IE922316A1 - Retroviral protease inhibitors - Google Patents
Retroviral protease inhibitorsInfo
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- IE922316A1 IE922316A1 IE231692A IE922316A IE922316A1 IE 922316 A1 IE922316 A1 IE 922316A1 IE 231692 A IE231692 A IE 231692A IE 922316 A IE922316 A IE 922316A IE 922316 A1 IE922316 A1 IE 922316A1
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- amino
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- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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- A61P31/12—Antivirals
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- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/68—Halogen atoms
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- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D—HETEROCYCLIC COMPOUNDS
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- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/91—Nitro radicals
- C07D233/92—Nitro radicals attached in position 4 or 5
- C07D233/95—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by nitrogen atoms, attached to other ring members
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- C07—ORGANIC CHEMISTRY
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- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/28—Radicals substituted by nitrogen atoms
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The present invention provides compounds, more particularly dipeptide analogs, which bind to retroviral proteases. These compounds are inhibitors of retroviral proteases and are useful for treating diseases related to infection by retroviruses.
Description
The present invention relates to retroviral protease inhibitor compounds, pharmaceutical compositions thereof, and a method of treating retroviral diseases therewith, including a method of treating disease states associated with human immunodeficiency virus (HIV-1, HIV-2).
Retroviruses, that is, viruses within the family of Retroviridae, are a class of viruses which transport their genetic material as ribonucleic acid rather than deoxyribonucleic acid. Also known as RNA-tumor viruses, their presence has been associated with a wide range of diseases in humans and animals. They are believed to be the causative agents in pathological states associated with infection by Rous sarcoma virus (RSV), murine leukemia virus (MLV), mouse mammary tumor virus (MMTV), feline leukemia virus (FeLV), bovine leukemia virus (BLV), Mason-Pfizer monkey virus (MPMV), simian sarcoma virus (SSV), simian acquired immunodeficiency syndrome (SAIDS), human TIE 922316 - 2 lymphotropic virus (HTLV-I, -II) and human immunodeficiency virus (HIV-1, HIV-2), which is the etiologic agent of AIDS (acquired immunodeficiency syndrome)and AIDS related complexes, and many others. Although the pathogens have, in many of these cases, been isolated, no effective method for treating this type of infection has been developed.
Retroviral replication occurs only in host cells. Critical to this replication is the production of functional viral proteins. Protein synthesis is accomplished by translation of the appropriate open reading frames into polyprotein constructs, which are processed, at least in part, by a viral protease into the functional proteins. The proteolytic activity provided by the viral protease in processing the polyproteins cannot be provided by the host and is essential to the life cycle of the retrovirus. In fact, it has been demonstrated that retroviruses which lack the protease or contain a mutated form of it, lack infectivity. See Katoh et al., Virology, 145, 280-92(1985), Crawford, et al., J. Virol., 53, 899-907(1985) and Debouk, et al., Proc. Natl. Acad. Sci. USA, 84, 8903-6(1987).
Inhibition of retroviral protease, therefore, presents a method of therapy for retroviral disease.
The use of isosteric replacements has been disclosed as a strategy for the development of protease inhibitors for HIV-1. European Patent Applications EP-A 337 714, EP-A 357 332, EP-A 346 847, EP-A 342 541, EP-A 352 000, EP-A 393 445 and EP-A 434 365 are representative, and are incorporated herein by reference. These references disclose dipeptide analogs of the natural polyprotein substrates of retroviral proteases. As discussed therein, these dipeptide analogs bind selectively and competitively to retroviral proteases; however, the protease is unable to cleave the carbon-carbon bond presented to it instead of the scissile amide bond of the natural substrate. Thus, such compounds are useful for inhibiting viral replication by inactivation of the protease. The incorporation of heterocyclic elements in the P3' and P4' substrate positions of compounds containing a dipeptide isostere has been disclosed by deSolms et al., J. Med. Chem., - 3 34, 2852 (1991). However, these compounds can be less than desirable for obtaining optimal drug delivery in mammalian organisms, particularly in humans. Some of these compounds can also have a less than desirable serum half-life, and therefore duration of action, because they contain amide bonds in relatively high proportion, and thus are prone to metabolic degradation, hepatic clearance, or other elimination mechanisms.
There exists a need for novel compounds which inhibit 10 retroviral protease activity, and a need for compounds which possess desirable pharmacokinetic properties for good drug delivery and metabolic stability for good serum half-life and duration of action. Such pharmaceutical uses provide therapies for retroviral diseases in mammals, especially in humans, which have been heretofore difficult to treat.
SUMMARY OF THE INVENTION The present invention provides compounds, hereinafter 20 represented as formula (I), which bind to retroviral proteases. These compounds are inhibitors of retroviral proteases and are useful for treating diseases related to infection by retroviruses.
The present invention also provides a pharmaceutical 25 composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.
The present invention additionally provides a method for treating retroviral disease, comprising administering to a mammal in need thereof an effective amount of a compound of formula (I).
DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention are illustrated 35 by formula (I): - 4 R1 R2r5A/y«‘ OH R3 (I) wherein: R1 and R3 are each independently Q, Q-Ci_6alkyl, Q-C2-6alkenyl, Q-C2-6Slkynyl or Cj^.galkyl substituted by one to five fluorine atoms, each optionally substituted by R23; Q is H, C3_6cycloalkyl, C5_gcycloalkenyl, Ar or Het R2 is H or OH; R4 isr6_nrH_ or CONR11CHR6R7; R5 is r6-nrH- or R1o-NRH-; R6 isx .R8 - X is NR11, 0 or S; R7 is H, C1_6alkyl, Ar-C^galkyl, Het-C^.galkyl, C2_galkenyl, Ar-C2_galkenyl, Het-C2_galkenyl, C3_gcycloalkyl15 Ci-6alkyl or C3_gcycloalkenyl-C1_galkyl ; R8 and R9 are each independently H, OH, halo, N02, CORl2, CF3, Ar, C^galkyl-Rl5, or Ri7 (r1®r19C)m, or together form a fused C2-4alkylene, aryl or heteroaryl moiety; RlO is A-(B)n-; rH is H or Ci_4alkyl; Rl2 is R7, OR7, NR7rH or an amino acid or amino alcohol; B is an amino acid; A is H, Ar, Het, R17(R18Rl9C)m, Ar-W, Het-W or Ri7 (R18Ri9c)m-W, or phthaloyl each optionally substituted by one to three groups chosen from Ri5 or Ci-6alkyl-R15; W is C=O, OC(=O), NRllC(=O), SC(=O), NRHC(=S), S02, NRHSO2 or P(=0) (OR22); RI5 is H, nitro, Ci-6alkoxy, C1_galkylthio, 0(0=0)R16, C=OR22, CO2R22, CON(Rl6)2, N(R22)2, NHC(=N)NH-A, I, Br, Cl, F or OH, provided that when Ri5 is a substituent of the carbon adjacent to W, R15 is not halogen or OH when W is OC(=O) or NHCO; R16 is H or Ci-6alkyl; - 5 R17, R18 and R19 are independently: i) H, R15 or Ci-4alkyl, C2-6alkenyl, phenyl, naphthyl, C3-6cycloalkyl or Het, each optionally substituted by one to three R15 or R18-Ci_galkyl groups, or ii) R17 is as above and (R18R19C) are joined together to form a phenyl, naphthyl, C3-6cycloalkyl or Het ring, or iii) R17 is as above and R18 and R19 together are =0; R22 is H, Ci_galkyl, phenyl or phenyl-Ci-4alkyl; R23 is -X'-(CH2)qNR24R25, X[((CH2)r0)3]R26, CH2X[((CH2) r0) s] R28, or benzofuryl, indolyl, azacycloalkyl, azabicyclo C7-ncycloalkyl or benzopiperidinyl, optionally substituted with Ci-4alkyl; q is 2-5; s is 1-6 and r is 1-3 within each repeating unit s; X' is CH2, 0, S or NH; X is CH2, NR', 0, S, SO or S02; R24 and R25 are i) Ci-6alkyl, optionally substituted by OH, Ci-3alkoxy, or N(R')2, ii) the same or different and joined together to form a 5-7 member heterocycle containing up to two additional heteroatoms selected from NR, O, S, SO, S02, said heterocycle optionally substituted with Ci-4alkyl, iii) aromatic heterocycle, optionally substituted with Ci-4alkyl or N(R’)2; R’ is H or Ci-4alkyl; R26 is H, Ci_4alkyl, C(=O)R27, C (=0) U [ (CH2) m0] nR', P (=0) (0M)2, CO2R27, C (=0) NR27R28, where M is a mono or divalent metal ion, and U is NR' or 0; R27 is Ci_6alkyl or Ar, optionally substituted with one or more hydroxy, carboxy, halo, Ci-3alkoxy, CONR’2, NR'2, C02R', SO2NR'2, CH2NR2, NR’COR', NR'S02R', X"[ (CH2)r0]sR' or CH2X[(CH2)r0] SR ' ; R28 is H, Ci-6alkyl or together with R27 forms a 5-7 membered heterocycle or a 6 membered heterocycle containing a heteroatom selected from N, 0 and S; m is 1-4; and n is 0 or 1; or a pharmaceutically acceptable salt thereof. - 6 Also included in this invention are pharmaceutically acceptable addition salts, complexes or prodrugs of the compounds of this invention. Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vivo.
Formula (I) is intended to encompass all unique nonracemic stereoisomers which may occur due to the presence of asymmetric carbon atoms in the molecule. Such compounds may occur as pure enantiomers or diastereomers or as a mixture of individual stereoisomers. The definition of any substituent moiety which may occur more than once in formula (I) is independent of any other occurrence. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
Compounds of this invention which include acyclic double bonds may be present in either the cis (Z) or trans (E) geometrical configuration with respect to any two substituents .
When X is NH, it will be appreciated that the heterocyclic ring is an imidazole which can undergo tautomerization. All tautomeric forms of the imidazole are within the scope of this invention.
Suitably R1 and R3 are Ci-6alkyl, Ar-Ci-6alkyl, Ar-C2-6alkenyl, Ar-C2-6alkyny1, Ci-6alkyl optionally substituted by one to five fluorine atoms or benzyl substituted in the 4-position by R23 . Preferably R1 is benzyl and R3 is benzyl, 4-hydroxybenzyl or phenylpropenyl.
Suitably R2 is H.
Suitably X is S or N-R11. Preferably X is NH.
Suitably R7 is H, Cj.galkyl, C3-6cycloalkyl, phenyl or benzyl. Preferably R7 is C1_6alkyl. Isopropyl is most preferred.
Suitably R8 is H, Ci-6alkyl, COR12, NO2 or Br . Preferably R8 is H.
Suitably R9 is Η, NO2, Br, COR12, CF3, Ar, Ci-ealkyl or Ci-6alkyl-R15, wherein R12 is H, Ci-6alkyl, Ar, OCi-6alkyl, NH2, and R15 is OH. Preferably R9 is H or COR12.
Suitably B is Ala or Val. Preferably m is 0 and B is absent.
Suitably A is Het, R17 (R18R19C)m-W, Ar-W or Het-W. Suitably R17, R18 and R19 are H, or Ci-4alkyl, Het or Ar optionally substituted by one or two R15 or Ci-6alkyl-R15, or (R18R19C) are joind together to form a phenyl, C3-6Cycloalkyl or Het ring.
Suitably W is C=0, 00(=0), NHC(=O) or SC(C=O).
Suitably R17(R18R19C)m- is Ar-CH2, Het, Het-CH2, Ci-galkyl or C3-6cycloalkyl optionally substituted by one to three groups selected from R15. Suitably R15 is OH. When R17 or (R18R19C) are Het, Het is suitably quinolinyl, pyridyl, imidazolyl, thiazolyl, thiolanyl or tetrahydropyranyl. Suitably Ar is phenyl.
Preferably R5 is t-butyloxycarbonylamino or isopropyloxycarbonylamino.
Suitably R23 is hydroxy-Ci_4alkoxy, Ci-4alkoxyCi-4alkoxy, -0(CH2)2NR24R25, wherein R24 and R25 are are a 5or 6-membered heterocycle, such as morpholino.
In one preferred embodiment W is C=O.
In another preferred embodiment W is OC(=0).
In a third preferred embodiment R10 is Ci-6alkylOC(=0) or C5_6CycloalkylOC(=0) substituted by one or two OH or CH2OH groups .
Representative compounds of this invention are: (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t-butoxycarbonyl)amino-6-phenyl-N-(1’-isopropyl-1'-(imidazo-2-yl))methy1hexanamide hydrochloride; (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t-butoxycarbonyl)30 amino-6-phenyl-N-[11-isopropyl-1’- (4-aminocarbonyl-thiazo-2yl)]methyl-hexanamide; (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t-butoxycarbonyl)amino-6-phenyl-N-[1'-isopropyl-1(thiazo-2-yl)]methylhexanamide; (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t-butoxycarbonyl) amino-6-phenyl-N-(1'-imidazo-2-yl)methyl-hexanamide hydrochloride; - 8 (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t-butoxycarbonyl) amino-6-phenyl-N-[1'-methyl-1'-(imidazo-2-yl)] methylhexanamide hydrochloride; (2R,4S,5S,11S)-2-phenylmethyl-4-hydroxy-5-(t-butoxycarbonyl) 5 amino-6-phenyl-N-[l'-benzyl-l(imidazo-2-yl)Jmethylhexanamide hydrochloride; (2R,4S,5S,1’S)-5-(carbobenzyloxy)amino-4-hydroxy-N-(1' — isopropyl-1’-imidazol-2-yl)methyl-6-phenyl-2-phenylmethylhexanamide; (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[ 1' — isopropyl-11 -(4,5-dimethyl)imidazol-2-yl]methyl-6-phenyl-2phenylmethy1-hexanamide; (2R,4S,5S,l'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'isopropyl-1’-(Ν’-methyl)imidazol-2-yl]methyl-6-pheny1-215 phenylmethy1-hexanamide; (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1 isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-(3phenylpropargyl)hexanamide; (2R,4S,5S,1'S)-5-(isopropoxycarbonyl)amino-4-hydroxy-N-(1'20 isopropyl-1’-imidazol-2-yl)methyl-6-phenyl-2-phenylmethylhexanamide; (2R,4S,5S,1'S)-5- (benzyloxyethoxycarbonyl) amino-4-hydroxy-N (1’-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2phenylmethy1-hexanamide; (2R,4S,5S,1'S)-5-(methoxycarbonyl)amino-4-hydroxy-N-(1 ’ — isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethylhexanamide; (2R,4S,5S,1'S)-5-(ethoxycarbonyl)amino-4-hydroxy-N-(1'isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl30 hexanamide; (2R,4S,5S,1’S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1'isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-(3-phenyl-2propenyl)hexanamide; (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[ 1' — isopropyl-1'-(4-nitroimidazol-2-yl)]methyl-6-phenyl-2phenylmethy1-hexanamide; - 9 (2R,4S,5S,1’S)-5-(t-butoxycarbonyl) amino-4-hydroxy-N-(11 — ethyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethylhexanamide; (2R,4S,5S,l'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(115 propyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethylhexanamide; (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[11isopropyl-1’-(4-bromoimidazol-2-yl)]methyl-6-phenyl-2phenylmethyl-hexanamide; (2R,4S,5S,l’S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N- [ 11 isopropyl-1'-(4,5-dibromoimidazol-2-yl)]methyl-6-pheny1-2phenylmethyl-hexanamide; (2R,4S,5S,1’S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N- [ 1 ’ — isopropyl-1'-(4-methylimidazol-2-yl)]methyl-6-phenyl-215 phenylmethyl-hexanamide; (2R,4S,5S,1’S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1’isopropyl-1’-(4-trifluoromethylimidazol-2-yl)]methyl-6phenyl-2-phenylmethyl-hexanamide; (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-methyl20 N-(11-isopropyl-1’-imidazol-2-yl)methyl-6-phenyl-2phenylmethyl-hexanamide; (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[ 1' — isopropyl-1'-(4-carbomethoxyimidazol-2-yl)]methyl-6-phenyl-2 phenylmethyl-hexanamide; (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[ 1' isopropyl-1'-(4-methylcarbonylimidazol-2-yl)]methyl-6-phenyl 2-phenylmethyl-hexanamide; (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'isopropyl-1'-(4-isopropylcarbonylimidazol-2-yl)]methyl-630 pheny1-2-phenylmethyl-hexanamide; (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[ 1 ’ — isopropyl-1’-(4-phenylcarbonyl-imidazol-2-yl)]methyl-ephenyl- 2 -pheny lmethy 1-hexanamide; (2R,4S,5S,l'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N- [ 1’35 isopropyl-1'-(4-formylimidazol-2-yl)]methyl-6-phenyl-2phenylmethy1-hexanamide; ΙΕ 92231θ - 10 (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[ 1 ’ — isopropyl-1'-(4-(hydroxymethyl)-imidazol-2-yl)]methyl-6pheny1-2-phenylmethyl-hexanamide; (2R,4S,5S,1'S)-5-((tetrahydrothiopyran-4-yl)oxycarbonyl)5 amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methy1-6pheny1-2-phenylmethyl-hexanamide; (2R,4S,5S,1’S)-5-((tetrahydro-4H-pyran-4-yl)oxycarbonyl)amino-4-hydroxy-N-(1’-isopropyl-l’-imidazol-2-yl)methyl-6phenyl-2-phenylmethyl-hexanamide; (2R,4S,5S,l'S)-5-(4-picolinyloxy) amino-4-hydroxy-N-(11isopropyl-l1-imidazol-2-yl)methyl-6-phenyl-2-phenylmethylhexanamide; (2R,4S,5S,1’S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(11 isopropyl-l*-imidazol-2-yl)methyl-6-phenyl-2-(4,4,415 trifluorobut-l-yl)hexanamide ; (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t-butoxycarbonyl) amino-6-phenyl-N-(1’-isobutyl-1'- (imidazo-2-yl))methylhexanamide hydrochloride; (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'20 isopropyl-l’-(4-((IRS)-1-hydroxyethyl)-imidazol-2-yl)]methyl 6-phenyl-2-phenylmethyl-hexanamide; (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[ 1'— (1— methyl)propyl-1'- (imidazol-2-yl)]methyl-6-phenyl-2phenylmethyl-hexanamide; (2R,4S,5S,1'R)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1’isopropyl-l’-(imidazol-2-yl)]methyl-6-pheny1-2-phenylmethylhexanamide; (2R,4S,5S,1'S)-5-[(6-quinolyl)methyloxycarbonyl]amino-4hydroxy-N-[1'-isopropyl-l'- (imidazol-2-yl)]methyl-6-phenyl-2 phenylmethyl-hexanamide; (2R,4S,5S,1'S)-5-(t-butylaminocarbonyl)amino-4-hydroxy-N-[1’ isopropyl-l'- (imidazol-2-yl)]methyl-6-phenyl-2-phenylmethylhexanamide; (2R,4S,5S,l'S)-5-(benzoyl)amino-4-hydroxy-N-[1'-isopropyl-l' (imidazol-2-yl)]methyl-6-pheny1-2-phenylmethy1-hexanamide; (2R,4S,5S,1’S)~5-(methylaminocarbonyl)amino-4-hydroxy-N-[1'isopropyl-l'-(imidazol-2-yl)]methyl-6-phenyl-2-phenylmethylhexanamide ; - 11 (2R,4S,5S,1’S)-5-(phenylaminocarbonyl)amino-4-hydroxy-N-[ 1' — isopropyl-1'-(imidazol-2-yl)]methyl-6-phenyl-2-phenylmethylhexanamide; (2R,4S,5S,l'S)-5-(t-butoxycarbonyl) amino-4-hydroxy-N-[1' 5 cyclopropyl-1'-(imidazol-2-yl)]methyl-6-phenyl-2phenylmethy1-hexanamide; (2R,4S,5S,1'S)-5-(isopropylthiocarbonyl)amino-4-hydroxy-N[1'-isopropyl-1'- (imidazol-2-yl)]methyl-6-phenyl-2phenylmethyl-hexanamide; (2R,4S,5S,1'S)-5-amino-4-hydroxy-N-[1’-isopropyl-1'— ( (1— isopropylthiocarbonyl)imidazol-2-yl)]methyl-6-phenyl-2phenylmethyl-hexanamide; (2R,4S,5S,l’S)-5-(4-imidazolylacetyl) amino-4-hydroxy-N-[ 1' — isopropyl-1'-(imidazol-2-yl)]methyl-6-phenyl-2-phenylmethy115 hexanamide; (2R, 4S,5S,1'S)-5-(propylaminocarbonyl)amino-4-hydroxy-N-[1'isopropyl-1'-(imidazol-2-yl)]methyl-6-phenyl-2-phenylmethylhexanamide.
Other preferred representative compounds are: (2R,4S,5S,1'S)-5-(1,1-dimethy1-2-hydroxyethoxycarbonyl) amino 4-hydroxy-N- (1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2 phenylmethyl-hexanamide; (2R,4S,5S,1'S)-5-(1,l-dimethyl-2-hydroxy-ethoxycarbonyl)amino-4-hydroxy-N-(11-isopropyl-1'-imidazol-2-yl)methyl-625 phenyl-2-phenylmethyl-hexanamide hydrochloride; (2R,4S,5S,1'S)-5-(hydroxyethoxycarbonyl)amino-4-hydroxy-N(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2phenylmethylhexanamide; (2R,4S,5S,1'S)-5-((IRS)-2-hydroxy-l-methylethoxycarbonyl)30 amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6pheny1-2-phenylmethy1-hexanamide; (2R,4S,5S,1'S)-5-(2-hydroxy-l-methylethoxycarbonyl)amino-4hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2phenylmethylhexanamide; and (2R,4S,5S,1'S)-5-(4-hydroxybutanoyl) amino-4-hydroxy-N-(1'isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2phenylmethylhexanamide. - 12 The term alkyl refers to a straight or branched chain alkyl radical of the indicated number of carbon atoms. Ci_4alkyl" as applied herein is meant to include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert5 butyl; Ci_galkyl includes additionally pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 2-ethylpropyl, neopentyl, nhexyl 2,2-dimethylbutyl, 2-methylpentyl, and the like. Alkoxy refers to an alkyl group of the indicated number of carbon atoms attached through a bridging oxygen atom.
Alkylthio refers to an alkyl group of the indicated number of carbon atoms attached through a bridging sulfur atom.
The term substituted alkyl as used herein is meant to include Ci_galkyl, Ar-Ci_galkyl, Het-Ci_galkyl, C2-6alkenyl, Ar-C2-6alkenyl, Het-C2-6 alkenyl, C3_gcycloalkyl-Ci_galkyl, C3-gcycloalkenyl-Ci_galkyl or Ci_galkyl substituted with acyl or hydroxyl.
Alkenyl refers to a straight or branched hydrocarbon chain of the indicated number of carbon atoms, which contains one or more carbon-carbon double bonds at any stable point along the chain, such as ethenyl, propenyl, butenyl, pentenyl, 2-methylpropenyl, hexenyl, and the like.
Alkynyl refers to a straight or branched hydrocarbon chain of the indicated number of carbon atoms which contains a carbon-carbon triple bond at any stable point along the chain, such as ethynyl, 2-propynyl, 2-butynyl, 4-pentynyl, 2-methyl-3-propynyl, hexynyl and the like.
The term acyl means R12-CO, wherein R^2 is H, Ci_galkyl, Ar-Cj-galkyl, Het-Ci_galkyl, C2-6alkenyl, Ar-C2-6alkenyl, Het-C2-6alkenyl, C3--gcycloalkyl- Ci_galkyl, C5_gcycloalkenyl-Ci_galkyl, OH, NHR13, wherein R13 is H, Ci_galkyl, Ar-Ci_galkyl, Het-Ci_galkyl, C2-galkenyl, Ar-C2-6alkenyl, Het-C2-galkenyl, C3_gcycloakyl-Ci_galkyl, or C3_gcycloalkyl, or C5_gcycloalkenyl-Ci_galkyl; or an a-amino acid or an α-amino alcohol bonded at the nitrogen.
Cycloalkyl refers to a saturated ring group of the indicated number of carbon atoms. C3-7cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkenyl refers to a saturated ring group of the indicated number of carbon atoms, having at least one endocyclic carbon-carbon double bond. C5_7cycloalkenyl includes cyclopentenyl, cyclohexenyl and cycloheptenyl.
Aryl, abbreviated as Ar, refers to phenyl or naphthyl, 5 optionally substituted with one to three halo, OH, Ci-6alkyl, Ci-galkoxy, Ci_6alkylthio, Ci-6alkylamino, CF3, amino, N02, carboxy, Ci-4alkylcarbonyl, aminocarbonyl, Ci-6alkyl-Het, Ci-6alkoxy-Het, Ci-6alkyl-phenyl, Ci-galkoxy-phenyl, Ci-6alkyl, Ci-6alkoxy-, HetCi-6alkyl-, HetCi-galkoxy-, phenylCi-6alkyl-, phenylCi-6alkoxy- or phenyloxy.
As used herein except where noted, the term heterocycle, abbreviated as Het, represents a stable 5to 7-membered monocyclic or a stable 7- to 10-membered bicyclic heterocyclic ring, which is either saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure, and may optionally be substituted with one to three halo, OH, alkyl, alkoxy, alkyl-Het, alkoxy-Het, alkyl-phenyl, alkoxy-phenyl.. Examples of such heterocyclic elements include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, furyl, pyranyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzoxazolyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl.
Amino acid means the D- or L- isomer of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine or trifluoroalanine. In general, the amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature as described in Eur. J. Biochem., 158, 9 (1984). Usually lipophilic amino acids are preferred for the moiety B, for instance, Val, Ala, Leu and lie. Amino alcohol refers to an amino acid in which the carboxyl group has been reduced to a methylene hydroxy group.
Certain chemical names are abbreviated herein for the sake of convenience. Boc refers to the t-butyloxycarbonyl radical. Dns refers to the dansyl radical, which is 1dimethylamino napthylene-5-sulfonyl. Cbz refers to the carbobenzyloxy radical. Bzl refers to the benyzl radical.
Ac refers to acetyl. Ph refers to phenyl. DCC refers to dicyclohexylcarbodiimide. DMAP refers to dimethylaminopyridine. HOBT refers to 1-hydroxybenzotriazole. NMM is Nmethylmorpholine. DTT is dithiothreitol. EDTA is ethylenediamine tetraacetic acid. DIEA is diisopropyl ethylamine. DBU is 1.8 diazobicyclo[5.4.0]undec-7-ene. DMSO is dimethylsulfoxide. DMF is dimethyl formamide and THF is tetrahydrofuran. HF refers to hydrofluoric acid and TFA refers to trifluoroacetic acid.
The compounds of formula (I): OH R3 (I) wherein R4 is CO-NR'CHR6R7, R5 is R10R1:LN-, and R1, R2, R3 and R6 are as defined in formula (I), are prepared by: 1)(a) coupling a compound of the formula (II): R1' R? O OPr1 R3' (II) with a compound of formula (III) : HR'N-CHR6'R7' (III) where R1’, R2', R3', R5’, R6' and R7' are as defined for formula (I) with any reactive groups protected, Pr1 is H or a hydroxyl protecting group, and L’ is OH or a leaving group; or (b) coupling a compound of the formula (IV): R1' R2, h^Wr4' OPr1 R3' (IV) with a compound of the formula (V): A’-(B')n-L’ (V) wherein A’ and B' are as defined in formula (I) with any reactive groups protected; or (c) coupling a compound of the formula (VI): R1' R* h-(b%nriX\<^r4 OPr1 R3' (VI) with a compound of the formula (VII): A'-L' (VII) and, 2) if appropriate, a coupling agent; and 3) removing any protecting groups and 4) forming a pharmaceutically acceptable salt thereof.
The coupling reactions may be accomplished by activating the substrate with a reactive functional group in situ or prior to the coupling reaction, such that it is reactive with an amino group. For instance, acids may be converted to acid chlorides, bromides, activated esters or anhydrides, or by adding a coupling reagent. Coupling agents are well known in the art for activating a functional group in situ, .
Exemplary of such agents are DCC and other carbodiimides, DMAPEC, BOP and PPA. These coupling agents may optionally be used with other reagents, such a HOBT, NMM and DMAP, which may facilitate the reaction.
Suitable leaving groups, L', are those which are 5 displaceable by an amino group, such as bromo, chloro, a substituted acyl (eg. trifluoroacetyl, bromobenzoyl, nitrobenzoyl) or a substituted phenol (eg. 4-nitrophenol) and the like. If L' is OH, so that A-OH is an acid, it will be appropriate to use a coupling agent as hereinbefore described.
For instance: When A is a substituted alkyl group, such as r17 (r18r19c)m, L' may be a bromo, chloro, iodo or an alkyl or aryl sulonate.
When A is R17 (R18R19C)m-W, Ar-W or Het-W, and W is C=O, A-L’ may be a carboxylic acid halide, activated ester or anhydride, or a carboxylic acid in the presence of a coupling agent. Methods for preparing such compounds are well known.
When W is OC=O, A-L1 may be a chloro- or bromo-formate, or an activated carbonate. Haloformates may be prepared by reacting the appropriate alcohol with phosgene or carbonyldibromide. Activated carbonates may be prepared by reacting the appropriate alcohol with a suitable carbonate such as bis (4-nitrophenyl)carbonate .
When W is SO2, A-L' may be a sulfonyl halide which may be prepared from the corresponding sulfonic acid.
When W is SC=O, A-L' may be a halothioformate, which may be prepared from a carbonyldihalide and an appropriate mercaptan .
When W is PO(OR22), A-L' may be a phosphonyl halide, which may be prepared from the corresponding phosphonic acid.
Compounds wherein A is R17 (R18R19C)m-W, Ar-W or Het-W, and W is NR'C=O are ureas, and may be prepared by reacting a compound of formula (VII) with an isocyanate of the formula R17 (R18R19C) m-NCO, Ar-NCO or Het-NCO, in a suitable solvent such as methylene chloride, optionally with heating.
Compounds of formula (III), wherein X is nitrogen, are imidazoles and may be prepared according to Scheme 1, wherein - 17 Pr2 is a removeable amino protecting group, and R7', R8' and R9' correspond to R7, R8 and R9 as defined for formula (I), or a group which may be converted into R7, R8 or R9, with any reactive groups protected.
Scheme 1 NHg CH3OH P^-NR' (VIII) The amino aldehydes are generally known or are prepared by methods well known in the art, for instance, by reduction of a suitable α-amino acid ester with diisobutylaluminum hydride. Further reaction of the aldehyde with a gem dialdehyde, or diketone, and ammonia yields the desired imidazole. Alkylation and further modification of the substituent groups of the imidazole are within the skill of the art. Such a method and other methods for preparing imidazoles are disclosed, for instance, by Baldwin et al., J. Med. Chem., 29, 1065 (1986), Angew. Chem. Int., 22, 560 (1983), and Hughey et al., Synthesis, 489 (1980).
Alternately, acyl imidazoles may be prepared by coupling an α-amino acid to a substituted 4-amino-isoxazole, and subsequent reduction and base catalyzed rearrangement as disclosed generally by Reiter, L.A., J. Org. Chem., 52, 2714 (1987). Intermediate compounds of formula (VIII) are a part of this invention. Preferably, R7' is Ci-galkyl and more preferably C3_6alkyl. Suitably, R8' and R9' are H, NO2, Br, COR12, CF3, Ar, Ci_6alkyl or Ci_6alkyl-R15, wherein R12 is H, Ci-galkyl, Ar, OCi_6alkyl, NH2, and R15 is OH or a protected hydroxyl group. Preferably R9 is H or COR12.
Compounds of formula (III), wherein X is sulfur, are thiazoles and may be prepared according to Scheme 2, wherein L is a suitable displaceable group.
Accordingly, a thioamide is reacted with a ketone or aldehyde. Thioamides are commonly prepared from carboxamides by reacting the corresponding carboxamides with a reagent such as Lawessons reagent, as disclosed, for instance, by Hamada et al., Tet. Lett., 931 (1991). Suitable displaceable groups are those which are displaced by a sulfur nucleophile, such as chloride, bromide, iodide, mesylate, p-tolunesufonate groups, and the like.
Compounds of formula (III), wherein X is oxygen, are oxazoles and may be prepared according to Scheme 3 from common amino acids .
Schemed R9 Typically the acid may be coupled to an appropriately substituted amino alcohol by common techniques, as described above, and cyclized by treatment with thionyl chloride to yield an oxazoline, as described by Meyers et al., J. Org. Chem., 43, 1372 (1978). Oxidation of the oxazoline, such as described by Evans et al., J. Org. Chem., 44, 497 (1979), yields an oxazole.
The compounds of formula (II), (IV) and (VI), wherein R2 is H, are prepared, for instance, according to Scheme 4.
Scheme 4 Boc-NH (Oi-Pr)3CITi 0 Ph-CK3, CH2CI2 Boc-NH' . GO2C2H5 OH Ac-OH 1) UOH,H20, MeOH 2) t-BuMe2Si-CI, imidazole BOC-NH R1 CO2H OH R3 Other methods for preparing protected 5-amino-4-hydroxy2,5-disubstituted-pentanoate esters and acids, and the corresponding γ-lactones, are well known and are disclosed, for instance, in Szelke et al., U.S. Patent 4,713,455, Boger et al., U.S. Patent 4,661,473, EP-A 0 352 000, Evans et al., J. Org. Chem., 50, 4615 (1985), Kempf, J. Org. Chem., 51, 3921 (1986), Fray et al., J. Org. Chem., 51, 4828 (1986), Halladay et al., Tett. Lett., 24, 4401 (1983), Wuts et al., J. Org. Chem., 53, 4503 (1988), DeCamp et al., Tett. Lett., 32,1867 (1991), and Szelke et al., WO 84/03044, all of which are incorporated herein by reference.
The compounds of formula (II), (IV) and (VI), wherein R2 is OH, are also prepared by methods common in the art such as those disclosed in U.S. Patent 4,864,017, and Thaisrivongs et al., J. Med. Chem., 30, 976 (1987).
Suitable protecting groups for the amino, hydroxyl, carboxylic acid, mercaptan group, and reagents for deprotecting these functional groups are disclosed in Greene et al., PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, Second Edition, John Wiley and Sons, New York, 1991. Deprotection indicates the removal of the protecting group and replacement with an hydrogen atom. In particular, suitably substituted acetyl, benzyl and silyl groups are useful for protecting the hydroxyl group. The acetyl group is commonly removed by reacting the compound with a base, such as an alkali metal hydroxide, in a mixture of an alcohol and water. The silyl group, such as trimethyl silyl, dimethyl-t-butyl silyl, and t-butyl-diphenyl silyl may be removed by a fluoride reagent, such as a tetra-alkyl ammonium fluoride, or by acid hydrolysis. The benzyl group may be removed by catalytic hydrogenation .
Suitable protecting groups for the amino group are those disclosed by Greene et al., as indicated previously. The benzyloxycarbonyl and t-butoxycarbonyl groups are especially useful amino protecting groups.
The present invention includes pharmaceutically acceptable acid addition salts. Acid addition salts of the present compounds are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, maleic, succinic or methanesulfonic. The acetate salt form is especially useful. If the final compound contains an acidic group, cationic salts may be prepared. Typically the parent compound is treated with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation. Cations such as Na+, K+, Ca++ and NH4+ are examples of cations present in pharmaceutically acceptable salts. Certain of the compounds form inner salts or zwitterions which may also be acceptable.
The compounds of the present invention selectively bind to retroviral proteases in the same manner as the virally coded natural substrates of the proteases and compete with these substrates for protease, thereby serving to inhibit - 21 viral replication by blocking the formation of crucial viral proteins from polyprotein precursors by the protease, and hence, to inhibit disease progression in vivo. The present compounds achieve such beneficial therapeutic effect because they contain unique structural features which impart desirable pharmacokinetic properties to the compounds. One such property is long duration of action. We have found that substitution of a heterocycle, especially imidazole, in the putative P2' position of the present compounds affords compounds which retain good enzyme binding affinity, good antiviral activity, a favorable duration of action and water solubility for good drug delivery.
When a compound of the present invention is administered to an animal infected or potentially infected with a retrovirus, viral replication is inhibited and hence disease progression is retarded. Inasmuch as the amino acid sequences of the protease binding and peptide bond cleavage sites of various retroviruses appear to be highly conserved, an inhibitor is likely to be broadly active against more than one retrovirus. Also, DNA viruses which are dependant upon virally encoded proteases, such as the hepatitis virus, may also be susceptible to such treatment.
The compounds of formula (I) are used to inhibit retroviral replication, and are useful in treating mammals, particularly human patients, who are infected with susceptible retroviruses and require such treatment. The method of treating a retroviral disease in a mammal, particularly a human, comprises internally administering (e.g. orally, parenterally, buccally, trans-dermally, rectally or by insufflation) to said mammal an effective amount of a compound of formula (I), preferably dispersed in a pharmaceutical carrier. Dosage units of the active ingredient are selected from the range of 0.01 - 50 mg/kg. These dosage units may be administered one to ten times daily for acute or chronic infection. No unacceptable toxicological effects are indicated when compounds of this invention are administered in the above noted dosage range. - 22 The present invention also provides a method of treating disease states associated with HIV infection, comprising administering an effective amount of a compound of formula (I), preferably dispersed in a pharmaceutical carrier.
Beneficial effects may be realized by co-administering, individually or in combination, other anti-viral agents with the protease inhibiting compounds of the present invention. Examples of anti-viral agents include nucleoside analogues, phosphonoformate, rifabutin, ribaviran, phosphonothioate oligodeoxynucleotides, castanospermine, dextran sulfate, alpha interferon and ampligen. Nucleoside analogues, which include 2',3'-dideoxycytidine(ddC) , 2’, 3’-dideoxyadenine(ddA) and 3’-azido-21,31-dideoxythymide (AZT), are especially useful. AZT is a preferred agent. Suitably, pharmaceutical compositions comprise an anti-viral agent, a protease inhibiting compound of the present invention, and a pharmaceutically acceptable carrier.
This invention is also a pharmaceutical formulation which comprises a compound of formula (I) and a pharmaceutically acceptable carrier. Pharmaceutical acceptable carrier are well known in the art and are disclosed, for instance, in SPROWL’S AMERICAN PHARMACY, Dittert, L. (ed.) , J.B. Lippincott Co., Philadelphia, 1974, and REMINGTON'S PHARMACEUTICAL SCIENCES, Gennaro, A. (ed.), Mack Publishing Co., Easton, Pennsylvania, 1985.
Pharmaceutical compositions of the compounds of the present invention, or derivatives thereof, may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use. The liquid formulation is generally a buffered, isotonic, aqueous solution. Examples of suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution. Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add - 23 excipients such as ethanol, polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
Alternately, these compounds may be encapsulated, tableted or prepared in a emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition. Liquid carriers include syrup, soy bean oil, peanut oil, olive oil, glycerin, saline, ethanol, and water.
Solubilizing agents, such as dimethylsulfoxide or formamide, may also be added. Carriers, such as oils, optionally with solubilizing excipients, are especially suitable. Oils include any natural or synthetic non-ionic water-immiscible liquid, or low melting solid, which is capable of dissolving lipophilic compounds. Natural oils, such as triglycerides, and synthetic oils, such as polyethylene glycols, are representative. In fact, another aspect of this invention is a pharmaceutical composition comprising a compound of formula (I) and an oil.
Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. Solubilizing agents, such as dimethylsulfoxide or formamide, may also be added.
The carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit. The pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
A suitable dosage form for oral administration has been prepared by dissolving the peptide of Example 1 (312.5 mg) in dimethyl sulfoxide (1 mL) and diluting to a concentration of 12.5 mg/mL with soybean oil. A suitable dosage form for intravenous administration has been prepared by dissolving the compound of Example 1 (0.02 g) in dimethyl sulfoxide (1 mL) and diluting to 20 mL with a 70% propylene glycol/30% ethanol solution.
For rectal administration, a pulverized powder of the 10 compounds of this invention may be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository. The pulverized powders may also be compounded with an oily preparation, gel, cream or emulsion, buffered or unbuffered, and administered through a transdermal patch.
The pharmacological activity of the compounds of this invention may be demonstrated by enzyme assays to determine the inhibitory activity of the retroviral protease, by in vitro cellular-based assays to determine the ability of the compounds to penetrate cells and inhibit viral replication, and by pharmacokinetic assays to determine oral bioavailability, drug half-life and clearance. These assays are well known in the art.
ENZYME ACTIVITY The ability of the compounds of this invention to inhibit the HIV-1 protease enzyme may be demonstrated by using the assay disclosed by Dreyer et al., Proc. Natl. Acad. Sci., U.S.A., 86, 9752 (1989), Grant et al., Biochemistry, 30 8441 (1992), and EP-A 352 000. The Ki for the compounds of this invention are in the range of 1 nM to 5 μΜ. Preferred compounds have Ki's of less than 100 nM.
INFECTIVITY The ability of the compounds of this invention to gain entry to cells infected with the human immunodeficiency virus, and to inhibit viral replication in vitro may be demonstrated using the assay described by Meek et al., Nature, 343, 90 (1990), and Petteway et al., Trends Pharmacol. Sci, 12, 28 (1991) . The IC50 for the compounds of this invention are in the range of 0.1 to 10 μΜ.
The Examples which follow serve to illustrate this invention. The Examples are not intended to limit the scope of this invention, but are provided to show how to make and use the compounds of this invention.
In the Examples, all temperatures are in degrees 10 Centigrade (°C) . Mass spectra were performed upon a VG Zab mass spectrometer using fast atom bombardment, unless otherwise indicated. ^H-NMR(hereinafter NMR) spectra were recorded at 250 MHz using a Bruker AM 250 spectrometer. Multiplicities indicated are: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet and br indicates a broad signal. Sat. indicates a saturated solution, eq indicates the proportion of a molar equivalent of reagent relative to the principal reactant. Celite® is filter aid composed of acid washed diatomaceous silica manufactured by Mansville Corp., Denver, Colorado.
Example 1 Preparation of (2R,4S,5S,1’S)-2-phenylmethyl-4-hydroxy-5-(t25 butoxycarbonyl) amirwrfi-pttenyl-M.-J 11 -isQprQpyl-1.' r iimidazp-2yhUinathy 1-hexanamide hydrochloride a) (1'S)-1'-carbobenzyloxyamino-1'-isopropyl-1’- (imidazo-2yl)methane Cbz-valinal (4.6 g, 1 eq) and glyoxal trimeric dihydrate (1.33 g, leq) were stirred in MeOH at -10°C. Ammonia was bubbled through the solution for several min and the mixture was allowed to stir for 4 h at -1O°C. The mixture was allowed to warm to room temperature over 14 h, then was poured into 250 mL water. The . ^pension was filtered and the filter cake washed twice with water to give the title compound as a white solid (1.9 g, 36%). NMR(CD3OD) δ 7.28 (5H, m), 6.89 (2H, s), 5.04 (2H, dd), 4.46 (1H, d), 2.10 (1H, m) , 0.91 (3H, d) , 0.70 (3H, d); MS(CI/CH4) m/e 274.2 [M+H]+, 230.1, 166.1, 123.1, 91.1. b) (1'S)-1'-amino-1'-isopropyl-1’- (imidazo-2-yl)methane 5 (1’S)-1'-carbobenzyloxyamino-1'-isopropyl-1'-(imidazo-2yl)methane (1.9 g) was stirred in methanol over 10% Pd/C (200 mg). Hydrogen was bubbled through the solution for 1 h and the solution was maintained under a positive hydrogen atmosphere overnight. The mixture was filtered through Celite and was evaporated to a tacky solid (720 mg, 75%). NMR(CDC13) δ 6.87 (2H, s), 3.88 (1H, d), 2.04 (1H, m), 0.81 (6H, dd); MS(DCI/NH3) m/e 190.2 [M+H]+.
C) (2R,4S,5S,1'S)-2-phenylmethyl-4-(t-butyldimethyl)siloxy-515 (t-butoxycarbonyl)amino-6-phenyl-N-[1’-isopropyl-1'-(imidazo2-yl)lmethy1-hexanamide To a solution of (2R,4S,5S)-2-phenylmethyl-4-(tbutylmethyl)siloxy-5-(t-butoxycarbonyl)amino-6-phenylhexanoic acid (200 mg, 0.38 mmol) in dichloromethane, (l'S)20 1'-amino-1'-isopropyl-1'-(imidazo-2-yl)methane (48 mg, 0.35 mmol), BOP reagent (168 mg, 0.38 mmol), and triethylamine (0.053 mL, 0.38 mmol) were added. The mixture was stirred under argon overnight, and washed successively with water, 5% aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The solution was dried over MgSO4, filtered, and evaporated to a white solid. The solid was chromatographed (silica, 4% methanol/dichloromethane) to afford the title compound as a white solid (0.154 g, 68%). NMR(CDC13) δ 7.18 (10H, m), 6.91 (2H, d), 6.32 (1H, d), 4.69 (1H, d), 4.40 (1H, t), 3.92 (1H, q), 3.63 (IH, m), 2.84 - 2.31 (6H, m) , 1.67 (4H, m), 1.24 (9H, s), 0.89 (9H, s), 0.74 (6H, dd), 0.05 (6H, d); MS(DCI/NH3) m/e 649.6 [M+H]+. d) (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t35 butoxycarbonyl)amino-6-phenyl-N-[1'-isopropyl-1'-(imidazo-2yl)Jmethyl-hexanamide hydrochloride The compound of Example 1(c) (0.140 g) was stirred in THF at room temperature under an argon atmosphere. - 27 Tetrabutyl ammonium fluoride (0.38 mL, 6 eq) was added and the solution was stirred overnight. The mixture was diluted with water and extracted with dichloromethane (3X). The combined organic extracts were washed with water and evaporated. The residue was treated with 1 eq of methanolic HC1, concentrated, and triturated with diethyl ether and ethyl acetate to give the title compound as a white solid (95 mg, 83%). NMR(DMSO-dg) δ 7.78 (1H, d) , 7.16 (10H, m), 6.71 (2H, s), 6.39 (1H, d), 4.68 (1H, m), 4.52 (1H, d), 2.71 (3H, m), 2.48 (3H, m), 1.97 (1H, m), 1.61 (1H, m), 1.30 (9H, s), 0.78 (3H, d), 0.61 (3H, d); MS(DCI/NH3) m/e 535.4 [M+H]+ .
Example 2 Preparation of (2R, 4S, 5S, 11 S) -2-phenylmethyl-4-hydroxy-.5-_i t.butcizy.carbQnyll amino-Srphenyl-N- f 11 .-isopjopyl-l ’ - (4aminQcarbQnyi-thiazQ-2-yl) Imethyl-hexanami.de a) Boc-valineamide To a solution of di-t-butyl-dicarbonate (7.15 g, 1 eq) in dry dichloromethane was added valinamide hydrochloride (5.0 g, 1 eq) and triethylamine (9.14 mL, 2 eq). The mixture was heated to reflux for 4 h, and cooled to room temperature. The organic layer was washed twice with water and evaporated to give the title compound (6.03 g, 85%). NMR(CDCl3) δ 6.00 (1H, br), 5.54 (1H, br), 5.01 (1H, br), 3.93 (1H, dd), 2.12 (1H, m) , 1.44 (9H, s) , 0.92 (6H, dd) . b) Boc-valinethioamide Boc-valineamide (0.5 g) was stirred in dry THF at room temperature under argon. Lawesson's reagent (1.56 g, 0.6 eq) was added and the mixture was stirred overnight. The solvent was evaporated and the residue chromatographed (silica, 2.5% methanol/dichloromethane) to give the title compound as a white solid (0.373 g, 70%). NMR(CDC13) δ 8.59 (1H, br s), 8.09 (IH, br s), 5.41 (1H, d (br)), 4.20 (1H, dd), 1.99 (1H, m), 1.39 (9H, s), 0.90 (6H, m). c) (1'S)-1'- (t-butoxycarbonyl)amino-1'-isopropyl-1 * — (4 — carboethoxythiazo-2-yl)methane Boc-valinethioamide (0.265 g) was stirred in dry acetone under argon at -10°C. Ethylbromopyruvate (0.16 mL, 1.1 eq) was added and stirred for 1 h at -10°C. The solution was poured into a well-stirred mixture of chloroform and water and then saturated with sodium bicarbonate. The organic phase was separated and the aqueous layer extracted with chloroform. The combined organic extracts were dried over MgSC>4, filtered, and evaporated to an oil. The oily residue was treated with trifluoroacetic anhydride (0.16 g) and pyridine (0.2 g) in dichloromethane for 1 h at -20°C. Excess solvent was removed in vacuo and the residue dissolved in dichloromethane. The solution was washed with sat. aqueous sodium bicarbonate and 1. ON KHSO4 until pH 7. The solution was dried over sodium sulfate, filtered, and evaporated to an oil which was chromatographed (silica, 4% methanol/ dichloromethane) to give the title compound as a tan solid. NMR(CDC13) δ 8.04 (1H, s) , 5.26 (1H, br d), 4.85 (1H, m) , 4.37 (2H, q), 2.40 (1H, m), 1.41 (9H, s), 1.34 (3H, t), 0.93 (3H, d), 0.84 (3H, d). d) (1'S)-1'- (t-butoxycarbonyl)amino-1’-isopropyl-1’- (4carboxythiazo-2-yl)methane The compound of Example 2(c) (50 mg) was stirred in THF at 0°C. Excess 1. ON NaOH was added and the mixture was stirred for 12 h at 0°C. The mixture was diluted with 1. ON citric acid and extracted with dichloromethane (3X). The combined organic extracts were evaporated and dried in vacuo to give the title compound (0.045 g, 98%). NMR(CDCl3) δ 8.08 (1H, s), 5.19 (1H, m), 4.80 (1H, m), 2.31 (1H, m), 1.38 (9H, s) , 0.86 (6H, dd). e) (1’S)-1’-(t-butoxycarbonyl)amino-1'-isopropyl-1'35 (4-aminocarbonylthiazo-2-yl)methane (1'S)-1’-(t-butoxycarbonyl)amino-1’-isopropyl-1’-(4carboxythiazo-2-yl)methane (0.078 g, 0.26 mmol) was stirred under argon in dry THF at -40°C. NMM (0.06 mL; 0.55 mM) and IE 922316 - 29 isobutyl chloroformate (0.034 mL; 0.26 mmol) were added.
After stirring 15 min, ammonia was bubbled through the mixture for several min. The solution was warmed to room termperature and the THF evaporated. The residue was diluted with ethyl acetate and washed successively with 1.0 N citric acid, 5% aqueous sodium bicarbonate, and sat. aqueous sodium chloride. The organic layer was dried over MgSO/j, filtered, and evaporated to a solid which was chromatographed (silica, 3% methanol/dichloromethane) to give the title compound as a white solid (0.052 g, 67%). NMR(CDCl3) δ 8.02 (1H, s), 7.14 (1H, s(br), 6.28 (1H, s (br)), 5.24 (1H, d(br)), 4.82 (1H, m), 2.30 (IH, m), 1.39 (9H, s), 0.92 (6H, dd). f) (2R,4S,5S,1’S)-2-phenylmethyl-4-(t-butyldimethylsiloxy)-515 (t-butoxy carbonyl)amino-6-phenyl-N-[1’-isopropyl-1’-(4aminocarbonyl-thiazo-2-yl)]methyl-hexanamide The compound of Example 2(e) (52 mg) was stirred in neat trifluoroacetic acid for 10 min and evaporated. The residue was diluted with methanol and treated with 2 eq of cone. HC1.
The solvents were evaporated and dried in vacuo to give a white solid. This solid (40 mg) was added to a solution of (2R,4S,5S)-2-phenylmethyl-4-(t-butyldimethyl)siloxy-5-(tbutoxycarbonyl)amino-6-phenyl-hexanoic acid (97 mg, 1.1 eq), DCC (38 mg, 1.1 eq), and HOBT (0.05 g, 2.2 eq) in DMF at room temperature under argon. N-methylmorpholine (0.04 mL; 2.2 eq) was added and the mixture was stirred overnight. The mixture was filtered through Celite®, evaporated, and diluted with ethyl acetate. The solution was washed successively with 1. ON citric acid, 5% aqueous sodium bicarbonate, and sat. aqueous sodium chloride. The organic layer was chromatographed (silica, 2.5% methanol/dichloromethane) to yield the title compound (60 mg, 55%). NMR(CDCl3) δ 7.89 (IH, s) , 7.60 (IH, d), 7.24 (10H, m), 6.82 (IH, m), 5.12 (IH, m) , ‘ 1.89 (IH, m) , 3.92 (IH, q), 3 .81 (IH, dd), 2.73 (4H, m) , 35 2.21 (IH, m) , 1.73 (2H, m), 1.40 (9H, s), 1.23 (IH, m) , 0.93 (9H, s) , 0.84 (6H, dd), 0.11 (6H, d) . - 30 g) (2R,4S,5S,1'S)-2-phenylmethy1-4-hydroxy-5-(tbutoxycarbonyl)amino-6-phenyl-N-[1’-isopropyl-1' - (4aminocarbonyl(thiazo-2-yl)]methyl-hexanamide The compound of Example 2(f) (60 mg) was stirred in dry THF under argon and tetrabutylammonium fluoride (0.50 mL, 6 eq) was added. The solution was stirred at room temperature overnight. After diluting with water, the aqueous layer was extracted with dichloromethane (3X). The combined organic extracts were washed with water, evaporated, and triturated with diethyl ether and ethyl acetate to give a tan solid.
The solid was chromatographed (silica gel, 4% methanol/dichloromethane) to give the title compound as a white solid (0.022 g) . NMR(CDC13) δ 7.90 (1H, s), (1H, br s), 5.06 (1H, dd), 7.15 (10H, m) , 6.39 (1H, d), 5.93 4.91 (1H, 15 d), 3.90 (1H, d), 3.67 (2H, m), 2.91 (4H, m), 2.64 (1H, d) , 2.13(1H, m), 1.87 (3H, m) , 1.36 (9H, s), 0.83 (6H, dd) ; MS(DCI/NH3) m/e 612 [M+NH4]+, 595 [M+H]+, 495, 413.1, 391, 374, 356, 239.1, 202, 185.
Example- 3 Preparation of (2R.4S.5S.11S)-2-phenylmethvl-4-hvdroxvr5^it^ butoxycarbonyl)amino-6-phenyl-N-Γ11-isopropyls1(thiazo-2yl)1methyl-hexanamide a) (1’S)-1’- (t-butoxycarbonyl)amino-1'-isopropyl-1'-(thiazo2-yl)methane The compound of Example 2(c) was stirred in neat quinoline. Cu powder (0.50 g) was added and the suspension was heated to 160°C for 2 h. After cooling to room temperature, the solution was diluted with ethyl acetate and washed with 2. ON citric acid (4Χ) . The organic layers were combined and dried over MgSO4, filtered, and evaporated to a dark oil. The oil was chromatographed (silica, 4% methanol/dichloromethane) to give the title compound as an orange oil. NMR(CDCl3) δ 7.68 (1H, d), 7.19 (1H, d), 5.26 (1H, d), 4.88 (1H, m), 2.31 (1H, m), 1.43 (9H, s), 0.92 (3H, d), 0.84 (3H, d). - 31 b) (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(tbutoxycarbonyl)amino-6-phenyl-N-[1’-isopropyl-l'-(thiazo-2yl)]methyl-hexanamide Following the procedure of Example 2(f)-2(g), except using the compound of Example 3(a) in place of (l'S)-l'-(tbutoxycarbonyl)amino-1’-isopropyl-l1-(4-aminocarbonylthiazo2-yl)methane, the title compound was prepared (88%). NMR(DMSO-dg) 8 8.31 (1H, d), 7.62 (1H, d), 7.49 (1H, d), 7.16 (10H, m), 2.61 (6H, m), 1.28 (9H, s), 0.89 (3H, dd); MS(DCI/NH3) m/e 552.3 [M+H]+, 413.2, 331.1, 183.1, 157.1, 142.0, 120.1.
Example 4 Preparation of (2R.4S.5S.1'S)-2-phenylmethyl-4-hydroxy-5-(tbutoxycarbonyl)amino-6-phenyl-N-Γ1'-isopropyl-l'-benzimidazo2-yl)1 methyl-hexanamide a) (1*S)-1’-carbobenzyloxyamino-1’-isopropyl-l(benzimidazo2-yl)methane Cbz-valine (2.0 g, 1 eq) was stirred at -10°C in dry THF under argon. Triethylamine (1.11 mL, 1.0 eq) was added, followed by isobutyl chloroformate (1.03 mL, 1 eq). The reaction mixture was stirred for 10 min. Phenylene diamine (0.944 g, 1.1 eq) was added slowly in 10 mL dry THF. The mixture was warmed to room temperature and stirred for 1 h. The solvents were evaporated and the residue partitioned between water and ethyl acetate. The ethyl acetate layer was washed with 5% aqueous sodium bicarbonate and brine. The organic layer was dried over MgSC>4, filtered, and evaporated. The residue was dissolved in glacial acetic acid and heated to 65°C for 16 h. The solvents were evaporated and the residue diluted with water. After neutralizing with saturated aqueous sodium bicarbonate, the solid was filtered and the filter cake was washed with hexane. The solid was recrystallized from ethyl acetate and hexane. NMR(CD3OD) δ - 32 7.48-7.11 (9H, m), 5.06 (2H, q) , 4.62 (IH, m), 2.27 (IH, m), 1.23 (IH, m), 1.02 (3H, d), 0.84 (3H, d) . b) (1’S)-1’-amino-1’-isopropyl-1’-(benzimidazo-2-yl)methane 5 The compound of Example 4(a) (2.76 g) was stirred in methanol. 10% palladium on activated carbon (Pd/C) (250 mg) was added and hydrogen gas was bubbled through the solution for 1 h. The reaction was maintained under an hydrogen atmosphere overnight. The mixture was filtered through Celite® and the solvents evaporated to give the title compound as a white solid (1.58 g, 98%). NMR(CDCl3) δ 7.487.10 (4H, m), 4.02 (IH, d), 2.24 (IH, m), 0.96 (3H, d), 0.83 (3H, d); MS(DCI/NH3) m/e 190.2 [M+H]+. c) (2R,4S,5S,1’S)-2-phenylmethyl-4-(t-butyldimethyl)siloxy-5(t-butoxycarbonyl)amino-6-phenyl-N-[1'-isopropyl-1 benzimidazo-2-yl]methyl-hexanamide To a solution of (2R,4S,5S)-2-phenylmethyl-4-(tbutyldimethyl)siloxy-5-(t-butoxycarbonyl)amino-6-phenyl20 hexanoic acid (75 mg, 1.1 eq) in dimethyl formamide under argon, the compound of Example 4(b) (25 mg, 1.0 eq), DCC (30 mg, 1.1 eq) and HOBT (44 mg, 2.2 eq) were added. The mixture was stirred overnight, then filtered through Celite® The solvents were evaporated and the residue was chromatographed (silica gel, 4% methanol/dichloromethane) to give the title compound (0.070 g, 78%). NMR(CDCl3) δ 7.88 (IH, d), 7.30 (14H, m), 6.80 (IH, d), 4.93 (2H, m), 4.26 (IH, q), 4.00 (IH, m), 2.92 (7H, m), 2.01 (2H, m), 1.53 (9H, s), 1.20 (9H, s), 1.14 (6H, d), 0.41 (6H, d); MS(DCI/NH3, m/e 699.6 [M+H]+. d) (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(tbutoxycarbonyl)amino-6-phenyl-N-[1'-isopropyl-1'-benzimidazo2-yl]methyl-hexanamide The compound of Example 4(c) was stirred in dry THF and tetrabutyl ammonium flouride (0.6 mL, 6 eq) was added. The mixture was stirred under argon overnight at room temperature. The solution was diluted with water and extracted with dichloromethane (3X). The combined organic layers were washed with water and evaporated to a residue which was chromatographed (silica, 2% methanol/CH2CL2) to give the title compound (0.029 g, 50%). NMR(CDCl3) δ 7.54 (1H, m), 7.11 (11H, m) , 6.69 (4H, s) , 4.98 (1H, d) , 4.69 (2H, m) , 3.66 (2H, m), 2.74 (5H, m), 2.31 (1H, m), 1.73 (2H, m), 1.32 (9H, s), 0.70 (6H, d); MS(DCI/NH3) m/e 585.4 [M+H]+, 413.3, 364.3, 296.2, 190.2, 173.1, 120.1.
Example 5 Preparation of (2R.4S.5S.l'S)-2-phenylmethyl-4-hydroxy-5-(tbutoxycarbonyl)amino-6-phenyl-N-(1'-imidazo-2-yl)methylhexanamide hydrochloride 15 a) 2-(carbobenzyloxyamino)methyl-imidazole Following the procedure of Example 1(a), except substituting Cbz-glycinal for Cbz-valinal, the title compound was prepared. NMR(CDC13) δ .33 (5H, s), 6.95 (2H, s), 5.95 (1H, s(br)), 5.12 (2H, s), 4.42 (2H, d); MS(DCI/NH3) m/e 232.2 [M+H]+, 188, 171. b) (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(tbutoxycarbonyl)amino-6-phenyl-N-(1’-imidazo-2-yl) methyl25 hexanamide hydrochloride (Compound 5) Following the procedure of Example 1(b)-1(d), except substituting the compound of Example 5(a) for (l'S)-l'carbobenzyloxyamino-1’-isopropyl-1'- (imidazo-2-yl)methane, the title compound was prepared. NMR(CD3<0D) δ 7.20 (10H,m), 6.94 (2H,s), 6.11 (lH,d), 4.24 (2H,dd), 3.61 (lH,m), 3.52 (lH,m), 2.69 (4H,m), 1.66 (2H,m), 1.28 (9H,s); MS (DCI/NH3) m/e 493.7 [M+HJ+, 475.7, 120.2, 98.2, 83.1, 69.1.
Example 6 Preparation of (2R.4S.5S.1'S)-2-phenylmethyl-4-hydroxv-5-(tbutoxycarbonyl)amino-6-phenyl-N-f1'-methvl-1'-(imidazo-2-yl)1 methyl-hexanamide hydrochloride a) (1'S)-1'-carbobenzyloxyamino-1'-methyl-1'- (imidazo-2yl)methane Following the procedure of Example 1(a), except 5 substituting Cbz-alanal for Cbz-valinal, the title compound was prepared. NMR(CDC13) 5 .35 (5H,s), 6.92 (2H,s), 5.52(lH,d), 5.12 (2H,q), 4.90 (lH,q); MS(DCI/NH3) m/e 246 [M+H]+, 202, 185. b) (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(fcbutoxycarbonyl)amino-6-phenyl-N-[1’-methyl-1’- (imidazo-2-yl)] methyl-hexanamide hydrochloride Following the procedure of Example 1(b)-1(d), except substituting the compound of Example 6(a) for (l’S)-l'15 carbobenzyloxyamino-1'-isopropyl-1'-(imidazo-2-yl) methane, the title compound was prepared. NMR(CD3OD) δ 7.11(10H, m), 6.86 (2H, s), 4.69 (IH, d), 3.62 (IH, d), 3.51 (IH, m), 2.68 (6H, m), 1.59 (2H, m), 1.30 (9H, s), 1.14 (3H, d); MS(DCI/NH3) m/e 507.5 [M+H]+, 489.4, 112.1.
Example 7 Preparation of (2R.4S.5S,l,S)-2-ph&nylmethvl-4-hvdrQxv-5-(tbutoxycarbonyl)amino-6-phenyl-N-ί11-benzyl-11-(imidazo-2yl)1methyl-hexanamide hydrochloride a) (1’S)-1'-carbobenzyloxyamino-1'-benzyl-1'-(imidazo-2yl)methane Following the procedure of Example 1 (a), except substituting Cbz-phenylalaninal for Cbz-valinal, the title compound was prepared. NMR(CDC13) δ 7.37-7.05 (10H,m), 6.95 (2H, s br), 5.52 (IH, d), 5.05 (2M, s), 4.95 (IH, q), 3.32 (2H, d); MS(DCI/NH3) m/e 322, 261, 171. b) (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t35 butoxycarbonyl)amino-6-phenyl-N-(1'-benzyl-1'- (imidazo-2-yl)) methyl-hexanamide hydrochloride Following the procedure of Example 1(a)-1(d), except substituting the compound of Example 7(a) for (l'S)-l'IE 922316 carbobenzyloxyamino-11-isopropyl-1’-(imidazo-2-yl)methane, the title compound was prepared. NMR(CD3OD) δ 7.15 (15H, m), 6.79 (2H, s), 5.78 (1H, d), 5.04 (1H, d) , 3.58 (1H, m), 3.47 (1H, m), 2.68 (8H, m), 1.59 (2H, m), 1.31 (9H, s).
Example 8 Preparation of (2R,4Sf5S,1’S)-5-icarbobenzyloxy)amino-4hydroxy-U-l1 ι..-ί^ορχοργ1·-Ι1-1ιηί^ζρ1-2-γ1) methyl-6-phenyl-2zio phenylmethyl-hexanamide A solution of (2R,4S,5S,1’S)-5-(t-butoxycarbonyl)amino4-hydroxy-N- (1’-isopropyl-1’-imidazol-2-yl)methyl-6-phenyl-2phenylmethyl-hexanamide (0.086 g) in trifluoroacetic acid was stirred for 10 min, then was evaporated in vacuo. To the residue were added dimethylformamide, benzylchloroformate (1 eq) and triethylamine (5 eq), and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was poured into H2O and extracted with dichloromethane . The combined organic extracts were evaporated, and the residue was triturated with diethyl ether to afford the title compound as a white solid. NMR(CD3OD) δ 7.36-6.94 (15H, m), 6.84 (2H, s), 4.99 (2H, s), 4.54 (2H, d), 3.76 (1H, m), 3.52 (1H, dd), 2.77 (5H, m), 2.04 (1H, m), 1.76 (1H, m), 1.58 (1H, m), 0.82 (3H, d), 0.66 (3H, d).
Example 9 Preparation of (2R.4Sf5S.1'S)-5-(t-butoxycarbonyl)amino-430 hydroxy-N-Γ1'-isopropyl-1' - (4 ,5-dimethyllimidazol-2y11 methyl-6-pheny1-2-phenylmethy1-hexanamide a) (IS)-1-carbobenzyloxyamino-l-isopropyl-l-(4,5dimethylimidazol-2-yl)methane Cbz-Valinal (4.14 g) was stirred in methanol with 2,3butanedione (1.54 mL, 1.0 eq). Ammonia was bubbled through the solution at -25°C for 5 min. The cooling bath was removed and the mixture allowed to warm to 20°C. The solution was stirred for 16 h under Ar. The solvents were removed by rotary evaporation, and the residue was diluted with dichloromethane and extracted with dilute aqueous HCl. The organic layer was concentrated to afford unreacted Cbz5 valinal (4.02 g). The acidic aqueous layer was basified with N NaOH and extracted with dichloromethane, the organic extract was concentrated and the residue purified by flash chromatography (4% methanol in dichloromethane) to provide the title compound as a white solid (50 mg) . NMR(CD3<0D) δ 7.29 (5H, m), 5.04 (2H, dd), 4.38 (1H, d), 2.06 (6H, s), 2.01 (1H, m), 0.93 (3H, d), 0.77 (3H, d). b) (IS)-1-(4,5-dimethylimidazol-2-yl)-2-methylpropylamine The benzyloxycarbonyl group was cleaved by 15 hydrogenolysis using the same procedure as described previously in Example 1(b) , except using the product of 1 (a) (50 mg), to afford the title compound as a white solid (24 mg, 87%). NMR(CDC13) δ 4.11 (2H, s(br)), 3.71 (1H, d), 2.06 (6H, s), 2.00 (1H, m), 0.71 (6H, dd). c) (2R,4S,5S,l'S)-5-(t-butoxycarbonyl)amino-4-tbutyldimethylsiloxy-N-[1’-isopropyl-l'-(4,5-dimethyl) imidazol-2-yl]methyl-6-phenyl-2-phenylmethyl-hexanamide Using the procedure of Example 1 (c), except substituting 25 (2R, 4S,5S)-5-(t-butoxycarbonyl)amino-4-t-butyldimethylsiloxy6-phenyl-2-phenylmethylhexanoic acid and (IS)-1-(4,5dimethylimidazol-2-yl)-2-methylpropylamine (24 mg), the title compound was prepared (55 mg, 57%). NMR(CDCl3) δ 7.26-6.80 (10H, m), 4.65 (1H, d), 4.24 (1H, dd), 3.87 (1H, q), 3.61 (1H, m), 2.77-2.39 (5H, m), 2.22 (1H, m), 1.98 (6H, s), 1.79 (1H, m), 1.58 (1H, m), 1.24 (9H, s), 0.85 (9H, s), 0.69 (6H, d) , 0.06 (6H, d). d) (2R,4S,5S,1’S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'35 isopropyl-l(4,5-dimethyl)imidazol-2-yl]methyl-6-phenyl-2phenylmethy1-hexanamide By following the deprotection procedure described in Example 1(d), except using (2R,4S,5S,1’S)-5-(tIE 922316 butoxycarbonyl)amino-4-t-butyldimethylsiloxy-N-[1'-isopropyl1’-(4,5-dimethyl)imidazol-2-yl]methyl-6-phenyl-2phenylmethyl-hexanamide (55 mg) and omitting the final treatment with methanolic HC1, the title compound was prepared (25 mg, 62%). NMR(CDCl3) δ 7.29-6.88 (10H, m), 4.98 (IH, br d), 4.47 (IH, m), 4.29 (IH, m), 3.58 (2H, m), 2.842.51 (5H, m), 2.20 (IH, m), 2.04 (6H, s), 1.71 (2H, m), 1.38 (9H, s), 0.69 (6H, dd). io Example IQ Preparation of (2R,4S,5S,1’S)-5-(t-butoxycarbonyl)amino-4hydroxy-N-Γ1'-isopropyl-11-(4.5-dimethyl)lmidazol-2yll.methyl-6.-phenyl-2-phenylmethyl-:hexan amide a) (IS)-l-carbobenzyloxyamino-l-isopropyl-l-(4phenylimidazol-2-yl)methane Using the procedure of Example 1 (a), except using Cbz(L)-valine (2.19 g) and α-ketophenylacetaldehyde instead of glyoxal, the title compound was prepared (1.54 g, 48%).
NMR(CDC13) δ 7.62 (IH, (br)), 7.24 (10H, m), 5.79 (IH, d), .04 (2H, dd), 4.32 (IH, dd), 2.31 (IH, m), 0.96 (3H, d), 0.79 (3H, d); MS m/e 350.4 [M+H]+, 199.0. b) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-tbutyldimethylsiloxy-N-[1’-isopropyl-1(4-phenyl)imidazol-2yl]methyl-6-pheny1-2-phenylmethy1-hexanamide Using the procedure of Example 1(b)-1(c), except using the compound of 10(a) (72 mg), the title compound was prepared (67 mg, 44%). NMR(CDC13) δ 7.70 (IH, d), 7.40-6.71 (16H, m), 4.73 (IH, d), 4.54 (IH, dd), 3.96 (IH, q), 3.69 (IH, m), 2.88-2.36 (5H, m), 1.73 (2H, m), 1.33 (9H, s), 0.91 (9H, s), 0.84 (6H, dd), 0.11 (6H, d) ; MS m/e 725.4 [M+H] + .
IE9»3'6 - 38 c) (2R, 4S, 5S, 1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N[1’-isopropyl-1’-(4-phenyl)imidazol-2-yl]methyl-6-phenyl-2phenylmethy1-hexanamide Using the procedure of Example 9(d), except starting 5 from (2R,4S,5S,1’S)-5-(t-butoxycarbonyl)amino-4-tbutyldimethylsiloxy-N-[1’-isopropyl-1’-(4-phenyl)imidazol-2yl)methyl-6-phenyl-2-phenylmethyl-hexanamide (67 mg), the title compound was prepared (30 mg, 54%). NMR(CDCl3> 8 7.526.67 (16H, m), 5.48 (IH, d), 3.60 (IH, q), 3.44 (IH, d) , 2.60 (4H, m), 1.96 (IH, m), 1.62 (2H, m), 1.23 (9H, s), 0.73 (3H, d) , 0.62 (3H, d); MS m/e 611.4 [M+H]+, 242.2, 195.0, 150.2.
Example 11 is Preparation.of (2R, 4S,.5S,1 ’.S) c5-.( t-butoxycarbonyl) aminorlhydroxy-N- Γ1 ’-isopropyl-1 ’- (Ν’-methyl) imidazol-2-yUmethyl--6r phenyiT-2-jphenylmethy 1-hexanamide a) (IS)-carbobenzyloxyamino-l-isopropyl-1-(N’-methylimidazol20 2-yl)methane The product of Example 1(a) (273 mg, 1 mmol) was heated at 40°C for 2 h in methyl iodide (5 mL). The reaction mixture was evaporated, and the residue was suspended in aqueous Na2CC>3. The mixture was extracted with dichloromethane, dried (Na2CO3) and concentrated. The crude product was purified by flash chromatography (silica, 2% methanol/dichloromethane) to yield the title compound (200 mg, 70%). NMR(CDCl3) δ 7.29 (5H, s) , 6.92 (IH, s), 6.69 (IH, s), 5.94 (IH, d), 5.03 (2H, q), 4.55 (IH, dd), 3.64 (3H, s), 2.20 (IH, m), 1.01 (3H, d), 0.82 (3H, d). b) (2R,4S,5S,1’S)-5-(t-butoxycarbonyl)amino-4-tbutyldimethylsiloxy-N-[1’-isopropyl-1’-(Ν’-methyl)imidazol-2y1]methyl-6-phenyl-2-phenylmethy1-hexanamide Following the procedure of Example 1(b)-1(c), except using the compound of 11(a) (90 mg), the title compound was prepared (104 mg, 50%). NMR(CDCl3) δ 7.32-6.89 (10H, m) , 6.81 (IH, s), 6.59 (IH, s), 6.08 (IH, d), 4.71 (2H, m), 3.94 - 39 (1H, q) , 3.70 (1H, m) , 3.25 (3H, S) , 2.80-2.36 (5H, m), 2.21 (1H, m) , 1.73 <2H, m), 1.31 (9H, S), 0.94 (9H, s), 0.85 (6H, dd), 0 . 11 (6H, s) . c) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[11 isopropyl-1'-(Ν’-methyl)imidazol-2-yl]methyl-6-phenyl-2phenylmethyl-hexanamide Following the procedure of Example 9(d), except using (2R,4S 5S,1’S)-5-(t-butoxycarbonyl)amino-4-fc10 butyldimethylsiloxy-N-[1'-isopropyl-1(N’-methyl)imidazol-2yl]methyl-6-phenyl-2-phenylmethyl-hexanamide (100 mg), the title compound was prepared (74 mg, 89%). NMR(CDCl3) δ 7.216.74 (11H, m), 6.70 (1H, s), 6.59 (1H, s) , 4.95 (1H, d) , 4.61 (1H, dd), 3.60 (3H, m), 3.48 (3H, s), 2.71 (5H, m), 2.06 (1H, m), 1.64 (2H, m), 1.32 (9H, s), 0.82 (3H, d), 0.63 (3H, d); MS m/e 549.3 [M+H]+.
Example- 12 Preparation of (2R,4S,5S,1 *S)-5-(t-butoxycarbonyl)amino-4hydroxy-N- (1'-isopropyl-1 *-imidazol-2-yl) methyl-6-phenyl.-2s (3-phenylpropargyl)hexanamide a) (3R,5S,1'S)-(1'-t-butoxycarbonylamino-2’-phenyl)ethyl-325 (3-phenylpropargyl)-tetrahydrofuran-2-one To a solution of lithium diisopropylamide (3.61 mL, 2.0 M in THF, 2.2 eq) in THF at -78°C under an argon atmosphere, (5S,1'S)-(1'-t-butoxycarbonylamino-2'phenyl)ethyl-tetrahydrofuran-2-one (1.0 g, 1.0 eq) was added.
After stirring at -78°C for 15 min, hexamethylphosphoramide (1.14 mL, 2 eq) was added, and stirring was continued an additional 10 min. Phenylpropargyl bromide (1.28 g, 2.0 eq), was added and the resulting mixture was stirred at -78°C for 2 h, then poured into dilute aqueous HC1 and extracted with dichloromethane. The combined organic extracts were evaporated under reduced pressure to an oil, which was chromatographed (silica, 20% ethyl acetate/hexanes) to afford the title compound as a white solid (0.455 g, 33%) .
NMR(CDCl3) δ 7.18 (10H, m) , 4.50 (2H, m) , 3.93 (1H, q), 2.79 (5H, m), 2.23 (2H, m), 1.24 (9H, s) . b) (2R,4S,5S)-5-(t-butoxycarbonyl)amino-4-t-butyldimethyl5 siloxy-6-phenyl-2-(3-phenylpropargyl)hexanoic acid The title compound (496 mg, 84%) was prepared by the procedure of Evans et al., J. Org. Chem. 50, 4615 (1985) from the product of 12(a) (450 mg). NMR(CDCl3) δ 7.49-7.10 (10H, m), 4.71 (1H, d), 3.94 (3H, m), 2.69 (4H, m), 1.90 (2H, m), 1.31 (9H, s), 0.89 (9H, s), 0.11 (6H, d). c) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-tbutyldimethylsiloxy-N-(1'-isopropyl-l’-imidazol-2-yl)methyl6-phenyl-2-(3-phenylpropargyl)hexanamide Following the procedure of Example 1 (c), except using (2R,4S,5S)-5-(t-butoxycarbonyl)amino-4-t-butyldimethylsiloxy6-phenyl-2-(3-phenylpropargyl)hexanoic acid (240 mg) and (IS)-l-imidazol-2-yl-2-methylpropylamine, the title compound was prepared (244 mg, 84%). NMR(CDCl3) δ 7.14 (12H, m), 6.72 (1H, d), 4.58 (1H, d), 4.49 (1H, dd), 3.92 (1H, q), 3.80 (1H, m), 2.54 (5H, m), 1.65 (2H, m), 1.20 (9H, s), 0.81 (9H, s), 0.80 (6H, dd), 0.05 (6H, d). d) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1’25 isopropyl-l’-imidazol-2-yl)methyl-6-phenyl-2-(3phenylpropargyl)hexanamide Following the procedure of Example 9(d), except using (2R, 4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-tbutyldimethylsiloxy-N-(1'-isopropyl-l’-imidazol-2-yl) methyl30 6-phenyl-2-(3-phenylpropargyl)hexanamide, the title compound was prepared (161 mg, 79%). NMR(CDC13) δ 7.24-6.98 (10H, m), 6.68 (2H, s), 5.20 (1H, m) , 4.52 (1H, d) , 3.49 (2H, m), 3.06 (1H, m), 2.56 (5H, m), 2.04 (1H, m), 1.61 (2H, m), 1.26 (9H, s), 0.68 (6H, dd); MS m/e 581.2 (M+Na)+, 559.2 [M+H]+, 541.4, 503.2, 485.2, 459.2, 441.2.
Example-13 Preparation of (2R,4S,5S,1'S)-5-(isopropoxycarbonyl)amino-4hydroxy-N-(11-isopropyl-11-imidazol-2-yl)methyl-6-phenyl-25 phenylmethy L-hexanamids a) (2R,4S,5S,1'S)-5-amino-4-t-butyldimethylsiloxy-N-(1 isopropyl-1'-imidazol-2-yl)methyl-6-pheny1-2-phenylmethylhexanamide The product of Example 1(c) (0.20 g, 0.31 mmol) was dissolved in trifluoroacetic acid and stirred at room temperature for 5 min, and partitioned between dichloromethane and saturated aqueous Na2CC>3. The organic extract was dried over Na2CC>3, filtered and evaporated to afford the title compound (0.17 g, 100%) which was used without further purification. b) (2R,4S,5S,1'S)-5-(isopropoxycarbonyl)amino-4-tbutyldimethylsiloxy-N-[1'-isopropyl-1'-(Ν'20 isopropoxycarbonyl)imidazol-2-yl]methyl-6-phenyl-2phenylmethy1-hexanamide A mixture containing the compound of 13(a) (0.17 g, 0.31 mmol), isopropyl chloroformate (0.62 mL of 1 M dichloromethane solution, 2 eq) and 4-dimethylaminopyridine (0.75 g, 2 eq) in dichloromethane (40 mL) was allowed to stir at room temperature overnight under an argon atmosphere. The mixture was then partitioned between dichloromethane and saturated aqueous Na2CC>3, and the organic extract was dried over Na2CO3. The solvent was removed in vacuo, and the residue was purified by flash chromatography (silica, 4% methanol/dichloromethane) to afford the title compound (0.214 g, 96%). NMR(CDCl3) δ 7.35-6.78 (12H, m), 6.57 (1H, d) , 5.61 (1H, dd), 5.19 (1H, m), 4.86 (1H, , m), 4.77 (1H, d), 3.97 (1H, q), 3.63 (1H, t), 2.88 (1H, dd), 2.70-2.48 (4H, m), 2.06 (1H, m), 2.00- 1.85 (1H, m), 1.79-1.64 (1H, m), j L.45 (6H, dd) , 0.94 (9H, s), 0.85 (6H, d), 0.12 (6H, d) . c) (2R,4S,5S,1’S)-5-(isopropoxycarbonyl)amino-4-hydroxy-Nil '-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2phenylmethyl-hexanamide To a solution of the compound of 13(b) (0.214 g) in methanol, excess aqueous HC1 (approx. 5 equiv.) was added.
The resulting solution was allowed to stir at room temperature overnight, and was concentrated under reduced pressure. The residue was diluted with H2O, and basified with aqueous Na2CO3. The mixture was extracted with dichloromethane, and the combined organic extracts were dried over Na2CC>3. The solvent was removed in vacuo, and the residue was purified by flash chromatography (silica, 4% methanol/dichloromethane) to afford the title compound (0.150 g, 97%). NMR(CDC13) δ 7.32-6.96 (13H, m) , 5.48 (IH, d), 5.08 (IH, m), 5.00 (IH, s (br)), 4.87 (IH, m), 3.78 (IH, m), 3.62 (IH, m), 3.25 (IH, m), 2.96-2.67 (4H, m) , 2.29 (IH, m), 1.951.65 (2H, m), 1.25-1.12 (6H, dd), 0.80-0.60 (6H, dd); MS m/e 521 [M+H]+, 519 (M-H)-. d) (2R,4S,5S,1’S)-5-(isopropoxycarbonyl)amino-4-hydroxy-N(1’-isopropyl-1’-imidazol-2-yl)methyl-6-phenyl-2phenylmethyl-hexanamide hydrochloride The product of 13(c) (100 mg, 0.192 mmol) was dissolved in methanol (10 mL) and a 1M solution of HC1 in ether (0.192 mL) was added. The solution was concentrated by rotary evaporation without heating, and the residue was trituated with ether and dried under vacuum to afford the title compound (104 mg, 98%) . NMR(CD3OD) δ 7.30 (2H, s), 7.21 - 6.88(10H, m) , 4.61 (2H, m) , 3.65 (IH, m) , 3 .48 (IH, d) , 2.99 30 (IH, m), 2.87 (IH, m) , 2.74-2.56 (2H, m) , 2 .12 (IH, m) , 1.75- 1.50 (2H, m), 1.17 -1.00 (6H, dd), 0.90 (3H, d) , 0.64(3H, d) .
Example 14 Preparation of (2R.4S.5S.1'S)-5-(benzyloxyethoxycarbonvl·) amino-4-hydroxy-N- (11-isopropyl-1'-imidazQl-2-vl) metAy-L^T. phenyl-2-phenylmethyl-hexanamide >E 922316 - 43 a) benzyloxyethyl-(4-nitro)phenylcarbonate To a solution of 2-benzyloxyethanol (2.5 g, 16.4 mmol) and bis (4-nitrophenyl)carbonate (5.0 g, 1 eq) in dichloromethane (200 mL), N-methylmorpholine (1.81 mL, 1 eq) was added. The resulting mixture was allowed to stir at room temperature for 3 d. The reaction mixture was washed successively with H2O and saturated aqueous NaCl and dried over Na2SC>4. The solvent was removed in vacuo, and the residue was purified by flash chromatography (silica, 20% ethyl acetate/hexanes) to afford the title compound (4.38 g, 84%). NMR(CDCl3) δ 8.26 (2H, m) , 7.34 (7H, m), 4.62 (2H, s), 4.49 (2H, t), 3.70 (2H, t). b) (2R,4S,5S,1'S)-5-(benzyloxyethoxycarbonyl)amino-4-t15 butyldimethylsiloxy-N-[1’-isopropyl-1'-(Ν'-benzyloxyethoxycarbonyl) imidazol-2-yl]methyl-6-pheny1-2-phenylmethy1hexanamide To a solution of the compound of Example 14(a) (134.5 mg, 0.24 mmol) in dichloromethane (40 mL) under an argon atmosphere, benzyloxyethyl 4-nitrophenyl carbonate (160 mg, 2 eq) and 4-dimethylaminopyridine (60 mg, 2 eq) were added.
The resulting mixture was allowed to stir at room temperature overnight, and was diluted with dichloromethane. The organic extract was washed successively with aqueous Na2CC>3, H2O, aqueous Na2CC>3 and H2O, and dried over Na2CO3. The solvent was removed in vacuo, and the residue was purified by flash chromatography (silica, 4% methanol/dichloromethane) to afford the title compound (180 mg, 82%). NMR(CDCl3) δ 7.456.80 (22H, m), 6.62 (IH, d), 5.60 (IH, t) , 5.06 (IH, d), 4.60 (2H, s), 4.52 (2H, s), 4.50 (2H, m), 4.31 (IH, m), 4.07 (2H, m), 3.80 (2H, t), 3.68 (IH, q), 3.57 (IH, q), 2.85 (IH, m), 2.77-2.41 (4H, m), 2.09 (IH, m), 1.90 (IH, m), 1.73 (IH, m), 0.95 (9H, s), 0.81 (6H, dd), 0.11 (6H, d). c) (2R,4S,5S,1'S)-5-(benzyloxyethoxycarbonyl)amino-4-hydroxyN-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2phenylmethyl-hexanamide Following the procedure of Example 13 (c) , except using 5 the compound of Example 14(b) (160 mg), the title compound was prepared (100 mg, 81%). NMR(CDC13, CD3OD) δ 7.40-6.79 (17H, m), 4.55 (2H, s), 4.45 (IH, d), 4.20 (2H, m), 3.80-3.45 (5H, m), 2.95-2.66 (4H, m), 2.59 (IH, dd), 2.07 (IH, m), 1.71 (2H, m), 0.80 (3H, d), 0.68 (3H, d).
Example. 15 Preparation of (2R, 4S,5S,llS).-5-.(methPxycarbonyl)aminQz4hydroxy-N-(1’-isopropyl-1’-imidazol-2-yl·)methyl-6-phenylT2r phenylmethyl-hexanamide a) (2R,4S,5S,l'S)-5-(methoxycarbonyl)amino-4-tbutyldimethylsiloxy-N-[1'-isopropyl-1'-(Ν'methoxycarbonyl)imidazol-2-yl]methyl-6-phenyl-2-phenylmethyl20 hexanamide Following the procedure of Example 13 (b), except using (2R,4S,5S,1’S)-5-amino-4-t-butyldimethylsiloxy-N-(1'isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethylhexanamide, the title compound was prepared (89%).
NMR(CDC13) δ 7.40-6.79 (12H, m), 6.52 (IH, d), 5.58 (IH, dd), 4.91 (IH, d), 3.96 (3H, s), 3.95 (IH, d), 3.66 (IH, t), 3.60 (3H, s), 2.85 (IH, m) , 2.73-2.40 (4H, m) , 2.08 (IH, m), 1.90 (IH, m), 1.69 (IH, m), 0.95 (9H, s) , 0.85 (6H, dd) , 0.14 (6H, d) . b) (2R,4S,5S,1'S)-5-(methoxycarbonyl)amino-4-hydroxy-N-(1 ’ — isopropyl-1’-imidazol-2-yl)methyl-6-phenyl-2-phenylmethylhexanamide Following the procedure of Example 13(c), except using 35 the compound of Example 15(a), the title compound was prepared (70%). NMR(CDC13, CD3OD) δ 7.23-6.60 (12H, m) , 4.38 (IH, d), 3.65 (IH, t), 3.54 <3H, s), 3.33 (IH, m), 2.95 (IH, - 45 m) , 2.82-2.40 (4H, m), 1.95 (1H, m), 1.64 (2H, m), 0.69 (6H, dd) .
Example 16 5 Preparation of (2R, 4S,5Sr1'S)-5-(ethoxycarbonyl)amino-4hydroxy-N-(1'-isopropyl-11-imidazol-2-yl)methyl-6-phenyl-2phenyimethyl-hexanamide a) (2R,4S,5S,1’S)-5-(ethoxycarbonyl)amino—4-fc— butyldimethylsiloxy-N-[1'-isopropyl-1’-(N'ethoxycarbonyl)imidazol-2-yl]methyl-6-phenyl-2-phenylmethylhexanamide Following the procedure of Example 13(b), except using 15 (2R,4S,5S,1’S)-5-amino-4-t-butyldimethylsiloxy-N-(1’isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethylhexanamide and ethylchloroformate, the title compound was prepared (90%; 1 . NMR(CDCl3) δ 7 .35-6.77 (12H, m), 6.55 (1H, d), 5.60 (1H, dd) , 4.86 (1H, d) , 4.41 (2H, m) , 4.15-3.9 0 (3H, m), 3.66 (1H, t), 2.87 (1H, m) , 2.75-2.45 (4H , m) , 2.08 (1H, m), 1.92 (1H, m), 1.70 (1H, m) , 1.45 (3H, t), 1.18 (3H, t) , 0.98 (9H, s) , 0.85 (6H, dd), 0. 13 (6H, d). b) (2R,4S,5S,1'S)-5-(ethoxycarbonyl)amino-4-hydroxy-N-(1’25 isopropyl-1’-imidazol-2-yl)methyl-6-phenyl-2-phenylmethylhexanamide Following the procedure of Example 13(c), except using the compound of Example 16(a), the title compound was prepared (95%) I . NMR(CDCl3, CD3OD) δ 7.25-6.75 (12H, m), 4.43 30 (1H, d) , 3.95 (2H, q), 3.61 (1H, q), 3.40 (1H, m), 2.85 (1H, m), 2.80- 2.40 (4H, m), 2.05 (1H, m), 1.61 (2H, t), 1.11 (3H, t), 0.72 (3H, d), 0.55 (3H, t) .
Example 17 Preparation of (2R.4S.5S.1’S)-5-1t-butQxvcarbonvl)amino-4hydroxy-N-(1'-isopropyl-1'-imida2ol-2-yl)methvl-6-phenvl-2(3-phenyl-2-propenyl)hexanamide a) (3R,5S,1'S)-(1'-t-butoxycarbonylamino-2'-phenyl)ethyl-3(3-phenylprop-2-enyl)-tetrahydrofuran-2-one Following the procedure of Example 12(a) , except using 5 cinnamyl bromide (0.485 mL) as the alkylating agent, the title compound was prepared (0.51 g, 75%). NMR(CDCl3) δ 7.35-7.10 (10H, m), 6.43 (1H, d), 6.09 (1H, m), 4.60 (1H, m), 4.48 (1H, q), 4.00 (1H, t (br)), 2.96-2.55 (4H, m), 2.53-2.21 (2H, m), 2.05 (1H, m), 1.35 (9H, s). b) (2R,4S,5S)-5-(t-butoxycarbonyl)amino-4-t-butyldimethylsiloxy-6-phenyl-2- (3-phenyl-2-propenyl)hexanoic acid Following the procedure of Example 12 (b), except using the compound of Example 17 (a), the title compound was prepared (77%) . NMR(CDCl3) δ 7.40-7.05 (10H, m), 6.48-6.00 (4H, m), 4.78 (1H, d), 3.94 (1H, q) , 3.80 (1H, m), 2.89 (1H, m) , 2.83- -2.2 6 (4H, m), 1.90 (1H, m), 1.59 (1H, m), 1.28 (9H, s), 0.90 (9H, s), 0.08 (6H, d) . c) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-tbutyldimethylsiloxy-N-(1’-isopropyl-1'-imidazol-2-yl)methyl6-phenyl-2-(3-phenyl-2-propenyl)hexanamide Following the procedure of Example 1(c), except using the compound of 17(b), the title compound was prepared (82%) . NMR(CDCl3) δ 7.35-7.15 (10H , m), 7.14-6.85 (2H, m), 6.73 (1H, s) , 6.20 (1H, d), 6.10- 5.88 (1H, m), 4.78 (1H, d), 4.65 (1H, t) , 3.97 (1H, q), 3.76 (1H, m) , 2.77 (2H, d), 2.50-2.25 (2H, m) , 2.12 (1H, m), 1.70 (1H, m) , 1.63 (1H, m) , 1.36 (9H, s) , 0.92 (9H, s), 0.81 (6H, d), 0.09 (6H, d). d) (2R,4S,5S,1'S)-5- (t-butoxycarbonyl)amino-4-hydroxy-N-(1'isopropyl-1’-imidazol-2-yl)methyl-6-phenyl-2-(3-phenyl-2propenyl)hexanamide Following the procedure of Example 9(d), except using 35 the compound of 17(c), the title compound was prepared (90%).
NMR(CDCl3, CD3OD) δ 7.30-7.00 (10H, m), 6.71 (2H, s), 6.26 (1H, d), 6.41 (1H, m), 3.66 (1H, d), 3.50 (1H, d), 2.88-2.45 - 47 (4H, m) , 2.36 (IH, m), 2.23 (1H, m), 2.06 (IH, m) , 1.70 (2H, m) , 1.34 (9H, s), 0.88 (3H, d) , 0.74 (3H, d).
MS m/e 561 [M+H]+.
Example 18 Preparation of (2R.4S.5S.11S)-5-(t-butoxycarbonyl)aminor4^ hydroxy-N-11'-isopropyl-1(4-nitroimidazol-2-yl)1methyl-6phenyl-2-phenylmethy1-hexanamide a) (IS)—N-(1-(imidazol-2-yl)-2-methyl)propylacetamide To a solution of the compound of Example 1(b) (175 mg) in dichloromethane (10 mL) at 0°C was added diisopropylethylamine (355 mg, 2.75 mmol) followed by acetyl chloride (215 mg, 2.75 mmol). The resulting mixture was stirred overnight, washed with saturated aqueous Na2CC>3, and concentrated. The residue was treated with methanol, stirred overnight and concentrated under reduced pressure to afford the title compound (181 mg, 78%) as a white solid.
NMR(CD3OD) δ 6.95 (2H, s) , 4.72 (IH, d, J=6 Hz), 2.35-2.10 (IH, m), 1.98 (3H, s), 0.98 (3H, d, J=5, 3 Hz), 0.82 (3H, d, J=5 Hz). b) (IS)-N-(1-(4-nitroimidazol-2-yl)-2-methyl)propylacetamide The compound of Example 18(a) (290 mg, 1.60 mmol) was dissolved in cold concentrated H2SO4 (2 mL), and after stirring for 15 min, 90% HNO3 (0.4 mL) was added dropwise.
The resulting mixture was slowly warmed to 40°C and stirred for 2 h. The mixture was then poured onto ice, and the pH was adjusted to 4 by the addition of solid NaHCO3. The mixture was extracted with ethyl acetate (6x), and the combined organic extracts were dried over MgSO4 and concentrated under reduced pressure to afford the title compound (153 mg, 42%). NMR(CD3OD) δ 7.98 (IH, s), 4.70 (IH, d, J=6 Hz), 2.35-2.15 (IH, m), 1.98 (3H, s), 0.95 (3H, d, J=5 Hz), 0.85 (3H, d, J=5 Hz); MS m/e 475.2 (2M+Na)+, 249.2 (M+Na)+, 227.2 [M+H]+, 185.2, 168.0. - 48 c) (IS)-1-(4-nitroimidazol-2-yl)-2-methylpropylamine, dihydrochloride salt A mixture of the compound of Example 18(b) (153 mg, 0.68 mmol) in 6 N HCl (2 mL) was heated at 90°C for 12 h, cooled and concentrated under reduced pressure. The title compound was obtained (138 mg, 80%) and used without further purification. NMR(CD3OD) δ 8.12 (1H, s), 4.30 (1H, d, J=4 Hz), 2.45-2.30 (1H, m), 1.12 (3H, d, J=4 Hz), 0.90 (3H, d, J=4 Hz). d) (2R,4S,5S,1’S)-5-(t-butoxycarbonyl)amino-4-tbutyldimethylsiloxy-N-[1'-isopropyl-l'-(4-nitroimidazol-2yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide Following the procedure of Example 1(c), except using 15 (2R,4S,5S)-5-(t-butoxycarbonyl)amino-4-t-butyldimethylsiloxy6-phenyl-2-phenylmethylhexanoic acid and (IS)-1-(4nitroimidazol-2-yl)-2-methylpropylamine, the title compound was prepared. NMR(CDCl3) δ 7.30-6.90 (10 H, m), 6.60 (1H, d, J=4 Hz), 4.70 (1H, d, J=5 Hz), 4.40 (1H, t, J=4 Hz), 3.90 (1H, q, J=4 Hz), 3.75 (1H, dd, J=8, 3 Hz), 2.75-2.30 (6H, m) , 1.80-1.50 (2H, m), 1.25 (9H, s) , 0.85 (9H, s), 0.70 (6H, m), 0.05 (6H, d, J=4 Hz). e) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[ 1' — isopropyl-l'-(4-nitroimidazol-2-yl]methyl-6-phenyl-2phenylmethy1-hexanamide Following the deprotection procedure of Example 1(d), except using the compound of Example 18(d), the title compound was prepared. NMR(CD3OD) δ 7.90 (1H, s), 7.40-6.90 (10H, m), 4.53 (1H, d, J=6 Hz), 3.70 (1H, m), 3.50 (1H, m), 2.90-2.60 (5H, m), 2.00 (1H, m), 1.90-1.55 (2H, m), 1.49 (9H, s), 0.85 (3H, d, J=4 Hz), 0.70 (d, 3H, J=4 Hz); MS m/e 602.4 (M+Na)+, 580.4 [M+H]+, 524.4, 480.4. - 49 Example 19 Preparation of (2Rf4Sf5S,l,S)-5-(t-butoxycarbonyl)aminQ-4hydroxy-N- (l.'-ethylrl ’-imidaaal-2=yI)methyl-:6-pheny.lr2r phenylmethy1-hexanamide a) (IS)-1-carbobenzyloxyamino-l-ethyl-l-(imidazol-2yl)methane Following the procedure of Example 1(a), except using 10 Cbz-(L)-α-ethylglycinal in place of valinal, the title compound was prepared. NMR(CDCl3) δ 7.45-7.10 (5H, m) , 6.90 (2H, s), 5.65 (1H, d, J=6Hz), 5.10-4.95 (2H, m), 4.40 (1H, q, J=5 Hz), 2.00-1.70 (2H, m) , 1.00-0.80 (3H, m) . b) (IS)-(l-imidazol-2-yl)propylamine Following the procedure of Example 1 (b), except using the compound of Example 19(a), the title compound was prepared. NMR(CDCl3) δ 6.90 (2H, s) , 5.00-4.50 (2H, br s), 4.00 (1H, t, J=5 Hz), 2.00-1.70 (2H, m) , 1.00-0.80 (3H, m) . c) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-tbutyldimethylsiloxy-N-[11-ethyl-1’-imidazol-2-yl]methyl-6pheny1-2-phenylmethy1-hexanamide Following the procedure of Example 1 (c), except using 25 (2R,4S,5S)-5-(t-butoxycarbonyl)amino-4-t-butyldimethylsiloxy6-phenyl-2-phenylmethylhexanoic acid and the compound of Example 19(c), the title compound was prepared. NMR(CDCl3) δ 7.35-6.90 (10H, m), 6.78 (2H, s), 6.20 (d, J=5 Hz), 4.80-4.65 (2H, m), 4.05 (1H, q, J=5 Hz), 3.72 (1H, dd, J=10, 3 Hz), 2.90-2.50 (5H, m), 2.10-2.05 (1H, m), 1.90-1.65 (3H, m), 1.40 (9H, s), 0.95 (9H, s), 0.90-0.85 (3H, m), 0.50 (6H, s). d) (2R,4S,5S,1’S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'ethyl-1'-imidazol-2-yl]methyl-6-pheny1-2-phenylmethy135 hexanamide Following the procedure of Example 9(d), except using the compound of Example 19(c), the title compound was prepared. NMR(CD3<0D) δ 7.40-7.00 (10H, m) , 6.85 (2H, s) , 3.60-3.50 (2H, m) , 2.95-2.60 (5H, m), 1.95-1.52 (4H, m) , 1.48-1.26 (9H, m), 0.8-0.9 (3H, m).
MS m/e 521.2 [M+H]+; 503.4, 447.4.
Example-2 Q.
Preparation of (2R.4S.5S,l'S)-5-(t-butoxycarbonyl)aminQ-4hydroxy-N-(l’-propyl-l'-imidazol-2-yl)methyl-6-phenyl-2phenylmelhy1-hexanamide io Following the procedure of Example 19(a)-19(d), except substituting Cbz-(L)-α-propylglycinal for Cbz-(L)-aethylglycinal, the title compound was prepared. Data for the intermediates of this synthesis were: a) (IS)-1-carbobenzyloxyamino-l-propyl-l-(imidazol-2yl)methane. NMR(CDCl3) δ 7.40-7.10 (10H, m), 6.65 (2H, s), 5.55 (IH, d, J=6 Hz), 5.10-4.90 <2H, m), 4.65 (IH, q, J=5 Hz), 2.05-1.93 (IH, m), 1.90-1.75 (IH, m) , 1.45-1.20 (4H, m) , 0.95-0.85 (3H, m). b) (IS)-1-(imidazol-2-yl)butylamine. NMR(CDCl3): δ6.90 (2H, s), 5.10-4.40 (2H, s (br)), 4.05 (IH, t, J=5 Hz), 1.90-1.55 (2H, m), 1.45-1.20 (4H, m) , 0.95-0.80 (3H, m) . c) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-tbutyldimethylsiloxy-N-[1'-propyl-1'-imidazol-2-yl]methyl-6phenyl-2-phenylmethyl-hexanamide. NMR(CDCl3) δ 7.35-7.00 (10H, m), 6.78 (2H, s), 6.22 (IH, d, J=5 Hz), 4.85-4.68 (2H, m), 4.00 (IH, q, J=3 Hz), 3.75 (IH, dd, J=10, 3 Hz), 2.802.50 (5H, m), 2.12-1.95 (IH, m) , 1.90-1.60 (3H, m), 1.40-1.20 (13H, m), 0.90 (9H, s), 0.87-0.80 (3H, m), 0.07 (6H, s). d) (2R,4S,5S,1’S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'35 propyl-1'-imidazol-2-yl]methyl-6-phenyl-2-phenylmethylhexanamide. NMR(CD3OD) δ 7.40-7.00 (10H, m), 6.90 (2H, s), 3.78-3.50 (2H, m) , 2.90-2.60 (5H, m), 1.90-1.55 (4H, m) , 1.45-1.20 (13H, m); MS m/e 535.4 [M+H]+.
Example.. 21 Preparation of (2R,4S,5S,11S)-5-(t-butoxycarbonyl)aminQ-4^ hydroxy-N-fl1-isopropyl-1'-(4-bromoimidazol-2-yl)lmethyl-6phenyl-2-phenylmethyl-hexanamide a) (IS)-N-l-(4-bromoimidazol-2-yl)-2-methylpropylacetamide and (IS)-N-l-(4,5-dibromoimidazol-2-yl)-2-methylpropylacetamide To a solution of (IS)-N-l-imidazol-2-yl-2methylpropylacetamide (1.58 g, 8.73 mmol) in 95% ethanol (30 mL), 2,4,4,6-tetrabromocyclohexadienone (3.93 g, 9.60 mmol) was added. The resulting mixture was stirred at room temperature for 30 min, and was concentrated in vacuo. The residue was dissolved in dichloromethane, washed with aqueous NaHCC>3 and dried over Na2SO4. The solvent was removed in vacuo, and the residue was purified by flash chromatography to afford the title compound (650 mg, 29%). NMR(CDCl3) δ 7.70 (IH, d, J=7 Hz), 6.85 (IH, s), 4.67 (IH, t, J=7 Hz), 2.35-2.25 (IH, m), 1.95 (3H, s), 1.05 (3H, d, J=5 Hz), 0.80 (3H, d, J=5 Hz) .
Also isolated was (IS)-N-l-(4,5-dibromoimidazol-2-yl)-2methylpropylacetamide (50 mg, 8%): NMR(CDCl3) δ 4.68 (IH, t, J=7 Hz), 2.38-2.25 (IH, m), 2.05 (3H, s), 1.05 (3H, d, J=5 Hz), 0.85 (3H, d, J=5 Hz); MS m/e 340.0 [M+H]+, 280.8. b) (IS)-1-(4-bromoimidazol-2-yl)-2-methylpropylamine, dihydrochloride Following the procedure of Example 18(c), except using (IS)-N-l-(4-bromoimidazol-2-yl)-2-methylpropylacetamide, the title compound was prepared. NMR(CD3<0D) δ 7.60 (IH, s) , 4.35 (IH, d, J=7 Hz), 2.50-2.38 (IH, m), 1.10 (3H, d, J=5 Hz), 0.82 (3H, d, J=5 Hz). - 52 c) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-tbutyldimethylsiloxy-N-[1'-isopropyl-l'-(4-bromoimidazol-2yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide Following the procedure of Example 1 (c), except using 5 (2R,4S,5S)-5-(t-butoxycarbonyl)amino-4-t-butyldimethylsiloxy6-phenyl-2-phenylmethylhexanoic acid and (lS)—l—(4— bromoimidazol-2-yl)-2-methylpropylamine dihydrochloride, the title compound was prepared. NMR(CDCl3) δ 7.40-7.00 (10H, m), 6.70 (1H, s), 6.45 (1H, d, J=5 Hz), 4.80 (1H, d, J=6 Hz), 4.40 (1H, t, J=5 Hz), 4.02 (1H, q, J=4 Hz), 3.78 (1H, dd, J=7, 2 Hz), 2.90-2.30 (9H, m), 1.85-1.60 (2H, m), 1.45 (9H, s), 1.00 (9H, s), 0.85 (6H, t, J=4 Hz), 0.10 (6H, d, J=6 Hz). d) (2R,4S,5S,l'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'— isopropyl-l'-(4-bromoimidazol-2-yl)]methyl-6-phenyl-2phenylmethy1-hexanamide Following the procedure of Example 9(d), except using (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t-butyldimethylsiloxy-N-[1'-isopropyl-l'-(4-bromoimidazol-2-yl)]methyl-620 pheny1-2-phenylmethy1-hexanamide, the title compound was prepared. NMR(CDCl3) δ 7.40-7.00 (10H, m), 6.70 (1H, s), 6.55 (1H, m), 4.90 (1H, d, J=5 Hz), 4.50 (1H, t, J=5 Hz), 3.75-3.55 (2H, m), 2.95-2.65 (5H, m) , 2.40-2.25 (1H, m) , 1.90-1.60 (2H, m), 1.48 (9H, s), 0.80 (6H, t, J=6 Hz).
MS m/e 613.2 [M+H]+; 535.2.
Example 22 Preparation of (2R.4S,5Sf1'S)-5-(t-butoxycarbonyl)amino-430 hydroxy-N- fl '-isopropyl-l' - (.4 ^S-dibromoimidazQl^ZnvD-ImethYl6-phenyl-2-phenylmethyl-hexanamide Following the procedures of Examples 18(c)-18(d) and 9(d), except substituting (IS)-N-l-(4,5-dibromoimidazol-235 yl)-2-methylpropylacetamide for (IS)-N-(l-4-nitroimidazol-2yl)-2methyl)propylacetamide, the title compound was prepared. Analytical data for the intermediates of this synthesis were: a) (IS)-1-(4,5-dibromoimidazol-2-yl)-2-methylpropylamine, dihydrochloride. NMR(CD3OD): 54.10-3.90 (1H, br s), 2.302.10 (1H, s(br)), 1.10 (3H, d, J=5 Hz), 0.85 (3H, d, J=5 Hz). b) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t-butyldimethylsiloxy-N-[1'-isopropyl-1’-(4,5-dibromoimidazol-2yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide. NMR(CDC13) δ 7.40-6.90 (10H, m), 6.38 (IH, d, J=5 Hz), 4.80-4.50 (3H, m, , 4.00 (IH, q, J=5 Hz), 3.72 (IH, dd, J=7, 2 Hz), 2.85-2.50 (5H, m), 2.30 (IH, br s), 2.20-2.05 (IH, m), 1.85-1.65 (2H, m) , 1.38 (9H, s), 0.90 (9H, s), 0.80-0.60 (6H, m) , 0.10 <6H, d, J=3 Hz). c) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'15 isopropyl-1(4,5-dibromoimidazol-2-yl)]methyl-6-phenyl-2phenylmethyl-hexanamide. NMR(CDC13) δ 7.35-6.85 (10H, m) , 6.65 (IH, br s), 4.92 (IH, d, J=4 Hz), 4.50 (IH, m), 3.723.50 (2H, m), 2.98-2.63 (5H, m), 2.15-2.02 (IH, m), 1.90-1.70 (2H, m), 1.40 (9H, s); MS m/e 693.0 [M+H]+; 637, 619, 593, 575, 291.
Example 23 Preparation of (2Rf 4S, 5S, 1' S)-5-(t-butoxycarbonyl)-amino-4hydroxy-N-Γ11-lsopropyl-1'-(4-methylimidazol-2-yl)1 methyl-6phenyl-2-phenylmethyl-hexanamide a) (IS)-l-carbobenzyloxyamino-l-isopropyl-l-(430 methylimidazol-2-yl)methane .
Cbz-(L)-valinal (1.0 g, 3.9 mmol) and pyruvaldehyde (4.3 mmol, 40% in H2O) were dissolved in methanol (10 mL) and chilled in an ice bath. Concentrated aqueous ammonia (2 mL) was added and the reaction mixture was stirred at 20°C overnight. The solvent was removed in vacuo and the residue dissolved in 5% HC1 (50 mL) and extracted with ethyl acetate (3x20 mL). The aqueous layer was basified to pH 10 with solid Na2CO3. A tan solid (463 mg) precipitated. The solid was purified by flash chromatography (silica, 2%-3% methanol/dichloromethane) to yield the title compound as a white solid (180 mg, 16%) . mp 163-164°C; NMR(CDCl3) δ 7.457.35 (5H, m), 6.60 (1H, s), 6.00 (1H, d, J=4 Hz), 5.05 (2H, q, J=4 Hz), 4.40 (1H, t, J=4 Hz), 2.45-2.30 (1H, m), 2.20 (3H, s), 0.95 (3H, d, J=4 Hz), 0.80 (3H, d, J=4 Hz); MS m/e 575.4 (2M+H)+, 288.0 [M+H]+. b) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t10 butyldimethylsiloxy-N-[1'-isopropyl-1'-(4-methylimidazol-2yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide Following the procedure of Example 1(b)-1(c), except using (2R,4S,5S)-5-(t-butoxycarbonyl)amino-4-tbutyldimethylsiloxy-6-phenyl-2-phenylmethylhexanoic acid and the compound of Example 23 (a), the title compound was prepared. NMR(CDCl3) δ7.37-6.90 (10H, m), 6.45 (1H, s), 6.38 (1H, d, J=3 Hz), 4.75 (1H, d, J=5 Hz), 4.40 (1H, t, J=5 Hz), 3.95 (1H, q, J=4 Hz), 3.72-3.68 (1H, m), 2.90-2.70 (4H, m), 2.60-2.48 (1H, m), 2.45-2.30 (1H, m), 2.17 (3H, s) , 1.90 1.80 (1H, m), 1.75-1.62 (1H, m), 1.40 (9H, s), 0.95 (9H, s), 0.75 (6H, t, J=3 Hz), 0.10 (6H, d, J=2 Hz). c) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'isopropyl-1’- (4-methylimidazol-2-yl)]methyl-6-phenyl-225 phenylmethyl-hexanamide Following the procedure of Example 9(d), except using the compound of Example 23(b), the title compound was prepared. NMR(CDC13) δ 7.38-7.00 (10H, m) , 6.52 (1H, s), 4.92 (1H, d, J=5 Hz), 4.42 (1H, t, J=4 Hz), 3.72-3.55 (2H, m), 2.95-2.65 (5H, m), 2.35-2.20 (1H, m), 2.18 (3H, s), 1.75 (2H, br s), 1.42 (9H, s), 0.75 (6H, d, J=3 Hz); MS m/e 549.2 [M+H]+.
Example 24 Preparation of (2R. 4S, 5S. 11S)-5-(t-butoxycarbonyl) aminQ-.4hydroxy-N- Π '-isopropyl-1'- (4-trif ΙηοΓΟΠίΘ^νΙίιΤίί^ζοίΓΣ-. yl) 1 methyl-6-phenyl-2-phenylmethvl-hexanamid£. a) (IS)-1-carbobenzyloxyamino-l-isopropyl-l-(4trifluoromethylimidazol-2-yl)methane.
Sodium acetate trihydrate (5.35 g, 2.2 eq) was dissolved 5 in water (16 mL) and 1,1 dibromotrifluoroacetone (5.31 g, 1.1 eq) was added. The solution was stirred for 30 min at 90°C . The solution was cooled to 0°C and poured into a 0°C solution of Cbz-Valinal (4.22 g, 1.0 eq) in anhydrous methanol (80 mL). Concentrated ammonium hydroxide (22 mL) was added and the mixture stirred overnight at room temperature. The solvents were evaporated to give a white precipitate which was covered with 150 mL of water. The suspension was filtered and the solid washed twice with water. The white solid was dissolved in ethyl acetate, dried over sodium sulfate, filtered, and evaporated to a white solid (5.24 g, 86%). 1HNMR(CD3OD) δ 7.45 (1H, s) , 7.40-7.20 (5H, m), 5.05 (2H, q, J=4 Hz), 4.50 (1H, d, J=4 Hz), 2.38-2.10 (1H, m), 1.00 (3H, d, J=4 Hz), 0.80 (3H, d, J=4 Hz), 13CNMR(CD3OD, ^-H-decoupled) 18.9, 19.4, 67, 117(q, J=3 Hz), 123.2(q, J=266 Hz), 128.7, 129.3, 133(q, J=39 Hz), 138.0, 151.7; MS m/e 342.0 [M+H]+. b) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t-butyldimethylsiloxy-N-[11-isopropyl-1'- (4-trifluoromethylimidazol2-yl))methyl-6-phenyl-2-phenylmethyl-hexanamide Following the procedure of Example 1(b)-1(c), except using the compound of Example 24(a) and (2R,4S,5S)-5- (tbutoxycarbonyl)amino-4-t-butyldimethylsiloxy-6-pheny1-2phenylmethylhexanoic acid, the title compound was prepared. NMR(CDCl3) δ 7.35-6.95 (11 H, m) , 6.50 (1H, d, J=4 Hz), 4.75 (1H, d, J=6 Hz), 4.25 (1H, t, J=4 Hz), 3.95 (1H, q, J=4 Hz), 3.80-3.68 (1H, m) , 2.90-2.40 (5H, m) , 1.80-1.60 (2H, m), 1.35 (9H, s), 0.90 (9H, s), 0.80 (3H, d, J=3 Hz), 0.70 (3H, d, J=3 Hz), 0.05 (6H, d, J=2 Hz). c) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N- [ 1’isopropyl-1'-(4-trifluoromethylimidazol-2-yl)]methyl-6phenyl-2-phenylmethyl-hexanamide Following the procedure of Example 9(d), except using 5 the compound of Example 24(b), the title compound was prepared. NMR(CDC13) δ 7.35 (1H, s) , 7.25-6.90 (10H, m), 4.53 (1H, d, J=5 Hz), 3.68 (1H, t, J=4 Hz), 3.52 (1H, d, J=6 Hz), 2.90-2.55 (5H, m), 2.10-1.95 (1H, m), 1.85-1.70 (1H, m), 1.65-1.50 (1H, m), 1.40-1.25 (9H, m), 0.90 (3H, d, J=4 Hz), 0.65 (3H, d, J=4 Hz); MS m/e 603.2 [M+H]+, 529.2, 503.2.
Example 25 Ereparation of (2R.4S.5S.11S)-5-(t-butoxycarbonyl)amino-415 hydroxy-N-methyl-N-(1'-isopropyl-1 '-imidazol^-ynmothyl^fphanylr2rphenylmethyl-hexanamide a) (IS)-1-carbobenzyloxyamino-l-isopropyl-l-(imidazol-2yl)methane Following the procedure of Example 1(a), except substituting N-methyl-Cbz-(L)-valinal for Cbz-(L)-valinal, the title compound was prepared. NMR(CDCl3) δ 7.45-7.30 (5H, m) , 6.90 (2H, s) , 5.12 (2H, s), 4.60 (1H, d, J=6 Hz), 2.95 (3H, s), 2.70-2.53 (1H, m), 1.02 (3H, d, J=3 Hz), 0.85 (3H, d, J=3 Hz). b) (IS)-1-methylamino-l-isopropyl-l-(imidazol-2-yl)methane Following the procedure of Example 1(b), except using the compound of Example 25(a), the title compound was prepared. NMR(CDC13) 6 6.95 (2H, s) , 3.52 (1H, d, J=3 Hz), 2.30 (3H, s), 2.10-1.90 (1H, m), 0.98 (3H, d, J=3 Hz), 0.82 (3H, d, J=3 Hz) . c) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t35 butyldimethylsiloxy-N-methyl-N-(1'-isopropyl-1'-imidazol-2yl)methyl-6-phenyl-2-phenylmethyl-hexanamide Following the procedure of Example 1(c), except using the compound of Example 25(b), the title compound was prepared. NMR(CDCl3) δ 7.40-6.72 (12H, m) , 4.82 (IH, d, J=5 Hz), 3.95 (IH, q, J=4 Hz), 3.82-3.75 (IH, m) , 2.95-2.70 (5H, m), 2.51 (2H, s), 2.50-2.38 (IH, m), 2.08 (IH, s), 1.87-1.68 (2H, m), 1.38 (9H, s), 0.95 (9H, s), 0.88 (3H, d, J=3 Hz), 0.75 (3H, d, J=3 Hz), 0.05 (6H, d, J=7 Hz). d) (2R,4S,5S,1'S)-5-(fc-butoxycarbonyl)amino-4-hydroxy-Nmethyl-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2phenylmethyl-hexanamide Following the procedure of Example 9(d), except using the compound of Example 28(c), the title compound was prepared. NMR(CDCl3) 67.35-6.82 (12H, m), 4.90-4.72 (IH, m), 3.70-3.00 (2H, m), 2.92-2.50 (8H, m), 1.90-1.60 (2H, m) , 1.40-1.30 (9H, m), 0.95-0.70 (6H, m).
MS m/e 549.2 [M+H]+.
Example 26 PreparatiQn_o£_ (2R, JS,.5S, 1 ’.S) -5- (Lrbutaxycarbonyl) amino-420 hydroxy-N- [11 -isopropyl-1 ’- (4-carbomethoxyimidazoI-_2yl)1 methyl-6-phenyl-2-phenylmethyl-hexanamide a) (IS)-1-carbobenzyloxyamino-l-isopropyl-l-(4trimethoxymethylimidazol-2-yl)methane .
Sodium methoxide (8 mL, 25% in methanol, 37.5 mmol) was added to a solution of the compound of Example 27 (a) (640 mg, 1.88 mmol) in anhydrous methanol (10 mL). The resulting mixture was heated at 55°C overnight, cooled, and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and H2O, and the organic extract was dried over Na2CO3. The solvent was removed in vacuo, and the residue was purified by flash chromatography (silica, 2% methanol/dichloromethane) to afford the title compound (545 mg, 77%). NMR(CDCl3) δ 7.40-7.20 (5H, m), 6.98 (IH, br s), 5.90 (IH, br s), 5.08 (2H, s), 4.50 (IH, br s), 3.15 (9H, s), 2.00 (IH, m (br)), 1.00-0.80 (6H, m); MS m/e 378.2 [M+H]+, 346, 332, 271, 195. b) (IS)-1-carbobenzyloxyamino-l-isopropyl-l-(4carbomethoxyimidazol-2-yl)methane A solution of the compound of Example 26(a) (540 mg) in 1:1 methanol/aqueous HC1 (10 mL) was stirred at room temperature for 2 h, and concentrated under reduced pressure. The residue was partitioned between aqueous Na2CO3 and dichloromethane, and the organic extract was dried over Na2CC>3 and concentrated in vacuo to afford the title compound (470 mg, 75%). NMR(CDCl3) δ 7.55 (1H, br s), 7.35 (5H, s), .90-5.65 (1H, m) , 5.10 (2H, t, J=4 Hz), 4.60-4.42 (1H, m), 3.88 (3H, s), 2.40 (1H, br s), 1.00-0.80 <6H, m); MS m/e 332.2 [M+H]+. c) (IS)-1-amino-l-isopropyl-l-(4-carbomethoxyimidazol-215 yl)methane Following the procedure of Example 1(b), except using the compound of Example 26(b), the title compound was prepared. NMR(CDC13) δ 7.62 (1H, s) , 3.97 (1H, d, J=4 Hz), 3.82 (3H, s), 2.27-2.05 (1H, m), 0.95-0.75 (6H, m) . d) (2R,4S,5S,1’S)-5-(t-butoxycarbonyl)amino-4-t-butyldimethylsiloxy-N-[1'-isopropyl-1'-(4-carbomethoxyimidazol-2yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide Following the procedure of Example 1(c), except using 25 the compound of Example 26(c), the title compound was prepared. NMR(CDCl3) δ 7.45-6.90 (12H, m), 6.48 (1H, d, J=4 Hz), 4.72 (1H, d, J=6 Hz), 4.35 (1H, s br), 4.02-3.87 (1H, m), 3.85 (3H, s), 3.75-3.60 (1H, m), 2.90-2.40 (5H, m), 1.901.60 (2H, m), 1.42 (9H, s), 0.90 (9H, s) , 0.72 (6H, d, J=4 Hz), 0.10 (6H, d, J=3 Hz). e) (2R, 4S, 5S, 1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N[1’-isopropyl-l(4-carbomethoxyimidazol-2-yl)]methyl-6phenyl-2-phenylmethyl-hexanamide Following the procedure of Example 9(d), except using the compound of Example 26(d), the title compound was prepared. NMR(CDCl3) δ 7.40-6.80 (12H, m), 4.90 (1H, d, J=5 Hz), 4.50 (1H, br s), 3.90 (3H, s), 3.80-3.60 (2H, m), 2.95IE 922316 2.68 (5H, m), 2.45-2.30 (1H, m), 1.80-1.60 (2H, m), 1.40 (9H, s), 0.72 (6H, d, J=4 Hz); MS m/e 593.2 [M+H]+, 537.2, 519.2, 493.2, 475.2.
Example 27 Preparation of (2R,4Sf5S,1'S)-5-(t-butoxycarbonyl)amino-4hydroxy-N-f11-isopropyl-l1-(4-methylcarbonylimidazol-2ylUm£thyl=6-zphanyl-2-pheny lmethyl-hexanamide io a) (IS)-1-carbobenzyloxyamino-l-isopropyl-l-(4hydroxymethylimidazol-2-yl)methane .
The compound of Example 26(b) (0.314 g, 1.0 eq) was stirred in anhydrous toluene at -78°C under an argon atmosphere. DIBAL (3.8 mL, 1.0M in hexanes, 4.0 eq) was added and the solution stirred at -78°C for 1 h. The reaction was quenched with methanol (0.2 mL, 1.0 eq). The solution was then diluted with Rochelles salt solution (sat.) and stirred for 1 h. The solution was extracted with dichloromethane twice and the combined organic extracts were washed successively with saturated aqueous Rochelles salt and brine. The organic layer was dried over magnesium sulfate, filtered, and evaporated to give the title compound as a white solid. (0.27 g, 94%). NMR(CDC13) δ 7.25 (5H, s) , 6.69 (1H, s), 6.14 (1H, d), 5.01 (2H, dd), 4.52 (2H, s), 4.37(1H, t), 2.19 (1H, m), 0.92 (3H, d), 0.73 (3H, d); MS m/e 304.0 [M+H]+. b) (IS)-1-carbobenzyloxyamino-l-isopropyl-l-(430 formylimidazol-2-yl)methane .
The compound of Example 27(a) (0.11 g, 1.0 eq) was stirred in anhydrous dichloromethane at room temperature under an inert argon atmosphere. Manganese dioxide (0.126 g,4.0 eq) was added and the mixture was stirred at room temperature overnight. After 16 h and additional 2.0 eq of manganese dioxide was added. The reaction was complete by TLC after 2 h. The mixture was filtered through a pad of Celite® and the filter cake was washed with dichloromethane.
The organic solvent was removed in vacuo to give the title compound as a white solid (0.075 g , 69%). NMR(CDCl3) δ 9.57 (1H,S), 7.54 (IH, s), 7.12 (5H, s) , 6.43 (IH, d), 4.96 (2H , dd), 4.43 (IH, t), 2.08 (IH , m), 0.91 (3H, d) , 0.62 (3H, t); MS m/e 302.0 [M+H]+. c) (IS,1’RS)-1-carbobenzyloxyamino-l-isopropyl-l- (4- (1 hydroxyethyl)imidazol-2-yl)methane .
The compound of Example 27(b) (0.1 g, 1.0 eq) was stirred in a 3:1 ether/THF mixture at 0°C under an argon atmosphere. Methyl magnesium bromide (0.47 mL, 3.0 M in THF, 4.0 eq) was added and allowed to stir at 0°C for 1.5 h. The solution was diluted with 5% aqueous HC1 and made basic with solid sodium carbonate. The solution was extracted with ethyl acetate three times and the combined organic extracts were dried over sodium carbonate, filtered, and evaporated to a white solid (0.1 g, 95%). NMR(CDCl3) δ 7.19 (5H,s), 6.59 (IH, s), 6.42 (IH, d), 4.92 (2H, dd), 4.73 (IH, m), 2.09 (IH, m), 1.37 (3H, d), 0.82 (3H, d), 0.66 (3H, d). d) (IS, 1'RS)-1-amino-l-isopropyl-l-(4-(1’hydroxyethyl)imidazol-2-yl) methane.
The compound of Example 27(c) (0.1 g, 1.0 eq) was stirred in anhydrous methanol with 10% Pd on activated carbon (0.020 g). Hydrogen gas was bubbled through the solution via balloon for 1 h and the reaction was maintained under a hydrogen atmosphere for 3 h. The mixture was filtered through a pad of Celite® and the filter cake washed with methanol. The methanol was evaporated to give the title compound as a white solid (0.05 g, 87%). NMR(CDC13) δ 6. 63 (IH, s), 4.72 (IH, dd), 3. 61 (IH, d), 1.92 (IH, m), 1.49 (3H, d), 0.84 (3H, d), 0.67 (3H , d) . e) (2R,4S,5S,11S,1’’RS)-5-(t-butoxycarbonyl)amino-4-t35 butyldimethylsiloxy-N-[1'-isopropyl-1'-(4-(1''-hydroxyethyl)imidazol-2-yl)]methyl-6-phenyl~2-phenylmethyl-hexanamide To a solution of (2R, 4S, 5S)-5-(t-butoxycarbonyl)amino-4t-butyldimethylsiloxy-6-pheny1-2-phenylmethylhexanoic acid (0.131 g, 1.0 eq) in anhydrous dimethylformamide, the compound of Example 27(d) (50 mg, 1.1 eq), BOP reagent (0.11 g, 1.0 eq), and triethylamine (0.04 mL, 1.0 eq) were added. The solution was stirred at room temperature for 16 h. The solution was diluted with water and extracted three times with dichloromethane. The combined organic extracts were washed with water, then brine. The solution was dried over magnesium sulfate, filtered, and evaporated to give a white foam. The foam was chromatographed (silica, 4% methanol/dichloromethane) to afford the title compound as a white foam (0.11 g, 65%). NMR(CDCl3) δ 7.31-6.54 (12H, m), 4.72 (IH, d), 4.48 (2H, d), 3.82 (IH, q), 3.61 (IH, m), 2.812.3 (6H, m), 1.65 (3H, m), 1.48 (3H, d), 1.22 (9H, s), 0.89 (9H, s), 0.70 (3H, d), 0.61 (3H, d), 0.06 (6H, s); MS m/e 693.4 [M+H]+. f) (2R,4S,5S,l'S)-5-(t-butoxycarbonyl)amino-4-tbutyldimethylsiloxy-N-[1'-isopropyl-1'-(4-methylcarbonylimidazol-2-yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide The compound of Example 27(e) (45 mg, 1.0 eq) was stirred in dry dichloromethane under an inert argon atmosphere. Manganese dioxide (23 mg, 4.0 eq) was added and the mixture was stirred at room temperature for 16 h. An additional 2.0 eq of manganese dioxide was added and the reaction was complete by TLC after 2.5 h. The mixture was filtered through a pad of Celite® and the filter cake was washed with dichloromethane. The organic solvent was evaporated to give the title compound as a white solid (0.038 g, 85%). NMR(CDC13) δ 7.49-6.76 (11H, m), 6.30 (IH, br d), 4.71 (2H, m), 3.86 (IH, q), 3.61 (IH, dd), 2.77-2.41 (5H, m), 2.31 (3H, s), 1.58 (2H, m), 1.20 (9H, s), 0.83 (9H, s), 0.69 (6H, dd), 0.04 <6H,d); MS m/e 691.4 [M+H]+. g) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[ 1' — isopropyl-1'-(4-methylcarbonylimidazol-2-yl)]methyl-6-phenyl2-phenylmethy1-hexanamide The compound of Example 27(f) (38 mg, 1.0 eq) was stirred in anhydrous THF under an argon atmosphere at room temperature. Tetrabutyl ammonium fluoride (0.33 mL, 1.0M in THF, 6.0 eq) was added and the solution stirred for 16 h.
The solution was diluted with water and extracted three times with dichloromethane. The combined organic extracts were washed with water and evaporated to a white solid. The solid was covered with diethyl ether, decanted twice, and dried to give the title compound as a white solid (25 mg, 79%).
NMR(CDC13) δ 7.14 (5H, m) , 6.86 (5H, m) , 5.14 (IH, d), 4.42 (IH, d), 3.58 (IH, q), 3.45 (IH, d) , 2.80-2.50 (5H, m) , 1.91 (IH, m), 1.63 (2H, m), 1.26 (9H, s) (rotamer observed), 0.70 (3H, d), 0.57 (3H, d); MS m/e 577.2 [M+H]+.
Example .28. is Preparation of (2R^4S, 5S, 1’.S)-SrJtrbutQxycarbQnyJ.) aminQ-4hydroxy-N- f 11-isopropyl-1(4-isopropylcarbQ.nylimidazQl-2yli1methyl-6-phenyl-2-phenylmethyl-hexanamide a) (IS, 1'RS)-1-carbobenzyloxyamino-l-isopropyl-l-(4-(1'20 hydroxy-2'-methyl)propylimidazol-2-yl)methane .
Following the procedure of Example 27(c), except using isopropyl magnesium bromide (1.024 mL, 2.0M solution, 4.0 eq) in place of methyl magnesium bromide, to yield a crude product. The crude product was chromatographed (silica, 4% methanol/dichloromethane) to yield the title compound as a white solid (0.155 g , 88%).NMR(CDCI3) δ 7.19 (5H, m), 6.58 (IH, s), 4.91 (2H, m), 4.38 (IH, q), 4.20 (IH, dd), 2.11 (IH, m), 1.83 (IH, m), 0.72 (12H, m); MS m/e 346.2 [M+H]+; 328.2, 279.0 , 254.0, 205.0, 177.0, 149.0, 118.0. b) (IS,1’RS)-1-amino-l-isopropyl-l-(4-(1'-hydroxy-2'methyl)propylimidazol-2-yl)methane Following the procedure of Example 27(d) , using the compound of Example 31(a), the title compound was prepared as a white foam (96 mg , 100%). NMR(CDC13) δ 6.65 (IH, s), 4.21 (IH, d), 3.90 (IH, s), 2.22 (IH, m), 1.94 (IH, m), 0.93 (6H, m) , 0.64 (6H, m) ; MS m/e 302.0 [M+H] + . c) (2R,4S,5S,1'S,1'’RS)-5-(t-butoxycarbonyl) amino-4-tbutyldimethylsiloxy-N-[1’-isopropyl-1'-(4-(1’'-hydroxy-2''methyl)propylimidazol-2-yl)]methyl-6-phenyl-2-phenylmethylhexanamide Following the procedure of Example 27 (e), except using the compound of Example 31(b) (96 mg, 1.1 eq), substituting dimethyl formamide as the solvent instead of dichloromethane, and purifying the product by chromatography, the title compound was prepared (168 g, 57%). NMR(CDCl3) δ 7.22-6.81 (11H, m), 6.62 (1H, d), 4.71 (1H, dd), 4.53 (1H, t), 4.19 (1H, d), 3.82 (1H, q), 3.58 (1H, dd) , 2.71-2.30 (5H, m) , 2.03 (1H, m), 1.70 (1H, m), 1.57 (1H, m), 1.14 (9H, s), 0.91 (3H, d), 0.88 (9H, s), 0.78 (3H, d), 0.67 <3H, d), 0.59 (3H, d) , 0.03 6H, d); MS m/e 721.4 [M+HJ+. d) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t-butyldimethylsiloxy-N-[1’-isopropyl-1(4-isopropylcarbonylimidazol-2-yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide Following the procedure of Example 27 (f), except using the compound of 31(c) (168 mg, 1.0 eq) and chromatographing the crude product (silica, 3% methanol/dichloromethane) the title compound was prepared as a white solid (132 mg, 79%). NMR(CDCl3) δ 7.20-6.76 (11H, m) , 5.05 (1H, br m), 3.88 (1H, q), 3.61 , m), 3.19 (1H, m), 2.80-2.46 (5H, m), 2.22 (1H, m), 2.07 (1H, m ), 1.63 (1H, m), 1.15 (16H, m), 0.89 (9H, s), 0.74 (6H, m), 0.08 (6H, d); MS m/e 719.4 [M+H]+. e) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'isopropyl-1'-(4-isopropylcarbonylimidazol-2-yl)]methyl-630 pheny1-2-phenylmethy1-hexanamide Following the procedure of Example 27(g), except using the compound of Example 31(d) (132 mg), the title compound was prepared as a white foam (90 mg, 81%). NMR(CDCl3) 6 7.48 (1H, s), 7.11 (5H, m), 6.82 (5H, m), 5.29 (1H, d), 4.46 (1H, m ), 3.54 (1H, q), 3.48 (1H, m), 3.14 (1H, m) , 2.74-2.44 (5H, m), 1.90 (1H, m), 1.61 (2H, m), 1.28 (9H, s) (rotamers observed), 1.13 (6H, m), 0.69 (3H, d), 0.48 (3H, d) ; MS m/e 605.2 [M+H]+.
Example 29 Preparation of (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-45 hydroxy-N-Γ1'-isopropyl-11- (4-phenylcarbonyl-imidazol-2y1)1 methyl-6-pheny1-2-phenylmethy1-hexanamide a) (IS,1'RS)-1-carbobenzyloxyamino-l-isopropyl-l-(4-(1'hydroxy)benzylimidazol-2-yl)methane Following the procedure of Example 27(c), except substituting phenylmagnesium bromide (0.45 mL, 3.0M solution, 4.0 eq) for methyl magnesium bromide, and chromatographing the crude product (silica, 3% methanol/dichloromethane) the title compound was prepared as a white solid (175 mg, 96%).
NMR(CDCl3) δ 7.26 (IH, d) , 7.11 (10H, m), 6.39 (IH, dd), 6.08 (IH, d), 5.63 (IH, d), 4.82 (2H, m), 4.29 (IH, m), 2.01 (IH, m), 0.76 (3H, m), 0.59 (3H, d). b) (IS,1'RS)-1-amino-l-isopropyl-l-(4-(1'-hydroxy)benzyl20 imidazol-2-yl)methane Following the procedure of Example 27(d) , except using the compound of Example 29(a) (98 mg) the title compound was prepared as a tacky white foam (65 mg, 98%). c) (2R,4S,5S,1'S,1'’RS)-5-(t-butoxycarbonyl)amino-4-tbutyldimethylsiloxy-N-[1'-isopropyl-1'-(4-(1' 1 hydroxy)benzylimidazol-2-yl)]methyl-6-phenyl-2-phenylmethy1hexanamide Following the procedure of Example 27(e), except using the compound of Example 29(b) (0.065 g, 1.1 eq), and chromatographing the crude product (2% methanol/ dichloromethane) the title compound was prepared as a white solid (109 mg, 55%). NMR(CDCl3) δ 7.48-6.79 (16H, m) , 4.77 (IH, m), 3.88 (IH, m), 3.61 (IH, m), 2.65 (4H, m), 2.39 (IH, m), 2.15 (IH, m), 1.94 (IH, m), 1.75 (IH, m), 1.56 (IH, m), 1.21 (9H, s) (rotamers observed), 0.86 (9H, s), 0.68 (6H, dd), 0.07 (6H, s); MS m/e 755.4 [M+H]+. - 65 d) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t-butyldimethylsiloxy-N-[1'-isopropyl-l'- (4-phenylcarbonylimidazol2-yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide Following the procedure Example 27(f), except using the 5 compound of Example 29(c) (109 mg, 1.0 eq), the title compound was prepared as a white solid (80 mg, 74%). NMR(CDC13) 5 7.49-6.84 (17H, m) , 3.88 (1H, q), 3.63 (1H, t), 2.87-2.49 (6H, m), 2.11 (2H, m), 1.64 (1H, m), 1.11 (9H, s), 0.82 (9H, s), 0.71 (6H, dd), 0.06 (6H, d); MS m/e 753.4 [M+H]+. e) (2R,4S,5S,1*S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N- [1 isopropyl-l’-(4-phenylcarbonylimidazol-2-yl)]methyl-6-phenyl 2-phenylmethy1-hexanamide Following the procedure of Example 27 (g), except using the compound of Example 29(d) (80 mg, 1.0 eq), the title compound was prepared as a white solid (45 mg , 74%). NMR(CDC13) δ 7.84-6.77 (16H, m), 4.48 (1H, d), 3.59 (1H, m) , 3.42 (1H, m), 2.80-2.54 (5H, m), 1.99 (1H, m), 1.63 (2H, m), 1.26 (9H, s) (rotamers observed), 0.73 (3H, d), 0.59 (3H, d) MS m/e 639.2 [M+H]+.
Example 30 Preparation of (2R.4S.5S,1'S)-5-(t-butoxycarbonyl)amino-4hydroxy-N-fl'-isopropyl-l1-(4-formylimidazol-2-yl)1 methyl-6phenyl-2-phenylmethy1-hexanamide a) (IS,1'RS)-1-amino-l-isopropyl-l-(4-(hydroxy)methyl30 imidazol-2-yl)methane .
Following the procedure of Example 27(d), except using the compound of Example 27 (a) (90 mg), the titled compound was prepared (50 mg, 100%). NMR(CDC13) δ 6.85 (1H, s) , 4.62 (2H, s), 3.85 (1H, d, J=4 Hz), 2.20-2.05 (1H, m), 0.88 (6H, d, J=5 Hz). b) (2R,4S,5S,1*S)-5-(t-butoxycarbonyl)amino-4-tbutyldimethylsiloxy-N-[1'-isopropyl-l1-(4-(hydroxy)methylimidazol-2-yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide Following the procedure of Example 27(e), except using 5 the compound of Example 30(a) (50 mg), and chromatographing the crude product (silica, 2% methanol/dichloromethane) the title compound was prepared (130 mg, 65%). NMR(CDCl3) δ 7.30-6.95 (11H, m), 4.82 (1H, d), 4.50-4.60 (1H, m), 4.40 (1H, d), 3.90-4.00 (1H, m), 3.60-3.68 (1H, m), 2.45-2.80 (5H, m), 2.20-2.30 (1H, m), 1.75-1.85 (1H, m) , 1.60-1.70 (1H, m), 1.30 (9H, s), 0.95 (9H, s), 0.75 (3H, d), 0.62 (3H, d), 0.05 (6H, d) . c) (2R,4S,5S,1’S)-5-(t-butoxycarbony1)amino-4-t15 butyldimethylsiloxy-N-[1'-isopropyl-l'-(4-formylimidazol-2yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide Following the procedure of Example 27(f), except using the compound of Example 30(b) (50 mg), the title compound was prepared (20 mg, 40%). NMR(CDCl3) δ 9.80(0.5H, s), 9.64 (0.5H, s) , 7. 50-6. 90 (11H, m) , 6.52-6 .42 (1H, m) , 4 . 88-4 .70 (2H, m), 4.42 -4.32 (1H, m), 4.02-3.93 (1H , m) , 3.78- •3.71 (1H, m) , 2.90- 2.40 (5H, m), 2.30 -2.19 (1H, m) , 1.87 -1.62 (2H, m) , 1.45 (9H, s) , 0.95 (9H, s), 0.87-0.72 (6H , m), 0.05 (6H, m) (rotamers). d) (2R,4S,5S,l'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'isopropyl-l'-(4-formylimidazol-2-yl)]methyl-6-phenyl-2phenylmethyl-hexanamide Following the procedure of Example 27(g), except using 30 the compound of Example 30(c) (20 mg), the title compound was prepared (12 mg, 71%). NMR(CD3OD) δ 9.60 (1H, s) , 7.65 (1H, s) , 7.20-6.90 (10H, m) , 4.52 (1H, d) , 3.60 (1H, m), 3.45 (1H, d) , 2.80-2.45 (5H, m), 2.00-1.88 (1H, m) , 1.75-1.65 (1H, m) , 1. 62-1.45 (1H, m) , 1.27 (9H, s) , 0.82 (3H, d), 0.62 (3H, d) ; MS m/e 563.4, 242.2, 204.8. - 67 Example 31 Preparation of (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4hydroxy-N-Γ1'-isopropyl-1(4-(hydroxymethyl)-imidazol-25 yl)1methyl-6-phenyl-2-phenylmethyl-hexanamide Following the procedure of Example 27 (g), except using the compound of Example 30(b) (40 mg), the title compound was prepared (20 mg). NMR(CD3OD) δ 7.27-6.92 (10H, s), 6.72 (IH, s), 4.52 (IH, d), 3.64-3.60( IH, m), 3.48( IH, d), 2.82-2.50 (5H, m), 2.03-1.92 (IH, m), 1.78-1.67 (IH, m), 1.63-1.49 (IH, m) , 1.28 (9H, s), 0.80 (3H, d), 0.65 (3H, d); MS m/e 565.4.
Example.. 32 Preparation of (2R,4S,5S,1'S)-5-((tetrahvdrothiopyran-4vl)oxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2yl)methyl-6-phenyl-2-phenylmethyl-hexanamide Following the procedures of Example 14 (a)-14 (c), except using 4-hydroxytetrahydrothiopyran in place of 2benzyloxyethanol, the title compound was prepared.
Analytical data for the intermediates of this synthesis were: a) (tetrahydrothiopyran-4-yl)-(4-nitro)phenylcarbonate.
NMR(CDCl3) δ 8.26 (IH, s) , 8.22 (1H, s), 7.38 (IH, s), 7.33 (IH, s), 4.79 (IH, m), 2.90-2.75 (2H, m), 2.70-2.52 (2H, m) , 2.31-2.16 (2H, m), 2.10-1.90 (2H, m) . b) (2R,4S,5S,1'S)-5-((tetrahydrothiopyran-4-yl)oxycarbonyl)amino-4-hydroxy-N- (1'-isopropyl-1'-imidazol-2-yl)methyl-6phenyl-2-phenylmethyl-hexanamide. NMR(CD3OD) δ 7.12-6.65 (10H, m), 6.64 (2H, s), 5.60 (IH, d), 4.36 (2H, m), 3.58 (IH, q), 3.49 (IH, d), 2.68-2.48 (6H, m), 2.44-2.30 (3H, m), 1.9335 1.74 (3H, m), 1.70-1.40 (4H, m), 0.61 (3H, d) , 0.50 (3H, d) .
IE 922346 Example 33 Preparation of (2R,4S,5S,1*S)-5-((tetrahydro-4H-pyranT4yl)oxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-11-imidazol-25 yl)methyl-6-phenyl-2-phenylmethyl-hexanamide Following the procedures of Example 14(a)-14(c), except using 4-hydroxytetrahydro-4H-pyran in place of 2benzyloxyethanol, the title compound was prepared.
Analytical data for the intermediates of this synthesis were: a) (tetrahydro-4H-pyran-4-yl)-(4-nitro)phenylcarbonate. NMR(CDC13) δ 8.32 (1H, s) , 8.28 (1H, s), 7.41 (1H, s), 7.38 (1H, s), 5.00 (1H, m), 4.05-2.90 (2H, m), 3.68-3.49 (2H, m) , 2.17-2.00 (2H, m) , 1.95-1.75 (2H, m) . b) (2R,4S,5S,1'S)-5-((tetrahydro-4H-pyran-4-yl)oxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-1’-imidazol-2-yl)methyl-6phenyl-2-phenylmethyl-hexanamide. NMR(CD3OD) δ 7.16-6.89 (10H, m), 6.79 (2H, s), 4.54 (2H, m), 3.82-3.70 (2H, m) , 3.69-3.62 (1H, m), 3.50-3.46 (1H, m), 3.45-3.35 (2H, m) , 2.79-2.65 (4H, m), 2.64-2.45 (3H, m), 2.00 (1H, m), 1.82-1.62 (3H, m), 1.55-1.45 (2H, m), 1.37 (1H, m) , 0.79 (3H, d), 0.63 (3H, d) .
Example 34 Preparation of (2R,j4S, 5S, 1'5)-5-(4-picolinvlgxv)amingr4r. hydroxy-N-(11-isopropyl-11-imidazol-2-yl) methyl-6-phenyJL-230 phenylmethyl-hexanamide The compound of Example 1(d) was dissolved in neat TFA. After 10 min the solution was concentrated to provide the amine salt, (2R,4S,5S,1'S)-5-amino-4-hydroxy-N-(1’-isopropyl35 1’-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide trifluoroacetate. This amine salt (25 mg, 1 eq) was dissolved in DMF, and 4-picolinium-(p-nitro)phenyl carbonate p-nitrophenylate (23 mg, 1 eq) and triethylamine (0.04 mL, 5 IE 92231θ - 69 eq) were added. The mixture was stirred under Ar for 17 h. Water was added and the mixture was extracted with dichloromethane. The organic extracts were concentrated and the residue was triturated with ether to yield the title compound (20 mg, 61%). NMR(CD3OD) δ 8.52 (2H, d) , 7.10 (14H, m), 6.87 (2H, s), 5.07 (2H, dd), 4.61 (IH, d), 3.80 (IH, m), 3.59 (IH, m), 2.77 (5H, m), 2.05 (IH, m), 1.83 (IH, m), 1.60 (IH, m), 0.84 (3H, d), 0.59 (3H, d).
MS m/e570.5 [M+H]+.
Example -15 Preparation of (2R. 4S. 5S, 11 S)-5-(t-butoxycarbonyl) amina-Ar. hydroxy-N- (1'-isopropyl-1 '-imidazol-2-yl) methyJ.-f-phenvl~.215 (4,4,4-trifluorobut-l-yl)hexanamide a) (3R,5S,1’S)-(1'-t-butoxycarbonylamino-2'-phenyl)ethyl-3(4,4,4-trifluorobut-l-yl)-tetrahydrofuran-2-one To a solution of lithium diisopropyl amide (1.8 mL of a 20 1.5M solution, 2.2 eq) in tetrahydrofuran (10 mL) was added (5S, 1'S)-(1’-t-butoxycarbonylamino-2'-phenyl)ethyltetrahydrofuran-2-one (0.50 g; 1.0 eq) in anhydrous THF (2 mL) at -78°C. After stirring for 15 min at -78°C, hexamethylphosphoramide (0.57 mL, 2.0 eq) was added to the solution. The solution was stirred for several min and 1,1,1-trifluoro-4-iodobutane (0.78 g, 2.0 eq) was added. After 2 h at -78°C, the reaction mixture was quenched with a 10% aqueous HC1 and extracted with dichloromethane. The organic extracts were combined and evaporated to a clear oil The oil was chromatographed (silica, 2% methanol/ dichloromethane) to give the title compound as a white foam (0.248 g, 37%). NMR: (CDC13) δ 7.18 (5H , m), 4.57 (IH; d), 4.41 (IH , dd), 3.95 (IH , q), 2.82 <2H, d), 2.55 (2H , m), 2.49-1.49 (7H , m), 1.32 (9H , s); MS m/e 438.0 (M+Na)+. - 70 b) (2R,4S,5S)-5-(t-butoxycarbonyl)amino-4-t-butyldimethylsiloxy-6-phenyl-2-(4,4,4-trifluorobut-l-yl)hexanoic acid Following the procedure of Example 12(b), except using the compound of Example 35(a) (245 mg), the title compound was prepared (215 mg, 67%). NMR(CDCl3) δ 7.18 (5H, m), 4.70 (1H, d), 3.88 (1H, q), 3.69 (2H, m), 2.73 (1H, m), 2.38 (1H, m), 1.91 (2H, m), 1.45 (6H, m), 1.31 (9H, s) (rotamers observed), 0.90 (9H, s), 0.08 (6H, d); MS m/e548.2 [M+H]+. c) (2R,4S,5S,1’S)-5-(t-butoxycarbonyl)amino-4-t-butyldimethylsiloxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6phenyl-2- (4,4,4-trifluorobut-l-yl)hexanamide Folowing the procedure of Example 1 (c), except using the compound of Example 35(b) (100 mg) and (IS)-l-imidazol-2-yl15 2-methylpropylamine, the title compound was prepared (83 mg, 68%). NMR(CDC13) δ 7.22 (5H, m) , 7.03 (1H, d), 6.89 (2H, s) , 4.72 (1H, d), 4.51 (1H, t), 3.91 (1H, q) , 3.65 (1H, m), 2.78 (2H, d), 2.33 (2H, m), 1.82 (4H, m), 1.48 (4H, m), 1.36 (9H, two singlets; rotamers present), 0.99 (9H, s), 0.91 (3H, d), 0.79 (3H, d), 0.07 (6H, d); MS m/e669.4 [M+H]+. d) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1'isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-(4,4,4trifluorobut-l-yl)hexanamide Following the procedure of Example 9(d), except using the compound of Example 35(c) (83 mg), the title compound was prepared (40 mg, 58%). NMR(CD3OD) δ 7.19 (5H, m), 6.92 (2H, s), 4.61 (1H, d), 3.64 (1H, q), 3.48 (1H, m), 2.79 (2H, m) , 2.49 (1H, m), 2.13 (4H, m) , 1.60 (5H, m) , 1.36 (9H, s), 0.90 (3H, d), 0.71 (3H, d); MS m/e555.2 [M+H]+.
Example 36 Preparation of (2R.4S.5S.1'S)-2-phenylmethyl-4-hydroxy-5-(t35 butoxycarbonyl)amino-6-phenvl-N-(11-isobutvl-1(imidazo-2yl) )methy1-hexanamide. hydrochloride a) 2-(1'-carbobenzyloxyamino-1'-isobutyl)methyl-imidazole Following the procedure of Example 1(a), except substituting Cbz-isoleucinal (1.83 g) for Cbz-valinal, the title compound was prepared (0.658 g, 31%). NMR(CDCl3) δ 6.96 (2H, s), 5.31 (1H, d) , 4.48 (1H, dd) , 2.15 (1H, m) , 1.44 (9H, s), 1.17 (2H, m), 0.92 (3H, t), 0.82 (3H, d) ; MS (DCI/NH3) m/e 254.2 [M+H]+. b) (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t10 butoxycarbonyl)amino-6-phenyl-N-(1’-isobutyl-1'- (imidazo-2yl))methyl-hexanamide hydrochloride Following the procedure of Example 1(b)-1(d), except substituting the compound of Example 36(a) for (l'S)-l'carbobenzyloxyamino-1'-isopropyl-l'-(imidazo-2-yl)methane, the title compound was prepared. NMR(DMSO-d6) δ 7.90 (lH,d), 7.29-7.02 (10H, m), 6.89 (2H,s), 6.50 (lH,d), 4.81 (lH,m), 4.55 (1H, dd), 3.56 (lH,m), 2.69 (5H,m), 1.80 (lH,m), 1.59 (2H, m), 1.30 (9H,s), 1.17 (2H, m), 0.78 (3H, t), 0.63 (3H, d); MS (DCI/NH3) m/e 549.7 [M+H]+.
Example 37 Preparation of (2Rf4S.5S.1'S)-5-(t-butoxycarbonyl)amino-4hydroxy-N-fl'-isopropyl-l'- (4- ((IRS)-1-hydroxyethyl)25 imidazol-2-yl)1methyl-6-phenyl-2-phenylmethyl-hexanamide The t-butyldimethylsiloxy-protected alcohol from Example 30(e) (20 mg, 1.0 eq) was stirred in anhydrous THF under an argon atmosphere at room temperature. Tetrabutyl ammonium fluoride (0.33 mL of a 1.0M solution in THF, 6.0 eq) was added and the solution stirred for 16 h. The solution was diluted with water and extracted with dichloromethane. The combined organic extracts were washed with water and evaporated to a white solid. The solid was covered with diethyl ether and decanted twice to give the title compound as a white solid. (0.012 g, 72%). NMR(CDC13) δ 7.22-6.84 (10H, m), 6.61 (1H, s), 5.42 (1H, d), 4.69 (1H, m), 4.41 (1H, d), 3.58 (1H, m) , 3.45 (1H, m), 2.78-2.40 (5H, m), 1.91 (1H, m), 1.59 (2H, m) , 1.41 (3H, d) , 1.26 (9H, s) (rotamers observed), 0.71 (3H, d), 0.59 (3H, d); MS m/e 579.2 [M+H]+.
Example 38 5 Preparation of (2R,4S,5S,11S)-5-(1.l-dimethyl-2hydroxyethoxycarbonyl)amino-4-hydroxy-N-(l'-isopropyl-l1imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide a) 2-t-butyldimethylsiloxy-l,1-dimethylethyl-(4nitrophenyl)carbonate A mixture containing bis(4-nitrophenyl)carbonate (0.996 g, 3.28 mmol), 2-t-butyldimethylsiloxy-l,1dimethylethanol (0.67 g, 1 eq) and 4-dimethylaminopyridine (0.4 g, 1 eq) in dichloromethane (50 mL) was stirred at room temperature for 5 d. The mixture was diluted with dichloromethane and washed successively with H2O and saturated aqueous NaCl, and dried over Na2CO3. The solvent was removed in vacuo, and the residue was purified by flash chromatography (silica, 20% ethyl acetate/hexanes) to afford the title compound (35%). NMR(CDC13) δ 8.25 (2H, m), 7.35 (2H, m), 3.76 (2H, s), 1.53 (6H, s), 0.94 (9H, s), 0.09 (6H, s) . b) (2R,4S,5S,1'S)-5-(2-t-butyldimethylsiloxy-l,1-dimethylethoxycarbonyl)amino-4-t-butyldimethylsiloxy-N-(1'-isopropyl1'-imidazol-2-yl)methyl-6-pheny1-2-phenylmethy1-hexanamide A solution of 2-t-butyldimethylsiloxy-l,1-dimethylethyl4-nitrophenyl carbonate (137 mg, 0.372 mmol), (2R,4S,5S,1'S)30 5-amino-4-t-butyldimethylsiloxy~N-(1'-isopropyl-1'-imidazol2-yl) methyl-6-phenyl-2-phenylmethyl--hexanamide (102 mg, 0.186 mmol) and DMAP (45 mg, 0.372 mmol) in methylene choride was stirred at 20°C under Ar for 24 h. The solution was washed with aqueous Na3CO3, dried over solid Na2CO3 and concentrated.
Flash chromatography (4% methanol/dichloromethane) provided the intermediate (2R, 4S, 5S, 1' S)-5--(2-t-butyldimethylsiloxy1,1-dimethylethoxycarbonyl)amino-4-t-butyldimethylsiloxy-N(1’-isopropyl-l'-(1-(2-t-butyldimethylsiloxy-l, 1IE 922316 - 73 dimethylethoxycarbonyl)imidazol-2-yl)methyl-6-phenyl-2phenylmethyl-hexanamide, which was dissolved in ether, washed with 10% NaOH, dried over Na2CC>3, and concentrated to provide the title compound (110 mg, 78% overall). NMR(CDCl3) δ 7.375 6.70 (13H, m), 6.39 (IH, d), 4.84 (IH, d), 4.55 (IH, t), 3.96 (IH, q) , 3.69 (2H, s), 3.60-3.42 (2H, m), 2.94 (IH, s(br)), 2.85-2.44 (4H, m), 2.39 (IH, q), 1.90-1.60 (2H, m), 1.31 (6H, d), 1.02-0.85 (18H, m), 0.83 (6H, t), 0.98 (12H, m). c) (2R,4S,5S,1'S)-5-(1,l-dimethyl-2-hydroxyethoxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-l'-imidazol-2yl)methyl-6-phenyl-2-phenylmethy1-hexanamide A mixture containing the compound of Example 38(b) (110 mg) and tetra-n-butylammonium fluoride (6 eq of 1 M solution in THF) under an argon atmosphere was allowed to stir at room temperature overnight. The solution was diluted with dichloromethane and washed with water, and the organic layer was concentrated. The residue was purified by flash chromatography (4% methanol/dichloromethane) to afford the title compound (0.05 g, 66%). NMR(CDCl3, CD3OD) δ 7.30-6.78 (12H, m), 4.42 (IH, d), 3.75-3.38 (4H, m) , 2.97-2.50 (5H, m) , 2.08 (IH, m), 1.70-1.56 (2H, m) , 1.30 (6H, s), 0.90-0.55 (6H, dd) .
Example 39 Preparation of (2R.4S.5S.1'S)-5-(1.l-dimethyl-2-hydroxyethoxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-l’-imidazol-2yl)methyl-6-phenyl-2-phenylmethyl-hexanamide hydrochloride A 1M solution of HC1 in ether (63.5 mL) was added to a solution of the compound of Example 38(c) (35 mg, 0.064 mmol) in methanol (5 mL). The solvent was removed by rotary evaporation at 20°C, and the solid residue was triturated with ether and dried to afford the title compound as the hydrochloride salt (35 mg, 95%). NMR(CD3OD) δ 7.37-6.85 (12H, m), 4.56 (IH, d), 3.59 (IH, m), 3.48-3.33 (3H, m), 2.85-2.48 (6H, m), 2.04 (1H, septet), 1.72-1.49 (2H, m), 1.22 (6H, d), 0.88(3H, d), 0.61 (3H, dd).
Example 4D 5 Preparation of (2R,4S,5S,1'S)-5-(2-hydroxyethoxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-11-imidazol-2-yl)methyir6r phenyl-2-phenylmethylhexanamide a) benzyloxyethyl-(4-nitro)phenylcarbonate To a solution of 2-benzyloxyethanol (2.5 g, 16.4 mmol) and bis (4-nitrophenyl)carbonate (5.0 g, 1 eq) in dichloromethane (200 mL), N-methylmorpholine (1.81 mL, 1 eq) was added. The resulting mixture was allowed to stir at room temperature for 3 d. The reaction mixture was washed successively with H2O and saturated aqueous NaCl and dried over Na2SC>4. The solvent was removed in vacuo, and the residue was purified by flash chromatography (silica, 20% ethyl acetate/hexanes) to afford the title compound (4.38 g, 84%). NMR(CDCl3) δ 8.26 (2H, m) , 7.34 (7H, m), 4.62 (2H, s), 4.49 (2H, t), 3.70 (2H, t). b) (2R,4S,5S,1'S)-5-(2-benzyloxyethoxycarbonyl)amino-4-tbutyldimethylsiloxy-N-[1'-isopropyl-1’-(N'-(225 benzyloxyethoxy)carbonyl)imidazol-2-yl]methyl-6-phenyl-2phenylmethyl-hexanamide To a solution of (2R,4S,5S,1'S)-5-amino-4-tbutyldimethylsiloxy-N-(1'-isopropyl-11-imidazol-2-yl)methyl6-phenyl-2-phenylmethyl-hexanamide (134.5 mg, 0.24 mmol) in dichloromethane (40 mL) under an argon atmosphere, benzyloxyethyl 4-nitrophenyl carbonate (160 mg, 2 eq) and 4dimethylaminopyridine (60 mg, 2 eq) were added. The resulting mixture was allowed to stir at room temperature overnight, and was diluted with dichloromethane. The organic extract was washed successively with aqueous Na2CC>3, H2O, aqueous Na2CC>3 and H20, and dried over Na2CO3. The solvent was removed in vacuo, and the residue was purified by flash chromatography (silica, 4% methanol/dichloromethane) to afford the title compound (180 mg, 82%). NMR(CDCl3) δ 7.456.80 (22H, m), 6.62 (1H, d) , 5.60 (1H, t) , 5.06 (1H, d), 4.60 (2H, s), 4.52 (2H, s), 4.50 (2H, m), 4.31 (1H, m), 4.07 (2H, m), 3.80 (2H, t), 3.68 (1H, q), 3.57 (1H, q), 2.85 (1H, m), 2.77-2.41 (4H, m), 2.09 (1H, m), 1.90 (1H, m), 1.73 (1H, m), 0.95 (9H, s), 0.81 (6H, dd), 0.11 (6H, d). c) (2R,4S,5S,1 * S)-5-(2-hydroxyethoxycarbonyl)amino-4-t-butyldimethylsiloxy-N-[1’-isopropyl-l'-(Ν’-2-benzyloxyethoxy10 carbonyl)imidazol-2-yl]methyl-6-phenyl-2-phenylmethylhexanamide The compound of Example 40(b) (68 mg, 0.44 mmol) was stirred as a solution in methanol (50 mL) with Pd(0) (10 mg) under 1 atm hydrogen for 12 h. The mixture was filtered, the solvent was removed in vacuo, and the residue was purified by flash chromatography (silica, 4% methanol/dichloromethane) to afford the title compound (44 mg, 74%). NMR(CDCl3) δ 7.366.72 (12H, m), 5.03 (1H, d), 4.80 (1H, dd), 4.50-4.32 (2H, m), 4.07-3.52 (5H, m), 2.96-2.32 (6H, m), 1.98-1.85 (2H, m), 0.95 (9H, s), 0.90-0.75 (6H, dd), 0.05 (6H, d). d) (2R,4S,5S,1'S)-5-(2-hydroxyethoxycarbonyl)amino-4-hydroxyN-(1'-isopropyl-l'-imidazol-2-yl)methyl-6-phenyl-2phenylmethyl-hexanamide To a solution of the compound of of Example 40(c) in methanol, excess aqueous HC1 (approx. 5 equiv.) was added. The resulting solution was stirred at room temperature overnight, and concentrated under reduced pressure. The residue was diluted with H2O, and made basic with aqueous Na2CO3. The mixture was extracted with dichloromethane, and the combined organic extracts were dried over Na2CC>3. The solvent was removed in vacuo, and the residue was purified by flash chromatography to afford the title compound.
NMR(CD3OD) δ 7.28-6.85 (12H, m) , 4.55 (1H, d), 3.95 (1H, m) , 3.73-3.40 (4H, m), 2.86-2.47 (5H, m), 1.99 (1H, m), 1.71 (1H, m), 1.22 (1H, m), 0.84 (3H, d), 0.62 (3H, d).
Example 41 Preparation of (2R,4S,5S,11S)-5-((IRS)-l-methyl-2hydroxyethoxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-115 imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide a) 2-fc-butyldimethylsiloxy-l-methylethyl-(4-nitrophenyl)carbonate A mixture containing bis(4-nitrophenyl)carbonate (3.20 g, 10.5 mmol), 2-t-butyldimethylsiloxy-l-methylethanol (2.0 g, 10.5 mmol) and 4-dimethylaminopyridine (1.30 g, 1 0. mmol) in dichloromethane (200 mL) was stirred at room temperature for 5 d. The mixture was then diluted with dichloromethane and washed successively with H2O and saturated aqueous NaCl and dried over Na2CC>3. The solvent was removed in vacuo, and the residue was purified by flash chromatography (silica, 10% ethyl acetate/hexane) to afford the title compound (88%). NMR(CDCl3) δ 8.28 (2H, m), 7.39 (2H, m), 4.98 (1H, m), 3.75 (2H, d) , 1.38 (3H, s) , 0.92 (9H, s) , 0.11 (6H, s) . b) (2R,4S,5S,1'S)-5-(2-t-butyldimethylsiloxy-l-methylethoxycarbonyl)amino-4-fc-butyldimethylsiloxy-N-(1'-isopropyl 1’-imidazol-2-yl) methyl-6-pheny1-2-phenylmethy1-hexanamide Following the procedure of Example 38(b), except substituting the compound of Example 4(a) for 2-tbutyldimethylsiloxy-1,1-dimethylethy1-4-nitrophenyl carbonate, the title compound was prepared. NMR(CDCl3) δ 7.40-7.00 (10H, m), 6.90 (1/2H, s), 6.72 (1/2H, s), 6.45 (1H dd), 4.92 (1H, dd), 4.84-4.61 (2H, m), 4.10 (1H, m), 3.76 (1H, m), 3.58 (1H, m), 2.92-2.73 (3H, m), 2.70-2.45 (3H, m) , 1.78 (2H, m), 1.22-1.08 (3H, m), 1.04-0.81 (24H, m), 0.170.09 (12H, m). c) (2R,4S,5S,1*S)-5-((IRS)-l-methyl-2-hydroxyethoxycarbonyl) amino-4-hydroxy-N-(1'-isopropyl-l'-imidazol-2-yl)methyl-6pheny1-2-phenylmethy1-hexanamide Following the procedure of Example 38(c), except using the compound of Example 4(b), the title compound is prepared. NMR(CD3OD) δ7.15-6.68 (12H, m), 5.72-5.60 (IH, dd), 4.58 (IH, m), 4.38 (IH, dd), 4.06 (IH, m), 3.62 (IH, m), 3.41 (IH, m), 2.79-2.55 (5H, m), 2.49 (IH, dd), 1.92 (IH, m), 1.67 (IH, m), 1.08-0.98 (3H, dd), 0.69 (3H, dd) , 0.58 (3H, dd) .
Example 42 Preparation of (2R.4S.5S.11S)-5-(2-hydroxy-lcyclopentyloxycarbonyl) amino-4-hydroxy-N- (1'-isoprop.vl.nl imidazol-2-yl)methyl-6-pheny1-2-phenylmethylhexanamide a) (trans)-2-(t-butyldimethysiloxy)-cyclopentanol To a mixture of t-butyldimethylsilyl chloride (5.08 g, 33.7 mmol) and imidazole (2.30 g, 33.7 mmol) in DMF (10 mL), a solution of trans-1,2-cyclopentanediol in DMF (4 mL) was added. The reaction mixture was stirred overnight at 25°C. The reaction mixture was diluted with ice water and extracted with ether. The ether extract was washed with water and brine, dried over magnesium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography (silica, 9:1 hexane:ethyl acetate) to the title compound as an oil (3.44 g, 49%) . b) ((trans)-2-(t-butyldimethysiloxy)-cyclopentyl)-(430 nitrophenyl)carbonate To a solution of the compound of Example 42(a) (1.08 g, mmol) and DMAP (0.611 g, 5 mmol) in dichloromethane (12 mL), bis (4-nitrophenyl)carbonate (1.52 g, 5 mmol) was added. The solution was stirred overnight at 25°C. The reaction mixture was diluted with dichloromethane (15 mL), and washed with water and brine. The organic extract was dried over magnesium sulfate, filtered, and the solvent was removed at reduced pressure. The residue was triturated with hexane:ethyl acetate (1:1) and filtered. The filtrate was evaporated to an oil and purified by flash chromatography (silica, 9:1 hexane:ethyl acetate) to yield the title compound as an oil (1.75 g, 92%). c) 5-((trans)-2-t-butyldimethylsiloxy-cyclopentyloxycarbonyl)amino-4-t-butyldimethysiloxy-N-[1'-isopropyl-l’- (1(2-t-butyldimethysiloxy-cyclopentyloxycarbonyl))imidazol-2yl]methyl-6-phenyl-2-phenylmethyl-hexanamide A solution of 5-amino-4-t-butyldimethylsiloxy-N-[1'isopropyl-1'-imidazol-2-yl]methyl-6-pheny1-2-phenylmethylhexanamide (171 mg, 0.311 mmol), DMAP (76.1 mg, 0.623 mmol) and the compound of Example 42(b) (238 mg, 0.623 mmol) in dichloromethane (9 mL) was stirred overnight at 25°C. The reaction mixture was diluted with dichloromethane, washed with water and saturated sodium bicarbonate solution, and dried with magnesium sulfate. The organic extract was filtered and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica, 4:1 hexane:ethyl acetate) to yield the title compound as an oil (150 mg, 47%). d) 5-( (trans)-2-hydroxy-cyclopentyloxycarbonyl)amino-4hydroxy-N-[1’-isopropyl-l'-imidazol-2-yl]methyl-6-phenyl-225 phenylmethyl-hexanamide To a solution of the compound of Example 42(c) (150 mg, 0.145 mmol) in methanol (5 mL) , 3N HCl (3 mL) was added. The solution was stirred overnight at 25°C. The methanol was evaporated in vacuo, and the residue was diluted with water and extracted with ether. The aqueous solution was neutralized with 5% sodium carbonate (~pH 7) and a solid precipitated. The solid was filtered, washed with water and dried in vacuo to yield the title compound (51.5 mg, 63%) . - 79 Example._4 2 Preparation of (2R,4S,5S,l'S)-5-(4-hydroxybutanoyl)aminQ-4_hydroxy-N-(11-isopropyl-l1-imidazol-2-yl)methyl-6-phenyl-25 phenylmethylhexanamide a) t-butyldimethylsilyl 4-(t-butyldimethylsiloxy)-butanoate To a suspension of t-butyldimethylsilyl chloride (29.9 g, 198 mmol) in dry DMF (20 mL), 4-hydroxybutyric acid, sodium salt (5.0 g, 397 mmol) and imidazole (27.0 g, 0.397 mol) were added. The reaction mixture was stirred overnight at 25°C. The solvent was removed under reduced pressure and the residue was diluted with 10% aqueous citric acid (200 mL). The residue was extracted with ether. The ether solution was dried with magnesium sulfate, filtered and evaporated to yield the title compound as an oil. b) 4-t-butyldimethylsiloxy-butanoic acid A solution of the compound of Example 43(a) (5.0 g) was dissolved in acetic acid: tetrahydrofuran: water (2:2:1, 50 mL) solution and stirred for 2.5 h. The solution was diluted with water and extracted with ether. The ether solution was dried with magnesium sulfate, filtered and evaporated to an oil. The oil was purified by flash chromatography (silica, hexane-ethyl acetate, 9:1) to yield the title compound as an oil (180 mg). c) (2R,4S,5S,1’S)-5-(4-t-butyldimethylsiloxy-butanoyl)amino4-hydroxy-N-(1’-isopropyl-l'-imidazol-2-yl)methyl-6-phenyl-230 phenylmethylhexanamide A solution of (2R,4S,5S,1’S)-5-amino-4-tbutyldimethylsiloxy-N-(1'-isopropyl-l'-imidazol-2-yl)methyl6-phenyl-2~phenylmethyl-hexanamide (175 mg, 0.319 mmol), 4-tbutyldimethylsiloxy-butanoic acid (84 mg, 0.41 mmol), BOP reagent (148, 0.335 mmol), triethylamine (46 gL, 0/335 mmol) and dichloromethane (4 mL) were stirred at 20°C under Ar for 24 h. The reaction mixture was diluted with dichloromethane, washed with aqueous Na2CO3, water and brine, and dried over solid magnesium sulfate. The organic phase was filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica, 2% methanol/chloroform) to provide the title compound. d) (2R,4S,5S,1'S)-5-(4-hydroxybutanoyl)amino-4-hydroxy-N-(l’isopropyl-l ’-imidazol-2-yl)methyl-6-phenyl-2phenylmethylhexanamide A solution of the compound of Example 43(c) (177 mg, 0.236 mmol) and tetra-n-butylammonium fluoride (2.84 mL, 2.84 mmol; 1M solution in THF) was stirred under an argon atmosphere at room temperature overnight. The solution was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, and water, and the organic layer was concentrated. The residue was precipitated from the ethyl acetate solution to afford the title compound.
Example 44 Preparation of (2R,4S,5S,l'S)-2-phenylmethyl-4-hydroxy-5(benzyloxycarbonyl)valylamino-6-phenyl-N-(1'-isobutyl-l'imidazo-2-yl)methy1-hexanamide (a) (2R,4S,5S,1'S)-2-phenylmethyl-4-butyldimethylsiloxy-525 (benzyloxycarbonyl)valylamino-6-phenyl-N-(1’-isobutyl-1'(imidazo-2-yl))methyl-hexanamide.
A solution of carbobenzyloxy-(L)-valine (50.4 mg, 0.20 mmol), the product of Example 13(a) (110 mg, 0.20 mmol), BOP reagent (88.7 mg, 0.20 mmol) and triethylamine (28 μΐ, 0.20 mmol) in methylene chloride (4 mL) was stirred at 25°C for 4 d. The reaction mixture was diluted with methylene chloride, washed with saturated sodium bicarbonate and the organic layer was concentrated. The product was purified by flash chromatography (silica gel, 4% CH2CI2/ MeOH) to give the title compound (104 mg, 67%) . - 81 (b) (2R,4S,5S,11S)-2-phenylmethyl-4-hydroxy-5(benzyloxycarbonyl-valyl)amino-6-phenyl-N-(1'-isobutyl-1'imidazo-2-yl)methyl-hexanamide.
To a solution of the compound of Example 44(a) (104 mg, 0.133 mmol) in MeOH (8 mL), 3 N HC1 (2 mL) was added. The solution was stirred for 16 hrs at 25°C. The methanol was removed at reduced pressure and 10% sodium carbonate was added to pH -7.5. Ether (10 mL) was added and the solid product was filtered and dried in vacuo to provide the title compound (58 mg, 65%) . NMR(CDCl3) 5 0.62 (d, 3H), 0.78 (d, 3H), 0.82 (d, 3H), 0.90 (d, 3H), 1.62 (m, 2H), 1.96 (m, 1H), 2.06 (m, 1H), 2.55 (m, 1H), 2.77 (m, 4H), 3.38 (s, 1H), 3.53 (m, 1H), 3.91 (Μ,1H), 3 .99 (m, 1H), 4.47 (d, 1H), 5.11 (s, 2H), 5.78 (d, 1H), 6.85 (s, 2H), 6.92-7.34 (m, 15H); MS m/e 667 [M+H] + .
Example 45 Preparation of (2R.4S.5S.1’S)-2-phenylmethyl-4-hvdroxv-5-(N~ agety-IvalyllaminQ-S-phenyl-N- (1 ’-isobutyl-1 '.-imidazQ-2yl)methyl-hexanamide (a) (2R,4S,5S,1'S)-2-phenylmethyl-4-t-butyldimethylsil)oxy-5(N-acetyl-valyl)amino-6-phenyl-N-(1’-isobutyl-11-imidazo-225 yl)methyl-hexanamide To a solution of N-acetyl-(L)-valine (40.3 mg, 0.253 mmol) in dry THF (8 mL) at -40°C was added n-methylmorpholine (55.7 μΐ, 0.506 mmol) followed by isobutyl chloroformate (33.5 μΐ, 0.253 mmol). The reaction mixture was stirred for min, and the compound of Example 13(b) (139 mg, 0.253 mmol) in THF (3 mL) was added. The reaction mixture was allowed to warm to room temperature and stirred for 2 d. The reaction was diluted with ethyl acetate, and washed with water and brine. The organic solution was dried with sodium sulfate, filtered and the solvent removed under reduced pressure. The residue was purified by flash chromatography (silica, 4% methanol/chloroform) to give the product as an oil (47 mg, 27%). - 82 (b) (2R,4S,5S,1’S)-2-phenylmethyl-4-hydroxy-5-(Nacetylvalyl)amino-6-phenyl-N-(1'-isobutyl-1'-imidazo-2yl)methyl-hexanamide.
To a solution of the compound of Example 45(a) (47 mg, 0.0681 mmol) in methanol (3 mL), 3N HC1 (0.5 mL) was added. The reaction was stirred for 16 h at 25°C. The methanol was removed under reduced pressure and the solution was diluted with water and neutralized with 5% sodium carbonate. The solid product was filtered, washed with water and ether, and dried in vacuo to yield the title compound (29.5 mg, (75%).
NMR (CD3OD) δ 0.70 (d, 3H) , 0.88 (m, 9H) , 1.57 (m, IH) , 1.70 (m, IH), 1.92 (s, 3H), 2.05 (m, IH), 2.55 (q, IH) , 2.77 (m, 4H) , 3.57 (d, IH) , 4.03 ϊ 2H), 4.60 (d, IH) , 6.87 (s, 2H) , 6.95 -6.20 (m, 10H) ; MS m/e 575 [M+H]+ Exampie_A-6 Preparation- Qi J.2R, iSL-L~JJimidazQl-2r yl)methyloxycarbonyl] ^ϊΩ0-,4-^γάΓ0χγ-Ν-11.1.-ΐ20ΡΓ0ργ·1=·11-imidazci-2-yl)methyL-6-phenyl-2rphenylmethyl-hexanamLde a) (1-(benzyloxymethyl)imidazol-2-yl)methyl-(4nitrophenyl)carbonate A mixture of bis(4-nitrophenyl)carbonate, (1benzyloxymethyl)imidazol-2-yl)methanol and 4dimethylaminopyridine was reacted according to the procedure of Example 14(a) to afford the title compound (58%). NMR(CDCl3, 400 MHz) δ 8.18 (d, 2 H, J=8.38 Hz), 7.44-7.23 (m, 7H), 7.11 (s, IH), 7.13 (S, IH), 5.48 (s, 2H), 5.44 (s, 2H), 4.49 (s, 2H) . b) (2R,4S,5S,1'S)-5-((1-benzyloxymethyl)imidazol-2yl)methyloxycarbonyl)amino-4-t-butyldimethylsiloxy-N-(1'35 isopropyl-l'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethylhexanamide.
A mixture of the compound of Example 46(a), (2R,4S,5S,1'S)-5-amino-4-hydroxy-N-(1'-isopropyl-l'-imidazol83 2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide, and 4dimethylaminopyridine was reacted according to the procedure of Example 14 (b) to afford the title compound (32%) . NMR(CDC13) 87.50-6.60 (m, 19H) , 5.25 (m, 2H), 5.11 (d, 2H, J=11.03 Hz), 4.68 (m, 1H), 4.39 (m, 2H), 3.97 (m, 1H), 3.67 (m, 1H), 2.88 (m, 1H), 2.72-2.28 (m, 6H), 1.85 (m, 1H), 1.60 (m, 1H), 0.92-0.81 (m, 15H), 0.80 (s, 3H) , 0.06 (s, 3H); MS(ES) m/e 793 [M+H]+. c) (2R, 4S, 5S, 1'S)-5-(imidazoyl-2-ylmethyloxycarbonyl)amino-4-t-butyldimethylsiloxy-N-(1 ’ — isopropyl-l'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethylhexanamide The compound of Example 46(b) (58 mg, 0.073 mmol), methanol (3 mL), and 10% Pd on carbon (50 mg) were combined and stirred under 1 atm of H2 for 24 h. Additional catalyst (50 mg) was added and stirring under H2 was continued for 8 h. The reaction was filtered through Celite, concentrated and flash chromatographed (silica, step gradient, 0-8% MeOH/CH2Cl2) to yield the title compound (28 mg, 57%).
NMR(CDC13) δ 7.29-6.83 (m, 14H); 5.05 (d, 1H, J=11.2 Hz), 4.91 (d, 1H, J=11.2 Hz), 4.71 (m, 1H), 3.92 (m, 1H), 3.61 (m, 1H), 3.02 (m, 1H), 2.81-2.54 (m, 4H), 2.36 (m, 1H), 1.93 (m, 1H), 1.59 (m, 1H), 0.91 (d, 3H, J=7.1 Hz), 0.89 (s, 9), 0.69 (d, 3H, J=7.1 Hz), 0.84-0.05 (m, 6H); MS(ES) m/e 673 [M+H]+. d) (2R,4S,5S,11S)-5-(imidazol-2-yl-methyloxycarbonyl)amino-4hydroxy-N-(1'-isopropyl-l’-imidazol-2-yl)methyl-6-phenyl-2phenylmethy1-hexanamide The compound of Example 46(c) (24 mg, 0.035 mmoL), 95% aqueous EtOH (0.50 mL), and concentrated aqueous HCl (0.050 mL) were stirred at 23°C for 24 h. The solution was diluted with H2O (5 mL) washed with EtOAc and then the aqueous phase was made basic by addition of solid K2CO3. Extraction with EtOAc, concentration of the organic extract and trituration with CH2CI2 afforded the title compound (14 mg, 72%). NMR (CDC13) 8 7.33-6.85 (m, 14H), 5.11 (d, 1H, J=10.8 Hz), 4.96 (d, 1H, J=10.8 Hz), 4.47 (m, 1H), 3.72 (m, 1H) , 3.38 (m, 1H), Έ922316 2.81 (m, 4Η), 2.59 (m, IH), 2.07 (m, IH), 1.72 (m, IH), 1.62 (m, IH), 0.78 (d, 3H, J=6.63 Hz), 0.67 (d, 3H, J=6.63 Hz); (m, 6H) ; MS(ES) m/e 559 [M+H]+.
Example 47 Preparation at (2R.4Sf 5S.1'S,1»RS)-5-((!-(imidazol-2-vl)-2methyl) propyloxycarbonyl) amino-4-hydroxy-N- (1' -isopropvl-JJimidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide a) (IRS)-1-((l-benzyloxymethylimidazol-2-yl)-2methyl) propyl-(4-nitrophenyl)carbonate A mixture of bis(4-nitrophenyl)carbonate, (IRS)-1-((1benzyloxymethylimidazol-2-yl)-2-methyl)propanol and 415 dimethylaminopyridine was reacted according to the procedure of Example 14(a) to afford the title compound (61%). NMR (CDCI3) δ 8.18 (d, 2H, J=8.31 Hz), 7.38-7.21 (m, 7H), 7.13 (s, IH), 6.94 (s, IH), 5.74 (d, IH, J=ll.l Hz), 5.47 (d, IH, J=10.2 Hz), 5.28 (d, IH, J=10.2 Hz), 4.53 (d, IH, J=11.3 Hz), 4.41 (d, IH, J=11.3 Hz), 2.64 (m, IH), 1.18 (d, 3H, J=6.02 Hz), 0.87 (d, 3H, J=6.02 Hz); MS(ES) m/e 426 [M+H]+. b) (2R,4S,5S,1'S,1RS)-5-((1-(l-benzyloxymethylimidazol-2yl)-2-methyl-propyl)oxycarbonyl)amino-4-t25 butyldimethylsiloxy-N-(1'-isopropyl-1'-(1- (1- (1benzyloxymethylimidazol-2-yl)-2methylpropyl)oxycarbonyl)imidazol-2-yl)methyl-6-phenyl-2phenylmethyl-hexanamide A mixture of the compound of Example 47(a) (145 mg, 0.33 mmol), the compound of Example 13(a) (75.9 mg, 0.14 mmol), 4dimethylaminopyridine (41 mg, 0.33 mmol) and DMF (0.5 mL) was stirred under argon for 18 h. The DMF was evaporated in vacuo and the residue was combined with 10% aq K2CO3 (10 mL) and extracted with EtOAc. The combined extracts were washed with saturated aq NaHCO3, dried (K2CO3), filtered and concentrated in vacuo. The residue was flash chromatographed (silica, step gradient, 0-4% MeOH/CH2Cl2) to afford the title compound (96.1 mg, 57%). NMR (CDCI3) δ 7.38-6.78 (m, 26H), .67 (m, 1H), 5.61-5.00 (m, 6H), 4.58-4.27 (m, 5H), 3.97-3.61 (m, 3H), 2.78-2.10 (m, 8H) , 1.95-1.51 (m, 2H), 1.10-0.55 (m, 27H), 0.50-0.05 (m, 6H). c) (2R, 4S, 5S, 1'S, 1RS)-5-[ (1’’-(1-benzyloxymethylimidazol-2-yl) -2’’-methyl-propyl) oxycarbonyl] amino-4-hydroxyN—(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2phenylmethy1-hexanamide A solution of the compound of Example 47(b) (81 mg, 0.07 10 mmol), CH3OH (0.75 mL), and 3N aqueous HC1 (0.25 mL) was stirred at 23°C for 20 h. The reaction mixture was diluted with H2O (10 mL) and washed with EtOAc (3 x 15mL). Solid K2CO3 was added to give a basic solution (pH>12), which was extracted with EtOAc. The extracts were dried (K2CO3), filtered, concentrated and flash chromatographed (silica, step gradient, 0-8% CH3OH/CH2CI2) to give the title compound (34.9 mg, 65%). XH NMR (CDCI3): δ 7.43-6.79 (m, 9H), 5.87, .66 (2d, 1H, J=10.66, 10.85 Hz), 5.28 (m, 2H), 4.68 (m, 1H), 4.42 (m, 2H) , 3.71 (m, 1H), 3.58 (m, 1H), 2.90-2.31 (m, 6H) , 2.11 (m, 1H) , 1.75, 1. 51 (2m, 2H), 1.05, 0.97 (2d, 3H, J=6 . 32,6. 45) , 0.68 (m, 9H) . d) (2R, 4S,5S,l'S , 1RS) -5- ( (!’’- (imidazol-2-yl) -2’’- methyl)propyloxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'25 imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide.
A mixture of the compound of Example 47(c) (34 mg, 0.047 mmol), CH3OH (4 mL), and 10% Pd/C (34 mg), was stirred under H2 (1 atm) for 26 h. The suspension was filtered through celite, concentrated, and triturated with CH2CI2 to yield the title compound (4 mg, 14%).XH NMR (CDCI3/CD3OD) δ 7.7.32-6.71 (m, 14H), 5. 38 (m, 1H), 4 .55 (m, 1H), 3.72 (m, 1H), 3.55 (m, 1H), 2.78 (m, 4H), 2.55 (m, 1H) , 2.15 (m, 2H), 1.60 (m, 2H), 1.03-0.61 (m, 12H) . - 86 Example 48 Preparation of (2R.4S.5S.l,S)-5-(t-butoxycarbonyl)amino-4hydroxy-N-Γ1’-isopropyl-l’-(4-(imidazol-2-yl)imidazol-25 yl)1methyl-6-phenyl-2-phenylmethyl-hexanamide (a, (l'S)-l’-(carbobenzyloxy)amino-1'-isopropyl-l'-(4(imidazol-2-yl)imidazol-2-yl)methane Cbz-(L)-valinal (0.45 g, 1.4 mmol) was stirred in anhydrous methanol at 0°C under argon. Glyoxal (40% in water) (0.22 mL, 1.4 mmol) and ammonium hydroxide (29% NH3) (0.88 mL, 14 mmol) were added and the mixture was allowed to stir at 0°C for 1 h. The cooling bath was removed and the solution stirred at room temperature for 16 h. The methanol was evaporated in vacuo and the residue was diluted with 5% aqueous HC1. After extracting with dichloromethane, the aqueous layer was made basic with solid sodium carbonate and extracted with dichloromethane. The combined organic extracts were dried over sodium carbonate, filtered, and evaporated to a solid which was chromatographed (silica, 4% methanol/dichloromethane) to give the title compound (0.216 g, 43%) as a white solid. NMR (CDCI3) δ 7.15 (6H, s(br)), 6.88 (2H, s), 6.30 (IH, d), 4.89 (2H, dd), 4.52 (IH, t), 2.05 (IH, m), 0.73 (3H, d), 0.62 (3H, d). MS m/e 340.2 [M+H]+ (b) (2R,4S,5S,1’S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N[1'-isopropyl-l’-(4-(imidazol-2-yl)imidazol-2-yl)]methyl-6pheny1-2-phenylmethy1-hexanamide The compound of Example 48(a) (0.13 gm.) was dissolved in anhydrous methanol with 10% Pd on activated carbon (0.02 g). Hydrogen gas was bubbled through the solution via balloon for 1 h and the solution was stirred overnight under a hydrogen atmosphere. The mixture was filtered through a pad of Celite and evaporated to yield 1'-amino-1'-isopropyl35 [4-(imidazol-2-yl)imidazol-2-yl]methane as a white solid (0.13 g, 100%).
This compound was combined with the compound of Example 13(a) (0.334 g, 0.63 mmol), BOP reagent (0.28 g, 0.63 mmol), and triethylamine (0.13 mL, 0.945 mmol) in DMF (1 mL) and allowed to stir under Ar for 3 d. The DMF was evaporated in vacuo and the residue was diluted with dichloromethane. The solution was washed with water and brine. The organic layer was dried over sodium carbonate, filtered, and evaporated to yield (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-tbutyldimethysiloxy-N-[1’-isopropyl-l'-(4-(imidazol-2yl)imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl hexanamide as a white solid.
A portion of the solid (0.100 g, 0.14 mmol) was stirred in THF at room temperature under argon. Tetrabutylammonium fluoride (0.84 mL, 0.84 mmol) was added and the mixture was allowed to stir for 16 h. The solution was diluted with water and extracted twice with dichloromethane. The combined organic extracts were washed with water and evaporated to an oily residue. The residue was dissolved in THF and several drops of diethyl ether were added until a white precipitate formed. The precipitate was collected by filtration and dried in vacuo to yield the title compound as a white solid (76 mg, 90%). NMR (CD3OD) δ 7.37-6.84 (13H, m), 4.61 (1H, d), 3.69 (2H, m), 3.54 (1H, d), 2.84-2.52 (5H, m), 2.06 (1H, m), 1.83 (2H, m), 1.57 (1H, m), 1.30 (9H, s), 0.87 (3H, d), 0.69 (3H, d); MS m/e 601.2 [M+H]+ Example 42 Preparation of (2R,4S.5S.l’S)-5-fdi(hydroxymethyl)methoxycarbonynamino-4-hydroxy-N-(l,-isopropyl-l,-imidazol2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide a) di(t-butyldimethylsiloxymethyl) methyl-(4-nitrophenyl) carbonate A mixture containing bis(4-nitrophenyl) carbonate (1.89 g, 6.21 mmol), di(t-butyldimethylsiloxymethyl)methanol (2.00 g, 1 eq) and 4-dimethylaminopyridine (757 mg, 1 eq) in dichloromethane (100 mL) was stirred at room temperature for 2 d. The mixture was diluted with dichloromethane and washed with saturated aqueous Na2CO3( brine, and dried over Na2SO4 .
The solvent was removed in vacuo, and the residue was purified by flash chromatography (silica, 10% ethyl acetate/hexanes) to afford the title compound (75%) . NMR (CDC13) δ 8.29 (2H, m), 7.37 (2H, m) , 3,96 (1H, m), 3.85 (2H, d), 3.82 (2H, d), 0.89 (18H, s), 0.09 (12H, s). b) (2R,4S,5S,l'S)-5-(di(tbutyldimethylsiloxymethyl)methyloxycarbonyl]amino-4-fcbutyldimethylsiloxy-N-(1’-isopropyl-l'-imidazol-2-yl)methyl10 6-phenyl-2-phenylmethyl-hexanamide A solution of di(t-butyldimethylsiloxymethyl)-methyl 4nitrophenyl carbonate (475 mg, 0.974 mmol), the compound of Example 13(a) (178 mg, 0.325 mmol) and dimethylaminopyridine (119 mg, 0.974 mmol) in methylene choride was stirred at 20°C under Ar for 24 h. The solution was washed with aqueous Na2CO3, dried over solid Na2CO3 and concentrated in vacuo. Flash chromatography (silica, 4% methanol/dichloromethane) of the residue provided the intermediate (2R,4S,5S,1'S)-5-(di(tbutyldimethylsiloxymethyl) methyloxycarbonyl)amino-4-t20 butyldimethylsiloxy-N-(1’-isopropyl-l'-(1-(di(tbutyldimethylsiloxymethyl) methyloxycarbonyl)imidazol-2yl)methyl-6-phenyl~2-phenylmethyl-hexanamide, which was dissolved in ether, washed with 10% NaOH, dried over Na2CO3, and concentrated to provide the title compound (197 mg, 71%).
NMR (CDCI3) δ 7.43-7.05 (10H, m) , 6.90 (2H, s), 6.65 (1H, bs), 5.09 (1H, d), 4.78 (1H, bd), 4.08 (1H, m), 3.89-3.50 (7H,m) 3.00-2.80 (4H, m), 2.65 (1H, m) , 2.55 (2H, m), 1.90 (1H, m), 1.78 (1H, m), 1.10-0.85 (33H, m), 0.20-0.06 (18H, m) . c) (2R,4S,5S,1’S)-5-(di(hydroxymethyl)methoxycarbonyl)amino4-hydroxy-N-(1'-isopropyl-l'-imidazol-2-yl)methyl-6-phenyl-2phenylmethyl-hexanamide A mixture containing the compound of Example 49(b) (50 mg) and ethereal HC1 (4 eq) was allowed to stir in methanol: water (9:1) at room temperature overnight. The solvent was removed in vacuo, and the residue was diluted with ethyl acetate and washed with saturated aqueous Na2CC>3.
The product was purified by flash chromatography (silica, 4% methanol/dichloromethane) to afford the title compound (29 mg, 94%). NMR (CD3OD) δ 7.20-6.80 (10H, m), 6.71 (2H, s), 4.50 (1H, d), 3.90 (lH,m), 3.65-3.34 (5H, m) , 2.82-2.45 (6H, m), 1.99 (1H, m), 1.74 (1H, m), 1.52 (1H, m), 0.78 (3H, d), 0.60 (3H, d).
Example 5Q Preparation of (2R. 4S. 5S. 1 1S)-5-(l-oxo-thian-4yl)oxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-l'-imidazol-2yl)methyl-6-phenyl-2-phenylmethylhexanamide Reacting the compound of Example 32(b) (81 mg, .133mmol) with m-chloro perbenzoic acid (23 mg, 0.133mmol)in CH2CI2 15 yielded the title compound. NMR (CD3OD): δ 7.20-6.85 (10H, m), 6.78 (2H, s), 4.51 (1H, d), 3.66 (1H, m), 3.42(1H, m), 2.95-2.41 (9H, m), 2.32-2.01 (2H, m), 1.99-1.63 (4H, m) , 1.60- 1.41 (2H, m), 0.78 (3H, d), 0.60 (3H, d); MS m/e 595.2 [M+H]+.
Example 51 Preparation of (2R, 4S, 5S, 11S)-5-( (Tetrahydrosulfonylpyran4-yl)oxycarbonyl)amino-4-hydroxy-N-(11-isopropyl-l'-imidazol25 2-yl)methyl-6-phenyl-2-phenylmethylhexanamide Reacting the compound of Example 50 (31 mg, 49.2gmol) with m-chloro perbenzoic acid (10 mg, 59.2gmol) in methylene chloride yielded the title compound. NMR (CD3OD) δ 7.20-6.85 (10H, m), 6.76 (2H, s), 4.48 (1H, d), 3.68 (1H, m), 3.44(1H, m), 2.96-2.42 (9H, m), 2.32-2.04 (2H, m), 1.97-1.62 (4H, m) , 1.61- 1.43 (2H, m) , 0.79(3H, d), 0.60 (3H, d); MS m/e 611.2 [M+H]+.
Example 52 35 Preparation of (2Rf 4S,5S,11S)-5-(1,l-dimethyl-2acetoxyethoxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-l1imidazol-2-yl)methyl-6-phenyl-2-phenvlmethyl-hexanamide - 90 (a) (2R,4S,5S,l'S)-5-(1,l-dimethyl-2hydroxyethoxycarbonyl)amino-4-(t-butyldimethylsilyl)oxy-N(1’-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-25 phenylmethyl-hexanamide The compound of Example 38(b) (223 mg, 0.221 mmol) was dissolved in 10% aqueous methanol and combined with 1 M HC1 in ether (0.221 mL, 1 eq) at room temperature. After completion of the reaction the solvents were removed in vacuo. The residue was dissolved in dichloromethane and washed with aqueous saturated Na2CC>3. The organic layer was concentrated and the residue was purified by flash chromatography (silica, 4% methanol/dichloromethane) to provide the title compound (138 mg, 94%). NMR (CDCI3) δ 7.38-6.81 (12H, m), 4.93 + 4.65 (1H, d, rotamers), 4.81+ 4.48 (1H, t, rotamers), 4.15 + 4.08 (lH,d, rotamers), 3.90 (lH,q), 3.72 (2H, m), 3.50+3.38 (1H, d, rotamers), 2.98-2.48 (5H, m), 2.35 (1H, m), 1.98 (1H, m) , 1.79 (1H, m), 1.60 (1H, m), 1.30 (3h, s), 1.29 (3H,s), 1.09-0.85 (15H, m), 0.79 (3H, d), 0.11 (6H, m) . (b) (2R,4S,5S,l'S)-5-(1,l-dimethyl-2acetoxyethoxycarbonyl)amino-4-hydroxy-N-(11-isopropyl-1’imidazol-2-yl)methyl-6-pheny1-2-phenylmethy1-hexanamide The compound of Example 52(a) (103 mg, 0.155 mmol) was stirred with acetic anhydride (30 mg, 0.309 mmol) and DMAP (40 mg, 0.309 mmol) in methylene chloride at room temperature under argon overnight. The solvent was removed in vacuo and the residue was flash chomatagraphed (silica, 4% methanol/dichloromethane).
The resulting 4-t-butyldimethylsiloxy intermediate (105 mg, 0.140 mmol) was stirred in methanol:water (9:1) with 1 M HC1 in ether (0.14 mL, 1 eq). The solvents were removed in vacuo, the residue was diluted with dichloromethane, and the solution was washed with aqueous Na2CC>3. The organic layer was concentrated and the residue was purified by flash chromatography (silica, 5% methanol/dichloromethane) to provide the title compound (82 mg, 91%). NMR (CD3OD) δ 7.29IE 922316 - 91 6.90 (10H, m), 6.81 (2H, s) , 4.51 (IH, d) , 4.05 (2H, s) , 3.59(1H, m), 3.42 (1H, m), 2.80-2.45 (5H, m) , 2.00 (IH, m), 1.98 (3H, s), 1.72 (IH, m), 1.50 (1H, m), 1.34 (6H, d), 0.81 (3H, d), 0.60 (3H, d).
Example 53 Ereparation of (2R,4S,5S.1'S)-5-((1.l-dimethyl-2(benzvloxycarbonylglycyloxy)ethoxycarbonyl)amino-4-hydroxy-N10 (1'-isopropvl-l1-J.mldazol-2-yl) methyl-6-phenyl-2phenylmethyl-hexanamide hydrochloride salt a) (2R,4S,5S,1’S)-5-((1,l-dimethyl-2carbobenzyloxyglycyloxy)ethoxycarbonyl)amino-4-(t15 butyldimethylsilyloxy)-N-(1’-isopropyl-l'-imidazol-2yl)methyl-6-phenyl-2-phenylmethy1-hexanamide The compound of Example 52(a) (100 mg, 0.151 mmol) was reacted with 2-chloro-l-methyl-pyridium iodide (92 mg, 0.36 mmol), DMAP (75 mg, 0.60 mmol) and Cbz-glycine (63 mg, 0.30 mmol) in methylene chloride (5 mL) under argon at reflux for 3 h. Solvents were removed in vacuo and the product was purified by flash chromatagraphy (silica, 4% methanol/dichloromethane) to provide the title compound (95 mg, 73%). NMR (CDCI3) 07.41-6.71 (17H, m), 6.62 (IH, bs), 6.00 (lH,m), 5.20 (IH, m), 5.15 (2H, s) , 4.83 + 4.55 (IH, d, rotamers), 4.65+ 4.48 (IH, t, rotamers), 4.81 + 4.38 (lH,q, rotamers), 4.03 (lH,q), 4.02 (2H, d), 3.85+3.68 (2H, d, rotamers), 2.85-2.48 (5H, m), 2.38 (IH, m), 1.90 (IH, m), 1.55 (IH, m), 1.38 (3h, s), 1.29 (3H,s), 0.90 (9H, m), 0.85 (3H, d), 0.70 (3H, d), 0.11 (6H, m). b) (2R,4S,5S,1’S)-5-((1,l-dimethyl-2(benzyloxycarbonyl)ethoxycarbonyl)amino-4-hydroxy-N-(l’isopropyl-l '-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl35 hexanamide hydrochloride salt The compound of Example 53(a) (12 mg, 0.014 mmol) was stirred in methanol:water (9:1) with 1 M HC1 (2 eq) in ether overnight. The solvents were removed in vacuo to give the - 92 title compound (8 mg, 73%). NMR(CD3OD): δ 7.35 (2H,s), 7.316.85 (15H, m), 5.00 (2H, s), 4.59 (1H, d),4.15 (1H, d, rotamers), 4.65+ 4.48(1H, t, rotamers), 4.81 + 4.38 (2H, dd), 3.80 (2H,d), 3.59 (1H, m), 3.40 (1H, d) , 2.85-2.48 (5H, m), 2.00 (1H, m), 1.60 (1H, m), 1.55 (1H, m), 1.31 (3h, s), 1.29 (3H,s), 0.91 (3H, d), 0.60 (3H, d) , Example 54 Preparation of (2R,4S,5S,1'S)-5-U1,l-dimethyl-2glycyloxy) ethoxycarbonyl) amino-4-hydroxy-N- (1 '-isopropvl-ll.imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide dihydrochloride salt a) (2R,4S,5S,1’S)-5-(1,l-dimethyl-2glycyloxyethoxycarbonyl)amino-4-(t-butyldimethylsilyl)oxy-N(1'-isopropyl-1’-imidazol-2-yl)methyl-6-phenyl-2phenylmethy1-hexanamide The compound of Example 53(a) (58 mg, ,0678mmol) was stirred in methanol with 10% Pd/C (50 mg) under 1 atm hydrogen overnight. The reaction mixture was filtered through Celite and the solvents were removed in vacuo to yield the title compound (48 mg, 98%). NMR(CD3OD) δ 7.32-7.02 (10H, m) , 6.99 (2H, s) , 4.68 (1H, d),4.40-4.28 (2H, dd), 3.81 25 (2H, d), 3.80-3.67 (2H, m) , 2.90-2.49 (5H, m) , 2.15 (1H, m) , 1.97 (1H, m), 1.48 (1H, m) , 1.40 (3H, s), 1.39 (3H,s), 1 . 15 (3H, d), 0.95 (9H, s) , 0.70 (3H, d), 0.11 (6H, d) . b) (2R,4S,5S,1'S)-5-((1,l-dimethyl-2-glycyloxy) ethoxy30 carbonyl)amino-4-hydroxy-N-(11-isopropyl-1'-imidazol-2yl)methyl-6-phenyl-2-phenylmethyl-hexanamide dihydrochloride salt The compound of Example 54(a) (43.5 mg, 0.060 mmol) was stirred in methanol: water (9:1) with 1 M HC1 in ether (0.12 mL, 2 eq) for 2 d. The solvents were removed in vacuo and the product was trituated with ether:methanol (20:1) to yield the title compound (40 mg, 98%). NMR(CD3OD) δ 7.35 (2H, s), 7.30-6.92 (10H, m), 4.60 (1H, d) , 4.25 (2H, dd) , 3.75 (2H, d) , 3.59 (IH, m) , 3.49 (IH, m) , 2.90-2.51 (6H, m) , 2 . .10 ( IH, m) , 1.65 (IH, m) , 1.54 (IH, m), 1.30 (6H, s) , 0.90 (3H, d) , 0 . 60 (3H, d) .
Example 55 Preparation of (2R,4S.5S,1'S)-5-((1.l-dimethyl-2hydroxy)ethoxycarbonyl)amino-4-hydroxy-N-(11-isopropvl-l'- (4 isopropylcarbonylimidazol-2-yl))methyl-6-phenyl-210 phenylmethyl-hexanamide dihydrochloride salt a) (2R,4S,5S,1'S)-5-amino-4-t-butyldimethylsiloxy-N-[1’isopropyl-l'-(4-isopropylcarbonyl-imidazol-2-yl)]methyl-6pheny1-2-phenylmethy1-hexanamide Using the procedure of Example 13(a), except substituting the compound of Example 28(d), the title compound was prepared. b) (2R,4S,5S,1'S)-5-((1,l-dimethyl-220 hydroxy)ethoxycarbonyl)amino-4-hydroxy-N-(1’-isopropyl-l'-(4 isopropylcarbonylimidazol-2-yl))methyl-6-phenyl-2phenylmethyl-hexanamide dihydrochloride salt Following the procedures of Example 38 (b)-38 (c), except substituting the compound of Example 55(a) for (2R,4S,5S,1'S)-5-amino-4-t-butyldimethylsiloxy-N-('isopropyl-l'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethylhexanamide, the title compound was prepared. NMR (CDCI3) δ (IH, s), 7.13 (5H, m), 6.84 (5H, m), 5.53 (IH, d), 4.47 d), 3.79 (IH, m), 3.60 (IH, m), 3.44 (2H, m), 3.16 (IH, 2.81-2.50 (5H, m), 1.92 (IH, m), 1.62 (2H, m), 1.18 (14H 0.72 (3H, d) , 0.58 (3H, d) ; MS m/e 621.4 [M+H]+.
Example- 56 Preparation of_(2R,4S,5S,1Έ)~5~((IS)-l~methyl-2hydroxyethoxycarbonyl)3ηϊηοτ4-ΗνάΓθχν-^-(11πί5θΡ£θΡν1-1'imidazol-2-yl)methyl-6-phenyl-2-phenylmethylhexanamide Using the procedure of Example 41, except substituting 2(S)-t-butyldimethylsiloxy-l-methylethanol in 41(a) (prepared from 2 (S)-1,2-propanediol) , the title compound was prepared.
NMR(CD30D) δ 7.38-6.90 (10H, m), 6.83 (2H, s), 4.58 (2H, m), 3.61 (IH, m), 3.34 (3H, m), 2.82-2.44 (5H, m), 2.00 (IH, m), 1.66 (IH, m), 1.52 (IH, m), 1.08 (3H, d) , 0.85 (3H, d), 0.60 (3H, d) .
Example 57 Preparation of (2R,4S,5S,1'S)-5-((1R)-l-methyl-2hydroxyethoxycarbonyl)amino-4-hydroxy-N-(l'-isopropyl-l1imidazol-2-yl)methyl-6-phenyl-2-phenylmethylhexanamide Using the procedure of Example 41, except substituting 15 2(R)-t-butyldimethylsiloxy-l-methylethanol in 41(a), the title compound was prepared. NMR(CD3OD) δ 7.39-6.88 (10H, m), 6.82 (2H, s), 4.56 (2H, m), 3.60 (IH, m), 3.36 (3H, m), 2.81-2.45 (5H, m), 1.99 (IH, m), 1.65 (IH, m), 1.51 (IH, m), 1.03 (3H, d), 0.84 (3H, d), 0.60 (3H, d).
Example 58 Preparation of (2R.4S.5S.1'S)-5-((1-acetvl)amino-4-hydroxv-N(1'-isopropyl-11-imidazol-2-yl)methyl-£-phenyl-225 phenylmethylhexanamide The title compound was prepared by the procedure of Example 13 (a)-(c), except substituting acetic anhydride in place of isopropyl chloroformate. NMR(CD3OD) δ 7.21-6.90 (10H, m), 6.81 (2H, s), 4.58 (IH, d), 3.98 (IH, m) , 3.51 (IH, m), 2.85-2.49 (5H, m), 1.99 (IH, m), 1.68 (3H, s), 1.61 (3H, m), 1.50 (IH, m), 0.80 (3H, d), 0.60 (3H, d).
Example 59 Preparation of (2R.4S.5S.11S)-5-(t-butoxycarbonyl)amino-4hydroxy-N- (11-isopropyl-11 imidazol-2-yl)methyl-6-phenyl-2-_L4benzyloxyphenylmethyl) hexanamide a) (3R, 5S, 1'S)-(1’-t-butoxycarbonylamino-2'-phenyl)ethyl-3(4-benzyloxy)phenylmethyl-tetrahydrofuran-2-one Following the procedure of Example 12 (a), except using (4-benzyloxy)benzyl bromide, the title compound was prepared (284 mg, 27%). NMR(CDCl3) δ 7.48-6.72 (14H, m) , 4.94 (2H, s), 4.43 (1H, d), 4.12 (1H, dd), 3.83 (1H, q) , 2.97-2.62 (5H m) , 2.12 (1H, m) , 1.85 (1H, m) , 1.27 (9H, s) . b) (2R,4S,5S)-5-(t-butoxycarbonyl)amino-4-t-butyldimethyl10 siloxy-6-phenyl-2-(4-benzyloxyphenylmethyl)hexanoic acid Folowing the procedure of Evans et al., J. Org. Chem. 50, 4615 (1985), except substituting the compound of Example 59(a) for benzyl bromide, the title compound was prepared. NMR(CDCl3) δ 7.42-6.76 (14H, m) , 4.99 (2H, s), 4.69 (1H, d), 3.91 (1H, q), 3.66 (1H, m), 2.98-2.36 (5H, m), 1.85 (1H, m), 1.52 (1H, m) , 1.30 (9H, s) , 0.88 (9H, s) , 0.04 (6H, m) . c) (2R,4S,5S,1'S)-5- (t-butoxycarbonyl)amino-4-tbutyldimethylsiloxy-N-(1’-isopropyl-l’-imidazol-2-yl)methyl20 6-phenyl-2-(4-benzyloxyphenylmethyl) hexanamide Following the procedure of Example 12 (c), except using (b), the title compound was prepared (284 mg, 92%) . NMR(CDCl3) δ 7.42-6.74 (16H, m), 5.04 <2H, s), 4.99 (1H, d) , 4.77 (1H, d), 4.51 (1H, dd), 3.93 (1H , q), 3.69 (1H, m) , 25 2.80-2.39 (5H, m), 1.81 (1H, m), 1.62 (1H, m), 1.33 (9H, s) , 0.92 (9H, s), 0.75 (6H, dd), 0.07 (6H , d) . d) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N- (1'isopropyl-l'-imidazol-2-yl)methyl-6-phenyl-2-(430 benzyloxyphenylmethyl)hexanamide Following the procedure of 12(d), except using (c), the title compound was prepared (100 mg, 94%). NMR(CD3OD) δ 7.41-7.09 (10H, m), 6.85 (2H, d), 6.79 (2H, s), 6.58 (2H, d), 5.41 (1H, d), 4.90 (2H, s), 4.47 (1H, d), 3.62 (1H, q), 3.48 (1H, d), 2.79-2.48 (6H, m), 2.02 (1H, m), 1.62 (2H, m), 1.33 (9H, s), 0.74 (3H, d), 0.61 (3H, d).
Example 60 Preparation of (2Rf4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4hydroxy-N-(1'-isopropyl-l’imidazol-2-yl)methyl-6-phenyl-2c (4hydroxyphenylmethy1) hexanamide Following the procedure of Example 4(b), except using the compound of 59(d), the title compound was prepared (56 mg, 86%). NMR(CD3OD) δ 7.18 (5H, m), 6.84 (2H, s), 6.73 (2H, d), 6.44 (2H, d), 5.32 (1H, d), 4.45 (1H, d), 3.61 (1H, q), 3.42 (1H, m), 2.80-2.42 (5H, m), 2.04 (1H, m), 1.61 (2H, m), 1.31 (9H, s), 0.70 (3H, d), 0.61 (3H, d) .
Example ,£1 a) a-(t-butoxycarbonyl)-amino-a-cyclopropylacetonitrile To a solution of cyclopropylmethanol (10.2 g, 141 mmol) in methylene chloride (250 mL) sodium acetate (1 g) and 20 g of Celite were added. Pyridinium chlorochromate (30 g, 140 mmol) was added in small portions over a period of 30 m.
After 1 h the reaction mixture was diluted with ether (lOOmL), filtered through Celite and washed with ether. The combined organic extracts (1 L) were concentrated in vacuo at 15-18°C to yield formyl cyclopropane.
The crude aldehyde was dissolved in water (50 mL), and ammonium chloride (6.51 g), potassium cyanide (7.16 g) and aqueous ammonium hydroxide (100 mL, 28% w/w). The reaction mixture was stirred at room temperature overnight, extracted with ethyl acetate, and the combined organic extracts were dried over MgSO4. Filtration and evaporation of the solvent in vacuo yielded α-amino-a-cyclopropyl acetonitrile as an oil.
To a solution of the crude aminonitrile (2 g) in THF (20 mL) di-tert-butyldicarbonate (1.53 g, 7 mmol) was added. The reaction was stirred overnight. Removal of the solvent in vacuo followed by flash chromatography (silica, 1:8 ethyl acetate:hexane) yielded the title compound (2.8 g). 1H NMR(CDC13, 200 MHz) δ 5.0 (bs, 1H) , 4.4 (bs, 1H), 1.4 (s, 9H), 1.2 (m, 1H), 0.7 (m, 2H), 0.5 (m, 2H). b) a-(t-butoxycarbonyl)-amino-a-cyclopropylacetaldehyde To a solution of the compound of Example 61(a) (1 g, 5.1 mmol) in THF (20 mL), diisobutylaluminium hydride (10.5 mL, .5 mmol, 1M in THF) was added at -78°C, over 5 min. The reaction mixture was allowed to warm to 0°C over a period of 2 h, and stirred at 0°C for an additional 1 h. The reaction mixture was quenched with MeOH (2 mL), and saturated potassium sodium tartrate solution (100 mL) was added.
Extraction with ether, drying over MgSO4 and removal of solvents in vacuo yielded an oil. Flash chromatography (silica, 1:10 ethyl acetate:hexane) gave the title compound as a colorless solid (225 mg). NMR(CDCl3, 400 MHz) δ 9.45 (bs, 1H), 4.95 (bs, 1H), 3.5 (bs, 1H), 1.3 (s, 9H), 0.7 (m, 1H), 0.3-0.6 (m, 4H). c) 1-(t-butoxycarbonyl)amino-1-(imidazol-2-yl)-1-cyclopropylmethane A mixture of the compound of Example 61(b) (178 mg, 0.89 mmol), glyoxal (150 mL, 1 mmol, 40% aq), ammonium hydroxide (5 mL, 28% aq) and MeOH (5mL) was stirred at room temperature for 10 h. The solvents were removed in vacuo and the residue was titurated with ether to yield a brown solid (53 mg). The solid was passed through Florisil and eluted with 5% MeOH/methylene chloride. Removal of the solvent in vacuo followed by trituration provided the title compound as a colorless solid (19 mg). MS(CI/NH3) m/e 238.3 [M+H]+· 1H NMR(CD3OD, 200 MHz) δ 6.9 (s, 2H) , 4.1 (bd, 1H), 1.4 (s, 9H) , 1.3 (m, 1H), 0.6 (m, 2H), 0.4 (m, 2H). d) 1-amino-l-(imidazol-2-yl)-1-cyclopropyl-methene, trifluoroacetate The compound of Example 61(c) (15 mg) was dissolved in 1 mL of TFA and stirred at room temperature for 20 min.
Solvents removed in vacuo to give the title compound as a semisolid residue. NMR(CD3OD, 200 MHz) δ7.1 (s, 2H), 3.8 (d, 1H, J=7 Hz), 1.5 (m, 1H), 0.5-0.8 (m, 4H) . e) (2R,4S,5S)-5-(t-butoxycarbonyl)amino-4- (tbutyldimethyl)siloxy-2-phenylmethyl-6-phenyl-N-[1'-isopropyl1'-imidazol-2-yl]methyl-hexanamide The compound of Example 61(d) was dissolved in DMF (2 5 mL) and NMM (26 mg, 0.25 mmol) was added and the solution was stirred at 0°C for 30 min. (2R,4S,5S)-2-phenylmethyl-4-(tbutyldimethyl)siloxy-5-(t-butoxycarbonyl)amino-6-phenyl hexanoic acid (38 mg, 0.07 mmol) and BOP reagent (30 mg, 0.07 mmol) were added and the reaction was stirred at room temperature for 24 h. The reaction was diluted with ethyl acetate (100 mL), washed with aqueous sodium bicarbonate and dried over anhydrous potassium carbonate. Removal of solvents in vacuo, followed by flash chromatography (silica, 5% methanol/methylene chloride) yielded the title compound as a mixture of diastereomers (25 mg). f) (2R,4S,5S)-5-(t-butoxycarbonyl)amino-4-hydroxy-2phenylmethyl-6-phenyl-N-[1’-isopropyl-l'-imidazol-2yl]methyl-hexanamide The compound of Example 61(c) was dissolved in THF (2 mL) and tetrabutyl ammonium fluoride (200mL, 1M in THF) was added. The reaction was stirred at room temperature overnight and methylene chloride (100 mL) and water (10 mL) were added. The organic layer was dried over potassium carbonate, and the solvent was removed in vacuo to give an oil. Flash chromatography (silica, 5% methanol/methylene chloride) gave a colorless solid which was a 1:1 diastereomeric mixture of the title compound.
Example 62 Preparation of (2R, 4Sf 5S. 1’R)-5-(t-iiutoxycarbonvl) amino-4hydroxy-2-phenylmethyl-6-phenyl-N- fl'-isopropvl-l'-imidazol2-yllmethyl-hexanamide; .and (2R,4S,5S.1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-2phenylmethyl-6-phenyl-N-f11-isopropyl-l'-imidazol-2y11methyl-hexanamide a) Purification of the 125 mg of the compound of Example 61(e) by flash chromatography (silica, 3% methylene chloride/methanol), yielded 48 mg of isomer 1, 15 mg of isomer 2 and 20 mg of combined fractions. ^-H NMR for isomer 1 (CDCI3, 400 MHz) 67.1-7.4 (m, 10H) , 6.95 (s, 2H) , 6.1 (d, 1H), 4.85 (d, 1H), 4.15 (dd, 1H), 3.75(q, 1H), 3.6(m, 1H), 2.9(dd, 1H), 2.7 (d, 2H), 2.6 (dd, 1H), 2.3 (m, 1H), 2.0 (m, 1H), 1.6 (m, 1H), 1. 4 (m, 1H), 1.35 (s, 9H), 0.95 (s, 9H), 0.7 (m, 1H), 0.4 (m, 1H), 0.25 (m, 1H), 0.1 (m, 1H) , 0.2 (s, 10 3H), 0.1 (s, 3H) , 1H NMR for isomer 2 (CDCI3 , 400 MHz) 67.1- 7.4 (m, 10H), 6.8 (s, 2H), . 6.26 (d, 1H) , 4, .6 (d, 1H) , 4, . 0 (m, 2H) , 2.5-3.0 (m, 4H), 1.8 (m, 1H), 1.7 (m, 1H), 1.5 (m, 1H), 1.4 (s, 9H), 1.0 (s, 9H), 0.7 (m, 2H), 0.2 (m, 2H), 0.1 (2 overlapping singlets, 6H). b) Following the procedure of Example 61(f), except substituting the compounds of Example 62(a) yielded the title compounds. NMR for isomer 1 (CD3OD, 400 MHz) 67.1-7.3 (m, 10H), 6.95 (s, 2H), 4.25 (d, 1H), 3.5-3.7 (m, 2H), 2.5-3.0 (m, 5H), 1.7 (m, 2H), 1.4 (s, 9H), 1.1 (m, 1H), 0.6 (m, 1H), 0.25-0.4 (m, 2H) , 0.05 (m, 1H) ; MS(ESMS) m/e 533.2 [M+H]+'‘ ΣΗ NMR for isomer 2 (CD3OD) 6 7.1-7.4 (m, 10H), 6.85 (s, 2H), 4.25 (d, 1H), 3.5-3.7 (m, 2H), 2.5-2.9 (m, 5H), 1.5-1.8 (m, 2H), 1.4 (s, 9H), 1.1 (m, 1H), 0.2-0.6 (m, 4H); MS(ESMS) m/e 533.4 [M+H]+.
Example 63 Preparation of (2R. 4S. 5S. 1 ’S)-5-((isopropylthioDoarbonvl.) 30 amino-4-hydroxy-2-phenylmethyl-6-phenyl-N-fl-isopropyl-11imidazol-2-yl1methyl-hexanamide a) 5-((isopropylthiol)carbonyl)amino-4-(tbutyldimethylsiloxy)-2-phenylmethyl-6-phenyl-N-[1'-isopropyl35 1'-(1-(isopropylthiol)carbonyl-imidazol-2yl)]methylhexanamide To a solution of (2R,4S,5S,1'S)-5-amino-4-tbutyldimethylsiloxy-2-phenylmethyl-6-phenyl-N-[1'-isopropylIE 922316 - 100 1'-imidazol-2-yllmethyl-hexanamide (81 mg, 148 mmol) and DMAP (37 mg, 303 mmol) in dichloromethane (8 mL), isopropylthiolchloroformate (42 mg, .303 mmol) in dichloromethane (1 mL) was added. The solution was stirred for 20 h and an additional equivalent of the chloroformate and DMAP were added. The reaction mixture was stirred for an additional 20 h, diluted with dichloromethane, and washed with saturated sodium bicarbonate. The organic extract was dried over magnesium sulfate, filtered and evaporated to an oil. The oil was dissolved in chloroform and purified by flash chromatography (silica, 1% methanol/chloroform) to give the title compound as an oil (79.5 mg). b) (2R,4S,5S,1'S)-5-((isopropylthiol)carbonyl)amino-415 hydroxy-2-phenylmethyl-6-phenyl-N-[1-isopropyl-l'-imidazol-2y 1)methyl-hexanamide To a solution of the compound of Example 63(a) (79 mg, 105 mmol) in methanol (8 mL), 10% hydrochloric acid (3 ml) was added. The reaction mixture was stirred overnight at °C. The methanol was evaporated in vacuo, and the residue was diluted with water. The solution was neutralized with 5% aqueous sodium carbonate, and a solid precipitated. The solid was filtered, washed with water, and triturated with ether. The solid was dried at high vacuum to yield the title compound (27 mg, 48%).
Example- £4.
Preparation of (2R. 4S.5S.1’S)5-(1-hydroxymethyl30 cyclopentyloxycarbonyl)amino-4-hydroxy-N-(V-isopropyl-l1imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-hexamide a) 1-(t-butyldimethysiloxy)methyl-cyclopentanol iTo a solution of 1-hydroxymethyl-l-cyclopentanol (4.07 g, 0.035 mole) in dichloromethane (30 mL) t-butyldimethylsilyl chloride (5.28 g, 0.035 mol) in dichloromethane (30 mL) was added. Triethylamine (5.37 mL, 0.0385 mol) and DMAP (0.171 g, 0.0014 mol) were added and the solution was stirred - 101 overnight at 25°C. The solution was diluted with dichloromethane (30 mL) and washed with water and saturated ammonium chloride solution. The organic solution was dried over sodium sulfate, filtered and the solvent removed at reduced pressure. The product was purified by flash chromatography (silica, 19:1 hexane:ethyl acetate) to yield the title compound as a colorless oil (6.95 g, 86%). b) 1-(t-butyldimethylsiloxy)methyl-cyclopentyl 4-nitrophenyl 10 carbonate A solution of the compound of 64(a) (1.15 g, 5 mmol), DMAP (0.611 g, 5 mmol) and bis (4-nitrophenyl)carbonate (1.52 g, 5 mmol) in dichloromethane (16 mL) was stirred overnight at 25°C. The reaction mixture was diluted with dichloromethane and washed with 5% sodium carbonate. The solvent was removed at reduced pressure and the residual oil was triturated with hexane:ethyl acetate (3:2) and filtered. The product was purified by flash chromatography (silica, 19:1 hexane:ethyl acetate) to give a colorless oil (0.599 g, %). c) J.2R, 4S, 5S, 1 ’ 5) -5- [1- (t-butyldimethylsiloxy) methylcyclopentyloxycarbonyl]amino-4-t-butyldimethylsiloxy-N-[1'isopropyl-1'-(t-butyldimethylsiloxy)methyl25 cyclopentyloxy)imidazol-2-yl]-6-phenyl-2-phenylmethylhexanamide A solution of the compound of Example 13(a) (173 mg, 0.316 mmol), DMAP (81 mg, 0.663 mmol) and the compound of Example 64(b) (262 mg, 0.663 mmol) in dichloromethane (10 mL) was stirred for 48 h at 25°C. The organic solution was diluted with dichloromethane, washed with 5% sodium carbonate solution and the solvent removed at reduced pressure. The product was purified by flash chromatography (silica, 4:lhexane:ethyl acetate) to yield the title compound as an oil (200 mg, 60%).
IE 92231® - 102 d) Preparation of (2R,4S,5S,1'S)5-(1-hydroxymethylcyclopentyloxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-l'imidazol-2-yl)methyl-6-pheny1-2-phenylmethyl-hexamide A solution of the silated derivative (200 mg, 0.188 5 mmol) in 7 ml methanol and 2.5 ml of 3N HC1 was stirred overnight at 25°C. The methanol was removed at reduced pressure and the solution was diluted with water (15 ml) and extracted with ether (25 ml). The aqueous solution was neutralized with 5% sodium carbonate solution to pH 7-7.5 and the product precipitated as a solid. The solid was filtered, washed with water and dried in vacuo (51 mg, 47%).
Example 65 Preparation of (2R,4S,5S,1'S)-5-f3-(R)- (lH-imidazol-2-yl) -3hydroxy-4-methylpentylamidol-4-hydroxy-N-(1'-isopropvl-l'imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide; and (2R,4S,5S,1'S)-5-[3-(S)-(lH-imidazol-2-yl)-3-hydroxy-4methylpentylamidol-4-hydroxy-N-(1’-isopropyl-l’-imidazol20 yl)methyl-6-phenyl-2-phenylmethy1-hexanamide a) 1-(l-benzyloxymethylimidazol-2-yl)-2-methyl-l-propanol 1-benzyloxymethylimidazole prepared according to the procedure of Ngochindo, R., «7. Chem. Res. (S) , 58 (1990)) (3.76 g, 20 mmol), and THF (40 mL) at -40°C, was treated dropwise with n-BuLi (8.4 mL, 21 mmol, 2.5 M in hexane). The resulting solution was stirred at -40°C for 15 min, and ibutyraldehyde (2.0 mL, 22 mmol) was added dropwise. The reaction was stirred at -40°C for 1.5 h, 0°C for 1 h, warmed to 23°C, poured into H2O, and extracted with EtOAc. The combined extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. Trituration of the residue with Et2O/hexane gave a white solid which was dried in vacuo overnight to afford of the title compound (3.57 g, 69%).
NMR(CDCl3, 400 MHz) δ 7.28 (m, 5H), 6.97 (S, IH), 6.92 (s, IH), 5.23 (d, IH, J=12 Hz), 5.42 (d, IH, J=12 Hz) , 4.48 (s, 2H) , 4.44 (d, IH, J=9 Hz) , 2.21 (m, IH) , 1.02 (d, 3H, J=7 Hz), 0.83 (d, 3H, J=7 Hz) . 103 b) 1-(benzyloxymethylimidazol-2-yl)-2-methyl-propan-l-one The compound of Example 65(a) (1.0 g, 3.88 mmol), MnC>2, (1.69 g, 19.4 mmol), and CH2CI2 (75 mL) were combined and stirred for 1 d. Additional MnO2 (1.69 g, 19.4 mmol) was added and stirring was continued for an additional 2 d. Filtration through Celite, concentration and flash chromatography (silica, 0-1% CH3OH/CH2CI2) afforded the title compound (0.773 g, 77%). ^-H NMR(CDCl3, 400 MHz) 7.28 (m, 6H), 7.18 (s, 1H), 5.85 (s, 2H), 4.52 (s, 2H) , 3.94 (m, 1H), l. 21 (d, 2H, J=5 Hz). c) t-butyl 3-(l-benzyloxymethylimidazol-2-yl)-3-hydroxy-4methyl-pentanoate Diisopropylamine (83 gL, 0.59 mmol) and THF (1.5 mL) were cooled to -40°C and n-BuLi (188 gL, 0.47 mmol, 2.5 M in hexane) was added. The reaction mixture was warmed to -10°C and stirred for 15 m, recooled to -70°C and t-butyl acetate (63 gL, 0.47 mmol) was added. The reaction was stirred for 5 m, and HMPA (254 gL, 1.41 mmol) was added. The reaction was stirred at -70°C for 5 m and 1-(benzyloxymethylimidazol-2yl)-2-methyl-propan-l-one (100 mg, 0.39 mmol) in THF (1.5 mL) was added dropwise. The mixture was stirred at -70°C for 30 m, -40°C for 30 m, -10°C for 30 m, warmed to 23°C, poured into 10% aqueous K2CO3 and extracted with EtOAc. The combined organic extracts were washed with brine, dried (K2CO3) , concentrated and flash chromatographed (silica gel, step gradient, 0-20% EtOAc/hexanes) to afford the title compound (131 mg, 90%). XH NMR(CDCl3, 400 MHz) δ 7.25 (m, 5H), 6.96 (s, 1H), 6.91 (s, 1H), 5.69 (d, 1H, J=10 Hz), 5.65 (d, 1H, J=10 Hz), 4.53 (d, 1H, J=ll Hz), 4.48 (d, 1H, J=ll Hz), 3.23 (d, 1H, J=6 Hz), 2.57 (d, 1H, J=6 Hz), 2.14 (m, 1H), 1.39 (s, 9H); 0.97 (d, 3H, J=7 Hz), 0.75 (d, 3H, J=7 Hz); MS(ES+) m/e 375 [M+H]+. d) 3-(l-benzyloxymethylimidazol-2-yl)-3-hydroxy-4-methyl pentanoic acid triflouroacetate. 104 The compound of Example 65(c) (93 mg, 0.24 mmol) was dissolved in TFA (1 mL) and stirred for 20 m. The TFA was removed in vacuo to give the title compound (102 mg, 100%).
XH NMR(CDC13, 400 MHz) 7.30 (m, 7H); 6.06 (d, 1 H, J=9 Hz), .74 (d, 1H, J=1 Hz), 4.67 (d, 1H, J=9 Hz), 4.61 (d, 1H, J=9 Hz), 3.62 (d, 1H, J=12 Hz), 2.93 (d, 1H, J=12 Hz), 2.04(m, 1H), 0.92 (d, 3H, J=12 Hz), 0.88 (d, 3H, J=12 Hz); MS(ES+) m/e 319 [M+H]+. e) (2R,4S,5S,l'S)-5-[3-(RS)- (l-benzyloxymethylimidazol-2-yl)3-hydroxy-4-methylpentanoyl]amino-4-t-butyldimethyIsilyloxyN—(1'-isopropyl-1'-imidazol-2-yl)methyl-6-pheny1-2pheny lmethy 1-hexanamide A mixture of the compound of Example 65(d) (1.0 equiv.) (2R,4S,5S,1'S)-5-amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol2- yl)methyl-6-phenyl-2-phenylmethyl-hexanamide (1.1 equiv.), BOP reagent (1.1 equiv.), and triethylamine (4 equiv.) were reacted according to the procedure of Example 1(c). The product was purified by flash chromatography to afford the title compound (57%) (silica, step gradient, 0-4% CH3OH/CH2CI2) . XH NMR(CDC13, 400 MHz) δ 7.36-6.76 (m, 19H), 5.65 (m, 2H), 4.66 (m, 1/2H), 4.51 (m, 2H), 4.39 (m, 1/2H), 4.30 (m, 1/2H), 4.02 (m, 1/2H), 3.68 (m, 1H), 3.28 (m, 1H), 2.90-2.35 (m, 6H), 2.13 (m, 1H), 1.76 (m, 1/2H), 1.68 (m, 1/2H), 1.40 (m, 1/2H), 1.00-0.70 (m, 21H), 0.10-0.00 (m, 6H); MS(ES+) m/e 849 [M+H]+. f) (2R,4S,5S,1*S)-5-[3-(RS)- (l-benzyloxymethylimidazol-2-yl)3- hydroxy-4-methylpentanoyl]amino-4-hydroxy-N-(1'-isopropyl30 1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide The compound of Example 65(e) (100 mg, 0.12 mmol) was desilylated by the procedure of 47(c) to cleanly afford the title compound (78 mg, 89%). XH NMR(CDC13, 400 MHz) 6 7.40- 6.80 (m, 19H) , 5.75 (m, 2H) , 4.97 (m, 1/2H), 4.78 (m, 1/2H), 35 4.51 (m, 2H) 3.94 (m, 1/2H) , 3.85 (m, 1/2H), 3.51 (m, 1H), 3.21 (m, 1H) , 2.97-2.43 (m, 6H);2. .00 (m, 1H), 1.60 (m, 1H) , 1.43 (m, 1H) , 0.97-0.49 (m, 12H) ; MS (ES + ) m/e 735 [M+H]+. - 105 g) (2R,4S, 5S, 1'S)-5-[3(R)-(imidazol-2-yl)-3-hydroxy-4methylpentanoyl]amino-4-hydroxy-N-(1'-isopropyl-l1-imidazol2-yl)methyl-6-pheny1-2-phenylmethy1-hexanamide; and (2R,4S,5S,1'S)-5-[3-(S)-(imidazol-2-yl)-3-hydroxy-45 methylpentanoyl]amino-4-hydroxy-N-(1'-isopropyl-l’-imidazol2-yl)methyl-6-pheny1-2-phenylmethy1-hexanamide Using the procedure of Example 47(d), the compound of Example 65(f) (72 mg, 0.98 mmol) was hydrogenated to afford a diastereomeric mixture of the title compounds. The mixture was purified by flash chromatography (silica, step gradient, 0-8% CH3OH/CH2CI2) to afford tail fractions containing the pure diastereomers (35 mg total, 58%).
Isomer 1, last eluting, (2R,4S,5S,1*S)-5-[3-(R)-(1HImidazol-2-yl)-3-hydroxy-4-methylpentylamido]-4-hydroxy-N15 (1'-isopropyl-l'-imidazol-2-yl)methyl-6-pheny1-2phenylmethyl-hexanamide. NMR(CDCl3, 400 MHz, δ 7.35-6.82 (m, 10H), 6.93 (s, IH), 6.84 (s, IH), 4.42 (d, IH, J=9 Hz), 3.77 (m, IH), 3.40 (m, IH), 3.00-2.40 (m, 5H), 2.14 (m, IH), 1.99 (m, IH), 1.56 (m, IH), 1.47 (m, IH), 0.93-0.64 (m, 12H); MS(ES+) m/e 615 [M+H]+.
Isomer 2, first eluting, (2R,4S,5S,1 *S)-5-[3 (S)-(1HImidazol-2-yl)-3-hydroxy-4-methylpentylamido]-4-hydroxy-N(1’-isopropyl-l’-imidazol-2-yl)methyl-6-phenyl-2phenylmethyl-hexanamide. ^-H NMR(CDCl3, 400 MHz) δ 7.35-6.81 (m, 10H) , , 6. 83 (S, IH) , , 6.81 (s, IH) , 4.4 6 (d, 1 H, J=9 Hz) , 3.93 (m, IH) , 3.40 (m, IH) , 3.00- -2.40 (m, 5H) , 2.13 (m, IH) , 1.91 (m, IH) , 1.41 (m, 1H), 1.10 (m, IH) , 0.93- -0.64 (m, 12H) ; MS(ES+) m/e 615 [M+HJ+.
Example 66 Preparation of (2R, 4S, 5S, 11 S)-5-f_L4~ methoxyphenoxy)carbonyllamino-4-hydroxy-N-(11-isopropyl-limidazol-2-yl) methyl-6-phenvl-2-phenvlmethvl-hexanamJ.de a) (2R,4S,5S,1'S)-5-[(4-methoxyphenoxy)carbonyl]amino-4-tbutyldimethylsiloxy-N-[1'-isopropyl-l'-(Ν'IE 922316 - 106 methoxycarbonyl)imidazol-2-yl]methyl-6-pheny1-2-phenylmethylhexanamide Following the procedure of Example 13(b), except using p-methoxyphenyl chloroformate and (2R,4S,5S,1'S)-5-amino-4-fc5 butyldimethylsiloxy-N-(1’-isopropyl-l1-imidazol-2-yl)methyl6-phenyl-2-phenylmethyl-hexanamide (114 mg, 0.21 mmol), the title compound was prepared (63%). NMR(CDCl3), δ 7.44-6.76 (m, 20H), 5.66 (m, 1H), 5.18 (d, 1H ), 4.40 (m, 1H), 3.83 (s,3H), 3.76 (m, 1H), 3.73 (s, 3H), 2.96-2.50 (m, 5H), 2.05 (m, 5H), 1.60 (m, 1H), 0.94 (s, 9H), 0.79 (d, 3 H, J=7 Hz), 0.74 (s, 3H), 0.12 (s, 3H), 0.11 (s, 3H).. b) (2R,4S,5S,1’S)-5-(methoxycarbonyl)amino-4-hydroxy-N-(1’isopropyl-l'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl15 hexanamide Following the procedure of Example 13(c), except using the compound of Example 66(a), the title compound was prepared (32%). NMR(CDCI3/CD3OD), δ 7.36-6.84 (m, 16H), 4.49 (d, 1H, J=9 Hz), 3.79 (s, 3H), 3.37 (m, 1H), 2.92-2.60 (m, 5H), 2.10-1.70 (m, 3H) , 0.78 (d, 3H, J=7 Hz), 0.67 (d, 3H, J=7 Hz); MS(ES+) m/e 585 [M+H]+.
Example 67 Preparation of (2R,4S,5S,11S)-5-(t-butylaminocarbonvl)amino -4-hydroxy-N-(1'-isopropyl-l'-imidazol-2-yl)methy1-6phenylmethy1-hexanamide a) (2R,4S,5S,1’S)5-(t-butylaminocarbonyl)amino-4-(t30 butyldimethylsiloxy)-N-(1’-isopropyl-l1-imidazol-2-yl)methyl6-phenylmethy1-hexamide The compound of Example 13(a) (0.13 g, 0.24 mmol) was dissolved in dichloromethane (3 mL) and t-butyl isocyanate (0.028 g, 0.29 mmol) was added. After stirring at 30°C for 18 h, the solvent was removed under reduced pressure and the residue was chromatographed (silica, 2:3 ethylacetate:hexane) to give the title compound as a white solid (0.12 g, 77%) . NMR(CDCl3), δ7.35-7.05 (12H, m) , 6.85 (2H, s) , 4.69 (1H, d, - 107 J=9 Hz), 4.60 (1H, t, J=8 Hz), 4.38 (1H, br), 4.24 (1H, q, J=8 Hz), 3.66 (1H, dd, J=4 Hz, 10 Hz), 2.95 (1H, dd, J=9Hz, 13Hz), 2.73(2H, m), 2.54 (1H, dd, J=5 Hz, 13 Hz), 2.42 (1H, m), 1.82 (1H, m), 1.67 (1H, m) , 1.22 (9H, s), 0.93 (9H, s), 0.84 (3H, d, J=7 Hz), 0.79 (3H, d, J=7 Hz), 0.08 (3H, s), 0.07 (3H, s); MS(ES) m/e 648.4 [M+H]+. b) (2R,4S,5S,1'S)-5-(t-butylaminocarbonyl)amino-4-hydroxy-N(1’-isopropyl-l*-imidazol-2-yl)methy1-6-phenylmethyl10 hexanamide.
The compound of Example 67(a) (0.033 g, 0.05 mmol) was stirred in dry THF (0.25 mL) and tetrabutylammonium flouride (0.25 mL, 0.25 mmol) in THF was added. After 18 h at 50°C the reaction was cooled, diluted with ethyl acetate (25 mL), washed with water (5 mL), and dried (MgSO4). The combined organic extracts were filtered and concentrated in vacuo. Chromatography (silica, 1:1 ethyl acetate:hexane) gave the title compound as a white solid (0.018 g, 66%). M.p 226°C (dec); NMR(CD3OD) 57.37-6.90 (10H, m), 6.90 (2H, s), 4.58 (1H, d, J=9 Hz), 3.71 (1H, t, J=7 Hz), 3.52 (1H, d, J=9 Hz), 2.75 (4H, m), 2.53 (1H, dd, J=4 Hz, 12 Hz), 2.03 (1H, m), 1.76 (1H, m), 1.66 (1H, m), 1.22 (9H, s), 0.79 (3H, d, J=7 Hz), 0.67 (3H, d, J=7 Hz); MS(ES+): m/e 534 [M+H]+· Example 68 Preparation of (2R. 4S. 5S. 11S)-5-(methylaminocarbonyl)amino-4-hydroxy-N-(1'-isopropyl-l'-imidazol-2-yl)methyl-6phenylmethyl-hexanamide.
Following the procedure of Examples 67 (a)-67(b), except substituting methyl isocyanate for t-butylisocyanate, the title compound was prepared (0.075 mg, 51%). M.p 253°C (dec); NMR(DMSOd6) 57.78 (1H, d, J=9 Hz), 7.80-6.96 (11H, m), 6.88 (2H, s), 5.78 (1H, d, J=5 Hz) , 5.72 (1H, d, J=9 Hz), 35 4.84 (1H, d, J=4 Hz ), 4.65 (1H, m) , 3.68 (1H, q, J=7 Hz), 3.44 (1H, br), 2.74 (3H, m) , 2.58 (1H, dd , J= 7 Hz, 13 Hz), 2.50 (3H, s), 2.41 (1H, d, J=8 Hz) , 1.92 (1H, m) , 1.46 (2H, - 108 m) , 0.72 (3H, d, J=7 Hz), 0.63 (3H, d, J=7 Hz); MS (ES+) : m/e 492 [M+H]+.
Example 69 (2R,4S.5S,1Έ)-5-Phenylaminocarbonyl)amino-4-hydroxy-N-¢1'isopropyl-l'-imidazol-2-yl)methyl-6-phenylmethyl-hexamide.
Following the procedure of Examples 67(a)-67(b), except substituting phenyl isocyanate for t-butylisocyonate, the title compound was prepared (87 mg, 79%). M.p 273°C (dec,; NMR(DMSO-d6), 8.50 (1H, s), 7.81 (1H, d, J=9 Hz), 7.34-6.83 (18H, m), 6.07 (1H, d, J=9 Hz), 4.99 (1H, d, J=4 Hz), 4.65 (1H, t, J=8 Hz), 3.75 (1H, m), 3.52 (1H, br), 2.77 (3H, m), 2.66 (1H, m), 2.42 (1H, d, J=7 Hz), 1.89 (1H, m), 1.50 (2H, m), 0.68 (3H, d, J=7 Hz), 0.61 (3H, d, J=7 Hz); MS (DCI/NH3) m/e 554.3 [M+H]+.
Example .IQ (2R. 4S. 5S. 1'S)-5-N-Propylureylo-4-hydroxv-N-(1'-isopropyl1 '-imidazol-2-yl) methyl-6-phenylmethyl-hexamide-.
Following the procedure of Examples 67(a)-67(b), except substituting n-propyl isocyanate for t-butylisocyanate, the title compound was prepared (0.048 g, 54%). Mp 247-9°C (dec); NMR(DMSO-d6) 87.75 (1H, d, J=8 Hz), 7.23-6.94 (11H, m), 6.85 (2H, s), 5.87 (1H, t, J=5 Hz), 5.65 (1H, d, J=9 Hz), 4.82 (1H, d, J=4 Hz), 4.64 (1H, t, J=8 Hz), 3.66 (1H, m), 3.38 (1H, br), 2.87 (2H, q, J=6 Hz), 2.74 (3H, m), 2.56 (1H, dd, J=7 Hz, 13 Hz), 2.39 (1H, d, J=7 Hz), 1.91 (1H, m), 1.43 (2H, m), 1.28 (2H, q, J=7 Hz), 0.77 (3H, t, J=7 Hz), 0.71 (3H, d, J=7 Hz), 0.62 (3H, d, J=7 Hz); MS(CI) m/e 520.2 [M+H]+.
Example 71 ®922316 - 109 Preparation.of (2R,4S,5S,11S)-5-(n-propylaminothiono)amino-4hydroxy-N-(1'isopropyl-1'-imidazol-2-yl)methyl-6phenylmethyl-hexamide.
Following the method of Example 67(a)-67(b), except using n-propyl thioisocyanate, the title compound was prepared (0.012 g, 21%). Mp 195-7°C (dec); NMR (CD3OD) δ 7.32-6.86 (12H, m), 4.59 (IH, m), 3.64 (IH, br), 3.34 (2H, br), 2.79 (5H, m), 2.03 (IH, m), 1.73 (IH, m), 1.58 (3H, m), 0.92 (3H, t, J=7Hz), 0.83 (3H, d, J=7Hz), 0, 68 (3H, d, J=7 Hz); MS (CI) m/e 536.2 [M+H]+.
Example 72 (2R,4S,5S,1'S)-5-(isopropylaminocarbonyl)amino-4-hydroxy-N(11-isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexamide Following the method of Example 67(a)-67(b), except substituting isopropyl isocyanate for t-butyl isocyanate, the title compound was prepared (0.034g, 46%). NMR(DMSO-d6) δ 7.78 (IH, d, J=8 Hz), 7.24-6.97 (11H, m) , 6.85 (2H, s), 5.74 (IH, d, J=8 Hz), 5.57 (IH, d, J=9 Hz), 4.83 (IH, d, J=4 Hz), 4.66 (IH, d, J=7 Hz), 3.62 (2H, m), 3.43 (IH, br), 2.73 (3H, m), 2.57 (IH, dd, J=7 Hz, 13.5 Hz), 2.41 (IH, d, J=7 Hz), 1.91 (IH, m), 1.45 (2H, m), 0.95 (3H, d, J=6.5 Hz), 0.93 (3H, d, J=6.5 Hz), 0.72 (3H, d, J=6.5 Hz), 0.63 (3H, d, J=6.5 Hz); MS (CI) m/e 520.2 [M+H]+.
Example 73 (2R, 4S.5S, 11 S)-5- (aminocarbonynamino^-hydroxy-N-d1-isopropvl-1'-imidazol-2-yl) methyl-6-phenylmethyl-.hexamide The compound of Example 67(a) (0.050g, 0.094 mmol) was dissolved in triflouroacetic acid (2 mL) and stirred at 50°C for 2 h. After cooling, the reaction mixture was poured into saturated sodium bicarbonate solution (50 mL) and was extracted into ethyl acetate (100 mL). The organic solution was washed with brine, dried (MgSO4) and the solvent removed - 110 under reduced pressure. Chromatography of the residue (silica, 19:1 dichloromethane:methanol) gave the title compound as a white solid (0.036g, 80%). Mp 235°C (dec); NMR(DMSO) δ 7.82 (IH, d) , 7.30-6.90 (11H, m), 6.85 (2H, d), .88 (IH, m), 4.86 (IH, d), 4.67 (IH, t), 3.67 (IH, m), 3.45 (IH, m), 2.75 (3H, m), 2.60 (IH, m), 2.43 (IH, m), 1.94 (IH, m), 1, 49 (2H, m), 0.73 (3H, d) , 0.62 (3H, d); MS (CI) m/e 478 [M+H]+. io ExampIe.JZ-4 Preparation of (2R.4S.5S,1’S)-5-(6-quinolinylmethvloxvcarbonyl)amino-4-hydroxy-N-(11-isopropyl-l'-imidazol-2y1 lmethy1-6-phenylmethy1-hexanamide 15 Using the procedure of Example 34, except substituting (6-quinolinylmethyl)-(4-nitrophenyl) carbonate for (4picolinyl)- (4-nitrophenyl) carbonate, the title compound was prepared.
By using the procedure of Example 43(c)-43(d) and the appropriate carboxylic acid, or by preparing the acid chloride from the appropriate carboxylic using the acid chloride and triethylamine, 5-amino-4-t-butyldimethylsiloxy25 N-(1’-isopropyl-l'-imidazol-2-yl)methy1-2-phenylmethy1-6phenyl-hexanamide was acylated with benzoic acid, furan-2carboxylic acid, 4-methoxybenzoic acid, 4-hydroxybenzoic acid, 2-hydroxybenzoic acid, cinnamic acid, phenylacetic acid, and imidazol-4-yl-acetic acid to yield the following compounds: . (2R. 4S. 5S. 1 ’S) -5- (benzoyl) amino-4-hydroxy-N- (12isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexanamide 76. (2R.4S.5S,1’S)-5-(2-furylcarbony1)amino-4-hydroxyrN-11'isopropyl-l' -imidazol-2-yl)methyl-6-phenvlmethvl-hexanamide . (2R. 4S, 5S, 1' S) -5-(4-methoxybenzoyl)amino-4-hydroxyrNHV-isopropy lr 11-imida zolr2-.yl)methylr 6-pheny lmethyl-hexanamids - Ill - 78. (2R.4S.5S.11S)-5-(benzvlcarbonvl)amino-4-hvdroxv-N-(1'- isobrobvl-1'-imidazol-2-vl)methvl-6-phenvlmethvl-hexanamide 79. (2R.4S.5S,1’S)-5-(4-hvdroxvbenzovl)amino-4-hvdroxv-N-(1'- isopropvl-1'-imidazol-2-vl)methvl-6-phenvlmethvl-hexanamide 80. (2R.4S.5S.1'S)-5-(cinnamovl)amino-4-hvdroxv-N-(1 i sopropvl-1'-imida zol-2-vl)methvl-6-phenvlmethvl-hexanamide 81. (2R,4S,5S.1'S)-5-(2-hvdro xvbenzovl)amino-4-hvdroxv-N-(1' - isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexanamide 82. (2R.4S.5S.l'S)-5-(imidazoyl-4-yl-acetyl)amino-4-hydroxvr N-(11-isopropyl-11-imidazol-2-yl)methyl-6-phenvlmethvlhexanamide Example 82 Preparation of (2R, 4S, 5S, 1’S)-5-(t-butoxvcarbonyl) amino-4_hydroxy-N-Γ1'-isopropyl-1(4-carbomethoxyethylimidazol-2yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide a) (IS) 1-carbobenzyloxyamino-l-isopropyl-l-[(4-(Ecarbomethoxyethylene)imidazol-2-yl)]methane The compound of Example 27(b) (100 mg, 0.33 mmol), lithium chloride (28 mg, 0.66 mmol) and trimethylphosphonoacetate (61 mg, 0.33 mmol) were dissolved in anhydrous acetonitrile (2mL). 1,8-Diazabicyclo[5.4.0]undec-7-ene (55 mg, 0.36 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silicaa, 2% methanol/ dichloromethane to afford the title compound (72 mg, 61%). NMR(CDCl3) δ 7.60-7.10 (6H, m) , 6.50 (1H, br s), 6.10 (1H, br 112 s), 5.15-4.95 (2H, m), 4.50 (1H, br m), 3.75 (3H, s), 2.30 (1H, br m), 1.10-0.80 (6H, m); MS m/e 358.2 [M+H]+. b) (IS)-1-amino-l-isopropyl-l-(4-carbomethoxyethylimidazol-25 yl)methane Following the procedure of Example 1 (b), except substituting the compound of Example 82(a) for the compound of Example 1(a), the title compound was prepared. NMR(CDCl3) δ 6.65 (1H, s), 4.40 (2H, br s), 3.82 (1H, d, J=3 Hz), 3.65 (3H, s), 2.90-2.55 (4H, m) , 2.05 (1H, m) , 0.90 (6H, d, J=3Hz). c) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-tbutyldimethylsiloxy-N-[11-isopropyl-l'-(415 carbomethoxyethylimidazol-2yl)]methyl-6-phenyl-2phenylmethy1-hexanamide Following the procedure of Example 1(c) except using the compound of Example 82(b), the title compound was prepared. NMR(CDCl3) δ 7.35-6.90 (12H, m), 6.55 (1H, s) , 20 4.75 (1H, d, J=4 Hz) , 4.45 (1H, m) 3.95 (1H, m) , 3.70 (3H, s), 2.90-2.40 (9H, m) , 1.90-1.60 (2H, m), 1.38 (9H, s) , 0.90-0.70 (15H, m), 0.10 (6H, d, J=2 Hz). d) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N25 [1'-isopropyl-l'-(4-carbomethoxyethylimidazol-2-yl)]methyl-6pheny1-2-phenylmethy1-hexanamide.
Following the procedure of Example of 9(d) except using the compound of Example 83(c), the title compound was prepared. NMR(CDCl3) δ 7.30-6.90 (10H, m), 6.55 (1H, s), .00 (1H, d, J=4 Hz), 4.45 (1H, m), 3.70 <3H, s), 2.95-2.50 (9H, m), 2.25 (1H, m), 1.80-1.60 (2H, m), 0.85 (9H, s), 0.70 (6H, d, J=3 Hz); MS m/e 621.4 [M+H]+.
Example 83 Preparation of (2R, 4S. 5S._1'Sl-5-(fc-butoxycarbonvl) amino-4hydroxy-N-il'-isopropyl-l'- (4-carboxamidoimidazol-2yl)1rnethyl-6-phenyl-2-phenvlmethvl-hexanamide 113 a) (IS)-1-carbobenzyloxyamino-l-isopropyl-l-[(4(hydrazinocarbonyl)imidazol-2-yl)]methane Anhydrous hydrazine (47 gL, 1.5 mmol) was added to a 5 solution of the compound of Example 26(b) (100 mg, 0.30 mmol) in anhydrous methanol. The resulting mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and 10% aqueous Na2CO3 and the organic extract was dried over Na2CC>3 and evaporated under reduced pressure. The residue was purified by flash chromatography (silica, 4% methanol/dichloromethane) to afford the title compound (52 mg, 52%). NMR(CD3OD) δ 7.50 (1H, s), 7.30-7.20 (5H, m) , .00-4.90 (2H, m), 4.45 (1H, d, J=6 Hz), 2.10 (1H, br m), 0.95-0.75 (6H, m); MS m/e 332.2 [M+H]+ b) (IS)-1-carbobenzyloxyamino-l-isopropyl-l-[(4azidocarbonyl)imidazol-2-yl]methane The compound of Example 83(a) was dissolved in 2N HC1 (1 mL) and glacial acetic acid (0.2 mL) and cooled in an ice bath. A solution of sodium nitrite (11 mg, 0.16 mmol) in H2O (200 gL) was added dropwise. The reaction mixture was stirred for 0.5 h, neutralized with cold concentrated ammonium hydroxide and extracted with ethyl acetate. The organic extract was dried over Na2CO3 and the solvent removed in vacuo to yield the title compound (54mg. 100%) .
NMR(CDCl3) δ 7.75 (1H, s) , 7.35-7.20 (5H, m), 5.20-5.00 (2H, m), 4.62 (1H, br m), 2.60 (1H br m), 1.10-0.80 (6H, m); IR 2123cm-1 (CON3). c) (IS)-1-carbobenzyloxyamino-l-isopropyl-l-(4carboxamidoimidazol-2-yl)methane The compound of Example 83(b) was dissolved in 2 mL of ethyl acetate and stirred with of concentrated ammonium hydroxide (1 mL) at 0°C for 0.5 h, then at room temperature overnight. The reaction mixture was diluted with H2O, extracted with ethyl acetate, and dried over Na2CO3. The solvent was removed in vacuo and the residue was purified by - 114 flash chromatography (silica, 4% methanol/ dichloromethane) to afford the title compound (50mg, 100%) . NMR(CDCl3) δ 7.45 (IH, s), 7.25-7.10 (5H, m) , 5.00-4.85 (2H, m), 4.35 (IH, d, J=3 Hz), 2.00 (IH, br m), 0.90-0.70 (6H, m); MS m/e 317.2 [M+H]+. d) (IS)-1-amino-l-isopropyl-l-(4-carboxamidoimidazol-2yl)methane.
Following the procedure of Example 1(b), except substituting the compound of Example 83(c) for the compound of Example 1(a), the title compound was prepared. NMR(CDCl3) δ 7.45 (IH, s), 3.47 (IH, d, J=3 Hz), 1.80 (IH, br m), 0.750.60 (6H, m) . e) (2R,4S,5S,1’S)-5-(t-butoxycarbonyl)amino-4-tbutyldimethylsiloxy-N-[1'-isopropyl-l'-(4carboxamidoimidazol-2-yl)]methyl-6-phenyl-2-phenylmethylhexanamide Following the procedure of Example 1(c), except using the compound of Example 83(d), the title compound was prepared. NMR(CDCl3) δ 7.50 (IH, s) , 7.45-6.90 (11H, m), 6.25 (IH, d, J=4 Hz), 4.50 (IH, d, J=6Hz), 4.10 (IH, br m), 3.60 (IH, m), 2.90-2.40 (5H, m), 1.90 (IH, br m), 1.70-1.50 (2H, br m), 1.35 (9H, s), 0.90 (9H, s), 0.70-0.60 (6H, m), 0.10 (6H, m). f) (2R,4S,5S,1*S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N[1'-isopropyl-l'- (4-carboxamidoimidazol-2-yl)]methyl-6pheny1-2-phenylmethy1-hexanamide Following the procedure of Example 9(d) except using the compound of Example 83(e) the title compound was prepared. NMR(CD3OD) δ 7.45 (IH, s) , 7.25-6.85 (10H, m), 4.50 (IH, d, J=6 Hz), 4.10 (IH, m), 3.60 (IH, m), 2.85-2.50 (5H, m), 2.00 (IH, br m), 1.80-1.50 (2H, m), 1.30 (9H, s), 0.80-0.65 (6H, m); MS m/e 578.2 [M+H]+.
Using the routine procedures, the following additional compounds were prepared: 115 85. (2R.4S.5S,1’S)-5-(thiazol-2-yl)amino-4-hydroxy-N-(1'isopropyl-l' -imidazQl-2tyllmethvl-6-Phenylmethyl-hexanamide 86. (2R, 4S, 5S, 1 ’S) -5- (5-propyl-thiazol-2-y-l) aminor4-hvdrQXVr 5 N-(1'-isopropyl-l'-imidazol-2-yl)methyl-6-phenvlmethylhexanamide 87. (2R,4S.5S,1'S)-5-(5-(1-oxo-propyl)-thiazol-2-yl)amino-4n hydroxy-N-(1'-isopropyl-l1-imidazol-2-yl)methyl-βτ phenylmethyl-hexanamide The above description fully discloses how to make and use the present invention. However, the present invention is not limited to the particular embodiments described hereinabove, but includes all modifications thereof within the scope of the following claims.
Claims (18)
1. A compound of the formula (I): R 1 R 2 5 OH R 3 (I) wherein : R 1 and R 3 are each independently Q, Q-Ci-6alkyl, Q-C2-6alkenyl, Q-C2-6alkynyl or C^.galkyl substituted by one 10 to five fluorine atoms, each optionally substituted by R 23 ; Q is H, C3_6cycloalkyl, C 5 _gcycloalkenyl, Ar or Het R 2 is H or OH; R 4 is r6_ N rH- or CONR 11 CHR 6 R 7 ; R 5 is r6_ N rU- or R 10 -NR 11 -; R 6 is x ^ r8 - X is NR 11 , O or S; R 7 is H, Ci-^alkyl, Ar-Cj.galkyl, Het-C 1 _ 6 alkyl, C 2 _ 6 alkenyl, Ar-C 2 _ 6 alkenyl, Het-C 2 _ 6 alkenyl, C3_ 6 cycloalkylCj.galkyl or C3_gcycloalkenyl-C 1 _ 6 alkyl; 20 R 8 and R 9 are each independently H, OH, halo, NO2, COR 12 , CF3, Ar, C^.galkyl-R 15 , or R 17 (R 18 R 19 C) m , or together form a fused C2-4alkylene, aryl or heteroaryl moiety; R 10 is A-(B) n -; R 11 is H or Ci_4alkyl; 25 R 12 is R 7 , OR 7 , NR 7 R 11 or an amino acid or amino alcohol; B is an amino acid; A is H, Ar, Het, R 17 (R 18 R 19 C) m , Ar-W, Het-W or r!7 (r18r19q) m -w, or phthaloyl each optionally substituted by one to three groups chosen from R 15 or Ci_6alkyl-R 15 ; 30 W is C=O, OC(=O), NR 11 C(=0), SC(=O), NR 11 C(=S), S0 2 , NR 11 SO 2 or P(=0)(OR 22 ); R 15 is H, nitro, Ci-6alkoxy, C^galkylthio, 0(0=0) R 16 , C=OR 22 , CO2R 22 , CON(R 16 )2, N(R 22 ) 2 , NHC(=N)NH-A, I, Br, Cl, F or OH, provided that when R 15 is a substituent of the carbon 117 adjacent to W, R 15 is not halogen or OH when W is OC(=O) or NHCO; R 16 is H or Ci-galkyl; R 17 , R 18 and R 19 are independently: i) H, R 15 or Ci-4alkyl, C2-6 al kenyl, phenyl, naphthyl, C3-6cycloalkyl or Het, each optionally substituted by one to three R 15 or R 15 -Ci_galkyl groups, or ii) R 17 is as above and (R 18 R 19 C) are joined together to form a phenyl, naphthyl, C3-6cycloalkyl or Het ring, or iii) R 17 is as above and R 18 and R 19 together are =0; r22 is H, C^galkyl, phenyl or phenyl-Ci-4alkyl; R 23 is -X '- (CH2) qNR 24 R 25 , X [ ( (0Η2) r 0) s ] R 26 , CH2X[((CH2) r O) s ] R 26 , or benzofuryl, indolyl, azacycloalkyl, azabicyclo C7-ncycloalkyl or benzopiperidinyl, optionally substituted with Ci_4alkyl; q is 2-5; s is 1-6 and r is 1-3 within each repeating unit s; X' is CH2, 0, S or NH; X is CH 2 , NR', 0, S, SO or SO2; R 24 and R 25 are i) Ci-6alkyl, optionally substituted by OH, Ci_3alkoxy, or N(R') 2 , ii) the same or different and joined together to form a 5-7 member heterocycle containing up to two additional heteroatoms selected from NR, 0, S, SO, SO 2 , said heterocycle optionally substituted with Ci-4alkyl, iii) aromatic heterocycle, optionally substituted with Ci_4alkyl or N(R') 2 ; R' is H or Ci-4alkyl; R 26 is H, Ci-4alkyl, C(=O)R 27 , C(=0)U[ (CH2)mO]nR', P (=0) (0M)2, CO 2 R 27 , C (=0) NR 27 R 28 , where M is a mono or divalent metal ion, and U is NR' or 0; R 27 is Ci-6alkyl or Ar, optionally substituted with one or more hydroxy, carboxy, halo, Ci-3alkoxy, CONR’2, NR'2, CO 2 R', SO 2 NR'2, CH2NR2, NR'COR', NR'S0 2 R', X[(CH 2 ) r 0] 3 R' or CH 2 X[(CH 2 ) r 0] s R*; R 28 is H, Ci-galkyl or together with R 27 forms a 5-7 membered heterocycle or a 6 membered heterocycle containing a heteroatom selected from N, 0 and S; m is 1-4; and 118 n is 0 or 1; or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 wherein: 5 R 1 and R 3 are Ci-6alkyl, Ar-Ci-6alkyl, Ar-C 2 -6alkenyl, Ar-C2-6alkynyl, or Ci-6alkyl optionally substituted by one to five fluorine atoms; X is N-R 11 ; R 7 is H, Ci-galkyl, 03-6cycloalkyl, phenyl or benzyl; 10 R 8 is H, Ci-6alkyl, COR 12 , NO 2 or Br; R 9 is H, NO 2 , Br, COR 12 , CF3, Ar, Ci-6alkyl or Ci-6alkyl-R 15 , wherein R 12 is H, Ci-6alkyl, Ar, OCi-galkyl, NH 2 , and R 15 is OH; A is H, Het, R 17 (R 18 R 19 C) m -W or Het-W; 15 R 17 , R 18 and R 19 are H, or Ci-galkyl, Het or Ar, each optionally substituted by one or two R 15 or R 15 Ci-6alkyl groups, or (R 18 R 19 C) are joind together to form a phenyl, C3-6cycloalkyl or Het ring; and W is C=O, 00(=0), NHC(=0), NHC(=S) or SC(=O).
3. A compound according to claim 1 wherein X is N-H.
4. A compound according to claim 3 wherein R 8 is H and R 9 is H or COR 12 .
5. A compound according to claim 4 wherein R 7 is C^.galkyl.
6. A compound according to claim 5 wherein R 1 is benzyl and R 3 is benzyl, 4-hydroxy-benzyl or phenylpropenyl.
7. A compound according to claim 3 wherein R 17 (R 18 R 19 C) m -W is Ci-6alkylOC(=0).
8. A compound according to claim 3 wherein W is C=0.
9. A compound according to claim 1 wherein the compound is: E922316 119 (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t-butoxycarbonyl) amino-6-phenyl-N-(1'-isopropyl-1’- (imidazo-2-yl))methylhexanamide hydrochloride; (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t-butoxycarbonyl) 5 amino-6-phenyl-N-[1’-isopropyl-1'-(4-aminocarbonyl-thiazo-2yl)]methyl-hexanamide; (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t-butoxycarbonyl) amino-6-phenyl-N-[1'-isopropyl-1'-(thiazo-2-yl)]methylhexanamide; 10 (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t-butoxycarbonyl) amino-6-phenyl-N-(1'-imidazo-2-yl)methyl-hexanamide hydrochloride ; (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t-butoxycarbonyl) amino-6-phenyl-N-[1'-methyl-1'-(imidazo-2-yl)] methyl15 hexanamide hydrochloride; (2R,4S,5S,1 'S)-2-phenylmethyl-4-hydroxy-5-(t-butoxycarbonyl) amino-6-phenyl-N-[1'-benzyl-1'-(imidazo-2-yl)]methylhexanamide hydrochloride; (2R,4S,5S,1'S)-5-(carbobenzyloxy)amino-4-hydroxy-N-(1'20 isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethylhexanamide; (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[l'isopropyl-l '-(4,5-dimethyl)imidazol-2-yl]methyl-6-phenyl-2phenylmethy1-hexanamide; 25 (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[l'isopropyl-l '-(Ν'-methyl)imidazol-2-yl]methyl-6-pheny1-2phenylmethy1-hexanamide ; (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(l'isopropyl-l '-imidazol-2-yl)methyl-6-phenyl-2-(330 phenylpropargyl)hexanamide; (2R,4S,5S,1'S)-5-(isopropoxycarbonyl)amino-4-hydroxy-N-(l'isopropyl-l '-imidazol-2-yl)methyl-6-phenyl-2-phenylmethylhexanamide; (2R,4S,5S,1'S)-5-(benzyloxyethoxycarbonyl) amino-4-hydroxy-N 35 (1'-isopropyl-1'-imidazol-2-yl)methyl-6-pheny1-2phenylmethy1-hexanamide; - 120 (2R,4S,5S,1’S)-5-(methoxycarbonyl)amino-4-hydroxy-N- (1'isopropyl-l’-imidazol-2-yl)methyl-6-phenyl-2-phenylmethylhexanamide; (2R, 4S,5S,1'S)-5-(ethoxycarbonyl)amino-4-hydroxy-N- (1’5 isopropyl-l’-imidazol-2-yl)methyl-6-phenyl-2-phenylmethylhexanamide; (2R,4S,5S,1’S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1'isopropyl-l'-imidazol-2-yl)methyl-6-phenyl-2-(3-phenyl-2propenyl)hexanamide; 10 (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1 isopropyl-l’-(4-nitroimidazol-2-yl)]methyl-6-phenyl-2phenylmethyl-hexanamide; (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1’ethyl-1’-imidazol-2-yl)methy1-6-pheny1-2-phenylmethy115 hexanamide; (2R,4S,5S,1’S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1’propyl-1 1 -imidazol-2-yl)methyl-6-phenyl-2-phenylmethylhexanamide ; (2R,4S,5S,1’S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[ 1 * — 20 isopropyl-l’-(4-bromoimidazol-2-yl)]methyl-6-phenyl-2phenylmethy1-hexanamide; (2R,4S,5S,1’S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1' — isopropyl-l'-(4,5-dibromoimidazol-2-yl)]methyl-6-pheny1-2pheny lmethyl-hexanamide ; 25 (2R, 4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N- [ 1' — isopropyl-l'-(4-methylimidazol-2-yl)]methyl-6-phenyl-2phenylmethyl-hexanamide; (2R,4S,5S,1’S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1’isopropyl-l'- (4-trifluoromethylimidazol-2-yl)]methyl-630 pheny1-2-phenylmethyl-hexanamide; (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-methylN-(1’-isopropyl-l'-imidazol-2-yl)methyl-6-pheny1-2pheny lmethy 1-hexanamide; (2R,4S,5S,1’S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[ 1' — 35 isopropyl-l'-(4-carbomethoxyimidazol-2-yl)]methyl-6-phenyl-2 phenylmethyl-hexanamide; 121 (2R,4S,5S,l'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[l’isopropyl-l ’-(4-methylcarbonylimidazol-2-yl)]methyl-6-phenyl 2-phenylmethyl-hexanamide; (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'5 isopropyl-l'-(4-isopropylcarbonylimidazol-2-yl)]methyl-6pheny1-2-phenylmethy1-hexanamide; (2R,4S,5S,l'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[l'isopropyl-l '-(4-phenylcarbonyl-imidazol-2-yl)]methyl-6pheny1-2-phenylmethy1-hexanamide;
10.(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[l'isopropyl-l '-(4-formylimidazol-2-yl)]methyl-6-phenyl-2phenylmethyl-hexanamide ; (2R,4S,5S,1’S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[l'isopropyl-l '-(4-(hydroxymethyl)-imidazol-2-yl)]methyl-615 phenyl-2-phenylmethy1-hexanamide; (2R,4S,5S,1'S)-5-((tetrahydrothiopyran-4-yl)oxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-l'-imidazol-2-yl)methyl-6pheny1-2-phenylmethy1-hexanamide; (2R,4S,5S,1'S)-5-((tetrahydro-4H-pyran-4-yl)oxycarbonyl)20 amino-4-hydroxy-N-(1'-isopropyl-l'-imidazol-2-yl)methyl-6pheny1-2-phenylmethy1-hexanamide; (2R,4S,5S,1'S)-5-(4-picolinyloxy)amino-4-hydroxy-N-(l’isopropyl-l ’-imidazol-2-yl)methyl-6-phenyl-2-phenylmethylhexanamide; 25 (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(l'isopropyl-l '-imidazol-2-yl)methyl-6-pheny1-2-(4,4,4trifluorobut-l-yl)hexanamide ; (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t-butoxycarbonyl) amino-6-phenyl-N-(1'-isobutyl-1'-(imidazo-2-yl)) methyl30 hexanamide hydrochloride ; or (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[l'isopropyl-l '-(4-((IRS)-1-hydroxyethyl)-imidazol-2-yl)]methyl 6-pheny1-2-phenylmethy1-hexanamide. 35 10. A compound according to claim 9 which is (2R,4S,5S,1'S) 2-phenylmethyl-4-hydroxy-5-(t-butoxycarbonyl)-amino-6-phenyl N-(1'-isopropyl-l'-(imidazo-2-yl))methyl-hexanamide. 122
11. A pharmaceutical composition comprising a compound according to Claim 1 and a pharmaceutically acceptable carrier . 5
12. A pharmaceutical formulation comprising a compound according to Claim 1 and an oil.
13. A method of treating disease states associated with HIV infection comprising administering an effective amount of a 10 compound according to Claim 1.
14. A compound of the formula: R r (VIII) wherein Pr 2 is an amino protecting group, and R 7 ', R 8 ' and R 9 ’ are as defined in Claim 1 with any reactive groups protected. 20 15. A compound of formula: OH R 3 wherein: Rl and R3 are each independently Ci_galkyl, Ar-Ci_galkyl, Het-Cx_galkyl, C2-galkenyl, Ar-C2-galkenyl, Het-C2-6alkenyl, C3_gcycloalkyl-Ci_galkyl or C3_gcycloalkenyl-Ci_galkyl; R2 is H or OH; R 4 is Rg-ΝΗ-, or —“~ ΝΗ R 6 ; R5 is Rg-ΝΗ- or R^q-NH; 123 X^ R 8 —X Rg is N ^H 9 wherein : X is NR|i, θι ° r S, R^l is H or Ci_3alkyl; Rg and Rg are each independently H, or substituted alkyl; or Rg is ^ N Xj OH, halo, acyl, wherein : X is NH, 0, or S; Y is a fused C2-4 alkylene, aryl or heteroaryl moiety; R7 is Ci_galkyl, Ar-Ci_galkyl, Het-Ci_galkyl, C2-6alkenyl, Ar-C2-6alkenyl, Het-C2-6alkenyl, C3_gcycloalkyl-Ci_g alkyl or C3_gcycloalkenyl-Ci_galkyl; Rjq is a moiety A-(B) n -, where n = 0 or 1; and B is, independently, an α-amino acid chosen from the group: Ala, Asn, Cys, Trp, Gly, Gin, lie, Leu, Met, Phe, Pro, Ser, Thr, Tyr, Val, His, or trifluoroalanine, wherein the amino group of B is bonded to A and the carboxy group of B is bonded to the structure; A is covalently attached to the amino group of the adjacent residue B or to the amino group of the structure if n = 0 and is: 1) trityl,
15. ) hydrogen,
16. ) Ci-6alkyl, 4, Ri4-C0-wherein R14 is: a) hydrogen, b) Ci-6alkyl, unsubstituted or substituted with one or more hydroxyl groups, chlorine atoms, or fluorine atoms, c) phenyl or naphthyl unsubstituted or substituted with one or more substituents R15 wherein R15 is: i) Ci-4alkyl, 124 /£ 922316 I, 10 5) 6) 7) 30 8) 35 9) ii) halogen, where halogen is F, Cl, Br or iii) hydroxyl, iv) nitro, v) Ci-3alkoxy, or vi) -CO-N(Ri6)2 wherein Ri6 is, independently, H or Ci-4alkyl; or d) a 5-7 member heterocycle such as pyridyl, furyl, or benzisoxazolyl; phthaloyl wherein the aromatic ring is unsubstituted or substituted with one or more substituents R15; R 17(^18^19^) m-CO- wherein m = 1-3 and R17, Rl8, and Rig are independently: a) hydrogen, b) chlorine or fluorine, c) Ci-3alkyl unsubstituted or substituted with one or more chlorine or fluorine atoms or hydroxyl groups, d) hydroxyl, e) phenyl or naphthyl unsubstituted or substituted with one or more substituents R15, f) Ci-3alkoxy, g) a 5-7 member heterocycle, or h) Ri7, Rl8, and R19 may be independently joined to form a monocylic, bicyclic, or tricycle ring system each ring of which is C3-6 cycloalkyl; Rl7(Rl8 R 19 c )m - W- wherein m = 1-3 and W is OCO or SO2 and R17, Rl8/ and R19 are as defined above, except R17, Rl8, and R19 are not chlorine, fluorine or hydroxyl if they are adjacent to W; R20 _w-wliere in R20 is a 5-7 member heterocycle such as pyridyl, furyl, or benzisoxazolyl; R21-W- wherein R21 is phenyl or naphthyl unsubstituted or substituted with one or more subsituents R15; 125 10) Rl7~(Rl8Rl9C) m -P(0)(OR22)“ wherein R22 is ¢^-4 alkyl or phenyl; 11) R20“ p °>(OR22)-; ° r 12) R 2 i-P(O)(OR 2 2)-; 5 or pharmaceutically acceptable salt thereof. •E 922316 - 126 16. A process for preparing a compound as defined by general formula (I) in claim 1, substantially as described herein by way of example.
17. A pharmaceutical composition comrpising a compound according to 5 claim 1, substantially as described herein by way of example.
18. Product of a process according to claim 16.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US73156391A | 1991-07-17 | 1991-07-17 | |
| US87097592A | 1992-04-20 | 1992-04-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IE922316A1 true IE922316A1 (en) | 1993-01-27 |
Family
ID=27112266
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE231692A IE922316A1 (en) | 1991-07-17 | 1992-07-16 | Retroviral protease inhibitors |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0602069A4 (en) |
| JP (1) | JPH07500577A (en) |
| AP (1) | AP9200410A0 (en) |
| AU (1) | AU2412992A (en) |
| CA (1) | CA2113644A1 (en) |
| IE (1) | IE922316A1 (en) |
| IL (1) | IL102534A0 (en) |
| MX (1) | MX9204233A (en) |
| PT (1) | PT100704A (en) |
| WO (1) | WO1993002057A1 (en) |
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|---|---|---|---|---|
| US6825169B1 (en) | 1991-10-22 | 2004-11-30 | Trustees Of Tufts College | Inhibitors of dipeptidyl-aminopeptidase type IV |
| US6071895A (en) * | 1992-03-11 | 2000-06-06 | Narhex Limited | Polar-substituted hydrocarbons |
| RU2126794C1 (en) * | 1992-03-11 | 1999-02-27 | Нархекс Лимитед | Amino-derivatives of oxo- or hydroxy-substituted hydrazines, method of their synthesis and pharmaceutical compositions for inhibition of retrovirus protease |
| US5888992A (en) * | 1992-03-11 | 1999-03-30 | Narhex Limited | Polar substituted hydrocarbons |
| DE69333270T2 (en) | 1992-03-11 | 2004-08-05 | Narhex Ltd. | AMINE DERIVATIVES OF OXO AND HYDROXY SUBSTITUTED CARBON HYDROGEN |
| GB9207380D0 (en) * | 1992-04-03 | 1992-05-13 | Ici Plc | Compounds |
| US5559256A (en) * | 1992-07-20 | 1996-09-24 | E. R. Squibb & Sons, Inc. | Aminediol protease inhibitors |
| ES2068739B1 (en) * | 1993-01-21 | 1995-11-01 | Smithkline Beecham Corp | RETROVIRABLE PROTEASE INHIBITORS. |
| IL110898A0 (en) * | 1993-09-10 | 1994-11-28 | Narhex Australia Pty Ltd | Polar-substituted hydrocarbons |
| US5932550A (en) * | 1995-06-30 | 1999-08-03 | Japan Energy Corporation | Dipeptide compound or pharmaceutically acceptable salt thereof and medical use thereof |
| US6222043B1 (en) | 1995-06-30 | 2001-04-24 | Japan Energy Corporation | Methods of preparing novel dipeptide compounds or pharmaceutically acceptable salts thereof |
| US5965532A (en) * | 1996-06-28 | 1999-10-12 | Trustees Of Tufts College | Multivalent compounds for crosslinking receptors and uses thereof |
| EP0900566A4 (en) | 1996-12-27 | 2001-04-25 | Japan Energy Corp | Novel tripeptide compounds and anti-aids drugs |
| PL335484A1 (en) * | 1997-02-26 | 2000-04-25 | Pfizer | Derivatives of heteroarylhexamide, their production and application as selective inhibitors of mip-1a being assimilated by its ccr1 receptor |
| US6100234A (en) | 1997-05-07 | 2000-08-08 | Tufts University | Treatment of HIV |
| US6040145A (en) | 1997-05-07 | 2000-03-21 | Tufts University | Potentiation of the immune response |
| CA2304206A1 (en) | 1997-09-29 | 1999-04-08 | Point Therapeutics, Inc. | Stimulation of hematopoietic cells in vitro |
| AU770319C (en) | 1998-05-04 | 2004-11-25 | Point Therapeutics, Inc. | Hematopoietic stimulation |
| WO1999062914A1 (en) | 1998-06-05 | 1999-12-09 | Point Therapeutics, Inc. | Cyclic boroproline compounds |
| US6890904B1 (en) | 1999-05-25 | 2005-05-10 | Point Therapeutics, Inc. | Anti-tumor agents |
| EP1666452A2 (en) | 2000-06-30 | 2006-06-07 | Elan Pharmaceuticals, Inc. | Compounds to treat Alzheimer's disease |
| PE20020276A1 (en) | 2000-06-30 | 2002-04-06 | Elan Pharm Inc | SUBSTITUTE AMINE COMPOUNDS AS ß-SECRETASE INHIBITORS FOR THE TREATMENT OF ALZHEIMER |
| UY30805A1 (en) * | 2006-12-21 | 2008-07-31 | Bayer Schering Pharma Ag | NON-STEROID MODULATORS OF PROGESTERONE RECEPTORS |
| CA3109778A1 (en) | 2018-08-16 | 2020-02-20 | Innate Tumor Immunity, Inc. | Substitued 4-amino-1h-imidazo[4,5-c]quinoline compounds and improved methods for their preparation |
| PE20240775A1 (en) | 2021-07-09 | 2024-04-17 | Aligos Therapeutics Inc | ANTIVIRAL COMPOUNDS |
| CN114605320B (en) * | 2022-04-06 | 2023-12-29 | 南京艾康生物科技有限公司 | Synthesis method of 5-nitro-6-methylnicotinic acid ethyl ester |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4431653A (en) * | 1982-03-18 | 1984-02-14 | Hoffmann-La Roche Inc. | Penicillanic acid derivatives |
| IE913840A1 (en) * | 1990-11-20 | 1992-05-20 | Abbott Lab | Retroviral protease inhibiting compounds |
-
1992
- 1992-07-16 IE IE231692A patent/IE922316A1/en not_active Application Discontinuation
- 1992-07-17 AU AU24129/92A patent/AU2412992A/en not_active Abandoned
- 1992-07-17 WO PCT/US1992/006047 patent/WO1993002057A1/en not_active Application Discontinuation
- 1992-07-17 EP EP92917238A patent/EP0602069A4/en not_active Withdrawn
- 1992-07-17 MX MX9204233A patent/MX9204233A/en unknown
- 1992-07-17 CA CA002113644A patent/CA2113644A1/en not_active Abandoned
- 1992-07-17 PT PT100704A patent/PT100704A/en not_active Application Discontinuation
- 1992-07-17 AP APAP/P/1992/000410A patent/AP9200410A0/en unknown
- 1992-07-17 JP JP5503016A patent/JPH07500577A/en active Pending
- 1992-07-17 IL IL102534A patent/IL102534A0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JPH07500577A (en) | 1995-01-19 |
| AU2412992A (en) | 1993-02-23 |
| WO1993002057A1 (en) | 1993-02-04 |
| EP0602069A4 (en) | 1995-05-03 |
| IL102534A0 (en) | 1993-01-14 |
| CA2113644A1 (en) | 1993-02-04 |
| PT100704A (en) | 1993-10-29 |
| EP0602069A1 (en) | 1994-06-22 |
| AP9200410A0 (en) | 1992-07-31 |
| MX9204233A (en) | 1994-06-30 |
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