JP2000509392A - HIV protease inhibitors effective for treating AIDS - Google Patents

Abstract

(57) Abstract: The compound represented by the formula (A) or a pharmaceutically acceptable salt thereof is an HIV protease inhibitor. These compounds can be used in combination with or without other antivirals, immunomodulators, antibiotics, or vaccines, as compounds, as pharmaceutically acceptable salts, as components of pharmaceutical compositions, as infections by HIV, For the prevention or treatment of AIDS, and the treatment of AIDS. Also disclosed are methods of treating AIDS and preventing or treating infection by HIV.

Description

DETAILED DESCRIPTION OF THE INVENTION       HIV protease inhibitors effective for treating AIDS   The present application relates to Merck Case 19531PV.   The present invention relates to proteases encoded by the human immunodeficiency virus (HIV). Or a pharmaceutically acceptable salt thereof, which inhibits HIV Of HIV infection, treatment of HIV infection, and resulting acquired immunodeficiency Compounds useful for treating Syndrome (AIDS). In addition, the present invention COMPOSITION CONTAINING PRODUCT AND TREATING VIRAL INFECTION BY AIDS AND HIV The use of the compounds of the present invention and other agents to accomplish the above.Background of the Invention   A retrovirus called the human immunodeficiency virus (HIV) is responsible for the development of the immune system. Sexual destruction (acquired immunodeficiency syndrome; AIDS) and alterations in the central and peripheral nervous systems It is the causative agent of complex diseases including gender. Previously, this virus was known as LAV, HTL V-III, also known as ARV. Retrovirus replication Common features generate mature viral proteins necessary for virus assembly and function. Precursor polytan with a virally encoded protease Extensive post-translational processing of protein. Inhibiting this processing This can normally prevent the production of infectious viruses. For example Kohl, N .; E. FIG. (Proc. Nat'l Acad. Sci., 85, 4686 (1988)) genetically encodes an HIV-encoded protease. Demonstrates that inactivation produces immature, non-infectious virions . These results indicate that inhibition of HIV protease is It represents a promising way to prevent or treat infection.   The nucleotide sequence of HIV consists of one open reading frame (read Pol gene is present [Ratner, L. et al. N ature, 313, 277 (1985)]. Amino acid sequence homology is pol Sequence encodes reverse transcriptase, endonuclease, and HIV protease [Toh, H .; Et al., EMBOJ. , 4, 1267 (198 5); Power, M .; D. Et al., Science, 231, 1567 (1986); Pearl, L .; H. N atature, 329, 351 (1987)]. Applicants believe that the compounds of the present invention Demonstrates that it is an IV protease inhibitor.BRIEF DESCRIPTION OF THE INVENTION   Disclosed are compounds of formula I as defined below. These compounds are used in other antiviral With or without drugs, immunomodulators, antibiotics, or vaccines As a compound or a pharmaceutically acceptable salt thereof, or with a component of a pharmaceutical composition. To inhibit HIV protease, prevent HIV infection, treat HIV infection, and And treatment of AIDS. The present application also describes methods of treating AIDS, Methods of preventing infection and treating HIV infection are also disclosed.DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS   The present invention relates to inhibition of HIV protease, prevention or treatment of HIV infection, and Formula I useful for the treatment of the resulting acquired immunodeficiency syndrome (AIDS) Compounds, mixtures thereof, or pharmaceutically acceptable salts thereof It is. Compounds of formula I are defined as follows: [In the formula:   X is -O-, -NH-, -NR^Four-Or -S-;   Y is ＝ O or, together with the carbon to which it is attached, Form;   Z is ＯO or, together with the carbon to which it is attached, Form;   R¹Is     a) H;     b) C_{1 ~Four}Alkyl;     c) C_{Three ~ 7}Cycloalkyl;     d) ants unsubstituted or substituted one or more times with hydroxy Tool;     e) CH_TwoR^FiveOr     f) 5- to 7-membered heterocycle And   R^TwoIs     a) C_{1 ~Four}Alkyl;     b) aryl unsubstituted or substituted with aryl;     c) CH_TwoR⁶Or     d) heterocycle And   R^ThreeIs     a) CH (OH) R⁷Or     b) CH (NH_Two) R⁷ And   R^FourIs     a) C_{1 ~Four}Alkyl;     b) C_{Three ~ 6}Cycloalkyl;     c) aryl unsubstituted or substituted with halo C or unsubstituted or substituted one or more times with hydroxy_{1 ~Four} Aryl substituted with alkyl     d) CH_TwoR¹Or     e) 5-7 membered heterocycle And   R_FiveIs     a) C_{1 ~Four}Alkyl; or     b) aryl And   R⁶Is     a) C_{1 ~Four}Alkyl;     b) aryl, unsubstituted or substituted with halo, or unsubstituted C substituted or substituted one or more times with hydroxy_{1 ~Four}Alkyl Substituted aryl; or     c) 5-7 membered heterocycle And   R⁷Is     a) H;     b) C_{1 ~Four}Alkyl;     c) unsubstituted or amino-substituted aryl;     d) unsubstituted or amino-substituted C_{1 ~ 3}Alkylaryl; also Is     e) 5-7 membered heterocycle Is] Or a pharmaceutically acceptable salt thereof.   One preferred embodiment has the formula: [In the formula:   R^TwoIs C_{1 ~Four}Alkylene-aryl,   R^FourIs an unsubstituted or aryl-substituted C_{1 ~Four}Is alkyl or C_{Three ~ 6} Cycloalkyl, or a 5- to 7-membered heterocyclic ring,   R⁷Is H, unsubstituted or amino-substituted benzyl] Or a pharmaceutically acceptable salt thereof.   Preferred compounds of the present invention include:Compound A Or a pharmaceutically acceptable salt thereof; andCompound B Or a pharmaceutically acceptable salt thereof.   The compounds of the present invention may have asymmetric centers and therefore are racemic, racemic mixtures and And individual diastereomers or enantiomers. All isomers Forms are encompassed by the present invention.   In any component or formula I, any variable component (eg, aryl, complex Ring, R¹, R^Two, X, Y or Z, etc.) occur more than once, the variable for each occurrence The definition of a component is independent of all other definitions. Also, substituents and / or variables Combinations of components may be used when such combinations result in stable compounds. Only acceptable.   Unless otherwise noted, the term “alkyl” as used herein refers to a particular number of Both branched and straight-chain saturated aliphatic hydrocarbon groups having carbon atoms (Me is methyl, Et is ethyl, Pr is propyl And Bu is butyl).   Unless otherwise noted, the term "aryl" as used herein refers to phenyl (P h) or naphthyl.   Unless otherwise specified, the term "heterocycle" or "heterocyclic" used herein is used. The term refers to a stable 5- to 7-membered monocyclic or bicyclic heterocyclic ring system, Represents a stable 7 to 10 membered bicyclic heterocyclic ring system. Combine these The ring to be formed may be saturated or unsaturated, and is a group consisting of carbon atoms and N, O and S From one to three heteroatoms selected from Made up of Wherein the nitrogen and sulfur heteroatoms may be optionally oxidized Also, the nitrogen heteroatom may optionally be quaternized. In addition, the above terms Is any of the above defined heterocyclic rings fused to a benzene ring Also encompasses bicyclic groups. Heterocyclic rings can be any as long as they result in a stable structure. The bond may be at a heteroatom or a carbon atom. Examples of such heterocyclic components are , Piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl Nil, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl , 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazoly , Imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl , Pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, Xazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl , Quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl Nil, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazoly , Benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl , Thienyl, benzothienyl, thiamorpholinyl, thiamorpholin Nyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl.   Pharmaceutically acceptable salts of the compounds of formula I (water- or oil-soluble, or Is in the form of a dispersible product), for example, from inorganic or organic acids or bases. Includes the usual non-toxic salts or quaternary ammonium salts formed. Such acid Examples of addition salts are acetate, adipate, alginate, aspartate, benzoate Flavor, benzenesulfonate, bisulfate, butyrate, citrate, camphor Acid, camphorsulfonate, cyclopentanepropionate, digluconic acid Salt, dodecyl sulfate, ethane sulfonate, fumarate, glucoheptanate, Glycerophosphate, hemisulphate, heptanoate, hexanoate, hydrochloride, bromide Borate, hydroiodide, 2-hydroxyethanesulfonate, lactate, male Phosphate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, Oxalate, pamoate, pectate, persulfate, 3-phenylpropionate, Picrate, pivalate, propionate, succinate, tartrate, thiocyanate Includes phosphate, tosylate, and undecanoate. The base salt is ammonium hydroxide. Salt, sodium salt and Alkali metal salts such as potassium salts, alkalis such as calcium salts and magnesium salts Salts with organic bases such as earth metal salts and dicyclohexylamine salts, N-methyl-D- Includes glucamine, and salts with amino acids such as arginine and lysine. Also base Nitrogenous groups, such as methyl, ethyl, propyl and butyl chlorides, bromides and Lower alkyl halides such as iodide and the like; dimethyl, diethyl, dibutyl sulfate Dialkyl sulfates such as salts; diamyl sulfate, decyl, lauryl, milli Long-chain halides such as chlorides, bromides and iodides of still and stearyl, Aralkyl halides such as benzyl and phenethyl bromide, and other substances May be quaternized. Other pharmaceutically acceptable salts include the sulfate salt ethanol Contains sulfate and sulfate salts.   Schemes I and II for preparing the novel compounds of the present invention are shown below. . Tables I and II following the reaction scheme are synthesized according to Reaction Schemes I and II. Schemes I and II are illustrated in Tables I and II above. Limited by the indicated compounds and the particular substituents used for illustration in the reaction schemes Not something. It also illustrates the application of the following reaction scheme to specific compounds In particular, some embodiments are shown ing.   Further information on the relevant synthesis background can be found in EPO 0337. 714.   One method of preparing compounds of Formula I is shown in Scheme I.                               Reaction scheme 1   Ester I in base with R^TwoX ′ (where X ′ represents halo) Kill to gain II. Rearrangement of II by reaction with MeONa gives III. R^Four NH_TwoAzabicyclic (3.3.1) nonane nucleus precursor IV is obtained by cyclization of Original and acidified It is hydrolyzed to V. One specific embodiment of Reaction Scheme I is illustrated in Example 1.                               Reaction scheme 2   Scheme II illustrates another general synthetic method. P in SO in DMSO_Three・ Pi Treatment with a lysine complex oxidizes the alcohol and silylates to give Q. Appropriate Alkylation with a Grignard reagent followed by acid treatment gives R. Reaction scheme Example 3 illustrates one specific embodiment of II.   The compounds of the present invention are useful in preparing antiviral compounds and performing screening assays. Useful in For example, the compounds of the present invention are useful for isolating mutants of the enzyme. Screening method to obtain more powerful antiviral compounds Becomes In addition, the compounds of the present invention may be used in combination with other antiviral agents, for example, by competitive inhibition. Useful for determining or determining the binding site of HIV to HIV protease. Follow Thus, the compounds of the present invention are commercial products for these purposes.   The compounds of the present invention can inhibit HIV protease or inhibit human immunodeficiency virus (H IV) Prevention or treatment of infections and resulting pathologies such as AIDS Useful for treating conditions and delaying the onset of such pathological conditions. Cure for AIDS Treatment or prevention or treatment of HIV infection is not limited to this. But involves treating a wide range of HIV infection conditions, such as: Are defined as: symptomatic and asymptomatic AIDS and ARC (AIDS-related Syndrome and actual or potential exposure to HIV. For example, the present invention Compounds can be used for transfusion, organ transplantation, fluid exchange, bites, accidental needles Past exposure to HIV due to puncture of the patient or exposure to the patient's blood during surgery. It is useful for treating HIV infection when suspected of exposure.   For these purposes, the compounds of the present invention can be administered orally, parenterally (subcutaneous injection, , Intravenous, intramuscular, intrasternal injection or infusion), by inhalation spray Or, rectally, the usual non-toxic pharmaceutically acceptable carriers, adjuvants and Can be administered in a unit dosage form containing the drug and vehicle.   Thus, the present invention further provides a method of treating or treating HIV infection and AIDS. Is provided. The treatment according to the invention is such a treatment. For the patient in need, a pharmaceutical carrier and a therapeutically effective amount of a compound of the present invention or pharmaceutically Administering a pharmaceutical composition comprising an acceptable salt thereof.   These pharmaceutical compositions include orally administrable suspensions and tablets; nasal sprays; Sterile injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions or suppositories. It may be in the form of an agent.   When administered orally as a suspension, these compositions are useful for pharmaceutical formulation Prepared by methods well known in the art, Microcrystalline cellulose to raise the bulk, alginic acid or algin as a suspending agent Sodium acetate, methylcellulose as a viscosity enhancer, and known in the art Some sweetening / flavoring agents may be included. When used as an immediate release tablet These compositions are used in microcrystalline cellulose, dicalcium phosphate, starch and starch. Magnesium thearate, and lactose and / or other known in the art Excipients, binders, extenders, disintegrants, diluents, and lubricants may be included.   When administered by nasal aerosol or inhalation, these compositions will Prepared by methods well known in the art of Or other suitable preservatives, absorption enhancers to enhance bioavailability, fluoro Using carbon and / or other solubilizing or dispersing agents known in the art, It can be prepared as a solution in physiological saline.   Solutions or suspensions for injection include mannitol, 1,3-butanediol, water, Can be used parenterally with non-toxic suitable non-toxic substances such as Ringer's solution or isotonic saline Diluents or solvents, or synthetic mono- or diglycerides Including sterilization And suitable dispersing agents such as oils containing hypoallergenic fixed oils and fatty acids including oleic acid. Can be formulated with known techniques using wetting agents and suspending agents.   When administered rectally in the form of suppositories, these compositions will usually Solid at temperature but liquefies and / or dissolves in the rectal cavity to release drug Cocoa butter, synthetic glyceride esters, polyethylene glycol, etc. It can be prepared by mixing an appropriate non-irritating excipient.   Treatment or prevention of the conditions indicated above requires about 0.02 grams per day. Dose levels of 5.0 grams or 10.0 grams are useful. However, oral If administered intensively, the dose will be two to five times higher. For example, infection by HIV Is 1.0 to 50 milligrams of the present invention per kilogram of body weight. By administering the compound once to four times a day, it can be treated effectively . In one preferred dosing regimen, a dose of 100 mg to 400 mg every 6 hours is Administered orally to patients. However, specific dose levels for individual patients and The frequency of dosing will depend on the activity of the particular compound used and the Metabolic stability and duration of action, age, weight, overall health, gender, eating status , Administration method and time, excretion rate, drug combination, severity of individual condition, It will be understood that it may vary depending on the treatment method and the like to which the administered patient is receiving. U.   The present invention also relates to the use of the HIV protease-inhibiting compound of the present invention for treating AIDS. It is also directed when used in combination with one or more active drugs . For example, the compounds of the present invention may be administered either before and / or after exposure. Also effective amounts of AIDS anti-virus known to those of ordinary skill in the art. Effectively in combination with ills, immunomodulators, anti-infectives, or vaccines Can be administered.   Compounds of the present invention may be combined with other AIDS antivirals, immunomodulators, anti-infectives, Or the range of combinations with vaccines is limited to those listed in the table above And, in principle, include any combination with any pharmaceutical composition effective for treating AIDS. Will be understood.   The specific compounds described in Table S are as follows. L-743,726 is (- ) 6-Chloro-4 (S) -cyclopropylethynyl-4 (S) -trifluorome Tyl-1,4-dihydro-2H-3,1benzoxazin-2-one, , Manufactured according to the teachings of EPO 582445.   The synthesis of ddC, ddI, and AZT is also disclosed in EPO 484071. You.   A preferred combination is an inhibitor of HIV protease and a non-inhibitor of HIV reverse transcriptase. Treatment using nucleoside inhibitors simultaneously or alternately. In that combination An optional third component in the nucleic acid of HIV reverse transcriptase such as AZT, ddC or ddI. It is a creoside inhibitor. Suitable HIV protease inhibitors are L-735,52 No. 4 (Compound J), including USP No. 5,413,999. ing. Advantage of HIV reverse transcriptase Preferred non-nucleoside inhibitors include L-743,726. These combinations Combination can have a synergistic effect in controlling the spread of HIV. Preferred combination For example, the following (1) L-735, 524 and L-743, 726 and optionally AZ T, ddI or ddC; (2) L-735, 524 and any AZT, ddI And / or ddC;             Microbial HIV protease inhibition assay   Protease and peptide substrate expressed in E. coli [Val at the start of the reaction] -Ser-Gln-Asn- (beta-naphthyl) Ala-Pro-Ile-Va concentration, 0.5 mg / mL] at 30 ° C. for 1 hour at pH 5.0. 5 in 50 mM sodium acetate. Various in 1.0 μl DMSO Various concentrations of inhibitor were added to 25 μl of aqueous peptide solution. 0.1 at pH 5.5 15 μl in a solution of 33 M sodium acetate and 0.1% bovine serum albumin The reaction was started by adding 0.33 nM protease (0.11 ng). And the reaction was stopped with 160 μl of 5% phosphoric acid. The reaction product is HPL C (VYDAC wide pore 5cmC-18 reverse phase, acetonitrile gradient Distribution, 0.1% phosphoric acid) separated. The degree of inhibition of the reaction was determined from the peak height of the product. Independent Quantitative standards were established by HPLC for those products synthesized in Has been confirmed. Tables I and II show the results for the various compounds.                               Example 1 5 (RS)-((4 ')-2 "-furanyl) methylphenyl-9 (RS) -hydr Roxy-1 (RS) -hydroxymethyl-3- (2'-methylpropyl-3-a Zabicyclo [3.3.1] nonan-7-one (Compound 10, Table 1) Stage 1 :Compound A   2-Carbomethoxy-4-ethylenedioxycyclohexane in 100 mL of acetone Xanone I (3.0 g, 14.0 mmol, Fuchs, PL et al., Syn. Comm, 13 (3), 243, 1983). Mid (3.67 g, 14.7 mmol), K_TwoCO_Three(9.69 g, 70.1 mm ol) and NaI (210 mg, 1.4 mmol). Heterogeneous reactants And heated under reflux for 16 hours. The reaction mixture was cooled and filtered through celite. Filtrate To 250 mL of Et_TwoDilute with O and remove the organics with water (2 × 20 mL), then (50 mL), MgSO 4_FourAnd dried. Solvent evaporation and flash Chromatography (SiO_Two4: 1 hexane / EtOAc) . 8 g (89%) of A were obtained. Stage 2:Compound B   Slurry of NaH (375 mg, 15.6 mmol) in THF (15 mL) To the solution at 0 ° C. was added MeOH (0.76 mL, 30.7 mmol). 5 minutes stirring After stirring, ketoester 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 hours. The reaction mixture is added to 50 mL of Et. Dilute with OAc then remove excess NaOMe with 10 mL of saturated NH_FourQuench with Cl I did. Separate the organic phase, wash with brine, and add MgSO_FourAnd dried. Solvent steaming And flash chromatography (SiO_Two4: 1 hexane / EtO Ac) gave 4.5 g (94%) of B. Step 3: Compound C   MeOH (45 mL) and aqueous formaldehyde (37%, Ketoester B (2.9 g, 7.57 m) in 5.6 mL (75.7 mmol). mol) in a solution of isobutylamine (0.9 mL, 9.1 mmol) and H OAc (0.52 mL, 9.1 mmol) was added. Add the whole under reflux for 16 hours Heated. The reaction was cooled to room temperature and the solvent was removed. The residue was treated with EtOAc (100 m L) and the resulting solution is washed with saturated NaHCO_Three(2 × 20 mL), water (2 × 20 mL), then brine (50 mL) and MgSO 4_FourAnd dried. solvent Evaporation and flash chromatography (SiO_Two  Gradients 4: 1, 2: 1, (1: 1 hexane / EtOAc) gave 2.5 g (70%) of C. Melting point 142-144 ° C. Stage 4:Compound D   18 mL of 1: 1: 1 EtOH, CH_TwoCl_Two, And H_TwoKetone C in O (1.8 g, 3.75 mmol) at 0 ° C. with NaBH_Four(142 mg, 3. 75 mmol) was added. The solution is stirred for 30 minutes and then excess NaBH_FourAse Quenched with 5 mL ton. Dilute the solution with EtOAc and add water (4 × 10 mL), Then washed with brine (10 mL). Solvent evaporation and column chromatography Eee (SiO_Two654 mg (65:35 hexane / EtOAc). 53%). Stage 5:Compound E   Ester of D (964 mg, 2.0 in THF (40 mL) mmol) at 0 ° C. with LiEt_ThreeBH (6.09 mL, 6.0 mmol) ) Was added. The solution was warmed to room temperature and stirred for 4 hours. Excess LiEt_ThreeBH 5m L saturated NaHCO_ThreeQuenched with Etch the solution_TwoDilute with O (50 mL) NaHCO_Three(3 × 10 mL), water (4 × 10 mL), and brine (10 mL). Evaporation of the solvent gave 800 mg (88%) of crude diol E And used directly in the next step without purification. 136-138 ° C. Stage 6:Compound F (L-770, 274)   Ketal E (453 mg, 1.0 m) in acetone (8 mL) mol) at 0 ° C. was added 8 mL of a 50% aqueous solution of HCl. Reflux the solution Heated under for 16 hours, then cooled to 0 ° C. NaHCO_ThreeAdd saturated solution and excess HCl was quenched. Next, the solution was washed with EtOAc (3 × 10 mL) and the combined Combined organic extract with MgSO_FourAnd dried. Evaporation of the solvent and the resulting white solid Et of the form_TwoTrituration with O provided 300 mg (73%) of F. Melting point 15 5-156 ° C. C₂₀H₂₈NO_ThreeAnalysis on Br: Calculated: C, 58.54; H, 6.88; N, 3.41. Found: C, 58.91; H, 6.88; N, 3.51.Stage 7 :Compound 10, Table I   Dissolution of aryl bromide (41 mg, 0.10 mmol) in DMF (0.4 mL) To the solution was added 2- (tri-n-butylstannyl) furan (53.5 mg, 0.15 m mol) and PdCl_Two(PPh_Three)_Two(1.5 mg, 0.0020 mmol) Was added. The resulting tan solution was stirred at 95 ° C. for 4 hours. Cool the reaction mixture , Diluted with ether and filtered through Celite. Filtrate with water (7 × 2 mL), brine (2 mL), MgSO 4_FourAnd dried. Flash chromatography of yellow oils Graphy (SiO_Two95: 5: 0.5 CHCl;_Three/ IPA / NH_FourOH) This afforded 25 mg (63%) of the title compound as a foam. C_{twenty four}H₃₁NO_Four・ 0.8H_TwoAnalysis on O: Calculated: C, 69.97; H, 7.98; N, 3.40. Found: C, 69.95; H, 7.70; N, 3.52.Example 2 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 Stage 1:Compound G   I (12.0 g, 56.0 mmol), acetone bromide in acetone (200 mL) Benzyl (10.1 g, 7.0 mL, 58.8 mmol), potassium carbonate (48. 4 g, 350 mmol) and sodium iodide (250 mg, 1.7 mmol) )) Was heated under reflux for 16 hours. Next, the heterogeneous mixture is (150 mL). Extract the aqueous mixture with ethyl acetate (2 × 200 mL) Was. The combined organic phases are_TwoSO_FourAnd concentrated to afford G as a colorless oil (18. 7g) [R_f= 0.16 (20% EtOAc / hexane)] The material was used without further purification. Stage 2:Compound H   Sodium hydride (2.40 g, 61 mmol, 60% by weight in mineral oil) To remove the mineral oil and then at 0 ° C. in tetrahydrofuran (80 mL). Suspended. Anhydrous methanol (2.15 g, 2.72 mL, 67.1 mmol) Three minutes The mixture was then warmed to 23 ° C. and stirred for 30 minutes. 0 ° C. And add G in tetrahydrofuran (40 mL) by dropping funnel for 30 min. Added. The reaction mixture was warmed to 23 ° C. over 1 hour, then Stirred for 16 hours. Carefully add aqueous acetic acid (10%, 10 mL) and saturate the mixture NaHCO_Three(100 mL), washed with EtOAc (2 × 150 mL), Dried (Na_TwoSO_Four) And concentrated to give a brown oil. For recrystallization from MeOH Thus, H was obtained as white columnar crystals (11.2 g). Concentrate the mother liquor and flush Purified by chromatography (20% EtOAc / hexane) to give a colorless An oil was obtained, Et_TwoFurther purification by recrystallization from O gave H as white columnar crystals ( A total of 11.4 g (67% yield between two stages) was obtained. R_f= 0.32 (30 % EtOAc / hexane), mp 110-115 <0> C. Stage 3:Compound I   Isobutylamine (4.07 mL, 40.9 mmol), glacial acetic acid (2.28 m L, 39.8 mmol), aqueous formaldehyde (37%, 25.0 mL, 37 3 mmol) and 3 (10.38 g, 34.1 mmol) in MeOH (2 (00 mL) under reflux for 48 hours. The reaction was then concentrated and EtOA c (125 mL) and saturated NaHCO_Three(100 mL). Two-phase system And the aqueous layer was washed with additional EtOAc (2 × 100 mL). Combined Dry the organics (Na_TwoSO_Four), Concentrate, Et_TwoElute with O (50 mL), then , Filtered through silica gel, Et_TwoWashed with O (500 mL). The filtrate is concentrated to 4 As a colorless oil [13.2 g, 96%, Rf = 0.27 (25% EtOA) c / hexane)]. This material was used without further purification. Stage 4:Compound J   Until the solution is homogeneous, add ethanol to dichloromethane: water: ethanol (20 0 mL, 1: 2: 1). TLC reports that I has been consumed Sodium borohydride was added 1 g at a time until indicated (7 × 1.0 g). Reaction mixture Was cooled to 0 ° C. and acetone was added slowly until no gas evolved. next, The resulting mixture was poured into saturated NaCl (150 mL) and EtOAc (2 × 250 mL). Dry the organic layer (Na_TwoSO_Four), Concentrate and flash chroma Purified by chromatography (30% EtOAc / hexane) to give J and And K as a colorless oil (9.49 g, 72% yield). R_f= 0. 23 (30% EtOAc / hexane). Step Compound L:   A mixture of J and K (2.16 g, 5.3 mmol) in pyridine (40 mL) 1: 1) was added to chlorotriethylsilane (4.03 g, 4.48 mL, 26.7). mmol). 4-Dimethylaminopyridine (2 mg) was added, and the mixture was mixed. The mixture was heated at 60 ° C. for 4 hours. The reaction mixture is then concentrated and the residue is_TwoO ( 100 mL) and saturated NaHCO_Three(100 mL). Organic layer N Wash with saturated aCl solution, dry (Na_TwoSO_Four) And concentrated. The resulting oil Purified by flash chromatography (5% EtOAc / hexane) To give L as a colorless oil (1.14 g, 41% yield of desired isomer). R_f = 0.33 (10% EtOAc / hexane). Stage 6:Compound M   Diisobutylaluminum hydride (1.0 M in toluene, 2.91 mL, 2. 91 mmol) was cooled to −78 ° C. and L (753 mg) in toluene (10 mL) was cooled. , 1.45 mmol) at -78 ° C via cannula. Reaction mixture The mixture was stirred for 20 minutes and then acetone (5 mL) was cannulated with -78. Excess reagent was destroyed by addition at 0 ° C. Warm the mixture to 23 ° C. and add saturated potassium tartrate Poured into sodium (100 mL) and the resulting suspension was treated with EtOAc (2 × 100 m L). Dry the organic layer (Na_TwoSO_Four), Concentrate and mix L and M Was obtained as a colorless oil, and this mixture was azeotroped with toluene (2 × 40 mL). Dried and used without further purification (720 mg, M: L 3: 1). Mixture, 75% yield of M). R_f= 0.41 (50% EtOAc / hexane). Step 7: Compound N   Mixture of M and L in anhydrous THF (10 mL) (955 mg, 3: 1, 1. 45 mmol L) at −78 ° C. with benzylmagnesium chloride (4.75 mL). , 9.80 mmol, 2.06 M in THF) for 3 minutes. Reaction mixing The thing was warmed to 0 ° C. and kept at that temperature for 1 hour. Saturated NH_FourAdd Cl (5 mL) , The heterogeneous mixture to saturated NaHCO_Three(100 mL) and EtOAc (2 × 1 00 mL). Dry the organic layer (Na_TwoSO_Four), Concentrated and flash chromatographed (5% EtOAc / Hexane) to give the desired isomer N as a colorless oil (374 mg, 4 4%). R_f= 0.23 (10% EtOAc / hexane). Stage 8:Compound 16   Aqueous HCl (3N, 10 mL) was added to N (374 mg) in acetone (10 mL). , 0.64 mmol). The mixture was heated at 65 ° C. for 16 hours. 2 After cooling to 3 ° C, mix the reaction NaHCO_Three(75 mL). The biphasic system is treated with EtOAc ( 2 × 150 mL) and the combined organic layers were dried (Na_TwoSO_Four), Concentrate , 16 as a white solid (265 mg, 99%). R_f= 0.13 (30 % EtOAc / hexane), mp 138-141 <0> C. C₂₇H₃₅NO_Three・ 0.30H_TwoAnalysis on O: Calculated: C, 75.95; H, 8.40; N, 3.28. Found: C, 75.91; H, 8.30; N, 3.55. C₂₇H₃₅NO_ThreeHRMS for: Calculated value: 422.2695, measured value: 422.2693.                               Example 3 5 (RS) -methylphenyl-9 (RS) -hydroxy-1 (RS)-((1 ′ -Hydroxy) -2'-phenyl) ethyl-3-benzyl-3-azabicyclo [ 3.3.1] Nonan-7-one (Compound 18), Table II Stage 1:Compound S   Mixture of diols (162 mg, 0.396 mmol) and SO_Three・ Pirigi Complex (189 mg, 1.19 mmol) was dissolved in dry DMSO (4 mL) did. Next, triethylamine (0.34 mL) was added dropwise via a syringe. When the reaction was allowed to proceed for 1.5 hours, NH_FourPoured into a saturated solution of Cl. EtO aqueous phase Extract with Ac (2 × 50 mL). Combine organics and add H_TwoWash with O, NaCl , Dried (Na_TwoSO_Four). The extract was filtered and concentrated to an oil (147 mg) And used for the next step without purification. The crude mixture of hydroxyaldehyde is Dissolve in lysine (6 mL) and triethylsilyl chloride (0.34 mL, 20 mmol) and a catalytic amount of 4-dimethylaminopyridine (10 mg) Processed. The reaction proceeded at 60 ° C. for 16 hours. Allow reaction to cool to room temperature and remove volatiles It was removed on a rotary evaporator. Et the residue_TwoDiluted with O (75 mL), NaHCO_Three, H_Two Washed successively with O and NaCl. Organic matter is Na_TwoSO_FourDried and concentrated did. Flash chromatography (9: 1, hexane / EtOAc) This afforded the desired compound (S) as an oil (62 mg, 28%). Stage 2:Compound 18   Solution of benzylmagnesium chloride in THF (2.06 M, 0.2 mL) with the aldehyde S from step 1 (61 ml) in dry THF (1 mL). g, 0.109 mmol) at -78 ° C. Bring the reaction to -78 ° C for 1 . Stir for 5 h, then slowly warm to room temperature and remove excess Grignard with NH_FourCl sat Quenched with the sum solution. The reaction was diluted with EtOAc (60 mL) and NH_FourCl , Washed with NaCl, Na_TwoSO_FourAnd dried. Immediately add this material to THF / 1N Hydrolyzed in HCl (4: 1, 2.5 mL). Flash desired compound Purify by chromatography (1: 1 EtOAc / hexane), Et_Two Crystallized from O / hexane. 145.5-147 ° C. Low-resolution FAB mass spectrometry (M⁺+1) m / z 456. C₃₀H₃₃NO_Three・ 0.65H_TwoAnalysis on O: Calculated: C, 77.10; H, 7.40; N, 3.0. Found: C, 71.15; H, 7.24; N, 3.0.Example 4 5 (RS) -methylphenyl-9 (RS) -hydroxy-1 (RS)-((1 ′ -Hydroxy) -2 ′-(2 ′ ″-(tetrahydro-1,2-thiazine 1, 1-dioxide))-ethyl-3-benzyl-3-azabicyclo [3.3.1] Nonan-7-one (Compound 23), Table II Stage 1:Compound T   Trimethylsulfoxonium iodide (298 mg, 1.35 mmol), Na H (32 mg, 1.35 mmol) and D A solution of MF (4 mL) was stirred at 0 ° C. for 30 minutes. In DMF (0.5 mL) The solution of aldehyde S was added by syringe. With two washes of DMF (2 × 0.25 mL) to complete the addition. The reaction was stirred at 0 ° C. for 1 hour, H_FourQuenched with a saturated solution of Cl. The reaction was poured into NaCl, Et._TwoO (3 × 3 5 mL). Collect organic matter, H_TwoO, washed with NaCl, Na_TwoSO_Fourso Dried. Flash chromatography using 8: 1 hexane / EtOAc , The first diastereomer 68 mg and the second diastereomer 2 5 mg were obtained (both oily). Stage 2:Compound 23   NaH (8 mg, 60% by weight in mineral oil, 200 μmol) was added to N, N-dimethyl Tetrahydro-1,2-thiazine-1,1-dioxin in formamide (1 mL) Cid (34 mg, 250 μmol) was added to the solution and the resulting mixture was added at 23 ° C. for 3 hours. Stirred for 0 minutes. T in N, N-dimethylformamide (1 mL) (27 mg, (50 μmol) was added and the mixture was heated at 65 ° C. for 16 hours. Room for reactants Cooled to warm, NH_FourA Cl solution (2 mL) was added. The reaction mixture was washed with water (50 mL) And the resulting aqueous mixture is added to Et._TwoExtracted with O (2 × 50 mL). Combined The organic extract was washed with water (25 mL), dried (Na_TwoSO_Four), Concentrate and start A mixture of the substance and the desired product is obtained, and this mixture is used without further purification. Was.   The above crude reaction mixture (30 mg) in acetone (3 mL) The containing solution was treated with hydrochloric acid solution (3N, 3 mL) and the colorless solution was heated at 65 ° C. Heat for 12 hours. The reaction mixture was cooled to room temperature and saturated NaHCO_Three(25mL) Slowly poured into. The resulting suspension was washed with EtOAc (30 mL) and the organic layer Is dried (Na_TwoSO_Four), Concentrated to give a crude oil, flash chromatograph (70% EtOAc / hexane) to afford 23 as a white solid ( 15 mg (58% over two steps). R_f= 0.13 (70% EtOAc / Hexane), mp = 163-164 ° C. C₂₈H₃₆N_TwoSO_Five・ 0.80H_TwoAnalysis on O: Calculated: C, 63.81; H, 7.19; N, 5.31. Found: C, 63.81; H, 7.02; N, 5.18. C₂₈H₃₆N_TwoSO_FiveHRMS for: Calculated value: 513.2423; actual value: 513.22437.Example 5 5 (RS) -methylphenyl-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 A.Stage 1:  Solution of t-butyllithium in pentane (1.7 M, 3.00 mL, 5.1 0 mmol, 9.64 eq) was added to tert-butyl- in THF (3.5 mL). 2-methylcarbanilate (515 mg, 2.48 mmol, 4.69 equiv.) At -40 ° C. over 1 minute. I got it. The resulting bright yellow mixture was stirred at −40 ° C. for 15 minutes, then THF ( Solution of aldehyde U (300 mg, 0.529 mmol, 1 eq) in 4 mL) Was added. The resulting mixture was warmed to 0 ° C and maintained at that temperature for 15 minutes. Product Was diluted with pH 7 phosphate buffer (100 mL) and the resulting aqueous mixture was , Extracted with EtOAc (2 x 75 mL). The combined organic layers are_TwoSO_FourDry with And concentrated. Flash chromatography of the residue (5% E in hexane initially) tOAc, gradient to 20% ethyl acetate in hexane). Cole as a colorless oil (85 mg, 21%) and the undesired diastereomer The alcohol was obtained as a colorless oil (81 mg, 20%).TLC (20% EtOAC-hexane), R_f: Desired alcohol: 0.36 ( UV), undesired alcohol: 0.44 (UV).Stage 2 :   In a mixture of 3M aqueous HCl (10 mL) and acetone (10 mL), A solution of the ketal (80 mg, 0.11 mmol) was heated at 60 ° C. for 16 hours . After cooling to 23 ° C., the product solution was_ThreeUse a saturated aqueous solution (100 mL) Heavily diluted. The resulting aqueous mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with Na_TwoSO_FourAnd concentrated. Flash chromatography of the residue Chromatography (40% EtOAc in hexanes first, then 40% EtOAc in EtOAc) Purification of the product ketone with a colorless oil (31 mg, 67%). I got it. The product oil is removed with Et_TwoCrushed with O, white crystals A solid was obtained (melting point = 164-165 ° C.).High resolution MS (FAB): C₂₇H₃₆N_TwoO_ThreeCalculated value for [M + H]⁺: 437.2804, found: 437.2281. C₂₇H₃₆N_TwoO_ThreeAnalysis on Calculated: C, 74.28; H, 8.31; N, 6.42. Found: C, 74.28; H, 8.34; N, 6.52. TLC (40% EtOAc-hexane), R_f: 0.06.   The foregoing description of the specification, together with the examples set forth by way of illustration, illustrates the principles of the invention. It is taught, however, that the practice of the invention should be within the scope of the appended claims and their equivalents. Is understood to encompass all ordinary changes, adaptations, or modifications contained in And

────────────────────────────────────────────────── ─── Continuation of front page    (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, L U, MC, NL, PT, SE), OA (BF, BJ, CF) , CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, KE, LS, MW, S D, SZ, UG), EA (AM, AZ, BY, KG, KZ , MD, RU, TJ, TM), AL, AM, AU, AZ , BA, BB, BG, BR, BY, CA, CN, CU, CZ, EE, GE, HU, IL, IS, JP, KG, K R, KZ, LC, LK, LR, LT, LV, MD, MG , MK, MN, MX, NO, NZ, PL, RO, RU, SG, SI, SK, TJ, TM, TR, TT, UA, U S, UZ, VN, YU (72) Inventor Fraley, Mark E             New Jersey, United States             07065, Lowway, East Linker             N Avenue 126 (72) Inventors Holloway, M. Kyasarin             New Jersey, United States             07065, Lowway, East Linker             N Avenue 126 (72) Inventor Hanggate, Randall D'Abrillou             New Jersey, United States             07065, Lowway, East Linker             N Avenue 126 (72) Inventor: Plendergast, Christine             New Jersey, United States             07065, Lowway, East Linker             N Avenue 126

Claims (1)

[Claims] 1. formula: [In the formula:   X is -O-, -NH-, -NR^Four-Or -S-;   Y is ＝ O or, together with the carbon to which it is attached, Form;   Z is ＯO or, together with the carbon to which it is attached, Form;   R¹Is     a) H;     b) C_{1 ~Four}Alkyl;     c) C_{Three ~ 7}Cycloalkyl;     d) ants unsubstituted or substituted one or more times with hydroxy Tool;     e) CH_TwoR^FiveOr     f) 5- to 7-membered heterocycle And   R^TwoIs     a) C_{1 ~Four}Alkyl;     b) aryl unsubstituted or substituted with aryl;     c) CH_TwoR⁶Or     d) heterocycle And   R^ThreeIs     a) CH (OH) R⁷Or     b) CH (NH_Two) R⁷ And   R^FourIs     a) C_{1 ~Four}Alkyl;     b) C_{Three ~ 6}Cycloalkyl;     c) aryl unsubstituted or substituted with halo or unsubstituted C substituted or substituted one or more times with hydroxy_{1 ~Four}Alkyl Substituted aryl     d) CH_TwoR¹Or     e) 5-7 membered heterocycle And   R_FiveIs     a) C_{1 ~Four}Alkyl; or     b) aryl And   R⁶Is     a) C_{1 ~Four}Alkyl;     b) aryl, unsubstituted or substituted with halo, or unsubstituted C substituted or substituted one or more times with hydroxy_{1 ~Four}Alkyl Substituted aryl; or     c) 5-7 membered heterocycle And   R⁷Is     a) H;     b) C_{1 ~Four}Alkyl;     c) unsubstituted or amino-substituted aryl;     d) unsubstituted or amino-substituted C_{1 ~ 3}Alkylaryl; also Is     e) 5-7 membered heterocycle Is] Or a pharmaceutically acceptable salt thereof. 2. formula: [In the formula:   R^TwoIs C_{1 ~Four}Alkylene-aryl,   R^FourIs an unsubstituted or aryl-substituted C_{1 ~Four}Is alkyl or C_{Three ~ 6} Cycloalkyl or 5-7 membered heterocycle And   R⁷Is H, unsubstituted or amino-substituted benzyl] Or a pharmaceutically acceptable salt thereof. 3. formula:Or a pharmaceutically acceptable salt thereof. 4. formula: Or a pharmaceutically acceptable salt thereof. 5. A compound according to any one of claims 1 to 4, and a pharmaceutical. A pharmaceutical composition comprising a pharmaceutically acceptable carrier. 6. Delaying the onset of AIDS, preventing HIV infection, treating HIV infection, or HI The medicament according to any one of claims 1 to 4, for use in inhibiting V protease. Composition. 7. A method for treating AIDS and delaying the onset of AIDS, wherein the method comprises the steps of: Administering to a mammal in need of such treatment an effective amount of a compound described in A method comprising: 8. A method for preventing infection by HIV, wherein the method according to any one of claims 1 to 4. Administering to a mammal in need of such treatment an effective amount of the compound. How to become. 9. A method for treating infection by HIV, according to any one of claims 1 to 4. Administering to a mammal in need of such treatment an effective amount of the compound. How to become. 10. A method for inhibiting HIV protease, comprising the steps of: Administering to a mammal in need of such treatment an effective amount of the indicated compound. The method that consists of. 11. Compound A and (-) 6-chloro-4 (S) -cyclopropylethynyl- 4 (S) -trifluoromethyl-1,4-dihydro-2H-3,1-benzooxy Sagin-2-one, and A combination of compounds, optionally with AZT or ddI or ddC. 12. Compound A or B with either AZT or ddI or ddC , A combination of compounds. 13. Chemical compound B and (-) 6-chloro-4 (S) -cyclopropylethynyl- 4 (S) -trifluoromethyl-1,4-dihydro-2H-3,1-benzooxy Compounds with sadin-2-one, and optionally with AZT or ddI or ddC Combinations.