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AP844A - Aspartyl protease inhibitors. - Google Patents

Aspartyl protease inhibitors. Download PDF

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Publication number
AP844A
AP844A APAP/P/1997/000961A AP9700961A AP844A AP 844 A AP844 A AP 844A AP 9700961 A AP9700961 A AP 9700961A AP 844 A AP844 A AP 844A
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compounds
formula
group
hiv
independently selected
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APAP/P/1997/000961A
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AP9700961A0 (en
Inventor
Roger D Tung
Francesco Gerald Salituro
David D Deininger
Govinda Rao Bhisetti
Christopher T Baker
Andrew Spaltenstein
Wieslaw Mieczyslaw Kazmierski
Iii Clarence Webster Andrews
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Vertex Pharma
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Priority claimed from US08/592,777 external-priority patent/US5883252A/en
Application filed by Vertex Pharma filed Critical Vertex Pharma
Publication of AP9700961A0 publication Critical patent/AP9700961A0/en
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Publication of AP844A publication Critical patent/AP844A/en

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    • 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
    • C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—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 one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • 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
    • 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
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
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    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
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    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
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    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
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    • 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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    • C07D401/14—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 three or more hetero rings
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
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    • C07D417/06—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 carbon chain containing only aliphatic carbon atoms
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Peptides Or Proteins (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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  • Indole Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
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Abstract

This invention relates to a novel class of compounds that are aspartyl protease inhibitors. In one embodiment, this invention relates to a novel class of aspartyl protease inhibitors characterized by specific structural and physicochemical features. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting HIV-1 and HIV-2 protease activity and consequently, may be advantageously used as anti-viral agents against the HIV-1 and HIV-2 viruses. This invention also relates to methods for inhibiting aspartyl protease activity and methods for treating viral infections using the compounds and compositions of this invention.

Description

technical field of the invention The present invention relates to "a novel class of compounds which are aspartyl protease inhibitors. In one embodiment, this invention relates to a novel class of HIV aspartyl protease inhibitors characterized by specific structural and physicochemical features. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting HIV-1 and·HIV-2_protease activity and consequently, may be advantageously used as antiviral agents against the HIV-1 and HIV-2 viruses. This invention also relates to methods for inhibiting aspartyl protease activity, methods for treating viral infections using the compounds and compositions of this invention, and methods for making intermediates and compounds of this invention.
BACKGROUND OF THE INVENTION
The human immunodeficiency virus ("HIV") is the causative agent for acquired immunodeficiency syndrome ("AIDS") — a disease characterized by the destruction of the immune system, particularly of CD4 ' T-cells, with attendant susceptibility to opportunistic infections — and its precursor AIDS-related complex ("ARC") — a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever and weight loss.
As in the case of several other retroviruses, HIV encodes the production of a protease which carries out post-translational cleavage of precursor polypeptides in a process necessary for the formation of infectious virions (S. Crawford et al., "A Deletion Mutation in the 5' Part of the pol Gene of Moloney Murine Leukemia Virus Blocks Proteolytic Processing of the gag and pol Polyproteins", J. Virol.. 53, p. 899 (1985)). These gene products include pol, which encodes the virion RNA-dependent DNA polymerase (reverse transcriptase), an endonuclease, HIV protease, and gag, which encodes the core-proteins of the virion (H. Toh et al., "Close Structural Resemblance Between Putative Polymerase of a Drosophila Transposable Genetic Element 17.6 and pol gene product of Moloney Murine Leukemia Virus", EMBO J., 4, p. 1267 (1985); L.H. Pearl et al., "A Structural Model for the Retroviral Proteases", Nature, pp. 329-351 (1987); M.D. Power et al., "Nucleotide Sequence of SRV-1, a Type D Simian Acquired Immune Deficiency Syndrome Retrovirus", Science, 231, p. 1567 (1986)). A number of synthetic anti-viral agents have been designed to target various stages in the replication cycle of HIV. These agents include compounds which block viral binding to CD4 T-lymphocytes (for example, soluble CD4), and compounds which interfere with viral replication by inhibiting viral reverse transcriptase (for example, didanosine and zidovudine (AZT)) and inhibit integration of viral DNA into cellular DNA (M.S. Hirsh and R.T. D'Aqulia, "Therapy for Human Immunodeficiency Virus Infection", N.Eno.J.Med., 328, p. 1686 (1993)). However, such agents, which are directed primarily to early stages cf viral replication, do not prevent the production of infectious virions in chronically infected cells. Furthermore, administration of some of these agents in effective amounts has led to cell-toxicity and unwanted side effects, such as anemia and bone marrow suppression.
More recently, drug design efforts have been directed toward creating compounds which inhibit the formation of infectious virions by interfering with the processing of viral polyprotein precursors. Processing of Xhese precursor proteins requires the action of virus-encoded proteases which are essential for replication (Kohl, N.E. et al. "Active HIV Protease is Required for Viral Infectivity" Proc. Natl. Acad, Sci, USA. 85, p. 4686 (1988)). The anti-viral potential of HIV protease inhibition has been demonstrated using peptidal inhibitors. Such peptidal compounds, however, are typically large and complex molecules that tend to exhibit poor bioavailability and are not generally consistent with oral administration. Accordingly, the need still exists for compounds that can effectively inhibit the action of viral proteases, for use as agents for preventing and treating chronic and acute viral infections. Such agents would be expected to act as effective therapeutic agents in their own right. In addition, since they act at a separate stage in the virus life cycle from previously described antiretroviral agents, the administration of a combination of agents would be expected to result in increased therapeutic efficacy.
SUMMARY OF THE INVENTION
The present invention provides a novel class of compounds, and pharmaceutically acceptable derivatives thereof, that are useful as inhibitors of aspartyl proteases, and in particular, HIV aspartyl protease. The compounds of this invention can be used alone or in combination with other therapeutic or prophylactic agents, such as anti-virals, antibiotics, immunomodulators or vaccines, for the treatment or prophylaxis of viral infection.
According to a preferred embodiment, the compounds of this invention are capable of inhibiting HIV viral replication m human CD4 cells including T-cells, monocytic lines including magrophages and dendrocytes and other permissive cells. These compounds are useful as therapeutic and prophylactic agents to treat or prevent infection by HIV-1 and related viruses which may result in asymptomatic infection, AIDS-related complex ("ARC"), acquired immunodeficiency syndrome ("AIDS"), or similar disease of the immune system.
It is a principal object of this invention to provide a novel class of compounds that are aspartyl protease inhibitors, and particularly, HIV aspartyl protease inhibitors. This novel class of compounds is represented by formula I:
wherein each Z is
wherein any Z may be optionally fused with R6; each X and X' is independently selected from the group consisting of -C (0)-, -C(O)C (0)-, -S{0)- and -S(0)2; , . ,.....- each Y and Y' is independently selected from the croup consisting of — (C(R2)2)p—, -NR2-, - (C (R2)2)p-M-, >C=C(R2)2, and -N(R2)-CH2-; each R1 is independently selected from the group consisting of hydrogen; R6; Cj-Cg alkyl; C2-C6 alkenyl; C2-Cg alkynyl; C3~Cg cycloalkyl optionally fused with 6 6 R ; Cs-Cg cycloalkenyl optionally fused with R ; and where R*'s are attached to adjacent atoms, the R*'s together with their attached adjacent atoms form a carbocvclic or heterocyclic ring system which may be 6 1 optionally fused with R ; where any member of R" may be 2 optionally suostituted by one or more R ;
each ?/ os independently selected from hydrogen; 3 R ; Ci-C6 alkyl; C2-Cg alkenyl; C2-Cg aikynyi; C3-Cg cycloalkyl optionally fused with R6; Cg-Cg cycloalkenyl 6 2 optionally fused with R ; and where two R 's are 2 attached to the same gemmal atom, the R *s togetner with their attached geminal atom may form a spirocarbocyclic or spiroheterocyclic ring system; 2 where any member of R may be optionally substituted by ? one or more R"; 3 9 each R is independently selected from oxo, OR , N(R9)2, N(R9)-X-R9,N(R9) -X-OR9, N(R9) -X-N(R9)2, SR9, X-R9, O-X-NiR9)2, C(O)N(R9)2, halogen, N02, CN, COOR9 and R6; 4 each R is independently selected from from the group consisting of OR9; N(R9)2; X-R9; C(O)N(R9)2; R6; ' C]_-Cg alkyl; C2-C4 alkenyl; C2-Cg cycloalkyl optionally fused with R6; C5-Cg cycloalkenyl optionally fused with 6 4 R ; where any member of R may be optionally substituted by one or more groups independently 9 3 selected from the group consisting of R and R ; each R5 is independently selected from the group consisting of H, OH, 0 and R1; each R6 is independently selected from the group consisting of aryl, carbocyclyl and heterocyclyl, wherein said aryl, carbocyclyl or heterocyclyl may be optionally substituted with one or more groups selected from the group consisting of oxo, -OR9, -R9, -N(R9) (R9), -N(R9)-X-R9, SR9, -X-R9, -O-X-N(R9)2, -R9-OR9, -CN, 9 9 9 -CO2R , -X-N(R ! (R ), halogen, -N02, and -CF3; each R is independently selected from the group consisting of hydrogen, OH and 0; 8 each R is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, carbocyclyl, and heterocyclyl; g each R is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, carbocyclyl, heterocyclyl, aralkyl, carbocyclylalkyl and heterocyclylalkyl wherein any aryl, carbocyclyl or g heterocyclyl may -be optionally fused with R and 8 wherein any member of R may be optionally substituted by one or more groups independently selected from the group consisting of -OR8, -N(R8)2, -CN, -N02, -X-R8, -X-N(R8)2, -C(O)OR8, -N(R8)-XNR8, and halogen; each Q is independently selected from CH and N; _each M is independently selected from the group consisting of NH, -NR2-, -0-, -S-, -S(0)- and -S(0)2~; each n is 1 or 2; each r is 0,1 or 2; each p is independently 1 or 2; each q is independently 1, 2 or 3; and each G is independently selected from the group consisting of -NH-, -NR2-, -0-, -S-, -S(0)-, S(0)2, -C(0)-, and -C(R2)2-.
An alternate object of this invention is a ~ novel class of compounds represented by formula IV:
wherein: X and X' are independently -C(0)- or -S(0)2-; Y is -(C(R2)2)-M-, -(C(R2)2)p-, -N(R2)- or -N(R2)- CH2-; and
i 2 ~ 4 each R , R , R', R , p and M is independently as defined for formula 1.
Another object of this invention is a novel class of compounds represented by formula V:
wherein: X is -C (0) - or -S (0) 2-; Y is -(C(R2)2)-M-, - (C(R2)2)p-, -N(R2)- or -N(R2)- CH2-; R10 is 0 or H2; each R11 is independently H, OH or 0, wherein both R11 are not simultaneously hydrogen; Z is a structure of formula VI:
wherein any structure of formula VI is optionally fused with an aryl, carbocyclic or heterocyclic ring and is optionally substituted with 1-3 substituents independently selected from Rz; and each R1, R2, R', R4, RS, p, q, G, M, Q and X' is independently as defined for formula I.
It is also an object of this invention to provide pharmaceutical compositions comprising the compounds of formulas I, IV and V and methods for their use as inhibitors of aspartyl protease, and particularly, HIV aspartyl protease.
It is a further object of this invention tc provide methods for treating viral diseases, and in particular HIV-related diseases, using the compounds and compositions of this invention. DETAILED DESCRIPTION OF THE INVENTION In order that the invention herein described may be more fully understood, the following detailed description is set forth. In the description, the following abbreviations are used:
Designation Reagent or Fragment
Ac acetyl
Me methyl
Et ethyl
Bn benzyl
Trityl triphenylmethyl
Asn D- or L-asparagine lie D- or L-isoleucine
Phe D- or L-phenylalanine
Val D- or L-valine
Boc tert-butoxycarbonyl
Cbz benzyloxycarbonyl (carbobenzyloxy)
Fmoc 9-fluorenylmethoxycarbonyl DCC dicyclohexylcarbodiimide DIC diisopropylcarbodiimide EDC 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride HOBt 1-hydroxybenzotriazole HOSu 1-hydroxysuccinimide TFA trifluoroacetic acid DIEA diisopropylethylamine DBU 1,8-diazabicyclo(5.4.0)undec-7-ene
EtOAc ethyl acetate t-Bu tert-butyl iBu iso-butyl DMF dimethylformamide THP tertrahydropyran THE tetrahydrofuran DMSO dimethylsulfoxide
The following terms are employed herein:
Unless expressly stated to the contrary, the terms ”-SO2-" and "-S(O)2-" as used herein refer to a sulfone or sulfone derivative (i.e., both appended grouos linked to the S), and not a sulfinate ester.
The term "alkoxy" refers to an alkyl ether radical, wherein the term "alkyl" is as defined above. Examples of suitable alkyl ether radicals include, but are not limited to, methoxy, ethoxy, n-propcxv, isopropoxy, n-butoxy, isobutoxy, sec-butoxv,_ tert- _butoxy and the like.
The term "alkyl", alone or in combination with any other term, refers to a straight-chain or branch-chain saturated aliphatic hydrocarbon radical containing the specified number of carbon atoms, or where no number is specified, preferably from 1-10 and more preferably from 1-5 carbon atoms. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, tert-butyl, pentyl, isoamyl, n-hexyl and the like.
The term "alkenyl", alone or in combination with any other term, refers to a straight-chain or branched-chain mono- or poly-unsaturated aliphatic hydrocarbon radical containing the specified number of carbon atoms, or where no number is specified, preferably from 2-10 carbon atoms and more preferably, from 2-6 carbon atoms. Examples of alkenyl radicals include, but are not limited to, ethenyl, Ξ- and Z-propenyl, iscprcpenyl, Ξ- and Z-butenyl, Ξ- and Z-iscbutenyl, Ξ- and Z-pentenyi, E- and Z-hexenyl, -Ε,Ε-, Ε,Ζ-, Z,E- and Z,Z-hexadienyl and the like.
The term "anti-viral agent" or "antiretroviral agent" refers to a compound or drug which possesses viral inhibitory activity. Such agents include reverse transcriptase inhibitors (including nucleoside and non-nucleoside analogs) and protease inhibitors. Preferably the protease inhibitor is an HIV protease inhibitor. Examples of nucleoside analog reverse transcriptase. inhibitors include, but are not limited to, zidovudine (AZT), dideoxycytidine (ddC,, didanosine (ddl), stavudine (d4T), 3TC, 935U83, 1592U89 and 524W91. Examples of non-nucleoside analog reverse transcriptase inhibitor include, but are not limited to TIBO, delavirdine (U90)-and nevirapine. Examples cf HIV protease inhibitors include, but are not limited to VX-478 (Vertex, also known as 141W94 (Glaxo-Wellcome) and KVX-478 (Kissei)), saquinavir (Ro 31-8959, Roche), indinavir (L-735,524, Merck)), ritonavir (ABT 538, Abbott), nelfinavir (AG 1343, Agouron) , .palinavir (Bila 2011 BS), U-103017 (Upjohn), XM 412 (DuPont Merck), XM 450 (DuPont Merck), BMS 186318 (Bristol-Meyers Squibb), CPG 53,437 (Ciba Geigy) , CPG 61,755 (Ciba Geigy), CPG 70,726 (Ciba Geigy), ABT 378 (Abbott), GS 3333 (Gilead Sciences), GS 3403 (Gilead Sciences), GS 4023 (Gilead
Sciences), GS 4035 (Gilead Sciences) , GS 4145 (Gilead
Sciences), GS 4234 (Gilead Sciences), and GS 4263 (Gilead Sciences) .
The term "aryl", alone or in combination with any other term, refers to a carbocyclic aromatic radical (such as phenyl or naphthyl) containing the specified number of carbon atoms, preferably from 6-14 carbon atoms, and more preferably from 6-10 carbon atoms. Examples cf aryl radicals include, but are not limited to phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl, anthracenyl and the like.
The term "carbocycle" and "carbocyclyl" radical, refers tc a non-aromatic stable 3- tc 5- membered carbcn ring which may be saturated, mcno-unsaturated or poly-unsaturated. The carbocycle may be attached at any endocyclic carbon atom which results in a stable structure. Preferred carbocycles have 5-6 carbcr.s .
The term "heterocycle" and "heterocyclyl" radical, unless otherwise defined herein, refers to a stable 3-7 membered monocyclic heterocyclic ring or e- 11 membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which may be optionally benzofused if monocyclic. Each heterocycle consists of one or more carbon atoms and from one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. As used herein, the terms "nitrogen and sulfur heteroatoms" include any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen. In addition, any ring nitrogen 2 may be optionally substituted with a substituent R , as defined herein for compounds of formula I. A heterocyclyl radical may be attached at any endocyclic carbon or heteroatom which results in the creation of a stable structure. .* Preferred heterocycles include 5-7 ·'- S..··. . membered monocyclic heterocycles and 8-10 memebered bicyclic heterocycles. Preferred heterocycles defined above include, for example, benzimidazolyl, imidazolyl, imidazolinoyi, imidazolidinyl, quinolyl, isoquinolyl, indolyl, indazolyl, indazolinolyl, perhydropyridazyl, pyridazyl, pyridyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazinyl, quinoxolyl, piperidinyl, pyranyi, pyrazolinyi, piperazinyl, pyrimidinyl, pyridazinvl, morpholinyl, thiamorpholinyl, furyl, thienyl, triazolyl, thiazolyl, β-carbolinyl, tetrazolyl, thiazo-lidinyl, benzcfuranoyl, thiamorpholinyl sulfone, cxazolyl, benzoxazclvl, oxopiperidinyl, oxopyrroldir.yi, oxoazepinyl, azepinyi, isoxazolyi, isothiazelyl, furazanyl, tetrahydropyranyi, tetrahydrofuranyl, thiazolyl, thiadiazoyl, dioxolyl, dioxinyl, oxathiolyl, benzodicxolyi, dithiolyl, thiophenyl, tetrahydrothioohenyl and sulfolanyl, dioxanyl, dioxolanyl, tetrahydrofurodihydrofuranyl, tetrahydrcpyranodihydrofuranyl, dihydropyranyl, tetrahydrofurofuranyl and tetrahydropyranofuranyl.
The term "halogen" refers to a radical cf fluorine, chlorine, ·bromine or iodine.
The terms "HIV protease" and "HIV aspartyl protease" are used interchangeably and refer tc the aspartyl protease encoded by the human immunodeficiency virus type 1 or 2. In a preferred embodiment of this invention, these terms refer to the human immunodeficiency virus type 1 aspartyl protease.
The term "inert solvent" refers to a solvent reaction medium which allows the reagents to react together at a substantially increased rate relative to any reagent reacting with the designated solvent.
The term "leaving group" or "LG" refers to groups readily displaceable by a nucleophile, such as an amine, alcohol, phosphorous or thiol nucleophile or their respective anions. Such leaving groups are well known and include carboxylates, N-hydroxysuccinimide, N-hydroxybenzotriazole, halogen (halides), triflates, tosylates, mesylates, alkoxy, thioalkoxy, phosphinates, phosphonates and the like. Other potential nucleophiles include organometallic reagents known to those skilled in the art.
The term "protecting group" refers to a suitable chemical group which may be attached tc a functional group and removed at a later stage to reveal the intact functional group. Examples of suitable protecting groups for various functional groups are described in 7.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis. 2d. Ed.. John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis. John Wiley and Sens (1994); L. Paquette, ed. Encyclopedia of Reagents for Organic Synthesis. John Wiley and Sons (1995).
The term "fused" whether preceded by the term "optionally" or not, refers to a structure wherein two distinct ring systems are joined together such that both rings share at least two common atoms. This can be envisioned as the replacement of a carbon-hydrogen or nitrogen-hydrogen bond on a ring atom with a carbon-carbon (from a second ring) or nitrogen-carbon (from a second ring) bond. For example, a cyclohexyl ring fused to a second cyclohexyl ring results in a decahydronaphthalene, a cyclohexyl ring fused to a piperidine ring results in a decahydroquinoline or decahydroisoquinoline, or a phenyl ring fused to a thiazole ring results in a“ benzothiazole.
The term "substituted", whether preceded by the term "optionally" or not, and substitutions contained in formulas of this invention, refer to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent.
When more than one position in a given structure may be substituted with more than one substituent selected from a specified group, the substituents may be either the same or different at every position (for example, 2 2 the moiety -N(R ) (R )) . Typically, when a structure may be optionally substituted, 0-5 substitutions are deferred, and C-i substitutions is more creferred.
Most preferred substituents are those which enhance protease inhibitory activity or intracellular antiviral vicy in nennissive rn.aim:aiian cells cr iim'.oncalizeci marrczalian cell lines, or which enhance celiverahilicy by enhancing solubility characteristics or enhancing pharmacokinetic or pharmacodynamic profiles as compared to the unsubstituted compound. Other more preferred substituents include those used in the compounds shown in Tables 1-5.
The term "pharmaceutically effective amount" refers to an amount effective in treating HIV infection in a patient either as monotherapy or in combination with other agents. The term "treating" as used herein refers to the alleviation of symptoms of a particular disorder in a patient or the improvement of an ascertainable measurement associated with a particular disorder. Specifically, with respect to HIV, effecnve treatment using the compounds and compositions of this invention would result in an improvement in an HIV associated ascertainable measurement. The term "prophylactically effective amount" refers to an amount effective in preventing HIV infection in a patient. As used herein, the term "patient" refers to a mammal, including a human.
The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the antiretroviral agent.
As used herein, the compounds of this invention, including the compounds of formula I are defined to include pharmaceutically acceptable derivatives or prodrugs thereof. A "pharmaceutically acceptable derivative or prodrug" means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention or an inhibitorily active metabolite or residue thereof. Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system; relative to the parent species.
Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic_acids. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(C^__4 alkyl)4 salts.
The term "thiocarbamates" refers to compounds -containing the functional group N-SO2-O.
The compounds of this invention contain one or more asymmetric carbon atoms and thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual dtastereomers. All such isomeric forms of these compounds are expressly included in the present invention. Each stereogenic carbon may be cf the R or S configuration. Although the specific compounds exemplified in this application may be depicted in a particular stereochemical configuration, compounds having either the opposite stereochemistry at any given chiral center or mixtures thereof are also envisioned.
Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term "stable", as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed' herein” (e.g., therapeutic or prophylactic administration to a mammal or for use in affinity chromatography applications). Typically, such compounds are stable at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
The compounds of the present invention may be used in the form of salts derived from inorganic or organic acids. Included among such acid salts, for example, are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camph-crsulfonate, cyolopentanepropionate, digluconate, dodecyisulfate, ethanesulfonate, fumarate, glucohepta-noate, glycerophosphate, hemisulfate, heptanoate, hexa-noate, hydrochloride, hydrobromide, hvdroiodide, 2-nycroxyetnanesuircnate, _actate, ma_eate, methanesulfonate, 2-naphthaIenesulfcnate, nicotinate, oxalane, pamoate, pectinate, persulfate, 5-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and unde can.c ate.
This invention also envisions the ouaternization of any basic nitrogen-containing groups of the compounds disclosed herein. The basic nitrogen can be cuaternized with any agents known to those of ordinary skill in the art including, for example, lower alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkyl sulfates including dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl. and stearyl chlorides, bromides and iodides; and aralkyl halides including benzyl and phenethyl bromides. Water or oil-soluble or dispersible products may be obtained by such quaternization.
The compounds of this invention are those of formula I:
wherein each Z is
wherein any Z may be optionally fused with R6; each X and X' is independently selected from the group consisting of -C(0)-, -0(0)0(0)-, -S(0)- and -s(0)2; each Y and Y' is independently selected from the group consisting of —{C(R2)2)p~* -NR2-, -(C(R )2)p~M-, >C=C(R2)2, and -N(R2)-CH2-; . each R' is independently selected from the group consisting of hydrogen; R6; Cj^-Cg alkyl; C2-Cg alkenyl; C2-C6 alkynyl; C3-C6 cycloalkyl optionally fused with R6; Ος-Οβ cycloalkenyl optionally fused with R6; and where R^s are attached to adjacent atoms, the R~’s together with their attached adjacent atoms form a carbocyclic or heterocyclic ring system which may be optionally fused with R6; where any member of R1 may be 2 optionally substituted by one or more R ; each R~ is independently selected from hydrogen; R3; C-L-Cg alkyl; C2-C6 alkenyl; C2-C6 alkynyl; C3-C6 £ cycloalkyl optionally fused with R ; C3-Cg cycloalkenyl 6 2 optionally fused with R ; and where two R ’s are 2 attacheo tc one same geminal atom, the R ’s together wioh their attached geminal atom may form a spirocarbccyclic or spiroheterocyclic ring system; 2 where any member of R may be optionally substituted by
each RJ is independently selected from oxo, OR", N(R9)2, NiRS)-X-RS, N(R9)-X-OR9, N (R9) -X-N (R“) 2 ' SR', x~ R9, O-X-N(R9)2, C(O)N(R9)2, halogen, NO2, CN, COOR' and R6; 4 each R' is independently selected from. from, me group consisting of OR9; N(R9)2; X-rR9; C(O)N(R')2; R”; C-i-Cg alkyl; C2-C4 alkenyl; C3-C6 cycloalkyl optionally fused with R6; Cg-Cg cycloalkenyl optionally fused with R6; where any member of R4 may be optionally substituted by one or more groups independently Q 7 selected from the group consisting of R" and R'; each R5 is independently selected from the group consisting of H, OH, 0 and R1; < each R6 is independently selected from the group ) consisting of aryl, carbocyclyl and heterocyclyl, wherein said aryl, carbocyclyl or heterocyclyl may be optionally substituted with ope or more groups selected 9 9 9 9 from the group consisting of oxo, -OR , -R , -N(R ) (R ) , -N(R9)-X-R9, SR9, -X-R9, -O-X-N(R9)2, -R9-OR9, -CN, -CO2R9, -X-N(R9) (R9) , halogen, -N02, and -CF3; 7 each R_ is independently selected from the group consisting of hydrogen, OH and 0; g each R is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, carbocyclyl, and heterocyclyl; 9 each R is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, carbocyclyl, heterocyclyl, aralkyl, carbocyclylalkyl and heterocycivlalkyi wherein any aryl, carbocyclyl or g heterocyclyl may be optionally fused with R and g wherein any member of R may be optionally substituted by one or more groups independently selected from the group consisting of -OR8, -N(R8)2, -CN, -N02, -X-R8, -X-N(R';n -0(0) OR8, -N{R8)-XNR8, and halogen; *- t each Q is independently selected from CH and N; . each M is independently selected from the croup consisting of NH, -NR2-, -0-, -S-, -S(0)- and —S (0) 2—; each n is 1 or 2; each r is 0,1 or 2; each p is independently 1 or 2; each c is independently 1, 2 or 3; and each G is independently selected from the group consisting of -NK-, -NR2-, -0-, -S-, -S(0)-, S(0)2, -C(0)-, and -C(R2)2-.
Except where expressly noted to the contrary, the term "[variable] as defined for formula I" refers to the definitions shown directly above. In addition, where no reference is made to a particular definition for a given variable, the definition is to be taken as that defined for formula I shown directly above.
Preferred compounds of formula I are those wherein each Y and Y' is independently selected from the 2 2 2 group consisting of -(C(R )2)p-, -NR —(C(R )2)p-> and -N(R2)-CK2-; and 3 9 each R is independently selected from oxo, OR , N(R9)2, N(R9)-X-R9, N(R9)-X-OR9, SR9, X-R9, O-X-N(R9)2, C(O)N(R9)2, halogen, N02, CN, COOR9 and R6.
Alternate preferred compounds of formula I are those having the structure of formula IA: wherein
each R“ is independently selected from the group consisting of R6; C--Gg alkyl optionally substituted
with Rfc; C7-Cg alkenyl; C2-C6 alkynyl; C3-C6 cycloalkyl 6 .... - . optionally fusee with R ; C3-C6 cyCiOa.Ker.y. cpcicna__y fused with R6; where any member of R*' may be optionally 2 substituted by one or more R .
Preferred compounds of formula I are these wherein n is equal to 1; those having tne scructure or
and those having the structure of formula III;
Also preferred are compounds according to formula I wherein X is -C(0)~ or -S(0)2- and Y is - (C (R^) 2 O-M-; these wherein X is -C(0)- or -S(Cj2-and Y is ;-C ,λ"" j ?-j D; chose .wherein X is -C(0)-, -C (0) C (0) - or -S(0)2~; and Y is -NCR2)- or -N(R2)-CH2-.
An alternate object of this invention is a novel class cf compounds represented by formula IV:
wherein: X and X' are independently -C (0) - or —S(0)2—; Y is - (C (R2) 2) -M-, - (C(R2)2)p-, -N(R2)- or -N(R2)- CH2-; and 12 7 4 each R , R , R , R , p and M is independently as defined for formula I.
Another object of this invention is a novel class of compounds represented by formula V:
wherein: X is -C(0)- or -S(0)2-; Y is - (C (R2 )2!-M-, -(C(R2)2)p~, -N(R2}- or -N;R2)- r'-'.z — · δ ' R is 0 or H2, each R“ is independently H, OH or 0, wherein both ?.** are not simultaneously hydrogen; Z is a structure of formula VI:
wherein any structure of formula VI is optionally fused with an aryl, carbocyclic or heterocyclic ring and is optionally substituted with 1-3 substituents 2 independently selected from R (wnere m rormu.a V, it 1 o R* is H2, a methylene is implied); and each R1, R2, R7, R4, R8, p, q, G, M, Q and X’ is independently as defined for formula I.
Also preferred are those compounds having the structure of formula V, wherein R10 and R11 are 0; compounds having the structure of formula V, wherein „10 , „11 ~ R and R are 0; q is 1; “G is S; and X’ is -C(0}-; - v > : compounds having the structure of formula V, wherein R10 and R11 are 0; q is 1; G is S! X' is -C(0)-; and 4 R is t-butylammo; compounds having the structure of formula V, wherein R" and Rx_ are 0; X is —C{0)·—; Y is -(C(R2)2)p-; and R7 is H; compounds having che structure of formula V wherein
X c π d Xr — s C i 0 t v 15 “(C( R ' is H; „10 . R is H2; ana „n . . „n . cne r is t- arc one λ is Or.;
Also preferred ere those compounds of formula V wherein X end X' is -C (0) Y is -(C(Rz)2)-; „7 R l s η ; R10 is H2; one Rx is H and one R is OH; and 2 R within the definition of Y is selected from 3 hydrogen, R or C^-Cg alkyl optionally substituted with R3; those compounds of formula V wherein Xand X' is —C(0)—; Y is - (C(R2)2)-; R7 is H; R10 is H2; one R11 is H and one R11 is OH; and 2 R within the definition of Y is selected from 9 hydrogen, -N(R )2(, or heterocyclyl, which may be optionally benzofused, and wherein said heterocyclyl may be optionally substituted with one or more groups
Q Q selected from the group consisting of oxo, -OR', -R , 99 999 9 99 -N (R ) (R ), -N(R )-X-R , SR , -X-R , -0-X-N(R )2, -R -OR9, -CN, -CO2R9, -X-N(R9)(R9), halogen, -N02, and-CF3; those compounds of formula V wherein X and X' is -C (0;-; Y is -(C(Rz)2)-; „ 7 R is n; „10 K - C —Λ. * -S -.z , one R** is H and one R" is OH; and R2 within the definition of Y is selected from the group consisting or :
those compounds according to formula V wherein: X and X' is -C(0)-; Y is -(C(R2 * * * *)2)-; R7 is H; R10 is H2; one R11 is H and one R11 is OH; and 2 at least one R within the definition of Y is aryl optionally substituted with one or more groups selected 9 9 9 9 _ from the group consisting of oxo,, -OR , -R , -N(R ) (R ) , -N(R9)-X-R9, SR9, -X-R9, -O-X-N(R9)2, -R9-OR9, -CN, g g " Q " '· -CO2R , -X-N(R)(R), halogen, -NO2, and -CF3; those compounds according to formula V wherein: X and X' is -C(0)-; Y is -(C(R2)2)-; R7 is H; „10 R is H2; 1' . 11 . one R * is H ana one R is OH; ana 2 . . at least one R within the definition or Y is C2-Cg alkyl optionally substituted· with R-5; those compounds according to formula V wherein: X and X' is -C(0)-; γ is - ;c ;r2) 2) -;
-J τ. κ i s Η f R*C i£.H2; one R" is' 14 and one R-1· is OH; 2 at least one R within the definition of Y is C--Og alkyl optionally substituted with RJ; and at least one R-5 ..within the definition of Y is pyridyl, triazclyl, oxazolyl, isoxazolyl, pyrimidyl, pyrazolyl, pyridazinyl, thiazolyl, imidazolyl, thienyl thiadiazolyl, cxadiazolyl, triazinyl or pyrazinyl wherein said R3 may be optionally substituted wind 1-3 g g 5 9 substituents selected from -OR , -R", -N(R") (RO , -N(RS)-X-RS, SRS, -X-R9, -O-X-N(R9)2, -R9~OR9, -OX, -CO2R9, -X-N(R9) (R9) , halogen, -N02, and -CF3. those compounds according to formula V wherein: X and X' is -C(0)-; Y is -(C(R2)2)-; R7 is H; R10 is H2; 11 11 one R" is H and one R is OH; 2 at least one R within the definition of Y is C3-Cg alkyl optionally substituted with R3; and 3 R within the definition of Y is aryl optionally 9 substituted with 1-3 substituents selected from -OR , 9 9 9 999 9 9 -R , -N(R)(R), -N(R )-X-R, SR, -X-R, -0-X-N(R )2, -R9-OR9, -OK, -CO2R9, -X-N(R9) (R5; , halogen, -N02, and -cf3.
Also preferred are those compounds according to any of the aforementioned preferred compounds of formula V wherein: R* is benzyl; and Z is
those compounds according to any of the aforementioned preferred compounds of formula V wherein: •Ί R“ is benzyl optionally substituted with 1-3 substituents selected from -OR9, -N(R9)(R9), SR9, -X-R9, -R9-OR9, -CN, halogen, -NO2, and -CF3; those compounds according to any of the aforementioned preferred compounds of formula V wherein: Ί * R is benzyl optionally substituted with 1-3 substituents selected from -OR9, -N(R9)(R9), SR9, -X-R9, -R-9-OR9, -CN, halogen, -N02, and -CF3; and Z is
those compounds according to any of the aforementioned - preferred compounds of formula V wherein R1 is benzyl optionally substituted with 1-3 substituents selected from the group consisting of OCH3, OH and NH2;
those compounds according to any of the afcremenozoned preferred compounds of formula V wherein R* is benzy_ optionally substituted with 1-3 substituents selected from the group consisting of OCH3, OH and NH2 and Wherein Z is
An alternate embodiment of this invention is compounds according to formula V, wherein: »
each R6 is independently selected from the group consisting of aryl, carbocyclyl and heterocyclyl, wherein said aryl, carbocyclyl or heterocyclyl is optionally substituted with one or more groups selected 9 9 9 9 from the group consisting of oxo, -OR , -R , -N (R ) (R ) , -N(R9)-X-R9, SR9, -X-R9, -O-X-N(R9)2, -R9-OR9, -CN, -CO2R9, -X-N;R9)(R9), halogen, -N02, -CF3, -0-(CK2)a-R6, s -0- ;cn2 ; q-OR'' , 2, 3-metnylenedioxy and 3,4- methyienedicxy; and each X, X', Y, Y’, Z, R1, R2, R3, r4, r5, r"7, r8, rs, q, M, n, r, p, q and G is independently as defined for
those compounds according to formula V, wherein: each R6 is independently selected from the group consisting of aryl, carbocyclyl and heterocyclyl, wherein said aryl, carbocyclyl or heterocyclyl is optionally substituted with one or more groups selected 9 5 5 5 from the group consisting of oxo, -OR , -R , -NiR ] (A ', o q q ‘ q Q c a -N(R'.-X-R', SR , -X-R , -O-X-N(R )2, -R'-OR', -OX, -CO2R', -X-N (R9) (R9) , halogen, -N02, -Cr3, -O-(CH2)q-Rc,
Q -O-(CH?)c-OR , 2,3-methylenedioxy and 3,4- methylenedioxy; 2 R within the definition of Y is selected from hydrogen, R3 or Ci_-O6 alkyl optionally substituted with 3 R ; and t each X, X’, Y, Y’, Z, R1, R3, R4, R5, R?, R8, R9, Q, M, c n, r, p, q and G is independently as defined for ‘ < formula I.
those compounds of formula V wherein I X and X' is -C(0)-; Y is -N(R2)-; ' ‘ | R7 is H; | R10 is H2; and . 1 one R11 is H and_one R11is OH; and those compounds of formula V wherein X and X' is -C(0)-; Y is -(C(R2)2)-M-; M is 0; R7 is H; R10 is H2; and 11 one R““ is H ano one R is OH.
Also preferred is the compound of formula 1 having the structure of formula IX:
wherein. X is —CiO) — or — S (0}2—; and the compounds cf formula IX wherein X is -C(0)-; Y is -(C(R2)2)-M-; and 7 R is H; and those compounds of formula IX wherein X is -C(0) -; Y is -N(R2)-; and 7 R is H; and those compounds of formula IX wherein X is -C(0)-; Y is -(C(R2)2)-; and R7 is H.
Also preferred are those compounds of formula I having the structure of formula XII:
wherein X and X' are inaependently —C<Cj— or -S(C,2-; those compounds of formula I having the structure of formula XII, wherein X and X' are independently -C(0)- or -Ξ?3.2-; and
R is I-aminc-2-hydroxyindanyI; and compounds of formula I having the structure of formula 4 XII, wherein R. is 1{S)-amino-2(R)-hydroxyinaanyl.
Also preferred are the compounds according to , formula 1, having the structure of formula XIII:
wherein X and X' are independently —C (0) — or —S (0) 2—; compounds according formula I having the structure of formula XIII, wherein X is -C(0)- or -S(0)2~; X' is -CIO)-; Y is - (C(R2)2)- or -N(R2)-; and R7 is H; compounds of formula I having the structure of formula XIII, wherein X is -C(0)-; X' is -C(0)-; Y is -(C(R2)2)and R7 is H; those compounds of formula XIII wherein X is -C {0)-,- X' is -C Ό) Y is - (C i Rz) 2) -; R7 is H; and

Claims (1)

  1. Original document published without claims.
APAP/P/1997/000961A 1996-01-26 1997-01-24 Aspartyl protease inhibitors. AP844A (en)

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US08/592,777 US5883252A (en) 1996-01-26 1996-01-26 Aspartyl protease inhibitors
US08/724,563 US5945413A (en) 1996-01-26 1996-09-30 Aspartyl protease inhibitors

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WO2013003801A2 (en) 2011-06-29 2013-01-03 The Trustees Of Columbia University In The City Of New York Inhibitor of neuronal connectivity linked to schizophrenia susceptibility and cognitive dysfunction
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AU1758097A (en) 1997-08-20
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CA2243121A1 (en) 1997-07-31
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HUP9901024A2 (en) 1999-09-28
CZ234498A3 (en) 1998-10-14
AU709239B2 (en) 1999-08-26
WO1997027180A1 (en) 1997-07-31
EP0882022A1 (en) 1998-12-09
BR9707086A (en) 1999-04-13
JP2000501111A (en) 2000-02-02
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NO983435D0 (en) 1998-07-24

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