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WO1996005180A1 - 1,2,4,-triazacycloheptanes inhibant la protease de retrovirus - Google Patents

1,2,4,-triazacycloheptanes inhibant la protease de retrovirus Download PDF

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Publication number
WO1996005180A1
WO1996005180A1 PCT/US1995/009472 US9509472W WO9605180A1 WO 1996005180 A1 WO1996005180 A1 WO 1996005180A1 US 9509472 W US9509472 W US 9509472W WO 9605180 A1 WO9605180 A1 WO 9605180A1
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Prior art keywords
benzyl
substituted benzyl
compound
loweralkyl
hydroxy
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PCT/US1995/009472
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English (en)
Inventor
Chen Zhao
Dale J. Kempf
Hing L. Sham
Daniel W. Norbeck
David A. Betebenner
Shuqun Lin
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Abbott Laboratories
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Priority to AU31503/95A priority Critical patent/AU3150395A/en
Publication of WO1996005180A1 publication Critical patent/WO1996005180A1/fr

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    • 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
    • C07D405/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C281/02—Compounds containing any of the groups, e.g. carbazates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D255/00—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00
    • C07D255/02—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00 not condensed with other rings
    • 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
    • C07D405/14—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 three or more hetero rings
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to novel compounds and a composition and method for inhibiting retroviral proteases and in particular for inhibiting human immunodeficiency virus (HIV) protease, a composition and method for treating a retroviral infection and in particular an HIV infection, processes for making such compounds and synthetic intermediates employed in these processes.
  • HIV human immunodeficiency virus
  • Retroviruses are those viruses which utilize a ribonucleic acid (RNA) intermediate and a RNA-dependent deoxyribonucleic acid (DNA) polymerase, reverse transcriptase, during their life cycle. Retroviruses include, but are not limited to, the RNA viruses of the Retroviridae family, and also the DNA viruses of the Hepadnavirus and Caulimovirus families. Retroviruses cause a variety of disease states in man, animals and plants.
  • RNA ribonucleic acid
  • DNA RNA-dependent deoxyribonucleic acid
  • retroviruses from a pathological standpoint include human immunodeficiency viruses (HIV-1 and HIV-2), which cause acquired immune deficiency syndrome (AIDS) in man, hepatitis B virus, which causes hepatitis and hepatic carcinomas in man, human T-cell lymphotrophic viruses I, II, IV and V, which cause human acute cell leukemia, and bovine and feline leukemia viruses which cause leukemia in domestic animals.
  • HIV-1 and HIV-2 human immunodeficiency viruses
  • HIV-2 acquired immune deficiency syndrome
  • hepatitis B virus which causes hepatitis and hepatic carcinomas in man
  • human T-cell lymphotrophic viruses I, II, IV and V which cause human acute cell leukemia
  • bovine and feline leukemia viruses which cause leukemia in domestic animals.
  • Proteases are enzymes which cleave proteins at specific peptide bonds. Many biological functions are controlled or mediated by proteases and their complementary protease inhibitors. For example, the protease renin cleaves the peptide angiotensinogen to produce the peptide angiotensin I. Angiotensin I is further cleaved by the protease angiotensin converting enzyme (ACE) to form the hypotensive peptide angiotensin II. Inhibitors of renin and ACE are known to reduce high blood pressure in vivo. An inhibitor of a retroviral protease will provide a therapeutic agent for diseases caused by the retrovirus.
  • protease renin cleaves the peptide angiotensinogen to produce the peptide angiotensin I.
  • Angiotensin I is further cleaved by the protease angiotensin converting enzyme (ACE) to form the hypotensive peptide angioten
  • retroviruses encode a protease that is responsible for the proteolytic processing of one or more polyprotein precursors such as the pol and gag gene products. See Wellink, Arch. Virol. 98 1 (1988). Retroviral proteases most commonly process the gag precursor into core proteins, and also process the pol precursor into reverse transciptase and retroviral protease. In addition, retroviral proteases are sequence specific. See Pearl, Nature 328 482 (1987).
  • Current treatments for viral diseases usually involve administration of compounds that inhibit viral DNA synthesis.
  • Current treatments for AIDS involve administration of compounds such as 3'-azido-3'-deoxythymidine (AZT), 2',3'- dideoxycytidine (ddC), 2',3'-dideoxyinosine (ddl) and 2',3'-didehydro-3'- deoxythymidine (d4T) and compounds which treat the opportunistic infections caused by the immunosuppression resulting from HIV infection. None of the current AIDS treatments have proven to be totally effective in treating and/or reversing the disease. In addition, many of the compounds currently used to treat AIDS cause adverse side effects including low platelet count, renal toxicity and bone marrow cytopenia.
  • Preferred compounds of the invention are compounds of the formula B:
  • R 1 , R 2 , R 3 , R 4 and X are defined as above.
  • Preferred compounds of the invention are compounds of the formula A or B wherein R 1 is loweralkyl or arylalkyi; R 2 is R 2a -C(O)- wherein R 2a is
  • More preferred compounds of the invention are compounds of the formula A or B wherein R 1 is loweralkyl, benzyl, alkoxy-substituted benzyl or halo-substituted benzyl; R 2 is R 2a -C(O)- wherein R 2a is loweralkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aryl or arylalkyi; R 3 and R 4 are independently selected from loweralkyl, loweralkenyl, cycloalkylalkyl, benzyl, hydroxy- substituted benzyl, hydroxyalkyl-substituted benzyl, alkoxy-substituted benzyl, amino-substituted benzyl, disubstituted benzyl wherein the substitutents are hydroxy and alkoxy or (heterocyclic)methyl wherein the heterocyclic is thiazolyl, oxazolyl
  • R 1 is isobutyl, benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl
  • R 2 is R 2a -C(O)- wherein R 2a is CH 3 -, CH 3 -(CH 2 ) 2 -.
  • R 1 is isobutyl, benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl
  • R 2 is R 2a -C(O)- wherein R 2a is CH 3 -, CH 3 -(CH 2 ) 2 -, (CH 3 ) 2 CHCH 2 -, CH 3 (CH 2 ) 3 -, (CH 3 (CH 2 ) 2 ) 2 CH-, cyclopentyl, HOCH 2 (CH 2 ) 3 -, HOCH 2 (CH 2 ) 2 - or HOCH 2 -;
  • R 3 and R 4 are independently selected from loweralkyl, allyl, cyclopropylmethyl, benzyl, hydroxy-substituted benzyl, methoxy-substituted benzyl, hydroxymethyl-substituted benzyl, amino- substituted benzyl
  • R 1 is benzyl, methoxy-substituted benzyl or fluoro- substituted benzyl
  • R 2 is R 2a -C(O)- wherein R 2a is CH 3 -, CH 3 -(CH 2 ) 2 -,
  • the especially preferred compounds of the invention are compounds of the formula A or B wherein R 1 is benzyl, methoxy-substituted benzyl or fluoro- substituted benzyl; R 2 is R 2a -C(O)- wherein R 2a is (CH 3 ) 2 CHCH 2 -; R 3 and R 4 are independently selected from 4-hydroxybenzyl, 4-aminobenzyl and
  • the compounds of the invention comprise asymmetrically substituted centers (i.e., asymmetrically substituted carbon atoms).
  • the present invention is intended to include all stereoisomeric forms of the compounds, including racemic mixtures, mixtures of diastereomers, as well as single diastereomers of the compounds of the invention.
  • the terms "S” and "R” configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13 - 30.
  • N-protecting group or “N-protected” as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, “Protective Groups In Organic Synthesis,” (John Wiley & Sons, New York (1981 )), which is hereby incorporated herein by reference. N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyi,
  • t-butylacetyl 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, ⁇ -chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl,
  • 2,2,2,-trichloroethoxycarbonyl 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like.
  • N-protecting groups are formyl, acetyl, benzoyl, pivaloyi, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
  • O-protecting group refers to a substituent which protects hydroxyl groups against undesirable reactions during synthetic procedures such as those O-protecting groups disclosed in Greene, "Protective Groups In Organic Synthesis,” (John Wiley & Sons, New York (1981 )).
  • O-protecting groups comprise substituted methyl ethers, for example,
  • tetrahydropyranyl ethers substituted ethyl ethers, for example, 2,2,2- trichloroethyl; silyl ethers, for example, trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; and esters prepared by reacting the hydroxyl group with a carboxylic acid, for example, acetate, propionate, benzoate and the like.
  • loweralkyl refers to straight or branched chain alkyl radicals containing from 1 to 10 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, n-pentyl,
  • alkylene refers to a straight or branched chain carbon diradical containing from 1 to 6 carbon atoms including, but not limited to, -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH 2 CH 2 - and the like.
  • loweralkenyl refers to a loweralkyl radical which contains at least one carbon-carbon double bond including, but not limited to, propenyl, butenyl and the like.
  • aryl refers to a C 6 monocyclic aromatic ring system or a C 9 or C 10 bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
  • Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyi, alkoxy, thioalkoxy, alkoxycarbonyl, alkanoyl, hydroxy, halo, mercapto, nitro, cyano, amino, alkylamino, dialkylamino, carboxaldehyde, carboxy, carboxamide, arylalkyi, arylalkoxy, (heterocyclic)alkyl, (heterocyclic)alkoxy, (heterocyclic)carbonylalkoxy, aminoalkyl, aminoalkoxy, alkylaminoalkyl, alkylaminoalkoxy, dialkylaminoalkyl, dialkylaminoalkoxy,
  • alkoxyalkyl)aminoalkyl (alkoxyalkyl)aminoalkyl, (alkoxyalkyl)aminoalkoxy, di-(alkoxyalkyl)aminoalkyl, di-(alkoxyalkyl)aminoalkoxy, (alkoxyalkyl)(alkyl)aminoalkyl,
  • substituted aryl groups include tetrafluorophenyl and
  • arylalkyi refers to an aryl group appended to a loweralkyl radical including, but not limited to, benzyl, 4-hydroxybenzyl, 1 - naphthylmethyl and the like.
  • aminoalkyl refers to -NH 2 appended to a loweralkyl radical.
  • hydroxyalkyl refers to -OH appended to a loweralkyl radical.
  • dihydroxyalkyl refers to a loweralkyl radical disubstituted with -OH groups.
  • polyhydroxyalkyl refers to a loweralkyl radical substituted with more than two -OH groups.
  • mercaptoalkyl refers to a loweralkyl radical to which is appended a mercapto (-SH) group.
  • hydroxyaminoalkyl refers to a hydroxyamino group (-NHOH) appended to a loweralkyl radical.
  • alkoxyaminoalkyl refers to alkoxyaminoalkyl
  • (alkoxy) (alkyl)aminoalkyl refers to (R 2 1 )(R 22 )N- wherein R 21 is alkoxy and R 22 is loweralkyl appended to a loweralkyl radical.
  • alkylamino refers to a loweralkyl radical appended to an NH radical.
  • cycloalkyl refers to an aliphatic ring having 3 to 7 carbon atoms including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl and the like. Cycloalkyl groups can be unsubstituted or substituted with one or two substituents independently selected from loweralkyl, haloalkyi, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, carboalkoxy and carboxamide.
  • cycloalkylalkyl refers to a cycloalkyl group appended to a loweralkyl radical, including but not limited to cyclohexylmethyl.
  • cycloalkenyl refers to an aliphatic ring having 5 to 7 carbon atoms and a carbon-carbon double bond including, but not limited to, cyclopentenyl, cyclohexenyl and the like.
  • Cycloalkenyl groups can be unsubstituted or substituted with one or two substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, carboalkoxy and carboxamide.
  • cycloalkenylalkyl refers to a cycloalkenyl group appended to a loweralkyl radical, including but not limited to
  • alkylaminocycloalkyl refers to an alkylamino group appended to a cycloalkyl radical.
  • dialkylaminocycloalkyl refers to a dialkylamino group appended to a cycloalkyl radical.
  • alkoxy and thioalkoxy refer to R 29 O- and R 29 S-, respectively, wherein R 29 is a loweralkyl group.
  • alkoxyalkyl refers to an alkoxy group
  • thioalkoxyalkyl refers to a thioalkoxy group appended to a loweralkyl radical.
  • alkenyloxy refers to R 32 O- wherein R 32 is a loweralkenyl group.
  • hydroxyalkoxy refers to -OH appended to an alkoxy radical.
  • dihydroxyalkoxy refers to an alkoxy radical which is disubstituted with -OH groups.
  • arylalkoxy refers R 33 O- wherein R 33 is a arylalkyl group as defined above.
  • (heterocyclic)alkoxy refers to R 34 O- wheeein R 34 is a (heterocyclic)alkyl group.
  • aryloxyalkyl refers to a R 35 O- group appended to a loweralkyl radical, wherein R 35 is an aryl group.
  • dialkylamino refers to dialkylamino
  • R 36 and R 37 are independently selected from loweralkyl groups.
  • N-protected aminoalkyl refers to -NHR 40 appended to a loweralkyl group, wherein R 40 is an N-protecting group.
  • alkylaminoalkyl refers to -NHR 41 appended to a loweralkyl radical, wherein R 41 is a loweralkyl group.
  • N-protecting group and R 43 is loweralkyl.
  • dialkylaminoalkyl refers to -NR 44 R 45 which is appended to a loweralkyl radical wherein R 44 and R 45 are independently selected from loweralkyl.
  • carboxyalkyl refers to a carboxylic acid group (-COOH) appended to a loweralkyl radical.
  • alkoxycarbonylalkyl refers to a R 46 C(O)- group appended to a loweralkyl radical, wherein R 46 is an alkoxy group .
  • carboxy alkoxyalkyl refers to a carboxylic acid group (-COOH) appended to an alkoxy group which is appended to a loweralkyl radical.
  • alkoxycarbonylalkoxyalkyl refers to an alkoxycarbonyl group (R 47 C(O)- wherein R 47 is an alkoxy group) appended to an alkoxy group which is appended to a loweralkyl radical.
  • (amino)carboxyalkyl refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and an amino group (-NH 2 ).
  • ((N-protected)amino)carboxyalkyl refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and -NHR 48 wherein R 48 is an N-protecting group.
  • (alkylamino)carboxyalkyl refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and an
  • ((N-protected)alkylamino)carboxyalkyl refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and an -NR 48 R 49 wherein R 48 is as defined above and R 49 is a loweralkyl group.
  • (dialkylamino)carboxyalkyl refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and -NR 49 R 49 wherein R 49 is as defined above.
  • (amino)alkoxycarbonylalkyl refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and an amino group (-NH 2 ).
  • ((N-protected)amino)alkoxy-carbonylalkyl refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NHR 50 wherein R 50 is an N-protecting group.
  • (alkylamino)alkoxycarbonylalkyl refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and an alkylamino group as defined above.
  • ((N-protected)alkylamino)alkoxy-carbonylalkyl refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NR 51 R 52 wherein R 51 is an N-protecting group and R 52 is a loweralkyl group.
  • (dialkylamino)alkoxycarbonylalkyl refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NR 53 R 54 wherein R 53 and R 54 are independently selected from loweralkyl.
  • aminocycloalkyl refers to an NH 2 appended to a cycloalkyl radical.
  • ((alkoxy)alkoxy)alkyl refers to an alkoxy group appended to an alkoxy group which is appended to a loweralkyl radical.
  • polyalkoxyalkyl refers to a polyalkoxy residue appended to a loweralkyl radical.
  • polyalkoxy refers to -OR 67 wherein R 67 is a straight or branched chain containing 1 -5, C n ,-O-C n" linkages wherein n' and n" are independently selected from 1 to 3, including but not limited to
  • halo or halogen as used herein refers to -Cl, -Br, -I or -F.
  • haloalkyl refers to a loweralkyl radical in which one or more of the hydrogen atoms are replaced by halogen including, but not limited to, chloromethyl, trifluoromethyl, 1-chloro-2-fluoroethyl and the like.
  • thioalkoxyalkyl refers to a thioalkoxy group appended to a loweralkyl radical.
  • alkylsulfonyl refers to R 93 SO 2 - wherein R 93 is loweralkyl group.
  • alkylsulfonylalkyl refers to an alkylsufonyl group appended to a loweralkyl radical.
  • arylthioalkyl refers to arylthioalkyl
  • aryloxyalkyl refers to aryloxyalkyl
  • R 94 -O-R 95 - wherein R 94 is an aryl group and R 95 is an alkylene group.
  • arylsulfonylalkyl refers to R 96 -S(O) 2 -R 97 - wherein R 96 is any aryl group and R 97 is an alkylene group.
  • (heterocyclic)oxyalkyl refers to R 98 -O-R 99 - wherein R 98 is a heterocyclic group and R 99 is an alkylene group.
  • (heterocyclic)thioalkyl refers to (heterocyclic)thioalkyl
  • (heterocyclic)sulfonylalkyl refers to (heterocyclic)sulfonylalkyl
  • arylalkoxyalkyl refers to R 104 -O-R 105 - wherein R 104 is an arylalkyi group and R 105 is an alkylene group, for example,
  • arylthioalkoxyalkyl refers to R 106 -S-R 107 - wherein R 106 is an arylalkyi group and R 107 is an alkylene group.
  • arylalkylsulfonylalkyl refers to R 108 -S(O) 2 -R 109- wherein R 108 is an arylalkyi group and R 109 is an alkylene group.
  • (heterocyclic)alkoxy refers to R 110 -O- wherein R 110 is a (heterocyclic)alkyl group, for example, 2-(morpholin-1 -yl)ethoxy and the like.
  • (heterocyclic)alkoxyalkyl refers to (heterocyclic)alkoxyalkyl
  • (heterocyclic)thioalkoxyalkyl refers to
  • (heterocyclic)alkylsulfonylalkyl refers to R 114 -S(O) 2 -R 115 - wherein R 114 is a (heterocyclic)alkyl group and R 115 is an alkylene group.
  • cycloalkyloxyalkyl refers to R 116 -O-R 117 - wherein R 116 is a cycloalkyl group and R 117 is an alkylene group.
  • cycloalkylthioalkyl refers to R 118 -S-R 119 - wherein R 118 is a cycloalkyl group and R 119 is an alkylene group.
  • cycloalkylsulfonylalkyl refers to cycloalkylsulfonylalkyl
  • cycloalkylalkoxyalkyl refers to cycloalkylalkoxyalkyl
  • cycloalkylthioalkoxyalkyl refers to cycloalkylthioalkoxyalkyl
  • cycloalkylalkylsulfonylalkyi refers to cycloalkylalkylsulfonylalkyi
  • R 126 -S(O)2-R 127 - wherein R 126 is a cycloalkylalkyl group and R 127 is an alkylene group.
  • alkanoyl refers to R k -C(O)- wherein R k is a loweralkyl group.
  • aminocarbonyl refers to aminocarbonyl
  • aminocarbonylalkyl refers to an aminocarbonyl group appended to a loweralkyl radical.
  • alkylaminocarbonyl refers to -C(O)NHR 128 wherein R 128 is loweralkyl.
  • alkylaminocarbonylalkyl refers to an alkylaminocarbonylalkyl
  • alkylaminocarbonyl group appended to a loweralkyl radical alkylaminocarbonyl group appended to a loweralkyl radical.
  • dialkylaminocarbonyl refers to dialkylaminocarbonyl
  • R 129 and R 130 are independently selected from loweralkyl.
  • dialkylaminocarbonylalkyl refers to a
  • dialkylaminocarbonyl group appended to a loweralkyl group
  • aroylalkyl refers to R 131 -C(O)-R 132 - wherein R 131 is an aryl group and R 132 is an alkylene group.
  • (heterocyclic)carbonylalkyl refers to
  • aminoalkoxy refers to an alkoxy radical to which is appended an amino (-NH 2 ) group.
  • alkylaminoalkoxy refers to an alkoxy radical to which is appended an alkylamino group.
  • dialkylaminoalkoxy refers to an alkoxy radical to which is appended a dialkylamino group.
  • (alkoxyalkyl)aminoalkyl refers to a loweralkyl radical to which is appended an (alkoxyalkyl)amino group.
  • (alkoxyalkyl)aminoalkoxy refers to an alkoxy radical to which is appended an (alkoxyalkyl)amino group.
  • (alkoxyalkyl)(alkyl)aminoalkyl refers to a loweralkyl radical to which is appended an (alkoxyalkyl)(alkyl)amino group.
  • (alkoxyalkyl)(alkyl)aminoalkoxy” as used herein refers to an alkoxy radical to which is appended an (alkoxyalkyl)(alkyl)amino group.
  • di-(alkoxyalkyl)aminoalkyl refers to a loweralkyl radical to which is appended an di-(alkoxyalkyl)amino group.
  • di-(alkoxyalkyl)aminoalkoxy refers to an alkoxy radical to which is appended an di-(alkoxyalkyl)amino group.
  • carboxyalkoxy refers to an alkoxy radical to which is appended a carboxy (-COOH) group.
  • aminocarbonylalkyl refers to a loweralkyl radical to which is appended an aminocarbonyl (H 2 NC(O)-) group.
  • alkylaminocarbonylalkyl refers to a loweralkyl radical to which is appended an alkylaminocarbonyl group.
  • dialkylaminocarbonylalkyl refers to a loweralkyl radical to which is appended an dialkylaminocarbonyl group.
  • (heterocyclic)carbonylalkoxy refers to
  • arylalkoxycarbonylalkyl refers to R 137 -O-C(O)- R 138 - wherein R 137 is an arylalkyi group and R 138 is an alkylene group.
  • alkanoyl refers to R 139 -C(O)- wherein R 139 is a loweralkyl group.
  • aroyl refers to R 140 -C(O)- wherein R 140 is an aryl group.
  • alkylsulfonyl refers to R 141 -S(O) 2 - wherein R 141 is a loweralkyl group.
  • arylsulfonyl refers to R 142 -S(O) 2 - wherein R 142 is an aryl group.
  • heterocyclic ring or “heterocyclic” as used herein independently refers to a 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two or three nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen and one sulfur atom; one nitrogen and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen and one sulfur atom in non-adjacent positions; or two sulfur atoms in non-adjacent positions.
  • the 5- membered ring has 0-2 double bonds and the 6-membered ring has 0-3 double bonds.
  • heterocyclic also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring.
  • Heterocyclics include: pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, tetrahydroqumolyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl,
  • Heterocyclics also include:
  • Preferred heterocyclics are pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, tetrahydrofuranyl, tetrahydrothienyl and
  • Heterocyclics can also be substituted with a heterocycle selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorphoHnyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, each of which can be unsubstituted or substituted with a substituent selected from halo, loweralkyl, hydroxy, alkoxy and thioalkoxy.
  • nitrogen containing heterocycles can be N-protected.
  • heterocyclicalkyl refers to a heterocyclic group appended to a loweralkyl radical, including but not limited to
  • naturally occurring ⁇ -amino acid refers to alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine,
  • glutamine aspartic acid, glutamic acid, lysine, arginine or histidine.
  • R 8 is hydrogen or an O-protecting group
  • R 9 and R 10 are independently selected from hydrogen and an N-protecting group; or an acid addition salt thereof.
  • Preferred compounds of the formula C are those wherein R 1 is loweralkyl or arylalkyi and R 2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl.
  • a preferred N-protecting group R 9 is t-butyloxycarbonyl or
  • a preferred N-protecting group R 10 is t-butyloxycarbonyl or
  • More preferred compounds are compounds of the formula C wherein R 1 is loweralkyl, benzyl, alkoxy-substituted benzyl or halo-substituted benzyl; and R 2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl.
  • R1 is isobutyl, benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl
  • R 2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl
  • R 1 is isobutyl, benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl
  • R 2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl.
  • Most highly preferred compounds are compounds of the formula C wherein R 1 is benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl; and R 2 is R 2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl.
  • Preferred compounds of the formula C also include compounds of the formula D:
  • R 8 is hydrogen or an O-protecting group
  • R 9 and R 10 are independently selected from hydrogen and an N-protecting group; or an acid addition salt thereof.
  • Preferred compounds of the formula D are those wherein R 1 is loweralkyl or arylalkyl and R 2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl.
  • a preferred N-protecting group R 9 is t-butyloxycarbonyl or
  • a preferred N-protecting group R 10 is t-butyloxycarbonyl or
  • More preferred compounds are compounds of the formula D wherein R 1 is loweralkyl, benzyl, alkoxy-substituted benzyl or halo-substituted benzyl; R 2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl,
  • R 1 is isobutyl, benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl
  • R 2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl
  • R 1 is isobutyl, benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl
  • R 2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl.
  • R 1 is benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl
  • R 2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl
  • R 2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl;
  • R 8 is hydrogen or an O-protecting group
  • Preferred compounds of the formula E are those wherein R 1 is loweralkyl or arylalkyi; R 2b is benzyl and R 8 is an O-protecting group.
  • Preferred compounds of formula E also include compounds of the formula F:
  • R 8 is hydrogen or an O-protecting group
  • Preferred compounds of the formula F are those wherein R 1 is loweralkyl or arylalkyi; R 2b is benzyl and R 8 is an O-protecting group.
  • the compounds of the invention can be prepared as shown in Schemes 1 - 5.
  • the schemes outline the preparation of the compounds of the invention having the preferred stereochemistry.
  • other stereoisomers of the compounds of the invention can be prepared by starting with the aminoalcohol having the opposite stereochemistry to that shown for compound 1 in Scheme 1.
  • oxidation for example, Swern oxidation
  • Olefination for example, by Wittig reaction
  • N-protected aldehyde 2 provides olefin 3.
  • Epoxidation of olefin 3 (for example, with m-chloroperbenzoic acid (MCPBA)) provides a mixture of epoxides 4 and 5. Separation of the epoxides (for example, by chromatography) provides the desired epoxide isomer 4.
  • reaction of N-protected hydrazine 6 (R 10 is an N-protecting group, for example, benzyloxycarbonyl) with an aldehyde or ketone derivative of substituent R2b provides hydrazone 7.
  • Reduction of hydrazone 7 (for example, by hydrogenation) provides hydrazine 8.
  • reaction of epoxide 4 with hydrazine 8 provides hydroxy hydrazine 9.
  • Protection of the hydroxyl group with an O-protecting group for example, trimethylsilylethoxymethyl, methoxyethoxymethyl or methoxymethyl and the like) provides 10.
  • Removal of N-protecting groups provides 11.
  • reaction of 11 with Q-X-Q' provides 12.
  • Q and Q" are, for example, independently selected from imidazolyl, N-succinimidyloxy, -O-phenyl, halogen and the like.
  • Q and Q' are, for example, imidazolyl and the like.
  • a sulfonate mesylate, tosylate, triflate and the like
  • a halogen and the like a halogen and the like
  • R 2 can be introduced by first removing the N-protecting group R 2b from compound 12 (by hydrogenation or other suitable N-debenzylation method) to give 13. Acylation or sulfonylation of 13 with R 2 -Z wherein R 2 -Z is a carboxylic acid halide or sulfonyl halide and the like provides 14.
  • a sulfonate mesylate, tosylate, triflate and the like
  • a halogen and the like a halogen and the like
  • triphenylmethylphosphonium bromide To this was added 70 ml of THF, cooled to 0°C and 4.42 g of 35% potassium hydride dispersion in oil was added. The mixture was stirred at RT for 24 h. To this mixture was added 30 ml of toluene and let stand for 30 min. The supernatant was cannulated over into a solution of 3.37 g of N-((benzyloxy)carbonyl)-D-phenylalaninal in 50 ml of toluene at -78°C. The reaction mixture was stirred at -78°C for 2 h, followed by 0.5 h at RT. Satd. ammonium chloride (50 ml) was added.
  • Example 1 D To a solution of 1.2 g of the product of Example 1 C in 36 ml of isopropanol was added 1.03 g of the hydrazine from Example 1 D. The solution was heated at reflux for 24 h; cooled to RT and concentrated in vacuo. Silica gel column chromatography (10% to 20% acetone/hexane) provided 1.5 g of desired product.
  • Example 1 G (in 5 ml of CH 2 CI 2 ) over a period of 2 h via a syringe pump. The solution was kept at RT for 72 h; concentration in vacuo and purification by silica gel column chromatography (20% EtOAc/CH 2 Cl 2 ) provided 400 mg of desired compound.
  • Example 1H To a suspension of 72 mg of 20% palladium hydroxide on carbon in 36 ml of methanol was added 360 mg of the product of Example 1H. The mixture was stirred vigorously under a hydrogen atmosphere (balloon filled with hydrogen) for 1 h. The catalyst was filtered off and the filtrate was concentrated in vacuo to provide 285.0 mg of the desired product.
  • Example 1L Using the procedure of Example 1L, but replacing the product of Example 1K with the product of Example 2B, provided the desired compound.
  • Example 1J Using the procedure of Example 1J, but replacing the benzoyl chloride with isobutyryl chloride, provided the desired compound.
  • 1 H NMR (CDCI 3 ) ⁇ 0.03 (s, 9H), 0.96 (t, 2H), 1.12 (d, 6H), 2.79 (m, 1H), 2.94 (m, 1H), 3.11 (m, 1H), 3.21 (m, 1H), 3.70 (m, 3H), 4.08 (m, 1H), 4.41 (br s, 1H), 4.71 (d, 1H), 4.77 (m, 1H), 4.85 (d, 1H), 6.74 (br s, 1H), 7.18 (m, 2H), 7.25-7.35 (m, 3H).
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 4A, provided the desired compound.
  • Example 1L Using the procedure of Example 1L, but replacing the product of Example 1K with the product of Example 4B , provided the desired compound.
  • 1H NMR (CDCI 3 ) ⁇ .65 (t, 3H), 0.99 (d, 3H), 1.03 (t, 3H), 1.14 (d, 3H),1.22 (m, 2H), 1.78 (m, 2H), 1.91 (m, 1H), 2.74 (m, 1H), 2.88 (dd, 1H), 3.03 (m, 3H), 3.15 (m, 1H), 3.41 (m, 1H), 3.92 (m, 1H), 4.06 (ddd, 1H), 4.58 (dd, 1H), 7.19-7.33 (m, 5H). Mass spectrum:
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 5A, provided the desired compound.
  • Example 1L Using the procedure of Example 1L, but replacing the product from Example 1K with the product of Example 7B and replacing the allyl bromide with bromomethyl cyclopropane, provided the desired compound.
  • Example 1J Using the procedure of Example 1J , but replacing the benzoyl chloride with 2-furoyl chloride, provided the desired compound.
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 2A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound.
  • 1 H NMR (DMSO-D 6 ) (mixture of three rotamers) ⁇ 1.83, 1.87 and 2.03 (three s, 3H), 2.33-2.45 (m, 1H), 2.60 (m, 1H), 2.73 (m, 1H), 2.83 (m, 1H), 3.13-3.23 (m, 1H), 3.55-3.68 (m, 1H), 3.95, 4.17 and 4.25 (three d, 1H), 4.28, 4.36 and 4.55 (three d, 1H), 4.89, 4.92 and 4.96 (three d, 1H), 5.36, 5.38 and 5.48 ( three d, 1H), 6.63 (m, 4H), 6.78 (m, 2H), 7.02 (m, 2H), 7.17-7.34
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 4A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound.
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 11 A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound.
  • 1 H NMR (DMSO-d 6 ) (mixture of three rotamers) 0.81 and 0.94 (three t, 3H), 1.44-1.57, (m, 2H), 2.34-2.67 (m, 1H), 2.73-2.97 (m, 2H), 3.22 (m, 1H), 3.63-3.72 (m, 1H), 3.98 (m, 1H), 4.12-4.23 (m, 1H), 4.22-4.56 (three d, 1H), 4.85-4.98 (three d, 1H), 5.33-5.47 (three d, 1H), 6.60-6.79 (m, 6H), 6.98-7.35 (m, 7H), 9.33 (br s, 1H), 9.46 (br s, 1H).
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 12A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound.
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 13A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound.
  • 1 H NMR (DMSO-D 6 ) (mixture of three rotamers) ⁇ .81, 0.87 and 0.92 (three t, 3H), 1.19, 1.37 and 1.52 ( three m, 4H), 1.90, 2.13 and 1.32 (three m, 2H), 2.39 (m, 1H), 2.62- 2.97 (m, 3H), 3.07-3.22 (m, 1H), 3.60-3.65 (m, 1H), 3.92, 3.96 and 4.03 (three d, 1H), 3.97, 4.16 and 4.21 (three d, 1H), 4.29, 4.38 and 4.52 (three d, 1H), 4.83, 4.89 and 4.95 (three d, 1H), 5.35, 5.38 and 5.47 (three d,
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 14A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound.
  • 1 H NMR (DMSO-D 6 ) (mixtures of three rotamers) ⁇ 0.75-0.96 (three m, 6H), 1.25-1.58 (three m, 4H), 2.36-2.46 (m, 1H), 2.65-2.85 (m, 3H), 3.15-3.25 (m, 2H), 3.68 (m, 1H), 3.95 (d, 1H), 4.10 (m, 1H), 4.38 (d, 1H), 4.95, 5.06 and 5.13 (three d, 1H), 5.38, 5.40 and 5.44 (three d, 1H), 6.57-6.63 (m, 4H), 6.87 (dd, 2H), 6.90 (dd, 1H), 7.12 (dd, 1H), 7.22-7.32
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 15A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound.
  • 1 H NMR (DMSO-D 6 ) (mixtures of three rotamers) ⁇ 0.72, 0.85 and 0.87 (three t, 6H), 1.18-1.57 (m, 8H), 2.28-2.38 (m, 1H), 2.58-3.18 (m, 5H), 3.67 (dd, 1H), 3.97 (d, 1H), 4.03, 4.07 and 4.11 (three d, 1H), 4.12, 4.37 and 4.58 (three d, 1H), 4.94, 5.08 and 5.15 (three d, 1H), 5.35, 5.40 and 5.42 (three d, 1H), 6.52-6.63 (m, 4H), 6.74-6.79 (m, 2H), 6.87 (m, 1H), 7.09-7.16(
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 16A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound.
  • 1 H NMR (DMSO-D 6 ) (mixtures of three rotamers) ⁇ 1.94-1.85 (m, 8H), 2.23-2.30 (m, 1H), 2.61-3.18 (m, 5H), 3.66 (d, 1H), 3.98, 4.01 and 4.03 (three d, 1H), 4.08, 4.17 and 4.22 (three d, 1H), 4.30, 4.42 and 4.57 (three d, 1H), 4.82, 4.84 and 5.01 (three d, 1H), 5.31, 5.35 and 5.46 (three d, 1H), 6.58-6.66 (m, 4H), 6.73-6.79 (m, 2H), 6.97-6.99 (m, 1H), 7.09-7.15 (m, 2H), 7.19
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 7B and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound.
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 18A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound.
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 21 C and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound.
  • 1 H NMR (DMSO-D 6 ) (mixtures of three rotamers) ⁇ 1.34-1.61 (m, 4H), 2.07-2.47 (m, 2H), 2.55-2.96 (m, 3H), 3.16-3.24 (m, 3H), 3.38-3.46 (m, 1H), 3.60-3.65 (m, 1H), 3.94- 4.02 (m, 1H), 4.09, 4.10 and 4.12 (three d, 1H), 4.15, 4.23 and 4.25 (three d, 1H), 4.37, 4.40 and 4.46 (three t, 1H), 4.54, 4.90 and 4.97 (three d, 1H), 5.34, 5.37 and 5.46 (three d, 1H), 6.60-6.62 (m, 4H
  • Example 21 A with the product of Example 22A, provided the desired compound. Mass spectrum: (M+NH) + 438.
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 22C and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound.
  • 1 H NMR (DMSO-D 6 ) (mixture of three rotamers) ⁇ 1.57-1.75 (m, 2H), 2.32-2.47 (m, 2H), 2.56-2.90 (m, 3H), 3.15-3.22 (m, 3H), 3.42-3.47 (m, 1H), 3.63 (m, 1H), 3.97 (m, 1H), 4.08, 4.10 and 4.13 (three d, 1H), 4.15, 4.24 and 4.38 (three d, 1H), 4.48, 4.54 and 4.56 (three t, 2H), 4.894.93 and 5.02 (three d, 1H), 5.36, 5.38 and 5.44 (three d, 1H), 6.61 (m, 4H), 6.76-6.79 (m,
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 23C and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound.
  • 1 H NMR (DMSO-D 6 ) (mixture of three rotamers) ⁇ 2.58-2.79 (m, 3H), 3.10-3.25 (m, 2H), 3.39-3.48 (m, 1H), 3.65 (m, 1H), 3.87 (m, 1H), 4.08 (d, 1H), 4.33, 4.39 and 4.46 (three d, 2H), 4.80, 4.94 and 4.95 (three d, 1H), 5.43, 5.46 and 5.61 (three d, 1H), 6.64-6.76 (m, 6H), 7.03-7.33 (m, 7H), 7.73, 7.98 and 8.12 (three s, 1H), 9.30,9.33, 9.35, 9.43, 9.47 and 9.50 (six s,
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 12A and replacing the allyl bromide with 3-nitrobenzyl bromide, provided the desired compound.
  • 1 H NMR (DMSO-d 6 ) (mixture of three rotamers) 0.65-0.94 (six d, 6H), 1.54-2.37 (m, 4H), 2.64-3.22 (m, 3H), 3.32-4.18 (m, 3H), 4.26-4.32 (m, 1H), 4.48-4.60 (m, 1H), 5.14, 5.17 and 5.18 (three d, 1H), 5.46, 5.50 and 5.51 (three d, 1H), 6.86-8.41 (m, 13H).
  • Mass spectrum: (M+ H)+ 576.
  • Example 1K Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 12A and replacing the allyl bromide with 4-nitrobenzyl bromide, provided the desired compound.
  • 1 H NMR (DMSO-d 6 ) (mixture of two rotamers) 0.68-0.94 (four d, 6H), 1.57-2.38, (m, 4H), 2.63-3.20 (m, 3H), 3.31-4.16 (m, 3H), 4.25 and 4.31 (two d, 1H), 4.49 and 4.57 (two dd, 1H), 5.15 and 5.16 (two d, 1H), 5.44 and 5.49 (two d, 1H), 6.86-8.32 (m, 13H).
  • Mass spectrum: (M+ H)+ 576.
  • Tables 1 -128 can be prepared.
  • Ph represents phenyl.
  • the inhibitory potency of the compounds of the invention can be determined by the following method.
  • a compound of the invention is dissolved in DMSO and a small aliquot further diluted with DMSO to 100 times the final concentration desired for testing.
  • the reaction is carried out in a 6 X 50 mm tube in a total volume of 300 microliters.
  • the final concentrations of the components in the reaction buffer are: 125 mM sodium acetate, 1 M sodium chloride, 5 mM dithiothreitol, 0.5 mg/ml bovine serum albumin, 1.3 ⁇ M fluorogenic substrate, 2% (v/v)
  • reaction mixture is placed in the fluorometer cell holder and incubated at 30°C for several minutes.
  • the reaction is initiated by the addition of a small aliquot of cold HIV protease.
  • the fluorescence intensity (excitation 340 nM, emmision 490 nM) is recorded as a function of time.
  • the reaction rate is determined for the first six to eight minutes. The observed rate is directly proportional to the moles of substrate cleaved per unit time. The percent inhibition is 100 X (1 - (rate in presence of inhibitor)/(rate in absence of inhibitor)).
  • Table I shows the inhibitory potencies of compounds of the invention against HIV-1 protease.
  • the anti-HIV activity of the compounds of the invention can be determined in MT4 cells according to the procedure of Kempf, et. al.
  • the IC 50 is the
  • the LC 50 is the concentration of compound at which 50% of the cells remain viable.
  • Table II shows the inhibitory potencies of compounds of the invention against HIV-1 38 in MT4 cells.
  • 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, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy- ethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate
  • the basic nitrogen- containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil- soluble or dispersible products are thereby obtained.
  • loweralkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates
  • 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.
  • esters examples include a hydroxyl-substituted compound of formula A or B which has been acylated with a naturally occurring ⁇ -amino acid residue which is optionally N-protected, a phosphate function, a hemisuccinate residue, an acyl residue of the formula R*C(O)- or R*C(S)- wherein R* is hydrogen, loweralkyl, haloalkyl, alkoxy, thioalkoxy, alkoxyalkyl, thioalkoxyalkyl or haloalkoxy, or an acyl residue of the formula R a -C(R b )(R d )-C(O)- or R a - C(R b )(R d )-C(S)- wherein R b and R d are independently selected from hydrogen and loweralkyl and R a is -N(R e )(
  • R 180 NH(CH 2 ) 2 OCH 2 C(O)- wherein R 1 80 is hydrogen, loweralkyl, arylalkyl. cycloalkylalkyl, alkanoyl, benzoyl or a naturally occurring ⁇ -amino acyl group.
  • the amino acid esters of particular interest are those derived from the naturally occurring ⁇ -amino acids, however, other amino acid residues can also be used, including those wherein the amino acyl group is -C(O)CH 2 NR 200 R 201 wherein R 200 and R 201 are independently selected from hydrogen and loweralkyl or the group -NR 200 R 201 forms a nitrogen containing heterocyclic ring.
  • esters serve as pro-drugs of the compounds of the present invention and also serve to increase the solubility of these substances in the gastrointestinal tract. These esters also serve to increase solubility for intravenous administration of the compounds.
  • Other prodrugs include a hydroxyl-substituted compound of formula A or B wherein the hydroxyl group is functionalized with a substituent of the formula -CH(R g )OC(O)R 181 or -CH(R g )OC(S)R 181 wherein R 181 is loweralkyl, haloalkyl, alkoxy, thioalkoxy or haloalkoxy and R g is hydrogen, loweralkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl.
  • Such prodrugs can be prepared according to the procedure of Schreiber (Tetrahedron Lett. 1983, 24, 2363) by ozonolysis of the corresponding
  • the prodrugs of this invention are metabolized in vivo to provide the hydroxyl-substituted compound of formula A or B.
  • the preparation of the prodrug esters is carried out by reacting a hydroxyl-substituted compound of formula A or B with an activated amino acyl, phosphoryl, hemisuccinyl or acyl derivative as defined above. The resulting product is then deprotected to provide the desired pro-drug ester.
  • Prodrugs of the invention can also be prepared by alkylation of the hydroxyl group with (haloalkyl)esters, transacetalization with bis-(alkanoyl)acetals or condensation of the hydroxyl group with an activated aldehyde followed by acylation of the intermediate hemiacetal.
  • the compounds of the invention are useful for inhibiting retroviral protease, in particular HIV protease, in vitro or in vivo (especially in mammals and in particular in humans).
  • the compounds of the present invention are also useful for the inhibition of retroviruses in vivo, especially human
  • immunodeficiency virus HIV
  • the compounds of the present invention are also useful for the treatment or prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection, in a human or other mammal.
  • Total daily dose administered to a human or other mammal host in single or divided doses may be in amounts, for example, from about 0.001 to about 1000 mg/kg body weight daily and more usually from about 0.1 to about 50 mg/kg body weight daily.
  • Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
  • the compounds of the present invention may be administered orally, parenterally, sublingually, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional 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.
  • parenteral as used herein includes
  • subcutaneous injections intravenous, intramuscular, intrasternal injection, or infusion techniques.
  • sterile injectable preparations for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-propanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules.
  • 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
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • 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.
  • the compounds of the present invention can also be administered in the form of liposomes.
  • liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically aceptable and metabolizable lipid capabale of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like.
  • the preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic.
  • the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more immunomodulators, antiviral agents, other antiinfective agents or vaccines.
  • Other antiviral agents to be administered in combination with a compound of the present invention include AL-721 , beta interferon,
  • reverse transcriptase inhibitors for example, zalcitabine (ddC), didanosine (ddl), BCH-189, AzdU, carbovir, DDA, D4C, stavudine (d4T), DP-AZT, FLT (fluorothymidine), BCH-189, 5-halo-3'-thia-dideoxycytidine, PMEA, zidovudine (AZT) and the like
  • non-nucleoside reverse transcriptase inhibitors for example, R82193, L-697,661 , BI-RG-587 (nevirapine
  • retroviral protease inhibitors for example, HIV protease inhibitors such as Ro 31 -8959, SC-52151 , KNI-227, KNI-272 and the like
  • HEPT compounds L,697,639, R82150, U- 87201 E and the like
  • TAT inhibitors for example, RO-24-7429 and the like
  • nucleophosphoprotein ansamycin LM 427, trimetrexate, UA001 , ribavirin, alpha interferon, oxetanocin, oxetanocin-G, cylobut-G, cyclobut-A, ara-M, BW882C87, foscamet, BW256U87, BW348U87, L-693,989, BV ara-U, CMV triclonal antibodies, FIAC, HOE-602, HPMPC, MSL-109, TI-23, trifluridine, vidarabine, famciclovir, penciclovir, acyclovir, ganciclovir, castanospermine, rCD4/CD4-lgG, CD4-PE40, butyl-DNJ, hypericin, oxamyristic acid, dextran sulfate and pentosan polysulfate.
  • Immunomodulators that can be administered in combination with a compound of the present invention include bropirimine, Ampligen, anti-human alpha interferon antibody, colony stimulting factor, CL246,738, lmreg-1 , lmreg-2, diethydithiocarbamate, interleukin-2, alpha- interferon, inosine pranobex, methionine enkephalin, muramyl-tripeptide, TP-5, erythropoietin, naltrexone, tumor necrosis facator, beta interferon, gamma interferon, interleukin-3, interleukin-4, autologous CD8+ infusion, alpha interferon immunoglobulin, IGF-1 , anti-Leu-3A, autovaccination, biostimulation, extracorporeal photophoresis, FK-565, FK-506, G-CSF, GM-CSF, hyperthermia, isopinosine, IVIG,
  • pentamidine isethionate Any of a variety of HIV or AIDS vaccines (for example, gp120 (recombinant), Env 2-3 (gp120), HIVAC-1 e (gp120), gp160 (recombinant), VaxSyn HIV-1 (gp160), Immuno-Ag (gp160), HGP-30, HIV-lmmunogen, p24 (recombinant), VaxSyn HIV-1 (p24) can be used in combination with a variety of HIV or AIDS vaccines (for example, gp120 (recombinant), Env 2-3 (gp120), HIVAC-1 e (gp120), gp160 (recombinant), VaxSyn HIV-1 (gp160), Immuno-Ag (gp160), HGP-30, HIV-lmmunogen, p24 (recombinant), VaxSyn
  • agents that can be used in combination with the compounds of this invention are ansamycin LM 427, apurinic acid, ABPP, AI-721 , carrisyn, AS-101 , avarol, azimexon, colchicine, compound Q, CS-85, N-acetyl cysteine, (2- oxothiazolidine-4-carboxylate), D-penicillamine, diphenylhydantoin, EL-10, erythropoieten, fusidic acid, glucan, HPA-23, human growth hormone, hydroxchloroquine, iscador, L-ofloxacin or other quinolone antibiotics, lentinan, lithium carbonate, MM-1 , monolaurin, MTP-PE, naltrexone, neurotropin, ozone, PAI, panax ginseng, pentofylline, pentoxifylline, Peptide T, pine cone extract, polymannoacetate, reticulose
  • agents that can be used in combination with the compounds of this invention are antifungals such as amphotericin B, clotrimazole, flucytosine, fluconazole, itraconazole, ketoconazole and nystatin and the like.
  • antibactehals such as amikacin sulfate, azithromycin,
  • anti-neoplasties such as alpha interferon, COMP
  • cyclophosphamide, vincristine, methotrexate and prednisone cyclophosphamide, vincristine, methotrexate and prednisone
  • etoposide mBACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine and dexamethasone)
  • PRO-MACE/MOPP prednisone, methotrexate (w/leucovin rescue)
  • vincristine vinblastine
  • angioinhibins pentosan polysulfate, platelet factor 4 and SP-PG and the like.
  • agents that can be used in combination with the compounds of this invention are drugs for treating neurological disease such as peptide T, ritalin, lithium, elavil, phenytoin, carbamazipine, mexitetine, heparin and cytosine arabinoside and the like.
  • agents that can be used in combination with the compounds of this invention are anti-protozoals such as albendazole, azithromycin, clarithromycin, clindamycin, corticosteroids, dapsone, DIMP, eflomithine, 566C80, fansidar, furazolidone, L, 671 , 329, letrazuril, metronidazole, paromycin, pefloxacin, pentamidine, piritrexim, primaquine, pyrimethamine, somatostatin, spiramycin, sulfadiazine, trimethoprim, TMP/SMX, trimetrexate and WR 6026 and the like.
  • anti-protozoals such as albendazole, azithromycin, clarithromycin, clindamycin, corticosteroids, dapsone, DIMP, eflomithine, 566C80, fansidar, furazolidone, L, 671 , 329, letrazuril, met
  • Among the preferred agents for treatment of HIV or AIDS in combination with the compounds of this invention are reverse transcriptase inhibitors.
  • agents which can be combined with the compounds of the present invention for the treatment or prophylaxis of AIDS or an HIV infection are not limited to those listed above, but include in principle any agents useful for the treatment or prophylaxis of AIDS or an HIV infection.
  • the therapeutic agents When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or different times, or the therapeutic agents can be given as a single composition.

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Abstract

L'invention concerne un composé d'inhibition de la protéase de rétrovirus représenté par la formule (A).
PCT/US1995/009472 1994-08-09 1995-07-26 1,2,4,-triazacycloheptanes inhibant la protease de retrovirus WO1996005180A1 (fr)

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AU31503/95A AU3150395A (en) 1994-08-09 1995-07-26 Retroviral protease inhibiting 1,2,4-triazacycloheptanes

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US28638094A 1994-08-09 1994-08-09
US08/286,380 1994-08-09
US40626995A 1995-03-17 1995-03-17
US08/406,269 1995-03-17

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Cited By (5)

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Publication number Priority date Publication date Assignee Title
US6184241B1 (en) 1998-08-24 2001-02-06 Kansas State University Research Foundation Aspartic protease inhibitors
US6313296B1 (en) * 1995-12-13 2001-11-06 Abbott Laboratories Retroviral protease inhibiting compounds
EP1242383A1 (fr) * 1999-11-12 2002-09-25 GPI NIL Holdings, Inc. Composes aza a activite neurale
RU2197483C2 (ru) * 1998-01-14 2003-01-27 Мерк Патент Гмбх Триазепиноны, способ их получения и фармацевтическая композиция
US7253169B2 (en) 1999-11-12 2007-08-07 Gliamed, Inc. Aza compounds, pharmaceutical compositions and methods of use

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WO1992009297A1 (fr) * 1990-11-30 1992-06-11 Smithkline Beecham Corporation Inhibiteurs de la protease du vih
EP0521827A1 (fr) * 1991-07-03 1993-01-07 Ciba-Geigy Ag Dérivés d'hydrazine pharmacologiquement actives et procédé pour leur préparation
WO1993018006A1 (fr) * 1992-03-11 1993-09-16 Narhex Limited Derives amines d'hydrocarbures a substitution oxo et hydroxy
WO1994008977A1 (fr) * 1992-10-22 1994-04-28 The Du Pont Merck Pharmaceutical Company Caprolactames substitues et leurs derives, utiles dans le traitement du sida
EP0604368A1 (fr) * 1992-12-23 1994-06-29 Ciba-Geigy Ag Dérivés antiviraux de hydrazine
WO1994019332A1 (fr) * 1993-02-25 1994-09-01 Abbott Laboratories Composes inhibiteurs de proteases retrovirales
WO1995002582A1 (fr) * 1993-07-14 1995-01-26 Ciba-Geigy Ag Composes d'hydrazines cycliques

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WO1992009297A1 (fr) * 1990-11-30 1992-06-11 Smithkline Beecham Corporation Inhibiteurs de la protease du vih
EP0521827A1 (fr) * 1991-07-03 1993-01-07 Ciba-Geigy Ag Dérivés d'hydrazine pharmacologiquement actives et procédé pour leur préparation
WO1993018006A1 (fr) * 1992-03-11 1993-09-16 Narhex Limited Derives amines d'hydrocarbures a substitution oxo et hydroxy
WO1994008977A1 (fr) * 1992-10-22 1994-04-28 The Du Pont Merck Pharmaceutical Company Caprolactames substitues et leurs derives, utiles dans le traitement du sida
EP0604368A1 (fr) * 1992-12-23 1994-06-29 Ciba-Geigy Ag Dérivés antiviraux de hydrazine
WO1994019332A1 (fr) * 1993-02-25 1994-09-01 Abbott Laboratories Composes inhibiteurs de proteases retrovirales
WO1995002582A1 (fr) * 1993-07-14 1995-01-26 Ciba-Geigy Ag Composes d'hydrazines cycliques

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H.L. SHAM ET AL.: "Facile Synthesis of Potent HIV-1 Protease Inhibitors containing a Novel Pseudo-symmetric Pipeptide Isostere", JOURNAL OF THE CHEMICAL SOCIETY, CHEMICAL COMMUNICATIONS., no. 13, 7 July 1993 (1993-07-07), LETCHWORTH GB, pages 1052 - 1053 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6313296B1 (en) * 1995-12-13 2001-11-06 Abbott Laboratories Retroviral protease inhibiting compounds
US6472529B2 (en) 1995-12-13 2002-10-29 Abbott Laboratories Retroviral protease inhibiting compounds
US7279582B2 (en) 1995-12-13 2007-10-09 Abbott Laboratories Retroviral protease inhibiting compounds
US7968707B2 (en) 1995-12-13 2011-06-28 Abbott Laboratories Retroviral protease inhibiting compounds
RU2197483C2 (ru) * 1998-01-14 2003-01-27 Мерк Патент Гмбх Триазепиноны, способ их получения и фармацевтическая композиция
US6184241B1 (en) 1998-08-24 2001-02-06 Kansas State University Research Foundation Aspartic protease inhibitors
EP1242383A1 (fr) * 1999-11-12 2002-09-25 GPI NIL Holdings, Inc. Composes aza a activite neurale
US7253169B2 (en) 1999-11-12 2007-08-07 Gliamed, Inc. Aza compounds, pharmaceutical compositions and methods of use

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IL114752A0 (en) 1995-11-27

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