WO1992005173A1 - Composes tricycliques substitues - Google Patents

Composes tricycliques substitues Download PDF

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Publication number
WO1992005173A1
WO1992005173A1 PCT/US1991/006815 US9106815W WO9205173A1 WO 1992005173 A1 WO1992005173 A1 WO 1992005173A1 US 9106815 W US9106815 W US 9106815W WO 9205173 A1 WO9205173 A1 WO 9205173A1
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Prior art keywords
group
compound
carbon
nitrogen atom
formula
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PCT/US1991/006815
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English (en)
Inventor
Siegfried H. Reich
Mary Ann M. Fuhry
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Agouron Pharmaceuticals, Inc.
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Priority to JP3516068A priority Critical patent/JPH06503814A/ja
Publication of WO1992005173A1 publication Critical patent/WO1992005173A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to certain
  • TS thymidylate synthase
  • antiproliferative agents includes antimetabolite compounds.
  • a particular subclass of antimetabolites known as antifolates or "antifols" are antagonists of the vitamin folic acid.
  • antifolates closely resemble the structure of folic acid, including the characteristic p-benzoyl glutamate moiety of folic acid.
  • TS has long been considered an important target enzyme in the design and synthesis of antitumor agents, and a number of folate analogues have been synthesized and studied for their ability to inhibit TS. See, for example, Brixner et al., Folate Analogues as Inhibitors of Thymidylate Synthase, J. Med. Chem. 30, 675 (1987); Jones et al., Quinazoline Antifolates Inhibiting Thymidylate
  • the present invention introduces a novel class of substituted tricyclic compounds which do not
  • the present invention also relates to pharmaceutical compositions containing these substituted tricyclic compounds and the use of these compounds to inhibit TS, including all effects derived from the inhibition of TS. Effects derived from the inhibition of TS include the
  • substituted tricyclic compounds of the invention are also disclosed.
  • the present invention relates to antiproliferative tricyclic compounds capable of inhibiting thymidylate synthase having the Formula (Q): (Q)
  • X and Y form a five- or six-membered heterocyclic ring containing at least one nitrogen;
  • Z is a hydrogen, halogen, carbon, oxygen or
  • U is a carbon or nitrogen atom
  • n 0 or the integer 1;
  • V is a carbon or nitrogen atom
  • W is a carbon or nitrogen atom
  • A is in the 1- or 2-position and is a nitrogen
  • Ar is an aryl or heteroaryl group having one or more rings
  • B is either (i) an oxygen or nitrogen atom, or a
  • -CO- or -SO 2 - group any of which is linked to an amino acid, aryl group, heterocyclic group or alkll group, or (ii) a substituted or unsubstituted alkyl group.
  • a compound capable of inhibiting thymidylate synthase denotes a compound with a TS inhibition constant K i of less than or equal to about 10 -4 M.
  • K i values in the range of less than about 10 -5 M, preferably less than about 10 -6 M, even more preferably less than about 10 -9 M and, most preferably, in the range from about 10 -12 to about 10 -14 M.
  • X and Y in Formula (Q) can form any five- or six- membered heterocyclic ring containing at least one nitrogen such as, for example, pyrrole, imidazole,pyrazole, pyridine, pyrazine, pyrimidine, and
  • X and Y form the ring:
  • P is hydrogen; a lower alkyl group such as methyl, ethyl, propyl, isopropyl, tert-butyl and the like; or an amino group -NR 1 R 2 wherein R 1 and R 2
  • Z in Formula (Q) can be a hydrogen atom; a halogen atom such as chloro, bromo, or fluoro; a carbon atom which, taken with other appropriate atoms, may form such groups as substituted or unsubstituted alkyl, alkenyl, alkynyl, alkyl-oxy-alkylene, allyl, benzyl, acetyl, carbamyl, carbalkoxy, cyano, phenylacetyl, aminoalkyl or the like; an oxygen atom which, taken together with other appropriate atoms, may form such groups as hydroxy, alkoxy, oxamido, oxamyl, acetoxy, phenoxy, phenylsulfamyl, phenylsulfonamido or the like; or a nitrogen atom which, taken with other appropriate atoms, may form such groups as amino, nitro, acetamido, anilino, benzamido,
  • n in Formula (Q) can be 0 or 1, but is preferably 0.
  • the left-hand ring in the formula as written above is either a 6- or 7- membered ring.
  • U, V.and W in Formula (Q) are each independently carbon or nitrogen atoms and, taken together with (CH 2 ) n and other appropriate carbon atoms as indicated in the formula, form a 6- or 7-membered ring such as, for example, a benzene, cyclohexene, pyridlne,
  • tetrahydropyridine pyridazine, pyrimidine, 1,2,3- triazine, cycloheptene, tetrahydroazepine or the like ring.
  • U is a carbon atom
  • V is a carbon atom
  • W is a nitrogen atom.
  • U, V and W are, taken together with (CH 2 ) n and one or more other carbon atoms as indicated in the above formula, form a ring having the following
  • a in Formula (Q) above is in the 1- or 2-position of the ring formed by U, -(CH 2 ) n , V, W and the other appropriate atoms referred to above.
  • A can be a nitrogen atom which, taken with other appropriate atoms, may form such groups as di- or trisubstituted amine or the like; a sulfur etom which, taken with other appropriate atoms, may form such groups as a thio linkage (-S-), thioalkylene, thioamide and the like; or any substituted or unsubstituted alkylene group such as, for example, methylene, ethylene, n-propylene, isopropylene, n-butylene, tert-butylene, n-hexylene or the like.
  • A is sulfur, then W and V should be carbon to produce a reasonably stable compound.
  • A is a substituted or unsubstituted alkylene group such as, for example, methylene, ethylene, n-propylene, isopropylene, n- butylene, tert-butylene, n-hexylene, or the like.
  • Ar can be any one of a large number of aryl or heteroaryl groups having one or more rings.
  • aryl ring groups include phenyl, 1,2,3,4-tetrahydronaphthyl, naphthy1,
  • heteroaryl groups include 5-membered monocyclic ring groups such as thienyl, pyrrolyl, 2H-pyrrolyl,
  • Ar is a monocyclic or bicyclic aryl group, such as phenyl or naphthyl.
  • B a substituent on the Ar grcJup discussed above, can be an oxygen atom which may be taken alone to form an ether linkage. (-0-) or which may be taken together with other appropriate atoms to form such groups as hydroxy, alkylenoxy, oxamido, oxamyl, acetoxy, phenoxy, phenylsulfamyl, phenylsulfonamido or the like; or a nitrogen atom which, taken with other appropriate atoms, may form such groups as amino NR 1 R 2 wherein R 1 and R 2 can each independently be alkyl, or the like, nitro, acetamido, anilino, benzamido, formamido, hydrazino, hydroxamino, isocyano, nitramino, nitroso, oxamido, sulfamido or the like; or a -CO- or -SO 2 - group.
  • Any one of the divalent B groups above may be further linked to an amino acid group such as alanine, arginine, aspargine, aspartic acid, cysteine,
  • B itself may be an alkyl group such as methyl, ethyl, n- propyl, isopropyl, n-butyl, tert-butyl, n-hexyl or the like.
  • B is an -CO- or -SO 2 - group linked to an aryl or heterocyclic group
  • B includes an aryl group
  • the aryl group may be
  • Typical substituents include halogen, hydroxy, alkoxy, alkyl, hydroxyalkyl,
  • B is an -SO 2 - group linked to a phenyl group which is either unsubstituted or
  • alkyl such as methyl
  • T is H or -CN.
  • Ar in Formula (Q) can also be substituted with one or more of a wide variety of electron-donating and electron- withdrawing substituents.
  • Typical substituents include halogen, hydroxy, alkoxy, alkyl, hydroxyalkyl,
  • fluoroalkyl amino, -CN, -NO 2 , carbalkoxy, carbamyl, carbonyl, carboxyldioxy, carboxy, amino acid carbonyl, amino acid sulfonyl, sulfamyl, sulfanilyl, sulfhydryl, sulfino, sulfinyl, sulfo, sulfonamido, sulfonyl or the like.
  • these additional substituents are selected from the group consisting of -CN, fluoroalkyl, and sulfonyl.
  • X and Y in Formula (Q) form the ring:
  • P is lower alkyl such as methyl, amino or hydrogen
  • U is carbon
  • n is 0
  • V is carbon
  • W is nitrogen
  • A is methylene
  • -Ar-B is selected from the group consisting of:
  • R is H or alkyl, such as methyl; and CH 2 -OH
  • T is H or -CN.
  • alkyl such as methyl
  • T is H or -CN .
  • P is selected from the group consisting of -NH 2 and methyl; U is carbon; n is 0; V is carbon; W is nitrogen; A is methylene; and -Ar-B is OCH 3
  • the invention also relates to a process for making the compounds of the present invention comprising the steps of:
  • X-precursor and Y-precursor are groups which, when cyclized with each other, form a five- or six- membered heterocyclic ring containing at least one nitrogen, to form a substituted compound having the formula: X-precursor
  • the displaceable group D can be any group which is displaceable under the reaction conditions used and is typically a halogeno such as fluoro, chloro or bromo; a substituted sulfonyloxy such as methanesulfonyloxy, trifluoromethanesulfonyloxy, toluene-p-sulfonyloxy, or 4-bromobenzenesulfonyloxy; an aldehyde; or the like.
  • a halogeno is a preferred displaceable group, with bromo being particularly preferred.
  • the first step, reacting B-Br-A-D with a compound of Formula (I), may be carried out in an organic solvent.
  • organic solvent typically, when an organic solvent is used, it is an aprotic solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, or
  • tetrahydrofuran Especially preferred solvents include dimethylformamide and dimethylacetamide.
  • the first step is carried out in the presence of a. weak base which will not itself react with one of the reactants.
  • a. weak base include, for example, organic bases such as a substituted amine such as diisopropylethylamine, dimethyl-sec-butylamine, N- methyl-N-ethylaniline, N,N-dimethylaniline or the like; and inorganic weak bases .such as sodium, potassium and/or calcium carbonate or the like.
  • the reaction temperature for the first step can vary from about room temperature to about 100°C, but preferably ranges from about 65°C to about 85°C.
  • the second step of cyclizing X-precursor and Y- precursor with each other to form a five- or six- membered heterocyclic ring containing at least one nitrogen atom is carried out in the presence of a cyclizing agent such as HC(OCH 3 ) 3 /HCl, CNBr,
  • the cyclizing agent is HC(OCH 3 ) 3 /HCl or CNBr.
  • the reaction may be carried out in the presence of an organic solvent, such as methanol, ethanol, butanol, acetonitrile, mixtures thereof or the like.
  • an organic solvent such as methanol, ethanol, butanol, acetonitrile, mixtures thereof or the like.
  • the cyclizing agent is CNBr, for example, a mixture of methanol and acetonitrile can advantageously be used.
  • the cyclizing agent is
  • the starting material is typically dissolved in the HC(OCH 3 ) 3 itself without any additional solvent, and a relatively small amount of HCI is then added to initiate the cyclizing step.
  • the temperature used for the cyclizing step ranges from just below room temperature to about 70°C, but is preferably from about 20 to about 60°C. It should be noted that one or more of X- precursor, Y-precursor, U, V and W may contain a chemical group or groups which, either before, after or during the course of either the substitution step (1) or the cyclizing step (2) :
  • (a) may be protected by a protecting group
  • (b) may have one or more of any protecting groups present removed.
  • a suitable protecting group for a ring nitrogen, such as U, V or W may be, for example, a
  • pivaloyloxymethyl group which may be removed by hydrolysis with a base such as sodium hydroxide; a tert-butyloxycarbonyl group, which may be removed by hydrolysis with an acid such as hydrochloric acid or with a base such as lithium hydroxide; or a 2- (trimethylsilyl)ethoxymethyl group, which may be removed by a fluoride salt such as tetra-n-butyl ammonium flouride or with an acid such as hydrochloric acid.
  • a base such as sodium hydroxide
  • a tert-butyloxycarbonyl group which may be removed by hydrolysis with an acid such as hydrochloric acid or with a base such as lithium hydroxide
  • a 2- (trimethylsilyl)ethoxymethyl group which may be removed by a fluoride salt such as tetra-n-butyl ammonium flouride or with an acid such as hydrochloric acid.
  • a suitable protecting group for a hydroxyl group is, for example, an esterifying group such as an acetyl or benzoyl group, which may be removed by hydrolysis with a base such as sodium hydroxide.
  • the protecting group may be, for example, an alpha-arylalkyl group such as a benzyl group, which may be removed by
  • a suitable protective group for a mercapto group is, for example, an esterifying group such as an acetyl group, which may be removed by hydrolysis with a base such as sodium hydroxide.
  • a suitable protective group for an amino group may be, for example, an alkylcarbonyl group such as an acetyl group (CH 3 CO-) or a benzoyl group, which may be removed by treatment with an inorganic acid such as nitric, sulfuric or hydrochloric acid, or by base hydrolysis with sodium hydroxide.
  • Another protective group for an amino group is an alkoxycarbonyl group such as a methoxycarbonyl or a tert-butyloxycarbonyl group. These groups may be removed by treatment with an organic acid such as trifluoroacetic acid.
  • the protective group may be a
  • a suitable protective group for a primary amino group is, for example, an alkylcarbonyl group such as acetyl, which may be removed by treatment with an inorganic acid such as nitric, sulfuric or hydrochloric acid, or a phthaloyl group, which may be removed by treatment with an alkylamine such as 3- dimethylaminopropyl amine, with hydrazine, or with ammonia.
  • an alkylcarbonyl group such as acetyl
  • an inorganic acid such as nitric, sulfuric or hydrochloric acid
  • a phthaloyl group which may be removed by treatment with an alkylamine such as 3- dimethylaminopropyl amine, with hydrazine, or with ammonia.
  • a suitable protective group for a carboxy group may be an esterifying group, for example, a methyl or an ethyl group, which may be removed by hydrolysis with a base such as sodium hydroxide.
  • Another useful protecting group is a tert-butyl group, which may be removed by treatment with an organic acid such as trifluoroacetic acid.
  • Preferred protective groups include an esterifying group, an alpha-arylalkyl group, an alkylcarbonyl group, a substituted or unsubstituted alkoxycarbonyl group, a phthaloyl group, a pivaloyloxymethyl group or a methyl oxyether-type group such as methoxymethyl or 2-(trimethylsilyl)ethoxymethyl.
  • a particular aspect of the invention relates to a process of making a substituted tricyclic compound capable of inhibiting thymidylate synthase from a starting compound of Formula (I), wherein the compound of Formula (I) has the structure of Formula (II):
  • a process of making this group of starting compounds may comprise the steps of:
  • adding a protective group to a compound of Formula II to form the corresponding acetamide is preferably performed by treating the amine compound of Formula (III) with an appropriate anhydride compound, such as acetic anhydride, in the presence of an oiganic solvent, such es pyridine or the like.
  • an oiganic solvent such es pyridine or the like.
  • a protective group occurs at a temperature between about -10 and +15°C and, most preferably, between about -10 and -5°C.
  • the second step of nitrating the acetamide formed by selectively protecting the amine compound can be carried out in the presence of one or more of the many known nitrating agents, such as (1) a mixture of nitric and sulfuric acids; (2) a mixture of nitric, sulfuric and acetic acids; or (3) a mixture of nitric acid and acetic anhydride.
  • the nitrating agent is a mixture of nitric and sulfuric acids.
  • the nitration step may be carried out over a wide range of
  • the amine compound of Formula (III) itself can be prepared by several different reaction schemes.
  • the amine compound of Formula (III) is prepared by reducing a compound corresponding to the amine having one or more sites of unsaturation in the 6- or 7-membered ring formed by U, V and W taken in combination with an appropriate number of carbon and hydrogen atoms.
  • the reduction can be performed under widely varying reduction conditions, but is preferably carried out in water or in an organic solvent such as methanol, ethanol, tetrahydrofuran, acetic acid or the like, in the presence of a reducing agent such as a hydrazine compound or hydrogen gas at a pressure of at least one atmosphere, preferably at a pressure from about 1 to about 50 psi.
  • a reduction catalyst is also used, such as platinum oxide (as described in Ishikawa et al., Chem. Pharm. Bull., 37, 2103 (1989) which is hereby incorporated by reference).
  • the compound corresponding to the amine having one or more sites of unsaturation has the formula:
  • the amine compound of Formula (III) is prepared by:
  • the reaction conditions for the nitration step (1) are cypically as described above for general nitration reactions.
  • the nitration step is performed in the presence of nitric acid and at a temperature between about -10 to about 20°C.
  • reaction conditions used for the reduction step (2) can vary greatly but, typically, include one or more of the following: (a) treatment with SnCl 2 in the presence of hydrochloric acid; (b) treatment with zinc in the presence of acetic acid; (c) treatment with Fe +3 (CO) 12 in benzene and methanol; (d) treatment with hydrogen gas in the presence of a palladium-on-charcoal catalyst; (e) treatment with hydrogen gas in the presence of a platinum oxide catalyst in an organic solvent such as glacial acetic acid; and (f) treatment with a hydrazine in the presence of a reduction
  • the reduction step (2) is carried out with hydrogen gas as the reducing agent in the presence of a palladium-on-charcoal catalyst in an organic solvent, for example, an alcohol such as methanol.
  • the compound of Formula (IV) has the formula:
  • Ac is an acetyl (CH 3 CO-) protective group which is removed between the nitration step and the reduction step.
  • the removal of this protective group can be accomplished by the general methods described above for removal of protective groups from amino groups.
  • the acetyl group is removed by treatment with an inorganic acid such as hydrochloric acid in a solvent, for example, water, an alcohol such as ethanol, or a mixture of water and an alcohol at a temperature about the boiling point of the solvent.
  • a solvent for example, water, an alcohol such as ethanol, or a mixture of water and an alcohol at a temperature about the boiling point of the solvent.
  • X-precursor is -NH-Ac and Y-precursor is -NO 2 .
  • the -NH-Ac and -NO 2 groups can be cyclized with each other using one of several alternative methods, two of which are described below as methods (A) and (B).
  • a deprotecting agent for example, an
  • inorganic acid such as hydrochloric acid, to convert the -NH-Ac group to a free amino group
  • a reducing agent for example, hydrazine in the presence of a reduction catalyst such as Raiiey nickel
  • a cyclizing agent such as HC(OCH 3 ) 3
  • the cyclizing agent selected will determine the identity of P. For example, if the cyclizing agent selected is HC(OCH 3 ) 3 , P will be hydrogen; if the cyclizing agent is CH 3 C(OCH 3 ) 3 , P will be a methyl group, and if the cyclizing agent is CNBr, P will be the amino.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a
  • composition preferably contains a total amount of a compound of the invention which is an efficacious amount.
  • substituted tricyclic compounds of the present invention which may be employed in the pharmaceutical compositions of the invention include all of those compounds described above, as well as the
  • Pharmaceutically acceptable salts of these compounds are formed where appropriate with strong or moderately strong organic or inorganic acids in the presence of a basic amine by methods known to the art.
  • Exemplary of the acid addition salts which are included in this invention are maleate, fumarate, lactate, oxalate, methanesulfonate, ethanesulfonate, benzenesulfonate, tartrate, citrate, hydrochloride, hydrobromide, sulfate, phosphate and nitrate salts.
  • Pharmaceutically acceptable base addition salts of compounds of the invention containing an acidic group are prepared by known methods from organic and inorganic bases and include, for example, nontoxic alkali metal and
  • alkaline earth bases such as calcium, sodium,
  • potassium and ammonium hydroxide potassium and ammonium hydroxide; and nontoxic organic bases such as triethylamine, butylamine, piperazine, and tri(hydroxymethyl)methylamine.
  • the compounds of the invention possess antiproliferative activity, a property which may express itself in the form of antitumor activity.
  • a compound of the invention may be active per se or it may be a pro-drug that is converted in vivo to an active compound.
  • Preferred compounds of the invention are active in inhibiting the ⁇ growth of the L1210 celi line, a mouse leukemia cell line which can be grown in tissue culture.
  • Such compounds of the invention are also active in inhibiting the growth of bacteria such as Escherichia coli, a gram-negative bacterium which can be grown in culture.
  • substituted tricyclic compounds according to the present invention may be incorporated into convenient dosage forms such as capsules, tablets or injectable preparations.
  • Solid carriers include starch, lnctose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid.
  • Liquid carriers include syrup, peanut oil, olive oil, saline and water.
  • the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. When a liquid carrier is used, the
  • preparation may be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid (e.g. solution), such as an ampoule, or an aqueous or nonaqueous liquid suspension.
  • sterile injectable liquid e.g. solution
  • an ampoule or an aqueous or nonaqueous liquid suspension.
  • the pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving steps such as mixing, granulating and
  • compositions of the invention may further comprise one or more other compounds which are
  • antitumor agents such as mitotic inhibitors (e.g., vinblastine), alkylating agents (e.g., cis-platin, carboplatin and cyclophosphamide), DHFR inhibitors (e.g., methotrexate, piritrexim or trimetrexate), antimetabolltes (e.g., 5-fluorouracil and cytosine arabinoside), intercalating antibiotics (e.g.,
  • enzymes e.g., adriamycin and bleomycin
  • enzymes e.g., adriamycin and bleomycin
  • etoposide or biological response modifiers (e.g., interferon).
  • biological response modifiers e.g., interferon
  • composition of the invention may also comprise one or more other compounds including antibacterial, antifungal, antiparasitic, antiviral, antipsoriatic and anticoccidial agents.
  • antibacterial agents include, for example, sulfonamides such as
  • DHFR inhibitors such as trimethoprim, bromodiaprim or trimetrexate
  • penicillins
  • cephalosporins aminoglycosides
  • bacteriostatic inhibitors of protein synthesis the
  • Another aspect of the invention relates to a therapeutic process of inhibiting thymidylate synthase, which process comprises administering to a vertebrate host such as a mammal or bird an amount effective to inhibit thymidylate synthase of a tricyclic compound according to the present invention.
  • the compounds of the invention are particularly useful in the treatment of mammalian hosts, such as human hosts, and in the treatment of avian hosts.
  • an efficacious quantity of active compound comprising an efficacious quantity of active compound.
  • an efficacious quantity is meant a quantity
  • An exemplary daily dosage unit for a vertebrate host comprises an amount of up to about 5,000 mg of active compound per square meter of the body area of the vertebrate host.
  • the selected dose may be administered to a
  • warmblooded animal or mammal for example a human patient, in need of treatment mediated by thymidylate synthase inhibition by any known method of
  • topically e.g., as an ointment or cream
  • rectally e.g., as a suppository
  • parentally by injection or continuously by infusion, intravaginally, intranasally,
  • the substituted tricyclic compounds according to the present Invention may be further characterized as producing any one or more of an antiproliferative effect, an antibacterial effect, an antiparasitic effect, an antiviral effect, an antipsoriatic effect, an antiprotozoal effect, an anticoccidial effect or an antifungal effect.
  • the compounds are especially useful in producing an antitumor effect in a vertebrate host harboring a tumor.
  • the compounds of the present invention are:
  • antagonists of a folate cofactor may affect one or more other folate-dependent enzymatic systems as well.
  • Examples of other folate-dependent enzymatic systems which may be affected include 5,10- methylenetetrahydrofolate reductase, serine
  • microanalysis or, in certain cases, by mass
  • Proton magnetic resonance spectra were determined using a General Electric QE-300 spectrometer operating at a field strength of 300MHz. Chemical shifts are reported in parts per million ( ⁇ ) and by setting the references such that, in CDCl 3 , the CHCl 3 peak is at 7.26 ppm and, in D 6 DMSO, the DMSO peak is at 2.49 ppm. Standard and peak multiplicities are designated as follows: s, singlet; d, doublet; dd, doublet of doublets; t, triplet; brs, broad singlet; brd, broad doublet; br, broad signal; and m, multiplet.
  • Mass spectra were determined using a VG 7070E-HF high resolution mass spectrometer using the direct insertion method, an ionizing voltage of 70eV, and an ion source temperature of 200°C. Infrared absorption spectra were taken on a Perkin-Elmer 457 spectrometer. Elemental microanalysis gave results for the elements stated with ⁇ 0.4% of the theoretical values.
  • N-N-Dimethylformamide (“DMF”) was dried over activated (250°) 3-A molecular sieves, and N,N- dimethylacetamide (“DMA”) ( ⁇ ldrich Gold Label grade) was similarly dried.
  • DMA N,N- dimethylacetamide
  • Tetrahydrofuran THF was distilled from sodium benzophenone ketyl under
  • ether refers to diethyl ether.
  • petrol refers to petroleum ether of b.p. 36- 53°C.
  • Flash chromatography was performed using Silica gel 60 (Merck Art 9385). Where the crude solid was insoluble in the chosen eluant, it was dissolved in a more polar solvent, and Merck Art 7734 silica was added. The slurry was evaporated to dryness on a rotary evaporator fitted with a course glass frit to prevent spraying of the silica. The coated silica was then applied to the column. Thin layer chromatographs ("TLC”) were performed on precoated sheets of silica 60 F 254 (Merck Art 5719). Extracts were dried over
  • 6-Nitrotetrahydroquinoline, 2 (29.00g, 0.16 mol), in 200 ml MeOH and 10% palladium-on-charcoal (3.00g) was shaken on a Parr hydrogenator with 35 psi H 2 for 1.5 hours. The mixture was filtered through a diatomaceous earth material sold under the trade name Celite, concentrated, and purified by flash chromatography (50%
  • 6-Aminoquinoline (1.00g, 6.93 mmol) in 20 ml glacial acetic acid over P t O 2 (0.06g, 0.30 mmol) was shaken at 45 psi for two hours in accordance with the procedure of Ishikawa et al., Chem. Pharm. Bull., 37, 2103 (1989). The mixture was filtered though a
  • diatomaceous earth material sold under the trade name Celite, basified with 6N NaOH, and extracted with CH 2 Cl 2 (2 x 100 ml). The organic layer was washed with water, dried over anhydrous Na 2 SO 4 , and concentrated to a grey solid, 0.62g (4.18 mmol, 60%).
  • Compound 17 was prepared by the following
  • Thymidylate synthase inhibition constants K i have been determined by the following method. All essays were run at 25°C and initiated by the addition of three different types of thymidylate synthase (“TS”): (1)
  • ETS Escherichia coli TS
  • CTS Candida TS
  • HTS human TS
  • TS exhibits ordered bireactant kinetics (Daron, H.H. and Aull, J.L., J. Biol. Chem. 253, 940-9451
  • All reaction mixtures contained 50 mM Tris at pH 7.8 (the final pH of the reaction was 7.6), 10 mM DTT (dithiothreitol), 1 mM EDTA
  • IC 50 values were determined in 150 microliter microcultures each containing 1500 (L1210), 4000 (CCRF- CEM) or 10,000 (GC 3 /M TK) cells established in 96 well plates in growth medium supplemented with 50 IU/ml penicillin and 50 mcg/ml streptomycin. Growth was measured over 3 days (L1210) or 5 days (CCRF-CEM and GC 3 /M TK) of continuous exposure to varying

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  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Communicable Diseases (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention se rapporte à des composés représentés par la formule (Q); où: X et Y forment une chaîne fermée hétérocyclique à 5 ou 6 éléments, contenant au moins un azote; Z représente un atome d'hydrogène, d'halogène, de carbone, d'oxygène ou d'azote; U représente un atome de carbone ou d'azote; n est égal à 0 ou au nombre entier 1; V représente un atome de carbone ou d'azote; W représente un atome de carbone ou d'azote; A, qui se trouve dans la position 1 ou 2, représente un atome d'azote, un atome de soufre ou un groupe alkylène substitué ou non substitué; Ar représente un groupe aryle ou hétéroaryle comportant une ou plusieurs chaînes fermées, et B représente soit (i) un atome d'oxygène ou d'azote ou un groupe -CO- ou -SO2-, élément qui, quel qu'il soit est lié à un acide aminé, à un groupe aryle, à un groupe hétérocyclique ou à un groupe alkyle; soit (ii) un groupe alkyle substitué ou non substitué. De tels composés ont le pouvoir d'inhiber l'enzyme thymidilate-synthase (TS). L'invention se rapporte également à des compositions pharmaceutiques contenant ces composés tricycliques et à l'utilisation de ces composés pour produire l'effet d'inhibition de l'enzyme TS, ainsi que tous les effets tirés de cet effet d'inhibition de l'enzyme TS. Les effets tirés de l'effet d'inhibition de l'enzyme TS sont l'inhibition de la croissance et de la prolifération des cellules d'organismes supérieurs et de microorganismes, tels que levures et champignons, ainsi qu'une action antitumorale.
PCT/US1991/006815 1990-09-25 1991-09-25 Composes tricycliques substitues WO1992005173A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP3516068A JPH06503814A (ja) 1990-09-25 1991-09-25 置換三環式化合物

Applications Claiming Priority (2)

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US58766690A 1990-09-25 1990-09-25
US587,666 1990-09-25

Publications (1)

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WO1992005173A1 true WO1992005173A1 (fr) 1992-04-02

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PCT/US1991/006815 WO1992005173A1 (fr) 1990-09-25 1991-09-25 Composes tricycliques substitues

Country Status (10)

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EP (1) EP0550589A1 (fr)
JP (1) JPH06503814A (fr)
CN (1) CN1062908A (fr)
AU (1) AU8628791A (fr)
CA (1) CA2091690A1 (fr)
IL (1) IL99551A0 (fr)
MX (1) MX9101228A (fr)
WO (1) WO1992005173A1 (fr)
YU (1) YU155791A (fr)
ZA (1) ZA917613B (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994003439A1 (fr) * 1992-07-29 1994-02-17 Agouron Pharmaceuticals, Inc. Composes tricycliques a activite antiproliferatrice
US5747499A (en) * 1994-05-05 1998-05-05 British Technology Group Limited Anti-cancer compounds
US5789417A (en) * 1992-11-06 1998-08-04 Zeneca Limited Tricyclic compounds with pharmaceutical activity
WO2006108488A1 (fr) * 2005-04-14 2006-10-19 F. Hoffmann-La Roche Ag Derives d'azole tricycliques, leur fabrication et leur utilisation en tant que principes pharmaceutiques
US7524635B2 (en) 2003-04-17 2009-04-28 Biosite Incorporated Methods and compositions for measuring natriuretic peptides and uses thereof
WO2011121309A1 (fr) * 2010-03-31 2011-10-06 Takeda Pharmaceutical Company Limited Dérivés phénylsulfonyle et leur utilisation comme antagonistes de l'histamine h3
US8791101B2 (en) 2005-07-15 2014-07-29 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US8987252B2 (en) 2007-05-10 2015-03-24 Albany Molecular Research, Inc. Aryloxy- and heteroaryloxy-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0365763A1 (fr) * 1988-09-30 1990-05-02 Agouron Pharmaceuticals, Inc. Composés cycliques antiproléfératifs

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0365763A1 (fr) * 1988-09-30 1990-05-02 Agouron Pharmaceuticals, Inc. Composés cycliques antiproléfératifs

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994003439A1 (fr) * 1992-07-29 1994-02-17 Agouron Pharmaceuticals, Inc. Composes tricycliques a activite antiproliferatrice
US5789417A (en) * 1992-11-06 1998-08-04 Zeneca Limited Tricyclic compounds with pharmaceutical activity
US5747499A (en) * 1994-05-05 1998-05-05 British Technology Group Limited Anti-cancer compounds
US7524635B2 (en) 2003-04-17 2009-04-28 Biosite Incorporated Methods and compositions for measuring natriuretic peptides and uses thereof
WO2006108488A1 (fr) * 2005-04-14 2006-10-19 F. Hoffmann-La Roche Ag Derives d'azole tricycliques, leur fabrication et leur utilisation en tant que principes pharmaceutiques
US8791101B2 (en) 2005-07-15 2014-07-29 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US9403776B2 (en) 2005-07-15 2016-08-02 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US8987252B2 (en) 2007-05-10 2015-03-24 Albany Molecular Research, Inc. Aryloxy- and heteroaryloxy-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
WO2011121309A1 (fr) * 2010-03-31 2011-10-06 Takeda Pharmaceutical Company Limited Dérivés phénylsulfonyle et leur utilisation comme antagonistes de l'histamine h3

Also Published As

Publication number Publication date
CN1062908A (zh) 1992-07-22
EP0550589A1 (fr) 1993-07-14
JPH06503814A (ja) 1994-04-28
YU155791A (sh) 1994-01-20
CA2091690A1 (fr) 1992-03-26
AU8628791A (en) 1992-04-15
MX9101228A (es) 1992-05-04
ZA917613B (en) 1992-08-26
IL99551A0 (en) 1992-08-18

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