EP1638566A2 - Sulfonamide substituted imidazoquinolines - Google Patents

Sulfonamide substituted imidazoquinolines

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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Withdrawn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)
French (fr)
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EP1638566A4 (en
Inventor
George W. Griesgraber
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Coley Pharmaceutical Group Inc
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3M Innovative Properties Co
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Publication date
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Publication of EP1638566A2 publication Critical patent/EP1638566A2/en
Publication of EP1638566A4 publication Critical patent/EP1638566A4/en
Withdrawn legal-status Critical Current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

Imidazoquinoline and tetrahydroimidazoquinoline compounds that contain sulfonamide functionality at the 1-position are useful as immune response modifiers. The compounds and compositions of the invention can induce the biosynthesis of various cytokines and are useful in the treatment of a variety of conditions including viral diseases and neoplastic diseases.

Description

Sulfonamide Substituted Imidazoquinolines
Field of the Invention 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.
Background of the Invention The first reliable report on the lH-imidazo[4,5-c]quinoline ring system, Backman et al., J. Ore. Chem. 15, 1278-1284 (1950) describes the synthesis of l-(6-methoxy-8- quinolinyl)-2-methyl-lH-imidazo[4,5-c]quinoline for possible use as an antimalarial agent. Subsequently, syntheses of various substituted lH-imidazo[4,5-c] quinolines were reported. For example, Jain et al., J. Med. Chem. 11, pp. 87-92 (1968), synthesized the compound l-[2-(4-piperidyl)ethyl]-lH-imidazo[4,5-c]quinoline as a possible anticonvulsant and cardiovascular agent. Also, Baranov et al., Chem. Abs. 85, 94362 (1976), have reported several 2-oxoimidazo[4,5-c]quinolines, and Berenyi et al., J. Heterocyclic Chem. 18, 1537-1540 (1981), have reported certain 2-oxoimidazo[4,5- c] quinolines. Certain lH-imidazo[4,5-c]quinolin-4-amines and 1- and 2-substituted derivatives thereof were later found to be useful as antiviral agents, bronchodilators and immunomodulators. These are described in, ter alia, U.S. Patent Nos. 4,689,338; 4,698,348; 4,929,624; 5,037,986; 5,268,376; 5,346,905; and 5,389,640, all of which are incorporated herein by reference. There continues to be interest in the imidazoquinoline ring system, as seen for example in WO 98/30562, EP 894 797 and WO 00/09506. 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. Despite these efforts, however, there is a continuing need for compounds that have the ability to modulate the immune response, by induction of cytokine biosynthesis or other mechanisms.
Summary of the Invention We have found a new class of compounds that are useful in inducing cytokine biosynthesis in animals. Accordingly, this invention provides compounds of Formula I:
wherein 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. In one embodiment, 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-imidazo[4,5-c]quinolin-l-yl)butyl]benzenesulfonamide; -amino-2-methyl-lH-imidazo[4,5-c]quinolin-l-yl)butyl]methanesulfonamide; -amino-2-butyl-lH-imidazo[4,5-c]quinolin-l-yl)propyl]methanesulfonamide; -amino-2-butyl-lH-imidazo[4,5-c]quinolin-l-yl)propyl]benzenesulfonamide; -amino-2-hexyl-lH-imidazo[4,5-c]quinolin-l-yl)butyl]methanesulfonamide; N-{8-[4-amino-2-(2-methoxyethyl)-lH-imidazo[4,5-c]quinolin-l- yl]octyl}benzenesulfonamide;
N-{8-[4-amino-2-(2-methoxyethyl)-lH-imidazo[4,5-c]quinolin-l- yl]octyl } methanesulfonamide; N-[8-(4-amino-2-butyl-lH-imidazo[4,5-c]quinolin-l-yl)octyl]methanesulfonamide;
N-[3-(4-amino-2-butyl-lH-imidazo[4,5-c]quinolin-l-yl)propyl]-5-
(dimethylamino)naphthalene- 1 -sulfonamide;
N-[3-(4-amino-2-butyl-lH-imidazo[4,5-c]quinolin-l-yl)propyl]-4- methylbenzenesulfonamide; N-{3-[4-amino-2-(2-methoxyethyl)-lH-imidazo[4,5-c]quinolin-l- yl]propyl} methanesulfonamide;
N-[8-(4-amino-2-butyl-lH-imidazo[4,5-c]quinolin-l-yl)octyl]benzenesulfonamide;
N-{3-[4-amino-2-(2-methoxyethyl)-lH-imidazo[4,5-c]quinolin-l- yl]propyl}benzenesulfonamide; N-[4-(4-amino-2-pentyl- lH-imidazo[4,5-c]quinolin- 1 -yl)butyl]methanesulfonamide;
N-[4-(4-amino-2-pentyl-lH-imidazo[4,5-c]quinolin-l-yl)butyl]benzenesulfonamide;
N-[8-(4-amino-lH-imidazo[4,5-c]quinolin-l-yl)octyl]methanesulfonamide;
N-{3-[4-amino-2-(2-methoxyethyl)-lH-imidazo[4,5-c]quinolin-l-yl]propyl}-4- methylbenzenesulfonamide; N-[4-(4-amino-2-pentyl-6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-l- yl)butyl]methanesulfonamide;
N-{3-[4-amino-2-(ethoxymethyl)-lH-imidazo[4,5-c]quinolin-l- yl]propyl} methanesulfonamide;
N-{3-[4-amino-2-(2-methoxyethyl)-lH-imidazo[4,5-c]quinolin-l-yl]-2,2- dimethylpropyl} methanesulfonamide;
N-{3-[4-amino-2-(2-methoxyethyl)-lH-imidazo[4,5-c]quinolin-l-yl]propyl}-5-
(dimethylamino)naphthalene- 1 -sulfonamide;
N-[3-(4-amino-2-methyl-lH-imidazo[4,5-c]quinolin-l-yl)propyl]methanesulfonamide;
N-{3-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-l- yl]propyl}methanesulfonamide;
N-{3-[4-amino-2-(ethoxymethyl)-6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-l- yl]propyl}methanesulfonamide; N-{3-[4-amino-2-(3-phenoxypropyl)-lH-imidazo[4,5-c]quinolin-l- yljpropyl} methanesulfonamide;
N- {4-[4-amino-2-(3-phenoxypropyl)- lH-imidazo[4,5-c]quinolin- 1 - yl]butyl}methanesulfonamide; N-[4-(4-amino-2-methyl-6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-l- yl)butyl]methanesulfonamide hydrochloride;
N-[2-(4-amino-2-butyl-lH-imidazo[4,5-c]quinolin-l-yl)ethyl]-4- methylbenzenesulfonamide;
N-[2-(4-amino-2-butyl-lH-imidazo[4,5-c]quinolin-l-yl)ethyl]methanesulfonamide; l-[4-(l,l-dioxidoisothiazolidin-2-yl)butyl]-2-(2-methoxyethyl)-lH-imidazo[4,5- c]quinolin-4-amine;
2-butyl-l-[4-(l,l-dioxidoisothiazolidin-2-yl)butyl]-lΗ-imidazo[4,5-c]quinolin-4-amine;
N- {2-[4-amino-2-(ethoxymethyl)- 1 H-imidazo[4,5-c]quinolin- 1 -yl]- 1 , 1 - dimethylethyl } methanesulfonamide; N-[4-(4-amino-2-methyl-lH-imidazo[4,5-c]quinolin-l-yl)butyl]ethanesulfonamide; l-(2-amino-2-methylpropyl)-2-(ethoxymethyl)-lH-imidazo[4,5-c]quinoline-4-amine; and
N- {4- [4-amino-2 -(cyclopropylmethyl)- 1 H-imidazo [4, 5 -c] quinolin- 1 - yl]butyl}methanesulfonamide; or a pharmaceutically acceptable salt thereof. In a particularly prefered embodiment, a compound or salt of the invention is N- {2-
[4-amino-2-(ethoxymethyl)- lH-imidazo[4,5-c]quinolin- 1 -yl]- 1,1- dimethylethyl} methanesulfonamide or a pharmaceutically acceptable salt thereof. In addition to desirable formulation and toxicity properties, 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. In addition, methods of synthesizing compounds of Formula I and intermediates useful in the synthesis of these compounds are provided. Detailed Description of the Invention As mentioned earlier, the invention provides compounds of Formula I:
(I) wherein
Ri is -alkyl-NR3-SO2-X-R4, -alkenyl-NR3-SO2-X-R4, or alkyl-NR6-SO2-R7; X is a bond or -NR5-; 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-ι-aryl; -O-(alkyl)0-ι -substituted aryl; -O-(alkyl)0-ι -heteroaryl; -O-(alkyl)0-ι -substituted heteroaryl; -O-(alkyl)0-ι -heterocyclyl; -O-(alkyl)o-ι -substituted heterocyclyl; -COOH; -CO-O-alkyl; -CO-alkyl; -S(O)o-2 -alkyl; -S(O)0-2-(alkyl)0-1-aryl; -S(O)0-2 — (alkyl)o-ι -substituted aryl; -S(O)0-2 -(alkyl)o-ι -heteroaryl; -S(O)0-2 -(alkyl)o-ι -substituted heteroaryl; -S(O)o-2 -(alkyl)o-ι -heterocyclyl; -S(O)o-2 -(alkyl)o-ι -substituted heterocyclyl; -(alkyl)o NR3R3; -(alkyl)o NR3-CO-O-alkyl; -(alkyl)o NR3-CO-alkyl; -(alkyl)o NR3-CO-aryl; -(alkyl)o NR3-CO-substituted aryl; -(alkyl)o NR3-CO-heteroaryl; -(alkyl)o NR3-CO-substituted heteroaryl; -N3; -halogen; -haloalkyl; -haloalkoxy; -CO-haloalkoxy; -NO2; -CN; -OH; -SH; and in the case of alkyl, alkenyl, or heterocyclyl, oxo;
R2 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(R3)2; -CO-N(R3)2; -CO-C]. ιo alkyl; -CO-O-Ci-io alkyl; - -N3; -aryl; -substituted aryl; -heteroaryl; -substituted heteroaryl; -heterocyclyl; -substituted heterocyclyl; -CO-aryl; -CO-(substituted aryl); -CO-heteroaryl; and -CO-(substituted heteroaryl); each R3 is independently selected from the group consisting of hydrogen and
CLIO alkyl; Rs is selected from the group consisting of hydrogen and CM O alkyl, or j and R5 can combine to form a 3 to 7 membered heterocyclic or substituted heterocyclic ring; Re is selected from the group consisting of hydrogen and CMO alkyl; R is selected from the group consisting of hydrogen and CMO alkyl, wherein R6 and R7 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.
Preparation of the Compounds Imidazoquino lines of the invention can be prepared according to Reaction Scheme I where R, Ri, R2 and n are as defined above. In step (1) of Reaction Scheme I a 4-chloro-3-nitroquinoline of Formula II is reacted with an amine of Formula RιNH2 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. Many quinolines of Formula II are known compounds (see for example, U.S. Patent 4,689,338 and references cited therein). In 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. Preferably, 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. In 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
Formula V. 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 R2 substituent in a compound of Formula V. For example, triethyl orthoformate will provide a compound where R2 is hydrogen and triethyl orthoacetate will provide a compound where R2 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. In 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. In 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. Pαrø-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. Alternatively, 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 I
(3)
VII VI V
Compounds of the invention where the Ri substituent contains a sulfonamide can also be prepared according to Reaction Scheme II where R, R2, R and n are as defined above and m is 1-20. In Reaction Scheme II an aminoalkyl substituted lH-imidazo[4,5-c]quinolin-4- amine of Formula VIII is reacted with a sulfonyl chloride of Formula IX 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. Many lH-imidazo[4,5-c]quinolin-4- amines of Formula VIII are known compounds, see for example US Patent 6,069,149 (Namba); others can be readily prepared using known synthetic methods. Many sulfonyl chlorides of Formula IX 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. Reaction Scheme II
Compounds of the invention where the Ri substituent contains a sulfonamide can also be prepared according to Reaction Scheme III where R, R2, 4 and n are as defined above and m is 1-20. In 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. Alternatively, the 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.
Reaction Scheme III
Tertiary sulfonamides of the invention can be prepared according to Reaction Scheme IV where R, R2, R3, R4 and n are as defined above and m is 1-20. In 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.
Reaction Scheme IV
Compounds of the invention where Ri contains a sulfamide group can be prepared according to Reaction Scheme V wherein R, R2, R4, R5 and n are as defined above and m is 1-20. In 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. The reaction is preferably canied out at a reduced temperature (-78°C). Optionally, after the addition is complete the reaction mixture can be allowed to warm to ambient temperature. In step (2) of Reaction Scheme V an amine of Formula R5R4NΗ 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). After the addition is complete 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. Reaction Scheme V
Tetrahydroimidazoquinolines of the invention can be prepared according to Reaction Scheme VI where R2, R3, R , and R5 are as defined above and m is 1-20. In 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. Preferably 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. The reaction can conveniently be carried out on a Pan apparatus. The product or a salt thereof can be isolated using conventional methods. In 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. When R3 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. When R3 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
Reaction TV using the tetrahydroimidazoquinoline analog of the imidazoquinoline. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods. In 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
Formula XIX which is a subgenus of Formula I. The reaction can be carried out according to the method described in Reaction Scheme V using a tetrahydroimidazoquinoline of Formula XVII in place of the imidazoquinoline of Formula VIII. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme VI
Tetrahydroimidazoquinolines of the invention can also be prepared according to
Reaction Scheme VII where R, R2, R3j R^ R5 and n are as defined above and m is 1-20. In 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. Alternatively, 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 tβrt-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. For example, compounds wherein the R4 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 R4 substituent contains a primary amine. As used herein, 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
20 carbon atoms, with alkenyl and alkynyl groups containing from 2 to 20 carbon atoms. Prefened groups have a total of up to 10 carbon atoms. 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. The term "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-". Examples of suitable haloalkyl groups are chloromethyl, trifluoromethyl, and the like. The term "aryl" as used herein includes carbocyclic aromatic rings or ring systems. Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl and indenyl. The term "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. Unless otherwise specified, the terms "substituted cycloalkyl", "substituted aryl", "substituted heteroaryl" and "substituted heterocyclyl" indicate 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. In structural formulas representing compounds of the invention certain 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.
Pharmaceutical Compositions and Biological Activity Pharmaceutical compositions of the invention contain a therapeutically effective amount of a compound of Formula I in combination with a pharmaceutically acceptable carrier. As used herein, the term "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. Although the exact amount of active compound used in a pharmaceutical composition of the invention will vary according to factors known to those of skill in the art, such as the physical and chemical nature of the compound as well as the nature of the carrier and the intended dosing regimen, it is anticipated that the compositions of the invention will contain sufficient active ingredient to provide a dose of about lOOng/kg to about 50mg/kg, preferably about lOμg/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. The compounds of the invention have been shown to induce the production of certain cytokines in experiments performed according to the tests set forth below. These results indicate 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 may be induced by the administration of compounds according to the invention generally include interferon-α (IFN-α) and tumor necrosis factor-α (TNF-α) as well as certain interleukins (IL). Cytokines whose biosynthesis may be induced by compounds of the invention include LFN-α, TNF-α, IL-1, 6, 10 and 12, and a variety of other cytokines. Among other effects, cytokines inhibit virus production and tumor cell growth, making the compounds useful in the treatment of viral diseases and tumors. In addition to the ability to induce the production of cytokines, 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. For example, although there is not believed to be any direct effect on T cells or direct induction of T cell cytokines, the production of the T helper type 1 (Thl) cytokine IFN-γ 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. 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. In view of the ability of compounds of Formula la to inhibit the Th2 immune response, 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. 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 the production of cytokines such as IFN-α and/or TNF-α, 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 including genital warts; common warts; plantar warts; Hepatitis B; Hepatitis C; Herpes Simplex Virus Type I and Type II; molluscum contagiosum; HIV;
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. pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection, leishmaniasis; and bacterial infections, e.g., tuberculosis, mycobacterium avium. 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. Accordingly, 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-α, TNF-α, 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 lOμg/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 lOμg/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. Again, 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 10μg/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.
Example 1 N-[4-(4-amino-2-ethyl-lH-imidazo[4,5-c]quinolin-l-yl)butyl]benzenesulfonamide
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. After 6 hours the reaction mixture was washed with brine (2 x 250 mL) and with water (1 x 100 mL), dried over magnesium sulfate and then concentrated under reduced pressure. The residue was recrystallized from N,N-dimethylformamide. The recrystallized material and the filtrate were both slurried with methanol. The resulting solids were isolated by filtration, combined, and then dried in an Abderhalden drying apparatus overnight to provide 0.80 g of N-[4-(4-amino-2-ethyl- lH-imidazo[4,5-c]quinolin-l-yl)butyl]benzenesulfonamide as a white solid, m.p. 180.6- 182.0°C. Analysis: Calculated for C22Η25Ν5θ2S ■ 0.25 H2O: %C, 61.73; %H, 6.00; %N, 16.36; Found: %C, 61.79; %H, 6.04; %N, 16.43.
Example 2 N-[4-(4-amino-2-propyl- lH-imidazo[4,5-c]quinolin-l-yl)butyl]benzenesulfonamide
Part A Tert-butyl 4-(2-propyl-lH-imidazo[4,5-c]quinolin-l-yl)butylcarbamate (5.00 g, 13.1 mmol) was combined with hydrochloric acid (50 mL of 4.0 M in dioxane) and stined for 1.5 hours. The reaction mixture was diluted with dichloromethane (-200 mL). Saturated sodium bicarbonate solution was added until a pΗ of 8 was obtained. A precipitate formed in the aqueous phase. The layers were separated. 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.
Benzenesulfonyl chloride (1.60 mL, 12.5 mmol) was added. The reaction mixture was stined at 40°C overnight. The reaction mixture was cooled to ambient temperature and then concentrated under reduced pressure. The residue was taken up in dichloromethane (-100 mL), washed with water (3 x 125 mL), dried over magnesium sulfate and then concentrated under reduced pressure to provide 3.96 g of N-[4-(2-propyl-lH-imidazo[4,5- c]quinolin-l-yl)butyl]benzenesulfonamide as a yellow crystalline solid, m.p. 155.9-
157.1°C.
Part C 3-Chloroperoxybenzoic acid (896 mg of 77%) was added over a period of 5 minutes to a solution of N-[4-(2-propyl- lH-imidazo[4,5-c]quinolin- 1 - yl)butyl]benzenesulfonamide (1.0 g, 2.4 mmol) in chloroform (100 mL). After 2.5 hours an additional 0.1 equivalent of 3-chloroperoxybenzoic acid was added. After 3 hours the reaction was stored at a reduced temperature overnight. The reaction mixture was washed with saturated sodium bicarbonate solution (3 x 150 mL) and then concentrated under reduced pressure to provide 1.44 g of crude product. This material was recrystallized from methyl acetate to provide 0.67 g of l-{4-[(phenylsulfonyl)amino]butyl}-2-propyl-lH- imidazo[4,5-c]quinolin-5Ν-oxide as a brown solid, m.p. 203.8-205.2°C. Part D Ammonium hydroxide (3.5 mL of 27%) was added to a mixture of the material from Part C and dichloromethane (15 mL). After 10 minutes tosyl chloride (0.35 g) was slowly added over a period of 5 minutes. After 45 minutes the reaction mixture was stored at a reduced temperature over the weekend. An additional 35 mg of tosyl chloride was added and the reaction mixture was stined for 1 hour. The organic phase was separated and then washed with saturated sodium bicarbonate solution (3 x 80 mL). A precipitate formed in the aqueous phase. This material was isolated by filtration and then recrystallized from methyl acetate. The resulting solid and the filtrate were combined, dissolved in dichloromethane containing a small amount of methanol, and then purified by column chromatography (silica gel eluting with 10% methanol in dichloromethane). The resulting material was purified by column chromatography (silica gel eluting with 0-7.5% methanol in dichloromethane). This material was recrystallized 3 times from methyl acetate to provide 42 mg of N-[4-(4-amino-2-propyl-lH-imidazo[4,5-c]quinolin-l- yl)butyl]benzenesulfonamide as a white solid, m.p. 158.8-160.8°C. Analysis: Calculated for C23Η27Ν5O2S • 0.25 C3H6O2: %C, 62.15; %H, 6.22; %N, 15.59; Found: %C, 62.41; %H, 5.91; %N, 15.41. Example 3 N-[4-(4-amino-2-hexyl-lH-imidazo[4,5-c]quinolin-l-yl)butyl]benzenesulfonamide
Part A Using the general method of Example 2 Part A, tert-butyl 4-(2-hexyl-lH- imidazo[4,5-c]quinolin-l-yl)butylcarbamate (33.85 g) was hydrolyzed to provide 3.43 g of 4-(2-hexyl-lH-imidazo[4,5-c]quinolin-l-yl)butan-l-amine as an off white solid, m.p. 172.2-174.2°C. Part B Using the general method of Example 2 Part B except that the reaction was run at ambient temperature, 4-(2-hexyl-lH-imidazo[4,5-c]quinolin-l-yl)butan-l-amine (1.20 g, 3.7 mmol) was reacted with benzenesulfonyl chloride (429 μL, 3.7 mmol) to provide 0.75 g of N-[4-(2-hexyl-lH-imidazo[4,5-c]quinolin-l-yl)butyl]benzenesulfonamide as a light yellow solid, m.p. 137.0-138.1°C. Part C Using the general method of Example 2 Part C, N-[4-(2-hexyl-lH-imidazo[4,5- c]quinolin-l-yl)butyl]benzenesulfonamide (0.95 g, 2.0 mmol) was oxidized to provide 1.21 g of crude l-{4-[(phenylsulfonyl)amino]butyl}-2-hexyl-lH-imidazo[4,5-c]quinolin- 5Ν-oxide. Part D Using the general method of Example 2 Part D, the material from Part C was aminated to provide 118 mg of N-[4-(4-amino-2-hexyl-lH-imidazo[4,5-c]quinolin-l- yl)butyl]benzenesulfonamide as an off white crystalline solid, m.p. 84.8-85.4°C. Analysis: Calculated for C26Η33Ν5O2S • 0.5 H2O: %C, 63.91; %H, 7.01; %N, 14.33; Found: %C, 63.63; %H, 6.93; %N, 14.80. Example 4 N-[4-(4-amino-2-propyl- lH-imidazo[4,5-c]quinolin-l-yl)butyl]methanesulfonamide
Part A Using the general method of Example 2 Part B except that the reaction was run at ambient temperature, 4-(2-propyl-lH-imidazo[4,5-c]quinolin-l-yl)butan-l-amine (2.00 g, 7.1 mmol) was reacted with methanesulfonyl chloride (1.65 mL, 21.3 mmol) to provide 1.23 g ofN-[4-(2-propyl-lH-imidazo[4,5-c]quinolin-l-yl)butyl]methanesulfonamide as a light yellow solid, m.p. 133.2-134.6°C.
Part B Using the general method of Example 2 Part C, N-[4-(2-propyl-lH-imidazo[4,5- c]quinolin-l-yl)butyl]methanesulfonamide was oxidized to provide 1.44 g of crude l-{4- [(methylsulfonyl)amino]butyl}-2-propyl-lH-imidazo[4,5-c]quinolin-5Ν-oxide asa light yellow solid.
Part C Using the general method of Example 2 Part D, the material from Part B was aminated to provide 0.21 g of N-[4-(4-amino-2-propyl-lH-imidazo[4,5-c]quinolin-l- yl)butyl]methanesulfonamide as an off white crystalline solid, m.p. 186.5-187.9°C. Analysis: Calculated for Cι8Η25Ν5O2S ■ 0.25 H2O: %C, 56.89; %H, 6.76; %N, 18.43;
Found: %C, 56.95; %H, 6.89; %N, 18.13. Example 5 N-[4-(4-amino-2-ethyl-lH-imidazo[4,5-c]quinolin-l-yl)butyl]methanesulfonamide
Part A Using the general method of Example 2 Part A, tert-butyl 4-(2-ethyl-lH- imidazo[4,5-c]quinolin-l-yl)butylcarbamate (20.69 g) was hydrolyzed to provide 14.94 g of 4-(2-ethyl-lH-imidazo[4,5-c]quinolin-l-yl)butan-l -amine as an off white solid, m.p.
84.8-88.7°C.
Part B Using the general method of Example 2 Part B, 4-(2-ethyl-lH-imidazo[4,5- c]quinolin-l-yl)butan-l -amine (4.00 g, 14. 9 mmol) was reacted with methanesulfonyl chloride to provide 1.78 g of N-[4-(2-ethyl-lH-imidazo[4,5-c]quinolin-l- yl)butyl]methanesulfonamide as a light yellow solid.
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-5Ν-oxide.
Part D Using the general method of Example 2 Part D, the material from Part C was aminated to provide 0.42 g of N-[4-(4-amino-2-ethyl-lH-imidazo[4,5-c]quinolin-l- yl)butyl]methanesulfonamide as a white solid, m.p. 203.3-204.4°C. Analysis: Calculated for C17Η23Ν5θ2S: %C, 56.49; %H, 6.41; %N, 19.37; Found: %C, 56.21; %H. 6.36; %N,
19.09. Example 6 N-[4-(4-amino-2-methyl- lH-imidazo[4,5-c]quinolin-l-yl)butyl]benzenesulfonamide
Using the general method of Example 1, l-(4-aminobutyι)-2-methyl-lH- imidazo[4,5-c]quinolin-4-amine (0.50 g, 1.9 mmol) was reacted with benzenesulfonyl chloride (0.24 mL, 1.9 mmol) to provide 0.38 g of N-[4-(4-amino-2-methyl-lH- imidazo[4,5-c]quinolin-l-yl)butyl]benzenesulfonamide as brown granules, m.p. 215.4- 216.0°C. Analysis: Calculated for C2ιΗ23Ν5O2S: %C, 61.59; %H, 5.66; %N, 17.10; Found: %C, 61.24; %H, 5.65; %N, 16.95.
Example 7 N-[4-(4-amino-2-methyl- lH-imidazo[4,5-c]quinolin-l-yl)butyl]methanesulfonamide
Using the general method of Example 1, l-(4-aminobutyl)-2-methyl-lH- imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.7 mmol) was reacted with methanesulfonyl chloride (0.46 mL, 5.9 mmol) to provide 0.16 g of N-[4-(4-amino-2-methyl-lH- imidazo[4,5-c]quinolin-l-yl)butyl]methanesulfonamide as an off white solid, m.p. 229.4- 230.5°C. Analysis: Calculated for d6Η2ιΝ5O2S • 0.25 H2O: %C, 54.60; %H, 6.16; %N,
19.90; Found: %C, 54.80; %H, 6.24; %N, 19.58. Example 8 N-[3-(4-amino-2-butyl- lH-imidazo[4,5-c]quinolin- 1 -yl)propyl]methanesulfonamide
Part A Jert-butyl 3-(2-butyl-lH-imidazo[4,5-c]quinolin-l-yl)propylcarbamate (-80 g) was dissolved in 1,4-dioxane (400 mL) with gentle heating. Hydrochloric acid (55 mL of
4.0 M in 1,4-dioxane) was added in a single portion and the reaction was heated to reflux. The reaction was monitored by HPLC. Additional acid (150-200 mL) was added and the reaction mixture was refluxed until the reaction was complete. The reaction mixture was cooled to ambient temperature. A solid was isolated by filtration to give -72 g of 3-(2- butyl-lH-imidazo[4,5-c]quinolin-l-yl)propylamine hydrochloride. This material was combined with that from a previous experiment and then dissolved in water (400 mL). The solution was neutralized with solid potassium carbonate. At pΗ 7 a solid precipitated.
The solid was isolated by filtration and then dissolved in water (1500 mL). The pΗ was adjusted to pΗ 10 with solid potassium carbonate. The solution was extracted with chloroform until ΗPLC analysis showed that no amine remained in the aqueous layer. The organic layers were combined and then concentrated under reduced pressure to provide 45 g of 3-(2-butyl-lH-imidazo[4,5-c]quinolin-l-yl)propylamine.
Part B Triethylamine (1.1 g, 10.6 mmol) was added with stining to a solution of 3-(2- butyl-lH-imidazo[4,5-c]quinolin-l-yl)propylamine (2.00 g, 7.08 mmol) in dichloromethane (-150 mL). Methanesulfonyl chloride (892 mg, 7.79 mmol) was added and the reaction was stined under nitrogen overnight. The reaction mixture was washed with aqueous 1% sodium bicarbonate solution (3 X 50 mL). The aqueous washes were extracted with dichloromethane (2 x 20 mL). The organics were combined, dried over magnesium sulfate and then concentrated under reduced pressure to provide 1.89 g of N- [3-(2-butyl-lH-imidazo[4,5-c]quinolin-l-yl)propyl]methanesulfonamide as a light brown solid. Part C Using the general method of Example 2 Part C, the material from Part B was oxidized to provide 1.24 g of N-[3-(2-butyl-5-oxido-lH-imidazo[4,5-c]quinolin-l- yl)propyl]methanesulfonamide. Part D Using the general method of Example 2 Part D, the material from Part C was animated to provide 690 mg of N-[3-(4-amino-2-butyl-lH-imidazo[4,5-c]quinolin-l- yl)propyl]methanesulfonamide as a light tan solid, m.p. 239.2-240.8°C. Analysis: Calculated for C18Η25Ν5O2S: %C, 57.58; %H, 6.71; %N, 18.65; Found: %C, 57.37; %H, 6.78; %N, 18.42. Example 9 N- [3 -(4-amino-2-butyl- lH-imidazo[4,5-c]quinolin-l-yl)propyl]benzenesulfonamide
Part A Using the general method of Example 8 Part B, 3-(2-butyl-lH-imidazo[4,5- c]quinolin-l-yl)propylamine (2.00 g, 7.08 mmol) was reacted with benzenesulfonyl chloride (1.38 g, 7.79 mmol) to provide 2.83 g of N-[3-(2-butyl-lH-imidazo[4,5- c]quinolin-l-yl)propyl]benzenesulfonamide as a light red foam.
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. Analysis: Calculated for C23Η27Ν5O2S: %C, 63.13; %H. 6.22; %N, 16.01; Found: %C, 62.89; %H, 6.16; %N, 15.74.
Example 10 N-[4-(4-amino-2-hexyl-lH-imidazo[4,5-c]quinolin-l-yl)butyl]methanesulfonamide
Part A Using the general method of Example 1, 4-(2-hexyl-lH-imidazo[4,5-c]quinolin-l- yl)butan-l -amine (1.00 g, 3.1 mmol) was reacted with methanesulfonyl choride (0.48 mL,
6.2 mmol) to provide 1.15 g of N-[4-(2-hexyl-lH-imidazo[4,5-c]quinolin-l- yl)butyl]methanesulfonamide as a white solid.
Part B Using the general method of Example 2 Part C, N-[4-(2-hexyl-lH-imidazo[4,5- c]quinolin-l-yl)butyl]methanesulfonamide (1.47 g, 3.7 mmol) was oxidized to provide
3.78 g of crude l-{4-[(methylsulfonyl)amino]butyl}-2-hexyl-lH-imidazo[4,5-c]quinolin- 5Ν-oxide as a yellow residue.
Part C Using the general method of Example 2 Part D, the material from Part B was animated to provide 0.28 g of N-[4-(4-amino-2-hexyl-lH-imidazo[4,5-c]quinolin-l- yl)butyl]methanesulfonamide as an off white solid, m.p. 170.2-171.1°C. Analysis: Calculated for C2iΗ3ιΝ5O2S: %C, 60.40; %H, 7.48; %N, 16.77; Found: %C, 59.97; %H,
7.26; %N, 16.33. Example 11 N-{8-[4-amino-2-(2-methoxyethyl)-lH-imidazo[4,5-c]quinolin-l- yl] octyl } benzenesulfonamide
Under a nitrogen atmosphere a solution of l-(8-aminooctyl)-2-(2-methoxyethyl)- lH-imidazo[4,5-c]quinolin-4-amine (1.0 g, 2.7 mmol) in dichloromethane (50 mL) was cooled to 0°C. Triethylamine (415 μL, 2.98 mmol) was added followed by benzenesulfonyl chloride (345 μL, 2.71 mmol). The reaction mixture was allowed to warm slowly to ambient temperature and then it was maintained overnight. The reaction mixture was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography (50 g of silica gel eluting with 7.5% methanol in dichloromethane). The purified material was recrystallized from propyl acetate, triturated with hexanes, and then dried in a vacuum oven to provide 590 mg of N-{8-[4-amino-2-(2-methoxyethyl)-lH-imidazo[4,5- c]quinolin-l-yl]octyl}benzenesulfonamide as a yellow powder, m.p. 146-149°C.
Analysis: Calculated for C27Η35Ν5O3S: %C, 63.63; %H, 6.92; %N, 13.74; Found: %C, 62.96; %H, 7.03; %N, 13.09. Karl Fisher showed 0.16% or 0.045 mole water. 1H NMR (300 MHz, DMSO-d6) δ 801 (d, J=7.8 Hz, IH), 7.78 (m, 2H), 7.65-7.55 (m, 5H), 7.45 (m, IH), 7.28 (m, IH), 6.71 (s, 2H), 4.50 (m, 2H), 3.83 (m, 2H), 3.5 (broad s, 3H), 3.18 (m, 2H), 2.71 (m, 2H), 1.77 (m, 2H), 1.38-1.17 (m, 10H);
13C NMR (75 MHz, DMSO-d6) 151.7, 151.3, 144.0, 141.0, 132.8, 132.6, 129.5, 127.0, 126.8, 125.9, 121.9, 120.4, 114.9, 70.5, 58.5, 45.3, 42.8, 30.0, 29.2, 28.8, 28.7, 27.5, 26.2, 26.1; MS w/z 510 (M + H). Example 12 N-{8-[4-amino-2-(2-methoxyethyl)-lH-imidazo[4,5-c]quinolin-l- yl]octyl}methanesulfonamide
Using the general method of Example 11, l-(8-aminooctyl)-2-(2-methoxyethyl)- lH-imidazo[4,5-c]quinolin-4-amine (800 mg, 2.17 mmol) was reacted with methanesulfonyl chloride (172 μL, 2.17 mmol) to provide 720 mg of N-{8-[4-amino-2-(2- methoxyethyl)-lH-imidazo[4,5-c]quinolin-l-yl]octyl}methanesulfonamide as a yellow powder, m.p. 109-110°C. Analysis: Calculated for C22Η33Ν5O3S: %C, 59.04; %H, 7.43; %N, 15.65; Found: %C, 58.78; %H, 7.38; %N, 15.48.
1H NMR (300 MHz, DMSO-d6) δ 8.01 (d, J=8.3 Hz, IH), 7.62 (d, J=8.3 Hz, IH), 7.42 (m, IH), 7.26 (m, IH), 6.91 (m, IH), 6.51 (s, 2H), 4.51 (t, J=7.3 Hz, 2H), 3.83 (t, J=6.8 Hz, 2H), 3.34 (s, 3H), 3.18 (t, J=6.8 Hz, 2H), 2.89 (m, 2H), 2.86 (s, 3H), 1.80 (m, 2H), 1.27 (m, 10H);
13C NMR (125 MHz, DMSO-d6) 152.0, 151.0, 145.0, 132.6, 132.6, 126.7, 126.6, 121.56, 120.3, 115.1, 70.5, 58.5, 45.3, 42.8, 30.0, 29.7, 28.9, 28.8, 27.5, 26.4, 26.2; MS m/z 448 (M + 1).
Example 13 N-[8-(4-amino-2-butyl-lH-imidazo[4,5-c]quinolin-l-yl)octyl]methanesulfonamide
Using the general method of Example 11, l-(8-aminooctyl)-2-butyl-lH- imidazo[4,5-c]quinolin-4-amine (1.2 g, 3.26 mmol) was reacted with methanesulfonyl chloride (260 μL, 3.26 mmol) to provide 0.70 g of N-[8-(4-amino-2-butyl-lH- imidazo[4,5-c]quinolin-l-yl)octyl]methanesulfonamide as a tan powder, m.p. 121-124°C. Analysis: Calculated for C23Η35Ν5O3S: %C, 61.99: %H, 7.92; %N, 15.72; Found: %C, 62.01; %H, 7.97; %N, 15.75.
]H NMR (300 MHz, DMSO-d6) δ 8.01 (d, J-8.3 Hz, IH), 7.61 (dd, J=8.3, 1.0 Hz, IH), 7.41 (dt, J=8.3 1.5 Hz, IH), 7.25 (dt, J=8.3, 1.5 Hz, IH), 6.91 (t, J=4.9 Hz, IH), 6.47 (s, 2H), 4.48 (t, J=7.3 Hz, 2H), 2.90 (m, 4H), 2.86 (s, 3H), 1.80 (m, 4H), 1.44 (m, 6H), 1.27 (m, 6H), 0.96 (t, J=7.3 Hz, 3H);
13C NMR (500 MHz, DMSO-d6) 153.3, 152.1, 145.1, 132.5, 126.8. 126.7, 126.6, 121.5, 120.2, 115.2, 45.1, 42.8, 39.6, 30.1, 30.0, 29.8, 28.9, 28.8, 26.5, 26.4, 26.2, 22.3, 14.1; MS m/z 446 (M + 1).
Example 14 N-[3-(4-amino-2-butyl-lH-imidazo[4,5-c]quinolin-l-yl)propyl]-5- (dimethylamino)naphthalene- 1 -sulfonamide
Under a nitrogen atmosphere triethylamine (765 mg, 7.56 mmol) was added to a solution of l-(3-aminopropyl)-2-butyl-lH-imidazo[4,5-c]quinolin-4-amine (1.5 g, 5.04 mmol) in l-methyl-2-pynolidinone (75 mL). A solution of 5-dimethylamino-l- naphthalenesulfonyl chloride (1.5 g, 5.55 mmol) in l-methyl-2-pynolidinone was added. The reaction was monitored by ΗPLC. The reaction mixture was combined with water (500 mL) and the pΗ was adjusted to 10 with solid potassium carbonate. The resulting yellow precipitate was isolated by filtration, rinsed with water and then purified by column chromatography (silica gel eluting with 1 - 5% methanol in chloroform). The purified material was recrystallized from acetonitrile to provide 1.76 g of N-[3-(4-amino-2-butyl- lH-imidazo[4,5-c]quinolin-l-yl)propyl]-5-(dimethylamino)naphthalene-l-sulfonamide as a solid, m.p. 216.5-217.5°C. Analysis: Calculated for C29Η34Ν6O2S: %C, 65.64; %H,
6.46; %N, 15.84; Found: %C, 65.52; %H, 6.44; %N, 15.90.
Example 15 N-[3-(4-amino-2-butyl-lH-imidazo[4,5-c]quinolin-l-yl)propyl]-4- methylbenzenesulfonamide
Using the general method of Example 14 l-(3-aminopropyl)-2-butyl-lH- imidazo[4,5-c]quinolin-4-amine (1.5 g, 5.04 mmol) was reacted with j9-toluenesulfonyl chloride (1.08 g, 5.55 mmol) to provide 1.57 g of N-[3-(4-amino-2-butyl-lH-imidazo[4,5- c]quinolin-l-yl)propyl]-4-methylbenzenesulfonamide as an off white powder, m.p. 197.0- 198.5°C. Analysis: Calculated for C24Η29Ν5O2S: %C, 63.83; %H, 6.47; %N, 15.51; Found: %C, 63.68; %H, 6.40; %N, 15.51.
Example 16 N-{3-[4-amino-2-(2-methoxyethyl)- lH-imidazo[4,5-c]quinolin-l-yl]propyl}methanesulfonamide
Using the general method of Example 11, l-(3-aminopropyl)-2-(2-methoxyethyl)- lH-imidazo[4,5-c]quinolin-4-amine (1.53 g, 5.11 mmol) was reacted with methanesulfonyl chloride to provide 800 mg of N-{3-[4-amino-2-(2-methoxyethyl)-lH- imidazo[4,5-c]quinolin-l-yl]propyl}methanesulfonamide as light yellow needles, m.p. 193-194°C. Analysis: Calculated for C,7H23N5O3S: %C, 54.09; %H, 6.14; %N, 18.55; Found: %C, 54.09; %H, 5.93; %N, 18.49.
Example 17 N-[8-(4-amino-2-butyl-lH-imidazo[4,5-c]quinolin-l-yl)octyl]benzenesulfonamide
Using the general method of Example 11, l-(8-aminooctyl)-2-butyl-lH- imidazo[4,5-c]quinolin-4-amine (1.0 g, 2.72 mmol) was reacted with benzenesulfonyl chloride (350 μL, 2.72 mmol) to provide 1.38 g of N-[8-(4-amino-2-butyl-lH- imidazo[4,5-c]quinolin-l-yl)octyl]benzenesulfonamide as an off white powder, m.p. 143-
144°C. Analsysis: Calculated for C28Η37Ν5O2S: %C, 66.24; %H, 7.35; %N, 13.79; Found: %C, 66.08; %H, 7.25; %N, 13.72. Karl Fisher titration found 0.23% water. 1H NMR (300 MHz, DMSO-d6) δ 7.98 (d, J=7.8 Hz, IH), 7.77 (m, 2H), 7.62-7.53 (m, 5H), 7.41 (m, IH), 7.25 (m, IH), 6.47 (s, 2H), 4.47 (m, 2H), 2.90 (m, 2H), 2.70 (q, J=6.3 Hz, 2H), 1.78 (m, 4H), 1.49-1.17 (m, 12H), 0.95 (t, J=7.3, 3H);
I3C NMR (125 MHz, DMSO-d6) 153.3, 152.0, 145.0, 141.0, 132.5, 129.5, 126.82, 126.76, 126.7, 126.6, 121.5, 120.3, 120.2, 115.1, 45.1, 42.8, 30.0, 29.2, 28.8, 28.7, 26.5, 26.2, 26.1, 22.3, 14.2, 14.1; MS m/z 507 (M + 1). Example 18 N-{3-[4-amino-2-(2-methoxyethyl)- lH-imidazo [4,5 -c] quinolin- 1 -yljpropyl} benzenesulfonamide
Using the general method of Example 11, 1 -(3-aminopropyl)-2-(2-methoxyethyl)- lH-imidazo[4,5-c]quinolin-4-amine (1.53 g, 5.11 mmol) was reacted with benzenesulfonyl chloride (993 mg, 5,62 mmol) to provide 1.37 g of N-{3-[4-amino-2-(2- methoxyethyl)-lH-imidazo[4,5-c]quinolin-l-yl]propyl}benzenesulfonamide as a white powder, m.p. 149-151°C. Analysis: Calculated for C22Η25Ν5O3S: %C, 60.12; %H, 5.73; %N, 15.93; Found: %C, 60.40; %H, 5.82; %N, 15.85.
Example 19 N-[4-(4-amino-2-pentyl- 1 H-imidazo [4, 5 -c] quinolin- 1 -yl)butyl] methanesulfonamide
Using the general method of Example 14, l-(4-aminobutyl)-2-pentyl-lH- imidazo[4,5-c]quinolin-4-arnine (1.50 g, 4.6 mmol) was reacted with methanesulfonyl chloride (0.57 mL, 7.4 mmol) to provide 636 mg of N-[4-(4-amino-2-pentyl-lH- imidazo[4,5-c]quinolin-l-yl)butyl]methanesulfonamide as an off white solid, m.p. 136.8- 138.1°C. Analysis: Calculated for C20Η29Ν5O2S: %C, 59.53; %H, 7.24; %N, 17.35;
Found: %C, 59.50; %H, 7.31; %N, 16.80. Example 20 N-[4-(4-amino-2-pentyl- lH-imidazo[4,5-c]quinolin- 1 -yl)butyl]benzenesulfonamide
Using the general method of Example 1, l-(4-aminobutyl)-2-pentyl-lH- imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.1 mmol) was reacted with benzenesulfonyl chloride (0.51 mL, 4.0 mmol) to provide 0.35 g of N-[4-(4-amino-2-pentyl-lH- imidazo[4,5-c]quinolin-l-yl)butyl]benzenesulfonamide as a yellow crystalline solid. Analysis: Calculated for C25Η3ιΝ5O2S • 0.5 H2O: %C, 63.27; %H, 6.80; %N, 14.76;
Found: %C, 62.99; %H, 6.61; %N, 14.42.
Example 21 N- [ 8 -(4-amino- 1 H-imidazo [4, 5 -c] quinolin- 1 -yl)octyl]methanesulfonamide
Using the general method of Example 11, l-(8-aminooctyl)-lH-imidazo[4,5- c]quinolin-4-amine (3.85 mmol) was reacted with methanesulfonyl chloride (310 μL, 3.85 mmol) to provide 0.43 g of N-{8-[4-amino-lH-imidazo[4,5-c]quinolin-l- yl]octyl}methanesulfonamide as an off white powder, m.p. 153-155°C. Analysis: Calculated for Cι9H27N5O2S: %C, 58.59; %H, 6.99; %N, 17.98; %S, 8.23; Found: %C, 58.40; %H, 6.99; %N, 17.71; %S, 8.14.
1H NMR (300 MHz, DMSO-d6) δ 8.20 (s, IH), 8.03 (d, J=7.8 Hz, IH), 7.63 (d, J=8.3 Hz, IH), 7.45 (m, IH), 7.27 (m, IH), 6.91 (m, IH), 6.63 (d, 2H), 4.59 (m, 2H), 2.89 (m, 2H), 2.86 (s, 3H), 1.86 (m, 2H), 1.41-1.25 (m, 10H);
13C NMR (125 MHz, DMSO-d6) 152.5, 145.2, 143.2, 132.0, 128.5, 127.1, 126.5, 121.6, 120.8, 115.2, 46.9, 42.8, 39.6, 30.0, 29.7, 28.81, 28.78, 26.4, 26.1; MS m/z 390 (M + 1). Example 22 N-{3-[4-amino-2-(2-methoxyethyl)-lH-imidazo[4,5-c]quinolin-l-yl]propyl}-4- methylbenzenesulfonamide
Using the general method of Example 11, l-(3-aminopropyl)-2-(2-methoxyethyl)- 1 H-imidazo [4, 5 -c] quinolin-4-amine (1.53 g, 5.11 mmol) was reacted with p- toluenesulfonyl chloride (1.07 g, 5,62 mmol) to provide 750 mg of N-{3-[4-amino-2-(2- methoxyethyl)-lH-imidazo[4,5-c]quinolin-l-yl]propyl}-4-methylbenzenesulfonamide as a solid, m.p. 189-191°C. Analysis: Calculated for C23Η27Ν5θ3S • 0.50 H2O: %C, 59.72; %H, 6.10; %N, 15.14; Found: %C, 59.73; %H, 5.95; %N, 15.08. Example 23 N-[4-(4-amino-2-pentyl-6,7,8,9-tetrahydro- lH-imidazo[4,5-c]quinolin-l-yl)butyl]methanesulfonamide
A solution of l-(4-aminobutyl)-2-pentyl-6,7,8,9-tetrahydro-lH-imidazo[4,5- c]quinolin-4-amine (1.50 g, 3.7 mmol) in chloroform (150 mL) was chilled in an acetone/ice bath. Methanesulfonic anhydride (0.79 g, 3.7 mmol) was slowly added. After 1.75 hr, 0.018 g of anhydride was added. At 2.5 hrs 0.079 g of anhydride was added. After 3 hrs, the reaction mixture was washed with aqueous 1% sodium carbonate solution (3 X 150 mL). 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 pΗ 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
2.18 g of a brown residue. This material was slurried with methyl acetate. The resulting solid was isolated to provide 1.25 g of N-[4-(4-amino-2-pentyl-6,7,8,9-tetrahydro-lH- imidazo[4,5-c]quinolin-l-yl)butyl]methanesulfonamide as a white solid, m.p. 167.0- 167.8°C. Analysis: Calculated for C20Η33Ν5O2S: %C, 58.94; %H, 8.16; %N, 17.18; Found: %C, 58.79; %H, 7.92; %N, 17.02. Example 24 N- (3-[4-amino-2-(ethoxymethyl)- lH-imidazo[4,5-c]quinolin-l-yl]propyl}methanesulfonamide
A mixture of 1 -(3-aminopropyl)-2-(ethoxymethyl)-lH-imidazo[4,5-c]quinolin-4- amine (2.0 g, 6.7 mmol), triethylamine (1.5 mL, 15 mmol) and acetonitrile (75 mL) was heated until a solution was obtained. Methanesulfonic anhydride (1.28 g, 7.4 mmol) was added in a single portion. After 5 minutes a small amount of anhydride was added. The reaction mixture was allowed to stir overnight. The reaction mixture was quenched with aqueous 1% sodium carbonate solution. The aqueous layer was extracted with chloroform. The organics were dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was dried under high vacuum for 3 hours to provide 2.73 g of a glassy solid. This material was recrystallized from methanol to provide 1.38 g of N-{3-[4-amino-2-(ethoxymethyl)-lH-imidazo[4,5-c]quinolin-l- yljpropyl} methanesulfonamide, m.p. 208.2-209.6°C. Analysis: Calculated for
C17Η23Ν5O3S: %C, 54.09; %H, 6.14; %N, 18.55; Found: %C, 53.97; %H, 6.29; %N, 18.32.
Example 25 N-{3-[4-amino-2-(2-methoxyethyl)- lH-imidazo[4,5-c]quinolin-l-yl]-2,2-dimethylpropyl}methanesulfonamide
Using the general method of Example 11, l-(3-amino-2,2-dimethylpropyl)-2-(2- methoxyethyl)-lH-imidazo[4,5-c]quinolin-4-amine (0.22 g, 0.672 mmol) was reacted with methanesulfonyl chloride (125 μL) to provide 270 mg of N-{3-[4-amino-2-(2- methoxyethyl)-lH-imidazo[4,5-c]quinolin-l-yl]-2,2-dimethylpropyl}methanesulfonamide as a cream colored powder, m.p. 204.0-206.0°C. Analysis: Calculated for Cι Η27Ν5O3S • 0.50 H20: %C, 55.05; %H, 6.81; %N, 16.89; %S, 7.74; Found: %C, 55.10; %H, 6.58; %N,
17.23; %S, 7.51. % H2O calculated: 2.17; found: 2.28 (Karl Fisher). 1H NMR (300 MHz, DMSO-d6) δ 8.36 (d, J=8.3 Hz, IH), 7.59 (d, J=8.3 Hz, IH), 7.38 (m, 2H), 7.20 (m, IH), 6.49 (s, 2H), 4.81 (br s, IH), 4.39 (br s, IH), 3.82 (m, 2H), 3.27 (s, 3H), 3.19 (br s, 2H), 3.02 (d, J=6.8 Hz, 2H), 2.94 (s, 3H), 0.82 (br s , 6H); 13C NMR (125 MHz, DMSO-d6) δ 152.5, 152.0, 145.3, 133.9, 126.8, 126.7, 126.6, 121.5,
120.7, 115.8, 71.0, 58.5, 51.8, 51.5, 39.7, 39.0, 28.3, 24.4, 23.1; MS m/z 406 (M + H).
Example 26 N-{3-[4-amino-2-(2-methoxyethyl)-lH-imidazo[4,5-c]quinolin-l-yl]propyl}- 5 -(dimethylamino)naphthalene-l -sulfonamide
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. 210-215°C. Analysis: Calculated for C28Η32Ν6O3S • 1.50 H2O: %C, 60.09; %H, 6.30; %N, 15.02; Found: %C, 59.89; %H, 6.22; %N, 14.86.
Example 27 N-[3-(4-amino-2-methyl- lH-imidazo[4,5-c]quinolin-l-yl)propyl]methanesulfonamide
Using the general method of Example 24, l-(3-aminopropyl)-2-methyl-lH- imidazo[4,5-c]quinolin-4-amine (2.0 g, 7.8 mmol) was reacted with methanesulfonic anhydride (1.49 g, 8.6 mmol) to provide 1.2 g of N-[3-(4-amino-2-methyl-lH- imidazo[4,5-c]quinolin-l-yl)propyl]methanesulfonamide as a solid, m.p. 236.0-238.0°C. Analysis: Calculated for Cι5H19N5O2S ■ 0.25 H2O: %C, 53.32; %H, 5.82; %N, 20.72; Found: %C, 53.35; %H, 5.72; %N, 20.57.
Example 28 N-{3-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro- 1 H-imidazo [4, 5 -c] quinolin- 1 -yljpropyl } methanesulfonamide
Using the general method of Example 24, l-(3-aminopropyl)-2-(2-methoxyethyl)- 6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-4-amine (2.0 g, 6.6 mmol) was reacted with methanesulfonic anhydride (1.26 g, 7.3 mmol) to provide 630 mg of N-IS-^-amino^-^- methoxyethy -ό^S^-tetrahydro-lH-imidazo^S-cjquinolin^ yl]propyl}methanesulfonamide as a solid, m.p. 150.0-152.0°C. Analysis: Calculated for C17Η27Ν5O3S: %C, 53.52; %H, 7.13; %N, 18.36; Found: %C, 53.27; %H, 7.12; %N, 18.37.
Example 29 N-{3-[4-amino-2-(ethoxymethyl)-6,7,8,9-tetrahydro- lH-imidazo[4,5-c]quinolin-l-yl]propyl}methanesulfonamide
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. 212.0-214.0°C. Analysis: Calculated for Cι7Η27Ν5O3S: %C, 53.52; %H, 7.13; %N, 18.36; Found: %C, 53.25; %H, 7.16; %N, 18.09.
Example 30 N-{3-[4-amino-2-(3-phenoxypropyl)- lH-imidazo[4,5-c]quinolin-l-yl]propyl}methanesulfonamide
Using the general method of Example 11, except that chloroform was used in place of dichloromethane, 1 -(3-aminopropyl)-2-(3-phenoxypropyl)-lH-imidazo[4,5-c]quinolin- 4-amine (2.00 g, 5.32 mmol) was reacted with methanesulfonyl chloride (3+ g) to provide 1.38 g ofN-{3-[4-amino-2-(3-phenoxypropyl)-lH-imidazo[4,5-c]quinolin-l- yljpropyl} methanesulfonamide as a solid, m.p. 176-178°C. Analysis: Calculated for C23Η27Ν5O3S: %C, 60.91; %H, 6.00; %N, 15.44; Found: %C, 60.71; %H, 5.98; %N,
15.45.
Example 31 N-{4-[4-amino-2-(3-phenoxypropyl)- lH-imidazo[4,5-c]quinolin-l-yl]butyl}methanesulfonamide
Using the general method of Example 24, except that pyridine was used in place of acetonitrile, 1 -(3-aminobutyl)-2-(3-phenoxypropyl)- lH-imidazo[4,5-c]quinolin-4-amine (2.00 g, 5.1 mmol) was reacted with an excess of methanesulfonic anhydride to provide 1.36 g of N-{4-[4-amino-2-(3-phenoxypropyl)-lH-imidazo[4,5-c]quinolin-l- yljbutyl} methanesulfonamide as a solid, m.p. 156.4-157.1°C. Analysis: Calculated for C24Η29Ν5O3S: %C, 60.48; %H, 6.34; %N, 14.69; Found: %C, 60.75; %H, 6.36; %N,
14.31.
Example 32 N-[4-(4-amino-2-methyl-6,7,8,9-tetrahydro- lH-imidazo[4,5-c]quinolin- 1 -yl)butyl]methanesulfonamide hydrochloride
Using the general method of Example 23, l-(4-aminobutyl)-2-methyl-6,7,8,9- tetrahydro-lH-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.7 mmol) was reacted with methanesulfonic anhydride (0.96 g, 5.5 mmol) in the presence of triethylamine (0.76 mL, 5.5 mmol) to provide 0.55 g of the free base of the desired product. This material was combined with methanol (-20 mL), warmed, allowed to cool to ambient temperature and then filtered to remove some insoluble material. The filtrate was reduced to a volume of -10 mL and then combined with IN hydrochloric acid (3 mL). Diethyl ether (15 mL) was added and then the mixture was concentrated under reduced pressure. The resulting residue was slurried with isopropyl alcohol to provide a white solid which was isolated by filtration and then dried to provide 0.46 g of N-[4-(4-amino-2-methyl-6,7,8,9-tetrahydro- lH-imidazo[4,5-c]quinolin-l-yl)butyl]methanesulfonamide hydrochloride, m.p. >250°C. Analysis: Calculated for C16Η25Ν5θ2S • 1.00 HCl • 1.00 H2O: %C, 47.34; %H, 6.95; %N, 17.25; Found: %C, 47.40; %H, 6.49; %N, 17.22. Example 33 N-[2-(4-amino-2-butyl-lH-imidazo[4,5-c]quinolin-l-yl)ethyl]-4- methylbenzenesulfonamide
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-
2-pyrrolidinone (100 mL). A solution of tosyl chloride (2.11 g, 11.1 mmol) in l-methyl-2- pynolidinone (20 mL) was slowly added in a dropwise fashion. The reaction was allowed to warm to ambient temperature and was maintained overnight. The reaction was poured into water (1500 mL) and adjusted to pΗ 9. A white precipitate was isolated by filtration and then recrystallized from acetonitrile (60 mL) to provide 3.9 g of N-[2-(4-amino-2- butyl-lH-imidazo[4,5-c]quinolin-l-yl)ethyl]-4-methylbenzenesulfonamide, m.p. 187.0- 188.0°C. Analysis: Calculated for C23Η27Ν5O2S • 0.3 H2O: %C, 62.29; %H, 6.28; %N, 15.79; Found: %C, 62.52; %H, 6.36; %N, 15.88. Example 34 N-[2-(4-amino-2-butyl-lH-imidazo[4,5-c]quinolin-l-yl)ethyl]methanesulfonamide
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
(60 mL). The reaction was maintained at ambient temperature overnight and then it was concentrated to dryness. The residue was combined with warm dichloroethane and water and then filtered to provide an off white solid. The dichloroethane layer was concentrated to provide an off white solid. The two solids were combined and then recrystallized from Ν,Ν-dimethylformamide to provide 1.1 g of N-[2-(4-amino-2-butyl- lH-imidazo[4,5- c]quinolin-l-yl)ethyl]methanesulfonamide as a white solid, m.p. 210.0-211.0°C. Analysis: Calculated for C17Η23Ν5O2S: %C, 56.49; %H, 6.41; %N, 19.37; Found: %C, 56.45; %H, 6.49; %N, 19.50. Example 35 l-[4-(l,l-dioxidoisothiazolidin-2-yl)butyl]-2-(2-methoxyethyl)- 1 H-imidazo [4, 5 -c] quinolin-4-amine
Under a nitrogen atmosphere, l-(4-aminobutyl)-2-(2-methoxyethyl)-lH- imidazo[4,5-c]quinolin-4-amine (500 mg, 1.6 mmol) was dissolved in dichloromethane (5 mL) and triethylamine (0.33 mL, 2.4 mmol). 3-Chloropropylsulfonyl chloride (0.19 mL, 1.6 mmol) was added dropwise and the reaction was stined for 2 hours. The solvent was removed in vacuo. The residue was dissolved in N,N-dimethylformamide (5 mL) and 1,8- diazabicyclo[5.4.0]undec-7-ene (0.48 mL, 3.2 mmol) was added. The reaction was stined for 72 hours and then poured into water and extracted with dichloromethane. The organic layer was washed with water followed by brine; dried (Na2SO4); decanted and evaporated to yield crude product as a brown oil. Purification involved flash column chromatography
(silica gel, gradient elution with methanol /dichloromethane 100:0 to 94:6) followed by recrystallization from acetonitrile to provide 289 mg of l-[4-(l,l-dioxidoisothiazolidin-2- yl)butyl]-2-(2-methoxyethyl)-lH-imidazo[4,5-c]quinolin-4-amine as a yellow crystalline solid, m.p. 156.4-157.7 °C. 1H-NMR (500MHz, DMSO-d6) δ 8.04 (d, J = 7.4 Hz, IH), 7.62 (dd, J = 8.3, 1.2 Hz, IH);
7.42 (ddd, J = 8.2, 7.0, 1.2 Hz, IH), 7.26 (ddd, J = 8.2, 7.0, 1.2 Hz, IH), 6.48 (bs, 2H), 4.54 (t, J = 7.6 Hz, 2H), 3.84 (t, J = 6.7 Hz, 2H), 3.29 (s, 3H), 3.22-3.12 (m, 6H), 2.93 (t, J = 6.6 Hz, 2H), 2.23-2.13 (m, 2H), 1.90-1.65 (m, 4H); 13C-NMR (125MHz, DMSO-d6) 6151.6, 150.6, 144.8, 132.2, 126.5, 126.3, 121.2, 120.0, 114.7, 70.2, 58.1, 46.5, 46.1, 44.5, 43.6, 27.1, 24.1, 18.3;
Anal calcd for C20H27N5O3S: %C, 57.53; %H, 6.52; %N, 16.77; %S, 7.68. Found: %C, 57.52; %H, 6.67; %N, 16.88; %S, 7.71.
Example 36 2-butyl- 1 - [4-( 1 , 1 -dioxidoisothiazolidin-2-yl)butyl] - 1 H-imidazo[4,5 -c] quinolin-4-amine
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. Η-NMR (300 MHz, DMSO-d6) δ 8.30 (d, J = 8.1 Hz, IH), 7.62 (d, J = 8.2 Hz, IH), 7.41 (t, J = 7.6 Hz, IH), 7.26 (t, J = 8.0 Hz, IH), 6.48 (bs, 2H), 4.51 (t, J = 7.5 Hz, 2H), 3.18- 3.11 (m, 4H), 2.96-2.89 (m, 4H), 2.22-2.12 (m, 2H), 1.92-1.63 (m, 6H), 1.45 (sextet, J =
7.4 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H);
13C-NMR (75 MHz, DMSO-d6) δ 153.0, 151.7, 144.7, 132.2, 126.4, 126.2, 121.1, 120.0, 114.7, 46.5, 46.1, 44.3, 43.6, 29.7, 27.1, 26.1, 24.1, 22.0, 18.3, 13.8; MS (Cl) m/e 416.2124 (416.2120 calcd for C2ιH30N5O2S, M+H); Anal calcd for C21H29N5O2S: %C, 60.70; %H, 7.03; %N, 16.85; %S, 7.72. Found: %C,
60.67; %H, 6.94; %N, 17.02; %S, 7.42.
Example 37 N-{2-[4-amino-2-(ethoxymethyl)-lH-imidazo[4,5-c]quinolin-l-yl]-l,l- dimethylethyl}methanesulfonamide
Part A A stined solution of 4-chloro-3-nitroquinoline (17.3 g, 83.2 mmol) in 200 mL of anhydrous CΗ2C12, under Ν2, was treated with triethylamine (23.2 mL, 166.4 mmol) and 1 ,2-diamino-2-methylpropane (9.57 mL, 91.5 mmol). After stirring overnight, the reaction mixture was diluted with 800 mL of CHCI3 washed with H2O (3 X 300 mL) and brine (300 mL). The organic portion was dried over Na2SO4 and concentrated to give 2- methyl-N1-(3-nitroquinolin-4-yl)propane-l,2-diamine (21.0 g) as a bright yellow solid. Part B A solution of 2-methyl-N1-(3-nitroquinolin-4-yl)propane-l,2-diamine (2.60 g, 10.0 mmol) in 50 mL of THF, under Ν2, was cooled to 0 °C and treated with 10 mL of IN NaOH solution. Di-tert-butyl dicarbonate (2.18 g, 10.0 mmol) was then added to the rapidly stined solution. The 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 H2O (2X) and brine. The organic portion was dried over Na SO4 and concentrated to give a yellow solid that was titurated with 10%
EtOAc/hexanes. The solid was isolated by filtration and dried under vacuum overnight to give tert-butyl l,l-dimethyl-2-[(3-nitroquinolin-4-yl)amino]ethylcarbamate (2.80 g) as a yellow powder. Part C A solution of tert-butyl l,l-dimethyl-2-[(3-nifroquinolin-4- yl)amino]ethylcarbamate (3.50 g, 9.72 mmol), in 150 mL of toluene was treated with 0.3 g of 5% Pt on carbon and shaken under H2 (3 arm, 3 Kg/cm2) for 6 h. The solution was then filtered through a Celite pad and concentrated to give 3.04 g of crude tert-butyl 2-[(3- aminoquinolin-4-yl]-l,l-dimethylethylcarbamate as a light orange foam. Part D A solution of tert-butyl 2-[(3-aminoquinolin-4-yl]-l,l-dimethylethylcarbamate (3.04 g, 9.21 mmol) in 50 mL of CH C12 was cooled to 0 °C and treated with triethylamine (1.41 mL, 10.13 mmol) and ethoxyacetyl chloride (1.02 mL, 10.17 mmol). After 2 h, the reaction mixture was concentrated under reduced pressure. The resulting syrup was taken up in 100 mL of EtOH and treated with 4.5 mL of triethylamine. The solution was heated to reflux overnight. The reaction mixture was concentrated and taken up in 100 mL of CH2CI2 and washed with H2O (2X) and brine. The organic portion was dried over Na2SO4 and concetrated. The resulting syrup was purified by column chromatography (Siθ2, 80% EtOAc/hexanes) to give tert-butyl 2-[2-(ethoxymethy)-lH-imidazo[4,5-c]quinolin-l-yl]- 1 ,1 -dimethyl ethylcarbamate (1.57 g) as a peach colored foam.
Part E A solution of tert-butyl 2-[2-(ethoxymethy)-lH-imidazo[4,5-c]quinolin-l-yl]-l,l- dimethylethylcarbamate (1.57 g, 3.94 mmol) in 30 mL of CΗ2C12 was treated with 3- chloroperoxybenzoic acid (77%, 1.01 g, 4.57 mmol). After stirring for 2 h, the reaction mixture was treated with 30 mL of additional CH C1 and was washed with 1% Na2CO3 solution (2 X 30 mL), H2O and brine. The organic portion was then dried over Na2SO4 and concentrated to give tert-butyl 2-[2-(2-(ethoxymethyl)-5-oxido-lH-imidazo[4,5- c] quinolin- l-yl]-l,l-dimethylethylcarbamate (1.58 g) as a light brown foam. Part F A solution of tert-butyl 2-[2-(2-(ethoxymethyl)-5-oxido-lH-imidazo[4,5- c]quinolin-l-yl]-l,l-dimethylethylcarbamate (1.57 g, 3.79 mmol) in 20 mL of 1,2- dichloroethane was heated to 70 °C and treated with 2 mL of concentrated NΗ OΗ solution. To the rapidly stined solution was added solid p-toluenesulfonyl chloride (795 mg, 4.17 mmol). The reaction mixture was then sealed in a pressure vessel and heating was continued for 2 h. The reaction mixture was then cooled and treated with 50 mL of CHCI3. The reaction mixture was then washed with H2O, 1% Na2CO3 solution (3X) and brine. The organic portion was dried over Na2SO4 and concentrated to give the product as a light brown oil. The resulting oil was purified by column chromatography (SiO2, 2-5% MeOH/CHCl3) to give tert-butyl 2-[4-amino-2-(ethoxymethyl)-lH-imidazo[4,5- c]quinolin-l-yl]-l,l-dimethylethylcarbamate (1.26 g) as a light yellow foam. Part G rert-butyl 2-[4-amino-2-(ethoxymethyl)-lH-imidazo[4,5-c]quinolin-l-yl]-l,l- dimethylethylcarbamate (1.26 g, 3.05 mmol) was dissolved in 10 mL of EtOΗ and treated with 10 mL of 2 M ΗC1 in EtOΗ. After heating at reflux for 2 h, the reaction mixture was cooled and concentrated under reduced pressure. The resulting yellow solid was dissolved in 50 mL of Η2O and extracted with CHCI3 (20 mL). The organic layer was discarded and the aqueous portion was made basic (pH - 12) by addition of concentrated NH4OH solution. This was then extracted with CHCI3 (4 x 20 mL) and the combined organic portions were dried with Na SO4 and concentrated to give l-(2-amino-2-methylpropyl)-2- (ethoxymethyl)-lH-imidazo[4,5-c]quinoline-4-amine (808 mg) as a light brown powder. m. p. 161.0-162.0 °C;
MS rø/z 314 (M + Η);
1H NMR (300 MHz, d6-DMSO) δ 8.30 (d, J = 7.7 Hz, IH), 7.59 (dd, J = 1.2, 8.3 Hz, IH), 7.40 (ddd, J = 1.0, 7.2, 8.1 Hz, IH), 7.21 (ddd, J = 1.2, 7.0, 8.2 Hz, IH), 6.57 (s, 2H), 4.94 (br s, 2H), 4.61 (br s, 2H), 3.52 (q, J = 7.0 Hz, 2H), 1.61 (s, 2H), 1.31 (t, J = 7.0 Hz, 3H), 1.07 (s, 6H);
13C NMR (75 MHz, d6-DMSO) δ 152.4, 151.1, 145.7, 134.3, 126.8, 126.7, 121.7, 120.8, 115.7, 65.6, 65.2, 55.8, 52.5, 29.2, 15.4. Anal. Calcd for C,7H23N5O: %C, 65.15; %H, 7.40; %N, 22.35. Found: %C, 65.04; %H,
7.52; %N, 22.07.
Part H l-(2-Amino-2-methylpropyl)-2-(ethoxymethyl)-lH-imidazo[4,5-c]quinoline-4- amine (111 mg, 0.355 mmol) was dissolved in 5 mL of anhydrous CΗ C12 and cooled to 0
°C under N2. To the stined solution were added Et3N (99 μL, 0.71 mmol) and methanesulfonyl chloride (28 μL, 0.36 mmol) and the reaction was allowed to warm to ambient temperature overnight. The reaction mixture was then quenched by addition of saturated NaHCO3 solution (5 L). The organic layer was separated and washed with H O (2 X 5 mL) and brine, dried over Na2SO4 and concentrated under reduced pressure to give a tan foam. Purification by column chromatography (SiO , 2.5%-5% MeOH/CHC ) gave N-{2-[4-amino-2-(ethoxymethyl)-lH-imidazo[4,5-c]quinolin-l-yl]- 1,1- dimethylethyl} methanesulfonamide (75 mg) as a white foam. m..p. 105.0-110.0 °C; MS m/z 392 (M + Η)+;
1H ΝMR (300 MHz, CDC13) δ 8.06 (dd, J = 1.0, 8.3 Hz, IH), 7.79 (dd, J = 1.1, 8.4 Hz, IH), 7.51 (ddd, J = 1.3, 7.0, 8.4 Hz, IH), 7.31 (ddd, J = 1.3, 7.0, 8.3 Hz, IH), 5.90 (br s, IH), 5.51 (br s, 2H), 4.96 (s, 2H), 4.92 (br s, 2H), 3.74 (q, J = 7.0 Hz, 2H), 3.02 (s, 3H), 1.55 (br s, 6H), 1.29 (t, J = 7.0 Hz, 3H); 13C ΝMR (75 MHz, CDC13) δ 152.0, 150.8, 145.5, 135.2, 127.8, 127.6, 127.2, 122.2,
120.6, 116.0, 67.2, 65.4, 58.4, 55.8, 45.3, 26.6, 15.3.
Anal. Calcd for Cι8H25Ν5O3S»0.75H2O: C, 53.38; %H, 6.60; %N, 17.29. Found: %C, 53.49; %H, 6.23; %N, 16.93.
Example 38 N-[4-(4-amino-2-methyl-lH-imidazo[4,5-c]quinolin-l-yl)butyl]ethanesulfonamide
Using the general method of Example 1, l-(4-aminobutyl)-2-methyl-lH- imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.7 mmol) was reacted with ethanesulfonyl chloride (2.11 mL, 22.3 mmol) to provide 85 mg of N-[4-(4-amino-2-methyl-lH- imidazo[4,5-c]quinolin-l-yl)butyl]ethanesulfonamide as an off-white solid, m.p. 210.7- 211.6°C. Example 39 N- {4- [4-amino-2-(cyclopropylmethyl)- 1 H-imidazo [4, 5 -c] quinolin- 1 - yl]butyl}methanesulfonamide
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 (α) (TEN and TNF, respectively) secreted into culture media as described by Testerman et. al. In "Cytokine Induction by the Immunomodulators
Imiquimod and S-27609", Journal of Leukocyte Biology, 58, 365-372 (September, 1995).
Blood Cell Preparation for Culture Whole blood is collected by venipuncture into EDTA vacutainer tubes from healthy human donors. Peripheral blood mononuclear cells (PBMCs) are separated from whole blood by density gradient centrifugation using Histopaque®-1077 (Sigma Chemicals, St. Louis, MO). The PBMCs are suspended at 3-4 x 106 cells/mL in RPMI 1640 medium containing 10 % fetal bovine serum, 2 mM L-glutamine and 1% penicillin/streptomycin solution (RPMI complete). The PBMC suspension is added to 48 well flat bottom sterile tissue culture plates (Costar, Cambridge, MA or Becton Dickinson
Labware, Lincoln Park, NJ) containing an equal volume of RPMI complete media containing test compound.
Compound Preparation The compounds are solubilized in dimethyl sulfoxide (DMSO). The DMSO concentration should not exceed a final concentration of 1 % for addition to the culture wells.
Incubation The solution of test compound is added at 60 μM 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 106 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 (α) 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 μM). A "***" indicates that no induction was seen at any of the tested concentrations (0.0001, 0.001, 0.01, 0.1, 1 and 10 μM).
The present invention has been described with reference to several embodiments thereof. The foregoing detailed description and examples have been provided for clarity of understanding only, and no unnecessary limitations are to be understood therefrom. It will be apparent to those skilled in the art that many changes can be made to the described embodiments without departing from the spirit and scope of the invention. Thus, the scope of the invention should not be limited to the exact details of the compositions and structures described herein, but rather by the language of the claims that follow.

Claims

WHAT IS CLAIMED IS:
1. N- {2-[4-amino-2-(ethoxymethyl)- lH-imidazo[4,5-c]quinolin- 1 -yl]- 1 , 1 - dimethylethyl} methanesulfonamide, or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 1 and a pharmaceutically acceptable carrier.
3. A method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or salt of claim 1 to the animal.
4. A method of treating a viral disease in an animal comprising administering a therapeutically effective amount of a compound or salt of claim 1 to the animal.
5. A method of treating a neoplastic disease in an animal comprising administering a therapeutically effective amount of a compound or salt of claim 1 to the animal.
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