EP0362299A1 - Composes bicycliques, leur utilisation comme produits pharmaceutiques, leur preparation et composes intermediaires utiles dans leur preparation - Google Patents

Composes bicycliques, leur utilisation comme produits pharmaceutiques, leur preparation et composes intermediaires utiles dans leur preparation

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Publication number
EP0362299A1
EP0362299A1 EP88906692A EP88906692A EP0362299A1 EP 0362299 A1 EP0362299 A1 EP 0362299A1 EP 88906692 A EP88906692 A EP 88906692A EP 88906692 A EP88906692 A EP 88906692A EP 0362299 A1 EP0362299 A1 EP 0362299A1
Authority
EP
European Patent Office
Prior art keywords
carbon atoms
formula
compound
group
substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP88906692A
Other languages
German (de)
English (en)
Inventor
David J. Blythin
Ho-Jane Shue
Dinesh Gala
Martin Steinman
Ashit Ganguly
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Sharp and Dohme LLC
Original Assignee
Schering Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US07/076,450 external-priority patent/US4794116A/en
Priority claimed from US07/178,176 external-priority patent/US4897487A/en
Application filed by Schering Corp filed Critical Schering Corp
Publication of EP0362299A1 publication Critical patent/EP0362299A1/fr
Pending legal-status Critical Current

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Classifications

    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

Definitions

  • the present invention relates to certain bicyclic compounds and to pharmaceutical compositions and methods of use employing such compounds, to their preparation, and to intermediates useful in their preparation.
  • This invention concerns compounds of the formula I
  • Z 1 and Z are the same or different and each independently represents 0 or S;
  • E is a group -NR 1 R 2 or -NR 1 R 2 R 3 ;
  • R 1 , R 2 , R 3 , R 4 and R 5 are the same or different and each may be independently selected from H, alkyl having from 1 to 12 carbon atoms, alkenyl having from 3 to 8 carbon atoms, alkynyl having from 3 to 8 carbon atoms, alkoxyalkyl having from 1 to 6 carbon atoms in the alkoxy portion and from 2 to 6 atoms in the alkyl portion thereof, hydroxyalkyl having from 2 to 8 carbon atoms, cycloalkyl having from 3 to 8 carbon atoms, acyloxyalkyl having from 1 to 6 carbon atoms in the acyloxy portion and from 2 to 8 carbon atoms in the alkyl portion thereof, and -R 7 -CO 2 R 0 wherein R 7 represents an alkylene group having from 1 to 6 carbon atoms and R 0 represents hydrogen or an alkyl group having from 1 to 6 carbon atoms, with the provisos that the OH of the hydroxyalkyl group and the
  • R 6 represents alkanoyl, -CO-R 10 , -CS-OR 17 , -CS-NR 15 R 16 , -C(R 11 ) 2 -OR 12 , -C(R 1 1 ) 2 -SR 12 or -C(R 11 ) 2 -NR 12 R 13 or, when E is -NR 1 R 2 R 3 , R 6 represents A- alone or any of the foregoing groups together with A-;
  • R 1 represents aryl, R 14 , aromatic heterocyclic, -OR 14 or -NR 15 R 16 ; each R 11 represents H, alkyl, -CCI 3 , -COOR 9 or aryl;
  • R 12 represents -R 14 , -CO-R 13 or -CS-R 17 ;
  • R 1 3 represents H, alkyl or aryl
  • R 14 represents alkyl of from 1 to 12 carbon atoms
  • R 15 and R 16 each independently represents H, alkyl or aryl, or R 15 and R 15 together represent a divalent polymethylene group of from 4 to 6 carbon atoms, said polymethylene group being optionally substituted with a carboxy group or alkyl ester thereof;
  • R 17 represents -R 14 or aryl; m is an integer of from 0 to 3; n is an integer of from 0 to 2;
  • Q represents an aryl or an aromatic heterocyclic group which can optionally be substituted with 1 to 3 substituents Y as defined below; each Y substituent is independently selected from hydroxy, alkyl having from 1 to 6 carbon atoms, halogen, NO 2 , alkoxy having from 1 to 6 carbon atoms, trifluoromethyl, cyano, cycloalkyl having from 3 to 7 carbon atoms, alkenyloxy having from 3 to 6 carbon atoms, alkynyloxy having from 3 to 6 carbon atoms, hydroxyalkyl having from 1 to 6 carbon atoms, -S(O) n -R 18 (wherein R 18 represents alkyl having from 1 to 6 carbon atoms and n is as defined above), -SO 2 NH 2 , -CO-R 19 (wherein R 19 represents OH, -NH-R 18 or -O-R 18 , where R 18 is as defined above), -O-B-(O) P -COR 19 (wherein
  • A- is one equivalent of a pharmaceutically acceptable anion or, when R 6 represents A alone, then A is an electron on Z; i.e., the group ZR 6 is Z-; together with their pharmaceutically acceptable salts with bases when ZR 6 is Z-.
  • R 6 represents -C (R 11 ) 2 -OR 12
  • the compounds are referred to herein as acetal ethers; when R 6 represents -C(R 11 ) 2 -SR 12 , they are referred to herein as thioethers; and when R 6 represents -C(R 11 ) 2 -NR 12 R 13 they are referred to herein as nitrogen-substituted derivatives.
  • the compounds are esters (e.g., alkyl esters, as when R 6 is -O(CO)CH 3 or -O(CO)C 2 H 5 ).
  • R 6 represents A- alone, the compounds exist as zwitterions.
  • Compounds of formula I can be used for the preparation of pharmaceutical compositions useful in the treatment of hyperproliferative skin disease.
  • alkyl and alkoxy - comprise straight and branched carbon chains and, unless otherwise specified, contain from 1 to 6 carbon atoms;
  • alkenyloxy - comprises straight and branched carbon chains and, unless otherwise specified, contains from 3 to 8 carbon atoms and a carbon- to-carbon double bond;
  • alkynyloxy - comprises straight and branched carbon chains and, unless otherwise specified, contains from 3 to 8 carbon atoms and a carbon- to-carbon triple bond;
  • aryl - a carbocyclic group containing at least one benzene ring, with the aryl groups preferably containing from 6 to 15 carbon atoms, more preferably being phenyl or Y- substituted phenyl, e.g., phenyl, naphthyl, indenyl, indanyl, 4-chlorophenyl, 4- fluorophenyl, etc.;
  • aromatic heterocyclic - cyclic groups having at least one O, S and/or N hetero atom interrupting the ring structure and having a sufficient number of unsaturated carbon-to- carbon bonds, nitrogen-to-carbon bonds, etc., to provide aromatic character
  • the aromatic heterocyclic groups preferably containing from 2 to 14 carbon atoms, e.g., pyridyl, furyl, thienyl, thiazolyl, imidazolyl, pyrimidiayl.
  • Many such heterocyclic groups can be bonded via various positions on the ring and all such variations are included, e.g. 2- or 3- furanyl, 2-, 3- or 4-pyridyl, etc;
  • heteroatom - an atom other than carbon or hydrogen; in particular this term designates nitrogen and oxygen.
  • the compounds of the invention contain a -(CR 4 R 5 ) m - substituent wherein each R 4 group and each R 5 group may vary independently.
  • m 2 the following patterns of substitution (wherein hydrogen and CH 3 are used to represent any substituent, R 4 or R 5 ) are among those included: -C(CH 3 ) 2 CH 2 -, -CH 2 C(CH 3 ) 2 -, -CH 2 CH(CH 3 )-, -CH(CH 3 )CH 2 -, -(C(CH 3 )H) 2 - and the like.
  • substituents such as -C(CH 3 ) 2 CH(C 2 H 5 )-CH 2 -, -CH(CH 3 )-CH 2 CH(C 2 H 5 )-, and CH 2 -CH(i-C 3 H 7 )CH(C 2 H 5 ) - are also included.
  • R 1 , R 2 and R 3 groups on the amino nitrogen in the compounds of the invention can be the same or different.
  • R 1 , R 2 and R 3 (or two of them) may together represent a heterocyclic ring system where the nitrogen of the amino group is a part of such ring, e.g., a monocyclic or bicyclic ring.
  • Suitable -NR 2 R 3 groups include. NH 2 , the monosubstituted amino groups such as -NH(CH 3 ),
  • Suitable -NR 1 R 2 R 3 groups include a protonated amino group -NH 3 ; protonated monosubstituted
  • the compounds of the invention may include one to three Y substituents on the bicyclic ring system.
  • the Q group may include one or two Y substituents. Where there is more than one such Y substituent, they may be the same or different. Thus, compounds having combinations of different Y substituents are within the scope of the invention.
  • Y substituents include OH, methyl, chloro, bromo, methoxy, cyclohexyl, allyloxy, 2-propynyloxy, hydroxyethyl, methylthio, methylsulfonyl, carboxy, acetoxy, N-methylaminocarbonyl, acetoxymethoxy, acetamido, methylsulfonamido and the like.
  • novel compounds of the present invention have the structural formula la or lb
  • At least one of W and X is N. More preferably, W is CH and X is N. Moreover, at least one of Z 1 and Z is preferably 0, and m and n are preferably zero.
  • R 1 , R 2 , R 3 , R 6 , Q, Z 1 and Z are as defined above
  • Z 1 and Z are 0.
  • Q is preferably an aryl group such as a phenyl group, which may be optionally substituted with one to three Y groups, more preferably one or two Y groups.
  • Suitable Z-esters include aryl esters, aralkyl esters, aromatic heterocyclic esters such as furyl or pyridinyl esters, carbamates such as N,N-dialkyl- carbamates, proline carbamate esters, etc.
  • Suitable ester groups exemplifying ZR include -O(CO)phenyl, -O(CO)-p-tolyl, -O(CO)N(C 2 H 5 ) 2 , -O(CO)C(CH 3 ) 3 ,
  • suitable Z-acetal ethers include those wherein both R 11 groups are H and where R 12 is C 8 -12 alkyl such as n-octyl or R 12 is CO-alkyl such as (CO)C(CH 3 ) 3 .
  • R 12 is C 8 -12 alkyl such as n-octyl or R 12 is CO-alkyl such as (CO)C(CH 3 ) 3 .
  • suitable thioethers and nitrogen-containing compounds include those wherein both R 11 groups are H and where R 12 is C 8 -12 alkyl such as n-octyl or R 12 is CO-alkyl such as (CO)C(CH 3 ) 3 .
  • ZR 6 includes -CH 2 -S-alkyl wherein the alkyl group contains 8-12 carbon atoms, e.g., n-octyl, and
  • the invention also concerns (1) pharmaceutical compositions comprising a compound of formula la or lb as defined above in combination with a pharmaceutically acceptable carrier and (2) methods of using the compounds of formula I, especially la or lb, as defined above to treat hyperproliferative skin disease, or of using the compounds of formula la or lb to treat asthma, allergic reactions, inflammation or peptic ulcers by administering such a compound to a mammal in an amount effective for such purpose.
  • the compounds of formula I wherein E is -NR 1 R 2 R 3 and ZR 6 is Z- are zwitterionic or inner salts, i.e., they are both positively and negatively charged. They form pharmaceutically acceptable salts, i.e., pharmaceutically acceptable acid addition or basic salts, which are also part of the present invention.
  • suitable acid addition salts include the chloride (from hydrochloric acid), methyl sulfate, (from methyl sulfuric acid) sulfate (from sulfuric acid) and bromide.
  • Basic salts can be formed when at least one of
  • R 1 , R 9 and R 3 is H.
  • suitable basic salts include sodium, potassium or calcium salts (from their corresponding hydroxides).
  • the compounds of the invention of formula I can exist in unsolvated as well as solvated forms, including hydrated forms, e.g., a hemihydrate.
  • solvated forms including hydrated forms, e.g., a hemihydrate.
  • pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of the invention.
  • Certain compounds of the invention may exist in isomeric and tautomeric forms.
  • the invention includes all such isomers and tautomers - the isomers both in pure form and in admixture, including racemic mixtures.
  • Those compounds of the invention that are zwitterionic provide good solubility in physiological fluids, such as blood, plasma, saliva, etc., and in general in polar solvents, such as water and ethanol, which can be used in compositions for delivering the compounds to patients.
  • physiological fluids such as blood, plasma, saliva, etc.
  • polar solvents such as water and ethanol
  • the invention includes various pharmaceutical methods, in particular a method for treating asthma/allergic reactions in a mammal, a method for treating inflammation in a mammal, and a method for treating peptic ulcers in a mammal, which comprise administering a compound of the invention or a pharmaceutical composition containing it to the mammal, in an amount sufficient to provide respectively an anti-asthma/anti-allergic effect, an anti-inflammatory effect, or a cytoprotective effect.
  • R 4 , R 5 , Q, X, Y, W, Z 1 , Z, m and n are as defined above and Lg is a substituent known to those skilled in the art as a "leaving group", by treatment with an amine of the formula
  • R 1 , H 2 ' and R 3 are as defined above
  • a suitable solvent such as pyridine, dimethylformamide, hexamethylphosphoramide, 2,6-lutidine, dimethylacetamide and the like.
  • the reaction depending upon the reactants chosen, can be performed at temperatures of about 60°C up to the reflux temperature of the particular solvent.
  • a "leaving group” is defined as a substituent which may be readily displaced, usually carrying a negative charge.
  • suitable leaving groups include chloride, bromide, iodide, trifluoroacetoxy, methanesulfonyloxy, trifluoro-methanesulfonyloxy, p-toluene-sulfonyloxy, -I-Ar, and the like.
  • a preferred leaving group is bromide.
  • the compound of formula IV above is generally a secondary or tertiary amine, i.e., one in which at most one of the groups R 1 , R 2 and R 3 is hydrogen.
  • Such materials are readily obtainable either commercially or by methods well known to one of ordinary skill in the art.
  • This reaction is preferably accomplished by contacting the two reactants V and VI in the presence of a base such as a metal alkoxlde, e.g., potassium tertiary butoxide or the like, at an elevated temperature, e.g., 60° to about
  • a base such as a metal alkoxlde, e.g., potassium tertiary butoxide or the like
  • reaction is preferably conducted in an inert atmosphere such as nitrogen.
  • reaction may be conducted in the presence of a non-reactive solvent such as toluene, xylene, etc.
  • a non-reactive solvent such as toluene, xylene, etc.
  • the compounds of formula VII above can be reacted with a suitable agent to provide the leaving group in the 3-position on the ring.
  • a suitable agent for example, direct bromination of the compound of formula VII above will provide a compound of formula III above where Lg equals
  • reaction of the compound of VII above with iodosobenzene results in the formation of a compound of formula III where Lg is -I-Ph.
  • Esters, acetal ethers, thioethers and nitrogen- substituted derivatives of the present invention may be prepared by reacting a compound of structural formula VIII with a compound of formula IX:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Q, X, Y, W, Z 1 , Z, m and n are as defined above (except that R 6 neither represents nor includes A-) and Lg is an appropriate leaving group such as halo, e.g., chloro.
  • suitable reagents include an appropriate anhydride or acid halide to prepare the esters, or a compound LgC(R 11 ) 2 OR 12 , LgC(R 11 ) 2 SR 12 or LgC(R 11 ) 2 -NR 12 R 13 to prepare the acetal ethers, thioethers or nitrogen-substituted compounds.
  • Exemplary reagents include acetyl chloride, pivaloyl chloride, N,N-diethyl carbamoyl chloride, methoxymethyl chloride, pivaloyloxymethyl chloride, N-(chloromethyl)- benzamide, chloromethyl phenyl sulfide, etc.
  • the reaction is performed in a basic solvent such as pyridine or 2,6-lutidine (with or without the addition of dimethylaminopyridine (DMAP)) or in a neutral solvent in the presence of an organic base such as triethylamine.
  • DMAP dimethylaminopyridine
  • the invention further provides an inventive process -- or a group of cognate inventive processes-- for the preparation of the compounds of formula I hereinbefore defined, and for the preparation of intermediates.
  • One such inventive process is directed toward the preparation of a bicyclic compound of the formula
  • W, X, R 2 , R 3 , R 4 , R 5 , m, n, Q and Y are as defined above; it comprises the step of cyclising, in the presence of a base and a solvent, a compound of the formula
  • R is any of the values for R 4 or R 5 with the proviso that R is not hydrogen, intramolecularly when L represents the group of the formula (VB), and intermolecularly with an amino-substituted acetic acid derivative of the formula
  • R 2 and R 3 are as defined hereinbefore and R is as defined above, when L represents H.
  • This process provides the compound of formula (VII) in high yield and good purity with little formation of by-products. Reaction conditions are mild, especially for the intramolecular cyclization. Furthermore, the compound of formula (X) is readily recovered from the reaction mixture .
  • this process comprises the step of contacting an amino acetamide compound of the formula
  • Y is hydrogen
  • X is nitrogen and W is CH
  • R is alkyl, more preferably methyl
  • m is 0,
  • R 2 and R 3 are joined together to represent a ring containing four carbon atoms
  • Q is phenyl.
  • the base is potassium t-butoxide.
  • this process comprises the step of contacting a secondary substituted amine of the formula
  • substituted secondary amine preferably Y is hydrogen, X is nitrogen, W is CH, R is alkyl, preferably methyl, Q is phenyl and m is zero.
  • R is alkyl, especially ethyl, and R 2 , R 3 and the adjacent N atom are joined together to represent a ring containing four carbon atoms.
  • a preferred base is sodium hydride or potassium t-butoxide.
  • the intermediate of the formula (VC) can be prepared by a process wherein a secondary amine compound of the formula
  • Hal is a halogen
  • Lg is a leaving group, e.g. halogen, sulfonyloxy, especially tosyloxy or mesyloxy, or acetoxy, haloacetoxy or 2,2-dimethylpropionyloxy;
  • Y is hydrogen
  • X is nitrogen
  • W is CH
  • R is alkyl, more preferably methyl
  • m is zero
  • Q is phenyl
  • Lg is halogen, more preferably chloro, or haloacetoxy, especially chloroacetoxy.
  • the proton-accepting compound is preferably an epoxide, most preferably propylene oxide. This process uses relatively mild reaction conditions to provide the compounds of formulae (XII) and (VC) in high yield and good purity, with little formation of by- products.
  • process A the amino acetamide of formula (VA) (wherein L is (VB)) can be contacted with the base at temperatures ranging from about -100°C to about 100°C, preferably from about -70° to about 40°C, for about 5 minutes to about 24 hours or more, depending upon the base employed.
  • the reactants are preferably stirred at ambient pressure in the presence of a solvent, e.g., a chlorinated hydrocarbon such as carbon tetrachloride (CCl 4 ), methylene chloride (CH 2 Cl 2 ), or dichloroethane; aliphatics such as C-4 to C-20 alkanes, cyclic or acyclic; aromatics such as benzene, toluene, xylene, alkylbenzenes and the like; ethers such as diethyl ether and tetrahydrofuran (THF) and t-butyl-methyl ether; dimethylformamide (DMF) or dimethylsulfoxide (DMSO); or mixtures thereof.
  • a solvent e.g., a chlorinated hydrocarbon such as carbon tetrachloride (CCl 4 ), methylene chloride (CH 2 Cl 2 ), or dichloroethane
  • aliphatics such as C-4 to C-20 alkanes
  • the base used in Process A is any substance which will remove a proton from the methylene (-CH 2 -) group of the moiety
  • Bases which can be used in process A are generally non-aqueous bases of the organo-alkali metal type, such as primary, secondary and tertiary butyl lithium, lithium diisopropyl amide, lithium hexamethyldisilazane, sodium hexamethyldisilazane, potassium hexamethyldisilazane, potassium t-butoxide or sodium methoxide; inorganic bases of alkali and alkaline earth metals including carbonates such as sodium, potassium and cesium carbonates, or hydroxides such as sodium and potassium hydroxides; hydrides such as sodium or potassium hydride can also be used.
  • organo-alkali metal type such as primary, secondary and tertiary butyl lithium, lithium diisopropyl amide, lithium hexamethyldisilazane, sodium hexamethyldisilazane, potassium hexamethyldisilazane, potassium t-butoxide or sodium methoxide
  • the base is sodium hydride or sodium methoxide, and preferably potassium t-butoxide.
  • the amount of base is used in mole ratios ranging from about 20:1 to 2:1, (moles of base:mole amino acetamide (VC)).
  • the desired bicyclic compound of formula (X) is recovered by conventional separatory and recovery methods such as chromatography, distillation, crystallization and the like.
  • the reactants in process B can be contacted neat, although preferably a solvent is used.
  • the bases and solvents used in process B are essentially the same as those described above in process A.
  • the secondary substituted amine of formula (V) is stirred with the amino-substituted acetic acid derivative of formula (XI) at temperatures ranging from about -40 to about 200°C, preferably from about 25 to about 180°C, until the reaction is substantially completed, preferably from about 1 hour to about 48 hours.
  • the base is employed in mole ratios ranging preferably from about 15:1 to 3:1 (moles base:mole secondary substituted amine (V)).
  • the substituted acetamide compound of formula (XII) is prepared by contacting a secondary amine compound of formula (V) with a substituted acetic acid derivative of formula HalCH 2 COLg (where Hal and Lg are as defined above) in the presence of a proton acceptor in amounts and under conditions effective to give the substituted acetamide compound (III).
  • HalCH 2 COLg (where Hal and Lg are as defined above) is preferably used in excess.
  • proton acceptor is defined as a compound which accepts either a proton from an acid or free protons in the reaction mixture, but generally will not accept a proton from the methylene group of the group of the formula
  • the proton acceptor should be compatible with the reactants and can be an organic base, especially a primary amine such as methylamine, n-butylamine, sec-butylamine, t-butylamine, benzylamine, cyclohexylamine, ethylamine, or ethylene- diamine; a secondary amine or a compound containing at least one secondary amine group such as dimethylamine, N- methylpropylamine, diethylamine, or diisopropyl amine; a tertiary amine such as trimethylamine, N,N-dimethyl-n- propylamine, N-methylpiperidine, N,N-diethylbutylamine, or triethylamine; a heterocyclic base such as piperazine, piperidine, pyrrolidine, morpholine, or pyridine, or an inorganic base such as ammonia and those bases of alkali or
  • T 1 , T 2 , T 3 and T 4 independently represent hydrogen atoms or alkyl groups.
  • Representative epoxides suitable as proton acceptors include but are not limited to ethylene oxide and especially propylene oxide. Alternatively, the epoxide can be prepared in situ in the reaction mixture. The proton acceptor can also include mixtures of the base and epoxide.
  • the proton acceptor is used in amounts effective to scavenge the liberated protons, i.e. in a few moles excess, e.g. about 20:1 to 1:1 mole (moles proton acceptor:mole secondary amine of formula (V)).
  • Process C can be conducted neat, although a solvent is preferred. The reaction is carried out until it is substantially complete, e.g. from about 15 minutes to about 4 hours. Generally the reactants are stirred during the process.
  • the process can be conducted in the presence of a catalyst such as N,N-dimethylaniline, 4-dimethylaminopyridine or phase-transfer catalysts.
  • Phase transfer catalysts suitable for carrying out the process of the present invention include quaternary ammonium and phosphonium salts, ethers, and tertiary amines, such as tributyl amine or those described in U.S. Patent 3,969,360.
  • the catalyst can be used in an amount ranging from about 0.0001 to about 0.5 parts by weight of reactants, preferably from about 0.001 to about 0.1 parts by weight.
  • Process C is generally carried out at about -40° to about 200°C, preferably from about 0 to about 80°C, depending upon the boiling point of the epoxide, solvent or starting materials, and preferably at ambient pressure.
  • the compounds having structural formula I above wherein Z 1 and Z are oxygen may be converted into the corresponding compounds wherein Z 1 and/or Z are sulfur by known methods.
  • treatment with Lawesson's Reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4- diphosphetane-2,4-disulfide] in an appropriate inert organic solvent such as hot toluene will effect this conversion.
  • the isomeric and tautomeric forms can be purified by chromatography of the reaction mixture.
  • the compounds of formulae la and lb may be employed as anti-allergy agents in the treatment of, for example, asthma, allergic or seasonal rhinitis, and/or chronic bronchitis.
  • male Hartley guinea pigs 250-300 g are sensitized with 5 mg ovalbumin injected i.p. and 5 mg injected s.c. in 1 ml saline on day 1 and 5 mg ovalbumin injected i.p. on day 4.
  • the sensitized animals are used 3-4 weeks later at which time they weigh 450-500 g.
  • the sensitized guinea pigs are fasted overnight and the following morning are anesthetized with 0.9 ml/kg i.p. of dialurethane (0.1 g/ml diallylbarbituric acid, 0.4 g/ml ethylurea and 0.4 g/ml urethane).
  • dialurethane 0.1 g/ml diallylbarbituric acid, 0.4 g/ml ethylurea and 0.4 g/ml urethane.
  • the trachea are cannulated and the animals are ventilated by a Harvard rodent respirator at 50 strokes/minute with a stroke volume of 5 ml.
  • a side arm to the tracheal cannula is connected to a Harvard pressure transducer to obtain a continuous measure of intratracheal pressure which is recorded on a Harvard polygraph.
  • the jugular vein is cannulated for the i.v.
  • the animals are challenged with antigen (0.5% ovalbumin) as an aerosol generated from a DeVilbiss Model 65 ultrasonic nebulizer and delivered through the tracheal cannula for 30 seconds. Bronchoconstriction is measured as the peak increase in intratracheal pressure occurring within 5 minutes after antigen challenge.
  • the sensitized guinea pigs are injected i.v. with 1 mg/kg propranolol, 5 mg/kg indomethacin and 2 mg/kg mepyramine given together in a volume of 1 ml/kg. Fifteen minutes later the animals are challenged with nebulized ovalbumin. Test compounds are administered orally 2 or 8 hours before challenge with ovalbumin. Suppression of anaphylactic bronchospasm is expressed as a percent inhibition of the peak increase in intratracheal pressure by comparison to a vehicle-treated control group. Results for representative compounds of the invention are shown in Table I below:
  • the compounds are effective non-adrenergic, non-anticholinergic , antianaphylact ic agents .
  • they When administered orally they are active at doses from about 0.1 to 10 mg/kg of body weight; when administered parenterally, e.g., intravenously, the compounds are active at dosages of from about 0.05 to 5 mg/kg body weight; when administered by inhalation (aerosol or nebulizer) the compounds are active at dosages of about 0.25 to 5 mg per puff, and one to four puffs may be taken every 4 hours.
  • the compounds of this invention are also useful for the treatment of inflammation. Thus, they are useful in the treatment of arthritis, bursitis, tendonitis, gout and other inflammatory conditions.
  • the anti-inflammatory use of the compounds of the present invention may be demonstrated by the Reversed Passive Arthus Reaction (RPAR) Synovitis technique as set forth below using male Lewis rats (obtained from Charles River Breeding Laboratories) weighing 200-250 grams and the RPAR Paw technique as also described below.
  • the potency of the compounds is determined using indomethacin as the standard. On the basis of the test results, an oral dosage range of about 5 milligrams per kilogram of body weight per day to about 50 milligrams per kilogram of body weight per day in divided doses taken at about 4 hour intervals is recommended.
  • the dosage to be administered and the route of administration depend upon the particular compound used, the age and general health of the patient and the severity of the inflammatory condition. Thus, the dose ultimately decided upon must be left to the judgment of a trained health-care practitioner.
  • RPAR Synovitis Technique A Lewis rat is dosed orally with drug or placebo one hour prior to intravenous administration of 2.28 mg of bovine serum albumin (BSA) in 0.2 cc of pyrogen-free saline followed by the intraarticular injection of 0.54 mg of rabbit anti-BSA antibody in 0.03 cc of pyrogen-free saline into one knee joint. The contralateral knee is injected with 0.03 cc of pyrogen free saline. All injections are made with the animal under light ether anesthesia. Three hours later the rat is again dosed orally with drug or placebo. All drug doses are split. That is, one-half of the dose is administered before lesion induction and one-half is administered after lesion induction.
  • BSA bovine serum albumin
  • the subpatellar areolar tissue with attendant synovium is excised and weighed. Differences between the weight of antibody and saline injected knees are considered to represent the inflammatory response for each animal (delta synovial weight). Differences in delta synovial weight between lesion controls and drugtreated rats are evaluated for statistical significance with an analysis of variance. Relative potencies are determined with a linear regression analysis.
  • RPAR Reversed Passive Arthus Response
  • Groups of animals (6/group) are dosed with drug in MC by gavage once daily for 3 days. The last dose is administered one hour prior to sensitization with BSA. Controls are given MC alone and a drug-standard is usually included in each assay for verification purposes. Drugs are prepared and diluted so as to provide a dose for a 200 gram animal which is equivalent to the mg/kg dose for each experiment. Thus each rat receives an oral dose in a volume of approximately 2.0 cc. One hour after the last dose the animals are lightly anesthetized with ether and "sensitized" by injection of 0.2 ml of PFS containing 1.0 mg of BSA into the penile vein.
  • the animals are "challenged" in the right rear paw with subplantar injections of 0.2 ml of PFS containing 0.1 mg of anti-BSA.
  • the right paw is dipped (up to the lateral maleolus) into the mercury well of a plethysmograph.
  • the volume of mercury displaced is converted to weight and recorded. This value is considered to be the control reading for the animal.
  • Paw volumes are subsequently recorded with a plethysmograph during the development of the inflammation at 2 and 4 hours post-challenge.
  • Results are expressed by the change in paw volume ( ⁇ paw volume) from the control reading for each animal to that recorded 2 and 4 hours post-challenge. All drug treated groups are compared to the MC control for significant differences with an analysis of variance. Differences from control in drug-treated groups are expressed as percent change from control. For example, 4-(N,N-diethylcarBamoyl)-1-phenyl-3-(1- pyrrolidinyl)-1,8-naphthyridin-2(1H)-one given at an oral dose of 25 mg/kg inhibited the paw edema by 54% and 17% at 2 hours and at 4 hours, respectively.
  • the compounds of this invention are also useful in the treatment of peptic ulcers. They display chemotherapeutic activity which enables them to relieve the symptoms of peptic ulcer disease, stress ulceration, and.promote healing of gastric and/or duodenal ulcers.
  • the antiulcer activity of the compounds of this invention is identified by tests which measure the cytoprotective effect in rats.
  • the compounds are also useful as conjunctive therapeutic agents for coadministration with such antiinflammatory/analgesic agejits as aspirin, indomethacin, phenylbutazone, ibuprofen, naproxen, tolmetin and other agents.
  • the compounds of this invention prevent the untoward side effects of irritation and damage to the gastrointestinal tract caused by such agents.
  • the compounds of this invention are evaluated for their antiulcer activity characteristics by standard biological testing procedures such as the indomethacininduced ulcer and/or ethanol-induced ulcer assays detailed below:
  • mice Male Charles River CD rats (250-260g) are fasted overnight.
  • the test compound is administered orally in methyl cellulose vehicle (2 ml/kg) to the animals one hour prior to indomethacin 10 mg/kg p.o.
  • the rats are sacrificed by CO 2 asphyxiation 4 hours after administration of indomethacin.
  • the stomachs are examined under a magnifying glass for lesions (Chiu et al., Arch. Int. Pharmacodyn. Ther., 270 128, 1984).
  • mice Male Charles River CD rats weighing 250-280 g are fasted and deprived of water for 20 hours before the experiments.
  • the test compound homogenized in aqueous methyl cellulose vehicle, is administered orally 30 minutes prior to oral administration of 1 ml of absolute ethanol.
  • One hour after ethanol the rats are sacrificed and the stomachs excised.
  • the stomachs are opened through the greater curvature and the length of each linear hemorrhagic lesion induced by ethanol is measured and summated for each stomach. Results are expressed as the mean lesion length (mm) per rat ( ⁇ SE).
  • the data are analyzed by Duncan's multiple range test and a P value of ⁇ .05 is considered significant.
  • the compounds of this invention are found to be effective at doses of about 0.05 - 50 mg/kg of body weight per day. Preferably the total dosages are administered in 2-4 divided doses per day. When administered parenterally, e.g. intravenously, the compounds are administered at a dosage range of about 0.01 - 10 mg/kg of body weight in single or multiple daily doses.
  • the active compounds of this invention can be administered in unit dosage forms such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, suppositories, mechanical delivery devices, e.g. transdermal, and the like.
  • the compounds of formula I are useful in the treatment of hyperproliferative skin-disease, e.g., psoriasis, which utility may be demonstrated by the Arachidonic Acid Mouse Ear Test described below.
  • mice Charles River, female, CD, (SD) BR mice, 6 weeks old, are caged 8/group and allowed to acclimate 1-3 weeks prior to use.
  • Arachidonic acid (AA) is dissolved in reagent grade acetone (2 mg/.01 ml) and stored at -20°C for a maximum of 1 week prior to use. Inflammatory reactions are induced by applying 10 id of AA to both surfaces of one ear (4 mg total).
  • Test drugs are dissolved in either reagent grade acetone or aqueous ethanol (only if insoluble in acetone) at the same doses selected by Opas et al., Fed. Proc. 43, Abstract 2983, p. 1927 (1984) and Young et al., J. Invest. Dermatol. 82, pp 367-371 (1984). These doses are employed to ensure maximum responses and to overcome any difference in topical absorption which could occur with any drug applied in an aqueous ethanol vehicle. The test drug is applied 30 minutes prior to challenge with AA.
  • the severity of the inflammation is measured as a function of increased ear weight.
  • a 6 mm punch biopsy is removed 1 hour after AA challenge and weighed to the nearest 0.1 mg.
  • Mean ⁇ standard error and all possible comparisons are made via Duncan's Multiple Range Statistic. For instance, 1-methyl-1-(1,2-dihydro-4- hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl)- pyrrolidinium-hydroxide, inner salt, when tested in the assay at a single dose of 0.5mg/ear, resulted in a 61% reduction of the severity of inflammation. At a dose of 0.1 mg/ear, the same compound gave a 43% reduction
  • the compounds of formula I When administered for the treatment of hyperproliferative skin disease, the compounds of formula I may be administered topically, orally, re ⁇ tally or parenterally. When administered topically, the amount of compound administered varies widely with the amount of skin being treated, as well as with the concentration of active ingredient applied to the affected area. When administered orally, the compounds of formula I are effective for the treatment of hyperproliferative skin disease at daily doses ranging from about 0.1 mg/kg to about 100 mg/kg, preferably from about 5 mg/kg to about 50 mg/kg, which may be administered in divided doses. When administered rectally, the compounds of formula I may be administered in daily doses ranging from about 0.1 mg/kg to about 100 mg/kg.
  • the compounds of formula I When administered parenterally, the compounds of formula I are effective for the treatment of hyperproliferative skin disease in daily doses ranging from about 0.1 mg/kg body weight to about 10 mg/kg body weight which may be administered in divided doses.
  • a remission of the symptoms of the psoriatic patient can in most cases be expected.
  • one affected by psoriasis can expect a decrease in scaling, erythema, size of the plaques, pruritus and other symptoms associated with psoriasis.
  • the dosage of medicament and the length of time required for successfully treating each individual psoriatic patient may vary, but those skilled in the art of medicine will be able to recognize these variations and adjust the course of therapy accordingly.
  • compositions for topical application to the skin whereby the compounds having structural formula I are effective in the treatment and control of skin diseases characterized by rapid rates of cell proliferation and/or abnormal cell proliferation, e.g. psoriasis.
  • a pharmaceutical formulation comprising a compound of formula I together with a non-toxic, pharmaceutically acceptable topical carrier, usually in concentrations in the range of from about 0.001 percent to about 10 percent, preferably from about 0.1 percent to about 5 percent, is applied several times daily to the affected skin until the condition has improved. Topical applications may then be continued at less frequent intervals (e.g. once a day) to control mitosis in order to prevent return of severe disease conditions.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
  • a solid carrier can be one or more substances which may 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 a finely divided solid which is in admixture with the finely divided active compound.
  • the active compound is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from 5 or 10 to about 70 percent of the active ingredient.
  • Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethyl-cellulose, a low melting wax, cocoa butter and the like.
  • the term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component (with or without other carriers) is surrounded by carrier, which is thus in association with it.
  • cachets are included. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.
  • Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by adding the active component in water and adding suitable colorants, flavors, stabilizing, sweetening, solubilizing and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e., natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents.
  • solid form preparations which are intended for conversion shortly before use, to liquid form preparations for either oral or parenteral administration.
  • Such liquid forms include solutions, suspensions and emulsions.
  • These particular solid form preparations are most conveniently provided in unit dose form and as such are used to provide a single liquid dosage unit.
  • sufficient solid may be provided so that after conversion to liquid form, multiple individual liquid doses may be obtained by measuring predetermined volumes of the liquid form preparation as with a syringe, teaspoon or other volumetric container.
  • the solid form preparations intended to be converted to liquid form may contain, in addition to the active material, flavorings, colorants, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like.
  • the solvent utilized for preparing the liquid form preparation may be water, isotonic water, ethanol, glycerine, propylene glycol and the like as well as mixtures thereof. Naturally, the solvent utilized will be chosen with regard to the route of administration, for example, liquid preparations containing large amounts of ethanol are not suitable for parenteral use.
  • the compounds of the invention may also be deliverable transdermally.
  • the transdermal compositions can take the form of creams, lotions and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • the pharmaceutical preparation is in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation; for example, packaged tablets, capsules and powders in vials or ampoules.
  • the unit dosage form can also be a capsule, cachet or tablet itself or it can be the appropriate number of any of these in packaged form.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from 1 mg to 100 mg according to the particular application and to the potency of the active ingredient.
  • the compositions can, if desired, also contain other therapeutic agents.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated and the particular compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small amounts until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
  • PCT/US86/01518 (published as WO 87/00752) describes, as novel compounds, zwitter ionic compounds falling within formula I (those wherein E is -NR 1 R 2 R 3 and ZR 6 is Z-), but does not disclose their activity against hyperproliferative skin disease (e.g. psoriasis).
  • reaction mixture was then poured over ice and the pH was adjusted to about 6 with acetic acid.
  • the resulting solution was extracted three times with ethyl acetate.
  • the organic extracts were combined, dried (Na 2 SO 4 ), filtered and evaporated to a solid which was recrystallized from isopropanol to yield the desired product, 2.03g (54%), m.p. 158-160°C.
  • reaction mixture is heated for 1 to 3 hours prior to the addition of portions of 0.32 g NaH followed by 1.05 mL of ethyl 1-pyrrolidineacetate as described above (total 3 portions). Following addition of the portions, the reaction mixture is cooled to 0°C and quenched with a slow addition of glacial acetic acid, and then water is added. The product is filtered off and washed with water, acetone, methylene chloride, and acetone. The soobtained solid is dried in vacuo to give 1.20 g (60% yield) of title compound, a white solid.
  • Step A To a stirred solution of 25.45 g (0.11M) of methyl 2-phenylamino-nicotinate in 160 mL of t-butylmethylether (tBuOMe) (dried over 3A° sieves) heated to 50° (under N 2 ), 19.5 mL (2.2 x 0.11M) of chloroacetylchloride was added, followed by 31 mL (4 x 0.11MM of propylene oxide. The reaction mixture was heated at 50°C for 1.5 hours and then 300 mL tBuOMe was added.
  • tBuOMe t-butylmethylether
  • Step B To the above solution at room temperature under N 2 , 37.2 mL (4 x 0.11M) of pyrrolidine was added and this solution was gently refluxed overnight. 9.3 mL (0.11M) of pyrrolidine was added, and the reaction was refluxed for an additional two hours. This mixture was diluted with 600 mL tBuOMe and washed with 300 mL H 2 O, and the aqueous layers were back- extracted with 200 mL tBuOMe.
  • Step C The solid from step B above was suspended in 600 mL of cold (0°C) tBuOMe (dried over 3A° sieves) under N 2 . To this cold stirred mixture, 27.5 g (2.2 x 0.11M) potassium t-butoxide was added, the reaction mixture was stirred for 1 hour, and then it was quenched with 15 mL (2.4 x 0.11M) of glacial acetic acid.
  • Bicyclic compounds are disclosed which are useful as anti-allergic, anti-inflammatory and/or cytoprotective agen and in the treatment of hyperproliferative skin desease.
  • Pharmaceutical compositions and methods of treatment employi such compounds are also disclosed. Many of the compounds are novel; inventive methods for their preparation and f the preparation of intermediates, are also disclosed.

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Abstract

La présente invention décrit des composés bicycliques utiles comme agents anti-allergiques, anti-inflammatoires et/ou cytoprotecteurs et utiles dans le traitement des affections de la peau hyperprolifératives. Des compositions pharmaceutiques et des procédés de traitement utilisant de tels composés sont également décrits. Un grand nombre de ces composés sont nouveaux; des procédés originaux pour leur préparation et pour la préparation de composés intermédiaires sont également décrits.
EP88906692A 1987-07-22 1988-07-20 Composes bicycliques, leur utilisation comme produits pharmaceutiques, leur preparation et composes intermediaires utiles dans leur preparation Pending EP0362299A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US07/076,450 US4794116A (en) 1985-07-29 1987-07-22 Anti-allergic esters, acetal ethers, thioethers and nitrogen substituted derivatives of bicyclic compounds
US07/076,469 US4782067A (en) 1985-07-29 1987-07-22 Anti-allergic composition containing zwitterionic bicyclic compounds
US76469 1987-07-22
US76450 1987-07-22
US07/178,176 US4897487A (en) 1988-04-06 1988-04-06 Process for preparing intermediates for pharmaceutically useful bicyclic compounds
US178176 1994-01-06

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DE3911064A1 (de) * 1989-04-06 1990-10-11 Bayer Ag Substituierte 1,8-naphthyridine
JPH0749430B2 (ja) * 1989-12-04 1995-05-31 シェリング・コーポレーション ヘテロ環置換ナフチリジノン並びにそれらの使用方法および組成物
ES2094772T3 (es) * 1990-06-01 1997-02-01 Kyowa Hakko Kogyo Kk Derivados de imidazonaftiridinas.
US5760034A (en) * 1990-11-30 1998-06-02 Schering Corporation Heterocyclic substituted naphthyridinones and methods and compositions employing them
GB9127252D0 (en) * 1991-12-23 1992-02-19 Boots Co Plc Therapeutic agents
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US3374264A (en) * 1962-10-04 1968-03-19 Hoffmann La Roche N-haloacetyl-anthranilic acids and esters
JPS5854152B2 (ja) * 1976-03-25 1983-12-02 久光製薬株式会社 新規なナフチリジン誘導体
EP0092786B1 (fr) * 1982-04-26 1987-01-07 Schering Corporation Dérivés de la 1,8-naphtyridine et de la 1,5,8-azanaphtyridine
US4452800A (en) * 1982-04-26 1984-06-05 Schering Corporation Salts of 3(n-butyl)-4-hydroxy-1-phenyl-1,8-naphthyridine-2(1H)-one and their use in treating chronic obstructive lung diseases
US4684727A (en) * 1985-07-29 1987-08-04 Schering Corporation Zwitterionic 1,8-naphthyridine and pyrazino[2,3-b]pyridine containing compounds useful as anti-allergic, anti-inflammatory and cycloprotective agents
NZ218774A (en) * 1986-01-06 1990-06-26 Carpibem 3-substituted phenylnaphthyridines and pharmaceutical compositions
JPS63159382A (ja) * 1986-10-15 1988-07-02 シェリング・コーポレーション １−置換ナフチリジンおよびピリドピラジン誘導体
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IL87186A0 (en) 1988-12-30
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AU632461B2 (en) 1993-01-07
MY103593A (en) 1993-08-28
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EP0302303A2 (fr) 1989-02-08
JPH02503675A (ja) 1990-11-01
JPH07116187B2 (ja) 1995-12-13
WO1989000571A3 (fr) 1989-03-09
DK15590D0 (da) 1990-01-19

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