CA2081970C - Hiv protease inhibitors useful for the treatment of aids - Google Patents
Hiv protease inhibitors useful for the treatment of aidsInfo
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- CA2081970C CA2081970C CA002081970A CA2081970A CA2081970C CA 2081970 C CA2081970 C CA 2081970C CA 002081970 A CA002081970 A CA 002081970A CA 2081970 A CA2081970 A CA 2081970A CA 2081970 C CA2081970 C CA 2081970C
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—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 carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- 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
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- 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
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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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
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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
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
Compounds of formula (see fig. I) where R1 and R2 are independently hydrogen or optionally-substituted C1-4alkyl or aryl, or R1 and R2 are joined together to form a monocyclic or bicyclic ring system, are HIV protease inhibitors.
Description
- 2û81970 - 1 - 18597y TITLE OF THE INVENTION
HIV PROTEASE INHIBITORS USEFUL FOR THE TREATMENT OF
AIDS
The present invention is concerned with compounds which inhibit the protease encoded by human immunodeficiency virus (HIV) or pharmaceutically acceptable salts thereof and are of value in the prevention of infection by HIV, the treatment of infection by HIV and the treatment of the resulting acquired immune deficiency syndrome (AIDS).
It also relates to pharmaceutical compositions containing the compounds and to a method of use of the present compounds and other agents for the treatment of AIDS and viral infection by HIV.
'f-A
_ , 208197~
BACKGROUN~ OF THE l~v~NllON
A retrovirus designated human immunode-ficiency virus (HIV) i8 the etiological agent of the complex disease that includes progreæsive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the extensive post-trans-lational processing of precursor polyproteins by avirally encoded protease to generate mature viral proteins required for virus assembly and function.
Inhibition of this processing prevents the production of normally infectious virus. For example, Kohl, N.E. et al., Proc. Nat'l Acad. Sci. 85, 4686 (1988) demonstrated that genetic inactivation of the HIV
encoded protease resulted in the production of immature, non-infectious virus particles. These results indicate that inhibition of the HIV protease represents a viable method for the treatment of AIDS
and the prevention or treatment of infection by HIV.
The nucleotide sequence of HIV æhows the presence of a pol gene in one open reading frame ~Ratner, L. et al., Nature, 313, 277(1985)]. Amino acid sequence homology`provides evidence that the ol æequence encodes reverse transcriptase, an endonuclease and an HIV protease ~Toh, H. et al., EMBO J. 4, 1267 (1985); Power, M.D. et al., Science, ~1, 1567 (1986); Pearl, L.H. et al., Nature 329, 351 (1987)]. Applicants demonstrate that the compounds of this invention are inhibitors of HIV protease.
BRIEF DESCRIPTION OF T~F I~V~N110N
Compounds of formula I, as herein defined, are disclosed. These compounds are useful in the inhibition of HIV protease, the prevention of infection by HIV, the treatment of infection by HIV
and in the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS, methods of preventing infection by HIV, and methods of treating infection by HIV are also disclosed.
Some abbreviations that may appear in this application are as follows.
ABBREVIATIONS
DesiPnation Protecting Group BOC (Boc) t-butyloxycarbonyl 2~ CBZ (Cbz) benzyloxycarbonyl(carbo-benzoxy) TBS (TBDMS) t-butyl-dimethylsilyl Activating Group 2s HBT(HOBT or HOBt) l-hydroxybenzotriazole hydrate 2~1970 Desi~nation Couplin ReAgent BOP reagent benzotriazol-l-ylo~ytris-(dimethylamino)phospho-nium hexafluorophosphate 5 BOP-Cl bis(2-oxo-3-oxazolidinyl) phosphinic chloride EDC l-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide hydrochloride Other (BOC)20 (BOC20) di-t-butyl dicarbonate n-Bu4N+F~ tetrabutyl ammonium fluoride nBuLi (n-Buli) n-butyllithium DMF dimethylformamide Et3N triethylamine EtOAc ethyl acetate TFA trifluoroacetic acid 20 DMAP dimethylaminopyridine DME dimethoxyethane LDA lithium diisopropylamide THF tetrahydrofuran Amino Acid Ile L-isoleucine Val L-valine DETAILED DESCRIPTION OF THE IN~NL10N AND PREFERRED
~MBODIMENTS
This invention is concerned with compounds of formula I, combinations thereof, or pharmaceutically acceptable salts thereof, in the inhibition of HIV protease, the prevention or treatment of infection by HIV and in the treatment of the resulting acquired immune deficiency syndrome (AIDS). Compounds of formula I are defined as follows:
Z R X R
J1 ~ N ~ B- J2 R2 z I
wherein X is -OE or -NH2;
Z is -O, -S, or -NE;
R is hydrogen or C1_4 alkyl;
R1 and R2 are independently:
1) hydrogen, 2) -Cl_4 alkyl unsubstituted or substituted with one or more of a) halo, b) hydroxy, 3~ c) Cl_3 alkoxy, d) aryl unsubstituted or substituted with one or more of Cl_4alkyl, hydroxy or aryl, 238197~
, e) -W-aryl or -W-benzyl, wherein W iæ -O-, -S-, or -NH-, f) a 5-7 membered cycloalkyl group unsubstituted or substituted with one or more of i) halo, ii) hydroxy, iii) Cl_3 alkoxy, or iv) aryl, g) heterocycle unsubstituted or substituted with one or more of hydroxy, Cl_4alkyl optionally substituted with hydroxy, or Boc, o h) -NE-COCl_3alkyl, i ) -NH-C-Cl_3alkyl, j ) -NH-so2cl-3alkyl, k) -NR2, l) -COOR, or m) -((CH2)mO)nR wherein m is 2-5 and n is zero, l, 2 or 3, or 3) aryl, unsubstituted or substituted with one or more of a) halo, b) hydroxy, c) -N02 or -NR2, d) Cl_4alkyl, e) Cl_3 alkoxy, unsubstituted or substituted with one or more of -OH or Cl_3 alkoxy, 208~970 , f) -COOR, 1l g) -CNR
h) -CH2NR2 i) -CH2NHCR, j) -CN, k) -CF3, lo 1) -NHCR, m) aryl Cl_3 alkoxy, n) aryl, o) -NRS02R, p) -OP(O)(ORX)2, or q) -R5, as defined below; or Rl and R2 can be joined together to form with the nitrogen to which Rl is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system which consists of the nitrogen to which Rl is attached and from 2 to 9 carbon atoms, and is unsubstituted or substituted with 1) hydroxy, 2) Cl_4 alkyl unsubstituted or substituted with one or more of a) halo, b) hydroxy, c) Cl_3 alkoxy, d) aryl, 0 2asls~3 e) a 5-7 membered cycloalkyl group unsubstituted or substituted with one or more of i) halo, ii) hydroxy, iii) Cl_3 alkoxy, or iv) aryl, f) heterocycle, or g) -NR2, 4) -N~-~OCl_3alkyl, 5) -NH-C-Cl_3alkyl, 6) -NH
HIV PROTEASE INHIBITORS USEFUL FOR THE TREATMENT OF
AIDS
The present invention is concerned with compounds which inhibit the protease encoded by human immunodeficiency virus (HIV) or pharmaceutically acceptable salts thereof and are of value in the prevention of infection by HIV, the treatment of infection by HIV and the treatment of the resulting acquired immune deficiency syndrome (AIDS).
It also relates to pharmaceutical compositions containing the compounds and to a method of use of the present compounds and other agents for the treatment of AIDS and viral infection by HIV.
'f-A
_ , 208197~
BACKGROUN~ OF THE l~v~NllON
A retrovirus designated human immunode-ficiency virus (HIV) i8 the etiological agent of the complex disease that includes progreæsive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the extensive post-trans-lational processing of precursor polyproteins by avirally encoded protease to generate mature viral proteins required for virus assembly and function.
Inhibition of this processing prevents the production of normally infectious virus. For example, Kohl, N.E. et al., Proc. Nat'l Acad. Sci. 85, 4686 (1988) demonstrated that genetic inactivation of the HIV
encoded protease resulted in the production of immature, non-infectious virus particles. These results indicate that inhibition of the HIV protease represents a viable method for the treatment of AIDS
and the prevention or treatment of infection by HIV.
The nucleotide sequence of HIV æhows the presence of a pol gene in one open reading frame ~Ratner, L. et al., Nature, 313, 277(1985)]. Amino acid sequence homology`provides evidence that the ol æequence encodes reverse transcriptase, an endonuclease and an HIV protease ~Toh, H. et al., EMBO J. 4, 1267 (1985); Power, M.D. et al., Science, ~1, 1567 (1986); Pearl, L.H. et al., Nature 329, 351 (1987)]. Applicants demonstrate that the compounds of this invention are inhibitors of HIV protease.
BRIEF DESCRIPTION OF T~F I~V~N110N
Compounds of formula I, as herein defined, are disclosed. These compounds are useful in the inhibition of HIV protease, the prevention of infection by HIV, the treatment of infection by HIV
and in the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS, methods of preventing infection by HIV, and methods of treating infection by HIV are also disclosed.
Some abbreviations that may appear in this application are as follows.
ABBREVIATIONS
DesiPnation Protecting Group BOC (Boc) t-butyloxycarbonyl 2~ CBZ (Cbz) benzyloxycarbonyl(carbo-benzoxy) TBS (TBDMS) t-butyl-dimethylsilyl Activating Group 2s HBT(HOBT or HOBt) l-hydroxybenzotriazole hydrate 2~1970 Desi~nation Couplin ReAgent BOP reagent benzotriazol-l-ylo~ytris-(dimethylamino)phospho-nium hexafluorophosphate 5 BOP-Cl bis(2-oxo-3-oxazolidinyl) phosphinic chloride EDC l-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide hydrochloride Other (BOC)20 (BOC20) di-t-butyl dicarbonate n-Bu4N+F~ tetrabutyl ammonium fluoride nBuLi (n-Buli) n-butyllithium DMF dimethylformamide Et3N triethylamine EtOAc ethyl acetate TFA trifluoroacetic acid 20 DMAP dimethylaminopyridine DME dimethoxyethane LDA lithium diisopropylamide THF tetrahydrofuran Amino Acid Ile L-isoleucine Val L-valine DETAILED DESCRIPTION OF THE IN~NL10N AND PREFERRED
~MBODIMENTS
This invention is concerned with compounds of formula I, combinations thereof, or pharmaceutically acceptable salts thereof, in the inhibition of HIV protease, the prevention or treatment of infection by HIV and in the treatment of the resulting acquired immune deficiency syndrome (AIDS). Compounds of formula I are defined as follows:
Z R X R
J1 ~ N ~ B- J2 R2 z I
wherein X is -OE or -NH2;
Z is -O, -S, or -NE;
R is hydrogen or C1_4 alkyl;
R1 and R2 are independently:
1) hydrogen, 2) -Cl_4 alkyl unsubstituted or substituted with one or more of a) halo, b) hydroxy, 3~ c) Cl_3 alkoxy, d) aryl unsubstituted or substituted with one or more of Cl_4alkyl, hydroxy or aryl, 238197~
, e) -W-aryl or -W-benzyl, wherein W iæ -O-, -S-, or -NH-, f) a 5-7 membered cycloalkyl group unsubstituted or substituted with one or more of i) halo, ii) hydroxy, iii) Cl_3 alkoxy, or iv) aryl, g) heterocycle unsubstituted or substituted with one or more of hydroxy, Cl_4alkyl optionally substituted with hydroxy, or Boc, o h) -NE-COCl_3alkyl, i ) -NH-C-Cl_3alkyl, j ) -NH-so2cl-3alkyl, k) -NR2, l) -COOR, or m) -((CH2)mO)nR wherein m is 2-5 and n is zero, l, 2 or 3, or 3) aryl, unsubstituted or substituted with one or more of a) halo, b) hydroxy, c) -N02 or -NR2, d) Cl_4alkyl, e) Cl_3 alkoxy, unsubstituted or substituted with one or more of -OH or Cl_3 alkoxy, 208~970 , f) -COOR, 1l g) -CNR
h) -CH2NR2 i) -CH2NHCR, j) -CN, k) -CF3, lo 1) -NHCR, m) aryl Cl_3 alkoxy, n) aryl, o) -NRS02R, p) -OP(O)(ORX)2, or q) -R5, as defined below; or Rl and R2 can be joined together to form with the nitrogen to which Rl is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system which consists of the nitrogen to which Rl is attached and from 2 to 9 carbon atoms, and is unsubstituted or substituted with 1) hydroxy, 2) Cl_4 alkyl unsubstituted or substituted with one or more of a) halo, b) hydroxy, c) Cl_3 alkoxy, d) aryl, 0 2asls~3 e) a 5-7 membered cycloalkyl group unsubstituted or substituted with one or more of i) halo, ii) hydroxy, iii) Cl_3 alkoxy, or iv) aryl, f) heterocycle, or g) -NR2, 4) -N~-~OCl_3alkyl, 5) -NH-C-Cl_3alkyl, 6) -NH
7) heterocycle, 8) -W-aryl, or 9) -W-ICl-aryl, wherein W is defined abo~e; or Rl and R2 can be joined together to form with the nitrogen to which Rl i8 attached a 3 to 10 membered monocyclic or bicyclic saturated ring system which consists of the nitrogen to which Rl is attached, from 1 to 8 carbon atoms and one or more unsubstituted or substituted heteroatom selected from 1) -N-V-Rl ~
wherein V is absent or -C-Q- or -S02-Q-, 2~1970 , Rl is defined as above for when Rl is independent from and not joined to R2, and wherein Q is absent or -0-, -NR-, or heterocycle optionally substituted with -Cl_4alkyl, 2) 7 heterocycle, 3) -N-Cl_4 alkenyl, unsubstituted or substituted with aryl, 4) 7 S02-Cl_4alkenyl, unsubstituted or substituted with aryl, 5) -S(O)p-, wherein p is zero, 1 or 2, or 6) -0-; or Rl and R2 can be joined together to form with the nitrogen to which Rl is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system, whic~
consists of the nitrogen to which Rl is attached and from 2 to 9 carbon atoms, in which the saturated ring system is fused to a phenyl ring and the phenyl ring is unsubstituted or substituted with one or more of 1) halo, 2) Cl_3 alkoxy~
3) hydroxy, 4) Cl_4 alkyl, 5) -N~Rl, wherein Rl is defined as above for when Rl is independent from and not joined to R2, or 6) -NH-heterocycle;
2081~70 R3 is 1 ) - (CH2 ) r~R4 ~
wherein r is zero through 5, 2) Cl_4alkenyl-R4, or 3) Cl_4alkynyl-R4;
R4 is 1) hydrogen, 2) Cl_4 alkyl, 3) C5-C10 cycloalkyl, optionally substituted with hydroxy, 4) C6-C10 aryl, unsubstituted or substituted with one or more of a) halo, b) hydroxy, c) -N02 or -NR2 d) Cl_4alkyl, e) Cl_3 alkoxy, unsubstituted or substituted with one or more of -OH or Cl_3 alkoxy, f) -COOR, g ) - ICINR2, o h) -CE2NR2 l i ) -CH2NHCR, j) -CN, k) -CF3, 1) -NHCR, m) aryl Cl_3 alkoxy, n) aryl, 2081~70 .
138/CSQ55 ~ 18597IA
o) -NRS02R, p) -OP(O)(ORX)2, or q) -R5, as defined below, or 5) monocyclic or bicyclic heterocyle containing from 1 to 3 heteroatoms chosen from the group consisting of N, O, and S and which is unsubstituted or substituted with R5 and optionally with one or more of a) halo, b) Cl_4 alkyl, or c) Cl_3 alkoxy;
Rx is H or aryl;
R5 is 1 ) -W- ( CH2 )m-NR6R7 wherein W is as defined above, m is 2-5, and R6 and R7 are independently a) hydrogen, b) Cl_6 alkyl, unsubstituted or substituted with one or more of i) Cl_3 alkoxy, ii) -OH, or iii) -NR2, c) the same or different and joined together to form a 5-7 member heterocycle, such as morpholino, containing up to two additional heteroatoms selected from R O
-N-, -O-, -S-, -S-, or -S02-, the heterocycle optionally substituted with Cl_4 alkyl, or 2~8i 970 d) aromatic heterocycle unsubstituted or ~ubstituted with one or more of i) Cl_4 alkyl, or ii) -NR2~
2) ~(CH2)q~NR6R7 wherein q is 1-5, and R6 and R7 are defined above, except that R6 or R7 are not H or unsubstituted Cl_6 alkyl, or 3) benzofuryl, indolyl, azacycloalkyl, azabicyclo C7_11 cycloalkyl, or benzopiperidinyl, unsubstituted or substituted with Cl_4 alkyl;
B is absent, or -NH C-~
wherein R8 is 1) -CH(CH3)2.
2) -CH(CH3)(CH2CH3), or 3) -phenyl;
Jl and J2 are independently 1) -YR9 wherein Y is -O- or -NH-, and R9 is a) hydrogen, b) Cl_6 alkyl, unsubstituted or substituted with one or more of i ) -NR2 , ii) -OR, iii) -NHS02Cl_4 alkyl.
2~1370 , iv) -NHS02 aryl, or -NHS02(dialkyl-aminoaryl), v) -CH20R, vi) -Cl_4 alkyl, vi i ) -eOR , vi i i ) -CNR2, ix) -NH NR2 or -NH NR2, NH N-CN
x) -NHCR13, wherein R13 is A) -H, B) -Cl_4 alkyl, C) -aryl, D) -heterocycle, or E) -NH-, -0- or ~(CH2)n~
wherein n is zero, 1, 2 or 3, ~ubstituted with I) -Cl_4 alkyl, unsubstituted or substituted with one or more of aryl or heterocycle, or II) aryl, unsubstituted or substituted with heterocycle, xi) -NR3~ A~ wherein A9 is a counterion, xii) -NRlORll wherein R10 and Rll are the same or different and are Cl_5 alkyl joined together directly to form a 5-7 membered heterocycle containing up to one additional heteroatom selected from -O-, -S-, or -NR-, xiii) aryl, xiv) -CHO, xv) -OP(O) (ORX)2 ~
,01 xvi) -O-C-Cl_4alkyl substituted with one or more of amine or quaternary amine. or -~((CH2)m)n~R' or -OP(O)(ORX)2~
o xvii) -OC-R, or o xviii) -OC-NH-CH2-heterocycle, or c) ~((CH2)mO)nCH3 or ~((CH2)m)n H~
wherein m and n are defined above, 2) -N(R9)2, 3) -NRlORll wherein R10 and Rll are defined above, or 4) /R12 ~ R9/ n wherein Y, R9 and n are defined above; and - 20~1970 R12 iS
1) hydrogen, 2) aryl, unsubstituted or subætituted with one or more of a) R14, wherein R14 is i) halo, ii) -OR, q iii) -CNR2, iv) -CH2NR2 v) -S02NR
vi) -NR2, vi i ) -NHeR, viii) Cl_4 alkyl, ix) phenyl x) -CF3.
gi ) -N-S02R, xii) -OP(O)(ORg)2, or giii) -60R, o b) -Cl_4 alkyl-NR2, or c) -O-C-Cl_4alkyl substituted with one or more of amine or guaternary amine or -OP(O)(ORg)2, 208~70 3) heterocycle, such as isochroman, chroman, i~othiochroman, thiochroman, benzimidazole, benzothiopyran, oxobenzothiopyran, benzopyran, benzothiopyranylsulfone, benzothiopyranylsulfoxide, the ring or rings being unsubstituted or substituted with one or more of a) R14, as defined above, b) -OCl_4 alkenyl, c) phenyl-Cl_4 alkyl, d) -0-e-Cl_4alkyl substituted with one or more of amine or quaternary ~ amine, or -OP(O)(ORx)2, or lS ~0((CH2)mO)n-R~ or e) -0-C-0-((CH2)mO)n-R, or 4) A 5 to 7 membered carbocyclic or 7-10 membered bicyclic carbocyclic ring, such as cyclopentane, cyclohexane, indane, norbornane, naphthalene, thiopyran, isothiopyran, or benzopyran, the carbocyclic ring being unsubstituted or substituted with 2S one or more of a) R14, as defined above, b) -CH20R, c) ~(CH2)n~NR2~ Cs_l6alkyl~ pyridine, ~ ( CH2 )nNR~ ( CH2 ) n-NR2, - ( CH2 )n~~~OR
20~197~
~((CH2)mO)n-R, quinuclidiniumyl substituted with R, piperazine-Cl_4alkyl-benzyl substituted once or more with R, or morpholino-Cl_4alkyl-benzyl, d) -0-C-Cl_4alkyl substituted with one or more of amine or quaternary amine, -OP(O)(ORx)2, or ~~((CH2)m)n~R~
e) -0-C-0-((CH2)mO)n-R, or f) -Cl_4alkyl-phenyl;
or a pharmaceutically acceptable salt thereof.
In a preferred embodiment of this invention, Rl and R2 are joined together to form with the nitrogen to which Rl is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system which consists of the nitrogen to which Rl is attached and from 2 to 9 carbon atoms, and is unsubstituted or substituted with 1) hydroxy, 2) Cl_4 alkyl unsubstituted or substituted with one or more of a) hydroxy, b) Cl_3 alkoxy, c) aryl, d) a 5-7 membered cycloalkyl group unsubstituted or substituted with one or more of i) halo, ii) hydroxy, iii) Cl_3 alkoxy, or iv) aryl, e) heterocycle, or f) -NR2, o 4) -NH-COCl_3alkyl, 0~
5) -NH-C-Cl_3alkyl, 6) -NH
7). -W-aryl, or 8) -W-lCI-aryl, . wherein W is -0-, -S-, or -NH-; or Rl and R2 are joined together to form with the nitrogen to which Rl is attached a 3 to 10 membered monocyclic or bicyclic Eaturated ring system which consists of the nitrogen to which Rl is attached, from 1 to 8 carbon atoms and one or more unsubstituted or substituted heteroatom selected from 1) -N-wherein V is absent or -C-Q- or -S02-Q-, Rl is defined as above for when Rl is independent from and not joined to R2, and wherein Q is absent or -0-, -NR-, or heterocycle optionally substituted with -Cl_4alkyl, 2~81S7~
2) -N-Cl_4 alkenyl, unsubstituted or substituted with aryl, 3) -S(O)p-, s wherein p is zero, 1 or 2, or 4) -0-; or Rl and R2 are joined together to form with the nitrogen to which Rl is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system, which consists of the nitrogen to which Rl is attached and from 2 to 9 carbon atoms, in which the saturated ring system is fused to a phenyl ring and the phenyl ring is unsubstituted or substituted with one or more of 1) Cl_3 alkoxy, 2) hydroxy, 3) Cl_4 alkyl, or 4) -NHRl, wherein Rl is defined as above for when is independent from and not joined to R2.
A second, more preferred embodiment of this invention is further limited to compounds where:
Rl and R2 are joined together to form with the nitrogen to which Rl is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system which consists of the nitrogen to which Rl is attached and from 2 to 9 carbon atoms, and is unsubstituted or substituted with 208197~
1) hydroxy, 2) Cl_4 alkyl unsubstituted or subætituted with one or more of a) hydroxy, b) Cl_3 alkoxy, c) aryl, d) a 5-7 membered cycloalkyl group unsubstituted or substituted with one or more of i) halo.
ii) hydroxy, iii) Cl_3 alkoxy, or iv) aryl, e) heterocycle, or f) -NR2, o 4) -NH-~OCl_3alkyl, 5) -NH-C-Cl_3alkyl~
6) -NH-S02Cl_3alkY
7) -W-aryl, or 8) -W-C-aryl, wherein W is -0-, -S-, or -NH-; or Rl and R2 are joined together to form with the nitrogen to which Rl is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system which consists of the nitrogen to which Rl is attached, from 1 to 8 carbon atoms and one or more unsubstituted or substituted heteroatom selected from 2081~70 ~ N-V-Rl , o wherein V is absent or -C-Q- or -SO2-Q-, Rl is defined as above for when Rl is independent from and not joined to R2, and wherein Q is absent or -O-, -NR-, or heterocycle optionally substituted with -Cl_4alkyl, 2) -S(O)p-, wherein p is zero, 1 or 2, or 3) _o_;
R3 is benzyl, unsubstituted or substituted with one or more of a) hydroxy, b) -NO2, or -NR2, c ) Cl_4alkyl, d) Cl_3 alkoxy, unsubstituted or substituted with one or more of -OH or Cl_3 alkoxy, e) -CNR2, o f) -CH2NR2, O
g ) -CH2NHCR, h) -C~3, i ) -N~IeR, j) -NRSO2R, k) -OP(O)(ORX)2, or 1) -R5;
and B is absent.
A third, most preferred embodiment of this invention is further limited to compounds where:
X is -OH;
Z is -0;
Rl and R2 are joined together to form with the nitrogen to which Rl is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system which consists of the nitrogen to which Rl is attached and from 2 to 9 carbon atoms, and is unsubstituted or substituted with -W-aryl or -W-lCI-aryl; or Rl and R2 are joined together to form with the nitrogen to which Rl is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system which consists of the nitrogen to which Rl is attached, from 1 to 8 carbon atoms and one of -N~-V-R
O
wherein V is absent or -C-Q- or -SO2-Q-, Rl is defined as above for when Rl is independent from and not joined to R2, and wherein Q is absent or -O-, -NR- or heterocycle optionally substituted with -Cl_4alkyl;
R3 is benzyl, unsubstituted or substituted with one or more of (1) hydroxy, (2) Cl_3 alkoxy substituted with one or more of -OH or (3) N O
2û8197~
Jl is -NH-Cl_4alkyl; and J2 is OH
H -- -NH/~
~J
The most preferred compounds of this invention are compounds A through H and J, shown below.
Compound A:
~ N
CO~nH +
N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(2-(3(S>-N'-(t-butylcarboxamido)-(4aS,8aS)-decahydroisoquinoline)yl)-pentaneamide, 20~1970 Compound B:
~`T'~ 'I '1 `' ` " `
N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-carbobenzyloxy-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide, Compound C:
~0 ~ OH ~ OH
~ N ~ N", Q
CONH t ~
N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-(2-(4-morpholinyl)ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(2-(3(S)-N'-(t-butylcarboxamido)-(4aS,8aS)-decahydroisoquinoline)yl)-pentaneamide, Compound D:
~ ~_~o ~N~_~N ~
O CONH t N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-(2-(4-morpholinyl)ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(4-carbobenzyloxy-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide, Compound E:
~ ~H OH
~ N~" Q
CONnH t ~
N-(2(R~-hydroxy-l(S)-indanyl)-2(R)-((4-((2-hydrogy)-etho~y)phenyl)methyl)-4(S)-hydroxy-5-(2-(3(S)-N'-(t-butylcarboxamido)-(4aS,8aS)-decahydroisoquinoline)-yl)-pentaneamide, 208~L970 Compound F:
~f--OH
~N~N~8 O CONH t N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-((2-hydrogy)-ethoxy)phenyl)methyl)-4(S)-hydrogy-5-(1-(4-carbobenzyloxy-2(S)-N'-(t-butylcarboxamido)-15 piperazinyl))-pentaneamide, Compound G:
~ OH ~
~1 ~[N/~ ~,0 CONH t N-(4~S)-3,4-dihydro-lH-2,2-dioxobenzothiopyranyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(2-(3(S)-N'-(t-butyl-carboxamido)-(4aS,8aS)-decahydroisoquinoline)yl)-pentaneamide, 20~1970 Compound H:
~ 5~o N-(4(S)-3,4-dihydro-lH-2,2-dioxobenzothiopyranyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-carbobenzyl-oxy-2(S)-N~-(t-butylcarboxamido)-piperazinyl))-pentaneamide, Compound J:
~.0 ~
OH I OH
~'J l\,N ,~N/", ~>
CONH ~ ~
N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(3-pyridylmethyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide.
Novel compounds of the present invention also include but are not limited to the following compounds:
N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(N'-(t-butyl)-4(S)-phenoxyproline-amid)yl)-pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(N'-t-butyl-4(S)-2-naphthyloxy-prolineamid)yl)-pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(N'-t-butyl-4(S)-l-naphthyloxy-prolineamid)yl)-pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S)-amino-5-(2-(3(S)-N'-(t-butylcarboxamido)-(4aS,8aS)-decahydroiso~uinoline)yl)-pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-phenylpropionyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-benzoyl-2(S)-N~-(t-butylcarbox-amido)-piperazinyl))-pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-phenylpropyl)-2(S)-N~-(t-butyl-carboxamido)-piperazinyl))-pentaneamide, 3~ N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S)-amino-5-(1-(4-carbobenzyloxy-2(S)-N'-(t-butyl-carboxamido)-piperazinyl))-pentaneamide, 208~970 N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-(2-(4-morph-olinyl)ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(N~-(t-butyl)-4(S)-phenoxyprolineamid)yl)-pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-(2-(4-morph-olinyl)ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(N'-t-butyl-4(S)-2-naphthyloxy-prolineamid)yl)-pentane-amide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-(2-(4-morph-olinyl)ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(N'-t-butyl-4(S)-l-naphthyloxy-prolineamid)yl)-pentane-amide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-(2-(4-morph-olinyl)ethoxy)phenyl)methyl)-4(S)-amino-5-(2-(3(S)-N'-(t-butylcarboxamido)-(4aS,8aS)-decahydroi 80-quinoline)yl)-pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-(2-(4-morph-olinyl)ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(4-(3-phenylpropionyl)-2($)-N~-(t-butylcarboxamido)-piperazinyl))-pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-(2-(4-morph-olinyl)ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(4-benzoyl-2(S)-NI-(t-butylcarboxamido)-piperazinyl))-pentaneamide, - 2~81~70 N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-(2-(4-morph-olinyl)ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(4-(3-phenylpropyl)-2(S)-N~-(t-butylcarboxamido))-pipera-zinyl)-pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-(2-(4-morph-olinyl)ethoxy)phenyl)methyl)-4(S)-amino-5-(1-(4-carbobenzyloxy-2(S)-N'-(t-butylcarboxamido)-piperazinyl)pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-((2-hydroxy)-ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(N'-(t-butyl)-4(S)-phenoxyprolineamid)yl)-pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-((2-hydroxy)-ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(N'-t-butyl-4(S)-2-naphthyloxy-prolineamid)yl)-pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-((2-hydrogy)-ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(NI-t-butyl-4(S)-l-naphthyloxy-prolineamid)yl)-pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-((2-hydrogy)-25 ethoxy)phenyl)methyl)-4(S)-amino-5-(2-(3(S)-NI-(t-butylcarboxamido)-(4aS,8aS)-decahydroisoquinoline)-yl)pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-((2-hydroxy)-ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(4-(3-phenyl-propionyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide, ~081970 , N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-((2-hydroxy)-ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(4-benzoyl-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide.
N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-((2-hydroxy)-ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(4-(3-phenyl-propyl)-2(S)-N~-(t-butylcarboxamido))-piperazinyl)-10 pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-((2-hydroxy)-ethoxy)phenyl)methyl)-4(S)-amino-5-(1-(4-carbobenzyl-oxy-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide~
N-(4(S)-3,4-dihydro-lH-2,2-dioxobenzothiopyranyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(N'-(t-butyl)-4(S)-phenoxyprolineamid)yl)-pentaneamide, N-(4(S)-3,4-dihydro-lH-2,2-dioxobenzothiopyranyl)-2-(R)-phenylmethyl-4(S)-hydroxy-5-(1-(N'-t-butyl-4(S)-2-naphthyloxy-prolineamid3yl)-pentaneamide, N-(4(S)-3,4-dihydro-lH-2,2-dioxobenzothiopyranyl)-2-(R)-phenylmethyl-4(S)-hydroxy-5-(1-(N'-t-butyl-4(S)-l-naphthyloxy-prolineamid)yl)-pentaneamide, N-(4(S)-3,4-dihydro-lH-2,2-dioxobenzothiopyranyl)-2-(R)-phenylmethyl-4(S)-amino-5-(2-(3(S)-N'-(t-butyl-carboxamido)-(4aS,8aS)-decahydroisoquinoline)yl)-pentaneamide, N-(4(S)-3,4-dihydro-lH-2,2-dioxobenzothiopyranyl)-2-(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(3-phenylprop-ionyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide, N-(4(S)-3,4-dihydro-lH-2,2-dioxobenzothiopyranyl)-2-(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-benzoyl-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide, N-(4(S)-3,4-dihydro-lH-2,2-dioxobenzothiopyranyl)-2-(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(3-phenyl-propyl)-2(S)-N~-(t-butylcarboxamido))-piperazinyl)-pentaneamide, or (4(S)-3,4-dihydro-lH-2,2-dioxobenzothiopyranyl)-2(R)-phenylmethyl-4(S)-amino-5-(1-(4-carbobenzyloxy-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide.
The compounds of the present invention, may have asymmetric centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention.
When any variable (e.g., aryl, heterocycle, R, Rl, R2, A-, n, Z, etc.) occurs more than one time in any constituent or in formula I, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of 3~ substituents and/or variables are permissible only if such combinations result in stable compounds.
2~81970 As used herein except where noted, "alkyl"
is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl);
"alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; and "cycloalkyl" is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl (Cyh) and cycloheptyl. "Alkenyl" is intended to include hydrocarbon groups of either a straight or branched configuration with one or more carbon-carbon double bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, butenyl, pentenyl, and the like. "Alkynyl~ is intended to include hydrocarbon groups of either a straight or branched configuration with one or more carbon-carbon triple bonds which may occur in any stable point along the chain, such as ethynyl, propynyl, butynyl, pentynyl, and the like. "Halo~, as used herein, means fluoro, chloro, bromo and iodo; and "counterion" is used to represent a small, single negatively-charged species, such as chloride, bromide, hydroxide, acetate, trifluroacetate, perchlorate, nitrate, benzoate, maleate, tartrate, hemitartrate, benzene sulfonate, and the like.
As used herein, with exceptions as noted, ~aryl" is intended to mean phenyl (Ph) or naphthyl.
'ICarbocyclic" is intended to mean any stable 5- to 7-membered carbon ring or 7- to 10-membered bicyclic carbon ring any ring of which may be saturated or unsaturated.
- 2~81970 The term heterocycle or heterocyclic, as used herein except where noted, represents a stable 5- to 7-membered mono- or bicyclic or stable 7- to - 10-membered bicyclic heterocyclic ring system any ring of which may be ~aturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, 0 and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic elements include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same as morpholinyl.
2~8197~
The pharmaceutically-acceptable salts of the compounds of Formula I (in the form of water- or oil-soluble or dispersible products) include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases. E2amples of such acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate.
Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl 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.
20~19~0 .
Schemes I-III for preparing the novel compounds of thiæ invention are presented below.
Tables I and II which follow the schemes illustrate the compounds that can be synthesized by Schemes I-III, but Schemes I-III are not limited by the compounds in the tables nor by any particular substituents employed in the schemes for illustrative purposes. The examples specifically illustrate the application of the following schemes to specific compounds.
Amide couplings used to form the compounds of this invention are typically performed by the carbodiimide method with reagents such as dicyclo-hexylcarbodiimide, or l-ethyl-3-(3-dimethylamino-propyl) carbodiimide. Other methods of forming theamide or peptide bond include, but are not limited to the synthetic routes via an acid chloride, azide, mixed anhydride or activated ester. Typically, solution phase amide coupling are performed, but solid-phase synthesis by classical Merrifield techniques may be employed instead. The addition and removal of one or more protecting groups is also typical practice.
Additional related information on synthetic background is contained in EPO 0337714.
One method for producing formula I compounds is provided by Scheme I. Dihydro-5(S)-(tert-butyldi-methylsilyloxymethyl)-3(2H~-furanone (compound 1 below) is prepared by standard methods known in the art from commercially available dihydro-5(S)-(hydroxy-methyl)-2(3E~-furanone. After alkylation of compound 1 to form compound 2, the protecting group of lactone 2 is removed with aqueous HF to afford compound 3.
The alcohol group of 3 is activated by conversion into a leaving group æuch aæ meæylate, tosylate or trifylate by treating the alcohol with a sulfonyl chloride or æulfonic anhydride, such as trifluoromethaneæulfonic anhydride, in the presence of a hindered amine baæe æuch aæ triethylamine, diethyl iæopropylamine or 2,6 lutidine, to afford a compound æuch aæ compound 4. The leaving group of compound 4 iæ diæplaced by an amine 5, æuch aæ
N~-t-butyl-(4aS,8aS)-(decahydroiæoquinoline)-3(S)-carboxamide, in a high boiling solvent such as DME or xylene to produce a compound æuch aæ 6. A
trifluoromethaneæulfonyloxy group can be diæplaced by an amine at room temperature in a æolvent æuch as isopropanol by treatment with N,N-diisopropylethyl-amine.
Compound 6 is hydrolyzed with aqueous lithium or æodium hydroxide and the reæultant hydroxy acid 7 iæ converted into a protected hydroxy acid 8.
The hydroxyl group iæ conveniently protected with a ætandard æilyl protecting group æuch aæ
t-butyldimethyl æilyl or t-butyldiphenyl æilyl.
The protected hydroxy-acid 8 iæ then coupled to the deæired R12 amine to produce compound 9, and the silyl protecting group iæ removed with fluoride ion to arrive at compound 10.
20~197~
... .
SCHEME I
o o TEISO~S ~ TBSo~R3 F
HO. ~ 3 2 ~ CH3SOzO~
~R3 Et 3N ~R3 ~ R3 LioH
~, xylene CONH+ 6 ~ +SlCl CONH+ N' NH
2 5 N~oOH
CONH+
208197~
SC~EME I (CONT'D~
H2 N- R1 2 ~_ Rl 2 EDC/H~Bt CONH +
n- ~3u4N F ~L Rl 2 CONH +
A second method for forming products of general formula I is shown in Scheme II. In Scheme II, alkylation of 11 is performed by a firæt step of deprotonation of 11 with n-butyllithium or lithium diisopropylamide (LDA) followed by a second step of adding an alkenyl halide (such as allyl bromide) to afford 12.
Dihydroxylation of the olefin of 12 with osmium tetroxide and N-methylmorpholine-N-oxide (NMO) produceæ a diasteriomeric mixture of diols, 13.
Selective mesylation of the primary alcohol of 13 with methanesulfonyl chloride and either triethylamine or pyridine gives a meæylate 14.
20~1970 Heating mesylate 14 with an amine in a refluxing alcoholic solvent such as methanol or isopropanol which contains an excess of potassium carbonate produces an amino alcohol such as compound 15. The diasteriomeræ can be separated at this ætep by standard techniques weli known to those of skill in the art. Alternatively, the separation can be done after removal of the ketal.
Removal of the ketal in compound 15 is accomplished by treatment with acid in the presence of methanol, or by aqueous acid or by lN ~Cl in THF, to form compound 16.
208197~
SC~EME II
nBuL
wherein V is absent or -C-Q- or -S02-Q-, 2~1970 , Rl is defined as above for when Rl is independent from and not joined to R2, and wherein Q is absent or -0-, -NR-, or heterocycle optionally substituted with -Cl_4alkyl, 2) 7 heterocycle, 3) -N-Cl_4 alkenyl, unsubstituted or substituted with aryl, 4) 7 S02-Cl_4alkenyl, unsubstituted or substituted with aryl, 5) -S(O)p-, wherein p is zero, 1 or 2, or 6) -0-; or Rl and R2 can be joined together to form with the nitrogen to which Rl is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system, whic~
consists of the nitrogen to which Rl is attached and from 2 to 9 carbon atoms, in which the saturated ring system is fused to a phenyl ring and the phenyl ring is unsubstituted or substituted with one or more of 1) halo, 2) Cl_3 alkoxy~
3) hydroxy, 4) Cl_4 alkyl, 5) -N~Rl, wherein Rl is defined as above for when Rl is independent from and not joined to R2, or 6) -NH-heterocycle;
2081~70 R3 is 1 ) - (CH2 ) r~R4 ~
wherein r is zero through 5, 2) Cl_4alkenyl-R4, or 3) Cl_4alkynyl-R4;
R4 is 1) hydrogen, 2) Cl_4 alkyl, 3) C5-C10 cycloalkyl, optionally substituted with hydroxy, 4) C6-C10 aryl, unsubstituted or substituted with one or more of a) halo, b) hydroxy, c) -N02 or -NR2 d) Cl_4alkyl, e) Cl_3 alkoxy, unsubstituted or substituted with one or more of -OH or Cl_3 alkoxy, f) -COOR, g ) - ICINR2, o h) -CE2NR2 l i ) -CH2NHCR, j) -CN, k) -CF3, 1) -NHCR, m) aryl Cl_3 alkoxy, n) aryl, 2081~70 .
138/CSQ55 ~ 18597IA
o) -NRS02R, p) -OP(O)(ORX)2, or q) -R5, as defined below, or 5) monocyclic or bicyclic heterocyle containing from 1 to 3 heteroatoms chosen from the group consisting of N, O, and S and which is unsubstituted or substituted with R5 and optionally with one or more of a) halo, b) Cl_4 alkyl, or c) Cl_3 alkoxy;
Rx is H or aryl;
R5 is 1 ) -W- ( CH2 )m-NR6R7 wherein W is as defined above, m is 2-5, and R6 and R7 are independently a) hydrogen, b) Cl_6 alkyl, unsubstituted or substituted with one or more of i) Cl_3 alkoxy, ii) -OH, or iii) -NR2, c) the same or different and joined together to form a 5-7 member heterocycle, such as morpholino, containing up to two additional heteroatoms selected from R O
-N-, -O-, -S-, -S-, or -S02-, the heterocycle optionally substituted with Cl_4 alkyl, or 2~8i 970 d) aromatic heterocycle unsubstituted or ~ubstituted with one or more of i) Cl_4 alkyl, or ii) -NR2~
2) ~(CH2)q~NR6R7 wherein q is 1-5, and R6 and R7 are defined above, except that R6 or R7 are not H or unsubstituted Cl_6 alkyl, or 3) benzofuryl, indolyl, azacycloalkyl, azabicyclo C7_11 cycloalkyl, or benzopiperidinyl, unsubstituted or substituted with Cl_4 alkyl;
B is absent, or -NH C-~
wherein R8 is 1) -CH(CH3)2.
2) -CH(CH3)(CH2CH3), or 3) -phenyl;
Jl and J2 are independently 1) -YR9 wherein Y is -O- or -NH-, and R9 is a) hydrogen, b) Cl_6 alkyl, unsubstituted or substituted with one or more of i ) -NR2 , ii) -OR, iii) -NHS02Cl_4 alkyl.
2~1370 , iv) -NHS02 aryl, or -NHS02(dialkyl-aminoaryl), v) -CH20R, vi) -Cl_4 alkyl, vi i ) -eOR , vi i i ) -CNR2, ix) -NH NR2 or -NH NR2, NH N-CN
x) -NHCR13, wherein R13 is A) -H, B) -Cl_4 alkyl, C) -aryl, D) -heterocycle, or E) -NH-, -0- or ~(CH2)n~
wherein n is zero, 1, 2 or 3, ~ubstituted with I) -Cl_4 alkyl, unsubstituted or substituted with one or more of aryl or heterocycle, or II) aryl, unsubstituted or substituted with heterocycle, xi) -NR3~ A~ wherein A9 is a counterion, xii) -NRlORll wherein R10 and Rll are the same or different and are Cl_5 alkyl joined together directly to form a 5-7 membered heterocycle containing up to one additional heteroatom selected from -O-, -S-, or -NR-, xiii) aryl, xiv) -CHO, xv) -OP(O) (ORX)2 ~
,01 xvi) -O-C-Cl_4alkyl substituted with one or more of amine or quaternary amine. or -~((CH2)m)n~R' or -OP(O)(ORX)2~
o xvii) -OC-R, or o xviii) -OC-NH-CH2-heterocycle, or c) ~((CH2)mO)nCH3 or ~((CH2)m)n H~
wherein m and n are defined above, 2) -N(R9)2, 3) -NRlORll wherein R10 and Rll are defined above, or 4) /R12 ~ R9/ n wherein Y, R9 and n are defined above; and - 20~1970 R12 iS
1) hydrogen, 2) aryl, unsubstituted or subætituted with one or more of a) R14, wherein R14 is i) halo, ii) -OR, q iii) -CNR2, iv) -CH2NR2 v) -S02NR
vi) -NR2, vi i ) -NHeR, viii) Cl_4 alkyl, ix) phenyl x) -CF3.
gi ) -N-S02R, xii) -OP(O)(ORg)2, or giii) -60R, o b) -Cl_4 alkyl-NR2, or c) -O-C-Cl_4alkyl substituted with one or more of amine or guaternary amine or -OP(O)(ORg)2, 208~70 3) heterocycle, such as isochroman, chroman, i~othiochroman, thiochroman, benzimidazole, benzothiopyran, oxobenzothiopyran, benzopyran, benzothiopyranylsulfone, benzothiopyranylsulfoxide, the ring or rings being unsubstituted or substituted with one or more of a) R14, as defined above, b) -OCl_4 alkenyl, c) phenyl-Cl_4 alkyl, d) -0-e-Cl_4alkyl substituted with one or more of amine or quaternary ~ amine, or -OP(O)(ORx)2, or lS ~0((CH2)mO)n-R~ or e) -0-C-0-((CH2)mO)n-R, or 4) A 5 to 7 membered carbocyclic or 7-10 membered bicyclic carbocyclic ring, such as cyclopentane, cyclohexane, indane, norbornane, naphthalene, thiopyran, isothiopyran, or benzopyran, the carbocyclic ring being unsubstituted or substituted with 2S one or more of a) R14, as defined above, b) -CH20R, c) ~(CH2)n~NR2~ Cs_l6alkyl~ pyridine, ~ ( CH2 )nNR~ ( CH2 ) n-NR2, - ( CH2 )n~~~OR
20~197~
~((CH2)mO)n-R, quinuclidiniumyl substituted with R, piperazine-Cl_4alkyl-benzyl substituted once or more with R, or morpholino-Cl_4alkyl-benzyl, d) -0-C-Cl_4alkyl substituted with one or more of amine or quaternary amine, -OP(O)(ORx)2, or ~~((CH2)m)n~R~
e) -0-C-0-((CH2)mO)n-R, or f) -Cl_4alkyl-phenyl;
or a pharmaceutically acceptable salt thereof.
In a preferred embodiment of this invention, Rl and R2 are joined together to form with the nitrogen to which Rl is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system which consists of the nitrogen to which Rl is attached and from 2 to 9 carbon atoms, and is unsubstituted or substituted with 1) hydroxy, 2) Cl_4 alkyl unsubstituted or substituted with one or more of a) hydroxy, b) Cl_3 alkoxy, c) aryl, d) a 5-7 membered cycloalkyl group unsubstituted or substituted with one or more of i) halo, ii) hydroxy, iii) Cl_3 alkoxy, or iv) aryl, e) heterocycle, or f) -NR2, o 4) -NH-COCl_3alkyl, 0~
5) -NH-C-Cl_3alkyl, 6) -NH
7). -W-aryl, or 8) -W-lCI-aryl, . wherein W is -0-, -S-, or -NH-; or Rl and R2 are joined together to form with the nitrogen to which Rl is attached a 3 to 10 membered monocyclic or bicyclic Eaturated ring system which consists of the nitrogen to which Rl is attached, from 1 to 8 carbon atoms and one or more unsubstituted or substituted heteroatom selected from 1) -N-wherein V is absent or -C-Q- or -S02-Q-, Rl is defined as above for when Rl is independent from and not joined to R2, and wherein Q is absent or -0-, -NR-, or heterocycle optionally substituted with -Cl_4alkyl, 2~81S7~
2) -N-Cl_4 alkenyl, unsubstituted or substituted with aryl, 3) -S(O)p-, s wherein p is zero, 1 or 2, or 4) -0-; or Rl and R2 are joined together to form with the nitrogen to which Rl is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system, which consists of the nitrogen to which Rl is attached and from 2 to 9 carbon atoms, in which the saturated ring system is fused to a phenyl ring and the phenyl ring is unsubstituted or substituted with one or more of 1) Cl_3 alkoxy, 2) hydroxy, 3) Cl_4 alkyl, or 4) -NHRl, wherein Rl is defined as above for when is independent from and not joined to R2.
A second, more preferred embodiment of this invention is further limited to compounds where:
Rl and R2 are joined together to form with the nitrogen to which Rl is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system which consists of the nitrogen to which Rl is attached and from 2 to 9 carbon atoms, and is unsubstituted or substituted with 208197~
1) hydroxy, 2) Cl_4 alkyl unsubstituted or subætituted with one or more of a) hydroxy, b) Cl_3 alkoxy, c) aryl, d) a 5-7 membered cycloalkyl group unsubstituted or substituted with one or more of i) halo.
ii) hydroxy, iii) Cl_3 alkoxy, or iv) aryl, e) heterocycle, or f) -NR2, o 4) -NH-~OCl_3alkyl, 5) -NH-C-Cl_3alkyl~
6) -NH-S02Cl_3alkY
7) -W-aryl, or 8) -W-C-aryl, wherein W is -0-, -S-, or -NH-; or Rl and R2 are joined together to form with the nitrogen to which Rl is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system which consists of the nitrogen to which Rl is attached, from 1 to 8 carbon atoms and one or more unsubstituted or substituted heteroatom selected from 2081~70 ~ N-V-Rl , o wherein V is absent or -C-Q- or -SO2-Q-, Rl is defined as above for when Rl is independent from and not joined to R2, and wherein Q is absent or -O-, -NR-, or heterocycle optionally substituted with -Cl_4alkyl, 2) -S(O)p-, wherein p is zero, 1 or 2, or 3) _o_;
R3 is benzyl, unsubstituted or substituted with one or more of a) hydroxy, b) -NO2, or -NR2, c ) Cl_4alkyl, d) Cl_3 alkoxy, unsubstituted or substituted with one or more of -OH or Cl_3 alkoxy, e) -CNR2, o f) -CH2NR2, O
g ) -CH2NHCR, h) -C~3, i ) -N~IeR, j) -NRSO2R, k) -OP(O)(ORX)2, or 1) -R5;
and B is absent.
A third, most preferred embodiment of this invention is further limited to compounds where:
X is -OH;
Z is -0;
Rl and R2 are joined together to form with the nitrogen to which Rl is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system which consists of the nitrogen to which Rl is attached and from 2 to 9 carbon atoms, and is unsubstituted or substituted with -W-aryl or -W-lCI-aryl; or Rl and R2 are joined together to form with the nitrogen to which Rl is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system which consists of the nitrogen to which Rl is attached, from 1 to 8 carbon atoms and one of -N~-V-R
O
wherein V is absent or -C-Q- or -SO2-Q-, Rl is defined as above for when Rl is independent from and not joined to R2, and wherein Q is absent or -O-, -NR- or heterocycle optionally substituted with -Cl_4alkyl;
R3 is benzyl, unsubstituted or substituted with one or more of (1) hydroxy, (2) Cl_3 alkoxy substituted with one or more of -OH or (3) N O
2û8197~
Jl is -NH-Cl_4alkyl; and J2 is OH
H -- -NH/~
~J
The most preferred compounds of this invention are compounds A through H and J, shown below.
Compound A:
~ N
CO~nH +
N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(2-(3(S>-N'-(t-butylcarboxamido)-(4aS,8aS)-decahydroisoquinoline)yl)-pentaneamide, 20~1970 Compound B:
~`T'~ 'I '1 `' ` " `
N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-carbobenzyloxy-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide, Compound C:
~0 ~ OH ~ OH
~ N ~ N", Q
CONH t ~
N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-(2-(4-morpholinyl)ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(2-(3(S)-N'-(t-butylcarboxamido)-(4aS,8aS)-decahydroisoquinoline)yl)-pentaneamide, Compound D:
~ ~_~o ~N~_~N ~
O CONH t N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-(2-(4-morpholinyl)ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(4-carbobenzyloxy-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide, Compound E:
~ ~H OH
~ N~" Q
CONnH t ~
N-(2(R~-hydroxy-l(S)-indanyl)-2(R)-((4-((2-hydrogy)-etho~y)phenyl)methyl)-4(S)-hydroxy-5-(2-(3(S)-N'-(t-butylcarboxamido)-(4aS,8aS)-decahydroisoquinoline)-yl)-pentaneamide, 208~L970 Compound F:
~f--OH
~N~N~8 O CONH t N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-((2-hydrogy)-ethoxy)phenyl)methyl)-4(S)-hydrogy-5-(1-(4-carbobenzyloxy-2(S)-N'-(t-butylcarboxamido)-15 piperazinyl))-pentaneamide, Compound G:
~ OH ~
~1 ~[N/~ ~,0 CONH t N-(4~S)-3,4-dihydro-lH-2,2-dioxobenzothiopyranyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(2-(3(S)-N'-(t-butyl-carboxamido)-(4aS,8aS)-decahydroisoquinoline)yl)-pentaneamide, 20~1970 Compound H:
~ 5~o N-(4(S)-3,4-dihydro-lH-2,2-dioxobenzothiopyranyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-carbobenzyl-oxy-2(S)-N~-(t-butylcarboxamido)-piperazinyl))-pentaneamide, Compound J:
~.0 ~
OH I OH
~'J l\,N ,~N/", ~>
CONH ~ ~
N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(3-pyridylmethyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide.
Novel compounds of the present invention also include but are not limited to the following compounds:
N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(N'-(t-butyl)-4(S)-phenoxyproline-amid)yl)-pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(N'-t-butyl-4(S)-2-naphthyloxy-prolineamid)yl)-pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(N'-t-butyl-4(S)-l-naphthyloxy-prolineamid)yl)-pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S)-amino-5-(2-(3(S)-N'-(t-butylcarboxamido)-(4aS,8aS)-decahydroiso~uinoline)yl)-pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-phenylpropionyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-benzoyl-2(S)-N~-(t-butylcarbox-amido)-piperazinyl))-pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-phenylpropyl)-2(S)-N~-(t-butyl-carboxamido)-piperazinyl))-pentaneamide, 3~ N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S)-amino-5-(1-(4-carbobenzyloxy-2(S)-N'-(t-butyl-carboxamido)-piperazinyl))-pentaneamide, 208~970 N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-(2-(4-morph-olinyl)ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(N~-(t-butyl)-4(S)-phenoxyprolineamid)yl)-pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-(2-(4-morph-olinyl)ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(N'-t-butyl-4(S)-2-naphthyloxy-prolineamid)yl)-pentane-amide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-(2-(4-morph-olinyl)ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(N'-t-butyl-4(S)-l-naphthyloxy-prolineamid)yl)-pentane-amide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-(2-(4-morph-olinyl)ethoxy)phenyl)methyl)-4(S)-amino-5-(2-(3(S)-N'-(t-butylcarboxamido)-(4aS,8aS)-decahydroi 80-quinoline)yl)-pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-(2-(4-morph-olinyl)ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(4-(3-phenylpropionyl)-2($)-N~-(t-butylcarboxamido)-piperazinyl))-pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-(2-(4-morph-olinyl)ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(4-benzoyl-2(S)-NI-(t-butylcarboxamido)-piperazinyl))-pentaneamide, - 2~81~70 N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-(2-(4-morph-olinyl)ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(4-(3-phenylpropyl)-2(S)-N~-(t-butylcarboxamido))-pipera-zinyl)-pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-(2-(4-morph-olinyl)ethoxy)phenyl)methyl)-4(S)-amino-5-(1-(4-carbobenzyloxy-2(S)-N'-(t-butylcarboxamido)-piperazinyl)pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-((2-hydroxy)-ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(N'-(t-butyl)-4(S)-phenoxyprolineamid)yl)-pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-((2-hydroxy)-ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(N'-t-butyl-4(S)-2-naphthyloxy-prolineamid)yl)-pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-((2-hydrogy)-ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(NI-t-butyl-4(S)-l-naphthyloxy-prolineamid)yl)-pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-((2-hydrogy)-25 ethoxy)phenyl)methyl)-4(S)-amino-5-(2-(3(S)-NI-(t-butylcarboxamido)-(4aS,8aS)-decahydroisoquinoline)-yl)pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-((2-hydroxy)-ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(4-(3-phenyl-propionyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide, ~081970 , N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-((2-hydroxy)-ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(4-benzoyl-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide.
N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-((2-hydroxy)-ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(4-(3-phenyl-propyl)-2(S)-N~-(t-butylcarboxamido))-piperazinyl)-10 pentaneamide, N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-((2-hydroxy)-ethoxy)phenyl)methyl)-4(S)-amino-5-(1-(4-carbobenzyl-oxy-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide~
N-(4(S)-3,4-dihydro-lH-2,2-dioxobenzothiopyranyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(N'-(t-butyl)-4(S)-phenoxyprolineamid)yl)-pentaneamide, N-(4(S)-3,4-dihydro-lH-2,2-dioxobenzothiopyranyl)-2-(R)-phenylmethyl-4(S)-hydroxy-5-(1-(N'-t-butyl-4(S)-2-naphthyloxy-prolineamid3yl)-pentaneamide, N-(4(S)-3,4-dihydro-lH-2,2-dioxobenzothiopyranyl)-2-(R)-phenylmethyl-4(S)-hydroxy-5-(1-(N'-t-butyl-4(S)-l-naphthyloxy-prolineamid)yl)-pentaneamide, N-(4(S)-3,4-dihydro-lH-2,2-dioxobenzothiopyranyl)-2-(R)-phenylmethyl-4(S)-amino-5-(2-(3(S)-N'-(t-butyl-carboxamido)-(4aS,8aS)-decahydroisoquinoline)yl)-pentaneamide, N-(4(S)-3,4-dihydro-lH-2,2-dioxobenzothiopyranyl)-2-(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(3-phenylprop-ionyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide, N-(4(S)-3,4-dihydro-lH-2,2-dioxobenzothiopyranyl)-2-(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-benzoyl-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide, N-(4(S)-3,4-dihydro-lH-2,2-dioxobenzothiopyranyl)-2-(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(3-phenyl-propyl)-2(S)-N~-(t-butylcarboxamido))-piperazinyl)-pentaneamide, or (4(S)-3,4-dihydro-lH-2,2-dioxobenzothiopyranyl)-2(R)-phenylmethyl-4(S)-amino-5-(1-(4-carbobenzyloxy-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide.
The compounds of the present invention, may have asymmetric centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention.
When any variable (e.g., aryl, heterocycle, R, Rl, R2, A-, n, Z, etc.) occurs more than one time in any constituent or in formula I, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of 3~ substituents and/or variables are permissible only if such combinations result in stable compounds.
2~81970 As used herein except where noted, "alkyl"
is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl);
"alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; and "cycloalkyl" is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl (Cyh) and cycloheptyl. "Alkenyl" is intended to include hydrocarbon groups of either a straight or branched configuration with one or more carbon-carbon double bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, butenyl, pentenyl, and the like. "Alkynyl~ is intended to include hydrocarbon groups of either a straight or branched configuration with one or more carbon-carbon triple bonds which may occur in any stable point along the chain, such as ethynyl, propynyl, butynyl, pentynyl, and the like. "Halo~, as used herein, means fluoro, chloro, bromo and iodo; and "counterion" is used to represent a small, single negatively-charged species, such as chloride, bromide, hydroxide, acetate, trifluroacetate, perchlorate, nitrate, benzoate, maleate, tartrate, hemitartrate, benzene sulfonate, and the like.
As used herein, with exceptions as noted, ~aryl" is intended to mean phenyl (Ph) or naphthyl.
'ICarbocyclic" is intended to mean any stable 5- to 7-membered carbon ring or 7- to 10-membered bicyclic carbon ring any ring of which may be saturated or unsaturated.
- 2~81970 The term heterocycle or heterocyclic, as used herein except where noted, represents a stable 5- to 7-membered mono- or bicyclic or stable 7- to - 10-membered bicyclic heterocyclic ring system any ring of which may be ~aturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, 0 and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic elements include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same as morpholinyl.
2~8197~
The pharmaceutically-acceptable salts of the compounds of Formula I (in the form of water- or oil-soluble or dispersible products) include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases. E2amples of such acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate.
Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl 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.
20~19~0 .
Schemes I-III for preparing the novel compounds of thiæ invention are presented below.
Tables I and II which follow the schemes illustrate the compounds that can be synthesized by Schemes I-III, but Schemes I-III are not limited by the compounds in the tables nor by any particular substituents employed in the schemes for illustrative purposes. The examples specifically illustrate the application of the following schemes to specific compounds.
Amide couplings used to form the compounds of this invention are typically performed by the carbodiimide method with reagents such as dicyclo-hexylcarbodiimide, or l-ethyl-3-(3-dimethylamino-propyl) carbodiimide. Other methods of forming theamide or peptide bond include, but are not limited to the synthetic routes via an acid chloride, azide, mixed anhydride or activated ester. Typically, solution phase amide coupling are performed, but solid-phase synthesis by classical Merrifield techniques may be employed instead. The addition and removal of one or more protecting groups is also typical practice.
Additional related information on synthetic background is contained in EPO 0337714.
One method for producing formula I compounds is provided by Scheme I. Dihydro-5(S)-(tert-butyldi-methylsilyloxymethyl)-3(2H~-furanone (compound 1 below) is prepared by standard methods known in the art from commercially available dihydro-5(S)-(hydroxy-methyl)-2(3E~-furanone. After alkylation of compound 1 to form compound 2, the protecting group of lactone 2 is removed with aqueous HF to afford compound 3.
The alcohol group of 3 is activated by conversion into a leaving group æuch aæ meæylate, tosylate or trifylate by treating the alcohol with a sulfonyl chloride or æulfonic anhydride, such as trifluoromethaneæulfonic anhydride, in the presence of a hindered amine baæe æuch aæ triethylamine, diethyl iæopropylamine or 2,6 lutidine, to afford a compound æuch aæ compound 4. The leaving group of compound 4 iæ diæplaced by an amine 5, æuch aæ
N~-t-butyl-(4aS,8aS)-(decahydroiæoquinoline)-3(S)-carboxamide, in a high boiling solvent such as DME or xylene to produce a compound æuch aæ 6. A
trifluoromethaneæulfonyloxy group can be diæplaced by an amine at room temperature in a æolvent æuch as isopropanol by treatment with N,N-diisopropylethyl-amine.
Compound 6 is hydrolyzed with aqueous lithium or æodium hydroxide and the reæultant hydroxy acid 7 iæ converted into a protected hydroxy acid 8.
The hydroxyl group iæ conveniently protected with a ætandard æilyl protecting group æuch aæ
t-butyldimethyl æilyl or t-butyldiphenyl æilyl.
The protected hydroxy-acid 8 iæ then coupled to the deæired R12 amine to produce compound 9, and the silyl protecting group iæ removed with fluoride ion to arrive at compound 10.
20~197~
... .
SCHEME I
o o TEISO~S ~ TBSo~R3 F
HO. ~ 3 2 ~ CH3SOzO~
~R3 Et 3N ~R3 ~ R3 LioH
~, xylene CONH+ 6 ~ +SlCl CONH+ N' NH
2 5 N~oOH
CONH+
208197~
SC~EME I (CONT'D~
H2 N- R1 2 ~_ Rl 2 EDC/H~Bt CONH +
n- ~3u4N F ~L Rl 2 CONH +
A second method for forming products of general formula I is shown in Scheme II. In Scheme II, alkylation of 11 is performed by a firæt step of deprotonation of 11 with n-butyllithium or lithium diisopropylamide (LDA) followed by a second step of adding an alkenyl halide (such as allyl bromide) to afford 12.
Dihydroxylation of the olefin of 12 with osmium tetroxide and N-methylmorpholine-N-oxide (NMO) produceæ a diasteriomeric mixture of diols, 13.
Selective mesylation of the primary alcohol of 13 with methanesulfonyl chloride and either triethylamine or pyridine gives a meæylate 14.
20~1970 Heating mesylate 14 with an amine in a refluxing alcoholic solvent such as methanol or isopropanol which contains an excess of potassium carbonate produces an amino alcohol such as compound 15. The diasteriomeræ can be separated at this ætep by standard techniques weli known to those of skill in the art. Alternatively, the separation can be done after removal of the ketal.
Removal of the ketal in compound 15 is accomplished by treatment with acid in the presence of methanol, or by aqueous acid or by lN ~Cl in THF, to form compound 16.
208197~
SC~EME II
nBuL
/--\ +~ ~ o CH3SO2Cl acetone/HzO 1 3 ~ OH
HO ~ \. K2C3 CH3SO20~N~ HN- R
14 ~ R2 1CONH~
R -N ~ - R~-N ~ ~ H
R2 CONH t ~ R~ CONH t 16 -A third method for forming products of general formula I is shown in Scheme III. Protection of the pyrrolidine -NH- group of compound 17 is carried out with BOC-anhydride and dimethylaminopyridine to give the protected compound 18. Alkylation of 18 i~ performed by a first step of deprotonation of 18 with a strong baæe such as lithium hexamethyldisilamide (LHMDS) or lithium diisopropylamide (LDA) followed by a second step of adding an alkyl halide (such as benzyl bromide) to afford compound 19.
The TBS protecting and BOC protecting group of 19 are removed by treatment with aqueous HF in acetonitrile to give alcohol 20. Mesylation of the primary alcohol of 20 with methanesulfonyl chloride and either triethylamine or pyridine gives mesylate 21 which is heated with an amine in a refluxing alcoholic solvent such as methanol or isopropanol which contains an exc.ess of potassium carbonate to produce an amino pyrrolidinone ~uch as compound 22.
The pyrrolidine -N~- group of 22 is reprotected as a BOC group as before and the resultant compound 23 is hydrolized open with a base such as lithium or ~odium hydroxide to afford the acid 24. Compound 24 is then coupled to an NH2R12 amine in a stan'dard manner and the BOC is removed with gaseous HCl or trifluoro-acetic acid to give the desired product, exemplified by compound 25.
SCEEME III
~o O N--l( 1 )LDA
T~SO~ DM~P' TBSO~ / 2) E~enzyIbrornde ~0 l O O~N~ ~ HF/CH3CN
TE~SO~ ~J~ HzO
l 5 HN~ ~ CH3SOzCl HO~l~ ~ Et3N
HN-HN~ ~ RzlCoNH~
CH3S020~/ ~~, lH, KzC03 o N~ J3 BOCzo 2 5 I DM~P
RZ~ONH +
-o 3 . R ~N~ LiOH
RZlCONH +
SC~EME III (CONT'D~
OH
R2 CONH+ +
2. H
~2`~
R CONH+
A compound of formula 26 2 0 P N~ OH R3 1~, 1~NH_ Rl 2 26 CONH +
25 wherein P is a nitrogen protecting group such as -BOC
or -CBZ, is preferably prepared according to the method described in Scheme I, preferably employing the 5-trifluoromethanesulfonyloxymethyl analog of lactone 4 therein (see Example 15, Step 1).
Compounds of formula 27 ~ -R1a 27 CONH ~
can be obtained by a variety of routes from compound ~1_ Rl 2 28 CONHt which is obtained after removal of the nitrogen protecting group in 26 using methods well known in the art, e.g., catalytic hydrogenation to remove a CBZ group, or treatment with trimethylsilyltriflate and 2,6 lutidine at about 0C in a solvent such as CE2C12 to remove a BOC group.
For example, the 4-position piperazinyl nitrogen of compound 28 can be alkylated with a compound of formula Rl-X in a solvent such as DMF in the presence of Et3N at room temperature, wherein X
is -Cl, Br or -I, or a sulfonamide group can be formed by treatment of 28 with a sulfonyl chloride compound of formula RlS02Cl under similar conditions. Also, standard amide coupling techniques can be used to form an amide group at the piperazinyl 4-position. Techniques for these procedures are well known to those skilled in the art. The Rl group of Rl-X or RlS02Cl i8 defined above in the definition of compounds of formula I wherein Rl is independent from and not joined to R2, except that Rl can not be hydrogen or a group with a free hydroxy substituent, such as -Cl_4alkyl substitued with hydroxy, with the further exception that Rl can be aryl substituted with a hydroxy group.
The compounds of this invention are also illustrated by Tables I-IV, which follow.
TABLE I
~ 3 CONH+ O
OH
- HN~", 15 -CH2- Ph -OH
20 -CH~-Ph -OH -HN~O
OH
- HN~ OH
-CH2- Ph -OH
OH
- HN~...~OH
- CH2 - Ph - OH
OH
- HN~ `~H2 -CH2- Ph -OH ~
.
T~RTF I. C0NT'D
o -CH2-Ph -OH -HN
-CH2-Ph -OH HN ~ N ~
-CH2-Ph -OH -HN ~ OH
~` OH
OH
-CH2-Ph -OH -HN~
r -CHz-Ph -OH -HN'~
`~ 2~8~970 TABT.F I. CONT'D
-CH2-Ph -OH -HN p o -CH2-Ph -HN
-HN ~ ~y,~
-CH2-Ph -OH H
-CH2-Ph -OH
O
-~ o~=~
-CH2-Ph -OH "~ H HN ~
- 20~1970 , T~RLE I. CONT'D
`NH
-CH2-Ph -OH
E
- CH2- Ph - NH2 ~ H
NH
- CH2- Ph - OH [~,~ROH
`NH
2 0 - CH2 - Ph - OH ~OH
238~970 TABT F T, C0NT ' D
~H
- CH2- Ph - NH2 ~ ~ OH
`NH
-CHz-Ph -OH
`NH
- CH2 - Ph ~=a `NH
-CH2-Ph -OH [~
- CH2~CH3 - OH [~"'OH
`NH
- CH2~OH - OH ~""~H
`NH
3 0 - CH2~OH - OH ~"n~H
OH
T~RLE I. CONT'D
NH
- CH2 ~.~OH - NH2 ~ ~ OH
- CH2 ~H - NH
-CH2~ -OH -IleN~
-CH2~ O~ H~
- CH2 ~ - NH2 ~ I le N~
- CH2~ / \ - OH - I leN
3 -CH2~o- OH -OH H~
20~1970 TABTF I. CONT'D
-CHz ~ ~ N -NH2 -IleN
- CH2 ~OH - OH - ValN OH
H
-CHz~ -OH -ValN~ OH
NH
1 5 ~PH
- CHz ~~N O OH ~J
~NH
2 0 - CHz ~~N O - NHz ~o~OH
~NH
- CHz ~~N\ O - OH ~mllOH
OH
~ 2~)81970 TABLE I~ CONT'D
NH
- CH2 ~~N O - OH ~ 'l'OH
NH
-CHz~~N O -NHz ~"""OH
NH
-CH2~o~0H -OH [~ OH
NH
2 0 - CH2 ~o ~OH - OH ~,,,~rOH
- CH2~~0H - NH2 [~u~H
NH
-CHz~O~OH - NH2 [~,OH
NH
3 - CH2 ~O OH - OH
208:~97~
.
TABLE I . C0NT ' D
HN-- CH2CH= CH- Ph - OH[~""'OH
- CH2CH= CH- Ph - OH ~ _O
HN-- CH2CH= CH~o~N O ~ OH
HN-2 0 - CH2C H= C H~o~N O - OH ~H
20~1970 , TABLE II
X ~
A ~,1 1~,D
A X D
,~CONH + OH
l~N - OH - HN"""O
~3 2 0 ~ONH + - OH
~ONH +
2 5 CNr- - NH2-~"""~S// O
2~8~970 TABLE IT Cont ' d A X D
~ ONH + OH
~ N- -NH2 -HN"", ~
"~_~CONH + OH
~ N- -OH -H~", r, ~ -'a'~H
OH
ONH t ~ ~H
OrH
~ t -OH -HN"h,. 8 208~970 _ TABLE II Cont ' d A X D
ONH ~ -OH -H~ ~
lo ~o~t ~ -~&
~ ONH + -OH
~ N- -H~,. o '~7 ONH + -OH ,O,H
~ N N- O
Q ~ ONH + -OH O"H
~ N N- Q
~ N N- -OH -HN~
~ ONH +
&
2~819~0 TABLE II C0NT'D
A X D
OH
8--o~C~ - OH- HN",8 8--~ -OH -NX~
ONH~ _ OH - ~3 CONHt OH
~ OH _ HN",.
20~197~
, TARLE II CONT'D
A X D
OH
CONH+ -, 10 ~ - OH- HN~,.8'~1H
OH
CONH+
~ - OH 8 CONH+ o H
20 ~3~ -OH ~ N~
TABLE II, CONT'D
A X D
10 ~JLN N- - OH OH
CONH~ - OH OH
~q ~N- OH
~f J t~ONH+ - OH - HN"".O
¢~ N N- - OH - HN~
CONH+ 8 0 rN N- - OH - HN""8 O '~ l CONHT ~=~
b 2 0 8 1 9 7 0 TARTF II CONT'D
A X D
OH
A ~\ -OH -HN'~
O CONH+
OH
~N N N- -OH - HN'~
CH~ J5 )=' 'CONH+ ~ ~
208197~
TABLE III
A-SO21~ OH ~P H OH
~--N~ O
CONH~
A A, con' t ~N CH3CH2CH2CH2-15 ~
CH3- ( CH3) 2CH-20CH3~ CH3~H3 CH3yS~
O ~
2 ~ 7 ~
TABLE IV
o ~h A- C- ~ OH
CONH+
¢~
( CH3) 3C-O-~
o Ph- CHzCH2-~081970 The compounds of the present invention are useful in the inhibition of EIV protease the prevention or treatment of infection by the human immunodeficiency virus (HIV) and the treatment of consequent pathological conditions such as AIDS. Treating AIDS or preventing or treating infection by HIV is defined as including, but not limited to, treating a wide range of states of HIV infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV. For example, the compounds of this invention are useful in treating infection by HIV after suspected past exposure to HIV
by, e.g., blood transfusion, organ transplant, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.
For these purposes, the compounds of the present invention may be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles.
Thus, in accordance with the present invention there is further provided a method of treating and a pharmaceutical composition for treating HIV infection and AIDS. The treatment involves administering to a patient in need of such treatment a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
These pharmaceutical compositions may be in the form of orally-administrable suspensions or tablets; nasal sprays; sterile injectable preparations, for example, as sterile injectable aqueous or oleagenous suspensions or suppositories.
When administered orally as a suspension, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as - a suspending agent, methylcellulose as a viscosity enhancer, and sweetners/flavoring agents known in the art. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium 15 phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.
When administered by nasal aerosol or inhalation, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
The injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic ~odium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
When rectally administered in the form of suppositories, these compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquidify and/or dissolve in the rectal cavity to release the drug.
Dosage levels of the order of 0.02 to 5.0 or 10.0 grams-per-day are useful in the treatment or prevention of the above-indicated conditions, with oral doses two-to-five times higher. For example, infection by HIV is effectively treated by the administration of 15 from 10 to 50 milligrams of the compound per kilogram of body weight from one to three times per day. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of 20 factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the 25 particular condition, and the host undergoing therapy.
The present invention is also directed to combinations of the ~IV protease inhibitory compounds with one or more agents useful in the treatment of AIDS. For example, the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the AIDS antivirals, 2~8197~
immunomodulators, anti-infectiveæ, or vaccines ~nown to those of ordinary skill in the art.
It will be understood that the scope of combinations of the compounds of this invention with AIDS antivirals, immunomodulators, anti-infectives or vaccines include in principle any combination with any pharmaceutical composition useful for the treatment of AIDS.
Assay for Inhibition of Microbial Expressed Viral Protease Inhibition studies of the reaction of the protease expressed in Eschericia coli with a peptide substrate ~Val-Ser-Gln-Asn-(betanapthyl)Ala-Pro-Ile-15 Val, 0.5 mg/mL at the time the reaction is initiated]were in 50 mM Na acetate, pH 5.5, at 30C for 1 hour.
Various concentrations of inhibitor in 1.0 ul DMS0 were added to 25 ul of the peptide solution in water. The reaction is initiated by the addition of 15 ul of 0.33 20 nM protease (O.ll ng) in a solution of 0.133 M Na acetate pH 5.5 and 0.1% bovine serum albumin. The reaction was guenched with 160 ul of 5% phosphoric acid. Products of the reaction were separated by HPLC
(VYDAC wide pore 5 cm C-18 reverse phase, acetonitrile 25 gradient, 0.1% phosphoric acid). The extent of inhibition of the reaction was determined from the peak heights of the products. HPLC of the products, independently synthesized, proved quantitation standards and confirmation of the product composition.
30 The products of synthesis in Examples 1-7 inclusive showed IC50 values in the range of 1-100 nM. Compounds A, B and J showed IC50 values of between about 0.3 and about 6 nM.
.. , ~ MPLE 1 Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(N'-(t-butyl)-4(S)-phenoxyprolineamide~yl)-pentaneamide Step 1: Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-3-phenylpropaneamide To a cold (0C) solution of methylene chloride (30 ml) containing 2(R)-hydroxy-l(S)-aminoindane (750 mg, 5.0 mmol) and triethylamine (606 mg, 6.0 mmol) was added a solution of hydrocinnamoyl chloride (843 mg, 5.0 mmol) in 5 ml of methylene chloride. After 2 hr the reaction was poured into a separatory funnel containing 50 ml of methylene chloride and washed with 10% citric acid solution (2 x 30 ml). The organic layer was dried, filtered and concentrated to afford a white solid.
Step 2: Preparation of N-(2(R)-hydro~y-l(S)-indan-N.O-isopropylidene-yl~-3-phenyl-propaneamide The crude white solid from step 1 above was dissolved in 50 ml of methylene chloride and 5 ml of dimethoxypropane was added followed by the addition of 100 mg of p-toluenesulfonic acid. The reaction was stirred at room temperature for 18 hr and then poured into a separatory funnel and washed with saturated NaHC03 solution (2 x 30 ml). The organic layer was dried, filtered and concentrated to afford an oil which was chromatographed (SiO2, 40% EtOAc/Hexane) to give an oil which eventually crystallized.
Step 3: Preparation of N-(2(R)-hydroxy-l(S)-indan-N,0-isopropylidene-yl)-2(S)-phenylmethyl-pent-4-eneamide To a solution of N-(2(R)-hydroxy-l(S)-indan-N,0-isopropylidene-yl)-3-phenyl-propaneamide (1.03 gm, 2.9 mmol) in 20 ml of THF cooled to -78C waæ added n-BuLi (2.5M, 1.40 ml, 3.5 mmol). After 20 min, allyl bromide (0.48 gm, 3.9 mmol) was added, the reaction was stirred at -78C for 1 hr and then 10 ml of saturated NH4C1 solution was added to quench the reaction. The reaction was diluted with 50 ml of water, extracted with ethyl acetate (2 x 50 ml), the organic phase was washed with saturated NaCl solution (50 ml), dried filtered and concentrated to afford the crude product.
The crude product was purified on silica gel to afford the title compound.
Step 4: Preparation of N-(2(R)-hydroxy-l(S)-indan-N,0-isopropylidene-yl)-2(S)-phenylmethyl-(4(RS).5-dihydroxy~-pentaneamide To 800 mg (2.2 mmol) of N-(2(R)-hydroxy-l(S)-indan-N,0-isopropylidene-yl)-2(S)-phenylmethyl-pent-4-en eamide dissolved in 40 ml of a 9:1 mixture of acetone/water was added 0.8 ml of a 60% solution of N-methylmorpholine-N-oxide in water followed by 4 ml of a 2~5~/o solution of osmium tetroxide in t-BuOH. After 18 hr, excess solid sodium bisulfate waæ added, the reaction was stirred for 2 hr and then filtered through a pad of celite. The filtrate was concentrated, diluted with 50 ml of water, extracted with methylene chloride (2 X 50 ml), the organic phase was dried, filtered and concentrated to give the product as a foam.
- 2~19~0 Step 5: Preparation of N-(2(R)-hydroxy-l(S)-indan-N,O-isopropylidene-yl)-2(S)-phenylmethyl-4(RS)-hydroxy-5-methanesulfonyloxy-pentaneamide To 200 mg (0.527 mmol) of N-(2(R)-hydroxy-l(S)-indan-N,O-isopropylidene-yl)-2(S)-phenylmethyl-(4(RS),5-dihydroxy)-pentaneamide dissolved in 7 ml of methylene chloride at 0C was added triethylamine (59 mg, 0.58 mmol), followed by methanesulfonyl chloride (66 mg, 0.579 mmol). After 4 hr the reaction was worked up by washing with 10% citric acid solution (2 X
50 ml) and the organic phase was dried, filtered and concentrated to afford the monomesylate as a mixture of alcohols.
Step 6: Preparation of N'-t-butyl-N-Boc-4(R)-hydroxy-L-prolineamide To a solution of N-Boc-4(R)-hydroxyproline (2.00 g) in DMF (20 mL) cooled to 0C was added EDC
(1.987 g), HOBt (1.401 g), tert butyl amine (1.09 mL) and triethylamine (2.41 mL). After 18 h the reaction mixture was diluted with ethyl acetate (150 mL) and washed with 10% HCl, saturated NaHCO3, water and brine. The solution was then dried over MgSO4 and concentrated to afford a white solid.
Step 7: Preparation of N'-t-butyl-N-Boc-4(S)-phenoxy-L-prolineamide To a solution of N'-t-butyl-N-Boc-4(R)-hydroxy-L-prolineamide (0.6 g) in THF (5 mL) was added phenol (0.295 g), triphenylphosphine (0.824 g) and then diethylazo-dicarboxylate (0.495 mL) dropwise. The reaction mixture stirred for 24 h at ambient 208~970 ._ temperature and was diluted with ethyl acetate (200 mL) and washed with saturated NaHCO3, water, brine and dried over MgSO4. Concentration in vacuo afforded a yellow oil which was purified by flash chromatography (elution hexane: EtOAc 1:1, 30 mm column).
Step 8: Preparation of N-t-butyl-4(S)-phenoxy-L-prolineamide trifluoroacetic acid salt To a solution of N'-t-butyl-N-Boc-4(S)-phenoxy-L-prolineamide (0.596 g) in methylene chloride (4 mL) at 0C was added trifluoroacetic acid (2 mL).
After 30 min the reaction was warmed to room temperature and stirred for two hours. The solvent was removed in vacuo and a slightly yellow oil was obtained.
Step 9: Preparation of N-(2(R)-hydroxy-l(S)-indan-N,O-isopropylidene-yl)-2-(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(N'-(t-butyl)-4(S)-phenoxy-prolineamide)yl~-pentaneamide To a solution of N-t-butyl-4(S)-phenoxy-L-prolineamide trifloroacetic acid salt (0.36 g) and N-(2(R)-hydroxy-l(S)-indan-N,O-isopropylidene-yl)-2(S)-phenylmethyl-4(RS)-hydroxy-5-methanesulfonyloxy-pentaneamide (0.226 g) in 3 mL of isopropanol was addedpotassium carbonate (0.441 g) and the reaction was warmed to 80C. After 18 h the reaction was cooled to room temperature, filtered through celite which was washed with further portions of EtOAc. The filtrate was concentrated, the residue was dissolved in EtOAc (lOOmL) and washed with water, brine and dried over MgSO4. The solvent was removed in vacuo and the resulting oil was purified by flash chromatography to afford the product as a mixture of diastereomers.
Step 10: Prep of N-(2(R)-hydroxy-l(S)-indanyl)-2-(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(N'-t-butyl-4(S)-phenoxyprolineamid~yl)-pentaneamide To a solution of N-(2(R)-hydroxy-l(S)-indan-N,O-isopropylidene-yl)-2-(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(N'-(t-butyl)-4(S)-phenoxyprolineamide)-yl)-pentaneamide (0.13 g) in MeO~ (5 mL) was added camphorsulfonic acid (CSA) (0.070 g) at ambient temperature. After 5 hours more CSA (0.025 g) was added and the reaction was ætirred for total of 18 hours. The reaction waæ quenched with saturated NaHC03 (5 mL) and the solvent was removed to a volume of 4 mL. The aqueous layer was thoroughly extracted with EtOAc and the organic layer was washed with water, brine and dried. After removal of the solvent in vacuo the resulting oil was purified via flash chromatography to provide the title compound as a white foam. The foam was dissolved in EtOAc : hexanes and the mother liquor was decanted away from the oil. The oil was then dried in a high vacuum desiccator to afford a white foam.
Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(N'-t-butyl-4(S)-2-naphthvloxy-prolineamid)yl)-pentaneamide Step 1: Preparation of N-t-butyl-4(S)-2-naphthyloxy-L-prolineamide trifluoroacetic acid salt Following substantially the same procedure 2 ~ 7 0 for syntheæizing N-t-butyl-4(S)-phenoxy-L-proline-amide trifluoroacetic acid salt as outlined in Example 1, Steps 6 through 8, but substituting 2-naphthol for the phenol used therein, the 2-naphthyloxy proline amide was produced.
Step 2: Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(N'-t-butyl-4(S)-2-naphthyloxy-prolineamid)yl)-pentaneamide The title compound was produced by followingsubstantially the same procedure outlined in Example 1, Steps 9 and 10, but substituting N-t-butyl-4(S)-2-naphthyloxy-L-prolineamide trifluoroacetic acid salt for the N-t-butyl-4(S)- phenoxy-L-prolineamide trifloroacetic acid salt used in step 9 therein.
Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(N'-t-butyl-4(S)-l-naphthyloxy-prolineamid)yl)-pentaneamide Step 1: Preparation of N-t-butyl-4(S)-l-naphthyloxy-T.-prolineamide trifluoroacetic acid salt Following substantially the same procedure for synthesizing N-t-butyl-4(S)-phenoxy-L-proline-amide trifluoroacetic acid salt as outlined in Example 1, Steps 6 through 8, but substituting l-naphthol for the phenol used therein, the l-naphthyloxy proline amide was produced.
, 2o8l97~
Step 2: Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(N'-t-butyl-4(S)-2-naphthyloxy-prolineamid)yl)-pentaneamide The title compound.waæ produced by following the procedure outlined in Example 1, Steps 9 and 10, but substituting N-t-butyl-4(S)-l-naphthyloxy-L-prolineamide trifluoroacetic acid salt for the N-t-butyl-4(S)-phenoxy-L-prolineamide trifluoroacetic acid salt used in Step 9.
Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(2-(3(S)-N~-(t-butyl-carboxamido)-(4aS,8aS)-decahydroisoquinoline)yl)-pentaneamide Step 1: Preparation of dihydro-5(S)-((t-butyldi-phenylsilyl)oxymethyl)-3(R)phenylmethyl-3(2H)-furanone A solution of lithium diisopropylamide (LDA) was generated by the addition 1.55 ml of n-BuLi (2.5M
in hexane) to 0.55 ml (3.9 mmol) of diisopropylamine in 10 ml of THF at -78C. After 30 minutes a solution of dihydro-5-(S)-((t-butyldiphenylsilyl)-oxymethyl)-3(2H)-furanone (1.38 g, 3.89 mmol~ in 5 ml of THF was added. After an additional 30 minutes of stirring, benzyl bromide (0.68 g, 3.9 mmol) was added and stirring was continued for 3 h after which time the reaction was quenched with the addition of a 10%
aqueous citric acid solution. The solution was 21181 97~
extracted with ethyl acetate (2 x 50 ml) which was backwashed with brine, dried, filtered and concentrated to afford an oil. The product was purified by chromatography (SiO2, 20% EtOAc/Hexane) to afford the title compound.
Step 2: Preparation of dihydro-5(S)-(hydroxy-methyl)-3(R)-phenylmethyl-3(2H)-furanone To 5.26 g of dihydro-5(S)-((t-butyldiphenyl-silyl)oxymethyl)-3(R)phenylmethyl-3(2H)-furanone in 40 ml of acetonitrile was added 1.34 ml of a 49% aqueous HF solution. After 18 hr at room temperature the reaction was concentrated to dryness and the residue was partitioned between water (50 ml) and ethyl acetate (50 ml). The organic layer was washed with brine, dried filtered and concentrated to afford the product as a tan solid (mp 69-72 C).
0 Step 3: Preparation of dihydro-5(S)-((methane-sulfonyl)oxymethyl)-3(R)phenylmethyl-3(2H)-furanone To a solution of 2.93 g (14 mmol) of dihydro-5(S)-(hydroxymethyl)-3(R)-phenylmethyl-3(2H)-fur anone in methylene chloride cooled to 0C was added triethylamine (1.98ml, 15.6 mmol) followed by the addition of methanesulfonyl chloride (1.20 ml, 15.6 mmol). After 1 hour at OoC, the reaction was poured into 10% aqueous citric acid solution, washed with ethyl acetate (2 x 100 ml) which was backwashed with water (100 ml), brine (100 ml), dried, filtered and concentrated to give the product as a waxy brown solid.
2~970 . .
Step 4: Preparation of dihydro-5(S)-(2-(3(S)-N-(t-butylcarboxamido)-(4aS, 8aS)-(decahydroiso-quinoline)yl)methyl)-3(R)-phenylmethyl-3(2H)-furanone To 70 mg of dihydro-5(S)-((methanesulfonyl)-oxymethyl)-3(R)phenylmethyl-3(2E)-furanone (0.25 mmol) in 10 ml of xylene containing 100 mg of potassium carbonate was added 65 mg (0.27 mmol) of N-t-butyl-(4aS,8aS)-(decahydroisoquinoline)-3(S)-carboxamide and the reaction was heated to 140C.
After 6 hours, the reaction was cooled, poured into 30 ml of water which was washed with ethyl acetate (2 x 30 ml). The organic phase was dried, filtered and concentrated to afford a residue which was chromatographed (50/50 EtOAc/Hexane) to give the product.
Step 5: Preparation of 2(R)-phenylmethyl-4(S)-(t-butyldimethylsilyloxy)-5-(2-(3(S)-N-(t-butylcarboxamido)-(4aS,8aS)-decahydroiso-~uinoline)yl)-pentanoic acid To 130 mg (0.305 mmol) of dihydro-5(S)-(2-(3(S)-N-(t-butylcarboxamido)-(4aS, 8aS)-(decahydro-isoquinoline)yl)methyl)-3(R)-phenylmethyl-3-(2H)furan-one in 2 ml of DME was added 1 ml lithium hydroxide solution. After 4 hours at room temperature, the reaction was concentrated to dryness and azeotroped with toluene (3X) to remove excess water. The residue was dissolved in 5 ml of DMF and 414 mg (6.10 mmol) of imidazole and 465 mg (3.05 mmol) of t-butyldimethyl-silyl chloride was added. After two days at room 2~L37() temperature, 1 ml of methanol was added to the reaction and after 1 hour the solution was evaporated to dryness. The residue was partitioned between saturated NH4Cl solution (aq) and washed with ethyl acetate which was dried, filtered and concentrated to give an oil which was a mixture of product and the furanone starting material. This material was carried on crude into the next reaction.
O Step 6: Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-(t-butyldimethyl-silyloxy-5-(2-(3(S)-N'-(t-butylcarboxamido)-(4aS,8aS)-decahydroisoquinoline)yl)-pentaneamide 5 The crude product of step 5, above, was dissolved in 3 ml of DME along with 47 mg (0.246 mmol) of EDC, 33 mg (0.246 mmol) of HOBT and 37 mg of 2(R)-hydroxy-l(S)-aminoindane. The pH of the solution was adjusted to 8.5-9.0 with triethylamine and after 18 hours it was worked up by concentrating to dryness, dissolving the residue in 10% aq. citric acid solution and washing the aqueous layer with ethyl acetate. The organic layer was dried, filtered and concentrated and the resultant oil was chromatographed (SiO2, 30%
EtOAc/Hexane) to yield the title compound.
Step 7: Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(2-(3(S)-N'-(t-butylcarboxamido)-(4aS,8aS)-decahydro-isoquinoline)yl~-pentaneamide The product from step 6, above, was dissolved in 1 ml of THF and 1 ml of a lM solution of tetrabutylammonium fluoride in THF was added. After 18 hr at room temperature the reaction was diluted with 20 ml of saturated NaHC03 solution (aq) and the product was extracted into ethyl acetate which was dried, filtered and concentrated to give a foam. The resultant material was chromatographed on a prep plate (0.5 mm, 5% MeOE/CHC13) and the title product isolated in the usual manner as a solid with mp 105-107C.
Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-amino-5-(2-(3(S)-N~-(t-butylcarbox-amido)-(4aS,8aS)-decahydroisoquinoline)yl)-pentaneamide Step 1: Preparation of 5(S)-((t-butyl-dimethyl-silyloxy)methyl)-3(R)-phenylmethyl-N-BOC-2-pyrrolidinone A solution of 5(S)-((t-butyl-dimethyl-silyloxy)methyl)-N-BOC-2-pyrrolidinone (400 mg, 1.26 mmol) in 2 ml of THF was added to a precooled (-78C) lM solution of lithium hexamethyldisilazide (1.3 ml) in 5 ml of THF. After 45 min, 0.15 ml of benzyl bromide (1.3 mmol) was added and the stirring was continued.
After 5 h the reaction was worked up by pouring into a separatory funnel containing 30 ml of an aqueous 10%
citric solution. The aqueous layer was extracted (2 x 30 ml EtOAc) which was backwashed with brine (50 ml) dried, filtered and concentrated to an oil. The residue was chromatographed (SiO2, 20% EtOAc/Hexane) to afford the product as an oil.
2~81970 Step 2: Preparation of 5(S)-hydroxymethyl-3(R)-phenylmethyl-2-pyrrolidinone To 130 mg (0.34 mmol) of 5(S)-((t-butyl-dimethylæilyloxy)methyl)-3(R)-phenylmethyl-N-BOC-2-pyrrolidinone in 5 ml of acetonitrile was added 0.1 mlof a solution of 48% HF in water. After 3 hr at room temperature the reaction was concentrated to dryness and diluted with 30 ml of an aqueous 10% NaHCO3 solution. This was extracted with EtOAc (2 X 30 ml), dried filtered and concentrated to afford the crude product.
Step 3: Preparation of 5(S)-(methanesulfonyloxy)-methyl-3(R~-phenylmethyl-2-pyrrolidinone To a solution of the crude product from Step 2, in 5 ml of methylene chloride cooled to 0C was added triethylamine (42 mg, 0.41 mmol) and methane-sulfonyl chloride (47 mg, 0.41 mmol). The reaction was slowly allowed to warm to room temperature and was stirred for 18 hr after which time it was diluted with 30 ml of methylene chloride, washed with 30 ml of 10%
citric acid solution, dried filtered and concentrated to afford the product as an oil.
5 Step 4: Preparation of 5(S)-(2-(3(S)-N-(t-butylcar-boxamido)-(4aS,8aS)-(decahydroisoquinoline)-yl)-methyl)-3(R)-phenylmethyl-2-pyrrolidinone To a solution of 380 mg (1.34 mmol) of 5(S)-(methanesulfonyloxy)methyl-3(R)-phenylmethyl-2-pyrrolidinone in 20 ml of isopropanol was added 350 mgof potassium carbonate and 360 mg of N-t-butyl-(4aS,8aS)-(decahydroisoquinoline)-3(S)-carboxamide and the reaction was heated to 85C. After 18 hr the 20819`70 -cooled reaction was filtered through celite, evaporated to dryness and the residue was dissolved in water which was extracted with EtOAc (2 X 50 ml). The organics were dried, filtered and concentrated, and the residue was chromatographed (SiO2, 50/50 EtOAc/Hexane) to afford the product as an oil.
Step 5: Preparation of 5(S)-(2-(3(S)-N~-(t-butylcar-boxamido)-(4aS,8aS)-(decahydroisoquinoline)-lo yl)-methyl)-3(R)-phenylmethyl-N-BOC-2-pyrrolidinone To a solution of the product from step 4, above, (260 mg, 0.611 mmol) in 10 ml of methylene chloride was added dimethylaminopyridine (74 mg, 0.6 mmol) and 133 mg (0.61 mmol) of BOC-anhydride. After 18 hr at room temperature the reaction was worked up by diluting with 30 ml of methylene chloride and the organics washed with 30 ml of 10% citric acid solution, brine (30 ml) dried, filtered and concentrated to afford an oil. Chromatography (SiO2, 40% EtOAc/Hexane) gave the title compound.
Step 6: Preparation of 5-(2-(3(S)-N'-(t-butylcar-boxamido)-(4aS,8aS)-decahydroisoquinoline)-yl)-4(S)-~(l',l')-(dimethylethoxycarbonyl)-aminol-2(R)-phenylmethyl-pentanoic acid To a solution of the product of step 5, above, (260 mg, 0.495 mmol) dissolved in 3 ml of di-methoxyethane was added 1.5 ml of a lM solution of aqueous lithium hydroxide (1.5 mmol). The reaction was worked up after 2 hr by concentrating to dryness, dissolving the residue in saturated aqueous ammonium chloride solution and the aqueous phase was washed with ~- 2û819~0 ethyl acetate (2 x 50 ml) which was dried, filtered and concentrated to afford the crude acid.
Step 7: Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-[(l~,l')-(dimethyl-ethoxycarbonyl)amino]-5-(2-(3(S)-N~-(t-butyl-carboxamido)-(4aS,8aS)-decahydroisoquinol-ine)yl~-pentaneamide To a solution of the product of step 6, lo above, (260 mg, 0.49 mmol) in methylene chloride was added EDC (94 mg, 0.49 mmol), HOBT (66 mg, 0.49 mmol), 2(R)-hydroxy-l(S)-aminoindane (73 mg, 0.49 mmol) and the pH of the reaction was adjusted to 8.5-9.0 using triethylamine. After 5 hr at room temperature the reaction was worked up by diluting with 50 ml of methylene chloride and washing the organics with saturated aqueou~ ammonium chloride solution. The organic phase was dried, filtered and concentrated and the residue was chromatographed to afford the title compound as a foam.
Step 8: Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(2-(3(S)-N'-(t-butylcarboxamido)-(4aS,8aS)-decahydro-isoquinoline~yl)-pentaneamide To a solution of the product of step 7, above, (180 mg, 0.28 mmol) in 5 ml of methylene chloride cooled to OoC wa~ added 1 ml of trifluoro-acetic acid. After 4 hr the reaction was worked up by concentrating to dryness and the residue was dissolved in 50 ml of methylene chloride and washed with 10%
aqueous Na~C03 solution. The organic layer was dried, filtered and concentrated to give the product as a - 2 ~ 7 0 solid which was chromatographed (SiO2, 7% MeOH/CH2C12) to afford the title compound, mp = 92-95C.
Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-carbobenzyloxy-2-(S)-N'-(t-butylcarboxamido~-piperazinyl)~-pentaneamide Employing substantially the same procedure lo used in Example 1, but substituting N-t-butyl-4-CBZ-piperazine-2(S)-carboxamide for N-t-butyl-4(S)-phenoxy-L-prolineamide used in step 9 therein, the title compound was obtained.
Preparation of N~-(N-(2-pyridyl)-valyl)-2(R)-phenyl-methyl-4(S)-hydroxy-5-(2-(3(S)-(N~-t-butylcarbox-amido)-(4aS,8aS)-decahydroi~oquinoline)yl)pentane-amide Employing substantially the same procedure used in Example 4, but substituting N-2-pyridyl-valine for the 2(R)-hydroxy-l(S)aminoindane used in step 6 therein, the title compound was obtained.
F.~MPLE 8 Preparation of N-(2(R)-hydroxy-l(S~-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(2(S)-(N~-t-butyl-3-phenyl-propionamide~amino)-pentaneamide Employing substantially the same procedure used in Example 1, but substituting N-t-butyl-phenyl-alanine amide for the N~-t-butyl-4(S)-phenoxy-., L-prolineamide used in step 9 therein, the title compound is obtained.
~MPLE 9 s Preparation of N-(4(S)-3,4-dihydro-lH-2,2-dioxobenzo-thiopyranyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(2-(3(S)-N'-(t-butylcarboxamido)-(4aS,8aS)-decahydro-isoquinoline)yl)-pentaneamide Step 1: Preparation of N-(4(S)-3,4-dihydro-lH-benzothiopyranyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(2-(3(S)-t-butylcarboxamido)-(4aS, 8aS)-decahydroisoquinoline)yl)-pentaneamide Employing substantially the same procedure used in Example 4 but substituting 4(S)-amino-3,4-dihydro-lH-benzothiopyran for the 2(R)-hydroxy-l(S)-aminoindane used in step 6 therein, the title compound is obtained.
Step 2: Preparation of N-(4(S)-3,4-dihydro-lH-2,2-dioxobenzothiopyranyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(2-(3(S)-t-butylcarboxamido)-(4aS,8aS)-decahydroisoquinoline)yl)-pentane-amide The compound from step 1 above is dissolved in a 1:1 mixture of methanol and water. To this is added 10 eq. of OXONE and the reaction is stirred at room temperature. When the reaction is complete, it is concentrated to dryness, water is added and extracted with ethyl acetate which iB dried, filtered and concentrated to give the title compound.
F.~MPLE 1 0 Preparation of N-(4(S)-3,4-dihydro-lH-2,2-dioxobenzo-thiopyranyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-carbobenzyloxy-2(S)-N'-(t-butylcarboxamido)-piperazinyl~)-pentaneamide Step 1: Preparation of dihydro-5(S)-(1-(4-carbo-benzyloxy-2(S)-N'-(t-butylcarboxamido)-piperazinyl)methyl)-3(R)-phenylmethyl-3(2H)-furanone Employing substantially the same procedure used in Example 4, ætep 4 but substituting 4-carbobenzyloxy-2(S)-N~-(t-butylcarboxamido)-piper-azine for the N~-t-butyl-(4aS,8aS)-(decahydroisoquino-line)-3(S)-carboxamide used therein, the title compound is produced.
Step 2: Preparation of 2(R)-phenylmethyl-4(S)-(t-butyldimethylsilyloxy)-5-(1-(4-carbo-benzyloxy-2(S)-N'-(t-butylcarboxamido)-piperazinyl~)-pentanoic acid Employing substantially the same procedure used in Example 4, step 5 but substituting dihydro-5(S)-(1-(4-carbobenzyloxy-2(S)-NI-(t-butylcarbox-amido)-piperazinyl)methyl)-3(R)-phenylmethyl-3(2H)-furanone for the dihydro-5(S)-(2-(3(S)-N~-(t-butyl-carboxamido)-(4aS,8aS)-(decahydroisoquinoline)yl)-methyl)-3(R)-phenylmethyl-3(2H) furanone used therein, the title compound is produced.
20819~
-Step 3: Preparation of N-(4(S)-3,4-dihydro-lH-benzothiopyranyl)-2(R)-phenylmethyl-4(S)-(t-butyldimethylsilyloxy)-5-(1-(4-carbobenzyloxy-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide The crude 2(R)-phenylmethyl-4(S)-(t-butyldimethylsilyloxy)-5-(1-(4-carbobenzyloxy-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentanoic acid is dissolved in 3ml of DMF along with 1 eq of EDC, 1 eq of HOBT and 1 eq of 4(S)-amino-3,4-dihydro-lH- benzothiop yran. The pH of the solution is adjusted to 8.5-9.0 with triethylamine and after 18 hours it is worked up by concentrating to dryness, dissolving the residue in 10% aq citric acid solution and washing the aqueous layer with ethyl acetate. The organic layer is dried, filtered and concentrated and the resultant residue is chromatographed to yield the title product.
Step 4: Preparation of N-(4(S)-3,4-dihydro-lH-benzothiopyranyl)-2(R)-phenylmethyl-4(S)-hydroxy)-5-(1-(4-carbobenzyloxy-2(S)-(t-butylcarboxamido)-piperazinyl~)-pentaneamide The product from step 3 above is dissolved in 1 ml of THF and 1 ml of a lM solution of tetra-butylammonium fluoride in l~ is added. After 18 hr atroom temperature the reaction is diluted with 20 ml of saturated NaHCO3 solution (aq) and the product is extracted into ethyl acetate which is dried, filtered and concentrated to give a residue. The residue is chromatographed to afford the product.
Step 5: Preparation of N-(4(S)-3,4-dihydro-lH-2,2-dioxobenzothiopyranyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-carbobenzyloxy-2(S)-N~-(t-butylcarboxamido)-piperazinyl))-pentane-amide The compound from step 4 above is dissolved in a 1:1 mixture of methanol and water. To this is added 10 eq of OXONE and the reaction is stirred at room temperature. When the reaction is complete, it is concentrated to dryness, water is added and extracted with ethyl acetate which is dried, filtered and concentrated to give the title compound.
Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-((2-hydroxy)ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(2-(3-(S)-N'-(t-butylcarboxamido)-(4aS,8aS)-decahydroisoquin-oline)yl~pentaneamide Step 1: Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-(2-allyloxy)phenyl)methyl)-4(S)-hydroxy-5-(2-(3(S)-t-butylcarboxamido)-(4aS,8aS)-decahydroisoquinoline)yl)-2s pentaneamide To a solution of N-(2(R)-hydroxy-l(S)-indan-yl)-2(R)-((4-hydroxyphenyl)methyl)-4(S)-hydroxy-5-(2-(3(S)-t-butylcarboxamido)-(4aS,8aS)-decahydroisoquino-line)yl)-pentaneamide in dioxane is added 6 eq of allyl bromide and 6 eq of cesium carbonate. The reaction is heated to 90C. When the reaction is complete, the precipitate is filtered off, the dioxane is concentrated to dryness and the residue is diluted with ._ water which is washed with ethyl acetate. The organic phase is dried, filtered and concentrated to afford the product.
Step 2: Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-((2-hydroxy)ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(2-(3(S)-N~-(t-butylcarbox-amido)-(4aS,8aS)-decahydroisoquinoline)yl)-pentaneamide The product from step 1 above is dissolved in methanol, 1 eq of p-toluenesulfonic acid is added and the reaction is cooled to -78C. Excess ozone is bubbled through the reaction until a blue color persists. The flask is purged with nitrogen to remove any ozone and excess sodium borohydride solution is added. The reaction is warmed to room temperature and then saturated Na~C03 solution is added. The methanol is concentrated off on the rotoevaporater and the aqueous residue is washed with ethyl acetate which is dried, filtered and concentrated to afford the title compound.
Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-((2-hydroxy)ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(4-carbobenzyloxy-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide Employing substantially the same prodecure used in Example 11 but substituting N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-hydroxyphenyl)methyl)-4(S)-hydroxy-5-(1-(4-carbobenzyloxy-2(S)-(t-butylcarbox-amido)-piperazinyl)-pentaneamide for the N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-hydroxyphenyl)methyl)-4(S)-hydroxy-5-(2-(3(S)-t-butylcarboxamido)-(4aS,8aS)-de cahydroisoquinoline)yl)-pentaneamide used therein, the title compound is obtained.
Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-(2-(4-morpholinyl)ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(2-(3(S)-N~-(t-butylcarboxamido)-(4aS,8aS)-decahydroiso~uinoline)yl~-pentaneamide To a æolution of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-hydroxyphenyl)methyl)-4(S)-hydroxy-5-(2-(3(S)-N'-(t-butylcarboxamido)-(4aS,8aS)-decahydroisoquinoline)yl)-pentaneamide in dioxane is added 6 eq of chloroethyl morpholine and 6 eq of cesium carbonate. The reaction is heated to 90C. When the reaction is complete, the precipitate is filtered off, the dioxane is concentrated to dryness and the residue is diluted with water which is washed with ethyl acetate. The organic phase is dried, filtered and concentrated to afford the title compound.
2s Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-(2-(4-morpholinyl~ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(4-carbobenzyloxy-2(S)-N~-(t-butyl-carboxamido~-piperazinyl~-pentaneamide To a solution of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-hydroxyphenyl)methyl)-4(S)-hydroxy-5-(1-(4-carbobenzyloxy-2(S)-(t-butylcarboxamido)-` -208197~
piperazinyl)-pentaneamide in dioxane i8 added 6 eq of chloroethyl morpholine and 6 eq of cesium carbonate.
The reaction is heated to 90C. When the reaction is complete, the precipitate is filtered off, the dioxane is concentrated to dryness and the residue is diluted with water which is washed with ethyl acetate. The organic phase is dried, filtered and concentrated to afford the title compound.
1o EXAMPLE 15 Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(3-pyridylmethyl)-2(S)-N'-(t-butylcarboxamido~-piperazinyl))-pentaneamide Step 1: Preparation of dihydro-5(S)-((trifluoro-methanesulfonyl)oxymethyl)-3(R)-phenylmethyl-3(2H)-furanone To a solution of 18.4g (89.2 mmol) of dihydro-5(S)-(hydroxymethyl)-3(R)-phenylmethyl-3(2H)-furanone in 350 mL of methylene chloride cooled to 0C
was added 13.51 mL 2,6-lutidine (115.98 mmol) followed by a dropwise addition of 16.51 mL of trifluoromethane-sulfonic anhydride (98.1 mmol). After 1.5 hours at 0C, the reaction was poured into a mixture of 300 mL
ice/brine and stirred for 0.5 hours. The aqueous layer was then extracted with methylene chloride (3 x 150 mL), the organic layers were washed with 10% HCl (2 x 75 mL), saturated NaHC03 (lOOmL), water (lOOmL), dried over MgS04, filtered and concentrated to give a solid residue. Purification via flash column chromatography (120 x 150 mm column, gradient elution of hexanes:EtOAc, 4:1 to 3:1) afforded the title product;
mp 53-540C.
Step 2: Preparation of 4-(1,1-dimethylethyl)-1-(phenylmethyl)-1,2(S),4-piperazinetri-carboxylate The title compound was prepared following the procedure of Bigge, C.F.; Hays, S.J.; Novak, P.M.;
Drummond, J.T.; Johnson, G.; Bobovski, T.P. Tetrahedron k~. 1989, 30, 5193; starting with 2(S)-piperazine-carboxylic acid. (see Felder, E.; Maffei, S.; Pietra, S.; Pitre, D.; Helv. Chim. Acta 1960, 117, 888.
Step 3: Preparation of N-t-butyl-4-(1,1-dimethyl-ethoxycarbonylamino)-l-(phenylmethylcarbonyl-amino)piperazine-2(S~-carboxamide To 9.90g (27.16 mmol) of 4-(1,1-dimethyl-ethyl)-1-(phenylmethyl)-1,2(S),4-piperazinetricarbox-ylate dissolved in 75 mL of DMF and cooled to 0C was added 5.73g (29.88 mmol) of EDC, 4.03g (29.88 mmol) of HOBt, 3.14 mL (29.88 mmol) of t-butylamine, and finally 4.16 mL (29.88 mmol) of triethylamine. The reaction 20 mixture was stirred for 18 hours and the reaction volume was concentrated by half. The mixture was then diluted with 600 mL of EtOAc and washed with 10% HCl (2 x 75 mL), saturated NaHC03 (1 x 75 mL), water (3 x 75 mL) and brine (1 x 50 mL), dried over MgS04 and concentrated to a solid. This solid was triturated with EtOAc: hexane (1:2) and filtered to provide the title product as a white solid;
mp 134-135 C .
Step 4: Preparation of N-t-butyl-4-(1,1-dimethyl-ethoxycarbonylamino)piperazine-2(S)-carboxamide To 1.20g (2.86 mmol) of N-t-butyl-4-(1,1-dimethylethoxycarbonylamino)-l-(phenylmethylcarbonyl-amino)piperazine-2(S)-carboxamide and l.lg (0.086 mmol) of 10% Pd/C waæ added 15 mL of methanol. The vessel was charged with hydrogen and the reaction stirred for 2 hours, filtered through celite and washed with ethanol. The solvents were removed in vacuo to provide the title product as a foam.
lH NMR (300 MHz, CDC13) ~ 6.65 (br, lH), 4.10 (m, lH), 3.81 (br, lH), 3.21 (dd, J=18 and 7 Hz, lH), 3.02-2.70 (m, 4H), 2.10-2.0 (br, lH), 1.50 (s, 9H), 1.41(s, 9H).
Step 5: Preparation of dihydro-5(S)-(4-(1,1-dimethylethoxycarbonylamino))-2(S)-N-(t-butylcarboxamido)-piperazinyl)methyl)-3(R)-phenylmethyl-3(2H)-furanone 2C To a solution of 22.40g (0.0662 mol) dihydro-5(S)-((trifluoromethanesulfonyl)oxymethyl)-3(R)-phenylmethyl-3(2H)-furanone (prep in step 1) and 18.0g (0.063mol) of n-t-butyl-4-(1,1-dimethylethoxy-carbonylamino)piperazine-2(S)-carboxamide dissolved in 180 mL of isopropanol was added 11.53 mL (0.0662 mol) of N,N-diisopropylethylamine. After 2.5 hours another 1.2g of dihydro-5(S)-((trifluoromethanesulfonyl)oxy-methyl)-3(R)-phenylmethyl-3(2E)-furanone was added.
The reaction was complete by thin layer chromatography (tlc) after 3.5 hours and was concentrated to a thick oil. Trituration with EtOAc:hexanes (1:2, 200mL) provided a white solid which was filtered and discarded. The oil was purified by flash column 20~1970 .
chromatography (120 x 150 mm column, EtOAc:hexanes gradient elution 1:1, 2:1, 3:1 to all EtOAc) to afford the title compound.
lH NMR (400 MHz, CDC13) ~ 7.34-7.17 (m, 5H), 6.31 (br s, lH), 4.38 (br m, lH), 3.96-3.92 (m, lH), 3.79 (br m, lH), 3.16 (dd, J=13.6 and 4.4 Hz, lH), 3.08-2.99 (m, 3H), 2.90-2.82 (m, lH), 2.80 (dd, J=13.5 and 8.9 Hz, lH), 2.78 (m, lH), 2.67-2.61 (m,lH), 2.58-2.49 (m, lH), 2.38-2.32 (m,lH), 2.32-2.04 (m, lH), 1.99-1.92 (m, lH,) 1.45 (s, 9H), 1.29 (s, 9H).
Step 6: Preparation of 2(R)-phenylmethyl-4(S)-(t-butyldimethylsilyloxy)-5-(1-(4-(1,1-di-methylethoxycarbonylamino)))-2(S)-N-(t-butylcarboxamido~-piperazinyl)~-pentaneamide To 25.50g (52.50 mmol) of dihydro-5(S)-(4-(l,l-dimethylethoxycarbonylamino))-2(S)-N-(t-butyl-carboxamido)-piperazinyl)methyl)-3(R)-phenylmethyl-3(2H)-furanone dissolved in 120 mL DME cooled to 0C
20 was added a solution of 60 mL of water and 1.512g (63.01 mmol) of lithium hydroxide. After 0.5 hours the reaction was quenched with the addition of 10% HCl until pH 6 and the solution was concentrated in vacuo.
The reæidue was dissolved in 50 mL water and extracted 25 with EtOAc (4 x 75 mL) and the organic layers were washed with water (1 x 20 mL), brine (1 x 20 mL). The aqueous was back extracted with EtOAc (2 x 75 mL) and the combined organic layers were dried over MgSO4 and concentrated to pro~ide a yellow solid. This crude product was dissolved in 100 mL of DMF and 17.87g (0.262 mol) of imidazole was added, cooled to 0C and then 31.50g (0.21 mol) of t-butyldimethylsilyl chloride was added. This stirred 1 hour at 0C and was then _ warmed to room temperature. After 20 hours the reaction was quenched with 10 mL methanol and concentrated to half the volume. 100 mL of pH 7 buffered water was added and the aqueous was extracted with EtOAc (4 x 100 mL), the combined organic layers were washed with 10% HCl (2 x 50 mL), water (3 x 75 mL), and brine (1 x 50 mL), dried over MgS04 and concentrated to obtain the title compound. This material was used directly in the next step.
Step 7: Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-(t-butyldimethylsilyl-oxy)-5-(1-(4-(1,1-dimethylethoxycarbonyl-amino)))-2(S)-N-(t-butylcarboxamido)-piper-azinyl)~-pentaneamide To 27.0g (0.0446mol) of the crude material from step 6 dissolved in 180 mL of DMF and cooled to 0C was added 8.98g (0.0468 mol) of EDC, 6.32g (0.0468 mol) of HOBt, and 7.31g (0.049 mol) aminohydroxy 2Q indane. Triethylamine (6.52 mL, 0.0468 mol) was added and the reaction stirred at 0C for 2 hours, room temperature for 16 hours and was quenched by diluting with 500 mL of EtOAc. The organic layer was washed with 10% ECl (2 x 100 mL), saturated NaHCO3 (1 x 100 mL), water (3 x 150 mL), brine (1 x 75 mL), dried over MgS04 and concentrated to yield the title compound as a white foam.
1H NMR (400 MHZ, CDC13) ~ 7.4-7.17 (m, 9H), 6.51 (br s, lH), 5.79 (br s, lH), 5.23 (m, lH), 4.23 (br s, lH), 4.06 (m, lH), 3.96-3.84 (m, 2H), 3.07-2.78 (m, 8H), 3.65 (dd, J=9.6 and 4.1 Hz, lH), 2.56-2.44 (m, 2H), 2.29 (dd, J=12.0 and 4.5 Hz, lH), 2.17-2.09 (m, lH), 1.79 (br s, lH), 1.44 (~, 9H), 1.35 (s, 9H), 1.10 (s, lH), 0.84 (s, 9H), 0.12 (s, 3H), 0.08 (s, 3H).
Step 8: Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-(hydroxy)-5-(1-(4-(1,1-dimethylethoxycarbonylamino)))-2(S)-N-(t-butylcarboxamido)-piperazinyl))-pentaneamide To 32.20g (0.0437 mol) of N-(2(R)-hydroxy-l-(S)-indanyl)-2(R)-phenylmethyl-4(S)-(t-butyldimethyl-silyloxy)-5-(1-(4-(1,1-dimethylethoxycarbonylamino)))-2(S)-N-(t-butylcarboxamido)-piperazinyl))-pentane-amide was added 437 mL (0.437 mol) of tetrabutyl-ammonium fluoride (l.OM solution in THF, Aldrich~. The reaction stirred for 18 hours and was then concentrated to 200 mL and diluted with 700 mL of EtOAc. This was washed with water (2 x 100 mL), brine (1 x 50 mL) and the aqueous layers were back extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over MgSO4 and concentrated to an oil. Purification via flash column chromatography (120 x 150 mm column, gradient elution CH2C12: CHC13/saturated with NH3:
methanol, increasing methanol from 1%, 1.5%, 2%) afforded the title compound as a white foam.
lH NMR (400 MHz, CDC13) ~ 7.31-7.11 (m, 9H), 6.41 (br s, lH), 6.23 (d, J=8.6 Hz, lH), 5.25 (dd, J=8.6 and 4.7Hz, lH), 4.21 (m, lH), 3.83-3.82 (m, 2E), 3.78-3.61 (m, 2H), 3.22-3.19 (m, 2H), 3.03-2.78 (m, 8H), 2.62-2.58 (m, lH), 2.41-2.35 (m, 2H), 2.04-2.02 (m, lH), 1.57-1.50 (m, lH), 1.45 (s, 9H), 1.32 (s, 9H).
20~3L970 , Step 9: Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-(hydroxy)-5-(1-(2(S)-N-(t-butylcarboxamido)-piperazinyl)-pentane-amide To 21.15g (0.034 mol) of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-(hydroxy)-5-(1-(4-(1,1-dimethylethoxycarbonylamino)))-2(S)-N-(t-butylcarboxamido)-piperazinyl))-pentaneamide dissolved in 350 mL of methylene chloride and cooled to 0C was added 22.43 mL (0.204 mol) 2,6-lutidine and then 32.85 mL (0.170 mol) of trimethylsilyltriflate over 5 minutes. After 0.5 hours the reaction was quenched with 10~/o HCl (80 mL) and this stirred 0.5 hours. To this was added 100 mL of saturated NaHCO3 and then solid NaHCO3 until pH 8. The aqueous layer was then extracted with EtOAc (4 x 100 mL) and the combined organic layers were washed with water (1 x 50 mL), brine (1 x 75 mL), dried over MgSO4 and concentrated.
The residue was purified via column chromatography (120 x 150 mm column, gradient elution CH2C12:CHC13 saturated with NH3: MeOH, slowly increasing methanol 2%, 3%, 4%, 5%, 6%, to 10%). This provided the title product as a white foam.
lH NMR (400 MHz, CDC13) ~ 7.53 (s, lH), 7.29-7.09 (m, 9H), 6.52 (d, J=8.3 Hz, lH), 5.24 (dd, J=8.2 and 4.9 Hz, lH), 4.23 (dd, J=4.7 and 4.03 Hz, lH), 4.25-4.00 (br s, lH), 3.83-3.81 (m, lH), 3.03-2.88 (m, 4H), 2 . 82-2 . 73 ~m, 7~), 2 . 50-1. 60 (br s, 2H), 2 . 45 (d, J=6 . 2 Hz, 2H), 2.32-2.29 (m, lH), 1.98 (m, lH), 1.51 (m, lH), 1.33 (s, 9H).
Step 10: Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-~3-pyridylmethyl)-2(S)-N'-(t-butylcarboxamido)-pi~erazinyl~-pentaneamide To 10.0g (0.019 mol) of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy)-5-(1(-2(S)-N-(t-butylcarboxamido)-piperazinyl)-pentaneamide and 3.45g (0.021 mol) of 3-picolyl chloride dissolved in 40 mL of DMF was added 5.85 mL (0.042 mol) of triethylamine. After 3 hours an additional 0.313g of 3-picolyl chloride was added. After an additional 2 hours the reaction was diluted with 400 mL of EtOAc and washed with water (3 x 75 mL), brine (1 x 100 mL), dried over MgSO4 and concentrated. The residue was triturated with 30 mL of EtOAc and the resulting white precipitate was collected. Further recrystallization from EtOAc provided the title product (mp 167.5-168C).
Employing subætantially the æame procedure as described in Example 15, but treating the N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(2(S)-N -(t-butylcarboxamido)-piperazinyl))-pentane-amide used therein (compound (i) below) with thealkylating agent (ii) indicated below in place of the 3-picolyl chloride used in Step 10 therein, the following products defined by formula (iii) were made:
20~1970 Ph ~ ~ OH R1_x CONH + ~ ii l RlN ~ OH ~Ph ~ N ~ " -.
CONH+ ~
iii ~N ~CH2- I
~J
OH
~CH2-Cl ~f Hz - Cl ~~CH2-N
Rl X
\ ~ CH2- Br o ~ H2_ Cl ~ H2- Cl ~0 Cl O ~CH2-Boc ~
~ CH2- I
~ H2- Cl .
R X
~CH2- Cl ~CH2- I
C~N~CH2- Cl ~N~CH2 - Cl ~rq Cl ~CH2-CH30( CH2CH20) 2- CH2CH2-~"~CH2-13~CH2_ 3 0 ~CH2 - Cl Ph~_,o~_~CH2- I
N ~ H2_ Cl NH
O~N~H2_ ll Cl HN
O
Cl N~o ~ CH2 Cl Preparation of dihydro-5(S)-(tert-butyldimethylsilyl-oxymethyl)-3(2H)-furanone To a solution of 3.00g (25.8 mmol) of dihydro-5(S)-(hydroxymethyl)-2(3H)-furanone dissolved in 25 mL
of dichloromethane was added 3.51g (51.6 mmol) of imidazole and then 4.67g (31.0 mmol) of tert-butyl-~081970 dimethylsilyl chloride. The reaction stirred at room temperature for 8 hours and was quenched with 2 mL of methanol. The mixture was concentrated to an oil and then diluted with 150 mL of ether and washed with 5%
HCl (2 x 10 mL), saturated NaHC03 (1 x 10 mL), water (1 x 10 mL), and brine (1 x 10 mL), dried over MgS04 and concentrated. The residue was purified by flash chromatography (40 x 150 mm column, gradient elution, hexanes:ethyl/acetate 5:1 to 4:1) to afford the product as a clear oil-lH NMR (300 MHz, CDC13) ~ 4.68-4.60 (m, lH), 3.89 (dd, J=3.3 and 11.3 Hz, lH), 3.71 (dd, J=3.2 and 5411.3 Hz,lH), 2.71-2.45 (m, 2H), 2.35-2.16 (m, 2H), 0.91 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H).
While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention emcompasses all of the usual variations, adaptations, or modifications, as come within the scope of the following claims and its equivalents.
HO ~ \. K2C3 CH3SO20~N~ HN- R
14 ~ R2 1CONH~
R -N ~ - R~-N ~ ~ H
R2 CONH t ~ R~ CONH t 16 -A third method for forming products of general formula I is shown in Scheme III. Protection of the pyrrolidine -NH- group of compound 17 is carried out with BOC-anhydride and dimethylaminopyridine to give the protected compound 18. Alkylation of 18 i~ performed by a first step of deprotonation of 18 with a strong baæe such as lithium hexamethyldisilamide (LHMDS) or lithium diisopropylamide (LDA) followed by a second step of adding an alkyl halide (such as benzyl bromide) to afford compound 19.
The TBS protecting and BOC protecting group of 19 are removed by treatment with aqueous HF in acetonitrile to give alcohol 20. Mesylation of the primary alcohol of 20 with methanesulfonyl chloride and either triethylamine or pyridine gives mesylate 21 which is heated with an amine in a refluxing alcoholic solvent such as methanol or isopropanol which contains an exc.ess of potassium carbonate to produce an amino pyrrolidinone ~uch as compound 22.
The pyrrolidine -N~- group of 22 is reprotected as a BOC group as before and the resultant compound 23 is hydrolized open with a base such as lithium or ~odium hydroxide to afford the acid 24. Compound 24 is then coupled to an NH2R12 amine in a stan'dard manner and the BOC is removed with gaseous HCl or trifluoro-acetic acid to give the desired product, exemplified by compound 25.
SCEEME III
~o O N--l( 1 )LDA
T~SO~ DM~P' TBSO~ / 2) E~enzyIbrornde ~0 l O O~N~ ~ HF/CH3CN
TE~SO~ ~J~ HzO
l 5 HN~ ~ CH3SOzCl HO~l~ ~ Et3N
HN-HN~ ~ RzlCoNH~
CH3S020~/ ~~, lH, KzC03 o N~ J3 BOCzo 2 5 I DM~P
RZ~ONH +
-o 3 . R ~N~ LiOH
RZlCONH +
SC~EME III (CONT'D~
OH
R2 CONH+ +
2. H
~2`~
R CONH+
A compound of formula 26 2 0 P N~ OH R3 1~, 1~NH_ Rl 2 26 CONH +
25 wherein P is a nitrogen protecting group such as -BOC
or -CBZ, is preferably prepared according to the method described in Scheme I, preferably employing the 5-trifluoromethanesulfonyloxymethyl analog of lactone 4 therein (see Example 15, Step 1).
Compounds of formula 27 ~ -R1a 27 CONH ~
can be obtained by a variety of routes from compound ~1_ Rl 2 28 CONHt which is obtained after removal of the nitrogen protecting group in 26 using methods well known in the art, e.g., catalytic hydrogenation to remove a CBZ group, or treatment with trimethylsilyltriflate and 2,6 lutidine at about 0C in a solvent such as CE2C12 to remove a BOC group.
For example, the 4-position piperazinyl nitrogen of compound 28 can be alkylated with a compound of formula Rl-X in a solvent such as DMF in the presence of Et3N at room temperature, wherein X
is -Cl, Br or -I, or a sulfonamide group can be formed by treatment of 28 with a sulfonyl chloride compound of formula RlS02Cl under similar conditions. Also, standard amide coupling techniques can be used to form an amide group at the piperazinyl 4-position. Techniques for these procedures are well known to those skilled in the art. The Rl group of Rl-X or RlS02Cl i8 defined above in the definition of compounds of formula I wherein Rl is independent from and not joined to R2, except that Rl can not be hydrogen or a group with a free hydroxy substituent, such as -Cl_4alkyl substitued with hydroxy, with the further exception that Rl can be aryl substituted with a hydroxy group.
The compounds of this invention are also illustrated by Tables I-IV, which follow.
TABLE I
~ 3 CONH+ O
OH
- HN~", 15 -CH2- Ph -OH
20 -CH~-Ph -OH -HN~O
OH
- HN~ OH
-CH2- Ph -OH
OH
- HN~...~OH
- CH2 - Ph - OH
OH
- HN~ `~H2 -CH2- Ph -OH ~
.
T~RTF I. C0NT'D
o -CH2-Ph -OH -HN
-CH2-Ph -OH HN ~ N ~
-CH2-Ph -OH -HN ~ OH
~` OH
OH
-CH2-Ph -OH -HN~
r -CHz-Ph -OH -HN'~
`~ 2~8~970 TABT.F I. CONT'D
-CH2-Ph -OH -HN p o -CH2-Ph -HN
-HN ~ ~y,~
-CH2-Ph -OH H
-CH2-Ph -OH
O
-~ o~=~
-CH2-Ph -OH "~ H HN ~
- 20~1970 , T~RLE I. CONT'D
`NH
-CH2-Ph -OH
E
- CH2- Ph - NH2 ~ H
NH
- CH2- Ph - OH [~,~ROH
`NH
2 0 - CH2 - Ph - OH ~OH
238~970 TABT F T, C0NT ' D
~H
- CH2- Ph - NH2 ~ ~ OH
`NH
-CHz-Ph -OH
`NH
- CH2 - Ph ~=a `NH
-CH2-Ph -OH [~
- CH2~CH3 - OH [~"'OH
`NH
- CH2~OH - OH ~""~H
`NH
3 0 - CH2~OH - OH ~"n~H
OH
T~RLE I. CONT'D
NH
- CH2 ~.~OH - NH2 ~ ~ OH
- CH2 ~H - NH
-CH2~ -OH -IleN~
-CH2~ O~ H~
- CH2 ~ - NH2 ~ I le N~
- CH2~ / \ - OH - I leN
3 -CH2~o- OH -OH H~
20~1970 TABTF I. CONT'D
-CHz ~ ~ N -NH2 -IleN
- CH2 ~OH - OH - ValN OH
H
-CHz~ -OH -ValN~ OH
NH
1 5 ~PH
- CHz ~~N O OH ~J
~NH
2 0 - CHz ~~N O - NHz ~o~OH
~NH
- CHz ~~N\ O - OH ~mllOH
OH
~ 2~)81970 TABLE I~ CONT'D
NH
- CH2 ~~N O - OH ~ 'l'OH
NH
-CHz~~N O -NHz ~"""OH
NH
-CH2~o~0H -OH [~ OH
NH
2 0 - CH2 ~o ~OH - OH ~,,,~rOH
- CH2~~0H - NH2 [~u~H
NH
-CHz~O~OH - NH2 [~,OH
NH
3 - CH2 ~O OH - OH
208:~97~
.
TABLE I . C0NT ' D
HN-- CH2CH= CH- Ph - OH[~""'OH
- CH2CH= CH- Ph - OH ~ _O
HN-- CH2CH= CH~o~N O ~ OH
HN-2 0 - CH2C H= C H~o~N O - OH ~H
20~1970 , TABLE II
X ~
A ~,1 1~,D
A X D
,~CONH + OH
l~N - OH - HN"""O
~3 2 0 ~ONH + - OH
~ONH +
2 5 CNr- - NH2-~"""~S// O
2~8~970 TABLE IT Cont ' d A X D
~ ONH + OH
~ N- -NH2 -HN"", ~
"~_~CONH + OH
~ N- -OH -H~", r, ~ -'a'~H
OH
ONH t ~ ~H
OrH
~ t -OH -HN"h,. 8 208~970 _ TABLE II Cont ' d A X D
ONH ~ -OH -H~ ~
lo ~o~t ~ -~&
~ ONH + -OH
~ N- -H~,. o '~7 ONH + -OH ,O,H
~ N N- O
Q ~ ONH + -OH O"H
~ N N- Q
~ N N- -OH -HN~
~ ONH +
&
2~819~0 TABLE II C0NT'D
A X D
OH
8--o~C~ - OH- HN",8 8--~ -OH -NX~
ONH~ _ OH - ~3 CONHt OH
~ OH _ HN",.
20~197~
, TARLE II CONT'D
A X D
OH
CONH+ -, 10 ~ - OH- HN~,.8'~1H
OH
CONH+
~ - OH 8 CONH+ o H
20 ~3~ -OH ~ N~
TABLE II, CONT'D
A X D
10 ~JLN N- - OH OH
CONH~ - OH OH
~q ~N- OH
~f J t~ONH+ - OH - HN"".O
¢~ N N- - OH - HN~
CONH+ 8 0 rN N- - OH - HN""8 O '~ l CONHT ~=~
b 2 0 8 1 9 7 0 TARTF II CONT'D
A X D
OH
A ~\ -OH -HN'~
O CONH+
OH
~N N N- -OH - HN'~
CH~ J5 )=' 'CONH+ ~ ~
208197~
TABLE III
A-SO21~ OH ~P H OH
~--N~ O
CONH~
A A, con' t ~N CH3CH2CH2CH2-15 ~
CH3- ( CH3) 2CH-20CH3~ CH3~H3 CH3yS~
O ~
2 ~ 7 ~
TABLE IV
o ~h A- C- ~ OH
CONH+
¢~
( CH3) 3C-O-~
o Ph- CHzCH2-~081970 The compounds of the present invention are useful in the inhibition of EIV protease the prevention or treatment of infection by the human immunodeficiency virus (HIV) and the treatment of consequent pathological conditions such as AIDS. Treating AIDS or preventing or treating infection by HIV is defined as including, but not limited to, treating a wide range of states of HIV infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV. For example, the compounds of this invention are useful in treating infection by HIV after suspected past exposure to HIV
by, e.g., blood transfusion, organ transplant, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.
For these purposes, the compounds of the present invention may be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles.
Thus, in accordance with the present invention there is further provided a method of treating and a pharmaceutical composition for treating HIV infection and AIDS. The treatment involves administering to a patient in need of such treatment a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
These pharmaceutical compositions may be in the form of orally-administrable suspensions or tablets; nasal sprays; sterile injectable preparations, for example, as sterile injectable aqueous or oleagenous suspensions or suppositories.
When administered orally as a suspension, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as - a suspending agent, methylcellulose as a viscosity enhancer, and sweetners/flavoring agents known in the art. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium 15 phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.
When administered by nasal aerosol or inhalation, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
The injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic ~odium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
When rectally administered in the form of suppositories, these compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquidify and/or dissolve in the rectal cavity to release the drug.
Dosage levels of the order of 0.02 to 5.0 or 10.0 grams-per-day are useful in the treatment or prevention of the above-indicated conditions, with oral doses two-to-five times higher. For example, infection by HIV is effectively treated by the administration of 15 from 10 to 50 milligrams of the compound per kilogram of body weight from one to three times per day. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of 20 factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the 25 particular condition, and the host undergoing therapy.
The present invention is also directed to combinations of the ~IV protease inhibitory compounds with one or more agents useful in the treatment of AIDS. For example, the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the AIDS antivirals, 2~8197~
immunomodulators, anti-infectiveæ, or vaccines ~nown to those of ordinary skill in the art.
It will be understood that the scope of combinations of the compounds of this invention with AIDS antivirals, immunomodulators, anti-infectives or vaccines include in principle any combination with any pharmaceutical composition useful for the treatment of AIDS.
Assay for Inhibition of Microbial Expressed Viral Protease Inhibition studies of the reaction of the protease expressed in Eschericia coli with a peptide substrate ~Val-Ser-Gln-Asn-(betanapthyl)Ala-Pro-Ile-15 Val, 0.5 mg/mL at the time the reaction is initiated]were in 50 mM Na acetate, pH 5.5, at 30C for 1 hour.
Various concentrations of inhibitor in 1.0 ul DMS0 were added to 25 ul of the peptide solution in water. The reaction is initiated by the addition of 15 ul of 0.33 20 nM protease (O.ll ng) in a solution of 0.133 M Na acetate pH 5.5 and 0.1% bovine serum albumin. The reaction was guenched with 160 ul of 5% phosphoric acid. Products of the reaction were separated by HPLC
(VYDAC wide pore 5 cm C-18 reverse phase, acetonitrile 25 gradient, 0.1% phosphoric acid). The extent of inhibition of the reaction was determined from the peak heights of the products. HPLC of the products, independently synthesized, proved quantitation standards and confirmation of the product composition.
30 The products of synthesis in Examples 1-7 inclusive showed IC50 values in the range of 1-100 nM. Compounds A, B and J showed IC50 values of between about 0.3 and about 6 nM.
.. , ~ MPLE 1 Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(N'-(t-butyl)-4(S)-phenoxyprolineamide~yl)-pentaneamide Step 1: Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-3-phenylpropaneamide To a cold (0C) solution of methylene chloride (30 ml) containing 2(R)-hydroxy-l(S)-aminoindane (750 mg, 5.0 mmol) and triethylamine (606 mg, 6.0 mmol) was added a solution of hydrocinnamoyl chloride (843 mg, 5.0 mmol) in 5 ml of methylene chloride. After 2 hr the reaction was poured into a separatory funnel containing 50 ml of methylene chloride and washed with 10% citric acid solution (2 x 30 ml). The organic layer was dried, filtered and concentrated to afford a white solid.
Step 2: Preparation of N-(2(R)-hydro~y-l(S)-indan-N.O-isopropylidene-yl~-3-phenyl-propaneamide The crude white solid from step 1 above was dissolved in 50 ml of methylene chloride and 5 ml of dimethoxypropane was added followed by the addition of 100 mg of p-toluenesulfonic acid. The reaction was stirred at room temperature for 18 hr and then poured into a separatory funnel and washed with saturated NaHC03 solution (2 x 30 ml). The organic layer was dried, filtered and concentrated to afford an oil which was chromatographed (SiO2, 40% EtOAc/Hexane) to give an oil which eventually crystallized.
Step 3: Preparation of N-(2(R)-hydroxy-l(S)-indan-N,0-isopropylidene-yl)-2(S)-phenylmethyl-pent-4-eneamide To a solution of N-(2(R)-hydroxy-l(S)-indan-N,0-isopropylidene-yl)-3-phenyl-propaneamide (1.03 gm, 2.9 mmol) in 20 ml of THF cooled to -78C waæ added n-BuLi (2.5M, 1.40 ml, 3.5 mmol). After 20 min, allyl bromide (0.48 gm, 3.9 mmol) was added, the reaction was stirred at -78C for 1 hr and then 10 ml of saturated NH4C1 solution was added to quench the reaction. The reaction was diluted with 50 ml of water, extracted with ethyl acetate (2 x 50 ml), the organic phase was washed with saturated NaCl solution (50 ml), dried filtered and concentrated to afford the crude product.
The crude product was purified on silica gel to afford the title compound.
Step 4: Preparation of N-(2(R)-hydroxy-l(S)-indan-N,0-isopropylidene-yl)-2(S)-phenylmethyl-(4(RS).5-dihydroxy~-pentaneamide To 800 mg (2.2 mmol) of N-(2(R)-hydroxy-l(S)-indan-N,0-isopropylidene-yl)-2(S)-phenylmethyl-pent-4-en eamide dissolved in 40 ml of a 9:1 mixture of acetone/water was added 0.8 ml of a 60% solution of N-methylmorpholine-N-oxide in water followed by 4 ml of a 2~5~/o solution of osmium tetroxide in t-BuOH. After 18 hr, excess solid sodium bisulfate waæ added, the reaction was stirred for 2 hr and then filtered through a pad of celite. The filtrate was concentrated, diluted with 50 ml of water, extracted with methylene chloride (2 X 50 ml), the organic phase was dried, filtered and concentrated to give the product as a foam.
- 2~19~0 Step 5: Preparation of N-(2(R)-hydroxy-l(S)-indan-N,O-isopropylidene-yl)-2(S)-phenylmethyl-4(RS)-hydroxy-5-methanesulfonyloxy-pentaneamide To 200 mg (0.527 mmol) of N-(2(R)-hydroxy-l(S)-indan-N,O-isopropylidene-yl)-2(S)-phenylmethyl-(4(RS),5-dihydroxy)-pentaneamide dissolved in 7 ml of methylene chloride at 0C was added triethylamine (59 mg, 0.58 mmol), followed by methanesulfonyl chloride (66 mg, 0.579 mmol). After 4 hr the reaction was worked up by washing with 10% citric acid solution (2 X
50 ml) and the organic phase was dried, filtered and concentrated to afford the monomesylate as a mixture of alcohols.
Step 6: Preparation of N'-t-butyl-N-Boc-4(R)-hydroxy-L-prolineamide To a solution of N-Boc-4(R)-hydroxyproline (2.00 g) in DMF (20 mL) cooled to 0C was added EDC
(1.987 g), HOBt (1.401 g), tert butyl amine (1.09 mL) and triethylamine (2.41 mL). After 18 h the reaction mixture was diluted with ethyl acetate (150 mL) and washed with 10% HCl, saturated NaHCO3, water and brine. The solution was then dried over MgSO4 and concentrated to afford a white solid.
Step 7: Preparation of N'-t-butyl-N-Boc-4(S)-phenoxy-L-prolineamide To a solution of N'-t-butyl-N-Boc-4(R)-hydroxy-L-prolineamide (0.6 g) in THF (5 mL) was added phenol (0.295 g), triphenylphosphine (0.824 g) and then diethylazo-dicarboxylate (0.495 mL) dropwise. The reaction mixture stirred for 24 h at ambient 208~970 ._ temperature and was diluted with ethyl acetate (200 mL) and washed with saturated NaHCO3, water, brine and dried over MgSO4. Concentration in vacuo afforded a yellow oil which was purified by flash chromatography (elution hexane: EtOAc 1:1, 30 mm column).
Step 8: Preparation of N-t-butyl-4(S)-phenoxy-L-prolineamide trifluoroacetic acid salt To a solution of N'-t-butyl-N-Boc-4(S)-phenoxy-L-prolineamide (0.596 g) in methylene chloride (4 mL) at 0C was added trifluoroacetic acid (2 mL).
After 30 min the reaction was warmed to room temperature and stirred for two hours. The solvent was removed in vacuo and a slightly yellow oil was obtained.
Step 9: Preparation of N-(2(R)-hydroxy-l(S)-indan-N,O-isopropylidene-yl)-2-(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(N'-(t-butyl)-4(S)-phenoxy-prolineamide)yl~-pentaneamide To a solution of N-t-butyl-4(S)-phenoxy-L-prolineamide trifloroacetic acid salt (0.36 g) and N-(2(R)-hydroxy-l(S)-indan-N,O-isopropylidene-yl)-2(S)-phenylmethyl-4(RS)-hydroxy-5-methanesulfonyloxy-pentaneamide (0.226 g) in 3 mL of isopropanol was addedpotassium carbonate (0.441 g) and the reaction was warmed to 80C. After 18 h the reaction was cooled to room temperature, filtered through celite which was washed with further portions of EtOAc. The filtrate was concentrated, the residue was dissolved in EtOAc (lOOmL) and washed with water, brine and dried over MgSO4. The solvent was removed in vacuo and the resulting oil was purified by flash chromatography to afford the product as a mixture of diastereomers.
Step 10: Prep of N-(2(R)-hydroxy-l(S)-indanyl)-2-(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(N'-t-butyl-4(S)-phenoxyprolineamid~yl)-pentaneamide To a solution of N-(2(R)-hydroxy-l(S)-indan-N,O-isopropylidene-yl)-2-(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(N'-(t-butyl)-4(S)-phenoxyprolineamide)-yl)-pentaneamide (0.13 g) in MeO~ (5 mL) was added camphorsulfonic acid (CSA) (0.070 g) at ambient temperature. After 5 hours more CSA (0.025 g) was added and the reaction was ætirred for total of 18 hours. The reaction waæ quenched with saturated NaHC03 (5 mL) and the solvent was removed to a volume of 4 mL. The aqueous layer was thoroughly extracted with EtOAc and the organic layer was washed with water, brine and dried. After removal of the solvent in vacuo the resulting oil was purified via flash chromatography to provide the title compound as a white foam. The foam was dissolved in EtOAc : hexanes and the mother liquor was decanted away from the oil. The oil was then dried in a high vacuum desiccator to afford a white foam.
Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(N'-t-butyl-4(S)-2-naphthvloxy-prolineamid)yl)-pentaneamide Step 1: Preparation of N-t-butyl-4(S)-2-naphthyloxy-L-prolineamide trifluoroacetic acid salt Following substantially the same procedure 2 ~ 7 0 for syntheæizing N-t-butyl-4(S)-phenoxy-L-proline-amide trifluoroacetic acid salt as outlined in Example 1, Steps 6 through 8, but substituting 2-naphthol for the phenol used therein, the 2-naphthyloxy proline amide was produced.
Step 2: Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(N'-t-butyl-4(S)-2-naphthyloxy-prolineamid)yl)-pentaneamide The title compound was produced by followingsubstantially the same procedure outlined in Example 1, Steps 9 and 10, but substituting N-t-butyl-4(S)-2-naphthyloxy-L-prolineamide trifluoroacetic acid salt for the N-t-butyl-4(S)- phenoxy-L-prolineamide trifloroacetic acid salt used in step 9 therein.
Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(N'-t-butyl-4(S)-l-naphthyloxy-prolineamid)yl)-pentaneamide Step 1: Preparation of N-t-butyl-4(S)-l-naphthyloxy-T.-prolineamide trifluoroacetic acid salt Following substantially the same procedure for synthesizing N-t-butyl-4(S)-phenoxy-L-proline-amide trifluoroacetic acid salt as outlined in Example 1, Steps 6 through 8, but substituting l-naphthol for the phenol used therein, the l-naphthyloxy proline amide was produced.
, 2o8l97~
Step 2: Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(N'-t-butyl-4(S)-2-naphthyloxy-prolineamid)yl)-pentaneamide The title compound.waæ produced by following the procedure outlined in Example 1, Steps 9 and 10, but substituting N-t-butyl-4(S)-l-naphthyloxy-L-prolineamide trifluoroacetic acid salt for the N-t-butyl-4(S)-phenoxy-L-prolineamide trifluoroacetic acid salt used in Step 9.
Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(2-(3(S)-N~-(t-butyl-carboxamido)-(4aS,8aS)-decahydroisoquinoline)yl)-pentaneamide Step 1: Preparation of dihydro-5(S)-((t-butyldi-phenylsilyl)oxymethyl)-3(R)phenylmethyl-3(2H)-furanone A solution of lithium diisopropylamide (LDA) was generated by the addition 1.55 ml of n-BuLi (2.5M
in hexane) to 0.55 ml (3.9 mmol) of diisopropylamine in 10 ml of THF at -78C. After 30 minutes a solution of dihydro-5-(S)-((t-butyldiphenylsilyl)-oxymethyl)-3(2H)-furanone (1.38 g, 3.89 mmol~ in 5 ml of THF was added. After an additional 30 minutes of stirring, benzyl bromide (0.68 g, 3.9 mmol) was added and stirring was continued for 3 h after which time the reaction was quenched with the addition of a 10%
aqueous citric acid solution. The solution was 21181 97~
extracted with ethyl acetate (2 x 50 ml) which was backwashed with brine, dried, filtered and concentrated to afford an oil. The product was purified by chromatography (SiO2, 20% EtOAc/Hexane) to afford the title compound.
Step 2: Preparation of dihydro-5(S)-(hydroxy-methyl)-3(R)-phenylmethyl-3(2H)-furanone To 5.26 g of dihydro-5(S)-((t-butyldiphenyl-silyl)oxymethyl)-3(R)phenylmethyl-3(2H)-furanone in 40 ml of acetonitrile was added 1.34 ml of a 49% aqueous HF solution. After 18 hr at room temperature the reaction was concentrated to dryness and the residue was partitioned between water (50 ml) and ethyl acetate (50 ml). The organic layer was washed with brine, dried filtered and concentrated to afford the product as a tan solid (mp 69-72 C).
0 Step 3: Preparation of dihydro-5(S)-((methane-sulfonyl)oxymethyl)-3(R)phenylmethyl-3(2H)-furanone To a solution of 2.93 g (14 mmol) of dihydro-5(S)-(hydroxymethyl)-3(R)-phenylmethyl-3(2H)-fur anone in methylene chloride cooled to 0C was added triethylamine (1.98ml, 15.6 mmol) followed by the addition of methanesulfonyl chloride (1.20 ml, 15.6 mmol). After 1 hour at OoC, the reaction was poured into 10% aqueous citric acid solution, washed with ethyl acetate (2 x 100 ml) which was backwashed with water (100 ml), brine (100 ml), dried, filtered and concentrated to give the product as a waxy brown solid.
2~970 . .
Step 4: Preparation of dihydro-5(S)-(2-(3(S)-N-(t-butylcarboxamido)-(4aS, 8aS)-(decahydroiso-quinoline)yl)methyl)-3(R)-phenylmethyl-3(2H)-furanone To 70 mg of dihydro-5(S)-((methanesulfonyl)-oxymethyl)-3(R)phenylmethyl-3(2E)-furanone (0.25 mmol) in 10 ml of xylene containing 100 mg of potassium carbonate was added 65 mg (0.27 mmol) of N-t-butyl-(4aS,8aS)-(decahydroisoquinoline)-3(S)-carboxamide and the reaction was heated to 140C.
After 6 hours, the reaction was cooled, poured into 30 ml of water which was washed with ethyl acetate (2 x 30 ml). The organic phase was dried, filtered and concentrated to afford a residue which was chromatographed (50/50 EtOAc/Hexane) to give the product.
Step 5: Preparation of 2(R)-phenylmethyl-4(S)-(t-butyldimethylsilyloxy)-5-(2-(3(S)-N-(t-butylcarboxamido)-(4aS,8aS)-decahydroiso-~uinoline)yl)-pentanoic acid To 130 mg (0.305 mmol) of dihydro-5(S)-(2-(3(S)-N-(t-butylcarboxamido)-(4aS, 8aS)-(decahydro-isoquinoline)yl)methyl)-3(R)-phenylmethyl-3-(2H)furan-one in 2 ml of DME was added 1 ml lithium hydroxide solution. After 4 hours at room temperature, the reaction was concentrated to dryness and azeotroped with toluene (3X) to remove excess water. The residue was dissolved in 5 ml of DMF and 414 mg (6.10 mmol) of imidazole and 465 mg (3.05 mmol) of t-butyldimethyl-silyl chloride was added. After two days at room 2~L37() temperature, 1 ml of methanol was added to the reaction and after 1 hour the solution was evaporated to dryness. The residue was partitioned between saturated NH4Cl solution (aq) and washed with ethyl acetate which was dried, filtered and concentrated to give an oil which was a mixture of product and the furanone starting material. This material was carried on crude into the next reaction.
O Step 6: Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-(t-butyldimethyl-silyloxy-5-(2-(3(S)-N'-(t-butylcarboxamido)-(4aS,8aS)-decahydroisoquinoline)yl)-pentaneamide 5 The crude product of step 5, above, was dissolved in 3 ml of DME along with 47 mg (0.246 mmol) of EDC, 33 mg (0.246 mmol) of HOBT and 37 mg of 2(R)-hydroxy-l(S)-aminoindane. The pH of the solution was adjusted to 8.5-9.0 with triethylamine and after 18 hours it was worked up by concentrating to dryness, dissolving the residue in 10% aq. citric acid solution and washing the aqueous layer with ethyl acetate. The organic layer was dried, filtered and concentrated and the resultant oil was chromatographed (SiO2, 30%
EtOAc/Hexane) to yield the title compound.
Step 7: Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(2-(3(S)-N'-(t-butylcarboxamido)-(4aS,8aS)-decahydro-isoquinoline)yl~-pentaneamide The product from step 6, above, was dissolved in 1 ml of THF and 1 ml of a lM solution of tetrabutylammonium fluoride in THF was added. After 18 hr at room temperature the reaction was diluted with 20 ml of saturated NaHC03 solution (aq) and the product was extracted into ethyl acetate which was dried, filtered and concentrated to give a foam. The resultant material was chromatographed on a prep plate (0.5 mm, 5% MeOE/CHC13) and the title product isolated in the usual manner as a solid with mp 105-107C.
Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-amino-5-(2-(3(S)-N~-(t-butylcarbox-amido)-(4aS,8aS)-decahydroisoquinoline)yl)-pentaneamide Step 1: Preparation of 5(S)-((t-butyl-dimethyl-silyloxy)methyl)-3(R)-phenylmethyl-N-BOC-2-pyrrolidinone A solution of 5(S)-((t-butyl-dimethyl-silyloxy)methyl)-N-BOC-2-pyrrolidinone (400 mg, 1.26 mmol) in 2 ml of THF was added to a precooled (-78C) lM solution of lithium hexamethyldisilazide (1.3 ml) in 5 ml of THF. After 45 min, 0.15 ml of benzyl bromide (1.3 mmol) was added and the stirring was continued.
After 5 h the reaction was worked up by pouring into a separatory funnel containing 30 ml of an aqueous 10%
citric solution. The aqueous layer was extracted (2 x 30 ml EtOAc) which was backwashed with brine (50 ml) dried, filtered and concentrated to an oil. The residue was chromatographed (SiO2, 20% EtOAc/Hexane) to afford the product as an oil.
2~81970 Step 2: Preparation of 5(S)-hydroxymethyl-3(R)-phenylmethyl-2-pyrrolidinone To 130 mg (0.34 mmol) of 5(S)-((t-butyl-dimethylæilyloxy)methyl)-3(R)-phenylmethyl-N-BOC-2-pyrrolidinone in 5 ml of acetonitrile was added 0.1 mlof a solution of 48% HF in water. After 3 hr at room temperature the reaction was concentrated to dryness and diluted with 30 ml of an aqueous 10% NaHCO3 solution. This was extracted with EtOAc (2 X 30 ml), dried filtered and concentrated to afford the crude product.
Step 3: Preparation of 5(S)-(methanesulfonyloxy)-methyl-3(R~-phenylmethyl-2-pyrrolidinone To a solution of the crude product from Step 2, in 5 ml of methylene chloride cooled to 0C was added triethylamine (42 mg, 0.41 mmol) and methane-sulfonyl chloride (47 mg, 0.41 mmol). The reaction was slowly allowed to warm to room temperature and was stirred for 18 hr after which time it was diluted with 30 ml of methylene chloride, washed with 30 ml of 10%
citric acid solution, dried filtered and concentrated to afford the product as an oil.
5 Step 4: Preparation of 5(S)-(2-(3(S)-N-(t-butylcar-boxamido)-(4aS,8aS)-(decahydroisoquinoline)-yl)-methyl)-3(R)-phenylmethyl-2-pyrrolidinone To a solution of 380 mg (1.34 mmol) of 5(S)-(methanesulfonyloxy)methyl-3(R)-phenylmethyl-2-pyrrolidinone in 20 ml of isopropanol was added 350 mgof potassium carbonate and 360 mg of N-t-butyl-(4aS,8aS)-(decahydroisoquinoline)-3(S)-carboxamide and the reaction was heated to 85C. After 18 hr the 20819`70 -cooled reaction was filtered through celite, evaporated to dryness and the residue was dissolved in water which was extracted with EtOAc (2 X 50 ml). The organics were dried, filtered and concentrated, and the residue was chromatographed (SiO2, 50/50 EtOAc/Hexane) to afford the product as an oil.
Step 5: Preparation of 5(S)-(2-(3(S)-N~-(t-butylcar-boxamido)-(4aS,8aS)-(decahydroisoquinoline)-lo yl)-methyl)-3(R)-phenylmethyl-N-BOC-2-pyrrolidinone To a solution of the product from step 4, above, (260 mg, 0.611 mmol) in 10 ml of methylene chloride was added dimethylaminopyridine (74 mg, 0.6 mmol) and 133 mg (0.61 mmol) of BOC-anhydride. After 18 hr at room temperature the reaction was worked up by diluting with 30 ml of methylene chloride and the organics washed with 30 ml of 10% citric acid solution, brine (30 ml) dried, filtered and concentrated to afford an oil. Chromatography (SiO2, 40% EtOAc/Hexane) gave the title compound.
Step 6: Preparation of 5-(2-(3(S)-N'-(t-butylcar-boxamido)-(4aS,8aS)-decahydroisoquinoline)-yl)-4(S)-~(l',l')-(dimethylethoxycarbonyl)-aminol-2(R)-phenylmethyl-pentanoic acid To a solution of the product of step 5, above, (260 mg, 0.495 mmol) dissolved in 3 ml of di-methoxyethane was added 1.5 ml of a lM solution of aqueous lithium hydroxide (1.5 mmol). The reaction was worked up after 2 hr by concentrating to dryness, dissolving the residue in saturated aqueous ammonium chloride solution and the aqueous phase was washed with ~- 2û819~0 ethyl acetate (2 x 50 ml) which was dried, filtered and concentrated to afford the crude acid.
Step 7: Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-[(l~,l')-(dimethyl-ethoxycarbonyl)amino]-5-(2-(3(S)-N~-(t-butyl-carboxamido)-(4aS,8aS)-decahydroisoquinol-ine)yl~-pentaneamide To a solution of the product of step 6, lo above, (260 mg, 0.49 mmol) in methylene chloride was added EDC (94 mg, 0.49 mmol), HOBT (66 mg, 0.49 mmol), 2(R)-hydroxy-l(S)-aminoindane (73 mg, 0.49 mmol) and the pH of the reaction was adjusted to 8.5-9.0 using triethylamine. After 5 hr at room temperature the reaction was worked up by diluting with 50 ml of methylene chloride and washing the organics with saturated aqueou~ ammonium chloride solution. The organic phase was dried, filtered and concentrated and the residue was chromatographed to afford the title compound as a foam.
Step 8: Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(2-(3(S)-N'-(t-butylcarboxamido)-(4aS,8aS)-decahydro-isoquinoline~yl)-pentaneamide To a solution of the product of step 7, above, (180 mg, 0.28 mmol) in 5 ml of methylene chloride cooled to OoC wa~ added 1 ml of trifluoro-acetic acid. After 4 hr the reaction was worked up by concentrating to dryness and the residue was dissolved in 50 ml of methylene chloride and washed with 10%
aqueous Na~C03 solution. The organic layer was dried, filtered and concentrated to give the product as a - 2 ~ 7 0 solid which was chromatographed (SiO2, 7% MeOH/CH2C12) to afford the title compound, mp = 92-95C.
Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-carbobenzyloxy-2-(S)-N'-(t-butylcarboxamido~-piperazinyl)~-pentaneamide Employing substantially the same procedure lo used in Example 1, but substituting N-t-butyl-4-CBZ-piperazine-2(S)-carboxamide for N-t-butyl-4(S)-phenoxy-L-prolineamide used in step 9 therein, the title compound was obtained.
Preparation of N~-(N-(2-pyridyl)-valyl)-2(R)-phenyl-methyl-4(S)-hydroxy-5-(2-(3(S)-(N~-t-butylcarbox-amido)-(4aS,8aS)-decahydroi~oquinoline)yl)pentane-amide Employing substantially the same procedure used in Example 4, but substituting N-2-pyridyl-valine for the 2(R)-hydroxy-l(S)aminoindane used in step 6 therein, the title compound was obtained.
F.~MPLE 8 Preparation of N-(2(R)-hydroxy-l(S~-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(2(S)-(N~-t-butyl-3-phenyl-propionamide~amino)-pentaneamide Employing substantially the same procedure used in Example 1, but substituting N-t-butyl-phenyl-alanine amide for the N~-t-butyl-4(S)-phenoxy-., L-prolineamide used in step 9 therein, the title compound is obtained.
~MPLE 9 s Preparation of N-(4(S)-3,4-dihydro-lH-2,2-dioxobenzo-thiopyranyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(2-(3(S)-N'-(t-butylcarboxamido)-(4aS,8aS)-decahydro-isoquinoline)yl)-pentaneamide Step 1: Preparation of N-(4(S)-3,4-dihydro-lH-benzothiopyranyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(2-(3(S)-t-butylcarboxamido)-(4aS, 8aS)-decahydroisoquinoline)yl)-pentaneamide Employing substantially the same procedure used in Example 4 but substituting 4(S)-amino-3,4-dihydro-lH-benzothiopyran for the 2(R)-hydroxy-l(S)-aminoindane used in step 6 therein, the title compound is obtained.
Step 2: Preparation of N-(4(S)-3,4-dihydro-lH-2,2-dioxobenzothiopyranyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(2-(3(S)-t-butylcarboxamido)-(4aS,8aS)-decahydroisoquinoline)yl)-pentane-amide The compound from step 1 above is dissolved in a 1:1 mixture of methanol and water. To this is added 10 eq. of OXONE and the reaction is stirred at room temperature. When the reaction is complete, it is concentrated to dryness, water is added and extracted with ethyl acetate which iB dried, filtered and concentrated to give the title compound.
F.~MPLE 1 0 Preparation of N-(4(S)-3,4-dihydro-lH-2,2-dioxobenzo-thiopyranyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-carbobenzyloxy-2(S)-N'-(t-butylcarboxamido)-piperazinyl~)-pentaneamide Step 1: Preparation of dihydro-5(S)-(1-(4-carbo-benzyloxy-2(S)-N'-(t-butylcarboxamido)-piperazinyl)methyl)-3(R)-phenylmethyl-3(2H)-furanone Employing substantially the same procedure used in Example 4, ætep 4 but substituting 4-carbobenzyloxy-2(S)-N~-(t-butylcarboxamido)-piper-azine for the N~-t-butyl-(4aS,8aS)-(decahydroisoquino-line)-3(S)-carboxamide used therein, the title compound is produced.
Step 2: Preparation of 2(R)-phenylmethyl-4(S)-(t-butyldimethylsilyloxy)-5-(1-(4-carbo-benzyloxy-2(S)-N'-(t-butylcarboxamido)-piperazinyl~)-pentanoic acid Employing substantially the same procedure used in Example 4, step 5 but substituting dihydro-5(S)-(1-(4-carbobenzyloxy-2(S)-NI-(t-butylcarbox-amido)-piperazinyl)methyl)-3(R)-phenylmethyl-3(2H)-furanone for the dihydro-5(S)-(2-(3(S)-N~-(t-butyl-carboxamido)-(4aS,8aS)-(decahydroisoquinoline)yl)-methyl)-3(R)-phenylmethyl-3(2H) furanone used therein, the title compound is produced.
20819~
-Step 3: Preparation of N-(4(S)-3,4-dihydro-lH-benzothiopyranyl)-2(R)-phenylmethyl-4(S)-(t-butyldimethylsilyloxy)-5-(1-(4-carbobenzyloxy-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide The crude 2(R)-phenylmethyl-4(S)-(t-butyldimethylsilyloxy)-5-(1-(4-carbobenzyloxy-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentanoic acid is dissolved in 3ml of DMF along with 1 eq of EDC, 1 eq of HOBT and 1 eq of 4(S)-amino-3,4-dihydro-lH- benzothiop yran. The pH of the solution is adjusted to 8.5-9.0 with triethylamine and after 18 hours it is worked up by concentrating to dryness, dissolving the residue in 10% aq citric acid solution and washing the aqueous layer with ethyl acetate. The organic layer is dried, filtered and concentrated and the resultant residue is chromatographed to yield the title product.
Step 4: Preparation of N-(4(S)-3,4-dihydro-lH-benzothiopyranyl)-2(R)-phenylmethyl-4(S)-hydroxy)-5-(1-(4-carbobenzyloxy-2(S)-(t-butylcarboxamido)-piperazinyl~)-pentaneamide The product from step 3 above is dissolved in 1 ml of THF and 1 ml of a lM solution of tetra-butylammonium fluoride in l~ is added. After 18 hr atroom temperature the reaction is diluted with 20 ml of saturated NaHCO3 solution (aq) and the product is extracted into ethyl acetate which is dried, filtered and concentrated to give a residue. The residue is chromatographed to afford the product.
Step 5: Preparation of N-(4(S)-3,4-dihydro-lH-2,2-dioxobenzothiopyranyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-carbobenzyloxy-2(S)-N~-(t-butylcarboxamido)-piperazinyl))-pentane-amide The compound from step 4 above is dissolved in a 1:1 mixture of methanol and water. To this is added 10 eq of OXONE and the reaction is stirred at room temperature. When the reaction is complete, it is concentrated to dryness, water is added and extracted with ethyl acetate which is dried, filtered and concentrated to give the title compound.
Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-((2-hydroxy)ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(2-(3-(S)-N'-(t-butylcarboxamido)-(4aS,8aS)-decahydroisoquin-oline)yl~pentaneamide Step 1: Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-(2-allyloxy)phenyl)methyl)-4(S)-hydroxy-5-(2-(3(S)-t-butylcarboxamido)-(4aS,8aS)-decahydroisoquinoline)yl)-2s pentaneamide To a solution of N-(2(R)-hydroxy-l(S)-indan-yl)-2(R)-((4-hydroxyphenyl)methyl)-4(S)-hydroxy-5-(2-(3(S)-t-butylcarboxamido)-(4aS,8aS)-decahydroisoquino-line)yl)-pentaneamide in dioxane is added 6 eq of allyl bromide and 6 eq of cesium carbonate. The reaction is heated to 90C. When the reaction is complete, the precipitate is filtered off, the dioxane is concentrated to dryness and the residue is diluted with ._ water which is washed with ethyl acetate. The organic phase is dried, filtered and concentrated to afford the product.
Step 2: Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-((2-hydroxy)ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(2-(3(S)-N~-(t-butylcarbox-amido)-(4aS,8aS)-decahydroisoquinoline)yl)-pentaneamide The product from step 1 above is dissolved in methanol, 1 eq of p-toluenesulfonic acid is added and the reaction is cooled to -78C. Excess ozone is bubbled through the reaction until a blue color persists. The flask is purged with nitrogen to remove any ozone and excess sodium borohydride solution is added. The reaction is warmed to room temperature and then saturated Na~C03 solution is added. The methanol is concentrated off on the rotoevaporater and the aqueous residue is washed with ethyl acetate which is dried, filtered and concentrated to afford the title compound.
Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-((2-hydroxy)ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(4-carbobenzyloxy-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide Employing substantially the same prodecure used in Example 11 but substituting N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-hydroxyphenyl)methyl)-4(S)-hydroxy-5-(1-(4-carbobenzyloxy-2(S)-(t-butylcarbox-amido)-piperazinyl)-pentaneamide for the N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-hydroxyphenyl)methyl)-4(S)-hydroxy-5-(2-(3(S)-t-butylcarboxamido)-(4aS,8aS)-de cahydroisoquinoline)yl)-pentaneamide used therein, the title compound is obtained.
Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-(2-(4-morpholinyl)ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(2-(3(S)-N~-(t-butylcarboxamido)-(4aS,8aS)-decahydroiso~uinoline)yl~-pentaneamide To a æolution of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-hydroxyphenyl)methyl)-4(S)-hydroxy-5-(2-(3(S)-N'-(t-butylcarboxamido)-(4aS,8aS)-decahydroisoquinoline)yl)-pentaneamide in dioxane is added 6 eq of chloroethyl morpholine and 6 eq of cesium carbonate. The reaction is heated to 90C. When the reaction is complete, the precipitate is filtered off, the dioxane is concentrated to dryness and the residue is diluted with water which is washed with ethyl acetate. The organic phase is dried, filtered and concentrated to afford the title compound.
2s Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-(2-(4-morpholinyl~ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(4-carbobenzyloxy-2(S)-N~-(t-butyl-carboxamido~-piperazinyl~-pentaneamide To a solution of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-((4-hydroxyphenyl)methyl)-4(S)-hydroxy-5-(1-(4-carbobenzyloxy-2(S)-(t-butylcarboxamido)-` -208197~
piperazinyl)-pentaneamide in dioxane i8 added 6 eq of chloroethyl morpholine and 6 eq of cesium carbonate.
The reaction is heated to 90C. When the reaction is complete, the precipitate is filtered off, the dioxane is concentrated to dryness and the residue is diluted with water which is washed with ethyl acetate. The organic phase is dried, filtered and concentrated to afford the title compound.
1o EXAMPLE 15 Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(3-pyridylmethyl)-2(S)-N'-(t-butylcarboxamido~-piperazinyl))-pentaneamide Step 1: Preparation of dihydro-5(S)-((trifluoro-methanesulfonyl)oxymethyl)-3(R)-phenylmethyl-3(2H)-furanone To a solution of 18.4g (89.2 mmol) of dihydro-5(S)-(hydroxymethyl)-3(R)-phenylmethyl-3(2H)-furanone in 350 mL of methylene chloride cooled to 0C
was added 13.51 mL 2,6-lutidine (115.98 mmol) followed by a dropwise addition of 16.51 mL of trifluoromethane-sulfonic anhydride (98.1 mmol). After 1.5 hours at 0C, the reaction was poured into a mixture of 300 mL
ice/brine and stirred for 0.5 hours. The aqueous layer was then extracted with methylene chloride (3 x 150 mL), the organic layers were washed with 10% HCl (2 x 75 mL), saturated NaHC03 (lOOmL), water (lOOmL), dried over MgS04, filtered and concentrated to give a solid residue. Purification via flash column chromatography (120 x 150 mm column, gradient elution of hexanes:EtOAc, 4:1 to 3:1) afforded the title product;
mp 53-540C.
Step 2: Preparation of 4-(1,1-dimethylethyl)-1-(phenylmethyl)-1,2(S),4-piperazinetri-carboxylate The title compound was prepared following the procedure of Bigge, C.F.; Hays, S.J.; Novak, P.M.;
Drummond, J.T.; Johnson, G.; Bobovski, T.P. Tetrahedron k~. 1989, 30, 5193; starting with 2(S)-piperazine-carboxylic acid. (see Felder, E.; Maffei, S.; Pietra, S.; Pitre, D.; Helv. Chim. Acta 1960, 117, 888.
Step 3: Preparation of N-t-butyl-4-(1,1-dimethyl-ethoxycarbonylamino)-l-(phenylmethylcarbonyl-amino)piperazine-2(S~-carboxamide To 9.90g (27.16 mmol) of 4-(1,1-dimethyl-ethyl)-1-(phenylmethyl)-1,2(S),4-piperazinetricarbox-ylate dissolved in 75 mL of DMF and cooled to 0C was added 5.73g (29.88 mmol) of EDC, 4.03g (29.88 mmol) of HOBt, 3.14 mL (29.88 mmol) of t-butylamine, and finally 4.16 mL (29.88 mmol) of triethylamine. The reaction 20 mixture was stirred for 18 hours and the reaction volume was concentrated by half. The mixture was then diluted with 600 mL of EtOAc and washed with 10% HCl (2 x 75 mL), saturated NaHC03 (1 x 75 mL), water (3 x 75 mL) and brine (1 x 50 mL), dried over MgS04 and concentrated to a solid. This solid was triturated with EtOAc: hexane (1:2) and filtered to provide the title product as a white solid;
mp 134-135 C .
Step 4: Preparation of N-t-butyl-4-(1,1-dimethyl-ethoxycarbonylamino)piperazine-2(S)-carboxamide To 1.20g (2.86 mmol) of N-t-butyl-4-(1,1-dimethylethoxycarbonylamino)-l-(phenylmethylcarbonyl-amino)piperazine-2(S)-carboxamide and l.lg (0.086 mmol) of 10% Pd/C waæ added 15 mL of methanol. The vessel was charged with hydrogen and the reaction stirred for 2 hours, filtered through celite and washed with ethanol. The solvents were removed in vacuo to provide the title product as a foam.
lH NMR (300 MHz, CDC13) ~ 6.65 (br, lH), 4.10 (m, lH), 3.81 (br, lH), 3.21 (dd, J=18 and 7 Hz, lH), 3.02-2.70 (m, 4H), 2.10-2.0 (br, lH), 1.50 (s, 9H), 1.41(s, 9H).
Step 5: Preparation of dihydro-5(S)-(4-(1,1-dimethylethoxycarbonylamino))-2(S)-N-(t-butylcarboxamido)-piperazinyl)methyl)-3(R)-phenylmethyl-3(2H)-furanone 2C To a solution of 22.40g (0.0662 mol) dihydro-5(S)-((trifluoromethanesulfonyl)oxymethyl)-3(R)-phenylmethyl-3(2H)-furanone (prep in step 1) and 18.0g (0.063mol) of n-t-butyl-4-(1,1-dimethylethoxy-carbonylamino)piperazine-2(S)-carboxamide dissolved in 180 mL of isopropanol was added 11.53 mL (0.0662 mol) of N,N-diisopropylethylamine. After 2.5 hours another 1.2g of dihydro-5(S)-((trifluoromethanesulfonyl)oxy-methyl)-3(R)-phenylmethyl-3(2E)-furanone was added.
The reaction was complete by thin layer chromatography (tlc) after 3.5 hours and was concentrated to a thick oil. Trituration with EtOAc:hexanes (1:2, 200mL) provided a white solid which was filtered and discarded. The oil was purified by flash column 20~1970 .
chromatography (120 x 150 mm column, EtOAc:hexanes gradient elution 1:1, 2:1, 3:1 to all EtOAc) to afford the title compound.
lH NMR (400 MHz, CDC13) ~ 7.34-7.17 (m, 5H), 6.31 (br s, lH), 4.38 (br m, lH), 3.96-3.92 (m, lH), 3.79 (br m, lH), 3.16 (dd, J=13.6 and 4.4 Hz, lH), 3.08-2.99 (m, 3H), 2.90-2.82 (m, lH), 2.80 (dd, J=13.5 and 8.9 Hz, lH), 2.78 (m, lH), 2.67-2.61 (m,lH), 2.58-2.49 (m, lH), 2.38-2.32 (m,lH), 2.32-2.04 (m, lH), 1.99-1.92 (m, lH,) 1.45 (s, 9H), 1.29 (s, 9H).
Step 6: Preparation of 2(R)-phenylmethyl-4(S)-(t-butyldimethylsilyloxy)-5-(1-(4-(1,1-di-methylethoxycarbonylamino)))-2(S)-N-(t-butylcarboxamido~-piperazinyl)~-pentaneamide To 25.50g (52.50 mmol) of dihydro-5(S)-(4-(l,l-dimethylethoxycarbonylamino))-2(S)-N-(t-butyl-carboxamido)-piperazinyl)methyl)-3(R)-phenylmethyl-3(2H)-furanone dissolved in 120 mL DME cooled to 0C
20 was added a solution of 60 mL of water and 1.512g (63.01 mmol) of lithium hydroxide. After 0.5 hours the reaction was quenched with the addition of 10% HCl until pH 6 and the solution was concentrated in vacuo.
The reæidue was dissolved in 50 mL water and extracted 25 with EtOAc (4 x 75 mL) and the organic layers were washed with water (1 x 20 mL), brine (1 x 20 mL). The aqueous was back extracted with EtOAc (2 x 75 mL) and the combined organic layers were dried over MgSO4 and concentrated to pro~ide a yellow solid. This crude product was dissolved in 100 mL of DMF and 17.87g (0.262 mol) of imidazole was added, cooled to 0C and then 31.50g (0.21 mol) of t-butyldimethylsilyl chloride was added. This stirred 1 hour at 0C and was then _ warmed to room temperature. After 20 hours the reaction was quenched with 10 mL methanol and concentrated to half the volume. 100 mL of pH 7 buffered water was added and the aqueous was extracted with EtOAc (4 x 100 mL), the combined organic layers were washed with 10% HCl (2 x 50 mL), water (3 x 75 mL), and brine (1 x 50 mL), dried over MgS04 and concentrated to obtain the title compound. This material was used directly in the next step.
Step 7: Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-(t-butyldimethylsilyl-oxy)-5-(1-(4-(1,1-dimethylethoxycarbonyl-amino)))-2(S)-N-(t-butylcarboxamido)-piper-azinyl)~-pentaneamide To 27.0g (0.0446mol) of the crude material from step 6 dissolved in 180 mL of DMF and cooled to 0C was added 8.98g (0.0468 mol) of EDC, 6.32g (0.0468 mol) of HOBt, and 7.31g (0.049 mol) aminohydroxy 2Q indane. Triethylamine (6.52 mL, 0.0468 mol) was added and the reaction stirred at 0C for 2 hours, room temperature for 16 hours and was quenched by diluting with 500 mL of EtOAc. The organic layer was washed with 10% ECl (2 x 100 mL), saturated NaHCO3 (1 x 100 mL), water (3 x 150 mL), brine (1 x 75 mL), dried over MgS04 and concentrated to yield the title compound as a white foam.
1H NMR (400 MHZ, CDC13) ~ 7.4-7.17 (m, 9H), 6.51 (br s, lH), 5.79 (br s, lH), 5.23 (m, lH), 4.23 (br s, lH), 4.06 (m, lH), 3.96-3.84 (m, 2H), 3.07-2.78 (m, 8H), 3.65 (dd, J=9.6 and 4.1 Hz, lH), 2.56-2.44 (m, 2H), 2.29 (dd, J=12.0 and 4.5 Hz, lH), 2.17-2.09 (m, lH), 1.79 (br s, lH), 1.44 (~, 9H), 1.35 (s, 9H), 1.10 (s, lH), 0.84 (s, 9H), 0.12 (s, 3H), 0.08 (s, 3H).
Step 8: Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-(hydroxy)-5-(1-(4-(1,1-dimethylethoxycarbonylamino)))-2(S)-N-(t-butylcarboxamido)-piperazinyl))-pentaneamide To 32.20g (0.0437 mol) of N-(2(R)-hydroxy-l-(S)-indanyl)-2(R)-phenylmethyl-4(S)-(t-butyldimethyl-silyloxy)-5-(1-(4-(1,1-dimethylethoxycarbonylamino)))-2(S)-N-(t-butylcarboxamido)-piperazinyl))-pentane-amide was added 437 mL (0.437 mol) of tetrabutyl-ammonium fluoride (l.OM solution in THF, Aldrich~. The reaction stirred for 18 hours and was then concentrated to 200 mL and diluted with 700 mL of EtOAc. This was washed with water (2 x 100 mL), brine (1 x 50 mL) and the aqueous layers were back extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over MgSO4 and concentrated to an oil. Purification via flash column chromatography (120 x 150 mm column, gradient elution CH2C12: CHC13/saturated with NH3:
methanol, increasing methanol from 1%, 1.5%, 2%) afforded the title compound as a white foam.
lH NMR (400 MHz, CDC13) ~ 7.31-7.11 (m, 9H), 6.41 (br s, lH), 6.23 (d, J=8.6 Hz, lH), 5.25 (dd, J=8.6 and 4.7Hz, lH), 4.21 (m, lH), 3.83-3.82 (m, 2E), 3.78-3.61 (m, 2H), 3.22-3.19 (m, 2H), 3.03-2.78 (m, 8H), 2.62-2.58 (m, lH), 2.41-2.35 (m, 2H), 2.04-2.02 (m, lH), 1.57-1.50 (m, lH), 1.45 (s, 9H), 1.32 (s, 9H).
20~3L970 , Step 9: Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-(hydroxy)-5-(1-(2(S)-N-(t-butylcarboxamido)-piperazinyl)-pentane-amide To 21.15g (0.034 mol) of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-(hydroxy)-5-(1-(4-(1,1-dimethylethoxycarbonylamino)))-2(S)-N-(t-butylcarboxamido)-piperazinyl))-pentaneamide dissolved in 350 mL of methylene chloride and cooled to 0C was added 22.43 mL (0.204 mol) 2,6-lutidine and then 32.85 mL (0.170 mol) of trimethylsilyltriflate over 5 minutes. After 0.5 hours the reaction was quenched with 10~/o HCl (80 mL) and this stirred 0.5 hours. To this was added 100 mL of saturated NaHCO3 and then solid NaHCO3 until pH 8. The aqueous layer was then extracted with EtOAc (4 x 100 mL) and the combined organic layers were washed with water (1 x 50 mL), brine (1 x 75 mL), dried over MgSO4 and concentrated.
The residue was purified via column chromatography (120 x 150 mm column, gradient elution CH2C12:CHC13 saturated with NH3: MeOH, slowly increasing methanol 2%, 3%, 4%, 5%, 6%, to 10%). This provided the title product as a white foam.
lH NMR (400 MHz, CDC13) ~ 7.53 (s, lH), 7.29-7.09 (m, 9H), 6.52 (d, J=8.3 Hz, lH), 5.24 (dd, J=8.2 and 4.9 Hz, lH), 4.23 (dd, J=4.7 and 4.03 Hz, lH), 4.25-4.00 (br s, lH), 3.83-3.81 (m, lH), 3.03-2.88 (m, 4H), 2 . 82-2 . 73 ~m, 7~), 2 . 50-1. 60 (br s, 2H), 2 . 45 (d, J=6 . 2 Hz, 2H), 2.32-2.29 (m, lH), 1.98 (m, lH), 1.51 (m, lH), 1.33 (s, 9H).
Step 10: Preparation of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-~3-pyridylmethyl)-2(S)-N'-(t-butylcarboxamido)-pi~erazinyl~-pentaneamide To 10.0g (0.019 mol) of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy)-5-(1(-2(S)-N-(t-butylcarboxamido)-piperazinyl)-pentaneamide and 3.45g (0.021 mol) of 3-picolyl chloride dissolved in 40 mL of DMF was added 5.85 mL (0.042 mol) of triethylamine. After 3 hours an additional 0.313g of 3-picolyl chloride was added. After an additional 2 hours the reaction was diluted with 400 mL of EtOAc and washed with water (3 x 75 mL), brine (1 x 100 mL), dried over MgSO4 and concentrated. The residue was triturated with 30 mL of EtOAc and the resulting white precipitate was collected. Further recrystallization from EtOAc provided the title product (mp 167.5-168C).
Employing subætantially the æame procedure as described in Example 15, but treating the N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(2(S)-N -(t-butylcarboxamido)-piperazinyl))-pentane-amide used therein (compound (i) below) with thealkylating agent (ii) indicated below in place of the 3-picolyl chloride used in Step 10 therein, the following products defined by formula (iii) were made:
20~1970 Ph ~ ~ OH R1_x CONH + ~ ii l RlN ~ OH ~Ph ~ N ~ " -.
CONH+ ~
iii ~N ~CH2- I
~J
OH
~CH2-Cl ~f Hz - Cl ~~CH2-N
Rl X
\ ~ CH2- Br o ~ H2_ Cl ~ H2- Cl ~0 Cl O ~CH2-Boc ~
~ CH2- I
~ H2- Cl .
R X
~CH2- Cl ~CH2- I
C~N~CH2- Cl ~N~CH2 - Cl ~rq Cl ~CH2-CH30( CH2CH20) 2- CH2CH2-~"~CH2-13~CH2_ 3 0 ~CH2 - Cl Ph~_,o~_~CH2- I
N ~ H2_ Cl NH
O~N~H2_ ll Cl HN
O
Cl N~o ~ CH2 Cl Preparation of dihydro-5(S)-(tert-butyldimethylsilyl-oxymethyl)-3(2H)-furanone To a solution of 3.00g (25.8 mmol) of dihydro-5(S)-(hydroxymethyl)-2(3H)-furanone dissolved in 25 mL
of dichloromethane was added 3.51g (51.6 mmol) of imidazole and then 4.67g (31.0 mmol) of tert-butyl-~081970 dimethylsilyl chloride. The reaction stirred at room temperature for 8 hours and was quenched with 2 mL of methanol. The mixture was concentrated to an oil and then diluted with 150 mL of ether and washed with 5%
HCl (2 x 10 mL), saturated NaHC03 (1 x 10 mL), water (1 x 10 mL), and brine (1 x 10 mL), dried over MgS04 and concentrated. The residue was purified by flash chromatography (40 x 150 mm column, gradient elution, hexanes:ethyl/acetate 5:1 to 4:1) to afford the product as a clear oil-lH NMR (300 MHz, CDC13) ~ 4.68-4.60 (m, lH), 3.89 (dd, J=3.3 and 11.3 Hz, lH), 3.71 (dd, J=3.2 and 5411.3 Hz,lH), 2.71-2.45 (m, 2H), 2.35-2.16 (m, 2H), 0.91 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H).
While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention emcompasses all of the usual variations, adaptations, or modifications, as come within the scope of the following claims and its equivalents.
Claims (13)
1. A compound of the formula:
I
wherein X is -OH or -NH2;
Z is -O, -S, or -NH;
R is hydrogen or C1-4 alkyl;
R1 and R2 are independently:
1) hydrogen,
I
wherein X is -OH or -NH2;
Z is -O, -S, or -NH;
R is hydrogen or C1-4 alkyl;
R1 and R2 are independently:
1) hydrogen,
2) -C1-4 alkyl unsubstituted or substituted with one or more of a) halo, b) hydroxy, c) C1-3 alkoxy, d) aryl unsubstituted or substituted with one or more of C1-4alkyl, hydroxy or aryl, e) -W-aryl or -W-benzyl, wherein W is -O-, -S-, or -NH-, f) a 5-7 membered cycloalkyl group unsubstituted or substituted with one or more of i) halo, ii) hydroxy, iii) C1-3 alkoxy, or iv) aryl, g) heterocycle unsubstituted or substituted with one or more of hydroxy, C1-4alkyl optionally substituted with hydroxy, or Boc, h) alkyl, i) alkyl, j) -NH-SO2C1-3alkyl, k) -NR2, l) -COOR, or m) -((CH2)mO)nR wherein m is 2-5 and n is zero, 1, 2 or 3, or
3) aryl, unsubstituted or substituted with one or more of a) halo, b) hydroxy, c) -NO2 or -NR2, d) C1-4alkyl, e) C1-3 alkoxy, unsubstituted or substituted with one or more of -OH or C1-3 alkoxy, f) -COOR, g) , h) -CH2NR2, i) , j) -CN, k) -CF3, l) , m) aryl C1-3 alkoxy, n) aryl, o) -NRSO2R, p) -OP(O)(ORx)2, or q) -R5, as defined below; or R1 and R can be joined together to form with the nitrogen to which R1 is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system which consists of the nitrogen to which R1 is attached and from 2 to 9 carbon atoms, and is unsubstituted or substituted with 1) hydroxy, 2) C1-4 alkyl unsubstituted or substituted with one or more of a) halo, b) hydroxy, c) C1-3 alkoxy, d) aryl, e) a 5-7 membered cycloalkyl group unsubstituted or substituted with one or more of i) halo, ii) hydroxy, iii) C1-3 alkoxy, or iv) aryl, f) heterocycle, or g) -NR2, 3) C1-3 alkoxy,
4) alkyl,
5) alkyl,
6) -NH-SO2C1-3alkyl,
7) heterocycle,
8) -W-aryl, or
9) aryl, wherein W is defined above; or R1 and R2 can be joined together to form with the nitrogen to which R1 is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system which consists of the nitrogen to which R1 is attached, from 1 to 8 carbon atoms and one or more unsubstituted or substituted heteroatom selected from 1) , wherein V is absent or or -SO2-Q-, R1 is defined as above for when R1 is independent from and not joined to R2, and wherein Q is absent or -O-, -NR-, or heterocycle optionally substituted with -C1-4alkyl, 2) heterocycle, 3) alkenyl, unsubstituted or substituted with aryl, 4) unsubstituted or substituted with aryl, 5) -S(O)p-, wherein p is zero, 1 or 2, or 6) -0-; or R1 and R2 can be joined together to form with the nitrogen to which R1 is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system, which consists of the nitrogen to which R1 is attached and from 2 to 9 carbon atoms, in which the saturated ring system is fused to a phenyl ring and the phenyl ring is unsubstituted or substituted with one or more of 1) halo, 2) C1-3 alkoxy, 3) hydroxy, 4) C1-4 alkyl, 5) -NHR1, wherein R1 is defined as above for when R1 is independent from and not joined to R2, or 6) -NH-heterocycle;
R3 is 1) -(CH2)r-R4, wherein r is zero through 5, 2) C1-4alkenyl-R4, or 3) C1-4alkynyl-R4;
R4 is 1) hydrogen, 2) C1-4 alkyl, 3) C5-C10 cycloalkyl, optionally substituted with hydroxy, 4) C6-C10 aryl, unsubstituted or substituted with one or more of a) halo, b) hydroxy, c) -NO2 or -NR2, d) C1-4alkyl, e) C1-3 alkoxy, unsubstituted or substituted with one or more of -OH or C1-3 alkoxy, f) -COOR, g) h) -CH2NR2, i) i) -CN, k) -CF3, l) m) aryl C1-3 alkoxy, n) aryl, o) -NRSO2R, p) -OP(O)(ORx)2, or q) -R5, as defined below, or 5) monocyclic or bicyclic heterocyle containing from 1 to 3 heteroatoms chosen from the group consisting of N, O, and S and which is unsubstituted or substituted with R5 and optionally with one or more of a) halo, b) C1-4 alkyl, or c) C1-3 alkoxy;
Rx is H or aryl;
R5 is 1) -W-(CH2)m-NR6R7 wherein W is as defined above, m is 2-5, and R6 and R7 are independently a) hydrogen, b) C1-6 alkyl, unsubstituted or substituted with one or more of i) C1-3 alkoxy, ii) -OH, or iii) -NR2, c) the same or different and joined together to form a 5-7 member heterocycle containing up to two additional heteroatoms selected from -O-, -S-, or -SO2-, the heterocycle optionally substituted with C1-4 alkyl, or d) aromatic heterocycle unsubstituted or substituted with one or more of i) C1-4 alkyl. or ii) -NR2, 2) (CH2)q-NR6R7 wherein q is 1-5, and R6 and R7 are defined above, except that R6 or R7 are not H or unsubstituted C1-6 alkyl, or 3) benzofuryl, indolyl, azacycloalkyl, azabicyclo C7-11 cycloalkyl, or benzopiperidinyl, unsubstituted or substituted with C1-4 alkyl;
B is absent, or , wherein R8 is 1) -CH(CH3)2.
2) -CH(CH3)(CH2CH3), or 3) -phenyl;
J1 and J are independently 1) -YR9 wherein Y is -0- or -NH-, and R9 is a) hydrogen, b) C1-6 alkyl, unsubstituted or substituted with one or more of i) -NR2, ii) -OR, iii) -NHSO2C1-4 alkyl, iv) -NHSO2 aryl, or -NHSO2(dialkyl-aminoaryl), v) -CH2OR, vi) -C1-4 alkyl, , vii) , viii) ix) or , X) , wherein R13 is A) -H, B) -C1-4 alkyl, C) -aryl, D) -heterocycle, or E) -NH-, -O- or -(CH2)n-wherein n is zero, 1, 2 or 3, substituted with I) -C1-4 alkyl, unsubstituted or substituted with one or more of aryl or heterocycle, or II) aryl, unsubstituted or substituted with heterocycle, xi) wherein is a counterion, xii) -NR10R11 wherein R10 and R11 are the same or different and are C1-5 alkyl joined together directly to form a 5-7 membered heterocycle containing up to one additional heteroatom selected from -O-, -S-, or -NR-, xiii)-aryl, xiv) -CHO, xv) -OP(O)(ORx)2, xvi) alkyl substituted with one or more of amine or quaternary amine. or -O-((CH2)mO)n-R, or -OP(O) (ORx)2, xvii) or xviii) -NH-CH2-heterocycle, or c) -((CH2)m0)nCH3 or -((CH2)m0)n H, wherein m and n are defined above, 2) -N(R9)2, 3) -NR10R11 wherein R10 and R11 are defined above, or 4) wherein Y, R9 and n are defined above; and R12 is 1) hydrogen, 2) aryl, unsubstituted or substituted with one or more of a) R14, wherein R14 is i) halo, ii) -OR, iii) iv) -CH2NR
v) -SO2NR
vi) -NR2, vii) viii)-C1-4 alkyl, ix) phenyl x) -CF3, xi) , xii) -OP(0)(ORx)2. or xiii) , b) -C1-4 alkyl-NR2, or c) alkyl substituted with one or more of amine or quaternary amine or -OP(O)(ORx)2, 3) heterocycle, the ring or rings being unsubstituted or substituted with one or more of a) R14, as defined above, b) -OC1-4 alkenyl, c) phenyl-C1-4 alkyl, d) alkyl substituted with one or more of amine or quaternary amine, or -OP(O)(ORx)2, or -O((CH2)m0)n-R, or e) ((CH2)m0)n-R, or 4) A 5 to 7 membered carbocyclic or 7-10 membered bicyclic carbocyclic ring, the carbocyclic ring being unsubstituted or substituted with one or more of a) R14, as defined above, b) -CH2OR, c) -(CH2)n-NR2, C5-16alkyl, pyridine, -(CH2)nNR-(CH2)n-NR2, - (CH2)n, -((CH2)mO)n-R, quinuclidiniumyl substituted with R, piperazine-C1-4alkyl-benzyl substituted once or more with R, or morpholino-C1-4alkyl-benzyl, d) C1-4alkyl substituted with one or more of amine or quaternary amine, -OP(O)(ORx)2, or -O-((CH2)mO)n-R, e) -((CH2)mO)n-R, or f) -C1-4alkyl-phenyl;
or a pharmaceutically acceptable salt thereof.
2. A compound according to Claim 1 wherein:
R1 and R2 are joined together to form with the nitrogen to which R1 is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system which consists of the nitrogen to which R1 is attached and from 2 to 9 carbon atoms, and is unsubstituted or substituted with 1) hydroxy, 2) C1-4 alkyl unsubstituted or substituted with one or more of a) hydroxy, b) C1-3 alkoxy, c) aryl, d) a 5-7 membered cycloalkyl group unsubstituted or substituted with one or more of i) halo, ii) hydroxy, iii) C1-3 alkoxy, or iv) aryl, e) heterocycle, or f) -NR2, 3) C1-3 alkoxy, 4) , 5) , 6 ) -NH-SO2C1-3alkyl, 7) -W-aryl, or 8) , wherein W is -O-, -S-, or -NH-; or R1 and R2 are joined together to form with the nitrogen to which R1 is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system which consists of the nitrogen to which R1 is attached, from 1 to 8 carbon atoms and one or more unsubstituted or substituted heteroatom seIected from 1) wherein V is absent or or -SO2-Q-, R1 is defined as above for when R1 is independent from and not joined to R2, and wherein Q is absent or -O-, -NR-, or heterocycle optionally substituted with -C1-4alkyl, 2) alkenyl, unsubstituted or substituted with aryl, 3) -S(O)p-, wherein p is zero, 1 or 2, or 4) -O-; or R1 and R are joined together to form with the nitrogen to which R1 is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system, which consists of the nitrogen to which R1 is attached and from 2 to 9 carbon atoms, in which the saturated ring system is fused to a phenyl ring and the phenyl ring is unsubstituted or substituted with one or more of 1) C1-3 alkoxy, 2) hydroxy, 3) C1-4 alkyl, or 4) -NHR1, wherein R1 is defined as above for when is independent from and not joined to R.
3. A compound according to Claim 2 wherein:
R1 and R are joined together to form with the nitrogen to which R1 is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system which consists of the nitrogen to which R1 is attached and from 2 to 9 carbon atoms, and is unsubstituted or substituted with 1) hydroxy, 2) C1-4 alkyl unsubstituted or substituted with one or more of a) hydroxy, b) C1-3 alkoxy, c) aryl, d) a 5-7 membered cycloalkyl group unsubstituted or substituted with one or more of i) halo, ii) hydroxy, iii) C1-3 alkoxy, or iv) aryl, e) heterocycle, or f) -NR2, 3) C1-3 alkoxy, 4) , 5) , 6) -NH-SO2C1-3alkyl, 7) -W-aryl, or 8) , wherein W is -O-, -S-, or -NH-; or R1 and R are joined together to form with the nitrogen to which R1 is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system which consists of the nitrogen to which R1 is attached, from 1 to 8 carbon atoms and one or more unsubstituted or substituted heteroatom selected from 1) , wherein V is absent or or -SO2-Q-, R1 is defined as above for when R1 is independent from and not joined to R, and wherein Q is absent or -O-, -NR-, or heterocycle optionally substituted with -C1-4alkyl, 2) -S(O)p-.
wherein p is zero, 1 or 2, or 3) -O-;
R3 is benzyl, unsubstituted or substituted with one or more of a) hydroxy, b) -NO2, or -NR2, c) C1-4alkyl, d) C1-3 alkoxy, unsubstituted or substituted with one or more of -OH or C1-3 alkoxy, e) , f) -CH2NR2, g) , h) -CF3, i) , j) -NRSO2R, k) _OP(O)(ORx)2. or l) -R5;
and B is absent.
4. A compound according to Claim 3 wherein:
X is -OH;
Z is -O;
R1 and R2 are joined together to form with the nitrogen to which R1 is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system which consists of the nitrogen to which R1 is attached and from 2 to 9 carbon atoms, and is unsubstituted or substituted with -W-aryl or ; or R1 and R2 are joined together to form with the nitrogen to which R1 is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system which consists of the nitrogen to which R1 is attached, from 1 to 8 carbon atoms and one of IMG>
wherein V is absent or or -SO2-Q-, R1 is defined as above for when R1 is independent from and not joined to R2, and wherein Q is absent or -O-, -NR- or heterocycle optionally substituted with -C1-4alkyl;
R3 is benzyl, unsubstituted or substituted with one or more of (1) hydroxy, (2) C1-3 alkoxy substituted with one or more of -OH or (3) ;
J1 is -NH-C1-4alkyl; and J2 is o r 5. The compound N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(2-(3(S)-N'-(t-butylcarboxamido)-(4aS,8aS)-decahydroisoquinoline)yl)-pentaneamide, N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-carbobenzyloxy-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide, N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-((4-(2-(4-morpholinyl)ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(2-(3(S)-N'-(t-butylcarboxamido)-(4aS,8aS)-decahydroisoquinoline)yl)-pentaneamide, N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-((4-(2-(4-morpholinyl)ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(4-carbobenzyloxy-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide, N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-((4-((2-hydroxy)-ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(2-(3(S)-N'-(t-butylcarboxamido)-(4aS,8aS)-decahydroisoquinoline)-yl)-pentaneamide, N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-((4-((2-hydroxy)-ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(4-carbobenzyloxy-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide, N-(4(S)-3,4-dihydro-1H-2,2-dioxobenzothiopyranyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(2-(3(S)-N'-(t-butyl-carboxamido)-(4aS,8aS)-decahydroisoquinoline)yl)-pentaneamide, N-(4(S)-3,4-dihydro-1H-2,2-dioxobenzothiopyranyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-carbobenzyl-oxy-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide, N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(3-pyridylmethyl)-2(S)-N'-(t-butyl-carboxamido)-piperazinyl))-pentaneamide, or a pharmaceutically acceptable salt thereof.
6. A compound of the structure:
or pharmaceutically acceptable salts thereof.
7. The compound according to Claim 1 wherein R5 is defined as a 5-7 member heterocycle, and said 5-7 member heterocycle is morpholino.
8. A pharmaceutical composition comprising a compound of Claim 1 or Claim 6 and a pharmaceutically acceptable carried.
9. The pharmaceutical composition of Claim 8 for use in the treatment of AIDS, in the prevention of infection by HIV, in the treatment of infection of HIV, or in the inhibition of HIV protease.
R3 is 1) -(CH2)r-R4, wherein r is zero through 5, 2) C1-4alkenyl-R4, or 3) C1-4alkynyl-R4;
R4 is 1) hydrogen, 2) C1-4 alkyl, 3) C5-C10 cycloalkyl, optionally substituted with hydroxy, 4) C6-C10 aryl, unsubstituted or substituted with one or more of a) halo, b) hydroxy, c) -NO2 or -NR2, d) C1-4alkyl, e) C1-3 alkoxy, unsubstituted or substituted with one or more of -OH or C1-3 alkoxy, f) -COOR, g) h) -CH2NR2, i) i) -CN, k) -CF3, l) m) aryl C1-3 alkoxy, n) aryl, o) -NRSO2R, p) -OP(O)(ORx)2, or q) -R5, as defined below, or 5) monocyclic or bicyclic heterocyle containing from 1 to 3 heteroatoms chosen from the group consisting of N, O, and S and which is unsubstituted or substituted with R5 and optionally with one or more of a) halo, b) C1-4 alkyl, or c) C1-3 alkoxy;
Rx is H or aryl;
R5 is 1) -W-(CH2)m-NR6R7 wherein W is as defined above, m is 2-5, and R6 and R7 are independently a) hydrogen, b) C1-6 alkyl, unsubstituted or substituted with one or more of i) C1-3 alkoxy, ii) -OH, or iii) -NR2, c) the same or different and joined together to form a 5-7 member heterocycle containing up to two additional heteroatoms selected from -O-, -S-, or -SO2-, the heterocycle optionally substituted with C1-4 alkyl, or d) aromatic heterocycle unsubstituted or substituted with one or more of i) C1-4 alkyl. or ii) -NR2, 2) (CH2)q-NR6R7 wherein q is 1-5, and R6 and R7 are defined above, except that R6 or R7 are not H or unsubstituted C1-6 alkyl, or 3) benzofuryl, indolyl, azacycloalkyl, azabicyclo C7-11 cycloalkyl, or benzopiperidinyl, unsubstituted or substituted with C1-4 alkyl;
B is absent, or , wherein R8 is 1) -CH(CH3)2.
2) -CH(CH3)(CH2CH3), or 3) -phenyl;
J1 and J are independently 1) -YR9 wherein Y is -0- or -NH-, and R9 is a) hydrogen, b) C1-6 alkyl, unsubstituted or substituted with one or more of i) -NR2, ii) -OR, iii) -NHSO2C1-4 alkyl, iv) -NHSO2 aryl, or -NHSO2(dialkyl-aminoaryl), v) -CH2OR, vi) -C1-4 alkyl, , vii) , viii) ix) or , X) , wherein R13 is A) -H, B) -C1-4 alkyl, C) -aryl, D) -heterocycle, or E) -NH-, -O- or -(CH2)n-wherein n is zero, 1, 2 or 3, substituted with I) -C1-4 alkyl, unsubstituted or substituted with one or more of aryl or heterocycle, or II) aryl, unsubstituted or substituted with heterocycle, xi) wherein is a counterion, xii) -NR10R11 wherein R10 and R11 are the same or different and are C1-5 alkyl joined together directly to form a 5-7 membered heterocycle containing up to one additional heteroatom selected from -O-, -S-, or -NR-, xiii)-aryl, xiv) -CHO, xv) -OP(O)(ORx)2, xvi) alkyl substituted with one or more of amine or quaternary amine. or -O-((CH2)mO)n-R, or -OP(O) (ORx)2, xvii) or xviii) -NH-CH2-heterocycle, or c) -((CH2)m0)nCH3 or -((CH2)m0)n H, wherein m and n are defined above, 2) -N(R9)2, 3) -NR10R11 wherein R10 and R11 are defined above, or 4) wherein Y, R9 and n are defined above; and R12 is 1) hydrogen, 2) aryl, unsubstituted or substituted with one or more of a) R14, wherein R14 is i) halo, ii) -OR, iii) iv) -CH2NR
v) -SO2NR
vi) -NR2, vii) viii)-C1-4 alkyl, ix) phenyl x) -CF3, xi) , xii) -OP(0)(ORx)2. or xiii) , b) -C1-4 alkyl-NR2, or c) alkyl substituted with one or more of amine or quaternary amine or -OP(O)(ORx)2, 3) heterocycle, the ring or rings being unsubstituted or substituted with one or more of a) R14, as defined above, b) -OC1-4 alkenyl, c) phenyl-C1-4 alkyl, d) alkyl substituted with one or more of amine or quaternary amine, or -OP(O)(ORx)2, or -O((CH2)m0)n-R, or e) ((CH2)m0)n-R, or 4) A 5 to 7 membered carbocyclic or 7-10 membered bicyclic carbocyclic ring, the carbocyclic ring being unsubstituted or substituted with one or more of a) R14, as defined above, b) -CH2OR, c) -(CH2)n-NR2, C5-16alkyl, pyridine, -(CH2)nNR-(CH2)n-NR2, - (CH2)n, -((CH2)mO)n-R, quinuclidiniumyl substituted with R, piperazine-C1-4alkyl-benzyl substituted once or more with R, or morpholino-C1-4alkyl-benzyl, d) C1-4alkyl substituted with one or more of amine or quaternary amine, -OP(O)(ORx)2, or -O-((CH2)mO)n-R, e) -((CH2)mO)n-R, or f) -C1-4alkyl-phenyl;
or a pharmaceutically acceptable salt thereof.
2. A compound according to Claim 1 wherein:
R1 and R2 are joined together to form with the nitrogen to which R1 is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system which consists of the nitrogen to which R1 is attached and from 2 to 9 carbon atoms, and is unsubstituted or substituted with 1) hydroxy, 2) C1-4 alkyl unsubstituted or substituted with one or more of a) hydroxy, b) C1-3 alkoxy, c) aryl, d) a 5-7 membered cycloalkyl group unsubstituted or substituted with one or more of i) halo, ii) hydroxy, iii) C1-3 alkoxy, or iv) aryl, e) heterocycle, or f) -NR2, 3) C1-3 alkoxy, 4) , 5) , 6 ) -NH-SO2C1-3alkyl, 7) -W-aryl, or 8) , wherein W is -O-, -S-, or -NH-; or R1 and R2 are joined together to form with the nitrogen to which R1 is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system which consists of the nitrogen to which R1 is attached, from 1 to 8 carbon atoms and one or more unsubstituted or substituted heteroatom seIected from 1) wherein V is absent or or -SO2-Q-, R1 is defined as above for when R1 is independent from and not joined to R2, and wherein Q is absent or -O-, -NR-, or heterocycle optionally substituted with -C1-4alkyl, 2) alkenyl, unsubstituted or substituted with aryl, 3) -S(O)p-, wherein p is zero, 1 or 2, or 4) -O-; or R1 and R are joined together to form with the nitrogen to which R1 is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system, which consists of the nitrogen to which R1 is attached and from 2 to 9 carbon atoms, in which the saturated ring system is fused to a phenyl ring and the phenyl ring is unsubstituted or substituted with one or more of 1) C1-3 alkoxy, 2) hydroxy, 3) C1-4 alkyl, or 4) -NHR1, wherein R1 is defined as above for when is independent from and not joined to R.
3. A compound according to Claim 2 wherein:
R1 and R are joined together to form with the nitrogen to which R1 is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system which consists of the nitrogen to which R1 is attached and from 2 to 9 carbon atoms, and is unsubstituted or substituted with 1) hydroxy, 2) C1-4 alkyl unsubstituted or substituted with one or more of a) hydroxy, b) C1-3 alkoxy, c) aryl, d) a 5-7 membered cycloalkyl group unsubstituted or substituted with one or more of i) halo, ii) hydroxy, iii) C1-3 alkoxy, or iv) aryl, e) heterocycle, or f) -NR2, 3) C1-3 alkoxy, 4) , 5) , 6) -NH-SO2C1-3alkyl, 7) -W-aryl, or 8) , wherein W is -O-, -S-, or -NH-; or R1 and R are joined together to form with the nitrogen to which R1 is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system which consists of the nitrogen to which R1 is attached, from 1 to 8 carbon atoms and one or more unsubstituted or substituted heteroatom selected from 1) , wherein V is absent or or -SO2-Q-, R1 is defined as above for when R1 is independent from and not joined to R, and wherein Q is absent or -O-, -NR-, or heterocycle optionally substituted with -C1-4alkyl, 2) -S(O)p-.
wherein p is zero, 1 or 2, or 3) -O-;
R3 is benzyl, unsubstituted or substituted with one or more of a) hydroxy, b) -NO2, or -NR2, c) C1-4alkyl, d) C1-3 alkoxy, unsubstituted or substituted with one or more of -OH or C1-3 alkoxy, e) , f) -CH2NR2, g) , h) -CF3, i) , j) -NRSO2R, k) _OP(O)(ORx)2. or l) -R5;
and B is absent.
4. A compound according to Claim 3 wherein:
X is -OH;
Z is -O;
R1 and R2 are joined together to form with the nitrogen to which R1 is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system which consists of the nitrogen to which R1 is attached and from 2 to 9 carbon atoms, and is unsubstituted or substituted with -W-aryl or ; or R1 and R2 are joined together to form with the nitrogen to which R1 is attached a 3 to 10 membered monocyclic or bicyclic saturated ring system which consists of the nitrogen to which R1 is attached, from 1 to 8 carbon atoms and one of IMG>
wherein V is absent or or -SO2-Q-, R1 is defined as above for when R1 is independent from and not joined to R2, and wherein Q is absent or -O-, -NR- or heterocycle optionally substituted with -C1-4alkyl;
R3 is benzyl, unsubstituted or substituted with one or more of (1) hydroxy, (2) C1-3 alkoxy substituted with one or more of -OH or (3) ;
J1 is -NH-C1-4alkyl; and J2 is o r 5. The compound N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(2-(3(S)-N'-(t-butylcarboxamido)-(4aS,8aS)-decahydroisoquinoline)yl)-pentaneamide, N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-carbobenzyloxy-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide, N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-((4-(2-(4-morpholinyl)ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(2-(3(S)-N'-(t-butylcarboxamido)-(4aS,8aS)-decahydroisoquinoline)yl)-pentaneamide, N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-((4-(2-(4-morpholinyl)ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(4-carbobenzyloxy-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide, N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-((4-((2-hydroxy)-ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(2-(3(S)-N'-(t-butylcarboxamido)-(4aS,8aS)-decahydroisoquinoline)-yl)-pentaneamide, N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-((4-((2-hydroxy)-ethoxy)phenyl)methyl)-4(S)-hydroxy-5-(1-(4-carbobenzyloxy-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide, N-(4(S)-3,4-dihydro-1H-2,2-dioxobenzothiopyranyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(2-(3(S)-N'-(t-butyl-carboxamido)-(4aS,8aS)-decahydroisoquinoline)yl)-pentaneamide, N-(4(S)-3,4-dihydro-1H-2,2-dioxobenzothiopyranyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-carbobenzyl-oxy-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide, N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(3-pyridylmethyl)-2(S)-N'-(t-butyl-carboxamido)-piperazinyl))-pentaneamide, or a pharmaceutically acceptable salt thereof.
6. A compound of the structure:
or pharmaceutically acceptable salts thereof.
7. The compound according to Claim 1 wherein R5 is defined as a 5-7 member heterocycle, and said 5-7 member heterocycle is morpholino.
8. A pharmaceutical composition comprising a compound of Claim 1 or Claim 6 and a pharmaceutically acceptable carried.
9. The pharmaceutical composition of Claim 8 for use in the treatment of AIDS, in the prevention of infection by HIV, in the treatment of infection of HIV, or in the inhibition of HIV protease.
10. The use of a compound of Claim 1 or Claim 6 for the preparation of a medicament useful for treating AIDS in a patient receiving AIDS therapy.
11. The use of a compound of Claim 1 or Claim 6 for the preparation of a medicament useful for preventing infection by HIV in a patient.
12. The use of a compound of Claim 1 or Claim 6 for treating infection by HIV in a patient receiving therapy for HIV infection.
13. The use of a compound of Claim 1 or Claim 6 for the preparation of a medicament useful for inhibiting HIV protease in a patient receiving HIV protease therapy.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002195027A CA2195027C (en) | 1991-11-08 | 1992-11-02 | Hiv protease inhibitors useful for the treatment of aids |
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|---|---|---|---|
| US78950891A | 1991-11-08 | 1991-11-08 | |
| US789,508 | 1991-11-08 | ||
| US88382592A | 1992-05-15 | 1992-05-15 | |
| US883,825 | 1992-05-15 |
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| CA002195027A Division CA2195027C (en) | 1991-11-08 | 1992-11-02 | Hiv protease inhibitors useful for the treatment of aids |
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| CA2081970C true CA2081970C (en) | 1997-07-08 |
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| US20040122000A1 (en) | 1981-01-07 | 2004-06-24 | Vertex Pharmaceuticals Incorporated. | Inhibitors of aspartyl protease |
| US6878728B1 (en) | 1999-06-11 | 2005-04-12 | Vertex Pharmaceutical Incorporated | Inhibitors of aspartyl protease |
| USH1649H (en) | 1987-07-31 | 1997-05-06 | Barrish; Joel C. | HIV protease inhibitor combinations |
| US5413999A (en) * | 1991-11-08 | 1995-05-09 | Merck & Co., Inc. | HIV protease inhibitors useful for the treatment of AIDS |
| US5888992A (en) | 1992-03-11 | 1999-03-30 | Narhex Limited | Polar substituted hydrocarbons |
| DE69333270T2 (en) | 1992-03-11 | 2004-08-05 | Narhex Ltd. | AMINE DERIVATIVES OF OXO AND HYDROXY SUBSTITUTED CARBON HYDROGEN |
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| GB8927913D0 (en) * | 1989-12-11 | 1990-02-14 | Hoffmann La Roche | Amino acid derivatives |
| CA2032259A1 (en) * | 1989-12-18 | 1991-06-19 | Wayne J. Thompson | Hiv protease inhibitors useful for the treatment of aids |
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