WO1994017096A1 - Peptides ayant une activite anti-vih - Google Patents

Peptides ayant une activite anti-vih Download PDF

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Publication number
WO1994017096A1
WO1994017096A1 PCT/US1994/000330 US9400330W WO9417096A1 WO 1994017096 A1 WO1994017096 A1 WO 1994017096A1 US 9400330 W US9400330 W US 9400330W WO 9417096 A1 WO9417096 A1 WO 9417096A1
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Prior art keywords
formula
compound
compounds
converted
pharmaceutically acceptable
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PCT/US1994/000330
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English (en)
Inventor
Frank Bennett
Viyyoor M. Girijavallabhan
Naginbhai M. Patel
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Schering Corporation
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Priority to US08/491,854 priority Critical patent/US5693815A/en
Priority to AU61617/94A priority patent/AU6161794A/en
Publication of WO1994017096A1 publication Critical patent/WO1994017096A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C247/08—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated
    • C07C247/10—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated and containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/28—Cinnolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/021—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
    • C07C2603/24—Anthracenes; Hydrogenated anthracenes

Definitions

  • the invention relates to compounds of the formula
  • Z is H or Z and Q taken together are -(CH 2 ) 3 - or -(CH 2 ) 4 - U is
  • R 20 is H or C 1 -10 -alkyl; and Ac is formyl or
  • R 21 is C 1-10 alkyl
  • n 0, 1 or 2;
  • p 0, 1 , or 2;
  • q 0, 1 , or 2;
  • R 2 is NH tBu or NHPh.
  • alkyl denotes straight or branched saturated hydrocarbons which contain from 1 to 12 carbon atoms. Representative examples include methyl, butyl, isobutyl, isoamyl, and the like.
  • C 1 -C 7 alkyl refers to an alkyl which may have one to seven carbon atoms.
  • Alkoxy denotes -O-alkyl wherein alkyl is as described above.
  • Ph denotes phenyl.
  • Ms denotes mesyl.
  • Halogen denotes chlorine, fluorine or bromine, and iodine.
  • a bold faced line denotes a bond that comes up above the plane of the page.
  • a dashed line denotes a bond that goes down below the plane of the page.
  • Exemplary compounds of the invention include:
  • the chemical names for these compounds are 1 -[(1 ,1 - dimethylethoxy)carbonyl]-N-[3-[[2-[[(1 ,1 - dimethylethyl)amino]carbonyl]phenyl]thio]-2(R and/or S)-hydroxy-1 (R and/or S)-(phenylmethyl)-propyl] octahydroindole-2-carboxamide.
  • the present invention includes within its scope, all possible stereoisomers of the formula U' set forth above.
  • the most preferred compound of the invention is:
  • the invention also relates to a pharmaceutical composition which comprises a compound of formula I in combination with a
  • the invention also relates to a method for treating AIDS which comprises administering to a patient in need of such treatment an anti-HIV effective amount of a compound of formula I.
  • the compounds of formula I, and all the other compounds of the invention, are also active against retroviruses including HIV; and also inhibit the action of renin and are therefore believed to active against hypertension.
  • retroviruses against which the compounds of the invention are active include the retrovirus which causes feline AIDS, and the retrovirus which causes Rous' sarcoma which is a disease of chickens.
  • the two intermediate compounds shown just below are also active against retroviruses including HIV; and also inhibit renin and are therefore believed to active against hypertension.
  • the synthesis of these intermediate compounds is set forth herein.
  • the compounds of formula I can exist in unsolvated as well as solvated forms, including hydrated forms, e.g. the hemihydrate.
  • solvated forms including hydrated forms, e.g. the hemihydrate.
  • pharmaceutically acceptable solvents such as water, ethanol, and the like are equivalent to the unsolvated forms for the purposes of the invention.
  • the compounds of formulas I form pharmaceutically acceptable salts.
  • the preferred pharmaceutically acceptable salts are nontoxic, acid addition salts formed by adding to a compound of the invention about a stoichiometric amount of a mineral acid such as HCI, HBr, H 2 SO 4 , or H 3 PO 4 or of an organic acid such as acetic acid, propionic, valeric, oleic, palmitic, stearic, lauric, benzoic, lactic, paratoluenesulfonic, methane sulfonic, citric, maleic, fumaric, succinic and the like, respectively.
  • a mineral acid such as HCI, HBr, H 2 SO 4 , or H 3 PO 4
  • organic acid such as acetic acid, propionic, valeric, oleic, palmitic, stearic, lauric, benzoic, lactic, paratoluenesulfonic, methane sulfonic, citric, male
  • the compounds of formula I may be prepared by the methods described below with reference to the Schemes 1 , 2, 3, 4, 5, and 6.
  • Compounds of formulas I', I", I IV , and l v may be prepared by processes analogous to those set forth in the examples herein.
  • the compounds of formula (2) are known, or can be prepared in accordance with known methods, or else their preparation is described herein.
  • compounds of formula (2) include particular stereoisomers that may be prepared by means analogous to those set forth in DRUGS OF THE FUTURE 1991 , 16(3) 210-212; J. Org.Chem., 1985, 50, 4615-4625; J. Org.Chem., 1987, 52 1487-1492; and J. Chem. Soc. Chem. Commun. 1992, 273-274, J. Chem. Soc. Chem. Commun. 1993,
  • a compound of formula (2) wherein and P is Ph CH 2 OCONH or P is N 3 may be converted to a compound of formula (3) by reaction with a compound of the formula, H-O-L, in an organic solvent such as ethanol, dimethylsulfoxide (DMSO), or more preferably,
  • dimethylformamide (DMF) at a temperature in the range of about 80°C to about 200°C, more preferably, about 120°C.
  • the resulting compound of formula (3) may be isolated by conventional means such as crystallization or chromatography, or it may be used directly in the next step of a synthesis of this invention to form a compound of formula (4).
  • Compounds of the formula H-O-L are known or may be prepared in accordance with known methods.
  • a compound of formula (3) may be converted to a compound of formula (4) in an organic solvent such as methanol or more preferably ethanol in the presence of hydrogen and a catalyst such as 10%
  • the reaction is carried out under about one atmosphere of hydrogen.
  • the resulting compound of formula (4) may be isolated by conventional means such as crystallization or
  • a compound of formula (4) may be converted to a compound of formula (5) in an organic solvent such as DMSO, DMF, or more preferably dioxane in the presence of di-tert-butyl dicarbonate and a base such as di-isopropylethylamine, or more preferably triethylamine at a temperature in the range of about 0°C to about 35°C, more preferably about 25°C .
  • the resulting compound of formula (5) may be isolated by conventional means such as crystallization or chromatography, or it may be used directly in the next step of a synthesis of this invention.
  • a compound of formula (2) wherein P is tBuOCONH may be converted directly to a compound of formula (5) by reaction in an organic solvent such as ethanol, DMSO, or more preferably DMF with a compound of formula, H-O-L, at a temperature in the range of about 80°C to about 200°C more preferably at about 120°C .
  • the resulting compound of formula (5) may be isolated by conventional means such as
  • a compound of formula (5) may be converted to a compound of formula (6) in the presence of methanesulfonyl chloride, in an organic solvent such as DMF, chloroform, or, more preferably dichloromethane in the presence of a base such as di-isopropylethylamine or more preferably triethylamine at a temperature in the range of about -10°C to about 35°C, more preferably about 25°C.
  • the resulting compound of formula (6) may be isolated by conventional means such as crystallization or
  • a compound of formula (6) may be converted to a
  • compound of formula (7) by treatment with sodium azide in an organic solvent such as DMSO or more preferably, DMF at a temperature in the range of about 50°C to about 120°C, more preferably about 80°C.
  • the resulting compound of formula (7) may be isolated by conventional means such as crystallization or chromatography, or it may be used directly in the next step of a synthesis of this invention to form a compound of formula (8).
  • a compound of formula (7) may be converted to a compound of formula (8) in the presence of trifluoroacetic acid in an organic solvent such as chloroform, or more preferably dichloromethane.
  • the reaction is carried out at a temperature in the range of about 0°C to about 35°C, more preferably about 25°C.
  • the resulting trifluoroacetate salt may be subsequently treated with a base such as di- isopropylethylamine or more preferably triethylamine at a temperature in the range of about 0°C to about 35°C, more preferably about 25°C.
  • the resulting free amine of formula (8) may be isolated by conventional means such as crystallization or chromatography, or it may be used directly in the next step of a synthesis of this invention to form a compound of formula (1 1 ) or (9) as shown in Formula Scheme 2.
  • a compound of formula (8) may be converted to a compound of formula (9) in the presence of an active ester or mixed anhydride of the formula
  • BOP reagent benzotriazol-1 -yloxy tris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent) in an organic solvent such as CHCI 3 or CH 2 CI 2 in the presence of a base such as di-isopropylethylamine or more preferably triethylamine at a
  • pivaloyl mixed anhydride can be made by conventional means preferably as pivaloyl mixed anhydride.
  • the pivaloyl mixed anhydride is made as follows: Pivaloyl chloride and the acid is reacted in the presence of a base such as triethylamine at a temperature in the range of about 0°C to about -60°C.
  • the resulting compound of formula (9) may be isolated by conventional means such as crystallization or chromatography, or it may be used directly in the next step of a synthesis of this invention to form a compound of formula (10).
  • a compound of formula (9) may be converted to a
  • reaction is carried out at a temperature in the range of about -20°C to about 35°C, more preferably about 25°C, followed by treatment with an amine base such as di-isopropylethylamine or more preferably
  • the resulting compound of formula (10) may be isolated by conventional means such as crystallization or chromatography, or it may be used directly in the next step of a synthesis of this invention.
  • a compound of formula (10) may be converted to a compound of formula (1 1 ), in the presence of an active ester or mixed anhydride or acid chloride of the acids, Ar-CO 2 H or ArSO 3 H.
  • the active ester or mixed anhydride of Ar-CO 2 H can be made by reacting with BOP reagent in an organic solvent, preferably CHCI 3 or CH 2 CI 2 in the presence of a base such as triethylamine.
  • the mixed anhydride of ArCO 2 H can be made by conventional means, preferably as pivaloyl mixed anhydride, using pivaloyl chloride in an organic solvent, preferably CHCI 3 or CH 2 CI 2 in the presence of a base such as triethylamine at a temperature in the range of about 0°C to about -60°C.
  • reaction of an acid chloride of the acids ArSO 3 H or ArCO 2 H and an amine of formula (10) is carried out in an organic solvent, preferably CHCI 3 or CH 2 CI 2 in the presence of a base such as triethylamine at a temperature in the range of about -20°C to about 25°C.
  • the resulting compound of formula (1 1 ) may be isolated by conventional means such as crystallization or chromatography, or it may be used directly in the next step of a synthesis of this invention to produce a compound of formula (12).
  • a compound of formula (8) may be directly converted to a compound of formula (1 1 ).
  • the reaction is carried out in the presence of an active ester or mixed anhydride of an acid the formula
  • BOP reagent in an organic solvent such as CHCI 3 or CH 2 CI 2 in the presence of a base such as triethylamine.
  • the resulting compound of formula (11 ) may be isolated by conventional means such as crystallization or chromatography, or it may be used directly in the next step of a synthesis of this invention to form a compound of formula (12).
  • a compound of formula (1 1 ) may be converted to a compound of formula (12) in an organic solvent such as methanol or more preferably ethanol in the presence of a catalyst such as 10% palladium on carbon.
  • the reaction is carried out under 1 atmosphere of hydrogen.
  • the resulting compound of formula (12) may be isolated by conventional means such as crystallization or chromatography, or it may be used directly in the next step of a synthesis of this invention to form a compound of formula (18).
  • a compound of formula (12) may be converted directly into a compound of formula (18) by reacting the amine of the formula (12) with an active ester or mixed anhydride or acid chloride of an acid.
  • the active ester or mixed anhydride of the acid is made by reacting the acid with BOP reagent in an organic solvent such as CH 2 CI 2 or CHCI 3 in the presence of a base such as triethylamine.
  • the mixed anhydride can be made by conventional means, preferably as the pivaloyl mixed anhydride using pivaloyl chloride in an organic solvent such as CH 2 CI 2 in the presence of a base such as triethylamine at a temperature in the range of about 0°C to about -60°C.
  • a compound of formula (12) may be converted to a compound of formula (18) by reaction with an acid chloride in an organic solvent such as CH 2 CI 2 or CHCI 3 in the presence of a base such as triethylamine at a temperature in the range of about -20°C to about 35°C.
  • an acid chloride in an organic solvent such as CH 2 CI 2 or CHCI 3 in the presence of a base such as triethylamine at a temperature in the range of about -20°C to about 35°C.
  • the resulting compound of formula (18) may be isolated by conventional means such as crystallization or chromatography.
  • a compound of formula (7) may be converted to a
  • a compound of formula (13) may be converted to a
  • the active ester or mixed anhydride is made by reacting the acid with benzothazol-1 -yloxytris(dimethylamino)phosphonium
  • the mixed anhydride of the acid can be made by conventional means, preferably as pivaloyl mixed anhydride using pivaloyl chloride in an organic solvent like CH 2 CI 2 in the presence of a base such as triethylamine at a temperature in the range of about -60°C to about 35°C.
  • the compound of formula (13) can also be converted to a compound of formula (14) in the presence of an acid chloride in an organic solvent such as CHCI 3 or CH 2 CI 2 in the presence of a base such as triethylamine at a temperature in the range of about -60°C to about 25°C.
  • a base such as triethylamine
  • a compound of formula (14) may be converted to a compound of formula (15) in the presence of trifluoroacetic acid in an organic solvent such as CH 2 CI 2 or CHCI 3 at a temperature in the range of about 0°C to about 35°C, preferably about 25°C, followed by treatment with triethylamine at a temperature in the range of about 0°C to about 25°C.
  • the resulting compound of formula (15) may be isolated by conventional means such as crystallization or chromatography, or it may be used directly in the next step of a synthesis of this invention to form a compound of formula (16) or formula (18).
  • a compound of formula (15) may be converted to a compound of formula (16) by reaction with an ester or mixed anhydride of the acid of the formula
  • P is as described above, in an appropriate solvent, preferably CHCI 3 or CH 2 CI 2 .
  • P" is as described above, is made by reacting the just above mentioned acid with BOP reagent in an organic solvent preferably CHCI 3 or CH 2 CI 2 in the presence of a base such as
  • triethylamine at a temperature in the range of about 0°C to about -60°C.
  • the resulting compound of formula (16) may be isolated by conventional means such as crystallization or chromatography, or it may be used directly in the next step of a synthesis of this invention to form a compound of formula (17).
  • a compound of formula (16) may be converted to a compound of formula (17) by removing the protecting group.
  • P" is Ph CH 2 OCONZ, or P" is N 3 (to obtain compounds of formula (17) where Z is H) removal is carried out in a solvent such as ethanol or methanol in the presence of a catalyst such as 10% Pd on carbon. The reaction is carried out under one atmosphere of hydrogen.
  • P" is t-BOCNZ
  • t-BOC removal is carried out in a solvent such as CHCI 3 or CH 2 CI 2 in the presence of trifluoroacetic acid at a temperature in the range of about 0°C to about 25°C followed by treatment with a base such as triethylamine.
  • the resulting compound of formula (17) may be isolated by conventional means such as crystallization or chromatography, or it may be used directly in the next step of a synthesis of this invention to produce a compound of formula (18).
  • a compound of formula (17) may be converted to a compound of formula (18) in the presence of an ester, mixed anhydride or acid chloride of the acids ArCO 2 H or ArSO 3 H.
  • the active ester or mixed anhydride of ArCO 2 H is made by reacting the acid with BOP reagent in an organic solvent like CH 2 CI 2 or CH 3 CI in the presence of a base such as triethylamine.
  • the mixed anhydride of ArCO 2 H can be made by
  • a compound of formula (17) may be converted to a compound of formula (18) in the presence of an acid chloride of ArCO 2 H or ArSO 3 H in an organic solvent like CH 2 CI 2 or CH 3 CI in the presence of a base such as triethylamine at about -20°C to about 25°C.
  • an acid chloride of ArCO 2 H or ArSO 3 H in an organic solvent like CH 2 CI 2 or CH 3 CI in the presence of a base such as triethylamine at about -20°C to about 25°C.
  • a compound of formula (15) may be converted directly to a compound of formula (18) by reaction with an active ester or mixed anhydride of the formula
  • a compound of formula (9) may be converted to a compound of formula (19) by procedures similar to the hydrogenation described above wherein a compound of formula (1 1 ) is converted to a compound of formula (12).
  • the resulting compound of formula (19) may be isolated by conventional means such as crystallization or chromatography, or used directly in the next step of the synthesis of this invention.
  • a compound of formula (19) may be converted to a compound of formula (16) by using procedures analogous to those described for the conversion of a compound of formula (12) into a compound of formula (18).
  • a compound of formula (16) may be converted to compounds of formula (17 & 18) by procedures shown in Formula Scheme 3 where P" is tBOCNZ.
  • a compound of formula (6) may be converted to a compound of formula (21 ) by reaction with a thiolate or a thiocarboxylate, such as potassium thiolacetate, in an organic solvent such as methanol, DMSO, or preferably ethanol at a temperature in the range of about -10°C to 80°C more preferably 25°C.
  • a thiolate or a thiocarboxylate such as potassium thiolacetate
  • organic solvent such as methanol, DMSO, or preferably ethanol
  • the resulting compound of formula (21 ) may be isolated by conventional means such as crystallization or chromatography or it may used directly in the next step of this invention to form a compound of formula (22).
  • a compound of formula (21 ) may be converted to a
  • a compound of formula (25), wherein R 3 is -COR 20 may be converted to a compound of formula (26) in organic solvent such as ethanol, methanol or water or a mixture of water and ethanol or methanol in the presence of a base such as sodium or potassium carbonate, or lithium, sodium or potassium hydroxide at a temperature in the range of about -10°C to about 80°C more preferably about 25°C.
  • organic solvent such as ethanol, methanol or water or a mixture of water and ethanol or methanol
  • a base such as sodium or potassium carbonate, or lithium, sodium or potassium hydroxide at a temperature in the range of about -10°C to about 80°C more preferably about 25°C.
  • the resulting compound of formula (26) may be isolated by conventional means.
  • a compound of formula (26) may be converted to compound of formula (25).
  • a compound of formula (27) may be converted to compound of formula (28).
  • a compound of formula (28) may be converted to compound of formula (25).
  • a compound of formula I' may be converted to a compound of formula I" by reaction with an oxidant such as dipyridine chromium trioxide complex or sodium dichromate or pyridinium dichromate in an organic solvent such as dichloromethane, dimethylformamide or pyridine at a temperature in the range of about 0-100°C.
  • an oxidant such as dipyridine chromium trioxide complex or sodium dichromate or pyridinium dichromate in an organic solvent such as dichloromethane, dimethylformamide or pyridine at a temperature in the range of about 0-100°C.
  • the resulting compound of formula I may be isolated by crystallization or
  • a compound of formula I" may be converted to a compound of formula I'" in an organic solvent such as tetrahydrofuran or diethyl ether at a temperature in the range -78° to + 35°C under an inert atmosphere of nitrogen or argon.
  • the reaction is carried out in the presence of
  • methylenetriphenylphosphorane generated by the action of a strong base such as lithium, sodium or potassium hexamethyl disilazide or butyl lithium on methyltriphenyl phosphonium chloride, bromide or iodide.
  • the resulting compound of formula I'" can be isolated by conventional means such as crystallization or chromatography or used in the next step of a synthesis of this invention for producing a compound of Formula
  • a compound of formula I"' can be converted to a compound of formula I IV in an organic solvent such as butanol in the presence of water and osmium tetroxide or a combination of potassium osmate dihydrate, potassium ferricyanide and potossium carbonate at a
  • the compound of formula I IV may be isolated by conventional means such as crystallization or
  • a compound of formula 3 or formula 5 may be converted to a compound formula 30.
  • the compound of formula 30 may be isolated by conventional means such as crystalization or chromatography or may be used directly in a synthetic step of this disclosure to prepare a compound of formula I", or used to prepare a compound of formula 31.
  • a compound of formula 30 can be converted to a compound of formula I".
  • a compound of formula 30 may be converted into a compound of formula 31.
  • a compound of formula 31 may be converted to a compound of formula I'".
  • a compound of formula 31 may be converted to a compound of formula 32
  • a compound of formula 32 may be converted to a compound of formula I IV .
  • the compounds of formula 1 are active against HIV
  • the compounds of formula I are active as agents for treating AIDS inasmuch as they are active against HIV.
  • the compounds of formula I are active as agents for inhibiting renin.
  • the anti-HIV activity of the compounds of formula 1 can be shown by the following test protocol: TEST 1-INHIBITION OF PROTEOLYTIC ACTIVITY OF HIV-1-
  • HIV-1 protease The ability of compounds of the invention to inhibit the proteolytic activity of HIV-1 protease can be determined by using the method of Louis, et al., Biochem. Biophys. Res. Comm. 159:87-94, (1989), which is herein incorporated by reference.
  • HIV Substrate III His-Lys-Ala-Arg-Val-Leu-pNO 2 Phe-Glu-Ala-Nle-Ser- NH 2 purchased from Bachem Bioscience, Inc. Philadelphia, PA. can be used in place of the nonapeptide substrate Val-Ser-Gln-Asn-Tyr-Pro-Ile- Val-Gln-amide.
  • CEM-SS cells human T- lymphocyte derived tissue culture cells
  • HIV-1 , isolate III B which was produced in tissue culture. After 7 days, the virus has killed the cells as monitored by extensive syncytia formation (cell fusion).
  • the test measured the capability of the chemical synthetic compounds to prevent syncytia formation and cell death.
  • CEM cells were grown at 37°C in an atmosphere of 5%CO 2 .
  • HIV isolate III B was prepared by growth in and crude purification from CEM cells. The chemical synthetic compound was added to 96 well microtiter plates and diluted in varying steps across the wells of the plate.
  • the SPA assay for HIV1 protease has been developed by Amersham Corporation, Arlington Heights, Illinois, and is available for commercial use.
  • the substrate for HIV1 protease AcN-(I 125 )Tyr-Arg-Ala- Arg-Val-Phe-Phe-Val-Arg-Ala-Ala-Lys-SPA bead
  • This event causes removal of detectable signal from the microsphere bead indicated by reduction in radioactivity
  • the substrate, and the HIV1 protease were incubated in presence of synthetic compound in various dilutions at room temperature for 40 minutes, and the concentration of the compound required to inhibit the proteolytic activity by 50% (IC 50 ) was determined.
  • FABMS fast atom bombardment mass spectrogram
  • the IC 50 S above indicate that the compounds of formula I are active against HIV and are therefore useful in treating AIDS.
  • the compounds of this invention can be administered in any number of conventional dosage forms, e.g., oral, parenteral, rectal, inhalation and the like.
  • Oral or rectal dosage forms include capsules, tablets, pills, powders, cachets, and suppositories.
  • Liquid oral dosage forms include solutions and suspensions.
  • Parenteral preparations include sterile solutions and suspensions.
  • Inhalation administration can be in the form of a nasal or oral spray, or by insufflation.
  • compositions and pharmaceutical compositions contemplated by the above dosage forms can be prepared with
  • Such pharmaceutically acceptable excipients and additives are intended to include carriers, binders, flavorings, buffers, thickeners, coloring agents, stabilizing agents, solubilizing agents, emulsifying agents, dispersing agents, suspending agents, perfumes, preservatives, lubricants, etc.
  • the compounds of this invention may be administered by any conventional mode of administration by employing an antiviral effective amount of a compound of this invention for such mode.
  • the dosages may be varied depending upon the requirements of the patient in the judgment of the attending clinician, the severity of the condition being treated and the particular compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Treatment can be initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage should be increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
  • dosages of from about 0.1 to about 100 mg/kg of body weight per day may be administered to provide antiviral activity.
  • dosages of from about 20 to about 60 mg/kg of body weight may be used; and when administered parenterally, e.g., intravenously, dosages of from about 5 to about 20 mg/kg body weight may be used.
  • the dosage to be administered and the route of administration depends upon the particular compound used, the age and general health of the patient and the severity of the viral condition. Thus, the dose ultimately decided upon must be left to the judgment of a trained health-care practitioner.
  • the compounds of this invention may also be
  • the compounds of this invention may also be administered either before or after the administration of other known antiviral agents such as AZT.
  • combination therapies is believed to result in a synergistic action between the particular compound of the invention, and the other anti-HIV agent administered.
  • Triethylamine (175 microliters) was added dropwise to a stirred solution of the amine (i) (0.4248 g) and di-tert-butylpyrocarbonate (0.251 g) in dioxane (50 ml) at room temperature under an atmosphere of nitrogen. The resulting mixture was stirred overnight, concentrated and purified by column chromatography on silica gel using ethyl acetate/hexane (1 :1 ) as the eluant to give 0.423 g of carbamate (ii).
  • Triethylamine (124 microlitres) was added a dropwise to a stirred solution of the alcohol (i) (0.2708 g) and mesylchloride (51 microlitres) in dichloromethane (5ml) at room temperature. The resulting mixture was stirred for 3 hours, partitioned between ethyl acetate and water. The organic phase was separated, washed twice with water, and concentrated to give the mesylate (ii) 0.306 g as a white solid.
  • Triethylamine (2x37 microliters) was added in two portions ( about 1/2 hour apart) to a stirred solution of the amine (ii) (0.1020 g), the acid (i) (76.8 mgs) and BOP reagent (0.1302 g) in CH 2 CI 2 (2 ml) .
  • BOP reagent 0.1302 g
  • CH 2 CI 2 2 ml
  • Triethylamine (2x 0.73 ml) was added in two portions ( about 1/2 hour apart) to a stirred solution of the amine (ii) (1.99 g), the acid (i) (1.33 g) and BOP reagent (2.54 g) in CH 2 CI 2 (20 ml). When the addition was complete the resulting mixture was stirred for 3 hours, and partitioned between ethyl acetate and water. Aqueous work-up and column
  • Triethylamine (2 x 31 microliters) was added in two portions (about 1/2 hour apart) to a stirred solution of the amine (ii) (99.5 mg), the acid (i) (38.4 mg) and BOP reagent (97.8 mg) in CH 2 CI 2 (5 ml) .
  • the resulting mixture was stirred for 3 hours, and partitioned between ethyl acetate and water. Aqueous work-up and column
  • Triethylamine (27 microlitres) was added dropwise to a stirred solution of the amine (ii) (94.8 mg) and sulfonyl chloride (i) (47.8 mg) in dichloromethane (4 ml) at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred for 3 hours, partitioned between EtOAc and water. Aqueous work-up and column chromatography on silica gel using EtOAc - hexane (7:3) gave desired product (iii) 39.4 mgs as a white solid.
  • Triethylamine (46 ⁇ l; 32.2 mg) was added to a stirred solution of the racemic ester (1 ) (54.4 mgs; 0.15mmol) and salt (2) (72.5 mgs;
  • Compound A was made by procedures analogous to those set forth in Examples 4, 5, 6, 7, and 8.
  • Compound D was made by procedures analogous to those set forth in Examples 4, 5, 6, 8, 12, 13 and 14.
  • Compound E was made by procedures analogous to those set forth in Examples 4, 5, 6, 12, 13 and 14.
  • Compound F was made by procedures analogous to those set forth in the Examples given for the preparation of Compound D.
  • Compound G was made by procedures analogous to those set forth in the Examples given for the preparation of Compound E.
  • Compound J was made by procedures analogous to those set forth in Examples 4, 5, 6, 8, 12, 13 and 15.
  • Compound K was made by procedures analogous to those set forth in Examples 4, 5, 6, 12, 13 and 15.
  • Compound L was made by procedures analogous to those set forth in the Examples given for the preparation of Compound D.
  • Compound M was made by procedures analogous to those set forth in the Examples given for the preparation of Compound E.
  • Compound P was made by procedures analogous to those set forth in Examples 3, 7, 9 and 10.
  • Compound T was made by procedures analogous to those set forth in Examples 1 , 2, 3, 4, 5, 6, 7 and 8.
  • Compound N can be made by procedures analogous to those set forth in this specification.
  • k(CN) 6 and 1.9 mg potassium osmate were added in order to a stirred solution of 31.7 mg of the alkene (1 ) in 1 ml of t-BuOH and 1 ml of H 2 O.
  • the reaction was stirred over night.
  • Thin layer chromatography (tlc) indicated that the reaction was not complete so a further portion of 8.5 mg of K 2 CO 3 and 25.9 mg of K 2 Fe(CN) 6 and 1.9 mg potassium osmate were added.
  • sodium sulfate was added and stirred for a further 1 hour.
  • chromium trioxide 0.3309 g was added to a mixture of pyridine (535 ⁇ l) in acetone (10 ml) and stirred at room temperature for 15 minutes and then an acetone (10 ml) solution of 0.4137 g of alcohol was added and the resulting mixture was stirred for 10 days.
  • Aqueous work-up and purification of the crude reaction product on silica gel (column chromatography) using Et OAc - MeOH (20:1 ) as eluant gave ketone (2), 0.1776g, as a white solid and recovered starting material (0.1913 g) .

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  • Organic Chemistry (AREA)
  • Biophysics (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention se rapporte à des composés de la formule (I) dans laquelle Ar, W, Z, Q, R1, U et L sont représentés. Ces composés agissent comme agents actifs contre le VIH et inhibent la rénine, et, par conséquent, sont également actifs contre l'hypertension. Des rétrovirus similaires contre lesquels les composés de l'invention sont actifs comprennent le rétrovirus provoquant le SIDA chez les félins, et le rétrovirus provoquant le sarcome de Rous chez les poulets.
PCT/US1994/000330 1993-01-17 1994-01-14 Peptides ayant une activite anti-vih WO1994017096A1 (fr)

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US08/491,854 US5693815A (en) 1993-01-17 1994-01-14 Peptides
AU61617/94A AU6161794A (en) 1993-01-17 1994-01-14 Peptides having anti-hiv activity

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US608693A 1993-01-17 1993-01-17
US08/006,086 1993-01-19
US14080893A 1993-10-21 1993-10-21
US08/140,808 1993-10-21

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0823424A1 (fr) * 1996-08-09 1998-02-11 F. Hoffmann-La Roche Ag Procédé pour la préparation de quinargine
US5811083A (en) * 1996-03-26 1998-09-22 Estee Lauder, Inc. Tocopherol derivatives for use in cosmetic compositions
US5914404A (en) * 1996-08-09 1999-06-22 Hoffmann-La Roche Inc. Process for the preparation of quinargine
WO2000059867A1 (fr) * 1999-03-30 2000-10-12 Pharmacor Inc. Derives d'hydroxyphenyle possedant des proprietes inhibitrices de l'integrase du vih
US6313177B1 (en) 1999-04-30 2001-11-06 Pharmacor Inc. D-mannitol derivatives as HIV aspartyl protease inhibitors
US6362165B1 (en) 1999-03-30 2002-03-26 Pharmacor Inc. Hydroxyphenyl derivatives with HIV integrase inhibitory properties
WO2004024675A1 (fr) * 2002-09-10 2004-03-25 Pharmacia & Upjohn Company Llc Aminoethers substitues pour le traitement de la maladie d'alzheimer

Families Citing this family (2)

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Publication number Priority date Publication date Assignee Title
AU2003286530A1 (en) * 2002-10-21 2004-05-13 Pharmacia And Upjohn Company Substituted peptides useful in the treatment of alzheimer's disease
JP2007517781A (ja) * 2003-12-19 2007-07-05 メルク　エンド　カムパニー　インコーポレーテッド アルツハイマー病治療用のフェニルアミドおよびピリジルアミド系β−セクレターゼ阻害薬

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EP0401676A1 (fr) * 1989-06-06 1990-12-12 Bio-Mega/Boehringer Ingelheim Research Inc. Inhibiteurs d'enzymes
EP0432695A2 (fr) * 1989-12-11 1991-06-19 F. Hoffmann-La Roche Ag Dérivés d'acides aminés
WO1992000750A1 (fr) * 1990-07-06 1992-01-23 Smithkline Beecham Corporation Inhibiteurs de proteases retrovirales
EP0526009A1 (fr) * 1991-07-10 1993-02-03 Eli Lilly And Company Inhibiteurs de la HIV protéase utiles dans le traitement du Sida
WO1993004043A1 (fr) * 1991-08-13 1993-03-04 Schering Corporation Agents anti-vih (sida)

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DK523288A (da) * 1987-10-06 1989-04-07 Hoffmann La Roche Aminosyrederivater
CA1340588C (fr) * 1988-06-13 1999-06-08 Balraj Krishan Handa Derive d'aminoacides
CA2010531A1 (fr) * 1989-03-06 1990-09-06 Werner Neidhart Derives d'acides amines
GB8927915D0 (en) * 1989-12-11 1990-02-14 Hoffmann La Roche Novel alcohols

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0401676A1 (fr) * 1989-06-06 1990-12-12 Bio-Mega/Boehringer Ingelheim Research Inc. Inhibiteurs d'enzymes
EP0432695A2 (fr) * 1989-12-11 1991-06-19 F. Hoffmann-La Roche Ag Dérivés d'acides aminés
WO1992000750A1 (fr) * 1990-07-06 1992-01-23 Smithkline Beecham Corporation Inhibiteurs de proteases retrovirales
EP0526009A1 (fr) * 1991-07-10 1993-02-03 Eli Lilly And Company Inhibiteurs de la HIV protéase utiles dans le traitement du Sida
WO1993004043A1 (fr) * 1991-08-13 1993-03-04 Schering Corporation Agents anti-vih (sida)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5811083A (en) * 1996-03-26 1998-09-22 Estee Lauder, Inc. Tocopherol derivatives for use in cosmetic compositions
EP0823424A1 (fr) * 1996-08-09 1998-02-11 F. Hoffmann-La Roche Ag Procédé pour la préparation de quinargine
US5914404A (en) * 1996-08-09 1999-06-22 Hoffmann-La Roche Inc. Process for the preparation of quinargine
WO2000059867A1 (fr) * 1999-03-30 2000-10-12 Pharmacor Inc. Derives d'hydroxyphenyle possedant des proprietes inhibitrices de l'integrase du vih
US6362165B1 (en) 1999-03-30 2002-03-26 Pharmacor Inc. Hydroxyphenyl derivatives with HIV integrase inhibitory properties
US6313177B1 (en) 1999-04-30 2001-11-06 Pharmacor Inc. D-mannitol derivatives as HIV aspartyl protease inhibitors
WO2004024675A1 (fr) * 2002-09-10 2004-03-25 Pharmacia & Upjohn Company Llc Aminoethers substitues pour le traitement de la maladie d'alzheimer

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US5693815A (en) 1997-12-02
IL108353A0 (en) 1994-04-12

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