WO1992014696A2 - α-AMINOALDEHYDES SUBSTITUES ET LEURS DERIVES - Google Patents

α-AMINOALDEHYDES SUBSTITUES ET LEURS DERIVES Download PDF

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WO1992014696A2
WO1992014696A2 PCT/US1992/001077 US9201077W WO9214696A2 WO 1992014696 A2 WO1992014696 A2 WO 1992014696A2 US 9201077 W US9201077 W US 9201077W WO 9214696 A2 WO9214696 A2 WO 9214696A2
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substituted
alkyl
group
compound
mammal
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PCT/US1992/001077
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WO1992014696A3 (fr
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Carl Nicholas Hodge
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The Du Pont Merck Pharmaceutical Company
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Priority to JP4507279A priority Critical patent/JPH06506921A/ja
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Publication of WO1992014696A3 publication Critical patent/WO1992014696A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • 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
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • 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
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • 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
    • C07C271/22—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 to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • 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
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • 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
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring

Definitions

  • This invention relates to substituted ⁇ -aminoaldehydes, compositions containing such compounds and methods of using such compounds as antiviral agents.
  • AIDS immunodeficiency syndrome
  • Proteases are enzymes which cleave proteins at specific peptide bonds. Many biological functions are controlled or mediated by proteases and their
  • protease renin cleaves the peptide angiotensinogen to produce the peptide angiotensin I.
  • Angiotensin I is further cleaved by the protease angiotensin converting enzyme (ACE) to form the hypotensive peptide angiotensin II.
  • ACE protease angiotensin converting enzyme
  • Inhibitors of renin and ACE are known to reduce high blood pressure in vivo. However, no
  • renin protease inhibitors have been developed, due to problems of oral availability and in vivo stability.
  • retroviruses encode a protease that is responsible for the proteolytic processing of one or more polyprotein precursors such as the pol and gag gene products. See Wellink, Arch. Virol . 98 1 (1988).
  • U.S. Patent No. 4,652,552 discloses methyl ketone derivatives of tetrapeptides as inhibitors of viral proteases.
  • U.S. Patent No. 4,644,055 discloses
  • European Patent Application No. WO 87/07836 discloses L-glutamic acid gammamonohydroxamate as an antiviral agent.
  • GB 2124233 discloses aromatic amino acid aldehyde derivatives that are inhibitors of chymotrypsin; and D.H. Rich (Research Monographs in Cell and Tissue Physiology. J. T. Dingle and J. L. Gordon, Editors, Elsevier, Amsterdam, 1986; p 201) discloses peptide aldehydes that are moderate renin inhibitors. None of these references disclose or suggest that the structurally diverse peptide aldehydes disclosed herein would inhibit HIV protease, would be efficacious in preventing human cells from being infected by HIV, or would be useful as antiviral therapies.
  • the aldehydes and derivatives of this invention provide significant improvements over protease inhibitors that are known in the art.
  • a large number of compounds have been reported to be renin inhibitors, but have suffered from lack of adequate bio-availability and are thus not useful as oral therapeutic agents, particularly if oral administration is desired.
  • This poor activity has been ascribed to the unusually high molecular weight of renin inhibitors, to inadequate solubility properties, and to the presence of a number of peptide bonds, which are vulnerable to cleavage by mammalian proteases.
  • ⁇ -aminoaldehydes and derivatives described herein have a distinct advantage in this regard, in that many do not contain peptide bonds, are of low molecular weight, and can be either hydrophobic or hydrophilic yet still inhibit the viral protease enzyme.
  • renin inhibitors do not inhibit HIV protease.
  • the structure-activity requirements of renin inhibitors differ from those of HIV protease inhibitors.
  • the aldehydes and derivatives of the invention are particularly useful as HIV protease inhibitors.
  • HIV protease inhibitors have been reported, but to date very few have shown activity against viral replication in human cells. This lack of cellular activity is probably due in part to the factors
  • aldehydes and derivatives disclosed herein show potent inhibition of viral replication in human cells.
  • aldehydes and derivatives disclosed herein are very easy to prepare. Many can be prepared in one or two steps from commercially available starting materials. This facile preparation results in low cost for reagents and equipment, which in turn increases the likelihood of lower costs for the final product when compared to other AIDS drugs.
  • R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of:
  • R 2A , R 3A and R 4A are independently selected from the following group consisting of:
  • each R 5 is selected from the group consisting of:
  • R 6 when a substituent on carbon, is selected from the group consisting of:
  • R 6 when a substituent on nitrogen, is selected from the group consisting of:
  • phenyl, benzyl, phenethyl, hydroxy, C 1 -C 4 alkoxy, nitro, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethyl, -NR 7 R 8 , C 2 -C 6 alkoxyalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylcarbonyl; -S(O) m R 7 , -SO 2 NR 7 R 8 , or R 6 may be a 3- or 4- carbon chain attached to adjacent atoms on the ring to form a fused 5- or 6- membered ring, said 5- or 6- membered ring being
  • R 7 is H, phenyl, benzyl or C 1 -C 6 alkyl
  • R 8 is H or C 1 -C 4 alkyl
  • R 7 R 8 can join to form (CH 2 ) 4 , (CH 2 ) 5 ,
  • R 9 is H or CH 3 ;
  • R 11 is H, phenyl, benzyl or C 1 -C 6 alkyl
  • R 12 is H or C 1 -C 4 alkyl
  • n 0, 1 or 2;
  • n 0 or 1
  • W is selected from the group consisting of:
  • X is selected from the group consisting of:
  • Y is selected from the group consisting of:
  • Q is selected from oxygen or sulfur
  • Q 1 is selected from oxygen, sulfur, NR 8 or a direct bond.
  • R 3A and R 4A , m, n, p, Q, W, X, Y, Z, etc. occurs more than one time in any constituent or in formula (I), its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms;
  • alkoxy represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge
  • cycloalkyl is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; and "biycloalkyl” is intended to include saturated bicyclic ring groups such as
  • alkenyl is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl and the like; and "alkynyl” is intended to include hydrocarbon chains of either a straight or branched
  • Halo refers to fluoro, chloro, bromo and iodo; and "counterion” is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate and the like.
  • aryl or “aromatic residue” is intended to mean phenyl or naphthyl;
  • carbocyclic is intended to mean any stable 5- to 7- membered monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic.
  • heterocycle is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is either saturated, unsaturated, or aromatic and which consists of carbon atoms and from 1 to 4 heteroatoms selected from the group consisting of N, O and S and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen may optionally be
  • heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure.
  • the heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
  • heterocycles include, but are not limited to, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl,
  • substituted means that an one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • stable compound or “stable structure” is meant herein a compound that is sufficiently robust to survive: isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • pharmaceutically acceptable salts and “prodrugs” refer to derivatives of the disclosed compounds that are modified by making acid or base salts, or by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
  • examples include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; acetate, formate and benzoate derivatives of alcohols and amines; and the like.
  • Preferred compounds of the present invention are compounds of formula (I) wherein:
  • R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of:
  • heterocyclic ring system composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom substituted with 0-2 R 6 ;
  • R 2A , R 3A and R 4A are hydrogen
  • R 5 , R 6 , R 7 , R 8 , and R 9 are as defined above;
  • R 11 is H
  • R 12 is H
  • n 0, 1 or 2;
  • n 0 or 1
  • W is selected from the following:
  • Y is selected from the group consisting of:
  • Q is oxygen or sulfur
  • Q 1 is oxygen, sulfur, NR 12 or a direct bond.
  • W is selected from the group consisting of:
  • X is selected from the group consisting of:
  • Y is selected from the group consisting of:
  • R 1 is C 1 -C 8 alkyl substituted with 0-3 R 5 ;
  • R 2 , R 3 and R 4 are independently selected from the group
  • each R 5 is selected from the group consisting of:
  • each R 6 when a substituent on carbon, is selected from the group consisting of:
  • alkylcarbonylamino, -S(O) m R 7 , -SO 2 NR 7 R 8 , -NHSO 2 R 8 , or R 6 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6- membered ring being optionally substituted on the aliphatic carbons with halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, or NR 7 R 8 , or when R 6 is attached to a saturated carbon atom it may be carbonyl or thiocarbonyl; and
  • each R 6 when a substituent on nitrogen, is selected from the group consisting of:
  • phenyl benzyl, phenethyl, hydroxy, C 1 -C 4 alkoxy, nitro, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethyl, -NR 7 R 8 , C 2 -C 6 alkoxyalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4
  • alkylcarbonyloxy C 1 -C 4 alkylcarbonyl, C 1 -C 4
  • alkylcarbonyl; -S(O) m R 7 , -SO 2 NR 7 R 8 , or R 6 may be a 3- or 4- carbon chain attached to adjacent atoms on the ring to form a fused 5- or 6-membered ring, said 5- or 6- membered ring being optionally substituted on the
  • R 7 is H, benzyl or C 1 -C 6 alkyl
  • R 8 is H or C 1 -C 4 alkyl
  • R 7 R 8 can join to form (CH 2 ) 4 , (CH 2 )5,
  • R 9 is H or CH 3 ;
  • W is selected from the group consisting of:
  • Still further preferred compounds of the present invention are compounds within the further preferred scope ([C] above) wherein:
  • R 1 is C 1 -C 4 alkyl substituted with:
  • R 2 and R 3 are independently selected from hydrogen, or C 1 -C 4 alkyl substituted with 0-2 R 5 ;
  • R 4 is C 1 -C 4 alkyl substituted with:
  • each R 5 is selected independently from the group consisting of:
  • each R 6 when a substituent on carbon, is selected from the group consisting of:
  • each R 6 when a substituent on nitrogen, is C 1 -C 4 alkyl, phenyl, benzyl or phenethyl;
  • R 7 is H or C 1 -C 2 alkyl
  • R 8 is H or C 1 -C 2 alkyl
  • R 7 R 8 can join to form (CH 2 ) 4 , (CH 2 ) 5 ,
  • W is selected from the following:
  • X is selected from the group consisting of:
  • R 1 is C 1 -C 4 alkyl substituted with:
  • aryl substituted with 0-2 R 6 or a heterocyclic ring system, composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom, substituted with 0-1 R 6 ;
  • R 3 is C 1 -C 4 alkyl substituted with 0-1 R 5 ;
  • R 4 is C 1 -C 4 alkyl substituted with:
  • each R 5 is selected independently from the group consisting of:
  • each R 6 when a substituent on nitrogen, is C 1 -C 2 alkyl or benzyl; m is 2;
  • n 0;
  • P is hydrogen or optionally an alcohol protecting group 1
  • R 10 is hydrogen or an aliphatic or substituted aromatic group
  • the preferred group is the 2-methoxyethoxymethyl group 3 .
  • Thioamides of structure (VII) and (VIII) can be made from the above protected hydroxyamides (IV) followed by treatment with a thionation reagent 4 , and deprotection followed by oxidation to the aldehyde.
  • a preferred thionation reagent is Lawesson's reagent, and a preferred protecting group is the 2-methoxyethoxymethyl group 2 .
  • Act is an activating group, preferably chloride, and P is optionally a protecting group.
  • LG is a leaving group such as halogen or OSO 2 R, as is described in the art 6 .
  • the preferred method employs a tosylate or iodide as leaving group, and a secondary amine as the nucleophile, i.e., R 12 is not hydrogen.
  • a preferred method for the preparation of compounds wherein R 12 is hydrogen is simply by LiAlH 4 reduction of the amides in
  • a final preferred method is the reaction of amines (II) with aldehydes (XXXIII), followed by reduction of the imine by catalyic hydrogenation or by borohydride reduction of the intermediate imine.
  • the compounds of the invention can be advantageously prepared by reaction of secondary amides or thioamides (XVII) with halogenating agents to produce imidoyl halides (X) 7 .
  • halogenating agents to produce imidoyl halides (X) 7 .
  • the imidoyl halides so produced can then be reacted with alcohols to produce imidates (XIX) 8 ; or with amines to produce amidines (XX) 9 , as shown.
  • Preferred halogenating reagents include phosphorous pentachloride and phosphorous oxychloride.
  • the compounds of the invention can be prepared by reacting amine (II) with a derivatizing agent to form the isocyanate or carbamate, followed by reaction with a primary or secondary amine, optionally in the presence of a base 10 .
  • the compounds of the invention can be prepared by reacting amine (II) with a derivatizing agent to form the isocyanate, followed by reaction with an alcohol in the presence of a base 10 .
  • aldehyde 11 can be readily oxidized to aldehyde 11 (I), following deprotection if necessary 1 , by techniques that are well known in the art.
  • Preferred methods include pyridinium dichromate, pyridinium chlorochrornate, pyridine/sulfur trioxide, and activated dimethyl sulfoxide.
  • the preferred method employs dimethylsulfoxide/oxalyl chloride 12 , also known as Swern oxidation, in dichloromethane or
  • contemplated scope that may not survive such oxidation.
  • examples of these are primary alcohols, amines, indoles, sulfides, thiols. If necessary, these groups can be protected prior to oxidation of the aldehyde.
  • the reductive conditions described below may be used to prepare the aldehyde when oxidative conditions cause difficulties with certain functional groups.
  • Amine (VIII) can be reacted with any of the above electrophiles, (III, IX or XIII) to form N-methoxyamide (XXIX). It is known that (XXIX) can be reduced cleanly to aldehyde by stoichiometric lithium aluminum hydride 13 , provided that sensitive functionality is not present.
  • the compounds of the invention can be obtained by reacting an amino alcohol or amino acid derivative (II), (XXIX) or (XXX) , with the appropriate left portion of the molecule, that is, carboxylic acid (III), activated sulfonic acid (IX) and alkyl halide or tosylate (XIII). Methods of preparation of these intermediates are described below.
  • aminoalcohols with values of R 4 that are not available can be easily synthesized by reduction of ⁇ -amino acids or esters (XXX) .
  • a preferred method is the direct reduction of amino acids employing borane•methyl sulfide in the presence of BF 3 etherate 16 .
  • ⁇ -amino acids or esters are available 17 , both natural and unnatural, and simple variations of known preparative methods 18 will provide amino acids with any R 4 value of interest.
  • N-methoxyamides (XXIX) can be prepared by techniques known in the art. 14
  • (III) can be prepared simply by reacting the amino group of an ⁇ -amino acid or ester (XXXI) with one of the following: R 1 CO 2 H (XXXII), R 1 NHR 12 (XXXIII), R 1 OH (XXXIV), R 1 LG (XXXV) , or RSO 2 Act (XXXVI)
  • carboxylic acids or esters (III) can be prepared by a number of techniques that are well known in the art.
  • R 1 -LG under conditions for condensing alcohols with alkyl halides or tosylates 19 , preferably in the presence of a base, preferably NaH, in a solvent. preferably a polar aprotic solvent such as pyridine or DMF, where LG is preferably bromide or tosylate;
  • R 1 CO 2 R 10 under the well-known conditions suitable for condensing alcohols and acids or esters 20 , wherein R 10 is preferably H , the preferred activating agent is thionyl chloride, and the preferred solvent is dimethyIformamide;
  • (III) can be prepared by means known in the art.
  • Preferred is the reaction of malonic half acid (XXXIX) with a group R 1 NHR 12 (see section [H.3]).
  • Many malonic acid derivatives are available commercially; the preparation of other compounds can be accomplished by procedures well known in the art.
  • Many carboxylic acid derivatives (XXXIX) are available commercially; the preparation of other compounds is well known in the art 22 .
  • (III) can be prepared by means known in the art.
  • Preferred is the oxidation of alcohols (XXXXI) prepared in [H.6], above.
  • Preferred oxidation reagents are pyridinium chlorochromate, pyridinium dichromate, or DMSO/oxalyl chloride.
  • Thionation preferably with Lawesson's reagent, can provide the thiocarbonyl.
  • (III) can be prepared by means known in the art. Preferred is the reaction of epoxides R 1 (CH 2 OCH 2 ) with an organometallic derivative of ester or acid (XXXX) 24 , preferably the cuprate 25 . The product is ß-hydroxycarboxyl derivative (XXXXII).
  • Epoxides R 1 (CH 2 OCH 2 ) can be prepared by the reaction of R 1 CHO, see above, with reagents known in the art. The prefered reagent for formation of epoxides from such aldehydes is dimethylsufoxonium methylide 26 .
  • (III) can be prepared by means known in the art.
  • Said ylides can be prepared by the reaction of R 1 LG, see [H.3], with reagents (Ar) 3 3P under conditions known in the art, preferably employing the condensation of triphenylphosphine and a primary alkyl bromide, followed by treatment with sodium hydride.
  • R 3 can be prepared from the malonic acid derivatives discussed above, preferably by diborane/methyl sulfide reduction of the malonic half acid to the alcohol, followed by oxalyl chloride/dimethyl sulfoxide oxidation to the aldehyde.
  • (III) can be prepared by means known in the art.
  • Preferred is the catalytic hydrogenation of the olefins (XXXXIV) produced in [H.9], above 28 .
  • Advantageous reagents are 10% palladium on carbon with ethanol or ethanol/THF as solvent under 50-100 PSI hydrogen gas.
  • hydrazine to form hydrazone (XLV) 30 .
  • hydrazone preferably with sodium borohydride,provides disubstituted hydrazine (XLVI).
  • (III) can be prepared by means known in the art.
  • Preferred is the acylation of hydrazone (XLV) with activated carboxylic acid R 1 COAct, wherein Act is preferably chloride. Hydride or catalytic reduction of the substituted hydrazone,
  • ⁇ -Aminosulfonic acids are readily available by the reaction of aldehydes R 3 CHO and amines R 12 NH 2 in the presence of sodium bisulfite. 32 This procedure is general for aromatic or aliphatic amines and aldehydes and proceeds in good yields.
  • the preparation of R 1 derivatives (XXXI) through (XXXVI) are commercially available or can be prepared as described in section [H]. Cleavage of the t-butylsulfonamide or other protecting can yield the sulfonic acid or directly provide the sulfonyl chloride (IX, Act - Cl) on treatment with aqueous hypochlorite.
  • sulfonic acids or esters (IX) can be prepared by a number of techniques that are well known in the art.
  • R 1 LG under conditions for condensing alcohols with alkyl halides or tosylates 19 , preferably in the presence of a base, preferably NaH, in a solvent, preferably a polar aprotic solvent such as pyridine, where LG is preferably tosylate;
  • the preferred activating agent is thionyl chloride
  • the preferred solvent is
  • aldehydes R 3 CHO reacts bisulfite or sulfur dioxide with aldehydes R 3 CHO to form the sulfonic acid. Conversion to the sulfonyl chloride and then the sulfonamide follows standard procedures 33 . Many aldehydes R 3 CHO are
  • sulfonic acids (IX) can be prepared by means known in the art. Preferred is the reaction of ß-hydroxysulfonic acid derivative
  • sulfonic acids can be prepared by means known in the art. Preferred is the reaction of ß-carboxysulfonic acid derivative
  • (IX) can be prepared by means known in the art.
  • Preferred is the reaction of sulfonamide (L) with a group R 1 CHO (see above) in the presence of base to form alcohol (LI).
  • Another advantageous method is the reaction of sulfite ion with epoxides, R 1 -(CHOCH)-R 3 34 .
  • Many sulfonic acids (L) are available commercially; the preparation of other compounds is well known in the art.
  • the preferred method is the reaction of alkyl halides R 1 X with sulfite ion 35 . Derivitization to values of J other than hydrogen is also well known 35 .
  • chlorochromate pyridinium dichromate, or DMSO/oxalyl chloride.
  • Thionation preferably with Lawesson's reagent, can provide the thiocarbonyl.
  • (IX) can be prepared by means known in the art. Preferred is the reaction of epoxides R 1 (CH 2 OCH 2 ) with the dianion of sulfonamide (L), preferably the dianion formed by
  • Epoxides R 1 (CH 2 OCH 2 ) can be prepared by the methods described in section [H.8].
  • R 1 P(Ar) 3 with an aldehyde (LIV), as described in section [H.9].
  • the sulfonaldehydes substituted with R 3 can be prepared from the sulfonic acid derivatives discussed above, preferably by diborane/methyl sulfide reduction of the sulfonamide to the alcohol, followed by oxalyl chloride/dimethyl
  • (IX) can be prepared by means known in the art. Preferred is the catalytic hydrogenation of the olefins (LV) produced in
  • Advantageous reagents are 10% palladium on barium sulfate with ethanol or ethanol/THF as solvent under 50-100 PSI hydrogen gas.
  • Advantageous reagents are catalytic osmium tetroxide in the presence of N-methylmorpholine-N- oxide, as discussed in section [H.11].
  • Leaving-group substituted derivatives (XIII) can be prepared by means known to one skilled in the art.
  • the preferred method employs the reduction of
  • the preferred reagent for the latter reaction is phosphorous tribromide.
  • Another preferred technique is the displacement of tosylate or bromide so formed with sodium iodide/dimethyl sulfoxide, and employing the alkyl iodide as the electrophile.
  • R may have functional groups that are sensitive to the reaction conditions described in section [I]. Should this be the case, standard protecting group chemistry 1 will obviate any difficulties.
  • N-Carbobenzyloxyalanine (6.63 g, 29.7 mmol; Sigma Chemical Company) was dissolved in 30 mL THF in a 100 mL oven-dried flask under N 2 and stirred at room temperature while adding 1,1'-carbonyl diimidazole (4.82 g, 29.7 mmol; Aldrich
  • isoleucine methylene 1.3 (m, 1H, isoleucine methine); 0.8- 1.1 (m, 6H, methyls) .
  • HIV gag polyprotein corresponding to all of pl7 and 78 amino acids of p24, produced by in vitro translation using rabbit reticulocyte lysate and mRNA prepared in vitro from plasmid encoding full length gag polyprotein linerized with the restriction enzyme Pst 1. (See S. Erickson-Viitanen et al.. Aids Research and Human Retroviruses, 5 (6), 577
  • Source of protease Either (A) crude E. coll lysate of bacteria harboring a plasmid containing HIV protease under the control of the lac prombtor, used at a final concentration of 0.5 mg/ml, or (B) inclusion bodies of E. coli harboring plasmid containing HIV protease under the control of the T7 promotor (Cheng et al., Gene, in press (1990). Such inclusion bodies were solubilized in 8 M urea, 50 mM Tris pH 8.0. Protease activity was recovered by dilution of the inclusion bodies 20-fold in buffer containing 50 mM Sodium Acetate, pH 5.5, ImM EDTA, 10% glycerol and 5% ethylene glycol. This protease source was used at a final concentration of 0.00875 mg/ml.
  • Inhibitory compounds were dissolved in sufficient DMSO to make a 2.5 mM stock concentration. All further
  • IC 50 is the concentration
  • MT-2 a human T-cell line
  • FCS heat inactivated fetal calf serum
  • Test compounds were dissolved in dimethylsulfoxide to 5 mg/ml and serially diluted into RPMI medium to ten times the desired final concentration.
  • MT-2 cells (5 ⁇ 10E5/ml) in 2.3 ml were mixed with 0.3 ml of the appropriate test compound solution and allowed to sit for 30 minutes at room temperature.
  • HIV(3b) or HIV(Rf) ( ⁇ 5 ⁇ 10E5 plaque forming units/ml) in 0.375 ml was added to the cell and compound mixtures and incubated for one hour at 36°C. The mixtures were centrifuged at 1000 rpm for 10 minutes and the
  • the virus titers of the progeny virus produced in the presence or absence of test compounds were determined by plaque assay.
  • Progeny virus suspensions were serially diluted in RPMI and 1.0 ml of each dilution was added to 9 ml of MT-2 cells in RPMI. Cells and virus were incubated for 3 hours at 36°C to allow for efficient attachment of the virus to cells. Each virus and cell mixture was aliquoted equally to two wells of a six well poly-L-lysine coated culture plate and incubated overnight at 36°C, 4% CO 2 .
  • Liquid and unattached cells were removed prior to the addition of 1.5 ml of RPMI with 0.75% (w/v) Seaplaque agarose (FMC Corp) and 5% FCS. Plates were incubated for 3 days and a second RPMI/agarose overlay was added. After an additional 3 days at 36°C, 4% CO 2 , a final overlay of phosphate-buffered saline with 0.75% Seaplaque agarose and Img MTT/ml was added. The plates were incubated overnight at 36°C. Clear plaques on a purple background were counted and the number of plaque forming units of virus was
  • test compounds were tested for each sample. The antiviral activity of test compounds was determined by the percent reduction in the virus titer with respect to virus grown in the absence of any inhibitors.
  • MT-2 a human T-cell line
  • FCS fetal calf serum
  • GEBCO gentamycin
  • Test compounds were dissolved in dimethyl-suIfoxide to 5 mg/ml and serially diluted into RPMI medium to ten times the desired final concentration.
  • MT-2 cells (5 ⁇ 10E4/0.1 ml) were added to each well of a 96 well culture plate and 0.02 ml of the appropriate test compound solution was added to the cells such that each compound concentration was present in two wells. The cells and compounds were allowed to sit for 30 minutes at room temperature.
  • HIV(3b) or HIV(Rf) ⁇ 5 ⁇ 10E5 plaque forming units/ml was diluted in medium and added to the cell and compound mixtures to give a multiplicity of infection of 0.01 plaque forming
  • the mixtures were incubated for 7 days at 36°C, during which time the virus replicated and caused the death of unprotected cells.
  • the percentage of cells protected from virus induced cell death was determined by the degree of metabolism of the tetrazolium dye, XTT. In living cells, XTT was metabolized to a colored formazan product which was quantitated spectrophotometrically at 450 nm. The amount of colored formazan was proportional to the number of cells protected from virus by the test compound. The concentration of compound protecting either 50% (IC 50 ) or 90% (IC 90 ) with respect to an uninfected cell culture was determined.
  • Examples I, J, K, L, M and N show activity in ther above tests.
  • Examples J and K show cell free enzyme inhibition IC 50 's of less than 5 ⁇ g/mL in the HIV low multiplicity assay.

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

Abstract

L'invention se rapporte à des α-aminoaldéhydes substitués, à des compositions pharmaceutiques qui les contiennent et à des procédés d'utilisation de tels composés comme agents antiviraux.
PCT/US1992/001077 1991-02-22 1992-02-21 α-AMINOALDEHYDES SUBSTITUES ET LEURS DERIVES WO1992014696A2 (fr)

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0611756A2 (fr) * 1993-02-19 1994-08-24 Takeda Chemical Industries, Ltd. Alcool et aldéhyde dérivés comme inhibiteur de cathepsin L et comme inhibiteur de la résorption osseuse
WO1994023045A1 (fr) * 1993-04-07 1994-10-13 Boehringer Ingelheim International Gmbh Procede d'inhibition de la transcription de genes
US5386215A (en) * 1992-11-20 1995-01-31 Massachusetts Institute Of Technology Highly efficient planar antenna on a periodic dielectric structure
WO1995009838A1 (fr) * 1993-10-01 1995-04-13 Merrell Pharmaceuticals Inc. INHIBITEURS DE LA PRODUCTION DE PROTEINES DE β-AMYLOIDE
US5413999A (en) * 1991-11-08 1995-05-09 Merck & Co., Inc. HIV protease inhibitors useful for the treatment of AIDS
US5492896A (en) * 1993-02-15 1996-02-20 Bayer Aktiengesellschaft Pseudopeptides having an antiviral action
WO1996020725A2 (fr) * 1995-01-06 1996-07-11 Sibia Neurosciences, Inc. Peptide, analogue peptidique et analogue d'acide amine agissant comme inhibiteurs de protease
US5559256A (en) * 1992-07-20 1996-09-24 E. R. Squibb & Sons, Inc. Aminediol protease inhibitors
US5714471A (en) * 1995-01-06 1998-02-03 Sibia Neurosciences, Inc. Peptide and peptide analog protease inhibitors
WO1998008941A1 (fr) * 1996-08-30 1998-03-05 Cephalon Inc. Inhibiteurs aldehydes de cysteine et serine proteases contenant un groupe thiomethylene
US5852007A (en) * 1995-11-28 1998-12-22 Cephalon, Inc. Cysteine and serine protease inhibitors containing D-amino acid at the P2 position, methods of making same, and methods of using same
US5977074A (en) * 1993-10-01 1999-11-02 Merrell Pharmaceuticals, Inc. Inhibitors of β-amyloid protein production
WO2000024704A1 (fr) * 1998-10-23 2000-05-04 Senju Pharmaceutical Co., Ltd. Procede de fabrication d'aldehydes de peptidyle
US6214800B1 (en) 1995-10-25 2001-04-10 Senju Pharmaceutical Co., Ltd. Angiogenesis inhibitor
US6551999B1 (en) 1995-10-25 2003-04-22 Senju Pharmaceutical Co., Ltd. Angiogenesis inhibitor
EP2271660B1 (fr) * 2008-03-26 2020-05-06 Novozymes A/S Compositions enzymatique liquides stabilisées

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US6071895A (en) * 1992-03-11 2000-06-06 Narhex Limited Polar-substituted hydrocarbons
ATE253050T1 (de) 1992-03-11 2003-11-15 Narhex Ltd Aminderivate von oxo- und hydroxy- substituierten kohlenwasserstoffen
US5888992A (en) * 1992-03-11 1999-03-30 Narhex Limited Polar substituted hydrocarbons
RU2126794C1 (ru) * 1992-03-11 1999-02-27 Нархекс Лимитед Аминопроизводные оксо- или гидроксизамещенных гидразинов, способ их получения и фармацевтические композиции для ингибирования ретровирусной протеазы

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Cited By (34)

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Publication number Priority date Publication date Assignee Title
US5413999A (en) * 1991-11-08 1995-05-09 Merck & Co., Inc. HIV protease inhibitors useful for the treatment of AIDS
US5776933A (en) * 1992-07-20 1998-07-07 E. R. Squibb & Sons, Inc. Method of inhibiting protease
US5559256A (en) * 1992-07-20 1996-09-24 E. R. Squibb & Sons, Inc. Aminediol protease inhibitors
US5760036A (en) * 1992-07-20 1998-06-02 E. R. Squibb & Sons, Inc. Aminediol protease inhibitors
US5386215A (en) * 1992-11-20 1995-01-31 Massachusetts Institute Of Technology Highly efficient planar antenna on a periodic dielectric structure
US5492896A (en) * 1993-02-15 1996-02-20 Bayer Aktiengesellschaft Pseudopeptides having an antiviral action
US5498728A (en) * 1993-02-19 1996-03-12 Takeda Chemical Industries, Ltd. Derivatives of L-tryptophanal and their use as medicinals
EP0611756A2 (fr) * 1993-02-19 1994-08-24 Takeda Chemical Industries, Ltd. Alcool et aldéhyde dérivés comme inhibiteur de cathepsin L et comme inhibiteur de la résorption osseuse
EP0611756A3 (fr) * 1993-02-19 1994-11-30 Takeda Chemical Industries Ltd Alcool et aldéhyde dérivés comme inhibiteur de cathepsin L et comme inhibiteur de la résorption osseuse.
US5716980A (en) * 1993-02-19 1998-02-10 Takeda Chemical Industries, Ltd. Alcohol or aldehyde derivatives and their use
US6090542A (en) * 1993-04-07 2000-07-18 Boehringer Ingelheim International Gmbh Process for inhibiting the transcription of genes
WO1994023045A1 (fr) * 1993-04-07 1994-10-13 Boehringer Ingelheim International Gmbh Procede d'inhibition de la transcription de genes
WO1995009838A1 (fr) * 1993-10-01 1995-04-13 Merrell Pharmaceuticals Inc. INHIBITEURS DE LA PRODUCTION DE PROTEINES DE β-AMYLOIDE
CN1078886C (zh) * 1993-10-01 2002-02-06 默里尔药物公司 抑制β－淀粉样蛋白产生的抑制剂
US5977074A (en) * 1993-10-01 1999-11-02 Merrell Pharmaceuticals, Inc. Inhibitors of β-amyloid protein production
WO1996020725A2 (fr) * 1995-01-06 1996-07-11 Sibia Neurosciences, Inc. Peptide, analogue peptidique et analogue d'acide amine agissant comme inhibiteurs de protease
US6015879A (en) * 1995-01-06 2000-01-18 Sibia Neurosciences, Inc. Peptide and peptide analog protease inhibitors
US5804560A (en) * 1995-01-06 1998-09-08 Sibia Neurosciences, Inc. Peptide and peptide analog protease inhibitors
WO1996020725A3 (fr) * 1995-01-06 1996-10-17 Salk Inst Biotech Ind Peptide, analogue peptidique et analogue d'acide amine agissant comme inhibiteurs de protease
US5863902A (en) * 1995-01-06 1999-01-26 Sibia Neurosciences, Inc. Methods of treating neurodegenerative disorders using protease inhibitors
US5872101A (en) * 1995-01-06 1999-02-16 Sibia Neurosciences, Inc. Methods of treating neurodegenerative disorders using protease inhibitors
US5962419A (en) * 1995-01-06 1999-10-05 Sibia Neurosciences, Inc. Peptide and peptide analog protease inhibitors
US5969100A (en) * 1995-01-06 1999-10-19 Sibia Neurosciences, Inc. Peptide, peptide analog and amino acid analog protease inhibitors
US6153171A (en) * 1995-01-06 2000-11-28 Sibia Neurosciences, Inc. Methods for identifying compounds effective for treating neurodegenerative disorders and for monitoring the therapeutic intervention therefor
US5714471A (en) * 1995-01-06 1998-02-03 Sibia Neurosciences, Inc. Peptide and peptide analog protease inhibitors
US6017887A (en) * 1995-01-06 2000-01-25 Sibia Neurosciences, Inc. Peptide, peptide analog and amino acid analog protease inhibitors
US6051684A (en) * 1995-01-06 2000-04-18 Sibia Neurosciences Inc. Methods of treating neurodegenerative disorders using protease inhibitors
US6214800B1 (en) 1995-10-25 2001-04-10 Senju Pharmaceutical Co., Ltd. Angiogenesis inhibitor
US6551999B1 (en) 1995-10-25 2003-04-22 Senju Pharmaceutical Co., Ltd. Angiogenesis inhibitor
US5852007A (en) * 1995-11-28 1998-12-22 Cephalon, Inc. Cysteine and serine protease inhibitors containing D-amino acid at the P2 position, methods of making same, and methods of using same
US5744339A (en) * 1996-08-30 1998-04-28 Cephalon, Inc. Thiomethylene group-containing aldehyde cysteine and serine protease inhibitors
WO1998008941A1 (fr) * 1996-08-30 1998-03-05 Cephalon Inc. Inhibiteurs aldehydes de cysteine et serine proteases contenant un groupe thiomethylene
WO2000024704A1 (fr) * 1998-10-23 2000-05-04 Senju Pharmaceutical Co., Ltd. Procede de fabrication d'aldehydes de peptidyle
EP2271660B1 (fr) * 2008-03-26 2020-05-06 Novozymes A/S Compositions enzymatique liquides stabilisées

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WO1992014696A3 (fr) 1993-02-18
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CA2104602A1 (fr) 1992-08-23
AU1531092A (en) 1992-09-15
ZA921279B (en) 1993-08-23

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