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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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  • 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
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  • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
  • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/81—Amides; Imides
  • C07D213/82—Amides; Imides in position 3
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  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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  • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
  • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
  • C07D295/182—Radicals derived from carboxylic acids
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  • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
  • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
  • C07D295/182—Radicals derived from carboxylic acids
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  • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
  • C07D295/26—Sulfur atoms

Definitions

• Retroviruses are a class of viruses which transport their genetic material as ribonucleic acid rather than as deoxyribonucleic acid. Retroviruses are associated with a wide variety of diseases in man, one of which is AIDS. Although there have been disclosures of other anti-viral agents useful in the treatment of AIDS, for example see patent applications EP 0 218 688, EP 0 352 000 and PCT/ ⁇ S 91/09741, the compounds of the present invention have not been previously disclosed. PCT/US 91/09741 is hereby incorporated by reference.
• the present invention relates to compounds having the following general formula (I);
• T is [(0)_.-W-R] and T' is [ (O) b '-W'-R * ] or hydrogen, wherein each of W and W are independently C ⁇ _ 6 alkylene or nothing, provided that W is C 2 - 6 alkylene when W is directl attached to a nitrogen atom in R, provided that W* is C 2 - 6 alkylene when W is directly attached to a nitrogen atom in R', provided that W or W are each independently C__ 6 alkylene when R or R' are each independently an aryl;
• P 2 is C x _ 6 alkyl, cyclopentyl, hydroxy C j ⁇ g alkyl, phenyl, benzyl or 3-tetrahydrofuryl;
• R and R' are each independently -CH 2 CHO, hydroxy C ⁇ _ 6 alkyl, C1-6 alkoxy C 1 - 6 alkyl, C__ 6 alkyl,
• R3 is Ci-6 allenyl Ci- 6 alkoxy, Ci- 6 alkylene, hydroxy C__6 alkyl, Ci- 6 alkyl or OH;
• R4 is C ⁇ _ 6 alkyl, phenyl or benzyl
• R' 4 is hydrogen or C__ 6 alkyl
• R 5 is hydrogen, C 1 - 15 alkyl, OH, hydroxy C 1 - 15 alkyl
• PDL is -(CH 2 ) a - -r 3- or 4-pyridyl, or p- substituted benzyloxy, wherein the substitution is wit a nitro, OH, amino, C__ 6 alkoxy, hydroxy Ci- ⁇ alkylene, or halogen;
• Y is C 1 - 15 alkyl, hydroxy C 1 - 15 alkyl, Ci- 6 alkyl or -(CH 2 ) e -C6H4-(V) e 1 ;
• Z is -(CH 2 ) d -0-CHO, C ⁇ - 6 alkylene-0-(CH 2 )d-(0-CH2-CH 2 )e-0-C ⁇ -6 alkyl, CHO, CO2R4, CO2NHR4, -(CH 2 )d-0-(CH2)d , -H'7r -(CH 2 ) e -OR4 or
• R 6 is as defined for R 5 with the proviso that Re is other than hydrogen when R 5 is hydrogen, or R 5 and R ⁇ are taken together with the nitrogen atom to which they are attached are selected from the group consisting of;
• R 7 is CH 2 OR4, C(0)NHR or CHO;
• R' is piperazinyl, substituted piperazinyl, piperidyl, morpholinyl, pyridyl, pyrazinyl, pyrimidinyl or phenyl, wherein substituted piperazinyl is piperazinyl substituted on one nitrogen atom thereof with CHO, C(0)NHR 4 , C 1 - 4 alkyl or CO 2 R 4 ;
• R's is pyrimidyl, pyridyl, pyrazinyl or phenyl; a is zero , 1 , 2 or 3 ; b and b' are each independently zero or 1; d and d' are each independently 1 or 2; e and e 1 are each independently zero, 1 or 2; and x is zero or one.
• halo refers to a chlorine, bromine or iodine atom.
• Isosteres of the compounds of Formula I include those wherein (a) the ⁇ -amino acid residues of the P- and P 2 substituents are in their unnatural configuration (when there is a natural configuration) or (b) when the normal peptide amide linkage is modified, such as for example, t form
• a compound of the invention should not be in an isosteric form.
• the ⁇ -amino acids are preferably in thei L-con iguration.
• a compound of the invention may be in free form, e.g. amphoteric form, or in salt, e.g., acid addition or anion salt, form.
• a compound in free form may be converted into salt form in an art-known manner and vice-versa.
• the pharmaceutically acceptable salts of the peptide Formula I include the conventional non-toxic salts or the quaternary ammonium salts of these peptides, which are formed, e.g., from inorganic or organic acids o bases.
• acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethane- sulfonate, lactate, maleate, methanesulfonate, 2-naphthal- enesulfonate, nicotinate, oxalate, paemoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thio
• Base salts include ammonium salts, alkalimetal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl- D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
• the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
• lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides
• dialkyl sulfates like dimethyl, diethyl, dibutyl
• diamyl sulfates long chain halides
• the hydrates of the compounds of Formula I are hydrated compounds having the partial structure
• alkyl includes the straight, branched-chain and cyclized manifestations thereof unless otherwise indicated, particularly such moieties as methyl, ethyl, isopropyl, n-butyl, t-butyl, -CH--t-butyl, cyclopropyl, n-propyl, pentyl, cyclopentyl, n-hexyl, cyclohexyl and cyclohexylmethyl.
• aralkyl when used, includes those aryl moieties attache to an alkylene bridging moiety, preferably methyl or ethyl
• Aryl includes both carbocyclic and hetereocyclic moieties of which phenyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, indazolyl, furyl and thienyl are of primary interest; these moieties being inclusive of their position isomers such as, for example, 2-, 3-, or 4-pyridyl, 2- or 3-furyl and thienyl, 1-, 2-, or 3-indolyl or the 1- and 3 indazolyl, as well as the dihydro and tetrahydro analogs o the furyl and thienyl moieties.
• aryl such fused carbocyclic moieties as pentalenyl, indenyl, naphthalenyl, azulenyl, heptalenyl, acenaphthylenyl, fluorenyl, phenalenyl, phenanthrenyl, anthracenyl, acephenanthrylenyl, aceanthrylenyl, triphenylenyl, pyrenyl, chrysenyl and naphthacenyl.
• aryl such other heterocycli radicals as 2- or 3-benzo[b]thienyl, 2- or 3-naphtho[2, - bjthienyl, 2- or 3-thianthrenyl, 2H-pyran-3-(or 4- or 5-)yl, 1-isobenzo- furanyl, 2H-chromenyl-3-yl, 2- or 3- phenoxathiinyl, 2- or 3-pyrrolyl, 4- or 3-pyrazolyl, 2-pyrazinyl, 2-pyrimidinyl, 3-pyridazinyl, 2-indolizinyl, 1-isoindolyl, 4H-quinolizin-2-yl, 3-isoquinolyl, 2- quinolyl, 1-phthalazinyl, 1,8-naphthyridinyl, 2- quinoxalinyl, 2-quinazolinyl, 3-cinnolinyl, 2-pteridinyl, 4aH-carbazol-2-
• alkylene includes straight or branched-chain moieties. Some examples of branched-chain alkylene moieties are ethylethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, and so on. For example, C 3 alkylene can mean
• the fluorenylmethyloxy moiety is that moiety generally called by its abbreviation FMOC, and is the fluorenyl moiety bearing -CH-0 attached to the 9-position of the fluo ⁇ renyl moiety.
• FMOC fluorenyl moiety bearing -CH-0 attached to the 9-position of the fluo ⁇ renyl moiety.
• Other terms defined herein are piperazinyl
• the substituents are one of CHO, C(0)NHR 4 , C ⁇ _ 4 alkyl or CO_R 4 .
• _ 0 is illustrated in one example by -CH 2 -OCH 3 , (although in each instance the C 1-6 alkylene may be straight or branched and the hydroxy radical is not limited to the terminal carbon atom of the alkyl moiety).
• an amino protecting group Pg
• the scope of those compounds of Formula I includes those R- moieties which, together with their adjacent carbonyl moiety form such groups as acetyl (Ac), succinyl (Sue), benzoyl (Bz),
• Rz is an aryl -- group as previously described suitably substituted by 1 to 3 members selected independently from the group consisting of fluoro, chloro, bromo, iodo, trifluoromethyl, hydroxy, alkyl containing from 1 to 6 carbons, alkoxy containing from 1 to 6 carbons, carboxy, alkylcarbonylamino wherein the alkyl group contains 1 to 6 carbons, 5-t
• acyl type protecting groups such as formyl, trifluoroacetyl, phthalyl, p-toluenesulfonyl (tosyl), benzenesulfonyl, nitrophenylsulfenyl, tritylsulfenyl, O-nitrophenoxyacetyl, and ⁇ -chlorobutyryl;
• aromatic urethane type protecting groups such as benzyloxycarbonyl and substituted benzyloxycarbonyls such as p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, l-(p-biphenylyl)-l-methylethoxycarbonyl, ⁇ -, ⁇ -dimethyl- 3,5-dimethoxybenzyloxycarbonyl, and
• the preferred ⁇ -amino protecting groups are tert-butyloxycarbonyl (Boc) or benzyloxycarbonyl (CBZ).
• Boc tert-butyloxycarbonyl
• CBZ benzyloxycarbonyl
• stereoisomers is a general term for all isomers of individuals molecules that differ only in the orientation of their atoms in space. It includes mirror image isomers (enantiomers) , geometric ⁇ cis/trans) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another
• the compounds of this invention may be prepared using standard chemical reactions analogously known in the art. More specifically, the preparation of compounds of structure (3) is well known in the art and described generally by Schirlin, D. and Van Dorsselaer, V. in PCT/US91/09741 published July 23, 1992 with an international publication number of WO 92/12123.
• step (a) the aldehyde of formula (3) is subjected to a condensation reaction under Reformatski conditions with an ester of bromodifluoroacetic acid, preferably the ethyl ester in the presence of zinc and in an anhydrous aprotic solvent, e.g., tetrahydrofuran, ether dimethoxyethane and the like under a nitrogen or argon inert atmosphere.
• an anhydrous aprotic solvent e.g., tetrahydrofuran, ether dimethoxyethane and the like under a nitrogen or argon inert atmosphere.
• the reaction is gently heated to about 60°C for about 1-12 hours or ultrasonicated to produce compounds (4).
• the condensation to produce compounds (4) can be achieved in greater yields and at lower reaction temperatures utilizin the following general method.
• an inert atmosphere such as nitrogen
• the aldehyde (3) is dissolved in a suitable anhydrous organic solvent.
• a suitabl anhydrous organic solvent are tetrahydrofuran, diethyl ether, t-butyl methyl ether and the like.
• the solution is cooled to approximately 0°C.
• To the solution is added abo 0.30 equivalents of silver acetate, about 2.1 equivalents of zinc dust, and about 2 equivalents of ethyl bromodifluoroacetate.
• diethylaluminum chloride (as a solution in toluene) is added slowly to the reaction keeping the temperature of th reaction below 12°C.
• the reaction is allowed to stir for to 3 hours at about 0°C and then at room temperature for 4 to 12 hours.
• the reaction is then cooled to about 10°C an quenched with saturated aqueous ammonium chloride.
• the compound (4) is then isolated and purified by techniques well known in the art. For example a solution of sodium hydrogen tartrate is added and the reaction is allowed to warm from 10°C to room temperature.
• the mixture is filtered, the solids washed with a suitable organic solvent, such as ethyl acetate and the layers of the filtrate are separated.
• the aqueous layer is extracted with ethyl acetate, the organic layer and extracts are combined, dried over anhydrous magnesium sulfate, filtered and concentrated.
• the residue is purified by flash chromatography on silica gel with a suitable eluent, such as cyclohexane/ethyl acetate to provide the compounds (4).
• step (b) formation of compounds (5) or (14) may be effected directly or undirectly.
• the esters of formula (4) or (13) are de-esterified using a suitable base, such as LiOH, KOH, NaOH and the like, in the presence of water and a partially water miscible solvent (such as tetrahydrofuran, dimethoxyethane, dioxane) at about room temperature.
• a suitable base such as LiOH, KOH, NaOH and the like
• a partially water miscible solvent such as tetrahydrofuran, dimethoxyethane, dioxane
• the resulting acid can then be aminated with the appropriate R 5 R 6 -substituted amine using standard peptide-like coupling conditions.
• the selection of the appropriate coupling reaction procedure is within the skill of the art.
• the coupling reaction can be carried out using standard coupling procedures such as the azide method, mixed carbonic acid anhydride (isobutyl chloroformate) method, carbodiimide [dicyclohexylcarbodiimide, diisopropylcarbodiimide, or water-soluble carbodiimide,1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDC)] method, active ester (p-nitrophenyl ester, N-hydroxy-succinic imido ester) method, Woodward reagent K method, carbonyldiimidazole method, phosphorus reagents such as BOP-Cl, or oxidation- reduction methods.
• standard coupling procedures such as the azide method, mixed carbonic acid anhydride (isobutyl chloroformate) method, carbodiimide [dicyclohexylcarbodiimide, diisopropylcarbodiimide,
• hydroxybenzotriazole for example the mixed anhydride method may be employed, using DCC and hydroxybenzotriazole at room temperature in solvents such as CH 2 C1 2 , tetrahydrofuran or dimethylformamide.
• esters (4) or (13) may be directly subjected to a reaction with the appropriate R 5 R 6 _ substituted amine without or with a solvent (tetrahydro ⁇ furan) at a temperature of from 0 to 80 ⁇ C.
• a suitable organic solvent such as dichloromethane under an inert atmosphere, such as nitrogen.
• An equivalent of a 2M solution of trimethylaluminum in toluene is added dropwise to the solution. After approximately 15 minutes this solution is added to approximately 0.3 equivalents of ester (4) or (13) dissolved in a suitable organic solvent, such as dichloromethane.
• the reaction is allowed to stir for about 15 to 24 hours at about room temperature to 40°C.
• the product is then isolated using techniques well known in the art. For example cold dilute aqueous hydrochloric acid and ethyl acetate is added. The organic layer is separated and washed with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the compounds (5) or (14).
• Step (c) compounds (6), (8) or (11) are prepared by removal of the P'- protecting group using standard procedures well known in the art [see T.H. Green,
• Step (ci) compound (13) is prepared by removal of the P' j ⁇ protecting group using standard procedures well known in the art[see T.H. Green, "Protective Groups in Organic Synthesis", John Wiley and Sons, 1981], such as, hydrogenation, POH being the compound obtained. POH being a free phenol.
• Step (C 2 ) compounds (6), (8) or (11) are prepared from the PoHderivatives (14), (16) or (17) by reaction with an appropriate alkylhalide in an inert solvent, in the presence of a base.
• a suitable organic solvent such as acetone.
• a catalytic amount of potassium iodide is then added and the reaction is stirred for 1 to 3 days.
• the product is isolated and purified by techniques well known in the art, such as extractive methods and recrystallization.
• the reaction is poured into a suitable solvent mixture, such as ethyl acetate/dilute aqueous sodium chloride and the organic layer is separated. The organic layer is then washed with dilute aqueous potassium hydroxide, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by recrystallization from a suitable solvent mixture, such as cyclohexane/ethyl acetate to provide compounds (6), (8) or (11).
• a suitable solvent mixture such as ethyl acetate/dilute aqueous sodium chloride
• the protecting groups Pg may readily be removed by standard procedures well known in the art [see T.H. Green, "Protective Groups in Organic Synthesis", John Wiley and Sons, 1981], preferably acid/base hydrolysis (e.g., formic acid at room temperature followed by extraction of the free base after treatment with sodium carbonate).
• Step (e) Compounds (7), (9) or (15) are subjected to a peptide coupling procedure with an appropriately protected acid of the formula R'-CONHCH(P 2 )C0 2 H or R'-CO-H, using the herein-described procedures (or by any other coupling procedure well known in the art, or as described in European Patent Application, Serial Number 93 401 785.6) to produce compounds (8) and (11) (from compound (7)); (10) and (12) (from compound (9)); and (16) and (17) (from compound (15)).
• R' ⁇ is defined as Ri except for those instances wherein protection of the R_ group may be requir as recognized by one of ordinary skill in the art. For example, a hydroxyl functionality on the alkyl portion of the R_ group must be protected prior to the oxidation in step (f).
• Step (f) the oxidation of compounds (8) and (11) may be effected by methods well known in the art, such as the Swern oxidation procedure, or with 1,1,l-triacetoxy-1,1 dihydro-l,2-benziodoxol-3(lH)-one to provide compounds of formulas IA and IB.
• the Swern oxidation [see Synthesis, (1981) 165] is effected by reacting about 2 to 20 equivalents of dimethylsulfoxide (DMSO) with about 1 to 10 equivalents o trifluoroacetic anhydride [(CF 3 CO) 2 0] or oxalyl chloride [(C0C1) 2 ], said reactants being dissolved in an inert solvent, e.g., methylene chloride (CH 2 CI 2 ), said reaction being under an inert atmosphere (e.g., nitrogen or equivalently functioning gas) under anhydrous conditions temperatures of about -70°C to -30°C to form an in situ sulfonium adduct to which is added about 1 equivalent of the appropriate alcohols, i.e., compounds (8) and (11).
• DMSO dimethylsulfoxide
• o trifluoroacetic anhydride (CF 3 CO) 2 0] or oxalyl chloride [(C0C1) 2 ]
• the alcohols are dissolved in an inert solven e.g., CH 2 CI 2 , tetrahydrofuran, or minimum amounts of DMSO, and the reaction mixture is allowed to warm to about -50° or -20°C (for about 20-60 minutes) and then the reaction completed by adding about 3 to 30 equivalents of a tertia amine, e.g., triethylamine, diisopropylethylamine, /-meth morpholine, etc.
• an inert solven e.g., CH 2 CI 2 , tetrahydrofuran, or minimum amounts of DMSO
• a tertia amine e.g., triethylamine, diisopropylethylamine, /-meth morpholine, etc.
• the oxidation can be carried out with t Dess-Martin periodinane (i.e., 1,1,l-triacetoxy-1,1- dihydro-l,2-benziodoxol-3(lH)-one) , [see Dess Martin, J_;_ Orq. Chem. , 48, 4155, (1983)].
• Dess-Martin periodinane i.e., 1,1,l-triacetoxy-1,1- dihydro-l,2-benziodoxol-3(lH)-one
• This oxidation is effected by contacting about 1 equivalent of the alcohol with 1 to 10 equivalents of periodinane (preferably greater than 5 equivalents) , said reagent being in suspension in an inert solvent (e.g., methylene chloride) under an inert atmosphere (preferably nitrogen) under anhydrous conditions at 0°C to 50°C (preferably room temperature) and allowing the reactants to interact for about 1 to 48 hours.
• an inert solvent e.g., methylene chloride
• an inert atmosphere preferably nitrogen
• Optional deprotection of the amine protecting groups may be effected as desired after the ketones have been isolated.
• the modified Jones oxidation procedure may conveniently be effected by reacting the alcohols with pyridinium dichromate by contacting the reactants together in a water-trapping molecular sieve powder, e.g., a grounded 3 Angstrom molecular sieve), wherein said contact is in the presence of glacial acetic acid at about 0°C to 50°C, preferably at room temperature followed by isolation and then optionally removing amine protecting groups.
• a water-trapping molecular sieve powder e.g., a grounded 3 Angstrom molecular sieve
• step (g) the compounds decribed by formulas IA and IB wherein R'_ is protected as required, are deprotected under conditions well known in the art [see T.H. Green, "Protective Groups in Organic Synthesis", John Wiley and Sons, 1981], to provide compounds of formula IA 1 and IB' wherein R" ⁇ are those substituents which required protection as required.
• a suitable organic solvent such as methylene chloride and treated with TFA/H 2 0.
• the reaction is allowed to stir at room temperature for about 4 to 10 hours and then it is concentrated under vacuum.
• the residue is purified by techniques well known in the art, such as extractive methods followed by flash chromatograph (silica gel, hexane/ethyl acetate) to provide the deprotected compound.
• PgHN-CHC0 2 R 9 wherein Pg is an amino protecting group, P 3 is either a P ' 1 or P' 2 moiety with P'- and P' 2 being as defined for P ⁇ and P 2 respectively, except that they are other than residues of naturally occuring amino acids, and the R g moiety is an alkyl radical, preferably methyl when P 3 is P' ⁇ , and ethyl when P 3 is P' 2 , alternative methods are available.
• P 3 is as previously defined and X is a leaving group, preferably halo or triflate, R 9 is methyl when P 3 is P'-, and ethyl when P 3 is P' 2 .
• the preparation of compounds (19) utilizes the Krapcho method [Tetrahedron Letters, 2.6, 2205 (1976)] for alkylation wherein compounds (18) are treated with a base, e.g., LDA, (lithium diisopropylamide) , followed by reaction with the desired P 3 X in the presence of TMEDA (i.e. tetramethylethylenediamine) in a solvent (tetrahydro ⁇ furan) with or without HMPA (i.e. hepamethylphosphonamide) according to the standard Krapcho conditions.
• a base e.g., LDA, (lithium diisopropylamide)
• TMEDA i.e. tetramethylethylenediamine
• solvent tetrahydro ⁇ furan
• HMPA i.e. hepamethylphosphonamide
• the compounds are then subjected to a reduction using diisobutyl alaminum hydride (Dibal) in a mixture of solvents, e.g., ether, toluene, hexane, tetrahydrofuran at about -78°C for about 1 hour.
• Dibal diisobutyl alaminum hydride
• solvents e.g., ether, toluene, hexane, tetrahydrofuran
• the compounds of (19) may be prepared by a Malonate/Curtius type sequence of reactions, [see Yamada, et al., J. Amer. Chem. Soc, (1972) 9_4, 6203] as illustrated by the following reaction scheme REACTION SCHEME C t-Bu0 2 CCH 2 C0 2 R 9
• step (a) compounds of formula (7) are subjected to a coupling reaction in a manner analogous to that described previously in Scheme A' step (e) with a suitably protected acid of the formula PgNHCH(P 2 )C ⁇ 2 H to provide compound of formula (23).
• step (b) compounds of formula (23) are deprotected in a manner analogous to that described in Scheme A, step (d) to provide compounds of formula (24).
• steps (c) and (d) compounds of formula (24) are first subjected to a coupling reaction with an acid of the formula R'_C ⁇ 2 H in a manner analogous to that described in Scheme A' step (e) and the coupled product is then oxidized in a manner analogous to that described in Scheme A' step (f) to provide the compounds of formula IA.
• Step A Preparation of Q-benzyl-N-( tert-butoxycarbonyl)-L- tyrosinal; the starting material in Reaction Scheme A, ⁇ [Following the procedure of Schirlin, D. and Van Dorsselaer, V.
• N-tert-butoxycarbony1-L-O-benzyltyrosine-N,0- dimethyl-hydroxamate (18.2 g, 44 mmol) is dissolved in a mixture of anhydrous diethyl ether/dimethoxyethane (300 mL, 4:1) and cooled to 0°C. To this is added lithium aluminum hydride (1.82 g, 48 mmol) portionwise. The reaction is stirred at 0°C for 1.5 hours. A 1M solution of potassium hydrogen sulfate (55 mL) is then added dropwise with stirring to the reaction. After addition is complete, the aqueous phase is decanted and extracted with ethyl acetate (2 x 200 mL).
• the temperature is kept below 12°C during the addition.
• the reaction is then allowed to stir at 0°C for 90 minutes and then at room temperature for 4 hours.
• the reaction is then cooled to 10°C and quenched with saturated aqueous ammonium chloride (200 mL).
• a 1M solution of sodium hydrogen tartrate (200 mL) is added and the reaction is allowed to warm to room temperature.
• the reaction is filtered and the solids rinsed with ethyl acetate.
• the filtrate layers are separated and the aqueous layer is extracted with ethyl acetate.
• the combined organic laye are dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum.
• the residue is purified by flash chromatography (cyclohexane/ethyl acetate, 4:1) to provide the title compound (8.34 g).
• the ratio of diastereomers is approximately 1:1.
• the reaction is stirre for 3 hours at 0°C, then at room temperature for 15 hours
• the reaction is then diluted with ethyl acetate (100 mL), washed with 0.1N aqueous hydrochloric acid (2 x 50 mL), water (50 mL), brine (50 mL) and dried over anhydrous magnesium sulfate. It is then filtered and concentrated under vacuum. The residue is recrystallized from ethyl acetate/pentane to provide the title compound (5.17 g) a white solid.
• the combined extracts are cooled to - 10°C and washed quickly with cold (-10°C) 1 N HC1, twice with cold water, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide 15.0 g of a yellow oil which is then dissolved in CH 3 OH (250 mL) and THF (80 mL).
• a solution of potassium carbonate (14 g, 100 mmol) in water (140 mL) is added with vigorous stirring. After 1 hour, the mixture is partially concentrated under vacuum and the remaining clear light yellow solution is diluted with brine (300 mL) .
• the cloudy mixture is cooled to -10°C and acidified to pH 5 with 1 M KHSO 4 .
• Step C Preparation of [5E,6S-(6R*, 9R*, 13S*) ]-4,4,-Difluoro-5- hydroxy-9-(1-methylethyl)-3,8,11-trioxo-1 ,13-diphenyl-6- [ [4-(phenylmethoxy)phenyl]methyl]-12-oxa-2,7,10- triazatetradecan-14-oic Acid, Methyl Ester.
• Reaction Scheme D steps (b) and (c): A flask containing the major diastereomer of [3 ⁇ ,4(S) ]-2,4, 5- Trideoxy-4-[ [ 2-[ [ (l,l-dimethylethoxy)carbonyl]amino]-3- methyl-l-oxobutyl]amino-5-[ 4-(phenylmethoxy)phenyl]-N- (phenylmethyl)-L-glycero-pentonamide (403 mg, 0.630 mmol) is submersed in an ice bath and ice-cold trifluoroacetic acid (TFA) (5 mL) is added with stirring.
• TFA trifluoroacetic acid
• reaction mixture is then allowed to warm to room temperature overnight. It is then diluted with ethyl acetate (60 mL) and filtered, washing the solids with ethyl acetate. The filtrate is washed with 0.1 M HC1 (3 x 15 mL), brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum.
• the above prepared alcohol is oxidized under Swern conditions in a manner analogous to that described previously in example 1, step G to provide the protected ketone as a light brown oil in 72% yield after flash chromatography (6% acetone in CH 2 CI 2 ).
• step G provides the title compound after flash chromatography (6, 10, and finally 15% acetone in CH 2 CI 2 ), 104 mg (58%) as a light yellow glass.
• Reaction Scheme D step(b): A solution of the above prepared amide (2.0 g, 2.8 mmol) in HC0 2 H (25 mL) is all to stir at room temperature for 6 hours. The solution concentrated under vacuum at 30°C and the residue is dissolved in ethyl acetate. Aqueous sodium bicarbonate added with vigorous stirring. White solids precipitate which are filtered and found to be the formate salt of (S)-amino alcohol. The organic layer of the filtrate i separated, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under vacu to provide an amber oil containing some white solids; the (R)- and (S)-amino alcohol and the lactam by-produc are present.
• Trifluoroacetic acid (15 mL) is added to the above prepared ester (1.00 g, 4.97 mmol). The solution is stirred for 5 hours and then concentrated under vacuum to provide a yellow oil. This is triturated with diethyl ether (25 mL) to provide the final title compound (A) (1.06 g, 82%) as an off white solid; mp 118-121°C.
• Step B Preparation of [1 (R) , 3 ⁇ , 4(S) -2,4,5-Trideoxy-2,2- difluoro-4-[ [3-methyl-2-[ [ [6-(4-morpholinylcarbonyl)-3- pyridinyllcarbonyl]amino]-l-oxobutyl3-amino3-N-[2-methyl-l- [ (phenylmethoxy)methyl3-propyl]-5-[4- (phenylmethoxy)phenyl3-L-qlycero-pentanamide.
• N-[ (3-pyridinylmethoxy)carbonyl]-L- valine, methyl ester can be prepared as follows: L-valine methyl ester (4.25 g, 34 mmol, freshly prepared from the hydrochloride salt by neutralization with 50% aqueous NaOH) is added to a stirred mixture of 1,1 '-carbonyldiimidazole (4.86 g, 30 mmol) in CH 2 CI 2 (30 mL) over 15 minutes. After 15 more minutes, 3-pyridylcarbinol (5.0 mL, 51 mmol) is added dropwise to the homogeneous solution. The resulting solution is heated at 45°C for 3 hours and then allowed to stir at room temperature overnight.
• the CH2CI2 is removed under vacuum, and the residue is dissolved in toluene (70 mL). The solution is heated at 70°C for 6 hours, and then concentrated under vacuum. The residue is dissolved in CH 2 CI 2 and the resulting solution is washed three times with water, dried over anhydrous magnesium sulfate, filtered and concentrate to provide an oil, which is purified by flash chromatography to provide 4.6 g (51%) of the N-[ (3-pyridinylmethoxy)carbonyl]-L-valine, methyl ester as a yellow oil.
• Reaction Scheme D step (d): In a manner analogous to that described in example 1 the above prepared alcohol (13 mg, 0.151 mmol) is oxidized under Swern conditions to provide 82 mg of a mixture of diastereomers of final title compound after flash chromatography (3:2 ethyl acetate/cyclohexane). The mixture partially crystallizes from cyclohexane/ethyl acetate upon evaporation of the solvent.
• Reaction Scheme D step (d): The above prepared alcohol is oxidized under Swern conditions as follows: To stirred solution of the above prepared alcohol (215 mg, 0.255 mmol) in anhydrous CH 2 CI 2 (3 mL) and anhydrous DMSO (0.36 mL, 5.1 mmol) at -45°C is added 2 M oxalyl chloride/CH 2 Cl 2 (1.0 mL) over 5 minutes. The solution is allowed to stir at -40 to -30°C for 2.5 hours. The soluti is then cooled to -70°C and diisopropylethylamine (0.67 m 3.8 mmol) is added over 5 minutes.
• reaction mixture is then washed with 0.5 N HC1 (2 x 500 mL), half- saturated sodium bicarbonate (2 x 500 mL), water (2 x 500 mL) and brine (300 mL).
• the reaction is dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (33.8 g, 98%) as a white solid; mp 74-76°C.
• the solid material is suspended in methylene chloride (2 L) and heated to reflux. It is then cooled to room temperature, treated with anhydrous magnesium sulfa and filtered. The filtrate is concentrated under vacuum provide the final title compound (42.2 g, 89%) as a whit solid; mp 194-196°C.
• Reaction Scheme D step (d): In a manner analogous to that described in example 1 the above prepared alcohol (206 mg, 0.274 mmol) is oxidized under Swern conditions to provide 170 mg (83%) of an orange glass after flash chromatography (3% CH 3 OH/CHCI 3 ) .
• Step B Preparation of [3 ⁇ , 4(S) ]-2,4,5-Trideoxy-2,2-difluoro-4- [ [3-methyl-l-oxo-2-[ [ (3- pyridinylmethoxy)carbonyl]amino]butyl]amino]-5-[4- (phenylmethoxy)phenyl]-N-(2-pyridinylmethyp-L-qlycero- pentanamide.
• step (b) The title compound is prepared in a manner analogous to that described in example 13, step A from 4-tert-butoxycarbonylamino-2,2-difluoro-3- hydroxy-5-(4-benzyloxy)phenylpentanoic acid, ethyl ester (1.5 g, 3.1 mmol) prepared in example 1 step B, and 3-(aminomethyl)pyridine (0.38 mL, 3.8 mmol).
• the ti compound is prepared from L-valine methyl ester hydrochloride (5.0 g, 30 mmol), triphosgene (4.66 g, 15. mmol), and (n-Bu) 3 N (0.05 mL, 0.4 mmol); however, 2-pyri carbinol (10.0 mL, 100 mmol, 3.3 equivalents) is added dropwise to the intermediate isocyanate.
• Step A 5 Preparation of [3 ⁇ , 4(S) ]-2,4,5-Trideoxy-2,2-difluoro-4- [ [3-methyl-l-oxo-2-[ [ (2- pyridinylmethoxy)carbonyl]amino]butyl]amino]-5-[ -(phenyl ⁇ methoxy)phenyl]-N-(3-pyridinylmethyl)-L-qlycero- pentanamide.
• the reaction is then stirred for 1.75 hours at - 15°C and then cooled to -78°C.
• Diisopropylethylamine (0.93 mL, 6.69 mmol) is added and the reaction is stirred an additional 10 minutes.
• the reaction is then allowed to warm to room temperature and is diluted with dichloromethane (25 mL).
• the reaction mixture is washed with water (2 x 25 mL) .
• the aqueous washes are extracted with dichloromethane (25 mL) .
• the combined organic extracts are dried over anhydrous sodium sulfate, filtered and concentrated under vacuum.
• step (d) The title compound is prepared in a manner analogous to the deprotection procedure of Example 17, step C, from N-[4-tert- butoxycarbonylamino-2,2-difluoro-3-hydroxy-l-oxo-5-(4- butyloxy)phenyl-pentyl]-O-methyl-D-valinol prepared above (quantitative yield); mass spectrum, m/z 451 (MH + ).
• Reaction Scheme A 1 step (e);
• the title compound is prepared in a manner analogous to the coupling method described in Example 17, step F, from N-[4-amino-2,2- difluoro-3-hydroxy-l-oxo-5-(4-benzyloxy)phenyl-pentyl]-O- methyl-D-valinol prepared above and the acid prepared in Example 8, Step A. Purification by crystallization (ethyl acetate plus 10% ethanol/pentane) provides the title compound in 58% yield; mass spectrum, m/z 685 (MH + ).
• Step C Preparation of N-[4-tert-butoxycarbonylamino-2,2-difluoro- 3-hydroxy-l-oxo-5-(4-benzyloxy)phenyl-pentyl3-O-(2- pyridylmethyl)-D-valinol.
• Reaction Scheme A, step (C 2 ); A mixture of N-[4-tert- butoxycarbonylamino-2,2-difluoro-3-hydroxy-l-oxo-5-(4- hydroxy)phenyl-pentyl]-0-(3-pyridylmethyl)-D-valinol (0.37 g, 0.7 mmol, prepared above), 3-picolyl chloride HCl (0.16 g, 0.98 mmol), cesium carbonate (0.775 g, 2.38 mmol) and potassium iodide (0.016 g, 0.098 mmol) in anhydrous DMF (7 mL) is stirred for 66 hours under an atmosphere of nitrogen.
• the reaction mixture is diluted with ethyl acetate (50 mL) and washed with water (2 x 50 mL) .
• the aqueous rinses are extracted with ethyl acetate (50 mL).
• the combined organic extracts are dried over anhydrous sodium sulfate, filtered and concentrated under vacuum.
• step (d) The title compound is prepared in a manner analogous to the deprotection procedure described in Example 17, step C from N-[4-tert- butoxycarbonylamino-2,2-difluoro-3-hydroxy-l-oxo-5-(4- hydroxy)phenyl-pentyl]-0-(3-pyridylmethyl)-D-valinol prepared above, in 84% yield; mass spectrum m/z 529 (MH + ).
• Reaction Scheme A 1 step (e);
• N-trityl-0-[2-( 2-methoxyethoxy)-l-ethy D-valinol (1.0 g, 2.28 mmol, prepared above) in dry ether saturated with hydrogen chloride (20 mL) is kept for 2.5 hours at room temperature.
• step (d) The title compound is prepared in a manner analogous to the deprotection procedure described in Example 17, step C from N-[4-tert- butoxycarbonylamino-2,2-difluoro-3-hydroxy-l-oxo-5-(4- benzyloxy)phenyl-pentyl]-0-[2-(2-methoxyethoxy)-1-ethyl]- valinol, prepared above, in 97% yield which is used directly in the next step; mass spectrum m/z 539 (MH + ) .
• Reaction Scheme A, step (C 2 ); A mixture of N-[4-tert- butoxycarbonylamino-2,2-difluoro-3-hydroxy-l-oxo-5-(4- hydroxy)phenyl-pentyl]-0-methyl-D-valinol (1.117 g, 2.43 mmol, prepared above), N-(2-chloroethyl)morpholine HCl (0.633 g, 3.40 mmol), cesium carbonate (2.69 g, 8.26 mmol) and potassium iodide (0.056 g, 0.34 mmol) in dry DMF (20 mL) is stirred for 140 hours at room temperature.
• reaction mixture is then diluted with ethyl acetate (100 mL) and washed with brine (2 x 100 mL).
• the aqueous washes are extracted with ethyl acetate (100 mL).
• the combined organic extracts are dried over anhydrous sodium sulfate, filtered and concentrated under vacuum.
• step (d) The title compound is prepared in a manner analogous to the deprotection procedure described in Example 17, step C from N-[4-tert- butoxycarbonylamino-2,2-difluoro-3-hydroxy-l-oxo-5-(4- ⁇ 2-N- morpholyl ⁇ ethyloxy)phenyl-pentyl3-O-methyl-D-valinol, prepared above, in 85% yield which is used directly in the next step.
• Step D Preparation of N-[4-(N- ⁇ 3-pyridylmethyl ⁇ oxycarbonyl-L- valyl)amino-2,2-difluoro-3-hydroxy-l-oxo-5-(4-.2-N- morpholyl ⁇ ethyloxy)phenyl-pentyl3-O-methyl-D-valinol.
• Reaction Scheme A', step (f) A mixture of the above prepared alcohol (0.280 g, 0.396 mmol), 1,1,1-triacetoxy- l,l-dihydro-l,2-benziodoxol-3(lH)-one (0.672 g, 1.583 mmol, Dess-Martin periodinane) and tert-butanol (0.075 mL, 0.792 mmol) in freshly distilled dichloromethane (10 mL, distilled over P 2 O 5 ) is stirred for 15 minutes at room temperature. The reaction mixture is then hydrolyzed with isopropanol (1.2 mL) and concentrated under vacuum.
• the present invention provides a method of treating a patient afflicted with a viral infection comprising the administration thereto of an effective antiviral amount of a compound of formula (I).
• viral infection refers to an abnormal state or condition characterized by viral transformation of cells, viral replication and proliferation.
• Viral infections for which treatment with a compound of formula (I) will be particularly useful include retroviruses such as but not limited to HTLV-I, HTLV-II, HTLV-III (HIV virus), murine leukemia virus, feline leukemia virus, cytomegalovirus(CMV) , avian sarcoma virus and the like.
• treatment with a compound of formula (I) would be useful in treating a wide range of states of .
• HIV infection AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV.
• the compounds of this invention are useful in preventing infection by HIV after suspected past exposure to HIV by, e.g., blood transfusion, accidental needle stick, or exposure to patient blood during surgery.
• an “effective antiviral amount” of a compound of formula (I) refers to an amount which is effective, upon single or multiple dose administration to the patient, in controlling the growth of the virus or in prolonging the survivability of the patient beyond that expected in the absence of such treatment.
• controlling a viral infection refers to slowing, interrupting, arresting or stopping the viral transformation of cells or the replication and proliferation of the virus and does not necessarily indicate a total elimination of the virus.
• the present invention further provides a method of inhibiting HIV protease in a patient in need thereof comprising administering to said patient an effective inhibitory amount of a compound of formula (I).
• HIV protea inhibitor such as a compound of formula (I).
• the term "patient” refers to a warm ⁇ blooded animal, such as a mammal, which is afflicted wit a particular viral infection. It is understood that humans, mice and rats are included within the scope of th term "patient”.
• a compound of formula (I) administered to a patient results in inhibition of HIV protease in the patient.
• retroviruses such as HTLV-III
• a patient is in need of treatment with an agent which inhibits HIV protease, such as a compound of formula (I), where the patient is suffering from certain viral infections for which HIV protease is implicated as a contributing factor in the progression of the disease.
• an agent which inhibits HIV protease such as a compound of formula (I)
• the patient is suffering from certain viral infections for which HIV protease is implicated as a contributing factor in the progression of the disease.
• an attending diagnostician can readily identify those patients who are i need of treatment with an agent which inhibits HIV protease, such as a compound of formula (I).
• an "effective inhibitory amount" of a compound of formula (I) is that amount which is effective, upon singl or multiple does administration to a patient, in providin an inhibition of HIV protease.
• the term "effective amount” refers to an effective antiviral or inhibitory amount of a compound of formula (I).
• An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances.
• the attending diagnostician including, but not limited to: the species of mammal; its size, age, and general health; the specific viral infection involved; the degree of or involvement or the severity of the viral infection; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
• An effective amount of a compound of formula (I) is expected to vary from about 0.1 milligram per kilogram of body weight per day (mg/kg/day) to about 100 mg/kg/day. Preferred amounts are expected to vary from about 0.5 to about 10 mg/kg/day.
• a compound of formula (I) can be administered in any form or mode which makes the compound bioavailable in effective amounts, including oral and parenteral routes.
• compounds of formula (I) can be administered orally, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, and the like.
• Oral administration is generally preferred.
• One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the compound selected, the viral infection to be treated, the stage of the infection, and other relevant circumstances.
• the compounds of formula (I) can be administered alone or in the form of a pharmaceutical composition in combination with pharmaceutically acceptable carriers or excipients, the proportion and nature of which are determined by the solubility and chemical properties of the compound selected, the chosen route of administration, and standard pharmaceutical practice.
• the compounds of the invention while effective themselves, may be formulated and administered in the form of their pharmaceutically acceptable salts for purposes of stability, convenience of crystallization, increased solubility and the like.
• compositions comprising a compound of formula (I) in admixture or otherwise in association with one or more inert carriers.
• These compositions are useful, for example, as assay standards, as convenient means of making bulk shipments, or as pharmaceutical compositions.
• An assayable amount of a compound of formula (I) is an amount which is readily measurable by standard assay procedures and techniques as are well known and appreciated by those skilled in the art. Assayable amounts of a compound of formula (I) will generally vary from about 0.001% to about 75% of the composition by weight.
• Inert carriers can be any material which does not degrade or otherwise covalently react with a compound of formula (I).
• Suitable inert carriers are water; aqueous buffers, such as those which are generally useful in High Performance Liquid Chromatography (HPLC) analysis; organic solvents, such as acetonitrile, ethyl acetate, hexane and the like; and pharmaceutically acceptable carriers or excipients.
• HPLC High Performance Liquid Chromatography
• compositions comprising a therapeutically effective amount of a compound of formula (I) in admixture or otherwise in association with one or more pharmaceutically acceptable carriers or excipients.
• the pharmaceutical compositions are prepared in a manner well known in the pharmaceutical art.
• the carrier or excipient may be a solid, semi-solid, or liquid material which can serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are well known in the art.
• the pharmaceutical composition may be adapted for oral or parenteral use and may be administered to the patient in the form of tablets, capsules, suppositories, solution, suspensions, or the like.
• the compounds of the present invention may be administered orally, for example, with an inert diluent or with an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets.
• the compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like.
• These preparations should contain" at least 4% of the compound of the invention, the active ingredient, but may be varied depending upon the particular form and may conveniently be between 4% to about 70% of the weight of the unit.
• the amount of the compound present in compositions is such that a suitable dosage will be obtained.
• Preferred compositions and preparations according to the present invention are prepared so that an oral dosage unit form contains between 5.0-300 milligrams of a compound of the invention.
• the tablets, pills, capsules, troches and the like may also contain one or more of the following adjuvants: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose, disintegrating agents such as alginic acid, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; and sweetening agents such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate or orange flavoring.
• a liquid carrier such as polyethylene glycol or a fatty oil.
• dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings.
• tablets or pills may be coated with sugar, shellac, or other enteric coating agents.
• a syrup may contain, in addition to the present compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.
• the compounds of the present invention may be incorporated into a solution or suspension. These preparations should contain at least 0.1% of a compound of the invention, but may be varied to be between 0.1 and about 50% of the weight thereof. The amount of the inventive compound present in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 5.0 to 100 milligrams of the compound of the invention.
• the solutions or suspensions may also include the one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylene diaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
• the parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic.
• the present invention is also directed to combinations of the HIV protease-inhibitory compounds with one or more agents useful in the treatment of AIDS, such as, for example, with known antiviral agents suitable for treating HIV 1 and HIV 2 viral infections, e.g., AZT, with or without a PNPase inhibitor, or in conjunctive therapy with DDI and a PNPase inhibitor.
• agents useful in the treatment of AIDS such as, for example, with known antiviral agents suitable for treating HIV 1 and HIV 2 viral infections, e.g., AZT, with or without a PNPase inhibitor, or in conjunctive therapy with DDI and a PNPase inhibitor.
• the compounds of this invention may be assayed fcr their HIV-protease inhibition using the following publishe techniques. Preparation of Retroviral Enzyme and Assay for Inhibition of the Protease
• Retroviral Enzyme To prepare the recombinant protease, the HIV protease is expressed via E. Coli by the published work of C. Guenet, et al. , in European Journal of Pharmacology Molecular Pharmacology Section, 172 (1989) 443-451.
• HPLC VYDAC wide pore 5 cm C-18 reverse phase, acetonitrile gradient, 0.1% trifluoroacetic acid. The extent of inhibition of the reaction is determined fro the peak heights of the products. HPLC of the products independently synthesized, provide quantitation standards and confirmation of the product composition.

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• 1995
  • 1995-06-06 CA CA002195125A patent/CA2195125C/en not_active Expired - Fee Related
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