Note: Descriptions are shown in the official language in which they were submitted.
W(~ 93/02~57 PCr/USg2/060~7
2~3~4
b
, ' '` ~ .
-- 1 --
~ . ,, ~
The present in~rention relates to retroviral protease
10: inhibitor compoundsr pharmaceutical compositions thereof, and
~a method ~of t:reating retro~iral diseases therewith, including
: :a method of treating disease states assoc:iated with hu~an
immunode:~iciency virus ~HIV-l, HIV-2).
Retroviru~es, that is, viruses within:the family of
: 15~ Retroviridae, are a class o~ viruses which transport their
: genetic material as ribonucleic acid rather ~han
deoxy~ibonucleic:acid. Also known as RNA-tumor ~iru~es,
their presence has been associated with a wide range of
~:: ` diseases in humansiand animals. They are believed to be the
20 causative agents in pathological states associated with
t infection by ~ous sarcoma ~irus (~SV~, murine leukemia virus
(M1V), mouse mammary tumor virus (MMTV), feline leukemia
virus (FeLV~, bovine leukemia virus ~BLV), Mason~P~izer
monkey virus (MPMV), simian sarcoma virus ~SSV), simian
s acquired immunodeficiency syndrome (SAIDS), human T-
lymphotropic virus ~HT1V~ II) and human immunodeficiency
;~ : virus (HIV-l, HIV-2), which is the etiologic agent of AIDS
,
W~93/02057 PCTJUS~/~7
2 - ?
tacquired immunodeficiency syndrome)and AIDS related
complexes, and many others. Although the pathogens ha~e, 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 t~ 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. T~e
proteolytic acti~ity proYided by the ~iral 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 re~roviruses 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
alO r Proc~ Natl. Acad. Sci . USA, 84, 8903-6tl987).
Inhibition of retroviral protease~ therefore, presents a
~ethod of therapy for retro~iral disease.
The use of isosteric replacements has been diselosed as
~ a strategy for the development o~ prvtease inhibitors for
: HI~-l. 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 re~roviral
proteases. As discussed therein, these dipeptide analogs
: bind selectively and competitively to retroviral proteases;
Aowever, the proteas is unable to cleave the carbon-carbon
bond prèsented 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 '
; 35 substrate positions of compounds containing a dipeptide
isostere has been disclosed by deSolms e~ al., J. Med. ~hem.,
34, 2852 tl991). However, these compounds can be less than
desirable for obtaining optimal drug delivery in mammalian
W~93/02~7 PC~/US92/~ ~7
21~3~
-- 3 --
organisms, particularly in humans. Some of these compounds
can also have a less than desirable serum half-life, and
therefore duration of ~ction, because they contain amide
bonds in relatively high proportion, and thus are prone to
metabolic degradatîon, hepatic clearance, or other -
elimination mechanisms.
There exi~ts a need for novel compounds which inhibit
retrovixal protease activity, and a need f~r compounds which
po~sess desirable pharmacokinetic properties for good drug
delivery and metabolic stability for good serum half-life and
duration of actio~. Such pharmaceutical uses provide
therapies for retro~iral diseases in mammals, especially in
humans, which h~ve been heretofore di~ficult to treat.
5~: Y~L~
The present invention provides e~o~pounds, hereinafter
represe~ted as formula (I), which ~ind to retroviral
proteases. The6e con~pounds are inhibitors c~f retroviral
: 20 proteases and~are use~ul for treating diseases related to
~ infec~ion by retroviruses.
;~ ~ T~e present i~vention also provides a pharmaceutical
~` composition comprising a compound of formula lI) and a
pharmaceutically acceptable carrier.
The prese~t~invention additionally provides a method for
treating retroviral disease, comprising administerin~ to a
mammal in need thereof an effe~tive amount of a compound of
formula (I).
~E~aILEnLDEs~RlpTI~N OF THE INVE~IQ~
.
. .
The compounds of the present invention are illustrated
~ by formula (I): -
; : 35
PClrJUS92/0~7
4 ~ `` ',
"., ,, , R1 RZ
Rs~R4
C)H R3
(I)
wherein:
Rl and R3 are each independently Q, Q-Cl_6alkyl, ;
5 Q-C2_6alkenyl, Q-C2_6alkynyl or C:1_6alkyl substituted by one
to five :Eluorine atoms, each optionally substituted by R23;
Q is ~1, C3_~cycloalkyl,. C5_6cycloalkenyl, Ar or Het
p~2 is ~ or OH;
R4 is R6-NRll- or CoNRl1CHR6R7;
R5 is R6-NRlI- or R10_
X R8 ,~ ,
R6 is ~ R9 ;
X is NR11, O or S;
: R7 is Q, Q ~1_6alkyl or Q-C2_6alkenyl;
R8 and ~9~ are each independently ~, OH, halo, NO2, COR12,
:~ 15 CF3, Ar, Cl_6alkyl-R15, or R17~18R19C)~, or together form a
~used C2 4alkylene, aryl or heteroaryl moiety;
~10 is ~ A--(B) n--;
Rl1 is H or C1 4alkyl;
: Rl2 is R7, oR7r ~ NR7R1l or an amino acid or amino alcohol;
B is an amino acid;
A :is H, Ar, Het~ R17 (R18R19C?m, Ar-W, Het -W or
R17 (R}8R19C) m-W, or phthaloyl each optionally substit;uted by
one to three groups chosen from Rl5 or Cl_6alkyl-Rl5;
W iS C--O, OC(=O~, NRllC(=O)j SC(=O), ~RllC~=S~, S02,
: : 25 ~ NRllSO~ or P(=O)(OR22);
~:~ R15 is H, nitro, C~_6alkoxy, Cl_6alkylthiv, O~C=O~R16,
C-OR22, C02R22, CON(Rl~)2, N(R22)2, NHC(=N)~H-A, I, Br, Cl, F,
OR10, or OH, provided that when R15 is a substituent of the
carbon adjacent to W, R15 is not halogen ar OH when W is
OC ~=O) or ~HCO;
16 is H or C1_6alkyl;
R17, R18 and R19 are independently: i1 H, R15 ~r
Cl_4alkyl, C2_6alkenyl, phenyl, naphthyl, C3_6cycloalkyl or
Het, each optionally substituted by one to three R15 or
W0~3/02057 PCT/US~2~06~7
2113~
-- 5 --
X15-Cl_6alkyl 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 toyether are
=O;
s R22 is H, C1_6alkyl, phenyl or phenyl-Cl galkyl;
R23 iS --X'--(CH2) ~NR24R25t X" [ ( ~CH2) r~ ~]R2~,
CH2X" [ ( (CH2) r) ~lR26~ or benzofuryl, indolyl, azacycloalkyl,
azabicyclo C7_11cycloalkyl or benzopiperidinyl, optionally
subs~i~uted with Cl_4alkyl; -~
q is 2-5;
s is 1-6 and r is 1-3 within each repeating unit s;
X' is CH2, O, S or NH;
X" is ~H2, NR', O, S, SO or SO2; .
R24 and R25 are i) Cl_~alkyl, optio~ally subs~ituted by
OH, C1_3alkoxy, or N~RI)2, ii) the same ox different and
joined togethex to form a 5-7 member he~erocycle containing
: up to two addi~ional heteroatoms selected from NR, O, S, SO,
SO2,~said heterocycle optionally substituted with Cl_4alkyl,
iii) aromatic~heterocyc~.e, optionally substituted with
Cl_4alkyl or ~(~')2;
R' is H or Cl_4alkyl;
R26 is~H, Cl_4alkyl, C(=3)R27, C(=O)Ut(CH2)~O]nR',
P(=o)(VM)2,~Co2R27~ C(=o)NR27R28, where M is a mono or
; divalent metal ion, and U is NR' or O;
s R27 is Cl.6alkyl or Arp optionally substituted with one
or more:hydroxy~, carboxy, halo, Cl_3alkoxy, CONR'2, NR'2,
C2~'~ 502NR~2,~CH2NR2, NR'COR', NR'SO2R', X~[(CH2~rC)]SR~ or
CH2X"[~CH2)r]~R i:
R28 is Hl Cl_6alkyl or together with R27 forms a 5-7
:~ 30 membered heterocycle orla 6 membered heterocycle containiny a
: heteroàtom selected from N, O and S;
m is 1-4; and
n is 0 or 1;
: or a pharmaceutically acceptable salt thereof.
3~ Al:so included in this invention are pharmaceutically
acceptable addition salts, complexes or prodrugs of the
: compounds of this invention Prodrugs are considered to be
WQ93/02~7 PCr/US92/~7
,. , 1
~ 6 - ;
a covalently bonded carriers which release the active
parent drug according to formula (I) in vivo.
Formula (I) is intended to encompass all unique
nonracemic skereoisomers which may occur due to the presence
s 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 occ'urrence. 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 configurati~n with respect to any two
substituents.
~hen X is N~, it will be appreciated that the
hetexocyclic ring is an imidazole which can undergo
tautomerization. All tautomeric forms of the imidazole are
within the scope of this invention.
Suitably Rl and R3 are Cl_6alkyl, Ar-Cl_6alkyl,
Ar-C2_6alkenyl, Ar-C2_6alkynyl, Cl_6alkyl optionally
substituted by one to fi~e fluorine atoms or benzyl
substituted in the 4-position by R23. Preferably Rl is
benzyl and R3 is benzyl, 4-hydroxybenzyl or phenylprvpenyl.
Suitably R2 is H.
5uitably X is S or N-R~l. Preferably X is NH.
Preferahly R4 is CoNRllCHR6R7.
;~ Suitably R5 is R10-NRll. Preferably R5 is t-
` butyloxycarbonylamino or isopropyloxycarbonylamino.
Suitably R7 is H, C1_6alkyl, C3~cycloalkyl, phenyl or
benzyl.' Preferably R7 is Cl_6alkyl. Isopropyl is most
preferred.
Suitably R8 is H, Cl_6alkyl, COR12, N02 or Br. Preferably
R8 is H.
Suitably R9 is H, NO2, Br, COR12, CF3, Ar, Cl_6alkyl or
C1_6alkyl-R15, wherein R12 is H, Cl_6alkyl, Ar, OCl_6alkyl,
NH2, and R15 is OH. Preferably R9 is H or COR1~.
WOg3/02~7 P~T/US92/06047
2~3-~
- _ 7
Suitably B is Ala or Val. Preferably m is 0 and B is
absent.
Suitably A is Het~ R17(R18Rl~C)m-W, Ar-W or Het-W.
Suitabiy R17, R18 and R19 are H~ or Cl_~alkyl, Het or Ar
optionally substituted by one or two R15 or C1_6alkyl-R15, or
(R18R19C~ are joind together to form a phenyl, C3_6cycloalkyl
or Het rihg.
Suitably W is C=O, OC(-O), NHC(=O), NHC~=S), or SC~C=O).
Suitably R17(R18R19C)m- is Ar-CH2, Ar, Het, Het-CH2,
Cl_6alkyl or C3_6cycloalkyl optionally substituted by one to
three groups ~elected from R15. Suitably R15 is OH~ When R17
or (R18R1gC) are ~et or Ar, Het is suitably quinolinyl,
pyridyl, imidazolyl, thiazolyl, tetrahydrothiopyranyl or
tetrahydropyranyl and Ar is phenyl.
- Suitably R23 is hydroxy-Cl_4alkoxy, C1_4alkoxy-
C1_4alk~xyj or -o~c~)2NR24R25~ wherein R24 and R25 are are a
5- or 6-membered heterocycle, such a morpholino.
In one preferred embodiment W is C=O.
In another preferred embodiment W is OC(=O).
~0 ~ In a third preferred embodiment R10 is Cl_6alkylOC~=O) or
Cs_6cycloalkylO~(=O) substituted by one or two O~ o~ CH20H
: ~ :
groups.
~:: Representati~e compounds of thîs invention are:
: ~2R,4S,5S,l'S)-2-phenylmethyl-4-hydroxy-5-(t-butoxycarbonyl)-
amino-6-phenyl-N t~ opropyl~ 4-aminocarbonyl-thiazo-2-
: : yl)]methyl-hexanamide;
(2R,4S,5S,l'S)-2-phenylmethyl-4-hydroxy-5-~t-~utoxycarbonyl)-
amino-6 phenyl-N-[1'-isopropyl-l'-(thiazo-2-yl~methyl-
~;~ hexanamide;
~2R,4S,5S,l'S)-2-phenylmethyl-4-hydroxy-5-(t-butoxycarbonyl~-
amino-6 phenyl-N-(l'-imidazo-2-yl)methyl-hexanamide
hydrochloride;
(2R,4S,5S,l'S)-~-phenylmethyl-4-hydroxy-5-~t-butoxycarbonyl)-
amino 6-phenyl-N~ methyl~ timida~o-2-yl)] methyl
hexanamide hydrochloride;
(2R,4S,5Srl'S)-2-phenylmethyl-4-hydroxy-5-(t-butoxycarbonyl~-
amino-6-phenyl-M-~l'-benzyl-l'-(imidazo-2-yl)]methyl-
hexanamide hydrochloridei
W093/02~7 P~T/US92/Q6~47
`'
~3~ 8 - ,
(2~ ,5S,l'S)-5-(carbobenzyloxy)amino-9-hydroxy-N-(l'-
isopropyl-l'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-
hexanamide;
~2R,4S,5S,l'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-tl'-
s isopropyl-1'-(4~5-dimethyl)imidazol-2-yl]methyl-6-phenyl-2-
phenylmethyl-hexanamide;
~2R,4S,5S,l'S)-5-(t-butoxycarbonyl)amino 4-hydroxy-N-[l'-
isopropyl-l'-(N'-methyl)imidazol-2-yl]methyl-6-phenyl-2-
phenylmethyl-hexanamide;
10 (2R,4S,5S,l'S)-5-~t-butoxycarbonyl)amino-4-hydroxy-N-(l'-
isopropy~-1'-imidazol-2-yl)methyl-6-phenyl-2-(3-
phenylpropargyl)hexanamide;
(2R,4S,5S,l:'S)-5-(benzyloxyethoxycarbo~yl) amino-4-hydroxy-N-
~l'-isopropyl-1'-imidazol-2-yl)methyl-6~phenyl~
pheny~methyl-hexanamide;
(2R,4S,5S,l'S)-5-~methoxycarbonyl)amino 4-hydroxy-N-
~
~: isopropyl~ imidazol-2-yl)methyl-6-phenyl 2-phenylmeth~l
~: hexanamide; ::
: ~ 2R, 4S, 5S, 1 ' S ) -S-~t ethoxycarbonyI)amino-4-hydroxy-N-(l'-
: 20 isopropyl-1'-imidazol-2-yl~methyl-6-phenyl-2-phenylmethyl-
hexanamide;
(2R,4S,5S,l'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1'-
isopropyl-l'-imidazol-2-yl)methyl-6-phenyl-2-(3-phenyl-2-
propenyl)hexanamide;.
(~2R,4S~,SS~ S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-~l'-
isopropyl~ (4-nitroimidazol-2-yl~]methyl-6-phenyl-2-
D . phenylmethyl-hexanamide;
2R,4S,5S,l'S)-5-tt-butoxycarbonyl)amino-4-hydroxy-N-(1'
:ethyl-l'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-
hexanamide;
(2R,4S,5S,l'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N~
propyl~l'-imidazol-2-yl)methyl-6-pheny~-2-phenylmethyl-
hexanamide;
(2R,4S,5S,l'S~-5-(t-butoxycarbonyl)amino-4-hydroxy-N-~l'-
~isopropyl-1'-(4-bromoimidazol-2-yl)]methyl-6-phenyl-2-
phenylmethyl-he~anamide;
;
WOg3/02~7 PCT~US92~6047
~ 21~3~
(2R,4S,5S,l'S)-5-(t~butoxycarbonyl~amino-4-hydroxy-N-[1~-
isopropyl~ (4,5-dibromoimidazol-2-yl)]methyl-6-phenyl-2-
phenylmethyl-hexanamide;
(2R,4S,5S,llS)-5 (t-butoxycarbonyl)amino-4-hydroxy-N-[1'-
s isopropyl-1'-~4-methylimidazol-2-yl)]methyl-6-phenyl-2-
phenylmethyl-hexanamide;
(2R~ 4S~ SSr 1~ S) -5-(t-butoxycarbonyl)amino-4-hydroxy-N~
isopropyl-1'-(4-trifluoromethylimidazol-2 yl)~methyl-6-
phenyl-2-phenylmethyl-hexanamide;
(2R,4S,SS,l'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-methyl-
N-tl'-isopropyl~ imidazol-2-yl)methyl~6-phenyl-2
phenylmethyl-hexanamide;
(2R,4S,5S,l'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[l'-
isopropyl 1'-~4-carbomethoxyimidazol-2-yl)~methyl-6-phenyl-2-
phenylmethyl-hexanamide;
52R,4S,5S~l~S)-5-~t~-butoxycarbonyl)amino-4-hydroxy-N~[l~-
isopropyl 1'-(4-methylcar~onylimidazol-2-yl)3methyl-6-phenyl-
2-phen~lmethyl-hexanamide;
(2R,4S,5S,l'S)-5-~t-butoxycarbonyl)amino-4-hydroxy-N-
~
~o isopropyl-1'-~4-phe~ylcarbonyl-imidazol-2-yl~jmethyl-6-
; phenyl-2-phenylmethyl-hexanamide;
(2R,45,5S~ S)-5-~t-butoxycarbony~amino 4-hydroxy-N-[1'-
isopropyl-l~ t4-formylimidazol-2-yl)]methyl-6-phenyl-2-
phenylmethyl-hexanamid~;
(2Re 4S~ 5S~ 1~S) -5-(t-butoxycarbonyl)amino~4-hydroxy-N~[1'-
isopropyl-1'-~4-~hydroxymethyl)-imidazol-2-yl)]methyl-6
phenyl-2-phenylmethyl-hexznamide;
2R, 4S, 5S, 1 ' S) -5- ( (tetrahydrothiopyran-4-yl)oxycarbonyl)-
amino-4-hydroxy-N-tI'-isopropyl~ imidazol-2-yl)methyl-6-
phenyl-2-phenylmethyl~hexanamide;
(2R,45,5S,l'S)-5-~tetrahydro-4H-pyran-4-yi)oxycarbonyl~-
;~ amino 4-hydroxy-N (1'-isopropyl-1'-imidazol-2-yl)methyl-6-
~: ~ phenyl-2-phenylmethyl-hexanamide;
: ~ (2R,4S,5S,l'S~-5-(4-picolinyloxy)amino-4-hydroxy-N-(1'-
: 35 isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-
hexanamide;
:~
W093/0~057 PCT/US92/06W7
,. :'' '':,': .
(~,4S,5S,l'S)-5-~t-butoxycarbonyl)amino-4-hydroxy-N-(1'-
isopropyl-1l-imidazol-2-yl)methyl-6-phenyl-2-(4,4,4-
trifluorobut-l-yl)hexanamide ;
(2R,4S,5S,l'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[l'-
s isopropyl-1'-(4-((lRS)-l-hydr.oxyethyl)-imidazol-2-yl)~methyl-
6-phenyl-2-phenylmethyl-hexanamide; -
(2R,4S,5S,l'S)-5 (t-butoxycarbonyl)amino-4-hydroxy-N-[l'-(1-
methyl~propyl-l'-(imidazol-2-yl)~methyl-6-phenyl-2-
phenylmethyl-hexanamide;
lo (2R,4S,5S,l'S~-5-(propylaminocarbonyl)amino-4-hydroxy-N-[1'-
isopropyl-1'-(imidazol-2-yl)]methyl-6-phenyl-2-phenylmethyl-
hexanamide;
(2R,4S,5S,l'S)-5-(4-hydroxybutanoyl)amino-g-hydroxy-N-(l'-
isopropyl-l'-imidazol-2-yl)methyl-6-phenyl-2-
phenylmethylhexanamide;~2R,4S,5S,l'S)~2-phenylmethyl-4-hydroxy-5-(benzyloxy-
c~rbonyl)~alylamino-6-phenyl-N~ isobutyl-l' imidazo-2-
yl~methyl-hexanamide,
~2R,4S,~5S,1'$~-2-phenylmethyl-4-hydroxy-5-(N-acetyl~alyl)-
amino-6-phenyl-N~ isobutyl-l'-imidazo-2-yI~methyl-
hexanamide;
~ (2R,45~5S,l:'S)-5-~(imidazol-2~yl)methyloxycarbonyl~amino-4-
:: hydroxy-N~ isopropyl-1'-imidazol-2-yl)methyl-6-phenyl~2-
phenylmethyl-hexanamide;
:~ ~ : 25 (2R94S,5S,l'S,l"RS)-5~ 5imidazol-2-yl)-2l'-methyl)-
: propyloxycarbonyl)amino-4-hydroxy-N-~l'-isopropyl~
, imidazol-2~yI)methyI-6-phenyl-2-phenylmethyl hexanamide;
~:~ (2R,4S,5S,l'S)-5-(t-butoxycarbonyl~amino-4-hydroxy-N 11'-
isopropyl~ (4-(imidazol-2-yl)imidazol-2-yl)3methyl-6-
phenyl-2-phenylmethyl-hexanamide;
: (2R~4s~5s~l~s)-5~ oxo-thian-4-yl)oxycarbonyl)amino-4-
hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-
phenylmethylhexanamide;
~2R,4S,5S,l'S)-5-((tetrahydrosulfonylpyran-4-
35 :yl)oxycarbonyl)a~ino-9-hydroxy-N-(1'-isopropyl~ imidazol-2-
yl)methyl-6-phenyl-2-phenylmethylhexan~mide;
~2R,4S,5S,l'S)-5-~(1,1-dimethyl-2-(benzyloxycarbonyl-
glycyloxy)ethoxycarbony~)amino-4-hydroxy-N~ isopropyl-l'-
W093/02057 - , PCT/US92/06~7
~ 2~ ~o~
imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide
hydrochloride salt;
(2R,4S,5S,l'S)-5-((1,1-dimethyl-2-glycyloxy)et~oxycarbonyl)-
amino-4-hydroxy-N-(l' isopropyl-l'-imidazol-~-yl)methyl-6-
phenyl~2-phenylmethyl-hexanamidedihydrochloridesalt;
(2R,4S,5S,l'S)-5-((1-acetyl)amino-4-hydroxy-Ni(1'-isopropyl-
1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethylhexanamide;
~2R,4S,5S,l'S)~5~t-butoxycarbonyl)amino-4-hydroxy-N~
isopropyl-llimidazol-2-yl)methyl-6-phenyl-2-(4-
0 benzylox~henylmethyl)hexanamide;
(2R,4S,5S,l'S)-5-~t-butoxycarbonyl)amino-9-hydroxy-N~
isopropyl-l'~imidazol-2-yl)methyl-6-phenyl-2-(4-
~ydroxyphe~ylma~hyl)hexanamide;
: (2R!4S,5S)-5-(t-butoxycarbonyl)amino-4-hydroxy-2-
phenylmethyl-6-phenyl-N-ll'-cyclopropyl-1' imidazol-2-
yl]methyl-hexanamide;
~2R,4S,5S,I'S~-5-:((isopropylthiol)carbonyl~-amino-4-hydroxy-
2-phenylmethyl 6-phe~yl-N-ll-isopropyl-l'-imidazol-2-
yl]methyl-hexanamide~
20 ~2R,45,5S,l'S3-5-~t3~ imidazol-2-yl~-3-hydroxy-4-
methylpentylamido]-4-hydroxy-N-(l'-isopropyl-l'-imidazol-2-
yl)methyl-6-phenyl-2~phenylmethyl-hexanamide;
(;2R,4S~5S,l'S)-5-[(4-methoxyphenoxy)carbonyl3amino-4-hydroxy-
N-(l'-isopropyl-1:'-imidazol-2-yl)methyl-6-phenyl-2-
phenylmethyl-hexanamide;
2R,4S,5S,l? S) -5-(t-butylaminocarbonyl)amino-4-hydroxy-N-(l'-
. isopropyl~ imidazol-2-yl)methyl-6-phenylmethyl-hexanamide;
2R,qS,5S,l'S)-5-(methylaminocarbonyl)-;
amino-4-hydroxy-N-(1'-isopropyl~ imidazol-2-yl)methyl-6-
phenylmethyl-hexanamide;
(2R,4Sp5S,1'S)-5-phe~ylaminocarbonyl)amino-4-hydroxy-N-(l'-
isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexamide;
(2R,4S,5S,l'S)-5-N-(propylaminocarbonyl)amino-4-hydroxy-N-
(l'-isopropyl-~'-imidazol-2-yl)methyl-6-phenylmethyl-
: 35 hexamide;
2R,4S,5S,l'S)-5-(n-propylaminothiono)amino-4-hydroxy-N-
~l'isopropyl 1'-imidazol-2-yl)methyl-6-phenylmethyl-hexamide;
~'
W~93~02~57 ~ 12 - PCT/US92/~M~7
2R,4S,5S,l'S~-5-(isopropylaminocarbonyl)-amino-4-hydroxy-N-
~l'-isopropyl-l'-imidazol-2-yl)methyl-6-phenylmethyl-
hexamide;
(2R,4S,5S,l'S)-5-~aminocarbonyl)amino-4-hydroxy-N-(1'-
s isopropyl-l'-imidazol-2-yl)me~hyl-6-phenylmethyl-hexamide;
(2R,4S,5S,l'S)-5-(6-quinolinylmethyloxy-carbonyl)amino-4-
hydroxy-N-~ isopropyl-1'-imidazol-2-yl)methyl-6-
phenylmethy~-hexanamide;
(2R,4S,5S,l'S)-5-(benzoyl~amino-4-hydroxy-N-(1'-isopropyl-1'-
lo imidazol-2-yl)methyl-6-phenylmethyl-hexanamide;
~2R,4S,5S,l'S3-5-(2-furylcarbonyl)amino-4-hydroxy-N-tl'-
isopropyl-l'-imidazol-2-yl)methyl-6-phenylmethyl-hexanamide;
(2R,4S,5S,l'S)-5-(4-methoxybenzoyl)amino-4-hydroxy-N~
isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexanamide;
15 (2R,4S,5S,l'S)-5-benzylcarbonyl)amino-4-hydroxy-N-~1'-
; isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexamide;
. (2R,4S~5S,l;'~S)-5-~(~4-hydroxybenzoyl)amino 4-hydroxy-N~
isopropyl-1'-imidazol-2-yl)methyl-6-phenyl~ethyl-hexanamide;
2R, 4S ~ 5S, l~'S)-5-;(cinnamoyl)amino-4-hydroxy-N~(l~-isopropyl-
: 20 1'-imidazol-2-yl)methyl-6-phenylmethyl-hexanamide;
2R,4S,~SS,l'S)-5-(2-hydroxybenzoyl)amino-4-hydroxy-N-~1'-
: isopropyl-l~'-imidazol-2-yl)methyl-6-phenylmethyl-hexanamide;
(2R,~4S,SS,l'S)~-S-~imidazoyl-4-yl-acetyl)amino-4-hydroxy-N-
isopropyl-1'-imidazol-2-yl~methyl-6-phenylmethyl-
2s hexanamide;~
2R,4S,5S,l'~S)-~5-(t-butoxycarbonyl~amino-4-hydroxy-~-[1'
isopropyl-l'-~4-carbomethoxyethylimidazol-2-yl)]methyl-6-
phenyl:-2-phenyImethyl-hexanamide;
2R,4S,5S,l'S~-5-~(t-butoxycarbonyl~amino-4-hydroxy-N-
~
isopropyl~ 4-carboxamidoimidazol-2-yl)~methyl-6-phenyl-?-
: phenylmethyl-~exanamide;
(2R,4S,5S,l'S)-2-phenylmethyl-4-hydroxy-5-(5~ oxopropyl)-2-
thiazolyl)amino)-6-phenyl-N-(l'-isopropyl-1'-~imidazo-2-
: yl))methyl-hexanamide;
3s (2R,4S,SS,l'S)-2-phenylmethyl-4-hydroxy-5-(5-(1-oxopropyl)-2-
: : thiazolyl)amino)-6-phenyl-N-(1'-isopropyl~ imidazo-2-
yl~)methyl-hexanamide;
W093/02057 P~r/U~g2/06047
-13_21~3~
(2R,4S,5S,l'S)-2-phenylmethyl-4-hydroxy-5-(5-propyl-2-
thiazolyl)~mino)-6-phenyl-N-(l'-isopropyl~ (imidazo-2-
yl))methyl-hexanamide; and
~2R,4S,55,1'S)-5-tnicotinyl)amino-4-hydroxy-N-~l'-isopropyl-
s l'-imidazol-2-yl)methyl-6-phenylmethyl-hexamide.
Another group of preferred representative compounds are:
t2R,4S,SS,1'S)-5-~di(hydroxymethyl)-methoxycarbonyl]amino-4-
hydroxy~-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl~-
phenylmethyl-hexanamide;
(2R,4S,5S,l~S)-5-tl,l-dimethyl-2-acetoxyethoxycarbonyl)amino-
4-hydroxy-M-(l'-isopropyl~ imidazol-2-yl)methyl-6-phenyl-2-
phenylmethyl-hexanamidev
(2R,4S,5S,l'S~-5-((1,1-dimethyl-2-hydroxy)ethoxy-
carbonyl)amino-4-hydroxy-N-(1 9 - isopropyl-1'-(4-
lS isopropylcarbonyl-imidaz~1-2-yl)~methyl-6-phenyl-2-
pheny~me~hyl-hexanamide dihydrochloride salt;
~2R,4S~5S,l'S)-5-~(lS)-1-m~thyl-2-hydroxyethoxycarbonyl)-
amino-4-hydroxy-N-~ isopropyl-1'-imidazol-2-yl)methyl-6-
phenyl-2-phe~ylme~hylhexa~amide;
20 (2R,4S,SS,1'5)-5-((lR)-1-methyl-2-hydroxyethoxycarbonyl)-
amino-4-hydroxy-N~ is~propyl~ imidazol-2-yl~methyl-6-
;; ~ phenyl-2-phenylmethylhexanamide;
(2R,4S~5S,l'S)S-(l hydroxymethyl-cyclopentyloxycarbonyl)-
amino-4-hydroxy-N~ isopropyl-1'-imidazol-2-yl)methyl-6-
phe~yl-2-phenylmethyl-hexamide;
~: ~ (2R,4S,5S,l'S)-5~ dimethyl-2-hydroxyethoxycarbonyl)amino-
4-hydroxy-N-~ isopropyl-l'-imidazol-2-yl)methyl-6-phenyl-2-
~: phenylmethyl-hexan~mide hydrochloride;
: (2R,4S,5S,l'S)-5-(hydroxyethoxycarbonyl)amino-4-hydroxy-N-
(1'-isopropyl~ imidazol-2-yl)methyl-6-phenyl-2-
phenylmethylhexanamide; and
: (2R,45,5S,l'S~-5-(2-hydroxy-1-methylethoxycarbonyl)amlno-4-
hydroxy-N-(1'-isopropyl-1~-imidazol-2-yl~methyl-6-phenyl-2-
phenylmethylhexanamide.
: 35 More preferred representative compounds are:
(2R,4S,5S,l'S~-2-phenylmethyl-4-hydroxy 5-~t-butoxycarbonyl)-
-~ amino-6-phenyl-N-(1'-isopropyl-1'-(imidazo-2-yl))methyl-
hexanamide hydrochloride;
W~93/02~ PCT/VS92/06~7
~ ..
- 14 -
(2R,9S,5S,l'S)-5-(isopropoxycarbonyl)amino-4-hydroxy-N-(l'-
isopropyl-1'-imi~azol-2-yl)methyl-6-phenyl-2-phenylmethyl-
hexanamide;
(2R,9S,5S,l'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'-
isopropyl-1'-(4-isopropylcarbonyl-imidazol-2-yl)]methyl-6-
phenyl-2-phenylmethyl-hexanamide;
(2R,4S,5S,l'S)-5-(1,1-dimethyl-2-hydroxyethoxycarbonyl~amino-
4-hydroxy-N~ isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-
phenylmethyl-hexanamide hydrochloride;
~2R,4S,5S,l'S)-5-(hydroxyethoxycarbonyl)amino-4-hydroxy-N-
(l'-isopropyl-l'~imidazol-2-yl)methyl-6-phenyl-2-
phenylmethylhexanamide; and :~ -
~2R,4S,5S,l'S)-5-~2-hydroxy-1-methylethoxycarbo~yl)amino-4-
hydroxy-N~ isopropyl-l'-imidazol-2-yl)methyl-6-phenyl-2-
phenylmethylhexanamide.
The term "alkyl" refers to a straight or branched chain
~: alkyl radical of the i~dicated number of carbon atoms.
"C1_4alkyl~ as applied herein is meant to include methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, se~-butylv tert-
butyl; "Cl_6alkyl~ include~ additionally pentyl, i~opentyl,
2-methylbutyl, l-methylbutyl, 2-ethylpropyl, neopentyl, n-
hexyl 2~2-dimethylbutyl, 2-methylpentyl, and the like.
: "Al~oxy" refers to an alkyl group of the indicated number of
carbon atoms attached through a bridging oxygen atom.
: 25 "Alkylthio" refers to an alkyl group of the indicated number
~ of carbon atoms attached through a brid~ing sulfur atom.
: ~ ~ The term "substituted alkyl" as used herein is meant to
: include C1_6alkyl, Ar-Cl_~alkyl, Het-Cl_6alkyl, C2_6alkenyl~
:~: Ar-C2_6~1kenyl, Het-C2_6 alkenyl, C3_6cycloalkyl~Cl_6alkyl,
C3_6cycloalkenyl-C1 6alkyl or Cl_6alkyl substituted with acyl
: or hydroxyl.
. . .
"Alkenyl" refers to a straight or branched hydrocarbon
chain of the indicated number of carbon atoms, whi~h contains
one or more carbon-carbon double bonds at any stable point
~: ~ 3s along the rhain, 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
W093/~2057 PCT/US~2/0~47
- 15 2 1 l~3~
a carbon-carbon triple bond at any s~able 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 Rl2-CO, wherein R12 is H,
s C1_6aikyl, Ar-C1_6alkyl, Het-Cl_6alkyl, C2_6alkenyl,
Ar-C2~6alkenyl, Het-C2_6alkenyl, C3_6cycloalkyl- Cl_6alkyl,
Cs_6cycloalkenyl-Cl_6alkyl, OR, NHR13, wherein R13 is H,
Cl_6alkyl, Ar-Cl_6alkyl, Het-Cl_6alkyl, C2_6alkenyl,
Ar C2_6alkenyl; Het-C2_6alkenyl, C3_6cycloakyl-C1-~alkyl, or
C3_6cyclcalkyl, or Cs_6cycloalkenyl-C1_6alkyl; or an a-amino
acid or an a-amino alcohol bonded at the ni~rogen.
"Cycl~alkyl" 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~ca~rbQ~ carbon double bond. ~Cs_7cycloalkenyl"
includes cyclopentenyl, ~yclohexenyl and cycloheptenyl.
~Aryl~ abbreviated as Ar, refers to phenyl or naphthyl,
op~ionally subs~ituted with one to ~hree halo, O~, ORl0,
6alkyl~cl-6alkoxy~ cl-6alkylthio~ ~1_6al~1ami~o, CF3,
ami:no, NO2,:carboxy, Cl_4alkylcarbonyl, aminocarbonyl,
Cl_6alkyl-Het, Cl_6alkoxy--~et, Cl_6alkyl-phenyl, Cl_6alkoxy-
phenylr:Cl_6alkyl-,~Cl_6alkoxy-~ HetCl_6alkyl-r HetCl_6al}coxy-,
phenylCl_6alkgl-, phenylCl 6alkoxy- or phenyloxy.
: As used h~rein except where noted, the term
"het:erocycle", abbreviated as ~He~", represents a stable 5-
: to 7membered monocyclic or a stabl~ 7- to 10-membered
~. :
bicy~lic heterocyclic ring, which is either saturated or
:~ 30 unsaturated, and which consists of carbon atoms and from one
: to thrèe h~teroatoms 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
:~
WOg3/02057 ~ P~T~US92/~7
~3~ - 16 -
one to three halo, OH, alkyl, alkoxy, alkyi-Het, alkoxy Het,
alkyl-phenyl, alkoxy-phenyl.. Examples of such heterocyclic
elements inciude piperidinyl, piperazinyl, 2-oxopiper~zinyl,
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,
benzoxa~olyl, thiamorpholinyl sulfoxide, thiamorpholinyl
sulfone, and oxadiazolyl. Heteroaryl refers ~o a heterocycle
which has aromatic character (eg., chalracterized by
delocalized electron resonance and the ability to sustain a
ring current). Pyridine, imidazole, thiazole, furan and
~xazole are examples of heteroaryl rings.
"Amino acid" means the D- or L- isomer of alanine,
arginine, asparagine, aspartic acid, cysteine, glutami~e,
glutamic acid, glycine, histidine, isoleucine, leucine,
lysin~,:methionine/ phenylalanine, proline, serine,
: threonine, tryptophan, tyrosine, valine or trifluoroalanine.
~: In general, the amino acid abbre~iations follow the IUPAC-IUB
Joint Commission on:Biochemical Nomenclature as described in
Eur. J. Bioc~em., 158, 9 (1984). Usually li~ophilic amino
acids are preferred for the moiety B, for instance, Val, Ala,
~` ~ Leu and Ile. It will be understood that a linkage B-O refers
b to an oxygen atom bonded to the carboxyl group of an amino
acid, and that a B-N linkage indicates a nitrogen atom bonded
to the carboxyl group of an amino acid, as in an amide bond.
~A~ino alcohol" refers to an amino acid in which the carboxyl
group has been reduced to a methylene hydroxy group.
Certain chemic 1 names are abbreviated herein for the
sake of convenience. Boc refers to the t-butoxycarbonyl
radical. Cbz refers to the carbobenzyloxy radical. Bzl
refers to the benyzl radical. Ac refers to acetyl. Ph
refers to phenyl. BOP refers to benzotriazol-l-yloxy-
tris(dimethylamino~phosphonium hexafluorophosphate. DCC
refers to dicyclohexylcarbodiimide. DMAP refers to
~:
W093/0~057 2 1 1 3 ~ ~ ~ PCT/V~g2/~7
- 17 -
dimethylamin opyridine. DMSO refers to dimethylsulfoxide.
HOBT refers to 1-hydroxybenzotriazole. NMM is N-
methylmorpholine. DTT is dithiothreitol~ EDTA is
ethylenediamine tetraacetic acid. DIEA is diisopropyl
s ethylamine. DBU is 1.8 diazobicyclo~5.4.0lundec-7-ene. DMSO
is dimethylsulfoxide. DMF is dimethyl formamide; Lawesson's
reagent is 2,4-bis(4-methoxyphenyl~-1,3-dithia-2,4-
diphosphetane-2,4-disulfide and THF is tetrahydrofuxan. HF
refers to hydroflu~ric acid and TFA refers to trifluoroacetic
aci~.
The compounds of formula tI):
Rl R2
R5~R4
O~ R3
- (I)
wherein R4 is Co-NR~cHR6R7~ R5 is Rl0RllN_, and Rl R2 R3 a~d
R6 are as defined in formula (I), are prepared by:
l)(a~ coupling a compound of the formula (II~:
Rl RZ o
Rs ~ L'
OPr~ R~
20(II)
with a compound of formula (III3:
HR'N-CHR6 R7
where Rl , R2 , R3 , R5 , R6 and R7 are as defined or
2s formula (I) with any reactive groups protected, prl is H or a
hydroxyl protecting group, and L' is OH or a lea~ing group;
or
tb) coupling a compound of the formula (IV~:
R1 RZ
H2N ~ R4
; 30OPr~ R3
~IV)
with a compound of the formula (Vj:
W~93/02~7 . PCT/U~2/~7
18
A'-(B'~n-L'
(V)
wherein A' and ~' are as de~ined in formula ~I) with any
reactive groups protected; or
(c) coupling a compound of the formula (VI):
Rl' RZ
H-~B')nNR' ~ R4
Oprl R3'
(VI)
with a compound of the formuIa (VII~: -
~7-L~
(VII)
and,
2) if appropriate, a coupling agent; and
3) removing any pro~ecting groups and
~5 4) forming a pharmaceutically acceptable salt thereof.
The coupling reac~ions ~ay be accomplished by activating
: the substrate ~ith a reactive functîonal group i~ situ or
prior to the coupling reaction, such that it is reactive with
an amino group. For i:nsta~ce, acids may be converted to acid
~:: 20 chlori~es, brom1des~ activated esters or anhydrides, or by
adding a c~upling reagent. Coupling a~ents are well known in
: the art ~or activating a functional group in situ,.
Exemplary of ~8UC~ agents are ~CC and other carbodiimides,
DMAPEC, BOP and~PPA. These coupling agents may op~ionally be
s used with other~reagents~ such a ~OBT, NMM and D~APr whîch
may facilitate the reaction.
~ Suitable leaving groupst L', are those which are
: displaceable by an amino group, such as bromo, chloro, a
~ substituted acyl (eg. trifluoroacetyl, bromobenzoyl~
....
ni~robenzoyl) 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 instan~e:
: ~:
~; ,
W093~02~7 2 ~ PCT~US92/~7
,~
- 19 -
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.
~ hen A is R17~18R19C)m-W, Ar-W or Het-W, and W is C=O,
A-Li 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-L' may be a chloro- or bromo-formate,
or an activated carbonate. Haloforma~es may be prepared by
react~ng the appropriate alcohoi with phosgene ox
carbonyldibromide. Activated carbonates may be prepared by
rea~ti~g the appropriate alcohol with a suitable carbonate
such as bis(4-nitrophenyl~carbonate.
When W is~ S02, 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
~ercaptan.
~: ~ When W is PO~R22),:A-L' may be a phosphonyl hal~de,
which may~be ~repared from the corresponding phosphonic acid~
Compounds~ wherein A is R17 (R18R19C)m-~, 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
Rl7 (R18R}9C)m-NCo~ Ar-NCO or Het-NCO, in a suitable solvent
:: 25 such as methylene chloride, optio~ally with heating.
Compounds~of formula (III), wherein X is nitrogen, are
imidazoles and may be prepared according to Scheme 1, wherein
pr2 is a re veable amino protecting gr~up, 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, RB or R9, with any
, , . ;~ ,
reactive groups protected.
. .
: ~ Scheme 1
P~N~H + ~ NH3 Pr2 NR ~~< 3~
3s ` R~ CH30H N R9
~:` tVIII~
W093~02~7 ~ PCT/US9~/06fl47
~ 20 -
The amino aldehydes are generally known or are prepared by
methods well known in the art, for instance, by reduction of
a suitable a-amino acid ester with diisobutylaluminum
hydride. Fux~her reaction of the aldehyde with a gem
dialdehyde, or diketone, and ammonia yields the desired
imidazole~ Alkylation and further modification of the
substituent groups sf the imidazole are within the skill of
the art. Such a method and other methods ~or preparing
imidazoles are disclosed, for instance, by Baldwin et al., J.
lo ~ed. ChemO, 29, 1065 ~1986), Angew. ~hem. Int., 22, 560
; ~1983), and Hughey et ~l., Synthesis, 489 ~1980).
Alternately, acyl imidazoles may be prepared by coupling an
a-amino acid to a substitu~ed g-amirlo-isoxazole, and
subsequen~ reduction and base catalyzed rearrangement as
lS disclosed generally by Reiter, 1.A., J. Or~. ~hem., 52, 2714
(1987). In~ermediate co~ounds of formula (VIII) are a part
of this invention . Preferably, R7 ~ is C~_6alkyl and more
preferably C3_6alkyl. Suitably, R8 and R9 are lHt N02, Br,
CORl~, CF3, Ar, Cl_~alkyl or Cl ~ 6alkyl-R15, wherein R12 îs ~,
C:l_6al:kyl, Ar, 0:1_6alkyl, NH2, and R15 i~ O~ or a protec:~ed
hydroxyl group. Preferably R9 is H or CORl2.
Compounds of formula (III), wherein X is ~ulfur, are
thiazoles and may be prepared according to Sche~e 2, wherein
Lt1 is a suitable displaceable group.
p,:2- ~NHz _L- p,2-
Rr . i h;
....
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
35 - groups are those which are displaced by a sulfur nucleophile,
W~93/~20~7 PCT/VSg2/0~047
~ 21 2113~
such as chloride, bromide, iodide, mesylate, p-tolunesufona~e
groups, and the like.
Compounds of formula (III~, wherein X is oxygen, are
oxa~oles and may be prepared according to Scheme 3 from
s common amino acids. ~.
cheme 3
R~
p~2~ ~OH ~ pr2~ ~NH-CHR9'CHR8'-OH
Rr: ~ . R7'
. SOC~
R~ F~a~
p~2-U~ 10~ p~2oN~R8'
F~' ; R;
~0 Typically the acid may be coupled to an appropriately
~:~ subs~ituted amino~alcohol by common techniques, as described
above, and~cyclized by treatment with thiony~ chloride to
yield an oxazoline, as described:by ~eyers et al., J. Org.
Chem., 43, 1;372 (1978). Oxidation ~f ~he oxazoline, such as
described by EU~DS et ~al., J. Org. Chem., 44, 497 (1979~,
yields an oxazole~ ~
: me compounds of formula (II), (IV) and ~VT), wherein R2
is:H, are prepared, Por inst.nce, according to Scheme 4.
:
' ~ :
~.
.
W0~3/~2~7 PC~/~S92/~7
,
22 -
-S~h~ç 4
~C2H5
P'~ (Oi-Pr)3ClTi O ~1
Boc-NH~ Ph~, CH2CI2 Boc-NH~1:~02C2Hs
OH
¦ Ac-OH
F~l ` ' R
Boc llH~ 3 _ ~P~2N Boc-NH~
.
O
1~ LiOH,H2g,MeOH
23 t-BuMe~S~CI, imidazol~
Rl
B~-NH~CO2H
H P~3:
Othçr methods~for~preparing protected 5-amino-4-hydrox~-
:: 5 2, 5-disubstituted-pentanoate esters and acids, and the
co~responding ~lacts:nes, are well known and are disclosed,
for instance, ~ln Szelke et al ., U.S Patent 4,713j455, soger
et al.:,~ lJ.S. Patent 4,661,473, EP~A 0 352 000, Evans et al.,
J.~Org. Chem., :50,: 4615 ~198~), Kempf, J. Org. C:hem., 51,
10 ~ 3921 (I986), Fray et :~al .; J. Org. Chem., 51, 4~28 (1986),
: Halladay et al~.t Tett. Lett., 24, 4401 ~1983), Wut~ et al .,
J. ~Org. Chem., 53, 4503 (1988~, OeCamp et al., Tett. Lett.,
32, 1867 (1991), and Szelke et al ., ~0 84/03044, all of which
are incorpo~ated herein by reference. I
The ~omp~unds 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., ~. Med. Chem., 30, 976 (1987).
Compou~ds o~ formula ~I~, wherein R5 is R6-NRll, are
prepared accordlng to Scheme 5, Scheme 6 or Scheme 7:
:
: : :
~: ~
WO 931~2057 P~/U~92/~6~47
23 ~ ~ 3 6 4 ~
~h~me 5
Rl RZ RCONCS S R1 R~ ~RY
H2N~ H2N N~ Lt
OPr~ R3 ~ H OPr1 R~
~ IV)
R~ J~ ~R~
,
SRl RZ S Rl RZ o
H2NJ~N~R4 ~ M~2N5CHNJ~N~' L~
H Oprl R~ M~CH(OMe~2 H OPr
.
,
R~ ~ pl8
~S pi1' RZ ~S Rl R2
N~l~l~' dePIotect <J~>~N~,R4
H ~ ~ OPr1 R~: ~ H OH 1:33
: :
:
1 0
H2N U R~ Nrl J~ ~84 R~ p~
~ ~ ~OPr~ H2~;04 HoPr1 ~ ~
R~ : H RB H~
, N R1 RZ N p,~ 2
~, ~. I 1 4. deprot~ct // ~ 3
R~-- N~N~''R ~ R9--~N~N~h~R4
H OPr~ R~ OH R3
~, :
~:
wherein R1'-R4 ~ R7 and R8 are as defined in formula ~I)
with any reactive groups protected, L ' is a leavi~g group,
5 such as halogen, and Pr1 is a hydroxy-protecting group
WOg3J02~7 PCT/V~92/~047
"",~,
Compounds wherein R4 is R6NR11- are prepared in an
analogous manner from a compound of formula (IX):
R~ R~
R5~N~2
OPr~ R~
(IX)
Suitable protecting groups for the amino, hydroxyl,
caxboxylic 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. ~eprotection
indicates the removal of the protecting group and replacement
wi~h an hydrogen atom. In particular, suitably substituted
acetyl, benzyl and silyl groups are us~ful for protecting the
hydroxyl group. The acetyl group is co~monly removed by
reacting the compound with a baser such as an alkali metal
hydroxide, in a mixture of an alcohol and water. The silyl
yroup, such as ~rimethyl sily}, dimethyl-t-butyl silyl, and
t-butyl-diphenyl silyl may be removed by a fluoride reagent,
su~h ~aB a tetra-alkyl~ammonium fluoride,~or by aci~
20: hydrolysis. The benzyl group may be removed by catalytic
hydrogenation~
Suitable protecting:groups for the amino group are those
disclosed by~ Gre~ene et al., as indica~ed previously. The
benzyloxycarbonyl and t-butoxycar~onyl groups axe especially
useful amino protecting groups.
The pre6ent invention includes pharmaoeu~ically
acceptable acid addition salts. Acid addition salts of the
present compounds are prepared in a standard manner in a
suitabl~e 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 qroup, cationic salts may be
prepared. Typically the parent compound is treated with an
: 35 excess of an alkaline reagent, such as a hydroxide, carbonate
~ or alkoxide, containing the appropriate cation. Cations such
::;
W0~3/02057 P~T/US92/~ ~7 :
~ 25 21i3~ l
as Na+, K~, caf+ and NH4+ are examples of cations present in
pharmaceutically acceptable salts. Certain of the compounds
form inner sa~ts or zwitterions which may also be acceptahle.
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
viral replication by blocking the formation of crucial viral
proteins from polyprotein precursors by the protease, and
hence, to ~nhibit disease progression in v~vo. The present
compounds achieve such beneficial therapeutic effect because
they contain unique`structural features which impart
desirable pharm~cokinetic properties to the compounds. One
such property is long duration of action. We have found that
substitu~ion of a heterocycle, especially imidazole, in the
putati~e P2' posit~on of the present compounds affords
compounds which retaln ~ood ~nzyme binding a~inity, good
antiviral activity, a~: favorable duration of action and water
solubility :Eor good~ drug: delivery.
When a compound of: the present invention is administered
~;~ to an animal infected or potentially infected with a
retrs:)virus, viral replication is inhibited and hence disease ~:
:progression is retarded. ~ asmuch as the amino acid :
se:quences of t~e ~ protease binding and peptide bond cleavage
2s sites of ~arious~retrovirus2s appear to be highly conserved,
- an inhibi~or is l~ikely to be broadly active against m~re than
one retrovirus. Also, DNA viruses which are dependant upon
virally encoded proteases, such as the hepatItis virus, may
aIso be susceptible to such treatment.
The compounds of formula (I) are used,to inhibit,
retxoviral replication, and are useful in treating mammals, ~:
. paxticularly human patients, who are infected with
: susceptible retroviruses and require such treatment. The
:
method of treating a retroviral disease in a mammal,
3s particularly a human, comprises internally administering
(e.g. orally, parenterally, buccally, trans-d~rmally,
re.ctally or by insufflation) to said mammal an effective --
amount of a compound of formula (I), preferably dispersed in
W093/02~7 PCT/US9~/06047
~ 26 -
a pharmaceutical carrier. Dosage units of the active
ingredient may be selected by procedures routine to one
skilled in the art, and are generally in the range of 0.01-50
mg/kg. These dosage units may be adminis~ered one to ten
times daily for acute or chronic infection~ Preferably the
compound is administered at a level of 1-10 mg/kg, two ~o
four times daily. No unacceptable toxicological effects are
indicated when compounds of this invention are a~ministered
in ~he above noted dosage ra~e.
The present invention also provides a method of treating
disease states associated with HIV infection or Acquired
Immune Deficiency Syndrome (~IDS~, comprising administering
an effective amount of a compound of f~rmula (I)~ preferably
dispersed in a pharmaceutical carrier.
Beneficial effects may be realized by co-administering,
indi~idually or in combinatio~, other anti-viral agents with
the protease inhibiting compounds of the present invention.
Examples of anti-viral age~ts include nucleoside analogues,
:: phosphonoformate, rifabutin, ribaviran, phosphonothioate
oligodeoxynucleotidesr castanospermine, dextran ~ulf~te~
alpha interferon and ampligen. Nucleoside analogues, which
include 2',3' dideoxycytidine(ddC), 2',3'-~ideoxyadeninetddA)
and 3'-azido-~',3'-dideoxythymide (AZT), are especially
: useful. AZT is a preferred agent. Suitablyr pharmaceutical
compositions comprise an anti-~iral agentr a prote~se
inhibiting compound of the present invention, and a
pharmaceutically acceptable carrier.
; This inYention i5 aIso a pharmaceutical formulation
which comprises a compound of formula ~I) and a
3~ pharmaceuticall5~ acceptable carrier. Pharmaceutical
acceptable carrier are well known in the axt and are
disclosed, for instanc~, in SPROWL'S A2~ERICAN P~RMACY,
Dittert, L. (ed.3, J.B. Lippincott Co., Philadelphia, 1974,
and REMINGTON'S PHARMACEUTICAL SCIENCES, Gennaro~ A. (ed.),
3s M~ck Publishing Co., Easton, Pennsylvania, 1985.
Pharmaceutical compositions of the compounds o~ the
:~ present in~ention, or derivatives thereof, may be formulated
as solutions or lyophilized powders for parenteral
.
WOg3/~2D57 . PCr/US92/06047
- 27 _ 2~3~
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
s diluents are normal igotonic 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
admini~tration or contai~ed in a metered dose inhaler or
nebulizer;~for insufflation. It may be desirable-to add
excipient~ such as ethanol, polyvinylpyrrolidone, gèlatin,
hydroxy cellulose, acacia, polyethylene glycol, mannitol,
sodium chloride or sodium citrate.
P.lternately, these compounds may be encapsulated,
15 tableted or prepared in a emulsion or syrup for oral ::
administration. Ph~rmaceutically acceptable solid or liquicl
c2lrrier~ may be added 'co enhance or stabilize the .-
c~mposition, or to~facilitate preparation of the composition.
~iquid carriers~in1ude syrup, soy bean oil, peanu~ oil,
olive oil, glycerin, saline, ethanol, and water.
So}ubi}i~ing ag~nts, such as dimethylsulfoxide, ethanol or
formamide, may also bs~ added. Carriers, such as oils,-
optionally with solubilizing excipients, are especially
suitable. Oils include any natural or synthetic non-ionic
water-immisc~ble liquid, or low melting solid, which is
capable of dissolving lipophilic compounds. Natural oils~
`such as triglycerides are representative. In fact, another
aspect of thi~ invention is a pharma~eutical composi~ion
comprising~a compound of formula (I) and an oil.
Solid carriers include starch, lactose, calcium sulfate
dihydrate, terra alba, ~agnesium stearate or stearic acid,
talc, pectin, acacia, agar or gelatin. Solubilizing agen~s,
such as dimethylsulfoxide or formamide, may also be added.
The carri~r may also include a sustained release material
~ 3~5 such as glyceryl monostearate or glyceryl distearate~ alone
;~ ~ or~with a wa~. The amount of solid carrier varies but,
preferably, will be between about 20 mg to abou~ 1 g per
dosage unit. The pharmaceutical preparations are made
.
WOg3/lJ2057 ~ 28 - PCI/USg2/06047
following the conventional techniques of pharmacy involving
milling, mixing, granulating, and compressing, when
necessa~y, 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 ~ay be administered directly p.o. or .-
filled into a soft ~elatin capsule.
A suitable dosage form for oral administration has been
. 10 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 wit~ soybean oil. A suitable dosage form for
i~travenous administration has been prepared by dissolving
the compound of Example 1-(0.02 g) in dimethyl sulfox~de ~l :
mL) and diluting to 20 mL with a 70~ propylene glycol/30
ethanol solution.
: For rectal a~minis~ration, a pulverized powder of the
compounds of this invention may be combined with excipients
:;; : such as cocoa butter, glycerin, gel~tin or polyethylene
: ~ 20 gly~ols and molded into:a suppository. The pulverized
~: powders may also~be:~compounded with an oily preparation, gel,
cream or emulsio~, buffered or unbufferedt and adm~ni~tered
through a transdermal patch.
The pharmacological acti~ity of the compounds of thi~
inve~tion may be demonstrated by enzyme assays to determine
the inhibitory :activity of the retroviral protease, by in
:: . Yitro cellular-based assays to determine the ability of the
ompounds:to penetra~e cells and inhibit viral repli~ation,
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
3s inhibit the HIV-l protease enzyme may be demonstrated by -.
. using the assay discl~sed by Dreyer et al., Proc. N~tl. Acad.
Sci., U.S.A.~ 86, 97S2 (1989), Grant et ~l., Biochemistry, 30
:~ 8441 (1992), and EP-A 352 000. The Ki for the compounds of
WO 93/02057 PCT/US92/06047
- 59 -
this invention are in the range of 1 nM to 5 ,UM. Preferred
compounds have Ki's of less than 100 nM.
INFECTIVITY
The ability of the compounds of thi~ 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.,
Natvre, 34-3, 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 ~M.
CYTOTOXICITY
Cytoitoxicity is assessed by both direc~ microscopic
examination of trypan blue stained cells (T-lymphocytes) and
by the treated culture`s ability to metabolize the
tetrazoliu~ salt XTT (2,3-bi~Z2 methoxy-4-nitro-5-
sulfophenyl]-2H--tetrazolium-5-carboxanilide sodium salt), ~o
i~s formazan dye.: The XTT assay allowx determination of the
50% toxic concentration of compounds for the cell/virus
system used. :
PHARM~COKINETICS
Dual jugular cannulated Sprague Dawley rats weighing 200-
~o 250 g:were;utili`zed in all studies. All dosing and sample
collection was~done from conscious rats. Before dosing, a
t:ime 0 blood sample, 300 ~L, was drawn using one of the
catheters. Util;izing the second catheter the rats were dose~
intra~enously. At 1, 10, 30, 60, 90, 120, 150, 180 and 210
min after dosing,:300 ~L blood sa~ples were drawn. The rats
dosed orally were adm:inistered the compound by utili~ing a 22
gauge gastric gaYage needle and samples were drawn at 30, 60,
90, 120, 240, 360, 480, 600, 720 and 1440 min. The blood
samples were placed in precooled tubes containin~ 30 mL of
sodium citrate and~centrifuged in a microfuge. The plasma
was transferred~then snap frozen on dry ice, and stored at
-70°C until analyzed.
W~93/02~7 PCT/US92/~047
30 -
Standard stock solutions ~l mg/m~) of inhibitor was
prepared in 100~ ~MSO. A dilution series of the stock
solutions were prepared in a total volume of 0.1 mL ~pooled
normal rat plasma/DMSO) to yield final concentrations of 0
and 0.5-120X the Ki Of the inhibitor. All dilutions were
performed in triplicate. These spiked plasma solutions were
extracted with 0.5 mL acetonitrile by vigorous vortexing/
followed by centrifugation for 10 min. An aliquot (0.4 mL)
of the supernatant was removed and dried in Eppen~orf tubes
using a Speed-vac. The resulting residue was xedissolved in
D~SO. The inhibition of the HIV-1 protease activity was
assayed as follows. ~n aliquot of the extracted sample was
added to a 50 ~L mixture containing lX MEN~T buffer, 1 ~M
substrate and incubated at 37C < 10 min. The reaction was
then initiated by the a~dition of HIV-l protease and
continued at 37C for an additional 15 min, then quenched by
the addition of TFA (0O5% final concentration). Initial
rates were determi~ed for each standard curve as ~he fraction
of remaining e~zymatic activity (vi~vo) at each inhibitor
concentration, in which vo is the velocity of the I
(inhibitor concentration)=0 sample. Assumin~ that all of the
original inhibitor in the spiked samples was ext~acted, the
~alues of vi~vo were plotted versus inhibitor concen~ration
Q~ the origi~al extracted sample and fitted ~o the equation:
~5 vi/vo=~AEt--It--Ki ~ ~Ki-AEt-It)o 5]Jt2AEt)
which Et is t~e total enzyme concentration at time zero,
:: . Ki is the apparent inhibition constant and A is the fraction
~ of a~tive enzyme.
::; Ex vivo animal plasma samples containing unknown levels
of protease inhibitor were prepared and analyzed as described
for the standard curve described above. The concentration of
.... .
inhibitor in these samp~es was then determined using the Ki
and A parameters from the fitted standard curve according to
the following equation: It=AEtEl-(vi//vo)~ + Ki~V0/vi)
35The data was plotted as the natural log ~ln) of the
plasma concentration versus time on semilogarithmic paper to
~: :generate the plasma concentration-vs-time curves. Using the
IV data, the apparent terminal rate constant was determined
W093/02057 2~3.~ P~T/US92/~7
( "', :'
- 31 -
form ~he linear regression analysis of the plasma
concentrat~on-vs-ti~e curve. The elimination half-life
(tl/2) was derived by dividing ln 0.5 (-0.693) by the
terminal rate constant. The area under the plasma
concentration-vs-time curve (AUC~ was determined by using the
ln/log trapezoidal rule. Cm~X represents the max~mal plasma
concentration and t~aX, the time following drug
administration at which CnaX was observed. Both ~alues were
estimated by inspection of the plasma concentrationvs time
curve. Total plasma clearance ~CL) was calculated by
di~iding the dose by the AUC. The fraction of the oral dose
available to the systemic circulation (the bioavailable
fraction, F~ was determined by the eguation: F =
[AUCpo/DOSEpo] x ~DosEiv/A~civ].
The Examples which follow serve to illu~trate this
in~ention. 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 ~his in~ention.
In the Examples, all temperatures are in degrees
Centigrade. Mass spectra were performed using fast akom
bombar~ment (F~B) or electro-spray (ES) ionization. Melting
points were taken on a Thomas-Hoover capillary melting point
apparatus and are u~corrected.
NMR were re~orded at 250 MHz using a Bruker AM 250
spectrometer, un~less otherwise indicated. Chemical shifts
are reported in ppm ~) downfield from tetramethylsilane.
;Multiplicities for NMR~spectra are indicated as: s-s~nglet,
~; ~ d=doublet, t=triplet, q=quartet, m=multiplet, dd=doublet of
doublets, dt=doublet of triplets etc. and br indicates a
broad signal. J indicates the NMR coupling constant in
Hertz. -^-
Celite~ is filter aid composed of acid washeddiatomaceous silica manufactured by Mansville Corp., Denverr
35 Colorado~ Fl~risil~ is an activated magnesium silicate ;
;~ chromatographic support and is a registered trademark of
~ Floridon Co., Pittsburgh, Pennsylvania. Sat. îndicates a
:: ~
: .
W093/0~7 . PCT/US92/~7
~ ~ d - 32 -
saturated solution~ eq indicates the proportion of a molar
equivalent o~ reagent relative to the principal reackant.
Exampl~_1
-.
a~ (l'S)~ carbobenzyloxyamino~ isopropyl-1'-(imidazo-2-
yl)methane
Cbz-valinal (4.6 g, 1 e~) and glyoxal trimer~c dihydra~e
~1.33 g, leq) were stirred in M~OH at -10C. ~mmonia was
bubbled through the solution for se~eral min and the mixture
was allowed to stir for 4 h at -10~C. The mixture was
allowed to warm to room temperature over 14 h~ then was
poured i~o 250 mL water. The suspension was f~ltered and
the filter cake washed twice with water to give the title
compound as a white solid ~1.9 g, 36%~. NMR~CD30D) ~ 7.28
~o ~5H, m), 6.89 (2~, s), 5.04 (2~, dd), 4.46 (lH, d), 2.10 tlH,
m) r 0- 91 (3H, d), 0.70 (3H, dl; MS(CI/CH4) mJe 274.2 lM~H]+,
230.1, ~66.1, 123~1r 91.1.
.
b) ~l'S)~ amino~ isopropyl~ imidazo-2-yl)methane
:~ 25 (l'S3~ carbohenzyloxyamino~ isopropyl-1'-~imidazo-2-
~: yl)methane (1.9 g) was stirred in methanol over 10% Pd/C (200
mg). ~ydrogen was bubbled through the solution for 1 h and
the solution was maintained under a positive hydrogen
: atmosphere overnight. The mixture was filtered through
30 Celite~ and was evaporat2d to a tacky solid (720 mg, 75%).
NMR~CDC13) ~ 6.8i (2H, s), 3.8~ ($H, d), 2.04 tlH, m), 0.81
(6H, dd~; ~S~DCI/NH3~ mJe 190.2 [~+Hl+.
c) (2R,4S,5S,l'S)-2-phenylmethyl-9-(t-butyldimethyl)siloxy 5-
(t-butoxycarbonyl)amino-6-phenyl-N-[1'-isopropyl-1'-~imidazo-
2-yl)]me~hyl-hexanamide
To a solution of (2R,4S,5S)-2-phenylmethyl-4-(t- . :
butylmethyl)siloxy-5-~t-butoxycarbonyl)amino-6-phenyl-
W093/~2~57 PCr~US92/~6~47
2 ~ 3 ~
hexanoic acid (200 mg, 0.38 mmol) in dichloromethane, (l'S~- :
l'-amino 1'-isopropyl~ imidazo-2-yl)methane (48 mg, 0.35
mmol), BOP reagent ~168 mgt 0.38 mmol), and triethylanine
~0.053 mL, 0.38 mmol) were added. The mixture was stirred
under argon overnight, and washed successi~ely with water, 5
aqueous sodium bicarbonate, and saturated aqueous sodium
chloride. The solution was dried over MgS04, filtered, and :~
evaporated to a white solid. The solid was chromatographed
(sil~ca, 4% methanol~dichloromethane) to affard the title
compound as a white solid (0.154 g, 68%). NMR(CDC13) ~ ~.18
~lOH, m), 6.91 (2H, d), 6.32 (lH, d), 4.69 (lH, d) r 4 .40 ~lH~
t), 3.92 (lH, q)D 3~63 (lH, m~, 2.84 - 2.31 ~6H, m), 1.~7
t4H, m), 1.29 ~H, s),- 0.89 (9H, s), 0.74 (6H, dd), 0.05 (6H,
d); MS(DCI/NH3) m/e 649.6 LM+H]~.
d) ~2R,4S,5S,l'S)-2-phenylmethyl-4-hydroxy-5-(~-
butoxycarbonyl)amino-6-phenyl-N-~1'-isopropyl-1'-(imidazo-2-
yl)]me~hyl-h~xanamide hydrochloride
The compound of Example l~c) ~0.140 g) was stirred in
T~F at roo~ temperature under an argon atmosphere.
Tetrabutyl ammonium fluoride tO.38 mL, 6 eq) was added and
the solution wa~ stirred overnight. The mixture was diluted
wi~h water and extracted with dichloromethane ~3X). The
~ comb~ned organic extracts were washed with water and
evaporated. The residue was treated with 1 eq of methanolic
HCI, concentrated, and triturated with die~hyl ether and
ethyl acetate to give the title compound as a white solid (95
mg, 83%). NMR(DMSO-d6) ~ 7.78 (lH, d), 7.16 ~lOH, m)~ 6.71
(2H, ~), 6.39 (lH, d~, 4.68 (lH, m~, 4.52 ~1~, d)~ 2.71 ~3H,
m), 2.48 (3H, m), 1.97 (lH, m), 1.61 (lH, m), 1.30 (9H, s),
0.78 (3H, d), 0.61 (3H, d); MS(DCI/NH3) m/e 535.4 ~M+H~+ . .
`;'''
:'
~u~xycarhony~ aminQ-~-phenyl-~-rl'-i~opro~yl~ (4
W~93/020~7 ~ PCT/USg2~06~7
- 34 -
a) Boc-~alineamide
To a solution of di-t-bu~yl-dicarbonate (7.15 g, 1 eq)
in dry dichloromethane was added valinamide hydrochloride
l5.0 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(CDC13) ~ 6~00
~lH, br), 5.54 (lH, br), 5.01 (lH, br), 3.93 ~lH, dd), 2~12
~lH, m), 1.94 t9H, s3, 0.92 (6H, dd).
: .
b) Boc~valinethioamide
Boc-~alineamide ~0.5 g) was stirred in dry THF at room
temperature under ar~on. Lawesscn's reagent (1.56 g, 0.6 eq~
was added and the mixture was stirred overn~ght. The solvent
was evaporated and the residue chromatogxaphed (silica, 2.5
methano~/dichloromethane) to give the ti~le compound as a
~hite solid (0.373 g, 70%). NMR(CDC13) ~ B.59 (1~, br s),
8.09 ~1~, br s), 5.41 (lH, d (br)), 4.20 ~lH, dd), 1.9~ ~lH,
m), 1.39 ~9~, s~, 0,90 (6H, m).
c~ ~l'S)~ t-butoxycarbonyl)amino~ isopropyl-1'-(4-
carboethoxythiazo-2-yl)~ethane
Boc-valinethioamide (O.265 g) was stirred in dry acetone
under argon at -10C. Ethylbromopyru~ate ~0.16 mL, 1.1 eq~
was added and stirred for 1 h at -lO~C. The solution was
poured into a well-stirred mixture of chloroform and water
:~ ~ and then saturated with sodium bicarbonate. The organic
phase was separa~ed and the aqueous layer extracted with ~.
chloroform. The combined organic extracts were dried over
30 MgSO~, 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 -20C. Excess ~-~
solvent was removed in vacuo and the residue dissolved in
dichloromethane. The solution was washed with sat. aqueous
sodium bicarbonate and l.ON KHSO4 until p~ 7. The solu~ion
was dried over sodium sulfate., ~iltered, and e~aporate~ to an
oîl which was chromatographed (silica, 4% methan~l/
dichloromethane3 ~o give the title compound as a tan solid. -.
W~93/0~057 PCT~U~92/06~7
21~ q
_ 35 _
NMR~CDCl3) ~ 8.04 ~lH, s), 5.26 (lH, br d), ~.85 (lH, m),
4.37 (2~, q), 2.40 ~lH, m), 1.41 (9H, s), 1.39 (3~, t3, 0.93
(3H, d), O . 84 (3H, d) . ~ -
d) (l'S)-1'-(t-butoxycarbonyl)amino-1'-isopropyl~ 4-
caxboxythiazo-2-yl)methane
The compound of Example 2 (c) (50 mg) was stirred in THF
at 0C. Excess 1.0N NaOH was added and the mixture was
stirred for 12 h at 0~C. The mixture was diluted with 1. ON
10 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, 9B~). 'NMR(CDCl~ ~ 8.08
~lH, s), 5.1g ~lH, m), 4.80 ~l~, m), ~.31 (lH~ m), 1.38 (9~
s), 0.86 (6Hr dd). ~;
e) ~l'S)~ (t-butoxycarbonyl~amino~ is~propyl~
(4-aminocarbony~thiazo-~-yl)meth~ne
~l'S)~ (t-hutoxycarbonyl)amino~ isopropyl~ (4-
: carboxythiaz~-2-yl~methane (0.078 g, 0.26 mmol) was stirred
under argon in dry THF at -40C. NMM ~0.06 ~L; 0.55 mM) and -.
isobutyl chloroformate ~0.034 mL; 0.26 mmol) were added.
After stirring 15 min, ammonia wa~ bub~led through the
mixture for several min. The solution was warmed to room ~-
. .,
termperature and the ~F evaporated. The residue was diluted ;-:
2s with ethyl acetate and washed successively with 1.0~ ci~ric
acid, 5% aqueous sodium bicarbonate, and sat. aqueous sodium
chloride. The organic layer was dried over MgSO4, filtered,
and~evaporated~to~a solid which was chro~atographed (silica, ~r
3% methanol/dichloromethane) to give the title compound as a
wh~te solid ~0.052 g, 67%). NMR(CDCl3) ~ 8.02 ~1~, s?, 7~14
: (lH, s~br), 6.28 (lH, s(br)), 5.29 ~lH, d(br)), 4.82 ~lH, m),
2.30 (lH, m), 1.39 t9H, s), Q.92 ~6H, dd).
: f) (2R,4S,5S,~'5)-2-phenylmethyl-4-(t-butyldimethylsiloxy)-5-
3s ~t-butoxy carbonyl~amino-6-phenyl-N-~1'-isopropyl~ 4-
~'~ : aminocarbonyl-thiazo-2-yl)]methyl-hexanamide
~: The compound o~ Example 2(e; (52 mg) was ~tirred in neat
trifluoroacetic acid for 10 min and evaporated. The residue
W093/02~7 PCT/US92/06047
~4~ 36 -
was diluted with methanol and treated with 2 eq of conc. HCl.
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-~t-
butoxycarbonyl)amin~-6-phenyl-hexanoic acid (97 mg, 1.1 eq),
DCC ~3~ mg, l.l 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 l.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 mgt S5%). NMR~CDC13) ~ 7.89
(lH, s), 7.60 (lH, d), 7.24 (lOH, m), 6.82 (lH, m), 5.12 (lH,
m), 4.89 (lH, m), 3.92 (lH, q), 3.81 ~lH, dd), 2.73 (4H, m),
2.21 ~lH, m) r 1.73 (2H~ m), 1.40 (5H, s) r 1.23 (lH~ m), 0.93 ~
(9H, s), 0.84 (6H,~ dd), 0.11 (6H, d~. -
g) (~Rr4S,5S,l;'S)-2-phenylmethyl-4-hydroxy-5-~t-
butoxycarbonyl)amino-6-phenyl-N~ isopropyl~ (4-
aminocarbonyl(thiazo-2-yl)lmethyl-hexanamide
The compound of~Example 2tf) (60 mg) was stirred in dry
THF under a~g~n and tetrabutylammonium fluoride (0.50 mL, 6
25 ~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%
methan~l/dichloromethane) to give the title compound as a
white soïid (0.022 g). NMR(CDCl3) ~ 7.90 ~lH, s), 7.15 (lOH, ~-
, ~
m), 6.39 (lH, d~, 5.93 (lH, br s), 5.06 (lH, dd~, 4.91 (lH,
d), 3.90 (lH, d), 3~. 67 (2H, m), 2.91 (4H, m), 2.64 (lH, d),
2.13~1H, m), 1~87 (3H, m), 1.36 (9H, s~, 0.83 ~6H, dd);
MS~DCI/NH3) mte 6I2 [M+NH4]+, 595 lM+H]+, 495, 413.1, 391,
37~, 35~, 239.1, 202, 185.
.~.
W~93/U2U~7 ~ ; PCT/US9Z/~6W7
f _ 37 2~ ~ 3~ ~
E~am~le ~
Preparation of f~Rr 4 ~ 5S ~ 1 ~ Sl -2-phenylmethy~-4-hydrQxy-5- (t-
s yLllm~h~hs~
a) ~l'S)~ t-butoxycarbonyl)amino-1'-isopropyl~ thiazo-
2-yl)methane
. The compound of Example 2~c) was stirred in neat
quinoline. Cu powder (0.50 g) was added and the su~pension
was heated to 160C for 2 h. After cooling to room
~emperature, the s~lution was diluted with ethyl acetate and
washed with 2.QN citric acid ~4X). The organic layers were ;
combined and dried o~er MgS04, filtered, and evap~ra~ed to a
dark oil. The oil was chromatographed (silica~ 4%
methanol~dichloromethane) to give the title co~pound as an
orange oil. ~(CDCl3) ~ 7.68 (lH, d~, 7019 (lH, d), 5~26
(1~, d)~, 4.38 ~lH, m~, 2.31 ~lH,-m), 1.43 (9H, s), 0.92 (3H, ~;
dj, 0 . 84 (3H, d~ . -
: : b) (2R,4S,55,1'5)-2-phenylmethyl-4-hydroxy-5-(t-
butoxycarbonyl)ami~o-6-phenyl-N-[1'-isopropyl~ (thiazo-2-
yl)lmethyl-hexanamide
Following the procedure of Example 2(f)-2(g~r except
2s using the compound of Example 3~a~ in place of (1'S~-l'-tt-
butoxycarbonyl~amino~ isopropyl~ (4-aminocarbonylthiazo-
2-yl)methane, the~title compound was prepared (88%).
~` NMR(DMSQ-d~ ~ 8.31:(lH, d), 7.62 (lH, d), 7.49 ~lH, d), 7.16
(lOH, m), 2.61 ~6H, m)j 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
repara~ion o~ (2R~4S~5S,l'S)-2-ph~nyl~t~ 4-hydroxy-5-(t-
_
2-yl)l methyl-he~an~mide
WO ~-2~7~,~3 c ~ PCT/US92/D~7
a) (l'S)~ carbobenzyloxyamino~l'-isopropyl~ benzimidazo-
2-yl)methane :
Cbz-valine ~2.0 g, 1 eq~ was stirred at 10C in dry THF
under argon. Triethylamlne ~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
(~.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 watex and ethyl acetate. The ethyl acetate layer was
washed with S% aqueous sodium bicarbonate and brine. The
organic layer was dried over MgS04, filtered,~and evaporated. ,
The residue was dissolved in glacial acetic acid and heated .
to 65C for 16 h. The solvents were evaporated and the
residue diluted with water. After neutralizing with
saturated aqueous sod~um bicarbonate, ~he solid was fil~ered
and the filter cake was washed with hexane. The ~olid was
recrystallized from ethyl acetate and hexa~e, NMR(CD30D) ~
7.48-7.11 ~H, m~, 5.06 (2~, q), 4.62 (lH, ~), 2.Z7 tlH, m),
1.23 (lH, m~, 1.02 (3H, d), 0.34 (3~, d).
b) (l'S~ amino-1'-isopropyl~ (benzimidazo-2-yl)methane ~.:
The compound of Example 4(a) (2.76 g) was stirred in
methanol. 10% palladium on activated carbon ~Pd/C) ~250 mg)
25 was added and hydr~gen gas was bubbled throu~h the solution
for l h.~ The reaction was maintained under an hydrogen
G atmosphere overnight. The mixture was filtered through ~-~
CeIite~ and the solvents evaporated to gi~e the title
compound as a whi~e solid (1.58 g, 98%). NMR~CDC13) ~ 7.48-
7.10 ~4H, m), 4 D02 (lH, d), 2.24 (lH, m~, 0.96 ~3H, d),
~ 0.83 (3H, d); ~S~(DCIiN~3~ m/e 1~0.2 ~M+H]+.
: :'
c) (2R,4S,5S,l'S)-2-phenylmethyl-4-~t-butyldimethyl)siloxy-5-
~ ~(t~butoxycarbonyl)amino-6-phenyl-N-[1'-isopropyl-1'~
: ~ 35 benzimidazo-2-y~methyl-hexanamide .~:
To a .colution of (2R,4S,5S)-2-phenylmethyl-4-(t- -
butyldimethyl)siloxy-5-(t-butoxycarbonyl)amino-6-phenyl-
hexanoic acid (75 mg, 1.1 eq) in dimethyl formamide under
: '
,'
:
WOg3/02057 PCr/US~2/U6~7
21i3~
- 39 -
argon, the compound of Example 4(b~ (25 mg, 1.0 eq), DCC
(30 mg, 1.1 eq) and HOBT (44 mg, 2.~ eq) were added. The
mixture was stirred overnight, then filtered through Celite~.
The solvents were e~aporated and the residue was ..
s chromatographed (silica gel, 4% methanol/dichloromethane) to
give the title compound ~0.070 g, 78%). NMR~CDC13~ ~ 7.88
(lH, d), 7.30 ~14H, m), 6.80 (lH, d), 4.g3 (2H, m), 4.26 (l~,
q), 4.00 (lH, m), 2.92 (7H, m), 2.01 (2H, m), 1.53 (9H, s~,
1.20 ~9H, s), 1.14 (6~, d), 0.41 (6H, d); MS(DCI/NH3) m/e
.699.6 lM+HJ+.
.~
d) t2R~4s~5s~l~s)-2-phenylmethyl-4-hydroxy-5-~t- -
butoxycarbonyl~amino-6-phenyl-N-ll'-isopropyl-1'-benzimidazo-
2-yl~methyl-hexanamide
The compound of Example 4(c) was stirred in dry THF and
tetrabutyl ammonium flouride ~0.6 mL, 6 e~) was added. The
miæture was stirred under argon overnight at room
temperature. The colution was diluted with water and
extracted with dichloromethane ~3X). The combined organic :~
20 layers were washed with water and evaporated to a residue :~
which was chromatographed (silica, 2% methanol/C~2CL2) to
give the title compound (0.029 g, 50%). NMR(CDCl3) ~ 7.54
~lH, m), 7.11 (llH, m)~ 6.69 (4H, s~, 4.98 (lH, d~, 4.69 (2H,
m), 3.66 (2H, m), 2.74 (5H, m), 2.31 (lH, m), 1.73 (2Hr m),
25 1.32 (9H~ s) ~ 0.70 (6H~ d); MS(DCI/NH3) m/e 585.4 lM+Hl~,
413.3~ ~i4.3~ 21~.2~ 190.2~ 173.1~ 120.1.
~xamnl~ 5 :
~
-- , "
~,
a~ 2-tcarbobenzyloxyamino)methyl-imidazole
3s Following the procedure of Example l(a), except
substi~uting Cbz-glycinal for Cb~-valinal, the title compound
was prepared. NMR(CDCl3) ~ .33 (5H, s), 6.95 (2~, s), 5.95
W0~3/U2057 ~ PCT/USg2/
(lH, s(br)), 5.12 ~2H, s~, 4.42 (2H, d); MS~DCI/NH3) m/e
232.2 ~M+H]+, 188, 171.
. . .
h) (2R,4S,5S,l'S)-2-phenylmethyl-4-hydroxy-5-(t-
s butoxycarbonyl)amino-6-phenyl-N (l' imidazo-2-yl) methyl-
hexanamide hydrochloride
Following the procedure of Example l~b)-l(d), except
substituting the compound of Example 5 (a) for ~l'S)-l'~
carbobenzyloxyamino~ isopropyl-1'-(imidazo 2-yl)methanei ;
the title compound was prepared. .NMR(CD30D~ ~ 7.20 (lOH~m)r
6.94 ~2H,s), 6~11 (lH,d), 4.24 (2Htdd), 3~61 ~lH,m), 3.52
(lH/m), 2.69 ~4H,m~, 1.66 (2H,m), 1.28 (9H,s); MS (~CIiNH3)
m/e 493.7 lM+H]+, 47S.7~ 120.2, 98.2, 83.1r 69.1.
15~a~
., . .~
_ ':
'
~; a) (l'S)~ carbobe~zyloxyamino~ methyl~ imidazo 2-
yl)methane :
Following the procedure of Example l(a), except
: substituting Cbz-alanal for Cbz-valinal, the title compound
~; 25 was prepared. NMR~CDCl3) ~ .35 ~5H,s), 6.92 t2H,s),
: 5.52(lH,d), 5.12 t2H~q)~ 4.90 ~lH,q); MS(DCI/NH3~ mJe 246
: ~ [M+H]+, 202, 185.: - `
b) ~2R,4S,~S,1'5)-2-phenylmethyl-4-hydroxy-S-(t- ;
butoxycarbonyl)amino-6-phenyl-N~ methyl-1'-(imidazo-2-yl)l
methyl-hex~namide hydrochloride
Following the procedure of Example l~b)-l(d~, except
substituting the compound of Example 6(a) for (l'S)~
carbobenzyloxyamino-l'-isopropyl-1'-(imidazo-2-yl)methane,
~ 35 the title compound was prepared. NMR~CD30D) ~ 7.11(lOH, m),
: 6.86 (2H, s~, 4.6g ~lH, d), 3.62 (lH, d), 3.51 (1~ 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.
. .
W0~3/02~57 2 1 ~ 3 ~ ~ ~ PcT/vs92/o6o47
- 41 - ::
~ . ,0
,. . .
Pr8~aratinn Qf (2~4S~5S,1'~!-2-~henylmethyl-4-hydrvYy-~-(t-
_~ . ...
,::
a) [l'S~-1'-carbobenzyloxyamino~ benzyl-1'-(~midazo-2-
yl)methane
10Following the procedure of Example l~a), except
substitu~ing Cbz-phenylala~inal for Cbz-valinal, the title
.......... ... .
compound was prepared. NMR(CDC13),~ 7.37-7.05 (lOH,m), 6.95
(2H, s br), 5.5~ SlH, d),.:~5,05 (2M, s), 4.95 ~lH, q), 3.32
(2H, d); MS(DCI/NH3) m/e 322, 261, 171.
b) (2R,4S,5S~l'S)-2-phenylmethyl-4-hydroxy-5-(t- ~.
bu~oxycarbonyl)amino-6-phenyl-N-(1'-benzyl~ imidazo-2-yl) )
methyl-hexanamide hydrochloride :
,
; ~ Following the procedure:of Example l(a)-l(d), excep~
substituti~g the compound of Example ~al for (l~S)ol'-
; carbobenzyloxyamin~o~ isopropyl~ timida~o-2-yl)m~tha~e,
the ~itle compound was prepared. NMR(CD30D) ~ 7.15 (lSH, m), ~;
6.79 (2H~ s) ~ 5.78: (lH~ d) ~ 5.04 (lH~ d) ~ 3.58 (l~r m), 3047
(lH~ m~, 2.68 (8H, m), 1.59 (2H, m), 1.31 IgH, s).
hvdroxy-N~11~ imidazol-2-yllmethyl~ h$~yl-2-.
~e:o~oo~L=~:L~r~lbe
, ''
A solution of (2R,4S,5S,l'S~-5-~t-butoxycarbonyl)amino-
4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-
phenylmethyl-hexanamide (0.086 g) in trifluoroacetic acid was
stirred for 10 min,~then was evaporated in vacuo. To the
residue were added dimethylformam-ide, benzylchloroformate (1
eq) and triethylamine (5 eq), and the resulting mixture was
~: :stirred at room temperature for 16 h. The reaction mixture
:
W~93/02~7 PCT/US92/06047 ..
, 3~ ~2
was poured into H20 and extracted with dichloromethane. The
combined organic extracts were evaporated, and the residue
was triturated with diethyl ether to afford the title
c~mpou~d as a white so~id. ~MR(CD30D) ~ 7.36-6.94 (15H, m),
6.84 (2H, s), 4.99 (2H, s~, 4.5~ ~2H, d), 3.76 (lH, m), 3.52
~lH, dd), 2.77 15H, m), 2.04 (lH, m), 1.76 ~lH, m), 1.58 (lH9
m), 0.82 (3H, d), 0.66 (3H,.d).
~2 - ':
P~e~ara~ion of_~2B~4S,5S~l'S~-5-(t-butoxy~Lbonyll~mino-4-
'.':
a) (lS)-1-carbobenzyloxyamino-1-isopropyl 1- (4 r 5~
dimethylimidazol-2-yl~methane
Cbz-Valinal (4.14:g) was stirred in m~tha~ol with 2,3-
butan~dione ~1.54 mL, 1.0 eq). Ammonia was bubbled ~hrough ;:~
the solution at -25~ ~or 5 min. The cooling bath was
20 r~moved and the mixture allowed to wanm to 20C. The ~:
solution was stirred for 16 h under Ar. The solvents were
removed by rotary evaporation, and the resi~ue was diluted
with dichloromethane and:extracted with dilute aqueous HCl.
The or~anic layer was concentrated to`afford unreacted Cbz-
valinal (4.02 g:~. The acidic aqueous layer was basified with
~; lN NaOH and extracted with di~hloromethane, the organic
extract was concentrated and the residue purified by flash
chromatography (4% methanol in dichlorometha~e) to pro~ide
the title compound as a white solid (SO mg). NMR(CD30D) ~
7.29 ~5H, m), 5.04 ~2H, dd), 4.38 (lH, d), 2.0~ (~H, s), 2.01
(lH~ mj, 0.93 (3H, d), 0.77 (3H, d~.
b) (lS)-1-(4,5-dimethylimidazol-2-yl~-2-methylpropylamine
~ The benzyloxycarbonyl group was cleaved by -
: 35 hydrogenolysis using the same procedure as described
- previously in EXample l(b) , except using the product of l~a) ~-
~ (50 mg), to afford the title compound as a white solid
. .
W093/~2~57 PCT/US92/&6047
2 :~ ~ 3 ~
(24 mg, 87%1. NMRtcDcl3) ~ 4.11 (2H, s(br~l, 3.71 ~lH, d),
2.06 (6H, s), 2.00 (1~, m), 0.71 (6H, dd).
c) (2R,4S,5$,1'S)-5-(t-butoxycarbonyl~amino-4-t-
butyldimethylsiloxy-N-[l'-isopropyl-1'-(4,5-dimethyl)
imidazol-2-yl3methyl-6-phenyl-2-phenylmethyl-hexanamide
Using the procedure of Example l(c), except substitu~ing
(2R,4S~5S)-5-(t-butoxycarbonyl)amino-4-t-butyldlmethylsiloxy~
6-ph~nyl-2-phenylmethylhexanolc acid and (lS)-1-~4,5-
dimethylimidazol-2 yl)-2-méthylpropylamine (24 mg), ~he title
compound was prepare~ (55 mg, 57%). NMR~CDC13) ~ 7.26-6.80
(lOH, m~, 4.65 (lH, d), 4.24`~1~, dd), 3.87 ~lH, q), 3.61
(lH, m), 2.77-2.39 ~5H, m)r 2.22 (lH, m~, 1.98 ~6H, s), 1.79
(lH, m), 1.58 tlH, m), 1.24 (9H, s), 0.85 (9H, s), 0.69 ~6H,
d), 0.06 (6H, d).
.
d~ t2~,45,5S,l's)-5-~t-butOxyc~rbonyl)amino-4-hydroxy-N~
i~opropyl 1~-(4rs-dimethyl~imidazol-2-yl~methy~-6-phenyl-2
phenyl~ethyl-hexanamide
: 20 By following the deprotection procedure described in .:
Example l~d)~ except using (2R,4S,5Sol'S)-5-(t-
butoxycarbonyI)amino-4-t-butyldimethylsiloxy-N-~l'-isopropyl-
(4,5-dimethyl~imidazol-2-yl]methyl-6-phenyl-~-
~: phenylmethyl-hexanamide (55 mg) and omitting the final
~reatment with methanolic HCl, the title compound was
: preparPd 525 mg,~ 62%). NMR(CDC13) ~ 7.29-6.B8 (lOH, m) 9 4.98
, br d), 4.47 (lHr m), 4.29 (1~, m), 3.58 t2H, m), 2.84
2.51 (SH, m~, 2;20 ~lH, m), 2.04 (6H, s), 1.71 ~2H, m), 1.38
~9H, s), 0.69 (6H, dd).
y~U~ hy~==~beDvl ? ~l~8D~ 4~:~ eibe
a~ (lS)-1-carbobenzyloxyamino-1-isopropyl-1-(4- `
phenylimidazol~2-yl)methane
W093/02057 ~ P~T/U~92/~ ~7
44 -
Using the procedure of Example l(a~ r except using Cbz-
~L)-valine (2.19 g) and a-ketophenylacetaldehyde instead of
glyoxal; the title compound was prepared (1.54 g, 48%).
NMR(C~Cl3) ~ 7.62 (lH, (br)), 7.24 (lOH, m~, 5.79 (lH, d3,
5.04 (2H, dd), 4.32 (lH, dd), 2.31 ~lH, m), 0.96 (3H, d),
0.79 (3H, d); MS m/e 350.4 lM~H]+, 199Ø
..
b~ (2R/4S,5S,l'S)-5-(t-butoxycarbonyl)amino-4-t-
butyldime~hylsiloxy N-~l'-isopropyl-1'-(4-phenyl)imidazol-2-
yl~methyl-6-phenyl-2-phenylmethyl-hexanamide
Using the proceduxe of Example l(b)-l(c), except using :.
the compound of lO(a) (72 mg), the title compound was
prepared ~67 mg, 44%). NMR(CDC13) ~ 7.70.~lH, d), 7.40-6.71
(16H, m), 4.73 (lH, d), 4.54 (lH, dd), 3.96 (1~, q~, 3.69 :~
(lH, m), 2.88-2.36 ~5H, m), 1.73 (2H, m), 1.33 (9H, s), 0.91
(9H, s), 0~84 (6~, dd), 0.11 (6H, d~; ~S m/e 725.4 [~fH~+~ ;
,
c) (2R~ 4S, 5S, 1'S~-5-(t-butoxycar~onyl)amino-4-hydroxy-N-
tl'-isopropyl~ (4-phenyl)im~dazol-2-yl~methyl-6-phenyl-2 ::
20 phenyl~ethyl-hexanamide .
Using the procedure of Example 9(d~, except startin~ ::
from (2R,4S,5S,llS)-5-(t-butoxycarbonyl)amino-4-t
butyldimethylsiloxy-N-ll'-isopropyl-lY-(4-phenyl)imidazol-2- -:
yl~methyl-6-phenyl-2-phenylmethyl-hexa~amide (67 mg), the ~:
title compound was prepared ~30 mg, 54%3. NMR~CDC13) ~ 7.52- ~.
6~67 ~16H, m), 5.48 (lH, d), 3.60 (lH, q), 3~44 (1~ d), 2.60 .
(4H, m), 1.96 (lH~ 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.
~ .
~8am~1~_11
... .
hy~xoxy-N- r.l ~-i sopro~y~ -(N~--mç~hylLimidazQl--2~-yl lm~
phenyl-2-phenylm~t yl-}lexanami de
:
~.
.
W093/0~7 2113~ PCTJUSg2/06047
- 45 -
a) (lS)-carbobenzyloxyamino-1-isopropyl-1-(N'-methylimidazol-
2-yl)methane
The product of Example l(a) (273 mg, 1 mmol) was heated
at 40C for 2 h in methyl iodide (5 mL~. The reac~ion
mixture was evaporated, and the residue was suspended in
aqueous Na2C03. The mixture was extracted with
dichloromethane, dried (Na2C03) and concentrated. The crude
product was purified by flash chromatography ~silica, 2%
methanol/dichloromethane) to yield the title compound (200
0 mg, 70%). NMRtCDC13) ~ 7.29 t5H, ~), 6.g2 ~lH, s), 6~69 (lH,
s), 5.94 (lH, d), 5.03 ~2H, q~, 4.55 (lH, dd), 3.64 (3H, s),
2.20 (lH, m), 1.01 (3H, d), 0.82 t3H, d). :~
b) (2R,4S,5S,l'S)-5-(t-butoxycarbonyl)amino-4-t-
15 butyldimethylsiloxy-N-~l'-isopropyl-l t_ (N'-methyl)imidazol-2- :
yl]methyl-6-phenyl-2-phenylmethylohexanamide
Following the~procedure o~ ~xample l~b)-l~c~, except
using the compouDd of ll(a) t90 mg), the ti~le compound was
; prepared (104~mg, 50%~. NMR~CDC13) ~7.32-6.89 ~10~, m),
: ~0 6.81 (l~,~s]~ 6~.59 (lH, s)~ 6.08 (lH, d), 4.71 t2Hr m), 3.94
~`~ (lH, q~, 3.70~tlH, m), 3.25 (3H, s~, 2.80-2.36 (5H, m), 2.21
, m), 1.73 (2H, m~, 1.31 (9H, s~, 0.94 (9H, s~, 0.85 (6H,
dd),~0.11 (6H~ s3.
c) ~2R,4S,5S,l'S)-5-~t-butoxycarbonyl)amino-4-hydroxy-N-[l'-
isopropyl~ (N'-methyl)~midazol-2-yl]methyl-6-phenyl-2-
phenylmethyl-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-1'-~N'-methyl)imidazol-2-
yl]methyl-6-phenyl-2-phenylmethyl-hexanamide (100 mg), the
title compound~was prepared (79 mg, 89%~. NMR(CDC13) ~ 7.21-
Ç.74 ~llHr ~), 6.70 (lHr s), 6.59 ~lHr s)~ 4.95 (lH, d), 4.61
~lH~ dd) r ~ 3. 60 (3H~ m), 3.43 (3H, s), 2.71 (5~, m), 2.06 tlH,
~:
: ~ 35 m)l 1.64 ~2H, m~, 1.32 t9H, s), 0.82 ~3H~ d)~ 0.63 (3Hr d);
MS m/e 549.3 lM+H]~.
. .
:: ~
W093/~2057 P~T/U592/06~7
~r 4 6
I ~ Exam~18_12
Pr~pa~ation of (2R,~ l'Sl-5-~t-bu~oxycarbonyl~mino-~-
;.
(3-~henyl~rQ~a~yl)hexanami~e
a~ (3R,SS,l'S)-tl'--t-butoxycarb~nylamino-2'-phenyl)ethyl-3-
~3-phenylpropargyl)-tetrahydrofuran-2-one
To a solution of lithium diisopropylamide ~3.61 mL,
0 2.0 ~ in THF, 2.2 eq) in THF at -78C under an argon
atmosphere, (5S, 1 ' S) - ~1 ' -t-butoxycarbonylamino-2 '- :
phenyl)ethyl-tetrahydrofuran-2-one (1.0 g, loO eq) was added.
After stirri~g at -78~C for 15 mi~, hexamethylphosphoramide
~1.lg mL, 2 eq) was added, and stirring was continued an
additional 10 min. Pheny~propargyl bromide 51.28 g~ 2.0 eq~,
was added a~d the resulting ~ix~ure was s~irred at -78C for
2 h, then poured into dil~te aqueous HCl and extrac~ed with
dichl~romethane. Th~ c~mbined or~anic extracts were :~
evaporated under reduced pressure to an oil, which w~s
chromatographed~silica, 20~ ethyl acetate/hexanes) to afford
the title compou~d as a: white solid (0.455 g, 33%).
NM~(CDCl3) ~ ?.18 (lO~, m), 4.50 (2H, m), 3.93 (lH, q3, 2.79
(5H, m), 2.23 (2H~ m~, 1.24 (9H, s). ~;
~5 b~ (2R,4S,5S)-5-~t-butoxycarbonyl)amino-4-t-butyldimethyl-
siloxy-6~phenyl-2-~3-phenylpropargyl~hexanoic acid ~:
The title compound (496 mg, 84%) was prepared ~y the
procedure of Evans et al., J~ Org. C~em. 50, 4615 ~}985~ from
the product of 12(a) (450 mg). NMR(CDC13~ ~ 7.49-7.10 (lOH,
m~, 4.71 (lH, 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,l'S)-5-~t-butoxycarbonyl)amino-4-t-
butyldimethylsil~xy-N-(l'-isopropyl-1'-imidazol-2-yl~methyl~
6-phenyl-2-(3-phenylpropargyl)hexanamide
Fo~lowing the procedure of Example l(c~, except using
(2R,4S,5S)-5-~t-butoxycarbonyl)amino-4-t-butyldimethylsiloxy-
6-phenyl-2-(3-phenylpropargyl)hexanoic acid (240 mg) and
W093/~7 PCr/U~92~ 7
_ 2~1 3 ~
(lS)-1-imidazol 2-yl-2~methylpropylamine, the title compound
was prepared (244 mg, 84%). NMR~DC13) ~ 7.14 (12H, m), 6.72
(lH, d), 4.58 (1~, d~, 4.49 (lH, dd), 3.92.(lH, q), 3.80 ~lH,
m~, 2.54 (SH, m), 1.65 (2H, m), 1.20 (9H, s), 0.81 ~9Hr s),
0.80 (6H, dd), 0.05 (6H, d).
, .
d) (2R,4S,SS,l'S)-5-~t-butoxycarbonyl)ami~o-4-hydroxy-N-(1'-
isopropyl~ imidazol-2-yl~methyl-6-phenyl-2-(3-
phenylpropargyl)hexanamide
Followi~g~the procedure of Example 9(d), except using
(2R,4S,5S,l'S)-5-tt-butoxycarbonyl)amino-4-t-
butyldimethylsiloxy-N-(1'-isopropyl-1'-imidazol-2 yl)methyl-
6-phenyl~2-~3-phenylpropargyl)hexanamide, the title compound
was pxepared (161 ~g, 7g%). NMR(CDC13) ~ 7.24-6.98 (lOH, m),
6.68 (2H, s), 5.20 ~1~, m), 4.52 ~lH, d), 3.49 ~2H, m), 3.06
(1~, m)~ 2.56 (5H, m), 2.04 (lH~ m)~ 1.61 ~2H, m3~ 1.26 (9H,
s), 0.68 (6H~ dd); MS m/e 581.2 (~Na)~, 559.2 ~M~H~+t 5~1.4,
503.2, 485.2, 459.2, 441.2.
E~am~lg 1
:
2S
: a) ~ 2R ~ 4S r 5S r 1 ~ S) -5-amino-4-t-butyldimethylsiloxy-N~
isopropyl~ imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-
hexanamide
The product of Example l~c) (0.20 g, 0.31 mmol~ was
dissolved in trifluoroacetic acid and stirred at room
temperat~re for 5 min, and partitioned between
dichloromethane and saturated aqueous Na2CO3. The organic
extract was dxied over Na2CO3, filtered and evaporated to
afford the title compound (0.17 g, 100~) which was used
without further purification.
~' ' .~.
; b) (2R,4S,5S,l'S)-5-~isopropoxycarbonyl)amino-4-t-
~: butyldimethylsiloxy-N-[l'-isopropyl-1'-(N'-
W093/02~7 PCTJUS92/~7
~ q8 -
isopropoxycarbonyl)imidazol-2-yl]methyl-6-phenyl-2-
phenylmethyl-hexanamide
A mixture containing the compound of 13(a) (0.17 g, 0.31
mmol), isopropyl chloroformate (0.62 mL, lM in
s dichloromethane, 2 eq) and 4-dimethylaminopyridine (0.75 g, 2
eq) in dichloromethane (40 mL) was allowed to stir at room
temperature overniqht under an argon atmosphere. The mixture
was then partitioned between dichloromethane and saturated
aqueous Na2C03, and the organic extract was dried over Na2C03.
The 801vent was removed in vacuo, and the residue was
purified by 1ash chromatography ~s~lica, 4~
methanol/dichloromethane) to afford the t~tle compound ~0.214
g, 96%). NMR(CDC13) ~ 7.3S-6.78 (12H, m), 6.57 ~lH, d), 5.61
~lH, dd), S.19 ~1~J m), 9.86 ~lH, m~, 4.77 ~lH, d), 3.97 ~lH,
lS q), 3.63 ~lH, t), 2.88 ~lH, dd), 2.70-2.48 ~4H, m), 2.06 (lH,
m), 2.00-1.85 ~lH, m), 1.79-1.64 (lH, m), 1.45 ~6H, dd), 0.94
(9H, s), 0.85 (6H, d), 0.12 (6H, d).
c) (2R,4S,SS,l'S)-5-~isopropoxyca~bonyl)am~no-~-hydroxy-N-
~ 80propyl~ im~da~ol-2-yl)methyl-6-phenyl-2-
phenylmethyl-~lexanam$de
To a solution o~ the compound o~ 13 (b) ~0 .214 g) in
methanol, exc~ qu~ou~ ~Cl ~~ S ~q) wa~ ~dded. The
resulting solut~on wa-~ 3110wed to ~t~r at room temperature
ov~rnight, and was concentrated under reduced pres8ure. The
residue was diluted with H20, and bas~fied w~th aqueous
Na2C03. The mixtu~e was extracted with dichloromethane, and
the combined organic extracts were dried over Na2C03. The
solvent was removed in ~acuo, and the residue was purified by
flash chromatography (silica, 4~ methanol/dichloromethane) to
afford the title compound (O.lS0 g, 97%) . NMR (CDCl3) ~ 7 . 32-
6.96 (13H, m), 5.48 (lH, d), 5.08 (lH, m), S.00 (lH, s~br)),
4.87 (lH, m), 3 .78 (lH, m), 3 . 62 (lH, m), 3.25 (lH, m), 2 . 96-
2.67 (4H, m), 2 .29 (lH, m), 1. 95-1. 65 ~2H, m), 1.25-1.12 (6H,
~5 dd), 0.80-0. 60 (6H, dd); MS m/e 521 [M~H]+, 519 ~M-H)-.
WO93102~57 PCI/U~392/~6047
', _ 49_ 21~3B~
d ) (2R, 4S, 5S, 1 ' S) -5- ~ isopropoxycarbonyl ) amino-4-hydroxy-N~
(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-
phenylmethyl-hexanamide hydrochloride
The product of 13(c) (100 mg, 0.192 mmol) was dissolved
in methanol (10 m~) and a lM solution of HCl in ether (0.192
mL) was added. The solution was concentrated by rotary
evaporation without heating, and the residue was trituated
with ethex and dried under vacuum to afford the title
;. compound (104 mg, 98%). NMR(CD30D) ~ 7.30 (2H, s), 7.21-
6.88(10H, m), 9.61 (2H, m), 3.65 (lH, m), 3.48 (lH, d)t 2.9
(lH, m), 2.87 (1~, m), 2.74-2.5& t2H, m), 2.12 (lH, m), 1.75-
1.50 (2H, m), 1.17-1.00 (6H,;dd), 0.90 (3H, d), 0.64(3H, d).
a) benzyloxyethyl-~4-nitro)phenylcarbonate
To a solutio~ 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. ~he reaction mixture was washed
successively with ~2 and saturated aqueous ~aCl and dried
over Na2SO4. 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~CDC13) ~ 8.26 (2H, m)~ 7.34 (7H, m), 4.62 (2H, s),
4.49 (2H, t), 3.70 (2H, t).
bj (2R,4S,5S,l'S)-5-(benzyloxyethoxycarbonyl)amino-4-t-
~ butyldimethylsiloxy-N-ll'-isopropyl~ N'-benzyloxyethoxy-
: 35 carbonyl)imidazol-2-yl]methyl-6-phenyl-2-phenylmethyl-
hexan~mide
To a solution of the compound of Example 14~a) (134.5 :.
~: mg, 0.24 mmol) in dichloromethane (40 mL) under an argon ~-
~,,
w~93~02o57 PCT/US~2/~6~47
~ 3~* - 50 -
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 a~ room temperature
overnight, and was diluted with dichloromethane. The organic
s extract was washed successively with aqueous Na2C03, H20,
aqueous Na2C03 and H20, and dried over Na~C03. 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(CDC13) ~ 7.45-
6.80 ~22H, m), 6.62 (lH, d), 5.60 ~lH, t)r 5.06 ~lX, d), 9.60(2H, s), 4.52 (2H, s), 4.50 (2H, m), 4.31 ~1~, m), 4.07 ~2H,
m), 3.80 (2H, t), 3.68 ~lH, q), 3.~7 (lH, q)~ 2.85 (lH~ m),
2.77-2.41 ~4H, m~, 2.09 (lH, m), l.~O ~lH, m), 1.73 ~lH, m),
0.95 ~9H, s), 0.81 (6Ht dd), 0.11 (6H, d).
c) ~2R,4S,55,1'S)-5-(benzyloxyethoxycarbonyl)amino-4-hydroxy-
N~ isopropyl-1'-imida~ol-2-yl)methyl-6-phenyl 2-
phenylmethyl-hexanamide
Following the ~rocedure of Example 13(c) r exeept using
the compound of Example 14~b) (160 mg), ~he title compoun~
was prepared ~100 mg, 81%). NMR(CDC13, CD30D) ~ 7.40-6.79
(17H, m), 4.55 S2H, s), 4.45 (lHt d), 4.20 ~2H, m), 3.80-3.45
~SH, m), 2.95-2.66 (4H~ m~, 2.5~ (lH, dd), 2.07 (1~, m), 1.71
(2H, m~, 0.80 ~3H, d~, 0.68 (3H, d).
. . .
a) (2R,4S,5S~l'S~-5-(methoxyc~rbonyl)amino 4-t-
butyldimethylsiloxy-N~ isopropyl-1'-(N'-
: methoxycarbonyl)imidazol-2-yl~methyl-6-phenyl 2-phenylmethyl-
hexanamide
Following the procedure of Example 13~b), except using
(2R,4S,5S,l'S)-S-amino-4-t-buty}dimethylsiloxy-N-~l'-
sopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-
W093/020S7 P~T/US92/06047
- 51 _ 21~3`~i
hexanamide, the title compound was prepared (89%).
NMR(CDC13) ~ 7.40-5.79 (12H, m), 6.52 (lH, d3, 5.58 (l~I, dd),
4.91 (lH, d~, 3.96 ~3H, s), 3.95 ~lH, d), 3.66 (lH,-t), 3.60
(3H, s), 2.85 (lH, m), 2.73-2.40 (4H, m), 2.08 ~lH, m), 1.90
(lH, m), 1.69 (lH, m), 0.95 (9~, s), 0.85 ~6H, dd), 0.14 (6H,
d).
b) t2R~qs~5s~l~s)-5-~methoxycarbonyl)amino-4~hydroxy-N
isopropyl-1'-imidazol-2-yl)methyl-6 phenyl-2-phenylmeth
lo hexanamide
Following ~he procedure of Example 13(c), except using
the compound of Example 15(a), ~he title compound was
prepared (70%). NMR(CDC13, CD3O~) ~ 7.23-6.60 (12H, m), 4.38
~lH, d), 3.65 (lH, t), 3.54 (3H, s), 3.33 ~lH, m)~ 2.g5 (lH,
m), 2.32-2~40 (4H, ~), 1.95 (1~, m), 1.64 ~2H, m), 0.69 t6H,
dd).
0
a) ~2R,4S,5S,1'S~-5-~(ethoxycaxbonyl~amino-4-t-
butyldimethylsiloxy-N-[l'-isopropyl~
: ethoxycarbonyl~imidazol-2-yl~methyl-6-phenyl-2-phenylmethyl-
hexanamide ~ ~:
Following~the procedure of Example 13~b~, except usin~
(2R,4S,5S,l'S)-5-amino-4-t-butyldimethylsiloxy-N~
isopropyl-1'-imidazol-2-yl~methyl-6-phenyl-2-phenylme~hyl-
hexàna~idé and ethylchloroformate, the title compound was
, .
:~ : prepared (90%). NMR(CDC13) ~ 7.35-6.77 (12H, m~, 6.55 (lH,
d), 5.60 (lH, dd), 9.B6 (lH, d), 4.41 (2H, m)~ 4.15-3.90 ~3H,
m), 3.66 (lH, t), 2.87 (lH, m), 2.75-2.45 (4H, m), 2.08 (lH,
3s m~, 1.92 (lH, m), 1.70 (lH, m), 1.45 (3H, t), 1.18 (3H, t),
,
0.98 ~9H, s), 0.85 (6H, dd), 0.13 (6H, d).
:
: ::
W093/'0205~ PCr/U~g2/~6~7
b~ (2R,4S,SS,l'S)-5-(ethoxycarbonyl)amino-q-hydroxy-N-(1'-
isopropyl l'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-
hexanamide
Following the procedure of Example 13(c), except using
the compound of Example 16(a), the title compound was
prepared ~95%). NMR(CDCl3, CD30D) ~ 7.25-6.75 ~12H, m), 4~43
(lH, d), 3.95 ~2H, q~, 3.61 (1~, q), 3.40 (lH, m), 2.85~(1H,
m), 2.80-2.40 ~4H, m), 2.05 (lH, m), 1.61 (2H, t), l.11 (3H,
t), 0~72 (3H, d), 0.55 (3H, t).
Ex~mple 17
15 ~
a) (3R,5S,l'S)~ t~butoxy arbonylamino-2'-phenyl~ethyl-3- :
(3-phenylprop-2-enyl~-tetrahydrofuran-2-one
Following the procedure of Example 12(a~, except using
: 20 cinnamyl bromide (0.485 mL~ as the alkylating agent~ the
title compound was prepared ~O.S1 g, 75%). N~R~CDC13) ~
7.35-7.10 (lOH, m), 6.43 (lH, d), 6.09 (lH, m), 4.60 (lH, m),
4.48 (lH, q), 4.00 ~lH, t (br)~, 2.96-2.55 (4H, m~, 2.53-2.21
~2~, mj, 2.05 (lH, m), 1.35 S9H, s).
.
b~ ~2R,4S,SS)-5~ batoxycarbonyl)amino-4-t-butyldimethyl-
, siloxy-6-phenyl-2-~3-phenyl-2-propenyl)hexanoic acid
: ~ ~ Following the procedure of Example 12(b), except using
the ompound of Exam~le 17(a), the title compound was
prepared (77%). NMR(CDCl3) ~ 7.40-7~05 (lOH, m~, 6.48-6.00
; ` ; .,
~4H, m)', 4~78 ~lH, d), 3.94 ~lH, q~, 3.80 (lH, m), 2.B9 ~lH,
m)~ 2.83-2.26 (4H, m~, 1.90 (lH, m), 1.59 ~lH, m), 1.28 (9H,
s), 0.90 ~9H, s), 0.08 (6H, d).
!
..
W093/02057 P~T/U~g2~ 7
i _ 53 _ 21i~
c~ (2R,4S,5S,l'S)-5-(t-butoxycarbonyl)amino-4-t-
butyldimethylsiloxy-N~(l'-isopropyl-1'-imidazol-2-yl)methyl-
6-phenyl-2-~3-phenyl-2-propenyl~hexanamide
FO11QWing the procedure of Example l~c), except using
the compound of 17tb), the title compound was prepared (82%).
NMR(CDC13) ~ 7.35-7.15 (lOH, m), 7.14-6.85 (2H, m)~ 6.73 (lH,
s), 6.20 llH, d), 6.10-5.88 ~lH, m), 4.78 (lH, d), 4.65 (lH,
t), 3.97 tlH, q), 3.76 (lH, m), 2.77 (2H, d), 2.50-2.25 (2H,
m), 2.12 (lH, m), 1.70 (lH, m), 1.63 (lH, m), 1.36 (9H, 5),
0.92 (9H, s), 0.81 (6H, d), 0.09 (6H, d).
d) ~2R,4S,SS,lqS)-5-tt-butox~carbonyl)amino-4-hydroxy-N~
isopropyl-1'-imidazol-2-yl)methyl-6-phenyl--2-(3--phenyl-2-
prope~yl)hexanamide
Following the procedure of Exa~ple 9~d), except using
the compound of 17(c), the title compound was prepared t90%).
N~R(CDC13, C~30D) ~ 7.30-7.00 (lOH, ~), 6.71 ~2H, s), 6.26
(lH, d), 6.41 ~lH, m), 3.56 (lH, d), 3.50 (lH, d), 2~88~2045
(4H, m~, 2.36 Sl~, m), 2.23 ~lH, m), 2.06 (lH, m), 1.70 (2~r
: 20 m~ 1.34 ~9H, s), 0.88 t3H, d), 0.74 (3~, d).
~ M5 m/e 561 lM+H]~.
: :
:~ ~ hy~r~xy-N- r 1'-i~2pro
~: a) ~lS)-N~ (imidazol-2-yl)-2-methyl)propylacetamide
To a so~ution o~ the comp~und of Example l~b) (175 mg~
in dichloromethane (lQ mL) at 0C was added diisopropyl-
: e~hylamine (355 mg, 2.75 mmol) followed by acetyl chloride
(215 mg, 2.75 mmol). The resulting mixture was stirred
overnight, washed with saturated aqueous Na~C03, and
; 35 concentrated. The residue was treated with methanol, stirred
overnight and cvncentrated under reduced pre sure to afford
the title compound (181 mg, 78%) as a white solid.
NMRtCD30D) ~ 6.95 (2H, s), 4.72 (lH, d, J=6 Hz), 2.35-2.10
W093/~2~7 ~ P~T/US92/06~7
~ ~ - 54 -
(lH, m), 1.98 (3H, s), 0.98 (3H, d, J=5, 3 Hz), 0.82 (3H, d,
J=5 Hz~.
b) (lS)-N ~1-(4~nltroimidazol-2-yl)-2-methyl)propylacetamide
s The compound of Example 18(a) (290 mg, 1.60 mmol) w s
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 ~o 40C 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 t6x), and the
rombined organic extracts were dried over MgS04 and
concentrated under reduced pressure to afford the title
compound (153 mg, 42%). NMR(CD30D) ~ 7.98 ~lH, s), 4.70 ~lH,
d, J=6 Hz), 2.35-2.15 (lH, m), 1.98 (3Ht s), 0.95 ~3H, d, J=5
Hz), ~.B5 (3H, d, J=5 Hz); MS m/e 475.2 t2M~Na)+~ 249.2
~Na)+, 2~7.2 1~+~1+, 185.2, 168Ø
c) ~lS)~ 4:-nitroimida~ol-2-yl)-2-methylpropylamine,
: 20 dihydrochloride salt
A mixture of the compound of Example 18(b) (153 mg, 0.68
: mmol) in 6N HCl t2 mL) was heated at 90C for 12 h, cooled
and concentrated under reduced pressure. The title compound
was obtained ~138 mg, 80%) and used without fur~her
: 2s purification, NMR(CD3OD) ~ 8.12 (lH, s~, 4.30 ~lH, d, J=4
Hz), 2.:45-2.30 llH, m), 1.12 (3H, d, J=4 Hz), Q.90 (3Ht d,
J=4 Hz).
d) ~2R,4S,5S,l'S)-5-(tobutoxycarbonyl~amino-4-t-
butyldimethylsiloxy-N-[1'-isopropyl~ (4-nitroimidazol-2-
yl)]methyl-6-phenyl-2-phenylmethyl~hexanamide
: Following the procedure of Example l(c), except using
(2R,4S~5S)-5-(t-butoxycarbonyl)amino-4-t-butyldimethylsiloxy-
6-phenyl-2-phenylmethylhexanoic acid and (lS)-1-(4-
35 : nitroimidazol-2 yl)-2-methylpropylamine, the title compound
was prepared. NMR(CDC13) ~ 7.30-6.90 ~10 H, m), 6.60 (lH, d,
J=4 Hz), 4.70 ~lH, d, J=5 Hz), 4.40 (lH, t, J=4 Hz), 3.90
~lH, q, J=4 Hz), 3.75 ~lH, dd, J=8, 3 Hzj, 2.75-2.30 (~H, m),
.
W093/02~7 PCT/U~92/~7
~1~3~
- 55 -
1.80-1.50 (2H, m), 1.25 t9H, s), 0.85 (9H, S), 0.~0 (6~l m),
0.05 (6H, d, J=4 Hz).
e) ~2R,4S,5S,l'S)~5-~t-butoxycarbonyl)amino-4-hydroxy-N~
isopropyl-1l_(4-nitroimidazol-2-yl~methyl-6-phenyl-2-
phenylmethyl-hexanamide
Following the deprotection procedure of Example l(d~,
except using the compound of Example 18(d), the title
compound was prepared. NMR(CD30D) ~ 7.90 (lH, s), 7.40-6.90
(lOH, m), 4.53 (lH, d, J=6 Hz), 3.70 (lH, m) r 3.50 (lH~ mt r
2090-2.~0 t5H, m), 2.00 (lH, m), 1.90-1.55 (2H, m), 1~49 (9H,
s), 0~85 (3H, d, J=4 Hæ), 0.70 (d, 3H, J-4 Hz); ~S m/e 602.4
(M+Na)+, 580.4 EM~H~, 524.4, 480~4.
:
~eb
a) ~lS?-l-carbobenzyloxyamino-1-ethyl-1-(imidaz~1-2-
yl)methane
Following the procedure of ~xample l(a~, except using
:: Cbz-(L)-~ ethylglycinal in place of valinal, the title
compound was prepared. NMR(CDC13) ~ 7.45-7.10 (5~, m), 6.90
t2H, s), 5.65 ~lH, d, J=6 Hz), 5.10-4.95 (2H, m), 4.40 (lH,
: ~ q, J=5 Hz), 2.00-1.70 (2H, m), 1.00-0~80 ~3H, m).
~: :
b~ (lS~ imidazol-2-yl~propylamine
Following the procedure of Example l(b), except using
~he co~pound of Example l9(a), the title compound was
prepared. NMR(CDC13) ~ 6.90 (2H, s), 5.00-4.50 (2H, br s),
~ 4.00 (lH, t, J=5 Hz), 2.00-1.70 ~2H, m), 1.00-0.80 (3H~ m).
:
W0~3/02~7 PCT/VS9~/06~47
~ 56 ~
c) (2R,4S,5S,l'S)-5-(t-butoxycarbonyl)amino-4-t-
butyldimethylsiloxy-N-[l'-ethyl~ imidazol-2-yl]methyl-6-
phenyl-2-phenylmethyl-hexanamide
Following the procedure of Example l(c), except using
s (2R,4S,5S3-5~(t-butoxycarb~nyl)amino-4-t-butyldimet~ylsiloxy-
6-phenyl-2-phenylmethylhexanoic acid and the compound of
Example l9(c), the title compound was prepared. NMR~CDC13) ~
7.35-6.90 (lOH, m), 6.78 (2~, s), 6.20 (d, J=5 H~), 4~80-4.65
(2~, m), 4.05 (lH~ q, J=5 Hz), 3.72 (lH, dd, J=l~t 3 Hz),
2.90-2.50 ~5H, m), 2~10-2.05 (lH, m), 1.90-1.65 (3H, m), 1.40
~9Hf s), 0.95 (9~, s) ~ 0.90-0.85 (3H, m), O.SO (6H, s)O
d) (2R,4S,55,1'S)-5-(t-butoxycarbonyl)amino-q~hydroxy-N-
ethyl-l' imidazol-2-yllmethyl-Ç-phenyl 2-phenylmethyl-
hexana~ide
Following the procedure of Example 9~d~, except usingthe compound of:Examp}e l9(c), the title compound was
prepared. NMR(CD30D)~ 7.40-7.00 (l~H, m~, 6.85 (2H, s),
3.60 3.50 t2H, m), 2.95-2.60 (5H~ m), 1.95 1.52 S4H, m),
1.4~-1.26 (9~, m), 0.8-0~9 ~3H, m).
MS mje 521.2 tM+Hl~; 503.4, 447.4.
xa~pl e ~D
: Following the procedure of Example l9~a)-l9(d), except
substituting Cbz-(L)-a-propylglycinal for Cbz-(L)-a-
ethylglyclnal, the title compound was prepared. Da~a for the
: intermediates of this synthesis were:
~: :
W0~3/~Q057 ~ P~T/US92/~7
- 57 -
a) (~S)-1-carbobenzyloxyamino-1-propyl 1-~imidazol-2-
yl)methane. NMR(CDC13) ~ 7.40-7.10 (lOH, m), 6.65 (2Ht S) r
5.55 (lH, d, Jz6 Hz), 5.10-4.90 ~2H, m), 4.65 (lHr ~ J=5
Hz)r 2.05-1.93 (lH, m), 1.90-1.75 ~lH, m), 1.45-1.20 (4H, m),
0.95-0.85 t3H, m).
b) (lS)-l-(imidazol-2-yl)butylamine. NMRtCDCl3) ~ 6~90 (2H,
5) ~ 5.10~4.40 (2H, s(br)), ~.05 (lH, t, J=5 Hz), 1.90-1.55
(2H, m), 1.45-1.20 t4H, m), 0.95-0.80 (3H, m).
c) 52R,4S,5S,l'S)-5-(t-butoxycarbonyl~amino-4-t-
butyldimethylsiloxy-N-~1'-propyl-1'-imidazol-2-yl]methyl-6-
phenyl-2 phenylmethyl hexanamide. NMR(CDCl3~ ~ 7.35-7.00
(lOH, m), 6.78 (2H, s), 6.22 (lH, d, J=5 Hz), 4.85-4.68 ~2H,
m), 4.00 tlH, q, J=3 ~z), 3.75 (lH, dd, J=10~ 3 Hz), 2.80-
2~50 (SH, m~, 2.12-1.95 (lH, m~, 1.90-1.60 (3H, m), 1.40-1.20
(13H, m~, 0.90 59Hr s), 0.87-0.80 (3H, m), O.07 (6H, s~.
.
d) (2R,4S,5S~l'S)^-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'-
: 20 propyl l'-~midazol-2-yl]methyl-6-phenyl-2-phenylmethyl-
hexanamide. ~MR~CD30D) ~ 7.40-7.00 ~lOH, m), 6.90 (2~
3.78-3.50 (2H, m~, 2.9Q-2.60 (5H, m), 1.90-1.55 (4H, m),
1.45-1.20 (13H, m); MS m~e 535.4 lM~H]+.
~5 : ; :
:~ hen~ nYlm~thyl-h~nami~
a) ~lS~;-N-1-(4-~romoimidazol-2-ylj-2~methylpropylacetamide
and
(~lS~-N-1-(4,5-dibromoimidazol-2-yl)-2-methylpropylacetamide
To a solution of (lS)-N-1-imidazol-2-yl-2-
: 3~ methylpropylacetamide (1.58 g, 8.73 mmol~ in 95% ethanol
: (30 mL), 2,4,4,6-tetrabromocyclohexadienone (3.~3 g, 9.60
~mol) was added. The resulting mixture was stirred at room
temperature f~r 30 min, and was concentrated in vacuo. The
W093/3 ~ ~ PCT/USg2/06~47
- 58 -
residue was dissolved in dichloromethane, washed with aqueous
NaHC03 and dried o~ex Na~SO~. The solvent was removed in
vacuo, and the residue was purified by flash chromatography
to a~ford the title compound (650 mg, 29%). NMR(CDC13)
7.70 (lH, d, J-7 Hz), 6.85 (lH, s), 4.67 (lH, t, J=7 Hz),
2.35-2.25 (lH, m), 1.95 (3H, s), l.V5 (3H, d, J=5 Hz), 0~80
(3H, d, J=5 Hz).
Also isolated was (lS)-N-1-(4,5-dibromoimidazol-2-yl)-2-
rnethylpropylacetamide (50 mg, 8%): NMR(CDC13) ~ 4.68 (lH, t,
J=7 Hz~, 2.3~-2.25 (lH, m), 2.05 (3H, s), 1.05 (3H, d, J=S
Hz), 0.85 (3~, d, J=5 Hz); ~S m/e 340.Q ~M+H]+, 280.8.
... . .
b) (lS)~ 4-bromoimidazol-2-yl)-2-meth~lpropylamine,
dihydrochloride
Following the procedure of Example 18(c), except~ using
(lS)-N 1-(4-bromoimidazol-2-yl)-2-methylpropylacetamide, the
title compound was prepared. N~RtCD30D~ ~ 7.60 (lH, ~), 4.35
(lHt d, ~=7 Hz~, 2050:2~38 (lH, m), 1.10 ~3H, d, J=S Hz),
0.82 (3H, d, J-5 Hz)o
: : 20,
c) (2R,4S,5S,l'S)-5-St-butoxycarbonyl)amino-4-t-
butyldimethylsiloxy N-t1'-isopropyl-1'-~4-bromoimidazol-2-
~ yl)lmethyl 6-phenyl-2-phenylmethyl-hexanamide
:~ Following the procedure of Example l(c), except using
(2R,4S~SS)-5-(t-butoxycarbonyl~amino 4-t-butyldimethylsiloxy-
6-phenyl-2-phenylmethylhexanoiC acid and (lS)-l-t4-
, bromoimidazol-2-yl)-2-methylpropylamine dihydrochloride, the
title compound was prepared. NMR(CDC13) ~ 7.40-7.00 ~lOH,
~; m), 6.70 (lH, s~, 6.95 (lH, d, J=5 ~z) ~ 4.80 ~lH, d, J=6 Hz),
4.40 (lH, t, ~=5 Hz~, 4.02 ~lH, q, J-4 Hz~, 3.78 ~lH, dd,
Ja7~ 2 Hz), 2.90-2.30 ~9H, m), 1.85-1.60 (2H, m), 1.45 ~9H,
s) ~ 1.00 ~9H~ s) ~ ~).B5 (6H~ t~ ~=4 Hz) ~ 0.10 (6H~ dr 3=6 Hz) .
d) ~2R,4S,5S,l'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'-
: ~ 35 isopropyl~ (4-bromoimidazol-2-yl)]methyl-6-phenyl-2-
phenylmethyl-hexanamide
Following the procedure of Example 9~d), except using
(2R,4S,5S,l~S)-5~t-butoxycarbonyl)amino-4-t-butyldim thy~-
W~3/02~7 PC~/US9~ 7
59 ~3~
siloxy-N-~l' -isopropyl-1'-(4-bromoimidazol-2-yl)]me~hyl-6-
phenyl-2-phenylmethyl-hexanamide, the title compound was
prepared. NMR(CDC13) ~ 7.40-7.00 (lOH, m), 6.70 (lH, s),
6.55 (lH, m), 4.90 (lH, d, J=5 Hz), 4.50 (lH, t, J=5 Hz),
3.75~3.55 (2H, m), 2.95-2.65 (5H, m), 2.40-2.25 (lH, m),
1.90-1.60 (2H, m), 1.48 (9H, s), 0.80 (6~1, t, J=6 Hz).
MS m/e 613.2 [M+H]~; 535.2.
~ :
, .
Following the procedures of Examples 18(c~-18~d3 and
9~d), except substituting (lS)-N-1-~4,5-dibromoimidazol-2-
yl)-~-methylpropylacetamide for (lS~-N-tl-4-nitroim~dazol-2-
yl)-2methyl)propylacetamide, the title compound was prepared.
Analytical data for the in~ermediates of this synthesis were:
) ~lS)~ 4,5-dibromoimidazol 2-yl)-2-methylpropylamine,
dihydrochloride~ NMR~CD30D) ~ 4.10-3.90 ~:lH, br s), 2.30-
: 2.10 (lH, s(br)), 1.10 (3H, d, Jz5 Hz~, 0.8S (3H, d, J=5 ~z~.
:
25~ b) (2R,4S,5S,l'S)-5-~t-butoxycarbonyl)amino-4-t-butyl-
dimethylsi~oxy-N-tl'-isopropyl~ (4,5-dibromoimidazol-2-
r ~ ~ yl~ ]methyl-6-phenyl-2-phenylmethyl-hexanamide. NMR~CDC13) ~i
7.40-6.90 (lOH, m)~, 6.38 ~lH, d, J=5 Hz), 4.80~4.50 (3H, m),
.
4.00 ~lH, q, J=5 Hz), 3.72 (lH, dd, J=7, 2 Hz), 2.85-2~50
~5H, m), 2~30 ~lH, br s~, 2.20-2.05 (lH, m), 1.85-1.65 (2H,
mj,~1 38 (9H, s), 0.90 (9H, s), 0 80-0.60 ~6H, m)~ 0.10 j6H,
. .
~ d, J=3 Hz).
,
c) (2R,4S,5S,l'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'-
3s isopropyl-1'-(4,5-dibromoimidazol-2-yl)]methyl-6-phenyl-2
phenylmethyl-hexanamide. NMR(CDC13) ~ 7.35-6.85 ~lOH, m),
6.65 (lH, br s), 4.92 (lH, d, J=4 Hz), 4.50 ~lH, m), 3.72-
3.50 (2H, m)~ 2.98-2.63 (5H, m), 2.15-2.02 ~lH, m), 1.90 1.70
::
W093/~2~7 PCT/VS~X/06~47
~2H, m), 1.4Q (9H, s); ~S m/e 693.0 [M+H~+; 537, 619, 593,
575, 291.
~ ample 23
hydroxy-N-~ u4D~yyL=L~ methylimida2ol-2-y~l~ ~ç~hy~-&~
phenyl-2-ph~nylm~tX~,yl .-.h~xa~mi~
a) ~lS~-l-carbobenzyloxyamino-l-isopropyl-1-(4-
methylimidazol-2-yl)methane. -
Cbz-(L)-valinal ~1.0 g, 3.9 mmol) and pyruvaldehyde (4.3
mmol, 40% in H20) were dissol~ed in methanol (10 mL) and
chilled in an ice bath. Concentra~ed aqueous ammonia ~2 m~)
W35 added and the reaction mix~ure was stirred at 20C
overnight. The solvent was re~oved in vacuo and the residue
dissolved in 5% ~C1 ~59 mL) and extracted with ethyl aceta~e
~; (3x2Q mL). The aqueous layer was basified to pH 10 with
~: 20 solid Na2CO3. A tan solid (463 mg~ precipitated. The solid
was purified by flash chromatography (silica, 2%-3%
methanol/dichloromethane) to yield the title compou~ as a
white solid tl80 mg~ 16%). mp 163-164C; NMR(CDC13) ~ 7.45-
7.35 (5H, m), 6.60 (}H, ~), 6.00 (1~, d, ~=4 Hz), 5.05 ~2H,
2s q, J=g Hz), 4.40 (lH, t~ J=4 Hz), 2,45-2.30 (lH, m), 2020
3H, s), 0.95~(3~,~ d~ J=4 Hz~, 0~80 (3H, d, J-4 Hz); MS m/e
, 575.4 ~2M+H)+, 288.0 ~M+H;~.
: b) (2R,~S,5S,l'S)-5-(t-butoxycarbonyl)amino-4-t-
butyldimethylsilQxy~N-[l'-isopropyl-1'-(4-methylimida~ol-2-
yl~}methyl-6-phenyl-2-phenylme~hyl-hexanamide
~-~ Following the procedure of Example l(b)-l(c), except
:~ ~ using ~2R,4S,5S)-5-(t-butoxycarbonyl)amino-4-t-
butyldimethylsiloxy-6-phenyl-2-phenylmethylhexanoic acid and
~: 35 the compound o~ Example 23(a3, the title compound was
prepared. NMR(CDC13) ~ 7.37-6.90 (lOH, m)~ 6.45 (lH, s~,
~:: 6.38 SlH, d, J=3 Hzl, 4.75 (lH, d, J=5 Hz), 4.40 ~lH, t, J=5
~z~, 3.95 (lH, q, J=4 Hz), 3.72-3.6~ (lH, m), 2.90-2.70 (4H,
W093J02~7 PCT/~S92/U60~7
- 21~3~
- 61 -
m), 2.60-2.48 ~lH, m), 2.45-2.30 (lH, m), 2.17 (3H, s), 1.90-
1.80 (lH, m), 1.75-1.62 (lH, m), 1.40 (9H, s), 0.95 (9H, s),
0.7S (6Hr t, J=3 Hz), 0.10 (6H, d, J=2 Hz).
c) (2R,4S,5S,l'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'-
isopropyl-1'-(9-methylimidazol-2-yl)]methyl-6-phenyl-2-
phenylmethyl-hexanamide
Following the procedure of Example ~(d), except using
the compound of Example 23(b), the title compound was
lo prepared. NMR~CDCl3) ~ 7.38-7.00 (lOH, m), 6.S2 (lH, s~,
4.92 (lH, d, J=5 Hz), 4.42 (lH, t, J=4 Hz), 3.72-3.55 (2H,
m), 2.95-2.65 t5H, m), 2.35-2.20 ~lH, 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]~.
~ _ ~
a) (lS)-~-carbobenzyloxyamino-l-isopropyl-1-~4-
trifluoromethylimidazol-2-yl)methane.
Sodium acetate trihydrate (5.35 g, 2.2 eq) was dissolYed
in uater ~16 mL~ and 1,1 dibromotrifluoroacetone ~5.31 g, 1~1
eq~ was added. The solution was stirred fox 30 min at 90C.
, The solution was cooled to 0C and poured into a 0C solution
~ of Cbz-Valinal 54.22 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 e~aporated t~ 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%).
HNMR~CD30D) ~ 7.45 (lH, s), 7.40-7.20 ~5H, m), 5.05 (2H, q,
J=4 Hz3, 4.50 (lH, d, J=4 Hz), 2.38-2.10 ~lH, m)~ l.00 (3~,
d, J=4 Hz3, 0.80 (3R, d, J=4 Hz), 13CNMR(CD30D, 1H-decoupled)
WO9~J~2~7 P~/US92/OC~7
62 -
18.9, 19.4, 67, ~17(q, J=3 Hz), 123.2(q, J-266 Hz), 128.7,
129.3, 133~q, J=3~ Hz), 138.0, 151.7; MS m/e 342.0 lM+H]+.
b) (2R,4S,5S,l'S~-5-(t-butoxycarbonyl)amino-4-t-butyl-
dimethylsiloxy-N-~1'-isopropyl-1'-(4-trifluoromethylimidazol-
2-yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide
Following the procedure of Example l(b)-l(c), except
using the compound of Example 24~a) and (2R,4S,5S)-5-~t-
butoxycarbonyl)amino-4-t-butyldimethylsiloxy-6-phenyl-2-
phenylmethylhexanoic acid, the title compound was prepared.
NMR(CDC13) ~ 7.35-6.95 (11 H, m3, 6.50 ~lH, d, J=4 Hz), 4.75
~lH, d, J=6 Hz~, 4.25 ~lH, t, J=4 Hz), i.95 (lH, q, J=9 Hz),
3.80-3.68 ~lH, m), 2.90-2.40 ~5H, m), ~.80-1.60 (2H, m), 1~35
(9~, s), 0.90 (9H, s~, 0.80 (3H, d, J=3 Hz3, 0.70 ~3H, d, J=3
15 Hz), 0.05 (6~, d, J=2 Hz).
c) (2R,4S,5S,l'S)-5 (t butoxycarbonyl)amino-4~ hydroxy-N-[l'-
isopropyl~ 4-trifluoromethylimidazol~2-yl)]methyl-6-
phenyl-2 phenylmethyl-hexana~ide
Following the procedure of Example 9(d), except using
the compound of Example 24(b), the ti~le compound was
prepared. NMR(CDCl3) ~ 7.35 tlH, s), 7.25-6.90 (lOH, m)~
4.53 (lH, d~ J=5 Hz), 3.68 (lHJ t, J=4 Hz), 3.S2 ~1~, d, J=6
: H~), 2.90-2.55 ~5H, m), 2.10-1~95 (lH, m~, 1.85-1.70 (lH, m),
25 1.65-1.50 ~lH, m~, 1.40-1.25 (gH, m), 0.90 ~3H, d~ J=4 ~z),
0.:65 (3H, d, J=4 Hz); MS m/e 603.2 lM~ , 529.2, 503.2.
Fxa~Rle 2
; ~ ,
30 P~*aratlon of (2R,4S,5S.l'S)-5-~t-~utoxycaxbQnyl2amino~-
.
~h~nyl-2-phenylmethyl-hexanam;d~
a) (lS)-l-carbobenzyloxyamino-1-isopropyl~l-(imidazol-2-
: 35 yl3methane
- Following the procedure of Example l(a), except
substituting N-methyl-Cbz-(L)-valinal for Cbz-(L)-valinal,
the title compound was prepared. NMR(CDCl3) ~ 7.45-7.30 (5H,
W093/~20~7 P~T/U~92/06047
63 ~
m), ~.90 (2H, s3, 5.12 (2H, s), 4.60 (lH, d, J=6 Hz), 2.95
(3H, s), 2.70-2.53 (lH, m3, 1.02 ~3H, d, J=3 Hz), 0.85 (3H,
d, J=3 Hz).
b) (lS~-l-methylamino-1-isopropyl-1-(imidazol-2-yl)methane
Following the procedure of Example l(b), except using
the compound of Example 25~), the title compound was
prepared. NMR(CDCl3) ~ 6.95 (2H, s), 3.52 (lH, d, J=3 Hz),
2.30 (3Hr s), 2.10-~.90 (lH, m), 0.98 (3H~ d, J=3 Hz)r 0.82
(3Hr dr ~=3 Hz).
C); (~r 4Sr 5Sr 1 ~S) ~5-(t-butoxycarbonyl)ami~o~9 t-
butyldimethylsiloxy-N-methyl-N-(1'-iso~ropyl-1'-imidazol-2-
yl)methyl-6-phenyl-2-phenylmethyl-hexanamide
Following the procedure of Example l~c) t except using
the compound of Example 25(b), the title compound was
prepared. ~MR~CDCl3) ~ 7.40-6.72 (12H, m), 4.82 ~1~, d, J=5
Hz), 95 tlH, ~ J=4~ Hz), 3.82-3.75 ~1~, m), 2.95-2.70 (5H,
m), 2.51 ~2H~ s) r 2.50-2.38 ~lH~ m), 2.08 (lH, s~, 1.87-1.6~ ;
t2H, m), 1.3& (9H, s~, 0.95 t9Ht s), 0.88 ~3H, d, J~3 Hz),
0.75 (3H, d, J=3 Hz), 0.05 ~&H, d, J-7 Hz).
: d) ~2R,4S,5S,l'S)o5-~t-bu~oxycarbonyl)amino 4-hydroxy-N-
methyl-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-
phenylmethyl-hex~namide
Following tbe~procedure of Example 9(d), except using
s the compound of Example 28~c), the title compound was
: ~ prepaxed. NMR(CDCl3~ ~ 7,35-6.82 (12H, m~, 4.90-4~72 (lH,
~;~ m), 3.70~3.00 (2H, m), 2.92-2.50 (8~, 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}~.
,.
y~lmetllyl-6-gherlyl-2-pherlvlmethyl-hexanamide
.
WOg3/02057 P~T~VS92/Q6W7
~ 64 -
a) (lS)-l-carbobenzyloxyamino-1-isopropyl-1-~4-
trimethoxymethylimidazo1-2-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,
5 1 . 88 mmol) ~n anhydrous methanol (10 m~). The resulting
mixture was heated at 55C overnight, cooled, and
concentrated under reduced pressuxe. 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 (5~5 mg, 77%). NMR(CDC13) ~ 7.40-7.20 (5H, m~, 6.98
(lH, br s)~ 5.90 ~lH, br s), 5.08 ~2H, s~, 4.50 (lH, br s),
3.15 ~9R, s), 2.00 (lH, m ~br)), 1.00-0.80 ~6H, m); MS m/e
378.2 [M+H]~, 3467 332, 271, 195.
b) (lS)-l-carbobenzyloxyamino-l-isopropyl~
carbomethoxyimidazol-2-yl)methane
solu~ion of the compound of Example 26ta) (540 mg) in
~0 1:1 methanol~aqueous~HCl (10 mL~ was stirred at room
temperature for~2 h, and concentrated under reduced pressure.
The residue was~partitioned between aqueous Na2C03 and
dichloromethane, and the organic extract was dried over
Na2CO3 and concentrated in vacuo to afford the title compound
25 ~470 mg, 75%). NMR~CDC13) ~ 7.55 (lH, br s~, 7.35 ~5H, s~,
5.90-5.65 ~lH, m), 5.10 (2H, t, J=4 Hz), 4.60-4.42 ~1~, m),
3.88 ~3H, s), 2.40 (lH, br s), 1.00-0.80 ~6H, m~; MS m/e
332.2 lM+H]+.
c) (lS)-l~amino-l-isopropyl~ carbomethoxyimidazol-2-
yl)methane
Following the procedure of Example l(b), except using
~:~ the compound of Example 2Ç(b), the title compound was
prepared. NMR(CDC13) ~ 7.62 (lH, s3, 3.97 (lH, d, J=4 Hz),
35 3.82 (3H~ S) r 2.27-2.05 (lH~ m), 0.95-0.75 ~6H, m).
W093/02057 PCT/US92/OSQ47
,,....................................... 21~3~
-- 6 5 --
d) (2R,gS!5S,l'S)-5-(t-butoxycarbonyl)amino-4-t~butyl-
dimethylsiloxy-N-[l'-isopropyl-1'-(4-carbomethoxyimidazol-2-
yl)Jmethyl~6~-phenyl-2-phenylmethyl-hexanamide
Following the procedure of Example l(c), except using
the compound of Example 26(c), the title compound was
prepared. NMR~CDC13) ~ 7.45-6.90 (12H, m), 6.98 (lH, d, J=4
Hz), 4~72 (lH, d, J-6 Hz), 4.35 (lH, s br), 4~02-3.87 ~lH,
m), 3.85 ~3H, s), 3.75-3.60 (lH, m), 2.90-2.40 ~5H, m), 1.90-
~.60 (2H, m), 1.42 ~9H, s), 0.90 (9H, s), 0.72 (6H, d, J=4
1.0 H~), 0.10 (6H, d; J=3 Hz).
e) ~2R, 4S, 5S, l'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-
isopropyl~ (4-carbomethoxyimidazol-2-yl)~methyl~6-
phenyl-2-phenylmethyl-hexanamide
Following the procedure of Example 9 (d), except using
~he compound of Example 26~d~, the title compound was
prepared. N~R(~D~13~ ~ 7.40-6.80 (12H, m), 4,90 ~lH, d, 3=5
~z~, 4.50-(lH, br s), 3.90 S3~, s~, 3.80-3.60 ~2H, ~), 2.95-
2.68 (5H, m), 2.45-2.30 (lH, m~, 1080-1.60 (2~, m), 1.40 (9~,
s~ 0.72 (6H, d, J=4 Hz3; MS m/e 593.2 ~M+H~+, 537.2, 519.2,
~ ~93.2, 475.2.
: 25
:: ;
: a~ (lS)-1-carbobenzyloxyamino-1-isopropyl-1 ~4-
hydroxymethylimidazol-2-yl)methane.
T~e compound of Example 26~b~ (0.314 g, l.Q eq) was
stirred in anhydrous toluene at -78~C under an argon
atmosphere. Diisobutylaluminum hydride ~3.8 mL, l.OM in
hexanes, ~.0 eq) was added and the solution stirred at -78C
: 35 for 1 h. The reaction was quenched with methanol ~0.2 mL, 1.O
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
W093/0~7 PCT/USg2/06047
~36~ 66 -
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~ ~ 7~25
(5H, s), 6.69 (lH, s), 6.14 (lH, d~, 5.01 (2H, dd), 4.52 l2H,
s), 4.37(lH, t), 2.19 ~lH, m), 0.92 ~3H, d), 0.73 ~3H, d); MS
m/e 304.0 [M+HI~.
b~ ~lS)-l-carbobenzyloxyamino-l-isopropyl~ 4-
formylimidazol-2-yl)methane. - .
The compound of ~xample 27(a) ~0.11 g, 1.0 eq) was
stirred in anhydrous dichloromethane at room temperatur~
under an inert argon atmosphere. Ma~ganese dioxide (0.126
g,4.0 e~) was addéd and the mixture was stirred at room
temperature overnight. After 16 h and additional ~.O eq of
manganese dioxide was added. The reaction was comE)lete by
TLC after 2 h. The mixture was filt~red t~rough ~ pacl of
Celitet~ Emd the f ilter cake was washed with dichlorome~hane .
The organic solYent was removed in vac:uo to gi~.re the title
compound as a white solid (0.075 g ~ 6996). N~R~CDC13~ ~ 9.57
(lElts), 7~54 (lHr s), 7.12 (5EI, s), 6.43 (lH, d), 4.96 ~2H,
dd), 4.43 (lH, t):, 2.08 (lEI, m~, O.gl (3H, d), 0.62 (3H, t);
MS m/e 302 . 0 ~M+H) + .
c) ~lS,l'RS)-l-carbobenzyloxyamino-l-isopropyl~ 4
hydroxye~hyl)imidaæol-2-yl)methane.
~: ~
The compound of Example 27 ~b) (0.1 g, 1.O eq) was
stirred in a 3 :1 etherJTHF mixture at 0C under an argon
:
atmosphere. Methyl magnesium bromide ~0.47 mL, 3.0M in THF,
4.0 eq) was added and allowed to stir a~ 0C for 1.5 h. The
solution was diiuted with 5% aqueous HCl and made basic with
....
solid sodium carbonate. The solution was extracted with
ethyl ac tate three times and the combined organic extracts
were dried over sodium:carbonate, filtered, and evaporated to
a white solid (0.1 g, 95%). NMR(CD~13) ~ 7.19 (5H,s), 6.59
; (lH, s), 6.42 ~lH, d), 4.92 ~2H, dd), 4.73 (lH, m), 2.09 ~lH,
~ m), 1.37 (3H, d), 0.82 (3H, d), 0.66 (3H, d).
W093/02~7 PCT/US92/~7
- 67 - ~2~1~3~
d) (lS, l'RS)-1-amino-1-isopropyl-1-(4-
~hydroxyethyl)imidazol-2-yl)methane.
The compound of Example 27~c) (0.1 g, l.Q eq) was
stirred in anhydrous methanol with 10% Pd on activated carbon
s ~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 ti~le
compound as a white solid (0.05 g, 87%). NMR(CDCl3) ~ ~.63
~lH, s)~ 4.72 (l~, dd), 3.61 (lH, d), 1.92 (lH, m), 1.49 (3H,
d), 0.84 (3H, d), 0.67 (3H, d~. ;
e) (2R,4S,5S,l'S,17~RS)-5-(t-butoxycarbonyl)amino-4-t-
butyldimethylsiloxy-N~ -isopropy~ (4-(l~-hydroxyethylt
imidazol-2-yl)]~ethy1 6-phenyl-2-phenylmethyl-hexanamide
To a solution of ~2R,4S,5S)-5-~t-~utoxycarbonyl~amino~4-
t-butyldimethylsiloxy-6-phenyl-2-phenylmethylhexanoic ac~d
~0.131 g, 1.0 eq) in anhydrous di~ethylformamide, the
compound of Examp~e 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 s~irred at room t~mperature for
:~ 16 h. The solution was diluted with water and extracted three
: times with dichlor~methane. The combined organic ex~racts
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%
: methanolldichloromethane) to a~ford the title compound as a
white foam (0.11 g, 65~). NMR(CDCl3) ~ 7.31-6.54 (12H, m),
4.72 ~lH, d~, 4.48 (2H, d), 3.82 (lH, q), 3.61 ~lH, m), 2.81-
2.3 (6H, m), 1.65 (3H, m), 1.48 (3H, d), 1.22 (9H, s), 0.
(9H, s~, 0.70 (3H, d), 0.61 (3H, d), 0.06 (6H, s); MS m/e
; 6g3.4 [M+~}+.
~; .
:: ~
W~g3/~2057 PCT/~92/~047
~ ~ ~3 6'~ 68 -
fS ~2R,4S,5S,l'S)-5-(t~butoxycarbonyl)amino-4-t-
butyldimethylsiloxy-N-[1'-isopropyl-1'-t4-methylcarbonyl-
imidazol-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
~iltered through a pad of Celite~'and the filter cake was
washed with dichloromethane. The organic solvent wa~ :
evaporated to give the title compound as a white solid
(0.038 g; 85%). NMR(CDC13) ~ 7.49-6.76 (llH, m), 6.30 (1~,
br d~ 4.71 (2H, m), 3.86 tlH, q), 3.61 (lH, dd), 2.77-2.41
~5H, m), 2.31 (3H, s), 1.58 ~2H, m), 1.20 (9H, s~, 0.83 ~9H,
s~ O.69 (6H, dd), 0.04 t6~,d); MS mJe 691.4 tM~H3~.
g) ~2Rr45,5S,l'S)-S-(t-butoxycarbonyl)amino-4-hydroxy-N~
isopropyl~ methylcarbonylimidazol-2-yl)~methyl-6-phenyl-
2-phenylmethyl-hexanamide
The compound~of Example 27(f3 (38 mg, 1.0 eq) was
stirred in anhydrous THF under an argon atmosphere at room
: ~ ~ temperature. Tet:rabutyl ammonium ~luoride tO.33 mL, l.OM in
: T~F, 6.0 eq) was added and the solution stirred for 16 h.
The solution was diluted with water and extracted three times
~:: wlth dichloromethane.: The combined organic extracts were
washed with water and evaporated ~o a white solid. The solid
: was co~ered with diethyl ether, decanted twice, and dried to
: gi~e the title :compound as a white solid 125 mg, 79~).
NMR(CDC13) ~ 7.14 (SH, m), 6.86 (5H, m), 5.14 tlH, d), 4.42
, .
(lH, d), 3.58 (lH, q), 3.45 (lH, d), 2.80-2.50 (5H, mi, 1.91
....
tlH, m), 1.63 ~2H, m), 1.26 t9H, s) (rotamer observed), 0.70
(3H, d~, 0.57 (3H, d); MS m/e 577.2 [M+H]+.
W093/02057 PCT/US~2/~7
~ 69 ~ 3~
Example 28
~repa~ation Qf ~2RF ~ ~ l'S)-5-(t-butoxycarb~nyl3~m mo-4
yl~lmethyl 6-~henyl-2~henylm~hyl=he~n~m1~9
a) ~lS, l'RS)-1-carbobenzylo~yamino-1-isopropyl-1-(4
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 chroma~ographed lsili~a, 4%
methanol/dichloromethane~ to yield the,title compound as a
whi~e solid (0~155 g , 88~3.NMR(CDC13) ~ 7.19 (5H, m3, 6.58
15(1~, s)~ 4.91 (2X, m)~ 4.38 ~lH, q~, 4.20 (1~, dd), 2.11 (lH,
m~, 1.8~ , m) t 0.7~ t~2H, m); MS m/e 346.2 lM~H]+; 328.2
279.0 , 254~0, ~05.0, ~77.0, 149.0, 1~Ø
b) (15,15RS)-1-amino~ isopropyl-1-(4~ hydroxy-2'-
~0 methyl)propylimidazol 2-yl)methane
Following the procedure o Example 27(d) , using the
compound of Example 31(a) r the title compound was prepared as
a white foam (96 mg:, 100%~. N~R~CDC13) ~ 6.Ç5 (lH~ s~,
4~21 (lH, d), 3.90 (lH, s), 2.22 (lH, m), 1O94 ~lH, m) t 0-93
25 : (~H, m), 0.64 i6Hr m); ~S m/e 302.0 tM+H]+.
c~ (2R,4S,5S,l'S,l''RS)-5-(t-butoxycarbonyl)amino 4-t-
butyldimethylsiloxy-N-[1'-isopropyl-1'-(4-(1/'-hydroxy-2''-
~:~ methyl)propylimidazol-2-yl)]methyl-6-phenyl-2-phenylmethyl-
hexanamide
:Following the procedure of Example 27i(e), except using
..~ .
the compound of Example 31(b3 (96 mg, 1.1 eq~, subs~ituting
: dimethyl formamide as the solvent Instead of dichloromethane,
and purifying the product by chromatography, the title
compound was prepared ~168 g, 57%). NMR(CDC13) ~ 7.2~-6.81
~llH, m), 6.62 ~lH, d), 4.71 (lH, dd), 4.53 (lH, t~, 4;19
(lH, d), 3082 (lH, q), 3.58 (lH, dd), ~.71-2.30 (5~, m), 2.03
(lH, mj, 1.70 ~lH, m), 1.57 (lH, m), 1.14 ~9H, s), 0.91 ~3H,
W093/02V57 PCT/US92/~0~7
~6~ - 70 -
d), 0.88 ~9~, s), 0.78 ~3H, d), 0.67 (3H, d), 0.59 (3H, d),
0.03 6H, d); MS m/e 721.4 lM+H]+
d) (2R,4S,5S,l'S)-5 (t-butoxycar~onyl)amino-4-t-butyl-
dimethylsiloxy-N-[1'-isopropyl-1'-t4-isopxopylcarbonyl-
imidazol-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 pr~duct (silica, 3% methanol/dichloromethane) the
title compound was prepared as a white solid (132 mg, 79~).
NMR~CDCl3) ~ 7.20 6.76 (llH, m), 5.05 (lH, br m), 3.88 (lH,
q), 3.~1 , m~, 3.19 ~lH, m)/ 2.80-2.46 (5H, m~, 2.22 (lH, m~,
2.07 ~lH~ m ), 1.63 ~lH, m), 1.15 (16H, m), 0.89 (9H~ S)r
0.74 ~6H, m), 0.08 (6~, d); MS m/e 719~4 [M+H~.
e) 52R,45~5S,l'S)-5-~t-butoxycarbonyl)amino-4-hydroxy-N-[ll-
isopropyl~ 4-iso~ropylcarbonylimidazol-2-yl)]~ethyl-6-
phenyl-2-phenylmethyl-hexanamide
Following the procedure of Example 27(g)~ except ~sing
~he compound of Example 31~d) ~132 mg), the title compound
was prepared as a white foam t90 mg, 81%3. NMRtCDC13) ~ 7.48
tlH, s~, 7.11 ~SH, m), 6.82 ~5H, m), 5.29 ~lH, d), 4.46 ~lH,
m ), 3.54 (lH, q), 3.48 ~lH, m), 3.14 (lH, m1, 2.74-2.44 ~5H~
m), 1.90 (lH, m), 1.61 (2H, m), 1.28 (9H, s) (rotamers
2s obserYed), 1.13 ~6H, mj, 0.6g (3Hr d3, 0.48 (3H, d); MS m/e
605.2 [~+H~+.
,
ExamDl e 2 9
30 ____ ~
:
a) (lS,l'RS)-l-carbobenzyloxyamino-1-isopropyl~ 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
:
W0~3/02057 PCT/U592/~7
~ - 71 -21~3~
the crude product ~silica, 3% methanol/dichloromethane) the
title compound was prepared as a white solid ~175 mg, g6%).
NMR(CDC13) ~ 7.26 (lH, d), 7.11 (lOH, m), 6.39 (lH, dd), 6.08
(lH, d), 5.63 (lH, d), 4.82 (2H, m), 4.29 (lH, m), 2.01 tlH,
s m) f 0.76 (3H, m) r 0.59 (3H~ d) .
b) (lS,l'RS)-l-amino~ opropyl-1-(4-(1'-hydroxy)benzyl-
imidazol-2-yl)methane
Following.the procedure of Example 27(d~, except using
the compound of Example 29(a) (98 mg) the title com~ound was
prepared as a tarky white foam (65 mg, 98%).
c) (2R,4S,5S,l'S,l''RS)-5-(t~butoxycarbonyl)amino-4-t-
butyldimethylsiloxy-N~ isopropyl-l' (4-(1''-
hydroxy)benzylimidazol-2-yl)~methyl-6-phenyl-2-phenylmethyl-
hexanamide
Following the procedure of Example 27(e), except using
the compound of Example 29(b) ~0.065 g, 1.1 eq~, and
chx~ma~ographing the crude product ~2~ methanol/
~ 20 dichloromethane) th~ title compound w~s prep~red as a white
:: solid ~109 mg, 55~)~. NMR(CDC13) ~ 7.48-6.79 (16~, m), 4.77
(lH, m), 3.88-(lH, m), 3.61 (lH, m~, 2.65 (4M, m), 2.39 (lH, ~.
m), 2.15 ~lH~ m), 1.94 ~lH~ m), 1.75 ~lH, m), 1.56 (lH, m)~
.21 (9H~ s) (rotamers observed), 0.86 (9H, s~, 0.68 ~6H,
~: 25 dd), 0.07 (6H, s); ~S m/e 755.4 [M~H]~.
~ ~ d) (2Rr4S,5S,l'S~-5-(t-butoxycarbonyl)amino-4 t-butyl-
:~ dimethylsiloxy-N~[1'-isopropyl-1'-(4-phenylcarbonylimidazol-
2-yl)~methyl-6-phenyl-2-phenylmethyl-hexanamide
Following the procedure Example 27(f~ f except usi~g the
compound of Example 29~c) ~109 mg, 1.0 eq) f the title
~: compound was prepared as a white solid ~80 mg, 74%).
NMR(CDC13) ~ 7.49-6.84 (17H, m) r 3.88 (lH~ q~ ~ 3.63 (lH~ t~ ~
2.87-2.4g (6H, m), 2.11 ~2H, m), 1.64 (lH, m~, I.ll (9H, s),
: 35 0.82 (9H~ S) ~ 0.71 (6H, dd), 0.06 ~6H, d); MS m/e 753.4
{ M+H ] + .
W09~/~2057 P~T/US92/06~47
- 72 - i
~e~ (2~,45,5S,l'S~-5-(t-butoxycarbonyl~amino-4-hydroxy-N-[1'-
isopropyl-1'-(4-phenylcarbonylimidazol-2-yl~]methyl-6-phenyl-
2-phenylmethyl-hexanamide
Following the procedure of Example 27~g), except using
S 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) ~ 7.84-6.77 (16H, m), 4.48 (lH, d~, 3.59 ~lH, m),
3.42 ~lH, m), 2.80-2.54 ~5H, m), 1.99 SlH, m), 1.63 12H, m),
1.26 (9H, s) (rotamers observed), 0.73 (3H, d), 0.59 (3H, d);
~S m/e 639.2 ~M~H]~.
~am~a~
.
~5
a) (lS,l'RS)-1-amino-1-isopropyl-1-(4-(hydroxy)methyl-
imidazol-2-yl)methaneO
: 20 Following the procedure of Example 27~d), except using
the compound of Example 27(a) (90 mg), the titled compound
was prepared ~S~ mg, 100%). NMR(CDC13) ~ 6.85 (lH, s~, 4.62
S2H, s), 3.85 tlH, d, J=4 Hz), 2.20-2.05 (lH, m), 0.88 (6H,
d, ~=5 Hz~
: 25
b) (2R,45,5S,l'S)-5-~t-butoxycarbonyl)amino-4-~-
, butyldimethylailoxy-N~ isopropyl~ (4-(hydroxy)methyl-
:~ : imidazol-2-yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide
.
Following the procedure of Example 27(e), except using
: 30 the compound of Example 30(a) (S0 mg~, and chromatographing
the crude product (silica, 2% methanolfdichloromethane~ the
title compound was prepared S130 mg, 65%). N~R(CVC13) ~
7.30-6.95 (llH, m), 4.82 SlH, d), 4.50-4.60 (lH, m); 4.40
(lH, d), 3.gO-4.00 (lH, m), 3.60-3.68 (lH, m)~ 2.45-2.80 (5H,
m), 2.20-2.30 (lH, m), 1.75-1.85 (lH, m~, 1.60-1.70 (lH, m),
~: : 1.30 ~9H, s), 0.95 S9H, s), 0.75 (3H, d), 0.62 (3~r d) ~ 0.05
6H, d).
~ ~ .
:;
W~93/02~7 PCT/US92/06047
- 21~4~ :
- 73
c) (2R,4S,5S,l'S)-S-~t-butoxycarbonyl)amino-4-t-
butyldimethylsiloxy-N-[l'-isopropyl-1'-(4 formylimidazol-2-
yl)~methyl-6-phenyl-2-phenylmethyl-hexana~ide
Following the procedure of Example 27(f~, except uslng
the compound of Example 30~b) (50 mg), the title compound was
prepared (20 mg, 40%~. NMR~CDC13) ~ 9.80(0~5H, s) t 9.64
(0.5H, s), 7.50-6.90 (llH, m), 6.52-6.42 (lH, m), 4.88-4.70
(2H, m), 4.42-4.32 ~1H, m~, 4.02-3.93 (lH, m), 3.78-3.71 (lH,
m)9 2.90~2.40 (5H, m), 2.30-2.19 (lH, m), 1.87-1.62 ~2H, m),
~0 1.45 ~9H, s), O.g5 ~9H, s~ 0.87-0.72 (6R, m), 0.05 (6H, m)
(rotamers).
d) (2R,4S,5S,l'S)-5-(t-butvx~carbonyl)amino-4Dhydroxy-N-[1'-
isopropyl~ 4-formylimidazol-2-yl)]methyl-6-phenyl-2-
phenylmethyl-hexanamide
Following the procedure of Example ~7(g), except using
the compound of:Exa~ple 30tc~ ~20 mg)~ the title compound was
prepared (12 mg, 71%~:. NMR(CD30D) ~ g.60 tl~, s), 7.65 ~
s), 7.20-6.90 (lOH, m), 4.52 (lH, d~, 3.60 (lH, m~, 3.~5 (lH,
20 d), 2.80-2.45::(5Hr m), 2.00-1.88 SlH, m), 1.75-1.6S (lH7 m~,
:~ 1.62-1.45 ~lH, m), 1.27 (9~, s), 0.82 (3H, d), 0.62 ~3H, d);
MS m/e 563.4, 242.2,~204.8.
2S
Following the proceduxe of Example 27(g~, except using
the compound of Example 30~b) (40 mg)~ the title compound was
~: prepared ~20 mg). NMR(CD30D) ~ 7.27-&.92 (10~ s3, 6.72 (lH,
s~, 4.52 (lH, d), 3.64-3.60( lH, ~), 3.48~ lH, d), 2.82 2.50
(5H, m), 2.03-1.92 ~lH, m), 1.78-1.67 ~lH, m~, 1.63-1.49 (lH,
m~, 1.28 (9H, s~, 0.80 (3H, d), 0.65 ~3H, d); MS m/e 565.g.
~ ' '
::
W093/02057 PCT/US92/06047
- 74 -
Example ~
yl)oxy~arbonyLL~mino-4-hydroxy-N~ isopropyl~ lmLI~ol=~=
yl)meth~l-6-phenyl- Z-phenylmethyl-hexanamid~
Following the procedures of Example 14 (a)-14 (c),
except using 4-hydroxytetrahydrothiopyran in place of 2-
benzyloxyethanol, the title compound was prepared.
10 Anaiytical data for the intermediates of this synthesis were: :
a) (tetrahydrothiopyran-4-yl)-(4-nitro)phenylcarbonate.
NMR(CDC13) ~ 8~6 ~lH, s), 8.22 (lH, s), 7.38 (lH, s3, 7.33
(lH, s), 4.79 ~lH, m), 2.90 2.75 ~2H, m), 2.70 2.52 ~2H, m~,
2.31-2.1~ (2H, m), 2.10-1.90 (2H, m).
b) ~2R, 45, 5S, 1 'S3 -5- ( ~tetrahydrothiopyran 4-yl) oxycarbonyl~ -
amino-4-hydroxy-N-tl'-isopropyl-1'-imidazol-2-yl)methyl-6-
phenyl-2-phenylmethyl-hexanamide. NMRtC~30D) ~ 7.12-6.65
: 29 ~lOH, m), 6.64 (2H, s)~ 5.60 ~lH, d), 4.36 (2H, m~, 3.58 (lH,
q), 3.49 (lH, d~r 2.68-2.48 (6H, m), 2.44-2.30 (3H, m), 1.93-
1.74 (3H, m~, 1.70-I.40 (4H, m), 0.61 ~3H, d), 0.50 (3H, d~.
.
~s
~ç~ara~iQn_Qf (2R.4S~5S,l'S~-5-((~etrahydro-~H~pyran-4-
l~oxycaI~nyl!aminQ~-hydroxy-N-(~ op~yl~l'-imidazol-2-
y~m~thyl-6-phenyl-2-phenylmethyl-he~an~mi~
Following the procedures of Example 14(a~-14(c), except
using 4-hydroxytetrahydro-4H-pyran in place of 2-
benzyloxyethanol, the title compound was prepared.
: Analytical data for the intermediates of this synthesis wexe:
a) (tetrahydro-4H-pyran-4-yl)-(4-nitro)phenylcarbonate.
NMR(CDC13) ~ 8.32 tlH, s), 8.28 (lH, s), 7.41 (lH, s), 7.38
(lH, s), 5.00 (lH, m), 4.05-2.90 (2H, m), 3.68-3.49 (2H, m~ r
2.17-2.00 (2H, m), 1.95-1.75 (2H, m).
W093/02057 PCT/USg2~ 7
_ 75 _ 2~
b) (2R,~S,5S~l~S)-5-((tetrahydro-4H-pyran-4-yl)oxycarbonyl)-
amino-4-hydroxy-N-(l'-isopropyl-1'-imidazol-2-yl)methyl-6-
phenyl-2-pheny~methyl-hexanamide. NMXtCD30D) ~ 7.16-6.8g
(lOH, m), 6.79 ~2H, s), 4.54 (2H, m), 3.82-3070 (2H~ m),
3.69-3.62 (lH, m), 3.50-3.46 (lH, m), 3.45 3.35 (2H, m),
2.79-2.65 t9H, m), 2.64~2.45 (3H, m), 2.00 (lH, m), 1.82-1.62
(3H, m), 1.55-1.45 (2H, m), 1.37 tlH, m), 0.79 (3H, d)~ 0.63
(3H, d).
~am~l~
, ~ , -
: :
The compound of Example l~d) was dissolved in ~eat TFA.
: A~ter lO min the solutio~ was concent~a~ed ~o provide ~he
:~ a~ine salt, (2R,4S,SS,l'S)-S amino 4-hydroxy~ opropyl-
~ 20 1'-imidazol 2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide
: trifluoroacetate. Thi~ amine salt (25 mg, 1 eq) was
dissolved in DMF, and~4-picolinium-(p~nitro~phenyl carbonate
p-nitrophen~late t23:mg~ 1 eq) and tr~ethylamine tO.04 mL, 5
~: eq) were added. The mixture wa~ stirred under Ar fo~ 17 h.
: 25 Water was added and the mixture was extracted with
dichloromethane.~ The organic extrac s were concentrated and
the residue was:triturated with ether to yield the title
compound ~20 mg, 61%). NMR(CD30D) 8 8.52 t2H, d), 7.10 (14H,
m),: 6.87 ~2H, s), 5.07 (2H, dd), 4.61 (1~, d), 3.8~ ~lH, m),
: : 30 3.59 (lH, m), 2.77 (SH, m), 2.05 (lH, m), 1.83 (lH, m), 1.60
(lH, m);, 0.84 t3H, d~, 0.59 (3H, d).
: MS m/e570.5 lM+H]+.
~: E~am~le 3
3s
(4~4,~-~rifluQ~obut-1-yl~hexana~
W~93~02~7 PCT/US92/o6047
36~ 76 -
a) ~3R,SS,l'S)-(1'-t~butoxycarbonylamino-2'-phenyl)ethyl-3-
(4,4,9-trifluorobut-1-yl)-tetrahydrofuran-2-one
To a solution of lithium diisopropyl amide (1.8 mL of a
1.5M solution, 2.2 eq) in tetrahydrofuran (10 mL) was added
~5S, l'S)-~1' t-butoxycarbonylamino-2'-phenyl)ethyl-
tetrahydrofuran-2-one ~0.50 g; 1.0 e~) in anhydrous THF (2
mL) at -78C. After stirring for 15 min at -78C,
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 -78C, the reaction mix~ure was quenched with a :~
10% aqueous HCl and~extracted with dichloromethaneO The
organic extracts were combined and evaporated to a clear oil.
The oil wa3 chromatographed (~ilica, 2% methanol/
dichloromethane~ to gi~e the title compound as a white foam
~0~248 ~, 37~). NMR: (CDC13~ ~ 7.18 ~5H , m) r 4 .57 ~lH; d)
4.41 (lH , dd), 3.95 ~lH , q), 2.82 (2H, d), 2.55 (2H , m),
2.49-104~ (7~ , m), 1.32 ~9H , s); MS m/e 438.0 (M~Na)+.
:
: b) ~2R,4S,SS)-S-~t-butoxycarbonyl)amino-4 ~ butyldimethyl-
siloxy-6-phenyl-2-~4,4,4-trifluorobut-l~yl)hexanoîc 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(CDC13~ ~ 7.18 (SH, m~, 4.70
~: ~lH, d), 3.88 ~lH, q), 3.69 ~2H, m)~ 2.73 tlH, m), 2.38 (lH,
m), 1.91 (2H, m~,~l.45 ~6H, m~, 1.31 ~9H, s) (rotamers
~: observed),:0.90 (9H, s), 0.08 (6H, d); MS m~eS48.2 [M~H~.
cj ~2R,4S,SS,l'S?-5-(t-butoxycarbonyl)amino-4-t-butyl-
dimethylsiloxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-
phenyl-2-(4,4,4-trifluorobut-1-yl)hexanamide
Folowing the procedure of Example 1 ~c), except using the
compound of Example 35 (b) (100 mg) and ~lS)-l-imidazol-2-yl-
2-methylpropylamine, the title compound was prepared (83 mg,
68%). NME~(CDCl3) ~ 7.22 (5H, m), 7.03 ~lEl, d~, 6.89 (2H, s),
4.72 (lH, d), 4.51 (lH, t), 3.91 (lH, q), 3.65 ~lH, m), 2.78
:: ~2H, d), 2.33 (2H, m), 1.8~ (4H, m), 1.48 ~4El, m), 1.36 (9H,
'
W093/02~7 PCr/U~92/06~47
' ` _ 77 2 1 ~
~wo singlets; rotamers present), 0.99 (9H, s), 0.91 (3H, d),
0.79 (3H, d), 0.07 (6H, d); MS m/e669.4 [M~HI+.
d) ~2R,4$r5S,l'S)-5-~t-butoxycarbonyl)amino-4-hydroxy-N~
isopropyl-1'-imidazol=2-yl)methyl-6-phenyl-2-~4,4,~-
trifluorobut-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(CD30D) ~ 7.19 ~5H, m), 6.92 ~2H,
s), 4.61 (lH, d), 3.64;(lH~ q), 3.48 ~lH, m), 2.79 (2H, m),
2.49 tlH, m), 2.13 (4H, m) 9 1.60 (5H, m), 1.36 ~9~, s~ 0.90
(3H, d), 0.71 (3H, d); MS m/e555.2 [M~]+.
.
a) 2~ carbobenzyloxyamino~ isobutyl)~ethyl-imidazole
Followin~ the procedure of Example l(a~, except
substituting Cbz-isoleucinal (1.83 g) for Cbz-valinal, the
~; title compound was prep red (0.658 g, 31%). NMR~CDC13) ~
6.96 (2H, s), 5.31 (lH, d~, 4.48 (lH, dd), 2.15 (lH, m~, 1044
~: 25 (9H, ~j, 1.17 (2H, m), 0.92 (3~, t), 0.82 ~3H, d); MS
(DCI/NH3) m/e 254.2 ~M+H3+.
~.
: b) (2R,4S,55,I'S)-2-phenylmethyl 4-hydro~y-5-~t-
butoxycarbonyl)amino-6-phenyl-N-(l~ isobutyl l' ~imidazo-2-
yl))methyl-hexanamide hydrochloride
Following~he procedure of Example l~b)-l(d), except
substitutiny the compound of Example 36(a) for (l'S)~
carbobenzyloxyamino~ isopropyl-1'-~imidazo-2-yl)methanet
the title compound was prepared. NMR(DMSO-d~ ~ 7~90 tlH,d~,
7.29-7.02 ~lOH, mj, 6.89 (2H,s), 6.50 ~lH,d), 4.81 (lH,m),
4.55 (lH, 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]~.
W093/02057 PCT/US92~060~7
~9~ - 78 -
Exa~ple ~1
~ . ~
~
,
- 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 o~ a l.OM solution in T~F, 6.0 eq) was
added and the solution stirred for 16 h. The soluti~n was
diluted with water and extracted with dichloromethane. The
combined organic extracts were washed with water and
lS evaporated to a white solid. The solid was covered with
diethyl ether and de~anted twice to give the title compound
as a white solid. ~0.012 g, 72%). NMR~CDC13) ~ 7.22-6.84
(lOH, m), 6.61 (lH, s), 5.42 (1~, d), 4.69 (lH, m), 4.41 ~lH,
: d), 3.58 (lH, m), 3.45 ~lH, m:), 2.78-2.40 ~SH, m), 1.91 (lH,
: 2Q m), 1.$~:~2H, m), 1.41 ~3H, d), 1.26 (9H, s) (rotamers
: observed), 0.71 (3H, d), 0.59 ~3~, d); ~S m/e S79.2 l~+H]+.
.
:::~ : a) 2-t-butyldimethylsiloxy~ dimethylethyl-(4-
nitrophenyl)carbonate
A mixture containing bis(4-nitrophenyl)carbonate
(0.996 g, 3.28 mmol), 2-t-butyldimethylsiloxy-1,1-
dimethylethanol (~.67 g, 1 eq) and 4-dimethylaminopyridine
0.4 g, 1 eq) in dichlorometh ne ~50 mL) was stirred at room
temperature for 5 d. The mixture was diluted with
~ ~ dichloromethane and washed successively with ~2 and
:~ saturated aqueous NaCl, and dried over Na2C03. The solvent
~ was removed in vacuo, and the residue was purified by flash
W093f02057 PCT/US92/06~47
21~
- 79 - .
chromatography ~silica, 20% ethyl acetate/hexanes) ~o afford
the title compound (35%). NMRtcDcl3~ ~ 8.25 (2H, m), 7.35
~2H, m), 3.76 ~2H, s), 1.53 (6H, s), 0.g4 (9H, 5)~ 0.09
(6H, s~.
s
b) (2R,4S,5S,l~S)-5-~2-t-butyldimethylsiloxy-1,1-dimethyl-
ethoxycarbonyl)amlno-g-t-butyldimethylsiloxy-N-(ll-isopropyl-
l'-imidazol-2 yl)me~hyl-6-phenyl-2-phenyimethyl-hexanamide
A solution of 2-t-butyldimethylsiloxy~ dimethylethyl-
4-nitrophenyl carbonate (137 mg, 0.372 mmol), ~2R,4S~5S,l'S)-
5-amino-4-t-butyldimethylsiloxy-N-(l'-isopropyl~ imidazol~
2-yl)methyl 6-phenyl-2-phenylmethyl-hexanamide ~102 mg, 0.186
mmol) a~d DMAP (45 m~, 0.372 mmol~ in methylene choride was
stirred at 20C u~der Ar for 24 h. The solution was wa~hed
with agueous Na2CO3, dried o~er solid Na2C03 and concentrated.
Fla h chromatography (4~ methanol/dichloromethane) provided
the intermediate (2~,4S,5S,l'S)-5-~2-~-butyld~me~hylsiloxy-
: 1,1-dimethylethoxycarbonyl)amino-4-~-bu~yldimethylsiloxy-N-
~ isopropyl~ 1-(2-t-butyldimethylsiloxy-lrl-
: 20 d~methylethoxycarbonyl~imidazol-2 yl)methyl-6-phenyl~2-
phenylmethyl-hexanamide, which was dissolved in ether, washed
with lQ% NaOH, dried o~er Na2CO3, and concentrated ~o provide
the ti~le compound (ll0 mg, 78% overall). NM~CDC13) ~ 7.37-
6.70 S13H, m), 6.39 (lH, d), 4.84 (lH, d), 4.55 (lH, t), 3.96
~1~, q3, 3 . 69 ~2H, s), 3.60-3.42 (2H, m), ~.94 ~lH, s(br)),
2.85-2.44 (4H, m:), 2.39 (lH, q), 1.90-1.60 ~2H, m), 1.31 ~6H,
r d), 1.02-0.85 (l8Hr m), 0.83 ~6H, t), 0.98 tl2Hf m~.
'
c~ (2R,4S,5S,l'S)-5-(1,1-dimethyl-2-hydroxyethoxy-
carbonyl3amino-4-hydroxy-N-(l'-isopropyl-1'-imidazol-~-
yl3methyl-6-phenyl-2-phenylmethyl-hexanamide
A mixture containing the compound of Example 38(b) (110
mg) and tetra-n-butylammonium fluoride (6 eq of lM solution
in THF) under an~ argon atmssphere was all3wed to stir at room
te~perature 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
Wl~ 93/020~7 PClr/US9~/~7
80- ~
title compound ~0 . 05 g, 66%) . N~ (CDC13, CD30D) ~ 7 . 30-6 . 78
~ 12H7 m), 4 . 42 ~lH, d), 3 .75-3 .38 (4H, m), 2 . ~7-2 .50 ~5H, m~,
2.08 (lH, m), 1.70-1.56 52H, m), 1.30 (6H, s), 0.90-0.55 ~6H"
dd) .
~2a::ation_0f_(2~45, S~i
______
A lM solution of HCl in e~her (63.5 mL) was added to a
solution of the compound of Example 38(c) 135 mg~ 0.064 mmol)
in methanol (5 mL). The solvent was remo~ed by rotary
~15 evaporatlon at 20C, and the solid residue was triturated
wit~ ether and dried to afford the ~itle co~pound as the
hydrochloride salt (35 mg, 95%). NMR~CD30~) ~ 7.37-6.85
(12H, m), 4.56 (lH, d~, 3.59 (lH, m), 3.48-3.33 (3~, m~,
:: ~ 2~8~2.48 (6H, m), 2.04 ~lH, septet~, 1.72-1.49 ~2H, m), 1.22
:0 (6~, d), 0.88(3H, d~, 0.61 (3H, dd).
:
E2~am~ 4 n
::
2S ~
D
a) benzyloxyethyl-(4-nitro)phenylcarbonate
~:: To a solution of 2-benzyloxyethanol (2.5 g, 16.4 mmol)
30: and bis (9-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
suGcessively with H20 and saturated aqueous NaCl and dried
35 over Na2S04. The solvent was removed in vacuo~ and the
residue was purified by flash chromatography (silica9 20%
ethyl acetate/hexanes) to afford the title compound ~4.38 g,
.
W093/02~7 ~ PCT/~Sg2/~W~7
- 81 -
84%). NMR(C~C13) ~ 8.26 (2H, m), 7.34 (7H, m) r 4 . 62 (2H~ s)
4 .49 (2H~ t) ~ 3.70 (2H~ t) .
b) (2~4S,SS,1'5)-5-(2-benæyloxyethoxycarbonyl)amino-4-t-
s butyldimethylsiloxy-N-[l'-isopropyl-1'-~N'-(2-
benzyloxyethoxy)carbonyl)imidazol-2-yl]methyl-6-phenyl-2
phenylmethyl-hexanamide
To a solution of (2R,4S~5S,l'S)-5-amino-4-t-
butyldimethylsiloxy-N-~ isopropyl-1'-imidazol-2-yl)methyl-
6-phenyl 2-phenylmethyl-hexanamide (134.5 mg, 0.24 mmol) in
dichloxomethane ~40 mL) under an argon atmosphere,
benzyloxyethyl 4-nitrophenyl caxbonate (160 mg, 2 eq) and 4-
dimethylaminopyridine ~60 mg, 2 eq~ were added. The
resulting mixture was allowed to stir at room tempera~ure
overnight, and was diluted with dichloromethane. The organic
; extract was washed successi~ely with aqueous Na2C~3, H20,
aqueous Na2C03 a~d H20, and dried over Na2C03. The so~vent
was removed in vacuo,: and the residue was purified by flash
: chromatography ~silica, 4% methanol/dichloromethane) to
afford the tltle compound (180 mg, 82~). NMR~CDC13) ~ 7.45-
6.80 (22H, m), 6.:62 (lH, d), 5.60 (lH, t~, 5.06 ~1~, d~, 4.60(2H, s), 4.52 (2H, ~), 4.50 (2H, m), 9.31 (lH, m), 4.07 ~2H,
m~ 3.~80 12H, t), 3.68 ~lH, q), 3.57 (lH, q), ~.~5 ~lH, m),
:~ . 2.77-2.41 (4H, m), 2.09:(lH, m)~ 1.90 (lH, m), 1.73 tlH, m),
C.95 (9H, s), 0.81 (6H, dd), 0.11 t6H~ d~.
c) (2R, 4S, 5S,lYS)~-5-(2-hydroxyethoxycarbonyl)amino-4-t-butyl-
dimethylsiloxy-N-tl~'-isopropyl~ NI-2-benzyloxyeth
carbonyl)imidazol-2-yl]methyl-6-phenyl-2-phenylmethyl-
hexanamide
The.compound of Example 40(b) (68 mg, 0.44 mmol) was
;~ stirred as a solution in methanol (S0 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
a~ford the title compound (44 mg, 74%). NMR(CDC13) ~ 7.36- :
6.72 (12H, m), 5,03 ~lH, d), 4.80 (lH, dd), 4.50-4.32 (2H,
W093/02~7 PCT/U~92/06047
~ 82 -
m)~ 4.07-3.52 (SH, m), 2.96-2.32 (6H7 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,l'S)-5-(2-hydroxyethoxycarbony})amino-4-hydroxy-
N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-
phe~ylmethyl-hexanamide
To a solution of the compound of of Example 40 tc~
in methanol, excess aqueous ~Cl ~approx. 5 equiv.) was added.
The resulting solution was stirred at room tempera~ure
.o overni~ht, and concentrated under reduced pressure. The
residue was diluted with H20, and made basic with aqueous
Na2CO3. The mixture was extracted w~h dichloromethane~ and
the ~ombined organic extracts were dried over Na2C03. The
solvent was removed in v~cuo, and the residue was purified by
flash chromatography to afford the title compound.
NMR~CD3OD) ~ 7.28-6.85 ~12H, m), 4.55 (lH~ d), 3.95 (lH, m),
3.73-3.40 ~4H, m), 2.86-2.47 (5H, m), 1.~ ~lH, m)r 1~71 (lH,
m), 1.22 ~lH, m), 0.84 (3H, d), 0O62 ~3H, d~.
Exnm~
a) 2-~-butyldimethylsiloxy-1-methylethyl-(4-nitrophenyl)-
, carbonate
A mixture eQntaining bis~4-nitrophen~l)carbonate
~3.20 g, lO.S mmol), 2-t-butyldimethylsiloxy-1-methylethanol
30 ~2.0 g, 10.5 ~mol~ and 4-dimethylaminopyridine ~1~30 g, 1 0.5
mmol~ in dichlorométhane ~200 ml) was stirred at room
,.. .
temperature for S d. The mixture was then diluted with
: dichloromethane and washed successively with H2O and
saturated aqueous NaCl and dried over Na2CO3. The so~ent
was removed in vacuo, and the residue was purified by flash
chromatography (silica, 10% ethyl acetate/hexane) to afford
the titl~ compound ~88%). NMR(CDC133 ~ 8.28 (2H, m), 7.39
.
WO93/5~2~7 P~T/US92/~6~47
-5 83 - 21 ~-3 ~
(2H, m)~ 4.98 (lH, m), 3.75 (2H, d), 1.38 (3H, s), 0.92 (9H,
s~, 0.11 (6H, s).
b) (2R,4S,5S,l'S)-5-(2-t-butyldimethylsiloxy l-methyl-
ethoxycarbonyl)amino-4-t-butyldimethylsiloxy-N-~l' isopropyl-
1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide
~ Following the procedure of Example 38(b) r except
substituting the compound of Example 4~a) for 2-t-
butyldimethylsiloxy~ dimethylethyl-4-nitrophenyl
carbonate, the title compound was prepared. NMR~CDC13)
7.40-7.00 ~lOH, m), 6.90 (1/2H, s), 6.72 (1/2H, s), 6.45 (lH,
dd), 9.92 (lH, dd), 4.84-4.61 ~2H, m), 4.10 (lH, m), 3.76
(lH, m), 3.58 ~lH, m), 2.92-2.73 (3H, m), 2..70-2,45 (3H, m),
1078 (2H, m), 1.22-1.08 (3H, m), 1.04 0.81 ~24H, m~, 0.17-
0.09 (12~, m3.
c) (2R,4S,5S,l'S)-5-((lRS)-l-methyl-2-hydroxyethoxycarbonyl)-
: amino-4-hydroxy-N-~ isopropyl~ imidazol 2-yl)mçthyl-6-
p~enyl-2-phenylmethyl-hexanamide
Following the proc~dure of Example 38(c), except using
the compound of Example 4(b), the title compound is prepared.
NMR(CD30D) ~ 7.15-6L68 ~1?~, m) r 5.72~5.60 ~lH~ dd) ~ 4 .58
: ~ (lH, m), 4.38 ~l~, dd), 4.06 (lH, m), 3.62 (lH, m~, 3.41 (lH,
~: ~ m), 2.79-2.55 (5H,:~m),: 2.49 (lH, dd), 1.92 (lH, m~, 1.67 (~H,
m),:1.08-0.98 (3~r: dd): ~ 0 . 69 (3H, dd), 0.58 (3H, dd).
: . :
~:
~
,
a) ~trans)-2-(t-butyldimethysiloxy)-cyclopentanol
~ ~: To a ~ixture of t-butyldimethylsilyl chloride (5.08 g,
:~ 35 33.7 mmol) and~imidazole (2.30 gt 33.7 mmol) in DMF (lO mL~,
~ a solution of trans-1,2-cyclopentanediol in DMF (4 mL) was
; added. The reaction mixture was stirred overnight at 25C.
Th50 reaction mixture was diluted with ice water and extract5ed
W093/02057 PCT/US92/06~7
- 84 -
with ether. The ether extract was washed with water and
brine, dxied over magnesium sulfate, filtered and the solvent
removed in vacuo. The residue was purified by flash
chromatography ~silica, 9:1 hexane:ethyl acetate) ~o the
title compound as an oil (3.44 g, 49%).
b) ~trans)-2-tt butyldimethysiloxy)-cyclopentyl)-(4-
nitrophenyl)carbonate
To a solution of the compound of Example 42ta) ~1.08 g, ~;
5 mmol) and D ~ (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 25C. The reacti~n
mixture was diluted wi~h 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
e~aporated to an oil and purified by flash chromatography
(silica~ ~:l hexane:ethyl ace~ate) to yield the title
compound as an oil ~1.75 g, ~2%).
c) 5-~trans)-2-t-butyldimethylsilo~y-cyclopentyloxy-
carbonyl)amino-4-t-butyldimethysiloxy-N-[1'-isopropyl-1'~
(2-t-butyldimethysiloxy-cyclopentyloxycarbonyl))imida~ol-2-
yl]methyl-6-phenyl-2-phenylmethyl-hexanami~e
A solution of 5-amino-4-t-butyldimethylsiloxy-N~
` isopropyl~ imidazol-2-yl~methyl-6-phenyl-2-phenylmethyl-
~: hexanamide (171 mg, 0.311 mmol~, DMAP ~76.1 mg, 0.623 mmol)
and the compound of Example 421b) (238 mg, 0.623 mmol) in
dichloromethane (9 mL~ was stirred overnight at 25C. 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 ~acuo . The residue
was purified by flash chromatography (silica, 4:1
- hexane:ethyl acetate) to yield the title compound as an oil
(150 mg, 47%).
W0~3/020~7 . PCT/~S92/~6047
' - 85 - 21~3~
d) 5~1(trans)-2-hydroxy-cyclopentyloxycarbonyl)amino 4
hydroxy-N-[l'-isopropyl-1'-imidazol-2-yl]mekhyl-6-phenyl-2-
phenylmethyl-hexana~ide
To a solution of the compound of Example 42(c) ~150 mg,
s 0.145 mmol) in methanol ~5 mL~, 3N HCl ~3 mL) was added. The
solution was stirred overnîght at 25C. The me~hanol 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 v~cuo to yield the title compound (51.5 mg, 63%).
~MR(CD3OD, 400 MHz) ~ 7.0-7.3 (m, lOH), ~.87 ~s, 2H), 4.63
(m, 2H), 3.88 ~m, lH~, 3.55 ~d, lH), 2.5-2.9 m, 5H), 1.4-2.1
~br, 9H), 0.88 ~d, 3H) r 0.71 td, 3H); TLC Rf 0.27 ~silica, 8%
methanol/chloroform~.
~am~
_
~0 ~ ~
a) t-bu~yldimethylsilyl 4-(t-butyldimethylsiloxy)-butanoate
To a suspension of t-butyldimethylsilyl chloride (29.9
g, 198 mm~ n 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 25C. The solvent was removed under reduced pres~ure and
:~ ~he xesidue 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 oilO
b3 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
~ ~3 3 PCr~US92/0~7
- 86 -
dried with magnesium sulf~te, 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,SS,l'S)-5-(4-t butyldimethylsiloxy-butanoyl)amino-
4-hydroxy-N-(l'~isopropyl-l'-imidazol-2-yl)methyl-6-phenyl-2-
phenylmethylhexanamide
A solution of (2R,4S,5S,l'S)-5-amino-4-t-
butyldimethylsiloxy-N--(l'-isopropyl-1'-imidazol-2-yl)methyl-
6 phenyl-2-phenylmethyl-hexanamide tl75 mg, 0.319 mmol), 4-t-
butyldimethylsiloxy-butanoic acid ~84 mg, 0.41 mmol), BOP
reagent tl48, 0.335 mxnol), triethylamine (46 ~L, 0;335 ~unol)
and dichloromethane (4 mL) were stirred at 20C under Ar for
24 h. The reaction mixture was diluted with dichloromethane,
wa~hed with aqueous Na~C03, water and brine, and dried over
solid magrlesium sulfate. The organic phase was :flltered, aQd
conce~trated in ~acuo- The resi~e was purified by flash
chromatography (silica, 2% methanol/chloroform) to pro~ide
;~: 20 the title compound.
:: :
d) (2R,4S,5$,1'S)-5-(4-hydroxybutanoyl)amino-4-hydroxy-N~
- isopropyl~ rimidazol-2-yl)methyl-6-phenyl-2-
phenylmethylhexanamide :
A solution of the compound of Example 43 (c) ~177 mg,
0.236 mmolj and: t~tra-n-butylammonium fluoride (2.84 mL, 2 .84
. mmol, lM soluti~on in THF) was stirred under an argon
atmosphere at room: temperature overnight. The solution was
diluted with ethyl acetate r washed with saturated sodium
30 bicarborlate solution/ and water, and the organic layer was
~: concentrated. The residue was precipitated from the ethyl
acetate solution to afford the title compound. NMR ~ tCD30Dp
400 MHz) 7~0-7.3 (m, lOH), 6.86 ts, 2Hl, 9,62 (d, lH), 9.05
;~ ~m, lH~, 3.43 (t, 2H), 2.55-2.90 (m, 4H), 2.60 tm, lH) t 2.17
: : 35 ~mt 2H), 2.05 (m~ lH), 1.76 (m, lH), 1.67 (m, 2H), 1.55 tm,
lH), .88 (d, 3H), .72 (d, 3H); TLC Rf 0.40 (silica, 10%
methanol/chloroform).
WO 93/02057 PC~/US92/06047
2 . ~
~Q~ :
Preparati thyl-4-hydrQ~cy-5-
imi~a~o-2-yl)methy~-hexa~amid~
(a) (2R,4S,55,1'S~-2-phenylmethyl 4-butyldimethylsiloxy-5-
~benzyloxycar~onyl)valylamino-6-phenyl-N-~l'-isobutyl-1'-
(imidazo-2-yl))methyl-hexa~amide.
A solution~of carbobenzyloxy-(L)-valine (50.4 mg, 0.20
mmol), the product o~ Example 13(a) (110 mg, 0.20 mmol), BOP
~eagent ~88.7 m~, 0.20 mmol~ and triethylamine ~28 ~l, 0.20
mmol) in methylene chloride (4 mL) was stirred at 25~C for 4
d. The reaction mixture~was diluted with me~hylene chloride,
washed with saturated sodium bicarbonate and the organic
}ayer was concentrated. The product was purified by flash
chromatography~(silica gel, 4% CH2C~2/ ~eOH) to give the
~:~ title compound ~(104 mg, 67%).
~. :
20 tb) t2R~4s~ss~ s)-2-phenylmethyl-4-hydroxy-5
(benzyloxycarbonyl-valyl):amino-6-phenyl-N-tl'-isobuty~
: : imidazo-2-yl)mèthyl-hexanamide.
,~
To a solution~of;the compound of Example 44(a) (104 mg,
0~.133~mmol) in MeOH (8~mL), 3N HCl (2 mL) was added. The
:2s solution was~stirred:~for 16 hrs at 25C. The methanol was
remov~d at reduced:pressure and 10% sodium carbonate w~s
added to~pH -7~.5.~ Ether (10 mL) was added and the solid
product was:filtered:anq dried in vacuo to proYide the title
compound (58 mg, 6S~). NMR(CDCl3) 8 0.62 (d, 3H), 0.7B (d,
3H), 0.82 (d, 3H), 0.90 (d, 3H), 1.62 ~m, 2H~, 1.96 tm, lH),
2.06 (m, IH), 2.55~lm, lH~, 2.77 ~m, 4H), 3.38 (s, lH~, 3.53
(m, lH~, 3.91 (M,lH), 3.99 (m, lH), 4.47 (d, lH), 5.11 (~,
: : 2H), 5.78 ~d, lH~, 6.85 (s, 2H), 6.92-7.34 (m, 15H);
MS m/e 667 [M+H] + .
3s
:: :
: ~
W093/02~7 PCT/US92/Q6~7
~ 88 -
PreparatiQ~ of ~2R~4S~ 1'S~-2-phe~ylmethyl-4-hydro~y-5-(~-
ace~ylval~l~min~-6-ph~nyl-~ l~g~o~L_L~=h~1~z~-2-
s yl)methyl-h~n~mi~
~a) (2R,4S,5S,liS)-2-phenylmethyl-4-t-butyldimethylsil)oxy-5-
~N-acetyl-valyl)amino-6-phenyl-N~ isobutyl-1'-imidazo-2-
yl)methyl-hexanamide
To a solution of N acetyl-~L)-valine ~40.3 mg, 0.253
mmol) in dry THF (8 mL) at -40C was added n-methylmorpholine
(55.7 ~1,Ø506 mmol) followed by isobutyl chloroformate
(33.5 ~l, 0.253 mmol). The reac~ion mixture was stirred for
15 min, and the compound of Example 13(b~ (139 mg, 0.253
mmol) in T~F ~3 m~) was added. The reaction mixture was
allowed to warm to room temperature and stirred for 2 d. The
reaction was diluted with ethyl aee~ate, and washed with
water and brine. The organic solution was dried with sodium
sulfate~ filtexed a~d the solve~t remo~ed under re~uced
pressure. Th~ xesidue was purified by flash chromatography
(silica~ 4~ methanol~chloroform) to gi~e the produc~ as an
oii ~47 mg, ~7%)~
~b) (2R,4S,5S,l'S) 2 phenylmethyl-4-hydroxy-5-(N-
acetyl~alyl~mino-6-phenyl-N~ -isobutyl~ imidazo-2-
yl)methyl-hexanamide.
To a solution of the compound of Example 45(a) (47 mg,
~ 0~0681 mmol) in methanol (3 mL), 3N HCl (0.5 mL) was added.
: The reac~ion was stirred for 16 h at 25C. The methanol was
removed under reduced pressure and the solution was dilutPd
with wa~er and neutralized with 5% sodium carbonate. The
solid product was filteredt washed with water and ether, and
dried in ~cuo to yield the title compound ~29.5 mg, ~75%).
:~ NMR (CD3OD) ~ 0.70 (d, 3H~, 0.88 (m, 9H), 1.57 (m, lH~, 1.70
(m, lH~, 1.92 ~s, 3H), 2.05 (m, lH), 2.55 (q, lH), 2.77 (m,
: 4H), 3.57 (d, lH), 4.03 (m, 2H), 4.60 ~d, lH), 6.87 (s, 2H),
6.95-6.20 (m, lOH); MS m/e 575 [M+H~.
W093/02057 PCT/US92~ 7
:; - 89 - 2l~3~
Exampl~ 46
~lLm~t~lQ~rbon~ll~mL~o-4-hydLoxy-N-(1'-i~Qprop~
5 imidazol-2-yl)me~hy1 6-phenyl-2-phenylmethyl-hexanami~
a~ (benzyloxymethyl)imidazol-2-yl)methyl-(9-
nitrophenyl)carbonate
A mixture of bis~4-nitrophenyl)carbonate, (1- :.
10 benzyloxymethyl)imidazol-2-yl)methanol and 4-
dimethylaminopyridine was reacted according to the procedure
of Example 14~a) to afford the title compound (58%).
NMR(CDC13, 400 MHz) ~ 8.18 (d, 2 H,`J-8.38 Hz), 7 .44-7.23 (m,
7H~, 7,11 (S, lH~, 7.13 (s, lH), 5.48 (s, 2H), 5.44 (s, 2H),
4.49 (s~ 2H).
b) ~2R,4S,SS,l'S)-5-~$1-benzyloxymethyl)imidazol-2-
yl)methyloxycarbonyl)amino-4-t-butyldimethylsiloxy-N-(l'-
isopropyl-1'-imidaz~1-2-yl)methyl-6-phenyl-2-phenylmethyl
20 hexanamide.
A mixture:of the compound of Example 46(a),
12R,4S,5S,~'S)-5-amino-4-hydroxy-N-(1 7-isopropyl~ imidazol-
2-yl3methyl-6-phenyl-2-phenylmethyl-hexanamide, and 4-
: dimethylaminopyridine was reacted according to the procedure ::
~2s of Example 14~b) to afford the title compound ~32%).
NMR(CDC13) ~ 7.50-6.60 ~m, l9H), 5.25 (m, 2H), 5.11 (~, 2H,
~-11.03 Hz), 4.68 ~m, lH), 4.39 (m, 2H), 3.97 (m, lH), 3.67
m, lH), 2.88 ~(m, lH), 2.72-2.28 (m, 6H), 1.85 (m, lH~, 1.60
m, lH), 0.92-0.81 (m, 15H), 0.80 (s, 3H), O.V6 (s, 3H);
~S(ES) m/e 793 lM+H]~.
., .
c) (2R~ 4Sr 5S~ l ~S) -5- ~imidazoyl-2-yl-
methylsxycarbonyl)amino-4-t-butyldimethylsiloxy-N~
~: . isopropyl-l'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-
: : 3S hexanamide
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
W0~3/02057 PCT/US9~/06~47
~3-~ 90 -
(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~CDCl3) ~ 7.29-6.83 (m, 14H); 5.05 (d, lH, J=11.2 Hz),
4.91 (d, lH, J=11.2 Hz), 4.71 (m, lH), 3.92 ~m, lH), 3.61 (m,
lH), 3.02 1~, lH3, 2.81-2.54 (m, 4H), 2~36 (m, lH~, 1.93 ~m,
lH), 1.59 (m, lH), 0.91 ~d, 3~, J=7.1 Hz~, ~.89 (s, 9), 0.69
(d, 3H, J=7.1 Hzt, 0.84-0.05 (m, 6H); MS(ES) m/e 673 [M+H]~.
d) (2R,4S,5S,l'S3-5-~imidazol-2-yl-methyloxycarbonyl)amino-4-
hydroxy-N~ isopropyl-1'-imidazol-2-yl)me~hy~-6-phenyl-2-
phenylmethyl-hexanamide
The compound of Example 46Sc) (24 mg, 0.035 mmoL) t 95%
aqueous EtOH (0.5Q mL3, and concentrated aqueous HCl (0.050
mL~ were stirred at 23~C for 24 h. The æolution was diluted
with H20 (5 mL) washed with EtO~c and then the aqueous phase
was made basic by ad~ition of solid K2C03. Extrac~ion wi~h
EtOAc, concentration of the organic extrac~ and tritura~on
with CH2C12 afforded the title compound (14 mg~ 72%~. NMR
(CDCl3) ~ 7.33-6.85 (m, 14~), 5.11 (d, lH, J=~0.8 Hz), 4.96
(d, lH, J=10.8 Hz3, 4.47 (m, lH), 3~72 (m, lH~, 3.38 (~t lH3,
2.81 (m, 4H), 2.59 (m, lH), 2.07 ~mD lH), 1.72 ~m, lH), 1.62
(m, lH), 0.78~(d, 3H, J-6.63 Hz), 0.67 (d, 3H, J=6.63 Hz~;
:: 25 (m, 6H~; MS~ES~ m~e 559 tM~H]+.
, Example 47
x~a~atin~
methyll~rQpyloxycarbo~yl~mino-4-hydxoxy-N~ isn~r~pyl-l'-
imud~zoL-2-yllmethyl-~.-ph~nyl-?-phenylmethyl-hexanamide
:
: a) ~lRS)-1-~1-benzyloxymethylimidazol-2-yl)-2-
methyl)propyl-~4~nitrophenyl)carbonate
3s A mixture of bis(4-nitrophenyl)carbonate, (lRS)-1 ((1-
benzyloxymethylimidazol-2-yl)-2-methyl)propanol and 4-
dimethylaminopyridine was reacted according to the procedure
: of Example 14~a) to afford the title compound (61%). NMR
W~93/02~7 PCT/U5~2/~7
.
- 91 2~ ~36 j~ ~ .
(CDC13) ~ 8.18 ~d, 2H, J=8.31 Hz), 7.38-7.21 (m, 7H), 7.13
~s, lH), 6.94 (s, lH), 5.74 (d, lH, J=11.1 Hz), 5.4~ ~d, lH,
J=10.2 Hz), 5.28 ~d, lH, J=10.2 Hz), 4.53 (d, lH, J=ll.-~ Hz),
4.41 (d, lH, J=11.3 Hz), 2.64 (m, lH), 1.18 ~d, 3H, J=6.0
s Xz), 0.87 (d, 3H, J=6.02 Hz); MS(ES) m~e 426 [M+H]+.
b~ (2R,4S,5S,l'S,l'iRS)-5-((1"-(1-benzyloxymethylimidaz~1-2-
yl)-2't-methyl-propyl)oxycarbonyl)amino-4-t-
butyldimethylsiloxy-N-(1'-isopropyl-1'~1-(1" (1
benzyloxymethylimidazol-2-yl)-2"-
methylpropyl~oxycarbonyl)imidazol-2-yl)methyl-6-phenyl-2-
phenylmethyl-hexanamide
A mixture of the compound of Examplé 47(a) (1~5 mg, 0.33
mmol), the compound of Example 13(a) ~75.9 m~, 0.14 mmol~, 4-
dimethylaminopyridine (41 mg~ 0.33 mmol~ and D~F (0.5 mL~ W2S
stirred under argon for 18 h. The ~MF was e~aporated ~n
~acuo and ~he resid~e was combined w~th 10% aq ~C~3 (10 mL)
and extracted with EtOAc. The c:om~ined extracts were washed
w:ith saturated aq NaHCO3, dried (R2CO3), filtered and
concentrated in vacuo. The residue was flash chromatographecl
(silica, step grodient~ 0 4% MeOH/CH2C12) ~ to afforc3 the ~itle
compound (96.1 mg, 57%). N~ ~CDC13) ~ 7.38-6.78 (m, 26H),
S . 6? (m, lH), 5 . 61-5 . 0û tm, 6H), 4 . 58--4 0 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,
: ~ 2s 27~), 0:. 50-0 . 05 (mr 6Hj.
c) ~2R,4S,55,1'S,l"RS)-5~[(1"-~1-benzyloxymethyl-
imidazol-2-yl)-2"-methyl-propyl)oxycarbonyllamino-4-hydroxy-
N~ isopropyl-l'-imidazol-2-yl)methyl~6-phenyl-2-
30~ phenylmethyl-hexanamide ! ~
, A s~lution of the compound of Example 47(b) ~81 mg, O.Q7
~: ~mol) r CH30H (0.75 mL), and 3N aqueous HCl ~0.25 mL) was
stirred at 23C for 20 h. The reaction mixture was diluted
with H20 (10 mL) and washed with EtOAc ~3 x 15mL). Solid
K2C03~was added to give a basic solution (pH>12~, which was
extracte~ with EtOAc. The extracts were dried ~K2C03),
filtered, concentrated and flash chxomatographed (silica,
step gradient, û-8% CH30H~CH2C12) to give the title compound
W093/02~7 PCT/US92/06~7
~3~ 92 -
(34.9 mg, 65%). lH NMR (CDCl3) ~ 7.43-~.79 (m, 9H), 5.87,
5.66 (2d, lH, J=10.66, 10.85 Hz), 5.28 (m, 2H), 4.68 ~m, lH),
4.42 (m, 2H), 3.71 ~m, lH), 3.58 (m, lH), 2.~0-2.31 (m, 6H),
2.11 (m, lH), 1.75, 1.51 (2m, 2H), 1.05, 0.97 (2d, 3H,
S J=6.32,6.45), 0.68 (mr 9H).
d) (2R,4S,55,1'S,lnRS)-5-t(1"-~imidazol-2-yl)-2"-
methyl)propyloxycarbonyl)amino-4-hydroxy-N-(1 t - isopropyl-1'-
imidazol 2-yl)methyl-6-p~enyl-2-phenylmethyl hexanamide.
R mixture o~ the compound of Example 47(c) ~34 mg,
0.047 mmol), CH30H (4 mL), and 10~ Pd/C (34 mg), was stirred
under H2 ~l atm) for 26 h. The suspension was`filtered
- through Celite~, concentrated, and tritura~ed with CH2Cl2 to
yield the title compound ~4 mg, 14%~. lH NMR ~CDC13tCD30D)
~.7.32-6.71 ~m, 14H), ~.38 (m, lH~, 4 . 55 ~m, 1~), 3 . 72 (m,
lH), 3.55 (m, lH~, 2.78 (m, 4H), 2.55 ~m~ lH), 2.15 (m, 2~,
1.60 (m, 2H~, l,03-0.61 ~m, 12~).
2~
,.
(a) ~l'S)~ (carbobenzyloxy)amino~ isopropy~ (4
(imidazo:1-2-yl)imid~zol-2-yl)methane
Cbz-(L)-valinal (0.45 g, 1.4 mmol) was stirred in
anhydrous methanol at 0C 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 alloiwed to
stir at ~~ for 1 h. The cooling bath was removed and the
solution stirr d at room temperature for 16 h. The methanol
was evaporated in vacuo and the residue was diluted with 5%
aqueous HCl. ~fter 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
e~aporated to a solid which was chromatographed ~silicar 4%
wo s3/n20s7 , PC~/USg2/060q7
,................................. - 93 21~ 4
methanol/dichloromethane) to give the title compound ~0.216
g, 43%) as a white solid. NMR (CDC13) ~ 7.15 (6H, s~br)),
6.88 (2H, s), 6.30 (lH, d), 4.89 (2H, dd), 9.52 (1~, t), 2.05
(lH, m), 0.73 (3H, d), 0.62 ~3H, d). MS m/e 340.2 lM+H]~
(b) (2R,4S,5S,l'S)-S-(t-butoxycarbonyl)amino-4-hydroxy-N-
[1'-isopropyl~ (4-~imidazol-2-yl)imidazol-2-yl)]methyl-6-
phenyl-2-phenylmethyl-hex~namide
The compound of F.xamp}e g8(a) (0.13 gm.~ was dissolved
in anhydrous methanol with 10% Pd on activated caxbon (0~02
g). Hydrogen gas was bubbled through the solution ~ia
balloon for 1 h and the solution was stirred overni~ht under
a hydrogen atmoephere. The mixture was filtered through a
pad of Celite~ and evaporated ~o yield 1 '-amino~ isopropyl-
~4- ~i~nidazol-2-yl) im~dazol-2-yl~methane as a white solid
3 g~ 1009~).
This co~plsund was co%~ined w~th ~he compound of Example
13~a) ~0.334 g, 0.63 ~unol), BOP reagerlt ~0.28 g, 0.63 Imnol),
and triethylamine (0.13 ml., 0.945 m~ol) in DMF (1 mI,) and
allowed to stir under Ar for 3 d~ The DMF ~as evaporated in
vacuo and the residue was diluted wi~h di:chloromethane. ~he
~ solution was washad with water ~nd~brine. The organic layer
: was dried over sodium:carbonate, iltered, and evaporated to
yield (2R, 4S, 5S, 1~' sj -5- (t-butoxycarboI yl) amino-4-t-
butyldimethysiloxy-N- [1 '-isopropyl~ (4- ~imidazol-2-
yl) imidazol-2-yl)~mPthy7-6-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 tempçrature under argon. Tetrabutylammonium
f luoride ~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 ex.tracts:were washed with water and evaporated to an
~ oily residue. The residue was dissolved in THF and several
: ~ 35 drops of diethyl ether were added until a white precipitate
for~ed. The precipitate was collected by filtration and
dried in vacuo to yield the title compound as a white solid
~ (76 mg, 90%). NMR (CD30D) ~ 7.37-6.84 ~13H, m), 4.61 ~lH,
:
WOg3/020S7 PCT/U~2/~6~7
2 ~ ~3 ~ 94 -
d), 3.69 (2H, m), 3.S4 (lH, d), 2.84-2.52 (5H, m~, 2.06 ~lH,
m), 1.83 ~2H, m), 1.57 (lH, m), 1.30 (9H, s), 0.87 (3H, d),
0.69 (3H, d); MS m/e 601.2 rM+H]+
E~am~ 2
~ .
a~ di~t-butyldimethylsiloxymethyl~ methyl-(4-nitrophenyl)
carbonate
A mixture containing bis~4 nitrophenyl) carbonatetl.89
g, 6.21 mmol), ditt-butyldimethylsiloxymethyl)methanol (2.00
g, 1 eq) and 4-dimethylaminopyridine (757 mg, 1 eq) in
dichloromethane (100 mL) was stirred ~t room temperature for
- 2 d. The mixture wa~ diluted with dichloromethane and washed
with saturated a~ueous Na2CO3, brine~ and dried over Na2SO~.
The solvent was removed in ~acuo, and the residue was
purified by flash dromatography (silica, 10% ethyl
acetate/hexanes) to afford the title compound (75%). NMR
(CDCl3) ~ 8.29 (2H, m), 7.37 (2~ m~, 3,96 ~1~, m~, 3.85
(2H, d), 3.82 (2~, d), 0.89 (18H, s)~ 0~09 (12H, s~,
2s ~) t2R,4~,5Sfl'5)-5-(di(t-
butyldimet~ylsiloxymethyl) methyloxycarbonyl 1 amino~ 4- t -
butyldimethylsiloxy-N~ isopropyl-l'-imidazol-2-yl)methyl-
6-phenyl-2-phenylmethyl hexanamide
~: : A solution of ditt-butyldimethylsiloxymethyl~-methyl 4-
3a nitropheny~ carbonate (475 mg, 0. 9?4 mmol), the compound of
~, i
Example!13(a) (178 mg, 0.325 mmol) and dimethylaminopyridine
: ~119 mg, 0.974 mmol) in methylene choride was stirred at 20C
under Ar for ~4 h. The solution was washed with aqueous
Na2CO3, dried over solid Na2CO3 and concentrated in vacuo.
3s Flash chromatography (silica, 4% methanol/dichloromethane) of
.
the residue provided the intermediate (2R,4S,5S,l'S)-5-(di(~-
bu~yldimethylsiloxymethyl) methyloxycarbonyl)amino-4-t-
butyldimethylsiloxy-N-(l'-isopropyl-1'-(1-(dilt-
:
W~93/02057 PCT/US9~ 7
- 95 - 2~ 13 ~
butyldimethylsiloxymethyl) methyloxycarbonyl)imidazol-2-
yl)methyl-6-phenyl-2-phenylmethyl-hexanamide, which was
dissolved in ether, washed with 10~ NaOH, dried over Na2C03,
and concenkrated to provide the title compound (197 mg, 71%).
NMR ~CDC13) ~ 7.43-7.~5 ~lOH, m~ 6.90 (2H, s), 6.65 ~
bs), 5.09 (lH~ d), 4.78 ~lH, bd), 4.08 (lH, m), 3~89~3.50
(7H,m) 3.00-2.80 (4H, m), 2.~5 ~lH, m), 2.55 (2H, m~, 1.90
(lH, m), 1.78 (lH, m), 1.10-0.85 (33H, m), 0.20-0.06 (lBH,
m).
c) (2R~4S,5S,l'S)-5-~di(hydroxymethyl)methoxycarbonyl)amino-
4-hydroxy--N~ isoprcpyl~ imidazol-2-yl)methyl-6-phenyl-2-
phenylmethyl-hexanamide
A mixture containing the compound of Example 49(b) ~50
lS mg) and ethereal HCl (4 eq) was allowed to stir in
methano~:water (9:1~ at room temperature overnigh~. The
:. sol~e~t wa~ remo~ed ~ vac~o, and the residue wa~ diluted
with ethyl acet~te and washed with saturated aquesus Na2C03.
The product was purified by flash chromatography (~ilicat 4%
methanol~d~chloromethane) to afford the title compound
~ (2~ mg, 94%). NMR (CD30D) ~ 7.20-6.80 ~10~, m), 6.71 (2H,
: s), 4.50 (lH, d);, 3.90 ~lH,m), 3.65-3,34 (SH, m), 2.82-2.45
: (6H, m), 1.99 (lH, m), 1.74 (lH, m), 1.52 ~lH, m), 0.78 (3H,
d), 0.60 (3H, d).
yllp~y~ ~nyl~a~r~ D~ N~ sopropy~ azQl=2
~
Reacting the compound of Example 32~b) (81 mg, .133mmol)
....
with m-chloro perbenzoic acid ~23 mg, O.133mmol)in CH2C12
yielded the title compol~nd. NMR ~C~30D) ~ 7.20-6.85 (lOH,
m), 6.78 ~2H~ s), 4.51 ~lH, d), 3.66 tlH, 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 t2H, m), 0.78 ~3H, d~, 0.60 t3H, d~; MS m/e 595.2
lM+H3+.
~ .
WO 93/02057 PCr/US92~6047
~ 3~ 96 -
Example 5~1
Pxeparation of ~2R, 4S, 5S, 1 ' S) -5- ( (tetrahydrQsulfonyll?yran-4-
yl~oxycarbony~)amino-4-:hydroxy-N~ pro~yl-1'-imidazo~2-
5 ~ me~ 6-phenyl-2-ph~e~byl~r C1~
Reacting the compound of Example 50 531 mg, 49.2~1mol)
with m-chloro perbenæoic acid ~10 mg, 59.2 ~lmol) in methylene
chloride yielded the title compound. NMR ~CD30D) ~ 7 . 20-6 0 85
(lOHr m), 6.76 ~2H, s), 4.48 ~lH, d), 3.68 (lH, m), 3.44(1H,
m), 2.96-2.42 (9H, m), 2.32-2.,04 (2H, m), 1.97-1.62 ~4H, m~,
1. 6ï-l . 4-~ (2H, m), O . 79 (3H, d), O . ~0 (3H, d); MS m/e 611 . 2
[ M+~ I f .
~am~l
: ~ : 20 (a~ ~2R,4$,5S,l'S)-5-(1,1-dimethyl-2-
hydroxyethoxycarbonyl~ami~o-4-~t-butyldi~ethyl~ilyl)oxy-N~
~l'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl~2-
phenylmethyl-hexanamide
The compound of Example 38(b) (223 mg, 0.221 mmol) was
; 25 dissolved in 10% aqueous methanol and combined with 1~ HCl in
ether tO~22I mI" 1 ~eq) at room temperature. APter completion
of the reaction the solvents were removed in v~cuo~, The
~ residue was di~ssolved in dichloromethane and washed with
::: aqueous saturated Na2C03. The organic layer was corlcentrated
3~ and the residue was purified by ~Elash chromatography ~sîlica,
4% methanol/dichloromethane) ~o provide the title compound
~ .
~138 mgr 94%~. N~R ~CDC13) ~ 7.38-6.81 (l~H, m3, 4.93 + 4.65
(lH, d, rotamers), 4.81f 4.48 ~lH, t, rotamers), 4.15 + 4.08
(lH,d, rotamers), 3.90 (lH,q), 3.72 (2H, m), 3.50+3.38 ~lH,
d, rotamers), 2.98-2.48 ~5H, m), 2.35 (lH, m), 1.98 (1~, m),
~; 1.79 (lH, m), 1.60 ~lH, m), 1.30 (3h, s), 1.29 (3H,s), l.Og
V.85 115H, m), 0.79 (3H, d), 0.11 (6H, m).
W093/02~7 PC~/~592/~7
2 ~ $~
- 97 -
(b) (2R~4S,5S,l'S)~5-(1,1-dimethyl-2-
acetoxyethoxy~arbonyl)amino-4-hydroxy-N-(1'-isopropyl~
imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide
The compound of Example 52~a) (103 mg, 0.155 mmol) was
stirred with acetic anhydride (30 mg, 0.309 mmol) and DM~P
(40 m~, 0O309 mmol) in methylene chloride at room ~emperature
under ar~on o~ernight. The solvent was removed iR vacuo and
~he residue was flash chomatagraphed ~silica, 4%
methanol/dichloromethane).
o The resulting 4-t-butyldimethylsiloxy intermediate (105
mg, 0.140 mmol) was stirred in methanoI:water (9:1) with lM
HCl in e~her ~0.14 mL, l eq). The solvents were removed in
vacuo, the residue-was diluted with dichloromethane~ and the
solution was washed with a~ueous Na2CO3. The orga~ic layer ;~
was concentrated and the xesidue was pur~fied by flash
chromatography ~s~lica, 5~ methanol/dichloromethane~ to
provide the title compound (82 mg, 91%~. NMR SCD3oD) ~ 7.29-
6.90 ~1O~J m)r 6.81: ~2H, s), 4.51 (lH, d), 4.05 ~ZH, s),
3.59~1H~ m~, 3.42;tlH, m), 2.80-2.45 (5~, m), 2.00 (lH, m),
20~ 8~3H, s), 1.72 (1H, m), 1.50 (1~, m~ 1,34 ~6H, d), 0.81
: ~3Hr d), 0. 60 (3H~ d) .
:
ZS ~
: 30 a~ (2R,4S,SS,l'S)-5-((1,1-dimethyl-2-
~ ~ carbobenzyloxyglycyloxy)ethoxycarbonyl~amino-4-~t-
~, . ..
butyldimethylsilyloxy)-N-~ isopropyl-1'-imidazol-2-
` yl)methyl-6-phenyl-2-phenylmethyl-hexanamide
: The compound of Example 52~a) (100 mg, 0.151 mmol) was
reacted with 2-chloro-~-methyl-pyridium iodide (92 mg, 0.35
: mmol), DMAP ~75 mg, 0.60 mmol) and Cbz-glycine ~63 mg, 0.30
:
; ~ mmol) in methylene chloride (5 mL3 under ar~n at reflux for
..
: 3 h. Sol~ents were removed in vacuo and the product was
;:
W093/02057 PCT/US~2/~W7
purified by flash chromatagraphy (silica, 4~
methanol/dichloromethane) to pro~ide the title compound (95
mg, 73%). NMR ~CDC13) ~ 7.41-6.71 ~17H, m), 6.62 (lH, bs),
6.00 (lH,m), 5.20 (lH, m), 5.15 (~H, s), 4.83 + 4.55 (lH, d,
s rotamers), 4.65~ 4.48 (lH, t, rotamers), 4.81 + 4.38 (lH,q,
rotamers), 4.03 (lH,q), 4.02 ~2~, d), 3.B5+3.68 (2H, d,
rotamers), 2.85-2.48 (5H, m~, 2.38 ~lH, m), 1.90 (lH, m),
1.55 ~lH, 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,l'S)-5-((1,1-dimethyl-2-
(benzyloxycarbonyl ) ethoxycarbonyl ) amino-4-hydroxy-N-~
isopropyl-l'-imidazol-2-yl)met21yl-6-phenyl-2-phenylmethyl-
. hexanamide hydrochloride-salt
The compound of Exar~ple 53 (a) (12 mg, 0 . 014 I~unol) was
stirred in methanol:water (9:1) with lM ~Cl (2 e~) in ether
overnight. The 801vent8 were removed ~n vacuo to gi-re the
title compound (8 mg,:~ ?3%). N~(CD30D) 8 7.35 (2H,s), 7~31-
6.85:~15H, m)~, 5.00 ~(2H, s), 4.59 (lH, d),4.15 (lH, d,
rotamers) r 4.65+ 4 .48~(1H, t, rotamers), 4.81 ~ 4.38 (2H, dd),
3.80 ~2H,d), 3.59 ~ m~, 3:.40 (}H, d), 2.85-2.48 ~5H, m),
2.00 (lH, m), 1.60 ~ ~1H, m), 1.55 (lH, m), 1.31 ~3h, s), 1.29
3H, s l, 0 . 91 (3H~, : d~:~, 0 . 60 (3H, d),
,
~ 2s~ Exa~ple 54
: ~ :
~ .
p~e~aration of~;(2R:.4S.5S~l'Sl-5-~lf1-dimet~yl-2-
lycyloxy~ethoxycarhonyl)am;no-4-hydr~xy-N~ iso~ro~yl~
; ~ . . :
:~: 30
'
a) (2R,4S,5S,l'S)-5-(1,1-dimethyl-2-
glycyloxyethoxycarbonyl)amino-4-~t-butyldimethylsilyl)oxy-N-
(1'-isopropyl-1':-imidazol-2-yllmethyl-6-phenyl-2-
:35 phenylmethyl-hexanamide
The compou~d of Example 53(a) (58 mg, .~678mmol) was
~ ` stirred in methanol with 10% Pd/C (50 mg) under 1 atm
:: : hydroge~ overnight. The rea~tion mixture was filtered
: `
WO 93/020!j7 PCl~/U~392/~7
2 ~ 1 3 S fi~ ~
through Celite~ and the solvents were removed in vacuo to
y ield the title compound (48 mg, 98%). NMR(CD30D~ ~ 7.32-7.02
~lOH, m), 6.99 (2H, s), 4.68 (lH, d),4.40-4.28 (2H, dd), 3.81
(2H, d), 3 . 80-3 . 67 (2H, m), 2.90-2.49 (5H, m), 2.15 (lH, m~,
1.97 ~lH, m), 1.48 (lH, 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) t2R,4s~5srl~s)-s~ dimethyl-2-glycyloxy)ethoxy-
carbonyl~amino~4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-
yl)me~hyl-6-phenyl-2-p~enylmethyl-hexanamide d~hydrochloride
salt
The compound of Example 54~a) (43.5 mg, 0.060 mmol) was
stirred in me~hanol:water (9:1) with lM HCl in ether (0.12
~L, 2 eq) for 2 d. The solvents were removed in vacuo and
the product was ~rituated wi~h ether:methanol (20:1~ to yield
~he title compound (40 mg, 98%). NMR(CD30D~ ~ 7.35 (2H, s),
7.30-6092~ (10~, m~, 4.60 (lH, d), 4.25 ~2H, dd), 3.75 (2H,
d), 3.59 (lH, m),3.49 (lH, m)r 2.90-2.51 (6Hr m), 2.10 ~lH,
m), 1.65 tlH, m), 1054 (lH, m), 1.30 (6~ ), 0.90 ~3H, d),
0.60 (3~, d)o
: : a) ~2R,4S,5S,l'S)-5-amino-4-t-butyldimethylsiloxy-N-[1'-
isopropyl~ 4-isopropylcarbonyl-imidazol-~-yl)lmethyl-6-
phenyl-2-phenylmet~yl-hexanamide
Using the procedure of Example 13(a), except
: substituting the compound of Example 28(d), the title
~: compound was prepared.
3s
2R,4S,5S,l'S)-5-((1,1-dimethyl-2-
hydroxy)ethoxycarbonyl)amino-4-hydroxy-N-~ isopropyl-1'-~4-
W093/02~57 P~r/US~2/~7
3~ 100 -
isopropylcarbonylimidazol-2-yl))methyl-6-phenyl-2- ~ .
phenylmethyl-hexanamide dihydrochloride salt
Following the procedures of Example 38~b)-38tc~, except
substituting the compound of Example 55~a) for .
(2R,4S,5S,l'S)-5-amino-4-t-butyldimethylsiloxy-N-('-
isopropyl-l'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-
hexanamide, the title compound was prepared. NMR (CDC1
7.49 tlH, s~, 7.13 (5H, m)t 6.84 (5H, m), 5.53 (lH~ d), 4047
(1~, d), 3.79 (lH, m), 3.60 ~lH, m), 3.44 (2~, m), 3.16 (lH,
m~, 2.81-2.50 ~5H, m), 1.92 (1~, m), 1.62 (2H, m), 1.18 (14H,
m), 0.72 (3H, d), 0.58 (3H, d3; MS m/e 621.4 l~+H]+.
. .~
'~' ;,
. . .
Using the procedure of Example 41/ except subst~tut~ng
2~5) t-butyldimethylsiloxy-l-methyletha~ol in 41(a) (prepared
from 2(S3-},2-propanediol~, the title cvmpound wa~ prepared,
NMR(CD30D) ~ 7.38-6.gO ~10~, m), ~.83 (2H, s), 4.58 S2H, m), .
3.61 ~lH, ~), 3.34 (3H, m), 2.B2-2.44 (5H, m), 2,00 ~lH, m),
1.66 (lH, m~, 1.52~1H~ m~, 1.08 (3H, d), 0.85 (3H, d), 0.60
S3H, d).
: ,:
30 ~y roxyekhn~y~axbonvl~amino-4-hydr~y-N~ -~sQ~xoDy~
Using the procedure of Example 41, except s~bstituting
2(R)-t-butyldimethylsiloxy-l-methylethanol in 41(a), the
title compound was prepared. NMR(CD30D) ~ 7.39-6.8~ ~lOH, ~:
m), 6.82 (2H, s), 4.56 ~2H, m), 3.60 (lH, m), 3.36 ~3H, m),
2.81-2.45 (5H, m), 1.99 tlH, m), 1.65 (lH, m), l.Sl ~lH, m),
1.03 (3H, d), 0.84 (3H, d), 0.60 (3H, d).
W~9~/02057 PST/U~g~/0~0~7
2 1 3L 3 ~ 4 4
1 0 1 - ' '
Example 58
Prepara~ion_of. (2R,~S,5S~1'S)-5~ acetyl~amino-4-hydrQxy-~-
(1'-iso~ropyl-1~-imidaz~1-2-yl)me~hyl~-phenyl-2= ::
~l~h~lhexanamide
The title compound was prepared by the procedure of
Example 13(a)-(c~, except substituting acetic anhydride in
place of isopropyl chloroformate. NMR(CD30D) ~ 7.21-6.90
~lOH, m~ 6.81 (2H, s), 4.58 ~lH, d), 3.9~ (lH, m), 3.51 ~lH,
0 m~, 2.85-2.49 ~5H, m), 1.99 (lH, m), 1.68 (3~, s), 1.61 (3H,
m), 1.50 (lH, m), 0.80 (3H, d), 0.60 (3H, d).
Exam~le ~
,~.,
a) ~3R,5S,l'S~ t butoxycarbonyl~mino-2'-phenyl)ethyl-3-
20 (4-benzyloxy)phenylmethyl-tetrahydrofuran-2-one -,,-
FO11QWing the~procedure of Example 12~a~, except using
(4-benzyloxy)benzyl bromide~ the title compound was prepared
(284 mg, 27~. NMR(CDCl3~ ~ 7.48-6.72 (14~, m), 4.94 (2H,
s), 4.43 (lH, d), 4.12 (lH, dd), 3.83 (lH, q), 2.g7-2.62 ~SH,
2s m), 2.12 (lH, m) r 1.85 (lH~ m?~ 1.27 l9Hr S). .
b) ~2R,4S,5S)-5-(t-butoxycarbonyl)amino-4-t-butyldimethyl-
siloxy-6-phenyl-2-~4-benzyloxyphenylmethyl)hex~noic acid
l?olowing the procedure of Evans et al., JO Org. Chem.
50, 4615 ~1985), except substituting the compound of Example
59 (a) ~or benzyl bromide, the title compound was prepared.
NMR~CDCl3) ~ 7.42-6.76 ~14H, m), 4.99 ~2H, s), 4.69 (lH, d),
3 . 91 (lH, q), 3 . 66 (lH, m), 2 . 98-2 .36 (5H, m), 1.85 (lH, m),
1.52~ ~lH, m), 1.30 (9H, s), 0.88 ~9H, s) ~ 0.04 (6H, m) .
c) ~2R, 4S; 5S, 1 ' S) -5- ~t-butoxycarbonyl) amino-4-t~
butyldimethylsiloxy-N-(1'-isopropyl-1'-imidazol-2-yl)me~hyl-
5-phenyl-2-~4-benzyloxyphenylmethyl) hexanamide --~
W0~3/02~7 PCr/US92/~ ~7
s'~ 102 -
Following the procedure of Example 12~c), except using ~.
(b), the title compound was prepared (284 mg, 92%3.
NMR(CDCl3) ~ 7.42-6.74 (16H, m), 5.04 (2H, s~, 4.99 (lH, d), .;
4.77 ~lH, d), 4.51 (lH, dd), 3.93 (lH, q), 3.69 (lH~ m),
2.80~2.39 (SH, m), 1.81 (lH, m), 1.62 (lH, m), 1.33 ~9H, s),
0.92 (3H, s), 0.75 (6H, dd~, 0.07 ~6H~ d). ~
, . :,,"':
~) (2R,4S,5S,l'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1'- :
isopxopyl~ imidazol-2-yl)meth~1-6-phenyl-2-~4-
0 benzyloxyphenylmethyl)hexanamide ; :;
Following the procedure of 12(d), except using (c), the
title compound was prepared (100 mg, 94~). NMR(CD30D) ~
7.41-7.09 (lOH, m), 6.85 ~2~, d), 6.~9 (2H, s), 6.S8 ~2H, d),
5.41 (lH, d~, 4.90 (2H, s), 4.47 (lH, d), 3.62 (lH, q~, ~.48
~lH, d), 2.79-2.48 ~6H~ m), 2.02 (lH, m), 1.62 t2H, m), 1.33
(9H, s)~ 0.74 (3H~ d~, 0.61 (3~, d).
,:
~ ~
~. ~
. .
"~
Following the procedure of Example 4~b), except using
: 25 the compound of 59(d), the t~tle compoun~ ~as prepared (56 -:.
: mg, 86%) o N~R~D30D) ~ 7.18 (5H, m), 6.84 (2H, sl, 6.73 (2H, ~
d), 6.44 (2H, d), 5.32 (lH, d), 4.45 (lH, d), 3.61 (lH, q), ~:
: 3.42 (lH, m), 2.8~-2.42 (SH, m), 2.04 ~lH, m~, 1.61 (2H, m) t
1.31 ~9H, s), 0.70 (3H, d~, 0.~1 (3H, d).
:
35 ~ ; :
a) a-(t-butoxycarbonyl)-amino-a-cyclopropylacetonitrile
'`"''
W093/02~7 P~T/USg2/~6~7
;' ` - 103 _ 2~ ~3~
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.
s After 1 h the reaction mixture was diluted with ether
(lOOm~), filtered through Celite~ and washed with ether, The s
combined organic extracts (l L) were concentrated in vacuo at
15-18C to yield formyl cyclopropane. .
The crude aldehyde was dissolved in water ~50 mL), and
0 ammonium chloride ~6.51 g), potassium cyanide ~7.16 g) and
aqueous ammonium hydroxide (100 mLr 28% w/w~. The reaction :~:
mixture was stirred at room tempera~ure overnight,. extracted~:
with ethyl acetate, and the cornbined organic extract~ were
dried over MgS04. Filtration and evaporation of the solvent
5 in ~cuo yielded ~-amino-a-cyclopropyl acetonitrile as an .:
o~
To a solution of the crude aminonitr~le (2 g) in T~F t20
~L~ di-ter~-butyldicarbonate (1.53 g, 7 mmol) was added. The
reaction was stirred overnight. Removal of the solvent i~
20 vacvo followed by fl~sh chroma~ography ~sil~ca, 1:8 e~hyl
acetate:hexa~e) yielded the title compound (2.8 g). lH
~MR(CDC13, 200 NHz) ~ 5.0 (bs, lH), 4.4 ~bs, 1~), 1.4 (s,
9H), I.2 ~m, lH), 0.7 (m, 2H), 0.5 (m, 2~
: 25 b) a-(t-bu~oxycarbonyl)-amino-a-cyclopropylacetaldehyde
To a olution of the compound of Example 61(a) (1 g, 5.1
mmol) in THF ~20 mL~, diisobutylaluminium hydride (10.5 mL,
10.5 ~mol, lM in THF) was added at -78C, o~er 5 min. The :~.
reaction mixture was allowed to warm to 0C over a period of
~o 2 h, and stirred at O~C for an additional 1 h. The reaction
mixtur2 was quenched with MeOH (2 mL), and saturated ~-~
potassium sodium tartrate solution (100 mL) was added.
Extraction with ether~ drying over MgS04 and removal of
solvents in vacuo yielded an oil. Flash chromatography
3s (silica, 1:10 ethyl acetate:hexane~ gave the title compound
as a colorless solid (225 mg). NMR(CDCl3, 400 MHz) ~ 9~45
(bs, lH~, 4.95 ~bs, lH), 3.5 (bs, lH), 1.3 ~s, 9H), 0.7 (m,
lH), 0.3-0.6 (m, 4H).
WOg3/~2~7 PCT/US92/~47
- 104 -
c) ~-~(t-butoxycarbonyl)amino-1-(imidazol-2-yl)-1-cyclopropyl- .-
methane :
A mixture of the compound of Example 61~b) (178 mg, 0.89 ~:
s 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 w~th 5%
MeOH/methylene chloride. Removal of the solventi in v~cuo
followed by trituration provided the title compound as a
colorless solid (19 mg). MS(CI/NH3) mfe 238.3 [M+H~ H
NMR~CD30D, 200 ~z~ ~ 6.9 ~s, 2H), 4.1 (bd,; lH),:1.4 (st 9H1
1.3 ~m, lH), 0.6 ~m, 2H), 0.4 (m, 2H).
d) 1-amino~ imidazol-2-y~ cyclopropyl-methene~ -~
trifluoroacetate
l`he compound of ~Exar~ple 61 tc) (15 mg) was d~sso~ved ~n 1 ~ -
mI. of TFA and stirred a~ room te~slpcrature for 20 mln. -~
20 Sol~e~ts removed in ~acuo to give the title compou~d as a ~.
semisolid residue. 1H NMR(CD3OD, 200 M~z) ~7.1 (s, 2H~, 3.8
, J=7 Hz), 1.5 (~, lH), 0.5-0.8 (~, 4~
,'.''.
e) (2R,4S,5S)-5-(t-butoxycarbonyl)amino-4-~t-butyldimethyl)
: 25 siloxy-2-phenylmethyl-6-phenyl-N-[l'-cyclopropyl~ imidazol- :~
2-yl]methyl-hexanamide
The compound of Example 61(d) was dissol~ed in D~F ~2
mL) and NMM (26 mg, 0.25 mmol) was added and the solution was
stirred at 0C for 3~ min. (2R,4S,5S)-2-phenylmethyl-4-(t-
butyldimethyl)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 dilut~d with ethyl
acetate (1~0 mL), washed with aqueous sodium bicarbonate and
dried over anhydrous potassium carbonate. Removal of
solvents in vacuo~ followed by flash chromatography ~sit ica9
5% methanol/methylene chloride) yielded the title compound as
a mixture of diastereomers ~25 mg).
. .
"''`'
'`,' ~,
"~ '
W093/OZ~57 P~T/US92/~7
,~!' '~.,~ 2 1 i ~ 4 4
105 -
f) (2R,4S,5S)-S-(t-butoxycaxbonyl~amino-4-hydroxy-2-
phenylmethyl-6-phenyl-N-[1'-cyclopropyl-1'-imida~ol-2-
yl~methyl-hexanamide .
The compound of Example 61(c) was dissol~ed in THF (2
mL) and tetrabutyl ammonium fluoride (200mL, lM in THF) was
added. The reaction was stirred at xoom 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
diastereomeric mixture of the title co~pound.
, . -
E~a~ 2
~. .
2~ ~ ,
. .
:: a) Purification of the 125 mg of the compound of Example
61(e) by flash chromatography (silica, 3% methylenechloride~methanol~, yielded 48 mg of isomer 1, 15 m~ of
. isomer 2 and 20 mg of combined fractions. lH N~R for isomer
1 (CDCl3, 400 MHæ) ~7.1-7.4 (m, lO~), 6.95 (~, 2H~, 6.1 (d,
., .
), 4.85 (d, lH), 4.15 ~dd, lH), 3.75~q, lH), 3.6(m, lH~
2.9(dd, lH), 2.7 ~d, 2H), 2.6 (dd, lH), 2.3 (m, lH), 2.0 ~m,
lH), 1.6 tm, lH), i.4 (m, lH), 1.35 ~s, 9H~, O.9S ~s, 9H), ~:
: 0.7 Sm, lH), 0.4 ~m, lH), 0.2~ (m, lH), 0.1 (m, lH), 0.2 ~s,
3H), 0.1 (s, 3H), 1H NMR for isomer 2 SCDCl3, 400 MHz) ~7.1- :
7.4 Sm, lOH), 6.8 ~s, 2H3, 6.26 (d, lH), ~.6 Sd, lH), 4.0 ~m,
2H), 2.5-3.0 ~m, 4H~, 1.8 (m, lH), 1.7 (m, lH), 1.5 Sm, lH),
1.4 (s, 9H), 1.0 (s, 9H), 0.7 (m, 2H), 0.2 (m, 2H), 0.1 (2
overlapping singlets, 6H).
:
W~93/02~7 PCT/USg~/06047
~ 106 -
b) Following the procedure of Example 61~f), except ;~
substituting the compounds of Example 62(a) yielded the title
compounds. 1H N~R for isomer 1 ~CD30D, 400 MHz) ~7.1-7.3 (m, :.
lOH) ~ 6.95 ~s! 2H) r 4.25 (d~ lH) ~ 3.5-3.7 (m, 2H), 2.5-3.0
(m, 5H), 1.7 (m, 2H), 1.4 (s, 9H), 1.1 (m, lH), 0.6 ~m, lH), ::
0.25-0.4 (m, 2H), 0.05 (m, lH); MStESMS) m/e 533.2 lM+Hl+; lH
NMR for isomer 2 (CD3OD) ~ 7.1-7.4 (m, lOH), 6.85 (s, 2H~,
4 .25 ~ lH), 3.5-3.7 ~m, 2H) r 2.5-2.9 (m, 5H), 1.5-1.8 (m, :
2H), 1.4 (s, 9~i), 1.1 (m, lH), 0.2-0.6 (m, 4H), MS(ESMS) m/e ~:
533.4 [M+HI+.
. Exa~pl~ 63
~ _ ~ ";~,
~::
..
a) 5-((isopropy}thiol)carbonyl~amino-4
butyldimethylsiloxy)-2~phenylmethyl-6-phenyl-N-~ isopropyl- :
1' ~ opropylthiol)carbonyl-imidazol-~yl)~methyl-
hexanamid~ :
To a solution of (2R,4S,5S,l'S)-5-amino~4 t-
butyldimethylsiloxy-2-phenylmethyl-6-phenyl-N-[1'-isopropyl- .-
1'-imidazol-2--yl]methyl-hexanamide (81 mg, 148 mmol) and DMUP
2S (37 mg, 303 mmol) in dichloromethane (8 mL),
isopropylthiolchloroform~te ~42 mg, .303 mmol~ ~n
dichloromethane (l mLj was added. The solution was stirred .-
for 20 h and an additional equiYalent of the chloroforma~e
and DMAP were adde~.~ The reaction mixture was stirred for an
30 additional 20 h, diluted with dichloromethane, and washed ~:.
with saturated sodlum 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 gi~e ~ .
35 the title compound as an oil (79.5 mg). ~;~
~' '
WOg3/02~7 P~T/U~92/~7 ~
2 ~ ~ 3 f 1 A
b) (2R,4S,5S,l'S)-5-(~isopropylthiol)carbonyl)amino-4-
hydroxy-2-phenylmethyl-6-phenyl-N-[l-isopropyl-1'-imidazol-2-
yl ~ methyl-hexanamide
To a solution of the compound of Example 63 ~a~ (79 mg,
105 ITunol) in methanol (8 mL), 10% hydrochloric acid (3 mL)
was added. The reaction mixture was stirred overnight at
25C. The methanol was evaporated in vacuo, and the residue
was diluted with water. ~he solution was neutralized with 5~ -
aqueous sodium carbonate, and a solid precipitated. The
0 solid was filtered, washed with water, and triturated with
ether. The solid was dried at high vacuum to yield the title
compound t27 mg, 48%). N~5CDCl3, 250 MHz) ~; 6.9-7.3 (m, ~:
lOH), 6.85 ~s, 2H~, 6~20 (d, lH), 4~ 4? (d, lH), 4.22 (m, lH~0
4.0 (m, lH), 3.55 ~m, 3~, 2.5-3.0 (m, 6H), ~.65- (t, 2~),
1.27 (m, 7H), -.71 (d of d, 6H); ~ FAB) m/e 537 tM~H3+; TI.C
Rf 0.30 (silica~ 4~ methanol/chloroform). .
i
~: .
,::
a) l-~t-butyldimethysiloxy)methyl-cyclopentanol :~
ITO a solution of l-hydroxyme~hyl l-cyc~opentanol ~4.07
g, 0.035 mole~ in dichloromethane ~30 mL~ t-butyldimethyl- ~:
silyl chloride (5.28 g, 0.035 mol) in dichloromethane (3V 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
overnight at 25C. The solution was diluted wi~h
dichloromethan (30 mL) and wzshed with wa`ter and saturated
anunonium chloride solution. The organic solution was dried
over sodium sulfate, filtered and the solvent removed at
reduced pressure. The product was purified by flash
35 chromatography (silica, 19 :1 hexane :ethyl acetate) to yield
the tit~e compound as a colorless oil (6.95 g, 86%).
W093/02057 ~ PCr/USg2/06047
- 108 -
b) 1-(t-butyldimethylsiloxy)methyl-cyclopentyl 4-nitrophenyl
carbonate
A solution of the compound of 64(a) (l.lS g, 5 mmol),
DMAP (0.611 ~, 5 mmol) and bis (4-nitrophenyl)c:arbonate (1.52
5 g, 5 mmol~ in dichloromethane (16 mL) was stirred overnight ::~
at 25C. The reaction mixture was diluted with ;~ :
dichloromethane and washed with 5~ sodium carbonate. The
solvent was removed at reduced pr~ssure and the residual oil -~
was triturated wi~h hexane:ethyl acetate (3:2) and filtered~ : ;
10 The product was puri~ied by flash chromatography ~silica, :~:
19:1 hexane:ethyl acetate) to give a colorless oil tO.599 g,
30~
. -
c) ~2R,4S,5S,1'5)-5~ (t-butyldimethylsiloxy)methyl- .
15 cyclopentyloxycarbonyl]amino-4-t-butyldimethylsiloxy-N-[1'- :
isopropyl-l'-(t-butyldimethylsiloxy)methyl :.
cyclopentyloxy~imid~zol-2-yl~-6-phenyl-2-phenylmethyl- :~
hexanamide .::
A s~lution sf ~he~compound of ~xample 13(a3 ~173 mg,
~.316 mmol), ~P ~81 ~, 0.663 mmol) and the compound of
Example 64~b) (262 mg, 0.663 mmol) in dichloromethane (10 m~
was stirred for 48 h at 25C. The organic solution was - -
diluted with dichloromethane, washed with 5% s~dium carbonate .. :
solution and the solvent removed at reduced pressure. The
: ~ 25 product was purified by flash chromatography (silica, ..
4:1hexane:e~hyl aceta~e~ to yield the title compound as an :.
oil t200 mg, 60~
-..
d) (2R,4S,5S,l'S~5~ hydroxymethyl-cyclopentyloxy- -
caxbonyl)amino-4-hydroxy-N-~ isopropyl~ imidazol 2
ylImethyl-6-phenyl-2-phenylmethyl-hexamide
A solution of the silated derivative (200 mg, 0.188
mmol) in methanol (7 mL) and 3N HCl (2.5 mL) was stirred ~-
overnight at 2~C. The methanol was removed at reduced
35 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,
W093/02~57 PCT/US92/~7
og - 2 ~ ~. 3 ~ ~ ~
washed with water and dried in vacuo to yield the title
compound (51 mg, 47%). NMR (CD30D, 400 MHz) ~ 7.0-7.3 (m,
lOH), 6.B7 (s~ 2H), 4.62 (d, lH), 3.70 (mr 3H), 3.55 (d, lH), ~::
2.5-2.9 (m, 5H), 2.05 (m, lH), 1.5-2.0 (br, lOH), 0.88 ~d,
3H), 0.70 ~d, 3H); TLC Rf O.S0 (silica, 8%
methanol/chloroform).
~L~ :
~ ,~.,
15 ~ ::
- . .~
a~ benzyloxymethylimidAzol-2-yl)~2-methyl-1-propanol
- 1-benzyloxymethylimidazole prepared according to the
procedure of ~gochindo, R., J. Chem~ Res. (S), 58 tl990)) :~
20 (3.76 g, 20 m~ol), and T~F (40 mL) at -40~C, was treated
dropwi~e with n BuLi~(8.4 mL, 21 mmol, 2.5M in hexane). The
resuiting solution was stirred at -40C fox 15 min, and i-
butyraldehyde (2.0 mL, 22 mmol) was added dropwise. The
reactio~ was stirred at -40~C for 1.5 h, 0C for 1 h, warmed
::25 to 23C, poured into H2O, and extracted with EtO~c. The
: combined extracts were washed with ~rine, dried (Na2SO4) and
~ concentrated in vacuo. Trituration of the residue with
. ~
Et20/hexane gave a white solid which was dried in vacuo
overnight to afford ~f the title compound ~3.57 g, Ç9%). lH :~
NMR(CDC13, 400 MH~) ~ 7.28 (m, SH) r 6 . 97 (S, lH) ~ 6. 92 (S,
lH), 5.23 (d~ lH, J=12 Hz), 5.42 (d, lH, J-12 Hz), 4.48 (s,
2Hj, 4.44 (d, lH, J=9 Hz), 2.21 (m, lH~, 1.02 (d, 3H, J=7
Hz~, 0.83 ~d, 3H, J=7 ~z).
b~ 1-lbenzyloxymethylimidazol-2-yl)-2-methyl-propan-1-one
The compound of Example 65~a) (1.0 g, 3.88 mm~l~, MnQ2,
~1.69 g, 19.4 mmol), and CH2C12 (75 mL) were combined and
~tirred for 1 d. Additional MnO2 ~1.69 g, 19.4 mmol) was
3~ - 110 - YCI/U592/~6047
added and stirring was continued for an additional 2 d.
Filtration through Celite~, concentration and flash
chromatography (silica, 0-1% CH3OH/CH2C12) afforded the title
compound (0.773 g, 77%), lH NMR(CDC13, 400 MHz~ 7.28 (m, ..
6H), 7.18 ~s, lH), 5.85 (s, 2H~, 4.52 (s, 2H), 3.94 ~m, lH),
1.21 (d, 2H, J=5 Hz).
:
c) t-butyl 3-(1-benæyloxymethylimidazol~2-yl)-3-hydroxy-4- . .
methyl~pentanoate . ,. ::
Diisopropylamine ~83 ~L, 0.59 mmol) and THF;(1.5 mL)
were cooled to -40~C and n-BuLi (188 ~L, 0.47 mmol, 2.5M in :.:
~ ,
hexa~e~. was added. The reac~ion mixture was-warmed to ~10~C . .
an~ stirred for 15 m~ xecooled to -70C and t-butyl acetate -:.
t63 ~L,. 0.47 mmol~ was added. The reaction was-stirred for 5::
m, and H~æA ~254 ~Lr 1~41 mmol) was added. The reac~ion was
stirred at -70~ for 5 m and 1-(benzylsxymethylim~dazol-2- .;
yl)-2-methyl-prQpan-l-one (100 mg, 0.39 mmol) in T~F (1.5 mL) ::
was added dropwise. The mixture was stirred at -70C for 30
m, -40C for 30 m, -1~C for 30 m, warmed to 23C, poured
into 10% aqueous K2C03 and extracted with ~tO~c. The combined
. ~ . .
organic extracts were washed with brine, dried (K2CO3),
concentrated and lash ohromatographed (silica gel, step
gradient, 0-20% EtO~c/hexanes) to afford the title compound ~:
~131 mg, 90%). lH NMR~CDC13, 400 MHz) ~ 7.25 (m, 5H)~ 6.96 ~:
(s, lH), 6~91 (s~ 1~), 5.69 (d~ lH, J=10 Hz), 5.65 ~d, 1~,
: J=10 Hz~, 4.53 (d, 1~, J=11 Hz), 4.48 ~d, lH, Jsll Hz~, 3.23 .
(d, lH, J=6 ~z), 2.57 ~d, lH, ~=6 Hz), 2.14 (m, lH~, 1.39 (s, :~
9H3; 0.97 ~d, 3H, J=7 Hz), 0.75 (d, 3H, J=7 Hz); MS(ES~ mJe
: 375 tM+~ f .
3~ :
d) 3 (1-benzyloxymethylimidazol-2-yl)-3-hydroxy-4-methyl
pentanoic acid triflouroacetate.
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%~
lH NMR~CDC13, 400 MElz~ 7.30 ~m,- 7H); 6.06 (d, 1 H, J=9 Hz),::
:: 5.74 (d, lH, J=l Hz), 4.67 (d, lH, J=9 Hz), 4.61 ~d, lE~, J=9
Hz~, 3 . 62 ~d, lH, J=12 Hz), 2 . 93 (d, lH, J=12 Hz), 2 . 04 ~m, ~
.';.
W~93/02~57 PCr/US92~ 7
2 ~ i 3 ~ q ~ ' ' '
lH), - 9? (d, 3H, J=12 Hz), 0.88 (d, 3H, J=12 Hz); ~S(ES) m/e
319 [M+H]+.
i
e ) (2R, 4S; 5S, l'S)-5-13-(RS)~ benzyloxymethylimidazol-2-yl)-
3-hydroxy-4-methylpentanoyl]amino-4-t-butyldimethylsilyloxy-
N-(l t -isopropyl-l'-imidazol-2-yl)methyl 6-phenyl-2-
phenylmethyl-hexanamide
A mixture of the compound of Example 65~d~ ~1.0 eq~
~2~,4S,5S,l'S~-5-amino-4-hydroxy-N-(l'-isopropyl l'-imidazol-
2-yllmethyl~-6-phenyl-2-phenylmethyl-hexanamide (1,1 eq), BOP
reagent (1.1 eq), and triethylamine (4 eq) were reacted
according to the procedure of Example l~c). The product was
purified by flash chromatography to afford the t~tle compound
(57%) (~ilica, ~tep gradient, 0-4% CH3OH/C~2C12). lH
NKR(CDC13, 400 MXz) ~ 7~36-6.76 (m, l9HS, 5.65 (m, 2H~, 4.66
~m~ 1/2~), 4.51 (m, 2H), 4.39 ~m, 1/2H), 4.30 (m, 1/2~), 4.02
~m, 1~2H), 3.68 (m, lH), 3.28 (m, lH), 2.90-2.35 tm, 6H),
2.13 (m, 1~), 1.76 (m, 1/2~), 1.68 (m, lJ2~), 1.40 (m, 1~2H3,
1.00-0.70 ~m, 21H), 0~10-0.00 (m, 6H); MS~ES) m~e 849 ~M~Hl~.
f~ (2R,4S,5S,l'S)-5-t3-~RS)-(l-benzyloxymethylim~dazol-2yl~- :
3-hydroxy-4-methylpentanoyl]amino-4-hydroxy-N-(l'-isopropyl-
imidazol-2-yl~methyl-6-phenyl 2-phenylmethyl-hexanam~de
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%). 1~ NMR(C~C13, 400 ~Hz~ ~ ?o40~
6.80 (mr l9H), 5.75 ~(m, 2H~, 4.97 (m, 1/2H~, 4.7B tm, 1/2H),
4.51 (m, 2H) 3.94:(m, 1/ZH), 3.85 (m, 1/2H), 3.51 (m, l~)r
3.21 ~m, lH~, 2.97-2.43 (m, 6H);2.00 (m, lH), 1.60 (m, lH),
1.43 (m, lH), 0.97-0.49 (m, 12H); MS(ES) m/e ~35 EM+~
: ,:
g) (2R,4S,5S,l'S~-5-13(R)-(imidazol-2-yl)~3-hydxoxy-4-
methylpentanoyl~amino-4-hydroxy-N-(l'-isopropyl-ll-imidazol-
2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide, and
~2R,4S,5S,l'S)-5-[3-(S)-timidazol-2-yl)-3-hydroxy-4~ :
methylpentanoyl]amino-4-hydroxy-N-~1'-isopropyl~ imidazol- ~`
2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide :-
;
W093/02057 ~ PCT/U~92~ ~7 :
112 -
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, ~;-
5 0 8% CH3OH/CH2Cl2) to afford tail fractions containing the ::
pure diastereomers (35 mg total, 58%). .:
Isomer l, last eluting, (2R,4S,5S,l'S)-5-13-~R)-(lH- `
Imidazol-2-yl)-3-hydroxy-4-methylpentylamido]-4-hydroxy-N- :
(l'-isopropyl-l'-imidazol-2-yltmethyl-6-phenyl-2-
phenylmethyl-hexanamide. lH NMR(CDC13, 400 ~Hzl ~ 7.35-6.82
(m, IOH~ 6.93 ~s, lH), 6.84 (s, lH), 4.42 ~d, lH, Js9 Hz),
3.77 (m~ lH), 3.40 (m, lH), 3.00-2.40 (m, 5~), 2.14 5m, lH), :
1.99 (m, lH~, 1.56 (m, lH), 1.47 (m, lH), 0.93-0.64 tm, 12H);
MS(ES) m/e 615 [M+H]+. ~.
Isomer 2, ~irst eluting, ~2R,4S,5S,l'S)-5-13lS)-(lH-
Imidazol-2-yl~-3-hydroxy-4-me~hylpentylamido]-4-hydroxy-N-
(l'-isopropyl-l'-imida~ol-2 yl)methyl-6-phenyl 2-
phenylmethyl-hexanamide. l~ NMR(CDCl3, 490 MHz~ 8 7~35-6.8l
(m, lOH), 6.83 (sr lN)~ 6~8l (sr lH~, 4.46 (d, l H, J=9 ~z),
3.93 (m, lH), 3.40 (m, l~), 3.00-2.40 (m, 5H), 2.l3 ~m, lH~ r
l.9l (m, lH), l.9l ~m, lH), I.lO ~m, lH), 0.93 0.64 (m, 12H~
MS~ES~ m/e 615 tM+~
.~
~xamp~ 6
25~
':
a) (2R,4S,5S,l'S)-5-[~4-methoxyphenoxy~carbonyl]amino-9-t
butyldImethylsi1Oxy-N-[l'-isopropyl~ (N'-
methoxycarbonyl)imidazol-2-yl]methyl-6-phenyl-2-phenylmethyl-
: ~ hexanamide
Following the procedure of Example 13(b), except using
p-methoxyphenyl chloroformate and ~2R,4S,5S,l'S)-5-amino-4-t-
~ butyldimethylsiloxy-N~ isopropyl-l'-imldazol-2-yl)methyl-
: 6-phenyl-2-phenylmethyl-hexanamide (ll4 mg, 0.2l mmol), the
title compound was prepared (63%). NMR(CDC13), ~ 7.44-6.76
W093/~2057 2 1 ~ 3 PCT/~592/06047
- 113 -
~m, 20H), 5.66 (m, lH), 5.18 ~d, lH ), 4.40 Sm, lH), 3.83
(s,3H), 3.76 (m, lH), 3.73 ~s, 3H), 2.9~-2.50 (m, 5H), 2.05
(m, 5H), 1.60 (m, lH), 0.94 (s, 9H) t 0.79 ~d, 3 H, J-7 Hz),:.
0.74 t5, 3H), 0.12 (s, 3H~, 0.11 ~s, 3H)..
b) (2R,4S,5S,l'S)-5-(methoxycarbonyl)amino-4-hydroxy-N~
isopropyl-~l-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-
hexanamide
Following the procedure of Example 13 ~c:), except using
the compound of Example 66~a), the title compound was
prepared (32%~. N~(C:DCl3/CD30D), ~ 7.36-6~84 (m, 16N), 4.49
(d, lH, J=9 Hz), 3.79 (s, 3H), 3.37 (m, lH), 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~ ~ .
,
~: 20
~; : a) (2R, 45, 5S, 1 'S) 5- ~t-butylaminocarbonyl~ amino-4e (t-
butyldimethylsilvxy)-N~ isopropyl~ imidazol-2-yl~methyl- .:
: 6-phenylmethyl-hexamide :~
:~ The compound~of~Example 131a3 (0.13 g, 0.24 mmol~ was
:~ : dissol~ed~in dichloromethane ~3 mL) and t~butyl isocyanate
0.028 g, 0.29 mm~l);was added. After stir~ing at 30~ for
h, the solve~ was remo~ed under reduced pre~suxe and the -~.
residue was chromatographed ~silica, 2:3 ethylacetate:hexane) ;~
to give the title compound as a white solid (0.12 g, 77%). ::
NMR(CDC13) r ~7.3`5_7.05~ 12H~ m), 6.85 (2H, ! S~, 4.69 ~H~ dr
: .- ~:.
~:: J=9 Hz), 4.60 (lH, t, J=8 Hz~, 4.38 (lH, br3, ~.24 (lH, q,
J=8 Hz) ~ 3 . 66 ~lH~ dd~ J=4 Hz~ 10 Hz) ~ 2 . g5 (lH~ dd~ 3=9Hz~
, .~
:` 13Hz), 2.73(2H, m), 2.54 ~lH, dd, J=5 Hz, 13 Hz), 2.42 (lH,
: :35 m), 1.82 (lH, m~, 1.67 (lH, m), 1.22 (9H, ~), 0.93 ~9H, s),
0.84 ~3H, d, Js7 Hz), 0.79 ~3H, d, J=7 Hz), 0.08 ~3H, s), .i-
0.07 (3H, s); MS(ES) m/e ~48.4 ~M+H]+. .-~
: ..
wog3/02 7 ~`~s~ 114 - PCT/US92/~6W7
b) (2R,4S,5S,l'S)-5-(t-butylaminocarbonyl)amino~4-hydroxy-N-
t1'-isopropyl-l'-imidazol-2-yl)methyl-6-phenylmethyl-
hexanamide.
The c~mpound o~ Example 67(a) (0.033 g, 0.05 mmol) was
stixred in dry THF (0.25 mL) and te~rabutylammonium flouride
(0.25 mL, 0.25 mmol) in THF was added. After 18 h at 50C ~;
the reaction was cooled, diluted with ethyl acetate ~25 mL),
washed with water (5 mL), and dried ~gS04). The combined -
organic extracts were filtered and concentrated in vacuo.
10 Chromatography tsilica, 1:1 ethyl acetate:hexane) gave the ~:
title compound as a white solid (0.018 g, 66~). M.p 226C ::
(dec~; N~RtCD30D) ~ 7.37-5.90 ~lOH, m), 6,90 (2H, s), 4.58 ~-
(lH~ d.~ J=9 Hz) r 3.71 (lHr t~ J--7 Hz) ~ 3.52 (lH~ d~ J--9 ~Iz)
2.75 (4H, m~, 2.53 (1~, dd, JD4 Hz, 12 Hz), 2.03 tlH, m),
1.76 tl~ m), 1.66 11~, m)~ 1.22 (9H, s), 0.79 (3H, d, J-7 ::
Hz), O.6? t3H, dp J=7 ~z); MStES) m~e 534 ~ ]+ -::.
.: ~
Following the procedure of Examples 67 (a)-67(b), except
substitu~ing methyl isocyanate for t-butylisocyznate, the .;~
title compound was prepared (0.075 mg, 51%). Mp 253C (dec);
NMR(DMSOd6~ ~7.78 (1~, d, J=9 Hz)~ 7,80-6.96 (llH, ~, 6.88 ~ :
(2~, s~, 5.78 (~H, d, J=5 Hz~, 5.72 ~lH, d, J=9 Hz), 4.84
(~H, d, J=4 Hz), 4.65 (lH, m), 3.68 (lH, q, J=7 Hz), 3.44 ~.-
(lH, br), 2.74 (3H, m), 2.5B ~lH, dd, J=7 Hz, 13 Hz), 2.50 ~:
(3H, s), 2.41 tlH, d, J=8 Hz), 1.92 ~lH, m), 1.46 (~H, m),
0.72 (3H, d, J=7 Hz), 0.63 (~H, d, J=7 Hz); MS(ES) m/e 492
~+H~+ .
Exa~ple 69 ; .
:::
.:
W~93/02~7 PCT/~g21 ~ 47
~ 115 2 1 ~ 3 ~ ~ 4
Following the procedure of Examples 67(a)-67(b), except
substituting~phenyl isocyanate for t-butylisocyonate, the
title compound was prepared (87 mg, 79%). Mp 273C ~dec);
NMR(DMSO-d6), 8.50 (lH, s), 7.81 (lH, d, J=9 Hz), 7.34-6.83
s (18H, m), 6.07 tlH, d~ J=9 Hz) ~ 4.99 ~lH, d, J=4 ~z), 4.65
tlH, t~ J=8 Hz~, 3.75 (lH, m), 3.52 (lH, br), 2.77 t3H, m) r
2.66 (lH, m), 2.42 (lH, d, J=7 Hz), 1.89 ~lH, m), 1.50 (2Hr
m), 0.68 (3H, d, J=7 Hz), 0.61 ~3H, d9 J=7 Hz); MS (DCI/NH3)
m/e~554.3 lM~H]+.
.
h~amiL~ '"
Followi~g the procedure of Examples 67(a), except
su~stituting n-propyl isocyanate for t-butyl~socyanate, the ~.
title compound was prepared (0.048 gl 54~). Mp 247-9C ~:
~dec~; NMR(DMSO-d6) ~7.75 (lH, d, ~=8 Hz), 7.23-6.94 ~llH,
m), 6.85 (2~, s)r 5.87 (lH, t, 3~5 Hz), 5.6S (lH, d, J~9 Hz),
4.82 ~lH, d, J-4 H~), 4.64 ~lH, t, J=8 Hz), 3.66 ~lH, m~,
3.38 ~lH, br), 2.87 (2H, q, J=6 Hz), 2.74 ~3H, m)~ 2.SÇ (1~,
dd, J=7 Hz, 13 ~z~ D 2.39 (lH, d, J=~ Hz), 1~1 (lH, ~)9 1.43 :~
(2H, m~, 1.28 t2H, q, J=7 Hz~, 0.77 (3H, t, J=7 Hz), 0.71
t3H, d~ Jz7 Hz), 0.62 (3H, d, J=7 Hz3; MS(CI) m/e 520.2 ~;
[P~+~I] ~ . ...
.:
~am~le 71 ~
~ `.~;
~ydrQxy~ s~opro~yI~ ;midaz~l-2-ylj met.hyl~
~b~h '. `"
Following the method of Example 67(al--67~b); except
using n-propyl thioisocyanate, the title compound was
prepared (0.012 g, 21%). Mp 195-7~C (dec~; NMR (CD30D) ~
7.32-6.86 (12H, m), 4.59 llH, m~, 3.64 tlH, br~, 3~34 (2H,
br), 2.79 ~5H, m), 2.03 (lH, m), 1.73 tlH, m~, 1.58 t3H, m~,
W093/02~7 ~ PCT/US9Z/06~47
~ - 116 -
0.92 ~3H, t, J=7Hz), 0.83 (3H, d, J=7Hz) t r 68 (3H, d, J=7 .
Hz3; MS (CI) m/e 53602 ~M+HJ+. ~;-
Exa~le 72
2~e~a~ation ~f (2~ 4$. ~Sr 1 ~ S! ~5~ ~iS
Following the method of Example 67(a)-67~b~-, except
substituting isopropyl isocyanate for t-butyl isocyanate, the
titIe compound was prepared (0.034g, 46%). NMR(DMS0-d6) ~
7.78 (lH, d, J=8 Hz), 7.24-6.97 (llH, m), 6.85 (2H, s), 5.74
51H, d,- J=8 ~z), 5.57 (lH, d, J=9 Hz),.4.83 (lH, d, ~34 Hz),
4.66 (lH, d, J27 Hz), 3.62 ~2H, m), 3.43 ~lH, br~, 2.73 ~3H,
m), 2.57 ~lH, dd, J=7 Hz, 13.5 Hz), 2.41 (lH, d, ~-7 Hz~
1.9~ ~lH~ m) J 1. 45 (2H, m), 0.95 (3H, d, J-6.5 Hz) ! 0~93 t3
d, J-6.5 H~), 0.72 ~3~ d, J=~.5 ~z), 0.63 (3H, d, J--6.5 Hz~;
MS ICI~ m/e 520.2 lN+H]+.
: ~ ~ E~am~ls l~
:.
~,
2s : ~he compound;of~:Example 671a~ (0.050 g, 0.094 mmol) was ..
dissolved in triflouroacetic acid ~2 mL~ and stirred at 50C
for~2~h. A~er cooling, the reaction mixture was poured into ~.
saturated sodium bicarbonate solution ~50 m~) and was ~`~
extracted ~n~o ethyl acetate (100 mL). The organic solution .:
was washed wi~h brine, dried IMgso4) and the solvent removed
under rëduced préssure. Chromatography of the residue ;
: (silica, l9:1 dichIoromethane:methanol) gave the title
campound as a white solid (0.036 g, 80%). Mp 235DC (dec); ~;~
;~ NMR~DMS0) ~ 7.82 (lH, d), 7.30-6.90 tllH, m), 6.85 (2Hr d~
3s 5.88 llH, m), 4.86 (lH, d), 4.67 (lH, t), 3.67 ~lH, m), 3.45
~lH, m), 2.75 (3H9 m~, 2.60 (lH, m), 2.43 (lH, m), 1.94 ~lH,
~m~ 49 (2H, m), 0.73 (3H, d), 0.62 (3H, d); MS (CI) m/e
478 lM+Hl+-
:,
WO 93/02057 2 1 1 3 ~ 1 '1 Pcr/u~g2/~6o47
, . .
J 1 1 7
.
Exam~le_74
:
S ~arb~nyl?am;no-4-~ydroxy-N~ isopropyl-1'-;midazol~2-
ylLmet~y~ h~ ~e~hYl=h ~4Y~id~
Using the procedure of Example 34, excspt substituting
t6-quinolinyl~ethyl)-(9-nitrophenyl) car~onate for (4-
picolinyl~-(4-nitrophenyl) carbonate, the title compound wa5
10 prepared. :~
E~am~le 7~
~5 ~ . :
: ~ : . .. .
a) (2~, 4Sf 5$,1~S~-5-ben~oyl)amino-4-t
: : butyldimethylsiloxy-N-(}~-isopropyl-l'-imidazol-2-y~)methyl- -;
6-phenylme~hyl-hexamide.
The compound of Example 13(a) ~0.11 g, 0.2 mm~l),
: ~ benzoyl chloride~0.025 g, 2.2 mmol) and
~; ~ di(isopropyljethylamine ~0.026 g, 0.2 mmol) w~re stirred
: ~ together in dichloromethane ~4 mL) at ambient temperature for ~.
: 25 48hr. The solvent was removed under reduced pressure and the
residue chromato~raphed ~silica, 1:1 e~hyl acetate:hexane) to
yield the title compound as a white solid (0.080 g, 61%).
NMR(CDC13)7.53 (2H, d), 7.40-7.04 ~ m), 6.93 ~2H, dl,
6.6!3 ~2H~ s) ~ 6.59 (lH~ d) r 6.37 ~lH~ d) ~ ~.54 ~2Hr m), 3.68
(lH, t), 2.78 (2H, mJ, 2.66 ~2H, m), 2.39 ~lH, dd), 2.13 (lH,
m); 1.62 ~2H, t;, d~87 (9H, s), 0.53 ~3H, d), 0048 ~3H, d),
: ~.02 (3H, s), 0.~00 (3H, s).
, -:
: b~ (2R,4S,5S,l'S)-5-~benzoyl)amino-4-hydroxy-N-~
: 35 isopropyl~ imidazol-2-yl)methyl-6-phenylmethyl-hexanamide ~:
, . .
: The compound of Example 75 ~a) ~0~080 g, 0.12 mmol) was
dissolved in THF ~1 mL) and to this was added tetrabutyl-
ammomium fluoride, 0.16 mL, 0.16 mmol, lM solution in T~F).
' ~
WO 93/~057 PCI~/~JS92/060~7
,~}~3;~ 118 -
After stirring at 40C for 24 hr, the solvent was removed
under reduced pressure and the residue was chromatographed
(silica, step gradient, 1:1 ethyl acetate:hexane, 9:9:2 ethyl
acetate:hexane:methanol) to give the title compound as a
white solid (0.051 g, 79%). Mp 253-6~C; NMR(DMSO-d6) ~ 7.99
(lH, d), 7.91 (lH, d), 7.72 (2H, d), 7.50-7.02 ~13H, m~, 6.94
(2H, s), 4.83 (lH, br), 4.68 (lH, d)r 4.14 (lH~ m)~ 3.58 ~lH~ :
d), 2.82 (4H, m), 2.49 (lH, m), 1.92 (lH, m), 1.73 ~1~, t~,
1.40 (lH, m;, 0.73 (3H, d), 0.63 (3H, d); MS ~ES) m/e 539.2
lM+H]~
Exar~le 76
. . .
15 ~
~b ~ ......
Following the procedure of Example 75 (a) I except using
furoyl chlc~ride i~ place of beIlzoyl chloride, ~he title -
, . . .
compound wa~ prepared as a white solid tO . t~l9 g, 18~
212-3C (dec~ CDC13/CD3C~D) ~; 7.46 (lH, s3, 7.30-6.88
(12H, m), 6.85 ~2~, s~, 6.~9 (lElr m~, 4.48 ~lH, d~, 4.20 tl~,
- m), 3.67 (lH, m), 2.96 (4Ht m), 2.77 (2H, nt), 2.58 ~l~I, d~,
2 . ()7 ( lH, m~, 1. 71 (2H, m), O . 74 ~3EI, d~, O, 65 (3H, d);
MS ~ES) m/e 528 .32 [~H] + .
25 ~
~ImRl~ "
,~
Following the procedure of Example 75 ~a), except using
9-methoxybenzoyl chloride in place of benzoyl chloride, the
title compound was prepared as a white solid (32%~. Mp 235-
7C (dec); NM~CDC13/CD30D) ~ 7.64 ~2H, d), 7.22--6.87 (14H, -~
m) ~ 6.80 (2H, m), 4.52 ~lH, d), 4.16 (lH, m), 3.81 ~3H, s~,
3.62 (lEI, d), 2.92 (2H, d~, 2.72 ~2H, m), 2.53 (lH, dd), 1.98
(lH, m), 1.73 ~lH, m), 1 . 63 ~lH, m), 0.71 ~3~, d), 0 . 62 ~3H,
d); MS~ES) mie 569.4 [M+H]f.
W093/~2~7 PCT/V~92/0~0~7
- 119- 2~3~
Example 7
P = ~ ~
s I_ "
a) (2R,9S,5S,llS) 5-benzylcarbonyl)amino-4-t-butyldimethyl
siloxy-N~ isopropyl~ imidazol-2-yl)methyl-6-phenylmethyl
--hexanamlde . , , ~ ~ . ,'',
Following the procedure of Examplç 75~a), except using :
phenylacetyl chloride in place of benzoyl chloride and . `
triethylamine in pla~e of di(isopropyl3ethylaminer the title . :
compound was prepared as:a white solid ~20%). N~R(CDC13)
7.40-6.75 ~19H, m), 5.40 ~lH, d), 4.73 (lH, t~, 4.41 ~lH, q),
3.68 (lH, m), 3.48 (2~,: s~, 2.96 (1~, dd), 2,69 (1~, m), 2.49
(4H, m), 1.61 ~2Ho m~, 0.92 (6H, t~, 0.77 (9H, s), 0.04 (3H, -
s) ~ O . 00 (3H, s) .;
~20 b) (2R:,4S,5S,l'S):-5-benzylcarbonyl~amino-4-~ydr~xy-N~
; ~ isopropyl~ imidazol-2-yl)methyl-6-phenylmethyl-hex~namide --
he product~of~Example 78 (a) ~0.018 g, 0.03 mmol) waQ
dissolved in ~ethànol (5 mL):and 2N hydro~hloric acid (0.027 ::-
mL, 0.:06 mmol~was;;~added. After stirring at ambient
temperature for~l8 h::~the solvent was removed under reduced
,
~:: pressure and the:residue w~s chromatographed (silica
gradient, dichloromethane/methanol3 to yield the ~itle
compound (O.Oll~g,~;66%). ~p 240-2~C; NMR~CD13/CD3OD~
7. 8-7.06 (l~H, m), 6.98 (2H, s), 4.72 (lH, d~, 4.14 ~lH, m),
3.67 (lH, m), 3, 54 (2H, s), 2.99 (4H, m), 2.67 (lH, m), 2.14
:: ~lH, m), 1.87 ilH, m~, 1.63 ~lH, m), 9.94 ~3H, d)~ 0.79 (3H,
d~; MS ~ES) mJe:553.2 lMfH]~
~: ; Exarr~le 79 .;
ydroxy-N~ ~oDro~>yL-l '-imidazol-2-yl)methyl--6- `:
':"'',
~:.,''
WOg3/02~7 P~T/US92/06047
~ 6~ 120 -
a) ~2R,4S,55,1'S)-5-(4-acetoxyphenyl)-4-t-butyl
dimethylsiloxy-N-~1'-isopropyl~ imidazol-2-yl)methyl-6-
phenylmethyl-hexanamide. :
The compound of Example 13(a) (0.11 g, 0.2 mmol) was
dissolved in dichloromethane (2 mL), and BOP reagent (0.089
g, 0.2 mmol), triethylamine ~0.028 mL, 0.2 mmol) an~ 4- ;
acetoxybenzoic acid ~0.043 g, 0.24 ~mol) were added. After
stirring at ambient temperature overnight ~he solvent was ;
removed under reduced pressure. The residue wa~
chromatographed ~silica, 49:1 dichloromethane:methanol~ to
give the title compound as a white solid (0.11 g, 78%). ::-
NM~(CDC13~ ~ 7.53 (2~, d), 7.28-6.97 (13H, m)l 6.83 (lH, d),
6.78 (2H, s)~ 6.44 (lH, d), 4.54 (2H, m), 3.72 tlH, dd), 2.79 :~.
15 ~4H, m), 2.49 tlH, dd), 2L24 ~3H, s), 2.20 (lH, m), 1.70 (2H,
m~ 0.91 ~9H, s)~ 0.66 (3H, d)~ 0.57 ~3H~ d), 0~07 (3~, s),
0.02 ~3H, s).
, :.
b) (2R,45,5S,l'S) 5-~4-hydroxybe~zoyl)amino-4-t-butyl :~
dimethylsiloxy-N~ isopropyl~ imidazol-2-yl)methyl-6
phenylmethyl-hexanamide
The product from~reaction 79(a) ~0.11 g, 0.15 mmol) was
: dissolved in methanol ~5 mL) and powdered potassium carbonate
~0~12 g, 0:.9 ~mol~ was a~ded. After stirring the suspension ~-
vigorously for 2 h, the mixture was $iltered and the solvent
remo~ed from the fi:ltrate at reduced pressure.
Chromatography of the residue (silica, 19:19:2 ethyl
acetate:hexane:methanol) gave the title compound as a white
solid (0 . 066 g, 669~ j . N~ (CDC13~ ~i 7 . 35 t2Hr d), 7 . 24--6 . 98
(12~, m), 6.67 ~4H, m), 6.32 (lH, d), 4.63 ~2H, m), 3.76 ~lH,
ddj t 2.78 (4H, m), 2.44 (lH, d), 2.12 ~lH, m), 1.64 ~2H, m~,
0.88 (9H, s), 0.44 (3H, d), 0.32 (3H, d), 0.05 (3H, s), 0.01: ~
~ ~3H, s). -;'
: 35 c~ (2R,4S,5S,l'S)-5-(4-hydroxybenzoyl)amino-4-hydroxy-N-(l'-isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexanamide ~;
Following the procedure of Example 75(b), except using
the compound of Example 79(b) in place of the compound of
.
WOg3/02057 PCT/US92/~60~7 ~
- 121 2:1136~4
Example 75(a), the ti~le compound was prepared as a white
solid (57%). Mp 267-8C (dec); NMR~CDC13/CD30D) ~ 7.57 (2H, i~
d3, 7.33-6.75 (17H, m), 4.48 (lH, d), ~.14 (lH, m), 3.58 (lH,
d), 2.90 ~2H, m), 2.82 (lH, m), 2.73 (lH! m), 2.53 ~lH, dd),
s 2.04 tlH, m), 1.65 ~2H, m), 0.73 (3H, d), 0.58 (3H, d); MS .;
(ES) m/e 555.2 i~+~]+-
. . .
E~n ' '
h~am~ -
Following the procedure of Exa~slple 75 ~a) ~ except using
cir~namoyl chloride in place of benæoyl chloride, the title
compound was prepared as a white solid (2596). Mp 273~C;
NMR~CDCl3/t::D30D) ~ 7.55-6.91 (19EI, m), 6.86 ~2H, s), 6.53 ~1}1,
cl), 4.37 (lH, d), 4.15: (lEI, dt), 3.62 (lH, d), 2.91 (2}~, m),
.
2.7~ ~2~, m), 2.59 (lH, dd~, 2.04 (lH, m), 1.76 ~l~, m), 1.65 ~:
(lH, m), 0.79 ~3H, d), 0.69 13H, d); MS (ES~ m/e 565.2
lM~]+.
~ ~ '
n~eG~
Follo~ing the procedure of Example 79~a), except using
2-acetoxybenzoic acid in place of 4-ace~oxybenzoic acid, the
title compoun~ wa~ prepared (50%~. Mp 197C; NMR(CD3~D)
7.77 (lH, d), 7.42-6.78 (17H, m), 4.62 (lH, d), 4.32 (lH,
dt), 3.71 ~lH, m), 2.94 (2H, m), 2.78 (2H, m), 2.57 tlH, m), ;:~
2.03 tlH, m), 1.84 (lH, m), 1.67 (lH, m), 0.82 (3H, d), 0.~8
(3H, d); MS ~ES) m/e 555.2 [M~H~
: ..
- :.
'~
W093/02~7 P~T/U~92/06047
- ~' ~ 22
~m~l~
.'.' :;
ar~iQn of (2R, 4~ S) -5-~imidazoyl~ aççt.yl)aminom
4-hy~Ln~y~ Qpro~y~ imi~zol-2-yl)me~hy~-6-
S ~hY~ ' ~''"
Following the procedure of Example 79~a)-79~c)~ except ~,t.
using (imidazol 4-yl)acetic acid in place of 4-acetoxy
benzoic acid, the title compound was prepared.
, .
Exam~le 8~
~ "-,
, , :
a) ~lS) l carbobenzyloxyam~no-l-isopropyl-l-[~-(E-
carbomethoxyethylene~imidazol-2-yl)]methane
The compound of Example 27(b) (100 mg, 0.33 mmol),
lith~pm chlor~de S~8 mgt O.66 mmol) and
trimethylphosphonoacetate (61 mg, 0.33 mmol) were dissolved
in anhydrou~ acetonitrile (2 m~). 1,8~Diazabicyclo[5.4.03-
~ undec-7-ene t55 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 ~:
~wa~ purified by flash chromatography (silicaa, 2% methanol/
: ~,
dichloromethane to afford the title compound ~72 mg, 61%).
NMR(CDC13) S 7.60-7.10 (6H, m), 6.50 (lH~ br s), 6.~0 (lH, ~r .
s), 5.15-4.95 ~2H, m), 4.50 ~lH, br m), 3.75 (3H, s), 2.30
~lH, br m3, 1.10-0.80 (6H, m)~ MS m/e 3~8.2 [M+H]~.
b) IlS)-l-amin~-1-isopropyl-1-(4-carbomethoxyethylimidazol-2~ ~-
yl)methane .
Following the procedure of Example l(b), except
substitu~ing the ccmpound of Example 821a) for the compound
of Example l(a), the title compound was prepared. NMR(CDC13)
6.65 (lH,.s), 4.40 (2H, br s), 3.82 (lH, d, J=3 Hz), 3.65
(3H, s), 2.90-2.55 ~4H, m), 2.05 (lH, m3, O.gO (6H, d,
: J=3Hz).
W093/~2~7 PCT/~S92/06047 ~;
... . .
~. - 123 - 2~3~1~
c) ~2R,4S,5S,l'S)-5-(t-butoxycarbonyl)amino-4-t-butyldi
methylsiloxy-N-[l'-isopropyl~ (4-carbomethoxyethylimidazol- :
2yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide
Following the procedure of Example l(c) except using
the compound of Example 82~b), the title compound was
prepared. N~R(C~C13) ~ 7.35-6.90 (12H, m), 6.55 (lH, s),
4.75 (lH, d, ~D4 Hz), 4.45 (lH, m) 3.95 tlH, 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, ~=2 Hz).
d) ~2R,45,SS,l'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-
~ isopropyl 1'-~4-carbomethoxyethylLmidazol-2-yl)]methyl-6-
phenyl-2-phenylmethyl-hexanamide.
Following the procedure of Example of 9~d~ except u~ing
the compound of Ex~mple 83(c), ~he ~itle co~pound wa3 ~
prepared. NMR(CDC13~ 7.30-6.90 (10~, m), 6.55 ~lH, 8), :~:
5.00 ~lH, d, ~J=4 Hz)~ 4.45 (lH, m), 3.70 (3H, s), 2.95-Z.50 -~
~9H, m), 2.25 (lH,~:m), 1.80-1.60 (2H,: m), 0.85 t9~, s), 0O70
~: 20 (6H, d, J~3 ~z~ S m/e 621.4 ~M+H]~.
E~am~le ~4
~.
..
~ 25 ~
.
a) (lS)-l-carbobenzyloxyamino-1-isopropyl~ (4
hydrazinocarbonyl)imidazol-2-yl)]methane
~nhydrous hydrazine (47 ~L, 1.5 ~mol) was added to a
solution o.f 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 Na2C03 and the organic extract was dried over
Na2CO3 and e~aporated u~der reduced pressure. The xesidue
was purified by flash chromatography ~silica, 4~
methanol/dichloromethane) to afford the title compound (52
'.
W093/02~7 PCT/US92/06~7
~ ~ - 124 -
mg, 52%). NMR(CD30D) ~ 7.50 (1~, s), 7.30-7.20 15H, m),
5.00-4.90 (2H, m), 4.45 ~lH, d, J=6 Hz), 2.10 (lH, br m), :~
0.95-0.75 (6H, m); MS m/e 332.2 [M~H]+
-
s b) (lS)-l-carbobenzyloxyamino-l-isopropyl-1-[14-
azidocarbonyl)imidazol-2-yl]methane
The compound of Example 83~a) was dissolved in 2N HCl tl
mL) and glacial acetic ~cid (0.2 mL) and cooled in an ice
bath. A solution of sodium nitri~e ~11 mg, 0.16 mmol) in H2O
(200 ~L) was added dropwise. ~he reac~ion mixture was
stirred for 0.5 hr neutralized with cold concentrated
ammonium hydroxide~and extracted with ethyl acetate. The
organic extract was dried ovéx Na2C03 and the solvent removed
in vacuo to yield the title compound (54mg. 100%).
NMR~CDCl3) ~ 7.75 (1~, s)~ 7.35-7.20 (5H, m), 5.20-5.00 (~
mt, 4.62 (lH, br m)t 2.60 (lH br m), 1.10-0.80 16~, m); IR ~:-
2123cm~1 (CON3). :-
c) ~lS)-l-carbobenzyloxyamino-l-isopropyl-1-t4-
carboxamidoimidazol-2-yl~methane
The compound of Example 83(b) was dissolved in 2 ~L of :~
ethyl acetate and stirred~with of concentrated ammonium :~
-
:: hydroxide (1 mL) at O~C for 0.5 h, then at room temperature
o~ernight. The reaction mixture was diluted with H2O,
2S ~extxacted with ethyl acetate, and dried over Na2CO3. The
solvent was removed in v acuo and the residue was purlfied ~y ~:~
~:~ flash chromatography (siIica, 4% methanol/ dichloromethane~ -
: to afford:the title compound (50mg, 100~. NMR(CDCl3) ~ 7.45
: .
(lHt s~, 7.25-7.10 (5H, m~, 5.00-4.8S (2H, m), 4.35 (lH, d,
30 J~3 Hz), 2.00 (lH, br m~ ,~ 0.90-0.70 ~6H, m); MS rn/e 317.2
rM~H~ + .
d) ~lS)-l-amino-1-isopropy~ 4-carboxamidoimidazol-2- ;
: yl)methane.
~ 3S Following the procedure of Example l(b), except
;~ substi~uting the compound of Example 83(c) for the compound
of Example lla), the title compound was prepared. NMRICDCl3)
,
W~93/02U57 PC~/U~9~ 47
21~b'4~
125 -
7.45 (lH, s), 3.47 (lH, d, J=3 Xz~, 1.80 ~lH, br m), 0.75-
0.60 (6~, m).
.
e) ~2R,4S,5S,l'S)-5-(t~butoxycarbonyl)amino-4-t-
butyldimethylsiloxy-N-ll'-isopropyl-1'-(4-
carboxamidoimidazol-2-yl)]methyl-6-phenyl-2-phenylmethyl-
hexanamide
Following the procedure of Example l(c), excep~ using :~
the compound of Example 83(d), the title compound was
prepared. NMR~CDC13) ~ 7.50 ~lH, s), 7.45-6.90 (11~, m),
6~25 (lH~ d~ J=4 ~z~ r 4.50 (lH, d, J=6Hz), 4.10 ~lH, br m~,
3.60 ~l~I, m)~ 2.90-2.40 (5H, m), 1.90 (1~, br m~, 1.70-1.50
~2H, br m), 1.35 (9H, s)~ 0.90 ~9H, s)r 0.70-0060 (6Ht m~, -
~.10 (~, m).
f) (2R,4S~5S,l'S)-5-(t-butoxycarbonyl)amino-4 hydroxy-~-
[1'-isopropyl-1 a_ (4-carbox~midoimidazol-2-yl~lmethyl-6-
phenyl-2~phenylm~t~yl hexanamide
Following the procedure of Example 9~d) except using the
2Q compound of Example 83(e) the title compound was prepared.
: ~MR(CD30D) ~ 7.45 (1~, s), 7.25-6.85 (lOH~ m3, 4.50 ~lH, ~, -
~:~ J=6 Hz), 4.10 ~lH, m)t 3.60 (lH, m)r 2.85-2.50 (5H, m)t 2.00
(lH, br m), 1.80-1.50 (2H, m)~ 1~30 (9~, s~, 0.80-0.65 ~6H, :::
m~; MS m/e 578.2 1M~H3+.
~5
Limi~ 2-yl~)methyl-hexa~amide
....
a) (2R,4S,5S,19S)-2-phenylmethyl-4-t-butyldimethyl-siloxy-5-
thioureido-6-phenyl-N-~1'-isopropyl~ imidazo-2-yl)~methyl- -
~: hexanamide
: A solution of benzoyl isothiocyanate (prepar~d from
ammonium thiocyanate (147 mg, 1.93 mmol) and benzoyl chloride
: (257 mg, 1.84 mmol) in of acetone (10 mL) according to the :~
.
W093/02~7 PCT/US92/~ ~7
~ 126 -
procedure of J. Amer. Chem. Soc., S6, 1408 (1934)) was
treated with a solution of (2R,4S,5S,l'S)-2-phenylmethyl-4-t-
butyld~methylsiloxy-S-amino-6-phenyl-N-(l'-isopropyl-1'-
(imidazo-2-yl))methyl-hexanamide (1.0 q, 1.83 mmol) in
s acetone. After 20 min at 23C, the solvent was evaporated,
and the residue was dissolved in diethyl ether. The ether
extract was washed with water, dried, and the solvent was
evaporated. This residue was dissolved in of MeOH ~25 mL),
treated with 2.5N NaOH (0.1 mL) and heated to 50C for 30
min. The solvent was evaporated, and the residue was
dissolved in EtOAc. The organic solution was washed with
water, dr~ed, and the solvent evaporated. The residue was
chromatograp~ed ~ ca, 5~ MeOH/CHC13) to yield the title
compound ~520 mg, 474~ NMR~DMSO) 8 7.80 ~lH, d), 7.3S ~lH,
d), 6.70-7.20 ~lSH, m), 4.69 ~lH, t), 4.54 (lH, m), 3.78 (lH,
m), 2.72-2.86 ~3H, m), 2.54 ~lh, dd), 2.42 (lH, dd), 2.04
~lH, m), 1.82 ~lH, m), 1.30 tlH, m), 0.92 ~9H, 8), 0.86 ~3H,
d), 0.74 ~3H, d), 0.15 (6H, d).
b) dimethylformam~dlno derlvatlve o (2R,4S,SS,l'S)-2-
phenylmethyl-4-ldimethyl-t-butyl s~lyloxy-5-th~oureido-6-
phenyl-N-(l'-~sopropyl-l'-~lm~d~o-2-yl))m~thyl~h~x~namld@
A solut~on of th~ compound o~ Ex~mp~ B~(~) (122 m~, 0.2
mmol) ~nd dimethylfor~amide dlm@~hy~ace~al ~26 mg, 0.22 mmol)
in CHCl3 (2 mL) was st~rred at 23C for 16 h~ The solvent
and excess reactant w~ removed under high vacuum, and the
residue was chromato~raphed (Florisil~, 2~ MeOH/CHCL3) to
y~eld the title compound (100 mg, 76~). NMR(CDC13) ~ 8.82
(lH, s), 7.05-7.40 (12H, m), 6.76 (lH, br s), 6.60 (lH, d),
5.32 (lH, m), 4.66 (lH, dd), 3.88 (lH, dd), 3.14 ~3H, s),
3.05 (3H, s), 2.70-3.04 (4H, m), 2.40 (2H, m), 1.68 (2H, m),
1.00 (9H, s), 0.80 (6H, dd), 0.14 (6H, d).
c). (2R,4S, 5S, l'S)-2-phenylmethyl-4-dimethyl-t-butyl
silyloxy-5-(5-(1-oxopropyl)-2-thiazolyl)amino)-6-phenyl-N-
(l'-isopropyl-l'-(imidazo-2-yl)~methyl-hexanamide
A solution of the compound of Example 85(b) (100 mg,
0.15 mmol), 1-bromo-2-butanone (25 mg, 0.165 mmol), and
W093/02~7 PCT/U~g2/0~047
~ ~ 127 21~3~
triethylamine t33 mg, 0~165 mmol) in acetonitrile (10 mL) was
heated at 80C for 3.5 h. The solvent was e~aporated, and
the residue shaken with a mixture of diethyl ether and
aqueous NaHCO3. The ether was seperated, washed with water,
dried, and the solvent was evaporated. The residue was
recrystallized from a mixture of CHCl3 and hexane to yield
the title compound (59 mg, 57%). NMR(CDCl3) ~ 7.75 ~1~, s),
7.02-7.38 (lOH, m), 6.88 (2H, m), 6.80 (lH, br s), 6.70 tlH,
d~, 6.6Q (lH,^ d), 4.62 (lH, t), 3.96 (lH, m), 3.78 (lH, t~,
a 2.82 (3H, m), 2.72 (2H, q), 2.54 (2H, m), 2.20 (lH, m), 2.04
(lH, m), 1.66 (lH, m), 1.15 53H, t), 0.96 (9H, sl, 0.72 (6~,
t), 0.10 ~6H, d). -
. .
d). (2R,4S, 5S, l'S)-2-phenylmethyl-4-hydroxy-5-(5~
oxopropyl)-2-thiazolyl)amino)-6-phenyl-~ isopropyl-l'-
(imidazo-2-yl))m~thyl-hexanamide :
A solution of ~he compound of Example 85(c) ~50 ~g, 0.07
mmol) in (2 m~) of THF was trea~ed with~ of tetrabutyl- ~
ammonium fluoride (0.2 mL, lN solution in THF) 58C for 1 h. .-
The solvents were ev porated, and the residue dissol~ed ~n
ether. The ether was~washed wit~ water, dried, a~d the
solvent evaporated. The residue was chromatographed ~neutra~
a~}umina, Activity V, impurities removed with 2~ MeOH/EtOAc,
product eluted with 5% MeO~/CHCl3) to yield the title
compound (~2 mg, 55%~). NMR~DMSO~ ~ 7.75 ~lH, s), 7.66 (lH, -~-
80-7.30 (13H, m), 4.93 (1~ br s), 4.78 (lH, tl, 3.78
, m), 3.68 ~lH, dd~, 3.00 (lH, dd)~ 2.92 (lH, dd), Z.86
(lH9 m), 2~80-2~90:(lH, br), 2.76 (2H, q), 2.56 (2H, m~, 2.12
~lH, m)~ 1.74~(lH, m), 1.69 (lH, m~ 0 (3~, t), 0.80 (3H,
d), 0.73 ~3H, d).
,
.
~m~le ~ ~
35 rl-oxoplQpyl)=2-~hi~zsly~ ~miDQ)-6-phenyl-N-~l'-isQ~r~pyl-1'- :
timl~z -7-v~l~m~tbvl-hexanamide
~;
,:
w~93/02~7 ,~3~ PCT/US~2/~7
- 128 -
a) (2R,4S,5S,l'S)-2-phenylmethyl-4-dimethyl-t-butyl silyloxy-
5-~2-thiazolylamino)-6-phenyl-N-(1'-isopropyl~ (imidazo-2-
yl))methyl-hexanamide.
The compound of Example B5(a) t50 mg, 0.08 mmol) in
s CHCl3 (2 mL) was treated with chloroacetaldehyde (50 mg~ 0.64
mmol). After 20 min the solvent and excess reagent were
evaporated. The residue was dissolved in EtOAc, washed with ~:
aqueous NaHCO3, dried and the solvent evaporated. The
residue was chrvmatographed ~Florisil~, 60~ EtOAc/hexane~ to
10 yield the title compound ~42 mg, 83%). NMR~CDC13) ~ 7.12-
?.30 (lQH, m), 7.02 (lH, d~, 6.92 ~2H, m), 6.82 ~lH, br),
6.62 (lH, br), 6.38 (lH, d), 5.86 (lH, br), 9.58 ~lH, t~,
4.00 (lHI m~, 3.86 ~lH, m), 2.85 13H, m3, 2.52 t2H, m), 2.26
(lH, m), 2.16 (lH, m), 1.68 (lH, m), 0.98 (9H, s), 0.70 (6H~
15 t~, 0.12 (6H, ~).
b) (2R,4S,5S,l'S)-2-phenylmethyl-4-hydroxy-5-(5
oxopropyl~-2-thiazolyl)amino~-6-phenyl-N-(l'-isopropy~
(imidazo-2-yl)~)methyl-hexanamide.
Followi~g the procedure of Example 85~d), except
: substituting the compound of Example 86~a) ~or the compound
:~ of Example 85(c~, the t~itle compound was prepared.
: NMR(CDC13/DMSO) ~6.80-7.42 (14H, m), 6.40 (2H, m), 5.18 ~lH,
; br), 4.74 (IH, t), 3.70 (lH, m), 3.62 (lH, m), 3.00 (2H, m),
2s 2.~8 ~2H, m), 2.58 ~lH, m), 2.18 (lH, m), 1.80 (2H,~ m~, 1.72
H~ dd).
E~amDle 8?
(Lmidazn-?-yl~)me~yl-hexanam;de
a~ (2R,4S,5S,l'S)-2 phenylmethyl-4-t-butyldimethylsilyloxy-5-
: 3s (5-propyl-2-thiazolyl)amino)-6-phenyl-N-(1'-isopropyl~
~imidazo-2~yl))methyl-hexanamide.
A solu~ion of the compound of Example 85(a) (120 mg~ 0.2
mmol) in CHCl3 (5 m1) was treated with 2-bromovaleraldehyde
: '
W093/02057 PCT/US92/060~7
- 29 2~ 1 3 6
(100 mg, 0.6 mmol~ and warmed to 60C for 30 min and 80C for ~;~
5 min. The solvent and excess reagent were remo~ed under
reduced pressure. The residue was dissolved in EtOAc, washed
with aqueou~ K2C03/ dried, and the solvent evaporated. The
residue was chromatographed (silica, 3% MeOHtCHC13) ~o yield
the title compound ~55 mg, 41%). NMR(CDC13) 8 7.10-7.30
(lOH, m), 6.88 (2H, m), 6.72 (lH, br), 6.68 ~lH, s), 6.60
(lH, br), 5.60 (lH, br), 4.62 (lH, t~, 3.94 (lH, m), 3.78
(lH, t), 2.82 (3H, m), 2.50 (4H, m), 2.26 ~lH, m), 2.04 (lH, ~;
0 m), 1.66 (lH, m), 1~55 ~2H, sextet), 0.94 (9H, s), 0.92 (3H,
t~, 0.70 ~6H, dd), 0.08 (6H, d).
b~. (2R,4S, 5S, l'S)-2-phenylmethyl-4-hydroxy-5-(5-propyl-2-
thiazolyl)amino) 6-phenyl-N-(l'-isopropyl 1'-timidazo-2-
yl))methyl-hexanamide.
Following the procedure of Example 85~d), except
substituti~g the compound of Example B7(a) for ~he compound
of ~xa~ple 85tc), ~he ti~le ompound waæ prepared. NMRlC~C13
7.~0 (lH, ~r), 6.90-7.24 ~lOH, m), ~.78 (2H, s~, 6060 ~lH,
s), 6.18 ~lH, br), 5.76 (lH, br), 4.60 ~lH, t), 3.68 (1~, m),
3.52 ~l~, m~, 3.05 ~lH, dd), 2.95 ~H, m), 2082 (lH, dd~,
2.62 (lH, m), 2.58 (2~H, t3, 2.32 tlHf m), 1.86 (2H, m), 1.60
~2H, sextet), 0.96 (6H, t~, 0.75 (6H, dd).
E~am
' Preparation of-(2R~s~5~ s)-~-(ni~QtiDylL~minQ-4-~ydr~xy-N -~
Following the procedure of Exa~ple 75~a) r except using
nicotinoyl chloride in place of benzoyl chloride, the title
compound w~s prepared as a wh~te solid (43%). Mp 233-4C
dec3; NMR(CDC13/CD30D) ~ 8.81 (lH, d), 8.59 ~lH, dd), 7.g9
~lH, m), 7.35-6.86 (14H, m), 6.79 (2H, s), 4.44 (lH, d), 4.19
(lH, dt), 3.59 (lH, m), 2.90 (2H, d), 2.68 ~2H, m~f 2.52 (2H, --
m), 1.96 ~lH, m), 1.71 (lH, m), 1.58 (lH, m), 0.70 t3~, d),
0.58 (3H, d); MS(ES) m/e 540.2 [M+H~
WOg3/02~7 PCT/~S92/06~47
The above description ~ully 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.
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