JPH05501879A - Methods of treating HIV and other retroviruses and compounds useful therein - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Methods and useful compounds for treating old and other retroviruses field of invention The present invention provides a method for inhibiting retroviruses in human cells infected with retroviruses. With respect to the method, the method comprises treating the cell with a retroviral proteinase inhibitor compound of formula I. comprising treating with an effective amount of. The present invention also provides novel compounds useful for this method. provide something.

Background of the invention An estimated 1 to 1.5 million people in the United States are infected with a type of human retrovirus. Human immunodeficiency virus [ Htv-i infection [7- Norman, C., Sci. Science, pp. 661-662 (1986). those infected Of these, an estimated 250,000 will progress to AIDS within five years. J. W. Curran et al., Science, 1352 - p. 1357 (1985)] oFDA, dated March 20, 1987, AIDS patients showing the very early stages of Mo/Stacey carinii pneumonia; - A+ns patients with symptoms other than Mo/Stace carini pneumonia or peripheral blood CD4 lymphocyte count is 200/I! Cures fewer patients infected with virus than 1In3 approved the use of the compound cytopsin (AZT) to treat cancer. AZT is human immune system It is a known inhibitor of viral reverse transcriptase, an enzyme required for the replication of defective viruses. Ru.

Unpublished Patent No. 4.724.232 describes 3'-azido-3'-deoxy-thymidine. (andthymidine, AZT) to treat humans with acquired immunodeficiency syndrome. How can I get it or have I complained?

Over the past 10 years, since the disease was first reported in January, AIDS, and its devastating consequences, are widely recognized in secular publications and science. It is a subject that is constantly and actively reported in all kinds of publications. . In fact, Scientific American The latest issue of ican) is entirely devoted to AIDS. Scientific American, 289 pages, 4 (1988)], the literature on this disease and virus is subject to detailed citation. The number is so huge that it seems like it will last forever. Currently, there is no effective treatment for this disease. 3'-azido-3'-deoxy, an inhibitor of viral reverse transcriptase (ed.) Cythymidine (AZT), despite its very harmful side effects, remains It is the treatment of choice.

The human immunodeficiency virus (formerly known as Duesberg, P., Proceedings of National Academy of Sciences Demie of the United States of America (Proc. Natl, Acad, Sci, IJsA), vol. 86, pp. 755-764. (1989)], but it has been recognized as a causative factor of AIDS for a long time. It has been. Complete genomes derived from several infectious and non-infectious former V monomers Sequence analysis of viruses is essential for virus assembly, replication, and maturation into infectious species. L. Ratner (L.) has shed considerable light on the types of molecules in Ratner) et al., Nature, vol. 313, 277-284 Page (19g5 years)]. Old V contains the same gag/p found in other retroviruses. ol/env structure [L, Ratner et al., Fuichi + (Nature), Vol. 313, pp. 277-284 (19,415); Varnish. Vain-Poplin (S, Vain-Hobson) et al., Cell, Volume 40, pp. 9-17 (1985) Niall Sanchez-Pescador (R, 5anchez-Pescador et al., Science, 22 7, pp. 484-492 (1985); and M.N. t,^,　Muesing) et al., Neichi + (Jlature), vol. 313, 4 50-458 (1985)].

Reverse transcriptase (RT) is an enzyme unique to retroviruses, and is an enzyme unique to retroviruses. catalyzes the conversion of DN8 to double-stranded DN8. AZT and other non-extendable mutated deoxins Interference with synucleoside triposphate at any point during transcription is This should have dramatic consequences for viral replication. More about RT targets Although research on It is based on the fact that it is transported. However, triphosphate Inefficiency of the oxidizing process and lack of specificity and resulting toxicity are AZT or similar compounds with or without blocked 3'hydroxyl groups. constitute a major drawback in using similar nucleosides.

The T4 cell receptor for HIV, the so-called CD4 molecule, is involved in AIDS treatment [R, A, F. isher) et al., Nature, vol. 331, pp. 76-78 (1 988): R.E. Hussey et al. + - (Nature), vol. 331, pp. 78-81 (1988): and K. ・K, C, Deen et al., Nature, 3 31, pp. 82-84 (1988)], a molecule consisting of 371 amino acids (sCD4), the outer part of this transmembrane protein It is expressed in tar ovary (CHO) cells and is available from Genentech. ) [D.H. Smith et al., Sci. ence), Vol. 238, pp. 1704-1707 (1987)] was published in 1987. The product has been undergoing clinical trials since the fall of . Until now, information on efficacy has been limited to recombinant Other than the fact that 5CD4 appears to be relatively non-toxic, there are few available do not have. The concept of CD4-based therapy is that these molecules bind T4 and C on its surface. Neutralizes old V by preventing virus attachment to other cells expressing D4 It is something that can be done. A variation on this theme is the glycoprotein gp on its surface. Cytotoxin to CD4 for specific binding and transport to infected cells exhibiting -120 [M, A, Ti1l et al., Sci. Science, vol. 242, pp. 1166-1168 (19B8); and BK Chaudhary (V, N. Chaudhary) et al., Naichi + - (Nature), Vol. 335, pp. 369-372 (1988)].

Another therapeutic target in AIDS involves processing the former V fusion polypeptide precursor. inhibits viral proteases (or proteases) essential for involves doing. HIV and some other retroviruses, such as gag and proteolytic maturation of gag/pol fusion polypeptide (infectious virus The process (essential for particle generation) is itself coded in the poll region of the viral genome. This has been shown to be mediated by encoded proteases [Wai Yoshinaka (Y, Yoshinaka) et al. Proceedings of National Academy of Sciences Demy of Science of the United Nations Stiso (Proc. Natl, Acad, Sci, USA), vol. 82, pp. 1618-1622. (1985): Y, Yoshinaka et al., Journal ・Of Pyrology (J, Virol, ), vol. 55, pp. 870-873 (1 985): Y, Yoshinaka et al., Journal O. Bu Pyrology (J■1ro1.), vol. 57, pp. 826-832 (1986) ); and Kei Fono der Helm (Lyon der He1m), professional Seeding Op National Academy of Sciences United Stiso (Proc.

Natl, Acad, Sci, USA), Vol. 74, pp. 911-915 ( (1977) Ko.

Protease (or protease) consisting of only 99 amino acids is known as One of the smallest enzymes, aspartyl, such as pepsin and renin, Homology demonstrated to proteases [L, H, Pea rl) and Hitafuri Nii R. Taylor (W.R. Taylor), Neich. Nature, Vol. 329, pp. 351-354 (1987): and Ai Kato (1, Katoh) et al., Nature, vol. 329 , pp. 654-656 (191117) and has since been experimentally corroborated by Estimates regarding the three-dimensional structure and mechanism of this enzyme [L.H. Barr ( L.H. Pearl) and D.R. Tiller (W.R.

Taylor), Fuichi + (Nature), volume 329, pages 351-354 ( 1987)] was carried out. Active old V proteases are expressed in bacteria [e.g. For example, P. L. Darke et al. Iological Chemistry (J, Biol, Chem), vol. 264, 2 307-2312 (1989)], and is chemically synthesized [ J./Uniter (J, 5chneider) and Niss P. Ghent (S, B, Kent), Cell, vol. 54, pp. 363-368 (19 1989) and R.F. Nutt et al., Pro/-D. National Academy Off Science Off The Unity Tenodo Stiso (Proc.

Natl, Acad, Sci. , LISA), Volume 85, Monthly 29-7133 Page (1988)]. Site-directed mutation processing “P.L. Dark (P, L, D arke) et al., Journal of Biological Chemistry (J, Bi ol, Chem, ), vol. 264, 23 (pp. 17-2312 (1989), 7 and F.E. Kohl et al., Proclaiming Off. National Academy of Sciences of the United States Proc, Natl, Acad, Sci, USA), Volume 85, 4 686-4690 (1988)] and pepstatin inhibition [P.L.D. P. L. Darke et al., Journal of Biological Chemistry Tory (J, Biol, CheIll,), vol. 264, 2307-2312 Page (1989): F. Seeelmeier et al. ROSSEDING OFF NATIONAL ACADEMY OFF SCIENCE OFF THE ・Unitenodo Stiso (Proc, Natl, Acad, Sci,... USA), Vol. 85, pp. 6612-6616 (1988) Am (C, -Z, Giam) and Ai Borsos (1, Borsos), Giam Journal of Biological Chemistry (J, Biol, Chea) ), vol. 263, pp. 14617-14720 (1988); J. Hansen et al., EMBOJ, vol. 7, pp. 1785-1791. (1988) as an HIV protease, aspartyl protease. provides evidence for the mechanistic action of Recent studies have shown that proteases The gag and pol precursor proteins are involved in the maturation of the virus. In this way, a pre-existing peptide is formed in the peptide that is modeled after the region actually cleaved by this enzyme. Indicates that the cut is to be made at the expected site [P. L. Dark (P, L, Darke et al., Biochemical and Phytochemical Research Committee Communications (Biochem, Biophys, Res.

Commun, ), vol. 156, pp. 297-303 (1988)]. Old ■P Rotease [M, A, Navia et al., Navia ture), vol. 337, 615-620Jj (1989)] and Rous sarcoma. Related retroviral enzymes derived from viruses [M. Miller] et al., Fuichi + - (Nature), vol. 337, pp. 576-579 (1989) )], X-ray crystallography reveals that it is different from that seen in other aspartyl proteases. The same active site in the protease dimer has been revealed and therefore Hypothesis 1 that the enzyme is active as a dimer ．． H, Pearl) and Y, R, Taylo. r), Nature, vol. 329, 351-354M (1987) )] was confirmed. To date, retroviruses in humans, the host of L. torovirus, After inhibiting viruses and thereby caused by such viruses What are the effective ways to effectively treat diseases like Innate Immunodeficiency Syndrome 71 (AIDS)? Not found.

Disclosure of information Pepsta, a common aspartyl proteinase inhibitor at relatively high concentrations; Inhibition of old V replication in H9 cells by Chin A (100 μg) was Phono der Helm (K, Yon der He1m) Heb's Letter Described in FEBS Letters, Volume 247, Page 349 (1989). It is.

British Patent No. 2.203.740 (Sandoz) states that retroviruses The use of renin inhibitors in treating diseases caused by Ru.

A.D. Richards et al., Hebbs Letter FEBS Letters, vol. 247, p. 113 (1989) is Other aspartyl proteases, including tBoc-His-Pro-Ph, a potent inhibitor of human renin e-old 5-LVA-11e-FIis7b', old V-1 pro in vitro Discloses inhibiting tease.

Smith-Kline-Beecham Recent information from researchers shows that the use of synthetic protease inhibitors in cell culture describes studies on inhibition of old V-1 replication. international x is Symposium (Int, AIDS Symposium), Montori All, Canada, June 1989.

The following patent applications relate to renin and retroviral proteases.

discloses peptides useful as inhibitors of: International Application No. PCT/US89/ -01672 (filed April 24, 1989), U.S. Patent Application No. 07/405 ．． No. 691 (filed on September 11, 1989); International Application No. PCT/US901 No. 03754 (filed July 9, 1990); and U.S. Patent Application No. 07157. 3.110 (filed on August 24, 1990).

European Application Publication No. 0357332 describes the prevention of AIDS by inhibition of old V protease. Discloses the use of renin inhibitors for therapy. These inhibitors have the formula R at the N-terminus. , "R', -X-C(0)-[wherein X is 10-1-S-1-C)I-1 or -NHCH-6, Ra" and R"5 are the same or different, hydrogen, Cl- 4 alkyl, unsubstituted or substituted aryl, and unsubstituted and substituted Cs+ 7-/chloroalkyl]. However, this application Disclosing the diol moiety as an insert (\na-(1゜European Application Publication No. 0352 No. 000 includes various alcohols and diols as transition state inserts. and t-butyloxycarbonyl, penzyloxycarbonyl and and R″C(0)- [wherein R″ is hydrogen or Cl-18 alkyl] Discloses a retroviral protease-binding peptide having a group at the N-terminus ( enter.

European Application Publication No. 0369141 inhibits retroviral proteases Discloses specific peptides useful for. However, these peptides β-alanine at position, transition state insertion↓thisstatin analog, or N-4 at C-terminus. -Amino-2-methyl-5-pyrimidinylmethylamide, the present invention %N unlike peptides.

European Application Publications Nos. 0337714 and 0358223, transition state insertion X) IIV protease inhibitors with amino acid analogs in the 9th position of the front leaf Disclosed.

Summary of the invention The present invention particularly provides for inhibiting retroviruses in mammalian cells infected with retroviruses. Formula ■ for preparing harmful drugs: X-C5-Di-Eta-F+1-Glt- Z Ib)-(cut)p-net.

C)-(CHt)p-Cs-C7 cycloalkyl, d) R5-0-(CH,), -C(0)-1e)Rs-cut-oc(o)-1f)R,-0-C(0) -1 gL-(cut). -C(0)-1 h) R, -(CHI). -C(S)-1i)R2H(R4)(CHt)n-C( 0)-1j)R,-SO,-(CH,)q-C(0)-1k)R,-SO,-( CHri, -0-C(0)-11)R, -(CL), -S-1 m) Z-C(0)-CH(OH) CH(CHJ,)-C(0)-1n)Rs- (CHt) qcH; cH-(CHt)p-C(0)-10)Rs(CHJp CH-CH-(CHI)p-0-C(0), or 1))R,? (CI(riq- C(0)-: C8 is absent or has the formula XL, XLt, XLt-1 xtt, a divalent moiety, or other aminoacyl derivative; D is of the formula XLs, XLt-, the divalent moiety of XLtb, or other aminoacyl derivative; E+o-F+1 Ha type XL,,xL,! ,,XL,eSXL,,,XLse,■ , ■, or the bivalent part of ■: G12 is absent or a divalent moiety of formula XL, XL4-, or other amino is a noacyl derivative; 2 is a) -0-R+. , b)'It(R,)R,,, c) C, ~C8 cyclic amino, d) -NHR,. , e) -NH-(CHt)r-bilinone, N-oxide, or or g)-NH(CHt)qNHHet; R is a) -(CHx)--isopropyl, b)-(C)I,), -isobutyl, c)-(CH2),, -phenyl, and is d)-(Ct+,). -〇, ~C7 chloroalkyl; R1 is d) C3-C7/chloroalkyl, e) -Bet, ")01~C3 alcoquine, or g) C+ to C, alkylthio: R7 is a) hydrogen, or b) -CH(R3)R4.

R3 is d) C3-C7 cycloalkyl, g) C+ to C, alkoxy, or h) C, ~C, C5 alkylthio; R4 is the same or different each time it appears, a) hydrogen; b) c, -C5 alkyl, R8 is a hydrogen, b) auto~C, alkyl, r>guanidinyl C8-C, alkyl-1 or g) (CL) t-C1-C7 is chloroalkyl; R8 is C) amino C, -C, alkyl, or d) guanidinyl 01-C, alkyl -; b) C, ~C, alkyl, c)-(CH,),,R,,, d)-(CD7)nR+2, e) C3-C7 cycloalkyl, f) a pharmaceutically acceptable cation; glcH(ts)-Ctlt-Rls, or h)-C[(2-C[((R11 )-Rls; R11 is -R or -R2: Rat is -(Cut)-R1,; C) mo/-, G or tree〇, ~C , alkylamino, f) C, ~C7 cycloalkyl, g) Cz-C5 alkenyl, h) c, ~C7 cycloalkenyl, k) C, ~C, alkanoyloxy, l) Mercapto, m) C+~C, alkylthio, n) -COOH.

o) -Co-0-C1~Cs alkyl, p) -co-o-cHt-(C, ~C, alkyl)-a(c+-cs alkyl)1, q)-Co-11RttRts: r) C4-C1 cyclic amino, 5) C4-C7 cycloalkylamino, W) cyanoamino, X) (hydroxyC3-C4 alkyl)amino, or y) di(hydroxyC 3-C4 alkyl)ami/;e)-(CHJ+IR+s, d)-(CHt)nR+s, e)-CD(as)-Cut-Rls, f)-(CHJ--CI(Rls)-R ls: g) (Hydroxy 01-C, alkyl), h) Hydroxy C3-C4 a Rukiaryl, or 1) (C, ~C, alkyl) C, C, alkyl: b) C, ~C, cycloalkyl, C) aryl, d) Ami/, e) mono-, di, or di(hydroxyC2-c4 alkyl)amine, i) C,-C3 alkanoyl tree/, j) Mercapto, k) C, ~C, C3 alkylthi e) 01-C5 alkyl, 1) C4-C7 cyclic amino, n) C,~C7-chloroalkylamino, o) C,=Cs alkenyloxy, 1)) C3-C7 chloroalkenyl.

b) amine, C) More or di(CI-C3 alkyl) ami/, f) C,~C7 cyclic ami /,or g) CI-Cs alkanoyloxy.

1) -Co-0-COt-(Cl-Cs alkyl)-N(C, -C, alkyl )! , j)-CO-NRttRt@, k)) Lee C, -C3 alkylami/, 0) (hydroxy C7-c4 alkyl) amino, p) di(hydroxyC,~C4alkyl)ami/, or b) mono- 1 or di(CI-C3 alkyl)amino, c) C4-C7 cyclic 7-mino, d) C4-C7 cycloalkylamino, or e) -CH(NH=)(Co, t l) and 1b)-let.

c) NorC1-C3 alkylamino, n) co-o-cH, -(e, -, -c, alkyl)-4(C, ~C3 alkyl)2, o)-Co 1lRtJte , r) N-anoguanidyl, S) cyanoamino, t)(hydroxy01-C4 alkyl)amino, U)U-(hydroxyC1-C 4alkyl)amino: or v)-3OJ: b) C, ~C, CI kill, or C) Aryl-CI-C, alkyl; Rut is a) -NHt, or b) -oH.

Ro is a) hydrogen, or b) c, -c, alkyl;

Ro is a)-(CHt)n-OHs b)-(CH,)n-NH,, C) aryl, or d) C, to C3 alkyl.

b)-(CH2)n-OH, or c) - (cn,). −N[(, is: Ls is, a)-(CHt). -RI3, b) hydrogen; c) C, ~C, CI kill, or d) phenyl-C3-C, alkyl; b) C, ~C, CI-kyl, or C) Phenyl-C8-C3 alkyl: R2? teeth, b) -coo~C6 alkyl, e) -CONRttRt@, or d) -CH(NH,)COOH; RltO is a) R+toC[(CHt)qOR+t+]t(CHt)q-1b) of formula xxx part, C) the part of formula XXX[, d) -CH-(CHOR+t1)xCH*0R1t+1e)R+*10CH2( CHOR+t+)yCH-(CHOR+t+)*CHtOR+*+, f) Formula XX part of XI, or g) R+t+0CHt-C (CHzOR+Jt-: b) C, -C@alk le, c)-(CH,)n-aryl, or d)-C(0)R,! , there is: R113 is a) C, ~C, CI kill, or b)-(C)I, ), -phenyl; RI2° is a) hydrogen, or b)(C)If)nOR,! , and Lts is a) hydrogen, or b) −(CHOR,,υ,CH,OR,,,; Q is, H) CHt, b) CHORI211 or c) C(0) and: j is 1 to 3: ■ is 1 or 2.

p is O~2.

r is 0 to 5; For each occurrence, n is independently an integer from 0 to 5.

q is an integer of 0 to 5.

U is an integer from O to 3.

■ is an integer from 0 to 4.

S is 0 or 1 so that the sum of Ll+V+S is 3 or 4.

t is an integer from 0 to 3.

W is an integer of 2 or 3.

X is an integer from 2 to 7.

y is an integer from 0 to 6, and Z is the phase of y+Z or an integer from O to 6 so as not to exceed 6, and the near reel is 0 to 3. The following:

a) CI-C3 alkyl, b) hydroxy; c) C, ~C, C3 alkyl m) C, -C3 alkylthio , n) C, ~C3 alkylsulfinyl, o) c+-cz alkylsulfonyl, p)-N(R,)-C, ~C3 alkylsulfinyl, q)-3O3H1 r) S02NHz, 5) -CN, or phenyl or naphthyl substituted by

-Het is 1 to 3 hets selected from the group consisting of nitrogen, oxygen, and sulfur; A saturated or unsaturated 5- or 6-membered ring containing a carbon atom; Any of the heterocycles is fused to a benzene ring or to another heterocycle, and a carbon or a second including bicyclic groups such as those bonded through a primary nitrogen or an exocyclic nitrogen, and Nitrogen and sulfur atoms may be in the oxidized form, as long as they are chemically fusionable. In addition, the chain ring may optionally be 0 to 3 of the following.

C) hydroxy (C, ~C5 alkyl), f) amino (C, ~C, CI kyl), g) -CHO.

i) C0z-(C+~C5 alkyl), co)-CONH2, k) -CONH-(C, -C5 alkyl), n) Mercapto (C, ~C5 alkyl) r)-0-C, ~C, CI kill, or s)-[0-(CHt)-]--O Ct(3).

however, 1) G, , C, and D9 both exist, and EIO-Fll is higher than LPA. Exists if outside: 2) X is Z-C(0)-CHCoH)-CH(CH,R,)-C(0)- If D, is His and Gl is lie: 3) X is R5-CH-0-C(0)- or R, -(CH,), -C(0)- Yes, and EIO-Fll is XL, xL6b, xLllc or l1XLaa' t", R5 is other than 01-C8 alkyl: 4) X has R3-0-C(0)-te, and Ego-F+1 is XL6, XL@b , XL, or XL, d, R3 is C, -C, alkyl, C8-C 7/ is other than chloroalkyl or aryl; 5) X is Ri-(C)It), -C(0)-[wherein R6 is cycloalkyl or Or with aryl iron, E+op++ is XL,, xt, ebSXL@c or xL6d, n is other than 1.

6) X is R, N(R,)-(CI(,),,-C(0)-te, and EIa- When FH is XL, XL8b, xL, lc or χLea, n is other than 1. (near) Z is N-4-amino-2-methyl-5-pyrimidinylmethyl-amide other than; 8) When E, , -F, is ■ or ■, X is benzylox7carponyl or 9) X is R6-(cHt), -c(o)- and when EIO-Fil is ■ or ■, R6 is C2-C8 alkyl or more. use of compounds that are outside the human body and retrovirus-infected human cells. To prepare drugs that inhibit loviruses, L-isoleucinamide, N”-(5-amino-4-hydroxy-2-(1-methane) ethylethyl)-1-oxooctyl]-N-(2-pyridinylmethyl)-, tri Fluoroacetate, (S, S, S) -; or H-LVA-11e-A mp　;Octaneamide, 5-[(3,3-dimethyl-1-oxobutyl)amide ]-4-hydroxy-7-methyl-2-(1-methylethyl)-1-[2-methyl Chyl-1-[[(2-pyridinylmethyl)ami/]carbonylcobutyl]-1[ 2S-[1(lR*, 2R*).

2R*, 4R*, 5R*] - or TBA-LVA-11e-^lap; lmil; cyclohexanehexanamide (3,3-dimethyl-1-oxobutyl ) amino]-τ-hydroxy-α-(1-methylethyl)-N-[:2-methyl -t-[[-pyridinylmethyl>aminococarbonyl 1-butyl]~, [αS-[ N(IR*, 2R*), a Ri, r Ri, δR*] - or TBA -CVA-11e-^mp; Cyclohe Beef Sanhe Beef Sanamide, δ-Amino-τ- Hydroxy-α-(1-methylethyl)-N-[[2-methyl-1-[[(2- pyridinylmethyl)ami71carbonyl]butyrate, dihydrochloride, [ α5-EN (lR*, 21?*).

a Ri, τR*, δR*] - or H-CVA-11e-Amp Nijiku Lohexanehexanamide, δ-(acetylamino)-τ-hydroxy-α-( 1-methylethyl)-N(2-methyl-1-[[(pyridinylmethyl)aminoco carbonylcobutyl], [αS-[N(IR*, 2R*), αR*, τR*.

δR*]]-; or Ac-CYA-11e-Ag+p: octanamide, 5 -(acetylamino)-4-hydroxy-7-methyl-2-(l-methylethyl )-11~[2-methyl-1-[[(2-pyridinylmethyl)amino)carbony Rucobutyl]-1[2S-[N(IR*, 2R*), 2R*, 411*, 5R*co]-, monoacetate (salt): or Ac-LVA-11e-Amp ; or IVA-LVA-11e-Amp.

Boc-Phe-His-Cha　psi[C)10HCHOH]Yal-1i e-Amp; or L-histidine amide, N-[(1, -dimethylethoxy /) carbonyl]-L-phenylalanyl-N-[1-(cyclohexylmethyl )-2,3-dihydroxy-5-methyl-4-[[[2-methyl-1-[[(2 -pyridinylmethyl)amino]carbonyl]butyl]aminococarbonylcohex Sil]-1[IS-[IR*, 2R*, 3S*, 4S*(IR*.

2R*)]]-; or]]BOC-Phe-His-CVD1e-Amp.

L-histidineamide, N-[(1,1-dimethylethoxy)carbonyl]-L -phenylalanyl-N-[2-hydroxy-1-(2-methylpropyl)-5 -[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butylene thyl]amino-5-oxo-4-(phenylmethyl)pentyl]-1[IS-[ IR*, 2R*, 4S*.

5(IR*, 2R*)]]-; or]]Boc-Phe-His-LPAi e-Amp; L-histidine amide, N-[(1,1-dimethylethoxy)ka [rubonyl]-L-phenylalanyl-N-[4-(cyclohexylmethyl)-2 -hydroxy-1-(2-methylpropyl)-5-[[2-methyl-1-[[( 2-pyridinylmethyl)amino]carbonyl]butyl]amino]-5-oxo Cutylco~, [Is-[tR*, 2R*.

4S*, 5(lR*, 2R*) Coco: or Boc-Phe4is-LC A-11e-Amp; L-talonamide, 6-cyclohexyl-2,5,6- Trideoxy-5-[N-[N-[(1,1-dimethylethoxy)carbonyl] -L-phenylalanyl]-L-histidylcoamino 1-2-(1-methylethyl )-N-[2-methyl-1-[[2-pyridinylmethyl)amino]carbonyl ]Butyl]-1 "5-(R tendon, R*)]-: Boc-Phe-His- CVD'-1ie-^mp;I, ~histidine amide, N-.:o, t-dime carbonyl]-L-phenylalanyl-N-[2,3- K/-5-methyl-1-(2-methylpropyl)-4(C2-methyl-I[( 2-pyridinylmethyl)amino]carbonylcobutyl]amino]carbonyl] xyl]-1[IS-[lRt, 2S*, 3R*, 4S*(lRt, 2 R*)]] -; or]] Boc-Phe-His-IJDA'ie-8mp : L-histidine amide, N-UJ5-(dimethylamido/)-tonaphthalenyl] sulushinyl]-L-phenylalanyl-N-[2-hydroxy-5-methyl-1 -(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinyl methyl)ami/]carbonyl]butyl]ami/]carbonyl]hexyl]-1[ +5-11: lRt.

2R*, It(lRt, 2R*)) (-: or DANS -Phe-Hi s-LVA-11e-Amp; L-histidine amide, L-phenylalanyl -N~[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-C[ C2-Methyl-1([(2-bily/nylmethyl)amino]carnanyl]butyl] Ami7 carbonyl]hexylz-1[lS-(lRt, 2R*, 4R*( lRt, 2R*)] co- or f(-Phe4is-148-e-Amp : L-valinamide, L-phenylalanyl-N-[2-hydroxy-5-methy -1-(2-methylpropyl)-4-CII2-methyl-1-[[(2-pyrypropyl) (dinylmethyl)aminococarbonyl]butyl]amino:1carbonyl]hex/l ]-5CIS-[lRt, 2R*, 4R*(IH non, 2R*)]l-Also is t(-Phe-Vai17A-1ie-AIIll): L-valinamide, L-val true N-[2-hydroxy-5-methyl-1-(2-methylpropyl )-4-[[[2-methyl-1-E(2-bilinonylmethyl)ami/]carbo [nyl]butyl]aminococarbonyl]hexyl]-1CIs-ErR*, 2R *.

4R*(lRt, 2R*)l]-, diacetate (salt), or [(-Val -Val-LVAile-Amp; or L-Valinamide, N-acetyl-L-valyl-N-[2-hydroxy-5-methane methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-methylpropyl) lysinylmethyl)amine]carbonyl]butyl]amino1carbonyl]hexyl ]-1 [lS-[lRt, 2Rt, 41'n (lRt, 2R Kyo)]]-, Monoacetate (salt): or Ac4aiVal-LVAile-Amp.

Nα-[(2S, 4S, 5S)-5-11:Nα[(S)-t-acetoquine -1-benzyl)methylcarbonyl]-histidyl]-amino]-4-hydro Roxy-7-methyl-2-(1-methylethyl)-tooxooctyl]-N-C 2-bily/l)ethyl 1-L-isoroinonamide, or Ac0-Phe-H is-LVA-11e-NH-(CI,), -villin 4-morpholinebutanamide, β-hydroxy-N[2-C[2-hydroxy -5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[ (2-pyridinylmethyl)amino]carbonyl]butyl]amino]luponylco hexyl]amino]-(1111-imidazol-4-ylmethyl)-2-o xoethyl]-a-(1-su7talenylmethyl)-τ-oxo1CIS-[l Rt[R*(αS*, βR*)co.

2R*, 4R*(lRt, 2R*)]-:11(-imidazole-4-propylene Ropanamide, α-[JJ5-(dimethylamino)-1-naphthalenylcosulfo Nyl]amino]-to[2-hydroxy-5-methyl-1-(2-methylpropyl )-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbo nyl]butyl]amino]carbonyl]hexyl E-1Os-[on(R*), 2R*, 4R* (lRt, 2R*)] (-: or] DANS-His-L VA-11eAmp: II (-imidazole-4-propanamide, α-amino No-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[ [[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butylene ]amino]carbonyl]hexyl]-1[IS-[lRt(R*), 2R* , 4R*(lRt, 2R*)] or Fl-His-LVA-+1e-A mp: octanamide, 5-[[2-(acetylamino)-3-methyl-1-o xobutyl]amino]-4-hydroxy-7-methyl-2-(1-methylethyl )-N-[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl ]Butyl]-1[2S-[N(lRt, 2Rt), 2R*, 4R*, 5 R*(R*)coJ-, diacetate (salt); or Ac-Yal-IJA-11 e-AIIlp, Ac-Asn-LVA-11e-Amp:Nα-[(2S, 4S, 5S)-5-[[(S)-(1-hydroxy-1-benzyl)methyl carbon [rubonyl]amino]-4-hydroxy)-7-methyl-2-(1-methylethyl )-1-oxooctyl]-N-(2-pyridylmethyl)-L-inleucine Mid.

or HO-Pbe-LVA-11e-Amp; IH-imidazole-4-amp Ropanamide, lf-[2-hydroxy-5-methyl=1-(2-methylpropylene) )-4-[[C2-methyl-1-[II(2-pyridinylmethyl)amino]carbohydrate carbonylcobutyl]amino]carbonyl]hexyl]-α-[(2-hydroxy -1-oxo-3-phenylpropyl)amine]-1[lS-[IR*[R*( R*) Co, 2R*, 4R* ([1,2R Ne) Coco-12-hydroxy-1, 2,3-propanetricarboxy L/-t (12) (salt) or 7 CHt-CH(OH)-C(0)-His-LVA-11e-Amp.

L-a-glutamine, N/u 2/d-[N-[[1,1-dimethylethoxy) carbonyl]-L-phenylalanyl]-N-[2-hydroxy-5-methyl- ni(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridiny methyl)amino]-carbonyl]butyl]amino]carponylcohexyl]- 1 [LS-[IR*, 2R*4H (IH, 2!?*) month-, monoacetate (salt ) or BOC-Phe-Glu-LVA-11e-^mp: L-histidineamide, N-[(1,1-dimethylethoxy)carbonyl]-3 -(2-pyridinyl)alanyl-N-[2-hydroxy-5-methyl-1-(2 -methylpropyl)-4-[[E2-methyl-1-[[(2-pyridinylmethyl ) ami7'Jcarbonylcobutyl]amino]carbonyl]hexyl]-1[lS -[IR*[R*(E)].

2R*, 4R* (IR*, 2R*) co]- or BOC-2-Py-Ala -His-LVA-11e-Amp; L-α-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-pyridinylmethyl)amino]carbonyl]butyl] amino] carbonyl] to bosyl]-1[lS-[IR*, 2R*.

4R*(IR*, 2R*)]]-, monoacetate (salt) or BOC-Ph e-Asl)-LVA-11e-Amp.

L-α-glutamine, N-[1,1-dimethylethoxy)carbonyl]-L-ph phenylalanyl-NO[1-(cyclohexylmethyl)-2-hydroxy-5- Methyl-4-[[[2-methyl-1-[[(2-pyridinylmethyl)aminococa [rubonyl]butyl]amino]carbonyl]hexyl]]-1[IS-[IR*, 2R*, 4Ft*CLR*.

2R*)] co, monoacetate (salt) or BOC-Phe-Glu-C1' Arle-Amp: L-histidine amide, N-[(1,l-dimethylethoxy c) carbonyl]-L-phenylalanyl-N-[3,3-difluoro-2-hypolymer Droxy-4-[[2-methyl-1-[[(2-pyridinylmethyl)aminococa [rubonyl]butyl]aminoco-4-oxo-1-(phenylmethyl)butyl]- Or C)! 3-C(0)-0-CFI(benzyl)-C(0)-His-LY A-11e-Amp; L-glycyl-L-histidyl-58-amino-6-cy Chlorhexyl-3R,4R-dihydroquino 2R-isopropyl-hexanoyl -Shi-inloin-2-pyridylmethylamide or Gly-His-CVA -11e-Amp; L-green-L-histidyl-58-amino-2R-he 6-cyclohexanoyl-3R,4R-dihydroxy-hexanoyl- isoloin-2-pyridylmethylamide or Gly-1 (is-CPD-1 1e-Aml); 5-ki/linylhydroxyacetyl-L-histidyl-58 -amino-6-cyclohexyl-48-hydroxy-28-isopropyl-hexyl Sanoyl-L-inloin-2-pidzylmethylamide or Qoa(b)- tlis-CVA-11e-Amp; Quinolinylhydroquine acetyl-histidyl-58-amino-6-cyclo Kinru 48-hydroxy-28-isopropyl-hexanoyl-L-isoroy 2-pyridylmethylamide Amp; N-tert-butyloxycarbonyl-alanyl-5S-a mino-6-cyclohexyl-48-hydroxy-28-isopropyl-hexano yl-L-inloin-2-pyridylmethylamide or BoC-^1a-C VA-11e-A+++p; N-tert-butyloxycarbonyl L-hi Stidyl-58-amine-6-/chlorohexyl-48-hydroxy-28-yne Propyl-hexanoyl-L-ynleucyl-2-pyridylmethylamide or BOC4ig-CI'A-11e-AmGl: Pencyloxycarbonyl -alanyl-L-alanyl-58-amino-6-cyclohexyl-48-hydro xy-28-inpropyl-hexanoyl-L-inleucyl-2-pyridylme Tyramide or CBZ-Ala-Ala-CVA-I le-Amp: L-histidineamide, N-[(t, l-dimethylethoxy)carbonyl]- L-Phenylalanyl-N-[4-[[[2-[(2. rimidinyl) aminoconityl] ami/cocarponyl co-2-hydroxy-5-mer Tyl-1-(2-methylpropyl)hexylco, [IS-(IR*, 2R* , 4R*)]-or]BOS-Phe-Bis-LVA (2.6-diami 2-4-pyrimedinyl)amino-ethylami/;GIy-CVD-Ile-A mp, and Gly-CPD-I 1e-Amp: Use of compounds; and compounds of formula ■ X-C. -D. -E. ,-F. ,-G. t-Z　1 [wherein, X is b) naphthyloxy/acetyl, c) t-butyloxycarbonyl, f) pyridinyl-(CH2)rl-carbonyl, g) phenyl-(cI(,), , -co(on)-c(o)-1h) indolycarbonyl, i) Pyridinyl-(CI(2), -0-C(-,co)phenyl-(CI+, ). -5Ot-1k) phenyl-〇-(CH,). -C(0)-11) Phenyl -HC;CH-(CH*)n-C(0)-5n)phenyl-pc=CH-(c ++,). -〇-C(0)　-1n)HO-(CH,)n-C(0)-10)K Norinoylhydroxyacetyl, p) quinoquinoylcarbonyl, q) penzyloxycarbonyl, or r) 5-(triethylene glycol mono) methyl ether) naphthyloxyacetyl.

C8 is a) does not exist; D9 is e) -NH-CH, -C(0), or L form or D form, and those skilled in the art It is well known and easily available.

Surprisingly and unexpectedly, the compounds of the present invention are effective at inhibiting old V proteases. and is a potent inhibitor. Furthermore, the compounds of the present invention can be used as described below. , has been found to inhibit old V protease in cell culture. However, Therefore, the compound of formula ■ inhibits retroviral proteases and therefore inhibits the replication of viruses. They are associated with acquired immunodeficiency syndrome (AIDS) and Treating patients infected with human immunodeficiency virus ()In, which causes cancer and related diseases. It is useful for

The novel compounds of the present invention have low to moderate renin inhibitory activity, but surprisingly Also, surprisingly, it is an inhibitor of retroviral proteases.

In addition, the peptide of the present invention is a novel inhibitor of human retrovirus protease. Useful as a peptide analog. Therefore, the peptide of the present invention inhibits viral proteases and therefore inhibits the replication of this virus. So These can lead to acquired immunodeficiency syndrome (AIDS) and/or related diseases. human immunodeficiency virus (formerly V-t or former V-2 strains) or human T-cell leukemia Human retroviruses such as disease viruses (HTLV-I or HTLV-11) It is useful in treating human patients infected with this virus.

Retroviral capsids and replication enzymes (e.g., proteases, reverse transcriptases) , integrase) converts the polyprotein from the virus Gag and Pol genes. This polyprotein is translated by viral protease (PR). Further processed and found in the viral capsid, Becomes a mature protein required for function and replication. PR does not exist or Otherwise, the virus cannot replicate. Retro like old VI PR Virus PI? is an aspartic protease, which is a more complex aspartic protease. It has active site properties similar to those exhibited by the rutile protease renin. It has been found that

The term human retrovirus (HRV) includes human T-cell leukemia virus 1. and 2 (HTLV-1 and HTLV-2) as well as human immunodeficiency virus. virus antibodies, human immunodeficiency virus antibodies, or strains thereof, or the same or It belongs to a related virus family and has a physiological physiology in humans similar to that of various human retroviruses. Includes strains that are obvious to those skilled in the art that produce a biological effect.

Patients to be treated must: 1) be infected with one or more strains of human retroviruses; patients, as determined by the presence of measurable viral antibodies or antigens in their serum. , and 2) in the case of HIY, 1) disseminated histoblasmosis, ii) impso isopsoriasis, 1ii) pneumogistics (pn eumocystic) bronchial and pulmonary candidiasis, including pneumonia, iv) non-holytic Symptomatic AIDS identifying infections such as Kin's lymphoma, or V) Kaposi's sarcoma. and are under 60 years of age, or have an absolute CD4 level in peripheral blood. Patients whose lymphocyte count is less than 200/m''. Treatment is according to the present invention. It consists of constantly maintaining the inhibitory level of the peptide used in the patient and prevents infection. until the appearance of a second symptomatic AIDS indicates that another treatment is required. It will continue.

More specifically, one example of such a human retrovirus is human acquired immunodeficiency virus. Human immunodeficiency virus (AIDS) is recognized as the causative agent of AIDS. HIV, also known as HTLV-I or LAY) ・Duesberg (P, Duesberg), Proceedings of Pear National Academy of Sciences of the United States of America (Proc, Natl, Acad.

Sci, USA), vol. 86, p. 755 (1989) Jo old V is a fused polype HI, a protease that cleaves peptides into functional proteins in mature virus particles. Containing a retrovirus encoding V protease [E. P, Li1lehoj) et al., Journal of Pyrology (J, Vir 62, p. 3053 (1988) Nigi Depack (C, De Buck) et al., Proceedings of the National Academy of Sci. Ens of the United Nations of America (Proc. N. 1t1. Acad, Sci, USA), vol. 84, p. 89o3 (1987) ]. This enzyme, formerly known as V-1 protease, is classified as aspartyl protease. In contrast to other seven subarthyl proteases, such as homology [L.H. Pearl et al. - (Nature), vol. 329, p. 351 (1987), Ai Kato (l Katob et al., Nature, vol. 329, p. 654 (198 7th year) Ko. Inhibition of old V, -1 protease prevents the replication of old E.D. Clark (E, D, C1erQ) is useful for the treatment of AIDS. ), Journal of Medical Chemistry (J, Wed, Chem ), vol. 29, p. 1561 (1,986)]. The light-damaging agent in the old ■Protease publication is , useful in the treatment of AIDS.

Pepstatin A, a common inhibitor of aspartyl protease, is a former V- “Nis-Sielmeyer (S),” which is disclosed as an inhibitor of I protease. Seelmeier et al., Blonding of Sus/Jonal Academy Of the Sciences of the United States of America (Pr. oc, Natl, ^cad, Sci, USA), vol. 85, p. 6612 (1 (986) at the 1° cleavage position with a reduced bond isostere or statin. Inhibitors derived from other substrates have also been disclosed, including M.L. Moore (111 , 1, Moo + a) et al., Biochemical and Biophysical Lisa - Thousand Comics, Niken Yons (Biochem, Biophys, ResC ommun, ), vol. 159, p. 420 (1989), Nis Bilinohi (S. B111ich) et al., Journal Sub Biological Chemistry (J , BioChem, ), volume 263, page +7905 (1,91'18), Sandoz, D, E, 3812-576-A.

Therefore, the peptides of the present invention can be used to treat diseases such as human acquired immunodeficiency syndrome (AIDS). It is useful in treating diseases caused by retroviruses.

Furthermore, the peptides of the present invention can be used to treat diseases such as cats infected with feline leukemia virus. It is useful in treating non-human animals infected with loviruses. infect cats Other viruses that may be present include, for example, feline infectious peritonitis virus, , rabies virus, feline immunodeficiency virus, pulpovirus (panleukopenia virus) Virus), and Focculaminoa. The peptide of the present invention can be used in non-human animals. The exact dosage, form and manner of administration to animals will be clear to those skilled in the art, such as veterinarians. It will be clear.

Compounds of formula I of the invention can be prepared as described in the publications listed in Table I below. easily known to those skilled in the art of peptide synthesis; prepared by methods similar to those available. These publications The entirety of the events is incorporated herein as a reference.

As will be apparent to those skilled in the art, the compounds of the present invention may have different configurations around an asymmetric carbon atom. Depending on the molecule, it can exist in several diastereomeric forms. This way All such diastereomeric forms are included within the scope of this invention. Preferably , the stereochemistry of the amino acids corresponds to that of naturally occurring amino acids.

The present invention provides a compound of formula I or a pharmacologically acceptable salt thereof and/or aqueous Provide Japanese food. Pharmacologically acceptable salts are defined by drug formulation, stability, and patient tolerance. Manufactured to be equivalent to the parent compound with respect to properties such as sex and bioavailability means such salts as are readily apparent to the medicinal chemist.

The compounds of the invention cause acquired immunodeficiency syndrome (AIDS) and related diseases. It is useful in treating patients infected with human immunodeficiency virus (formerly ■). child , the compound of formula I can be administered orally, nasally, transdermally and parenterally (intramuscularly and (including intravenously) at a dose of loomg to 1 μg per kg of body weight. administered.

Those skilled in the art will know how to formulate the compounds of the invention into suitable pharmaceutical dosage forms. I know it. Examples of dosage forms include oral preparations such as tablets or capsules, Alternatively, parenteral preparations, such as sterile solutions, are included.

When the compounds of this invention are administered orally, the effective amount is approximately 1/kg body weight per day. It is μg to 100 mg. Solid or liquid dosage forms may be prepared for oral administration. I can do it. Solid compositions incorporate the compounds of the invention with conventional ingredients such as talc, steroids, etc. Magnesium phosphate, dical/rum phosphate, magnesium aluminum silicate , calcium sulfate, starch, lactose, arabicum, methylcellulose, or prepared by mixing with a functionally similar pharmaceutical diluent and carrier . Capsules are prepared by mixing a compound of the invention with an inert pharmaceutical diluent, and into hard gelatin capsules of appropriate size. soft gel Latin capsules contain a compound of the invention and a liquid such as vegetable oil or light liquid petrolatum. prepared by mechanically encapsulating a slurry with an acceptable inert oil. It will be done.

A syrup is made by dissolving the compound of the invention in an aqueous solvent and adding sugar, aromatic flavoring and It is prepared by adding preservatives and preservatives. Elixirs are like ethanol a suitable hydroalcoholic solvent, a suitable sweetener such as sugar or saccharin, and an aromatic Prepared using aromatic flavoring agents. Suspending agents include aqueous solvents, gum arabic, and It is prepared using a suspending agent such as ragacant, or methylcellulose.

When the compounds of the invention are administered parenterally, they may be administered by injection or intravenously. It can be given by infusion. The effective dose is approximately 1 μg per kg per day. mg. Parenteral solutions are prepared by dissolving the compound of the invention in water and filter sterilizing the solution. and then placed in a suitable sealable glass bottle or ampoule. It will be done. Parenteral suspensions may be prepared using sterile @turbidity by diluting the compounds of the invention with ethylene oxide. Practically no treatment is required except for sterilization with cid or a suitable gas and suspension in this solvent. It is prepared in a similar manner.

The precise route of administration, dosage, or frequency of administration is readily determined by one of ordinary skill in the art. may vary depending on age, weight, general physical condition, or specific to the patient being treated. Depends on other clinical symptoms.

The patient to be treated must: 1) be infected with one or more strains of human immunodeficiency virus; infected, as determined by the presence of measurable viral antibodies or antigens in the serum. and 2) patients with 1) disseminated histoplasmosis, ii) inboriasis (i) soporiasis), 111) pneumodystis (pneu+5ocys) tis) bronchial and pulmonary candidiasis, including pneumonia, iv) non-Hodgkin's lymphoma or V) have symptomatic AIDS identifying an infection such as Kabosi's sarcoma, and 6 Are under 0 years of age or have an absolute peripheral blood CD4 lymphocyte count of 200 /m+n3. Treatment involves in-patient administration of compounds of the invention. A second symptomatic AIDS that consists of constantly maintaining the level of inhibition and identifies the infection. This will continue until the appearance of symptoms indicates that another treatment is required.

The utility of representative compounds of the present invention is demonstrated by several biological mechanisms, as discussed below. Shown in tests.

HIV-1 protease was extracted from E. coli as follows. Inhibition of expressed, isolated, characterized, and potential inhibitory compounds in was used to measure the constant (Kυ).

Synthetic peptide H-Val-3er-Gin-Asn-Tyr-Pro-11e4 al-OH serves as a substrate for measuring Old V-1 protease activity. This page putide corresponds to the sequence of residues 128 to 135 in the 1111-1 gear protein. I am responding.

Cleavage of synthetic peptides occurs at the Tyr-Pro bond, similar to gebutin puffs. . IJIV-1 protease activity was determined by adding 10% glycerol in a total volume of 50 μl. , 5% ethylene glycol, 0.1% Nonidet P-40, and in 50a+M sodium acetate (pH 5,5) containing 2.8n+M substrate. Measured at 30°C. After incubation for 30 min, 1% of 75 μm Trifluoroacetic acid (TFA) is added and the reaction mixture is subjected to FIPLC analysis. F IPLC is Vydac C+s column (0.46X 15c+a) using a linear gradient of 0-30% acetonitrile over 25 minutes. Elute at a flow rate of 1.0 ml/min.

KI values for representative compounds of formula I of the present invention are listed in Table 1 below.

Some of the compounds of the present invention have been shown to be effective against old V replication in primary cultures of human peripheral blood lymphocytes. It is further evaluated for its ability to inhibit production.

This analysis is performed using the following screening method.

The following characteristics characterize the primary screening test: Performed using human lymphocytes.

whereby host cells and viruses may undergo a method of mutual adaptation. Undesirable testing of transformed cell lines is avoided. Cells in serum containing medium Culture practices closely mimic in vivo conditions.

True antiviral effects of test compounds are easily distinguished from cytostatic/cytotoxic responses be done.

Accurately track virus replication with kinetic measurements of viral nucleic acids and proteins be done.

Levels of nucleic acids (all 14 RVs, - RNA intracellular and extracellular) and proteins (min. Parallel testing of levels of secreted p24) revealed that virus replication and The effects of test compounds on Tabak expression are distinct. This means that the test compound yields additional information regarding the efficacy of

The tolerance of cell cultures to small amounts of organic solvents also allows the study of hydrophobic substrates .

The dose of test compound that causes half-maximal inhibition of viral replication is determined.

Screening systems are standardized and highly automated.

1.Toxicity test The effect of test compounds on cell proliferation is determined by lymphocyte proliferation assay. 1 Starting from a 0.00 micromolar solution, test compounds are serially diluted 10 times.

1/10 of the concentration of test compound that causes half-maximal inhibition of cell proliferation was Used for testing.

2 In vitro infection of lymphocytes Human peripheral lymphocytes are isolated by density gradient centrifugation. stimulated by mitogens After that, the cells are infected with a standard preparation of HRV. The infected cells are then treated with the test compound Culture for 4 days in the presence of On days 2, 3, and 4 after infection, the virus Establish individual cultures to measure replication.

Untreated cells and AZT-treated cells were controlled in parallel with the test compound under study. Included as .

21 Detection of secreted virus P24 Synthesized and released by infected cells The amount of virus core protein p24 was determined in the supernatant by capture ELISA method. , measured on the second, third and fourth day. Mark 1! By comparing with the preparation The amount of protein produced by virus-infected cells is modified.

2. Analysis related to 28IV-RNA The total amount of viral RNA synthesized by infected lymphocytes is determined by a special nucleic acid hybrid. It is measured on the 2nd, 3rd and 4th day of culture by the Daizeshin method. H By including a standard preparation of RV-RNA, the amount of synthetic 1'lNA was quantified. Ru.

If the test compound shows antiviral effects in the primary screening, - The entire screening 9 process is repeated. Furthermore, the viability of oRvg-stained cells was Measured in parallel with analysis for viral p24 and RNA. of the test compound To assess the half-maximal antiviral efficacy, the concentration dependence of the effect of the test compound is determined. determined.

The results of testing these compounds of the invention in these assays are given in Table ■ below. It is.

Some of the compounds of the present invention may further be used in cell analysis of CV- as described below. It is evaluated. There, the retrovirus inhibitory effect is I (IV-1 protea). This was shown to be due to the inhibition of enzymes.

CV-1 cells were plated 2 x 10-' in a 24-well Costar dish. Cells/well were seeded and 6-12 hours later infected with VVK-1 at 5 PFU/cell. [Guy Karacostas (V, Karacostas) et al., [Vaccinia Viral expression vector (retrovirus/AI DS/virus assembly -/Human immunodeficiency virus-like particles produced by reverse transcriptase (Human 1 mmunodefi-science Virus-Like Particle s Produced by a Vaccinia Virus Express sion Vector (retrovirus/AIDS/virus as assembly/reverse transcriptase) I, Blondie National Academy of Sciences of the Unite Nodo Stiso of America (Proc, Natl, Acad, Sc i, USA), in press, 1989].

Test compounds were dissolved in DMEM containing 2.5% fetal calf serum and virus was added. Immediately after addition, the wells were added in triplicate. After 24 hours of infection, remove the culture medium and The monolayers were washed with liter of PBS and added with O, liter of loading buffer (62.5mM Tri. Su-[IC1pn6. s, 2.3% SDS, 5% B-mercaptoethanol, Cells were lysed by adding 10% glycerin). Cell lysate They were collected in boiling water for 3 minutes, and then 0.025 ml of each was mixed with 12% 5DS- Subject to electrophoresis on polyacrylamide gel.

Proteins were electroplotted onto nitrocellulose and Western blotting It was analyzed by - The following antibodies are sheep anti-Pr24 and sheep anti-Pr17. The secondary antibody in both cases was an alkaline phosphatase-conjugated heron anti-sheep antibody. IgG [all Kirkegard & Berry Laboratories (Kirke Gaard & Perry Laboratories), Gaithersburg , MD].

The test compound was grown in a recombinant cotton cinia vii expressing the old V-1 gear goopol gene. In the above cells infected with Rus, the old V-1 Cag polyprotein (Pr55) significantly inhibits proteolysis of the mature viral structural proteins Pr24 and Pr17. inhibited. Old V-1-like particles released from cells treated with inhibitors Contained exclusively Pr55 and other Gag precursors, but not Pr24. There wasn't.

The following compounds of the invention are preferred.

1-Noa-■1s-Cha PSl[C[10HCHOH]Val-11e- ^mp; or lH-imidazole-4-propanamide, N-[1-(cyclo hexylmethyl)-2,3-dihydroxy-5-methyl-4-[[[2-methyl -1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]-[ami/ ] Carbonyl j to bovine zirco-α ~ [[(1-naphthalenyloxy)acetyl core Mino]-1[lS-[IR*(1?*), 2S*, 3S*, 4S*(lR *, 2R*)]-; or]]N0A-His-CVD-1e-Amp: Nα-C(2S, 4S, 5S)-5-[N-[Nα- L-histidylcoamino-4-hydroxy-2-isopropylulf -Methyl-1-oxooctyl]-N-[2-<2-pyridinylamino)ethyl ]-L-isoleucinamide, acetate; or POA-His-LVA-I 1 e-NH(CI(-)tNH-pyridine; or POA-His-LVA-1 1e-NH(CHJ, NI(-pyridine:IH-imidazole-4-propane) Amide, N-[1-(cyclohexylmethyl)-2-hydroxy-5-methyl- 4-[[[2-methyl~1-[[(2-pyridinylmethyl)amino]carbonyl ]butyl]amino]carbonyl]hexyl]-α-[(phenoxyacetyl)a Minoko-1 [lS-[IR*(lit), 2R*, 4R*(IR*.

2R*) co]-; or POA4is-CVA-11e-A+ip; IH-i Midazole-4-propanamide, N-[1-(cyclohebutylmethyl)-2- Hydroxy-5-methyl-4-[[[2-methyl-1-[[(2-pyridinylmethyl thyl)amine]carbonyl]butyl]aminococarbonyl]hexyl]-α-[ (phenoxyacetyl)amino J-1[IS-[11? *(R*), 2R*, 4R*(IR*.

2R*) Coco: or POA-flis-chpVA-11e-Amp; Kurohe Beef Sanhe Beef Sanamide, δ-(acetyl amide/)-τ-hydroxy~α- (1-methylethyl)-N-+2-methyl-1-[[(pyridinylmethyl)ami ]carbonyl]butyl], [a S-[+1(IR*, 2R*), a R *, r　R*.

δR*]]-, or Ac-CvA-11e-Amp; Nα-[(2S, 4 S, 5S)-5-[N-[+1α-(1-naphthalenyloxyacetyl)~L -Histidyl]amino-6-7chlorohexyl-4-hydroxy-2-isopropyl -1-oxohexyl]-N-(2-pyridinylmethyl)-cyinleucine Amide or N0A-His-CVA-11e-Amp:Nα-[(2S, 4S, 5S)-5-(N-INα-(1-naphthalenyloxyacetyl)(2 -pyridinyl)alanylkoamino)-5-7chlorohexyl-4-hydroxy-2 -isopropyl-I-oxyhebyl]-N-(2-pyridinylmethyl)-L- Inleucinamide or N0A-His-CVA-11e-Amp; Nα- [(2S, 4S, 5S)-5-[N-[Nα-(1-naphthalenyloxia cetyl)-L-histidyl]amino]-6-cyclohexyl-4-hydroxy- 2-isopropyl-■-oxohexyl]-N-[2-(2-pyridinylamino ) ethyl]-L-isoleucinamide or N0A-His-CVA-11e- NH-(CHt)t-NH-(2-pyridine).

Pentane L 5-[[1-(/Chlohekiflumethyl)-2-hydroxy-5-methane thyl-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]car [bonyl]butylcoamino]carbonyl]hexyl]amino]-4-[(IH-i (ndol-2-ylcarbonyl)aminoco-5-oxo-1[IS-[IR*( R*), 2R*, 4R*(IR*.

2R*)]]-or]]IH-indole-2-yl-carboniGlu-CV A-11e-Amp; 2,5.11.14-tetraazapentadecanoic acid, 7-hydroxy-3-(LH -imidazol-4-ylmethyl)-9-(1-methylethyl)-12-(1- methylpropyl)-6-(2-methylpropyl)-4,10,13-trioxo -15-(2-pyridinyl)-13-phenyl-2-propenyl ester, [3 S-[1(E), 3R), 6R*, 7R*.

9R*, 12R* (R1 month coco or phenyl-CH-CH-CH, -0-C (Q)-His-IJA-11e-Amp; Phenoxyacetyl-L-histidyl-53-amino-6-cyclohexyl-3 R,4R-dihydroxy-2R-isopropyl-hexanoyl-L-inleuci -2-pyridylmethylamide or POA-Hls-CVA-11e-Amp ;■-naphthoxyacetyl-histidyl-53-amino-6-cyclohexyl Silu-3R,4R-dihydroxy/-2R-isobutyl-hexanoyl-cy-yne loin-ru 2-pyridylmethylamide or NOA-His-CLD-11e- Amp: 1-naphthoki/acetyl-histidyl-53-amino-2R-be Njiru-3R.

4R-dihydroxy-6-phenyl-hexamyl-di-inroin-2-pi Lysyl methylamide or N0A-His-PPDlle-^mp; 1-naphtho quinacetyl-1-histidyl-55-amine-6-encroquinol 3R,4 R-dihydroxy/-2R-isopropyl-hexanoyl-L-inroy/ru2 -Pyridinylamino-ethylamide or N0A-His-CVD-11e-^ pr: 5-quinolinylhydroquinacetyl-histidyl-58-amino-6-cyc lohequine-48-hydroxy-28-isopropyl-hexanoyl-L-yne loin-2-pyridinylmethylamide or Qoa(b)-His-CVA- 11e-Amp.

1-naphthoquinacetyl-L-histidyl-5S-ami/-3R,4R-dihi Doroquino 2R-inbutyl-7-methyl-octanoyl-L-isoleucyl- 2-Pyridylmethylamide or NOA-Hls-L[, d-11e-^mp: 2-chimerinylcarbonyl-58-amino-6-7chlorohexyl~3R,4R- dihydroxy/-2R-isopropyl-hexanoyl-17-isoleucyl-2- Pyridinylamino-ethylamide or Qc-Asn-CVD-11e-Apr ; Quinolinyl-2-carbonyl-toasparaquinyl-58-amino-6-cyc lohequinrue 43-hydroxy-23-isopropyl-hexamethyl-1,-i Inroin Ru 2~Pyridylmethylamide or QC-Asn-CVA-11e- ArQp: L-asparaginamide, i(naphthoxy)acetyl-N-[2-h Droxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl- 1-[[J2-(N-oxide)pyridinylmethyl]amino]carbonyl]buty ]amino]carbonyl]hexyl]-N-α-methyl-1[ts-[tR*, 2R*, 4R*(IR*, 2R*)]] or NOA-AsI)-CVA -11e-Amp; L-asparaginamide, [5-(1-lyethylene glycol) monomethyl ether) naphthoxycoacetyl-L[2-hydroxy-5- Methyl-1-(2-methylpropyl)-4-C[[2-methyl-1-[II[2 -(N-oxu/do)pyridinylmethyl]ami/]carbonylcobutyljami/co carbonyl]hexyl-N-α-methyl, [IS~[IR*, 2R*, 4R*(lR*, 2R1) co]- or 5-(triethylene glycol monomer ethyl ether)-NOA-Asp-CVA-11e-mp: and Asparaginamide, [4-(triethylene glycol monomethyl ether) ) naphthoxycoacetyl ~N-[2-hydroxy-5-methyl-1-(2-methy 2-methyl-1-[[[2-(N-oxide)pyridi nylmethyl]amino]carbonyl]butyl]amino]carbonyl]hexyl]- N-α-methyl-1[lS-[IR*, 2R*, 4R*(IR*, 2R* ) Coco- or 4-(triethylene glycol monomethyl ether)-NOA- Asp-CVA-+1e-Amp.

The following compounds of the present invention are most preferred: 1-Noa-Flis-Cha PSl [C[10HCHOH]Val-11e-Amp: or IH-imidazole -4-propanamide, N-[1-(cyclo-\xylmethyl)-2,3-dihydrogen Droxy-5-methyl-4-[[[2-methyl-1-[[(2-pyridinylmethyl ) aminococarbonylbutyl](aminococarbonyl]hexyl]-α-[ [(t-naphthalenyloxy)acetyl]ami/]-1[IS-[IR*(R* ), 2S*, 3S*.

4S*(IR*, 2R*)]]-:or]]NO^-H-H15-CVD- 1ie: quinolinyl-2-carbonyl-mono-asparaginy-5S-amino- 6-Cyclohequin-48-hydroxy-2S-isopropyl-hexamyl- L-isoleufluor 2-pyridylmethylamide or QC-Asn-CVD-1 1e-Amp: L-asparaquinamide, [5-(triethylene glycol mono methyl ether) naphthoxycoacetyl-N-[2-L-asparaquinamide, [5-(triethylene glycol monomethyl ether) naphthoquine coacetyl- N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[ 2-Methyl-1-[[[2-(N-oxide)pyridinylmethyl]ami/]cal [bonyl]butylcoaminococarbonyl]hexylcoat α-methyl-1[1s- [IR*, 2R*, 4R*(xR*, 2R*)]]- or 5-(Trie (ethylene glycol monomethyl ether)-NOA-Asp-CVAile-Aa +p.

L-asparaginamide ether) naphthoxycoacetyl-N-[2-hydroxy C-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[ [[2-(N-oxide)pyridinylmethyl]amino]carbonyl]butyl]a Mino]carbonyl]hexyl]-N-α-methyl-1[IS-[IR*, 2R *, 4R*(IR*, 2R*)]- or 4-(+-lyeethylene glycol monomethyl ether)-NOA-Asp-CVA-11e-A+il): Nα-[(2S, 4S, 5S)-5-[N-[Nα-(1-naphthalenyl) xyacetyl)(2-pyridinyl)alanyl]aminoco-6-cyclohexyl- 4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridi nylmethyl)-L-inleucinamide or N0A-His-CVA-11e -^mp;Nα-[(2S, 4S, 5S)-5-[N-[Nα-(1-naf (talenyloxyacetyl)-L-histidyl]amino]-6-cyclohequinyl 4-Hydroxy-2-isopropyl-1-oxohexyl]-N-[2-(2- pyridinylamino)ethyl]-L-isoleucinamide or NO^-Hls- CVA-11e-NH-(CH,) *-NH-(2-pyridine); 2-Bovine nolinylcarbonyl-53-amino-6-cyclohexyl-3R,4R- Dihydro a-xy-2R-isopropyl-hexanoyl-L-ynleucyl-2-p Lysinylamino-ethylamide or Qc-^5n-CvD-11e-Apr ; and l-naphthoxyacetyl-histidyl-55-amino-2R-ben Jill-3R.

4R-dihydroxy-6-phenyl-hexanoyl-L-ynleucyl-2-p Lysyl methylamide or N0A-His-PPD-11e-^mpa preferred Description of implementation In the following Preparations and Examples and throughout this document:') l-NMR Nuclear magnetic resonance; Ac is acetyl.

Aco is acetyloxy; Amp is 2-(aminomethyl)pyridine; Amp-No is (2-pyridine) methyl)amino, pyridine N-oxide: Apr is 2-pyridinylamino-ethylamide; Asn is asparagine can be; Boc is t-butoboxydicarbonyl; BOP is benzotriazole-1-y Oxytris(dimethylamino)phosphonium hexafluorophosphate Yes; Bz is benzyl: C is Celsius; Cbz is benzyloxycarbonyl; CcD is of formula X [wherein R1 is cyclo hexyl, Rt is α-hydroxy, Ra is α-hydroxy and R3 is β-CH , -cyclohexyl]: CCD is a moiety of formula X [wherein R1 is cyclohexyl] Rt is α-hydroxy, R31;! α-C) It-cyclohexyl and R 4 is α-hydroxy].

CDCl3 is deuterated chloroform; Celite is a filter aid; CVA is represented by formula X [where %RI is cyclohexyl, Rt is hydrogen, and R3 is Pill and R4 are α-hydroxycoChalF [CH(OH)C)I, CoV al: chpV^ is the formula XU, where R+ is cyclohebutyl, R, is hydrogen, R 8 is α-isopropyl, and R4 is α-hydroxy]: CLA is Formula X [wherein R1 is cyclohexyl, R2 is hydrogen, R3 is -α-isobutyl, or and R4 is a moiety of the formula X [wherein R8 is cyclo R1 is α-hydroxy, Rt is α-hydroxy and R5 is α-in. butyl]; CPD is a moiety of the formula x [wherein R1 is cyclohexyl and R6 is α -hydroxy, R4 is α-hydroxy and R3 is α-hensyl] :CVD has the formula X [wherein R3 is cyclohexyl, R2 is α-hydroxy, α-isopropyl and R4 are α-hydroxy] moieties; CVD′ is of formula [In the formula, R is cyclohexyl, R7 is β-hydroxyl, R4 is α-hydroxy , and R3 is a moiety of α-isopropyl; -dimethylaminonaphthalenesulfonyl: DCC is synchhexylcarbodiimide; DEPC is diethylphosphoryl lucyanide: EtOAc is ethyl acetate; g is Durham; τ-GILI is τ-glutamic acid; any is glycine: His is histidine; N-MeHis is Nα-methylhistidine; HOBT is 1-hydroxybeta HPLC is high performance liquid chromatography.

11e is inleucine; IR is infrared spectrum.

IV^ is isovaleryl.

LCA is Formula X1, where R8 is isopropyl, R7 is hydrogen, and R3 is -a-CH2- α-Rohexyl and R4 are α-hydroxy] moieties.

LFA is published in PCT Publication No. 086106379 (November 6, 1985). It is a difluoro form of LVA, and has the formula ■ [wherein, R1 is isopropyl.

LLA is Formula X1, where R is isopropyl, R2 is hydrogen, and R3 is -α-isobutylene. and R4 are α-hydroxy] moieties.

ID is the formula X [wherein R1 is isopropyl, R7 is β-hydroxy, R4 is β- Hydroxy and R5 are the β-inbutylco moieties.

LLd is represented by formula X [wherein R3 is isopropyl, R1 is α-hydroxy, R4 is α- hydroxy, and R1 is β-isobutyl.

LLD is the formula x [where R1 is isopropyl, R2 is α-hydroxy, R4 is α- Hydroxy and R3 are α-isobutyl moieties.

LFA is 2X [wherein, R is isopropyl, R7 is hydrogen, and R5 is and R4 is a moiety of formula X [wherein R1 is iso propyl, R2 is hydrogen, R3 is α-inoprobil and R4 is α-hydroxy I, eu'F (CH (OH)CHt)Val: LVD is PCT Publication No. 1087105302 issue of LVA (September 11, 1987). It is an all form, and has the formula χ [wherein R, It isopropyl, R7 is α-hydroxy, R4 is an α-hydroxy and R3 (yoα-isopropyl) moiety.

LVDA' is represented by the formula X [where R, i! Isopropyl, R8 is β-hydroxy, R4 i±α-hydroxy, and R1 is α-isopropyl.

M or -o1 is mole.

Mba is 2S-methylbutylamine.

Me is methyl: ml is milliliter: MPLC is medium pressure liquid chromatography.

MS is mass spectrometry: No^ is (1-naphthyloxy)acetyl.

ph is phenyl.

Phehaphenylalanine; POA is phenyloxy/acetyl; PPD has the formula x "wherein R, is phenyl , Rt is α-hydroxy, R4 is α-hydroxy and R3 is α-penzylco. There are parts.

Pro is proline; 2-PY-^1a or L-2-pyridylalamine; RIP is A known renin inhibiting peptide, with the formula H-Pro-His-Phe-His-P he-Pbe-Val-Tyr-Lys-OH,2(CH3C(0)OH), means a compound having XH,0.

TB^ is t-butylacetyl: TBAP is tetra-n-butylammonium phosphate; TEA is tetra-n-butylammonium phosphate; Ethylamine: TFA is trifluoroacetic acid.

THF is tetrahydrofuran: TLC is aR chromatography.

Tos is p-)luenesulfonyl.

TsOH p-toluenesulfone Tyr is tyrosine.

(QC)l,)Tyr is O-methyltyrosine: and Val is valine. Ru.

In formula X, where the variables are defined above, "α" indicates that the substituent is below the drawing. "β" is used to indicate that the substituent is above the drawing. It is used for

Wedge-shaped lines indicate bonds extending above the plane of the paper relative to the plane of the compound.

Dotted lines indicate bonds extending below the plane of the paper relative to the plane of the compound.

The following Preparations and Examples illustrate the invention: Examples 1-103 Publications listed in Table 1 below, all of which are readily known and available to those skilled in the art. Chemical methods and starting materials described in the article (which are incorporated herein by reference) , and the reactants, the following compounds of the invention with the indicated physical properties were prepared. (1) L-inleucinamide, N'-(5-amino-4-hydroxy- 2-(1-methylethyl)-1-oxooctyl]-N-(2-pyridinylmethy R)-, trifluoroacetic acid, (S, S, S)-; or R-LM^-1i e-^ip; (2) IH-imidazole-4-propanamide, N-[2-hydro Roxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1 -[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino 1 carbo nyl]hexyl]-α-[(phenoxyacetyl)-amino]-1[lS-[I R*, 2R*, 4R* (IR*, 2R*)]-: POA-His-LY A-11e-Amp; (3) 1) 1-imidazole-4-propanamide, N -[1-(cyclohexylmethyl)-3,3-difluoro-4-[[2-methyl -1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]- 2,4-dioxobutyl]-α-[[(1-naphthalenyloxy)acetyl core Mino]-1[15~(IR*(αR*), 21?*]]~: or 0^-old 5-LF^-11e-AIIlp; (4) IH-imidazole-4-propane Amide, α-[[2-(acetyloxy)-3-(1-naphthalenyl)-1-o xopropyljamino]-N-[1(cyclohexylmethyl)-3,3-diflu Oro-4-[[2-methyl-1-U[(2-pyridinylmethyl)amino]carbo nyl]butyl]amine]-2,4-dioxobutyl]-1[IS-[IR*[α R*(R*)], 2R*]]-; (5) L-histidine amide, N-[(1, 1-dimethylethoxy)carbonyl 1-L-phenylalanyl-N-[1-(cy Chlohexylmethyl)-3,3-difluoro-4-[[2-methyl-1-[[( 2-pyridinylmethyl)amine]carbonyl]butylcoamino]-2,4-dio xobutyl]-: or Boc-Phe-His-LFA-11e-Amp; (6) 1B-imidazole-4-propanamide, N-[1-(cyclohexyl methyl)-2-hydroxy-6-methyl-4-[[[2-methyl-1-[[(2 -pyridinylmethyl)amine]carbonyl]butyl]amino]carbonyl]heb thyl]-α-[(phenoxyacetyl)aminoco-1[lS-[IR*(R*) , 2R*, 4S*(IR*.

2R*) Coco; or POA-His-CLA-11e-Amp: (mH-I Midazole-4-propanamide, N-[2,3-dihydroxy-5-methyl- 1-(2-Methylpropyl)-4-[C[2-methyl-1-[[(2-pyridiny methyl)aminococarbonyl]butyl]amino]carbonylco to bovine zirco-α -[(phenoxyacetyl)amino]-[15-[IR*(R*), 2S*, 3R*, 4R* (IR*.

2R*)]]-;or]]POA-His-LVDA-11Amp: (8)I H-imidazole-4-propanamide, N-[2,3-dihydroxy-5-methane thyl-4-[[(2-methylbutyl)aminococarbonyl]-1-(2-methyl propyl)hexyl]~α-[(phenoxyacetyl)amino]-1[IR-[ IR*(S*), 2S*, 3S*, 4S*(S*)]]-; or]]P OA-His-LVDA-Mba(9) Boc-Phe-His-Cha ps i[cHOHcFlo)1]Val-11e-4mp; or L-histidine Amide, N-[(1,1-dimethylethquin)carbonyl]-L-phenylara Nyl-11-[1-(cyclohedylmethyl)-2,3-dihydrohyl-5-methyl Chyl-4-[[[2-methyl-1-[[(2-pyridinylmethyl)ami/]cal Bonylcobutyl]ami/]carbonylcohexyl]-1[LS-[IR*, 2 S*, 3S*, 4S* (IR*.

2R*)]]-; or]]BOC-Phe-His-CVD1e-Amp:( 10) 1-Noa-His-Cha PSl [CHOHCHO former Yal-11e -Amp; or IH-imidazole-4-furopanamide, N-[1-(cy (chlorohexylmethyl)-2,3-dihydroxy-5-methyl-4-[[[2-methyl Chyl~1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]-[A carbonyl]hexyl]-α-[[(1-naphthalenyloxy)acetyl core amino]-1[IS-[IR*(R*), 2S*.

3S*, 4S*(IR*, 2RJ)]]-;or]]NOA-His-C VD-11Amp: (11) LH-imidazole-4-propanamide, N- [2-hydroxy-6-methyl-1-(2-methylpropyl)-4-I[2-methyl Chyl-1-[[(2-pyridinylmethyl)amine]carbonyl]butyl]amino ]carbonyl]hebutyl]-α-[(phenoxyacetyl)aminoco-1[IS -[IR*(R*), 2R*, 4S*(IR*.

2R*)]]-; or]]POA-His-LLA-1e-Amp; (L2 ) 1111-imidazole-4-propanamide, N-[2-hydroxy-1- (2-Methylpropyl)-5-[[2-methyl-1-[[(2-pyridinylmethyl )amino]carbonylcobutyl]aminoco-5-oxo-4-(phenylmethylene) pentyl]-α-[(phenoxyacetyl)aminoco-1[15-[11? *(R*), 2Rt, 4S*.

5(IR*, 2R*)]]-;or]]po^-Flis-LPA-11A mp; (13) 1B-imidazole-4-propanamide, N-[4-(sic) lohexylmethyl)-2-hydroxy-1-(2-methylpropyl)-5-[[ 2-Methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl] Amino]-5-oxopentyl]-α-[(phenoxyacetyl)amino]-1 [IS-[IR*(R*).

2R*, 4S*, 5(LRt, 2R*)]]-:or]]POA-Hi s-LCA-11Amp: (14) L-histidineamide, N-[(1,1- carbonyl]-L-phenylalanyl-N-[2-hydroxy C-1-(2-methylpropyl)-5-[[2-methyl-1-[[(2-pyridi nylmethyl)amino]carbonyl]butyl]amino-5-oxo-4-(phenylene methyl)pentyl]-1[lSiIR*.

2R*, 4S book, 5 (LRt, 2R*) co]-: or Boa-Phe- His-LPA-11e-Amp: (15) L-histidine amide, N-[( 1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-[4- (cyclohexylmethyl)-2-hydroxy-1-(2-methylpropyl)-5 ~[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]but thyl]amino]-5-oxopentyl]-1[is-[LRt, 2R*, 4 S*, 5(LRt, 2R*)]]-:or]]Boc-Phe-His- LC^1e-Amp; (16) L-talonamide, 6-cyclohexyl 2. 5.6-Trideoxy-5-[N-[N-((1,1-dimethylethoxy)ka [rubonyl]-L-phenylalanyl]-L-histidineamide]-2-(1- methylethyl)-II-[2-methyl-1-[[(2-bilinylmethyl)ami ]carbonyl]butyl]-1[5-(R*, R*)]-: or]Boc -Phe-His-CVD'-11e-Amp; (17) L-histidine amide 11-[(1,1-dimethylethoxy)carbonyl]-L-phenylalan Ru-N-(2,3-dihydroxy/-5-methyl-1-(2-methylpropyl)- 4-C[(2-methyl-1-[[(2-pyridinylmethyl)amino 1carbonyl ]Butyl]amino]carbonyl]hexyl 1-1[1S-IIR*, 2S*.

3R*, 4-^lp: or Boc-Phe4is-LVD^'-11e- Amp: FAB-MSEm + H]”835.5084; (18) 4-morpholinebutanamide, β-hydroxy-N-[2-[[2-hydroxy Droxy-5-methyl-1-(2-methylpropyl) to 4-[[[2-methyl- 1-[[(2-pyridinylmethyl)amine]carbonyl]butyl]amine]car [bonyl]hexyl]amino]-1-(IH-imidazol-4-ylmethyl)- 2-oxoethyl]-α-(l-naphthalenylmethyl)-τ-oxo, [lS −[LRt[R*(αS*.

βR*)], 2R*, 4R*(LRt, 21) co]-; (19) IF! −Imida Sole-4-furopanamide, II-[1-(cyclopexylmethyl)-2-hyde Droxy-5-methyl-4-[[[2-methyl-1-[[(2-pyridinylmethyl )amino]carbonyl]butyl]aminococarbonyl]hexyl]-α-[( phenoxy/acetyl)amino]-1[IS-[LRt(R*), 2R*, 4 R*(LRt.

2R*)]]-;or]]POA-His-CVA-11Amp;FAB-M S: [m + H door 46.4598; (20) IH-imidazole-4-pro Panamide, α-[[lS-(dimethylamino>-1-naphthalenyl]sulfony) 1-amino/]-N-[2-hydroxy-5-methyl-1-(2-methylpropyl )-4-[[[2-methyl-1-[[(2-pyridinylmethyl)ami/]carbo nyl]butyl]amino]carbonyl]hexyl]-1[IS-[LRt(R*) , 2S*, 4R*(LRt, 2R*)]]-; or]]DANS-Hi s-LVA-11Amp: (21) LH-imidazole-4-propanamide, 11-[1-(cyclohebutylmethyl)-2-hydroxy-5-methyl-4-[ [[2-methyl-t-[[(2-pyridinylmethyl)ami/]carbonyl]buty [amino]carbonyl]hexyl]-α-[(phenoxyacetyl)aminoco -1[IS-[LRt(R*), 2R*, 4R*(LRt.

2R*) ] Co: or POA-His-chpYA-11e-^mp; (2 2) L-histidineamide, N-[[5-(dimethylamino)-1-naphthalene ]sulfonyl]-L-phenylalanyl-N-[2-hydroxy-5-methyl -1-(2-methylpropyl)-4-[[2-methyl-1-[E(2-pyridi nylmethyl)amino]carbonyl]butyl]amino/]carponylcohexyl l- [IS-[LRt, 2R*, 4R*(LRt, 2R not)]]-; or] ]DANS-Phe-His-LVA1e-+1+++l): (23) Octa amide, 5-[(3,3-dimethyl-1-oxobutyl)amine]=4-hydro Roxy-7-methyl-2-(1-methylethyl)-N-[2-methyl-1-[[ (2-pyrinnylmethyl)aminococarbonyl]butyl]-1[2S[1(LR t, 2R*).

2R*, 4R1, 5R1] - or TBA-LVA-11e-Amp: FAB-MS: [m + H)' 533; (24) Cyclobeef Sanhexane Amide, δ-[(3,3-dimethyl-1-oxobutyl)amino]-τ-hydro xy-α-(1-methylethyl)-N-[2-methyl-1-[C(2-pyridiny) methyl)amino/]carbonyl]butyl]-1[αS-[N(LRt, 2R* ), a R*, r R*, δR*] - or TBA-CVA-11e-A a+p: FAB-MS: (25) IH-imidazole-4-propanamide, α -Amine-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)- 4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl ]butyl]amino]carbonyl]hexyl]-1[lS-[11(R*), 2 R*, 4R*(LRt, 2R*)]] or ]]H-His-LVA-11 e-＾en p26) L-histidineamide, L-phenylalanyl-N-[2-hydroxy C-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[ [(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl ]Hexyl]-1[1S-(IR*, 2R*, 4R*(11?*, 2R* ) CoJ- or H-Phe-His-LVA-+ 1e-AIIlp; (27) Cyclohegyusanhebeefsanamide, δ-amino-τ-hydroxy-α-( l-methylethyl)-N-[[2-methyl-1-[[(2-pyridinylmethyl) coaminococarbonylcobutyl]-, dihydrochloride, [αS-[NCI R*.

2R*), a R*, r R*, δR*] - or) l-CVA-11e -Amp;FAB-MS:[i+H]”475; (28) Cyclohegyusanhegyosanamide, δ-(acetylamino)-τ-hydro x-α-(1-methylethyl)-N-[2-methyl-1-[[(pyridinylmethyl) thyl)amine]carbonyl]butyl]-1[αS-[%(lR*, 2R*): αR*, τR*.

δR*]]-; or kc-CVA-1ie-Amp; FAB-MS: [m + H Co゛5I7; (29) Octanamide, 5-(acetylamino)-4- Hydroxy-7-methyl-2-(1-methylethyl)-N-[2-methyl-1- [[(2-pyridinylmethyl)amino]carbonyl]butyl]-1[2S-[N (IR*, 2R*), 2R*, 4R*, 5R*co]-, monoacetate (salt); or ＾c-IJA-11e-Amp:FAB-MS:Cm+H]” 477; (30) L-valinamide, L-phenylalanyl-L[2-hydro xy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1( [(2-pyridinylmethyl)amino]carbonyl]butyl]amine]carbonyl ]Hexyl]-1[xs-[tR*, 2R*, 4R* (IR*, 2R*) ]]-; or]]H-Phe4al-LVA-11emp; (31) Octane Amide, 5-[[2-(acetylamino)-3-methyl-1-oxobutyl]a Mino]-4-hydroxy-7-methyl-2-(1-methylethyl)-N-[2- Methyl-1-[[(2-pyridinylmethyl)amine]carbonyl]butyl]-1 [2S-[1t(lR*, 2R*), 2R*, 4R*, 5RMR*) ]-, monoacetate (salt); or Ac-Val-LVA-11e-Amp ; FAB-MS: [m + H1' 576; (:12) L-valinamide , L-valyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl )-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbo Nyl]butyl J amino]carbonylcohexyl]-1[1s-[to, 2R*.

4R*(IR*, 2R*)]]-, diacetate (salt): or H-Val- Val-LVA-11e-Amp: FAB-MS: [m + H]” 633 (33) Ac-Asn-IJA-IIe-Amp; FAB-MS: [a + +H co”591; (34) L-valinamide, N-acetyl-valyl -N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[ [2-Methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl ]amino]carbonyl]hexyl]-1[IS-[IR*, 2R*, 4R* (lR*, 2R*)]-, monoacetate (salt): or AC-Val-1 al-LVA-11e-Arnp; FAB-MS: [m + + (]” 6 75; (35) NU-[(2S, 4S, 5S)-5-[N ~ [NU-(Full) enoxymethylcarbonyl)-L-histidylcoamino-4-hydroxy~2- isopropyl-1-methyl-1-oxooctyl]4-[2-(2-pyridinyl) /)ethyl]-L-inleucinamide, acetate: or POA-H1s-L VA-11e-NU (CHt), NU-pyridine; FAB-MS: [m + H code 735; (36) IV^-LVA-11e-AH: FA B-MS: [m + Ill]” 519; (37) N-[(2S, 4S, 5S)-5-[N(Z-[NU-(tert-butoxycarbonyl)-〇-meth Chi-L-tyrosyl]-L-histidyl]amino-4-hydroxy-7-methyl -2-phenylmethyl-1-oxooctyl]-N-[(S)-2-hydroxy propyl]amine: or Boa-OMeTyr-)(is-LPA-Nu-C IT, -C1((CH,)(OH); FAB-Ms: [m + H]” 75 1; (38) NU-[(2S, 4S, 5S)-5-[N-[NU-(feedback) L-histidyl]amino]-4-hydroxy-2- isopropyl-7-methyl-1-oxooctyl]-N-(2,3-dihydroxy cypropyl)-L-inleucinamide; or POA-His-LVA-11 e-NH-CB, -CH(OH)-CH,OH: FAB-MS: [m + H]’689; (39) NU-[(2S, 4S, 5S)-5-[N-[NU-(phenoxy methylcarbonyl)-L-histidyl]-amino/-4-hydroxy-2-isopropylene Lopyl-7-methyl-1-oxooctyl]-N-(2-hydroxypropyl) -L-isoleucinamide; or POA-tlis-LVA-11e-811 -CB, -CI((CH3XOH); FAB-MS: [Il+H]"673; <40') NU-[(2S, 4S, 5S)-5-[[NU[(S)-1-a Setoxyl 1-benzyl)methylcarbonyl]-L-histidyl]aminoco-4 -hydroxy-7-methyl-2-(1-methylethyl)-1-oxooctyl] -N-[2-pyridyl)ethyl]-L-inleucinamide: or Ac0-P he-His-LVA-11e-NH-(CHt)z-pyridine, FAB-fertilizer : [m + 11 pieces 776; (41) NU-[(2S, 4S, 5S)- 5-[[(S)-(1-hydroxy-1-benzyl)methylcarbonyl]amino ]-4-hydroxy)-7-methyl-2-(1-methylethyl)-1-oxo [cutyl]-N-(2-pyridinylmethyl)-L-isoleucinamide 7 or 8 0-Phe-LVA-11e-AmP: High resolution MS 1583.3880 :(42) Na-(2S, 4S, 5S)-5-1'N-CNa-(l-naf (talenyloxyacetyl)-1,-histidyl]amine]-6-chlorohexyl -4-hydroxy-2-isopropyl-1-oxohexyl]-N,, -(2- pyridinylmethyl)-L-isoleucinamide, pyridine N-oxide or N OA-His-CvA-11e-Amp-NOlHRFAB MS [m + Fl]' m/z 812.4748; (43) Na-J (2S, 4S, 5S)-5-IN-'lllα-(P-toluenesulfonyl)-L-histidyl ]-amino]-6-7chlorohexyl-4-hydroxy-2-isopropyl-1-o xohexfur]-N~(2-pyridinylmethyl)-L-isoleucinamide or is p-toluenesulfonyl-His-CVA-11e-Amp, HRFAB MS [a+ + Hl” IQ/2766, 4348: (44) Na-[(2 S, 4S, 5S)-5-1N-[Na-(1-naphthalenyloxyacetyl )-L-Histidylcoaminony 6-cyclohexine-4-hydroxy-2-y Sopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L-iso Roy/Namide or NOA-old s-CVA-11e-Amp, HRFAB M S l’, m + H1” m/z796, 4794; <45>Na -[<28.43.5S)-5-[N-[Na-(7E/Beef Jime tylcarbonyl)-1,-histidyl faminoto-6-cy-chlorohequino--4-hy Dokute no 2-inpropyl- is 2-pyridinylmethyl )-L-isoleucinamide, tri'; Tis-CVA-1ie-Amp-NO.

HRFAB MS Jm + Hl” m/z 762.4574: (46) Na-[(2S, 4S, 5S)-5-[N-[Na-(p-toluenesulfur) (bonyl)-L-histi/rutsuamino]-8-cyclohexyl+hydroxy-2- Isopropyl-14K' is quinyl]-L(2-pyridinylmethyl)-L-iso Icinamide, pyridine N-oxide or p-toluenesulfonyl-former 5-C VA-11e-AIIlp-NO, HRFAB MS "a + H'J" a /z 782.4238; (47) lfε((23,4S, 5S)-5-[ N-[Na-(1-naphthalenyloxyacetyl)-L~histidyl]amino] -6-cyclohexylhydroxy-2-isopropyl-1-cyclohexyl- L-lysine, trifluoro vinegar! Shiomata HaN0A-H1s-CVA-1,-') Syn, trifluoroacetate, HRFAB MS [m + H]'m/z 721 ．． 4309: (48) N-[(2S, 4S, 5s)-s-(N-[Na-(1-naphthalene) nilox/acetyl)-L-histidyl]amino]-6-cyclohex/ru4- Hydroxy-2-isopcobyl-l-oxohexyl 1-N-[2-(2-pyri dinylamino]ethyl]-amine*TahaN0A-1(+5-CVA-V-(CH =)t-NH-(2-bili/7), HRFAB MS[i++(]”ra /z 712.4195; (49) N-[(2S, 4S, 5S)-5-I N-[Na-(l-naphthalenylox/acetyl)-L-histidyl 1-amino] -6-Fuclohexyl-4-hydroxy to 2-isopropyl-1-oxohexy ]-N-[2-(2-pyridinylaminoconityl]-amine, pyridine N-o oxide or N0A4is-CVA-111 ((C[(,)t-NH-C2- pyridine), HRFAB lll5 [01+ Hl” @/Z 728.41 44; (50) Na-EC28,4S,5S)-5-[11-[Na-(l -naphthalenyloxyacetyl)(2-pyridinyl)alanyl]amino]-6- cyclohexyl-4-hydro-L-inleucinamide or NOA-) is -CVA-11e-Amp, HRFAB kls [s+ + H de mHz 8 07.4795; (51) Na-[(2S, 4S, 5s)-s-'J-N ~[Nα-[(3-pyridinyl)-methylcarbonyl 1-L-histinol]ami ]-6-7chlorohexyl-4-hydroxy-2-isopropyl-1-oxohe xyl]-N-(2-pyridinylmethyl)-L-isoleucinamide or (3 -pyridinyl)-methyl-carbonyl-His-CV to -1le-Amp, H RFAB MS [m + 1(]’ m/z 731.4t325; (52 )Na-[Na-[(2S, 4S, 5S)-5-[N-CNa-(1~naf talenyloki/acetyl)-L-histidyl]amino]-6-cyclohexyl- 4-Hydroxy-2-isopropyl-1-oxyhexyl]-L-ynleucyl ]-L-lysine, trifluoroacetate or N0A-)is-CVA-11e -L-lysine, trifluoroacetate, HRFAB MS Cm + H]' * /z 834.5151; (53) Na-[(2S, 4S, 5S)-5- [11-[Na-(1-naphthalenyloxyacetyl)~L-histidyl]ami ]-6-cyclohequine to 4-hydroxy-2-inpropyl-1-oxo Oxil]-N-[2-(2-pyridinylamino]ethyl]-L-ia0isin-a mido or N0A-His-CVA-+1e4H-(CI(t)-NH-(2- pyridine), HRFAB MS [m + [11’ @/z 825.504 0; (54) II(-imidazole-4-propanamide%'N-[2-hydro Roxy-5-methyl-1-(2-methylpropyl)-4-[[:C2-methyl- 1-CC(2-pyridinylmethyl)amino]carbonyl]butyl]aminococal [bonyl]hexylcoα-[(2-hydroxy-1-oxy-3-phenylpro pyru)amine]-1[IS-[IR*[Rt(o)], 2R*, 4R*(I R*, 2R*)]]-]]12-hydroxy-12.3-propanetricarbo Xylate (12) (salt) or phenyl-CH,-CH(Of()-C(0) -His-LVA-11e-^alp, HRFAB MS [m + H de: 720.4456; (55) IH-imidazole-4-propanamide, N -[2-hydroxy-4-[[[1-[[(2-hydroxy-2-phenylethyl aminococarbonyl]-2-methylbutylcoaminococarbonyl]-5-methyl Tyl-1-(2-methylpropyl)hexylco α-[(phenoxyacetyl) amino]-, monoacetate (salt) or POA-His-LVA-11e-N H-CHt-C! I(OH)-phenyl, HRFAB MS [m10': 7 35.4444 + (56) L-ff-glutamine, N/u 2/d-[N-[ [1,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-N-[ 2-Hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl Thyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino ]carbonyl]hexyl]-1[IS-[IR*, 2R*4R*(IR*, 2 R*)] l-, monoacetate (salt) or BOC-Phe-Glu-LVA- 11e-/mp, HRFAB MS [a++H]’: 811.49 88; (57) Hentanoic acid, 5-[[1-(cyclohexylmethyl)-2-hydroxy Droxy-4-[[(2-hydroxypropyl)amine]carbonyl-5-methane tylhexyl]amino]-5-oxo-4-[(phenoxyacetyl)amino] - or POA-Glu-CVA-NH-CHtCH(CH*)(OH), HR FAB MS [m 10H]”: 630.3146; (5g) IH-I Midazole-4-propanamide, N-[1-(cyclohexylmethyl)-2- Hydroxy-4-[[(2-hydroxypropyl)amino]carbonyl]-5- methylhexyl] α-[(phenoxyacetyl)aminoco-, monoacetate ( salt) or POA-His-CVA-NH-Cut-CH(OH)(CHa), HRFABMS [m + Hl”: 600.3770; (59) Penta acid, 5-[[1-(cyclohexylmethyl)-2-hydroxy-5-methyl- 4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl ]butyl]amino]carbonyl]hexyl]amino]-4-[(IH-indo (R-2-ylcarbonyl) ahenoco-5-oxy[1s-[IR*(Rt), 2R*, 4R* (IR*, 2R*)]]-or]]IH-Indoru 2-ylcarbonyGlu-CVA-11e-Aa+p, HRFARMS [m + Hl”: 747.4437; (60) L-α-glutamine, N-[ 1-(cyclohexylmethyl)-2-hydroxy-5-methyl-4-C[E2- Methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]ami ]carbonyl]hexyl]-N/u　2/d-L-phenylalanyl-1[l S-[IR*, 2R*, 4R*(lR*, 2R*)]]-, bis(trif fluoroacetate) (salt) or Phe-Glu-CVA-11e-Aml), ) IRFAB MS [m + H de.

751, 4756; (61) 2-Pyridineacetamide, N-[2-[[2-hydroxy-5-methy -1-(2-methylpropyl)-4-[[2-methyl-1-[[(2-pyrypropyl) [dinylmethyl]amine]carbonyl]butyl]amino]carponylcohexylco amino]-1-(IH-imidazol-4-ylmethyl)-2-oxoethyl] -[IS-[IR*(Rt), 2R*, 4R*(IR*, 2R*)]]- or (]]2-pyridylcetyl-old 5-LVA-11e-^mp.

(62) 4-Pyridineacetamide, N-[2-[[2-hydroxy-5-methy -1-(2-methylpropyl)-4=[[[2methyl-1-[[(2-pyridi nylmethyl)amine]carbonyl]butyl]amino]carbonyl]hexyl]a [mino]-1-(ll’l-imidazol-4-ylmethyl)-2-oxoethyl ]-[IS-[IR*(Rt).

2R*, 4R*(IRJ, 2R*)]]- or (]]4-pyridylcetyl -His-LVA-11e-Amp; (63) L-histidine amide, N-[(1,1-dimethylethoxy)carbonyl ]-3-(2-pyridinyl)alanyl-N-[2-hydroxy-5-methyl- 1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyrinni methyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-2 [IS-[IR*[Rt(E)], 2R*, 4R*(IR*, 2R*)] ]-or]]BOC-2-Py-Ala-HiLVA-11e-Amp, HR FAB MS [m + Hl”: 820.5112; (64) L-Histidy N-amide, N-[(1,1-dimethylethoxy)carbonyl]-L-phenyla ranyl-N-[4-[[[2-[(2,6-diamitwo-4-pyrimidinyl)ami [ethyl]amino]carbonyl]-2-hydroxy-5-methyl-1-(2- methylpropyl)hexylco, [lS-(IR*, 2R*, 4R*)]- or] BOC-Phe-His-LVA (2,6-diamy2-4-pyrimidinyl ) Amino-ethylamino, HRFAB MS [m + H co°: 766 ．． 4727; (65) L-α-asparagine, N/u 2/d-[N-[(1 ,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-N-[2- Hydroxy-5-methyl-1-(2methylpropyl)-4-[[2-methyl-1 -[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbo nyl]hexyl]-1[IS-[IR*, 2Rt.

4R*(IR*, 2R*)]]-, monoacetate (salt) or BOC-Ph e-Asp-LVAile-^mp, l (RFAR breeding S [m + H de: 797.4857; (66) Il+-indole-2-carboxinamide, N -[2-([2-hydroxy-5-methyl-1-(2-methylpropyl)-4- [[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butylene ]carbonyl]hequinyl]amino]-1-(+++midazole~4-ilme thyl)-2-oxoethyl 1-1[lS-[IR*(R*), 2R*, 4R t(lR*, 2R*)]- or N-(indoyl-2-carbonyl)-H is-LVA-Ice-Aa+p; (67) L-α-glutamine, If-[1,1-dimethylethquine)carbonyl ]-L-phenylalanyl]-NO[1-(cyclohexylmethyl)-2-hydro Roxy-5-methyl-4-[[[2-methyl-1-[[(2-pyridinylmethyl )amino]carbonyl]butylcoami/cocarbonyl]hequinyl]-1[IS- [IR*, 2R*, 4R* (1, R*, 2R1)]]-, monoacetate (salt) or BOC-Phe-Glu-CYA-11e-Amp, HRFAB MS [m + H]’: 851.5297; (68) 2.5.11.1 4-tetraazapentadecanoic acid, 7-hydroxy-3-(11(-imidazole) -4-ylmethyl)-9-(1-methylethyl)-12-(1-methylpropyl )-6-(2-methylpropyl)-4,10,13-trioxo-15-(2- pyridinyl)-14-pyridinyl methyl ester, [3S-[3R*, 6R* , 7R*, 9R*, 12R*(R1)]]-or]]1oc-His- LVman-11Amp; (69) L-histidine amide, N-[(1,l-dimethyl carbonyl]-L-phenylalanyl-N-[3,3-difluoro -2-hydroxy-4-[[2-methyl-1-[[(2-pyridinylmethyl)a Mino]carbonyl]butylcoami/]-4-oxo-1-(phenylmethyl)butyl Circo or CH3-C(0)-0-CH(benzyl)-C(0)-His- LVA-11e-Amp, HRFAB lis [i + Hl”: 76 2゜4521: (70) IH-imidazole-4-propanamide, N-[2 -Hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl Ru-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]ami/] carbonyl]hexyl]-α-[(1-oxo-3-phenoxyprobyl)amino /]-1[IS-[IR*(R*), 2R*.

4R*(lR*, 2Rt)]l-1 or fenoki/-propionyl-former 5- IJA-11e-Amp; (71) IH-imidazole-4-propanamide, N-[2-hydroxy-5 -Methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[[( 2-Bilinonylmethyl)amino[carbonyl[butyl[amino[carbonyl[heta] xyl]-α-[(1-oxyl-3phenyl-2-propenyl)amine]-1[ xs-[tR*CR*(E)].

2R*, 4R* (IR*, 2R*)]]-or]]Phenyl-CH=forcep- C)-His-LVA-11e-Amp, tlRFAB! IIs [i + H Co゛゛　・　702.4343　; (72) IH-imidazole-4-propane Amide, N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4 -[[[2-Methyl-1-[[[(2-pyrinylmethyl)amine[carbonyl ][Butylcoamino[carbonyl[hexyl]-α-[(1-oxo-4-phene nyl-3-butenyl)amine]-1[lS-[IR*[R*(E)co.

21? *, 4Rne(10,2R*)Fco or phenyl-CH=CH-CH , -C(0)-His-IJA-11e~^mp, HRFAB MS [m + Hl”: 716.4474: (73) 2.5.11.14-tetraa Zapentadecanoic acid, 7-hydroxy-3-(LH-imidazol-4-ylmethyl )-9-(1-methylethyl)-12-(1-methylpropyl)-6-(2- methylpropyl)-4,10,13-trioxo-15-(2-pyridinyl)- 53-phenyl-2-propenyl ester, [3S-[1(E), 3R*, 6R*, 7R*.

9R*, 12R*(R*)]]-or]]phenyl-CH-CH-CH,- C(0)-His-LVA-11e-Amp, HRFAB MS [m + Hl”: 732.4463; (74) 1B-imidazole-4-propa amide, N-C2-hydroxy-5-methyl-1-(2-methylpropyl)- 4-E[[2-methyl-1-[[(2-pyridinylmethyl)ami/]carbonyl ]butyl]aminococarbonyl]hexyl]-α-[[(2-phenylethynyl ) sulfonylcoamino]-1[lS-[IR*[R1(E)].

2R*, 4R*(lR*, 2R*)]]-or]]phenylCHt)t- 3Ot-t(is-LVA-11e-Amp, HRFAB MS [m + H Do: 738.4061; (75) N-tert-7' tyloxycarbonyl -S-phenylalanyl-L-histidyl-53-ami/-3R,4R-dihy Droxy-2R-isopropyl-7-methyl-octanoyl-2S-methylbutylene Ruamide or BOC-Phe-His-LVA-Mba, FAB-MS (real Measured value’): 701.4634; (76) Hydroxyacetyl-shi-histi Zyl-58-amino-6-cyclohequinru 3R,4R-dihydroxy-2R- Isopropyl-hexamyl-L-isoleucyl-2-pyridylmethylamide Or ([0) Ac-His-CVA-11e-Amp, FAB-1lls (actual measurement Value): 686.4244 + (77) L-glycyl-s = histidyl-5s -Amino-6-cyclohekinru 3R.

4R-dihydroxy-2R-isopropyl-hexanoyl-isoleucyl- 2-Pyridylmethylamide or Gly-His-CVA-11e-AmpSF AB-MS (actual value): 6g5.4382.

(78) Hydroxyacetyl-L-histidyl-53-amino-2R-benzyl -6-cyclohexyl-3R,4R-dihydroxy-hexanoyl-shi-isoro isyl-2-pyridylmethylamide or (HO)Ac-His-CPD-11 e-^mp, FAB-MS (actual value): 734.4248 + (79) hydro to xyacetyl-histidyl-5S-amino-2R-benzyl-6-cyclo xyl-3R,4R-dihydroxy-hexanoyl-isoleucyl-2-p Lysyl methylamide, N-oxide or (HO)Ac-His-CPD-11 e-Amp, FAB-MS (actual value) near 50.4202; (80) Hue /xyacetyl-L-histidyl-58-amino-2R-benzyl-6-cyclo hexanoyl-3R,4R-dihydro-half-hexanoyl-isoleucyl-2- Pyridylmethylamide or POA-Bis-CPD-11e-Amp, FA B-MS (actual value): 810.4557; (81) L-glycyl-silica Stidyl-53-amino-2R-benzyl-6-cyclohexyl-3R,4R- Dihydroxy-hexanoyl-cylinleucyl-2-pyridylmethylamide or Gly-His-CPD-11e-Amp, FABJS (actual value) = 733 , 4409: (82) To phenoxyacetyl-histidyl-58-amino-6-cyclo Bovine sil-3R,4R-dihydroxy-2R-isopropyl-hexanoyl-L- isoleucyl-2-pyridylmethylamide or POA-old s-CVA-11e -AmpsFAB-MS (actual value): 762.4574; (83) l- naphthoxyacetyl-histidyl-58-amino/-6-cyclohexyl-3 R,4R-dihydroxy-2R-inbutyl-hexanoyl-L-inleucyl -2-Pyridylmethylamide or NOA-Hls-CLD-11e-Asp.

FAB-MS (actual value): 826; (84) 1-naphthoxyacetyl -Histidyl-58-amino-6-cyclohexyl-2R-cyclohexylmethylene -3R,4R-dihydroxy-hexanoyl-isoleucyl-2-pyridi methylamide or NOA-Bis-CCD-11e-AmpSFAB-MS (Actual measurement value): 866, 5189.

(85) 1-naphthobovine diacetyl-L-histidyl-58-amino-2R-be 3R,4R-dihydroxy-6-phenyl-hexanoyl-L-inlo isyl-2-pyridylmethylamide or N0A-old s-PPD-11e-Am p, FAB-MS (actual value): 854.4230; (86) 1-Naphthoxyacetyl-1-histidyl-56-amino/-6-cyclo hexyl-3R,4R-dihydroxy-2R-isopropyl-hexanoyl -inleucyl-2-pyridinylamino-ethylamide or N0A-f(is -CvD-11e-Apr, FAB-MS (actual value): 841.4964 .

(87) 1-Naphthoxyacetyl-histidyl-58-amino-6-cyclo Hexyl-28-cyclohexylmethyl-3R,4R-dihydroxy-hexano yl-L-isoleucyl-2-pyridylmethylamide or N0A-His-C cD-11e-Asp, FAB-MS (actual value): 866, 5194; ( 88) 1-Naphthoxyacetyl-histidyl-58-amino-38-48- Dihydroxy-28-isobutyl-7-methyl-octanoyl-L-isoloin -2-pyridylmethylamide or IIOA-His-LID-11e-Am plFAB-MS (actual value): 786.4540: (89) 5-quinolinylhydroxyacetyl-L-histidyl-58-amino- 6-cyclohexyl-48-hydroxy-28-impyl-hexanoyl- L-ynleucyl-2-pyridylmethylamide or Qoa(b)-His-C VA-11e-^mp, FAB-MS (actual value): 797; (9(1) 4-Chimerinylhydroxyacetyl-histidyl-58-amino-6-cyc Rhohexyl-48-hydroxy-28-inpropyl-hexanoyl-L-yne Leucyl-2-pyridylmethylamide or Qoa(a)-Hls-CVA- 11e-Aip, FAB-MS (actual value): 797; (91) l-naf Toxyacetyl-histidyl-53-amino-3R,4R-dihydroxy- 28-Imbutyl-7-methyl-octanoyl-L-isoleucyl-2-pyridi methylamide or NOA-His-LLd-11e-AmpSFAB-MS (Actual value): 786.4579; (92) l-naphthoxyacetyl-histidyl-56-amino-3S, 4 R-dihydroxy-28-isobutyl-7-methyl-octanoyl-isoiso isyl-2-pyridylmethylamide or N0A4is-LLd-11e-^m p, FAB-MS (actual value'): 786.4556; (93) 1-naphthoxyacetyl-1,-histidyl-58-ami/-3R, 4R-dihydroxy-2R-isobutyl-7-methyl-octanoyl-L-iso Leucyl-2-pyridylmethylamide or NOA-)1is-LLD-11e -Amp, FAB-MS (actual value): 786.4540; (94) 2-quinolinylcarbonyl-58-amino-6-cyclohexyl-3R .

4R-dihydroxy-2R-y nobrovir-hexa/il-L-inleucyl -2-pyridinylamino-ethylamide MS (actual value): 789. 4670.

(95) N-tert-butyloxycarbonyl-L-alanyl-5S-ami/ -6-7 chloroheki/ru-48-hydroxy-23-isopropyl-hexanoyl -L-inloy/L-2-pyridylmethylamide or Boc-Ala-CVA -11e-Aml).

FAB MS [m + H do: 546: (96) N-tert-butyloxy Carbonyl-L ~ Histidyl-58-amino-6-7 Chlohequin-48-hydro Roxy-2S-isopropyl-hexamethyl-14-isoloin-2-pyridi methylamide or BOC-)1is-CVA-11e-8mp, FAB MS [m + 11 degrees near 12; (97) -Delete- (98) Cow/Linyl-2-Carbonyl-L-Histidyl-5S-Amino-6-S Chloheki/L-43-hydroxy-23-isopropyl-hexanoyl-L Soleucyl-2-pyridylmethylamide or QC-His-CVA-11e- Amp, FAB-MS [@ + H de: 768; (99) Quinolinyl-2-carbonyl-cycloasparaginyl-55-amino-6 -Cyclohequin-4S-hydroxy-2S-isopropyl-hexanoyl-L -isoleucyl-2-pyridylmethylamide or QC-^sn-CVA-11 e-Amp.

FAB-MS [m + H do: 744; (100) benzyl ox 7 carbo Nilu L-alanyl-L-alanyl-5S-amino-6-cyclohekinru 4S -Hydroxy-2S-inpropyl-hexamyl-iso-isoleufluor-2-p Lysyl methylamide or CBZ-Ala-Ala-CVA-11e-Amp% FAB-MS [IIl+H]”: 751; (101) l-naphthalene maleoxyacetyl-histidyl-58-amine-6-cyclohequinol 4S-Hydroxy-23-isopropyl-to-bovine sharkyl-isoleucylamide or Noa4is-CVA-11e-NHt, FAB-MSErn + H Co: 705.

(102) POA His-CVA-NH-(CHz)+-CI(CONHXN Ht), FAB-MS [m + H]”: 671.

(103) L-asparaginamide, 1-(naphthoquine)acetyl-L[2-hyperglyceride] Droxy5-methyl-1-(2-methylpropyl)-4-[[[2-methyl- 1-[[[2-methyl+[[[2-(N-oxide)pyridinylmethyl]amino cocarbonyl]butyl]amino]carbonyl]hexyl]-N-α-methyl-, [IS-[IR*, 2R*.

4R*(IR*, 2R*month)- or NOA-Asp-CVA-11e-Am p, mass spectrum: M + H” ions are weak, so accurate mass cannot be obtained It was. Other ions are m/z 665, 535, 348, 354, 23 6, 222, 157, 126, 109. Obtained at 86; Preparations 1-4 (DCL (OCLCllt) Socho S preparation magnetic stirrer, nitrogen inlet and Add 16 mL of pyridine to a 100a+L 20 round bottom flask equipped with a reaction thermometer and a reaction thermometer. [Mallinckrodt] and 8. OfIIL Liethylene glycol monomethyl ether [Aldrich Put in. The solution was cooled to 0 °C (water bath) under a nitrogen atmosphere, then the temperature was increased to 5 °C. 114 g of p-)luenesulfonylchloride over 20 minutes without exceeding C. Process it in several parts during the ride. A dark white precipitate forms around halfway through the addition process. begin to accomplish. Once the addition is complete, the resulting mixture is stirred at 0°C for 2 hours. mouth Pour the mixture into a water-cooled solution of 30 mL of concentrated hydrochloric acid in loo+nL of water. nothing.

This mixture was extracted with ethyl acetate (3×100 mL) and these extracts were diluted with water. (4 x 100 mL, final wash by addition of saturated aqueous solution of M sodium carbonate) Wash with clean PI (adjusted to 7), combine (MgSO.) and dry. Dry, filter, concentrate under reduced pressure, 15. 54g of desired tosylate in colorless oil Obtained as: 'H NMR (300MHz + CDCI,) δ7. 80 , 7. 35, 4. 16, 3. 69.

3, 59, 3. 59. 3. 54, 3. 35, 2. 45; Mass Spectrum (El), 1m/Z 318 [M]”.

286, 273, 259, 243, 229, 199, 155, 9 1, and 59: TLC R, = 0. 33, 50% ethyl acetate/hexa (phosphomolybdic acid). This material is used without purification.

(2) Preparation of 4-[CH-(OCHeCHz)so]-1-naphthoxyacetic acid 1 , 4-[C)1, (OCI (,C old), O]-1-naphthol preparation all 1 0.50 g of 1,4-naphthalenedi in 0 ml of dimethylformamide (Aldrich) and 1 in Preparation 1, 0 g of C) 13 (QCH, A solution of CO, ), OTS is placed under a nitrogen atmosphere and then cooled to -60 °C. . 60% mineral oil emulsion of sodium hydride (130 mg; 3.3 mmo Add L) (Aldrich) in portions over 2 minutes. the resulting mixture Stir and gradually warm to -30°C over 1.5 hours. Remove cooling bath and warm the mixture to room temperature over 1 hour. At this time, the mixture was then added to 50 Heat to °C and stir for 1 hour. The reaction is stopped by ammonium hydroxide in IN. diluted with methanol and pumped under reduced pressure, first under indoor pressure and then with a vacuum pump. Concentrate under low pressure to obtain a black solid. Dissolve this material in ethyl acetate and Wash with saline (3 times). The aqueous washings were back-extracted with ethyl acetate and the combined organic The extracts were dried (NatSO4), filtered, and concentrated to a black solid (starting material diluted). A mixture of ol, tonrate and desired product) is obtained.

Chromatography of this material on 100g of 7-force gel (63-200μ) (after discarding the initial solvent) 00n+L, while collecting 9 mL fractions. , eluting with 25% acetone/hexane. Combine both parts 25~6o, concentrate and TO , 51 g of impure 4[CH3(OCHtCut)J]-1-naphthol are obtained. .

TLCR, = 0.19.25% in acetone/hexane (UV).

I[,4-[CH3(OCR,C[+,),0]-1-naphthoxyacetic acid methyl ester Preparation of Stell Dissolve the substance in item 1 in 15 mL of dimethylformamide and add 0.3 2 mL:) treated with methyl bromoacetate (Aldrich) and incubated at 0° under nitrogen atmosphere. C and then treated with 0.15 g of a 60% mineral oil emulsion of sodium hydride. Understand. The resulting green mixture was stirred at 0 °C for 1.5 h and then diluted with saturated ammonium chloride. quench in a vacuum chamber, dilute with methanol, and then under reduced pressure - first at room pressure, then at room pressure. Concentrate under low pressure using a vacuum pump.

The resulting brown solid is suspended in 5 hL of water and extracted with ethyl acetate.

The aqueous phase was backwashed with ethyl acetate, the combined organic extracts were dried (*atso4), Filter and concentrate to a brown oil (mainly 4-[CH,(OCI(,C)!, )30]-1-+7 toxyacetic acid methyl ester, 1.4-[CHa(OCHtC Ht)so]-+79ren and CH3(OCl(,C)I,)307S mixture Get compound. This material was chromatographed on 50g of silica gel (63-200μ). 25% acetone/hexane while collecting 9 mL fractions. Extract with Fractions 33-49 were combined and concentrated to obtain a small amount of CH3 (OCHaCH- 285 mg of 4-[CH3(OCR,Cl,)30]- contaminated with )30Ts Obtain 1-naphthoxyacetic acid methyl ester: 'HIIMR (3 times MI (z: CDCl5) δ8.30~g, 22.7.56~7.50.6.67, 6.6 1.4.77, 4.25°3, 97.3.82.3.80.3.69.3.55 ．． 3.37: TLCR1.031.25% in acetone/hexane (UV).

Fractions 57-80 are 1.4-[CI(,1(OCR2CI(,)30]-naphtha gave a lene byproduct.

DIl, 4-[CH3(QC)l,C)I,),+O]-1-naphthoxyacetic acid Preparation Dissolve the methyl ester (263 mg) in Section 2 in 3 mL of methanol. Ru. Water (1a+L) and IN sodium hydroxide (1 mL) were added and the obtained The solution is stirred at room temperature for 2 hours. This solution was then diluted with 10 mL of IN sodium hydroxide. and extracted three times with ethyl ether. Discard the combined organic extracts. , the aqueous phase is acidified to pH 5 with hydrochloric acid and extracted three times with methylene chloride. Combined with The extract was dried (NatSOj), filtered and concentrated to give 187 mg of 4-[C H3(OCH,CL) 301-1-Naphthoxyacetic acid is obtained as a brown oil.

TLC analysis was performed using 20% ethyl acetate/chloroform to detect only the origin spot. showed that. This material will be used in the next coupling experiment without purification. .

(3) Preparation of 5-[CH3(OCH-CH-)sO coco-naphthoxyacetic acid I , 5-[CHs (OCH-CH-) 5 via 3ol-1-naphthol -[CH8(OCHtCHt)30]-1-Naphthoquine acetic acid methyl ester preparation [One-pot reaction] All in 15 ml of dimethylformamide. 50 g 1,5-naphthalenediol (Aldrich), 1.1 g Preparation 1C )lbar0CHZCH-)+OTs, and 027g of 60% sodium hydride ether. The Marsicon solution is placed under a nitrogen atmosphere and heated to 50°C. the resulting mixture The mixture was stirred for 1.5 h and then 0.44 mL (4.6 mmol) of bromoacetic acid solution was added. Treat with Chill (Aldrich). Continue stirring and heating for an additional 1.5 hours. . The reaction solution was cooled to room temperature, then quenched with saturated ammonium chloride and methanol. and then under reduced pressure, first under indoor pressure and then at low pressure using a vacuum pump. Concentrate under 100 mL to obtain a mixture containing the product as a yellow solid. This solid is acetic acid Dissolve in ethyl and wash with 5 hL of water (2 times). Reverse the aqueous wash with ethyl acetate. The washed and combined organic extracts were dried (MgSO-), filtered, concentrated and A orange oil is obtained.

TLC analysis of this oil revealed the desired product [5-[CH, (OCH,CH,)3 0]-1-naphthoxyacetic acid methyl ester], unidentified component, 1, 5-[CH3 (OCHtCHJsO]-1-naphthalene, l, 5-[CH,O,CC1(, 01-1-naphthalene and 5-[CH3(OCI(.

CH,)30m-1-naphthol. Add this mixture to 5 0g/chromatographed on lica gel (63-200μ), 6sL Elute with 20% ethyl acetate/chloroform, collecting fractions. Fraction 51 -60 were combined and concentrated to give 241 mg of 5-[CI+3(OCH-CH30] Obtain -1-naphthoxyacetic acid methyl ester 'HNMR (300MHz: CDCl5) δ7.92.7.91.7.37.7.31.683.6.71. 4.78.4.25.3.95.3.77, 3.79°3, 67, 3.52.3 ．． 35; TLCR, 046.20% in ethyl acetate/chloroform (UV) .

Preparation of n,5-[CH3(OCH,CH2)301-1-naphthoxyacetic acid Section 1 methyl ester (241 mg; 0.63 ml) was added to 3 sL of methanol. Dissolve in the liquid. Add water (l ml) and IN sodium hydroxide (1 ml) , the resulting solution is stirred at room temperature for 2 hours. This solution was then added to 10 sL of IN water. Pour into sodium oxide and extract three times with ethyl ether. Combined organic extraction The output is discarded and the aqueous phase is acidified to pH 5 with hydrochloric acid and extracted three times with methylene chloride.

The combined organic extracts were dried (Na2S04), filtered and concentrated to 206 m g of 5-[Ct(3(OCH-Ctlt)-□] + naphthoquine acetic acid as a brown oil. Obtain it as a thing. TLC analysis was performed using 20% ethyl acetate/chloroform at the origin. Only the spots shown are shown. This material can be used in subsequent coupling experiments without purification. Used for testing.

(4) Preparation of l(-Asn-CVA-11e-An+p. 134 mg Boc-L-asparagine (Nguma) in chillformamide and 202 mg of I(-CVA-11e-Aap) in 370 μL diiso Propylethylamine (Aldrich) and then (160 μL of diethyl treatment with L/anophosphonate (Aldrich). The resulting solution was placed in a nitrogen atmosphere. Stir for 17 hours under a It was confirmed. This solution was washed with 10 (24/40) 2 Transfer the 00+nL round bottom flask (into the vacuum), then (X) first under indoor pressure, then in the vacuum The crude B was concentrated in a rotary evaporator under low pressure using a oc-Asn-C'/A-11e-Amp is obtained. Add this material to 3 sL of methoxychloride. and 3 sL of trifluoroacetic acid (Aldrich).

The resulting yellow mixture is stirred at room temperature for 2 hours and then concentrated under reduced pressure. (about 2 of this material (preadsorbed on silica gel) was added to 55 g of silica gel (63-2 00μ)" 2 and collecting 6 mL fractions, Elute with 10% (4MNH*/MeOH)/CI (C13. Fractions 51-86 Combine and concentrate to obtain 158 mg of product. Dual mass spectrum (FAB) ions , m/z 589 [M + H de.

571, 481.236.222.126.109.86 and 69°TLCR 1.0.32.10% (4M NH3/MeOH)/C1 (C1, medium (UV).

Examples 104-105 (104) L-asparaginamide, [5-(triethylene glycol monomethylene) naphthoquine coacetyl-N-[2-hydroxy-5-methyl-1- (2-methylpropyl)-4-[[[2-methyl-1-[[[2-(N-oxy pyridinylmethylcoamino]carbonyl]butyl]amino]carbonyl]he xyl]-N-α-methyl-1[15-[IR*, 2R*, 4R*(lR* , 2R*)EE or 5[CHs(OCt(-Cl7)301-1-Noa- ^5n-CVA-l　1e-Amp All in 3sL of dimethylformamide Preparation 3 of 47.6 mg (0,131 mmol) of 5-(cH+(ocotc Ht)3o]-r-naphthoquinoacetic acid and 50.7 mg of H-Asn- of Preparation 4 The solution of CVA-11e-Amp was added to 74 μL of diisopropylethylamine (Amp). rudrich) and then 32 μl of diethyl/anophosphonate (alkaline Dritch). The resulting solution is stirred for 13 hours under nitrogen atmosphere, but this Throat TLC analysis confirmed that the coupling was complete. This solution, Transfer to 10 (24/40) 2Q O mL round bottom flasks while washing with methanol. and then one rotary first under indoor pressure and then one under low pressure using a vacuum pump. Concentration via enoiporator gives the crude product as a yellow solid. ( This material (preadsorbed on approximately 2 g of silica gel) was added to 50 g of silica gel (63 ~200μ), collecting both 6sL aliquots, Elutes at 8% (411NHs/MeO[+)/CFICIs. Fractions 16-30 are combined and concentrated to give the desired product contaminated with a small amount of polar impurity. 6% (4 This material was similarly re-chlorinated using MNH3/MeOH)/CHCl-. Attach to the woodpecker phi. Fractions 44-54 were combined and concentrated to greater than 99% purity. Two mass spectra (FAB) yielding 24.8 mg of product with [M+H ]゛Actual value: 935.5476, other ions, m/z 827.416.36 7, 348.330.318.305°236, 222.177, 126.10 9. and 86°I (PLC retention time 18.6 minutes. TLCRr-〇, 53.1 0% (4M NH3/MeOH)/CHC] in (t+V). Fractions 34-43 are An additional amount of slightly less pure material was given.

(105) L-asparaginamide, [4-(triethylene glycol monomethylene) naphthoxycoacetyl-N-[2-hydroxy-5-methyl-1- (2-methylpropyl)-4-[[[2-methyl-1-[[[2-(N-oxy [d)pyridinylmethyl]aminococarbonyl]butyl]amine]carbonyl]he xyl]-N-α-methyl-1[15-[IR*, 2R*, 4R*(IR* , 2R*)] or 4-[CHa(OCHtCtlJtO]-1-Noa- Asn-CVA-11e-Amp in 3 mL of dimethylformamide Preparation 2 of 52.6 mg of 4-[CH3(OCHtCH*)soi-1-naphtho xyacetic acid and 51.0 mg of Preparation 4 H-Asn-CVA-11e-Amp. The solution was treated with 75 μL of diisopropylethylamine (Aldrich) and then and treated with 32 μL of diethyl shea/phosphonate (Aldrich). Obtained The solution was stirred under a nitrogen atmosphere for 25 hours, at which point TLC analysis I confirmed that the process was completed. While washing this solution with methanol, Transfer to 10 (24/40) 200 iL round-bottomed flasks and then place under pressure indoors for the first time. and then concentrated by one rotary evaporator under low pressure using a vacuum pump. The crude product is obtained as a yellow solid. (About 2g of silica gel is adsorbed in advance) This material was chromatographed on 50 g of silica gel (63-200μ). 6% (4M NH3/MeOH) while collecting 6mL fractions. )/CHCl5. Fractions 39-57 were combined and concentrated to >99% Two mass spectra (FAB) to obtain 70.2 mg of product with purity + H value: 935-5494; other ions, s/z 827.348 ．． 330.318°305, 236.222.147.126.109. and 86°HPLC retention time: 17.6 minutes. TLCR, = 0.55.10% (4M NH-/MeO)I)/CHCl5 (UV).

Examples 106-107 (106) L-glycyl-55-amino-6-cyclohexyl-3R,4R-di Hydroxy-2R-isopropyl-hexyl-=L-ynleucyl-2-pyridi methylamide- or Gly-CVD-11e-8mp, FAB-MS (actual Measured value’): 548.3844.

(107) L-glinol-58-amif~2R-benzyl-6-cyclohequinyl -3R.

4R-dihydroxy-hexamethyl-2-pyridyl-methyla Mido or Gly-CPD-11e-Amp, FAB-MS (actual value): 596.3835; Table 1 Preparation of compounds useful in the invention Example No. Compound Publications (1),' PCT Publication No. 1087102986 (May 21, 1987 Date); PCT International Application No. 108715909 (dated October 8, 1987); Varnish ・Thaisrivongs (S) et al., Journal of ・Medicinal Chemistry (J, Wed, Chew,), Volume 31 (7), Pages 1369-76; S, Thaisrivongs ) et al., Journal of Medicinal Chemistry (J, Med, Che ), vol. 29(10), pp. 2088-93.

(2) EPO Publication No. 0173481 (dated March 5, 1986) Preparation C5 9, C66 (3) PCT Publication No. WO36106379 (dated November 6, 1986) Example 10 (4) PCT Publication No. WO36106379 (dated November 6, 1986) Example 10 (5) PCT Publication No. 1086106379 (dated November 6, 1986) Example 9 (s) EPO Publication No. 0173481 (dated March 5, 1986) PCT Publication No. Opening No. WO37102986 (dated May 21, 1987) (7) PCT Public Opening No. 1087705302 (dated September 11, 1987) Example 6 (8) PCT Publication No. l'0871053C12 (September 11, 1987 Appendix) Example 7 (9) PCT Publication No. 1i1087105302 (September 11, 1987 Attachment) Example 12 (10) PCT Publication No. 1087105302 (Dated September 11, 1987 ) Example 15 (11) EPO condyle protrusion publication number 0173481 dated March 5, 986) Table I ( Continued) Preparation of compounds useful in the invention Example No. Compound Publications (12)’ EPO Application Publication No. 0173481 (dated March 5, 1986) P CT Publication No., WO37102986 (dated May 21, 1987) (13) EPO Application Publication No. 0173481 (dated March 5, 1986) PCT Publication No. 1087102986 (dated May 21, 1987) (14) EPO application publication No. 0173481 (dated March 5, 1986) PCT Publication No. 110871 02986 (dated May 21, 1987) (15) EPO Application Publication No. 01734 No. 81 (dated March 5, 1986) PCT Publication No. 101117102986 (dated May 21, 1987) (16) PCT Publication No., WO37/(153 02 (dated September 11, 1987) Example 12 (17) PCT Publication No. WO37105302 (dated September 11, 1987) ) (18) PCT Publication No. 1089100161 (dated January 12, 1989 ) Example 2 (19) EPO Application Publication No. 0173481 (dated March 5, 1986) PCT Publication No. 1087102986 (dated May 21, 1987) (20) EP O Application Publication No. 0173481 (dated March 5, 1986).

D. E. Enovs (D, E, Epps), Analytical Biochemistry Stoli (^na1. BioChem, ), volume 181 (1), pages 172-81 .

(21) EPO Application Publication No. 0173481 (dated March 5, 1986) PCT Publication No. WO87102986 (dated May 21, 1987) (22) EP O Application Publication No. 0173481 (dated March 5, 1986) Table I (Pecked) Preparation of compounds useful in the invention Example No. Compound Publications (23) PCT Publication No. WO87102986 (dated May 21, 1987 ) (24) EPO Application Publication No. 0173481 (dated March 5, 1986) PC T Publication No. 1087102986 (dated May 21, 1987) (25) P CT Publication No., WO37102986 (dated May 21, 1987): EPO issue Application Publication No. 0173481 (dated March 5, 1986) (26) PCT Publication No. , WO37102986 (dated May 21, 1987) (54) PCT Publication N o, WO37102986 (dated May 21, 1987) (55) PCT publication No, WO37102986 (dated May 21, 1987) (56) PCT Public Opening No. WO37102986 (dated May 21, 1987) (57) PCT Publication No. WO87102986 (dated May 21, 1987) (5g) EP O Application Publication No. 0173481 (dated March 5, 1986) PCT Publication No., W O87102986 (dated May 21, 1987) (59) EPO Application Publication No. 0 No. 173481 (dated March 5, 1986) PCT Publication No. WO371029 86 (dated May 21, 1987) (ao) EPO Application Publication No. 0173481 (Dated March 5, 1986) PCT Publication No. 108710298B (1987 (dated May 21, 2016) (61) PCT Publication No., WO37102986 (198 (dated May 21, 2007) (62) PCT Publication No. 1087102986 (19 May 21, 1987) (63) PCT Publication No. WO37102986 (1 May 21, 987) (64) PCT Publication No. 1087102986 ( (dated May 21, 1987) Table 1 (continued) Preparation of compounds useful in the invention Example No. Compound Publications (65) PCT Publication No. 1087102986 (dated May 21, 1987) ) (66) PCT Publication No. 1087702986 (May 21, 1987 Attachment) (67) EPO Application Publication No. 0174481 (dated March 5, 1986) P CT Publication No. 1087102986 (dated May 21, 1987) (68) ' PCT Publication No. 1087102986 (dated May 21, 1987) (6 9) EPO Application Publication No. 0173481 (dated March 5, 1986) PCT Publication No, 1087102986 (dated May 21, 1987) Table■ Example No. HIV protease inhibitory compound K (nM) (1) 60% at 10-’M (2) <t.

(3) 94% at 2.5X 10-’ (4) 90% at 2.5X 10-’ (5) 2. sx 73% at 10-' (8) 15% at 2.5X to-' (9) 100% at 2.5X 1G-’ (13) 45% at to-7 (14) 51% at 10-’ (16) 87% at 2.5X to-’ (19) 48% at 5X 10-’ (25) 30% for to-1 Table (continued) I'llV protease inhibitory activity of Example No. (35) 2.5X 10-7 100% (37) 2.5X 13.5% at 1o-7 (33) 2.5X 1 (86% at 17 (39) 2.5X 100% at 10-7 (40) 2.5X 10-' 925% (75) 360r+M (76) 4nM (77) 11nM (78) 18nM (79) 20nM (80) 28nM (81,) > 250%M (89) 33nM (g□)　＞　250%M (g4) > 250%M (92) 223%M (93) 6.5nM structure chart X-C@-D9°ELO°'11-'12-Z IL2 L21 Structure chart (continued) Structure chart (continued) one Structure chart (continued) international search report international search report S^　41399

Claims (23)

[Claims] 1. drugs that inhibit retroviruses in mammalian cells infected with retroviruses Formula I for preparing: X-C8-D8-E10-F11-G12-Z [wherein, X is a)-(CH2)p-aryl, b)-(CH2)p-Het, c) -(CH2)p-C3-C7 cycloalkyl, 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)-, l) R4N(R4)-(CH2)n-C(O)-, j) R5-SO2-(CH2 )q-C(O)-,k)R5-SO2-(CH2)q-O-C(O)-,l)R 5-(CH2)n-SO2, m) Z-C(O)-CH(OH)-CH(CH2R1)-C(O)-, n) R5 -(CH2)qCH=CH-(CH2)p-C(O)-, o)R5(CH2)p CH=CH-(CH2)p-O-C(O), or p)R27(CH2)q-C (O)-: C8 is absent or formula XL1, XL2, XL2a, X The divalent moiety of L2b or other aminoacyl derivatives: ▲Mathematical formula, chemical formula, table There are ▼ (XL1) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (XL2) ▲ Mathematical formulas , chemical formulas, tables, etc. ▼ (XL2a) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ ( XL2b) D8 is the divalent moiety of formula XL3, XL2a, XL2b or other amino is an acyl derivative; ▲There are mathematical formulas, chemical formulas, tables, etc.▼(XL3)▲There are mathematical formulas, chemical formulas, tables, etc. ▼(XL2a)▲Contains mathematical formulas, chemical formulas, tables, etc.▼(XL2b) E10-F11 is a divalent of formula XL6, XL6c, XL6d, XL6a, II, III, or IV is a part; ▲There are mathematical formulas, chemical formulas, tables, etc.▼(XL6)▲There are mathematical formulas, chemical formulas, tables, etc. ▼ (XL6b) ▲ Contains mathematical formulas, chemical formulas, tables, etc. ▼ (XL6c) G12 does not exist or the divalent moiety of formula XL4, XL4a, or other aminoacyl derivatives And; ▲There are mathematical formulas, chemical formulas, tables, etc.▼(XL4)▲There are mathematical formulas, chemical formulas, tables, etc. ▼(XL4a) or f) Het bonded via a nitrogen atom, or g) -NH(CH2)qNH　H et; R is a)-(CH2)n-isopropyl, b)-(CH2)n-butyl, o)-(CH2)n-phenyl, or d)-(CH2)n-C3-C7cyclo is alkyl: R1 is a) Hydrogen, b) C1-C5 alkyl, c) aryl, d) C3-C7 cycloalkyl, e)-Het, f) C1-C3 alkoxy, or g) C1-C3 alkylthio; R2 is a) hydrogen, or b) -CH(R3)R4; R3 is a) Hydrogen, b) hydroxy; c) C1-C5 alkyl, d) C3-C7 cycloalkyl, e) aryl, f)-Het, g) C1-C3 alkoxy, or h) C1-C3 alkylthio; R4 is the same or different each time it appears, a) hydrogen; b) C1-C5 alkyl, c)-(CH2)p-aryl, d)-(CH2)p-Het, e) -(CH2)-C3-C7 cycloalkyl, or f) 1- or 2-ada Mantyl: R5 is a) C1-C6 alkyl, b) C3-C7 cycloalkyl, c) aryl, d)-Het, e) 5-oxo-2-pyrrolidinyl, or f) 1 or 2-adamantyl. ri;R6 is a) Hydrogen, b) C1-C5 alkyl, c)-(CH2)p-aryl, d)-(CH2)p-Het, e) -(CH2)p-C3-C7 cycloalkyl, or f) 1- or 2-a Damantyl; R7 is a) Hydrogen, b) C1-C5 alkyl, c) hydroxy; d) amino C1-C4 alkyl-, e) guanidinyl C1-C3 alkyl-, f) aryl, g)-Het, h) methylthio, i)-(CH2)p-C3-C7 cycloalkyl, j) amino, k)-(CH2)n-COOH, l)-(CH2)n-COOCr~C6 alkyl, or m)-(CH2)n- CONR22R26; R6 is a) Hydrogen, b) C1-C5 alkyl, c) hydroxy; d) aryl, e)-Het f) Guanidinyl C1-C3 alkyl-, or g) -(CH2)p-C3-C 7 cycloalkyl; R9 is a) Hydrogen, b) hydroxy; c) amino C1-C4 alkyl-, or d) guanidinyl C1-C3 alkyl -; R10 is a) Hydrogen, b) C1-C5 alkyl, c)-(CH2)nR16, d)-(CH2)nR17, e) C3-C7 cycloalkyl, f) a pharmaceutically acceptable cation; g) -CH(25)-CH2-R15, or h) -CH2-CH(R12)- R15; R11 is -R or -R2; R12 is -(CH2)n-R13; R13 is a) aryl, b) amino, c) mono-, mono- or tri-C1-C3 alkylamino, d) -Het, e) C1-C5 alkyl, f) C3-C7 cycloalkyl, g) C2-C5 alkenyl, h) C3-C7 cycloalkenyl, i) hydroxy; j) C1-C3 alkoxy, k) C1-C3 alkanoyloxy, I) Mercapto, m) C1-C3 alkylthio, n)-COOH, o) -CO-O-C1-C6 alkyl, P) -CO-O-CH2-(C1-C3 alkyl)-N(C1-C3 alkyl)2, q)-CO-NR22R20; r) C4-C7 cyclic amino, s) C4-C7 cycloalkylamino, t) guanidyl, u) cyano, v) N-cyanoguanidyl, w) cyanoamino, x) (hydroxyC2-C4 alkyl)amino, or y) Ru-(hydroxyC 2-C4 alkyl)amino; R14 is a) Hydrogen, b) C1-C10 alkyl, c)-(CH2)nR16, d)-(CH2)nR18, e) -CH(25)-CH2-R15, f)-(CH2)q-CH(R12)- R15; g) (Hydroxy C1-C8 alkyl), h) Hydroxy C1-C8 alkyl rukyaryl, or i) (C1-C3 alkoxy)C1C8 alkyl; R15 is a) hydroxy; b) C3-C7 cycloalkyl, c) aryl, d) amino; e) mono-, mono- or tri-C1-C3 alkylamino, f) mono- or -(hydroxyC2-C4 alkyl)amino, g)-Het, h) C1-C3 alkoxy, i) C1-C3 alkanoyloxy, j) Mercapto, k) C1-C3 alkylthio, l) C1-C5 alkyl, m) C4-C7 cyclic amino, n) C4-C7 cycloalkylamino, o) C1-C5 alkenyloxy, p) C3-C7 cycloalkenyl; R16 is a) aryl, b) amino; c) mono- or -(C1-C3 alkyl)amino, d) hydroxy, e) C3-C7 cycloalkyl, f) C4-C7 cyclic amino, or g) C1-C3 alkanoyloxy; R17 is a)-Het, b) C1-C5 alkenyl, c) C3-C7 cycloalkenyl, d) C1-C3 alkoxy, e) mercapto, f) C1-C3 alkylthio, g) -COOH, h) -CO-O-C1-C8 alkyl, i) -CO-O-CH2-(C1-C3 alkyl)-N(C1-C3 alkyl)2, j)-CO-NR22R26, k) tri-C1-C3 alkylamino, l) guanidyl, m) cyano, n) N-cyanoguanidyl, o) (hydroxy C2-C4 alkyl)amino, p) di-(hydroxy C2-C 4 alkyl) amino, or q) cyanoamino; R18 is a) amino, b) mono- or di-(C1-C3 alkyl)amino, c) C4-C7 cyclic a Mino, d) C4-C7 cycloalkylamino, or e) -CH(NH2)(CO2H); R18 is a) aryl, b)-Het, c) tri-C1-C3 alkylamino, d) C3-C7 cycloalkyl, e) C2-C5 alkenyl, f) C3-C7 cycloalkenyl, g) hydroxy; h) C1-C3 alkoxy, i) C1-C3 alkanoyloxy, j) Mercapto, k) C1-C3 alkylthio, l)-COOH, m) -CO-O-C1-C0 alkyl, n) -CO-O-CH2-(C1-C3 alkyl)-N(C1-C3 alkyl)2, o)-CO-NR22R26, P) guanidyl, q) Cyano, r) N-thia/guanidyl, s) cyanoamino, t) (hydroxyC2-C4 alkyl)amino, u) di-(hydroxyC2-C 4alkyl)amino; or v)-SO3H; R20 is a) Hydrogen, b) C1-C5 alkyl, or c) aryl-C1-C5 alkyl; R21 is a) -NH2, or b) -OH; R22 is a) hydrogen, or b) C1-C3 alkyl; R23 is a)-(CH2)n-OH, b)-(CH2)n-NH2, c) aryl, or d) C1-C3 alkyl; R24 is a)-R1, b)-(CH2)n-OH, or c)-(CH2)n-NH2: R25 is a)-(CH2)n-R13, b) hydrogen; c) C1-C3 alkyl, or d) phenyl-C1-C3 alkyl; R26 is a) Hydrogen, b) C1-C3 alkyl, or c) phenyl-C1-C3 alkyl; R27 is a) -COOH, b) -COOC1-C6 alkyl, c) -CONR22R26, or d) -CH(NH2)COOH; R120 is a) R120C[(CH2)qOR121]2(CH2)q-, b) ▲There are mathematical formulas, chemical formulas, tables, etc.;;masu▼(XXX)▲There are mathematical formulas, chemical formulas, tables, etc. ;;Masu▼(XXXI)d)-CH2(CHOR 121)xCH2OR121, e)R 121OCH2 (CHOR 121)yCH-(CHOR121 )zCH2OR121, f) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(XXXII) or g) R121OCH2-C(CH2OR121)2-; R121 is a) Hydrogen, b) C1-C8 alkyl, c) -(CH2)n-aryl, or d) -C(O)R123; R123 is a) C1-C5 alkyl, or b)-(CH2)n-phenyl; R126 is a) hydrogen, or b) (CH2)nOR121; R125 is a) hydrogen, or b) -(CHOR121)tCH2OR121; Q is a) CH2, b) CHOR121, or c) C(O); j is 1 to 3; m is 1 or 2; p is 0-2; r is 0 to 5; For each occurrence, n is independently an integer from 0 to 5; q is an integer from 1 to 5; u is an integer from 0 to 3; v is an integer from 0 to 4; s is 0 or 1 so that the sum of u+v+s is 3 or 4; t is 0 to 3 is an integer; w is an integer of 2 or 3; x is an integer from 2 to 7; y is an integer from 0 to 6; z is an integer from 0 to 6 so that the sum of y + z does not exceed 6; aryl is 0 to 3 The following: a) C1-C3 alkyl, b) hydroxy; c) C1-C3 alkoxy, d) halo, e) amino, f) mono- or -C1-C3 alkylamino, g) -CHO, h) -COOH, i) COOR26, j) CONHR26, k) Nitro; I) Mercapto, m) C1-C3 alkylthio, n) C1-C3 alkylsulfinyl, o) C1-C3 alkylsulfonyl, p)-N(R4)-C1-C3 alkylsulfinyl, q)-SO3H, r) SO2NH2, s)-CH, or t)-CH2NH2, -Het is phenyl or naphthyl substituted by nitrogen, oxygen, saturated or unsaturated containing 1 to 3 heteroatoms selected from the group consisting of a 5-membered ring or a 6-membered ring; in which any of the above heterocycles is a benzene ring; or fused to another heterocycle, and the ring is a carbon or a secondary nitrogen in the ring or contains bicyclic groups such as those attached via an exocyclic nitrogen; and chemically fused If possible, nitrogen and sulfur atoms may be in their oxidized form. and the ring optionally contains 0 to 3 of the following: a) C1-C5 alkyl; b) hydroxy; c) hydroxy (C1-C5 alkyl), d) halogen, e) amino, f) amino (C1-C5 alkyl), g) -CHO, h) -CO2H, i) -CO2-(C1-C5 alkyl), j) -CONH2, k) -CONH-(C1-C5 alkyl), I) nitro, m) mercapto, n) mercapto (C1-C5 alkyl), o) -SO3H, P)-SO2NH2, q)-CN, r)-O-C1-C5 alkyl, or s)-[O-(CH2)2]n-OCH 3, is replaced by; however, 1) G12 has both C6 and D6 and E10-F11 is greater than or equal to LPA. Exists if outside; 2) X is Z-C(O)-CH(OH)-CH(CH2R1)-C(O)- If D9 is His and G12 is IIe; 3) X is R5-CH2-O-C(O)- or R5-(CH2)n-C(O)- and E10-F11 is XL8, XL8b, XL8c or XL8d. , R5 is other than C1-C6 alkyl; 4) X is R5-O-C(O)-, and E10-F11 is XL6, XL6b , XL6c or XL6d, R5 is C1-C6 alkyl, C3-C7 other than cycloalkyl or aryl; 5) X is R5-(CH2)n-C(O)-[wherein R5 is cycloalkyl or aryl], and E10-F11 is XL6, XL6b, XL6c or If L6d, n is other than 1; 6) X is R4N(R4)-(CH2)n-C(O)-, and E10-F1 1 is XL6, XL6b, XL6c or XL6d, n is other than 1 ;7) Z is other than N-4-amino-2-methyl-5-pyrimidinylmethyl-amide And; 6) When E10-F11 is II or IV, X is benzyloxycarbonyl or or other than butyloxycarbonyl; 9) X is R5-(CH2)n-C(O )- and E10-F11 is II or IV, R5 is C1-C6 a use of compounds that are other than rukyls. 2. E10 to F11 are formulas XL6', XL6b', XL6c', XL6d', X L6a', II', III', or IV'; ▲There are mathematical formulas, chemical formulas, tables, etc.▼(XL6')▲There are mathematical formulas, chemical formulas, tables, etc. ▼ (XL6b') ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (XL6c') ▲ Mathematical formulas, There are chemical formulas, tables, etc.▼(XL6d')▲There are mathematical formulas, chemical formulas, tables, etc.▼( XL6e') ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II') ▲ Mathematical formulas, chemical formulas, tables, etc. There are ▼ (III') ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IV') Here In this case, the variables have the same meaning as in claim 1. 3. Use according to claim 1, wherein the cells are in humans. 4. A claim wherein a disease caused by said retrovirus is treated in said human. Use of Section 3. 5. Use according to claim 4, wherein C8, D9 and G12 are present. 6. The compound of formula I is 1H-i midazole-4-propanamide do, a-[[2-(acetyloxy)-3-(1-naphthalenyl)-1-oxo propyl]amino]-N-[1-(cyclohexylmethyl)-3,3-difluoro rho-4-[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl ]butyl]amino]-2,4-dioxobutyl]-, [1S-[1R*[aR *(R*)],2R*]-;L-histidineamide, N-[(1,1-dimethyl ethoxy)carbonyl]-L-phenylalanyl[1-(cyclohexylmethyl) methyl)-3,3-difluoro-4-[[2-methyl-1-[[(2-pyridinyl methyl)amino]carbonyl]butyl]amino]-2,4-dioxobutyl]- or Boc-Phe-His-LFA-IIe-AmP; and L-a-glutamine, N/u2/d-[N-[[1,1-dimethylethoxy)ka [rubonyl]-L-phenylalanyl]-N-[2-hydroxy-5-methyl-1 -(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinyl methyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-, [ IS-[1R*,2R*4R*(1R*,2R*)]]-, monoacetate (salt ) or BOC-Phe-Glu-LVA-11e-Amp. The use of claim 5. 7. Use according to claim 4, wherein C6 is absent, D8 is present and G12 is present. 8. The compound of formula I is 1H-imidazole-4-propanamide, N-[2-hydroxy-5-methyl -1-(2-methylpropyl)-4[[[2-methyl-1-[[(2-pyridiny methyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-a -[(phenoxyacetyl)-amino]-, [1S-[1R*, 2R*, 4R* (1R*.2R*)]-;POA-His-LVA-IIe-Amp; 1H-imidazole-4-propanamide, N-[1-(cyclohexylmethyl )-3,3-difluoro-4-[[2-methyl-1[[(2-pyridinylmethyl )amino]carbonyl]butyl]amino]-2,4-dioxobutyl]-a-[ [(1-naphthalenyloxy)acetyl]amino]-, [1S-(1R*(aR *), 2R*]]-; or NOA-His-LFA-IIe-Amp; 1H- Imidazole-4-propanamide, N-[1-(cyclohexylmethyl)-2 -Hydroxy-6-methyl-4-[[[2-methyl-1-[[(2-pyridinyl methyl)amino]carbonyl]butyl]amino]carbonyl]hebutyl]-a- [(phenoxyacetyl)amino]-, [1S[1R*(R*),2R*,4S *(1R*,2R*)]-;POA-His-CLA-IIe-Amp;1H -imidazole-4-propanamide, N-[2,3-dihydroxy-5-methy -1-(2-methylpropyl)-4-[[2-methyl-1-[[(2-pyrypropyl) [dinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl] -a-[(phenoxyacetyl)amino]-, [1S[1R*(R*),2S* , 3R*, 4S*(1R*, 2R*)]]-: or POA-His-LVD- IIe-AmP; 1-Noa-His-Cha PSI[CHOHCHOH]V al-IIe-Amp; or 1H-imidazole-4-propanamide, N- [1-(Cyclohexylmethyl)-2,3-dihydroxy-5-methyl-4-[ [[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butylene ][amino]carbonyl]hexyl]-a-[[(1-naphthalenyloxy) acetyl]amino]-, [1S[1R*(R*),2S*,3S*,4S*(1 R*, 2R*) ] -; or NOA-His-CVD-IIe-Amp: 1H -imidazole-4-propanamide, N-[2-hydroxy-6-methyl-1 -(2-Methylpropyl)-4[[[2-methyl-1[[(2-pyridinylmethyl )amino]carbonyl]butyl]amino]carbonyl]hexyl]-a-[( phenoxyacetyl)amino]-, [1S-[1R*(R*),2R*,4S* (1R*,2R*)]-; or POA-His-LLA-IIe-Amp: 1H-imidazole-4-propanamide, N-[2-hydroxy-1-(2- methylpropyl)-5[[2-methyl-1-[[(2-pyridinylmethyl)ami ]carbonyl]butyl]amino]-5-oxo-4-(phenylmethyl)pen thyl]-a-[(phenoxyacetyl)amino]-, [1S[1R*(R*), 2R*, 4S*, 5(1R*, 2R*)] -; or POA-His-LPA -IIe-Amp; 1H-imidazole-4-propanamide, N-[4-(Si Chlohexylmethyl)-2-hydroxy-1-(2-methylpropyl)-5-[ [2-Methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl ]Amino]-5-oxopentyl]-a-[(phenoxyacetyl)amino]- , [1S[1R*(R*),2R*,4S*,5(1R*,2R*)]]-; or POA-His-LCA-IIe-AmP:1H-imidazole-4-pro Panamide, N-[1-(cyclohexylmethyl)-2-hydroxy-5-methy Ru-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbo nyl]butyl]amino]carbonyl]hexyl]-a-[(phenoxyacetyl ) amino]-, [1S[1R*(R*),2R*,4R*(1R*,2R*)] -: or POA-His-CVA-IIe-Amp; 1H-imidazole-4 -propanamide, N-[1-(cyclohebutylmethyl)-2-hydroxy-5 -Methyl-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino] carbonyl]butyl]amino]carbonyl]hexyl]-a-[(phenoxia cetyl)amino]-, [1S[1R*(R*),2R*,4R*(1R*,2R *)]]-: or POA-His-chpVA-IIe-Amp:Na-[( 2S,4S,5S)-5-[Na-(phenoxymethylcarbonyl)-L-his [tidyl]amino-4-hydroxy-2-isopropyl-7-methyl-1-oxo octyl]-N-[2-(2-pyridinylamino)ethyl]-L-isoleucine Amide, acetate: or POA-His-LVA-IIe-NH(CH2)2N H-pyridine; Na-[(2S,4S,5S)-5-[N-[Na-(phenoxylene) dimethylcarbonyl)-L-histidyl]amino]-4-hydroxy-2-iso Propyl-7-methyl-1-oxooctyl]-N-[2,3-dihydroxypyl] or POA-His-LVA-IIe- NH-CH2-CH(OH)-CH2OH; Na-[(2S,4S,5S)-5 -[N-[Na-(phenoxymethylcarbonyl)-L-histidyl]-amino -4-hydroxy-2-isopropyl-7-methyl-1-oxooctyl]-N -(2-hydroxypropyl)-L-isoleucinamide: or POA-Hi s-LVA-IIe-NH-CH2-CH(CH3)(OH);Na-[(2S ,4S,5S)-5-[N-[Na-(1-naphthalenyloxyacetyl)-L -Histidyl]amino-6-cyclohexyl-4-hydroxy-2-isopropyl -1-oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucine amide, pyridine N-oxide or NOA-His-CVA-IIe-Amp -NO;Na-[(2S,4S,5S)-5-[Na-(f-toluenesulfony )-L-histidyl]amino]-6-cyclohexyl-4-hydroxy-2- isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L-i Soleucinamide or p-toluenesulfonyl-His-CVA-IIe-A mp; Na-[(2S,4S,5S)-5-[N-[Na-(1-naphthalenyl (oxyacetyl)-L-histidyl]amino]-6-cyclohexyl-4-hydro Roxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl )-L-isoleucinamide or NOA-His-CVA-IIe-Amp :Na-[(2S,4S,5S)-5-[N-[Na-(phenoxymethylcal (bonyl)-L-histidyl]amino]-6-cyclohexyl-4-hydroxy- 2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L -isoleucinamide, pyridine N-oxide or POA-His-CVA- IIe-Amp-NO: Na-[(2S,4S,5S)-5-[N-[Na-( p-Toluenesulfonyl)-L-histidyl]amino]-6-cyclohexyl- 4-Hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridi nylmethyl)-L-isoleucinamide, pyridine N-oxide or p-tolu Ensulfonyl-His-CVA-IIe-AmP-NO; Na-[(2S,4S,5S)-5-[N-[Na-(1-naphthalenyloxy acetyl)(2-pyridinyl)alanyl]amino]-6-cyclohexyl-4- Hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinyl methyl)-L-isoleucinamide or NOA-His-CVA-IIe-A mp; Na-[(2S,4S,5S)-5-[N-[Na-[(3-pyridinyl )-methylcarbonyl]-L-histidyl]amino]-6-cyclohexyl-4 -Hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridiny (3-methyl)-L-isoleucinamide or (3-pyridinyl)-methyl-cal Bonyl-His-CVA-IIe-AmP; Nε-[N2-[(2S,4S,5S)-5-[N-[Na-[(1-naphthalene Nyloxyacetyl)-L-histidyl]amino]-6-cyclohexyl-4- Hydroxy-2-isopropyl-1-oxohexyl]-L-isoleucyl]- L-lysine, trifluoroacetate or NOA-His-CVA-IIe-L- Lysine, trifluoroacetate: Na-[(2S,4S,5S)-5-[N-[Na-(1-naphthalenyloxy acetyl)-L-histidyl]amino]-6-cyclohexyl-4-hydroxy -2-isopropyl-1-oxohexyl]-N-[2-(2-pyridinylmethyl ) ethyl]-L-isoleucinamide or NOA-His-CVA-IIe -NH-(CH2)2-NH-(2-pyridine): 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]-a-[(phenoxyacetyl)amino]-, monoacetate (salt ) or POA-His-LVA-IIe-NH-CH2-CH(OH)-Fe 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, [1S[1R*( R*), 2R*, 4R* (1R*, 2R*)]]- or 1H-indole-2 -ylcarbonyl-Glu-CVA-IIe-Amp; L-a-glutamine, N -[1-(cyclohexylmethyl)-2-hydroxy-5-methyl-4-[[[ 2-Methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl] amino]carbonyl]hexyl]-N/2u/d-L-phenylalanyl-, [ 1S-[1R*,2R*,4R*(1R*,2R*)]]-, bis(trifluoro) (salt) or Phe-Glu-CVA-IIe-Amp; Lysine acetamide, N-[2[[2-hydroxy-5-methyl-1-(2-methyl methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)a [mino]carbonyl]butyl]amino]carbonyl]hexyl]amino]-1-( 1H-imidazol-4-ylmethyl)-2-oxoethyl][1S-[1R* (R*), 2R*, 4R* (1R*, 2R*)] - or (2-pyridyl)a Cetyl-His-Lva-IIe-Amp; 4-pyridineacetamide, N-[ 2[[2-Hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[ 2methyl-1[[(2-pyridinylmethyl)amino]carbonyl]butyl]ami ]carbonyl]hexyl]amino]-1-(1H-imidazol-4-ylme thyl)-2-oxoethyl]-[1S-[1R*(R*),2R*,4R*(1 R*,2R*)]-or (4-pyridyl)acetyl-His-LVA-IIe -Amp: 1H-indole-2-carboxamide, N-[2-([2-hydro Roxy-5-methyl-1-(2-methylpropyl)-4-[[2-methyl-1- [[(2-pyridinylmethyl)amino]carbonyl]butyl]carbonyl]hex syl]amino]-1-(1H-imidazol-4-ylmethyl)-2-oxoe Chill]-, [1S-[1R*(R*),2R*,4R*(1R*,2R*)]] - or N-(indolyl-2-carbonyl)-His-LVA-IIe-Am P; 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-pyridinyl methyl ester, [3S-[3 R*, 6R*, 7R*, 9R*, 12R*(R*)]]- or Ioc-His -LVA-IIe-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]-a-[(1-oxo-3-phenoxypropyl)a Mino]-, [1S[1R*(R*),2R*,4R*(1R*,2R*)]]- , or phenoxypropionyl-His-LVA-IIe-Amp; Midazole-4-propanamide, N-[2-hydroxy-5-methyl-1-( 2-methylpropyl)-4-[[(2-methyl-1-[[[(2-pyridinyl methyl)amino[carbonyl[butyl[amino[carbonyl[hexyl]-a-] [(1-oxo-3phenyl-2-propenyl)amino]-, [1S[1R*[ R*(E)], 2R*, 4R*(1R*, 2R*)]]- or phenyl-CH =CH-C(O)-His-LVA-IIe-Amp:1H-imidazole-4 -propanamide, N-[2-hydroxy-5-methyl-1-(2-methylpropanamide) Pyr)-4-[[[2-Methyl-1-[[[(2-pyridinylmethyl)amino[ carbonyl][butyl]amino[carbonyl[hexyl]-a-[(1-oxo -4-phenyl-3-butenyl)amino]-, [1S-[1R*[R*(E)] ,2R*,4R*(1R*,2R*)]]- or phenyl-CH=CH-CH 2-C(O)-His-LVA-IIe-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, [3 S[1(E), 3R*, 6R*, 7R*, 9R*, 12R*(R*)]] - also is phenyl-CH=CH-CH2-OC(O)-His-LVA-IIe-A mp:U-77407 1H-imidazole-4-propanamide, N-[2-hydroxy-5-methyl -1-(2-methylpropyl)-4[[[2-methyl-1-[[(2-pyridiny methyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-a -[[(2-phenylethenyl)sulfonyl]amino]-, [1S-[1R*[ R*(E)], 2R*, 4R*(1R*, 2R*)]]- or phenyl-(C H2)-SO2-His-LVA-IIe-AmLp; Hydroxyacetyl-L -Histidyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy -2R-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethyl Amide or (HO)Ac-His-CVA-IIe-Amp; Hydroxyacetate Tyl-L-histidyl-5S-amino-2R-benzyl-6-cyclohexyl- 3R,4R-dihydroxy-hexanoyl-L-isoleucyl-2-pyridylmeth Tyramide or (HO)Ac-His-CPD-IIe-Amp; Hydroxy Acetyl-L-histidyl-5S-amino-2R-benzyl-6-cyclohexy -3R,4R-dihydroxy-hexanoyl-L-isoleucyl-2-pyridi methylamide, N-oxide or (HO)Ac-His-CPD-IIe- Amp; Phenoxyacetyl-L-histidyl-5S-amino-2R-benzyl-6-cy Chlorhexyl-3R,4R-dihydroxy-hexanoyl-L-isoloinyl- 2-pyridylmethylamide or POA-His-CPD-IIe-Amp: Phenoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-3R ,4R-dihydroxy-2R-isopropyl-hexanoyl-L-isoleucyl -2-Pyridylmethylamide or POA-His-CVA-IIe-Amp: 1-Naphthoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl -3R,4R-dihydroxy-2R-isobutyl-hexanoyl-L-isoroy Cyl-2-pyridylmethylamide or NOA-His-CLD-IIe-Am p; 1-naphthoxyacetyl-L-histidyl-5S-amino-6-cyclohex sil-2R-cyclohexylmethyl-3R,4R-dihydroxy-hexanoyl -L-isoleucyl-2-pyridylmethylamide or NOA-His-CCD -IIe-Amp: 1-naphthoxyacetyl-L-histidyl-5S-amino-2R-benzyl-3 R,4R-dihydroxy-6-phenyl-hexanoyl-L-isoleucyl-2 -Pyridylmethylamide or NOA-His-PPD-IIe-Amp:1- naphthoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-3 R,4R-dihydroxy-2R-isopropyl-hexanoyl-L-isoleucy -2-pyridinyl aconoethylamide or NOA-His-CVD-II e-Apr; 1-Naphthoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl -2S-cyclohexylmethyl-3R,4R-dihydroxy-hexanoyl-L -isoleucyl-2-pyridylmethylamide or NOA-His-CCD-I Ie-AmP: 1-Naphthoxyacetyl-L-histidyl-5S-amino-3S-4S-dihyde Roxy-2S-isobutyl-7-methyl-octanoyl-L-isoleucyl-2 -Pyridylmethylamide or NOA-His-LID-IIe-Amp;1- naphthoxyacetyl-L-histidyl-5S-acono-3R-4R-dihydroxy C-2S-isobutyl-7-methyl-octanoyl-L-isoleucyl-2-pi Lysyl methylamide or NOA-His-LlD-IIe-Amp:1-naph Toxyacetyl-L-histidyl-5S-amino-3S-4R-dihydroxy- 2S-isobutyl-7-methyl-octanoyl-L-isoleucyl-2-pyridi 1-naphthomethylamide or NOA-His-LlD-IIe-Amp; Cyacetyl-L-histidyl-5S-amino-3R-4R-dihydroxy-2R -isobutyl-7-methyl-octanoyl-L-isoleucyl-2-pyridylme Tyramide or NOA-His-LlD-IIe-Amp; 2-quinolinylka rubonyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2 R-isopropyl-hexanoyl-L-isoleucyl-2-pyridinylamino- Ethylamide or Qc-Asn-CVD-IIe-Apr: quinolinyl-2- Carbonyl-L-histidyl-5S-amino-6-cyclohexyl-4S-hydro Roxy-2S-isopropyl-hexanoyl-L-isoleucyl-2-pyridyl Methylamide or QC-His-CVA-IIe-Amp; quinolinyl-2- Carbonyl-L-asparaginyl-5S-amino-6-cyclohexyl-4S- Hydroxy-2S-isopropyl-hexanoyl-L-isoleucyl-2-pyri Dylmethylamide or QC-Asn-CVA-IIe-Amp; 1-naphthalene Nyloxyacetyl-L-histidyl-5S-amine-6-cyclohexyl-4 S-Hydroxy-2S-isopropyl-hexanoyl-L-isoleucylamide or Noa-His-CVA-IIe-NH2:L-asparaginamide, 1 -(naphthoxy)acetyl-N-[2-hydroxy-5-methyl-1-(2-methyl tylpropyl)-4[[[2-methyl-1[[[2-(N-oxide)pyridiny] methyl]amino]carbonyl]butyl]amino]carbonyl]hexyl]-N -a-methyl-, [1S-[1R*,2R*. 4R*(1R*, 2R*)]]- or NOA-Asp-CVA-IIe-Amp; L-asparaginamide, [ 5-(triethylene glycol monomethyl ether) naphthoxy]acetyl-N -[2-Hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2 -Methyl-1-[[[2-(N-oxide)pyridinylmethyl]amino]carbo nyl]butyl]amino]carbonyl]hexyl]-N-a-methyl-, [1S- [1R*, 2R*, 4R* (1R*, 2R*)]]- or 5-(triethylene Glycol monomethyl ether-NOA-Asp-CVA-IIe-Amp; and L-asparaginamide, [4-(triethylene glycol monomethyl ether) naphthoxy]acetyl-N-[2-hydroxy-5-methyl-1-(2- methylpropyl)-4-[[[2-methyl-1-[[[2-(N-oxide)pi lysinylmethyl]amino]carbonyl]butyl]amino]carbonyl]hexyl ]-N-a-methyl-, [1S-[1R*,2R*,4R*(1R*,2R*) ]]- or 4-(triethylene glycol monomethyl ether)-NOA-A 8. The use of claim 7 selected from the group consisting of sp-CVA-IIe-Amp. 9. Use of claim 4 where C8 is absent, D9 is present and G12 is absent . 10. The compound of formula I is 1H-imidazole-4-propanamide, N-[2,3-dihydroxy-5- Methyl-4[[(2-methylbutyl)amino]carbonyl]-1-(2-methyl propyl)hexyl]-a-[(phenoxyacetyl)amino]-[1R-[1 R*(S*), 2S*, 3S*, 4S*, (S*)]]-; or POA-Hi s-LVDA-Mba;Nε-[(2S,4S,5S)-5-[N-[Na-( 1-Naphthalenyloxyacetyl)-L-histidyl]amino]-6-cyclohe xyl-4-hydroxy-2-isopropyl-1-oxohexyl]-L-lysi trifluoroacetate or NOA-His-CVA-L-lysine, trifluoroacetate or NOA-His-CVA-L-lysine, trifluoroacetate Oroacetate; N-[(2S,4S,5S)-5-[N-[Na-(1-naphthalene Nyloxyacetyl)-L-histidyl]amino]-6-cyclohexyl-4- Hydroxy-2-isopropyl-1-oxohexyl]-N-[2-(2-pyri dinylamino]ethyl]-amine or NOA-His-CVA-NH-(CH 2) 2-NH-(2-pyridine); N-[(2S,4S,5S)-5[N-[N a-(1-naphthalenyloxyacetyl)-L-histidyl]amino]-6-cy Chlohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N -[2-(2-pyridinylamino]ethyl]amine, pyridine N-oxide or is NOA-His-CVA-NH(CH2)2-NH-(2-pyridine); Pentanoic acid, 5-[[1-(cyclohexylmethyl)-2-hydroxy-4-[ [(2-hydroxypropyl)amino]carbonyl]-5-methylhexyl]a [mino]-5-oxo-4[(phenoxyacetyl)amino]- or POA-G lu-CVA-NH-CH2CH(CH3)(OH):1H-imidazole4- Propanamide, N-[1-(cyclohexylmethyl)-2-hydroxy-4[ [(2-hydroxypropyl)amino]carbonyl]-5-methylhexyl]a -[(phenoxyacetyl)amino]-, monoacetate (salt) or POA- His-CVA-NH-CH2-CH(OH)(CH3); N-tert-buty L-oxycarbonyl-L-phenylalanyl-L-histidyl-5S-amino- 3R,4R-dihydroxy-2R-isopropyl-7-methyl-octanoyl- 2S-Methylbutyramide or BOC-Phe-His-LVA-Mba; call POA-His-CVA-NH-(CH2)4-CH(CONH)(NH2); The use of claim 9 selected from the group consisting of. 11. Drugs that inhibit L-torovirus in human cells infected with L-torovirus L-isoleucinamide, N2-(5-amino-4-hydroxy-2-(1-methane) ethylethyl)-1-oxooctyl]-N-(2-pyridinylmethyl)-, trifluoroacetate, (S,S,S)-; or H-LVA-IIe-Amp; octanamide, 5-[(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-IIe-Amp; cyclohexanehexanamide, δ-[(3,3-dimethyl-1- oxobutyl)amino]-τ-hydroxy-a-(1-methylethyl)-N-[2-methyl-1[[(2-pyridinylmethyl)amino]carbonyl]butyl]-, [aS-[N(1R*, 2R*), aR*, τR*, δR*]- or TBA-CVA-IIe-Amp; cyclohexanehexanamide, δ-amino-τ-hydroxy-a-(1-methylethyl)-N-[[2 -Methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]-, dihydrochlora [aS-[N(1R*, 2R*), aR*, τR*, δR*]]- or H-CVA-IIe-Amp; cyclohexanehexanamide, δ-(acetylamino)-τ-hydroxy- a-(1-methylethyl)-N[2-methyl-1[[(pyridinylmethyl)amino]carbonyl]butyl], [aS-[H(1R*, 2R*), aR*, τR*, δR*] ]- or Ac-CVA-IIe-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-LYA-IIe- Amp : or IVA-LVA-IIe-Amp. Boc-Phe-His-Cha psi[CHOHCHOH]Va1-IIe -Amp; or L-histidineamide, N-[(1,1-dimethylethoxy) carbonyl]-L-phenylalanyl-N-[1-(cyclohexyl methyl)-2,3-dihydroxy-5-methyl-4-[[[2-methyl-1-[[(2-methyl lysinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl ]-, 1S-[1R*,2R*,3S*,4S*(1R*,2R*)]]-; or BOC-Phe-His-CVD-IIe-Amp; L-histidineamide, N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-[2-hydroxy-1-(2 -methylpropyl)-5[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino-5-o xo-4-(phenylmethyl)pentyl]-, [1S-[1R*,2R*,4S*,5(1R*,2R*)]]-; or Boc-Phe-His-LPA-I Ie-Amp :L-histidineamide, N-[(1,1-dimethylethoxy)ka [rubonyl]-L-feralanyl-N-[4-(cyclohexylmethyl)-2-hydroxy-1-(2-methylpropyl)-5-[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl ]butyl]amino]-5-oxopene or Boc-Phe-His-LCA-IIe-Amp; L-talonamide, 6-cyclohexyl- 2,5,6-trideoxy-5-[N-[N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-L-histidyl]amino]-2-(1-methylethyl) -N-[2-methyl-1-[[2-pyri dinylmethyl)amino]carbonyl]butyl]-, [S-(R*,R*)]-; or Boc-Phe-His-CVD'-IIe-Amp; Mido, N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalani Ru-N-[2,3-dihydroxy-5-methyl-1-(2-methylpropyl)-4-[[2-methyl-1[[(2-pyridinylmethyl)amino]carbonyl]butyl thyl]amino]carbonyl]hexyl]-, [1S[1R*,2S*,3R*, 4S*(1R*,2R*)]]-; or Boc-Phe-His-LVD'- IIe-Amp;L -Histidineamide, N-[[5-(dimethylamino)-1-naphthalenyl]sulfonyl]-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*)] ]-; or DANS-Phe-His-LVA-IIe-Amp; mido, L-phenylalanyl-N[2-hydroxy-5-methyl-1-(2-methyl tylpropyl)-4[[[2-methyl-1-[[(2-pyridinylmethyl)ami ]carbonyl]butyl]amino]carbonyl]hexyl]-, [1S-(lR*,2R*,4R*(1R*,2R*)]]- or H-Phe-His-LV A-IIe-AmP: L-Valinamide, L-phenylalanyl-N-[2-hypolyamide Droxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]car [1S-[1R*,2R*,4R*(1R*,2R*)]]-; or H-Phe-Val-LVA-IIe-Amp: L-valine amino L-valyl-N-[2-hydroxy-5-methyl-1-(2-methylpropylene) )-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]car [bonyl]butyl]amino]carbonyl]hexyl]-, [1S-[1R*,2R*,4R*(1R*,2R*)]]-, diacetate (salt): or H-Va1 -Va1-LVA- IIe-AmP: or L-valinamide, N-acetyl-L-valyl-N-[2-hydroxy-5-methane Thyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-methylpropyl) lysinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl ]-, [1S-[1R*,2R*,4R*(1R*,2R*)]-, monoacetate or Ac-Val-Val-LVA-IIe-AmP. Na-[(2S,4S,5S)-5-[[Na[(S)-1-acetoxy-1-benzyl)methylcarbonyl]-L-histidyl]amino]-4-hydroxy-7-methyl thyl-2-(1-methylethyl)-1-oxooctyl]-N-[2-pyridyl)ethyl]-L-isoleucinamide; or AcO-Phe-His-LVA-IIe-NH-(CH2)2- Pyridine. 4-morpholymptanamide, β-hydroxy-N-[2[[2-hydroxy-5-methyl-1-(2-methylpropylene) pyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]ka carbonyl]butyl]amino]carbonyl]hexyl]amino]-1-(1H-i midazol-4-ylmethyl)-2-oxoethyl]-a-(1-naphthalenyl methyl)-τ-oxo-, [1S-[1R*[R*(aS*, βR*)], 2R*, 4R*( 1R*,2R*)]-:1H-imidazole-4-propanamide de, a-[[[5-(dimethylamino)-1-naphthalenyl]sulfonyl]ami de]-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl ]-, [1S-[1R*(R*),2R*, 4R*(1R*,2R*)]]-; or DANS-His-LVA-IIe- Amp; octane amide , 5-[[2-(acetylamino)-3-methyl-1-oxobutyl]amino]-4-hydroxy-7-methyl-2-(1-methylethyl )-N-[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl ]-, [2S-[N(1R*,2R*),2R*,4R*,5R*( R*)]]-, diacetate (salt): or Ac-Val-LVA-IIe- A mP: Ac-Asn-LVA-IIe-AmP; Na-[(2S,4S,5S)-5-[[(S)-(1-hydroxy-1-benzyl)methylcarbonyl]ami ]-4-Hydroxy)-7-methyl-2-(1-methylethyl)-1-oxo-octyl]-N-(2-pyridylmethyl)-L-isoleucinamide or OH -Phe-LVA-IIe-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]-a-[(2-hydroxy-1-oxo-3-phenylpropyl)amino]-, [1S-[1R*[R*(R*)], 2R*, 4R*(1R*,2R*)]-,2-hydroxy-1,2,3-propanto recarboxylate (12) (salt) or phenyl-CH2-CH(OH)-C(O)-His-LVA-IIe-Amp; L-a-glutamine, N/u2/d-[N-[[1 ,1-dimethylethoxy)ka [[2-Methyl-1-[[(2-pyridinyl) methyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-, [1S-[1R*,2R*4R*(1R*,2R*)]]-, monoacetate (salt) or BOC-Phe-Glu- LVA-IIe-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]carbonyl]butyl]amino]carbonyl]hexyl]-, [1S- [1R*[R*(E)], 2R*,4R*(1R*,2R*)]- or BO C-2-Py-Ala-His-LVA-Ile-Amp; L-a-asparagi N/u2/d-[N-[[1,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-N-[2-hydroxy-5-methyl-1-(2-methylpropylene) ropyru)-4-[[2-methyl-1-[[(2-pyridinylmethyl)amino]ka [rubonyl]butyl]amino]carbonyl]hexyl]-, [1S-[1R*,2R*,14R*(1R*,2R*)]-, monoacetate (salt) or BOC-Phe-Asp-LVA-IIe -Amp:U-77808E L-a-glutamine, N-[1,1-dimethylethoxy)carbonyl]-L-ph Phenylalanyl-NO[1-(cyclohexylmethyl)-2-hydroxy-5-methyl-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]ka [rubonyl]butyl]amino]carbonyl]hexyl]]-, [1S-[1R*, 2R*, 4R* (1R*, 2R*)]-, monoacetate (salt) or BOC-Phe-Glu-CVA-IIe -Amp: L-histidineamide, N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-[3,3-difluoro-2-hydroxy-4-[[2-methyl-1 −[[(2-pyridiny methyl)amino]carbonyl]butyl]amino]-4-oxo-1-(phenylene (methyl)butyl]- or CH3-C(O)-O-CH(benzyl)-C(O)-His-LVA-IIe-Amp: L-glycyl-L-histidyl-5S-amino-6-cyclohexyl-3R , 4R-dihydroxy-2R-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or Gly-His-CVA-IIe-Amp: L-glycyl-L-histidyl-5S-amide Nor-4R-benzyl-6-cyclohexyl-3R,4R-dihydroxy-hexa Noyl-L-isoleucyl-2-pyridylmethylamide or Gly-His-CPD-IIe-Amp; 5-quinolinylhydroxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S-isopropyl- Hexanoyl-L-isoleucyl-2-pyridylmethylamide or Qoa(b)-His-CVA-IIe-Amp; Quinolinylhydroxyacetyl-L-histidyl-5S-amino-6-cyclohe xyl-4S-hydroxy-2S-isopropyl-hexanoyl-L-isoroy Cyl-2-pyridylmethylamide or Qoa(a)-His-CVA-IIe-Amp: N-tert-butyloxycarbonyl-L-alanyl-5S-amido No-6-cyclohexyl-4S-hydroxy-2S-isopropyl-hexanoyl L-L-isoleucyl-2-pyridylmethylamide or Boc-Ala-CV A-IIe-Amp: N-tert-butyloxycarbonyl-L-histidyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S-isopropyl -hexanoyl-L-isoleucyl-2-pyridylmethylamide or BOC-His-CVA-IIe-Amp; benzyloxycarbonyl-L-alanyl-L-alanyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S-isopropyl -hexanoyl-L-isoleucyl-2-pyridylmethylamide or CBZ-Ala-Ala-CVA-11e-Amp: L-histidineamide, 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-methylpropylene) [1S-(lR*,2R*.4R*)]- or BOS -Phe-His-LVA-(2,6-diamino-4-pyrimidinyl)amino- ethylamino: Gly-CVD- IIe-Amp: and Gly-CPD-IIe-Amp: Use of a compound selected from the group consisting of: 12. Cyclohexanehexanamide, δ-(acetylamino)-τ-hydroxy C-a-(1-methylethyl)-N-[2-methyl-1-[[(pyridinylmethythyl) [amino]carbonyl]butyl], [aS-[N(1R*,2R*),aR* , τR*, δR*] -: or Ac-CVA-IIe-AmP: octane amide 5-(acetylamino)-4-hydroxy-7-methyl-2-(1-methyl ethyl)-N-[2-methyl-1-[[(2-pyridinylmethyl)amino)car [bonyl]butyl]-, [2S-[N(1R*,2R*),2R*,4R*,5R *]]-, monoacetate (salt); or Ac-LVA-IIe-Amp; L- Valinamide, L-phenylalanyl-N-[2-hydroxy-5-methyl-1 -(2-methylpropyl)-4-[[[2-methyl-1[[(2-pyridinylmethyl thyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-, [1 S-[1R*, 2R*, 4R* (1R*, 2R*)]]-: or H-Phe- Val-LVA-IIe-Amp; octaneamide, 5-[[2-(acetyl acetate) (mino)-3-methyl-1-oxobutyl]amino]4-hydroxy-7-methyl -2-(1-methylethyl)-N-[2-methyl-1-[[(2-pyridinylmethyl) thyl)amino]carbonyl]butyl]-, [2S-[N(1R*,2R*),2 R*, 4R*, 5R*(R*)]]-, diacetate (salt); or Ac-Va l-LVA-IIe-Amp: L-valinamide, do, L-valyl-N-[2- Hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl -1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]ka rubonyl]hexyl]-, [1S-[1R*,2R*,4R*(1R*,2R* )]]-, diacetate (salt); or H-Val-Va1-LVA-IIe- Amp; Ac-Asn-LVA-IIe-Amp: L-valinamide, N-acetyl-L -Balyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)- 4-[[[2-methyl-1-[[(2-pyridinylmethyl)ami ]carbonyl]butyl]amino]carbonyl]hexyl]-, [1S-[1R *,2R*,4R*(1R*,2R*)]]-, monoacetate (salt); or Ac-Va1-Va1-LVA-IIe-Amp; or N-[(2S,4S, 5S)-5-[Na-[Na-(tert-butoxycarbonyl)-O-methyl -L-tyrosyl]-L-histidyl]amino-4-hydroxy-7-methyl-2 -phenylmethyl-1-oxooctyl]-N-[(S)-2-hydroxypro or Boc-OMeTyr-His-LPA-NH-CH2- A compound selected from the group consisting of CH(CH3)(OH). 13. Compounds of formula I X-C8-D9-E10-F11-G12-Z I [wherein, X is a) Hydrogen, b) naphthyloxyacetyl, c) t-butyloxycarbonyl, d) toluene-sulfonyl, e) phenyloxyacetyl, f) Pyridinyl-(CH2)n-carbonyl, g) Phenyl-(CH2)n-C H(OH)-C(O)-, h) indolycarbonyl, i) Pyridinyl-(CH2)n-O-C(O)-, j) Phenyl-(CH2)n -SO2-, k) Phenyl-O-(CH2)n-C(O)-, l) Phenyl-H C=CH-(CH2)n-C(O)-, m) phenyl-HC=CH-(CH2) n-O-C(O)-, n)HO-(CH2)n-C(O)-, o) quinolinoyl hydroxyacetyl, p) quinolinoylcarbonyl, q) benzyloxycarbonyl, or r) 5-(triethylene glycol mono methyl ether) naphthyloxyacetyl; C6 is a) does not exist; b) 2-py-Ala, c) -NH-CH2-C(O)-, d) Phe, or e) Ala; D8 is a) His, b) Glu, c) AsP, d) Asn; e) -NH-CH2-C(O), or f) is Ala; 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 l) LLD; G12 is a) does not exist; or b) IIe: 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 a or g)-NH-(CH2)n-NH-(2,6-diamino-4-pi rimidinyl); n is 0 to 5]. 14. Compound of claim 13 [In the formula, X is a) 1-naphthyloxyacetyl, b) p-toluene-sulfonyl, c) phenyloxyacetyl, or d) 3-pyridinyl-methylcarbonyl: Ca is not present; D9 is His: E10 to F11 are CVA; G12 is a) does not exist or b) IIe; Z is a) Amp, b) Amp-NO, c) L-lysine, or d) -NH-(CH2)2-NH-2-pyridine]. 15. Na-[(2S,4S.5S)-5-[N-[Na-(1-naphthalenyl (oxyacetyl)-L-histidyl]amino]-6-cyclohexyl-4-hydro Roxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl )-L-isoleucinamide, pyridine N-oxide or NOA-His- CVA-IIe-Amp-NO; Na-[(2S,4S,5S)-5-[N-[ Na-(f-toluenesulfonyl)-L-histidyl]amino]-6-cyclohe xyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2 -pyridinylmethyl)-L-isoleucinamide or p-toluenesulfonyl -His-CVA-IIe-Amp:Na-[(2S,4S,5S)-5-[N -[Na-(1-naphthalenyloxyacetyl)-L-histidyl]amino]- 6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl ]-N-(2-pyridinylmethyl)-L-isoleucinamide or HOA-H is-CVA-IIe-Amp:Na-[(2S,4S,5S)-5-[N-[ Ha-(phenoxymethylcarbonyl)-L-histidyl]amino]-6-cyc lohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N- (2-pyridinylmethyl)-L-isoleucinamide, pyridine N-oxide or POA-His-CVA-IIe-Amp-NO;Na-[(2S,4S, 5S)-5-[N-[Na-(P-toluenesulfonyl)-L-histidyl]a [mino]6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohe xyl]-N-(2-pyridinylmethyl)-L-isoleucinamide, pyridine N-oxide or p-toluenesulfonyl-His-CVA-IIe-Amp -NO: Nε-[(2S,4S,5S)-5-[N-[Na-(1-naphthalenyloxy acetyl)-L-histidyl]amino]-6-cyclohexyl-4-hydroxy -2-isopropyl-1-oxohexyl]-L-lysine, trifluoroacetate or NOA-His-CVA-L-lysine, trifluoroacetate:N-[(2 S,4S,5S)-5-[N-[Na-(1-naphthalenyloxyacetyl)- L-Histidyl]amino]-6-cyclohexyl-4-hydroxy-2-isopropylene Lopyl-1-oxohexyl]-N-[2-(2-pyridinylamino]ethyl] -amine or NOA-HiS-CVA-NH-(CH2)2-NH-(2-pi lysine):N-[(2S,4S,5S)-5-[N-[Na-(1-naphthalene hydroxyacetyl)-L-histidyl]amino]-6-cyclohexyl-4-h Droxy-2-isopropyl-1-oxohexyl]-N-[2(2-pyridiny) Ruamino]ethyl]-amine, pyridine N-oxide or NOA-His-C VA-NH(CH2)2-NH-(2-pyridine); Na-[(2S,4S,5S)-5-[N-[Na-(1-naphthalenyloxy acetyl)(2-pyridinyl)alanyl]amino]-6-cyclohexyl-4- Hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinyl amino)-L-isoleucinamide or NOA-His-CYA-IIe-A mp; Na-[(2S,4S,5S)-5-[N-[Na-[(3-pyridinyl )-methylcarbonyl]-L-histidyl]amino]-6-cyclohexyl-4 -Hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridiny (3-methyl)-L-isoleucinamide or (3-pyridinyl)-methyl-cal Bonyl-His-CVA-IIe-Amp; Nε-[N2-[(2S,4S,5S)-5-[N-[Na-(1-naphthalene hydroxyacetyl)-L-histidyl]amino]-6-cyclohexyl-4-h Droxy-2-isopropyl-1-oxohexyl]-L-isoleucyl]-L - Lysine, trifluoroacetate or NOA-His-CVA-IIe-L-lysine Gin, trifluoroacetate: Na-[(2S,4S,5S)-5-[N-[Na-(1-naphthalenyloxy acetyl)-L-histidyl]amino]-6-cyclohexyl-4-hydroxy -2-isopropyl-1-oxohexyl]-N-[2-(2-pyridinylamine) [ethyl]-L-isoleucinamide or NOA-His-CVA-IIe -NH-(CH2)2-NH-(2-pyridine) Compound of Item 14. 16. Compound of claim 13 [In the formula, x is a) Phenyl-CH2-CH(OH)-C(O)-, b) Phenyloxyacetyl le, 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) Phyl phenyl-HC=CH-(CH2)n-O-C(O)-, or k) phenyl-( CH2)2-SO2-; C6 is a) does not exist; b) 2-Py-Ala, or c) Phe; D8 is a) His, b) Glu, or c) is an ASP; E10-F11 is a) LVA, or b) CVA; G12 is a) does not exist, or b) IIe; Z is a) Amp, b) -NH-CH2-CH(OH)-phenyl, f) -NH-CH2-CH(O H)-CH3, or g)-NH-(CH2)2NH-(2,6-diamino-4 -pyrimidinyl)]. 17.1H-imidazole-4-propanamide, N-[2-hydroxy-5- Methyl-1-(2-methylpropyl)-4[[[2-methyl-1[[(2-pyri [dinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl] -a-[(2-hydroxy-1-oxy-3-phenylpropyl)amino]-, [1S-[1R*[R*(R*)], 2R*, 4R*(1R*, 2R*)]]- , 2-hydroxy-1,2,3-propanetricarboxylate (12) (salt) or phenyl-CH2-CH(OH)-C(O)-His-LVA-IIe- 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]-a-[(phenoxyacetyl)amino]-, monoacetate (salt ) or POA-His-LVA-IIe-NH-CH2-CH(OH)-Fe Nyl; L-a-glutamine, N/u2/d-[N-[[1,1-dimethylethoxy c) carbonyl]-L-phenylalanyl]-N-[2-hydroxy-5-methy -1-(2-methylpropyl)-4-[[2-methyl-1-[[(2-pyrypropyl) [dinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl] -, [1S-[1R*,2R*4R*(1R*,2R*)]]-, monoacetate (salt) or BOC-Phe-Glu-LVA-IIe-Amp; pentanoic acid , 5-[[1-(cyclohexylmethyl)-2-hydroxy-4-[[(2-hydroxy droxypropyl)amino]carbonyl]-5-methylhexyl]amino]-5 -oxo-4-[(phenoxyacetyl)amino]- or POA-Glu-C VA-NH-CH2CH(CH3)(OH); 1H-imidazole-4-propyl amide, N-[1-(cyclohexylmethyl)-2-hydroxy-4-[[( 2-hydroxypropyl)amino]carbonyl]-5-methylhexyl]a-[ (phenoxyacetyl)amino]-, monoacetate (salt) or POA-Hi s-CVA-NH-CH2-CH(OH)(CH3); Pentanoic acid, 5-[[1 -(cyclohexylmethyl)-2-hydroxy-5-methyl-4-[[[2-methyl Thyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino ]carbonyl]hexyl]amino]-4-[(1H-indol-2-ylcar (bonyl)amino]-5-oxo, [1S-[1R*(R*),2R*,4R*( 1R*, 2R*)]- or 1H-indol-2-yl-carbonyl-Gl u-CVA-IIe-Amp; L-a-glutamine, N-[1-(cyclohexylmethyl)-2-hydroxy- 5-Methyl-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino ]carbonyl]butyl]amino]carbonyl]hexyl]-N/u2/d-L- Phenylalanyl-, [1S-[1R*,2R*,4R*(1R*,2R*)] ]-, bis(trifluoroacetate) (salt) or Phe-Glu-CVA- IIe-Amp: 2-pyridineacetamide, N-[2[[2-hydroxy-5 -Methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2 -pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hex syl]amino]-1-(1H-imidazol-4-ylmethyl)-2-oxoe Chill] - [1S[1R*(R*), 2R*, 4R*(1R*, 2R*)]] - or (2-pyridyl)acetyl-His-LVA-IIe-Amp; 4-pyridyl acetamide, N-[2-[[2-hydroxy-5-methyl-1-(2-methyl lupropyl)-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 L-His-LVA-IIe-Amp; L-histidine amide, N-[(1,1 -dimethylethoxy)carbonyl]-3-(2-pyridinyl)alanyl-N-[ 2-Hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl Thyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino ]carbonyl]hexyl]-, [1S-[1R*[R*(E)]'2R*,4R *(1R*,2R*)]- or BOC-2-Py-AIa-His-LVA -IIe-Amp: L-histidineamide, N-[(1,1-dimethylethoxy )carbonyl]-L-phenylalanyl-N-[4-[[[2-[(2,6-di Amino-4-pyrimidinyl)amino]ethyl]amino]carbonyl]-2-hydro Roxy-5-methyl-1-(2-methylpropyl)hexyl]-, [1S-(1 R*, 2R*, 4R*)]- or BOC-Phe-His-LVA-(2,6 -diamino-4-pyrimidinyl)amino-ethylamino; L-a-asparagine , N/u2/d-[N-[(1,1-dimethylethoxy)carbonyl]-L-ph phenylalanyl]-N-[2-hydroxy-5-methyl-1-(2-methylpropylene) pyl)-4-[[2-methyl-1-[[(2-pyridinylmethyl)amino]car [bonyl]butyl]amino]carbonyl]hexyl]-, [1S-[1R*,2R *,4R*(1R*,2R*)]]-, monoacetate (salt) or BOC-P he-Asp-LVA-IIe-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*(R*), 2R*, 4R*(1R*, 2R*)]]-;-(I ndyl-2-carbonyl)-His-LVA-IIe-Amp: L-a-glutamine, N-[1,1-dimethylethoxy)carbonyl]-L-ph phenylalanyl]-NO[1-(cyclohexylmethyl)-2-hydroxy-5 -Methyl-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino] carbonyl]butyl]amino]carbonyl]hexyl]]-, [1S-[1R* ,2R*,4R*(1R*,2R*)]]-, monoacetate (salt) or BO C-Phe-Glu-CVA-IIe-Amp: 2,5,11,14-tetraa Zapentadecanoic 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-pyridinyl methyl 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-pyridi nylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]- a-[(1-oxo-3-phenoxypropyl)amino]-, [1S-[1R* (R*), 2R*, 4R* (1R*, 2R*)]]-, or phenoxypropyl Onyl-His-LVA-IIe-Amp; 1H-imidazole-4-propane Amide, N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4 -[[[2-methyl-1-[[[(2-pyridinylmethyl)amino[carbonyl [Butyl[amino[carbonyl[hexyl]-a-[(1-oxo-3phenyl] -2-propenyl)amino]-, [1S-[1R*[R*(E)], 2R*. 4 R*(1R*,2R*)]]- or phenyl-CH=CH-C(O)-His -LVA-IIe-Amp: IH-imidazole-4-propanamide, N-[ 2-Hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl Chyl-1-[[[(2-pyridinylmethyl)amino[carbonyl][butyl]a mino[carbonyl[hexyl]-a-[(1-oxo-4-phenyl-3-butene amino]-, [1S-[1R*[R*(E)], 2R*, 4R*(1R* ,2R*)]]- or phenyl-CH=CH-CH2-C(O)-His-L VA-IIe-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, [3 S-[1(E), 3R*, 6R*, 7R*, 9R*, 12R*(R*)]]- or phenyl-CH=CH-CH2-OC(O)-His-LVA-IIe- Amp; and 1H-imidazole-4-propanamide, N-[2-hydroxy-5-methyl -1-(2-methylpropyl)-4-[[2-methyl-1-[[(2-pyridi nylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]- a-[[(2-phenylethenyl)sulfonyl]amino]-, [1S-[1R* [R*(E)], 2R*, 4R*(1R*, 2R*)]]- or phenyl-( CH2)2-SO2-His-LVA-IIe-Amp; 17. The compound of claim 16. 18. Compound of claim 13 [In the formula, X is a) t-butyloxycarbonyl, b) (OH)acetyl, c) hydrogen; d) phenyloxyacetyl, e) 1-naphthyloxyacetyl, f) 5-quinolinylhydroxyacetyl, g) 4-quinolinylhydroxyacetyl or h) 2-quinolinylcarbonyl; Ca is a) does not exist; b) Phe, or c) -NH-CH2C(O)-; D9 is a) His, b) Asn, or c) -NH-CH2C(O); 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; G12 is a) does not exist, or b) IIe; Z is a) Mba, b) Amp, c) Amp-NO, or d) April]. 19. N-tert-butyloxycarbonyl-L-phenylalanyl-L-hyperoxycarbonyl Stidyl-5S-amino-3R,4R-dihydroxy-2R-isopropyl-7 -Methyl-octanoyl-2S-methylbutyramide or BOC-Phe-H is-LVA-Mba: Hydroxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-3 R,4R-dihydroxy-2R-isopropyl-hexanoyl-L-isoleucy -2-pyridylmethylamide or (HO)Ac-His-CVA-IIe- Amp: L-glycyl-L-histidyl-5S-amino-6-cyclohexyl- 3R,4R-dihydroxy-2R-isopropyl-hexanoyl-L-isoroy Syl-2-pyridylmethylamide or Gly-His-CVA-IIe-Am p: hydroxyacetyl-L-histidyl-5S-amino-2R-benzyl-6 -cyclohexyl-3R,4R-dihydroxy-hexanoyl-L-isoleucy -2-pyridylmethylamide or (H0)Ac-His-CPD-IIe- Amp: hydroxyacetyl-L-histidyl-5S-amino-2R-benzyl -6-Cyclohexyl-3R,4R-dihydroxy-hexanoyl-L-isolo isyl-2-pyridylmethylamide, N-oxide or (HO)Ac-His -CPD-IIe-Amp; Phenoxyacetyl-L-histidyl-5S-amino-2R-benzyl-6-cy Clohexyl-3R,4R-dihydroxy-hexanoyl-L-isoleucyl- 2-Pyridylmethylamide or POA-His-CPD-IIe-Amp:L -Glycyl-L-histidyl-5S-amino-2R-benzyl-6-cyclohexyl Cyl-3R,4R-dihydroxy-hexanoyl-L-isoleucyl-2-pyri Dylmethylamide or G1y-His-CPD-IIe-Amp; phenoxy Acetyl-L-histidyl-5S-amino-6-cyclohexyl-3R,4R- Dihydroxy-2R-isopropyl-hexanoyl-L-isoleucyl-2-p Lysyl methylamide or POA-His-CVA-IIe-Amp; 1-naph Toxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-3R, 4R-dihydroxy-2R-isobutyl-hexanoyl-L-isoleucyl-2 -Pyridylmethylamide or NOA-His-CLD-IIe-Amp:1- naphthoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-2 R-cyclohexylmethyl-3R,4R-dihydroxy-hexanoyl-L-y Soleucyl-2-pyridylmethylamide or NOA-His-CCD-IIe -Amp; 1-naphthoxyacetyl-L-histidyl-5S-amino-2R-benzyl-3 R,4R-dihydroxy-6-phenyl-hexanoyl-L-isoleucyl-2 -Pyridylmethylamide or NOA-His-PPD-IIe-Amp;1- naphthoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-3 R,4R-dihydroxy-2R-isopropyl-hexanoyl-L-isoleucy -2-pyridinylamino-ethylamide or NOA-His-CVD-II e-Apr; 1-Naphthoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl -2S-cyclohexylmethyl-3R,4R-dihydroxy-hexanoyl-L -isoleucyl-2-pyridylmethylamide or NOA-His-CcD-I Ie-Amp: 1-Naphthoxyacetyl-L-histidyl-5S-amino-3S-4S-dihyde Roxy-2S-isobutyl-7-methyl-octanoyl-L-isoleucyl-2 -Pyridylmethylamide or NOA-His-Lld-IIe-Amp;5- Quinolinylhydroxyacetyl-L-histidyl-5S-amino-6-cyclohe xyl-4S-hydroxy-2S-isopropyl-hexanoyl-L-isoroy Syl-2-pyridylmethylamide or Qoa(b)-His-CVA-IIe -Amp: 4-quinolinylhydroxyacetyl-L-histidyl-5S-amino-6-cyc lohexyl-4S-hydroxy-2S-isopropyl-hexanoyl-L-yne Leucyl-2-pyridylmethylamide or Qoa(a)-His-CVA-I Ie-Amp: 1-Naphthoxyacetyl-L-histidyl-5S-amino-3R-4R-dihyde Roxy-2S-isobutyl-7-methyl-octanoyl-L-isoleucyl-2 -Pyridylmethylamide or NOA-His-LLd-IIe-Amp:1- naphthoxyacetyl-L-histidyl-5S-amino-3S-4R-dihydroxy C-2S-isobutyl-7-methyl-octanoyl-L-isoleucyl-2-pi Lysyl methylamide or NOA-His-LLd-IIe-Amp; 1-naph Toxyacetyl-L-histidyl-5S-amino-3R-4R-dihydroxy- 2R-isobutyl-7-methyl-octanoyl-L-isoleucyl-2-pyridi methylamide or NOA-His-LLD-IIe-Amp; 2-quinolinyl carbonyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy -2R-isopropyl-hexanoyl-L-isoleucyl-2-pyridinylamine No-ethylamide or Qc-Asn-CVD-IIe-Apr: L-glycyl -5S-acono-6-cyclohexyl-3R,4R-dihydroxy-2R-iso Propyl-hexyl-L-isoleucyl-2-pyridylmethylamide- or G ly-CVL-IIe-Amp; L-glycyl-5S-amino-2R-benzyl -6-Cyclohexyl-3R,4R-dihydroxy-hexanoyl-L-isolo Isyl-2-pyridyl-methylamide or Gly-CPD-IIe-Amp 19. The compound of claim 18 selected from the group consisting of. 20. Compound of claim 13 [In the formula, X is a) t-butyloxycarbonyl, b) 2-quinolinylcarbonyl, c) benzyloxycarbonyl, d) 1-naphthyloxyacetyl, or e) phenyloxyacetyl; C■ is a) does not exist, or b) AIa; D9 is a) Ala, b) His, or c) Asn; E10-F11 is CVa, G12 is a) does not exist, or b) IIe; Z is a) Amp, b) -NH2, or c) -NH-(CH2)4-CH(CONH)(NH2)]. 21. N-tert-butyloxycarbonyl-L-alanyl-5S-amino- 6-Cyclohexyl-4S-hydroxy-2S-isopropyl-hexanoyl- L-isoleucyl-2-pyridylmethylamide or Boc-Ala-CVA- IIe-Amp: N-tert-butyloxycarbonyl-L-histidyl-5S-amino-6- Cyclohexyl-4S-hydroxy-2S-isopropyl-hexanoyl-L- isoleucyl-2-pyridylmethylamide or BOC-His-CVA-II e-Amp; quinolinyl-2-carbonyl-L-histidyl-5S-amino-6 -cyclohexyl-4S-hydroxy-2S-isopropyl-hexanoyl-L -isoleucyl-2-pyridylmethylamide or QC-His-CVA-II e-Amp; quinolinyl-2-carbonyl-L-asparaginyl-5S-amino -6-cyclohexyl-4S-hydroxy-2S-isopropyl-hexanoyl -L-isoleucyl-2-pyridylmethylamide or QC-Asn-CVA- IIe-Amp; Benzyloxycarbonyl-L-alanyl-L-alanyl-5 S-amino-6-cyclohexyl-4S-hydroxy-2S-isopropyl-hexyl xanoyl-L-isoleucyl-2-pyridylmethylamide or CBZ-Al a-A1a-CVA-IIe-Amp; 1-naphthalenoyloxyacetyl-L-histidyl-5S-amine-6-cyc lohexyl-4S-hydroxy-2S-isopropyl-hexanoyl-L-iso Leucylamide or Noa-His-CVA-IIe-NH2; and POA -His-CVA-NH-(CH2)4-CH(CONH)(NH2) 21. The compound of claim 20 selected from the group. 22. Compound of claim 13 [In the formula, x is a) 1-naphthyloxyacetyl, or b) 5-(triethylene glycol molybdenum) (methyl ether) naphthoxyacetyl; C6 does not exist, D8 is Asp; E10-F11 is CVA; G12 is IIe; Z is Amp]. 23. L-asparaginamide, 1-(naphthoxy)acetyl-N-[2-hydro Roxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1 -[[[2-(N-oxide)pyridinylmethyl]amino]carbonyl]butyl ]amino]carbonyl]hexyl]-N-a-methyl-, [1S-[1R*,2 R*,4R*(1R*,2R*)]- or NOA-Asp-CVA-IIe -Amp; L-asparaginamide, [5-(triethylene glycol monomethylene) ether)naphthoxy]acetyl-N-[2-hydroxy-5-methyl-1- (2-methylpropyl)-4-[[[2-methyl-1-[[[2-(N-oxy pyridinylmethyl]amino]carbonyl]butyl]amino]carbonyl]he xyl]-N-a-methyl-, [1S-[1R*,2R*,4R*(1R*,2 R*)]]- or 5-(triethylene glycol monomethyl ether-NOA -Asp-CVA-IIe-Amp; and L-asparaginamide, [4-( triethylene glycol monomethyl ether)naphthoxy]acetyl-N-[2 -Hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl Ru-L-[[[2-(N-oxide)pyridinylmethyl]amino]carbonyl] butyl]amino]carbonyl]hexyl]N-a-methyl-, [1S-[1R* ,2R*,4R*(1R*,2R*)]- or 4-(triethylene glycol (monomethyl ether)-NOA-Asp-CVA-IIe-Amp 23. The compound of claim 22 selected from.