EP1638566A2 - Imidazo-quinolines a substitution sulfonamide - Google Patents

Imidazo-quinolines a substitution sulfonamide

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Publication number
EP1638566A2
EP1638566A2 EP04756208A EP04756208A EP1638566A2 EP 1638566 A2 EP1638566 A2 EP 1638566A2 EP 04756208 A EP04756208 A EP 04756208A EP 04756208 A EP04756208 A EP 04756208A EP 1638566 A2 EP1638566 A2 EP 1638566A2
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EP
European Patent Office
Prior art keywords
imidazo
quinolin
amino
butyl
mmol
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.)
Withdrawn
Application number
EP04756208A
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German (de)
English (en)
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EP1638566A4 (fr
Inventor
George W. Griesgraber
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Coley Pharmaceutical Group Inc
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3M Innovative Properties Co
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Publication of EP1638566A2 publication Critical patent/EP1638566A2/fr
Publication of EP1638566A4 publication Critical patent/EP1638566A4/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61P37/02—Immunomodulators
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • 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

Definitions

  • This invention relates to imidazoquinoline compounds that have sulfonamide substitution at the 1 -position and to pharmaceutical compositions containing the compounds.
  • a further aspect of this invention relates to the use of these compounds as immunomodulators, for inducing cytokine biosynthesis in animals and in the treatment of diseases including viral and neoplastic diseases.
  • EP 894 797 discloses amide substituted imidazoquinoline compounds that are disclosed to be useful as immune response modifying compounds, while WO 00/09506 discloses imidazoquinoline compounds that contain a sulfonamide substituent wherein the sulfonamide nitrogen is part of a saturated heterocyclic ring.
  • R, Ri and R are as defined herein.
  • the compounds of Formula I 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 makes the compounds useful in the treatment of a variety of conditions such as viral diseases and tumors that are responsive to such changes in the immune response.
  • compounds of the invention are selected from the group consisting of -amino-2-ethyl- lH-imidazo[4,5-c]quinolin- 1 -yl)butyl]benzenesulfonamide; -amino-2-propyl-lH-imidazo[4,5-c]quinolin-l-yl)butyl]benzenesulfonamide; -amino-2-hexyl- lH-imidazo[4,5-c]quinolin- 1 -yl)butyl]benzenesulfonamide; -amino-2-propyl-lH-imidazo[4,5-c]quinolin-l-yl)butyl]methanesulfonamide; -amino-2-ethyl-lH-imidazo[4,5-c]quinolin-l-yl)butyl]methanesulfonamide; -amino-2-methyl-lH-
  • a compound or salt of the invention is N- ⁇ 2-
  • this compound has unexpectedly high IL-12 inducing activity relative to interferon ( ) inducing activity.
  • the invention further provides pharmaceutial compositions containing a therapeutically effective amount of a compound or salt of Formula I or of the above embodiments and methods of inducing cytokine biosynthesis in an animal, treating a viral infection and/or treating a neoplastic disease in an animal by administering a effective amount of a compound or salt of Formula I or of the above embodiments to the animal.
  • methods of synthesizing compounds of Formula I and intermediates useful in the synthesis of these compounds are provided.
  • the invention provides compounds of Formula I:
  • Ri is -alkyl-NR 3 -SO 2 -X-R 4 , -alkenyl-NR 3 -SO 2 -X-R 4 , or alkyl-NR 6 -SO 2 -R 7 ;
  • X is a bond or -NR 5 -;
  • R_j is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents selected from the group consisting of: -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -substituted aryl; -substituted heteroaryl; -substituted heterocyclyl; -O-alkyl; -O-(alkyl) 0- ⁇ -aryl; -O-(alkyl) 0- ⁇ -substituted aryl; -O
  • R 2 is selected from the group consisting of: -hydrogen; -alkyl; -alkenyl; -aryl; -substituted aryl; -heteroaryl; -substituted heteroaryl; - alkyl-O-alkyl; - alkyl-O- alkenyl; and - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of: -OH; -halogen; -N(R 3 ) 2 ; -CO-N(R 3 ) 2 ; -CO-C].
  • each R 3 is independently selected from the group consisting of hydrogen and
  • C LIO alkyl is selected from the group consisting of hydrogen and C M O alkyl, or j and R 5 can combine to form a 3 to 7 membered heterocyclic or substituted heterocyclic ring;
  • Re is selected from the group consisting of hydrogen and C MO alkyl;
  • R is selected from the group consisting of hydrogen and C MO alkyl, wherein R 6 and R 7 combine to form a 3 to 7 membered heterocyclic or substituted heterocyclic ring;
  • n is 0 to 4 and each R present is independently selected from the group consisting of C O alkyl, C O alkoxy, halogen and trifluoromethyl, or a pharmaceutically acceptable salt thereof.
  • Step (1) of Reaction Scheme I a 4-chloro-3-nitroquinoline of Formula II is reacted with an amine of Formula R ⁇ NH 2 where Ri is as defined above to provide a 3- nitroquinolin-4-amine of Formula III.
  • the reaction can be carried out by adding amine to a solution of a compound of Formula II in a suitable solvent such as chloroform or dichloromethane and optionally heating.
  • a suitable solvent such as chloroform or dichloromethane
  • step (2) of Reaction Scheme I a 3-nitroquinolin-4-amine of Formula III is reduced to provide a quinoline-3,4-diamine of Formula TV.
  • 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 isopropyl alcohol or toluene.
  • step (3) of Reaction Scheme I a quinoline-3,4-diamine of Formula TV is reacted with a carboxylic acid or an equivalent thereof to provide a lH-imidazo[4,5-c]quinoline of
  • 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 V.
  • triethyl orthoformate will provide a compound where R 2 is hydrogen and triethyl orthoacetate will provide a compound where R 2 is methyl.
  • the reaction can be run in the absence of solvent or in an inert solvent such as toluene. The reaction is run with sufficient heating to drive off any alcohol or water formed as a byproduct of the reaction.
  • step (4) of Reaction Scheme I a lH-imidazo[4,5-c]quinoline of Formula V is oxidized to provide a lH-imidazo[4,5-c]quinoline-5N-oxide of Formula VI using a conventional oxidizing agent that is capable of forming N-oxides. Prefened reaction conditions involve reacting a solution of a compound of Formula V in chloroform with 3- chloroperoxybenzoic acid at ambient conditions.
  • step (5) of Reaction Scheme I a lH-imidazo[4,5-c]quinoline-5N-oxide of Formula VI is aminated to provide a lH-imidazo[4,5-c]quinolin-4-amine of Formula VII which is a subgenus of Formula I.
  • Step (5) involves (i) reacting a compound of Formula VI with an acylating agent and then (ii) reacting the product with an aminating agent. Part (i) of step (5) involves reacting an N-oxide of Formula VI with an acylating agent.
  • Suitable acylating agents include alkyl- or arylsulfonyl chlorides (e.g., benezenesulfonyl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride). Arylsulfonyl chlorides are preferred. P ⁇ r ⁇ -toluenesulfonyl chloride is most prefened. Part (ii) of step (5) 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 VI in an inert solvent such as dichloromethane, adding the aminating agent to the solution, and then slowly adding the acylating agent.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (5) may be carried out by (i) reacting an N-oxide of Formula VI with an isocyanate and then (ii) hydrolyzing the resulting 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 chloroform or dichloromethane.
  • Part (ii) involves hydrolysis of the product from part (i). The hydrolysis 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.
  • Reaction Scheme III where R, R 2 , 4 and n are as defined above and m is 1-20.
  • Reaction Scheme III an aminoalkyl substituted lH-imidazo[4,5-c]quinolin-4- amine of Formula VIII is reacted with a sulfonic anhydride of Formula XI to provide a compound of Formula X which is a subgenus of Formula I.
  • the reaction can be run at ambient temperature in an inert solvent such as dichloromethane in the presence of a base such as pyridine or N,N-diisopropylethylamine.
  • reaction can be run at ambient temperature in acetonitrile.
  • Many sulfonic anhydrides of Formula XI are commercially available; others can be readily prepared using known synthetic methods.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • Tertiary sulfonamides of the invention can be prepared according to Reaction Scheme IV where R, R 2 , R 3 , R 4 and n are as defined above and m is 1-20.
  • Reaction Scheme IV a lH-imidazo[4,5-c]quinolinyl sulfonamide of Formula X is reacted with a halide of Formula XII to provide a compound of Formula XIII which is a subgenus of Formula I.
  • the reaction can be carried out at ambient temperature by adding sodium hydride to a solution of a compound of Formula X in N,N-dimethylformamide and then adding the halide.
  • Many halides of Formula XII are commercially available; others can be readily prepared using known synthetic methods.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • Step (1) of Reaction Scheme V an aminoalkyl substituted lH-imidazo[4,5- c]quinolin-4-amine of Formula VIII is reacted with sulfuryl chloride to generate in situ a sulfamoyl chloride of Formula XIV.
  • the reaction can be carried out by adding a solution of sulfuryl chloride in dichloromethane to a solution of a compound of Formula VIII in dichloromethane in the presence of one equivalent of 4-(dimethylamino)pyridine.
  • reaction is preferably canied out at a reduced temperature (-78°C).
  • a reduced temperature -78°C
  • the reaction mixture can be allowed to warm to ambient temperature.
  • step (2) of Reaction Scheme V an amine of Formula R 5 R 4 N ⁇ is reacted with the sulfamoyl chloride of Formula XTV to provide a lH-imidazo[4,5-c]quinolinyl sulfamide of Formula XV which is a subgenus of Formula I.
  • the reaction can be carried out by adding a solution containing 2 equivalents of the amine and 2 equivalents of triethylamine in dichloromethane to the reaction mixture from step (1).
  • the addition is preferably carried out at a reduced temperature (-78°C).
  • the reaction mixture can be allowed to warm to ambient temperature.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • Tetrahydroimidazoquinolines of the invention can be prepared according to Reaction Scheme VI where R 2 , R 3 , R , and R 5 are as defined above and m is 1-20.
  • step (1) of Reaction Scheme VI an aminoalkyl substituted lH-imidazo[4,5- c]quinolin-4-amine of Formula XVI is reduced to provide an aminoalkyl substituted 6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-4-amine of Formula XVII.
  • the reduction is carried out by suspending or dissolving the compound of Formula XVI in trifluoroacetic acid, adding a catalytic amount of platinum (IV) oxide, and then subjecting the mixture to hydrogen pressure.
  • step (2a) of Reaction Scheme VI an aminoalkyl substituted 6,7,8,9-tetrahydro- lH-imidazo[4,5-c]quinolin-4-amine of Formula XVII is reacted to provide a compound of Formula XVIII which is a subgenus of Formula I.
  • R 3 is hydrogen
  • the reaction can be carried out in one step according to the methods described in Reaction Schemes II and III above using a tetrahydroimidazoquinoline of Formula XVII in place of the imidazoquinoline of Formula VIII.
  • R 3 is other than hydrogen
  • the reaction can be carried out in two steps with step one being carried out according to the methods of Reaction Schemes II and III and step two being carried out according to the method of
  • step (2b) of Reaction Scheme VI an aminoalkyl substituted 6,7,8,9-tetrahydro- lH-imidazo[4,5-c]quinolin-4-amine of Formula XVII is reacted to provide a compound of
  • Tetrahydroimidazoquinolines of the invention can also be prepared according to
  • Reaction Scheme VII where R, R 2 , R 3j R ⁇ R 5 and n are as defined above and m is 1-20.
  • step (1) of Reaction Scheme VII a 6,7,8,9-tetrahydro-lH-imidazo[4,5- cjquinolinyl tert-butylcarbamate of Formula XX is hydrolyzed to provide an aminoalkyl substituted 6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-4-amine of Formula XXI.
  • the reaction can be carried out dissolving the compound of Formula XX in a mixture of trifluoroacetic acid and acetonitrile and stirring at ambient temperature.
  • the compound of Formula XX can be combined with dilute hydrochloric acid and heated on a steam bath.
  • Tetrahydro-lH-imidazo[4,5-c]quinolinyl t ⁇ rt-butylcarbamates of Formula XX can be prepared using the synthetic route disclosed in U.S. Patent 5,352,784 (Nikolaides). The product or a salt thereof can be isolated using conventional methods. Steps (2a) and (2b) can be carried out in the same manner as in Reaction Scheme VI. Reaction Scheme VII
  • Some compounds of Formula I can be readily prepared from other compounds of Formula I.
  • compounds wherein the R 4 substituent contains a chloroalkyl group can be reacted with an amine to provide an R substituent substituted by a secondary or teriary amino group; compounds wherein the P substituent contains a nitro group can be reduced to provide a compound wherein the R 4 substituent contains a primary amine.
  • the terms "alkyl”, “alkenyl”, “alkynyl” and the prefix "-alk” are inclusive of both straight chain and branched chain groups and of cyclic groups, i.e. cycloalkyl and cycloalkenyl. Unless otherwise specified, these groups contain from 1 to
  • haloalkyl is inclusive of groups that are substituted by one or more halogen atoms, including groups wherein all of the available hydrogen atoms are replaced by halogen atoms. This is also true of groups that include the prefix "haloalk-”.
  • Suitable haloalkyl groups are chloromethyl, trifluoromethyl, and the like.
  • 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, imidazo, pyrazolo, thiazolo, oxazolo, and the like.
  • 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, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl, and the like.
  • substituted cycloalkyl indicates that the rings or ring systems in question are further substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, alkylthio, hydroxy, halogen, haloalkyl, haloalkylcarbonyl, haloalkoxy (e.g., trifluoromethoxy), nitro, alkylcarbonyl, alkenylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocycloalkyl, nitrile, alkoxycarbonyl, alkanoyloxy, alkanoylthio, and in the case of cycloalkyl and heterocyclyl, oxo.
  • substituents independently selected from the group consisting of alkyl, alkoxy, alkylthio, hydroxy, halogen, haloalkyl, haloal
  • bonds are represented by dashed lines. These lines mean that the bonds represented by the dashed line can be present or absent. Accordingly, compounds of Formula I can be either imidazoquinoline compounds or tetrahydroimidazoquinoline compounds.
  • the invention is inclusive of the compounds described herein in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, solvates, polymorphs, and the like.
  • compositions of the invention contain a therapeutically effective amount of a compound of Formula I 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, antitumor activity and/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 the like.
  • Cytokines that may be 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). Cytokines whose biosynthesis may be induced by compounds of the invention include LFN- ⁇ , TNF- ⁇ , IL-1, 6, 10 and 12, and a variety of other cytokines.
  • IFN- ⁇ interferon- ⁇
  • TNF- ⁇ tumor necrosis factor- ⁇
  • IL interleukins
  • cytokines inhibit virus production and tumor cell growth, making the compounds useful in the treatment of viral diseases and tumors.
  • the compounds of the invention 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.
  • T helper type 1 (Thl) cytokine IFN- ⁇ is induced indirectly and the production of the T helper type 2 (Th2) cytokines IL-4, IL-5 and IL-13 are inhibited upon administration of the compounds.
  • Th2 T helper type 2
  • the compounds are expected to be useful in the treatment of atopic diseases, e.g., atopic dermatitis, asthma, allergy, and allergic rhinitis; and systemic lupus erythematosis; as a vaccine adjuvant for cell mediated immunity; and possibly as a treatment for recunent fungal diseases and chlamydia.
  • atopic diseases e.g., atopic dermatitis, asthma, allergy, and allergic rhinitis
  • systemic lupus erythematosis e.g., atopic dermatitis, asthma, allergy, and allergic rhinitis
  • systemic lupus erythematosis e.g., a vaccine adjuvant for cell mediated immunity
  • possibly as a treatment for recunent fungal diseases and chlamydia e.g., atopic dermatitis, asthma, allergy, and allergic rhinitis
  • the immune response modifying effects of the compounds make
  • This immunomodulating activity suggests that compounds of the invention are useful in treating diseases such as, but not limited to, viral diseases including genital warts; common warts; plantar warts; Hepatitis B; Hepatitis C; Herpes Simplex Virus Type I and Type II; molluscum contagiosum; HIV;
  • diseases such as, but not limited to, viral diseases including genital warts; common warts; plantar warts; Hepatitis B; Hepatitis C; Herpes Simplex Virus Type I and Type II; molluscum contagiosum; HIV;
  • CMV CMV
  • VZV intraepithelial neoplasias such as cervical intraepithelial neoplasia; human papillomavirus (HPV) and associated neoplasias; fungal diseases, e.g.
  • Candida aspergillus, and 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; discoid lupus; Bowen's disease; Bowenoid papulosis; and to enhance or stimulate the healing of wounds, including chronic wounds.
  • the invention provides a method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound of Formula I 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, rFN- ⁇ , 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 also provides a method of treating a viral infection in an animal, and a method of treating a neoplastic disease in an animal, comprising administering an effective amount of a compound of Formula I 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.
  • An amount of a compound effective to treat a neoplastic condition is an amount that will cause a reduction in tumor size or in the number of tumor foci.
  • 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 10 ⁇ 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.
  • Triethylamine (1.18 mL, 8.5 mmol) was added to a mixture of l-(4-aminobutyl)-2- ethyl-lH-imidazo[4,5-c]quinolin-4-amine (2.00 g, 7.1 mmol) and chloroform (200 mL). The resulting solution was chilled in an acetone/ice bath for 10 minutes. Benzenesulfonyl chloride (0.90 mL, 8.5 mmol) was slowly added over a period of 5 minutes. After 45 minutes 0.2 equivalents of triethylamine was added.
  • the precipitate in the aqueous layer was isolated by filtration, slurried with water and then isolated by filtration to provide 3.6 g of 4-(2-propyl-lH-imidazo[4,5-c]quinolin-l-yl)butan-l-amine.
  • Part B The material from Part A was combined with chloroform (600 mL) and warmed to 40°C. Triethylamine (3.48 mL, 25 mmol) was added and a solution was obtained.
  • Part C Using the general method of Example 2 Part C, the material from Part B was oxidized to provide -2.00 g of crude l- ⁇ 4-[(methylsulfonyl)amino]butyl ⁇ -2-ethyl-lH- imidazo[4,5-c]quinolin-5 ⁇ -oxide.
  • Part B Using the general method of Example 2 Part C, the material from Part A was oxidized to provide 3.28 g of N-[3-(2-butyl-5-oxido-lH-imidazo[4,5-c]quinolin-l- yl)propyl]benzenesulfonamide.
  • Part C Using the general method of Example 2 Part D, the material from Part B was animated to provide 1.08 g of N-[3-(4-amino-2-butyl-lH-imidazo[4,5-c]quinolin-l- yl)propyl]benzenesulfonamide as a light tan solid, m.p. 210.5-212.0°C.
  • the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to provide 2.2 g of a light yellow residue.
  • the residue was combined with aqueous 1% sodium carbonate solution (200 mL) and the p ⁇ was adjusted to 13 by the addition of solid sodium carbonate and 50% sodium hydroxide.
  • the organic phase was separated, washed with aqueous 1% sodium carbonate solution (3 X 200 mL), dried over magnesium sulfate and then concentrated under reduced pressure to provide
  • Example 14 Using the general method of Example 14 except that chloroform was used as the solvent, l-(3-aminopropyl)-2-(methoxyethyl)-lH-imidazo[4,5-c]quinolin-4-amine (1.53 g, 5.11 mmol) was reacted with 5-dimethylamino-l-naphthalenesulfonyl chloride (5.87 mmol) to provide 1.45 g of N- ⁇ 3-[4-amino-2-(2-methoxyethyl)-lH-imidazo[4,5- c]quinolin-l-yl]propyl ⁇ -5-(dimethylamino)naphthalene-l-sulfonamide as a yellow solid, m.p.
  • Example 24 Using the general method of Example 24, except that chloroform was used in place of aceotnitrile, l-(3-aminopropyl)-2-(2-ethoxymethyl)-6,7,8,9-tetrahydro-lH-imidazo[4,5- c]quinolin-4-amine (2.6 g, 8.35 mmol) was reacted with methanesulfonic anhydride (3+ g) to provide 850 mg of N- ⁇ 3-[4-amino-2-(2-ethoxymethyl)-6,7,8,9-tetrahydro-lH- imidazo[4,5-c]quinolin-l-yl]propyl ⁇ methanesulfonamide as a solid, m.p.
  • Triethylamine (1.1 g, 15.9 mmol) was added to a cooled (0°C) solution of l-(2- aminoethyl)-2-butyl-lH-imidazo[4,5-c]quinolin-4-amine (3.0 g, 10.6 mmol) in 1-methyl-
  • Methanesulfonyl chloride (1.27 g, 11.1 mmol) was slowly added to a solution of 1- (2-aminoethyl)-2-butyl-lH-imidazo[4,5-c]quinolin-4-amine (3.0 g, 10.6 mmol) in pyridine
  • Example 35 Using the general method of Example 35 except that l-methyl-2-pynolidinone was used in place of dichloromethane, l-(4-aminobutyl)-2-butyl-lH-imidazo[4,5-c]quinolin-4- amine (5.0 g, 16.0 mmol) was reacted with 3-chloropropanesulfonyl choride (2.83 g, 16.0 mmol) to provide 0.75 g of 2-butyl-l-[4-(l,l-dioxidoisothiazolidin-2-yl)butyl]-lH- imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 173.0-176.0°C.
  • reaction mixture was then allowed to warm to ambient temperature and was stined overnight. An additional 400 mg of di-tert-butyl dicarbonate was added and stirring was continued for 3 d. The reaction was then treated with ethyl acetate (200 mL) and washed with H 2 O (2X) and brine. The organic portion was dried over Na SO 4 and concentrated to give a yellow solid that was titurated with 10%
  • Example 38 Part B Using the general method of Example 38 Part B except that chloroform was used instead of dichloromethane, l-(4-aminobutyl)-2-(cyclopropylmethyl)-lH-imidazo[4,5- c]quinolin-4-amine (1.00 g, 3.2 mmol) was reacted with methanesulfonic anhydride (1.29 g, 7.4 mmol) to provide 0.42 g of N- ⁇ 4-[4-amino-2-(cyclopropylmethyl)-lH-imidazo[4,5- c]quinolin-l-yl]butyl ⁇ methanesulfonamide as a brown solid, m.p. 199.7-200.7°C.
  • 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 ( ⁇ ) (TEN and TNF, respectively) secreted into culture media as described by Testerman et. al. In "Cytokine Induction by the Immunomodulators
  • PBMCs Peripheral blood mononuclear cells
  • Histopaque®-1077 Sigma Chemicals, St. Louis, MO
  • the PBMCs are suspended at 3-4 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).
  • RPMI complete penicillin/streptomycin solution
  • the compounds are solubilized in dimethyl sulfoxide (DMSO).
  • DMSO concentration should not exceed a final concentration of 1 % for addition to the culture wells.
  • test compound is added at 60 ⁇ M to the first well containing RPMI complete and serial (three fold or ten fold) dilutions are made.
  • the PBMC suspension is then added to the wells in an equal volume, bringing the test compound concentrations to the desired range.
  • the final concentration of PBMC suspension is 1.5-2 X 10 6 cells/mL.
  • the plates are covered with sterile plastic lids, mixed gently and then incubated for 18 to 24 hours at 37°C in a 5% carbon dioxide atmosphere. Separation Following incubation the plates are centrifuged for 5-10 minutes at 1000 rpm (-200 x g) at 4°C.
  • the cell culture supernatant is removed with a sterile polypropylene pipet and transfened to sterile polypropylene tubes. Samples are maintained at -30 to - 70°C until analysis. The samples are analyzed for interferon ( ⁇ ) and tumor necrosis factor ( ) by ELISA
  • Interferon ( ) and Tumor Necrosis Factor (a) Analysis by ELISA Interferon ( ) concentration is determined by ELISA using a Human Multi-Species kit from PBL Biomedical Laboratories, New Brunswick, NJ. Tumor necrosis factor ( ) (TNF)concentration is determined using ELISA kits available from Genzyme, Cambridge, MA; R&D Systems, Minneapolis, MN; or Pharmingen, San Diego, CA.
  • the table below lists the lowest concentration found to induce interferon and the lowest concentration found to induce tumor necrosis factor for each compound.
  • a "**” indicates that no induction was seen at any of the tested concentrations (0.12, 0.37, 1.11, 3.33, 10 and 30 ⁇ M).
  • a "***” indicates that no induction was seen at any of the tested concentrations (0.0001, 0.001, 0.01, 0.1, 1 and 10 ⁇ M).

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Abstract

L'invention concerne des composés d'imidazo-quinoline et de tétrahydroimidazoquinoline contenant une fonctionnalité sulfonamide à la position 1 que l'on utilise comme modificateurs de la réponse immune. Les composés et les compositions de cette invention peuvent induire la biosynthèse de différentes cytokines et servent dans le traitement d'un large éventail de pathologies, y compris les maladies virales et les maladies néoplasiques.
EP04756208A 2003-06-27 2004-06-25 Imidazo-quinolines a substitution sulfonamide Withdrawn EP1638566A4 (fr)

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Families Citing this family (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040265351A1 (en) 2003-04-10 2004-12-30 Miller Richard L. Methods and compositions for enhancing immune response
JP2007502293A (ja) 2003-08-12 2007-02-08 スリーエム イノベイティブ プロパティズ カンパニー ヒドロキシルアミン置換イミダゾ含有化合物
RU2006105101A (ru) 2003-08-27 2007-10-10 3М Инновейтив Пропертиз Компани (US) Арилокси и арилалкиленокси замещенные имидазохинолины
CA2537763A1 (fr) 2003-09-05 2005-03-17 3M Innovative Properties Company Traitement pour le lymphome a cellules b cd5<sp>+</sp>
US7544697B2 (en) 2003-10-03 2009-06-09 Coley Pharmaceutical Group, Inc. Pyrazolopyridines and analogs thereof
MY146124A (en) 2003-10-03 2012-06-29 3M Innovative Properties Co Pyrazolopyridines and analogs thereof
AU2004278014B2 (en) 2003-10-03 2011-04-28 3M Innovative Properties Company Alkoxy substituted imidazoquinolines
US8598192B2 (en) 2003-11-14 2013-12-03 3M Innovative Properties Company Hydroxylamine substituted imidazoquinolines
JP2007511527A (ja) 2003-11-14 2007-05-10 スリーエム イノベイティブ プロパティズ カンパニー オキシム置換イミダゾ環化合物
WO2005051317A2 (fr) 2003-11-25 2005-06-09 3M Innovative Properties Company Systèmes cycliques d'imidazo substitués et procédés
US8940755B2 (en) * 2003-12-02 2015-01-27 3M Innovative Properties Company Therapeutic combinations and methods including IRM compounds
WO2005066170A1 (fr) 2003-12-29 2005-07-21 3M Innovative Properties Company Imidazoquinolines a substitution arylalcenyle et arylalkynyle
CA2551399A1 (fr) 2003-12-30 2005-07-21 3M Innovative Properties Company Sulfonamides d'imidazoquinolinyle, d'imidazopyridinyle et d'imidazonaphtyridinyle
US8697873B2 (en) 2004-03-24 2014-04-15 3M Innovative Properties Company Amide substituted imidazopyridines, imidazoquinolines, and imidazonaphthyridines
US8017779B2 (en) 2004-06-15 2011-09-13 3M Innovative Properties Company Nitrogen containing heterocyclyl substituted imidazoquinolines and imidazonaphthyridines
US8026366B2 (en) 2004-06-18 2011-09-27 3M Innovative Properties Company Aryloxy and arylalkyleneoxy substituted thiazoloquinolines and thiazolonaphthyridines
US8541438B2 (en) 2004-06-18 2013-09-24 3M Innovative Properties Company Substituted imidazoquinolines, imidazopyridines, and imidazonaphthyridines
US7897609B2 (en) 2004-06-18 2011-03-01 3M Innovative Properties Company Aryl substituted imidazonaphthyridines
US7915281B2 (en) 2004-06-18 2011-03-29 3M Innovative Properties Company Isoxazole, dihydroisoxazole, and oxadiazole substituted imidazo ring compounds and method
JP5543068B2 (ja) 2004-12-30 2014-07-09 スリーエム イノベイティブ プロパティズ カンパニー キラル縮合［１，２］イミダゾ［４，５−ｃ］環状化合物
EP1830880A4 (fr) * 2004-12-30 2008-03-26 Coley Pharm Group Inc Administration par voies multiples de composes modificateurs de reponse immunitaire
JP5313502B2 (ja) 2004-12-30 2013-10-09 スリーエム イノベイティブ プロパティズ カンパニー 置換キラル縮合［１，２］イミダゾ［４，５−ｃ］環状化合物
JP2008530022A (ja) 2005-02-04 2008-08-07 コーリー ファーマシューティカル グループ，インコーポレイテッド 免疫反応調節物質を含む水性ゲル処方物
EP1846419B1 (fr) 2005-02-09 2014-04-16 3M Innovative Properties Company Thiazoloquinolines et thiazolonaphthyridines à substitution alcoxy
AU2006213746A1 (en) 2005-02-11 2006-08-17 Coley Pharmaceutical Group, Inc. Oxime and hydroxylamine substituted imidazo(4,5-c) ring compounds and methods
WO2006107853A2 (fr) 2005-04-01 2006-10-12 Coley Pharmaceutical Group, Inc. Pyrazolopyridine-1,4-diamines et analogues associes
AU2006232375A1 (en) 2005-04-01 2006-10-12 Coley Pharmaceutical Group, Inc. 1-substituted pyrazolo (3,4-c) ring compounds as modulators of cytokine biosynthesis for the treatment of viral infections and neoplastic diseases
ZA200803029B (en) 2005-09-09 2009-02-25 Coley Pharm Group Inc Amide and carbamate derivatives of alkyl substituted /V-[4-(4-amino-1H-imidazo[4,5-c] quinolin-1-yl)butyl] methane-sulfonamides and methods
CA2621831A1 (fr) 2005-09-09 2007-03-15 Coley Pharmaceutical Group, Inc. Derives amide et carbamate de n-{2-[4-amino-2-(ethoxymethyl)-1h-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide et procedes associes
EP1937683A4 (fr) * 2005-09-23 2010-08-25 Coley Pharm Group Inc Procede de preparation de 1h-imidazoý4,5-c¨pyridines et d'analogues de ceux-ci
EP3085373A1 (fr) 2006-02-22 2016-10-26 3M Innovative Properties Company Conjugués de modificateur de réponse immunitaire
WO2008008432A2 (fr) 2006-07-12 2008-01-17 Coley Pharmaceutical Group, Inc. Composés à cycle [1,2] imidazo [4,5-c] fusionné chiral substitué et procédés correspondants
NZ588183A (en) * 2008-03-24 2012-05-25 4Sc Discovery Gmbh Novel substituted imidazoquinolines
ES2617451T3 (es) 2010-08-17 2017-06-19 3M Innovative Properties Company Composiciones lipidadas de compuestos modificadores de la respuesta inmunitaria, formulaciones, y métodos
EP3366311B1 (fr) 2011-06-03 2020-02-26 3M Innovative Properties Co. Hydrazino-1h-imidazoquinoléine-4-amines et conjugués obtenus à partir de celles-ci
WO2012167088A1 (fr) 2011-06-03 2012-12-06 3M Innovative Properties Company Lieurs hétérobifonctionnels comportant de segments de polyéthylène glycol et conjugués modificateurs de réponse immunitaire obtenus à partir de ceux-ci
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MX2018003215A (es) * 2015-09-14 2018-06-08 Pfizer Derivados de imidazo[4,5-c]quinolina e imidazo[4,5-c][1,5]naftirid ina novedosos como inhibidores de lrrk2.
WO2018009916A1 (fr) 2016-07-07 2018-01-11 The Board Of Trustees Of The Leland Stanford Junior University Conjugués d'adjuvant d'anticorps
CA3056030A1 (fr) 2017-03-10 2018-09-13 Pfizer Inc. Nouveaux derives imidazo[4,5-c]quinoleine utilises en tant qu'inhibiteurs de lrrk2
LT3679025T (lt) 2017-09-06 2022-06-27 BioNTech SE Pakeistieji imidazochinolinai, kaip tlr7 agonistai
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
JP2022525594A (ja) 2019-03-15 2022-05-18 ボルト バイオセラピューティクス、インコーポレーテッド Ｈｅｒ２を標的とする免疫結合体
EP4076445A1 (fr) * 2019-12-20 2022-10-26 Nammi Therapeutics, Inc. Compositions liposomales formulées et/ou co-formulées contenant des promédicaments agonistes de récepteurs de type toll (« tlr ») utiles dans le traitement du cancer et méthodes associées

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000076519A1 (fr) * 1999-06-10 2000-12-21 3M Innovative Properties Company Imidazoquinolines substituees sulfonamide et sulfamide
US6677349B1 (en) * 2001-12-21 2004-01-13 3M Innovative Properties Company Sulfonamide and sulfamide substituted imidazoquinolines

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005513021A (ja) * 2001-11-16 2005-05-12 スリーエム イノベイティブ プロパティズ カンパニー Ｉｒｍ化合物およびトール様受容体経路に関する方法および組成物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000076519A1 (fr) * 1999-06-10 2000-12-21 3M Innovative Properties Company Imidazoquinolines substituees sulfonamide et sulfamide
US6677349B1 (en) * 2001-12-21 2004-01-13 3M Innovative Properties Company Sulfonamide and sulfamide substituted imidazoquinolines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO2005003065A2 *

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