WO1992021647A1 - Carbocyclic and heterocyclic hiv protease inhibitors - Google Patents
Carbocyclic and heterocyclic hiv protease inhibitors Download PDFInfo
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- WO1992021647A1 WO1992021647A1 PCT/US1992/004705 US9204705W WO9221647A1 WO 1992021647 A1 WO1992021647 A1 WO 1992021647A1 US 9204705 W US9204705 W US 9204705W WO 9221647 A1 WO9221647 A1 WO 9221647A1
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- 0 *C(Cc1ccccc1)(CS(CC1(Cc2ccccc2)CO)(=O)=O)C1O Chemical compound *C(Cc1ccccc1)(CS(CC1(Cc2ccccc2)CO)(=O)=O)C1O 0.000 description 1
- MSSITLCKEXWWIT-UHFFFAOYSA-N OCC(Cc1ccccc1)(CS(CC1(Cc2ccccc2)CO)=O)C1O Chemical compound OCC(Cc1ccccc1)(CS(CC1(Cc2ccccc2)CO)=O)C1O MSSITLCKEXWWIT-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/46—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings substituted on the ring sulfur atom
- C07D333/48—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings substituted on the ring sulfur atom by oxygen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C35/21—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a non-condensed ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
- C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
- C07C45/59—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom in five-membered rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
- C07C49/747—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups containing six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
Definitions
- This invention relates to non-peptide inhibitors of proteases encoded in retroviruses, in particular, to inhibitors of the virally encoded protease of the Human Immunodeficiency Virus.
- Retroviruses that is, viruses within the family of Retroviridae, are a class of viruses which transport their genetic material as ribonucleic acid rather than deoxyribonucleic acid. Also known as RNA-tumor viruses, their presence has been associated with a wide range of diseases in humans and animals.
- Rous sarcoma virus RSV
- MLV urine leukemia virus
- MMTV mouse mammary tumor virus
- FeLV feline leukemia virus
- BLV bovine leukemia virus
- MPMV ason-Pfizer monkey virus
- SSV simian sarcoma virus
- SAIDS simian acquired immunodeficiency syndrome
- HSV human T- lymphotropic virus
- HTLV-I, -II human immunodeficiency virus
- HIV-1 HIV-1, HIV-2
- the pathogens have, in many of these cases, been isolated, no effective method for treating this type of infection has been developed.
- retroviruses which lack a protease or contain a mutated form of it, lack infectivity. See Katoh et al . r Virology, 145, 280-92(1985), Crawford, et al . , J. Virol . , 53, 899-907(1985) and Debouck, et al . , Proc Natl . Read. Sci . USA, 84, 8903-6(1987). Inhibiton of retroviral protease, therefore, presents a method of therapy for retroviral disease.
- This invention comprises compounds, hereinafter, of the formula (I), which inhibit the retroviral protease of HIV-1, and are useful for treating Acquired Immunodeficiency Syndrome (AIDS) .
- This invention is also a pharmaceutical composition, which comprises a compound of formula (I) and a pharmaceutically acceptable carrier.
- This invention further constitutes a method for treating retroviral disease, which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) •
- R l and R 4 are OH, (CHR 5 ) m COR6, (CHR 5 ) m CH(OH)R 5 or R 5 ;
- R2 and R3 are H, Ci- ⁇ alkyl, Het, C3_ ⁇ ocycloalkyl, Het- Ci- ⁇ alkyl, C2-8alkenyl, Het-C 2 -8alkenyl, C3- ⁇ ocycloalkyl- Ci- ⁇ alkyl or C3_ ⁇ ocycloalkyl-C2-8alkenyl;
- R5 is R2 or R2 mono- or di-substituted by G;
- R7 is H, CN, COR' or S02R';
- R' is H, C ⁇ -6alkyl, C3_ ⁇ ocycloalkyl or C ⁇ _8alkylC3_ ⁇ ocycloalkyl;
- R" is R', COR « , C(0)OR' or CON(R') 2 ;
- G is OR 1 , OC(0)R ? , OC(0)N(R')2, halogen, COR ⁇ , NR'-AA, NHCOR', S0 2 N(R * )2.
- NHS0 2 N(R')2, NHC( NR 7 )NHR", CF3 or N(R') 2 ;
- AA is one or two amino acids;
- Q is CHOH, S, SO or SO2; m is 0, 1 or 2; n is 0 or 1; or pharmaceutically acceptable salts thereof, provided that:
- Ri - R 4 are not simultaneously chosen from the group of H, OH and C ⁇ -4alkyl, and
- i and R2 are not simultaneusly H.
- Ri and R 4 are not H.
- n is 0 or 1.
- n is 1.
- R3 are C3- ⁇ ocycloalkyl-C ⁇ _6alkyl.
- R2 and R3 are benzyl.
- Ri and R 4 are OH, CO2R', C2-salkenyl, (CHR5) m CH(OH)R 5 or R 2 mono- or di-substituted by G.
- Ri and R 4 are OH, CH 2 OH or (CHR5) m CH(OH)R 5 .
- Ri and R 4 are the same, and R2 and R3 are the same.
- i and R 4 are in a trans configuration relative to one another.
- Q is CHOH or SO2.
- Q is CHOH.
- Certain representative compounds of this invention are: trans,trans,trans-2, 6-dibenzyl-2, 6-bis(methoxycarbonyl) 1,4- cyclohexanediol; trans,trans,trans-2, 6-dibenzyl-2, 6-bis(hydroxymethyl)-1,4- cyclohexanediol; trans,trans,cis-2, 6-dibenzyl-2,6-bis(hydroxymethyl)-1,4- cyclohexane-diol; trans,trans-2, 6-dibenzyl-2, 6-bis(hydroxymethyl)-4-oxo-l- cyclohexanol; 1,2,6-trihydroxy-2, 6-dibenzyl, -cyclohexanone; trans,trans-2,5-dibenzyl-2,5-bis(hydroxymethyl)-1- cyclopentanol; trans,trans-2-5-dibenzyl-2,5-bis-(hydroxymethyl)- tetrahydrothiophene-1,1-di
- Preferred compounds of this invention are 1,2,6-trihydroxy- 2,6-dibenzyl,4-cyclohexanone; 4-hydroxy-3,5-dibenzyl-3,5- bis(hydroxymethyl)-tetrahydrothiopyran-1-oxide; and 4-hydroxy-3,5-dibenzyl-3-hydroxymethyl-5-(l-hydroxy-4- methylpentyl) tetrahydrothiopyran-1-oxide.
- Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vivo.
- the compounds of this invention have favorable pharmacokinetic properties, and are useful, in particular, for the treatment of infections by the human immunodeficiency virus.
- the definition of any substituent moiety which may occur more than once in formula (I) is independent of any other occurrence.
- Formula (I) is intended to encompass all unique nonracemic-stereoisomers which may occur due to the presence of asymmetric carbon atoms in the molecule.
- Ar, or aryl, as applied herein, means phenyl or naphthyl, or phenyl or naphthyl substituted by one to three C ⁇ - 4 alkyl, C ⁇ - 4 alkoxy, C ⁇ _ 4 alkthio, trifluoroalkyl, OH, Cl, Br or I.
- Het, or heteroaryl indicates a five or six membered aromatic ring, or a nine or ten-membered aromatic ring containing one to three heteroatoms chosen from the group of nitrogen, oxygen and sulfur, which are stable and available by conventional chemical synthesis.
- Illustrative heterocycles are imidazole, benzimidazole, pyrrole, indole, pyridinyl, quinoline, benzofuryl, furyl, benzopyranyl, benzothiophene or thiophene. Any accessible combination of up to three substituents on the phenyl, naphthyl or Het ring which is available by chemical synthesis and is stable are within the scope of this invention.
- C 3 _ ⁇ ocycloalkyl refers to a carbocyclic system of three to ten carbon atoms, which may be monocyclic or bicyclic and contain up to five unsaturated carbon-carbon bonds, which may be substituted with one or more of halogen, hydroxy, amino, C ⁇ _ 4 alkyl, C ⁇ _ 4 alkylcarbonyl, C ⁇ - 4 alkoxycarbonyl, C ⁇ _ 4 alkylaminocarbonyl, C ⁇ - 4 alkylthio, C ⁇ - 4 alkyloxy or trifluromethyl groups.
- C 3 _ ⁇ ocycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, indanyl, indenyl, phenyl and naphthyl.
- Boc refers to the t-butyloxycarbonyl radical
- Cbz refers to the benzyloxycarbonyl radical
- Bzl refers to the benzyl radical
- Ac refers to acetyl
- Ph refers to phenyl
- EDTA is ethylenediamine tetraacetic acid
- DIEA diisopropyl ethylamine
- DMF dimethyl formamide
- THF tetrahydrofuran.
- C-*__galkyl as applied herein is meant to include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl and hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, and 1-ethylbutyl.
- C2-6alkenyl as applied herein means C2-6 ⁇ 1kyl wherein one carbon-carbon single bond is replaced by a carbon-carbon double bond.
- Ar-C- ⁇ -galkyl and Ar-C2-6alkenyl mean C ⁇ -galkyl or C2-6 a l ⁇ en yl wherein a carbon-hydrogen bond is replaced by a carbon-Ar bond.
- Het-Ci-galkyl and Het-C2-6alke yl mean C ⁇ _galkyl or
- C 3 - ⁇ ocycloalkylC ⁇ - 6 alkyl means a Ci- ⁇ alkyl wherein a carbon-hydrogen bond is replaced by a carbon- C 3 - ⁇ ocycloalkyl bond.
- AA as used herein indicates one or two amino acids, which may be:
- AA is two amino acids
- the amino acids are joined by an amide bond, via the amino terminus of one amino acid and the carboxy terminus of the other, to yield a di- or tri-peptide substituent.
- G is CO-AA
- the amino acid, dipeptide or tripeptide is coupled via its amino terminus to the CO group, and the carboxy terminus of the amino acid/peptide may be a carboxyl, carboxamide or ester group (eg. CO 2 H, C0 2 ' or CONR' 2 ) .
- the amino acid, dipeptide or tripeptide is coupled via its carboxy terminus to the N(R') 2 group, and the amino terminus of the amino acid/peptide may be an alkyl, acyl or Ci-galkyl- or aryl-oxycarbonyl amino group (eg. R', R'CO or R'OCO) .
- the compounds of this invention are prepared by conventional methods of organic chemistry. Representative methods for preparing the compounds of formula (I) wherein n is 1, Q is CHOH, and Ri and R 4 are CH(OH)Rs, C ⁇ R' or CON(R') 2 are illustrated in Schemes 1-3.
- a suitably Z-protected cyclohexanone is functionalized alternately in the 2-position and the 6-position, by base-catalysed nucleophilic addition of an appropriate electrophile to introduce the carboalkoxy or hydroxyl-containing groups Ri and R 4 , such as methyl cyanoformate, methyl formate, an acyl halide, such as 4- methyl pentanoyl chloride, or an aldehyde, such as 4- methylpentanal, and an electrophile to introduce the group R 2 and R3, such as an alkyl or aralkyl halide, such as benzyl bromide . Subsequent reduction and deprotection, and optionally further reduction, provides the desired compounds .
- an appropriate electrophile to introduce the carboalkoxy or hydroxyl-containing groups Ri and R 4 , such as methyl cyanoformate, methyl formate, an acyl halide, such as 4- methyl pentanoyl chloride, or an
- Cyclopentanol-type compounds wherein n is 0, are prepared in an analogous manner, starting with cyclopentanone or a suitably protected 3-substituted cyclopentanone derivative.
- p-TSA p-toluenesulfonic acid
- MCPBA m-chloroperbenzoic acid
- oxidation state of the sulfur moiety is readily controlled by oxidation methods well known in the art.
- sulfoxides may be prepared from oxidation of the corresponding sulfide by one equivalent of sodium metaperiodate, while 2 equivalents of m-chloroperbenzoic acid or periodate may be used to prepare the corresponding sulfone.
- Starting the reaction sequence with sulfolane yields the corresponding cyclopentyl product wherein Z is CH 2 .
- the oxidation state of the sulfur is controlled via conventional methods for selective oxidation of the sulfur moiety .
- an acid addition salt may be prepared.
- Acid addition salts of the compounds are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, maleic, succinic or methanesulfonic. The acetate salt form is especially useful.
- cationic salts may be prepared.
- the parent compound is treated with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation. Cations such as Na + , K + , Ca ++ and NH + are examples of cations present in pharmaceutically acceptable salts. Certain of the compounds form inner salts or zwitterions which may also be acceptable.
- the compounds of formula (I) are used to inhibit the endogenous protease enzyme of viruses, especially retroviruses.
- these compounds have been shown to inhibit the endogenous protease of the human immunodeficiency virus.
- These compounds further have an anti-viral effect and reduce viral infectivity in cell culture. As such they are believed to induce anti-viral activity in patients which are infected with susceptible viruses and require such treatment.
- the method of treatment comprises the administration orally, parenterally, buccally, trans-dermally, intra-vaginally, rectally or by insufflation, of an effective quantity of the chosen compound, preferably dispersed in a pharmaceutical carrier.
- Dosage units of the active ingredient are generally selected from the range of 0.1 to 25 mg/kg, but will be readily determined by one skilled in the art depending upon the route of administration, age and condition of the patient. These dosage units may be administered one to ten times daily for acute or chronic infection.
- the compounds of this invention are particularly useful for the treatment of HIV-1.
- the compounds of formula (I) are useful in the manufacture of a medicament, particularly a medicament for the treatment of retroviral infections, such as infection by the human immunodeficiency virus.
- Pharmaceutical compositions of the compounds of this invention, or derivatives thereof may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
- the liquid formulation is generally a buffered, isotonic, aqueous solution.
- suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution.
- Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
- a composition for parenteral administration may additionally be comprised of a quantity of the compound encapsulated in a liposomal carrier.
- the liposome may be formed by dispersion of the compounds in an aqueous phase with phospholipids, with or without cholesterol, using a variety of techniques, including conventional handshaking, high pressure extrusion, reverse phase evaporation and microfluidization.
- a carrier may be optionally directed toward its site of action by an immunoglobulin or protein reactive with the viral particle or infected cells. The choice of such proteins would of course be dependent upon the antigenic determinants of the infecting virus.
- An example of such a protein is the CD-4 T-cell glycoprotein, or a derivative thereof, such as sCD-4 (soluble CD-4) , which is reactive with the glycoprotein coat of the human immunodeficiency virus (HIV) .
- these compounds may be encapsulated, tableted or prepared in an emulsion or syrup for oral administration.
- Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
- Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline and water.
- Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
- the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
- the amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit.
- the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
- a liquid carrier When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension.
- Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
- a pulverized powder of the compounds of this invention may be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
- the pulverized powders may also be compounded with an oily preparation, gel, cream or emulsion, buffered or unbuffered, and administered through a transdermal patch.
- Beneficial effects may be realized by co-administering, individually or in combination, other anti-viral agents with the protease inhibiting compounds of this invention.
- anti-viral agents include nucleoside analogues, phosphonoformate, rifabutin, ribaviran, phosphonothioate oligodeoxynucleotides, castanospermine, dextran sulfate, alpha interferon and ampligen.
- Nucleoside analogues which include 2 ' ,3 '-dideoxycytidine (ddC) , 2 ' ,3'-dideoxyadenine (ddA) and 3'-azido-2 ' ,3'-dideoxythymide (AZT) , are especially usef l.
- AZT is one preferred agent .
- pharmaceutical compositions comprise an anti-viral agent, a protease inhibiting compound of this invention and a pharmaceutically acceptable carrier. The protease inhibiting properties of the compounds of this invention, are demonstrated by their ability to inhibit the hydrolysis of a peptide substrate by rHIV protease in the range of about 1 ⁇ M to about 2 mM.
- HIV protease activity The ability of the compounds of this invention to inhibit the HIV-1 protease enzyme may be demonstrated by using the assay disclosed by Dreyer et al . , Proc. Natl . Acad. Sci . , U. S.A. , 86, 9752 (1989), Grant et al . , Biochemistry, 30 8441 (1992), and EP-A 352 000.
- Preferred compounds have Ki's of less than 25 ⁇ M.
- Tnh-ih-i ion of Viral Infectivitv The ability of the compounds of this invention to gain entry to cells infected with the human immunodeficiency virus, and to inhibit viral replication in vitro may be demonstrated using the assay described by Meek et al . , Nature, 343, 90 (1990), and Petteway et al . , Trends Pharmacol . Sci, 12, 28 (1991) .
- the compound of Example 6 showed an IC50 for inhibition of viral infectivity in the above assay of less than 100 ⁇ M.
- FAB indicates fast atom bombardment mass spectrometr .
- FAB mass spectra were performed upon a VG Zab mass spectrometer using fast atom bombardment.
- ESMS indicates electrospray ionization mass spectrometry.
- Lithium bistrimethylsilylamide (116 mL, 1M in THF, 116 mmol) was added to THF (400 mL) and cooled in a dry-ice acetone bath. To this solution was added 4,4- ethylenedioxycyclohexanone (15.6 g, 100 mmol) in THF (100 mL) over a period of 15 min. The reaction mixture was allowed to warm to 0°C over a period of 2 h. The temperature was lowered again to -78° C, HMPA (917.9 g, 100 mmol) was added, followed by methylcyanoformate (9.35 g, 110 mmol) .
- ketodiester ⁇ (37.5 mg) in methanol (3 mL) was added sodium borohydride (25 mg) .
- the reaction mixture was stirred at room temperature for 3 h, quenched with water, filtered through celite, washed with ether and the solvents were removed in vacuo to give the titled compound £ as a colorless solid (31.5 mg, 84%) .
- ketodiester ⁇ (76 mg, 0.168 mmol) in THF (3 mL) was added lithium aluminumhydride (IM solution in ether, 1.8 mL, 1.8 mmol).
- IM solution in ether 1.8 mL
- methanol/water aqueous ethanol
- Diepoxide 12 (40 mg, 0.11 mmol) was dissolved in tetrahydrofuran (5 mL) , cooled in an ice bath and lithiumaluminium hydride (1 mL, IM in THF, 1 mmol) was added and allowed to react overnight.
- the reaction mixture was quenched with sodium hydroxide (10%, 100 mL) , diluted with ether (50 mL) , and filtered through celite. The filter cake was washed with ethyl acetate and the combined organic extracts were concentrated in vacuo. Flash chromatography (silica, 2% methanol/methylene chloride) yielded the title compound' l ⁇ (10 mg) .
- step (7a) The product of step (7a) (2.28 g, 10 mmol) was added to a slurry of 100 mmol NaH in THF (50 ml) .
- Benzyl bromide (5.9 ml, 50 mmol) was added and the mixture was stirred under Ar for 20 hr.
- the mixture was poured into cold 0.3 N HCl (300 ml), then extracted with ethyl acetate (3 x 150 ml) .
- Concentration of the organic layer and flash chromatography of the residue (silica gel, gradient elution, 0% - 4% ethyl acetate/hexane) provided the title compound (2.15 g, 53%).
- MS (CI/NH 3 ) m/z 409 ( +H)+.
- step (7b) trans-2.5-bis(ethoxycarbonyl)-2.5-dibenzyl-l- cyclopentano. _2i
- the product of step (7b) (309 mg) was reacted with aBH 4
- step (7c) trans,trans-2,5-dibenz ⁇ l-2 r 5-bis (ethoxycarbonyl)-1- benzyloxy-cyclopentane 22
- step (7c) (494 mg, 1.2 mmol) was added to a mixture of NaH (3 mmol) and benzyl bromide (0.6 ml, 5 mmol) in THF (2 ml) at 5°C. The mixture was stirred with warming to 25°C over 5 h, poured into 0.3N HCl (10 ml), and extracted with ethyl acetate (3 x 25 ml) .
- step (7d) To a solution of the product of step (7d) (250 mg, 0.50 mmol) in methylene chloride (2.5 ml) at -30°C under Ar was added diisobutylaluminum hydride (4 mmol) in toluene (4 ml) . The solution was stirred 45 min, then water (1 ml) was added. After 5 min the mixture was diluted with methylene chloride and filtered through Celite. The filtrate was washed with water, dried over sodium sulfate, and concentrated to provide the title compound (200 mg, 96%) .
- the reaction was cooled in ice and quenched with water (35 mL) and extracted with ethyl acetate (35 mL) .
- the ethyl acetate was washed with water and brine, dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure.
- the resultant oil was purified by flash column chromatography (silica gel, 19:1 hexane:ethyl acetate) to yield the title compound as an oil (1.90 g, 59%) .
- composition which contains 25 mg of a compound of this invention is prepared as follows:
- 25 mg of the compound is dissolved in 15 mL of distilled water.
- the solution is filtered under sterile conditions into a 25 mL multi-dose ampoule and lyophilized.
- the powder is reconstituted by addition of 20 L of 5% dextrose in water(D5W) for intravenous or intramuscular injection. The dosage is thereby determined by the injection volume.
- This solution is also suitable for use in other methods for administration, such as addition to a bottle or bag for IV drip infusion.
- a capsule for oral administration is prepared by mixing and milling 200 mg of the compound with 450 mg of lactose and 30 mg of magnesium stearate. The resulting powder is screened and filled into a hard gelatin capsule.
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP92914474A EP0641306A1 (en) | 1991-06-04 | 1992-06-04 | Carbocyclic and heterocyclic hiv protease inhibitors |
JP5500653A JPH06508146A (en) | 1991-06-04 | 1992-06-04 | Carbocyclic and heterocyclic HIV protease inhibitors |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US71073491A | 1991-06-04 | 1991-06-04 | |
US710,734 | 1991-06-04 |
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WO1992021647A1 true WO1992021647A1 (en) | 1992-12-10 |
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PCT/US1992/004705 WO1992021647A1 (en) | 1991-06-04 | 1992-06-04 | Carbocyclic and heterocyclic hiv protease inhibitors |
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EP (1) | EP0641306A1 (en) |
JP (1) | JPH06508146A (en) |
WO (1) | WO1992021647A1 (en) |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0617968A1 (en) * | 1993-03-31 | 1994-10-05 | Merck & Co. Inc. | HIV protease inhibitors in pharmaceutical combinant for the treatment of AIDS |
US5508400A (en) * | 1994-04-20 | 1996-04-16 | The Du Pont Merck Pharmaceutical Company | Preparation of cyclic urea compounds |
US5559110A (en) * | 1994-03-09 | 1996-09-24 | The Dupont Merck Pharmaceutical Company | Pharmaceutical formulations of cyclic urea type compounds |
US5610294A (en) * | 1991-10-11 | 1997-03-11 | The Du Pont Merck Pharmaceutical Company | Substituted cyclic carbonyls and derivatives thereof useful as retroviral protease inhibitors |
US5616578A (en) * | 1993-08-26 | 1997-04-01 | The Dupont Merck Pharmaceutical Company | Method of treating human immunodeficiency virus infection using a cyclic protease inhibitor in combination with a reverse transcriptase inhibitor |
US5683999A (en) * | 1995-03-17 | 1997-11-04 | The Dupont Merck Pharmaceutical Company | Cyclic urea HIV protease inhibitors |
US5705524A (en) * | 1994-11-04 | 1998-01-06 | Gilead Sciences, Inc. | Thiepane compounds |
US5763469A (en) * | 1995-08-22 | 1998-06-09 | The Dupont Merck Pharmaceutical Company | Substituted cyclic ureas and derivatives thereof useful as retroviral protease inhibitors |
US5990341A (en) * | 1993-11-08 | 1999-11-23 | Emory University | Diastereoselective synthesis hydroxyethylene dipeptide isosteres |
US6034118A (en) * | 1994-11-04 | 2000-03-07 | Gilead Sciences, Inc. | Thiepane compounds |
US6313110B1 (en) | 1999-06-02 | 2001-11-06 | Dupont Pharmaceuticals Company | Substituted 2H-1,3-diazapin-2-one useful as an HIV protease inhibitor |
USRE37781E1 (en) | 1991-10-11 | 2002-07-02 | Dupont Pharmaceuticals Company | Substituted cyclic carbonyls and derivatives thereof useful as retroviral protease inhibitors |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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EP0402646A1 (en) * | 1989-05-23 | 1990-12-19 | Abbott Laboratories | Retroviral protease inhibiting compounds |
-
1992
- 1992-06-04 EP EP92914474A patent/EP0641306A1/en not_active Withdrawn
- 1992-06-04 WO PCT/US1992/004705 patent/WO1992021647A1/en not_active Application Discontinuation
- 1992-06-04 JP JP5500653A patent/JPH06508146A/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0402646A1 (en) * | 1989-05-23 | 1990-12-19 | Abbott Laboratories | Retroviral protease inhibiting compounds |
Non-Patent Citations (5)
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Bulletin de la Société Chimique de France, no. 4, April 1972 (Paris, FR) J.-M. Bec et al.: "Etude du dioxo-2,4' dicyclohexylméthane et de ses produits de réduction", pages 1627-1636, see compound 22 * |
Chemical Abstracts, vol. 57, no. 5, 3 September 1962, (Columbus, Ohio, US) R.D. Obolentsev et al.: "Synthesis of cis-2,5-dibenzylthiophane", see column 5870a, & Khim. Sera-Organ, Soedin., Soderzhashch. v. Neft.i. Nefteprod., Akad. Nauk SSSR Bashkirsk. Filial 4, 20-3 (1961) * |
Journal of Medicinal Chemistry, vol. 17, no. 12, December 1974, (Washington, DC, US) I.H. Hall et al.: "Cycloalkanones. 4. Antifertility activity", pages 1253-1257, see compounds 21,22 * |
Journal of the American Chemical Society, vol. 96, no. 14, 10 July 1974, (Washington, DC, US) J.M. Photis et al.: "Lithium aluminum hydride promoted ring contraction of cyclic five-membered alpha-sulponyl carbanions and its application to the synthesis of 1,2-dialkylcyclobutenes", pages 4715-4717, see page 4716, compounds 19,20 * |
Tetrahedron, vol. 34, no. 1, January 1978 (Oxford, GB) M.-M. Claudon et al.: "Effet stérique sur les vitesses de transfert protonique: cyclohexanols substitués dans le diméthylsulfoxide", pages 95-100; see table 3, compounds B3-B8 * |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6503898B1 (en) | 1991-10-11 | 2003-01-07 | Bristol-Myers Squibb Pharma Company | Substituted cyclic carbonyls and derivatives thereof useful as retroviral protease inhibitors |
US5610294A (en) * | 1991-10-11 | 1997-03-11 | The Du Pont Merck Pharmaceutical Company | Substituted cyclic carbonyls and derivatives thereof useful as retroviral protease inhibitors |
USRE37781E1 (en) | 1991-10-11 | 2002-07-02 | Dupont Pharmaceuticals Company | Substituted cyclic carbonyls and derivatives thereof useful as retroviral protease inhibitors |
WO1994022480A1 (en) * | 1993-03-31 | 1994-10-13 | Merck & Co., Inc. | Hiv protease inhibitors in pharmaceutical combinations for the treatment of aids |
EP0617968A1 (en) * | 1993-03-31 | 1994-10-05 | Merck & Co. Inc. | HIV protease inhibitors in pharmaceutical combinant for the treatment of AIDS |
US5616578A (en) * | 1993-08-26 | 1997-04-01 | The Dupont Merck Pharmaceutical Company | Method of treating human immunodeficiency virus infection using a cyclic protease inhibitor in combination with a reverse transcriptase inhibitor |
US5990341A (en) * | 1993-11-08 | 1999-11-23 | Emory University | Diastereoselective synthesis hydroxyethylene dipeptide isosteres |
US5559110A (en) * | 1994-03-09 | 1996-09-24 | The Dupont Merck Pharmaceutical Company | Pharmaceutical formulations of cyclic urea type compounds |
US5508400A (en) * | 1994-04-20 | 1996-04-16 | The Du Pont Merck Pharmaceutical Company | Preparation of cyclic urea compounds |
US5705524A (en) * | 1994-11-04 | 1998-01-06 | Gilead Sciences, Inc. | Thiepane compounds |
US6034118A (en) * | 1994-11-04 | 2000-03-07 | Gilead Sciences, Inc. | Thiepane compounds |
US5683999A (en) * | 1995-03-17 | 1997-11-04 | The Dupont Merck Pharmaceutical Company | Cyclic urea HIV protease inhibitors |
US5763469A (en) * | 1995-08-22 | 1998-06-09 | The Dupont Merck Pharmaceutical Company | Substituted cyclic ureas and derivatives thereof useful as retroviral protease inhibitors |
US6313110B1 (en) | 1999-06-02 | 2001-11-06 | Dupont Pharmaceuticals Company | Substituted 2H-1,3-diazapin-2-one useful as an HIV protease inhibitor |
Also Published As
Publication number | Publication date |
---|---|
EP0641306A1 (en) | 1995-03-08 |
JPH06508146A (en) | 1994-09-14 |
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