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WO1989011279A1 - Compose heteropolycyclique non fusionne ayant une interaction avec des acides nucleiques - Google Patents

Compose heteropolycyclique non fusionne ayant une interaction avec des acides nucleiques Download PDF

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Publication number
WO1989011279A1
WO1989011279A1 PCT/US1989/002104 US8902104W WO8911279A1 WO 1989011279 A1 WO1989011279 A1 WO 1989011279A1 US 8902104 W US8902104 W US 8902104W WO 8911279 A1 WO8911279 A1 WO 8911279A1
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Prior art keywords
substituted
aromatic
general formula
bis
nhx
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PCT/US1989/002104
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English (en)
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Raymond F. Schinazi
Lucjan Strekowski
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Georgia State University Foundation, Inc.
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Publication of WO1989011279A1 publication Critical patent/WO1989011279A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/32—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/08—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/38—One sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to unfused heteropolycyclic compounds having biological activity due to their ability to interact with nucleic acids.
  • a variety of compounds have antiviral or cytotoxic activity due to interaction with DNA or RNA which interferes with translation of the genes into the encoded proteins.
  • Much research is presently being directed at compounds which interact with nucleic acids as a means for treating or preventing the disease commonly known as Acguired Immunodeficiency Syndrome, or "AIDS”.
  • HIV-1 human immunodeficiency virus
  • HIV-2 the two related but distinct retroviruses termed human immunodeficiency virus HIV-1 and HIV-2. HIV-1 is the predominant cause of AIDS in the United States. Although the genomes are only about 50% homologous at the nucleotide level, the viruses contain the same complement of genes and appear to attack and kill the same human cells by the same mechanisms. Antibodies to HIV-1 are present in over 80% of patients diagnosed as having AIDS or pre-AIDS syndrome, and have been found with high frequency in the identified risk groups.
  • AIDS is known to develop in at least 10% of the individuals infected with HIV, although this percentage is suspected to be much higher.
  • a patient is generally diagnosed as having AIDS when a previously healthy adult with an intact immune system acquires impaired T-cell immunity.
  • the impaired immunity usually appears over a period of eighteen months to three years.
  • the patient becomes susceptible to opportunistic infections, various types of cancer such as Kaposi's sarcoma, and other disorders associated with reduced functioning of the immune system.
  • Another condition associated with HIV is AIDS-related complex, or ARC. This condition is thought to lead eventually to AIDS.
  • AZT appears to be the drug of choice at this time. However, AZT exhibits toxicity in a clinical setting. See Yarchoan et al.. Lancet 575-580 (1986) and Richman, et al., N.E.J.Med. 317(4),192-197 (1987). AZT was originally synthesized by Horwitz et al., J. Pro. Chem. 29, 2076-2078, 1974. The effectiveness of AZT against HIV is described in U.S. Patent No.
  • the compounds of the present invention are derivatized unfused heteropolycyclic compounds, primarily heterotricyclic compounds.
  • diazines are derivatized by replacing halogen atoms adjacent to the diazine ring nitrogens with one of a variety of common nucleophiles such as hydroxide ion, alkoxides, mercaptides, and amines.
  • Pyridine derivatives are made by reacting 2,6-di-p-tolylpyridine with N-bromo succinimide, to form 2,6-bis[4'-(bromomethyl)phenyl]pyridine.
  • the benzylic bromine atoms are also replaced with a variety of common nucleophiles. These compounds interact with nucleic acids, thereby inhibiting translation and interfering with viral replication processes.
  • Compounds which are useful are those having a therapeutic index of greater or equal to 10, toxicity at levels of greater than or equal to 100 ⁇ M, and antiviral activity at concentrations of less than or equal to 10 ⁇ M.
  • the preferred compounds at this time are 2,6-bis[4'-[(dimethylamino)methyl]phenyl]pyridine (DH-23);
  • DH-42 bis-4,6-[4'-[[2"-(dimethylamino)ethyl]thio]phenyl] pyrimidine (LS-20); 1-methyl-4-[2'-[[4"-(naphth-2"'-yl)quinazolin-2"-yl]thio] ethyl]piperazine (M-69);
  • heteropolycyclic compounds of the present invention are produced using the method described in U.S. Serial Number 153,998 filed February 9, 1988 by Lucjan Strekowski, et al., entitled “Novel Diazines and Their Method of Preparation”.
  • Substituted halogenodiazines are used as intermediates in the synthesis of the unfused heteropolycyclic compounds containing a diazine and other aromatic moieties, such as thiophene, benzene, naphthalene, furan, pyridine or pyrrole, or a substituted aromatic. These compounds are then evaluated for antiviral activity, cytotoxicity, and toxicity in animals.
  • the method to produce the substituted halogenodiazines which are useful as intermediates in the synthesis of the novel unfused heteropolycyclic compounds, and the products thereof, is easy, efficient and results in a high yield of product.
  • the reaction consists of the addition of an organolithium reagent to a halogenodiazine with subsequent dehydrogenation of the addition product.
  • the entire reaction takes place in one reaction vessel, without isolation of the substituted halogenodihydrodiazine intermediate.
  • the reactions proceed at moderate temperature and in a short period of time, which decreases side reactions and increases yield.
  • the recovery is conducted under two-phase conditions thereby minimizing hydrolysis of the substituted halogenodiazine to a substituted hydroxydiazine.
  • the general reaction scheme in which substituted halogenodiazines are converted into unfused heteropolyaromatic compounds that may have biological application is illustrated as follows:
  • the chloro derivative was treated with a 50-fold excess of the appropriate amine.
  • the mixture was heated at 70-80 oC for one hour and the amine recovered by distillation.
  • the oily residue was treated with 5% NaOH and extracted with ether.
  • the ether solution was dried over Na 2 SO 4 , evaporated, and the product purified by flash chromatography on SiO 2 . Further purification was done via crystallization from a toluene-hexane mixture.
  • Pyridine derivatives can be made from readily available 2,6-di-p-tolylpyridine.
  • This compound is brominated with N-bromosuccinimide in a carbon tetrachloride solution under reflux conditions to give 2,6-bis[4'-(bromomethyl)phenyl]pyridine.
  • the benzylic bromine atoms in this product are readily replaced with a variety of nucleophiles such as N-methylpiperazine, dimethylamine, or 2-(dimethylamino)ethanethiolate ion to furnish final compounds.
  • Examples of the general formulas for the new classes of unfused heteropolyaromatic compounds include: A substituted phthalazine of the general formula
  • R 1 is -NHX, -NX 2 , -OX, or -SX, where X is H or an organic group and
  • R 2 is an aromatic or substituted aromatic group.
  • Aromatic groups include furanyl, thienyl, phenyl, naphthyl, and pyridyl.
  • aromatic groups can be substituted with alkoxy, alkylthio, dialkylamino, and hydrocarbon groups. If the substitution contains an -OH or -SH, the quantity and nature of the organometallic reagent should be adjusted in the preparation of these derivatives as necessary for reaction with the -OH or -SH. Examples are described in Table I.
  • R 1 is -NHX, -NX 2 , -OX, or -SX, where X is H or an organic group and
  • R 2 is any aromatic or substituted aromatic.
  • R 1 is any aromatic or substituted aromatic
  • R 2 is -NHX, -NX 2 , -OX, or -SX, where X is H or an organic group. Examples are described in Table II.
  • R is -NHX, -NX 2 , -OX, or -SX, where X is H or an organic group.
  • R 1 is any aromatic or substituted aromatic
  • R 2 is -NHX, -NX 2 , -OX, or -SX, where X is H or an organic group. Examples are described in Table IV.
  • R is -NHX, -NX 2 , -OX, or -SX, where X is H or an organic group. Examples are described in Table V.
  • R is -NHX, -NX 2 , -OX, or -SX, where X is H or an organic group.
  • Table VI An example is described in Table VI.
  • R 1 is aromatic, substituted aromatic, heteroaromatic or substituted heteroaromatic and
  • R 2 is H or alkyl. Examples are described in Table VIII.
  • R 1 and R 2 are -NHX, -NX 2 , -OX, or -SX, where X is H or an organic group and R 3 is aromatic, substituted aromatic, heteroaromatic or substituted heteroaromatic groups.
  • Table IX An example is described in Table IX.
  • R 1 and R 2 are aromatic or substituted aromatic groups and R 3 is -NHX, -NX 2 , -OX, or -SX, where X is H or an organic group.
  • R 3 is -NHX, -NX 2 , -OX, or -SX, where X is H or an organic group.
  • R 1 and R 2 are an aromatic or substituted aromatic group
  • R 3 is H or an alkyl group. Examples are described in Tables XI and XII. Screening for Antiviral Activity and Toxicity.
  • antiviral activity refers to the ability of a composition to inhibit the growth of HIV.
  • the claimed composition also exhibits antiviral activity towards other retroviruses.
  • the ability of the present compositions to inhibit HIV may be measured by various experimental techniques. One such technique involves the inhibition of viral replication in human peripheral blood mononuclear cells. The amount of virus produced is determined by measuring the virus-coded reverse transcriptase (an enzyme found in retroviruses).
  • PBM Human Peripheral Blood Mononuclear
  • PHA phytohemagglutinin
  • HIV-1 (strain LAV-1) was obtained from the Center for Disease Control, Atlanta, and propagated in PHA-stimulated human PBM cells using RPMI 1640 medium as above without PHA and supplemented with 7% interleuken-2 (Advanced Biotechnologies, Inc., Silver Spring, MD), 7 ⁇ g/ml DEAE-dextran (Pharmacia, Uppsala, Sweden), and 370 U/ml anti-human leukocyte (alpha) interferon (ICN, Lisle, IL). Virus was obtained from cell-free culture supernatant and stored in aliquots at -70°C until used.
  • Uninfected PHA-stimulated human PBM cells were uniformly distributed among 25 cm 2 flasks to give a 5 ml suspension containing about 2 ⁇ 10 6 cells/ml. Suitable dilutions of HIV were added to infect the cultures.
  • the mean reverse transcriptase (RT) activity of the inocula was 50,000 dpm/ml which was equivalent to about 100 TCID 50 , determined as described in AIDS Res.Human Retro.3.71-85 (1987).
  • the drugs at twice their final concentrations in 5 ml of RPMI 1640 medium, supplemented as described above, were added to the cultures.
  • Uninfected and untreated PBM cells were grown in parallel as controls. The cultures were maintained in a humidified 5% CO 2 -95% air incubator at 37oC for five days after infection at which point all cultures were sampled for supernatant RT activity. Preliminary studies had indicated that maximum RT levels are obtained at that time.
  • RT activity assay Six ml of supernatant from each culture was clarified from cells at 300 x g for 10 minutes. Virus particles were then pelleted from 5 ml samples at 40,000 rpm for 30 minutes using a Beckman 70.1 Ti rotor and suspended in 200 ⁇ l of virus disrupting buffer (50 mM Tris-HCl, pH 7.8, 800 mM NaCl, 20% glycerol, 0.5 mM PMSF, and 0.5% Triton X-100).
  • virus disrupting buffer 50 mM Tris-HCl, pH 7.8, 800 mM NaCl, 20% glycerol, 0.5 mM PMSF, and 0.5% Triton X-100.
  • the RT assay was performed by a modification of the method of Spira, et al, in J. Clin.Microbiol. 25,97-99 (1987) in 96-well microtiter plates.
  • the radioactive cocktail (180 ⁇ l) which contained 50 mM Tris-HCl pH 7.8, 9 mM MgCl 2 , 5 mM dithiothreitol 4.7 ⁇ g/ml Poly (rA) n ⁇ (dT) 12-18 , 140 ⁇ M dATP and 0.22 ⁇ M[ 3 H]dTTP (specific activity 78.0 Ci/mmol, equivalent to 17,300 cpm/pmol; NEN Research Products, Boston, MA) was added to each well.
  • the sample (20 ⁇ l) was added to the reaction mixture and incubated at 37°C for two hours.
  • the reaction was terminated by the addition of 100 ⁇ l 10% trichloroacetic acid (TCA) containing 0.45 mM sodium pyrophosphate.
  • TCA trichloroacetic acid
  • the acid insoluble nucleic acid which precipitated was collected on glass filters using a Skatron semi-automatic harvester (setting 9) .
  • the filters were washed with 5% TCA and 70% ethanol, dried, and placed in scintillation vials.
  • Four ml of scintillation fluid (Econofluor, NEN Research Products, Boston MA) was added and the amount of radioactivity in each sample determined using a
  • the drugs were evaluated for their potential toxic effects on uninfected PHA-stimulated human PBM cells. Flasks were seeded so that the final cell concentration was 3 ⁇ 10 5 cells/ml. The cells were cultured with and without drug for 6 days at which time aliquots were counted for cell viability.
  • EC 50 is the median effective concentration of the compound as determined from the reverse transcriptase assay. Although these compounds exhibit reduced toxicity to normal cells, administration of a high concentration, a dosage which would result in a blood serum concentration of approximately 100 ⁇ M or higher, of such a drug would nevertheless produce some adverse side effects. Thus, compositions having a high concentration of the active ingredient are not considered to be therapeutically effective.
  • the therapeutic index of a compound is determined by dividing the inhibitory or lethal dose for 50% of the population (IC 50 or LD S0 ) by the effective dose for 50% of the population (EC 50 ).
  • the EC 50 for a variety of compounds according to the present invention are shown in Tables I - XVII. Compounds which are toxic at 10 ⁇ M are marked with an + . Compounds which are toxic at 100 ⁇ M are marked with an *. Compounds which are toxic at an excess of 100 ⁇ M are marked with >*.
  • R 1 is aromatic or substituted aromatic groups
  • R 2 is -NHX, -NX 2 , -OX, or -SX, where X is H or an organic group
  • R 3 is H or an alkyl. Examples are described in Table XIII below.
  • R 1 and R 2 are -NHX, -NX 2 , -OX, or -SX, where X is H or an organic group, and R 3 and R 4 is H or an alkyl. Examples are described in Table XIV.
  • R 1 and R 2 are aromatic, substituted aromatic, heteroaromatic, or substituted heteroaromatic.
  • An example is described in Table XVI.
  • Most of the compounds included in the present invention are in the form of free amines or hydrobromide salts.
  • One compound was prepared as a hydrochloride. All basic compounds may be prepared in the form of salts. Non-limiting examples are hydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates, and quaternary alkylammonium derivatives. Animal Toxicity Studies.
  • mice Compounds having low cytotoxicity and good anti-HIV activity are screened in mice for systemic toxicity.
  • the following specific compounds were injected into mice under the following conditions: 4-[3'-[[2"-(dimethylamino)ethyl]thio] phenyl]-2-[[2"'- (dimethylamino)ethyl]thio ⁇ pyrimidine (DH-19), 4,6-bis[4'-[[2''-(dimethylamino)ethyl]thio]phenyl]-5-methylpyrimidine (LS-22);
  • the least toxic compounds in BALB/C mice were M-116 and LS-22.
  • M-69 produced some toxicity at 60 mg/kg per day, given once a day for 10 days. Less toxicity is present in vivo than in vitro. Toxicity at concentrations of greater than 100 ⁇ M in cell culture is generally considered to be acceptable
  • Toxicity at concentrations of greater than 100 ⁇ M in cell culture is generally considered to be acceptable
  • Even chimpanzees are not considered to be good models since HIV apparently does not replicate well in non-human primates.
  • the data obtained from in vitro testing and in vivo toxicity studies is considered to be of sufficient predictive value that the Food and Drug Administration accepts them as the basis for an Investigational New Drug application for testing in humans infected with HIV.
  • the compounds of the present invention can be delivered using a variety of pharmaceutical vehicles and modes of delivery.
  • the preferred dosage is that which results in a plasma concentration of 10 ⁇ M.
  • the compound should show a half-life close to one hour.
  • Humans suffering from diseases caused by HIV can be treated by administering to the patient a pharmaceutically effective amount of the compound in the presence of a pharmaceutically acceptable carrier or diluent.
  • a preferred carrier/diluent for oral administration is water, especially sterilized water. If administered intravenously, preferred carrier/diluents are physiological saline or phosphate buffered saline (PBS).
  • the compounds according to the present invention are included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to exert a therapeutically useful inhibitory effect on HIV in vivo without exhibiting adverse toxic effects on the patient treated.
  • HIV inhibitory amount is meant an amount of active ingredient sufficient to exert an HIV inhibitory effect as measured by, for example, an assay such as the ones described herein.
  • the active materials can also be mixed with other active materials which do not impair the desired action and/or supplement the desired action.
  • the active materials according to the present invention can be administered by any route, for example,, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, in liquid or solid form.
  • a preferred mode of administration of the compounds of this invention is oral.
  • Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets.
  • the aforesaid compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like.
  • These preparations should produce a serum concentration of active ingredient of from about 0.2 to 40 ⁇ M.
  • a preferred concentration range is from 0.2 to 20 ⁇ M and most preferably about 1 to 10 ⁇ M.
  • the concentration of active ingredient in the drug composition itself will depend on bioavailability of the drug and other factors known to those of skill in the art.
  • dosage values will also vary with the specific severity of the disease condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted to the individual need and the professional judgment of the person administering or supervising the administration of the aforesaid compositions. It is to be further understood that the concentration ranges set forth herein are exemplary only and they do not limit the scope or practice of the invention.
  • the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.
  • the tablets, pills, capsules, troches and the like may contain the following ingredients: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, corn starch and the like; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; and a sweetening agent such as sucrose or saccharin or flavoring agent such as peppermint, methyl salicylate, or orange flavoring may be added.
  • a liquid carrier such as a fatty oil.
  • dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings.
  • tablets or pills may be coated with sugar, shellac, or other enteric coating agents.
  • a syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.
  • the solutions or suspensions may also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraphens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents
  • antibacterial agents such as benzyl alcohol or methyl paraphens
  • antioxidants such as ascorbic acid or sodium bisulfite
  • chelating agents such as ethylenediaminetetraacetic acid
  • buffers such
  • compositions of the present invention are prepared as formulations with pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carriers Preferred are those carriers that will protect the active compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as polyanhydrides, polyglycolic acid, collagen, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • Liposomal suspensions are also preferred as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811 (the pertinent portions of which are incorporated herein by reference). For example, liposome formulations may be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container.
  • appropriate lipid(s) such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol

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Abstract

Les composés de la présente invention sont des composés hétéropolycycliques non fusionnés dérivés, essentiellement des composés hétérotricycliques, formés en remplaçant les atomes d'halogène adjacents aux atomes d'azote de l'anneau diazine ou l'halogénine benzylique 2,6-bis[4-(bromométhyle)phényle]pyridine avec un nucléophile d'une variété de nucléophiles communs tels que l'ion hydroxyde, des alcoxydes, des mercaptides et des amines. Ces composés ont une interaction avec des acides nucléiques, inhibant ainsi la translation et interférant avec des procédés de réplication virale, tels que la réplication de HIV, le virus provoquant le SIDA. Les composés préférés sont 2,6-bis[4'-[diméthylamino]méthyle]phényle]pyridine (DH-23); 4,6-bis[4'-[[2''-(diméthylamino)éthyle]thio]phényle]-5-méthylpyrimidine (LS-22); N-[2''-(diméthylamino)éthyle]-4-(benzo[b]thiophène-2'-yle)quinazoline-2-amine (M-116); N,N-bis(2''''-hydroxyéthyle)-2-[[4'-(benzo[b]thiophène-2''-yle)-6'-(thiène-2'''-yl)pyrimidine-2'-yle]oxy]éthylamine (DH-42); bis-4,6-[4'-[[2''-(diméthylamino)éthyle]thio]phényle]pyrimidine (LS-20); 1-méthyle-4-[2'-[[4''-(naphth-2'''-yle) quinazoline-2''-yle]thio]éthyle]pipérazine (M-69); N,N-bis-(2'-hydroxyéthyle)-4,6-bis(thiène-2''-yle)pyrimidine-2-amine (M-103); N,N-bis(2'-hydroxyéthyle)-2-[[4'',6''-bis(thiène-2'''-yle)pyrimidine-2''yle]oxy]éthylamine (M-105); et 4-[3'-[[2''-(diméthylamino)éthyle]thio]phényle]-2-[[2'''-(diméthylamino)éthyle]thio] pyrimidine (DH-19). Ces composés sont avantageux car ils sont peu coûteux et faciles à produire.
PCT/US1989/002104 1988-05-16 1989-05-16 Compose heteropolycyclique non fusionne ayant une interaction avec des acides nucleiques WO1989011279A1 (fr)

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5366982A (en) * 1990-07-24 1994-11-22 Rhone-Poulenc Rorer S.A. Substituted bicyclic bis-aryl compounds exhibiting selective leukotriene B4 antagonist activity, their preparation and use in pharmaceutical compositions
WO1994027604A1 (fr) * 1993-05-28 1994-12-08 Taisho Pharmaceutical Co., Ltd. Utilisation medicale d'un derive de pyridine
WO1996035678A1 (fr) * 1995-05-08 1996-11-14 Pharmacia & Upjohn Company UTILISATION DE COMPOSES A BASE DE PYRIMIDINE-THIOALKYLE A SUBSTITUTION α ET D'ALKYLETHER EN TANT QU'INHIBITEURS DE LA TRANSCRIPTASE INVERSE VIRALE
WO1997044326A1 (fr) * 1996-05-23 1997-11-27 F. Hoffmann-La Roche Ag Derives d'aryl pyrimidine
US5949330A (en) * 1992-09-16 1999-09-07 Caterpillar Inc. Method and apparatus for displaying sensor outputs in a diagnostic system
US5952331A (en) * 1996-05-23 1999-09-14 Syntex (Usa) Inc. Aryl pyrimidine derivatives
US5958934A (en) * 1996-05-23 1999-09-28 Syntex (U.S.A.) Inc. Aryl pyrimidine derivatives and uses thereof
US6384060B1 (en) 1997-12-11 2002-05-07 American Home Products Corporation 2,4,6-trisbstituted pyridines with estrogenic activity and methods for the solid phase synthesis thereof
US6503917B1 (en) 1998-12-10 2003-01-07 Wyeth, Five Giralda Farms 2,4,6-trisubstituted pyridines with estrogenic activity and methods for the solid phase synthesis thereof
JP2009516697A (ja) * 2005-11-18 2009-04-23 イーライ リリー アンド カンパニー 癌および炎症性疾患の治療のためのｉｋｋ−ベータ阻害剤としての［４−（ベンゾ［ｂ］チオフェン−２−イル）ピリミジン−２イル］アミン誘導体
US7612105B2 (en) 1998-04-27 2009-11-03 Kumiai Chemical Industry Co., Ltd. 3-arylphenyl sulfide derivative and insecticide and miticide
US9975886B1 (en) 2017-01-23 2018-05-22 Cadent Therapeutics, Inc. Potassium channel modulators
US10774064B2 (en) 2016-06-02 2020-09-15 Cadent Therapeutics, Inc. Potassium channel modulators
US11618751B1 (en) 2022-03-25 2023-04-04 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 derivatives
US11993586B2 (en) 2018-10-22 2024-05-28 Novartis Ag Crystalline forms of potassium channel modulators
US12281112B2 (en) 2021-04-07 2025-04-22 Ventus Therapeutics U.S., Inc. Compounds for inhibiting NLRP3 and uses thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BROWN ET AL: "Unfused Heterobicycles as Amplifiers of Phleomycin. VI. Some Thienyl - and Thiazolyl Pyrimidines with Strongly Basic Side Chains.", AUSTRALIAN JOURNAL OF CHEMISTRY, vol. 35, 1982, pages 1209 - 1214 *
ELMOGHAYAR ET AL: "Nickel-Catalyzed Addition or Coupling Reaction of Grignard Reagents with Halopyrimidines.", ACTA CHEMICA SCANDINAVICA, vol. B37, 1983, pages 109 - 114 *
GRONOWITZ: "The reaction of 5 Bromo-and 2-Bromopyrimidine.", ACTA CHEMICA SCANDINAVICA, vol. 19, no. 7, 1965, pages 1741 - 1748 *
STREKOWSKI ET AL: "The Cine-Substitution Reaction of 5-Bromo-pyrimidines by Lithium.", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 51, 1986, pages 3226 - 3228 *

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5366982A (en) * 1990-07-24 1994-11-22 Rhone-Poulenc Rorer S.A. Substituted bicyclic bis-aryl compounds exhibiting selective leukotriene B4 antagonist activity, their preparation and use in pharmaceutical compositions
US5949330A (en) * 1992-09-16 1999-09-07 Caterpillar Inc. Method and apparatus for displaying sensor outputs in a diagnostic system
WO1994027604A1 (fr) * 1993-05-28 1994-12-08 Taisho Pharmaceutical Co., Ltd. Utilisation medicale d'un derive de pyridine
US6043248A (en) * 1995-05-08 2000-03-28 Pharmacia & Upjohn Company Alpha-substituted pyrimidine-thioalkyl and alkylether compounds as inhibitors of viral reverse transcriptase
WO1996035678A1 (fr) * 1995-05-08 1996-11-14 Pharmacia & Upjohn Company UTILISATION DE COMPOSES A BASE DE PYRIMIDINE-THIOALKYLE A SUBSTITUTION α ET D'ALKYLETHER EN TANT QU'INHIBITEURS DE LA TRANSCRIPTASE INVERSE VIRALE
EP1449835A2 (fr) * 1995-05-08 2004-08-25 PHARMACIA & UPJOHN COMPANY Composés thioalkylés et alkyléthérés de pyrimidine
EP1449835A3 (fr) * 1995-05-08 2004-09-15 PHARMACIA & UPJOHN COMPANY Composés thioalkylés et alkyléthérés de pyrimidine
US5863924A (en) * 1996-05-23 1999-01-26 Syntex (U.S.A.) Inc. Aryl pyrimidine derivatives
WO1997044326A1 (fr) * 1996-05-23 1997-11-27 F. Hoffmann-La Roche Ag Derives d'aryl pyrimidine
US5952331A (en) * 1996-05-23 1999-09-14 Syntex (Usa) Inc. Aryl pyrimidine derivatives
US5958934A (en) * 1996-05-23 1999-09-28 Syntex (U.S.A.) Inc. Aryl pyrimidine derivatives and uses thereof
US6384060B1 (en) 1997-12-11 2002-05-07 American Home Products Corporation 2,4,6-trisbstituted pyridines with estrogenic activity and methods for the solid phase synthesis thereof
US6384057B1 (en) 1997-12-11 2002-05-07 American Home Products Corporation 2,4,6-trisubstituted pyridines with estrogenic activity and methods for the solid phase synthesis
US6384058B1 (en) 1997-12-11 2002-05-07 American Home Products Corporation 2,4,6-trisubstituted pryridines with estrogenic activity and methods for the solid phase synthesis thereof
US7612105B2 (en) 1998-04-27 2009-11-03 Kumiai Chemical Industry Co., Ltd. 3-arylphenyl sulfide derivative and insecticide and miticide
US7767626B2 (en) 1998-04-27 2010-08-03 Kumiai Chemical Industry Co., Ltd. 3-arylphenyl sulfide derivative and insecticide and miticide
US6503917B1 (en) 1998-12-10 2003-01-07 Wyeth, Five Giralda Farms 2,4,6-trisubstituted pyridines with estrogenic activity and methods for the solid phase synthesis thereof
JP2009516697A (ja) * 2005-11-18 2009-04-23 イーライ リリー アンド カンパニー 癌および炎症性疾患の治療のためのｉｋｋ−ベータ阻害剤としての［４−（ベンゾ［ｂ］チオフェン−２−イル）ピリミジン−２イル］アミン誘導体
US10774064B2 (en) 2016-06-02 2020-09-15 Cadent Therapeutics, Inc. Potassium channel modulators
US9975886B1 (en) 2017-01-23 2018-05-22 Cadent Therapeutics, Inc. Potassium channel modulators
US10351553B2 (en) 2017-01-23 2019-07-16 Cadent Therapeutics, Inc. Potassium channel modulators
US10717728B2 (en) 2017-01-23 2020-07-21 Cadent Therapeutics, Inc. Potassium channel modulators
US11993586B2 (en) 2018-10-22 2024-05-28 Novartis Ag Crystalline forms of potassium channel modulators
US12281112B2 (en) 2021-04-07 2025-04-22 Ventus Therapeutics U.S., Inc. Compounds for inhibiting NLRP3 and uses thereof
US11618751B1 (en) 2022-03-25 2023-04-04 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 derivatives
US12168657B2 (en) 2022-03-25 2024-12-17 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 derivatives
US12195460B2 (en) 2022-03-25 2025-01-14 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 inhibitors

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