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  • 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
• • A—HUMAN NECESSITIES
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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/12—Radicals substituted by oxygen atoms
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  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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  • C07—ORGANIC CHEMISTRY
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  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
  • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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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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  • C07—ORGANIC CHEMISTRY
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  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • 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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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention is concerned with compounds which inhibit the reverse transcriptase encoded by human immunodeficiency virus (HTV) or pharmaceutically acceptable salts thereof and are of value in the prevention of infection by HTV, the treatment of infection by HTV and the treatment of the resulting acquired immune deficiency syndrome (AIDS). It also relates to pharmaceutical compositions containing the compounds and to a method of use of the present compounds and other agents for the treatment of AIDS and viral infection by HTV.
• HTV human immunodeficiency virus
• AIDS acquired immune deficiency syndrome
• a retroviras designated human immunodeficiency virus is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This vims was previously known as LAV, HTLV-i ⁇ , or ARV.
• a common feature of retrovirus replication is reverse transcription of the RNA genome by a virally encoded reverse transcriptase to generate DNA copies of HTV sequences, a required step in viral replication. It is known that some compounds are reverse transcriptase inhibitors and are effective agents in the treatment of AIDS and similar diseases, e.g., azidothymidine or AZT.
• Nucleotide sequencing of HIV shows the presence of a . gene in one open reading frame [Ratner, L. et al., Nature, 313. 277(1985)].
• Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, an endonuclease and an HTV protease [Toh, H. et aL, EMBO J. 4, 1267 (1985); Power, M.D. et aL, Science, 231, 1567 (1986); Pearl, L.H. et al., Nature 222, 351 (1987)].
• the compounds of this invention are inhibitors of HTV reverse transcriptase. Furthermore, the compounds of the present invention do not require bioactivation to be effective.
• This invention is concerned with the compounds of formula A described below, combinations thereof, or pharmaceutically acceptable salts or esters thereof, in the inhibition of HTV reverse transcriptase, the prevention or treatment of infection by HIV and in the treatment of the resulting acquired immune deficiency syndrome (AIDS).
• the compounds of this invention include those with structural formula A:
• W is O, S, -N-CN, or -N-OR2
• n is defined above
• -C ⁇ _3alkyl substituted with one or more of: a) aryl, unsubstituted or substituted with one or more of: i) -C ⁇ _ 5 alkyl, ii) -C ⁇ _5alkoxy, iii) -OH, iv) halogen, or v) -NR2R2, or b) heterocycle, unsubstituted or substituted with one or more of:
• -C ⁇ _5alkoxy 0 a) -C ⁇ _5alkoxy, b) -OH, c) aryl, unsubstituted or substituted with one or more of: i) -Ci- 5 alkyl, ii) -C ⁇ _5alkoxy, iii) -OH, ' iv) halogen, or v) -NR2R2, or d) heterocycle, unsubstituted or substituted with one or more of: i) -C ⁇ _ 5 alkyl, ii) -Ci-5alkoxy, 0 iii) -OH, iv) halogen, or v) -NR2R2,
• heterocycle unsubstituted or substituted with one or more of: i) -C ⁇ _ 5 alkyl, ii) -C _5alkoxy, iii) -OH, iv) halogen, or v) -NR2R2 ;
• Z is not -CH2-SO-Ph, -COH,
• One embodiment of this invention encompasses compounds of Formula A further limited to: X is -H, -Cl or -F;
• Y is -S(0)n-
• R is -Ph, -tolyl, 3-Cl-phenyl, 2-pyridyl or 2-thiazolyl;
• R6 is -H; and Z is
• One class of compounds within the first embodiment is further limited to compounds wherein X is -H or -Cl;
• Y is -S(0)n-
• R is -Ph, -tolyl, 3-Cl-phenyl or 2-thiazolyl
• R 6 is -H
• R2 is -H and W is -O, -S or -NCN, or
• a sub-class of compounds within this class is further limited to compounds wherein X is -Cl;
• Y is -S(0)n-; n is 1 or 2;
• R is -Ph, 3-Cl-phenyl or 2-thiazolyl
• R6 is -H
• W wherein R 2 is -H, and W is -O, -S or -NCN;
• R3 is selected from the group consisting of:
• Ci-3alkyl substituted with heterocycle wherein heterocycle is substituted with one or more of: a) halogen, b) oxo, c) -N0 2 , d) -NR2R2, e) -NHCO-C ⁇ _3alkyl, or f) -NHS02-C ⁇ _3alkyl.
• a fourth embodiment of this invention encompasses compounds of formula A wherein Y is -S(0) n - and R is -NR2R3.
• the compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, individual diastereomers, or enantiomers, with all isomeric forms being included in the present invention.
• variable e.g., aryl, heterocycle, Rl, R2, R3 5 etc.
• its definition on each occurrence is independent of its definition at every other occurrence.
• 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.
• Halogen or “halo” as used herein, means fluoro, chloro, bromo and iodo.
• aryl is intended to mean any stable monocyclic, bicyclic or tricyclic carbon ring of up to
• heterocycle or heterocyclic represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to three 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 heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
• the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
• heterocyclic elements include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolid
• the pharmaceutically-acceptable salts of the novel compounds of this invention that are capable of salt formation include the conventional non-toxic salts or the quaternary ammonium salts of these compounds, which are formed, e.g., from inorganic or organic acids or bases.
• acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bissulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, to
• the basic nitrogen-containing groups may be quatemized 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.
• Esters are also encompassed by the present invention, and include those which would readily occur to the skilled artisan, for example, Cl-4 alkyl esters.
• Schemes I-VIQ for preparing the novel compounds of this invention are presented below.
• Tables I - VII which follow the schemes illustrate the compounds that can be synthesized by Schemes I-VUI, but Schemes I - VTJI are not limited by the compounds in the tables nor by any particular substituents employed in the schemes for illustrative purposes.
• the examples specifically illustrate the application of the following schemes to specific compounds.
• Scheme I, below is a general route for synthesizing, e.g., the compounds shown in Table I, infra.
• the substituent groups (e.g., X, R, Rl, etc.) employed in Scheme I correspond to the substituent groups as defined in Table I, but Scheme I is not limited by the defined substituents or compounds of Table I.
• amide in can be produced directly from H by treatment with BOP reagent (benzotriazol-1- yloxytris-(dimethylamino)-phosphonium hexafluorophosphate) in the presence of the desired primary or secondary amine and triethylamine, in a solvent such as dimethyl-formamide.
• BOP reagent benzotriazol-1- yloxytris-(dimethylamino)-phosphonium hexafluorophosphate
• carboxyl group activating reagents such as l,l'-carbonyl-diimidazole can also be used for this step.
• Saponification of ethyl 5-chloro-3-benzylindole-2- carboxylate (prepared as described below) by methods familiar to those skilled in the art, yields 5-chloro-3-benzylindole-2-carboxylic acid, which can be converted to the desired amides in the manner described for the synthesis of amides m.
• 3-phenylthioindole-2-carboxylic acid ⁇ can be converted to the corresponding acid chloride with oxalyl chloride in refluxing chloroform, and reacted with an alcohol to give the ester IV.
• la may be converted to IV by reaction with N-phenylmio-succinimide in chloroform at room temperature with a Lewis acid, such as boron trifluoride etherate, as catalyst (as shown in Scheme ⁇ ).
• a Lewis acid such as boron trifluoride etherate
• Scheme IE is a general route for synthesizing, e.g., the compounds shown in Table ED, infra.
• the substituent groups employed in Scheme HI correspond to the substituent groups as defined in Table HI, but Scheme m is not limited by the defined substituents or compounds of Table HI.
• Compound VIE can be N- alkylated, if desired, by methods familiar to those trained in the art, e.g., by treatment with sodium hydride in dimethylformamide at 0°C in the presence of an alkylating agent such as iodomethane, to give compound DC. Thereafter, compound VIE (or DC) is treated with one equivalent of peracid such as monoperoxyphthahc acid, magnesium salt (MMPP), or meta-chloroperoxy-benzoic acid in methanol or chloroform-methanol at 0°C for 30 minutes to 3 hours, to give predominately sulfoxide X.
• peracid such as monoperoxyphthahc acid, magnesium salt (MMPP), or meta-chloroperoxy-benzoic acid in methanol or chloroform-methanol at 0°C for 30 minutes to 3 hours
• Schemes IV-A and IV-B show a general route for synthesizing, e.g., the compounds shown in Tables IV-A and IV-B, infra.
• the substituent groups employed in Schemes IV-A and IV-B, respectively, correspond to the substituent groups as defined in Tables IV-A and IV-B, respectively, but Schemes IV-A and IV-B are not limited by the defined substituents or compounds of Tables IV-A and
• 3-phenylthioindole- 2-carboxamides XI can be reduced to primary or secondary amines XE by reaction with an excess of borane-dimethylsulfide complex in refluxing tetrahydrofuran for 6-24 hours.
• the primary amine XE-A can be acylated with an acid chloride, such as benzoyl chloride, in chloroform in the presence of pyridine, to give the amide XIE.
• Scheme V is a general route for synthesizing, e.g., the compounds shown in Table V-A and Table V-B, infra.
• the substituent groups employed in Scheme V correspond to the substituent groups as defined in Tables V-A and V-B, but Scheme V is not limited by the defined substituents or compounds of Tables V-A and V-B.
• the dianion formed by the reaction of XVI with t-butyllithium could be reacted with an isocyanate, such as phenyliso-cyanate, to give a mixture of monoacylated product and diacylated product XVE (see Table V-B).
• the dianion formed by the reaction of XVI with t-butyllithium could be reacted with an N-methoxy-N-methyl amide such as N-methoxy-N- methyl-furan-2-carboxamide (prepared in a manner familiar to those skilled in the art, e.g., by the methods described in Scheme 1) to produce ketones XVEI.
• the methodology described above is essentially that used by A. J. Katritsky and K. Akutagawa to prepare 2-indoleacetic acids, and is published in J. Am. Chem. Soc. 108. 6808 (1986).
• Scheme VI is a general route for synthesizing, e.g., the compounds shown in Table VI, infra.
• the substituent groups employed in Scheme VI correspond to the substituent groups as defined in Table VI, but Scheme VI is not limited by the defined substituents or compounds of Table VI.
• N-methoxy-N-methyl-3-phenyl- thioindole-2-carboxamide XIX (or N-methoxy-N-methyl-5-chloro-3- phenylthioindole-2-carboxamide) (prepared as in Scheme 1) can be reacted with Grignard reagents (wherein Rl is not hydrogen) such as phenylmagnesium chloride, in tetrahyrodrofuran at -78°C to 20°C for 18-48 hours, or XIX can be reacted with other organometallic reagents well known in the art to one of ordinary skill, to produce ketones XX.
• Grignard reagents wherein Rl is not hydrogen
• XIX can be reacted with other organometallic reagents well known in the art to one of ordinary skill, to produce ketones XX.
• N-methoxy-N-methyl-3- phenylthioindole-2-carboxamide XXI can be reduced to aldehyde XXE with lithium aluminum hydride in tetrahydrofuran at 0°C to 20°C for 2- 4 hours.
• Aldehyde XXE could be reacted with the hthium salt of [(benzoxal-2-yl)methyl]diethyl-phosphonate to produce olefin XXEI, which is then hydrogenated in the presence of 10% palladium on charcoal in methanol under one atmosphere of hydrogen to give compound XXIV.
• the compound 5-chloro-2-cyano-3-phenylthioindole in Table VE can be prepared by dehydro-sulfurization of 5-chloro-3- phenyl-thioindole-2-thiocarboxamide with, e.g., Hg(OAc)2-
• compounds of formula A where Y is -SO- or -S02- can be synthesized by treatment of compounds where Y is -S- with a suitable oxidizing agent such as, for example, meta-chloroperoxybenzoic acid (MCPBA), sodium periodate or hydrogen peroxide in an appropriate solvent such as MeOH, CHC13 or acetic acid, or potassium persulfate in a solvent such as MeOH/H2 ⁇ .
• MCPBA meta-chloroperoxybenzoic acid
• sodium periodate or hydrogen peroxide in an appropriate solvent such as MeOH, CHC13 or acetic acid
• potassium persulfate in a solvent such as MeOH/H2 ⁇ .
• Y -SO- or -SO2- ester intermediate XXVI which on reaction with ammonia or a primary amine with heating is converted to compounds of formula XXVE.
• the compounds of the present invention are useful in the inhibition of HTV reverse transcriptase, the prevention or treatment of infection by the human immunodeficiency virus (HIV) and the treatment of consequent pathological conditions such as ADDS.
• Treating AIDS or preventing or treating infection by HTV is defined as including, but not limited to, treating a wide range of states of HTV 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 treating infection by HTV after suspected past exposure to HTV by, e.g., blood transfusion, organ transplant, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.
• the compounds of this invention are also useful in the preparation and execution of screening for antiviral compounds.
• the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds.
• the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HTV reverse transcriptase e.g., by competitive inhibition.
• the compounds of this invention are commercial products to be sold for these purposes.
• the compounds of the present invention may be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrastemal injection or infusion techniques), by inhalation spray, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles.
• a method of treating and a pharmaceutical composition for treating HTV infection and AIDS involves administering to a patient in need of such treatment a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically- effective amount of a compound of the present invention.
• compositions may be in the form of orally-administrable suspensions or tablets; nasal sprays; sterile injectable preparations, for example, as sterile injectable aqueous or oleagenous suspensions or suppositories.
• these compositions When administered orally as a suspension, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweetners/flavoring agents known in the art.
• these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.
• compositions When administered by nasal aerosol or inhalation, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
• the injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally- acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
• suitable non-toxic, parenterally- acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
• these compositions When rectally administered in the form of suppositories, these compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride, esters, or polyethylene glycols, which are solid at ordinary temperatures, but liquidify and/or dissolve in the rectal cavity to release the drug.
• a suitable non-irritating excipient such as cocoa butter, synthetic glyceride, esters, or polyethylene glycols, which are solid at ordinary temperatures, but liquidify and/or dissolve in the rectal cavity to release the drug.
• the compounds of this invention can be administered orally to humans in a dosage range of 1 to 100 mg/kg body weight in divided doses.
• One preferred dosage range is 1 to 10 mg/kg body weight orally in divided doses.
• Another preferred dosage range is 1 to 20 mg/kg body weight orally in divided doses.
• the present invention is also directed to combinations of the HTV reverse transcriptase inhibitor compounds with one or more agents useful in the treatment of AIDS.
• the compounds of this invention can be administered in combination with other compounds that are HTV reverse transcriptase inhibitors, and/or with compounds that are HTV protease inhibitors.
• the compounds of this invention may be effectively administered, whether at periods of pre- exposure and/or post-exposure, in combination with effective amounts of the AIDS antivirals, such as those in the following Table VIE.
• HTV protease inhibitors When used in a combination treatment with compounds of the instant invention, dosage levels of HTV protease inhibitors of the order of 0.02 to 5.0 or 10.0 grams-per-day are useful in the treatment or prevention of the above-indicated conditions, with oral doses two-to- five time higher.
• infection by HTV is effectively treated by the administration of from 10 to 50 milligrams of the HTV protease inhibitor per kilogram of body weight from one to three times per day.
• NC Kaposi's sarcoma, asymptomatic HTV infection, less severe HTV disease, neurological involvement, in combination with other therapies.
• L-697,661 is 3-([(4,7-dichloro-l,3-benzoxazol-2-yl)-methyl]-amino)-5-ethyl-6- methyl-pyridin-2(lH)-one
• L-696,229 is 3-[2-(l,3-benzoxazol-2- yl)ethyl]-5-ethyl-6-methyl-pyridin-2(lH)-one
• L-735,524 is an HTV protease inhibitor with the chemical name N-(2(R)-hydroxy-l(S)- indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(l-(4-(3-pyridyl-methyl)- 2(S)-N'-(t-butylcarboxamido)piperazinyl))pentaneamide
• L-738,372 is 6-chloro-4(S)-cyclopropyl
• the assay measures the incorporation of tritiated deoxy- guanosine monophosphate by recombinant HIV reverse transcriptase (HTV RTR) (or other RT) into acid-precipitable cDNA at the Km values of dGTP and poly r(C)-oligo d(G)l2-18-
• HTV RTR HIV reverse transcriptase
• the tubes were cooled in ice for 5 minutes. Ice-cold 13% TCA containing 10 mM NaPPi (200 ⁇ l) are added and the mixture incubated on ice for 30 minutes. The precipitated cDNA is removed by filtration using presoaked glass filters [TCA, NaPPi]. The precipitate is then washed with IN HCI, 10 mM NaPPi.
• the filter discs are then counted in a scintillation counter.
• the mixture was incubated overnight at 37 °C in 5% CO2 atmosphere.
• the settled cells were resuspended and a 125 ⁇ l harvested into a separate microtiter plate. After the settling of the cells, the plates were frozen for subsequent assay of the supernatant for HTV p24 antigen.
• the concentration of HTV p24 antigen was measured by an enzyme immunoassay, described as follows. Aliquots of p24 antigen to be measured were added to microwells coated with a monoclonal antibody specific for HTV core antigen. The microwells were washed at this point, and at other appropriate steps that follow. Biotinylated HTV- specific antibody was then added, followed by conjugated streptavidin- horseradish peroxidase. A color reaction occurs from the added hydrogen peroxide and tetramethylbenzidine substrate. Color intensity is proportional to the concentration of HTV p24 antigen.
• the cell culture inhibitory concentration (CIC95) for each compound is defined as that concentration which inhibited by greater than 95% the spread of infection, as assessed by a greater than 95% reduction in p24 antigen production relative to untreated controls.
• the tested compounds of the present invention were found to have CIC95 values ranging from about 3 nM to about 400 nM for preferred species, and up to about 40 ⁇ M for others.
• the aqueous layer was separated and the pH adjusted to pHl with 10% aqueous hydrochloric acid.
• the aqueous phase was extracted with ethyl acetate, and the ethyl acetate extract was washed with water and saturated brine, and dried over magnesium sulfate.
• the crude product was recrystallized from ethyl acetate in hexane to afford the title compound as an off-white solid.
• Step B N-(3-pyridylmethyl)-5-chloro-3-phenylthioindole-2- carboxamide
• Benzotriazol- 1 -yloxytris(dimethylamino)phosphonium hexafluorphosphate (0.73 g, 1.6 mmol) was added to a solution of 5- chloro-3-phenylthio-indole-2-carboxylic acid (0.50 g, 1.6 mmol), 3- aminomethylpyridine (0.35 g, 3.2 mmol) and triethylamine (0.50 mL, 3.2 mmol) in degassed dimethylformamide (25 mL). The reaction was stirred at room temperature overnight. The precipitated product was filtered and the filter cake washed well with water. The solid was
• Step D 2-Phenylsulfinylmethyl-3-phenylthioindole
• the title compound was prepared from 3-phenylthioindole- 2-carboxylic acid (prepared according to the procedure described by Atkinson, J.G. et al., Synthesis, p. 480-481 (1988), (4.01 g, 0.015 mol), ammonia (large excess), and benzotriazol-l-yloxytris(dimethyl- amino)phosphonium hexafluorphosphate (7.2 g, 0.016 mol) in dimethylformamide according to the general procedure described in Example 1 for the preparation of N-(3-pyridylmethyl)-5-chloro-3- phenylthio-2-carboxamide. The title compound was obtained as a pale yellow solid.
• 2-Methyl-3-phenylthioindole (0.50 g, 2.1 mmol) (prepared according to the procedure described by Atkinson, J. G., et al., Synthesis, p. 480-481 (1988), was dissolved in dry tetrahydrofuran and cooled under nitrogen to -78°C. A solution of n-butyllithium in hexane (0.83 mL, 2.5 M) was added via syringe. Carbon dioxide was bubbled into the reaction mixture over a period of several minutes; unreacted carbon dioxide was removed by freezing the reaction at liquid nitrogen temperature under high vacuum and warming to -78°C.
• the title compound was prepared from furan-3-carboxylic acid (3.4 g, 0.030 mol), N,0-dimethylhydroxylamine hydrochloride hydrochloride (2.9 g, 0.030 mol) triethylamine (8.3 mL, 0.060 mol) and benzotriazol-1 -yloxytris(dimethylamino)phosphonium hexafluorphosphate (13.3 g, 0.030 mol) according to the general procedure described in Example 1 for N-(3-pyridylmethyl)-5-chloro-3- phenylthio-2-carboxamide.
• Step B 2-(2-Oxo-2-furan-3-ynethyl-3-phenylthioindole
• the title compound was prepared from N-methoxy-N- methylfuran-3-carboxamide (0.32 g, 2.1 mmol), and 2-methyl-3- phenylthioindole (0.50 g, 2.1 mmol) according to the general procedure described in Example 6 for the preparation of 2-(N-phenylacetamido)- 3-phenyl-thioindole.
• the crude product was chromatographed on silica gel with chloroform. The title compound was obtained as a pale yellow solid, mp 127-129°C.
• Step A N Mem'oxy-N-methyl-5-chloro-3-phenylthioindole-2- carboxamide
• the title compound was prepared from 5-chloro-3-phenyl- thioindole-2-carboxylic acid (1.0 g, 3.30 mmol)) N,0-dimethyl- hydroxylamine hydrochloride (0.64 g, 6.6 mmol), triethylamine (1.0 mL, 7 mmol) and benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorphosphate (1.64 g, 3.6 mmol) in dimethylformamide according to the general procedure described in Example 1 for the preparation of N-(3-pyridylmethyl)-5-chloro-3-phenylthio-2- carboxamide.
• Step B 2-Benzoyl-5-chloro-3-phenylthioindole
• N-Methoxy-N-methyl-5-chloro-3-phenylthioindole-2- carboxamide (0.24 g, 0.69 mmol) was dissolved in dry tetrahydrofuran (5 mL) and cooled to -78°C under nitrogen. A solution of phenylmagnesium chloride in tetrahydrofuran (0.81 mL, 2M) was added via syringe and the reaction warmed to 20°C overnight. Water and ethyl acetate were added to the reaction and then separated. The organic phase was washed with water, 5% aqueous hydrochloric acid, saturated sodium bicarbonate, saturated brine, and dried over magnesium sulfate.
• the title compound was prepared from 3-phenylthioindole- 2-carboxylic acid (1.0 g, 3.7 mmol), N,0-dmiethylhydroxylamine hydrochloride (0.54 g, 5.5 mmol), triethylamine (1.5 mL, 11 mmol) and benzotriazol- 1 -y loxytris(dimethylamino)phosphonium hexafluorphosphate (1.64 g, 3.7 mmol) according to the procedure described in Example 1 for N-(3-pyridylmethyl)-5-chloro-3-phenylthio- 2-carboxamide.
• Step B 3-Phenylthioindole-2-carboxaldehvde
• N-Methoxy-N-methyl-3-phenylthioindole-2-carboxamide (1.57 g, 5.26 mmol) was dissolved in tetrahydrofuran (150 mL) and cooled to 0°C under nitrogen.
• a solution of lithium aluminum hydride in tetrahydrofuran (5.76 mL, IM) was added slowly via syringe and the reaction stirred a total of 1.5 h.
• Ethyl acetate (30 mL) was added, followed by saturated sodium potassium tartrate solution. The layers were separated and the organic phase washed with saturated brine and dried over magnesium sulfate. Filtration and evaporation of solvent gave the title compound as a yellow solid.
• Step C trans-2-(2-Benzoxazol-2-ylethenylV3-phenylthioindole n-Butyllithium in hexane (3.47 mL, 2.5 M) was added to a solution of [(benzoxal-2-yl)-methyl]diethylphosphonate (2.34 g, 8.68 mmol) in tetrahydrofuran (50 mL) at -78°C under nitrogen. The reaction was stirred for 20 min., and warmed to -20°C.
• Step D 2-(2-Benzoxazol-2-ylethyl ' )-3-phenylthioindole
• the title compound was prepared according to the procedure described for 5-chloro-3-phenyl-thioindole-2- thiocarboxamide except substituting N-2-furanylmethyl-5-chloro-3- phenylthioindole-2-carboxamide for 5-chloro-3-phenylthioindole-2- carboxamide.
• the crude product was chromatographed on silica gel with 3% ethyl acetate in hexane. The title compound was obtained as a bright yellow solid, mp 143-144°C.
• Step 3 Preparation of N-(3-methoxy-4-pyridylmethyl)-5-chloro-3- phenylthioindole-2-carboxamide
• Step A 5-chloro-3-phenylsulfonylindole-2-carboxylic acid To a suspension of 5-chloro-3-phenylthio-indole-2- carboxylic acid (4.84 g, 0.016 mol) in chloroform (1200 mL) was added 55% m-chloroperoxybenzoic acid (12.5 g, 0.04 mol). The mixture was allowed to stir at room temperature for 40 hours. Filtration afforded the title compound as a colorless solid, mp 277- 280°C (dec). On partial evaporation a second crop of product was obtained.
• Step B Product of reaction of 5-chloro-3-phenyl-sulfonylindole-
• Step C N-(2,6-difluorobenzyl)-5-chloro-3-phenyl-sulfonylindole-
• 2,6-Difluorobenzylamine (0.430 g, 3.0 mmol) was added dropwise to the solution of the "acid chloride equivalent" from Step B (0.354 g, 1.0 mmol) in tetrahydrofuran solution (10 mL) cooled in an ice-acetone bath. The reaction mixture was allowed to warm to room temperature and left overnight. For work-up, ethyl acetate and water were added. The ethyl acetate phase was washed well with dilute hydrochloride acid, saturated aqueous sodium bicarbonate, and brine.
• Step A Preparation of 5-chloro-3-phenylsulfinyl-indole-2- carboxylic acid
• Step B N-(4-pyridylmethyl)-5-chloro-3-phenylsulfinylindole-2- carboxamide
• Step C Product of Reaction of 5-CMoro-3-(2-thiazolyl)sulfonyl- indole-2-carboxylic Acid with Oxalyl Chloride
• Step D N-(3-methoxybenzyl)-5-chloro-3-(2-thiazolyl-sulfonyl)- indole-2-carboxamide
• Step C (0.50 g, 1.4 mmol) in tetrahydrofuran (25 mL) was added slowly to a solution of tetrahydrofuran saturated with ammonia at
• N-chlorosuccinimide (3.34 g, 25 mmol) in dry methylene chloride (30 mL), cooled in an ice bath and under an inert atmosphere, was added thiophenol (2.05 mL, 20 mmol) via syringe. After stirring for 1 hour, additional N-chlorosuccinimide (0.40 g, 3 mmol) was added. After 2.5 hours total, triethylamine (3.9 mL, 28 mmol) was added drop wise. Within 15 minutes the reaction mixture was diluted with methylene chloride, the solvent washed with dilute aq. HCI and the solvent then dried (Na2S ⁇ 4), filtered through a pad of charcoal and evaporated.
• Step B Ethyl 3-phenylthio-5-chloroindole-2-carboxylate
• ethyl 5-chloroindole-2- carboxylate 698 mg, 3.1 mmol
• N-(phenylthio)succinimide 683 mg, 3.3 mmol
• boron trifluoride etherate 0.12 mL, 1.0 mmol
• the reaction was momtored by tic (thin layer chromatography) until complete. After 2 hours, the reaction was diluted with chloroform and neutralized with aq. NaHC ⁇ 3.
• Step C Ethyl 3 -phenylsulf onyl-5 -chloroindole-2-carboxylate
• Ethyl 3-phenylthio-5-chloroindole-2-carboxylate (642 mg, 1.94 mmol) was dissolved in chloroform (35 mL) and a dried (Na2S04) solution of m-chloroperoxybenzoic acid (55% pure, 1.30 g, 4.1 mmol) in chloroform (20 mL) was added dropwise. The progress of the oxidation was monitored by tic until complete. After 5 hours, the reaction was diluted with chloroform and some methanol and the solution washed with aq. NaHC03 and aq. Na2C ⁇ 3. The dried (Na2S04) organic layer was filtered through a pad of charcoal and the solvents removed under reduced pressure.
• Step A 2-Aminomethyl-l -methylimidazole
• Step B N-[(l -methylimidazol-2-yl)methyl]-3-phenyl-sulfonyl-5- chloroindole-2-carboxamide
• the hydrochloride salt was obtained by addition of one equivalent of ethanolic HCI to the free base, mp 284-285°C with decomposition.
• Example 35 Using the procedure described in Example 35, except for substituting the dimeric acid chloride derived from 3-(3-chlorophenyl- sulfonyl)-5-chloroindole-2-carboxylic acid for that derived from 3- (phenylsulfonyl)-5-chloroindole-2-carboxylic acid, the title compound was obtained, mp 232-234°C.
• Step A 2-Carboethoxy-5-chloro- 1 -phenylsulfonylindole-3- sulfonic acid
• Step B 2-Carboethoxy-5-chloro-l -phenylsulfonyl-indole-3- cyclopropylsulfonamide
• Oxalyl chloride (0.90 ml, 10.3 mmol) was added to a stirred solution of 2-carboethoxy-5-chloro-l-phenylsulfonylindole-3- sulfonic acid (1.505 g, 3.39 mmol) in dry dichloromethane (15 ml) at 0°C. DMF (2 drops) was added and the solution was warmed to room temperature. More DMF (1 drop) was added and the reaction was heated to reflux. After 2 hours, the solution was cooled and evaporated in vacuo to give the sulfonylchloride as a tan solid.
• the solid was suspended in acetone (10 ml) and 9:1 ammonium hydroxide/acetone solution (20 ml) was added. After 15 min the solution was evaporated in vacuo to 2 ml in volume and the residue was acidified with 1 M HCI solution and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with sodium hydrogen carbonate solution, dried (Na2S04) and evaporated in vacuo.
• Step A 2-Carboethoxy-5-chloro- 1 -pheny lsulf onylindole-3- phenylsulfonamide
• Step B 5-Chloro-3- ⁇ henylsulfonamidoindole-2-carboxylic acid
• Oxalyl chloride (0.087 ml, 1.00 mmol) and DMF (1 drop) were added to a stirred solution of 5-chloro-3-phenylsulfonamido- indole-2-carboxylic acid (123 mg, 0.35 mmol) in dry THF (3 ml) at 0°C. After 1 hour at room temperature the solution was evaporated in vacuo to give a tan solid. The solid was dissolved in acetone (1 ml) and 9:1 ammonium hydroxide/acetone solution (2 ml) was added.
• Step A 2-Carboethoxy-5-chloro- 1 -phenylsulf onylindole-3- methyKphenyPsulfonamide
• Step B 5-Chloro-3-methyl(phenyl)sulfonamidoindole-2- carboxylic acid
• Step C 2-Carboxamido-5-chloroindole-3-methyl(phenyl)- sulfonamide
• Step C Reaction of ethyl 5-nitroindole-2-carboxylate (J. Amer. Chem. Soc. 80. 4621 (1958)) with N-( henyl-mio)succinimide under the conditions of Example 33, Step B, followed by oxidation to the sulfonyl product (Step C) provides a product which may be converted to the title compound with ammonium hydroxide at elevated temperature and pressure.
• Step B 3-Phenylsulfonyl-5-aminoindole-2-carboxamide
• Step C 3-Phenylsulfonyl-5-methylsulfonylaminoindole-2- carboxamide
• Step A N-(2-methoxy-4-pyridylmethyl)-5-chloro-3-phenyl- sulfonylindole-2-carboxamide
• Step B 4-[(5-CMoro-3-phenylsulfonylindole-2-carboxamido)- methyll -pyridin-2( 1 H)-one
• Step B N-(2-Amino-4-pyridylmethyl)-5-chloro-3-phenylsulfonyl- indole-2-carboxamide
• 5-Chloro-3-phenylsulfonylindole-2-carboxamide reacts with methyl (carboxysulfamoyl)triethylammonium hydroxide inner salt (Burgess reagent) in tetrahydrofuran (THF) solvent as described by D.A. Claremon and B.T. Phillips (Tetrahedron Lett..22, 2155 (1988)) to provide the title compound.
• THF tetrahydrofuran
• Step B Ethyl 5-chloro-3-phenylsulfonylindole-2-carboximidate
• Step C N-Cyano-5-chloro-3-phenylsulfonylindole-2-carboximid- amide
• Step A N-[(Imidazol-4(or 5)-ylmethyl]-3-phenylsulfonyl-5- chloroindole-2-carboxamide
• Step B N-[(l -methylimidazol-4-yl)methyl]-3-phenylsulfonylindole- 5-chloroindole-2-carboxamide; N-[(l -methy limidazol-5- yl)methyll-3-phenylsulfonyl-5-chloroindole-2-carboxamide
• N-[(imidazol-4(or 5)-yl)methyl]-3-phenylsulfonyl-5-chloroindole-2-carboxamide Employing the procedure of Example 36, but substituting N-[(imidazol-4(or 5)-yl)methyl]-3-phenylsulfonyl-5-chloroindole-2- carboxamide for N-[(imidazol-2-yl)methyl]-3-phenylsulfonyl-5- chloroindole-2-carboxamide, there is obtained each of the

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