WO2008021745A2 - Hepatitis c virus entry inhibitors - Google Patents

Hepatitis c virus entry inhibitors Download PDF

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Publication number
WO2008021745A2
WO2008021745A2 PCT/US2007/075110 US2007075110W WO2008021745A2 WO 2008021745 A2 WO2008021745 A2 WO 2008021745A2 US 2007075110 W US2007075110 W US 2007075110W WO 2008021745 A2 WO2008021745 A2 WO 2008021745A2
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substituted
alkyl
ethyl
carbazole
amino
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PCT/US2007/075110
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French (fr)
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WO2008021745A3 (en
Inventor
Timothy J. Cuthbertson
Maureen Ibanez
Cornelis A. Rijnbrand
Andrew Jeremiah Jackson
Gopi Kumar Mittapalli
Fang Zhao
James E. Macdonald
Flossie Wong-Staal
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Itherx Pharmaceuticals, Inc.
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Publication of WO2008021745A2 publication Critical patent/WO2008021745A2/en
Publication of WO2008021745A3 publication Critical patent/WO2008021745A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 

Definitions

  • the present invention relates to tricyclic diphenylamine derivative compounds for prevention and/or treatment of Hepatitis C virus (HCV) infection by inhibiting HCV entry into permissive cells. More specifically, these compounds have the formula:
  • Hepatitis C is caused by infection with Hepatitis C Virus (HCV), which is carried by more than 100 million people worldwide.
  • HCV Hepatitis C Virus
  • the currently FDA-approved Hepatitis C therapies for example, non-specific antiviral substances that boost the host's antiviral responses and target virus replication, are only moderately efficacious and cause significant adverse reactions.
  • interferons and PEGylated interferons are non-specific antiviral and antineoplastic proteins that act by inhibiting viral replication.
  • Ribavirin is a non-specific, antiviral, nucleotide analog prodrug that interferes with RNA metabolism and is not effective in monotherapy for the treatment of HCV infection.
  • HCV infection leads to chronic Hepatitis in up to 85% of patients, and is responsible for an estimated 10,000 deaths per year in the United States.
  • HCV has a poorly understood method of cell entry. Despite the ubiquity of
  • HCVs receptors CD81 and SRBl
  • HCV entry can be studied separately from its other functions utilizing HCV pseudoparticles ("HCVpp") that maintain an HCV envelope and yet contain a Human Immunodeficiency Virus (HIV) based genomic backbone that can be used to express reporter genes. This has led to the discovery of the invention described herein.
  • HCVpp HCV pseudoparticles
  • the present invention is directed to tricyclic diphenylamine derivative compounds for the prevention and/or treatment of HCV infection by inhibiting HCV entry into permissive cells.
  • the diphenylamine derivatives described herein selectively inhibit HCV entry into permissive cells but allow viruses with divergent entry mechanisms to cross into the cytoplasm. More specifically, these tricyclic diphenylamine derivative compounds have the formula: with the depicted variables having the meaning described below.
  • Figure 2 shows the structure of the recombinant HCV2a-Neo virus used to validate entry inhibitors of the present invention.
  • Figure 3 shows the validation of compound "2302" utilizing the recombinant HCV2aNeo virus.
  • Huh7 cells were infected with similar amounts of HCV2aNeo containing supernatants.
  • the cell cultures were treated with either CD 81 or IgG antibody as control for the assay, and with either compound “2302” or compound “2243” as a negative control.
  • the number of colonies was counted as shown in Figure 4.
  • Figure 5 shows the validation of compounds "2241", “2281”, “2282”, "2302",
  • Huh7 cells were infected with similar amounts of HCV2aNeo containing supernatants. The cell cultures were treated with the compounds and incubated in the presence of G418 for 2 weeks prior to staining of the cells with crystal violet. The number of colonies was counted and shown in Figure 6.
  • the present invention is directed to methods for inhibiting the entry of HCV into permissive cells. More specifically, the present invention is directed to tricyclic diphenylamine derivative compounds for the prevention and/or treatment of HCV infection by inhibiting HCV entry into permissive cells.
  • the tricyclic diphenylamine derivatives described herein selectively inhibit HCV entry into permissive cells but allow viruses with divergent entry mechanisms to cross into the cytoplasm. More specifically, these tricyclic diphenylamine derivative compounds have the formula:
  • R 4 and R 5 are hydrogen. Even more preferably, Ri and Rs are hydrogen.
  • X is O
  • the dotted lines are one bond
  • R 4 and R5 are hydrogen. Even more preferably, Ri and Rs are hydrogen.
  • R 4 and R5 are hydrogen. Even more preferably, Ri and Rs are hydrogen.
  • R 4 and R 5 are hydrogen. Even more preferably, Ri and Rg are hydrogen. Yet, more preferably, R 2 and R 7 are hydrogen. Most preferably, R3 and R 6 are methyl.
  • Ri to Rs is not - C(O)WYZ, where W is oxygen or N-alkyl, Y is alkyl and Z is an optionally substituted amino.
  • each variable, especially Y, is, independently, not alkyl or haloalkyl.
  • A is hydrogen, Ci to C 4 alkyl or Ci to C 4 substituted alkyl, aryl, or a 5-6 membered heteroaryl containing one to three heteroatoms selected from oxygen, nitrogen, or sulfur; and B is hydrogen, Ci to C 4 alkyl or Ci to C 4 substituted alkyl, preferably halo-substituted alkyl; or A and B taken together form an optionally substituted aromatic six-membered heterocyclic ring, where said heterocyclic ring contains 1 to 2 nitrogen ring atoms, or an optionally substituted aromatic six-membered carbocyclic ring (preferably, the aromatic six-membered carbocyclic ring is mono- substituted); a pharmaceutically acceptable salt thereof, a prodrug of the compound or the salt, or a solvate or hydrate of the compound, the salt or the prodrug.
  • Preferred compounds of the above embodiment include 9-ethyl-3-(5-methyl-4- phenyl-lH-imidazol-2-yl)-9H-carbazole; 9-ethyl-3-(4-phenyl-5-trifluoromethyl-lH- imidazol-2-yl)-9H-carbazole; 9-ethyl-3-(5-methyl-4-pyridin-2-yl-lH-imidazol-2-yl)- 9H-carbazole; 3-(4,5-dimethyl-lH-imidazol-2-yl)-9-ethyl-9H-carbazole; 9-ethyl-3- (lH-imidazo[4,5-c]pyridin-2-yl)-9H-carbazole; 3-(lH-benzoimidazol-2-yl)-9-ethyl-9H- carbazole; 9-ethyl-3-(3H-imidazo[4,5-b]pyridin
  • X is absent
  • Ri, R 2 and R 4 to Rs are, independently, from hydrogen, halogen, hydroxyl, nitro, cyano, Ci to C 6 alkyl, Ci to C 6 alkoxy, the formulas -NR 9 Ri 0 , -CH 2 NR 9 Ri 0 , -CH 2 OR 9 , -C(O)NR 9 Ri 0 , Ci to C 6 alkylaryl; and any two of R5 to Rs, when ortho to each other, may be joined to form a ring, which may optionally include up to two heteroatoms selected from O, NRn or S; Y is Ci to C 5 alkyl, alkylaryl, alkenyl, (cycloalkyl)alkyl, or mono or polyfluoroalkyl; R 3 is NRn, CORi 2 , CONR H R I2 or NRnSO 2 Ri 2 ; Rn is hydrogen, Ci to C 3 alkyl, Ci to C 3 alkylaryl, Ci to
  • Y is Ci to C 5 alkyl and R 3 is -CONR H R I2 , then when one of Rn or Ri 2 is an azacycloalkyl alkyl group, the other must be a group other than hydrogen or Ci to C 6 alkyl.
  • Preferred compounds under this embodiment include 2-Dimethylamino-N-(9- ethyl-9H-carbazol-3-yl)-acetamide; 3-Diethylamino-N-(9-ethyl-9H-carbazol-3-yl)- propionamide; N-(9-Ethyl-9H-carbazol-3-yl)-2-fluoro-benzamide; 2-Pyridin-2-yl- thiazole-4-carboxylic acid (9-ethyl-9H-carbazol-3-yl)-amide; N-(9-Ethyl-9H-carbazol- 3-yl)-2-pyridin-2-yl-acetamide; N-(9-Ethyl-9H-carbazol-3-yl)-2-pyridin-3-yl- acetamide; N-(9-Ethyl-9H-carbazol-3-yl)-isonicotinamide; lH-Indole-2-carboxy
  • Ri to R 4 are independently - CONRR" or -NRR" where R and R" are independently hydrogen or Ci to C 6 alkyl; Y is hydrogen, Ci to C 6 alkyl, or -COR” where R" is Ci to C 6 alkyl; and one of Ri to R 4 (preferably Ri or R 2 ) is -C(O)NWZ, where W is hydrogen or Ci to C 6 alkyl; and Z is an azacycloalkylalkyl
  • X is absent, the ring attached to R 5 to Rs (designated "A") is a 5- to 7-membered hydrocarbonic ring, wherein the ring may have one or more substituents selected from the group consisting of a hydroxyl group, a lower alkyl group, a lower acyl group, a lower alkoxy group and a halogen atom, and wherein the lower alkyl group, the lower acyl group and the lower alkoxy group may have one or more substituents);
  • R3 is the formula L-M-W-Z, where L is a linking group selected from the group consisting of-NR' ⁇ CO ⁇ , -CO— NR'-, -NR'-CS-, -CS- NR'-, -NR'- SO 2 - and -SO 2 -NR'-, where R' is a hydrogen atom, a lower alkyl group or a lower acyl group, wherein the lower alkyl group and the lower acyl group
  • W is a linking group selected from the group consisting of -S-, -O-, -NR"-, -NR" '-CO-, -NR" '-CS- or -NR" '-SO 2 -, where R" is a hydrogen atom, an alkyl group or a lower acyl group, wherein the alkyl group and the lower acyl group may have one or more substituents, and the alkyl group may contain a ring structure, R" ' is a hydrogen atom, a lower alkyl group or
  • A is a 5- to 7-membered hydrocarbon ring (the ring may have one or more substituents selected from the group consisting of a hydroxyl group, a lower alkyl group, a lower acyl group, a lower alkoxy group and a halogen atom, wherein the lower alkyl group, the lower acyl group and the lower alkoxy group may have one or more substituents);
  • L is a linking group selected from the group consisting of-NR'-CO-, -CO-NR'-, -NR'-CS-, -CS- NR'-, -NR' — SO 2 - and -SO 2 — NR'- (where R' is a hydrogen atom, a lower alkyl group or a lower acyl group, wherein the lower alkyl group and the lower acyl group may have one or more substituents);
  • M is an alkylene linking group having 2 to 10 carbon atoms [the alkylene linking group
  • a compound of the invention has the formula: where A is a fused unsubstituted or substituted benzo ring, or a fused unsubstituted or substituted cyclopentenyl, cyclohexenyl or cycloheptenyl group; M is Ci to C 6 alkyl or Ci to C 6 substituted alkyl; R is aryl, heteroaryl, oxyaryl, oxyheteroaryl or absent; Q is -NHCO, -NR 4 CO, CO, SO 2 or absent; and E is -OR 4 or -NR 4 R 5 ;
  • R 2 is -COOR 6 , -CONHR 6 or -COR 6 ;
  • R3 is hydrogen, halo, Ci to C 6 alkyl, Ci to C 6 substituted alkyl, -CN or OR 4 ;
  • R 4 is Ci to C 6 alkyl or Ci to C 6 substituted alkyl
  • R 5 is Ci to C 6 alkyl or Ci to C 6 substituted alkyl; where -NR4R5 may form heterocyclic or heterobicyclic ring system, such as pyrrolidine, morpholine, tetrahydroisoquinoline or indole, optionally substituted; or M-R-Q-E is a Ci to C 6 alkyl substituted with a 4-piperidinyl group;
  • R 6 is Ci to C 6 alkyl, Ci to C 6 substituted alkyl or R-Q-E as defined above.
  • the present invention is also directed to the compositions described above.
  • the compounds of the present invention were shown by luciferase assay to inhibit HCV entry into Huh7 cells (see Example 143 A and Figure 1, top panel) and to have a low level of toxicity (see Figure 1, lower panel). The compounds did not inhibit entry of either Sindbis or VSV-G coated pseudoparticles (see Figure 1, middle panel).
  • the compounds used in the present invention can be prepared according to known methods, such as Gilman and Shirley, J. Am. Chem. Soc. 66:890 (1944), US Patent 2512520, US Patent 2645640 and US Patent 3081305, as well as by the methods of Examples 1 to 142 and 144 to 161 below or appropriate modifications of these examples.
  • the preferred compounds used in the present invention may be prepared as illustrated in the schemes below.
  • a tricyclic diphenylamine derivative (1) can be alkylated using an appropriate alkyl halide or sulfonate using strong bases such as potassium tert- butoxide (tBuOK), sodium hydride (NaH), lithium amide bases, or alkyl lithium in suitable solvents such as dimethylsulfoxide (DMSO), dimethylformamide (DMF), or ethers such as tetrahydrofuran (THF) to form an intermediate or target (2).
  • Y contains an additional halogen or sulfonate (2) can be aminated by treatment with an amine using tetrabutylammonium iodide (TBAI) in dimethylformamide (DMF) to form amine products (3).
  • TBAI tetrabutylammonium iodide
  • Preferred tricyclic diphenylamine derivatives in the form of phenothiazines (4) may also be synthesized by cyclizing appropriately substituted diphenylamines using sulfur with catalytic iodine in 1 ,2-dichlorobenzene (see Scheme 2). When Y is hydrogen, these phenothiazines can then be alkylated as in Scheme 1. See Scheme 2.
  • Preferred diphenylamine derivatives in the form of 3,7-dimethylphenothiazines may also be synthesized by cyclizing appropriately substituted diphenylamines (1) using sulfur with catalytic iodine in 1 ,2-dichlorobenzene (Scheme 3). When Y is hydrogen, these 3,7-dimethylphenothiazines can then be alkylated as in Scheme 1, converting then to the desired products.
  • the stereochemistry of such chiral centers can independently be in the R or S configuration, or a mixture of the two.
  • the chiral centers can be further designated as R or S or R,S or d,D, 1,L or d,l, D,L.
  • the suffix "ene” added to any of the described terms means that two parts of the substituent are each connected to two other parts in the compound (unless the substituent contains only one carbon, in which case such carbon is connected to two other parts in the compound, for example, methylene).
  • Ci to C12 alkyl denotes such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, amyl, tert-amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like.
  • Preferred “Ci to Ci 2 alkyl” groups are methyl, ethyl, iso-butyl, sec-butyl and iso-propyl.
  • Ci to Ci 2 alkylene denotes radicals of 1 to 12 carbons connected to two other parts in the compound.
  • C 2 to Ci 2 alkenyl denotes such radicals as vinyl, allyl, 2-butenyl, 3- butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5- hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, (as well as octenyl, nonenyl, decenyl, undecenyl, dodecenyl radicals attached at any appropriate carbon position and the like) as well as dienes and trienes of straight and branched chains.
  • C 2 to Ci 2 alkynyl denotes such radicals as ethanol, propynyl, 2- butynyl, 2-pentynyl, 3-pentynyl, 2- hexynyl, 3-hexynyl, 4-hexynyl, 2-heptynyl, 3- heptynyl, 4- heptynyl, 5-heptynyl (as well as octynyl, nonynyl, decynyl, undecynyl, dodecynyl radicals attached at any appropriate carbon position and the like) as well as di- and tri-ynes of straight and branched chains.
  • Ci to C i2 substituted alkyl denote groups are substituted by one or more, and preferably one or two, halogen, hydroxy, protected hydroxy, oxo, protected oxo, C3 to C 7 cycloalkyl, phenyl, naphthyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, guanidino, protected guanidino, heterocyclic ring, substituted heterocyclic ring, imidazolyl, indolyl, pyrrolidinyl, Ci to C 12 alkoxy, Ci to C 12 acyl
  • oxo denotes a carbon atom bonded to two additional carbon atoms substituted with an oxygen atom doubly bonded to the carbon atom, thereby forming a ketone moiety.
  • the term "protected oxo” denotes a carbon atom bonded to two additional carbon atoms substituted with two alkoxy groups or twice bonded to a substituted diol moiety, thereby forming an acyclic or cyclic ketal moiety.
  • the term "Ci to Ci 2 alkoxy” as used herein denotes groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like groups. A preferred alkoxy is methoxy.
  • the term “Ci to Ci 2 substituted alkoxy” means the alkyl portion of the alkoxy can be substituted in the same manner as in relation to Ci to Ci 2 substituted alkyl.
  • the term "Ci to Ci 2 phenylalkoxy” as used herein means "Ci to Ci 2 alkoxy” bonded to a phenyl radical.
  • Ci to Ci 2 acyloxy denotes herein groups such as formyloxy, acetoxy, propionyloxy, butyryloxy, pivaloyloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, nonanoyloxy, decanoyloxy, undecanoyloxy, dodecanoyloxy and the like.
  • Ci to Ci 2 acyl encompasses groups such as formyl, acetyl, propionyl, butyryl, pentanoyl, pivaloyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, benzoyl and the like.
  • Preferred acyl groups are acetyl and benzoyl.
  • Ci to Ci 2 substituted acyl denotes the acyl group substituted by one or more, and preferably one or two, halogen, hydroxy, protected hydroxy, oxo, protected oxo, cyclohexyl, naphthyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, guanidino, heterocyclic ring, substituted heterocyclic ring, imidazolyl, indolyl, pyrrolidinyl, Ci to Ci 2 alkoxy, Ci to C 12 acyl, Ci to C 12 acyloxy, nitro, Ci to C 12 alkyl ester, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, N-(Ci to C 12 alkyl)carboxamide, protected N-(Ci to C 12 alkyl)carboxamide, N 5 N-CI
  • C 3 to C 7 cycloalkyl includes the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl rings.
  • a substituent that can be C 3 to C 7 cycloalkyl can also be "C 5 to C 7 cycloalkyl,” which includes the cyclopentyl, cyclohexyl or cycloheptyl rings.
  • C3 to C 7 substituted cycloalkyl indicates the above cycloalkyl rings substituted by one or two halogen, hydroxy, protected hydroxy, Ci to C 10 alkylthio, Ci to C 10 alkylsulfoxide, Ci to C 10 alkylsulfonyl, Ci to C 10 substituted alkylthio, Ci to C 10 substituted alkylsulfoxide, Ci to Cio substituted alkylsulfonyl, Ci to C 12 alkyl, Ci to C 12 alkoxy, Ci to C 12 substituted alkyl, Ci to C 12 alkoxy, oxo, protected oxo, (monosubstituted)amino, (disubstituted)amino, trifluoromethyl, carboxy, protected carboxy, phenyl, substituted phenyl, phenylthio, phenylsulfoxide, pheny
  • cycloalkylene means a cycloalkyl, as defined above, where the cycloalkyl radical is bonded at two positions connecting together two separate additional groups.
  • substituted cycloalkylene means a cycloalkylene where the cycloalkyl radical is bonded at two positions connecting together two separate additional groups and further bearing at least one additional substituent.
  • C 5 to C 7 cycloalkenyl indicates a 1,2, or 3-cyclopentenyl ring, a 1,2,3 or 4-cyclohexenyl ring or a 1,2,3,4 or 5-cycloheptenyl ring
  • substituted C5 to C 7 cycloalkenyl denotes the above C5 to C 7 cycloalkenyl rings substituted by a Ci to Ci 2 alkyl radical, halogen, hydroxy, protected hydroxy, Ci to Ci 2 alkoxy, trifluoromethyl, carboxy, protected carboxy, oxo, protected oxo,
  • C5 to C 7 cycloalkenylene is a cycloalkenyl ring, as defined above, where the cycloalkenyl radical is bonded at two positions connecting together two separate additional groups. Examples of C5 to C 7 cycloalkenylenes include 1,3-cyclopentylene and 1,2-cyclohexylene.
  • substituted C5 to C 7 cycloalkenylene means a cycloalkenylene further substituted by halogen, hydroxy, protected hydroxy, Ci to C 10 alkylthio, Ci to C 10 alkylsulfoxide, Ci to C 10 alkylsulfonyl, Ci to C 10 substituted alkylthio, Ci to C 10 substituted alkylsulfoxide, Ci to C 10 substituted alkylsulfonyl, Ci to C 12 alkyl, Ci to C 12 alkoxy, Ci to C 12 substituted alkyl, Ci to C 12 alkoxy, oxo, protected oxo, (monosubstituted)amino, (disubstituted)amino, trifluoromethyl, carboxy, protected carboxy, phenyl, substituted phenyl, phenylthio, phenylsulfoxide, phenylsulfonyl, amino, or protected amino
  • heterocycle or “heterocyclic ring” denotes optionally substituted f ⁇ ve-membered to eight-membered rings that have 1 to 4 heteroatoms, such as oxygen, sulfur and/or nitrogen, in particular nitrogen, either alone or in conjunction with sulfur or oxygen ring atoms.
  • heteroatoms such as oxygen, sulfur and/or nitrogen, in particular nitrogen, either alone or in conjunction with sulfur or oxygen ring atoms.
  • These f ⁇ ve-membered to eight-membered rings may be saturated, fully unsaturated or partially unsaturated, with fully saturated rings being preferred.
  • Preferred heterocyclic rings include morpholino, piperidinyl, piperazinyl, 2-amino-imidazoyl, tetrahydrofurano, pyrrolo, tetrahydrothiophen-yl, hexylmethyleneimino and heptylmethyleneimino.
  • substituted heterocycle or "substituted heterocyclic ring” means the above-described heterocyclic ring is substituted with, for example, one or more, and preferably one or two, substituents which are the same or different which substituents can be halogen, hydroxy, protected hydroxy, cyano, nitro, Ci to C 12 alkyl, Ci to C 12 alkoxy, Ci to C 12 substituted alkoxy, Ci to C 12 acyl, Ci to C 12 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino carboxamide, protected carboxamide, N- (Ci to C 12 alkyl)carboxamide, protected N-(Ci to C 12 alkyl)carboxamide, N, N-(Ii(C 1 to C 12 alkyl)carboxamide
  • heteroaryl means a heterocyclic aromatic derivative which is a five- membered or six-membered ring system having from 1 to 4 heteroatoms, such as oxygen, sulfur and/or nitrogen, in particular nitrogen, either alone or in conjunction with sulfur or oxygen ring atoms.
  • heteroaryls include pyridinyl, pyrimidinyl, and pyrazinyl, pyridazinyl, pyrrolo, furano, oxazolo, isoxazolo, phthalimido, thiazolo and the like.
  • substituted heteroaryl means the above-described heteroaryl is substituted with, for example, one or more, and preferably one or two, substituents which are the same or different which substituents can be halogen, hydroxy, protected hydroxy, cyano, nitro, Ci to C12 alkyl, Ci to Ci 2 alkoxy, Ci to Ci 2 substituted alkoxy, Ci to Ci 2 acyl, Ci to Ci 2 substituted acyl, Ci to Ci 2 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, carboxamide, protected carboxamide, N-(Ci to Ci 2 alkyl)carboxamide, protected N-(Ci to Ci 2 alkyl)carboxamide, N, N-di(Ci to Ci 2 alkyl)carboxamide, N, N
  • C 7 to C 18 phenylalkyl denotes a Ci to Ci 2 alkyl group substituted at any position within the alkyl chain by a phenyl.
  • the definition includes groups of the formula: -phenyl-alkyl, -alkyl-phenyl and -alkyl-phenyl-alkyl. Examples of such a group include benzyl, 2-phenylethyl, 3-phenyl(n-propyl), 4-phenylhexyl, 3-phenyl(n- amyl), 3-phenyl(sec-butyl) and the like.
  • Preferred C 7 to C 18 phenylalkyl groups are any one of the preferred alkyl groups described herein combined with a phenyl group.
  • Ci to Ci 2 heterocycloalkyl denotes a Ci to Ci 2 alkyl group substituted at any position within the alkyl chain by a "heterocycle,” as defined herein.
  • the definition includes groups of the formula: -heterocyclic-alkyl, -alkyl-heterocyclic and -alkyl-heterocyclic-alkyl. Examples of such a group include 2-pyridylethyl, 3- piperydyl(n-propyl), 4-furylhexyl, 3-piperazyl(n-amyl), 3-morpholyl(sec-butyl) and the like.
  • Ci to Ci 2 heterocycloalkyl groups are any one of the preferred alkyl groups described herein combined with any one of the preferred heterocycle groups described herein.
  • the terms "C 7 to C 18 substituted phenylalkyl” and "Ci to C 12 substituted heterocycloalkyl” denote a C 7 to C 18 phenylalkyl group or Ci to C 12 heterocycloalkyl substituted (on the alkyl or, where applicable, phenyl or heterocyclic portion) with one or more, and preferably one or two, groups chosen from halogen, hydroxy, protected hydroxy, oxo, protected oxo, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, guanidino, protected guanidino, heterocyclic ring, substituted heterocyclic ring, Ci to C12 alkyl, Ci to Ci 2 substituted alkyl, Ci to
  • C 7 to C 18 phenylalkylene specifies a C 7 to C 18 phenylalkyl, as defined above, where the phenylalkyl radical is bonded at two different positions connecting together two separate additional groups.
  • the definition includes groups of the formula: -phenyl-alkyl-, -alkyl-phenyl- and -alkyl-phenyl-alkyl-. Substitutions on the phenyl ring can be 1,2, 1,3 or 1,4.
  • C 7 to C 18 phenylalkylenes include, for example, 1,4-tolylene and 1,3-xylylene.
  • Ci to C 12 heterocycloalkylene specifies a Ci to C 12 heterocycloalkyl, as defined above, where the heterocycloalkyl radical is bonded at two different positions connecting together two separate additional groups.
  • the definition includes groups of the formula: -heterocyclic-alkyl-, -alkyl-heterocyclic and -alkyl- heterocyclic-alkyl-.
  • C 7 to C 18 substituted phenylalkylene and "Ci to C12 substituted heterocycloalkylene” means a C 7 to C 18 phenylalkylene or Ci to Ci 2 heterocycloalkylene as defined above that is further substituted by halogen, hydroxy, protected hydroxy, Ci to C 10 alkylthio, Ci to C 10 alkylsulfoxide, Ci to C 10 alkylsulfonyl, Ci to Cio substituted alkylthio, Ci to C 10 substituted alkylsulfoxide, Ci to C 10 substituted alkylsulfonyl, Ci to Ci 2 alkyl, Ci to Ci 2 alkoxy, Ci to Ci 2 substituted alkyl, Ci to Ci 2 alkoxy, oxo, protected oxo, (monosubstituted)amino, (disubstituted)amino, trifluoromethyl, carboxy, protected carboxy, phenyl, substituted phenyl,
  • substituted phenyl specifies a phenyl group substituted with one or more, and preferably one or two, moieties chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, Ci to Ci 2 alkyl, Ci to Ci 2 substituted alkyl, Ci to Ci 2 alkoxy, Ci to Ci 2 substituted alkoxy, Ci to Ci 2 acyl, Ci to Ci 2 substituted acyl, Ci to Ci 2 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, carboxamide, protected carboxamide, N-(Ci to Ci 2 alkyl)carboxamide, protected N-(Ci to Ci 2 alkyl)carboxamide, N, N-di(Ci to Ci 2 alkyl)carboxamide, N,
  • phenoxy denotes a phenyl bonded to an oxygen atom, wherein the binding to the rest of the molecule is through the oxygen atom.
  • substituted phenoxy specifies a phenoxy group substituted with one or more, and preferably one or two, moieties chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, Ci to Ci 2 alkyl, Ci to Ci 2 alkoxy, Ci to Ci 2 substituted alkoxy, Ci to Ci 2 acyl, Ci to Ci 2 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, carboxamide, protected carboxamide, N-(Ci to C 12 alkyl)carboxamide, protected N-(Ci to C 12 alkyl)carboxamide, protected N-(
  • C 7 to C 18 substituted phenylalkoxy denotes a C 7 to C 18 phenylalkoxy group bonded to the rest of the molecule through the oxygen atom, wherein the phenylalkyl portion is substituted with one or more, and preferably one or two, groups selected from halogen, hydroxy, protected hydroxy, oxo, protected oxo, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino,
  • substituted alkyl or phenyl groups may be substituted with one or more, and preferably one or two, substituents which can be the same or different.
  • phthalimide means a cyclic imide which is made from phthalic acid, also called 1 ,2-benzenedicarboxylic acid.
  • substituted phthalimide specifies a phthalimide group substituted with one or more, and preferably one or two, moieties chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, Ci to Ci 2 alkyl, Ci to Ci 2 alkoxy, Ci to Ci 2 substituted alkoxy, Ci to Ci 2 acyl, Ci to C 12 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, carboxamide, protected carboxamide, N-(Ci to C 12 alkyl)carboxamide, protected N-(Ci to C 12 alkyl)carboxamide, protected N-(
  • substituted naphthyl specifies a naphthyl group substituted with one or more, and preferably one or two, moieties either on the same ring or on different rings chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, Ci to C 6 alkyl, Ci to C 7 alkoxy, Ci to C 7 acyl, Ci to C 7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, carboxamide, protected carboxamide, N-(Ci to C 12 alkyl)carboxamide, protected N-(Ci to C 12 alkyl)carboxamide, N, N-(Ii(C 1 to C 12 alkyl)carboxamide, trifluoromethyl, N-((Ci to)
  • naphthylene means a naphthyl radical bonded at two positions connecting together two separate additional groups.
  • substituted napthylene means a naphthylene group that is further substituted by halogen, hydroxy, protected hydroxy, Ci to C 10 alkylthio, Ci to C 10 alkylsulfoxide, Ci to C 10 alkylsulfonyl, Ci to Cio substituted alkylthio, Ci to C 10 substituted alkylsulfoxide, Ci to C 10 substituted alkylsulfonyl, Ci to Ci 2 alkyl, Ci to Ci 2 alkoxy, Ci to Ci 2 substituted alkyl, Ci to Ci 2 alkoxy, oxo, protected oxo, (monosubstituted)amino, (disubstituted)amino, trifluoromethyl, carboxy, protected carboxy, phenyl, substituted phenyl, phenylthio,
  • halo and halogen refer to the fluoro, chloro, bromo or iodo atoms. There can be one or more halogens, which are the same or different. Preferred halogens are chloro and fluoro.
  • (monosubstituted)amino refers to an amino group with one substituent chosen from the group consisting of phenyl, substituted phenyl, Ci to Ci 2 alkyl, Ci to Ci 2 substituted alkyl, Ci to Ci 2 acyl, Ci to Ci 2 substituted acyl, C 2 to Ci 2 alkenyl, C 2 to Ci 2 substituted alkenyl, C 2 to Ci 2 alkynyl, C 2 to Ci 2 substituted alkynyl, C 7 to Ci8 phenylalkyl, C 7 to C 18 substituted phenylalkyl, heterocyclic ring, substituted heterocyclic ring, Ci to C 12 heterocycloalkyl and Ci to C 12 substituted heterocycloalkyl.
  • the (monosubstituted)amino can additionally have an amino-protecting group as encompassed by the term "protected (monosubstituted)amino.”
  • (disubstituted)amino refers to an amino group with two substituents chosen from the group consisting of phenyl, substituted phenyl, Ci to C12 alkyl, Ci to C 12 substituted alkyl, Ci to Ci 2 acyl, C 2 to Ci 2 alkenyl, C 2 to Ci 2 alkynyl, C 7 to C 18 phenylalkyl, C 7 to C 18 substituted phenylalkyl, Ci to Ci 2 heterocycloalkyl and Ci to Ci 2 substituted heterocycloalkyl.
  • the two substituents can be the same or different.
  • amino-protecting group refers to substituents of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups of the molecule.
  • protected (monosubstituted)amino means there is an amino-protecting group on the monosubstituted amino nitrogen atom.
  • protected carboxamide means there is an amino-protecting group on the carboxamide nitrogen.
  • protected N-(Ci to Ci 2 alkyl)carboxamide means there is an amino-protecting group on the carboxamide nitrogen.
  • protected guanidino refers to an "amino-protecting group" on one or two of the guanidino nitrogen atoms. Examples of “protected guanidino” groups are described by T. W. Greene and P. GM. Wuts; M. Bodanzsky; and Stewart and Young, supra.
  • epimino means -NH-.
  • substituted epimino means - N(R)-, where R is a substitution group listed above under the definition of "(monosubstituted)amino.”
  • Ci to Cs alkylene epimino refers to a one to five carbon alkylene chain with an epimino at any point along the chain.
  • Ci to C 5 substituted alkylene epimino refers to a Ci to C5 alkylene epimino group that is substituted a) at the epimino position (in the same way as “substituted epimino,” described above); and/or b) at one or more of the alkylene positions (in the same way as “substituted alkylene,” as described above).
  • thio refers to -SH or, if between two other groups, -S-.
  • Ci to Cio alkylene thio refers to a one to ten carbon alkylene chain with a thio at any point along the chain.
  • the term "Ci to C 10 substituted alkylene thio” refers to a Ci to Cio alkylene thio group that is substituted at one or more of the alkylene positions (in the same way as “substituted alkylene,” as described above).
  • sulfonyl refers to -S(O) 2 -.
  • Ci to Ci 0 alkylene sulfonyl refers to a one to ten carbon alkylene chain with a sulfonyl at any point along the chain.
  • Ci to C 10 substituted alkylene sulfonyl refers to a Ci to C 10 alkylene sulfonyl group that is substituted at one or more of the alkylene positions (in the same way as "substituted alkylene,” as described above).
  • Ci to C 10 substituted alkylsulfonyl refers to a Ci to C 10 alkylsulfonyl group that is substituted at one or more of the alkyl positions (in the same way as “substituted alkyl,” as described above).
  • substituted phenylsulfonyl refers to a phenylsulfonyl group that is substituted at one or more of the phenyl positions (in the same way as
  • sulfmyl refers to -S(O)-.
  • Ci to Ci 0 alkylene sulfmyl refers to a one to ten carbon alkylene chain with a sulfmyl at any point along the chain.
  • Ci to C 10 substituted alkylene sulfinyl refers to a Ci to C 10 alkylene sulfinyl group that is substituted at one or more of the alkylene positions (in the same way as
  • oxy refers to -O-.
  • Ci to Ci 0 alkylene oxy refers to a one to ten carbon alkylene chain with, respectively, one, two or three -O- at any point along the chain, provided that no two oxygen atoms are consecutive, and provided that any two oxygen atoms are separated by at least two carbons.
  • Ci to C 10 substituted alkylene oxy refers, respectfully to "Ci to Cio alkylene oxy,” “Ci to Cio alkylene dioxy” and “Ci to Cio alkylene trioxy” that are substituted at one or more of the alkylene positions (in the same way as “substituted alkylene,” as described above).
  • thiocarbonyl refers to -C(S)H or, if between two other groups, -
  • carboxy-protecting group refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound.
  • a related term is "protected carboxy,” which refers to a carboxy group substituted with one of the above carboxy-protecting groups.
  • hydroxy-protecting group refers to readily cleavable groups bonded to hydroxyl groups, such as the tetrahydropyranyl, 2-methoxypropyl, 1-ethoxyethyl, methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, t-butyl, t-amyl, trityl, 4- methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityl, benzyl, allyl, trimethylsilyl, (t-butyl)dimethylsilyl, 2,2,2-trichloroethoxycarbonyl groups and the like.
  • Ci to C 10 alkylthio refers to sulfide groups such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, t-butylthio and like groups.
  • the term "Ci to C 10 alkylsulfoxide” indicates sulfoxide groups such as methylsulfoxide, ethylsulfoxide, n-propylsulfoxide, isopropylsulfoxide, n- butylsulfoxide, sec-butylsulfoxide and the like.
  • Ci to Ci 0 alkylsulfonyl encompasses groups such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, t-butylsulfonyl and the like, it should also be understood that the above thio, sulfoxide or sulfonyl groups can be at any point on the alkyl chain (e.g., 2-methylmercaptoethyl).
  • Ci to C 10 substituted alkylthio Ci to C 10 substituted alkylsulfoxide
  • Ci to C 10 substituted alkylsulfonyl denote the Ci to C 10 alkyl portion of these groups may be substituted as described above in relation to "substituted alkyl.”
  • phenylthio phenylsulfoxide
  • phenylsulfonyl specify a thiol, a sulfoxide, or sulfone, respectively, containing a phenyl group.
  • substituted phenylthio substituted phenylsulfoxide
  • substituted phenylsulfonyl means that the phenyl of these groups can be substituted as described above in relation to "substituted phenyl.”
  • Ci to C12 alkylaminocarbonyl means a Ci to Ci 2 alkyl attached to a nitrogen of the aminocarbonyl group.
  • Examples of Ci to Ci 2 alkylaminocarbonyl include methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl and butylaminocarbonyl.
  • Ci to Ci 2 substituted alkylaminocarbonyl denotes a substituted alkyl bonded to a nitrogen of the aminocarbonyl group, which alkyl may be substituted as described above in relation to Ci to Ci 2 substituted alkyl.
  • Ci to Ci 2 substituted alkylaminocarbonyl include, for example, methoxymethylaminocarbonyl, 2-chloroethylaminocarbonyl, 2- oxopropylaminocarbonyl and 4-phenylbutylaminocarbonyl.
  • Ci to C12 alkoxycarbonyl means a “Ci to Ci 2 alkoxy” group attached to a carbonyl group.
  • Ci to Ci 2 substituted alkoxycarbonyl denotes a substituted alkoxy bonded to the carbonyl group, which alkoxy may be substituted as described above in relation to "Ci to Ci 2 substituted alkyl.”
  • phenylaminocarbonyl means a phenyl attached to a nitrogen of the aminocarbonyl group.
  • substituted phenylaminocarbonyl denotes a substituted phenyl bonded to a nitrogen of the aminocarbonyl group, which phenyl may be substituted as described above in relation to substituted phenyl.
  • substituted phenylaminocarbonyl include 2-chlorophenylaminocarbonyl, 3- chlorophenylaminocarbonyl , 2-nitorphenylaminocarbonyl, 4-biphenylaminocarbonyl, and 4-methoxyphenylaminocarbonyl.
  • Ci to Ci 2 alkylaminothiocarbonyl means a Ci to Ci 2 alkyl attached to an aminothiocarbonyl group, wherein the alkyl has the same meaning as defined above.
  • Ci to Ci 2 substituted alkylaminothiocarbonyl denotes a substituted alkyl bonded to an aminothiocarbonyl group, wherein the alkyl may be substituted as described above in relation to Ci to Ci 2 substituted alkyl.
  • phenylaminothiocarbonyl means a phenyl attached to an aminothiocarbonyl group, wherein the phenyl has the same meaning as defined above.
  • substituted phenylaminothiocarbonyl denotes a substituted phenyl bonded to an aminothiocarbonyl group, wherein phenyl may be substituted as described above in relation to substituted phenyl.
  • phenylene means a phenyl group where the phenyl radical is bonded at two positions connecting together two separate additional groups.
  • substituted phenylene means a phenyl group where the phenyl radical is bonded at two positions connecting together two separate additional groups, wherein the phenyl is substituted as described above in relation to "substituted phenyl.”
  • substituted Ci to Ci 2 alkylene means a Ci to Ci 2 alkyl group where the alkyl radical is bonded at two positions connecting together two separate additional groups and further bearing an additional substituent.
  • cyclic C 2 to C 7 alkylene defines such a cyclic group bonded ("fused") to the phenyl radical resulting in a bicyclic ring system.
  • the cyclic group may be saturated or contain one or two double bonds.
  • the cyclic group may have one or two methylene or methine groups replaced by one or two oxygen, nitrogen or sulfur atoms which are the cyclic C 2 to C 7 heteroalkylene.
  • the cyclic alkylene or heteroalkylene group may be substituted once or twice by the same or different substituents which, if appropriate, can be connected to another part of the compound (e.g., alkylene) selected from the group consisting of the following moieties: hydroxy, protected hydroxy, carboxy, protected carboxy, oxo, protected oxo, Ci to C 4 acyloxy, formyl, Ci to Ci 2 acyl, Ci to Ci 2 alkyl, Ci to C 7 alkoxy, Ci to Cio alkylthio, Ci to C 10 alkylsulfoxide, Ci to C 10 alkylsulfonyl, halo, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, hydroxymethyl or a protected hydroxymethyl.
  • the cyclic alkylene or heteroalkylene group fused onto the benzene radical can contain two to ten ring members, but it preferably contains three to six members.
  • saturated cyclic groups are when the resultant bicyclic ring system is 2,3-dihydro-indanyl and a tetralin ring.
  • unsaturated examples occur when the resultant bicyclic ring system is a naphthyl ring or indolyl.
  • fused cyclic groups which each contain one nitrogen atom and one or more double bond, preferably one or two double bonds, are when the benzene radical is fused to a pyridino, pyrano, pyrrolo, pyridinyl, dihydropyrrolo, or dihydropyridinyl ring.
  • fused cyclic groups which each contain one oxygen atom and one or two double bonds are when the benzene radical ring is fused to a furo, pyrano, dihydrofurano, or dihydropyrano ring.
  • fused cyclic groups which each have one sulfur atom and contain one or two double bonds are when the benzene radical is fused to a thieno, thiopyrano, dihydrothieno or dihydrothiopyrano ring.
  • Examples of cyclic groups which contain two heteroatoms selected from sulfur and nitrogen and one or two double bonds are when the benzene radical ring is fused to a thiazolo, isothiazolo, dihydrothiazolo or dihydroisothiazolo ring.
  • Examples of cyclic groups which contain two heteroatoms selected from oxygen and nitrogen and one or two double bonds are when the benzene ring is fused to an oxazolo, isoxazolo, dihydrooxazolo or dihydroisoxazolo ring.
  • cyclic groups which contain two nitrogen heteroatoms and one or two double bonds occur when the benzene ring is fused to a pyrazolo, imidazolo, dihydropyrazolo or dihydroimidazolo ring or pyrazinyl.
  • carbamoyl means an -NC(O)- group where the radical is bonded at two positions connecting two separate additional groups.
  • One or more of the compounds of the invention may be present as a salt.
  • salt encompasses those salts that form with the carboxylate anions and amine nitrogens and include salts formed with the organic and inorganic anions and cations discussed below.
  • the term includes salts that form by standard acid-base reactions with basic groups (such as amino groups) and organic or inorganic acids.
  • Such acids include hydrochloric, hydrofluoric, trifluoroacetic, sulfuric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic, D- glutamic, D-camphoric, glutaric, phthalic, tartaric, lauric, stearic, salicyclic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic, cinnamic, and like acids.
  • organic or inorganic cation refers to counter-ions for the carboxylate anion of a carboxylate salt.
  • the counter-ions are chosen from the alkali and alkaline earth metals, (such as lithium, sodium, potassium, barium, aluminum and calcium); ammonium and mono-, di- and tri-alkyl amines such as trimethylamine, cyclohexylamine; and the organic cations, such as dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, bis(2-hydroxyethyl)ammonium, phenylethylbenzylammonium, dibenzylethylenediammonium, and like cations.
  • a cation for a carboxylate anion will exist when a position is substituted with a (quaternary ammonium)methyl group.
  • a preferred cation for the carboxylate anion is the sodium cation.
  • the compounds of the invention can also exist as solvates and hydrates. Thus, these compounds may crystallize with, for example, waters of hydration, or one, a number of, or any fraction thereof of molecules of the mother liquor solvent. The solvates and hydrates of such compounds are included within the scope of this invention.
  • One or more compounds of the invention can be in the biologically active ester form, such as the non-toxic, metabolically-labile ester-form. Such ester forms induce increased blood levels and prolong the efficacy of the corresponding non-esterified forms of the compounds.
  • Ester groups which can be used include the lower alkoxymethyl groups, for example, methoxymethyl, ethoxymethyl, isopropoxymethyl and the like; the -(Ci to Ci 2 ) alkoxyethyl groups, for example methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl and the like; the 2-oxo-l,3-diooxlen-4- ylmethyl groups, such as 5-methyl-2-oxo-l,3-dioxolen-4-ylmethyl, 5-phenyl-2-oxo- l,3-dioxolen-4-ylmethyl and the like; the Ci to C 10 alkylthi
  • amino acid includes any one of the twenty naturally-occurring amino acids or the D-form of any one of the naturally-occurring amino acids.
  • amino acid also includes other non-naturally occurring amino acids besides the D-amino acids, which are functional equivalents of the naturally-occurring amino acids.
  • non-naturally-occurring amino acids include, for example, norleucine ("NIe"), norvaline (“Nva”), L- or D- naphthalanine, ornithine (“Orn”), homoarginine (homoArg) and others well known in the peptide art, such as those described in M.
  • any position of the claimed invention has up to three serial “substitutions.”
  • a "substituted alkyl” that is substituted with a "substituted phenyl” that is, in turn, substituted with a “substituted alkyl” can, in turn, be susbstitued by one more group and no longer further substituted.
  • the invention contemplates, if appropriate, more than three parallel susbstitutions.
  • more than threee hydrogens on an alkyl moiety may be susbstituted with any one or more of a variety of groups, including halo and hydroxy.
  • inert, pharmaceutically acceptable carriers are used.
  • the pharmaceutical carrier can be either solid or liquid.
  • Solid form preparations include, for example, powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • a solid carrier can be one or more substances that can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
  • the carrier is generally a finely divided solid which is in a mixture with the finely divided active component.
  • the active compound is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • a low- melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient-sized molds and allowed to cool and solidify.
  • Powders and tablets preferably contain between about 5% to about 70% by weight of the active ingredient.
  • Suitable carriers include, for example, magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter and the like.
  • compositions can include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier, which is thus in association with it.
  • a carrier which is thus in association with it.
  • cachets are also included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
  • Liquid pharmaceutical compositions include, for example, solutions suitable for oral or parenteral administration, or suspensions, and emulsions suitable for oral administration.
  • Sterile water solutions of the active component or sterile solutions of the active component in solvents comprising water, ethanol, or propylene glycol are examples of liquid compositions suitable for parenteral administration.
  • Sterile solutions can be prepared by dissolving the active component in the desired solvent system, and then passing the resulting solution through a membrane filter to sterilize it or, alternatively, by dissolving the sterile compound in a previously sterilized solvent under sterile conditions.
  • Aqueous solutions for oral administration can be prepared by dissolving the active compound in water and adding suitable flavorants, coloring agents, stabilizers, and thickening agents as desired.
  • Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
  • the pharmaceutical composition is in unit dosage form.
  • the composition is divided into unit doses containing appropriate quantities of the active 2-aminobenzoxazole compound.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, for example, packeted tablets, capsules, and powders in vials or ampules.
  • the unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.
  • the compounds of the present invention are generally in a pharmaceutical composition so as to be administered to a subject at dosage levels of from 0.7 to 7000 mg per day, and preferably 1 to 500 mg per day, for a normal human adult of approximately 70 kg of body weight, this translates into a dosage of from 0.01 to 100 mg/kg of body weight per day.
  • the specific dosages employed can be varied depending upon the requirements of the patient, the severity of the condition being treated, and the activity of the compound being employed. The determination of optimum dosages for a particular situation is within the skill of the art.
  • Example 15 2-acetyl-9-[3-(cis-3,5-dimethylpiperazin-l-yl)propyl]-9H-carbazole
  • 9-(3-chloropropyl)-2-acetyl-9H-carbazole 50 mg, 0.175 mmol
  • cis-2,6- dimethylpiperazine 80 mg
  • tetrabutylammonium iodide 97 mg, 0.26 mmol
  • dimethylformamide dimethylformamide
  • acetone acetone
  • Example 23 To the crude mixture from the first paragraph of Example 23 (200 mg, 0.73 mmol) was added c ⁇ -3,5-dimethylpiperazine (334 mg, 2.92 mmol), tetrabutylammonium iodide (405 mg, 1.1 mmol) and dimethylformamide. After 96 hours at 37 0 C, the reaction was quenched with water and extracted with dichloromethane. The combined organic layers were placed on silica in vacuo, and purified by flash chromatography (1 :9 methanol: dichloromethane) to yield an oil. This was taken up in methanol and ethyl acetate and maleic acid (400 mg) was added. A solid formed that was filtered with the aid of methanol and ethyl acetate. This was the title compound (75 mg, 18 %).
  • Example 24 The title compound was prepared in a manner similar to that of Example 24.
  • Example 35 The title compound was prepared in a manner similar to that of Example 3.
  • Example 35 The title compound was prepared in a manner similar to that of Example 3.
  • the tube was rinsed with toluene to remove solids.
  • the hexanes and toluene fractions were combined and evaporated.
  • the resulting orange oil was passed through flash silica, a 2 by 1 inch column, with hexanes to give the named compound as an orange oil.
  • the mix was stirred at 0 C for 30 minutes, and then a room temperature for 2 days. TLC of the reaction after 2 days with hexanes on silica showed 2 new higher RF spots relative to the 2-chlorophenothiazine.
  • the reaction was treated with water, 10 ml, hexanes, 4 ml and ethyl acetate, 10 ml. The layers were separated, and the organic layer was evaporated to give 0.29 g of oil that solidifies on standing.
  • the waxy solids were dissolved in 10 ml of hexanes, and chromatographed on a silica column, 5X1 inch, with hexanes, 400 ml, and then 5% dichloromethane in hexanes, 200 ml. Fractions were examined with hexanes on silica, and pure fractions of the more mobile and less mobile products were individually pooled and evaporated. NMR allowed the assignment of more mobile compound, example 43, as 10-(z-3chloropropene)-2-chlorophenothiazine.
  • Example 47 9-(isopropyl)carbazole
  • carbazole 5.5 g
  • isopropyl bromide 10 ml, 50 % aqueous sodium hydroxide, 10 ml, tetrabutylammonium hydroxide, 0.22g, and toluene, 10 ml were added.
  • the mixture was placed under N2, and warmed in a 70 0 C oil bath. After 18 hours, the mixture was cooled to room temperature. The mix was treated with 40 ml of hexanes and 50 ml of water, and the resulting solids collected by filtration.
  • TLC of solids and filtrate organic layer showed new spot RF 0.4 with 10% Ethyl acetate in hexanes on silica.
  • the solids were combined with the organic layer.
  • the aqueous layer was extracted once with 40 ml of ethyl acetate.
  • the combined organic layers were combined and evaporated in vacuo.
  • the residue was taken up in 120 ml of methanol at reflux, and then cooled with an ice/water bath.
  • the resulting solids were collected by filtration.
  • TLC of the solids on silica with 1 :10 ethyl acetate/hexanes showed an RF of 0.5, and carbazole showed an RF of of 0.2.
  • the yield of solids was 5 g.
  • Example 50 9-Ethyl-9H-carbazole-3-carboxylic acid propylamide
  • Example 61 (1062-167) 3 -[(9-Ethyl-9H-carbazole-3-carbonyl)-amino] -propionic acid
  • Example 62 The synthesis was carried out using the aforementioned method in Example 62 with the exception of 3- [(9-Ethyl-9H-carbazole-3-carbonyl)-amino] -propionic acid (Example 61) in place of [9-Ethyl-9H-carbazole-3-carbonyl]-amino]-acetic acid. After 8 hours TLC showed new spot with higher Rf. Diluted mix with ethyl acetate, washed with NaHCO 3aq , brine, dried over MgSO 4 , evaporated organic layer. Chromatographed the resulting oil using Biotage SP4TM 12+M silica column with methanol / dichloromethane solvent system. The resulting oil provided 9-Ethyl-9H-carbazole-3- carboxylic acid [3-(4-methyl-piperazin- 1 -yl)-3-oxo-propyl]-amide.
  • 9-Ethyl-9H-carbazole-3-carboxylic acid methyl ester A sample of 9-Ethyl-9H-carbazole-3-carboxylic acid (Example 49), lOOmg (0.416 x 10 "3 mol), was placed in a 15ml round bottom flask with a magnetic stirring bar. The flask was capped with a rubber septum, evacuated then back filled with nitrogen. Added methanol, 10ml, via syringe, cooled mix to 0 0 C, followed by addition of 95.5% H 2 SO 4 , lOO ⁇ l. Attached distillation condenser, heated to 80 0 C, distilled off methanol.
  • the named compound of the example was prepared from 9-Isopropyl-9H- carbazole-3-carboxaldehyde (example 48) following the method of example 49.
  • Example 74 (1062-69) 4-(3-Carbazol-9-yl-propoxy)-isophthalic acid dimethyl ester
  • NMR 500 MH D6DMS0 8.31, d, IH, 8.14, d, 2H, 8.08, dd, IH, 7.63, d, 2H, 7.38,-7.35, m, 2H, 7.18, t, 2H, 7.13, d, IH, 4.64, t, 2H, 4.07-4.01, m, 2H, 3.94, s, 3H, 2.55, d, 3H, 2.27-2.22, m, 2H.
  • Example 79 (1062-117) 8-Chloro-l,2,3,4-tetrahydrocarbazole A sample of 2-chlorophenylhydrazine -HCl, 1.7g (9.5 x 10 "3 mol), acetic acid,
  • 6-Chloro-9-(4-phenoxy-butyl)-2, 3, 4, 9-tetrahydro-l H-carbazole A sample of 6-Chloro-2,3,4,9-tetrahydro-l H-carbazole (Example 82), 173mg (0.840 x 10 " mol), 4-phenoxybutyl bromide, 289mg (1.26 x 10 " mol), were combined in a 15ml round bottom flask with magnetic stirring bar. The flask was capped with a rubber septum, evacuated then back filled with nitrogen.
  • Example 85 The synthesis was carried out using the aforementioned method in Example 81 with exception of 4-Chloro-5,6, 7,8,9, 10-hexahydro-cyclohepta[b]indole (Example 85) in place of 8-Chloro- 1 ,2,3 ,4-tetrahydrocarbazole.
  • 9-ethylcarbazole-3 -carboxaldehyde oxime O-methyl ether A sample of 9-ethylcarbazole-3-carboxaldehyde, 223 mg, O- methylhydroxylamine hydrochloride, 109 mg, 4-methylmorpholine, 0.11 ml, and THF, 1 ml, then 0.2 ml water were combined in a 20 ml vial. The resulting 2 phase mix was stirred at room temperature. TLC after several hours with DCM on silica showed mostly a new spot, slightly higher RF than SM. The mix was treated with 0.5 ml ethanol to give a slightly cloudy single phase. No solids formed on standing for 2 days.
  • the mixture was then poured into 100 ml of cold water, giving a gummy precipitate.
  • the mix was treated with 80 ml of ethyl acetate and 20 ml of hexanes.
  • the layers were separated, and the organic layer was washed with 100 ml of water.
  • the organic layer was then stirred with 20 g of sodium bicarbonate in 100 ml of water.
  • the ethyl acetate was evaporated in vacuo.
  • the residue was treated with 100 ml of hexanes, heated to a boil, and diluted with ethyl acetate hot until a solution was obtained, then hexanes was added to a total volume of 200 ml.
  • TLC of the solids with 1 :20 ethyl acetate in dichloromethane shows a new lower RF spot, blue fluorescent with long wave UV, and adsorbing at 254nm.
  • the crude product was recrystallized from toluene, 50 ml.
  • reaction mixture was quenched with sodium hydro sulfite and acidified to pH 2 with IN HCl.
  • the mixture was transferred into a separating funnel, the aqueous layer separated and extracted with EtOAc (2 x 50 ml).
  • EtOAc 2 x 50 ml.
  • the THF layer was concentrated in vacuo, taken into EtOAc (100 ml) and washed with H 2 O (40 ml).
  • the combined organic layers were dried over anhyd MgSO 4 and the solvents were removed in vacuo to afford 2.06 g of the desired product.
  • 9-(isopropyl) carbazole-3-carboxylic acid propylamide A sample of 9-(isopropyl) carbazole-3-carboxylic acid (0.145 g, 0.57 mmol) was taken in 2 ml of dry DMF. To this solution, NEt 3 (0.158 ml, 1.14 mmol) was added followed by the addition of HATU (0.216 g, 0.57mmol). After stirring for 5 min., propyl amine (0.056 ml, 0.684 mmol) was added and the reaction mixture was stirred at room temperature for overnight.
  • the compound was prepared, as described for example 92, from 9-(isopropyl) carbazole-3-carboxylic acid and 3-(4-methyl-piperazin-l-yl)-propylamine.
  • the compound was prepared, as described for example 47, from carbazole and bromo cyclohexane.
  • the compound was prepared, as described for example 48, from 9-(Cyclohexyl) carbazole.
  • the compound was prepared, as described for Example 49, from 9- (Cyclohexyl) carbazole-3-carboxaldehyde.
  • reaction mixture was stirred at room temperature for 2 hrs and the mixture was poured on crushed ice. After melting ice, the mixture was extracted with CH 2 Cl 2 (2 x 25 ml), washed with water (20 ml), sat.NaHCO 3 (20 ml) and the organic layer was dried over anhyd. MgSO 4 . The solvents were removed in vacuo and the crude was purified by column chromatography to obtain 0.18 g of the product.
  • the compound was prepared, as described for example 105, using 1.1 equiv. of acetyl chloride and AlCl 3 .
  • 6-Propylcarbamoyl-2,3,4,9-tetrahydro carbazole-3-carboxylic acid ethyl ester The compound was prepared, as described for example 92, 2,3,4,9-Tetrahydro carbazole ⁇ -dicarboxylic acid 3-ethyl ester and propylamine.
  • the compound was prepared, as described for example 111, from 2,3,4,9- tetrahydro carbazole-3,6-dicarboxylic acid diethyl ester and 3-phenoxy-propyl bromide
  • 9-Ethyl-6-[3-(4-methyl-piperazin-l-yl)-propylcarbamoyl]-carbazole-3- carboxylic acid ethyl ester The compound was prepared, as described for example 92, from 9-Ethyl carbazole ⁇ -dicarboxylic acid monoethyl ester and 3-(4-methyl-piperazin-l-yl)- propylamine.
  • the compound was prepared, as described for example 98, from 6,6-Dimethyl- 5,6,7,8-tetrahydro carbazole-3-carboxylic acid and methanol.
  • the compound was prepared, as described for example 115, from 6,6- Dimethyl-5,6,7,8-tetrahydro carbazole-3-carboxylic acid methyl ester and diethyl sulfate.
  • the compound was prepared, as described for example 118, from 4-hydrazino benzoic acid hydrochloride and 4-methyl eye Io hexanone.
  • 1H NMR 500 MHz D 6 DMSO: 12.26, s, IH, 11.1, s, IH, 7.99, d, J 0.6, IH,
  • the compound was prepared, as described for example 98, from 6-Methyl- 5,6,7,8-tetrahydro carbazole-3-carboxylic acid and methanol.
  • the compound was prepared, as described for example 118, from 3-chloro-4- hydrazino benzoic acid hydrochloride and cyclo hexanone.
  • Example 125 l-Chloro-5,6,7,8-tetrahydro carbazole-3-carboxylic acid methyl ester
  • the compound was prepared, as described for example 98, from 1-Chloro- 5,6,7,8-tetrahydro carbazole-3-carboxylic acid and methanol.
  • 9-(3'-chloro-propyl)-carbazole-3-carboxylic acid propyl amide A sample of 9H-carbazole-3-carboxylic acid propyl amide, 50mg, and Cs2CO3, 214mg were dissolved in 5ml DMF followed by the addition of 64.7 ⁇ of l-bromo-3- chloropropane. The mixture was stirred at room temperature overnight. TLC showed a new spot with a slightly higher Rf. The mixture was evaporated and treated by 100ml water and 100mlx2 ethyl acetate. The organic layer was combined, brined, dried over MgSO 4 , filtered and evaporated in vacuo. The crude mixture was purified by chromatography to yield 9-(3'-chloro-propyl)-carbazole-3-carboxylic acid propyl amide, 21mg.
  • HCV pseudoparticles of Hepatitis C virus envelope glycoproteins containing a packaging-competent retrovirus-derived genome harboring a marker gene are known, and reviewed by Voisset and Dubuisson.
  • l HCV pseudoparticles incorporating a lentiviral backbone harboring the luciferase gene has been used to assay for HCV pseudoparticle entry as follows. Huh7 cells seeded in 96-well plates were incubated with a concentration range of the tested compounds in the presence of 2% DMSO for 1 hour prior to infection by HCV or VSV pseudoparticles. Three days post infection, luciferase was evaluated by a standard luminescence assay. See Figure 1 , upper panel.
  • HCV cannot normally be grown in tissue culture
  • viral genomes containing the sequence of a HCV genotype 2a isolated from a fulminant case of hepatitis in Japan is able to support replication in Huh7 cells.
  • a recombinant HCV 2a virus was made by inserting the Neomycin coding sequence and encephalomyocarditis virus internal ribosome entry site sequence into the existing 2a clone sequence ( Figure 2).
  • Figure 2 Several compounds that were able to prevent HCVpp entry were validated using the HCV2aNeo virus. If the virus is successfully able to infect cells that are subsequently maintained in the presence of G418, the substrate for the neomycin protein, it will be able to generate colonies. When the presence of a specific inhibitor reduces the entry of the virus, fewer colonies will be able to form.
  • CD81 is the only undisputed protein involved in HCV entry and can be used as a positive control. Titration of CD81 specific antibodies dramatically reduced the number of colonies formed. However, a control IgG antibody did not reduce colony formation, indicating that the effect of CD81 is target specific.
  • a concentration range for compound "2302" (2-chloro-10-[4-(cis-3,5- dimethylpiperazin-l-yl)-butyl]-10H-phenothiazine) was tested for its ability to prevent HCV2aNeo entry.
  • a control compound, compound "2243” (clozapine-N-oxide) was tested. Both CD81 and compound “2302” were able to inhibit HCV2aNeo induced colony formation, while IgG and compound "2243” did not significantly alter the number of colonies, confirming that compound "2302" was able to prevent HCV entry (See Figures 3 and 4).
  • reaction mixture was added to 100 ml of ice cold H 2 O, the mixture was extracted with EtOAc (2x100 ml) and the combined organic layers were washed with sat. brine solution (75 ml). The organic layer was separated, dried over anhyd.MgSO 4 , solvents were concentrated in vacuo to obtain 2g of NMR pure product.
  • the compound was prepared, as described for example 92, from 5-Ethyl- 10,ll-dihydro-5H-dibenzo[/ ⁇ /]azepine-2-carboxylic acid and n-propyl amine.
  • the compound was prepared, as described for example 92, from 5-Ethyl- 10,ll-dihydro-5H-dibenzo[/ ⁇ /]azepine-2-carboxylic acid and 3-(4-methyl-piperazin- l-yl)-propyl amine.
  • 6-Bromo-9-ethyl-2,3,4,9-tetrahydro carbazole A sample of 6-Bromo-2,3,4,9-tetrahydro carbazole (0.498g, 2 mmol) was dissolved in 4 ml of dry DMF. To this stirred solution, NaH (60% suspension; 0.24g, 6 mmol) was added portion wise followed by the addition of diethyl sulfate (0.79ml, 6 mmol). The reaction mixture was heated to 80 0 C overnight. The TLC of mixture, with 4:6 dichloromethane/hexane, showed complete consumption of starting material and a new spot with higher R f value.
  • reaction mixture was added to 60 ml of ice cold H 2 O, the mixture was extracted with EtOAc and washed with sat. brine solution. The organic layer was dried over anhyd.MgSO4, solvents were concentrated in vacuo and the crude was purified by column chromatography to obtain 0.4g of the pure product.
  • 9-Ethyl-3 -phenyl carbazole The compound was prepared, as described for example 110, from 9-Ethyl-6- phenyl-2,3 ,4,9-tetrahydro carbazole.
  • NMR 500 MH D6DMSO 9.03, t, 3H, 8.77, s, IH, 8.18, d, IH, 8.07, dd, IH, 7.68, t, 2H, 7.51, t, IH, 7.38-7.32, m, 4H, 7.27, q, 2H, 4.56, d, 2H, 4.50, q, 2H, 1.33, t, 3H.
  • 9-Ethyl-9H-carbazole-3-carboxylic acid 4-Morpho line-amide A sample of 9-(ethyl) carbazole-3-carboxylic acid, 200mg (0.836 x 10 "3 mol), was placed in a 50ml round bottom flask with magnetic stirring bar. The flask was capped with a rubber septum, evacuated then back filled with nitrogen. Anhydrous toluene 1OmL, was added via syringe followed by diphenyl phosphoryl azide, 198 ⁇ l (0.920 x 10 "3 mol), triethylamine, 120 ⁇ l (0.836 x 10 "3 mol).
  • NMR 500 MH CDCL3 8.82, s, IH, 8.17-8.14, m, 2H, 7.50-7.46, m, 3H, 7.30- 7.26, m, IH, 4.46-4.41, m, 4H, 3.00-2.95, m, 2H, 2.71, dd, 2H, 2.28, t, 2H, 2.08, q, 2H, 1.47, t, 3H, 1.08, d, 6H.

Abstract

The present invention relates to the use of tricyclic diphenylamine derivative compounds for prevention and/or treatment of Hepatitis C virus (HCV) infection by inhibiting HCV entry into permissive cells.

Description

HEPATITIS C VIRUS ENTRY INHIBITORS
FIELD OF THE INVENTION
The present invention relates to tricyclic diphenylamine derivative compounds for prevention and/or treatment of Hepatitis C virus (HCV) infection by inhibiting HCV entry into permissive cells. More specifically, these compounds have the formula:
Figure imgf000002_0001
with the depicted variables having the meaning described below.
BACKGROUND INFORMATION
Hepatitis C is caused by infection with Hepatitis C Virus (HCV), which is carried by more than 100 million people worldwide. The currently FDA-approved Hepatitis C therapies, for example, non-specific antiviral substances that boost the host's antiviral responses and target virus replication, are only moderately efficacious and cause significant adverse reactions.
There are currently 4 FDA approved Hepatitis C combination therapies: Intron A and Rebetol (Interferon Alpha-2b and ribavirin, respectively); Roferon A (Interferon Alpha-2a) and Ribavirin ; Pegasys and Copegus (PEGylated Interferon Alpha-2a and ribavirin, respectively); and PEG-Intron and Rebetol (PEGylated Interferon Alpha-2b and ribavirin, respectively). These are in addition to the 5 FDA approved monotherapies: Infergen (Interferon alfacon-1), Roferon A, Intron A, PEG-Intron, and Pegasys. Generally, interferons and PEGylated interferons are non-specific antiviral and antineoplastic proteins that act by inhibiting viral replication. Ribavirin is a non- specific, antiviral, nucleotide analog prodrug that interferes with RNA metabolism and is not effective in monotherapy for the treatment of HCV infection.
The currently FDA approved Hepatitis C treatments are generally accepted to be effective in less than half of HCV infections. If not cured, HCV infection leads to chronic Hepatitis in up to 85% of patients, and is responsible for an estimated 10,000 deaths per year in the United States.
Despite significant efforts, no efficacious vaccine has been developed that can protect against HCV During infection, the host produces a wide array of antibodies targeting viral structural and nonstructural proteins. However, these antibodies fail to clear the virus. In addition, the E2 outer membrane protein contains two hyper- variable regions that most likely contribute to the virus's ability to escape clearance by the immune system.
Thus, a need clearly exists to develop more effective treatments against HCV The subject invention satisfies this need and provides related advantages as well. HCV has a poorly understood method of cell entry. Despite the ubiquity of
HCVs receptors (CD81 and SRBl), only lymphocytes, monocytes, and hepatocytes are permissive to HCV entry. However, HCV entry can be studied separately from its other functions utilizing HCV pseudoparticles ("HCVpp") that maintain an HCV envelope and yet contain a Human Immunodeficiency Virus (HIV) based genomic backbone that can be used to express reporter genes. This has led to the discovery of the invention described herein.
SUMMARY OF THE INVENTION
The present invention is directed to tricyclic diphenylamine derivative compounds for the prevention and/or treatment of HCV infection by inhibiting HCV entry into permissive cells. The diphenylamine derivatives described herein selectively inhibit HCV entry into permissive cells but allow viruses with divergent entry mechanisms to cross into the cytoplasm. More specifically, these tricyclic diphenylamine derivative compounds have the formula:
Figure imgf000004_0001
with the depicted variables having the meaning described below.
BRIEF DESCRIPTION OF THE DRAWINGS Figures IA, IB and 1C show the screening of compounds of the present invention in the HCVpp, VSV-Gpp and alama Blue™ assays, respectively.
Figure 2 shows the structure of the recombinant HCV2a-Neo virus used to validate entry inhibitors of the present invention.
Figure 3 shows the validation of compound "2302" utilizing the recombinant HCV2aNeo virus. Huh7 cells were infected with similar amounts of HCV2aNeo containing supernatants. The cell cultures were treated with either CD 81 or IgG antibody as control for the assay, and with either compound "2302" or compound "2243" as a negative control. The number of colonies was counted as shown in Figure 4. Figure 5 shows the validation of compounds "2241", "2281", "2282", "2302",
"2339" and "2284" utilizing the recombinant HCV2aNeo virus (compound "2243" included as negative control). Huh7 cells were infected with similar amounts of HCV2aNeo containing supernatants. The cell cultures were treated with the compounds and incubated in the presence of G418 for 2 weeks prior to staining of the cells with crystal violet. The number of colonies was counted and shown in Figure 6.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to methods for inhibiting the entry of HCV into permissive cells. More specifically, the present invention is directed to tricyclic diphenylamine derivative compounds for the prevention and/or treatment of HCV infection by inhibiting HCV entry into permissive cells. The tricyclic diphenylamine derivatives described herein selectively inhibit HCV entry into permissive cells but allow viruses with divergent entry mechanisms to cross into the cytoplasm. More specifically, these tricyclic diphenylamine derivative compounds have the formula:
Figure imgf000005_0001
wherein: the dotted lines are 0, 1, 2 or 3 bonds; when the dotted lines are 0 or 1 bond, X is absent;when the dotted lines are two bonds, X is S-O(n), C=O, or O, and n is 0, 1 or 2; when the dotted lines are three bonds, X is -CH=CH- or -CH2-CH2- and R1, R2, R3, R4, R5, Re, R7, Rs and Y are, independently, hydrogen, halo, hydroxy, amino, aminocarbonyl, nitro, cyano, thio, Ci to Ci2 alkyl, C2 to Ci2 alkenyl, C2 to Ci2 alkynyl, Ci to Ci2 substituted alkyl, C2 to Ci2 substituted alkenyl, C2 to Ci2 substituted alkynyl, Ci to Ci2 acyl, Ci to Ci2 substituted acyl, C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocycle and substituted heterocycle, heteroaryl, substituted heteroaryl, C7 to C18 phenylalkyl, C7 to Ci8 substituted phenylalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, (monosubstituted)amino, (disubstituted)amino, sulfonyl, substituted sulfonyl, Ci to C10 alkylsulfonyl, Ci to C10 substituted alkylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl, Ci to C10 alkylthio, Ci to C10 substituted alkylthio, Ci to Ci2 alkylaminocarbonyl, Ci to Ci2 substituted alkylaminocarbonyl, phenylaminocarbonyl, and substituted phenylaminocarbonyl, cyclic C2 to C7 alkylene, substituted cyclic C2 to C7 alkylene, cyclic C2 to C7 heteroalkylene, substituted cyclic C2 to C7 heteroalkylene or the formulas -C(O)-O-R, -0-C(O)-R or -C(O)-R-O-R, where R is Ci to C12 alkyl or Ci to Ci2 substituted alkyl; or a pharmaceutically acceptable salt, pro-drug, or ester of the compound.
In a preferred embodiment, X is S-0(n); and R1, R2, R3, R4, R5, R6, R7, Rs and Y are, independently, hydrogen, halo, Ci to Ci2 alkyl, Ci to Ci2 alkoxy, Ci to Ci2 alkoxyalkyl, phenyl, phenoxy, C3 to C7 cycloalkoxy, Ci to Ci2 alkylthio, Ci to Ci2 alkenyl, Ci to Ci2 alkynyl, C3 to C7 cycloalkyl, Ci to Ci2 haloalkyl, Ci to Ci2 acyl, substituted phenyl where at least one substitution is an acid or cyano, Ci to Ci2 substituted alkyl where at least one substitution is cyano, halo or carboxy, CH2=CHCH2-, aminosulfonyl, Ci to Ci2 alkylsulfonylamino, aminocarbonyl, Ci to Ci2 substituted acyl where at least one substitution is amino or alkoxy, C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl, heterocycle and substituted heterocycle, heteroaryl, substituted heteroaryl, or the formulas -C(O)-O-R, -0-C(O)-R or -C(O)-R-O-R, where R is Ci to Ci2 alkyl; where, optionally, one of the benzyl rings depicted in the above formula is instead a fused substituted or unsusbstituted cyclocpentenyl, cyclocheptenyl or cycloheptenyl group, wherein the substitutions for each open position of the ring are, independently, as described for Ri above.
More preferably, R4 and R5 are hydrogen. Even more preferably, Ri and Rs are hydrogen.
In another embodiment of the subject invention, X is O; and
R1, R2, R3, R4, R5, R6, R7, Rs and Y are, independently, hydrogen, halo, Ci to Ci2 alkyl, Ci to Ci2 alkoxy, Ci to Ci2 alkoxyalkyl, phenyl, phenoxy, C3 to C7 cycloalkoxy, Ci to Ci2 alkylthio, Ci to Ci2 alkenyl, Ci to Ci2 alkynyl, C3 to C7 cycloalkyl, Ci to Ci2 haloalkyl, Ci to Ci2 acyl, substituted phenyl where at least one substitution is an acid or cyano, Ci to Ci2 substituted alkyl where at least one substitution is cyano, halo or carboxy, CH2=CHCH2-, aminosulfonyl, Ci to Ci2 alkylsulfonylamino, aminocarbonyl, Ci to Ci2 substituted acyl where at least one substitution is amino or alkoxy, C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl, heterocycle and substituted heterocycle, heteroaryl, substituted heteroaryl, or the formulas -C(O)-O-R, -0-C(O)-R or -C(O)-R- 0-R, where R is Ci to Ci2 alkyl. More preferably, R4 and R5 are hydrogen. Even more preferably, Ri and Rs are hydrogen.
In still a further embodiment, the dotted lines are one bond; and
R1, R2, R3, R4, R5, Re, R7, Rs and Y are, independently, hydrogen, halo, Ci to Ci2 alkyl, Ci to C12 alkoxy, Ci to Ci2 alkoxyalkyl, phenyl, phenoxy, C3 to C7 cycloalkoxy, Ci to Ci2 alkylthio, Ci to Ci2 alkenyl, Ci to Ci2 alkynyl, C3 to C7 cycloalkyl, Ci to Ci2 haloalkyl, Ci to Ci2 acyl, substituted phenyl where at least one substitution is an acid or cyano, Ci to Ci2 substituted alkyl where at least one substitution is cyano, halo or carboxy, CH2=CHCH2-, aminosulfonyl, Ci to Ci2 alkylsulfonylamino, aminocarbonyl, Ci to Ci2 substituted acyl where at least one substitution is amino or alkoxy, C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl, heterocycle and substituted heterocycle, heteroaryl, substituted heteroaryl, or the formulas -C(O)-O-R, -0-C(O)-R or -C(O)-R- O-R, where R is Ci to Ci2 alkyl.
More preferably, R4 and R5 are hydrogen. Even more preferably, Ri and Rs are hydrogen.
In yet another embodiment, X is C=O; and R1, R2, R3, R4, R5, R6, R7, Rs and Y are, independently, hydrogen, halo, Ci to Ci2 alkyl, Ci to Ci2 alkoxy, Ci to Ci2 alkoxyalkyl, phenyl, phenoxy, C3 to C7 cycloalkoxy, Ci to Ci2 alkylthio, Ci to Ci2 alkenyl, Ci to Ci2 alkynyl, C3 to C7 cycloalkyl, Ci to Ci2 haloalkyl, Ci to Ci2 acyl, substituted phenyl where at least one substitution is an acid or cyano, Ci to Ci2 substituted alkyl where at least one substitution is cyano, halo or carboxy, CH2=CHCH2-, aminosulfonyl, Ci to Ci2 alkylsulfonylamino, aminocarbonyl, Ci to Ci2 substituted acyl where at least one substitution is amino or alkoxy, C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl, heterocycle and substituted heterocycle, heteroaryl, substituted heteroaryl, or the formulas -C(O)-O-R, -0-C(O)-R or -C(O)-R-O-R, where R is Ci to Ci2 alkyl.
More preferably, R4 and R5 are hydrogen. Even more preferably, Ri and Rs are hydrogen.
In another embodiment, X is S; and R1, R2, R3, R4, R5, R6, R7, Rs and Y are, independently, hydrogen, halo, Ci to Ci2 alkyl, Ci to Ci2 alkoxy, Ci to Ci2 alkoxyalkyl, phenyl, phenoxy, C3 to C7 cycloalkoxy, Ci to Ci2 alkylthio, Ci to Ci2 alkenyl, Ci to Ci2 alkynyl, C3 to C7 cycloalkyl, Ci to Ci2 haloalkyl, Ci to C 12 acyl, substituted phenyl where at least one substitution is an acid or cyano, Ci to C 12 substituted alkyl where at least one substitution is cyano, halo or carboxy, CH2=CHCH2-, aminosulfonyl, Ci to C 12 alkylsulfonylamino, aminocarbonyl, Ci to C12 substituted acyl where at least one substitution is amino or alkoxy, C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl, heterocycle and substituted heterocycle, heteroaryl, substituted heteroaryl, or the formulas -C(O)-O-R, -0-C(O)-R or -C(O)-R- 0-R, where R is Ci to Ci2 alkyl.
More preferably, R4 and R5 are hydrogen. Even more preferably, Ri and Rg are hydrogen. Yet, more preferably, R2 and R7 are hydrogen. Most preferably, R3 and R6 are methyl.
In another preferred embodiment, when X is absent, Ri to Rs is not - C(O)WYZ, where W is oxygen or N-alkyl, Y is alkyl and Z is an optionally substituted amino.
In all of the embodiments described above, each variable, especially Y, is, independently, not alkyl or haloalkyl.
Other compounds of the claimed invention include N-(9-Ethyl-9H-carbazol-3- yl)-2-[4-(2- oxo-2,3-dihydro-benzoimidazol-l-yl)- piperidin-l-yl]-acetamide, N-(9- Ethyl-9H-carbazol-3-yl)-succinamic acid, tetrahydro-furan-3-carboxylic acid (9- ethyl- 9H-carbazol-3-yl) — amide, N-(9-Ethyl-9H-carbazol-3-yl)-2-(2- methoxy-ethoxy)- acetamide, N-(9-ethyl-9H-carbazol-3-yl)-isonicotin- amide, N-(9-ethyl-9H-carbazol-3- yl)- nicotinamide, pyridine -2-carboxylic acid (9-ethyl-9H- carbazol-3-yl)-amide, N-(9- ethyl-9H-carbazol-3-yl)-2-phenyl- acetamide, N-(9-ethyl-9H-carbazol-3-yl)-4-fluoro- benzamide, 4-chloro-N-(9-ethyl-9H-carbazol-3-yl)- benzamide, 4-dimethylamino-N- (9-ethyl-9H- carbazol-3-yl)-benzamide, N-(9-ethyl-9H-carbazol-3-yl)-4-nitro- benzamide, 3-chloro-N-(9-ethyl-9H-carbazol-3-yl)- benzamide, N-(9-ethyl-9H- carbazol-3-yl)-3-phenyl-acrylamide, N-(9-ethyl-9H-carbazol-3-yl)~2,2-dimethyl- propionamide, N-(9-ethyl-9H-carbazol-3-yl)-4-oxo-4- phenyl-butyramide, 4-methyl- [l,2,3]thiadiazole-5-carboxylic acid (9-ethyl-9H-carbazol-3-yl)-amide, 5-tert-butyl-2- methyl-2H-pyrazole-3-carboxylic acid (9-ethyl-9H-carbazol-3- yl)-amide, 1-methyl- lH-pyrrole-2-carboxylic acid (9-ethyl-9H-carbazol-3-yl)-amide, isoxazole-5- carboxylicacid (9-ethyl-9H- carbazol-3-yl)-amide, lH-indole-2-carboxylic acid (9- ethyl-9H- carbazol-3-yl)-amide, N-(9-Ethyl-9H-carbazol-3-yl)-2-phenoxy-acetamide, 1 -(9-ethyl-9H-carbazol-3-yl)-3-isopropyl- urea, 1 -tert-butyl-3-(9-ethyl-9H-carbazol-3- yl)-urea, l-(9-ethyl-9H-carbazol-3-yl)-3-(2- hydroxy-ethyl)-urea, 9-ethyl-9H- carbazole-3-carboxylic acid phenylamide, 9-ethyl-9H-carbazole-3-carboxylic acid isopropylamide, 9-ethyl-9H-carbazole-3-carboxylic acid tert-butylamide, 9-ethyl-9H- carbazole-3-carboxylic acid diethylamide, 9-ethyl-9H-carbazole-3-carboxylic acid cyclopropylamide, 9-ethyl-9H-carbazole-3-carboxylic acid (3-imidazol-l-yl-propyl)- amide, N-(9-methyl-9H-carbazol-3-yl)- benzamide, 2-dimethylamino-N-(9-methyl-9H- carbazol-3-yl)-acetamide, 2-methoxy-N-(9-methyl-9H-carbazol-3- yl)-acetamide, N-(9- methyl-9H-carbazol-3-yl)- succinamic acid, N-(9-methyl-9H-carbazol-3-yl)-2-phenyl- acetamide, N-(9-methyl-9H-carbazol-3-yl)-isobutyramide, 2,2-Dimethyl-N-(9-methyl- 9H-carbazol- 3-yl)-propionamide, cyclohexanecarboxylic acid (9-methyl- 9H-carbazol- 3-yl)-amide, cyclopropanecarboxylic acid (9-methyl- 9H-carbazol-3-yl)-amide, N-(9- methyl-9H-carbazol-3-yl)-isonicotinamide, N-(9-benzyl-9H-carbazol-3-yl)-benzamide, N-(9-benzyl-9H-carbazol-3-yl)-2-dimethylamino-acetamide, N-(9-benzyl-9H-carbazol- 3-yl)-2- methoxy-acetamide, N-(9-benzyl-9H-carbazol-3-yl)-succinamic acid, N-(9- benzyl-9H-carbazol-3-yl)-2-phenyl- acetamide, N-(9-benzyl-9H-carbazol-3-yl)- isobutyr- amide, N-(9-benzyl-9H-carbazol-3-yl)-acetamide, cyclohexanecarboxylic acid (9-benzyl- 9H-carbazol-3-yl)-amide, cyclopropanecarboxylic acid (9-benzyl- 9H- carbazol-3-yl)-amide, N-(9-benzyl-9H-carbazol- -3-yl)- isonicotinamide, N-(9H- carbazol-3-yl)-2-di- methylamino- acetamide, N-(9H-carbazol-3-yl)-2-met- hoxy- acetamide, N-(9H-carbazol-3-yl)-succinamic acid, N-(9H-carbazol-3-yl)-2-phenyl- acetamide, N-(9H-carbazol-3-yl)-isobutyramide, cyclohexanecarboxylic acid (9H- carbazol-3-yl)-amide, cyclopropanecarboxylic acid (9H- carbazol-3-yl)-amide and N- (9H-Carbazol-3-yl)-isonicotinamide. See US App. 2004/0147752. In another preferred embodiment, X is absent, Y is hydrogen, Ci to C4 alkyl or
Ci to C4 substituted alkyl; R3 is
Figure imgf000009_0001
Where A is hydrogen, Ci to C4 alkyl or Ci to C4 substituted alkyl, aryl, or a 5-6 membered heteroaryl containing one to three heteroatoms selected from oxygen, nitrogen, or sulfur; and B is hydrogen, Ci to C4 alkyl or Ci to C4 substituted alkyl, preferably halo-substituted alkyl; or A and B taken together form an optionally substituted aromatic six-membered heterocyclic ring, where said heterocyclic ring contains 1 to 2 nitrogen ring atoms, or an optionally substituted aromatic six-membered carbocyclic ring (preferably, the aromatic six-membered carbocyclic ring is mono- substituted); a pharmaceutically acceptable salt thereof, a prodrug of the compound or the salt, or a solvate or hydrate of the compound, the salt or the prodrug. Preferred compounds of the above embodiment include 9-ethyl-3-(5-methyl-4- phenyl-lH-imidazol-2-yl)-9H-carbazole; 9-ethyl-3-(4-phenyl-5-trifluoromethyl-lH- imidazol-2-yl)-9H-carbazole; 9-ethyl-3-(5-methyl-4-pyridin-2-yl-lH-imidazol-2-yl)- 9H-carbazole; 3-(4,5-dimethyl-lH-imidazol-2-yl)-9-ethyl-9H-carbazole; 9-ethyl-3- (lH-imidazo[4,5-c]pyridin-2-yl)-9H-carbazole; 3-(lH-benzoimidazol-2-yl)-9-ethyl-9H- carbazole; 9-ethyl-3-(3H-imidazo[4,5-b]pyridin-2-yl)-9H-carbazole; 9-ethyl-3-(7H- purin-8-yl)-9H-carbazole; and 2-(9-ethyl-9H-carbazol-3-yl)-lH-benzoimidazole-5- carboxylic acid; a pharmaceutically acceptable salt thereof or a solvate or hydrate of the compound or the salt. See U.S. Pat. No. 6,949,564.
In another embodiment of the invention, X is absent, Ri, R2 and R4 to Rs are, independently, from hydrogen, halogen, hydroxyl, nitro, cyano, Ci to C6 alkyl, Ci to C6 alkoxy, the formulas -NR9 Ri0, -CH2NR9Ri0, -CH2OR9, -C(O)NR9Ri0, Ci to C6 alkylaryl; and any two of R5 to Rs, when ortho to each other, may be joined to form a ring, which may optionally include up to two heteroatoms selected from O, NRn or S; Y is Ci to C5 alkyl, alkylaryl, alkenyl, (cycloalkyl)alkyl, or mono or polyfluoroalkyl; R3 is NRn, CORi2, CONRHRI2 or NRnSO2Ri2; Rn is hydrogen, Ci to C3 alkyl, Ci to C3 alkylaryl, Ci to C3 alkylheteroaryl, C2 to C4 alkenyl, C2 to C4 alkynyl, or Ci to C5 polyfluoroalkyl; Ri2 is Ci to C6 mono or polyfluoroalkyl, heteroaryl, Ci to C6 alkyl (preferably excluding methyl), C3 to Cg cycloalkyl, C2 to C6 alkenyl, C5 to Cg cycloalkenyl, C2 to C6 alkynyl, or C4 to C8 cycloazaalkyl; where, preferably, the above moieties can be independently substituted with one to three substituents selected from the group consisting of F, Br, Cl, aryl, heteroaryl, aryloxy, heteroaryloxy, NRi3Ri4, Ci to C6 alkoxy, NO2, OH, CN, COOH, and Ci to C6 thioalkyl; Ri3 and Ri4 are, independently, H, Ci to C6 alkyl, C2 to C6 alkenyl, C3 to C6 cycloalkyl, C5 to Cg cycloalkenyl, C2 to C6 alkynyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl; optionally substituted with 1-2 substituents independently selected from Ri5; or Ri3 and R14 are taken together to be C3 to Cg cycloalkyl, optionally substituted with 1-2 substituents independently selected from Ri 5; C5 to Cg cycloalkenyl, optionally substituted with 1-2 substituents independently selected from R15; or a heterocyclic ring containing up to two heteroatoms selected from the group consisting of — O— , --NR9 — , and — (O)m— (m=0-2), optionally substituted with 1-3 substituents independently selected from Ri5; Ri5 is selected independently from hydrogen; halogen; nitro; cyano; hydroxy, Ci to C6 alkyl; Ci to C6 hydroxyalkyl, Ci to C6 aminoalkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, alkoxy; acyloxy; Ci to C4 alkylthio; mono-, di-, or trihaloalkyl, or (CH2)J1NR9RiO where n is 1-3; R9 and Ri0 are independently selected from Ci to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, aryl, or heteroaryl, and may be joined to form a carbocyclic or hetercyclic ring, which may optionally include up to two heteroatoms selected from O, NRn, or S, and optical and geometric isomers thereof or tautomeric isomers thereof; and nontoxic pharmacologically acceptable acid addition salts, N- oxides, esters, and quaternary ammonium salts thereof. Preferably, if Y is Ci to C5 alkyl and R3 is -CONRHRI2, then when one of Rn or Ri2 is an azacycloalkyl alkyl group, the other must be a group other than hydrogen or Ci to C6 alkyl. Preferred compounds under this embodiment include 2-Dimethylamino-N-(9- ethyl-9H-carbazol-3-yl)-acetamide; 3-Diethylamino-N-(9-ethyl-9H-carbazol-3-yl)- propionamide; N-(9-Ethyl-9H-carbazol-3-yl)-2-fluoro-benzamide; 2-Pyridin-2-yl- thiazole-4-carboxylic acid (9-ethyl-9H-carbazol-3-yl)-amide; N-(9-Ethyl-9H-carbazol- 3-yl)-2-pyridin-2-yl-acetamide; N-(9-Ethyl-9H-carbazol-3-yl)-2-pyridin-3-yl- acetamide; N-(9-Ethyl-9H-carbazol-3-yl)-isonicotinamide; lH-Indole-2-carboxylic acid (9-ethyl-9H-carbazol-3-yl)-amide; 4-Dimethylamino-N-(9-ethyl-9H-carbazol-3- yl)-butyramide; N-(9-Ethyl-9H-carbazol-3-yl)-2-pyridin-4-yl-acetamide; N-(9-Ethyl- 9H-carbazol-3-yl)-2-piperidin- 1 -yl-acetamide; N-(9-Ethyl-9H-carbazol-3-yl)-3- morpholin-4-yl-propionamide; N-(9-Ethyl-9H-carbazol-3-yl)-3-piperidin- 1 -yl- propionamide; N-(9-Ethyl-9H-carbazol-3-yl)-2-hydroxy-2,2-diphenyl-acetamide; N-(9-Ethyl-9H-carbazol-3-yl)-2-hydroxy-2-methyl-propionamide; N-(9-Ethyl-9H- carbazol-3-yl)-2-hydroxy-2-methyl-butyramide; N-(9-Ethyl-9H-carbazol-3-yl)-2- hydroxy-2-phenyl-propionamide; (R)-N-(9-Ethyl-9H-carbazol-3-yl)-2-hydroxy-2- phenyl-propionamide; 2-Bromo-N-(9-ethyl-9H-carbazol-3-yl)-acetamide; and 3-Dimethylamino-N-(9-ethyl-9H-carbazol-3-yl)-propionamide; N-(9-Ethyl-9H- carbazol-3-yl)-2-[l,2,4]triazol-l-yl-acetamide; N-(9-Ethyl-9H-carbazol-3-yl)-2-(4- methyl-piperazin- 1 -yl)-acetamide; 2-[Bis-(2-hydroxy-ethyl)-amino]-N-(9-ethyl-9H- carbazol-3-yl)-acetamide; N-(9-Ethyl-9H-carbazol-3-yl)-2-pyrrolidin- 1 -yl-acetamide; 2-Benzylamino-N-(9-ethyl-9H-carbazol-3-yl)-acetamide; N-(9-Ethyl-9H-carbazol-3- yl)-3-(4-phenyl-piperidin-l-yl)-propionamide; 3-(3,4-Dihydro-lH-isoquinolin-2-yl)-N- (9-ethyl-9H-carbazol-3-yl) propionamide; 3-(2,5-Dihydro-pyrrol- 1 -yl)-N-(9-ethyl-9H- carbazol-3-yl)-propionamide; N-(9-Ethyl-9H-carbazol-3-yl)-3-indol-l-yl- propionamide; 3-Diphenylamino-N-(9-ethyl-9H-carbazol-3-yl)-propionamide; 3-(5-Chloro-quinolin-8-yloxy)-N-(9-ethyl-9H-carbazol-3-yl)-propionamide; 3- Carbazol-9-yl-N-(9-ethyl-9H-carbazol-3-yl)-propionamide; N-(9-Ethyl-9H-carbazol-3- yl)-3-(4-piperidin- 1 -ylmethyl-phenoxy)-propionamide; N-(9-Ethyl-9H-carbazol-3-yl)- 3-[methyl-(l,2,3,4-tetrahydro-naphthalen-2-yl) -amino] -propionamide; N-(9-Ethyl-9H- carbazol-3-yl)-3-(quinolin-7-yloxy)-propionamide; N-(9-Ethyl-9H-carbazol-3-yl)-3- pyrrolidin- 1 -yl-propionamide; 2-[Bis-(2-hydroxy-ethyl)-amino]-N-(9-ethyl-9H- carbazol-3-yl)-acetamide; 2-[4-(4-Chloro-phenyl)-4-hydroxy-piperidin- 1 -yl]-N-(9- ethyl-9H-carbazol-3-y l)-acetamide; N-(9-Ethyl-9H-carbazol-3-yl)-2-(4-hydroxy-4- phenyl-piperidin-l-yl)-acetamide; 3-Bromo-N-(9-ethyl-9H-carbazol-3-yl)- propionamide; N-(9-Isopropyl-9H-carbazol-3-yl)-trifluoroacetamide; N-(9-Isopropyl- 9H-carbazol-3-yl)-3-(4-phenyl-piperidin- 1 -yl)-propionamide; N-(9-Ethyl-9H-carbazol- 3-yl)-3-(4-hydroxy-4-phenyl-piperidin- 1 -yl)-propiona mide; 3-[4-(4-Chloro-phenyl)-4- hydroxy-piperidin- 1 -yl]-N-(9-ethyl-9H-carbazol-3-y l)-propionamide; 4- Dimethylamino-N-(9-ethyl-9H-carbazol-3-yl)-N-methyl-butyramide; 3-
[l,4']Bipiperidinyl-r-yl-N-(9-ethyl-9H-carbazol-3-yl)-propionamide; N-(9-Ethyl-9H- carbazol-3-yl)-3-(4-phenyl-piperazin- 1 -yl)-propionamide; 3-(4-Benzyl-piperidin- 1 -yl)- N-(9-ethyl-9H-carbazol-3-yl)-propionamide; 3-(4-Dimethylamino-piperidin- 1 -yl)-N- (9-ethyl-9H-carbazol-3-yl)-propionamide; 3-(4-Dimethylaminoethyl-piperidin-l-yl)-N- (9-ethyl-9H-carbazol-3-yl)-propionamide; N-(9-Methyl-9H-carbazol-3-yl)- trifluoroacetamide; 1-Hydroxy-cyclopropanecarboxylic acid (9-ethyl-9H-carbazol-3- yl)-amide; N-(9-Ethyl-9H-carbazol-3-yl)-3-(4-cyano-4-phenyl-piperidin- 1 -yl)- propionamide; 2-(4-Chloro)-benzylamino-N-(9-ethyl-9H-carbazol-3-yl)-acetamide; N-(9-Ethyl-9H-carbazol-3-yl)-2-(4-phenyl-piperidin- 1 -yl)-acetamide; N-(9-Ethyl-9H- carbazol-3-yl)-2-(4-(4-fluoro)-phenyl-piperazin- 1 -yl)-acetamide; N-(9-Ethyl-9H- carbazol-3-yl)-2-(4-pyridin-2-yl-piperazin-l-yl)-acetamide; N-(9-Ethyl-9H-carbazol-3- yl)-3-(4-pyridin-2-yl-piperazin- 1 -yl)-propionamide; N-(9-Ethyl-9H-carbazol-3-yl)-3- (4-(4-fluoro)-phenyl-piperazin- 1 -yl)-propion amide; 2-(4-fluoro)-benzylamino-N-(9- ethyl-9H-carbazol-3-yl)-acetamide; (R)-N-(9-Ethyl-9H-carbazol-3-yl)-2-(l-phenyl- ethylamino)-acetamide; (R)-N-(9-Ethyl-9H-carbazol-3-yl)-2-(l-(4-chloro)-phenyl- ethylamino)-acetamide; N-(9-isopropyl-9H-carbazol-3-yl)-3-pyrrolidin-l-yl- propionamide; 2-(3-Diethylamino-2-hydroxy-propylamino)-N-(9-ethyl-9H-carbazol-3- yl)-acetamide; 2-(Benzyl-isopropyl-amino)-N-(9-ethyl-9H-carbazol-3-yl)-acetamide; N-(9-Ethyl-9H-carbazol-3-yl)-2-(4-pyrrolidin-l-yl-piperidin-l-yl)-acetamide; N-(9-Ethyl-9H-carbazol-3-yl)-2-(6-isopropylamino-3-aza-bicyclo[3.1. 0]hex-3-yl)- acetamide; N-(9-Ethyl-9H-carbazol-3-yl)-2-(6-amino-3-aza-bicyclo[3.1. 0]hex-3-yl)- acetamide; N-(9-Ethyl-9H-carbazol-3-yl)-2-(6-benzylamino-3-aza-bicyclo[3.1. 0]hex- 3-yl)-acetamide; N-(9-Ethyl-9H-carbazol-3-yl)-2-(6-isobutylamino-3-aza-bicyclo[3.1. 0]hex-3-yl)-acetamide; N-3-Bromo-(9-ethyl-9H-carbazol-6-yl)-trifluoroacetamide; N-(9-Ethyl-6formyl-9H-carbazol-3-yl)-trifluoroacetamide; N-(9-Ethyl-6- hydroxymethyl-9H-carbazol-3-yl)-trifluoroacetamide; N-(9-Ethyl-9H-carbazol-3-yl)- methanesulfonamide; N-[6-(3 ,4-Dihydro- 1 H-isoquinolin-2-ylmethyl)-9-ethyl-9H- carbazol-3-yl]-trif luoro-acetamide; N-(9-Ethyl-9H-carbazol-3-yl)- chloromethanesulfonamide; N-(9-Ethyl-9H-carbazol-3-yl)-2-pyridin-3-yl-N- methylacetamide; 2-Bromo-N-(9-ethyl-9H-carbazol-3-yl)-acetamide; and 3-Dimethylamino-N-(9-ethyl-9H-carbazol-3-yl)-propionamide; N-(9-Ethyl-9H- carbazol-3-yl)-2-[l,2,4]triazol-l-yl-acetamide; N-(9-Ethyl-9H-carbazol-3-yl)-2-(4- methyl-piperazin- 1 -yl)-acetamide; 2-[Bis-(2-hydroxy-ethyl)-amino]-N-(9-ethyl-9H- carbazol-3-yl)-acetamide; N-(9-Ethyl-9H-carbazol-3-yl)-2-pyrrolidin- 1 -yl-acetamide; 2-Benzylamino-N-(9-ethyl-9H-carbazol-3-yl)-acetamide; N-(9-Ethyl-9H-carbazol-3- yl)-3-(4-phenyl-piperidin-l-yl)-propionamide; 3-(3,4-Dihydro-lH-isoquinolin-2-yl)-N- (9-ethyl-9H-carbazol-3-yl)-propionamide; 3-(2,5-Dihydro-pyrrol-l-yl)-N-(9-ethyl-9H- carbazol-3-yl)-propionamide; N-(9-Ethyl-9H-carbazol-3-yl)-3-indol-l-yl- propionamide; 3-Diphenylamino-N-(9-ethyl-9H-carbazol-3-yl)-propionamide; 3-(5-Chloro-quinolin-8-yloxy)-N-(9-ethyl-9H-carbazol-3-yl)-propionamide; 3-Carbazol-9-yl-N-(9-ethyl-9H-carbazol-3-yl)-propionamide; N-(9-Ethyl-9H-carbazol- 3-yl)-3-(4-piperidin-l-ylmethyl-phenoxy)-propionamide; N-(9-Ethyl-9H-carbazol-3- yl)-3-[methyl-(l ,2,3,4-tetrahydro-naphthalen-2-yl) -amino] -propionamide; N-(9-Ethyl- 9H-carbazol-3-yl)-3-(quinolin-7-yloxy)-propionamide; N-(9-Ethyl-9H-carbazol-3-yl)- 3-pyrrolidin-l-yl-propionamide; 2-[Bis-(2-hydroxy-ethyl)-amino]-N-(9-ethyl-9H- carbazol-3-yl)-acetamide; 2-[4-(4-Chloro-phenyl)-4-hydroxy-piperidin- 1 -yl]-N-(9- ethyl-9H-carbazol-3-y l)-acetamide; N-(9-Ethyl-9H-carbazol-3-yl)-2-(4-hydroxyl-4- phenyl-piperidin-l-yl)-acetamide; 3-Bromo-N-(9-ethyl-9H-carbazol-3-yl)- propionamide; 4- N-(9-Isopropyl-9H-carbazol-3-yl)-acetamide; N-(9-Isopropyl-9H- carbazol-3-yl)-3-(4-phenyl-piperidin- 1 -yl)-propionamide; N-(9-Ethyl-9H-carbazol-3- yl)-3-(4-hydroxy-4-phenyl-piperidin-l-yl)-propionamide; 3-[4-(4-Chloro-phenyl)-4- hydroxy-piperidin- 1 -yl]-N-(9-ethyl-9H-carbazol-3-y l)-propionamide; 4- Dimethylamino-N-(9-ethyl-9H-carbazol-3-yl)-N-methyl-butyramide; 3- [1 ,4']Bipiperidinyl- 1 '-yl-N-(9-ethyl-9H-carbazol-3-yl)-propionamide;
N-(9-Ethyl-9H-carbazol-3-yl)-3-(4-phenyl-piperazin-l-yl)-propionamide; 3-(4-Benzyl-piperidin-l-yl)-N-(9-ethyl-9H-carbazol-3-yl)-propionamide; 3-(4-Dimethylamino-piperidin-l-yl)-N-(9-ethyl-9H-carbazol-3-yl)-propionamide; 3-(4-Dimethylaminoethyl-piperidin-l-yl)-N-(9-ethyl-9H-carbazol-3-yl)-propionamide; N-(9-Methyl-9H-carbazol-3-yl)-trifluoroacetamide; 1-Hydroxy- cyclopropanecarboxylic acid (9-ethyl-9H-carbazol-3-yl)-amide; N-(9-Ethyl-9H- carbazol-3-yl)-3-(4-cyano-4-phenyl-piperidin-l-yl)-propionamide; 2-(4-Chloro)- benzylamino-N-(9-ethyl-9H-carbazol-3-yl)-acetamide; N-(9-Ethyl-9H-carbazol-3-yl)- 2-(4-phenyl-piperidin- 1 -yl)-acetamide; N-(9-Ethyl-9H-carbazol-3-yl)-2-(4-(4-fluoro)- phenyl-piperazin- 1 -yl)-acetamide; N-(9-Ethyl-9H-carbazol-3-yl)-2-(4-pyridin-2-yl- piperazin- 1 -yl)-acetamide; N-(9-Ethyl-9H-carbazol-3-yl)-2-(4-pyridin-2-yl-piperazin- 1 -yl)-propionamide; N-(9-Ethyl-9H-carbazol-3-yl)-3-(4-(4-fluoro)-phenyl-piperazin- 1 - yl)-propionamide; 2-(4-fluoro)-benzylamino-N-(9-ethyl-9H-carbazol-3-yl)-acetamide; (R)-N-(9-Ethyl-9H-carbazol-3-yl)-2-(l-phenyl-ethylamino)-acetamide; (R)-N-(9-Ethyl-9H-carbazol-3-yl)-2-(l-(4-chloro)-phenyl-ethylamino)-acetamide; N-(9-isopropyl-9H-carbazol-3-yl)-3-pyrrolidin-l-yl-propionamide; (R)- or (S)-N-(9- Ethyl-9H-carbazol-3-yl)-2-(oxiranylmethyl-amino)-acetamide; (S), (R), or a mixture of (S) and (R) 2-(3-Diethylamino-2-hydroxy-propylamino)-N-(9-ethyl-9H-carbazol-3-yl)- acetamide; (S)-N-(6-tert-Butyl-9-ethyl-9H-carbazol-3-yl)-2-(3-diethylamino-2- hydroxy-p ropylamino)-acetamide; 2-(Benzyl-isopropyl-amino)-N-(9-ethyl-9H- carbazol-3-yl)-acetamide; N-(9-Ethyl-9H-carbazol-3-yl)-2-(4-pyrrolidin- 1 -yl-piperidin- 1 -yl)-acetamide; N-(9-Ethyl-9H-carbazol-3-yl)-2-(6-isopropylamino-3-aza-bicyclo[3.1. 0]hex-3-yl)-acetamide; N-(9-Ethyl-9H-carbazol-3-yl)-2-(6-amino-3-aza-bicyclo[3.1. 0]hex-3-yl)-acetamide; N-(9-Ethyl-9H-carbazol-3-yl)-2-(6-benzylamino-3-aza- bicyclo[3.1. 0]hex-3-yl)-acetamide; N-(9-Ethyl-9H-carbazol-3-yl)-2-(6-isobutylamino- 3-aza-bicyclo[3.1. 0]hex-3-yl)-acetamide; N-3-Bromo-(9-ethyl-9H-carbazol-6-yl)- trifluoroacetamide; N-(9-Ethyl-6-formyl-9H-carbazol-3-yl)-trifluoroacetamide; N-(9- Ethyl-6-hydroxymethyl-9H-carbazol-3-yl)-trifluoroacetamide; N-[6-(3,4-Dihydro-lH- isoquinolin-2-ylmethyl)-9-ethyl-9H-carbazol-3-yl] -trif luoroacetamide; N-(9-Ethyl-9H- carbazol-3-yl)-2-pyridin-3-yl-N-methylacetamide; 9-Ethyl-9H-carbazole-3-carboxylic acid (pyridin-3-ylmethyl)-amide; (9-Ethyl-9H-carbazol-3-yl)-(4-hydroxyl-4-phenyl- piperidin-l-yl)-methanone; 9-Ethyl-9H-carbazole-3-carboxylic acid (2-benzylamino- ethyl)-amide; 9-Ethyl-9H-carbazole-3-carboxylic acid benzylamide; 9-Ethyl-9H- carbazole-3-carboxylic acid (3-morpholin-4-yl-propyl)-amide; 9-Ethyl-9H-carbazole-3- carboxylic acid (l-benzyl-pyrrolidin-3-yl)-amide; 9-Ethyl-9H-carbazole-3-carboxylic acid (2-isopropylamino-ethyl)-amide; 9-Ethyl-9H-carbazole-3-carboxylic acid (2- hydroxy-ethyl)-amide; N-(9-Ethyl-9H-carbazol-3-yl)-methanesulfonamide; N-(9-Ethyl- 9H-carbazol-3-yl)-chloromethanesulfonamide; 9-Ethyl-9H-carbazole-3-carboxylic acid [2-(bis-pyridin-4-ylmethyl-amino)-ethyl]-amide; 9-Ethyl-9H-carbazole-3-carboxylic acid {2-[bis-( 1 -methyl- 1 H-indol-3-ylmethyl)-amino]-ethyl} -amide; 9-Ethyl-9H- carbazole-3-carboxylic acid {2-[(thiazol-2-ylmethyl)-amino]-ethyl} -amide; 9-Ethyl- 9H-carbazole-3-carboxylic acid [2-(bis-quinolin-2-ylmethyl-amino)-ethyl]-amide; 9-Ethyl-9H-carbazole-3-carboxylic acid {2-[(quinolin-2-ylmethyl)-amino]-ethyl} - amide; 9-Ethyl-9H-carbazole-3-carboxylic acid phenethyl-amide; 9-Ethyl-9H- carbazole-3-carboxylic acid (3-phenyl-propyl)-amide; 9-Ethyl-9H-carbazole-3- carboxylic acid (2-diisopropylamino-ethyl)-amide; and 9-Ethyl-9H-carbazole-3- carboxylic acid [3-(2-methyl-piperidin-l-yl)-propyl]-amide. See U.S. Pat. No. 6,399,631. Another embodiment of the invention is where X is absent and two of Ri to R4 (preferably R3 and R4) are hydrogen, Cito C6 alkyl, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, Ci to C6 alkoxy, -O2CR, -NHCOR, -COR, -SOmR', where R' is Ci to C6 alkyl and m is 0, 1 or 2; or Ri to R4 are independently - CONRR" or -NRR" where R and R" are independently hydrogen or Ci to C6 alkyl; Y is hydrogen, Ci to C6 alkyl, or -COR" where R" is Ci to C6 alkyl; and one of Ri to R4 (preferably Ri or R2) is -C(O)NWZ, where W is hydrogen or Ci to C6 alkyl; and Z is an azacycloalkylalkyl group. See WO 98/06717.
In another embodiment of the invention, X is absent, the ring attached to R5 to Rs (designated "A") is a 5- to 7-membered hydrocarbonic ring, wherein the ring may have one or more substituents selected from the group consisting of a hydroxyl group, a lower alkyl group, a lower acyl group, a lower alkoxy group and a halogen atom, and wherein the lower alkyl group, the lower acyl group and the lower alkoxy group may have one or more substituents); R3 is the formula L-M-W-Z, where L is a linking group selected from the group consisting of-NR'~CO~, -CO— NR'-, -NR'-CS-, -CS- NR'-, -NR'- SO2- and -SO2-NR'-, where R' is a hydrogen atom, a lower alkyl group or a lower acyl group, wherein the lower alkyl group and the lower acyl group may have one or more substituents); M is an alkylene linking group having 2 to 10 carbon atoms, where the alkylene linking group may have one or more substituents, and the carbon atoms constituting the carbon chain of the alkylene linking group
(except for at least one carbon atom) may be replaced with a nitrogen atom, an oxygen atom, a sulfur atom or a 3- to 8-membered cycloalkylene group, wherein the nitrogen atom may be substituted with a lower alkyl group or a lower acyl group, and the cycloalkylene group may have one or more substituents, provided that M may be a single bond when L represents -NR'- CO— ; W is a linking group selected from the group consisting of -S-, -O-, -NR"-, -NR" '-CO-, -NR" '-CS- or -NR" '-SO2-, where R" is a hydrogen atom, an alkyl group or a lower acyl group, wherein the alkyl group and the lower acyl group may have one or more substituents, and the alkyl group may contain a ring structure, R" ' is a hydrogen atom, a lower alkyl group or a lower acyl group, wherein the lower alkyl group and lower acyl group may have one or more substituents, and R' ' may bond to M to form a ring, or a single bond, provided that W represents -NR"- when M represents a single bond, wherein R" is a hydrogen atom or an alkyl group, and wherein the alkyl group may contain a ring structure and may have one or more substituents, and W represents a linking group selected from the group consisting of -NR" '-CO-, -NR" '-CS- and -NR" '-SO2- mentioned above (in the formulas, R' ' ' has the same meaning as that defined above) when A represents a benzene ring; Z is an alkyl group having 1 to 20 carbon atoms (the alkyl group may contain a ring structure), an aryl group having 6 to 12 carbon atoms, an amino group, a monoalkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 16 carbon atoms, an azacycloalkyl group having 4 to 8 carbon atoms, a phosphoryl group, a monoalkylphosphoryl group having 1 to 8 carbon atoms, a dialkylphosphoryl group having 2 to 16 carbon atoms, an aromatic heterocyclic group and a 5- to 7-membered non-aromatic heterocyclic group (said groups may further have one or more substituents, and may bind to R.sup.5 to form a ring), provided that Z represents an aromatic heterocyclic group or a 5- to 7-membered non-aromatic heterocyclic group when W represents a single bond, and R" and Z may bind to each other to form a ring together with the nitrogen atom to which they bind when M represents a single bond (the ring may contain one or more hetero atoms as ring- constituting atoms in addition to the nitrogen atom bound with R' ' and Z, and may have one or more substituents); Y is a lower alkyl (up to 6 carbons) group, a lower alkenyl group, a lower alkynyl group and a lower acyl group (where these groups may contain a ring structure, and may have one or more substituents); and R4, R2 and Ri are each independently a hydrogen atom, a hydroxyl group, a lower alkyl group, a lower acyl group, a lower alkoxy group, a halogen atom, an amino group, a mono (lower alkyl)amino group, a di(lower alkyl)amino group, a lower acylamino group and an amido group (the substituent optionally having one or more substituents) and salts thereof.
Preferably, in the aforementioned embodiment, A is a 5- to 7-membered hydrocarbon ring (the ring may have one or more substituents selected from the group consisting of a hydroxyl group, a lower alkyl group, a lower acyl group, a lower alkoxy group and a halogen atom, wherein the lower alkyl group, the lower acyl group and the lower alkoxy group may have one or more substituents); L is a linking group selected from the group consisting of-NR'-CO-, -CO-NR'-, -NR'-CS-, -CS- NR'-, -NR' — SO2- and -SO2 — NR'- (where R' is a hydrogen atom, a lower alkyl group or a lower acyl group, wherein the lower alkyl group and the lower acyl group may have one or more substituents); M is an alkylene linking group having 2 to 10 carbon atoms [the alkylene linking group may have one or more substituents, and the carbon atoms constituting the carbon chain of the alkylene linking group (except for at least one carbon atom) may be replaced with a nitrogen atom, an oxygen atom, a sulfur atom or a 3- to 8-membered cycloalkylene group, wherein the nitrogen atom may be substituted with a lower alkyl group or a lower acyl group, and the cycloalkylene group may have one or more substituents]; W is a linking group selected from the group consisting of -S-, -O-, -NR"-, ~NR"'~CO~, -NR" '-CS- and -NR" '-SO2- (where R" and R'" each independently represent a hydrogen atom, a lower alkyl group or a lower acyl group, wherein the lower alkyl group and lower acyl group may have one or more substituents, and R' ' may bind to M to form a ring) or a single bond, provided that W is a linking group selected from the group consisting of -NR"'- CO— , — NR"'- CS- and -NR'" — SO2- mentioned above (in the formulas, R'" has the same meaning as that defined above) when A represents a benzene ring; Z is a substituent selected from the group consisting of an alkyl group having 1 to 12 carbon atoms, an aryl group having 6 to 12 carbon atoms, an amino group, a monoalkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 16 carbon atoms, an azacycloalkyl group having 4 to 8 carbon atoms, a phosphoryl group, a monoalkylphosphoryl group having 1 to 8 carbon atoms, a dialkylphosphoryl group having 2 to 16 carbon atoms, an aromatic heterocyclic group and a 5- to 7-membered non-aromatic heterocyclic group (said groups may further have one or more substituents, and may bind to R" ' to form a ring), provided that Y represents an aromatic heterocyclic group or a 5- to 7-membered non-aromatic heterocyclic group when X represents a single bond; Y is a lower alkyl group, a lower alkenyl group, a lower alkynyl group and a lower acyl group (said groups may contain a ring structure, and may have one or more substituents); and R4, R2 and Ri are each independently a hydrogen atom, a hydroxyl group, a lower alkyl group, a lower acyl group, a lower alkoxy group, a halogen atom, an amino group, a mono(lower alkyl)amino group, a di(lower alkyl)amino group, a lower acylamino group and an amido group (the substituent may have one or more substituents). See U.S. Pat. No. 6,713,473.
In another preferred embodiment, a compound of the invention has the formula:
Figure imgf000019_0001
where A is a fused unsubstituted or substituted benzo ring, or a fused unsubstituted or substituted cyclopentenyl, cyclohexenyl or cycloheptenyl group; M is Ci to C6 alkyl or Ci to C6 substituted alkyl; R is aryl, heteroaryl, oxyaryl, oxyheteroaryl or absent; Q is -NHCO, -NR4CO, CO, SO2 or absent; and E is -OR4 or -NR4R5;
R2 is -COOR6, -CONHR6 or -COR6;
R3 is hydrogen, halo, Ci to C6 alkyl, Ci to C6 substituted alkyl, -CN or OR4;
R4 is Ci to C6 alkyl or Ci to C6 substituted alkyl;
R5 is Ci to C6 alkyl or Ci to C6 substituted alkyl; where -NR4R5 may form heterocyclic or heterobicyclic ring system, such as pyrrolidine, morpholine, tetrahydroisoquinoline or indole, optionally substituted; or M-R-Q-E is a Ci to C6 alkyl substituted with a 4-piperidinyl group;
R6 is Ci to C6 alkyl, Ci to C6 substituted alkyl or R-Q-E as defined above.
The compounds in the following table are prepared following the methods of
Examples 1 to 142 and 144 to 161.
Table 1.
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
The present invention is also directed to the compositions described above.
The compounds of the present invention were shown by luciferase assay to inhibit HCV entry into Huh7 cells (see Example 143 A and Figure 1, top panel) and to have a low level of toxicity (see Figure 1, lower panel). The compounds did not inhibit entry of either Sindbis or VSV-G coated pseudoparticles (see Figure 1, middle panel).
The compounds used in the present invention can be prepared according to known methods, such as Gilman and Shirley, J. Am. Chem. Soc. 66:890 (1944), US Patent 2512520, US Patent 2645640 and US Patent 3081305, as well as by the methods of Examples 1 to 142 and 144 to 161 below or appropriate modifications of these examples. The preferred compounds used in the present invention may be prepared as illustrated in the schemes below.
More specifically, a tricyclic diphenylamine derivative (1) can be alkylated using an appropriate alkyl halide or sulfonate using strong bases such as potassium tert- butoxide (tBuOK), sodium hydride (NaH), lithium amide bases, or alkyl lithium in suitable solvents such as dimethylsulfoxide (DMSO), dimethylformamide (DMF), or ethers such as tetrahydrofuran (THF) to form an intermediate or target (2). When Y contains an additional halogen or sulfonate (2) can be aminated by treatment with an amine using tetrabutylammonium iodide (TBAI) in dimethylformamide (DMF) to form amine products (3). See Scheme 1.
Preferred tricyclic diphenylamine derivatives in the form of phenothiazines (4) may also be synthesized by cyclizing appropriately substituted diphenylamines using sulfur with catalytic iodine in 1 ,2-dichlorobenzene (see Scheme 2). When Y is hydrogen, these phenothiazines can then be alkylated as in Scheme 1. See Scheme 2.
Preferred diphenylamine derivatives in the form of 3,7-dimethylphenothiazines may also be synthesized by cyclizing appropriately substituted diphenylamines (1) using sulfur with catalytic iodine in 1 ,2-dichlorobenzene (Scheme 3). When Y is hydrogen, these 3,7-dimethylphenothiazines can then be alkylated as in Scheme 1, converting then to the desired products.
Scheme 1
Figure imgf000024_0001
1) amine, TBAI
Figure imgf000024_0002
Figure imgf000024_0003
Scheme 2
Figure imgf000024_0004
Scheme 3 sulfur, iodine
Figure imgf000024_0005
O-dichlorobenzene
(1)
Figure imgf000024_0006
When the above-described compounds include one or more chiral centers, the stereochemistry of such chiral centers can independently be in the R or S configuration, or a mixture of the two. The chiral centers can be further designated as R or S or R,S or d,D, 1,L or d,l, D,L.
Regarding the compounds and combinatorial libraries described herein, the suffix "ene" added to any of the described terms means that two parts of the substituent are each connected to two other parts in the compound (unless the substituent contains only one carbon, in which case such carbon is connected to two other parts in the compound, for example, methylene).
The term "Ci to C12 alkyl" denotes such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, amyl, tert-amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. Preferred "Ci to Ci2 alkyl" groups are methyl, ethyl, iso-butyl, sec-butyl and iso-propyl. Similarly, the term "Ci to Ci2 alkylene" denotes radicals of 1 to 12 carbons connected to two other parts in the compound.
The term "C2 to Ci2 alkenyl" denotes such radicals as vinyl, allyl, 2-butenyl, 3- butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5- hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, (as well as octenyl, nonenyl, decenyl, undecenyl, dodecenyl radicals attached at any appropriate carbon position and the like) as well as dienes and trienes of straight and branched chains.
The term "C2 to Ci2 alkynyl" denotes such radicals as ethanol, propynyl, 2- butynyl, 2-pentynyl, 3-pentynyl, 2- hexynyl, 3-hexynyl, 4-hexynyl, 2-heptynyl, 3- heptynyl, 4- heptynyl, 5-heptynyl (as well as octynyl, nonynyl, decynyl, undecynyl, dodecynyl radicals attached at any appropriate carbon position and the like) as well as di- and tri-ynes of straight and branched chains.
The terms "Ci to Ci2 substituted alkyl," "C2 to Ci2 substituted alkenyl," "C2 to Ci2 substituted alkynyl," "Ci to C12 substituted alkylene," "C2 to C12 substituted alkenylene" and "C2 to Ci2 substituted alkynylene" denote groups are substituted by one or more, and preferably one or two, halogen, hydroxy, protected hydroxy, oxo, protected oxo, C3 to C7 cycloalkyl, phenyl, naphthyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, guanidino, protected guanidino, heterocyclic ring, substituted heterocyclic ring, imidazolyl, indolyl, pyrrolidinyl, Ci to C12 alkoxy, Ci to C12 acyl, Ci to C12 acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, N- (Ci to C12 alkyl)carboxamide, protected N-(Ci to C12 alkyl)carboxamide, N5N-(Ii(C1 to C12 alkyl)carboxamide, cyano, methylsulfonylamino, thiol, Ci to C10 alkylthio or Ci to Cio alkylsulfonyl groups. The substituted alkyl groups may be substituted once or more, and preferably once or twice, with the same or with different substituents.
The term "oxo" denotes a carbon atom bonded to two additional carbon atoms substituted with an oxygen atom doubly bonded to the carbon atom, thereby forming a ketone moiety.
The term "protected oxo" denotes a carbon atom bonded to two additional carbon atoms substituted with two alkoxy groups or twice bonded to a substituted diol moiety, thereby forming an acyclic or cyclic ketal moiety. The term "Ci to Ci2 alkoxy" as used herein denotes groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like groups. A preferred alkoxy is methoxy. The term "Ci to Ci2 substituted alkoxy" means the alkyl portion of the alkoxy can be substituted in the same manner as in relation to Ci to Ci2 substituted alkyl. Similarly, the term "Ci to Ci2 phenylalkoxy" as used herein means "Ci to Ci2 alkoxy" bonded to a phenyl radical.
The term "Ci to Ci2 acyloxy" denotes herein groups such as formyloxy, acetoxy, propionyloxy, butyryloxy, pivaloyloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, nonanoyloxy, decanoyloxy, undecanoyloxy, dodecanoyloxy and the like. Similarly, the term "Ci to Ci2 acyl" encompasses groups such as formyl, acetyl, propionyl, butyryl, pentanoyl, pivaloyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, benzoyl and the like. Preferred acyl groups are acetyl and benzoyl.
The term "Ci to Ci2 substituted acyl" denotes the acyl group substituted by one or more, and preferably one or two, halogen, hydroxy, protected hydroxy, oxo, protected oxo, cyclohexyl, naphthyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, guanidino, heterocyclic ring, substituted heterocyclic ring, imidazolyl, indolyl, pyrrolidinyl, Ci to Ci2 alkoxy, Ci to C12 acyl, Ci to C12 acyloxy, nitro, Ci to C12 alkyl ester, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, N-(Ci to C 12 alkyl)carboxamide, protected N-(Ci to C12 alkyl)carboxamide, N5N-CIi(C1 to C12 alkyl)carboxamide, cyano, methylsulfonylamino, thiol, Ci to C10 alkylthio or Ci to C10 alkylsulfonyl groups. The substituted acyl groups may be substituted once or more, and preferably once or twice, with the same or with different substituents.
The substituent term "C3 to C7 cycloalkyl" includes the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl rings. Similarly, a substituent that can be C3 to C7 cycloalkyl" can also be "C5 to C7 cycloalkyl," which includes the cyclopentyl, cyclohexyl or cycloheptyl rings.
The substituent term "C3 to C7 substituted cycloalkyl" or "C5 to C7 substituted cycloalkyl" indicates the above cycloalkyl rings substituted by one or two halogen, hydroxy, protected hydroxy, Ci to C10 alkylthio, Ci to C10 alkylsulfoxide, Ci to C10 alkylsulfonyl, Ci to C10 substituted alkylthio, Ci to C10 substituted alkylsulfoxide, Ci to Cio substituted alkylsulfonyl, Ci to C12 alkyl, Ci to C12 alkoxy, Ci to C12 substituted alkyl, Ci to C12 alkoxy, oxo, protected oxo, (monosubstituted)amino, (disubstituted)amino, trifluoromethyl, carboxy, protected carboxy, phenyl, substituted phenyl, phenylthio, phenylsulfoxide, phenylsulfonyl, amino, or protected amino groups. The term "cycloalkylene" means a cycloalkyl, as defined above, where the cycloalkyl radical is bonded at two positions connecting together two separate additional groups. Similarly, the term "substituted cycloalkylene" means a cycloalkylene where the cycloalkyl radical is bonded at two positions connecting together two separate additional groups and further bearing at least one additional substituent.
The term "C5 to C7 cycloalkenyl" indicates a 1,2, or 3-cyclopentenyl ring, a 1,2,3 or 4-cyclohexenyl ring or a 1,2,3,4 or 5-cycloheptenyl ring, while the term "substituted C5 to C7 cycloalkenyl" denotes the above C5 to C7 cycloalkenyl rings substituted by a Ci to Ci2 alkyl radical, halogen, hydroxy, protected hydroxy, Ci to Ci2 alkoxy, trifluoromethyl, carboxy, protected carboxy, oxo, protected oxo,
(monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, phenyl, substituted phenyl, amino, or protected amino. The term "C5 to C7 cycloalkenylene" is a cycloalkenyl ring, as defined above, where the cycloalkenyl radical is bonded at two positions connecting together two separate additional groups. Examples of C5 to C7 cycloalkenylenes include 1,3-cyclopentylene and 1,2-cyclohexylene. Similarly, the term "substituted C5 to C7 cycloalkenylene" means a cycloalkenylene further substituted by halogen, hydroxy, protected hydroxy, Ci to C10 alkylthio, Ci to C10 alkylsulfoxide, Ci to C10 alkylsulfonyl, Ci to C10 substituted alkylthio, Ci to C10 substituted alkylsulfoxide, Ci to C10 substituted alkylsulfonyl, Ci to C12 alkyl, Ci to C12 alkoxy, Ci to C12 substituted alkyl, Ci to C12 alkoxy, oxo, protected oxo, (monosubstituted)amino, (disubstituted)amino, trifluoromethyl, carboxy, protected carboxy, phenyl, substituted phenyl, phenylthio, phenylsulfoxide, phenylsulfonyl, amino, or protected amino group. Examples of substituted C5 to C7 cycloalkenylenes include 4-chloro- 1,3-cyclopentylene and 4-methyl- 1,2-cyclohexylene.
The term "heterocycle" or "heterocyclic ring" denotes optionally substituted fϊve-membered to eight-membered rings that have 1 to 4 heteroatoms, such as oxygen, sulfur and/or nitrogen, in particular nitrogen, either alone or in conjunction with sulfur or oxygen ring atoms. These fϊve-membered to eight-membered rings may be saturated, fully unsaturated or partially unsaturated, with fully saturated rings being preferred. Preferred heterocyclic rings include morpholino, piperidinyl, piperazinyl, 2-amino-imidazoyl, tetrahydrofurano, pyrrolo, tetrahydrothiophen-yl, hexylmethyleneimino and heptylmethyleneimino.
The term "substituted heterocycle" or "substituted heterocyclic ring" means the above-described heterocyclic ring is substituted with, for example, one or more, and preferably one or two, substituents which are the same or different which substituents can be halogen, hydroxy, protected hydroxy, cyano, nitro, Ci to C12 alkyl, Ci to C12 alkoxy, Ci to C12 substituted alkoxy, Ci to C12 acyl, Ci to C12 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino carboxamide, protected carboxamide, N- (Ci to C12 alkyl)carboxamide, protected N-(Ci to C12 alkyl)carboxamide, N, N-(Ii(C1 to C12 alkyl)carboxamide, trifluoromethyl, N-((Ci to C12 alkyl)sulfonyl)amino, N- (phenylsulfonyl)amino, heterocycle or substituted heterocycle groups. The term "heteroaryl" means a heterocyclic aromatic derivative which is a five- membered or six-membered ring system having from 1 to 4 heteroatoms, such as oxygen, sulfur and/or nitrogen, in particular nitrogen, either alone or in conjunction with sulfur or oxygen ring atoms. Examples of heteroaryls include pyridinyl, pyrimidinyl, and pyrazinyl, pyridazinyl, pyrrolo, furano, oxazolo, isoxazolo, phthalimido, thiazolo and the like.
The term "substituted heteroaryl" means the above-described heteroaryl is substituted with, for example, one or more, and preferably one or two, substituents which are the same or different which substituents can be halogen, hydroxy, protected hydroxy, cyano, nitro, Ci to C12 alkyl, Ci to Ci2 alkoxy, Ci to Ci2 substituted alkoxy, Ci to Ci2 acyl, Ci to Ci2 substituted acyl, Ci to Ci2 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, carboxamide, protected carboxamide, N-(Ci to Ci2 alkyl)carboxamide, protected N-(Ci to Ci2 alkyl)carboxamide, N, N-di(Ci to Ci2 alkyl)carboxamide, trifluoromethyl, N-((Ci to Ci2 alkyl)sulfonyl)amino or N- (phenylsulfonyl)amino groups.
The term "C7 to C18 phenylalkyl" denotes a Ci to Ci2 alkyl group substituted at any position within the alkyl chain by a phenyl. The definition includes groups of the formula: -phenyl-alkyl, -alkyl-phenyl and -alkyl-phenyl-alkyl. Examples of such a group include benzyl, 2-phenylethyl, 3-phenyl(n-propyl), 4-phenylhexyl, 3-phenyl(n- amyl), 3-phenyl(sec-butyl) and the like. Preferred C7 to C18 phenylalkyl groups are any one of the preferred alkyl groups described herein combined with a phenyl group.
Similarly, the term "Ci to Ci2 heterocycloalkyl" denotes a Ci to Ci2 alkyl group substituted at any position within the alkyl chain by a "heterocycle," as defined herein. The definition includes groups of the formula: -heterocyclic-alkyl, -alkyl-heterocyclic and -alkyl-heterocyclic-alkyl. Examples of such a group include 2-pyridylethyl, 3- piperydyl(n-propyl), 4-furylhexyl, 3-piperazyl(n-amyl), 3-morpholyl(sec-butyl) and the like. Preferred Ci to Ci2 heterocycloalkyl groups are any one of the preferred alkyl groups described herein combined with any one of the preferred heterocycle groups described herein. The terms "C7 to C18 substituted phenylalkyl" and "Ci to C12 substituted heterocycloalkyl" denote a C7 to C18 phenylalkyl group or Ci to C12 heterocycloalkyl substituted (on the alkyl or, where applicable, phenyl or heterocyclic portion) with one or more, and preferably one or two, groups chosen from halogen, hydroxy, protected hydroxy, oxo, protected oxo, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, guanidino, protected guanidino, heterocyclic ring, substituted heterocyclic ring, Ci to C12 alkyl, Ci to Ci2 substituted alkyl, Ci to Ci2 alkoxy, Ci to Ci2 substituted alkoxy, Ci to Ci2 acyl, Ci to Ci2 substituted acyl, Ci to Ci2 acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, N-(Ci to Ci2 alkyl)carboxamide, protected N-(Ci to Ci2 alkyl)carboxamide, N, N-(Ci to Ci2 dialkyl)carboxamide, cyano, N-(Ci to Ci2 alkylsulfonyl)amino, thiol, Ci to Ci0 alkylthio, Ci to Ci0 alkylsulfonyl groups; and/or the phenyl group may be substituted with one or more, and preferably one or two, substituents chosen from halogen, hydroxy, protected hydroxy, cyano, nitro, Ci to Ci2 alkyl, Ci to Ci2 substituted alkyl, Ci to Ci2 alkoxy, Ci to Ci2 substituted alkoxy, Ci to Ci2 acyl, Ci to Ci2 substituted acyl, Ci to Ci2 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, carboxamide, protected carboxamide, N-(Ci to Ci2 alkyl)carboxamide, protected N-(Ci to Ci2 alkyl)carboxamide, N, N-CIi(C1 to Ci2 alkyl)carboxamide, trifluoromethyl, N-((Ci to Ci2 alkyl)sulfonyl)amino, N- (phenylsulfonyl)amino, cyclic C2 to Ci2 alkylene or a phenyl group, substituted or unsubstituted, for a resulting biphenyl group. The substituted alkyl, phenyl or heterocyclic groups may be substituted with one or more, and preferably one or two, substituents which can be the same or different.
The term "C7 to C18 phenylalkylene" specifies a C7 to C18 phenylalkyl, as defined above, where the phenylalkyl radical is bonded at two different positions connecting together two separate additional groups. The definition includes groups of the formula: -phenyl-alkyl-, -alkyl-phenyl- and -alkyl-phenyl-alkyl-. Substitutions on the phenyl ring can be 1,2, 1,3 or 1,4. C7 to C18 phenylalkylenes include, for example, 1,4-tolylene and 1,3-xylylene. Similarly, the term "Ci to C12 heterocycloalkylene" specifies a Ci to C12 heterocycloalkyl, as defined above, where the heterocycloalkyl radical is bonded at two different positions connecting together two separate additional groups. The definition includes groups of the formula: -heterocyclic-alkyl-, -alkyl-heterocyclic and -alkyl- heterocyclic-alkyl-.
The terms "C7 to C18 substituted phenylalkylene" and "Ci to C12 substituted heterocycloalkylene" means a C7 to C18 phenylalkylene or Ci to Ci2 heterocycloalkylene as defined above that is further substituted by halogen, hydroxy, protected hydroxy, Ci to C10 alkylthio, Ci to C10 alkylsulfoxide, Ci to C10 alkylsulfonyl, Ci to Cio substituted alkylthio, Ci to C10 substituted alkylsulfoxide, Ci to C10 substituted alkylsulfonyl, Ci to Ci2 alkyl, Ci to Ci2 alkoxy, Ci to Ci2 substituted alkyl, Ci to Ci2 alkoxy, oxo, protected oxo, (monosubstituted)amino, (disubstituted)amino, trifluoromethyl, carboxy, protected carboxy, phenyl, substituted phenyl, phenylthio, phenylsulfoxide, phenylsulfonyl, amino, or protected amino group on the phenyl ring or on the alkyl group.
The term "substituted phenyl" specifies a phenyl group substituted with one or more, and preferably one or two, moieties chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, Ci to Ci2 alkyl, Ci to Ci2 substituted alkyl, Ci to Ci2 alkoxy, Ci to Ci2 substituted alkoxy, Ci to Ci2 acyl, Ci to Ci2 substituted acyl, Ci to Ci2 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, carboxamide, protected carboxamide, N-(Ci to Ci2 alkyl)carboxamide, protected N-(Ci to Ci2 alkyl)carboxamide, N, N-di(Ci to Ci2 alkyl)carboxamide, trifluoromethyl, N- ((Ci to Ci2 alkyl)sulfonyl)amino, N- (phenylsulfonyl)amino or phenyl, wherein the phenyl is substituted or unsubstituted, such that, for example, a biphenyl results.
The term "phenoxy" denotes a phenyl bonded to an oxygen atom, wherein the binding to the rest of the molecule is through the oxygen atom. The term "substituted phenoxy" specifies a phenoxy group substituted with one or more, and preferably one or two, moieties chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, Ci to Ci2 alkyl, Ci to Ci2 alkoxy, Ci to Ci2 substituted alkoxy, Ci to Ci2 acyl, Ci to Ci2 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, carboxamide, protected carboxamide, N-(Ci to C 12 alkyl)carboxamide, protected N-(Ci to C12 alkyl)carboxamide, N, N-di(Ci to C12 alkyl)carboxamide, trifluoromethyl, N- ((Ci to C12 alkyl)sulfonyl)amino and N- (phenylsulfonyl)amino.
The term "C7 to C18 substituted phenylalkoxy" denotes a C7 to C18 phenylalkoxy group bonded to the rest of the molecule through the oxygen atom, wherein the phenylalkyl portion is substituted with one or more, and preferably one or two, groups selected from halogen, hydroxy, protected hydroxy, oxo, protected oxo, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino,
(disubstituted)amino, guanidino, heterocyclic ring, substituted heterocyclic ring, Ci to C12 alkoxy, Ci to Ci2 acyl, Ci to Ci2 acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, N-(Ci to Ci2 alkyl)carboxamide, protected N-(Ci to Ci2 alkyl)carboxamide, N, N-(Ci to Ci2 dialkyl)carboxamide, cyano, N-(Ci to C12 alkylsulfonyl)amino, thiol, Ci to C10 alkylthio, Ci to C10 alkylsulfonyl groups; and/or the phenyl group can be substituted with one or more, and preferably one or two, substituents chosen from halogen, hydroxy, protected hydroxy, cyano, nitro, Ci to C12 alkyl, Ci to Ci2 alkoxy, Ci to Ci2 acyl, Ci to Ci2 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected
(monosubstituted)amino, (disubstituted)amino, carboxamide, protected carboxamide, N-(Ci to C12 alkyl) carboxamide, protected N-(Ci to Ci2 alkyl) carboxamide, N, N- (Ii(C1 to C12 alkyl)carboxamide, trifluoromethyl, N-((Ci to Ci2 alkyl)sulfonyl)amino, N-(phenylsulfonyl)amino or a phenyl group, substituted or unsubstituted, for a resulting biphenyl group. The substituted alkyl or phenyl groups may be substituted with one or more, and preferably one or two, substituents which can be the same or different.
The term "phthalimide" means a cyclic imide which is made from phthalic acid, also called 1 ,2-benzenedicarboxylic acid. The term "substituted phthalimide" specifies a phthalimide group substituted with one or more, and preferably one or two, moieties chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, Ci to Ci2 alkyl, Ci to Ci2 alkoxy, Ci to Ci2 substituted alkoxy, Ci to Ci2 acyl, Ci to C 12 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, carboxamide, protected carboxamide, N-(Ci to C 12 alkyl)carboxamide, protected N-(Ci to C12 alkyl)carboxamide, N, N-di(Ci to C12 alkyl)carboxamide, trifluoromethyl, N- ((Ci to C12 alkyl)sulfonyl)amino and N-(phenylsulfonyl)amino.
The term "substituted naphthyl" specifies a naphthyl group substituted with one or more, and preferably one or two, moieties either on the same ring or on different rings chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, Ci to C6 alkyl, Ci to C7 alkoxy, Ci to C7 acyl, Ci to C7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, carboxamide, protected carboxamide, N-(Ci to C12 alkyl)carboxamide, protected N-(Ci to C12 alkyl)carboxamide, N, N-(Ii(C1 to C 12 alkyl)carboxamide, trifluoromethyl, N-((Ci to C 12 alkyl)sulfonyl)amino or N-(phenylsulfonyl)amino .
The term "naphthylene" means a naphthyl radical bonded at two positions connecting together two separate additional groups. Similarly, the term "substituted napthylene" means a naphthylene group that is further substituted by halogen, hydroxy, protected hydroxy, Ci to C10 alkylthio, Ci to C10 alkylsulfoxide, Ci to C10 alkylsulfonyl, Ci to Cio substituted alkylthio, Ci to C10 substituted alkylsulfoxide, Ci to C10 substituted alkylsulfonyl, Ci to Ci2 alkyl, Ci to Ci2 alkoxy, Ci to Ci2 substituted alkyl, Ci to Ci2 alkoxy, oxo, protected oxo, (monosubstituted)amino, (disubstituted)amino, trifluoromethyl, carboxy, protected carboxy, phenyl, substituted phenyl, phenylthio, phenylsulfoxide, phenylsulfonyl, amino, or protected amino group. The terms "halo" and "halogen" refer to the fluoro, chloro, bromo or iodo atoms. There can be one or more halogens, which are the same or different. Preferred halogens are chloro and fluoro.
The term "(monosubstituted)amino" refers to an amino group with one substituent chosen from the group consisting of phenyl, substituted phenyl, Ci to Ci2 alkyl, Ci to Ci2 substituted alkyl, Ci to Ci2 acyl, Ci to Ci2 substituted acyl, C2 to Ci2 alkenyl, C2 to Ci2 substituted alkenyl, C2 to Ci2 alkynyl, C2 to Ci2 substituted alkynyl, C7 to Ci8 phenylalkyl, C7 to C18 substituted phenylalkyl, heterocyclic ring, substituted heterocyclic ring, Ci to C12 heterocycloalkyl and Ci to C12 substituted heterocycloalkyl. The (monosubstituted)amino can additionally have an amino-protecting group as encompassed by the term "protected (monosubstituted)amino."
The term "(disubstituted)amino" refers to an amino group with two substituents chosen from the group consisting of phenyl, substituted phenyl, Ci to C12 alkyl, Ci to C12 substituted alkyl, Ci to Ci2 acyl, C2 to Ci2 alkenyl, C2 to Ci2 alkynyl, C7 to C18 phenylalkyl, C7 to C18 substituted phenylalkyl, Ci to Ci2 heterocycloalkyl and Ci to Ci2 substituted heterocycloalkyl. The two substituents can be the same or different.
The term "amino-protecting group" as used herein refers to substituents of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups of the molecule. The term "protected (monosubstituted)amino" means there is an amino-protecting group on the monosubstituted amino nitrogen atom. In addition, the term "protected carboxamide" means there is an amino-protecting group on the carboxamide nitrogen. Similarly, the term "protected N-(Ci to Ci2 alkyl)carboxamide" means there is an amino-protecting group on the carboxamide nitrogen.
The term "protected guanidino" as used herein refers to an "amino-protecting group" on one or two of the guanidino nitrogen atoms. Examples of "protected guanidino" groups are described by T. W. Greene and P. GM. Wuts; M. Bodanzsky; and Stewart and Young, supra.
The term "epimino" means -NH-. The term "substituted epimino" means - N(R)-, where R is a substitution group listed above under the definition of "(monosubstituted)amino."
The term "Ci to Cs alkylene epimino" refers to a one to five carbon alkylene chain with an epimino at any point along the chain. The term "Ci to C5 substituted alkylene epimino" refers to a Ci to C5 alkylene epimino group that is substituted a) at the epimino position (in the same way as "substituted epimino," described above); and/or b) at one or more of the alkylene positions (in the same way as "substituted alkylene," as described above). The term "thio" refers to -SH or, if between two other groups, -S-. The term
"Ci to Cio alkylene thio" refers to a one to ten carbon alkylene chain with a thio at any point along the chain. The term "Ci to C10 substituted alkylene thio" refers to a Ci to Cio alkylene thio group that is substituted at one or more of the alkylene positions (in the same way as "substituted alkylene," as described above).
The term "sulfonyl" refers to -S(O)2-. The term "Ci to Ci0 alkylene sulfonyl" refers to a one to ten carbon alkylene chain with a sulfonyl at any point along the chain. The term "Ci to C10 substituted alkylene sulfonyl" refers to a Ci to C10 alkylene sulfonyl group that is substituted at one or more of the alkylene positions (in the same way as "substituted alkylene," as described above). Similarly, the term "Ci to C10 substituted alkylsulfonyl" refers to a Ci to C10 alkylsulfonyl group that is substituted at one or more of the alkyl positions (in the same way as "substituted alkyl," as described above). Similarly, the term "substituted phenylsulfonyl" refers to a phenylsulfonyl group that is substituted at one or more of the phenyl positions (in the same way as
"substituted phenyl," as described above).
The term "sulfmyl" refers to -S(O)-. The term "Ci to Ci0 alkylene sulfmyl" refers to a one to ten carbon alkylene chain with a sulfmyl at any point along the chain. The term "Ci to C10 substituted alkylene sulfinyl" refers to a Ci to C10 alkylene sulfinyl group that is substituted at one or more of the alkylene positions (in the same way as
"substituted alkylene," as described above).
The term "oxy" refers to -O-. The terms "Ci to Ci0 alkylene oxy," "Ci to Ci0 alkylene dioxy" and "Ci to C10 alkylene trioxy" refer to a one to ten carbon alkylene chain with, respectively, one, two or three -O- at any point along the chain, provided that no two oxygen atoms are consecutive, and provided that any two oxygen atoms are separated by at least two carbons. The terms "Ci to C10 substituted alkylene oxy," "Ci to Cio substituted alkylene dioxy" and "Ci to C10 substituted alkylene trioxy" refer, respectfully to "Ci to Cio alkylene oxy," "Ci to Cio alkylene dioxy" and "Ci to Cio alkylene trioxy" that are substituted at one or more of the alkylene positions (in the same way as "substituted alkylene," as described above).
The term "thiocarbonyl" refers to -C(S)H or, if between two other groups, -
C(S)-. The term "thioester" refers to -C(O)SH or, if between two other groups, -
C(O)S-. The term "carboxy-protecting group" as used herein refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound. A related term is "protected carboxy," which refers to a carboxy group substituted with one of the above carboxy-protecting groups.
The term "hydroxy-protecting group" refers to readily cleavable groups bonded to hydroxyl groups, such as the tetrahydropyranyl, 2-methoxypropyl, 1-ethoxyethyl, methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, t-butyl, t-amyl, trityl, 4- methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityl, benzyl, allyl, trimethylsilyl, (t-butyl)dimethylsilyl, 2,2,2-trichloroethoxycarbonyl groups and the like.
The term "Ci to C10 alkylthio" refers to sulfide groups such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, t-butylthio and like groups. The term "Ci to C10 alkylsulfoxide" indicates sulfoxide groups such as methylsulfoxide, ethylsulfoxide, n-propylsulfoxide, isopropylsulfoxide, n- butylsulfoxide, sec-butylsulfoxide and the like. The term "Ci to Ci0 alkylsulfonyl" encompasses groups such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, t-butylsulfonyl and the like, it should also be understood that the above thio, sulfoxide or sulfonyl groups can be at any point on the alkyl chain (e.g., 2-methylmercaptoethyl).
The terms "Ci to C10 substituted alkylthio," "Ci to C10 substituted alkylsulfoxide," and "Ci to C10 substituted alkylsulfonyl," denote the Ci to C10 alkyl portion of these groups may be substituted as described above in relation to "substituted alkyl."
The terms "phenylthio," "phenylsulfoxide," and "phenylsulfonyl" specify a thiol, a sulfoxide, or sulfone, respectively, containing a phenyl group. The terms "substituted phenylthio," "substituted phenylsulfoxide," and "substituted phenylsulfonyl" means that the phenyl of these groups can be substituted as described above in relation to "substituted phenyl."
The term "Ci to C12 alkylaminocarbonyl" means a Ci to Ci2 alkyl attached to a nitrogen of the aminocarbonyl group. Examples of Ci to Ci2 alkylaminocarbonyl include methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl and butylaminocarbonyl. The term "Ci to Ci2 substituted alkylaminocarbonyl" denotes a substituted alkyl bonded to a nitrogen of the aminocarbonyl group, which alkyl may be substituted as described above in relation to Ci to Ci2 substituted alkyl. Examples of Ci to Ci2 substituted alkylaminocarbonyl include, for example, methoxymethylaminocarbonyl, 2-chloroethylaminocarbonyl, 2- oxopropylaminocarbonyl and 4-phenylbutylaminocarbonyl.
The term "Ci to C12 alkoxycarbonyl" means a "Ci to Ci2 alkoxy" group attached to a carbonyl group. The term "Ci to Ci2 substituted alkoxycarbonyl" denotes a substituted alkoxy bonded to the carbonyl group, which alkoxy may be substituted as described above in relation to "Ci to Ci2 substituted alkyl."
The term "phenylaminocarbonyl" means a phenyl attached to a nitrogen of the aminocarbonyl group. The term "substituted phenylaminocarbonyl" denotes a substituted phenyl bonded to a nitrogen of the aminocarbonyl group, which phenyl may be substituted as described above in relation to substituted phenyl. Examples of substituted phenylaminocarbonyl include 2-chlorophenylaminocarbonyl, 3- chlorophenylaminocarbonyl , 2-nitorphenylaminocarbonyl, 4-biphenylaminocarbonyl, and 4-methoxyphenylaminocarbonyl.
The term "Ci to Ci2 alkylaminothiocarbonyl" means a Ci to Ci2 alkyl attached to an aminothiocarbonyl group, wherein the alkyl has the same meaning as defined above. The term "Ci to Ci2 substituted alkylaminothiocarbonyl" denotes a substituted alkyl bonded to an aminothiocarbonyl group, wherein the alkyl may be substituted as described above in relation to Ci to Ci2 substituted alkyl. The term "phenylaminothiocarbonyl" means a phenyl attached to an aminothiocarbonyl group, wherein the phenyl has the same meaning as defined above.
The term "substituted phenylaminothiocarbonyl" denotes a substituted phenyl bonded to an aminothiocarbonyl group, wherein phenyl may be substituted as described above in relation to substituted phenyl.
The term "phenylene" means a phenyl group where the phenyl radical is bonded at two positions connecting together two separate additional groups.
The term "substituted phenylene" means a phenyl group where the phenyl radical is bonded at two positions connecting together two separate additional groups, wherein the phenyl is substituted as described above in relation to "substituted phenyl."
The term "substituted Ci to Ci2 alkylene" means a Ci to Ci2 alkyl group where the alkyl radical is bonded at two positions connecting together two separate additional groups and further bearing an additional substituent. The terms "cyclic C2 to C7 alkylene," "substituted cyclic C2 to C7 alkylene," "cyclic C2 to C7 heteroalkylene," and "substituted cyclic C2 to C7 heteroalkylene," defines such a cyclic group bonded ("fused") to the phenyl radical resulting in a bicyclic ring system. The cyclic group may be saturated or contain one or two double bonds. Furthermore, the cyclic group may have one or two methylene or methine groups replaced by one or two oxygen, nitrogen or sulfur atoms which are the cyclic C2 to C7 heteroalkylene.
The cyclic alkylene or heteroalkylene group may be substituted once or twice by the same or different substituents which, if appropriate, can be connected to another part of the compound (e.g., alkylene) selected from the group consisting of the following moieties: hydroxy, protected hydroxy, carboxy, protected carboxy, oxo, protected oxo, Ci to C4 acyloxy, formyl, Ci to Ci2 acyl, Ci to Ci2 alkyl, Ci to C7 alkoxy, Ci to Cio alkylthio, Ci to C10 alkylsulfoxide, Ci to C10 alkylsulfonyl, halo, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, hydroxymethyl or a protected hydroxymethyl.
The cyclic alkylene or heteroalkylene group fused onto the benzene radical can contain two to ten ring members, but it preferably contains three to six members.
Examples of such saturated cyclic groups are when the resultant bicyclic ring system is 2,3-dihydro-indanyl and a tetralin ring. When the cyclic groups are unsaturated, examples occur when the resultant bicyclic ring system is a naphthyl ring or indolyl. Examples of fused cyclic groups which each contain one nitrogen atom and one or more double bond, preferably one or two double bonds, are when the benzene radical is fused to a pyridino, pyrano, pyrrolo, pyridinyl, dihydropyrrolo, or dihydropyridinyl ring. Examples of fused cyclic groups which each contain one oxygen atom and one or two double bonds are when the benzene radical ring is fused to a furo, pyrano, dihydrofurano, or dihydropyrano ring. Examples of fused cyclic groups which each have one sulfur atom and contain one or two double bonds are when the benzene radical is fused to a thieno, thiopyrano, dihydrothieno or dihydrothiopyrano ring. Examples of cyclic groups which contain two heteroatoms selected from sulfur and nitrogen and one or two double bonds are when the benzene radical ring is fused to a thiazolo, isothiazolo, dihydrothiazolo or dihydroisothiazolo ring. Examples of cyclic groups which contain two heteroatoms selected from oxygen and nitrogen and one or two double bonds are when the benzene ring is fused to an oxazolo, isoxazolo, dihydrooxazolo or dihydroisoxazolo ring. Examples of cyclic groups which contain two nitrogen heteroatoms and one or two double bonds occur when the benzene ring is fused to a pyrazolo, imidazolo, dihydropyrazolo or dihydroimidazolo ring or pyrazinyl. The term "carbamoyl" means an -NC(O)- group where the radical is bonded at two positions connecting two separate additional groups. One or more of the compounds of the invention may be present as a salt. The term "salt" encompasses those salts that form with the carboxylate anions and amine nitrogens and include salts formed with the organic and inorganic anions and cations discussed below. Furthermore, the term includes salts that form by standard acid-base reactions with basic groups (such as amino groups) and organic or inorganic acids. Such acids include hydrochloric, hydrofluoric, trifluoroacetic, sulfuric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic, D- glutamic, D-camphoric, glutaric, phthalic, tartaric, lauric, stearic, salicyclic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic, cinnamic, and like acids.
The term "organic or inorganic cation" refers to counter-ions for the carboxylate anion of a carboxylate salt. The counter-ions are chosen from the alkali and alkaline earth metals, (such as lithium, sodium, potassium, barium, aluminum and calcium); ammonium and mono-, di- and tri-alkyl amines such as trimethylamine, cyclohexylamine; and the organic cations, such as dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, bis(2-hydroxyethyl)ammonium, phenylethylbenzylammonium, dibenzylethylenediammonium, and like cations. See, for example, "Pharmaceutical Salts," Berge et al., J. Pharm. ScL, 66:1-19 (1977), which is incorporated herein by reference. Other cations encompassed by the above term include the protonated form of procaine, quinine and N-methylglucosamine, and the protonated forms of basic amino acids such as glycine, ornithine, histidine, phenylglycine, lysine and arginine. Furthermore, any zwitterionic form of the instant compounds formed by a carboxylic acid and an amino group is referred to by this term. For example, a cation for a carboxylate anion will exist when a position is substituted with a (quaternary ammonium)methyl group. A preferred cation for the carboxylate anion is the sodium cation. The compounds of the invention can also exist as solvates and hydrates. Thus, these compounds may crystallize with, for example, waters of hydration, or one, a number of, or any fraction thereof of molecules of the mother liquor solvent. The solvates and hydrates of such compounds are included within the scope of this invention.
One or more compounds of the invention can be in the biologically active ester form, such as the non-toxic, metabolically-labile ester-form. Such ester forms induce increased blood levels and prolong the efficacy of the corresponding non-esterified forms of the compounds. Ester groups which can be used include the lower alkoxymethyl groups, for example, methoxymethyl, ethoxymethyl, isopropoxymethyl and the like; the -(Ci to Ci2) alkoxyethyl groups, for example methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl and the like; the 2-oxo-l,3-diooxlen-4- ylmethyl groups, such as 5-methyl-2-oxo-l,3-dioxolen-4-ylmethyl, 5-phenyl-2-oxo- l,3-dioxolen-4-ylmethyl and the like; the Ci to C10 alkylthiomethyl groups, for example methylthiomethyl, ethylthiomethyl, iso-propylthiomethyl and the like; the acyloxymethyl groups, for example pivaloyloxymethyl, pivaloyloxyethyl, - acetoxymethyl and the like; the ethoxycarbonyl-1 -methyl group; the -acetoxyethyl; the 1-(Ci to C12 alkyloxycarbonyloxy)ethyl groups such as the l-(ethoxycarbonyloxy)ethyl group; and the 1-(Ci to Ci2 alkylaminocarbonyloxy)ethyl groups such as the 1- (methylaminocarbonyloxy)ethyl group .
The term "amino acid" includes any one of the twenty naturally-occurring amino acids or the D-form of any one of the naturally-occurring amino acids. In addition, the term "amino acid" also includes other non-naturally occurring amino acids besides the D-amino acids, which are functional equivalents of the naturally-occurring amino acids. Such non-naturally-occurring amino acids include, for example, norleucine ("NIe"), norvaline ("Nva"), L- or D- naphthalanine, ornithine ("Orn"), homoarginine (homoArg) and others well known in the peptide art, such as those described in M. Bodanzsky, "Principles of Peptide Synthesis," 1st and 2nd revised ed., Springer- Verlag, New York, NY, 1984 and 1993, and Stewart and Young, "Solid Phase Peptide Synthesis," 2nd ed., Pierce Chemical Co., Rockford, IL, 1984, both of which are incorporated herein by reference. Amino acids and amino acid analogs can be purchased commercially (Sigma Chemical Co.; Advanced Chemtech) or synthesized using methods known in the art.
It should be understood that any position of the claimed invention has up to three serial "substitutions." For example, a "substituted alkyl" that is substituted with a "substituted phenyl" that is, in turn, substituted with a "substituted alkyl" can, in turn, be susbstitued by one more group and no longer further substituted. However, it should also be understood that the invention contemplates, if appropriate, more than three parallel susbstitutions. For example, if appropriate, more than threee hydrogens on an alkyl moiety may be susbstituted with any one or more of a variety of groups, including halo and hydroxy.
For preparing pharmaceutical compositions containing compounds of the invention, inert, pharmaceutically acceptable carriers are used. The pharmaceutical carrier can be either solid or liquid. Solid form preparations include, for example, powders, tablets, dispersible granules, capsules, cachets, and suppositories.
A solid carrier can be one or more substances that can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
In powders, the carrier is generally a finely divided solid which is in a mixture with the finely divided active component. In tablets, the active compound is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
For preparing pharmaceutical composition in the form of suppositories, a low- melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient-sized molds and allowed to cool and solidify.
Powders and tablets preferably contain between about 5% to about 70% by weight of the active ingredient. Suitable carriers include, for example, magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter and the like.
The pharmaceutical compositions can include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier, which is thus in association with it. In a similar manner, cachets are also included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
Liquid pharmaceutical compositions include, for example, solutions suitable for oral or parenteral administration, or suspensions, and emulsions suitable for oral administration. Sterile water solutions of the active component or sterile solutions of the active component in solvents comprising water, ethanol, or propylene glycol are examples of liquid compositions suitable for parenteral administration.
Sterile solutions can be prepared by dissolving the active component in the desired solvent system, and then passing the resulting solution through a membrane filter to sterilize it or, alternatively, by dissolving the sterile compound in a previously sterilized solvent under sterile conditions.
Aqueous solutions for oral administration can be prepared by dissolving the active compound in water and adding suitable flavorants, coloring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
Preferably, the pharmaceutical composition is in unit dosage form. In such form, the composition is divided into unit doses containing appropriate quantities of the active 2-aminobenzoxazole compound. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, for example, packeted tablets, capsules, and powders in vials or ampules. The unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.
As pharmaceutical compositions for treating infections, pain, or any other indication the compounds of the present invention are generally in a pharmaceutical composition so as to be administered to a subject at dosage levels of from 0.7 to 7000 mg per day, and preferably 1 to 500 mg per day, for a normal human adult of approximately 70 kg of body weight, this translates into a dosage of from 0.01 to 100 mg/kg of body weight per day. The specific dosages employed, however, can be varied depending upon the requirements of the patient, the severity of the condition being treated, and the activity of the compound being employed. The determination of optimum dosages for a particular situation is within the skill of the art.
The following examples are provided to illustrate but not limit the present invention.
Example 1
9-(4-chlorobutyl)-9H-carbazole
To a solution of carbazole (1.2 g, 7.2 mmol) in tetrahydrofuran was added potassium tert-butoxidc (IM in tetrahydrofuran, 7.2 mL) and l-bromo-4-chlorobutane (1.5 g, 8.8 mmol). After 18 hours, the reaction mixture was evaporated onto silica in vacuo and purified by automated flash chromatography to give the title compound (1.5O g, 97%).
Example 2 2-Chloro- 10-(4-chlorobutyl)- 1 OΗ-phenothiazine
As for example 1, except starting with 2-chlorophenothiazine. Hl NMR 500 MHz, (DMSOD6), 7.25-7.20, m, IH, 7.18-7.15, m, 2H, 7.09, d, J=2.0, IH, 7.06, d, J=I.6, IH, 7.01-6.97, m, 2H, 3.92 t, J=6.6, 2H, 3.65, t, J=6.3, 2H, 1.83-1.76, m, 4H
Example 3
9-(3-chloropropyl)-9H-phenoxazine
To a solution of phenoxazine (I g, 5.46 mmol) in dimethylsulfoxide was added sodium hydride (60 % in mineral oil, 437 mg, 10.9 mmol), and l-bromo-3-chloropropane (1.7 g, 10.9 mmol). After stirring for 72 hours, the reaction was quenched with water and extracted with methylene chloride. The combined organic layers were evaporated onto silica in vacuo and eluted by automated flash chromatography to give the title compound (0.93 g, 65 %).
Example 4
3 ,7-dimethyl-9H-phenothiazine To a solution of 4-methyl-JV-(4-methylphenyl)aniline (2 g, 10 mmol) in 1,2- dichlorobenzene was added sulfur (0.7 g) and a catalytic amount of iodine. This was warmed to reflux for 6 hours, then cooled to room temperature and placed on silica. This was purified by automated flash chromatography to give the title compound (1.2 g, 52 %).
Example 5
10-(3 -bromopropyl)-2 -methyl- 1 OH-phenothiazine To a solution of 2-methylphenothiazine (1 g, 4.08 mmol) in tetrahydrofuran and dimethylsulfoxide was added sodium hydride (60 % in mineral oil, 0.1 g, 4.08 mmol) and 1,3-dibromopropane (0.86 g, 4.28 mmol). After 5 hours, this was quenched with ice and extracted with dichloromethane. The combined organic layers were placed on silica purified by flash chromatography (1 :9 dichloromethane :hexanes) to yield the title compound (0.05 g 4%).
Example 6
10-(3-bromopropyl)-2-acetyl- 1 OH-phenothiazine
To 2-acetylphenothiazine (2.4 g, 10 mmol) was added sodium hydroxide (50 % in water, 0.8 g), 1,3-dibromopropane (10 ml), and tetrabutylammonium bromide (50 % in water, 20 drops). This was warmed to 50 0C for 18 hours, then cooled and placed on silica. This was purified by flash chromatography (1 :4 ethyl acetate :hexanes) to yield the title compound (500 mg, 14 %).
Example 7 2-methyl- 10- [3 -(4-methy lpiperazin- 1 -yl)propyl] - 1 OH-phenothiazine dimaleate
To 10-(3-bromopropyl)-2-methyl-l OH-phenothiazine was added 1-methylpiperazine (60.1 mg, 0.6 mmol), dimethylformamide, and tetrabutyl ammonium iodide (83 mg, 0.225 mmol). After 72 hours, the reaction was quenched with saturated sodium carbonate and extracted with dichloromethane. The combined organics were placed on silica in vacuo and purified by flash chromatography (9:1 dichloromethane methanol) to give an oil. To this oil was added ethyl ether and maleic acid (60 mg). This yielded a precipitate that was filtered with the aid of ethyl acetate and ether to yield the title compound (40 mg, 46%).
Example 8 2-acetyl- 10-[3-(4-methylpiperazin- 1 -yl)propyl]- 1 OH-phenothiazine dimaleate
The title compound was prepared in a manner similar to that of Example 7.
Example 9
2-acetyl- 10-[3-(diethylamino)propyl]-l OH-phenothiazine maleate To a solution of 10-(3 -bromopropyl)-2-acetyl- 1 OH-phenothiazine (50 mg, 0.138 mmol) in dimethylformamide was added JV,iV-diethylamine (40 mg, 0.552 mmol) and tetrabutylammonium iodide (76.5 mg, 0.207 mmol). After 6 days, the reaction was quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined organic layers were evaporated to yield an oil. To this oil was added ether, ethyl acetate, and maleic acid (50 mg). The resulting mixture was taken up in water and freeze-dried. This was free-based with saturated sodium bicarbonate and extracted with dichloromethane. The solvent was removed in vacuo to yield an oil. This oil was taken up in ether, which resulted in the formation of a precipitate. This precipitate was filtered off, and the eluate was treated with maleic acid (50 mg). This resulted in an oily precipitate that was rinsed with ether, and was the title compound (30 mg, 46 %).
Example 10
2-acetyl-9-(3-chloropropyl)-9H-carbazole
To 2-acetyl-9H-carbazole (500 mg, 2.4 mmol) was added sodium hydroxide (100 mg, 2.5 mmol), l-bromo-3-chloropropane (453 mg, 2.9 mmol), toluene, water, and tetrabutylammonium bromide (50 % in water, 5 drops). After re fluxing for 6 hours, the reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The combined organic layers were placed on silica in vacuo and purified by flash chromatography (4:1 hexanes: ethyl acetate) to yield the title compound (200 mg, 32 %). Example 11
10-(3 -chloropropyl)-3 ,7-dimethyl- 1 OH-phenothiazine The title compound was prepared in a manner similar to that of Example 3.
Example 12
3 ,7-dimethyl- 10- [3 -(4-methyl- 1 -piperazinyl)propyl] - 1 OH-phenothiazine dimaleate
To 10-(3-chloropropyl)-3,7-dimethyl-10H-phenothiazine (20 mg, 0.0658 mmol) was added DMF, N-methylpiperazine (26 mg, 0.263 mmol), and tetrabutyl ammonium iodide (36 mg, 0.1 mmol). After 8 days, water was added and the mixture was extracted with dichloromethane. The combined organic layers were placed on silica and purified by flash chromatography to yield an oil. This oil was taken up in methanol and ethyl acetate. Maleic acid (30 mg) was added, and a precipitate formed that was filtered with the aid of methanol and ethyl acetate. This was the title compound (30 mg, 76 %).
Example 13
2-acetyl-9- [3 -(4-methyl- l-piperazinyl)propyl]-9H-carbazole The title compound was prepared in a manner similar to that of Example 12.
Example 14
9-(chloropropyl)-9H-carbazole
To carbazole (5 g, 25.5 mmol) was added sodium hydroxide (1.2 g) and toluene. This was refluxed with a Dean-Stark apparatus until water stopped being removed.
Then, l-bromo-3-chloropropane (5 g, 31.8 mmol) was added. After 1 hour, the reaction was cooled to room temperature, water was added, and the products were extracted with ethyl acetate. The combined organic layers were placed on silica and purified by flash chromatography to yield the title compound (200 mg, 3%).
Example 15 2-acetyl-9-[3-(cis-3,5-dimethylpiperazin-l-yl)propyl]-9H-carbazole To 9-(3-chloropropyl)-2-acetyl-9H-carbazole (50 mg, 0.175 mmol) was added cis-2,6- dimethylpiperazine (80 mg), tetrabutylammonium iodide (97 mg, 0.26 mmol), dimethylformamide, and acetone. This was warmed to 37 0C for 18 hours, then placed on silica. This was purified by flash chromatography (9:1 dichloromethane methanol) to yield and oil. This was slurried with acetone and filtered to yield the title compound (21 mg, 30 %).
Example 16
2-acetyl- 10-[3-(cis-3,5-dimethylpiperazin- 1 -yl)propyl]- 1 OH-phenothiazine dihydrochloride
To 10-(3-bromopropyl)-2-acetyl-l OH-phenothiazine (33 mg, 0.091 mmol) was added cis-3,5-dimethylpiperazine (42 mg, 0.36 mmol), tetrabutylammonium iodide (50 mg, 0.14 mmol) and dimethylformamide. After 18 hours at 37 0C, the reaction mixture was placed on silica and purified by flash chromatography to yield an oil. This was taken up in ethanol and to it was added hydrochloric acid. The solvent was removed in vacuo, and the resulting amorphous solid was sonicated in the presence of acetone to yield crystals as the title compound (16 mg, 37%).
Example 17 9- [3 -(4-methyl- 1 -piperazinyl)propyl] -9H-carbazole dimaleate
The title compound was prepared in a manner similar to that of Example 12.
Example 18
9-[3-(diethylamino)propyl]-9H-carbazole To 9-(3-chloropropyl)-9H-carbazole (34 mg, 0.205 mmol) was added N, N- diethylamine (60 mg, 0.821 mmol), tetrabutylammonium iodide (114 mg, 0.308 mmol) and dimethylformamide. After 48 hours at 37 C, the mixture was quenched with water and extracted with dichloromethane. The combined organics were placed on silica and purified by flash chromatography (9:1 dichloromethane methanol) to yield the title compound (37 mg, 95 %). Example 19
2-acetyl-9-[3-(diethylamino)propyl]-9H-carbazole
The title compound was prepared in a manner similar to that of Example 18.
Example 20
2-chloro- 10- [4-(cis-3 ,5 -dimethylpiperazin- 1 -yl)-butyl] - 1 OH-phenothiazine
The title compound was prepared in a manner similar to that of Example 15.
Example 21
9-[4-(l-butenyl)]-9H-carbazole
The title compound was prepared in a manner similar to that of Example 3.
Example 22 9-(4-methyltetrahydropyranyl)-9H-carbazole
To carbazole (111 mg, 0.66 mmol) was added 4-(iodomethyl)tetrahydro-2H- pyran (150 mg, 0.66 mmol), sodium hydride (60% in mineral oil, 27 mg, 0.8 mmol), and dimethylsulfoxide. After 9 days, the mixture was placed on silica and purified by flash chromatography (15 % ethyl acetate, 85 % hexanes) to yield the title compound (24 mg, 14 %).
Example 23
N- [3 -(4-methyl- 1 -piperazinyl)propyl] -ditolylamine dimaleate
To 4-methyl-JV-(4-methylphenyl)aniline (1 g, 5.1 mmol) was added DMSO and sodium hydride (60% in mineral oil, 406 mg, 10.1 mmol), and l-bromo-3- chloropropane (2.4 g, 15.3 mmol). After 96 hours, the reaction mixture was quenched with saturated ammonium chloride and extracted with ether. The combined organic layers were placed on silica and purified by flash chromatography (1 :9 to 2:8 methanol :dichloromethane) to yield a crude mixture that was used in the next reaction. To this crude mixture (200 mg, 0.73 mmol) was added JV-methylpiperazine (293 mg, 2.92 mmol), tetrabutylammonium iodide (405 mg, 1.1 mmol) and dimethylformamide. After 96 hours at 37 0C, the reaction was quenched with water and extracted with dichloromethane. The combined organic layers were placed on silica in vacuo, and purified by flash chromatography (1 :9 to 2:8 methanol: dichloromethane) to yield an oil. This was taken up in methanol and ethyl acetate and maleic acid (400 mg) was added. A solid formed that was filtered with the aid of methanol and ethyl acetate. This was the title compound (81 mg, 19 %).
Example 24
N- [3 -(cis-3 ,5 -dimethylpiperazin- 1 -yl)propyl] -ditolylamine dimaleate
To the crude mixture from the first paragraph of Example 23 (200 mg, 0.73 mmol) was added cώ-3,5-dimethylpiperazine (334 mg, 2.92 mmol), tetrabutylammonium iodide (405 mg, 1.1 mmol) and dimethylformamide. After 96 hours at 37 0C, the reaction was quenched with water and extracted with dichloromethane. The combined organic layers were placed on silica in vacuo, and purified by flash chromatography (1 :9 methanol: dichloromethane) to yield an oil. This was taken up in methanol and ethyl acetate and maleic acid (400 mg) was added. A solid formed that was filtered with the aid of methanol and ethyl acetate. This was the title compound (75 mg, 18 %).
Example 25 N-[3-(cis-3,5-dimethylpiperazin-l -yl)propyl]-diphenylamine
The title compound was prepared in a manner similar to that of Example 24.
Example 26
2-chloro- 10-(4-chlorobutyryl)- 1 OH-phenothiazine To 2-chloro- 1 OH-phenothiazine (1 g, 4.28 mmol) was added 4-chlorobutyryl chloride (2 ml, 17.0 mmol), and this was warmed to 150 0C. Toluene was added, and this temperature was maintained for 30 minutes. The reaction was cooled to room temperature, and the solvent was removed in vacuo. The residue was purified by flash chromatography (4:1 hexanes:ethyl acetate) to yield the title compound (1.2 g, 83%).
Example 27
2-chloro- 10-(4-fluorobutyl)- 1 OH-phenothiazine The title compound was prepared in a manner similar to that of Example 3.
Example 28
9-(4-fluorobutyl)-9H-carbazole The title compound was prepared in a manner similar to that of Example 3.
Example 29
9-(4-chlorobutyryl)-9H-carbazole
To carbazole (1 g, 6 mmol) was added 4-chlorobutyryl chloride (2 ml, 17.9 mmol), and this mixture was warmed to 150 0C. After 30 minutes, the mixture was cooled to room temperature and methanol was added. This resulted in a precipitate that was filtered with the aid of methanol that was the title compound (725 mg, 45%).
Example 30 2-chloro- 10-(3 -chloropropyl)- 1 OH-phenothiazine
The title compound was prepared in a manner similar to that of Example 3.
Example 31
9-(4,4,4-trifluorobutyl)-9H-carbazole The title compound was prepared in a manner similar to that of Example 3.
Example 32
10-(3 -chloropropyl)-2-trifluoromethyl- 1 OH-phenothiazine The title compound was prepared in a manner similar to that of Example 3.
Example 33
10-(3 -chloropropyl)-2-methylthio- 1 OH-phenothiazine
The title compound was prepared in a manner similar to that of Example 3.
Example 34
9-[3-(pyrrol-l-yl)-propyl]-9H-carbazole
The title compound was prepared in a manner similar to that of Example 3. Example 35
9-(3-phenoxypropyl)-9H-carbazole
The title compound was prepared in a manner similar to that of Example 3.
Example 36
9-[3-(indolin-l-yl)-propyl]-9H-carbazole
To 9-(3-chloropropyl)-9H-carbazole (100 mg, 0.41 mmol) was added dimethylformamide, indoline (195 mg, 1.64 mmol) and tetrabutylammonium iodide (227 mg, 0.62 mmol). This mixture was maintained at 37 0C for 72 hours, at which time the mixture was placed on silica and purified by automated flash chromatography. This yielded the title compound (60 mg, 45 %).
Example 37
1 -(I O-Butyl- 10Η-phenothiazin-2-yl)-ethanone To l-(10H-phenothiazin-2-yl)-ethanone, 2 g, was added butylbromide, 2 ml,
50% tetrabutylammonium bromide, 0.3 ml, 50% sodium hydroxide, 1 ml, and toluene,
3 ml. The mix was placed under nitrogen, and warmed to reflux for 3 hours. After three hours the mixture was cooled to room temperature. The mix was treated with ethyl acetate, 10 ml, and water, 5 ml. The organic layer was separated, and evaporated in vacuo to provide a yellow oil. The yellow oil was chromatograpehed on a 4 inch by
4 inch column of flash silica with 1 :2 hexanes/toluene, 500 ml, toluene, 500 ml, and 4:1 toluene/dichloromethane. Fractions showing a yellow spot RF 0.3 on silica plates with toluene were combined and evaporated to give the title compound
Example 38
1 -(10-Butyl- 10H-phenothiazin-2-yl)-ethanol
A sample of l-(10-Butyl-10H-phenothiazin-2-yl)-ethanone, 61 mg, was dissolved in 4 ml anhydrous ethanol giving a yellow solution. The mix was treated with of sodium borohydride, 18 mg, and stirred at room temperature. After 1 hour the mixture had become colorless. The ethanol was evaporated in vacuo. The residue was treated with ethyl acetate, 4 ml, and the solution was washed twice with water, 3 ml. The ethyl acetate was evaporated in vacuo to give a clear oil, 57 mg. Hl NMR 500 MHz, (CDC13) 7.16-7.04, m, 3 H, 6.92-6.86, m, 4H, 4.85, q, J=6.4, IH, 3.87, t, J=7.0, 2H, 1.81-1.75, m, 2H, 1.50-1.45 m, 5H(contains dublet, J=6.4), 0.93, t, J=7.5, 3H.
Example 39
2-Chloro- 10-pentyl- 1 OH-phenothiazine
A sample of 2-chlorophenothiazine, 1.03 g, was placed in a 20 by 150 ml tube with a stirring bar. Then pentyl bromide, 1 ml, was added, followed 50% 50% tetrabutylammonium bromide, 0.2 ml, 50% sodium hydroxide, 1 ml, and toluene, 2 ml. The tube was capped with a rubber septa, and placed under nitrogen. The mixture was warmed to reflux for 4 hours. The mixture was cooled to room temperature, and hexanes, 20 ml, and water, 5 ml was added. The layers were separated, and the hexanes layer passed through a cotton plug to remove solids. The tube was rinsed with toluene to remove solids. The hexanes and toluene fractions were combined and evaporated. The resulting orange oil was passed through flash silica, a 2 by 1 inch column, with hexanes to give the named compound as an orange oil.
Hl NMR 500 MHz, (CDC13), 7.16-7.11, m 2H, 7.01, d, j=8.0, IH, 6.92, t, J=7.6, IH, 6.88-6.84, m, 2H, 6.81, D, J=2.0, IH, 3.80, t, J=7.2, 2H, 1.82-1.76, m, 2H, 1.41-1.25, m, 4H, 0.89, t, j=7.1, 3H
Example 40
2-Chloro- 10-propyl- 1 OH-phenothiazine
As for example 39, except that propyl bromide was used.
Hl NMR 500 MHz, (CDC13), 7.15-7.11, m 2H, 7.02, d, J=8.24, IH, 6.94-6.91, m, IH, 6.89-6.84, m, 2H, 6.81, d, J=2, IH, 3.78, t, J=7.1, 2H, 1.85-1.78, m, 2H, 1.01, t, J=7.4, 3H
Example 41
2-Chloro- 10-(3 -methylbutyl)- 1 OH-phenothiazine As for example 39, except 3-methylbutylbromide was used. Hl NMR 500 MHz, (CDC13), 7.17-7.11, m, 2H, 7.02, d, J=8.1, IH, 6.93, dd, J= 6.45, 7.4, IH, 6.89-6.86, m, 2H, 6.83, d, J=2.0, IH, 3.83, t, J=7.2, 2H, 1.79-1.72, m, IH, 1.71-1.66, m, 2H, 0.96, d, J=6.5, 6H.
Example 42
2-Chloro- 10-butyl- 1 OH-phenothiazine As for example 39, except butyl bromide was used.
Hl NMR 500 MHz, (CDC13), 7.16-7.11, m, 2H, 7.01, d, J=8.2, IH, 6.94-6.92, m, IH, 6.91-6.85, m, 2H, 6.82, d, J=2, IH, 3.81, t, J=7.1, 2H, 1.80-1.75, m, 2H, 1.49-1.42, m, 2H, 0.95, t, J=7.4, 3H
Examples 43 and 44
10-(z-3chloropropene)-2-chlorophenothiazine and 10-(e-3chloropropene)-2-chlorophenothiazine A sample of 2-chlorophenothiazine, 0.229 g, was placed in a 16X150 m tube with a stirring bar. The tube was sealed with septa, and flushed with nitrogen. Then tetrahydrofuran, 2 ml, was added, followed by IM potassium-t-butoxide in Tetrahydrofuran, 1 ml. The mix was stirred at 0 C for 1 minute, the 1,3- dichloropropene, 0.11 ml was added. The mix was stirred at 0 C for 30 minutes, and then a room temperature for 2 days. TLC of the reaction after 2 days with hexanes on silica showed 2 new higher RF spots relative to the 2-chlorophenothiazine. The reaction was treated with water, 10 ml, hexanes, 4 ml and ethyl acetate, 10 ml. The layers were separated, and the organic layer was evaporated to give 0.29 g of oil that solidifies on standing. The waxy solids were dissolved in 10 ml of hexanes, and chromatographed on a silica column, 5X1 inch, with hexanes, 400 ml, and then 5% dichloromethane in hexanes, 200 ml. Fractions were examined with hexanes on silica, and pure fractions of the more mobile and less mobile products were individually pooled and evaporated. NMR allowed the assignment of more mobile compound, example 43, as 10-(z-3chloropropene)-2-chlorophenothiazine. Hl NMR 500 MHz, (CDC13), 7.16-7.10, m, 2H, 7.02, D, J=8.2, IH, 6.94, td, J=7.5, 0.9, IH, 6.90, dd, J=8.1, 2.0, IH, 6.77, d, J=7.6, IH, 6.35, dt, J=7.2, 2.3, IH, 5.98, dt, 1=12, 5.3, IH, 4.60, dd, J=5.3, 2.3, 2H. And the less mobile product, example 44, was assigned as 10-(e-3chloropropene)-2- chlorophenothiazine .
Hl NMR 500 MHz, (CDC13), 7.15-7.10, m, IH, 7.08, dd, J=9.0, 1.4, IH, 6.98, d, J=8.0, IH, 6.93, dt, J=8.3, 0.8, IH, 6.88, dd, J= 7.9, 2.0, IH, 6.81, d, J=8.3, IH, 6.75, d, J=2.0, IH, 6.20, dt, J=13.6, 1.8, IH, 6.09, dt, 13.6, 4.6, IH, 4.46, dd, J=4.6, 1.8, 2H
Example 45
1 -(10H-Phenothiazin-2-yl)-ethanone O-ethyl-oxime A sample of 2-acetylphenothiazine, 120 mg, and O-ethylhydroxylamine hydrochloride, 65 mg, was in a 13 X 100 ml tube with ethanol, 1 ml, and pyridine, 50 ul. The mixture was warmed to 50 C and stirred. After one hour, TLC on silica with 1 :20 ethyl acetate / dichloromethane showed 2-acetylphenothiazine consumed, and two new higher RF spots. The mix was diluted with ethanol, 3 ml, then water, 1 ml. The mixture was allowed to cool to room temperature, and stand 30 minutes. The resulting solids were collected by filtration, washed with 1 :3 water / ethanol, and air dried to provide the named compound, mp 108.5-109 C
Example 46
1 -(10H-Phenothiazin-2-yl)-ethanone O-methyl-oxime As for example 45, except with O-methylhydroxylamine hydrochloride.
Named product mp 148-149 C
Example 47 (1087-02) 9-(isopropyl)carbazole A sample of carbazole, 5.5 g, was placed in a 250 ml flask with magnetic stirring bar. Then isopropyl bromide, 10 ml, 50 % aqueous sodium hydroxide, 10 ml, tetrabutylammonium hydroxide, 0.22g, and toluene, 10 ml were added. The mixture was placed under N2, and warmed in a 70 0C oil bath. After 18 hours, the mixture was cooled to room temperature. The mix was treated with 40 ml of hexanes and 50 ml of water, and the resulting solids collected by filtration. TLC of solids and filtrate organic layer showed new spot RF 0.4 with 10% Ethyl acetate in hexanes on silica. The solids were combined with the organic layer. The aqueous layer was extracted once with 40 ml of ethyl acetate. The combined organic layers were combined and evaporated in vacuo. The residue was taken up in 120 ml of methanol at reflux, and then cooled with an ice/water bath. The resulting solids were collected by filtration. TLC of the solids on silica with 1 :10 ethyl acetate/hexanes showed an RF of 0.5, and carbazole showed an RF of of 0.2. The yield of solids was 5 g.
Example 48
9-(isopropyl)carbazole-3-carboxaldehyde
A sample of 9-(isopropyl)carbazole (2.09 g, 10 mmol) was dissolved in DMF, 8ml, cooled to 0 0C, then phosphorus oxychloride (1.38 ml, 15 mmol) was added drop wise and the reaction mixture was stirred at 0 0C for 30 min. The mixture was brought to r.t., and heated to 100 0C for 4 hrs. The TLC of reaction mixture, with 1 :1 dichloromethane/hexane, showed a new spot with lower Rf. The mixture was treated with 100 ml Of H2O for 3 hrs, resulting gummy solids. The mixture was extracted with EtOAc (2 x 150 ml), the organic layers combined, washed with H2O and dried over anhyd.MgSO4. The solvents were evaporated in vacuo and the residue was purified by column chromatography to obtain 1.96 g of the product.
1H NMR 500 MHz CDCl3: 8.62, d, J=1.5, IH, 8.18-8.16, m, IH, 7.98, dd, J=2, 8.6, IH, 7.60-7.52, m, 2H, 7.52-7.49, m, IH, 7.33-7.30, m, IH, .5.09-4.99, m, IH, 1.74, d, J=7, 6H.
Example 49 (1062-103)
9-Ethyl-9H-carbazole-3-carboxylic acid
A sample of 9-Ethyl-3-carbazolecarboxaldehyde, 5.Og (22.4 x 10"3 mol), tetrahydrofuran, 23ml, were combined in a 100ml round bottom flask with magnetic stirring bar. The mix was cooled to 00C, followed by addition of 35% H2O2 aq, 2.24ml (22.4 x 10"3 mol), and 0.67M NaH2PO4 aq, 10ml (6.67 x 10"3 mol). A 1.0 M NaClO3aq solution, 33ml (33.6 x 10"3 mol), was added drop-wise via addition funnel. The reaction mixture was returned to room temperature after addition was complete. After 18 hours, TLC with 1 :9 methanol / dichloromethane showed complete conversion to new spot with lower R/ Treated mixture with sodium hydrosulfite then acidified with HCl. Vacuum filtered off solvents. Placed solids in 200ml beaker, treated solids with warm ethyl acetate, 40ml, cooled to room temp, collected resulting solids by filtration, rinsed with hexanes to aide drying. Yielded off-white solids, 4.95 g. TLC of solids on silica with 1 :1 ethyl acetate / hexanes showed an Rf of 0.3, the 9-Ethyl-3- carbazolecarboxaldehyde showed an Rf of 0.6. NMR 500 MH D6DMSO: 8.79, d, IH, 8.28, d, IH, 8.08, dd, IH, 7.68, q, 2H,
7.52-7.49, m, IH, 7.27, q, IH, 4.49, q, 2H, 1.33, t, 3H.
Example 50 (1062-88) 9-Ethyl-9H-carbazole-3-carboxylic acid propylamide A sample of 9-(ethyl) carbazole-3-carboxylic acid, 500mg (2.09 x 10"3 mol), HATU, 795mg (2.09 x 10"3 mol), were combined in a 50ml round bottom flask with magnetic stirring bar. The flask was capped with a rubber septum, evacuated then back filled with nitrogen. Anhydrous N,N-Dimethylformamide, 5mL, was added via syringe followed by triethylamine, 600μl (4.18 x 10" mol). Stirred mixture for 10 minutes at room temperature, followed by addition of propylamine, 176μl (2.09 x 10" mol). After 4 hours at room temperature reaction was complete. Diluted mix with 50ml of ethyl acetate, washed with NaHCO3aq, brine, evaporated organic layer. Dissolved residue in warm ethyl acetate, allowed to cool, then placed in -200C freezer for 3 hours. The resulting crystals were collected to provide 9-(ethyl) carbazole-3-propylcarboxamide, 350mg.
NMR 500 MH D6DMSO: 8.70, d, IH, 8.42, t, IH, 8.18, d, IH, 7.99, dd, IH, 7.66 dd, 2H, 7.49, t, IH, 7.26, t, IH, 4.48, q, 2H, 3.27, q, 2H, 1.58, m, 2H, 1.33, t, 3H, 0.93, t, 3H.
Example 51 (1062-110)
9-Ethyl-9H-carbazole-3-carboxylic acid N-2-ethyl morpholine
The synthesis was carried out using the aforementioned method in Example 50 with the exception of N-(2-aminoethyl) morpholine in place of propylamine. TLC with 1 :9 methanol/dichloromethane showed new spot with higher Rf. Removed solvents by rotary evaporation, the resulting solids were recrystallized using hot ethyl acetate to provide 9-Ethyl-9H-carbazole-3-carboxylic acid N-2-ethyl morpholine.
NMR 500 MH D6DMSO: 8.69, d, IH, 8.38, t, IH, 8.18, d, IH, 7.99-7.97, dd, IH, 7.66-7.64, m, 2H, 7.51-7.48, m, IH, 7.27-7.24, m, IH, 4.83, q, 2H, 3.58, t, 4H, 3.45, q, 2H, 2.52, m, 2H, 2.44, s, 4H, 1.32, t, 3H.
Example 52 (1062-111) 9-Ethyl-9H-carbazole-3-carboxylic acid (3-morpholin-4-yl-propyl)-amide
The synthesis was carried out using the aformentioned method in Example 50 with the exception of N-(3-Aminopropyl)morpholine in place of propylamine. TLC with 1 :9 methanol/dichloromethane showed new spot with higher Kf. The mix was column purified using Biotage SP4™ 12+M silica cartridge with methanol / dichloromethane solvent system. The solvents were removed by rotary evaporation, followed by hexane rinse. The resulting solids were collected to provide 9-Ethyl-9H-carbazole-3-carboxylic acid (3-morpholin-4-yl-propyl)-amide.
NMR 500 MH D6DMSO: 8.68, d, IH, 8.46, t, IH, 8.18, d, IH, 7.99, dd, IH, 7.65, dd, 2H, 7.51-7.48, m, IH, 7.25, t, IH, 4.48, q, 2H, 3.57, t, 4H, 3.35, q, 2H, 2.38- 2.35, m, 6H, 1.75-1.70, m, 2H, 1.32, t, 3H.
Example 53 (1062-105)
9-Ethyl-9H-carbazole-3-carboxylic acid [3-(4-methyl-piperazin-l-yl)-propyl]- amide The synthesis was carried out using the aformentioned method in Example 50 with the exception of l-(3-Aminopropyl)-4-methylpiperazine in place of propylamine. After 4 hours TLC with 1 :9 methanol / dichloromethane showed a new spot with lower Rf. Evaporated solvents, dissolved resulting oil in dichloromethane, washed with NaHC03aq, brine, evaporated organic layer. Freeze dried resulting oil. After 3 hours, solids were collected to provide 9-Ethyl-9H-carbazole-3-carboxylic acid [3-(4-methyl- piperazin- 1 -yl)-propyl]-amide.
NMR 500 MH D6DMSO: 8.68, d, IH, 8.48, t, IH, 8.19, d, IH, 7.99, q, IH, 7.68, t, 2H, 7.51-7.48, m, IH, 7.27, q, 1H4.49, q, 2H, 4.10, d, 2H, 3.17, d, 2H, 2.37- 2.20, m, 8H, 2.12, d, 3H, 1.74-1.68, m, 2H, 1.34, t, 3H.
Example 54 (1062-127)
9-Ethyl-9H-carbazole-3-carboxylic acid methylamide The synthesis was carried out using the aformentioned method in Example 50 with the exception of heptamethyldisilizane in place of propylamine. After 18 hours TLC with 1 :9 methanol / dichloromethane showed new spot with higher Rf. Diluted mix with dichloromethane, washed with 0.1M HCl, NaHCC>3aq, H2O, brine, evaporated organic layer. The resulting mixed solids were column purified using Biotage SP4™ 12+M silica cartridge with methanol / dichloromethane solvent system. Evaporated solvents, the solids were collected to provide 9-Ethyl-9H-carbazole-3-carboxylic acid methylamide.
NMR 500 MH D6DMSO: 8.68, d, IH, 8.41, d, IH, 8.18, d, IH, 7.99, q, IH, 7.66, q, 2H, 7.51, t, IH, 7.26, t, IH, 4.49, q, 2H, 2.85, d, 3H, 1.34, t, 3H.
Example 55 (1062-176)
9-Ethyl-9H-carbazole-3-carboxylic acid phenylethylamide The synthesis was carried out using the aformentioned method in Example 50 with the exception of phenylethylamine in place of propylamine. After 18 hours TLC with 1 :9 methanol / dichloromethane showed new spot with higher Rf. Diluted mix with ethyl acetate, washed with 1.0 M HCl, NaHCO3aq, brine, dried over MgSO4.
Evaporated organic layer, collected solids to provide 9-Ethyl-9H-carbazole-3- carboxylic acid phenylethylamide. NMR 500 MH D6DMSO: 8.68, d, IH, 8.55, t, IH, 8.17, d, IH, 7.98, q, IH,
7.66, d, 2H, 7.51, t, IH, 7.32-7.24, m, 5H, 7.22-7.19, m, IH, 4.49, q, 2H, 3.56, q, 2H,
2.91, t, 2H, 1.33, t, 3H.
Example 56 (1062-159) 4- [(9-Ethyl-9H-carbazole-3-carbonyl)-amino] -butyric acid ethyl ester
A sample of 9-Ethyl-9H-carbazole-3-carboxylic acid (Example 49), l.Og (4.18 x 10"3 mol), HATU, 1.5g (4.18 x 10"3 mol), and magnetic stirring bar were placed in a 50ml round bottom flask. The flask was capped with rubber septum, evacuated, and back filled with nitrogen. Anhydrous N,N-dimethylformamide, 10ml, was added via syringe followed by triethylamine, 1.8ml (12.5 x 10 3 mol). Stirred mixture for 10 minutes at room temperature, followed by addition of ethyl 4-aminobutyrate -HCl, 701 mg (4.18 x 10~3 mol). After 18 hours TLC in 1 :9 methanol / dichloromethane showed a new spot with higher Rf. Dissolved mix in ethyl acetate, washed with NaHCθ3aq, brine, evaporated organic layer. Chromatographed the resulting residue using Biotage SP4™ 25+M silica column with methanol / dichloromethane solvent system. The resulting oil was dissolved in hot ethyl acetate, allowed to cool, the solids collected provided 4- [(9-Ethyl-9H-carbazole-3-carbonyl)-amino] -butyric acid ethyl ester.
Example 57 (1062-156)
3 -[(9-Ethyl-9H-carbazole-3-carbonyl)-amino] -propionic acid ethyl ester
The synthesis was carried out using the aformentioned method in Example 56 with the exception of β-alanine ethyl ester -HCl in place of 4-aminobutyrate -HCl. After 18 hours TLC with 1 :9 methanol / dichloromethane showed new spot with higher Rf. Diluted mix with ethyl acetate, washed with NaHCC>3aq, brine, evaporated organic layer. Column purified the resulting oil using Biotage SP4™ 25+M silica column with methanol / dichloromethane solvent system. The resulting solids provided 3-[(9-Ethyl- 9H-carbazole-3-carbonyl)-amino]-propionic acid ethyl ester.
NMR 500 MH D6DMSO: 8.69, d, IH, 8.54, t, IH, 8.18, d, IH, 7.99, q, IH, 7.66, q, 2H, 7.51-7.47, m, IH, 7.27, t, IH, 4.49, q, 2H, 4.10, q, 2H, 3.57, q, 2H, 2.64, t, 2H, 1.33, t, 3H, 1.19, t, 3H.
Example 58 (1062-158)
[9-Ethyl-9H-carbazole-3-carbonyl] -amino] -acetic acid ethyl ester The synthesis was carried out using the aforementioned method in Example 56 with the exception of glycine ethyl ester -HCl in place of 4-aminobutyrate -HCl. After 18 hours TLC with 1 :9 methanol / dichloromethane showed new spot with higher Rf. Diluted mix with ethyl acetate, washed with NaHCC>3aq, brine, dried over over MgSO4. Evaporated organic layer, chromtographed the resulting oil using Biotage SP4™ 25+M silica column with methanol / dichloromethane solvent system. Removed solvents by rotary evaporation, the resulting solids provided [9-Ethyl-9H-carbazole-3-carbonyl]- amino]-acetic acid ethyl ester. NMR 500 MH D6DMSO: 8.91, t, IH, 8.74, d, IH, 8.19, d, IH, 8.02, dd, IH,
7.69, q, 2H, 7.52-7.49, m, IH, 7.28, t, IH, 4.50, qm 2H, 4.16, q, 2H, 4.05, d, 2H, 1.34, t, 3H, 1.23, t, 3H. Example 59 (1062-172)
4- [(9-Ethyl-9H-carbazole-3-carbonyl)-amino] -butyric acid A sample of 4-[(9-Ethyl-9H-carbazole-3-carbonyl)-amino]-butyric acid ethyl ester (Example 56), 314mg (0.890 x 10"3 mol), tetrahydrofuran, 2ml, 1.0 M NaOHaq, 1.4 ml (1.34 x 10" mol), was placed in a 15ml round bottom flask with magnetic stirring bar. The mixture was stirred at room temperature. After 4 hours, TLC with 1 :9 methanol / dichloromethane showed a new spot with lower Kf. The mix was diluted with water, 10ml, and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and evaporated to remove solvent. The resulting clear oil was dissolved in warm methanol, and allowed to cool. The resulting solids were collected to provide 4- [(9-Ethyl-9H-carbazole-3-carbonyl)-amino] -butyric acid.
NMR 500 MH D6DMSO: 8.70, d, IH, 8.47, t, IH, 8.18, d, IH, 8.00, dd, IH, 7.65, d, 2H, 7.51-7.47, m, IH, 7.27, q, IH, 4.49, q, 2H, 3.35, q, 2H, 2.33, t, 2H, 1.83- 1.77, m, 2H, 1.33, t, 3H.
Example 60 (1062-166)
[9-Ethyl-9H-carbazole-3-carbonyl]-amino]-acetic acid
The synthesis was carried out using the aformentioned method in Example 59 with exception [9-Ethyl-9H-carbazole-3-carbonyl]-amino]-acetic acid ethyl ester used in place of 4- [(9-Ethyl-9H-carbazole-3-carbonyl)-amino] -butyric acid ethyl ester. After 4 hours TLC with 1 :9 methanol / dichlormethane showed a new spot with lower Kf. Treated mix with 1.0 M HCl, until pH 2, extracted with ethyl acetate, washed organics with brine, dried over MgSO4. Evaporated organic layer, the resulting solids provided [9-Ethyl-9H-carbazole-3-carbonyl]-amino]-acetic acid.
NMR 500 MH D6DMSO: 8.18, t, IH, 8.74, d, IH, 8.19, d, IH, 8.03, dd, IH, 7.69, q, 2H, 7.52-7.49, m, IH, 7.28, t, IH, 4.50, q, 2H, 4.03-3.98, m, 2H, 1.35, t, 3H.
Example 61 (1062-167) 3 -[(9-Ethyl-9H-carbazole-3-carbonyl)-amino] -propionic acid
The synthesis was carried out using the aformentioned method in Example 59 with exception of 3- [(9-Ethyl-9H-carbazole-3-carbonyl)-amino] -propionic acid ethyl ester in place of 4- [(9-Ethyl-9H-carbazole-3-carbonyl)-amino] -butyric acid ethyl ester. After 4 hours TLC with 1 :9 methanol / dichloromethane showed a new spot with lower Rf. Treated mix with 1.0 M HCl, until pH 2, extracted with ethyl acetate, washed organics with brine, dried over MgSO4. Evaporated organic layer, the resulting solids provided 3 -[(9-Ethyl-9H-carbazole-3-carbonyl)-amino] -propionic acid.
NMR 500 MH D6DMSO: 8.70, d, IH, 8.52, t, IH, 8.18, d, IH, 8.00, dd, IH, 7.66, q, 2H, 7.51-7.47, m, IH, 7.27, t, IH, 4.48, q, 2H, 3.55, q, 2H, 2.59, t, 2H, 1.33, t, 3H.
Example 62 (1062-169)
9-Ethyl-9H-carbazole-3carboxylic acid [2-(4-methyl-piperazin- 1 -yl)-2-oxo- ethyl] -amide
A sample of [9-Ethyl-9H-carbazole-3-carbonyl]-amino]-acetic acid (Example 60), lOOmg (0.337 x 10"3 mol), HATU, 128mg (0.337 x 10"3 mol), were combined in a 15ml round bottom flask with magnetic stirring bar. The flask was capped with a rubber septum, evacuated then back filled with nitrogen. Anhydrous N, N- Dimethylformamide, 2ml, was added via syringe followed by triethylamine, 94μl (0.674 x 10"3 mol). Stirred mixture for 10 minutes at room temperature, followed by addition of 4-methylpiperidine, 32μl (0.270 x 10"3 mol). After 8 hours TLC showed a new spot with higher Rf Diluted mix with ethyl acetate, washed with NaHCO3aq, brine, dried over MgSO4, evaporated organic layer. Chromatographed the resulting oil using Biotage SP4™ 12+M silica column with methanol / dichloromethane solvent system. The resulting solids provided 9-Ethyl-9H-carbazole-3carboxylic acid [2-(4-methyl- piperazin- 1 -yl)-2-oxo-ethyl]-amide. NMR 500 MH D6DMSO: 8.74, s, IH, 8.48, t, IH, 8.19, d, IH, 8.02, d, IH,
7.68, t, 2H, 7.51, t, IH, 7.27, t, IH, 4.50, q, 2H, 4.35, d, IH, 4.18, d, 2H , 3.91, d, IH, 3.04, t, IH, 2.61, t, IH, 1.69-1.58, m, 3H, 1.34, t, 3H, 1.12, t, IH, 0.98-0.89, m, 4H.
Example 63 (1062-170) 9-Ethyl-9H-carbazole-3-carboxylic acid [3-(4-methyl-piperazin-l-yl)-3-oxo- propyl]-amide
The synthesis was carried out using the aforementioned method in Example 62 with the exception of 3- [(9-Ethyl-9H-carbazole-3-carbonyl)-amino] -propionic acid (Example 61) in place of [9-Ethyl-9H-carbazole-3-carbonyl]-amino]-acetic acid. After 8 hours TLC showed new spot with higher Rf. Diluted mix with ethyl acetate, washed with NaHCO3aq, brine, dried over MgSO4, evaporated organic layer. Chromatographed the resulting oil using Biotage SP4™ 12+M silica column with methanol / dichloromethane solvent system. The resulting oil provided 9-Ethyl-9H-carbazole-3- carboxylic acid [3-(4-methyl-piperazin- 1 -yl)-3-oxo-propyl]-amide.
NMR 500 MH D6DMSO: 8.69, s, IH, 8.48, t, IH, 8.18, d, IH, 7.98, t, IH, 7.66, d, 2H, 7.51, t, IH, 7.27, t, IH, 4.49, q, 2H, 4.39, d, IH, 3.88, d, IH, 3.52, q, 2H, 3.0, q, IH.
Example 64 (1062-171)
9-Ethyl-9H-carbazole-3-carboxylic acid (2-carbomoyl-ethyl)-amide
The synthesis was carried out using the aformentioned method in Example 62 with the exception of ammonium chloride in place of 4-methylpiperidine. After 18 hours TLC with 1 :9 methanol / dichloromethane showed a new spot with higher Kf. Diluted mix with ethyl acetate, washed with NaHCO3aq, brine, dried over MgSO4, evaporated organic layer. The resulting oil was dissolved in hot methanol, allowed to cool, the solids collected provided 9-Ethyl-9H-carbazole-3-carboxylic acid (2- carbomoyl-ethyl)-amide.
NMR 500 MH D6DMSO: 8.69, d, IH, 8.47, t, IH, 8.18, d, IH, 7.99, q, IH, 7.65, d, 2H, 7.51-7.48, m, IH, 7.37, s, IH, 7.27, q, IH, 6.84, s, IH, 4.49, q, 2H, 3.52, q, 2H, 2.52-2.49, m, 6H, 2.41, t, 2H, 1.33, t, 3H.
Example 65 (1062-120)
9-Ethyl-9H-carbazole-3-carboxylic acid methyl ester A sample of 9-Ethyl-9H-carbazole-3-carboxylic acid (Example 49), lOOmg (0.416 x 10"3 mol), was placed in a 15ml round bottom flask with a magnetic stirring bar. The flask was capped with a rubber septum, evacuated then back filled with nitrogen. Added methanol, 10ml, via syringe, cooled mix to 00C, followed by addition of 95.5% H2SO4, lOOμl. Attached distillation condenser, heated to 800C, distilled off methanol. Diluted resulting residue with water, extracted with dichloromethane, evaporated organic layer. Column purified mixed material using Biotage SP4™ 12+M silica cartridge with methanol / dichloromethane solvent system. Removed solvent, collected resulting solids to provide 9-Ethyl-9H-carbazole-3-carboxylic acid methyl ester. NMR 500 MH D6DMSO: 8.18, d, IH, 8.31, d, IH, 8.08, q, IH, 7.2, q, 2H,
7.54,-7.50, m, IH, 7.28, q, IH, 4.51, q, 2H, 3.89, s, 3H, 1.34, t, 3H.
Example 66 (1062-87)
9-Ethyl-9H-carbazole-3-carboxylic acid isopropylamide A sample of 9-(ethyl) carbazole-3-carboxylic acid, 200mg (0.832 x 10"3 mol),
DMT-MM, 276mg (0.998 x 10"3 mol), methanol, 2ml, were combined in a 20ml vial with a magnetic stirring bar. The vial was evacuated then back filled with nitrogen. Triethylamine, 361mg (2.49 x 10"3 mol), was added to the solution then stirred for 10 minutes at room temperature, followed by addition of isopropylamine, 84μl (0.998 x 10"3 mol). After 18hrs TLC with 1 :9 methanol/dichloromethane showed a new spot with higher Rf. Removed the solvent by rotary evaporation, diluted residue in dichloromethane. Washed organic layer with HCl, H2O, NaHCO3aq, brine, then dried over MgSO4. Evaporated organic layer, purified the resulting mixed solids using Biotage SP4™ 12+M silica column with hexane/ethyl acetate solvent system. The resulting oil was dissolved in hot ethyl acetate, allowed to cool, and the solids were collected to provide 9-Ethyl-9H-carbazole-3-carboxylic acid isopropylamide.
NMR 500 MH D6DMSO: 8.70, d, IH, 8.17, t, 2H, 7.99, dd, IH, 7.64, q, 4H, 7.49, t, IH, 7.25, t, IH, 4.7, q, 2H, 4.18-4.14, m, IH, 1.30, t, 3H, 1.20, t, 6H.
Example 69
9-Isopropyl-9H-carbazole-3-carboxylic acid
The named compound of the example was prepared from 9-Isopropyl-9H- carbazole-3-carboxaldehyde (example 48) following the method of example 49.
Example 70 (1062-148)
3 -[(9-Isopropyl-9H-carbazole-3-carbonyl)-amino] -propionic acid ethyl ester A sample of 9-Isopropyl-9H-carbazole-3-carboxylic acid, l.Og (3.95 x 10" mol), HATU, 1.5g (3.95 x 10~3 mol), and magnetic stirring bar were placed in a 50ml round bottom flask. The flask was capped with a rubber septum, evacuated then back filled with nitrogen. Anhydrous N,-N-Dimethylformamide, 8ml, was added via syringe followed by triethylamine, 1.7ml (11.9 x 10~3 mol). Stirred mixture for 10 minutes at room temperature, followed by addition of β-alanine ethyl ester -HCl, 0.728g (4.74 x 10"3 mol). After 4 hours TLC with 1 :9 methanol / dichloromethane showed a new spot with higher Rf. Diluted mix with ethyl acetate, washed with NaHCO3aq, brine, dried over MgSO4, evaporated organic layer. Resulting solids were collected to provide 3- [(9-Isopropyl-9H-carbazole-3-carbonyl)-amino] -propionic acid ethyl ester. NMR 500 MH D6DMSO: 8.68, d, IH, 8.53, t, IH, 8.17, d, IH, 7.95, dd, IH,
7.75, d, 2H, 7.47, q, IH, 7.25, t, IH, 5.18-5.12, m, IH, 4.10, q, 2H, 3.57, q, 2H, 2.63, t, 2H, 1.64, t, 6H, 1.20, t, 3H.
Example 71 (1062-150) 4-[9-Isopropyl-9H-carbazole-3-carbonyl]-amino]-butyric acid ethyl ester
The synthesis was carried out using the aforementioned method in Example 70 with the exception of ethyl 4-aminobutyrate ΗC1 in place of β-alanine ethyl ester -HCl. After 4 hours TLC with 1 :9 methanol / dichloromethane showed a new spot with higher Rf. Diluted mix with ethyl acetate, washed with NaHCO3aq, brine, dried over MgSO4, evaporated organic layer. The resulting mixed solid was dissolved in warm ethly acetate / hexanes mixture (4:1), allowed to cool, and the collected solids provided 4-[9- Isopropyl-9H-carbazole-3-carbonyl]-amino]-butyric acid ethyl ester. NMR 500 MH D6DMSO: 8.69, d, IH, 8.46, t, IH, 8.18, d, IH, 7.96, dd, IH, 7.75, dd, 2H, 7.48-7.44, m, IH, 7.25, t, IH, 5.18-5.12, m, IH, 4.07, q, 2H, 2.40, t, 2H, 1.85-1.80, m, 2H, 1.64, t, 6H, 1.19, t, 3H.
Example 72 (1062-147)
9-Isopropyl-9H-carbazole-3-carboxylic acid (2-morpholin-4-yl-ethyl)-amide The synthesis was carried out using the aforementioned method in Example 70 with the exception of 2-morpholinoethylamine in place of β-alanine ethyl ester -HCl. After 4 hours TLC with 1 :9 methanol / dichloromethane showed new spot with higher Rf Dissolved mix in ethyl acetate, washed with NaHCO3aq, HCl, brine, dried over MgSO4, evaporated organic layer. The resulting solids were collected to provide 9- Isopropyl-9H-carbazole-3-carboxylic acid (2-morpholin-4-yl-ethyl)-amide.
NMR 500 MH D6DMS0: 8.68. d, IH, 8.38, s, IH, 8.25, d, IH, 7.97, dd, IH, 7.77. d, 2H, 7.48-7.44, m, IH, 7.26, t, IH, 5.18, q, IH, 3.65, s, 4H, 3.46, d, 2H, 3.33, dd, 2H, 2.45, s, 4H, 1.64, d, 6H.
Example 73 (1062-68)
4-(3-Bromo-propoxy)-isophthalic acid dimethyl ester
A sample of dimethyl 5-hydroxyisophthalate, 3.Og (14.3 x 10"3 mol), acetone (dried with K2CO3), 14ml, 1,3-dibromopropane, 1.75ml (17.1 x 10"3 mol), were combined in a 100ml round bottom flask with magnetic stirring bar. Anhydrous potassium carbonate, 2.4g (17.1 x 10"3 mol), was added followed by flush with nitrogen. After 8 hours TLC of 1 :4 ethyl acetate / hexanes showed a new spot with higher Rf. Diluted the mix with toluene, 40ml, filtered off solids, evaporated filtrate. The resulting oil was dissolved in anisole, 8ml, stirred for 5 minutes, and evaporated under vacuum. Repeated anisole wash, followed by evaporation. Column purified the resulting oil using Biotage SP4™ 25 +M silica cartridge with hexane / ethyl acetate solvent system. Evaporation provided solids, 4-(3-Bromo-propoxy)-isophthalic acid dimethyl ester. NMR 500 MH D6DMSO: 8.08, t, IH, 7.70, d, 2H, 4.21, t, 2H, 3.88, s, 6H, 3.70, t, 2H, 2.29, t, 2H.
Example 74 (1062-69) 4-(3-Carbazol-9-yl-propoxy)-isophthalic acid dimethyl ester A sample of carbazole, 200mg (1.19 x 10" mol), 4-(3-Bromo-propoxy)- isophthalic acid dimethyl ester (Example 73), 394mg (1.31 x 10"3 mol), anhydrous tetrahydrofuran, 2ml, were combined in a 20ml vial with magnetic stirring bar. The vial was capped, evacuated, then back filled with nitrogen. Potassium tert-butyloxide, 1.4ml IM m THF (1.43 x 10"3 mol), was added via syringe. After 18 hours TLC with 1 :4 ethyl acetate / hexanes showed new spot with lower Rf. Diluted mix with water, 4ml, extracted with dichloromethane, dried over MgSO4, evaporated organic layer. The resulting mixed solids were chromatographed using Biotage SP4™ 12+M silica cartridge with ethyl acetate / hexanes solvent system. Evaporated solvents, collected solids provided 4-(3-Carbazol-9-yl-propoxy)-isophthalic acid dimethyl ester.
NMR 500 MH D6DMS0: 8.14, d, 2H, 8.05, t, IH, 7.61, q, 4H, 7.39-7.36, m, 2H, 7.18, q, 2H, 4.61, t, 2H, 4.06, t, 2H, 3.87, s, 6H, 2.27, q, 2H.
Example 75 (1062-84)
5-Acetyl-2-(3-bromo-propoxy)-benzoic acid methyl ester
A sample of 1,3-dibromopropane, 3.7g (18.5 x 10"3 mol), tertbutylammonium iodide, 569mg (1.54 x 10"3 mol), acetone (dried over KCO3), 15.5ml, were combined in a 100ml round bottom flask with magnetic stirring bar. Stirred mix for 5 minutes at room temperature, followed by addition of methyl 5-acetylsalicylate, 3.0g (15.4 x 10"3 mol), and potassium carbonate, 2.6g (18.5 x 10"3 mol). After 18 hours at room temperature, TLC with 1 :4 ethyl acetate / hexanes showed a new spot with lower Rf. Diluted mix with toluene, 40ml, filtered off solids, evaporated filtrate. Column purified the resulting oil using Biotage SP4™ 25+M silica cartridge with ethyl acetate / hexanes solvent system. Evaporated solvents, resulting solids provided 5-Acetyl-2-(3-bromo- propoxy)-benzoic acid methyl ester.
NMR 500 MH D6DMSO: 8.24, d, IH, 8.14, dd, IH, 7.30, d, IH, 4.26, t, 2H, 3.82, s, 3H, 3.74, t, 2H, 2.55, s, 3H, 2.29-2.24, m, 2H.
Example 76 (1062-85)
5-Acetyl-2-(3-carbazol-9-yl-propoxy)-benzoic acid methyl ester
A sample of 5-Acetyl-2-(3-bromo-propoxy)-benzoic acid methyl ester (Example 75), 871mg (2.63 x 10"3 mol), tert-butylammonium iodide, 660mg (1.79 x 10" mol), anhydrous tetrahydrofuran, 4ml, were combined in a 50 ml round bottom flask with magnetic stirring bar. Stirred mix for 5 minutes at room temperature, followed by addition of carbazole, 400mg (2.39 x 10"3 mol), IMTHF potassium tert-butyloxide soln., 3.0ml (3.0 x 10"3 mol), heated to 5O0C. After 18 hours TLC with 1 :4 ethyl acetate / hexanes showed new spot with lower Rf. Diluted mix with water, 15ml, extracted with dichloromethane, evaporated organic layer. Column purified resulting oil using Biotage SP4™ 25+M silica cartridge with ethyl acetate / hexanes solvent system. Evaporated solvents, collected solids to provide 5-Acetyl-2-(3-carbazol-9-yl-propoxy)-benzoic acid methyl ester.
NMR 500 MH D6DMS0: 8.31, d, IH, 8.14, d, 2H, 8.08, dd, IH, 7.63, d, 2H, 7.38,-7.35, m, 2H, 7.18, t, 2H, 7.13, d, IH, 4.64, t, 2H, 4.07-4.01, m, 2H, 3.94, s, 3H, 2.55, d, 3H, 2.27-2.22, m, 2H.
Example 77 (1062-47)
9-Chlorobutyl-carbazole
A sample of carbazole, 1.5g (8.97 x 10"3 mol), anhydrous tetrahydrofuran, 10ml, were combined in a 100ml round bottom flask with magnetic stirring bar. The mix was cooled to O0C, followed by addition of IM in THF potassium tert-butyloxide, 9ml (9.0 x 10"3 mol). Stirred mix for 5 minutes at O0C, added l-bromo-4-chlorobutane, 1.5ml (13.5 x 10"3 mol), and returned to room temperature. After 3 hours TLC with 1 :4 ethyl acetate / hexanes showed a new spot with higher Kf. Diluted mix with water, 50ml, extracted with ethyl acetate, dried over MgSO4, evaporated organic layer.
Dissolved resulting solids with hot hexanes, 40ml, allowed to cool, collected resulting solids to provide 9-Chlorobutyl-carbazole.
NMR 500 MH D6DMSO: 7.30, d, IH, 7.04, d, IH, 6.93, t, IH, 2.73, t, 2H, 2.62, t, 2H, 1.85-1.76, m, 4H.
Example 78 (1062-49)
9-(4-Benzenesulfonyl-butyl)-9H-carbazole
A sample of 9-(4-Chloro-butyl)-9H-carbazole, 500mg (1.94 x 10"3 mol), sodium iodine, 290mg (1.94 x 10"3 mol), were combined in a 100ml round bottom flask with magnetic stirring bar. The flask was capped with a rubber septum, evacuated, and back filled with nitrogen. Dissolved solids in anhydrous N,N-dimethylformamide, 14ml, stirred for 5 minutes, added benzenesulfmic acid, 480mg (2.91 x 10"3 mol), heated mix to 8O0C. After 18 hours TLC with 1 :4 ethyl acetate / hexanes showed a new spot with lower Rf. Diluted mix with water, extracted with dichloromethane, dried over MgSO4, evaporated organic layer. Dissolved solids in hot ethyl acetate, allowed to cool, collected resulting solids to provide 9-(4-Benzenesulfonyl-butyl)-9H-carbazole.
NMR 500 MH D6DMSO: 8.13, d, 2H, 7.77-7.75, m, 2H, 7.72-7.69, m, IH, 7.60, q, 4H, 7.45-7.42, m, 2H, 7.20, t, 2H. 4.39, t, 2H, 1.83, q, 2H, 1.63-1.56, m, 2H.
Example 79 (1062-117) 8-Chloro-l,2,3,4-tetrahydrocarbazole A sample of 2-chlorophenylhydrazine -HCl, 1.7g (9.5 x 10"3 mol), acetic acid,
2.5ml, cyclohexanone, 984μl, (9.5 x 10" mol), were combined in a 25ml round bottom flask with magnetic stirring bar. Heated mix to reflux at 12O0C for 4 hours then cooled to 4O0C. After 18 hours TLC with 1 :4 ethyl acetate / hexane showed a new spot with higher Rf. Diluted mix with equal parts ethanol / water, stirred for several hours, extracted with ethyl acetate and evaporated organic layer. Column purified using Biotage SP4™ 40+M silica cartridge with ethyl acetate / hexanes solvent system. Freeze dried the resulting oil, collected solids provided 8-Chloro-l,2,3,4- tetrahydrocarbazole.
NMR 500 MH D6DMSO: 7.30. d. IH, 7.04, d, IH, 6.93, t, IH, 2.73, t, 2H, 2.62, t, 2H, 1.98-1.76, m, 4H.
Example 80 (1062-107)
(4-Chlroro-butane- 1 -sulfonyl)-benzene
A sample of l-Bromo-4-chlorobutane, 3.36ml (29.2 x 10"3 mol), benzenesulfmic acid sodium salt, 5.27g (32.0 x 10"3 mol), N,N-dimethylformamide,
30ml, were combined in a 100ml round bottom flask with magnetic stirring bar. Heated mix to 6O0C. After 4 hours TLC with 1 :9 methanol / dichloromethane showed a new spot with higher Rf. Diluted mix with water, 30ml, extracted with dichloromethane, evaporated organic layer. The resulting oil was chromatographed using Biotage SP4™ 40+M silica cartridge with methanol / dichloromethane solvent system. The resulting solids were collected to provide (4-Chlroro-butane-l-sulfonyl)-benzene.
NMR 500 MH D6DMSO: 7.91-7.89, m, 2H, 7.77-7.74, m, IH, 7.68-7.65, m, 2H, 3.36, t, IH, 3.52, t, IH, 3.37,-3.34, m, 2H, 1.88-1.83, m, IH, 1.79, q, IH, 1.70- 1.63, m, 2H.
Example 81 (1062-115)
9-(4-Benzenesulfonyl-butyl)-8-chloro-o-2,3,4,9-tetrahydro-lH-carbazole A sample of 8-Chloro- 1,2,3, 4-tetrahydrocarbazole (Example 79), 200mg (0.972 x 10"3 mol), (4-Chlroro-butane-l-sulfonyl)-benzene (Example 80), 215mg (0.923 x 10"3 mol), were combined in a 15ml round bottom flask with magnetic stirring bar. The flask was capped with a rubber septum, evacuated, and back filled with nitrogen. Anhydrous tetrahydrofuran, 4ml, IM inχHF potassium tert-butyloxide, 1 ml (1.0 x 10" mol), were added via syringe. After 18 hours TLC with 1 :4 ethyl acetate / hexanes showed a new spot with lower Kf. Diluted mix with water, 10ml, extracted with dichloromethane, evaporated organic layer. Column purified the resulting oil using Biotage SP4™ 25+M silica cartridge with ethyl acetate / hexanes solvent system. Collected resulting solids to provide 9-(4-Benzenesulfonyl-butyl)-8-chloro-o-2,3,4,9- tetrahydro- 1 H-carbazole.
NMR 500 MH D6DMSO: 7.83, t, 2H, 7.75, t, IH, 7.65, q, 2H, 7.32, t, IH, 7.04, d, IH, 6.94, t, IH, 4.30, t, 2H, 2.64-2.57, m, 4H, 1.85, t, 2H, 1.77-1.67, m, 4H, 1.57- 1.51, m, 2H.
Example 82 (1038-188)
6-Chloro-l,2,3,4,-tetrahydrocarbazole
The synthesis was carried out using the aforementioned method in Example 79 with exception of 3-chlorophenylhydrazine -HCl in place of 2-chlorophenylhydrazine -HCl. After 18 hours TLC with 1 :4 ethyl acetate / hexanes showed a new spot with higher Rf. Diluted mix in equal parts ethanol and water and stirred for 2 hours. The resulting solids were collected by filtration with aide of 1 : 1 water / ethanol mix to provide 6-Chloro-l ,2,3,4, -tetrahydrocarbazole.
NMR 500 MH D6DMSO: 10.79, s, IH, 7.32, d, IH, 7.25, d, 2H, 6.92, dd, IH, 2.69, t, 2H, 2.60, t, 2H, 1.84-1.75, m, 4H.
Example 83 (1062-54)
6-Chloro-9-(4-phenoxy-butyl)-2, 3, 4, 9-tetrahydro-l H-carbazole A sample of 6-Chloro-2,3,4,9-tetrahydro-l H-carbazole (Example 82), 173mg (0.840 x 10" mol), 4-phenoxybutyl bromide, 289mg (1.26 x 10" mol), were combined in a 15ml round bottom flask with magnetic stirring bar. The flask was capped with a rubber septum, evacuated then back filled with nitrogen. Anhydrous tetrahydrofuran, 2ml, followed by IM in THF potassium tert-butyloxide, 1.3ml (1.3 x 10~3 mol), were added via syringe. After 18 hours TLC with 1 :4 ethyl acetate / hexanes showed a new spot with higher Rf. Diluted mix with water, extracted with ethyl acetate and evaporated organic layer. The resulting residue was dissolved in warm solvent (5% ethyl acetate / 95% hexanes), allowed to cool, collected solids provided 6-Chloro-9-(4- phenoxy-butyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole.
NMR 500 MH D6DMSO: 7.42, d, IH, 7.37, d, IH, 7.27, q, 2H, 7.03, dd, IH, 6.91-6.87, m, 3H, 4.13, t, 2H, 3.95, t, 2H, 2.72, t, 2H, 2.61, t, 2H, 1.86, q, 2H, 1.78, t, 4H, 1.72, q, 2H.
Example 84 (1062-63)
4-[2-(4-Chloro-phenoxy)-ethyl]-l,2,3,4-tetrahydro-cyclopenta[b]indole
The synthesis was carried out using the aforementioned method in Example 83 with exceptions of 1,2,3, 4-tetrahydro-cyclopent-[b]indole and 4-chlorophenyl 2- bromoethyl ether in place of 6-Chloro-2, 3,4, 9-tetrahydro-l H-carbazole and 4- phenoxybutyl bromide respectively. After 18 hours TLC with 1 :4 ethyl acetate / hexanes showed a new spot with higher Rf. Diluted mix with water, extracted with dichloromethane and evaporated organic layer. Column purified the resulting oil using Biotage SP4™ 25+M silica cartridge with ethyl acetate / hexanes solvent system. Collected solids provided 4-[2-(4-Chloro-phenoxy)-ethyl]-l,2,3,4-tetrahydro- cyclopenta[b]indole.
NMR 500 MH D6DMSO: 7.44, d, IH, 7.31-7.26, m, 3H, 7.04-7.01, m, IH, 6.97-6.94, m, IH, 6.89-6.87, m, 2H, 4.45, t, 2H, 4.23, t, 2H, 2.92, t, 2H, 2.75, q, 2H, 2.47, q, 2H.
Example 85 (1058-12)
4-Chloro-5,6,7,8,9,10-hexahydro-cyclohepta[b]indole
The synthesis was carried out using the aforementioned method in Example 79 with exceptions of 2-chloropehnylhydrazine -HCl, cycloheptanone in place of 2- chlorophenylhydrazine -HCl and cyclohexanone respectively. Column purified the resulting oil using Biotage SP4™ 25+M silica cartridge with ethyl acetate / hexanes solvent system. Collected solids to provide 4-Chloro-5,6,7,8,9,10-hexahydro- cyclohepta[b]indole.
NMR 500 MH D6DMSO: 10.94, s, IH, 7.35, d, IH, 7.02, dd, IH, 6.93, t, IH, 2.88, t, 2H, 2.73, t, 2H, 1.85-1.82, m, 2H, 1.70-1.64, m, 4H.
Example 86 (1062-116)
5-(4-Benzenesulfonyl-butyl)-4-chloro-5,6,7,8,9,10-hexahydro- cyclohepta[b]indole
The synthesis was carried out using the aforementioned method in Example 81 with exception of 4-Chloro-5,6, 7,8,9, 10-hexahydro-cyclohepta[b]indole (Example 85) in place of 8-Chloro- 1 ,2,3 ,4-tetrahydrocarbazole. Column purified the resulting oil using Biotage SP4™ 12+M silica cartridge with methanol / dichloromethane solvent system. Collected solids to provide 5-(4-Benzenesulfonyl-butyl)-4-chloro-5,6,7,8,9,10- hexahydro-cyclohepta[b]indole.
Example 87
9-ethylcarbazole-3-carboxaldehyde oxime
A sample of 9-ethylcarbazole-3-carboxaldehyde, 229 mg, hydroxylamine hydrochloride, 170 mg, 4-methylmorpholine, 0.2 ml, and ethanol, 4 ml were combined in a 20 ml vial with a magnetic stirring bar. The vial was warmed with a heat gun to dissolve all solids, and then stirred at room temperature. After 3 hours TLC with 1 :8 ethyl acetate / hexanes showed a new spot, lower RF. The mix was diluted slowly with water, 8 ml, giving gummy solids. The mix was extracted with 6 ml of ethyl acetate, and the organic layer was evaporated. The resulting gum was dissolved hot in ethanol and water, allowed to cool, and the solids collected to provide 9-ethylcarbazole-3- carboxaldehyde oxime, 145 mg.
NMR 500 MH D6DMSO: 10.92, s, IH, 8.32, d, IH, 8.26, s, 1 H, 8.16, d, IH, 7.75 dd, IH, 7.64-7.60, m, 2H, 7.47, dd, 1 H, 7.24-7.20, m, 1 H, 4.45, q, 2 H, 1.32, t, 3H.
Example 88
9-ethylcarbazole-3 -carboxaldehyde oxime O-methyl ether A sample of 9-ethylcarbazole-3-carboxaldehyde, 223 mg, O- methylhydroxylamine hydrochloride, 109 mg, 4-methylmorpholine, 0.11 ml, and THF, 1 ml, then 0.2 ml water were combined in a 20 ml vial. The resulting 2 phase mix was stirred at room temperature. TLC after several hours with DCM on silica showed mostly a new spot, slightly higher RF than SM. The mix was treated with 0.5 ml ethanol to give a slightly cloudy single phase. No solids formed on standing for 2 days. The mix was extracted with 6 ml of hexanes. The organic layer was evaporated in vacuo. The residue was taken in 4 ml of methanol, and stirred 2 hours at room temperature. The solds were collected by filtration to give 9-ethylcarbazole-3- carboxaldehyde oxime O-methyl ether.
NMR 500 MH D6DMSO: 8.36, d, IH, 8.34, s, IH, 8.18, d, IH, 7.74, dd, IH, 7.66-7.62, m, 2H, 7.50-7.46, m, IH, 7.25-7.21, m, IH, 4.6, q, 2H, 3.32, s, 3H, 1.31, T, 3H.
Example 89
Carbazole-2,7-dicarboxylate dimethyl ester
Part A.
2-nitro-4,4'-biphenyldicarboxylate dimethyl ester
A sample of 4,4'-biphenyldicarboxylate dimethyl ester, 2.0 g, was place in a 50 ml 2 neck 24/40 flask with stirring bar. Then trifluoroacetic acid, 10 ml, was added, and the mix was cooled to 0 0C. The cooled mixture was treated with 90% nitric acid, 0.38 ml, and then trifluoroacetic anhydride , 1.91 ml was added dropwise. TLC with 1 :8 ethyl acetate/hexanes on silica ant 30 minutes post TFAA showed some SM, and a new lower RF product. The mix was stirred 1 hour at 0 0C, then 3 hours at room temperature. The mixture was then poured into 100 ml of cold water, giving a gummy precipitate. The mix was treated with 80 ml of ethyl acetate and 20 ml of hexanes. The layers were separated, and the organic layer was washed with 100 ml of water. The organic layer was then stirred with 20 g of sodium bicarbonate in 100 ml of water. The ethyl acetate was evaporated in vacuo. The residue was treated with 100 ml of hexanes, heated to a boil, and diluted with ethyl acetate hot until a solution was obtained, then hexanes was added to a total volume of 200 ml. The mix was cooled to room temperature, and the resulting solids were collected by filtration, washed with 10 ml hexanes, and air dried to give 2-nitro-4,4'-biphenyldicarboxylate dimethyl ester, 1.319 g.
NMR 500 MH D6DMS0: 8.51, d, J=IJ, IH, 8.31, dd, J=U, 8.1, IH, 8.06, dd, J=1.8, 8.3, 2H, 7.76, d, J=8, IH, 7.56, dd, J=1.8, 8.4, 2H, 3.94, s, 3H, 3.89, s, 3H Part B.
Carbazole-2,7-dicarboxylate dimethyl ester
A sample of 2-nitro-4,4'-biphenyldicarboxylate dimethyl ester from part A, 0.4534g, was place in a 2OX 200 mm tube with a stirring bar. Then triphenylphosphine, 0.96 g, was added. The tube was capped with a septum, and placed under N2. Then 1 ,2-dichlorobenzene, 2 ml, was added. The tube was then placed in a heating block, and warmed from room temperature to 210 0C. After 95 minutes at 210C, the reaction was cooled to room temperature and methanol, 10 ml, was added. After 15 minutes, the resulting suspension of solids was collected by filtration. TLC of the solids with 1 :20 ethyl acetate in dichloromethane shows a new lower RF spot, blue fluorescent with long wave UV, and adsorbing at 254nm. The crude product was recrystallized from toluene, 50 ml.
NMR 500 MH, DΛDMSO: 11.8, s, IH, 8.33, d, j=8.4, 2H, 8.18, d, J=Ll, 2H, 7.82, dd, J=1.4, 8.1, 2H, 3.91, s, 6H
Example 90
9-ethyl-6-nitrocarbazole-3-carboxaldehyde
A sample of 9-ethylcarbazole-3-carboxaldehyde, 2.23 g, was placed in a 100 ml RB flask with a stirring bar and a thermometer. Then acetic acid, 20 ml, was added, and the mixture stirred at room temperature until the solids had dissolved. Then 70% nitric acid, 1 ml, was added drop wise. The solution became dark. After 10 minutes the mix had warmed to 35 0C. after 40 minutes the solution had cooled to 25 0C, and was thick with solids. The solids were collected by filtration, washed 2X4 ml of acetic acid, then 3 X 10 ml of water, and air dried to give 9-ethyl-6-nitrocarbazole-3-carboxaldehyde. TLC with 1 : 1 dichloromethane/hexanes showed a new spot, lower RF than starting material. NMR 500 MH CDC13: 10.15, s, IH, 9.08, d, J=2.3, IH, 8.67, d, J=1.3, IH, 8.46, dd, J=2, 9, IH, 8.13, dd, J=I.5, 8.4, IH, 7.59, d, J=8.5, IH, 7.50, d, J=9, IH, 4.48, q, J=7.3, 2H, 1.53, t, J=7.4, 3H.
Example 91
9-(isopropyl) carbazole-3-carboxylic acid
A sample of 9-(isopropyl)carbazole-3-carboxaldehyde (1.9 g, 8 mmol) was taken in 25 ml of THF and aq. 35%H2O2 (0.842 ml, 8.42 mmol) was added, at 0 0C, followed by the addition of 12 ml of aq.NaH2Pθ4. To this reaction mixture, IM aq. NaClO2 (12 ml, 12 mmol) was added, at 0 0C, drop wise through addition funnel and the mixture was left stirred overnight. The TLC of the mixture showed the complete consumption of starting material and a new spot with lower Rf value. The reaction mixture was quenched with sodium hydro sulfite and acidified to pH 2 with IN HCl. The mixture was transferred into a separating funnel, the aqueous layer separated and extracted with EtOAc (2 x 50 ml). The THF layer was concentrated in vacuo, taken into EtOAc (100 ml) and washed with H2O (40 ml). The combined organic layers were dried over anhyd MgSO4 and the solvents were removed in vacuo to afford 2.06 g of the desired product.
1H NMR 500 MHz D6DMSO: 12.6, s, IH, 8.78, d, J=I.5, IH, 8.27, d, J=7.8, IH, 8.02, dd, J=I.6, 8.6, IH, 7.77-7.74, m, 2H, 7.49-7.46, m, IH, 7.25, t, J=7.5, IH, 5.21-5.12, m, IH, 1.63, d, J=7, 6H.
Example 92
9-(isopropyl) carbazole-3-carboxylic acid propylamide A sample of 9-(isopropyl) carbazole-3-carboxylic acid (0.145 g, 0.57 mmol) was taken in 2 ml of dry DMF. To this solution, NEt3 (0.158 ml, 1.14 mmol) was added followed by the addition of HATU (0.216 g, 0.57mmol). After stirring for 5 min., propyl amine (0.056 ml, 0.684 mmol) was added and the reaction mixture was stirred at room temperature for overnight. The DMF was removed in vacuo, the residue was taken into EtOAc (50 ml), washed with H2O (20 ml) and sat. NaHCO3 (20 ml). The organic layer was separated, dried over anhyd. MgSO4, the solvents were removed in vacuo and the residue was purified by column chromatography to obtain 0.145 g of the product.
1H NMR 500 MHz D6DMSO: 8.70, d, J=IJ, IH, 8.42, t. J=5.5, IH, 8.18, d, J=7.8, IH, 7.96, dd, J=I.8, 8.7, IH, 7.74, dd, J=I.7, 8.3, 2H, 7.48-7.44, m, IH, 7.24, t, J=7.6, IH, 5.21-5.12, m, IH, 3.28, q, J=6.4, 2H, 1.64, d, J=6.9, 6H, 1.62-1.55, m, 2H, 0.92, t, J=IA, 3H.
Example 93
9-(isopropyl) carbazole-3-carboxylic acid [3-(4-methyl-piperazin-l-yl)-propyl]- amide
The compound was prepared, as described for example 92, from 9-(isopropyl) carbazole-3-carboxylic acid and 3-(4-methyl-piperazin-l-yl)-propylamine.
1H NMR 500 MHz CDCl3: 8.58, d, J=I.6, 8.16, d, J=7.7, IH, 8.15-8.12, m, IH, 7.58-7.49, m, 2H, 7.49-7.44, m, IH, 7.25, t, J=IA, 2H, 5.07-4.97, m, IH, 3.64, q, J=5.2, 2H, 2.6, t, J=5.8, 4H, 2.5, s, 4H, 2.24, s, 3H, 1.87-1.78, m, 2H, 1.73, d, J=I Λ, 8H.
Example 94
9-(Cyclohexyl) carbazole
The compound was prepared, as described for example 47, from carbazole and bromo cyclohexane.
1H NMR 500 MHz CDCl3: 8.11, d, J=8, 2H, 7.56, d, J=8.3, 2H, 7.47-7.39, m, 2H, 7.21, t, J=7.6, 2H, 4.54, m, IH, 2.45-2.36, m, 2H, 2.04-1.94, m, 4H, 1.88-1.83, m, IH, 1.6-1.51, m, 3H.
Example 95
9-(Cyclohexyl) carbazole-3-carboxaldehyde
The compound was prepared, as described for example 48, from 9-(Cyclohexyl) carbazole.
1H NMR 500 MHz CDCl3: 10.1, s, IH, 8.61, d, J=1.5, IH, 8.17, d, J=7.8, IH, 7.98, dd, J=1.5, 8.6, IH, 7.68-7.59, m, 2H, 7.53-7.47, m, IH, 7.31, t, J=7.6, IH, 4.58- 4.99, m, IH, 2.45-2.34, m, 2H, 2.07-1.87, m, 4H, 1.91-1.85, m, IH, 1.58-1.50, m, 2H, 1.47-1.37, m, IH. Example 96
9-(Cyclohexyl) carbazole-S-carboxylic acid
The compound was prepared, as described for Example 49, from 9- (Cyclohexyl) carbazole-3-carboxaldehyde.
1H NMR 500 MHz D6DMSO: 8.92, d, J=1.3, IH, 8.22, dd, J=I.6, 8.8, IH, 8.19, d, J=7.9, IH, 7.6, t, J=9.5, 2H, 7.49, t, J=7.3, IH, 7.3, t, J=7.5, IH, 4.58-4.47, m, IH, 2.46-2.33, m, 2H, 2.08-1.97, m, 4H, 1.87-1.84, m, IH, 1.61-1.52, m, 2H, 1.47-1.36, m, IH.
Example 97
9-(Cyclohexyl) carbazole-3-carboxylic acid propylamide
The compound was prepared, as described for example 92, from 9-(Cyclohexyl) carbazole-3-carboxylic acid and propylamine. 1H NMR 500 MHz CDCl3: 8.54, d, J=I.5, IH, 8.14, d, J=7.3, IH, 7.86, dd,
J=1.5, 8.6, IH, 7.61-7.53, m, 2H, 7.46, t, J=7.4, IH, 7.25, t, J=7.3, IH, 6.27-6.21, m, IH, 4.55-4.46, m, IH, 3.49, q, J=6.5, 2H, 2.43-2.32, m, 2H, 2.05-1.94, m, 4H, 1.89- 1.83, m, IH, 1.75-1.64, m, 2H, 1.57-1.49, m, 2H, 1.03, t, J=7.4, 3H.
Example 98
9-(isopropyl) carbazole-3-carboxylic acid ethyl ester
A sample of 9-(isopropyl) carbazole-3-carboxylic acid (0.095 g, 0.375 mmol) was taken in a mixture Of EtOHZH2SO4 (4/0.4 ml) and refluxed overnight. The solvent was removed in vacuo, the residue was taken in EtOAc (40 ml), washed with H2O (20 ml) and sat. NaHCO3 (20 ml). The organic layer was separated, dried over anhyd.MgSO4, solvents were removed in vacuo and the crude was purified by column chromatography to yield 0.08g of the product.
1H NMR 500 MHz CDCl3: 8.28, d, J=IJ, IH, 8.18-8.14, m, 2H, 7.53, d, J=8.2, IH, 7.52-7.46, m, 2H, 7.30-7.26, m, IH, 5.07-4.98, m, IH, 4.40, q, J=7.2, 2H, 1.73, d, J=7.2, 6H, 1.45, t, J=6.9, 3H. Example 99
1 -(9-Isopropyl carbazol-3-yl)-3-propyl-urea
A sample of 9-(isopropyl) carbazole-S-carboxylic acid (0.152 g, 0.6 mmol) was placed in a two-neck round-bottom flask, with a stir bar, fitted with a refluxing condenser. To the sample, dry toluene (10 ml) was added under N2 followed by addition of triethyl amine (0.083 ml, 0.6 mmol) and diphenyl phosphoryl azide (0.142 ml, 0.66 mmol). The reaction mixture was stirred at room temperature for 1 h and then refluxed for Ih. The heating was removed, propyl amine (0.148 ml, 1.8 mmol) was added and the reaction mixture was stirred at room temperature for 16 hrs. The solvents were removed in vacuo, the residue was taken into EtOAc (50 ml), washed sequentially with IN HCl (20 ml), H2O (20 ml) and sat.NaHCO3 (20 ml). The organic layer was separated, dried over anhyd.MgSO4, solvents were removed in vacuo and the crude was purified by column chromatography to yield 0.11 g of the product. 1H NMR 500 MHz D6DMSO: 8.31, s, IH, 8.17, d, J=2.1, IH, 8.02, d, J=7.5,
IH, 7.62, d, J=8.3, IH, 7.55, d, J=8.8, IH, 7.40-7.35, m, IH, 7.33, dd, J=2.1, 8.8, IH, 7.12, t, J=7.6, IH, 6.07, t, J=5.7, IH, 5.08-4.99, m, IH, 3.07, q, J=6.7, 2H, 1.60, d, J=6.9, 6H, 1.52-1.43, m, 2H, 0.89, t, J=7.3, 3H.
Example 100
9-(isopropyl) carbazole-3-carboxylic acid amide
A sample of 9-(isopropyl) carbazole-3-carboxylic acid (0.5 g, 2 mmol) was taken in 6 ml of dry DMF. To this solution, NEt3 (0.84 ml, 6 mmol) was added followed by the addition of HATU (0.76 g, 2 mmol). The reaction mixture was stirred for 5 min., solid NH4Cl (0.32 g, 6 mmol) was added and the reaction mixture was stirred at room temperature for overnight. The reaction mixture was filtered and the filtrate was treated with 60 ml of H2O and stirred for 30 min. The resulting precipitate was filtered off to obtain 450 mg of the crude product. The crude product was crystallized from a mixture of CH2Cl2/Me0H. 1H NMR 500 MHz D6DMSO: 8.74, d, J=1.7, IH, 8.17, d, J=7.8, IH, 7.99, dd,
J=1.8, 8.7, IH, 7.95, s, IH, 7.75-7.71, m, 2H, 7.48-7.43, m, IH, 7.27-7.18, m, 2H, 5.21- 5.11, m, IH, 1.64, d, J=7, 6H. Example 101
9-(isopropyl) carbazole-3-carbonitrile
A sample of 9-(isopropyl) carbazole-S-carboxylic acid amide (0.152 g, 0.6 mmol) was taken in 3 ml of dry CHCI3 and to this stirred suspension, p-toluene sulfonyl chloride (0.84 ml, 0.66 mmol) was added followed by the addition of pyridine
(0.09 ml, 1.2 mmol). The reaction mixture was stirred at room temperature for 36 hrs.
The solvents were removed in vacuo, the residue was taken into EtOAc (60ml), washed sequentially with IN HCl (25 ml), H2O (25 ml) and sat.NaHCO3 (25 ml). The organic layer was separated, dried over anhyd.MgSO4, solvents were removed in vacuo and the crude was purified by column chromatography to obtain 0.11 g of the product.
1H NMR 500 MHz CDCl3: 8.4, d, J=I.5, IH, 8.11, d, J=7.7, IH, 7.67, dd, J=I.6, 8.6, IH, 7.6-7.49, m, 3H, 7.31, t, J=7.5, IH, 5.07-4.97, m, IH, 1.73, d, J=7, 6H.
Example 102 9-(isopropyl) carbazole-3-carbothioic acid amide
A sample of 9-(isopropyl) carbazole-3-carboxylic acid amide (0.176 g, 0.7 mmol) and Lawesson's reagent (0.142 g, 0.35 mmol) were placed, with a stir bar, in a R.B. flask, fitted with refluxing condenser. To this, 5 ml of dry THF was added under N2 and the reaction mixture was refluxed overnight. The solvents were removed in vacuo, the residue was taken into EtOAc (60ml), washed with H2O (25 ml) and sat.brine solution (25 ml). The organic layer was separated, dried over anhyd.MgSO4, solvents were removed in vacuo and the crude was purified by column chromatography to obtain 0.145 g of the product.
1H NMR 500 MHz CDCl3: 8.72, d, J=1.9, IH, 8.15, d, J=7.3, IH, 8.06, dd, J=2, 8.8, IH, 7.61, s, IH, 7.55, d, J=8.3, IH, 7.51-7.46, m, 2H, 7.34-7.26, m, 2H, 5.05-4.95, m, IH, 1.72, d, J=6.9, 6H.
Example 103
2-(9-Isopropyl carbazol-3-yl)-3-thiazole-4-carboxylic acid ethyl ester A sample of 9-(isopropyl) carbazole-3- carbothioic acid amide (0.129 g, 0.48 mmol) was taken in 5 ml of EtOH. To this solution, ethyl bromo pyruvate (0.06 ml, 0.48 mmol) was added followed by addition of solid NaHCO3 (0.043 g, 0.48 mmol) and the reaction mixture was refluxed for 6 hrs. The solvents were removed in vacuo, the residue was taken in EtOAc (50 ml), washed with H2O (20 ml) and sat.brine solution (20 ml). The organic layer was separated, dried over anhyd.MgSO4, and solvents were evaporated in vacuo to obtain brown syrup. The brown syrup was taken in 2ml of dimethoxy ethane and treated with trifluoro acetic anhydride (0.139 ml, 1 mmol) and pyridine (0.151 ml, 2 mmol) at 0 0C for 1 hr. The solvents were concentrated in vacuo, the residue dissolved in EtOAc (40 ml), washed with sat.brine solution (20 ml) and stirred with 28% aq.ammonia at 0 0C. After stirring for 15 min, the reaction mixture was washed with brine (2 x 20 ml) and dried over anhyd. MgSO4. The solvents were removed in vacuo and the crude was purified by column chromatography to obtain 0.12 g of the product.
1H NMR 500 MHz CDCl3: 8.79, d, J=IJ, IH, 8.19, d, J=7.6, IH, 8.12, s, IH, 8.06, dd, J=1.9, 8.8, IH, 7.57-7.52, m, 2H, 7.5-7.46, m, IH, 7.27, t, J=7.7, 2H, 5.06- 4.96, m, IH, 4.48, q, J=6.8, 2H, 1.74, d, J=7, 6H, 1.46, t, J=7.5, 3H.
Example 104
6-Bromo-9-(isopropyl) carbazole-3-carboxylic acid ethyl ester
A sample of 9-(isopropyl) carbazole-3-carboxylic acid ethyl ester (0.15 g, 0.53 mmol) was taken in 1 ml of AcOH and the solution was cooled to 0 0C. To this, solution of bromine (0.03 ml, 0.58 mmol), in ImI of AcOH, was added portion wise and the reaction mixture was further stirred for 10 min. The reaction mixture was poured in water and the product was extracted with EtOAc (2 x 25 ml). The organic layer was washed with sat. NaHCO3 (20 ml) and sat. brine solution (20 ml). The organic layer was dried over anhyd. MgSO4, solvents were removed in vacuo and the crude was purified by column chromatography to obtain 0.14 g of the product.
1H NMR 500 MHz CDCl3: 8.77, d, J=I.7, IH, 8.27, d, J=I.9, IH, 8.16, dd, J=1.8, 88, IH, 7.55, dd, J=2, 8.8, IH, 7.51, d, J=8.8, IH, 7.42, d, J=8.8, IH, 5.02-4.93, m, IH, 4.44, q, J=7.3, 2H, 1.71, d, J=I, 6H, 1.45, t, J=I, 3H.
Example 105
1 -(6-Acetyl-9-isopropyl carbazol-3-yl)-ethanone A sample of 9-(isopropyl) carbazole (0.209 g, 1 mmol) was taken in 10 ml of dry CH2Cl2. To this solution, AICI3 (0.28 g, 2.1 mmol) was added and the suspension was stirred for 5 min at room temperature. The reaction mixture was cooled to 0 0C, and freshly distilled acetyl chloride (0.15 ml, 2.1 mmol), in 10 ml of dry CH2Cl2, was added drop wise through dropping funnel over a period of 1 hr. After addition, the reaction mixture was stirred at room temperature for 2 hrs and the mixture was poured on crushed ice. After melting ice, the mixture was extracted with CH2Cl2 (2 x 25 ml), washed with water (20 ml), sat.NaHCO3 (20 ml) and the organic layer was dried over anhyd. MgSO4. The solvents were removed in vacuo and the crude was purified by column chromatography to obtain 0.18 g of the product.
1H NMR 500 MHz CDCl3: 8.8, d, J=1.3, 2H, 8.15, dd, J=1.6, 8.6, 2H, 7.58, d, J=8.7, 2H, 5.08-4.96, m, IH, 2.74, s, 6H, 1.75, d, J=7.1, 6H.
Example 106 l-(9-Isopropyl carbazol-3-yl)-ethanone
The compound was prepared, as described for example 105, using 1.1 equiv. of acetyl chloride and AlCl3.
1H NMR 500 MHz CDCl3: 8.75, d, J=1.5, IH, 8.17, d, J=7.9, IH, 8.1, dd, J=1.7, 8.6, IH, 7.58-7.47, m, 3H, 7.32-7.27, m, IH, 5.07-4.95, m, IH, 2.72, s, 3H, 1.73, d, J=7.2, 6H.
Example 107
2,3,4,9-Tetrahydro carbazole-3,6-dicarboxylic acid 3-ethyl ester
A sample of 4-hydrazino benzoic acid hydrochloride (5 g, 26.5 mmol) was taken in 40 ml of AcOH. To this stirred suspension, 4-cyclo hexanone carboxylic acid ethyl ester (4.22 ml, 26.5 mmol) was added and the mixture was refluxed overnight. The resulting precipitate was filtered off and washed with CH2Cl2 to obtain 4.28 g of the pure product. The filtrates were concentrated in vacuo, the residue suspended in CH2Cl2, filtered, and washed with CH2Cl2 to obtain 3.22 g of the product. 1H NMR 500 MHz D6DMSO: 12.24, s, IH, 11.1, s, IH, 8.03, s, IH, 7.64, dd,
J=1.3, 8.4, IH, 7.29, d, J=8.4, IH, 4.18-4.06, m, 2H, 2.99-2.92, m, IH, 2.86-2.74, m, 4H, 2.23-2.14, m, IH, 1.94-1.83, m, IH, 1.21, t, J=7, 3H. Example 108
6-Propylcarbamoyl-2,3,4,9-tetrahydro carbazole-3-carboxylic acid ethyl ester The compound was prepared, as described for example 92, 2,3,4,9-Tetrahydro carbazole^ό-dicarboxylic acid 3-ethyl ester and propylamine.
1H NMR 500 MHz D6DMSO: 10.94, s, IH, 8.23, t, J=5.6, IH, 7.97, d, J=I.3, IH, 7.56, dd, J=I.6, 8.4, IH, 7.25, d, J=8.4, IH, 4.18-4.07, m, 2H, 3.22, q, J=6.4, 2H, 3.01-2.94, m, IH, 2.85-2.75, m, 4H, 2.25-2.17, m, IH, 1.94-1.84, m, IH, 1.58-1.49, m, 2H, 1.22, t, J=7.2, 3H, 0.89, t, J=7.4, 3H.
Example 109
2,3,4,9-Tetrahydro carbazole-3,6-dicarboxylic acid diethyl ester The compound was prepared, as described for example 98, from 2,3,4,9- Tetrahydro carbazole-3,6-dicarboxylic acid 3-ethyl ester. 1H NMR 500 MHz CDCl3: 8.23, s, IH, 7.96, s, IH, 7.85, dd, J=I.6, 8.5, IH,
7.27, d, J=8.8, IH, 4.39, q, J=7, 2H, 4.2, q, J=7.4, 2H, 3.11, dd, J=5.3, 15.5, IH, 2.97- 2.88, m, IH, 2.87-2.78, m, 3H, 2.35-2.27, m, IH, 2.09-1.99, m, IH, 1.41, t, J=7.2, 3H, 1.30, t, J=7, 3H.
Example 110
Carbazole-3,6-dicarboxylic acid diethyl ester
A sample of 2,3,4,9-Tetrahydro carbazole-3,6-dicarboxylic acid diethyl ester (0.8 g, 2.53 mmol) and 10% Pd-C (0.4g) were taken in 15 ml of mesitylene and the contents were refluxed under N2 for 16 hrs. The reaction mixture was filtered, while hot, over celite through sintered funnel and washed with MeOH. The filtrates were concentrated to 8 ml, resulting precipitation. The precipitate was filtered off and washed with hexane to obtain 640 mg of the pure product.
1H NMR 500 MHz D6DMSO: 12.09, s, IH, 8.90, d, J=Ll, 2H, 8.07, dd, J=IJ, 8.7, 2H, 7.61, d, J=8.5, 2H, 4.36, q, J=7.1, 4H, 1.38, t, J=7.1, 6H.
Example 111
9-(Isopropyl) carbazole-3,6-dicarboxylic acid diethyl ester A sample of carbazole-3,6-dicarboxylic acid diethyl ester (0.125g, 0.4 mmol) and Cs2CO3 (0.26g, 0.8 mmol) were taken in 2 ml of dry DMF. To this stirred suspension, under N2, isopropyl bromide (.075 ml, 0.8 mmol) was added and the mixture was heated to 55 0C for overnight. The reaction mixture was taken into EtOAc (50 ml), washed with H2O (20 ml) and sat. brine solution (20 ml). The organic layer was dried over anhyd.MgSO4, solvents were removed in vacuo and the crude was purified by column chromatography to obtain 0.12 g of the product.
1H NMR 500 MHz CDCl3: 8.8, d, J=I.8, 2H, 8.19, dd, J=I.8, 8.8, 2H, 7.55, d, J=8.7, 2H, 5.05-4.99, m, IH, 4.45, q, J=7, 4H, 1.74, d, J=7, 6H, 1.46, t, J=7.1, 6H.
Example 112
9-(3-Chloro-propyl) carbazole^ό-dicarboxylic acid diethyl ester
The compound was prepared, as described for example 111, from carbazole- 3,6-dicarboxylic acid diethyl ester and l-bromo-3-chloro-propane. 1H NMR 500 MHz CDCl3: 8.87, d, J=I.5, 2H, 8.23, dd, J=I.7, 8.7, 2H, 7.54-
7.48, m, 2H, 4.59-4.54, m, 2H, 4.46, q, J=7.2, 4H, 3.52, t, J=5.9, 2H, 2.4-2.32, m, 2H, 1.46, t, J=7, 6H.
Example 113 9-(3-Phenoxy-propyl)-2,3,4,9-tetrahydro carbazole-3,6-dicarboxylic acid diethyl ester
The compound was prepared, as described for example 111, from 2,3,4,9- tetrahydro carbazole-3,6-dicarboxylic acid diethyl ester and 3-phenoxy-propyl bromide
1H NMR 500 MHz CDCl3: 8.24, d, J=I.3, IH, 7.83, dd, J=I.5, 8.7, IH, 7.31- 7.26, m, 3H, 6.96, t, J=7.4, IH, 6.87, dd, J=0.8, 8.8, 2H, 4.38, q, J=7.1, 2H, 4.30-4.24, m, 2H, 4.18, q, J=7.1, 2H, 3.87, t, J=5.6, 2H, 3.14-3.08, m, IH, 2.97-2.82, m, 2H, 2.78-
2.67, m, 2H, 2.33-2.25, m, IH, 2.24-2.18, m, 2H, 2.02-1.93, m, IH, 1.41, t, J=7.1, 3H,
1.29, t, J=7, 3H.
Example 114
9-Isopropyl-6-propylcarbamoyl-2,3,4,9-tetrahydro carbazole-3-carboxylic acid ethyl ester The compound was prepared, as described for example 111, from 6- propylcarbamoyl-2,3,4,9-tetrahydro carbazole-3-carboxylic acid ethyl ester and isopropyl bromide.
1H NMR 500 MHz CDCl3: 7.9, d, J=1.6, IH, 7.56, dd, J=IJ, 8.6, IH, 7.41, d, J=8.7, IH, 6.19-6.12, m, IH, 4.64-4.55, m, IH, 4.2, q, J=7.2, 2H, 3.45, q, J=6.8, 2H, 3.13-3.07, m, IH, 2.96-2.89, m, 2H, 2.82-2.73, m, 2H, 2.41-2.33, m, IH, 1.72-1.65, m, 2H, 1.63-1.55, m, 6H, 1.29, t, J=7.1, 3H, 1.0, t, J=IA, 3H.
Example 115 9-Ethyl carbazole-3,6-dicarboxylic acid diethyl ester
A sample of carbazole-3,6-dicarboxylic acid diethyl ester (0.622 g, 2 mmol) and Cs2CO3 (1.3 g, 4 mmol) were taken in 10 ml of dry DMF. To this stirred suspension, diethyl sulfate (0.524 ml, 4 mmol) was added and the mixture was stirred at room temperature for 16 hrs. The solvent was removed in vacuo, the residue taken in EtOAc (75 ml), washed with H2O (30 ml) and sat. NaHCO3 (30 ml). The organic layer was separated, dried over anhyd. MgSO4, solvents were removed in vacuo and the crude was purified by column chromatography to obtain 0.56 g of the desired product.
1H NMR 500 MHz CDCl3: 8.87, d, J=I.4, 2H, 8.22, dd, J=I.5, 8.6, 2H, 7.44, d, J=8.6, 2H, 4.49-4.38, m, 6H, 1.53-1.43, m, 9H.
Example 116
9-Ethyl carbazole-3,6-dicarboxylic acid monoethyl ester
A sample of 9-Ethyl carbazole-3,6-dicarboxylic acid diethyl ester (0.5 g, 1.47 mmol) was taken in 8 ml of EtOH. To this, 2N NaOH (0.365 ml, 0.73 mmol) was added and the mixture was refluxed for 5 hrs. The solvent was removed in vacuo, water was added, acidified to pH 2 with IN HCl and the mixture was extracted with EtOAc (2 x 40 ml). The organic layer was separated, dried over anhyd/MgSO4, solvents were removed in vacuo and the crude product was purified by column chromatography to obtain 0.15 g of the product. 1H NMR 500 MHz D6DMSO: 12.7, s, IH, 8.91, t, J=2.1, 2H, 8.12, dd, J=IA,
8.5, 2H, 7.79-8.09, m, 2H, 4.53, q, J=I, 2H, 4.36, q, J=I, 2H, 1.38, t, J=I, 3H, 1.35, t, J=7.1, 3H. Example 117
9-Ethyl-6-[3-(4-methyl-piperazin-l-yl)-propylcarbamoyl]-carbazole-3- carboxylic acid ethyl ester The compound was prepared, as described for example 92, from 9-Ethyl carbazole^ό-dicarboxylic acid monoethyl ester and 3-(4-methyl-piperazin-l-yl)- propylamine.
1H NMR 500 MHz D6DMSO: 8.84-8.81, m, 2H, 8.5, t, J=5.3, IH, 8.11, dd, J=I.6, 8.6, IH, 8.05, dd, J=I.6, 8.6, IH, 7.78-7.72, m, 2H, 4.52, q, J=7, 2H, 4.37, q, J=7, 2H, 3.38-3.29, m, 6H, 2.45-2.23, m, 8H, 2.12, s, 3H, 1.77-1.68, m, 2H, 1.38, t, J=7.1, 3H, 1.34, t, J=7.1, 3H.
Example 118
6,6-Dimethyl-5,6,7,8-tetrahydro carbazole-3-carboxylic acid A sample of 4-hydrazino benzoic acid hydrochloride (0.75g, 4 mmol), 4,4- dimethyl cyclo hexanone (0.505g, 4 mmol), were taken in 6 ml of AcOH and the mixture was refluxed overnight. The mixture was cooled to room temperature and kept in refrigerator for 2 hrs. The solidified mixture was suspended in CH2Cl2 (10 ml), filtered and washed with CH2Cl2 to obtain 0.85 g of the product. 1U NMR 500 MHz D6DMSO: 12.21, s, IH, 11.08, s, IH, 7.98, d, J=0.9, IH,
7.62, dd, J=1.6, 8.5, IH, 7.28, d, J=8.4, IH, 2.69, t, J=6.3, 2H, 2.45, s, 2H, 1.61, t, J=6.4, 2H, 1.01, s, 6H.
Example 119 6,6-Dimethyl-5,6,7,8-tetrahydro carbazole-3-carboxylic acid methyl ester
The compound was prepared, as described for example 98, from 6,6-Dimethyl- 5,6,7,8-tetrahydro carbazole-3-carboxylic acid and methanol.
1H NMR 500 MHz CDCl3: 8.2, s, IH, 8.03, s, IH, 7.82, dd, J=I.2, 8.6, IH, 7.27, d, J=8.7, IH, 3.91, s, 3H, 2.72, t, J=6.3, 2H, 2.52, s, 2H, 1.67, t, J=6.4, 2H, 1.05, s, 6H. Example 120
9-Ethyl-6,6-dimethyl-5,6,7,8-tetrahydro carbazole-3-carboxylic acid methyl ester
The compound was prepared, as described for example 115, from 6,6- Dimethyl-5,6,7,8-tetrahydro carbazole-3-carboxylic acid methyl ester and diethyl sulfate.
1H NMR 500 MHz CDCl3: 8.21, d, J=1.3, IH, 7.85, dd, J=1.7, 10.4, IH, 7.26, d. J=8.6, IH, 4.1, q, J=7.25, 2H, 3.92, s, 3H, 2.7, t, J=6.4, 2H, 2.55, s, 2H, 1.7, t, J=6.4, 2H, 1.33, t, J=6.4, 3H, 1.05, s, 6H.
Example 121
6-Methyl-5,6,7,8-tetrahydro carbazole-3-carboxylic acid
The compound was prepared, as described for example 118, from 4-hydrazino benzoic acid hydrochloride and 4-methyl eye Io hexanone. 1H NMR 500 MHz D6DMSO: 12.26, s, IH, 11.1, s, IH, 7.99, d, J=0.6, IH,
7.61, dd, J=0.8, 9.1, IH, 7.27, d, J=8.5, IH, 2.83-2.78, m, IH, 2.79-2.70, m, 2H, 2.25- 2.16, m, IH, 1.93-1.83, m, 2H, 1.53-1.44, m, IH, 1.09, d, J=6.5, 3H.
Example 122 6-Methyl-5,6,7,8-tetrahydro carbazole-3-carboxylic acid methyl ester
The compound was prepared, as described for example 98, from 6-Methyl- 5,6,7,8-tetrahydro carbazole-3-carboxylic acid and methanol.
1H NMR 500 MHz CDCl3: 8.21, d, J=I.4, IH, 7.91, s, IH, 7.83, dd, J=1.7, 8.6, IH, 7.26, d, J=8.4, IH, 3.92, s, 3H, 2.91-2.84, m, IH, 2.8-2.73, m, 2H, 2.34-2.28, m, IH, 2.03-1.95, m, 2H, 1.62-1.55, m, IH, 1.14, d, J=6.5, 3H.
Example 123
9-Isopropyl-6-methyl-5,6,7,8-tetrahydro carbazole-3-carboxylic acid methyl ester The compound was prepared, as described for example 111, from 6-Methyl-
5,6,7,8-tetrahydro carbazole-3-carboxylic acid methyl ester and isopropyl bromide. 1H NMR 500 MHz CDCl3: 8.20, d, J=I.6, IH, 7.79, dd, J=I.6, 8.7, IH, 7.39, d, J=8.6, IH, 4.68-4.57, m, IH, 3.92, s, 3H, 2.92-2.85, m, IH, 2.84-2.71, m, 2H, 2.35- 2.26, m, IH, 2.06-1.97, m, IH, 1.95-1.86, m, IH, 1.59, t, J=7, 6H, 1.14, d, J=6.6, 3H.
Example 124 l-Chloro-5,6,7,8-tetrahydro carbazole-3-carboxylic acid
The compound was prepared, as described for example 118, from 3-chloro-4- hydrazino benzoic acid hydrochloride and cyclo hexanone.
1H NMR 500 MHz D6DMSO: 12.6, s, IH, 11.4, s, IH, 7.97, d, J=0.8, IH, 7.61, d, J=I.2, IH, 2.73, t, J=5.3, 2H, 2.65, t, J=5.8, 2H, 1.87-1.78, m, 4H.
Example 125 l-Chloro-5,6,7,8-tetrahydro carbazole-3-carboxylic acid methyl ester The compound was prepared, as described for example 98, from 1-Chloro- 5,6,7,8-tetrahydro carbazole-3-carboxylic acid and methanol.
1H NMR 500 MHz D6DMSO: 11.47, s, IH, 7.99, d, J=I.2, IH, 7.62, d, J=I.4, IH, 3.84, s, 3H, 2.73, t, J= =5.5, 2H, 2.65, t, J=6, 2H, 1.87-1.75, m, 4H.
Example 126 5,6,7,8-tetrahydro-9H-carbazole-3-carboxylic acid
A sample of 4-Hydrazinobenzoic acid hydrochloride, 5g, cyclohexanone 2.5g was suspended in 10 ml acetic acid in a 50 ml round bottom flask. The mix was stirred and refluxed for 4 hours. The mix was cooled to room temperature, and the resulting solids were collected by filtration, washed with 10 ml hexanes, and air dried to give 6,7,8,9- tetrahydro-9H-carbazole-3-carboxylic acid, 5.5g.
Example 127
5,6,7,8-tetrahydro-9H-carbazole-3-carboxylic acid ethyl ester
A sample of 5,6,7,8-tetrahydro-9H-carbazole-3-carboxylic acid, 2g, ethanol, 90ml and sulfuric acid, 10ml were combined in a 250ml round bottom flask. The mix was stirred and refluxed overnight. The resulting mixture was cooled to room temperature and neutralized to pH 7 using Sat. NaHCO3. The mix was evaporated till all ethanol was gone and treated with 200ml x 2 of ethyl acetate and 20 ml of hexanes. The layers were separated, and the organic layer was combined, brined, dried over MgSO4 and filtered. The ethyl acetate was evaporated in vacuo to yield 5,6,7,8- tetrahydro-9H-carbazole-3-carboxylic acid ethyl ester, 2.4g. NMR 500 MH CDCl3: 8.22, d, J=7, IH; 7.84, br, IH; 7.37, dd, Jl=8.5, J2= 2.0,
IH; 7.27, d, J=8.5, IH; 4.39, q, J=7.5, 2H; 2.74-2.72, m, 4H; 1.95-1.85, m, 4H; 1.41, t, J=7.5, 3H.
Example 128 5,6,7,8-tetrahydro-9H-carbazole-3-carboxylic acid propyl amide
A sample of 6,7,8,9 tetrahydro-9H-carbazole-3-carboxylic acid, Ig, triethyl amine, 2ml, was dissolved in 5ml DMF in a 25ml round bottom flask followed by addition of HATU, 1.98g. The mix was stirred at room temperature for 10 minutes and 0.586ml of propyl amine was added. The reaction was stirred at room temperature for 3 hours and evaporated. The mixture was treated with 250ml water and 250mlx2 ethyl acetate. The organic layer combined, brined, dried over MgSO4 and filtered. The ethyl acetate was evaporated in vacuo. The crude mixture was purified by chromatography to give 6,7,8,9 tetrahydro-9H-carbazole-3-carboxylic acid propyl amide, 0.95g.
NMR 500 MH CDCl3: 7.91, d, J=1.5, IH; 7.53, dd, Jl=8, J2= 1.5, IH; 7.27, d, J=LO, IH; 6.16, br, IH; 3.47-3.43, m, 2H; 2.74-2.71, m, 4H; 1.93-1.86, m, 4H; 1.70- 1.63, m, 2H; 1.00, t, J=7.5, 3H.
Example 129
9H-carbazole-3-carboxylic acid ethyl ester A sample of 6,7,8,9 tetrahydro-9H-carbazole-3-carboxylic acid ethyl ester, Ig,
5% Pd/C, lOOmg and xylene, 10ml were combined in a 50ml round bottom flask. A lOOmg portion of 5% Pd/C was added to the reaction every 24 hours. The mix was heated to 1400C for 96 hours till all starting material was gone and a new spot with slightly lower Rf showed up on the TLC. The mix was evaporated and purified by chromatography to give 9H-carbazole-3-carboxylic acid ethyl ester, 0.85g.
NMR 500 MH CDCl3: 8.82, d, J=O.9,1H; 8.31, br, IH; 8.15-8.13, m, 2H; 7.46- 7.42, m, 3H; 7.31-7.28, m, IH; 4.44, q, J=7.0, 2H; 1.45, t, J=7.0, 3H. Example 130
9H-carbazole-3-carboxylic acid
A sample of 9H-carbazole-3-carboxylic acid ethyl ester, 500mg, was dissolved in 2ml EtOH followed by the addition of 2ml of IM NaOH aqueous solution. The mixture was heated to 800C for 2 hours. TLC showed the starting material disappeared and a new spot with much lower Rf showed up. The mixture was diluted by 100ml water and acidified to pH 3 using IM HCl. The resulting solution was extracted with
100ml x2 ethyl. The organic layer was combined, brined, dried over MgSO4 and filtered. The ethyl acetate was evaporated in vacuo to yield 9H-carbazole-3-carboxylic acid, 400mg.
Example 131
9H-carbazole-3-carboxylic acid propyl amide The compound was prepared in a manner similar to example 128.
Example 132
9-(3'-chloro-propyl)-carbazole-3-carboxylic acid propyl amide A sample of 9H-carbazole-3-carboxylic acid propyl amide, 50mg, and Cs2CO3, 214mg were dissolved in 5ml DMF followed by the addition of 64.7λ of l-bromo-3- chloropropane. The mixture was stirred at room temperature overnight. TLC showed a new spot with a slightly higher Rf. The mixture was evaporated and treated by 100ml water and 100mlx2 ethyl acetate. The organic layer was combined, brined, dried over MgSO4 , filtered and evaporated in vacuo. The crude mixture was purified by chromatography to yield 9-(3'-chloro-propyl)-carbazole-3-carboxylic acid propyl amide, 21mg.
NMR 500 MH CDCl3: 8.55, d, IH, J=1.5; 8.13, d, J= 12.5, IH; 7.90, dd, Jl= 8.5, J2=l, IH; 7.53-7.47, m, 3H; 7.29, td, Jl=8, J2=1.5, IH; 6.25, br, IH; 4.54-4.52, m, 2H; 3.53-3.48, m, 4H; 2.38-2.33, m, 2H, 1.74-1.67, m, 2H; 1.04, t, J=7.5, 3H. Example 133
9-(3 '-chloro-propyl)-5,6,7,8-tetrahydro-9H-carbazole-3-carboxylic acid ethyl ester
The compound was prepared in a manner similar to example 132 NMR 500 MH CDCl3: 8.23, d, IH, J=1.5; 7.87, dd, Jl= 8.5, J2=1.5, IH; 7.31, t, J= 9.5, IH; 4.39, q, J= 7.0, 2H; 4.22, q, J= 6.5, 2H; 3.51, t, 6.0; 2.76-2.72, m, 4H; 2.24-2.18, m, 2H; 1.98-1.93, m, 2H; 1.89-1.84, m, 2H; 1.41, t, J=7.0, 3H.
Example 134 9-(3'-chloro-propyl)-carbazole-3-carboxylic acid ethyl ester
The compound was prepared in a manner similar to example 132 NMR 500 MH CDCl3: 8.83, d, IH, J=2.0; 8.09, dd, Jl= 9.0, J2=2.0, IH; 8.16, d, J= 7.5, IH; 7.54-7.47, m, 3H; 7.32-7.29, m, IH; 4.56-4.52, m, 2H; 4.44, q, J= 7.0, 2H; 3.52, t, J= 6.0, 2H; 2.39-2.34, m, 2H; 1.45, t, J=7.0, 3H.
Example 135
5-(3-carbazol-9-yl-propoxy)-isophthalic acid dimethyl ester A sample of 9H-carbazole-3-carboxylic acid ethyl ester, 200mg, 5-(3-bromo- propoxy)-isophthalic acid dimethyl ester (Example 73) and Cs2CO3 were dissolved in 10ml DMF in a 25ml round bottom flask. The mixture was stirred at room temperature overnight. TLC showed a new spot with a slightly higher Rf. The mixture was evaporated and treated by 100ml water and 100mlx2 ethyl acetate. The organic layer was combined, brined, dried over MgSO4, filtered and evaporated in vacuo. The crude mixture was purified by chromatography to yield 5-(3-carbazol-9-yl-propoxy)- isophthalic acid dimethyl ester, 120mg.
NMR 500 MHz CDCl3: 8.29, m, s, IH; 8.22, s, IH; 7.80-7.78, m, IH; 7.71,m,2H; 7.25, d, J=6.0, IH; 4.38, q, J=6.0, 2H; 4.28, t, J=7.0, 2H; 2.74, t, J=6.0, 2H; 2.68, t, J=6.0, 2H; 2.26-2.23, m, 2H; 1.90-1.81, m, 4H; 1.40, t, J=7.5, 3H.
Example 136
5-[(3-(l, 2,3,4 tetrahydro-carbazol-9-yl)-propoxy]-isophthalic acid dimethyl ester The compound was prepared in a manner similar to example 135 NMR 500 MHz CDCl3: 8.81, d, IH, J=1.5; 8.29, t, Jl=1.5, IH; 8.15, dd, Jl= 8.5, J2= 1.5, IH; 7.70, d, J=I.5, 2H; 7.44-7.43, m, 2H; 7.40, d, J=8.5, IH; 7.29-7.26, m, IH; 4.60, t, J= 6.0, 2H; 4.43, q, J=6.0, 2H; 4.00, t, J=6.0, 2H; 3.93, s, 6H; 2.41-2.39, m, 2H; 1.44, t,J=7.0, 3H.
Example 137
9-(3 '-chloro-propyl)-5,6,7,8-tetrahydro-9H-carbazole-3-carboxylic acid propyl amide The compound was prepared in a manner similar to example 132
NMR 500 MHz CDCl3: 7.93, s, IH; 7.56, dd, Jl=8.5, J2=1.5, IH; 7.15, d, J= 6.0, IH; 6.17, br, IH; 4.21, t, J=IO, 2H; 3.51-3.43,m, 4H; 2.74-2.72, m, 4H; 2.22-2.17, m, 2H; 1.98-1.91, m, 2H; 1.89-1.85, m, 2H, 1.70-1.63, m, 4H; 1.00, t, J=7.5, 3H.
Example 138
9-(3'-phenoxy-propyl)-5,6,7,8-tetrahydro-9H-carbazole-3-carboxylic acid propylamide
The compound was prepared in a manner similar to example 135 NMR 500 MHz CDCl3: 7.92, s, IH; 7.51-7.49, m, IH; 7.29-2.27, m, 2H; 6.97, td, J=7.5, J=LO, IH; 6.86, d, 9.0, IH; 6.12, br, IH; 4.27, t, J=6.5, 2H; 3.87, t, J=5.5,
2H; 3.44, q, J=7.0, 2H; 2.74-2.68, m, 4H; 2.23-2.18, m, 2H; 1.90-1.81, m, 4H; 1.69-
1.63, m, 2H; 1.00, t, J=7.5, 3H.
Example 139 5,6,7,8-tetrahydro-9H-carbazole-3-carboxylic acid methyl ester
The compound was prepared in a manner similar to example 127 NMR 500 MHz CDCl3: 8.22, d, J=7, IH; 7.88, br, IH; 7.31, dd, Jl=8.5, J2= 1.5, IH; 7.27, d, J=8.5, IH; 3.93, s, 3H; 2.74-2.72, m, 4H; 1.95-1.85, m, 4H.
Example 140
9-isopropyl-6,7,8,9 tetrahydro-9H-carbazole-3-carboxylic acid methyl ester The compound was prepared in a manner similar to example 135 NMR 500 MHz CDCl3: 8.21, d, J=0.9, IH; 7.80, dd, Jl=8.5, J2=1.5, IH; 7.40, d, J=9.0, IH; 4.64-4.59, m, IH; 3.92, s, 3H; 2.75-2.73, m, 4H; 1.96-1.92, m, 2H; 1.87- 1.84,m, 2H; 1.58, d, J=7, 6H.
Example 141
9-(4-benzenesulfonyl-butyl)-5,6,7,8-tetrahydro-9H-carbazole-3-carboxylic acid methyl ester
A sample of 6,7,8,9 tetrahydro-9H-carbazole-3-carboxylic acid methyl ester,
150mg, (4-chloro-butane-l-sulfonyl)-benzene, 758mg and Cs2CO3, 1.4g, were dissolved in 15ml DMF in a 25ml round bottom flask. The mixture was stirred at room temperature overnight. TLC showed a new spot with a slightly higher Rf. The mixture was evaporated and treated by 100ml water and 100mlx2 ethyl acetate. The organic layer was combined, brined, dried over MgSO4, filtered and evaporated in vacuo. The crude mixture was purified by chromatography to yield 9-(4-benzenesulfonyl-butyl)- 5,6,7,8-tetrahydro-9H-carbazole-3-carboxylic acid methyl ester, 80mg.
NMR 500 MHz CDCl3: 8.21, d, J=1.5, IH; 7.82-7-78, m, 3H; 7.63, t, J=7.5, IH; 7.51, t, J=5.5,2H; 7.14, d, J=9.0, IH; 4.02, t, J=7.0, 2H; 3.93, s, 3H; 3.00, t, J=8.0, 2H; 2.72, t, J=6.0, 2H; 2.64, t, J=6.0, 2H; 1.94-1.91, m, 2H; 1.88-1.82, m, 4h; 1.76-1.71, m, 2H.
Example 142
9-(4-benzenesulfonyl-propyl)-5,6,7,8-tetrahydro-9H-carbazole-3-carboxylic acid methyl ester
The compound was prepared in a manner similar to example 141 NMR 500 MHz CDCl3: 8.21, d, J=1.5, IH; 7.86-7.81, m, 3H; 7.66-7.63, m, IH;
7.55-7.52, m,2H; 7.19, d, J=8.5, IH; 4.19, t, J=7.0, 2H; 3.92, s, 3H; 3.05, t, J=7.0, 2H; 2.72, t, J=7.0, 2H; 2.65, t, J=7.0, 2H; 2.22-2.16, m, 2H;1.96-1.91, m, 2H; 1.87-1.84, m, 2H.
Example 143
A. Screening of compounds Functional HCV pseudoparticles of Hepatitis C virus envelope glycoproteins containing a packaging-competent retrovirus-derived genome harboring a marker gene are known, and reviewed by Voisset and Dubuisson. l HCV pseudoparticles incorporating a lentiviral backbone harboring the luciferase gene has been used to assay for HCV pseudoparticle entry as follows. Huh7 cells seeded in 96-well plates were incubated with a concentration range of the tested compounds in the presence of 2% DMSO for 1 hour prior to infection by HCV or VSV pseudoparticles. Three days post infection, luciferase was evaluated by a standard luminescence assay. See Figure 1 , upper panel. Compounds that were able to reduce viral entry limited the amount of HCV pseudoparticle that was transduced into the host cells and thus reduced the luciferase levels and resulting luminescence. The most efficacious compounds induced the most significant reduction in luminescence.
Specificity of the compounds was tested by evaluating the inhibitory effect on VSV pseudoparticles. See Figure 1, middle panel. Compounds that inhibit HCV pseudoparticle entry and did not block infections mediated by VSV pseudoparticles were judged to be specific. Compounds that reduced luciferase values for VSV- pseudoparticles are considered not specific for HCV and most likely affect a general viral entry pathway or act on the HIV backbone. Compound "2279" (chloroquine) is an example of such a non-specific compound. To test whether the compounds can have a direct toxic effect on the cells, an alamarBlue™ assay was performed in parallel with the luciferase assay. See Figure 1, lower panel. The level of alamarBlue™ reading is indicative of toxic effects of the compounds. An example of such a toxic compound is rimcazole dihydrochloride (compound "2241"). As shown in this figure, the compounds of the invention showed little toxicity on cells.
Table 2 below provides the structure of compounds of the invention, some of which are referenced in Figure 1.
Voisset, C, and Dubuisson, J, Biology of the Cell, 96, (2004) 413-420 Table 2.
Figure imgf000093_0001
Figure imgf000093_0002
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000096_0002
Figure imgf000097_0001
Figure imgf000098_0001
B. Validation by colony formation assay
Although HCV cannot normally be grown in tissue culture, viral genomes containing the sequence of a HCV genotype 2a isolated from a fulminant case of hepatitis in Japan is able to support replication in Huh7 cells. A recombinant HCV 2a virus was made by inserting the Neomycin coding sequence and encephalomyocarditis virus internal ribosome entry site sequence into the existing 2a clone sequence (Figure 2). Several compounds that were able to prevent HCVpp entry were validated using the HCV2aNeo virus. If the virus is successfully able to infect cells that are subsequently maintained in the presence of G418, the substrate for the neomycin protein, it will be able to generate colonies. When the presence of a specific inhibitor reduces the entry of the virus, fewer colonies will be able to form.
CD81 is the only undisputed protein involved in HCV entry and can be used as a positive control. Titration of CD81 specific antibodies dramatically reduced the number of colonies formed. However, a control IgG antibody did not reduce colony formation, indicating that the effect of CD81 is target specific.
A concentration range for compound "2302" (2-chloro-10-[4-(cis-3,5- dimethylpiperazin-l-yl)-butyl]-10H-phenothiazine) was tested for its ability to prevent HCV2aNeo entry. In parallel, a control compound, compound "2243" (clozapine-N-oxide) was tested. Both CD81 and compound "2302" were able to inhibit HCV2aNeo induced colony formation, while IgG and compound "2243" did not significantly alter the number of colonies, confirming that compound "2302" was able to prevent HCV entry (See Figures 3 and 4).
In a follow up study, compounds "2243" and "2302" were tested, as well as compounds "2241," "2281" (2-acetyl-9-(3-chloropropyl)-9H-cabazole), "2282" (3,7- dimetyl-10-(30chloropropyl)-10H-phenothiazine), "2339" (clorpromazine) and "2284" (9-(3-chloropropyl)-9H-carbazole) (Figures 4 and 5). As shown in these figures, all tested compounds of the invention prevented HCV entry.
Example 144
5-Ethyl- 10,11 -dihydro-5H-dibenzo[δ/]azepine
A sample of 10,ll-dihydro-5H-dibenzo[/λ/]azepine (1.95g, 10 mmol) was dissolved in 15 ml of dry DMF. To this stirred solution, NaH (60% suspension; 1.2g, 30 mmol) was added portion wise followed by the addition of diethyl sulfate (3.92 ml, 30 mmol). The reaction mixture was heated to 80 0C, under N2, overnight. The TLC of mixture, with 2.5:7.5 dichloromethane/hexane, showed complete consumption of starting material and a new spot with higher Rf value. The reaction mixture was added to 100 ml of ice cold H2O, the mixture was extracted with EtOAc (2x100 ml) and the combined organic layers were washed with sat. brine solution (75 ml). The organic layer was separated, dried over anhyd.MgSO4, solvents were concentrated in vacuo to obtain 2g of NMR pure product.
1H NMR 500 MHz CDCl3: 7.16-7.05, m, 6H, 6.94-6.88, m, 2H, 3.80, q, J=7, 2H, 3.17, s, 4H, 1.15, t, J=7, 3H.
Example 145
5-Ethyl- 10,11 -dihydro-5H-dibenzo[δ/]azepine-2-carbaldehyde
The compound was prepared, as described for example 48, from 5-Ethyl-
10,11 -dihydro-5H-dibenzo[/λ/]azepine.
1H NMR 500 MHz CDCl3: 9.8, s, IH, 7.63, dd, J=2, 8.5, IH, 7.56, d, J=I.9,
IH, 7.20-7.09, m, 4H, 7.04, t, J=6.2, IH, 3.88, q, J=7, 2H, 3.21-3.14, m, 4H, 1.17, t,
J=7, 3H.
Example 146
5-Ethyl- 10,11 -dihydro-5H-dibenzo[δ/]azepine-2-carboxylic acid
The compound was prepared, as described for example 49, from 5-Ethyl-
10,11 -dihydro-5H-dibenzo[/λ/]azepine-2-carbaldehyde.
1H NMR 500 MHz CDCl3: 12.5, brs, IH, 7.68, dd, J=2.1, 8.5, IH, 7.64, d,
J=2.1, IH, 7.19-7.13, m, 4H, 7.01-6.95, m, IH, 3.80, q, J=6.9, 2H, 3.09, s, 4H, 1.05, t,
J=7, 3H.
Example 147
5-Ethyl- 10,ll-dihydro-5H-dibenzo[δ/]azepine-2-carboxylic acid methyl ester The compound was prepared, as described for example 98, from 5-Ethyl-
10,ll-dihydro-5H-dibenzo[/λ/]azepine-2-carboxylic acid and MeOH.
1H NMR 500 MHz CDCl3: 7.78, dd, J=2.2, 8.6, IH, 7.75, d, J=2.1, IH, 7.19-
7.13, m, 2H, 7.12-7.04, m, 2H, 7.02-6.98, m, 2H, 3.86, s, 3H, 3.84, q, J=7, 2H, 3.16, s,
4H, 1.15, t, J=7, 3H. Example 148
5-Ethyl-10,l l-dihydro-5H-dibenzo[b,f]azepine-2-carboxylic acid propyl amide
The compound was prepared, as described for example 92, from 5-Ethyl- 10,ll-dihydro-5H-dibenzo[/λ/]azepine-2-carboxylic acid and n-propyl amine.
1H NMR 500 MHz CDCl3: 7.53-7.48, m, 2H, 7.18-7.11, m, 2H, 7.09-7.04, m, 2H, 7.01-6.94, m, IH, 6.02, brt, IH, 3.82, q, J=7, 2H, 3.39, q, J=6.3, 2H, 3.16, s, 4H, 1.66-1.59, m, 2H, 1.15, t, J=7, 3H, 0.96, t, J=7.4, 3H.
Example 149
5-Ethyl-10,l l-dihydro-5H-dibenzo[δ/]azepine-2-carboxylic acid [3-(4- methyl-piperazin- 1 -yl)-propyl] -amide
The compound was prepared, as described for example 92, from 5-Ethyl- 10,ll-dihydro-5H-dibenzo[/λ/]azepine-2-carboxylic acid and 3-(4-methyl-piperazin- l-yl)-propyl amine.
1H NMR 500 MHz CDC13:7.92, brt, IH, 7.59, dd, J=2.3, 8.4, IH, 7.55, d, J=2.1, IH, 7.18-7.11, m, 2H, 7.07, t, J=7, 2H, 6.99-6.94, m, IH, 3.83, q, J=7, 2H, 3.53, q, J=5.5, 2H, 3.23-3.14, m, 4H, 2.54, t, J=6, 4H, 2.46, brs, 4H, 2.27, s, 3H, 1.80- 1.72, m, 4H, 1.15, t, J=7, 3H.
Example 150
6-Bromo-2,3,4,9-tetrahydro carbazole
A sample of 4-bromo phenyl hydrazine hydrochloride (2.235g, 10 mmol) and 4-cyclohexanone (1.03ml, 10 mmol), in 15 ml of AcOH, were refluxed for 6 hrs. The TLC of mixture showed complete consumption of starting material and a new spot with higher Rf value. The mixture was cooled to room temperature, the resulting precipitate was filtered off, dried in vacuo to obtain 1.8g of the pure product.
1H NMR 500 MHz CDCl3: 7.70, brs, IH, 7.56, d, J=1.6, IH, 7.18, dd, J=1.8, 8.5, IH, 7.13, d, J=8.5, IH, 2.72, t, J=6, 2H, 2.65, t, J=6.2, 2H, 1.95-1.83, m, 4H.
Example 151
6-Bromo-9-ethyl-2,3,4,9-tetrahydro carbazole A sample of 6-Bromo-2,3,4,9-tetrahydro carbazole (0.498g, 2 mmol) was dissolved in 4 ml of dry DMF. To this stirred solution, NaH (60% suspension; 0.24g, 6 mmol) was added portion wise followed by the addition of diethyl sulfate (0.79ml, 6 mmol). The reaction mixture was heated to 80 0C overnight. The TLC of mixture, with 4:6 dichloromethane/hexane, showed complete consumption of starting material and a new spot with higher Rf value. The reaction mixture was added to 60 ml of ice cold H2O, the mixture was extracted with EtOAc and washed with sat. brine solution. The organic layer was dried over anhyd.MgSO4, solvents were concentrated in vacuo and the crude was purified by column chromatography to obtain 0.4g of the pure product.
1H NMR 500 MHz CDCl3: 7.57, s, IH, 7.2, d, J=8.7, IH, 7.12, d, J=8.7, IH, 4.04, q, J=7.2, 2H, 2.73-2.64, m, 4H, 1.98-1.90, m, 2H, 1.88-1.81, m, 2H, 1.30, t, J=7.3, 3H.
Example 152
9-Ethyl-6-phenyl-2,3 ,4,9-tetrahydro carbazole
A sample of 6-Bromo-9-ethyl-2,3,4,9-tetrahydro carbazole (0.277g, 1 mmol) and phenyl boronic acid (0.134g, 1.1 mmol) were taken in 3 ml of toluene. To this mixture, 1 ml of 2M aq.K2CO3 (2mmol) was added, N2 was bubbled into the reaction mixture for 5 min., then Pd(PPtLs)4 was added and N2 was bubbled further 5 min. The reaction mixture was re fluxed under N2 for 36 hrs. The TLC of mixture showed a new spot with lower Rf value. The mixture was filtered through sintered funnel and washed with EtOAc. To the filtrate, 50 ml of EtOAc was added, washed with H2O (25 ml) and sat. brine solution (25 ml). The organic layer was dried over anhyd.MgSO4, solvents were concentrated in vacuo and the crude was purified by column chromatography to obtain 0.14g of the pure product.
1H NMR 500 MHz CDCl3: 7.68, dd, J=I.6, 4.6, 2H, 7.65, s, IH, 7.43, t, J=7.6, 2H, 7.39, dd, J=I.8, 8.5, IH, 7.33, d, J=8.4, IH, 7.31-7.27, m, IH, 4.10, q, J=7.2, 2H, 2.77, t, J=6, 2H, 2.73, t, J=6.2, 2H, 2.01-1.93, m, 2H, 1.91-1.85, m, 2H, 1.35, t, J=7.2, 3H.
Example 153
9-Ethyl-3 -phenyl carbazole The compound was prepared, as described for example 110, from 9-Ethyl-6- phenyl-2,3 ,4,9-tetrahydro carbazole.
Example 154
9-Ethyl-9H-carbazole-3-carboxylic acid benzylamide
The synthesis was carried out using the aforementioned method in Example 50 with the exception of benzylamine in place of propylamine to provide 9-Ethyl-9H- carbazole-3-carboxylic acid benzylamide.
NMR 500 MH D6DMSO: 9.03, t, 3H, 8.77, s, IH, 8.18, d, IH, 8.07, dd, IH, 7.68, t, 2H, 7.51, t, IH, 7.38-7.32, m, 4H, 7.27, q, 2H, 4.56, d, 2H, 4.50, q, 2H, 1.33, t, 3H.
Example 155
9-Ethyl-9H-carbazole-3-carboxylic acid [2-4-methoxy-phenyl] -ethyl] -amide The synthesis was carried out using the aforementioned method in Example 50 with the exception of 2-(4-methoxyphenyl)ethylamine in place of propylamine to provide 9-Ethyl-9H-carbazole-3-carboxylic acid [2-4-methoxy-phenyl]-ethyl]-amide. NMR 500 MH D6DMSO: 8.68, d, IH, 8.52, t, IH, 8.17, d, IH, 7.98, dd, IH,
7.66, d, 2H, 7.51, t, IH, 7.27, t, IH, 7.20-7.17, m, 2H, 6.88, d, 2H, 4.49, q, 2H, 3.71, s, 3H, 3.51-3.47, m, 2H, 2.84, t, 2H, 1.33, t, 3H.
Example 156
9-Ethyl-9H-carbazole-3-carboxylic acid [2-(3-methoxy-phenyl)-ethyl] -amide The synthesis was carried out using the aforementioned method in Example 50 with the exception of 2-(3-methoxyphenyl)ethylamine in place of propylamine to provide 9-Ethyl-9H-carbazole-3-carboxylic acid [2-(3-methoxy-phenyl)-ethyl]-amide. NMR 500 MH D6DMSO: 8.68, d, IH, 8.54, t, IH, 8.17, d, IH, 7.99, dd, IH,
7.66, dd, 2H, 7.51, t, IH, 7.27-7.20, m, 2H, 6.85-6.84, m, 2H, 6.78-6.76, m, IH, 4.49, q, 2H, 3.72, s, 3H, 3.56, q, 2H, 2.89, t, 2H, 1.33, t, 3H .
Example 157
9-Ethyl-9H-carbazole-3-carboxylic acid [2-(4-chloro-phenyl)-ethyl] -amide The synthesis was carried out using the aforementioned method in Example 50 with the exception of 2-(4-chlorophenyl)-ethylamine in place of propylamine to provide 9-Ethyl-9H-carbazole-3-carboxylic acid [2-(4-chloro-phenyl)-ethyl]-amide.
NMR 500 MH D6DMSO: 8.67, d, IH, 8.54, t, IH, 8.17, d, IH, 7.97, dd, IH, 7.66, d, 2H, 7.51, t, IH, 7.36-7.34, m, 2H, 7.30, q, 2H, 7.30-7.24, m, IH, 4.49, q, 2H, 3.55, q, 2H, 2.90, t, 2H, 1.33, t, 3H.
Example 158
9-Ethyl-9H-carbazole-3-carboxylic acid [2-(3-chloro-phenyl)-ethyl] -amide The synthesis was carried out using the aforementioned method in Example 50 with the exception of 2-(3-chlorophenyl)-ethylamine in place of propylamine to provide 9-Ethyl-9H-carbazole-3-carboxylic acid [2-(3-chloro-phenyl)-ethyl]-amide. NMR 500 MH D6DMSO: 8.66, d, IH, 8.54, t, IH, 8.17, d, IH, 7.97, dd, IH,
7.66, d, 2H, 7.51, t, IH, 7.36-7.31, m, 2H, 7.27-7.23, m, 3H, 4.49, q, 2H, 3.57, q, 2H,
2.92, t, 2H, 1.33, t, 3H.
Example 159
9-Ethyl-9H-carbazole-3-carboxylic acid (2-pyridin-4-yl-ethyl)-amide
The synthesis was carried out using the aforementioned method in Example 50 with the exception of 4-(2-aminoethyl)pyridine in place of propylamine to provide 9-
Ethyl-9H-carbazole-3-carboxylic acid (2-pyridin-4-yl-ethyl)-amide.
NMR 500 MH D6DMSO: 8.66, d, IH, 8.57, t, IH, 8.47, dd, 2H, 8.17, d, IH,
7.97, dd, IH, 7.66, d, 2H, 7.51, t, IH, 7.30, dd, 2H, 7.27, t, IH, 4.49, q, 2H, 3.61, q,
2H, 3.17, d, 2H, 2.94, t, 2H, 1.33, t, 3H.
Example 160
9-Ethyl-9H-carbazole-3-carboxylic acid 4-Morpho line-amide A sample of 9-(ethyl) carbazole-3-carboxylic acid, 200mg (0.836 x 10"3 mol), was placed in a 50ml round bottom flask with magnetic stirring bar. The flask was capped with a rubber septum, evacuated then back filled with nitrogen. Anhydrous toluene 1OmL, was added via syringe followed by diphenyl phosphoryl azide, 198μl (0.920 x 10"3 mol), triethylamine, 120μl (0.836 x 10"3 mol). The mix was stirred at room temperature for one hour, heated to reflux for one hour, returned to room temperature then morpholine, 219μl (0.836 x 10"3 mol), was added. After 18 hours, TLC with 1 :9 methanol / dichloromethane showed new spot with higher Rf. Evaporated solvents, dissolved residue in ethyl acetate, washed with IN HCl, water, NaHC03aq, brine, evaporated organic layer. The resulting oil was column purified using Biotage SP4™ 12+M silica cartridge with methanol / dichloromethane solvent system. Collected solids provide morpholine-4-carboxylic acid (9-ethyl-9H- carbazole-3-yl)-amide.
NMR 500 MH D6DMSO: 8.53, s, IH, 8.16, d, IH, 8.04, d, IH, 7.56, d, IH, 7.50-7.45, m, 2H, 7.43-7.40, m, IH, 7.16, t, IH, 4.42, q, 2H, 3.64, t, 4H, 3.46, t, 4H, 1.30, t, 3H.
Example 161
9-[3-((3R,5S)-3,5-Dimethyl-piperazin-l-yl)-propyl]-9H-carbazole-3- carboxylic acid ethyl ester
A sample of 9-chloropropyl-9H-carbazole-3-carboxylic acid ethyl ester, 65mg (0.208 x 10"3 mol), tetrabutylammonium iodide, 115mg (0.312 x 10"3 mol), were placed in a 20ml vial with magnetic stirring bar. Flushed vial with nitrogen, followed by addition of anhydrous N,N-dimethylformamide, stirred at room temperature for 10 minutes. To the mix added cis-2,6-dimethylpiperazine, 95mg (0.832 x 10"3 mol), heated to 37°C. After 18 hours, TLC with 1 :9 methanol / dichloromethane showed new spot with lower Rf Evaporated solvents, dissolved residue in dichloromethane, washed with water, brine, evaporated organic layer. The resulting oil was column purified using Biotage SP4™ 12+M silica cartridge with methanol / dichloromethane solvent system. Collected solids provided 9-[3-((3R,5S)-3,5-Dimethyl-piperazin-l- yl)-propyl]-9H-carbazole-3-carboxylic acid ethyl ester.
NMR 500 MH CDCL3: 8.82, s, IH, 8.17-8.14, m, 2H, 7.50-7.46, m, 3H, 7.30- 7.26, m, IH, 4.46-4.41, m, 4H, 3.00-2.95, m, 2H, 2.71, dd, 2H, 2.28, t, 2H, 2.08, q, 2H, 1.47, t, 3H, 1.08, d, 6H.
All references cited herein are incorporated in their entirety. It is appreciated that the detailed description above is intended only to illustrate certain preferred embodiments of the present invention. It is in no way intended to limit the scope of the invention, as set out in the claims.

Claims

We claim:
1. A method of inhibiting HCV entry into cells, comprising contacting said cells with a compound of the formula:
Figure imgf000106_0001
wherein the dotted lines are 1 or 2 bonds; and when dotted lines are 1 bond, X is absent; when X is present, it is S-O(n), O or S, and n is 0, 1 or 2;
R1, R2, R3, R4, R5, Re, R7, Rs and Y are, independently, selected from the group consisting of hydrogen, halo, hydroxy, amino, aminocarbonyl, nitro, cyano, thio, Ci to C12 alkyl, C2 to Ci2 alkenyl, C2 to Ci2 alkynyl, Ci to Ci2 substituted alkyl, C2 to Ci2 substituted alkenyl, C2 to Ci2 substituted alkynyl, Ci to Ci2 acyl, Ci to Ci2 substituted acyl, C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocycle and substituted heterocycle, heteroaryl, substituted heteroaryl, C7 to Ci8 phenylalkyl, C7 to Ci8 substituted phenylalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, (monosubstituted)amino, (disubstituted)amino, sulfonyl, substituted sulfonyl, Ci to Cio alkylsulfonyl, Ci to C10 substituted alkylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl, Ci to C10 alkylthio, Ci to C10 substituted alkylthio, Ci to Ci2 alkylaminocarbonyl, Ci to Ci2 substituted alkylaminocarbonyl, phenylaminocarbonyl, and substituted phenylaminocarbonyl, cyclic C2 to C7 alkylene, substituted cyclic C2 to C7 alkylene, cyclic C2 to C7 heteroalkylene, substituted cyclic C2 to C7 heteroalkylene and the formulas -C(O)-O-R, -0-C(O)-R or -C(O)-R-O-R, where R is Ci to Ci2 alkyl or Ci to Ci2 substituted alkyl; where, optionally, one of the benzyl rings depicted in the above formula is instead a fused substituted or unsusbstituted cyclopentenyl, cyclohexenyl or cycloheptenyl group, wherein the substitutions for each open position of the ring are, independently, as described for Ri above; or a pharmaceutically acceptable salt, pro-drug, or ester of said compound.
2. The method of claim 1 , wherein: X is S-O(n); and
R1, R2, R3, R4, R5, Re, R7, Rs and Y are, independently, selected from the group consisting of hydrogen, halo, Ci to C12 alkyl, Ci to C12 alkoxy, Ci to C12 alkoxyalkyl, phenyl, phenoxy, C3 to C7 cycloalkoxy, Ci to C12 alkylthio, Ci to C12 alkenyl, Ci to Ci2 alkynyl, C3 to C7 cycloalkyl, Ci to Ci2 haloalkyl, Ci to Ci2 acyl, substituted phenyl where at least one substitution is an acid or cyano, Ci to Ci2 substituted alkyl where at least one substitution is cyano, halo or carboxy, CH2=CHCH2-, aminosulfonyl, Ci to Ci2 alkylsulfonylamino, aminocarbonyl, Ci to Ci2 substituted acyl where at least one substitution is amino or alkoxy, C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl, heterocycle and substituted heterocycle, heteroaryl, substituted heteroaryl, and the formulas -C(O)-O-R, -0-C(O)-R or -C(O)- R-O-R, where R is Ci to Ci2 alkyl.
3. The method claim 2, wherein R4 and R5 are hydrogen.
4. The method of claim 3, wherein Ri and Rs are hydrogen.
5. The method of claim 1 , wherein X is O; and
R1, R2, R3, R4, R5, Re, R7, Rs and Y are, independently, selected from the group consisting of hydrogen, halo, Ci to Ci2 alkyl, Ci to Ci2 alkoxy, Ci to Ci2 alkoxyalkyl, phenyl, phenoxy, C3 to C7 cycloalkoxy, Ci to Ci2 alkylthio, Ci to Ci2 alkenyl, Ci to Ci2 alkynyl, C3 to C7 cycloalkyl, Ci to Ci2 haloalkyl, Ci to Ci2 acyl, substituted phenyl where at least one substitution is an acid or cyano, Ci to Ci2 substituted alkyl where at least one substitution is cyano, halo or carboxy, CH2=CHCH2-, aminosulfonyl, Ci to Ci2 alkylsulfonylamino, aminocarbonyl, Ci to Ci2 substituted acyl where at least one substitution is amino or alkoxy, C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl, heterocycle and substituted heterocycle, heteroaryl, substituted heteroaryl, and the formulas -C(O)-O-R, -0-C(O)-R or -C(O)- R-O-R, where R is Ci to Ci2 alkyl.
6. The method of claim 5, wherein R4 and R5 are hydrogen.
7. The method of claim 6, wherein Ri and Rs are hydrogen.
8. The method of claim 1, wherein the dotted lines are one bond; and
Ri, R2, R3, R4, R5, Re, R7, Rs and Y are, independently, selected from the group consisting of hydrogen, halo, Ci to Ci2 alkyl, Ci to Ci2 alkoxy, Ci to Ci2 alkoxyalkyl, phenyl, phenoxy, C3 to C7 cycloalkoxy, Ci to Ci2 alkylthio, Ci to Ci2 alkenyl, Ci to Ci2 alkynyl, C3 to C7 cycloalkyl, Ci to Ci2 haloalkyl, Ci to Ci2 acyl, substituted phenyl where at least one substitution is an acid or cyano, Ci to Ci2 substituted alkyl where at least one substitution is cyano, halo or carboxy, CH2=CHCH2-, aminosulfonyl, Ci to Ci2 alkylsulfonylamino, aminocarbonyl, Ci to Ci2 substituted acyl where at least one substitution is amino or alkoxy, C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl, heterocycle and substituted heterocycle, heteroaryl, substituted heteroaryl, and the formulas -C(O)-O-R, -0-C(O)-R or -C(O)- R-O-R, where R is Ci to Ci2 alkyl.
9. The method of claim 8, wherein R4 and R5 are hydrogen.
10. The method of claim 9, wherein Ri and Rs are hydrogen.
11. The method of claim 1 , wherein: X is C=O; and
Ri, R2, R3, R4, R5, Re, R7, Rs and Y are, independently, selected from the group consisting of hydrogen, halo, Ci to Ci2 alkyl, Ci to Ci2 alkoxy, Ci to Ci2 alkoxyalkyl, phenyl, phenoxy, C3 to C7 cycloalkoxy, Ci to Ci2 alkylthio, Ci to Ci2 alkenyl, Ci to Ci2 alkynyl, C3 to C7 cycloalkyl, Ci to Ci2 haloalkyl, Ci to Ci2 acyl, substituted phenyl where at least one substitution is an acid or cyano, Ci to Ci2 substituted alkyl where at least one substitution is cyano, halo or carboxy, CH2=CHCH2-, aminosulfonyl, Ci to Ci2 alkylsulfonylamino, aminocarbonyl, Ci to Ci2 substituted acyl where at least one substitution is amino or alkoxy, C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl, heterocycle and substituted heterocycle, heteroaryl, substituted heteroaryl, and the formulas -C(O)-O-R, -0-C(O)-R or -C(O)- R-O-R, where R is Ci to Ci2 alkyl.
12. The method of claim 11 , wherein R4 and R5 are hydrogen.
13. The method of claim 12, wherein Ri and Rs are hydrogen.
14. The method of claim 13, wherein R3 and R6 are methyl.
15. The method of claim 14, wherein R7 is hydrogen.
16. The method of claim 1 , wherein both rings depicted in the formula are optionally substituted benyl rings.
17. A compound of the formula:
Figure imgf000109_0001
wherein X is absent and the dotted lines are one bond or X is S; Y is chlorobutyl; R6 is methyl or hydrogen; R3 is methyl or hydrogen; R2 is CHsC(O)- or hydrogen; and the remaining variables are hydrogen.
18. The compound of claim 17, wherein X is absent and the dotted lines are one bond; Y is chlorobutyl; R2 is CH3C(O)-; and the remaining variables are hydrogen.
19. The compound of claim 17, wherein X is S; Y is chlorobutyl; R6 is methyl; R3 is methyl; and the remaining variables are hydrogen.
20. The compound of claim 17, wherein X is absent and the dotted lines are one bond; Y is chlorobutyl; and the remaining variables are hydrogen.
21. A compound of the formula:
Figure imgf000110_0001
where A is a fused unsubstituted or substituted benzo ring, or a fused unsubstituted or substituted cyclopentenyl, cyclohexenyl or cycloheptenyl group; M is Ci to C6 alkyl or Ci to C6 substituted alkyl; R is aryl, heteroaryl, oxyaryl, oxyheteroaryl or absent; Q is -NHCO, -NR4CO, CO, SO2 or absent; and E is -OR4 or -NR4R5;
R2 is -COOR6, -CONHR6 or -COR6;
R3 is hydrogen, halo, Ci to C6 alkyl, Ci to C6 substituted alkyl, -CN or OR4;
R4 is Ci to C6 alkyl or Ci to C6 substituted alkyl;
R5 is Ci to C6 alkyl or Ci to C6 substituted alkyl; where -NR4R5 may form heterocyclic or heterobicyclic ring system, optionally substituted; or M-R-Q-E is a Ci to C6 alkyl substituted with a 4-piperidinyl group;
R6 is Ci to C6 alkyl, Ci to C6 substituted alkyl or R-Q-E as defined above.
22. The compound of claim 21, wherein A is a fused and optionally substituted benzyl.
23. The compound of claim 21, wherein -NR4R5 forms an optional substituted pyrrolidine, morpholine, tetrahydoisoquinoline or indole.
24. The compound of claim 21 , wherein R3 is hydrogen.
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