CA2089268A1 - Renin inhibitors - Google Patents
Renin inhibitorsInfo
- Publication number
- CA2089268A1 CA2089268A1 CA002089268A CA2089268A CA2089268A1 CA 2089268 A1 CA2089268 A1 CA 2089268A1 CA 002089268 A CA002089268 A CA 002089268A CA 2089268 A CA2089268 A CA 2089268A CA 2089268 A1 CA2089268 A1 CA 2089268A1
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- loweralkyl
- compound
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/14—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A renin inhibiting compound of formula (I), wherein X is O, NH or S and G is a mimic of the Leu-Val cleavage site of angiotensinogen; or a pharmaceutically acceptable salt, ester or prodrug thereof; with the proviso that the compound is not N-(3-(4-Morpholino)propyl)-5(S)-(2(S)-(1(S)-(4-(methoxymethoxy)piperidin-1-yl_ )carbonyl-2-phenyl)ethoxyhexanamido)-6-cyclohexyl-4(S)-hydroxy-2(S)-isop ropylhexanamide.
Description
W~92/034~9 2 ~ g ~ PCT/US9ltO55~
IM~.TBITO~i This is a continuation-in-part or U.S~ patent application Se-lal No. 568,557, fi'ed Augus_ 15, 1990, which is incorporated herein ~y re'erence. This is also a continuation-in-part or U.S. pa.e?.t ap?lica_ion Serial No.
580,811, filed April 3, 1991, ~hich is inco~porated herein by reference.
c~ni~aL F;eld The present invention relates to novel compounds and compositions which inhibit renin, processes for making the compounds and a method of treating hypertension or I congestive heart failure, glaucoma, vascular disease, renal failure or psoriasis with a compound of the in~ention. In addition, the present invention relates to a method for inhibiting a retroviral protease or treating a retroviral infection with a compound of the invention.
.~
i '` ~ .
.l Renin is a proteolytic enzyme synthesized and stored principally in a specific part of the kidney called the juxtaglomerular apparatus. ~ny of three different physiologic circumstances may cause the release of renin .
. .
. .
:' .
;.: .: ... . ..
~ . ' ;
.. . . .~
WO9~/0~29 PCT/US91105~ ~
2o~,9268 ';
into the circulation: (a) a decrease in the blood pressure entering or within the kidney itself; (b) a decrease in the blood volume in the body; or ~c) a fall in the concentra~ion of sodium in the distal tubules of the kidney.
When renin is released into the blood from the kidney, the renin-angiotensin system is activated, leading to vasoconstriction and conservation of sodium, both of which result in increased blood pressure. Renin acts on a circulating p~otein, angiotensinogen! to cleave out a fragment called angiotensin I (AI). AI itself has only slight pharamacologic activity but, after additional cleavage by a second enzyme, angiotensin converting enzyme (ACE), forms the potent molecule angiotensin II (AII). The major pharmacological effects of AII are vasoconstriction and stimulation of the adrenal cortex to release aldosterone, a hormone which causes sodium retention.
Sodium retention causes blood volume to increase, which leads to hypertension. AII is cleaved by an aminopeptidase to form angiotensin III (AIII), which, compared to AII, is a less potent vasoconstrictor but a more potent inducer of aldosterone release.
The renin-angiotensin system has been modulated or manipulated, in the past, with ACE inhibitors. However, ACE acts on several substrates other than angiotensin I
(AI), most notably the kinins which cause such-undesirable side effects as pain, "leaky"-capillaries, prostaglandin release and a variety of behavorial and neurologic effects.
Further, ACE inhibition leads to the accumulation of AI.
Althougn AI has much le55 vasoconstric~or activity than :~ .
. , .
.
': ~ - " " ' ;
~' ' . , ' '~ ' wo g2~03429 2 ~ ~ ~ 2 ~ ~ PCT/US91/0~5~
~ -3-AII, its presence may negate some of the hypotensive effects of the blockade of AII synthesis.
Inhibition of other targets in the renin-angiotensin sys.em such as AII with compounds such as saralasin can block AII activity, but would leave unimpaired and perhaps enhance the hypertensive effects of AIII.
Inhibitors of renin have been sought as agents for con~rol of hypertension and as diagnostic agents for identification of cases of hypertension due to renin excess.
In efforts to identify compounds which inhlbit renin, compounds have been prepared which mimic angiotensinogen, the natural substrate for renin. In particula_, compounds have been prepared which incorporate mimics of the dipeptide sequence of angiotensinosen preceeding the renin cleavage site ~i.e., mimics of Phe-~is) and which also incorporate non-cleavable mimics of the renin cleavage site of angiotensinogen (i.e., Leu-Val). Compounds comprising mimics of both portions of angiotensinogen bind to renin, but are not cleaved. Thus, renin is inhibited from acting on its natural substr~te.
, .. '... ~
W~92/~3429 P~T/US91/~55~._~
2o~92~8 .........
In accordance with the present invention, there are compounds O r the formula:
O
G
C~"
(I) wherein X is 0, ~:~ o~ S and G is a mimle of ~:~e Leu-V2l cleavage site of angiotensinogen; or a pharmaceutically acceptable salt, ester or prodrug thereof; with the proviso that the compound is not N- (3- (4-Morpholino)propyl)-5(S)-(2(S)-~l(S)-(4-(methoxymethoxy)piperidin-1-yl)carbonyl-2-phenyl)ethoxyhexanamido)-6-cyclohexyl.-4(S)-hydroxy-2(S)-isopropylhexanamide.
Preferred compounds of ~he invention are compounds of the formula:
'~ O O ~
N~x~NJ--D
CH3~o~^~o ~ ~ C~, ' ... . . . . . .
. : : ,, , , , , , ., . ,: . .
: , , :: " , : , ." , , , , " ' ::
:, : : , . ~ , . . , : :
~- ~ . . . .
.
.
~92t03429 PCT/US9ltOS~
~ 2~8~2~8 wherein X is O, NH or S; and D is O
HO ¦ H
( i ) C~3~C'~-13 wherein Y is C1 to C~ alkylene o- C; ~o C6 s~s_ituted alkylene; and Rl is -CN, terrazolyl, ~yridyl, ?yrlmidinyl, . imidazolyl, thiazolyl, morphol-n-~1, s-lbsti___eA
. morpholinyl, thiomo~~hol ryl, subs.i~ .eA t~ .or~holi~
~ thiomorpholinyl dioxide, substituted thiomorpholinyl dioxide, ~C(O)OR24 wherein R24 is hydrogen, loweralkyl or benæyl or -NHR2 wherein R2 is hydrogen, alkanoyl, 3 hydroxyalkyl, an N-protecting group, -C~O)NHR17 wherein R17 is hydrogen or loweralkyl, -C(S]NHR1~ wherein R1g is hydrogen or loweralkyl, -C(=N-CN)-NHRlg wherein R1g is hydrogen or loweralkyl, -C(=N-CN)-SR22 wherein R22 is loweralkyl, .. . .
N 1~ NH2 H , ~ , -C(O)O-benzyl, -C(O)R23 wherein - R23 is loweralkyl, ~SO2NR26aR26b wherein R26a and R26b are independently selected from loweralkyi o- -SOzRz7 wherein ~' '.
. .
., W092/0~29 PCT/US91/0~5~
.
~9~ 6~ -6-R27 is loweralkyl or -Y-R1 is - NH--<
N,N
H , -N~2, -NHC(O)NH2, -NHC(S)NX2, -NHSO2R27 wherein R27 is as defined herein, -NHC(=N-CN)NHR1g wherein R19 is as defined herein, -NHC(=N-CN)SR22 wherein R22 is as defined herein or -NHSO2NHR26wherein R26 is as defined herein;
(ii) -CH(OH)CH(OH)CF2CH2N(R20)(R2l) wherein R20 and R21 are independently selected f.om hydrogen and loweralkyl;
(iii) -CH(O~)C(O)CF2CH2N~R20)(R21) wherein R20 and R21 are defined as herein;
(iv) -CH(OH)CF2CH2N(R20)(R21) wherein R20 and R21 are defined as herein;
(v) -C(O)CF2CH2N(R20)(R2l) wherein R20 and R21 are defined as herein;
~vi) -CH(OH)CH2CH(CH(CH3)2)C~O)-N=C~N(cH3)2)(N(cH3)2);
(vii) -CH(OH)CH2CH(CH(CH3)2)CH2Rso wherein R50 is (a) -OR
wherein Rs1 is hydrogen, -CH20CH3 or -CH20CH2CH20CH3, (b) -SRs2 wherein Rs~ is loweralkyl, phenyl, benzyl, pyridyl, pyrimidyl, imidazolyl, loweralkyl substituted imidazolyl, piperidinyl or -Rs4-O-Rss wherein Rs4 is alkylene or substituted alkylene and Rss is -CH20CH3 or -CH20CH2CH20CX3, (c) S(0)2Rs3 wherein Rs3 is-loweralkyl, phenyl, benzyl, pyridyl, pyrimidyl, imidazolyl, loweralkyl substituted imida olyl, thiazolyl, loweralkyl substituted ~ thiazolyl, piperidinyl or -Rs4-0-Rss wherein Rs4 is :' alkylene or substituted alkylene and R55 is W~92/0~29 2 ~ ~ 9 2 6 8 PCT/US9l/0~5~
_7~
-CH2OCH3 or -cH2ocH2cH2ocH3r (d) -N(Rs6)(Rs7) wherein Rs6 and Rs7 are independently selected from hydrogen, loweralkyl, cycloalkyl and hydroxy substituted cvcl~alkyl, ~ .
- N R~
~e) \___/ wherein R59 is O, S, S(O)~ or N(Rsg) wherein Rsg is hydrogen, loweralkyl or benzyl, or -S(0)2~
(f) wherein R33 is -~(R3~) whe-ein R3~ is hydrogen, lowe-alkyl or benzyl; or .
(viii) ~CH(~H) ~ ; or a pharmaceutically acceptable salt, ester or prodrug thereof; with the proviso that the compound is not N-~3-~4-Morpholino)propyl)-5tS)-~2(S)-~l~S)-(4-~methoxymethoxy)piperidin-1-yl)carbonyl-2-phenyl)ethoxyhexanamido)-6-cyclohexyl-4~S)-hydroxy-2~S)-isopropylhexanamide.
'''`
..
, .
, , . :
.
WOg2/0~29 PCT/US91/0~5~ _~
. .
9?~6~ ` -8-More prefe-r~d compounds o. ~he invention are compounds of the .~ormula:
O ~ ~0 1--' M ~ ~ N ~ ~ ~1 C~3~3lC~13 wherein X is O, N~ or S; and Y is C1 to C6 alkylene or C1 to C~ substituted alkylene;
and R1 is -CN, tetrazolyl, pyridyl, pyrimidi~yl, imidazolyl, thiazolyl, morpholinyl, substituted morpholinyl, thiomorpholinyl, substitu~ed thiomorpholinyl, thiomorpholinyl dioxide, substituted thiomorpholinyl dioxide, -C(O)OR24 wherein R24 is hydrogen, loweralkyl or benzyl or -NHR2 wherein R2 is hydrogen, alkanoyl, hydroxyalkyl, an N-protecting group, -C(O)NHRl7 wherein R17 is hydrogen o_ loweralkyl, -C~S)N~R1~ wherein R1g is hydrogen or loweralkyl, -C~=N-CN)-NHR1g wherein Rlg is hydrogen or lowera1kyl, -C(-N-CN) SR22 wherein Rzz i5 -.
: :, , ', , ~O92/0~29 2 ~ ~ ~ 2 ~ ~ P~T/US91/~
.. . , . ~
_ ! ;". ~' S
loweralkyl, N~NH2 H , N~ C(O)O-benzyl, -C(O)R23 wherein R23 is loweral~yl, -SO2NR2s2R26D wherein R26a and R26~ are independently selected rom lowe_alkyl or -SO2R27 wherein R~7 is lowe-alkyl o_ -Y-~1 is N NH., . NH~</ 1¦
,N
H , -N~.~, -NHC(O)NY~2, -~IHC(S)N-.Y.~ so2R27 wherein R27 is as defined herein, -.~1YC~=N--C~ g wherein R1g is as defined herein, -NHC(=N-CN)S~22 wnerein R22 is as defined herein or -NHSO2NHR26wherein R26 is as defined herein; or a pharmaceutically acceptable salt, ester or prodrug thereof; with the proviso that the compound is not N-~3-(4-Morpholino)propyl)-5(S)-(2(S~-(l(S)-(4-(methoxymethoxy)piperidin-1-yl)carbonyl-2-phenyl)ethoxyhexanamido)-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanamide.
The term "mimic of the Leu-~al cleavage site of angiotensinogen" as used herein refers to the substituent G having the formula:
. ~ .
1 ~l J O
~,, ` N~N R
H HO ¦ H
CH3~C~3 .:
W092/0~29 PCT/US91/055~ ~
~o~9~6~ 10-wherein Y and R1 are defined as above.
The term "mimic of the Leu-Val cleavage site of angiotensinogen" as used herein also refers to the substituents corresponding to G which are disclosed in the following references:
U.S. Patent No. 4,851,387, issued July 25, 1989, which is incorporated herein by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula -N~R4)CH(Rs)CH(OH)CH2CH(R6)C(O)R7 whereln R4, Rs, R6 and R~ are as defined therein;
European Patent Ap~lication No. EP355796, publ-shed Ma~ch 7, 1990, discloses mimics o-^ the Leu-Val cleavage site o,~
angiotensinogen having the formula -NHCH(Rl)CH(OR2)CH(CH2CHNHR3)C(O)-~-R4 wherein R1, R2, R3, R4 and F are as defined thereini German Patent Application No. DE3829594, published March 15, 1990, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula -NHCH(Rl)CH(OH)CH2CH(R2)N(R3)(R4) whe:rein R1, R2, R3 and R4 are as defined therein;
U.S. Patent No. 4,889,869, issued December 26, 1989, which is incorporated herein by reference, discloses mimics of the heu-Val cleavage site of angiotensinogen ha~ing the formula -N(R2)CH~R3)CH(R4)CH2CH(R5)C(O)R6 wherein R2, R3, R4, Rs and R6 are as defined therein;
~uropean Patent Application No. EP320204, published June 14, 1989, discloses mimics of-the Leu-Val cleavage site of angiotensinogen having the formula -NHCH(CH2R2)CH(OH)CH2CH(R3)C(O)NH-X3-N(R4)(Rs) wher~in ~2, R3, R4, Rs and X3 are as defined therein;
; .
, . , , ' , ,, . . ; ;: .,,, ; :
. . ~, . . . : . . ~:
. : ~ '"''; : "`,'', ` ' , ' :, , , WO92~G~29 2 0 8 9 2 6 ~ PCT/US91/05524 . ~ .
1 1 !: .', .:
European Patent Application No. EP320205, published June 14, 1989, discloses mimics of the Leu-Val cleavage site or angiotensinogen having the formula -NHCH(CH~R2)CH(OH)CH2CH(R3)C(O)NH-X3-N(R4)(Rs) whereir R2, R3, Rq, Rs and X3 are as defined therein;
European Patent Application No. EP350163, published January 10, 1990, discloses mimics of the Leu-Val cleavage site of angiotensinogen having th~ formula ~NHCH(R3)CH(OH)(CH2)p(CH~Rz))q~A~R4 wherein R3, R4, Rz, A, p and q are as defined therein;
European Patent Application No. EP316965, published May 24, 1989, discloses mimics of the Leu-Val cleavage site o-angiotensinogen havir.g the formula -~-3-Z-~ wherein A, B, Z and W are as defined therein;
European Patent Application No. EP353211, published January 31, 1990, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula ~NHCH~R3)CH~OH)CH2CH~R4)CH2S~O)qRs wherein R3, R4, Rs and q are as defined therein;
European Patent Application No. EP329013, published August 23, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula -NHCH(R1)CH(ORg)CH(R2)(R3) wherein R1, R2, R3, and Rg are as defined therein;
European Patent Application No. EP370454, published May 30, 1990, discloses mimics of the Leu-Yal cleavage site of angiotensinogen having the formula -N(R1)CH((CH2)mR2)CH~OR3)CH~OR4)~CH2)nD wherein R1, R2, R3, R4, n and D are as defined ther`ein;
:, . ; . . :~ ,, , :
w~92io~29 PCTJUS91/055~ ~
~9~6~ -12-European Patent Application No. EP332008, published August23~ 1989, discloses mimics or the Leu-Val cleavage site of angiotensinogen having the formula -NHCH(R3)C~(OR~C~ ORs)(R6) ~hereln R3, R4, R5 and R6 are as defined the~ein;
European Patent A?pli^ation No. _?272444, published June 29, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen ~a~ ng thQ formula ~ R2jcH(R3)cH(R4)(c-;. (R; ) ) n) C (O) ~ -W-V wherein R2, R3, R4, Rs,n, E, W and Y are as defined ther-in;
European Paten. ADP1i cation ~o. _?328978, pub ished August 23, 1989, dlscloses ",im cs of the Leu-Val cleavage site OI
angiotensinogen having the formula -N(R2)CH(R3)CH(R4)(C:~(Rs)) n) C (O) N:~-_-Q-Y wherein R2~ R3, R4, Rs,n, E, Q and Y are as defined therein;
European Patent Application No. EP330925, published September 6, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula -N(R2)CH(R3)CH~R4)tCH(Rs))n)C(O)NH-E--Q-Y An~ wherein R2, R3, R4, Rs, n, E, Q, Y and An~ are as defined therein;
European Patent Application No. EP339483, published Novmber 2, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula -N (R2) CH (R3)CH~R4)CH2C~Rs)(R6)(Y) wherein R2, R3, R4, R5~ R6 and Y are as defined therein;
European Patent Application No. E~326364, published August
IM~.TBITO~i This is a continuation-in-part or U.S~ patent application Se-lal No. 568,557, fi'ed Augus_ 15, 1990, which is incorporated herein ~y re'erence. This is also a continuation-in-part or U.S. pa.e?.t ap?lica_ion Serial No.
580,811, filed April 3, 1991, ~hich is inco~porated herein by reference.
c~ni~aL F;eld The present invention relates to novel compounds and compositions which inhibit renin, processes for making the compounds and a method of treating hypertension or I congestive heart failure, glaucoma, vascular disease, renal failure or psoriasis with a compound of the in~ention. In addition, the present invention relates to a method for inhibiting a retroviral protease or treating a retroviral infection with a compound of the invention.
.~
i '` ~ .
.l Renin is a proteolytic enzyme synthesized and stored principally in a specific part of the kidney called the juxtaglomerular apparatus. ~ny of three different physiologic circumstances may cause the release of renin .
. .
. .
:' .
;.: .: ... . ..
~ . ' ;
.. . . .~
WO9~/0~29 PCT/US91105~ ~
2o~,9268 ';
into the circulation: (a) a decrease in the blood pressure entering or within the kidney itself; (b) a decrease in the blood volume in the body; or ~c) a fall in the concentra~ion of sodium in the distal tubules of the kidney.
When renin is released into the blood from the kidney, the renin-angiotensin system is activated, leading to vasoconstriction and conservation of sodium, both of which result in increased blood pressure. Renin acts on a circulating p~otein, angiotensinogen! to cleave out a fragment called angiotensin I (AI). AI itself has only slight pharamacologic activity but, after additional cleavage by a second enzyme, angiotensin converting enzyme (ACE), forms the potent molecule angiotensin II (AII). The major pharmacological effects of AII are vasoconstriction and stimulation of the adrenal cortex to release aldosterone, a hormone which causes sodium retention.
Sodium retention causes blood volume to increase, which leads to hypertension. AII is cleaved by an aminopeptidase to form angiotensin III (AIII), which, compared to AII, is a less potent vasoconstrictor but a more potent inducer of aldosterone release.
The renin-angiotensin system has been modulated or manipulated, in the past, with ACE inhibitors. However, ACE acts on several substrates other than angiotensin I
(AI), most notably the kinins which cause such-undesirable side effects as pain, "leaky"-capillaries, prostaglandin release and a variety of behavorial and neurologic effects.
Further, ACE inhibition leads to the accumulation of AI.
Althougn AI has much le55 vasoconstric~or activity than :~ .
. , .
.
': ~ - " " ' ;
~' ' . , ' '~ ' wo g2~03429 2 ~ ~ ~ 2 ~ ~ PCT/US91/0~5~
~ -3-AII, its presence may negate some of the hypotensive effects of the blockade of AII synthesis.
Inhibition of other targets in the renin-angiotensin sys.em such as AII with compounds such as saralasin can block AII activity, but would leave unimpaired and perhaps enhance the hypertensive effects of AIII.
Inhibitors of renin have been sought as agents for con~rol of hypertension and as diagnostic agents for identification of cases of hypertension due to renin excess.
In efforts to identify compounds which inhlbit renin, compounds have been prepared which mimic angiotensinogen, the natural substrate for renin. In particula_, compounds have been prepared which incorporate mimics of the dipeptide sequence of angiotensinosen preceeding the renin cleavage site ~i.e., mimics of Phe-~is) and which also incorporate non-cleavable mimics of the renin cleavage site of angiotensinogen (i.e., Leu-Val). Compounds comprising mimics of both portions of angiotensinogen bind to renin, but are not cleaved. Thus, renin is inhibited from acting on its natural substr~te.
, .. '... ~
W~92/~3429 P~T/US91/~55~._~
2o~92~8 .........
In accordance with the present invention, there are compounds O r the formula:
O
G
C~"
(I) wherein X is 0, ~:~ o~ S and G is a mimle of ~:~e Leu-V2l cleavage site of angiotensinogen; or a pharmaceutically acceptable salt, ester or prodrug thereof; with the proviso that the compound is not N- (3- (4-Morpholino)propyl)-5(S)-(2(S)-~l(S)-(4-(methoxymethoxy)piperidin-1-yl)carbonyl-2-phenyl)ethoxyhexanamido)-6-cyclohexyl.-4(S)-hydroxy-2(S)-isopropylhexanamide.
Preferred compounds of ~he invention are compounds of the formula:
'~ O O ~
N~x~NJ--D
CH3~o~^~o ~ ~ C~, ' ... . . . . . .
. : : ,, , , , , , ., . ,: . .
: , , :: " , : , ." , , , , " ' ::
:, : : , . ~ , . . , : :
~- ~ . . . .
.
.
~92t03429 PCT/US9ltOS~
~ 2~8~2~8 wherein X is O, NH or S; and D is O
HO ¦ H
( i ) C~3~C'~-13 wherein Y is C1 to C~ alkylene o- C; ~o C6 s~s_ituted alkylene; and Rl is -CN, terrazolyl, ~yridyl, ?yrlmidinyl, . imidazolyl, thiazolyl, morphol-n-~1, s-lbsti___eA
. morpholinyl, thiomo~~hol ryl, subs.i~ .eA t~ .or~holi~
~ thiomorpholinyl dioxide, substituted thiomorpholinyl dioxide, ~C(O)OR24 wherein R24 is hydrogen, loweralkyl or benæyl or -NHR2 wherein R2 is hydrogen, alkanoyl, 3 hydroxyalkyl, an N-protecting group, -C~O)NHR17 wherein R17 is hydrogen or loweralkyl, -C(S]NHR1~ wherein R1g is hydrogen or loweralkyl, -C(=N-CN)-NHRlg wherein R1g is hydrogen or loweralkyl, -C(=N-CN)-SR22 wherein R22 is loweralkyl, .. . .
N 1~ NH2 H , ~ , -C(O)O-benzyl, -C(O)R23 wherein - R23 is loweralkyl, ~SO2NR26aR26b wherein R26a and R26b are independently selected from loweralkyi o- -SOzRz7 wherein ~' '.
. .
., W092/0~29 PCT/US91/0~5~
.
~9~ 6~ -6-R27 is loweralkyl or -Y-R1 is - NH--<
N,N
H , -N~2, -NHC(O)NH2, -NHC(S)NX2, -NHSO2R27 wherein R27 is as defined herein, -NHC(=N-CN)NHR1g wherein R19 is as defined herein, -NHC(=N-CN)SR22 wherein R22 is as defined herein or -NHSO2NHR26wherein R26 is as defined herein;
(ii) -CH(OH)CH(OH)CF2CH2N(R20)(R2l) wherein R20 and R21 are independently selected f.om hydrogen and loweralkyl;
(iii) -CH(O~)C(O)CF2CH2N~R20)(R21) wherein R20 and R21 are defined as herein;
(iv) -CH(OH)CF2CH2N(R20)(R21) wherein R20 and R21 are defined as herein;
(v) -C(O)CF2CH2N(R20)(R2l) wherein R20 and R21 are defined as herein;
~vi) -CH(OH)CH2CH(CH(CH3)2)C~O)-N=C~N(cH3)2)(N(cH3)2);
(vii) -CH(OH)CH2CH(CH(CH3)2)CH2Rso wherein R50 is (a) -OR
wherein Rs1 is hydrogen, -CH20CH3 or -CH20CH2CH20CH3, (b) -SRs2 wherein Rs~ is loweralkyl, phenyl, benzyl, pyridyl, pyrimidyl, imidazolyl, loweralkyl substituted imidazolyl, piperidinyl or -Rs4-O-Rss wherein Rs4 is alkylene or substituted alkylene and Rss is -CH20CH3 or -CH20CH2CH20CX3, (c) S(0)2Rs3 wherein Rs3 is-loweralkyl, phenyl, benzyl, pyridyl, pyrimidyl, imidazolyl, loweralkyl substituted imida olyl, thiazolyl, loweralkyl substituted ~ thiazolyl, piperidinyl or -Rs4-0-Rss wherein Rs4 is :' alkylene or substituted alkylene and R55 is W~92/0~29 2 ~ ~ 9 2 6 8 PCT/US9l/0~5~
_7~
-CH2OCH3 or -cH2ocH2cH2ocH3r (d) -N(Rs6)(Rs7) wherein Rs6 and Rs7 are independently selected from hydrogen, loweralkyl, cycloalkyl and hydroxy substituted cvcl~alkyl, ~ .
- N R~
~e) \___/ wherein R59 is O, S, S(O)~ or N(Rsg) wherein Rsg is hydrogen, loweralkyl or benzyl, or -S(0)2~
(f) wherein R33 is -~(R3~) whe-ein R3~ is hydrogen, lowe-alkyl or benzyl; or .
(viii) ~CH(~H) ~ ; or a pharmaceutically acceptable salt, ester or prodrug thereof; with the proviso that the compound is not N-~3-~4-Morpholino)propyl)-5tS)-~2(S)-~l~S)-(4-~methoxymethoxy)piperidin-1-yl)carbonyl-2-phenyl)ethoxyhexanamido)-6-cyclohexyl-4~S)-hydroxy-2~S)-isopropylhexanamide.
'''`
..
, .
, , . :
.
WOg2/0~29 PCT/US91/0~5~ _~
. .
9?~6~ ` -8-More prefe-r~d compounds o. ~he invention are compounds of the .~ormula:
O ~ ~0 1--' M ~ ~ N ~ ~ ~1 C~3~3lC~13 wherein X is O, N~ or S; and Y is C1 to C6 alkylene or C1 to C~ substituted alkylene;
and R1 is -CN, tetrazolyl, pyridyl, pyrimidi~yl, imidazolyl, thiazolyl, morpholinyl, substituted morpholinyl, thiomorpholinyl, substitu~ed thiomorpholinyl, thiomorpholinyl dioxide, substituted thiomorpholinyl dioxide, -C(O)OR24 wherein R24 is hydrogen, loweralkyl or benzyl or -NHR2 wherein R2 is hydrogen, alkanoyl, hydroxyalkyl, an N-protecting group, -C(O)NHRl7 wherein R17 is hydrogen o_ loweralkyl, -C~S)N~R1~ wherein R1g is hydrogen or loweralkyl, -C~=N-CN)-NHR1g wherein Rlg is hydrogen or lowera1kyl, -C(-N-CN) SR22 wherein Rzz i5 -.
: :, , ', , ~O92/0~29 2 ~ ~ ~ 2 ~ ~ P~T/US91/~
.. . , . ~
_ ! ;". ~' S
loweralkyl, N~NH2 H , N~ C(O)O-benzyl, -C(O)R23 wherein R23 is loweral~yl, -SO2NR2s2R26D wherein R26a and R26~ are independently selected rom lowe_alkyl or -SO2R27 wherein R~7 is lowe-alkyl o_ -Y-~1 is N NH., . NH~</ 1¦
,N
H , -N~.~, -NHC(O)NY~2, -~IHC(S)N-.Y.~ so2R27 wherein R27 is as defined herein, -.~1YC~=N--C~ g wherein R1g is as defined herein, -NHC(=N-CN)S~22 wnerein R22 is as defined herein or -NHSO2NHR26wherein R26 is as defined herein; or a pharmaceutically acceptable salt, ester or prodrug thereof; with the proviso that the compound is not N-~3-(4-Morpholino)propyl)-5(S)-(2(S~-(l(S)-(4-(methoxymethoxy)piperidin-1-yl)carbonyl-2-phenyl)ethoxyhexanamido)-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanamide.
The term "mimic of the Leu-~al cleavage site of angiotensinogen" as used herein refers to the substituent G having the formula:
. ~ .
1 ~l J O
~,, ` N~N R
H HO ¦ H
CH3~C~3 .:
W092/0~29 PCT/US91/055~ ~
~o~9~6~ 10-wherein Y and R1 are defined as above.
The term "mimic of the Leu-Val cleavage site of angiotensinogen" as used herein also refers to the substituents corresponding to G which are disclosed in the following references:
U.S. Patent No. 4,851,387, issued July 25, 1989, which is incorporated herein by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula -N~R4)CH(Rs)CH(OH)CH2CH(R6)C(O)R7 whereln R4, Rs, R6 and R~ are as defined therein;
European Patent Ap~lication No. EP355796, publ-shed Ma~ch 7, 1990, discloses mimics o-^ the Leu-Val cleavage site o,~
angiotensinogen having the formula -NHCH(Rl)CH(OR2)CH(CH2CHNHR3)C(O)-~-R4 wherein R1, R2, R3, R4 and F are as defined thereini German Patent Application No. DE3829594, published March 15, 1990, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula -NHCH(Rl)CH(OH)CH2CH(R2)N(R3)(R4) whe:rein R1, R2, R3 and R4 are as defined therein;
U.S. Patent No. 4,889,869, issued December 26, 1989, which is incorporated herein by reference, discloses mimics of the heu-Val cleavage site of angiotensinogen ha~ing the formula -N(R2)CH~R3)CH(R4)CH2CH(R5)C(O)R6 wherein R2, R3, R4, Rs and R6 are as defined therein;
~uropean Patent Application No. EP320204, published June 14, 1989, discloses mimics of-the Leu-Val cleavage site of angiotensinogen having the formula -NHCH(CH2R2)CH(OH)CH2CH(R3)C(O)NH-X3-N(R4)(Rs) wher~in ~2, R3, R4, Rs and X3 are as defined therein;
; .
, . , , ' , ,, . . ; ;: .,,, ; :
. . ~, . . . : . . ~:
. : ~ '"''; : "`,'', ` ' , ' :, , , WO92~G~29 2 0 8 9 2 6 ~ PCT/US91/05524 . ~ .
1 1 !: .', .:
European Patent Application No. EP320205, published June 14, 1989, discloses mimics of the Leu-Val cleavage site or angiotensinogen having the formula -NHCH(CH~R2)CH(OH)CH2CH(R3)C(O)NH-X3-N(R4)(Rs) whereir R2, R3, Rq, Rs and X3 are as defined therein;
European Patent Application No. EP350163, published January 10, 1990, discloses mimics of the Leu-Val cleavage site of angiotensinogen having th~ formula ~NHCH(R3)CH(OH)(CH2)p(CH~Rz))q~A~R4 wherein R3, R4, Rz, A, p and q are as defined therein;
European Patent Application No. EP316965, published May 24, 1989, discloses mimics of the Leu-Val cleavage site o-angiotensinogen havir.g the formula -~-3-Z-~ wherein A, B, Z and W are as defined therein;
European Patent Application No. EP353211, published January 31, 1990, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula ~NHCH~R3)CH~OH)CH2CH~R4)CH2S~O)qRs wherein R3, R4, Rs and q are as defined therein;
European Patent Application No. EP329013, published August 23, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula -NHCH(R1)CH(ORg)CH(R2)(R3) wherein R1, R2, R3, and Rg are as defined therein;
European Patent Application No. EP370454, published May 30, 1990, discloses mimics of the Leu-Yal cleavage site of angiotensinogen having the formula -N(R1)CH((CH2)mR2)CH~OR3)CH~OR4)~CH2)nD wherein R1, R2, R3, R4, n and D are as defined ther`ein;
:, . ; . . :~ ,, , :
w~92io~29 PCTJUS91/055~ ~
~9~6~ -12-European Patent Application No. EP332008, published August23~ 1989, discloses mimics or the Leu-Val cleavage site of angiotensinogen having the formula -NHCH(R3)C~(OR~C~ ORs)(R6) ~hereln R3, R4, R5 and R6 are as defined the~ein;
European Patent A?pli^ation No. _?272444, published June 29, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen ~a~ ng thQ formula ~ R2jcH(R3)cH(R4)(c-;. (R; ) ) n) C (O) ~ -W-V wherein R2, R3, R4, Rs,n, E, W and Y are as defined ther-in;
European Paten. ADP1i cation ~o. _?328978, pub ished August 23, 1989, dlscloses ",im cs of the Leu-Val cleavage site OI
angiotensinogen having the formula -N(R2)CH(R3)CH(R4)(C:~(Rs)) n) C (O) N:~-_-Q-Y wherein R2~ R3, R4, Rs,n, E, Q and Y are as defined therein;
European Patent Application No. EP330925, published September 6, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula -N(R2)CH(R3)CH~R4)tCH(Rs))n)C(O)NH-E--Q-Y An~ wherein R2, R3, R4, Rs, n, E, Q, Y and An~ are as defined therein;
European Patent Application No. EP339483, published Novmber 2, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula -N (R2) CH (R3)CH~R4)CH2C~Rs)(R6)(Y) wherein R2, R3, R4, R5~ R6 and Y are as defined therein;
European Patent Application No. E~326364, published August
2, 1989, discloses mimics o the Leu-Val clea~aqe site of angiotensinogen having the ~ormula -NHCH~CH2R4)CH~OH)CH2CH~C~OH)~Rs)(R6))C(O)N~R7)~Rg) wherein R4, Rs, R6, R7 and R8 are as defined therein;
, . ' ~, WO 92/03429 2 ~ 3 ~ 2 ~ 8 PCr/US91/oS~
13-- ~r ~, j .
European Patent Application No. EP331105, published September 6, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula -NHCH(R3)CH(OH)P(=M) (Z ' -R2 )(Z-R1) wne_ein R1, R2, R3, M, Z' and Z are as defined therein;
PCT Patent Application No. ~089/03842, published May 5, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the fo-mul -NHc(Rgo)(R~l)cH(OH)(c~(Rloo))n-N(~ l)(Rlo?) wherein Rgo, R31, Rloo, ~101, R132 ~nd n a-Q as Aef r.ed therQin;
PCT ~atent Appl~^2tion No. W089/Qg833, p~blished June 1, 1989, discloses mim~cs of the Leu-Val cleavage site of angiotensinogen having the formula -N'~.CY~(CH2R2)(X) wherein R2 and X are zs defined therein;
European Patent Application No. EP331921, published September 13, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula -W-U-V
wherein W, U and V are as defined thereir.;
PCT Patent Application No. WO90/07521, published July 12, 1990, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula -NHC~R4)CH~OH)CH~C~Rs)~R6)~7) wherein R4, Rs, R6 and R7 are as defined therein;
European Patent Application No. EP391179, published October 10, 1990, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula ~NHCH~R3)CH~OH)CH2CH~CH(CH3)2)(Rq) wherein R3 and R4 are as defined therein;
European Patent Application No. EP391180, published October 10, 1990, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the fo-mula ' :
'' : , ;' '' :
.:.
W092/0~29 PCT/US91/05 ~ o~9~ 6~ 14-; -NHCH(R3)CH(R4)(CH2)nRs wherein R3, R4, Rs and n are as defined therein;
British Patent Application No. GB2196958, published May 11, 1988, discloses mimics of the Leu-Val cleavage site o angiotensinogen having the formula -NHCH(R)C(R1)(R2)CH(R3)(R4)C(Rs)(R6)C(O)-B wherein R, R1, R2, R3, R4r Rs, R6 and B are as defined therein;
European Patent Application No. EP373549, published June 20, 1990, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula -NHCH~R2)CH(=~(O)~R4)) wherein R2 and R4 are as defined therein;
German Patent Application No. DE3840452, published June 7, 1990, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the foxmula i -NHCH(~4)CH(B(OR6)(OR7))-Rs wherein R4, Rs, R6 and R7 are as defined therein;
European Patent Application No. EP3734g7, published June 20, 1990, discloses mimic.~ of the Leu-Val cleavage site of angiotensinogen having the formula -NHCH(R2)CH~OH)CH(R3)(R4) wherein R2, R3 and R4 are as defined therein;
European Pa~ent Application No. EP372537, published J~ne 13, 1990, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula ~NHCH(R2)CH(OH)CH(R3)(CH2)p~X~(CH2)q~R4 wherein R2, R3, R4, X, p and q are as defined therein; -PCT Patent Application No. WO91~01327, published February 7, 1991~ discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula -NHCH(CH2Rl)CH(OH)CH(OH)CH2C(R2)(R3)(NHX1) wherein Rl, R2, ; ~3 and X1 are as defined therein; and . .
: .: . . , ~
: - ~ ' ;- . . ~: . ., ' ' , -. ~ ' .
wo92io~29 PCT/US9i/055~
200~268 `~"`
Australian Patent Application No. AU39445/89, published January 3, 1990, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula -NHCH(R1)CH(OR2~CH(CH2NHR3)C(O)-F-R4 wherein R1, R2, R3, R4 and F are as defined therein.
The term "loweralkyl" as used herein refers to straight or branched chain alkyl radicals containing from 1 to 7 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-buty , sec-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, n-hep,yl and the like.
~- ~he term "cycloalkyl" as used herein refers to an aliphatic ring having 3 to 7 carbon atoms including, but :; not limited to, cyclopropyl, cyclopentyl, cyclohexyl and the like.
:.~ The term "cycloalkylalkyl" as used herein refers to a cycloalkyl group appended to a loweralkyl radical including, but not limited ~o, cyclohexylmethyl and the like.
The term "alkylene" as used herein refers to a 1 to 6 carbon straight or branched chain diradical including, but not limited tol -CH2-, -CH(CH3)-, -CH2CH~CH2-, -C~(CH3)C~2CH2- and the like.
The term "substituted alkylene" as used herein refers to an alkylene group which is substituted with one or two groups independently selected from loweralkyl, alkoxy and ; ~hioalkoxy.
'' :
., , ~.
''.' :
:. ".. " . . ' ,~, . ,, ., , , . , : ~
~ : ' ' ' .
WO9~/0~29 P~T/US91/0~5 ~ 16-The term "hydroxyalkyl" as used herein refers to an -OH group appended to a loweralkyl radical including, but not limited to, hydroxymethyl, hyd_oxyethyl, hydroxypropyl and the like.
The term "nalo-substituted loweralkyl" or "haloalkyl"
as used herein refers to a lo~eralkyl g-oup which is substituted with one or more halo groups including, but not limited to, chlorome~hyl, .ri luo-omethyl, trichloroethyl, bromoerhvl and the li.ko.
The te-m "alkanovl" as used ~.e-o' ?. -ororS to _r (o) R~
wherein R4 is a loweralkvl grou?.
The term "al'.~oxyca-bonyl" 25 ~se- ho-ein; e~ers to -C(O)ORs wherein ~5 is Ioweralkyl c- halo-substituted loweralkyl.
The terms "alkoxy" and "thioal~oxy" as used herein refer to -OR7 and -SR7, respectively, wherein R7 is a loweralkyl group.
The term "alkylamino" as used herein refers to -NHRg wherein R8 is a loweralkyl group.
The term "dialkylamino" as used herein refers to -NRgRlo wherein Rg and Rlo are independently selected from loweralkyl.
The term "halogen" or '?halo" as used herein refers to I, Br, Cl or F.
; The term "aroyl" as used herein refers to -C(O)R6 - wherein R6 is an aryl group.
The term "aryl" as used herein refers to a C6 monocyclic aromatic ring system or a Cg or Clo bicyclic carbocyclic ring system having one or more aromatic rings ~` including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenvl and the like. Aryl ., ~' .
~, , ~'`. .
', .
~, . , . : ..
: , .
' ,. . . '' . . ., ~
WO'~2/0~29 ~ ~ g ~ 2 ~ ~ PCT/~S9l/055 -17~ s~~
groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, alkoxycarbonyl, alkanoyl, hydroxy, halo, me-c~?to,-nlt-o, amino, alkylamino, dialkylamino, carboxaldehyde, ca-boxy and carboxamide.
The term 'IN-protecting group" o_ "N-protected" 25 used herein refers to those groups intended to protect nitrogen atoms against undes~rabl~ reac'ions during synthetic procedures or to preven_ ~he attac~ of exopeptidases on the final compound3 or tO increase the solubility of the -inal com?ounds. N-protec.ing groups include alkanovl, al~oxyca-bonvl o- 2' oyl 2nd il.clude b -are not lim_.ed to for~yl, acety:, pivaloyl, t-butylacet~f~, trichloroethoxy~arbonyl, t-butyloxycarbonyl (Boc), benzyloxycarbonyl tCbZ) or benzoyl groups or an L- or D-aminoacyl residue, which may itself be N-protected similarly.
The terms "substituted morpholinyl" ~Z is O), "substituted thiomorpholinyl" (Z is S) and "substituted thiomorpholinyl dioxide" ~Z is S~O)2) as used herein refer to a morpholinyl group, a thiomorpholinyl group or a thiomorpholinyl dioxide group, respectively, which is substituted with one, two, three o- four groups independently selected from loweralkyl including, but no~
~, .~.
'~
, :-"', .
,, .
. : : : . ,, . :
~;, , . .: . . . , :
.~ ,. .. ...... .
WO9~/0~29 PCT/U~91/05~
~9~ 18-limited to, -N Z . -N Z . -N z, -N Z
-N Z , -N ~ . -N Z and -N
Substituted morpholinyl, substituted thiomorpholinyl or substltuted thiomorpholinyl dioxide also include -N~ -N~
and z)3~
In addition, the term "substituted morpholinyl" as - used herein also refers to [~ or [~
: / O / R~
wherein R~ is loweralkyl.
The compounds of formula I contain two or more asymmetric carbon atoms and thus can exist as pure " .
., ,, .
, . . .
W~92/0~29 2 ~ 8 ~ 2 ~ 8 PCT/US91/05524 ~ ,, .
diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates. The present invention includes within its scope all of the isomeric forms. The terms "R" and "S" configuration used herein are as defined by IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem (1976) 45, 13-30.
.The compounds of the invention can be pr~pared as shown in Schemes 1-9. In Scheme 1, the diprotected hydroxyethylene dipeptide isostere 1 ~European Patent Application No. EP364804, published April 25, 1991), or an activated derivative thereof, is coupled to an appropriately functionalized amine 2 (Y and R1 are defined as above) to provide the amide 3. Standard peptide coupling conditions known to those skilled in the art can be used. In particular, the scheme :Lllustrates ~he use of l-hydroxybenzotriazole ~HOBT), 1-(3-dimethylaminopropyl)-
, . ' ~, WO 92/03429 2 ~ 3 ~ 2 ~ 8 PCr/US91/oS~
13-- ~r ~, j .
European Patent Application No. EP331105, published September 6, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula -NHCH(R3)CH(OH)P(=M) (Z ' -R2 )(Z-R1) wne_ein R1, R2, R3, M, Z' and Z are as defined therein;
PCT Patent Application No. ~089/03842, published May 5, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the fo-mul -NHc(Rgo)(R~l)cH(OH)(c~(Rloo))n-N(~ l)(Rlo?) wherein Rgo, R31, Rloo, ~101, R132 ~nd n a-Q as Aef r.ed therQin;
PCT ~atent Appl~^2tion No. W089/Qg833, p~blished June 1, 1989, discloses mim~cs of the Leu-Val cleavage site of angiotensinogen having the formula -N'~.CY~(CH2R2)(X) wherein R2 and X are zs defined therein;
European Patent Application No. EP331921, published September 13, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula -W-U-V
wherein W, U and V are as defined thereir.;
PCT Patent Application No. WO90/07521, published July 12, 1990, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula -NHC~R4)CH~OH)CH~C~Rs)~R6)~7) wherein R4, Rs, R6 and R7 are as defined therein;
European Patent Application No. EP391179, published October 10, 1990, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula ~NHCH~R3)CH~OH)CH2CH~CH(CH3)2)(Rq) wherein R3 and R4 are as defined therein;
European Patent Application No. EP391180, published October 10, 1990, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the fo-mula ' :
'' : , ;' '' :
.:.
W092/0~29 PCT/US91/05 ~ o~9~ 6~ 14-; -NHCH(R3)CH(R4)(CH2)nRs wherein R3, R4, Rs and n are as defined therein;
British Patent Application No. GB2196958, published May 11, 1988, discloses mimics of the Leu-Val cleavage site o angiotensinogen having the formula -NHCH(R)C(R1)(R2)CH(R3)(R4)C(Rs)(R6)C(O)-B wherein R, R1, R2, R3, R4r Rs, R6 and B are as defined therein;
European Patent Application No. EP373549, published June 20, 1990, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula -NHCH~R2)CH(=~(O)~R4)) wherein R2 and R4 are as defined therein;
German Patent Application No. DE3840452, published June 7, 1990, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the foxmula i -NHCH(~4)CH(B(OR6)(OR7))-Rs wherein R4, Rs, R6 and R7 are as defined therein;
European Patent Application No. EP3734g7, published June 20, 1990, discloses mimic.~ of the Leu-Val cleavage site of angiotensinogen having the formula -NHCH(R2)CH~OH)CH(R3)(R4) wherein R2, R3 and R4 are as defined therein;
European Pa~ent Application No. EP372537, published J~ne 13, 1990, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula ~NHCH(R2)CH(OH)CH(R3)(CH2)p~X~(CH2)q~R4 wherein R2, R3, R4, X, p and q are as defined therein; -PCT Patent Application No. WO91~01327, published February 7, 1991~ discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula -NHCH(CH2Rl)CH(OH)CH(OH)CH2C(R2)(R3)(NHX1) wherein Rl, R2, ; ~3 and X1 are as defined therein; and . .
: .: . . , ~
: - ~ ' ;- . . ~: . ., ' ' , -. ~ ' .
wo92io~29 PCT/US9i/055~
200~268 `~"`
Australian Patent Application No. AU39445/89, published January 3, 1990, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula -NHCH(R1)CH(OR2~CH(CH2NHR3)C(O)-F-R4 wherein R1, R2, R3, R4 and F are as defined therein.
The term "loweralkyl" as used herein refers to straight or branched chain alkyl radicals containing from 1 to 7 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-buty , sec-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, n-hep,yl and the like.
~- ~he term "cycloalkyl" as used herein refers to an aliphatic ring having 3 to 7 carbon atoms including, but :; not limited to, cyclopropyl, cyclopentyl, cyclohexyl and the like.
:.~ The term "cycloalkylalkyl" as used herein refers to a cycloalkyl group appended to a loweralkyl radical including, but not limited ~o, cyclohexylmethyl and the like.
The term "alkylene" as used herein refers to a 1 to 6 carbon straight or branched chain diradical including, but not limited tol -CH2-, -CH(CH3)-, -CH2CH~CH2-, -C~(CH3)C~2CH2- and the like.
The term "substituted alkylene" as used herein refers to an alkylene group which is substituted with one or two groups independently selected from loweralkyl, alkoxy and ; ~hioalkoxy.
'' :
., , ~.
''.' :
:. ".. " . . ' ,~, . ,, ., , , . , : ~
~ : ' ' ' .
WO9~/0~29 P~T/US91/0~5 ~ 16-The term "hydroxyalkyl" as used herein refers to an -OH group appended to a loweralkyl radical including, but not limited to, hydroxymethyl, hyd_oxyethyl, hydroxypropyl and the like.
The term "nalo-substituted loweralkyl" or "haloalkyl"
as used herein refers to a lo~eralkyl g-oup which is substituted with one or more halo groups including, but not limited to, chlorome~hyl, .ri luo-omethyl, trichloroethyl, bromoerhvl and the li.ko.
The te-m "alkanovl" as used ~.e-o' ?. -ororS to _r (o) R~
wherein R4 is a loweralkvl grou?.
The term "al'.~oxyca-bonyl" 25 ~se- ho-ein; e~ers to -C(O)ORs wherein ~5 is Ioweralkyl c- halo-substituted loweralkyl.
The terms "alkoxy" and "thioal~oxy" as used herein refer to -OR7 and -SR7, respectively, wherein R7 is a loweralkyl group.
The term "alkylamino" as used herein refers to -NHRg wherein R8 is a loweralkyl group.
The term "dialkylamino" as used herein refers to -NRgRlo wherein Rg and Rlo are independently selected from loweralkyl.
The term "halogen" or '?halo" as used herein refers to I, Br, Cl or F.
; The term "aroyl" as used herein refers to -C(O)R6 - wherein R6 is an aryl group.
The term "aryl" as used herein refers to a C6 monocyclic aromatic ring system or a Cg or Clo bicyclic carbocyclic ring system having one or more aromatic rings ~` including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenvl and the like. Aryl ., ~' .
~, , ~'`. .
', .
~, . , . : ..
: , .
' ,. . . '' . . ., ~
WO'~2/0~29 ~ ~ g ~ 2 ~ ~ PCT/~S9l/055 -17~ s~~
groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, alkoxycarbonyl, alkanoyl, hydroxy, halo, me-c~?to,-nlt-o, amino, alkylamino, dialkylamino, carboxaldehyde, ca-boxy and carboxamide.
The term 'IN-protecting group" o_ "N-protected" 25 used herein refers to those groups intended to protect nitrogen atoms against undes~rabl~ reac'ions during synthetic procedures or to preven_ ~he attac~ of exopeptidases on the final compound3 or tO increase the solubility of the -inal com?ounds. N-protec.ing groups include alkanovl, al~oxyca-bonvl o- 2' oyl 2nd il.clude b -are not lim_.ed to for~yl, acety:, pivaloyl, t-butylacet~f~, trichloroethoxy~arbonyl, t-butyloxycarbonyl (Boc), benzyloxycarbonyl tCbZ) or benzoyl groups or an L- or D-aminoacyl residue, which may itself be N-protected similarly.
The terms "substituted morpholinyl" ~Z is O), "substituted thiomorpholinyl" (Z is S) and "substituted thiomorpholinyl dioxide" ~Z is S~O)2) as used herein refer to a morpholinyl group, a thiomorpholinyl group or a thiomorpholinyl dioxide group, respectively, which is substituted with one, two, three o- four groups independently selected from loweralkyl including, but no~
~, .~.
'~
, :-"', .
,, .
. : : : . ,, . :
~;, , . .: . . . , :
.~ ,. .. ...... .
WO9~/0~29 PCT/U~91/05~
~9~ 18-limited to, -N Z . -N Z . -N z, -N Z
-N Z , -N ~ . -N Z and -N
Substituted morpholinyl, substituted thiomorpholinyl or substltuted thiomorpholinyl dioxide also include -N~ -N~
and z)3~
In addition, the term "substituted morpholinyl" as - used herein also refers to [~ or [~
: / O / R~
wherein R~ is loweralkyl.
The compounds of formula I contain two or more asymmetric carbon atoms and thus can exist as pure " .
., ,, .
, . . .
W~92/0~29 2 ~ 8 ~ 2 ~ 8 PCT/US91/05524 ~ ,, .
diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates. The present invention includes within its scope all of the isomeric forms. The terms "R" and "S" configuration used herein are as defined by IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem (1976) 45, 13-30.
.The compounds of the invention can be pr~pared as shown in Schemes 1-9. In Scheme 1, the diprotected hydroxyethylene dipeptide isostere 1 ~European Patent Application No. EP364804, published April 25, 1991), or an activated derivative thereof, is coupled to an appropriately functionalized amine 2 (Y and R1 are defined as above) to provide the amide 3. Standard peptide coupling conditions known to those skilled in the art can be used. In particular, the scheme :Lllustrates ~he use of l-hydroxybenzotriazole ~HOBT), 1-(3-dimethylaminopropyl)-
3-ethyl-carbodiimide ~EDCI) and N-mel:hylmorpholine (NMM).
This coupling reaction can be achieved by other standard peptide coupling methods (active ester method, BOP-chloride, as well as other carbodiimides, e.g. DCC, DIC).
The derived amide then can be deprotected by the two-stage method of 1) BOC-removal with trifluoroacetic acid, followed by 2) aqueous hydrolysis of the aminal, whicn produces the aminoalcohol 4. Standard peptide coupling of
This coupling reaction can be achieved by other standard peptide coupling methods (active ester method, BOP-chloride, as well as other carbodiimides, e.g. DCC, DIC).
The derived amide then can be deprotected by the two-stage method of 1) BOC-removal with trifluoroacetic acid, followed by 2) aqueous hydrolysis of the aminal, whicn produces the aminoalcohol 4. Standard peptide coupling of
4 to 5 yields the product 6. Again, any peptide coupling method could be used for this transformation.
Activated deri~atives of carboxylic acids as mentioned herein refer to acid halides such as acid chlorides, and activated esters including, but not limited to, formic and acetic acid derived anhydrides, anhydrides derived from . ,:
~ `, .
:
., :
WG92/0~ PCT/US91/05~
20~9 ~,~ i ~ ~
alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, N-hydroxysuccinimide derived esters, N-hydroxyphthalimide derived esters, N-hydroxybenzotriazole derived esters, N-hyd-oxy-5-norbo_nene-2,3-dica~bo~amide derived esters, 2,4,5-trichlorophenol derived esters and the like.
Scheme 2 illustrates a method to prepare compounds of the invention ~herein the C-term nus is furthe-functionali7ed. ~o_ exam?la, th~ am no-'e-~in21 di?rotectad hyG-v~ --nylena v'p-_-'da isostere 7 can be reac~ed wi-h a~?ro?~ia~e elec~rov;.iles 8 to produce amides, ca oamates, ureas or amidines or guanidines, using methods availa~le in the chemical lilerature. The same deprotection/cou?ling sequence described in Scheme 1 then leads to the N-terminal functionalized compound 10. It should be noted that amines such as 7 also may be reacted with sulfur-based electrophiles (sulfenyl, sulfinyl, sulfonyl, or sulfamoyl halides) to produce sulfenamides, sulfinamides, sulfonamides or sulfamides, respectively.
In addition, it should be apparent to those skilled in the art that the method of Scheme 1 can be used to prepare compound 10 wherein in~ermediate 2 i3 appropriately functionalized.
Scheme 3 illustrates an alternate preparation of compound 6. Alkylation of (~)-2-~-omohexanoic acid with the sodium salt of alcohol 11 ~Eu-opean ~atent Application No. EP364804, published April 25, 1991), provides carboxylic acid 5a as a single diastereomer after silica gel column chromatography. ~Alternatively, crude compound 5a can be converted to an active ester derivative (such as the mono- or di-nitrophenylester) ?rior to chromatographic . ., ; .
. . ~
.: .
.~
.
,, .. : ., . ~ :, . ..
wo9~io~29 2 ~ g 9 ~ ~ ~ PCTt~S91/055~
separation of the diastereomers). The acid 5a (or an active ester derivative) is then coupled to the amino lactone 1~ (Bradbury, R. H.; Revill, J. M.; Rivett, J. E.;
Waterson, D. Te~rahedro.n Lett. 1999, 3~4~) using stand2rd peptide coupling procedures to give the key intermediate 13. Lactone 13 is then reacted with am ne 2 to give the amide 6.
Scheme 4 illustra.es ~he pre?ar2_ion of a representati-~e com~ound of the inventior. having a C-terminal carbo~yl-de-i-ia~ e. ~ ?-o-e^ e~ acid 1 and beta-alanine ethyl ester ~rc cou?led .o give amide 15, which is then deprotec_ed and caz~led ~o ~he desired ac-~5 in a manner analogous to ~hat cescribed i~ Scheme 1.
The derived C-terminal ester 16 is hydrolyzed to the corresponding carboxylic acid 17 by standard methods.
As illustrated in Scheme 5, benzyl carbamates 18 serve as convenient sources of the primary amines 19, by catalytic hydrogenation. The derived amines l9 can be derivati~ed by standard methods. Thus, elaboration with N-acetoxy-norbornene-2,3-dicarboximide gives the N-acetyl compound 20. Treatme~t with trimethylsilyl isocyanate ; gives urea 21. Se~aen.tial r~action with N,N'-thiocarbonyldiimidazole and an a}~ylzmine gives N-substituted thiourea 22. Sulfamide 2~ may be prepared by reaction of 19 with a sulfamoyl chloride.
-Scheme 6 illustrates the preparation of guanidine derivatives and the related 1,2,3-triazoles and 1,3,4-oxadiazoles from amines 19. Amine 19 can be reacted with dimethyl N-cyanoimidodithiocarbonate to give N cyano S-methylisothiourea 24. Compound 24 can be further elaborated by reaction with hydrazine to give 3,5-.
:
., .
i W092/0~29 PCT/US91/055~ _~
.;.
2 a ~9 2~ -22-`
diaminotriazole 25, with hydroxylamine to give 2,5-diamino-oxadiazole 2S, or with ammonia (R1g = H) or an alkylamine (Rlg = alkyl) to give N-unsubstituted or N-substituted guanidine 27.
Scheme 7 illustrates another method for preparing the compounds of the invention (6). The protected amino lactone 28 may be converted to amido carbamates 29 by reaction with neat amines at temperatures ranging from 25-75 C. Alternatively, alkylaluminum-mediated lactone openings of ~8 have been desc_ibed to effect this transformation (Ch~kravarty, ~. K.; de Laszlo, S. E.;
Sarnella, C. S.; S~ringer, J. P.; Schuda, P. F.
Tetrahedron Lett. 1989, 30, 415-8). The Boc group can be removed with TFA, and the resulting amine (preferably as the free base) can be coupled to acids 5a, Sb or 5c using standard peptide coupling methodology to provide the compound 6.
Scheme 8 illustrates the preparation of C-terminal derivatives in which the C-terminal ;2mide has been replaced by methyleneoxy, methyleneamino, methylenethio or methylenesulfonyl-derivatives. Boc-lactone 28 i~ reduced with, for example, sodium borohydride-calcium chloride to the diol carbamate 30. The procedures of Karlsson, J. O.;
Lundblad, A.; ~alm, B.; Nilsson, I.; Nitenberg, T.;
Starke, I.; Sorenson, H.; Westerlund, C. Tetrahd~on Lett.
1989, 30, 2653-6, are adapted for the following transformations. The secondardary alcohol is internally protected by conversion to the oxa~olidinone 31, and the primary hydroxyl group is derivatized. Fox example, the primary hydroxyl group is converted to the methoxymethyl ether 32, or transformed to the sulfide 34 via the ,.. i :, ~' W~92/03429 2 ~ ~ ~ 2 $ 8 PCT/US~1/05s24 ~~3~ ; .
intermediate mesylate 33. The sulfide is oxidized to the corresponding sulfone 35 with a peroxyacid (e.g. m-CPBA or Oxone and the like). Treatment of oxazolines 32, 34, and 35 with barlum hydroxide affords amino alcohols 36, 37, and 38, respectively. Standard peptide co~pling of amino alcohols 36, 37, and 38 with acids 5a or 5b afford products 39.
Scheme 9 illustrates an alternative method for the preparation of compound 5a. ~eaction of aldehyde 40 with an n-butyl organometallic reagent (for example, n-butyl magnesium bromide and the like), followed by o~idative resolution using (-) DT~T t-3uOOH Ti(OCH(CH3)2)4, provides 41 as a sinsle enantiomex. (DIPT is diisopropyl tartrate). Reaction of the alcohol 41 with a halo acetic acid, optionally followed by esterification, or a halo acetic acid ester provides 42 or 43. Alternatively, reaction with t-butyl bromoacetate pr.ovides 44.
Alkylation with a benzyl halide ~for example, benzyl bromide and the like) provides a mixt:ure of 45 and the desired 46. Compound 46 can be separated from the mixture by silica gel chromatography. Hydrogenolysis or hydrolysis of the ester, coupling with 4-methoxymethoxypiperidine and oxidation provides the desired carboxylic acid 5a ~` Scheme 10 illustrates an alternative preparation of intermediate 41. 2-Valeryl furan 47 (prepared by Friedel-Crafts acylation of furan):is stereoselectively reduced ` with diborane and a chiral catalyst (10-20 mole% of a compound such as 48, 49 or 50 and the like (see Scheme 11)) in a solvent such as tetrahydxofuran and the like.
: .
.
W092/0~29 PCT/US91/05~ ;
20~9~ 6~ -2~-Scheme 11 illustrates the preparation of the chiral catalysts ~ and ~9. The known (;S or 5R) 4-(t-butoxyca-bonylamino)-5-(substitu~ed)-2.H-1,4-oxazine-2-ones tPCT Ap?llcation `io. WO90/03971, ?ublished April 19, 1990) are alkylated to give 51 R80 and ~81 are independently selected from hyd-3gen, loweralk~i`, cycloalkyalkyl, phenyl and benzyl and R8~ and R~3 are independently selected from hydrogen, loweralkvl, cycloalkyla kvl and ben~yl). The alkylated compound ;1 is reduced ~ith diborane ~o the Boc diol wh ch is de~-ot-c.ed .o siv_ ~he ~he amine diol 52.
Reaclion o' 5~ ~i_h BU3, t- ...ethi; bo ate, trimeLhyl aluminum or ti~an um isopropoxiàe and the like gives ~8 (M
= B, Al, TiOisopropyl). Similarli, 51 can be deprotected with HCl dioxane and the crude sa ~ reacted with excess Grignard reagent (Rg2 = loweralkyi, cycloalkylalkyl, phenyl or benzyl) to give the amine diol 53. Reaction of 53 with BH3, trimethyl borate, trimethyl aluminum or titanium isopropoxide and the like gives compound 49 ~M =
~, Al, TiOisopropyl). Catalyst 50 and DAIB are prepared by literature procedures.
Scheme 12 illustrates the preparation of compound 5b.
. N-CBz-L-phenylalanine (5~) is coupled to the 4-methoxymethyl ether of 4-hydroxy~iperidine.
.:
Hydrogenolysis of the CBz group gives amine 55, which is used without further purification. Alkylation o. 55 with optically active ~2R) ethyl 2-brom.ohexanoate in a polar - solvent such as DMSO, nitromethzne or ~MF and the like (ni~romethane prererred) with a base presen~ ~or example, ~ triethylamine, sodium carbonate, ammonium carbonate and ., the like ~ammonium carbonate prere-red) gives ester 56.
'.''''', ' .
.
. .
. , .
, .
' , :' ' ~`
W~92/0~29 2 ~ ~ ~ 2 6 8 PCT/~S91/~524 Base hydrolysis of 56 with sodium hydroxide, lithium hydroxide, potassium hydroxide and the like, gives 5b.
Sch~n8 1 Me~_ Me Ma 1. EDCl,~lOBT Me~t_ Me~,MP~ 1. TFACH2CI2.0C
OH NM~.CMF.0C ~ccN ~,N y ~1 2. H?O.THF
BocN _ _ 3. NaHCO3orNaOH
:~ H2N'~`R, H2N~N y R1 ~ F~70~ ~N
- O NMM, DMF o ~ O
O~ -20to25C ~
,`', ,~X .
: ,' Me O^O
Me X ~ O (5a), NH (5~),S (Sc~
~, , ~; .
. . .
~ ' ' .
..
......... ...
WO 92/03429 PCr/US91/0~
2Q8926.8.~......................................................... ' Scheme 2 Me ~ Me~Me R J~z ~0 H H 2. H20,THF
BocN ~5 N y NH2 71 B ~ BocN ~N y N b~ R7l 3- NRaHcoq or NaO,H
O~ 7 f~ EDCI, HOaT
9 NMhl DMF
-20 to 25 C
iUe Me H HO ll' H H
R70 ~ N ~ N y N b~ R71 R7~ ~ N H2, -N HR1 9, -SR22, loY~eralky 1, all<oxy or thioalkoxy ; O W Yl~O. NH, NCN,S
CS Z~ Cl, SC~3 : 10 O
R70- f N~x Me.O~O~J~
~ Me X . O (Sa), NH (5b), S (5c) ., I
, .
.,, . ., . ;
: . , ~ , . .
WO 92/03~9 PCI`/l~S91/05524 . ~ 2~8~2~ .
- " . ~ ;; ---~7--Scheme 3 ,C~N~OH Br~9H ,CNJ~ --~OH
~ Me F DM Me.O~O ~ ;>
Sa + H N ,~ EDDI,HOET ~GN~ J~N~Me NMM Dh;F M~ o~o ~ Me c /=\ < O
~J ~ Me ~ 12 13 .
... .
, H2N y Rl ,CN~O .J~N~. .~N'Y'R
.~ EDcl~Ho9T Me-O~O --~ ~;?`' H HO _ H
: `~ NMM, DMF /- -\ Me M~
`' ~C ~ Me ~,~ 6 i ~
`` .
WOg2/03429 PCI`/US91/05~i24 2o89C~?~6~ -28-Scheme 4 Me~L Me Me 1. EDCI. HO8T ~O H
BocN~ C51 ~IM~MF,0C BocNJ~_ ~CO Et O~ 2. C~ H3N+~CO2Et o~ O
1 ~
~A~ M~
1. TFA, CJ i2C~2, 0 ac HO ~ H R;~CO2H
2. H~O. THF , H2N ~ ~C ~ E~CI. tlOBT "
~j 3. NaHCO3 O 2 N,~. CMF
O~ -20 to 25 ~C
Me Mq Me Me H HO 1' H 1 LiOH, THF, H20 H HO H
R70b,N~fN--C02Et 2 N HSO 70b~ ~ --CO2H
16 ~ 17 O
,GN J~ X
Me.O~O ~ ;?
Me ~, X . O (Sa), NH (5b), S (Sc) ., ~'. .
'' , ., WO 92/03429 P(~/US91/05~2~
2~8~2~8 --2 9~ ~ r~ .
Scheme 5 o ~0 0 H2 ~4 atm) O /0 Il ,~ U 10% DVC I ~ ~
R70a N ~' ` NYNHCbz EtOAc ~Oa H NYNH2 Me~Me - Me~Me '` 6~ 1 O ~ O
., 1 9 ~7~a~NJ--JI`NYNHAC
C5 i2CI2 H HO H
MP--Me ., ,` 19 TMSN-C-O ~
THF, 25 ~ R70a H s . NYNHJI` NH2 Me~hle ~:, 21 1. (im)2C~S o '' 9 --R70ctJ~N~--`NYNHJ~NHR
2. RNH2 H HO _ H
Me~M~ 2 2 ,, ~
, , R26aR26bNSO2Gl ~J o Et3N, C~12CI2 70 H HO N(CH2)nNHs02NR26aR26b - ~ 23 O
R70a=otBu~ Me~O_Of~
Me - X=O,NH,S
WO 92/~3429 PCI~/US91/05524 -. .
~` 2~8 -:
Sch~me 6 :~ R f ~ (CH3S)2C~NCN ,ll, ~ ,CN
R70a N NYNH2 ' R70a N . . NYNH~SCH3 H HO - H CH3CN, r~fluxH HO - H
Me~Me Me~Me 2 2 ., R aJ~N~NYNH--~N~H2 Cl 13CN, 80 oc H HO _ H H
Me~Me 2 5 2 4~ R70a N~NYNH--~N'~--NH2 ~! . Et3N,CH3CN H HO _ H
.~, ` Me~Me 2 6 2 4 RNH2 ~ J~ f ~ N CN
R70a N . . NYNH NHR19 CH3CN, 80 ~c H HO - H
Me~Me 2 7 -, .
R 70a~ C~tBU~Me.O~O~
Me 3t=O,NH,S
.~
.
` .
.
., ~ .
WO 92/03429 2 0 g ~ 2 ~ ~ PCI`/lJS91/05~24 Schem~ 7 O Me~Me 1. rA,cH2c~oLc 04 Me R~YNH2 HO ¦ H 2. Na2CO3 BocNH J--~ Me ~-aa~. 6t~;5 ~ BocNH ~ y R1 3. 5a, 5b or 5~. EDCI
~ HO8T, DMF, -20 ~ 25 C
` ~J 2 8 ~ 2 9 :, ."~ ,0 .
o o ~ o ~~ N J~ X I~ N J--J~ N Y - R~
Me o~o~ H HO H
<M Me~Me :', 6 .
. . .
W~ 92/03~29 PCr/USsl/05s24 Scheme 8 o4 I~Ae Ca(BH") P~ie Me ~Lo O
;: BocNH~ ~Me ~ocNH ~ OH 30cN~,~,O-S-Me 0~ 23 o~ 30 O~ ~Me>_ Me Me Me~ Me ~1 M~ Me Me E'3~1,THF
Lo ~C~C~ ' Me_l e Me Me BocN J~ O O BocN ~ OH ro `~ Me (I-P~r)7NEI : BocN~,S~
~/ - 34 Me ~J ., 1 ~Y
~' Ba~oH)2 aH2 Ba~oH~ ~ ) , MCPBA
Me Me Me Me :~ . HO lr HO `~ MeMe Me MeyMe N~O~OMe ~ o Me
Activated deri~atives of carboxylic acids as mentioned herein refer to acid halides such as acid chlorides, and activated esters including, but not limited to, formic and acetic acid derived anhydrides, anhydrides derived from . ,:
~ `, .
:
., :
WG92/0~ PCT/US91/05~
20~9 ~,~ i ~ ~
alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, N-hydroxysuccinimide derived esters, N-hydroxyphthalimide derived esters, N-hydroxybenzotriazole derived esters, N-hyd-oxy-5-norbo_nene-2,3-dica~bo~amide derived esters, 2,4,5-trichlorophenol derived esters and the like.
Scheme 2 illustrates a method to prepare compounds of the invention ~herein the C-term nus is furthe-functionali7ed. ~o_ exam?la, th~ am no-'e-~in21 di?rotectad hyG-v~ --nylena v'p-_-'da isostere 7 can be reac~ed wi-h a~?ro?~ia~e elec~rov;.iles 8 to produce amides, ca oamates, ureas or amidines or guanidines, using methods availa~le in the chemical lilerature. The same deprotection/cou?ling sequence described in Scheme 1 then leads to the N-terminal functionalized compound 10. It should be noted that amines such as 7 also may be reacted with sulfur-based electrophiles (sulfenyl, sulfinyl, sulfonyl, or sulfamoyl halides) to produce sulfenamides, sulfinamides, sulfonamides or sulfamides, respectively.
In addition, it should be apparent to those skilled in the art that the method of Scheme 1 can be used to prepare compound 10 wherein in~ermediate 2 i3 appropriately functionalized.
Scheme 3 illustrates an alternate preparation of compound 6. Alkylation of (~)-2-~-omohexanoic acid with the sodium salt of alcohol 11 ~Eu-opean ~atent Application No. EP364804, published April 25, 1991), provides carboxylic acid 5a as a single diastereomer after silica gel column chromatography. ~Alternatively, crude compound 5a can be converted to an active ester derivative (such as the mono- or di-nitrophenylester) ?rior to chromatographic . ., ; .
. . ~
.: .
.~
.
,, .. : ., . ~ :, . ..
wo9~io~29 2 ~ g 9 ~ ~ ~ PCTt~S91/055~
separation of the diastereomers). The acid 5a (or an active ester derivative) is then coupled to the amino lactone 1~ (Bradbury, R. H.; Revill, J. M.; Rivett, J. E.;
Waterson, D. Te~rahedro.n Lett. 1999, 3~4~) using stand2rd peptide coupling procedures to give the key intermediate 13. Lactone 13 is then reacted with am ne 2 to give the amide 6.
Scheme 4 illustra.es ~he pre?ar2_ion of a representati-~e com~ound of the inventior. having a C-terminal carbo~yl-de-i-ia~ e. ~ ?-o-e^ e~ acid 1 and beta-alanine ethyl ester ~rc cou?led .o give amide 15, which is then deprotec_ed and caz~led ~o ~he desired ac-~5 in a manner analogous to ~hat cescribed i~ Scheme 1.
The derived C-terminal ester 16 is hydrolyzed to the corresponding carboxylic acid 17 by standard methods.
As illustrated in Scheme 5, benzyl carbamates 18 serve as convenient sources of the primary amines 19, by catalytic hydrogenation. The derived amines l9 can be derivati~ed by standard methods. Thus, elaboration with N-acetoxy-norbornene-2,3-dicarboximide gives the N-acetyl compound 20. Treatme~t with trimethylsilyl isocyanate ; gives urea 21. Se~aen.tial r~action with N,N'-thiocarbonyldiimidazole and an a}~ylzmine gives N-substituted thiourea 22. Sulfamide 2~ may be prepared by reaction of 19 with a sulfamoyl chloride.
-Scheme 6 illustrates the preparation of guanidine derivatives and the related 1,2,3-triazoles and 1,3,4-oxadiazoles from amines 19. Amine 19 can be reacted with dimethyl N-cyanoimidodithiocarbonate to give N cyano S-methylisothiourea 24. Compound 24 can be further elaborated by reaction with hydrazine to give 3,5-.
:
., .
i W092/0~29 PCT/US91/055~ _~
.;.
2 a ~9 2~ -22-`
diaminotriazole 25, with hydroxylamine to give 2,5-diamino-oxadiazole 2S, or with ammonia (R1g = H) or an alkylamine (Rlg = alkyl) to give N-unsubstituted or N-substituted guanidine 27.
Scheme 7 illustrates another method for preparing the compounds of the invention (6). The protected amino lactone 28 may be converted to amido carbamates 29 by reaction with neat amines at temperatures ranging from 25-75 C. Alternatively, alkylaluminum-mediated lactone openings of ~8 have been desc_ibed to effect this transformation (Ch~kravarty, ~. K.; de Laszlo, S. E.;
Sarnella, C. S.; S~ringer, J. P.; Schuda, P. F.
Tetrahedron Lett. 1989, 30, 415-8). The Boc group can be removed with TFA, and the resulting amine (preferably as the free base) can be coupled to acids 5a, Sb or 5c using standard peptide coupling methodology to provide the compound 6.
Scheme 8 illustrates the preparation of C-terminal derivatives in which the C-terminal ;2mide has been replaced by methyleneoxy, methyleneamino, methylenethio or methylenesulfonyl-derivatives. Boc-lactone 28 i~ reduced with, for example, sodium borohydride-calcium chloride to the diol carbamate 30. The procedures of Karlsson, J. O.;
Lundblad, A.; ~alm, B.; Nilsson, I.; Nitenberg, T.;
Starke, I.; Sorenson, H.; Westerlund, C. Tetrahd~on Lett.
1989, 30, 2653-6, are adapted for the following transformations. The secondardary alcohol is internally protected by conversion to the oxa~olidinone 31, and the primary hydroxyl group is derivatized. Fox example, the primary hydroxyl group is converted to the methoxymethyl ether 32, or transformed to the sulfide 34 via the ,.. i :, ~' W~92/03429 2 ~ ~ ~ 2 $ 8 PCT/US~1/05s24 ~~3~ ; .
intermediate mesylate 33. The sulfide is oxidized to the corresponding sulfone 35 with a peroxyacid (e.g. m-CPBA or Oxone and the like). Treatment of oxazolines 32, 34, and 35 with barlum hydroxide affords amino alcohols 36, 37, and 38, respectively. Standard peptide co~pling of amino alcohols 36, 37, and 38 with acids 5a or 5b afford products 39.
Scheme 9 illustrates an alternative method for the preparation of compound 5a. ~eaction of aldehyde 40 with an n-butyl organometallic reagent (for example, n-butyl magnesium bromide and the like), followed by o~idative resolution using (-) DT~T t-3uOOH Ti(OCH(CH3)2)4, provides 41 as a sinsle enantiomex. (DIPT is diisopropyl tartrate). Reaction of the alcohol 41 with a halo acetic acid, optionally followed by esterification, or a halo acetic acid ester provides 42 or 43. Alternatively, reaction with t-butyl bromoacetate pr.ovides 44.
Alkylation with a benzyl halide ~for example, benzyl bromide and the like) provides a mixt:ure of 45 and the desired 46. Compound 46 can be separated from the mixture by silica gel chromatography. Hydrogenolysis or hydrolysis of the ester, coupling with 4-methoxymethoxypiperidine and oxidation provides the desired carboxylic acid 5a ~` Scheme 10 illustrates an alternative preparation of intermediate 41. 2-Valeryl furan 47 (prepared by Friedel-Crafts acylation of furan):is stereoselectively reduced ` with diborane and a chiral catalyst (10-20 mole% of a compound such as 48, 49 or 50 and the like (see Scheme 11)) in a solvent such as tetrahydxofuran and the like.
: .
.
W092/0~29 PCT/US91/05~ ;
20~9~ 6~ -2~-Scheme 11 illustrates the preparation of the chiral catalysts ~ and ~9. The known (;S or 5R) 4-(t-butoxyca-bonylamino)-5-(substitu~ed)-2.H-1,4-oxazine-2-ones tPCT Ap?llcation `io. WO90/03971, ?ublished April 19, 1990) are alkylated to give 51 R80 and ~81 are independently selected from hyd-3gen, loweralk~i`, cycloalkyalkyl, phenyl and benzyl and R8~ and R~3 are independently selected from hydrogen, loweralkvl, cycloalkyla kvl and ben~yl). The alkylated compound ;1 is reduced ~ith diborane ~o the Boc diol wh ch is de~-ot-c.ed .o siv_ ~he ~he amine diol 52.
Reaclion o' 5~ ~i_h BU3, t- ...ethi; bo ate, trimeLhyl aluminum or ti~an um isopropoxiàe and the like gives ~8 (M
= B, Al, TiOisopropyl). Similarli, 51 can be deprotected with HCl dioxane and the crude sa ~ reacted with excess Grignard reagent (Rg2 = loweralkyi, cycloalkylalkyl, phenyl or benzyl) to give the amine diol 53. Reaction of 53 with BH3, trimethyl borate, trimethyl aluminum or titanium isopropoxide and the like gives compound 49 ~M =
~, Al, TiOisopropyl). Catalyst 50 and DAIB are prepared by literature procedures.
Scheme 12 illustrates the preparation of compound 5b.
. N-CBz-L-phenylalanine (5~) is coupled to the 4-methoxymethyl ether of 4-hydroxy~iperidine.
.:
Hydrogenolysis of the CBz group gives amine 55, which is used without further purification. Alkylation o. 55 with optically active ~2R) ethyl 2-brom.ohexanoate in a polar - solvent such as DMSO, nitromethzne or ~MF and the like (ni~romethane prererred) with a base presen~ ~or example, ~ triethylamine, sodium carbonate, ammonium carbonate and ., the like ~ammonium carbonate prere-red) gives ester 56.
'.''''', ' .
.
. .
. , .
, .
' , :' ' ~`
W~92/0~29 2 ~ ~ ~ 2 6 8 PCT/~S91/~524 Base hydrolysis of 56 with sodium hydroxide, lithium hydroxide, potassium hydroxide and the like, gives 5b.
Sch~n8 1 Me~_ Me Ma 1. EDCl,~lOBT Me~t_ Me~,MP~ 1. TFACH2CI2.0C
OH NM~.CMF.0C ~ccN ~,N y ~1 2. H?O.THF
BocN _ _ 3. NaHCO3orNaOH
:~ H2N'~`R, H2N~N y R1 ~ F~70~ ~N
- O NMM, DMF o ~ O
O~ -20to25C ~
,`', ,~X .
: ,' Me O^O
Me X ~ O (5a), NH (5~),S (Sc~
~, , ~; .
. . .
~ ' ' .
..
......... ...
WO 92/03429 PCr/US91/0~
2Q8926.8.~......................................................... ' Scheme 2 Me ~ Me~Me R J~z ~0 H H 2. H20,THF
BocN ~5 N y NH2 71 B ~ BocN ~N y N b~ R7l 3- NRaHcoq or NaO,H
O~ 7 f~ EDCI, HOaT
9 NMhl DMF
-20 to 25 C
iUe Me H HO ll' H H
R70 ~ N ~ N y N b~ R71 R7~ ~ N H2, -N HR1 9, -SR22, loY~eralky 1, all<oxy or thioalkoxy ; O W Yl~O. NH, NCN,S
CS Z~ Cl, SC~3 : 10 O
R70- f N~x Me.O~O~J~
~ Me X . O (Sa), NH (5b), S (5c) ., I
, .
.,, . ., . ;
: . , ~ , . .
WO 92/03~9 PCI`/l~S91/05524 . ~ 2~8~2~ .
- " . ~ ;; ---~7--Scheme 3 ,C~N~OH Br~9H ,CNJ~ --~OH
~ Me F DM Me.O~O ~ ;>
Sa + H N ,~ EDDI,HOET ~GN~ J~N~Me NMM Dh;F M~ o~o ~ Me c /=\ < O
~J ~ Me ~ 12 13 .
... .
, H2N y Rl ,CN~O .J~N~. .~N'Y'R
.~ EDcl~Ho9T Me-O~O --~ ~;?`' H HO _ H
: `~ NMM, DMF /- -\ Me M~
`' ~C ~ Me ~,~ 6 i ~
`` .
WOg2/03429 PCI`/US91/05~i24 2o89C~?~6~ -28-Scheme 4 Me~L Me Me 1. EDCI. HO8T ~O H
BocN~ C51 ~IM~MF,0C BocNJ~_ ~CO Et O~ 2. C~ H3N+~CO2Et o~ O
1 ~
~A~ M~
1. TFA, CJ i2C~2, 0 ac HO ~ H R;~CO2H
2. H~O. THF , H2N ~ ~C ~ E~CI. tlOBT "
~j 3. NaHCO3 O 2 N,~. CMF
O~ -20 to 25 ~C
Me Mq Me Me H HO 1' H 1 LiOH, THF, H20 H HO H
R70b,N~fN--C02Et 2 N HSO 70b~ ~ --CO2H
16 ~ 17 O
,GN J~ X
Me.O~O ~ ;?
Me ~, X . O (Sa), NH (5b), S (Sc) ., ~'. .
'' , ., WO 92/03429 P(~/US91/05~2~
2~8~2~8 --2 9~ ~ r~ .
Scheme 5 o ~0 0 H2 ~4 atm) O /0 Il ,~ U 10% DVC I ~ ~
R70a N ~' ` NYNHCbz EtOAc ~Oa H NYNH2 Me~Me - Me~Me '` 6~ 1 O ~ O
., 1 9 ~7~a~NJ--JI`NYNHAC
C5 i2CI2 H HO H
MP--Me ., ,` 19 TMSN-C-O ~
THF, 25 ~ R70a H s . NYNHJI` NH2 Me~hle ~:, 21 1. (im)2C~S o '' 9 --R70ctJ~N~--`NYNHJ~NHR
2. RNH2 H HO _ H
Me~M~ 2 2 ,, ~
, , R26aR26bNSO2Gl ~J o Et3N, C~12CI2 70 H HO N(CH2)nNHs02NR26aR26b - ~ 23 O
R70a=otBu~ Me~O_Of~
Me - X=O,NH,S
WO 92/~3429 PCI~/US91/05524 -. .
~` 2~8 -:
Sch~me 6 :~ R f ~ (CH3S)2C~NCN ,ll, ~ ,CN
R70a N NYNH2 ' R70a N . . NYNH~SCH3 H HO - H CH3CN, r~fluxH HO - H
Me~Me Me~Me 2 2 ., R aJ~N~NYNH--~N~H2 Cl 13CN, 80 oc H HO _ H H
Me~Me 2 5 2 4~ R70a N~NYNH--~N'~--NH2 ~! . Et3N,CH3CN H HO _ H
.~, ` Me~Me 2 6 2 4 RNH2 ~ J~ f ~ N CN
R70a N . . NYNH NHR19 CH3CN, 80 ~c H HO - H
Me~Me 2 7 -, .
R 70a~ C~tBU~Me.O~O~
Me 3t=O,NH,S
.~
.
` .
.
., ~ .
WO 92/03429 2 0 g ~ 2 ~ ~ PCI`/lJS91/05~24 Schem~ 7 O Me~Me 1. rA,cH2c~oLc 04 Me R~YNH2 HO ¦ H 2. Na2CO3 BocNH J--~ Me ~-aa~. 6t~;5 ~ BocNH ~ y R1 3. 5a, 5b or 5~. EDCI
~ HO8T, DMF, -20 ~ 25 C
` ~J 2 8 ~ 2 9 :, ."~ ,0 .
o o ~ o ~~ N J~ X I~ N J--J~ N Y - R~
Me o~o~ H HO H
<M Me~Me :', 6 .
. . .
W~ 92/03~29 PCr/USsl/05s24 Scheme 8 o4 I~Ae Ca(BH") P~ie Me ~Lo O
;: BocNH~ ~Me ~ocNH ~ OH 30cN~,~,O-S-Me 0~ 23 o~ 30 O~ ~Me>_ Me Me Me~ Me ~1 M~ Me Me E'3~1,THF
Lo ~C~C~ ' Me_l e Me Me BocN J~ O O BocN ~ OH ro `~ Me (I-P~r)7NEI : BocN~,S~
~/ - 34 Me ~J ., 1 ~Y
~' Ba~oH)2 aH2 Ba~oH~ ~ ) , MCPBA
Me Me Me Me :~ . HO lr HO `~ MeMe Me MeyMe N~O~OMe ~ o Me
5 \ /EDCI, HOBT Ba(OH)2 3H20 EDCI. hOBT\ ~ NM~ DMF
-20 to 25 C f ~-20 to 25 C ~eO Me H2N O~Me ~`N~XJ~N~' R -- -- / 3 Me~O~O~J~ ~ Me~Me EDCI, HOBT
Me 3 9 NMM~ DMF
-20 to 25 C
P~ M -_~~ or --S~ or --S--<
Me o Me X . O, NH, S
~' .
.
.:
.. : , :, .~. .
WO 92/03429 2 ~ ~ ~ 2 ~ ~ P~T/US9110S~24 Sc~ern~ ~
~10 -- H0~ _'~ R750 ~0 ~ 41 ~: vie~ Me~
4~ R75= H
4:3 R7~ = CH(Ph)2 44 R75 = t-Butyl ~Me~ ~ o~7 ~ 4 5 _ 4 6 ' Reagen1s: a) n-BuMgBr, b) (-) DiPT t-BuOOH Ti(OCH(CH3)2)4, c) NaH 8rCH2C02H. d) CH2N2 or C(Ph)2N2, e) KN(TMS)2 3rCH~CO2t-Bu, fl NaN~TMS)2 BnBr, g) when R7s = CH(Ph)2 H2 Pd/C, when R7s = t-Bu HCI methanol, h) EDC 4 methoxym~thoxypip~ridine, i) O3 or NalO4 RuCI3 :
'~
.
WO 92/03429 PCI/US9ltO~524 20~ 68 SC~OE 10 , (n-3uco) 2- o~ 48, 49 or 50 10-20 mol~
o 3F3 Et 2~
`~ 47 Ho~3 . .
', :
, ' .
`, , .. ,. - : : ,,. :.. ., . :
: : . . :-... : ' ' : :
WO92io3429 2~ 8 P~/US~l/o.524 - ....... ... , . ~.. ~ ;
SC~IE~D3 11 `.' O
Il R83 R8~ Ra1 Ra2 9~3 N 3(0-e)3 R~ Ra3 R~2 ---- HO~ ~OH _ ~<'~ N ~>
~ `BOC Ra;~ Ra~8~ R82 O~M_O
Ra~ RB1 5 1 5~! a ~a4 = c~O~_ I 4 8 :., b Rg, -- H I I
~Ci dioxaneM = 3 1. nCl d~ oxane ., 2- ~82Mg3r H R.31 Ho~N ~`OH ~ N k 92 Ph ~, Ph < O
\~ N ~ ~
Ph . .
:' .
., : ` . ,. ~: ,. :
W092/0~29 PCT/US91/05~
,; ., 2 ~8 92 ~8 -36-SC~E~E 12 :`
O 1. E''C, :103T
HoJ~NHC~ ,. f N~NH2 Br C02Et ~O{~MH M3~o~~
- 2. ;.y~ Y3 S M~
/
/ ( 4 ) 2 3 n ~ t r omet h ane ., I' N J~ N~ OR
o~o~G~ ~
56 R, Et ~
5b R = H ~J NaOH
~' The following Examples will serve to further illustrate preparation OL the novel compounds of the present invention.
!
.- . .
,f ~ .
: ' .
""' ~ ' ~ , ~ ,',, ' :
: ' ' ' ' WO 9;!io3429 2 ~ S ~ P(~/US91/0~;~;24 ~ ',4 '~ r - 37 - ~ si -2 ~) ~ LL(~L- ( 4- (MQt~-O~Ym~thO~) ~lpe~ld;n-1-yl-car~onyl)-.~ ~c~
1(5)-(4-~Methoxymethoxy)piperidin-1-yl-carbonyl)-2-phenylethan.ol ~u-ope~n Patent Application No. EP364804, published April 25, 1991) ~43.13 g, 147.2 mmol) in 200 mL
-~ dry TYF w2S added dropwise to the suspension of sodium hvdride (60% dispersion in oil, 12.36 g, 309.1 mmol) in 136 ml dry T:~ and 22.7 ml 3~L~E at 45 C oil bath temperature under N2 atmos?here. The addition tOO.~ appro~-mately 1 h.
~he mixture was allowed to stir at 45 C for additional 3 h. The gray suspension turned white after stiring for an hour and became very viscous. An additional 36 mL of dry THF was added to facilitate stirring. A solution of (R)-2-bromohexanoic acid ~31. 57 g, 161.9 mmol) in 180 mL THF was added dropwise to the thick, white suspension a~ 45 C.
The addition took approximately 1.75 h. The suspension was removed from the oil bath 45 min after addition was completed and quenched immediately with careful addition of 120 mL of pH 7 phosphate buffer (0.3 M). The solution was then concentrated under reduced pressure at 35 C and the resul~ing liquid extracted wlth 3 x 100 mL of diethyl ether to remo~e the unreacted alcohol. The aqueous phase was mixed with 300 mL of CH2C12 and acidified to pH 2 with 200 mL of 1 M sodium hydrogen sulfate. The layers were shaken and separated, then the aqueous phase was extracted with 2 x 300 mL of C~2C12. The com~ined organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was puriried ~y column chromatograpyhy (silica gel, 1.5% HOAc-5~ iPrOH-35% THF-... .
~, ':,: ' ' . , . : ~ ,. ,: .: : , , :: .
, W092/03429 PCT/US9~/055~ _ .
2 a ~9 2 68 ~ ~ -38-hexane~ to obtain 36.35 g (88.32 mmol, 60%) of the desired compound as a low-melting solid: ~f 0.30 (EtOAc-hexane 5:2); lH NMR (CDC13) ~ 0.8 (d, 3 H), 0.95 (m, 5 r.), 1.2-1.9 (m, 22 H), 3.0 (q, 2 H), 3.2 (m, 9 H), 3.55 (~ 2 ~), 3.65 . (m, 2 H), 3.8 (t, 1 H),4.4 ~q, 1 H), 7.3 (m, 5 H).
E;~m~l~
N-~3-(Be~zyloxycarbonyl~m;no)pro~yl~ 2(~$~ S)-~a-~etho~ymet~y~ e~id;~-l-~l)c2~b~nvl-?-e~ e~hoxyh~xanam~.d~l-6-~vcloheY~ (S~ J~-cxv-2(5~-. . -S52~ ~ y 1 h ~' x A !l A '~`I;L~.
~ . 3~ xlQxycarbo~ minQ)p~Qy~ln~ 1,3-Diaminopropane (35.5 g, 0.48 mol) was dissolved '~ 300 ~L
C~Cl3, and the solution was cooled to 0 C. A solutio~ or N-(benzyloxycarbonyloxy)succinimide ~4.5 g, 0.018 mol) in 150 mL CHCl3 was added dropwise over 6 h, with the internal temperature maintained below 10 C. After addition was complete, the reaction solution was s~:irred at room temperature overnigh~. The solution was washed with water, dried (Na2SO4), filtered and concentrated in vacuo to prsvide 3.0 g (80%) of the title compound as a lo~ melting solid: 1~ NMR (CDC13) ~ 1.25 (bs, 2 H), 1.63 (quintet, 2 H), 2.77 (t, 2 H), 3.2-3.34 ~bmr 2 H), 5.09 (s, 2 H), 5.37 (bm, 1 H), 7.28-7.40 (m, 5 H); MSr m/e 209 ((M+H)+).
.
2~L-((3-~tert-Bu~yloxycarbonyl-2,2-dimethyl-4l~L-cyclohexylmethyl-5L~)-oxazolidinyl)methyl)-3-methylbutanoic acid ~European Patent Application No. EP364804r published April 25, 1991) (1.50 g, 3.64 mmol), HOBT (837 mg, 5.47 mmol), 3-, ' :
`, '`` .
' y~n 92/03429 2 ~ 8 ~ 2 ~i 8 PCr/US91/05524 :
. ~
~benzyloxycarbonylamino)propylamine ~949 mg, 4.56 m~mol) and N-methylmorpholine ~601 mg, 5.47 mmol) were dissolved in 36.5 mL dry DMF, and the solution was cooled te -20 C
under a nitrogen atmosphere. N-Ethyl-N'-(di.methylamino)propylcarbodiimide hydrochlo-ide (978 mg, 5.10 mmol~ was added as a solid, and the result ng mixture was stirred at -20 C for 4 h, then the resultln~ solu_ion was stirred 16 h at room temperature. The vola~iles ~ere removed by high vacuum distillation, the residue was dissolved in 150 mL CH2C12 and extracted with 2 .c 300 mL
80% saturated aq. NaHCO3, water (300 mL), and b-ine (300 mL), then the organic phase was drie~ (Na2SOi) a?.d concentrated to a foam. Purification by flash chromatography (silica gel, 10% EtOAc-CH2C12) provided 1.98 g (3.28 mmol, 90%) of the desired compound as a wnite foam:
Rf 0.11 (25% EtOAc-hexane); lH NMR (CDC13) ~ O.94 (m, 8 H), 1.0-1.5 (vbm, 8 H), 1.48 (s, 9 H), 1.52-1.90 m, 14 H), 2.05 (m, 1 H), 3.25 (m, 2 H), 3.34 (m, 2 H), 3.65 (bm, 1 H), 3.71 (m, 1 H), 5.10 (s, 2 H), 5.48 (bt, 1 H), 6.00 (bt, 1 H), 7.3-7.36 (m, 5 H); MS m/e 602 ((M+H)~), 619 ((M+NH4)~).
` C. Paxt 1. A solution of the resultant compound from Example 2B (119 mg, 0.198 mmol) in 1.5 mL CH2C12 was cooled to 0 C, and 1.5 mL trifluoroacetic acid was added dropwise over 2 min. The resulting solution was stirred at 0 C fo~
4 h, then was concen~rated in vacuo to give an oil. Tne crude aminal salt was dissolved in 3 mL THF and 1 mL H2O
and the solution was stirred at-0 C for 18 h. The mixture ` was concentrated in vacuo to give an aqueous suspencion, which was then partitioned between 20 mL saturated aq.
NaHCO3 and 20 mL CH2C12. The aqueous phase was extracted ` .
- . : ~ :
: , :' - . , .
W092/03~29 PCT/US91/05524 -~
2~'~9~
with 2 x 20 mL CH2Cl2, then the combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo to ~ive 95 mg (104~) of the crude amino alcohol N-(3-(benzyloxycarbonylamino)pro?yl) 5(5)-amino-6-cyclohexyl-4(~)-hydroxy-2(5)-isopropylhexanamide; Rf 0.30 (10% MeOH-CH2C12); lH NMR (CDCl3) S O.92 (m, 6 H), 0.7-1.9 (several bm, 18H approx.), 2.15 (m, 1 H), 2.59 (m, 1 H), 3.10 (m, ; lHr), 3.20-3.42 (bm, 5 H), 5.09 (s, 2 H), 5.43 (bm, 1 H),
-20 to 25 C f ~-20 to 25 C ~eO Me H2N O~Me ~`N~XJ~N~' R -- -- / 3 Me~O~O~J~ ~ Me~Me EDCI, HOBT
Me 3 9 NMM~ DMF
-20 to 25 C
P~ M -_~~ or --S~ or --S--<
Me o Me X . O, NH, S
~' .
.
.:
.. : , :, .~. .
WO 92/03429 2 ~ ~ ~ 2 ~ ~ P~T/US9110S~24 Sc~ern~ ~
~10 -- H0~ _'~ R750 ~0 ~ 41 ~: vie~ Me~
4~ R75= H
4:3 R7~ = CH(Ph)2 44 R75 = t-Butyl ~Me~ ~ o~7 ~ 4 5 _ 4 6 ' Reagen1s: a) n-BuMgBr, b) (-) DiPT t-BuOOH Ti(OCH(CH3)2)4, c) NaH 8rCH2C02H. d) CH2N2 or C(Ph)2N2, e) KN(TMS)2 3rCH~CO2t-Bu, fl NaN~TMS)2 BnBr, g) when R7s = CH(Ph)2 H2 Pd/C, when R7s = t-Bu HCI methanol, h) EDC 4 methoxym~thoxypip~ridine, i) O3 or NalO4 RuCI3 :
'~
.
WO 92/03429 PCI/US9ltO~524 20~ 68 SC~OE 10 , (n-3uco) 2- o~ 48, 49 or 50 10-20 mol~
o 3F3 Et 2~
`~ 47 Ho~3 . .
', :
, ' .
`, , .. ,. - : : ,,. :.. ., . :
: : . . :-... : ' ' : :
WO92io3429 2~ 8 P~/US~l/o.524 - ....... ... , . ~.. ~ ;
SC~IE~D3 11 `.' O
Il R83 R8~ Ra1 Ra2 9~3 N 3(0-e)3 R~ Ra3 R~2 ---- HO~ ~OH _ ~<'~ N ~>
~ `BOC Ra;~ Ra~8~ R82 O~M_O
Ra~ RB1 5 1 5~! a ~a4 = c~O~_ I 4 8 :., b Rg, -- H I I
~Ci dioxaneM = 3 1. nCl d~ oxane ., 2- ~82Mg3r H R.31 Ho~N ~`OH ~ N k 92 Ph ~, Ph < O
\~ N ~ ~
Ph . .
:' .
., : ` . ,. ~: ,. :
W092/0~29 PCT/US91/05~
,; ., 2 ~8 92 ~8 -36-SC~E~E 12 :`
O 1. E''C, :103T
HoJ~NHC~ ,. f N~NH2 Br C02Et ~O{~MH M3~o~~
- 2. ;.y~ Y3 S M~
/
/ ( 4 ) 2 3 n ~ t r omet h ane ., I' N J~ N~ OR
o~o~G~ ~
56 R, Et ~
5b R = H ~J NaOH
~' The following Examples will serve to further illustrate preparation OL the novel compounds of the present invention.
!
.- . .
,f ~ .
: ' .
""' ~ ' ~ , ~ ,',, ' :
: ' ' ' ' WO 9;!io3429 2 ~ S ~ P(~/US91/0~;~;24 ~ ',4 '~ r - 37 - ~ si -2 ~) ~ LL(~L- ( 4- (MQt~-O~Ym~thO~) ~lpe~ld;n-1-yl-car~onyl)-.~ ~c~
1(5)-(4-~Methoxymethoxy)piperidin-1-yl-carbonyl)-2-phenylethan.ol ~u-ope~n Patent Application No. EP364804, published April 25, 1991) ~43.13 g, 147.2 mmol) in 200 mL
-~ dry TYF w2S added dropwise to the suspension of sodium hvdride (60% dispersion in oil, 12.36 g, 309.1 mmol) in 136 ml dry T:~ and 22.7 ml 3~L~E at 45 C oil bath temperature under N2 atmos?here. The addition tOO.~ appro~-mately 1 h.
~he mixture was allowed to stir at 45 C for additional 3 h. The gray suspension turned white after stiring for an hour and became very viscous. An additional 36 mL of dry THF was added to facilitate stirring. A solution of (R)-2-bromohexanoic acid ~31. 57 g, 161.9 mmol) in 180 mL THF was added dropwise to the thick, white suspension a~ 45 C.
The addition took approximately 1.75 h. The suspension was removed from the oil bath 45 min after addition was completed and quenched immediately with careful addition of 120 mL of pH 7 phosphate buffer (0.3 M). The solution was then concentrated under reduced pressure at 35 C and the resul~ing liquid extracted wlth 3 x 100 mL of diethyl ether to remo~e the unreacted alcohol. The aqueous phase was mixed with 300 mL of CH2C12 and acidified to pH 2 with 200 mL of 1 M sodium hydrogen sulfate. The layers were shaken and separated, then the aqueous phase was extracted with 2 x 300 mL of C~2C12. The com~ined organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was puriried ~y column chromatograpyhy (silica gel, 1.5% HOAc-5~ iPrOH-35% THF-... .
~, ':,: ' ' . , . : ~ ,. ,: .: : , , :: .
, W092/03429 PCT/US9~/055~ _ .
2 a ~9 2 68 ~ ~ -38-hexane~ to obtain 36.35 g (88.32 mmol, 60%) of the desired compound as a low-melting solid: ~f 0.30 (EtOAc-hexane 5:2); lH NMR (CDC13) ~ 0.8 (d, 3 H), 0.95 (m, 5 r.), 1.2-1.9 (m, 22 H), 3.0 (q, 2 H), 3.2 (m, 9 H), 3.55 (~ 2 ~), 3.65 . (m, 2 H), 3.8 (t, 1 H),4.4 ~q, 1 H), 7.3 (m, 5 H).
E;~m~l~
N-~3-(Be~zyloxycarbonyl~m;no)pro~yl~ 2(~$~ S)-~a-~etho~ymet~y~ e~id;~-l-~l)c2~b~nvl-?-e~ e~hoxyh~xanam~.d~l-6-~vcloheY~ (S~ J~-cxv-2(5~-. . -S52~ ~ y 1 h ~' x A !l A '~`I;L~.
~ . 3~ xlQxycarbo~ minQ)p~Qy~ln~ 1,3-Diaminopropane (35.5 g, 0.48 mol) was dissolved '~ 300 ~L
C~Cl3, and the solution was cooled to 0 C. A solutio~ or N-(benzyloxycarbonyloxy)succinimide ~4.5 g, 0.018 mol) in 150 mL CHCl3 was added dropwise over 6 h, with the internal temperature maintained below 10 C. After addition was complete, the reaction solution was s~:irred at room temperature overnigh~. The solution was washed with water, dried (Na2SO4), filtered and concentrated in vacuo to prsvide 3.0 g (80%) of the title compound as a lo~ melting solid: 1~ NMR (CDC13) ~ 1.25 (bs, 2 H), 1.63 (quintet, 2 H), 2.77 (t, 2 H), 3.2-3.34 ~bmr 2 H), 5.09 (s, 2 H), 5.37 (bm, 1 H), 7.28-7.40 (m, 5 H); MSr m/e 209 ((M+H)+).
.
2~L-((3-~tert-Bu~yloxycarbonyl-2,2-dimethyl-4l~L-cyclohexylmethyl-5L~)-oxazolidinyl)methyl)-3-methylbutanoic acid ~European Patent Application No. EP364804r published April 25, 1991) (1.50 g, 3.64 mmol), HOBT (837 mg, 5.47 mmol), 3-, ' :
`, '`` .
' y~n 92/03429 2 ~ 8 ~ 2 ~i 8 PCr/US91/05524 :
. ~
~benzyloxycarbonylamino)propylamine ~949 mg, 4.56 m~mol) and N-methylmorpholine ~601 mg, 5.47 mmol) were dissolved in 36.5 mL dry DMF, and the solution was cooled te -20 C
under a nitrogen atmosphere. N-Ethyl-N'-(di.methylamino)propylcarbodiimide hydrochlo-ide (978 mg, 5.10 mmol~ was added as a solid, and the result ng mixture was stirred at -20 C for 4 h, then the resultln~ solu_ion was stirred 16 h at room temperature. The vola~iles ~ere removed by high vacuum distillation, the residue was dissolved in 150 mL CH2C12 and extracted with 2 .c 300 mL
80% saturated aq. NaHCO3, water (300 mL), and b-ine (300 mL), then the organic phase was drie~ (Na2SOi) a?.d concentrated to a foam. Purification by flash chromatography (silica gel, 10% EtOAc-CH2C12) provided 1.98 g (3.28 mmol, 90%) of the desired compound as a wnite foam:
Rf 0.11 (25% EtOAc-hexane); lH NMR (CDC13) ~ O.94 (m, 8 H), 1.0-1.5 (vbm, 8 H), 1.48 (s, 9 H), 1.52-1.90 m, 14 H), 2.05 (m, 1 H), 3.25 (m, 2 H), 3.34 (m, 2 H), 3.65 (bm, 1 H), 3.71 (m, 1 H), 5.10 (s, 2 H), 5.48 (bt, 1 H), 6.00 (bt, 1 H), 7.3-7.36 (m, 5 H); MS m/e 602 ((M+H)~), 619 ((M+NH4)~).
` C. Paxt 1. A solution of the resultant compound from Example 2B (119 mg, 0.198 mmol) in 1.5 mL CH2C12 was cooled to 0 C, and 1.5 mL trifluoroacetic acid was added dropwise over 2 min. The resulting solution was stirred at 0 C fo~
4 h, then was concen~rated in vacuo to give an oil. Tne crude aminal salt was dissolved in 3 mL THF and 1 mL H2O
and the solution was stirred at-0 C for 18 h. The mixture ` was concentrated in vacuo to give an aqueous suspencion, which was then partitioned between 20 mL saturated aq.
NaHCO3 and 20 mL CH2C12. The aqueous phase was extracted ` .
- . : ~ :
: , :' - . , .
W092/03~29 PCT/US91/05524 -~
2~'~9~
with 2 x 20 mL CH2Cl2, then the combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo to ~ive 95 mg (104~) of the crude amino alcohol N-(3-(benzyloxycarbonylamino)pro?yl) 5(5)-amino-6-cyclohexyl-4(~)-hydroxy-2(5)-isopropylhexanamide; Rf 0.30 (10% MeOH-CH2C12); lH NMR (CDCl3) S O.92 (m, 6 H), 0.7-1.9 (several bm, 18H approx.), 2.15 (m, 1 H), 2.59 (m, 1 H), 3.10 (m, ; lHr), 3.20-3.42 (bm, 5 H), 5.09 (s, 2 H), 5.43 (bm, 1 H),
6.19 (bm, 1 h), 7.28-7.40 (m, 5 H).
~ r ~ The crude amin~ alcohol from Example 2C, Part 1 (90.5 mg, 0.196 mmol), the resultant compound from Example 1 t87-9 mg, 0.216 mmol), HOBT (34.5 mg, 0.225 mmol), and N-methylmorDholine (22 mg, 0.22 mmol) were dissolved in 2.0 mL DMF, and the resulting solution was cooled to -23 C. EDCI (52.6 mg, 0.275 mmol) was added, and the mixture was stirred at -23 C for 4 h, and allowed to warm to room temperature was stir overnight (18 h). The solvent was removed by high vacuum dis1:illation, and the residue was partitioned between 25 mL CH2Cl2 and 80 saturated aq. NaHCO3. The organic phase was washed sequentially with H2O (25 mL) and brine (25 mL), then dried (Na2SO4), filtered and concentrated in vacuo to a foamy solid (174 mg). Flash chromatography (silica gel, 2.5%
MeOH-CH2C12) provided 106 mg (0.125 mmol, 64%) or the title compound as a white foami mp 64-68 C; 1H NMR tCDC13) ~ O.9 tm, 9 H), 0.65-1.90 (severzl bm, 28H approximately), 2.05 tm, 1 H), 2.9-3.1 tm, 2 H), 3.1-3.4 (bm, 17H
approximately), 3.37 ~s, 3 H), 3.5 ~bm, 1 H), 3.6-4.0 tvbm, 5 H), 4.50 (bm, 1 H), 4.67 (s, 2 H), 5.10 (AB, 2 H), 5.51 (bt, 1 H), 5.77-5.9 (2 d, 1 H), 6.09 (bt, 1 H), 7.27-7.4 (m, 10 H); MS m/e 851 ((M+H)+). Anal. Calcd for :: i ~, :` ~
,:
,` , `
. .
;, :,,. .~ , , ;, .-..
" . ~ ~ , . ",~
~Q92/~29 ~ 9 8 ~ ~ 6 ~ P~T/US91/0~5~
t ~ r r~
:
C4gH7: ~Og-0.5 H2O: C, 67.03; H, 8.79; N, 6.51. Found: C, 6~.91; H, 8.64; N, 6.48.
E~zmple ~
N-~3-.3m1no~ro~yl) 5(~)-(2(S)-(L(SL=(4-~henyl)eth~xyhe~an~midQ~-6-~c~hexyl-~(S)-hydroxy-2(~
The resuitant compound rom Example 2 t50 mg, G.0587 mmol) W2S s~irred with 10~ palladium on carbon (13 mg~ in 3 mL EtOAc under 1 atmosphere of hydrogen for 3 days. The mixture was filtered, and the filtrate was concentrated to a foam. Thin-layer chromatography (silica gel, 10% MeOH-1% concentrated aq. NH4OH-CH2Cl2) gave 26.4 mg (0.0368 mmol, 63%) of the title compound as a white foamy solid: mp 58-60 C; Rf 0.26 tl0% MeOH-1% concentrated aq. NH4OH-CH2Cl2); 1H NMR (CDC13) ~ 0.90-0.92 (m, 9 H), 0.65-2.0 (vbm, 28H totzl approximately), 2.05 (m, 1 H), 2.82 ~dd, 2 H), 2.9-3.1 (m, 2 H), 3.13-3.28 (bm, 2 H), 3.37 (s, 3 H), 3.3-3.55 (bmr 5 H), 3.6-4.0 (vbm, 5 H), 4.50 (dd, 1 H), 4.67 (s, 2 ~), 5.79 (d) and 5.87 (d, lH total), 6.52 (~m, 1 H), 7.30 (bs, 5 H); MS m/e 717 (~M+H)+). HRMS.
Calcd for ((M+H)+) of C40H6gN4O7: 717.~166. Found:
717.5178.
~ An alternative procedure for the preparation of - this compound follows. A mixture of the resultant compound of Example 9 t2.3 g, 3.58 mmol) and 20 equivalents of 1,3-diaminopr~opane W2S s~irred at 55 C for 4 h and at 65 C
for 6 h. The mixture was diluted with EtOAc and washed with water. The organic portion was dried, filtered and evaporated. The residue was colu~n c:-=omatographed (silica :`:
- : : . , . . . :
. : !
' ' ~
', WO 92/03429 PCT/~lS91/05~4-~
, ~ 2 ~ 8 9 2 ~ -42-gel, 4% MeOH-1% concentrated aq. NH40H-CHCl3) to produce 2.0 g (2.79 mmol, 78~) of the desired product as a hygroscopic foa~. The compound obtained from this procedure was identical in all respects to t:^e co~ou~d obtained from the previous procedure.
Exam~
N-~3-~.~e~amidopro~yl) 5(S)-(2(C)-~l(c)-(~-(m~t~Qxym~t~ p;~e~
ghenyl ) etho~yhe ~arA~ml~o ~ - 5 - cyc l ~h ~ ~ y - _ A ( 5~ - -` 'if '.'~ ~'V- ~ ( ~S) -iso~ro~vvlh~xan~m~d~
A solution or the resultant compound rro~. Example 3 (23.4 mg, 0.0326 mmol) in 5.4 mL CH2C12 was cooied to O C, and N-acetoxy-norbornene-2,3-dicarboximide (21.7 m~, 0.122 mmol) was added. The solution was stirred ror 3 days at ambient temperature, then was concentrated and purified by preparative ~hin-layer chromatography (silica gel, 10%
MeOH-1% concentrated aq. NH40H-CH2C12) provided 19.6 mg (0.0258 mmol, 79%) of the title compound as a white foam:
mp 62-67 C; Rf 0.29 (10% MeOH-1% concentrated aq. NH40H-CH2Cl2); lH NMR (CDCl3) ~ 0.65-1.95 (s~veral bm, 29H
approximately~, 0.90 (t) and 0.92 (d, 9H total), 2.00 (s! 3 H), 2.0-2.11 (m, 1 H), 2.97 (m, 1 H), 3.06 (dd, 1 H), 3.1-~i 3.5 (bm, 6 H), 3.37 (s, 3 H), 3.5-4.0 vbm, 6 H), 4.52 (dd, '"! 1 H), 4.68 (s, 2 H), 5.85 (d) and 5.93 (d, lH total), 6.30 (bt, 1 H), 6.-48 (bt, 1 H), 7.33 (bm, 5 H); MS m/e 759 ; ((M+H)+). Anal. Calcd for C42H70N40g 1.25 H20: C, 64.54;
E, 9.34: N, 7.17. Eound: C, 64.,9; N, 9.02; N, 7.09.
j ' ' .
:. .", :
.
"
.. : ,.. : , , , ' : :
W092/03429 PCT~S91/055~
-` 2~89268 .. ... ,., .. , . . , ,.. i~
. ~43_ ~ ~,., Exam~
N~ (2-~.ydroYye~hyl)aminQ)~ro~yl) 5(~)-(2(5`~ $)-(~-(metho~y~ethox~ e ~dl?~ ~ C ?~
~hsnyl)etho~he~anamido)-6-c~clo~xyl-9(.C)-hvcrox~-2(~)-;~opro~lhPx~mi~e ~ . _N-(~--(2-hydroyyethyl)a~;~.o)~o~yl~ 2(~C)~ -(tP; -~
b~tylo~ycarbonyl)-2 2-d~yl-4(~-c~ic'o.~e~ r,~ (S~ -Q~ gL~ L~ ,thylb~te?~m~dP ~;.e ? ocedu~e o Example 2B was followed, uslns th~ -o cwi.. ~u- ies:
2~L-((3-(tert-butyloxycarbonyl-2,2-c~me h~
cyclohexylmethyl-5l~L-oxazolidinyl)me~ )-3-."~ lbu a^~__ acid (European Patent Application No. r~364804, publisned April 25, 1991) (100 mg, 0.243 mmol), H09T (5i.3 mg, 0.36q mmoI), N-methylmorpholine (37 mg, 0.364 mmol) and 3-(2-~hydroxyethyl)aminopropylamine ~37.3 mg, 0.316 mmol, prepared according to the procedure of Surrey, H. J Am.
Chem. Soc. 1950, 72, 1814) and EDCI (65.2 mg, 0.340 mmol) in 2.4 mL DMF. Purification by flash chromatography ~silica gel, 10% MeOH-0.5% concentrated aq. NH40H-CH2Cl2) gave 80.6 mg ~0.158 mmol, 65%) of the title compound as a low-melting, hygroscopic solid; Rf 0.34 ~10% MeOH-1%
concentrated aq. NH40H-CH2Cl2); 1H N~R (CDCl3) ~ O.94 (2d, 9 H), 1.10-1.45 (vbm, 13 H), 1.48 ~s, 9 H), 1 . 58 (bs, 3 H), 1.6-1.9 (bm,~5 H), 2.0-2.1 (bm, 1 r.), 2.28 (bs, 4 H), 2.75 (t, 2 H), 2.82 ~m, 2 H), 3.40 (dd, 2 H), 3.57-3.8 (m, 4 H), 6.35 (bt, 1 H).
~ _ The prooedure of Example 2C w2S followed, in which the resultant compound from Example 5A was deprotected and coupled to the resultant compound -rom Example 1. For Part l, the following quantities were used: the resultant . .
;
-~ ~, . . . . . . .
. -- . .
, :
WO92/0~29 ?RCT/US9l/055 2 ~9 2 6~ _44-compound f-om Example 5A (33 mg, 0.0645 mmol) was deprotected ln 1 mL CH2Cl2 and 1 mL trifluoroacetic acid, followed by removal of the acetonide in 1.5 mL T~ and 0.75 mL H2O, to give 13.o mg of crude amino alcohol. For Part 2, the following quantities were used: crude amino alcohol (15.0 mg, 0.040 mmol), HOBT (7.1 mg, 0.045 mmol), the resultant compound f-om Example 1 (18.1 mg, 0.044 mmol), N-me,hvlmorpholine (4.5 mg, 0.045 mmol) and EDCI (10.9 mg, 0.56 ~ol) were reacted in 1 mL DMF. Puriflcation by ~-epararive thir-layer chromatography (silica gel, 15~
ieO:i-C.5% concentrateà aq. NH4OH-C~.2Cl2) produced 7.5 mg (0.010 mmol, 25~) of a hvc-oscopic glass; Rf 0Ø34 (1 MeO~-0.5~ concentrated aq. ~H4OH-C~2Cl2); lH NMR (CDCl3) ~
0.65-1.93 (several bm, 28H approximately), 0 87-0.965 (m, 9 H), 2.05 (m, 1 ~), 2.5-2.9 (bm, 9H, includes H2O), 2.9-3.1 ; (m, 4 H), 3 1-3.35 (bm, 4 H), 3.37 (2s, 3 H), 3.41-3.58 (bm, 4 H), 3.68-4.1 (bm, 7 H), 4.61 (bm, 1 H), 4 68 (d, 2 : H), 5.78 (d) and 5.86 (d, lH total), 6.90-7.13 (bm, 1 H),
~ r ~ The crude amin~ alcohol from Example 2C, Part 1 (90.5 mg, 0.196 mmol), the resultant compound from Example 1 t87-9 mg, 0.216 mmol), HOBT (34.5 mg, 0.225 mmol), and N-methylmorDholine (22 mg, 0.22 mmol) were dissolved in 2.0 mL DMF, and the resulting solution was cooled to -23 C. EDCI (52.6 mg, 0.275 mmol) was added, and the mixture was stirred at -23 C for 4 h, and allowed to warm to room temperature was stir overnight (18 h). The solvent was removed by high vacuum dis1:illation, and the residue was partitioned between 25 mL CH2Cl2 and 80 saturated aq. NaHCO3. The organic phase was washed sequentially with H2O (25 mL) and brine (25 mL), then dried (Na2SO4), filtered and concentrated in vacuo to a foamy solid (174 mg). Flash chromatography (silica gel, 2.5%
MeOH-CH2C12) provided 106 mg (0.125 mmol, 64%) or the title compound as a white foami mp 64-68 C; 1H NMR tCDC13) ~ O.9 tm, 9 H), 0.65-1.90 (severzl bm, 28H approximately), 2.05 tm, 1 H), 2.9-3.1 tm, 2 H), 3.1-3.4 (bm, 17H
approximately), 3.37 ~s, 3 H), 3.5 ~bm, 1 H), 3.6-4.0 tvbm, 5 H), 4.50 (bm, 1 H), 4.67 (s, 2 H), 5.10 (AB, 2 H), 5.51 (bt, 1 H), 5.77-5.9 (2 d, 1 H), 6.09 (bt, 1 H), 7.27-7.4 (m, 10 H); MS m/e 851 ((M+H)+). Anal. Calcd for :: i ~, :` ~
,:
,` , `
. .
;, :,,. .~ , , ;, .-..
" . ~ ~ , . ",~
~Q92/~29 ~ 9 8 ~ ~ 6 ~ P~T/US91/0~5~
t ~ r r~
:
C4gH7: ~Og-0.5 H2O: C, 67.03; H, 8.79; N, 6.51. Found: C, 6~.91; H, 8.64; N, 6.48.
E~zmple ~
N-~3-.3m1no~ro~yl) 5(~)-(2(S)-(L(SL=(4-~henyl)eth~xyhe~an~midQ~-6-~c~hexyl-~(S)-hydroxy-2(~
The resuitant compound rom Example 2 t50 mg, G.0587 mmol) W2S s~irred with 10~ palladium on carbon (13 mg~ in 3 mL EtOAc under 1 atmosphere of hydrogen for 3 days. The mixture was filtered, and the filtrate was concentrated to a foam. Thin-layer chromatography (silica gel, 10% MeOH-1% concentrated aq. NH4OH-CH2Cl2) gave 26.4 mg (0.0368 mmol, 63%) of the title compound as a white foamy solid: mp 58-60 C; Rf 0.26 tl0% MeOH-1% concentrated aq. NH4OH-CH2Cl2); 1H NMR (CDC13) ~ 0.90-0.92 (m, 9 H), 0.65-2.0 (vbm, 28H totzl approximately), 2.05 (m, 1 H), 2.82 ~dd, 2 H), 2.9-3.1 (m, 2 H), 3.13-3.28 (bm, 2 H), 3.37 (s, 3 H), 3.3-3.55 (bmr 5 H), 3.6-4.0 (vbm, 5 H), 4.50 (dd, 1 H), 4.67 (s, 2 ~), 5.79 (d) and 5.87 (d, lH total), 6.52 (~m, 1 H), 7.30 (bs, 5 H); MS m/e 717 (~M+H)+). HRMS.
Calcd for ((M+H)+) of C40H6gN4O7: 717.~166. Found:
717.5178.
~ An alternative procedure for the preparation of - this compound follows. A mixture of the resultant compound of Example 9 t2.3 g, 3.58 mmol) and 20 equivalents of 1,3-diaminopr~opane W2S s~irred at 55 C for 4 h and at 65 C
for 6 h. The mixture was diluted with EtOAc and washed with water. The organic portion was dried, filtered and evaporated. The residue was colu~n c:-=omatographed (silica :`:
- : : . , . . . :
. : !
' ' ~
', WO 92/03429 PCT/~lS91/05~4-~
, ~ 2 ~ 8 9 2 ~ -42-gel, 4% MeOH-1% concentrated aq. NH40H-CHCl3) to produce 2.0 g (2.79 mmol, 78~) of the desired product as a hygroscopic foa~. The compound obtained from this procedure was identical in all respects to t:^e co~ou~d obtained from the previous procedure.
Exam~
N-~3-~.~e~amidopro~yl) 5(S)-(2(C)-~l(c)-(~-(m~t~Qxym~t~ p;~e~
ghenyl ) etho~yhe ~arA~ml~o ~ - 5 - cyc l ~h ~ ~ y - _ A ( 5~ - -` 'if '.'~ ~'V- ~ ( ~S) -iso~ro~vvlh~xan~m~d~
A solution or the resultant compound rro~. Example 3 (23.4 mg, 0.0326 mmol) in 5.4 mL CH2C12 was cooied to O C, and N-acetoxy-norbornene-2,3-dicarboximide (21.7 m~, 0.122 mmol) was added. The solution was stirred ror 3 days at ambient temperature, then was concentrated and purified by preparative ~hin-layer chromatography (silica gel, 10%
MeOH-1% concentrated aq. NH40H-CH2C12) provided 19.6 mg (0.0258 mmol, 79%) of the title compound as a white foam:
mp 62-67 C; Rf 0.29 (10% MeOH-1% concentrated aq. NH40H-CH2Cl2); lH NMR (CDCl3) ~ 0.65-1.95 (s~veral bm, 29H
approximately~, 0.90 (t) and 0.92 (d, 9H total), 2.00 (s! 3 H), 2.0-2.11 (m, 1 H), 2.97 (m, 1 H), 3.06 (dd, 1 H), 3.1-~i 3.5 (bm, 6 H), 3.37 (s, 3 H), 3.5-4.0 vbm, 6 H), 4.52 (dd, '"! 1 H), 4.68 (s, 2 H), 5.85 (d) and 5.93 (d, lH total), 6.30 (bt, 1 H), 6.-48 (bt, 1 H), 7.33 (bm, 5 H); MS m/e 759 ; ((M+H)+). Anal. Calcd for C42H70N40g 1.25 H20: C, 64.54;
E, 9.34: N, 7.17. Eound: C, 64.,9; N, 9.02; N, 7.09.
j ' ' .
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.
"
.. : ,.. : , , , ' : :
W092/03429 PCT~S91/055~
-` 2~89268 .. ... ,., .. , . . , ,.. i~
. ~43_ ~ ~,., Exam~
N~ (2-~.ydroYye~hyl)aminQ)~ro~yl) 5(~)-(2(5`~ $)-(~-(metho~y~ethox~ e ~dl?~ ~ C ?~
~hsnyl)etho~he~anamido)-6-c~clo~xyl-9(.C)-hvcrox~-2(~)-;~opro~lhPx~mi~e ~ . _N-(~--(2-hydroyyethyl)a~;~.o)~o~yl~ 2(~C)~ -(tP; -~
b~tylo~ycarbonyl)-2 2-d~yl-4(~-c~ic'o.~e~ r,~ (S~ -Q~ gL~ L~ ,thylb~te?~m~dP ~;.e ? ocedu~e o Example 2B was followed, uslns th~ -o cwi.. ~u- ies:
2~L-((3-(tert-butyloxycarbonyl-2,2-c~me h~
cyclohexylmethyl-5l~L-oxazolidinyl)me~ )-3-."~ lbu a^~__ acid (European Patent Application No. r~364804, publisned April 25, 1991) (100 mg, 0.243 mmol), H09T (5i.3 mg, 0.36q mmoI), N-methylmorpholine (37 mg, 0.364 mmol) and 3-(2-~hydroxyethyl)aminopropylamine ~37.3 mg, 0.316 mmol, prepared according to the procedure of Surrey, H. J Am.
Chem. Soc. 1950, 72, 1814) and EDCI (65.2 mg, 0.340 mmol) in 2.4 mL DMF. Purification by flash chromatography ~silica gel, 10% MeOH-0.5% concentrated aq. NH40H-CH2Cl2) gave 80.6 mg ~0.158 mmol, 65%) of the title compound as a low-melting, hygroscopic solid; Rf 0.34 ~10% MeOH-1%
concentrated aq. NH40H-CH2Cl2); 1H N~R (CDCl3) ~ O.94 (2d, 9 H), 1.10-1.45 (vbm, 13 H), 1.48 ~s, 9 H), 1 . 58 (bs, 3 H), 1.6-1.9 (bm,~5 H), 2.0-2.1 (bm, 1 r.), 2.28 (bs, 4 H), 2.75 (t, 2 H), 2.82 ~m, 2 H), 3.40 (dd, 2 H), 3.57-3.8 (m, 4 H), 6.35 (bt, 1 H).
~ _ The prooedure of Example 2C w2S followed, in which the resultant compound from Example 5A was deprotected and coupled to the resultant compound -rom Example 1. For Part l, the following quantities were used: the resultant . .
;
-~ ~, . . . . . . .
. -- . .
, :
WO92/0~29 ?RCT/US9l/055 2 ~9 2 6~ _44-compound f-om Example 5A (33 mg, 0.0645 mmol) was deprotected ln 1 mL CH2Cl2 and 1 mL trifluoroacetic acid, followed by removal of the acetonide in 1.5 mL T~ and 0.75 mL H2O, to give 13.o mg of crude amino alcohol. For Part 2, the following quantities were used: crude amino alcohol (15.0 mg, 0.040 mmol), HOBT (7.1 mg, 0.045 mmol), the resultant compound f-om Example 1 (18.1 mg, 0.044 mmol), N-me,hvlmorpholine (4.5 mg, 0.045 mmol) and EDCI (10.9 mg, 0.56 ~ol) were reacted in 1 mL DMF. Puriflcation by ~-epararive thir-layer chromatography (silica gel, 15~
ieO:i-C.5% concentrateà aq. NH4OH-C~.2Cl2) produced 7.5 mg (0.010 mmol, 25~) of a hvc-oscopic glass; Rf 0Ø34 (1 MeO~-0.5~ concentrated aq. ~H4OH-C~2Cl2); lH NMR (CDCl3) ~
0.65-1.93 (several bm, 28H approximately), 0 87-0.965 (m, 9 H), 2.05 (m, 1 ~), 2.5-2.9 (bm, 9H, includes H2O), 2.9-3.1 ; (m, 4 H), 3 1-3.35 (bm, 4 H), 3.37 (2s, 3 H), 3.41-3.58 (bm, 4 H), 3.68-4.1 (bm, 7 H), 4.61 (bm, 1 H), 4 68 (d, 2 : H), 5.78 (d) and 5.86 (d, lH total), 6.90-7.13 (bm, 1 H),
7.3-7.4 (bm, 5 H); MS m/e 761 ((M+H)+).
, E~mDle 6 ~5 ( S) -2 ( S) - Ll ( ~! - ( G -(methoxyme~hoxy)Di~er1dln-1-y~ c2~ponyl-?-~h~nyl)-i ethQ~yh=~a~amido)-6-cyelohe~yl-4(S~-hydroxy-2($)-vl h.~ r ` A~
. A. ~-(3-A~;no~-oDyl) 2(S)-((3-(tert-:.~ butyloxycarboryL)-2.2- d~et byl -4 !5! -cyc Loh~xyl.methyL-~.s?
oxa~olidi~l)n~thyl~?-~-m~hyl~ut~namide~ The title compound from Example 2B ~1.02 g, 1 70 mmol) was dissolved in 100 mL EtOAc containing 10% palladium on carbon catalyst ~- (0 10 g, 0.094 mmol). The mixture was shaken under a :.
: ``
:, ~,~. :. . .. . . ... .
~ ,.. . ~: : .
.. ... .
W092/03429 2 ~ ~ ~ 2 ~ ~ PCT/US91/05524 pressure of 4 atmospheres of hydrogen at ambient temperature for 24 hours. The catalyst was removed by filtration through Celite and the filtrate was concentrated to a sticky glass. Purification by flash ch-oma~ograpy (silica gel, 10~ MeO~-0.5~ concentrated aq. NH4OH-CH2Cl2) provided 641 mg ~1.37 mmol, 81%) of the title compound as a hygroscopic stic~y white foam; Rf 0.26 (10% MoOH-1%
concentrate~ aq. ~TH4OH-CH2C12); lH NMR (CDC13) ~ O.94 (m,
, E~mDle 6 ~5 ( S) -2 ( S) - Ll ( ~! - ( G -(methoxyme~hoxy)Di~er1dln-1-y~ c2~ponyl-?-~h~nyl)-i ethQ~yh=~a~amido)-6-cyelohe~yl-4(S~-hydroxy-2($)-vl h.~ r ` A~
. A. ~-(3-A~;no~-oDyl) 2(S)-((3-(tert-:.~ butyloxycarboryL)-2.2- d~et byl -4 !5! -cyc Loh~xyl.methyL-~.s?
oxa~olidi~l)n~thyl~?-~-m~hyl~ut~namide~ The title compound from Example 2B ~1.02 g, 1 70 mmol) was dissolved in 100 mL EtOAc containing 10% palladium on carbon catalyst ~- (0 10 g, 0.094 mmol). The mixture was shaken under a :.
: ``
:, ~,~. :. . .. . . ... .
~ ,.. . ~: : .
.. ... .
W092/03429 2 ~ ~ ~ 2 ~ ~ PCT/US91/05524 pressure of 4 atmospheres of hydrogen at ambient temperature for 24 hours. The catalyst was removed by filtration through Celite and the filtrate was concentrated to a sticky glass. Purification by flash ch-oma~ograpy (silica gel, 10~ MeO~-0.5~ concentrated aq. NH4OH-CH2Cl2) provided 641 mg ~1.37 mmol, 81%) of the title compound as a hygroscopic stic~y white foam; Rf 0.26 (10% MoOH-1%
concentrate~ aq. ~TH4OH-CH2C12); lH NMR (CDC13) ~ O.94 (m,
8 H), 1.1-1.5 (vbm, 4 H), 1.48 (s, 9 H), 1.54-1.90 (several m, 20 H), 2.04 (m, 1 ;J.)~ 2.81 (m, 2 H), 3.49 (m, 2 H), 3.64 (bm, 1 H), 3.74 (m, 1 H), 6.18 (m, 1 H).
3.~ } .~ L~nyla~no)~ro~yl) 2(~ -( ~r_ Y.~ Qrl~ 2, ~ m.~thy ~ ~ ( .C~ l o~ e Y~ hy l - 5 ( S) ~
h l~ The resultant compound from Example 6A (125 mg,0.267 mmol) was dissolved in 4 mL dry THF and trimethylsilyl isocyanate (46.2 mg, 0.401 mmol) was added dropwise. The resulting solution was stirred overnight ~18 h) at ambient temperature under a nitrogen atmosphere and then concentrated to a whi~e foam.
Purification by flash chromatography (silica gel, 4% MeOH-CH2C12) provided 111 mg (0.218 mmol, 82%) of the title compound as a white foam; Rf 0.56 (10~ MeOH-1% concentrated aq. NH4OH-CH2Cl2); 1H NMR (CDC13) ~ O.95 (m, 8 H), 1.10-1.45 (m, 5 H), 1.48 (s, 9 H), 1.52-1.90 (several m, 17 H), 2.10 (m, 1 H), 3.23 (m, 2 H), 3.37 (m, 2 H), 3.67 (bm, 1 H), 3.73 (m, 1 H), 4.40 (bs, 2 H), 5.53 (bs, 1 H), 6.08 (m, 1 H).
C. The procedure of Exa~mple 2C was followed, in which the resultant compound from Example 63 was deprotected and coupled to the resultant compound from Example 1. For Part l, the following quantities were u3ed: the resul~ant , ~, .................... . . . . .
.,., - -:' .
W092/0~29 PCT/US91/0
3.~ } .~ L~nyla~no)~ro~yl) 2(~ -( ~r_ Y.~ Qrl~ 2, ~ m.~thy ~ ~ ( .C~ l o~ e Y~ hy l - 5 ( S) ~
h l~ The resultant compound from Example 6A (125 mg,0.267 mmol) was dissolved in 4 mL dry THF and trimethylsilyl isocyanate (46.2 mg, 0.401 mmol) was added dropwise. The resulting solution was stirred overnight ~18 h) at ambient temperature under a nitrogen atmosphere and then concentrated to a whi~e foam.
Purification by flash chromatography (silica gel, 4% MeOH-CH2C12) provided 111 mg (0.218 mmol, 82%) of the title compound as a white foam; Rf 0.56 (10~ MeOH-1% concentrated aq. NH4OH-CH2Cl2); 1H NMR (CDC13) ~ O.95 (m, 8 H), 1.10-1.45 (m, 5 H), 1.48 (s, 9 H), 1.52-1.90 (several m, 17 H), 2.10 (m, 1 H), 3.23 (m, 2 H), 3.37 (m, 2 H), 3.67 (bm, 1 H), 3.73 (m, 1 H), 4.40 (bs, 2 H), 5.53 (bs, 1 H), 6.08 (m, 1 H).
C. The procedure of Exa~mple 2C was followed, in which the resultant compound from Example 63 was deprotected and coupled to the resultant compound from Example 1. For Part l, the following quantities were u3ed: the resul~ant , ~, .................... . . . . .
.,., - -:' .
W092/0~29 PCT/US91/0
9~26~ -96-compound from Example 6B (83 mg,0.162 mmol) W25 deprotected in 2 mL CH2Cl2 and 2 mL trifluoroacetic acid, fellowed by removal of the acetonide in 3 mL THF and 1.5 r_ H2O, to give 55.3 mg of crude amino alcohol as a s~ic.`~ e solid; Rf 0.09 (20% MeOH-1% concentrated aq. N~OH-CH2C12); 1H NMR (CDCl3) ~ 0.95 (m, 9 H), 1.05-2.25 (se;er_' m, 18 H), 2.63 (m, 1 H), 3.01-3.36 (several m, 5 H), 3.93 (m, 1 H), 4.73 (bs, 2 H), 5.65 (m, 1 H), 6.47 (~, 1 n) .
For Part 2, the following quantit~es we_e used: c-ude amino alcohol (48.0 mg, 0.130 mmol), HO~ ~2^.~ m~, 0.
mmol), the resultant compound from Exam?le 1 (.~.i mg, 0.142 mmol), N-met~ylmorpholine (14.4 mg, 0.192 .~mol) anà
EDCI (34.8 mg, 0.181 mmol) were reacted in 1.3 mh D~.
Purification by flash chromatography (silica gel, 5~ MeO~-CH2C12) provided 69.0 mg of the title compound as a white powder; mp 87-92 C; Rf 0.58 (15~ MeOH-CH2C12); 1H NMR
(CDCl3) ~ 0.65-2.10 (several m, 33 H~, 0.93 (m, 9 H), 2.92-3.35 (several m, 6 H), 3.37 (s, 3 H), 3.41-3.63 (m, 3 H), 3.68-3.87 (m, 3 H), 3.87-4.05 (bm, 1 H), 4.60 (m, 1 H), 4.69 (s, 2 H), 5.75 (bm, 1 H), 5.80 (m, 1 H), 6.44 (m, 1 H), 7.33 (m, 5 H); MS m/e 760 ((M+H)+). Anal. Calcd for C4lH69N5O8-1.0 H2O: C, 63.29; H, 9.20; N, 9.00. Found: C, 63.28: ~, 9.02: ~, 8.85.
~ ~ ' .
, .~
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W092/03429 2 ~ g ~ .~ 6 ~ PCT/USgl/05~
-47- ~_ EX~Im~;> 1~ 1 N-(3-(~mi~Qthionylamino)~rs~yl) 5(.5~-~2(5)-(1(5)-(4-(meth~Yymethoxy~R~ 1-yl)carbonyl 2-~henyl)etho~yhexanami~o~_~-cyslohexvl-4(~)-hvdro~y-2(5)-; isopropylhexanamlde.
A N (3-(AminothiQnylamin~RI~yl ~(5~-((3-(te-t-butyloxycarbony~ m~thyl-~(S)-~clohex~lm~e~hvl-5(~
xazQlidlnyl)methyl)-~m~b~l~ut~emi~. To a solu.ion o-the resultant compound from Example 6A ~127 mg, 0.271 mmol?
in 3.4 mL THF at 0 C was added N,N'-thiocarbonyldiimidazole (67 mg, 0.338 mmol). The solu~ion was allowed to warm to room temDerature and stir 18 h. TL~
~4~ MeOH-CH2Cl2) indicated complete conversion ~o a ne-~
;product. The yellow solution was recooled to 0 C and treated with concentrated aq. NH40H (0.5 mL, 4 mmol). The reaction was stirred at room temperature for 48 h. The olution was concentrated in vacuo to a solid (210 mg), which was purified by flash chromato~raphy (silica gel, 4%
MeOH-CH2C12) to produce 134 mg (0.254 mmol, 94%) of a white solid; Rf 0.31 (5% MeOH-CH2Cl2~; 1H NMR (CDC13) ~ 0.93 (d, 3 H), 0.96 (d, 3 H), 0.8-1.0 (bm, 2 H), 1.05~1.S ~bm, 7 H), 1.98 (s, 9 H), l.S7 (bs~, 1.66 (bs) and 1.55-1.90 (several bm, 15H total), 2.1 (bm, 1 H), 3.30-3.42 (bm, 2 H), 3.5-3.75 (bm, 4 H), 5.72 (bs, 1 H), 6.08 (bs, 1 H), 7.45 (bs, 1 H); MS m/e 527 ((M+H)+).
Using the procedure of Example 2C, the resultant compound of Example 7a was deprotected and coupled to the resul~ant compound from Example 1 to provide the desired compound as a white solid (59%): mp 83-89 C; Rf 0.38 ~5%
MeOH-CH2Cl2); lH NMR (CDC13) ~ 0Ø73 (br m, 2 H), 0.8-1.0 (m, 10 H), 1.05-1.94 (several br m, approximately 25 H
'' , .
.,. ~
, , , , ~ ~ , . . . . .
' : '' ,, , .: , W092/0~29 PCT/US9l/05~
~o~9~68 -48-total), 2.0 ~br m, 1 H), 2.9-3.13 (m, 3 H), 3.2 (br m, 1 H), 3.25-3.4 (br m, 1 H),. 3.38 (2 s, 3 H), 3.4-3.67 (br m, 4 H), 3.72 (m, 1 H), 3.75-3.9 (br m, 2 H), 4.0 (br m, 1 H), 4.62 (br m, 1 H), 4.70 (2 s, 2 H), 5.72 (dd, 1 H), 6.18 (br s, 1 H), 6.45 (br s, 1 H), 7.33 (br s, 5 H); MS m/e 776 ((M~H)~). ~nal. Calcd for C41H6gN5O7S 0.75 H2O: C, 62.37;
H, 9.00i N, 8.87. Found: C, 62.38; H, 8.88; N, 8.87.
Le ~
r~-^r~ 5(~)-(?(S~ (S)-!~-J~ r ~ :n o ~y ) ~ ) ca ~ bQn-v l= 2 -b n,r n,~ 'f ~ , ' dQl ~ o~cyC l ohex~ 1-4 ( S) -hydroxy-2 ( ~! -i sopropyln~x~n~mid~
. N- (Cyan.omQ~u~ - 2(s!-((3-(tert-~utyl~y~ Q~lL=
2l~=.di.me~byl-4(5)-cy~ lohexylmethyl-~(S)-oxazclidinyl~methyl)-3-methylbutanamide The procedure of Example 2B was used, substituting aminoacetonitrile hydrochloride for 3-~benzyloxycarbonylamino)propylamine.
Purification by flash chromatography (silica gel, EtOAc-hexane 1:3) pro~ided 513 mg (1.14 mmol, 94%) of the title compound as a white foamy solid: Rf 0.20 (EtOAc-hexane 1:3); 1H NMR (CDC13) ~ 0.94 ~d, 3 H), 0.97 (d, 3 H), 0.85-1.05 (bm, 2 H~, 1.05-1.53 (several bm, 5 H), l. 48 (s, 9 H), 1.49 (s, 3 H), 1.59 (s, 3 H~, 1.55-1.85 (several bm, 8 H), 1.85-1.98 ~m, 1 H), 2.1-2.2 (bm, 1 H), 3.55-3.7; ~bm, 2 H), 4.21 (ABX, 2 H), 6.06 (bt, 1 H).
:: `
~_ The procedure of Example 2C can be used, in which ` the resultant compound from Example 8A is deprotected and coupled to the resultant compound from Example 1 to provide the desired compound.
.' .
~ .
:'~
. . .
. , W~92/0~29 P~T/~S91/05524 20~9268 -i .. ?
. Y.~
vl)ca banv7-2-?he~ )o~hoYvhexanami~o)~thyl 3(5~-iso~oropyl-2.~.4.5-~et~ahydr~rura~-2-one.
The resultant com?ound from Example 1 was coupled .o (2S,4S, 5â) -5-amino-6-cyclohexyl-4-hydroxy-2-isopro?ylhe;~.anoic acid lactone (3ra~bury, R. H.; ~evill, J.
M.; Rivett, J. E.; ~at~-sor., D. Tet_ahedron Let.. 1989, 3845) according to the orocedure of _~ample 2C, Part 2, to obtain the deslre~ product in 80% yleid: 1 N~R (CDC13) 0.89 (m), 0.91 (d), and 1.0 (d, 9H total), 0.70-1.9 (several bm, 27H app-^xim~Lely), 2.1 (m, 1 H), 2.~5 (m, 2 H), 2.8; (m, 1 H), 3.0~ (dd, 1 H), _.5-3.8 (m, 4 H), 4.5 (m, 1 H), 4.7 (d, 2 H), 5.35 (d) and 5.45 (d, 1 H total), 7.4 (bm, 5 H); MS m/e 643 ((M+H)~).
!-(2(~-(l(S)-~4-(m~thoxym~thQ~yLpi~ri~in~l-yl)carhonyl-2-~h~nyl!ethQxy~=~D~m~s~-6-~ycLohex~l-4(s)-hyd~oxy-2(s) isQ~opylhexanamid~
The resultant compound from Example 9 (50.3 mg, 0.0782 mmol) was combined with 1,2-diamino-2-methylpropane (138 mg, 1.56 mmol) and the mixture was warmed to 60 C for 3 days. The reaction mixture was partitioned between 20 mL
EtOAc and 10 m~ water. The organic phase was washed sequentially with 5 mL water, 10 mL brine, then dried ~Na2SO4), filtered, and concentrated in vacuo to yeild 52.6 mg of white solid. The crude product was purifed by preparative TLC (10~i MeOH-0.5% concentrated aq. NH40H-CH2Cl2) to produce 41.6 mg (0.0563 mmol, 73% of a foamy - . .
- : : : ~ ~ .
.. . ...
:~ , ' ;'' '. . , , :.
WO 92/03429 PCr/US91/0~524 -_ solid: mp 48-56 C; Rf 0.44 (15% MeOH-l~ concentrated aq.
NH4OH-CH2Cl2); 1H NMR ~CDCl3) ~ 0.88-0.97 (m, 9 H), 1.14 (s), 1.16 (s) and 0.6-2.2 (several bm, 33H approx-ma_e'y), 2.93-3.2 (bm, 4 H), 3.2-3.46 (bm, 4 H), 3.36 ~s, 3 ~
3.46-3.6 (bm, 1 H), 3.6-3.95 (several bm, 4 H), 4.50 (dd, 1 H), 4.67 (AB, 2 H), 5.85 (d) and 5.94 (d, lu totzl), 5.~3 (bs, 1 H), 7.32 (bm, 5 H); MS m/e 731 ((M+H)+)).
N-(~-~4-~o-?hQ' ro~rQ~yl) -(S) - (2 (S) - ! ~ ( `~ - ( '-(~eti~xym~th phe~ t:~o::yne~an2m~ d~-)-6-cycl~eY~J~ -4~S)-~yd ~:v-^~
~Q~rQ~lh~a~e~
'' A mixture of the resultant p-oduct from Example 9 (60 - mg, 0.093 mmol) and 3-~4-morpholino)propylamine (150 mg, 1.04 mmol) was stirred at 60-65 C for 32 h. The mixture was diluted with EtOAc and washed with water. The organic portion was dried, filtered and evaporated. The residue `, was column chromatographed ~silica gel, 2 to 5% MeOH-CHCl3), providing 73 mg (0 058 mmol, 62~) of the desired product. The product obtained from t:his procedure is I spectroscopically identical to the compound prepared -I prevlously (PCT Patent Application WO 90/03971, 19-4-30) .
~-~ E~aTn~?~ 1?
A. 4-(4-Morpholinolhut;~lamine. A mixture of 4-chlorobutyronitrile (4.23 g, 40.86 mmo ) and morpholine . .
`
W~92/0~29 PCT/~S91/0~5~
~3~
: . . ..... . ~.. . ~.. .... . . . . .
(10.68 g, 122.59 mmol) was stirred at room temper2ture until the mixture solidified. It was diluted with EtOAc, washed with water. The organic portion was dried, .iltered and evaporated to obtain 4.0 g (25.3 mmol, 65~) of a yellowish liquid: 1H NMR (CDCl3) ~ 1.85 (q, 2 H), 2.95 (m, 8 H), 3.7 (m, 4 H); MS m/e 155 ((tM+H)+). 2.0 g (13 mmol) of the above resultant liquid was hydrogenated under a atmospheres hydrogen with ethanolic ammonia and ~an~y nickel for 16 h. The mixture was filtered and t:~e filtr~
-- was evaporated to obtain 1.5 g (9.5 ~mol, 73~) o. the desired product: 1H NMR (CDCl3) ~ 1.55-1.8 (m, ~ H), 2.5 (m, 8 H), 3.75 (m, 4 H); MS m/e 159 (((M+H)+).
literature procedure, see J. Amer. rhem. So_. 19~ 3, ;~ 156.
B. The title campound was prepared according to the procedure of Example 10 by replacing 3-(4-morpholino)propylamine with the resu:Ltant compound from Example 12A, to produce the desired amide ~55% yield): lH
NMR (CDCl3) ~ 0.90 ~m, 9H), 0.70-1.90 ~several br m, 30H
. total), 2.02 ~m, lH), 2.35 ~br m, 6H), 2.95 ~m, lH), 3.05 (dd, lH), 3.20 (br m, 2H), 3.40 (s, .~H), 3.60-4.0 (several br m, 10H total), 4.50 (dd,lH), 5.78(d) and 5.85 (d, lH
total), 6.20 (bt, lH), 7.30 (br m, 5H); MS m/e 802 . ((M+H)I).
.
:, .
.
,~ :
: .
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W092/03q29 PCTtVS91/0~S2q~
~9'~6~ -52-Exam~le 13 N-(5-(4-Mor~holinQ)Denty~ ~(5)-(2(.sL ~4-(me'ho:-~re~o~v~iperidi~.-l-yl)ca~bonyL=2-; ph~l)P~hoxvh~ ?.~id~-6-cycLoh.eYy~ -h.yd-oYv 2--(~-.~ lso~ro~ylhexa~amid~.
A. 5-(4-~.,o-~k.olino!_~entY1am1ne. The title compound may be ~re~ared according ~o the procedure of r.xample 12A, by subslituling ~-chloropentanonitrile for 4-chlorobulyronl--ile.
The titie compound may be prepared according to the procedure of Exam~le 10 by replacing 3-(4-mo-phollno)pro?ylamine with the resultant produc_ of Example 13A.
, .
N-t3-t3-Oxa-9-azahicyclor3.3 ll~Qna~-9-~l)~ropyl) 5(S)-t2tS)-(4.-tmethoxym~ho~yLeiperidin-1-yl)carbonyl-2-_ -4l5)-hYdroxy-2-(S)-A. 3-(3-O~-~-a~biGyclo[3.3.LLnonan-q-:,yl)pro~yla~l2e. This compound can be prepared according to .the procedure of Example 12A, but replacing morpholine with 3-oxa-9-azabicyclo~3.3.1]nonane.
B. The title compound can be prepared according to the procedure of Example 10 by replacing 3-(4-.morpholino)propylamine with the resuitant amine from Example 14A.
.
.
': :' ~'' ' ' WO92/03429 2 ~ PCT/~JS91/05524 N-(3-(~-O~ ~æ~oy~1o r ~ . 2 .1~ ~ n--8--y1~ ~L~y1~ 5 t S) ~
(2(c~ hQ~:y~P~tho~ pl~ rdln-~ .)ca-~Qny~-2-Dh~nyl)etho~yhP~anamldo)-6-cyclQhexvl-4LS)-hycrQ~y-2-(~
i~o~ro~y'hex~n.amide.
y'~ o~vlzmtnP~ T:~is compound can be prepared according to t:n- ?rocedurP ~ ample 12A, by re?lacing mor?holine wlth 3-o:~a-8-a-a blc~;_ or3.2.1]oc_ane.
. T~e z ~le com?ound can be prepared according to thP procedure o- rxample 10 by re~lacing 4-(3-aminopropyl)morpholine with the resultant amine from Example 15A.
~xa~le 1~
M-l2-~ml~Qet~lL_~lS)-(2(S)-(9-(methoxymethoxy)piperidi~L-1-yl)~ar~Qnyl-2-phenyl)ethoxyhexanamidQ)-6-cyclQhexyl~lS~-h~r~xy-2~t~ Q~y~b98an~mL~ç~
The title compound was preparecl according to the procedure of Example 10 by replacincJ 4-(3-aminopropyl)morpholine with 1,2-diaminoethane:as a white foam (87% yield): mp 62-67 C; Rf 0.28 (10% MeOH-1% conc aq. NH4OH-CH2CL2); lH NMR ~CDCl3) ~ 0.67-1.92 (several br m, approx. 35 H ), 2.08 (m, 1 H), 2.37-4.00 ~several br m, ap~rox. 17 H ), 3.37 (s, 3 H), 4.54 (m, 1 H), 4.68 (s, 2 H), 5.83 (dd, 1 H~, 6.36 (m, 1 H), 7.28-7.38 (m, 5 H); MS
m/e 703 ((M+H)+). Anal. Calcd for C3gH66N4o7 o-5 H2O: C, 65.79; H, 9-.48; N, 7.86. Found: C, 65.68; ~, 9.27; N, 7.8S.
.~ .
. .
:
WO 92/03429 PCT/~S91/0S5~ -_ 0 ~ 54-E~am~le 17 N-(~-Aminohutyl) 5(~)-(2(5)-~4-(merho~:yme.ho y)~lp~r~din-~-~ y1)ca~o~l~l-2-~hen~l)etho~yhe~an2~id^~-~-cyo ~h~Yy~ S)-:j hyd~oxy-2,,-(5)-iso~ro~ylhe~anami~e.
The title compound was prepared according .o the -~ procedure of Example 10 by replacing 4-(3-aminopropyl)morpholine with 1,4-dia~.inobutan~: m~ 88-9G
C; 1H NMR (CDCl3) ~ 0.80-0.90 (m, 9 ~), 1.05-1.8C (b/ ~, 30 H), 2.13 (dd, 1 H), 2.5~ (br t, 2 ~), 3.00 (.~., 9 H), 3.20-3.65 (m, approx. 7 H), 3.75 (.,~, 2 H), 3.85 ~m, 1 n), 4.50 (m, 2 H), 4.60 (br s, 2 H), 6.72 (d, 1 H), 6.76 (d, 1 H), 7.25 (br s, 5 E~), 7.80 (m, 2 H); ~S m/e 732 ((M~H)~) . E~am~l~
N-(5-Amino~entyl) 5($)-~2ls)-~4-LmethoKy~etho~)pi~e~id~i~-L-yl!car~Q~y1-2-phenyl)etho~yhe~anamido!-6-cyclohexyl-~LS)-LSL~bL4~ namide.
The title compound can be prepared according to the procedure of Example 10 by replacing 4-(3-aminopropyl)morpholine with 1,5-diaminopentane.
.c Example l9 N-(3-Amlno-3-methyLbutyl~ s(s)-(2Ls)-(l(s)-(a (methoxy~m~thoxy)~iper;d~ -yl)oa~onyl-2-.,......... -- -- .
,~ ~
A~ 1-~z~do-2-L~en~lQ~ycarbonylam~no)-2-methylbutane.
2-(Benyloxycarbonylamino)-2-methyI-1-butanol (1.358 g, 5.722 mmol) and triphenylphosphine (1.800 g, 6.86 mmol) were dissolved in 10 mL CH2Cl2, and the resulting solution ~- , , .. . ~ - . :
... : . :.: .
~, : ., " .,. :. ~ . , , : . :
:. .: : , ~ ,., .~ , ... : ,, , W092/0~29 2 ~ ~ ~ 2 ~ 8 PCT/US91/055~
., .. . . .. . .
.
was cooled to 0 C. A solution of hydrazoic acid (prepared from sodium azide (1.30 g, 20.0 mmol), 0.~33 mL
concentrated sulfuric acid and 1.3 mL water) i.. 20 mL
CH2Cl2 was passed through a plug o~ MgSO4, the iltrate was added to the above alcohol solution, then diisc?-opyl azodicarboxylate (1.35 mL, 1.40 g, 6.91 mmol) h-as added dropwise over 3 min. The reaction mixture was stirred a~ C
C for 1 h, then at room temperature ror 5 h. ~ - mlxture was concentrated in vacuo, and the residue was ap~lied to 300 g of silica gel in a fritted disc runnel 2-.~ eluted with 3 x 500 mL of 10% EtOAc-hexane. The secon~ fraction contained pure desired azide (0.822 g, 3.13 mm^l, 55~) as 2 colorless oil: Rf 0.17 (10~ EtOAc-hexane); 1~ CDCl3) 1.33 (s, 6 H), 2.02 (bt, J = 7.5 Hz, 2 ~), 3.32 (bt, J =
7.5 Hz, 2 H), 4.74 (br s, 1 H), 5.05 (s, 2 H), 7.3-7.4 (m, 5 H); MS m/e 263 ((M~H)+), 280 (M+NH~)+).
r ~ yl) 2 ~ ( (3~t-cyclohexylm~hyl-5(S)-oxa7~11~inyl)meth~1L=3=o~LhylbL~3c~mi~_ The resultant compound from Example 19A (102 mg, 0.389 mmol) was stirred with 10% palladium on carbon (20 mg) in 1 mL EtOAc under 1 atm H2 for 17 h. The solvent was removed with a stream of N2, the residue was suspended in 3 mL MeOH, and then a solution of HCl in dioxane (0.16 mL, 4.8 M, 0.758 mmol) was added. After stirring for 1 h, the mixture was filtered through celite, and the ~iltrate was rotoevaporated and the residue placed under high vacuum to produce the corresponding diamine dihydrochloride (72 mg, 0.40 mmol, 103~ as a white foamy solid: lH NMR (CD30D) ~ 1.40 (s, 6 H), 2.04 (m, 2 H), 3.06 ~m, 2 H). The above crude diamine dihydrochloride (60.2 mg, 0.344 mmol) was coupled according ' : .:
: . : . ,., :, :.
, W092/03429 P~T/~S9~/05524 _ to the procedure of Example 2B to provide (after flash chromatography, eluting with 12.5% MeOH-1% concentra~ed aq.
~ NHgOH-CH2Cl2) the title compound (85.5 mg, 0.186 mmol, 67%) - as a glass: ~f 0~34 (10~ MeOH-1% concentrated aq. NH40H-; CH2Cl2); lH NMR (CDC13) ~ 0.93 t2 d, 6 H), 1.17 (2s, 6 H), 1.48 (s, 9 H), 0.8-1.8 (several br m, approximately 23H
total), 1.85 (m, 1 H), 2.02 (m, l H), 3.36 (m, l H), 3.44 ~m, 1 H), 3.6q (br m, 1 H), 3.76 (m, l H), 6.96 (bt, l H);
~S m/~ 436 ((M~H) ).
C The proceaure of Example 2C was used. The resui~ant compound from Example 13~ (73.5 mg, 0.148 mmol) was deprotected to give 55.5 mg (01156 mmol, 105%) of the corresponding crude diamino alcohol as a yellow viscous ; oil: 1H NMR (CDCi3) ~ O.93 (2 d) and 0.75-1.05 (br m, 9H
total), 1.15 (s, 6 H), 1.05-1.9 (several br m, approximately 24 H), 2.09 (m, 1 H), 2.60 (br m, 1 H), 3.39 (m, 2 H), 7.09 (br m, 1 H); MS m/e 356 ((M+H)+). The crude amino alcohol was then coupled using the following i quantities: crude diamino alcohol (52.4 mg, 0.127 mmol), , the resultant compound from Example 1 (55.0 mg, 0.134 mmol), HOBT (31.2 mg, 0.204 mmol), N-methylmorpholine (28 mL, 26 mg, 0.255 mmol) and EDCI ~32 mg, 0.167 mmol) in 0.6 mL DMF. Purification by flash chromatography (10% MeOH-0.5% concentrated aq. NHqOH-CH2Cl2) produced 59.0 mg (0.079 mmol, 62~) of the title compound as a white foam: mp 44-49 C; 1H N~R (CDCl3) ~ 0.86-0.95 (m, 10 H), 1.195-1.21 (2 s, 6 H), 0.65-2.5 (several br m, approximately 33 H), 2.96 (m, ~
l H), 3.04 (dd, 1 H), 3.36 (s, 3 H), 3.72 (t, 2 H), 3.1-4.0 (several br m, approximately 8H total), 4.57 (m, 1 H), 4.68 (s, 2 H), 5.85 and 5.91 (2 d, lH to.al), 7.32 (br s, 5 H), 7.41 (br m, 1 H); MS m/e 745 ((M+H) T) ~ Anal. Calcd for '' . : ~ : ' ' ' . '. '' . :
., . ' .~:
,, : - . ~ . . .
: ' ~ ' ' . : ''-'' :
2~8~2~g WO9~/0~29 PCT/US9l/055 .;
. . , . , . i "
C42H72NaO7 1.5 H2O: C, 65.34; H, 9.79; N, 7.26. Found: C, 65.57; H, 9.41; N, 7.24.
.
N-~2-Ureido)e~hyl 5(5~-r2(~
(Tnetho~yme~noxy)~l~eridin-l-yl)ca~honyl-2 h ~a~2mldo)-6-cy~lohey~yl-4(s)-hyd~oy~y-2(s) lsQ~ro~yl h.ex~n.?!nide .
The procedure or Example 6~ was used, substituting the resultan~ p-oduct from Example 16 for the resultant product from Exampie 6A, to provide the title compound as a ~hite powder (39~ yield): mp 85-92 C; Rf 0.43 (10 ~ MeOH-CH2Cl2); 1H NMR (CDCl3) ~ 0.55-1.98 ~several br m, 36H
approximately), 2.84-3.88 (several br m, 14 H), 3.38 ~d, 3 H), 3.95-4.18 (br m, 1 H), 4.68 (s, 2 H), 4.71 (br m, 1 H), 5.09 (br m, 2 H), 5.50 (br m, 1 H), 5.66 (dd, 1 H), 6.22 (br m, 1 H), 7.27-7.38 (br m, 5 H); MS m/e 746 ((M+H)~).
Anal. Calcd for C40H67NsOg-1.25 H20: C, 62.51; H, 9.11; N, 9 11. Found: C, 62.38; H, 8.72; N, 8.95.
E~am~Le 21 N- (2- (Thioureido! ethyl 5 ! s) - (2 (~) - (L(S) - (4-~o ~j~-yl) car~2on~-2 `~'' iSo~roF)y~ h.e~canam.;~e .
The procedu~e of Example 7A was used, substituting the resultant product from Example 16 for the resultant product from Example 6A, to provide the title ~ompound as a white powder (52% yield): mp 98-112 C; Rf 0.40 ~5~ MeOH-~; CH2Cl2); 1H NMR (CDCl3) ~ 0.51-1.96 (several br m, 37H
approximately), 2.81-4.26 ~several ~r m, 15 H), 3.48 (d, 3 :, ~,., ,. . . ..
,:
W~92/0~29 PCT/US9~/0~5~ .~
. :
... , .. , . ~. ~ ,. .. . . ..... .
~ 2~ 8 -58-H), 4.69 (s, 2 H), 4.74 (m, 1 H), 5.64 (dd, I H), 5.19 (m!
1 H), 6.52 (m, 1 H), 6.92 (m, 1 H), 7.23-7.40 (m, 5 H); ~S
m/e 762 ((M+H)+). Anal. Calcd for C40H~7NsO7S: C, 63.0~;
H, 8.86; N, 9.19. Found: C, 62.95; ~., 8.63; ~, 9.03.
E~ampl~ 22 N-(2-(l3erlzyloyyo-7~hQ~ aTn~no)eth-yl) '(S)-(~(Sl-(' (S!-(A.-(methoxymetho~y~ipe idin-l-~;.')~a=-o~
~;?henyl~ethoxyhe:ca~2midQ~ yclo~eX~ -4 (S) -hvd~ 2 (.s~ -lso~ro~yl~2~an~mld~
A. N-(2-Am7noe~hyl~ nzylca.bam~a~. ~ ssiution o ethylenediamine ~33.4 mL, 30.0 g, 0.500 ~mol) i-. 300 mL
CHC13 was cooled to 0 C, and a solution of N-~benzyloxycarbonyloxy)succinimide (5.0 g, 20.1 mmol) in 150 mL CHC13 was added dropwise over 5 h. The resulting solution was stirred at room temperature overnight. The reaction was extracted with water ~5 x 500 mL) and brine (500 mL), dried ~Na2SO4), filtered and concentrated in vacuo to provide the title coupound (2.58 g, 13.3 mmol, 66 %) as a colorless oil (which solidified upon standing): 1H
NMR (CDC13) ~ 2.81 ~m, 2 H), 3.24 (m, 2 H), 5.10 ~s, 2 P.), 5.25 (br s, 1 H), 7.25-7.40 (m, 5 H).
bu~yloxycarkQnyl~-2~-dim~hyl-4~S)-cyclQhexylmethyl-5(5)-The resultant compound from Example l (1.50 g, 3.64 m~ol), HOR~ (0.837 g~ -5.45 mmol), and N-methylmorpholine tO.600 mL, 0.55 g, 5.45 mmol) were dissolved in 36.5 mL DMF, and the resulting solution was cooled to -15 C. EDCI (978 mg, 5.10 mmol) was added as a solid. The mixture was stirred at -15 C
for 6 h, after which the vessel was se_led and allowed to . .
. .
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..:
~ ' ";'' ' : ' " ' ' ; , : , , ~ , . . , .. . .
.~q92/03429 PCT/US91/055~
~- 2 3 ~ 8 . .
stand at 0 C for 24 h. The resultant compound from Example 22A (885 mg, 4.56 mmol) was added to the solutlon of active ester, and the resultlng solution was stirred at -23 C for 5 h and an additional 24 h at room tem~era~ure.
The reaction mixture was concentrated by dist-llatlon under high vacuum, and the residue was partitioned between 250 mL
80% saturated NaHCO3 and 250 mL CH2Cl2. The or~_nic phase was washed sequentially with 250 mL 80~ sat. ac. Na.~:CO3, 250 mL water and 250 mL brine, dried (Na2SO4), - ltered and concentrated in vacuo. Purirication by _lash chromatography (35% EtOAc-hexane) produced 2.017 ~ (3.43 mmol, 94%) of the title compound as a white po~ N~
(CDCl3) ~ 0.8-1.0 (br m, 8 H), 1.48 (s), 1.57 (bs), 1.63 (bs) and 1.0-1.95 (several br m, ap2roximately 31H total), 2.02 (br m, 1 H), 3.34 (br m, 3 H), 3.46 (br m, l H), 3.56- .
3.7 (br m, 1 H), 3.72 ~br m, 1 H), 5.09 (s, 2 H), 5.47 (br m, l H), 5.99 (br m, 1 H), 7.3 (br m, 5 H); MS m/e 588 ((M+H)+).
C. The procedure of Example 2C was employed, with the substitution of the resultant compound from Example 22B for the resultant compound from Example 2B, to provide the title compound: mp 65-72 C; Rf 0.51 (5~ MeOH-C~2Cl2); 1H
NM~ (CDCl3) ~ O.64-2.10 (several br m, approx. ~6 H), 2.95-3.00 (m, 1 H), 3.04 (dd, 1 H), 3.10-3.59 (br m), 3.35 (s) and 3.37 (s, 13 H total), 3.60-4.00 (br m, 4 H), 4.46-4.57 (br m, 1 H), 4.67 (s, 2 H), 5.10 ~s, 2 H), 5.72-~.90 (br m, 2 H), 6.10-6.20 (br m, 1 H), 7.2-7.45 (m, 10 H); MS m/e 837 ((M+H)+). Anal. Calcd for C47H72N4Og: C, 67.44; H, 8.67;
N, 6.69. Found: C, 67.33; H, 8.79; N, .
.
~,.' " , :
: : . : :- :: ; :.
:,' ~, , . : : , WO92t03429 PCT/US91/05~ -` 2~9~68 -60-N-!?-~e~a~l~eth~l.l 5(.C)-(2(5)-(1(5~-(4-(~e-ho~ym~th~ eridi?~ y1)carhQn~1-2=
Dhenyl)~hoxyheYanamid~L-~-cyclohexyl-~,~s)-llydroxy-2~s)-i so~roDyl~.e:~anamide .
The procedure of Example 4 was employed, with the substitu.ion of the resultant compound from Example 16 fo-the resultant com~ound from Exam~le 3, to provide the title com?ound as a ~h~ e po~der (26~ ~iield): mp 95-99 C; Rf 0.18 (5% MeO-~.-CH2Cl2); 1H N~ (CDCl3) ~ 0.87-0.96 ~ove_~appir.g t ar.d 2 d) and 0.65-1.07 (br m, 8 H ~o~al), 1.07-1.90 (several br m, approx. 26 H), 1.99 (s) and 1.95-2.06 (br m, 4 H total), 2.94 (dd, 1 H), 3.05 (dd, 1 H), 3.13-3.35 (br m, 4 H), 3.38 (s, 3 H), 3.40-3.58 (br m, 5 H), 3.65-3.92 (br m, 3 H), 3.92-4.02 ~br m, 1 H), 4.49-4.57 ~br m, 1 H), 4.68 ~s, 2 H), 5.77 ~2 br d, 1 H), 6.18-6.27 ~br m, 1 H), 6.78-6.84 ~br m, 1 H), 7.32 ~br s, 5 H); MS
m/e 745 ~M+H)+). Anal. Calcd for C41~68N4O8-0.75 H20: C, 64.92; H, 9.23; N, 7.38. Found: C, 64.97; H, 9.16j N, 7.39.
~xam~le 2~
N-(2-(~-Me~hyl-N'-~yanolsothiou~i~Q?ethyl) 5lS)-(2(5)-(1(~s)-(4-~me~h.Qxym~ethoxy)~i~eridi~-L-yl)czrbcny~2-~henyl)ethoxyhexa~amido)-6-~yclQh~yl-4(5)-hydroxy-2($)- --isQ~oRylhexanamld~.
The compound resulting from Example 16 (255.4 mg, 0.3633 ~mmol) and dimethyl N-cyanodithioiminocarbonate (69.1 mg, 0.4732 mmol, 30% excess) were combined in acetonitrile (8 mL) and heated at reflux (90 C oil bath) for 36 hours `~ ' . ~ ~
:,.~, .
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~'~92/0~29 2 0 ~ 8 P~T/US91/~5~
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, under nitrogen. The reaction mixture was concentrated under reduced pressure, and the residue obtained was chromato~raphed on a silica gel column eluting with 3.5~
methanol in methylene chloride to afford the title compound as a white amorphous solid (180 mg, 62~): mp 72-82 C; Rf 0.29 (5~ MeOH-C;i2Cl2); 1H NMR (CDCl3) ~ 0.82-0.98 (m) and 0.65-1.95 (several br m, approx. 38 H total), 1.99-2.09 (m, 1 H), 2.55 (br s, 3 H), 2.94 (dd, 1 H), 3.03 (dd, 1 H), 3.11-3.65 (br m) and 3.39 (2 s, 12 H total), 3.72 (t) and 3.7-3.98 (br m, 4 H total), 3.98-4.10 ~br m, 1 H), 4.52-4.66 (br m, 1 H), 4.69 (s, 2 H), 5.74-5.&7 (m, 1 H), 6.50-6.65 (br m, 1 H), 7.33 (br s, 5 H), 7.85-8.00 (~r s, 1 H);
MS m/e 801 ((M ~)+). Anal. Calcd for C42H63N6O7S: C, 62.97; H, 8.55; N, 10.49. Found: C, 62.68; H, 8.66; N,
For Part 2, the following quantit~es we_e used: c-ude amino alcohol (48.0 mg, 0.130 mmol), HO~ ~2^.~ m~, 0.
mmol), the resultant compound from Exam?le 1 (.~.i mg, 0.142 mmol), N-met~ylmorpholine (14.4 mg, 0.192 .~mol) anà
EDCI (34.8 mg, 0.181 mmol) were reacted in 1.3 mh D~.
Purification by flash chromatography (silica gel, 5~ MeO~-CH2C12) provided 69.0 mg of the title compound as a white powder; mp 87-92 C; Rf 0.58 (15~ MeOH-CH2C12); 1H NMR
(CDCl3) ~ 0.65-2.10 (several m, 33 H~, 0.93 (m, 9 H), 2.92-3.35 (several m, 6 H), 3.37 (s, 3 H), 3.41-3.63 (m, 3 H), 3.68-3.87 (m, 3 H), 3.87-4.05 (bm, 1 H), 4.60 (m, 1 H), 4.69 (s, 2 H), 5.75 (bm, 1 H), 5.80 (m, 1 H), 6.44 (m, 1 H), 7.33 (m, 5 H); MS m/e 760 ((M+H)+). Anal. Calcd for C4lH69N5O8-1.0 H2O: C, 63.29; H, 9.20; N, 9.00. Found: C, 63.28: ~, 9.02: ~, 8.85.
~ ~ ' .
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W092/03429 2 ~ g ~ .~ 6 ~ PCT/USgl/05~
-47- ~_ EX~Im~;> 1~ 1 N-(3-(~mi~Qthionylamino)~rs~yl) 5(.5~-~2(5)-(1(5)-(4-(meth~Yymethoxy~R~ 1-yl)carbonyl 2-~henyl)etho~yhexanami~o~_~-cyslohexvl-4(~)-hvdro~y-2(5)-; isopropylhexanamlde.
A N (3-(AminothiQnylamin~RI~yl ~(5~-((3-(te-t-butyloxycarbony~ m~thyl-~(S)-~clohex~lm~e~hvl-5(~
xazQlidlnyl)methyl)-~m~b~l~ut~emi~. To a solu.ion o-the resultant compound from Example 6A ~127 mg, 0.271 mmol?
in 3.4 mL THF at 0 C was added N,N'-thiocarbonyldiimidazole (67 mg, 0.338 mmol). The solu~ion was allowed to warm to room temDerature and stir 18 h. TL~
~4~ MeOH-CH2Cl2) indicated complete conversion ~o a ne-~
;product. The yellow solution was recooled to 0 C and treated with concentrated aq. NH40H (0.5 mL, 4 mmol). The reaction was stirred at room temperature for 48 h. The olution was concentrated in vacuo to a solid (210 mg), which was purified by flash chromato~raphy (silica gel, 4%
MeOH-CH2C12) to produce 134 mg (0.254 mmol, 94%) of a white solid; Rf 0.31 (5% MeOH-CH2Cl2~; 1H NMR (CDC13) ~ 0.93 (d, 3 H), 0.96 (d, 3 H), 0.8-1.0 (bm, 2 H), 1.05~1.S ~bm, 7 H), 1.98 (s, 9 H), l.S7 (bs~, 1.66 (bs) and 1.55-1.90 (several bm, 15H total), 2.1 (bm, 1 H), 3.30-3.42 (bm, 2 H), 3.5-3.75 (bm, 4 H), 5.72 (bs, 1 H), 6.08 (bs, 1 H), 7.45 (bs, 1 H); MS m/e 527 ((M+H)+).
Using the procedure of Example 2C, the resultant compound of Example 7a was deprotected and coupled to the resul~ant compound from Example 1 to provide the desired compound as a white solid (59%): mp 83-89 C; Rf 0.38 ~5%
MeOH-CH2Cl2); lH NMR (CDC13) ~ 0Ø73 (br m, 2 H), 0.8-1.0 (m, 10 H), 1.05-1.94 (several br m, approximately 25 H
'' , .
.,. ~
, , , , ~ ~ , . . . . .
' : '' ,, , .: , W092/0~29 PCT/US9l/05~
~o~9~68 -48-total), 2.0 ~br m, 1 H), 2.9-3.13 (m, 3 H), 3.2 (br m, 1 H), 3.25-3.4 (br m, 1 H),. 3.38 (2 s, 3 H), 3.4-3.67 (br m, 4 H), 3.72 (m, 1 H), 3.75-3.9 (br m, 2 H), 4.0 (br m, 1 H), 4.62 (br m, 1 H), 4.70 (2 s, 2 H), 5.72 (dd, 1 H), 6.18 (br s, 1 H), 6.45 (br s, 1 H), 7.33 (br s, 5 H); MS m/e 776 ((M~H)~). ~nal. Calcd for C41H6gN5O7S 0.75 H2O: C, 62.37;
H, 9.00i N, 8.87. Found: C, 62.38; H, 8.88; N, 8.87.
Le ~
r~-^r~ 5(~)-(?(S~ (S)-!~-J~ r ~ :n o ~y ) ~ ) ca ~ bQn-v l= 2 -b n,r n,~ 'f ~ , ' dQl ~ o~cyC l ohex~ 1-4 ( S) -hydroxy-2 ( ~! -i sopropyln~x~n~mid~
. N- (Cyan.omQ~u~ - 2(s!-((3-(tert-~utyl~y~ Q~lL=
2l~=.di.me~byl-4(5)-cy~ lohexylmethyl-~(S)-oxazclidinyl~methyl)-3-methylbutanamide The procedure of Example 2B was used, substituting aminoacetonitrile hydrochloride for 3-~benzyloxycarbonylamino)propylamine.
Purification by flash chromatography (silica gel, EtOAc-hexane 1:3) pro~ided 513 mg (1.14 mmol, 94%) of the title compound as a white foamy solid: Rf 0.20 (EtOAc-hexane 1:3); 1H NMR (CDC13) ~ 0.94 ~d, 3 H), 0.97 (d, 3 H), 0.85-1.05 (bm, 2 H~, 1.05-1.53 (several bm, 5 H), l. 48 (s, 9 H), 1.49 (s, 3 H), 1.59 (s, 3 H~, 1.55-1.85 (several bm, 8 H), 1.85-1.98 ~m, 1 H), 2.1-2.2 (bm, 1 H), 3.55-3.7; ~bm, 2 H), 4.21 (ABX, 2 H), 6.06 (bt, 1 H).
:: `
~_ The procedure of Example 2C can be used, in which ` the resultant compound from Example 8A is deprotected and coupled to the resultant compound from Example 1 to provide the desired compound.
.' .
~ .
:'~
. . .
. , W~92/0~29 P~T/~S91/05524 20~9268 -i .. ?
. Y.~
vl)ca banv7-2-?he~ )o~hoYvhexanami~o)~thyl 3(5~-iso~oropyl-2.~.4.5-~et~ahydr~rura~-2-one.
The resultant com?ound from Example 1 was coupled .o (2S,4S, 5â) -5-amino-6-cyclohexyl-4-hydroxy-2-isopro?ylhe;~.anoic acid lactone (3ra~bury, R. H.; ~evill, J.
M.; Rivett, J. E.; ~at~-sor., D. Tet_ahedron Let.. 1989, 3845) according to the orocedure of _~ample 2C, Part 2, to obtain the deslre~ product in 80% yleid: 1 N~R (CDC13) 0.89 (m), 0.91 (d), and 1.0 (d, 9H total), 0.70-1.9 (several bm, 27H app-^xim~Lely), 2.1 (m, 1 H), 2.~5 (m, 2 H), 2.8; (m, 1 H), 3.0~ (dd, 1 H), _.5-3.8 (m, 4 H), 4.5 (m, 1 H), 4.7 (d, 2 H), 5.35 (d) and 5.45 (d, 1 H total), 7.4 (bm, 5 H); MS m/e 643 ((M+H)~).
!-(2(~-(l(S)-~4-(m~thoxym~thQ~yLpi~ri~in~l-yl)carhonyl-2-~h~nyl!ethQxy~=~D~m~s~-6-~ycLohex~l-4(s)-hyd~oxy-2(s) isQ~opylhexanamid~
The resultant compound from Example 9 (50.3 mg, 0.0782 mmol) was combined with 1,2-diamino-2-methylpropane (138 mg, 1.56 mmol) and the mixture was warmed to 60 C for 3 days. The reaction mixture was partitioned between 20 mL
EtOAc and 10 m~ water. The organic phase was washed sequentially with 5 mL water, 10 mL brine, then dried ~Na2SO4), filtered, and concentrated in vacuo to yeild 52.6 mg of white solid. The crude product was purifed by preparative TLC (10~i MeOH-0.5% concentrated aq. NH40H-CH2Cl2) to produce 41.6 mg (0.0563 mmol, 73% of a foamy - . .
- : : : ~ ~ .
.. . ...
:~ , ' ;'' '. . , , :.
WO 92/03429 PCr/US91/0~524 -_ solid: mp 48-56 C; Rf 0.44 (15% MeOH-l~ concentrated aq.
NH4OH-CH2Cl2); 1H NMR ~CDCl3) ~ 0.88-0.97 (m, 9 H), 1.14 (s), 1.16 (s) and 0.6-2.2 (several bm, 33H approx-ma_e'y), 2.93-3.2 (bm, 4 H), 3.2-3.46 (bm, 4 H), 3.36 ~s, 3 ~
3.46-3.6 (bm, 1 H), 3.6-3.95 (several bm, 4 H), 4.50 (dd, 1 H), 4.67 (AB, 2 H), 5.85 (d) and 5.94 (d, lu totzl), 5.~3 (bs, 1 H), 7.32 (bm, 5 H); MS m/e 731 ((M+H)+)).
N-(~-~4-~o-?hQ' ro~rQ~yl) -(S) - (2 (S) - ! ~ ( `~ - ( '-(~eti~xym~th phe~ t:~o::yne~an2m~ d~-)-6-cycl~eY~J~ -4~S)-~yd ~:v-^~
~Q~rQ~lh~a~e~
'' A mixture of the resultant p-oduct from Example 9 (60 - mg, 0.093 mmol) and 3-~4-morpholino)propylamine (150 mg, 1.04 mmol) was stirred at 60-65 C for 32 h. The mixture was diluted with EtOAc and washed with water. The organic portion was dried, filtered and evaporated. The residue `, was column chromatographed ~silica gel, 2 to 5% MeOH-CHCl3), providing 73 mg (0 058 mmol, 62~) of the desired product. The product obtained from t:his procedure is I spectroscopically identical to the compound prepared -I prevlously (PCT Patent Application WO 90/03971, 19-4-30) .
~-~ E~aTn~?~ 1?
A. 4-(4-Morpholinolhut;~lamine. A mixture of 4-chlorobutyronitrile (4.23 g, 40.86 mmo ) and morpholine . .
`
W~92/0~29 PCT/~S91/0~5~
~3~
: . . ..... . ~.. . ~.. .... . . . . .
(10.68 g, 122.59 mmol) was stirred at room temper2ture until the mixture solidified. It was diluted with EtOAc, washed with water. The organic portion was dried, .iltered and evaporated to obtain 4.0 g (25.3 mmol, 65~) of a yellowish liquid: 1H NMR (CDCl3) ~ 1.85 (q, 2 H), 2.95 (m, 8 H), 3.7 (m, 4 H); MS m/e 155 ((tM+H)+). 2.0 g (13 mmol) of the above resultant liquid was hydrogenated under a atmospheres hydrogen with ethanolic ammonia and ~an~y nickel for 16 h. The mixture was filtered and t:~e filtr~
-- was evaporated to obtain 1.5 g (9.5 ~mol, 73~) o. the desired product: 1H NMR (CDCl3) ~ 1.55-1.8 (m, ~ H), 2.5 (m, 8 H), 3.75 (m, 4 H); MS m/e 159 (((M+H)+).
literature procedure, see J. Amer. rhem. So_. 19~ 3, ;~ 156.
B. The title campound was prepared according to the procedure of Example 10 by replacing 3-(4-morpholino)propylamine with the resu:Ltant compound from Example 12A, to produce the desired amide ~55% yield): lH
NMR (CDCl3) ~ 0.90 ~m, 9H), 0.70-1.90 ~several br m, 30H
. total), 2.02 ~m, lH), 2.35 ~br m, 6H), 2.95 ~m, lH), 3.05 (dd, lH), 3.20 (br m, 2H), 3.40 (s, .~H), 3.60-4.0 (several br m, 10H total), 4.50 (dd,lH), 5.78(d) and 5.85 (d, lH
total), 6.20 (bt, lH), 7.30 (br m, 5H); MS m/e 802 . ((M+H)I).
.
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W092/03q29 PCTtVS91/0~S2q~
~9'~6~ -52-Exam~le 13 N-(5-(4-Mor~holinQ)Denty~ ~(5)-(2(.sL ~4-(me'ho:-~re~o~v~iperidi~.-l-yl)ca~bonyL=2-; ph~l)P~hoxvh~ ?.~id~-6-cycLoh.eYy~ -h.yd-oYv 2--(~-.~ lso~ro~ylhexa~amid~.
A. 5-(4-~.,o-~k.olino!_~entY1am1ne. The title compound may be ~re~ared according ~o the procedure of r.xample 12A, by subslituling ~-chloropentanonitrile for 4-chlorobulyronl--ile.
The titie compound may be prepared according to the procedure of Exam~le 10 by replacing 3-(4-mo-phollno)pro?ylamine with the resultant produc_ of Example 13A.
, .
N-t3-t3-Oxa-9-azahicyclor3.3 ll~Qna~-9-~l)~ropyl) 5(S)-t2tS)-(4.-tmethoxym~ho~yLeiperidin-1-yl)carbonyl-2-_ -4l5)-hYdroxy-2-(S)-A. 3-(3-O~-~-a~biGyclo[3.3.LLnonan-q-:,yl)pro~yla~l2e. This compound can be prepared according to .the procedure of Example 12A, but replacing morpholine with 3-oxa-9-azabicyclo~3.3.1]nonane.
B. The title compound can be prepared according to the procedure of Example 10 by replacing 3-(4-.morpholino)propylamine with the resuitant amine from Example 14A.
.
.
': :' ~'' ' ' WO92/03429 2 ~ PCT/~JS91/05524 N-(3-(~-O~ ~æ~oy~1o r ~ . 2 .1~ ~ n--8--y1~ ~L~y1~ 5 t S) ~
(2(c~ hQ~:y~P~tho~ pl~ rdln-~ .)ca-~Qny~-2-Dh~nyl)etho~yhP~anamldo)-6-cyclQhexvl-4LS)-hycrQ~y-2-(~
i~o~ro~y'hex~n.amide.
y'~ o~vlzmtnP~ T:~is compound can be prepared according to t:n- ?rocedurP ~ ample 12A, by re?lacing mor?holine wlth 3-o:~a-8-a-a blc~;_ or3.2.1]oc_ane.
. T~e z ~le com?ound can be prepared according to thP procedure o- rxample 10 by re~lacing 4-(3-aminopropyl)morpholine with the resultant amine from Example 15A.
~xa~le 1~
M-l2-~ml~Qet~lL_~lS)-(2(S)-(9-(methoxymethoxy)piperidi~L-1-yl)~ar~Qnyl-2-phenyl)ethoxyhexanamidQ)-6-cyclQhexyl~lS~-h~r~xy-2~t~ Q~y~b98an~mL~ç~
The title compound was preparecl according to the procedure of Example 10 by replacincJ 4-(3-aminopropyl)morpholine with 1,2-diaminoethane:as a white foam (87% yield): mp 62-67 C; Rf 0.28 (10% MeOH-1% conc aq. NH4OH-CH2CL2); lH NMR ~CDCl3) ~ 0.67-1.92 (several br m, approx. 35 H ), 2.08 (m, 1 H), 2.37-4.00 ~several br m, ap~rox. 17 H ), 3.37 (s, 3 H), 4.54 (m, 1 H), 4.68 (s, 2 H), 5.83 (dd, 1 H~, 6.36 (m, 1 H), 7.28-7.38 (m, 5 H); MS
m/e 703 ((M+H)+). Anal. Calcd for C3gH66N4o7 o-5 H2O: C, 65.79; H, 9-.48; N, 7.86. Found: C, 65.68; ~, 9.27; N, 7.8S.
.~ .
. .
:
WO 92/03429 PCT/~S91/0S5~ -_ 0 ~ 54-E~am~le 17 N-(~-Aminohutyl) 5(~)-(2(5)-~4-(merho~:yme.ho y)~lp~r~din-~-~ y1)ca~o~l~l-2-~hen~l)etho~yhe~an2~id^~-~-cyo ~h~Yy~ S)-:j hyd~oxy-2,,-(5)-iso~ro~ylhe~anami~e.
The title compound was prepared according .o the -~ procedure of Example 10 by replacing 4-(3-aminopropyl)morpholine with 1,4-dia~.inobutan~: m~ 88-9G
C; 1H NMR (CDCl3) ~ 0.80-0.90 (m, 9 ~), 1.05-1.8C (b/ ~, 30 H), 2.13 (dd, 1 H), 2.5~ (br t, 2 ~), 3.00 (.~., 9 H), 3.20-3.65 (m, approx. 7 H), 3.75 (.,~, 2 H), 3.85 ~m, 1 n), 4.50 (m, 2 H), 4.60 (br s, 2 H), 6.72 (d, 1 H), 6.76 (d, 1 H), 7.25 (br s, 5 E~), 7.80 (m, 2 H); ~S m/e 732 ((M~H)~) . E~am~l~
N-(5-Amino~entyl) 5($)-~2ls)-~4-LmethoKy~etho~)pi~e~id~i~-L-yl!car~Q~y1-2-phenyl)etho~yhe~anamido!-6-cyclohexyl-~LS)-LSL~bL4~ namide.
The title compound can be prepared according to the procedure of Example 10 by replacing 4-(3-aminopropyl)morpholine with 1,5-diaminopentane.
.c Example l9 N-(3-Amlno-3-methyLbutyl~ s(s)-(2Ls)-(l(s)-(a (methoxy~m~thoxy)~iper;d~ -yl)oa~onyl-2-.,......... -- -- .
,~ ~
A~ 1-~z~do-2-L~en~lQ~ycarbonylam~no)-2-methylbutane.
2-(Benyloxycarbonylamino)-2-methyI-1-butanol (1.358 g, 5.722 mmol) and triphenylphosphine (1.800 g, 6.86 mmol) were dissolved in 10 mL CH2Cl2, and the resulting solution ~- , , .. . ~ - . :
... : . :.: .
~, : ., " .,. :. ~ . , , : . :
:. .: : , ~ ,., .~ , ... : ,, , W092/0~29 2 ~ ~ ~ 2 ~ 8 PCT/US91/055~
., .. . . .. . .
.
was cooled to 0 C. A solution of hydrazoic acid (prepared from sodium azide (1.30 g, 20.0 mmol), 0.~33 mL
concentrated sulfuric acid and 1.3 mL water) i.. 20 mL
CH2Cl2 was passed through a plug o~ MgSO4, the iltrate was added to the above alcohol solution, then diisc?-opyl azodicarboxylate (1.35 mL, 1.40 g, 6.91 mmol) h-as added dropwise over 3 min. The reaction mixture was stirred a~ C
C for 1 h, then at room temperature ror 5 h. ~ - mlxture was concentrated in vacuo, and the residue was ap~lied to 300 g of silica gel in a fritted disc runnel 2-.~ eluted with 3 x 500 mL of 10% EtOAc-hexane. The secon~ fraction contained pure desired azide (0.822 g, 3.13 mm^l, 55~) as 2 colorless oil: Rf 0.17 (10~ EtOAc-hexane); 1~ CDCl3) 1.33 (s, 6 H), 2.02 (bt, J = 7.5 Hz, 2 ~), 3.32 (bt, J =
7.5 Hz, 2 H), 4.74 (br s, 1 H), 5.05 (s, 2 H), 7.3-7.4 (m, 5 H); MS m/e 263 ((M~H)+), 280 (M+NH~)+).
r ~ yl) 2 ~ ( (3~t-cyclohexylm~hyl-5(S)-oxa7~11~inyl)meth~1L=3=o~LhylbL~3c~mi~_ The resultant compound from Example 19A (102 mg, 0.389 mmol) was stirred with 10% palladium on carbon (20 mg) in 1 mL EtOAc under 1 atm H2 for 17 h. The solvent was removed with a stream of N2, the residue was suspended in 3 mL MeOH, and then a solution of HCl in dioxane (0.16 mL, 4.8 M, 0.758 mmol) was added. After stirring for 1 h, the mixture was filtered through celite, and the ~iltrate was rotoevaporated and the residue placed under high vacuum to produce the corresponding diamine dihydrochloride (72 mg, 0.40 mmol, 103~ as a white foamy solid: lH NMR (CD30D) ~ 1.40 (s, 6 H), 2.04 (m, 2 H), 3.06 ~m, 2 H). The above crude diamine dihydrochloride (60.2 mg, 0.344 mmol) was coupled according ' : .:
: . : . ,., :, :.
, W092/03429 P~T/~S9~/05524 _ to the procedure of Example 2B to provide (after flash chromatography, eluting with 12.5% MeOH-1% concentra~ed aq.
~ NHgOH-CH2Cl2) the title compound (85.5 mg, 0.186 mmol, 67%) - as a glass: ~f 0~34 (10~ MeOH-1% concentrated aq. NH40H-; CH2Cl2); lH NMR (CDC13) ~ 0.93 t2 d, 6 H), 1.17 (2s, 6 H), 1.48 (s, 9 H), 0.8-1.8 (several br m, approximately 23H
total), 1.85 (m, 1 H), 2.02 (m, l H), 3.36 (m, l H), 3.44 ~m, 1 H), 3.6q (br m, 1 H), 3.76 (m, l H), 6.96 (bt, l H);
~S m/~ 436 ((M~H) ).
C The proceaure of Example 2C was used. The resui~ant compound from Example 13~ (73.5 mg, 0.148 mmol) was deprotected to give 55.5 mg (01156 mmol, 105%) of the corresponding crude diamino alcohol as a yellow viscous ; oil: 1H NMR (CDCi3) ~ O.93 (2 d) and 0.75-1.05 (br m, 9H
total), 1.15 (s, 6 H), 1.05-1.9 (several br m, approximately 24 H), 2.09 (m, 1 H), 2.60 (br m, 1 H), 3.39 (m, 2 H), 7.09 (br m, 1 H); MS m/e 356 ((M+H)+). The crude amino alcohol was then coupled using the following i quantities: crude diamino alcohol (52.4 mg, 0.127 mmol), , the resultant compound from Example 1 (55.0 mg, 0.134 mmol), HOBT (31.2 mg, 0.204 mmol), N-methylmorpholine (28 mL, 26 mg, 0.255 mmol) and EDCI ~32 mg, 0.167 mmol) in 0.6 mL DMF. Purification by flash chromatography (10% MeOH-0.5% concentrated aq. NHqOH-CH2Cl2) produced 59.0 mg (0.079 mmol, 62~) of the title compound as a white foam: mp 44-49 C; 1H N~R (CDCl3) ~ 0.86-0.95 (m, 10 H), 1.195-1.21 (2 s, 6 H), 0.65-2.5 (several br m, approximately 33 H), 2.96 (m, ~
l H), 3.04 (dd, 1 H), 3.36 (s, 3 H), 3.72 (t, 2 H), 3.1-4.0 (several br m, approximately 8H total), 4.57 (m, 1 H), 4.68 (s, 2 H), 5.85 and 5.91 (2 d, lH to.al), 7.32 (br s, 5 H), 7.41 (br m, 1 H); MS m/e 745 ((M+H) T) ~ Anal. Calcd for '' . : ~ : ' ' ' . '. '' . :
., . ' .~:
,, : - . ~ . . .
: ' ~ ' ' . : ''-'' :
2~8~2~g WO9~/0~29 PCT/US9l/055 .;
. . , . , . i "
C42H72NaO7 1.5 H2O: C, 65.34; H, 9.79; N, 7.26. Found: C, 65.57; H, 9.41; N, 7.24.
.
N-~2-Ureido)e~hyl 5(5~-r2(~
(Tnetho~yme~noxy)~l~eridin-l-yl)ca~honyl-2 h ~a~2mldo)-6-cy~lohey~yl-4(s)-hyd~oy~y-2(s) lsQ~ro~yl h.ex~n.?!nide .
The procedure or Example 6~ was used, substituting the resultan~ p-oduct from Example 16 for the resultant product from Exampie 6A, to provide the title compound as a ~hite powder (39~ yield): mp 85-92 C; Rf 0.43 (10 ~ MeOH-CH2Cl2); 1H NMR (CDCl3) ~ 0.55-1.98 ~several br m, 36H
approximately), 2.84-3.88 (several br m, 14 H), 3.38 ~d, 3 H), 3.95-4.18 (br m, 1 H), 4.68 (s, 2 H), 4.71 (br m, 1 H), 5.09 (br m, 2 H), 5.50 (br m, 1 H), 5.66 (dd, 1 H), 6.22 (br m, 1 H), 7.27-7.38 (br m, 5 H); MS m/e 746 ((M+H)~).
Anal. Calcd for C40H67NsOg-1.25 H20: C, 62.51; H, 9.11; N, 9 11. Found: C, 62.38; H, 8.72; N, 8.95.
E~am~Le 21 N- (2- (Thioureido! ethyl 5 ! s) - (2 (~) - (L(S) - (4-~o ~j~-yl) car~2on~-2 `~'' iSo~roF)y~ h.e~canam.;~e .
The procedu~e of Example 7A was used, substituting the resultant product from Example 16 for the resultant product from Example 6A, to provide the title ~ompound as a white powder (52% yield): mp 98-112 C; Rf 0.40 ~5~ MeOH-~; CH2Cl2); 1H NMR (CDCl3) ~ 0.51-1.96 (several br m, 37H
approximately), 2.81-4.26 ~several ~r m, 15 H), 3.48 (d, 3 :, ~,., ,. . . ..
,:
W~92/0~29 PCT/US9~/0~5~ .~
. :
... , .. , . ~. ~ ,. .. . . ..... .
~ 2~ 8 -58-H), 4.69 (s, 2 H), 4.74 (m, 1 H), 5.64 (dd, I H), 5.19 (m!
1 H), 6.52 (m, 1 H), 6.92 (m, 1 H), 7.23-7.40 (m, 5 H); ~S
m/e 762 ((M+H)+). Anal. Calcd for C40H~7NsO7S: C, 63.0~;
H, 8.86; N, 9.19. Found: C, 62.95; ~., 8.63; ~, 9.03.
E~ampl~ 22 N-(2-(l3erlzyloyyo-7~hQ~ aTn~no)eth-yl) '(S)-(~(Sl-(' (S!-(A.-(methoxymetho~y~ipe idin-l-~;.')~a=-o~
~;?henyl~ethoxyhe:ca~2midQ~ yclo~eX~ -4 (S) -hvd~ 2 (.s~ -lso~ro~yl~2~an~mld~
A. N-(2-Am7noe~hyl~ nzylca.bam~a~. ~ ssiution o ethylenediamine ~33.4 mL, 30.0 g, 0.500 ~mol) i-. 300 mL
CHC13 was cooled to 0 C, and a solution of N-~benzyloxycarbonyloxy)succinimide (5.0 g, 20.1 mmol) in 150 mL CHC13 was added dropwise over 5 h. The resulting solution was stirred at room temperature overnight. The reaction was extracted with water ~5 x 500 mL) and brine (500 mL), dried ~Na2SO4), filtered and concentrated in vacuo to provide the title coupound (2.58 g, 13.3 mmol, 66 %) as a colorless oil (which solidified upon standing): 1H
NMR (CDC13) ~ 2.81 ~m, 2 H), 3.24 (m, 2 H), 5.10 ~s, 2 P.), 5.25 (br s, 1 H), 7.25-7.40 (m, 5 H).
bu~yloxycarkQnyl~-2~-dim~hyl-4~S)-cyclQhexylmethyl-5(5)-The resultant compound from Example l (1.50 g, 3.64 m~ol), HOR~ (0.837 g~ -5.45 mmol), and N-methylmorpholine tO.600 mL, 0.55 g, 5.45 mmol) were dissolved in 36.5 mL DMF, and the resulting solution was cooled to -15 C. EDCI (978 mg, 5.10 mmol) was added as a solid. The mixture was stirred at -15 C
for 6 h, after which the vessel was se_led and allowed to . .
. .
`', ' :. .
..:
~ ' ";'' ' : ' " ' ' ; , : , , ~ , . . , .. . .
.~q92/03429 PCT/US91/055~
~- 2 3 ~ 8 . .
stand at 0 C for 24 h. The resultant compound from Example 22A (885 mg, 4.56 mmol) was added to the solutlon of active ester, and the resultlng solution was stirred at -23 C for 5 h and an additional 24 h at room tem~era~ure.
The reaction mixture was concentrated by dist-llatlon under high vacuum, and the residue was partitioned between 250 mL
80% saturated NaHCO3 and 250 mL CH2Cl2. The or~_nic phase was washed sequentially with 250 mL 80~ sat. ac. Na.~:CO3, 250 mL water and 250 mL brine, dried (Na2SO4), - ltered and concentrated in vacuo. Purirication by _lash chromatography (35% EtOAc-hexane) produced 2.017 ~ (3.43 mmol, 94%) of the title compound as a white po~ N~
(CDCl3) ~ 0.8-1.0 (br m, 8 H), 1.48 (s), 1.57 (bs), 1.63 (bs) and 1.0-1.95 (several br m, ap2roximately 31H total), 2.02 (br m, 1 H), 3.34 (br m, 3 H), 3.46 (br m, l H), 3.56- .
3.7 (br m, 1 H), 3.72 ~br m, 1 H), 5.09 (s, 2 H), 5.47 (br m, l H), 5.99 (br m, 1 H), 7.3 (br m, 5 H); MS m/e 588 ((M+H)+).
C. The procedure of Example 2C was employed, with the substitution of the resultant compound from Example 22B for the resultant compound from Example 2B, to provide the title compound: mp 65-72 C; Rf 0.51 (5~ MeOH-C~2Cl2); 1H
NM~ (CDCl3) ~ O.64-2.10 (several br m, approx. ~6 H), 2.95-3.00 (m, 1 H), 3.04 (dd, 1 H), 3.10-3.59 (br m), 3.35 (s) and 3.37 (s, 13 H total), 3.60-4.00 (br m, 4 H), 4.46-4.57 (br m, 1 H), 4.67 (s, 2 H), 5.10 ~s, 2 H), 5.72-~.90 (br m, 2 H), 6.10-6.20 (br m, 1 H), 7.2-7.45 (m, 10 H); MS m/e 837 ((M+H)+). Anal. Calcd for C47H72N4Og: C, 67.44; H, 8.67;
N, 6.69. Found: C, 67.33; H, 8.79; N, .
.
~,.' " , :
: : . : :- :: ; :.
:,' ~, , . : : , WO92t03429 PCT/US91/05~ -` 2~9~68 -60-N-!?-~e~a~l~eth~l.l 5(.C)-(2(5)-(1(5~-(4-(~e-ho~ym~th~ eridi?~ y1)carhQn~1-2=
Dhenyl)~hoxyheYanamid~L-~-cyclohexyl-~,~s)-llydroxy-2~s)-i so~roDyl~.e:~anamide .
The procedure of Example 4 was employed, with the substitu.ion of the resultant compound from Example 16 fo-the resultant com~ound from Exam~le 3, to provide the title com?ound as a ~h~ e po~der (26~ ~iield): mp 95-99 C; Rf 0.18 (5% MeO-~.-CH2Cl2); 1H N~ (CDCl3) ~ 0.87-0.96 ~ove_~appir.g t ar.d 2 d) and 0.65-1.07 (br m, 8 H ~o~al), 1.07-1.90 (several br m, approx. 26 H), 1.99 (s) and 1.95-2.06 (br m, 4 H total), 2.94 (dd, 1 H), 3.05 (dd, 1 H), 3.13-3.35 (br m, 4 H), 3.38 (s, 3 H), 3.40-3.58 (br m, 5 H), 3.65-3.92 (br m, 3 H), 3.92-4.02 ~br m, 1 H), 4.49-4.57 ~br m, 1 H), 4.68 ~s, 2 H), 5.77 ~2 br d, 1 H), 6.18-6.27 ~br m, 1 H), 6.78-6.84 ~br m, 1 H), 7.32 ~br s, 5 H); MS
m/e 745 ~M+H)+). Anal. Calcd for C41~68N4O8-0.75 H20: C, 64.92; H, 9.23; N, 7.38. Found: C, 64.97; H, 9.16j N, 7.39.
~xam~le 2~
N-(2-(~-Me~hyl-N'-~yanolsothiou~i~Q?ethyl) 5lS)-(2(5)-(1(~s)-(4-~me~h.Qxym~ethoxy)~i~eridi~-L-yl)czrbcny~2-~henyl)ethoxyhexa~amido)-6-~yclQh~yl-4(5)-hydroxy-2($)- --isQ~oRylhexanamld~.
The compound resulting from Example 16 (255.4 mg, 0.3633 ~mmol) and dimethyl N-cyanodithioiminocarbonate (69.1 mg, 0.4732 mmol, 30% excess) were combined in acetonitrile (8 mL) and heated at reflux (90 C oil bath) for 36 hours `~ ' . ~ ~
:,.~, .
' .
:: . - - .
. .
,. ~ . .. : , .: . . . :. .. . . .
~. .: . .~: ' '" ' .
:
: :, ~ .. > .:
,. :. . : .
~'~92/0~29 2 0 ~ 8 P~T/US91/~5~
~ . ,. . ~ .; .
, under nitrogen. The reaction mixture was concentrated under reduced pressure, and the residue obtained was chromato~raphed on a silica gel column eluting with 3.5~
methanol in methylene chloride to afford the title compound as a white amorphous solid (180 mg, 62~): mp 72-82 C; Rf 0.29 (5~ MeOH-C;i2Cl2); 1H NMR (CDCl3) ~ 0.82-0.98 (m) and 0.65-1.95 (several br m, approx. 38 H total), 1.99-2.09 (m, 1 H), 2.55 (br s, 3 H), 2.94 (dd, 1 H), 3.03 (dd, 1 H), 3.11-3.65 (br m) and 3.39 (2 s, 12 H total), 3.72 (t) and 3.7-3.98 (br m, 4 H total), 3.98-4.10 ~br m, 1 H), 4.52-4.66 (br m, 1 H), 4.69 (s, 2 H), 5.74-5.&7 (m, 1 H), 6.50-6.65 (br m, 1 H), 7.33 (br s, 5 H), 7.85-8.00 (~r s, 1 H);
MS m/e 801 ((M ~)+). Anal. Calcd for C42H63N6O7S: C, 62.97; H, 8.55; N, 10.49. Found: C, 62.68; H, 8.66; N,
10.33.
, :
_)--(2ts)--(l(s)--(4--;`tmethoxymethoxy!~ipe~ yl)~arbonyL-2-Dhenyl)ethoxyhexan~midQ)-6-cyclohexy~-4(S)-hydroxy-2(S)-isopropylhexanamide.
To the compound resulting from Exam?le 24 (75 mg, 0.09~6 mmol) dissolved in ethanol (2 mL) was added ammonium hydroxide (732 ~L, 13.724 mmol, 200 equivalents). The reaction vessel was sealed and heated at 90 C for 72 hours. The reac.ion mixture was concentrated under reduced pressure to afford crude material (67.1 mg).
Chromatography on silica gel eluting with 4% methanol in methylene chloride afforded the title compound as a white powder (35.7 mg, ~0%): mp 92-99 C; Rf 0.53 (10% MeOH-CH2Cl2): 1H N~R (CDCl3) 6 0.50-1.94 (several br m, 36 3 .
:. . ': : . .:. ;.:
,: .: : .,; .:, .
- . ", ' ' . ' . ' ' ' '~' ' ' ' .
W092/03429 PCT/US91/055~ -~
20~92~8 .. . .. ... . ~
. .
approximately), 2.82-4.15 (several br m, 15 H
approximately), 3.48 (d, 3 H), 4.65 (m, 1 H), 4.71 (d, 2 H), 5.60 (dd, 1 H), 5.83 (m, 0.5 H), ~.04 (m, 1 H), 5.22 (m, 2 H), 6.31 (m, 0.5 H), 7.29-7.40 (m, 5 H); ~S m/~ 77 ((M+H)+). Anal. Calcd for C41H67N7O7: C, 63.95; H, 8.77 N, 12.73. Found: C, 62.05; H, 8.38; N 13.03.
Ey~ 2 (N-~e~ L-N'-cyan~ur~1do)?th.yl~ 5(~`~-(2(~CI-( (m~tho~ym~hQxy)~pe~id~ n - 1 - ~ ) C~ - DO?.
~ ~henyllethox~,~hey.~n~ido)~ y~l^n;~ 7-4(c~ o--~-;: i so~rogyl hex~r,,z~l The procedure of Example 25 can be employed, wlth th~
substitution of 40% aq. methyl amine for 30~ aq. N~40~., tO
provide the title compound.
E~m~le 27 ~-(2-~L~i~minQ=1fiL-1 2~4-~iazol-5-yl)aminQ)ethyl) 2(S)-((3-(tert-~utyloxycarbonyl)-2 2-dim~hyl-4(~L~ycl~h~ylm~thyl-~(S)-oxazolidinyl!methyl)-3-m~thyl~u~n~mide.
The procedure of Example 25 W2S employed, with the substitution of hydrazine hydrate ror 30~ aq. NHqOH, to provide the title compound as a white powder ~69% yield):
mp 99-112 C; Rf 0.42 (10% MeOH-CH2Cl2 w/1% conc NH40H
. added); 1H NMR (CDCl3) ~ 0.53-1.90 tseveral br m, 35H
approximately),~l.99 (m, 1 H), 2.50-5.00 (vbr m, 3H
, - approximately), 2.88-4.1-0 (several br m, 15 H), 3.38 (d, 3 H), 4.68 (d, 2 H), 9.71 ~m, 1 H), 5.11 (br s, 1 H), 5.73 (dd, 1 H), 6.78 (br s, 1 H), 7.29-7.39 (m, 5 H); MS m/e 785 ((M+H)+). Anal. Calcd for C41H68N8O7-1.0 H2O: C, 61.32;
H, 8.78; N, 13.95. Found: C, 61.~7; :~, 8.75i N 13.58.
~ .
.. .
. .~
: . .. ,,, : : .. . .
, : - -: ,, . :
~ W~2/03429 2 0 8 9 2 ~ ~ PCT/U~9l/0~5~
. . . .~ _ .
, . ,; .
: -63-~L~
N-(2-((5-~mino-l 2,a-oxa~iazQl-5-yl)am~o)eth~l) 2~5)~
(~r~hutylQ~yca~bony~ -2 2-dimeth.yl-4(5)-cyc'~he~:yl m~5 5(.S)-oxazolid~n~l)methyl)-8-me_hyl~lltan~m-de.
The procedure of Example 25 can be employed, witn ~ne substitution of hydroxylamine hydrochloride and a mola~
equivalent quantit~i~ of triethylamine for 3C~ a . Ni4OH, ~o provide the title compound F.~am~l 5 29 ~- (5- ~Tetrazolyl)m~thyl 5 (S) - (? (~S~
(met~oxyrnet ho~cy~ erid;.n~ 1 ) ca~ ' -2-envl)ethQxyhexan~mido)-6-~yslo~s~yl-4(.C)-h~d~o~y-2(5)-i soDroDyl~canarnA- N-(5-(TetrazolylLmethyl 2(S)-((3-(tert-cyclohexylmethyl-5(S)-oxazolidin~l)methyl)-3-methylhutanami~s_ A solution of the resultant compound from Example 8A ~150 mg, 0.334 mmol), triethylamine hydrochloride (68.9 mg, 0.500 mmol) and sodium azide (65.1 mg, 1.00 mmol) in 3.3 mL DM~ was warmed to 125 C for 24 h. The dark solution was conce?.tr2ted under high vacuum, and the resulting oil was poured into a mixture of 10 mL water and 10 mL CH2C12. The mixture was acidified to pH 1 with 1 N HCl. The layers were stirred, then separated, and the aqueous phase was extracted with 2 x 20 mL CH2C12. The com~ined organic phases were ~ashed with brine, dried (Na2SO4), filtered and concentrated in vacuo to produce 168 mg (0.341 mmol, 102%) of crude tetrazole: Rf 0.32 ~5% MeOH-0.5~ HOAc-CH2C12); lH NMR
(CDC13) ~ 0.91 (d), 0.96 (d), and 0.8-1.0 ~br m, 8H total), .
, . .
. .
.- ~ ,... , ,.,,, ., .~.
.
. .: . , .
: . . . . .. . . . . .
WO92/03429 PCT/U~91/05~24-~.
20892~ -64-1.49 (s, 9 H), 1.55 (br s, 3 H), 1.60 (br s, 3 H), 1.0-1.98 (several br m, approximately 14H total), 2.15 (br m, 1 H), 3.65-3.77 (m, 2 H), 4.62 (dd, 1 H), 5.03 (dd, 1 H), 6.55 (bt, 1 H); MS m/e 5i5 ((M+Na)+); HRMS Calcd for (M+Na)+
for C2sH4sN6O4Na: 516.3900. Found: 516.3333.
B. The procedure of Example 2C was followed, with the substitution of the resultant product from Example 29A for the resultant product from Example 2B, to provide the title com~ound as a wnite powder: mp 95-123 C; Rf 0.33 (15%
MeO~ conc NH40;-.-C;i2C12); lH NMR (CDCl3) ~ 0.50-1.98 (several br m, 36H approximately), 2.24 (m, 1 H), 2.20-3.00 (vbr m, 1 H), 2.83-4.62 (several br m, 11 H), 3.39 (d, 3 ~), 4.70 (d, 2 H), i.19 (br m, 1 H), 5.49 (br m, 1 H), 7.02 (br m, 2 H), 9.19-7.36 (m, 5 H); MS m/e 742 ((M+H)+).
Anal. Calcd for C39H67N7O7-1.5 H20: C, 60.91i H, 8.65; N, 12.74. Found: C, 60.80; H, 8.21; N 12.01.
~8~
N (2-Methyl-2-t4-mQ~hQllDQ)pro~yl~ 5~)-(2~ $l-(4-henyl)ethoxyhex~nam;~Q~-6-cyGlo~exyl-4(5)-hyd~oxy-2(~)-.~
Through`a solution of dihydrofuran (15 ~L, 14 mg, 0.198 mmol) dissolved in methanol (0.1 mL) and methylene chloride (0.4 mL) and cooled to -65 C under argon was passed a stream of ozone/oxygen for approximately 30 seconds to give a pale blue solution. Oxygen was then bubbled through the solution to drive off the excess ozone and then sodium cyanoborohydride (6.9 mg, 0.110 mmol) was added. The reaction mixture was stirred at -65 C to -60 C for 25 minutes and then a solu~ion of the compound .
:' , :
: . ,,.. : .~. . ..
~r~92/0~29 2 ~ ~ 9 2 ~ 8 PCY/V~91/~
; s~
resulting from E.~ample 10 (33.4 mg, 0.0457 mmol) dissolved in methanol (0.6 mL) was added. The reaction mixture was stirred at -60 C for 30 minutes, allowed to warm to 0 C, and then stirred at 0 C for 6 nours. It was then allowed to warm to ambient temperature and stirred for 24 hours.
The reaction mixture was partitioned between lM sodium carbonate (10 mL) and methylene c:~loride (20 mL). The aqueous phase ~as extracted with methylene chloride (2 x 10 mL). The co~ined organic extracts were washed with brine ~15 mL), dried over sodium sulfate, and concentrated in vacuo to afford crude product (36.1 mg). Preparative tlc on silica g~l elut~ng w~th 4% methanol in methylene chloride afrorded pure title compound as a white amorphous solid (26.3 mg, 58%): mp 46-52 C; Rf 0.24 (5% MeOH-CH2C12); 1H NMR (CDCl3) ~ 0.66-1.48 (br m), 0.91 (t), 0.92-0.97 (2 d) and 1.04 ~s, 31 H total), 1.49-1.90 (br m, 17 H), 2.11-2.17 (m, 1 H), 2.47-2.54 ~m, 4 H), 2.93-3.00 (m, 2 H), 3.06 (dd, 1 H), 3.11 (dd, 1 H), 3.17-3.29 (br m, 3 H), 3.37 (s) and 3.30 3.49 (br m, 5 H), 3.64-3.84 (br m, 6 H), 3.84-3.97 (br m, 1 H), 4.49 (dd, 1 H), 4.69 (s, 2 H), 5.83 (d) and 5.90 (d, 1 H total), 6.28 (br t, 1 H), 7.38-7.48 (m, 5 H); MS m/e 801 ((M+H)+). Anal. Calcd for C4s~76N4Og-H~0: C, 65.98; H, 9.60; N, 6.84. ~ound: C, 65.57; H, 9.18; N, 6.82.
' , , ' .' : : , . . .
WO 92/03429 PCT/US91/05~
- 20892~
` -66-~m~le 31 N-(3-(S-M~thyl-N'-cyanoisotll~ourc~iAo)~--rQ9~ (5)-(2(C~-(1(s?-(4-(m~ xvm~o~ r;~ )c2-~ony'-~-pherlyl)etho~yh~an~ A~Q) -6-cyClor~yl-~ (~S~
isopro~ylhexanami~
The procedure of Example 24 was em?lcyeA, wi :~
the substitution of the resultant compour.d ^ om E.~am?le 3 for the resultant compound from Example 16, ~o ~-ovide t^.e title compound as a white powder (84~ yie ~ 88-3' ^
Rf 0.49 (10~ MeOH-CH2C12)i lH N~ (CDCl~ .6--:.9~
~several br m, aoprox. 37 H), 2.08 (m, } H), ~. 9 (s, 3 .-:j, 2.90-9.04 several br m, 15 H), 3.38 (s, 3 ;i), ~.~0 (~., 1 H), 4.68 (s, 2 H), 5.82 (dd, 1 H), 6.21 (m, 1 H), 7.27-7.39 (m, 5 H), 7.89 (m, 1 H); MS m/e 815 ((M+H)+). .~al. Ca:_d for C43H70N6O7S-O.5H2O: C, 62.67; H, 8.68; N, 10.20.
Found: C, 62.83; H, 8.57i N, 10.20.
E~am;~l~
N-t3-lN-Methyl-N'-cyanQ~reido)p~Qpy~ 5(~)-(?(s) - ( 1 (5) ~ (4-~rl ) carh~nY~-2-pheny ~ ethoxyhe~anam;dQ)-6-cyclohQ~yl-4(5)-hydroxy-2(5)-~ 3 _-o~=lkle.
The procedure of Example 25 was employed, with the substitution of 40% aq. methyl amine and the resultant compound from Example 31 for 30% aq. NH4GH and the resultant compound from Example 24, to provide the tltle compound as a white powder (80% yield): mp 101-107 C; Rf 0.34 (7.5% MeOH-CH2Cl2), lH NMR (CDCl3) ~ 0.64-1.93 (several br m, 37H approximately),- 2.13 (m, 1 H), 2.88 (d, 3 H), 2.93-4.10 ~several br m, 15 H), 3.38 (d, 3 H), 4.61 (m, 1 H), 4.69 (s, 2 H), 5.75 (dd, 1 H), 5.90 br s, 1 H), . ~ .
~.
:;
~q 92/03429 2 ~ ~ 9 ~ ~ 8 PCrlUS91/05524 , ..... . .. ..... ~ , . . `
6.31 (br s, 2 H), 7.28-7.40 (br m, 5 H); MS m/e 798 ((M~H)+), 815 ((M+NH4)+). Anal. Calcd for C43r.71N7O7: C, 64.71; H, 8.97; N, 12.28. Found: C, 64.35; H, 8~00; N, 12.15.
.
E~am~
N-(~-(N'-cyanou~ido~-o~yl) S(S~-(2~S)~ S
~=== ~
Dhenyl)ethoxyhe.~anamldQ)-6-cyclohexyl-4(5)-nyà-oxy-2(~)-i ~0~ rQ~ y~h~x~n~?. ~
The p~ocedure of Example 25 was employed, with the ~ubstitution of the resultant compound from Ex2~?1e 3' fo~
the resultant compound from Example 24, to pro~ e tr.e title compound as a white foam (54~ yield): mp 116-126 C;
j Rf 0.37 (7.5~ MeOH-CH2Cl2); 1H NMR (CDCl3) ~ O.51-1.93 ; (several br m, 38 H), 2.00 ~m, 1 H), 2.90-3.91 (several br .. m, 13 H), 3.39 (d, 3 H), 4.00 (m, 1 H), 4.61 (m, 1 H), 4.70 `` (d, 2 H), 5.71 (dd, l H), 5.96 (m, 2 H), 6.27 (m, 1 H), 6.39 (m, 1 H), 7.28-7.39 (m~ 5 H); MS m/e 784 ((M+H)+), 801 ~. ((M+NH4)+).
. , ` N-!3-!(3-~ino-h~-l.2r4-t~lazQl-~-yLLaminoLsro~yl) ~rs)-.
p-rQ~y~ canam~d~
The procedure of Exampl~e 25 was employed, with the substitution of hydrazine hydrate and the resultant ~ compound from Example 31 for 30~ aq. NH40H and the :. resultant compound from Example 24, to provide the title .j compound as a white powder (91% yield); mp 110-120C; Rf `i.
' . , . -- .
, ' :, '. : ' '' . ':
' WO92/0~29 PCT/US9l/05~
20~9268 0.24 (10% MeOH-l~ conc NH4OH-CH2Cl2); lH NMR (CDC13) S
0.58-1.90 (several br m, 37H approximately), 2.11 (br m, 1 H), 2.90-4.04 (several br m, 15 H), 3.47 (d, 3 H), 4.60 (m, 1 H), 4.68 (à, 2 H), 4.50-5.50 (v br m, 3 H), 5.70 (dd, 1 H), 7.13-7.43 (br m, 2 H), 7.29 (m, 5 H); MS m/e 799 ((M+Y.)+). Anal. Calcd for C42H70N~O7-1.0 H2O: C, 61.74;
H, 8.88; N, 13.71. Found: C, 61.76; ~, 7.86; N, 13.56.
le ~
3-((5-. m-?.~ . -Qxadiazol-5-yl~a~no)~Q~yl) 2(5)-~(3-,3~ r~ n~fl)-2,2-d~met~ (S)-Cyc'Q~.~Y~;lmeth~ -5~S)-^x-~olid niyl)~.e hyl~-~-methylhuta~2.~de-The procedure of Exam~le 25 can be employed, with thesubstitution of the resultant compound from Example 31 anà
hydroxylamine hydrochloride and a molar equivalent quantity of triethylamine for the resultant compound from Example 24 and 30% aq. NH40H, to provide the title compound.
.:
F.xampl~ 36 _ 5~5)-12~ )-(4-I~,=hs2~3s~b~g~ =yl?~arhonyl-2-;( phenyl)ethoxyheY~na~.idQL-~-~y~_ohe~yl-4(5)-hydroxy-2(5)_ .~ - d~.
,'7, A solution of the resultant compound from Example 11 (44.1 mg, 0.056 mmol) in 0.22 mL MeOH was treated with 30~
aq. H~O2 (17 mL, 5.7 mg H2O2, 0.16 mmol). The solution was l stirred at ambient temperature for 4 d, then an additional ;~ 18 h at 50 C. The solution was concentrated and partitioned between 20 mL CHC13 and 10 mL of 1:1 water:brine. The aqueous phase was extracted (3 x 10 mL
CHC13), the combined organic phases were washed with brine, dried (Na2SO~), filtered and concentraaed to a foam.
' .
.
~'~92t0~29 20~92~8 PCT/US91/oSS~
Preparative TLC ~silica gel, 15~ MeOH-CHCl3) provided 24.8 mg (30.9 ~mol, 55~) of the title compound as a white foam:
mp 71 83 C; lH NMR (CDCl3) ~ O.60-2.20 (several br m) and 0.83-0.97 (m, approx. 38 H total), 2.88-3.08 (br m, 3 H), 3.08-3.25 (m, 3 H), 3.25-3.55 ~br m), 3.35 (s) and 3.37 (s,
, :
_)--(2ts)--(l(s)--(4--;`tmethoxymethoxy!~ipe~ yl)~arbonyL-2-Dhenyl)ethoxyhexan~midQ)-6-cyclohexy~-4(S)-hydroxy-2(S)-isopropylhexanamide.
To the compound resulting from Exam?le 24 (75 mg, 0.09~6 mmol) dissolved in ethanol (2 mL) was added ammonium hydroxide (732 ~L, 13.724 mmol, 200 equivalents). The reaction vessel was sealed and heated at 90 C for 72 hours. The reac.ion mixture was concentrated under reduced pressure to afford crude material (67.1 mg).
Chromatography on silica gel eluting with 4% methanol in methylene chloride afforded the title compound as a white powder (35.7 mg, ~0%): mp 92-99 C; Rf 0.53 (10% MeOH-CH2Cl2): 1H N~R (CDCl3) 6 0.50-1.94 (several br m, 36 3 .
:. . ': : . .:. ;.:
,: .: : .,; .:, .
- . ", ' ' . ' . ' ' ' '~' ' ' ' .
W092/03429 PCT/US91/055~ -~
20~92~8 .. . .. ... . ~
. .
approximately), 2.82-4.15 (several br m, 15 H
approximately), 3.48 (d, 3 H), 4.65 (m, 1 H), 4.71 (d, 2 H), 5.60 (dd, 1 H), 5.83 (m, 0.5 H), ~.04 (m, 1 H), 5.22 (m, 2 H), 6.31 (m, 0.5 H), 7.29-7.40 (m, 5 H); ~S m/~ 77 ((M+H)+). Anal. Calcd for C41H67N7O7: C, 63.95; H, 8.77 N, 12.73. Found: C, 62.05; H, 8.38; N 13.03.
Ey~ 2 (N-~e~ L-N'-cyan~ur~1do)?th.yl~ 5(~`~-(2(~CI-( (m~tho~ym~hQxy)~pe~id~ n - 1 - ~ ) C~ - DO?.
~ ~henyllethox~,~hey.~n~ido)~ y~l^n;~ 7-4(c~ o--~-;: i so~rogyl hex~r,,z~l The procedure of Example 25 can be employed, wlth th~
substitution of 40% aq. methyl amine for 30~ aq. N~40~., tO
provide the title compound.
E~m~le 27 ~-(2-~L~i~minQ=1fiL-1 2~4-~iazol-5-yl)aminQ)ethyl) 2(S)-((3-(tert-~utyloxycarbonyl)-2 2-dim~hyl-4(~L~ycl~h~ylm~thyl-~(S)-oxazolidinyl!methyl)-3-m~thyl~u~n~mide.
The procedure of Example 25 W2S employed, with the substitution of hydrazine hydrate ror 30~ aq. NHqOH, to provide the title compound as a white powder ~69% yield):
mp 99-112 C; Rf 0.42 (10% MeOH-CH2Cl2 w/1% conc NH40H
. added); 1H NMR (CDCl3) ~ 0.53-1.90 tseveral br m, 35H
approximately),~l.99 (m, 1 H), 2.50-5.00 (vbr m, 3H
, - approximately), 2.88-4.1-0 (several br m, 15 H), 3.38 (d, 3 H), 4.68 (d, 2 H), 9.71 ~m, 1 H), 5.11 (br s, 1 H), 5.73 (dd, 1 H), 6.78 (br s, 1 H), 7.29-7.39 (m, 5 H); MS m/e 785 ((M+H)+). Anal. Calcd for C41H68N8O7-1.0 H2O: C, 61.32;
H, 8.78; N, 13.95. Found: C, 61.~7; :~, 8.75i N 13.58.
~ .
.. .
. .~
: . .. ,,, : : .. . .
, : - -: ,, . :
~ W~2/03429 2 0 8 9 2 ~ ~ PCT/U~9l/0~5~
. . . .~ _ .
, . ,; .
: -63-~L~
N-(2-((5-~mino-l 2,a-oxa~iazQl-5-yl)am~o)eth~l) 2~5)~
(~r~hutylQ~yca~bony~ -2 2-dimeth.yl-4(5)-cyc'~he~:yl m~5 5(.S)-oxazolid~n~l)methyl)-8-me_hyl~lltan~m-de.
The procedure of Example 25 can be employed, witn ~ne substitution of hydroxylamine hydrochloride and a mola~
equivalent quantit~i~ of triethylamine for 3C~ a . Ni4OH, ~o provide the title compound F.~am~l 5 29 ~- (5- ~Tetrazolyl)m~thyl 5 (S) - (? (~S~
(met~oxyrnet ho~cy~ erid;.n~ 1 ) ca~ ' -2-envl)ethQxyhexan~mido)-6-~yslo~s~yl-4(.C)-h~d~o~y-2(5)-i soDroDyl~canarnA- N-(5-(TetrazolylLmethyl 2(S)-((3-(tert-cyclohexylmethyl-5(S)-oxazolidin~l)methyl)-3-methylhutanami~s_ A solution of the resultant compound from Example 8A ~150 mg, 0.334 mmol), triethylamine hydrochloride (68.9 mg, 0.500 mmol) and sodium azide (65.1 mg, 1.00 mmol) in 3.3 mL DM~ was warmed to 125 C for 24 h. The dark solution was conce?.tr2ted under high vacuum, and the resulting oil was poured into a mixture of 10 mL water and 10 mL CH2C12. The mixture was acidified to pH 1 with 1 N HCl. The layers were stirred, then separated, and the aqueous phase was extracted with 2 x 20 mL CH2C12. The com~ined organic phases were ~ashed with brine, dried (Na2SO4), filtered and concentrated in vacuo to produce 168 mg (0.341 mmol, 102%) of crude tetrazole: Rf 0.32 ~5% MeOH-0.5~ HOAc-CH2C12); lH NMR
(CDC13) ~ 0.91 (d), 0.96 (d), and 0.8-1.0 ~br m, 8H total), .
, . .
. .
.- ~ ,... , ,.,,, ., .~.
.
. .: . , .
: . . . . .. . . . . .
WO92/03429 PCT/U~91/05~24-~.
20892~ -64-1.49 (s, 9 H), 1.55 (br s, 3 H), 1.60 (br s, 3 H), 1.0-1.98 (several br m, approximately 14H total), 2.15 (br m, 1 H), 3.65-3.77 (m, 2 H), 4.62 (dd, 1 H), 5.03 (dd, 1 H), 6.55 (bt, 1 H); MS m/e 5i5 ((M+Na)+); HRMS Calcd for (M+Na)+
for C2sH4sN6O4Na: 516.3900. Found: 516.3333.
B. The procedure of Example 2C was followed, with the substitution of the resultant product from Example 29A for the resultant product from Example 2B, to provide the title com~ound as a wnite powder: mp 95-123 C; Rf 0.33 (15%
MeO~ conc NH40;-.-C;i2C12); lH NMR (CDCl3) ~ 0.50-1.98 (several br m, 36H approximately), 2.24 (m, 1 H), 2.20-3.00 (vbr m, 1 H), 2.83-4.62 (several br m, 11 H), 3.39 (d, 3 ~), 4.70 (d, 2 H), i.19 (br m, 1 H), 5.49 (br m, 1 H), 7.02 (br m, 2 H), 9.19-7.36 (m, 5 H); MS m/e 742 ((M+H)+).
Anal. Calcd for C39H67N7O7-1.5 H20: C, 60.91i H, 8.65; N, 12.74. Found: C, 60.80; H, 8.21; N 12.01.
~8~
N (2-Methyl-2-t4-mQ~hQllDQ)pro~yl~ 5~)-(2~ $l-(4-henyl)ethoxyhex~nam;~Q~-6-cyGlo~exyl-4(5)-hyd~oxy-2(~)-.~
Through`a solution of dihydrofuran (15 ~L, 14 mg, 0.198 mmol) dissolved in methanol (0.1 mL) and methylene chloride (0.4 mL) and cooled to -65 C under argon was passed a stream of ozone/oxygen for approximately 30 seconds to give a pale blue solution. Oxygen was then bubbled through the solution to drive off the excess ozone and then sodium cyanoborohydride (6.9 mg, 0.110 mmol) was added. The reaction mixture was stirred at -65 C to -60 C for 25 minutes and then a solu~ion of the compound .
:' , :
: . ,,.. : .~. . ..
~r~92/0~29 2 ~ ~ 9 2 ~ 8 PCY/V~91/~
; s~
resulting from E.~ample 10 (33.4 mg, 0.0457 mmol) dissolved in methanol (0.6 mL) was added. The reaction mixture was stirred at -60 C for 30 minutes, allowed to warm to 0 C, and then stirred at 0 C for 6 nours. It was then allowed to warm to ambient temperature and stirred for 24 hours.
The reaction mixture was partitioned between lM sodium carbonate (10 mL) and methylene c:~loride (20 mL). The aqueous phase ~as extracted with methylene chloride (2 x 10 mL). The co~ined organic extracts were washed with brine ~15 mL), dried over sodium sulfate, and concentrated in vacuo to afford crude product (36.1 mg). Preparative tlc on silica g~l elut~ng w~th 4% methanol in methylene chloride afrorded pure title compound as a white amorphous solid (26.3 mg, 58%): mp 46-52 C; Rf 0.24 (5% MeOH-CH2C12); 1H NMR (CDCl3) ~ 0.66-1.48 (br m), 0.91 (t), 0.92-0.97 (2 d) and 1.04 ~s, 31 H total), 1.49-1.90 (br m, 17 H), 2.11-2.17 (m, 1 H), 2.47-2.54 ~m, 4 H), 2.93-3.00 (m, 2 H), 3.06 (dd, 1 H), 3.11 (dd, 1 H), 3.17-3.29 (br m, 3 H), 3.37 (s) and 3.30 3.49 (br m, 5 H), 3.64-3.84 (br m, 6 H), 3.84-3.97 (br m, 1 H), 4.49 (dd, 1 H), 4.69 (s, 2 H), 5.83 (d) and 5.90 (d, 1 H total), 6.28 (br t, 1 H), 7.38-7.48 (m, 5 H); MS m/e 801 ((M+H)+). Anal. Calcd for C4s~76N4Og-H~0: C, 65.98; H, 9.60; N, 6.84. ~ound: C, 65.57; H, 9.18; N, 6.82.
' , , ' .' : : , . . .
WO 92/03429 PCT/US91/05~
- 20892~
` -66-~m~le 31 N-(3-(S-M~thyl-N'-cyanoisotll~ourc~iAo)~--rQ9~ (5)-(2(C~-(1(s?-(4-(m~ xvm~o~ r;~ )c2-~ony'-~-pherlyl)etho~yh~an~ A~Q) -6-cyClor~yl-~ (~S~
isopro~ylhexanami~
The procedure of Example 24 was em?lcyeA, wi :~
the substitution of the resultant compour.d ^ om E.~am?le 3 for the resultant compound from Example 16, ~o ~-ovide t^.e title compound as a white powder (84~ yie ~ 88-3' ^
Rf 0.49 (10~ MeOH-CH2C12)i lH N~ (CDCl~ .6--:.9~
~several br m, aoprox. 37 H), 2.08 (m, } H), ~. 9 (s, 3 .-:j, 2.90-9.04 several br m, 15 H), 3.38 (s, 3 ;i), ~.~0 (~., 1 H), 4.68 (s, 2 H), 5.82 (dd, 1 H), 6.21 (m, 1 H), 7.27-7.39 (m, 5 H), 7.89 (m, 1 H); MS m/e 815 ((M+H)+). .~al. Ca:_d for C43H70N6O7S-O.5H2O: C, 62.67; H, 8.68; N, 10.20.
Found: C, 62.83; H, 8.57i N, 10.20.
E~am;~l~
N-t3-lN-Methyl-N'-cyanQ~reido)p~Qpy~ 5(~)-(?(s) - ( 1 (5) ~ (4-~rl ) carh~nY~-2-pheny ~ ethoxyhe~anam;dQ)-6-cyclohQ~yl-4(5)-hydroxy-2(5)-~ 3 _-o~=lkle.
The procedure of Example 25 was employed, with the substitution of 40% aq. methyl amine and the resultant compound from Example 31 for 30% aq. NH4GH and the resultant compound from Example 24, to provide the tltle compound as a white powder (80% yield): mp 101-107 C; Rf 0.34 (7.5% MeOH-CH2Cl2), lH NMR (CDCl3) ~ 0.64-1.93 (several br m, 37H approximately),- 2.13 (m, 1 H), 2.88 (d, 3 H), 2.93-4.10 ~several br m, 15 H), 3.38 (d, 3 H), 4.61 (m, 1 H), 4.69 (s, 2 H), 5.75 (dd, 1 H), 5.90 br s, 1 H), . ~ .
~.
:;
~q 92/03429 2 ~ ~ 9 ~ ~ 8 PCrlUS91/05524 , ..... . .. ..... ~ , . . `
6.31 (br s, 2 H), 7.28-7.40 (br m, 5 H); MS m/e 798 ((M~H)+), 815 ((M+NH4)+). Anal. Calcd for C43r.71N7O7: C, 64.71; H, 8.97; N, 12.28. Found: C, 64.35; H, 8~00; N, 12.15.
.
E~am~
N-(~-(N'-cyanou~ido~-o~yl) S(S~-(2~S)~ S
~=== ~
Dhenyl)ethoxyhe.~anamldQ)-6-cyclohexyl-4(5)-nyà-oxy-2(~)-i ~0~ rQ~ y~h~x~n~?. ~
The p~ocedure of Example 25 was employed, with the ~ubstitution of the resultant compound from Ex2~?1e 3' fo~
the resultant compound from Example 24, to pro~ e tr.e title compound as a white foam (54~ yield): mp 116-126 C;
j Rf 0.37 (7.5~ MeOH-CH2Cl2); 1H NMR (CDCl3) ~ O.51-1.93 ; (several br m, 38 H), 2.00 ~m, 1 H), 2.90-3.91 (several br .. m, 13 H), 3.39 (d, 3 H), 4.00 (m, 1 H), 4.61 (m, 1 H), 4.70 `` (d, 2 H), 5.71 (dd, l H), 5.96 (m, 2 H), 6.27 (m, 1 H), 6.39 (m, 1 H), 7.28-7.39 (m~ 5 H); MS m/e 784 ((M+H)+), 801 ~. ((M+NH4)+).
. , ` N-!3-!(3-~ino-h~-l.2r4-t~lazQl-~-yLLaminoLsro~yl) ~rs)-.
p-rQ~y~ canam~d~
The procedure of Exampl~e 25 was employed, with the substitution of hydrazine hydrate and the resultant ~ compound from Example 31 for 30~ aq. NH40H and the :. resultant compound from Example 24, to provide the title .j compound as a white powder (91% yield); mp 110-120C; Rf `i.
' . , . -- .
, ' :, '. : ' '' . ':
' WO92/0~29 PCT/US9l/05~
20~9268 0.24 (10% MeOH-l~ conc NH4OH-CH2Cl2); lH NMR (CDC13) S
0.58-1.90 (several br m, 37H approximately), 2.11 (br m, 1 H), 2.90-4.04 (several br m, 15 H), 3.47 (d, 3 H), 4.60 (m, 1 H), 4.68 (à, 2 H), 4.50-5.50 (v br m, 3 H), 5.70 (dd, 1 H), 7.13-7.43 (br m, 2 H), 7.29 (m, 5 H); MS m/e 799 ((M+Y.)+). Anal. Calcd for C42H70N~O7-1.0 H2O: C, 61.74;
H, 8.88; N, 13.71. Found: C, 61.76; ~, 7.86; N, 13.56.
le ~
3-((5-. m-?.~ . -Qxadiazol-5-yl~a~no)~Q~yl) 2(5)-~(3-,3~ r~ n~fl)-2,2-d~met~ (S)-Cyc'Q~.~Y~;lmeth~ -5~S)-^x-~olid niyl)~.e hyl~-~-methylhuta~2.~de-The procedure of Exam~le 25 can be employed, with thesubstitution of the resultant compound from Example 31 anà
hydroxylamine hydrochloride and a molar equivalent quantity of triethylamine for the resultant compound from Example 24 and 30% aq. NH40H, to provide the title compound.
.:
F.xampl~ 36 _ 5~5)-12~ )-(4-I~,=hs2~3s~b~g~ =yl?~arhonyl-2-;( phenyl)ethoxyheY~na~.idQL-~-~y~_ohe~yl-4(5)-hydroxy-2(5)_ .~ - d~.
,'7, A solution of the resultant compound from Example 11 (44.1 mg, 0.056 mmol) in 0.22 mL MeOH was treated with 30~
aq. H~O2 (17 mL, 5.7 mg H2O2, 0.16 mmol). The solution was l stirred at ambient temperature for 4 d, then an additional ;~ 18 h at 50 C. The solution was concentrated and partitioned between 20 mL CHC13 and 10 mL of 1:1 water:brine. The aqueous phase was extracted (3 x 10 mL
CHC13), the combined organic phases were washed with brine, dried (Na2SO~), filtered and concentraaed to a foam.
' .
.
~'~92t0~29 20~92~8 PCT/US91/oSS~
Preparative TLC ~silica gel, 15~ MeOH-CHCl3) provided 24.8 mg (30.9 ~mol, 55~) of the title compound as a white foam:
mp 71 83 C; lH NMR (CDCl3) ~ O.60-2.20 (several br m) and 0.83-0.97 (m, approx. 38 H total), 2.88-3.08 (br m, 3 H), 3.08-3.25 (m, 3 H), 3.25-3.55 ~br m), 3.35 (s) and 3.37 (s,
11 H to~al), 3.55-3.3.67 (br m, 2 H), 3.67-3.95 (br m, 4 H), 4.00-4.22 (br m, 1 H), 4.26-4.40 (m, 2 H), 4.53-4.63 (m, 1 H)~ 4.67 (s) and 4.68 (s, 2 H total), 5.70 (br t, 1 H), 7.2,-7.43 (m, 5 H), 8.12-8.21 (br m, 1 H); MS m/e 803 ((M+r.)+). Anal. Calcd for C~4H74N40g 1. 5 H20: C, 63.66; H, 9.35; ~l, 6.75. Found: C, 63.41; H, 9.03; N, 6.55.
, , E~am~L~
N- ( 2-~a-boxyethyl) 5(5)-(2l5~-~1(.$)-(4-(methoxy~ ho~ylpiperi~in-~_yl~c~r~Qny1~2-. N-((2-(O-Eth~l~carhoxy)e~h~rl~ 2(s!-((3-(~rt-butylsx~Garbonyl)-2.2-dimethyl-4(5)-cyGLQhexylmethyl-5(5)-oxaz~lidlnyllm~t~yl~-3-m~thylbu~a~amj~ The procedure o~
Example 2~ was employed, with the substitution of ~-alanine ethyl ester hydrochloride for the resultant compound from , Example 2A, to provide the title compoundoil (quantitative ;~ yield): Rf 0.55 ~2.5% MeOH-CH2Cl2); 1H NMR (CDCl3) ~ 0.80-1.90 (several br m, 16 H approximately), 0.92 ~dd, 6 H), 1.28 (t, 3 H), 1.49 (s, 9 H), 1.58 (br s, 3 H), 1.64 (br s, .~ 3 H), 2.03 (m, 1 H), 2.55 (m, 2 H), 3.41-3.76 (several m, 4 :~ H), 4.16 (m, 2 H), 6.12 ~m, 1 H); MS m/e 511 ((M+H)+), 528 ((M+NH4)+).
;
' :.
,. ; . .
:
W092/0~29 PCT/US91/055~
2ossæ68 -70~
B. N-(2-~2~boY~Q~hyl) 5~S~ C~ C~
(methoxy~etho~y)piDerldin-1-~l~cz-~on~,1-2-phe~y~_)eth~hexanam.;.do~-6-cyclQ~Qxy'-4(.~)-hyd-oxv-2(5)-i.~oproDylhexanamide. The proceàu_e of ~xam?le 2C was employed, with the substltution o- the resul'ant compound from Example 37A for the resultan~ compound from Example 2B, to provide the title com~oundsQmi-solid mass (61~
yield): Rf 0.28 (5% MeOH C~2Cl2); ~ ~ (C~Cl3~ ~ 0.64-1.90 (several br m, 27 H approxim2tely), 0.91 (m, 9 H), 1.29 (t, 3 H), 2.06 (m, 1 H), 2.5~ (m, 2 H), 2.~'-3.96 ~several br m, 12 H), 3.37 (s, 3 ~.), 4.18 (dq, 2 H), 4.5C
(m, 1 H), 4.68 (s, 2 H), 5.81 (dd, 1 ~), 6.20 (-, 1 H), 7.28-7.38 (m, 5 H); MS m~e 760 (('-:~.)+), 777 ((M ~H4)+).
Anal. Calcd for C42H6gN3O9 0.5 H2O: C, 65.59; H, 9.17; N, 5.~6. Found: C, 65.66; H, 8.91; N, 5.54.
To the compound resulting from Example 37B (125.7 mg, 0.1654 mmol) dissolved in tetrahydrofuran (2.5 mL) and cooled to 0 C was added a solution of lithium hydroxide ~13.9 mg, 0.3308 mmol) in water (0.3 mL). After stirring at 0 C under nitrogen for 2 hours, the cooling bath was removed and stirring was continued for 2 hours at ambient temperature. The reaction mixture was diluted with water (10 mL) and co~centrated under reduced pressure to remove the tetrahydrofuran. The aqueous solution was acidified to pH 2 with lN sodium hydrogen sulfa.e (3 mL) and extracted with methylene chloride (4 x 20 mL). The combined organic extracts were washed with brine, d-ied over sodium sulfate, and concentrated under reduced pressure to afford crude product as an amorphous solid (112.7 mg). Chromatography on silica gel eluting with 3% methanol in methylene chloride containing 0.5% acetic ac d afroràed 80 mg of .
, .
~ 92io~29 2 ~ ~ 9 ~ ~ ~ PCT/US91/OS~
. ' ., ; 71 material. This material was further purified by preparative thin layer chromatography on sillca gel el~ting with 5% methanol in methylene chlo-ide contai~. ng 0 5%
acetlc acid to afford the title compound as 2 ~;n~ ~e amorphous solid (53.1 mg, 44%): m? 115-124 Ci Rf 0.45 (5%
MeOH-CH2Cl2 w/1.0% HOAc added)~ IR (CDC13) ~ 0.33-2 C5 ~several br m, 37 H approximately), 2.86-4.28 (several br m, 15 H), 3.38 (d, 3 H), 4.69 (d, 2 ~), 9.7~ (r~
(br m, 1 H), 7.05-7.80 vbr m, 1 Y.,, 7.27-7.~8 ~m,, 5 ~); ,I~
m/e 754 ((M+Na)+); (FA3-) mi~ 73G ;(.~'-.")~).
~` .
.' ~
~-(2-Cy2~oe~h~l) 5(~ ~lS~ c)-(~_ ~ et}loxyr~.Gthoxy)~,lp~-id~ n_-_yl ) C~, ~)or;;'~-2-phenyl)etho~yh~ana~ido)-h=syslo:neyyl-a~)-hvd-oxy-2(5)-A~ 2-Cya~e~hyl~. 2l~-((3-(t~rt-butyloxycarbonyl~-( S)--i~Q~ The procedure of Example 2B can be followed, with the substitution of 2-' aminopropionitrile hydrochloridé plus an additlonal ?-' e~uivalent of N-methylmorpholine for (benzyloxycarbonylamino)propylamine, to provide the title compound.
~ _ The procedure of Example 2C can be followed, wlth the~substitution of the resultant product from Example 38A
; for the resultant product from Exam~le 2B, to ~rovide the title compound.
. .
WO 92/03429 PCT/US91/0~24 -~
208~2~8 Ex~m~le 39 N-12-(5-(Tet~azolyl)ethyl~ ~(S)-(2(S)-(l(S)-(4-(met~Qxym~hoxy)pi~eridi n-1 -yl )carhonyL-2-~henyl)ethoxvhe~a~amidn)-k-cyclo~yl-a(s)-hyd~oxy-2( i.~o~ro~ylhexanamlde.
N-(2-(~-(Tetra~Qlyl)ethyl) 2(~S)-((3-(tert~
b-~'ylo~yca~bony])-2 2-dimethyl-4($~-cyc~ohe~ylmethyl-5(5)-oxazol~d;~yl)meth~l)-3-methylbutanamide The procedure of Example 29A can be followed, with the substitution of the resultant product from Example 38A for the resultant roduct from Example 8A, to provide the title compound.
_. The procedure of Example 2C may be followed, with the substitution of the resultant product from Example 39A
for the resultant product from Example 2B, to provide the ~ title compound.
:~ .
cyanou~idnL_~15L=12~$?~~1(5)~(4~
~`(methoxymethQxy)DiDeridin-1-!~L~ ~lnyl=2~
~~ yl-4(S)-hydroxy-?(S)-'1, A~
A. N-~mino 5 (~! - (2 !s) - (1 (s) - (4-methoxymçthoxv?~iper;~d~n-l-Yl~cark~onyl-?-h~yl~ethoxyh~anamido)-6-cyc1ohexyl-4(5)-hy~rQxy-2~5)-5 ~D~a~ The procedure or Example 10 may befollowed, with the substitution of hydrazine hydrate for ~
1,2-diamino-2-methylpropane, to give the desired compound.
(.1 (.S) - (4- (~ethQxymethoxy~Riperid m -l-yl)carho~l=2~
hen.yl)ethoxyhexa~amido)-fi-cyclQhexyl-A(S)-hyd~o~y-~(S)~
. .
wn92/03429 2~3~ 9 2 6 8 PCT/US91/0 i~QprQ~yl~e:~2nam;de. The procedure of Example 24 can be employed, with the substitution of the resultant compound from Example 40A for the resultant compound from Exam~le 16, to provide the title compound.
~ _ The procedure of Example 25 can be employed, with the substitution of the resultant compound from Example 40B
fo- the resultant compound from Example 24, to provide the - 'itle compound.
.
., ~
N-t3-~mino~ ,2 4-~riazol-5-yl) 2~Q) 5 (.S) -(2(S)-(l(S~-~he~y~)etho~cy~e~anamido)-6-cyclohexyL-4(5)-hyd-o~y-2(.s) iso~ ylhe~ana~ide.
The procedure of Example 25 can be employed, with the :j 3 substitution of the resultant compound from Example 40B and ~;, hydrazine hydrate for the resultant c:ompound from Example 24 and 30% aq. NH40H, to provide the title compound.
Example ~2 ~R) 4(R)--dihyd~yhs~n-5(S)-yl) 2(s)-(1(s?-(4-.~ (met~o2~thoxy) piper;~lin~:L-yl-~` ~ar~onyl!~henyl~thQ~lhg~namide p" ~A~S, 5R..L~ ~~~ lt~?~-- ~ l~ yc:arbonyu -G
-(cycloh~ylme~hyll=5=(2',2'-d~fluoro-2'-ethQxycarbony~-1'-~ To (4S~ 5R) ~3~
:;
(tert-butyloxycarbonyl)-4-(cyclohexylmethyl)-2,2-(dimethyl)oxazolidine-5-carboxaldehyde (1.20 g, 3.70 mmol, Rcsenberg, S. H., et al, J. Med. Chem., 1990, 33, 1582) in tetrahydrofuran (15 mL) w~s added bromodifluoroe~hyl .
~.~
`:
. ; ' ' '' .
., .
, W092/0~29 PCT/US91/055~-~
2~2~
acetate ~1.50 g, 7.39 mmol) and zlnc (0.60 g, 9.2 mmol).
The reaction flask was placed in an ultrasonic cleaning bath for 1 h. The mixture was ~oured into saturated NaHCO3 solution and extracted into ethyl acetate which was dried over Na2SO4 and evaporated. Chromarog-aphy of the residue on silica gel with 10~ ethyl acetate in hexane afforded 1.30 g (78~) of the desired produc~ as an oil: Rf 0.26 (20~ ethyl acetatei80~ he~ane); 1 ~T~ (C3C13) o a.35 (q, 2 H), 4.20-3.97 (m, 3 ~.), 1.54 (s, 3 :-.), 1.50 (s, 3 H), 1.48 (s, 9 H)! 1~37 (t, 3 H).
~ S,~5Æ~ 3-lter~-~tylox~c2rbon-vl)-4 .. ( cvc l ohe xv ln~ot h ~ - r 1, ~
(2'.2'difllloro)pro~vll-2 2-(d me~^,')oxa~o]idino. The .
resultant compound from Example 42A (1.28 g, 2.85 mmol) in methanol (10 mL) was treated with NaBH4 (0.22 g, 5.82 mmol). After 8 h, MaBH4 (0.11 g, 2.91 mmol) was added and the mixture was stirred for 14 h. After solvent evaporation, the mixture was partitioned between ether and saturated NaHCO3 solution and the organic layer was dried over Na2SO4 and evaporated. Chromatography of the residue on silica gel with 20% ethyl acetate in hexane afforded 0.79 g (68%) of the desired produc~ as a solid: mp 148-199 C; Rf 0.45 (50% ethyl acetate/50~ hexane); 1H NMR (CDCl3) 4.31 4.23 (m, 1 H), 4.07-~.8~ (m, 4 H), 1.62 (s, 3 H), 1.54 (s, 3 H), 1.48 (s, 9 H).
C. ~45.5R.l'R)-3-(t~e~t-ButyLo~ycar~Qnyl)-~=
(cyclohe~ylm~hyl)-5- r 2'.2'-difluoro-1'-hydroxy-3'-(p-The resultant compound from Example 42B (0.374 g, 0.918 mmol) in pyridine (5 mL) at 0 C was trQared with p-toluenesulfonyl chloride (0.195 g, i.02 mmol). After 260 h ~'~92/03429 P~TtUS91/055~
'''''' 208~2g~ -at 0 C, the mixture was evaporated, dissolved in ether, washed sequentially wi~h 0.5 M H3PO4, saturated NaHCO3 solution and brine, and then was d_ied over Na2SO4 and evaporated to arro-d 0.510 g (99~) of a .oam: Rf 0.70 (50%
ethyl acetate/50% hexane); lH NMR (CDC13) ~ 4.56-4.42 (m, 1 H), 4.32-4.12 (m, 2 n), 4.05-3.80 (m, 2 H), 2.47 (s, 3 H), 1.53 (s, 3 H), 1.50 (s, 3 H), 1.48 (s, 9 H).
~ . ( 4 S, 5~ ~y~ ^ ~=~ ~ n y ' ) _ 4 _ (~yclohexylm~tnyL)-~-i8~-a~ido-2~ -ài_luQro-1~-(hyd~Qxy)~rQ~ylL-2 2-l?; ~ oxe-o`:.d~ne The resultant compound rom Example 42C (0.300 g, 0.534 mmol) and ~iN3 (0.130 g, 2.66 mmol) in dimethylfo-mamide (2 m~) were heated at 90 C fO~ 48 h. The mi:~-ur~ was diluted with ethyl acetate, washed with water and brine, and then was dried over Na2SO4 and evaporated. Chromatography o~ the residue on silica gel with 8-12% ethyl acetate in hexane afforded 0.165 g (72%) of the desired product as an oil:
Rf 0.35 (20% ethyl acetate/80% hexane); 1H NMR (CDC13) ~
4.27-4.18 (m, 1 H), 4.00-3.60 ~m, 4 H)~ 1.60 (s, 3 H), 1.52 (s, 3 H), 1.48 (s, 9 H).
E. l4~.5R l'R~-3-~t r~-Rutyloxycar~yl)-4-(cyclohe~y~ h~l~-5- r2 ~ fluoro-~ '-di~hyl?~inQ-l 1-~ The resultant compound from Example 42D (0.~65 g, 0.381 mmol), 35 ~
aqueous formaldehyde (0.3 mL) and iO% Pd/C (0.1; g) in methanol (5 mL) were stirred under a hydrogen a~mosphere for 16 h. The reaction was filte_ed and evaporated to "
afford 0.157 g (95%) of the desired product as a solid: mp 120-121 C; Rf 0.39 (50~ ethyl acetate/50% hexane); lH NMR
(CDC13) ~ 4.28-4.15 (br, 1 H), 4.02 (d, 1 H), 3.96-3.83 (m, 1 H), 3.08-2.76 (m, 2 H), 2.39 (s, 6 ~), 1.59 (s, 3 H), .
' ~`
,."': ' W092/0~29 PCT/US91/0~
20892~
1.53 ~s, 3 H), 1.49 ~s, 9 H). Anal. Calcd for C22H40N2o4F2: C, 60.81; H, 9.28; N, 6.45. Found: C, 60.70; H, 9.22; N, 6.25.
F. The resultant compound from Example 42E (0.028 g, 0.064 mmol) was stirred for 1 h in 4 M HCl/ethanol and evaporated with ether chasers. To this residue was added the resultant acid from Example 1 (0.027 g, 0.066 mmol), 1-hydroxybenzotriazole (0.028 g, 0.207 mmol), dimethylformamide (0.5 mL) and N-methylmorpholine (0.021 mL, 0.191 mmol). The mi~ture was cooled to -23 C and treated with l-ethyl 3-~dimethylaminopropyl)carbodiimide hydrochloride (0.018 g, 0.094 mmol). After 2 h at -23 C
and 14 h at ambient temperature the mixture was poured into saturated NaHCO3 solution and extracted into ethyl acetate.
The organic phase was washed with water and brine, and then was dried over Na2SOg and evaporated. Chromatography of the residue on silica gel with ethyl acetate afforded 0.0134 g (30%) of the desired product as a glass: Rf 0.15 (ethyl acetate). Anal. Calcd for C36H59N37F2: C~ 63-23;
H, 8.70; N, 6.14. Found: C, 63.13; ~, 8.69; N, 5.92.
N-16-~yclohe_yl-2.~-di1~oro-1-dime~hylam;no-3R-hydroxy-4-~XQhe~a~-5(s~-y ~ ~S~-(1(~ -(4-(m~hoxymetho~y)pi~;d; n,_ A. ~45.5R, ) -3- (tert-~utylnxycar~Qnyl)-~-(cycl~he~ylm~thyl)-5- ~'.2'-di~luoro-3'-dimet~ylaminQ-1'-To oxalyl chloride (0.030 mL, 0.35 mmol) in CH2C12 (1 mL) at -60 C was added dimethylsulfoxide (0.040 mL, 0.56 ~mol) in CH2Cl2 (1 mL).
After 15 min, The resultant compound from Example 64 :
' ~;: ', `; ~' , 20892~8 ~92/0~29 PCT/U~9l/Oa5~
_ , .
(0.0509 g, 0.117 mmol) in CH2Cl2 13 mL) was added and the mixture was stirred for 30 min at which point triethylamine (0.125 mL, 0.892 mmol) was added. After 30 min, the reaction was quenched with saturated NaHC03 solution (2 mL), diluted with ether, washed with saturated NaHC03 solution and brine, and then was dried over MgSO4 and evaporated to afford 0.046 g, (91%) of the desired product as an oil: Rf 0.58 (50% ethyl acetate/53% hexane); 1H NMR
(CDCl3) ~ 4.73 (d, 1 H), 2.32 (s, 6 H), 1.48 (s, 9 H).
. Using the procedure of Exampie 42F with the resultant compound from Example 43A gave the desired product as a glass: Rf 0.29 (ethyl acetate). HRMS: calcd for ((M+H)+) of C36HssN37F2 682.4243. Found: 682.4218.
Example 44 Lmethylamino-3(R)-hydroxy~ntan-4(5~-y1L ~L~)-(1~s)-(4-yl-ra~br~vll~e~vl--~h~ h,~
A. (5R.4S)-4-CyclohexyLm~th~l-5- r~ di~luorQ-~ ~-_ (5R,4S)-4-Cyclohexylmethyl-5~[2'-azido-(1',1'-difluoro)ethyl]-2-oxazolidinone IRosenberg, S. H., et al, US 4,857,507) was converted in 73% yield to the desired product using the procedure of Example 42E: R~ 0.26 (50% ethyl acetate/50%
hexane); 1H NMR (CDC13) ~ 2.94 ~ddd, 1 H)-, 2.71 (ddd, 1 H), --2.36 Is, 6 H). --B. ~-4-Amino-5-cyclohe~1-2A2-di~luo~Q-1-The resultant compound from Example 44A (0.243 g, 0.840 mmol) and barium hydroxide octahydrate (0.530 g, 1.68 mmol) in dioxane (9 mL), and , : , :, ;
WO92/~3429 PCT/US91/055~ -~
; 2!j)~9'268 water (6 mL) were heated at reflux for 17 h. The mixtllre was filtered, diluted with water and extracted lnto ether which was dried over Na2SO4 and evaporated to afford 0.185 g (83~) or tr.e desired product as a solid: mp 47-49 C; 1 NMR (CDC13) ~ 3.57 (dd, 1 H), 3.34 (dd, 1 H), 2.98 (ddd, 1 H), 2.72 (ddd, 1 H), 2.37 (s, 6 H). ~al. Calcd ror C13H26N2OF2: C, 59.06; H, 9.91; N, 10.60. Found: C, 59.41; H, 9.90; N, 10.43.
C. Using th~ procedure OL Ex-.~ple 42F wi~:~ tne resultant com~oun~ ~rom r x2m~1e A ~3 ca-ve .:ne desired product as a glass: Rr 0.34 (5~ me~hanol~95~ c~.loroform).
Anal. Calcd for C37H57N3O6F2: C, 6.29; H, 8.79; N, 6.43.
Found: C, 64.41; H, 8.42; N, 6.43.
E;.~am~ 45 hylamino-3-oxo~e~an-4(51-Yl) 2(5)~ (methQxym~thox~)pipe~dL~-1-yl-car~onyl)phenylethoxy)he~an~m1de Using the procedure of Example 43~ with the resultant compound from Example 44C gave the desired product as a glass: R~ 0.49 (5% methanol/95~ c~.lor~form); MS m/e 652 ((M+H)+).
.' ~
-(Bl~(d`methylam;.no)methyLe~e) 5tS~-(2(.$)-t~!S)-~4-(~e$ho~methoxvl~ ridi~-~-v]~car~onyl-~-Dhenyl)ethoxyh~na~do)-6-cyclo~Qxyl-4(~s)-hyd-oxy-2~s)-A. t45.55.2'5)-3-Lter~=~yloxy&2rbcnyl)-~.-(cyclohexylmethyl)-~- r3 ~ -meth~L-2'-r (tet~th~lauan~dln_l)c.a~nyllh~ To 2l~-((3-~;
:', : ~ ,. ::::
.
2~2~8 ~'~92/03429 P~T/VS91/~24 ~. . .
.
_79_ ttert-Butyloxycar3onyl-2~2-dimethvl-4(s)-cyclohexylmeth 5(S)-oxazolidinyl)methyl)-3-methvlbutanoic acid (Fung, et al. PCT Pater._ ~ 9003971) (50.0 -~,g, 0.121 ~ol) and 1-hydroxybenzotriazole (25.0 mg, 0.185 mmol) in dimethylformamide (2 mL) at 0 C ~as added N-methylmorpholine (0.013 mL, 0.12 ~Imol) and N-ethyl-N'-(dimethylamino)p_opy1ca_30diimide :~ydrochlo_idQ (33.0 mg, 0.170 mmol). The mixture was sti--Qd at 0-10 C for 24 h, cooled to -23 C, 2~d t-e~rQ~ w~th 1,1,3,3-tetramethylsuanicine (0.060 mL, C~478 mmol). After 2 h as -23 C and 40 h ~- a.~bient tempe-~-u-e thQ mix~~l~e was poured into salura~ed ~aHC~3 solu lon and e~t-ac~eà into ethyl acetate. Th~ organic phase was washed with water and brine, and then was dried over Na2S04 and evaporated to afford 64.4 mg (100~) of an oil: Rf 0.22 (10~ methanol/90%
chloroform); 1H NMR (CDCl3) ~ 2.90 (s, 12 H), 1.48 (s, 9 H), 1.01 (d, 3 H), 0.95 (d, 3 H).
B. The resultant compound from Example 46A was deprotected and coupled according to the procedure of Example 2C to give the desired product as a glass: Rf 0.12 (10% methanol~90% chloroform); lX NMR (CDCl3) ~ 6.14, 6.05 (2d, total 1 H), 3.34 (s, 3 H), 2.31 (s, 12 ~).
"
E~mDle ~7 ! 2(~ L~(4- (Methoxymethoxy~p~p~rld~ -yl-carhonyL)-Amirlo-3-cycLohexyl-'-hydrt xy)-4-(3,S, SS. 4 ' .SI 5 'R) -5- ~3 '- (t~ utylo~y~a~bony~ -4 ' -(c~ hexylme~hyl~-2' ~ im~thyi~oxaz~olid;~ yll-3-_ cc ~ 1 ~ To . .
~.
.
- . , : . :. .
: ~
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, ~ :, .: :
2 ~ ~2 ~ 29 PCT/U~91/055~ -.., . ., .. ~ ~ .. . ..
(SS,4'S,5'R)-5-[3'-(tert-Butyloxycarbonyl)-4'-(cyclohexylmethyl)-2',2'-(dimethyl)oxazolidin-5'-yl]-3-(methylene)dihydrofuran-2(4 H)-one (905 mg, 2.30 mmol, Rosenberg, S. H., et al., J. Med. Chem. 1990, 33, 1582) in dimethylformamide (10 mL) was added triethylamine (0.42 mL, 3.0 mmol) and benzyl mercaptan (0.31 mL, 2.6 mmol).
The mixture was heated at 50 C for 48 h, cooled, and diluted with ether, which was washed with water and brine, and then was dried over MgSO4 and evaporated.
Chromatography of the residue on silica gel wi~h 10~ ethy acetate in hexane afforded 315 mg (26~) of the 5R-isomer:
mp 144-146 C; Rf 0.36 (20~ ethyl acetate/80% hexane).
Anal. Calcd for C2gH43NOsS: C, 67.28; H, 8.37; N, 2.71.
Found: C, 66.89; H, 8.36; N, 2.62. The SS-isomer (483 mg, 41%) ~as also isolated: mp 114-115 C; Rf 0.26 (20% ethyl acetate/80% hexane). Anal. Calcd for C2gH~3NO5S: C, 67.28; H, 8.37; N, 2.71. Found: C, 67.36; H, 8.45; N, 2.64.
B. ~45. SR~ 1 ' S.3 ' S) -3-(tert-3~yloxycar~nnyl)-4-_~ ~
~ The resultant 55-isomer from Example 47A (399.6 mg, 0.772 mmol) in ethanol (2 mL) was treated wi~h CaCl2 (156 mg, 1.55 mmol).~ After a homogeneous solution was obtained, tetrahydrofuran ~1.2 mL) was added followed by NaBH4 (117 mg, 3.09 mmol). After 20 h at ambient temperature the mixture was diluted with ether, washed with 0.5 M H3PO4, saturated aqueous NaHCO3 solution, and brine, and then was dried over MgS04 and evaporated. Chromatography of the residue on silica gel with 25% ethyl acetate in hexane afforded 379.1 mg (94%) of the desired product as a solid:
~'' ,.
:
~" ' .: ~ : .. ,.,.. , : . : ~
~r~ 92/03429 2 0 ~ ~ 2 6 8 PCT~US91/0;~2J
mp 99-101 C; Rf 0.47 (50% ethyl acetate/50% hexane).
Anal. Calcd for C2gH47NOsS: C, 66.76; H, 9.08; N, 2.68.
Found: C, 66.76; H, 9.03; N, 2.76.
C . ( 4 S. ~R. 2 ' S, 4'$~ -3- ~t~rt-R~ 2~yc~ rbonyl)-4-(~enzy1~lL~2~e~hy~ trahydrofur2n-2'-yl~ O~Ql ~din~. The resultant compound from Example 47B (341.1 mg, 0.654 mmol) and triphenylphosphine (393 mg, 1.50 mmol) in tetrahydrofuran ~6 mL) at -10 C were treated with dietn~
azodicarboxylate (0.20 mL, 1.3 mmol). After 90 min at -10 C and 18 h at ambient temperature the solvenr was evapora~ed and the residue was chromatographed on silica gel with 4% e~hyl acetate in hexane to afford 274 mg (83~) of a white solid: mp 67-69 C; Rf 0.52 (20% ethyl acetate/80% ~exane). Anal. Calcd for C2gH45NO4S: C, 69.15; H, 9.00; N, 2.78. Found: C, 69.03; H, 8.95i N, 2.73 1') . ( 4 S, 5R! 2 ' ~. 4 ' ~ 3- ~ -Buty~c~Ç~
, _ The resultant compound from Example 47C (145.0 mg, 0.288 mmol) in CH2Cl2 (8 mL) w s treated with meta-chloroperbenzoic acid (300 mg, 0.9 mmol, 50% pure). After 30 min at ambient temperature, the mixture was evaporated and dissolved in ethyl acetate which was washed with 1:1 10% aqueous Na2S03 solution/saturated aqueous NaHCO3 solution, saturated aqueous NaXCO3 solution, and brlne, and then was dried over Na2SO4 and evaporated to afford 152 mg (99%) of a white solid: mp 178-179 C; Rf 0.52 (50% ethyl acetate/50% hexane). Anal. Calcd for C2gH4sNO6S-0~5 H2O:
.
, ...
::.
:~
.; .
.
: .
.
W092/0~29 PCT/US91/055~-~
92~3.
C, 64.21; H, 8.50; N, 2.64. Found: C, 63.94; H, 8.51; N, 2.57.
~ The resultant compound from Example 47D was deprotected and coupled according to the procedure of Example 2C to give the desired product as a foam: Rf 0.22 (ethyl aceta-te). Anai. Calcd Ior C43H64N2OgS-0.75 H20: C, 64.68i H, 8.27; N, 3.51. Found: C, 69.47; H, 8.06; N, 3.55.
.
~ ^ Q~
5(C)~ S)-(4-(Methoxy~er:noxy)piper;d~n-Lyl)car~on~vl-2-~n~ .h.~.~vh~Y~n~m ~)-5-~ ~Y~ (S)-hvd~o~y-~ ro~y~-'-hexanol A . ( 2 S, 4 S, i ~ - 6-cy~lohexyL-~ Q~ro~vl=l~-hexan~ Ql A solution of (2S,4S,5S)-5-amino-6-cyclohexyl-4-hydroxy-2-isopropylhexanoic acid lactone-(1.0 g, 2.6 mmol, Bradbury et. al, J. Med. Chem. 1990, 33, 2335-42), calcium chloride (O.573 g, 5.2 mmol) and sodium borohydride (0.39 g, 10.5 mmol) in 40 mL of THF were stirred at 0-5 C for 2 h, then at room temperature for 2 h. The reaction was recooled to 0-5 C, ether was added, and 1 M potassium hydrogen sul~ate was added until gas evolution ceased. The separated organic layer was washed seauentially with saturated sodium bicarbonate and sodium chloride, then dried (MgSO4).
Evaporation of the solvent gave 0.910 g of a crude white solid which was purified by column chromatography using 1:3 ethyl acetate-hexane, to give 0.754 g (74~) of diol: mp 112 C; 1H NMR (CDC13) ~ 7.41-7.27 ~m, 5 H, Ph), 5.11 (s, 2 H, O-CH2), 4.91 (br d, lH~ J = 9 Hz, N H), 3.77-3.56 br m, 3 H, HOCH2 and HOC H), 3.05 (b= a, 1 H, O H), 2.25 - ., ~, ~ ., . : :.
: , . , : . ............... .
.. : ..... ~ . . .
, ~
~92/034~9 PCT/~S9l/~S~
2~92 J ~
~br s, 1 H, O H), 0.87 (dd, 5 H, J = 3 and 7 Hz, isopropyl); IR (CDCl3) 3617, 3428, 2957-2835, 1707, 1505, 1442, 1223, and 1038 cm~1. Anal. Calcd for C23H37NO4: C, 70.55; H, 9.52, N; 3.58. Found: C, 70.98; H, 9.63; N, 3.55.
~ . (25.45.~5~-5-.~ino-k-o~lohexyl-2-lso~ro~yl-1 4-heYanediol~ A s~mple of diol fror ~amplo 48A (0.350 g, O.89 mmol) and 4Q mg of 10~ Pd/C 1-. 100 mL me~hanol ~as hydrogenated at 4 atm. Filtration of the catalyst and evaporation ol .he solvent gave 230 mg of amino diol which was used without further purification.
C. Thè ~rocedure o~ Exam~le 2C, ~art 2, was adapted:
191 mg (0.4 ~ol) or acid rrom E.Ya.?.?le 1, amino àiol from Example 48B (110 mg, 0.427 mmol), and HOBT (95 mg, 0.7 mmol), in 1.5 mL DMF cooled at -23 C was added EDCI (90 mg, 0.44 mmol). The reaction mixture was stirred and allowed to warm slowly to room temperature over 18 h. The DME was evaporated and the residue was purified by flash chromatography (3% methanol/methylene chloride). The desired product was isolated in 40% yield (108 mg): mp 47-54 C; lH NMR ~CDCl3) ~ 7.38-7.26 (m, 5 H, Ph), 5.87-5.7 (br dd, two rotomers, 1 H, amide N i), 4.65 (s, 2 H, OCH2O), 4.59-4.51 (4 line m, 1 H, COCHO), 3.35 (s, 3 H, CH30), 0.96-0.83 (6 line m, 6 H, isopropyl); IR (CDC13) 3380, 2949-2840, 1644, 1520, 1444, 1142, 1090/ 1038, 870-950, and 795-600 cm 1. Anal. Calcd ,or C37H62N2O7: C, 68.70; H, 9.66; N; 4.33. Found: C, 67.99; H, 9.53; N, 4.41.
;.
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, W092/0~29 PCT/US91/0~
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,' ~m~2 N-(3-(4-Morpholino)~ropyl) 5(5)-(N-(1(~5)-(~-(methoxvm~ho~y)piperidtn-1-yl?ca~o~l-2-Dhenyl) ethyl-_-noFl~llc~ idQl 6-cyclQh~xyl-4 (~)-hyd~oYy-2 (~C~-sQ~rc~vlh~xanz~
A. N-(3-(a-Mor~hsl1nQ)propy1) (2.C. .S ~$)-5-~ ar'_-buty~Q~yca~honyl)~LL~o-4-hyd-Qxy-2-isQ~ vLh~;~.n~mi~e 2-Isopropyl-4-[1-(tert-butyloxycarbonylamino)-2-cyclohexyl]ethyl-y-butyrolactone ~4.0018 g, 11.32 ~mol, Bradburv, R. H., et al ., Tetrahed-on Lett. 19~9, 30, 3845) and 4-(3-aminopropyl)morpholine ('~.5 mL, 0.1124 m~mo ) ~e__ warmed at 60 C for 96 hours. The reaction mix.ure was partitioned between water (150 mL) and methylene chloride (120 mL). The organic phase was washed with water (3 x lC
mL) and brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford a solid whic was recrystallized from hot ethyl acetate to afford the title compound ~4.719 g, 84%): mp 161-2 C; Rf 0.18 (7.5%
MeOH CHCl3); lH NMR (CDC13) ~ 0.73-1.04 (br m) and 0.93 (2 overlapping d, 8 H total), 1.05-1.50 (br m) and 1.45 (s, 17 H total), 1.58-1.77 (br m, 10 H), 1.79-2.03 (m, 4 H), 2.41-2.52 (m, 6 H), 3.2S-3.45 (m, 2 H), 3.43-3.59 (br m, 2 H), : 3.68-03~74 (m, 4 H), 3.90 4.10 (br m, l H), 4.65 (br d, 1 H), 7.04 (br m, 1 Hj; MS m/e 498 ((M+H)+). Anal. Calcd for C27Hs1N3Os- H20: C, ; H, ; N, . Found: C, ; H, ; N, .
1~ To the compound resulting from Example 49a (3.1765 g, 6.38 mmol) suspended in methylene chloride (16 mL) and cooled to 0 C was added trifluoroacetic acid (16 mL) over 30 minutes. The resulting solution ~as stirred at 0 C for 4 hours and then additional TFA (6 mL) . .
.
.. . . .
W092/0~29 2 ~ 6 8 PCT/US91/0~5~
; , . , was added. After 2 hours, the flask was sealed and allowed to stand in the refrigerator for 12 hours. The mixture was concentrated under reduced pressure and the residue obtained basified with 4M sodium hydroxide solution. Tr.e solution was saturated with sodium chloride and extracte~
with 5% isopropanol in chloroform (4 x 25 mL~. The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, and concentrated in vacuo to give N-[(4-morpholino)propyl]-5(S)-amino-6-cyclohexyl-4(~)-hydroxy-2 (S)-isopropylhexanamide (2.8851 g, lOO~) as a waxy solid: 1~ NMR (CDCl3) ~ 0.70-1.00 (br m), 0.92 (d) and 0.95 (d, 8 H total), 1.00-1.93 (several br m, a?pr~:~
l9 H), 2.03-2.14 (m, 1 H), 2.40-2.S1 (m, 6 H), 2.52-2.62 (m, 1 H), 3.02-3.14 (m, 1 H), 3.25-3.45 (m, 2 H), 3.65-3.80 (m, ~ H), 6.77-6.85 (br m, 1 H); MS m/e 398 ((M+H)+).
Anal. Calcd for C22H43N303 1.5H20: C, 62.23; H, 10.92; N, 9.90. Found: C, 62.63; H, 10.57; N, 9.76.
~ a~_2~ To the above amino alcohol (2.7942 g, 6.38 mmol), the compound resulting from Example 74 (2.7217 g, 6.695 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (1.4626 g, 9.55 mmol), and N-methylmorpholine (NMM) (l.Oa mL, 0.966 g, 9.55 mmol) dissol~ed in dimethylformamide (DMF) (24 m ) and cooled to -10 C was added 1-ethyl-3-(3'-dimethylamino)-propylcarbodiimide ~EDC) (1.5910 g, 8.30 mmol). The reaction mixture was stirred at -10 C, allowed to gradually warm to ambient temperature, and stirred at ambient temperature for 3 days. The reaction mixture was concentrated under reduced pressure and then partitioned between methylene chloride (75 mL) and 4:1 saturated sodium bicarbonate/water (2 x 25 mL). The organic phase was washed with brine (25 mL), dried over sodium sulfate, and . . , . ~ .
,, :
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W092/0~29 PCT/~S91/055~ ..
: ~ o~9 2 6~ . -86-concentrated under reduced pressure to afford an amorphous solid (2.0314 g, 2.5325 mmol, 94%). Flash chromatography on silica gel eluting with a gradient (10%,15%) of methanol ln methylene chloride afforded the title compound as an amorphous solid (1.74 g, 65%): m? 85-95 C; Rf 0.19 (6%
MeOH-CH2Cl2); 1H NM~ (CDCl3) ~ 0.67-1.00 (br m), 0.89 (t) and 0.94 (d, 11 H total), 1.00-2.00 (several br m, 29 H), 2.0-2.14 (m, 1 H), 2.20-2.43 br m) and 2.~0-2.60 (br m, 6 H
total), 2.67-2.87 (m, 3 H), 2.95-3.07 (br m) and 3.3.15-3.34 (br m, 3 H ~5~âl) ~ 33.36 (2 s) and 3.34-3.95 (several br m, 14 H total), 4.65 (2 s, 2 H), 6.73-5.91 (br m, 2 H), 7.20-7.35 (m, 5 H); ~S m/e 786 ((M+H)+). Anal. Calcd for C44H7~N507- H20: C, ; H, ; N, . Found: C, ; H, ; N, .
E~?m~le ~Q
~-(2-Py~idy.lmethyl) 5~S)-(N-(1(5)-(4-(methQx~m~thQ~)pipe~;d~ yl)car~onyl-2-~henyl~ L-L-L-hyd~o~y-2(~)-; so~ro~yllleXarlami~
A~ ~-(2-Pyridylm~thyl! (2~ .5S)-5-(t~-The ~roeedure of Ex2mple 49A W2~ employed, with the substitution of 2-(aminomethyl)pyridine, to provide the title compound: mp 128-9 C; lH NMR ~CDCl3) ~ O.95 (d, 6 i H), 1.06-1.25 (br m, 6 H), 1.45 (s, 9 H), 1.63 (m, 7 H), 1.75-1.96 (br m, 4 ~), 2.17 .(ddd, 1 H), 3.44 (d, 1 H), . 3.54 (br s, 1 H), 4.28 ~dd, 1 H), q.72 ~d, 1 H), 5.02 (dd, 1 H), 7.50 ~br s, 1 H) r 7.22 (dd, 1 H), 7.28 (d, 1 . H), 7.69 (ddd, 1 H), 8.43 (d, 1 H); ~S m/e 462 ((M+H)+).
An21. Calcd for C26H43N3O4: C, 67.65i H, 9.39; N, 9.10.
Found: C, 67.60; H, 9.29; N, 9..12.
~:;
.
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W~ 92/03429 PCr/US91/055~
."`' , 2~9268 i ~
87~ , E~. The procedure of Example 49B was employed, with the substitution ol the resultant compound from Example 50A
for the resulLant compound from Example 45A, to provide the title compound: mp C; Rf 0.32 (5~ MeOH-CH~Cl2); 1H NMR
(CDCl3) â ; MS m/e (M+NH4)+. Anal. Calcd for CnHmNC,Op-H20: C, ; H, ; N, . Found: C, ; H, ; N, 3,Q S l tho~ræ~ ~ ~ ~== -- ~~
norle~lclna~idQ)-6-cyclohe~ (s)-hydrQx~-2( iso~ro~ylhexana~.~de.
(.3-~yridylrneth.yl.) (2.C. 45. 5~s~ -5- (t~rt-butylQ~yc~70nyl~ amino-4-hydrox~-2-~ ~o~ro~ylhe~anarn~de.
The procedure of Example 49A was employed, with the substitution or 3-(aminomethyl)pyridi.ne for 4-(3-aminopropyl)morpholine, to provide the title compound as white needles ~50% yield): mp 147-49 C; [a]2sD = -36.4o (c 1.12, CHCl3); lH NMR (CDCl3) ~ 0.~1 (d, J = 6 Hz, 3 H), 0.93 (d, J -- 6 Hz, 3 H), 1.43 (s, 9 H), 3.35-3.56 (br m, 2 H), 4.37-4.55 (8 line m, 2 H)i 4.62 (b~ d, 1 ~), 6.35-6.45 ~br .i s, 1 H), 7.24-7.34 (br s, 1 H), 7.63 (br d, 1 H), 8.47-8.63 .j (br d, 2H ); MS m~e 462 ((M+H)+). Anal. Calcd for C26H43N3O4: C, 67.67; H, 9.32; N, 9.11. Found: C,67.97;
H,9.20; N,9.15.
The procedure of Example 49B was employed, with the substitutian of the resultant compound from Example 5lA
for the resultant compaund from Example 49A, co provide the title compound as a pale yellow foam (75% yield): mp 60-68 C; Rf 0.45 (10% MeOH-CH2C12); 1H NMR (CDC13) ~ O.64-2.0 ~ ' .
' .
,...
: , " ~ . : .
. . . .
, . .; ." , .. .. .
2 ~ ~ 9 2 ~ 8` -88-(several br m, approx. 36 H), 2.13-2.25 (br m, 1 H), 2.63-2.77 (br m, 1 ~), 2.77~2.90 (br m, 2 H), 3.00-3.31 (br m, 2 H), 3.34 (s), 3.35 (s) and 3.31-3.81 (several or m, 8 H), 3.81-3.94 (br m, 1 H), 4.35 (dd, 1 H), 4.55-5.70 (m, 3 H), 6.20-6.30 (m, 1 H), 6.79 (d) and 6.85 (d, 1 H total), 7.19-7.37 (br m, approx. 5 H), 7.66 (br d, 1 H), 8.52 (br d, 2 H); MS m/e 750 ((M~)+).
Exam~le_52 N-(4-~yridv~me~hyl) 5(~ N-(l(~s)-(a (methoxy~e~.hoYy~pl~e-ldin-1-yl)c~-bonvl 2- hen~
nor~e~cin~m~o)-6-cyclohexy'-4!s)-hydro~y-2(~) -(4-Pyr~dylm3~hyl) (?sl 4.S,5S)-5-(tert-hutyl~o~ycarbonylka~ino ~-hydroxy=2-isopropylha~anamlde.
The procedure of Example 49A was employed, with the substitution of 4-(aminomethyl)pyridine for 4-(3-aminopropyl)morpholine, to provide the title compound: mp 145-6 C; Rf 0.32 ~10% MeOH-CH2C12); lH NMR (CDCl3) 8 0.95 (d, 6 H), 1.14-1.36 (br m, 6 H), 1.43 (s, 9 H), 1.58-1.82 (m, 10 H), 1.94 (m, 1 H), 2.18 (br s, 1 H), 3.47 (m, 2 H), 4.47 (dd, 2 H), 4.56 (br s, 1 ~), 6.19 ~br s, 1 H), 7.22 (d, 2 H), 8.57 (d, 2 H); MS m/e 461 ((M+H)+).
Anal. Calcd for C26H43N3O4: C, 67.65; H, 9.39;N, 9.10.
Found: C, 67.2B; H, 9.30; N, 9.07.
B ! The procedure of Example 49B was employed, with the substitution of the resultant compound from Example 52A
for the resultant compound from Example 49A, to provide the title compound as an off-white foam (67% yield): mp 71-6 C; Rf 0.50 (5~ MeOH-CH2Cl2); 1H NMR (CDC13) ~ O.65-1.95 (several br m, approx. 3S 3), 2.17-2.30 (br m, 1 3), 2,65-:
: .
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~og~/034~9 2 ~ 8 9 2 6 8 PCT/VSgl/o~
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2.91 (br m, 3 H), 2.97-3.13 (br m, 1 H), 3.14-3.29 (br m, 2 H),3.35 (2 s) and 3.30-3.80 (br m, 9 H total), 3.80-3.91 (br m, 1 H), 4 .28-4.40 (m, 1 H), 4 .55-4.60 (m, 3 H), 6.27-6.40 (m, 1 H), 6.82-6.98 (m, 1 H), 7.18-7.35 (m, approx. 8 H), 8.55 (d~ 2 H); MS m/e 750 ((M+H)+). Anal. Calcd fo~
C43H67NsO6: C, 68.86; H, 9.00; N, 9.34. Found: C, 68.79;
H, 8.99; N, 9.30.
Example ~3 N-(2-(~ Qr~hi211n~)e~hy~ s~ )-(4-~metnoxymethoxy)~ din-1-vllG~onyl-2-~henyl~eth~l-T-norleucinamido)-6-cyclQhe~yl-4(5)-hydrQ~y-2(5L-,oprcDylhexanamide A~_ N-(2-(4-Morpholino)ethyl) (2~ ~S.55)-5-(te~t-~;,ylQxycarbonyl)am~nQ-4-hydroxy-2-;soprQpylh~car~m~de.
The procedure of Example 49A was employed, with the substitution of 4-(2-aminoethyl)morpholine for 4-(3-aminopropyl)morpholine, to provide the title compound as a white needles ~rom EtOAc-hexane (1:1) (58~ yield): mp 151-2 C; lH NMR (CDC13) ~ 0.68-0~98 (br m, 8 H), 1.05-1.35 (m, 7 H3, 1.43 Is, 9 H), 1.54-1.75 ~m~ 6 H), 1.77-1.95 ~m, 2 H), 1.97-2.08 (br m, 1 H), 2.30-2.69 ~m, 6 H), 3.17-3.30 ~m, 1 H), 3.~0-3.61 (m, 3 H), 3.64-3.77 (m, 4 H), 4.73 (br d, 1 H), 6.04 ~br s, 1 H); MS m/e 484 ((M+H)+). Anal.
Calcd for C26H4gN3Os-0.25H20: C, 63.97; H, 10.22; N, 8.61.
Found: C, 64.07; H, 10.05; N, 8.68.
B_ T~e procedure of Example 49B was employed, with the substitution of the resultant compound from Example 52A
for the resultant compound from Example 49A, to provide the title compound as an off-white solid ~77% yield): mp 59-69 C; Rf 0.38 ~5~ MeOH-CH2Cl2); 1H NMR (CDC13) ~ 0.66-1.00 . . . .. . .. .
:
' :.,. i WO~/0~2g PCT/~S91/~55~ t 2~9~6~ - -90-(br m), 0.89 (t) and 0.94 (d, 11 H total), 1.00-1.95 (several br m, approx. 26 H), 2.05-2.16 (m, 1 ~.), 2.302.51 (m, 6 H), 2.52-2.64 (m, 1 H), 2.75-2.86 (m, 2 H), 2.90-3.01 (m) and 3.16-3.33 (br m, 2 H total), 3.35 (s) and 3.37-3.60 (m, 8 H total), 3.60-3.93 (br m, 7 H), 4.65 (d, 2 H), 6.01-6.10 (br m, 1 H), 6.84 (d) and 6.9~ (d, 1 H total), 7.20-7.36 (m, 5 H); MS m/e 772 ((M+H)+). Anal. Calcd for C43'i73NsO7 0.5X20: C, 66.12; H, 9.5~; N, 8.97. Found: C, 66.12; H, 9.54; N, 3.97.
F~m?~ 59 m;no-2-methyl~ro~yl) '!s~-(N-Ll~-(4-~methoxymethoxyL~,~2e.ridin-L-yl)carbonyl-2-phenyl2~thyl-L-nor~Quo~n2~QL-~-cyclQhQ~yl-4(~s)-hydroxy-2~s)-A. N-(2-~m;no-2-methylpropyl) (25,45.55)-5- (tert-~utylo~ ycarbonyl? amir~o-~-hyc~3;.o~2;v-2-i~o~ o~ylhaxa~
The procedure of Example 49A was employed, with the substitution of 1,2-diamino-2-methylp:ropane for 4-(3-aminopropyl)morpholine, to provide the title compound as white needles (EtOAc-hexane) (71 % yi~eld): mp 133-6 Cj 1H
NMR (CDCl3) ~ 0.70-1.03 ~br ml and 0.94 (d, 8 H total), 1.03-1. 50 ~br m), 1.12 (s), 1.17 (s) and 1.49 ~s, 21 H
total), 1.52-2.00 (br m, 9 H), 2.01-2.12 (m, 1 H), 2.96 (br dd, 1 H), 3.40 (br dd, 1 H), 3.47-3.59 (br m, 2 H), 9.66 (br d, 1 H), 6.04-6.13 (br m, 1 H); I!qS m/e 442 ((M+H)+).
Anal. Calcd for C24H47N3O4 0.25 H20: C, 64.61; H, 10.71; N, 9.42. Eound: C, 64.64; H, 10.75; N, 9.28.
B. The procedure of Example 49B may be employed, with the substitution of the result:nt compound from Example 54A
, ', . .
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W092/0~29 PCT/VS91/05524 2~8926~
for the resultant compound from Example 49A, to provide the title compound.
,,~ S
N-(2-Methyl-2-(4-mor~holino)p~Q~yl! 5(~)-(N-(l(S)~(4-^~ Q-hQ~ erid r-'~ )ca-bonyl-2-~henyl~ethyl-L-norL~ucln~ml~o)-6-cvcl~he~yl-4(5~-hydro~y-~
_SO?r"~'l h.''~!''~'ni~'', A. N- (2-.~ `a,~1-2- (a-~Q~ ho~ ~ ~o) ,~rQ~yl~ i aS. 55) -5-(~e-.~-bllr~lo~ Qon~`~)~2~0-a-h~ x~-2 -~_D~ e~_ _~ The crude ~as pu-i~ied by flash chromatography (0.5~ MeOH-EtOAc) to afford the desired compound as a white solid: mp 132-5 C; Rf 0.26 (5% MeOH-CH2Cl2); 1H NMR (CDC13) ~ 0.76-1.01 (br m), 0.94 (d) and 0.97 (d, 8 H total), 1.04 (2 s, 6 H), 1.09-1.50 (br m) and 1.46 (s, 16 H total), 1.52-2.00 tbr m, approx. 8 H), 2.04-2.15 (br m, 1 H), 2.49-2.S6 (m, 4 H), 3.19 (d, 2 H), 3.45-3.60 (br m, 2 H), 3.67-3.77 (m, 4 H), 4.65 (br d, 1 H), 6.31 (br t, 1 H); MS m/e 512 ttM~H)+). Anal. Calcd for C2gHs3N3Os: C, 65.72; H, 10.44; N, 8.21. Found: C, 65.67;
H, 10.25; N, 8.1~.
B The procedure of Example 49B was employed, with the substitution of the resultant compound from Example 55A
for the resultant compound from Example 49A, to provide the title compound as a foam (71% yield): mp 55-60 C; Rf 0.13 t4% Me-CH2Cl2); 1H N~R tCDC13) ~ 0.67-1.00 (br m), 0.89 (t) and 0.94 (d, 11 H total), 1.00-1.20 (br m), 1.05 (s) and 1.06 ts~ 11 H total), 1.22-1.92 (several br m, approx. 20 H), 2.13-2.26 (m, 1 H), 2.26-2.50 (vbr m, 1 H), 2.51 (m, 4 H), 2.65-2.86 ~br m, 3 H), 2.95-3.08 (br m, 1 H), 3.08-3.34 (br m, 4 H~, 3.36 (5) ~nd 3.35-53 60 ~b~ m, 6 3 total), W092/03429 PCT/U~9l/0~5~
~: . - .. ,, , - , i ~ 5 ~ -' ~ 92-3.60-3.9~ (br m, 6 H), 4.65 ~d, 2 H), 6.24-6.31 (br m, 1 H), 6.79 (d) and 6.88 (d, 1 H total), 7.20-7.36 (m, 5 H).
Anal. Calcd for C4sH77NsO7-H20: C, 66.06; H, 9.73; N, 8.56.
Found: C, 66.03; H, 9.43; N, 8.48.
E~am~le 56 N-(2~(?-Pvr;dyl)~th~l) 5~5)-(~1-(l(S)-('-(methoxymethoxy)~i~er;di~-l-yl)car4o~yl-2-~h~nvl)er.h~vl-T-norleueinamido)-6-cyclQh~yl-4(~-nvd-~Yv-2!~-A. N- (?- ~2-~y~(?S, 45 5S) -'- (- ~
but~lQxycar~onvl)a~inQ-~=hy1~ç~ s^~ vl~ a-.2-l-.d~, The procedure of Example 49A was employed, with th~
substitution of 2-(2-aminoethyl)pyrldine for 9-(3-aminopropyl)morpholine, to provide the title compound as needles (58% yield): mp 124-26 C; [~]25D = +17.7 (c 1.9, CHCl3); 1H NMR (CDCl3) ~ 0.86 (d, J = 6 Hz, 3 H), 0.91 (d, J
= 6 Hz, 3 H), 1.44 ~s, 9 H), 2.95 (t, J = 6 Hz, 2 H), 3.18 3.31 (br m, 1 H), 3.50-3.63 (br m, 2 H), 4.00-4.13 (br m, 1 H), 4.71~br d, J = 9 Hz, 1 H~, 6.30-6.38 (br s, 1 H), 7.18-7.25 (br d, 2 H), 7.69 (t d, J = 9, 1 Hz, 1 H), 8.45-8.52 (br d, 1 H); MS m/e 476 ((M~H)+). Anal. Calcd for C27H4sN304: C, 68.21; H, 9.47; N, 8.84. Found: C,68.33i H,9.55; N,8.85.
~ _ The procedure of Example 49B was employed, with the substitution of the resultant compound from Exam?le 56~
for the resultant compound from Example 49A, to provide the title compound as a white foam ~79% yield): mp 52-6 C; Rf 0.11 (5% MeOH-CH2Cl2); 1H NMR (CDC13) ~ 0.62-1.00 (br m) and 0.84-0.92 (overlapping t and d, 11 H total), l.OQ-1.96 (several br m, approx. 27 H), 2.04-2.14 (m, 1 H), 2.20-2.57 (vbr m, 1 H), 2.80-2.90 (m, 3 H), 2.98 (t, 2 ~), 3.07-3.20 . :
WO92/0~29 2 ~ ~ ~ 2 ~ 8 PCT/~S91/05~
(m), 3.33 (s) and 3.27-3.57 (br m, 7 H total), ~.57-3.98 (br m, 5 H), 4.20-4.55 (vbr m, 1 H), 4.62 (2 s, 2 H), 6.40 (br t, l H), 7.00 (d) and 7.07 (d; 1 H total), 7.15-7.34 (m, approx. 6 H), 7.66 (td, l H), 8.51 (dd, 1 H) and ; ~IS
m/e 769 ((M+H)+). Anal. Calcd for C44H69N56 -5~2: C, 68.36; H, 9.13; N, 9.05. Found: C, 68.55i H, ~.9~; N, 9.04.
~xam~le 57 N-~3-~a-Oxido-~-morphollno)~r~yl? ~ (s)~
(methgxymethQ~iDeridin~L-yl~cz~onyl-2-~henyl)ethyl-E-norleuGin~mi~o)-6-cyclohexyl-4(.C)-hvd oxv-2(.S)-i.sQprQQylhe~a~mide.
A.. N-(~-(4-~x;do-4-morpholino)~LQ~yl) (2~.4~5S)-5-(te~L~hl~h~vcarbQnvl)am1no-a-hvdro~v~2-9~_L~y_b~m~s_ The procedure of Example 36 wasemployed, with the substitution of the resultant compound from Example 49A for the resultant compound from Example 11, to provide the title compound as a white powder (92%
yield): mp 154-7 C; 1H NMR (CDCl3) l~ 0.69-1.03 (br m), 0.91 (d) and 0.93 (d, 8 H total), 1.03-1.40 (br m, 6 H), 1.43 (s, 9 H), 1.50-1.75 ~br m, 6 H), 1.80-1.95 (b- m, 3 H), 1.97-2.30 (br m, 6 ~), 3.05-3.38 ~br m, 6 H), 3.36~3.50 (m, 2 H), 3.50-3.71 (br m, 2 H), 3.75-3.86 Ibr d, 2 H), 4.30-4.44 (m, 2 H), 4.81 (br d, 1 H), 7.96-8.05 (br s, 1 H); MS m/e 514 ((M+H)+), 498 (M-16+H)+. Anal. Calcd for 27HslN36 H20: C, 60.99; H,-10.05; N, 7.90. Found: C, 61.05; ~, 9.98; N, 7.93.
~ The procedure of Example 493 was employed, with the substitution of the resultant compound from Example 57A
for the resultant compound from Example 49A, to provide the ,~
:$
;
, ' , W092/03429 - PCT/~S91/05524 ~,o~9~6~ .
title compound as a tan foam ~65~ yleld): mp 85-95 C; Rf O.lS ~10~ MeOH-CH2Cl2); 1H NMR ~CDCl3) ~ 068-l.00 ~m, 11 H), 1.00-1.41 ~br m, 12 H), 1.41-2.20 ~br m, approx. 18 H), 2.20-2.40 ~br m, 2 H), 2.70-2.88 ~m, 3 H), 2.94-3.06 ~br m, 2 H), 3.06-3.27 ~br m, 2 H), 3.27-3.55 ~br m), 3.35 ~s) and 3.36 (s, 9 ~ total), 3.35-4.16 ~several br m, 7 H), 4.24-4.40 (m, 2 H), 4.65 ~2 s, 2 H), 6.87-6.96 (dd, 1 H), 7.25-7.39 (m, 5 U), 8.'0-8.19 (br m, 1 H) and ; MS m/e (M~N~4)+. Anal. Calcd for C44~75N5Gô-3H20: C, 61.73; H, 9.~4; N, ~.13. Found: C, 61.74; H, 9.15; N, 8.05.
Ex~le 58 N-(~-(2-uyd~x~thy~L~ n~prA~y~ ~?-(~-(l(s)-(4-(metho~yme~hoxy)~iper1din-1-yl)c~_~onyl-2-~henyl)e~hyl-L-ncrleucinamido)-6-cyclohe~yl-4(5)-hyd~oxy-2(~)-isopropylhexanamide.
The procedure of Example 5B can be employed, with the substitution of the resultant compound from Example 74 for the resultant cumpound from Example 1, to provide the title compound.
;~ ~a~ple ~
(me~ho~y~ethQ~y)~L~erid1n-1-yl?caxbonyl-2-phenyl)ethy~-L-norleucln~mido)-6-c~lQhe~ L-h~l~oxY-2(s)-The procedure of Example 2C may be employed, with the substitution of the resultant compound from Example 74 for the resultant compound from Example 1, to provide the title compound. ~' .
, , WO ~2io3429 ~CT/US91/05524 2~268 i. ~
~hQ
N-(3-.~ o~ro~yl) 5(~)-(M~ L-(4-(methoxyme~ho~y~ Qridln-1-yl)c2r~Qnyl-2-~henyl!ethyl-T.-orleucin~midQ)-6-~yclohPxyl-4(5)-ht~dro~y-2(SI-,i soDropylhe~2nalrude .
The procedure of Example 3 can be employed, with the ~,substitution of the resultant compound from Example 59 fo~
the resultant com~ound from E~ample 2, to provide the title compound.
'`'~a~, 1 Q 6 ;~N-(3-~ hy1~-4-mor~holinium)gro~yl~ 5(5)-~N-(l(.SL-(4-(~etho~yme~hoxy)~i~srldin-1-yl!carbQnyL-2-~hen.yl~ethyl-~-norleucin2midQ)-6-cyclohexyl-~(S)-hydroxy-2~5)-isoDropy~hexanamide iQdide~
~;~The resultant product from Example 49 (49.9 mg, 63.5 ~mol) was dissolved in 0.4 mL THF, cooled to 0 C, and iodoethane (5.2 mL, lO.1 mg, 65.0 mmol) was added. The solution was stirred at 0 C for 6 h, then at room 'Jtemperature for an additional 12 h.
N~l~-Ll~LmidazolyLL~IQD~1) 5~C)-~N-(~(S~-(4-:,' .,, ~
i. .~opropylhe2~nam~
~:2~ N-(3- U-Im;da~Qlyl~rQ~yl) (~. 4S. ~5~-5- (tert-. . .
but~loxycar~onyl)am;no-4-hydroxy-2-isoprQ~ylhexanami~_ `The procedure of Example 49A was employed, with the substitution of 1-(3-aminopropyl)imidazole for 4-(3-.~ .
.
, ,:
. ' :: . .
WO92/03429 PC~tUS91/055~
... ..
0~ 96-aminopropyl)morpholine, to pro~ide the tltle com~ound as white needles (27% yield): mp 148-150 C; I~ 1620-1740 cm~
l; lH NMR (CDCl3) ~ 7.56 (s, 1 H), 7.07 ~s, 1 H), 6.96 (~, 1 H), 5.87 (br d, 1 H), 4.64 (br à, J = 9 H-, 1 H), 4.02 (t, J = 6 Hz, 2 H), 3.57-3.38 (br m, 2 H), 3.27 (A~, J = 6,
, , E~am~L~
N- ( 2-~a-boxyethyl) 5(5)-(2l5~-~1(.$)-(4-(methoxy~ ho~ylpiperi~in-~_yl~c~r~Qny1~2-. N-((2-(O-Eth~l~carhoxy)e~h~rl~ 2(s!-((3-(~rt-butylsx~Garbonyl)-2.2-dimethyl-4(5)-cyGLQhexylmethyl-5(5)-oxaz~lidlnyllm~t~yl~-3-m~thylbu~a~amj~ The procedure o~
Example 2~ was employed, with the substitution of ~-alanine ethyl ester hydrochloride for the resultant compound from , Example 2A, to provide the title compoundoil (quantitative ;~ yield): Rf 0.55 ~2.5% MeOH-CH2Cl2); 1H NMR (CDCl3) ~ 0.80-1.90 (several br m, 16 H approximately), 0.92 ~dd, 6 H), 1.28 (t, 3 H), 1.49 (s, 9 H), 1.58 (br s, 3 H), 1.64 (br s, .~ 3 H), 2.03 (m, 1 H), 2.55 (m, 2 H), 3.41-3.76 (several m, 4 :~ H), 4.16 (m, 2 H), 6.12 ~m, 1 H); MS m/e 511 ((M+H)+), 528 ((M+NH4)+).
;
' :.
,. ; . .
:
W092/0~29 PCT/US91/055~
2ossæ68 -70~
B. N-(2-~2~boY~Q~hyl) 5~S~ C~ C~
(methoxy~etho~y)piDerldin-1-~l~cz-~on~,1-2-phe~y~_)eth~hexanam.;.do~-6-cyclQ~Qxy'-4(.~)-hyd-oxv-2(5)-i.~oproDylhexanamide. The proceàu_e of ~xam?le 2C was employed, with the substltution o- the resul'ant compound from Example 37A for the resultan~ compound from Example 2B, to provide the title com~oundsQmi-solid mass (61~
yield): Rf 0.28 (5% MeOH C~2Cl2); ~ ~ (C~Cl3~ ~ 0.64-1.90 (several br m, 27 H approxim2tely), 0.91 (m, 9 H), 1.29 (t, 3 H), 2.06 (m, 1 H), 2.5~ (m, 2 H), 2.~'-3.96 ~several br m, 12 H), 3.37 (s, 3 ~.), 4.18 (dq, 2 H), 4.5C
(m, 1 H), 4.68 (s, 2 H), 5.81 (dd, 1 ~), 6.20 (-, 1 H), 7.28-7.38 (m, 5 H); MS m~e 760 (('-:~.)+), 777 ((M ~H4)+).
Anal. Calcd for C42H6gN3O9 0.5 H2O: C, 65.59; H, 9.17; N, 5.~6. Found: C, 65.66; H, 8.91; N, 5.54.
To the compound resulting from Example 37B (125.7 mg, 0.1654 mmol) dissolved in tetrahydrofuran (2.5 mL) and cooled to 0 C was added a solution of lithium hydroxide ~13.9 mg, 0.3308 mmol) in water (0.3 mL). After stirring at 0 C under nitrogen for 2 hours, the cooling bath was removed and stirring was continued for 2 hours at ambient temperature. The reaction mixture was diluted with water (10 mL) and co~centrated under reduced pressure to remove the tetrahydrofuran. The aqueous solution was acidified to pH 2 with lN sodium hydrogen sulfa.e (3 mL) and extracted with methylene chloride (4 x 20 mL). The combined organic extracts were washed with brine, d-ied over sodium sulfate, and concentrated under reduced pressure to afford crude product as an amorphous solid (112.7 mg). Chromatography on silica gel eluting with 3% methanol in methylene chloride containing 0.5% acetic ac d afroràed 80 mg of .
, .
~ 92io~29 2 ~ ~ 9 ~ ~ ~ PCT/US91/OS~
. ' ., ; 71 material. This material was further purified by preparative thin layer chromatography on sillca gel el~ting with 5% methanol in methylene chlo-ide contai~. ng 0 5%
acetlc acid to afford the title compound as 2 ~;n~ ~e amorphous solid (53.1 mg, 44%): m? 115-124 Ci Rf 0.45 (5%
MeOH-CH2Cl2 w/1.0% HOAc added)~ IR (CDC13) ~ 0.33-2 C5 ~several br m, 37 H approximately), 2.86-4.28 (several br m, 15 H), 3.38 (d, 3 H), 4.69 (d, 2 ~), 9.7~ (r~
(br m, 1 H), 7.05-7.80 vbr m, 1 Y.,, 7.27-7.~8 ~m,, 5 ~); ,I~
m/e 754 ((M+Na)+); (FA3-) mi~ 73G ;(.~'-.")~).
~` .
.' ~
~-(2-Cy2~oe~h~l) 5(~ ~lS~ c)-(~_ ~ et}loxyr~.Gthoxy)~,lp~-id~ n_-_yl ) C~, ~)or;;'~-2-phenyl)etho~yh~ana~ido)-h=syslo:neyyl-a~)-hvd-oxy-2(5)-A~ 2-Cya~e~hyl~. 2l~-((3-(t~rt-butyloxycarbonyl~-( S)--i~Q~ The procedure of Example 2B can be followed, with the substitution of 2-' aminopropionitrile hydrochloridé plus an additlonal ?-' e~uivalent of N-methylmorpholine for (benzyloxycarbonylamino)propylamine, to provide the title compound.
~ _ The procedure of Example 2C can be followed, wlth the~substitution of the resultant product from Example 38A
; for the resultant product from Exam~le 2B, to ~rovide the title compound.
. .
WO 92/03429 PCT/US91/0~24 -~
208~2~8 Ex~m~le 39 N-12-(5-(Tet~azolyl)ethyl~ ~(S)-(2(S)-(l(S)-(4-(met~Qxym~hoxy)pi~eridi n-1 -yl )carhonyL-2-~henyl)ethoxvhe~a~amidn)-k-cyclo~yl-a(s)-hyd~oxy-2( i.~o~ro~ylhexanamlde.
N-(2-(~-(Tetra~Qlyl)ethyl) 2(~S)-((3-(tert~
b-~'ylo~yca~bony])-2 2-dimethyl-4($~-cyc~ohe~ylmethyl-5(5)-oxazol~d;~yl)meth~l)-3-methylbutanamide The procedure of Example 29A can be followed, with the substitution of the resultant product from Example 38A for the resultant roduct from Example 8A, to provide the title compound.
_. The procedure of Example 2C may be followed, with the substitution of the resultant product from Example 39A
for the resultant product from Example 2B, to provide the ~ title compound.
:~ .
cyanou~idnL_~15L=12~$?~~1(5)~(4~
~`(methoxymethQxy)DiDeridin-1-!~L~ ~lnyl=2~
~~ yl-4(S)-hydroxy-?(S)-'1, A~
A. N-~mino 5 (~! - (2 !s) - (1 (s) - (4-methoxymçthoxv?~iper;~d~n-l-Yl~cark~onyl-?-h~yl~ethoxyh~anamido)-6-cyc1ohexyl-4(5)-hy~rQxy-2~5)-5 ~D~a~ The procedure or Example 10 may befollowed, with the substitution of hydrazine hydrate for ~
1,2-diamino-2-methylpropane, to give the desired compound.
(.1 (.S) - (4- (~ethQxymethoxy~Riperid m -l-yl)carho~l=2~
hen.yl)ethoxyhexa~amido)-fi-cyclQhexyl-A(S)-hyd~o~y-~(S)~
. .
wn92/03429 2~3~ 9 2 6 8 PCT/US91/0 i~QprQ~yl~e:~2nam;de. The procedure of Example 24 can be employed, with the substitution of the resultant compound from Example 40A for the resultant compound from Exam~le 16, to provide the title compound.
~ _ The procedure of Example 25 can be employed, with the substitution of the resultant compound from Example 40B
fo- the resultant compound from Example 24, to provide the - 'itle compound.
.
., ~
N-t3-~mino~ ,2 4-~riazol-5-yl) 2~Q) 5 (.S) -(2(S)-(l(S~-~he~y~)etho~cy~e~anamido)-6-cyclohexyL-4(5)-hyd-o~y-2(.s) iso~ ylhe~ana~ide.
The procedure of Example 25 can be employed, with the :j 3 substitution of the resultant compound from Example 40B and ~;, hydrazine hydrate for the resultant c:ompound from Example 24 and 30% aq. NH40H, to provide the title compound.
Example ~2 ~R) 4(R)--dihyd~yhs~n-5(S)-yl) 2(s)-(1(s?-(4-.~ (met~o2~thoxy) piper;~lin~:L-yl-~` ~ar~onyl!~henyl~thQ~lhg~namide p" ~A~S, 5R..L~ ~~~ lt~?~-- ~ l~ yc:arbonyu -G
-(cycloh~ylme~hyll=5=(2',2'-d~fluoro-2'-ethQxycarbony~-1'-~ To (4S~ 5R) ~3~
:;
(tert-butyloxycarbonyl)-4-(cyclohexylmethyl)-2,2-(dimethyl)oxazolidine-5-carboxaldehyde (1.20 g, 3.70 mmol, Rcsenberg, S. H., et al, J. Med. Chem., 1990, 33, 1582) in tetrahydrofuran (15 mL) w~s added bromodifluoroe~hyl .
~.~
`:
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, W092/0~29 PCT/US91/055~-~
2~2~
acetate ~1.50 g, 7.39 mmol) and zlnc (0.60 g, 9.2 mmol).
The reaction flask was placed in an ultrasonic cleaning bath for 1 h. The mixture was ~oured into saturated NaHCO3 solution and extracted into ethyl acetate which was dried over Na2SO4 and evaporated. Chromarog-aphy of the residue on silica gel with 10~ ethyl acetate in hexane afforded 1.30 g (78~) of the desired produc~ as an oil: Rf 0.26 (20~ ethyl acetatei80~ he~ane); 1 ~T~ (C3C13) o a.35 (q, 2 H), 4.20-3.97 (m, 3 ~.), 1.54 (s, 3 :-.), 1.50 (s, 3 H), 1.48 (s, 9 H)! 1~37 (t, 3 H).
~ S,~5Æ~ 3-lter~-~tylox~c2rbon-vl)-4 .. ( cvc l ohe xv ln~ot h ~ - r 1, ~
(2'.2'difllloro)pro~vll-2 2-(d me~^,')oxa~o]idino. The .
resultant compound from Example 42A (1.28 g, 2.85 mmol) in methanol (10 mL) was treated with NaBH4 (0.22 g, 5.82 mmol). After 8 h, MaBH4 (0.11 g, 2.91 mmol) was added and the mixture was stirred for 14 h. After solvent evaporation, the mixture was partitioned between ether and saturated NaHCO3 solution and the organic layer was dried over Na2SO4 and evaporated. Chromatography of the residue on silica gel with 20% ethyl acetate in hexane afforded 0.79 g (68%) of the desired produc~ as a solid: mp 148-199 C; Rf 0.45 (50% ethyl acetate/50~ hexane); 1H NMR (CDCl3) 4.31 4.23 (m, 1 H), 4.07-~.8~ (m, 4 H), 1.62 (s, 3 H), 1.54 (s, 3 H), 1.48 (s, 9 H).
C. ~45.5R.l'R)-3-(t~e~t-ButyLo~ycar~Qnyl)-~=
(cyclohe~ylm~hyl)-5- r 2'.2'-difluoro-1'-hydroxy-3'-(p-The resultant compound from Example 42B (0.374 g, 0.918 mmol) in pyridine (5 mL) at 0 C was trQared with p-toluenesulfonyl chloride (0.195 g, i.02 mmol). After 260 h ~'~92/03429 P~TtUS91/055~
'''''' 208~2g~ -at 0 C, the mixture was evaporated, dissolved in ether, washed sequentially wi~h 0.5 M H3PO4, saturated NaHCO3 solution and brine, and then was d_ied over Na2SO4 and evaporated to arro-d 0.510 g (99~) of a .oam: Rf 0.70 (50%
ethyl acetate/50% hexane); lH NMR (CDC13) ~ 4.56-4.42 (m, 1 H), 4.32-4.12 (m, 2 n), 4.05-3.80 (m, 2 H), 2.47 (s, 3 H), 1.53 (s, 3 H), 1.50 (s, 3 H), 1.48 (s, 9 H).
~ . ( 4 S, 5~ ~y~ ^ ~=~ ~ n y ' ) _ 4 _ (~yclohexylm~tnyL)-~-i8~-a~ido-2~ -ài_luQro-1~-(hyd~Qxy)~rQ~ylL-2 2-l?; ~ oxe-o`:.d~ne The resultant compound rom Example 42C (0.300 g, 0.534 mmol) and ~iN3 (0.130 g, 2.66 mmol) in dimethylfo-mamide (2 m~) were heated at 90 C fO~ 48 h. The mi:~-ur~ was diluted with ethyl acetate, washed with water and brine, and then was dried over Na2SO4 and evaporated. Chromatography o~ the residue on silica gel with 8-12% ethyl acetate in hexane afforded 0.165 g (72%) of the desired product as an oil:
Rf 0.35 (20% ethyl acetate/80% hexane); 1H NMR (CDC13) ~
4.27-4.18 (m, 1 H), 4.00-3.60 ~m, 4 H)~ 1.60 (s, 3 H), 1.52 (s, 3 H), 1.48 (s, 9 H).
E. l4~.5R l'R~-3-~t r~-Rutyloxycar~yl)-4-(cyclohe~y~ h~l~-5- r2 ~ fluoro-~ '-di~hyl?~inQ-l 1-~ The resultant compound from Example 42D (0.~65 g, 0.381 mmol), 35 ~
aqueous formaldehyde (0.3 mL) and iO% Pd/C (0.1; g) in methanol (5 mL) were stirred under a hydrogen a~mosphere for 16 h. The reaction was filte_ed and evaporated to "
afford 0.157 g (95%) of the desired product as a solid: mp 120-121 C; Rf 0.39 (50~ ethyl acetate/50% hexane); lH NMR
(CDC13) ~ 4.28-4.15 (br, 1 H), 4.02 (d, 1 H), 3.96-3.83 (m, 1 H), 3.08-2.76 (m, 2 H), 2.39 (s, 6 ~), 1.59 (s, 3 H), .
' ~`
,."': ' W092/0~29 PCT/US91/0~
20892~
1.53 ~s, 3 H), 1.49 ~s, 9 H). Anal. Calcd for C22H40N2o4F2: C, 60.81; H, 9.28; N, 6.45. Found: C, 60.70; H, 9.22; N, 6.25.
F. The resultant compound from Example 42E (0.028 g, 0.064 mmol) was stirred for 1 h in 4 M HCl/ethanol and evaporated with ether chasers. To this residue was added the resultant acid from Example 1 (0.027 g, 0.066 mmol), 1-hydroxybenzotriazole (0.028 g, 0.207 mmol), dimethylformamide (0.5 mL) and N-methylmorpholine (0.021 mL, 0.191 mmol). The mi~ture was cooled to -23 C and treated with l-ethyl 3-~dimethylaminopropyl)carbodiimide hydrochloride (0.018 g, 0.094 mmol). After 2 h at -23 C
and 14 h at ambient temperature the mixture was poured into saturated NaHCO3 solution and extracted into ethyl acetate.
The organic phase was washed with water and brine, and then was dried over Na2SOg and evaporated. Chromatography of the residue on silica gel with ethyl acetate afforded 0.0134 g (30%) of the desired product as a glass: Rf 0.15 (ethyl acetate). Anal. Calcd for C36H59N37F2: C~ 63-23;
H, 8.70; N, 6.14. Found: C, 63.13; ~, 8.69; N, 5.92.
N-16-~yclohe_yl-2.~-di1~oro-1-dime~hylam;no-3R-hydroxy-4-~XQhe~a~-5(s~-y ~ ~S~-(1(~ -(4-(m~hoxymetho~y)pi~;d; n,_ A. ~45.5R, ) -3- (tert-~utylnxycar~Qnyl)-~-(cycl~he~ylm~thyl)-5- ~'.2'-di~luoro-3'-dimet~ylaminQ-1'-To oxalyl chloride (0.030 mL, 0.35 mmol) in CH2C12 (1 mL) at -60 C was added dimethylsulfoxide (0.040 mL, 0.56 ~mol) in CH2Cl2 (1 mL).
After 15 min, The resultant compound from Example 64 :
' ~;: ', `; ~' , 20892~8 ~92/0~29 PCT/U~9l/Oa5~
_ , .
(0.0509 g, 0.117 mmol) in CH2Cl2 13 mL) was added and the mixture was stirred for 30 min at which point triethylamine (0.125 mL, 0.892 mmol) was added. After 30 min, the reaction was quenched with saturated NaHC03 solution (2 mL), diluted with ether, washed with saturated NaHC03 solution and brine, and then was dried over MgSO4 and evaporated to afford 0.046 g, (91%) of the desired product as an oil: Rf 0.58 (50% ethyl acetate/53% hexane); 1H NMR
(CDCl3) ~ 4.73 (d, 1 H), 2.32 (s, 6 H), 1.48 (s, 9 H).
. Using the procedure of Exampie 42F with the resultant compound from Example 43A gave the desired product as a glass: Rf 0.29 (ethyl acetate). HRMS: calcd for ((M+H)+) of C36HssN37F2 682.4243. Found: 682.4218.
Example 44 Lmethylamino-3(R)-hydroxy~ntan-4(5~-y1L ~L~)-(1~s)-(4-yl-ra~br~vll~e~vl--~h~ h,~
A. (5R.4S)-4-CyclohexyLm~th~l-5- r~ di~luorQ-~ ~-_ (5R,4S)-4-Cyclohexylmethyl-5~[2'-azido-(1',1'-difluoro)ethyl]-2-oxazolidinone IRosenberg, S. H., et al, US 4,857,507) was converted in 73% yield to the desired product using the procedure of Example 42E: R~ 0.26 (50% ethyl acetate/50%
hexane); 1H NMR (CDC13) ~ 2.94 ~ddd, 1 H)-, 2.71 (ddd, 1 H), --2.36 Is, 6 H). --B. ~-4-Amino-5-cyclohe~1-2A2-di~luo~Q-1-The resultant compound from Example 44A (0.243 g, 0.840 mmol) and barium hydroxide octahydrate (0.530 g, 1.68 mmol) in dioxane (9 mL), and , : , :, ;
WO92/~3429 PCT/US91/055~ -~
; 2!j)~9'268 water (6 mL) were heated at reflux for 17 h. The mixtllre was filtered, diluted with water and extracted lnto ether which was dried over Na2SO4 and evaporated to afford 0.185 g (83~) or tr.e desired product as a solid: mp 47-49 C; 1 NMR (CDC13) ~ 3.57 (dd, 1 H), 3.34 (dd, 1 H), 2.98 (ddd, 1 H), 2.72 (ddd, 1 H), 2.37 (s, 6 H). ~al. Calcd ror C13H26N2OF2: C, 59.06; H, 9.91; N, 10.60. Found: C, 59.41; H, 9.90; N, 10.43.
C. Using th~ procedure OL Ex-.~ple 42F wi~:~ tne resultant com~oun~ ~rom r x2m~1e A ~3 ca-ve .:ne desired product as a glass: Rr 0.34 (5~ me~hanol~95~ c~.loroform).
Anal. Calcd for C37H57N3O6F2: C, 6.29; H, 8.79; N, 6.43.
Found: C, 64.41; H, 8.42; N, 6.43.
E;.~am~ 45 hylamino-3-oxo~e~an-4(51-Yl) 2(5)~ (methQxym~thox~)pipe~dL~-1-yl-car~onyl)phenylethoxy)he~an~m1de Using the procedure of Example 43~ with the resultant compound from Example 44C gave the desired product as a glass: R~ 0.49 (5% methanol/95~ c~.lor~form); MS m/e 652 ((M+H)+).
.' ~
-(Bl~(d`methylam;.no)methyLe~e) 5tS~-(2(.$)-t~!S)-~4-(~e$ho~methoxvl~ ridi~-~-v]~car~onyl-~-Dhenyl)ethoxyh~na~do)-6-cyclo~Qxyl-4(~s)-hyd-oxy-2~s)-A. t45.55.2'5)-3-Lter~=~yloxy&2rbcnyl)-~.-(cyclohexylmethyl)-~- r3 ~ -meth~L-2'-r (tet~th~lauan~dln_l)c.a~nyllh~ To 2l~-((3-~;
:', : ~ ,. ::::
.
2~2~8 ~'~92/03429 P~T/VS91/~24 ~. . .
.
_79_ ttert-Butyloxycar3onyl-2~2-dimethvl-4(s)-cyclohexylmeth 5(S)-oxazolidinyl)methyl)-3-methvlbutanoic acid (Fung, et al. PCT Pater._ ~ 9003971) (50.0 -~,g, 0.121 ~ol) and 1-hydroxybenzotriazole (25.0 mg, 0.185 mmol) in dimethylformamide (2 mL) at 0 C ~as added N-methylmorpholine (0.013 mL, 0.12 ~Imol) and N-ethyl-N'-(dimethylamino)p_opy1ca_30diimide :~ydrochlo_idQ (33.0 mg, 0.170 mmol). The mixture was sti--Qd at 0-10 C for 24 h, cooled to -23 C, 2~d t-e~rQ~ w~th 1,1,3,3-tetramethylsuanicine (0.060 mL, C~478 mmol). After 2 h as -23 C and 40 h ~- a.~bient tempe-~-u-e thQ mix~~l~e was poured into salura~ed ~aHC~3 solu lon and e~t-ac~eà into ethyl acetate. Th~ organic phase was washed with water and brine, and then was dried over Na2S04 and evaporated to afford 64.4 mg (100~) of an oil: Rf 0.22 (10~ methanol/90%
chloroform); 1H NMR (CDCl3) ~ 2.90 (s, 12 H), 1.48 (s, 9 H), 1.01 (d, 3 H), 0.95 (d, 3 H).
B. The resultant compound from Example 46A was deprotected and coupled according to the procedure of Example 2C to give the desired product as a glass: Rf 0.12 (10% methanol~90% chloroform); lX NMR (CDCl3) ~ 6.14, 6.05 (2d, total 1 H), 3.34 (s, 3 H), 2.31 (s, 12 ~).
"
E~mDle ~7 ! 2(~ L~(4- (Methoxymethoxy~p~p~rld~ -yl-carhonyL)-Amirlo-3-cycLohexyl-'-hydrt xy)-4-(3,S, SS. 4 ' .SI 5 'R) -5- ~3 '- (t~ utylo~y~a~bony~ -4 ' -(c~ hexylme~hyl~-2' ~ im~thyi~oxaz~olid;~ yll-3-_ cc ~ 1 ~ To . .
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(SS,4'S,5'R)-5-[3'-(tert-Butyloxycarbonyl)-4'-(cyclohexylmethyl)-2',2'-(dimethyl)oxazolidin-5'-yl]-3-(methylene)dihydrofuran-2(4 H)-one (905 mg, 2.30 mmol, Rosenberg, S. H., et al., J. Med. Chem. 1990, 33, 1582) in dimethylformamide (10 mL) was added triethylamine (0.42 mL, 3.0 mmol) and benzyl mercaptan (0.31 mL, 2.6 mmol).
The mixture was heated at 50 C for 48 h, cooled, and diluted with ether, which was washed with water and brine, and then was dried over MgSO4 and evaporated.
Chromatography of the residue on silica gel wi~h 10~ ethy acetate in hexane afforded 315 mg (26~) of the 5R-isomer:
mp 144-146 C; Rf 0.36 (20~ ethyl acetate/80% hexane).
Anal. Calcd for C2gH43NOsS: C, 67.28; H, 8.37; N, 2.71.
Found: C, 66.89; H, 8.36; N, 2.62. The SS-isomer (483 mg, 41%) ~as also isolated: mp 114-115 C; Rf 0.26 (20% ethyl acetate/80% hexane). Anal. Calcd for C2gH~3NO5S: C, 67.28; H, 8.37; N, 2.71. Found: C, 67.36; H, 8.45; N, 2.64.
B. ~45. SR~ 1 ' S.3 ' S) -3-(tert-3~yloxycar~nnyl)-4-_~ ~
~ The resultant 55-isomer from Example 47A (399.6 mg, 0.772 mmol) in ethanol (2 mL) was treated wi~h CaCl2 (156 mg, 1.55 mmol).~ After a homogeneous solution was obtained, tetrahydrofuran ~1.2 mL) was added followed by NaBH4 (117 mg, 3.09 mmol). After 20 h at ambient temperature the mixture was diluted with ether, washed with 0.5 M H3PO4, saturated aqueous NaHCO3 solution, and brine, and then was dried over MgS04 and evaporated. Chromatography of the residue on silica gel with 25% ethyl acetate in hexane afforded 379.1 mg (94%) of the desired product as a solid:
~'' ,.
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~r~ 92/03429 2 0 ~ ~ 2 6 8 PCT~US91/0;~2J
mp 99-101 C; Rf 0.47 (50% ethyl acetate/50% hexane).
Anal. Calcd for C2gH47NOsS: C, 66.76; H, 9.08; N, 2.68.
Found: C, 66.76; H, 9.03; N, 2.76.
C . ( 4 S. ~R. 2 ' S, 4'$~ -3- ~t~rt-R~ 2~yc~ rbonyl)-4-(~enzy1~lL~2~e~hy~ trahydrofur2n-2'-yl~ O~Ql ~din~. The resultant compound from Example 47B (341.1 mg, 0.654 mmol) and triphenylphosphine (393 mg, 1.50 mmol) in tetrahydrofuran ~6 mL) at -10 C were treated with dietn~
azodicarboxylate (0.20 mL, 1.3 mmol). After 90 min at -10 C and 18 h at ambient temperature the solvenr was evapora~ed and the residue was chromatographed on silica gel with 4% e~hyl acetate in hexane to afford 274 mg (83~) of a white solid: mp 67-69 C; Rf 0.52 (20% ethyl acetate/80% ~exane). Anal. Calcd for C2gH45NO4S: C, 69.15; H, 9.00; N, 2.78. Found: C, 69.03; H, 8.95i N, 2.73 1') . ( 4 S, 5R! 2 ' ~. 4 ' ~ 3- ~ -Buty~c~Ç~
, _ The resultant compound from Example 47C (145.0 mg, 0.288 mmol) in CH2Cl2 (8 mL) w s treated with meta-chloroperbenzoic acid (300 mg, 0.9 mmol, 50% pure). After 30 min at ambient temperature, the mixture was evaporated and dissolved in ethyl acetate which was washed with 1:1 10% aqueous Na2S03 solution/saturated aqueous NaHCO3 solution, saturated aqueous NaXCO3 solution, and brlne, and then was dried over Na2SO4 and evaporated to afford 152 mg (99%) of a white solid: mp 178-179 C; Rf 0.52 (50% ethyl acetate/50% hexane). Anal. Calcd for C2gH4sNO6S-0~5 H2O:
.
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.
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.
W092/0~29 PCT/US91/055~-~
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C, 64.21; H, 8.50; N, 2.64. Found: C, 63.94; H, 8.51; N, 2.57.
~ The resultant compound from Example 47D was deprotected and coupled according to the procedure of Example 2C to give the desired product as a foam: Rf 0.22 (ethyl aceta-te). Anai. Calcd Ior C43H64N2OgS-0.75 H20: C, 64.68i H, 8.27; N, 3.51. Found: C, 69.47; H, 8.06; N, 3.55.
.
~ ^ Q~
5(C)~ S)-(4-(Methoxy~er:noxy)piper;d~n-Lyl)car~on~vl-2-~n~ .h.~.~vh~Y~n~m ~)-5-~ ~Y~ (S)-hvd~o~y-~ ro~y~-'-hexanol A . ( 2 S, 4 S, i ~ - 6-cy~lohexyL-~ Q~ro~vl=l~-hexan~ Ql A solution of (2S,4S,5S)-5-amino-6-cyclohexyl-4-hydroxy-2-isopropylhexanoic acid lactone-(1.0 g, 2.6 mmol, Bradbury et. al, J. Med. Chem. 1990, 33, 2335-42), calcium chloride (O.573 g, 5.2 mmol) and sodium borohydride (0.39 g, 10.5 mmol) in 40 mL of THF were stirred at 0-5 C for 2 h, then at room temperature for 2 h. The reaction was recooled to 0-5 C, ether was added, and 1 M potassium hydrogen sul~ate was added until gas evolution ceased. The separated organic layer was washed seauentially with saturated sodium bicarbonate and sodium chloride, then dried (MgSO4).
Evaporation of the solvent gave 0.910 g of a crude white solid which was purified by column chromatography using 1:3 ethyl acetate-hexane, to give 0.754 g (74~) of diol: mp 112 C; 1H NMR (CDC13) ~ 7.41-7.27 ~m, 5 H, Ph), 5.11 (s, 2 H, O-CH2), 4.91 (br d, lH~ J = 9 Hz, N H), 3.77-3.56 br m, 3 H, HOCH2 and HOC H), 3.05 (b= a, 1 H, O H), 2.25 - ., ~, ~ ., . : :.
: , . , : . ............... .
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~92/034~9 PCT/~S9l/~S~
2~92 J ~
~br s, 1 H, O H), 0.87 (dd, 5 H, J = 3 and 7 Hz, isopropyl); IR (CDCl3) 3617, 3428, 2957-2835, 1707, 1505, 1442, 1223, and 1038 cm~1. Anal. Calcd for C23H37NO4: C, 70.55; H, 9.52, N; 3.58. Found: C, 70.98; H, 9.63; N, 3.55.
~ . (25.45.~5~-5-.~ino-k-o~lohexyl-2-lso~ro~yl-1 4-heYanediol~ A s~mple of diol fror ~amplo 48A (0.350 g, O.89 mmol) and 4Q mg of 10~ Pd/C 1-. 100 mL me~hanol ~as hydrogenated at 4 atm. Filtration of the catalyst and evaporation ol .he solvent gave 230 mg of amino diol which was used without further purification.
C. Thè ~rocedure o~ Exam~le 2C, ~art 2, was adapted:
191 mg (0.4 ~ol) or acid rrom E.Ya.?.?le 1, amino àiol from Example 48B (110 mg, 0.427 mmol), and HOBT (95 mg, 0.7 mmol), in 1.5 mL DMF cooled at -23 C was added EDCI (90 mg, 0.44 mmol). The reaction mixture was stirred and allowed to warm slowly to room temperature over 18 h. The DME was evaporated and the residue was purified by flash chromatography (3% methanol/methylene chloride). The desired product was isolated in 40% yield (108 mg): mp 47-54 C; lH NMR ~CDCl3) ~ 7.38-7.26 (m, 5 H, Ph), 5.87-5.7 (br dd, two rotomers, 1 H, amide N i), 4.65 (s, 2 H, OCH2O), 4.59-4.51 (4 line m, 1 H, COCHO), 3.35 (s, 3 H, CH30), 0.96-0.83 (6 line m, 6 H, isopropyl); IR (CDC13) 3380, 2949-2840, 1644, 1520, 1444, 1142, 1090/ 1038, 870-950, and 795-600 cm 1. Anal. Calcd ,or C37H62N2O7: C, 68.70; H, 9.66; N; 4.33. Found: C, 67.99; H, 9.53; N, 4.41.
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,' ~m~2 N-(3-(4-Morpholino)~ropyl) 5(5)-(N-(1(~5)-(~-(methoxvm~ho~y)piperidtn-1-yl?ca~o~l-2-Dhenyl) ethyl-_-noFl~llc~ idQl 6-cyclQh~xyl-4 (~)-hyd~oYy-2 (~C~-sQ~rc~vlh~xanz~
A. N-(3-(a-Mor~hsl1nQ)propy1) (2.C. .S ~$)-5-~ ar'_-buty~Q~yca~honyl)~LL~o-4-hyd-Qxy-2-isQ~ vLh~;~.n~mi~e 2-Isopropyl-4-[1-(tert-butyloxycarbonylamino)-2-cyclohexyl]ethyl-y-butyrolactone ~4.0018 g, 11.32 ~mol, Bradburv, R. H., et al ., Tetrahed-on Lett. 19~9, 30, 3845) and 4-(3-aminopropyl)morpholine ('~.5 mL, 0.1124 m~mo ) ~e__ warmed at 60 C for 96 hours. The reaction mix.ure was partitioned between water (150 mL) and methylene chloride (120 mL). The organic phase was washed with water (3 x lC
mL) and brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford a solid whic was recrystallized from hot ethyl acetate to afford the title compound ~4.719 g, 84%): mp 161-2 C; Rf 0.18 (7.5%
MeOH CHCl3); lH NMR (CDC13) ~ 0.73-1.04 (br m) and 0.93 (2 overlapping d, 8 H total), 1.05-1.50 (br m) and 1.45 (s, 17 H total), 1.58-1.77 (br m, 10 H), 1.79-2.03 (m, 4 H), 2.41-2.52 (m, 6 H), 3.2S-3.45 (m, 2 H), 3.43-3.59 (br m, 2 H), : 3.68-03~74 (m, 4 H), 3.90 4.10 (br m, l H), 4.65 (br d, 1 H), 7.04 (br m, 1 Hj; MS m/e 498 ((M+H)+). Anal. Calcd for C27Hs1N3Os- H20: C, ; H, ; N, . Found: C, ; H, ; N, .
1~ To the compound resulting from Example 49a (3.1765 g, 6.38 mmol) suspended in methylene chloride (16 mL) and cooled to 0 C was added trifluoroacetic acid (16 mL) over 30 minutes. The resulting solution ~as stirred at 0 C for 4 hours and then additional TFA (6 mL) . .
.
.. . . .
W092/0~29 2 ~ 6 8 PCT/US91/0~5~
; , . , was added. After 2 hours, the flask was sealed and allowed to stand in the refrigerator for 12 hours. The mixture was concentrated under reduced pressure and the residue obtained basified with 4M sodium hydroxide solution. Tr.e solution was saturated with sodium chloride and extracte~
with 5% isopropanol in chloroform (4 x 25 mL~. The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, and concentrated in vacuo to give N-[(4-morpholino)propyl]-5(S)-amino-6-cyclohexyl-4(~)-hydroxy-2 (S)-isopropylhexanamide (2.8851 g, lOO~) as a waxy solid: 1~ NMR (CDCl3) ~ 0.70-1.00 (br m), 0.92 (d) and 0.95 (d, 8 H total), 1.00-1.93 (several br m, a?pr~:~
l9 H), 2.03-2.14 (m, 1 H), 2.40-2.S1 (m, 6 H), 2.52-2.62 (m, 1 H), 3.02-3.14 (m, 1 H), 3.25-3.45 (m, 2 H), 3.65-3.80 (m, ~ H), 6.77-6.85 (br m, 1 H); MS m/e 398 ((M+H)+).
Anal. Calcd for C22H43N303 1.5H20: C, 62.23; H, 10.92; N, 9.90. Found: C, 62.63; H, 10.57; N, 9.76.
~ a~_2~ To the above amino alcohol (2.7942 g, 6.38 mmol), the compound resulting from Example 74 (2.7217 g, 6.695 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (1.4626 g, 9.55 mmol), and N-methylmorpholine (NMM) (l.Oa mL, 0.966 g, 9.55 mmol) dissol~ed in dimethylformamide (DMF) (24 m ) and cooled to -10 C was added 1-ethyl-3-(3'-dimethylamino)-propylcarbodiimide ~EDC) (1.5910 g, 8.30 mmol). The reaction mixture was stirred at -10 C, allowed to gradually warm to ambient temperature, and stirred at ambient temperature for 3 days. The reaction mixture was concentrated under reduced pressure and then partitioned between methylene chloride (75 mL) and 4:1 saturated sodium bicarbonate/water (2 x 25 mL). The organic phase was washed with brine (25 mL), dried over sodium sulfate, and . . , . ~ .
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W092/0~29 PCT/~S91/055~ ..
: ~ o~9 2 6~ . -86-concentrated under reduced pressure to afford an amorphous solid (2.0314 g, 2.5325 mmol, 94%). Flash chromatography on silica gel eluting with a gradient (10%,15%) of methanol ln methylene chloride afforded the title compound as an amorphous solid (1.74 g, 65%): m? 85-95 C; Rf 0.19 (6%
MeOH-CH2Cl2); 1H NM~ (CDCl3) ~ 0.67-1.00 (br m), 0.89 (t) and 0.94 (d, 11 H total), 1.00-2.00 (several br m, 29 H), 2.0-2.14 (m, 1 H), 2.20-2.43 br m) and 2.~0-2.60 (br m, 6 H
total), 2.67-2.87 (m, 3 H), 2.95-3.07 (br m) and 3.3.15-3.34 (br m, 3 H ~5~âl) ~ 33.36 (2 s) and 3.34-3.95 (several br m, 14 H total), 4.65 (2 s, 2 H), 6.73-5.91 (br m, 2 H), 7.20-7.35 (m, 5 H); ~S m/e 786 ((M+H)+). Anal. Calcd for C44H7~N507- H20: C, ; H, ; N, . Found: C, ; H, ; N, .
E~?m~le ~Q
~-(2-Py~idy.lmethyl) 5~S)-(N-(1(5)-(4-(methQx~m~thQ~)pipe~;d~ yl)car~onyl-2-~henyl~ L-L-L-hyd~o~y-2(~)-; so~ro~yllleXarlami~
A~ ~-(2-Pyridylm~thyl! (2~ .5S)-5-(t~-The ~roeedure of Ex2mple 49A W2~ employed, with the substitution of 2-(aminomethyl)pyridine, to provide the title compound: mp 128-9 C; lH NMR ~CDCl3) ~ O.95 (d, 6 i H), 1.06-1.25 (br m, 6 H), 1.45 (s, 9 H), 1.63 (m, 7 H), 1.75-1.96 (br m, 4 ~), 2.17 .(ddd, 1 H), 3.44 (d, 1 H), . 3.54 (br s, 1 H), 4.28 ~dd, 1 H), q.72 ~d, 1 H), 5.02 (dd, 1 H), 7.50 ~br s, 1 H) r 7.22 (dd, 1 H), 7.28 (d, 1 . H), 7.69 (ddd, 1 H), 8.43 (d, 1 H); ~S m/e 462 ((M+H)+).
An21. Calcd for C26H43N3O4: C, 67.65i H, 9.39; N, 9.10.
Found: C, 67.60; H, 9.29; N, 9..12.
~:;
.
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W~ 92/03429 PCr/US91/055~
."`' , 2~9268 i ~
87~ , E~. The procedure of Example 49B was employed, with the substitution ol the resultant compound from Example 50A
for the resulLant compound from Example 45A, to provide the title compound: mp C; Rf 0.32 (5~ MeOH-CH~Cl2); 1H NMR
(CDCl3) â ; MS m/e (M+NH4)+. Anal. Calcd for CnHmNC,Op-H20: C, ; H, ; N, . Found: C, ; H, ; N, 3,Q S l tho~ræ~ ~ ~ ~== -- ~~
norle~lclna~idQ)-6-cyclohe~ (s)-hydrQx~-2( iso~ro~ylhexana~.~de.
(.3-~yridylrneth.yl.) (2.C. 45. 5~s~ -5- (t~rt-butylQ~yc~70nyl~ amino-4-hydrox~-2-~ ~o~ro~ylhe~anarn~de.
The procedure of Example 49A was employed, with the substitution or 3-(aminomethyl)pyridi.ne for 4-(3-aminopropyl)morpholine, to provide the title compound as white needles ~50% yield): mp 147-49 C; [a]2sD = -36.4o (c 1.12, CHCl3); lH NMR (CDCl3) ~ 0.~1 (d, J = 6 Hz, 3 H), 0.93 (d, J -- 6 Hz, 3 H), 1.43 (s, 9 H), 3.35-3.56 (br m, 2 H), 4.37-4.55 (8 line m, 2 H)i 4.62 (b~ d, 1 ~), 6.35-6.45 ~br .i s, 1 H), 7.24-7.34 (br s, 1 H), 7.63 (br d, 1 H), 8.47-8.63 .j (br d, 2H ); MS m~e 462 ((M+H)+). Anal. Calcd for C26H43N3O4: C, 67.67; H, 9.32; N, 9.11. Found: C,67.97;
H,9.20; N,9.15.
The procedure of Example 49B was employed, with the substitutian of the resultant compound from Example 5lA
for the resultant compaund from Example 49A, co provide the title compound as a pale yellow foam (75% yield): mp 60-68 C; Rf 0.45 (10% MeOH-CH2C12); 1H NMR (CDC13) ~ O.64-2.0 ~ ' .
' .
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. . . .
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2 ~ ~ 9 2 ~ 8` -88-(several br m, approx. 36 H), 2.13-2.25 (br m, 1 H), 2.63-2.77 (br m, 1 ~), 2.77~2.90 (br m, 2 H), 3.00-3.31 (br m, 2 H), 3.34 (s), 3.35 (s) and 3.31-3.81 (several or m, 8 H), 3.81-3.94 (br m, 1 H), 4.35 (dd, 1 H), 4.55-5.70 (m, 3 H), 6.20-6.30 (m, 1 H), 6.79 (d) and 6.85 (d, 1 H total), 7.19-7.37 (br m, approx. 5 H), 7.66 (br d, 1 H), 8.52 (br d, 2 H); MS m/e 750 ((M~)+).
Exam~le_52 N-(4-~yridv~me~hyl) 5(~ N-(l(~s)-(a (methoxy~e~.hoYy~pl~e-ldin-1-yl)c~-bonvl 2- hen~
nor~e~cin~m~o)-6-cyclohexy'-4!s)-hydro~y-2(~) -(4-Pyr~dylm3~hyl) (?sl 4.S,5S)-5-(tert-hutyl~o~ycarbonylka~ino ~-hydroxy=2-isopropylha~anamlde.
The procedure of Example 49A was employed, with the substitution of 4-(aminomethyl)pyridine for 4-(3-aminopropyl)morpholine, to provide the title compound: mp 145-6 C; Rf 0.32 ~10% MeOH-CH2C12); lH NMR (CDCl3) 8 0.95 (d, 6 H), 1.14-1.36 (br m, 6 H), 1.43 (s, 9 H), 1.58-1.82 (m, 10 H), 1.94 (m, 1 H), 2.18 (br s, 1 H), 3.47 (m, 2 H), 4.47 (dd, 2 H), 4.56 (br s, 1 ~), 6.19 ~br s, 1 H), 7.22 (d, 2 H), 8.57 (d, 2 H); MS m/e 461 ((M+H)+).
Anal. Calcd for C26H43N3O4: C, 67.65; H, 9.39;N, 9.10.
Found: C, 67.2B; H, 9.30; N, 9.07.
B ! The procedure of Example 49B was employed, with the substitution of the resultant compound from Example 52A
for the resultant compound from Example 49A, to provide the title compound as an off-white foam (67% yield): mp 71-6 C; Rf 0.50 (5~ MeOH-CH2Cl2); 1H NMR (CDC13) ~ O.65-1.95 (several br m, approx. 3S 3), 2.17-2.30 (br m, 1 3), 2,65-:
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2.91 (br m, 3 H), 2.97-3.13 (br m, 1 H), 3.14-3.29 (br m, 2 H),3.35 (2 s) and 3.30-3.80 (br m, 9 H total), 3.80-3.91 (br m, 1 H), 4 .28-4.40 (m, 1 H), 4 .55-4.60 (m, 3 H), 6.27-6.40 (m, 1 H), 6.82-6.98 (m, 1 H), 7.18-7.35 (m, approx. 8 H), 8.55 (d~ 2 H); MS m/e 750 ((M+H)+). Anal. Calcd fo~
C43H67NsO6: C, 68.86; H, 9.00; N, 9.34. Found: C, 68.79;
H, 8.99; N, 9.30.
Example ~3 N-(2-(~ Qr~hi211n~)e~hy~ s~ )-(4-~metnoxymethoxy)~ din-1-vllG~onyl-2-~henyl~eth~l-T-norleucinamido)-6-cyclQhe~yl-4(5)-hydrQ~y-2(5L-,oprcDylhexanamide A~_ N-(2-(4-Morpholino)ethyl) (2~ ~S.55)-5-(te~t-~;,ylQxycarbonyl)am~nQ-4-hydroxy-2-;soprQpylh~car~m~de.
The procedure of Example 49A was employed, with the substitution of 4-(2-aminoethyl)morpholine for 4-(3-aminopropyl)morpholine, to provide the title compound as a white needles ~rom EtOAc-hexane (1:1) (58~ yield): mp 151-2 C; lH NMR (CDC13) ~ 0.68-0~98 (br m, 8 H), 1.05-1.35 (m, 7 H3, 1.43 Is, 9 H), 1.54-1.75 ~m~ 6 H), 1.77-1.95 ~m, 2 H), 1.97-2.08 (br m, 1 H), 2.30-2.69 ~m, 6 H), 3.17-3.30 ~m, 1 H), 3.~0-3.61 (m, 3 H), 3.64-3.77 (m, 4 H), 4.73 (br d, 1 H), 6.04 ~br s, 1 H); MS m/e 484 ((M+H)+). Anal.
Calcd for C26H4gN3Os-0.25H20: C, 63.97; H, 10.22; N, 8.61.
Found: C, 64.07; H, 10.05; N, 8.68.
B_ T~e procedure of Example 49B was employed, with the substitution of the resultant compound from Example 52A
for the resultant compound from Example 49A, to provide the title compound as an off-white solid ~77% yield): mp 59-69 C; Rf 0.38 ~5~ MeOH-CH2Cl2); 1H NMR (CDC13) ~ 0.66-1.00 . . . .. . .. .
:
' :.,. i WO~/0~2g PCT/~S91/~55~ t 2~9~6~ - -90-(br m), 0.89 (t) and 0.94 (d, 11 H total), 1.00-1.95 (several br m, approx. 26 H), 2.05-2.16 (m, 1 ~.), 2.302.51 (m, 6 H), 2.52-2.64 (m, 1 H), 2.75-2.86 (m, 2 H), 2.90-3.01 (m) and 3.16-3.33 (br m, 2 H total), 3.35 (s) and 3.37-3.60 (m, 8 H total), 3.60-3.93 (br m, 7 H), 4.65 (d, 2 H), 6.01-6.10 (br m, 1 H), 6.84 (d) and 6.9~ (d, 1 H total), 7.20-7.36 (m, 5 H); MS m/e 772 ((M+H)+). Anal. Calcd for C43'i73NsO7 0.5X20: C, 66.12; H, 9.5~; N, 8.97. Found: C, 66.12; H, 9.54; N, 3.97.
F~m?~ 59 m;no-2-methyl~ro~yl) '!s~-(N-Ll~-(4-~methoxymethoxyL~,~2e.ridin-L-yl)carbonyl-2-phenyl2~thyl-L-nor~Quo~n2~QL-~-cyclQhQ~yl-4(~s)-hydroxy-2~s)-A. N-(2-~m;no-2-methylpropyl) (25,45.55)-5- (tert-~utylo~ ycarbonyl? amir~o-~-hyc~3;.o~2;v-2-i~o~ o~ylhaxa~
The procedure of Example 49A was employed, with the substitution of 1,2-diamino-2-methylp:ropane for 4-(3-aminopropyl)morpholine, to provide the title compound as white needles (EtOAc-hexane) (71 % yi~eld): mp 133-6 Cj 1H
NMR (CDCl3) ~ 0.70-1.03 ~br ml and 0.94 (d, 8 H total), 1.03-1. 50 ~br m), 1.12 (s), 1.17 (s) and 1.49 ~s, 21 H
total), 1.52-2.00 (br m, 9 H), 2.01-2.12 (m, 1 H), 2.96 (br dd, 1 H), 3.40 (br dd, 1 H), 3.47-3.59 (br m, 2 H), 9.66 (br d, 1 H), 6.04-6.13 (br m, 1 H); I!qS m/e 442 ((M+H)+).
Anal. Calcd for C24H47N3O4 0.25 H20: C, 64.61; H, 10.71; N, 9.42. Eound: C, 64.64; H, 10.75; N, 9.28.
B. The procedure of Example 49B may be employed, with the substitution of the result:nt compound from Example 54A
, ', . .
' ' ' ' ' .:
., ' , , . ~ . ' :, .
W092/0~29 PCT/VS91/05524 2~8926~
for the resultant compound from Example 49A, to provide the title compound.
,,~ S
N-(2-Methyl-2-(4-mor~holino)p~Q~yl! 5(~)-(N-(l(S)~(4-^~ Q-hQ~ erid r-'~ )ca-bonyl-2-~henyl~ethyl-L-norL~ucln~ml~o)-6-cvcl~he~yl-4(5~-hydro~y-~
_SO?r"~'l h.''~!''~'ni~'', A. N- (2-.~ `a,~1-2- (a-~Q~ ho~ ~ ~o) ,~rQ~yl~ i aS. 55) -5-(~e-.~-bllr~lo~ Qon~`~)~2~0-a-h~ x~-2 -~_D~ e~_ _~ The crude ~as pu-i~ied by flash chromatography (0.5~ MeOH-EtOAc) to afford the desired compound as a white solid: mp 132-5 C; Rf 0.26 (5% MeOH-CH2Cl2); 1H NMR (CDC13) ~ 0.76-1.01 (br m), 0.94 (d) and 0.97 (d, 8 H total), 1.04 (2 s, 6 H), 1.09-1.50 (br m) and 1.46 (s, 16 H total), 1.52-2.00 tbr m, approx. 8 H), 2.04-2.15 (br m, 1 H), 2.49-2.S6 (m, 4 H), 3.19 (d, 2 H), 3.45-3.60 (br m, 2 H), 3.67-3.77 (m, 4 H), 4.65 (br d, 1 H), 6.31 (br t, 1 H); MS m/e 512 ttM~H)+). Anal. Calcd for C2gHs3N3Os: C, 65.72; H, 10.44; N, 8.21. Found: C, 65.67;
H, 10.25; N, 8.1~.
B The procedure of Example 49B was employed, with the substitution of the resultant compound from Example 55A
for the resultant compound from Example 49A, to provide the title compound as a foam (71% yield): mp 55-60 C; Rf 0.13 t4% Me-CH2Cl2); 1H N~R tCDC13) ~ 0.67-1.00 (br m), 0.89 (t) and 0.94 (d, 11 H total), 1.00-1.20 (br m), 1.05 (s) and 1.06 ts~ 11 H total), 1.22-1.92 (several br m, approx. 20 H), 2.13-2.26 (m, 1 H), 2.26-2.50 (vbr m, 1 H), 2.51 (m, 4 H), 2.65-2.86 ~br m, 3 H), 2.95-3.08 (br m, 1 H), 3.08-3.34 (br m, 4 H~, 3.36 (5) ~nd 3.35-53 60 ~b~ m, 6 3 total), W092/03429 PCT/U~9l/0~5~
~: . - .. ,, , - , i ~ 5 ~ -' ~ 92-3.60-3.9~ (br m, 6 H), 4.65 ~d, 2 H), 6.24-6.31 (br m, 1 H), 6.79 (d) and 6.88 (d, 1 H total), 7.20-7.36 (m, 5 H).
Anal. Calcd for C4sH77NsO7-H20: C, 66.06; H, 9.73; N, 8.56.
Found: C, 66.03; H, 9.43; N, 8.48.
E~am~le 56 N-(2~(?-Pvr;dyl)~th~l) 5~5)-(~1-(l(S)-('-(methoxymethoxy)~i~er;di~-l-yl)car4o~yl-2-~h~nvl)er.h~vl-T-norleueinamido)-6-cyclQh~yl-4(~-nvd-~Yv-2!~-A. N- (?- ~2-~y~(?S, 45 5S) -'- (- ~
but~lQxycar~onvl)a~inQ-~=hy1~ç~ s^~ vl~ a-.2-l-.d~, The procedure of Example 49A was employed, with th~
substitution of 2-(2-aminoethyl)pyrldine for 9-(3-aminopropyl)morpholine, to provide the title compound as needles (58% yield): mp 124-26 C; [~]25D = +17.7 (c 1.9, CHCl3); 1H NMR (CDCl3) ~ 0.86 (d, J = 6 Hz, 3 H), 0.91 (d, J
= 6 Hz, 3 H), 1.44 ~s, 9 H), 2.95 (t, J = 6 Hz, 2 H), 3.18 3.31 (br m, 1 H), 3.50-3.63 (br m, 2 H), 4.00-4.13 (br m, 1 H), 4.71~br d, J = 9 Hz, 1 H~, 6.30-6.38 (br s, 1 H), 7.18-7.25 (br d, 2 H), 7.69 (t d, J = 9, 1 Hz, 1 H), 8.45-8.52 (br d, 1 H); MS m/e 476 ((M~H)+). Anal. Calcd for C27H4sN304: C, 68.21; H, 9.47; N, 8.84. Found: C,68.33i H,9.55; N,8.85.
~ _ The procedure of Example 49B was employed, with the substitution of the resultant compound from Exam?le 56~
for the resultant compound from Example 49A, to provide the title compound as a white foam ~79% yield): mp 52-6 C; Rf 0.11 (5% MeOH-CH2Cl2); 1H NMR (CDC13) ~ 0.62-1.00 (br m) and 0.84-0.92 (overlapping t and d, 11 H total), l.OQ-1.96 (several br m, approx. 27 H), 2.04-2.14 (m, 1 H), 2.20-2.57 (vbr m, 1 H), 2.80-2.90 (m, 3 H), 2.98 (t, 2 ~), 3.07-3.20 . :
WO92/0~29 2 ~ ~ ~ 2 ~ 8 PCT/~S91/05~
(m), 3.33 (s) and 3.27-3.57 (br m, 7 H total), ~.57-3.98 (br m, 5 H), 4.20-4.55 (vbr m, 1 H), 4.62 (2 s, 2 H), 6.40 (br t, l H), 7.00 (d) and 7.07 (d; 1 H total), 7.15-7.34 (m, approx. 6 H), 7.66 (td, l H), 8.51 (dd, 1 H) and ; ~IS
m/e 769 ((M+H)+). Anal. Calcd for C44H69N56 -5~2: C, 68.36; H, 9.13; N, 9.05. Found: C, 68.55i H, ~.9~; N, 9.04.
~xam~le 57 N-~3-~a-Oxido-~-morphollno)~r~yl? ~ (s)~
(methgxymethQ~iDeridin~L-yl~cz~onyl-2-~henyl)ethyl-E-norleuGin~mi~o)-6-cyclohexyl-4(.C)-hvd oxv-2(.S)-i.sQprQQylhe~a~mide.
A.. N-(~-(4-~x;do-4-morpholino)~LQ~yl) (2~.4~5S)-5-(te~L~hl~h~vcarbQnvl)am1no-a-hvdro~v~2-9~_L~y_b~m~s_ The procedure of Example 36 wasemployed, with the substitution of the resultant compound from Example 49A for the resultant compound from Example 11, to provide the title compound as a white powder (92%
yield): mp 154-7 C; 1H NMR (CDCl3) l~ 0.69-1.03 (br m), 0.91 (d) and 0.93 (d, 8 H total), 1.03-1.40 (br m, 6 H), 1.43 (s, 9 H), 1.50-1.75 ~br m, 6 H), 1.80-1.95 (b- m, 3 H), 1.97-2.30 (br m, 6 ~), 3.05-3.38 ~br m, 6 H), 3.36~3.50 (m, 2 H), 3.50-3.71 (br m, 2 H), 3.75-3.86 Ibr d, 2 H), 4.30-4.44 (m, 2 H), 4.81 (br d, 1 H), 7.96-8.05 (br s, 1 H); MS m/e 514 ((M+H)+), 498 (M-16+H)+. Anal. Calcd for 27HslN36 H20: C, 60.99; H,-10.05; N, 7.90. Found: C, 61.05; ~, 9.98; N, 7.93.
~ The procedure of Example 493 was employed, with the substitution of the resultant compound from Example 57A
for the resultant compound from Example 49A, to provide the ,~
:$
;
, ' , W092/03429 - PCT/~S91/05524 ~,o~9~6~ .
title compound as a tan foam ~65~ yleld): mp 85-95 C; Rf O.lS ~10~ MeOH-CH2Cl2); 1H NMR ~CDCl3) ~ 068-l.00 ~m, 11 H), 1.00-1.41 ~br m, 12 H), 1.41-2.20 ~br m, approx. 18 H), 2.20-2.40 ~br m, 2 H), 2.70-2.88 ~m, 3 H), 2.94-3.06 ~br m, 2 H), 3.06-3.27 ~br m, 2 H), 3.27-3.55 ~br m), 3.35 ~s) and 3.36 (s, 9 ~ total), 3.35-4.16 ~several br m, 7 H), 4.24-4.40 (m, 2 H), 4.65 ~2 s, 2 H), 6.87-6.96 (dd, 1 H), 7.25-7.39 (m, 5 U), 8.'0-8.19 (br m, 1 H) and ; MS m/e (M~N~4)+. Anal. Calcd for C44~75N5Gô-3H20: C, 61.73; H, 9.~4; N, ~.13. Found: C, 61.74; H, 9.15; N, 8.05.
Ex~le 58 N-(~-(2-uyd~x~thy~L~ n~prA~y~ ~?-(~-(l(s)-(4-(metho~yme~hoxy)~iper1din-1-yl)c~_~onyl-2-~henyl)e~hyl-L-ncrleucinamido)-6-cyclohe~yl-4(5)-hyd~oxy-2(~)-isopropylhexanamide.
The procedure of Example 5B can be employed, with the substitution of the resultant compound from Example 74 for the resultant cumpound from Example 1, to provide the title compound.
;~ ~a~ple ~
(me~ho~y~ethQ~y)~L~erid1n-1-yl?caxbonyl-2-phenyl)ethy~-L-norleucln~mido)-6-c~lQhe~ L-h~l~oxY-2(s)-The procedure of Example 2C may be employed, with the substitution of the resultant compound from Example 74 for the resultant compound from Example 1, to provide the title compound. ~' .
, , WO ~2io3429 ~CT/US91/05524 2~268 i. ~
~hQ
N-(3-.~ o~ro~yl) 5(~)-(M~ L-(4-(methoxyme~ho~y~ Qridln-1-yl)c2r~Qnyl-2-~henyl!ethyl-T.-orleucin~midQ)-6-~yclohPxyl-4(5)-ht~dro~y-2(SI-,i soDropylhe~2nalrude .
The procedure of Example 3 can be employed, with the ~,substitution of the resultant compound from Example 59 fo~
the resultant com~ound from E~ample 2, to provide the title compound.
'`'~a~, 1 Q 6 ;~N-(3-~ hy1~-4-mor~holinium)gro~yl~ 5(5)-~N-(l(.SL-(4-(~etho~yme~hoxy)~i~srldin-1-yl!carbQnyL-2-~hen.yl~ethyl-~-norleucin2midQ)-6-cyclohexyl-~(S)-hydroxy-2~5)-isoDropy~hexanamide iQdide~
~;~The resultant product from Example 49 (49.9 mg, 63.5 ~mol) was dissolved in 0.4 mL THF, cooled to 0 C, and iodoethane (5.2 mL, lO.1 mg, 65.0 mmol) was added. The solution was stirred at 0 C for 6 h, then at room 'Jtemperature for an additional 12 h.
N~l~-Ll~LmidazolyLL~IQD~1) 5~C)-~N-(~(S~-(4-:,' .,, ~
i. .~opropylhe2~nam~
~:2~ N-(3- U-Im;da~Qlyl~rQ~yl) (~. 4S. ~5~-5- (tert-. . .
but~loxycar~onyl)am;no-4-hydroxy-2-isoprQ~ylhexanami~_ `The procedure of Example 49A was employed, with the substitution of 1-(3-aminopropyl)imidazole for 4-(3-.~ .
.
, ,:
. ' :: . .
WO92/03429 PC~tUS91/055~
... ..
0~ 96-aminopropyl)morpholine, to pro~ide the tltle com~ound as white needles (27% yield): mp 148-150 C; I~ 1620-1740 cm~
l; lH NMR (CDCl3) ~ 7.56 (s, 1 H), 7.07 ~s, 1 H), 6.96 (~, 1 H), 5.87 (br d, 1 H), 4.64 (br à, J = 9 H-, 1 H), 4.02 (t, J = 6 Hz, 2 H), 3.57-3.38 (br m, 2 H), 3.27 (A~, J = 6,
12 Hz, 2 H), 2.08-1.57 (several br m, 14 H), 1.45 (s, 3 ;i), 1.40-1.10 (several br m, 5 H), 0.93 (d, J = 6 Hz), 0.91 (d, J = 6 Hz,) and 0.82-1.10 (br m, 8 H to al); MS ~/~ 179 ((M+H)+). Anal. Calcd .or C26~46~44: C, 65.24; :~, 3-o3;
N, 11.70. Found: C, 65.24; X, 9.75; ~i, 11./5.
. The procedure of Example 49~ wzs em~loyed, WiL:~
the substitution of the resultant comsound f_om Exam~le 62A
for the resultant compound from Example 49A, to providQ he title compound as a white foam (65~ yield): mp 59-65 C;
Rf 0.34 (10% MeOH-1% conc. aq. NH4OH-CH2Cl2); lH NMR
(CDC13) ~ 0 . 67-1. 00 (m, 11 H)~ 1.00-2.10 (several br m, approx. 29 H~, 2.10-2.60 (vbr m, 2 H), 2.65-2.76 (m, 1 H), 2.76-2.86 (m, 2 H), 3.00-3.82 (several br m~ and 3.36 (2 s, 10 H total), 3. 82-3 . 95 (br m, 1 H), 3 . 95-4 .10 (m, 2 H), 4 . 67 (d, 2 H), 5 . 83-5 . 90 (m, 1 H), 6 .84 (d) and 6.90 (d, H total~, 6.97 (s, 1 H), 7.07 ~S, 1 H), 7.20-7.34 (m, 5 u,), 7.59 (d, 1 H); MS m/e 767 (M+NH4)+. Anal. Calcd for C43H70N6o6-o.sH2o: C, 66.55; H, 9.22; N, 10.83. Found: C, 66.37; H, 9.11; N, 10.62.
. .. .
-W092/0~29 2 ~ & ~ PCT~USg 1/055~
. . . . . . . . ~ . ., E~
N-(?-(~ et~yL-N~-cy-anQ~othioureldo)~t~yl) ~(.S~-(~-(1(~C)-(a-(metho~ym~thoxy)~i~eridin-1-yl)c2r~Qnvl-?-~ yl)~thy~-L-~QLl~--~in~do)-6-cyGLohe~yl-~(S)-:-~Jd~ -?(~
,i ~oR-vl~namid~
A . N- (2-~2~ml~noet-~yll (2S, 4 '~, 5S) -5-butyloxyc2rbonyl,~ ~Q-9-l~ydroxy-2-iso~r The procedure of Example 49A was emploved, substitution of ethylene diamine ~or 4-~3-aminopropyl)morpholine, to provide the t-~1~ com~ound 25 a white foam ~98% yield): mp 55-62 C; Rc 0.2' (lO~ MeOH-i~
conc NH4OH-~H2Cl2); lH N~ (CDCi3) ~ 0.63-l.G6 (D- m) anà
0.93 ~d, 8 H total), 1.06-1.33 (br m, 5 H), i.33-1.50 (b-m) and 1.45 ~s, lO H total), 1.50-1.98 ~br m, 10 H), l.99-2.09 ~m, 1 H), 2.74-2.89 (m, 1 H)2.90-3.03 (br m, 1 H), 3.03-3.19 (br m, 1 H), 3.40-3.75 (br m, 3 H), 4.68 (br d, 1 H), 6.00-6.09 (br m) and 6.21-6.33 (br m, 1 H total); MS
m/e 414 (~M+H)+).
B. N-(2-(S-~ethyl-~'-cyanoisothtaure;do)ethyl) (2S, 4S. 5s! -5- (te~t-bu~ylQxycarbony~ amlAQ-4-hydroxy-2-~QgrQ~ylhexanamide~ The procedure of Example 24 was employed, with the substitution of the resultant compound from Example 63A for the resultant compound from Example ,16 to provide the title compound (100% yield): mp 96-102 C; Rf 0.34 t5% MeOH-CH2Cl2); lH NMR (CDCl3) ~ 0.70-1.06 (br m), 0.91 (d) and 0.94 (d, 8 H total), 1.06-1.50 (br m) and 1.44 (s, 15 H total), 1.55-1.93 (br m, 10 H), 2.11-2.22 (m, 1 H), 2.55 (br s) and 2.64 (br s, 3 H total), 3.33-3.75 (br m, 6 H), 4.58-4.85 (br m, 1 H), 6.80-6.95 (br m, 1 H), 7.82-8.01 (br m, 1 H); MS m/e 529 (M+NH4)+, 512 (M+NH4)+
.
.. . ~. , . . ;, :
. . . .
:. . , : ~
:. - . :. : .
-: , :: . . , W~92/03429 PCT/US91/055~ ~
2~8926~
' ' -98-Anal. Calcd for C2sH4sNsO4S: C, 58.68; H, 8.86; N, 13.68.
Found: C, 58.33; H, 8.98; N, 12.95.
^ The procedure of Example 49B may be employed, with -,the subs.itution o_ the resultant compound from Example,63B
for the resultant compound from Example 49A, to provide the .i.le compound.
le 6~
~`Y-(2-(~ ienou~e;~o~ethyl,) 5fS)-(N-(l(.~)-(a-(~C-'~ 77,er~,7,r~ ~7~1~-I-vl)c2-bo~1-2-~?~enyl)~thyl -T~-72_1e~ na.,!ldo) -6-c-~lQhe~:yl-~(S~-hydroxy ~
The procedure of Example 25 may be employed, with the substltution of the resultant compound from Example 63 for the resultant compound from Example 24, to provide the title compound.
, Examp]e 65 N-(2-((3-~mino-lH=1,2,4-triazgl-5-yl)amino)ethyl~ 5(S)-(N-(Ll~ -(4=(metho~ymethoxy)piperidin-1-yl)carbo~yl-2-~henyl)e~hyl-L-nn~ n~ml~o)-~-~yclohexyl-4(s)-hyd~oxy-", 2(~)-iso~roQ?t~lh~n~id~
The procedure of Example 25 can be employed, with the ~'~substitution of the resultant compound from Example 63 and hydrazine hydrate for the resultant compound from Example 24 and 30% aq. NH40H, to provide the title compound.
.. ~ ' .
~.'' .
, ::
: . . ~ . -.. .... ...
j, : ' . " ~ . " ' " ' ' ' wo92io3429 2 ~ ~ ~ 2 6 ~ PCT~US91/~55~
J ~ 7 `
_ 9 9 ~
E,~m~le 66 N-(2-((5-.~..ino-L 2.~-o~ad1a~o1-5-yl)am'~nQ)et~hyl) 5(~)-(N-(1(.~!-(4-(~e..hoxymeLho~v~ eridin-~ l)~al~nyl-2-pheryl)e~hyl-L-n~rleucin2m-do)-~-cyclohe~yl-4_(5)-hydroxy-2(5)-iso~ropyLhe~a~amlde.
The procedure or Example 25 can be employed, with the substitution or^ the resultant compound from Example 63, hydroxylamine hydrochloride and a molar equivalent quantity of triethylamine ror the resultant compound from Example 24 and 30% aq. NH40n, to provide the title compound.
E~amDt~ 67 ~L2-(Methvls~lfamoylami.nQ)ethylL ~ L~(N-(l(-~L-(4-; (methoxy~hoxy)~i~er;.di~-1-yl)c2~.bonyl-2-~henyL)ethyl-I.-norleucinamido)-6-~c~loh~yl-4(5)-hydroxy-2(5)-isQeropy~.hexanamid~_ ~ ~. N-(2-(Methylsul~mQyl~m~nlEth~l) (2S 4S.5S)-5-.~ ~tert-hutyLoxyc~}20Qyl) amino-,4,-hydrQx5~2-9~15~il~. A solution of the resultant compound , from Example 63A (SOO mg, 1.21 mmol) and triethylamine (0.50 mL, 3.62 ~mol) in 3 mL CH2C12 was cooled to O C, and a solution of methyl sulfamoyl chloride (173 mg, 1.33 mmol) in 1.5 mL CH2C1~ was added dropwise. The resulting solution was stirred 6 h at O C and a further 48 h at ambient temperature-. The mixture was partitioned betwwen 25 mL CH2C12 and 25 mL sat. aq. NaHC03. The aqueous phase was extracted (3 x 25 m~ CH2C12), then the combined organic phases were dried (Na2S04), filtered and concentrated to a white solid (582 mg). Flash chroma~ography (silica gel, 3.5~ MeOH-CH2C12) afforded 327 mg (0.645 mmol, 53 %) of the , .. , , ~ , .................... .. . . . . .
- ~ .
.: , : : '' ' ~:' ' ' ' W092/0~29 P~T/~91/055~ _ - -~ æoss~68 - '' title compound as a white foam: mp 75-95 C; R 0.22 (5 MeOH-CH2C12); 1H NMR (CDCl3) ~ 0.77-1.06 (br m), 0.92 (d) : and 0.95 (d, 8 H total), 1.05-1.40 (br m, 6 H), 1.4~ 6S, 9 H), 1.56-2.03 (br m, 9 H), 2.04-2.18 (m, 1 H), 2.73 (d, 3 H), 3.10-3.30 ~br m, 3 H), 3.45-3.58 (br m, 2 H), 3.7-3.84 (br m, 1 H), 4.6-4.82 (br m, 1 H), 4..82-4.95 (br m, 1 H), 5.32-5.51 (br m, 1 H), 6.35-6.45 (br m) and 6.61-6.75 (b-m, 1 H total); MS m/e 524 (M+NH4)+, 507 (~+NH~ nal.
Calcd for C23H46N~O6S: C, 54.52; H, 9.15; N, ll.Oo. Found:
C, 54.41; H, 9.38; N, 10.59.
B. The procedure of Example 49B can be employed, with the substitution of the resultant compou~.d --om ~:;a~pl~ ~7.'.
for the resultant compound from Example 49~, to provide tne title compound.
~2~mRl~ ~
N-(~-(l.L-~ioxo-4-thiom.olq~hoL~ethyl) 5(S)-(N-(l(S)-. (methoxymethoxy).~i~er~in-l-yl) ca~orlyL-2-~?h~,lLethyl-T,-(s) -hydroxy-2 (s? -., _i~
A. N-(2-(1, ~-~i~8Q=~=~hiQmQ~holino)ethyl) 2(S)-((3-(te-t-butyloxyc~rbQnyl_?-2.2~dimeth~ (.S~ clo~.e~ met~
~ The procedure of Example 2B was employed, with the substitution ~ of 4-(2-aminoethyl)thiomorpholine~ dioxide for 4-(3-: aminopropyl)morpholine, to provide the title compound as a white foam (100%): lH N~R -(CDC13) ~ 0.83-1.04 (m, 8 H), 1.04-1.44 (br m, 6 H), 1.48 ~s, 9 H), 1.53-1.95 tseveral b_ m, 18 H), 2.03-2.14 (br m, 1 H), 2.66 (t, 2 H), 2.98-3.15 : (br m, 8 H), 3.20-3.53 (br m, 2 H), 3.56-3.85 (br m, 2 H), 5.83-5.94 (br m, 1 H~/ MS m/e 572 ((~+8)+~.
.
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W0~2/0~29 2 ~ 6 ~ PCT/US91/05~
... . ..
--101~
The procedure of Example 2C can be em?loyed, wlth the substitution of the resultant compound }rom Example 68A
for the resultant compound from Example 2~, to proviae the title compound.
F. ~ a~.l~ ~q ~ =~reido 5(s)-(N~ s!-(4-(m~tho~vmetho~ ryer~ln=~
yl)carbonyl-2-~h~n~l)ethyl-~,-nor]elc~ n~ o~ , cl ~h 4(5)-hvd~nxy-2(5~-lsoDr~?yl`~e~2~ .e.
mi.no ~25, 4 ~. 5 ~ t~r~--2~1tyl5:~ ~C~ . _?.C`--4-hydro~y-2~iso~ro~ylhe~an~m1de. Tiîe procedurQ o~ ~.xample 49A was employed, with the subs~itu~lon o_ hydrazine hydrate for 4-(3-aminopropyl)morpholine, to provide the title compound as a white foam (73~ yield): mp 55-62 C;
Rf 0.45 (5% MeOH-CH2C12); 1H NMR (CDCl3) ~ 0.55-1.94 tseveral~br m, 16 H approximately), 0.94 (dd, 6 H), 1.49 ~s, 9 H), 1.58 (s, 3 H), 1.64 (s, 3 H), 2.05 ~m, 1 H), 2.50-3.50 (vbr m, 2 H), 3.69 (m, 2 H), 6.92 (m, 1 H); MS
m/e 426 ~(M+H)+), 443 ((M+NH4)+). An~al. Calcd for C23H43N3O4: C, 64.91; H, 10.18; N, 9.87. Found: C, 65.00i H, 10.04; N, 9.64.
4-hydro~y=2-isopr pylhexa~amide. The procedure of Example 6B was employed, with the substitution of the resultant compound from Example 69A for the resultant compound from Example 6A, to provide the title compound as a white powder (100% yield): mp 95-102 C; Rf 0.22 (5% MeOH-CH2Cl2); 1H
NMR (CDC13) ~ 0.85-2.03 (several br m, 16 H approximately), 0.97 (dd, 6 H), 1.49 (s, 9 H), 1.59 (s. 3 H), 1.65 (s, 3 H), 2.11 (m, 1 H), 3.69 (m, 1 H), 3.83 (m, 1 H), 5.31 (m, 2 H), 7.07 (m, 1 H), 7.49 (br s, 1 H); MS m/e 469 ((M+H)+?, ': . : :: :
: ' ' .: . ...
2/03429 P~r/U~91/~
9 ~ ~ 8 -102-486 ((M+NH4)+). Anal. Calcd for C24H44N4Os: C, 61.51; H, 9.46; N, 11.95. Eound: C, 61.32; H, 9.43; N, 11.33.
C. The procedure of Example 493 was employed, with the substitution o_ the resultant comDound from Exampie 69B
for the resultant compound from Example 49A, to provide the t tle compound as a white powder (34% yield): mp 115-121 C; Rf 0.33 (10% MeOH-C~2C12); 1H NMR (CDC13) ~ 0.74-2.00 (several br m, app-ox. 17 H), 0.96 (d, 6 H), 1.50 (s, 9 H), 2.58 (m, 1 H), 2.90 (m, 1 H), 3.36 (m, 1 ~.), 3.70 (m, 1 ~), 5.00-7.70 (v-b_ ~.., a?prox. 2 H), 5.78 (m, 1 ~), li.33 (m, 1 H); MS m~e 429 ((M~X)+), 445 ((M+NY.4)+). Anal.
^~lc~ for C21:iio~T4o~ 0.25 H2O: C, ~3.24; H, 9.42; ~, 12.93.
Found: C, 58.17i ;i, 9.22; N, 12.93.
E~amDle 70 N~ thylsulfamoylami~o) 5(S)-(N-(l(S)-(4-~met~oxymethQxy)piperidin-l-yl)ca~bonyl-2-phenyl)ethyl-L-A. N-(Methyl~uLfamoylamlno) (2~,4~ ~S)-~-(ter~-yloxycalbonyl)aminQ-4-h~d~Q~-~2~-is~p~opyLh~a~am; de .
The procedure of Example 67A can be employed, with the substitution of the resultant compound from Example 69A for the resultant compound from Example 63A, to provide the title compound.
~ _ The procedure of Example 43B can be employed, with the substitution of the resultant compound from Example 70A
for the resultant-compound from Example 49A, to provide the tit1e compound.
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2~3~8 W092/0~29 PCT/US91/05~
, :
! ~ 5 . ' N-(MQthylsulfQnylami no) S (S) - (~- (1 (S~- (4-(r~Ql ho.~yr.ner:n~Yy) ~ r~ n-l -yl ) c~-hony~ henyl ~ et ~orl~uc namido)-6-cyclohexyL-4(.~-hydroxy-2(s)-i~Q~-o~ylhe~;aræTnide ~
~ . ~- (M~thvl s~l fonyl amino) (2S 4S 5S) -5- (tert-b~ y~ca-rl~?~ n~Q-~-~h~J~oyv---~Q~--o~ylLhe~n2mi~
The procedure of E~ampie 67A can be employed, with the substitltion o-^ me_hanesulfonyl c..loride for me~hylsulfamoyl chloride, ~o provide the title compound.
B. The procedure of Example 49B can be employed, with ; the substitution of the resultant compound from Example 71A
for the resultant compound from Example 49A, to provide the title compound.
~, ~ample 72 ~-(CarboxyethylL_5~Sl~(N-(1(S)-(4-(m~i:hoxymethQxy~=ylls~
norleucinamido)=6-~y~lQhexyl-4(5)-hydroxy-2(5)-' so~Dyl~an~
a. N- ~thyl car~Q~ye~h~L~ s)-(N-(l(sL-(4 (me~hoxymethoxy)~lpPr-d.n-1-y1icar~onvl-2-~henvl!ethy~
0~ 3 ' A~ The procedure of Example 37B can be employed, with the substi~ution of the resultant compound from Example 74 for the resultant compound from Example 1, to provide the titLe compound.
~ _ The procedure or Example 37C can be employed, with the substitution of the resultant ompound from Example 72A
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208~2~
for the resultant compound from Example 37B, to provide the title compound.
E X ? ~ 7~
-(2~ ip~ldlnyl)ethyl~ 5L.~)-tN-(1($)-~4-(~ethoxymethQxy~ ~Li~1~-l-yl)car~onyl-2-p'~enyl)e-h~
norleu~amido) -6-cy~lohexyl,-,4 L~-hy~'~roxv-2 (S) -iso~Q~ylhexanamide.
A~ N-(2-(l-pi~eridinyll-e~hyl) (25.4.~.55~-5-~er~-butylo~a~ nvl)a~lno-4-`~ydroxy-2-i~o~ro~v1 hQ`;an~mide .
The procedure of Example 49A can be employed, with the substitution of 1-~2-aminoethyl)piperidine for 4-(3-aminopropyl)morpholine, to provide the title compound as a white crystalline solid (90~ yield): mp 149-50 C; [a] 25D
+1.5 ~c 2.4, CHC13).
~ _ The procedure of Example 49B can be employed, with the substitution of the resultant compound from Example 74A
for the resultant compound from Example 49A, to provide the title compound.
Example 7~
_ .n-1-yl)ca~Qnvl-2-~he~lLe~hy1=l=norleucine ~ ,.
~ 4-(Methoxymethoxy)-piperidine (50.0 g, 0.344 mol), ~L)-N-(carbobenzyloxy)phenylalanine (113 g, 0.379 mol), and 1-hydroxybenzotriazole hydrate (106 g, 0.690 mol) were dissolved in 300 mL DMF and cooled to -20 C under dry nitrogen. A solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (86 g, 0.448 mol) in 300 ~.L
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WV92/03429 2 ~ ~ 9 2 6 ~ PCT/US91/05;~
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DMF was added. After warming to room temperature i overnight, the DMF was removed under reduced pressure at 35 C. The crude product was partitioned between -tOAc and 10% citric acid. The organic phase was washed sequentially with 10% citric acid, 5~ NaHCO3, and brine, dried (MgSO4), and evaporated to give 132 g (90~) of the desi-eà amide: 1H
NMR (CDCl3) ~ 1.01 (m, 1 H), 1.18 (m, 1 H), 1.42 (m, 1 ~), 1.65 (m, 1 H), 2.99 (m, 2 H), 3.13 (m, 1 H), 3.3' (m, 2 u)r 3.33 (s, 3 H), 3.64 (m, 1 H), 3.81 (m, 1 H), 4.o2 (s, 2 .i), 4.91 (m, 1 H), 5.09 (s, 2 H), 5.71 (t, J = 9 H~ ), 7.2 (m, 10 H); MS m/e 427 ((M+H)+).
~ aLt _~, The above benzyl carDamate (122 c, 0.286 mol) was hydrogenated under 4 atm. H2 in 2 L MeOH usin~ 24.5 g 20% Pd/C. After 16 h, an additional portion of catalyst (25 g) was added. The mixture was shaken for a total of 48 h, then filtered and evaporated in vacuo to provide 75.4 g (90%) of the title compound as a waxy solid: lH N~R ~CDCl3) 1.08 (m, 1 H), 1.27 (m, l H), 1.4S (m, 1 H~, 1.70 (m, 1 H), 3.07-(dd, 2 H), 3.2 (m, 2 H), 3.35 (m, 2 H), 3.35~s, 3 H), 4.67 ~s, 2 H), 7.29 ~m, 5 H~; MS m/e 293 ~M+~)+).
~ _ The resultant compound ~rom Example 74A ~75.0 g, 0.257 mol) was added to a solu~lon of ammonium carbonate ~27.26 g, 0.29 mol) in 200 mL water. The mixture was stirred at 35 C, and (R)-ethyl 2-bromohexanote ~S3.52 g, 0.24 mol) in 100 mL of nitromethane was added. The reaction mixture was stirred at 42 C for 48 h, and at 48 C for an additional 12 h.
The mixture was cooled and extracted with ethyl acetate, the organic extract was dried ~MgSO4), filtered, and the f1ltrate evaporated under reduced pressure to zr oil. The ~' .
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20892~8 crude product was purified by sho-t-path silica gel column chromatography, eluting with a gradient of 2-5% MeOH-CHCl3, to give 81.4 g (78~ based on 5 g c~ recovered starting amine) of th~ t~tle com~ound~ ~ (DMSO-d6) ~ 0.82 (t, 3 H), 1.15 (dd, 3 H), 1.2 (m, 4 H) 1.3 (m, 2 H), 1.4 (m, 2 H), 1.6 ~m, 2H ), 2.7 (br d, 2 H), 2.6-3.15 (several br m, 4 H), 3.22 (2 s,3 H, rotamers), 3.85 (m, 1 H), 4.03 (m, 2 H), 4.57 (2 s, 2:i, roramers), 7.2 (m, 5 H).
C. The ~esul_a~.t com~ound _~m Exam?le 743 (35 g, 0.081 mol) was s.~-_ed in 112.5 r.._ 2 N NaOH (0.227 mol) at room temperature ror 24 h, by wh -~ time tne cloudy mix.ure turneà clear. The mixture was ac dified with aqueous ci~ric acid to pH 5.5, causing a ~hite solid to 2recipitate. After standing at room temperature for 2 h, the solid was filtered, then washed sequentially with cold water and 20% ether/hexane, and dried under high vacuum to afford 28.4 g of crude product. The crude material was recrystallized from hot ethyl acetate to give the desired compound (27 g, 82%) as a white powder: mp 155-7 C;
[~]D25 +26.3 ~c 0.28, CH30~ H NMR (DMSO-d6) ~ 0.85 (t, 3 H), 1.25 (br m, 6 H), 1.5 (br m, 4 H), 2.75 (dd, 2 H), 2.82 ~m, 2 H), 3.02 ~m, 2 H), 3.22 (2 s, 3 H, rotamers), 3.45 (m, 1 H), 3.58 (m, 1 H), 4.0 (m, 1 H), 4.55 (2 s, 2 H, rotamers), 7.25 (m, 5 H); MS m/e 407 ~(M+H)+).
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, ~09~io~29 2 ~ o 9 2 ~ 8 P~T/U~1/055~
~, r --10 7-- -i N-(( d _D~ idyl)m~hyl) ~(S)-(N-(~ (4-(~.elh~Ymeth?Y.~ e~ n-l -y~ )ca-~Q~.yl-~-~heny1)ethyl-T-,n ~--l P l ~ d ? ) --7 ~ ,Q h t~ l--d ( C ~ --n ~ o " ~--2 .( ~ C ) -- ( ~--hydro~yethyl ) octænamide .
The proceàure of ~xample 493 can be employed, with the substitution of the resultant compound from Example 27(a), United Sta,es Patent 4,851,387, fo_ the resultant compound from Example ~a~, to p-ovide the t ~le compound.
~ :a~.?1~ 76 ~- (2-~1n~-' -~. jCl o:-e ~:y' -3 (~), a (S) -~- hyd~o~y-~-~ethyl-2i.$)-hexyl) 5(5)-(~-(1(5~-(4-(metho~ thoxy~pi~eridln-1-yl)ca~onyl-2-~henyl)e~hy1-~-nor1~eucin2i~ide A. N-(5-Benzyloxycarhonylami~Q=1-cyclohexyL-3(R! ~(S)-dihydroxy-5-metby~-2LS)-h~xyl) 5l~l-(N-Ll(S)-(4-t~ethoxymet~Q~yLpiperidin-1-yl)carbonyl-2-p~enyL)ethyl-L-~ Is~ m_a-_ The procedure of Example 49~, part 2 can be employed, with the substitution of the resultant compound from Example 5, PCT Patent WO 91/01327, for the resultant compound from Example 49~, part 2, to provide the title cor,pour.d.
~ . The procedure of Example 3 can be employed, with the substitution of the resultant compound frsm Example 76A
for the resultant compound from Example 2, to provide the title compound.
.
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WO92/03429 PCT/US91~05 `
` ` - 2~8~6~ 108-xam~1~ Z7 (2~ S)-2- r (N-(1(5)-(~-(me~hQ~ym~ho~y)~ rl dl~
yl!carbon~l-2-phenyl)e~hyl-L-nQxleuci~amido)l-l-cv~lohe~
~ . 5(s)-(~ert-Bu~ylQ~y~l~Qnyl)-6-cyclohe~ -4(s) hydrox~-2-(S)-i~op~opylhe~anol, The title compound was prepared using the procedure described in the literature (Karlsson, J. O.; Lundblad, A.; Malm, I.; Milsson, _.;
Niten~erg, T.; Starke, I.; Sorensen, H.; Westerlund, C.
Tetrahedron Lett. 1989, 2653) for the 6-methyl cor~ound, however the analogous isopropyl precursor was used instead.
H NMR (CDCl3, 300 MHz) ~ 0.90 (ad, J = 6Hz, 6H), 1.13-1.40 (bm, 6H), 1.45 (s, 9H), 1.57-1.90 (bm, 12H), 3.58-3.72 ~m, SH), 4.68 (bd, J = 9Hz, lH). Anal calcd for C20H3gNO~-0.25H20: C, 66.30; H, 10.62; N, 3.76. Found: C, 66.14; H, 10.67; N, 3.77. MS tDCI/NH3) m/e 358 (M+H)+.
The compound resulting ~rom Example 77A was converted to the! title compound using the method described in the literature (Karlsson, J. O.;
Lundblad, A.; Malm, I.; Nilsson, I.; Nitenberg, T.; Starke, I.; Sorensen, H.; Westerlund, C. Tetrahedron Lett. 198g, 2653) for the 4-methyl compound. m.p. 85-86 C. lH NMR
(CDCl~, 300 MHz) ~ 0.92 (t, J = 6Hz, 6H), 1.15-1~84 (several bm, 17H), 3.52 (m, lH), 3.68 (dd, J = 4.SHz, 2H), 4.35 (m, lH), 5.62 (bs, lH). Anal calcd for C16H2gNO3: C, 67.89; H, 10.25; N, 4.95. Found: C; 67.72; H, 10.14; N, 4.92. MS (DCI/NH3) m/e 301 (M+a+NH3)+.
C. 4-Cyçlohexylmet~yl-5-l3-~ethyl-2=
~e~hoxymethoxymethy~utyl-2~-o~azQli~Qne To the compound resulting from Example 77B (650 mg, 2.30 mmol) dissolved ir s , :
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WO 9~/0342~ 2 ~ ~ 9 2 ~ 8 PCT/US~ s24 .. . , .. ... , ~ ~ .. . .
anhydrous methylene chloride (20 mL) at ambient temperature was added technical grade chloromethyl methyl ether (0.26 mL, 1.5 equivalents) followed by diisopropylethylamin~ (0.8 mL, 2 equivalents). The resulting mixture was sti-red for 2.0 hours at ambient temperature, at which time additional chloromethyl methyl ether (1.0 mL) and diisoproyle~hylamine (0.5 mL) were added. After stirring for an add~tional hour, the solvent was removed under reduced pressure. The residue obtained was flash chroma~ographed on sllic~ gel eluting with a gradient (25%,30%) of ethyl ace~ate in hexane to afford the title compound as a white sol-d (640 mg, 85%). lH NMR (CDCl3, 300 MHz) ~ O.88-0.98 (m, dd, J =
3.6Hz, 7H), 1.12-1.85 ~several bm, 16H), 3.~7 (s, 3H), 3.47-3.58 (M, 3H), 4.28 (m, lH), 4.60 (s, 2H), 5.74 (bs, lH).
MS (DCI/NH3) m/e 328 (M~H)+, 345 ~M+H~NH3)+.
D! The compound resulting from E.xample 77C and 3 equivalents of barium hydroxide octahydrate 0.1 ~ in 3:2 dioxane/water was heated at reflux overnight. The cloudy solution was then cooled, filtered through Celite and concentrated under reduced pressure to dryness. ~he residue obtained was dissolved in ethyl acetate and filtered through Celite again. After removing the solvent under reduced pressure, the amine obtained (>90~) was used without isola~ion or further purification.
The above amine ~260 mg, 0.86 mmol) was coupled with-the compound resulting from Example 1 (350 mg, 0.86 mmol) by the procedure described in Example 49B, part 2 to afford, after column chromatography on silica gel eluting with 3:1 hexane/ethyl acetate, the title compound (505 mg, 84%) as an oil. lH NMR (CDCl3, 300 MHz) ~ O.74-0.96 (m, t, `:
.. ,, : .~,. . .
WO 92/03429 PCT/US91/055~
2~268 J = 6.6Hz, lOH~, 1.07-1.80 (several bm, 33H), 2.67-2.89 (m, 5H), 3.33 (s, 3H), 3.40 (s, 3H), 3.52-3.78 (bm, 4~), 4.65 (dd, J = 1.5H~, 4H), 7.27 (m, 5H). MS (FAB) m/e 690 (M+H) .
(2~ ~C~-2-r(N-(ll~c)-(5- (me~hoY~yme~oi~y)~lpe-i~; n-1-yl)c~Q~-2-~han.vl~at~l-T.-~o;lo cL~mldo)l-1-cycloh~yl---nydo~r~v--5--isQ~2r~ yl t;,h,l o~t~v~--5--mar~ylhe~tzna A. I.s~yro?yl r5(S~.-(ta~t-~u ylo:~yca~bon~l)-~-cycloha~yl-~(S)-nydroxy-2-(S)- qQ~~~pylhe~yll tk;Qether.
The title com~ound was prepared usln.g the procedure desc-lbed in the literature (Karlsson, J. O.; Lundblad, A.;
Malm, I.; Nilsson, I.; Nitenberg, T.; Starke, I.; Sorensen, H.; Westerlund, C. Tetrahedron Lett . ~ 989, 2653) for the . 6-methyl compound, however the analogous isopropyl :. precursor was used instead. m.p. 107-108 C. lH NMR
(CDCl3, 300 MHz) ~ 0.85-1.00 (m, ddr J = 6Hz, 7H), 1.15-.~ 1.38 (m, d, J = 6Hz, 9H), 1.45 (p, J = 6Hz, lH), 1.58-1.92 (m, 12H), 2.52 (dd, J = 6Hz, lH), 2.63 (dd, J = 4.5Hz, lH), 2.87 (p, J - 6Hz, lH), 3.64 (~, J = 7.5Hz, lH), 4.29 (m, lH), 5.20 (bs, lH). MS (DCI/NH3) m/e 342 (M+H)~, 359 s (M+H+NH3) .
B_ The compound resulting from Example 78A was treated with barium hydroxide octahydrate by the procedure described in Example 77D. This compound was coupled with the compound resulting from Example 1 (250 mg, 0.62 mmol) by the procedure described in Example 49B, part 2 to afford the title compound (357 mg,-82~) as an oil. Rf = 0.28 (50%
~i hexane-ethyl acetate) 1H NMR tCDCl3, 300 MHz) ~ 0.75 0.95 (m, lOH), 1.08-1.39 (m, d, J = 6.9;iz, 20H), 1.48-1.86 tbm, ... .
' ~' .
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wo92io~29 ~ ~ 8 ~ 2 ~ ~ PCT/~S91/055~
;i . . iJ ", ~ ~ _ 18n), 2.40-2.59 (m, 3H), 2.81 (bm, 3H), 2.92 (p, lH), 3.26-3.48 (m, s, 4H), 3.68 (bm, 3H), 4.64 (d, J = 3Hz, 2H), 7.26 (m, 5H).
E x a~ R 1.~ 7 9 (~;, 4~) -;~- r (~ S) - (~1- (meth~ethoxy~ eri~ ]-yl~ hon~1-2 ~hQ.n.yl)ethyl-~-no~le~cinzmido)l-l-cy~lohe~yl-~-hydoxy-~ so ~
TCO~rO~Vl r ~ (S) - ~t ert.-bulyl.oxyc2rhQ~L) -ij-c~c onexyl-a(S~-hJir-oxy-?-(~)-ico~-opy~.h~xyl~
th~o.~ulfonate~ lhe compound resul.ing from Example 78a was oxidized usina the procedure descr bed in the litera~ure (Ka-lsson, J. O ; Lundblad, A.; Malm, I.; Nilsson, I.;
Nitenberg, T.; Starkef I.; Sorensen, H.; Westerlund, C.
Tetrahedron Lett. 1989, 2653) fo- the 6-methyl compound to afford the title compound. m.p. 135-136 C. lH NMR
(CDC13, 300 MHz~ ~ O.98-1.03 (m, dd, J = 6Hz, 7H), 1.10-1.35 (m, 4H), 1.37-1.48 (m, d, J = 6Hz, 7H), 1.57-2.30 (several bm, llH), 2.77-2.97 (m, 2H), 3.11 (p, J = 6Hz, lH), 3.58 (q, J = 7.5Hz, lH), 4.33 (m, lH), 5.15 (bs, lH).
The compound resulting from Example 79A was treated with barium hydroxide octahydrate by the procedure described in Example 77D. This compound is then coupled with the compound resulting from Example 1 by the procedure described in Example 43B, part 2 to afford the title compound.
;
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.
.
w092io~29 PCT/US91/055~
20~9268 Exam~Le 8Q
hexar.oL~
~xam~le 80a L=yslQh~yL~l~ni~e m8~hyl es ~r. hydroc~l?~ c~
L-Phenylalanine (215 g, 1.3 mole) was hyàrogenated over Pd/C in HOAc, filtered and concentrated. The ; resulting cyclohexylalanine was ta~en up in ~!e~H ~120~
mL). Thionyl chloride (427 g, 3.59 mole) was slowly added to the slurry, which eventually became homogeneous. The reaction was cooled in an ice/water bath and addition of thionyl chloride was continued. The reaction -i~ was heated to reflux for 2h, cooled and concentrated to a~_ord a solid, which was taken up in ether and filtered. The white solid was washed with ether in the filter funnel and dried ;n v~cuo to give 271 g of product, 94% yield over two steps. mp 150-152 C; [a]D =+21.8 (c= 1.09, MeO~); IR
(KBr, cm~l) 2930(br), 2860, 1748; lH NMR (300 MHz, CDCl3) 3.99 (t, J= 6.3 Hz, lH), 3.9 (bs, 2H), 3.83 (s, 3H), 1.82-1.65 (m, 7H), 1.5 (m, lH), 1.35-1.10 (m, 3H) 1.05-0.9 ~m, 2H); 13C NMR (75.5 Hz, CDCl3) ppm 170.5, 53.3, i0.8, 38.3, 33.6, 33.0, 32.8, 26.3, 26.1, 25.9.
E~am~ Ob ;~ The product of Example 80a (88 ~, 398 mmol) was taken up in chloroform (400 mL). Triethylamine (84.6 g, 836 mmol) was then added in one portion to the slu;ry and stirred five minutes. Triphenylmethylchloride ~111 g, 398 mmol) was then added, and the reac~ion was stirred for 5h at ambient temperature. The interna1 temperature of the ., .
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WO9~/03429 2 ~ ~ ~ 2 6 8 PCT/~S91/OSj24 `. .i, .. . .. ... .. .. . .
. . .
reaction reached 50 C, however, external cooling was not employed. The reaction mixture was washed with lM KHSO4 solution (2 X 200 mL), saturated NaHCO3 (200 mL), brine ~100 mL), then dried over MgSO4. The solution was then concentrated to give 200 g of resldue which was filtered through 900-1000 g of silica gel (elution gradient hexane-10:1 hexane: ethyl acetate) affording 157 g o- ~roduct (93%), which could be crystallized from he.~anes: e.hyl acetate to afford large white crystals.
mp 86-87 C; [a]D =+73.6 (c =1.38, C~Cl3); IR (XBr, cm 34SO(br), 2930, 1722; lH N~R (300 MHz, CDCl3) ~ 7.52-7.47 (m, 6H), 7.28-7.12 (m, 9H), 3.32-3.41 (m, 1:~), 3.12 (âr 3H), 2.60 (d, J=lO.S Hz, lH), 1.56-1.46 (m, 7H), 1.35-i.l (m, 4H), 0.77-0.97 (m, 2H); 13C NMR (75.5 Hz, CDC13) ppm 176.1, 146.0, 128.8, 127.7, 126.3, 71.0, S4.2, Sl.2, 44.4, 34.1, 33.9, 32.9, 26.5, 26.1.
" ~;~m~
im~ha~_ U~L=~-Cycl~hexyl-~-~~tr:~?henylmethyl~amino-2 .' oxo}2lltylDho~phorlate .
;To a -78C solution of dimethyl methylphosphonate (272.S g, 2.2 mol) in 1.6 L THF wzs added n-BuLi (2.5 ~ , 800 mL, 2.0 mmol) and stirred 45 minutes. The product of Example 80b (156 g, 366 mmol) in 90 mL THF was then added dropwise. The reaction mixture was stirred at -50C for 3 :.. .
h, then at -40C for 6 h, then finally warmed to ambient temperature overnight. The reaction mixture was concentrated, taken up in ether, washed with 1~ KHSO4, ~i saturated NaHCO3 (twice) and brine, dried and . concentrated. The residue (200 g) W2S filtered through ;~:
.. . .
~NO92t03429 PCT/US91/D55~
~, , 2 0 ~ ~ 2 ~ 8 - -114-1000 g silica sel, (1:1 hexanes:ethyl acetate) to give 135 g of ~-keto phosphonate (72~) as an oil.
[alD =+39.7 (c =2.0, CH30H)i IR (CDCl3, cm~1) 2920, 1717, 1425, 1226, 1019i lH NMR (300 MHz, CDCl3) ~ 7.45-7.38 (m, 6H), 7.30-7.18 (m, 9H), 3.67 (dd, J= 11.1, 2.7 Hz, 6H), 3.47 (m, lH), 2.83 (d, J= 6.6 Hz, lH), 2.67 (dd, J= 21.0, 15.3 Hz, lH), 2.32 (dd, J= 21.0, 15.3 Hz, lH), 1.6S (bs, 5H), 1.49 ~m, 2H), 1.10-1-53 (m, 4H), 0.81 (m, 2H); 13C
: NMR (75.5 Hz, CDC13) ppm 205.8, 145.9, 123.1, 127.9, 127.7, 126.7, 71.2, 61.4, 61.3, 52.8, 52.7, 52.6, 41.4, 37.1, 35.2, 33.8, 33.5, 33.4, 26.4, 26.2, 26.1.
E~am~L~
(6S~-7-Cyclohexyl-2-methyl-6-~N-~ h~nylmethyl)-{ am~no-5-oxohe~-2-~nQ-~-o~c a~id The product of Example 80c ~117.2 g, 229 mmol) was dissolved in 600 ml THF and cooled to 0C. To this solution was added hexanes washed NaH (60%, 9.6 g ~wet), 240 mmol) and stirred 30 min. Next WéaS added methyl 3-methyl-2-oxobutyrate (29.8 g, 229 mmo:L) in 100 ml T~F and stirred at 0 C-for 4 h. Volatiles were removed at reduced pressure, the residue was dissolved in 1:1 hexanes: ether (500 ml) and washed with water (200 ml), NaHCO3 ~200 ml), brine ~200 ml), dried ~MgSO4) and concentrated to afford 129 g of the desired ester as an j oil. This material (123 g) was taken up in 460 ml THF, 229 ml ~eOH, cooled to 0 C, then 18.86 g of LiOH-H2O in 229 m! of distilled water was added. This solution was ' allowed to warm to room temperature'and stirred for 3 days. Volatiles we!e removed at reduced pressure and the resulting aqueous solution was wa'shed with ether (100 ml ': ~
W092/0~29 2 ~ ~ 9 2 ~ ~ PC~`JUS91/0~
.-:
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x2) then acidified to pH 3 with 6N HCl. The aqueous solution was then extracted with EtOAc (300 ml x2), washed wlth brlne, drled (MgS04) and concentrated to glve 116 g of a yellow foam. This material was recrystallized from 525 ml of hot hexanes/EtOAc (12/1) to give 72.4 g of a white solid (62~ for three steps).
mp 97-98 C; [a]D =+6.0 (c=1.0, CH30H); IR (KBr, cm~1) 3450(br), 2530, 171S, 1682, 1442; lH NMR ~300 MHz, CDC13) 7.48-7.36 (m, 6H), 7.31-7.12 (m, 9H), 3.5 (bs, lH), 3.25 (d, J= 18 Hz, 1~), 2.99 (d, J='18H, lH), 2.1 (bs, 4H), 1.6 (bs, 8H), 1.2-1.05 (m, 6H), 0.8-0.6 (m, 2H).
. .
~
~5~6S)-6-Cvclohexylmethyl-3-~o~ro~ylldene-5-~ridine-2-Qn~
A solution of 3.06 g (6.0 mmol~ of the product of Example 80d in 50 ml THF was added to 6.8 g (60 mmol) N-' hydroxysuccinimide. This homogeneous solution was cooled to O C, ~hen DCC (1.25 g, 12 mmol) in 5 ml THF was added.
The cooling bath was removed and the reaction was stirred for 2h. Then an additional 1.25 g of DCC was added.
` ~~ter 5h of-total reaction time, the mixture was filtered, ~` concentrated and dissolved in ether. The organics were ~ washed with NaHC03 (aq, 50 ml x2), brine, dried ~MgS04) J and concentrated at reduced pressure to give 5.2 g of ' product as an oil, wh-ich was dissolved in 20 ml ether. A
' lN solution of HCl/Ether (30 ml) was added. A gummy solid immediately precipitated out of solutioni CH2C12 (25 ml) was added and the clear reaction mixture was stirred overnight. After 12 h, the product, which precipitated from the mixture was collected by'filtration and washed :
.', W092/03429 PCT/US91/0~
~ 2~892~8 -116 with ether to give, after drying, 2.1 g of a whl e soiid in 87% for two steps, which was taken on in the f311OT~ing step.
To a 0C slurry of the above-montioned wh t~ solid from the first step of Example 80e (1.2 g, 3.0 ~mol) in 20 ml CH2Cl2 was added imidazole (204 mg, 3.0 ~mol). hQ
resulting reaction mixture was stirr~d f?r 1 ;~, -hen washed with 20 ml of KHS04, water, satur ted N_:CO3, and brine. The organic portion was dri~d over MgSG~, filt~ed and cooled to -78 C. To the cold solution was added L-Selectride~ (Aldrich, 1.0 M, 5.0 ml, 5.0 mmol) a~.d sti_-ed for 10 min. The reaction mixture was he~ w-~m~ -4C
C and quenched with 20% citric acid solution. The organics were washed with 20 ml of water, saturated NaHCO3 solution, brine, dried over MgSO4, and concentra~ed to afford a clear oil. The oil was purified on silica gel ~50% hexanes/ethyl acetate) to give an oil which was triturated with ether to afford a whi.te solid, 545 mg, 72%
yield.
mp 128-130 C; [a]D =-66.3 (c =1.0, CH30H); IR (KBr, cm~l) 3350(br), 2930, 1640, 1603; lH NMR (300 MHz, CDCl3) ~ 5.82 ~bs, lH), 3.95 (bs, lH), 3.42 (m, lH), 2.88 (bs, lH), 2.72 (m, lH), 2.55 (m, lH), 2.25 (s, 3H), 1.8 (s, 3H), 1.77-1.6 (m, SH), 1.52-1.34 (m, 3H), 1.28-1.12 (m, 3H), 1.0-0.83 (m, 2H); 13C NMR (75.5 Hz, CDC13) ppm 168.1, 148.0, 119.4, .
66.3, 53.1, 38.4, 35.3, 33.7, 33.6, 32.9, 26.4, 26.1, 26.0, 23.2, 23Ø
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WO 92/03429 2 ~ ~ ~ 2 ~ ~ PCT/US91/0~5~
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E~ e 80f L3~,5S,6S)-6-Cyclohe~yL-5-~ydro~y-3-iso~-oDyl-p~erid~n-2-one A solution of the product of Example 80e (24.7 g, 9~.4 mmol) in 500 ml of ethyl ac-tate ~as treated with 2.5 g of dry Pd/C and hyd-ogenated at ~ atm for 4h at ambient temperature. The reaetion mixture was filtered and concentrated to a white oam~ solld wnich was taken on without further purification.
mp 97-99 C; [a]D = -95.1 (c= 1.075, C:~.Cl3)~ 3-, cm~
1) 3605, 3400, 2925, 1642; iH NMR ~30v ~.z, CDCl3) ~ ~.3 (bs, lH), 4.11 ~m, J= 4.5, 1~), 3.~7 ~ .), 2 . 72 (DS, lH) r 2.5 (m, 1~), 2.3 (m, lH), 1.9 (m, lH), 1.~-1.5 (m, 8H), 1.43-1.12 (m, 6H), 0.97 (d, 3H), 0.87 (m, 3H); 13C
NMR (75.5 Hz, CDC13) ppm 174.2, 67.1, 52.6, 44.3, 37.7, 34.5, 33.8, 32.4, 27.6, 26.4, 26.3, 26.2, 26.0, 20.2, 17.4.
(2S 4S.5$l 5-Amino-~-cyclohexy~ Qpropyl-4-hexanoLide - The product of Example 80f was d-ssolved ir. 200 ml of 6N HCl and 50 ml of ethanol then heated to reflux for 14 h. The reaction mixture was concentrzted at reduced pressure and aæeotropically dried with toluene to af.ord a pale oil. This material was taken up in water and extracted with hexane, then made basic by addition of a solution of NaHCO3. Extraction with e_hyl acetate followed by drying (MgSO4) and removal of volatiles afforded a yellowish oil which solidi^ied to a white solid upon standing. Recrystallization f-ol hexane gave 20.7 g (90%) of product as white needles.
'' '~
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mp 49-SG C (lit. mp 48-49C); ~KBr, cm~l) 2925, 1760; 1H
NMR (300 MHz, CDCl3) ~ 4.2 (q, J= 6.1 Hz, lH), 2.82 (q, J=
6.2 Hz, lH), 2.64 (ddd, J= 9.1, 6.0, 5.4 Hz, lH), 2.15 (m, lH), 2.08 (m, 2H), 1.8-1.61 (m, 6H), 1.46 (m, lH), 1.37-1.13 (m, 8H), 1.02 (d, J= 6.0 Hz, 3H), Ø96 (d, J= 6.0 Hz, 3H); 13C NMR ~75.5 Hz, CDCl3) ppm 178.9, 83.1, 52.6, 46.0, 41.3, 34.4, 33.7, 32.3, 29.2, 26.8, 26.5, 26.3, 26.0, 20.3, 18.5. [a~D =+6.5 (c= 1.0, EtOH).
F.~r~ R ' ~
~ac~uc l-t2-furyl!-1-pentanol Freshly distilled furfural (233.5 g, 2.43 mol) was dissolved in 200 mL freshly distilled THF and added dropwise to a solution of butylmagnesium bromide (2.0 M in THF, 1460 mL, 2.92 mol) at 0 C under dry nitrogen. After the addition was complete, the mixture was allowed to warm to room temperature overnight. The reaction was recooled to 0 C and carefully poured into 2 L oî cold sat. NH4Cl.
The layers were separated, and the aqueous phase was extracted with ether. The combined organic layers were washed with saturated NaCl, dried over MgSO4, evaporated, and vacuum distilled to give 325.6 g ~87%): bp 72-73 C
(0.6 mmHg~, lH NMR (300 MHz, CDC13) d 7.38 (lHr dd J = 1 Hz), 6.33 (lH, m-), 6.22 (lH, dd, J = 3 Hz), 4.67 (lH, t, J
= 6 Hz), 2.9 (3H, m), 1.35 (4H, m), 0.90 (3H, t, J = 7 Hz~; mass spectrum (r7~): 170 (M ~H4) .
'' .
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W092/0~29 2 ~ ~ ~ 2 ~ ~ P~T/US9l/055~
Exam~le ~B
t~ 2-~l~rv~ ne~t2n~l To a room t~mperature solution of the racemic 1-~2-.uryl)pentanol (20 g, 0.1298 mol) and diisopropyl D-tartrate (4.45 g, 0.019 mol) in methylene chloride (80 mL) were added acti-v-atQd powdered molecular sieves 4 A ~6 g).
The sLirred mixture was cooled to -35 C, treated with titanium te_-aiso?ropoxide (3.7 g, 0.1298 mol), and stixred ror 30 m at tne same temperature. The reaction mixture was tre2ted with a solution of t-butylhyà_ope-o,~ide in 2,2,4-trimet'.ylpen~ane (30 mL, 0.0308 mol) and was stirred at -35 C for 3 h and allowed to warm up to -10 C in 2 h. A freshly prepared solution of iron II sulfate-7H20 (7.2 g, 20 mmol) and dl-tartrate (23 g) in 120 mL water was added to the reaction mixture at -~0 to -30 C and the resulting mixture was stirred vigorously without cooling for 30 m until two clear phases appeared. The organic layer was separated and the aqueous phase was extracted with methylene chloride. The combined organic layer-was washed with brine and dried over sodium sulfate. Evaporation of ~he solvent gave the crude product, which was distilled to give 6 g of the desired product, bp 70-75 C (0.7 mmHg) and 12 g of the pyranol, bp 115 C (0.7 mmHg). Redistillation of the mixed fractions gave additional 0.4 g. A total of 6.4 g of the desired product was obtained (75% theoretical yield based on 60% conversion to the pyranol): ~] 25D = -18 (C 1 . 0, CHCl3), 99% ee by chiral column chromatography analysis (Lil. reported -9, 94~ ee).
.
.
WO g2/0~29 PCT/~S91/05524 '. . .
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2~ 120-F~a~le 82 AltQrnative Preparation of (S)-1-(2~ ~yl)=l-~en.~a~o To a solution of optically active (-) 3-exo- --(dimethylamino) isoborneol (DAIB, see ~oyori et. al. J
Am. Chem. Soc. 1986, 108, 6071-2 and Noyori et al. J.
Organomet. Chem. 1990, 382, 19-37, 371 mg, 1.88 ~mol) in 200 mL of dry toluene under an argon atmosphere is added a 4.2 M solution of di-butylzinc (25 mL, 15~ ~ol) zt room temperature. The reaction mixture is s~ red ~o- 15 m an~
then cooled to -78 C. To the cooled solution is added freshly distilled furfural (9.0 g, 94 mmol) in ono por.ion. The reaction mixture is s~i-red a 0 ~_ -o 6 :.
Saturated ammonium chloride solution (100 mL) is added.
The mixture is extracted three times with diethyl ether.
The combined organic layers are dried (MgSOq) and concentrated under reduced pressure. Bulb-to-bulb distillation of the residue ~100 C 20 mmHg) gives the alcohol which is identical to the santple prepared in example 8lB.
E~m~l~ 8 lter~at~ivQ Pr~ara~lon of ~ ~-1 (2~ Y11-1-p2nt~o 2-Valeryl furzn Furan ~12 g, 0.177 mol) and valeryl anhydride (37.2 g, 0.2 mol) were placed in the flask. The reaction mixture was cooled at 0 C in an ice-bath. To the rapidly stirring reaction mixture, 3 g of freshly distiIled boron trifluoride-etherate was added all at once. The ice-bath w2S removed and the temperature of the reaction mixture xose to 65 C. Stirring was continued for 2 h at 60 C, :
~''' ' ;: .
W092/03429 2 ~ ~ 9 2 ~ 8 P~T/US9~/055~
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, and about 200 mL water was adied and st --ed for additional ~ h. The phases were separated and the aqueous phase was extracted with chloroform. The chlo-o^orm portion was added with 200 mL of saturated sodium bicarbonate and stirred for 1/2 h. The org~ni^ laye- was separated, washed with water, dried and filtered. The filtrate was evaporated to a liqu i whlch was dis~ ed a~
65-70 C (2 m~Yg) to yield 20 g (7~) of the desi-ed product: 1H N~R ~ O.95 (t, 3H), ~.4 (m, 2H), 1.7 (m, ; 2H), 2.82 (t, 2H), 6.S2 ~dd, lH), 7.2 (d, l.i), 7.~ (d,lH).
~, .
`' _ C~rr.~ ~ ~ ~,, ( 2--~ u r ~ ;) a - ~ ?. 0 ~
~ 10.4 mmol (10.4 mL) of diborane (1 M solution in THF) .~ was added dropwise in a period of 10 m at room temperature to a solution of 2-valeryl furan ~2.62 g, 17.2 mmol) and 1.68 mmol (4.2 mL) of (3aR)-1,3,3-tr:Lphenyl pyrrolidino [1,2-c] ~1,3,2] oxazaborole (see E. ~J. Corey et al. J. Am.
Chem. Soc. 1987, lO9, 7925-~6, 0.4 M solution in THF) in 25 mL THF. The reaction mixture was stirred for 20 m and was cooled to 10 C. 6 mL methanol was cautiously added and followed by adding 62 mg ~Cl (5y welght) ln ether.
Stirred for 0.5 h, white solid was precipitated out. The cloudy mixture was poured into 100 mL e~her and 100 mL
~`water. The organic layer was separated, washed with saturated sodium bicarbonate, wate-, brine, dried and ;-filtered. The filtrate was evaporated to an yellowish oil which was chromatographed eluting -~ith 10~ ethyl acetate in hexane to obtain 70% of the product. []25D = -13, 60%
~ee by Mosher' ester analysis.
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WO 92/0~29 PCT/USgl/055~
~ 7~8 -122-~
(4.5) 4-~2-ruryl)-3-Q~cta~oic zcid N2H (16.3 g, 680.9 mmol) and freshly distilled THF
(170 mL) were stirred at room temperatu.re as (~ (2-fu-yl)-l-pentanol ([a]2sD -17.2, 30.0 g, 46.0 mmol) in THF
(170 mL) was added dropwise. After the addition was com?lete, the mixture was stirred for 15 m before cau~iousl~ hea~ing to reflux for l h. The mi~ture was cooled to 0 C bero e adding dropwise ~ solution of brc~oacetic acid (27.3 g, 196.5 mmol) n THF (40 mL). The mi~ure was reflu~ed 2 days before cooling and carefully pourina in~o 600 mL ice water. The aqueous was washed with ether and acidified with HCl to pH 4, and extracted with ether. The combined organic extracts were washed with brine, dried over MgSO4, and evaporated to give a quantitative yield of crude product which was used in the next step without further purification.
~m (4S) Methy- 4-(2-fury1)-3-c~ Ln23~
Crude acid from example 84 (25 CJ, 118 mmol) was dissolved in ether and treated with excess diazomethane (generated by adding 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) to a mixture of 40% KOH (aq) and ether at 0 C).
., .
~; Excess dlazomethane was quenched with acetic acid after 30 :i m. Vacuum distillation gave 18.8 g (70%): [~] 25D -100;
bp 100-109 C ~0.5 mmHg); 1H NMR ~300 ~Hz, CDCl3) ~ 7.40 (lH, dd, J = 1 Hz), 6.34 ~lH, dd, J = 1 Hz), 6.29 (lH, dd, J - l Hz), 4.43 (lH, t, J = 7 Hz), 4.00 (2H, q, J = 16 :'' : , - . . . .. . . .. .
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W092/03429 2 ~ 8 ~ PCT/US91/05~
Hz), 3.72 (3H, s), 1.92 (2H, m), 1.33 (4H, m), 0.89 (3H, t, J = 7 Hz); mass spectrum (FAB): 244 (M+NH4).
le ~6 S) ~-ButyL-4-(2-furyl)-3-oxaoct~Q~
A solu~ion of (S)-1-(2-furyl)-1-pentanol [[a]25D -15 (c 1, CHCl3), 30.0 g, 194.5 mmol] in 250 mL dry DMF was stirred at 0 C under dry nitrogen as KN(TMS)2 (0.5 M in ~oluene, 390 mL, 135 mmol) was added dropwise. After s.irr~ng 15 m, t-butyl bromoaceta~e was added. The .l m x~urQ was sti.red a~ 0 C for 2 h before slowly warming to rt and stirring overnight. The reaction mix~ure was cooled to 0 C, diluted with an equal volume of ether, and ~reated with 1 L saturated NH4Cl. The combined ether extracts were washed with saturated NH4Cl, 5% NaHCO3, and brine, dried over MgSO4, and evaporated to give 54 g crude product. Vacuum distillation gave 21.0 g (40%) pure product and a side fraction of 8.0 g (15~: [a~25D ~73 (c 1.19, CHCl3~; bp 110 C (0.5 mmHg~; lH NMR (300 MXz, CDC13) ~ 7.40 (lH, dd, J = 1 Hz), 6.34 (lH, dd, J = 3 Hz), 6.28 (lH, dd, J = 5 Hz), 4.44 (lH, t, J = 7 Hz), 4.37 (2H, 3, J = 21 Hz), l.9 (2H, m), 1.47 (9H, s), 1.4 (6H, m), 0.89 (3H, t, J = 7Hz); mass spectrum (FAB): 286 (M~NH4).
l4S! ae~zhydryl 4-(~-furyl)-3-oxaQc~a~oat~ ~
To a suspension of 4.08 g (165 mmol) of 97% sodium hydride in 50 mL of dry THF at rt was added 10.5 g (Ç8 mmol)of ~S) 1-(furyl)-1-pentanol. After addition, the reaction was heated at reflux temperature for 2 h, cooled to 0-5 C in an ice-water bath, and 9.5 g (102 mmol) of :
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W092/0~29 PCT/US91/0~
2~3~92~ ~ -12q-bromoacetic acid in 50 mL of THF was added. After addition was complete, the reaction mixture was heated at reflux temperature for 2 d, cooled to 0-5 C 2nd water slowly added. The re2cture mixture was e~tracto~ ~ith ether. The aqueous layer was acidified with lN HCl to pH
5-6 and the crude acid was e~tract~ wi.;~ e_he-, dried (MgSO4) and concentrated to a crude oil.
Benzophenone hydrazone (13.3 g, 63 mmol) zn~ i9.7 y (68 mmol) of HgO in 1;0 mL o' hexane wer- sti_r_d ~o_ 24 h. The resulting purple solution w2s -rilt~r~d 2nd concentrated to 1/3 the volume. Tne c-u~e a_id in et:n~e-was added to the purple hexane solution or diphenyldiazomethane and was s~irred ror 24 h. E~c~ss acetic acid (5 mL) was added and the reaction stirred an additional 30 m, poured into saturated NaHCO3. After ethyl acetate extraction the crude benzhydryl ester ~19 g) was purified by silica gel chromatogr~phy usiny ~3:97) ethyl acetate:hexane as eluant to give 18 g (72% yield) of benzhydryl ester as a yellow oil.
[a~25D = -74.86.9o ~c 2.3, CHCl3); IR (film) 1740, cm~l; lH NMR (300 MHz, CDCl3) ~ 7.2-7.40 (m, llH), 6.95 ts, lH), 6.29 ~dd, J = 1.5, 3Hz, lH), 6.21 (br d, lH), 4.46 tt, J = 7 Hz, lH), 4.14 (d, J = 16Hz, lH) 4.01 (d, J = 16 Hz, lH), 1.77-2.05 ~m, 2H), 1.13-1.44 ~m, 4H), 0.86 (t, J
= 7Hz, 3H); mass spectrum ~FAB) 379 (M+H).
Anal. Calcd for C24H2604: C, 76.19; H, 6.87. Found: C, 76.94~ ~, 6.77.
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WO 92io3429 2 ~ ~ 3 2 6 ~ PCr/1~5gl/05~
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Example 88 (2S,4S) MethyL ~-henzyl-4-(2-furyl)-3-o:~oct~n~-2te ~ns (2~_4Sl Methyl 2-nenzyl-4-(2-rur~l)-3-~ er~oat~
(4S) Methyl 4-(2-furyl)-3-oxaoctanoate (5.0 g, 22.1 mmol) in 40 mL freshly distilled ~r - was a~.ded d_o?w se to a solution of NaN(TMS)2 (1.0 M in THF, 22.1 mL, 22.1 mmol) at -80 + 5 C. After 5 m, freshlv f~ltered (~:nrougr basic alumina) benzyl bromide (3.0 mL, 25.2 rumol) ~ as added dropwise maintaining the reaczion tem?era~lre at -8 + 5 C. Afte- 30 m, the reaction t7as w2 me~i to 0 C ro h before quenching with water. The mixture was extracted with ether. The combined ether extracts were washed witr saturated NH4Cl, 5~ NaHCO3, brine, and dried o~e_ MgSO4.
Purification of the residue by flash silica gel chromatography gave 1.2 g of the less polar (2S, lS) diastereomer and 1.6 g of the more polar (2R, lS) diastereomer, ~18 and 25%, respectively, based upon a 7%
recovery of unreacted starting material [~C~]25D -84 (c 1.14, CHCl3)]. (2~ ) diastereomer: [a]25D -74 (c 1.11, CHC13); lH N~R (250 ~Hz, CDCl3) ~ 7.19 (6H, m), 6.21 (lHr dd, J = lHz), 5.91 llH, dd, J = 1 Hz), 4.37 ~lH, t, J
= 7 Hz), 4.06 (lH, dd, J = 7 Hz), 3.69 (3E~, s) 2.94 (2H, m), 1.83 (2H, m), 1.29 (4H, m), 0.88 (3H, t, J= 7 Hz);
mass spectrum (FAB): 334 (M+NH4). (2~, lS) diastereomer:
[OC]25D -53 (C 1.23, CHCl3); lH NMR (250 MHz, CDC13) ~ 7.37 (lH, m), 7.27 (5H, m), 6.-38, (lH, dd, J = 1 Hz), 6.19 (lH, dd, J = 1 Hz), 4.08 (2H, m), 3.49 (3H, s), 2.98 (2H, d, J
= 7 Hz), 1.91 (lH, m), 1.72 ~lH, m)-, 1.2 (4H, m), 0.79 (3H, t, J = 7 Hz); mass spectrum ~F.~ 334 (M+NH4).
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WO 92/0~9 PCT/US9l/055 2 ~ 3 ~ ~ ~ 8 -126-. E~ample ~ 2~S, 4~) t-311tyl 2-~zyl -G- (?-~Yl~-3-o~aoc~a~oate ~n~
-' (2~, 4S) t-Butvl 2-b~nzyl-~-(2-furyl)-~=Qxa~ctanQate 4S)t-Butyl 4-(2-furyl)-3-oxaoctanoate ([a~25D -73 (c 1.19, CHC13), 10.0 g, 37.3 mmol) in 100 mL freshly distilled THF was added dropwise to a solution of NaN(TMS)2 (1.0 ~ in THF, 37.3 mL, 37.3 mmol) at -85 + 5 C. After 5 m, _reshly distilled and filtered (through bas'c alumina) benzyl bromide (5.0 mL, 42.0 mmol) was added dropwise malntai~ing the reac_ion temperature at -85 + 5 C. After 30 m, the reaction ~as warmed to 0 C for 1 h be-or~ ~uench~g with water. The mi~tu_e was e~tracted with ether. The com~ined ether extracts were washed with saturated NH4C1, 5~ NaHCO3, brine, and dried over MgSO4 ~ Purification by flash silica gel chromatography (1:1) ; ethyl acetate:hexane gave 2.1 g (15%) of the less polar (2S,lS) diastereomer, 2.4 g tl8%) of the more polar (2R,lS) diastereomer, and 2.0 g of a mixture of starting material and the two diastereomers. ~2S, lS) diastereomer: ~a]D25 -65 (c 1.19, C:HC13); 1H NMR (300 MHæ, CDC13) ~ 0.88 (3H, t, J = 7 Hz), 1.3 (4H, m), 1.40 (9H, s), 1 83 (2H, m), 2.93 (2H, m), 3.91 (lH, dd, J = 6 Hz), 4.38 (lH, t, J = 7 Hz), 5.92 (lH, d, J = 4 Hz), 6.22 (lH, dd, J = lHz), 7.20 16H, m); mass spectrum (FAB): 376 ~M+NH4). (2~ ) diastereomer: ~a]25D -30 (c 1.26, CHC13); lH N~R -(300 ~Hz, CDC13) ~ 0.79 (3H, t, J = 7 Hz), 1.15 (4H, m), 1.29 (9H, s), 1.69 (lH, m), 1.85 (lH, m), 2.95 ~2H, m), 3.98 ~lH, dd, J = 7 Hz), 4.10 (lH, t, J = 7 ~` Hz), 6.20 (lH, dd, J = 1 Hz), 6.28, (lH, dd, J = 1 Hz), 7.26 (5H, m), 7.36 (lH, dd, J = 1 Hz); mass spectrum (FAB): 376 (M+NH4).
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W~92i~29 2 ~ 6 $ PCT/US91/~55 ' E.Y~m~le 90 (2S 4S) ~er7`~ydr~1 2-~e~zy~ 2-furyl)-3-oxaocta~Qa~e -~ (4S) Benzhydryl 4-(2-ruryl)-3-oxaoctanoate (2.0 g, 5.28 mmol) was dissolved in 20 mL freshly distilled THF
and cooled to -ao ~ S oc under dry argon. Sodium bis(trlmethylsllvl)- amide (1.0 M in THF, 5.6 mL, 5.6 mmol) was slowlv added keeping the temperature at -80 ~ 5 C. After }5 m, ;^reshly distilled and filtered (through basic alum-..a) ben~yl bromide (0.7 mL, 5.81 mmol) in HMPA
~ mL) was added dropwise maintaining the reaction temperature a. -75 + 5 C. After 15 m, the reaction was allowed to wa~m to 0 C for 1 h before quenching with water and extraction with ether. The combined ether extracts were washed with saturated NH4Cl, 5% NaHCO3, brine,dried over MgSO4, and purified by flash silica gel chromatography to give 771.3 mg (31%): [a]25D -65.5i lH
NMR (300 MHz, CDC13) ~ 0.81 (t, 3H, J = 7 Hz), 1.22 (m, 4H), 1.80 ~m, 2H), 2.91 (m, 2H), 4.12 (dd, 1~, J = 9 Hz), ; 4.30 (t, lH, J = 7 Hz), 5.86 (m, lH), 6.19 (m, lH), 6.69 (5, lH), 7.2 (m, 16H); mass spectrum (FAB): 486 (M+NH4).
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~2R!4.S) Benzhydxyl 2-Renzvl-4-~?-~u~yl~-3-QxaoctanQate Using the procedure in example 90 and (4S) ben7hydryl 4-(2-furyl)-3-oxaoctanoate ~5.0 g, 13.2 mmol), THF (50 mL), sodium bis(trimethylsilyl)amide (1.0 M in THF, 14 mL, 14 mmol), and benzyl bromide (1.7 mL, 14 mmol) in 10 mL
HMPA gave (2R,4S) benzhydryl 2-Benzyl-4-(2-furyl)-3-oxaoctanoate, 645.6 mg (10%) and 723 mg (12~) of the (2S
4S) diastereomer which was identical to the sample .
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prepared in example 90. (2R,4S) dlastereomer: [a] 25D ~
34.8 (c 1.12, CHCl3); lH NMR (300 .~Hz, CDCl3) ~ 0.78 (t, 3H, J = 7 Hz), 1.12 (m, 4H), 1.69 (m, lH), 1.83 (m, lH), 2.98 ~m, 2H), 4.11 (t, lH, J = 7 H~), 4.21 (dd, 1;~, J = 3 Hz), 6.07 (m, 2H), 6.72 (s, lH), 7.26 (m, 15~); mass spectrum (FA8): 486 (M+NH4).
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N-4-~etho~ymetho~y~i~erid7ne .~ude ~- (2~ 4s) ~ enz-~ -a-( 2-f~7ryl) -3-ox;70ct~ .c ~i (2S,4S) Benzhydryl 2-benzyl-4-(2-furyl)-3-oxaoctanoate (502 mg, 1.07 mmol) w2s dissolved 7n EtOAc (3 mL) and shaken under 4 atm. H2 witr. 10% Pd~C (50 mg) a~
room temperature. Filtration and evapora~ion gave 468.
mg of product which contains diphenylmethane: 1H NMR ~
0.88 (t, 3H, J = 7 Hz), 1.29 ~m, 4H), 1.83 (m, 2H), 2.99 (m, 2H), 4.42 (m, lH), 4.53 (dd, lH, ~J = 8 ~z), 5.96 (d, lH, J = 3 Hz), 6.22 (dd, lH, J = 3 Hz), 7.21 (m, SH); mass spectrum (FAB) 320 (M+NH4).
The product from above reaction, 4-methoxymethoxy-piperidine (0.16 g, 1.07 mmol), and 4-hydoxybenzotriazole (0.44 g, 2.89 mmol) were dissolved in DMF (10 m~) and cooled to -23 C under dry argon. EDC (0.31 g, 1.61 mmol) was added, and the reaction was allowed to warm to rt overnight. 5% NaHCO3 was addedt and the mixture was extracted with EtOAc. The combined EtOAc e~tracts were washed with water and brine, dried over MgSO4 and purified by flash silica gel chromatography ~1:1) ethyl acetate:hexane) to give 230 mg (50%): [a]2~D -24.1 (c 1.02, CHC13); 1H NM~ (300 MHz, CDCl3) ~ 0.86 (t, 3H, J = 7 Hz), 0.89 ~m, lH), l.11 (m, lH), 1.28 (m, 5H), 1.53 (m, , ~
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lH), 1.85 (m, 2H~, 2.95, (d, 2H, J = 7 Hz), 3.25 (rn, lH), 3.36 (s, 3H), 3.48 ~m, lH), 3.6a (m, 3H), 3.93 (m, lH), 4.31 (m, 2H), 4.66 (s, 2H), 6.07 (dd, lH, J = 10 Hz), 6.29 (m, lH), 7.21 (m, 6H); m~ss spectrum (FAB) 430 (M+r~).
Exam~le 92 N-a-M~tho~ymet~oxyp~ in~ A~nld~ of (2~ S~ 2-~
Carb~ Cta?.O''' ZC r~
The compound prepared from exampi~ 52-~ (326.7 mg, 0.761 mmol) was dissolved in 5 mL glaclal :iOAc wi_h 2.5 m EtOAc and cooled in an ice bath as ozone was bubbled into the solution. After 30 m, 1 mL of water ~as added, 2nd the mixture was allowed to stir at -t ove-~.~ght. The reaction was evaporated to dryness, partitioned between e~her and 5~ NaHCO3, and extracted wlth 5~ NaHCO3. The combined aqueous extracts were carefully acidified to pH 3 with 1 M HCl and extracted with EtOAc. The EtOAc extracts were combined, dried over MgSO4, and evaporated to give crude product which was dissolved in a minimum amount of EtOAc and triturated with CHCl3 to remove most of the polar impurities to give 125.5 mg (40%): [CC]25D -17.1 (c 1.13, CHC13); lH NMR (300 MHz, CDCl3) ~ 0.85 (m, lH), 0.89 (t, 3H, J = 7Hz), 1.32 (m, 6H), 1.61 (m, lH), 1.79 (m, 2H), 3.06 (m, 2H), 3.25 (m, lH), 3.38 (s, 3H), 3.47 (m, lH), 3.58 (m, lH), 3.74 (m, lH), 3.86 ~m, lH), 3.98 (m, lH), 4.57 (m, lH), 4.68 (s, 2H), 7.29 (m, 5H); mas spectrum (FAB) 408 (~+H).
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E~ 23 (3 5S) 3.5-Dihen~yl-~ r -hutQxycarbo~ -2H-lr4-Qxazi~
~ 2-one ; To a solution of 17 ml (lM, 17 mmol) of sodium bis(hexamethylsilyl) amide in THF cooled to -70 C
(limited liquid nitrogen-diethyl ether bath) was added 5g (17 mmol) of 4-(tert-butyloxycarbonyl)-5S-(benzyl)-2H-1,4-oxazin-2-one (PCT Patent Application No. W090/03971, published A~ril 19, 1990) in 20 ml THF. Af_er addition was com~lete 5.97 ml of dry HMPA was added. The reaction was s,'rred fo- 15 m between -70 and -30 C and S.1 ml of benzyi bromide was added. The reac.ion was stirred at -80 to -90 C for a 40 m period. A dilute solulion of sodium ~` bisulfate was added and the reaction warmed to rt, poured into chloroform and the aqueous layer separated. The aqueous layer was extracted once with chloroform. The combined chloroform extracts were washed once with water,dried (MgS04), and evaporated to give 10.9 g of an oil. The pure lactone was obtained by silica gel chromato~raphy using ethyl acetate:hexane as eluent: 3.9 g (60% yield) of a white solid. mp 149-150 C; [a] 25D =
J +105.07 (c 1.28, CXCl3); mass spectrum (FAB) 399 (M+NH4).
Anal. Calcd for C23H~7N04: C, 72.42; H, 7.13; N, 3.67.
:~, Found: C, 72.76; H, 7.25; N, 3.67.
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(3R,5R) 3.5-Dibenzyl-4-(ter~-butoxy~a~onyl)-2H-1.4-oxazin ~ To a solu~ion of 53 ml (lM, 53.1 mmol) of sodium .. bis(hexamethylsilyl) amide in T~F cooled to -70 C
1 (limited liquid nitrogen-diethyl ether bath) was added `~ 15.8 g (54.2 mmol) of 4-(tert-butyloxycarbonyl)-SR-::
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(benzyl)-2H-1,4-oxazin-2-one (prepared using the procedure disclosed in PCT Patent Application No. WO90/03971, publlshed A~ril 19, 1990, example 153 and replacing L-phenylalan-nol with 3-pnenylalaninol) in 63 ml THF. After addition was complete 18.6 ml of dry HMPA was added. The reaction was s_lr-ed for 5 min between -70 and -80 C and 16 ml of benzyl bromide was added. The reaction was stirred at -80 to -90 C for a 40 m period. A dilute solu.ion Gf sodium bisul~ate was added and the reaction warmed to r temperature, poured into chloroform and the aqueous la~e- separated. The aqueous layer was extracted once with cnloroform. The combined chloroform extracts were washed oncç with water, (dried with MgSO4), and evaporated to give 23 g of a crude oil. The pure lactone was obtained by silica gel chromatography using ethyl acetate:hexane as eluent: 12 g ~58%) as white solid: mp 149-150 C; ~a]25D = -107.9 (c 1.28, CHC13); IR (CHCl3) 1743, 1690 cm~l; lH NMR (DMSO-d6, 55 C) S 7.31 (m, 4H), 7.24 (m, 2H), 7.15 (m, 4H), 4.54 (dd, lH, J = 2, 3.5 Hz), 3.88 (d, lH, J = 6Hz), 2.89 (dd, lHf 2, 7.5 Hz), 2.68 (dd, 1~., J = 6, 9 Hz), 1.a6 (s, 9H); mass spectrum (FAB) 382 (M~H).
`-i Anal. Calcd ror C23H27NO4: C, 72.42; H, 7.13; N, 3.67.
~` Found: C, 72,21; H, 7.1~; N, 3.65.
, ?1Q 45 (2~. 4S) ~- ~(tert-Butnxyca~bQnyli a7al -?, 4-di~ y1-1~5-_ ., ~=il~s~
~ A solution of 0.8 g (2.1 mmol) of the product of ~, Example 93 in 5 mL of THF and 4.1 mL (lM, 4.1 mmol) of diborane were stirred in an ice wate- ba~h for 18 h.
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~,o~9~68 Methanol was added followed by aq. sodium bisulfate. The product was extracted ~ith ethyl acetate, dried (MgSO4), and evaporated. The crude residue was purified bv ~lash chromatography using (1:2) ethyl acetate:hexane to afforded 72? mg (89%) of product. [a]25D = -85.03 (c 0.63 CHCl3); IR (CDCl3) 3120-3720 (OH), 1700 (carbamate C=O) cm~l; lH NMR (DMSO-d6) 7.33-7.09 (m, 10~, Co~5), 1.~4 (s, 9H, t-butyl); mass spectrum (FA~) 385 (M',~), Anal. Calcd for C23H31NO4: C, 71.68; H, 8.05; N, 3.63. Found: C, 71.25; H, 8.07; N, 3.61.
(2~.4~) 3-~t~rt-3uto~yca~honyl) 2Z2 1-2 4-~b~yl-1 5-~a~
Using the procedure in example 95 and replacing the the product of Example 93 with the product of Example 94 gave the title compound.
, xam~le 97 2R,4R)-3-Aza-2,4-dibenzyl-1,5-penta~ediQl ~oron Complex .3, A solution of 0.846 g of ~2R, 4R) N-Boc amino diol ~ from example 96 was stirred with 10 mL Or 4M HCl dioxane -~ at room temperature for 1 h. The solvents were evaporated to give a white solid. Aqueous sodium bicarbonate was ~ ~ .
added and the amine was extracted with chloroform. The chloroform extracts were dried (MgSO4), filtered, and concentrated to give a clear oil. Triethylborate (0.37 mL, 1 equivO) was added to the oil and the homogenous solution solidified. The solid was heated at 100 C for 2 h under high vacuum to remove excess ethanol to give the boron complex 13. mp 95-100 C~ llB N~ (CH2C12, BF3 E.20 '' . . .
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internal standard) 10.5; mass spectrum ~F~s) 311 (M+NH4), 286 (M~H, amino diol).
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(5R) 4-(tert-Butoxyc~rbonyl)-2-pher.~ 2H~' 9~ .-2-one The title compound was prepared using the ^-ocedure disclosed in PCT Patent Application No. Wo90/0397i, published Aprll 19, 1990, e~ample 153 and re?l~ ~g L-phenylalaninol with D-phenylglycinol to g~e ~r~ ces red product (see J. Dellaria et al. Tetra.~edron ~ s 1988, 29, 6079-82).
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(2R) 3-Aza-2.5~-triphenyl-1 5-~e~ n~ ol Re-^^ C~m~lex A solution of 2.7 g of the product o~Example 98 was stirred with 10 mL of 4M HCl in dioxane. Solvents were removed under reduced pressure to give ~he amine salt.
The crude salt was suspended in THF, cooled in an ice-water bath and 5 equiv. (45 mL) of lM phenylmagnesium bromide was added and the reaction m:Lxture stirred for 24 h at room temperature. The crude product was purified by flash chromatography using (1:1) etnyl acetate:nexane then ~2-5:98-95) methanol:ethyl acetate to give t~e amino diol.
Recrystallization of the amino diol f_om toluene:hexane gave a white crystalline solid, 500 mg. mp 117-19 C;
[a]25D = -28-5o (c 0.91, CHC13); IR ~C~C13) 3720-3200 (OH) cm~1; lH NMR (CDCi3) ~ 7.47-7.19 (m, 15~), 3.82 ~dd, J =
4,7 Hz, lH), 3.70 (dd, J - 4, 12 Hz, lH), 3.55 (dd, J = 7, 12 Hz, lH), 3.27 (d, J = 12Hz, lH), 3.18 (dd, J = 12 Hz, lH), 1.70-1.48 (br s, lH); mass spe~t-um (FAB) 334 (M+H).
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Anal. Calcd for C22~23NO3: C, 79.27; H, 6.90; N, 4.20.
Found: C, 79.27; H, 6.84; N, 4.14.
Using the procedure in example 97, and 109 mg of (2R) 3-aza-2,5,5-triphenyl-1,5-pentanediol that was prepared above and 0.055 mL (1 equiv.) of triethylborate in 2 mL of THr gave the boron complex. mp 125-32 C; mass spectrum (FA~) 334 (M+H for amino dlol), 342 (~+H), 359 (M+NH4).
ExamRl~ 100 "-?.~ Vi' 3--'t~7~r_t~1~0n ~r (S)-l-('~ en~r,anol Using the procedure in example 83~, and replacing (3a3~)-1,3,3-trlphenvl pvrrolidino [1,2-c] [1,3,2]
o~.a~aborole with the boron catalyst from example 98 gives the product.
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~lternative PreDaLa~iQn of (S)-1-(2-Fury~ ent.anol Using the procedure in example 83B, and replacing (3aR)-1,3,3-triphenyl pyrrolidino ~1,2-c] [1,3,2]
oxazaborole with the boron catalyst from example 99 gives the product.
The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids.
These salts include but are not limited to the following:
acetate, ad1pate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptonate, glycerophosphate, hemisulfate, heptcnate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, ~`'` ' "
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2~92~ , 2-hydroxi~-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxaLate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Also, the basic nit-ogen-containing groups can be quaterni~ed with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, dietnyl, dibu~yl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and steary chlo-ides, ~romides and icdides, aral:~l halides like benzyl and phenethyl bromides, and o~hers. Water or oil-soluble or dispersible products are thereby obtained.
Examples or acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases.
The compounds of the present invention can also be used in the form of prodru~s which include esters.
.
Examples of such esters include a hyd-oxyl-substituted compound of formula (I~ which has been acylated with a blocked or unblocked amino acid residue, a phosphate function, or a hemisuccinate residue. The amino acid esters of particular interest are glvcine and lysine;
however, other amino acid residues c2n also be used. These esters serve as prodrugs of the compounds of the present " , . .
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W092/0~29 P~T/~.~91/OS5~
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2 ~ 39i~v~ention and serve to inc-e~se the solubility o-^ these substances in the gastrointestinal trac~. The ~rodrugs are metabolically converted ln v~vo to h2 pa_ent compound o~
formula (I). The preparation of th~ ~_o-c-ug es-ers is carried out by reacting a hydro~v'-slbsli-uted c^~v^und c_ formula (I) with an activated amino acvl, phosphoryl or hemisuccinyl derivative. The resul_in? ~-odue_ s ~hen deprotected to provide the desi.~d _r__-u~ es~e_.
The novel compounds of the prese~ r.ver.tio?. possesses an excellent degree o~ activity ar.d s~e^i~~ ^ity in ~reatlna hypertension in a human or other ma?~al. The novel - compounds of the presen~ lnven.tlor _re ~ use-_1 or treating congestive heart failure in _ human or o~her ` mammal. The present invention also relates to the use of the novel compounds of the invention for treating vascular abnormalities in a human or other mammal, especially those vascular diseases associated with diabetes, such as diabetic nephropathy, diabetic neuropathy and diabetic , retinopathy. The compounds of the invention are also useful for the treatment of renal diseases in a human or other mammal, in particular acute and chronic renal failure. The compounds of the inver.tion are also useful for the treatment of psoriasis in a human or other mammal.
The ability of the compounds of th~ invention to inhibit human renal renin can be demonstrated Ln vit~ by reacting a selected compound at varied concentra~ions with human renal renin, free from acid proteolytic activi~y, and with renin substrate ~human angiotensinoger.) at 37 degrees ; C and pH of 6Ø ~t the end of the incubation, the amount ~` of angiotensin I formed is measured bv radioi~munoassay and the molar concentration required to cause 50% inhibition, ...~, ..' .
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2~o92~8 : expressed as the IC50 is calculated. When tes~ed ln accordance with the foregolng procedure, the compounds of the invention demonstrated ICso's _n tne -ange of iC-~ M as seen in Table 1.
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:: 2c 2.1 3 1.3 Sb 2.9 6c 1.8 7b 0.78 `, 10 3.0 11 2.4 12b 2.6 16 1.8 . 17 1.5 :~ l9c 1.6 ;`~ 20 1.3 21 1.3 22c 3.4 ' 23 1.1 ^ 24 l.0 .` 25 ~ 1.0 : 27 0.8 29b 1.2 , 30 2.3 31 2.C
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, 77d 5.2 Total daily dose of a compound o- the invention -: administered to a human or other mammai in single or divided doses may be in amounts, fo- e:;ampIe, from 0.001 to 10 mg/kg boày weight daily and more usually 0.01 to 10 mg.
.~ Dosage unit compositions may contal~. such amounts of submulti?les thereof to make up the da'ly dose.
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wn 92/03429 2 ~o~ 2 6 ~ PCT/US91/055 The amoun-t o~ ac~ive ingredient that may be combined with the carrier materials to produce a single dosage form wi'l varv depe~dins u?on the host treated and the particular mode or a~ministration.
It ~ill be ur.derstood, howeve-, that the specific dose level for anv par~icula- patient will depend upon a variety o- fac~ors including Lhe ac~-vity of the specific compound em?loye~, the age, body ~elgh., general health, sex, diet, ~- tlme o- a~inist-a-ion, route of adminis~ration, rate of exc-etion, drug combina-tion, and the severity of the pa-~icular disease undergoinc therapy.
~ he compc~n~s o- :~e ?-e3ent nven. on may be a~-"inis_ered oraliy, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations containing conven~ional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired.
Topical administration may also involve the use of ~; transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, ~` intramuscular, intrasternal injection, or infusion techni~ues.
~ Injectable preparations, for example, sterile -~ injectable aqueous or oleagenous suspensions may be formulated according to the ~nown art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solu.ion or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solven~s that may be employed are water, Ringer's ', :, ': '. , , :' : . ~ .~
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~ 2 &~ -140-solution, and isotonic sodium chlor de sol-~tion. In addition, sterile, fixed oils are conventinally employed as a solvent or suspending medium. Fo- this ?U-?ose anv blar.à
fi~ed oil may be employed including syntnQ~ic mono- or diglycerides. In addition, fat~v ac-ds suc`n as O'IQlC ao d find use in the preparation of injectables.
Suppositories for rectal a~n-. s~-a_ on o- -h- d_ug can be prepared by mixing the à-ug ~- r h _ SU' _a `1-nonirritating excipient such as co_oa bu~e- and polyethylene glycols which are so~ - a_ __d n2-i temperatures but liquid at the rec-a1 tem?era~ure and will therefore melt in the rectum and re e~se -:~ i-ug~
Solid dosage forms for oral a~minis--2tiGn may- in^ UdQ
capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or-starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with ente- c coa_ings.
Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
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WO 92io3429 ~ ~ ) ~ ~ ~' 8 PCT/US91/05;~
compounds and the use of the compounds and com?ositions to inhlbit renin for treating glaucoma or reàucing and/or controlling intraocular pressure. The present lnvenLior also relates to the use of novel compounds and pharmaceutical compositions which nhibit reni-. in combination with a beta-adrenergic antagonis. agent or an angiotensin converting enzyme inhibiting com?cun- ~o-treating glaucoma or reducing anà/or con -_l -s.g intraocular pressure.
The present invention also re ates ~o pha-maceu_ic__ . -~
compositions for treating the inc-ease in intraocular pressure associated with the a~mi- s,-atlc- o- s~e-olda' antiinflammatory agents comprisiny novel -enin nh'_i~ .ng compounds in combination with a steroidal antiinflammatorv compound in a pharmaceutically acceptable vehicle.
The present invention also relates to a kit comprising in individual containers in a single package a novel renin inhibiting compound in a suitable pharmaceutical vehicle and a steroidal antiinflammatory compound in a suitable pharmaceutical vehicla and/or a beta-adrenergic antagonist agent in a suitable pharmaceutical vehicle or an angiotensin converting enzyme inhi~iting com~ound in a suitable pharmaceutical vehicle. ' The compositions of the invention are administered as topical or systemic pharmaceutical compositions when used for treating or reducing andtor controlling intraocular pressure.
These compositions are preferably a~ministered as topical pharmaceutical compositions suitable for ophthalmic administration, in a pharmaceutically acceptable vehicle such as pharmaceutically acceptable s.erile aqueous or `
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nonz~l-Q^us solutions, suspensions, emulsions, cintments and solld inserts.
E~.am?les of suitable ?hzrmaceutically acceptable veh cies for o~n~nalmic administration are wate-, propylene glycol and other pharmaceutically acce?.able alcohols, sesame or peanut oil and other pharmaceutically acceptable vegQt~le oils, pe_-olQum jelly, wa~er soluble op:._hz`..~^ o~ ca lv a^cep~able non-~oxic polymers such as methyl cell~lose, car30xvme~hyl ce'lulose salts, hy~-o.;;e_.y ce~lulose, hya-oxyp_o~vl cellulosei acrylates SUC- 2S polvacrylic acid salts; ethylacrylates;
polvac-ylam des ~.z~ural ?roducts slch as gela_~ ?., Z'C~.n2-eS/ pec~ins, ~-agacanth, karaya, agar, aczcia;
sta-ch derivatives such as starch acetate, hydroxyethyl sta-ch ethers, hydroxypropyl starch, as well as other synthetic derivatives such as polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether, polyethylene oxide, carbopol and xantham gum; and mixtures of these polymers.
Such compositions may also contain adju~ants such as buffering, preserving, wetting, emulsifying, and dis?ersing aqents. Suitable preserving agents include antibacterial agents~such as quaternary ammonium com?ounds, phenylmercuric salts, benzyl alcohol, phenyl ethanol; and antioxidants such as sodium metabisulfite, butylated hydroxyanisole and butylated hydroxytoluene. Suitable buffering agents include borate, acetate, gluconate and phosphate buffers.
The pharmaceutical ophthalmic compositions of the invention may also be in the form o- a solid insert. A
solid water soluble or water swell=31e polymer such as dextran, hydro~yloweralkyl dextran, czrboxymethyl dextran, :--W092/~29 ~ ~ 9 2 ~ g PCT/VS91/055 hvdroxyloweralkyl cellulose, loweralkyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, dextrin, starch, polyvinyl pyrrolidone and polyalkylene glycols may be used as ,he carrier for the drug.
Dosage levels of the active compound in the compositions for treating glaucoma or reducing and/or controlllng in.raocular pressure may be varled so as to ob~ain a d-a'~ed th-_a~eutic response to a particular composi~ion. ~-enerally, the active compound will be aamlnis~e-e~ as an isotonic aqueous solu~ion o_ from 0.vOOOl to 1.0 ~w/v) percent concentration. More ~re~erably the 2c.ive com~ound will be admi?.is.ered as an ~so~-onlc aqueous solu~ion of from 0.00001 to 0.1 (w/v) percent concentration.
The term "controlling intraocular pressure" as used herein means the regulation, attenuation and modulation of increased intraocular tension. The term also means that the decrease, in the otherwise elevated intraocular pressure, obtained by the methods nd compositions of the invention is maintained for a signi:Eicant period of time as, for example, between consecutive doses of the composition of the invention.
The novel renin inhibiting compounds of the invention may be the only active ingredient for controlling intraocular pressure in the methods and compositions of the invention or may be used in combination with other :.
ingredients which control intraocular pressure such as beta-adrenergic antagonist compounds.
The term "beta-adrenergic antagonist" as used herein means a compound which by binding to beta-adrenergic plasma membrane receptors reduces or elim na-es sympathetic , .
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W~92/0~29 P~T/US91/055 activity or blocks the effects or exogenouslv aA~minsterQdcatecholamines or adrenergic drugs. E~am~les of beta-adrenergic antagonists are atenolol! meto?-o?ol nadolol, propranolol, timolol, labetalol, be_a~oio , ca-_eolol and dilevalol and pharmaceutically acre?table s21_s _herQo~.
Most preferably the beta-adrenergic antagonis~ is Limolol.
Timolol is currently used fo- ~reati-!g g'~uc3m- o-reducing and/or controlling intraoc~,a- p.~ Sa ' `~_~ `OU., i _ has a number of adverse side effecta. Accorcin~
administration o- a composition crm--i Si-l~ â SC.~ ~-nz~ion __ a be_a-adrenergic antagonist and a novel renin innibitins compound OL the invention could p_educQ a _Q~US: ' 0?. i~.
intraocular pressure equivalent tc -:~at ?-od ^e~ bv 2 be~a-~ adrenergic antagonist alone, but aL a reduced dose level or ., the beta-adrenergic antagonist. ~nis will resul_ .in a reduced level of the beta-adrenergic antagonist related adverse side effects.
: The combination composition is administered as a single dosage form containing both the novel renin inhibitor and the beta-adrenergic an~agonist. The beta ~- adrenergic antagonist may comprise from 5 mg to about 125 mg of the composition of the inventor.. The pre~erred ranges of the components in ~he composition of the invention in unit dosage form are:
Renin inhibitor: 1 ng to 0.1 mg Beta-adrenergic antagonis~: 5 us to 125 ug When the be~a-adrenergic antagonist and the novel renin inhibitor are administered as separate compositions the present invention relates to a kit comprising in two separate containers a pharmaceutically acceptable beta-adrenergic antagonist compositior. and a pha."iacQL_ically `' :
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, acceptable novel renin inhibitor composition, in a sin~ie package. A preferred kit comprises a beta-adrenergic antagonist composition and a topical ncJel renin nhiD ~o~
composition. A most preferred ki. co..p_ises a ~o?ical ophthalmological beta-adrenergic antagonis_ compositio-. an.
a topical ophthalmological novel renin inhibi_or composition.
The novel renin inhibitlng compou-.-s o ~ e-. -~may also be administered in comrina~ o^ wi_:~ an an~io.~~.s-~
converting enzyme (ACE) inhibitln~ com_o~n~. ~A~ S __ angiotensin converting enzyme inhlbi_ing compounds are captopril and enalapril. As was --evi3usl~; menrione~
inhibitors have some undesirable s de e~fe~ts.
Accordingly, administration of an ACE inhibitor in combination with a renin inhibitor could produce a reduction in intraocular pressure greater than or equivalent to that of an ACE inhibitor alone, but at a reduced dose level of the ACE inhibitor. This will result in a reduced level of the ACE inhibitor related adverse side effects.
The combination composition is administered as a single dose form containing both the novel renin inhib o-and the angiotensin converting enzyme inhibitor. The ACE
` inhibitor may comprise from 5 ng to about 50 ug of the compositon of the invention. The prer^erred ranges or t;~e components in the composition of the invention in unit dosage form are: ~
Renin inhibitor: 1 ng to 0.1 mc ACE inhibitor: 5 ng to 50 ug When the ACE inhibitor and the novel renin inhibi.or are administered as separate composltlons the presen.
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~nver.lion re'ates to a kit comprising in two se~arate containers a pharmaceutically acceptable ACE inhibitor com?osition and a ~harmaceutically acceptable novel renin inhibitor composiLion, in a single package. A preferred k ~ comprises an .~.C~ inhibitor co~?osition and a topical novel renin inhibitor composition. A most preferred kit c^m?rises a ,opical o?hthalmolog cal AC~ inhibitor com?os ~ion and a .o~ical novel _e~in inhibitor composition.
~ osaye levels or Lhe active compounds in the com?osltions or the invention ma~ oe varied so as to obtain 2 des -ed the zpeutic res?onse de-ending on the route o a~m n s~ra~io~, seve ity of the disease and the response of ~he patient.
Topical, ophthalmic and systemic administration of steroidal antiinflammatory agents can cause an increase in intraocular pressure. The increase in intraocular pressure can be reduced by the administration of a novel renin inhibiting compound of the invention. Steroidal antiinflammatory agents include hydrocortisone, cortisone, prednisone, prednisolone, dexamethasone, me_hy'?-ednisolone, triamcinolone, betamethasone, alclometasone, flunisolide, beclomethasone, clorocortolone, difloxasone, halcinonide, fluocinonide, fluocinolone, desox}metasone, medrysone, parame~hasone, and fluorometholone, and their pharmaceutically acceptable salts and esters. Preferred stero dal antiinflammatory agents are hydrocortisone, prednisolone, dexamethasone, medrysone and fluorometholone and ~heir pharmaceutically acceprable salts and esters. The novel renin inhibitor is administered after use of a steroi~al antiinflammatory ., .
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W092/0~29 % ~ PCTJUS91/0~5 agen o_ zt the same time, causing reduction and/or control or intraocular pressure.
Various combinations of a to~ical or oral or ~njectibie aosage form of a steroiàal antiinflammatory agent and a topical or oral dosage form of the novel renin innibiLor mav be used. A preferred combination comprises a -Gpical s eroidal antiinflammatory and a topica' novel renin in:nlib__or. More preferred is a topical c~h,halmic dosage form comprisin both a steroidal antiinflammatory and a novel -e~.in inhiblLor.
Wnen ~he steroidal antiinflammatory agent ar.d the nove'l renin. in:~ibito- a-e administered as sepa a e _om~o_ -ions the p-esent invention relates to a ~it com?rising in two separate containers a pharmaceu~ically acceptable steroidal antiinflammatory agent composition and a pharmaceutically acceptable novel renin inhibitor composition, in a single package. A preferred kit comprises a steroidal antiinflammatory composition and a topical novel renin inhibitor composition. A most preferred kit comprises a topical ophthamological steroidal antiinflammatory composition and a topical ophthamological no~-el renin inhibitor composition.
The combination composition of the invention may contain from about 0.00001 to 1.0 (w/v) percent of the novel renin inhibitor for combined or separate to~ical a~ministration. More preferably the amount of the novel -enin inhibitor is about 0.00001 to 0.1 (w/v) pe;cent of the composition. The amount of the novel renin inhibitor in a unit dosage form for topical administratior. to the eye is from about 5 ng to about 0.5 mg, preferably f-om about 5 ng to abouL 25 ng. The dose requi-ed will depend on the . .
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G~ 198-potency of the particular novel ren-î inhibitor, the severity of the intraocular press~re lncrease ar.~ tne response of the individual patien The combination composi~iorl o_ -`-_ inve-n i^-. may contain from about 0.05 to 1.5 ~w/~,) ?ercen_ o- ~:ne steroidal antiinflamr.atory Lor cor3 --~ o- se~ar^-_e topica administration. ~he amount of t:~- s_e-oid2 antiinflammatory in a un_ dosage -s=~
administration to the eye is rrom z^^~ _v ~g ._ a^o~~ 6~v ug The dose required wi' àepen~ -- ~:^e _c ^-._ ^ _r_ par_icular steroidal antiinflamm2-~ he seve-~ y o_ ,;~-disease and the response or the --d_v -~al ~C'-iQ-.-.
When the ste-oidal antiinfla.~-a-~ y a5er.~ c- :~e combination therapeutic method or ~he invertion is i~ administered other than ophthalmically, appropri2.e doses are well known in the art.
The compositions of the invention may include other therapeutic agents in addition to the novel renin inhibitor, and other agents which re~uce and/or control intraocular pressure~
The effect on intraocular pressure of the novel compounds of the invention can be de~e-~ined in ~abbi~s by using the following method.
E~f~cts of To~ic~ minis~~-ed ~e~ ~ rnhl~ _ na (`oln~ound ~ raocula~ ?ressll~o ~r ?~abb~r~:
~ a. ~hQ~ -The antiglaucoma 2e~ ivity of the compounds - was tested by measuring the efrec~ on ln~raocular pressure in rabbits as described by Tinjum, A.M., Acta Ophthalmologica, ~n, 677 (1972). Male albino, New 2ealand rabbits were placed in restrainins -e; -es ar.d the . . ..
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intraocular pressure was measured w th an =pplamatic tonometer. Exactly 0.1 ml of an isotonlc s~line solution containing a test compound was ins.llled into the conjuctival sac and the intraocular pressure was measure~
at 5, lS, 30, 60, 90, 120 and 180 minutes afte-wards.
The ability of a compound of ~:~e invention to trea.
vascular diseases, especially those assoc ated ~.~ith diabetes, can be demonstrated by compa~ing -- na-~! prcrei~.
excretion in control diabetic Wista rats with urinarv protein excretion in diabetic Wis.a- ~a.s trea~e~L ~1Lh a compound of the invention. Wistar rats are made diabe~lc by streptozocin treatment.
The present invention is also iir-c~_d to ~h~ us~ o 2 compound of the formula I in combination with one or more ~:
cardiovascular agents independently selected from diuretics, adrenergic blocking agents, vasodilators, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, potassium channel activators, antiserotoninergic agents, thromboxane synthetase inhibitors, angiotensin II ~AII) antagonists and other agents useful for treating (in a human or other mammal) hypertension, congestive heart fail~-e, vascular diseases related to diabetes or for treating renal diseases sucA as ~ acute or chronic renal failure.
-~ Representati~e diure~ics include hydrochlorothiazide, `~- chlorothiazide, acetazolamide, amiloride, bumetanide, benzthiazide, ethacrynic acid, furosemide, indacrinone, ~;~ metolazone, spironolactone, triamterene, chlorthalidone and the like or a pharmaceutically acceptable salt thereof.
Representative adrenergic blocking agents include ~. phentolamine, phenoxybenzamine, pxazosin, terazosin, .:-..' , ~, :
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WO 92/03429 PCT/US91/0~24 20~2~
tolazine, atenolol, metoprolol, nadolol, propranolol, timolol, carteolol and the like or a pharmaceutlcally acceptable salt thereof.
Representative vasodilators include hydralazine, minoxidil, diazoxide, nitroprusside, flosequinan and the like or a pharmaceutically acceptable salt thereof.
Repres2ntative calcium channel blockers include amrinone, bencyclane, diltiazem, fendiline, flunarizine, nicarà~pine, nimodipine, perhe~ilene, verapamil, gallo~amil, ni_edipine and the like or a p;~armaceutically acce?table salt thereof.
~ epresentative ACE inhibitors include captoDril, er.alapril, lisinopril and the like or a pharmaceutically acceptable salt thereof.
Representative potassium channel activators include pinacidil and the like or a pharmaceutically acceptable salt thereof.
Representative antiserotoninergi.c agents include ketanserin and the like or a pharmaceutically acceptable salt thereof.
Representative angiotensin II antagonists include DUP527 and the like or a pharmaceutically acceptable salt thereof.
Other representative cardiovascular agents include sympatholytic agents such as methyldopa, clonidine, ~ :.
guanab~nz, reserpine and the like or a pharmaceutically ;~ acceptable salt thereof.
The compound of formula I and the antihypertensive ~ agent can be administered at the recommended maximum - clinical dosage or at lower doses. Dosage levels of the ` active compounds in the compositior.s of the invention may ~. , .:
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be varied so as to obtain a desired therapeutic response depending on the route of administration, severity of the disease and the response of the patient. The combination ; c2n be a~m~niste ed as separate compositions or as a single dosage form containing both agents.
In addition, the present in~-eatlo~ is directed to the use of a comDound of formula I to inhibit Candida àcid pro.ease in mammals, especially humans. The compounds of ~he p-esen. inven~ion a-e also use ul fo- preven_ing or ~-^ati..g i..~-ctions caused Dy Candida species in mammals, es?ecially humans The present invention also _elates to tne use o~ tne com~ounàs or the invention in co~bination wi_h one or more other antifungal agen~s. Other antifungal agents are selected rrom the group consisting of amphotericin B, nystatin, flucytosine, ketoconazole, miconazole, clotrimazole, fluconazole and itraconazole.
The ability of the compounds of the lnvention to inhibit Candida acid protease can be demonstrated Ln Yl~Q
by the following method.
a alki~ns A~id ~ O~gani m and growth co~ditions. Candida al~ica~s ,".,J, ATCC10231 was grown overnight in Sabouraud broth (Difco) ~, at 30C. Cells were centrifuged a~ 10,000xg for 10 min ` (4C) and the cell pellet washed once with 10mM phosphate buffered saline (PBS), pH7Ø Wasned cells (6x105 colony forming units per mL) were grown in yeast nitrogen base without ammonium sulfate or amino acids (Difco), plus 2 ~` glucose and 0.1% casein (nitrogen sou-se) at 37C.
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' !, ' 2~ 29 Prr/lJssl/0~s24 Protoina~e i~olation. Maximum ~rOr~LnaSQ 2-~ductLon was attained when the culture reac;~ed a pH of 3.~ to 4.0 (about 48 hrs). Cells were then ha-vestec at ~,000x~ fo-20 min (4C) and the supernatanL rilter~à tnrough a 0.2 acetate filter unit (Nalgen). The filtrate was concentrated on an Amicon concen~ra-or (PM30 o- Y~10 membrane, 75mm) and 30mL of the ccncen ---- wa- loaded : ,, onto a Cibacron blue F3GA-Q~ agarcae (?ie--~ C~ .j co'~ilmr (1.5x44cm) equilibrated with 10m~l sodium ci~ra~_, pH 6.5 containing lm~l EDTA and 0.G2~ sod~ ~ a~ d~ (æ , T._., a-.
?ayne, C.D. Infection and l~munity ~8:50~-~14, 330).
Bovine serum albumin (BSA) was use~ _s su---~-a-- rc monitor the column for proteinase a^~ ~ ar~ -c determine total proteolytic units. One BSA pro~eolytic unit was defined as an optical density (750nm ~a~elength) increase of 0.100 under incubation conditions of 37C for 60 min ~Remold, H., Fasold, H., and Staib, F. Biochimica et Biophysica Acta 167:399-406, 1968). Fractions with proteolytic activity were eluted in l:he void volume with equilibration buffer, pooled and stored at -70C.
Proteinase purity and molecular weight was determined by the Phast-~el ~12.5~ acryla~ide) elec_ro~ho-esis system (Pharmacia). Protein was determined by the Lowry method (Lowry, O.H., Rosenbrough, N.J., Fa-r, A.L., and Randall, R.J. Journal of Biological Chemist-y 193:263-27~, 1951).
A fluorogenic substrate, A78331, may also be used to monitor proteinase production and purificatlon. This substrate, DABCYL-Gaba-Ile-His-Pro-~he-His-Leu-Val-Ile-. ~
His-Thr-EDANS ~Holzman, T.F., Chungj C.C., Edal~L, R., ~! Egan, D.A., Gubbins, ~.J., Rueter, A., Howard, C-., Yang, L.~., Pederson, T.M., Krafft, G.A., and Wang, G.-. Journal ~` .
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the DABCYL group, 4-(4-dimethyl-amino?henvlazo)~en70ic acid, as long as it ls part of the molQ-ule (Ma~alos~i, E.D., Wang, G.T., Krafft, G.A., and Erickson, J. Science 247:954 958, 1990). Proteoly~is c_ .;~ls -~l~!~-.d D ~
fungal proteinase releases Th~-~D~a, -.~;-ic~ .e-. a^ _ ' 'v'a- e~.
at 340 nm fluoresces at 490nm ~ith ~;~G same in~Qnsi~y ~s equimolar EDANS. Ac.ivi~y is expressed in t~rms of nmol EDANS released from 32~M A78331 under incub2tior.
conditions of 22C for 60 min.. One 3~, p~ e eo'''.-'- ~'~'~
was equivalent to 1.03 nmol E3~Ya -e'eased.
In Vitr~ Inhi~itor A~say MethQ~.
Microtiter as~y. The assay for inhibitors of C.
albicans acid proteinase is done in microtiter trays with the fluorogenic substrate A78331. Test compounds are ., initially tested at l~M, followed by a dose study ranging down to 0.2nM for compounds having greater then 80%
inhibition from control at the lUM dose. The reaction mixture consists of 5~L test compound or dime.hv sulfoxide and 45~L of fungal proteinase (0.13 BSA
proteolytic units or 0.13 nmol EDANS released) ' n 50m.M
sodium citrate, pH 4.5, which is preincubated at 22C for 30 min. The reaction is started with the addition or 50~L
fluorogenic substrate in citrate buffer and the incubation is continued at 22C for 90 min. The reaction is terminated with 150~L pepstatin (final concentration of l~M) and ~lO~L samples are transferGd to mlc-ofluo- pl2tes for fluorescence quantitation in a luminescence .
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The ability of a compound of the invention to treat a~l irfection caused by a Candida s?ecies can be de-vrs.-a`_eA _~ v~ acco-ding to the me :~ods ou~lined a~ a-i, e. al., Cli... Ex~. Dermatol. 1 183 (lg9C); Ghannoum, J. ADP1. Dac~er-lo ~ io3 (1930); ana Ray, et al., J. Invest. Dermatol. ~ 37 (1984).
The ability of a compound of the invention to treat an infection caused by a Candida species can be demons~rated in vivo according to the methods outlined by Ray, et al., J. Invest. Dermatol. 66 29 (1976); Ray, et al., Infect. Immun. ~ 1942 (1988); Van Cutsem, et al., Sabouraudia 2 17 (1971); Sohnie, et al., J.
Immunol. 111 523 (1976); Kobayashi, et al., Microb.
Immunol. ~ 709 (1989); Shimizu, et ~l., Microb.
;
Immunol. ~1 1045 (1987); Zotter, et al., Dermatol. Mon.
Schr. 176 189 ~1990); and Ruchel, et al., Zbl. Bakt. 21 391 ~1990).
The ability of a compound of the invention to prevent an infection caused by a Candida species can be demonstrated according to tne methods outlined by Meitne~, et al., Infect. Immun. ~8 2228 (1990) and Cole, et al., Mycoses ~ 7 (1990).
Total daily dose of a compound of the invention administered to a human or othe_ mammal for inhibiting ., . . ~ ., ~"''`', .
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~92/0~29 PCT/US91/055 Canàida acid protease or treating or preventing an infection caused by a Candida species in single or divided doses may be in amounts, for example, from O.OC1 to 10 mg/kg body weight daily and more usually 0.01 to 10 mg.
Dosage unit compositions may contain sucA amounts of submultiples thereof to make up the daily dose.
The amount of ac~ive ingredien~ that may be combined wi~h the carrier materials to produce a single dosage form wi l varv de~ending upon the host t_eated and t;~e pa-~icula- mode of administration.
T_ will be unde-stood, howeve~, _hat the s?es-ric dose ; ievel fo- any particular pa~ient w~: àepend upon a variety or factors including the activity o the specific compound employed, the age, body weight, gene_al health, se~, diet, ` time of administration, route of administration, rate of excretion, drug combination, and the severity of the ~ particular disease undergoing therapy.
- In addition, the present invention is directed to the use of a compound of formula I to inhibit retroviral .
proteases and in particular to inhibit HIV-1 protease and ~3 HIV-2 protease. Compounds of formula I are useful for t-eatment or prophylaxis of diseases caused by retroviruses, especially acquired i.~mune deficiency ~- syndrome or an HIV infection.
The inhibitory potency of the compound of the .` invention against HIV protease can be determined by the followin~ method.
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A compound of the invention is dissolved in D~SO and a small aliquot further dilucPd with ~ISO to 100 t~mes tne final concentration desirod fo- tes lny. The _eac~ion s carried out in a 6 X 50 ~ 'U2e '^. a ~o~a' i3' '~~e O~
microliters. The final concenlra_ions o- tne com~onQn~S ' n the reacr ion buffe- a-e~ c~ Qr 7 chloride, 5 m~ dithioth-e-to , 3. ~c/mi oovi^_ se- m aibumln, 1.3 u~' fluo;o~.eai~ sub~ , 2 dimethylsulfo;~ide, p.~ . A-r~- e ~d' _` or. o nAi~ -o-~the re`action mi~tu=e is ?laced i~. -he .luoromQ~Q- ce'' holder and incubated at 30C fo- seve-al minutes. ~he reaction is initia~ed by the addition of a small aliquot or cold HIV protease. The fluorescence intensity (excitation 340 nM, emmision 490 nM) is recorded as a function of time.
The reaction rate is cletermined for the first six to eisht minutes. The observed rate is directly proportional to the moles of substrate cleaved per unit time. The percent inhibition is 100 X tl - ~rate in ~resence of inhibi~or)/~rzte in absence o_ ir.r. ~i~or)).
Fluorogenic substrate: Dabcyl-Ser-Gln-As~-Tyr-~ro-Ile-Val-Gln-EDANS wherein DA3CYL = 4-~4~dimethylam~no-phenyl)azobenzoic acid and EDANS = ~-~(2-aminoerhyl)amino)-nz~hthalene-1-sulfonic acid.
, The antiviral activity oî com~ound of the invention can be demonstrated using the following method ;~. A mixture of 0.1 ml (4 X 106 cells/ml) of H9 cells and 0~1 ml (100 infectious units) of .i-~i-13g is incuDated on a - shaker for 2 h. The resulting cul~~re is washed three " ~92/0~29 ~ ~ O~ 2 ~ ~ PCT/US91/0 times, resuspended into 2 ml o- medium, and treated with 10 ~1 of the com?ound of the inventio-. ~5 ~,M in dimethylsulroxide). The cor.~rcl cu_-_-~ s ~-e_-ed in an identical manner except the last s_ep W2â omitted. After incubation of the culture for ei 3h da~1â w' thout ch~nge o-medium, an aliquot (0.1 ml) of the supe-r.atent is wl~hdrawn and incubated with f-esh ;9 cells ~ s:^a:ce- fo- 2 .. The resulting culture is wasr.ed three ~ mes, -esus_e?.~e~ nto 2 ml of me~iu~, an.d ~ n,~ ~Q ~r` -~determined uslng tre ADbc~t ;~T_V-~__ an :~_n ~ ..e-:^o_ ('aul, et al., J. ~ed. Vi-o'~, ~ __. (: _ )).
The fo~egoing is mereiy il us -a~iv-e o~~ the n~en_lo.l and is not intended to limit the i..~entic-. to ~he cisclosed compounds. Variations and changes which are obvious ~o one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.
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N, 11.70. Found: C, 65.24; X, 9.75; ~i, 11./5.
. The procedure of Example 49~ wzs em~loyed, WiL:~
the substitution of the resultant comsound f_om Exam~le 62A
for the resultant compound from Example 49A, to providQ he title compound as a white foam (65~ yield): mp 59-65 C;
Rf 0.34 (10% MeOH-1% conc. aq. NH4OH-CH2Cl2); lH NMR
(CDC13) ~ 0 . 67-1. 00 (m, 11 H)~ 1.00-2.10 (several br m, approx. 29 H~, 2.10-2.60 (vbr m, 2 H), 2.65-2.76 (m, 1 H), 2.76-2.86 (m, 2 H), 3.00-3.82 (several br m~ and 3.36 (2 s, 10 H total), 3. 82-3 . 95 (br m, 1 H), 3 . 95-4 .10 (m, 2 H), 4 . 67 (d, 2 H), 5 . 83-5 . 90 (m, 1 H), 6 .84 (d) and 6.90 (d, H total~, 6.97 (s, 1 H), 7.07 ~S, 1 H), 7.20-7.34 (m, 5 u,), 7.59 (d, 1 H); MS m/e 767 (M+NH4)+. Anal. Calcd for C43H70N6o6-o.sH2o: C, 66.55; H, 9.22; N, 10.83. Found: C, 66.37; H, 9.11; N, 10.62.
. .. .
-W092/0~29 2 ~ & ~ PCT~USg 1/055~
. . . . . . . . ~ . ., E~
N-(?-(~ et~yL-N~-cy-anQ~othioureldo)~t~yl) ~(.S~-(~-(1(~C)-(a-(metho~ym~thoxy)~i~eridin-1-yl)c2r~Qnvl-?-~ yl)~thy~-L-~QLl~--~in~do)-6-cyGLohe~yl-~(S)-:-~Jd~ -?(~
,i ~oR-vl~namid~
A . N- (2-~2~ml~noet-~yll (2S, 4 '~, 5S) -5-butyloxyc2rbonyl,~ ~Q-9-l~ydroxy-2-iso~r The procedure of Example 49A was emploved, substitution of ethylene diamine ~or 4-~3-aminopropyl)morpholine, to provide the t-~1~ com~ound 25 a white foam ~98% yield): mp 55-62 C; Rc 0.2' (lO~ MeOH-i~
conc NH4OH-~H2Cl2); lH N~ (CDCi3) ~ 0.63-l.G6 (D- m) anà
0.93 ~d, 8 H total), 1.06-1.33 (br m, 5 H), i.33-1.50 (b-m) and 1.45 ~s, lO H total), 1.50-1.98 ~br m, 10 H), l.99-2.09 ~m, 1 H), 2.74-2.89 (m, 1 H)2.90-3.03 (br m, 1 H), 3.03-3.19 (br m, 1 H), 3.40-3.75 (br m, 3 H), 4.68 (br d, 1 H), 6.00-6.09 (br m) and 6.21-6.33 (br m, 1 H total); MS
m/e 414 (~M+H)+).
B. N-(2-(S-~ethyl-~'-cyanoisothtaure;do)ethyl) (2S, 4S. 5s! -5- (te~t-bu~ylQxycarbony~ amlAQ-4-hydroxy-2-~QgrQ~ylhexanamide~ The procedure of Example 24 was employed, with the substitution of the resultant compound from Example 63A for the resultant compound from Example ,16 to provide the title compound (100% yield): mp 96-102 C; Rf 0.34 t5% MeOH-CH2Cl2); lH NMR (CDCl3) ~ 0.70-1.06 (br m), 0.91 (d) and 0.94 (d, 8 H total), 1.06-1.50 (br m) and 1.44 (s, 15 H total), 1.55-1.93 (br m, 10 H), 2.11-2.22 (m, 1 H), 2.55 (br s) and 2.64 (br s, 3 H total), 3.33-3.75 (br m, 6 H), 4.58-4.85 (br m, 1 H), 6.80-6.95 (br m, 1 H), 7.82-8.01 (br m, 1 H); MS m/e 529 (M+NH4)+, 512 (M+NH4)+
.
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' ' -98-Anal. Calcd for C2sH4sNsO4S: C, 58.68; H, 8.86; N, 13.68.
Found: C, 58.33; H, 8.98; N, 12.95.
^ The procedure of Example 49B may be employed, with -,the subs.itution o_ the resultant compound from Example,63B
for the resultant compound from Example 49A, to provide the .i.le compound.
le 6~
~`Y-(2-(~ ienou~e;~o~ethyl,) 5fS)-(N-(l(.~)-(a-(~C-'~ 77,er~,7,r~ ~7~1~-I-vl)c2-bo~1-2-~?~enyl)~thyl -T~-72_1e~ na.,!ldo) -6-c-~lQhe~:yl-~(S~-hydroxy ~
The procedure of Example 25 may be employed, with the substltution of the resultant compound from Example 63 for the resultant compound from Example 24, to provide the title compound.
, Examp]e 65 N-(2-((3-~mino-lH=1,2,4-triazgl-5-yl)amino)ethyl~ 5(S)-(N-(Ll~ -(4=(metho~ymethoxy)piperidin-1-yl)carbo~yl-2-~henyl)e~hyl-L-nn~ n~ml~o)-~-~yclohexyl-4(s)-hyd~oxy-", 2(~)-iso~roQ?t~lh~n~id~
The procedure of Example 25 can be employed, with the ~'~substitution of the resultant compound from Example 63 and hydrazine hydrate for the resultant compound from Example 24 and 30% aq. NH40H, to provide the title compound.
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E,~m~le 66 N-(2-((5-.~..ino-L 2.~-o~ad1a~o1-5-yl)am'~nQ)et~hyl) 5(~)-(N-(1(.~!-(4-(~e..hoxymeLho~v~ eridin-~ l)~al~nyl-2-pheryl)e~hyl-L-n~rleucin2m-do)-~-cyclohe~yl-4_(5)-hydroxy-2(5)-iso~ropyLhe~a~amlde.
The procedure or Example 25 can be employed, with the substitution or^ the resultant compound from Example 63, hydroxylamine hydrochloride and a molar equivalent quantity of triethylamine ror the resultant compound from Example 24 and 30% aq. NH40n, to provide the title compound.
E~amDt~ 67 ~L2-(Methvls~lfamoylami.nQ)ethylL ~ L~(N-(l(-~L-(4-; (methoxy~hoxy)~i~er;.di~-1-yl)c2~.bonyl-2-~henyL)ethyl-I.-norleucinamido)-6-~c~loh~yl-4(5)-hydroxy-2(5)-isQeropy~.hexanamid~_ ~ ~. N-(2-(Methylsul~mQyl~m~nlEth~l) (2S 4S.5S)-5-.~ ~tert-hutyLoxyc~}20Qyl) amino-,4,-hydrQx5~2-9~15~il~. A solution of the resultant compound , from Example 63A (SOO mg, 1.21 mmol) and triethylamine (0.50 mL, 3.62 ~mol) in 3 mL CH2C12 was cooled to O C, and a solution of methyl sulfamoyl chloride (173 mg, 1.33 mmol) in 1.5 mL CH2C1~ was added dropwise. The resulting solution was stirred 6 h at O C and a further 48 h at ambient temperature-. The mixture was partitioned betwwen 25 mL CH2C12 and 25 mL sat. aq. NaHC03. The aqueous phase was extracted (3 x 25 m~ CH2C12), then the combined organic phases were dried (Na2S04), filtered and concentrated to a white solid (582 mg). Flash chroma~ography (silica gel, 3.5~ MeOH-CH2C12) afforded 327 mg (0.645 mmol, 53 %) of the , .. , , ~ , .................... .. . . . . .
- ~ .
.: , : : '' ' ~:' ' ' ' W092/0~29 P~T/~91/055~ _ - -~ æoss~68 - '' title compound as a white foam: mp 75-95 C; R 0.22 (5 MeOH-CH2C12); 1H NMR (CDCl3) ~ 0.77-1.06 (br m), 0.92 (d) : and 0.95 (d, 8 H total), 1.05-1.40 (br m, 6 H), 1.4~ 6S, 9 H), 1.56-2.03 (br m, 9 H), 2.04-2.18 (m, 1 H), 2.73 (d, 3 H), 3.10-3.30 ~br m, 3 H), 3.45-3.58 (br m, 2 H), 3.7-3.84 (br m, 1 H), 4.6-4.82 (br m, 1 H), 4..82-4.95 (br m, 1 H), 5.32-5.51 (br m, 1 H), 6.35-6.45 (br m) and 6.61-6.75 (b-m, 1 H total); MS m/e 524 (M+NH4)+, 507 (~+NH~ nal.
Calcd for C23H46N~O6S: C, 54.52; H, 9.15; N, ll.Oo. Found:
C, 54.41; H, 9.38; N, 10.59.
B. The procedure of Example 49B can be employed, with the substitution of the resultant compou~.d --om ~:;a~pl~ ~7.'.
for the resultant compound from Example 49~, to provide tne title compound.
~2~mRl~ ~
N-(~-(l.L-~ioxo-4-thiom.olq~hoL~ethyl) 5(S)-(N-(l(S)-. (methoxymethoxy).~i~er~in-l-yl) ca~orlyL-2-~?h~,lLethyl-T,-(s) -hydroxy-2 (s? -., _i~
A. N-(2-(1, ~-~i~8Q=~=~hiQmQ~holino)ethyl) 2(S)-((3-(te-t-butyloxyc~rbQnyl_?-2.2~dimeth~ (.S~ clo~.e~ met~
~ The procedure of Example 2B was employed, with the substitution ~ of 4-(2-aminoethyl)thiomorpholine~ dioxide for 4-(3-: aminopropyl)morpholine, to provide the title compound as a white foam (100%): lH N~R -(CDC13) ~ 0.83-1.04 (m, 8 H), 1.04-1.44 (br m, 6 H), 1.48 ~s, 9 H), 1.53-1.95 tseveral b_ m, 18 H), 2.03-2.14 (br m, 1 H), 2.66 (t, 2 H), 2.98-3.15 : (br m, 8 H), 3.20-3.53 (br m, 2 H), 3.56-3.85 (br m, 2 H), 5.83-5.94 (br m, 1 H~/ MS m/e 572 ((~+8)+~.
.
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W0~2/0~29 2 ~ 6 ~ PCT/US91/05~
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--101~
The procedure of Example 2C can be em?loyed, wlth the substitution of the resultant compound }rom Example 68A
for the resultant compound from Example 2~, to proviae the title compound.
F. ~ a~.l~ ~q ~ =~reido 5(s)-(N~ s!-(4-(m~tho~vmetho~ ryer~ln=~
yl)carbonyl-2-~h~n~l)ethyl-~,-nor]elc~ n~ o~ , cl ~h 4(5)-hvd~nxy-2(5~-lsoDr~?yl`~e~2~ .e.
mi.no ~25, 4 ~. 5 ~ t~r~--2~1tyl5:~ ~C~ . _?.C`--4-hydro~y-2~iso~ro~ylhe~an~m1de. Tiîe procedurQ o~ ~.xample 49A was employed, with the subs~itu~lon o_ hydrazine hydrate for 4-(3-aminopropyl)morpholine, to provide the title compound as a white foam (73~ yield): mp 55-62 C;
Rf 0.45 (5% MeOH-CH2C12); 1H NMR (CDCl3) ~ 0.55-1.94 tseveral~br m, 16 H approximately), 0.94 (dd, 6 H), 1.49 ~s, 9 H), 1.58 (s, 3 H), 1.64 (s, 3 H), 2.05 ~m, 1 H), 2.50-3.50 (vbr m, 2 H), 3.69 (m, 2 H), 6.92 (m, 1 H); MS
m/e 426 ~(M+H)+), 443 ((M+NH4)+). An~al. Calcd for C23H43N3O4: C, 64.91; H, 10.18; N, 9.87. Found: C, 65.00i H, 10.04; N, 9.64.
4-hydro~y=2-isopr pylhexa~amide. The procedure of Example 6B was employed, with the substitution of the resultant compound from Example 69A for the resultant compound from Example 6A, to provide the title compound as a white powder (100% yield): mp 95-102 C; Rf 0.22 (5% MeOH-CH2Cl2); 1H
NMR (CDC13) ~ 0.85-2.03 (several br m, 16 H approximately), 0.97 (dd, 6 H), 1.49 (s, 9 H), 1.59 (s. 3 H), 1.65 (s, 3 H), 2.11 (m, 1 H), 3.69 (m, 1 H), 3.83 (m, 1 H), 5.31 (m, 2 H), 7.07 (m, 1 H), 7.49 (br s, 1 H); MS m/e 469 ((M+H)+?, ': . : :: :
: ' ' .: . ...
2/03429 P~r/U~91/~
9 ~ ~ 8 -102-486 ((M+NH4)+). Anal. Calcd for C24H44N4Os: C, 61.51; H, 9.46; N, 11.95. Eound: C, 61.32; H, 9.43; N, 11.33.
C. The procedure of Example 493 was employed, with the substitution o_ the resultant comDound from Exampie 69B
for the resultant compound from Example 49A, to provide the t tle compound as a white powder (34% yield): mp 115-121 C; Rf 0.33 (10% MeOH-C~2C12); 1H NMR (CDC13) ~ 0.74-2.00 (several br m, app-ox. 17 H), 0.96 (d, 6 H), 1.50 (s, 9 H), 2.58 (m, 1 H), 2.90 (m, 1 H), 3.36 (m, 1 ~.), 3.70 (m, 1 ~), 5.00-7.70 (v-b_ ~.., a?prox. 2 H), 5.78 (m, 1 ~), li.33 (m, 1 H); MS m~e 429 ((M~X)+), 445 ((M+NY.4)+). Anal.
^~lc~ for C21:iio~T4o~ 0.25 H2O: C, ~3.24; H, 9.42; ~, 12.93.
Found: C, 58.17i ;i, 9.22; N, 12.93.
E~amDle 70 N~ thylsulfamoylami~o) 5(S)-(N-(l(S)-(4-~met~oxymethQxy)piperidin-l-yl)ca~bonyl-2-phenyl)ethyl-L-A. N-(Methyl~uLfamoylamlno) (2~,4~ ~S)-~-(ter~-yloxycalbonyl)aminQ-4-h~d~Q~-~2~-is~p~opyLh~a~am; de .
The procedure of Example 67A can be employed, with the substitution of the resultant compound from Example 69A for the resultant compound from Example 63A, to provide the title compound.
~ _ The procedure of Example 43B can be employed, with the substitution of the resultant compound from Example 70A
for the resultant-compound from Example 49A, to provide the tit1e compound.
: .
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2~3~8 W092/0~29 PCT/US91/05~
, :
! ~ 5 . ' N-(MQthylsulfQnylami no) S (S) - (~- (1 (S~- (4-(r~Ql ho.~yr.ner:n~Yy) ~ r~ n-l -yl ) c~-hony~ henyl ~ et ~orl~uc namido)-6-cyclohexyL-4(.~-hydroxy-2(s)-i~Q~-o~ylhe~;aræTnide ~
~ . ~- (M~thvl s~l fonyl amino) (2S 4S 5S) -5- (tert-b~ y~ca-rl~?~ n~Q-~-~h~J~oyv---~Q~--o~ylLhe~n2mi~
The procedure of E~ampie 67A can be employed, with the substitltion o-^ me_hanesulfonyl c..loride for me~hylsulfamoyl chloride, ~o provide the title compound.
B. The procedure of Example 49B can be employed, with ; the substitution of the resultant compound from Example 71A
for the resultant compound from Example 49A, to provide the title compound.
~, ~ample 72 ~-(CarboxyethylL_5~Sl~(N-(1(S)-(4-(m~i:hoxymethQxy~=ylls~
norleucinamido)=6-~y~lQhexyl-4(5)-hydroxy-2(5)-' so~Dyl~an~
a. N- ~thyl car~Q~ye~h~L~ s)-(N-(l(sL-(4 (me~hoxymethoxy)~lpPr-d.n-1-y1icar~onvl-2-~henvl!ethy~
0~ 3 ' A~ The procedure of Example 37B can be employed, with the substi~ution of the resultant compound from Example 74 for the resultant compound from Example 1, to provide the titLe compound.
~ _ The procedure or Example 37C can be employed, with the substitution of the resultant ompound from Example 72A
``, . .
,~
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208~2~
for the resultant compound from Example 37B, to provide the title compound.
E X ? ~ 7~
-(2~ ip~ldlnyl)ethyl~ 5L.~)-tN-(1($)-~4-(~ethoxymethQxy~ ~Li~1~-l-yl)car~onyl-2-p'~enyl)e-h~
norleu~amido) -6-cy~lohexyl,-,4 L~-hy~'~roxv-2 (S) -iso~Q~ylhexanamide.
A~ N-(2-(l-pi~eridinyll-e~hyl) (25.4.~.55~-5-~er~-butylo~a~ nvl)a~lno-4-`~ydroxy-2-i~o~ro~v1 hQ`;an~mide .
The procedure of Example 49A can be employed, with the substitution of 1-~2-aminoethyl)piperidine for 4-(3-aminopropyl)morpholine, to provide the title compound as a white crystalline solid (90~ yield): mp 149-50 C; [a] 25D
+1.5 ~c 2.4, CHC13).
~ _ The procedure of Example 49B can be employed, with the substitution of the resultant compound from Example 74A
for the resultant compound from Example 49A, to provide the title compound.
Example 7~
_ .n-1-yl)ca~Qnvl-2-~he~lLe~hy1=l=norleucine ~ ,.
~ 4-(Methoxymethoxy)-piperidine (50.0 g, 0.344 mol), ~L)-N-(carbobenzyloxy)phenylalanine (113 g, 0.379 mol), and 1-hydroxybenzotriazole hydrate (106 g, 0.690 mol) were dissolved in 300 mL DMF and cooled to -20 C under dry nitrogen. A solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (86 g, 0.448 mol) in 300 ~.L
: ,, .. ,. : -: . " ' ........... . . . .
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WV92/03429 2 ~ ~ 9 2 6 ~ PCT/US91/05;~
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DMF was added. After warming to room temperature i overnight, the DMF was removed under reduced pressure at 35 C. The crude product was partitioned between -tOAc and 10% citric acid. The organic phase was washed sequentially with 10% citric acid, 5~ NaHCO3, and brine, dried (MgSO4), and evaporated to give 132 g (90~) of the desi-eà amide: 1H
NMR (CDCl3) ~ 1.01 (m, 1 H), 1.18 (m, 1 H), 1.42 (m, 1 ~), 1.65 (m, 1 H), 2.99 (m, 2 H), 3.13 (m, 1 H), 3.3' (m, 2 u)r 3.33 (s, 3 H), 3.64 (m, 1 H), 3.81 (m, 1 H), 4.o2 (s, 2 .i), 4.91 (m, 1 H), 5.09 (s, 2 H), 5.71 (t, J = 9 H~ ), 7.2 (m, 10 H); MS m/e 427 ((M+H)+).
~ aLt _~, The above benzyl carDamate (122 c, 0.286 mol) was hydrogenated under 4 atm. H2 in 2 L MeOH usin~ 24.5 g 20% Pd/C. After 16 h, an additional portion of catalyst (25 g) was added. The mixture was shaken for a total of 48 h, then filtered and evaporated in vacuo to provide 75.4 g (90%) of the title compound as a waxy solid: lH N~R ~CDCl3) 1.08 (m, 1 H), 1.27 (m, l H), 1.4S (m, 1 H~, 1.70 (m, 1 H), 3.07-(dd, 2 H), 3.2 (m, 2 H), 3.35 (m, 2 H), 3.35~s, 3 H), 4.67 ~s, 2 H), 7.29 ~m, 5 H~; MS m/e 293 ~M+~)+).
~ _ The resultant compound ~rom Example 74A ~75.0 g, 0.257 mol) was added to a solu~lon of ammonium carbonate ~27.26 g, 0.29 mol) in 200 mL water. The mixture was stirred at 35 C, and (R)-ethyl 2-bromohexanote ~S3.52 g, 0.24 mol) in 100 mL of nitromethane was added. The reaction mixture was stirred at 42 C for 48 h, and at 48 C for an additional 12 h.
The mixture was cooled and extracted with ethyl acetate, the organic extract was dried ~MgSO4), filtered, and the f1ltrate evaporated under reduced pressure to zr oil. The ~' .
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20892~8 crude product was purified by sho-t-path silica gel column chromatography, eluting with a gradient of 2-5% MeOH-CHCl3, to give 81.4 g (78~ based on 5 g c~ recovered starting amine) of th~ t~tle com~ound~ ~ (DMSO-d6) ~ 0.82 (t, 3 H), 1.15 (dd, 3 H), 1.2 (m, 4 H) 1.3 (m, 2 H), 1.4 (m, 2 H), 1.6 ~m, 2H ), 2.7 (br d, 2 H), 2.6-3.15 (several br m, 4 H), 3.22 (2 s,3 H, rotamers), 3.85 (m, 1 H), 4.03 (m, 2 H), 4.57 (2 s, 2:i, roramers), 7.2 (m, 5 H).
C. The ~esul_a~.t com~ound _~m Exam?le 743 (35 g, 0.081 mol) was s.~-_ed in 112.5 r.._ 2 N NaOH (0.227 mol) at room temperature ror 24 h, by wh -~ time tne cloudy mix.ure turneà clear. The mixture was ac dified with aqueous ci~ric acid to pH 5.5, causing a ~hite solid to 2recipitate. After standing at room temperature for 2 h, the solid was filtered, then washed sequentially with cold water and 20% ether/hexane, and dried under high vacuum to afford 28.4 g of crude product. The crude material was recrystallized from hot ethyl acetate to give the desired compound (27 g, 82%) as a white powder: mp 155-7 C;
[~]D25 +26.3 ~c 0.28, CH30~ H NMR (DMSO-d6) ~ 0.85 (t, 3 H), 1.25 (br m, 6 H), 1.5 (br m, 4 H), 2.75 (dd, 2 H), 2.82 ~m, 2 H), 3.02 ~m, 2 H), 3.22 (2 s, 3 H, rotamers), 3.45 (m, 1 H), 3.58 (m, 1 H), 4.0 (m, 1 H), 4.55 (2 s, 2 H, rotamers), 7.25 (m, 5 H); MS m/e 407 ~(M+H)+).
0~ .
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, ~09~io~29 2 ~ o 9 2 ~ 8 P~T/U~1/055~
~, r --10 7-- -i N-(( d _D~ idyl)m~hyl) ~(S)-(N-(~ (4-(~.elh~Ymeth?Y.~ e~ n-l -y~ )ca-~Q~.yl-~-~heny1)ethyl-T-,n ~--l P l ~ d ? ) --7 ~ ,Q h t~ l--d ( C ~ --n ~ o " ~--2 .( ~ C ) -- ( ~--hydro~yethyl ) octænamide .
The proceàure of ~xample 493 can be employed, with the substitution of the resultant compound from Example 27(a), United Sta,es Patent 4,851,387, fo_ the resultant compound from Example ~a~, to p-ovide the t ~le compound.
~ :a~.?1~ 76 ~- (2-~1n~-' -~. jCl o:-e ~:y' -3 (~), a (S) -~- hyd~o~y-~-~ethyl-2i.$)-hexyl) 5(5)-(~-(1(5~-(4-(metho~ thoxy~pi~eridln-1-yl)ca~onyl-2-~henyl)e~hy1-~-nor1~eucin2i~ide A. N-(5-Benzyloxycarhonylami~Q=1-cyclohexyL-3(R! ~(S)-dihydroxy-5-metby~-2LS)-h~xyl) 5l~l-(N-Ll(S)-(4-t~ethoxymet~Q~yLpiperidin-1-yl)carbonyl-2-p~enyL)ethyl-L-~ Is~ m_a-_ The procedure of Example 49~, part 2 can be employed, with the substitution of the resultant compound from Example 5, PCT Patent WO 91/01327, for the resultant compound from Example 49~, part 2, to provide the title cor,pour.d.
~ . The procedure of Example 3 can be employed, with the substitution of the resultant compound frsm Example 76A
for the resultant compound from Example 2, to provide the title compound.
.
, ,:, . ., .
.. . . .
WO92/03429 PCT/US91~05 `
` ` - 2~8~6~ 108-xam~1~ Z7 (2~ S)-2- r (N-(1(5)-(~-(me~hQ~ym~ho~y)~ rl dl~
yl!carbon~l-2-phenyl)e~hyl-L-nQxleuci~amido)l-l-cv~lohe~
~ . 5(s)-(~ert-Bu~ylQ~y~l~Qnyl)-6-cyclohe~ -4(s) hydrox~-2-(S)-i~op~opylhe~anol, The title compound was prepared using the procedure described in the literature (Karlsson, J. O.; Lundblad, A.; Malm, I.; Milsson, _.;
Niten~erg, T.; Starke, I.; Sorensen, H.; Westerlund, C.
Tetrahedron Lett. 1989, 2653) for the 6-methyl cor~ound, however the analogous isopropyl precursor was used instead.
H NMR (CDCl3, 300 MHz) ~ 0.90 (ad, J = 6Hz, 6H), 1.13-1.40 (bm, 6H), 1.45 (s, 9H), 1.57-1.90 (bm, 12H), 3.58-3.72 ~m, SH), 4.68 (bd, J = 9Hz, lH). Anal calcd for C20H3gNO~-0.25H20: C, 66.30; H, 10.62; N, 3.76. Found: C, 66.14; H, 10.67; N, 3.77. MS tDCI/NH3) m/e 358 (M+H)+.
The compound resulting ~rom Example 77A was converted to the! title compound using the method described in the literature (Karlsson, J. O.;
Lundblad, A.; Malm, I.; Nilsson, I.; Nitenberg, T.; Starke, I.; Sorensen, H.; Westerlund, C. Tetrahedron Lett. 198g, 2653) for the 4-methyl compound. m.p. 85-86 C. lH NMR
(CDCl~, 300 MHz) ~ 0.92 (t, J = 6Hz, 6H), 1.15-1~84 (several bm, 17H), 3.52 (m, lH), 3.68 (dd, J = 4.SHz, 2H), 4.35 (m, lH), 5.62 (bs, lH). Anal calcd for C16H2gNO3: C, 67.89; H, 10.25; N, 4.95. Found: C; 67.72; H, 10.14; N, 4.92. MS (DCI/NH3) m/e 301 (M+a+NH3)+.
C. 4-Cyçlohexylmet~yl-5-l3-~ethyl-2=
~e~hoxymethoxymethy~utyl-2~-o~azQli~Qne To the compound resulting from Example 77B (650 mg, 2.30 mmol) dissolved ir s , :
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WO 9~/0342~ 2 ~ ~ 9 2 ~ 8 PCT/US~ s24 .. . , .. ... , ~ ~ .. . .
anhydrous methylene chloride (20 mL) at ambient temperature was added technical grade chloromethyl methyl ether (0.26 mL, 1.5 equivalents) followed by diisopropylethylamin~ (0.8 mL, 2 equivalents). The resulting mixture was sti-red for 2.0 hours at ambient temperature, at which time additional chloromethyl methyl ether (1.0 mL) and diisoproyle~hylamine (0.5 mL) were added. After stirring for an add~tional hour, the solvent was removed under reduced pressure. The residue obtained was flash chroma~ographed on sllic~ gel eluting with a gradient (25%,30%) of ethyl ace~ate in hexane to afford the title compound as a white sol-d (640 mg, 85%). lH NMR (CDCl3, 300 MHz) ~ O.88-0.98 (m, dd, J =
3.6Hz, 7H), 1.12-1.85 ~several bm, 16H), 3.~7 (s, 3H), 3.47-3.58 (M, 3H), 4.28 (m, lH), 4.60 (s, 2H), 5.74 (bs, lH).
MS (DCI/NH3) m/e 328 (M~H)+, 345 ~M+H~NH3)+.
D! The compound resulting from E.xample 77C and 3 equivalents of barium hydroxide octahydrate 0.1 ~ in 3:2 dioxane/water was heated at reflux overnight. The cloudy solution was then cooled, filtered through Celite and concentrated under reduced pressure to dryness. ~he residue obtained was dissolved in ethyl acetate and filtered through Celite again. After removing the solvent under reduced pressure, the amine obtained (>90~) was used without isola~ion or further purification.
The above amine ~260 mg, 0.86 mmol) was coupled with-the compound resulting from Example 1 (350 mg, 0.86 mmol) by the procedure described in Example 49B, part 2 to afford, after column chromatography on silica gel eluting with 3:1 hexane/ethyl acetate, the title compound (505 mg, 84%) as an oil. lH NMR (CDCl3, 300 MHz) ~ O.74-0.96 (m, t, `:
.. ,, : .~,. . .
WO 92/03429 PCT/US91/055~
2~268 J = 6.6Hz, lOH~, 1.07-1.80 (several bm, 33H), 2.67-2.89 (m, 5H), 3.33 (s, 3H), 3.40 (s, 3H), 3.52-3.78 (bm, 4~), 4.65 (dd, J = 1.5H~, 4H), 7.27 (m, 5H). MS (FAB) m/e 690 (M+H) .
(2~ ~C~-2-r(N-(ll~c)-(5- (me~hoY~yme~oi~y)~lpe-i~; n-1-yl)c~Q~-2-~han.vl~at~l-T.-~o;lo cL~mldo)l-1-cycloh~yl---nydo~r~v--5--isQ~2r~ yl t;,h,l o~t~v~--5--mar~ylhe~tzna A. I.s~yro?yl r5(S~.-(ta~t-~u ylo:~yca~bon~l)-~-cycloha~yl-~(S)-nydroxy-2-(S)- qQ~~~pylhe~yll tk;Qether.
The title com~ound was prepared usln.g the procedure desc-lbed in the literature (Karlsson, J. O.; Lundblad, A.;
Malm, I.; Nilsson, I.; Nitenberg, T.; Starke, I.; Sorensen, H.; Westerlund, C. Tetrahedron Lett . ~ 989, 2653) for the . 6-methyl compound, however the analogous isopropyl :. precursor was used instead. m.p. 107-108 C. lH NMR
(CDCl3, 300 MHz) ~ 0.85-1.00 (m, ddr J = 6Hz, 7H), 1.15-.~ 1.38 (m, d, J = 6Hz, 9H), 1.45 (p, J = 6Hz, lH), 1.58-1.92 (m, 12H), 2.52 (dd, J = 6Hz, lH), 2.63 (dd, J = 4.5Hz, lH), 2.87 (p, J - 6Hz, lH), 3.64 (~, J = 7.5Hz, lH), 4.29 (m, lH), 5.20 (bs, lH). MS (DCI/NH3) m/e 342 (M+H)~, 359 s (M+H+NH3) .
B_ The compound resulting from Example 78A was treated with barium hydroxide octahydrate by the procedure described in Example 77D. This compound was coupled with the compound resulting from Example 1 (250 mg, 0.62 mmol) by the procedure described in Example 49B, part 2 to afford the title compound (357 mg,-82~) as an oil. Rf = 0.28 (50%
~i hexane-ethyl acetate) 1H NMR tCDCl3, 300 MHz) ~ 0.75 0.95 (m, lOH), 1.08-1.39 (m, d, J = 6.9;iz, 20H), 1.48-1.86 tbm, ... .
' ~' .
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wo92io~29 ~ ~ 8 ~ 2 ~ ~ PCT/~S91/055~
;i . . iJ ", ~ ~ _ 18n), 2.40-2.59 (m, 3H), 2.81 (bm, 3H), 2.92 (p, lH), 3.26-3.48 (m, s, 4H), 3.68 (bm, 3H), 4.64 (d, J = 3Hz, 2H), 7.26 (m, 5H).
E x a~ R 1.~ 7 9 (~;, 4~) -;~- r (~ S) - (~1- (meth~ethoxy~ eri~ ]-yl~ hon~1-2 ~hQ.n.yl)ethyl-~-no~le~cinzmido)l-l-cy~lohe~yl-~-hydoxy-~ so ~
TCO~rO~Vl r ~ (S) - ~t ert.-bulyl.oxyc2rhQ~L) -ij-c~c onexyl-a(S~-hJir-oxy-?-(~)-ico~-opy~.h~xyl~
th~o.~ulfonate~ lhe compound resul.ing from Example 78a was oxidized usina the procedure descr bed in the litera~ure (Ka-lsson, J. O ; Lundblad, A.; Malm, I.; Nilsson, I.;
Nitenberg, T.; Starkef I.; Sorensen, H.; Westerlund, C.
Tetrahedron Lett. 1989, 2653) fo- the 6-methyl compound to afford the title compound. m.p. 135-136 C. lH NMR
(CDC13, 300 MHz~ ~ O.98-1.03 (m, dd, J = 6Hz, 7H), 1.10-1.35 (m, 4H), 1.37-1.48 (m, d, J = 6Hz, 7H), 1.57-2.30 (several bm, llH), 2.77-2.97 (m, 2H), 3.11 (p, J = 6Hz, lH), 3.58 (q, J = 7.5Hz, lH), 4.33 (m, lH), 5.15 (bs, lH).
The compound resulting from Example 79A was treated with barium hydroxide octahydrate by the procedure described in Example 77D. This compound is then coupled with the compound resulting from Example 1 by the procedure described in Example 43B, part 2 to afford the title compound.
;
:
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.
w092io~29 PCT/US91/055~
20~9268 Exam~Le 8Q
hexar.oL~
~xam~le 80a L=yslQh~yL~l~ni~e m8~hyl es ~r. hydroc~l?~ c~
L-Phenylalanine (215 g, 1.3 mole) was hyàrogenated over Pd/C in HOAc, filtered and concentrated. The ; resulting cyclohexylalanine was ta~en up in ~!e~H ~120~
mL). Thionyl chloride (427 g, 3.59 mole) was slowly added to the slurry, which eventually became homogeneous. The reaction was cooled in an ice/water bath and addition of thionyl chloride was continued. The reaction -i~ was heated to reflux for 2h, cooled and concentrated to a~_ord a solid, which was taken up in ether and filtered. The white solid was washed with ether in the filter funnel and dried ;n v~cuo to give 271 g of product, 94% yield over two steps. mp 150-152 C; [a]D =+21.8 (c= 1.09, MeO~); IR
(KBr, cm~l) 2930(br), 2860, 1748; lH NMR (300 MHz, CDCl3) 3.99 (t, J= 6.3 Hz, lH), 3.9 (bs, 2H), 3.83 (s, 3H), 1.82-1.65 (m, 7H), 1.5 (m, lH), 1.35-1.10 (m, 3H) 1.05-0.9 ~m, 2H); 13C NMR (75.5 Hz, CDCl3) ppm 170.5, 53.3, i0.8, 38.3, 33.6, 33.0, 32.8, 26.3, 26.1, 25.9.
E~am~ Ob ;~ The product of Example 80a (88 ~, 398 mmol) was taken up in chloroform (400 mL). Triethylamine (84.6 g, 836 mmol) was then added in one portion to the slu;ry and stirred five minutes. Triphenylmethylchloride ~111 g, 398 mmol) was then added, and the reac~ion was stirred for 5h at ambient temperature. The interna1 temperature of the ., .
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WO9~/03429 2 ~ ~ ~ 2 6 8 PCT/~S91/OSj24 `. .i, .. . .. ... .. .. . .
. . .
reaction reached 50 C, however, external cooling was not employed. The reaction mixture was washed with lM KHSO4 solution (2 X 200 mL), saturated NaHCO3 (200 mL), brine ~100 mL), then dried over MgSO4. The solution was then concentrated to give 200 g of resldue which was filtered through 900-1000 g of silica gel (elution gradient hexane-10:1 hexane: ethyl acetate) affording 157 g o- ~roduct (93%), which could be crystallized from he.~anes: e.hyl acetate to afford large white crystals.
mp 86-87 C; [a]D =+73.6 (c =1.38, C~Cl3); IR (XBr, cm 34SO(br), 2930, 1722; lH N~R (300 MHz, CDCl3) ~ 7.52-7.47 (m, 6H), 7.28-7.12 (m, 9H), 3.32-3.41 (m, 1:~), 3.12 (âr 3H), 2.60 (d, J=lO.S Hz, lH), 1.56-1.46 (m, 7H), 1.35-i.l (m, 4H), 0.77-0.97 (m, 2H); 13C NMR (75.5 Hz, CDC13) ppm 176.1, 146.0, 128.8, 127.7, 126.3, 71.0, S4.2, Sl.2, 44.4, 34.1, 33.9, 32.9, 26.5, 26.1.
" ~;~m~
im~ha~_ U~L=~-Cycl~hexyl-~-~~tr:~?henylmethyl~amino-2 .' oxo}2lltylDho~phorlate .
;To a -78C solution of dimethyl methylphosphonate (272.S g, 2.2 mol) in 1.6 L THF wzs added n-BuLi (2.5 ~ , 800 mL, 2.0 mmol) and stirred 45 minutes. The product of Example 80b (156 g, 366 mmol) in 90 mL THF was then added dropwise. The reaction mixture was stirred at -50C for 3 :.. .
h, then at -40C for 6 h, then finally warmed to ambient temperature overnight. The reaction mixture was concentrated, taken up in ether, washed with 1~ KHSO4, ~i saturated NaHCO3 (twice) and brine, dried and . concentrated. The residue (200 g) W2S filtered through ;~:
.. . .
~NO92t03429 PCT/US91/D55~
~, , 2 0 ~ ~ 2 ~ 8 - -114-1000 g silica sel, (1:1 hexanes:ethyl acetate) to give 135 g of ~-keto phosphonate (72~) as an oil.
[alD =+39.7 (c =2.0, CH30H)i IR (CDCl3, cm~1) 2920, 1717, 1425, 1226, 1019i lH NMR (300 MHz, CDCl3) ~ 7.45-7.38 (m, 6H), 7.30-7.18 (m, 9H), 3.67 (dd, J= 11.1, 2.7 Hz, 6H), 3.47 (m, lH), 2.83 (d, J= 6.6 Hz, lH), 2.67 (dd, J= 21.0, 15.3 Hz, lH), 2.32 (dd, J= 21.0, 15.3 Hz, lH), 1.6S (bs, 5H), 1.49 ~m, 2H), 1.10-1-53 (m, 4H), 0.81 (m, 2H); 13C
: NMR (75.5 Hz, CDC13) ppm 205.8, 145.9, 123.1, 127.9, 127.7, 126.7, 71.2, 61.4, 61.3, 52.8, 52.7, 52.6, 41.4, 37.1, 35.2, 33.8, 33.5, 33.4, 26.4, 26.2, 26.1.
E~am~L~
(6S~-7-Cyclohexyl-2-methyl-6-~N-~ h~nylmethyl)-{ am~no-5-oxohe~-2-~nQ-~-o~c a~id The product of Example 80c ~117.2 g, 229 mmol) was dissolved in 600 ml THF and cooled to 0C. To this solution was added hexanes washed NaH (60%, 9.6 g ~wet), 240 mmol) and stirred 30 min. Next WéaS added methyl 3-methyl-2-oxobutyrate (29.8 g, 229 mmo:L) in 100 ml T~F and stirred at 0 C-for 4 h. Volatiles were removed at reduced pressure, the residue was dissolved in 1:1 hexanes: ether (500 ml) and washed with water (200 ml), NaHCO3 ~200 ml), brine ~200 ml), dried ~MgSO4) and concentrated to afford 129 g of the desired ester as an j oil. This material (123 g) was taken up in 460 ml THF, 229 ml ~eOH, cooled to 0 C, then 18.86 g of LiOH-H2O in 229 m! of distilled water was added. This solution was ' allowed to warm to room temperature'and stirred for 3 days. Volatiles we!e removed at reduced pressure and the resulting aqueous solution was wa'shed with ether (100 ml ': ~
W092/0~29 2 ~ ~ 9 2 ~ ~ PC~`JUS91/0~
.-:
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x2) then acidified to pH 3 with 6N HCl. The aqueous solution was then extracted with EtOAc (300 ml x2), washed wlth brlne, drled (MgS04) and concentrated to glve 116 g of a yellow foam. This material was recrystallized from 525 ml of hot hexanes/EtOAc (12/1) to give 72.4 g of a white solid (62~ for three steps).
mp 97-98 C; [a]D =+6.0 (c=1.0, CH30H); IR (KBr, cm~1) 3450(br), 2530, 171S, 1682, 1442; lH NMR ~300 MHz, CDC13) 7.48-7.36 (m, 6H), 7.31-7.12 (m, 9H), 3.5 (bs, lH), 3.25 (d, J= 18 Hz, 1~), 2.99 (d, J='18H, lH), 2.1 (bs, 4H), 1.6 (bs, 8H), 1.2-1.05 (m, 6H), 0.8-0.6 (m, 2H).
. .
~
~5~6S)-6-Cvclohexylmethyl-3-~o~ro~ylldene-5-~ridine-2-Qn~
A solution of 3.06 g (6.0 mmol~ of the product of Example 80d in 50 ml THF was added to 6.8 g (60 mmol) N-' hydroxysuccinimide. This homogeneous solution was cooled to O C, ~hen DCC (1.25 g, 12 mmol) in 5 ml THF was added.
The cooling bath was removed and the reaction was stirred for 2h. Then an additional 1.25 g of DCC was added.
` ~~ter 5h of-total reaction time, the mixture was filtered, ~` concentrated and dissolved in ether. The organics were ~ washed with NaHC03 (aq, 50 ml x2), brine, dried ~MgS04) J and concentrated at reduced pressure to give 5.2 g of ' product as an oil, wh-ich was dissolved in 20 ml ether. A
' lN solution of HCl/Ether (30 ml) was added. A gummy solid immediately precipitated out of solutioni CH2C12 (25 ml) was added and the clear reaction mixture was stirred overnight. After 12 h, the product, which precipitated from the mixture was collected by'filtration and washed :
.', W092/03429 PCT/US91/0~
~ 2~892~8 -116 with ether to give, after drying, 2.1 g of a whl e soiid in 87% for two steps, which was taken on in the f311OT~ing step.
To a 0C slurry of the above-montioned wh t~ solid from the first step of Example 80e (1.2 g, 3.0 ~mol) in 20 ml CH2Cl2 was added imidazole (204 mg, 3.0 ~mol). hQ
resulting reaction mixture was stirr~d f?r 1 ;~, -hen washed with 20 ml of KHS04, water, satur ted N_:CO3, and brine. The organic portion was dri~d over MgSG~, filt~ed and cooled to -78 C. To the cold solution was added L-Selectride~ (Aldrich, 1.0 M, 5.0 ml, 5.0 mmol) a~.d sti_-ed for 10 min. The reaction mixture was he~ w-~m~ -4C
C and quenched with 20% citric acid solution. The organics were washed with 20 ml of water, saturated NaHCO3 solution, brine, dried over MgSO4, and concentra~ed to afford a clear oil. The oil was purified on silica gel ~50% hexanes/ethyl acetate) to give an oil which was triturated with ether to afford a whi.te solid, 545 mg, 72%
yield.
mp 128-130 C; [a]D =-66.3 (c =1.0, CH30H); IR (KBr, cm~l) 3350(br), 2930, 1640, 1603; lH NMR (300 MHz, CDCl3) ~ 5.82 ~bs, lH), 3.95 (bs, lH), 3.42 (m, lH), 2.88 (bs, lH), 2.72 (m, lH), 2.55 (m, lH), 2.25 (s, 3H), 1.8 (s, 3H), 1.77-1.6 (m, SH), 1.52-1.34 (m, 3H), 1.28-1.12 (m, 3H), 1.0-0.83 (m, 2H); 13C NMR (75.5 Hz, CDC13) ppm 168.1, 148.0, 119.4, .
66.3, 53.1, 38.4, 35.3, 33.7, 33.6, 32.9, 26.4, 26.1, 26.0, 23.2, 23Ø
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WO 92/03429 2 ~ ~ ~ 2 ~ ~ PCT/US91/0~5~
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E~ e 80f L3~,5S,6S)-6-Cyclohe~yL-5-~ydro~y-3-iso~-oDyl-p~erid~n-2-one A solution of the product of Example 80e (24.7 g, 9~.4 mmol) in 500 ml of ethyl ac-tate ~as treated with 2.5 g of dry Pd/C and hyd-ogenated at ~ atm for 4h at ambient temperature. The reaetion mixture was filtered and concentrated to a white oam~ solld wnich was taken on without further purification.
mp 97-99 C; [a]D = -95.1 (c= 1.075, C:~.Cl3)~ 3-, cm~
1) 3605, 3400, 2925, 1642; iH NMR ~30v ~.z, CDCl3) ~ ~.3 (bs, lH), 4.11 ~m, J= 4.5, 1~), 3.~7 ~ .), 2 . 72 (DS, lH) r 2.5 (m, 1~), 2.3 (m, lH), 1.9 (m, lH), 1.~-1.5 (m, 8H), 1.43-1.12 (m, 6H), 0.97 (d, 3H), 0.87 (m, 3H); 13C
NMR (75.5 Hz, CDC13) ppm 174.2, 67.1, 52.6, 44.3, 37.7, 34.5, 33.8, 32.4, 27.6, 26.4, 26.3, 26.2, 26.0, 20.2, 17.4.
(2S 4S.5$l 5-Amino-~-cyclohexy~ Qpropyl-4-hexanoLide - The product of Example 80f was d-ssolved ir. 200 ml of 6N HCl and 50 ml of ethanol then heated to reflux for 14 h. The reaction mixture was concentrzted at reduced pressure and aæeotropically dried with toluene to af.ord a pale oil. This material was taken up in water and extracted with hexane, then made basic by addition of a solution of NaHCO3. Extraction with e_hyl acetate followed by drying (MgSO4) and removal of volatiles afforded a yellowish oil which solidi^ied to a white solid upon standing. Recrystallization f-ol hexane gave 20.7 g (90%) of product as white needles.
'' '~
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2~
mp 49-SG C (lit. mp 48-49C); ~KBr, cm~l) 2925, 1760; 1H
NMR (300 MHz, CDCl3) ~ 4.2 (q, J= 6.1 Hz, lH), 2.82 (q, J=
6.2 Hz, lH), 2.64 (ddd, J= 9.1, 6.0, 5.4 Hz, lH), 2.15 (m, lH), 2.08 (m, 2H), 1.8-1.61 (m, 6H), 1.46 (m, lH), 1.37-1.13 (m, 8H), 1.02 (d, J= 6.0 Hz, 3H), Ø96 (d, J= 6.0 Hz, 3H); 13C NMR ~75.5 Hz, CDCl3) ppm 178.9, 83.1, 52.6, 46.0, 41.3, 34.4, 33.7, 32.3, 29.2, 26.8, 26.5, 26.3, 26.0, 20.3, 18.5. [a~D =+6.5 (c= 1.0, EtOH).
F.~r~ R ' ~
~ac~uc l-t2-furyl!-1-pentanol Freshly distilled furfural (233.5 g, 2.43 mol) was dissolved in 200 mL freshly distilled THF and added dropwise to a solution of butylmagnesium bromide (2.0 M in THF, 1460 mL, 2.92 mol) at 0 C under dry nitrogen. After the addition was complete, the mixture was allowed to warm to room temperature overnight. The reaction was recooled to 0 C and carefully poured into 2 L oî cold sat. NH4Cl.
The layers were separated, and the aqueous phase was extracted with ether. The combined organic layers were washed with saturated NaCl, dried over MgSO4, evaporated, and vacuum distilled to give 325.6 g ~87%): bp 72-73 C
(0.6 mmHg~, lH NMR (300 MHz, CDC13) d 7.38 (lHr dd J = 1 Hz), 6.33 (lH, m-), 6.22 (lH, dd, J = 3 Hz), 4.67 (lH, t, J
= 6 Hz), 2.9 (3H, m), 1.35 (4H, m), 0.90 (3H, t, J = 7 Hz~; mass spectrum (r7~): 170 (M ~H4) .
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W092/0~29 2 ~ ~ ~ 2 ~ ~ P~T/US9l/055~
Exam~le ~B
t~ 2-~l~rv~ ne~t2n~l To a room t~mperature solution of the racemic 1-~2-.uryl)pentanol (20 g, 0.1298 mol) and diisopropyl D-tartrate (4.45 g, 0.019 mol) in methylene chloride (80 mL) were added acti-v-atQd powdered molecular sieves 4 A ~6 g).
The sLirred mixture was cooled to -35 C, treated with titanium te_-aiso?ropoxide (3.7 g, 0.1298 mol), and stixred ror 30 m at tne same temperature. The reaction mixture was tre2ted with a solution of t-butylhyà_ope-o,~ide in 2,2,4-trimet'.ylpen~ane (30 mL, 0.0308 mol) and was stirred at -35 C for 3 h and allowed to warm up to -10 C in 2 h. A freshly prepared solution of iron II sulfate-7H20 (7.2 g, 20 mmol) and dl-tartrate (23 g) in 120 mL water was added to the reaction mixture at -~0 to -30 C and the resulting mixture was stirred vigorously without cooling for 30 m until two clear phases appeared. The organic layer was separated and the aqueous phase was extracted with methylene chloride. The combined organic layer-was washed with brine and dried over sodium sulfate. Evaporation of ~he solvent gave the crude product, which was distilled to give 6 g of the desired product, bp 70-75 C (0.7 mmHg) and 12 g of the pyranol, bp 115 C (0.7 mmHg). Redistillation of the mixed fractions gave additional 0.4 g. A total of 6.4 g of the desired product was obtained (75% theoretical yield based on 60% conversion to the pyranol): ~] 25D = -18 (C 1 . 0, CHCl3), 99% ee by chiral column chromatography analysis (Lil. reported -9, 94~ ee).
.
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WO g2/0~29 PCT/~S91/05524 '. . .
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2~ 120-F~a~le 82 AltQrnative Preparation of (S)-1-(2~ ~yl)=l-~en.~a~o To a solution of optically active (-) 3-exo- --(dimethylamino) isoborneol (DAIB, see ~oyori et. al. J
Am. Chem. Soc. 1986, 108, 6071-2 and Noyori et al. J.
Organomet. Chem. 1990, 382, 19-37, 371 mg, 1.88 ~mol) in 200 mL of dry toluene under an argon atmosphere is added a 4.2 M solution of di-butylzinc (25 mL, 15~ ~ol) zt room temperature. The reaction mixture is s~ red ~o- 15 m an~
then cooled to -78 C. To the cooled solution is added freshly distilled furfural (9.0 g, 94 mmol) in ono por.ion. The reaction mixture is s~i-red a 0 ~_ -o 6 :.
Saturated ammonium chloride solution (100 mL) is added.
The mixture is extracted three times with diethyl ether.
The combined organic layers are dried (MgSOq) and concentrated under reduced pressure. Bulb-to-bulb distillation of the residue ~100 C 20 mmHg) gives the alcohol which is identical to the santple prepared in example 8lB.
E~m~l~ 8 lter~at~ivQ Pr~ara~lon of ~ ~-1 (2~ Y11-1-p2nt~o 2-Valeryl furzn Furan ~12 g, 0.177 mol) and valeryl anhydride (37.2 g, 0.2 mol) were placed in the flask. The reaction mixture was cooled at 0 C in an ice-bath. To the rapidly stirring reaction mixture, 3 g of freshly distiIled boron trifluoride-etherate was added all at once. The ice-bath w2S removed and the temperature of the reaction mixture xose to 65 C. Stirring was continued for 2 h at 60 C, :
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W092/03429 2 ~ ~ 9 2 ~ 8 P~T/US9~/055~
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, and about 200 mL water was adied and st --ed for additional ~ h. The phases were separated and the aqueous phase was extracted with chloroform. The chlo-o^orm portion was added with 200 mL of saturated sodium bicarbonate and stirred for 1/2 h. The org~ni^ laye- was separated, washed with water, dried and filtered. The filtrate was evaporated to a liqu i whlch was dis~ ed a~
65-70 C (2 m~Yg) to yield 20 g (7~) of the desi-ed product: 1H N~R ~ O.95 (t, 3H), ~.4 (m, 2H), 1.7 (m, ; 2H), 2.82 (t, 2H), 6.S2 ~dd, lH), 7.2 (d, l.i), 7.~ (d,lH).
~, .
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~ 10.4 mmol (10.4 mL) of diborane (1 M solution in THF) .~ was added dropwise in a period of 10 m at room temperature to a solution of 2-valeryl furan ~2.62 g, 17.2 mmol) and 1.68 mmol (4.2 mL) of (3aR)-1,3,3-tr:Lphenyl pyrrolidino [1,2-c] ~1,3,2] oxazaborole (see E. ~J. Corey et al. J. Am.
Chem. Soc. 1987, lO9, 7925-~6, 0.4 M solution in THF) in 25 mL THF. The reaction mixture was stirred for 20 m and was cooled to 10 C. 6 mL methanol was cautiously added and followed by adding 62 mg ~Cl (5y welght) ln ether.
Stirred for 0.5 h, white solid was precipitated out. The cloudy mixture was poured into 100 mL e~her and 100 mL
~`water. The organic layer was separated, washed with saturated sodium bicarbonate, wate-, brine, dried and ;-filtered. The filtrate was evaporated to an yellowish oil which was chromatographed eluting -~ith 10~ ethyl acetate in hexane to obtain 70% of the product. []25D = -13, 60%
~ee by Mosher' ester analysis.
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WO 92/0~29 PCT/USgl/055~
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(4.5) 4-~2-ruryl)-3-Q~cta~oic zcid N2H (16.3 g, 680.9 mmol) and freshly distilled THF
(170 mL) were stirred at room temperatu.re as (~ (2-fu-yl)-l-pentanol ([a]2sD -17.2, 30.0 g, 46.0 mmol) in THF
(170 mL) was added dropwise. After the addition was com?lete, the mixture was stirred for 15 m before cau~iousl~ hea~ing to reflux for l h. The mi~ture was cooled to 0 C bero e adding dropwise ~ solution of brc~oacetic acid (27.3 g, 196.5 mmol) n THF (40 mL). The mi~ure was reflu~ed 2 days before cooling and carefully pourina in~o 600 mL ice water. The aqueous was washed with ether and acidified with HCl to pH 4, and extracted with ether. The combined organic extracts were washed with brine, dried over MgSO4, and evaporated to give a quantitative yield of crude product which was used in the next step without further purification.
~m (4S) Methy- 4-(2-fury1)-3-c~ Ln23~
Crude acid from example 84 (25 CJ, 118 mmol) was dissolved in ether and treated with excess diazomethane (generated by adding 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) to a mixture of 40% KOH (aq) and ether at 0 C).
., .
~; Excess dlazomethane was quenched with acetic acid after 30 :i m. Vacuum distillation gave 18.8 g (70%): [~] 25D -100;
bp 100-109 C ~0.5 mmHg); 1H NMR ~300 ~Hz, CDCl3) ~ 7.40 (lH, dd, J = 1 Hz), 6.34 ~lH, dd, J = 1 Hz), 6.29 (lH, dd, J - l Hz), 4.43 (lH, t, J = 7 Hz), 4.00 (2H, q, J = 16 :'' : , - . . . .. . . .. .
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Hz), 3.72 (3H, s), 1.92 (2H, m), 1.33 (4H, m), 0.89 (3H, t, J = 7 Hz); mass spectrum (FAB): 244 (M+NH4).
le ~6 S) ~-ButyL-4-(2-furyl)-3-oxaoct~Q~
A solu~ion of (S)-1-(2-furyl)-1-pentanol [[a]25D -15 (c 1, CHCl3), 30.0 g, 194.5 mmol] in 250 mL dry DMF was stirred at 0 C under dry nitrogen as KN(TMS)2 (0.5 M in ~oluene, 390 mL, 135 mmol) was added dropwise. After s.irr~ng 15 m, t-butyl bromoaceta~e was added. The .l m x~urQ was sti.red a~ 0 C for 2 h before slowly warming to rt and stirring overnight. The reaction mix~ure was cooled to 0 C, diluted with an equal volume of ether, and ~reated with 1 L saturated NH4Cl. The combined ether extracts were washed with saturated NH4Cl, 5% NaHCO3, and brine, dried over MgSO4, and evaporated to give 54 g crude product. Vacuum distillation gave 21.0 g (40%) pure product and a side fraction of 8.0 g (15~: [a~25D ~73 (c 1.19, CHCl3~; bp 110 C (0.5 mmHg~; lH NMR (300 MXz, CDC13) ~ 7.40 (lH, dd, J = 1 Hz), 6.34 (lH, dd, J = 3 Hz), 6.28 (lH, dd, J = 5 Hz), 4.44 (lH, t, J = 7 Hz), 4.37 (2H, 3, J = 21 Hz), l.9 (2H, m), 1.47 (9H, s), 1.4 (6H, m), 0.89 (3H, t, J = 7Hz); mass spectrum (FAB): 286 (M~NH4).
l4S! ae~zhydryl 4-(~-furyl)-3-oxaQc~a~oat~ ~
To a suspension of 4.08 g (165 mmol) of 97% sodium hydride in 50 mL of dry THF at rt was added 10.5 g (Ç8 mmol)of ~S) 1-(furyl)-1-pentanol. After addition, the reaction was heated at reflux temperature for 2 h, cooled to 0-5 C in an ice-water bath, and 9.5 g (102 mmol) of :
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2~3~92~ ~ -12q-bromoacetic acid in 50 mL of THF was added. After addition was complete, the reaction mixture was heated at reflux temperature for 2 d, cooled to 0-5 C 2nd water slowly added. The re2cture mixture was e~tracto~ ~ith ether. The aqueous layer was acidified with lN HCl to pH
5-6 and the crude acid was e~tract~ wi.;~ e_he-, dried (MgSO4) and concentrated to a crude oil.
Benzophenone hydrazone (13.3 g, 63 mmol) zn~ i9.7 y (68 mmol) of HgO in 1;0 mL o' hexane wer- sti_r_d ~o_ 24 h. The resulting purple solution w2s -rilt~r~d 2nd concentrated to 1/3 the volume. Tne c-u~e a_id in et:n~e-was added to the purple hexane solution or diphenyldiazomethane and was s~irred ror 24 h. E~c~ss acetic acid (5 mL) was added and the reaction stirred an additional 30 m, poured into saturated NaHCO3. After ethyl acetate extraction the crude benzhydryl ester ~19 g) was purified by silica gel chromatogr~phy usiny ~3:97) ethyl acetate:hexane as eluant to give 18 g (72% yield) of benzhydryl ester as a yellow oil.
[a~25D = -74.86.9o ~c 2.3, CHCl3); IR (film) 1740, cm~l; lH NMR (300 MHz, CDCl3) ~ 7.2-7.40 (m, llH), 6.95 ts, lH), 6.29 ~dd, J = 1.5, 3Hz, lH), 6.21 (br d, lH), 4.46 tt, J = 7 Hz, lH), 4.14 (d, J = 16Hz, lH) 4.01 (d, J = 16 Hz, lH), 1.77-2.05 ~m, 2H), 1.13-1.44 ~m, 4H), 0.86 (t, J
= 7Hz, 3H); mass spectrum ~FAB) 379 (M+H).
Anal. Calcd for C24H2604: C, 76.19; H, 6.87. Found: C, 76.94~ ~, 6.77.
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Example 88 (2S,4S) MethyL ~-henzyl-4-(2-furyl)-3-o:~oct~n~-2te ~ns (2~_4Sl Methyl 2-nenzyl-4-(2-rur~l)-3-~ er~oat~
(4S) Methyl 4-(2-furyl)-3-oxaoctanoate (5.0 g, 22.1 mmol) in 40 mL freshly distilled ~r - was a~.ded d_o?w se to a solution of NaN(TMS)2 (1.0 M in THF, 22.1 mL, 22.1 mmol) at -80 + 5 C. After 5 m, freshlv f~ltered (~:nrougr basic alumina) benzyl bromide (3.0 mL, 25.2 rumol) ~ as added dropwise maintaining the reaczion tem?era~lre at -8 + 5 C. Afte- 30 m, the reaction t7as w2 me~i to 0 C ro h before quenching with water. The mixture was extracted with ether. The combined ether extracts were washed witr saturated NH4Cl, 5~ NaHCO3, brine, and dried o~e_ MgSO4.
Purification of the residue by flash silica gel chromatography gave 1.2 g of the less polar (2S, lS) diastereomer and 1.6 g of the more polar (2R, lS) diastereomer, ~18 and 25%, respectively, based upon a 7%
recovery of unreacted starting material [~C~]25D -84 (c 1.14, CHCl3)]. (2~ ) diastereomer: [a]25D -74 (c 1.11, CHC13); lH N~R (250 ~Hz, CDCl3) ~ 7.19 (6H, m), 6.21 (lHr dd, J = lHz), 5.91 llH, dd, J = 1 Hz), 4.37 ~lH, t, J
= 7 Hz), 4.06 (lH, dd, J = 7 Hz), 3.69 (3E~, s) 2.94 (2H, m), 1.83 (2H, m), 1.29 (4H, m), 0.88 (3H, t, J= 7 Hz);
mass spectrum (FAB): 334 (M+NH4). (2~, lS) diastereomer:
[OC]25D -53 (C 1.23, CHCl3); lH NMR (250 MHz, CDC13) ~ 7.37 (lH, m), 7.27 (5H, m), 6.-38, (lH, dd, J = 1 Hz), 6.19 (lH, dd, J = 1 Hz), 4.08 (2H, m), 3.49 (3H, s), 2.98 (2H, d, J
= 7 Hz), 1.91 (lH, m), 1.72 ~lH, m)-, 1.2 (4H, m), 0.79 (3H, t, J = 7 Hz); mass spectrum ~F.~ 334 (M+NH4).
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WO 92/0~9 PCT/US9l/055 2 ~ 3 ~ ~ ~ 8 -126-. E~ample ~ 2~S, 4~) t-311tyl 2-~zyl -G- (?-~Yl~-3-o~aoc~a~oate ~n~
-' (2~, 4S) t-Butvl 2-b~nzyl-~-(2-furyl)-~=Qxa~ctanQate 4S)t-Butyl 4-(2-furyl)-3-oxaoctanoate ([a~25D -73 (c 1.19, CHC13), 10.0 g, 37.3 mmol) in 100 mL freshly distilled THF was added dropwise to a solution of NaN(TMS)2 (1.0 ~ in THF, 37.3 mL, 37.3 mmol) at -85 + 5 C. After 5 m, _reshly distilled and filtered (through bas'c alumina) benzyl bromide (5.0 mL, 42.0 mmol) was added dropwise malntai~ing the reac_ion temperature at -85 + 5 C. After 30 m, the reaction ~as warmed to 0 C for 1 h be-or~ ~uench~g with water. The mi~tu_e was e~tracted with ether. The com~ined ether extracts were washed with saturated NH4C1, 5~ NaHCO3, brine, and dried over MgSO4 ~ Purification by flash silica gel chromatography (1:1) ; ethyl acetate:hexane gave 2.1 g (15%) of the less polar (2S,lS) diastereomer, 2.4 g tl8%) of the more polar (2R,lS) diastereomer, and 2.0 g of a mixture of starting material and the two diastereomers. ~2S, lS) diastereomer: ~a]D25 -65 (c 1.19, C:HC13); 1H NMR (300 MHæ, CDC13) ~ 0.88 (3H, t, J = 7 Hz), 1.3 (4H, m), 1.40 (9H, s), 1 83 (2H, m), 2.93 (2H, m), 3.91 (lH, dd, J = 6 Hz), 4.38 (lH, t, J = 7 Hz), 5.92 (lH, d, J = 4 Hz), 6.22 (lH, dd, J = lHz), 7.20 16H, m); mass spectrum (FAB): 376 ~M+NH4). (2~ ) diastereomer: ~a]25D -30 (c 1.26, CHC13); lH N~R -(300 ~Hz, CDC13) ~ 0.79 (3H, t, J = 7 Hz), 1.15 (4H, m), 1.29 (9H, s), 1.69 (lH, m), 1.85 (lH, m), 2.95 ~2H, m), 3.98 ~lH, dd, J = 7 Hz), 4.10 (lH, t, J = 7 ~` Hz), 6.20 (lH, dd, J = 1 Hz), 6.28, (lH, dd, J = 1 Hz), 7.26 (5H, m), 7.36 (lH, dd, J = 1 Hz); mass spectrum (FAB): 376 (M+NH4).
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W~92i~29 2 ~ 6 $ PCT/US91/~55 ' E.Y~m~le 90 (2S 4S) ~er7`~ydr~1 2-~e~zy~ 2-furyl)-3-oxaocta~Qa~e -~ (4S) Benzhydryl 4-(2-ruryl)-3-oxaoctanoate (2.0 g, 5.28 mmol) was dissolved in 20 mL freshly distilled THF
and cooled to -ao ~ S oc under dry argon. Sodium bis(trlmethylsllvl)- amide (1.0 M in THF, 5.6 mL, 5.6 mmol) was slowlv added keeping the temperature at -80 ~ 5 C. After }5 m, ;^reshly distilled and filtered (through basic alum-..a) ben~yl bromide (0.7 mL, 5.81 mmol) in HMPA
~ mL) was added dropwise maintaining the reaction temperature a. -75 + 5 C. After 15 m, the reaction was allowed to wa~m to 0 C for 1 h before quenching with water and extraction with ether. The combined ether extracts were washed with saturated NH4Cl, 5% NaHCO3, brine,dried over MgSO4, and purified by flash silica gel chromatography to give 771.3 mg (31%): [a]25D -65.5i lH
NMR (300 MHz, CDC13) ~ 0.81 (t, 3H, J = 7 Hz), 1.22 (m, 4H), 1.80 ~m, 2H), 2.91 (m, 2H), 4.12 (dd, 1~, J = 9 Hz), ; 4.30 (t, lH, J = 7 Hz), 5.86 (m, lH), 6.19 (m, lH), 6.69 (5, lH), 7.2 (m, 16H); mass spectrum (FAB): 486 (M+NH4).
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~2R!4.S) Benzhydxyl 2-Renzvl-4-~?-~u~yl~-3-QxaoctanQate Using the procedure in example 90 and (4S) ben7hydryl 4-(2-furyl)-3-oxaoctanoate ~5.0 g, 13.2 mmol), THF (50 mL), sodium bis(trimethylsilyl)amide (1.0 M in THF, 14 mL, 14 mmol), and benzyl bromide (1.7 mL, 14 mmol) in 10 mL
HMPA gave (2R,4S) benzhydryl 2-Benzyl-4-(2-furyl)-3-oxaoctanoate, 645.6 mg (10%) and 723 mg (12~) of the (2S
4S) diastereomer which was identical to the sample .
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prepared in example 90. (2R,4S) dlastereomer: [a] 25D ~
34.8 (c 1.12, CHCl3); lH NMR (300 .~Hz, CDCl3) ~ 0.78 (t, 3H, J = 7 Hz), 1.12 (m, 4H), 1.69 (m, lH), 1.83 (m, lH), 2.98 ~m, 2H), 4.11 (t, lH, J = 7 H~), 4.21 (dd, 1;~, J = 3 Hz), 6.07 (m, 2H), 6.72 (s, lH), 7.26 (m, 15~); mass spectrum (FA8): 486 (M+NH4).
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N-4-~etho~ymetho~y~i~erid7ne .~ude ~- (2~ 4s) ~ enz-~ -a-( 2-f~7ryl) -3-ox;70ct~ .c ~i (2S,4S) Benzhydryl 2-benzyl-4-(2-furyl)-3-oxaoctanoate (502 mg, 1.07 mmol) w2s dissolved 7n EtOAc (3 mL) and shaken under 4 atm. H2 witr. 10% Pd~C (50 mg) a~
room temperature. Filtration and evapora~ion gave 468.
mg of product which contains diphenylmethane: 1H NMR ~
0.88 (t, 3H, J = 7 Hz), 1.29 ~m, 4H), 1.83 (m, 2H), 2.99 (m, 2H), 4.42 (m, lH), 4.53 (dd, lH, ~J = 8 ~z), 5.96 (d, lH, J = 3 Hz), 6.22 (dd, lH, J = 3 Hz), 7.21 (m, SH); mass spectrum (FAB) 320 (M+NH4).
The product from above reaction, 4-methoxymethoxy-piperidine (0.16 g, 1.07 mmol), and 4-hydoxybenzotriazole (0.44 g, 2.89 mmol) were dissolved in DMF (10 m~) and cooled to -23 C under dry argon. EDC (0.31 g, 1.61 mmol) was added, and the reaction was allowed to warm to rt overnight. 5% NaHCO3 was addedt and the mixture was extracted with EtOAc. The combined EtOAc e~tracts were washed with water and brine, dried over MgSO4 and purified by flash silica gel chromatography ~1:1) ethyl acetate:hexane) to give 230 mg (50%): [a]2~D -24.1 (c 1.02, CHC13); 1H NM~ (300 MHz, CDCl3) ~ 0.86 (t, 3H, J = 7 Hz), 0.89 ~m, lH), l.11 (m, lH), 1.28 (m, 5H), 1.53 (m, , ~
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lH), 1.85 (m, 2H~, 2.95, (d, 2H, J = 7 Hz), 3.25 (rn, lH), 3.36 (s, 3H), 3.48 ~m, lH), 3.6a (m, 3H), 3.93 (m, lH), 4.31 (m, 2H), 4.66 (s, 2H), 6.07 (dd, lH, J = 10 Hz), 6.29 (m, lH), 7.21 (m, 6H); m~ss spectrum (FAB) 430 (M+r~).
Exam~le 92 N-a-M~tho~ymet~oxyp~ in~ A~nld~ of (2~ S~ 2-~
Carb~ Cta?.O''' ZC r~
The compound prepared from exampi~ 52-~ (326.7 mg, 0.761 mmol) was dissolved in 5 mL glaclal :iOAc wi_h 2.5 m EtOAc and cooled in an ice bath as ozone was bubbled into the solution. After 30 m, 1 mL of water ~as added, 2nd the mixture was allowed to stir at -t ove-~.~ght. The reaction was evaporated to dryness, partitioned between e~her and 5~ NaHCO3, and extracted wlth 5~ NaHCO3. The combined aqueous extracts were carefully acidified to pH 3 with 1 M HCl and extracted with EtOAc. The EtOAc extracts were combined, dried over MgSO4, and evaporated to give crude product which was dissolved in a minimum amount of EtOAc and triturated with CHCl3 to remove most of the polar impurities to give 125.5 mg (40%): [CC]25D -17.1 (c 1.13, CHC13); lH NMR (300 MHz, CDCl3) ~ 0.85 (m, lH), 0.89 (t, 3H, J = 7Hz), 1.32 (m, 6H), 1.61 (m, lH), 1.79 (m, 2H), 3.06 (m, 2H), 3.25 (m, lH), 3.38 (s, 3H), 3.47 (m, lH), 3.58 (m, lH), 3.74 (m, lH), 3.86 ~m, lH), 3.98 (m, lH), 4.57 (m, lH), 4.68 (s, 2H), 7.29 (m, 5H); mas spectrum (FAB) 408 (~+H).
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E~ 23 (3 5S) 3.5-Dihen~yl-~ r -hutQxycarbo~ -2H-lr4-Qxazi~
~ 2-one ; To a solution of 17 ml (lM, 17 mmol) of sodium bis(hexamethylsilyl) amide in THF cooled to -70 C
(limited liquid nitrogen-diethyl ether bath) was added 5g (17 mmol) of 4-(tert-butyloxycarbonyl)-5S-(benzyl)-2H-1,4-oxazin-2-one (PCT Patent Application No. W090/03971, published A~ril 19, 1990) in 20 ml THF. Af_er addition was com~lete 5.97 ml of dry HMPA was added. The reaction was s,'rred fo- 15 m between -70 and -30 C and S.1 ml of benzyi bromide was added. The reac.ion was stirred at -80 to -90 C for a 40 m period. A dilute solulion of sodium ~` bisulfate was added and the reaction warmed to rt, poured into chloroform and the aqueous layer separated. The aqueous layer was extracted once with chloroform. The combined chloroform extracts were washed once with water,dried (MgS04), and evaporated to give 10.9 g of an oil. The pure lactone was obtained by silica gel chromato~raphy using ethyl acetate:hexane as eluent: 3.9 g (60% yield) of a white solid. mp 149-150 C; [a] 25D =
J +105.07 (c 1.28, CXCl3); mass spectrum (FAB) 399 (M+NH4).
Anal. Calcd for C23H~7N04: C, 72.42; H, 7.13; N, 3.67.
:~, Found: C, 72.76; H, 7.25; N, 3.67.
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(3R,5R) 3.5-Dibenzyl-4-(ter~-butoxy~a~onyl)-2H-1.4-oxazin ~ To a solu~ion of 53 ml (lM, 53.1 mmol) of sodium .. bis(hexamethylsilyl) amide in T~F cooled to -70 C
1 (limited liquid nitrogen-diethyl ether bath) was added `~ 15.8 g (54.2 mmol) of 4-(tert-butyloxycarbonyl)-SR-::
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(benzyl)-2H-1,4-oxazin-2-one (prepared using the procedure disclosed in PCT Patent Application No. WO90/03971, publlshed A~ril 19, 1990, example 153 and replacing L-phenylalan-nol with 3-pnenylalaninol) in 63 ml THF. After addition was complete 18.6 ml of dry HMPA was added. The reaction was s_lr-ed for 5 min between -70 and -80 C and 16 ml of benzyl bromide was added. The reaction was stirred at -80 to -90 C for a 40 m period. A dilute solu.ion Gf sodium bisul~ate was added and the reaction warmed to r temperature, poured into chloroform and the aqueous la~e- separated. The aqueous layer was extracted once with cnloroform. The combined chloroform extracts were washed oncç with water, (dried with MgSO4), and evaporated to give 23 g of a crude oil. The pure lactone was obtained by silica gel chromatography using ethyl acetate:hexane as eluent: 12 g ~58%) as white solid: mp 149-150 C; ~a]25D = -107.9 (c 1.28, CHC13); IR (CHCl3) 1743, 1690 cm~l; lH NMR (DMSO-d6, 55 C) S 7.31 (m, 4H), 7.24 (m, 2H), 7.15 (m, 4H), 4.54 (dd, lH, J = 2, 3.5 Hz), 3.88 (d, lH, J = 6Hz), 2.89 (dd, lHf 2, 7.5 Hz), 2.68 (dd, 1~., J = 6, 9 Hz), 1.a6 (s, 9H); mass spectrum (FAB) 382 (M~H).
`-i Anal. Calcd ror C23H27NO4: C, 72.42; H, 7.13; N, 3.67.
~` Found: C, 72,21; H, 7.1~; N, 3.65.
, ?1Q 45 (2~. 4S) ~- ~(tert-Butnxyca~bQnyli a7al -?, 4-di~ y1-1~5-_ ., ~=il~s~
~ A solution of 0.8 g (2.1 mmol) of the product of ~, Example 93 in 5 mL of THF and 4.1 mL (lM, 4.1 mmol) of diborane were stirred in an ice wate- ba~h for 18 h.
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~ W092/0~29 PC~/US91/0~
~,o~9~68 Methanol was added followed by aq. sodium bisulfate. The product was extracted ~ith ethyl acetate, dried (MgSO4), and evaporated. The crude residue was purified bv ~lash chromatography using (1:2) ethyl acetate:hexane to afforded 72? mg (89%) of product. [a]25D = -85.03 (c 0.63 CHCl3); IR (CDCl3) 3120-3720 (OH), 1700 (carbamate C=O) cm~l; lH NMR (DMSO-d6) 7.33-7.09 (m, 10~, Co~5), 1.~4 (s, 9H, t-butyl); mass spectrum (FA~) 385 (M',~), Anal. Calcd for C23H31NO4: C, 71.68; H, 8.05; N, 3.63. Found: C, 71.25; H, 8.07; N, 3.61.
(2~.4~) 3-~t~rt-3uto~yca~honyl) 2Z2 1-2 4-~b~yl-1 5-~a~
Using the procedure in example 95 and replacing the the product of Example 93 with the product of Example 94 gave the title compound.
, xam~le 97 2R,4R)-3-Aza-2,4-dibenzyl-1,5-penta~ediQl ~oron Complex .3, A solution of 0.846 g of ~2R, 4R) N-Boc amino diol ~ from example 96 was stirred with 10 mL Or 4M HCl dioxane -~ at room temperature for 1 h. The solvents were evaporated to give a white solid. Aqueous sodium bicarbonate was ~ ~ .
added and the amine was extracted with chloroform. The chloroform extracts were dried (MgSO4), filtered, and concentrated to give a clear oil. Triethylborate (0.37 mL, 1 equivO) was added to the oil and the homogenous solution solidified. The solid was heated at 100 C for 2 h under high vacuum to remove excess ethanol to give the boron complex 13. mp 95-100 C~ llB N~ (CH2C12, BF3 E.20 '' . . .
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internal standard) 10.5; mass spectrum ~F~s) 311 (M+NH4), 286 (M~H, amino diol).
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(5R) 4-(tert-Butoxyc~rbonyl)-2-pher.~ 2H~' 9~ .-2-one The title compound was prepared using the ^-ocedure disclosed in PCT Patent Application No. Wo90/0397i, published Aprll 19, 1990, e~ample 153 and re?l~ ~g L-phenylalaninol with D-phenylglycinol to g~e ~r~ ces red product (see J. Dellaria et al. Tetra.~edron ~ s 1988, 29, 6079-82).
~ .
(2R) 3-Aza-2.5~-triphenyl-1 5-~e~ n~ ol Re-^^ C~m~lex A solution of 2.7 g of the product o~Example 98 was stirred with 10 mL of 4M HCl in dioxane. Solvents were removed under reduced pressure to give ~he amine salt.
The crude salt was suspended in THF, cooled in an ice-water bath and 5 equiv. (45 mL) of lM phenylmagnesium bromide was added and the reaction m:Lxture stirred for 24 h at room temperature. The crude product was purified by flash chromatography using (1:1) etnyl acetate:nexane then ~2-5:98-95) methanol:ethyl acetate to give t~e amino diol.
Recrystallization of the amino diol f_om toluene:hexane gave a white crystalline solid, 500 mg. mp 117-19 C;
[a]25D = -28-5o (c 0.91, CHC13); IR ~C~C13) 3720-3200 (OH) cm~1; lH NMR (CDCi3) ~ 7.47-7.19 (m, 15~), 3.82 ~dd, J =
4,7 Hz, lH), 3.70 (dd, J - 4, 12 Hz, lH), 3.55 (dd, J = 7, 12 Hz, lH), 3.27 (d, J = 12Hz, lH), 3.18 (dd, J = 12 Hz, lH), 1.70-1.48 (br s, lH); mass spe~t-um (FAB) 334 (M+H).
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Anal. Calcd for C22~23NO3: C, 79.27; H, 6.90; N, 4.20.
Found: C, 79.27; H, 6.84; N, 4.14.
Using the procedure in example 97, and 109 mg of (2R) 3-aza-2,5,5-triphenyl-1,5-pentanediol that was prepared above and 0.055 mL (1 equiv.) of triethylborate in 2 mL of THr gave the boron complex. mp 125-32 C; mass spectrum (FA~) 334 (M+H for amino dlol), 342 (~+H), 359 (M+NH4).
ExamRl~ 100 "-?.~ Vi' 3--'t~7~r_t~1~0n ~r (S)-l-('~ en~r,anol Using the procedure in example 83~, and replacing (3a3~)-1,3,3-trlphenvl pvrrolidino [1,2-c] [1,3,2]
o~.a~aborole with the boron catalyst from example 98 gives the product.
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~lternative PreDaLa~iQn of (S)-1-(2-Fury~ ent.anol Using the procedure in example 83B, and replacing (3aR)-1,3,3-triphenyl pyrrolidino ~1,2-c] [1,3,2]
oxazaborole with the boron catalyst from example 99 gives the product.
The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids.
These salts include but are not limited to the following:
acetate, ad1pate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptonate, glycerophosphate, hemisulfate, heptcnate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, ~`'` ' "
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2~92~ , 2-hydroxi~-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxaLate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Also, the basic nit-ogen-containing groups can be quaterni~ed with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, dietnyl, dibu~yl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and steary chlo-ides, ~romides and icdides, aral:~l halides like benzyl and phenethyl bromides, and o~hers. Water or oil-soluble or dispersible products are thereby obtained.
Examples or acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases.
The compounds of the present invention can also be used in the form of prodru~s which include esters.
.
Examples of such esters include a hyd-oxyl-substituted compound of formula (I~ which has been acylated with a blocked or unblocked amino acid residue, a phosphate function, or a hemisuccinate residue. The amino acid esters of particular interest are glvcine and lysine;
however, other amino acid residues c2n also be used. These esters serve as prodrugs of the compounds of the present " , . .
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W092/0~29 P~T/~.~91/OS5~
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2 ~ 39i~v~ention and serve to inc-e~se the solubility o-^ these substances in the gastrointestinal trac~. The ~rodrugs are metabolically converted ln v~vo to h2 pa_ent compound o~
formula (I). The preparation of th~ ~_o-c-ug es-ers is carried out by reacting a hydro~v'-slbsli-uted c^~v^und c_ formula (I) with an activated amino acvl, phosphoryl or hemisuccinyl derivative. The resul_in? ~-odue_ s ~hen deprotected to provide the desi.~d _r__-u~ es~e_.
The novel compounds of the prese~ r.ver.tio?. possesses an excellent degree o~ activity ar.d s~e^i~~ ^ity in ~reatlna hypertension in a human or other ma?~al. The novel - compounds of the presen~ lnven.tlor _re ~ use-_1 or treating congestive heart failure in _ human or o~her ` mammal. The present invention also relates to the use of the novel compounds of the invention for treating vascular abnormalities in a human or other mammal, especially those vascular diseases associated with diabetes, such as diabetic nephropathy, diabetic neuropathy and diabetic , retinopathy. The compounds of the invention are also useful for the treatment of renal diseases in a human or other mammal, in particular acute and chronic renal failure. The compounds of the inver.tion are also useful for the treatment of psoriasis in a human or other mammal.
The ability of the compounds of th~ invention to inhibit human renal renin can be demonstrated Ln vit~ by reacting a selected compound at varied concentra~ions with human renal renin, free from acid proteolytic activi~y, and with renin substrate ~human angiotensinoger.) at 37 degrees ; C and pH of 6Ø ~t the end of the incubation, the amount ~` of angiotensin I formed is measured bv radioi~munoassay and the molar concentration required to cause 50% inhibition, ...~, ..' .
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W~92/0~29 PCT/US91/055~
2~o92~8 : expressed as the IC50 is calculated. When tes~ed ln accordance with the foregolng procedure, the compounds of the invention demonstrated ICso's _n tne -ange of iC-~ M as seen in Table 1.
T.~
:: 2c 2.1 3 1.3 Sb 2.9 6c 1.8 7b 0.78 `, 10 3.0 11 2.4 12b 2.6 16 1.8 . 17 1.5 :~ l9c 1.6 ;`~ 20 1.3 21 1.3 22c 3.4 ' 23 1.1 ^ 24 l.0 .` 25 ~ 1.0 : 27 0.8 29b 1.2 , 30 2.3 31 2.C
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, 49b 2.8 Slb '.0 52b 1.4 53b 1.2 55b 2.4 56b 1.1 57b 0.94 62b 2.4 73b 1.2 i~
, 77d 5.2 Total daily dose of a compound o- the invention -: administered to a human or other mammai in single or divided doses may be in amounts, fo- e:;ampIe, from 0.001 to 10 mg/kg boày weight daily and more usually 0.01 to 10 mg.
.~ Dosage unit compositions may contal~. such amounts of submulti?les thereof to make up the da'ly dose.
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wn 92/03429 2 ~o~ 2 6 ~ PCT/US91/055 The amoun-t o~ ac~ive ingredient that may be combined with the carrier materials to produce a single dosage form wi'l varv depe~dins u?on the host treated and the particular mode or a~ministration.
It ~ill be ur.derstood, howeve-, that the specific dose level for anv par~icula- patient will depend upon a variety o- fac~ors including Lhe ac~-vity of the specific compound em?loye~, the age, body ~elgh., general health, sex, diet, ~- tlme o- a~inist-a-ion, route of adminis~ration, rate of exc-etion, drug combina-tion, and the severity of the pa-~icular disease undergoinc therapy.
~ he compc~n~s o- :~e ?-e3ent nven. on may be a~-"inis_ered oraliy, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations containing conven~ional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired.
Topical administration may also involve the use of ~; transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, ~` intramuscular, intrasternal injection, or infusion techni~ues.
~ Injectable preparations, for example, sterile -~ injectable aqueous or oleagenous suspensions may be formulated according to the ~nown art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solu.ion or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solven~s that may be employed are water, Ringer's ', :, ': '. , , :' : . ~ .~
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~ 2 &~ -140-solution, and isotonic sodium chlor de sol-~tion. In addition, sterile, fixed oils are conventinally employed as a solvent or suspending medium. Fo- this ?U-?ose anv blar.à
fi~ed oil may be employed including syntnQ~ic mono- or diglycerides. In addition, fat~v ac-ds suc`n as O'IQlC ao d find use in the preparation of injectables.
Suppositories for rectal a~n-. s~-a_ on o- -h- d_ug can be prepared by mixing the à-ug ~- r h _ SU' _a `1-nonirritating excipient such as co_oa bu~e- and polyethylene glycols which are so~ - a_ __d n2-i temperatures but liquid at the rec-a1 tem?era~ure and will therefore melt in the rectum and re e~se -:~ i-ug~
Solid dosage forms for oral a~minis--2tiGn may- in^ UdQ
capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or-starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with ente- c coa_ings.
Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
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; The present invention also rela~es to the use of novel compounds, pharmaceutical composi~lons containing the nove , : ;.
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WO 92io3429 ~ ~ ) ~ ~ ~' 8 PCT/US91/05;~
compounds and the use of the compounds and com?ositions to inhlbit renin for treating glaucoma or reàucing and/or controlling intraocular pressure. The present lnvenLior also relates to the use of novel compounds and pharmaceutical compositions which nhibit reni-. in combination with a beta-adrenergic antagonis. agent or an angiotensin converting enzyme inhibiting com?cun- ~o-treating glaucoma or reducing anà/or con -_l -s.g intraocular pressure.
The present invention also re ates ~o pha-maceu_ic__ . -~
compositions for treating the inc-ease in intraocular pressure associated with the a~mi- s,-atlc- o- s~e-olda' antiinflammatory agents comprisiny novel -enin nh'_i~ .ng compounds in combination with a steroidal antiinflammatorv compound in a pharmaceutically acceptable vehicle.
The present invention also relates to a kit comprising in individual containers in a single package a novel renin inhibiting compound in a suitable pharmaceutical vehicle and a steroidal antiinflammatory compound in a suitable pharmaceutical vehicla and/or a beta-adrenergic antagonist agent in a suitable pharmaceutical vehicle or an angiotensin converting enzyme inhi~iting com~ound in a suitable pharmaceutical vehicle. ' The compositions of the invention are administered as topical or systemic pharmaceutical compositions when used for treating or reducing andtor controlling intraocular pressure.
These compositions are preferably a~ministered as topical pharmaceutical compositions suitable for ophthalmic administration, in a pharmaceutically acceptable vehicle such as pharmaceutically acceptable s.erile aqueous or `
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nonz~l-Q^us solutions, suspensions, emulsions, cintments and solld inserts.
E~.am?les of suitable ?hzrmaceutically acceptable veh cies for o~n~nalmic administration are wate-, propylene glycol and other pharmaceutically acce?.able alcohols, sesame or peanut oil and other pharmaceutically acceptable vegQt~le oils, pe_-olQum jelly, wa~er soluble op:._hz`..~^ o~ ca lv a^cep~able non-~oxic polymers such as methyl cell~lose, car30xvme~hyl ce'lulose salts, hy~-o.;;e_.y ce~lulose, hya-oxyp_o~vl cellulosei acrylates SUC- 2S polvacrylic acid salts; ethylacrylates;
polvac-ylam des ~.z~ural ?roducts slch as gela_~ ?., Z'C~.n2-eS/ pec~ins, ~-agacanth, karaya, agar, aczcia;
sta-ch derivatives such as starch acetate, hydroxyethyl sta-ch ethers, hydroxypropyl starch, as well as other synthetic derivatives such as polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether, polyethylene oxide, carbopol and xantham gum; and mixtures of these polymers.
Such compositions may also contain adju~ants such as buffering, preserving, wetting, emulsifying, and dis?ersing aqents. Suitable preserving agents include antibacterial agents~such as quaternary ammonium com?ounds, phenylmercuric salts, benzyl alcohol, phenyl ethanol; and antioxidants such as sodium metabisulfite, butylated hydroxyanisole and butylated hydroxytoluene. Suitable buffering agents include borate, acetate, gluconate and phosphate buffers.
The pharmaceutical ophthalmic compositions of the invention may also be in the form o- a solid insert. A
solid water soluble or water swell=31e polymer such as dextran, hydro~yloweralkyl dextran, czrboxymethyl dextran, :--W092/~29 ~ ~ 9 2 ~ g PCT/VS91/055 hvdroxyloweralkyl cellulose, loweralkyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, dextrin, starch, polyvinyl pyrrolidone and polyalkylene glycols may be used as ,he carrier for the drug.
Dosage levels of the active compound in the compositions for treating glaucoma or reducing and/or controlllng in.raocular pressure may be varled so as to ob~ain a d-a'~ed th-_a~eutic response to a particular composi~ion. ~-enerally, the active compound will be aamlnis~e-e~ as an isotonic aqueous solu~ion o_ from 0.vOOOl to 1.0 ~w/v) percent concentration. More ~re~erably the 2c.ive com~ound will be admi?.is.ered as an ~so~-onlc aqueous solu~ion of from 0.00001 to 0.1 (w/v) percent concentration.
The term "controlling intraocular pressure" as used herein means the regulation, attenuation and modulation of increased intraocular tension. The term also means that the decrease, in the otherwise elevated intraocular pressure, obtained by the methods nd compositions of the invention is maintained for a signi:Eicant period of time as, for example, between consecutive doses of the composition of the invention.
The novel renin inhibiting compounds of the invention may be the only active ingredient for controlling intraocular pressure in the methods and compositions of the invention or may be used in combination with other :.
ingredients which control intraocular pressure such as beta-adrenergic antagonist compounds.
The term "beta-adrenergic antagonist" as used herein means a compound which by binding to beta-adrenergic plasma membrane receptors reduces or elim na-es sympathetic , .
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W~92/0~29 P~T/US91/055 activity or blocks the effects or exogenouslv aA~minsterQdcatecholamines or adrenergic drugs. E~am~les of beta-adrenergic antagonists are atenolol! meto?-o?ol nadolol, propranolol, timolol, labetalol, be_a~oio , ca-_eolol and dilevalol and pharmaceutically acre?table s21_s _herQo~.
Most preferably the beta-adrenergic antagonis~ is Limolol.
Timolol is currently used fo- ~reati-!g g'~uc3m- o-reducing and/or controlling intraoc~,a- p.~ Sa ' `~_~ `OU., i _ has a number of adverse side effecta. Accorcin~
administration o- a composition crm--i Si-l~ â SC.~ ~-nz~ion __ a be_a-adrenergic antagonist and a novel renin innibitins compound OL the invention could p_educQ a _Q~US: ' 0?. i~.
intraocular pressure equivalent tc -:~at ?-od ^e~ bv 2 be~a-~ adrenergic antagonist alone, but aL a reduced dose level or ., the beta-adrenergic antagonist. ~nis will resul_ .in a reduced level of the beta-adrenergic antagonist related adverse side effects.
: The combination composition is administered as a single dosage form containing both the novel renin inhibitor and the beta-adrenergic an~agonist. The beta ~- adrenergic antagonist may comprise from 5 mg to about 125 mg of the composition of the inventor.. The pre~erred ranges of the components in ~he composition of the invention in unit dosage form are:
Renin inhibitor: 1 ng to 0.1 mg Beta-adrenergic antagonis~: 5 us to 125 ug When the be~a-adrenergic antagonist and the novel renin inhibitor are administered as separate compositions the present invention relates to a kit comprising in two separate containers a pharmaceutically acceptable beta-adrenergic antagonist compositior. and a pha."iacQL_ically `' :
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, acceptable novel renin inhibitor composition, in a sin~ie package. A preferred kit comprises a beta-adrenergic antagonist composition and a topical ncJel renin nhiD ~o~
composition. A most preferred ki. co..p_ises a ~o?ical ophthalmological beta-adrenergic antagonis_ compositio-. an.
a topical ophthalmological novel renin inhibi_or composition.
The novel renin inhibitlng compou-.-s o ~ e-. -~may also be administered in comrina~ o^ wi_:~ an an~io.~~.s-~
converting enzyme (ACE) inhibitln~ com_o~n~. ~A~ S __ angiotensin converting enzyme inhlbi_ing compounds are captopril and enalapril. As was --evi3usl~; menrione~
inhibitors have some undesirable s de e~fe~ts.
Accordingly, administration of an ACE inhibitor in combination with a renin inhibitor could produce a reduction in intraocular pressure greater than or equivalent to that of an ACE inhibitor alone, but at a reduced dose level of the ACE inhibitor. This will result in a reduced level of the ACE inhibitor related adverse side effects.
The combination composition is administered as a single dose form containing both the novel renin inhib o-and the angiotensin converting enzyme inhibitor. The ACE
` inhibitor may comprise from 5 ng to about 50 ug of the compositon of the invention. The prer^erred ranges or t;~e components in the composition of the invention in unit dosage form are: ~
Renin inhibitor: 1 ng to 0.1 mc ACE inhibitor: 5 ng to 50 ug When the ACE inhibitor and the novel renin inhibi.or are administered as separate composltlons the presen.
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~nver.lion re'ates to a kit comprising in two se~arate containers a pharmaceutically acceptable ACE inhibitor com?osition and a ~harmaceutically acceptable novel renin inhibitor composiLion, in a single package. A preferred k ~ comprises an .~.C~ inhibitor co~?osition and a topical novel renin inhibitor composition. A most preferred kit c^m?rises a ,opical o?hthalmolog cal AC~ inhibitor com?os ~ion and a .o~ical novel _e~in inhibitor composition.
~ osaye levels or Lhe active compounds in the com?osltions or the invention ma~ oe varied so as to obtain 2 des -ed the zpeutic res?onse de-ending on the route o a~m n s~ra~io~, seve ity of the disease and the response of ~he patient.
Topical, ophthalmic and systemic administration of steroidal antiinflammatory agents can cause an increase in intraocular pressure. The increase in intraocular pressure can be reduced by the administration of a novel renin inhibiting compound of the invention. Steroidal antiinflammatory agents include hydrocortisone, cortisone, prednisone, prednisolone, dexamethasone, me_hy'?-ednisolone, triamcinolone, betamethasone, alclometasone, flunisolide, beclomethasone, clorocortolone, difloxasone, halcinonide, fluocinonide, fluocinolone, desox}metasone, medrysone, parame~hasone, and fluorometholone, and their pharmaceutically acceptable salts and esters. Preferred stero dal antiinflammatory agents are hydrocortisone, prednisolone, dexamethasone, medrysone and fluorometholone and ~heir pharmaceutically acceprable salts and esters. The novel renin inhibitor is administered after use of a steroi~al antiinflammatory ., .
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W092/0~29 % ~ PCTJUS91/0~5 agen o_ zt the same time, causing reduction and/or control or intraocular pressure.
Various combinations of a to~ical or oral or ~njectibie aosage form of a steroiàal antiinflammatory agent and a topical or oral dosage form of the novel renin innibiLor mav be used. A preferred combination comprises a -Gpical s eroidal antiinflammatory and a topica' novel renin in:nlib__or. More preferred is a topical c~h,halmic dosage form comprisin both a steroidal antiinflammatory and a novel -e~.in inhiblLor.
Wnen ~he steroidal antiinflammatory agent ar.d the nove'l renin. in:~ibito- a-e administered as sepa a e _om~o_ -ions the p-esent invention relates to a ~it com?rising in two separate containers a pharmaceu~ically acceptable steroidal antiinflammatory agent composition and a pharmaceutically acceptable novel renin inhibitor composition, in a single package. A preferred kit comprises a steroidal antiinflammatory composition and a topical novel renin inhibitor composition. A most preferred kit comprises a topical ophthamological steroidal antiinflammatory composition and a topical ophthamological no~-el renin inhibitor composition.
The combination composition of the invention may contain from about 0.00001 to 1.0 (w/v) percent of the novel renin inhibitor for combined or separate to~ical a~ministration. More preferably the amount of the novel -enin inhibitor is about 0.00001 to 0.1 (w/v) pe;cent of the composition. The amount of the novel renin inhibitor in a unit dosage form for topical administratior. to the eye is from about 5 ng to about 0.5 mg, preferably f-om about 5 ng to abouL 25 ng. The dose requi-ed will depend on the . .
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G~ 198-potency of the particular novel ren-î inhibitor, the severity of the intraocular press~re lncrease ar.~ tne response of the individual patien The combination composi~iorl o_ -`-_ inve-n i^-. may contain from about 0.05 to 1.5 ~w/~,) ?ercen_ o- ~:ne steroidal antiinflamr.atory Lor cor3 --~ o- se~ar^-_e topica administration. ~he amount of t:~- s_e-oid2 antiinflammatory in a un_ dosage -s=~
administration to the eye is rrom z^^~ _v ~g ._ a^o~~ 6~v ug The dose required wi' àepen~ -- ~:^e _c ^-._ ^ _r_ par_icular steroidal antiinflamm2-~ he seve-~ y o_ ,;~-disease and the response or the --d_v -~al ~C'-iQ-.-.
When the ste-oidal antiinfla.~-a-~ y a5er.~ c- :~e combination therapeutic method or ~he invertion is i~ administered other than ophthalmically, appropri2.e doses are well known in the art.
The compositions of the invention may include other therapeutic agents in addition to the novel renin inhibitor, and other agents which re~uce and/or control intraocular pressure~
The effect on intraocular pressure of the novel compounds of the invention can be de~e-~ined in ~abbi~s by using the following method.
E~f~cts of To~ic~ minis~~-ed ~e~ ~ rnhl~ _ na (`oln~ound ~ raocula~ ?ressll~o ~r ?~abb~r~:
~ a. ~hQ~ -The antiglaucoma 2e~ ivity of the compounds - was tested by measuring the efrec~ on ln~raocular pressure in rabbits as described by Tinjum, A.M., Acta Ophthalmologica, ~n, 677 (1972). Male albino, New 2ealand rabbits were placed in restrainins -e; -es ar.d the . . ..
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intraocular pressure was measured w th an =pplamatic tonometer. Exactly 0.1 ml of an isotonlc s~line solution containing a test compound was ins.llled into the conjuctival sac and the intraocular pressure was measure~
at 5, lS, 30, 60, 90, 120 and 180 minutes afte-wards.
The ability of a compound of ~:~e invention to trea.
vascular diseases, especially those assoc ated ~.~ith diabetes, can be demonstrated by compa~ing -- na-~! prcrei~.
excretion in control diabetic Wista rats with urinarv protein excretion in diabetic Wis.a- ~a.s trea~e~L ~1Lh a compound of the invention. Wistar rats are made diabe~lc by streptozocin treatment.
The present invention is also iir-c~_d to ~h~ us~ o 2 compound of the formula I in combination with one or more ~:
cardiovascular agents independently selected from diuretics, adrenergic blocking agents, vasodilators, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, potassium channel activators, antiserotoninergic agents, thromboxane synthetase inhibitors, angiotensin II ~AII) antagonists and other agents useful for treating (in a human or other mammal) hypertension, congestive heart fail~-e, vascular diseases related to diabetes or for treating renal diseases sucA as ~ acute or chronic renal failure.
-~ Representati~e diure~ics include hydrochlorothiazide, `~- chlorothiazide, acetazolamide, amiloride, bumetanide, benzthiazide, ethacrynic acid, furosemide, indacrinone, ~;~ metolazone, spironolactone, triamterene, chlorthalidone and the like or a pharmaceutically acceptable salt thereof.
Representative adrenergic blocking agents include ~. phentolamine, phenoxybenzamine, pxazosin, terazosin, .:-..' , ~, :
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WO 92/03429 PCT/US91/0~24 20~2~
tolazine, atenolol, metoprolol, nadolol, propranolol, timolol, carteolol and the like or a pharmaceutlcally acceptable salt thereof.
Representative vasodilators include hydralazine, minoxidil, diazoxide, nitroprusside, flosequinan and the like or a pharmaceutically acceptable salt thereof.
Repres2ntative calcium channel blockers include amrinone, bencyclane, diltiazem, fendiline, flunarizine, nicarà~pine, nimodipine, perhe~ilene, verapamil, gallo~amil, ni_edipine and the like or a p;~armaceutically acce?table salt thereof.
~ epresentative ACE inhibitors include captoDril, er.alapril, lisinopril and the like or a pharmaceutically acceptable salt thereof.
Representative potassium channel activators include pinacidil and the like or a pharmaceutically acceptable salt thereof.
Representative antiserotoninergi.c agents include ketanserin and the like or a pharmaceutically acceptable salt thereof.
Representative angiotensin II antagonists include DUP527 and the like or a pharmaceutically acceptable salt thereof.
Other representative cardiovascular agents include sympatholytic agents such as methyldopa, clonidine, ~ :.
guanab~nz, reserpine and the like or a pharmaceutically ;~ acceptable salt thereof.
The compound of formula I and the antihypertensive ~ agent can be administered at the recommended maximum - clinical dosage or at lower doses. Dosage levels of the ` active compounds in the compositior.s of the invention may ~. , .:
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be varied so as to obtain a desired therapeutic response depending on the route of administration, severity of the disease and the response of the patient. The combination ; c2n be a~m~niste ed as separate compositions or as a single dosage form containing both agents.
In addition, the present in~-eatlo~ is directed to the use of a comDound of formula I to inhibit Candida àcid pro.ease in mammals, especially humans. The compounds of ~he p-esen. inven~ion a-e also use ul fo- preven_ing or ~-^ati..g i..~-ctions caused Dy Candida species in mammals, es?ecially humans The present invention also _elates to tne use o~ tne com~ounàs or the invention in co~bination wi_h one or more other antifungal agen~s. Other antifungal agents are selected rrom the group consisting of amphotericin B, nystatin, flucytosine, ketoconazole, miconazole, clotrimazole, fluconazole and itraconazole.
The ability of the compounds of the lnvention to inhibit Candida acid protease can be demonstrated Ln Yl~Q
by the following method.
a alki~ns A~id ~ O~gani m and growth co~ditions. Candida al~ica~s ,".,J, ATCC10231 was grown overnight in Sabouraud broth (Difco) ~, at 30C. Cells were centrifuged a~ 10,000xg for 10 min ` (4C) and the cell pellet washed once with 10mM phosphate buffered saline (PBS), pH7Ø Wasned cells (6x105 colony forming units per mL) were grown in yeast nitrogen base without ammonium sulfate or amino acids (Difco), plus 2 ~` glucose and 0.1% casein (nitrogen sou-se) at 37C.
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' !, ' 2~ 29 Prr/lJssl/0~s24 Protoina~e i~olation. Maximum ~rOr~LnaSQ 2-~ductLon was attained when the culture reac;~ed a pH of 3.~ to 4.0 (about 48 hrs). Cells were then ha-vestec at ~,000x~ fo-20 min (4C) and the supernatanL rilter~à tnrough a 0.2 acetate filter unit (Nalgen). The filtrate was concentrated on an Amicon concen~ra-or (PM30 o- Y~10 membrane, 75mm) and 30mL of the ccncen ---- wa- loaded : ,, onto a Cibacron blue F3GA-Q~ agarcae (?ie--~ C~ .j co'~ilmr (1.5x44cm) equilibrated with 10m~l sodium ci~ra~_, pH 6.5 containing lm~l EDTA and 0.G2~ sod~ ~ a~ d~ (æ , T._., a-.
?ayne, C.D. Infection and l~munity ~8:50~-~14, 330).
Bovine serum albumin (BSA) was use~ _s su---~-a-- rc monitor the column for proteinase a^~ ~ ar~ -c determine total proteolytic units. One BSA pro~eolytic unit was defined as an optical density (750nm ~a~elength) increase of 0.100 under incubation conditions of 37C for 60 min ~Remold, H., Fasold, H., and Staib, F. Biochimica et Biophysica Acta 167:399-406, 1968). Fractions with proteolytic activity were eluted in l:he void volume with equilibration buffer, pooled and stored at -70C.
Proteinase purity and molecular weight was determined by the Phast-~el ~12.5~ acryla~ide) elec_ro~ho-esis system (Pharmacia). Protein was determined by the Lowry method (Lowry, O.H., Rosenbrough, N.J., Fa-r, A.L., and Randall, R.J. Journal of Biological Chemist-y 193:263-27~, 1951).
A fluorogenic substrate, A78331, may also be used to monitor proteinase production and purificatlon. This substrate, DABCYL-Gaba-Ile-His-Pro-~he-His-Leu-Val-Ile-. ~
His-Thr-EDANS ~Holzman, T.F., Chungj C.C., Edal~L, R., ~! Egan, D.A., Gubbins, ~.J., Rueter, A., Howard, C-., Yang, L.~., Pederson, T.M., Krafft, G.A., and Wang, G.-. Journal ~` .
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' ,: ,, :. ~,, i5~ 2 ~ 8 W092/0~29 P~T/~Sgl~055 of Protein Chemistry 9:663-672, 1990) co~.~ains ~he fluorescent EDANS group, [5-(2-aminoethyl)-amino]naphthalene-1-sulfonic zcid ~hich is c--en.^ne~ b~
the DABCYL group, 4-(4-dimethyl-amino?henvlazo)~en70ic acid, as long as it ls part of the molQ-ule (Ma~alos~i, E.D., Wang, G.T., Krafft, G.A., and Erickson, J. Science 247:954 958, 1990). Proteoly~is c_ .;~ls -~l~!~-.d D ~
fungal proteinase releases Th~-~D~a, -.~;-ic~ .e-. a^ _ ' 'v'a- e~.
at 340 nm fluoresces at 490nm ~ith ~;~G same in~Qnsi~y ~s equimolar EDANS. Ac.ivi~y is expressed in t~rms of nmol EDANS released from 32~M A78331 under incub2tior.
conditions of 22C for 60 min.. One 3~, p~ e eo'''.-'- ~'~'~
was equivalent to 1.03 nmol E3~Ya -e'eased.
In Vitr~ Inhi~itor A~say MethQ~.
Microtiter as~y. The assay for inhibitors of C.
albicans acid proteinase is done in microtiter trays with the fluorogenic substrate A78331. Test compounds are ., initially tested at l~M, followed by a dose study ranging down to 0.2nM for compounds having greater then 80%
inhibition from control at the lUM dose. The reaction mixture consists of 5~L test compound or dime.hv sulfoxide and 45~L of fungal proteinase (0.13 BSA
proteolytic units or 0.13 nmol EDANS released) ' n 50m.M
sodium citrate, pH 4.5, which is preincubated at 22C for 30 min. The reaction is started with the addition or 50~L
fluorogenic substrate in citrate buffer and the incubation is continued at 22C for 90 min. The reaction is terminated with 150~L pepstatin (final concentration of l~M) and ~lO~L samples are transferGd to mlc-ofluo- pl2tes for fluorescence quantitation in a luminescence .
.
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: ., , '~ " ' / ~ '' .. ~ , ' . ' ' W09~/~34~9 PCT/US91/05~24 ^--2~3o!~6'~ ' spectrophotometer (Perkin-Elmer model LS-50). The e~cita~ion wavelength is 340nm and the emission is moni_ored at 490nm (430nm ~ilter employed). Inhibition is e.~:?-essed as ~ c~ange in relative intensity from the àimethyl sulfoxide control group (no inhibitor). ICSo's are determined from plots of log dose versus ~ inhibltion from control.
The ability of a compound of the invention to treat a~l irfection caused by a Candida s?ecies can be de-vrs.-a`_eA _~ v~ acco-ding to the me :~ods ou~lined a~ a-i, e. al., Cli... Ex~. Dermatol. 1 183 (lg9C); Ghannoum, J. ADP1. Dac~er-lo ~ io3 (1930); ana Ray, et al., J. Invest. Dermatol. ~ 37 (1984).
The ability of a compound of the invention to treat an infection caused by a Candida species can be demons~rated in vivo according to the methods outlined by Ray, et al., J. Invest. Dermatol. 66 29 (1976); Ray, et al., Infect. Immun. ~ 1942 (1988); Van Cutsem, et al., Sabouraudia 2 17 (1971); Sohnie, et al., J.
Immunol. 111 523 (1976); Kobayashi, et al., Microb.
Immunol. ~ 709 (1989); Shimizu, et ~l., Microb.
;
Immunol. ~1 1045 (1987); Zotter, et al., Dermatol. Mon.
Schr. 176 189 ~1990); and Ruchel, et al., Zbl. Bakt. 21 391 ~1990).
The ability of a compound of the invention to prevent an infection caused by a Candida species can be demonstrated according to tne methods outlined by Meitne~, et al., Infect. Immun. ~8 2228 (1990) and Cole, et al., Mycoses ~ 7 (1990).
Total daily dose of a compound of the invention administered to a human or othe_ mammal for inhibiting ., . . ~ ., ~"''`', .
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~92/0~29 PCT/US91/055 Canàida acid protease or treating or preventing an infection caused by a Candida species in single or divided doses may be in amounts, for example, from O.OC1 to 10 mg/kg body weight daily and more usually 0.01 to 10 mg.
Dosage unit compositions may contain sucA amounts of submultiples thereof to make up the daily dose.
The amount of ac~ive ingredien~ that may be combined wi~h the carrier materials to produce a single dosage form wi l varv de~ending upon the host t_eated and t;~e pa-~icula- mode of administration.
T_ will be unde-stood, howeve~, _hat the s?es-ric dose ; ievel fo- any particular pa~ient w~: àepend upon a variety or factors including the activity o the specific compound employed, the age, body weight, gene_al health, se~, diet, ` time of administration, route of administration, rate of excretion, drug combination, and the severity of the ~ particular disease undergoing therapy.
- In addition, the present invention is directed to the use of a compound of formula I to inhibit retroviral .
proteases and in particular to inhibit HIV-1 protease and ~3 HIV-2 protease. Compounds of formula I are useful for t-eatment or prophylaxis of diseases caused by retroviruses, especially acquired i.~mune deficiency ~- syndrome or an HIV infection.
The inhibitory potency of the compound of the .` invention against HIV protease can be determined by the followin~ method.
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A compound of the invention is dissolved in D~SO and a small aliquot further dilucPd with ~ISO to 100 t~mes tne final concentration desirod fo- tes lny. The _eac~ion s carried out in a 6 X 50 ~ 'U2e '^. a ~o~a' i3' '~~e O~
microliters. The final concenlra_ions o- tne com~onQn~S ' n the reacr ion buffe- a-e~ c~ Qr 7 chloride, 5 m~ dithioth-e-to , 3. ~c/mi oovi^_ se- m aibumln, 1.3 u~' fluo;o~.eai~ sub~ , 2 dimethylsulfo;~ide, p.~ . A-r~- e ~d' _` or. o nAi~ -o-~the re`action mi~tu=e is ?laced i~. -he .luoromQ~Q- ce'' holder and incubated at 30C fo- seve-al minutes. ~he reaction is initia~ed by the addition of a small aliquot or cold HIV protease. The fluorescence intensity (excitation 340 nM, emmision 490 nM) is recorded as a function of time.
The reaction rate is cletermined for the first six to eisht minutes. The observed rate is directly proportional to the moles of substrate cleaved per unit time. The percent inhibition is 100 X tl - ~rate in ~resence of inhibi~or)/~rzte in absence o_ ir.r. ~i~or)).
Fluorogenic substrate: Dabcyl-Ser-Gln-As~-Tyr-~ro-Ile-Val-Gln-EDANS wherein DA3CYL = 4-~4~dimethylam~no-phenyl)azobenzoic acid and EDANS = ~-~(2-aminoerhyl)amino)-nz~hthalene-1-sulfonic acid.
, The antiviral activity oî com~ound of the invention can be demonstrated using the following method ;~. A mixture of 0.1 ml (4 X 106 cells/ml) of H9 cells and 0~1 ml (100 infectious units) of .i-~i-13g is incuDated on a - shaker for 2 h. The resulting cul~~re is washed three " ~92/0~29 ~ ~ O~ 2 ~ ~ PCT/US91/0 times, resuspended into 2 ml o- medium, and treated with 10 ~1 of the com?ound of the inventio-. ~5 ~,M in dimethylsulroxide). The cor.~rcl cu_-_-~ s ~-e_-ed in an identical manner except the last s_ep W2â omitted. After incubation of the culture for ei 3h da~1â w' thout ch~nge o-medium, an aliquot (0.1 ml) of the supe-r.atent is wl~hdrawn and incubated with f-esh ;9 cells ~ s:^a:ce- fo- 2 .. The resulting culture is wasr.ed three ~ mes, -esus_e?.~e~ nto 2 ml of me~iu~, an.d ~ n,~ ~Q ~r` -~determined uslng tre ADbc~t ;~T_V-~__ an :~_n ~ ..e-:^o_ ('aul, et al., J. ~ed. Vi-o'~, ~ __. (: _ )).
The fo~egoing is mereiy il us -a~iv-e o~~ the n~en_lo.l and is not intended to limit the i..~entic-. to ~he cisclosed compounds. Variations and changes which are obvious ~o one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.
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Claims (9)
1. A compound of the formula:
wherein X is O, NH or S; and Y is C1 to C6 alkylene or C1 to C6 substituted alkylene;
and R1 is -CN, tetrazolyl, pyridyl, pyrimidinyl, imidazolyl, thiazolyl, morpholinyl, substituted morpholinyl, thiomorpholinyl, substituted thiomorpholinyl, thiomorpholinyl dioxide, substituted thiomorpholinyl dioxide, -C(O)OR24 wherein R24 is hydrogen, loweralkyl or benzyl or -NHR2 wherein R2 is hydrogen, alkanoyl, hydroxalkyl, an N-protecting group, -C(O)NHR17 wherein R17 is hydrogen or loweralkyl, -C(S)NHR18 wherein-R18 is hydrogen or loweralkyl, -C(=N-CN)-NHR19 wherein R19 is hydrogen or loweralkyl, -C(=N-CN)-SR22 wherein R22 is loweralkyl, , , -C(O)O-benzyl, -C(O)R23 wherein R23 is loweralkyl, -SO2NR26aR26b wherein R26a and R26b are independently selected from loweralkyl or -SO2R27 wherein R27 is loweralkyl or -Y-R1 is , -NH2, -NHC(O)NH2, -NHC(S)NH2, -NHSO2R27 wherein R27 is as defined herein, -NHC(=N-CN)NHR19 wherein R19 is as defined herein, -NHC(=N-CN)SR22 wherein R22 is as defined herein or -NHSO2NHR26wherein R26 is as defined herein; or a pharmaceutically acceptable salt, ester or prodrug thereof; with the proviso that the compound is not N-(3-(4-Morpholino)propyl)-5(S)-(2(S)-(1(S)-(4-(methoxymethoxy)piperidin-1-yl)carbonyl-2-phenyl)ethoxyhexanamido)-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanamide.
wherein X is O, NH or S; and Y is C1 to C6 alkylene or C1 to C6 substituted alkylene;
and R1 is -CN, tetrazolyl, pyridyl, pyrimidinyl, imidazolyl, thiazolyl, morpholinyl, substituted morpholinyl, thiomorpholinyl, substituted thiomorpholinyl, thiomorpholinyl dioxide, substituted thiomorpholinyl dioxide, -C(O)OR24 wherein R24 is hydrogen, loweralkyl or benzyl or -NHR2 wherein R2 is hydrogen, alkanoyl, hydroxalkyl, an N-protecting group, -C(O)NHR17 wherein R17 is hydrogen or loweralkyl, -C(S)NHR18 wherein-R18 is hydrogen or loweralkyl, -C(=N-CN)-NHR19 wherein R19 is hydrogen or loweralkyl, -C(=N-CN)-SR22 wherein R22 is loweralkyl, , , -C(O)O-benzyl, -C(O)R23 wherein R23 is loweralkyl, -SO2NR26aR26b wherein R26a and R26b are independently selected from loweralkyl or -SO2R27 wherein R27 is loweralkyl or -Y-R1 is , -NH2, -NHC(O)NH2, -NHC(S)NH2, -NHSO2R27 wherein R27 is as defined herein, -NHC(=N-CN)NHR19 wherein R19 is as defined herein, -NHC(=N-CN)SR22 wherein R22 is as defined herein or -NHSO2NHR26wherein R26 is as defined herein; or a pharmaceutically acceptable salt, ester or prodrug thereof; with the proviso that the compound is not N-(3-(4-Morpholino)propyl)-5(S)-(2(S)-(1(S)-(4-(methoxymethoxy)piperidin-1-yl)carbonyl-2-phenyl)ethoxyhexanamido)-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanamide.
2. The compound of Claim 1 wherein X is O or NH and R1 is -NHR2 wherein R2 is hydrogen, alkanoyl, hydroxyalkyl, an N-protecting group, -C(O)NHR17 wherein R17 is hydrogen or loweralkyl, -C(S)NHR18 wherein R18 is hydrogen or loweralkyl, -C(=N-CN)-NHR19 wherein R19 is hydrogen or loweralkyl, -C(=N-CN)-SR22 wherein R22 is loweralkyl, , , -C(O)O-benzyl, -C(O)R23 wherein R23 is loweralkyl, -SO2NR26aR26b wherein R26a and R26b are -SO2R27 wherein R27 is loweralkyl.
3. A compound selected from the group consisting of:
N-(3-(4-Morpholino)propyl) 5(S)-(N-(1(S)-(4-(methoxymethoxy)piperidin-1-yl)carbonyl-2-phenyl)ethyl-L-norleucinamido)-5-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanamide;
N-(2-(4-Morpholino)ethyl) 5(S)-(N-(1(S)-(4-(methoxymethoxy)piperidin-1-yl)carbonyl-2-phenyl)ethyl-L-norleucinamido)-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanamide;
N-(3-(1-Imidazolyl)propyl) 5(S)-(N-(1(S)-(4-(methoxymethoxy)piperidin-1-yl)carbonyl-2-phenyl)ethyl-L-norleucinamido)-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanamide;
N-(2-((3-Amino-1H-1,2,4-54iazol-5-yl)amino)ethyl) 5(S)-(N-(1(S)-(4-(methoxymethoxy)piperidin-1-yl)carbonyl-2-phenyl)ethyl-L-norleucinamido)-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanamide; and (2S,4S)-2-[(N-(1(S)-(4-(methoxymethoxy)piperidin-1-yl)carbonyl-2-phenyl)ethyl-L-norleucinamido)]-1-cyclohexyl-4-hydoxy-5-isopropylsulfonylmethyl-6-methylheptane; or a pharmaceutically acceptable salt, ester or prodrug thereof.
N-(3-(4-Morpholino)propyl) 5(S)-(N-(1(S)-(4-(methoxymethoxy)piperidin-1-yl)carbonyl-2-phenyl)ethyl-L-norleucinamido)-5-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanamide;
N-(2-(4-Morpholino)ethyl) 5(S)-(N-(1(S)-(4-(methoxymethoxy)piperidin-1-yl)carbonyl-2-phenyl)ethyl-L-norleucinamido)-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanamide;
N-(3-(1-Imidazolyl)propyl) 5(S)-(N-(1(S)-(4-(methoxymethoxy)piperidin-1-yl)carbonyl-2-phenyl)ethyl-L-norleucinamido)-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanamide;
N-(2-((3-Amino-1H-1,2,4-54iazol-5-yl)amino)ethyl) 5(S)-(N-(1(S)-(4-(methoxymethoxy)piperidin-1-yl)carbonyl-2-phenyl)ethyl-L-norleucinamido)-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanamide; and (2S,4S)-2-[(N-(1(S)-(4-(methoxymethoxy)piperidin-1-yl)carbonyl-2-phenyl)ethyl-L-norleucinamido)]-1-cyclohexyl-4-hydoxy-5-isopropylsulfonylmethyl-6-methylheptane; or a pharmaceutically acceptable salt, ester or prodrug thereof.
4. A compound of the formula:
wherein X is O, NH or S; and D is (i) wherein Y is C1 to C6 alkylene or C1 to C6 substituted alkylene; and R1 is -CN, tetrazolyl, pyridyl, pyrimidinyl, imidazolyl, thiazolyl, morpholinyl, substituted morpholinyl, thiomorpholinyl, substituted thiomorpholinyl, thiomorpholinyl dioxide, substituted thiomorpholinyl dioxide, -C(O)OR24 wherein R24 is hydrogen, loweralkyl or benzyl or -NHR2 wherein R2 is hydrogen, alkanoyl, hydroxyalkyl, an N-protecting group, -C(O)NHR17 wherein R17 is hydrogen or loweralkyl, -C(S)NHR18 wherein R18 is hydrogen or loweralkyl, -C(=N-CN)-NHR19 wherein R19 is hydrogen or loweralkyl, -C(=N-CN)-SR22 wherein R22 is loweralkyl, , , -C(O)O-benzyl, -C(O)R23 wherein R23 is loweralkyl, -SO2NR26aR26b wherein R26a and R26b are independently selected from loweralkyl or -SO2R27 wherein R27 is loweralkyl or -Y-R1 is , -NH2, -NHC(O)NH2, -NHC(S)NH2, -NHSO2R27 wherein R27 is as defined herein, -NHC(=N-CN)NHR19 wherein R19 is as defined herein, -NHC(=N-CN)SR22 wherein R22 is as defined herein or -NHSO2NHR26wherein R26 is as defined herein;
(ii) -CH(OH)CH(OH)CF2CH2N(R20) (R21) wherein R20 and R21 are independently selected from hydrogen and loweralkyl;
(iii) -CH(OH)C(O)CF2CH2N(R20) (R21) wherein R20 and R21 are defined as herein;
(iv) -CH(OH)CF2CH2N(R20) (R21) wherein R20 and R21 are defined as herein;
(v) -C(O)CF2CH2N(R20) (R21) wherein R20 and R21 are defined as herein;
(vi) -CH(OH)CH2CH(CH(CH3)2)C(O)-N=C(N(CH3)2)(N(CH3)2);
(vii) -CH(OH)CH2CH(CH(CH3)2)CH2R50 wherein R50 is (a) -OR51 wherein R51 is hydrogen, -CH2OCH3 or -CH2OCH2CH2OCH3, (b) -SR52 whereln R52 is loweralkyl, phenyl, benzyl, pyridyl, pyrimidyl, imidazolyl, loweralkyl substituted imidazolyl, piperidinyl or -R54-O-R55 wherein R54 is alkylene or substituted alkylene and R55 is -CH2OCH3 or -CH2OCH2CH2OCH3, (c) S(O)2Rs3 wherein Rs3 is loweralkyl, phenyl, benzy', pyridyl, pyrimidyl, imidazolyl, loweralkyl substituted imidazolyl, thiazolyl, loweralkyl substituted thiazolyl, piperidinyl or -R54-O-R55, wherein R54 is alkylene or substituted alkylene and R55 is -CH2OCH3 or -CH2OCH2CH2OCH3, (d) -N(R56) (R57) wherein R56 and R57 are independently selected from hydrogen, loweralkyl, cycloalkyl and hydroxy substituted cycloalkyl, (e) wherein R58 is O, S, S(O)2 or N(R59) wherein R59 is hydrogen, loweralkyl or benzyl, or (f) wherein R33 is N(R34) wherein R34 is hydrogen, loweralkyl or benzyl; or (viii) ; or a pharmaceutically acceptable salt, ester or prodrug thereof; with the proviso that the compound is not N-(3-(4-Morpholino)propyl)-5(S)-(2(S)-(1(S)-(4-(methoxymethoxy)piperidin-1-yl)carbonyl-2-phenyl)ethoxyhexanamido)-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanamide.
wherein X is O, NH or S; and D is (i) wherein Y is C1 to C6 alkylene or C1 to C6 substituted alkylene; and R1 is -CN, tetrazolyl, pyridyl, pyrimidinyl, imidazolyl, thiazolyl, morpholinyl, substituted morpholinyl, thiomorpholinyl, substituted thiomorpholinyl, thiomorpholinyl dioxide, substituted thiomorpholinyl dioxide, -C(O)OR24 wherein R24 is hydrogen, loweralkyl or benzyl or -NHR2 wherein R2 is hydrogen, alkanoyl, hydroxyalkyl, an N-protecting group, -C(O)NHR17 wherein R17 is hydrogen or loweralkyl, -C(S)NHR18 wherein R18 is hydrogen or loweralkyl, -C(=N-CN)-NHR19 wherein R19 is hydrogen or loweralkyl, -C(=N-CN)-SR22 wherein R22 is loweralkyl, , , -C(O)O-benzyl, -C(O)R23 wherein R23 is loweralkyl, -SO2NR26aR26b wherein R26a and R26b are independently selected from loweralkyl or -SO2R27 wherein R27 is loweralkyl or -Y-R1 is , -NH2, -NHC(O)NH2, -NHC(S)NH2, -NHSO2R27 wherein R27 is as defined herein, -NHC(=N-CN)NHR19 wherein R19 is as defined herein, -NHC(=N-CN)SR22 wherein R22 is as defined herein or -NHSO2NHR26wherein R26 is as defined herein;
(ii) -CH(OH)CH(OH)CF2CH2N(R20) (R21) wherein R20 and R21 are independently selected from hydrogen and loweralkyl;
(iii) -CH(OH)C(O)CF2CH2N(R20) (R21) wherein R20 and R21 are defined as herein;
(iv) -CH(OH)CF2CH2N(R20) (R21) wherein R20 and R21 are defined as herein;
(v) -C(O)CF2CH2N(R20) (R21) wherein R20 and R21 are defined as herein;
(vi) -CH(OH)CH2CH(CH(CH3)2)C(O)-N=C(N(CH3)2)(N(CH3)2);
(vii) -CH(OH)CH2CH(CH(CH3)2)CH2R50 wherein R50 is (a) -OR51 wherein R51 is hydrogen, -CH2OCH3 or -CH2OCH2CH2OCH3, (b) -SR52 whereln R52 is loweralkyl, phenyl, benzyl, pyridyl, pyrimidyl, imidazolyl, loweralkyl substituted imidazolyl, piperidinyl or -R54-O-R55 wherein R54 is alkylene or substituted alkylene and R55 is -CH2OCH3 or -CH2OCH2CH2OCH3, (c) S(O)2Rs3 wherein Rs3 is loweralkyl, phenyl, benzy', pyridyl, pyrimidyl, imidazolyl, loweralkyl substituted imidazolyl, thiazolyl, loweralkyl substituted thiazolyl, piperidinyl or -R54-O-R55, wherein R54 is alkylene or substituted alkylene and R55 is -CH2OCH3 or -CH2OCH2CH2OCH3, (d) -N(R56) (R57) wherein R56 and R57 are independently selected from hydrogen, loweralkyl, cycloalkyl and hydroxy substituted cycloalkyl, (e) wherein R58 is O, S, S(O)2 or N(R59) wherein R59 is hydrogen, loweralkyl or benzyl, or (f) wherein R33 is N(R34) wherein R34 is hydrogen, loweralkyl or benzyl; or (viii) ; or a pharmaceutically acceptable salt, ester or prodrug thereof; with the proviso that the compound is not N-(3-(4-Morpholino)propyl)-5(S)-(2(S)-(1(S)-(4-(methoxymethoxy)piperidin-1-yl)carbonyl-2-phenyl)ethoxyhexanamido)-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanamide.
5. A method for inhibiting renin or treating hypertension or treating congestive heart failure comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1.
6. A pharmaceutical composition for treating hypertension or congestive heart failure, comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.
7. A method for inhibiting renin or treating hypertension or treating congestive heart failure comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 4.
8. A pharmaceutical composition for treating hypertension or congestive heart failure, comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 4.
9. A process for the preparation of a compound of the formula:
wherein X is O, NH or S; and D is (i) wherein Y is C1 to C6 alkylene or C1 to C6 substituted alkylene; and R1 is -CN, tetrazolyl, pyridyl, pyrimidinyl, imidazolyl, thiazolyl, morpholinyl, substituted morpholinyl, thiomorpholinyl, substituted thiomorpholinyl, thiomorpholinyl dioxide, substituted thiomorpholinyl dioxide, -C(O)OR24 wherein R24 is hydrogen, loweralkyl or benzyl or -NHR2 wherein R2 is hydrogen, alkanoyl, hydroxyalkyl, an N-protecting group, -C(O)NHR17 wherein R17 is hydrogen or loweralkyl, -C(S)NHR18 wherein R18 is hydrogen or loweralkyl, -C(=N-CN)-NHR19 wherein R19 is hydrogen or loweralkyl, -C(=N-CN)-SR22 wherein R22 is loweralkyl, , , -C(O)O-benzyl, -C(O)R23 wherein R23 is loweralkyl, -SO2NR26aR26b wherein R26a and R26b are independently selected from loweralkyl or -SO2R27 wherein R27 is loweralkyl or -Y-R1 is , -NH2, -NHC(O)NH2, -NHC(S)NH2, -NHSO2R27 wherein R27 is as defined herein, -NHC(=N-CN)NHR19 wherein R19 is as defined herein, -NHC(=N-CN)SR22 wherein R22 is as defined herein or -NHSO2NHR26wherein R26 is as defined herein;
(ii) -CH(OH)CH(OH)CF2CH2N(R20)(R21) wherein R20 and R21 are independently selected from hydrogen and loweralkyl;
(iii) -CH(OH)C(O)CF2CH2N(R20)(R21) wherein R20 and R21 are defined as herein;
(iv) -CH(OH)CF2CH2N(R20)(R21) wherein R20 and R21 are defined as herein;
(v) -C(O)CF2CH2N(R20)(R21) wherein R20 and R21 are defined as herein;
(vi) -CH(OH)CH2CH(CH(CH3)2)C(O)-N=C(N(CH3)2)(N(CH3)2);
(vii) -CH(OH)CH2CH(CH(CH3)2)CH2R50 wherein R50 is (a) -OR51 wherein R51 is hydrogen, -CH2OCH3 or -CH2OCH2CH2OCH3, (b) -SR52 wherein R52 is loweralkyl, phenyl, benzyl, pyridyl, pyrimidyl, imidazolyl, loweralkyl substituted imidazolyl, piperidinyl or -R54-O-R55 wherein R54 is alkylene or substituted alkylene and R55 is -CH2OCH3 or -CH2OCH2CH2OCH3, (c) S(O)2R53 wherein R53 is loweralkyl, phenyl, benzyl, pyridyl, pyrimidyl, imidazolyl, loweralkyl substituted imidazolyl, thiazolyl, loweralkyl substituted thiazolyl, piperidinyl or -R54-O-R55 wherein R54 is alkylene or substituted alkylene and R55 is -CH2OCH3 or -CH2OCH2CH2OCH3, (d) -N(R56)(R57) wherein R56 and R57 are independently selected from hydrogen, loweralkyl, cycloalkyl and hydroxy substituted cycloalkyl, (e) wherein R58 is O, S, S(O)2 or N(R59) wherein R59 is hydrogen, loweralkyl or benzyl, or (f) wherein R33 is -N(R34) wherein R34 is hydrogen, loweralkyl or benzyl; or (viii) ; or a pharmaceutically acceptable salt, ester or prodrug thereof; with the proviso that the compound is not N-(3-(4-Morpholino)propyl)-5(S)-(2(S)-(1(S)-(4-(methoxymethoxy)piperidin-1-yl)carbonyl-2-phenyl)ethoxyhexanamido)-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanamide, comprising reacting a compound of the formula:
wherein X is as defined above, or an activated derivative thereof, with a compound of the formula:
wherein D is as defined above.
wherein X is O, NH or S; and D is (i) wherein Y is C1 to C6 alkylene or C1 to C6 substituted alkylene; and R1 is -CN, tetrazolyl, pyridyl, pyrimidinyl, imidazolyl, thiazolyl, morpholinyl, substituted morpholinyl, thiomorpholinyl, substituted thiomorpholinyl, thiomorpholinyl dioxide, substituted thiomorpholinyl dioxide, -C(O)OR24 wherein R24 is hydrogen, loweralkyl or benzyl or -NHR2 wherein R2 is hydrogen, alkanoyl, hydroxyalkyl, an N-protecting group, -C(O)NHR17 wherein R17 is hydrogen or loweralkyl, -C(S)NHR18 wherein R18 is hydrogen or loweralkyl, -C(=N-CN)-NHR19 wherein R19 is hydrogen or loweralkyl, -C(=N-CN)-SR22 wherein R22 is loweralkyl, , , -C(O)O-benzyl, -C(O)R23 wherein R23 is loweralkyl, -SO2NR26aR26b wherein R26a and R26b are independently selected from loweralkyl or -SO2R27 wherein R27 is loweralkyl or -Y-R1 is , -NH2, -NHC(O)NH2, -NHC(S)NH2, -NHSO2R27 wherein R27 is as defined herein, -NHC(=N-CN)NHR19 wherein R19 is as defined herein, -NHC(=N-CN)SR22 wherein R22 is as defined herein or -NHSO2NHR26wherein R26 is as defined herein;
(ii) -CH(OH)CH(OH)CF2CH2N(R20)(R21) wherein R20 and R21 are independently selected from hydrogen and loweralkyl;
(iii) -CH(OH)C(O)CF2CH2N(R20)(R21) wherein R20 and R21 are defined as herein;
(iv) -CH(OH)CF2CH2N(R20)(R21) wherein R20 and R21 are defined as herein;
(v) -C(O)CF2CH2N(R20)(R21) wherein R20 and R21 are defined as herein;
(vi) -CH(OH)CH2CH(CH(CH3)2)C(O)-N=C(N(CH3)2)(N(CH3)2);
(vii) -CH(OH)CH2CH(CH(CH3)2)CH2R50 wherein R50 is (a) -OR51 wherein R51 is hydrogen, -CH2OCH3 or -CH2OCH2CH2OCH3, (b) -SR52 wherein R52 is loweralkyl, phenyl, benzyl, pyridyl, pyrimidyl, imidazolyl, loweralkyl substituted imidazolyl, piperidinyl or -R54-O-R55 wherein R54 is alkylene or substituted alkylene and R55 is -CH2OCH3 or -CH2OCH2CH2OCH3, (c) S(O)2R53 wherein R53 is loweralkyl, phenyl, benzyl, pyridyl, pyrimidyl, imidazolyl, loweralkyl substituted imidazolyl, thiazolyl, loweralkyl substituted thiazolyl, piperidinyl or -R54-O-R55 wherein R54 is alkylene or substituted alkylene and R55 is -CH2OCH3 or -CH2OCH2CH2OCH3, (d) -N(R56)(R57) wherein R56 and R57 are independently selected from hydrogen, loweralkyl, cycloalkyl and hydroxy substituted cycloalkyl, (e) wherein R58 is O, S, S(O)2 or N(R59) wherein R59 is hydrogen, loweralkyl or benzyl, or (f) wherein R33 is -N(R34) wherein R34 is hydrogen, loweralkyl or benzyl; or (viii) ; or a pharmaceutically acceptable salt, ester or prodrug thereof; with the proviso that the compound is not N-(3-(4-Morpholino)propyl)-5(S)-(2(S)-(1(S)-(4-(methoxymethoxy)piperidin-1-yl)carbonyl-2-phenyl)ethoxyhexanamido)-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanamide, comprising reacting a compound of the formula:
wherein X is as defined above, or an activated derivative thereof, with a compound of the formula:
wherein D is as defined above.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US56855790A | 1990-08-15 | 1990-08-15 | |
| US568,557 | 1990-08-15 | ||
| US07/680,811 US5122514A (en) | 1990-04-23 | 1991-04-09 | Psoriasis treatment |
| US680,811 | 1991-04-09 | ||
| PCT/US1991/005524 WO1992003429A1 (en) | 1990-08-15 | 1991-08-02 | Renin inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2089268A1 true CA2089268A1 (en) | 1992-02-16 |
Family
ID=27074822
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002089268A Abandoned CA2089268A1 (en) | 1990-08-15 | 1991-08-02 | Renin inhibitors |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0543936A4 (en) |
| JP (1) | JPH06500111A (en) |
| CA (1) | CA2089268A1 (en) |
| WO (1) | WO1992003429A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008058387A1 (en) * | 2006-11-17 | 2008-05-22 | Merck Frosst Canada Ltd. | Renin inhibitors |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2181551A1 (en) * | 1994-01-25 | 1995-07-27 | Mark A. Russell | Malarial aspartic protease inhibitors |
| US8168616B1 (en) * | 2000-11-17 | 2012-05-01 | Novartis Ag | Combination comprising a renin inhibitor and an angiotensin receptor inhibitor for hypertension |
| EP2163245A1 (en) * | 2008-09-10 | 2010-03-17 | Novartis Ag | Renin inhibitors for the treatment of psoriasis |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL91780A (en) * | 1988-10-04 | 1995-08-31 | Abbott Lab | Renin inhibiting hexanoic acid amide derivatives, process for their preparation and pharmaceutical compositions containing them |
-
1991
- 1991-08-02 EP EP19910916458 patent/EP0543936A4/en not_active Withdrawn
- 1991-08-02 CA CA002089268A patent/CA2089268A1/en not_active Abandoned
- 1991-08-02 WO PCT/US1991/005524 patent/WO1992003429A1/en not_active Application Discontinuation
- 1991-08-02 JP JP3515076A patent/JPH06500111A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008058387A1 (en) * | 2006-11-17 | 2008-05-22 | Merck Frosst Canada Ltd. | Renin inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0543936A4 (en) | 1993-06-30 |
| WO1992003429A1 (en) | 1992-03-05 |
| EP0543936A1 (en) | 1993-06-02 |
| JPH06500111A (en) | 1994-01-06 |
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