WO1999029693A1 - Imidazonaphthyridines and their use in inducing cytokine biosynthesis - Google Patents
Imidazonaphthyridines and their use in inducing cytokine biosynthesis Download PDFInfo
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- WO1999029693A1 WO1999029693A1 PCT/US1998/026473 US9826473W WO9929693A1 WO 1999029693 A1 WO1999029693 A1 WO 1999029693A1 US 9826473 W US9826473 W US 9826473W WO 9929693 A1 WO9929693 A1 WO 9929693A1
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- 0 *C1=C(*)C2=N*=**2C2C1CC*CCC2 Chemical compound *C1=C(*)C2=N*=**2C2C1CC*CCC2 0.000 description 1
- DDCGQPGLEBRCAW-UHFFFAOYSA-N CC(C)C[n]1c(C(CCNC2)C2N=C2N)c2nc1C Chemical compound CC(C)C[n]1c(C(CCNC2)C2N=C2N)c2nc1C DDCGQPGLEBRCAW-UHFFFAOYSA-N 0.000 description 1
- SVUHSQUGVXGJDE-UHFFFAOYSA-N CC(C)C[n]1c2c(cccn3)c3nc(N)c2nc1 Chemical compound CC(C)C[n]1c2c(cccn3)c3nc(N)c2nc1 SVUHSQUGVXGJDE-UHFFFAOYSA-N 0.000 description 1
- OQVONIYULORIOW-UHFFFAOYSA-N CCCCc1nc2c(N)nc(cccn3)c3c2[n]1CC(C)C Chemical compound CCCCc1nc2c(N)nc(cccn3)c3c2[n]1CC(C)C OQVONIYULORIOW-UHFFFAOYSA-N 0.000 description 1
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Definitions
- This invention relates to imidazonaphthyridine and tetrahydroimidazonaphthyridine compounds, processes for making these compounds and intermediates used in their preparation.
- This invention additionally relates to pharmaceutical compositions containing imidazonaphthyridine and tetrahydroimidazonaphthyridine compounds.
- a further aspect of this invention relates to the use of these compounds as inimunomodulators and for inducing cytokine biosynthesis in animals.
- this invention provides imidazonaphthyridine compounds of Formula I:
- R t and R 2 are as defined hereinafter.
- the invention also provides tetrahydroimidazonaphthyridine compounds of Formula II:
- the compounds of Formula I and Formula II are useful as immune response modifiers due to their ability to induce cytokine biosynthesis and otherwise modulate the immune reponse when administered to animals. This ability makes the compounds useful in the treatment of a variety of conditions, e.g. viral diseases and tumors that are responsive to such changes in the immune response.
- the invention further provides pharmaceutial compositions containing a compound of Formula I or Formula II and methods of inducing cytokine biosynthesis in an animal and/or treating a viral infection in an animal by administering a compound of Formula I or Formula II to the animal.
- the invention provides a method of inducing interferon biosynthesis in an animal comprising the step of administering to said animal a compound of Formula I or Formula II in an amount effective to induce said interferon biosynthesis, and a method of treating a viral infection in an animal comprising the step of administering to said animal a compound of Formula I or Formula II in an amount effective to inhibit the viral infection.
- Ri is selected from the group consisting of: - hydrogen;
- Q is -CO- or - SO 2 -;
- X is a bond, -O- or -NR 3 - and
- R 4 is aryl; heteroaryl; heterocyclyl; or -C 1-20 alkyl or C 2-20 alkenyl that is unsubstituted or substituted by one or more substituents selected from the group consisting of:
- Y is -N- or -CR-;
- R 2 is selected from the group consisting of: -hydrogen; -C ⁇ -10 alkyl; -C 2- ⁇ o alkenyl;
- each R 3 is independently selected from the group consisting of hydrogen and C 1-10 alkyl; .and each R is independently selected from the group consisting of hydrogen, Ci-io alkyl, C MO alkoxy, halogen and trifluoromethyl, or a pharmaceutically acceptable salt thereof.
- This invention also provides compounds of Formula II
- B is -NR-C(R) 2 -C(R) 2 -C(R) 2 -; -C(R) 2 -NR-C(R) 2 -C(R) 2 -;
- Ri is selected from the group consisting of: - hydrogen;
- X is a bond, -O- or -NR 3 - and R4 is aryl; heteroaryl; heterocyclyl; or -C ⁇ -2 o alkyl or C 2-2 o alkenyl that is unsubstituted or substituted by one or more substituents selected from the group consisting of:
- Y is -N- or -CR-;
- R 2 is selected from the group consisting of: -hydrogen;
- each R 3 is independently selected from the group consisting of hydrogen and C M O alkyl; and each R is independently selected from the group consisting of hydrogen, Ci-io alkyl, C MO alkoxy, halogen and trifluoromethyl, or a pharmaceutically acceptable salt thereof.
- alkyl As used herein, the terms “alkyl”, “alkenyl”, and the prefix “-alk” are inclusive of both straight chain and branched chain groups and of cyclic groups, i.e. cycloalkyl and cycloalkenyl. These cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 10 ring carbon atoms. Exemplary cyclic groups include cyclopropyl, cyclopentyl, cyclohexyl and adamantyl.
- aryl as used herein includes carbocyclic aromatic rings or ring systems. Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl .and indenyl.
- heteroaryl includes aromatic rings or ring systems that contain at least one ring hetero atom (e.g., O, S, N). Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, tetrazolyl, imid.azo, .and so on.
- Heterocyclyl includes non-aromatic rings or ring systems that contain at least one ring hetero atom (e.g., O, S, N).
- exemplary heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thi-azolidinyl, and imidazolidinyl.
- the aryl, heteroaryl and heterocyclyl groups may be unsubstituted or substituted by one or more substituents selected from the group consisting of C 1-2 0 alkyl, hydroxy, halogen, N(R 3 ) 2 , NO , C 1-2 o alkoxy, C ⁇ - 0 alkylthio, trihalomethyl, C ⁇ -20 acyl, arylcarbonyl, heteroarylcarbonyl, (C ⁇ -10 alkyl)o- ⁇ -aryl, (C ⁇ - ⁇ oalkyl)o- ⁇ -heteroaryl, nitrile, C ⁇ - 2 o alkoxycarbonyl, oxo, arylalkyl wherein the alkyl group has from 1 to 10 carbon atoms, and heteroarylalkyl wherein the alkyl group has from 1 to 10 carbon atoms.
- the invention is inclusive of the compounds described herein in .any of their ph.armaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, solvates, polymorphs, and the like. Preparation of the Compounds
- Reaction Scheme I a 2-aminonicotinic acid of Formula III is reacted with acetic anhydride by heating to provide a 2-methyl-4H-pyrido[2,3--i][l,3]oxazin-4-one of Formula IV.
- R is hydrogen
- the compound of Formula IV where R is hydrogen is known and its preparation has been disclosed in U.S. Patent No. 3,314,941 (Littell), the disclosure of which is incorporated herein by reference.
- step (2) of Reaction Scheme I a compound of Formula IV is reacted with sodium .azide in a suitable solvent such as acetic acid to provide a tetrazolyl nicotinic acid of Formula V.
- the reaction conveniently may be run at ambient conditions.
- step (3) of Reaction Scheme I an acid of Formula V is esterified to provide a compound of Formula VI.
- the esterification may be carried out using conventional methods.
- the acid may be esterified in acetone using potassium carbonate and ethyl iodide.
- a compound of Formula VI is cyclized to provide a tetrazolo[l,5- ⁇ ][l,8]naphthyridin-5-ol of Formula VII.
- the reaction may be carried out by reacting the compound of Formula VI with an alkoxide in a suitable solvent, e.g., potassium ethoxide in N,N-dimethylformamide, at ambient conditions.
- step (5) of Reaction Scheme I a compound of Formula VII is nitrated using a suitable nitrating agent such as nitric acid to provide a 4-nitrotetrazolo[l,5 ⁇ ⁇ ][l,8]naphthyridin-5-ol of Formula VIII.
- step (6) of Reaction Scheme I a compound of Formula VIII is converted to a triflate of Formula IX.
- the reaction is preferably carried out by combining a compound of Formula VIII with a base, preferably a tertiary amine such as triethyl amine, in a suitable solvent such as dichloromethane and then adding trifluoromethanesulfonic anhydride.
- the addition is preferably carried out in a controlled manner, e.g., adding dropwise at a reduced temperature such as, for example, at about 0°C.
- the product can be isolated by conventional methods or it can be carried on without isolation as described below in connection with step (7).
- step (7) of Reaction Scheme I a compound of Formula IX is reacted with an amine of formula R ⁇ NH 2 where Ri is as defined above to provide a 4-nitrotetrazolo[l,5- ⁇ ][l,8]naphthyridin-5-amine of Formula X.
- the reaction can be carried out by adding the amine to the reaction mixture resulting from step (6).
- the reaction can also be carried out by adding the amine to a solution of the compound of Formula IX and a tertiary amine in a suitable solvent such as dichloromethane.
- step (8) of Reaction Scheme I a compound of Formula X is reduced to provide a tetrazolo[l,5- ⁇ ][l,8]naphthyridin-4,5-diamine of Formula XL
- the reduction is carried out using a conventional heterogeneous hydrogenation catalyst such as platinum on carbon or palladium on carbon.
- the reaction can conveniently be carried out on a Pan apparatus in a suitable solvent such as ethanol.
- a compound of Formula XI is reacted with a carboxylic acid or an equivalent thereof to provide a 7H-tetrazolo[l,5- ⁇ ]imidazo[4,5- c][l,8]naphthyridine of Formula XII.
- Suitable equivalents to carboxylic acid include acid halides, orthoesters, and 1,1-dialkoxyalkyl alkanoates.
- the carboxylic acid or equivalent is selected such that it will provide the desired R 2 substituent in a compound of Formula XII. For example, diethoxymethylacetate will provide a compound where R 2 is hydrogen and valeryl chloride will provide a compound where R 2 is butyl.
- the reaction can be run in the absence of solvent, in a carboxylic acid such as acetic acid, or in an inert solvent in the presence of a carboxylic acid.
- the reaction is run with sufficient heating to drive off any alcohol or water formed as a byproduct of the reaction.
- step (10) of Reaction Scheme I a compound of Formula XII is reacted with triphenylphosphine to provide a N-triphenylphosphinyl-iH-imidazo[4,5- c][l,8]naphthyridin-4- .amine of Formula XIII.
- the reaction can be carried out by combining a compound of Formula XII with triphenylphosphine in a suitable solvent such as 1 ,2-dichlorobenzene and heating.
- step (11) of Reaction Scheme I a compound of Formula XIII is hydro lyzed to provide a 7H-imidazo[4,5-c][l,8]naphthyridin-4-amine of Formula XIV which is a subgenus of Formula I.
- the hydrolysis can be carried out by conventional methods such as by heating in a lower alkanol in the presence of an acid.
- the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
- step (12) of Reaction Scheme I a compound of Formula XIV is reduced to provide a 6,7,8,9-tetrahydro-77J-imidazo[4,5-c][l,8]naphthyridin-4-amine of Formula XV which is a subgenus of Formula II.
- the reduction is carried out by suspending or dissolving a compound of Formula XIV in trifluoroacetic acid, adding a catalytic amount of platinum (IV)oxide, and then subjecting the mixture to hydrogen pressure.
- the reaction can be conveniently carried out in a Pan apparatus.
- the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
- amine of Formula XV can be prepared by reduction of a compound of Formula XII. The reduction is carried out by suspending or dissolving a compound of Formula XII in trifluoroacetic acid, adding a catalytic amount of platinum (IV)oxide, and then subjecting the mixture to hydrogen pressure. The reaction can be conveniently carried out in a Pan apparatus. As above, the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
- R, R ⁇ and R 2 are as defined above can be prepared according to Reaction Scheme II.
- step (1) of Reaction Scheme II a 3-aminoisonicotinic acid of Formula XVI is reacted with acetic anhydride by heating to provide a 2-methyl- H-pyrido[3,4- £tj[l,3]oxazin-4-one of Formula XVII.
- R is hydrogen
- step (2) of Reaction Scheme II a compound of Formula XVII is reacted with sodium azide in a suitable solvent such as acetic acid to provide a tetrazolyl isonicotinic acid of Formula XVIII.
- the reaction conveniently may be run at ambient conditions.
- step (3) of Reaction Scheme II an acid of Formula XVIII is esterified to provide a compound of Formula XIX.
- the esterification may be carried out using conventional methods.
- the acid may be esterified in acetone using potassium carbonate and ethyl iodide or by reacting with dimethylformamide diethyl acetal in a suitable solvent such as dichloromethane.
- step (4) of Reaction Scheme II a compound of Formula XIX is cyclized to provide a tetrazolo[l,5- ⁇ ][l,7]naphthyridin-5-ol of Formula XX.
- the reaction may be carried out by reacting the compound of Formula XIX with an alkoxide in a suitable solvent, e.g., potassium ethoxide in N,N-dimethylformamide, at ambient conditions.
- a compound of Formula XX is chlorinated using a suitable chlorinating agent such as thionyl chloride, oxalyl chloride, phosphorus pentachloride or preferably phosphorus oxychloride to provide a 5-chlorotetrazolo[l,5- fl][l,7]naphthyridine of Formula XXI.
- a suitable chlorinating agent such as thionyl chloride, oxalyl chloride, phosphorus pentachloride or preferably phosphorus oxychloride to provide a 5-chlorotetrazolo[l,5- fl][l,7]naphthyridine of Formula XXI.
- the reaction can be carried out in an inert solvent or if appropriate in neat chlorinating agent.
- Preferred reaction conditions involve reaction in neat phosphorus oxychloride with heating at about 90°C.
- step (6) of Reaction Scheme II a compound of Formula XXI is reacted with an amine of formula R1NH 2 where Rj is as defined above to provide a tetrazolo[l,5- ⁇ ][l,7]naphthyridin-5-amine of Formula XXII.
- the reaction can be carried out by heating with an excess of the amine.
- step (7) of Reaction Scheme II a compound of Formula XXII is nitrated using a suitable nitrating agent such as nitric acid to provide a 4-nitrotetrazolo[l,5- ⁇ ][l,7]naphthyridin-5-amine of Formula XXIII.
- the reaction is carried out in acetic acid with mild heating and .an excess of nitric acid.
- step (8) of Reaction Scheme II a compound of Formula XXIII is reduced to provide a tetrazolo[ 1 ,5-a] [ 1 ,7]naphthyridin-4,5-diamine of Formula XXIV.
- the reduction is carried out using an excess of sodium hydrogensulfide in a suitable solvent such as acetic acid.
- step (9) of Reaction Scheme II a compound of Formula XXIV is reacted with a carboxylic acid or an equivalent thereof to provide a 7H-tetrazolo[l,5- ⁇ ]imidazo[4,5- c][l,7]naphthyridine of Formula XXV.
- Suitable equivalents to carboxylic acid include acid halides, orthoesters, and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent is selected such that it will provide the desired R substituent in a compound of
- diethoxymethylacetate will provide a compound where R 2 is hydrogen and valeryl chloride will provide a compound where R 2 is butyl.
- the reaction can be run in the absence of solvent, in a carboxylic acid such as acetic acid, or in an inert solvent in the presence of a carboxylic acid. The reaction is run with sufficient heating to drive off any alcohol or water formed as a byproduct of the reaction.
- step (10) of Reaction Scheme II a compound of Formula XXV is reacted with triphenylphosphine to provide a N-triphenylphosphinyl-7H-imidazo[4,5- c][l,7]naphthyridin-4-amine of Formula XXVI.
- the reaction can be carried out by combining a compound of Formula XXV with triphenylphosphine in a suitable solvent such as 1 ,2-dichlorobenzene and heating.
- step (11) of Reaction Scheme II a compound of Formula XXVI is hydro lyzed to provide a 7H-imidazo[4,5-c][l,7]naphthyridin-4-amine of Formula XXVII which is a subgenus of Formula I.
- the hydrolysis can be carried out by conventional methods such as by heating in a lower alkanol in the presence of an acid.
- the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
- step (12) of Reaction Scheme II a compound of Formula XXVII is reduced to provide a 6,7,8,9-tetrahydro-77J-imidazo[4,5-c][l,7]naphthyridin-4- .
- amine of Formula XXVIII which is a subgenus of Formula II.
- the reduction is carried out by suspending or dissolving a compound of Formula XXVII in trifluoroacetic acid, adding a catalytic amount of platinum (IV)oxide, and then subjecting the mixture to hydrogen pressure.
- the reaction can be conveniently carried out in a Pan apparatus.
- the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
- a 6,7,8,9- tetrahydro-77/-imidazo[4,5-c][l,7]naphthyridin-4-amine of Formula XXVIII can be prepared by reduction of a compound of Formula XXV.
- the reduction is carried out by suspending or dissolving a compound of Formula XXV in trifluoroacetic acid, adding a catalytic amount of platinum (IV)oxide, and then subjecting the mixture to hydrogen pressure.
- the reaction can be conveniently carried out in a Parr apparatus.
- the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
- step (1) of Reaction Scheme III a 3-nitro[l,5]naphthyridin-4-ol of Formula XXIX is chlorinated using a suitable chlorinating agent such as phosphorus oxychloride to provide a 4-chloro-3-nitro[l,5]naphthyridine of Formula XXX.
- the reaction can be carried out by reacting a compound of Formula XXIX with phosphorus oxychloride in a suitable solvent such as N,N-dimethylformamide with mild heating (-55° C).
- the compound may be isolated by conventional methods or it can be carried on without isolation as described below in connection with step (2).
- the compound of Formula XXIX where R is hydrogen is known and its preparation has been disclosed in Hart,
- XXX is reacted with an amine of Formula R 1 NH 2 where Ri is as defined above to provide a 3-nitro[l ,5]naphthyridin-4-amine of Formula XXXI.
- the reaction can be carried out by adding water then excess amine to the reaction mixture resulting from step (1) then heating on a steam bath.
- the reaction can also be carried out by adding excess amine to a solution of a compound of Formula XXX in a suitable solvent such as dichloromethane and optionally heating.
- Rj is hydrogen
- XXXI is reduced to provide a [l,5]naphthyridine-3,4-diamine of Formula XXXII.
- the reduction is carried out using a conventional heterogeneous hydrogenation catalyst such as platinum on carbon or palladium on carbon.
- the reaction can conveniently be carried out on a Parr apparatus in a suitable solvent such as ethyl acetate.
- step (4) of Reaction Scheme III a compound of Formula XXXII is reacted with a carboxylic acid or an equivalent thereof to provide a IH- imidazo[4,5-c][l,5]naphthyridine of Formula XXXIII.
- Suitable equivalents to carboxylic acid include acid halides, orthoesters, and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent is selected such that it will provide the desired R 2 substituent in a compound of Formula
- XXXIII diethoxymethylacetate will provide a compound where R 2 is hydrogen and trimethylorthovalerate will provide a compound where R 2 is butyl.
- the reaction can be run in the absence of solvent, in a carboxylic acid such as acetic acid, or in an inert solvent in the presence of an acid. The reaction is run with sufficient heating to drive off any alcohol or water formed as a byproduct of the reaction.
- step (4) may be carried out by (i) reacting a compound of Formula
- Part (i) involves reacting a compound of Formula XXXII with an acyl halide of formula R2C(O)X wherein R 2 is as defined above and X is chloro or bromo.
- the reaction can be carried out by adding the acyl halide in a controlled fashion (e.g. dropwise) to a solution of a compound of Formula XXXII in a suitable solvent such as dichloromethane at a reduced temperature (e.g., 0°C).
- a suitable solvent such as dichloromethane
- Part (ii) involves cyclizing the product of part (i) by reacting it with methanolic ammonia at an elevated temperature (e.g. 150°C) and pressure.
- step (5) of Reaction Scheme III a compound of Formula XXXIII is oxidized to provide a IH- imidazo[4,5-c][l,5]naphthyridine-5N-oxide of Formula XXXIV using a conventional oxidizing agent that is capable of forming N-oxides.
- Prefened reaction conditions involve reacting a solution of a compound of Formula XXXIII in chloroform with 3-chloroperoxybenzoic acid at ambient conditions.
- step (6) of Reaction Scheme III a compound of Formula XXXIV is aminated to provide a IH- imidazo[4,5-c][l,5]naphthyridin-4-amine of Formula XXXV which is a subgenus of Formula I.
- Step (6) involves (i) reacting a compound of formula XXXIV with an acylating agent; and then (ii) reacting the product with an aminating agent.
- Part (i) of step (6) involves reacting an N-oxide with an acylating agent.
- Suitable acylating agents include alkyl- or arylsulfonyl chlorides (e.g., benzenesulfonyl chloride, methanesulfonyl choride, p-toluenesulfonyl chloride).
- Arylsulfonyl chlorides are prefened.
- p- Toluenesulfonyl chloride is most prefened.
- Part (ii) of step (6) involves reacting the product of part (i) with an excess of an aminating agent.
- Suitable aminating agents include ammonia (e.g., in the form of ammonium hydroxide) and ammonium salts (e.g., ammonium carbonate, ammonium bicarbonate, ammonium phosphate).
- Ammonium hydroxide is prefened.
- the reaction is preferably carried out by dissolving the N-oxide of Formula XXXIV in an inert solvent such as dichloromethane, adding the aminating agent to the solution, and then adding the acylating agent. Preferred conditions involve cooling to about 0°C to about 5°C during the addition of the acylating agent.
- the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
- step (6) may be carried out by (i) reacting a compound of Formula XXXFV with an isocyanate; and then (ii) hydrolyzing the product.
- Part (i) involves reacting the N-oxide with an isocyanate wherein the isocyanato group is bonded to a carbonyl group.
- Prefened isocyanates include trichloroacetyl isocyanate and aroyl isocyanates such as benzoyl isocyanate.
- the reaction of the isocyanate with the N-oxide is carried out under substantially anhydrous conditions by adding the isocyanate to a solution of the N-oxide in an inert solvent such as dichloromethane. The resulting product can be isolated by removal of the solvent.
- Part (ii) involves hydrolysis of the product from part (i).
- the reaction can be carried out by conventional methods such as heating in the presence of water or a lower alkanol optionally in the presence of a catalyst such as an alkali metal hydroxide or lower alkoxide.
- step (7) of Reaction Scheme III a compound of Formula XXXV is reduced to provide a 6,7,8,9-tetrahydro-777- imidazo[4,5-c][l,5]naphthyridin-4-amine of Formula XXXVI which is a subgenus of Formula II.
- the reduction is carried out by suspending or dissolving a compound of Formula XXXV in trifluoroacetic acid, adding a catalytic amount of platinum (IV) oxide, and then subjecting the mixture to hydrogen pressure.
- the reaction can be conveniently carried out in a Pan apparatus.
- the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
- Certain functional groups recited in connection with Ri and R 2 may be incompatible with some of the reagents of Reaction Schemes I, II and III.
- Compounds containing such functional groups can be prepared by those skilled in the art using well known methods of functional group protection and manipulation. For example, amine groups may be protected when necessary by derivatizing with di-tert-butyl dicarbonate.
- Some compounds of Formula I or Formula II containing certain functional groups may be readily prepared from other compounds of Formula I or Formula II.
- compounds wherein the Ri substituent contains an amide group may conveniently be prepared by reacting an acid chloride with a compound of Formula I or Formula II wherein the R] substituent contains a primary amine.
- compounds wherein the Ri substituent contains a urea group may be prepared by reacting an isocyanate with a compound of Formula I or Formula II wherein the Ri substituent contains a primary amine.
- compounds wherein the R] substituent contains a carbamate group may be prepared by reacting a chloro formate with a compound of Formula I or Formula II wherein the Ri substituent contains a primary amine.
- R 1 ⁇ R2 and A are as defined above for compounds of Formula I and Formula II.
- R, Ri, and R 2 are as defined above for compounds of Formula I and Formula II.
- R, Ri and R 2 are as defined above for compounds of Formula I and Formula II.
- R 7 is OH, halogen or NHR t (.and A and Ri are as defined above for compounds of Formula I) and R 8 is H, NO2 or NH2.
- A is as defined above for compounds of Formula I and R is H or Ci-io alkyl.
- R and Ri are as defined above for compounds of Formula I and Formula II with the proviso that Ri is other than hydrogen, and R 10 is NO 2 or NH2.
- compositions of the invention contain a therapeutically effective amount of a compound of Formula I or Formula II as defined above in combination with a pharmaceutically acceptable carrier.
- a therapeutically effective amount means an amount of the compound sufficient to induce a therapeutic effect, such as cytokine induction or antiviral activity.
- compositions of the invention will contain sufficient active ingredient to provide a dose of about lOOng/kg to about 50mg/kg, preferably about lO ⁇ g/kg to about 5mg/kg of the compound to the subject.
- Any of the conventional dosage forms may be used, such as tablets, lozenges, parenteral formulations, syrups, creams, ointments, aerosol formulations, transdermal patches, transmucosal patches and so on.
- the compounds of the invention have been shown to induce the production of certain cytokines in experiments performed according to the Test Method set forth below. This ability indicates that the compounds are useful as immune response modifiers that can modulate the immune response in a number of different ways, rendering them useful in the treatment of a variety of disorders.
- Cytokines that are induced by the administration of compounds according to the invention generally include interferon (IFN) and tumor necrosis factor (TNF) as well as certain interleukins (IL).
- IFN interferon
- TNF tumor necrosis factor
- IL interleukins
- the compounds induce IFN- ⁇ , TNF- ⁇ , IL-1, 6, 10 .and 12, and a variety of other cytokines.
- cytokines inhibit virus production and tumor cell growth, making the compounds useful in the treatment of tumors and viral diseases.
- the compounds affect other aspects of the innate immune response. For example, natural killer cell activity may be stimulated, an effect that may be due to cytokine induction.
- the compounds may also activate macrophages, which in turn stimulates secretion of nitric oxide and the production of additional cytokines. Further, the compounds may cause proliferation and differentiation of B-lymphocytes.
- Compounds of the invention also have an effect on the acquired immune response.
- the production of the T helper type 1 (Thl) cytokine LFN- ⁇ is induced indirectly and the production of the Th2 cytokine IL-5 is inhibited upon administration of the compounds.
- This activity means that the compounds are useful in the treatment of diseases where upregulation of the Thl response and/or downregulation of the Th2 response is desired.
- the compounds are expected to be useful in the treatment of atopy, e.g., atopic dermatitis, asthma, allergy, allergic rhinitis; as a vaccine adjuvant for cell mediated immunity; and possibly as a treatment for recurrent fungal diseases and chlamydia.
- the immune response modifying effects of the compounds make them useful in the treatment of a wide variety of conditions. Because of their ability to induce cytokines such as IFN- ⁇ and TNF- ⁇ , the compounds are particularly useful in the treatment of viral diseases and tumors.
- This immunomodulating activity suggests that compounds of the invention are useful in treating diseases such as, but not limited to viral diseases e.g. genital warts, common warts, plantar warts, Hepatitis B, Hepatitis C, Herpes Simplex Type I and Type II, molluscum contagiosm, HIV, CMV, VZV, cervical intraepithelial neoplasia, human papillomavirus and associated neoplasias; fungal diseases, e.g.
- Candida aspergillus, cryptococcal meningitis
- neoplastic diseases e.g., basal cell carcinoma, hairy cell leukemia, Kaposi's sarcoma, renal cell carcinoma, squamous cell carcinoma, myelogenous leukemia, multiple myeloma, melanoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, and other cancers
- parasitic diseases e.g., basal cell carcinoma, hairy cell leukemia, Kaposi's sarcoma, renal cell carcinoma, squamous cell carcinoma, myelogenous leukemia, multiple myeloma, melanoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, and other cancers
- parasitic diseases e.g.
- Additional diseases or conditions that can be treated using the compounds of the invention include eczema, eosinophilia, essential thrombocythaemia, leprosy, multiple sclerosis, Ommen's syndrome, rheumatoid arthritis, systemic lupus erythematosis, discoid lupus, Bowen's disease and Bowenoid papulosis.
- the invention provides a method of inducing cytokine biosynthesis in an animal comprising administering an effective .amount of a compound of Formula I or Formula II to the animal.
- An amount of a compound effective to induce cytokine biosynthesis is an amount sufficient to cause one or more cell types, such as monocytes, macrophages, dendritic cells and B-cells to produce an amount of one or more cytokines such as, for example, INF- , TNF- ⁇ , IL-1,6,10 and 12 that is increased over the background level of such cytokines.
- the precise amount will vary according to factors known in the art but is expected to be a dose of about lOOng/kg to about 50mg/kg, preferably about lO ⁇ g/kg to about 5mg/kg.
- the invention further provides a method of treating a viral infection in .an animal comprising administering an effective amount of a compound of Formula I or Formula II to the animal.
- An amount effective to treat or inhibit a viral infection is an amount that will cause a reduction in one or more of the manifestations of viral infection, such as viral lesions, viral load, rate of virus production, and mortality as compared to untreated control animals.
- the precise amount will vary according to factors known in the art but is expected to be a dose of lOOng/kg to about 50mg/kg, preferably about lO ⁇ g/kg to about 5mg/kg.
- the invention is further described by the following examples, which are provided for illustration only and are not intended to be limiting in any way.
- 2-Aminonicotinic acid (5 g, 36 mmole) was suspended in acetic anhydride (25 mL) then heated at reflux for 2 hours. The reaction mixture was concentrated under vacuum.
- the material from Part A was covered with acetic acid (75 mL), sodium azide (2 g) was added and the reaction mixture was stined at ambient temperature over the weekend.
- Nitric acid (1.33 mL of 16M) was added to a suspension of tetrazolo[l,5- ⁇ ][l,8]naphthyridin-5-ol (4 g, 21 mmole) in acetic acid (50 mL).
- the reaction mixture was heated on a steam bath for 5 minutes then cooled to ambient temperature.
- Sodium acetate (0.3 eq) in a small amount of water was added to the reaction mixture.
- the resulting solid was isolated by filtration and dried to provide 5 g of 4-nitrotetrazolo[l,5- ⁇ ][l,8]naphthryidin-5-ol as a solid, m.p. 278°C (decomposition).
- Example 6 Compound of Formula X N 5 -(2-Methylpropyl)-4-nitrotetrazolo [1 ,5- ⁇ ] [1 ,8] naphthyridin-5-amine 4-Nitrotetrazolo[l,5- ⁇ ][l,8]naphthryidin-5-ol (3 g, 13 mmole) was suspended in dichloromethane (3.8 mL), triethylamine (1.8 mL) was added, and the reaction mixture was cooled in an ice bath. Trifiuoromethanesulfonic anhydride (2.2 mL) was added dropwise. Isobutylamine (3.8 mL) was added in a single aliquot and the reaction mixture exothermed.
- N 5 -(2-methylpropyl)tetrazolo[ 1 ,5-a] [ 1 ,8]naphthyridin-4,5-diamine from Example 7 was combined with diethoxymethylacetate (2 mL) and heated on a steam bath for 3 hours. The reaction mixture was allowed to stand at ambient temperature overnight and then it was diluted with dichloromethane and methanol. The resulting solution was heated to remove the dichloromethane and reduce the volume of methanol to 50 mL and then cooled.
- Triphenylphosphine (1.0 g, 3.7 mmole) was added to a solution of l-(2- methylpropyl)-7H-tetrazolo[l,5- ⁇ ]imid ⁇ o[4,5-c][l,8]naphthyridine (0.5 g, 1.87 mmole) in 1 ,2-dichlorobenzene (15 mL). The reaction mixture was heated at reflux for 2 hours then concentrated under vacuum to remove the majority of the 1 ,2-dichlorobenzene. The residue was slurried with hexanes for 30 minutes.
- the solution was refluxed to remove the methanol then cooled to ambient temperature.
- the resulting precipitate was isolated by filtration then coated onto silica gel.
- the silica gel was eluted with 10-20% methanol in ethyl acetate.
- the eluant was concentrated to dryness.
- the resulting material was recrystallized from methanol and water to provide 0.35 g l-(2-methylpropyl)-7H-imidazo[4,5- c][l,8]naphthyridin-4-amine hydrate as a solid, m.p. 325-330°C (decomposition).
- Triphenylphosphine (0.9 g, 3.7 mmole) was added to a solution of 2-butyl-l-(2- methylpropyl)-7H-tetrazolo[l,5- ⁇ ]imid ⁇ o[4,5-c][l,8]naphthyridine (0.6 g, 1.8 mmole) in 1,2-dichlorobenzene (15 mL). The resulting mixture was heated at reflux for 2 hours then concentrated under vacuum to remove most of the 1,2-dichlorobenzene. The residue was slurred with hexanes then taken up in dichloromethane and filtered through a layer of silica gel.
- silica gel was eluted initially with dichloromethane to remove the 1,2- dichlorobenzene and then with 10% methanol in dichloromethane to recover 2-butyl-l-(2- methylpropyl)-N-triphenylphosphinyl-7H-imid.azo[4,5-c] [ 1 ,8]naphthyridin-4- amine.
- Example 14 Compound of Formula XVIII 3-(5-Methyl-2 -tetrazol-l-yl)pyridine-4-carboxylic acid 3-Aminopyridine-4-carboxylic acid (50.0 g, 0.36 mol) was suspended in acetic anhydride (250 mL) then heated at reflux for 2 hours. The reaction mixture was concentrated under vacuum. The solid residue was slurried with heptane then concentrated under vacuum. The resulting solid was covered with acetic acid (300 mL), then sodium azide (23.5 g, 0.36 mol) was added. The reaction exothermed to 50°C. The reaction mixture was allowed to stir at ambient temperature overnight. The precipitate was isolated by filtration then slurried with methanol and filtered. The solid was dissolved in 10% sodium hydroxide. The solution was heated on a steam bath for 30 minutes, allowed to cool to ambient temperature then neutralized with 6N hydrochloric acid. The resulting precipitate was isolated by filtration, washed with water and dried to
- Nitric acid (2 equivalents of 16M) was added to a solution of N 5 -(2- methylpropyl)tetrazolo[l,5- ⁇ ][l,7]naphthyridin-5-amine (2.0 g, 8.26 mmol) in acetic acid.
- the reaction mixture was heated on a steam bath for about an hour then concentrated under vacuum. The residue was poured into ice water and the resulting mixture was neutralized with sodium bicarbonate. The resulting precipitate was extracted with dichloromethane. The dichloromethane extracts were combined, washed with water, and dried over magnesium sulfate. Thin layer chromatography indicated a mixture so the material was filtered through a layer of silica gel eluting with 5% ethyl acetate in dichloromethane. The reaction was rerun on 4 g of starting material but using only one equivalent of nitric acid. The resulting material was also a mixture.
- N 5 -(2-Methylpropyl)-4-nitrotetrazolo[l,5- ⁇ ][l,7]naphthyridin-5-amine (1.5 g, 5.22 mmol) was suspended in acetic acid (75 mL). An excess of sodium hydrogen sulfide was dissolved in a minimum of water and added to the suspension. The reaction mixture turned red and all of the material went into solution. The reaction mixture was extracted twice with dichloromethane (150 mL).
- N 5 -(2-Methylpropyl)tetrazolo[l,5- ⁇ ][l,7]naphthyridin-4,5-diamine (1.1 g, 4.3 mmol) was combined with diethoxymethylacetate (2 mL) and heated on a steam bath overnight. The reaction mixture was partitioned between dichloromethane and ammonium hydroxide. The dichloromethane layer was separated, washed with water, dried over magnesium sulfate and concentrated under vacuum.
- Example 22 Compound of Formula I l-(2-Methylpropyl)-7/ -imidazo[4,5-c] [l,7]naphthyridin-4-amine
- Triphenylphosphine (0.49 g, 1.8 mmol) was added to a suspension of l-(2- methylpropyl)-777-tetrazolo[l,5- ⁇ ]imidazo[4,5-c][l,7]naphthyridine (0.24 g, 0.9 mmol) in dichlorobenzene (15 mL). The reaction mixture was heated at reflux overnight then concentrated under vacuum. The residue was slurried with hexane and the resulting solid 1 -(2-methylpropyl)-N-triphenylphosphinyl-7H-imidazo[4,5-c] [ 1 ,7]naphthyridin-4-amine was isolated by filtration.
- Part B The 1 -(2-methylpropyl)-N-triphenylphosphinyl-7H-imidazo[4,5- c][l,7]naphthyridin-4-amine from Part A was dissolved in methanol (30 mL). Hydrochloric acid (3 mL of 3N) was added to the solution and the reaction mixture was heated at reflux overnight before being concentrated under vacuum to remove the methanol. The aqueous residue was neutralized with sodium bicarbonate then extracted with dichloromethane. The extract was dried over magnesium sulfate then concentrated under vacuum.
- the aqueous layer was made basic with 10% sodium hydroxide then the dichloromethane layer was separated, dried over magnesium sulfate and concentrated under vacuum.
- the residue was purified by flash chromatography (silica gel eluting with 2-5% methanol in dichloromethane) to provide 0.25 g of 2-methyl-l-(2-methylpropyl)- 7H-tetrazolo[l,5- ⁇ ]imidazo[4,5-c][l,7]naphthyridine as a solid, m.p. 157-158°C.
- Triphenylphosphine (2.5 g, 9.6 mmol) was added to a suspension of 2-methyl-l- (2-methylpropyl)-777-tetrazolo[l,5- ⁇ ]imidazo[4,5-c][l,7]naphthyridine (1 g, 4 mmol) in dichlorobenzene. The reaction mixture was heated at reflux overnight then concentrated under vacuum. The residue was slurried with hexane and the
- a catalytic amount of platinum oxide was added to a solution of 2-methyl- 1 -(2- methylpropyl)-777-imidazo[4,5-c][l,7]naphthyridin-4-amine (0.1 g, 0.4 mol) in trifluoroacetic acid.
- the reaction mixture was reduced on a Parr apparatus at 50 psi (3.5 Kg/cm 2 ) hydrogen pressure overnight.
- the reaction mixture was filtered and washed with methanol to remove the catalyst, and the filtrate was concentrated under vacuum. The residue was combined with dichloromethane and aqueous sodium bicarbonate was added until the mixture was basic.
- dichloromethane layer was separated, and the aqueous layer was extracted three times with dichloromethane (100 mL).
- the combined dichloromethane extracts were dried over magnesium sulfate and concentrated under vacuum.
- the resulting residue was recrystallized from toluene to provide 6,7,8,9- tetrahydro-2-methyl-l-(2-methylpropyl)-7H-imidazo[4,5-c][l,7]naphthyridin-4-amine as a solid, m.p. 226-230°C.
- Valeryl chloride (0.76 mL, 6.4 mmol) was added to a solution of N 5 -(2- methylpropyl)tetrazolo[l,5- ⁇ ][l,7]naphthyridin-4,5-diamine (1.5 g, 5.8 mmol) in acetonitrile (15 mL). The reaction mixture was allowed to stir at ambient temperature for several hours. The resulting precipitate was isolated by filtration. Thin layer chromatography indicated that the material contained two components. The solid was dissolved in acetic acid and heated at reflux overnight. The reaction mixture was concentrated under vacuum, and the residue extracted with dichloromethane.
- the crude solid from Part A was combined with diethoxymethylacetate (2 mL) then heated on a steam bath overnight.
- the reaction mixture was taken up in dichloromethane, washed with water, dried over magnesium sulfate then filtered through a layer of silica gel.
- the silica gel was eluted with dichloromethane to remove excess diethoxymethylacetate then with 5% methanol in dichloromethane to recover the product.
- the eluant was concentrated to provide an oil which was purified by flash chromatography (silica gel eluting with 50% ethyl acetate/hexane then with ethyl acetate) to provide 0.25 g of 1 -(2-methylpropyl)-77/-imidazo[4,5-c] [ 1 ,5]naphthyridine as a solid m.p. 82-84°C.
- a catalytic amount of platinum oxide was added to a solution of l-(2- methylpropyl)-777-imidazo[4,5-c][l,5]naphthyridin-4-amine (0.46 g) in trifluoroacetic acid (10 mL).
- the reaction mixture was reduced on a Parr apparatus under 45 psi (3.15 Kg/cm 2 ) hydrogen pressure for 4 hours.
- the reaction mixture was filtered to remove the catalyst and the filtrate was concentrated under vacuum.
- the residue was combined with aqueous sodium bicarbonate then a small amount of 10% sodium hydroxide was added.
- the resulting precipitate was extracted with dichloromethane.
- the dichloromethane extract was dried over magnesium sulfate then concentrated under vacuum.
- 3-Chloroperoxybenzoic acid (4.5 g of 50%, 13.1 mmol) was added in small portions over a period of 30 minutes to a solution of 2-methyl- 1 -(2-methylpropyl)-7H- imidazo[4,5-c][l,5]naphthyridine (2.1 g, 8.7 mmole) in chloroform at ambient temperature. After 3 hours the reaction mixture was diluted with chloroform, washed twice with 2.0 M sodium hydroxide, once with water, and once with brine, dried over magnesium sulfate then concentrated under vacuum.
- Phosphorus oxychloride (4 mL, 0.31 mole) was combined with N,N- dimethylform.amide (100 mL) while cooling in .an ice bath. The resulting mixture was added to a solution of 3-nitro[l,5]naphthyridin-4-ol (50 g, 0.26 mole) in N,N- dimethylformamide (500 mL). The reaction mixture was stined at ambient temperature for 6 hours. The reaction mixture was poured into ice water and then extracted with dichloromethane (1800 mL). The organic layer was separated and then combined with triethylamine (45 mL).
- Example 43 Compound of Formula XXXIII 1,1-Dimethylethyl N-[4-(2-Butyl-l/J-imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl]carbamate
- Ammonium hydroxide (20 mL) was added to a solution of l- ⁇ 4-[(l,l- dimethylethylcarbonyl)amino]butyl ⁇ -2-butyl- 177-imidazo[4,5-c] [ 1 ,5 ]naphthyridine-5N- oxide (19.4 g) in chloroform.
- Tosyl chloride (9 g) was slowly added. Thin layer chromatography indicated that the reaction was proceeding slowly. Additional tosyl chloride was added twice. After thin layer chromatography indicated that the reaction was complete, the layers were separated. The organic layer was washed with dilute aqueous sodium carbonate, dried over magnesium sulfate and then concentrated under vacuum.
- phenyl isocyanate 52 ⁇ L, 0.48 mmol
- 4-(4-amino-2-butyl- lH-imidazo[4,5-c] [ 1 ,5]naphthyridin- 1 -yl)butaneamine (0.15 g, 0.48 mmole) in anhydrous tetrahydrofuran (60 mL).
- the reaction mixture was stined for 20 minutes at which time it had turned homogeneous and thin layer chromatography indicated no starting material remained.
- Aminomethyl resin (280 mg of 1% cross linked, 100-200 mesh available from BACHEM, Torrance, California) was added and the reaction mixture was allowed to stir for 0.5 hr.
- Silica gel (0.4 g) was added and the mixture was concentrated under vacuum to provide a solid.
- the solid was purified by flash chromatography eluting with 95/5 dichloromethane/methanol to give a white solid which was dried under vacuum at 60°C to provide 0.12 g of N-[4-(4-amino-2-butyl-lH- imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl]- N'-phenylurea.
- cyclohexyl isocyanate (61 ⁇ L, 0.48 mmol) was reacted with 4-(4-amino-2-butyl-lH-imidazo[4,5-c][l,5]naphthyridin-l- yl)butaneamine (0.15 g, 0.48 mmole) to provide 0.14 g of N-[4-(4-amino-2 -butyl- 177- imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl]- N'- cyclohexylurea as a white solid.
- Benzyl isocyanate (59 ⁇ L, 0.48 mmol) was added at ambient temperature to a suspension of 4-(4-amino-2-butyl-177-imidazo[4,5-c] [ 1 ,5]naphthyridin- 1 -yl)but.aneamine (0.15 g, 0.48 mmol) in tetrahydrofuran (60 mL).
- a solution was obtained in less than 30 minutes and thin layer chromatography (9:1 dichloromethane:methanol) showed one major new spot with a higher R f and only a trace of starting material.
- Aminomethyl resin (280 mg) was added and the reaction mixture was stined for 15 minutes. The solvent was removed under vacuum.
- Phenylacetyl chloride (21 ⁇ L, 0.16 mmol) was added to a suspension of 4-(4- amino-2-butyl-lH-imidazo[4,5-c][l,5]naphthyridin-l-yl)butaneamine (0.050 g, 0.16 mmol) in tetrahydrofuran (30 L). The reaction mixture was stirred at ambient temperature for 1 hour by which time a solution was obtained. Thin layer chromatography (9:1 dichloromethane :methanol) showed one major new spot with a higher R f and only a trace of starting material. Aminomethyl resin (100 mg) was added and the reaction mixture was stined for 5 minutes.
- benzyl chloroformate (83 ⁇ L, 0.58 mmol) was reacted with 4-(4-amino-2-butyl-lH-imidazo[4,5-c][l,5]naphthyridin-l- yl)butaneamine (0.15 g, 0.48 mmol) to provide 0.18 g of benzyl N-[4-(4-amino-2-butyl- lH-imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl]carbamate as a white powder.
- 9-fluorenylmethyl chloroformate (0.085 g, 0.33 mmol) was reacted with 4-(4-amino-2-butyl-lH-imidazo[4,5-c][l,5]naphthyridin- l-yl)butaneamine (0.105 g, 0.33 mmol) to provide 0.125 g of 9H-9-fluorenylmethyl N-[4- (4-amino-2-butyl-lH-imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl]carbamate as a white powder.
- Trimethylorthovalerate (3.6 mL, 20 mmol) was added to a suspension of 1,1 - dimethyl-2-[(3-amino[l,5]naphthyridin-4-yl)amino]ethanol 3.5 g, 13 mmol) in xylene (100 mL).
- the reaction mixture was heated at reflux for two days.
- the mixture was diluted with methanolic ammonia, placed in a Pan vessel and then heated at 110°C for 4 hours.
- the reaction mixture was concentrated under vacuum.
- the residue was partitioned between dichloromethane and water. The layers were separated. The organic layer was washed with water, dried over magnesium sulfate and then concentrated under vacuum to provide an oil.
- Phenylacetyl chloride (2.0 mL, 20 mmol) was added to a suspension of 1,1- dimethyl-2-[(3-amino[l,5]naphthyridin-4-yl)amino]ethanol 3.5 g, 13 mmol) in dichlorometha. ne (100 mL). The reaction mixture was heated at reflux until thin layer chromatography indicated that the reaction was complete. The reaction mixture was taken on to the next step.
- Example 66 Compound of Formula XXXI N-PhenylmethyI-3-nitro [1 ,5] naphthyridin-4-amine Phosphorus oxychloride (3.5 mL, 37.7 mmol) was reacted with N,N- dimethylformamide (15 mL) while chilling in an ice bath. This mixture was added to a solution of 3-nitro[l,5]naphthyridin-4-ol (6.0 g, 31.4 mmol) in N,N-dimethylformamide (60 mL). The reaction mixture was warmed in an oil bath to 60°C. After 3 hours the reaction mixture was poured into ice water. The resulting precipitate was isolated by filtration and then washed with water.
- N-(4-Phenylmethylamino[l,5]naphthyridin-3-yl)-ethoxyacetamide hydrochloride (5.8 g, 15.5 mmol) was combined with a 7 % solution of ammonia in methanol (100 mL), placed in a sealed Parr vessel and then heated at 150°C for 6 hours. The reaction mixture was concentrated under vacuum. The residue was partitioned between water and dichloromethane. The dichloromethane layer was separated, washed with water, dried over magnesium sulfate and then concentrated under vacuum.
- Valeryl chloride (1.53 mL, 12.9 mmol) was added dropwise over a 15 minute period to a chilled (ice bath) solution of N 4 -(3-isopropoxypropyl)[l,5]naphthyridine-3,4- diamine (3.2 g, 12.3 mmol) in dichloromethane (40 mL). The cooling bath was removed and the reaction mixture was maintained at ambient temperature for 1 hour. The solvent was removed under vacuum to provide a dark tan solid. Part B
- the material from Part A and a 7.5% solution of ammonia in methanol (100 mL) were placed in a pressure vessel. The vessel was sealed and then heated at 150°C for 6 hours. After the mixture was cooled to ambient temperature it was concentrated under vacuum. The residue was partitioned between dichloromethane (150 mL) and water (150 mL). The fractions were separated and the aqueous fraction was extracted with dichloromethane (100 mL). The organic fractions were combined, dried over magnesium sulfate, filtered and then concentrated under vacuum to provide a brown oil.
- N 4 -(3-butoxypropyl)-3-nitro[l,5]naphthyridin-4- amine (4.9 g, 16 mmol) was reduced to provide 4.3 g of N 4 -(3- butoxypropyl)[l,5]naphthyridine-3,4-diamine as a bright yellow oil.
- N 4 -(3- butoxypropyl)[l,5]naphthyridine-3,4-diamine (3.7 g, 13.5 mmol) was reacted with valeryl chloride (1.7 mL, 14.3 mmol) and the resulting amide intermediate was cyclized to provide 2.9 g of l-(3-butoxypropyl)-2-butyl-lH-imidazo[4,5-c][l,5]naphthyridine as a colorless oil.
- Example 75 l-(3-butoxypropy ⁇ )-2-butyl-lH- imidazo[4,5-c][l,5]naphthyridine-5N-oxide (1.2 g, 3.4 mmol) was reacted with trichloroacetyl isocyanate (0.6 mL, 5.0 mmol) and the resulting intermediate was hydrolyzed to provide 0.86 g of l-(3-butoxypropyl)-2 -butyl- lH-imidazo[4,5- c][l,5]naphthyridin-4-amine as a white powder, m.p. 101.0-101.5°C.
- N 4 -(2-Phenoxyethyl)-3-nitro[l,5]naphthyridin-4-amine Using the general method of Example 76, 4-chloro-3 -nitro [ 1 ,5]naphthyridine (5.0 g, 24 mmol) was reacted with 2-phenoxyethylamine (3.5 mL, 27 mmol) to provide 6.6 g of N 4 -(2-phenoxyethyl)-3-nitro[l,5]naphthyridin-4-amine as a yellow solid, m.p. 107-108°C.
- N 4 -(2-Phenoxyethyl)[l,5]naphthyridine-3,4-diamine Using the general method of Example 77, N 4 -(2-phenoxyethyl)-3- nitro[l,5]naphthyridin-4-amine (5.4 g, 17.4 mmol) was reduced to provide 4.6 g of N 4 -(2- phenoxyethyl)[l,5]naphthyridine-3,4-diamine as a bright yellow oil.
- Example 84 Compound of Formula XXXTV 2-Butyl-l-(2-phenoxyethyl)-li -imidazo[4,5-c][l,5]naphthyridine-5N-oxide Using the general method of Example 74, 2-(2-butyl-17J-imidazo[4,5- c][l,5]naphthyridin-l-yl)ethyl phenyl ether (0.6 g, 1.7 mmol) was oxidized to provide 0.44 g of 2-butyl-l-(2-phenoxyethyl)-177-imidazo[4,5-c][l,5]naphthyridine-5N-oxide as a yellow powder.
- This solid was purified by flash chromatography (silica gel eluting with dichloromethane) to provide 24.8 g of 1,1 -dimethylethyl N- ⁇ 2-[(3-nitro[l,5]naphthyridin-4-yl)amino]ethylcarbamate as a canary yellow solid.
- a portion (0.3 g) was recrystallized from toluene (10 mL) and heptane (10 mL) to provide 0.2 g of canary yellow needles, m.p. 149-151°C.
- Example 87 Compound of Formula XXXII 1,1-Dimethylethyl N- ⁇ 2- [(3- Amino [1 ,5]naphthyridin-4-yl)amino] ethyl ⁇ carbamate
- Trichloroacetyl isocyanate (4.8 mL, 40 mmol) was added via a syringe to a solution of l- ⁇ 2-[(l, l-dimethylethoxycarbonyl)amino]ethyl ⁇ -2-butyl-lH-imidazo[4,5- c][l,5]naphthyridine-5N-oxide (10.4 g, 27 mmol) in dichloromethane (75 mL). The reaction mixture was stined at ambient temperature for 1 hour. Sodium methoxide (9 mL of 25% sodium methoxide in methanol) was added and the reaction mixture was stined at ambient temperature overnight.
- Trifluoroacetic acid (5 mL) was added to a solution of 1,1 -dimethylethyl N-[2-(4- amino-2-butyl-lH-imidazo[4,5-c][l,5]naphthyridin-l-yl)ethyl]carbamate (5.7 g, 15 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with dichloromethane and then extracted with 10% hydrochloric acid. The hydrochloric acid extract was washed twice with dichloromethane and then it was made basic with ammonium hydroxide.
- This material was purified by column chromatography (silica gel eluting with dichloromethane) to provide 0.2 g of a solid.
- This solid was recrystallized from acetonitrile (30 mL) to provide 0.18 g of N 1 -[2-(4-amino-2-butyl-lH-imidazo[4,5- c][l,5]naphthyridin-l-yl)ethyl]acetamide as a white powder, m.p.228-230°C.
- crotonyl chloride (68 ⁇ L, 0.7 mmol) was reacted with 2-(4-amino-2-butyl-lH-imidazo[4,5-c] [ 1 ,5 jnaphthyridin- 1 -yl)ethaneamine (0.2 g, 0.7 mmol) to provide 0.2 g of N 1 -[2-(4-amino-2-butyl-lH-imidazo[4,5- c][l,5]naphthyridin-l-yl)ethyl]-(E)-2-butenamide as a white powder, m.p. 198-200°C.
- reaction mixture was stirred at ambient temperature for 30 minutes and then a solution of l-[3-(dimethoxyamino)propyl]-3- ethylcarbodiimide hydrochloride (0.37 g, 1.9 mmol) in anhydrous dichloromethane (50 mL) was added dropwise.
- the reaction mixture was stined at ambient temperature overnight and then filtered to remove solids. The filtrate was washed twice with 10% sodium hydroxide and then with brine, dried, and then concentrated under vacuum to provide 0.3g of crude product.
- citronellic acid 0.3 g, 1.7 mmole
- 2-(4-amino-2 -butyl- lH-imidazo[4,5 -c] [ 1 ,5]naphthyridin- 1 -yl)ethaneamine 0.5 g, 1.7 mmol
- 2-(4-amino-2-butyl-177-imidazo[4,5- c][l,5]naphthyridin-l-yl)ethyl]-3,7-dimethyl-6-octenamide as a white whispy solid, m.p. 163-164°C.
- 6-morpholinonicotinic acid (0.12 g, 64 mmol) was reacted with 4-(4-amino-2-butyl-177-imidazo[4,5-c][l,5]naphthyridin-l- yl)butaneamine (0.2 g, 0.64 mmol) to provide N 1 -[4-(4-.amino-2 -butyl -lH-imid ⁇ o[4,5- c][l,5]naphthyridin-l-yl)butyl]-6-morpholmonicotinamide as a white solid, m.p. 95- 100°C.
- Example 105 6-quinolinecarboxylic acid (0.11 g, 64 mmol) was reacted with 4-(4-amino-2-butyl-lH-imidazo[4,5-c][l,5]naphthyridin-l- yl)butaneamine (0.2 g, 0.64 mmol) to provide N -[4-(4-amino-2-butyl -lH-imidazo[4,5- c][l,5]naphthyridin-l-yl)butyl]-6-quinolinecarboxamide as a white solid, m.p. 190-191°C.
- Example 105 (4-pyridylthio)acetic acid (0.11 g, 64 mmol) was reacted with 4-(4-amino-2-butyl-lH-imidazo[4,5-c][l,5]naphthyridin-l- yDbutaneamine (0.2 g, 0.64 mmol) to provide 0.1 g of N 1 -[4-(4-amino-2-butyl -177- imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl]-2-(4-pyridylsulfanyl)acetamide as a solid, m.p. 127.5-129°C.
- the toluene supernatant was decanted off and concentrated under vacuum to provide 1.1 g of 1,1- dimethylethyl N-[4-(177-imidazo[4,5-c][l,5]naphthyridin-l-yl)butyl]carbamate.
- the oil was identified as 4-(177-imidazo[4,5-c][l,5]naphthyridin-l-yl)butaneamine.
- Tosyl chloride (0.64 g, 3.37 mmol) was slowly added in small portions to a solution of the material from Part B (1.2 g, 3.37 mmol) in dichloromethane (20 mL).
- reaction mixture was partitioned between diethyl ether and saturated aqueous sodium bicarbonate (the aqueous layer was basic). The aqueous layer was extracted with an additional lOOmL of diethyl ether. The combined organic layers were dried and then concentrated under vacuum. The residue was purified by flash chromatography (silica gel eluting with 5%, then 10% methanol in dichloromethane) to provide 2.49 g of methyl 4- [ -(2-N,N-dimethylaminoethoxy)benzyl]benzoate as a colorless oil.
- Example 112 Part B D-desthiobiotin (151 mg, 0.70 mmole) was reacted with 4-(4-amino-2-butyl-lH-imidazo[4,5-c][l,5]naphthyridin-l- yDethaneamine (200 mg, 0.70 mmol) to provide 231 mg of N 1 -[4-(4-amino-2-butyl-lH- imidazo[4,5-c] [ 1 ,5]naphthyridin- 1 -yl)ethyl]-
- Examples 118-152 shown in the table below were prepared according to the following method. 4-(4-Amino-2-butyl-lH-imidazo[4,5- c][l,5]naphthyridin-l-yl)ethaneamine (50 ⁇ mol) was dissolved in dichloromethane (5 mL) in a screw-capped test tube and the solution was cooled in an ice-water bath. An acid chloride (50 ⁇ mol) of the formula R A COCI was added as a solution in 100 ⁇ L of dichloromethane (Acid chlorides that are solids were either dissolved or suspended in -400 ⁇ L of dichloromethane and then added).
- the mixture was vortexed for 15 seconds to 1 minute, becoming cloudy, and then -80 mg of an aminomethyl polystyrene resin (0.62 meq/g, 100-200 mesh, 1% crosslink, Bachem #D-2100, lot # FM507) was added, and the mixture was vortexed for another 30 seconds.
- the mixture was applied to a short column (3 x 1 cm ) of silica gel conditioned with dichloromethane.
- the product was eluted with 10:1 dichloromethane:methanol, collecting -2 mL fractions. Thin layer chromatography of the fractions was performed, and fractions with the product spot were pooled and stripped to dryness in a Savant SpeedVac.
- Examples 153-190 shown in the table below were prepared according to the following method. 4-(4-Amino-2-butyl-lH-imidazo[4,5- c][l,5]naphthyridin-l-yl)butaneamine (25 ⁇ mol) was dissolved in dichloromethane (10 mL) in a screw-capped test tube and the solution was cooled in an ice-water bath. An acid chloride (25 ⁇ mol) of the formula R A COCl was added as a solution in 100 ⁇ L of dichloromethane (Acid chlorides that are solids were added directly.).
- the mixture was vortexed for 15 seconds to 1 minute, becoming cloudy, and then -80 mg of an aminomethyl polystyrene resin (0.62 meq/g, 100-200 mesh, 1% crosslink, Bachem #D- 2100, lot # FM507) was added, and the mixture was vortexed for another 30 seconds.
- the mixture was applied to a short column (3 x 1 cm ) of silica gel conditioned with dichloromethane.
- the product was eluted with 10:1 dichloromethane methanol, collecting -2 mL fractions. Thin layer chromatography of the fractions was performed, and fractions with the product spot were pooled and stripped to dryness in a Savant SpeedVac.
- the coupling agent, l-(3-dimethylaminopropyl)-3- ethyl carbodiimide hydrochloride (-10.5 mg, 55 ⁇ mol) was added and the mixture was vortexed at 400 rpm for 1-2 h at ambient temperature, giving a clear solution in most cases.
- the mixture was applied to a short column (3 x 1 cm ) of silica gel conditioned with dichloromethane.
- the product was eluted with 10:1 dichloromethane:methanol, collecting -2 mL fractions. Thin layer chromatography of the fractions was performed, and fractions with the product spot were pooled and stripped to dryness in a Savant SpeedVac. Purity was checked by reversed phase-HPLC
- Gradient elution linear gradient from 100% water +0.1% trifluoroacetic acid to 100% acetonitrile + 0.1% trifluoroacetic acid over 5 min. at 1 mL per minute. Detection is at 220 nm and 254 nm).
- APCI-mass spectral data confirmed presence of the expected molecular ion, and proton nmr data supported the expected structure.
- CYTOKINE INDUCTION IN HUMAN CELLS An in vitro human blood cell system was used to assess cytokine induction by compounds of the invention. Activity is based on the measurement of interferon and tumor necrosis factor ( ⁇ *) (IFN and TNF, respectively) secreted into culture media as described by Testerman et. al. In "Cytokine Induction by the Inimunomodulators
- PBMCs Peripheral blood mononuclear cells
- Histopaque®-1077 Sigma Chemicals, St. Louis, MO
- the PBMCs are suspended at 1.5-2 x 10 6 cells/mL in RPMI 1640 medium containing 10 % fetal bovine serum, 2 mM L-glutamine and 1% penicillin/streptomycin solution (RPMI complete). 1 mL portions of PBMC suspension are added to 24 well flat bottom sterile tissue culture plates.
- the compounds are solubilized in dimethyl sulfoxide (DMSO).
- DMSO concentration should not exceed a final concentration of 1 % for addition to the culture wells.
- the compounds are generally tested in a concentration range of from 0.1 to 100 ⁇ M. Incubation
- test compound is added to the wells containing 1 mL of PBMCs in media.
- the plates are covered with plastic lids, mixed gently and then incubated for 18 to
- Interferon Analysis/Calculation Interferon is determined by bioassay using A549 human lung carcinoma cells challenged with encephalomyocarditis.
- the details of the bioassay method have been described by G. L. Brennan and L. H. Kronenberg in "Automated Bioassay of Interferons in Micro-test Plates", Biotechniques, June/July, 78, 1983, incorporated herein by reference. Briefly stated the method is as follows: A549 cells are incubated with samples and standard interferon dilutions at 37°C for 24 hours. The incubated cells are then infected with an inoculum of encephalomyocarditis virus.
- the infected cells are incubated for an additional 24 hours at 37°C before quantifying for viral cytopathic effect.
- the viral cytopathic effect is quantified by staining followed by visual scoring of the plates. Results are expressed as alpha reference units/mL based on the value obtained for NTH Human
- Tumor necrosis factor ( «) (TNF)concentration is determined using an ELISA kit available from Genzyme, Cambridge, MA. The results are expressed as pg/mL. In the table below, a "+” indicates that the compound induced the indicated cytokine at that particular concentration, a “-” indicates that the compound did not induce the indicated cytokine at that particular concentration, and a “ ⁇ ” indicates that the results were equivocal at that particular concentration.
- Peripheral blood mononuclear cells were separated from whole blood by using either LeucoPREPTM Brand Cell Separation Tubes (available from Becton Dickinson) or Ficoll-Paque® solution (available from Pharmacia LKB Biotechnology Inc, Piscataway, NJ).
- the PBM's were suspended at 1 x 10 6 /mL in RPMI 1640 media (available from GIBCO, Grand Island, NY) containing 25 mM HEPES (N-2-hydroxyethylpiperazine-N'-2- eth.anesulfonic acid) and L-glutamine (1% penicillin-streptomycin solution added) with
- the compounds were solubilized in ethanol, dimethyl sulfoxide or tissue culture water then diluted with tissue culture water, 0.01N sodium hydroxide or 0.01N hydrochloric acid (The choice of solvent will depend on the chemical characteristics of the compound being tested.). Ethanol or DMSO concentration should not exceed a final concentration of 1% for addition to the culture wells. Compounds were initially tested in a concentration range of from about 0.1 ⁇ g/mL to about 5 ⁇ g/mL. Compounds which show induction at a concentration of 0.5 ⁇ g/mL were then tested in a wider concentration range.
- test compound was added in a volume (less than or equal to 50 ⁇ L) to the wells containing 200 ⁇ L of diluted whole blood or of PBM's in media. Solvent and/or media was added to control wells (wells with no test compound) and as needed to adjust the final volume of each well to 250 ⁇ L.
- the plates were covered with plastic lids, vortexed gently and then incubated for 48 hours at 37°C with a 5% carbon dioxide atmosphere.
- Interferon was determined by bioassay using A549 human lung carcinoma cells challenged with encephalomyocarditis. The details of the bioassay method have been described by G. L. Brennan and L. H. Kronenberg in "Automated Bioassay of Interferons in Micro-test Plates", Biotechniques. June/July, 78, 1983, incorporated herein by reference. Briefly stated the method is as follows: interferon dilutions and A549 cells are incubated at 37°C for 12 to 24 hours. The incubated cells are infected with an inoculum of encephalomyocarditis virus.
- the infected cells are incubated for an additional period at 37°C before quantifying for viral cytopathic effect.
- the viral cytopathic effect is quantified by staining followed by spectrophotometric absorbance measurements. Results are expressed as alpha reference units/mL based on the value obtained for NTR HU IF-L standard.
- the interferon was identified as essentially all interferon alpha by testing in checkerboard neutralization assays against rabbit anti-human interferon (beta) and goat anti-human interferon (alpha) using A549 cell monolayers challenged with encephalomyocarditis virus.
Priority Applications (28)
Application Number | Priority Date | Filing Date | Title |
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UA2000074070A UA67760C2 (uk) | 1997-12-11 | 1998-11-12 | Імідазонафтиридин та тетрагідроімідазонафтиридин, фармацевтична композиція, спосіб індукування біосинтезу цитокінів та спосіб лікування вірусної інфекції, проміжні сполуки |
EEP200000349A EE04314B1 (et) | 1997-12-11 | 1998-12-11 | Imidasonaftüridiinid ja nende kasutamine tsütokiini biosünteesi induktsioonil |
JP2000524286A JP4283438B2 (ja) | 1997-12-11 | 1998-12-11 | イミダゾナフチリジンおよびサイトカイン生合成の誘導にそれを使用すること |
IL13655698A IL136556A0 (en) | 1997-12-11 | 1998-12-11 | Imidazonaphthyridines and their use in inducing cytokine biosynthesis |
EP98963888A EP1040112B1 (en) | 1997-12-11 | 1998-12-11 | Imidazonaphthyridines and their use in inducing cytokine biosynthesis |
PL98341159A PL193915B1 (pl) | 1997-12-11 | 1998-12-11 | Imidazonaftyrydyny, kompozycje farmaceutyczne je zawierające i ich zastosowanie oraz związki pośrednie |
DK04022441T DK1512686T3 (da) | 1997-12-11 | 1998-12-11 | Imidazonaphtyridiner og deres anvendelse til at inducere cytokinbiosyntese |
DK98963888T DK1040112T3 (da) | 1998-12-11 | 1998-12-11 | Imidazonaphthyridiner |
SK5035-2007A SK286304B6 (en) | 1997-12-11 | 1998-12-11 | Imidazonaphthyridines and their use in inducing cytokine biosynthesis |
NZ504776A NZ504776A (en) | 1997-12-11 | 1998-12-11 | Imidazonaphthyridines and their use in inducing cytokine biosynthesis |
BR9814275-5A BR9814275A (pt) | 1997-12-11 | 1998-12-11 | Imidazonaftiridinas e seu uso na indução da biossìntese de citocinas |
CA2311456A CA2311456C (en) | 1997-12-11 | 1998-12-11 | Imidazonaphthyridines and their use in inducing cytokine biosynthesis |
AU19123/99A AU753864B2 (en) | 1997-12-11 | 1998-12-11 | Imidazonaphthyridines and their use in inducing cytokine biosynthesis |
AT98963888T ATE277046T1 (de) | 1997-12-11 | 1998-12-11 | Imidazonaphthyridinderivate und ihre verwendung zur induzierung von biosythese von cytokin |
HU0101155A HUP0101155A3 (en) | 1997-12-11 | 1998-12-11 | Imidazonaphthyridines, pharmaceutical compositions thereof and intermediates |
DE69826518T DE69826518T2 (de) | 1997-12-11 | 1998-12-11 | Imidazonaphthyridinderivate und ihre verwendung zur induzierung von biosythese von cytokin |
SI9830711T SI1040112T1 (en) | 1997-12-11 | 1998-12-11 | Imidazonaphthyridines and their use in inducing cytokine biosynthesis |
SK835-2000A SK285872B6 (sk) | 1997-12-11 | 1998-12-11 | Imidazonaftyridíny a ich použitie na indukovanie biosyntézy cytokínu |
KR1020037016103A KR100563175B1 (ko) | 1997-12-11 | 1998-12-11 | 이미다조나프티리딘, 및 그의 시토킨 생합성 유발시의 용도 |
KR1020007006369A KR100642703B1 (ko) | 1997-12-11 | 1998-12-11 | 이미다조나프티리딘, 및 그의 시토킨 생합성 유발시의 용도 |
KR1020037016102A KR100642702B1 (ko) | 1997-12-11 | 1998-12-11 | 이미다조나프티리딘, 및 그의 시토킨 생합성 유발시의 용도 |
NO20002663A NO316687B1 (no) | 1997-12-11 | 2000-05-24 | Imidazonaftyridiner, farmasoytiske blandinger inneholdende imidazon og deres anvendelse til a indusere cytokin biosyntese |
HR20000363A HRP20000363B1 (en) | 1997-12-11 | 2000-06-02 | Imidazonaphthyridines and their use in inducing cytokine biosynthesis |
IL136556A IL136556A (en) | 1997-12-11 | 2000-06-05 | 1H – imidazo [5,4– C] naphthyridine – 4 – amines |
NO20035718A NO328045B1 (no) | 1997-12-11 | 2003-12-19 | Imidazonaftyridiner og deres anvendelse til a indusere cytokin biosyntese |
NO20035719A NO20035719D0 (no) | 1997-12-11 | 2003-12-19 | Imidazonaftyridiner og deres anvendelse til å indusere cytokin biosyntese |
IL178092A IL178092A (en) | 1997-12-11 | 2006-09-14 | 2 – methyl – 1– (2 – methylprofile) –1H– imidazo [5,4– C] [5,1] naphthyridine – 4 – amine or its pharmaceutical salt and pharmaceutical preparations containing it or its salt |
IL178091A IL178091A (en) | 1997-12-11 | 2006-09-14 | 1– (2 – methylprofile) –1H– imidazo [5,4– C] [5,1] naphthyridine – 4 – amine or its pharmacy salt and pharmaceutical preparations containing it or its salt |
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PCT/US1998/026473 WO1999029693A1 (en) | 1997-12-11 | 1998-12-11 | Imidazonaphthyridines and their use in inducing cytokine biosynthesis |
Country Status (28)
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AU2007275815A1 (en) * | 2006-07-18 | 2008-01-24 | Wirra Ip Pty. Ltd. | Immune response modifier formulations |
CA2659733A1 (en) * | 2006-07-31 | 2008-02-07 | 3M Innovative Properties Company | Sterilized topical compositions of 1-(2-methylpropyl)-1h-imidazo[4,5-c]quinolin-4-amine |
US8178539B2 (en) * | 2006-09-06 | 2012-05-15 | 3M Innovative Properties Company | Substituted 3,4,6,7-tetrahydro-5H-1,2a,4a,8-tetraazacyclopenta[cd]phenalenes and methods |
US20080149123A1 (en) * | 2006-12-22 | 2008-06-26 | Mckay William D | Particulate material dispensing hairbrush with combination bristles |
CN101568351B (zh) * | 2006-12-22 | 2012-05-30 | 3M创新有限公司 | 控制释放的组合物和方法 |
WO2008098232A1 (en) * | 2007-02-08 | 2008-08-14 | Graceway Pharmaceuticals, Llc | Methods of treating dermatological disorders and inducing interferon biosynthesis with shorter durations of imiquimod therapy |
US20100160368A1 (en) | 2008-08-18 | 2010-06-24 | Gregory Jefferson J | Methods of Treating Dermatological Disorders and Inducing Interferon Biosynthesis With Shorter Durations of Imiquimod Therapy |
RS58566B1 (sr) | 2008-12-19 | 2019-05-31 | Medicis Pharmaceutical Corp | Formulacije imikuimoda niže dozne jačine i kratkih režima doziranja za lečenje aktinične keratoze |
AU2010229835B2 (en) | 2009-03-25 | 2015-01-15 | The Board Of Regents Of The University Of Texas System | Compositions for stimulation of mammalian innate immune resistance to pathogens |
AU2010232731A1 (en) * | 2009-03-31 | 2011-10-20 | Arqule, Inc. | Substituted dipyrido-pyrimido-diazepine and benzo-pyrido-pyrimido compounds |
US8511006B2 (en) * | 2009-07-02 | 2013-08-20 | Owens Corning Intellectual Capital, Llc | Building-integrated solar-panel roof element systems |
GEP20156418B (en) | 2009-07-13 | 2016-01-11 | Medicis Pharmaceutical Corp | Lower dosage strength imiquimod formulations and short dosing regimens for treating genital and perianal warts |
US20110033515A1 (en) * | 2009-08-04 | 2011-02-10 | Rst Implanted Cell Technology | Tissue contacting material |
US8461328B2 (en) * | 2010-01-12 | 2013-06-11 | Genentech, Inc. | Tricyclic heterocyclic compounds, compositions and methods of use thereof |
DK2584900T3 (en) | 2010-06-25 | 2019-04-01 | Medicis Pharmaceutical Corp | Combination therapy with cryosurgery and low-dose imiquimod for the treatment of actinic keratosis |
EP2606047B1 (en) | 2010-08-17 | 2017-01-25 | 3M Innovative Properties Company | Lipidated immune response modifier compound compositions, formulations, and methods |
US9475804B2 (en) | 2011-06-03 | 2016-10-25 | 3M Innovative Properties Company | Heterobifunctional linkers with polyethylene glycol segments and immune response modifier conjugates made therefrom |
AU2012261959B2 (en) | 2011-06-03 | 2015-12-03 | Solventum Intellectual Properties Company | Hydrazino 1H-imidazoquinolin-4-amines and conjugates made therefrom |
US20130023736A1 (en) | 2011-07-21 | 2013-01-24 | Stanley Dale Harpstead | Systems for drug delivery and monitoring |
US9492682B2 (en) | 2011-09-14 | 2016-11-15 | Medicis Pharmaceutical Corporation | Combination therapy with low dosage strength imiquimod and photodynamic therapy to treat actinic keratosis |
CA2857664A1 (en) | 2011-11-30 | 2013-06-06 | Sarepta Therapeutics, Inc. | Antisense oligonucleotides targeting within the smn2 pre-mrna for use ininduced exon inclusion in spinal muscle atrophy |
CA2871490C (en) | 2012-04-27 | 2022-10-04 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Use of cpg oligonucleotides co-formulated with an antibiotic to accelerate wound healing |
WO2013164754A2 (en) | 2012-05-04 | 2013-11-07 | Pfizer Inc. | Prostate-associated antigens and vaccine-based immunotherapy regimens |
CN112587658A (zh) | 2012-07-18 | 2021-04-02 | 博笛生物科技有限公司 | 癌症的靶向免疫治疗 |
CN105025854A (zh) | 2013-01-07 | 2015-11-04 | 宾夕法尼亚大学董事会 | 治疗皮肤t细胞淋巴瘤的组合物和方法 |
WO2015011254A1 (en) | 2013-07-26 | 2015-01-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment of bacterial infections |
KR102258645B1 (ko) | 2013-11-05 | 2021-05-28 | 쓰리엠 이노베이티브 프로퍼티즈 캄파니 | 참기름을 베이스로 하는 주사 제제 |
AU2015205753A1 (en) | 2014-01-10 | 2016-07-21 | Birdie Biopharmaceuticals Inc. | Compounds and compositions for treating HER2 positive tumors |
DK3166976T3 (da) | 2014-07-09 | 2022-04-11 | Birdie Biopharmaceuticals Inc | Anti-pd-l1-kombinationer til behandling af tumorer |
CN112546230A (zh) | 2014-07-09 | 2021-03-26 | 博笛生物科技有限公司 | 用于治疗癌症的联合治疗组合物和联合治疗方法 |
CN112546238A (zh) | 2014-09-01 | 2021-03-26 | 博笛生物科技有限公司 | 用于治疗肿瘤的抗-pd-l1结合物 |
WO2016180852A1 (en) | 2015-05-12 | 2016-11-17 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for preparing antigen-specific t cells from an umbilical cord blood sample |
EP3298131B1 (en) | 2015-05-20 | 2023-04-26 | The Regents of The University of California | Method for generating human dendritic cells for immunotherapy |
US10150768B2 (en) | 2015-08-31 | 2018-12-11 | 3M Innovative Properties Company | Guanidine substituted imidazo[4,5-c] ring compounds |
CN107922416B (zh) | 2015-08-31 | 2021-07-02 | 3M创新有限公司 | 含有取代的胍基团的咪唑并[4,5-c]环化合物 |
US10526309B2 (en) | 2015-10-02 | 2020-01-07 | The University Of North Carolina At Chapel Hill | Pan-TAM inhibitors and Mer/Axl dual inhibitors |
CN115252792A (zh) | 2016-01-07 | 2022-11-01 | 博笛生物科技有限公司 | 用于治疗肿瘤的抗-egfr组合 |
CN115554406A (zh) | 2016-01-07 | 2023-01-03 | 博笛生物科技有限公司 | 用于治疗肿瘤的抗-cd20组合 |
CN106943598A (zh) | 2016-01-07 | 2017-07-14 | 博笛生物科技(北京)有限公司 | 用于治疗肿瘤的抗-her2组合 |
JP6883806B2 (ja) * | 2016-03-09 | 2021-06-09 | 国立大学法人大阪大学 | 化合物、及びこれを含む有機半導体材料 |
BR112018073676B1 (pt) | 2016-05-16 | 2023-10-03 | University Of Virginia Patent Foundation | Lipossomas peguilados e métodos de uso |
EP3458475B1 (en) | 2016-05-16 | 2022-07-27 | Access to Advanced Health Institute | Formulation containing tlr agonist and methods of use |
EP3504215B1 (en) | 2016-08-26 | 2022-04-06 | 3M Innovative Properties Company | Fused [1,2]imidazo[4,5-c]ring compounds substituted with guanidino groups |
CA3033542A1 (en) | 2016-08-30 | 2018-03-08 | Dana-Farber Cancer Institute, Inc. | Compositions and uses of biomaterials and activators of innate immunity |
MX2019005502A (es) | 2016-11-09 | 2020-10-01 | Univ Texas | Metodos y composiciones para inmunomodulacion adaptativa. |
CA3045666A1 (en) | 2016-12-14 | 2018-06-21 | Progenity, Inc. | Treatment of a disease of the gastrointestinal tract with a jak inhibitor and devices |
US11426566B2 (en) | 2016-12-14 | 2022-08-30 | Biora Therapeutics, Inc. | Treatment of a disease of the gastrointestinal tract with a TLR modulator |
AU2017378406A1 (en) | 2016-12-14 | 2019-06-13 | Biora Therapeutics, Inc. | Treatment of a disease of the gastrointestinal tract with an immunosuppressant |
EP3554345A1 (en) | 2016-12-14 | 2019-10-23 | Progenity, Inc. | Treatment of a disease of the gastrointestinal tract with a smad7 inhibitor |
EP3554541B1 (en) | 2016-12-14 | 2023-06-07 | Biora Therapeutics, Inc. | Treatment of a disease of the gastrointestinal tract with a chemokine/chemokine receptor inhibitor |
CN110072551B (zh) | 2016-12-14 | 2023-05-23 | 比奥拉治疗股份有限公司 | 使用利用可摄入装置释放的il-12/il-23抑制剂治疗胃肠道疾病 |
WO2018160552A1 (en) | 2017-03-01 | 2018-09-07 | 3M Innovative Properties Company | IMIDAZO[4,5-c] RING COMPOUNDS CONTAINING GUANIDINE SUBSTITUTED BENZAMIDE GROUPS |
US11596670B2 (en) | 2017-03-30 | 2023-03-07 | Biora Therapeutics, Inc. | Treatment of a disease of the gastrointestinal tract with IL-10 or an IL-10 agonist |
CN108794467A (zh) | 2017-04-27 | 2018-11-13 | 博笛生物科技有限公司 | 2-氨基-喹啉衍生物 |
AR111760A1 (es) | 2017-05-19 | 2019-08-14 | Novartis Ag | Compuestos y composiciones para el tratamiento de tumores sólidos mediante administración intratumoral |
EP3641771A4 (en) | 2017-06-23 | 2020-12-16 | Birdie Biopharmaceuticals, Inc. | PHARMACEUTICAL COMPOSITIONS |
ES2951817T3 (es) | 2017-08-22 | 2023-10-25 | Dynavax Tech Corp | Derivados de imidazoquinolina de cadena alquílica modificada como agonistas de TLR7/8 y usos de los mismos |
US10722591B2 (en) | 2017-11-14 | 2020-07-28 | Dynavax Technologies Corporation | Cleavable conjugates of TLR7/8 agonist compounds, methods for preparation, and uses thereof |
JP7197244B2 (ja) | 2017-12-20 | 2022-12-27 | スリーエム イノベイティブ プロパティズ カンパニー | 免疫応答調節剤として使用するための分岐鎖連結基を有するアミド置換イミダゾ[4,5-c]キノリン化合物 |
JP7251893B2 (ja) | 2018-02-28 | 2023-04-04 | スリーエム イノベイティブ プロパティズ カンパニー | N-1分枝基を有する置換イミダゾ[4,5-c]キノリン化合物 |
KR20200128116A (ko) | 2018-02-28 | 2020-11-11 | 화이자 인코포레이티드 | Il-15 변이체 및 이의 용도 |
MX2020012607A (es) | 2018-05-23 | 2021-01-29 | Pfizer | Anticuerpos especificos para gucy2c y sus usos. |
MX2020012539A (es) | 2018-05-23 | 2021-02-16 | Pfizer | Anticuerpos especificos para cd3 y sus usos. |
CN112218864B (zh) | 2018-05-24 | 2023-09-08 | 3M创新有限公司 | N-1支链环烷基取代的咪唑并[4,5-c]喹啉化合物、组合物和方法 |
EP3887369A1 (en) | 2018-11-26 | 2021-10-06 | 3M Innovative Properties Company | N-1 branched alkyl ether substituted imidazo[4,5-c]quinoline compounds, compositions, and methods |
WO2020128893A1 (en) | 2018-12-21 | 2020-06-25 | Pfizer Inc. | Combination treatments of cancer comprising a tlr agonist |
WO2020245706A1 (en) | 2019-06-06 | 2020-12-10 | 3M Innovative Properties Company | N-1 branched alkyl substituted imidazo[4,5-c]quinoline compounds, compositions, and methods |
CN113906027A (zh) | 2019-06-12 | 2022-01-07 | 3M创新有限公司 | 具有N-1支链基团的苯乙基取代的咪唑并[4,5-c]喹啉化合物 |
WO2021116420A1 (en) | 2019-12-13 | 2021-06-17 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of tlr7 and/or tlr8 agonists for the treatment of leptospirosis |
JP7369297B2 (ja) | 2019-12-17 | 2023-10-25 | ファイザー・インク | Cd47、pd-l1に特異的な抗体、およびその使用 |
WO2022009157A1 (en) | 2020-07-10 | 2022-01-13 | Novartis Ag | Lhc165 and spartalizumab combinations for treating solid tumors |
EP4182346A1 (en) | 2020-07-17 | 2023-05-24 | Pfizer Inc. | Therapeutic antibodies and their uses |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4689338A (en) * | 1983-11-18 | 1987-08-25 | Riker Laboratories, Inc. | 1H-Imidazo[4,5-c]quinolin-4-amines and antiviral use |
US4929624A (en) * | 1989-03-23 | 1990-05-29 | Minnesota Mining And Manufacturing Company | Olefinic 1H-imidazo(4,5-c)quinolin-4-amines |
WO1993009119A1 (en) * | 1991-11-06 | 1993-05-13 | Minnesota Mining And Manufacturing Company | Antiviral 2-ethyl-1h-imidazo(4,5-c)quinolin-4-amines |
US5268376A (en) * | 1991-09-04 | 1993-12-07 | Minnesota Mining And Manufacturing Company | 1-substituted 1H-imidazo[4,5-c]quinolin-4-amines |
US5389640A (en) * | 1991-03-01 | 1995-02-14 | Minnesota Mining And Manufacturing Company | 1-substituted, 2-substituted 1H-imidazo[4,5-c]quinolin-4-amines |
US5482936A (en) * | 1995-01-12 | 1996-01-09 | Minnesota Mining And Manufacturing Company | Imidazo[4,5-C]quinoline amines |
US5627281A (en) * | 1993-07-15 | 1997-05-06 | Minnesota Mining And Manufacturing Company | Intermediate compounds of fused cycloalkylimidazopyridines |
WO1997048704A1 (en) * | 1996-06-21 | 1997-12-24 | Minnesota Mining And Manufacturing Company | Process for preparing imidazoquinolinamines |
Family Cites Families (91)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3314941A (en) | 1964-06-23 | 1967-04-18 | American Cyanamid Co | Novel substituted pyridodiazepins |
US3764681A (en) * | 1970-07-08 | 1973-10-09 | Lilly Co Eli | Certain tetrazolo-(1,5-a) quinoline compounds as fungus control agents |
US3917624A (en) | 1972-09-27 | 1975-11-04 | Pfizer | Process for producing 2-amino-nicotinonitrile intermediates |
ZA848968B (en) | 1983-11-18 | 1986-06-25 | Riker Laboratories Inc | 1h-imidazo(4,5-c)quinolines and 1h-imidazo(4,5-c)quinolin-4-amines |
US5238944A (en) | 1988-12-15 | 1993-08-24 | Riker Laboratories, Inc. | Topical formulations and transdermal delivery systems containing 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine |
US5756747A (en) | 1989-02-27 | 1998-05-26 | Riker Laboratories, Inc. | 1H-imidazo 4,5-c!quinolin-4-amines |
US5037986A (en) | 1989-03-23 | 1991-08-06 | Minnesota Mining And Manufacturing Company | Olefinic 1H-imidazo[4,5-c]quinolin-4-amines |
NZ232740A (en) | 1989-04-20 | 1992-06-25 | Riker Laboratories Inc | Solution for parenteral administration comprising a 1h-imidazo(4,5-c) quinolin-4-amine derivative, an acid and a tonicity adjuster |
US4988815A (en) | 1989-10-26 | 1991-01-29 | Riker Laboratories, Inc. | 3-Amino or 3-nitro quinoline compounds which are intermediates in preparing 1H-imidazo[4,5-c]quinolines |
EP0553202B1 (en) | 1990-10-05 | 1995-04-12 | Minnesota Mining And Manufacturing Company | Process for the preparation of imidazo[4,5-c]quinolin-4-amines |
US5175296A (en) | 1991-03-01 | 1992-12-29 | Minnesota Mining And Manufacturing Company | Imidazo[4,5-c]quinolin-4-amines and processes for their preparation |
US5378698A (en) * | 1991-10-21 | 1995-01-03 | Shionogi & Co., Ltd. | Benzothiazepine derivatives |
IL105325A (en) | 1992-04-16 | 1996-11-14 | Minnesota Mining & Mfg | Immunogen/vaccine adjuvant composition |
US5395937A (en) | 1993-01-29 | 1995-03-07 | Minnesota Mining And Manufacturing Company | Process for preparing quinoline amines |
US5352784A (en) | 1993-07-15 | 1994-10-04 | Minnesota Mining And Manufacturing Company | Fused cycloalkylimidazopyridines |
KR100341341B1 (ko) | 1993-07-15 | 2002-11-25 | 미네소타 마이닝 앤드 매뉴팩춰링 캄파니 | 이미다조[4,5-c]피리딘-4-아민 |
US5644063A (en) | 1994-09-08 | 1997-07-01 | Minnesota Mining And Manufacturing Company | Imidazo[4,5-c]pyridin-4-amine intermediates |
US5585612A (en) | 1995-03-20 | 1996-12-17 | Harp Enterprises, Inc. | Method and apparatus for voting |
JPH09208584A (ja) | 1996-01-29 | 1997-08-12 | Terumo Corp | アミド誘導体、およびそれを含有する医薬製剤、および合成中間体 |
JPH09255926A (ja) | 1996-03-26 | 1997-09-30 | Diatex Co Ltd | 粘着テープ |
US5693811A (en) | 1996-06-21 | 1997-12-02 | Minnesota Mining And Manufacturing Company | Process for preparing tetrahdroimidazoquinolinamines |
ATE367159T1 (de) | 1996-10-25 | 2007-08-15 | Minnesota Mining & Mfg | Verbindungen, die die immunantwort verändern, zur behandlung von th2-vermittelten und -verwandten krankheiten |
PT839810E (pt) * | 1996-11-04 | 2003-01-31 | Bayer Cropscience Sa | 1-poliarilpirazois como pesticidas |
US5939090A (en) | 1996-12-03 | 1999-08-17 | 3M Innovative Properties Company | Gel formulations for topical drug delivery |
EP0894797A4 (en) | 1997-01-09 | 2001-08-16 | Terumo Corp | NEW AMID DERIVATIVES AND INTERMEDIATES ON YOUR SYNTHESIS |
UA67760C2 (uk) | 1997-12-11 | 2004-07-15 | Міннесота Майнінг Енд Мануфакчурінг Компані | Імідазонафтиридин та тетрагідроімідазонафтиридин, фармацевтична композиція, спосіб індукування біосинтезу цитокінів та спосіб лікування вірусної інфекції, проміжні сполуки |
JPH11222432A (ja) | 1998-02-03 | 1999-08-17 | Terumo Corp | インターフェロンを誘起するアミド誘導体を含有する外用剤 |
JPH11255926A (ja) | 1998-03-13 | 1999-09-21 | Toray Ind Inc | シリコーン成型品およびその製造方法 |
US6110929A (en) | 1998-07-28 | 2000-08-29 | 3M Innovative Properties Company | Oxazolo, thiazolo and selenazolo [4,5-c]-quinolin-4-amines and analogs thereof |
JP2000119271A (ja) * | 1998-08-12 | 2000-04-25 | Hokuriku Seiyaku Co Ltd | 1h―イミダゾピリジン誘導体 |
US6518280B2 (en) * | 1998-12-11 | 2003-02-11 | 3M Innovative Properties Company | Imidazonaphthyridines |
US20020058674A1 (en) | 1999-01-08 | 2002-05-16 | Hedenstrom John C. | Systems and methods for treating a mucosal surface |
CA2361936C (en) | 1999-01-08 | 2009-06-16 | 3M Innovative Properties Company | Formulations comprising imiquimod or other immune response modifiers for treating mucosal conditions |
US6545485B1 (en) * | 1999-01-21 | 2003-04-08 | Radar Engineers | Ultrasonic pinpointer for power system sources of interference |
US6558951B1 (en) | 1999-02-11 | 2003-05-06 | 3M Innovative Properties Company | Maturation of dendritic cells with immune response modifying compounds |
JP2000247884A (ja) | 1999-03-01 | 2000-09-12 | Sumitomo Pharmaceut Co Ltd | アラキドン酸誘発皮膚疾患治療剤 |
US6756382B2 (en) * | 1999-06-10 | 2004-06-29 | 3M Innovative Properties Company | Amide substituted imidazoquinolines |
US6451810B1 (en) | 1999-06-10 | 2002-09-17 | 3M Innovative Properties Company | Amide substituted imidazoquinolines |
US6541485B1 (en) | 1999-06-10 | 2003-04-01 | 3M Innovative Properties Company | Urea substituted imidazoquinolines |
US6573273B1 (en) * | 1999-06-10 | 2003-06-03 | 3M Innovative Properties Company | Urea substituted imidazoquinolines |
US6331539B1 (en) | 1999-06-10 | 2001-12-18 | 3M Innovative Properties Company | Sulfonamide and sulfamide substituted imidazoquinolines |
US6660260B1 (en) * | 1999-09-21 | 2003-12-09 | Mayo Foundation For Medical Education And Research | Bioprosthetic heart valves |
US6376669B1 (en) | 1999-11-05 | 2002-04-23 | 3M Innovative Properties Company | Dye labeled imidazoquinoline compounds |
US6894060B2 (en) * | 2000-03-30 | 2005-05-17 | 3M Innovative Properties Company | Method for the treatment of dermal lesions caused by envenomation |
US20020055517A1 (en) | 2000-09-15 | 2002-05-09 | 3M Innovative Properties Company | Methods for delaying recurrence of herpes virus symptoms |
JP2002145777A (ja) | 2000-11-06 | 2002-05-22 | Sumitomo Pharmaceut Co Ltd | アラキドン酸誘発皮膚疾患治療剤 |
UA74852C2 (en) | 2000-12-08 | 2006-02-15 | 3M Innovative Properties Co | Urea-substituted imidazoquinoline ethers |
UA74593C2 (en) | 2000-12-08 | 2006-01-16 | 3M Innovative Properties Co | Substituted imidazopyridines |
US6545016B1 (en) | 2000-12-08 | 2003-04-08 | 3M Innovative Properties Company | Amide substituted imidazopyridines |
US6664265B2 (en) * | 2000-12-08 | 2003-12-16 | 3M Innovative Properties Company | Amido ether substituted imidazoquinolines |
US6660747B2 (en) * | 2000-12-08 | 2003-12-09 | 3M Innovative Properties Company | Amido ether substituted imidazoquinolines |
US6660735B2 (en) * | 2000-12-08 | 2003-12-09 | 3M Innovative Properties Company | Urea substituted imidazoquinoline ethers |
US6545017B1 (en) | 2000-12-08 | 2003-04-08 | 3M Innovative Properties Company | Urea substituted imidazopyridines |
CA2430206A1 (en) * | 2000-12-08 | 2002-06-13 | 3M Innovative Properties Company | Screening method for identifying compounds that selectively induce interferon alpha |
US6667312B2 (en) * | 2000-12-08 | 2003-12-23 | 3M Innovative Properties Company | Thioether substituted imidazoquinolines |
US6664264B2 (en) * | 2000-12-08 | 2003-12-16 | 3M Innovative Properties Company | Thioether substituted imidazoquinolines |
US6525064B1 (en) | 2000-12-08 | 2003-02-25 | 3M Innovative Properties Company | Sulfonamido substituted imidazopyridines |
US6677348B2 (en) * | 2000-12-08 | 2004-01-13 | 3M Innovative Properties Company | Aryl ether substituted imidazoquinolines |
US6677347B2 (en) * | 2000-12-08 | 2004-01-13 | 3M Innovative Properties Company | Sulfonamido ether substituted imidazoquinolines |
US6664260B2 (en) * | 2000-12-08 | 2003-12-16 | 3M Innovative Properties Company | Heterocyclic ether substituted imidazoquinolines |
CN1523987A (zh) | 2001-06-15 | 2004-08-25 | 3M创新有限公司 | 治疗牙周疾病的免疫反应调节剂 |
JP2005501550A (ja) | 2001-08-30 | 2005-01-20 | スリーエム イノベイティブ プロパティズ カンパニー | 免疫反応調整剤分子を用いた形質細胞様樹状細胞を成熟させる方法 |
US6667347B2 (en) * | 2001-09-14 | 2003-12-23 | Chevron U.S.A. Inc. | Scrubbing CO2 from methane-containing gases using an aqueous stream |
AU2002360278A1 (en) * | 2001-10-12 | 2003-11-11 | Coley Pharmaceutical Gmbh | Methods and products for enhancing immune responses using imidazoquinoline compounds |
DK1719511T3 (da) * | 2001-11-16 | 2009-04-14 | Coley Pharm Group Inc | N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methansulfonamid, en farmaceutisk sammensætning omfattende samme, og anvendelse deraf |
CA2467828C (en) * | 2001-11-29 | 2011-10-04 | 3M Innovative Properties Company | Pharmaceutical formulations comprising an immune response modifier |
US6677349B1 (en) * | 2001-12-21 | 2004-01-13 | 3M Innovative Properties Company | Sulfonamide and sulfamide substituted imidazoquinolines |
BR0307788A (pt) * | 2002-02-22 | 2006-04-04 | 3M Innovative Properties Co | método de redução e tratamento de imunossupressão induzida por uv-b |
GB0211649D0 (en) | 2002-05-21 | 2002-07-03 | Novartis Ag | Organic compounds |
JP2005531599A (ja) * | 2002-05-29 | 2005-10-20 | スリーエム イノベイティブ プロパティズ カンパニー | イミダゾ[4,5−c]ピリジン−4−アミンのための方法 |
WO2003103584A2 (en) * | 2002-06-07 | 2003-12-18 | 3M Innovative Properties Company | Ether substituted imidazopyridines |
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-
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Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4689338A (en) * | 1983-11-18 | 1987-08-25 | Riker Laboratories, Inc. | 1H-Imidazo[4,5-c]quinolin-4-amines and antiviral use |
US4929624A (en) * | 1989-03-23 | 1990-05-29 | Minnesota Mining And Manufacturing Company | Olefinic 1H-imidazo(4,5-c)quinolin-4-amines |
US5389640A (en) * | 1991-03-01 | 1995-02-14 | Minnesota Mining And Manufacturing Company | 1-substituted, 2-substituted 1H-imidazo[4,5-c]quinolin-4-amines |
US5268376A (en) * | 1991-09-04 | 1993-12-07 | Minnesota Mining And Manufacturing Company | 1-substituted 1H-imidazo[4,5-c]quinolin-4-amines |
US5346905A (en) * | 1991-09-04 | 1994-09-13 | Minnesota Mining And Manufacturing Company | 1-substituted 1H-imidazo-[4,5-C]quinolin-4-amines |
WO1993009119A1 (en) * | 1991-11-06 | 1993-05-13 | Minnesota Mining And Manufacturing Company | Antiviral 2-ethyl-1h-imidazo(4,5-c)quinolin-4-amines |
US5627281A (en) * | 1993-07-15 | 1997-05-06 | Minnesota Mining And Manufacturing Company | Intermediate compounds of fused cycloalkylimidazopyridines |
US5482936A (en) * | 1995-01-12 | 1996-01-09 | Minnesota Mining And Manufacturing Company | Imidazo[4,5-C]quinoline amines |
WO1997048704A1 (en) * | 1996-06-21 | 1997-12-24 | Minnesota Mining And Manufacturing Company | Process for preparing imidazoquinolinamines |
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