CA2066644A1 - Method for treating hiv and other retroviruses and compounds useful therefor - Google Patents

Abstract

The present invention relates to a method of inhibiting a retrovirus in a mammalian cell infected with said retrovirus which comprises treating said cell with an effective amount of a compound of formula (I): X-C8-D9-E10-F11-G12-Z. The present invention also provides novel compounds useful in this method.

Description

WO 91/06561 PCl`/US90~05818 2~66644 MErHOD FOR TREATING HIV AND OTHER REIROVIRUSES
AND COMPOUNDS USEFUL THEREFOR
FIELD OF THE INVENTION
The present invention relates to a method of inhibitin~ a retrovirus in a human 5 cell infected with said retrovirus which comprises treating said cell with an effective amount of a retroviral proteinase inhibitory compound of formula I~ The present invention also provides novel compounds which are useful in this method~
BACKGROUND OF THE IN~tE~IlON
An estimated one to one and one~half million people in the United States are la infected with a human retrovirus~ the human immunodeficiency virus type I, HIV-l, which is the etiolo~ical agent of acquired immunodeficiency syndrome, AIDS ~C~
Norman~ Science, 661-662 (1986))~ Of those infected~ an estimated two hundred and fifty thousands people will develop AIDS in the next five ye~rs tJ.W. Curran, et al., Science, 1352-1357 (198S))~ On March 20, 1987, the FDA approved the use of the 15 compound~ zidovudine (A~I'), to treat AIDS patients with a recent initial episode of pneumocystis carinii pneumonia, AIDS patients with conditions other than pneumocystis carinii pneumonia or patients infe~ted with the virus with an absolute CD4 1ymphocyte count of less than 2~0/mm3 in the peripheral blood. AZT is a known inhibitor of viral reverse transcriptase, an enzyme necessary for human immunodeficiency virus replica-20 tion.
U.S. Patent 4~?24,232 claims a method of treating humans having acquiredimmunodeficiency syndrome utilizing 3'-azido-3'-deoxy-thymidine (azidothymidine, A~
Since the first description of the malady in the early part of this decade, acquired 25 immunodeficiency disease syndrome (AIDS) and its devastating consequences have been subjects of condnuous and intense coverage in both the lay and scientific press. Indeed, a recent edidon of Scientific American was endrely devoted to AIDS (Scientific American 289, #4 (1988)), and the literature on the disease and the virus is already so vast as to defy thorough citatiom At present, there is no effecdve treatment of the 30 disease, and 3'-azido-3'-deoxythymidine (AZT), an inhibitor of the viral reverse transcriptase (RT) remains the the~py of choice, despite its highly toxic side effects.
Human immunodeficiency virus (HIV) has long been recognized as the causative agent in AIDS, although a minority opinion to the contrary has been e~pressed (e~g~, P~

wo 91/06561 Pcr/US90/05818 2~ 44 Duesberg, Proc. Natl. Acad. Sci., USA, 86:755-764 (1989)). Sequence analysis of the complete genomes from several infective and non-infective HlV-isolates has shed considerable light on the make-up of the virus and the types of molecules that are essential for its replication and maturation to an infec ive species ~L. Ratner~ et al.~
S Nature~ 313:277 284 (1985)). HIV exhibits the same ga~ipol~env organization seen in other retrovir~ses (L. Ratner~ et al~, Nature, 313:~77-284 (19SS)); S~ Wain~Hobson, et al., Cell, 40:9 17 (1985~; R~ Sanchez-Pescador~ et al~, Science, 227:~84-492 ~1985); and ~A~ Muesin~, et al~, Nature, 313: 450-458 ~lg8~
Reverse transcnptasc (RT) is an enzyme unique to retroviruses that catalyzes the10 conversion of viral RNA into double stranded DNA~ Blockage at any point during the transcription process, by AZT or any other aberrant deoxynucleoside triphosphateincapable of elongation, should have dramatic consequences relative to viral replication.
Much work on the RT target is in progress based, in large measure, upon the fact that nucleosides like AZT are easily delivered to cells. However, the inefficiency of15 phosphorylation steps to the triphosphate, and the lacX of specificity and consequent toxicity, constitute major drawbacl~s to use of AZT and similar nucleosides having a blocked, or missing, 3`hydro~tyl group~
The T4 cell receptor for ~V, the so called CD4 molecule, has also been targeted as an intervention point in AIDS therapy ( ~A~ Fisher, et al~, Nature, 331 :7~78 (1988);
20 R~E~ Hussey, et al~, Nature, 331:78-81 (1988); and K~C Deen, et ah, Nature, 331:82-84 (1988)). The exterior portion of this transmembrane protein, a molecule of 371 amino acids (sCD4) has been expressed in Chinese hamster ovary (CHO) cells and Genentech ( D~H~ Smith, et al., Science, 238:1704-1707 (1987)) has had a product in clinical trials since the fall of 1987~ Thus far, little informstion on efficacy is available 25 beyond the fact that the recombinsnt sCD4 appears to be relatively non-toxic. The idea behind CD4 based therapy is that the molecules csn neutTalize HIV by interfering with viral attachment to T4, and other cells which e~press CD4 on their surfaces. A variant on this theme is to attach cell toxins to CD4 for specific binding and delivery to infected cells which display glycoprotein gp-120 on their surfaces ( M~A. Till, et al., Science, 30 242:116~1168 (1988); and V~K~ Chaudhary, et al~, Nature, 335:369-372 (1988)).Another therapeutic target in AIDS involves inhibition of the vi~l protease (or proteinase) that is essential for pro~essing HIV-fusion polypeptide precursors. In HIV
and several other retrm~iruses, the proteolytic maturation of the gag as~d gag/pol fusion WO 91/06~61 PCI/OS90/0:~818 -3- 2~&~4 polypeptides (a process indispensable for generation of infestive viTal particles) has been shown to be mediated by a protease that is~ itself~ encoded by the pol region of the viral ~enome tY~ Yoshina~;a~ et al., Proc. Natl. Acad. Scu USA~ 8':1618-1622 (1985); Y.
YoshinaXa. et al.~ J~ Viroh~ 55:870-873 (1985): Y. Yoshin~a~ et al., J~ Viroh, 57:825-5 83' (1986); and ~ von der Helm, Proc~ Nath Acad. Sci.~ USA, 74:911-915 (1977))~
The protease (or proteinase), consisting of only 9g amino acids, is among the smallest enzvmes known~ and its demonstrated homology to aspartyl proteases such as pepsin and renin ( L~H~ Pearl and W~R. Taylor, Nature, 329: 351-35-1 (1987); and 1.
Katoh, et ah, Nature~ 329:65~ 656 (1987)~,1~ to inferences regarding the three-dimen 10 sional structure and mechanism of the enzyme ~L~H~ Pearl and W~R~ Taylor, Nature, 3~9:351 354 (198") that have since boen borne out experimentally~ Active HIV
protea~e has been expressed in bacteria (see, e~g~, P~L Darke, et ah, J. Biol. Chem~, 264:2307 2312 (1989)) and chemically synthesized ~ J~ Schneider and S~B~ Kent, Cell, 54:363 368 (1988); and R~F~ Nutt, et ah, Proc~ Natl~ Aoad~ Sci~, USA, 85:7129-7133 15 (1988))~ Site directed muta~enesis (P~L. Darke, et al~, J~ Bioh Chem~, 264: 2307 2312 (1989); and N~E~ Kohl, et al., ~oc. Nath Acad~ Sci~, USA, 85:4686-4690 (1988) and pepstatin inhibition (P.L~ Darke, et al~ Biol~ Chem~, 264:2307-2312 (1989); S.Seelmeier, et al., Proc. Natl. Acad. Sci., USA, 85:6612-6616 (1988); C.-Z. Giarn and I. Borsos, J. Biol. Chem., 263:14617-14?20 (1988); and J. Hansen, et al., EMBO J., 20 7: 1?85-1791 (1988)) have provided evidence for Hl~l protease's mechanistic function as an aspartyl protease. A recent study has demonstrated that the protease cleaves at the sites expected in peptides modeled after the regions actually cleaved by the enzyme in the gag and pol precursor proteins during viral maturation (P.L. Darke, et al., Biochem.
Biophys~ Res~ Communs~, 156:297-303 (1988)). X-ray crystallographic analysis of the 25 HIV-protease (M~A~ Navia, et al~, Nature, 337:615-620 (1989)) and a related retroviral enzyme from Rous sarcoma virus (M. Miller, et al., Nature, 337:576-579 (1989)) reveal an active site in the protease dimer that is identical to that seen in other aspartyl prote-ases, thus supporting the supposition ~L~H. Pearl and W.R~ Taylor, Nature, 329:351-354 (1987)) that the HIV enzyme is active as a dimer. To date, an e~fective means of 30 inhibiting retrovirus~s in a human hosting such a virus, and thereby effectively treating diseases caused by such a virus, such as acquired immunodeficiency syndrome ~AIDS), has not been found~
INI:ORMATION DISCLOSURE

WO 91/06S61 PCr/US90/0~81X
X~6~4 ~-The inhibition by relatively high concentrations of pepstatin A (100 ~LM), a general aspartyl proteinase inhibitor, of HIV replication in H9 cells is described in K.
Von der Helm~ et ah, FEBS Le~ters, 247:349 (1989)~
Great Britain 2,203,740 (Sandoz) claims the use of renin inhibitors for treating5 diseases caused by retroviruses~
A~D~ Richards, et al~, FEBS Letters, ~47:113 (198g) disclose ~ His-Pro-Phe-His LVA-Ile His, a potent inhibitor of another aspartyl protease human renin, which also contains a hydroxyethylene isoterc, inhibits the HI~I prot~ase in vitro~
Recent information from Smith~Kline Beecham rcsearchers has described work 10 on the inhibition of HIV l replication in cell culture with synthedc protease inhibitors~
Int~ AIDS Symposium, Montreal, Canada, June 1989 The following patent applicatdons disclose pepddes that are useful as inhibitorsof renin and retroviral proteases: Intemational Applicadon, Serial No~ PCT/US891-01672, filed 24 April l9X9; U~S~ Patent Applicadon, Serial No~ 07/405,691, filed 11 15 September 1989; Intemadonal Application, Serial No. PCI`/US90/03754, filed 9 July l9gO; and U.S~ Patent Application, Senal No~ 07/573,110~ filed 24 August 1990.
European Published Applicatdon 0 357 332 discloses the use of renin inhibitors for the treatment of AIDS by inhibidon of HIV protease. These inhibitors may have a moiety of the formula R~2R2b-X-C(O)- at the N-terminus, wherein X is -O-, -S-, -CH-, 20 or -NHCH-, and wherin R,~ and Rl~, are the same or different and are hydrogen, C,~
alkyl, unsubstituted or substituted aryl, and unsubstituted and substituted C3~7 cycloalkyl.
However, this application does not disclose diol moieties as the transition state insert.
European Published Application 0 352 000 discloses retroviral protease binding peptides, having a variety of moieties as the transition state insert, including alcohols and 25 diols, and ha~ing such substituents as t-butylo~ycaTbonyl, benzylo~ycarbonyl and R"C(O)-, wherein R~ is hydrogen or Cl.t~ alkyl, at the N-terminus.
Eur~pean Published Application 0 369 141 discloses specific peptides which are useful for inhibiting retroviral protcases~ However, these peptides differ from the pepddes of the prescnt invention by ha~ing a ,B-alanine at the D9-position, statine analogs 30 at the t~ansition state insert or N-4-amino-2-methyl-5-pyriTnidinylmethyl amide at the C-terminus~ ' European Published Applications 0 337 714 and 0 356 223 disclose HIV proteaseinhibitors which do not have an an~ino acid analog at the ~9 position in front of the WO 91/06~61 PCI'/US90/O~BlX
^5- 20~66~'1 transition state inser~
SUMMARY OF THE ~NVENl~ON
The present inven~ion particularly provides:
Use of a compound of formula I
X-C~-D9-E~o~FIl~Gl2~~ 1 to prepare a medicament for inhibitin~ a retrovirus in a mammalian cell infected with said retrovirus;
wherein X is a~ (CH2)p a~yl, b) (CH2)p Het, c) ~(CH2)p~C3~C7cycloalkyl, d) Rs O-(CH~ C(O), e) R, CH2 0-C(O), f) R~ O-C(O)-, g) R5 (CH2)~ C(O)-, h) Rs-(CH2)~ C(S)-, i) R~N(R.)'(CH2),'C(O)', j) R5~SO~(CH~)q C(O) ~
k) R5 SO2-(CH2)~-~C(O)-, 1) R5 (CH2)o-S02~
m) Z-C(O)-CH(OH)-CH(CH~Rl)-C(O)-n) R5-(CH2~pCH=CH-~CH2)p C(oj-, o) R5(CH,~p CH=CH-(CH2)p 0-C(O), or p) R27(cH2),l'c(o)-;
25 wherein C~ is absent or a divalent moiety of the formula XL" XL2. XL~, ~2b or other amino acyl derivative;
wherùn D9 is a divalent moiety of the formula XL." XL~ b or other amino acyl derivative;
wherein E,o-Fll is a divalent moiety of the formula XL~, XL6~, XL6C, XL~d, XL.6" II, m, 30 or IV;
wherein G,2 is absent or a divalent moiety of the formula XL~ , or other amino acyl derivative;
wherein Z is wO 91tO6~61 Pcr/us90/05818 ~0~6~4 a) -O-RIo~
b) -N(R~)Rl~
c) C,-C,~cyclic amino, d) -NHR~20, e) -NH-tCH2),-pyridine, N-oxide, or f) Het bonded via a nitrogen atom, or g) -NH(CH~)~,NH Het;
wherein R is a) -(CH2)~ isopropyl, bl (CH,)o-isobutyl, c) -(CH~-phenyl, or d) -(CH2)c-C3 C7cycloalkyl;
wherein R, is a) hydrogen, b) C,-C,alkyl, c) aryl, d) C,-C,cycloalkyl, e) -Het, f) C,-C3alko~y, or g) Cl-C3alkylthio;
wherein R2 is a) hydrogen, or b) -CH(R3)R,;
wherein R3 is a) hydrogen, b) hydro~y, c) C,-Csalkyl, d) C3-C7cycloalkyl, e) aryl, f) -Het, g) C,-C3all~o~cy, or h) C, C3al~ylthio;
wherein R, at each occurrence is the same or different as is WO 91/06~61 PCr/lJS90tO~818 a) hydrogen, 2 ~ ~ 6 `~ ~ 4 b) Cl-C5alkyl, c) -(CH2)p-aryl, d) -(CH2)p-He~
e) -(CH2)p-C3-C~cycloalkyl~ or f) 1- or 2-adarnantyl;
wherein Rs is a~ C, C~alkyl, b) C3-C7cycloalkyl, 1~ c) aryl, d) -Het, e) 5-oxo-2-pyrrolidinyl, or f~ 1 or 2-adamantyl;
wherein R6 is a) hydrogen, b) C,-C5alkyl, c) -tCH2)p-aryl, d) -(CH~)"-Het, e) -(CH~p-C3-C~cycloalkyl, or f) 1- or 2-adamantyl;
wherein R, is a) hydrogen, b) C,-C~alkyl, c) hydro~ty, d) amino C~-C4alkyl-, e) guanidinyl C,-C3alkyl-, ~) aryl, g) -Hct, h) mcthylthio, i) -(CH2)p-C3-C7cycloalkyl, j) an~ino, k) -(CH2).-COOH, I) -(CH2).-COOC,-C6 al~yl, or wo 91/06561 pcrJus9o/o5glx ~6~ 14 -8-m) -~CH~)o^CONR22R26;
wherein R8 is a) hydrogen b) C,-Csalkyl, c) hydroxy, d) aryl, e) -Het, t) ~uanidinyl C,-C3alkyl, or g~ ~(CH2)p~C3~C7cycloalkyl;
10 wherein R~ is a) hydrogen, b) hydroxy, c) arnino C, C,alkyl, or d) guanidinyl C~ C3alkyl^;
wherein R~o is a) hydrogen, b) C~-C5alkyl, c) -(CH2)~RI6.
d) -(CH2lRI7, e) C3-C?cycloalkyl, f) a phannaceutically acdeptable cation~
g) -CH~-CH2-R,s, or h) -CH2-CH(R,~)-RI5;
wherein Rll is -R or -R2;
25 wherein R~2 is -(CH2),,-RI3;
wherein Rl3 is a) aryl, b) amino, c) mono-, di- or tri-CI-C3allcylamino, d) -Het, e) Cl-C~ yl, f) C3-C7cydoalkyl, g) C2-C5~yl~

WO 9t/06~61 PCl`/US90/OSX18 2 0 ~
h) C3-C7cycloalkenyl, i) hydroxy, j) C,-C3alkoxy, k) Cl-C3alkanoyloxy, 1) merupto, m) C,-C3allcylthio, n) COOH, o) -C~C,~C~alkyl, p) -c~cH2-(cl~c3alkyl)-N~cl-c3askyl) q) `co-N~22R~;
r) C4 C7cyclic amino, s) C,-C7cycloalkylamino, t) guanidyl, u~ cyano, v) N-cyanoguanidyl, w) cya soamino, x) (hydroxy C2-C,alkyl)s~nino, or y) di-(hydro~yC2-C,alkyl)amino;
wherein R,4 is a) hydrogen, b) C~-C,Oalkyl, c) -(CH2)~-R
d) -(CH2)~~R~s~
e) -CH(R25)-CH2~R~s.
f) -(CH2)~,-CH(R~2)-R~5-g) (hydroxy C,-C,alkyl), h) hydroxy C,-C, alkyaryl, or i) (C,'C3 alkoxy) C~C, aL~cyl;
whereirs Rss is a) hydroxy, b) C3-C7cycloalkyl, c) aryl, d) amirso, Wo 9t/06561 Pcr/ussoto~

e) mono-, di-, or tri-C,-C~alkylamino, f) mono- or di-(hydroxy C2-CJall;yl)amino, g) -Het, h) Cl-C3alkoxy-, i) C,-C3alkanoyloxy-~
j) mercapto, k) C~ C3al~1thio-, I) Cl-C5alkyl, m) C,-C7cyclic amino, n) CJ C7cycloalkylamino, o) Cl~Csalkenyloxy, p) C3^C7cycloalkenyl;
wherein R,6 is a) aryl, b) amino, c) mono- or di-(C,-C3alkyl)amino, d) hydro~cy, e) C3-C7cycloalkyl, f) C~-C1cyclic a nino, or g) C,-C3alkanoyloxy;
wherein R,7 is a) -Het, b) C,-C~alkenyl, c) C3-C7cycloalkenyl, d) C,-C3alkoxy, e) mer~apto, fJ C,~C3alkylthio, g) -COOH, h) -C~C,-Cbalkyl, i) -c~cH2-~cl-c3alkyl)-N(cl-c3alkyl) j) -CO-NR22R26.
k) tri-C,-C3alkylamino, 1) guanidyl, wo gl/06~61 Pcr/uS90/05818 -11- 2~6~4 m) cyano, n) N-cyanoguanidyl~
o) (hydroxy C~-C~alkyl)amino~
p) di-(hydroxy C2-CIalkyl)amino. or q? Cyanoamino;
wherein R,~ is a) amino, b~ mono-, or di-~C, C~alkyl)amino~
c) C~-C7cyclic amino, d) C~-C7cycloalky1amino~ or e) -CH(NH~)(CO~H);
wherein R19 iS
a) aryl, b) -Het, c) tri-CI-C3alkylamino~
d) C3-C7cycloalkyl, e) C2-C,alkenyl, f) C3-C,cycloalkenyl, g) hydroxy, h) Cl-C3alko~ty, i) C,-C3alkanoyloxy, j) me~apto, k) Cl-C3alkylthio, I) -COOH, m) -C~O-C,-C6alkyl, n) -~:O-O-CHt-(C,-C3alkyl)-N(C,-C3alkyl)~, o) -CO-NRttRt6.
p) guanidyl, q,) cyano, r) N-cyanoguanidyl, s) cyanoamino, t) (hydro~cy C2-C,alkyl)amino, u) di-(hydro~cy C~-C4alkyl)amino; or wo 91/06~61 Pcr/usso/0~818 v) -SO3H;
wherein R20 is a) hvdrogen, b) C,-C~alkylt or S c) aryl-C,-C5alkyl;
wherein R2, is a) -NH~, or b~ -OH;
wherein R22 is lQ a) hydrogen, or b) C,-C3alkyl;
wherein R23 is a) ~(CH,)~-OH, b) -(CH2)~-NH2, c) aryl, or d) C1-C3alkyl;
wherein R2~ is a) b) -(CH2)~-OH, or c) -(CH2)o~NH2;
wherein R~s is a) -(CH2)~-RI3.
b) hydrogen, c) C,-C~alkyl, or d) phenyl-CI-C3a~yl;
wherein R26 is a) hydrogen, b) Cl-C~ yl, or c) phenyl-CI-C~allcyl;
30 wheTein Rn is a) -COOH, b) -COOCI-C6 alkyl, c) -CONR22R~6, or wo 91/06561 Pcr/uS9û/0~818 -13- 206~
d) -CH(NH,)COOH;
wherein Rl2Q is a) RI~sc~(cH2)qoRl2l~2(cH~
b) a moiety of fonnula XXX
c) a moiety of formula ~XXI
d) -CH2~CHORl2l)~cH2OR
e~ Rl2lOCH2(CHORI2l)yCH~(CHOR~2l)2CH~OR
f~ a moiety of forrnula XXXII,or g~ R,2,0CH2`C(cH20Rl2~2-;
l0 wherein R12, is a) hydrogen, b) C,~alkyl, c) -(CH2)~-aryl, or d) -C(O)R1z3;
15 wherein Rl2, is a) Cl-C5 aLkyl, or b) -(CH2)~-phenyl;
wherein Rl26 is a) hydrogen, or b) (CH2)~,ORl2l;
wherein R12~ is a) hydrogen, or b) -(`CHOR,2,)~CH~OR121;
wherein Q is a) CH3, b) CHOR~2~, or c) C(O);
wherein j is one to three, inclusive;
wherein m is one or two;
30 wherein p is ~ero to two, inclusive;
wherein r is zero to five, inclusive;
wherein for each occurrence n is independently an integer of æro to five, inclusive;
wherein q is an integer of one to five, inclusive;

wo 91/06~61 Pcr/usgo/0581x ~,~ 6 ~ 14-erein u is an integer of zero to three, inclusive;
wherein v is an integer of æro to four~ inclusive;
wherein s is an inte~er of zero or one so that the sum of u plus v plus s is three or four;
wherein t is an inte~er of zero to three~ inclusive;

5 wherein w is an integer of two or three;
wherein x is an integer of two to seven, inclusive;
wherein y is an integer of zero to six, inclusive; and whercin z is an integer of zero to six so that the sum of y plus z does not exceed six;
wherein aryl is phenyl or naphthyl substituted bv zero to three of the following:
a) C,-C3alkyl, b) hydro~y~
c) Cl-C3alkoxy, d) halo, e) amino, f) mono- or di-C,-C,alkylamino, g) -CHO, h) -COOH, i) COOR26, CON~26-~0 k) nitro, 1) mercapto, m) Cl-C3alkylthio, n) C,-C3alkylsulfinyl, o) C,-C3alkylsulfonyl, p) -N(R~)-C,-C3allcylsulfinyl, q) -SO3H, r) SO,NH2, s) -CN, or t) -CH~NH2;
30 wherein -Het is a 5- or ~membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group consistir.g of nitrogen, o~ygen, and sulfur;
and including any bicyclic group in which any of the above heterocyclic rings is fused to a ben~ene nng or another heterocycle and the ring may be connected through a caroon ~'0 91/()6~61 PCr/~:S91~/O~X
-1~- 2~
or secondar nitro~en in the rin~ or an exocvclic nitro_en: and if chemicallv feasible~
the nitro~en and sulfur atoms mav be in the oxidize~ t`orms and optionallv substitute~
b~ zero to three of the followin~
a ) Cl-C~alk~ h b ) hvàroxy c) hvdroxy (C~-C~al~yl)~
d) halo~en~
e) amino~
~) amino ~Cl-c~alk~
g) -CHO~
h ) -CO~H
i ) -CO~(C~ -C~al~yl j ) -CONH2 k) -CONH-iCI -Csalkyl) 1~ 1) nitro, m) mercapto, n) mercapto (Ct-Csalkyl)~
o) -SO3H, p) -SO.NH2`
''O q) -CN~
r) -O-CI-Galkvl~ or 5) ~lo-~cH2)2~n-ocH3 with the provisos that:
1) G,2 is present when both C~ and D, are present and Elo-FIl is other ~an "5 LPA;
O when X is ~-C(O~-CH(OH)-CH(CH.R,)-C(O)-~ D9 is His and G" is Ile:
3) when X is R5-CH~-O-C(O)-or R5-(CH~,-C(O)- and Elo-F" is XL6~ XL~ or XL~d~ R5 is other than C,-C6 alkyl;
4) when X is R5-O-C(O)- and Elo-F" is XL6~ XL6~ XL{,, 30 or X~ R5 is other than C,-C6alkyl~ C3-C. cycloalkvl or aryl;
S) when X is R5-(CH2)"-C(O)-wherein Rs is cycloalkyl or aryl, and Elo F" is XL6, XL6;" XL6~ or XL~d, n is other than one;

6) when X is R,N(R,)-(CH2)o-C(O)- and E~o-FIl is XL6, Xl~b, XL6~ or XL6d, ~?0 sl/n6~6l PC~ i9~
2 ~
n is other than one;

7) Z is other than l~-~-amino-~-meth~1-5-p~nmidin~lmelhyl-amide:

8) ~; is other than benzvloxvc~rbonyl or butyloxyc~rbonvl~ ~ hen E,~ F" i Il or 1~!: an~
S 9) ~hen ~; is R~-~CH.!~-C(O!- and E~ is 11 or l~h R~ is other than C,-C~
all~ and Use ot` a compound sele~ted ~rom the ~roup consis~in~ ot~
L~lsoleucmamide ~ N'~ amino-~hydroxv~2~ methvlcthyl)~ 1 ~oxooctvl]~N~2-pvridinylmethyl)~ trifluoroacetate~ (S~S~S)~ or H~L~A~Ile~Amp~
IQ Oct~namide~ 5-t(3~3-dimethvl-1-oxobutvl)amino]-1-hvdroxy-7~methvl~
methvlethyl)~N~2~methyl 1 ~t~(~ pyridlnylmethvl)amino)wrbonyl~buty~ s ~ I ( I R~2R-~)~2R~4R~SR~]]~ or TBA~LVA~Ile~Amp~
Cyclohexanehexanamide~ ~[~3 ~3-dimethvl- 1 -oxobutyl ~amino]-r-hydroxv-~
methvlethyl)~N~2~methyl~ 1 -[[(2-pvridLnvlmethyl)arnino~carbonyl~butyl~- ~ [cYS-~N~ I R~ ~2R-')~R~,rR~,~R~]~- or TBA-CVA-Ile-Amp~
Cyclohexanehexanamide, ~amino-r-hydroxy-~-( I-methylethyl)-N-[[2-methyl- I -[[(2-pyridinylmethyl)]amino)carbonyl]butyl~- dihydrochloride,[~YS-rN(lR~2R~),cYR~,r-R~R~])- or H-CVA-Ile-Amp:
Cyclohexanehexanamide~ ~-(acetylamino)-r-hvdroxv-~-(l-methvlethvl)-N-~2-methyl-l-[[~pvridinvlmethyl)amino~carbonvl~butyl~ S-~N(lR~R~ R~TR~R~
or Ac-C~'A-lle-Amp;
Oct~LnarnideS-(acetylamino)~-hydroxy-~-methyl-2-( I -methylethyl)-N-[2-methyl-1 -[[(2-pyridinylmethyl)amino)carbonyl~butyl~ 'S-~N( I R ~ ~ 2R ~) ~2R ~ ~4R ~ ~5R ~]-monoacetate ~salt); or Ac-LVA~Ile-Amp; or IVA-LVA-Ile-Amp~
Boc-Phe-His-Cha psitCHOHCHOHlVal-lle-Amp; or L-Histidinamide, N-[(l,l-dimethylethoxy)carbonyl)-L-phenylalanyl-N-~ cvclohexvlmethyl)-2,3-dihydroxy-5-methyl-4-r[~2-methyl-1-[t(2-pyridin~methyl)amino]oarbonyl~bu~l]arnLno]car~onyl]hexyl]-, ~lS-~lR~,2S*,3S~,4S''(lR~,2R~ -; or BOC-Phe-His-CVD-Ile-Amp;
L-Histidinamide, N-[(l ~ l-dimethylethoxy)calbonyl~-L-phenylalanyl-N-~2-hydroxy-1-(2-methylpropyl)-5-[~2-methyl-1 -t~(2-pyridinylmethyl)arnino~carbonyl]butyl]amin~-5-oxo~-(phenylmethyl)pentyl]-, ~lS-~lR~,2R-,4S*,5(1R*~2R*)]~-; or Boc-Phe-His-LPA-Ile-Amp;

~o 91~06~61 PC r/~9~/O~lX
_17 2~6~
L-Histidinamide~ N-~ l-dimethvlethoxy)carbonyl)-L-phenvlalanvl-N-[4-~cyclohexvlmethyl)-2-hvdroxy- I -(2-methvlpropvl)-5-[[2-methyl^ I -[~(2 pvridinvlmethvl )-aminolcarbonvl~butyl)amino]-~-oxopentyl]-~ tlS-tlR#~'R~4S'~5tlR~R~))]-: or Bo-Phe-His-LCA-lle-Amp:
L-Talonamide~cvclohexyl-2~ -trideoxy-5-r~ I-dimethvle~hoxy)c~rbo-nyl)-L phenylalanvl~L-histid,vllamino] 2-~1-methvlethyl)-N-[2-me~hvl-1-[[~2-p~Tidinylmel-hvl)amino~rbonvl~butyl] ~ [S-~R~R~ ; or Boe Phe~ CVD`-lle~Amp; L
Histidinami~e~ N-t~ dimethvlethoxy)carbon.vl]-L-phenylalanyl-N ~2~3-dihydroxy-~
methyl~ 2-methylpropyl)~5 tt(~ n~thyl l-[t(''-pvndinylmcthyl)arnino)c~r~nyl]bu~l~am ino~carbonvl]hexvl] ~ tlS tlR~''S~3R~S~lR~"R~ or B~ Phe His-L~'DA`-lle Amp:
L-Histidinamidel~`-tt~ (dimethvlamino)-I-naphthalenyl]sulfonyl]-L-phenylalan~
N-[2-hydroxy-5-methyl- 1 -(2-methylpropyl)-4-t[t2-methvl- 1 -[[~2-pyridinvlmethyl)amino~c arbonyl)butyl)amino)carbonvl)hexyl), tlS-tlR'~'R~R~lR~'R~)~]-; or DANS-Phe His-LVA-Ile-Amp;
L-Histidinamide~ L-phenvlalanyl-N-[2-hydroxy-~-methyl-1-(2-methylpropyl)~
[[12-methyl- 1 -~1(2-pyridinylmethyl)amino)carbonyl)butvl~amino]carbonyl]hexyl)- ~ [ 1 S-(lR*,2R~,4R~(lR~,2R~)])- or H-Phe-His-LVA-lle-Amp~
L-Valinamide~L-phenvlalanyl-N-[2-hvdroxv-5-methvl-1 -(2-methylpropyl)-4-[[~2-methvl- l -[[(2-pvridinvlmethvl)amino]carbonyl)bu~yl)amino)carbonyl]hexyl]-, l l S -~IR~'R~4R~(IR~2R~ or H-Phe-Val-LVA-Ile-Amp:
L-Valinamide, L-~alvl-N-~-hydroxy-5-methyl- 1 -(~-me~hylpropyl)-4-[[[2-methyl- 1-[~(2-pyridinylmethyl~amino]c~arbonyl)butyl]amino~c~onyl)hexyl]{IS-[lR'~2R~4R'(I -R#~2R~)]}-, diacetate (salt~ or H-Val-Val-LVA-lle-Amp; or L-Valinamide~ N-ace~vl-L-valyl-N-t'~-hydroxy~5-methvl-1-t2-methylpropyl) ~-[[['`methyl- 1 -~[(2-pyridinylmethyl)amino)carbonyl)butyl)amino)carbonyl]hexyl]-, [ 1 S -tlR~,2R~4R~(lR~,2R~)]]-~ monoacetate (salt); or Ac-Val-Val-LVA-Ile-Amp.
N~x-[(2S ~4S,5S)-5-[rN~[(S)- 1 -Acetoxy- I -benzyl)methylcarbonyl]-L-histidyl] -amino]-4-hydroxy-7-methyl-2-(1-methylethyl)-1-oxooctyl]-N- [2-pyridyl)ethyl]-L-30 isoleucinunide; or AcO-Phe-His-LVA-Ile-NH-(CH2)~-pyridine.
4-Morpholinebutanamide,B-hydroxy-N-[2-[[2-hydroxy-5-methyl-1-(2-methylpr~
pyl)-4-11~2-methyl- 1 -[[(2-pyridinylmethyl)amino]carbonyl]butyl~amino)carbonyl-)hexyl~arnino]-l-(lH-imida~ol-4-ylmethyl)-2~xoethyl]-cr-( 1 -naphthalenylmethyl)-r~xo- .

~O 91/06:`61 PCT/~`~9~)/O;XIX
2~6~4~ -18-~lS-[lR*rR~(~S~R~)~.2R~4R~(lR#,2R#)]~-;
IH-lmida~ole-4-propanamide~ ~x-[[[5-~dimethvlamino)-1-naphthalenyl]su-Il`onyl]amino]-N-~2-hvdroxv-5-methyl- I -(2-me~hylpropvl)-~-[~t -me~h~ 2-pvridinyl methyl)amino)carbon~l]butvl]amino~c~rbon~l]hexyl) ~ ~ I S
I R*~R~).'R~4R~IR~2R*)~ or DANS His-LV~-Ile~mp~
IH Imida~ole-~-propanamide~ ~amino-N ~2~hydroxy~5 methyl~ methylpro pyl) ~ [t~2 methyl-1-[t~2~pyridinylmethyl)amino~onyl~butyl)amino)Parbonyl]hexyl]~IS`tlR~R~)~2R~4R~tlR~2R#~) or H~His~LVA~Ile~Amp;
Octanamide~ 5~t~ acetylamino)-3-methyl~1~xobutyl~amino)~hvdroxy-7 methyl-10 2~1-methylethyll-N-t2-methyl-1-[1t2~pyridinylmethyl)amino)rarbonyl]butyl]-~ [2S
tN~lR#~2R~2R~4R~SR#(R#)]~ ~ monoacetate ~s~lt~; or Ac \~`al~LVA-Ile~Amp:
Ac-Asn-L~iA-Ile-Amp;
No~t(~S~4S~5S) 5-~t(S~-( I Hydroxy- I -benzyl)methylcarbonyl~amino)-4 hydroxy)-7-methyl-2-( 1 -methylethyl)- I -oxooctyl]-N-(2-pvridinvlmethyl) L-isoleucinamide:or HO
15 Phe LVA-Ile-Amp;
lH-Imida~ole~-propanamide~N-[2-hydroxy-5-methyl-1-(2-methylpropyl)~-[1~2-methyl- I -~[t2-pyridinylmethyl)amino~carbonyl~butyl~amino~carbonyl~hexyl~-cY-[(2-hvdroxy-l-oxo-3-phenylpropyl)amino~-,[lS-~lR~rR~(R~ 2R'~4R~lR~2R#)~ 2-hvdroxy-l ~'~3-propanetricarboxylate (12) (salt) orphenyl-CH~ CH(OH)-C(O)-His-LVA-20 Ile-Amp;
L-~-Glutamine~ Nfu 2id -~N-[[l~l-dimethylethoxy)caroonyl]-L-phenylalanyl]-l~'-[2-hydroxy-5-methyl- 1 -(2-methylpropyl)~-~[[2-methyl- 1 -[[(2-pyridinylmethyl )amino]
carbonyl~butyUamino~car~onyl~hexyl~-~[lS-[lR~2R~4R#tlR~2R#)~ ~monacetate(salt) or BOC-Phe-Glu-LVA-Ile-Amp;
"5 L-Histidinamide~ N-~ dimethylethoxy)carbonyl~-3-(2-pyridinyl)alanyl-N-[2 hydroxy-5-methyl-1-~2-methylpropyl) 4-[[[2-methyl-1-[[(2-pyridinylmethyl~amino~carbo-nyl~butyl~amino3car~onyl~hexyl~ lS-[lR~ ,2R~4R~(lR~2R#)]]-or BOC-2-Py-Ala-His-LVA-ne-Amp, L-.alpha~-Aspara~ine~ N/u 2/d-rN-[(l,l-dimethylethoxy)carbonyl]-L-phenylala-30 nyl~-N-[2-hydro~y-S-methyl-1-(2-methylpropyl)-4-[[2-methyl-1-[[(2-pyridinylme-thyl)amino~carbonyl]butyl~amino~carbonyl~hexyl~-,[lS-llR~,2R#,4R*(lR~,2R~)~]-,monoacetate (salt) or BOC-Phe-Asp LVA-Ile-Amp;
L-.alpha~-Glutamine, N-[ 1,1 -dimethyletho~y)carbonyl]-L-phenylalanyl-N0[ 1-~ 0 9 1 /06:~6 1 PCT/ ~ S9~/O~X l X
-19- 2 ~
(cvclohexvlmethyl)-2-hydroxy-5-methvl-4-[~-methv~ (2-pvridinylmethyl)amino)carb-onyl]butyl]amino]c~bonvl~hexy1~]-,~ lS-~ IR#~2R~4R~(lR~'R~)]~-~ monoacetate (salt or BOC-Phe-Glu-CVA-lle-Amp:
L-Histidinamide~ N-~ l-dimethvlethoxy~carbonvl~-L-phenylalanvl-N-~3 ditluoro-~-hvdroxv-~ -meth~l-l-[~(~-pyridinvlmethyl)amino]c~rbonvl]butyl~amino)-~ox~l-~phenvlmethyl)butyl~- or CH~-C(O)-O-CH(ben2yl)-C(O)-His-LVA-lle-Amp;
L-Glycyl-L-histidvl-~S-amino-~-cyclohexyl~3R~R-dihydroxy-2R-isopropyl-hexanoyl-L-isolellcyl-2-pyridylmethylamide or Gly-His-CV~Ile~Amp:
L-Glycyl-L-histidyl-5S-amin~R-ben~yl~yclohexyl~3R~4R~ihydroxv-hexanoyl-IQ L~isoleucyl~2~pvridylmethylamide or Gly~His~CPD~lle~Amp~
5~Quinolinylhydroxyacetyl~L~histidyl~5S~amino~cvclohexyl~S -hvdroxy-2S-isopropyl~hexano~ L~isoleucvl~-pyridylmethylamide or Qoa~ His-CVA~Ile~Amp:
Quinolinylhydroxyacetyl~L~histidyl~5S~amino~cyclohexyl~4S~hydroxy~2S-isopropyl~hexanoyl~L~isoleucyl-~pyridylmethylamide or Qoa(a)-His-CVA-lle-Amp; N
15 tert-Butyloxycarbonvl~L~alanyl~5S~amino~6-cyclohexyl~4S~hydroxy-'S-isopropyl- hexanoyl-L~isoleucyl-2-pyridylmethylarnide or Boc-Ala-CVA-Ile-Amp;
N-tert-Butyloxycarbonyl-L-histidyl-SS-amino-6-cyclohexyl-4S-hydroxy-2S-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or BOC-His-CVA-Ile-Amp;
Benzyloxyca~bonyl-L-alanyl-L-alanyl-SS-amino-6-cyclohexyl-4S-hydroxy-2S -'0 isopropvl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or CBZ-Ala-Ala~CVA-lle-Amp:
L-Histidinamide~ N-~t I ~ I -dimethylethoxy)carbonyl]~L~phenylalanyl-N-[4~[[[2-~('2~6-diamino~4~pyrimidinyl!amino~ethyl)amino3carbonyl)~2~hydroxy~5~methyl- 1 ~(2-methylpropyl)he~yl]-,tlS-(lR#~2R~4R#)]- or BOG-Phe-His-LVA-(2~6 diamino 1-pynme-dinyl~amino-ethylamino;
~5 Gly~CVD~Ile~Amp~ and Gly-CPD~Ile-Amp;
to prepare a medicament for inhibiting a retrovirus in a human cell infected with said retrovirus; and A compound of formula I
X-C~-D9-EIo~Fll-Gl2`z wherein X is a) hydrogen~
b) naphthyloxyacetyl, ~'O 91/06~61 PCT/~:S911/O~XIX
2~6~
c) t-butvloxvcarbonyl~
d) toluene-sulfonyh e! phenvloxvacetvh f) pvndinyl-(CH7)n-carbon~h ~) phenvl-(CH,)O-CH(OH)-C(O)~
h) indolyc~arbonvl~
i) pvridinyl-(CH2)O C~C~O)-~
j) phenyl~(CH2)n so2~~
k) phenyl-~(CH2)0-Ct~
1) phenyl-HC=CH-(CHl)"-C(O)~
m) phenvl-HC=CH-~CH2)n-~C~O)~
n) H~(CH2)n`C(O)-~
o) quinolinoylhydro~yacetyl, p] ~uinolinoylcar~onyl~
lS q) benzvloxycarbonyl, or r) 5-(tnethylene~lycolmonomethylether~ naphthyloxyacetyl;
wherein C, is a) absent, b) 2-Py-Ala~
c) -NH-CH.-C(O)-~
d) Phe~ or e) Ala;
wherein D9 is a) His, ^'5 b) Glu, c) Asp, d) Asn~
e~ -NH-CH2-C(O~, or f) Ala;
30 wherein E~o~FIl is a) CVAt b) LVA, c) CVD, ~VO 91/()6"61 PC'r/~S9~)/0-`Xl~

~6~
d) LVD~
e) CPD~
CLD
g) CcD~
h) CCD~
i) PPD~
j) LID~
k~ LLd~ or 1) LLD;
10 wherein G~ is a) absent~ or b) Ile;
wherein Z is a) Amp~
b) Amp-NO~
c) lysine, d) -NH-(CH~)D-NH-pyridine e) -NH-(CH~)D-CH(OH)-phenyl ~
n -NH-(CH2)D-CH(OH)-C,-C~ all~ or ~0 g) -NH-(CH2)D-NH~ ~diamino~-pyrimidiny.l).
wherein n is O to five~ inclusive~
By "amino acyl derivatives`' is meant anv of the naturallv occurring amino acidssuch as: glvcine~ alanine~ valine~ leucine~ isoleucine~ phenvlalanine, Ivsine, proline~
tryptophan~ methionine~ senne, threonine~ cysteine~ tvrosine~ asparagine, glutamine~
~ aspartic acid, ~lutamic acid, arginine~ ornithine~ and histidine~ and svnthetic derivatives thereofi These compounds may be in the L or D configuration and are well known and readily available to those skilled in the art~
Susprisingly and unexpec~edly~ the compounds of the present invention are effective and potent inhibitors of HIV protease~ The compounds of the present invention 30 have also been found to inhibit HIV protease in cell cultures, as described below~
Therefore, the compounds of formula I inhibit retroviral proteinases and thus inhibit the replication of the virus~ They are useful for treating patients infected with human immunodeficiency virus (HIV) which results in ac~uired immunodeficiency syndrome ~o ~l/06~61 PCr/~S9~)/0~
2 ~ 4 ~ -2~-(AIDS) and related diseases~
The novel compounds of the present invention have low to moderate renin inhibitory activity but are surprisin~ly and une~pectedly potent retro~ iral pro~ease inhibitors S The peptides o~ th~ presem invenùon are 31~o usPtul ~s nnvel human retroviral protease inhibitory peptiàe analogs~ Theret`ore~ the peptides of the presen~ invention inhibit retroviral proteases and ~hus inhibit the repli~ion of the virus~ The- are useful t`or treaùn~ human patients in~eet~ ~ith a human re~rovlrus~ such as human immunode~
ficiency ~irus ~strains of H1~'-1 or HIV-2) or human T cell leukemia viruses ~HTLV I
10 or HTL~ I) which results in acquired immunodeficiencv syndrome ~AII)S) andJor related dis~s~
The capsid and repli~tive enzvmes ~i~e~ prote~se~ reverse transcriptase~
integrase) of retroviruses are translated from the viral ga~ and pol genes as polyproteins that are further processed bv the viral protease ~PR) to the mature proteins found in the 15 viral capsid and necessary for viral functions and replication. If the PR is absent or nonfimctional~ the virus cannot replicate. The retroviral PR~ such as HIV I PR has been found to be an aspartic protease with active site characteristics similar to those exhibited by the more complex aspartic proteace~ renim The term human retrovirus (FIRV) includes human immunodeficiency virus type 'O 1~ human immunodeficiencv virus type Il~ or strains thereof~ as well as human T cell leukemia virus 1 and 2 (HTL~'-I and HTL~ -2) or strains apparent to one s~;illed in the art~ which belong to the same or related viral families and which create similarphvsiological effects in humans as various human retroviruses~
Patients to be tre~ted would be those individuals: I~ infected wi~h one or more S strains of a human retrovirus as determined bv the presence of either measurable viral antibody or antigen in the serum and 2) in the c ce of HIV~ having either a symptomatic AIDS defining infe tion such as i) disseminated histoplasmosis ii) isopsoriasis. iii) bronchial and pulmonarv candidiasis including pneumocystic pneumonia iv) non-Hodgkin's Iymphoma or v) Kaposi's sarcoma and bein8 less than sixty years old; or 30 having an ~bsolute CD4 Iymphocyte count of less than 200/m3 in the peripheral blood~
Treatment would consist of maintaining an inhibitory level of the peptide used according to this invention in the patient at all times and would continue until the occurrence of a second symptomatic AIDS defining infection indicates alternate therapy is needed.

~o 91/~)6~61 Pcr/~S91~/O~Xl~
-23- 2~6~
More specific~lb,~ an example Ot` one such human retrovirus is tne human immunodeficiencv virus (HIV~ also known as HTLV-III or LAV) which has been reco nized as the causative ac ent in human acquired immunodeficiencv disease svndrome tAIDS)~ P~ l)uesberg~ Proc~ Nath Ac~d~ Sch US~ 80~?~ 9S9)~ HI~I' contains a retro ~iral encoded protease~ HI~'-I prote~ that cl~es the fusion polvpeptides into the functional proteins ot` the mature virus p~icle~ E~P~ Lillehoj~ et ah~ J~ ~`irology~
6~:3053 ~1~8~); C~ Debuc~ et ah~ Proc~ Nath Ac~d~ Sch~ 84:8903 ~ 7)~ This enz!,~m~ HI~'~I protease~ has been classitied as an asp rtyl prote~se and has a demonstrat~ homology to o~her aspartvl protea~es such as renin~ LH~ Pearl~ e~ al.~
10 Na~ure ~9:351 ~1987); 1~ Katoh~ ~ al~ Nature 3''~:~5~5 ~1987)~ Inhibition of HIV-I
protease blocl;s the replication of HIV and thus is useful in the treatment of human AIDS~ E~D~ Clerq~ J~ Med~ Chem~ 29:1~1 (1986)~ Inhibitors of HT~'-I protease areuses`ul in the treatment of AIDS~
Pepstatin A~ a general inhibitor of aspartyl proteases~ has been disclosed as an15 inhibitor of HIV~l protease~ S~ Seelmeier~ e~ Pro~ Nath Acad. Sch USA~ 85:661' (1986)~ Other substrate derived inhibitors containing reduced bond isosteres or statine at the scissle position have also been disclosed~ M:L~ Moore, et al~, Biochem~ Biophys, Res~ Commum 159:4~0 (1989); S~ Billich~ et al~ J~ Biol~ Chem. 263:17905 (1988);
Sandoz~ D~E. 3812-576-A~
~O Thus~ the p~eptides of the present invention are useful for treatinC diseases ~aused bv retrovirus~s~ such as human ac~uired immunodeficiencv disease svndrome~AIDS~
The peptides of the pres nt invention are also useful for treating non-human animals infected with a retrovirus~ such as cats infected with feline leukemia virus~
"S Other viruses that infect cats include~ for example~ feline infectious peritonitis virus, calicivirus~ rabies virus~ ~eline immunodeficiency virus~ feline parvovirus (panleukopenia virus)~ and feline chlamydia~ Exact dosages~ forms and modes of administration of the peptides of the present invention to non-human animals would be apparent to one of ordinar,v skill in the art~ such as a veterinariam The compounds of forrnula I of the present invention are prepared as described in the publicaùons listed in Table I below, all of which are incorporated by reference herein~ or are prepared by methods analogous there~o, which are readily known and available to one of ordinary skill in the art of peptide synthesis.

~o 91/Ofi~61 Pcr/~s9~ xlx 2 0 ~ 4~
As is apparent to those of ordinary s};ill in the an~ the compounds of the presenl invention can occur in several diastereomeric t`orms~ dependino on the configuration around the as,vmmetric carbon atoms~ All such diastereomeric forms are included wiLhin the scope ot' the presen~ inventiom Preferabi~n the stereochemistr,v of the amino acids corresponds to that of the naturall~ occurring amino acids~
The present invention provides t`or compounds ot` t^ormula I or pharmacolo~i-call~ acceptable salts andior hydrates thereot~ Pharmacolo~i~lly acceptable salts ret^ers to those sal~s ~.~hich would be readily app~rent to a m~nufacturing pharmaceuti~l chemist to be equivalent to thc p~rent compound in propcrties such as formulation~ stability~
lU patlent acceptance and bioavailablility~
The compounds of the present invention are useful for treating patients infected~ith human immunodeficiencv virus (HIV) which results in ac~uired immunodeficiency syndrome (AIDS) and related diseases~ For this indicaùon~ the compounds of formula I are administered by oral~ nasal~ transdermal and parenteral ~including i~m and i~v~) 15 routes in doses of I ~g to 100 mgikg of bodv wei~ht~
Those skilled in the art would know how to formulate the compounds of this invention into appropnate pharrnaceutical dosagç forms~ Examples of the dosage forms include oral formulations~ such as tablets or capsules~ or parenteral formulations~ such as sterile solutions~
'O W'hen the compounds in this invention are administered orally~ an effective amount is from about I ~,g to 100 mg per ko per day Either solid or fluid dosage forms can be prepared for oral administratiom Solid compositions are prepared by mix~ng the compounds of this imention with conventional ingredients such as talc~ ma~nesiumstearate~ dicalcium phosphate~ ma~nesium aluminum silicat~ calcium sulfate, starch~
~5 lactose~ acacia~ methvl cellulose~ or functionally similar pharmaceutical diluents and carriers~ Capsules are prepared by mixin~ the compolmds of this invention with an inert phannaceutical diluent and placin~ the mixture into an appropriately sized hard gelatin capsule. Soft ~elatin capsules are prepared b,v machine encapsulation of a slurry of the compounds of this invention with an ac~ceptable inert oil such as vegetable oil or light 30 liquid petrolatum~ Syrups are prepared b,v dissolving the compounds of this invention in an aque~us vehicle and adding sugar, aromatic slavoring agents and preservatives~
ElLltirs are prepared using a hydroalcoholic vehicle such as ethanol, suitable sweeteners such as sugar or saccharin and an aromatic flavoring agent~ Suspensions are prepared ~`O 91/~16~61 PCT/~`S91~/O~lX
~5 20~6~
with an aqueous vehicle and a suspending agent such as acacia~ ~ra_acanth. or methyl cellulose.
~ 'ihen ~he compounds of this invention are administered parenterall~ thev can be ~iven b~ injection or b~ intravenous infusiom An etfective amount is from about I
LL~ to 100 mg per 1;, per das~ Parenteral soluùons are prepared b~ dissolving the compounds of this invention in water and filter sterilizinP the solution before placin~ in a suitable s~lable ~ial or arnpule~ Parenterai suspensions arc preparc~ in subst~nùall~
the same wav except a sterile suspension vehicle is us~ anà the compounds of this invention are steriliz~ with ethvlene oxide or suitable g~s before it is suspende~ in the 10 vehicle~
The exact route of adminisu-aùon~ dose~ or frequencv of adminisuaùon would be readilv determlned bv those s}~ill in the art ~nd is dependant on the age~ weight~
general phvsical condiùon~ or other clinical symptoms specific to the patient to be treated~
Paùents to be ureated would be those individuals: I) infected with one or more than one strain of a human immunodeficiency virus as determined by the presence of either measurable ViTal antibody or antigen in the serum and 2) having either a symptomatic AIDS definin~ infection such as i) disseminated histoplasmosis, ii) isopori-asis~ iii) bronchial and pulmonary candidiasis including pneumocvstis pneumonia~ iv) ~0 non-Hod~kin's lvmphoma~ or ~ Kaposi`s sarcoma and bein_ less than sixty vears old;
or havin_ an absolute CD4 l~mphocvte count of less than 'OOlmm3 in the peripheral blood~ Treatment would consist of maintaining an inhibitorv level of the compounds of this invenùon in the patient at all times and would continue until the occurrence of a second svmptomatic AIDS defining infection indicates alternate therapy is needed.
The uùlitv of representative compounds of the present invention has been demonstrated in several biological tests as described below.
The HIV-I protease has been expressed in E~ coli~ isolated, characterized and used to determine the inhibitory constants (Ki) of potential inhibitory compounds as follows:
The synthetic peptide H-Val-Ser-Gln-Asn-Tvr-Pro-Ile-Val-OH serves as the substrate for the measurement of HIV-I prot~ase activity. This peptide corresponds to the sequence from residue 128 to 135 in the HIV gag protein. Cleavage of the synthetic peptide~ as well as the gag protein, takes place at the Tyr-Pro bond. HIV-l protease ~`0 91/n6:`61 PCT/~S9û/O~XlX

20~1o~ 26-activitv is measured at 303C in 50 m~l sodium acetate~ pH 5.5~ containing 10%
glvcerol~ S~c ethvlene glvcol~ 0~1% Nonide~ P-~0 and '~8 mM substrate in a tota)volume of 50 ~h After 30 minutes of incubation~ 75 ~1 of 1~ trifluoroacetic acid (TFA) is added and the re~c~ion mixture subjected to HPLC analvsis~ HPLC is c~rried out with a Vvdac C,~ column (o~ lb x 1~ cm)~ eluting ~ith a line~r gradient of 0-30~c acetonitrile over a period of ~5 minutes at a flow rate Ot 1~O ml/minute~
The l; values of representative compounds of forrnula I of the present inventionare listed in Table 1I belo~s Several compounds of the present invention have been further evaluated for 10 their ability to inhibit HIV replication in primarv cultures of human peripheral blood Ivmphocytes~ This assay is done by ~he following screening procedure~
The followin~ features characteri~ the primarv srreening:
The screening tests are performed with primary human Ivmphocytes~ Thereby~
undesired testin~ of transformed cell lines is avoided in which host cell and virus mav have under~one processes of mutual adaptatiom Performance of cell culture in serum containing media closely mimics the in vivo situation~
True antiviral effects of test compounds are readilv distinguished from cytostaticlcytoto~ic reactions~
E~v kinetic measurement of viral nucleic acids and proteins the viral replication is followed precisely~
Testin in parallel on the level of nucleic acids (total HRV-RNA intra- and extracellular) and on the level of proteins (secreted p'~) allows to differentiate the test compound's effects on virus replication and on the e~pression of viral proteins. This leads to additional information regarding the etficacy of the test compound.
"5 Tolerance of the cell culture against low amounts of organic solvents permits the investi~ation of hydrophobic substances also~
The dose of the test compound causin~ half maximal suppression of virus replication is detern~ined.
The screening system is standardized and automated to a high degree.
1. TEST FOR TOXICITY
Effects of the test compound on cell proliferation are determined bv Iymphocyte proliferation assays. Starting with a 100 micromolar solution~ the test compound is 10 fold serially diluted.

~:0 91/0~S~61 PCT/~`S9()/O~XlX
~7 2~6~
One tenth ot the concentration of the test compound causin~ half maximal inhibition of cellular proliseration is emploved for all subsequent testin~.
IN VllRO INFECTION OF LYMPHOCYTES
Peripheral human l~mphocvtes are isolated bv density ~radient centrifugation~
After stimulation bv mito~en the cells are infected with a st~ndardized preparation o~^
HRV~ Subsequentl~ the infected cells are cultured in the presence of the test compound t`or four davs~ Individual cultures are established to me~sure viral replication two~ ~hree and four davs following intection~
~ Jntreated cells and AZT-treated cells are included as controls in parallel with 10 the test compounds under investigation~
~ 1 DETECTION OF SECRETED VIRAL P24 The amount of viral core protein p24 svnthesized and released by the infected cells is determined in the supernatant by capture-ELISA technique on da~s two, three and four~ Bv comparing with a standard preparation~ the amount of protein produced by the 1~ virus infected cells will be calibrated.
2.2 ASSAY FOR HIV-RNA
The total arnount of viral RNA synthesized by the infected Iymphocytes is determined by a special nucleic acid hybridization tcchnique on days two, three and four of culture~ Bv includinc a standard preparation of HRV-RNA the amount of synthesized 'O RNA will be quantified.
In case a test compound shows antiviral eftects in the primarv screeninV, all steps of the primary screening will be repeated. In addition~ viability of HRV-infected cells will be determined in parallel with assays for viral p'~ and RNA. In order to evaluate the half maximal antiviral effectofthetestcompound.aconcentrationdependen-~5 cv of the test compound action will be measured~
The results of the testin~ of these compounds of the present invention in these assavs is given in Table III below~
Some of the compounds of the present invention have been further evaluated in a CV- 1 cellular assay described below~ where it was demonstrated that the retrovirus-30 inhibitin~ effect was due to the inhibition of HIV-l protease~
CV-l cells were seeded at 2 x IU5 cells/well in 24 well Costar dishes and infected 6 to 12 hours later with vVK-l at 5 PFU/cell (V~ ~Caracostas, et al., ~Human Immunodeficiency Virus-Like Particles Produced by a Vaccinia Virus E~pression Vector ~'O 91/()6~61 PCT/~S9~/O~XIX
2 ~ 28-(retrovirus/AlDS/virus assemblvfreverse transcriptase~ Proc~ Natl. Acad~ Sci.~ USA~
in press~ 1989). The test compounds were dissolved in DMEM conlainin~ '.5~ fet~lbo~ine serum and added to triplicate wells immediately after virus addition. Twenly-~our hours at`~er int`ection the culture medium was removed. the monolaver washed with S I ml of PBS and the cells lvs~ bv the addition ot 0.1 ml of loading but`ter ~6'.5 ml~l Tris~Hcl pH 6.8~ ~.3~c SDS~ 5~o B-mercaptoethanol~ 10~ glvcerol~. The cells Ivsates were colleet~d indi~idually, placed in boiling water for 3 minutes~ and then 0.0'5 ml of each is subJected to electrophoresis on 1' ~ SDS~polvacrvlamide gels~ The proteins were electroblotted onto nitrocellulose and analyzed b~ Western blottin~. The primary10 antibodies were sheep anti Pr'~ and sheep anti~Prl7 and the secondarv antibodv in both caces was alkaline phosphatase conjugated rabbit-anti sheep I~G ~all obtained from ~;iri:e~aard ~: Pem~ Laboratories~ Gaithersburg~ ~ID)~
Test compounds si~nificantlv inhibited proteolvsis of the HIV- I gag polyprotein(Pr55) to the mature viral structural proteins Pr2~ and Prl7 in the above cells infected 15 with the recombinant vaccina virus expressin~ the HIV l ~a~ pol ~enes. The HIV I like particles released from inhibitor treated cells contained almost exclusively Pr5S and other gag precursors~ but not Pr24.
The following compounds of the present invention are preferred:
I-Noa-His-Cha PSI[CHOHCHOH~Val-Ile-Amp; or lH-lmidazole~-propanam-'O ide. N-[1-(cyclohexvlmethvl)-''~3-dihydroxv-5-methvl-4-[[~ -methvl- 1 -[[(2-pyridinyl-methvllamino~carbonvl]butvl]-[amino~carbonyl]hexvl]-c~-[[(l-naphthalenvloxv)acetyl~-amino~-, [lS-[lR*(R*),'S''~3S*~4S*(lR~'R~ -; or NOA-His-CVD-Ile-Amp:
N~-[(2S ~4S~5S)-5-[N-~N~-(Phenoxvmethvlcarbonyl)-L-histidyl~amino-4-hydroxy-2-isopropyl-7-methyl-1 -oxooctyl~-N-[2-(~-pyridinylamino)ethyl~-L-isoleucinam-"S ide~ aeetic acid salt; or POA-His-LVA-lle-NH(CH.~.NH-pyridine; or POA-His-LVA-Ile-N,H~CH2)2NH-pyridine;
lH-Imidazole-4-propanamide~ N-[ I -~cyclohexylmethyl)-2-hydroxy-5-methyl~-[[t~-methyl- 1 -t[(2-pyridinylmethyl)amino~carbonyl]butyl]amino]carbonyl]hexyl~-cr [(phenoxyacetyl)arnino~-, [lS-[lR*(R*)~2R*~4R*(lR#,2R*)]]-; or POA-His-CVA-Ile-30 Amp;lH-Imidazole~-propanamide~-[ 1 -(cycloheptylmethyl)-2-hydroxy-5-methyl~-[[[2-methyl- 1 -[[(2-pyridinylmethyl)amino]carbonyl~butyl]amino~carbonyl~hexyl]-c~-[(phenoxyacetyl)an~ino]-, [lS-[lR*~R#), R*,4R*(lR*,2R*)]]-; or POA-His~hpVA-Ile-~o 91/n6:61 Pcr/-s9n/n~XI~
-29- 20~6g~
Amp;
Cvclohexanehexanamide~ ~-(acetvlamino)-J-hvdroxy-~-(l-methylethyl)-N-~2-methvl-l-[[(p~ndinvlmethyl)amino]carbonvl]butyl~ [c~S-~N~lR~2R~ R~rR~R~];
or Ac-CvA-lle-Amp:
NCY-[~S~ ~S~ 5S)-5-[N-~N~ -Naphthalenyloxyacptyl)-L-histidyl)amino)-6 cvclohexvl-~-h~droxy~-isopropyl- l-oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucinamide or NOA-His-CVA-Ile-Amp;
NC~-[t2s~ ~S~ 5S)-5-~N rN~-~I-Naphthalenyloxyacetyll ~2-pyndinyl)alanyl]-amino]-6-cyclohexyl-~-hydroxy-2 isopropyl-1-oxohexyl]-N-~2-pyridinylmethyl)-L-10isoleucinamide or NOA-His-CVA-Ile-Amp;
N~-t~S~ ~S~ 5S)-S-~N-rN~-~ I-Naphthalenyloxvacetyl)-L-histidvl]amino]-~
cyclohexvl-~-hvdroxv-2-isopropyl- l-oxohexvl]-N-[~ -pvridinvlamino)ethvl]-L-isoleucinamide or NOA-His-CVA-lle-NH-(CH~-NH-~2-pyridine):
Pentanoic acid~ 5-[[1-(cyclohexvlmethyl~-2-hvdroxv-5-methvl~-[[~2-methyl-l-15[[(2-pyridinylmethyl)amino]carbonyl~butyl~amino~carbonyl]hexvl~amino]~-[(lH-indol-2-ylcarbonyl)amino~-5-oxo-,[lS-[1R~(R~)~2R~,4R~(lR~" R7~orlH-indol-2-yl carbonyl-Glu-CVA-Ile-Amp;
2,5,11~14-Tetraa~pentadecanoic acid~ 7-hydroxy-3-(lH-imidazol~-ylmethyl)-9-( 1 -methylethyl)- 12-(1 -methylpropyl)-6-(2-methylpropyl)~ ~ 1 0~1 3-trioxo- 15-(2-pyridinyl)-20~3-phenyl-2-propenvl ester~ t3S-~l(E)~3R~6R~7R'~9R~l'R*(R~)]]- or phenyl-CH =CH-CH.-O-C(O)-His-LVA-lle-Amp~
Phenoxyacetyl-L-histidyl-5S-amino~cyclohexyl-3R~4R-dihydroxy-~R-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or POA-His-CVA-Ile-Amp;
1 -Naphtoxyacetyl-L-histidyl-~S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R-''5isobutyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-CLD-Ile-Amp;
l-Naphthoxyacetyl-L-histidyl-5S-amino-2R-ben2yl-3R~4R-dihydroxy-6-phenyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-PPD-Ile-Amp;
I -Naphthoxyacetyl-L-histidyl-5S -amino-6-cyclohexyl-3R,4R-dihydroxy-2R-isopropyl-hexanoyl-L-isoleucyl-2-pyridinvlamino-ethylamideor NOA-His-CVD-Ile-Apr;
305-Quinolinylhydroxyacetyl-L-histidyl-SS-amino-6 cyclohexyl~S-hydroxy-2S-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethvlamide or Ooa~b)-His-CVA-Ile-Amp;
1 -Naphthoxyacetyl-L-histidyl-5S -amino-3R~R-dihydroxy-2R-isobutyl-7-methyl-octanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-LLd-Ile-Amp;

~0 91/()6~61 PC r/~S9(~ X
2 Q ~ -3~
2-Quinolinvlcarbonvl-5S-amino-6-cyclohexvl-3R~4R-dihydroxy-2R-isopropyl-hexanovl-L-isoleucvl-2-pvridinylamino-ethylamide or Qc-Asn-CVD-Ile-Apr;
Quinolinvl-~-carbonvl-L-aspara~inyl-55-amino-6-cvclohexvl- lS-hvdroxy-2S
isopropyl-hexanovl-L-isoleucyl-2-pyridylmethvlamide or QC-Asn-CVA-Ile~Amp;
S L-Asparaginamide~ l-(naphthoxy)acetyl-N-~-hydroxv-5-meth.~1-1-(2-methyl-propyl) ~-[[t2-methyl-1-[[[2-(N-oxido~pyridinylmethyl)amino~c~rborlyl)butyl]amino~carb-onylJhexvl)-N-alpha-methyl-~ [lS-[lRY,2R~4R~lR*~'R*)]]- or NOA-Asp-C~A-lle-Amp:
L-Asparaginamide~ t~-(triethylene~lycolmonomethvlether)naph~hoxy]acetyl-N-~hy~roxy~5~methyl~ 2~methylpropyl)-4~t~2~me~hvl~ 1~t[~2~ oxido)pyridinylmethyl]-amino]carbonyl~butyl~amino]carbonyl~hexyl]~N~alpha~methyltlS~tlR~'R~4R*~lR*~2-R~)]]~ or ~triethylene~lycol monomethyl ether)~NOA Asp CVA~lle~Amp: and L~Aspara~inamide, [4~triethyleneglycolmonomethvlether)naphthoxy]acetyl-N-~2-hydroxv-5-methvl- 1-(2-methylpropyl)~-t[[2-methvl- 1 -1[[2-~N-oxido)pyridinylmethyl]-amino~car~onyl]butyl~amino)carbonyl]hexyl]-N-alpha-methylElS-~lR*~2R#~4R*(lR*~2-R*)]]- or 4 (triethyleneglycol monomethyl ether)-NOA-Asp-CVA-Ile-Amp~
The following compounds of the present invention are most preferred:
I-Noa-His-Cha PSI~CHOHCHOHlVal-Ile-Amp; or lH-lmidazole-4-propanam-ide~ N-~ 1 -(cvclohexvlmethvl)-' ~3-dihydroxy-5-methvl-4-l[[2-methyl- 1 -[[(2-pyridinyl -methyl)amino]carbonyl~butvl]-lamino]carbonyl]hexyl]-cr-[[(l-naphthalenvloxy)acetyl]-amino]-~ [lS-[lR#(R')~2S'~3S*~4S#(lR#~"R#)]]-; or NOA-His-CVD-lle-Amp:
Quinolinyl-2-carbonyl-L-aspara~invl-SS-amino-~cyclohexyl-4S-hydroxy-2S-isopropyl-hexanoyl-L-isoleucyl-2-pyridvlmethylamide or QC-Asn-CVA-Ile-Amp;
L-Asparaginamide~ ~5-(triethylene~lycol monomethyl ether)naphthoxy]acetyl-N-[2-L-Asparaginamide~ [5-(triethyleneglycolmonomethylether)naphthoxy]acetyl-N-~2-hydroxy-5-methyl- 1-(2-methylpropyl)-4-~[[2-methyl- 1 -[[[2-(N-oxido)pyridinyl-methyl]amino]urbonyl~butyl]amino]carbonyl]hexyl]-N-alpha-methyl-~ [lS-[lR*,2R*,-4R#(lR#,2R#)]]- or 5-~triethyleneglycol monomethyl ether)-NOA-Asp-CVA-lle-Amp.
L-Aspara~inamide ether)naphthoxy~acetyl-N-[2-hydroxy-5-methyl- 1-(2-methylpropyl)~-[~12-methyl-1-[[[2-(N-oxido)pyridinylmethyl]amino~carbonyl]butyl]amin-o~carbonyl~hexyl~-N-alpha-methyl-, [lS-[lR*~'R#,4R*(lR*,2R*)]]- or 4-(triethylenegl-ycol monomethyl ether)-NOA-Asp-CVA-Ile-Amp;
N~x-[(2S, 4S, 5S)-5-[N-[Ntr-(l-Naphthalenyloxyacetyl) (2-pyridinyl)alanyl]-~o 91/~)fi~61 PCr/~S9~/0~XlX
-31- 2~
amino]-6-cvclohexvl-~-hvdroxv-2-isopropvl- 1 -oxohexyl]-N-(2-pyridinvlme~hvl)-L-isoleucinamide or NOA-His-CVA-lle-Amp;
Nc~ S~ lS~ ~S)-5-~N-~Ncr-( I-Naphthalenvloxvacetyl)-L-histidvl~amino3-o-cyclohe.Yvl-~-hvdrox~-~-isopropvl- I -oxohexyll-N-~ -pvridinylamino)ethyl]-L-isoleucinamide or NOA-His-CVA-lle-NH-~CH~-NH-~-pyridine);
~ -Quinolinvlcarbonyl-~S-amino-~-cyclohexvl-3R~4R-dihvdroxv-~R-isopropvl-hexanoyl-L isoleucyl-~-pyridinylamin~ethylamide or Qc-Asn-cvD-lle-Apr: and I-Naphthoxyacet~ L-histidyl~SS-amin~2R-benzvl-3R~R~ihydroxv-~-phenyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-PPD-lle-Amp~
DESCRIPI'ION OF lHE PREFERRED E~IBODIMENTS
In the Preparaùons and Ex~mples below and throughout this document 'H-NMR is nuclear ma~neùc resonance;
Ac is acetyl;
Aco is acetvloxy;
Amp is 2-(aminomethyl) pyridine:
Amp-NO is (2-pyridylmethyl) arnino, pyridine N-oxide:
Apr is 2-pyridinylamino-ethylamide.
Asn is asparagine;
Boc is ~-butoxycarbonyl;
'û BOP is benzotriazol-l-vloxytris~dimethvlamino)phosphonium hexafluorophos-phate Bz is benzyl;
C is centigrade;
Cbz is benzyloxyc~rbonyl;
CcD is the moiety of formula X wherein R, is cyclohexyl~ R2 is cY-hydroxy, R4 is ~-hydroxy and Rl is ~B-CH.-cyclohexyl;
CCD is the moiety of formula X wherein R, is cyclohexyl, R, is cr-hydroxy, R3 is c~-CH.-cyclohexyl and R~ is tr-hydroxy;
CDC13 is deuteriochloroform;
Celile is a filter aid:
CVA is Cha~[CH(OH)CH,~Val of formula X wherein R, is cyclohe~yl, R2 is hydrogen~ R3 is ~-isopropyl and R~ is ~-hydroxy;
chpVA is the moiety of formula X wherein R, is cycloheptyl, R, is hydrogen, `O 91/Oh~thl PCT/~`S91~ `N,lX
--3_-and Rl is Q^-isopropyl~ and R, is Q-hydroxy CLA is the moiety of formula X wherein R, is cvclohexvl~ R, is hvdroP~em R~
is -~-isobutyl~ and R~ is c~-hydrox~;
CLD is ~he moietv of forrnula X wherein R! is cyclohexyh R~ is c~-hydroxy~
R~, i5 ~ hydroxy and R, is Q~-isobutyl;
CPD is the moiety of formula X wherein R, is cyclohexyl~ R! is cr-hydroxy~ R~, is Q~-hydroxy and R~ is Q-~enzyl;
CVD is the moiety of formula X wherein Rl is cyclohexyl~ R, is ~-hvdroxy~
R!, is ~-isopropyl and R, is Q~-hydroxy;
C~J'D` is the moiety of formula Y wherein R, is cyclohexyl~ R is p'-hydroxy~
is a~-hvdroxv~ and R~ is Q~-isopropyl;
DANS is dans~,yl or 5-dimethylaminonaph~halenesulfonyl;
DCC is dicvclohexylcarbodiimide;
DEPC is diethylphosphor~,~l cyanide;
EtOAc is ethyl acetate;
g is gTams;
~-GIu is T-glutamic acid;
Gly is g,lycine;
His is histidine;
N-MeHis is Ncl~-methyl histidine HOBT is l-hydroxyben20triazole HPLC is high perforrnance liquid chromato_raphy;
Ile is isoleucine;
IR is infrared spectra;
~5 IVA is isovaleryl;
LCA is the moiety of formula X wherein R~ is isopropyl, R, is hydrogen, R3 is -c~-CH,~yclohexyl and R, is c~-hvdroxy;
LFA is the difluoro version of LVA as described more fully in PCT Pub No W086106379 (6 November 1985), and is the moietv of formula IV wherein R, is 30 isopropyl;
LLA is the moiety of formula X wherein R, is isopropyl, R2 is hydrogen, R3 is -cY-isobutyl, and R~ is ~-hydroxy;
LlD is the moiety of formula X wherein R, is isopropyl, R2 is ,B-hydroxy, R~

~O 91/~)6~61 I C~ `S9~ XlX
-3~-is B-hydroxy and R~ is B-isobutyl; 2 0 6 6`~
LLd is the moiety of formula X wherein R, is isopropyl~ R~ is a-hydroxy, R~
is a-hydroxy~ and R~ is ~-isobutyl:
LLD is the moietv of formula X wherein R, i5 isopropyl R~ is a-hvdrox~ R~
is a-hvdroxy~ and R? is a-isobutvl:
LPA is the moiety of formula ~ wherein R, is isopropyl~ R~ is hvdro~en~ R~
is -a-benz.vl and R~ is a-hydroxy;
LVA is Leu~(CH(OH)CH~)Val wi~h the ~ eonfi~uration at C~ ~the hydroxyl~
bearin~ carbon atom) of the forrnula X wherein R, is isopropyl, R. is hydrogen, R3 is 10 a-isopropyl and R~ is a-hydroxy;
L~JD is the diol version of LVA as described more fully in PCr Pub. No~
W08710530~ (11 September 1987) and is the moietv of formula ~: wherein R, is isopropyl~ R. is a-hydroxy, R~ is a-hydroxy and R3 is a-isopropyl;
LVDA' is the moietv of formula X wherein R, is isopropyl~ R. is B-hydroxy~
15 R, is a-hydroxy, and R3 is a-isopropyl;
M or mol is mole;
Mba is 2S-methv!butylamine~
Me is methyl;
ml is mil}iliter:
MPLC is medium pressure liquid chromato~raphy:
~IS is mass spectros~py:
NOA is (I-naphthvloxy)acetyl;
Ph is phenyl;
Phe is phenylalanine;
2~ POA is phenyloxyacetyl;
PPD is the moiety of formula X wherein R, is phenyl~ R, is a-hydroxy, R4 is a-hydroxy and R3 is a-benzyl;
Pro is proline;
'-Py-Ala is D~L-2-pyridyl-alamine.
RIP means a compound having the formula H-Pro-His-Phe-His-Phe-Phe-Val-Tyr-Lys-OH.?(CH3C(O)OH).XH.O which is a Icnown renin-inhibiting pep~ide;
TBA is t-butylacetyl;
TBAP is tetra-n-butylammonium phosphate;

~'O 91//)6~hl PCT/-`S91~/O:`~lX

2 0 ~ 4 TEA is triethvlamine:
TFA is trifluoroaceùc acid:
THF is tetrahvdrofuran:
TLC is thin laver chromato~raphy;
Tos is p-toluenesulfonyl:
TsOH is p-toluenesulfonic acid~
Tyr is tyrosine;
(OCH~)Tyr is O-methyl tyrosine; and Val is valine~
In formula ~;~ wherein the variables are as define~ abov~ is use~ to indicate ~he substituent is below the plane of the drawing and ~'` is used to indicate the substituent is above the plane of ~he drawin~
The wedge-shape line indicates a bond which extends abo~e the plane of the paper relative to the plane of the compound thereom The dott d line indicates a bond which extends below the plane of the paper relative to the plane of the compound thereom The following Preparations and Examples illustrate the present invention:
Examples I - 103.
Usin~ the chemical procedures~ starting materials~ and reactants described in 20 the publications listed in Table I below~ which are incorporated bv reference hereim or methods analo~ous thereto~ all of which are readilv known and available to one of ordinarv skill in the art~ the followin~ compounds of the present invenùon, having the indicat~d physical characteristics~ are pr~pared:
( I ) L-lsoleucinamide~ N2-(s-amtno ~-hydroxy-2-( 1 -me~hvlethyl)- 1 -oxooctyl]-25 N-(2-pyridinylmethyl~-~ trifluoroacetate~ (S~S~S)-; or H-LVA-Ile-Amp;
(2) lH-lmidazole-4-propanamide~ N-~2-hydroxy-S-methyl- 1-(2-methylpr-opyl~-4-[~r2-me~hyl- 1-~(2-pyridinylmethyl!amino]carbonyl]butyl]amino]carbonyl]hexyl]-cr-[(phenoxyacetyl)-amino]-, [lS-[lR~,2R~4R~(lR~,2R~)]~-; POA-His-LVA-Ile-Amp;
(3) lH-Tmidazole~-propanamide~ N-[l-(cyclohexylmethyl)-3,3~ifluor~-30 [[2-methyl-1-[[(2-pyridinylmethyl)amino]car~onyl]butyl]amino]-2~4-dioxobutyl]-~-[[(1-naphthalenyloxj)acetyl]amino]-, [lS-(lR~ R*),2R~]]-; or NOA-His-LFA-Ile-Amp;
(4) lH-Imidazole~-propanamide~ c~-[[2-(acetyloxy)-3-(1-naphthalenyl)-1-oxopropyl~amino~-N-[l-(cyclohexylmethyl)-3,3-difluoro-4-[[2-methyl-1-[[(2-pyridinyl-~'0 91/(~ 61 PCl`/l`S9n/O:`XlX
2 ~
-3~ -meth~l)amino]carb~onyl]butyl~amino]-2~4-dioxobutyl]-~ llS-[lR~R#tR~)]~'R#]]-;
(o L-Histidinamide~ N-[( I ~ I-dimethylethoxy)c~rbonvl)-L-phenvlalanvl-N-[ 1-(cyclohexvlmethvl)-~3-ditluoro-4-[~-me~hvl-1-[[(2-pvridinvlmethvl)amino)c~rbonvl]-butyl~amino]-~4-dioxobutvl~-: or Boc-Phe-His-LFA-Ile-Amp:
(~) IH-lmidazole~-propanamide~ N-[l-(cvclohex~lmethyl)-'-hvdroxv-~-meth~ -[[[~-methvl- I -[t(2-pyridin~lmethyl!amino]carbonvl]butyl)amino~carbonyl]-heptyl]-~-[~phenoxyacetyl)amino]-~ ~IS`[IR~R~)~''R'~4S~(IR~''R~3]]-; or POA-His-CLA-lle-Amp;
(7) IH-lmidazole-4 propanamide~ N~[',3~dihydroxy~methyl 1-~2-methvlpropyl)-4~[tt2~methyl~1~t~2~pyridinylmethyl)amino~carbonyl]butyl]amino]~
c~rbonyl]hexyl~ [(phenoxyacetyl)amino]~[lS-tlR~R#)~2S#~3R~4R#(lR#~'R~)]]~;or POA-His-LVDA~lle-Amp;
(8! lH~Imidazole~4-propanamideN-[2~3-dihydroxy-5-methvl-4-[[t2-methyl-butvl)amino]carbonyl]-I-~2-methylpropyl)hexyl~ [(phenoxyacetyl?amino]-, [IR-~IR-(S#)~ S#~3S#~4S#(S~)]~-; or POA~His~LVDA~Sba:

(9) Boc-Phe-His-Cha psilCHOHCHOHlVal~Ile-Amp; or L-Histidinamide~
N- [( I, I -dimethylethoxy)carbonyl]-L-phenylalanyl-N-l I -(cyclohexylme~hyl)-2 ,3-dihydroxy-5-methyl 4-1[[2-methvl-1-[[(2-pyridinylmethyl)amino~carbonyl]butyl]amino]-carbonyl]hexyl]-, rlS-llR#~2S#~3S~4S#(lR~,2R#)]]-;orBOC-Phe-His-CVD-Ile-Amp;
(10! l-Noa-His-Cha PSIlCHOHCHOHlVal-Ile-Amp; or IH-Imidazole~-propanamide~ N-[ I -(cvclohexvlmethvl)-' ~3-dihydroxy-5-methvl~-[[[2-methyl- 1-[[(2 -pvridinvlmethvl)amino~carbonvl)butyl]-[amino~carbonyl~hexyl~-ct-[[( l-naphthalenvloxy)-acetyl~amino~-, [lS-[lR'~R~)~2S#,3S#~4S~(lR~''R~ -; or NOA-His-CVD-Ile-Amp;
(11~ lH-lmida~ole~-propanamide, N-[2-hydroxy-~methyl-1-t2-methyl-2~ propyl~-[[['~-methyl- 1-[[(2-pyridinylmethyl)amino~ca~bonyl~butyl]amino~carbonyl]hep-tyl~-~-[(phenoxyacetyl~amino]-, [lS-[lR~(R#),2R'~,4S#(lR~2R~)]]-;or POA-His-LLA-Ile-Amp;
(12) lH-Imidazole~-propanamide, N-[2-hydroxy-1-(2-methylpropyl)-5-[~2-methyl- 1 -[~(2-pyridinylmethyl)amino]carbonyl]butyl]amino]-S-oxo-4-(phenylmethyl)-pentyl~ -[(phenoxyacetyl3amino]-, 11S-[lR*(R#),2R~,4S~,5(1R~,2R~)]]-; or POA-His-LPA-Ile-Amp;
(13) lH-Imidazole-4-propanamideN-[4-(cyclohexylmethyl)-2-hydroxy-1-(2-methylpropyl)-5-[12-methyl- 1 -[[(2-pyridinylmethyl3amino]carbonyl~butyl~amino]-5-~`O 91 /nh~6 1 Pcr/ ~ S9~ X I x 2 ~ 3~
oxopentvl~ [(phenoxyacetyl)amino]-~ tlS-~lR-(RJl~2R-~4S~,5(lR-,2R~)]]- or POA-His-LCA-lle-Amp;
(14) L-His~dinamide~ N-[~l~l~imethvle~hoxy)ca~onyl]-L-phem,lalanyl-N-t'-hvdroxy- I -(2-methylpropyl)-5-[t2-methyl- 1 -~('-pyridinylmethyl)amino~carbonyl]butyl]-amino--5-oxo-~ (phenvlmethyl)pentyl]-~ tlS-tlR~'R~4S'~5(1R~'R-)]]- or Boc Phe-His LPA-lle-~mp;
(15) L-Histidinamide~ N-[~l~l~imethyle~hoxv)~rbonyl~-L-phenylalanyl-N-~4-~cvclohexylme~hyl)~2 hydroxy~ ' met~hylpropyl)-5-~t2 methyl 1 t~(2 pyridinylmethyl)-arnino]car~onyl]butyl~amino]-5 oxopentyl~ ~ tlS tlR~2R~4S~(lR~R~)]]-; or Boc-10 Phe His LCA-lle-Amp;
~ 16) L-Talonarnide~ ~cyclohexyl-2~5~trideoxy 5-rN-rN-~ I-dimethyleth-oxv)carbonyl]-L-phenvlalanyl]-L-histidyl~amino]-2-~ 1-methylethyl)-N-~2-methvl~
pyridinvlmethyl)amino~carbonyl]butyl~ S-(R-~R-l]-; or Boc-Phe-His-CVD`-Ile-Amp;
(17) L-Histidinarnide~ N~ I-dimethylethoxy)carbonyl]-L-phenylalanyl-N-15 ('~3-dihydroxv-S-methyl-1-(2-methvlpropyl~-4-~('-methvl-1-~[( -pyridinylmethyl)-amino~c~rbonyl]butyl]amino]carbonyl]he~yl]-, [lS-[lR-~S~,3R-~4-Amp; or Boc-Phe-His-LVDA`-Ile-Amp; FAB-MS tm + Hl~ at 835~5084;
(18) 4-Morpholinebutanamide~ B-hydroxv-N-[2-[~2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[12-methyl- 1 -~t(2-pyridinvlmethyllamino]carbonyl]butyl]amino] -20 carbonyl]hexvl]amino]-1-(1H-imidazol~-ylmethyl)-2-oxoethvl]-~-(1-naphthalenvlmethyl)-t-OXO-~ ~lS-~lR'tR-(o~S ~R')]~'R~4R-(lR ~R~)~]-;
(19) lH-lmidazole~-propanamide~ N-~l-(cyclohexylmethyl)-2-hydroxy-5-methvl~-~2-methyl-1-t~(2-pyridinylmethyl)amino~carbonyl~butyl~an~ino)calbonyl~hexyl~-~-~(phenoxyacetyl)amino]-, ~lS-~lR~(R~)~'R~4R~(lR'~'R-)~3-; or POA-His-CVA-Ile-~5 Amp; FAB-MS tm ~ Hl~ at 746~4598;
(20) lH-lrnid ~ole-1-propanamide~ 5-(dimelhylamino)-1-naphthalenyl]su-lfonyl~amino]-N-~2-hydroxy-5-methyl- 1 -(2-methylpropyl)-4-~[2-methyl- 1-[[(2-pyridinylmethyl)arnino~car~onyl]butyl~amino~carbonyl]he~yl]-~ [lS-~lR-(R-)~2R-,-4R~(lR-,~R-)]~-; or DANS-His-LVA-Ile-Amp;
(21) lH-lmidazole-4-propanamide~ N-[l-(cycloheptylmethyl)-2-hydro~y-5-methyl~-[[[2-methyl- 1 -[[(2-pyridin~lmeshyl)amino~rbonyl~butyl]amino]carbonyl]hexyl~-c~-[(phenoxyacetyl)amino~-,[lS-[lR-(R-~,2R- ~4R-(lR-,2R7]~-;o~'OA-His~hpVA-Ile-Amp;

~O 91/06~61 PCT/~S91)/O~Xl~
-37- 2~S~
('') L-Histidinamide~ N-[[5-(dimethvlamino)-1-naphthalenyl~sulfonyl]-L-phenvlalanyl-N-t2-hydroxy-5-methyl- 1 -(2-methylpropyl)-4-[[~2-methvl- 1-[[(2-pvndinvlmethvl)amino)carbonyl)butyl]amino)carbonyl~hexyl~-~lS-~lR~2R~4R~( IR~-'R~)]]-: or DANS-Phe-His-LVA-lle-Amp;
('3) Octanamide~-[~3~3-dimethyl-1-oxobutyl)amino]-4 hydroxy-7-methyl-`-(I-methvle~hyl) N ~2 methyl 1 [~(2 pyridinylmethvl)amino~carbonyl~buty~ t2S-tl~lR~2R~)~2R~,4R''~5R~ or TBA LVA-lle^Amp; FAB MS: [m + H)~ at 533:
~4) Cyclohexanehexanamide~ ~[(3~3~imeshyl-1-oxobutyl)amino~-r~hydroxv-~-~1 me~hylethyl) N 12 methvl 1 [~(" pyridinylmethyl)amino~carbonyl]butyl], [c~S-[NtlR~'`R~ R~,rR~R~ or TE~A CVA~lle Arnp; FAB MS: tm + Hl~ at 573:
125) IH Imida201e 4 prop~namide~ ~-amino-N [2 hydroxy 5 methyl 1 ~2-methylpropyl)~4~[[[2~methvl~ 1 ~[[(2~pyridinvlmethyl)amino~carbonyl~butyl~amino~-~arbonvl]hexyl] . tIS [IR~ ),2R#~4R~(IR~''R~ or H-His-LVA-lle-Amp;
( 6) L-Histidinarnide~ L-phenylalanvl-N-t~-hydroxy-S-methyl-1-(2-methylpro pyl)~-[[['-methyl- 1-[[(2-pyridinylmethyl)amino)carbonyl]butyl~amino)carbonyl]hexyl]-, [lS-(lR~2R~,4R~(lR~,2R~)~]- or H-Phe-His-LVA-Ile-Amp;
(27) Cyclohexanehexanamide~ ~amino-J-hydroxy-tY-(l-me~hylethyl)-N-[[2-methyl-1-[[(2-pyridinylmethyl)]amino]carbonyl]butyl)-dihydrochloride,[~S-rN(lR~,2R-YR~TR~,~R~))- or H-CVA-Ile-Amp; FAB-~IS: lm ~ H)~ at 475;
-- 20 (28) Cvclohexanehexanamide~ ~(acetylamino)-J-hydroxy-~r-( I -methylethyl)-N-[2-methyl-1-[1~pyridinylmethyl)amino]c~r~onvl]butvl), ~CYS-rN(lR~'R''),~RY~JR~~R~]~-; or Ac-CVA-Ile-Amp; FAB-MS: [m ~ H]~ at 517;
(29) (~namide~ 5-(ace~ylamino)-4-hvdroxy-7-methyl-2-(1-methylethyl)-N-~2-me~hyl- 1-[[~2-py,ridinylmethyl,~arnino)wt)onyl)butyl]-, rS-[N(lR~,2R~),2R~,4R~,5R~]]-, '`5 monoacetate ~salt); or Ac-LVA-Ile-Amp: FAB-MS: [m ~ H~ ' at 477;
~ 30) L-Valinamide~ L-phenylalanyl-N-t2-hydroxy-5-methyl-1-(2-methylpropy-1)-~-[[[2-methvl- 1 -[[(2-pyridinylmethyl)amino)carbonyl)butyl)amino)carbonyl)hexyl]-, tlS-~lR~,2R~,4R~(lR#,2R~)]~-; or H-Phe-Val-LVA-Ile-Amp;
(31~ Octanamide~ 5-lt2-(a~esylamino)-3-methyl- 1 -oxobutyl]amino]~hydroxy-30 7- methyl-2-( 1-methylethyl)-N-~2-methyl- 1 -[~(2-pyridinylmethyl)amino]carbonyl]butyl] -, [2S-[N(lR~,2R~),2R~,4R~SR~(R~)I]-, monoacetate (salt); or Ac-Val-LVA-Ile-Amp;
FAB-MS: [m ~ Hl ` at 576;
(32) L-Valinamide~ L-valyl-N-[2-hvdroxy-5-me~hyl-1-(2-me~hylpropyl)~-[[

~0 91/~)6~hl Pcr/~'s9n/o~xlx 2 ~ 4 -38-methvl- I -[[(2-pvridinvlmethyl )amino]carbonyl]butyl)amino)carbonyl]hexyl]- ~ [1 S-[lR~,2R~,4R~(lR~2R~)]]-, diacetate (salt); or H-Val-Val-LVA-lle-Amp; FAB-MS: lm + H]l at 633:
(33) Ac-Asn-LVA-lle-Amp; FAB-~S: lm ~ H]' at 591;
(34) L-Valinamide~ N-acetvl-L-valvl-N-tr'-hvdroxv-5-methvl- 1-(~-methylpro~
yl)-4-[[t2-methyl- 1 -[[(~-pyridinylmethyl)amino~carbonyl]butyl~amino)carbonyl]hexyl]-[ IS-~ lR#.2R~4R~( lR'~2R~)]~-~ monoacetate ~alt); or Ac-~`al-Val-L~,'A-Ile-Amp; }:AB-I~IS: tm + Hl~ at 67~;
~3~) Nc~-t(~S~4S~5S)-5~rN~rN~^(Phenoxymethylcar~onyl)~L-histidyl]amin~5-10 hydroxy~2~isopropyl~7~methyl~1-oxooctyl]~N-~2~2~pyridinylamino)ethyl]-L~isoleucin-amide~ acetic acid sa~t; or POA~His~LVA~lle~ CH2~2NH~pyridine; FAB~MS: [m +
Hl~ at 735;
(36) IVA-LVA-lle-Amp; FAB-MS: tm + H~ at 519~
(37) N~[~S~4S~5S)~S~rNcY-rNtY-~tert-Butoxycarbonyl)-O-methyl-L-tyrosyl]-L-15 histidyl~aminol-4-hydroxy-7-methyl-2-phenylmethyl- 1 -oxooctyl]-N-[(S)-2-hydroxy-propyl]amine; or Boc-OMe'I`yr-His-LPA-NH-CHl-CH(CH3)(0H); FAB-MS: [m + H]~
at 751;
(38) N~-[(2S,4S,5S)-5-rN{N~-(Phenoxyrnethylcarbonyl~-L-histidyl]an~ino]~-hydroxy-2-isopropyl-?-methyl- 1 -o~ooct,vl]-N-(2,3-dihydroxypropyl)-L-isoleucinamide:
20 or POA-His-LVA-lle-NH-CH.-CH(OH)-CH.OH; FAB-MS: lm + Hl~ at 689;
(39) N~-t(2S~4S~5S)-5-rN~NcY-(Phenoxvmethvlcarbonvl)-L-histidyl]-amino~-hydroxy-2-isopropyl-7-methvl- 1-oxooctyl]-N-(2-hydroxypropyl)-L-isoleucinamide: or POA-His-LVA-Ile-NH-CH~-CH(CH3)(0H); FAB-MS: [m + H]~ at 673:
(40) N~-1(2S,4S ,5S)-5-[lN~[(S)- 1 -Acetoxy- 1 -benzyl)rnethylcarbonyl]-L-25 histidyl]an~ino]~-hydroxy-7-methyl-2-(1 -methylethyl)- 1 -oxooctyl]-N-[2-pyridyl)ethyl]-L-isoleucinamide; or AcO-Phe-His-LVA-Ile-NH-(CH,~-pyridine; FA~MS: [m + Hl ' at 776;
(41,~ NcY-~t2S~4S,~S)-S-t[(S)-(l-Hydroxy-l-benzyl)methylcarbonyl]arnino]~-hydro~y)-7-methyl-2-(1 -methylethyl)- 1 -oxooctyl]-N-(2-pyridinylme~hyl)-L-isoleucinan~ide;
30 or H~Phe-LYA-Ile-Amp; Hi~h Resolution MS: 583~3880;
(42) NCY-[(2S~ 4S~ SS)-S-rN-rNcr-(l-Naphthalenylo~yacetyl)-L-histidyl]amino]-~cyclohexyl~-hydro~y-2-isopropyl-1-o~ohe~yl]-N-(2-pyridinylmethyl)-L-isoleucinamide, pyridine N-o~ide or NOA-His-CVA-Ile-Am~NO, HR FAB MS [m+H~t at m/z ~O 91/Oh~61 PCT/~S9~ XI~
2~66~

812~4748;
(43) Ncr-[~2S~ 4S~ 5S)-5-~N-rNcr-(P-toiuenesulfonyl)-L-histidyl]amino]-6-cvclohexvl-~-hvdroxy-~-isopropvl- I-oxohexvl~-N-~'-pyndinvlmethvl~-L-isoleucinamide or p-Tolunesulfonvl-His-CVA-lle-Amp. HR FAB t~,lS ~m ~ Hl' at miz 766.4348:
S (~) N~ S~S~5s)-5-~N-~ -Naphthalenvloxvacetyl)-L-histidyl~aminol ~cyclohexyl ~hydrox~ ~-isopropvl-l-oxohexyl~-N-('-pvridinylmethyl)~L-isoleucinamide or NOA His CVA~Ile Amp~ HR F~B ~iS [m + Hl-' at m/z 7~ 4794;
~45) Nct [~2S ~ ~S ~ 5S)-S-tN-rNc~-~Phenoxvmethylwbonyl~-L-histidyl~amino]-~-cyclohexyl~-hydroxy-2-isopropyl~ 1 -oxohexyll-N-~2-pyridinylmethyl)-L-isoleucinamide~
pyridine N-oxide Ot POA-His-CVA-Ile-Amp-NO~ HR FAB MS lm + Hl~ at m/2 7~2~4574;
(4~) N~ ~(2S~ 4S~ 5s)-5-rN-rNtr-t~Toluenesulfonyl) L histid~vl]amino] 6 cyclohexyl-4-hydroxy 2 isopropvl-1-oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucinamide~
pyridine N-oxide or ~Toluenesulfonvl-His-CVA-Ile-Amp-NO~ HR FAB ~IS [m + H]~
at m/z 782.4 38:
(47)N~-[(2S~4S,5S)-5-rN-~Nc~-(l-Naphthalenyloxyacetyl)-L-hisidyl]amino]-~
cyclohexyl-4-hydroxy-2-isopropyl- 1 -oxohexyl]-L-lysine, trifluoroacecticacid saltorNOA-His-CVA-L-lysine~tnfluoroacetic acid salt~ HR FAB MS lm + H~ ` at m/z 721.4309:
(48) N-[(2S~ 4S ~ 5S)-5-rN-rN~-( I -Naphthalenyloxyacetyl)-L-histidyl]amino]-~
20 cvclohexyl~-hydroxv-2-isopropyl-1-oxohexyl]-N-['-(2-pyridinylamino]ethyl]-arnine or NOA-His-CVA-NH-(CH~!.-NH-(2-pyridine) HR FAB MS [m + Hl at m/z 712.4195:
(49) N-[(2S~ 4S~ 5S)-5-rN-rNc~-( l-Naphthalenyloxyacetyl)-L-hisidyl]amino]-~cyclohexvl~-hvdroxy-2-isopropyl- 1-oxohexyl]-N-[2-(2-pyridinylamino)]ethyl]amine, -pyridine N-oxide or NOA-His-CVA-NH(CH.)2-NH-(2-pyridine)~ HR FAB MS [m +
~5 Hl~ at m/z 728~41 l4;
(50)N~-t( S~4S~5S)-5-1N-rNc~-(l-Naphthalenyloxyacetyl)(2-pyridinyl)alanyl]-amino~-6-cyclohexyl-4 hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucinamide or NOA-His-CVA-Ile-Amp. HR FAB MS [m + H~+ at m/z 807.4795;
~ 51) N~-[(2S~ 4S, 5S)-5-rN-[N~-[(3-Pyridinyl)-methylcarbonyl]-L-histidyl]-30 amino]-6-cyclohexyl-~-hydroxy-2-isopropyl- 1 -oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucinamide or (3-pyridinyl)-methyl car~onyl-His-CVA-Ile-Amp. HR FAB MS [m + Hl~ at mlz 731.4625;
(52) N~-rN~-[(2S, 4S~ Ss)-5-rN-rNcr-(l-Naphthalenyloxyacetyl)-L-histidyl]

~`0 91 /Oh:`6 1 PC'r/ ~ S9(~/O~ I X

ohexyl-~-hydroxv-2-isopropyl-1-oxohexyl~^L-isoleuncyl]-L-lysine~
tritluoroaceùc acid salt or NOA-His-CVA-lle-L-lvsine~ tnfluoroacetic acid salt~ HR
FAB I~S Im~Hl~ at miz 8~.5151:
(53)N~-[(2S ~S ~5S)-5-rN-~Nct-( I -Naphth~lenyloxyacetyl)-L-hisùdyl]amino~-6-5 cyclohexyl-~ hydroxy- -isopropvl-1-oxohexvl]-N-t2-(2-pvridinyl~mino)ethyl]-L-isoleucinamide or NOA His-CVA-lle-NH-~CH~h-NH-(2-pyridine)~ HR FAB hIS
[m+Hl~ at mlz 8~5~50~0;
(5~! lH-lmid~ol~-propan~mide~N~t~-hydroxv~5-methy~ 2-methylpropyl) ~-~[~-methyl-l t[(2-pyridinylmethyl)amino]c~rbonyl]butyl]amino]earbonyl]hexyl~ [~2-10 hydroxv-l~x~3-phenylpropyl)amino]-~tlS-tlR~rR~)]~''R~4R~(lR~'R~)]]~ 2-hydroxv- I ~ ~3-propanetricarboxylate ( I 2~ ~salt) orphenyl-CH. CH~OH) C~O) His-LVA-Ile-Amp~ HR FAB hIS ~m +H]~: 720~4~56:
(55) lH-Imidazole~-propanarnide~N-t2 hydroxv l-~[tl t[(2-hydr~xy-2-phenylet-hyl)amino~carbonyl]-2-meth~butyl]amino]carbonvl]-5-methyl-1-(2 methylpropyl)hexyl~
15 [(phenoxyacetyl)arnino]-~monoacetate (salt) or POA-His-LVA-Ile-NH-CH.-CH(OH)- phenyl. HR FAB MS lm +Hl~: 735.4444;
(56) L-~Y Glutamine~ N/u 2/d rN [[I~l-dimethylethoxy)carbonyl]-L-phenylal-anyl]-N-[2-hydroxy-5-methyl- 1 -(2-methylpropyl)-4-[[[2-methyl- 1 -[[(2-pyridinyl-methyl)amino~carbonyl]butyl~amino]carbonyl]hexyl]-,[lS-~lR~2R"'4R'~(lR'~2R#)]]-'O ~monace~ate (salt) or BOC-Phe-Glu-LVA-lle-Amp~ HR FAB MS [m +Hl ': 811.4988:
t57) Pentanoic acid~ 5-[[1-(cvclohexvlmethyl)-2-hvdroxv ~-[[(2-hydroxy-propyl)amino]carbonyl~-5-methylhexyl~amino~-5-oxo~-[(phenoxyacetyl)amino]orPOA-Glu-CVA NH-CH,CH(CH3)~OH)~ HR FAB MS [m +H~: 630.3146;
(58) lH-lmidazole~-propanamide~ N-[l-(cyclohexylmethyl)-2-hydroxv-4-[[(2-25 hydroxypropyl~amino~carbonyl~-5-methylhexyl~ct-[(phenoxyacetyl)amino]-,monoacetate (salt) or POA His-CVA-NH CH, CH(OH)(CH3)~ HR FAB MS [m +H~: 600.3770;
(59) Pentanoic acid~ 5-[[l (cyclohexylme~hyl)-2-hydroxy-5-meshyl~[[r2-me~hyl-I [[(2 pyridinylmethyl)amino~carbonyl~butyl~amino]carbonyl~hexyl]amino]-4-[(lH-indol-2-ylcarbonyl)amino~-5-oxo-,[lS-[lR*(R~'),2Rt~4R'~(lR~,2R~'~)]]- or lH-indol-2-yl-30 carbonyl-Glu-CVA-lle-Amp~ HR FAB MS [m ~Hl~: 747~4437;
(60) L-.alpha.-Glutamine~ N-[ l-(cyclohexylmethyl)-2-hydroxy-5-methyl~-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-N/u 2/d-L-phenylalanyl-, [lS-[lR~,2R'~,4R~(lR~,2R~)]]-, bis(trifluoracetate) (salt) or Phe-Glu-~o 91/~6~61 Pcr/~ssn/ûsxlx - 2~6~
CVA-lle-Amp. HR FAB MS [m +H]~: 751.4756:
(61 ~-PvridineacetamideN-['-[[2-hydroxy-~-methyl- 1 -(2-methylpropyl)-4-[[[2-methyl- I -[t(2-pvridinvlmethyl)amino]~bonvl]butyl~nino)~rbonyl]hexyl]amino] - I -( I H-imid~zoi~-ylmeth~ l)-'~xoeth~l]-~ l S-t l R~R~)~'R ~4R~( l R~ 2R~)] i-or ~2-Pvridvt)a~etyl-5 His-LV.~-Ile-Amp~
(~) 4-Pyridineacetamide~ N-[2-t[2~hvdroxy^~methyl-1 (2-methvlpropyl)-4-[[[2methyl- 1-~[~2~pyridinylme~hyl)amino]carbonyl)butyl]~mino~&arbonvlJhexyt]amino]- I -~IH-imida~ol-~-ylmethyl)-~-ox~eth~ [lS-[lR~R~)~2R~4R~(lR~2R~]~-or (4-Pyridyl)acetvl-His-L~A-lle~Amp;
(~3) L-Hisùdinamide~ N-t(l~l-dime~hylethoxy~rbonyl]-3-(2-pvridinyl)alanyl-N-t2-hydroxv-~-methyl- 1 -(2-methylpropyl!-4-[t[2-methyl- 1 -[t(2-pyridinylmethyl)aminolc-arbonyl]butyl]amino]c~rbon~l]hexyl]-~[lS-tlR~tR~tE)]~2R~4R~(lR~'R~)]]~orBOC-2-Py~Ala-His-LVA-lle-Amp~ HR FAB ~S [m +H]~: 820~5112:
(64~ L-Histidinamide~ N-[(l~l-dimethvlethoxy)earbonyl]-L-phenylalanyl-N-t4-[[[2-[(2~o diamino-4-pyrimidinyl)amino]ethyl]amino~carbonyl]-2-hydroxy-5-methyl-1-( -methylpr~pyl)hexyl]-,[lS-(lR~,2R~,4R~)]- or BOC-Phe-His-LVA-(2,o-dian~lno-4-pyrime-dinyl)amino-ethylamino~ HR FAB MS [m + H]~: 766~4727;
(65) L-~alpha~-Aspara~ine~ N/u 21d-lN-[(l,l-dimethylethoxy)carbonyl]-L-phenylalanyl]-N-12-hydroxv-5-rnethyl- 1 -(2-methylpropvl)~-~[2-methvl- 1 -[[(2-pyridinylme-thyl)amino]carbonyl]butvl]amino]carbonyl]hexyl]-~llS-tlR~2R~4R~(lR~,2R~)]]-~monoacetate ~sal~) or BOC-Phe-Asp-LVA-Ile-Amp~ HR FAB MS [m +H] ~: 797.4857:
(66) lH-lndole- carboxamide~ N-[2-([2-hydroxy-5-methyl- 1 -(2-methylpropyl)-~-[t2-methyl-1-[[(2-pyridinylmethyl~amino]carbonyl]butyl]carbonyl]he~yl]amino]- 1-( lH-imidazol~-ylmethyl~-2-oxoethyl]-,[lS-[lR#(R~)~'R~4R~(lR~,2R~)]]-or N-(Indolyl-2-carbonyl!-His-LVA-lle-Amp;
(67) L-~alpha~-Glutamine~ N-[l,l-dimethylethoxy)carbonyl]-L-phenylalanyl-N0[1-~cyclohe~ylmethyl)-2-hydroxy-5-methyl 1-[[[2-methyl-1-[[(2-pyridinylmethyl)amin-o~c~r~onyl]butyl]amino]car~onyl]hexyl]~-,[lS-[lR~,'R~,4R~(lR~,2R~)]]-, monoacetate (salt) or BOC-Phe-Glu-CVA-Ile-Amp~ HR FAB ~IS [m + Hl~: 851.5297;
(68) ~,5,11,14-Tetraazapentadecanoic acid, 7-hydroxy-3-(lH-imida~ol~-ylmethyl)-9-( 1 -methylethyl)- 12-(1 -rr.ethylpropyl)~(2-methylpropyl)-4 ,10,1 3-t~ioxo- 15-(2-pyridinyl)-,~-pyridinylmethyl ester, [3S-[3R~,6R~,7R~,9R~,12R~ )]]- or Ioc-His-LVA-Ile-Amp;

wo 91 /06~61 PC r/ ~`S9/)/~ I x t69~L-HistidinamideN-[( I ~ I -dimethyleLhoxy)carbonvl]-L-phenylalanyl-N-13~3-difluoro-2-hvdroxy~-[['-methyl- 1 -~[(2~pvndinylmethyl)amino]carbonyl]butyl)amino~
oxo-l-(phenvlmethyl)butyl]- or CH~-C(O)-O-CH(benzvl)-C(O)-His-LVA-lle-Amp. HR
FAB MS lm + H]~: 76~.45~1:
(70) I H-lmidazole~-propanamide, N-~'^hvdroxv~5-methyl- I -~'-methvlpropyl)-~-[[~-methvt-1 [[(2-pvridinvlmethyl~amino~c~rbonyl]butyl~amino~c~rbonyl~hexvl~
oxo-3-phenoxypropyl)amino]-~[ls-[lR#tR#!~2R#~4R~lR~R~ or Phenoxv propionyl-His-LVA-Ile-Amp;
~71) lH-lmidazole-4-propanan~de~N~2~hydroxy3~methvl~ 1 ~t2~methylpropyl) ~-[t~2~methyl~1~t~[(2~pyridinylmethyl)amino[carbonylrbutvl~amino[earbonyl~hexyl] c oxo-3phenyl~2~propenyl)amino]~,[1S~lR#[R~E)],2R~-SR~lR~. R#)])~ or phenvl~
CH=CH~C~O)-His-LVA-lle-Amp. HR FAB MS [m + Hl~: 702~4343;
tr) lH-lmidazole~ propanamide,N-r2 hydroxv 5 methyl 1-t2-methylpropyl)~-~[~2~methyl- 1 -[[[(2-pyridinylmethyl)amino[carbonyl]rbutvl]amino~carbonyl[hexyl]-~-[(1 -oxo-4-phenyl-3-butenyl)arnino]-,~lS-[lR'rR#(E)]~2R~4R~(lR#~2R#)]~- or phenvl-CH=CH-CH.-C(O)-His-LVA-Ile-Amp. HR FAB MS [m + H~: 716~4474;
(73) ',5,11~14-Tetraazapentade~anoic acid, 7-hydroxy-3-(lH-imidazol-4-ylmethyl)-9-(1-methylethyl)-12-(1-methylpropyl~(2-methylpropyl)-4~10~13-trioxo-15-(2-pyridinyl)-,3-phenyl-2-propenyl ester~ ~3S-lI(E)~3R~6R~7R#~9R#~12R#~#)]]- or phenyl-CH=CH-CH2-~C(O)-His-LVA-lle-Amp~ HR FAB MS [m + H~t: 732.4463:
(74) lH-Imidazole 4-propanamide~N-~-hvdroxv-5-methvl-1-(2-methylpropyl) 1-[[[2-methyl-1-[[(2-pyridinvlmethYl~amino~carbonyl]butyl~amino]carbonyl~hexyl~-ct-[[(-phenvlethenyl)sul~onyl~amino]-,[lS-[lR#rR#(E)],2R#,4R#(lR#~2R#)~]-or phenyl -(CH2h-SO.-His-LVA-Ile-Amp~ HR FAB MS [m ~ H~: 738.4061;
(75) N-tert-Butyloxycarbonyl-L-phenylalanyl-L-histidyl-5S-amin~3R,4R-dihydroxv-2R~isopropyl-7-methyl octanoyl-2S-methvlbutvlamideorBOC-Phe-His-LVA-~Iba. FAB-MS (found): 701.4634;
(76] Hydroxyacetyl-L-histidyl-5s-amino-~cycloh~xyl-3R~4R~ihydroxy-2R
isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or (HO)Ac-His-CVA-Ile-Amp.
FA~MS (found): 686~424~;
(77) L-Glycyl-L-histidyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or Gly-His-CVA-Ile-Amp. FAB-MS (found): 685.4382;

0 91 /~h~61 r,~ s9~/o ~~ l x (78) Hvdroxyacetvl-L-histidyl-SS-amino-2R-benzyl-6-cyclohexyl-3R~4R-dihvdroxv-hexanovl-L-isoleucvl-~-pyridvlmethvlamide or ~HO)Ac-His-CPD-Ile-Amp~
FAB-I~IS (found!: 734~4~4~
(79~ Hvdroxyacetvl-L-histidy!-SS-amino-~R benzvl-6-cyclohexyl-3R.4R-S dihvdroxv-hex~novl-L-isoleucyl-~-pyndvlmethylamide~ N-oxide or ~HO)Ac-His-CPD
lle Amp~ FAB-1-tS ~tound): 750.4'0~;
~ 80) Phenoxyacetyl-L his~idyl-SS-amino-'R-benzyl-6-cyclohexyl-3R~4R-dihydroxy-hexanoyl~L-isoleucyl- '-pyndylmethylamideorPOA-His-CPD-Ile-Amp~ FAB
MS ~ound~: 810.45~;
1~ ~81) L-Glycyl-L histidyl-5S-amino-2R-benzyl-6-cyclohexyl-3R~4R-dihydroxy hexanovl-L-isoleucyl-2-pyridylmethylamideorGly-His-CPD-lle-Amp, FAB-I~S~found):
733.4~
(8 ') Phenoxyacetyl-L-histidyl 5S-amino-6-cyclohexyl-3R~4R-dihydroxv-2R
isopropyl-hexanoyl-L-isoleucyl-2-pyridvlmethylamideorPOA-His-CVA-Ile-Amp, FAB-15 MS (found): 76- 4574;
(83)1-Naphtoxyacetyl-L-histidyl-5S-amin~6-cyclohexyl-3R~4R-dihydroxy-2R-isobutyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-CLD-lle-Amp, FAB-MS (found): 826:
(84) 1-Naphthoxyacetyl-L-histidvl-5S-amino~cyclohexyl-2R-cyclohexylmethyl-20 3R,4R-dihvdroxy-hexanoyl-L-isoleucyl-'-pvridylmethvlamide or NOA-His-CCD-lle- Amp~ FAB-~S (found~: 866.S189;
(85~ 1-Naphthoxyacetyl-L-hisùdvl-SS-amino-2R-benzyl-3R,4R-dihydroxy-6-phenyl-hexanoyl-L-isoieucyl-2-pvridylmethylamide or NOA-His-PPD-Ile-Amp~
FAB-MS (found): 854.4'30;
'5 (86~ 1-Naphthoxyacetyl-L-histidyl-5S-amino~cyclohexyl-3R,4R-dihydroxy-2R-isopropvl-hexanoyl-L-isoleucvl-~-pvridinylamino-ethylamideor NOA-His-CVD-lle-Apr~
FAB-MS (found): 841,4964;
(87~ -Naphthoxvacetyl-L-histidyl-5S-amino-~cyclohexyl-2S-cyclohexylmethyl-3R 4R dihydr~xy-hexanoyl-L-isoleucyl-2-pyridvlmethyla~lude or NOA-His-CcD-Ile-Amp.
30 FAB-MS (found): 866.S194~
(88) 1-Naphthoxyacetvl-L-histidvl-SS-amino-3S-4S-dihydroxy-2S-isobutyl-7-methyl-octanoyl-L-isoleucyl-2-pyridylmethylamideorNOA-His-LlD-Ile-Amp, FAB-MS
(found): 786,4540;

~`0 91/~h~61 PCT/~`S9~)/O:`XIX

2 ~ ~ ~89~5-Quinolinvlhvdroxvacetvl-L-histidvl-55-amino-o-cyclohexvl-~S-hvdroxy-2S-isopropyl-hexanovl-L-isoleucvl-2-pvridvlmethylamide or Qoa(b)-His C~ lle-Amp~FAB-MS (t`ound~: 797:
(90) ~-Quinolinvlhydroxvacetyl-L-histidyl-5S-amino-~-cvclohexvl--~ S-hydroxv-2S isopropyl-hexanovl-L-isoleucvl-'-pvridvlme~h~vlamid~ or Qoa~a)-His-C~ ~-lle-Amp.
FAB-MS (tound~: 797:
(9 l ) I -Naphthoxvacetvl~L-histidvl~55~amin~3R-~R-dihvdroxv~S~isobu~
me~hyl~octanoyl~L~isolcucvl~2~pyridylmethylamideorNC)A~His~LLd~Iie~Amp~ FAB~MS
~tound~: 7S~ 7 (92) 1~Naphthoxvacetyl~L~histidvl~5S~amino-3S~R~dihvdroxy~2S~isobutvl~7 methyl~octanovl L~isoleucvl~pvridylmethylamideorNOA~His~LL~-Ile Amp~ FAB-MS
(found): 78~4556:
t93 ) 1 -Naphthoxvacetvl-L-histidvl~5S~amino-3R-4R-dihydroxy-' R-isobutvl-7-methvl-octanovl-L-isoleucvl-2-pyridylmethvlamideorNOA-His-LLD-Ile-Amp~ FAB-MS
15 (found): 786~5~0:
(9~) 2-Quinolinylcari~onyl-5S-amino-6-cvclohexyl-3R~4R-dihvdroxv-2R-isopropyl-hexanovl-L-isoleucyl-2-pyridinylamino-ethvlamide or Qc-Asn-CVD-Ile-Apr.
FAB-MS (found~: 789~4670:
(95) N-tert-Butvloxvcar~onyl-L-alanyl-5S-amino-~cvclohexyl-4S-hydroxv-2S-20 isopropyl-hexanovl-L-isoleucvl-~-pyridvlmethvlamide or Boc-Ala-CVA-Ile-Amp. FAB-MS ~m H~-: 5~6:
(96)~-tert-Butvloxyc~rbQnyl-L-histidyl-SS-amino-~cyclohexyl~S-hydroxy-2S-isoprop,vl-hexano,vl-L-isoleucyl-2-pyridvlmethylamideorBOC-His-CVA-Ile-Amp. FAB-MS lm + Hl~: 7l2:
'5 (97~ -Deleted-(9O Quinolinyl-2~bonyl-L-histidyl-5S-amino-~cyclohexyl~S-hydroxy-2S-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or QC-His-CVA-Ile-Amp. FAB-2~11S [m + H~: 768;
(99) Quinolinyl-2 carbonyl-L-asparaRinvl-5S-amino-~cyclohexyl~S-hydroxy-30 'S-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or QC-Asn-CVA-Ile-Amp. FAB-MS [m +Hl: 744;
(100) Benzyloxycar~onyl-L-alanyl-L-alanyl-5S-an~ino~cyclohexvl~iS-hydroxy-2S-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamid~DICBZ-Ala-Ala-CVA-Ile-Amp.

~o 91/06~61 Pc~ s91~/n~xlx ~s- 2~S6~4 FAB-MS [m +H~: 751;
( 101 ) I -Naphthalenvloxvacetvl-L-hisodvl-5S-amine-6-cvclohexvl-4S-hvdroxv-'`S-isopropyl-hexanoyl-L-isoleuc~iamide or Noa-His-CVA-II~ FAB-MS [m + H~ ~:
705:
S tlO~) POA-His-C~ -NH-(CH!)I-CH(CONH~(NH~)~ FAB-MS lm + H]~:
671;
~103~ L-~sparaginamide~ l-(naphthox~)acety~ t~h~droxv~methyl~
methvlpropyl ~ 4-t[t~ methvl- I ttt~ o~ido)pvridinvlmeth,~l)amino~c~r~onvl]butyl]ami-no~carbonvl]hexyl]-N alpha-methvl- ~ I S-t I R~R~R#~ I R~ ~R~)]~-orNOA~Asp-CVA-10 Ile-Amp~ ss Spectrum: No exact mass obt~ined because of wea}; ~ + H~ ion~
Other ions at mlz ~5~53~348~35l~''30~ 15~1'6~109~86:
Preparations 1'1 ( I ) Preparaùon of CH3(0CH.CH~),OTs A 100 mL two-necked round~bottomed tlasl;~ e~uipped with magnetic soirring lS bar~ nitrogen inlet and reacùon thermometer~ is char~ed with 16 mL of p,vridine (Mallinckrodt) and 8.0 mL of trieth,vlene glvcol monomethyl ether (Aldrich)~ This solution is cooled to 0C (ice bath) under a nitro~en atmosphere and then is treat~d portionwise over 20 min with 11.4 g of ~toluenesulfonvl chloride so that the temperature does not exceed 5C~ About half wav throuPh the addition process a thic~;
''O white precipit~te be~an to form. Upon complete addition the resulting mixture is sorre~d at 0C for tu~o h. The mixture is poured into an ice cold solution of 30 mL of concentrated hydrochloric acid in 100 mL of water. This mixture is extracted with ethyl acetate (3 x 100 mL) and these extracts are ~ashed with ~ater (4 x 100 mL with the pH
of the final u~ash being adjusted to 7 by the addition of saturated aqueous sodium 25 bic~arbonate)~ combined~ dried ~gSOl)~ filtered and concentrated under reduced pressure to give 15.5~ ~ of the desired tosylate as a colorless oil: 'H NMR (300 MHz; CDCI3) 7~80~ 7~35~ 4.16~ 3.69~ 3.59~ 3.59~ 3.5~ 3.35~ .45; mass spectrum (EI), ions at m/~
318 ~ 2S6~ 273~ 259~ 243. '''9~ 199~ 155~ 91~ and 59: TLC R~ = 0.33 in 50%
ethyl acetateJhexane (phosphomolvbdic acid). This material is used without purificatiom 30 (2) Preparation of 4-[CH3(0CH.CH.)30]-l-naphthoxyacetic acid I. Preparation of 4-~CH3(0CH.CH.)30)-l-naphthol A solution of 0.50 g of 1~4-naphthalene diol (Aldrich) and 1.0 g of CH3(0CH.,-CH~30Ts of Preparation 1 all in 10 ml of dimethylformamide is placed under a nitrogen Wo 91/06~61 Pcr/~s9n/o~xlx 6 ~
atmosphere and then cooled to -60C A 60% minera~ oil emulsion of sodium hydnde (130 mg; 3 3 mmoL) tAldrich)is added por~ionwise over two minutes The resulting mixture is allowed to sùr and ~raduallv warm to -30C over 1 5 h~ The cooling bath is removed and the mixture is allowed to warm to room temperature over one h at which 5 ùme the mixture is then heated to 50C and stirred t^or one h~ The re~cùon is quenched with IN ammonium hvdroxide~ diluted with methanol and concentrated under reducedpressurc first undér house vacuum and then under lower pressure using ~ vacuum pump - to give a black colored solid~ This material is dissolved in ethyl acetate and washed with brine ~3~)~ Thc aqucous washes are ~acl;-exu~acted with ethyl acetate and the 10 combined or~anic extracts are dried (Na2SO~)~ ftltered and concentrated to give a black colore~ solid ~a mixture of staning diol~ tosylate and desired product)~ This material is chromato~raphed over 100 g of silic~ gel (63-200~)~ elutin~ with 'S~ acetonelhexane while collectin~ 9 mL fractions ~after a 100 mL solvent precut) Fractions 25 oO are combined and concentrated to give 0~51 g of impure 4-~CH3(0CH.CH,~30~-l-naphthol15 TLC Rr=O~l9 in 25% acetonelhexane (IJV).
II~ Preparation of 4-~CH3(0CH2CH~)30]-l-naphthoxyacetic acid~ methyl ester The material of Section I is dissolved in-15 mL of dimethylformarnide, treated with 0~32 mL of methyl bromoacetate (Aldrich)~ cooled to 0C under a nitrogen atmosphere followed by t~eatment with 0~ lS g of a 60~ mineral oil emulsion of sodium 20 hydride~ The resulting ~reen colored mi~ture is stirred at 0C for R5 h~ quenched with saturated ammonium chloride~ diluted with methanol and then concentrated under reduced pressure - first under house vacuum and then under lower pressure using a vacuum pump~ The resulting brown colored solid is suspended in 50 nlL of water and extracted with ethyl acetate~ The aqueous phase is back-washed with ethyl acetate and ''5 the combined or~anic extracts are dried (Na,SO,), filtered and c~ncentrated to give a brown colored oil (primarily a mixture of 4-~CH3(0CH,CH.)30]- 1 -naphthoxyacetic acid, methyl ester~ 1,4-[CH3(0CH,CH.)30]-naphthalene and CH3(0CH,CH.)30Ts)~
This material is chromato~raphed over 50 g of silica gel (63-200~), eluting with 25 %
acetoneihexane while collecting 9 mL fractions~ Fractions 33-49 are combined and30 concentrated to give 285 mg of 4-~CH3(0CH.CH.)30]-l-naphthoxyacetic acid, methyl ester contaminated with a small amount of CH3(0CH,CH2)30Ts 'H NMR (300 MHz;
CDCl3) ô 8~30-8.2~ 7~56-7~50, 6.67, 6.61, 4~77, 4~25, 3~97, 3~82, 3~80, 3~69, 3.S5, 3.37; TLC Rf=0.31 in 25% acetone/hexane (UV)~ Fractions 57-80 yielded the 1,4-~O 9~ 6~61 Pcr/~s9n/o;xl~
~7- 2~5~
~CH3(0CH.CH2)30)-naphthalene by-producs.
III ~ Preparation of 4-~CH'(OCH.CH~)30]- 1 -naphthoxyacetic acid The methvl ester of Secùon ' ('63 m~): is dissolved in 3 mL ot methanol.
Water (I mL) and IN sodium hvdroxide (I mL) are added and the resultin~ soiution is 5 let stir at room temperature îor ~ h~ The solution is then poured into 10 mL of IN
sodium hydroxide and extracted 3~; ~ith ethvl ether~ The combined organic extracts are disc~rded and the aqueous phase is acidified to pH S wit~h aqueous hydrochloric acid and then extracted 3X with methvlene chloride~ The combin~d organic extracts are dried ~Na.SO~ tered and concentrat~d to ~ive I S 1 mg of 4-[CH3(0CH.CH~)30]- 1-10 naphthoxyacetic acid as a brown colored oih TLC analysis showed only a spot at the ori~in using '0% ethyl acetate/chloroform~ This material is used without purification in the subsequent coupling experiment~
(3) Preparaùon of S-[CH3(0CH.CH2),0]-l-naphthoxvaceùc acid 1. Preparation of S-[CH3(0CH~CH~)10]-l-naphthoxyacetic acid~ methyl ester ~ S-[CH3(0CH2CH.)30]-l-naphthol ~One pot reaction]
A soluùon of 0~50 g of 1,5-naphthalene diol (Aldrich), 1~1 g of CH3(0CH2CH2-)30Ts of Preparation I and 0~27 g of a 605~ sodium hydride emulsion all in 15 ml of dimethylformamide is placed under a nitrogen atmosphere and heated to SOC~ The resultin~ mixture is allowed to stir for 1~5 h and then treated with 0.44 mL (4.6 mmoL) 20 of methvl bromoacetate (Aldrich). Stirring and heaùn~ is continued for an additional 1.5 h. The reaction solution is allowed to cool to room temperature and then quenched with saturated ammonium chloride~ diluted with methanol and then concentrated under reduced pressure - first under house vacuum and then under lower pressure using a vacuum pump - to give a product containing mixture as a yellow solid. This solid is ~S dissolved in ethyl acetate and washed with 50 mL of water (2X). The aqueous washes are bacl;-washed with ethyl acetate and the combined organic extracts are dried (MgSO4), filtered and concentrated to give an orange colored oil. TLC analysis of this oil indicates a five component mixture comprised of the desired product [S-[CH3(0CH2CH~)30]-l-naphthoxyacetic acid~ methvl ester], an unidentified component, I ,5-[CH3(0CH,CH2)30]-30 naphthalene~ 1,5-~CH302CCH,O]-naphthalene and 5-[CH3(0CH,CH2)30]-1-naphthol.
111is mixture is chromatographed over 50 g of silica gel (63-200~), eluting wi~ 20%
ethyl acetate~chloroform while collecting 6 mL fracùons. Fracuons Sl-oO are combined and concentrated to give 241 mg of S-[CH3(0CH.CH2)30]-1-naphthoxyacetic acid, ~vo 91/06:~1 Pcr/-S9~/O~lX

rnethvl ester: 'H NMR (300 MHz; CDCI,) li;~9'', 7~9l~ 7~37 ~ 7.31~ 6.83~ 6.71~ 4.78~
.~5. 3.95~ 3.77~ 3.79~ 3~67~ 3~5~ 3.35: TLC R~=0~46 in 20% ethvl ace-tate.'chloroforrn ~JV)~
Il. Preparation of 5-f~CH3(OCH~CH~)~,O~ naphthoxvace~ic acid The methvl ester of Section I ( 41 mg; 0~o3 mmoL) is dissolved in 3 mL of methanoh Water ~I mL) and IN sodium hydroxide ~l mL~ are added and the resultin ` solution is let stir at room temperature for ' h~ The solution is then poured into 10 mL
of lN sodium hydroxide and extracted 3X with ethyl ether. The combined organic extracts a~e ~is~arded and the aqueous pha~e is acidified to pH S with aqueous lû hydrochloric acid and then extracted 3~ ~vith methylene chloride~ The combined organic extracts are dried (Na?SO~), filtered and concentrated to ~ive 20~ mo of 5-~CH3(0CH?C
H~)30]- I-naphthoxyaceùc acid as a brown colored oil. TLC analysis showed onl.~ a spo~
at the origin using 20% ethyl acetate/chloroform. This ma~erial is used without purification in the subsequent couplin~ experiment.
15 (4) Preparation of H-Asn^CVA-Ile-Amp.
A solution of 134 mg of Boc-L-Asparagine (Sigma) and ~02 mg of H-CVA-Ile-Amp all in 10 mL of dimethylformamide is treated with 370 ~LL of diisopropylethylarnine (Aldrich) followed by treatment with 160 ~L of diethyl cvanophosphonate (Aldrich).
The resulting solution is stirred under a nitrogen atmosphere for 17 h at which time TLC
20 analysis confirmed the coupling is complete. The solution is transferred with washing with methanol to a l-neclced (24/40) 200 mL round-bottomed flaslc and then concentrated on a rotary evaporator - first under house vacuum and then under lower pressure using a vacuum pump - to give the crude Boc-~sn-CVA-Ile-Amp. This material is suspended in a solution of 3 mL of meth,vlene chloride and 3 mL of trifluoroacetic acid (Aldrich).
25 The resulting yellow colored mi~ture is stirred at room temperature for 2 h and then concentrated under reducPd pressure. This material (preabsorbed on ~ 2 g of silica gel) is chromatographed over S~ g of silica gel (63-200~), eluting w~th 10% (4M NH3/Me~
H~/CHCl3 while collecting 6 mL fractions. Fractions 51 -86 are combined and concentrated to give 158 mg of product: mass spectrum (FAB) ions at m/z 589f,M+Hl ', 30 571, 481, 236, 22", 126, 109, 86 and 69. TLC Rf=0.32 in 10% (4M Nl~f3/MeOH)/CH-Cl, (UV).
E~amples 104-105 (104) L-Asparaginamide~ [5-(triethyleneglycol monomethyl wo 91/06561 PCr/l~S90/0~81X
~9 2 ~ 4 ether)naphthoxy3acetvl-N-[2-hydroxv-S-methvl- I -(2-methylpropyl)-4-~[[2-methyl- 1 -[1[2-(N-o~ido)pvridinvlmethvl~amino~carbonyl]butyl]amino3carbonyl]hexyl]-N-alpha-me~hyl-[IS-[IR~'R~4R~(IR~'R~)]~ or 5-lCH~OCH.CH~)3O~-I-Noa-Asn-CVA-Ile-Amp.
A solution of 17~ mg ~0~ 131 mmoL~ of S-~CH~OCH.CH.)3O]-I-naphthoxya-5 cetic acid of Preparation 3 and S0~7 mg of H-~sn-C~ -Ile-Amp of Preparation 4 all in 3 mL of dime~hylformamide is treated with 7~ ~L of diisopropylethylamine ~AIdrich~
followed bv treatment with 3~ ~L of dieth~l cyanophosphonate (Aldrich)~ The resulting solution is stirred under a nitrogen atmosphere for 13 h at which time TLC analysis confirrned the coupling is complete~ The soluùon is transferred with washing with 10 methanol to a l~necked (241~0) 200 mL round-bottomed tlask and then concentrated on a rotary e~aporator - first under house vacuum and then under lower pressure using a vacuum pump ~ to give the crude product as a yellow solid~ This material ~preabsor~ed on ~ 2 g of silica gel) is chromatographed over 50 g of silica gel (63-200~), eluting with 8% (4~ NH~/MeOH)lCHCI3 while collecting 6 mL fractions~ Fractions 16-30 are15 combined and concentrated to give the desired product contaminated with a less polar impurity. This material is rechromatographed in a similar fashion using 6% (4M
NH3/MeOH)lCHCI3~ Fractions 44-54 are combined and concent~ated to give 24.8 mg the product with a puritv of >99%: mass spectrum (FAB) lM+H~' found: 935~5476;
other ions at m/~ 8'7~ 416~ 367~ 348~ 330~ 318~ 30S, '36~ 2'2~ 177, 126, 109, and 86.
20 HPLC retention time = 18~6 mim TLC R,=0~53 in 10% (4M NH3/MeOH)/CHCI~
(UV)~ Fractions 34-43 afforded addiional amounts of sli~htly less pure material. (105) L-Asparaginamide~ [4-(triethyleneglycol monomethyl ether)naphthoxy~acetyl-N-~2-hvdroxy-S-methyl- 1 -(,-methylpropyl)-4-[~2-methyl- 1 -[[[2-(N-oxido)pyridinvlmethyl]amino]c~rbonyl]butyl~arnino~carbonyl]he~yl] -N-alpha-methyl-, 2S ~ lS-[ lR~ ~2R*~4R~( lR~2R~)]~ or 4-[CH3(0CH?CH2)30]- 1 -Noa-Asn-CVA-Ile-Amp A solution of S'~6 mg of 4-~CH3(0CH?CH2)30]-l-naphtho~cyacetic acid of Preparation 2 and Sl~0 mg of H-Asn-CVA-Ile-Amp of Preparadon 4 all in 3 mL of dimethylformunide is treated with 75 ~LL of diisopropylethylamine (Aldrich) followed by treatment with 32 ~L of diethyl cyanophosphonate (Aldrich)~ The resulting solution 30 is stirred under a nitrogen atmosphere for 25 h at which time TLC analysis confirmed the coupling is complete~ The solution is ~ansferred with washing with methanol to a l-neclced (24/40) 200 mL round-bottomed flask and then concentrated on a rotary evaporator - first under house vacuum and then under lower pressure using a vacuum ~O 91/~)6~61 PC'r/l~S91)/()~81X

~ 0 ~ 4 -~o pump - to ~i~e the crude pro~uct as a ~ello~ solid~ This materiai (pre~bsorbed on -' cr of silica oei~ is chromato~raphed o~er ~0 ~ ot` silica ~el ~63`~ eluting ~ ith 6~
(~r~ leOH)iCHCi, ~hile collectin~ O mL tractions~ Fractions 39-~ are combineà
~nd concentrated tn ~i~e '~' m~ the pr~uct ~ith a punty ot >99~: mass spectrum ~FAB) [~1 ' H]' ~`ound~ 93~ r~1: other ions a~ m~ 8'-~ 3~8~ 330~ 318~ 305~ '3 r,~ and 8~ HPLC retention t~me = 17~ min~ TLC R~=O~ in 10 ~rl~rl NH~ IeOH),rCHCI
Examples lOfi 107 ( 10~) L- :il,vcvl~SS-amino-~-cvclohexvl~3R~rR-dihvdroxv~R-isoprop,vl~
IU hcxanovl-=L-isoleucvl ' pyridylmethylamide-orGlv ~'D lle-.~mp~ FAB-t-iS (found):
8 ~ ~ S ~
~ 10 /) L-Glycvl-SS-amino-~R-ben2yl-~-cyclohe~yl-3R~rR-dihy-droxy-hexanovlL-isoleucvl-'-pyrid~l-methylamide or Glv-CPD-lle-Amp~ FAB-~IS
(found~: 590~383 1~

~O 91/06~61 Pc~ sgn/o~xlx 2~S4~

Table I
Preparaùon of the Compounds Useful in ~he Present Invenùon Compound o, Example No~ Publieation (1) PCT Pub~ No~ W087,~02986 ~'1 Ivlav 1987); PCT
Internation~l Application WO 87/590g (8 Oct~
1987): S~ Thaisrivon~s et al.~ J~ Me~ Chem~ 31 (7)~ 13~9~76; S~ Thcùsnvongs et al~ ~ J~ Med~ Chem~
o)~ 208~3~
t') EPO Pub~ Appl~ 0173l81 ~5 March 1986) 1~ Prep~ C59~ C~
~) PCT Pub~ No~ W086/0637~ (6 November 1986) Example 10 ~0 (4) PCT Pub~ No~ W086106379 (6 November 1986) Example 10 (5) PCI` Pub~ No~ W086/06379 (6 November 1986) Example (6) EPO Pub. Appl. 0173481 (5 March 1986) PCI Pub~ No. W087/02986 (''1 ~ay 1987) (7) PCT Pub. No. W087/05302 (11 September 1987) Example 6 (8) PCI Pub~ No~ W087/OS302 (11 September 1987) Example 7 (9) PCI Pub~ No~ W087/05302 (11 September 1987) Example 12 (10) PCI Pub~ No~ W087/OS302 (11 September 1987) Example 15 (11) EPO Pub~ Appl~ 0173481 (S March 1986) ~O 91/~6~61 PCT/~`S9~/O~lX

-5~ -Table I (continued) Preparation of the Compounds Useful in the Present lnvention Compound ot`
Example No~ Public~tion .

(1 ) EPO Put~ ~ppl~ 0173481 (5 March 1986) PCI Pub~ No~ W087~02g86 ~ lay 1987) (13) EPO Pub~ Appl~ 0173481 ~5 ~arch 1986) PC~r Pub~ ~`o~ W087102986 ~21 ~ay 1987) 1~
tl~) EPO Pub~ Appl~ 0173481 (5 March 1986) PCT Pub~ No~ W08710.986 (21 May 1987) ( 1~) EPO Pub~ .~pph 0173481 (~ ~arch 1986) PCT Pub~ No~ W087/0 986 (21 ~lay 1987) (16) PCTPub~ No~ W08710530 (11 September 198~) Example 1~
(17) PCT Pub~ No~ W087/OS302 (1 I September 1987) (18) PCT Pub. No~ W089100161 (12 ~anuary 1989 Example ~
(19) EPO Pub~ Appl 0173481 (5 March 1986) PCT Pub~ ~o~ W087/02986 (21 ~ay 1987) (~0) EPO Pub~ Appl. 0173481 (5 M~ch 1986); D.E.
Epps~ Anal~ BioChem~ 181 (1),172-81.
(~1) EPO Pub .~ppl. 0173481 (5 ~arch 1986) PCT Pub. No. W087/02986 (21 May 1987) (22) EPO PUb. Appl. 0173481 (5 March 1986) ~o 91/06~61 PCr/-S9~/0~81X
-53- 20~5~4 Table I tcontinued) Prepara~ion o~ the Compounds Useful in the Present Invention ComDound of E~ample No~ Publlcat~on . _ PCr Pub~ No~ W0871t)~986 ~ Say 1987 ('~) EPO Pub~ Appl~ t)l73~81 (5 March 1986~
PCI Pub~ No~ W087/02986 t21 Ma~. 1987) ~'S~ PCr Pub~ No~ W087/02986 ~ ay 1987); EPO
Pub~ Appl~ 0173481 (5 Marth 1986) ( 6) PCr Pub~ No~ W08710'986 ~''1 May 1987) ~0 (54) PCI` Pub~ No~ W087/02986 (21 May 1987) (5S) PCT Pub~ No. W087102986 (21 May 1987) '5 (56) PCI Pub~ No~ W087/02986 (21 May 1987) (57) PCT Pub~ No~ W087/02986 (21 May 1987) t58) EPO Pub~ Appl~ 0173481 (5 March 1986) PCT Pub~ No~ W08710.986 ('1 May 1987) (S9) EPO Pub~ Appl~ 0173481 (5 ~5arch 1986~
PCT Pub~ No~ W087/02986 (21 May 1987) (60) EPO Pub~ Appl~ 0173481 t5 March 1986) PCI` Pub~ No~ W0871~2986 (21 May 1987) (61) Pt~ Pub~ No~ W087/02986 ( I May 1987) (6~) PCr Pub~ No~ W087/02986 (21 May 1987) (63) PCI Pub~ No~ W087/02986 (21 May 1987) (64~ PCT Pub~ No~ W087/0~986 ( 1 May 1987) wo 91//)6~61 PC r/~ls9~ XlX

5~-Table I (continued) Preparation of the Compounds Useful in the Present lnvention s Compound of Example No~ Publi~ation (65) PCT Pub~ No~ W087~02~86 ~21 hlay 1987) (66) PCT Pub~ No~ ~'08710''986 ~r~l May 1987) (67) EP0 Pub~ Appl~ 0173~81 ~5 March 1986) PCT Pub~ No~ W087/02986 ~''1 May 1987) (68) PCT Pub~ No~ W08710'g86 (- I May 1987) (69) EP0 Pub~ Appl~ 0173~81 (5 March 1986) PCT Pub~ No~ W08710.986 (21 May 1987) WO 91/06~61 PCr/l~S9(~/O~XlX

5~
Table Il 2 a ~
Compound of Hl~ Prot~se Inhibitor Acùvit~
~; Example No K,~nhS
-(1) 60~ at 10~1 I O
~3) 94 fi at 2~5 x 10"
(~) gO~ at '~5 x 10 ' ~5) 73% at '~5 x 10~`
~) 10 (7) ~ < 10 (8) 15 ~o at ~5 x 1~' 1~ (9) 100% at "~5 x 1~' ~10~ < < 10 (1~) 7 ~13~ 459~, at 10' ~14) 51~, at 1~' (15) 76~, at 5 x 10' (16) 87% at '.5 x 10 ' (17) 15~ at 2~5 x 10 (18) 43 -5 (19) 48% at5 x 10~~
(20) 480 (21) 4.3 (2~) 148 (~3) 88 (24~ 74 (25) 30% at 10~1 (26) '~
(27) 800 (28) 8 (29) 70 ~0 91/Oh:~61 PC'r/~S9()/O~XlX
2 ~
Table Il (continue~) Compound or Hl~' Prote~se Inhibi~or Activit~
Example No. K(n (30) (3 1 ) 1 ~5 (3_) _ (33) 7 (30 1~
(35) 1~9~ ~t ~ x 10`
'36) ~50 (3-) 13~5~ a~ '~5 x 10"
~3~) 8~æ at ''~ x 10`~
1~ ~3~ t '~3 x 10"
~0) g'~ t '~3 x 10' t7~) 360 n~l f76) 1 n~
~77) 11 n~l '0 (78) 18 n~l (79) '0 nM
(80) "8 nM
t8 1 ) ~ 250 nM
(82) nM
''5 (83) 5 nM
(84) 26 nM
(85) 12 nM
(87) > 250 nM
(88) 53 nM
(89) 33 nM
(90) ~ ~'50 n~
(91 ) > '50 nM
(92) "3 nM
(93) 6.5 nh~
(9S) 17 nh~
(96) 10~1 nM
(98) 18~ 8 nM
(99) 8~7 nhl (100) 17 n~
(101) 7 nM
(106) 182 nM
(107~ >'50 nhl WO 91 /(~6~6 I PCr/~`S9~1/O~lX
2 ~

Table III
Upiohn HIV Protease Inhibitors Tested for Antiviral Activity (DlAGEN) Compoun~ of Concentration ,~r Inhibition of Example No~ Tested Cell Infectivi~

(23) 8~0 x 10~ ~I No si~nifieant inhibition observe~
~4) 1~0 x 10~1~1 8~ (p24 synthesis) on d~y 3 9~ (RNA synthesis) on day~
75~O ~p'' l synthesis! on dav-4 37~ (RNA svnthesis) on day~
~7) 1~0 x 10~1-1 29~ ~p~4 synthesis! on dav-3 60~ (RNA synthesis) on day 3 15% (p24 svnthesis) on day-4 17~ (RNA synthesis) on dav-4 (12) 1.0 x 10' M 98% (p24 synthesis) on day^3 "5 90% (RNA synthesis) on day-3 10050 (p24 synthesis) on day-4 72% (RNA synthesis) on day-4 WO 91/06~61 PCI/l S91\/O;XlX

~g 2 ~ . STRUCl-URE CH~R~

~ - C8 - D9 Elo ` Fll -cl~ ` 2 _",1 "J~

H ~' R3 4 R~, \ /

-o/ \ C` ~1 4~ ~R~
4 Q o I I 1`
--~--C~--C ~
~L2 7~o ~ 2--C~O)--C~3 ~ C~3 I ~C(O)-_11 ~2b ~O 91/~)6~61 PC'r/-`S9~/O~XIX
-59- 2 0 ~
STRUCTURE CHART (conùnue~) \ /
R,~ CH C

~ " ~ 1 NH ~~X \
N OA

~;;~Xc\ ~22 R2 R22 R2~
CH H O ~ 2 ~H

~2N 11 H B~ll HO
~L6d ~L6e ~O 91/06;61 PCT/~`59~/O:~lX
2 ~ 4 4 STRUCTURE CHART (continucd) RlCH~ H li OH 0 RlC~ H H OH
~H~C ~ \NH~CH~OH

HO H H Rl 1 HO H H Rl 1 II III
Rl~ ~11 F F

H. H~R~ O

NH
H OH 'R
~1 H,~CH2R1 \ /

\NH~ H R1l C

rL6b HO H h Rl 1 R~ R24 CH H RlCH2 ~H

\ NH~ \ --NH~ CH 2 H2N H RllHO H H R

~L6dl XL6e ~O 91/06~61 pcr~s9n/o~xlx -61- 2~S~
STRUCTURE CHART ~con~nued) H2 ~ ~ OH ~

U~' CH20H
HQ H 'Rll HCH H Rll n III ' ~1~7 ~11 r ~
~H~-- , O o I~' R4 / R8 R7~ H
R~ Cll O
--N--CH--C--- H O
XL~,a f CH ~ f (CH~R121)w (R1210CH)~1 ~CHOR121)v Q CH- (CHOR121)t (Q) s CH-R128 ' CH2-~
.~YX I
XXX
0~ ~
-CH~,-C tCH-ORl2l)w XXXII
O H
R128; or

Claims (23)

-62-

1. Use of a compound of formula I

to prepare a medicament for inhibiting retrovirus in a mammalian cell infected with said retrovirus:
wherein X is a) -(CH2)p-aryl, b) -(CH2)p-Het, c) -(CH2)p-C3-C7cycloalkyl, d) R5-O-(CH)2q-C(O)-, e) R5-CH2-O-C(O)-, f) R5-O-C(O)-, g) R5-(CH2)n-C(O)-, h) R5-(CH2)n-C(S)-, i) R4N(R4)-(CH2)n-C(O)-, j) R5-SO2-(CH2)q-C(O)-, k) R5-SO2-(CH2)q-O-C(O)-, l) R5-(CH2)n-SO2, m) Z-C(O)-CH(OH)-CH(CH2R1)-C(O)-n) R5(CH2)p CH=CH-(CH2)p-C(O)-, o) R5(CH2,p CH=CH-(CH2)p-O-C(O), or p) R?(CH2)q-C(O)-;
wherein C8 is absent or a divalent moiety of the formula XL1, XL2, XL2a, XL2b or other amino acyl derivative:
XL2a XL2b wherein D9 is a divalent moiety of the formula XL3, XL2a, XL2b or other amino acyl derivative:

XL3 XL2a XL2b wherein E10-F11 is a divalent moiety of the formula XL6, XL6b, XLc, XL6d, II, III, or IV:

XL6 XL6b XL6c XL6b XL6c II III

IV

wherein G12 is absent or a divalent moiety of the formula XL4, XL4a or other amino acyl derivative:

XL4 XL4a wherein Z is a) -O-R10, b) -N(R4)R14, c) C4-C8cyclic amino, d) -NHR120, e) or f) Het bonded via a nitrogen atom, or g) -NH(CH2)qNH Het;
wherein R is a) -(CH2)n-isopropyl, b) -(CH2)n-isobutyl, c) -(CH2)n-phenyl, or d) -(CH2)n-C3-C7cycloalkyl;
wherein R1 is a) hydrogen, b) C1-C5alkyl, c) aryl, d) C3-C7cycloalkyl, e) -Het, f) C1-C3alkoxy, or g) C1-C3alkylthio;
wherein R2 is a) hydrogen, or b) CH(R3)R4;
wherein R3 is a) hydrogen, b) hydroxy, c) C1-C5alkyl, d) C3-C7cycloalkyl, e) aryl, f) -Het, g) C1-C3alkoxy, or h) C1-C3alkylthio:
wherein R4 at each occurrence is the same or different as is a) hydrogen, b) C1-C5alky, c) -(CH2)p-aryl, d) -(CH2)p-Het, e) (CH2)p-C3-C7cycloalkyl, or f) 1- or 2-adamantyl;
wherein R5 is a) C1-C6alkyl, b) C3-C7 cycloalkyl, c) aryl, d) -Het, e) 5-oxo-2-pyrrolidinyl, or f) 1 or 2-adamantyl;
wherein R6 is a) hydrogen, b) C1-C5alkyl, c) -(CH2)p-aryl, d) -(CH2)p-Het, e) -(CH2)p-C3-C7cycloalkyl, or f) 1- or 2-adamantyl;
wherein R7 is a) hydrogen, b) C1-C5alkyl, c) hydroxy, d) amino C1-C4alkyl-, e) guanidinyl C1-C3alkyl-, f) aryl, g) -Het, h) methylthio, i) -(CH2)p-C3-C7cycloalkyl, j) amino, k) -(CH2)n-COOH, l) -(CH2)n-COOC1-C6 alkyl or m) -(CH2)n-CONR22R26;
wherein R8 is a) hydrogen b) C1-C5alkyl, c) hydroxy, d) aryl, e) Het, f) guanidinyl C1-C3alkyl-, or g) -(CH2)p,-C3-C7cycloalkyl;
wherein R9 is a) hydrogen, b) hydroxy, c) amino C1-C4alkyl-, or d) guanidinyl C1-C3alkyl-;
wherein R10 is a) hydrogen, b) C1-C5alkyl, c) -(CH2)nR16, d) -(CH2)nR17, e) C3-C7cycloalkyl, f) a pharmaceutically acdeptable cation, g) -CH(25)-CH2-R15, or h) -CH2-CH(R12)-R15;
wherein R11 is -R or-R2;
wherein R12 is -(CH2)n-R13;
wherein R13 is a) aryl, b) amino, c) mono-, di- or tri-C1-C3alkylamino, d) -Het, e) C1-C5 alkyl, f) C3-C7cycloalkyl, g) C2-C5alkenyl, h) C3-C7cycloalkenyl, i) hydroxy, j) C1-C3alkoxy, k) C1-C3alkanoyloxy, l) mercapto, m) C1-C3alkylthio, n) -COOH, o) -CO-O-C1-C8alkyl, p) -CO-O-CH2-(C1-C8alkyl)-N(C1-C3alkyl)2, q) -CO-NR22R26;
r) C4-C7cyclic amino, s) C4-C7cycloalkylamino, t) guanidyl, u) cyano, v) N-cyanoguanidyl, w) cyanoamino, x) (hydroxy C2-C4alkyl)amino, or y) di-(hydroxyC2-C4alkyl)amino;
wherein R14 is a) hydrogen, b) C1-C10alkyl, c) -(CH2)n-R18, d) -(CH2)n-R19, e) -CH(R25)-CH2-R15, f) -(CH2)q-CH(R12)-R15, g) (hydroxy C1-C8alkyl), h) hydroxy C1-C8 alkaryl, or i) (C1-C3 alkoxy) C1C8alkyl;
wherein R15 is a) hydroxy, b) C3-C7cycloalkyl, c) aryl, d) amino, e) mono-, di-, or tri-C1-C3alkylamino, f) mono- or di-(hydroxy C2-C4alkyl)amino, g) -Het, h) C1-C3alkoxy-, i) C1-C3alkanoyloxy-, j) mercapto, k) C1-C3alkylthio-, l) C1-C5alkyl, m) C4-C7cyclic amino, n) C4-C7cycloalkylamino, o) C1-C5alkenyloxy, p) C3-C7cycloalkenyl;
wherein R16 is a) aryl, b) amino, c) mono- or di-(C1-C3alkyl)amino, d) hydroxy, e) C3-C7cycloalkyl, f) C4-C7cyclic amino, or g) C1-C3alkanoyloxy;
whrein R17 is a) -Het, b) C1-C5alkenyl, c) C3-C7cycloalkenyl, d) C1-C3alkoxy, e) mercapto, f) C1-C3alkylthio, g) -COOH, h) -CO-O-C1-C6alkyl, i) -CO-O-CH2-(C1-C3alkyl)-N(C1-C3alkyl)2, j) -CO-NR22R26, k) tri-C1-C3alkylamino, I) guanidyl, m) cyano, n) N-cyanoguanidyl, o) (hydroxy C2-C4alkyl)amino, p) di-(hydroxy C2-C4alkyl)amino, or q) cyanoamino:
wherein R14 is a) amino, b) mono-, or di-(C1-C3alkyl)amino, c) C4-C7cyclic amino, d) C4-C7cycloalkylamino, or e) -CH(NH2)(CO2H);
wherein R19 is a) aryl, b) -Het, c) tri-C1-C1alkylamino, d) C3-C7cycloalkyl, e) C3-C5alkenyl, f) C3-C7cycloalkenyl, g) hydroxy, h) C1-C3alkoxy, i) C1-C3alkanoyloxy, j) mercapto, k) C1-C3alkylthio, l) -COOH, m) -CO-O-C1-C6alkyl, n) -CO-O-CH2-(C1-C3alkyl)-N(C1-C3alkyl)2, o) -CO-NR22R26, p) guanidyl, q) cyano, r) N-cyanoguanidyl, s) cyanoamino, t) (hydroxy C1-C4alkyl)amino, u) di-(hydroxy C2-C4alkyl)amino: or v) -SO3H;
wherein R20, is a) hydrogen, b) C1-C5alkyl, or c) aryl-C1-C5alkyl:
wherein R21 is a) -NH2, or b) OH:
wherein R22 is a) hydrogen, or b) C1-C3alkyl;
wherein R23 is a) -(CH2)a-OH, b) -(CH2)a-NH2, c) aryl, or d) C1-C3alkyl:
wherein R24 is a) -R1, b) -(CH2)n-OH, or c) -(CH2)n-NH2;
wherein R25 is a) (CH2)n-R13, b) hydrogen, c) C1-C3alkyl, or d) phenyl-C1-C3alkyl;
wherein R26 is a) hydrogen, b) C1-C3alkyl, or c) phenyl-C1-C3alkyl, wherein R27 is a) -COOH, b) -COOC1-C6 alkyl, c) -CONR22R26, or d) -CH(NH2)COOH;
wherein R120 is a) R120C[(CH2)qOR121](CH2)4-, b) XXX
c) XXXI
d) -CH.(CHOR121)xCH2OR121 e) R121OCH2(CHOR121)yCH-(CHOR121)2CH2OR121, f) XXXII or g) R121OCH2-C(CH2OR121)2-;
wherein R121 is a) hydrogen, b) C1-C6alkyl, c) -(CH2)n-aryl, or d) -C(O)R123;
wherein R123 is a) C1-C5 alkyl, or b) -(CH2)n-phenyl;
wherein R126 is a) hydrogen, or b) (CH2)nOR121;
wherein R128 is a) hydrogen, or b) -(CHOR121)1CH2OR121;
wherein Q is a) CH2, b) CHOR121, or c) C(O);
wherein j is one to three, inclusive;
wherein m is one or two;
wherein p is zero to two, inclusive;
wherein r is zero to five, inclusive;
wherein for each occurrence n is independently an integer of zero to five, inclusive;
wherein q is an integer of one to five, inclusive;
wherein u is an integer of zero to three, inclusive;
wherein v is an integer of zero to four, inclusive;
wherein s is an integer of zero or one so that the sum of u plus v plus s is three or four;
wherein t is an integer of zero to three, inclusive;
wherein w is an integer of two or three;
wherein x is an integer of two to seven, inclusive;
wherein y is an integer of zero to six, inclusive; and wherein z is an integer of zero to six so that the sum of y plus z does not exceed six;
wherein aryl is phenyl or naphthyl substituted bv zero to three of the following:
a) C1-C3alkyl, b) hydroxy, c) C1-C3alkoxy, d) halo, e) amino, f) mono- or di-C1-C3alkylamino, g) -CHO, h) -COOH, i) COOR26, j) CONHR26, k) nitro, l) mercapto, m) C1-C3alkylthio, n) C1-C3alkylsulfinyl, o) C1-C3alkylsulfonyl, p) -N(R4)-C1-C3alkylsulfinyl, q) SO3H, r) SO2NH2, s) CN, or t) -CH2NH2;
wherein -Het is a 5- or 6-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur;
and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another heterocycle and the ring may be connected through a carbon or secondary nitrogen in the ring or an exocyclic nitrogen: and if chemically feasible, the nitrogen and sulfur atoms may be in the oxidized forms: and optionally substituted by zero to three of the following:
a) C1-C5alkyl, b) hydroxy, c) hydroxy (C1-C5alkyl), d) halogen, e) amino, f) amino (C1-C5alkyl), g) -CHO, h) -CO2H, i) -CO2-(C1-C5alkyl) j) -CONH2, k) -CONH-(C1-C5alkyl), l) nitro, m) mercapto, n) mercapto (C1-C5alkyl), o) -SO3H, p) -SO2NH2, q) -CN, r) -O-C1-C5alkyl, or s) -[O-(CH2)2]n-OCH3;
with the provisos that:
1) G,2 is present when both C8 and D9 are present and E10-F11 is other than LPA;
2) when X is Z-C~O)`CH(OH) CH~CH.R,)-CtO)-~ DD is His and G,2 is lle:
3) when X is R5-CH3-O-C(O)-or RR5-(CH2)n-C(O) and E10-F11 is XL6, XL6b, XL6c or X6d, R5 is other than C1-C6 alkyl;
4) when X is R5-O-C(O)- and E10-F11 is XL6, X6b, XL6c or XL6d, R5 is other than C1-C6alkyl, C3-C7 cycloalkyl or aryl;
5) when X is R5 (CH2)n,-C(O)-wherein R5 is cycloalkyl or aryl, and Elo F11 is XL6, XL6b, XL6c or XL6d, n is other than one;
6) when X is R4N(R4)-(CH2)n-C(O)- and E10-F11 is XLD6, XL6b, XL6c or XL6d, n is other than one;
7) Z is other than N-4-amino-2-methyl-5-pyrimidinylmethyl-amide;
8) X is other than benzyloxycarbonyl or butyloxycarbonyl, when E10-F11 is II or IV; and 9) when X is R5-(CH2)n-C(O)- and E10-F11 is II or IV, R5 is other than C1-C6 alkyl.

2. The use of claim 1 wherein E10-F11 is a divalent moiety of the formula XL6', XL6b', XL6c', XL6d', XL6e', II', III', or IV';

XL6' XL6b' XL6c' XL6d' XL6c' II' III' IV' wherein the variables are as defined in claim 1.

3. The use of claim 1 wherein the cell is in a human.

4. The use of claim 3 wherein diseases caused by said retrovirus are treated in said human.

5. The use of claim 4 wherein C8, D9 and G12 are present.

6. The use of claim 5 wherein the compound of formula I is selected from the group consisting of:
1H-Imidzole-4-propanamide, .alpha.[[2-(acetyloxy)-3-(1-naphthalenyl)-1-oxopropyl]amino)-N-[1-(cyclohexylmethyl)-3,3-difluoro-4-[[2-methyl-1-[[(2-pyridinyl-methyl]amino)carbonyl]butyl)amino]-2,4-dioxobutyl]-, [1S-[1R*[.alpha.R*(R*)],2R*]]-;
L-Histidinamide, N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-[1-(cyclohexylmethyl)-3,3-difluoro-4-[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]-butyl]amino]-2,4-dioxobutyl]-; or Boc-Phe-His-LFA-Ile-Amp; and L-.alpha.-Glutamine.N/u2/d-[N-[[1,1-dimethylethoxy)carbonyl]-L-phenylal-anyl]-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinyl-methyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-,[1S-[1R*,2R*4R*(1R*, -2R*)]]-,monacetate (salt) or BOC-Phe-Glu-LVA-Ile-Amp.

7. The use of claim 4 wherein C8 is absent, D9 is present and G12 is present.

8. The use of claim 7 wherein the compound of formula I is selected from the group consisting of:
1H-Imidzole-4-propanamide, N-[2-hydroxy-5-methyl-1-(2-methyl-propyl)-4-1[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]he-xyl]-.alpha.-[(phenoxyacetyl)-amino]-, [1S-[1R*]2R*,4R*(1R*,2R*)]]-; POA-His-LVA-Ile-Amp;
1H-Imidazole-4-propanamide, N-[1-(cyclohexylmethyl)-3,3-difluoro-4-[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]-2 ,4-dioxobutyl]-.alpha.-[[(1-naphthalenyloxy)acetyl]amino]-, [1S-(1R*(R*).2R*]]-; or NOA-His-LFA-Ile-Amp;
1H-Imidazole-4-propanamide, N-[1-(cyclohexylmethyl)-2-hydroxy-6-methyl-4-[[[2-methyl-1-1[[(2-pyridinylmethyl)amino]carbonyl]butyl)amino]carbonyl]hep-tyl]-.alpha.-[(phenoxyacetyl)amino]-, [1S-[1R*(R*),2R*,4S*(1R*,2R*)]]-; or POA-His-CLA-Ile-Amp:
1H-Imidazole-4-propanamide. N-[2,3-dihydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]car-bonyl]hexyl]-.alpha.-[(phenoxyacetyl)amino]- [1S-[1R*(R*).2S*,3R*,R4*(1R*,2R*)]]-; or POA-His-LVD-Ile-Amp:
1-Noa-His-Cha PSI[CHOHCHOH]Val-Ile-Amp: or 1H-Imidazole-4-propanamide, N-[1-(cyclohexylmethyl)-2,3-dihydroxy-5-methyl-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]-[amino]carbonyl]hexyl]-.alpha.-[[(1-naphthalenyloxy)ac-etyl]amino]-, [1S-[1R*(R*),2S*,3S*,4S*(1R*,2R*)]]-: or NOA-His-CVD-Ile-Amp;
1H-Imidazole-4-propanamide, N [2-hydroxy-6-methyl-1-(2 methyl-propyl)-4-[[[2-methyl-1-[[(2-pyndinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hep-tyl]-.alpha.-[(phenoxyacetyl)amino]-, [1S-[1R*(R*),2R*,4S*(1R*,2R*)]]-; or POA-His-LLA-Ile-Amp;
1H-Imidazole-4 propanamide, N-[2-hydroxy-1-(2-methylpropyl)-5-[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]-5-oxo-4-(phenylmethyl)pen-tyl]-.alpha.-[(phenoxyacetyl)amino]-[1S-[1R*(R*),2R*,4S*,5(1R*,2R*)]]-orPOA-His-LPA-Ile-Amp;
1H-Imidazole-4-propanamide,N-[4-(cyclohexylmethyl)-2-hydroxy-1-(2-methylpropyl)-5-[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]-5-oxopentyl]-.alpha.-[(phenoxyacetyl)amino]-, [1S-[1R*(R*),2R*,4S*.5(1R*.2R*)]]-; or POA-His-LCA-Ile-Amp:
1H-Imidazole-4-propanamide, N-[1-(cyclohexylmethyl)-2-hydroxy-5 -methyl-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]anino]carbonyl]hexyl]-.alpha.-[(phenoxyacetyl)amino]-,[1S-[1R*(R*),2R*,4R*(1R*2R*)]6-; orPOA-His-CVA-Ile-Amp;
1H-Imidazole-4-propanamide, N-[1-(cycloheptylmethyl)-2-hydroxy-5-methyl-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-.alpha.-[(phenoxyacetyl)amino]-,[1S-[1R*(R*),2R*,4R*(1R*,2R*)]]-orPOA-His-chpVA-Ile-Amp;
N.alpha.-[(2S,4S,5S)-5-[N-[N.alpha.-(Phenoxymethylcarbonyl)-L-histidyl]amino-4-hydroxy-2-isopropyl-7-methyl- 1-oxooctyl]-N-[2-(2-pyridinylamino)ethyl]-L-isoleucin-amide, acetic acid salt; or POA-His-LVA-Ile-NH(CH2)2NH-pyridine;
N.alpha.-[(2S,4S,5S)-5-[N-[N.alpha.-(Phenoxymethylcarbonyl)-L-histidyl]amino]-4-hydroxy-2-isopropyl-7-methyl-1-oxooctyl]-N-(2,3-dihydroxypropyl)-L-isoleucinamide;
or POA-His-LVA-Ile-NH-CH2-CH(OH)-CH2OH;
N.alpha.-[(2S,4S,5S)-5-[N-[N.alpha.-(Phenoxymethylcarbonyl)-L-histidyl]-amino-4-hydroxy-2-isopropyl-7-methyl-1-oxooctyl]-N-(2-hydroxypropyl)-L-isoleucinamide; or POA-His-LVA-Ile-NH-CH2-CH(CH3)(OH);
N.alpha.-[(2S,4S,5S)-5-[N-[N.alpha.-(1-Naphthalenyloxyacetyl)-L-histidyl]amino]-6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucinamide pyridine N-oxide or NOA-His-CVA-Ile-Amp-NO;
N.alpha.-[(2S, 4S, 5S)-5-[N-[N.alpha.-(f-toluenesulfonyl)-L-histidyl]amino]-6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucinamide, or p-Tolunesulfonyl-His-CVA-Ile-Amp;
N.alpha.-[(2S,4S,5S)-5-[N-[N.alpha.-(1-Naphthalenyloxyacetyl)-L-histidyl]amino]-6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucinamide.
pyridine N-oxide or POA-His-CVA-Ile-Amp-NO;
N.alpha.-[(2S, 4S, 5S)-5-[N-[N.alpha.-(p-Toluenesulfonyl)-L-histidyl]amino]-6-6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucinamide.
pyridine N-oxide or p-Toluenesulfonyl-His-CVA-Ile-Amp-NO;
N.alpha.-[(2S,4S,5S)-5-[N-[N.alpha.-(1-Naphthalenyloxyacetyl)(2-pyridinyl)ala-nyl]amino]-6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucinamide or NOA-His-CVA-Ile-Amp;
N.alpha.-[(2S,4S,5S)-5-[N-[N.alpha.-[(3-Pyridinyl)-methylacarbonyl]-L-histidyl]-amino]-6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]N-(2-pyridinylmethyl)-L-isoleucinamide or (3-pyridinyl)-methyl-carbonyl-His-CVA-Ile-Amp;
N.epsilon.[N2-[(2S, 4S, 5S)-5-[N-N.alpha.-(1-Naphthalenyloxyacetyl)-L-histidyl]-amino]-6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-L-isolencyl]-L-lysine.
triflouroacetic acid salt or NOA-His-CVA-Ile-L-lysine, trifluoroacetic acid salt;
N.alpha.-[(2S,4S,5S)-5-[N-[N.alpha.-(1-Naphthalenyloxyacetyl)-L-histidyl]amino]-6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-[2-(2-pyridinylamino)ethyl]-L-isoleucinamide or NOA-His-CVA-Ile-NH-(CH2)2-NH-(2-pyridine);
1H-Imidazole-4-propanamide,N-[2-hydroxy-4-[[[(1-[[(2-hydroxy-2-WO 91/06561 PCT/US91)/05818 phenylethyl)amino]carbonyl]-2-methylbutyl)amino]carbonyl]-5-methyl-1-(2-methyl-propyl)hexyl)-.alpha.-[(phenoxyacetyl)amino]-,monoacetate (salt) or POA-His-LVA-Ile-NH-CH2-CH(OH)-phenyl:
Pentanoic acid. 5-[[1-cyclohexylmethyl)-2-hydroxy-5-methyl-4-[[[2-methyl-1-[[2-pyridinylmethyl)amino)carbonyl]butyl]amino]carbonyl]hexyl)amino)-4-[(1H-indol-2-ylcarbonyl)amino]-5-oxo-,[1R*(R*),2R*,4R*(1R*,2R*)])-or 1H-indol-2-yl carbonyl-Glu-CVA-Ile-Amp;
L-.alpha.-Glutamine, N-[1-(cyclohexylmethyl)-2-hydroxy-5-methyl-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl)-N/?/d-L-phenylalanyl-, [1S-[1R*,2R*,4R*(1R*,2R*)]-, bis(trifluoracetate) (salt) or Phe-Glu-CVA-Ile-Amp;
2-Pyridineacetamide. N [2-[[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl)hexyl]amino]-1-(1H-imidazol-1-ylmethyl)-2-oxoethyl]-[1S-[1R*(R*),2R*,4R*(1R*.2R*)]]-or (2-Pyridyl)acetyl-His-Lva-Ile-Amp;
4-Pyridineacetunide, N-[2-[[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2methyl-1-[[(2-pyridinylmethyl)amino)carbonyl]butyl]amino]carbonyl]hexyl]amino]-1-(1H-imidazol-4-ylmethyl)-2-oxoethyl]-[1S-[1R*(R*),2R*,4R*(1R*,2R*)]]-or (4-Pyridyl)acetyl-His-LVA-Ile-Amp;
1H-Indole-2-carboxamide. N-[2-(2-hydroxy-5-methyl-1-(2-methylpr-opyl)-4-[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]carbonyl]hexyl]amino]-1-(1H-imidazol-4-ylmethyl)-2-oxoethyl]-,[1S-[1R*(R*),2R*,4R*(1R*,2R*)]]- or N-(Indolyl-2-carbonyl)-His-LVA-Ile-Amp;
2,511.14-Tetraazapentadecanoic acid, 7-hydroxy-3-(1H-imidazol-4-ylmethyl)-9-(1-methylethyl)-12-(1-methylpropyl)-6-(2-methylpropyl)-4,10.13-trioxo-15-(2-pyridinyl)-,4-pyridinylmethyl ester, [3S-[3R*,6R*,7R*,9R*,12R*(R*)]]- or Ioc-His-LVA-Ile-Amp;
1H-Imidazole-4-propanamide, N-[2-hydroxy-5-methyl-1-(2-methyl-p r o p y l )- 4 -[ [ [ 2 - m e t h y l - 1 - [ [ ( 2 - p y r i d i n y l m e t h y l ) a m i n o ] -carbonyl]butyl]amino]carbonyl]hexyl]-.alpha.-[(1-oxo-3-phenoxypropyl)amino]-, [1S-[1R*(R*).2R*,4R*(1R*,2R*)]]-,or Phenoxypropionyl-His-LVA-Ile-Amp;
1H-Imidazole-4-propanamide,N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[[(2-pyridinylmethyl)amino[carbonyl[butyl[amino[carbonyl[hexyl]-.alpha.-[(1-oxo-3phenyl-2-propenyl)amino]-[1S-[1R*(E)].2R*4R*(1R*,2R*)]]- or phenyl-CH=CH-C(O)-His-LVA-Ile-Amp:
1H-Imidazole-4-propanamide.N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[[(2-pyndinylmethyl]amino[carbonyl][butyl]amino[carbonyl[hexyl]-.alpha.-[(1-oxo-4-phenyl-3-butenyl)amino]-,[1S-[1R*[R*-(E).2R*4R*(1R*,2R*)]]- or phenyl-CH=CH-CH2-C(O)-His-LVA-Ile-Amp;
2.5.11.14-Tetraazapentadecanoic acid, 7-hydroxy-3-(1H-imidazol-4-ylmethyl)-9-(1-methylethyl)-12-(1-methylpropyl)-6-(2-methylpropyl)-4, 10, 13-trioxo-15-(2-pyridinyl)-,3-phenyl-2-propenyl ester, [3S-[1(E)3R*,6R*,7R*,9R*,12R*(R*)]]- or phenyl-CH=CH-CH2-O-C(O)-His-LVA-Ile Amp; U-77407 1H-Imidazole-4-propanamide.N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinvlmethyl)amino]carbonyl]butyl]amino]carbonyl)hexyl]-.alpha.-[[(2-phenylethenyl)sulfonyl]amino]-,[1S-[1R*[R*(E),2R*,4R*,(1R*,2R*)]]-orphenyl-(CH2)-SO2-His-LVA-Ile-Amp;
Hydroxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or (HO)Ac-His-CVA-Ile-Amp;
Hydroxyacetyl-L-histidyl-5S-amino-2R-benzyl-6-cyclohexyl-3R,4R-dihydroxy-hexanoyl-L-isoleucyl-2-pyridylmethylamide or (HO)Ac-His-CPD-Ile-Amp;
Hvdroxyacetyl-L-histidyl-5S-amino-2R-benzyl-6-cyclohexyl-3R,4R-dihydroxv-hexanoyl-L-isoleucyl-2-pyridylmethylamide,N-oxideor(HO)Ac-His-CPD-Ile-Amp:
Phenoxyacetyl-L-histidyl-5S-amino-2R-benzyl-6-cyclohexyl-3R,4R-dihydroxy-hexanoyl-L-isoleucyl-2-pyridylmethylamide or POA-His-CPD-Ile-Amp;
Phenoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or POA-His-CVA-Ile-Amp:
1-Naphtoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R-isobutyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-CLD-Ile-Amp;
1-Naphthoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-2R-cyclohexylme-thyl-3R,4R-dihydroxy-hexanoyl-L-isoleucyl-2-pyridylmethylamideorOA-His-CCD-Ile-Amp;
1 -Naphthoxyacetyl-L-histidyl-5S-amino-2R-benzyl-3R,4R-dihydroxy-6-phenyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-PPD-Ile-Amp;
1-Naphthoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R-isopropyl-hexanoyl-L-isoleucyl-2-pyridinylamino-ethylamide or NOA-His-CVD-Ile-Apr;
1-Naphthoxyacetyl-L-histidyl-5S-amino-cyclohexyl-2S-cyclohexyl me-thyl-3R,4R-dihydroxy-hexanoyl-L-isoleucyl-2-pyridylmethylamideorNOA-His-CCD-Ile-Amp;
1-Naphthoxyacetyl-L-histidyl-5S-amino-3S-4S-dihydroxy-2S-isobutyl-methyl-octanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-LlD-Ile-Amp;
1-Naphthoxyacetyl-L-histidyl-5S-amino-3R-4R-dihydroxy-2S-isobutyl-7-methyl-octanoyl-L-isoleucyl-2-pyridylmethylamide or NOA His LlD-Ile-Amp;
1-Naphthoxyacetyl-L-histidyl-5S-amino-3R-4R-dihydroxy-2S-isobutyl-7-methyl-octanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-LlD-Ile-Amp;
1-Naphthoxyacetyl-L-histidyl-5S-amino-3R-4R-dihydroxy-2R-isobutyl-7-methyl-octanoyl-L-isoleucyl-2-pyridvlmethylamide or NOA-His-LlD-Ile-Amp;
2-Quinolinylcarbonyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R-isopropyl-hexanoyl-L-isoleucyl-2-pyridinylamino-ethylamide or Qc-Asn-CVD-Ile-Apr;
Quinolinyl-2-carbonyl-L-histidyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or QC-His-CVA-Ile-Amp;
Quinolinyl-2-carbonyl-L-asparaginyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or QC-Asn-CVA-Ile-Amp;
1-Naphthalenyloxyacetyl-L-histidyl-5S-amine-6-cyclohexyl-4S-hydroxy-2S-isopropyl-hexanoyl-L-isoleucylamide or Noa-His-CVA-Ile-NH2;
L-Asparaginamide, 1-(naphthoxy)acetyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[[2-(N-oxido)pyridinylmethyl)amino]carbonyl]butyl]ami-no]carbonyl]hexyl]-N-alpha-methyl-[1S-[1R*,2R*,4R*(1R*,2R*)]]-orNOA-Asp-CVA-Ile-Amp;
L-Asparaginamide, [5-(triethyleneglycol monomethyl ether)naphthoxy)acetyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)4-[[[2-methyl-1-[[[2-(N-oxido)pyridinylmethyl]amino]carbonyl]butyl]amino]carbonyl]hexyl]-N-alpha-methyl-, [1S-[1R*,2R*,4R*(1R*,2R*)]]-or 5-(triethyleneglycol monomethyl ether-NOA-Asp-CVA-Ile-Amp; and L-Asparaginamide, [4-(triethyleneglycol monomethyl ether)naphthoxy]acetyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[[2-(N-oxido)pyridinylmethyl]amino]carbonyl]butyl]amino]carbonyl]hexyl]-N-alpha-methyl-, [1S-[1R*, 2R*,4R*(1R*,2R*)]]- or 4-(triethyleneglycol monomethyl ether)-NOA-Asp-CVA-Ile-Amp:

9. The use of claim 4 wherein C8 is absent, D9 is present and G12 is absent.

10. The use of claim 9 wherein the compound of formula I is selected from the group consisting of:
1H-Imidazole-4-propanamideN-[2,3-dihydroxy-5-methyl-4-[[(2-methyl-butyl)amino]carbonyl]-1 -(2-methylpropyl)hexyl]-.alpha.-[(phenoxyacetyl)amino]-, [1R-[1R*(S*),2S*,3S*,4S*(S*)]]-;or POA-His-LVDA-Mba;
N.epsilon.-[(2S,4S,5S)-5-[N-[N.alpha.-(1-Naphthalenyloxyacetyl)-L-histidyl)amino]-6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-L-lysine,triflouroacectic acid salt or NOA-His-CVA-L-lysine,triflouroacetic acid salt;
N-[(2S,4S ,5S)-5-[N-[N.alpha.-(1-Naphthalenyloxyacetyl)-L-histidyl]amino]-6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-[2-(2-pyridinylamino)ethyl]-aminor NOA-His-CVA-NH-(CH2)2-NH-(2-pyridine);
N-[(2S,4S,5S)-5-[N-[N.alpha.-(1-Naphthalenyloxyacetyl)-L-histidyl]amino]-6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-[2-(2-pyridinylamino)]ethyl)amine,-pyridine N-oxide or NOA-His-CVA-NH(CH2)2-NH-(2-pyridine);
Pentanoic acid, 5-[[1-(cyclohexylmethyl)-2-hydroxy-4-[[(2-hydroxy-propyl)amino]carbonyl]-5-methylhexyl]amino]-5-oxo-4-[(phenoxyacetyl)amino)orPOA-Glu-CVA-NH-CH2CH(CH3)(OH);
1H-Imidazole-4-propanamide, N-[1-(cyclohexylmethyl)-2-hydroxy-4-[[(2-hydroxypropyl)amino]carbonyl]-5-methylhexyl].alpha.-[(phenoxyacetyl)amino]-,monoacetate (salt) or POA-His-CVA-NH-CH,-CH(OH)(CH3);
N-tert-Butyloxycarbonyl-L-phenylalanyl-L-histidyl-5S-amino-3R,4R-dihydroxy-2R-isopropyl-7-methyl-octanoyl-2S-methylbutylamideor BOC-Phe-His-LVA-Mba; and POA-His-CVA-NH-(CH2)4-CH(CONH)(NH2);

11. Use of a compound selected from the group consisting of L-Isoleucinamide, N2-(5-amino-4-hydroxy-2(1-methylethyl)-1-oxooctyl]-N-(2-pyridinylmethyl)-, trifluoroacetate, (S,S,S)-; or H-LVA-Ile-Amp;

Octanamide5[(3,3-dimethyl-1-oxobutyl)amino]-4-hydroxy-7-methyl-2-(1-methylethyl)-N-[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]-, [2S
[1(1R*,2R*),2R*,4R*,5R*]]-or TBA-LVA-Ile-Amp;
Cyclohexanehexanamide, .delta.-[(3,3-dimethyl-1-oxobutyl)amino]-.lambda.-hydroxy-.alpha.-(1-methylethyl)-N-[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]-, [.alpha.S-[N(1R*,2R*),.alpha.R*,.lambda.R*,.delta.R*]]-or TBA-CVA-Ile-Amp;
Cyclohexanehaxanamide, .delta.-amino-.lambda.-hydroxy-.alpha.-(1-methylethyl)-N-[[(2-methyl-1-[[(2-pyridinylmethyl)]amino]carbonyl]butyl]-dihydrochloride,[.alpha.S-[N(1R*,2R-*),.alpha.R*,.lambda.R*,.delta.R*]]- or H-CVA-Ile-Amp;
Cyclohexanehexanamide, .delta.-(acetylamino)-.lambda.-hydroxy-.alpha.-(1-methylethyl)-N-[2-methyl-1-[[(pyridinylmethyl)amino]carbonyl]butyl].alpha.S-[N(1R*,2R*),.alpha.R*,.lambda.R*,.delta.R-*]]-' or Ac-CVA-Ile-Amp;
Octanamide, 5-(acetylamino)-4-hydroxy-7-methyl-2-(1-methylethyl)-N-[2-methyl-1-[[(2-pyridinylmethyl)amino)carbonyl]butyl]-, [2S[N(1R*,2R*),2R*, 4R*,5R*]]-, monoacetate (salt); or Ac-LVA-Ile-Amp; or IVA-LVA-Ile-Amp.
Boc-Phe-His-Cha psi[CHOHCHOH]Val-Ile-Amp; or L-Histidinamide, N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-[1-(cyclohexylmethyl)-2,3-dihydroxy-5-methyl-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]car-bonyl]hexyl]-, [1S-[1R*,2S*,3S*,4S*(1R*,2R*)]]-; or BOC-Phe-His-CVD-Ile-Amp:
L-Histidinamide, N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-[2-hydroxy-1-(2-methylpropyl)-5-[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]
butyl]amino-5-oxo-4-(phenylmethyl)pentyl], [1S-[1R*,2R*,4S,5(1R*,2R*)]]-; or Boc-Phe-His-LPA-Ile-Amp;
L-Histidinamide, N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-[4-(cyclohexylmethyl)-2-hydroxy-1-(2-methylpropyl)-5-[[2-methyl-1-[[(2-pyridinylmethyl amino]carbonyl]butyl]amino]-5-oxopentyl-,[1S-[1R*,2R*,4S*,5(1R*,2R*)]]-; or Boc-Phe-His-LCA-Ile-Amp;
L-Talonamide, 6 cyclohexyl-2,5,6-trideoxy-5-[N-[N-[(1,1-dimethyleth-oxy)carbonyl]-L-phe??lalanyl]-L-histidyl]amino]-2-(1-methylethyl)-N-[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]-, [S-(R*,R*)]-; or Boc-Phe-His-CVD'-Ile-Amp;
L-Histinamide, N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-(2,3-dihydroxy-5-methyl-1-(2-methylpropyl)-4-[[(2-methyl-1-[[(2-pyridinylmethyl)amino]-carbonyl]butyl)amino]carbonyl]hexyl]-,[1S-[1R*,2S*,3R*,4S*(1R*.2R*)]]-:orBoc-Phe-His-LVDA'-Ile-Amp;
L-Histidinamide. N-[[5-(dimethylamino)-1-naphthalenyl]sulfonyl]-L-phenylalanyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4[[[2-methyl-1-[[(2-pyridinyl-methyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-, [1S-[1R*,2R*4R*(1R*.2R*)]]-;or DANS-Phe-His-LVA-Ile-Amp;
L-Histidinamide, L-phenylalanyl-N-[2-hydroxy-5-methyl-1-(2-methylpro-pyl)-4-[[[2- methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl)hexyl]-, [1S-(1R*,2R*,4R*(1R*,2R*)]]- or H-Phe-His-LVA-Ile-Amp;
L-Valinamide, L-phenylalanyl-N-[2-hydroxy-5 methyl-1-(2-methylpropy-1)-4-[[[2-methyl-1-[[2-pyridinylmethyl)amino)carbonyl]butyl]amino]carbonyl]hexyl]-, [1S-[1R*,2R*,4R*(1R*,2R*)]]-; or H-Phe-Val-LVA-Ile-Amp:
L-Valinamide, L-valyl-N-[2-hydroxy-5-methyl-1-(2 methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino)carbonyl]hexyl]-, [1S-[1R*,2R*,4R*(1R*,2R*)]]-, diacetate (salt); or H-Val-Val-LVA-Ile-Amp; or L-Valinamide, N acetyl-L-valyl-N [2-hydroxy-5-methyl-1-(2-methylprop-yl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino)carbonyl]butyl]amino]carbonyl]hexyl]-, [1S-[1R*,2R*,4R*(1R*,2R*)]]-, monoacetate (salt); or Ac-Val-Val-LVA-Ile-Amp.
N.alpha.-[(2S,4S,5S)-5-[[N.alpha.[(S)-1-Acetoxy-1-benzyl)methylcarbonyl)-L-histidyl]amino]-4-hydroxy-7-methyl-2-(1-methylethyl)-1-oxooctyl]-N-[2-pyridyl)ethyl]
-L-isoleucinamide; or AcO-Phe-His-LVA-Ile-NH-(CH2)2-pyridine.
4-Morpholinebutanamide, .beta.-hydroxy-N-[2-[[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino)carbonyl-]hexyl]amino]-1-(1H-imidazol-4-ylmethyl)-2-oxoethyl]-.alpha.-(1-naphthalenylmethyl)-.lambda.-oxo-, [1S-[1R*[R*(.alpha.S*,.beta.R*)],2R*,4R*(1R*,2R*)]]-;
1H-Imidazole-4-propanamide, .alpha.-[[[5-(dimethylamino)-1-naphthalenyl]su-lfonyl]amino)-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinyl-methyl)amino]carbonyl]butyl]amino]carbonyl]hexyl] -, [1S-[1R*(R*),2R*,4R*(1R*,2R*)]]-; or DANS-His-LVA-Ile-Amp;
1H-Imidazole-4-propanamide, .alpha.-amino-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl-]hexyl]-, [1S-[1R*(R*),2R*,4R*(1R*,2R*)]] or H-His-LVA-Ile-Amp;
Octanamide, 5-[[2-(acetylamino)-3-methyl-1-oxobutyl]amino]-4-hydroxy-7-methyl-2-(1-methylethyl)-N-[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]-, [S-[N(1R*,2R*),2R*,4R*,5R*(R*)]]-, monoacetate (salt): or Ac-Val-LVA-Ile-Amp;
Ac-Asn-LVA-lle-Amp:
N.alpha.-[(2S,4S,5S)-5-[[(S)-(1-Hydroxy-1-benzyl)methylcarbonyl)amino]-4-hydroxy)-7-methyl-2-(1-methylethlyl)-1-oxooctyl]-N-(2-pridinylmethyl)-L-isoleucinamide:
or HO-Phe-LVA-Ile-Amp;
1H-imidazole-4-propanamide.N-[2-hydroxy-5-methyl-1-2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl)butyl)amino)carbonyl]hexyl]-.alpha.-[(2-hydroxy-1-oxo-3-phenylpropyl)amino]-,[1S-[1R*[R*(R*)],2R*,4R*(1R*,2R*)]]-, 2-hydroxy- 1,2,3-propanetricarboxylate(12)(salt) or phenyl-CH2CH(OH)-C(O)-His-LVA
Ile-Amp;
L-.alpha.-Glutamine.N/u2/d-[N-[[1,1-dimethylethoxy)carbonyl)-L-phenylal-anyl]-N-[2-hvdroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinyl-methyl)amino]carbonyl]butyl)amino]carbonyl]hexyl]-,[1S-[1R*,2R*4R*(1R*.2R*))]-,monacetate (salt) or BOC-Phe-Glu-LVA-Ile-Amp;
L-Histidinamide, N-[(1,1-dimethylethoxy)carbonyl]-3-(2-pyridinyl)alanyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino)c-arnonyl]butyl]amino]carbonyl]hexyl]-,[1S-[1R*[R*(E)].2R*,4R*(1R,2R*)]-orBOC-2-Py-Ala-His-LVA-Ile-Amp;
L-.alpha.-Asparagine. N/u 2/d-[N-[(1,1-dimethylethoxy)carbonyl)-L-phenylalanyl]-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[2-methyl-1-[[(2-pyridinylme-thyl)amino]carbonyl]butyl]amino]carbonyl]hexyl)-,[1S-[1R*,2R*,4R*(1R*,2R*)]]-,monoacetate (salt) or BOC-Phe-Asp-LVA-Ile-Amp; U-77808E
L-.alpha.-Glutamine, N-[1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-NO[1-(cyclohexvlmethyl)-2-hydroxy-5-methyl-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amin-o]carbonyl]butyl]amino]carbonyl]hexyl]]-,[1S-[1R*,2R*,4R*(1R*.2R*)]]-, monoacetate (salt) or BOC-Phe-Glu-CVA-Ile-Amp;
L-Histidinamide N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-[3,3-difluoro-2-hydroxy-4-[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]am-ino]-4-oxo-1-(phenylmethyl)butyl]-orCH3-C(O)-O-CH(benzyl)-C(O)-His-LVA-Ile-Amp;
L-Glycyl-L-histidyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or Gly-His-CVA-Ile-Amp;
L-Glycyl-L-histidyl-5S-amino-2R-benzyl-6-cyclohexyl-3R,4R dihydroxy-hexanoyl-L-isoleucyl-2-pyridylmethylamide or Gly-His-CPD-Ile-Amp;
5-Quinolinylhydroxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or Qoa(b)-His-CVA-Ile-Amp;
Quinolinylhydroxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or Qoa(a)-His-CVA-Ile-Amp;
N-tert-Butyloxycarbonyl-L-alanyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S-isopropyl hexanoyl-L-isoleucyl-2-pyridylmethylamide or Boc-Ala-CVA-Ile-Amp;
N-tert-Butyloxycarbonyl-L-histidyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or BOC-His-CVA-Ile-Amp;
Benzyloxycarbonyl-L-alanyl-L-alanyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamideorCBZ-Ala-Ala-CVA-Ile-Amp; L-Histidinamide, N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-[4-[[[2-[(2,6 diamino-4-pyrimidinyl)amino]ethyl)amino]carbonyl]-2-hydroxy-5-methyl-1-(2-methylpropyl)hexyl]-,[1S-(1R*,2R*,4R*)]- or BOC-Phe-His-LVA-(2,diamino-4-pyrime-dinyl)amino-thylamino;
Gly-CVD-Ile-Amp; and Gly-CPD-Ile-Amp;
to prepare a medicament for inhibiting a retrovirsus in a human cell infected with said retrovirus.

12. A compound selocted from the group consisting of:
Cyclohexanehexanamide,.delta.-(acetylamino)-.lambda.-hydroxy-.alpha.-(1-methylethyl)-N-[2-methyl-1-[[(pyridinylmethyl)amino]carbonyl]butyl].alpha.S-[N(1R*,2R*),.alpha.R*,.lambda.R*,.delta.R-*]]-; or Ac-CVA-Ile-Amp;
Octanamide, 5-(acetylamino)-4-hydroxy-7-methyl-2-(1-methylethyl)-N-[2-methyl-1-[[(2-pyridinylmethyl)amino)carbonyl]butyl]-, [2S-[N(1R*,2R*),2R*,4R*,5R*]]-, monoacetate (salt); or Ac-LVA-Ile-Amp;
L-Valinamide, L-phenylalanyl-N-[2-hydroxy-5-methyl-1-(2-methylpropy-l)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-, [1S-[1R*,2R*,4R*(1R*,2R*)]]-; or H-Phe-Val-LVA-Ile-Amp;
Octanamide, 5-[[2-(acetylamino)-3-methyl-1-oxobutyl]amino]-4-hydroxy-7-methyl-2-(1-methylethyl)-N-[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]-, [2S-[N(1R*,2R*),2R*,4R*.5R*(R*)]]-, monoacetate (salt); or Ac-Val-LVA-Ile-Amp;

L-Valinamide. L-valyl-N-12-hvdroxy-5-methyl-1-(2-methylpropyl) 4-[[[2 -methyl-1-[[(2-pyridinylmethyl)amino]carbonyl)butyl]amino]carbonyl]hexyl]-, [1S-[1R*,2R*,4R*(1R*,2R*)]]-, diacetate (salt); or H-Val-Val-LVA-Ile-Amp;
Ac-Asn-LVA-Ile-Amp;
L-Valinamide, N-acetyl-L-valyl-N-[2-hydroxy-5-methyl-1-(2-methylprop-yl)-4-methyl-1-[[2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-[1S-[1R*,2R*,4R*(1R*,2R*)]]-,monoacetate (salt); or Ac-Val-Val-LVA-Ile-Amp; or N-[(2S,4S,5S)-5-[N.alpha.-[N.alpha.-(tert-Butoxycarbonyl)-O-methyl-L-tyrosyl]-L-histidyl]amino]-4-hydroxy-7-methyl-2-phenylmethyl-1-oxooctyl]-N-[(S)-2-hydroxypropyl]-amine; or Boc-OMeTyr-His-LPA-NH-CH2-CH(CH3)(OH).

13. A compound of fonnula I

wherein X is a) hydrogen, b) naphthyloxyacetyl, c) t-butyloxycarbonyl, d) toluene-sulfonyl, e) phenyloxvacetyl, f) pyridinyl-(CH2)a-carbonyl, g) phenyl-(CH2)n-CH(OH)-C(O)-, h) indolycarbonyl, i) pyridinyl-(CH2)n-O-C(O)-, j) phenyl-(CH2)n-SO2-, k) phenyl-(CH2)n-C(O)-, l) phenyl-HC=CH-(CH2)n-C(O), m) phenyl-HC=CH-(CH2)n-O-C(O)-, n) HO-(CH2)n-C(O)-, o) quinolinoylhydroxyacetyl, p) quinolinoylcarbonyl, q) benzyloxycarbonyl, or r) 5-(triethyleneglycolmonomethylether) naphthyloxyacetyl:
wherein C8 is a) absent, b) 2-Py-Ala, c) -NH-CH.-C(O)-d) Phe, or e) Ala:
wherein D9 is a) His, b) Glu, c) Asp, d) Asn, e) -NH-CH2-C(O), or f) Ala:
wherein E10 F11 is a) CVA, b) LVA, c) CVD, d) LVD, e) CPD, f) CLD, g) CcD, h) CCD, i) PPD, j) LlD, k) LLd, or wherein G12 is a) absent, or b) Ile;
wherein Z is a) Amp, b) Amp-NO, c) lysine, d) -NH-(CH2)n-NH-pyridine, e) -NH-(CH2)n-CH(OH)-phenyl, f) -NH-(CH2)n-CH(OH)-C1-C5 alkyl, or g) -NH-(CH2)n-NH-(2,6-diamino-4-pyrmidinyl).
wherein n is 0 to five, inclusive.

14. A compound of claim 13 wherein X is a) 1-naphthyloxyacetyl, b) p-toluene-sulfonyl, c) phenyloxyacetyl, or d) 3-pyridinyl-methylcarbonyl:
wherein C8 is absent:
wherein D9 is His:
wherein E10-F11 is CVA:
wherein G12 is a) absent, or b) Ile;
wherein Z is a) Amp, b) Amp-NO
c) L-lysine, or d) -NH-(CH2)2-NH-2-pyridine.

15. A compound of claim 14 selected from the group consisting of:
N.alpha.-[(2S, 4S, SS)-5-[N-[N.alpha.-(1-Naphthalenyloxyacetyl)-L-histidyl]amino]-6-cyclohexyl-4-hydroxy-2-isopropvl-1-oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucinamide.
pyridine N-oxide or NOA-His-CVA-Ile-Amp-NO;
N.alpha.-[(2S, 4S, 5S)-S-[N-[N.alpha.-(1-toluenesulfonyl)-L-histidyl]amino]-6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl)-N-(2-pyridinylmethyl)-L-isoleucinamide or p-Tolunesulfonyl-His-CVA-Ile-Amp;
N.alpha.-[(2S, 4S, 5S)-5-[N-[N.alpha.-(1-Naphthalenyloxyacetyl)-L-histidyl]amino]-6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucinamide or NOA-His-CVA-Ile-Amp;
N.alpha.-[(2S, 4S, 5S)-5-[N-[N.alpha.-(Phenoxymethylcarbonyl)-L-histidyl]amino]-6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucinamide, pyridine N-oxide or POA-His-CVA-Ile-Amp-NO;

N.alpha.-[(2S,4S5S)-5-[N-[N.alpha.-(p-Toluenesulfonyl)-L-histidyl]amino]-6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucinamide,pyridineN-oxide or p-Toluenesulfonyl-His-CVA-Ile-Amp-NO;
N.epsilon.-[(2S, 4S, 5S)-5-[N-[N.alpha.-(1-Naphthalenyloxyacetyl)-L-histidyl)amino]-6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl)-L-lysine,triflouroacecticacid saltorNOA.
His-CVA-L-lysine,triflouroacetic acid salt;
N-[(2S, 4S, 5S)-S-[N-[N.alpha.-(1-Naphthalenyloxyacetyl) L-histidyl]amino]-6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-[2-(2-pyridinylamino]ethyl]-amine or NOA-His CVA-NH (CH2)2-NH-(2-pyridine);
N-[(2S, 4S, 5S)-5-[N-[N.alpha.-(1-Naphthalenyloxyacetyl)-L-histidyl]amino]-6-cyclohexyl-4-hvdroxy-2-isopropyl-1-oxohexyl)-N-[2-(2-pyridinylamino))ethyl]amine,-pyridine N-oxide or NOA-His-CVA-NH(CH2)2-NH-(2-pyridine);
N.alpha.-[(2S, 4S, 5S)-5-[N-[N.alpha.-(1-Naphthalenyloxyacetyl) (2-pyridinyl)alanyl]-amino]-6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucinamide or NOA-His-CVA-Ile-Amp;
N.alpha.-[(2S,4S,5S)-5-[N-[N.alpha.-[(3-Pyridinyl)-methylcarbonyl]-L-histidyl]amino]-6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucinamide or (3-pyridinyl)-methyl-carbonyl-His-CVA-Ile-Amp;
N.epsilon.-[N2-[(2S, 4S, 5S)-5-[N-[N.alpha.-(1-Naphthalenyloxyacetyl)-L-histidyl]amino]-6 cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-L-isolencyl]-L-lysine,triflouroacetic acid salt or NOA-His-CVA-Ile-L-lysine/ trifluoroacetic acid salt:
N.alpha.-(2S, 4S, 5S)-5-[N.alpha.-(1-Naphthalenyloxyacetyl)-L-histidyl]amino]-6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-[2-(2-pyridinylamino)ethyl]-L-isoleucinamide or NOA-His-CVA-Ile-NH-(CH2)2-NH-(2-pyridine).

16. A compound of claim l3 wherein X is a) phenyl-CH2-CH(OH)-C(O)-, b) phenyloxyacetyl, c) t-butyloxycarbonyl, d) 1H-indol-2-ylcarbonyl, e) 2-pyridyl-acetyl, f) 4-pyridyl-acetyl, g) 4-pyridyl-CH2-O-C(O)-, h) phenyl-O-(CH2)2-C(O)-, i) phenyl-HC=CH-(CH2)n-C(O)-, j) phenyl-HC=CH-(CH2)n-O-C(O)-, or k) phenyl-(CH2)2-SO2-;
wherein C8 is a) absent b) 2-Py-Ala, or c) Phe;
wherein D9 is a) His, b) Glu, or c) Asp;
wherein E10-F11 is a) LVA, or b) CVA;
wherein G12 is a) absent, or b) Ile;
wherein Z is a) Amp, b) -NH-CH2-CH(OH)-phenyl, c) -NH-CH2-CH(OH)-CH3, or d) -NH(CH2),NH-(2,6-diamino-4-pyrimidinyl).

17. A compound of claim 16 selected from the group consisting of:
1H-Imidazole-4-propanamide,N-[2-hydroxy-5-methyl-1-(2-methylpropyl)4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-.alpha.-[(2-hydroxy-1-oxo-3-phenylpropyl)amino]-,[2S-[1R*[R*(R*),2R*,4R*(1R*,2R*)]]-, 2-hydroxy-l,2,3-propanetricarboxylate(12)(salt) or phenyl-CH2-CH(OH)-C(O)-His-LVA-Ile-Amp;
1H-Imidazole-4-propanamide,N-[2-hydroxy-4-[[[1-[[(2-hydroxy-2-phenylethyl)-amino]carbonyl]-2-methylbutyl]amino]carbonyl]-5-methyl-1-(2-methylpropyl)hexyl]-.alpha.-[(phenoxyacetyl)amino]-,monoacetate (salt) or POA-His-LVA-Ile-NH-CH2-CH(OH)-phenyl;

L-.alpha.-Glutamine,N/u2/d-[N-[[1,1-dimethylethoxy)carbonyl]-L-phenylalanyl)-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]-carbonyl]butyl]amino]carbonyl]hexyl]-,[1S-[1R*,2R*,4R*,(1R*,2R*)]]-,monacetate(salt) or BOC-Phe-Glu-LVA-Ile-Amp;
Pentanoic acid, 5-[[1-cyclohexylmethyl)-2-hydroxy-4-[[(2-hydroxypropyl)-amino]carbonyl]-5-methylhexyl]amino]-5-oxo-4-[(phenoxyacetyl)amino]- or POA-Glu-CVA-NH-CH2CH(CH3)(OH);
1H-Imidazole-4-propanamide, N [1-(cyclohexylmethyl)-2 hydroxy-4-[[(2-hydroxypropyl)amino)carbonyl]-5-methylhexyl].alpha.-[(phenoxyacetyl)amino]-,monoacetate (salt) or POA-His-CVA-NH-CH2-CH(OH)(CH3);
Pentanoic acid. 5-[[1-cyclohexylmethyl)-2-hydroxy-5-methyl-4-[[[2-methyl-1-[[(2-pyidinylmethvl)amino]carbonyl]butyl]amino]carbonyl]hexyl]amino-4-[(1H-indol-2-ylcarbonyl)amino]-5-oxo-,[1S-[1R*(R*),2R*,4R*(1R*,2R*)]]or1H-indol-2-yl-carbonyl-Glu-CVA-Ile-Amp;
L-.alpha.-Glutamine, N-[1-(cyclohexylmethyl)-2-hydroxy-5-methyl 1-[[[(2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-N/u 2/d-L-phenylalanyl-, [1S-[1R*,2R*,4R*(1R*,2R*)]]-, bis(trifluoracetate) (salt) or Phe-Glu-CVA-Ile-Amp;
2-Pyridineacetamide, N-[2-[[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl)butyl)amino]carbonyl]hexyl]amino]-1-(1H-imidazol-4-ylmethyl)-2-oxoethyl]-[1S-[1R*(R*),2R*,4R*(1R*,2R*)]]-or (2-Pyridyl)acetyl-His-LVA-Ile-Amp;
4-Pyridineacetamide, N-[2-[[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl)amino)carbonyl]hexyl]amino]-1-(1H-imidazol-4-ylmethyl)-2-oxoethyl)-[1S-[1R*(R*),2R*,4R*(1R*,2R*)] -or (4-Pyridyl)acetyl-His-LVA-Ile-Amp;
L-Histidinamide,N-l(1,1-dimethylethoxy)carbonyl)-3-(2-pyridinyl)alanyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-1[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbo-nyl]butyl]amino]carbonyl]hexyl]-,[1S-[1R*,R*(E)],2R*,4R*(1R*,2R*)]]-or BOC-2-Py-Ala-His-LVA-Ile-Amp;
L-Histidinamide, N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-[4-[[[2-[(2,6-diamino-4-pyrimidinyl)amino]ethyl)amino]carbonyl]-2-hydroxy-5-methyl-1-(2-methylpropyl)hexyl]-,[1S-(1R*,2R*,4R*)]- or BOC-Phe-His-LVA-(2,6-diamino-4-pyrimi-dinyl)amino-ethylamino;
L-.alpha.-Asparagine,N/u2/d-[N-[(1,1-dimethylethoxy)carbonyl]-L-phenylala-nyl]-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[2-methyl-1-[[(2-pyridinylme-thyl)amino]carbonyl)butyl]amino]carbonyl)hexyl]-,[1S-[1R*,2R*,4R*(1R*,2R*)]]-,monoacetate(salt) or BOC-Phe-Asp-LVA-Ile-Amp;
1H-Indole-2-carboxamide,N-[2-([2-hydroxy-5-methyl-1-(2-methylpropyl)4-[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl)butyl]carbonyl]hexyl)amino]-1-(1H-imidazol-4-ylmethyl)-2-oxoethyl]-,[1S-[1R*[1R*),2R*,4R*(1R*,2R*)]]-?-(Indolyl-2-carbonyl)-His-LVA-Ile-Amp;
L-.alpha.-Glutamine, N[1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-NO[1-(cyclohexylmethyl)-2-hydroxy-5-methyl-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carb-onyl]butyl]amino]carbonyl]hexyl]]-,[1S-[1R*,2R*,4R*(1R*,2R*]]-, monoacetate (salt) or BOC-Phe-Glu-CVA-Ile-Amp;
2,5,11,14-Tetraazapentadecanoic acid, 7-hydroxy-3-(1H-imidazol-4-ylmethyl)-9-(1-methylethyl)-12-(1-methylpropyl)-6-(2-methylpropyl)-4,10,13-trioxo-15-(2-pyridinyl)-,4-pyridinylmethyl ester, [3S-[3R*,6R*,7R*,9R*,12R*(R*)]]-;
1H-Imidazole-4-propanamide, N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-.alpha.-[(1-oxo-3-phenoxypropyl)amino]-,[1S-[1R*(R*),2R*,4R*(1R*2R*)]]-,or Phenoxypropionyl-His-LVA-Ile-Amp;
1H-Imidazole-4-propanamide,N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[[(2-pyridinylmethyl)amino[carbonyl]butyl[amino[carbonyl[hexyl)-.alpha.-[(1-oxo-3phenyl-2-propenyl)amino]-,[1S-[1R*[R*(E)],2R*,4R*(1R*,2R*)]]-orphenyl-CH=CH-C(O]-His-LVA-Ile-Amp;
1H-Imidazole-4-propanamide,N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[[(2-pyndinylmethyl)amino[carbonyl][butyl]amino[carbonyl[hexyl)-.alpha.-[(1-oxo-4-phenyl-3-butenyl)amino]-,[1S-[1R*R*(E)],2R*,4R*(1R*,2R*)]]- or phenyl-CH=CH-CH2-C(O)-His-LVA-Ile-Amp;
2,5,11,14-Tetraazapentadecanoic acid, 7-hydroxy-3-(1H-imidazol-4-ylmethyl)-9-(1-methylethyl)-12-1-methylpropyl)-6-(2-methylpropyl)-4,10,13-trioxo-15-(2-pyridinyl)-,3-phenyl-2-propenyl ester, [3S-[1(E),3R*,6R*,7R*,9R*,12R*(R*)]]- or phenyl-CH=CH-CH2-O-C(O)-His-LVA-Ile-Amp; and 1H-Imidazole-4-propanamide,N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-WO 91/06561 PCT/US90.05818 methyl-1-[[(2-pvridinylmethyl)amino)carbonyl]butyl]amino]carbonyl]hexyl]-.alpha.-[[(2-phenylethenyl)sulfonyl]amino]-[1S-[1R*[R*(E)]2R*,4R*(1R*,2R*)]]-or phenyl-(CH2)-SO2-His-LVA-lle-Amp:

18. A compound of claim 13 wherein X is a) t-butyloxycarbonyl, b) (HO) acetyl, c) hydrogen, d) phenyloxyacetyl, e) 1-naphthyloxyacetyl, f) 5-quinolinylhydroxyacetyl, g) 4-quinolinylhydroxyacetyl, or h) 2-quinolinylcarbonyl;
wherein C1 is a) absent b) Phe, or c) -NH-CHcC(O)-;
wherein D9 is a) His, b) Asn, or c) -NH-CH7C(O)-;
wherein E10-F11 is a) CVD, b) LVD, c) CPD, d) ?CLD, e) CCD, f) CcD, g) PPD, h) LID, i) CVA, j) LLd, or k) LLD;

wherein G12 is a) absent, or b) lle:
wherein Z is a) Mba, b) Amp, c) Amp-NO, or d) Apr;

19. A compound of claim 18 selectd from the group consisting of:
N-tert-Butyloxycarbonyl-L-phenylalanyl-L-histidyl-5S-amino-3R,4R-dihydroxy-2R-isopropyl-7-methyl-octanoyl-2S-methylbutylamide or BOC-Phe-His-LVA-Mba:
Hydroxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or (HO)Ac-His-CVA-lle-Amp;
L-Glycyl-L-histidyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or Gly-His-CVA-Ile-Amp;
Hydroxyacetyl-L-histidyl-5S-amino-2R-benzyl-6-cyclohexyl-3R,4R-dihydroxy-hexanoyl-L-isoleucyl-2-pyridylmethylamide or (HO)Ac-His-CPD-lle-Amp;
Hydroxyacetyl-L-histidyl-5S-amino-2R-benzyl-6-cyclohexyl-3R,4R-dihydroxy-hexanoyl-L-isoleucyl-2-pyridylmethylamide, N-oxide or (HO)Ac-His-CPD-Ile-Amp:
Phenoxyacetyl-L-histidyl-5S-amino-2R-benzyl-6-cyclohexyl-3R,4R-dihydroxy-hexanoyl-L-isoleucyl-2-pyridylmethylamide or POA-His-CPD-Ile-Amp;
L-Glycyl-L-histidyl-5S-amino-2R-benzyl-6-cyclohexyl-3R,4R-dihydroxy-hexanoyl-L-isoleucyl-2-pyridylmethylamide or Gly-His-CPD-Ile-Amp;
Phenoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or POA-His-CVA-Ile-Amp;
1-Naphtoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R-isobutyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-CLD-Ile-Amp;
1-Naphthoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-2R-cyclohexylmethyl-3R,4R-dihydroxy-hexanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-CCD-Ile-Amp;
1-Naphthoxyacetyl-L-histidyl-5S-amino-2R-benzyl-3R,4R-dihydroxy-6-phenyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-PPD-Ile-Amp;
1 -Naphthoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R-isopropyl-hexanoyl-L-isoleucyl-2-pyridinylamino-ethylamideorNOA-His-CVD-Ile-Apr;1-Naphthoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-2S-cyclohexylmethyl-3R,4R-dihydroxy-hexanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-CcD-Ile-Amp;
1-Naphthoxyacetyl-L-histidyl-5S-amino-3S-4S-dihydroxy-2S-isobutyl-7-methyl -octanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-Lld-Ile-Amp;
5-Quinolinylhydroxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or Qoa(b)-His-CVA-Ile-Amp;
4-Quinolinylhydroxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or Qoa(a)-His-CVA-Ile-Amp;
1-Naphthoxyacetyl-L-histidyl-5S-amino-3R-4R-dihydroxy-2S-isobutyl-7-methyl-octanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-LLd-Ile-Amp;
1-Naphthoxyacetyl-L-histidyl-5S-amino-3S-4R-dihydroxy-2S-isobutyl-7-methyl-octanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-LLd-Ile-Amp;
1-Naphthoxyacetyl-L-histidyl-5S-amino-3R-4R-dihydroxy-2R-isobutyl-7-methyl-octanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-LLD-Ile-Amp;
2-Quinolinylcarbonyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R-isopropyl-hexanoyl-L-isoleucyl-2-pyridinylamino-ethylamide or Qc-Asn-CVD-Ile-Apr;
L-Glycyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R-isopropyl-hexanoyl-=L-isoleucyl-2-pyridylmethylamide-or Gly-CVD-Ile-Amp;
L-Glycyl-5S-amino-2R-benzyl-6-cyclohexyl-3R,4R-dihydroxy-hexanoyl-L-isoleucyl-2-pyridyl-methylamide or Gly-CPD-Ile-Amp.

20. A compound of claim 13.
wherein X is a) t-butyloxycarbonyl, b) 2-quinolinylcarbonyl, c) benzyloxycarbonyl, d) 1-naphthyloxyacetyl, or e) phenyloxyacetyl;
wherein C8 is a) absent, or b) Ala;
wherein D9 is a) Ala, b) His, or c) Asn:
wherein E10-F11 is CVA;
wherein G10 is a) absent or b) Ile;
wherein Z is a) Amp, b) -NH2, or c) -NH-(CH2)4-CH(CONH)(NH2)

21. A compound of claim 20 selected from the group consisting of:
N-tert-Butyloxycarbonyl-L-alanyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or Boc-Ala-CVA-Ile-Amp;
N-tert-Butyloxycarbonyl-L-histidyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or BOC-His-CVA-Ile-Amp;
Quinolinyl-2-carbonyl-L-histidyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or QC-His-CVA-Ile-Amp;
Quinolinyl-2-carbonyl-L-asparaginyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or QC-Asn-CVA-Ile-Amp;
Benzyloxycarbonyl-L-alanyl-L-alanyl-5S-amino-o-cyclohexyl-4S-hydroxy-2S-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or CBZ-Ala-Ala-CVA-Ile-Amp;
1-Naphthalenyloxyacetyl-L-histidyl-5S-amine-6-cyclohexyl-4S-hydroxy-2S-isopropyl-hexanoyl-L-isoleucylamide or Noa-His-CVA-Ile-NH2; and POA-His-CVA-NH-(CH2)4-CH(CONH)(NH2).

22. A compound of claim 13 wherein X is a) 1-naphthyloxyacetyl, or b) 5-(triethyleneglycolmonomethyl ether) naphthoxyacetyl;
wherein C8 is absent;
wherein D9 is Asp;
wherein E10-F11 is CVA;
wherein G12 is Ile;

wherein Z is Amp.

23. A compound of claim 22 selected from the group consising of:
L-Asparaginamide, 1-(naphthoxy)acetyl-N-[2-hydroxy-5-methyl-1-(2-methyl-propyl)4-[[[2-methyl-1-[[[2-(N-oxido)pyndinylmethyl]amino]carbonyl]butyl]amino]carb-onyl]hexyl]-N-alpha-methyl-, [1S-[1R*,2R*,4R*(1R*,2R*)]]- or NOA-Asp-CVA-Ile-Amp;
L-Asparaginamide, [5-(triethyleneglycolmonomethylether)naphthoxy]acetyl-N
[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[[2-(N-oxido)pyridinyl-methyl]amino]carbonyl]butyl]amino]carbonyl]hexyl]-N-alpha-methyl-, [1S-[1R*,2R*,4R*-(1R*,2R*)]]-or 5-(triethyleneglycol monomethyl ether-NOA-Asp-CVA-Ile-Amp; and L-Asparaginamide,[4-(triethyleneglycolmonomethylether)naphthoxy]acetyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[[2-(N-oxido)pyridinyl-methyl]amino]carbonyl]butyl]amino]carbonyl]hexyl]-N-alpha-methyl-, [1S-[1R*,2R*,-4R*(1R*,2R*)]]- or 4-(triethyleneglycol monomethyl ether)-NOA-Asp-CVA-Ile-Amp.