NZ238395A - 1,4-diamino-2,3-dihydroxy butane derivatives; preparatory processes and pharmaceutical compositions - Google Patents

1,4-diamino-2,3-dihydroxy butane derivatives; preparatory processes and pharmaceutical compositions

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Publication number
NZ238395A
NZ238395A NZ238395A NZ23839591A NZ238395A NZ 238395 A NZ238395 A NZ 238395A NZ 238395 A NZ238395 A NZ 238395A NZ 23839591 A NZ23839591 A NZ 23839591A NZ 238395 A NZ238395 A NZ 238395A
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NZ
New Zealand
Prior art keywords
benzyl
butyl
propyl
substituted
compound
Prior art date
Application number
NZ238395A
Inventor
Prabhakar Kondaji Jadhav
Lawrence Ray Mcgee
Ashok Shenvi
Carl Nick Hodge
Original Assignee
Du Pont Merck Pharma
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US07/714,042 external-priority patent/US5294720A/en
Application filed by Du Pont Merck Pharma filed Critical Du Pont Merck Pharma
Publication of NZ238395A publication Critical patent/NZ238395A/en

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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
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    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
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    • C07C217/10—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical containing six-membered aromatic rings
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Description

New Zealand Paient Spedficaiion for Paient Number £38395 238395 Patents Form No. 5 i .1: .2,S;..?3l.
...... ..... - , : ...Lfc.;5?;frll ccq£S loz;. colcz.-\ Conc>.v \o<*,• . Col Oloj lzj, 3y>}..3.35/., Coloxt3 /vh; 3VCcnggisf^, Col0233*.Cd 03*53lo(o;- £.<r?7£V£?fl!'.Vj T7 SEP » . . . 1..i-V&V I C'?B8 Cont: XQZQAuAto; C<rtC.Z3j}', .Gfei *Z-/ ' f\<o\W . $05, i$"3SJ, 3^3»a>^.^ * j pv ->* rT^fll'^^O f~"- ^ 2^2\Jf uJ' ii C i! i* ^ NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION XV?E!>1 V 1,4-DIAMINO-2,3-DIHYDROXYBOTANES &. p» fe^v\oc) WE, THE DU PONT MERCK PHARMACEUTICAL COMPANY, a corporation' 4o -VKe. ^v<=a/ i &io—s> cf" 4W_ Dekxixj^u'e. LMi|o»-»-s F%tv4^xue=i-vip AcJy organiaod and existi-ngunderthe lawg-of—the State of-loc^wtcA <=4- iccq t/Wkttf Dolawaro/ U.S.A. of—3rQ%h—&-Markot Streets, Wilmington, Delaware 19898, U.S.A., hereby declare the invention, for which We pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: (followed by Page la) ? 3 8 3 9 5 CR-8S22-A lex title 1,4-DIAMINO-2,3-DIHYDROXYBUTANES FIELD OF THE TNVF.NTTON This invention relates to 1,4-diamino 2,3-5 aihydroxybutanes, a process to prepare these compounds, compositions comprising such compounds and a method of treating viral infection.
RACKr.ROITND OF THE TNVF.NTTON Current treatments for viral diseases usually 10 involve administration of compounds that inhibit viral DNA synthesis. Current treatments for AIDS (Dagani, Chem. Eng. News, November 23, 1987 pp. 41-49) involve administration of compounds such as 2',3'-dideoxy-cytidine, trisodium phosphonoformate, ammonium 21-15 tungsto-9-antimoniate, 1-b-D-ribofuranoxyl-l,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 20 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 25 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 30 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 angiotensin converting . 19 AUG 1991 \ A r \fcer'' (followed by page 2) - 338395 2 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 5 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 sag gene products. See Wellink, Arch.
Virol. IB. 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. 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. 52, 899 (1985); Katohfital., Virology 145. 280 (1985). Therefore, retroviral protease inhibition provides an attractive possible target for antiviral therapy. See Mitsuya, Nature 325 775 (1987). (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. derivatives of tetrapeptides as inhibitors of viral proteases. U.S. Patent No. 4,644,055 discloses halomethyl derivatives of peptides as inhibitors of viral proteases. European Patent Application No.
The correct processing of the precursor Moore, Biochem. Biophys. Res. Commun., 159 420 U.S. Patent No. 4,652,552 discloses methyl ketone 2 238395 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 5 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 10 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 15 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 20 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 25 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 30 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 258395 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 10 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 15 olefins (Behrens and Sharpless, J. Org. Chem., (1985), 50, 5696), ring opening of epoxides (Wai fital., J- Am.
Chem. Soc. (1989), 111, 1123), reduction or alkylation of a-hydroxy/alkoxy carbonyls (Davis fit. ai., J. Org.
Chem., (1989), 54, 2021). Common to all of these 20 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, 25 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 30 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 fit. al. report the preparation of a 1,2-diol by pinacol coupling of a dialdehyde in the presence of A* V 4 \ 19 AUG 1991 23 8 3; T1CI3(dimethoxyethane)2Zn-Cu in dimethoxyethane (McMurry fital./ 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 5 valent titanium complexes (Pons and Santelli, Tetrahedron, (1988), 44, 4295). Finally, Freudenberger at al-, J. Am. Chem. Soc., (1989), 111, 8014-8016 disclose a method which utilizes a vanadium (II) complex, [V2CI3(THF)g]2[ZN2CI6] to couple aldehydes. 10 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 15 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, 20 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 25 the formula: in whereirv N.z.f\Vtf?::roFrs« -1 JUL 1993 • 238395 R1 through R4 and R7 through R10 are independently selected from the following groups: * hydrogen; C1-C8 alkyl substituted with 0-3 R11; C2-C8 alkenyl substituted with 0-3 R11; C3-C8 alkynyl substituted with 0-3 R11; C3-C8 cycloalkyl substituted with 0-3 R11; C6~Cio bicycloalkyl substituted with 0-3 R11; 1 0 aryl substituted with 0-3 R12; a C6-C14 carbocyclic residue substituted with 0-3 R12; and a heterocyclic ring system substituted with 0-2 R12, composed of 5 to 10 atoms including at least 1 5 one nitrogen, oxygen or sulfur atom; R^A through R^A and R7A through R^A are independently selected from the following groups: hydrogen; C1-C4 alkyl substituted with halogen or C1-C2 alkoxy; and benzyl substituted with halogen or C1-C2 alkoxy; R5 and R6 are independently selected from the following groups: hydrogen; C1-C6 alkoxycarbonyl; C1-C6 alkylcarbonyl; benzoyl; phenoxycarbonyl; and N.Z. PATENT 16 7 phenylaminocarbony; wherein said alkyl residues are substituted with 0-3 R11, and said aryl residues are substituted with 0-3 R12; or any other group that, when administered to a mammalian subject, cleaves to form the original diol in which R5 and R6 are hydrogen; Rll is selected from one or more of the following: keto, halogen, cyano, -NR13R14, -CO2R13, -0C(=0)R13, -OR13, C2-C6 alkoxyalkyl, -S(0)mR13, -NHC(=NH)NHR13, -C (=NH) NHR13, -C(=0)NR13R14, -NR14C (=0) R13, -NR14C(=O)0R14, -0C(=0)NR13R14, -NR13C(=0)NR13R14, 1 5 -NR14S02NR13R14, -NR14S02R13, -S02NR13R14, C1-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethy], a C5-C14 carbocyclic residue substituted with 0-3 20 R12, aryl substituted with 0-3 R12, and a heterocyclic ring system substituted with 0-2 25 R12, composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom; R12, when a substituent on carbon, is selected from one 30 or more of the following: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl,C7-C10 arylalkyl, N.Z. PATENT OFFICE 1 7 16 MAR 1994 I Q 395 8 alkoxy, -NR13R14, C2-C6 alkoxyalkyl, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, Ci-C4 alkoxycarbonyl, Ci-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 5 alkylcarbonylamino, -S(0)mR13/ -S02NR13R14, and -NHS02R14; or R12 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 1 0 optionally substituted on the aliphatic carbons with halogen, C1-C4 alkyl, C3.-C4 alkoxy, hydroxy, or NR13R14; or, when R12 is attached to a saturated carbon atom it may be =0 or =S; and R12, when a substituent on nitrogen, is selected from one or more of the following: phenyl, benzyl, phenethyl, hydroxy, C3.-C4 hydroxyalkyl, C1-C4 alkoxy, , C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -NR13R14, C2~Cq alkoxyalkyl, C1-C4 haloalkyl, C3.-C4 and alkoxycarbonyl, C1-C4 alkylcarbonyloxy,/C1-C4 alkylcarbonyl, R13 is H, phenyl, benzyl or C1-C5 alkyl; R14 is H or C1-C4 alkyl; or R13R14 can join to form (CH2>4r (CH2)5, (CH2CH2N(R1^)CH2CH2), or (CH2CH2OCH2CH2) ; r!5 is H or CH3; j o?rice 8 i "" 16 MAR i994 9 m is 0, 1 or 2; n and n1 are independently 0 or 1; W and W1 are independently selected from the following -NR16C(=Q)NR16-' -C(=Q)NR16-; -C(=Q)0-; -NR16C(=Q)0-; -OC(=Q)NR16-; -nr16c(=q)~; -C(=Q) -c(=q)ch2-; 1 5 -nr16S02NR16~ —nr16s02~ -s02nr16--s02-; -QCH2-; -Q-; -(CH2)pNR16-; -ch2ch2-; -ch=ch-; -ch(oh) ch (oh) -ch (oh) ch2-; —ch2ch (oh) -ch(oh) -nh-nh-; -c(«0)nh-nh-; -c (ci) "n-; -c(-or16)«n-; -c(-nr16r17)=n-; -OP(-O) (Q1R16)0-; -P (-0) (Q1R16)0-; and orim.
IB MAR 1804 238 -s02nhc(=0)nh-; X and X1 are independently selected from the following: -c(=q)nr16-; -C(=Q)0-; -C(=Q) -ch2c(=q)-; -CH2C(=Q)CH2-; -c(=q)ch2-'- -so2nr16- -s02-; -ch2qch2-'* -ch2q-; 1 5 -ch2nr16-; -ch2ch2-; -ch=ch-; -ch (oh) ch (oh) -ch (oh) ch2--; -ch2ch (oh) -; -ch(oh)-; -c (=0) nh-nh-; -c (-or16)«n-; -C(-NR16R17)-N-; and 25 -C (L)-N-; Y and Y1 are independently selected from the following: -C(-Q) NR16-; -(CH2)pC(*Q)NRl6-; -S02NR16-; -(ch2)pNRl6-; -C(L)-N- wherein L represents CI or Br; -C(-OR16)-N-; n.,~ ' icl tRf/AR!1"-| ; ;•* -v- 11 -C(-NR16R17)=N-; -NR12C(=0)NR16-; - (CH2) PNR12C (=0) NR16-; -0C(=0)NR16-; and -(CH2)p0C(=0)NR16-; R16 is H, benzyl or C1-C4 alkyl; R17 is H or C1-C4 alkyl; p is 1 or 2; Q is selected from oxygen andsulfur; and Q1 is selected from oxygen, sulfur, NR14 and a direct bond; and pharmaceutical^ acceptable salts and prodrugs thereof.
There is provided a process to prepare the compound of formula I comprising contacting an aldehyde of the formula: with an aldehyde of the formula: ■'v* > is' 11 !MAR j 12 O H R7A R8* R9/ nl in the presence of Caulton's reagent to form the compound of Claim 1 wherein R5 and R6 are H and 5 optionally contacting one or both of the alcohols with a derivatizing agent; wherein: R1 through R4 and R7 through R10 are independently selected from the following groups: R12, composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom; R2A through R4A and R7A through R^A are independently 25 selected from the following groups: 1 5 hydrogen; C1-C8 alkyl substituted with 0-3 R11; C2~C8 alkenyl substituted with 0-3 R11; C3-C8 alkynyl substituted with 0-3 R11; C3-C8 cycloalkyl substituted with 0-3 R11; C6~CiO bicycloalkyl substituted with 0-3 R11; aryl substituted with 0-3 R12; a C6~Ci4 carbocyclic residue substituted with 0-3 R12; and a heterocyclic ring system substituted with 0-2 hydrogen; C1-C4 alkyl substituted with halogen or C1-C2 alkoxy; and benzyl substituted with halogen or C1-C2 alkoxy; fi.2. PAT.hWT Of F ICS 18 MAR 1994 12 13 R5 and R6 are independently selected from the following groups: hydrogen; C1-C6 alkoxycarbonyl; C1-C6 alkylcarbonyl; benzoyl; phenoxycarbonyl; and phenylaminocarbony; wherein said alkyl residues are 10 substituted with 0-3 R11, and said aryl residues are substituted with 0-3 R12; or any other group that, when administered to a mammalian subject, cleaves to form the original diol in which R5 and R6 are 15 hydrogen; R11 is selected from one or more of the following: keto, halogen, cyano, -NR13R14, -CO2R13, -0C(=0)R13, 20 -OR13, C2-C6 alkoxyalkyl, -S(0)mR13, -NHC (=NH) NHR13, -C (=NH) NHR13, -C(=0)NR13R14, -NR14C (=0) R13 , -NR14C<-0)0R14, -0C(«0)NR13R14, -NR13C(~0)NR13R14, -NR14S02NR13R14, -NR14S02R13, -S02NR13R14, C1-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C3-C6 25 cycloalkylmethyl, a C5-C14 carbocyclic residue substituted with 0-3 R12, aryl substituted with 0-3 R12, and ■we- a heterocyclic ring system substituted with 0-2 R12, composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom.
I 13 '■ r !>tV ICE is MAR 1994 238395 14 R12, when a substituent on carbon, is selected from one or more of the following: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl,C7-C1O arylalkyl, alkoxy, -NR13R14, C2-C6 alkoxyalkyl, C1-C4 10 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, Ci~ C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(0)mR13, -S02NR13R14, and -NHS02R^4; or R12 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, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or 20 NR13R14; or, when R12 is attached to a saturated carbon atom it may be =0 or =S; and R12, when a substituent on nitrogen, is selected from one or more of the following:. phenyl, benzyl, phenethyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, , C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -NR13R14, C2-C6 alkoxyalkyl, C1-C4 haloalkyl, C1-C4 and 30 alkoxycarbonyl, C1-C4 alkylcarbonyloxy,/C1-C4 alkylcarbonyl, R13 is H, phenyl, benzyl or C1-C6 alkyl; CiT 14 ■ is mar rm t i 70^0 J y w R14 is H or C1-C4 alkyl; or R13R14 can join to form (CH2)4, (CH2) 5, 5 (CH2CH2N(R15)CH2CH2) , or (CH2CH2OCH2CH2) ; R15 is H or CH3; m is 0, 1 or 2; n and n1 are independently 0 or 1; W and W1 are independently selected from the following: 1 5 -nr16c (=q)nr16"'" -c(=q)nr16-; -C(=Q)0-; -nr16c(=q)0-; -oc(=q)nr16-; -nr16c («=q) -c (=q) -C(=Q)CH2-; -nr16s02nr16~ -nr16so2~ -S02NR16- -so2-; -QCH2-; -q-; -(CH2)pNR16-; -CH2CH2-' -ch=ch-; -CH(OH)CH(OH)--CH(OH)CH2~; 238395 16 -CH^CH (OH) -CH(OH) -NH-NH-; -C(=0)NH-NH-; -C(CI)=N-; -C(-0R16)=N-; -C(-NRl6R17)=N-; -0P(=0) (Q1R16)0-; -P (=0) (Q1R16) 0-; and 10 -so2NHC (=0) NH-; X and X1 are independently selected from the following; -c(=q)nr16-; -c(=q)0-; ~C(=Q) -ch2c(=q)-'" ~ch2c(=q)ch2-; -c(=q)ch2-; -so2nr16- -S02-; -ch2qch2-; -ch2q-; -CH2NR16-; -CH2CH2-' -ch=ch-; —ch(oh)ch(oh) -ch(0h)ch2-; -ch2ch(0h)-; -ch(oh) -c(mo)nh-nh-; -c(-0r16)-n-; -c (-nr16r* 6) =n- ; and 16 *:p Q 17 -C(L)=N- wherein L represents CI or Br; Y and Y1 are independently selected from the following: -C<=Q)NR16-; -(CH2)PC<=Q)NR16-; -SO2NR16-; -(CH2)pNR16-; -C(L)=N- wherein L represents CI or Br; 10 -C(-OR16)=N-; -C (-NR1 6Rx6) =N-; -NR12C(=0)NR16-; - (CH2) PNR12C (=0) NR16- ; -0C(=0)NR16-; and 15 - (CH2) pOC (=0) NR16- ; R16 is H, benzyl or C1-C4 alkyl; R17 is H or C1-C4 alkyl; p is 1 or 2; Q is selected from oxygen and sulfur; L is CI or Br; and Ql is selected from oxygen, sulfur, NR14 and a direct bond; and pharmaceutical^ 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. 17 238395 18 A process for preparing an intermediate compound of the formula: r20 r21 cXo n3 n3 (III) comprises: (a) reacting an organometallic derivative R18M or R19M in the presence of copper (I) salts and an ether-10 containing, aprotic solvent system with a diepoxide of the formula: R20 R21 0 0 VK? 0 o (IV) 1 5 (b) reacting the product of step (a) of the formula: r20 r21 o*o r18 r19 ho oh (V) with R22R23R24P and Ci~C6 dialkyl azodicarboxylate in the presence of an azide anion and an aprotic organic 18 '.1;| < '■«' v i § 23s o y 3 19 solvent generally at a temperature between -20 to 100°C; wherein: R18 and R19 are independently C2-C8 alkyl; C3-C8 cycloalkyl substituted, with 0-3 R2^; a C6-C10 carbocyclic aromatic residue, selected frcm phenyl or naphthyl, substituted with 0-3 r2 6; a heterocyclic ring system substituted with 0-2 10 R^G, composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom; selected from example, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, 15 indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl,and octahydroisoquinolinyl; 20 R^S is selected from one or more of the following groups: keto; halogen; -NR27R28; -CC>2R27; -0C(=0)R27; -OR27, -S(0)mR27 wherein m is 0, 1 or 2; -NHC(=NH)NHR27; -C(=NH)NHR27; -C(=0)NHR27; cyano; C-j-Cg cycloalkyl substituted with 0-3 R26; a C6-C10 carbocyclic aromatic residue, selected frcm phenyl or naphthyl, substituted with 0-3 r26; and a heterocyclic ring system substituted with 0-2 R26, composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom; selected fron oxamplor pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, ' - ' - — ♦ - -K. J 19 f 23 b ^ a 5 benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, 5 tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, andoctahydroisoquinolinyl; r26 is selected from one or more of the following groups: phenyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, C2-C6 alkoxyalkyl,methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 15 alkylcarbonyl, alkylsulfonyl, S02NR27R28, and R27S02NH; R20 and R21 are independently H, Ci-Cs alkyl, a C6~ C10 carbocyclic aromatic residue, selected from phenyl and naphthyl, substituted with 0-3 R^6, or 20 C1-C3 alkyl substituted with a C6-C10 carbocyclic aromatic residue selected from phenyl and naphthyl, substituted with 0-3 R2^; M is lithium or magnesium; R22, R23 and R24 are independently phenyl or C1-C6 alkyl, 25 ^ and R are as defined above for R"^ and R^, respectively.
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, 30 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: 23 e 21 comprising, carrying out an intramolecular Mitsunobu 5 reaction on a compound of the formula: wherein: Z is C00CH2Ph. A process for preparing a 10 compound of formula: comprises: (a) preparation of the required catalyst by mixing VCI3 (THF)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°C- 21 238395 22 100°C where the ratio of zinc-copper couple: VCI3 (THF)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: 1 0 1 5 "V'JVo* 1 w1 R^n1 310 (I) wherein: R1 through R4 and R7 through R10 are independently selected from the following groups: hydrogen; C1-C8 alkyl substituted with 0-3 R11; C2-C8 alkenyl substituted with 0-3 R11; C3-C8 alkynyl substituted with 0-3 R11; C3-C8 cycloalkyl substituted with 0-3 R11; Ce-Cio bicycloalkyl substituted with 0-3 R11; aryl substituted with 0-3 R12; a C6-C14 carbocyclic residue substituted with 0-3 R12; and a heterocyclic ring system substituted with 0-2 R12, composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom; r2A through R4a and R7A through r^A are independently selected from the following groups: 22 3839 23 hydrogen; C1-C4 alkyl substituted with halogen or C1-C2 alkoxy; and benzyl substituted with halogen, or C1-C2 alkoxy; R5 and R6 are independently selected from the following groups: 1 0 hydrogen; C1-C6 alkoxycarbonyl; C1-C6 alkylcarbonyl; benzoyl; phenoxycarbonyl; and 15 phenylaminocarbony; wherein said alkyl residues are substituted with 0-3 R11, and said aryl residues are substituted with 0-3 R12; or any other group that, when administered to a mammalian subject, cleaves 20 to form the original diol in which R5 and R6 are hydrogen; R11 is selected from one or more of the following: keto, halogen, cyano, -NR13R14, -C02R13, -OC(«0)R13, -OR13, C2-C6 alkoxyalkyl, -S(0)mR13, -NHC(-NH)NHR13, -C<-NH)NHR13, -C(«0)NR13R14, -NR14C (-0) R13 , -NR14C(-0)0R14, -0C(-0)NR13R14, -NR13C(»0)NR13R14, -NR14S02NR13R14, -NRl4S02R13, -S02NR13Rl4, Cl-C4 alkyl, 30 C2-C4 alkenyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl , a C5-C14 carbocyclic residue substituted with 0-3 Rl2, 23 ! 238395 24 aryl substituted with 0-3 R12, and •©«■ a heterocyclic ring system substituted with 0-2 R12, composed of 5 to 10 atoms .including at least one nitrogen, oxygen or sulfur atom; R12, when a substituent on carbon, is selected from one 10 or more of the following: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl,C7-C10 arylalkyl, 1 5 alkoxy, -NR13R14, C2-C6 alkoxyalkyl, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, Ci-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(0)mR13, -S02NR13R14, and -NHS02R^4; or R12 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 25 halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or NR13R14; or, when R12 is attached to a saturated carbon atom it may be =0 or =S; and R12, when a substituent on nitrogen, is selected 30 from one or more of the following: phenyl, benzyl, phenethyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, , C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -NR13R14, C2-C6 24 , 5? - 3 alkoxyalkyl, C1-C4 haloalkyl, C1-C4 and alkoxycarbonyl, C1-C4 alkylcarbonyloxy,/C1-C4 alkylcarbonyl; R13 is H, phenyl, benzyl or C1-C6 alkyl; R14 is H or C1-C4 alkyl; or R13R14 can join to form (CH2>4, (CH2) 5, (CH2CH2N(R15)CH2CH2) , or (CH2CH2OCH2CH2); R15 is H or CH3; m is 0, 1 or 2; n and n1 are independently 0 or 1; W and W1 are independently selected from the following -NR16C (=Q)NR16"' -C(=Q)NRie-; -C(=Q)0-; -NR16C(«Q)0-; -0C(«Q)NR16-; -NR16C -C (=>Q) -C(=Q)CH2-' -NR16S02NR16~ 3 0 -nr16502" -S02NR16--s02-; -qch2-; -Q-; 238395 26 -(CK2)pNR16-; -CH2CH2-'" -CH=CH-; -CH (OH) CH (OH) -CH(OH)CH2-; -CH2CH(OH)-; -CH (OH) -; -NH-NH-; -C(=0)NH-NH-; -C (CI)=N~; -C(-OR16)=N-; -C(-NR16R17)=N-; -OP(=0) (Q1R16)0-; -P (=0) (Q^-R16)©-; and -S02NHC(=0)NH-; X and X1 are independently selected from the following -C(=Q)NR16-; -C(=Q)0-; -C(-Q)-'* -CH2C(-Q)-; -CH2C(-Q)CH2-'* -C(«Q)CH2-' -SO2NR16- -SO2-; -CH2QCH2-'" -CH2Q-; -ch2nr16-; -CH2CH2-' -CH-CH-; -CH(OH)CH(OH) -CH (OH) CH2-; , .. 26 23 27 -CH2CH(OH) -CH(OH) -C(=0)NH-NH-; -C(-OR16)=N-; -C(-NR16R17)=N-; and -C(L)=N-; m Y and Y1 are independently selected from the following -C(=Q)NR16-; -(CH2)PC(=Q)NR16-; -SO2NR16-; -(CH2)pNR16-; -C(L)=N-; 15 -C(-0R16)=N-; -C(-NR16R17)=N-; -NR12C(=0)NR16-; - (CH2) pNR12C (=0) NR16-; -0C(=0)NR16-; and 20 - (CH2) p0C (=0) NR16-; R16 is H, benzyl or C1-C4 alkyl; R17 is H or C1-C4 alkyl; p is 1 or 2; Q is selected from oxygen and sulfur; L is CI or Br; and Q1 is selected from oxygen, sulfur, NR14 and a direct bond; N.Z. PATENT OPHC6 27 16 MAR 1994 R^C-~!VrD 238395' 28 and pharmaceutically acceptable salts and prodrugs thereof.
PREFERRED EMBODIMENTS Compounds preferred for use in the method of this invention include those of formula I wherein: n and n-*- are both 0; R1 and R10 are independently selected from the following: hydrogen; Ci~C6 alkyl substituted with 0-2 R11; C2-C4 alkenyl substituted with 0-2 R11; C3-C6 cycloalkyl substituted with 0-2 R11; Ce-Cio bicycloalkyl substituted with 0-2 R11; aryl substituted with 0-3 R12; a C6-C14 carbocyclic residue substituted with 0-2 20 R12; and a heterocyclic ring system substituted with 0-2 R12, composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom; R3 and R8 are independently selected from the following groups: hydrogen; C1-C5 alkyl substituted with 0-2 R11; and 30 C2-C4 alkenyl substituted with 0-2 r11; 28 r:.:-\ omce 18 MAR 1894 38 29 C3-C6 cycloalkyl substituted with 0-2 R11; with the proviso that the total number of non-hydrogen atoms comprising R3 is less than or equal 5 to 6/ and the total number of npn-hydrogen atoms comprising R8 is less than or equal to 6; R4 and R7 are independently selected from the following groups: hydrogen; C1-C4 alkyl substituted with 0-3 R11; and C2-C3 alkenyl substituted with 0-3 R11; 1 5 r3a, R4a, r7A and R^A are independently selected from the following groups: hydrogen; and C1-C2 alkyl; R5 and R6 are independently;aolcotod -from-tho following- hydrogen, or any other group that, when 25 administered to a mammalian subject, cleaves to form the original diol in which R5 and R6 are hydrogen; R11 is selected from one or more of the following: keto, halogen, cyano, -NR13R14, -CO2R13, -0C(»0)R13, -OR13, C2-C6 alkoxyalkyl, -S(0)mR13, -NHC(-NH)NHR13, -C(-NH)NHR13, -C(«0)NR13R14, -NR14C (-0) R13, -NR14C(«0)0R14, -0C(»0)NR13R14, NR13C(-0)NR13R14, 29 ' I:.-,MAR 1994 238395 -NR14S02NR13R14, -NR14S02R13, ~S02NR13R14, C1-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl; a C5-C14 carbocyclic residue substituted with 0-3 R12; aryl substituted with 0-3 R12; and -e« a heterocyclic ring system substituted with 0-2 R12, composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom; 1 5 r12, when a substituent on carbon, is selected from one or more of the following: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C3-C6 20 cycloalkyl, C3-C6 cycloalkylmethyl,C7-C10 arylalkyl, alkoxy, -NRl3R14, C2-C6 alkoxyalkyl, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, Ci-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 25 alkylcarbonylamino, -S -S02NR13R14, and -NHS02r14; or R12 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 30 optionally substituted on the aliphatic carbons with halogen, C3.-C4 alkyl, C1-C4 alkoxy, hydroxy, or NR13R14; or, when R12 is attached to a saturated carbon atom it may be carbonyl or thiocarbonyl; '25859 31 and R12, when a substituent on nitrogen, is selected from one or more of the following: benzyl, hydroxy, C3.-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 cycloalkyl,.C3-C6 cycloalkylmethyl, C1-C4 alkoxycarbonyl, C1-C4 and alkylcarbonyloxy,/ C1-C4 alkylcarbonyl, Ri3 is H, benzyl or C1-C4 alkyl; R14 is H or C3.-C4 alkyl; or R13R14 can join to form (CH2M, (CH2)5, (CH2CH2N(R15)CH2CH2), or (CH2CH20CH2CH2); R15 is H or CH3; m is 0, 1 or 2; W and W1 are independently selected from the following: -NR16C(»Q)NR16-'* ~C («=Q) NR16-; -OC(-Q)NR16-; -NR16S02NR16~ -SO2NR16--(CH2)pNR16-; -P(-O) (Q1R16)0-; and -S02NHC(-O)NH-; Y and Y1 are independently selected from the following: -C(«=Q)NR16-; .Y'",' '/l* ■ -i . » 5 'i A 32 -NR12C(=0)NR16-; -0C(=0)NR16-; and -(CH2)pNR16-? R16 is H or C1-C2 alkyl; R17 is H or C1-C2 alkyl; p is 1 or 2; Q is selected from oxygen and sulfur; and Q* is selected from oxygen, sulfur, NR14and a direct bond; and pharmaceutically acceptable salts and prodrugs thereof.
More preferred for greater activity and/or ease of R1 and R10 are independently selected from the following hydrogen; Ci-Cg alkyl substituted with 0-1 R18; C2-C4 alkenyl substituted with 0-1 R18; aryl substituted with 0-1 R19; .. i 2 b APR 1394 32 t , 4. •_ '/ f\ ' ■ : -4 Ita W v 33 a heterocyclic ring system, substituted with 0-1 R19, selected from pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and decahydroisoquinolinyl; wherein R18 is chosen from the following group: keto, halogen, cyano, -NR13R14, -C02R13/ -0C{=0)R13, -OR13, C2-C6 alkoxyalkyl, -S(0)mR13, 15 -NHC (=NH)NHR13, -C (=0) NR13R14, -NR14C (=0) Ri3 , -NR14C (=0)0R14, -0C(=0)NR13R14, -NR13C(=0)NR13R14, -NR14S02NR13R14, -NR14S02R13, -S02NR13R14, C1-C4 alkyl, C2-C4 alkenyl,and C3-C6 cycloalkyl; a C5-C14 carbocyclic residue substituted with 0-3 R19; aryl substituted with 0-2 R19; or a heterocyclic ring system substituted with 0-2 R19, oclccfccd from selected from pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, Imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, 30 isoquinolinyl, benzimidazolyl, piperidinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and decahydroisoquinolinyl; 33 . r "T • 238395 34 Wherein R19, when a substituent on carbon, is selected from the following: halogen, hydroxy, nitro, cyano, methyl, methoxy, -NR13R14, C1-C4 haloalkyl, C1-C2 alkoxycarbonyl, C1-C2 alkylcarbonyloxy, C1-C2 alkylcarbonylamino, -S02NR13R14, and -NHSO2R14; and R19, when a substituent on nitrogen, is 1 0 C1-C4 alkyl; R3 and R8 are independently selected from the following groups: hydrogen; C3.-C5 alkyl substituted with 0-3 halogen or 0-1 R20; C2-C4 alkenyl substituted with 0-3 halogen or 0-1 R20; and C3-C6 cycloalkyl substituted with 0-3 halogen or 0-1 R20; Wherein R20 is selected from the following groups: keto, amino, methylamino, dimethylamino, -C(«0)nH2/ C(-0)NMe2, C(0)NHMe, and C3-C5 cycloalkyl; with the proviso that the total number of non-30 hydrogen atoms comprising R3 is less than or equal to 6, and the total number of non-hydrogen atoms comprising R8 is less than or equal to 6; • 5 1 5 N.Z. PATuKT OPFICC 34 16 MAR 1994 • "C::!VrD 238395 R4 and R7 are independently selected from the following groups: C1-C4 alkyl substituted with 0-3 halogen or 0-1 5 R^l wherein r21 is selected from the following groups: keto, halogen, cyano, -NR13R14, -CO2R13, -0C(=0)R13, -OR13, C2-C4 alkoxyalkyl, , an<J ~S (0)mR13,/ -C3-C6 cycloalkyl; a Cg-Cio carbocyclic residue substituted with 0-1 R22; 1 5 aryl substituted with 0-1 R22; and -©*• a heterocyclic ring system, substituted with 0-1 R22, selected from pyridyl, thienyl, indolyl, piperazyl, N-methylpiperazyl, and 20 imidazolyl; Wherein R22 is selected from one or more of the following groups: benzyl, benzyloxy, halogen, hydroxy, nitro, C1-C4 alkyl, C1-C4 alkoxy, amino, methylamino, dimethylamino, C1-C4 haloalkyl, C^-C^j haloalkoxy, -C(=0)r14, and -OC (=0) ; R3A, R4a, R7a and R8A are hydrogen; R5 and R6 are independently; oolootod from ■■ tho following ■ggoupo; fJ.2. PAT'v"," C'i1 •16 MAR 1994 238395 36 hydrogen, or any other group that, when administered to a mammalian subject, cleaves to form the original diol in which R5 and R6 are 5 hydrogen; R13 is .04 are independently selected from H or C1-C2 alkyl; r!4 is C]_~C4 alkyl; m is 0, 1 or 2; n and n1 are 0; W and W1 are independently selected from the following: -NR16C(=Q)NR16-'" -C(=0)NR16-; -0C(=0)NR16-; and -(CH2)pNR16-; Y and Y1 are independently selected from the following: -C(«0)NR16-; -NR12C(«0)NR16-; -0C(«C>)NR16-; and -(CH2)PNR16-; R1S is H or methyl; p is 1 or 2; and Q is selected from oxygen and sulfur; ?38395 37 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-(lH-pyrrol-l-yl)-1-[(lH-pyrrol-1-y1)methyl]pentyl]-N2~formy1-L-valinamide b) (S,R,R,S)-N-[4—[[(1,1— dimethylethoxy)carbonyl]amino]-2,3-dihydroxy--5-phenyl-l-(phenylmethyl)pentyl]-N2-[[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]-N2-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)-l--(4-pyridinylmethyl)pentyl]carbamate e) (S,R,R,S)-N-[4-[[(1,1- dimethylethoxy)carbonyl]amino]-2,3-dihydroxy-5—(4-pyridinyl)-1-(4-pyridinylmethyl) pentyl ] -N2-[(phenylmethoxy)carbonyl ] - 37 38 -L-valinamide <S,R,R,S)-N2-[[1- (dimethylamino)cyclopropyl]carbonyl]-N-[4-[[(1,1-dimethyl-ethoxy)carbonyl]amino]-2,3-dihydroxy-5-phenyl-l-(phenylmethyl)pentyl]-N--L-valinamide (S,R,R,S)-N-[4-[ [(1,1- dimethylethoxy)carbonyl]amino]-2, 3-dihydroxy-1— (phenylmethyl) hexyl ] -N2- (N-methyl-L-alanyl)-L-valinamide (S,R,R,S)- (1,1-dimethylethyl) [4- [ [ [2-[(dimethylamino)methyl]-1H—imidazol-5-yl]carbonyl]amino]-2,3-dihydroxy-5-phenyl-l-(phenylmethyl)-pentyl]carbamate (S,R,R,S)-N2-[[[2- [(dimethylamino)carbonylJphenyl]methoxy]carbon yl]-N~[4-[[(l,l- dimethylethoxy)carbonyl]amino]-2,3-dihydroxy-5-phenyl-l—(phenylmethyl)pentyl]-L-valinamide (S,R,R,S)-N,N'-[2,3-dihydroxy-l, 4-bis(phenylmethyl)-1,4-butanediyl]-bis[N2-(4-aminobenzoyl)-L-valinamide] (S,R,R,S)-N2-[[[4- (dimethylamino)phenyl]methoxy]carbonyl]-N-[4-[[(1,1—dimethylethoxy)carbonyl]amino]-2,3-dihydroxy-5-phenyl-l-(phenylmethyl)-pentyl]-L-valinamide 38 ?38395 39 1) (S,R,R,S)-N2-[[ [4- [(dimethylamino)methyl]phenyl]methoxy]carbonyl ]-N—[4-[[(1,1-dimethylethoxy)carbonyl]amino]-2,3-dihydroxy-5-phenyl-l-5 -(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 10 isomers of olefins, C=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, R1 through R17, R2a 15 through R^A, 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 20 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 25 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 cyclopropy1, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; and 30 "biycloalkyl" is intended to include saturated bicyclic ring groups such as [3.3.0]bicyclooctane, [4.3,0] bicyclononane, [4.4.O]bicyclodecane (decalin), [2.2.2]bicyclooctane, and so forth. "Alkenyl" is intended to include hydrocarbon chains of either a 39 f 19 AUG 1991'/ ? 3 8 3 9 5 40 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 5 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 10 "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 15 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 20 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, 0 and S and wherein the 25 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 30 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 stabley^fTNT /fQ O \ Examples of such heterocycles include, but are not ^ V A. 19 AUG 1991"; 40 v V ' / # O- 0 70 B 39 5 41 limited to, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl or benzimidazolyl, 5 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 10 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 15 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. % 238395 42 DETAILED DESCRIPTION OF THE INVENTION Synthesis Compounds of formula (I) are synthesized according 5 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 10 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 1 5 novel processes for the preparation of key intermediates used in the mannitol route.
Reductive Coupling of Aldehydes A preferred method for the preparation of 20 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 25 is based on a process disclosed by Pederson sL 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 30 is Caulton's Reagent, [V2C13(THF)6]2tZN2Cl6] .
Preparation of this reagent has been disclosed. Bouma St ai. Inorg. Chem., 23, 2715-2718. The process is shown in Scheme I. *■ 4» * 42 -s V 43 r2 -.1 r3 r3a r4 r44 0 »v A^XH.HVyy^ w x_ y v r44r4 *91. (1) r7a r r*t\ r9jni (2) tV2Cl3(THF)6]2[Zn2Cl6] R2 1 R3 R4 OR6 I R^ I jP" ' I r56 r? r7a r8 rw (i) Scheme I: Coupling of aldehydes with Caulton's reagent.
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 R5, R6 ■ H. Many of the compounds of formula (I) are available through the 1 0 operation of the process of Pederson fi£. al. on the corresponding aldehydes. However, the improved process for the reductive coupling of aldehydes, discussed below, is preferred over the method of Pederson &£. al. Improved Process for the Reductive Coupling of Aldehydes 1 5 Another aspect of the present invention is an improvement of the process disclosed by Pederson al. 43 1 v.1 43 ■r2-.lrv?v 0 R7A n R8/ X'V{WN r9 jl r9; . n- R10 (1) (2) [V2Cl3(THF)6]2[Zn2Cl6] "3 R3AR4R4AOR6 R7 r7A R8 rM (I) Scheme I: Coupling of aldehydes with Caulton's reagent.
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 R5, R6 ■ H. Many of the compounds of formula (I) are available through the 1 0 operation of the process of Pederson at aX. on the corresponding aldehydes. However, the improved process for the reductive coupling of aldehydes, discussed below, is preferred over the method of Pederson at al. Improved Process for the Reductive Coupling of 1 5 Another aspect of the present invention is an improvement of the process disclosed by Pederson at al- 43 ?38395 44 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 fit. al., affords reagents of higher quality and reliability than those of the 5 method of Pederson fit al., and results in a higher yield of product than that obtained by Pederson fit al- In practicing the improved reductive coupling process of the present invention, the catalyst is prepared by placing VCl3(THF)3 in a dry, oxygen-free 10 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 15 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 20 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 25 that filtration with schlenkware was used instead of decanting solvent. L. Fieser and M. Fieser, Reagents for Organir. Synthesis. Volume I, pp. 1292-1293, Wiley,New York, 1967. The use of a glovebag or drybox instead of schlenkware would be equally satisfactory. 30 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 •V u J 19 AUG 1991") ■'38395 45 commercially obtained or activated zinc dust. This material reduced V(lll) to V(II) in dichloromethane within 10 minutes, whereas the use of commercial zinc dust or activated zinc required several hours and 5 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° to 100°C. The preferred range is from 0° to 40°C. The most preferred 10 range is from 15° to 25°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 15 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 20 run over the time period of 0.3 to 2 hours. However, as expressed above, in practice it is most desirable to m'oniter the progress of the reaction by thin layer chromatography.
In practicing the improved reductive coupling 25 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 30 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. 1 19 AUG 1991" 45 ,.«•/ ?: ?• cr, 46 The molar ratio of each reagent is also important. The process operates where the ratio of zinc-copper couple:VCl3(THF)3:aldehyde is 1-3:1-3:1 respectively. The preferred ratio of reagents is 1-1.5:2-2.5:1. The 5 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 IN HC1 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.
Sterensel&r.t i ve PreparaHnn of Compounds of Formula m Another aspect of the present invention is a method for the stereoselective preparation of compounds of formula (1) via a modification of the method of Pederson 20 al. The reductive coupling of an aldehyde using the disclosed procedure of Pederson aJL al- can be expected to produce a number of stereo isomers.
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: (Is,2s,3s,4s), 1 5 (ls,2r,3r,4s), and (Is,2r,3s,4s) . One aspect of the present discovery is the surprising observation that 46 2583 47 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 5 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 fit al- The usual method to carry out the reductive coupling of aldehydes in the presence of Caulton's reagent is to add the 15 reagent under inert atmosphere to a solution of the aldehyde in a nonpolar halocarbon solvent, usually dichloromethane. This procedure produces predominantly the (Is,2r,3r,4s) isomer. However, if a polar, non-protic solvent such as dimethylformamide ( DMF ) is 20 added to the aldehyde solution, before the addition of Caulton's reagent, the predominant isomer is the (Is,2s,3s,4s) isomer. Pederson fit 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), R5, R6 = H) can then be converted to a derivative (R5 not equal to H, R6 - H; R6 not equal to H, R5 - H; or R5 and R6 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., R5- H, R6^;^^ 't ^ /y ^ not equal to H) can be prepared by employing less than.^^ V -r ! 47 ^*19 AUG 199! ? n: ^ J xj 48 or equal to one molar equivalent of derivatizing agent; and the difunctionalized compounds (R5, R6 not equal to H) can be prepared by employing more than two molar equivalents of derivatizing agent. Suitable 5 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, 10 heterocyclic amines, metal carbonates and metal hydrides.
Preparation of Aldehydes of Formula m anri Formula (7) It is anticipated that all aldehydes will work 15 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 20 aldehyde carbon, as discussed by Pederson £&. 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 25 statistical mixture of products, or by reacting an unactivated aldehyde with an activated aldehyde as discussed in the references of Pederson j&L al. Where the aldehyde of formula (1) has a structure identical to that of formula (2), the resultant compound of formula 30 (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.
"V . ii ' 19 AUG 1991 48 > „ , o 258395 49 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 R2 rv .K X W X R3 R4 n-V O (1) Compounds wherein Z is H, n is zero, and Y is -C(=Q)NR12-, and the other variables are as described above, can be prepared by reaction of the amine (II) with a carboxylic acid or derivative (III): R1 R2 R3 0 (iii) wherein P is hydrogen or optionally an alcohol protecting group, R10 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 methodff>r? o\ - 4 -*■ \\ «A\ V 49 " 19 AUG 1991 ml r or 238395 50 employing 1,1'-carbonyldiimidazole as the activating agent, THF as solvent, and 0-40°C as temperature, and P=H. If a protecting group is necessary, the preferred group is the 2-methoxyethoxymethyl group. Greene, 5 Protert-inn firmips in Organic? P-hemi st-.ry. Wiley, Mew York, 1981. Removal of the protecting group if employed, followed by oxidation (see below), provides aldehydes of formulae (V) or (VI). made from the above protected hydroxyamides (IV) followed by treatment with a thionation reagent (Bodansky and Bodansky, The Prarrtirg of Peptide Chemistryr 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 Organir. Chemistry. Wiley, New York, 1981) .
V VI MftthPti B Thioamides of structure (VII) and (VIII) can be 50 o T Q 7 o r •■■■ jo jy J 51 S R' VII VIII Method C Compounds of structure (XI) and (XII) wherein Y is -SO2NR12- can be prepared by the reaction of (II) with an activated sulfonate such as (IX), obtained as described by Bodansky and Bodansky, to produce 10 optionally protected alcohols (X): 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).
R2 R3 (IX) (II) (X) w f f R" 0 ax^'n^Ah R4 XII XI XII ■: 7 . — f-^ 19 AUG 1991171 / 51 258395 52 Method D Compounds wherein Y is -CH2NR12- can be prepared by the reaction of (II) with an alkylating agent such as Wherein LG is a leaving group such as halogen or Oso2R, 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., R12 is not hydrogen. A preferred method for the 1 5 preparation of compounds wherein R12 is hydrogen is simply by LiAlH4 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 20 imine by catalyic hydrogenation or by borohydride reduction of the intermediate imine.
(XIII) : (XIII) (II) (XIV) 0 o (XXXIII) 52 « ?583?5 53 Removal of the protecting group, if employed, followed by oxidation (see below), provides aldehydes (XV) and (XVI).
E} When Y is -C (CI) =N-, -C (-OR11) =N-, or -C(-10 NR11R12)=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 15 and thioamides (XVII) is described above (formula II, R12 = 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 Ami dines and Imidates. Patai. Ed., Wiley, London, 20 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. Patair Ed., Wiley, London, 1975, pp. 297-301. Preferred halogenating reagents include phosphorous 25 pentachloride and phosphorous oxychloride.
(XV) (XVI) Method E 53 238395 Cleavage of the protecting group and oxidation to the aldehyde as described below produces (XXI), with the 5 indicated Y values. r3 R4 r,\A W Y V o (XXI) Met.hod F When Y is -NR12C («0)NR12-, the compounds of the invention can be prepared by reacting amine (II) with/l^EN^ o' 54 19 AUG 1991™ 238 395 55 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 -0C(=0)NR12, 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).
(II), R» H v.A.A w (XXIII) - o-c- r2 RvV r3 'nh, (XXIV) f T o «• f T 8 r R,v K KA A R,v X . . n N> . . n h N> h i h i op op (XXV) (XXVI) Cleavage of the protecting group and oxidation to the aldehyde as described below produces (XXII), with the indicated Y values. 55 258395 56 R2 R3 R« 0 (XXII) Method G: Oxidation of Alrohol Intermediates The alcohols or protected alcohols discussed above and represented here by formula (XXVIII), 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 15 (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 20 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 25 dimethylsulfoxide/oxalyl chloride, also known as Swern oxidation in dichloromethane or tetrahydrofuran/dichloromethane at -60°C, followed by R2 R3 r* OP (XXVIII) 56 07o 7 Q rr jo d s j) 57 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 5 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 10 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 15 (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).
Finally, there are functional groups within the contemplated scope that will survive neither lithium aluminum hydride nor oxidation. In this occasion, 25 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). 0 (XXIX) 57 238395 58 o R12HN 'OR8 r4 (XXX) 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 10 the starting material. The process relies on the key intermediate 1,2,5,6-diepoxy-3,4-0- (alkylidene)hexane.
This intermediate is prepared from the hexitol derivative, 2,3-0-alkylidinehexitol, which is itself derived from mannitol. The intermediate may be either 15 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 2,3-0-alkylidinehexitol to suitable leaving groups, followed 20 by reaction with a base to effect epoxide formation. The intermediate, 1,2,5,6-diepoxy-3,4-0-(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 25 intermediate, 1,2,5,6-diepoxy-3,4-0-(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 30 compounds such as triphenylphosphine and dialkylazodicarboxylate. This procedure gives a 2,5- f/.V/ ^ >.< * * V 19 AUG 1991 58 \A A , <0 - P38395 59 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, eg., 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.
CuBr DMS, RM Ph3P/DEAD/ (Ph0)2P(0)N3 Ph Nx^y0 0 0 * PhCHjOCOHN 0 \NHC00CHjl COHN Or OH NHR ,Ph l) H2SO4/CH3OH * I R 2) H2/Pd/C NHR OH 6: R - COOCK2Ph 7: R - H 59 IN V 19 AUG 1991 A O^OTQ'- 60 Scheme II: Synthesis of compounds of formula (I) from mannitol.
Synthesis of Dihvdroxv Interned!ate 5 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-3,4-0-(alkylidene)hexane, represented by formula 1 in Scheme II. This is a novel 10 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 15 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-di.epoxy-3, 4-0-(alkylidene)hexane, represented by formula'l in Scheme 20 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 25 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. 30 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 &"" °x •V 60 «*19AUG199I n - P ? £ N O 7 o 7 o r J 0 0 y ;j 61 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 5 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 15 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 -20 78° to 25°C. The preferred temperature range is -78° to -20°C. It is desirable to add the solution of the organometallic reagent to the solution of the copper salt at about -20°C. After adding the 1,2,5, 6-diepoxy-3,4-0-(alkylidene)hexane it is desirable to stir the 25 resultant mixture at 0°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 30 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-3,4-0- 7 * - ° 61 19 AUG 1991 > 62 (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 5 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 10 compounds of formula (I) as shown in Scheme II.
Synthesis of Aziridings Another aspect of the present invention is a novel process for the conversion of the N-protected diamino 15 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 20 the conversion of a hydroxy group to another functional group, eg., to an amino group. Mitsunobu, 0., Svnthesi s 1981, 1. The process of the present invention is distinguished from the known Mitsunobu reaction by being an intramolecular reaction which yields an aziridine. 25 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 30 hydrogenolysis. Other protecting groups such as tosylamides are removed with difficulty and need drastic conditions. 7 V 62 \'19AUGI99I \C p 1\J ? 3 8 3 9 5 63 (i) LiN(SiMe3)2 (ii) B114NF. (iii) Z-OSu ZHN NHZ RLi/CuBr SMe2 65% 8:2- COOCH2Ph Ph3P/DEAD Scheme III: Alternative synthesis of intermediate utilized in mannitol route.
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 63 19 AUG 1991' 1/ ? 7 g 7 o ' n*S W / 64 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 5 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 10 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 15 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 20 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 25 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 30 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. r N % V 64 4 19 AUG 1991* *.<) ■? O 7 o 7 n r 'jOj/J 65 This process operates over a temperature range of 25° to 85°C. The preferred temperature range is 55° to 85°C. The most preferred temperature range is 70° to 85°C.
The process may be carried out over a time range of 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 10 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 15 molecule containing a protected nitrogen atom and a hydroxyl group separated by 2-6 atoms.
Hydrogenal-inn of Bi s (N-CBZ1 -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 1-100° volume % acetic acid, and 0.1 weight equivalents of 10% palladium on carbon, and stir under hydrogen at ambient temperature and pressure for 24 XfEN'r\ °a C a 65 U 3 t9 AUG 1991 J V. 0 p \ M ?38395 66 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 10 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 15 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 20 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-1-25 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-30 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 t <w 66 -38395 67 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 10 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 15 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 25 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 67 9 58 68 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, 5 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 10 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 15 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 20 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, 25 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 30 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 68 * 19 AUG 1991 ?3839 69 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 Pharmarenti ra 1 SrienceB. A. Osol, a standard reference text in this field.
Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be 10 illustrated as follows: Capsules A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules 15 each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
Soft Gelatin Capsules 20 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 25 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 30 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 •' ')* 19 AUG 19914 69 ^ 70 applied to increase palatability or delay absorption. ?38395 71 EXAMPLES Procedure I: Preparation of TntormeriiatPfi A. 1,1'-Carbonyl diimidazole fx o « 1 „ o [X) u^°yn/-nh-loh o A HjN, O CH3 Cf k0H B 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 N2 and stirred at room temperature while adding 1,1'-carbonyl diimidazole (4.82 10 g, 2 9.7 mmol; Aldrich Chemical Company) neat. Copious bubbling occurred, indicating CO2 formation. The mixture was stirred 30 minutes and (s)-2-amino-l-phenylpropanol (4.5 g, 29.7 mmol; Sigma Chemical Company) was added neat. Stirring was continued for 18 15 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 20 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 25 properties consistent with alcohol (III) . 71 ^19 AUG 1991^ Vv*C - , V ■ 0"07Qr u 0 7 J J u J7 D 72 Melting Point: 120-121°C NMR (300 MHz, CDCI3); 3, ppm: 7.1-7.5 (m, 10 H); 6.45 (broad d, 1H, NH); 5.35 (d, 1H, NH); 5.1 (broad s, 2H, 0CH2Ph); 4.1-4.2 (m, 2H, alanine a-CH); 3.6 (m, 2H, 5 CH2OH); 2.85 (m, 2H, phenylalaninol b-CH2); 1.2-1.4 (d, 3H, methyl).
Using the above conditions, the following a-aminoalcohols were prepared: Melting Point: 158-160°C NMR (300 MHz, CDCI3) : 7.1-7.6 (m, 10 H) ; 6.2 (broad d, 1H, NH); 5.25 (d, 1H, NH); 5.1 (broad s,"2H, OCH2Ph); 4.2 (m, 1H, isoleucine a-CH)/ 3.95 (dd, 1H, isoleucine a-CH); 3.6 (m, 2H, CH2OH); 2.85 (m, 2H, phenylalaninol b-CH2); 1.85 (m, 2H, isoleucine methylene)1.3 (m, 1H, 20 isoleucine methine); 0.8-1.1 (m, 6H, methyls).
Melting Point 173-180°C NMR (300 MHz, DMSO-d6): (m, 7.65, 1H, NH); 7.2-7.4 (11H, m, aromatic and NH); 5.05 (2H, m, OCH2); 3.9 (nt, 1H, CH2OH); 3.8 (dd, 1H, isoleucine a-CH); 3.35-3.5 (m, D: 72 # 9 - o o s o 1_ ::-yj 73 2H, CH2OH); 2.6-2.9 (m, 2H, phenylalaninol b-CH2>; 1.6 (m, 2H, isoleucine methylene)1.3 (m, IH, isoleucine methine); 0.8-1.1 (m, 6H, methyls).
Melting point 147.5-149 . 5°C NMR (300 MHz, DMSO-d6) : 7.65 (d, 1H, NH) ; 7.2-7.4 (6H, m, aromatic and NH); 5.05 (2H, m, OCH2); 4.7 (dd, 1H, isoleucine a-CH); 3.8 (m, 1H, methionine a-CH); 3.25-3.4 (m, 2H, CH2OH); 2.3-2.5 (m, 2H, methione g-CH2); 1.9 (s, 3H, SCH3); and 0.7-1.9, aliphatics.
NMR (300 MHz, CDCI3): 7.2-7.2 (m,10H, aromatic); 6.2 (d, IH, NH); 5.1-5.2 (m, 3H, OCH2, NH); 4.15 (m, 1H, 20 phenylalaninol 3-CH) 3.95 (dd, IH, valine a-CH); 3.5-3.7 (m, 2H, CH2OH); 2.8-2.9 (m, 2H, phenylalaninol fi-CH2); 2.1 (m, IH, valine b-CH); 0.9 (d, 3H, methyl); 0.8 (d, 3H, methyl).
Procerinrft TT: Synthesis of Aldehydes -t £ T v Q ff 73 V 19 AUG1991 o\\ m J? E1H # 1 7 8 595 74 CHgCfc ^UM2UI2 I II Oxalyl chloride 0 = H A nitrogen-filled, oven-dried 500 ml flask was charged with 35 mL CH2CI2 and 2.90 g oxalyl chloride (25.25 mmol) under N2 and cooled to -60. Dry dimethylsulfoxide (2.42 g, 33.6 mmol) in 40 mL CH2CI2 was added over about 10 min. The mixture was stirred 15 10 min at -60, and alcohol C (6.00 g, 16.8 mmol) was added in 100 mL 1:1 THF/CH2CI2. After stirring 25 min at -60, triethylamine (6.8 g, 67.2 mmol) was added in 20 mL CH2CI2. Stirred 30 min at -60 and quenched with 20% aqueous KHSO4 (150 mL) at ~60. A white solid formed as 15 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. NaHC03, water and brine, and dried over MgS04. 20 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. 25 Additionally, variable amounts of aldehyde trimers oligermers may be observed if the aldehyde is exposed to strong acids in organic solvents.
Melting Point: 125-126°C t iv a fa y 74 * 19 AUG 1991 v .c C p 5 V v c38395 75 NMR (300 MHz, CDCI3): 9.6 (br s, IH, CH0) ; 7.1-7.4 (m, 10H, aromatic); 6.5 (br, IH, NH); 5.1-5.2 (m, 3H, NH and OCH2); 4.65 (m, IH, phenylalaninal a-CH); 4.25 (m, IH, alanine a-CH); 3.15 (m, 2H, phenylalaninal B-CH2); 1.35 5 (d, 3H, CH3).
Using the above procedure, the following aminoaldehydes were prepared: Melting Point 116-117°C NMR (300 MHz, CDCI3): 9.6 (br s, IH, CHO); 7.1-7.5 (m, 15 10H, aromatic); 6.45 (br d, IH, NH) ; 5.1-5.2 (m, 3H, NH and OCH2); 4.65 (m, IH, phenylalaninal a-CH); 4.1 (m, IH, isoleucine a-CH); 3.15 (m, 2H, phenylalaninal fi-CH2); 1.85 (m, 2H, isoleucine methylene) 1.4 (m, IH, isoleucine B-CH2); 0.8-1.1 (m, 6H, methyls). ms (fab): m+h (measured) 391.21; (calculated) 397.17 75 238395 76 NMR (300 MHz, CDCI3): 9.6 (br s, IH, CHO); 7.1-7.4 (m, 10H, aromatic); 6.4 (br d, IH, NH); 5.1-5.2 (m, 3H, NH and OCH2); 4.75 (m, IH, phenylalaninal a-CH); 4.0 (m, IH, valine a-CH); 3.15 (m, 2H, phenylalaninal B-CH2); 5 2.1 (m, IH, valine fi-CH) ; 0.8-1.0 (ni, 6H, methyls).
MS (FAB): M+H (measured) 383.13; (calculated) 383.20 NMR (300 MHz, CDCI3) : 9.6 (br s, IH, CHO); 7.1-7.5 (m, 10H, aromatic); 6.45 (br d, IH, NH); 5.1-5.2 (m, 3H, NH and OCH2); 4.7 (m, IH, 4-chlorophenylalaninal a-CH); 4.1 (m, IH, isoleucine a-CH); 3.1 (m, 2H, 4-chlorophenylalaninal B-CH2); 1.85 (m, 2H, isoleucine 20 methylene) 1.4 (m, IH, isoleucine B-CH2); 0.8-1.1 (m, 6H, methyls).
L: NMR (300 MHz, CDCI3): 9.6 (br s, IH, CHO). / 76 258395 77 M: NMR (300 MHz, DMSO-d6; mixture of isomers; major isomer): 9.4 (s, IH, CHO).
Pronsdure III: Preparation of Aldehydes Method A O II C-0 1 0 1.1-Dimpthylethyl 1-fnrmyl-2-phenvlethylcarbamate Step 1: A solution of 11.0 g (41.5 mmol) of N-tert-butoxycarbonyl-L-phenylalanine (Sigma Chemical Co., St. Louis, MO) in 100 mL of CHCI3 at 0°C was treated with 15 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,0-dimethylhydroxylaminehydrochloride followed by 5.8 mL of triethylamine. Upon stirring at 0°C for 1 hour followed 20 by 16 hours at room temperature, the reaction mixture was worked up by washing with 2X50 mL of 0.2N HC1, 2X50 mL of 0.5N NaOH and 50 mL of saturated NaCL. The organic layer was dried with MgS04 and concentrated under reduced pressure to yield 12.4 grams of an oil 25 which was used in the next step without further purification. This material showed NMR (CDCI3): 1.4 (s, 9H), 3.0 (m, 2H), 3.2 (s, 3H), 3.65 (s,3H), 4.95 (m, IH), 5.2 (m, IH), 7.2 (m,5H); MS cal 309.18 f 309.33. 77 0 7 C> 7 Ci 78 Step 2: The above material was dissolved in 250 mL of ether, cooled to 0°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 5 was quenched with a solution of 0.35 mole KHSO4 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 2X100 mL 10% HCl, 100 mL NaHC03 and dried over MgS04. Upon concentration 10 under reduced pressure, 9.8 g of a pale yellow oil was obtained which solidified upon standing in the refrigerator. The product showed NMR(CDCl3): 1.4 (s, 9H), 2.9 (m, 2H),7 ;2 (m,5H), 9.6 (s,lH). purified by chromatography to yield a pure sample which showed the following NMR (CDCL3): 1.4(S<9H), 3.1 (d,J=10HZ,2H), 4.4 (m,lH), 5.05 (m,IH), 7.05 (m,5H), 9.6(s,IH) .
Method B Organic Synthesis, volume 67, 69 (1988) was used. Thus, 9.75 grams of N,0-dimethyhydroxylamine hydrochloride in 60 mL of CH2CI2 was cooled below 5°C and treated with 7.35 mL of triethylamine through an addition funnel to 30 keep the temperature below 5°C. This material was maintained below 5°C and added to the reaction mixture 2 minutes after the addition of 7.73 mL of me.thylchloroformate to a solution A sample prepared in another experiment was NHt-Boc 1.1-Dimethvlet.hvl l-formvl-4-thia-pentvlcarbamate Step 1: A method similar to that reported in 78 ? 3 8 3 9 5 79 of N-tert-butoxycarbonyl-L-methionine (Sigma Chemical Co., St. Louis, MO) in 400 mL of CH2CI2 containing 10.97 mL of N-methylmorpholine. After the addition, the reaction mixture was warmed to room temperature and 5 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(CDCl3): 1.4 (s,9H), 1.95 (m, 10 2H), 2.55 (t, J=8Hz, 2H), 2.8 (s, 6H),4.35 (m,lH).
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°C at such a rate that the temperature remained below -35°C. Upon 15 completion of the addition, the reaction mixture was warmed to 5°C , then cooled to -35°C and treated with 24.85 grams of NaHS04 in 65 mL of water at such a rate that temperature was below 2°C. The resulting slurry was stirred for 1 hour and then filtered through a pad 20 of celite. The celite pad was washed with 2X100 mL of ether and the combined ether layers were washed with 3X100 mL of IN HCl, 2X100 mL NaHC03 and 100 mL of saturated NaCl. The organic layer was dried over MgS04 and concentrated under reduced pressure to yield 17.67 25 grams of an oil which was used without further purification. The product showed NMR (CDCI3): 1.4 (S, 9H), 1.9 (m,2H), 2.08 (s, 3H), 2.55 (t, J-lOHz, 2H), 4.25 (m, IH), 5.2 (m, IH).
The following aldehydes were prepared by the method 30 of Method B: 1.l-Dlmethvlethvl 2-oxoethvlcarbamate: fCH° NHt-Boc 79 23839: 80 NMR (CDCI3): 1.45 (S, 9H), 4.05 (d, J«8Hz, 2H), 5.3 (m, IH), 9.65 (S, IH). 1.1-Dimethylethyl 1-formvlethvl carbamate : ,CHO V NHt-Boc NMR (CDCI3) : 1.35 <d, J=10Hz, 3H), 1.45 <s, 9H), 4.2 (m, IH), 5.15 (m, IH), 9.55 (s, IH). 1 0 1.1 -Dimethylethvl 1-f Qrmvl-2-Tnethvlpropvlcarbamate : CHO NHt-Boc NMR (CDCI3): 0.95 (d, J=7Hz, 1.5H), 1.05 (d, j=7Hz, 15 1.5H), 1.45 (S, 9H), 2.3 (m, IH), 4.25 (m, IH), 5.15 (m, IH), 9.65 (S, IH) . 1 .1-nimethylethyl 1-fnrmvl-3-methvlhutvlcarbamate : yy I NU CHO NHt-Boc NMR (CDCL3) : 0.95 (m, 6H), 1.4 (s, 9H), 1.6 (m, IH), 4.2 (m, IH), 5.0 (m, IH) 9.55 (s, IH). 1.1-Dimethylethyl 2-formyl-l-pyrrQlldinecarbamate: CX "CHO 1 2 5 t-Boc 1.48 (s, 9H), 1.72-2.20 (m, 4H), 3.23-3.72 (m, 3H) 1 .1 -Dimethylethyl 2-nxnethyl-l-phenvlcarbamate: 80 f" °x X 19 AUG 199! \ El v ?38395 81 ■^X^CHO NHt-Boc NMR (CDCL3): 1.4 (s) , 7.2 (m), 9.45 (s) . Benryl 1 -fnrmyl -2-phenylethvlcarbamat.e : fVY010 cbz - VY*, NHCbz || J NMR (CDCI3): 3.15 (d, J=6Hz, 2H) , 4.5 (d, j=12.6Hz, IH), 5.1 (s, 2H), 5.35 (m, IH), 7.1-7.4 (m, 10 10H), 9.6 <s, IH). 1.1-DimethylPthvl 1-formyl-3-phenylprnpylcarbamate: Ou, CHO NHt-Boc NMR (CDCL3): 1.45 (s, 9H), 1.9 (m, 2H) , 2.75 (m, 2H), 4.25 (m, IH), 5.1 (m, IH), 7.2 (m, 5H), 9.55 (s, IH) . 1.1-Dlmethvlethvl l-formvl-2-(4-fluorophenvl)ethvlcarbamate: f*r fcl NH«"! CHO Boc NMR (CDCL3): 1.45 (s, 9H), 3.1 (m, 2H), 4.4 m, IH), 5.05 (m, IH), 7.0 (m, 4H), 9.65 (s, IH). 25 1.1-Dimethvlethvl l-formvl-2-(4- iodophenvllethvlcarbamate: °\ c 19 AUG 1991/ 238395 82 CHO jTY^T NHt-Boc NMR (CDCL3) : 1.4 (s, 9H), 3.1 (m, 2H) , 4.4 (s, IH), 5.1 (m, IH), 6.9 (d, j-8Hz, IH), 7.2 <m, 2H), 7.6 (d, j=8Hz, IH), 9.6 (S, IH). 1 . 1-D^Pt-hylPt-hyl l-formvl-2- (4— benzyioxyphenyl)ftf.hylcarbamaf.e: jfYV010 j NHt-Boc NMR (CDCI3): 1.45 (s,9H), 3.05 (d, J«12Hz, 2H) , 4.4 (m, IH), 5.05 (s, 2H), 6.9 (d, J-12Hz, 2H), 7.05 (d, j=12Hz, 2H), 7.3 (m, 5H),9.6 (s,lH).
Coupling of Aldehydes With Caulton's Reagent F.xampl p 1A and IB HO OH CH3-S>-V^V^S^CH3 HN NH I I t-Boc t-Boc Bis(1,1-dimethylethyl) (2.3-dlhydroxy-l.4-bia<2- fme1-.hvlf.hio> ethyl! -1 ■ 4-hntanerHyl) hlacarhwmate; To a solution of 1,1-dimethylethyl l-formyl-4-thia-butylcarbamate, from Method B, in 1 mL of CH2CI2, under argon, was added 5 mL of the Caultons reagent (prepared 25 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% K0H, filtered through celite and the celite pad was rinsed with CH2CI2. The organic 82 4 19AUG199t"t * - If«/ .•/O .
' C ] ?3 8395 83 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 IB,) . Example IB had MS: cal 469.24 F 469.19.
Example 2A OH it t-Boc t-Boc 1 5 Bis(1. l-dimethylethyl) (2.3-dihydroxv-i.4- (phenylmethyl>-1.4-butaneHiyl)hi scarbamatfi /IS.2S.3S.4S) : A solution of 1.06 g 1,1-dimethylethyl l-formyl-2-phenylethylcarbamate, from Method A, in 10 mL of CH2CI2, was treated with 3 mL of DMF followed by 10 20 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 3X50 mL of 25 ether and the organic layer was separated from the filtrate. Upon washing with 2X20 mL of NaCl solution, drying over Na2S04 and concentration under reduced pressure the organic layer gave a crude product which was chromatographed over 50 grams of silica gel using 30 2:1 Hex:EtOAc as eluant. This afforded 0.35 g of the desired product, mp « 210-213; NMR: (CDCI3) 1.4 (s,18H), 3.0 (dd, J-10Hz,2H), 3.2 (m 4H), 4.05 (m,2H), // * \ 19 AUG 1991 ? 3 8 3 9 5 84 4.4 (m,4H), 7.2 (m,10H). Upon D20 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 5 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 10 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 15 100 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 CHCI3, cooled to 0°C and 0.28 mL of 20 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 IN HCl, 10 mL of NaHC03, dried and concentrated under 25 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 (CDCI3) of this material showed a coupling of 7.5 Hz between the protons attached to the 30 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 Is,2s,3s,4s.
V 84 t:- K 19 AUG 1991 ? 3 8 3 9 5 85 F.yamnlP 2B HO OH t-Boc t-Boc Risii.i-dimoi-hyiPt-hyi! (2,3-dihydroxy-l,4- /phPnylmet-hyn-1 .4-bntanpriiyl Ihisrarbamate (is.2R.3R.4S): To 10 mL of Caulton's reagent, 1.06 g (4 mmol) of 1,1-Dimethylethyl l-formyl-2-phenylethyl-carbamate, from Method A, was added and after all the 10 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 202-204°, NMR(CDCI3): 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) . 15 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 ls,2r,3r,4s by the method described in Example 2A; the oxazolidinone produced showed a coupling constant of 5.5 20 Hz between the protons attached to oxygen and nitrogen bearing carbon atoms.
Examples 2£ HO OH 2 5 t-Boc t-Boc Bis(1,1-dimethylethvl) (2,3-dihydrQxy-1.4- (phenylmet-.hyl 1 -1. 4-hnfanPfH yl 1 hi srarhamat.p (IS.2S.3R.4S): The ls,2s,3r,4s isomer was prepared by .'/V "p QC u gi . O \ 19 AUGI991 \ A 1/ A '/ ft \ 86 adding a solution of 1.0013 grams of 1,1-Dimethylethyl l-formyl-2-phenylethylcarbamate, from Method A, in 2 mL of dry CH2CI2, to 15 mL of Caulton's reagent followed by 3 mL of DMF. This was stirred for 16 h, treated with 10 5 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 Na2S04 and concentrated under reduced pressure to give a crude product. This material was chromatographed over 80 grams of silica 10 gel eluting with 20% EtOAc to give 0.166 g of product, mp = 172-174°C. MS: calcd. 501.30, found 501.66.
Bis(1.1-dimethylethvl) (2.3-dihydroxy-l . 4- (phenylmethyl!-1.4-butanedly1)biscarhamate (IS,2R.3R.4S): To 0.997 gram (4 mmol) of 1,1-dimethylethyl l-formyl-2-phenylethylcarbamate, from 20 Method A, under argon, 10 mL of dry CH2CI2 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 25 that of Example 2B.
Example ?11 HO OH t-Boc t-Boc Example 3 HO OH HN NH 1 1 t-Boc t-Boc 86 25839 87 btsm . T-HimPt-.hyifit.hyi > f2,3-dihyriroxy-l. 4- butanediyl) biscarbamat.e : 1,1-Dimethylethyl 2-oxoethyl-carbamate was coupled as described in Example 2B to give 5 from 0.997 grams of the aldehyde 39 mg of the desired product. NMR (CDCI3, D20) 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.
FiXflmplf! 4 HO OH HN NH t-Boc t-Boc Bis n . i-riimethviethvi) (?, 3-dihydroxy-l, 4-dimethyl-1,4- butanediyl)biscarbamate: 1,1-Dimethylethyl 2-oxoethyl-15 carbamate was coupled as described in Example 2B to give from 0.693 g of the aldehyde 0.342 g of the desired product. NMR (CDCI3, D2O): 1.2 (d, J=10Hz, 6H), 1.4 (s, 18H), 3.35 (s, 2H), 3.85 <m, 2H)f 4.95 (m, 2H); MS Calcd 349.23; F 349.35.
Example 5 HN NH I I t-Boc t-Boc Bis(1.1-dimethvlethvl) (2.3-dihvdroxv-l.4-< 1- methvlethvl)-1.4-butanedivl\biscarbamate: 1,1-Dimethylethyl l-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 87 258395 88 156-159; NMR (CDCI3, D2O): 1.0 (d, J«10Hz) 1.45 (s, 18H), 2.0 (m, 2K), 3.2 (t, J-lOHz, 2H), 3.65 <s, 2H),5.0 (d, J=10Hz, 2H).
RxamnlP 6 HO OH yrVr 1 HN NH 1 t-Boc t-Boc Bis fl. 1 -dim&thvlethy] ) (2. 3-dihvdroxy-l . 4-(?.-methvloropyl) -1. 4-hntanedivl) hi snarhamat.ft : 1, 1-10 Dimethylethyl l-formyl-3-methylbutylcarbamate was coupled as described in Example 2D to give, from 0.933 g of the aldehyde, 0.17 99 g of the desired product, mp 152-153, NMR (CDCI3, D2O): 0.95 (m,12H), 1.4 (s, 18H), 1.6-1.8 (m, 6H), 3.2 (s, 2H), 3.8 (m, 2H), 4.95 15 (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 HO OH -N N- 2 0 t-Boc t-Boc Bis(1.1-dimethvlethvl) 2.2'-11.2-dihvdroxv-l.2-ethanedivl 1 -1-bis (pyrrr.1 i rii nfrcsrhnxyl ate > : 1,1-Dimethylethyl 2-formyl-l-pyrrolidinecarbamate was 25 coupled as described in Example 2D to give, from 1.99 grams of the aldehyde, 1.14 grams of the desired product. NMR (CDCI3) 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.
£ N . lb 88 L 19 AUG 199 J V -e 0 C jt 1 r A WBf 9 7 0. 7. Q i. >/ u J / J 89 F.xample B HN NH i i t-Boc t-Boc Bis (1.1-dimethvlethvH 12.3-dihvdroxv-l.4-diphenvl-l.4- butanedivl\biscarbamate: 1,1-Dimethylethyl 2-oxoethyl-1-phenylcarbamate was coupled as described in Example 2D to give, from 1.13 grams of the aldehyde, 0.51 grams of 10 the product which upon crystallization from EtOAc gave .089 g of the desired product. NMR (CDCI3, D2O): 1.4 (s, 9H) , 3.8(m, 2H), 7.2 (m, 5H); MS Calcd 473.27 Found 473.35.
Example 3 Bis (Plmethvlethyl) (2. 3-dihvdroxv-l. 4- fphenvlmethvH - 1.4-butanedivl\biscarbamate: Benzyl l-formyl-2-phenyl-20 ethylcarbamate was coupled as described in Example 2D to give, from 2.02 grams of the aldehyde, 0.407 grams of the desired product, mp 201-205°C; NMR (DMS0-d6) 2.7 (ra, 4H), 3.3 (s, 2H), 4.2 (m, 4H), 7.2 (m, 20H). Material prepared in another similar experiment showed MS Cal 25 569.27 Found 569.31. 89 E * ;'V tV' ' ii* f /: \ 19 AUG 1991 ? 3 8 3 9 5 90 F.xamnlP 10 HN NH i i t-Boc t-Boc Bis(1.1-dimethylethyl) < 2.3-dihvdroxv-i.4-/2- phenvlmethvl)-1.4-butanedivl)blscarbamate: 1,1- Dimethylethyl l-formyl-3-phenylpropylcarbamate was coupled as described in Example 2D to give, from 2.86 grams of the aldehyde, 0.75 grams of the desired 10 product, mp 174-175°C. NMR (CDCI3, CD3OD) : 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 HO OH 1 5 t-Boc t-Boc Bis /1.1-dimethvlethvl) 12.3-dihvdroxv-l .4-/4- fluorophenvl)methvll-1.4-butanedivl)biscarbamate: 1,1-Dimethylethyl l-formyl-2-(4-fluorophenyl)ethylcarbamate 20 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 189-91°C, NMR (CDCI3, D2O): 1.3 (2 peaks), 2.8 (m, 4H), 3.4 (m, 2H), 3.7 (m, 2H), 7.0 (m, 10H); MS 25 calcd 537.28 Found 537.41. 90 238395 91 Example 12 HO OH I I t-Boc t-Boc Bis H • 1-dAmet.hvlathvn <7. 3-dd hydrnxv-1. 4-M- f luorophenyl 1 methyl 1-1.4—hntanedi vl) hi srarhamate: 1,1-Dimethylethyl l-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 10 product, mp 191-194 NMR (CDCI3): 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).
Bis (1. 1-dimethylethyl) (? . 3-di hydroxy-! . 4- <4-hvdroxyphenvl)methvl)-1.4-bntanei dyl)hiscarbamatft: 1,1-Dimethylethyl l-formyl-2-(4-benzyloxyphenyl)ethyl-20 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 25 was dissolved in 20 mL of MeOH:EtOAc 1:1,treated with 50 mg of 10% Pd/C and H2 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 ExampTp 13 HO OH 91 07 O 7 Q r - JO.) / J 92 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 (CDCI3) 1.35 (s, 18H), 2.8 (m, 4H), 3.4 (s, 2H), 3.7 (m, 2H), 6.7 d,J=15Hz, 4H), 7.0 5 (d, J=15Hz, 4H); MS Calcd 533.29 F 532.82.
Example 14 HO OH N.N'-f(2.3-dihvdrQxv-l.4-fphenvlmethvl)-1. 4- butanedivinbisacetamide: 100 mg (0.2 mM) of bis(l,l-dimethylethyl) (2,3-dihydroxy-l,4-(phenylmethyl)-1,4-butanediyl)biscarbamate, (IS,2R,3R,4S), from Example 2D, was stirred in 2 ml of 4N HCl in dioxane. The dioxane 15 and HCl were removed under vacuum and the residual material was taken up in 2 ml of CHCI3, 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 20 of ethyl acetate, washing the organic layer with IN HCl, saturated NaHC03, 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 25 product.
Example 15 92 n 7k * O ■ / ^ P ^ 19 AUG 1991 C. J u / 93 2.5-TDi amino-1.6-diphenvl-3.4-hexanediol dihvdrochloride: 20 mg of bis(1,1-dimethylethyl) (2,3-dihydroxy-l,4-(phenylmethyl)-1,4-butanediyl)biscarbamate, (IS,2Sf3S,4S), from Example 2A, was treated with 2 ml of 5 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 10 groups. NMR showed that the Boc groups were gone. 2.5-niamino-1.fi-diphenvl-3.4-hexanediol dihvdrochloride: 20 mg of Bis(1,1-dimethylethyl) (2,3-dihydroxy-l, 4-(phenylmethyl)-1,4-butanediyl)biscarbamate (IS,2R,3R,4S), from Example 2B, was treated as described in Example 15.
Example; 17 2.5-niamino-3.4-hexanftdlol dihvdrochloride: 20 mg of 25 Bis(1,1-dimethylethyl) (2,3-dihydroxy-l,4-dimethyl-l,4-butanediyl)biscarbamate from Example 4 was treated as described in Example 15.
Example 16 ho oh ho oh h2n nh2 93 238395 94 Example 1fl 0-Y~Y~^ HO OH Boc-Thr-Ala-Thr-Ala-N N-Ab-Thr-Ata-Tkr-Boc i i H H FHsfBnr.-Thr-Ala-Thr-Alal . N.N'((2.3-riihydroxy-3.4- (phenylmethyl)-1,4-butanediyl))biscarbanifltfi: 29.4 mg of Bis(1,1-dimethylethyl) (2,3-dihydroxy-l,4-(phenylmethyl) -1, 4-butanediyl) biscarbamate (IS,2S,3S,4S), from Example 2C, was reacted with Boc-Thr-Ala-Thr-Ala-O-10 Succinamide and triethylamine in 2 ml of acetonitrile. Filtration gave 0.1083 g of product which was tested without further purification.
Alternative Synthesis of Product of Example 2B From D- Mannitol via Cuprate Addition Synthesis Of carbamic acid. 1(2.3-dihydroxy-l.4- (phenylmethyl)-1,4-butanediyl))-bis-, bis (1« 1- riimethvlethyll ester.(IS.2R.3R.4S> from d-mannitol: 1. fi-Di-Q- (p-toliienPSiiT fonyll-?. 3-O-i snprnpvl idene-D-mannitol 2: A solution of 6.667 g (30 mmol) of 2,3-0-25 isopropylidine-D-mannitol 1 (purchased from Aldrich Chemical Co.) in 30 mL pyridine was cooled to -20°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°C and 20 minutes at room HO OH 1 5 t-Boc t-Boc 94 ? 3 8 3 9 5 95 temperature. The reaction mixture was diluted with dichloromethane and washed with IN HCl and saturated NaHC03. The extract after drying over anhydrous magnesium sulfate was concentrated and the residue 5 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 (CDC13): d 1.278 (s, 6H), 2.458 (s, 6H) , 3.783 (m, 4H), 4.095 (q, 2H, Jab-10.66Hz, Jax=5.67Hz), 1 0 4.33 (q, 2H, Jab=10.6Hz, Jex®!^), 7.35 (d, 2H, J-1.74HZ), 7.81 (d, 2H, J=1.76Hz). 1.2.5.6-ni epoxv-3.4-0-(i sopropvl idene)hexane 3 : in 200 mL of anhydrous methanol was cooled at 0°C and treated with 10.86 g (78.58 mmol) of K2CO3. 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 20 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 25 (CDCI3) : d 1.45 (s, 6H), 2.4 (q, 2H, Jab«4.94Hz, Jax~2.65Hz), 2.86 (q, 2H, Jab-4.94Hz, Jbx-4.2Hz), 3.13 (m, 2H), 3.85 (dd, 2H, Ji«2.3Hz, J2«1.46) 1.6-Dlphenyl—3.4-Q-isopropvlldene-2.5-hexanediol 4 : 30 A suspension of 9.25 g (45 mmol) of cuprous bromide-dimethyl sulfide complex in 40 mL anhydrous ether was stirred at -20°C and 1.8M 50 mL (1.8 M, 90 mmol) solution of phenyllithium was added dropwise. The contents were stirred for 30 minutes at -20°C an<" "" A solution of 10.425 g (19.65 mmol) of compound 2 95 238395 96 warmed up to 0°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°C. The excess reagent was quenched with saturated ammonium chloride 5 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 10 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 (CDCI3): d 1.455 (s, 6H), 2.7 (q, 2H, Jab=13.8Hz, Jax=7.9Hz), 3.15 (q, 2H, Jab^IS.SHz, JBx=2.5Hz), 3.75 (m, 4H), 7.28 (m, 10H). 2.5-Diazirio-l.6-riiphenyl-3.4-Q-(isoprQpylidftne)hftxanft 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 20 sieves 2A at -78°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°C. This was followed by the addition of 1.66 mL (10.52 mmol) of diethylazodicarboxylate. The mixture was then allowed 25 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°C. After stirring the mixture for 30 minutes at room temperature, it was concentrated to a small volume and 30 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.
^ \ ^ AUG J99J V A :N 238395 97 ?.5-nia7-irio-1 .6-diphenvl-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 5 mL of water was stirred with 1.67 g of Bio-Rad AG-50-W-X8 acid exchange resin at 70°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 10 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 (CDCI3): d 2.95 15 (q, 2H, JAB13.7KZ, Jax=7.9Hz), 3.06 (q, 2H, Jab=13.7Hz, JBx=6.3Hz), 3.55 (m, 2H), 3.62 (bs, 2H), 7.3 (m, 10H) . 9.S-niaminn-l.6-riiphftnv]-3.4-hexanediol 7: 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 25 were concentrated to provide 45 mg (79% yield) of 7.
This material showed NMR (CDCI3): d 2.64 (m, 8H), 7.283 (m, 10H). 2.5-(N.N-Di-terfc-butoxvcarbonvl)diamino-1,6-diphenv-3.4- compound 7 in 2 mL pf absolute ethanol was stirred with 152 mg (0.58 mmol) of N-(tert-butoxy-carbonyDphthalimide for 18 hours at room temperature. The reaction mixture was diluted with 20 mL water and A solution of 67 mg (0.19 mmol) of 6 in 4 mL of 97 ?383°5 98 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 (33g silica gel coulmn using 7% isopropanol in 5 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- (2S, 3Re4R,5S)-1,2,5,6-Diepoxy-3,4-0-(isopropylidene)hexane 1: This compound was prepared 15 following the literature procedure (Y. L. Merrer et al, Heterocycles, 25, 541, 1987). This material showed NMR (cdci3): d 1.45 (s, 6H), 2.4 (q, 2H, Jab - 4.94Hz, Jax -2.65Hz), 2.86 (q, 2H, Jab = 4.94Hz, JBx - 4.2Hz), 3.13 (m, 2H), 3.85 (dd, 2H, Ji - 2.3Hz, J2 « 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°C and 1.8 M 100 mL 25 (1„8 M, 180 mmol) solution of phenyllithium was added dropwise. The contents were stirred for 30 minutes at -20° C and then warmed up to 0° 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 30 0° 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 Mannitol via Cuprate Addition 98 99 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 (CDCI3): d 1.455 (s, 6H), 2.7 (q, 2H, Jab" 13.8Hz, Jax = 7.9Hz), 3.15 (q, 2H, Jab - 13.8Hz, JBx - 2.5Hz), 3.75 (m, 4H), 7.28 (m, 10H). (2S, 3R, 4R,5S)-2,5-Diazido-l,6-diphenyl-3,4-0-10 (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 15 behind shield. 31.7 mL (147 mmol) of diphenylphosphorylazide (Caution - this reagent should be stored at 0° C and handled with care. Some azides may be explosive I) was added to the above mixture and the contents were further stirred at 0° C for 5 minutes. 20 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 25 methanol at 0° 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 30 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 ft 99 ■V \ 19 AUGI991 " O r » v °385?5 100 elutes the desired compound (3000 mL)] to provide 15.523g 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-l,6-diphenyl-3,4-0-(isopropylidene)hexane 4: The above material (15.523g) was divided in 3 equal portions and each portion dissolved in 75 mL absolute ethanol, flushed with 10 nitrogen and each portion stirred with 1.5g 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 0.5g of 10% palladium on carbon and stir 15 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-dipheny1-3,4-0-(isopropylidene)hexane 5: A solution of 20 13.67g (40.2 mmol) of compound 4 in 100 ml dimethylformamide was stirred in ice-bath and treated with 21.93g (88 mmol) of benzyloxycarnonyloxysuccinimide. The ice-bath was removed and the contents were stirred for 18 hours at 25 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 (3x of ethanolamine. The mixture after complete removal of solvents was purified (500g silica gel column using 30 1:5 followed by 1:4 EtOAc:Hexane) to provide 20.457g (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 20.457g 100 101 (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 5 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 15.02g (77% yield) of compound 6 (M. P. 209-210).. (2S, 3R, 4R, 5S) -2, 5-diamino-3, 4-di'nydroxy-l, 6-diphenylhexane 7:A solution of 10.432g (18.36 mmol) of compound 6 in 500 ml THF and 500 ml ethyl alcohol was stirred with 1.043g of 10% palladium on carbon at room 15 temperature. for 18h over 1 atmosphere hydrogen pressure. The mixture was filtered through celite pad and the filtrate was concentrated to provide 6.06g ( yield) of compound 7. The oil was triturated with diethyl ether and the white solid was filtered and 20 washed to provide pure 7 (M. P. 92-94).
Example 19C Alternative Synthesis of Aziririinp Product of Example 2B From D-Mannitol via Biszairidine Intermediate 1. 6-Dl(N.-(benzvloxvcarbonvl)amino)-2.5-dihvdroxv-3.4-0-(isopropylidene)hexaneriiol 8: In a 250 mL Round Bottom Flask was placed 20 mL of 1M (20 mmol) of Lithium Bis 30 (trimethylsilyl)amide and the contents cooled in ice bath and 1.87g(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 ?3B395 102 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° C and then immediately warmed-up to room temperature 5 and stirred for additional 2 hours. It was then cooled to 0° C and then treated with 5.98g (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 10 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 2.44g (yield 50%) of 8. (2S. 3R.4R. SS)-1.2:5. 6- (N. N' -DihPny.vloxvnarbonvl) di imino-3.4-Q-H Rnprnpylidpne)hexanpriiol 9: In a 500 mL Round Bottom Flask was placed 12.147g (24.89g mmol) of above compound, 15.669g (59.7 mmol) of triphenylphosphine 20 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 25 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 7.147g ( yield, 64 %) of compound 9. (2S.3R.4R.5S)-2.5-Di(N-((benzvloxv)carbonvl)diamino)- 1 . 6-rt-iphpnvT-3. 4-0- /lsopropvlldene)hexane 5: In a 50 mL R. B. Flask under nitrogen and in a glove bag was placed 1.37g (6.66 mmol) of cuprous bromide-dimethylsulfid^ tur // v / -9. ^ G /l ^ /O 102 \ 19 AUG 1991H ? 3 8 5 9 5 103 complex and suspended in 2 mL ether and cooled to -20° 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° C. The mixture stirred at -20° C for 30 5 minutes and then warmed to 0° C. 754 mg of above bisaziridine derivative in 2 mL ether and 6 mL THF was added to to the mixture at 0° C and stirred for 30 minutes at 0° C. TLC in 1:3 ethyl acetate/hexane indicated disappearance of the starting material. The 10 excess reagent was quenched with saturated ammonium chloride, the mixture filtered, diluted with 20 mL of water and extracted with 2X25 mL of dichloromethane. The mixture was chromatgraphed (33g silica gel column and 1:5 ethyl acetate/ hexane as the eluting solvent) to 15 provide 475mg (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. N2-Pvridvlarfttyl—L—T1 cH ami no— 1.6-diphenyl-3.4-hpxanPdiol: H J | ?H "rVWvS OH Example 21 Synthesis of 2.5-m-2-Pyridvl-L-Ile.N'-2-pvridyl-D-30 He! diamino-1. 6-diphenvl-3. 4-hexanediol; ft* ? " H 7 c ^ o J / j 104 Ph itnoO1 Step 1: 2-Pyridylacetyl~Ile allyl ester 2-Pvridylacetyl-lie allvl ester: A mixture of 1.717 g (5 mmol) pyridylacetic acid hydrochloride, 868 mg (5 10 mmol) of isoleucine allyl ester p-toluene sulfonate salt, molecular sieves 4° A type in dimethylformamide were stirred at 0°C and 1.74 ml (10 mmol) of diisopropylethylamine was added to generate free amines. After stirring the contents at 0°C for 15 minutes it was 15 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 20 solvent) to provide 712 mg (49% yield) of 2 pyridylacetyl-Ile allyl ester. This material showed XH NMR (CDCI3): d 0.87 (d, 3H, J-6.9Hz), 0.894 (t, 3H, J=7.4Hz), 1.15 (m, IH), 1.42 (m, IH), 1.92 (m, IH), 4.6 (m, 3H), 5.2-5.7 (m, 2H), 5.85 (m, IH), 7.25 (m, IH), 25 7.668 (d x t, IH, Ji-3.84, J-7.7HZ), 8.01 (bm, IH), 8.577 (bd, IH) . ? 3 8 3 9 5 105 Step 2: 2-Pyridylacetyl-Ile 2-Pyridylacetyl-Tle: A mixture of 276 mg (0.95 mmol) of 2-pyridylacetyl allyl ester in 2 ml of 1,4-dioxane was stirred at room temperature and 1 ml of 1.0 N sodium hydroxide was added in three equal portions after 15 minute intervals and the contents were stirred at room 10 temperature for a total of 2 hours. The mixture was neutralized with addition of 1.0 ml (1 mmol) of IN 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 15 chloroform. The combined organic extracts after removal of solvents provided 174 mg (74% yield) of 2-pyridylacetyl-Ile. This material showed 1H NMR (CDCI3) : 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 20 x d, IH, Ji=5.21Hz, J2«8.22 Hz), 7.32 (d x d x d, IH), 7.52 (bm, IH), 7.785 (d x t, IH, Ji«7.71Hz, J2-1.8Hz), 8.53 (d x d x d, IH).
Step 3: A solution of 101 mg (0.336 mmol) of 2,5-25 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 30 removal of solvent was purified (33 silica gel columpbs=- f oil 105 fl9AUGI99l"f „ O . < / 238395 loe 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 5 of Example 20 had C-2 symmetry and showed 13C NMR (CDCI3): 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 10 Example 21 had no C-2 symmetry and showed twice the number of 13C NMR resonances (CDCI3): 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, 15 126.140, 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.
Bis(Dimethylethyl) (2.3-dihydroxy-l.4-(phenylmethyl)-25 1. 4-hutanedi vl) blsrarbamate : Step A: Preparation of V(C1)^(THF)2 V(C1)3 (Aldrich, 25g) was added to 400 mL argon-sparged THF and the suspension heated to reflux under air-free conditions. 30 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 Example 23 Improved Method to Couple Aldehydes: Synthesis of Compound of Example 9 and evacuated at 0.1 torr for 1 hour.
!N V • £J J?? #•» . o 106 ? J b j y 'j 107 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, 5 the material turns to dusty orange,., then tan, and must be discarded.
Step B: Preparation of 7.n»Cu. Zinc-copper couple was prepared following the procedure of Fieser and Fieser^ 10 (L. Fieser and M. Fieser, Reagents for Organic Synthesis r 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 15 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 20 frequently did not provide the color change characteristic of complete reduction (see below).
Step C; HnnpHno Procedure. VCI3 (THF) 3 (1.32g, 3.53 mmol) was weighed into an argon-filled 35 mL RBF using a 25 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 30 mixture was stirred for 10 minutes, by which time it had turned deep green with suspended black. 1,1-Dimethylethyl l-formyl-3-phenylpropylcarbamate (l.OOg, 3.53 mmol), freshly prepared by Swern oxidati<^£~^ 107 238395 108 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 CH2Cl2f rigorous exclusion of air is necessary; before addition, exercise reasonable care. When exposed to even small amounts of air, the reduced material rapidly 10 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 1 5 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 20 funnel containing 50 mL dichloromethane and 100 mL 10% aqueous disodium tartrate (IN 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 25 layers were washed with saturated sodium bicarbonate and dried with magnesium sulfate. Solvent was removed, the crude solid was taken up in minimum CHCI3, and 0.5 volumes hexane added. On sitting overnight, copious white crystals formed. Isolated 0.62g (62%) product 30 diol, mp 202-204°C. Spectral data are consistent with the assigned structure. 108 ^ <• o 19 AUGI99I% 258395 109 Examples ?4-QR Examples 24-98 were prepared by one of the methods 5 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 10 prepare a number of the compounds shown in Table I.
Method 3 (Hydroaenation of Bis-N-CBZ-Diaminodiols) : The (bis-N-CBZ)-diaminodiols obtained either by vanadium coupling reaction or D-mannitol route can be 15 hydrogenated and further elaborated at the amine residues. Table I shows examples prepared via this route.
Synthesis of Compound of Example 39: In a 200ml R.B. 20 Flask a suspension of 3.432g(4.32mmol) of the above intermediate in 25ml ethanol and 25ml methanol was stirred with a suspension of 343mg 10% palladium on • carbon under 1 atmospheric hydrogen pressure at room temperature for 18 hours. The suspension of starting 25 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(130g silica gel column using first 3% and finally 6% methanol in 30 chloroform as the eluting solvent) to provide 1.848g(81.3%) of 39 as a white solid. 109 238395 no Method 4 (Coupling of Diflminodipls): The diamines obtained via Method 3 can be further elaborated by reaction with various electrophiles. Some preferred reaction conditions that provide active compounds are 5 given below. Many other conditions^and reagents can, of course, be employed. 4A; Diryrlohexyloarhoriiimide (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 ?6: A solution of 101 mg (0.336 mmol) of 2,5-diamino-l,6-diphenyl-3, 4-hexanediol, 108mg (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 86mg (33% yield) of 26. The compound has C-2 symmetry and showed NMR (CDC13): 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; EOF Coupling BOP-Benzotriazol-l-yloxytris (dimethylamino)phosphonium hexafluorophosphate coupling was carried out according^ A * •/si „ ^ <~> 110 \ 19 AUG 1991 « <0// 258395 in to the procedure by B. Castro sL al* (Tetrahedron Lett.,1975, 14, 1219-1222). A representative synthesis is described below.
Synthesis of Compound nf Example RT: BOC-Thiozolidine-4-carboxylic acid (0.94g; 0.40 mmol) and [NH2CH(isopropyl)-C(0)-NH-CH(Bzl)-CH(OH)-]2 (0,lOOg; 0.20 mmol) were dissolved in 10 ml of DMF, and BOP (0.177g; 0.4 mmol) and triethylamine (0.056 ml; 0.40 10 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 31 as amorphous solid (0.137 g) . FAB/MS calculated for C46H68N6OIOS2 1 5 (928.44). Found 929.64 (M + H) . 4C: Carbonyldiimidazole Coupling Synthesis of Compound of Example 88: N-MSOC-isoleucine 20 (393 mg, 2.1 equivalents) was dissolved in THF; added carbonyldiimidazole (227 mg, 2.1 equivalents) at room temperature. Stirred until TLC showed loss of starting material. The reaction mixture was diluted with chloroform and 10% aqueous disodium L-tartrate was 25 added. The layers were separated and the aqueous layer washed lx 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. 30 Recrystallized from hot chloroform/hexane to obtain 343 mg fine white crystals; NMR consistent with 88. Melting point 222-225°C (dec) . 56 £' 111 19 AUGI99|"7 O 7 O ~ ri «- J C ,) / j 112 4D: N-Hydroxysncrrininnde Ester Coupling N-hydroxysuccinimide esters, available from Sigma Chemical Company or Advanced ChemTech, were used.
Synthesis of Compound of Example RQ: In a 300ml R.B. flask a solution of 6.000g (20mmol) of diamino diol in 60ml of dimethylformamide was cooled in an ice bath. 10 The mixture was treated with 14.070g (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. 15 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 20 solid was contaminated with N-Hydroxysuccinimide. It was further purified (750g silica gel column using first 1% followed by 1.5% methanol in chloroform as the eluting solvent) to provide 9.723g (61.2%) of 89. 4E: p-Nit-rophenvlester Coupling (1) With hydroxybenzotriazole hydrate: Synthesis of Compound of Example 92: Diaminodiol of 30 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 112 238395 113 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 5 structure. (2) Without hydroxybenzotriazole hydrate: Synthesis nf Compound of Example 90:Diaminodiol of 10 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 15 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 500ml R.B. Flask, 2.500g (4.75mmol) of the above intermediate in 100ml dimethylformamide was cooled in an ice bath. The 25 mixture was treated with 1.29ml (10.45mmol) 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 100ml more dimethylformamide was added to aid stirring. After 30 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 3.230g (85.7%) of 67 as a white solid. 113 2 :>8395 114 4G: Condensat- i on With Epoxides Epoxides can be condensed with diaminodiols. A 5 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 10 and treatment with potassium tert-butoxide. The adamantyl ethylene oxide was reacted with [NH2-Val-Phe[CH(OH)-]]2 in methanol refluxing at 70 degrees Celsius overnight and chromatogrammed using Sephadex LH-2 0 column. (2 equivalents of oxide was used for 1 5 every 1 equivalent of diol). 114 Table I u> EXAMPLE RX-W R3 R4 IC50 GAG mg/ml IC90 CELLS mg/ml MP PHYSICAL DATA METHOD 24 ^-CH2-C-N— H 2-butyl Ph 0.056 I 232-234 4A ^-CH,-C-N- H 2-butyl Ph 0.69 >30 191-194 4A 27 OcYr 2-butyl Ph 0.177 >30 207-213 4A 28 0 J 1 oso 1 i-z 1 2-butyl a- 0.155 2.4 (777.99) 4A 29 /-N S ^)-ch2-c-n— h 2-propyl Ph 0.041 0.95 248-252 4A en f'J C."J CC OJ vO CJ".
H o> EXAMPLE RX-W R3 R4 IC50 GAG mg/ml IC90 CELLS mg/ml PHYSICAL DATA METHOD -N-a. E ^J-ch2-c-n— H 2-butyl Ph 0.082 2.8 (7G5.45) 4A 31 0 0 J 1 oso 1 i-z 1 2-butyl Ph 0.03 2.9 256-260 4A 32 CH3 ° CHg-f— CHz-C-n— CH, H 2-butyl Ph >9 >30 NMR 4A 33 zr n E ^-CH2-C-N— H 2-methyl-propane Ph >9 >30 179-182 4A 34 /_ o {^avc-iy- 2-butyl Ph >9 >30 (775.51) 4A ^-CH2-C-N— H 2-butyl Ph 0.019 0.3 247-250 4F 36 ho—^^-ch2—c-n— H 2-butyl Ph 0.085 0.95 NMR 4A 37 O ^^-CHaO-C-N— H 2-butyl Ph 0.024 0.15 NMR 4D m ■•j CO UJ ^-O Ul •» c z £ 3 , v- ^ x*v V .. 1 M * ' EXAMPLE R1—W R3 R4 ic5o GAG mg/ml IC90 CELLS mg/ml PHYSICAL DATA METHOD 38 o HN^NH ° V^CH^C-N- H 2-butyl Ph 0.055 >30 NMR 4D 39 H2N- 2-butyl Ph 0.937 184-190 4D;3 40 H 0 t-BOC^V^N- cr * 2-butyl Ph 0.03 2.2 228-232 4D 41 0 0 & 1 0=0 1 I-Z 1 2-butyl Ph 0.21 2.8 NMR 4A 42 0 ^^-CHjO-C-N— H 2-propyl Ph 0.025 0.05 216-221 4D 43 H O CBZ NV^N- Or* 2-butyl Ph 0.055 0.11 263-266 4D si; -y/' ."O t^~J cc OJ VO Ul 00 ■y <0 O ^ vO 5 vO £ *// 3 0V .O EXAMPLE RX-W R3 R4 IC50 GAG mg/ml IC90 CELLS mg/ml PHYSICAL DATA METHOD 44 H O CBZ NV^N- cr ' 2-butyl Ph 0.028 0.09 200-206 4A without HOBT 45 f—\ 9 0 N-C-N— ^ H 2-butyl Ph 1.24 8.9 141-144 4F 46 O CHaO-C-N— H 0 II H2N—C—CH2CH2— Ph 0.245 >30 241-244 4E 47 O ^^-CHaO-C-N— H 0 11 H2N—C—(CH2)4— Ph 1.12 >30 264-267 4E 48 O ^^-C^O-C-N— H 2-propyl o- >9 >30 160-164 IB; 4D 49 <y"-N- 06" 2-propyl Ph 0.036 0.2 217-220 4A 50 ^^-CHaNH-C-N— H 2-propyl Ph O O 0.6 194-197 4F i—1 M cd C-J cc O-J VO (Jl EXAMPLE Rx-w R3 R4 IC50 GAG mg/ml ICgo CELLS mg/ml PHYSICAL DATA METHOD 51 o^n 0 • h 2-butyl Ph 0.019 >30 257-260 4A 52 ch3ch2ov^n^n_ 0 h h 2-butyl Ph 0.004 2.7 226-230 4F 53 0 ^^-chzo-c-n— h ch, ho Ph 0.2 2.6 NMR 4C 54 o ^^-chzo-c-n-— h 2-butyl ci-0~ 3.4 .0 130-134 2C 55 o ^^-chao-c-n— ~~ h ch3 y— ho Ph >9 >30 >250 4C 56 (chgjoco-nh ch conh ph*^ 2-butyl Ph 0.03 2.2 228-232 4D :n®7 - 0 ch3-c-n— h 2-propyl Ph 0.044 8.9 >250 sinters at 220 4C vo m "'J CH CC O-J v EXAMPLE R1-W R3 R4 IC50 GAG mg/ml IC90 CELLS mg/ml PHYSICAL DATA METHOD 58 O 11 0 NH— O^D 2-propyl Ph 0.31 >30 198-199 4C 59 O ch3-c-n- H H2C:CHCH2— Ph 0.58 >30 119-123 4C 60 0 ch3-c-n— H CHj-S-CHgCHj— Ph 0.82 >30 229-236 4C 61 O NHaH 2-propyl Ph 0.04 2.9 212-216 4D; 3 62 H O CBZ NA- cr * 2-propyl Ph 0.05 - >245 4D 63 H2N- 2-propyl Ph 215-216 2C -j o-j co o-j vO (J1 m EXAMPLE R1—W R3 R4 ic50 GAG mg/ml IC90 CELLS mg/ml PHYSICAL DATA METHOD 64 o cf3-s-n- 3ii 1 oh 2-propyl Ph >9 >30 65* o ^^-chjo-c-n— h 2-butyl Ph >10.4 >30 147-151 4A 66" 0 ^^-chao-c-n— h 2-propyl Ph 235-238 4A 67 o h h 2-propyl Ph 288-292 4F 68 o ^^-chao-c-n— 2-propyl o >9 >30 190-192 4F 69 OOCH 2-butyl Ph 0.065 - 212-215 4D;3 70 o han^n-h 2-propyl Ph 4E C-J cc O-J VO U7 • • • • EXAMPLE RX-W R3 R4 ic50 GAG mg/ml IC90 CELLS mg/ml PHYSICAL DATA METHOD 71 OH Yr~A—CHCHaNH- 2-propyl Ph >n >30 (855.63) 4G 72 OH CH CHjNH- 2-propyl Ph >9.2 >30 (739.37) 4G 73 Ph o i Q Ph^O^N^?-^- £ OCHg methyl Ph 1.62 >30 (1071.6) 4B 74 H Boc-N 0 cirV 2-propyl Ph 3.72 (937.55) 4B 75 hUN O 6rY 2-propyl Ph 1.22 (NMR) 4B 76 IS O ryy Boc-N~^ H 2-propyl Ph 0.296 >30 (937.71) 4B * O ' * 3 y v . ~"1 _ . \ # EXAMPLE RX-W R3 R4 IC50 GAG mg/ml IC90 CELLS mg/ml PHYSICAL DATA METHOD 77 J&r 2-propyl Ph 0.15 (737.55) 4B 78 " O BOC-N • H 2-propyl Ph 0.061 (869.67) 4B 79 H2N^v^n_ H 2-propyl Ph 0.185 (669.60) 4B 80 BpC 0 <V%- S-* H 2-propyl Ph 13 >30 (929.64) 4B 81 H 0 <yv S-* H 2-propyl Ph 0.201 >30 (729.59) 4B 82 H 1 0 CBZ-N^^^Xn_ • H 2-propyl Ph 0.625 >30 (993.81) 4B 83 H 2-propyl Ph 0.317 >30 (725.66) 4B 84 O ^^-CHaO-C-N— H CH3 Ph 0.151 >30 236-237 2C vO 2* e: | c> 1 Co 3 o > k & v\. m] 2rl *v/ .O, EXAMPLE R1-** R3 R4 ic50 GAG mg/ml IC90 CELLS mg/ml PHYSICAL DATA METHOD 85 0 H2Ny*N_ H O 2-propyl Ph 0.007 >30 229-233 4D; 3 86 O H 2-propyl Ph 0.3 >30 162-168 sinters at 94 4D;3 87 jcr»- 2-propyl Ph 3.3 >30 M. P.>245 sinters 120-130 4D; 3 88 O q CH3-s^,0AN_ o H 2-butyl Ph 0.039 8.5 222-225 4C 89 H 0 cbznY^N~ HzN^J H O 2-propyl Ph 0.04 >30 M.P.>245 4E 90 H O CBZ ^N- cT' 2-propyl Ph 0.67 M.P.>245 4E ro »£* s rj O-J CC Os) vO 07 M to U1 : ft > ^ - ■Uc C) ' 3 >0 - lo.ijX mjl 9 EXAMPLE R1-W R3 R4 IC50 GAG mg/ml IC90 CELLS mg/ml PHYSICAL DATA METHOD 91 H 0 CBZNx^N- H 2-propyl Ph 0.042 0.2 239-241 4E 92 » O cbznV^N- f " CONH, 2-propyl Ph 0.08 >30 >245 4E 93 ? O CBZNr^N-* • Y H 2-propyl Ph 0.099 1.0 237-238 4D 94 o UI H 2-propyl PhCHpO 0.123 >30 (979.2) 2C 95 6h3 o CH3~f-0-C-N-CH, H 2-propyl Ph 12.5 >30 209 4A 96 cr^t 2-propyl Ph 0.100 0.7 274 4A 97 i z-x °\ \S O X 2-propyl Ph 0.250 0.9 168-170 4A ro en # r-O L/-J CO o; v£) LM • • ♦ EXAMPLE RX-W R3 R4 ic50 GAG mg/ml IC90 CELLS mg/ml PHYSICAL DATA METHOD 98 2-propyl Ph 0.050 0.3 247 4A 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. t indicates that the diol is protected as an acetonide. tt indicates that this compound is a stereoisomer of the compound of Example 20. m ro to <r> 127 Tables II to XVI include additional preferred embodiments of the invention. However, these embodiments are not exemplified herein. t "38395 128 TABLE II R1 I O R2 I O R3 HN °K R4 NH ^=0 EX NO.
R1 R2 R3 R4 99 CH3C ("0) CH3C (mO) PhCH2 PhCH2 100 CH3C («0) CH3C ("O) 4-HO-C6H4CH2 4-HO-C6H4CH2 101 CH3C (-0) CH3C (■O) 3,4-dichloro-benzvl PhCH2 102 CH3C(-0) CH3C(~0) CH3SCH2 CH3SCH2 103 CH3C ("0) CH3CimO) CH3SCH2 PhCH2 104 CH3C(-0) CH3C("O) (CH3)2CHCH2 (CH3)2CHCH2 105 CH3C("0) CH3C(-0) 3-indolvl 3-indolvl 106 CH3C("0) CH3C("O) CH3OC("0)(CH2)5 CH3OC("0)(CH2)5 107 CH3C(-0) CH3C(™0) (CH3)2N(CH2)3 (CH3)2N(CH2)3 108 CH3(CH2)NHC(-0) CH3(CH2)NHC(-0) PhCH2 PhCH2 109 PhNHC(-O) PhNHC(-O) PhCH2 PhCH2 110 PhC(-O) PhC(-O) PhCH2 PhCH2 111 4-Cl-CfiH4C(-0) 4-CI-C6H4C ("0) PhCH2 PhCH2 112 3-Me-C6H4C(-0) CH3C ("0) PhCH2 PhCH2 113 PhCH20C(-0) PhCH20C(-0) PhCH2 PhCH2 128 1 19 AUG 1991^ a '/ Ex.
No. 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 738395 R7 R8 R3 R4 (CH3) 3C <CH3)3C PhCH2 PhCH2 (CH3) 3C (CH3)3C SO?NH SOgNH.
(CH3) 3C (CH3)3C 4-HO-C6H4CH2 4-HO-C6H4CH2 (CH3)3C (CH3)3C SO?NH PhCH2 (CH3)3C (CH3)3C 4-cyanobenzyl 4-cyanobenzvl (CH3)3C (CH3) 3C 2-nitrobenzyl PhCH2 (CH3) 3C CF3CH2 CF3CH2 (CH3) 3C (CH3)3C CH3(CHg)g CK3fCH2)6 (CH3)3C (cH2) 2c (CH3)2C-CHCH2 (CH3)2C—CHCH2 (CH3) 3C (CH3) 3C CH2-CHCH2 CH2-CHCH2 (CH3)3C (CH3) 3C CH3Q2C(CH2)4 CH3Q2C(CH2)4 (CH3) 3C (CH3) 3C 2-naphthyl 2-naphthyl 122(naphthvlmethyl) 123(naphthvlmethyl) (CH3)3C (CH3) 3C 1-naphthyl 1-naphthyl <C"3>3C tCH3>3C cvclohexylreethyl cvclohexylmethyl (CH3)3C 1-naphthyl 3,4-dichlorobenzyl (CH3)3C (CH3) 3C 2-(pyridylmethyl) 2-(pyridylmethyl) (CH3) 3C (CH3) 3C 3- (pyridylmethyl) 3-(pyridylmethyl) 129 V <*\\ -V 19 AUG 1991 Of, 1 130 Ex. No.
R7 R8 R3 R4 132 (CH3)3C (CH3)3C 4-(pyridylmethyl) 4-(pyridylmethyl) 133 (CH3)3C (CH3) 3C 4-pyridazylmethyl) 4-pyridazylroethyl) 134 (CH3)3c (CH3) 3C 4-(imidazolylmethvl) 4-(imidazolvlroethyl) 135 PhCH2 PhCH? PhCH2 PhCH2 136 PhCH2 PhCH2 4-HO-C6H4CH2 4-HO-C6H4CH2 137 PhCH2 PhCH2 CH3SCH2 CH3SCH2 138 PhCH2 PhCH2 2-thiophenyl 2-thiophenyl 139 PhCH2 PhCH2 HS(CH2)4 HS (CH2) 4 140 PhCH2 PhCH2 4-(benzyloxy)benzyl 4-(benzyloxy)benzyl 141 PhCH2 PhCH2 3-(methane-aulfonvl)benzyl 3- (methane-sulfonvl)benzyl 142 PhCH2 PhCH2 3,4-methylene-dioxybenzyl 3,4-methylene-dioxybenzyl 143 PhCH2 PhCH2 CF, "ipr CF, 144 PhCH2 PhCH2 CH3NHC(-0) CH2CH2 O 145 PhCH2 PhCH2 cyclohexylmethyl cyclohexylmethyl 146 PhCH2 PhCH2 cvclopropylmethyl cyclopropylmethvl 147 PhCH2 PhCH2 0 O 130 >^0 .w «*\ -*Y f 19 AUG 1991 \ A - 0 mm 131 Ex.
No.
R7 R8 R3 R4 146 (4-CF3)C6H4CH2 (4-CF3) C6H4CH2 PhCH2 PhCH2 149 2-C5H5NCH2 2-C5H5NCH2 PhCH2 PhCH2 150 4- [(CH3)3C]C6H4CH5 4- [ (CH3) 3C] C 5H4CH2 PhCH2 PhCH2 151 (CH.3)2C-CHCH2 (CH3)2C-CHCH2 PhCH2 PhCH2 152 4- [SO2NH2]C6H4CH2 4- [SO2NH2] C6H4CH2 PhCH2 PhCH2 153 PhCH2 PhCH2 CH3CH2CH2 CH3CH2CH2 154 (CH3)3C (CH3)3C CH3CH2CH2 CH3CH2CH2 155 4- [SO2NH2]C6H4CH2 4- [SO2NH2] C6H4CH2 CH3CH2CH2 CH3CH2CH2 131 19 AUG 1991^1 238395 132 TftBLE IV HN NH R7-X1' *-R« EX. NO.
R7-X1 R8~X2 156 PhC(-0) PhC(-O) 157 (CH3)3CC(-0) (CH3)3CC{-0) 158 2-pvridvlcarbonvl 2-pvridvlcarbonvl 159 H-Val-Val Val-Val-OH 160 H-Ser-Ala-Ala Val-Val-OH 1 161 Boc-Ser-Ala-Ala Val-Val-OMe 162 H-Ala-Ala Val-Val-OMe 163 H-Val-Ser-Gln-Asn Ile-Val-OH 164 Ac-Leu-Val Val-Leu-OMe 165 Ac-Lva-Val Val-Lva-Ac 166 Val-Boc-Val-Val Ara-Val-OMe 167 H-Arcr-Glv-Val Va1-G1v-Ara-OH 168 cvclohexvlcarbonvl cvclohexvlcarbonvl 169 PhC(-O) CH3(C-0) 170 PhNHC(-O) PhNH(C-O) 171 PhCH2NHC(-0) PhCH2NHC(-0) 172 4-Br-CgH4CH (CHgJNHC (-0) 4-Br-CgH4CH (CH3) NHC (-0) 173 Ph(C-S) Ph(C-S) 174 ch3 ch3 175 PhS02 PhS02 176 2-pvridvlmethylaminocarbonvl 2-pyridylmethvlaminocarbonyl 177 2-pvridvlacetyl-Aan 2-pyridylacetyl-Aan 178 2-pvridvlacetyl-Val 2-pvridvlacetvl-Asn 179 2-pvridylacetvl-I«eu 2-pyridylacetyl-Leu 180 2-pvridvlacetvl-Gln 2-pvridylacetvl-Gln 181 phenylacetvl-lle phenvlacetvl-Ile 182 phenvlacetyl-Asn phenvlacetvl-Asn 183 phenylacetvl-Gln phenylacetvl-Gln 184 phenylacetvl-Val phenylacetvl-Val 185 phenylacetvl-Leu phenvlacetvl-Leu 186 cruinoline-2-carbonvl-Aan qu.inoline-2-carbonyl-Aan 187 quinoline-2-carbonyl-Gln cruinoline-2-carbonvl-Xle 188 croinoline-2-carbonvl-Ile ouinoline-2-carbonvl-Ile 189 quinoline-2-carbonyl-Leu cruinoline-2-carbonvl-Val c 5 8 9 5 # 133 EX. NO.
Re"X2 190 2-pipecolinvl-Ile 2-pipecolinvl-Aan 191 2-pipecolinvl-Asn 2-pipecolinvl-Aan 192 2-pipecolinvl-Ile 2-pipecolinvl-Ile 193 t-butvlacetvl-Aan t-butvlacetvl-Asn 194 t-butvlacetvl-Asn t-butvlacetvl-Ile 195 t-butvlacetvl-Ile t-butvlacetvl-Ile 196 isoouinoline-3-formvl-Asn iaoouinoline-3-formvl-Aan 197 iaooruinoline-3-formvl-Asn iaoQruinoline-3-foEinvl-Ile 196 iaoquinoline-3-formvl-Ile isociuinoline-3-fonnvl-Ile 199 2-naphthovl-Aan 2-naphthovl-Aan 200 2-naphthovl-Gln 2-naphthovl-Ile 201 2-naphthovl-He 2-naphthovl-Ile 202 2-naphthoyl-Ile 2-naphthovl-Asn 203 2-naphthovl-Val 2-naphthovl-Xle 204 cvclohexvlacetvl-Aan cvclohexvlacetvl-Aan 205 cvclohexvlacetvl-He cvclohexvlacetvl-Ile 206 cvclohexvlacetvl-Aan cvclohexvlacetvl-Ile 133 % TABLE V u> Ex. No. 207 208 209 210 211 213 RIB 2- pyridylmethy 1 2- pyridylmethy 1 benzyl benzyl benzyl benzyl n-propyl naphthyl phenyl thiophenyl A(-0) B(-O) C(-O) D(-O) E(-O) F(-O) G(-O) H{-0) I(-O) J(=0) 2-propyl 2-butyl 2-butyl 2-propyl 2-propyl benzyl 2-propyl 2-propyl 2-propyl 2-propyl benzyl 4-imidazolylmethyl cycloheKylrnethyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl H H H H CH3 H H H H H u> r-j u-l co OnI VO Ex.
No. 218 219 220 221 222 223 224 225 226 227 228 229 230 231 trlfluoromet hyl benzyl 2- pyridylmethy 1 benzyl benzyl benzyl benzyl benzyl methyl phenylethyl benzyl benzyl benzyl benzyl benzyl K{-0) L(-0)CH2 M(-0)NH N(«0)NH 0(-0)NH P(-0)NH R(-0)NH S<«0)NH T(-0)NH U(-0)NH V(-0)NHNH W(-0)0 X(-S) Y(-S)NH C (CI) "N 2-propyl 2-propyl 2-butyl 2-butyl 2-butyl 2-butyl cyclobutyl cyclobutylm ethyl 2-butyl 2-butyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl % r1B benzyl H benzyl H benzyl H benzyl H benzyl CH3 q (- h trif luoromethylbenzyl 1-1 u> benzyl H 01 benzyl H benzyl H benzyl H benzyl H benzyl H benzyl H benzyl H benzyl H ro o-j co oj vo U1 Ex.
No. 233 234 235 236 237 238 M (*> o> 239 240 241 242 R1 2- pyridylinethy 1 3- methylpropyl benzyl . benzyl benzyl 2- pyridylethyl 3- naphthylmeth yi AA(-t- butylbenzyl benzyl benzyl benzyl W C(NHMe)-N C(NHMe)-N C(NHMe)"N C(NHMe)"N C(NHMe)«N C(CX:H2CH3) -N C(OCH2CH3) -N C(OCH2CH3) *»N C(OCH2CH3) -N C (OCH2CH3) -N C(OCH2CH3) <=N R3 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl R4 benzyl benzyl benzyl benzyl Z((HCF20)C6H4CH2 benzyl benzyl benzyl benzyl BB(- ytrifluoromethylbenzy 1 CC(-chlorobenzyl Ex.
No. h 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 % m\ benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl c(och2ch3) -n c(och2ch3) -n c(och2ch3) -n c(och2ch3> -n c(och3)-n ch2och2 ch2ch2 ch2choh ch2o ch2oh ch-ch chohch2 chohchoh hnc(-s)nh hns02 hnso2nh DD< NH-NH 2-propyl cyclobutyl cyclobutylm ethyl eyelopropy1 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-butyl 2-butyl 2-propyl 2-propyl R4 cyclohexylmethyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl % Rl8 h h h h h h h h h h h h h h h h h O) -J O C • J OS OJ ^o Ex.
No. r1 W 262 263 264 u> a> 265 266 267 ^ 268 - X > c: o (- CH2CH2CH2CH2 ch2~) {- CHZCH2OCH2CH 2~) 2-hydroxy-3,3-diroethylprop y! 2-hydroxy-3,3-dimethylprop yi 2-hydroxy-indanylraethy 1 3,5-dimethoxyphe nyl 3-hydroxy-n-propyl NHC(-0)NH NHC(-0)NH NHC(-0)NH NHC(-0)NH NHC("O)NH NHC(-0)NH NHC(=0)NH 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl rov. rr> R4 benzyl benzyl benzyl benzyl benzyl benzyl benzyl % rIB H H u> CH3 oo H H O OJ CC' O-J vo Ex.
No.
R1 W R3 269 270- nltrobenzyl 271 4-benzyloxy-phenylmethyl 272 4-cyano-n- butyl 273 4-phenoxy-phenylmsthyl 274 4-t-butyl-phenylmethyl 275 adamant yl 276 benzyl 277 benzyl 278 benzyl 279 benzyl 280 benzyl 281 benzyl 282 benzyl 283 benzyl 284 benzyl benzyl 2M^, benzyl mtt NHC imO) NH NHC(-0)NH NHC(-0)NH NHC(-0)NH NHC(-0)NH NHC (• NHC (« NHC (■ NHC (■ NHC (■ NHC (> NHC (■ NHC (■ NHC (■ NHC (■ NHC (« NHC (a ■O) NH ■O) NH ■O) NH ■O) NH ■O) NH ■O) NH ■O) NH ■0)NH ■O) NH >0)NH ■O) NH =0)NH 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl % R4 R18 benzyl H benzyl H benzyl H benzyl H benzyl H M oj benzyl H benzyl H benzyl ch3 benzyl H 2-naphthylmethyl H 3-naphthylmethyl H 1-adamantylmethul H FF(-hydroxybenzyl H 2-imidazolylethyl H 4-pyridinylmethyl H 4-bromophenyl H fv> i cycloheptylmethyl H • q-., 0 I VO 1 <- Ex.
No.
R1 H R3 287 288 289 benzyl benzyl benzyl NHC(m0)NH NHC(-0)NH NHC(-O)NH 2-propyl 2-propyl 2-propyl 290 benzyl NHC("O)NH 2-propyl 291 292 293 294 295 296 297 298 299 < ^Op f \ s] benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl NHC(~0)NH NHC("O)NH NHC(-0)NH NHC(-0)NH NHC(~0)NH NHC(-0)NH NHC <-0)NH NHC("0)NH NHC(-0)NH NHC<-0)NH 2- thiazolyl-methyl benzyl CH2CF3 CH2CH2C (-O) NH2 CH2CH2OH CH2CHOHCH3 cyclobutyl cyclobutyl cyclobutylm ethyl cyclopentyl -methyl 2-thiophenylmethyl H 3-pyrrazolylmethyl H GG((trifluoromethane- H sulfonyl)propyl HH((1— H methyl)piperidinyl-methyl benzyl H benzyl H ° benzyl H benzyl H benzyl H benzyl H benzyl H benzyl CH3 benzyl H benzyl H Ex.
No.
R1 H 301 302 303 304 305 306 307 308 309 n 4, rft v *o jo cr i CD } . 1 4 ' m .> |T> zji *v// benzyl benzyl cls-2-decahydro-naphthylmeth • yi cis-2-decabydro-naphthylmeth yi benzyl (CH2CH2CH) CH 2CH2 1- piperidyleth yl 2-benzimlda-zolylmethyl 2- naphthylmeth yi NHC(-0)NH NHC("O)NH NHC(-O)NH NHC(-0)NH O 0C(-0)NH 0C(-0)NH 0C(-0)NH 0C(-0)NH cyclopropyl cyclopropyl -methyl 2-butyl 2-butyl 2-propyl 2-butyl 2-butyl 2-butyl 2-butyl R4 benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl % r!8 H H H CH3 »-» ■b H H H H H '•o l-i (X CrO MD Ex.
No.
R1 310 311 312 •fk ro 313 314 315 316 317 pyridylmethy 1 2-quinazo-linylmethyl 3,4-methylene-dioxyphenylm ethyl 3- chlorobenzyl 3- phenylpropyl II (-acetamldoben zyl 4- imidazolylme thyl 4-methane-sulfonylbenz yi H 0C(«0)NH 0C(-0)NH 0C(-0)NH OC(-Q)NH 0C(-0)NH 0C(-0)NH OC (-O) NH 0C(-0)NH R3 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl R4 benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl H H H H ■c* fo H H ro C-i cc V-T' Ex.
No. r1 H 318 319 320 321 322 323 324 4- methoxybenzy 1 4- pyridylroethy 1 4-trifluoro-methylbenzyl 9- fluoreny lniet hyl adamantylmet hyl benzyl benzyl 0C(-0)NH 0c(-0)nh QC(-0)NH oc(-q)nh OC lmO) NH OC(-0)NH 0C(-0)NH 126 benzyl OC("O)NH 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 1-methoxy-2-propyl 325-hydroxycycl o- pentylmethy 1 2,2,2-tri-chloroethyl R4 benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl % r18 H h H (a> H H i'J CO Osl VO (J- Ex.
No.
R1 H R- 327 328 329 330 331 "332 333 334 benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl 0C(-0)NH OC("O)NH 0C(-0)NH 0C(-0)NH OC (*O) NH 0C(-0)NH OC(-0)NH OC("0)NH 2,2,2-tri-fluoroethyl 2-butyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 335 336 benzyl benzyl 0C(-0)NH OC ("O) NH 2-propyl 2-propyl 337 338 benzyl benzyl OC (-O) NH 0C(-0)NH 2-propyl 2-propyl 339 340 rti, benzyl benzyl OC O)NH OC ("O) NH 2-propyl 2-propyl benzyl benzyl benzyl benzyl 3-naphthylmethyl KK(-phenoxybenzyl LL(-benzyloxybenzyl MM(- (5-tetrazolyl)benzyl NN (,5'-bis(trifluore-methyl)benzyl 00 (- trifluoromethylbenzyl 2-phenylethyl 2- benzimidazolylroethyl PP((4-chlorophenyl)ethyl 2- decahydronaphthylmeth yi Ex.
NO.
W 341 benzyl 0C(-0)NH 342 benzyl 0C(-0)NH 343 benzyl 0C(-0)NH 344 benzyl 0C(-0)NH 345 benzyl 0C(-0)NH i_, 346 benzyl 0C(-0)NH tn 347 benzyl 0C(-0)NH 348 benzyl 0C(-0)NH 349 benzyl 0C(-0)NH 350 benzyl 0C(-0>NH 351 CH3SO2CH2CH2 OC («0) NH 352 cyclopentyle 0C(-0)NH thyl 353 F2HC0C6H4CH2 0C(-0)NH Rl8 QQ((3,4-methylene- H dioxyphenyl)ethyl benzyl H benzyl H 4-pyridylmethyl H 2-pyridylmethyl H benzyl H benzyl H benzyl H 2-pyridylmethyl H 3-pyridylmethyl H % benzyl H benzyl H •Cfc benzyl H 01 ro CM cc OJ r> Ja. <t> 354 355 356 357 358 359 360 361 362 N,N-dimethylamin o-3-propyl benzyl benzyl . benzyl 2,4-difluorophen yi SS (— methylphenyl benzyl benzyl benzyl benzyl benzyl benzyl 0c(-0)nh OCH2 OP(-0)(OMe )0 so2 so2nh so2nh so2nh so2nh so2nh so2nh so2nh so2nh 2-butyl 2-propyl 2-propyl 2-propyl 2-butyl 2-butyl TT{(methyl-amino)ethyl 2- furanylmeth yi 2-propyl 2-propyl 2-propyl 2-propyl Rl8 benzyl H benzyl h 2-pyridylmethyl h benzyl h 2-pyridylmethyl h benzyl H benzyl benzyl benzyl H benzyl Et uu(- h trifluoromethylbenzyl W(, 4 '-dif luorobenzyl H ' ^ OJ CO OJ ( 'i Ex.
No.
H R3 366 367 368 benzyl benzyl benzyl so2nh so2nh so2nh 2-propyl 2-propyl 2-propyl -j 369 370 371 372 373 374 375 376 377 378 benzyl benzyl benzyl benzyl benzyl cyclohexylet hyl nonafluorobu tyl phenyl trlfluoromet hyl 2,4-difluorophen yi so2nh so2nh so2nh so2nh so2nh so2nh so2nh so2nh so2nh s02nhc(-0) nh 2-propyl 3-hydroxy- 1-propyl cyclobutyl cyclopropyl methylthiom ethyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl * R4 R1B 3-phenylpropyl h 1-pyrrolylethyl h ww((4- h chlorophenyl)ethyl 1-phenylethyl h 1-phenylethyl h benzyl benzyl 1-phenylethyl 2-pyridylmethyl benzyl h 2-pyridylmethyl h benzyl h benzyl h h h h j-* u* h > ■' i ~o j ' o Ex.
No.
W •£> co 379 380 381 382 383 384 385 386 387 388 XX <-inethylphenyl ZZ(-nethylphenyl aaa (-methylphenyl BBB (— inethylphenyl CCC{-methylphenyl DDD (— methylphenyl SEE (-methylphenyl FFF(-methylphenyl benzyl cyclohexylet hyl S02NHC(-O) NH S02NHC(-0) NH S02NHC(-0) NH S02NHC(-0) NH S02NHC(-0) NH S02NHC(-O) NH S02NHC(-0) NH S02NHC(-O) NH S02NHC("O) NH S02NHC(-0) NH YY((dimethy 1- amino)ethyl 2-butyl 2-butyl benzyl CH2CH2OH cyclobutyl cyclohexylm ethyl cyclopropyl 2-butyl 2-butyl 3-pyridylmethyl benzyl 4-pyridylmethyl benzyl benzyl benzyl 4-pyridylmethyl benzyl benzyl 2-pyridylmethyl Ex.
NO. •t* v> /■ —* o r/Q |HJ e < o 3 389 390 391 392 393 394 395 396 397 398 A" R1 methyl nonafluorobu tyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl N s02nhc(-0) nh s02nhc(-o) nh s02nhc(-0) nh s02nhc(-0) nh s02nhc(-0) nh s02nhc(-0) nh s02nhc(-0) nh s02nhc(-0) nh s02nhc(-o) nh s02nhc(-0) nh s02nhc(=0) nh 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl cyclopropyl >7 .O / R4 benzyl benzyl 3-pyridylmethyl benzyl GGG(-chlorobenzyl 3-naphthylmethyl hhh((4-fluorophenyl)ethyl 2-phenylethyl HI (-carbomethoxybenzyl 2-pyridylmethyl benzyl Ex.
No. 400 trlfluoromet hyl 401 trlfluoromet hyl 402 trlfluoromet hyl 403 trlfluoromet hyl CJ1 O w S02NHC (-0) NH S02NHC(«0) NH S02NHC(-0) NH S02NHC(-0) NH 2-butyl 2-butyl cyclobutyl cyclopropyl • • •» r4 r18 benzyl H benzyl H 3-pyridylmethyl H 4-pyridylmethyl H cn o •O OJ OD OJ vO U1 TABLE VI U1 Ex. No. 404 405 406 R1 benzyl benzyl benzyl c(-0)nh c(-0)nh c(-0)hh c(-0)nh c(-0)0 c(-o) r2 benzyl benzyl benzyl 407 408 benzyl benzyl c (-0) hh c{-0)nh ch2c(-0) ch2c(-0)ch2 benzyl benzyl 409 410 411 benzyl benzyl benzyl c («0) nh c(-0)nh c(-0)nh C(-Q)CH2 s02nh so2 benzyl benzyl benzyl benzyl benzyl c(-0)nh c(=0)nh ch2och2 ch2o benzyl benzyl R3 R4 Rl8 2-butyl benzyl H 2-butyl benzyl H 2-butyl 2-pyridyl H methyl 2-butyl benzyl H 2-butyl 3-pyridyl- H methyl 2-butyl benzyl H 2-butyl benzyl H 2-butyl 4-pyridyl H methyl 2-butyl benzyl H 2-butyl benzyl H O-J cc CaJ VC O'- Ex.
No.
R1 w r2 r3 414 benzyl c (-o) nh ch2nch3 benzyl 415 416 417 benzyl benzyl benzyl c (-0) nh c(-0)nh c(-0)nh ch2nh ch2ch2 ch-ch benzyl benzyl benzyl tn to 418 419 420 421 422 423 424 benzyl benzyl benzyl benzyl benzyl benzyl benzyl c(-0)nh c(-0)nh c (-o) nh c(-0)nh c(-0)nh c(-0)nh c(-0)nh CH(OH)CH(OH) CH(OH)CH2 CH2CH(OH) CH(OH) C(-N[Me]2)-N C(-OEt)-N C (CI—)"N benzyl benzyl benzyl benzyl benzyl benzyl benzyl 425 426 427 429 o OJ. ■g s f, $ *© & 39^1^ ''■A X' benzyl benzyl 2- pyridylmethyl 2-pyrimidinyl benzyl c (-0) nh nhc(-0)nh nhc(-0)nh nhc(-0)nh nhc (*°0) nh s02nh c(-0)nh c (-0) nh c(-0)nh c(-0)nh benzyl benzyl benzyl benzyl 3-(methyl-amino)propyl r4 r18 2-butyl 2-pyridyl H methyl 2-butyi benzyl H 2-butyl benzyl H 2-butyl 3-pyridyl- H methyl 2-butyl benzyl H 2-butyl benzyl H 2-butyl benzyl H 2-butyl benzyl H 2-butyl benzyl H 2-butyl benzyl H 2-butyl 2-pyridyl H methyl 2-butyl benzyl CH3 2-butyl benzyl H 2-butyl 3-pyridyl- H methyl 2-butyl benzyl H 2-butyl benzyl H rv> C-J oo La> VO u~ Ex.
No. 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 ') R1 w R2 R3 R« Rl8 naphthyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl naphthyl benzyl benzyl 2- pyridylroethyl benzyl benzyl benzyl NHC(-0)NH NHC(-0)NH NHC(-O)NH NHC(-0)NH NHC(-0)NH NHC(-0) NH NHC(™0)NH NHC(-O)NH NHC (""O) NH NHC (~O) NH NHC{-0)NH OC("0)NH 0C<«0)NH OC(-0)NH OC(-0)NH 0C(«0)NH C(-0)NH C(-0)NH C(-0)NH C(-0)NH C(-0)NH C (-0) NH S02NH S02NH so2nh so2nh so2nh C(-0)NH C(-0)0 C(-O) CH2C(-0) CH2C(»0)CH2 benzyl benzyl benzyl 2-acetamido 2-(dimethyl-aminoethyl) benzyl benzyl 3-(methyl-amino)propyl iaobutyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl cyclopropyl cyclopropyl 2-butyl 2-butyl 2-propyl 2-butyl 2-butyl n-propyl 2-propyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl benzyl 4-chloro-benzyl 4-pyridyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl 2-pyridylmethyl benzyl benzyl benzyl benzyl H K H H H H H H H H CH3 H cn (a> H H H Ex. R1 No. w x 446 benzyl 0C(-0)nh c(-o)ch2 447 benzyl 0c(-0)nh SQ2nh in R3 R4 Rl8 benzyl benzyl 2-butyl 2-butyl benzyl benzyl h h ui •t* r-O O-J OC' O-J vO O-" rfA • II 448 449 450 451 452 453 454 455 456 457 458 459 2!! ,o/ y table vii r1 W R3 r4 Rl8 benzyl benzyl benzyl benzyl 2,4-difluorophonyl 4 *-methylphenyl benzyl benzyl benzyl benzyl benzyl c(-s> 2-propyl cimS]nh 2-propyl hnso^nh 2-butyl S02 2-propyl s02nh 2-butyl SO2NH 2-butyl S02nh 2- (methylamino)ethyl SO2NH 2-furanylmethyl sojnh 2-propyl s02nh 2-propyl SO2NH 2-propyl benzyl H benzyl H 2-pyridylmethyl H benzyl H 3-pyridylmethyl H benzyl H benzyl H 4-pyridylmethyl H benzyl H benzyl Et 3'- H trifluoromethylb enzyl Ex. No.
R1 W R3 460 benzyl so2nh 2-propyl 461 462 463 benzyl benzyl benzyl s02nh so2nh so2hh 2-propyl 2-propyl 2-propyl 464 benzyl so2nh 2-propyl 465 benzyl so2nh 3-hydroxy-l-propyl m 466 benzyl so2nh cyclobutyl ol cn 467 benzyl so2nh cyclopropyl 468 benzyl so2nh methylthlomethyl 469 cyclohexylethyl so2nh 2-butyl 470 nonafluorobutyl so2nh 2-butyl 471 phenyl so2nh 2-butyl 472 trifluoromethyl so2nh 2-butyl 473 benzyl hhc(-s)nh 2-butyl 474 benzyl nhc(-s)hh 2-butyl 475 benzyl nkc(-s)nh 2-propyl ;/■*> <0 476 ^>*77 ^478 benzyl benzyl benzyl nhc«-s)nh ch2o ch2och2 2-propyl 2-propyl 2-propyl fc £ \\ * <?> 2',4'- h difluorobenzyl 3-phenylpropyl H 1-pyrrolylethyl H 2-(4- H chlorophenyl)eth yi 1-phenylethyl H 1-phenylethyl H 2-pyridylmethyl H (_» cn benzyl H 1-phenylethyl H benzyl K benzyl H 2-pyridylmethyl H benzyl H benzyl H 3-pyridylmethyl CH3 benzyl H 2-naphthylmethyl H benzyl H ro 2-pyridylmethyl H o-J CO O-J M3 O^ Ex. No. R1 W 479 benzyl CH2CH2 480 benzyl CH-CH cn • • R3 R4 Rl8 2-propyl benzyl H 2-propyl benzyl H cn ro L/J CO w MD CP • • TABLE VIII i/i 00 Ex.
R1 W X R2 R3 R4 Rl8 No. 481 482 483 benzyl C(-0)HH C(-0)NH benzyl 2-butyl benzyl H 484 benzyl C(-0)NH C(-0)0 benzyl 2-butyl 4- chlorobenzyl H 485 benzyl C(-O)NH C(-O) benzyl 2-butyl benzyl H 486 benzyl C(-0)NH CH2C(-0) benzyl 2-butyl 2-pyridyl-methyl H 487 benzyl NHC(-0)NH C(-0)NH 2-(dimethyl-aminoethyl) 2-propyl benzyl H 488 benzyl NHC (-KD) NH C (-O) NH benzyl 2-butyl benzyl H 489 benzyl NHC(-0)NH so2nh benzyl 2-butyl benzyl H \ fiv >£5 v<5 VD x- '3 O >3^ tn cd ro o > o.
V" c • • TABLE IX cn KO Ex. No. 490 491 492 493 494 495 496 497 498 R1 benzyl benzyl benzyl phenyl phenyl benzyl benzyl benzyl benzyl benzyl W so2nh so2nh so2nh s02nhc(-0)nh s02nhc(-0)nh oc ("0)nh 0c(-0)nh oc (-o) nh oc (—o) nh c(-0)nh R3 2-propyl 3-hydroxy-l-p ropy1 methylthiomethyl 2-butyl 2-butyl 2-propyl 2-propyl 2-propyl 2-propyl 2-butyl R4 R18 1-phenylethyl H 1-phenylethyl H 1-phenylethyl . H 2-phenylethyl H 3 *-carbomethoxybenzyl H 3-naphthylmethyl H 4'—(5- H tetrazolyl)benzyl 4'-benzyloxybenzyl H 4'-phenoxybenzyl H 4'- H trifluoromethylbenzyl Ex. R1 No. 501 2-pyridylmethyl 502 benzyl 503 benzyl 504 benzyl 505 benzyl 506 methyl 507 phenylethyl 508 benzyl 509 benzyl 510 Ot o 511 benzyl benzyl 512 benzyl 513 benzyl 514 benzyl 515 benzyl 516 benzyl 517 adanmntyl 518 benzyl 519 benzyl 520 benzyl **■521 O 22 cr tn. CD •• *1 benzyl benzyl w c(«0)nh c(-0)nh c<-0)nh c(-0)mh c(-0)nh c(-0}nh c(-0)nh c(-0)nhnh c(-0)0 ch20ch2 ch2ch2 ch2o ch-ch hns02nh n-n nh-nh nhc(-o)nh nhc(—o)nh nhc{—0)nh nhc(—o)nh nhc(-0)nh nhc(**0)nh R3 R4 r18 2-butyl benzyl h 2-butyl benzyl h 2-butyl 2-pyridylmethyl chj cyclobutyl benzyl h cyclobutylmethyl benzyl h 2-butyl benzyl h 2-butyl 3-pyridylmethyl h 2-propyl benzyl h 2-propyl benzyl h 2-propyl benzyl h 2-propyl 4-pyridylmethyl h 2-propyl benzyl h 2-propyl benzyl h 2-butyl benzyl h 2-propyl benzyl h 2-propyl benzyl h 2-butyl 2-pyridylmethyl h 2-butyl benzyl h 2-butyl benzyl cf3 2-propyl benzyl h benzyl 3-pyridylmethyl h ch2cf3 benzyl h CO OJ vO on Ex.
No.
H 523 benzyl NHC (-O) NH CH2CH2C(-0)NH2 524 benzyl NHC (-0) NH cyclobutyl 525 benzyl NHC(-0)NH cyclobutyl 526 benzyl NHC("0)NH cyclobutylmethyl 527 benzyl NHC("0)NH cyclopentylmethyl 528 benzyl NHC(-0)NH cyclopropyl 529 - benzyl NHC(~0)NH cyclopropylmethyl 530 cis-2- NHC(-O)NH 2-butyl decahydronaphth ylmethyl 531 cis-2- NHC(*"0)NH 2-butyl decahydronaphth ylmethyl 532 2-hydroxy-3,3- NHC(—0)NH 2-butyl dimethylpropyl 533 2-hydroxy-3»3- NHC(-0)NH 2-butyl diioethylpropyl 534 2-hydroxy- NHC(-0)NH 2-butyl indanylmethyl 535 benzyl OC("0)NH l-methoxy-2-propyl O y\ Rl8 benzyl H benzyl H benzyl CF3 4-pyridylmethyl H benzyl H benzyl H benzyl H benzyl H benzyl CF3 benzyl H benzyl CF3 2-pyridylmethyl H benzyl H Ex.
No.
W 536 benzyl 0c(«o)nh trv K) 537 538 539 540 541 542 543 544 545 546 547 548 benzyl benzyl benzyl benzyl benzyl 2-benximida-zolylxnethyl 2- naphthylmethyl 2-pyridylinethyl ch3s02ch2ch2 cyclopentylethy 1 F2HCOC6H4CH2 2,4-di fluorophenyl 4'-methylphenyl benzyl benzyl 0c(-0)nh oc (-0) nh oc(-0)nh 0c(-0)nh oc(—0)nh 0c(-0)nh oc (-0) nh oc (-0) nh oc (—o)nh oc("o)nh oc (-0) nh so2nh so2nh so2nh so2nh R3 RIB 2'- hydroxycyclopentylme thyl 2,2,2-trlchloroethyl 2,2,2-trifluoroethyl 2-butyl 2-propyl 2-propyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-(methylamino)ethyl 2-furanylmethyl benzyl H 3-pyridylmethyl H benzyl H benzyl H benzyl H benzyl CF3 benzyl H 4-pyridylmethyl H '■o benzyl H benzyl H benzyl H benzyl H benzyl H benzyl H benzyl H 2-pyridylmethyl H * O-J OO OJ VO on Ex.
No.
R1 W R3 552 benzyl 553 benzyl 554 benzyl 555 4•-methylphenyl to s02nh so2nh so2nh s02nhc(-0)nh 2-propyl cyclobutyl cyclopropyl 2-(dimethylamino) ethyl 556 4' -inethylphenyl s02nhc(-0)nh 2-butyl 557 4 • -inethylphenyl s02nhc(-0)nh 2-butyl 558 4 • -inethylphenyl s02nhc(-0)nh benzyl 559 4•-methylphenyl s02nhc(-0)nh ch2ch2oh 560 4'-methylphenyl s02nhc(-0)nh cyclobutyl 561 phenyl so2nhc(-o>nh 2-butyl 562 phenyl s02nhc(-0)nh cyclopropyl 563 trifluoromethyl s02nhc(-o)nh 2-butyl 564 trifluoromethyl s02nhc(-0)nh 2-butyl 565 trifluoromethyl s02nhc(-o)nh cyclobutyl 566 trifluoromethyl sojnhc (-o) nh cyclopropyl R4 R18 benzyl H benzyl H benzyl H benzyl H benzyl H benzyl H benzyl H 3-pyridylmethyl H benzyl H 4-pyridylmethyl CF3 benzyl H benzyl H benzyl H benzyl H benzyl H oj r-o rv C. -J ■ OC' o o i (.
VO v C" < • • TABLE X ex. ho. 567 r1 r2 r3 r4 R12 m 568 benzyl c(-0)nh c(«0)nh benzyl 2-butyl benzyl Hf-» 2 569 benzyl c(-0)nh c(-0)0 benzyl 2-propyl benzyl Ol h** 570 benzyl c(-0>nh ch2c(«0)ch2 4-chlorophenyl cyclopropyl benzyl h 571 benzyl c(-0)nh c(»0)ch2 benzyl ethyl .•benzyl h 572 benzyl c(-0)nh so2nh benzyl cyclobutyl benzyl h 573 benzyl c(-0>nh ch2nch3 2-(dimethyl-aminoethyl) 2-butyl benzyl h 574 benzyl c (—0) nh ch2nh benzyl 2-butyl benzyl h 575 benzyl c(-0)nh ch2ch2 naphthyl 2-butyl 4- fluorophenyl h 576 benzyl c (-o) nh ch-ch benzyl 2-butyl ' benzyl h //:*> -* *hq f/2* o -y V. benzyl c(-0)nh ch(oh)ch(oh) 2-acetamido 2-butyl naphthyl h CP. o Ex.
No.
H x 578 3-trifluoro-methylbenzyl 579 benzyl c(-0)nh c(-0)nh ch(0h)ch2 ch2ch{0h) 580 581 benzyl benzyl c(—o)nh c(-0)nh ch(oh) s02nh h* CT) Cn 582 benzyl 583 2-pyridylmethyl 584 2, 4-diiaethoxy-benzyl 585 benzyl nhc(-0)nh nhc("o)nh nhc(-0>nh nhc(™0)nh c(-0)nh c(-0)nh c (-o) nh c(-0)nh 586 587 naphthyl benzyl nhc(-0)nh nhc(-0)nh c(-0)nh c(-0)nh 588 / ' «»* «c\\ NO ■ £ < g> ; t'a ^3 <3 \0 rnV, J benzyl benzyl nhc(-0)nh nhc(-0)nh c(-0)nh c(-0)nh R2 r3 R4 >12 benzyl 2-butyl benzyl benzyl 2-butyl 4-methanesulfonyl 2-butyl benzyl 2-butyl benzyl 2-butyl benzyl 2-butyl 4- methoxypheny 1 benzyl 2,4- dichloro-phenyl benzyl benzyl h ch3 H»-» cn benzyl 3-(methylamino)-propyl benzyl 2- imidazolylmethy1 benzyl 2-acetamido 2-butyl 2-butyl cyclopropyl cyclopropyl 2-butyl 2-butyl benzyl H benzyl h benzyl h 4- h chlorobenzyl 4-pyridyl h benzyl h rv> oj co oj vo on Ex.
No. w X 590 benzyl nhc(«0)nh c(-o)nh 591 benzyl nhc (—o) nh c(-0)nh 592 benzyl nhc(-0)nh so2nh 593 benzyl nhc(—o)nh so2nh 594 benzyl nhc(-0)nh so2nh 595 naphthyl nhc(-0)nh so2nh 596 benzyl nhc(-0)nh so2nh 597 benzyl oc (~o) nh c(-0)nh 598 benzyl oc (-o)nh c(-0)0 599 benzyl 0c(-0)nh ch2c(-0)ch2 600 adamantyl oc ("0) nh c(-0)ch2 601 benzyl oc (-0)nh so2nh 602 benzyl oc (—o) nh ch2nch3 603 cyclohexylnethy 1 oc (-0) nh ch2nh 604 JL benzyl 0c(-0)nh ch2ch2 R2 R3 R4 Rl2 2-(dimethyl-aminoethyl) benzyl benzyl 3-(methyl-amino)propyl aminoethyl) benzyl 2-propyl 2-butyl 2-butyl n-propyl benzyl benzyl benzyl benzyl H H H iaobutyl 2-propyl benzyl h benzyl 2-butyl benzyl k 3-indolylmethyl 2-butyl benzyl ch3 benzyl 2-butyl benzyl 166 X X benzyl 2-propyl benzyl 4-chlorophenyl cyclopropyl benzyl h benzyl ethyl benzyl h benzyl cyclobutyl benzyl h -(dimethyl- 2-butyl benzyl h 2-butyl benzyl naphthyl 2-butyl 4- £ luorophenyl ro o-J CO CM vO cr TABLE XI <t\ -J Ex. R1 No. €05 2-pyridylmethl 606 benzyl 607 benzyl 608 trifluoromethyl 609 benzyl 610 2-pyridylmethyl 611 benzyl 612 benzyl 613 benzyl W CC-O) c(-o) c(-o) c(-0) c(-0)ch2 c{-0)nh c(-0)nh c («0) nh c(-0)nh R3 2-propyl 2-butyl 2-propyl 2-propyl 2-propyl 2-butyl 2-butyl 2-butyl 2-butyl 614 -> benzyl benzyl methyl c(-0)nh c(-0)hh c(-0)nh cyclobutyl. cyclobutylmethyl 2-butyl r4 benzyl cyclohexylmethyl benzyl 2-pyridylmethyl benzyl 3-pyridylmethyl benzyl benzyl 41 - t ri fluoromethylbenzyl benzyl benzyl 3-pyridylmethyl Ex.
No. 617 618 619 620 621 622 623 624 625 M 626 CT5 oo 627 628 629 630 631 632 633 634 phenylethyl benzyl benzyl benzyl benzyl benzyl 2-pyridylmethyl 3-raethylpropyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl C(-0)NH C (-0)NHNH C(«0)0 C(-S) C(-S)NH C (CI) -N C(NHMe)-N C (NHMe) —N C(NHMe)-N C(NHMe)-N C (NHMe) —N C (och2ch3) -N C (och2ch3) -N c(och2ch3)—n CH2OCH2 CH2CH2 ch2choh CH2O CH2OH CH-CH CH0HCH2 R3 R4 Rl8 2-butyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl benzyl benzyl benzyl 4-pyridylmethyl benzyl benzyl benzyl benzyl 2-pyridylmethyl benzyl 4-(HCF20)C6H4CH2 benzyl 4'- trifluoromethylbenzyl 4'-chlorobenzyl benzyl benzyl 3-pyridylmethyl benzyl benzyl benzyl 4-pyridylmethyl H H H H H H H H H CH3 H H H H H H H H H H <T> 00 ro oj CO oj vo ul Ex.
No. r1 638 benzyl 639 benzyl 640 benzyl 641 benzyl 642 benzyl 643 benzyl 644 2-hydroxy-3,3- dlmethylpropyl 645 4—t— butylphenylmethyl 646 adamantyl 647 benzyl 648 benzyl 649 benzyl 650 benzyl 651 benzyl 652 benzyl 653 "^5 o > c: . cd i 3 vO fn 2r <*// benzyl benzyl benzyl h chohchoh hnc(-s)nh hnso2 hnso2nh n-n nh-nh nhc (-o) nh nhc(-o)nh nhc(-o)nh nhc("o)nh nhc(-o)nh nhc(-0)nh nhc("o)nh nhc(-0)nh nhc("0)nh nhc(-o)nh nhc(»0)nh nhc(-0)nh R3 r4 R10 2-propyl 2-propyl 2-butyl 2-butyl 2-propyl 2-propyl 2-butyl benzyl benzyl benzyl benzyl 2-pyridylmethyl benzyl benzyl h h h h h h h 2-butyl benzyl 2-butyl 2-butyl 2-butyl 2-propyl 2-propyl 2-propyl 2-propyl 2-thiazolylmethyl cyclobutyl cyclobutylmethyl benzyl h 2-pyridylmethyl h benzyl CH3 benzyl h 3-pyrrazolylmethyl H 3-(trifluoro- H methanesulfonyl)propyl 4-{l-roethyl)piperi- H dinylmethyl benzyl h 3-pyridylmethyl ch3 benzyl h o\ VD ro OJ OO O-J MD on Ex.
No.
R1 W -j o 656 2-pyridylmethyl 0C(-0)NH 657 9-fluorenylmethyl OC ("0)NH 658 adamantylmet hyl 0C(«0)NH 659 benzyl OC ("O) NH 660 benzyl OC ("O) NH 661 benzyl 0C(-0)NH 662 benzyl OC (-O) NH 663 benzyl OC («"0) NH 664 benzyl OC (—O) NH 665 benzyl OC(-0)NH 666 benzyl 0CH2 667 benzyl 0P(-0)(0Me)0 668 benzyl S02 669 2,4-difluorophenyl S02NH 670 4»-inethylphenyl so2nh 671 benzyl so2nh 672 benzyl so2nh is \f> -sg -o "^V m i o 1> cr cd ~Y,'. benzyl so2nh R3 r4 R18 2-butyl 2-butyl 2-butyl l-methoxy-2-propyl 2 '- hydroxycyclopentylm ethyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-butyl 2-butyl 2-propyl 2-propyl 2-propyl benzyl H 4-pyridylmethyl H benzyl H benzyl H benzyl H benzyl ch3 3-naphthylmethyl H 4'-phenoxybenzyl H 4 *-benzyloxybenzyl H 4■-(5- H tetrazolyl)benzyl benzyl H benzyl H 2-pyridylmethyl H benzyl H benzyl H 3-pyridylmethyl Et 3'- H trif.luoromethylbenzyl 2', 4'-difluorobenzyl H -j o ro O-J OC o vr C" Ex.
No.
R1 W 674 nonafluorobutyl so2nh 675 phenyl so2nh 676 trifluoromethyl so2nh 677 2,4-difluorophenyl s02nhc(-0)nh 678 4•-methylphenyl s02nhc(-0)nh 679 4'-methylphenyl S02NHC(-0)NH 680 4'-methylphenyl S02NHC(-0)NH 681 4'-methylphenyl S02NHC(-0)NH 682 4'-methylphenyl S02NHC(-O)NH 683 methyl S02NHC(-0)NH 684 phenyl S02NHC(-0)NH 685 phenyl S02HHC(-0)NH 686 phenyl S02NHC(-0)NH 687 phenyl S02NHC(-0)NH 688 phenyl S02NHC(-0)NH CT f * 2 ' (2 n? »o >© 689 690 691 •y\92 mV 3 0 -V j phenyl phenyl phenyl phenyl s02hhc(-o)nh s02nhc(-0)nh s02nhc(«0)nh s02nhc(-o)nh R3 2-butyl 2-butyl 2-butyl 2-butyl 2- (dimethylamino)ethy 1 2-butyl CH2CH2OH cyclobutyl cyclohexylmethyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl cyclopropyl benzyl H benzyl H 4-pyridylmethyl H benzyl H benzyl H benzyl H 2-pyridylmethyl H benzyl H M -j benzyl H H 3-pyridylmethyl H benzyl H benzyl H 2•-chlorobenzyl H 3-naphthylmethyl H 2-(4- H fluorophenyl)ethyl 2-phenylethyl H 3'-carbomethoxybenzyl H benzyl ch3 ^ O-i 4-pyridylmethyl H CX O V (J Ex.
No, R1 W 693 trifluoromethyl 694 trifluoromethyl 695 trifluoromethyl 696 trifluoromethyl S02NHC(-0)NH SOzNHC(-O)NH S02NHC(-0)NH S02NHC("0)NH -o fO 2-butyl 2-butyl cyclobutyl cyclopropyl benzyl benzyl 2-pyridylmethyl benzyl H H H H -j N) fO O-l CO OJ vD on • • TABLE XII (d Ex. No. 697 698 699 700 701 702 703 704 R1 benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl H 0c(-0)nh 0c(-0)kh oc(—o)nh oc (—0) nh oc(—0)nh oc(—o)nh oc (—o) nh oc ("o) nh oc (-0) nh c(-0)nh c(«0)0 c(-o) ch2c(-0) ch2c (-0) ch2 c(-q>ch2 s02nh S02 ch2och2 r2 benzyl benzyl 2-(dimethylamino) ethyl benzyl benzyl benzyl 3-(methyl-amino)propyl benzyl benzyl r3 2-butyl 2-butyl 2-butyl 2-propyl 2-propyl 2-propyl ethyl 2-thiazolyl-methyl cyclobutyl R4 R18 benzyl h benzyl h benzyl h benzyl H. 4- h chlorobenzyl benzyl h 2-pyridyl- h methyl benzyl h benzyl h Ex.
No.
Rl W r2 R3 R4 r18 •to. 706 benzyl 707 benzyl 798 benzyl 709 benzyl 710 benzyl 711 2-pyridylxnethy 1 712 benzyl 714 715 716 oc(-c)nh OC (-0) NH OC (-O) NH HNC(-O)NH C(-0)NH benzyl 2,3-difluorobenz yi benzyl OC (-O) NH 0C(-0)NH OC (-O) NH ch20 CH2NCH3 ch2nh ch2ch2 ch-ch benzyl cyclobutylme thyl cyclohexylmet 2-butyl hyl 0C(«0)NH ch(OH)ch(OH) oc(-o)nh ch(oh)ch2 benzyl benzyl benzyl benzyl benzyl 713 naphthyl oc(-q)hh ch2ch(oh) 4- pyrldylmethyl ch(oh) benzyl C(-N[Me]2)-N 4- imldazolylmet hyl C(—OEt)—N benzyl 3-cyanopropy 2-butyl l-methoxy-2- propyl 2'-hydroxycyclopentylm ethyl 2-propyl 2-propyl benzyl 2-propyl 2-propyl 3-pyridyl- h methyl benzyl CH3 benzyl H 3-indolyl H 4-pyrldyl- H methyl benzyl H 4- h fluorobenzyl benzyl H naphthyl H benzyl H benzyl -j fO U4 CO L-rJ vC w Ex.
No. r1 w R2 717 1- oc(-c»nh C(Cl-)-n benzyl cyclohexenyl methyl R4 Rl8 2-propyl benzyl h -j ot ro u-i CP ^r c TABLE XIII -4 O Ex.
R1 W R3 R4 Y No. 718 2-pyridyImeth1 C(-O) 2-propyl benzyl C(C1)-N 719 benzyl C(-O) 2-butyl cyclohexylmethyl C(OEt)-N 720 benzyl C(-0)CH2 2-propyl benzyl C(0Et)-N 721 2-pyridylmethyl C(-0)NH 2-butyl 2-pyridyl-methyl C(NMe2)-N 722 benzyl C(-0)NH 2-butyl benzyl C(KHMe)-N 723 benzyl C(-0)HH 2-butyl benzyl C(C1)-N 724 benzyl C(-0)NH 2-butyl 4 '-trifluoro methylbenzyl C(NHMe)-N 725 benzyl C(-0)HHNH 2-propyl benzyl C(NHMe)-N 726 benzyl C(-0)0 2-propyl benzyl C(OMe)-N 727 benzyl C(-S) 2-propyl 3-pyridyl-methyl C(NMe2)-N 728 benzyl C(«S)NH 2-propyl benzyl C(NHMe)-N V benzyl C(C1)-N 2-propyl benzyl C(0Et)-N If0 :/ 2-pyridyImet hyl C(NHMe)"N 2-propyl benzyl C(0Et)-N -j cn rO u' CP O-i vJD O" Ex.
No. r1 W 731 3-methylpropyl 732 benzyl 733 2-pyridylethyl 734 benzyl 735 benzyl 736 benzyl 737 benzyl 738 benzyl 739 benzyl 740 benzyl 741 benzyl 742 benzyl 743 benzyl 744 benzyl 745 benzyl 746 benzyl 747 benzyl 748 (-CH2CH2CH2CH2CH2) 749 (-CH2CH2OCH2CH2-) 2-hydroxy-3,3-dimethylpropyl C(NHMe)-N C(NHMe)-N C(OCH2CH3)-N C(OCH3)-N CH20CH2 ch2ch2 ch2choh ch2o ch2oh CH-CH chohch2 chohchoh hnc(—s)nh hns02 hnso2nh N-H NH-NH NHC (-o) NH NHC(—O)NH NHC(—0)NH r3 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-butyl 2-butyl 2-propyl 2-propyl 2-butyl 2-butyl 2-butyl y benzyl benzyl benzyl benzyl benzyl 4-pyridyl—methyl benzyl benzyl 2-py r idy 1-nve t hy 1 benzyl benzyl 3-pyridyl-methyl benzyl benzyl benzyl 4-pyridyl-methyl benzyl benzyl benzyl benzyl C(NHMe)-N C(NHMe)—N C(NHMe)-N C(OEt)-N C(OEt)—N C(NMe2)-N C(NHMe)—N C(OEt)-N C(OEt)—N C(NHMe)-N C(NHMe)"N C(OEt)-N C(OMe)-N C(OEt)-N C(OEt)-N C(NHMe)—N C(NHMe)—N C(NHMe)-N C(OEt)-N C(OMe)-N 751 2-hydroxy-3,3-dimethylpropyl 752 2-hydroxyindanylmet hyl 753 adanantyl 754 benzyl 755 benzyl 756 benzyl 757 benzyl oo 758 759 760 761 762 benzyl 2- benz imida zoly Imet hyl 2-naphthylmethyl 2-pyridylmethyl benzyl NHC(-0)NH NHC(-O)NH NHC(-0)NH NHC(-0)NH NHC(-0)NH NHC(-0)NH NHC("O)NH O OC ("O) NH 0C(-0)NH OC (—O) NH OC (—0) NH 763 benzyl 0C(-0)NH 764 benzyl OC (-O)NH 765 benzyl 0C(-0)NH r3 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-propyl 2-propyl 2-propyl 2-butyl 2-butyl 2-butyl 1-methoxy-2-propyl 2-butyl 2-propyl 2-propyl r4 y benzyl C(C1)-N benzyl C(NHMe)-N benzyl 2-pyridyl-methyl benzyl benzyl 2-naphthyl methyl benzyl 3-pyridyl-methyl C(0Et)-N C<0Et)-N C(C1)-N C(NHMe)~N C(NHMe)-N C(OEt)-N C(0Et)-N CD benzyl benzyl benzyl C(OEt)"N C(OEt)-N C(NMe2)-N benzyl 4-pyridyl-methyl benzyl C(NHMe)-N C(NHMe)-N C(C1)-N 'Nj Oy ct> Cv C'7 Ex.
No.
R1 W R3 766 767 768 769 770 771 772 »-» •J U3 773 774 775 776 777 778 779 780 781 benzyl benzyl benzyl 2,4-di £luorophenyl 4 • -inethylphenyl benzyl benzyl benzyl benzyl benzyl cyclohexylethyl methyl nona fluorobutyl phenyl phenyl trifluoromethyl och2 op(-o) (OMe)O so2 s02nh so2nh so2nh so2nh so2nh so2nh s02nhc (-0) nh s02nhc(-0)nh s02nhc(-0)nh s02nhc<-c)nh s02nhc(-0)nh SOjnhc(-o)nh s02nhc (-o) nh 2-propyl 2-propyl 2-propyl 2-butyl 2-butyl 2-(methylam ino)ethyl 2-furanyl-tnethyl 2-propyl 2-propyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl cyclopropyl R< benzyl benzyl benzyl benzyl C(0Me)-N C(0Et)-N C(NHMe)~N C(NHMe)-N benzyl benzyl C(NHMe)™N C(NHMe)~N benzyl 2-pyridyl-methyl benzyl benzyl 3-pyridyl-methyl benzyl benzyl 4-pyridyl-methyl benzyl benzyl C(NHMe)-N C(NHMe)-N C(C1)-N C(0Et)-N . C(0Et)-N C(OMe)-N C(OMe)-N C(NHMe)-N C(NMe2)-N C(NHMe)-N $ o? • • TABLE XIV Ex. No.
M 782 cd O 783 784 785 786 787 R1 2-pyridylraethyl benzyl benzyl benzyl benzyl benzyl benzyl C(-0)MH C(-0)NH C(-0)NH C(-0)HH C(-0)NHNH C(-0)0 C(-S) C(-0)NH C(-O)NH C (-O) NH C(-0)NH C(-0)NH C(=0)NH C(-0)NH R2 benzyl 3- (diemthylamino)propyl cyclopentylmethyl benzyl 4-chloro-benzyl 3,3,3-trif1- uoroethyl 2-imidazol-ylmethyl R3 2-butyl cyclobutyl 2-butyl cyclopropyl 2-propyl 2-propyl 2-propyl R4 benzyl benzyl benzyl benzyl benzyl benzyl benzyl C(NMe2)-N M C (NKMe) -N S C(C1)-N C(NHMe)~N C(NHMe)-N C(OMe)-N C(NMe2)-N '\j Qo (_v Vo C.'? 00 M Ex. R* No. 789 2-pyridylethyl 790 2-pyridylmethyl 791 792 793 > - < 25 ,;0 f, n O < NO sO rn n oj 1 -3 benzyl benzyl benzyl benzyl n-propyl C(-O) C(-0) C(-O) C(-O) C(-O) C(«0> C(-O) R3 2-propyl 2-butyl 2-butyl 2-propyl 2-propyl benzyl 2-propyl R4 benzyl 4-imidazolyl-methyl R8 3-(dimethylamino) -1-propyl benzyl cyclohexylmet CH2NHC(-0)NHCH3 hyl benzyl CH2NHS02CH3 2-pyridyl- cyclobutyl methyl benzyl cyclobutylmethyl benzyl cyclopropyl rlo 2,4- difluorophe nyl 4 ' — methylpheny 1 benzyl benzyl benzyl benzyl benzyl od H* <'v> OC C-M • • M CD to Ex.
R1 w R3 R4 NO. 796 naphthyl C(-O) 2-propyl 3-pyridylmethyl 797 phenyl C(-O) 2-propyl benzyl 798 thiophenyl C(-O) 2-propyl benzyl 799 trifluoromethyl C(-O) 2-propyl benzyl 800 benzyl C(-0)CH2 2-propyl benzyl 801 2-pyridylavethyl C(-0)NH 2-butyl 3-pyridyl methyl 802 benzyl C(-0)HH 2-butyl benzyl 803 benzyl C(-0)NH 2-butyl benzyl 804 benzyl C(-0)NH cyclobutyl 4-pyridyl methyl 80S benzyl C(-0)NH cyclobutylmethy 1 benzyl 806 methyl C(-0)NH JL 2-butyl benzyl 807 phenylethyl C(-0)HH 2-butyl benzyl 808 benzyl C(-0)NHHH 2-propyl benzyl 809 benzyl C(-0)0 2-propyl benzyl cyclopropylmethyl benzyl methyl 2-butyl 2-butyl 2-butyl 2-propyl benzyl benzyl benzyl benzyl benzyl 2-propyl 2-propyl 2-butyl benzyl benzyl benzyl cd ro 2-butyl 2-(methyl-amlno)ethyl 2-furanylmethyl 2-propyl 2-propyl eyelohexyle thyl nonafluorob utyl phenyl trifluorome thyl 2,4- difluorophe nyl Oj CO Cm vo Ln Ex. R1 No. 810 benzyl 811 benzyl 812 benzyl M 813 2-pyridylmethyl oo u> 814 3-methylpropyl 815 benzyl 816 benzyl w r3 C("«S) 2-propyl C(-S)NH 2-propyl C(CI)"N 2-propyl C(NHMe)-N 2-propyl C(NHMe)-N 2-propyl C(NHMe)-N 2-propyl C(NHMe)-N 2-propyl r4 r8 benzyl 2-propyl benzyl 2-propyl benzyl 2-propyl benzyl 2-propyl benzyl 2-propyl benzyl 2-propyl benzyl 3-hydroxy-l- propyl rlo 4 • — methylpheny 1 4' — methylpheny 1 4 1 — methylpheny 1 4'" a> methylpheny to 1 4 methylpheny 1 4' — methylpheny 4 ' — methylpheny 1 r-o CO O-J vo <_n Ex.
No.
R1 R3 R4 817 2-pyridylethyl C(OCH2CH3) -N 2-propyl benzyl 818 3-naphthylmethyl C{OCH2CH3) -N 819 4*-t-butylb8nzyl C(OCH2CH3) oo 820 821 822 823 824 825 ,<'<> —* /0\\ o 82®' \\ : c: ^ CD Srj O *"/j iS °' benzyl benzyl benzyl benzyl benzyl benzyl benzyl «N C(OCH2CH3) -N C(OCH2CH3) -N 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl cyclobutyl benzyl benzyl benzyl 4' - ytrifluoromethylbenzyl 4 1 — chlorobenzyl 2-propyl cyclohexylmet hyl benzyl C(OCH2CH3) -N C(OCH2CH3) -N C(OCH2CH3) -N C(OCK2CH3) cyclobutylmethy benzyl -N 1 C(OCH2CH3) cyclopropyl benzyl -N R8 cyclobutyl cyclopropyl methylthiomethyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl R10 4' - methylpheny 1 benzyl cyclohexyle thyl methyl nona£luorob utyl phenyl phenyl phenyl 2-(dimethylamino) ethyl 2-butyl phenyl phenyl Ex.
No. w 827 828 829 830 831 benzyl benzyl benzyl benzyl benzyl c(och3)-n ch20ch2 ch2ch2 ch2choh ch20 832 833 cd cn 834 835 benzyl benzyl benzyl benzyl CH20H ch-ch ch0hch2 chohchok 836 benzyl HNC(-S)NH 837 838 2 8%.
C rn\ cn ^ >o benzyl benzyl benzyl benzyl hns02 hnso2nh n-n nh-nh 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-butyl 2-butyl 2-propyl 2-propyl A R4 R8 R10 benzyl 2-butyl phenyl benzyl benzyl phenyl benzyl CH2CH2OH phenyl benzyl cyclobutyl phenyl benzyl cyclohexylmethyl trifluorome thyl benzyl cyclopropyl trifluorome thyl benzyl 2-butyl trifluorome thyl benzyl 2-butyl trifluorome thyl benzyl 2-butyl 2- pyridylethy i benzyl 2-butyl X 2- pyridylmeth yi benzyl 2-butyl benzyl benzyl 2-butyl benzyl benzyl 2-butyl benzyl benzyl 2-butyl benzyl CO O-J vO on 00 o> 841 <-ch2ch2ch2ch2ch2) 842 (-CH2CH2OCH2CH2-) 843 2-hydrosy-indanylmethyl 844 3,5-dlmethoxyphenyl 845 3-hydroxy-n- propyl 846 4,-nitrobenzyl 847 4-benzyloxy-phenylraethyl nhc(-o)nh nhc(-0)nh nhc(-0)nh nhc(-o)nh nhc(-0)nh nhc(-o)nh nhc(-0)nh 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 848 4-cyano-n-butyl 849 4-phenoxy-phenylnethyl 850 4-t-butylphenyl-mothyl 851 adanantyl 852 benzyl 853 benzyl 854 benzyl nhc(-o)nh nhc(-0)nh nhc<-0)nh nhc(-0)nh nhc(-0)nh nhc("o)nh nhc("o)nh 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-propyl R4 benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl 2-butyl n-propyl 2-butyl 2-butyl naphthyl phenyl 2-butyl cyclopropyl 2-butyl 2-butyl cyclobutyl cyclopropyl thlophenyl trifluorome thyl benzyl 2- pyridylmeth yl benzyl benzyl 00 cr* cyclobutyl benzyl 2-propyl 2-butyl 2-butyl 2-propyl benzyl methyl phenylethyl benzyl fO Isi OD O-J vO en Ex.
NO.
R1 r3 855 benzyl NHC(-0)NH 2-propyl 856 benzyl NHC(-0)NH 2-propyl 857 benzyl NHC<-0)NH 2-propyl cd -J 858 859 benzyl benzyl nhc("O)nh 2-propyl nhc(-0)nh 2-propyl 860 benzyl NHC(-0)NH 2-propyl 861 862 benzyl benzyl NHC(-0)NH 2-propyl NHC("OJNH 2-propyl f 5 cr , C> "A ^ O NO ^-863 fn r 2r ' .O// benzyl NHC(-0)NH 2-propyl r4 R8 rIO 2- naphthylmethy 1 3- naphthylmethy 1 1- adamantylmeth ul 4' - hydroxybenzyl 2- imidazolyleth yi 4- pyridinylmeth yi 4-bromophenyl cycloheptylme thyl 2-thiophenyl-methyl 2-propyl benzyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-butyl benzyl benzyl benzyl benzyl 2-pyridylmethyl . 3-methyl-propyl benzyl benzyl 2-pyridyl-ethyl od ro oj oo o>J \Q en tlA • NO. 864 865 866 867 868 869 870 871 872 873 874 875 876 R1 W R3 R« R8 benzyl NHC(-0)NH 2-propyl 3-pyrrazolyl 2-butyl methyl benzyl NHC(-O)NH benzyl benzyl 2-butyl benzyl NHC(-0)NH CH2CF3 benzyl cyclobutyl benzyl NHC(-0)NH CH2CH2C(-0)NH2 benzyl cyclobutylmethyl benzyl NHC(~0)NH CH2CH2OH benzyl 2-butyl benzyl NHC(-0)HH CH2CHOHCH3 benzyl 2-butyl benzyl NHC(-0)NH cyclobutyl benzyl 2-propyl benzyl NHC(-O)NH cyclobutyl benzyl 2-propyl benzyl NHC (-O) NH cyclobutylmethy 1 benzyl 2-propyl benzyl NHC(-0)NH cyclopentylmeth benzyl 2-propyl yi benzyl NHC(-0)NH cyclopropyl benzyl 2-propyl benzyl NHC(«0)NH cyclopropylmeth benzyl 2-propyl yi NHC(-O)NH 2-butyl benzyl 2-propyl decahydronaphthy lraethyl a> VO 877 878 879 880 881 882 883 884 885 886 887 cis-2- decahydronaphthy Inethyl benzyl (ch2ch2ch) ch2ch2 1-piperidylethyl 2- benrimidazolylme thyl 2-naphthy Inethyl 2-pyridylmethyl 2- quinazolinylmeth yi 3,4-methyle- nedioxyphenylmet hyl 3-chlorobenzyl 3-phenylpropyl hhc(-0)nh O oc(-0)nh 0c(-0)nh oc(-o)nh 0c(-0)nh oc (-o) nh oc (—o) nh oc (-o)nh 0c(-0)nh oc(—o)nh 2-butyl 2-propyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 888 4' - acetantidobenzyl oc (-0) nh 2-butyl r< benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl 2-propyl benzyl 2-propyl 2-propyl 2-propyl 2-propyl benzyl benzyl benzyl benzyl 2-propyl 2-propyl 2-propyl benzyl benzyl benzyl CD u> 2-propyl benzyl cyclobutyl cyclobutylmethyl cyclopropyl benzyl (ch2ch2ch2ch 2ch2-> (ch2ch2och2c h2-> fO U-J CX) Ovl VO U1 • • Ex.
No.
R1 889 4- 0C<-0)NH Imida zolylmethy 1 890 4- OC("O)NH methanesulfonylb enzyl 891 4-methoxybenzyl OC(-O)NH 892 4-pyridylmethyl 0C(«0)NH U) o 893 4- trifluoromethylb enzyl 894 9- fluorenylmethyl 895 adamanty lmethyl OC(-O)NH OC(—O)NH OC(-O)NH R3 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl R4 benzyl benzyl benzyl benzyl benzyl benzyl benzyl 896 benzyl ^ /on ft « T- I OC(-O)NH l-methoxy-2-propyl benzyl R8 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl Rl° 2-hydroxy-indanylmeth yi 3,5- dimethoxyph enyl 3-hydroxy-n-propyl 4 '-nitro- benzyl M V£> 4-benzyl- ° oxyphenylme thyl 4-cyano-n- butyl 4-phenoxy- phenylmethy 1 4-t-butyl- phenylmethy 1 U-J CD Ovl vO LT! • • id Ex.
No. 897 898 899 900 901 902 903 904 905 906 R1 benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl 0C(-0)NH OC(-0)NH OC (-0) NH OC (-0) NH 0C(-0)NH 0C(-0)NH OC (-0) NH 0C(-O)NH OC ("O) NH 0C(-0)NH R3 2' - hydroxycyclopen tylraethyl 2,2,2- trichloroethyl 2,2,2- trifluoroethyl 2-butyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl R4 benzyl benzyl benzyl benzyl benzyl benzyl 3- naphthylmethy 1 4' — phenoxybenzyl 41 - benzyloxybenz yi 4 * — (5— tetrazolyl)be nzyl R0 RlO 2-propyl adamantyl 2-propyl benzyl 2-butyl benzyl 2-butyl 2-propyl 2-propyl 2-butyl benzyl benzyl benzyl benzyl so 2-butyl 2-butyl benzyl benzyl 2-butyl benzyl r-o o-j co o-j VO (_n 907 908 909 910 911 M VO N> 912 913 914 915 916 917 R1 W R3 benzyl 0C("0)NH 2-propyl benzyl OC("O)NH 2-propyl benzyl OC(-O)NH 2-propyl benzyl OC(-0)NH 2-propyl benzyl OC(«K»NH 2-propyl benzyl 0C(-0)NH 2-propyl benzyl OC(-0)NH 2-propyl benzyl OC(-O)NH 3- (dimethylamino) -1-propyl benzyl OC(—O)NH benzyl benzyl 0C(-0)NH CH2NHC(-O)NHCH3 benzyl OC(-0)NH CH2NHS02CH3 r4 r8 r!0 3',5'- bis(trifluore inethyl) benzyl 4'-trifluoromethylbenzyl 2-phenylethyl 2-benzirni-dazolylmethyl 2-(4-chlorophenyl) ethyl 2- decahydrona-phthyImethyl 2-(3,4-methylenediox yphenyl)ethyl benzyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl vo N> benzyl benzyl benzyl 2-butyl 2-propyl 2-propyl benzyl benzyl benzyl rO oj oo OvJ vo on • • Ex.
No.
R1 h R3 918 919 920 921 922 benzyl benzyl benzyl benzyl benzyl 0C(~O)NH cyclobutyl 0C("O)NH cyclobutylmethy 1 OC(-0)NH cyclopropyl OC(-O)NH cyclopropylmeth yi 0C{-0)NH inethyl W 923 CH3S02CH2CH2 0C(-0)NH 2-butyl 924 cyclopentylethyl OC(-O)NH 2-butyl 925 F2HC0C6H4CH2 0C(-0)NH 2-butyl 926 927 benzyl benzyl OCH2 OP (-O) (OMe )0 2-propyl 2-propyl R8 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl benzyl R10 benzyl benzyl benzyl benzyl cis-2-decahydrona phthylmethy 1 cis-2-decahydrona phthylmethy 1 benzyl (CH2CH2CH)CH 2ch2 1-piper-ldylethyl 2-benzi-mldazolylme thyl Ex. R1 No. 928 benzyl 930 2,4- di £luorophenyl 931 4•-methylphenyl 932 benzyl 933 benzyl 934 benzyl 936 benzyl W R3 S02 2-propyl s02nh 2-butyl s02nh 2-butyl s02nh 2- (roethylamino)et hyl S02nh 2-furanylroethyl s02nh 2-propyl s02nh 2-propyl R4 benzyl benzyl benzyl benzyl benzyl benzyl benzyl R8 R10 ch2cf3 ch2ch2c(-0)nh2 ch2ch2oh ch2chohch3 cyclobutyl cyclobutyl cyclobutylmethyl 2-naphthylmethyl 2-pyridyl-methyl 2-quina-zolinylmeth yi 3,4— methylenedi oxyphenylme thyl 3- chlorobenzy 1 3- phenylpropy 1 4 ' — acetamidobe nzyl Ex.
No.
Rl r3 r4 r8 RlO IS Tt\ V H 937 938 939 940 vo 941 942 943 *- ^ 944 <© C 2 CH >o M, m)1 Z! V / benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl S02NH so2nh so2nh so2nh so2nh so2nh so2nh so2nh so2nh so2nh 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 3'- cyclopentylmethyl trifluorometh ylbenzyl 2',4'- cyclopropyl difluorobenzy 1 3— cyclopropylmethyl phenylpropyl 1- pyrrolylethyl 2-<4- chlorophenyl) ethyl 1-phenylethyl 3-hydroxy-l- 1-phenylethyl propyl cyclobutyl benzyl cyclopropyl benzyl methylthiomethy 1-phenylethyl 1 2-butyl 2-butyl 2-propyl 2-butyl 2-butyl 2-butyl 2-butyl 4- imidazolylm ethyl 4- methanesulf onylbenzyl 4-methoxy-benzyl 4-pyridylmethyl 4- trifluorome thylbenzyl 9- fluorenyl-roothyl adamantyl-methyl benzyl benzyl benzyl Ln 3 0 *3 O // b A ro o-i OO vp c Ex.
No.
R1 R3 947 cyclohexylethyl 948 nonafluorobutyl 949 phenyl 950 trifluoromethyl 951 2,4- difluorophenyl 952 4'-methylphenyl 953 4' -methylphenyl 954 4'-methylphenyl 955 4 *-methylphenyl 956 4•-methylphenyl 957 4•-methylphenyl ^ 95§ 4' -methylphenyl * \ u> a\ m & § * SO V./ - o y ^ S so2nh so2hh so2nh so2hh s02nhc (-o) nh so2nhc <-0> nh sojnhc (-o) nh SOjNHC (-O) NH S02NHC(-0) NH S02NHC(-0) NH s02nhc (-0) nh s02nhc(-co nh 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2- (dlmethylamlno) ethyl 2-butyl 2-butyl benzyl CH2CH2OH cyclobutyl cyclohexylraethy 1 R4 benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl R8 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl rIO benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl Ex.
No.
R1 W R3 959 4'-methylphenyl S02NHC (-O) NH 960 benzyl S02NHC<-0) NH 961 cyclohexylethyl S02NHC(-O) nh 962 inethyl S02NHC(-0) NH 963 nonafluorobutyl S02NHC{"0) \o 964 965 966 967 <96,8 £ t) cry sr phenyl phenyl phenyl phenyl phenyl O nh s02nhc(-0) nh so2nhc (-o) nh s02nhc(-0) nh s02nhc (-o) nh s02nhc(-0) nh cyclopropyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl R4 R8 R10 benzyl benzyl benzyl benzyl benzyl benzyl benzyl 2' - chlorobenzyl 3- naphthylmethy 1 2- (4- fluorophenyl) ethyl 2-butyl benzyl l-methoxy-2- benzyl propyl 21-hydroxy- benzyl eyelopentylmethyl 2,2,2- benzyl trichloroethyl 2,2,2- benzyl trifluoroethyl 2-butyl benzyl 2-propyl benzyl 2-propyl benzyl 2-propyl benzyl 2-propyl benzyl H VO CO Osl vO U" • • Ex.
No.
R1 H R3 969 970 phenyl phenyl S02NHC(-O) NH S02NHC <-0) NH 2-butyl 2-butyl «© cd 971 phenyl S02NHC(-0) 2-butyl NH 972 phenyl SOjNHCC-O) cyclopropyl NH 973 trifluoromethyl SO2NHCI-O) 2-butyl NH 974 trifluoromethyl S02NHC("0) 2-butyl NH 975 trifluororaethyl S02NHC(-0) cyclobutyl NH 976 trifluoromethyl S02nhc(~0) cyclopropyl NH £ * ^ cr o m 1 R^ R8 r10 2-phenylethyl 2-propyl benzyl 3'- carbomethoxy-benzyl benzyl 2-propyl 2-propyl benzyl CH3S02CH2CH2 benzyl benzyl benzyl benzyl 2-propyl 2-propyl 2-propyl 2-propyl cyclopentyl ethyl F2HCOC6H4CH2 benzyl benzyl to oo benzyl 2-propyl benzyl r-O O-J OO O-J VO U1 • • TABLE XVI vo vo N.
—I Ex.
R1 W R3 No. 977 2-pyridylethyl C(-O) 2-propyl 978 2-pyridylmethyl CC-O) 2-butyl 979 benzyl C(-O) 2-butyl 980 2-pyridyl-methyl C(-O) 2-propyl 981 benzyl C(-O) 2-propyl 982 3-pyridyl-methyl C(-O) 2-propyl 983 n-propyl C<-0) 2-propyl 984 naphthyl C(-O) 2-propyl 985 phenyl C<-0) 2-propyl 986 thiophenyl C(-O) 2-propyl 987 trifluoromethyl C<-0) 2-propyl 988 benzyl C(-0)CH2 2-propyl 989 2-pyridylmethyl C(-0)NH 2-butyl 990 benzyl C(-0)NH 2-butyl 991 benzyl C(-0)NH 2-butyl 992 benzyl C(-0)HH cyclobutyl 993 benzyl C<-0)HH cyclobutylmethyl 7\\ R® R4 R8 benzyl t-butyl 4-imidazolylmethyl t-butyl cyclohexylmethyl t-butyl benzyl t-butyl 2-pyridyl-methyl t-butyl benzyl t-butyl benzyl t-butyl 3-pyridyl-methyl t-butyl benzyl t-butyl benzyl t-butyl 3-pyridyl-methyl t-butyl benzyl t-butyl 2-pyridyl-methyl t-butyl 3-pyridyl-methyl t-butyl benzyl t-butyl benzyl t-butyl benzyl t-butyl to o o >■<? « cr . * £? VO Ex. Rl No. 994 methyl 995 phenylethyl 996 benzyl 997 benzyl 998 benzyl 999 benzyl 1000 benzyl 1001 2-pyridylmethyl 1002 3-methylpropyl 1003 benzyl 1004 benzyl 1005 2-pyridylethyl 1006 3-naphthylmethyl 1007 4•—t—butylbenzyl 1008 benzyl 1009 benzyl fJ. 1010 1011 1012 1013 /C A -cY- •A m benzyl benzyl benzyl benzyl 3 3 V* ih w R3 C(-0)NH 2-butyl C(-0)NH 2-butyl C(-0)NHNH 2-propyl C(-0)0 2-propyl c<-s> 2-propyl C(-S)NH 2-propyl C(CI)—N 2-propyl C(NHMe)-N 2-propyl C(NHMe)—N 2-propyl C (NHMe) ™N 2-propyl C (NHMe) "N 2-propyl C(OCH2CH2) 2-propyl -N C(OCH2CH2) 2-propyl -N C(OCH2CH2) 2-propyl -N C(OCH2CH2) 2-propyl -N C(OCH2CH2) 2-propyl -N C(OCH2CH2) 2-propyl -N C(OCH2CH2) 2-propyl -N C(OCH2CH2) cyclobutyl -N C(OCH2CH2) cyclobutylmetl -N R4 3-pyridyl-methyl benzyl 3-pyridyl-methyl benzyl benzyl 3-pyridyl-methyl benzyl benzyl benzyl benzyl 3-pyridyl-methyl benzyl benzyl 3-pyridyl-methyl benzyl 4 1 - ytrifluoromethylbenzyl 4'-chlorobenzyl cyclohexylmethyl benzyl 3-pyridyl-methyl R8 t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl Ex. Rl W r3 No. 1014 benzyl c(och2ch2) aU cyclopropyl 101s benzyl "n c(0ch2)-n 2-propyl 1016 benzyl ch2och2 2-propyl 1017 benzyl ch2ch2 2-propyl 1018 benzyl chJchoh 2-propyl 1019 benzyl ch2o 2-propyl 1020 benzyl ch2oh 2-propyl 1021 benzyl ch-ch 2-propyl 1022 benzyl chohch2 2-propyl 1023 benzyl chohchoh 2-propyl 1024 benzyl hnc(-s)nh 2-propyl 1025 benzyl hnso2 2-butyl 1026 benzyl hns02nh 2-butyl 1027 benzyl n-n 2-propyl 1028 benzyl nh-nh 2-propyl 1029 <-ch2ch2ch2ch2ch2-\ nhc(-0)nh 2-butyl 1030 t <-ch2ch2och2ch2-) nhc(—o)nh 2-butyl 1031 2-hydroxyindanyl- nhc(—o)nh 2-butyl methyl 1032 3,5- nhc(-0)nh 2-butyl dimethoxyphenyl 1033 3-hydroxy-n-propyl nhc("o)nh 2-butyl 1034 4'-nitrobenzyl nhc(-0)nh 2-butyl 1035 4-benzyloxypheny- nhc(—o)nh 2-butyl lmethyl 1036 4-cyano-n-butyl nhc(—o)nh 2-butyl R4 benzyl benzyl 3-pyridyl-methyl benzyl 4-pyridyl-methyl benzyl 2-pyridyl-methyl benzyl 3-pyridyl-methyl benzyl 4-pyridyl-methyl benzyl benzyl benzyl 4-pyridyl-methyl benzyl 4-pyridyl-methyl benzyl 4-pyridyl-methyl benzyl benzyl 4-pyridyl-methyl benzyl R8 t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl Ex. Rl W No. 1037 4-phenoxyphenyl- NHC(-0)NH methyl 1038 4-t-butylphenyl- NHC(-o)NH inethyl 1039 adamanty1 NHC<-0)NH 1040 benzyl NHC(-0)NH 1041 benzyl NHC(-0)NH 1042 benzyl NHC(-0)NH 1043 benzyl NHC(-0)NH 1044 benzyl NHC(-0)NH 1045 benzyl NHC(-0)NH 1046 benzyl NHC(-0)NH 1047 benzyl NHC<-0)NH 1048 benzyl NHC(-0)NH 1049 benzyl NHC<-0)NH 1050 benzyl NHC(-0)NH 1051 benzyl NHC(-0)NH 1052 benzyl NHC(-0)NH 1053 benzyl NHC(-0)NH 1054 benzyl NHC(-0)NH 1055 benzyl NHC(-0)NH 1056 benzyl NHC(-0)NH 1057 benzyl NHC(-O)NH 1058 benzyl NHC(-0)NH 1059 benzyl NHC(-0)NH 1060 benzyl NHC(-0)NH 1061 benzyl NHC(-0)NH R3 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl benzyl ch2cf3 ch2ch2c(-0)nh2 ch2ch2oh ch2chohch2 cyclobutyl cyclobutyl cyclobutylmethyl cyclopentylmethy 1 R8 benzyl t-butyl benzyl t-butyl benzyl t-butyl 4-pyrIdyl-methyl t-butyl benzyl t-butyl 3-pyridyl-methyl t-butyl 2-naphthylmethyl t-butyl 3-naphthylmethyl t-butyl l-adamantylmethul t-butyl 4•-hydroxybenzyl 2-propyl 2-imidazolylethyl 2-propyl 4-pyridinylmethyl 2-propyl 4-bromophenyl 2-propyl cycloheptylmethyl 2-propyl 2-thiophenylmethyl 2-propyl 3-pyrrazolylmethyl 2-propyl benzyl benzyl 2-propyl benzyl 2-propyl benzyl 2-propyl benzyl 2-propyl 4-pyridyl-methyl 2-propyl benzyl 2-propyl benzyl 2-propyl 3-pyridyl-methyl 2-propyl Ex. NO.
R1 W N> O u> 1062 benzyl 1063 benzyl 1064 cis-2-decahydronaphthylm ethyl 1065 cls-2-decahydronaphthylm ethyl 1066 benzyl 1067 (CH2CH2CH)CH2CH2 106B 1-piperldylethyl 1069 2-benzlralda zolylroeth yi 1070 2-naphthylraethyl 1071 2-pyridylmethyl 1072 2-quinazolinylmethyl 1073 3,4-methylenedioxyphen ylmethyl 1074 3-chlorobenzyl 1075 3-phenylpropyl 1076 4• -acetantidobenzyl 1077 4-imidazolylmethyl 1078 4-methaneaulfonylben zyl 4-methoxybenzyl nhc(~0)nh nhc(-0)nh nhc <-0)nh nhc (-o) nh O 0c(~0)nh oc("o)nh oc(—0)nh oc (—o) nh oc(—o)nh oc(-0)nh oc(-o)nh oc("o)nh oc («*0) nh 0c(-0)nh 0c(-0)nh oc(-0)nh 0c(-0)nh R3 cyclopropyl cyclopropylmethy 1 2-butyl 2-butyl 2-propyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl R4 R8 benzyl benzyl 3-pyridyl-methyl benzyl 2-propyl 2-propyl 2-propyl 2-propyl benzyl 3-pyridyl-methyl benzyl benzyl 2-propyl 2-propyl 2-propyl 2-propyl benzyl 3-pyridyl-methyl benzyl benzyl 2-propyl 2-propyl 2-propyl 2-propyl K> o CO benzyl 3-pyridyl-methyl benzyl benzyl benzyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl benzyl 2-propyl -o Co (-v vO • • Ex, R1 M R3 No. 1080 4-pyridylmethyl 0C(-0)NH 2-butyl 1081 4- OC(—O)NH 2-butyl trifluoromethylben zyl 1082 9-fluorenyInethyl OC ("0) NH 2-butyl 1083 adamantyImethyl OC (-O) NH 2-butyl 1084 benzyl OC (-0) NH l-methoxy-2- propyl 1085 benzyl OC ("O) NH 2'- hydroxycyclopent ylmethyl 1086 benzyl OC (—O) NH 2,2,2- trichloroethyl 1087 benzyl 0C(-O)NH 2,2,2- trifluoroethyl 1088 benzyl OC (—0) NH 2-butyl 1089 benzyl OC (—O) NH 2-propyl 1090 3-pyridyl-methyl OC (—O) NH 2-propyl 1091 3-pyridyl-methyl OC (—O) NH 2-propyl 1092 benzyl 0C(-O)NH 2-propyl 1093 benzyl OC (—O) NH 2-propyl 1094 benzyl 0C(-0)NH 2-propyl 1095 benzyl OC(—O)NH 2-propyl 1096 benzyl OC (—O) NH 2-propyl 1097 benzyl OC (~0) NH 2-propyl 1098 benzyl OC(—O)NH 2-propyl 1099 benzyl OC(-O)NH 2-propyl R4 R0 benzyl benzyl benzyl benzyl benzyl benzyl 2-propyl 2-propyl 2-propyl lso-butyl lso-butyl iso-butyl benzyl lso-butyl benzyl iso-butyl benzyl iso-butyl 3-pyridyl-methyl iso-butyl benzyl iso-butyl 3-naphthyImethyl iso-butyl 4'-phenoxybenzyl iso-butyl 41-benzyloxybenzyl iso-butyl 4(5-tetrazolyl)benzyl iso-butyl 3',5'- iso-butyl bis(tri£luoremethyl)benz yi 4*-trifluoromethylbenzyl iso-butyl 2-phenylethyl iso-butyl 2-benzimidazolylmethyl iso-butyl 2-(4-chlorophenyl)ethyl iso-butyl Ex.
R1 W R3 No. 1100 benzyl oc(—0)nh 2-propyl 1101 benzyl 0c(«*0)nh 2-propyl 1102 benzyl oc (-0) nh 3- (dimethylamino)- 1-propyl 1103 benzyl oc (-o)nh benzyl 1104 benzyl 0c(-0)nh ch2nhc(-0)nhch2 1105 benzyl oc(-0)nh ch2nhso2ch2 1106 benzyl 0c{-0)nh cyclobutyl 1107 benzyl oc(-0)nh cyclobutylmethyl 1100 benzyl oc("0)nh cyclopropyl 1109 benzyl oc (-0) nh eyelopropyImethy 1 1110 benzyl oc (-o)nh X methyl 1111 ch2so2ch2ch2 oc (-o) nh 2-butyl 1112 cyclopentylethyl 0c(-0)nh 2-butyl 1113 F2HCOC6H4CH2 oc (-o) nh 2-butyl 1114 benzyl 0CH2 2-propyl 1115 benzyl OP (-O) (OMe 10 2-propyl 1116 benzyl 1 v s02 2-propyl 1117 2,4-difluorophenyl so2nh 2-butyl 1118 4•-methylphenyl so2nh 2-butyl 1119 benzyl so2nh 2- (methylamino)eth yi 2- iso-butyl decahydronaphthylmethyl 2-(3,4- iso-butyl methylenedioxyphenyl)eth yi benzyl iso-butyl benzyl 3-pyridyl-methyl benzyl 3-pyridyl-methyl benzyl benzyl 3-pyridyl-methyl benzyl 3-pyridyl-methyl benzyl 3-pyridyl-methyl benzyl 3-pyridyl-nvethyl benzyl benzyl benzyl benzyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl O cn !\> Uj CD U; VO O7 Ex. r1 w No. 1120 benzyl so2nh 1121 3-pyridyl-methyl so2nh 1122 benzyl so2nh 1123 3-pyridyl-methyl so2nh 1124 benzyl so2nh 1125 benzyl so2nh 1126 benzyl so2nh 1127 2-pyridyl-methyl so2nh 1128 benzyl so2nh 1129 3-pyridyl-methyl so2nh 1130 benzyl so2nh 1131 benzyl so2nh 1132 benzyl so2nh 1133 2-pyridyl-methyl so2nh 1134 nonafluorobutyl so2nh 1135 phenyl so2nh 1136 trifluoromethyl so2nh 1137 2,4-difluorophenyl s02nhc(-< nh 4 ' -inethylphenyl SO^NHC (—O) nh 4 • -inethylphenyl S02NHC (-O) nh 4•-methylphenyl S02nhc(-0) NH 4'-methylphenyl s02nhc(-0) NH 1138 1139 1140 1141 R3 2-furanylmethyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 2-propyl 3-hydroxy-l-propyl cyclobutyl cyclopropyl methylthiomethyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2- (dimethylamino)e thyl 2-butyl 2-butyl benzyl R4 R8 benzyl 3-pyridyl-methyl benzyl 3•-trifluoromethylbenzyl 2 *,4•-difluorobenzyl 3-phenylpropyl 1-pyrrolylethyl 2-(4-chlorophenyl)ethyl 1-phenylethyl 1-phenylethyl benzyl benzyl 1-phenylethyl benzyl benzyl benzyl benzyl benzyl benzyl iso-butyl iso-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl fo o cn 2-pyridyl-methyl benzyl 2-pyridyl-methyl t-butyl t-butyl t-butyl '~V> Uf Co- VO C-7 NJ O -J Ex.
R1 w No. 1142 4'-methylphenyl S02NHC<-0) NH 1143 4'-methylphenyl S02NHC (-O) NH 1144 4•-methylphenyl S02NHC(-0) NH 1145 4'-methylphenyl S02NHC(-O) NH 1146 benzyl S02NHC (-O) NH 1147 cyclohexylethyl SOjNHC(-O) NH 1146 methyl S02NHC(-O) NH 1149 nona fluorobutyl S02NHC (-O) NH 1150 phenyl S02NHC(-O) NH 1151 phenyl S02NHC (-O) NH 1152 phenyl S02NHC (~O) NH 1153 phenyl S02NHC(-O) NH 1154 phenyl S02NHC(-O) NH 1155 phenyl S02NHC ("O) NH 1156 phenyl S02NHC (-0) NH R3 CH2CH2OH cyclobutyl cyclohexylmethyl cyclopropyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-butyl 2-bUtyl 2-butyl 2-butyl 2-butyl R4 R8 benzyl t-butyl benzyl t-butyl benzyl t-butyl 2-pyridyl-methyl t-butyl benzyl t-butyl benzyl t-butyl benzyl t-butyl 2-pyridyl-methyl t-butyl benzyl t-butyl benzyl t-butyl 2 '-chlorobenzyl t-butyl 3-naphthylmethyl t-butyl 2-(4-fluorophenyl)ethyl t-butyl 2-phenylethyl t-butyl 3' -ca rbomethoxybenzyl t-butyl Cai CO Ow vo Ln M O co Ex. Rl NO. 1157 phenyl 1158 phenyl 1159 trifluoromethyl 1160 trifluoromethyl 1161 trifluoromethyl 1162 trifluoromethyl 1163 Bonximidazolylmeth yi 1164 Benxiraidazolylmeth yi 1165 (CH2)2NCH-(CH2) 1166 2-amino-2-propyl 1167 dimsthylaninomethy 1 1168 dimethylaminomethy 1 1169 4-amino-benzoyl w R3 s02nhc(«0) 2-butyl nh s02hhc(»0) cyclopropyl nh s02nhc(-0) 2-butyl nh s02nhc(-0) 2-butyl nh s02nhc(-0) cyclobutyl nh s02nhc(-0) cyclopropyl nh N(ch2)c(-0 2-propyl ) nh nc<-0)nh 2-propyl c(-0)nh 2-propyl c(-0)nh cf3 c(-0)nh 2-propyl c(-0)nh 2-propyl c(-0)nh 2-propyl R4 R8 benzyl 2-pyridyl-methyl benzyl benzyl 2-pyridyl-methyl benzyl 4-pyridyl-methyl 4-pyridyl-methyl 4-fluoro-benzyl benzyl benzyl benzyl benzyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-prbpyl t-butyl N> o oo -'--o CD UsI O"? *38395 209 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 Materialr: HIV gag polyprotein corresponding to all of pl7 and 78 amino acids of p24, produced by in vitro translation using rabbit reticulocyte lysate and mRNA prepared in 10 vitro from plasmid encoding full length gag polyprotein linerized with the restriction enzyme Pst 1. (See S. Erickson-Viitanen fit 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 20 protease under the control of the T7 promotor (Cheng fit &1., Gene, in press (1990). Such inclusion bodies were solubilized in 8 M 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 25 Acetate, pH 5.5, ImM 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 anM stock concentration. All further 30 dilutions were done in DMSO.
Set Up Into sterile test tubes were placed the following: 1 uL inhibitor dilutions 209 '?jsj95 210 14 ul HIV protease in Phosphate Buffered Saline (Gibco) ul of in vitro translation products. Reactions were incubated at 30°C, then quenched by 5 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 10 were fixed, impregnated with Enhance (Du Pont NEN, Boston, MA) and dried according to manufacturers instructions (NEN). Dried fluorographs were exposed to film and/or quantitated using an Ambis radioanalytic scanner. 1 5 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 (IC50) is determined from plots of log concentration inhibitor versus % inhibition of protease 20 activity.
Biological Activity: IC50 is the concentration necessary for reducing the activity of the enzyme by 50%.
HIV YIELD REDUCTION CELL ASSAY 25 Materials : MT-2, 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 30 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 fiL al. (Science 1985 229:563-566). MTT, 3-(4,5-dimethyl- 210 \ l*AU6>99r v*a ^ "C c 5 - ? 7 n J 8 J Q r J 211 thiazol-2yl) -2,5-diphenyltetrazolium bromide, was obtained from Sigma.
Method: Test compounds were dissolved in dimethylsulfoxide 5 to 5 mg/ml and serially diluted into RPMI medium to ten times the desired final concentration. MT-2 cells (5 x 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) 10 (~5 x 10E5 plaque forming units/ml) in 0.375 ml was added to the cell and compound mixtures and incubated for one hour at 36°C. The mixtures were centrifuged at 1000 rpm for 10 minutes and the supernatants containing unattached virus were discarded. The cell pellets were 1 5 suspended in fresh RPMI containing the appropriate concentrations of test compound and placed in a 36°C, 4% C02 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 20 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 25 dilution was added to 9 ml of MT-2 cells in RPMI. Cells and virus were incubated for 3 hours at 36°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 30 and incubated overnight at 36°C, 4% C02. 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 211 -r \ *9 AUG 1991"/I *38395 212 additional 3 days at 36°C, 4% C02, a final overlay of phosphate-buffered saline with 0.75% Seaplaque agarose and lmg MTT/ml was added. The plates were incubated overnight at 36°C. Clear plaques on a purple background 5 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-2, 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-[(phenyl-amino) 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 x 10E4/0.1 ml) were added to each well of a 96 well 25 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) (-5 x 10E5 30 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°C, during which time the virus replicated and caused the death of °X ?V ':i \\-± — Oil 212 4 '9 AUG!99|", V?e *38395 213 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 5 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% (ICs0) or 90% (IC90) with respect to an uninfected cell culture was determined. 213

Claims (54)

* 238395 214 Table XVII Cell Free Cell Assay Compound ♦ Assay IC5o ic90 Example 1A 12 2* 6* Example IB 37 5* NA Example 2A 12 10 30 Example 2B 0.17 1.9 3.0 Example 2C 31 — _ Example 3 383 — Example 4 435 — Example 5 65 _ — Example 6 4.8 NA NA Example 7 502 Example 8 590 Example 9 0.52 NA NA Example 10 600 _ Example 11 20 NA NA Example 12 4.1 NA NA Example 13 3.3 2.3 25 Example 14 480 NA NA Example 15 260 Example 16 260 _ Example 17 278 — — Example 18 2.3 6* 12* Example 20 0.01 <1 <1 Example 21 0.002 6 ~ 214 t WHAT VWE CLAIM IS: 215 238395 What is claimed is:-
1. A compound of the formula: R10 10 wherein: R1 through R4 and R7 through R10 are independently selected from the following groups: 15 20 25 hydrogen; C1-C8 alkyl substituted with 0-3 R11; C2-C8 alkenyl substituted with 0-3 R11; C3-C8 alkynyl substituted with 0-3 R11; C3-C8 cycloalkyl substituted with 0-3 R11; C6-C10 bicycloalkyl substituted with 0-3 R11; aryl substituted with 0-3 R12; a C6-C14 carbocyclic residue substituted with 0-3 R12; and a heterocyclic ring system substituted with 0-2 R12, composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom; r2a through R4A and R7A through R®A are independently selected from the following groups: 30 215 1 * 5 23839 V 216 hydrogen; C1-C4 alkyl substituted with halogen or C1-C2 alkoxy; and benzyl substituted with halogen or Ci~C2 alkoxy; R5 and R6 are independently selected from the following groups: hydrogen; 10 Ci~Cg alkoxycarbonyl; C1-C6 alkylcarbonyl; benzoyl; phenoxycarbonyl; and phenylaminocarbony; wherein said alkyl residues are 1 5 substituted with 0-3 R11, and said aryl residues are substituted with 0-3 R12; or any other group that, when administered to a mammalian subject, cleaves to form the original diol in which R5 and R6 are 20 hydrogen; R11 is selected from one or more of the following: keto, halogen, cyano, -NR13R14, -CO2R13, -0C(-0)R13, 25 -OR13, C2-C6 alkoxyalkyl, -S(0)mR13, -NHC("NH)NHR13, -C(-NH)NHR13, -C(-0)NR13R14, -NR14C (-0) R13 , -NR14C(-0)0R14, -0C(»0)NR13R14, -NR13C(-0)NR13R14, -NR14S02NR13R14, -NR14S02R13, ~S02NR13R14, C1-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C3-C6 3 0 cycloalkylmethyl, a C5-C14 carbocyclic residue substituted with 0-3 R12, 217 12 aryl substituted with 0-3 R , and •©a? a heterocyclic ring system substituted with 0-2 R12, composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom; R12, when a substituent on carbon, is selected from one or more of the following: 10 phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C3-c6 cycloalkyl, C3-C6 cycloalkylmethyl,C7-C10 arylalkyl, alkoxy, -NR13R14, C2-C6 alkoxyalkyl, C1-C4 15 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, c3-C4 haloalkoxy, c3.-c4 alkoxycarbonyl, Ci-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(0)mR13# -S02NR13R14, and -NHSO2R14; 20 or R12 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, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or 25 NR13R14; or, when R12 is attached to a saturated carbon atom it may be =0 or =S; and R12, when a substituent on nitrogen, is selected from one or more of the following: 30 phenyl, benzyl, phenethyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, , C1-C4 alkyl, C3-C6 cycloalkyl, C3-c6 cycloalkylmethyl, -NR13R14, C2- C6 alkoxyalkyl, C1-C4 haloalkyl, C1-C4 217 218 and alkoxycarbonyl, C1-C4 alkylcarbonyloxy,/C3.-C4 alkylcarbonyl, 5 R13 is H, phenyl, benzyl or C1-C6 alkyl; R14 is H or C1-C4 alkyl; or R13R14 can join to form (CH2)4, (CH2)5» 10 (CH2CH2N(R15)CH2CH2) , or (CH2CH2OCH2CH2) ; R15 is H or CH3; m is 0, 1 or 2; 1 5 n and n1 are independently 0 or 1; W and are independently selected from the following 20 -NR16C(=Q)NR16"'' -C(«Q)NR16-; ~C(-Q)0-; ~NR16C(-Q)0-; -OC ("«Q)NR1®-; 25 -NR16C(«Q)-; -C(-Q)-'' -C{-Q)CH2~; -NR16S02NR16~ -NR16S02~ 30 -SO2NR16- -SO2-; -QCH2-; -Q-; -(CH2)pNR1€-; j r«' z. r .vrr-vn 218 I IC MAR 19S4 15 238395 219 -ch2ch2-' -ch-ch-; -ch(oh)ch(oh)-' -ch(oh) CH2~; 5 -ch2ch(oh)-; -ch (oh)-; -nh-nh-; -c("o)nh-nh-; —C(CI)-N-; 10 -C(-0R16)=N-; -C(-NR16R17)=N-; -OP (-0) (Q1R16)0-; -P(=0) (Q1R16)0-; and -S02NHC ("=0) NH-; X and X1 are independently selected from the following: -c(=q)nr16-; ~C(=Q)0-; 20 -c(-q)-'* -ch2c(«q)-' -ch2c(-q)ch2-'* -c(-q)ch2-'* -so2nr16-25 -so2-; -ch2qch2-; -ch2q-; -ch2nr16-; —ch2ch2-» 30 -ch-ch-; -ch(oh)ch(oh)-' -ch(oh) ch2-; -ch2ch (oh)-; -ch(oh)-; 219 ! 15 MAR 383 220 -C (-O)NH-NH-; -C(-OR16)-N-; -C (-NR16R17)«N- ; and -C(L)«N-, wherein L represents CI or Br; 5 Y and Y1 are independently selected from the following: -C (-Q)NR16-; -(CH2)PC(-Q)NR16-; 1 0 -so2nr16-; -(CH2)pNRl6_. -C(L)«N-, wherein L represents CI or Br; -C(-OR16)-N-; -C(-NR16R17)-N-; 15 -NR12C («0)NR16-; -(CH2)pNR12C(=0)NR16-; -OC(=0)NR16-; and -(CH2)P0C(«0)NR16-; 20 R16 is H, benzyl or C1-C4 alkyl; R17 is H or C1-C4 alkyl; p is 1 or 2; 25 Q is selected from oxygen and sulfur; and Q1 is selected from oxygen, sulfur, NR14 and a direct bond; 30 and pharmaceutically acceptable salts and prodrugs thereof. 220 J if MAR : •jt V N", ... 221 23839 5
2. A compound of formula I as claimed in Claim 1 wherein: n and n^" are both 0; 1 10 R and R~ are independently selected from the following: hydrogen; Cj-Cg alkyl substituted with 0-2 R11; C2-C4 alkenyl substituted with 0-2 R11; C3-C6 cycloalkyl substituted with 0-2 R11; c6~ci0 bicycloalkyl substituted with 0-2 R11; aryl substituted with 0-3 R12; a C6-C14 carbocyclic residue substituted with 0-2 R12; and a heterocyclic ring system substituted with 0-2 R12, composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom; R3 and R8 are independently selected from the following groups: hydrogen; C1-C5 alkyl substituted with 0-2 R11; C2-C4 alkenyl substituted with 0-2 R11; and c3"c6 cycloalkyl substituted with 0-2 R11; with the proviso that the total number of non-hydrogen atoms comprising R3 is less than or equal 221 1Jf * «c# *#+ . .au 10 222 to 6, and the total number of non-hydrogen atoms comprising R8 is less than or equal to 6; R4 and R7 are independently selected from the following 5 groups: hydrogen; C1-C4 alkyl substituted with 0-3 R11; and C2-C3 alkenyl substituted with 0-3 R11; R3A, R4a, R7a and R8a are independently selected from the following groups: hydrogen; and 15 C1-C2 alkyl; R5 and R6 are independently: oclcctcd from the following- 20 hydrogen, or any other group that, when administered to a mammalian subject, cleaves to form the original diol in which R5 and R6 are hydrogen; 25 R11 is selected from one or more of the following: keto, halogen, cyano, -NR13R14, -CO2R13, -OC (-O)R13, -OR13, C2-C6 alkoxyalkyl, -S(0)mR13, -NHC(»NH)NHR13, -C(-NH)NHR13, -C(-0)NR13R14, -NR14C (-0) R13, 30 -NR14C(-0)0R14, -0C(-0)NR13R14,-NR13C<-0)NR13R14, -NR14S02NR13R14, -NR14S02R13f "S02NR13R14, C1-C4 alkyl, C2-C4 alkenyl, C3-CS cycloalkyl, C3-C6 cycloalkylmethyl; i> -a i 222 Vr § 10 30 238395 a C5-C14 carbocyclic residue substituted with 0-3 R12; aryl substituted with 0-3 R12; and -©* a heterocyclic ring system substituted with 0-2 R12, composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom; R12, when a substituent on carbon, is selected from one or more of the following: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, 1 5 halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C3-C5 cycloalkyl, C3-C6 cycloalkylmethyl,C7-C10 arylalkyl, alkoxy, -NR13R14, C2-C6 alkoxyalkyl, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, Ci- 20 C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 and alkylcarbonylamino, -S(0)mR13, -S02NR13R14,/-NHS02R14; or R12 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-25 membered ring, said 5- or 6- membered ring being optionally substituted on the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or NR13R14; or, when R12 is attached to a saturated carbon atom it may be =0 or =S; and R12, when a substituent on nitrogen, is selected from one or more of the following: 223 ^ J-) 224 benzyl, hydroxy, C1-C4 alkoxy, Ci~C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, and C1-C4 alkylcarbonyl; 5 R13 is H, benzyl or C1-C4 alkyl; R14 is H or C1-C4 alkyl; 10 or R13R14 can join to form (CH2M, (CH2)5, (CH2CH2N(R15)CH2CH2), or (CH2CH2OCH2CH2); R15 is H or ch3; 15 m is 0, 1 or 2; W and W1 are independently selected from the following: -NR16C(«Q)NR16-' 20 -C ("Q) NR16-; -0C(-Q)NR16-; -NR16S02NR16--SO2NR16--(CH2)pNR16-; 25 -P(»0) (q1r16)0~; and -S02NHC (-0) NH-; 30 Y and Y1 are independently selected from the following: -C(«Q)NR16-; -NR12C («0)NR16-; -OC (-0)NR16-; and -(CH2)pNRl6-; U.7. P.\Tt.WT OFFICE 224 18 MAR 1994 383 225 R16 is H or C1-C2 alkyl; R17 is H or C1-C2 alkyl; p is 1 or 2; Q is selected from oxygen and sulfur; and Q1 is selected from oxygen, sulfur, NR14and a direct bond; and pharmaceutically acceptable salts and prodrugs thereof.
3. A compound of formula I as claimed in Claim 1 wherein: i n and n are both 0; R* and R*® are independently selected from the following: hydrogen; C1-C6 alkyl substituted with 0-1 R18; C2-C4 alkenyl substituted with 0-1 R18; aryl substituted with 0-1 R19; a heterocyclic ring system, substituted with 0-1 R19, selected from pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl^ 225 238395 226 benzimidazolyl, piperidinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and decahydroisoquinolinyl; 5 wherein R18 is chosen from the following groups: keto, halogen, cyano, -NR13R14, -C02R13/ 0C(«0)R13, -OR13, C2-C6 alkoxyalkyl, -S(0)mR13, 10 -NHC (*NH)NHR13, -C (-0) NR13R14, -NR14C (-0) R13, - NR14C (-0) OR14, -OC (-0) NR13R14, -NR13C (-0) NR13R14, -NR14S02NR13R14, -NR14502R13/ -S02NR13R14, C1-C4 alkyl, C2-C4 alkenyl, and C3-C6 cycloalkyl; 15 a C5-C14 carbocyclic residue substituted with 0-3 R19; aryl substituted with 0-2 R19; 20 or a heterocyclic ring system substituted with 0-2 R19, selected from selected from pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, 25 isoquinolinyl, benzimidazolyl, piperidinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and decahydroisoquinolinyl; 30 wherein R19, when a substituent on carbon, is selected from the following: halogen, hydroxy, nitro, cyano, methyl, methoxy, -NR13R14, C1-C4 haloalkyl, Ci~C2 alkoxycarbonyl, (. _. j 226 ' I 238 227 Ci-C2 alkylcarbonyloxy, C1-C2 alkylcarbonylami.no, -S02NR13R14, and -NHSO2R14; and R19, when a substituent on nitrogen, is 5 C1-C4 alkyl; R3 and R8 are independently selected from the following groups: 10 hydrogen; C1-C5 alkyl substituted with 0-3 halogen or 0-1 R20; C2-C4 alkenyl substituted with 0-3 halogen or 0-1 R20; and 15 C3-C6 cycloalkyl substituted with 0-3 halogen or 0 1 R20; Vherein R20 is selected from the following groups: 20 keto, amino, methylamino, dimethylamino, - C(«0)NH2, C(-0)NMe2f C(»0)NHMe, andC3~C5 cycloalkyl; with the proviso that the total number of non-25 hydrogen atoms comprising R3 is less than or equal to 6, and the total number of non-hydrogen atoms comprising R8 is less than or equal to 6; R4 and R7 are independently selected from the following 3 0 groups: C1-C4 alkyl substituted with 0-3 halogen or 0-1 R21 wherein R21 is selected from the following groups: * 10 15 228 238395 keto, halogen, cyano, -NR13R14, -CO2R13, -0C(«0)R13, -OR13, C2-C4 alkoxyalkyl, ., and -S (0)mR13»/-C3-C6 cycloalkyl; a Cg-Cio carbocyclic residue substituted with 0-1 R22; aryl substituted with 0-1 R22; and -e*- a heterocyclic ring system, substituted with 0-1 R22, selected from pyridyl, thienyl, indolyl, piperazyl, N-methylpiperazyl,and imidazolyl; wherein R22 is selected from one or more of the following groups: benzyl, benzyloxy, halogen, hydroxy, 20 nitro, C1-C4 alkyl, C1-C4 alkoxy, amino, methylamino, dimethylamino, C^-C^ haloalkyl C1-C4 haloalkoxy,-C(=0)r!4f and -0C(=0)R14; 25 R3A/ R4A, R7a and r8a are hydrogen; R5 and R6 are independently: oclootcd from-tho following groups;■ 30 hydrogen, or any other group that, when administered to a mammalian subject, cleaves to form the original diol in which R5 and R6 are hydrogen; 228 ■ "" ' tet * Y J v v • 238 229 R13 is H or C2-C2 alkyl; 14 . R is C1-C4 alkyl; m is 0, 1 or 2; 5 W and W1 are independently selected from the following: 10 -NR16C(=Q)NR16-' -C(=0)NR16-; -0C(=0)NR16-; and -(CH2)pNR16-; 15 Y and Y1 are independently selected from the following: C(»0)NR16-; NR12C(«0)NR16-/ 0C(«0)NR16-; and (CH2)pNR16-; R16 is H or methyl; 25 p is 1 or 2; and Q is selected from oxygen and sulfur; and pharmaceutically acceptable salts and prodrugs 30 thereof.
4. The compound of Claim 1 which is: (S,R,R,S)-N-I4-[[(1,1- dimethylethoxy)carbonyl]amino]-2,3-dihydroxy- 229 •v; -r* fi Y 230 5-(lH-pyrrol-l-yl)-1-[(lH-pyrrol-1-yl) methyl ] pentyl ] -H2-f ormyl-L-valinamide •
The confound of Claim 1 which is: {S,R,R,S)-N-[4-[[(l,l- . dimethylethoxy) carbonyl] amino] -2,3-dihydroxy--5-phenyl-l-(phenylmethyl)pentyl]-N2-[[N-[ (IH benzimidazol-2-yl)methyl]--N-methylamino] carbonyl]-L-valinamide.
The compound of Claim 1 which is: (S,R,R,S)-N-[4-[ [(1,1- dimethylethoxy)carbonyl] amino] -2, 3-dihydroxy--5-(4-pyridinyl)-1-(4-pyridinylmethyl)pentyl] n2-formyl-L-valinamide,
The compound of Claim 1 which is: [S,R,R,S(2S*,3S*)]-(l,1-dimethylethyl) [2,3-dihydroxy-4-[[3-hydroxy--4-methoxy-2-(1-methylethyl)-1-oxobutyl]amino]-5-(4-pyridinyl)-1-- (4-pyridinylmethyl)pentyl] carbamate.
The compound of Claim 1 which is: <S,R,R,S)-N-t4-[[(lrl- dimethylethoxy) carbonyl ] amino] -2,3-dihydroxy-5- (4-pyridinyl) -1-(4-pyridinylmethyl)pentyl] N2-[(phenylmethoxy)carbonyl]--L-valinamide.
The conqpound of Claim 1 which is: (S,R,R,S)-N2-[[1- (dimethylamino)cyclopropyl]carbonyl]-N-[4-t[(1,l-dimethyl~ 230 231 ethoxy)carbonyl]amino]-2,3-dihydroxy-5~phenyl- 1-(phenylmethyl)pentyl]-N- -L-valinamide.
The compound of Claim 1 which is: (S,R,R,S)-N-[4-[[(l,l- dimethylethoxy)carbonyl]amino]-2, 3-dihydroxy- 1-(phenylmethyl)hexyl]-N2-(N-methyl-L-alanyl)-L-valinamide.
The compound of Claim 1 which is: (S,R,R,S)-(1,1-dimethylethyl) [4-[[[2-[(dimethylamino)methyl]-lH- -imidazol-5-yl]carbonyl]amino]-2,3-dihydroxy-5-phenyl-l-(phenylmethyl)-pentyl]carbamate.
The compound of Claim 1 which is: (S, R, R, S)-N2-t[[2- [ (dimethylamino)carbonyl]phenyl]methoxy]carbon yl]-N- -[4-[[(1,1-dimethylethoxy)carbonyl]amino]-2,3-dihydroxy-5-phenyl-l--(phenylmethyl)pentyl]-L-valinamide.
The compound of Claim 1 which is: (S,R,R,S)-N,N'-[2,3-dihydroxy-l, 4-bis(phenylmethyl)-1,4-butanediyl]-bis[N2-(4-aminobenzoyl)-L-valinamide] .
The compound of Claim 1 which is: >xn v r*. ] 1 JUL 1333 ! 231 232 (S,R,R,S)-N2-[[[4- (dimethylamino)phenyl]methoxy]carbonyl]-N- [ 4-[[(1,1- -dimethylethoxy)carbonyl] amino]-2,3-dihydroxy-5 5-phenyl-l-(phenylmethyl)- pentyl]-L-valinamide.
15. The compound of Claim 1 which is:
(S,R,R,S)-N2-[[[4- 1 0 [(dimethylamino)methyl]phenyl]methoxy]carbonyl
J-N-[4-[[(1,1-dimethylethoxy)carbonyl]amino]-2,3-dihydroxy-5-phenyl-l-- (phenylmethyl)pentyl]-L-valinamide . 15 16. A method for treatment of viral infections in non-humans which comprises administering to a host in need of such treatment a pharmaceutically effective antiviral amount of a compound of Claim 1. 20 17. A method for treatment of viral infections in non-humans which comprises administering to a host in need of such treatment a pharmaceutically effective antiviral amount of a compound of Claim 2. 25
18. A method for treatment of viral infections in non-humans which comprises administering to a host in need of such treatment a pharmaceutically effective antiviral amount of a compound of Claim 3. 30
19. A method for treatment of viral infections in non-humans which comprises administering to a host in need of such treatment a pharmaceutically effective antiviral amount of the compound of Claim 4. 232 f*. E»? o 3 5 233
20. A method for treatment of viral infections in non-humans which comprises administering to a host in need of such treatment a pharmaceutically effective antiviral amount of the compound of Claim 5. 5
21. A method for treatment of viral infections in non-humans which comprises administering to a host in need of such treatment a pharmaceutically effective antiviral amount of the compound of Claim 6. 10
22. A method for treatment of viral infections in non-humans which comprises administering to a host in need of such treatment a pharmaceutically effective antiviral amount of the compound of Claim 7. 15
23. A method for treatment of viral infections in non-humans which comprises administering to a host in need of such treatment a pharmaceutically effective antiviral amount of the compound of Claim 8. 20
24. A method for treatment of viral infections in non-humans which comprises administering to a host in need of such . treatment a pharmaceutically effective antiviral amount of the compound of Claim 9. 25
25. A method for treatment of viral infections in non-humans which comprises administering to a host in need of such treatment a pharmaceutically effective antiviral amount of the compound of Claim 10. 30
26. A method for treatment of viral infections in non-humans which comprises administering to a host in need of such treatment a pharmaceutically effective antiviral amount of the compound of Claim 11. 233 fir 234
27. A method for treatment of viral infections in non-humans which comprises administering to a host in need of such treatment a pharmaceutically effective antiviral amount 5 of the compound of Claim 12.
28. A method for treatment of viril infections in non-humans which comprises administering to a host in need of such treatment a pharmaceutically effective antiviral amount 10 of the compound of Claim 13.
29. A method for treatment of viral infections in non-humans which comprises administering to a host in need of such treatment a pharmaceutically effective antiviral amount 15 of the compound of Claim 14.
30. A method for treatment of viral infections in non-humans which comprises administering to a host in need of such treatment a pharmaceutically effective antiviral amount 20 of the compound of Claim 15.
31. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective antiviral amount of a. 25 compound of Claim 1.
32. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective antiviral amount of a 30 compound of Claim 2.
33. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a -1 JUL 1993 # C vJ 235 pharmaceutically effective antiviral amount of a compound of Claim 3.
34. A pharmaceutical composition comprising a 5 pharmaceutically acceptable carrier and a pharmaceutically effective antiviral amount of the compound of Claim 4.
35. A pharmaceutical composition comprising a 10 pharmaceutically acceptable carrier and a pharmaceutically effective antiviral amount of a compound of Claim 5.
36. A pharmaceutical composition comprising a 15 pharmaceutically acceptable carrier and a pharmaceutically effective antiviral amount of a compound of Claim 6.
37. A pharmaceutical composition comprising a 20 pharmaceutically acceptable carrier and a pharmaceutically effective antiviral amount of a compound of Claim 7.
38. A pharmaceutical composition comprising a 25 pharmaceutically acceptable carrier and a pharmaceutically effective antiviral amount of a compound of Claim 8.
39. A pharmaceutical composition comprising a 30 pharmaceutically acceptable carrier and a pharmaceutically effective antiviral amount of a compound of Claim 9. Oi 235 ^ " AUGI991"f p ; * 10 15 20 25 30 395 236
40. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective antiviral amount of a compound of Claim 10.
41. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective antiviral amount of a compound of Claim 11.
42. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective antiviral amount of a compound of Claim 12.
43. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective antiviral amount of a compound of Claim 13.
44. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective antiviral amount of a compound of Claim 14.
45. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective antiviral amount of a compound of Claim 15.
46. A process for preparing a compound of formula: 236 237 23839 (I) ^ . 1 2 2A 3 3A d4 4A d5 d6 7 p7A. 8 _8A „9 wherein R,R,R ,R,R , R , R , R , R , R , R ,R,R , R , QA 1Q _1 " 1 J 2 R" , R , W, VT, X, X , Y, Y , n and n are as defined in claim 1, comprising: 5 (a) preparation of the required catalyst by mixing VCI3 (THF)3 with freshly prepared zinc-copper couple under strictly anhydrous, deoxygenated conditions in an aprotic solvent at room temperature; and 10 (b) reacting the product of step (a) with an aldehyde of the formula: r7a r8a X1 W X' . R6> WN R10 , . 7 _7A 8 8A _9 _9A _10' rJ V1 „1 , 1 , .. , wherein R , R ,R,R ,R,R , R „ w , X , Y and n are as defined in claim 1, in an aprotic solvent at -78°C-100°C where the nolar ratio of zinc-copper couple: VCI3 (THF) 3: aldehyde is 1-3:1t3:1. Formula I in
47. A process to prepare a compound of/Claim 1 comprising contacting an aldehyde of the formula: *3 R3* ?4 R4* wherein: r\ R^, R^, R^, R^A, R4, R^~\ W, X, Y and n~are-as~dei:xned_in claim 1, i -- f"ATS?»T QPKjrs* with an aldehyde of the formula: j ~ 16 f- > WAR 1334 : - (fQllow.ed__by page 237a) 237a 238 39 5 ^Cx. R7A RaA xv rb/| R8\ •WN RIO , . _7 _7A _8 _8A _9 „9A _10. TT1 V1 „1 , 1 . . wherein R , R , R , R ,R,R ,R , w , X , Y and n are as defined in claim 1, 238 in the presence of Caulton's reagent to form the compound of Claim 1 wherein R5 and R6 are H and proceed optionally contacting one or both of the alcohols/with a derivatizing agent.
48. The process of Claim 47 wherein the derivatizing agent is selected from compounds from the group consisting of acyl chlorides or anhydrides, diphenyl carbonates and isocyanates.
49. An intermediate of the formula: wherein R18 and R19 are independently C2~Ce alkyl; C3-C8 cycloalkyl substituted with 0-3 r25; a C6-C10 carbocyclic aromatic residue selected from phenyl or naphthyl, substituted with 0-3 r26. or a heterocyclic ring system substituted with 0-2 r26, composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom, selected from pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, 16 MAR 1994 239 238395 tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, and octahydroisoquinolinyl; 25 . R is selected from one or more of the following groups: keto; halogen; -NR27R28; -CC>2R27; -0C(=0)R27; -OR27, -S(0)mR27 wherein lis 0, 1 or 2; -NHC(=NH)NHR27; -C(=NH)NHR27; -C(=0)NHR27; cyano; C3-Cg cycloalkyl substituted with 0-3 R26; a Ce-Cio carbocyclic aromatic residue selected from phenyl or naphthyl, substituted with 0-3 R26; and a heterocyclic ring system substituted with 0-2 R2^, composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom, selected from pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, Isoquinolinyl, benzimidazolyl, piperidinyl, pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl,and octahydroisoquinolinyl; r26 £s selected from one or more of the following groups: phenyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, C2-C6 alkoxyalkyl,methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C3.-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, alkylsulfonyl, S02NR27R28, and R27S02NH; R20 and R21 are independently H, Ci-Ca alkyl, a C6~ C10 carbocyclic aromatic residue selected from phenyl and naphthyl, substituted with 0-3 R2**, or C1-C3 alkyl substituted with a C6-C10 carbocyclic aromatic residue, selected from phenyl and naphthyl, substituted with 0-3 R26; and 27 28 1 fi 17 R and R are as defined for R rand._R. ,._r.espectfciYely, in claim 1. iDi'! C'HwE <16 MAR 1994 240 OX fi t &. u w -J
50. An intermediate of the formula: 20
(IV) 20 21 wherein R and R are as defined in claim 49. 51. An intermediate of the formula: 18 19 20 21 wherein R , R , R and R are as defined in claim 49.
52. A process for preparing an intermediate compound of the formula: (ill) comprising: (a) reacting an organometallic derivative R10M or 1 0 R19M in the presence of copper (I) salts and an ether-containing aprotic solvent system with a diepoxide of the formula: -I JUL 1333 . | 241 23 8 ^9 RV o//^o (IV) (b) reacting the product of step (a) of the formula: with R22R23R24P and Ci-Cg dialkyl azodicarboxylate in the presence of an azide anion and an aprotic organic 5 solvent wherein: iq ?n R , R , R , and R are as defined in claim 49 j -30 M is lithium or magnesium; 31x1 R22, R23 and R24 are independently phenyl or. C1-C6 alkyl. * x q 0 0 '•is W %J w 242
53. The compound of Claim 1 wherein R1 and R2 are identical, R3 and R4 are identical, R5 and R6 are identical, X and X"1" are identical and R7 and R8 are identical. 5
54. A process for preparing a compound of formula: 10 comprising: (a) reacting compound of the formula (8) 8 2 - COOCH^Ph 15 wherein n-1-5, with diethylazodicarboxylate and • v triphenylphosphine under strictly anhydrous, deoxygenated conditions in an aprotic organic solvent at I a temperature range of 25°C-85°C over a 24-hour period 20 wherein the molar ratio of triphenylphosphine: diethylazo dicarboxylate: diol is 1-4:1-4:1. THE DU PONT MERCK PHARMACEUTICAL COMPANY By theimattorneys ] BALDWIN. SON & CAREY • " { 1 — " ; 242
NZ238395A 1990-06-01 1991-06-04 1,4-diamino-2,3-dihydroxy butane derivatives; preparatory processes and pharmaceutical compositions NZ238395A (en)

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