2-propyl benzyl 903 benzyl OC(O)NH 2-propyl3-naphth- 2-butyl benzyl ylmethyl 904 benzyl OC(O)NH 2-propyl4'-phenoxy- 2-butyl benzyl benzyl 905 benzyl OC(O)NH 2-propyl4'-benzyl- 2-butyl benzyl oxybenzyl 906 benzyl OC(O)NH 2-propyl4 '-(5-tetra- 2-butyl benzyl zolyl)benzyl 907 benzyl OC(O)NH 2-propyl 3',5'-bis(tri- 2-butyl benzyl fluoremethyl)- benzyl 908 benzyl OC(O)NH 2-propyl 4'-trifluoro- 2-butyl benzyl methylbenzyl 909 benzyl OC(O)NH 2-propyl 2-phenylethyl 2-butyl benzyl 910 benzyl OC(O)NH 2-propyl 2-benzimi- 2-butyl benzyl dazolylmethyl 911 benzyl OC(O)NH 2-propyl 2-(4-chloro- 2-butyl benzyl phenyl)ethyl 912 benzyl OC(O)NH 2-propyl 2-decahydro- 2-butyl benzyl naphthylmethyl 913 benzyl OC(O)NH 2-propyl 2-(3,4-methylene- 2-butyl benzyl dioxyphenyl)ethyl 914 benzyl OC( O)NH 3-(dimethyl- benzyl 2-butyl benzyl amino)-1-propyl 915 benzyl OC(O)NH benzyl benzyl 2-butyl benzyl 916 benzyl OC(O)NH CH.sub.2 NHC(O)NHCH.sub.3 benzyl 2-propyl benzyl 917 benzyl OC(O)NH CH.sub.2 NHSO.sub.2 CH.sub.3 benzyl 2-propyl benzyl 918 benzyl OC(O)NH cyclobutyl benzyl 2-propyl benzyl 919 benzyl OC(O)NH cyclobutyl- benzyl 2-propyl benzyl methyl 920 benzyl OC(O)NH cyclopropyl benzyl 2-propyl benzyl 921 benzyl OC(O)NH cyclopropyl- benzyl 2-propyl benzyl methyl 922 benzyl OC(O)NH methyl benzyl 2-propyl cis-2-deca- hydronaphthyl- methyl 923 CH.sub.3 SO.sub.2 CH.sub.2 CH.sub.2 OC(O)NH 2-butyl benzyl 2-propyl cis-2-deca- hydronaphthyl- methyl 924 cyclopentylethyl OC(O)NH 2-butyl benzyl 2-propyl benzyl 925 F.sub.2 HCOC.sub.6 H.sub.4 CH.sub.2 OC(O)NH 2-butyl benzyl 2-propyl (CH.sub.2 CH.sub.2 CH)CH.sub.2 CH.sub.2 926 benzyl OCH.sub.2 2-propyl benzyl 2-propyl 1-piperidyl- ethyl 927 benzyl OP(O)(OMe)O 2-propyl benzyl benzyl 2-benzimidazolyl- methyl 928 benzyl SO.sub.2 2-propyl benzyl CH.sub. 2 CF.sub.3 2-naphthyl- methyl 930 2,4-difluoro- SO.sub.2 NH 2-butyl benzyl CH.sub.2 CH.sub.2 C(O)NH.sub.2 2-pyridyl phenyl methyl 931 4'-methylphenyl SO.sub.2 NH 2-butyl benzyl CH.sub.2 CH.sub.2 OH 2-quinazolinyl- methyl 932 benzyl SO.sub.2 NH 2-(methyl- benzyl CH.sub.2 CHOHCH.sub.3 3,4-methylene- amino)ethyl dioxyphenylmethyl 933 benzyl SO.sub.2 NH 2-furanylmethyl benzyl cyclobutyl 3-chlorobenzyl 934 benzyl SO.sub.2 NH 2-propyl benzyl cyclobutyl 3-phenylpropyl 936 benzyl SO.sub.2 NH 2-propyl benzyl cyclobutylmethyl 4'-acetamidobenzyl 937 benzyl SO.sub.2 NH 2-propyl 3'-trifluoro- cyclopentylmethyl 4-imidazolyl- methylbenzy l methyl 938 benzyl SO.sub.2 NH 2-propyl 2',4'-difluoro- cyclopropyl 4-methanesulfonyl- benzyl benzyl 939 benzyl SO.sub.2 NH 2-propyl 3-phenyl- cyclopentylmethyl 4-methoxy- phenylpropyl benzyl 940 benzyl SO.sub.2 NH 2-propyl 1-pyrrolyl- 2-butyl 4-pyridyl- ethyl methyl 941 benzyl SO.sub.2 NH 2-propyl 2-(4-chloro- 2-butyl 4-trifluoro- phenyl)ethyl methylbenzyl 942 benzyl SO.sub.2 NH 2-propyl 1-phenylethyl 2-propyl 9-fluoroenyl- methyl 943 benzyl SO.sub.2 NH 3-hydroxy-1- 1-phenylethyl 2-butyl adamantyl- propyl methyl 944 benzyl SO.sub.2 NH cyclobutyl benzyl 2-butyl benzyl 945 benzyl SO.sub.2 NH cyclopropyl benzyl 2-butyl benzyl 946 benzyl SO.sub.2 NH methylthiomethyl 1-phenylethyl 2-butyl benzyl 947 cyclohexylethyl SO.sub.2 NH 2-butyl benzyl 2-butyl benzyl 948 nonafluorobutyl SO.sub.2 NH 2-butyl benzyl 2-butyl benzyl 949 phenyl SO.sub.2 NH 2-butyl benzyl 2-butyl benzyl 950 trifluoromethyl SO.sub.2 NH 2-butyl benzyl 2-butyl benzyl 951 2,4-difluoro- SO.sub.2 NHC(O)NH2-butyl benzyl 2-butyl benzyl phenyl 952 4'-methylphenyl SO.sub.2 NHC(O)NH2-(dimethyl- benzyl 2-butyl benzyl amino)ethyl 953 4'-methylphenyl SO.sub.2 NHC(O)NH2-butyl benzyl 2-butyl benzyl 954 4'-methylphenyl SO.sub.2 NHC(O)NH2-butyl benzyl 2-butyl benzyl 955 4'-methylphenyl SO.sub.2 NHC(O)NHbenzyl benzyl 2-butyl benzyl 956 4'-methylphenyl SO.sub.2 NHC(O)NHCH.sub.2 CH.sub.2 OH benzyl 2-butyl benzyl 957 4'-methylphenyl SO.sub.2 NHC(O)NHcyclobutyl benzyl 2-butyl benzyl 958 4'-methylphenyl SO.sub.2 NHC(O)NHcyclohexylmethyl benzyl 2-butyl benzyl 959 4'-methylphenyl SO.sub.2 NHC(O)NHcyclopropyl benzyl 2-butyl benzyl 960 benzyl SO.sub.2 NHC(O)NH2-butyl benzyl 1-methoxy-2- benzyl propyl 961 cyclohexylethy l SO.sub.2 NHC(O)NH2-butyl benzyl 2'-hydroxy- benzyl cyclopentylmethyl 962 methyl SO.sub.2 NHC(O)NH2-butyl benzyl 2,2,2-tri- benzyl chloroethyl 963 nonafluoro butyl SO.sub.2 NHC(O)NH 2-butyl benzyl 2,2,2-tri- benzyl fluoroethyl 964 phenyl SO.sub.2 NHC(O)NH 2-butyl benzyl 2-butyl benzyl 965 phenyl SO.sub.2 NHC(O)NH 2-butyl benzyl 2-propyl benzyl 966 phenyl SO.sub.2 NHC(O)NH 2-butyl 2'-chloro- 2-propyl benzyl benzyl 967 phenyl SO.sub.2 NHC(O)NH 2-butyl 3-naphthyl- 2-propyl benzyl methyl 968 phenyl SO.sub.2 NHC(O)NH 2-butyl 2-(4-fluoro- 2-propyl benzyl phenyl)ethyl 969 phenyl SO.sub.2 NHC(O)NH 2-butyl 2-phenylethyl 2-propyl benzyl 970 phenyl SO.sub.2 NHC(O)NH 2-butyl 3'-carbo- 2-propyl benzyl methoxybenzyl 971 phenyl SO.sub.2 NHC(O)NH 2-butyl benzyl 2-propyl CH.sub.3 SO.sub.2 CH.sub.2 CH.sub.2 972 phenyl SO.sub.2 NHC(O)NH cyclopropyl benzyl 2-propyl cyclophenyl ethyl 973 trifluoromethyl SO.sub.2 NHC(O)NH 2-butyl benzyl 2-propyl F.sub.2 HCOC.sub.6 H.sub.4 CH.sub.2 974 trifluoromethyl SO.sub.2 NHC(O)NH 2-butyl benzyl 2-propyl benzyl 975 trifluoromethyl SO.sub.2 NHC(O)NH cyclobutyl benzyl 2-propyl benzyl 976 trifluoromethyl SO.sub.2 NHC(O)NH cyclopropyl benzyl 2-propyl benzyl
TABLE XVI__________________________________________________________________________ ##STR187##Ex.No. R.sup.1 W R.sup.3 R.sup.4 R.sup.8__________________________________________________________________________ 977 2-pyridylethyl C(O) 2-propyl benzyl t-butyl 978 2-pyridylmethyl C(O) 2-butyl 4-imidazolylmethyl t-butyl 979 benzyl C(O) 2-butyl cyclohexylmethyl t-butyl 980 2-pyridyl-methyl C(O) 2-propyl benzyl t-butyl 981 benzyl C(O) 2-propyl 2-pyridyl-methyl t-butyl 982 3-pyridyl-methyl C(O) 2-propyl benzyl t-butyl 983 n-propyl C(O) 2-propyl benzyl t-butyl 984 naphthyl C(O) 2-propyl 3-pyridyl-methyl t-butyl 985 phenyl C(O) 2-propyl benzyl t-butyl 986 thiophenyl C(O) 2-propyl benzyl t-butyl 987 trifluoromethyl C(O) 2-propyl 3-pyridyl-methyl t-butyl 988 benzyl C(O)CH.sub.2 2-propyl benzyl t-butyl 989 2-pyridylmethyl C(O)NH 2-butyl 2-pyridyl-methyl t-butyl 990 benzyl C(O)NH 2-butyl 3-pyridyl-methyl t-butyl 991 benzyl C(O)NH 2-butyl benzyl t-butyl 992 benzyl C(O)NH cyclobutyl benzyl t-butyl 993 benzyl C(O)NH cyclobutylmethyl benzyl t-butyl 994 methyl C(O)NH 2-butyl 3-pyridyl-methyl t-butyl 995 phenylethyl C(O)NH 2-butyl benzyl t-butyl 996 benzyl C(O)NHNH 2-propyl 3-pyridyl-methyl t-butyl 997 benzyl C(O)O 2-propyl benzyl t-butyl 998 benzyl C(S) 2-propyl benzyl t-butyl 999 benzyl C(S)NH 2-propyl 3-pyridyl-methyl t-butyl1000 benzyl C(Cl)N 2-propyl benzyl t-butyl1001 2-pyridylmethyl C(NHMe)N 2-propyl benzyl t-butyl1002 3-methylpropyl C(NHMe)N 2-propyl benzyl t-butyl1003 benzyl C(NHMe)N 2-propyl benzyl t-butyl1004 benzyl C(NHMe)N 2-propyl 3-pyridyl-methyl t-butyl1005 2-pyridylethyl C(OCH.sub.2 CH.sub.2)N 2-propyl benzyl t-butyl1006 3-naphthylmethyl C(OCH.sub.2 CH.sub.2)N 2-propyl benzyl t-butyl1007 4'-t-butylbenzyl C(OCH.sub.2 CH.sub.2)N 2-propyl 3-pyridyl-methyl t-butyl1008 benzyl C(OCH.sub.2 CH.sub.2)N 2-propyl benzyl t-butyl1009 benzyl C(OCH.sub.2 CH.sub.2)N 2-propyl 4'-ytrifluoromethylbenzyl t-butyl1010 benzyl C(OCH.sub.2 CH.sub.2)N 2-propyl 4'-chlorobenzyl t-butyl1011 benzyl C(OCH.sub.2 CH.sub.2)N 2-propyl cyclohexylmethyl t-butyl1012 benzyl C(OCH.sub.2 CH.sub. 2)N cyclobutyl benzyl t-butyl1013 benzyl C(OCH.sub.2 CH.sub.2)N cyclobutylmethyl 3-pyridyl-methyl t-butyl1014 benzyl C(OCH.sub.2 CH.sub.2)N cyclopropyl benzyl t-butyl1015 benzyl C(OCH.sub.2)N 2-propyl benzyl t-butyl1016 benzyl CH.sub.2 OCH.sub.2 2-propyl 3-pyridyl-methyl t-butyl1017 benzyl CH.sub.2 CH.sub.2 2-propyl benzyl t-butyl1018 benzyl CH.sub.2 CHOH 2-propyl 4-pyridyl-methyl t-butyl1019 benzyl CH.sub.2 O 2-propyl benzyl t-butyl1020 benzyl CH.sub.2 OH 2-propyl 2-pyridyl-methyl t-butyl1021 benzyl CHCH 2-propyl benzyl t-butyl1022 benzyl CHOHCH.sub.2 2-propyl 3-pyridyl-methyl t-butyl1023 benzyl CHOHCHOH 2-propyl benzyl t-butyl1024 benzyl HNC(S)NH 2-propyl 4-pyridyl-methyl t-butyl1025 benzyl HNSO.sub.2 2-butyl benzyl t-butyl1026 benzyl HNSO.sub.2 NH 2-butyl benzyl t-butyl1027 benzyl NN 2-propyl benzyl t-butyl1028 benzyl NHNH 2-propyl 4-pyridyl-methyl t-butyl1029 (CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 ) NHC(O)NH 2-butyl benzyl t-butyl1030 (CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 ) NHC(O)NH 2-butyl 4-pyridyl-methyl t-butyl1031 2-hydroxyindanyl-methyl NHC(O)NH 2-butyl benzyl t-butyl1032 3,5-dimethoxyphenyl NHC(O)NH 2-butyl 4-pyridyl-methyl t-butyl1033 3-hydroxy-n-propyl NHC(O)NH 2-butyl benzyl t-butyl1034 4'-nitrobenzyl NHC(O)NH 2-butyl benzyl t-butyl1035 4-benzyloxyphenylmethyl NHC(O)NH 2-butyl 4-pyridyl-methyl t-butyl1036 4-cyano-n-butyl NHC(O)NH 2-butyl benzyl t-butyl1037 4-phenoxyphenyl-methyl NHC(O)NH 2-butyl benzyl t-butyl1038 4-t-butylphenyl-methyl NHC(O)NH 2-butyl benzyl t-butyl1039 adamantyl NHC(O)NH 2-butyl benzyl t-butyl1040 benzyl NHC(O)NH 2-butyl 4-pyridyl-methyl t-butyl1041 benzyl NHC(O)NH 2-butyl benzyl t-butyl1042 benzyl NHC(O)NH 2-propyl 3-pyridyl-methyl t-butyl1043 benzyl NHC(O)NH 2-propyl 2-naphthylmethyl t-butyl1044 benzyl NHC(O)NH 2-propyl 3-naphthylmethyl t-butyl1045 benzyl NHC(O)NH 2-propyl 1-adamantylmethul t-butyl1046 benzyl NHC(O)NH 2-propyl 4'-hydroxybenzyl 2-propyl1047 benzyl NHC(O)NH 2-propyl 2-imidazolylethyl 2-propyl1048 benzyl NHC(O)NH 2-propyl 4-pyridinylmethyl 2-propyl1049 benzyl NHC(O)NH 2-propyl 4-bromophenyl 2-propyl1050 benzyl NHC(O)NH 2-propyl cycloheptylmethyl 2-propyl1051 benzyl NHC(O)NH 2-propyl 2-thiophenylmethyl 2-propyl1052 benzyl NHC(O)NH 2-propyl 3-pyrrazolylmethyl 2-propyl1053 benzyl NHC(O)NH benzyl benzyl1054 benzyl NHC(O)NH CH.sub.2 CF.sub.3 benzyl 2-propyl1055 benzyl NHC(O)NH CH.sub.2 CH.sub.2 C(O)NH.sub.2 benzyl 2-propyl1056 benzyl NHC(O)NH CH.sub.2 CH.sub.2 OH benzyl 2-propyl1057 benzyl NHC(O)NH CH.sub.2 CHOHCH.sub.2 benzyl 2-propyl1058 benzyl NHC(O)NH cyclobutyl 4-pyridyl-methyl 2-propyl1059 benzyl NHC(O)NH cyclobutyl benzyl 2-propyl1060 benzyl NHC(O)NH cyclobutylmethyl benzyl 2-propyl1061 benzyl NHC(O)NH cyclopentylmethyl 3-pyridyl-methyl 2-propyl1062 benzyl NHC(O)NH cyclopropyl benzyl 2-propyl1063 benzyl NHC(O)NH cyclopropylmethyl benzyl 2-propyl1064 cis-2-decahydronaphthylmethyl NHC(O)NH 2-butyl 3-pyridyl-methyl 2-propyl1065 cis-2-decahydronaphthylmethyl NHC(O)NH 2-butyl benzyl 2-propyl1066 benzyl O 2-propyl benzyl 2-propyl1067 (CH.sub.2 CH.sub.2 CH)CH.sub.2 CH.sub.2 OC(O)NH 2-butyl 3-pyridyl-methyl 2-propyl1068 1-piperidylethyl OC(O)NH 2-butyl benzyl 2-propyl1069 2-benzimidazolylmethyl OC(O)NH 2-butyl benzyl 2-propyl1070 2-naphthylmethyl OC(O)NH 2-butyl benzyl 2-propyl1071 2-pyridylmethyl OC(O)NH 2-butyl 3-pyridyl-methyl 2-propyl1072 2-quinazolinylmethyl OC(O)NH 2-butyl benzyl 2-propyl1073 3,4-methylenedioxyphenylmethyl OC(O)NH 2-butyl benzyl 2-propyl1074 3-chlorobenzyl OC(O)NH 2-butyl benzyl 2-propyl1075 3-phenylpropyl OC(O)NH 2-butyl 3-pyridyl-methyl 2-propyl1076 4'-acetamidobenzyl OC(O)NH 2-butyl benzyl 2-propyl1077 4-imidazolylmethyl OC(O)NH 2-butyl benzyl 2-propyl1078 4-methanesulfonylbenzyl OC(O)NH 2-butyl benzyl 2-propyl1079 4-methoxybenzyl OC(O)NH 2-butyl benzyl 2-propyl1080 4-pyridylmethyl OC(O)NH 2-butyl benzyl 2-propyl1081 4-trifluoromethylbenzyl OC(O)NH 2-butyl benzyl 2-propyl1082 9-fluorenylmethyl OC(O)NH 2-butyl benzyl 2-propyl1083 adamantylmethyl OC(O)NH 2-butyl benzyl iso-butyl1084 benzyl OC(O)NH 1-methoxy-2-propyl benzyl iso-butyl1085 benzyl OC(O)NH 2'-hydroxycyclopentylmethyl benzyl iso-butyl1086 benzyl OC(O)NH 2,2,2-trichloroethyl benzyl iso-butyl1087 benzyl OC(O)NH 2,2,2-trifluoroethyl benzyl iso-butyl1088 benzyl OC(O)NH 2-butyl benzyl iso-butyl1089 benzyl OC(O)NH 2-propyl 3-pyridyl-methyl iso-butyl1090 3-pyridyl-methyl OC(O)NH 2-propyl benzyl iso-butyl1091 3-pyridyl-methyl OC(O)NH 2-propyl 3-naphthylmethyl iso-butyl1092 benzyl OC(O)NH 2-propyl 4'-phenoxybenzyl iso-butyl1093 benzyl OC(O)NH 2-propyl 4'-benzyloxybenzyl iso-butyl1094 benzyl OC(O)NH 2-propyl 4'-(5-tetrazolyl)benzyl iso-butyl1095 benzyl OC(O)NH 2-propyl 3',5'- iso-butyl bis(trifluoremethyl)benzyl1096 benzyl OC(O)NH 2-propyl 4'-trifluoromethylbenzyl iso-butyl1097 benzyl OC(O)NH 2-propyl 2-phenylethyl iso-butyl1098 benzyl OC(O)NH 2-propyl 2-benzimidazolylmethyl iso-butyl1099 benzyl OC(O)NH 2-propyl 2-(4-chlorophenyl)ethyl iso-butyl1100 benzyl OC(O)NH 2-propyl 2-decahydronaphthylmethyl iso-butyl1101 benzyl OC(O)NH 2-propyl 2-(3,4- iso-butyl methylenedioxyphenyl)ethyl1102 benzyl OC(O)NH 3-(dimethylamino)- benzyl iso-butyl 1-propyl1103 benzyl OC(O)NH benzyl benzyl iso-butyl1104 benzyl OC(O)NH CH.sub.2 NHC(O)NHCH.sub.2 3-pyridyl-methyl iso-butyl1105 benzyl OC(O)NH CH.sub.2 NHSO.sub.2 CH.sub.2 benzyl iso-butyl1106 benzyl OC(O)NH cyclobutyl 3-pyridyl-methyl iso-butyl1107 benzyl OC(O)NH cyclobutylmethyl benzyl iso-butyl1108 benzyl OC(O)NH cyclopropyl benzyl iso-butyl1109 benzyl OC(O)NH cyclopropylmethyl 3-pyridyl-methyl iso-butyl1110 benzyl OC(O)NH methyl benzyl iso-butyl1111 CH.sub.2 SO.sub.2 CH.sub.2 CH.sub.2 OC(O)NH 2-butyl 3-pyridyl-methyl iso-butyl1112 cyclopentylethyl OC(O)NH 2-butyl benzyl iso-butyl1113 F2HCOC6H4CH.sub.2 OC(O)NH 2-butyl 3-pyridyl-methyl iso-butyl1114 benzyl OCH.sub.2 2-propyl benzyl iso-butyl1115 benzyl OP(O)(OMe)O 2-propyl 3-pyridyl-methyl iso-butyl1116 benzyl SO.sub.2 2-propyl benzyl iso-butyl1117 2,4-difluorophenyl SO.sub.2 NH 2-butyl benzyl iso-butyl1118 4'-methylphenyl SO.sub.2 NH 2-butyl benzyl iso-butyl1119 benzyl SO.sub.2 NH 2-(methylamino)ethyl benzyl iso-butyl1120 benzyl SO.sub.2 NH 2-furanylmethyl benzyl iso-butyl1121 3-pyridyl-methyl SO.sub.2 NH 2-propyl 3-pyridyl-methyl iso-butyl1122 benzyl SO.sub.2 NH 2-propyl benzyl t-butyl1123 3-pyridyl-methyl SO.sub.2 NH 2-propyl 3'-trifluoromethylbenzyl1124 benzyl SO.sub.2 NH 2-propyl 2',4'-difluorobenzyl t-butyl1125 benzyl SO.sub.2 NH 2-propyl 3-phenylpropyl t-butyl1126 benzyl SO.sub.2 NH 2-propyl 1-pyrrolylethyl t-butyl1127 2-pyridyl-methyl SO.sub.2 NH 2-propyl 2-(4-chlorophenyl)ethyl t-butyl1128 benzyl SO.sub.2 NH 2-propyl 1-phenylethyl t-butyl1129 3-pyridyl-methyl SO.sub.2 NH 3-hydroxy-1-propyl 1-phenylethyl t-butyl1130 benzyl SO.sub.2 NH cyclobutyl benzyl t-butyl1131 benzyl SO.sub.2 NH cyclopropyl benzyl t-butyl1132 benzyl SO.sub.2 NH methylthiomethyl 1-phenylethyl t-butyl1133 2-pyridyl-methyl SO.sub.2 NH 2-butyl benzyl t-butyl1134 nonafluorobutyl SO.sub.2 NH 2-butyl benzyl t-butyl1135 phenyl SO.sub.2 NH 2-butyl benzyl t-butyl1136 trifluoromethyl SO.sub.2 NH 2-butyl benzyl t-butyl1137 2,4-difluorophenyl SO.sub.2 NHC(O)NH 2-butyl benzyl t-butyl1138 4'-methylphenyl SO.sub.2 NHC(O)NH 2-(dimethylamino)ethyl benzyl t-butyl1139 4'-methylphenyl SO.sub.2 NHC(O)NH 2-butyl 2-pyridyl-methyl t-butyl1140 4'-methylphenyl SO.sub.2 NHC(O)NH 2-butyl benzyl t-butyl1141 4'-methylphenyl SO.sub.2 NHC(O)NH benzyl 2-pyridyl-methyl t-butyl1142 4'-methylphenyl SO.sub.2 NHC(O)NH CH.sub.2 CH.sub.2 OH benzyl t-butyl1143 4'-methylphenyl SO.sub.2 NHC(O)NH cyclobutyl benzyl t-butyl1144 4'-methylphenyl SO.sub.2 NHC(O)NH cyclohexylmethyl benzyl t-butyl1145 4'-methylphenyl SO.sub.2 NHC(O)NH cyclopropyl 2-pyridyl-methyl t-butyl1146 benzyl SO.sub.2 NHC(O)NH 2-butyl benzyl t-butyl1147 cyclohexylethyl SO.sub.2 NHC(O)NH 2-butyl benzyl t-butyl1148 methyl SO.sub.2 NHC(O)NH 2-butyl benzyl t-butyl1149 nonafluorobutyl SO.sub.2 NHC(O)NH 2-butyl 2-pyridyl-methyl t-butyl1150 phenyl SO.sub.2 NHC(O)NH 2-butyl benzyl t-butyl1151 phenyl SO.sub.2 NHC(O)NH 2-butyl benzyl t-butyl1152 phenyl SO.sub.2 NHC(O)NH 2-butyl 2'-chlorobenzyl t-butyl1153 phenyl SO.sub.2 NHC(O)NH 2-butyl 3-naphthylmethyl t-butyl1154 phenyl SO.sub.2 NHC(O)NH 2-butyl 2-(4-fluorophenyl)ethyl t-butyl1155 phenyl SO.sub.2 NHC(O)NH 2-butyl 2-phenylethyl t-butyl1156 phenyl SO.sub.2 NHC(O)NH 2-butyl 3'-carbomethoxybenzyl t-butyl1157 phenyl SO.sub.2 NHC(O)NH 2-butyl benzyl t-butyl1158 phenyl SO.sub.2 NHC(O)NH cyclopropyl 2-pyridyl-methyl t-butyl1159 trifluoromethyl SO.sub.2 NHC(O)NH 2-butyl benzyl t-butyl1160 trifluoromethyl SO.sub.2 NHC(O)NH 2-butyl benzyl t-butyl1161 trifuloromethyl SO.sub.2 NHC(O)NH cyclobutyl 2-pyridyl-methyl t-butyl1162 trifluoromethyl SO.sub.2 NHC(O)NH cyclopropyl benzyl t-butyl1163 Benzimidazolylmethyl N(CH.sub.2)C(O)NH 2-propyl 4-pyridyl-methyl t-butyl1164 Benzimidazolylmethyl NC(O)NH 2-propyl 4-pyridyl-methyl t-butyl1165 (CH.sub.2)2NCH(CH.sub.2) C(O)NH 2-propyl 4-fluoro-benzyl t-butyl1166 2-amino-2-propyl C(O)NH CF.sub.3 benzyl t-butyl1167 dimethylaminomethyl C(O)NH 2-propyl benzyl t-butyl1168 dimethylaminomethyl C(O)NH 2-propyl benzyl t-propyl1169 4-amino-benzyl C(O)NH 2-propyl benzyl t-butyl__________________________________________________________________________
Standard procedures were used for detecting and comparing the activity of the compounds of this invention. The results are summarized in Table VII.
CELL FREE PROTEASE INHIBITION ASSAY
Materials
HIV gag polyprotein corresponding to all of p17 and 78 amino acids of p24, produced by in vitro translation using rabbit reticulocyte lysate and mRNA prepared in vitro from plasmid encoding full length gag polyprotein linerized with the restriction enzyme Pst 1. (See S. Erickson-Viitanen et al., Aids Research and Human Retroviruses, 5 (6), 577 (1989) for plasmid construction, and basis for assay).
Source of protease: Either (A) crude E. coli lysate of bacteria harboring a plasmid containing HIV protease under the control of the lac promotor, used at a final concentration of 0.5 mg/ml, or (B) inclusion bodies of E. coli harboring plasmid containing HIV protease under the control of the T7 promotor (Cheng et al., Gene, in press (1990). Such inclusion bodies were solubilized in 8M urea, 50 mM Tris pH 8.0. Protease activity was recovered by dilution of the inclusion bodies 20-fold in buffer containing 50 mM Sodium Acetate, pH 5.5, 1 mM EDTA, 10% glycerol and 5% ethylene glycol. This protease source was used at a final concentration of 0.00875 mg/ml.
Inhibitory compounds were dissolved in sufficient DMSO to make a 25 mM stock concentration. All further dilutions were done in DMSO.
Set Up
Into sterile test tubes were placed the following:
1 uL inhibitor dilutions
14 ul HIV protease in Phosphate Buffered Saline (Gibco)
5 ul of in vitro translation products.
Reactions were incubated at 30.degree. C., then quenched by the addition of Sample buffer. See U. K. Laemmli, Nature, 1970, 227:680-685.
One fourth of each sample was analyzed on an 8-16% gradient denaturing acrylamide gel (Novex, Inc), according to Laemmli. Following electrophoresis, gels were fixed, impregnated with Enhance (Du Pont NEN, Boston, Mass.) and dried according to manufacturers instructions (NEN). Dried fluorographs were exposed to film and/or quantitated using an Ambis radioanalytic scanner.
Each group of test compounds was compared to the values obtained for pepstatin, a well known inhibitor of acid proteases. Inhibitory concentration for 50% inhibition (IC.sub.50) is determined from plots of log concentration inhibitor versus % inhibition of protease activity.
Biological Activity: IC.sub.50 is the concentration necessary for reducing the activity of the enzyme by 50%.
HIV YIELD REDUCTION CELL ASSAY
Materials
MT2, a human T-cell line, was cultured in RPMI medium supplemented with 5% (v/v) heat inactivated fetal calf serum (FCS), L-glutamine and gentamycin. Human immunodeficiency virus strains, HIV(3B) and HIV(Rf) were propagated in H-9 cells in RPMI with 5% FCS. Poly-L-lysine (Sigma) coated cell culture plates were prepared according to the method of Harada et al. (Science 1985 229:563-566). MTT, 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide, was obtained from Sigma.
Method
Test compounds were dissolved in dimethylsulfoxide to 5 mg/ml and serially diluted into RPMI medium to ten times the desired final concentration. MT-2 cells (5.times.10E5/ml) in 2.3 ml were mixed with 0.3 ml of the appropriate test compound solution and allowed to sit for 30 minutes at room temperature. HIV(3b) or HIV(Rf) (.about.5.times.10E5 plaque forming units/ml) in 0.375 ml was added to the cell and compound mixtures and incubated for one hour at 36.degree. C. The mixtures were centrifuged at 1000 rpm for 10 minutes and the supernatants containing unattached virus were discarded. The cell pellets were suspended in fresh RPMI containing the appropriate concentrations of test compound and placed in a 36.degree. C., 4% CO.sub.2 incubator. Virus was allowed to replicate for 3 days. Cultures were centrifuged for 10 minutes at 1000 rpm and the supernatants containing cell free progeny virus were removed for plaque assay.
The virus titers of the progeny virus produced in the presence or absence of test compounds were determined by plaque assay. Progeny virus suspensions were serially diluted in RPMI and 1.0 ml of each dilution was added to 9 ml of MT-2 cells in RPMI. Cells and virus were incubated for 3 hours at 36.degree. C. to allow for efficient attachment of the virus to cells. Each virus and cell mixture was aliquoted equally to two wells of a six well poly-L-lysine coated culture plate and incubated overnight at 36.degree. C., 4% CO.sub.2. Liquid and unattached cells were removed prior to the addition of 1.5 ml of RPMI with 0.75% (w/v) Seaplaque agarose (FMC Corp) and 5% FCS. Plates were incubated for 3 days and a second RPMI/agarose overlay was added. After an additional 3 days at 36.degree. C., 4% CO.sub.2, a final overlay of phosphate-buffered saline with 0.75% Seaplaque agarose and 1 mg MTT/ml was added. The plates were incubated overnight at 36.degree. C. Clear plaques on a purple background were counted and the number of plaque forming units of virus was calculated for each sample. The antiviral activity of test compounds was determined by the percent reduction in the virus titer with respect to virus grown in the absence of any inhibitors.
HIV LOW MULTIPLICITY ASSAY
Materials
MT-Z2, a human T-cell line, was cultured in RPMI medium supplemented with 5% (v/v) heat inactivated fetal calf serum (FCS), L-glutamine and gentamycin (GIBCO). Human immunodeficiency virus strains HIV(3b) and HIV (Rf) were propagated in H-9 cells in RPMI with 5% FCS. XTT, benzene-sulfonic acid, 3,3'-[1-[(phenylamino)carbonyl]-3,4-tetrazolium]bis(4-methoxy-6-nitro)-, sodium salt, was obtained from Starks Associates, Inc.
Method
Test compounds were dissolved in dimethyl-sulfoxide to 5 mg/ml and serially diluted into RPMI medium to ten times the desired final concentration. MT-2 cells (5.times.10E4/0.1 ml) were added to each well of a 96 well culture plate and 0.02 ml of the appropriate test compound solution was added to the cells such that each compound concentration was present in two wells. The cells and compounds were allowed to sit for 30 minutes at room temperature. HIV(3b) or HIV(Rf) (.about.5.times.10E5 plaque forming units/ml) was diluted in medium and added to the cell and compound mixtures to give a multiplicity of infection of 0.01 plaque forming unit/cell. The mixtures were incubated for 7 days at 36.degree. C., during which time the virus replicated and caused the death of unprotected cells. The percentage of cells protected from virus induced cell death was determined by the degree of metabolism of the tetrazolium dye, XTT. In living cells, XTT was metabolized to a colored formazan product which was quantitated spectrophoto-metrically at 450 rm. The amount of colored formazan was proportional to the number of cells protected from virus by the test compound. The concentration of compound protecting either 50% (IC.sub.50) or 90% (IC.sub.90) with respect to an uninfected cell culture was determined.
TABLE XVII______________________________________ Cell Free Cell AssayCompound # Assay IC.sub.50 IC.sub.90______________________________________Example 1A 12 2* 6*Example 1B 37 5* NAExample 2A 12 10 30Example 2B 0.17 1.9 3.0Example 2C 31 -- --Example 3 383 -- --Example 4 435 -- --Example 5 65 -- --Example 6 4.8 NA NAExample 7 502 -- --Example 8 590 -- --Example 9 0.52 NA NAExample 10 600 -- --Example 11 20 NA NAExample 12 4.1 NA NAExample 13 3.3 2.3 25Example 14 480 NA NAExample 15 260 -- --Example 16 260 -- --Example 17 278 -- --Example 18 2.3 6* 12*Example 20 0.01 <1 <1Example 21 0.002 6 --______________________________________

Number	Date	Country
2026382	Sep 1990	CAX
0361341	Apr 1990	EPX
0402646	Dec 1990	EPX

1,4-diamino-2,3-dihydroxybutanes

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Haber et al., J. Cardiovase. Pharmacol., 1987(10) (Supp. 7), pp. 554-558.
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Bolis et al., J. Med. Chem., 1987, 30(10), pp. 1729-1737.
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Denkewalter et al., Progress in Drug Research, 1966, vol. 10, pages 510-512.