CA2252915A1 - Hiv protease inhibitors useful for the treatment of aids - Google Patents

Hiv protease inhibitors useful for the treatment of aids Download PDF

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Publication number
CA2252915A1
CA2252915A1 CA002252915A CA2252915A CA2252915A1 CA 2252915 A1 CA2252915 A1 CA 2252915A1 CA 002252915 A CA002252915 A CA 002252915A CA 2252915 A CA2252915 A CA 2252915A CA 2252915 A1 CA2252915 A1 CA 2252915A1
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compound
hiv
aids
treatment
substituted
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French (fr)
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Mark E. Fraley
M. Katharine Holloway
Craig A. Coburn
Randall W. Hungate
Kristine Prendergast
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Merck and Co Inc
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D221/00Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/22Bridged ring systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • A61P31/18Antivirals for RNA viruses for HIV
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic 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
    • C07D405/02Heterocyclic 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
    • C07D405/10Heterocyclic 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 aromatic rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic 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
    • C07D417/02Heterocyclic 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
    • C07D417/06Heterocyclic 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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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Communicable Diseases (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Oncology (AREA)
  • Veterinary Medicine (AREA)
  • Virology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Molecular Biology (AREA)
  • AIDS & HIV (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Compounds such as formula (A) or pharmaceutically acceptable salts thereof are HIV protease inhibitors. These compounds are useful in the prevention or 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 and methods of preventing or treating infection by HIV are also described.

Description

CA 022~291~ 1998-10-29 TITLE OF THE INVENTION
HIV PROTEASE lNHIBITORS USEFUL FOR THE TREATMENT
OF AIDS

This application is related to Merck Case 19531PV.
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 cont~ining 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.

BACKGROUND OF THE INVENTION
A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the imrnune system (acquired immllne 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-translational processing of precursor polyproteins by a virally 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 imm~tllre, 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 shows the presence of a gene in one open reading frame [Ratner, L. et al., Nature, 313, 277(1985)]. Amino acid sequence homology provides evidence that the ~1 sequence encodes reverse transcriptase, an endonuclease and an HIV

CA 022~291~ 1998-10-29 ~UO 97/40833 PCTIUS97/07131 protease [Toh, H. et al., EMBO J., 4, 1267 (~985); Power, M.D. et al., Science, 231, 1567 (1986); Pearl, L.H. et ~l., Nature, 329, 351 (1987)].
Applicants demonstrate that the compounds of this invention are inhibitors of HIV protease.

BRIEF DESCRIPTION OF THE INVENTION
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 10 in the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharrnaceutical 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.
DETAILED DESCRIPTION OF THE INVENTION AND
PREFERRED EMBODIMENTS
This invention is concerned with compounds of Formula I, combinations thereof, or pharmaceutically acceptable salts thereof, in 20 the inhibition of ~IIV protease, the prevention or treatment of infection by HIV and in the treatment of the resulting acquired imrnune deficiency syndrome (AIDS). Compounds of Formula I are defined as follows:

~Z R4 ~NR1 y R3 wherein X is -O-, -NH-, -NR4- or-S-;
Y is =O, or forms, with the carbon to which it is attached, ~0 97/40833 PCT/US97fO7131 -~ ,OH
/C'H

Z is =0, or forms, with the carbon to which it is attached, ~C~OH
/ ' s Rl is a) H;
b) C1 4 alkyl;
c) C3 7 cycloalkyl;
d) aryl, unsubstituted or substituted one or more times with hydroxy;
e) CH2RS; or f) 5-7 membered heterocycle; and CA 022~291~ 1998-10-29 WO 97140833 PCT/US97/~7131 R2 is a) C1 4 alkyl;
b) aryl, unsubstituted or substituted with aryl;
c) CH2R6; or Sd) heterocycle; and R3 is a) CH(oH)R7; or b) CH(NH2)R7; and R4 is a) Cl 4 alkyl;
b) C3-6 cycloalkyl;
c) aryl unsubstituted or substituted with halo or with Cl 4 alkyl unsubstituted or substituted one or more times with hydroxy;
d) CH2R 1; or e) 5-7 membered heterocycle; and 20 R5 is a) Cl 4 alkyl; or b) aryl; and R6 is 25 a) C1 4 alkyl;
b) aryl unsubstituted or substituted with halo or with Cl 4 alkyl unsubstituted or substituted one or more times with hydroxy; or c) 5-7 membered heterocycle; and R7 is a) H;
b) C1 4 alkyl;
c) aryl unsubstituted or substituted with amino;

WO 97/40833 PCT/US97/û7131 d) Cl 3 alkylaryl unsubstituted or substituted with amino; or e) 5-7 membered heterocycle;
or pharmaceutically acceptable salt thereof.

One preferred embodiment is a compound of the formula - ~o R27[~ N
HO~--Ho~R7 wherein R2 is C1 4 alkylene-aryl; and R4 is Cl 4 alkyl, unsubstituted or substituted with aryl, C3-6 cycloalkyl, or 5-7 membered heterocycle;

R7 is H, ben~yl unsubstituted or substituted with amino;

or pharmaceutically acceptable salt thereof.

Preferred compounds of this invention are shown below.

Compound A:

~O 97/40833 ~ N J--HO~

HHo~ ~
H2N ~3 or pharmaceutically acceptable salts thereof; and CA 022~291~ 1998-10-29 WD 97/40833 PCTIUS97/û7131 Compound B:

~ N
HO~/
H ~ ~

or phalmaceutically acceptable salts thereof.

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.
VVhen any variable (e.g., aryl, heterocycle, Rl, R2, X, Y, or 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 substituents and/or variables are permissible only if such combinations result in stable 1 5 compounds.
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).
As used herein, with exceptions as noted, "aryl" is intended to mean phenyl (Ph) or naphthyl.
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 saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group CA 022~291~ 1998-10-29 consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene 5 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, 10 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, 15 benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl.
The ph~ ceutically-acceptable salts of the compounds of Formula I (in the form of water- or oil-soluble or dispersible products) 20 include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases.
Examples of such acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, 25 dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, 30 succinate, tartrate, thiocyanate, tosylate, and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, ~lk~line earth metal salts such as calcium and magnesium salts, salts with organic bases such a.s dicyclohexylarnine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, Iysine, and so CA 022~291~ 1998-10-29 WO g7/40833 PCT/US97/07131 _ 9 _ forth. Also, the basic nitrogen-cont~ininp 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, 5 lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others. Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.
Schemes I and II for preparing the novel compounds of this 10 invention are presented below. Tables I and II which follow the schemes illustrate the compounds that can be synthesized by Schemes I
and II, but Schemes I and II 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 15 of the following schemes to specific compounds.
Additional related information on synthetic background is contained in EPO 0337714.
One method for producing Formula I compounds is provided by Scheme I.
SCHEME I

[~ROMe ~OMe R2~

o o K2CO3/R2X' O O ~ O O
\ J acetone/reflux \ J MeONa/THF

ll lll CH20/MeOH R ~N_R4 1) LiAlH4lTHFR2~ 4 ~O/CH3 ~/

lV V

Alkylation of ester I by reaction with R2X' (wherein X' is halo) in base gives II. Reaction with MeONa rearranges II to afford III. Cyclization of R4NH2 gives the azabicyclic (3.3.1) nonane core precursor IV which, after reduction and acid hydrolysis, provides V.
Scheme I is illustrated as one embodiment in Exarnple 1.

SCHEME II
~,~4 ~4 Ph ~? DMS3/TEA Ph,~>
HO 2) Et3SiCI/pyr Et~Si_o 'OH DMAP(cat.)60~C ~0 P Q

Et3Si--o 2) H30+ HO~
~0 ~h Q R

Scheme II outlines another general synthetic method.
Alcohol oxidation by treatment of P with S03-pyridine complex in DMSO, followed by silylation, gives Q. Alkylation with the appropriate Grignard reagent, followed thereafter with acid treatment, affords R. Scheme II is also illustrated in one embodiment in Example 3.

The compounds of this invention are also illustrated by Tables I-II, which follow.

~0 R ~- N--R4 HO ~ /
H '--OH

Enzym e % concentration IC50 Compound R4 R2 inhibition (IlM) (llM) ~ ~,Ph 77 250 CH2 ~ CH2Ph 56 250 CH2 + CH2Ph 69 250 4 CH2Ph CH2Ph 82 250 ~< CH2Ph 63 250 6 ~< CH2 ~Br 250 244 )~< CH2 ~ 56 100 OMe 8 3~ CH2 ~ 68 CH2 ~ CH2 ~ 89 lU ~< CH2~ 62 100 X~ CH2 ~) 76 100 30 12 ~ ~ 43 1()0 ., .

PCTrUS97/07131 TABLE I (Cont'd) 13,~;l~ CH2 ~ 75 44 CHz OH
= < CH2 ~ 62 CH2--, OH

TABLE II

-~o r/ ,R4 /~

y R

Enzyme ~0 concentration IC50 Compound R7 R2 R4inhibition (IlM) (~M) n-Bu CH2 ~ 1,~ 73 100 14 1 6 CH2 ~ CH2 ~ ~ 82 (85o8) 17 ~ CH2 ~ CH2 ~ 52 50 1 8 CH2 ~ CH2 ~ CH2 ~ 63 50 CH2 ~ CH2 ~ 3~ 44 50 ~,~\1~3CH2 ~ ~ 1.6 2 1 ~ CH2 ~ 80 25 1.8 CA 022~291~ 1998-10-29 WO 97/40833 PCT/US97/~17131 TABLE II (Cont'd) 2 2 ~ CH2 ~ 84 100 10.4 2 3 o~O~\~ ~ ~ 69 100 29 The compounds of this invention are useful in the 5 preparation and execution of screening assays for antiviral compounds.
For example, the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other antivirals 10 to HIV protease, e.g., by competitive inhibition. Thus the compounds of this invention are commercial products to be sold for these purposes.
The compounds of the present invention are useful in the inhibition of HIV protease the prevention or treatment of infection by the human immunodeficiency virus (HIV) and the treatment of, and 15 delaying of the onset 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 20 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 25 may be ~llministered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techni~ues), by inhalation spray, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles.

CA 022~291~ 1998-10-29 WO 97/40833 PCI/US97/~7131 Thus, in accordance with the present invention there is further provided a method of treating and a ph~ ceutical composition for treating HIV infection and AIDS. The treatment involves a(lministering to a patient in need of such treatment a pharmaceutical 5 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 forrn of orally-~-lministrable suspensions or tablets; nasal sprays; sterile 10 injectable preparations, for example, as sterile injectable aqueous or oleagenous suspensions or suppositories.
When a-lministered orally as a suspension, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may contain microcrystalline 15 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 phosphate, starch, magnesium stearate and lactose and/or 20 other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.
When administered by nasal aerosol or inh~l~tion, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in 25 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-30 acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium 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.

CA 022~291~ 1998-10-29 When rectally ~lmini.stered 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 S 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 a-lmini.~tration of from 1.0 to 50 milligrams of the compound per kilogram of body weight from one to four times per day. In one preferred regimen, dosages of 100-400 mg every six hours are ~-lmini.stered orally to each patient. 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 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 ~lministration~ rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
The present invention is also directed to combinations of the HIV protease inhibitory compounds with one or more agents useful in the treatment of AIDS. For example, the compounds of this invention may be effectively ~clministered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the AIDS antivirals, immunomodulators, anti-infectives, or vaccines known to those of ordinary skill in the art.

TABLE C

ANTIVIRALS

Drug Name Manufacturer Indication AL-721 Ethigen ARC, PGL
(Los Angeles, CA) HIV positive, AIDS

Recombinant Human Triton Biosciences AIDS, Kaposi's Interferon Beta (Almeda, CA) sarcoma, ARC

Acem~nn~n Carrington Labs ARC
(Irving, TX) (See also immunomodulators) Cytovene Syntex sight threatening CMV

Drug Name Manufacturer Indication Ganciclovir (Palo Alto, CA) peripheral CMV
retinitis d4T Bristol-Myers AIDS, ARC
Didehydrodeoxy- (New York, NY) thymidine ddI Bristol-Myers AIDS, ARC
Dideoxyinosine (New York, NY) EL10 Elan Corp, PLC HIV infection (Gainesville, GA) (See also immunomodulators) WO 97/40833 rCT/US97107131 Drug Name Manufacturer Indication Trisodium Astra Pharm. CMV retinitis, HIV
Phosphonoformate Products, Inc infection, otherCMV
(Westborough, MA) infections Dideoxycytidine; Hoffman-LaRoche AIDS, ARC
ddC (Nutley, NJ) Novapren Novaferon Labs, Inc. HIV inhibitor (Akron, OH) Diapren, Inc.
(Roseville, MN, marketer) Peptide T PeninsulaLabs AIDS
Octapeptide (Belmont, CA) Sequence Zidovudine; AZT Burroughs Wellcome AIDS, adv, ARC
(Rsch. Triangle Park, pediatric AIDS, NC) Kaposi's sarcoma, asymptomatic HIV
infection, less severe HIV disease, neurological involvement, in combination with other therapies.

Ansamycin LM427 Adria Laboratories ARC
(Dublin, OH) - Erbamont (Stamford, CT) ~0 97140833 PCTIUS97/07131 Drug Name Manufacturer Indication Dextran Sulfate Ueno Fine Chem. AIDS, ARC, HIV
Ind. Ltd. positive asymptomatic (Osaka, Japan) Virazole Viratek/~CN asymptomatic HIV
Ribavirin (Costa Mesa, CA) positive, LAS, ARC

Alpha Interferon Burroughs Wellcome Kaposi's sarcoma, (Rsch. Triangle HIV in combination Park, NC) w/Retrovir Acyclovir Burroughs Wellcome AIDS,ARC, asymptomatic HIV
positive, in combination with AZT.

Antibody which Advanced Biotherapy AIDS, ARC
neutralizes pH Concepts labile alpha aberrant (Rockville, MD) Interferon in an immuno -adsorption column L-743,726 Merck AIDS,ARC, (Rahway, NJ) asymptomatic HIV
positive, also in combination with AZT.

_ IMMUNO-MODULATORS

Dru Name Manufacturer Indication AS-101 Wyeth-Ayerst Labs. AIDS
(Philadelphia, PA) Bropirimine Upjohn advanced AIDS
m~oo, MI) Acem~nn~n Carrington Labs, Inc. AIDS, ARC (See also (Irving, TX) anti-virals) CL246,738 American Cyanamid AIDS, Kaposi's (Pearl River, NY) sarcoma Lederle Labs (Wayne, NJ) EL10 Elan Corp, PLC HIVinfection (Gainesville, GA) (See also anti-virals) Gamma Interferon Genentech ARC, in combination (S. San Francisco, w/TNF (tumor CA) necrosis factor) Granulocyte Genetics Institute AIDS
Macrophage Colony (Cambridge, MA) Stim~ ting Sandoz Factor (East Hanover, NJ) Granulocyte Hoeschst-Roussel AIDS
Macrophage Colony (Sommerville, NJ) Stimulating Immunex Factor (Seattle,WA) -Dru~ Name Manufacturer Indication Granulocyte Schering-Plough AIDS
Macrophage Colony (Madison, NJ) Stimulating Factor AIDS, in combination w/AZT

HIV Core Particle Rorer seropositive HIV
Immunostimulant (Ft. Washington, PA) IL-2 Cetus AIDS, in combination Interleukin-2 (Emeryville, CA) w/AZT

IL-2 Hoffman-La Roche AIDS, ARC, HIV, in Interleukin-2 (Nutley, NJ) combination w/AZT
Immunex Immune Globulin CutterBiological pediatric AIDS, in Intravenous (Berkeley, CA) combination w/AZT
(human) IMREG-1 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma, ARC, PGL

IMREG-2 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma, ARC, PGL

Imuthiol Diethyl Merieux Institute AIDS, ARC
Dithio Carbamate (Miami, FL) Alpha-2 Schering Plough Kaposi's sarcoma Interferon (Madison, NJ) w/AZT: AIDS
-Drug Name Manufacturer Indication Methionine- TNI Pharrnaceutical AIDS, ARC
Enkephalin (Chicago, IL) MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma Muramyl- (Summit, NJ) Tripeptide Granulocyte Amgen AIDS, in combination ColonyStim~ ting (Thousand Oaks, CA) w/AZT
Factor rCD4 Genentech AIDS, ARC
Recombinant (S. San Francisco,CA) Soluble Human CD4 rCD4-IgG AIDS, ARC
hybrids Recombinant Biogen AIDS, ARC
Soluble Human CD4 (Cambridge, MA) Interferon Hoffman-LaRoche Kaposi's sarcoma Alfa 2a (Nutley, NJ) AIDS, ARC, in combination w/AZT

SK&F106528 Smith, Kline & HIV infection Soluble T4 French Laboratories (Philadelphia, PA) WO 97/40833 PCT/US97/~7131 Drug Name Manufacturer Indication Thymopentin Immunobiology HIV infection Research Institute (Annandale, NJ) Tumor Necrosis Genentech ARC, in combination Factor; TNF (S. San Francisco, w/gamrna Interferon CA) ANTI -INFECTIVES

Drug Name Manufacturer Indication Clindamycin with Upjohn PCP
Primaquine (~ m~7oo~ MI) Fluconazole Pfizer cryptococcal (New York, NY) meningitis, candidiasis Pastille Squibb Corp. prevention of NystatinPastille (Princeton, NJ) oral candidiasis Ornidyl Merrell Dow PCP
Eflornithine (Cincinnati, OH) Pentamidine LyphoMed PCP treatment Isethionate (IM & IV) (Rosemont, IL) Trimethoprim antibacterial - Trimethoprim/sulfa antibacterial WO 97/40833 PCT/US97~07131 Drug Name Manufacturer Indication Piritrexim Burroughs Wellcome PCP treatment (Rsch. Triangle Park, NC) Pentamidine Fisons Corporation PCP prophylaxis isethionate for (Bedford, MA) inhalation Spiramycin Rhone-Poulenc cryptosporidial Pharmaceuticals diarrhea (Princeton, NJ) Intraconazole- 3anssen Pharm. histoplasmosis;
R51211 (Piscataway, NJ) cryptococcal meningitis Trimetrexate Warner-Lambert PCP

OTHER

Drug Name Manufacturer Indication Recombinant Human Ortho Pharm. Corp. severe anemia Erythropoietin (Raritan, NJ) assoc. with AZT
therapy Megestrol Acetate Bristol-Myers treatment of (New York, NY) anorexia assoc.
w/AIDS

Total Enteral Norwich Eaton diarrhea and Nutrition Pharmaceuticals malabsorption (Norwich, NY) related to AIDS

CA 022~291~ 1998-10-29 WO 97/40833 PCT/US97~07131 It will be understood that the scope of combinations of the compounds of this invention with AIDS antivirals, immunomodulators, anti-infectives or vaccines is not limited to the list in the above Table, but includes in principle any combination with any pharmaceutical 5 composition useful for the treatment of AIDS.
Certain compounds of Table S are the following:
L-743,726 is (-) 6-chloro-4(S)-cyclopropylethynyl-4(S)-trifluoromethyl- l ,~-dihydro-2H-3,1 -benzoxazin-2-one, and is synthesized according to EP 0 582,455.
The synthesis of ddC, ddI and AZT are also described in EPO 484071.
Preferred combinations are simultaneous or alternating treatrnents of an inhibitor of HIV protease and a non-nucleoside inhibitor of HIV reverse transcriptase. An optional third component in 15 the combination is a nucleoside inhibitor of HIV reverse transcriptase, such as AZT, ddC or ddI. A preferred inhibitor of HIV protease is L-735,524 (Compound J), disclosed and synthesized according to U. S.
Patent No. 5,413,999. Preferred non-nucleoside inhibitors of HIV
reverse transcriptase include L-743,726. These combinations may have 20 synergistic effects on limiting the spread of HIV. Preferred combinations include the following (1) L-735,524, with L-743,726, and, optionally, AZT or ddI or ddC; (2) L-735,524, and any of AZT or ddI
or ddC.

Assay for Inhibition of Microbial Expressed HIV 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-Val, 0.5 mg/mL at the time the reaction is 30 initiated] were in 50 mM Na acetate, pH 5.5, at 30~C for 1 hour.
Various concentrations of inhibitor in 1.0 ,ul DMSO were added to 25 ~l of the peptide solution in water. The reaction i.s initiated by the addition of 15 !ll of 0.33 nM protease (0.11 ng) in a solution of 0.133 M
Na acetate pH 5.5 and 0.1 % bovine serum albumin. The reaction was quenched 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 gradient, 0.1% phosphoric acid). The extent of inhibition of the reaction was determined from the peak heights of the products.
5 HPLC of the products, independently synthesized, proved quantitation standards and confirmation of the product composition. Tables I and II
provide results for a variety of compounds.

EXAMPLE l ~ ~OH

5(RS)-((4')-2"-furanyl)methylpheny-9(RS)-hydroxy- 1 (RS)-hydroxy-methyl-3-(2'-methylpropyl-3-azabicyclo[3.3. l ]nonan-7-one 15 (Compound l O~ Table 1 ) Step 1: Compound A

J~ K2CO31acetone ~

0~0 Br 13~ O\>~/~Br A

To a solution of 2-carbomethoxy-4-ethylenedioxycyclo-hexanone I, (3.0 g, 14.0 mmol, Fuchs, P. L. et al., Syn. Comm, 13(3), 243, 1983) in 100 mL of acetone was added 4-bromobenzyl bromide (3.67 g, 14.7 mmol), K2CO3 (9.69 g, 70.1 mmol) and NaI (210 mg, 1.4 S mmol). The heterogenous reaction was heated at reflux for 16 h. The reaction mixture was cooled and filtered through Celite. The filtrate was diluted with 250 mL of Et2O and the organics were washed with water (2 x 20 mL) then brine (50 mL) and dried over MgSO4.
Evaporation of the solvent and flash chromatography (sio2; 4: 1 10 Hexane/EtOAc) gave 4.8 g (89%) of A.

1H NMR (CDC13) ~ 7.40 (d, J = 7.8 Hz, 2H), 7.05 (d, J = 7.8 Hz, 2H), 3.98 (m, SH), 3.60 (s, 3H), 3.00 (m, 3H), 2.50 (m, 2H), 1.95 (m, 2H).

15 Step 2: Compound B

NaOMe/THF. ~ ¦ 3 A B

To a slurry of NaH (375 mg, 15.6 mmol) in THF (15 mL) 20 at 0~C was added MeOH (0.76 mL, 30.7 mmol). After stirring for 5 min, keto ester A (4.8 g, 12.5 mmol) in THF (30 mL) was added dropwise and the solution was warmed to room temperature and stirred - for 16 h. The reaction mixture was diluted with 50 mL of EtOAc, then excess NaOMe was quenched with 10 mL of saturated NH4Cl. The 25 organic phase was separated, washed with brine and dried over MgSO4.
- Evaporation of the solvent and flash chromatography (sio2; 4; 1 Hexane/EtOAc) gave 4.5 g (94%) of B.

W~) 97140833 PCT/US97/û7131 lH NMR (400 MHz, CDC13) ~ 12.6 (s, lH), 7.40 (d, J = 7.8 Hz, 2H), 7.05 (d, J = 7.8 Hz, 2H), 3.98 (m, 4H), 3.75 (s, 3H), 3.25 (m, lH), 2.99 (m, lH), 2.78 (m, lH), 2.4-1.8 (m, 4H).

5 Step 3: Compound C

O O O
,~OCH3 ~ N
Br O CH20/HOAc/MeOH O~/
O~ NH2CH2CH(CH3)2 , ~OCH3 B C

To a solution of keto ester (2.9 g, 7.57 mmol) B in MeOH
10 (45 mL) and an aqueous solution of formaldehyde (37%, 5.6 mL, 75.7 mmol) was added isobutyl amine (0.9 mL, 9.1 mmol) and HOAc (0.52 mL, 9.1 mmol). The whole was heated at reflux for 16 h. The reaction was cooled to room temperature and the solvent was removed. The residue was dissolved in EtOAc (100 mL) and the resulting solution was 15 washed with sat'd NaHCO3 (2 x 20 mL), water (2 x 20 mL) then brine (50 mL) and dried over MgSO4. Evaporation of the solvent and flash chromatography (SiO2 gradient; 4:1, 2:1, 1:1 Hexane/EtOAc gave 2.5 g (70%) of C. m.p. 142-144~C.

lH NMR (400 MHz, CDC13) ~ 7.40 (d, J = 7.8 Hz, 2H), 7.05 (d, J =
7.8 Hz, 2H), 3.98 (m, 4H), 3.80 (s, 3H), 3.65 (m, lH), 3.00 (dd, J = 2.5, 11.0 Hz, lH), 2.85 (d, J = 14.1 Hz, lH), 2.70 (m, 4H), 2.56 (d, J = 13.2 Hz, lH), 2.40 (d, J = 13.2 Hz, lH), 2.20 (m, 3H), 1.70 (m, lH), 0.90 m, 6H).

.

Step 4: Compound D

Br ~ ~ $ / Br o NaBH4/EtOH
~OCH3 THF 0~C H ~OCH3 C D

S To a solution of ketone (1.8 g, 3.75 mrnl) C in 18 mL of 1:1:1 EtOH, CH2C12 and H2O at 0~C was added NaBH4 (142 mg, 3.75 mmol). The solution was stirred for 30 min, then excess NaBH4 was quenched with S mL of acetone. The solution was diluted with EtOAc and washed with water (4 x 10 mL) then brine (10 mL). Evaporation of the solvent and column chromatography (SiO2; 65:35 Hexane/EtOAc) gave 964 mg (53%) of D.

lH NMR (400 MHz, CDC13) ~ 7.40 (d, J = 7.8 Hz, 2H), 7.05 (d, J =
7.8 Hz, 2H), 4.50 (d, J = 11 Hz, lH), 4.20-3.90 (m, 4H), 3.75 (s, 3H), lS 3.40 (d, J = 11.2 Hz, lH), 2.90 (d, J = 13.5 Hz, lH), 2.80 (d, J = 12.2 Hz, lH), 2.60 (m, 2H), 2.40 (d, J = 10.6 Hz, lH), 2.20 (d, J = 10.4 Hz, lH), 2.00-1.80 (m, SH), 1.70 (m, lH), 0.90 m, 6H).

Step S: Compound E
Br~ ~ N

H OCH3 LiEt3BH/THF 0~C H OH
D E

CA 022~291~ 1998-10-29 WO 97/40833 PCT/US97/~)7131 To a solution of ester (964 mg, 2.0 mmol) of D in THF (40 mL) at 0~C was added LiEt3BH (6.09 mL, 6.0 mmol). The solution was warmed to room temperature and stirred for 4 hours. Excess LiEt3BH was quenched with 5 mL of saturated NaHCO3. The solution 5 was diluted with Et20 (50 mL) and washed with saturated NaHCO3 (3 x 10 mL), water (4 x 10 mL) and brine (10 mL). Evaporation of the solvent left 800 mg (88%) of crude diol E which was used directly in the next step without purification. m.p. 136-1 38~C.

lH NMR (400 MHz, CDC13) ~ 7.39 (d, J = 8.2 Hz, 2H), 7.13 (d, J =
8.2Hz,2H),4.74(d,J= ll.9Hz, lH),4.05 (m,4H),3.57 (d,J= 10.8 Hz, lH), 3.39 (t, J = 10.82 Hz, lH), 3.-6 (d, J = 11.9 Hz, lH), 2.96 (d, J
= 13.4 Hz, 2H), 2.50 (d, J = 13.4 Hz, lH), 2.34 (d, J = 10.6 Hz, lH), 2.27 (d, J = 10.6 Hz, lH), 2.09 (t, J = 11.7 Hz, 2H), 1.95 (d, J = 17.3 15 Hz, 2H), 1.85 (d, J = 14.3 Hz, lH), 1.77 (m, lH), 1.63 (t, J = 11.1 Hz, 3H),0.90(d,J= 12.4Hz,6H).

Step 6: Compound F (L-770.274) Br Br~o H OH HCI/acetone H OH
E F

To a solution of ketal (453 mg, 1.0 mmol) E in acetone (P~
mL) at 0~C was added 8 mL of 50% HCI in water. The solution was heated at reflux for 16 h, then cooled to 0~C. Saturated NaHCO3 25 solution was added to quench excess HCI. The solution was then washed with EtOAc (3 x 10 mL) and the combined organic extracts were dried - over MgSO4. Evaporation of the solvent and trituration of the resulting white solid with Et2O gave 300 mg (73%) of F. m.p. 155-156~C

lH NMR (400 MHz, CDC13) ~ 7.40 (d, J = 7.8 Hz, 2H), 7.05 (d, J =
7.8 Hz, 2H), 3.95 (s, lH), 3.65 (dd, J = 4.4, 10.4 Hz, lH), 3.49 (s, lH), 3.45 (dd, J = 4.6, 10.4 Hz, lH), 2.80 (m, 2H), 2.60 (d, J = 14.2 Hz, 2H), 2.52 (t, J = 3.7 Hz, lH), 2.43 (d, J = 11.4 Hz, lH), 2.35 (d, J = 11.1 Hz, lH), 2.00 (m 4H), 1.83 (d, J = 11.2 Hz, lH), 1.69 (d, J = 11.2 Hz, lH), 1.60 (m, lH), 0.76 (m, 6H).

Anal calc'd for C20H2gNO3Br:
C, 58.54; H, 6.88; N, 3.41.
10 Found: C, 58.91; H, 6.88; N, 3.51.

Step 7: Compound 10. Table I

B~,O ~3'~f ~

H OH PdCI2(PPh3)2/DMF HO ~--F ¢3' H OH
o Sn(n-Bu)4 To a solution of the aryl bromide (41 mg, 0.10 mmol) in DMF (0.4 mL) was added 2-(tri-n-butylstannyl) furan (53.5 mg, 0.15 mmol) and PdC12(PPh3)2 (1.5 mg, 0.0020 mmol). The resulting yellow-brown solution was stirred at 95~C for 4 h. The reaction 20 mixture was cooled, diluted with ether and filtered through Celite. The filtrate was washed with water (7 x 2 mL), brine (2 rnL) and dried over MgSO4. The yellow oil was subjected to flash chromatography (sio2;
95:5:0.5 CHC13/IPA/NH40H) to afford 25 mg (63%) of the title compound as a foam.
1 H NMR (400 MHz, CDC13) ~ 7.60 (d, J = 7.8 Hz, 2H), 7.45 (d, J =
0.8Hz, lH),7.21 (d,J=7.8Hz,2H),6.62(d,J=4.2Hz, lH),6.44 (dd, J = 4.2, 0.~ Hz, lH), 3.81 (s, lH), 3.63 (m, 3H), 3.50 (m, 2H), 2.85 WO 97/40833 PCTIUS97/û7131 (m, 2H), 2.60 (m, 4H), 2.45 (d, J = 14 Hz, lH), 2.35 (d, J = 14 Hz, lH), 1.8-2.1 (m, 6H), 1.7 (d, J = 14 Hz, lH), 1.6 (m, 2H), 0.77 (d, J = 8 Hz, 6H).

5 Anal calc'd for C24H31NO4-0.8 H2O:
C, 69.97; H, 7.98; N, 3.40.
Found: C, 69.95; H, 7.70; N, 3.52.

5(RS)-methylphenyl-9(RS)-hydroxy- 1 (RS)-((1 '-hydroxy)-2'-phenyl)-ethyl-3-(2"-methyl)propyl-3-azabicyclo[3.3.1] nonan-7-one (Compound 16)~ Table II
o Ph~NJ\
HO
Ph Step 1: Compound G
O O K2C~3 0 o benzyl bromide ~ I~
~OMecat. Nal ~ OMe acetone \J \
G

A mixture of I (12.0 g, 56.0 mmol), benzyl bromide (10.1 20 g, 7.0 mL, 58.8 mmol), potassium carbonate (48.4 g, 350 mmol), and sodium iodide (250 mg, 1.7 mmol) in acetone (200 mL) was heated at reflux for 16 h. The heterogeneous mixture was then poured into water (150 mL). The aqueous mixture was extracted with ethyl acetate (2 x 200 ml). The combined organic layers were dried over Na2SO4 and W P 97/40833 PCT~US97/~7131 concentrated to give G as a colorless oil (18.7 g). Rf = 0.16 (20%
EtOAc/Hexane)] which was used without further purification.

lH NMR (400 MHz, CDC13) ~ 7.17-7.26 (m, SH), 3.91-4.03 (m, 4H), 5 3.63 (s, 3H), 3.15 (d, lH, J = 13.6 Hz), 3.03 (d, lH, J = 13.6 Hz), 2.97 (ddd, lH, J = 15.0, 8.1, 12.3 Hz), 2.58 (dd, lH, J = 14.1, 2.9 Hz), 2.49 (ddd, lH, J = 15.0, 4.8, 3.7 Hz), 1.91-1.95 (m, 2H), 1.78 (d, lH, J =
13.9 Hz).
10 Step 2: Compound H

O O O O
[~OMe THF ~OMe O O O O
\ J l G H

Sodium hydride (2.40 g, 61 mmol, 60 wt% in mineral oil) 15 was washed with hexane to remove mineral oil and then was suspended in tetrahydrofuran (80 mL) at 0~C. Anhydrous methanol (2.15 g, 2.72 mL, 67.1 mmol) was added dropwise over 3 min., followed by warming to 23~C and stirred for 30 min. The resulting suspension was cooled to 0~C and G was added via dropping funnel in tetrahydrofuran 20 (40 mL) over 30 min. The reaction mixture was allowed to warm to 23~C over 1 h and then was stirred at that temperature for 16 h.
Aqueous acetic acid (10%, 10 mL) was carefully added and the mixture was poured into saturated NaHCO3 (100 mL), washed with EtOAc (2 x 150 mL), dried (Na2SO4) and concentrated to give a brown oil.
25 Recryst~11i7~tion from MeOH afforded H as white prisms (11.2 g). The mother liquor was concentrated and purified by flash chromatography (20% EtOAc/Hexane) to give a colorless oil which was further purified by recrystallization from Et2O to give H as white prisms (11.4 g CA 022~291~ 1998-10-29 WO 97/40833 PCT/US97/~7131 overall, 67% yield for two steps), Rf = 0.32 (30% EtOAc/Hexane), mp = 110-115~C.

lH NMR (CDC13) o 7.13-7.29 (m, SH), 3.90-4.00 (m, 4H), 3.81 (dd, lH, J = 13.9, 5.7 Hz), 3.77 (s, 3H), 3.22 (dd, lH, J = 14.1, 5.0 Hz), 2.97-3.05 (m, lH), 2.45 (dd, lH, J = 14.1, 8.6 Hz), 2.35 (t, IH, J = 13.6 Hz), 2.18 (ddd, lH, J = 13.4, 5.7, 3.8 Hz), 1.98 (ddd, lH, J = 13.2, 5.9, 3.8 Hz), 1.76 (t, lH, J = 13.4 Hz).
10 Step 3: Compound I

o o isobutyllamine o~\
ll 11CH20 OMe HOAc ~O
MeOH Ph~N~J~

Isobutylamine (4.07 mL, 40.9 mmol), glacial acetic acid lS (2.28 mL, 39.8 mmol), aqueous formaldehyde (37%, 25.0 mL, 373 mmol), and 3 (10.38 g, 34.1 mmol) were heated at reflux in MeOH
(200 mL) for 48 h. The reaction was then concentrated, diluted with EtOAc (125 mL), and poured into saturated NaHCO3 (100 mL). The biphasic system was partitioned and the aqueous layer was washed with 20 additional EtOAc (2 x 100 mL). The combined organics were dried (Na2SO4), concentrated, eluting with Et20 (50 mL), and then filtered through silica gel washing with Et20 (500 mL). The filtrate was concentrated to give 4 as a colorless oil [13.2 g, 96%, Rf =0.27 (25%
EtOAc/Hexane)]. Ttlis material was used without further purification.
lH NMR (CDC13) ~ 7.15-7.29 (m, SH), 3.87-4.03 (m, 4H), 3.80 (s, 3H), 3.02 (dd, lH, J = 11.0, 3.1 Hz), 2.90 (d, lH, J = 13.9 Hz), 2.87 (d, WD 97/40833 PCTIUS97/~7131 lH, J = 14.1 Hz), 2.75 (d, 2H, J = 11.0 Hz), 2.68 (dd, lH, J = 13.2, 3.5 Hz), 2.54 (d, lH, J = 13.0 Hz), 2.38 (d, lH, J = 13.2 Hz), 2.14-2.26 (m, 3H), 2.11 (dd, lH, J = 13.2, 3.5 ), 1.57-1.74 (m, lH), 0.91 (d, 3H, J =
6.6 Hz), 0.89 (d, 3H, J = 6.6 Hz).
s Step 4: Compound J

Ph,~ NCJ~ CH2C12/H20/EtOH ph~N>

o CO2CH3 co2CH3 J: equatorial isomer K: axial isomer Ethanol was added to a suspension of I in dichloromethane:
10 water:e~anol (200 mL, 1:2:1) until the solution became homogeneous.
Sodium borohydride was added in one gram portions until TLC
indicated that I had been consumed (7 x 1.0 g). The reaction mixture was cooled to 0~C and acetone was slowly added until it no longer provoked gas evolution. The resulting mixture was then poured into 15 saturated NaCl (150 mL) and washed with EtOAc (2 x 250 mL). The organic layer was dried (Na2so4)~ concentrated, and purified by flash chromatography (30% EtOAc/Hexane) to give a mixture of J and K as a colorless oil (9.49 g, 72% yield), Rf = 0.23 (30% EtOAc/Hexane).

20 Compound J: lH NMR (400 MHz, CDC13) ~ 7.22-7.30 (m, 5H), 4.55 (d, lH, J = 11.2 Hz), 3.95-4.15 (m, 4H), 3.73 (s, 3H), 3.47 (d, lH, J =
11.3 Hz), 2.96 (d, lH, J = 13.4 Hz), 2.83 (dd, lH, J = 14.6, 2.1 Hz), 2.68 (d, lH, J = 13.4 Hz), 2.53 (dd, lH, J = 10.6, 2.1 Hz), 2.42 (dd, lH, J= 10.8, 2.2 Hz), 2.19 (d, lH, J = 10.4 Hz), 1.91-2.05 (m, SH), 1.85 (d, lH, J = 10.7 Hz), 1.58-1.67 (m, lH), 0.85 (t, 6H, J = 7.4 Hz).

CA 022~291~ 1998-10-29 WO 97/40833 PCT/US97/~7131 -Compound K: lH NMR (400 MHz, CDC13) ~ 7.19-7.29 (m, SH), 4.24 (s, lH), 3.70-4.08 (m, 4H), 3.70 (s, 3H), 2.89 (d, lH, J= 13.2 Hz), 2.84 (d, lH, J = 10.0 Hz), 2.62 (d, lH, J = 10.8 Hz), 2.49 (d, lH, J = 13.4 Hz), 2.46 (d, lH, J = 11.9 Hz), 2.26 (d, lH, J = 10.8 Hz), 2.20 (d, lH, J
S = 14.1 Hz),2.14(d,2H,J=7.3Hz), 1.96(d, lH,J= 14.5Hz), 1.90(d, lH, J= 14.0 Hz), 1.79 (d, lH, J = 14.1 Hz), 1.76-1.81 (m, lH), 0.89 (d, 3H,J=3.9Hz),0.88(d,3H,J=4.0Hz).

Step Compound L:

TESC I ~~~
pyridine ,~ o J + K ~ o~N

~ CO2CH
L

A mixture of J and K (2.16 g, 5.3 mmol, 1:1) in pyridine (40 mL) at 0~C was treated with chlorotrie~hylsilane (4.03 g, 4.48 rnL, 26.7 mmol). 4-Dimethylaminopyridine (2 mg) was added and the 15 reaction mixture was heated at 60~C for 4 h. The reaction mixture was then concentrated, and the residue was partitioned between Et20 (100 mL) and saturated NaHCO3 (100 mL). The organic layer was washed with saturated NaCl solution, dried (Na2S04), and concentrated. The resulting oil was puri~led by flash chromatography (5% EtOAc/Hexane) 20 to give L as a colorless oil (1.14 g, 41 % yield of desired is~mer), Rf =
0.33 (10% EtOAc/Hexane).

1H NMR (400 MHz, CDC13) ~ 7.14-7.31 (m, SH), 4.04 (s, lH), 3.76-3.83 (m, 4H), 3.71 (s, 3H), 2.83 (dd, lH, J = 11.3, l.S Hz), 2.78 (s, 2H), 2.62 (dd, lH, J = 11.6, 1.5 Hz), 2.40 (dd, lH, J = 11.8, 3.3 Hz), 2.08 (dd, 2H, J = 7.3, l.S Hz), 2.00 (d, 2H, J = 11.6 Hz), 1.88 (d, lH, J =
11.6 Hz), 1.82 (dd, lH, J = ll.S, 3.4 Hz), 1.71 (d, lH, J = 11.4 Hz), CA 022.,291., 1998-10-29 W ~ 97/40833 PCTAUS97/~7131 1.65-1.70 (m, lH), 0.97 (t, 9H, J = 8.0 Hz), 0.83 (d, 3H, J = 7.2 Hz), 0.85 (d, 3H, J = 6.7 Hz), 0.63 (q, 6H, J = 7.9 Hz).

Step 6: Compound M
s Ph~>J~ o~N

CO2CH3 ~ ~ CHO
L M

Diisobutylalllminllm hydride (I.0 M in toluene, 2.91 rnL, 2.91 mmol) was cooled to -78~C and added via c~nn~ to a solution of 10 L (753 mg, 1.45 mmol) in toluene (10 mL) at -78~C. The reaction mixture was stirred for 20 min and then acetone (5 mL) at -78~C was added via cannula to destroy excess reagent. The mixture was allowed to warm to 23~C, poured into saturated sodiurn potassium tartrate (100 mL), and the resulting suspension was washed with EtOAc (2 x 100 15 mL). The organic layer was dried (Na2S04) and concentrated to give a mixture of L and M as a colorless oil which was azeotropically dried with toluene (2 x 40 mL) and used without further purification (720 mg, 3:1 mixture of M:L, 75% yield of M), Rf = 0.41 (50%
EtOAc/Hexane)] .
lH NMR (400 MHz, CDCl3) â 9.66 (s, lH), 7.13-7.32 (m, SH), 3.71-3.82 (m, SH), 2.78 (d, 2H, J = 3.4 Hz), 2.74 (dd, lH, J = 11.8, 2.0 Hz), 2.66 (dd, lH, J = 11.8, 2.0 Hz), 2.21 (dd, lH, J = 11.9, 2.6 Hz), 2.10 (dd, 2H, J = 7.5, 1.6 Hz), 1.93 (d, lH, J = 1.8 Hz), 1.92 (d, IH, J = 11.9 25 Hz), 1.83-1.87 (m, 3H), 1.65-1.73 (m, lH), 0.97 (t, 9H, J = 8.0 Hz), 0.85 (d,3H,J=6.7Hz),0.83 (d,3H,J=7.2Hz),0.63 (q,6H,J=7.9 Hz).

W.O 97/40833 PCT~US97/07131 -Step 7: Compound N

BenzylMgCI Ph~N

~ ~ HH~
N

A mixture of M and L (955 mg, 3:1, 1.45 mmol of L) in 5 anhydrous THF (10 mL) at -78~C was treated with benzylrnagnesium chloride (4.75 mL, 9.80 mrnol, 2.06 M in THF) over 3 min. The reaction mixture was warmed to 0~C and was kept at that temperature for 1 h. Saturated NH4Cl was added (5 mL), and the heterogeneous mixture was poured into saturated NaHCO3 (100 mL) and was washed 10 with EtOAc ( 2 x 100 mL). The organic layer was dried (Na2S04), concentrated and purified by flash chromatography (5% EtOAc/
Hexane), to isolate the desired isomer N as a colorless oil (374 mg, 44%). Rf= 0.23 (10% EtOAc/Hexane).

lH NMR (400 MHz, CDCl3) ~ 7.13-7.35 (m, 10H), 3.74-3.84 (m, 6H), 2.88 (d, lH, J = 13.7 Hz), 2.80 (d, lH, J = 13.4 Hz), 2.77 (d, lH, J =
11.4 Hz), 2.75 (d, lH, J = 13.4 Hz), 2.62 (d, lH, J = 11.4 Hz), 2.47 (dd, lH, J = 13.7, 10.9 Hz), 2.10 (dd, J = 7.2, 4.9 Hz), 1.99 (d, lH, J = 11.4 Hz), 1.90 (d, lH, J = 11.5 Hz), 1.85 (d, lH, J = 11.4 Hz), 1.85 (s, lH), 1.70-1.78 (m, 4H), 0.99 (t, 9H, J = 8.0 Hz), 0.86 (d, 3H, J = 6.2 Hz), 0.85 (d, 3H, J = 6.2 Hz), 0.65 (q, 6H, J = 8.0 Hz).

Step 8: Compound 16 Ph~NJ~ 3 N HCI HO~
--Si~O~/ Acetone, HO~
HO~

Aqueous HCI (3 N, 10 mL) was added to a solution of N
(374 mg, 0.64 mmol) in acetone (10 rnL). The mixture was heated at 65~C for 16 h. After cooling to 23~C, the reaction mixture was slowly poured into saturated NaHCO3 (75 mL). The biphasic system was extracted with EtOAc (2 x 150 mL), and the combined organic layers were dried (Na2S04), and concentrated to give 16 as a white solid (265 mg, 99%). Rf = 0.13 (30% EtOAc/Hexane), mp = 138-141~C.

1H NMR (CDC13) ~ 7.16-7.37 (m, 10H), 3.88 (s, lH), 3.83 (s, lH), 3.66(d, lH,J= 11.2Hz),2.98(d, lH,J= 15.9Hz),2.90(d, lH,J=
lS 13.4 Hz), 2.69 (m, lH), 2.81 (s, 2H), 2.65 (d, 2H, J = 13.9 Hz), 2.48 (d, 2H, J = 11.4 Hz), 2.00-2.09 (m, SH), 1.91 (d, lH, J = 11.5 Hz), 1.53-1.66 (m, lH), 0.79 ( d, 3H, J = 6.4 Hz), 0.78 (d, 3H, J = 6.6 Hz).

Anal. Calcd for C27H35NO3-0.30 H20:
C, 75.95; H, 8.40; N, 3.28.
Pound: C, 75.91; H, 8.30; N, 3.55.

HRMS calcd for C27H35NO3 422.2695, found 422.2693.

WO 97140833 PCT/US97/n7131 5(RS)-methylpheny-9(RS)-hydroxy- 1 (RS)-(( 1 '-hydroxy)-2'-phenyl)-ethyl-3-benzyl-3-azabicyclo~3.3.11nonan-7-one (Compound 1~). Table II

~N~, Ph H HO Ph Step 1: Compound S

0~ O~
~o> ~) SO3:pyr/DMSO ~ ~0~
~;N~, Ph TEA , ~N~, Ph H ~OH 2) Et3SiCllPyr Et3SI ~O

A mixture of diols (162 mg, 0.396 mmol), and SO3-pyridine complex (189 mg, 1.19 mmol) were dissolved in dry DMSO (4 mL). Triethylamine (0.34 mL) was then added dropwise via 15 syringe. The reaction was allowed to proceed for 1.5 hours at which point it was poured into saturated NH4CI solution. The aqueous phase was extracted with EtOAc (2 x 50 mL). The organics were combined and washed with H2O, NaCI and dried (Na2SO4). The extracts were filtered, concentrated to an oil (147 mg) that was used in the next step 20 without purifcation. The crude mixture of hydroxyaldehydes were dissolved in pyridine (6 mL) and treated with triethylsilyl chloride (0.34 mL, 20 mmol) and catalytic amounts of 4-dimethylaminopyridine (10 mg). The reaction was allowed to proceed at 60~C for 16 hours.

WD 97/40833 PCT/US97/(~7131 The reaction was cooled to room temperature and the volatiles were removed via rotorevaporater. The residue was diluted with Et2O (75 mL) and washed succesively with NaHCO3, H2O and NaCI. The organics were dried over Na2SO4 and concentrated. Flash 5 chromatography (9:1, Hexanes/EtOAc) gave the desired compound (S) as an oil (62 mg, 28%).

1H NMR (400 MHz, CDC13) ~ 9.54 (s, lH), 7.14-7.31 (m, 10H), 3.82 (m, SH),3.54 (AB, JAB = 13Hz, 2H ), 2.78 (AB, JAB = 13.5Hz, 2H), 10 2.71 (m, 2H), 2.19 (dd, J = 11.7Hz, 3.1Hz, lH), 1.96 (m, 4H), 0.99 (t, J
= 8Hz, 9H), 0.65 (q, J = 8Hz, 6H).

Step 2: Compound 1 ~

N Ph ~1--N~,Ph H0~/
Et3Si' ~ 0 1) PhCH2MgCllTHF H~Ph 2) H30+/acetone A solution of benzyl magnesium chloride in THF (2.06M, 0.2 mL) was added to a solution of the aldehyde S from step 1 (61 mg, 0.109 mmol) in dry THF (1 mL) at -78~C. The reaction was stirred at 20 -78~C for 1.5 hours then slowly warmed to room temperature and excess Grignard was quenched with saturated NH4Cl solution. The reaction was diluted with EtOAc (60 rnL) and washed with N~4Cl, NaCI and dried over Na2SO4. The material was immediately hydrolyzed in THF/lN HCI (4:1, 2.5rnL). The desired compound wa.s 25 puri~ied via flash chromatography 1: 1 EtOAc/Hexanes and crystallized from Et20/Hexanes. m. p. 145.5-147~C.

WO 97/40833 PCT/US971û7131 lH NMR (400 MHz, CDC13) o 7.17-7.34 (m, ISH), 3.90 (d, J = 9.9 Hz, 2H), 3.58 (m, 2H), 3.35 (d, J = 13.4 Hz, lH),3.00 (d, J = 15.7 Hz, lH), 2.43-2.84 (m, SH), 2.81 (AB, JAB = 13.5 Hz, 2H), 2.0-2.12 (m, 3H).

S Low resolution FAB Mass spec (M+ + 1) m/z 456.

Anal calc'd for C30H33NO3-0.65 H2O:
C, 77.10; H, 7.40, N, 3Ø
Found: C, 71.15; H, 7.24; N, 3.10.

5(RS)-methylpheny-9(RS)-hydroxy- 1 (RS)-(( l '-hydroxy)-2'-(2"'-(tetra-hydro- l ,2-thiazine 1,1 -dioxide))-ethyl-3-benzyl-3-azabicyclo [3.3.1] -15 nonan-7-one (Compound 23)~ Table II

~~
/--N
\ ~SO2 Step 1: Compound T

~ ~) Me3S(O)I/NaH ~ ~o~
E~N~Ph DMFO~C E~ ~N~Ph S T

CA 022~291~ 1998-10-29 A solution of trimethylsulfoxonium iodide (298 mg, 1.35 mmol), NaH (32 mg, 1.35 mmol) and DMF (4 mL) were stirred at 0~C
for 30 minutes. A solution of aldehyde S from above (152 mg, 0.2709 mmol) in DMF (0.5 mL) was added via syringe. The transfer was S completed with two w~hin~s of DMF (2x0.25 mL). The reaction was stirred at 0~C for 1 hour and quenched with a saturated solution of NH4Cl. The reaction was poured into NaCI and extracted with Et20 (3 x35 mL). The organics were combined and washed with H20, NaCl, and dried over Na2S04. Flash chromatography using 8:1 10 Hexane/EtOAc gave 68 mg of one diastereomer and 25 mg of a second diastereomer (both oils).

Major more polar isomer 1H NMR (400 MHz,CDC13),~ 7.14-7.3(m, lOH),3.81 (m, 4H),3.60(s,lH),3.50 (AB, JAB = 13.2 Hz,2H),2.67 15 (br t, J = 3 Hz, lH), 2.78 (AB, JAB = 13.5 Hz,2H),2.72 (d, J = 11.4 Hz,lH),2.66 (m, 2H),2.60(d, J = 11.4 Hz,lH),1.96(d, J = 11.4 Hz, lH),1.89(d, J = 11.5 Hz, lH), 1.82 (dd, J = 11.5 Hz,2.9 Hz,lH),1.76 (dd, J = 11.4 Hz,9.4 Hz, lH), 1.53 (dd, J = 11.9 Hz,3.1 Hz, lH),l.00 (t, J = 7.5 Hz,9H),0.65(q, J = 7.5 Hz,6H).
Minor less polar isomer 1H NMR (400 MHz,CDC13),~ 7.10-7.32 (m, lOH),3.79 (m, 4H),3.50 (AB, JAB = 13.2 Hz,2H),3.23(s,lH),2.62-2.77 (m, 7H),1.80-1.96 (m, 4H), 1.70 (dd, J = 11.5 Hz,2.5 Hz,lH), 0.98 (t, J = 7.7 Hz, 9H), 0.64(q, J = 7.7 Hz,6H).
Step 2: Compound 23 E ' i~ S0z~N~Ph H 0 1) NaH/THF ~j H~""OH

T 2)H30+ /acetone \ "SO2 CA 022~291~ 1998-10-29 WO 97/40833 PCT/US97/~)7131 NaH (8 mg, 60 wt% in mineral oil, 200 }lmol) was added to a solution of tetrahydro-1,2-thiazine-1,1-dioxide (34 mg, 250 ,umol) in N,N-dimethylformamide (1 mL) and the resulting mixture was stirred at 23~C for 30 min. A solution of T (27 mg, 50 ~mol) in N,N-5 dimethylformamide (1 mL) was added and the mixture was heated at65~C for 16 h. The reaction was cooled to room temperature and NH4CI solution (2 mL) was added. The reaction mixture was poured into water (50 mL) and the resulting aqueous mixture was extracted with Et20 (2 x 50 mL). The combined organic extracts were washed 10 with water (25 mL), dried (Na2S04), and concentrated to give a mixture of starting material and desired product which was used without further purification.
A solution containing the crude reaction mixture from above (30 mg) in acetone (3 mL) was treated with aqueous hydrochloric 15 acid (3 N, 3 mL) and the colorless solution was heated at 65~C for 12 h.
The reaction mixture was cooled to room temperature and slowly poured into saturated NaHCO3 (25 mL). The resulting suspension was washed with EtOAc (30 mL) and the organic layer was dried (Na2S04), and concentrated to give a crude oil which was purified by flash 20 chromatography (70% EtOAc/Hexane) to give 23 as a white solid (15 mg, 58% for 2 steps). Rf = 0.13 (70% EtOAc/Hexane), mp = 163-164 ~C.

lH NMR (400 MHz, CDC13) ~ 7.13-7.33 (m, 10H), 3.80 (bs, lH), 3.63 (bd, lH, J = 10.1 Hz), 3.59 (bs, lH), 3.51 (d, lH, J = 13.4 Hz), 3.21-3.39 (m, 4H), 3.01-3.06 (m, 3H), 2.86 (d, lH, J = 15.6 Hz), 2.79 (d, lH, J = 13.4 Hz), 2.73 (d, lH, J = 13.4 Hz), 2.66 (d, lH, J = 15.6 Hz), 2.53 (dd, lH, J = 11.3, 1.8 Hz), 2.37 (dd, lH, J = 10.9, 1.9 Hz), 2.20 (quintet, 2H, J = 6.0 Hz), 1.93-2.09 (m, 4H), .1.64-1.66 (m, 2H).
Anal calcd. for C28H36N2S05-0.80 H20:
C, 63.81; H, 7.19; N, 5.31.
Found: C, 63.81; H, 7.02; N, 5.18;

WO 97/40833 PCT/US97/~7131 HRMS calcd for C2gH36N2SO5 513.2423, found 513.2437.

5 5(RS)-methylpheny-9(RS)-hydroxy-1(RS)-((1'-hydroxy)-2'-(2"-amino)-phenyl)-ethyl-3-benzyl-3-azabicyclo[3.3.1]nonan-7-one (Compound 20), Table II

O

~NJ--HO~

HHo - ~ \
H2N ~3 A. Step 1:

BocNLi ~/~ O
¢~,CH2Li ~_ TESO ~N THF, ~0 ~C HOs~
CHO BocHN~3 U V

CA 022~291~ 1998-10-29 WD 97/40833 PCT/US97/1~7131 A solution of tert-butyllithium in pentane (1.7 M, 3.00 mL, 5.10 mrnol, 9.64 equiv) was added over 1 min to a solution of tert-butyl 2-methylcarb~nil~te (515 mg, 2.48 mmol, 4.69 equiv) in THF (3.5 mL) at -40 ~C. The resulting bright yellow mixture was stirred at -40 ~C for S 15 min, then a solution of the aldehyde, U, (300 mg, 0.529 mrnol, 1 equiv) in THF (4 mL) was added. The resulting mixture was warmed to 0~C and was held at that temperature for lS min. The product solution was diluted with pH 7 phosphate buffer solution (100 mL), and the resulting aqueous mixture was extracted with EtOAc ( 2 x 75 m~).
l'he combined organc layers were dried over Na2S04 and were concentrated. The residue was purified by flash chromatography (5%
EtOAc in hexanes initially, grading to 20% ethyl acetate in hexanes) to provide the desired alcohol as a colorless oil (85 mg, 21%) as well as the undesired diastereomeric alcohol as a colorless oil (81 mg, 20%).
1H NMR (400 MHz, CDC13), ~ 7.78 (br s, lH, NH), 7.59 (br d, lH, J =
7.9 Hz, ArH), 7.32-7.07 (m, 7H, PhH and ArH), 7.00 (br t, lH, J = 7.3 Hz, ArH), 3.81 (m, 2H, OCH2CH20), 3.75 (m, 2H, OCH2CH2O), 3.67 (s, lH, (CH3CH2)3SiOCH), 3.11 (br d, lH, J = 5.1 Hz, HOCH), 2.77-2.56 (m, 6H, PhCH2~ ArCH2 and NcH2)~ 2.10 (m, 2H, NCH2CH(CH3)2 and NCH2 or CH2), 2.03 (d, lH, J = 11.2 Hz, ~CH2 or CH2), 1.94 (d, lH, J = 11.4 Hz, NCH2 or CH2), 1.84 (m, 2H, NCH2CH(CH3)2 and NCH2 or CH2), 1.71 (m, 3H, NCH2 and/or CH2 and NCH2CH(CH3)2, 1.52 (s, 9H, OC(CH3)3), 0.98 (t, 9H, J = 7.9 Hz, (CH3CH2)3Si), 0.86 (d, 3H, J = 6.4 Hz, CH(CH3)2), 0.85 (d, 3H, J = 6.4 Hz, CH(CH3)2), 0.64 (q, 6H, J = 7.9 Hz, (CH3CH2)3Si).

TLC (20% EtOAc-hexanes), ~f: desired alcohol: 0.36 (UV), undesired alcohol: 0.44 (UV) WO 97/40833 PCI/US97/~7131 Step 2:

BocHN H2N

A solution of the ketal (80 mg, 0.11 mmol) in a mix~re of S aqueous 3 M HCI solution (10 mL) and acetone (10 mL) was heated at 60~C for 16 h. After cooling to 23~C, the product soiution was carefully diluted with aqueous saturated NaHCO3 solution (100 mL).
The resulting aqueous mixture was extracted with EtOAc (2 x 50 mL).
The combined organic layers were dried over Na2so4 and were 10 concentrated. The residue was purified by flash chromatography (40%
EtOAc in Hexanes initially, then 40% Hexanes in EtOAc) to afford the product ketone as a colorless oil (31 mg, 67%). The product oil was triturated with Et20 to produce a white crystalline solid (mp - 164-165~C).
lH NMR (400 MHz, CDC13) ~ 7.32-7.12 (m, SH, PhH), 7.08 (td, lH, J
- 7.6, 1.4 Hz, ArH), 7.00 (dd, lH, J = 7.5, 1.3 Hz, ArH), 6.80 (td, lH, J
= 7.5, 1.1 Hz, ArH), 6.71 (dd, lH, J = 7.9, 0.7 Hz, ArH), 3.98 (br s, lH, OH), 3.88 (br s, lH, HOCH), 3.74 (br s, 2H, NH), 3.68 (dd, lH, J =
20 10.4, 1.7 Hz, HOCH), 2.87 (d, lH, J = 15.9 Hz, NCH2), 2.77 (m, 3H, PhCH2 and ArCH2), 2.65 (br d, lH, J = 14.7 Hz, ArCH2), 2.62 (d, lH, J = 16.1 Hz, NCH2), 2.46 (m, 2H, NCH2CH(CH3)2), 2.04 (m, SH, NCH2 and CH2), 1.91 (d, lH, J = l l.S Hz, NCH2 or CH2)~ 1.61 (m, lH, NCH2CH(CH3)2), 0.77 (d, 3H, J = 6.6 Hz, CH(CH3)2), 0.76 (d, 3H, J =
25 6.4 Hz, CH(CH3)2)-WO 97/40833 rCT/US971~713 High-Res MS (FAB): Calcd for C27H36N203 [M+H]+: 437.2804 Found: 437.2813 Calcd for C27H36N203:
C, 74.28; H, 8.31; N, 6.42.
Found: C, 74.28; H, 8.34; N, 6.52 TLC (40% EtOAc-hexanes), Rf: 0.06 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)

WHAT IS CLAIMED IS:
1. A compound of the formula:

wherein X is -O-, -NH-, -NR4- or -S-;
Y is =O, or forms, with the carbon to which it is attached, Z is =O, or forms, with the carbon to which it is attached, R1 is a) H;
b) C1-4 alkyl;
c) C3-7 cycloalkyl;
d) aryl, unsubstituted or substituted one or more times with hydroxy;
e) CH2R5; or f) 5-7 membered heterocycle; and R2 is a) C1-4 alkyl;
b) aryl, unsubstituted or substituted with aryl;
c) CH2R6; or d) heterocycle; and R3 is a) CH(OH)R7; or b) CH(NH2)R7; and R4 is a) C1-4 alkyl;
b) C3-6 cycloalkyl;
c) aryl unsubstituted or substituted with halo or with C1-4 alkyl unsubstituted or substituted one or more times with hydroxy;
d) CH2R1; or e) 5-7 membered heterocycle; and R5 is a) C1-4 alkyl; or b) aryl; and R6 is a) C1-4 alkyl;
b) aryl unsubstituted or substituted with halo or with C1-4 alkyl unsubstituted or substituted one or more times with hydroxy; or c) 5-7 membered heterocycle; and R7 is a) H;
b) C1-4 alkyl;
c) aryl unsubstituted or substituted with amino;

d) C1-3 alkylaryl unsubstituted or substituted with amino; or e) 5-7 membered heterocycle;

or pharmaceutically acceptable salt thereof.
2. A compound of the formula wherein R2 is C1-4 alkylene-aryl; and R4 is C1-4 alkyl, unsubstituted or substituted with aryl, C3-6 cycloalkyl, or 5-7 membered heterocycle;

R7 is H, benzyl unsubstituted or substituted with amino;

or pharmaceutically acceptable salt thereof.
3. The compound or pharmaceutically acceptable salts thereof.
4. The compound or pharmaceutically acceptable salts thereof.
5. A pharmaceutical composition comprising the compound of any of Claims 1-4, and a pharmaceutically acceptable carrier.
6. The pharmaceutical composition of any of Claims 1-4, for use in the treatment of and the delaying of the onset of AIDS, in the prevention of infection by HIV, in the treatment of infection of HIV, or in the inhibition of HIV protease.
7. A method of treating and delaying the onset of AIDS, comprising administering to a mammal in need of such treatment an effective amount of a compound any of Claims 1-4.
8. A method of preventing infection by HIV, comprising administering to a mammal in need of such treatment an effective amount of a compound of any of Claims 1-4.
9. A method of treating infection by HIV, comprising administering to a mammal in need of such treatment an effective amount of a compound of any of Claims 1-4.
10. A method of inhibiting HIV protease, comprising administering to a mammal in need of such treatment an effective amount of a compound of any of Claims 1-4.
11. A combination of compounds, which is Compound A
with (-) 6-chloro-4(S)-cyclopropylethynyl-4(S)-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one, and, optionally, AZT or ddI or ddC.
12. A combination of compounds, which is Compound A
or B, and any of AZT or ddI or ddC.
13. A combination of compounds, which is Compound B
with (-) 6-chloro-4(S)-cyclopropylethynyl-4(S)-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one, and optionally, AZT or ddI or ddC.
CA002252915A 1996-05-02 1997-04-29 Hiv protease inhibitors useful for the treatment of aids Abandoned CA2252915A1 (en)

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