WO2015166398A1 - 3h-imidazo[4,5-b]pyridine derivatives as dihydroorotate dehydrogenase inhibitors - Google Patents

3h-imidazo[4,5-b]pyridine derivatives as dihydroorotate dehydrogenase inhibitors Download PDF

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Publication number
WO2015166398A1
WO2015166398A1 PCT/IB2015/053051 IB2015053051W WO2015166398A1 WO 2015166398 A1 WO2015166398 A1 WO 2015166398A1 IB 2015053051 W IB2015053051 W IB 2015053051W WO 2015166398 A1 WO2015166398 A1 WO 2015166398A1
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Prior art keywords
compound
imidazo
pyridine
biphenyl
pharmaceutically acceptable
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PCT/IB2015/053051
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French (fr)
Inventor
Subramanya Hosahalli
Siva Sanjeeva Rao Thunuguntla
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Aurigene Discovery Technologies Limited
Um Pharmauji Sdn. Bhd
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Publication of WO2015166398A1 publication Critical patent/WO2015166398A1/en

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    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

Definitions

  • the present invention relates to novel 3H-imidazo[4,5-b]pyridine derivatives of formula (I) which are inhibitors of dihydroorotate dehydrogenase.
  • the invention refers to novel compounds, which inhibits DHODH enzyme activity, to a process for their manufacture and pharmaceutical compositions containing them, and to their use for the treatment and prevention in diseases or disorder, in particular their use in diseases or disorder where there is an advantage in inhibiting DHODH.
  • DHODH is a protein that catalyzes one of the steps in denovo pyrimidine nucleotide biosynthetic pathway.
  • Inhibitors of dihydroorotate dehydrogenase have been found to possess wider applications as chemotherapeutic agents. (Kensler et al.
  • the quinoline derivative Brequinar (6-Fluoro- 2-(2'-fluoro[l, -biphenyl]-4-yl)-3-methyl-4-quinolinecarboxylic acid) exhibits an anticancer activity towards L1210 murine leukemia (Andreson LW. Et al.Cancer Commun. 1989; 1(6), 381-7; Chen SF. et al. Cancer Res. 1986 Oct; 46 (10): 5014-9). It has also been shown that Brequinar potentiates 5-fluorouracil antitumor activity in a murine model colon 38 tumor by tissue-specific modulation of uridine nucleotide pools. (G Pizzorno et al. Cancer Res. 1992 Apr 1; 52: 1660-5).
  • DHODH inhibitors may also be useful in the treatment of viral mediated diseases (see US 6,841,561). Furthermore, inhibition of DHODH is known to be among promising target for treating transplant rejection, rheumatoid arthritis, psoriasis as well as autoimmune diseases (Kovarik, J. M. et al. Expert Opin. Emerg. Drugs 2003, 8, 47; Allison, A.C. Transplantation Proc. (1993) 25(3) Suppl. 2, 8-18); Makowka, L., Immunolog Rev. (1993) 136, 51-70; Davis J.P et al. Biochemistry 1996, 35: 1270-3).
  • Leflunomide a well known DHODH inhibitor is a synthetic drug currently marketed, a low-molecular weight drug of the isoxazole class (see EP0527736, JP1993506425, JP1999322700, JP1999343285, US5494911, US5532259, WO19991017748) and used in the treatment of Rheumatoid arthritis and is also under evaluation for use in the treatment of inflammatory bowel disease and chronic allograft rejection.
  • Teriflunomide In vivo, Leflunomide is quickly transformed in its active metabolite Teriflunomide that exerts its anti-inflammatory, antiproliferative and immunosuppressive effects via mechanisms that are not completely understood. Teriflunomide is not only a potential inhibitor of protein tyrosine kinase in vivo but a 100-1,000-fold greater inhibitor of DHODH (Davis J.P et al. FASEB J 1996, 10(6): Abst C23; Davis J.P et al. Biochemistry 1996, 35: 1270-3).
  • immunosuppressive agents that are further useful in a wide variety of autoimmune and chronic inflammatory diseases, including systemic lupus erythematosus, chronic rheumatoid arthritis, multiple sclerosis, type I diabetes mellitus, inflammatory bowel diseases, biliary cirrhosis, uveitis and other disorders such as Crohn's diseases, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves ophthalmopathy, atopic dermatitis and asthma. They may also be useful as part of chemotherapeutic regimens for the treatment of cancers, lymphomas and leukemias, alone or in combination with antitumoral compounds well known by the one
  • the present invention relates to 3H-imidazo[4,5-b]pyridine derivatives as dihydroorotate oxygenase inhibitors (also known as Dihydroorotate dehydrogenase inhibitors). These derivatives may be useful as medicament in treatement of autoimmune and inflammatory disorders such as multiple sclerosis, rheumatoid arthritis and diseases like cancer.
  • Ri is hydroxy or amino
  • R 2 is optionally substituted aryl, optionally substituted heterocyclyl or -0-(CH 2 )i_ 2 aryl; wherein the substituent at each occurrence is one to four R 4 ;
  • R 3 is hydrogen, halogen, alkyl, alkoxy, amino, amide, cyano, carboxy or hydroxyl;
  • R 4 is halogen or -NHC(0)cycloalkyl
  • 'n' is an integer ranging from 1 to 4, both inclusive.
  • composition comprising 3H-imidazo[4,5-b]pyridine derivatives of formula (I) and processes for preparing thereof.
  • the invention relates to use of compounds of formula (I) and pharmaceutically acceptable salts thereof, including mixtures thereof in all ratios as a medicament, by inhibiting dihydroorotate oxygenase enzyme activity in treating autoimmune and inflammatory disorders such as multiple sclerosis, rheumatoid arthritis and diseases like cancer.
  • the present invention provides 3H-imidazo[4,5-b]pyridine derivatives as dihydroorotate oxygenase inhibitors.
  • These derivatives are useful as medicament in treatement of autoimmune and inflammatory disorders such as multiple sclerosis, rheumatoid arthritis and diseases like cancer.
  • Ri is hydroxy or amino
  • R 2 is optionally substituted aryl, optionally substituted heterocyclyl or -0-(CH 2 )i_ 2 aryl; wherein the substituent at each occurrence is one to four R 4 ;
  • R 3 is hydrogen, halogen, alkyl, alkoxy, amino, amide, cyano, carboxy or hydroxyl;
  • R 4 is halogen or -NHC(0)cycloalkyl;
  • 'n' is an integer ranging from 1 to 4, both inclusive.
  • R 2 is -0-CH 2 -aryl; in particular aryl is phenyl.
  • R 2 is optionally substituted aryl; in particular aryl is phenyl.
  • R 3 is hydrogen or halogen (such as fluoro).
  • the compounds of formula (I) is a compounds of formula (la)
  • the invention provides use of compounds of formula (I) or a pharmaceutically acceptable salt thereof, including mixtures thereof in all ratios as a medicament, by inhibiting dihydroorotate oxygenase enzyme activity in treating disorder like multiple sclerosis and other diseases such as inflammatory disorders, rheumatoid arthritis and cancer.
  • 3H-imidazo[4,5-b]pyridine derivatives of compounds of formula (I) of the present invention possess therapeutic role of inhibiting the dihydroorotate dehydrogenase (DHODH or DHOD) enzyme.
  • the compounds of formula (I) may be useful for treating and/or preventing, but not restricted to, autoimmune and chronic inflammatory diseases, including systemic lupus erythematosus, chronic rheumatoid arthritis, multiple sclerosis, type I diabetes mellitus, inflammatory bowel diseases, biliary cirrhosis, uveitis and other disorders such as Crohn's diseases, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves ophthalmopathy, atopic dermatitis and asthma.
  • autoimmune and chronic inflammatory diseases including systemic lupus erythe
  • the compounds of formula (I) and related formulae can be also useful as part of chemotherapeutic regimens for the treatment of cancers, lymphomas and leukemias alone or in combination with classic antitumoral compounds well known by the one skilled in the art. It is understood that substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skilled person in the art to result chemically stable compounds which can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
  • alkyl refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms; in particular alkyl is Ci-Cio alkyl group which may have 1 to 10 (inclusive) carbon atoms in it; in more particular alkyl is Ci-Ce alkyl group which may have 1 to 6 (inclusive) carbon atoms in it and in more preferred particular alkyl is Ci-C 4 alkyl group which may have 1 to 4 (inclusive) carbon atoms in it.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec -butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.
  • An alkyl group can be unsubstituted or substituted with one or more suitable groups.
  • Alkoxy- refers to the group Ak-O- or -O-Ak, where Ak is an alkyl group, as defined above.
  • Exemplary Ci-Cioalkyl group containing alkoxy- groups include but are not limited to methoxy, ethoxy, n-propoxy, 1-propoxy, n-butoxy and t-butoxy.
  • An alkoxy group can be unsubstituted or substituted with one or more suitable groups or having linear or branched chain of alkyl chain;
  • Amino refers to an -N- group, the nitrogen atom of said group being attached to a hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl or any suitable groups.
  • Representative examples of an amino group include, but are not limited to -NH 2 , -NHCH3 and -NH- cyclopropyl.
  • An amino group can be optionally substituted with one or more of the suitable groups.
  • Aryl refers to an optionally substituted monocylic or bicyclic aromatic carbocyclic ring system of about 6 to 14 carbon atoms.
  • Examples of a C 6 -Ci 4 aryl group include, but are not limited to phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl and acenaphthyl and the like.
  • Aryl group which can be optionally substituted with one or more suitable groups.
  • Cycloalkyl refers to a non-aromatic, saturated or unsaturated, monocyclic, bicyclic or polycyclic hydrocarbon ring system.
  • Representative examples of a cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl and the like.
  • a cycloalkyl can be unsubstituted or substituted with one or more suitable groups.
  • cyano refers to an -CN group.
  • Halogen or "halo” includes fluorine, chlorine, bromine and iodine.
  • Hydroxy or “Hydroxyl” refers to -OH group.
  • Heterocyclyl or “Heterocycloalkyl” refers to a non-aromatic, saturated or partially saturated, monocyclic or polycyclic ring system of 3 to 10 member having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(0) 2 , NH or C(O).
  • heterocyclyl groups include piperdinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,3- dioxolanyl, 1,4-dioxanyl, 3,4-dihydroquinolin-2(lH)-one, 4,5-dihydro-lH-azepino[5,4,3- cd]indol-6(3H)-one and the like.
  • a heterocyclyl group can be optionally substituted with one or more suitable groups.
  • Hetero atom refers to a sulfur, nitrogen or oxygen atom.
  • the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, for use in the treatment of inflammatory disorders and autoimmune diseases or overactive immune response. More preferably, the present invention relates to the use of compounds of formula (I) for the treatment of multiple sclerosis, rheumatoid arthritis and transplant rejection.
  • Further embodiments of the invention includes use of compounds of formula (I) or pharmaceutically acceptable derivatives and salts thereof, including mixtures thereof in all ratios as a medicament.
  • dihydroorotate dehydrogenase associated disorder is an autoimmune disorder or condition associated with an overactive immune response.
  • the present invention relates to a pharmaceutical formulation
  • a pharmaceutical formulation comprising at least one compound according to compounds of formula (I) and/or pharmaceutically acceptable derivatives and salts thereof, including mixtures thereof in all ratios, and at least one further active ingredient.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound according to compounds of formula (I) and/or pharmaceutically acceptable derivatives and salts thereof, including mixtures thereof in all ratios, eventually one further active ingredient, and excipients.
  • pharmaceutically acceptable salt or “pharmaceutically acceptable derivatives” is taken to mean an active ingredient, which comprises a compound of the formula (I) in the form of one of its salts, in particular if this salt form imparts improved pharmacokinetic properties on the active ingredient compared with the free form of the active ingredient or any other salt form of the active ingredient used earlier.
  • the pharmaceutically acceptable salt form of the active ingredient can also provide this active ingredient for the first time with a desired pharmacokinetic property which it did not have earlier and can even have a positive influence on the pharmacodynamics of this active ingredient with respect to its therapeutic efficacy in the body.
  • Examples of 'pharmaceutically acceptable salts' are salts of an amino group formed with inorganic acids such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, 4-methylbenzenesulfonate or p-toluenesulfonate salts.
  • inorganic acids such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, isonicotinate, acetate, lactate
  • Certain compounds of the invention can form pharmaceutically acceptable salts with various organic bases such as lysine, arginine, guanidine, diethanolamine or metformin.
  • Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium or zinc salts.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • composition refers to a composition(s) containing a therapeutically effective amount of at least one compound of formula (I) or its pharmaceutically acceptable salt; and a conventional pharmaceutically acceptable carrier.
  • the pharmaceutical composition(s) usually contain(s) about 1% to 99%, for example, about 5% to 75%, or from about 10% to about 30% by weight of the compound of formula (I) or pharmaceutically acceptable salts thereof.
  • the amount of the compound of formula (I) or pharmaceutically acceptable salts thereof in the pharmaceutical composition(s) can range from about 1 mg to about 1000 mg or from about 2.5 mg to about 500 mg or from about 5 mg to about 250 mg or in any range falling within the broader range of 1 mg to 1000 mg or higher or lower than the afore mentioned range.
  • pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
  • compositions can be adapted for administration via any desired suitable method, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods.
  • oral including buccal or sublingual
  • rectal nasal
  • topical including buccal, sublingual or transdermal
  • vaginal or parenteral including subcutaneous, intramuscular, intravenous or intradermal
  • parenteral including subcutaneous, intramuscular, intravenous or intradermal
  • compositions adapted for oral administration can be administered as separate units, such as, for example, capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or oil-in-water liquid emulsions or water- in-oil liquid emulsions.
  • the active- ingredient component in the case of oral administration as tablet or capsule, can be combined with an oral, non-toxic and pharmaceutically acceptable inert excipient, such as, for example, ethanol, glycerol, water and the like.
  • an oral, non-toxic and pharmaceutically acceptable inert excipient such as, for example, ethanol, glycerol, water and the like.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a pharmaceutical excipient comminuted in a similar manner, such as, for example, an edible carbohydrate, such as, for example, starch or mannitol.
  • a flavour, preservative, dispersant and dye may likewise be present.
  • Capsules are produced by preparing a powder mixture as described above and filling shaped gelatine shells therewith.
  • Glidants and lubricants such as, for example, highly disperse silicic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture before the filling operation.
  • a disintegrant or solubiliser such as, for example, agar-agar, calcium carbonate or sodium carbonate, may likewise be added in order to improve the availability of the medica-ment after the capsule has been taken.
  • suitable binders include starch, gelatine, natural sugars, such as, for example, glucose or beta-lactose, sweeteners made from maize, natural and synthetic rubber, such as, for example, acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • the lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • the disintegrants include, without being restricted thereto, starch, methylcellulose, agar, bentonite, xanthan gum and the like.
  • the tablets are formulated by, for example, preparing a powder mixture, granulating or dry-pressing the mixture, adding a lubricant and a disintegrant and pressing the entire mixture to give tablets.
  • a powder mixture is prepared by mixing the compound comminuted in a suitable manner with a diluent or a base, as described above, and optionally with a binder, such as, for example, carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, a dissolution retardant, such as, for example, paraffin, an absorption accelerator, such as, for example, a quaternary salt, and/or an absorbant, such as, for example, bentonite, kaolin or dicalcium phosphate.
  • a binder such as, for example, carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone
  • a dissolution retardant such as, for example, paraffin
  • an absorption accelerator such as, for example, a quaternary salt
  • an absorbant such as, for example, bentonite, kaolin or dicalcium phosphate.
  • the powder mixture can be granulated by wetting it with a binder, such as, for example, syrup, starch paste, acadia mucilage or solutions of cellulose or polymer materials and pressing it through a sieve.
  • a binder such as, for example, syrup, starch paste, acadia mucilage or solutions of cellulose or polymer materials
  • the powder mixture can be run through a tableting machine, giving lumps of non-uniform shape which are broken up to form granules.
  • the granules can be lubricated by addition of stearic acid, a stearate salt, talc or mineral oil in order to prevent sticking to the tablet casting moulds. The lubricated mixture is then pressed to give tablets.
  • the active ingredients can also be combined with a free-flowing inert excipient and then pressed directly to give tablets without carrying out the granulation or dry-pressing steps.
  • a transparent or opaque protective layer consisting of a shellac sealing layer, a layer of sugar or polymer material and a gloss layer of wax may be present. Dyes can be added to these coatings in order to be able to differentiate between different dosage units.
  • Oral liquids such as, for example, solution, syrups and elixirs, can be prepared in the form of dosage units so that a given quantity comprises a pre-specified amount of the compounds.
  • Syrups can be prepared by dissolving the compounds in an aqueous solution with a suitable flavour, while elixirs are prepared using a non-toxic alcoholic vehicle.
  • Suspensions can be for-mulated by dispersion of the compounds in a non-toxic vehicle.
  • Solubilisers and emulsifiers such as, for example, ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavour additives, such as, for example, peppermint oil or natural sweeteners or saccharin, or other artificial sweeteners and the like, can likewise be added.
  • the dosage unit formulations for oral administration can, if desired, be encapsulated in microcapsules.
  • the formulation can also be prepared in such a way that the release is extended or retarded, such as, for example, by coating or embedding of particulate material in polymers, wax and the like.
  • 3H-imidazo[4,5-b]pyridine derivatives of formula (I) and its pharmaceutically acceptable salts and physiologically functional derivatives thereof and the other active ingredients can also be administered in the form of liposome delivery systems, such as, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from suitable lipids or phospholipids or both, such as, for example, cholesterol, stearylamine or phosphatidylcholines or the like.
  • Pharmaceutical formulations adapted for transdermal administration can be administered as independent plasters for extended, close contact with the epidermis of the recipient.
  • the active ingredient can be delivered from the plaster by iontophoresis, as described in general terms in Pharmaceutical Research, 3(6), 318 (1986).
  • Pharmaceutical compounds adapted for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the formulations are preferably applied as topical ointment or cream.
  • the active ingredient can be employed either with a paraffinic or a water - miscible cream base.
  • the active ingredient can be formulated to give a cream with an oil-in-water cream base or a water-in-oil base.
  • compositions adapted for topical application to the eye include eye drops, in which the active ingredient is dissolved or sus-pended in a suitable carrier, in particular an aqueous solvent.
  • compositions adapted for topical application in the mouth encompass lozenges, pastilles and mouthwashes.
  • compositions adapted for rectal administration can be administered in the form of suppositories or enemas.
  • compositions adapted for nasal administration in which the carrier substance is a solid comprise a coarse powder having a particle size, for example, in the range 20-500 microns, which is administered in the manner in which snuff is taken, i.e. by rapid inhalation via the nasal passages from a container containing the powder held close to the nose.
  • suitable formulations for administration as nasal spray or nose drops with a liquid as carrier substance encompass active-ingredient solutions in water or oil.
  • compositions adapted for administration by inhalation encompass finely particulate dusts or mists, which can be generated by various types of pressurised dispensers with aerosols, nebulisers or insuf-flators.
  • compositions adapted for vaginal administration can be administered as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions comprising antioxidants, buffers, bacteriostatics and solutes, by means of which the formulation is rendered isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions, which may comprise suspension media and thickeners.
  • the formulations can be administered in single-dose or multidose containers, for example sealed ampoules and vials, and stored in freeze-dried (lyophilised) state, so that only the addition of the sterile carrier liquid, for example water for injection purposes, immediately before use is necessary.
  • sterile carrier liquid for example water for injection purposes
  • Injection solutions and suspensions prepared in accordance with the recipe can be prepared from sterile powders, granules and tablets.
  • formulations may also comprise other agents usual in the art with respect to the particular type of formulation; thus, for example, formulations which are suitable for oral administration may comprise flavours.
  • a therapeutically effective amount of a compound of the formula (I) and of the other active ingredient depends on a number of factors, including, for example, the age and weight of the animal, the precise disease condition which requires treatment, and its severity, the nature of the formulation and the method of administration, and is ultimately determined by the treating doctor or vet.
  • an effective amount of a compound is generally in the range from 0.1 to 100 mg/kg of body weight of the recipient (mammal) per day and particularly typically in the range from 1 to 10 mg/kg of body weight per day.
  • the actual amount per day for an adult mammal weighing 70 kg is usually between 70 and 700 mg, where this amount can be administered as an individual dose per day or usually in a series of part-doses (such as, for example, two, three, four, five or six) per day, so that the total daily dose is the same.
  • An effective amount of a salt or solvate or of a physiologically functional derivative thereof can be determined as the fraction of the effective amount of the compound per se.
  • the present invention relates to a process for preparing 3H- imidazo[4,5-b]pyridine derivatives of compounds of formula (I).
  • the dihydroorotate dehydrogenase inhibitors according to formula (I) may be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimisation procedures. Moreover, by utilizing the procedures described in detail, one of ordinary skill in the art can prepare additional compounds of the present invention claimed herein. All temperatures are in degrees Celsius (°C) unless otherwise noted.
  • the compounds of the present invention can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the present invention also embraces isotopically-labeled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses.
  • Exemplary isotopes that can be incorporated in to compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as 2 H ("D"), 3 H, U C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 32 P, 33 P, 35 S, 18 F, 36 C1, 123 I and 125 I.
  • Isotopically labeled compounds of the present inventions can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • Another embodiment of the present invention provides process for preparation of the compounds of general formula (I) are set forth in the below Examples and generalized scheme-I.
  • Scheme I can be adapted to produce the compounds of general formula (I) and pharmaceutically acceptable salts of compounds of general formula (I) according to the present invention. Wherein all symbols/variables are as defined earlier unless otherwise stated.
  • Step-a Compounds of general formula-2 can be prepared by reacting with compounds of general formula- 1 (wherein X is chloro) and appropriate aldehyde using the conditions that are described in General procedure-A.
  • Step-b Compounds of general formula-2 can further be subjected to carbonation in presence of palladium catalyst using the conditions that are described in General procedure-B to afford compounds of general formula-3.
  • Step-e Compounds of general formula-6 can be prepared by reacting with compounds of general formula- 1 (wherein X is methyl) and appropriate aldehyde using the conditions that are described in General procedure-A.
  • compositions of this invention can be isolated in association with solvent molecules by crystallization from evaporation of an appropriate solvent.
  • the pharmaceutically acceptable acid addition salts of the compounds of general formula (I), which contain a basic center may be prepared in a conventional manner. For example, a solution of the free base may be treated with a suitable acid, either neat or in a suitable solution, and the resulting salt isolated either by filtration or by evaporation under vacuum of the reaction solvent.
  • Pharmaceutically acceptable base addition salts may be obtained in an analogous manner by treating a solution of compound of general formula (I) with a suitable base. Both types of salts may be formed or interconverted using ion-exchange resin techniques.
  • MS data provided in the examples described below were obtained as followed: Mass spectrum: LC/MS Waters ZMD (ESI) or a Waters Acquity SQD (ESI).
  • Step-i Synthesis of 4-chloro-3-nitropyridin-2-amine.
  • Step-ii Synthesis of 4-chloropyridine-2,3-diamine.
  • the resulting reaction mixture is stirred at reflux temperature in the presence of carbon monoxide gas at (70-90 psi preferably 90 psi) for 12h .
  • the reaction mixture is cooled to RT, filtered through a Celite ® pad and washed with organic solvent.
  • the combined filtrates are concentrated under reduced pressure.
  • the product is purified by crystallization or trituration from an appropriate solvent or solvents or by preparative HPLC or flash chromatography.
  • Example-I Synthesis of 2-(4'-(cyclopropanecarboxamido)-rU'-biphenyll-4-yl)-3H-imidazo r4,5-blpyridine-7-carboxylic acid (Com ound- 1).
  • Example-II Synthesis of 2-(4'-(cvclopropanecarboxamido)-riJ'-biphenyll-4-yl)-3H-imidazo r4,5-bl yridine-7-carboxamide (Compound-2).
  • reaction mixture was then stirred at about 25°C for 12h and the progress of the reaction was monitored by TLC.
  • the reaction mixture was quenched with water (50 mL).
  • the separated solid was collected by filtration and dried under vacuum to obtain the desired compound as brown solid (0.09 g, 70%).
  • Example-Ill Synthesis of 2-(rU'-biphenyll-4-yl)-3H-imidazor4,5-blpyridine-7-carboxylic acid (Compound-3 .
  • Example-IV Synthesis of 2-(4-(6-oxo-3 A5,6-tetrahydro-lH-azepinor5 A3-cdlindol-2-yl) phenyl) - 3 H-imidazo ⁇ 4 ,5 -bl pyridine-7 -carboxylic acid . 2,2,2-trifluoroacetic acid (Compound- 181
  • Step-i Synthesis of N-(3-amino-4-methylpyridin-2-yl)-4-bromobenzamide.
  • Step-ii Synthesis of 2-(4-bromophenyl)-7-methyl-3H-imidazo ⁇ 4, 5-bl pyridine.
  • N-(3-amino-4-methylpyridin-2-yl)-4-bromobenzamide (0.95 g, 3.1 mmol) was dissolved in acetic acid (20 mL) and heated 130°C for 12h. The progress of the reaction was monitored by TLC and after the completion of the reaction solvent was removed added water (100 mL). The separated solid was collected by filtration and dried under vacuum to obtain the get the desired compound as brown solid (0.7 g, 78%).
  • Step-iii Synthesis of 2-(4-bromophenyl)-3H-imidazor4,5-blpyridine-7-carboxylic acid.
  • Step-iv Synthesis of methyl 2-(4-bromophenyl)-3H-imidazo ⁇ 4, 5-bl pyridine-7-carboxylate.
  • Step-v Synthesis of methyl 2-(4-(4, 4, 5, 5-tetramethyl- 3, 2-dioxaborolan-2-yl) phenyl)- 3H-imidazo ⁇ 4, 5-bl pyridine-7-carboxylate:
  • the DHODH activity assay is a coupled enzyme assay in which oxidation of DHO and subsequent reduction of ubiquinone are stoichiometrically equivalent to the reduction of DCIP (2,6-dichlorophenol).
  • the reduction of DCIP is accompanied by a loss of absorbance at 610 nm.
  • Buffer Preparation 50 mM tris HC1, 150 mM KC1, and pH 8.0, 0.8% triton.
  • Protein along with buffer was added, so that the total volume including the DMSO was 87 ⁇ L ⁇ .
  • Compound and protein were incubated for half an hour at room temperature after mixing. 5 ⁇ ⁇ of 20 mM solution of L-Dihydroorotic acid, 5 ⁇ ⁇ of 2 mM solution of Decylubiquinone and 3 ⁇ ⁇ of 2 mM solution of 2, 6-Dichloroindophenol sodium salt hydrate were added to the above solution (total assay volume 100 ⁇ ). The mixture was stirred for 2 min and absorbance was recorded at every 10 min at 610 nanometers.
  • Reaction containing compound has compound, buffer, enzyme and substrates.
  • Positive control contains DMSO, buffer, enzyme and substrates.
  • No Enzyme reaction contains DMSO, buffer and substrates.
  • a 2 mM DMSO stock solution of the selected compound of formula (I) of the present invention to be examined was prepared. Subsequent l/3rd dilutions were made.
  • IC50 values of the selected compounds of present invention were provided in below table. Compounds exhibiting IC50 values ⁇ 300 nM were grouped as 'a' and the compounds exhibiting IC50 value >300 nM were grouped as 'b' .

Abstract

The present invention provides 3H-imidazo[4,5-b]pyridine derivatives as dihydroorotate oxygenase inhibitor compounds of formula (I) wherein, R1, R2, R3 and 'n' have the meanings given in the specification, and pharmaceutically acceptable salts thereof that are useful in the treatment and prevention in diseases or disorder, where there is an advantage in inhibiting DHODH. The present invention also provides methods for synthesizing 3H-imidazo[4,5-b]pyridine derivatives of formula (I). The present invention also provides pharmaceutical formulations comprising at least one of the DHODH inhibitory compound of formula (I) together with a pharmaceutically acceptable carrier, diluent or excipient.

Description

"3H-IMIDAZO[4,5-b]PYRIDINE DERIVATIVES AS DIHYDROOROTATE
DEHYDROGENASE INHIBITORS"
This application claims the benefit of Indian provisional application number 2192/CHE/2014 filed on 30th April, 2014 which hereby incorporated by reference.
FIELD OF INVENTION
The present invention relates to novel 3H-imidazo[4,5-b]pyridine derivatives of formula (I) which are inhibitors of dihydroorotate dehydrogenase. In particular, the invention refers to novel compounds, which inhibits DHODH enzyme activity, to a process for their manufacture and pharmaceutical compositions containing them, and to their use for the treatment and prevention in diseases or disorder, in particular their use in diseases or disorder where there is an advantage in inhibiting DHODH.
BACKGROUND OF THE INVENTION
DHODH is a protein that catalyzes one of the steps in denovo pyrimidine nucleotide biosynthetic pathway. (Greene et al. Biochem Pharmacol 1995, 50:861-7; Davis J.P et al. FASEB J 1996, 10(6): Abst C23). It catalyzes the only oxidation/reduction reaction in that pathway, which is the step of converting DHO (dihydroorotate) to orotate with the aid of flavin cofactor and an electron acceptor. Inhibitors of dihydroorotate dehydrogenase have been found to possess wider applications as chemotherapeutic agents. (Kensler et al. 1989 in: Design of Enzyme Inhibitors as Drugs; Sandler, M., and Smith, H. J. Eds., pp 379-401 Oxford Univ Press, Oxford England; Cody et al. Am. J. Clin. Oncol. 16, 526-528 (1993)).
As an example for DHODH inhibitors, the quinoline derivative Brequinar (6-Fluoro- 2-(2'-fluoro[l, -biphenyl]-4-yl)-3-methyl-4-quinolinecarboxylic acid) exhibits an anticancer activity towards L1210 murine leukemia (Andreson LW. Et al.Cancer Commun. 1989; 1(6), 381-7; Chen SF. et al. Cancer Res. 1986 Oct; 46 (10): 5014-9). It has also been shown that Brequinar potentiates 5-fluorouracil antitumor activity in a murine model colon 38 tumor by tissue-specific modulation of uridine nucleotide pools. (G Pizzorno et al. Cancer Res. 1992 Apr 1; 52: 1660-5).
DHODH inhibitors may also be useful in the treatment of viral mediated diseases (see US 6,841,561). Furthermore, inhibition of DHODH is known to be among promising target for treating transplant rejection, rheumatoid arthritis, psoriasis as well as autoimmune diseases (Kovarik, J. M. et al. Expert Opin. Emerg. Drugs 2003, 8, 47; Allison, A.C. Transplantation Proc. (1993) 25(3) Suppl. 2, 8-18); Makowka, L., Immunolog Rev. (1993) 136, 51-70; Davis J.P et al. Biochemistry 1996, 35: 1270-3). Leflunomide, a well known DHODH inhibitor is a synthetic drug currently marketed, a low-molecular weight drug of the isoxazole class (see EP0527736, JP1993506425, JP1999322700, JP1999343285, US5494911, US5532259, WO19991017748) and used in the treatment of Rheumatoid arthritis and is also under evaluation for use in the treatment of inflammatory bowel disease and chronic allograft rejection.
In vivo, Leflunomide is quickly transformed in its active metabolite Teriflunomide that exerts its anti-inflammatory, antiproliferative and immunosuppressive effects via mechanisms that are not completely understood. Teriflunomide is not only a potential inhibitor of protein tyrosine kinase in vivo but a 100-1,000-fold greater inhibitor of DHODH (Davis J.P et al. FASEB J 1996, 10(6): Abst C23; Davis J.P et al. Biochemistry 1996, 35: 1270-3).
With the rise in number of patients affected by autoimmune and related diseases, there is unmet need for new drugs that can treat such diseases more effectively. There is still a crucial need for immunosuppressive agents, that are further useful in a wide variety of autoimmune and chronic inflammatory diseases, including systemic lupus erythematosus, chronic rheumatoid arthritis, multiple sclerosis, type I diabetes mellitus, inflammatory bowel diseases, biliary cirrhosis, uveitis and other disorders such as Crohn's diseases, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves ophthalmopathy, atopic dermatitis and asthma. They may also be useful as part of chemotherapeutic regimens for the treatment of cancers, lymphomas and leukemias, alone or in combination with antitumoral compounds well known by the one skilled in the art.
SUMMARY OF THE INVENTION
The present invention relates to 3H-imidazo[4,5-b]pyridine derivatives as dihydroorotate oxygenase inhibitors (also known as Dihydroorotate dehydrogenase inhibitors). These derivatives may be useful as medicament in treatement of autoimmune and inflammatory disorders such as multiple sclerosis, rheumatoid arthritis and diseases like cancer.
In one aspect of the present invention relates to com ounds of formula (I)
Figure imgf000003_0001
or a pharmaceutically acceptable salt thereof; wherein,
Ri is hydroxy or amino;
R2 is optionally substituted aryl, optionally substituted heterocyclyl or -0-(CH2)i_2 aryl; wherein the substituent at each occurrence is one to four R4;
R3 is hydrogen, halogen, alkyl, alkoxy, amino, amide, cyano, carboxy or hydroxyl;
R4 is halogen or -NHC(0)cycloalkyl;
'n' is an integer ranging from 1 to 4, both inclusive.
In another aspect of the present invention, it relates to process for preparation of 3H- imidazo[4,5-b]pyridine derivatives of formula (I).
In a yet another aspect of the present invention, it relates to pharmaceutical composition comprising 3H-imidazo[4,5-b]pyridine derivatives of formula (I) and processes for preparing thereof.
In yet further another aspect of the present invention, the invention relates to use of compounds of formula (I) and pharmaceutically acceptable salts thereof, including mixtures thereof in all ratios as a medicament, by inhibiting dihydroorotate oxygenase enzyme activity in treating autoimmune and inflammatory disorders such as multiple sclerosis, rheumatoid arthritis and diseases like cancer.
DETAILED DESCRIPTION OF THE INVENTION
In an embodiment, the present invention provides 3H-imidazo[4,5-b]pyridine derivatives as dihydroorotate oxygenase inhibitors.
These derivatives are useful as medicament in treatement of autoimmune and inflammatory disorders such as multiple sclerosis, rheumatoid arthritis and diseases like cancer.
In a particular embodiment the present invention provides compounds of formula (I),
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof;
wherein,
Ri is hydroxy or amino;
R2 is optionally substituted aryl, optionally substituted heterocyclyl or -0-(CH2)i_2 aryl; wherein the substituent at each occurrence is one to four R4;
R3 is hydrogen, halogen, alkyl, alkoxy, amino, amide, cyano, carboxy or hydroxyl; R4 is halogen or -NHC(0)cycloalkyl;
'n' is an integer ranging from 1 to 4, both inclusive.
The embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified.
According to one embodiment, specifically provided are compounds of formula (I), in which Ri is hydroxy or amino.
According to another embodiment, specifically provided are compounds of formula (I), in which R2 is -0-CH2-aryl; in particular aryl is phenyl.
According to another embodiment, specifically provided are com ounds of formula
(I), in which R2 is heterocyclyl; in particluar heterocyclyl is
Figure imgf000005_0001
According to another embodiment, specifically provided are compounds of formula (I), in which R2 is optionally substituted aryl; in particular aryl is phenyl.
According to the preceding embodiment, specifically provided are compounds of formula (I), wherein the optionally substituent is one to two R4; in which R4 is halogen (such
O as fluoro) or -NHC(0)cycloalkyl (such as H V )
According to yet another embodiment, specifically provided are compounds of formula (I), in which R3 is hydrogen or halogen (such as fluoro).
According to another embodiment, it specifically provided are compounds of the formula (I), in which 'n' is T.
According to yet another particular embodiment, the compounds of formula (I) is a compounds of formula (la)
Figure imgf000005_0002
wherein, Ri, R3 and R4 are same as described in compounds of formula (I).
In another embodiment of the present invention, it provides the process preparation of 3H-imidazo[4,5-b]pyridine derivatives of compounds of formula (I). The procedure for the compounds of formula (I) is detailed herein below in the specification stepwise including the general synthesis of various intermediates involved in process of manufacture of the compounds according to the present invention.
More particularly, the invention provides use of compounds of formula (I) or a pharmaceutically acceptable salt thereof, including mixtures thereof in all ratios as a medicament, by inhibiting dihydroorotate oxygenase enzyme activity in treating disorder like multiple sclerosis and other diseases such as inflammatory disorders, rheumatoid arthritis and cancer.
3H-imidazo[4,5-b]pyridine derivatives of compounds of formula (I) of the present invention possess therapeutic role of inhibiting the dihydroorotate dehydrogenase (DHODH or DHOD) enzyme. The compounds of formula (I) may be useful for treating and/or preventing, but not restricted to, autoimmune and chronic inflammatory diseases, including systemic lupus erythematosus, chronic rheumatoid arthritis, multiple sclerosis, type I diabetes mellitus, inflammatory bowel diseases, biliary cirrhosis, uveitis and other disorders such as Crohn's diseases, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves ophthalmopathy, atopic dermatitis and asthma. The compounds of formula (I) and related formulae can be also useful as part of chemotherapeutic regimens for the treatment of cancers, lymphomas and leukemias alone or in combination with classic antitumoral compounds well known by the one skilled in the art. It is understood that substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skilled person in the art to result chemically stable compounds which can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
Without limiting the scope of present invention, the following definitions are provided in order to aid those skilled in the art in understanding the detailed description of the present invention. The term "or" means "and/or" unless stated otherwise.
The term "including" as well as other forms, such as "include", "includes" and "included" is not limiting. The term "Alkyl" refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms; in particular alkyl is Ci-Cio alkyl group which may have 1 to 10 (inclusive) carbon atoms in it; in more particular alkyl is Ci-Ce alkyl group which may have 1 to 6 (inclusive) carbon atoms in it and in more preferred particular alkyl is Ci-C4 alkyl group which may have 1 to 4 (inclusive) carbon atoms in it. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec -butyl, tert-butyl, isopentyl, neopentyl, and isohexyl. An alkyl group can be unsubstituted or substituted with one or more suitable groups.
"Alkoxy-" refers to the group Ak-O- or -O-Ak, where Ak is an alkyl group, as defined above. Exemplary Ci-Cioalkyl group containing alkoxy- groups include but are not limited to methoxy, ethoxy, n-propoxy, 1-propoxy, n-butoxy and t-butoxy. An alkoxy group can be unsubstituted or substituted with one or more suitable groups or having linear or branched chain of alkyl chain;
"Amino" refers to an -N- group, the nitrogen atom of said group being attached to a hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl or any suitable groups. Representative examples of an amino group include, but are not limited to -NH2, -NHCH3 and -NH- cyclopropyl. An amino group can be optionally substituted with one or more of the suitable groups.
"Aryl" refers to an optionally substituted monocylic or bicyclic aromatic carbocyclic ring system of about 6 to 14 carbon atoms. Examples of a C6-Ci4 aryl group include, but are not limited to phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl and acenaphthyl and the like. Aryl group which can be optionally substituted with one or more suitable groups.
The term "Cycloalkyl" refers to a non-aromatic, saturated or unsaturated, monocyclic, bicyclic or polycyclic hydrocarbon ring system. Representative examples of a cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl and the like. A cycloalkyl can be unsubstituted or substituted with one or more suitable groups.
"cyano" refers to an -CN group.
"Halogen" or "halo" includes fluorine, chlorine, bromine and iodine.
"Hydroxy" or "Hydroxyl" refers to -OH group.
The term "Heterocyclyl" or "Heterocycloalkyl" refers to a non-aromatic, saturated or partially saturated, monocyclic or polycyclic ring system of 3 to 10 member having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(0)2, NH or C(O). Exemplary heterocyclyl groups include piperdinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,3- dioxolanyl, 1,4-dioxanyl, 3,4-dihydroquinolin-2(lH)-one, 4,5-dihydro-lH-azepino[5,4,3- cd]indol-6(3H)-one and the like. A heterocyclyl group can be optionally substituted with one or more suitable groups.
"Hetero atom" refers to a sulfur, nitrogen or oxygen atom.
"Optionally substituted or unsubstituted" as used herein means that at least one hydrogen atom of the optionally substituted group has been substituted with suitable substitutions as exemplified but not limited to (Ci-Ce) alkyl, (Ci-Ce) alkoxy, amino, carboxy (-COOH), halogen, nitro, cyano, hydroxy, oxo (=0), -N(Ci-C3alkyl)C(0)(Ci-C6alkyl), - NHC(0)(Ci-C6alkyl), -NHC(0)(cycloalkyl), -NHC(0)(aryl), -NHC(0)(heterocyclyl), - NHC(0)H, -C(0)NH2, -C(0)NH(aryl), -C(0)NH(Ci-C6alkyl), -C(0)NH(cycloalkyl) or - C(0)NH(heterocyclyl).
The particular compounds of the present invention without departing from the scope of the definitions given under compounds of formula (I) and particular compounds emanated from compounds of formula (I) are summarized herein below.
2-(4'-(cyclopropanecarboxamido)-[l, -biphenyl]-4-yl)-3H-imidazo[4,5-b]pyridine-7- carboxylic acid (Compound- 1);
2-(4'-(cyclopropanecarboxamido)-[l, -biphenyl]-4-yl)-3H-imidazo[4,5-b]pyridine-7- carboxamide (Compound-2);
2-([l, -biphenyl]-4-yl)-3H-imidazo[4,5-b]pyridine-7-carboxylic acid (Compound-3);
2-([l, -biphenyl]-4-yl)-3H-imidazo[4,5-b]pyridine-7-carboxamide (Compound-4);
2-(3-fluoro-[l, -biphenyl]-4-yl)-3H-imidazo[4,5-b]pyridine-7-carboxylic acid (Compound-5);
2-(3-fluoro-[l, -biphenyl]-4-yl)-3H-imidazo[4,5-b]pyridine-7-carboxamide
(Compound-6);
2-(4'-(cyclopropanecarboxamido)-3-fluoro-[l, -biphenyl]-4-yl)-3H-imidazo[4,5- b]pyridine-7-carboxylic acid (Compound-7);
2-(2',3-difluoro- [1,1 '-biphenyl] -4-yl)-3H-imidazo[4,5-b]pyridine-7-carboxylic acid (Compound-8);
2-(4'-(cyclopropanecarboxamido)-2',3-difluoro-[l, -biphenyl]-4-yl)-3H-imidazo[4,5- b]pyridine-7-carboxylic acid (Compound-9);
2-(4'-(cyclopropanecarboxamido)-2',3-difluoro-[l, -biphenyl]-4-yl)-3H-imidazo[4,5- b]pyridine-7-carboxamide (Compound- 10);
2-(2'-(cyclopropanecarboxamido)-3-fluoro-[l, -biphenyl]-4-yl)-3H-imidazo[4,5-b] pyridine-7-carboxylic acid (Compound- 11); 2-(2'-(cyclopropanecarboxamido)-3-fluoro-[l, -biphenyl]-4-yl)-3H-imidazo[4,5-b] pyridine-7-carboxamide (Compound- 12);
2-(3'-(cyclopropanecarboxamido)-3-fluoro-[l, -biphenyl]-4-yl)-3H-imidazo[4,5-b] pyridine-7-carboxylic acid (Compound- 13);
2-(3'-(cyclopropanecarboxamido)-3-fluoro-[l, -biphenyl]-4-yl)-3H-imidazo[4,5-b] pyridine-7-carboxamide (Compound- 14);
2-(2-fluoro-4-(2-oxo-l,2,3,4-tetrahydroquinolin-7-yl)phenyl)-3H-imidazo[4,5-b] pyridine-7-carboxylic acid (Compound- 15);
2-(4-(benzyloxy)phenyl)-3H-imidazo[4,5-b]pyridine-7-carboxylic acid (Compound- 16);
2-(4-(benzyloxy)phenyl)-3H-imidazo[4,5-b]pyridine-7-carboxamide (Compound- 17); and
2-(4-(6-oxo-3,4,5,6-tetrahydro-lH-azepino[5,4,3-cd]indol-2-yl)phenyl)-3H-imidazo [4,5-b]pyridine-7-carboxylic acid (Compound- 18),
or a pharmaceutically acceptable salt thereof.
In yet another embodiment, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, for use in the treatment of inflammatory disorders and autoimmune diseases or overactive immune response. More preferably, the present invention relates to the use of compounds of formula (I) for the treatment of multiple sclerosis, rheumatoid arthritis and transplant rejection.
Further embodiments of the invention includes use of compounds of formula (I) or pharmaceutically acceptable derivatives and salts thereof, including mixtures thereof in all ratios as a medicament.
Use of compounds of formula (I) as above or pharmaceutically acceptable derivatives and salts thereof, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment and/or prophylaxis of a dihydroorotate dehydrogenase associated disease or disorder.
Use of compounds as above wherein the dihydroorotate dehydrogenase associated disorder is an autoimmune disorder or condition associated with an overactive immune response.
Use of compounds of formula (I) as above and pharmaceutically acceptable derivatives and salts thereof, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment and/or prophylaxis of an immunoregulatory abnomality. Use of compounds as above wherein the immunoregulatory abnormality is multiple sclerosis or rheumatoid arthritis.
Use of compounds of formula (I) as above and pharmaceutically acceptable derivatives and salts thereof, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment and prophylaxis of cancer diseases or inflammatory bowel disease.
In a further embodiment, the present invention relates to a pharmaceutical formulation comprising at least one compound according to compounds of formula (I) and/or pharmaceutically acceptable derivatives and salts thereof, including mixtures thereof in all ratios, and at least one further active ingredient.
The present invention further provides a pharmaceutical composition comprising at least one compound according to compounds of formula (I) and/or pharmaceutically acceptable derivatives and salts thereof, including mixtures thereof in all ratios, eventually one further active ingredient, and excipients.
The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable derivatives" is taken to mean an active ingredient, which comprises a compound of the formula (I) in the form of one of its salts, in particular if this salt form imparts improved pharmacokinetic properties on the active ingredient compared with the free form of the active ingredient or any other salt form of the active ingredient used earlier. The pharmaceutically acceptable salt form of the active ingredient can also provide this active ingredient for the first time with a desired pharmacokinetic property which it did not have earlier and can even have a positive influence on the pharmacodynamics of this active ingredient with respect to its therapeutic efficacy in the body. Examples of 'pharmaceutically acceptable salts' are salts of an amino group formed with inorganic acids such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, 4-methylbenzenesulfonate or p-toluenesulfonate salts. Certain compounds of the invention (compound of formula (I)) can form pharmaceutically acceptable salts with various organic bases such as lysine, arginine, guanidine, diethanolamine or metformin. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium or zinc salts. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
As used herein, the term "pharmaceutical composition" refers to a composition(s) containing a therapeutically effective amount of at least one compound of formula (I) or its pharmaceutically acceptable salt; and a conventional pharmaceutically acceptable carrier.
The pharmaceutical composition(s) usually contain(s) about 1% to 99%, for example, about 5% to 75%, or from about 10% to about 30% by weight of the compound of formula (I) or pharmaceutically acceptable salts thereof. The amount of the compound of formula (I) or pharmaceutically acceptable salts thereof in the pharmaceutical composition(s) can range from about 1 mg to about 1000 mg or from about 2.5 mg to about 500 mg or from about 5 mg to about 250 mg or in any range falling within the broader range of 1 mg to 1000 mg or higher or lower than the afore mentioned range.
The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. The term "subject" refers to an animal, preferably a mammal, and most preferably a human.
Pharmaceutical formulations can be adapted for administration via any desired suitable method, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods. Such formulations can be prepared using all processes known in the pharmaceutical art by, for example, combining the active ingredient with the excipient(s) or adjuvant(s).
Pharmaceutical formulations adapted for oral administration can be administered as separate units, such as, for example, capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or oil-in-water liquid emulsions or water- in-oil liquid emulsions.
For example, in the case of oral administration as tablet or capsule, the active- ingredient component can be combined with an oral, non-toxic and pharmaceutically acceptable inert excipient, such as, for example, ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a pharmaceutical excipient comminuted in a similar manner, such as, for example, an edible carbohydrate, such as, for example, starch or mannitol. A flavour, preservative, dispersant and dye may likewise be present.
Capsules are produced by preparing a powder mixture as described above and filling shaped gelatine shells therewith. Glidants and lubricants, such as, for example, highly disperse silicic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture before the filling operation. A disintegrant or solubiliser, such as, for example, agar-agar, calcium carbonate or sodium carbonate, may likewise be added in order to improve the availability of the medica-ment after the capsule has been taken.
In addition, if desired or necessary, suitable binders, lubricants and disintegrants as well as dyes can likewise be incorporated into the mixture. Suitable binders include starch, gelatine, natural sugars, such as, for example, glucose or beta-lactose, sweeteners made from maize, natural and synthetic rubber, such as, for example, acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. The lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. The disintegrants include, without being restricted thereto, starch, methylcellulose, agar, bentonite, xanthan gum and the like. The tablets are formulated by, for example, preparing a powder mixture, granulating or dry-pressing the mixture, adding a lubricant and a disintegrant and pressing the entire mixture to give tablets. A powder mixture is prepared by mixing the compound comminuted in a suitable manner with a diluent or a base, as described above, and optionally with a binder, such as, for example, carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, a dissolution retardant, such as, for example, paraffin, an absorption accelerator, such as, for example, a quaternary salt, and/or an absorbant, such as, for example, bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting it with a binder, such as, for example, syrup, starch paste, acadia mucilage or solutions of cellulose or polymer materials and pressing it through a sieve. As an alternative to granulation, the powder mixture can be run through a tableting machine, giving lumps of non-uniform shape which are broken up to form granules. The granules can be lubricated by addition of stearic acid, a stearate salt, talc or mineral oil in order to prevent sticking to the tablet casting moulds. The lubricated mixture is then pressed to give tablets. The active ingredients can also be combined with a free-flowing inert excipient and then pressed directly to give tablets without carrying out the granulation or dry-pressing steps. A transparent or opaque protective layer consisting of a shellac sealing layer, a layer of sugar or polymer material and a gloss layer of wax may be present. Dyes can be added to these coatings in order to be able to differentiate between different dosage units.
Oral liquids, such as, for example, solution, syrups and elixirs, can be prepared in the form of dosage units so that a given quantity comprises a pre-specified amount of the compounds. Syrups can be prepared by dissolving the compounds in an aqueous solution with a suitable flavour, while elixirs are prepared using a non-toxic alcoholic vehicle. Suspensions can be for-mulated by dispersion of the compounds in a non-toxic vehicle. Solubilisers and emulsifiers, such as, for example, ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavour additives, such as, for example, peppermint oil or natural sweeteners or saccharin, or other artificial sweeteners and the like, can likewise be added.
The dosage unit formulations for oral administration can, if desired, be encapsulated in microcapsules. The formulation can also be prepared in such a way that the release is extended or retarded, such as, for example, by coating or embedding of particulate material in polymers, wax and the like.
3H-imidazo[4,5-b]pyridine derivatives of formula (I) and its pharmaceutically acceptable salts and physiologically functional derivatives thereof and the other active ingredients can also be administered in the form of liposome delivery systems, such as, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from suitable lipids or phospholipids or both, such as, for example, cholesterol, stearylamine or phosphatidylcholines or the like. Pharmaceutical formulations adapted for transdermal administration can be administered as independent plasters for extended, close contact with the epidermis of the recipient. Thus, for example, the active ingredient can be delivered from the plaster by iontophoresis, as described in general terms in Pharmaceutical Research, 3(6), 318 (1986).
Pharmaceutical compounds adapted for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
For the treatment of the eye or other external tissue, for example mouth and skin, the formulations are preferably applied as topical ointment or cream. In the case of formulation to give an ointment, the active ingredient can be employed either with a paraffinic or a water - miscible cream base. Alternatively, the active ingredient can be formulated to give a cream with an oil-in-water cream base or a water-in-oil base.
Pharmaceutical formulations adapted for topical application to the eye include eye drops, in which the active ingredient is dissolved or sus-pended in a suitable carrier, in particular an aqueous solvent.
Pharmaceutical formulations adapted for topical application in the mouth encompass lozenges, pastilles and mouthwashes.
Pharmaceutical formulations adapted for rectal administration can be administered in the form of suppositories or enemas.
Pharmaceutical formulations adapted for nasal administration in which the carrier substance is a solid comprise a coarse powder having a particle size, for example, in the range 20-500 microns, which is administered in the manner in which snuff is taken, i.e. by rapid inhalation via the nasal passages from a container containing the powder held close to the nose. Suitable formulations for administration as nasal spray or nose drops with a liquid as carrier substance encompass active-ingredient solutions in water or oil.
Pharmaceutical formulations adapted for administration by inhalation encompass finely particulate dusts or mists, which can be generated by various types of pressurised dispensers with aerosols, nebulisers or insuf-flators.
Pharmaceutical formulations adapted for vaginal administration can be administered as pessaries, tampons, creams, gels, pastes, foams or spray formulations. Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions comprising antioxidants, buffers, bacteriostatics and solutes, by means of which the formulation is rendered isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions, which may comprise suspension media and thickeners. The formulations can be administered in single-dose or multidose containers, for example sealed ampoules and vials, and stored in freeze-dried (lyophilised) state, so that only the addition of the sterile carrier liquid, for example water for injection purposes, immediately before use is necessary.
Injection solutions and suspensions prepared in accordance with the recipe can be prepared from sterile powders, granules and tablets.
It goes without saying that, in addition to the above particularly mentioned constituents, the formulations may also comprise other agents usual in the art with respect to the particular type of formulation; thus, for example, formulations which are suitable for oral administration may comprise flavours.
A therapeutically effective amount of a compound of the formula (I) and of the other active ingredient depends on a number of factors, including, for example, the age and weight of the animal, the precise disease condition which requires treatment, and its severity, the nature of the formulation and the method of administration, and is ultimately determined by the treating doctor or vet. However, an effective amount of a compound is generally in the range from 0.1 to 100 mg/kg of body weight of the recipient (mammal) per day and particularly typically in the range from 1 to 10 mg/kg of body weight per day. Thus, the actual amount per day for an adult mammal weighing 70 kg is usually between 70 and 700 mg, where this amount can be administered as an individual dose per day or usually in a series of part-doses (such as, for example, two, three, four, five or six) per day, so that the total daily dose is the same. An effective amount of a salt or solvate or of a physiologically functional derivative thereof can be determined as the fraction of the effective amount of the compound per se.
In a further aspect, the present invention relates to a process for preparing 3H- imidazo[4,5-b]pyridine derivatives of compounds of formula (I).
The dihydroorotate dehydrogenase inhibitors according to formula (I) may be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimisation procedures. Moreover, by utilizing the procedures described in detail, one of ordinary skill in the art can prepare additional compounds of the present invention claimed herein. All temperatures are in degrees Celsius (°C) unless otherwise noted.
In a further aspect, the compounds of the present invention can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the present invention also embraces isotopically-labeled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses. Exemplary isotopes that can be incorporated in to compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as 2H ("D"), 3H, UC, 13C, 14C, 13N, 15N, 150, 170, 180, 32P, 33P, 35S, 18F, 36C1, 123I and 125I. Isotopically labeled compounds of the present inventions can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
The following abbreviations refer respectively to the definitions below:
AcOH (Acetic acid), ACN (Acetonitrile), ATP (Adenoside Triphosphate), BSA (Bovine Serum Albumin), CHCb (Chloroform), CS2CO3 (Cesium carbonate), CO (carbon monoxide), DCM (Dichlorome thane), DIPEA (di-isopropyl ethylamine), DMSO (Dimethyl Sulfoxide), DMF (Ν,Ν-Dimethylformamide), EDCI.HC1 (l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride), Et3N (Triethylamine), EtOAc (Ethyl acetate), EtOH (Ethanol), HOBT (Hydroxybenzotriazole), HN03 (Nitric acid), HATU (0-(7- Azabenzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate), HC1 (Hydrogen chloride), K2C03 (Potassium Carbonate), LiOH (Lithium hydroxide), min (minute), MeOH (Methanol), NH4C1 (Ammonium chloride), NH4(C03)2 (ammonium carbonate), Pd(dppf)2Cl2 ([l,l-bis(diphenylphosphino)-ferrocene]dichloropalladium (II)), NaH (Sodium hydride), NaN02 (Sodium nitrite), NaHC03 (Sodium bicarbonate), PetEther (Petroleum ether), PBS (Phosphate Buffered Saline), RT-room temperature (25°C-35°C), TEA (Triethyl amine), TFA (Trifluoroacetic acid), THF (Tetrahydrofuran), i-BuOK (Potassium tert-butoxide), TMSI (Trimethylsilyl iodide), TLC (Thin Layer Chromatography), H20 (Water), mL (Milli Liter), hr/h (Hour), Na2S205 (Sodium metabisulfite), N (Normality), M (Molarity), s (Singlet), d (Doublet), t (Triplet), m (Multiplet), XHNMR (Proton nuclear magnetic resonance), MS (Mass spectroscopy), LC (Liquid chromatography), HPLC (High Performance Liquid Chromatography), (Coupling Constant), lH (Proton); MHz (Mega Hertz), Hz (Hertz), ppm (Parts per million), bs (Broad singlet), ES (Electro spray), Cone. (Concentrated), g (Gram), mmol or mM (Milli molar), μΜ (Micro molar), nM (Nano molar), UV (Ultraviolet), °C (degree Celsius), M+ (Molecular ion), % (Percentage), μ (Micron), δ (Delta), aq. (Aqueous), and pH (potential of Hydrogen).
Another embodiment of the present invention provides process for preparation of the compounds of general formula (I) are set forth in the below Examples and generalized scheme-I. One of skill in the art will recognize that Scheme I can be adapted to produce the compounds of general formula (I) and pharmaceutically acceptable salts of compounds of general formula (I) according to the present invention. Wherein all symbols/variables are as defined earlier unless otherwise stated.
General Synthetic Scheme
Scheme-I:
Figure imgf000017_0001
Compounds of the invention may be prepared using the synthetic transformations illustrated in Scheme-I. Starting materials are commercially available, may be prepared by the procedures described herein, by literature procedures, or by procedures that would be well known to one skilled in the art of organic chemistry. Starting materials are commercially available. Step-a: Compounds of general formula-2 can be prepared by reacting with compounds of general formula- 1 (wherein X is chloro) and appropriate aldehyde using the conditions that are described in General procedure-A.
Step-b: Compounds of general formula-2 can further be subjected to carbonation in presence of palladium catalyst using the conditions that are described in General procedure-B to afford compounds of general formula-3.
Step-c: Compounds of general formula-3 can be subjected to base hydrolysis using the condition such as those described in General Procedure-C to afford compounds of present invention (Compounds of formula-4; wherein Ri = OH).
Step-d: Compounds of general formula-4 (wherein Ri = OH) can be treated with ammonium chloride using the conditions that are described in General procedure-D to afford the compounds of general formula-5 (wherein Ri = NH2).
Step-e: Compounds of general formula-6 can be prepared by reacting with compounds of general formula- 1 (wherein X is methyl) and appropriate aldehyde using the conditions that are described in General procedure-A.
Step-f: Alternatively compounds of general formula-4 (wherein Ri = OH) can be prepared from the compounds of general formula-6 on oxidiation by using conditions that are described in General procedure-E of present invention (compounds of formula-4; wherein Ri = OH).
If the above set of general synthetic method is not applicable to obtain compounds according to formula (I) and/or necessary intermediates for the synthesis of compounds of general formula (I), suitable methods of preparation known by a person skilled in the art should be used. In general, the synthetic pathways for any individual compound of general formula (I) will depend on the specific substituents of each molecule and upon the ready availability of intermediates necessary; again such factors being appreciated by those of ordinary skill in the art.
Compounds of this invention can be isolated in association with solvent molecules by crystallization from evaporation of an appropriate solvent. The pharmaceutically acceptable acid addition salts of the compounds of general formula (I), which contain a basic center, may be prepared in a conventional manner. For example, a solution of the free base may be treated with a suitable acid, either neat or in a suitable solution, and the resulting salt isolated either by filtration or by evaporation under vacuum of the reaction solvent. Pharmaceutically acceptable base addition salts may be obtained in an analogous manner by treating a solution of compound of general formula (I) with a suitable base. Both types of salts may be formed or interconverted using ion-exchange resin techniques.
EXAMPLES
Although the invention has been illustrated by certain of the preceding examples, it is not to be construed as being limited thereby; but rather, the invention encompasses the generic area as hereinbefore disclosed. Various modifications and embodiments can be made without departing from the spirit and scope thereof.
The MS data provided in the examples described below were obtained as followed: Mass spectrum: LC/MS Waters ZMD (ESI) or a Waters Acquity SQD (ESI).
The NMR data provided in the examples described below were obtained as followed: ^-NMR: Bruker DPX-300MHz or a Bruker DPX 400 MHz.
The procedure for the preparation of compounds of general formula (I) are detailed herein below, including the general synthesis of various intermediates involved in process of manufacture of the compounds according to the present invention.
Intermediate- 1 : Synthesis of 4-chloropyridine-2, 3-diamine.
Figure imgf000019_0001
Step-i: Synthesis of 4-chloro-3-nitropyridin-2-amine.
To a stirred solution of 2-amino-4-chloropyridine (5.00 g, 0.0389 mol) in sulfuric acid (40.8 mL) was added a solution of nitric acid (2.72 g, 0.0389 mol) and sulfuric acid (3.89 g, 0.0389 mol) at 0°C. The mixture was stirred for lh then poured into 200 g crushed ice and 100 mL water. The separated solid was filtered and collected. The filtrate was neutralized with 28% NH3 in water to pH 5 and was extracted with EtOAc (3 x 300 mL). The solid also was dissolved in EtOAc and neutralized with 28% NH3 in water. The organic layers were combined, concentrated and purified by flash chromatography (20 to 60% EtOAc/hexanes as an eluent) to afford the title compound (2.40 g, 36%) as a yellow solid. lH NMR (400 MHz, DMSC fc): δ 8.12-8.11 (d, 7=5.6 Hz, IH), 7.23 (bs, 2H), 6.87-6.85 (d, 7=8.0 Hz, IH); and LC-MS m/z = 174.1 (M+H)+.
Step-ii: Synthesis of 4-chloropyridine-2,3-diamine.
To a stirred solution of 4-chloro-3-nitropyridin-2-amine (2.5 g, 14.4 mmol) in THF/Water (50/10 mL) was added zinc dust (7.39 g, 115.6 mmol) followed by ammonium chloride (7.65 g, 144.5 mmol) at room temperature and stirred for lh. The progress of the reaction was monitored by TLC. The reaction mixture was filtered through Celite® and separated both the layers. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to get the title compound (Intermediate- 1) as a dark brown colored solid (1.9 g, 92%). lH NMR (400 MHz, DMSO-ifc): δ 7.21-7.20 (d, 7=4.0 Hz, 1H), 6.51-6.497 (d, 7=6.0 Hz, 1H), 5.8 (bs, 2H), 4.9 (bs, 2H); and LC-MS m/z = 144.1 (M+H)+.
Figure imgf000020_0001
4-methyl-3-nitropyridin-2-amine (2.0 g, 13.07 mmol) was dissolved in methanol (40 mL). After a catallytic amount of 5% Pd/C (0.200 g) was added the mixture was stirred under 1 atm of hydrogen at room temperature for 2h. The reaction mixture was filtered through a pad of Celite®. The filtrate was concentrated under a reduced pressure to afford 4- methylpyridine-2,3-diamine (Intermediate-2) as a brown solid (1.4 g, 86%). This material was used in the next step without purification. XH NMR (400 MHz, DMSO-ifc): δ 7.192- 7.180 (d, 7=4.8 Hz, 1H), 6.283-6.270 (d, 7=5.2 Hz, 1H), 5.26 (bs, 2H), 4.36 (bs, 2H), 2.0 (s, 3H); and LC-MS m/z = 124.2 (M+H)+.
Intermediate- 3: S nthesis of N-(4-bromophenyl) cyclopro ane carboxamide.
Figure imgf000020_0002
To a cold solution of 4-bromoaniline ( 4.0 g, 23.2 mmol,) and TEA (3.5 g, 34.8mmol) in DCM (50 mL) was added cyclopropanecarbonyl chloride (2.9 g, 27.9 mmol). The reaction mixture was slowly warmed to RT and stirred for about lh. The reaction mixture was diluted with DCM (20 mL) and washed with water (2 x 15 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The obtained crude material was purified by using silica gel column chromatography eluted with 2-3% methanol in DCM to afford N-(4-bromophenyl) cyclopropanecarboxamide (Intermediate- 3) as an off white solid (4.0g, 78%). lH NMR (400 MHz, DMSO-d6): δ 10.3 (s, 1H), 7.57-7.55 (d, 7=8.8 Hz, 2H), 7.47-7.44 (d, 7=8.8 Hz, 2H), 1.77- 1.74 (m, 1H), 0.80-0.78 (m, 4H); and LC-MS m/z = 243.1(M+H)+.
The below intermediates were prepared using the procedure of Intermediate-3 with appropriate variations in reactants, quantities of reagents and reaction conditions.
Int Structure Analytical data
Figure imgf000021_0001
1H), 0.80-0.78 (m, 4H); and MS m/z = 242.9 (M+H)+.
Figure imgf000021_0002
A mixture of 1,4 dioxane (10 mL) and water (2 mL) was degassed with nitrogen for 10 minutes CS2CO3 (1.01 g, 3.09 mmol) was added followed by N-(4-bromophenyl) cyclopropane carboxamide (0.48 g, 2.08 mmol) and 4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)benzaldehyde (0.5 g, 2.08 mmol). The reaction mixture was again degassed for 15 min. Further, bis (triphenylphosphine) palladium (II) dichloride (0.029 g, 0.041mmol) was added and then the reaction mixture was stirred at reflux temperature for 12h under nitrogen. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to RT and evaporated to dryness under reduced pressure. The obtained residue was dissolved in EtOAc, washed with water and brine solution, dried over sodium sulphate and concentrated. The crude compound was purified by column chromatography over silica gel (100-200 mesh) using 15% ethyl acetate in hexane to get the desired compound as an off white solid (0.4g, 72%). lH NMR (400 MHz, DMSO-d6): δ 10.36 (bs,lH), 10.03 (s,lH), 7.97-7.95 (d, 7=8 Hz, 2H), 7.90-7.88 (d, 7=8 Hz, 2H), 7.74 (m, 4H), 1.80 (m, 1H), 0.80 (m, 4H); and LC-MS m/z = 266.2 (M+H)+.
The below intermediates were prepared using the procedure of Intermediate-4 with appropriate variations in reactants, quantities of reagents and reaction conditions.
Figure imgf000022_0001
General procedure-A: Cyclization.
To a flask containing an appropriate amine and aldehyde in an organic solvent (such as DMF, DMSO or 1,4 dioxane preferably DMF) is added sodium metabisulfite (1-2 equiv, preferably about 1.3 equiv) and the reaction mixture is stirred at 80°C-130°C temperature under nitrogen for about 3h to 18h (preferably about 12h). The reaction mixture is cooled to RT. The separated solid upon addition of water is collected by filtration and dried under vacuum to obtain the cyclized derivative. The product is purified by crystallization or trituration from an appropriate solvent or solvents or by preparative HPLC or flash chromatography. Illustrative example of General Procedure-A:
Preparation-A.l: Synthesis of N-(4'-(7-chloro-3H-imidazor4,5-blpyridin-2-yl)-rU'- biphenyll-4-yl)cvclo ropanecarboxamide.
Figure imgf000023_0001
To a solution of 4-chloropyridine-2,3-diamine (0.16 g, 1.13 mmol, Intermediate- 1) and N-(4'-formyl-[l,l'-biphenyl]-4-yl)cyclopropane carboxamide (0.3 g, 1.13 mmol, Intermediate-4) in DMF (lOmL) was added sodium metabisulfite (0.27 g, 1.47 mmol). The resulting reaction mixture was heated to 100°C for 12h. The progress of the reaction was monitored by TLC and after the completion of the reaction water (50 mL) was added. The separated solid was collected by filtration and dried under vacuum to get the desired compound as an off white solid (0.3 g, 70%). lH NMR (400 MHz, DMSO-d6): δ 13.91 (bs, 1H), 10.34 (s, 1H), 8.33-8.26 (m, 3H), 7.89-7.87 (d, =8 Hz, 2H), 7.77-7.72 (m, 4H), 7.40 (m, 1H), 1.80 (m, 1H), 0.80 (m, 4H); MS: m/z = 389.2 (M+H)+.
General procedure B: Carbonation.
To a autoclave reactor vessel containing an appropriate halo compound (General procedure A) in organic solvent (such as methanol, ethanol, isopropanol preferably ethanol ) is added in organic base (such as Na2C03, K2C03, NaOAC preferably NaOAc) followed by [l,l,-bis(diphenyl phosphino)ferrocine]dichloropalladium(II) complex with DCM (0.1-0.05 equiv preferably 0.05 equiv). The resulting reaction mixture is stirred at reflux temperature in the presence of carbon monoxide gas at (70-90 psi preferably 90 psi) for 12h .The reaction mixture is cooled to RT, filtered through a Celite® pad and washed with organic solvent. The combined filtrates are concentrated under reduced pressure. The product is purified by crystallization or trituration from an appropriate solvent or solvents or by preparative HPLC or flash chromatography.
Illustrative example of General Procedure-B:
Preparation-B.l: Synthesis of ethyl 2-(4'-(cyclopropanecarboxamido)-rU'-biphenyll-4-yl)- 3 H-imidazo Γ4 ,5 -bl pyridine-7 -c arboxylate .
Figure imgf000023_0002
A 100 niL autoclave reactor vessel was charged with N-(4'-(7-chloro-3H-imidazo[4,5- b]pyridin-2-yl)-[l,r-biphenyl]-4-yl)cyclopropanecarboxamide(0.3 g 0.77 mmol, preparation -A. l), [l,l,-bis(diphenylphosphino)ferrocine]dichloro palladium (II) complex with DCM (0.031 g, 0.038 mmol), sodium acetate (0.19 g, 2.31 mmol) and ethanol (20 mL). The reaction mixture was heated to reflex in the presence of carbon monoxide gas at 90 psi for about 12h. The reaction mixture was cooled to RT, filtered through a Celite® pad and washed with ethanol (2 x 100 mL). The combined filtrates were concentrated and obtained crude compound was purified by column chromatography over silica gel (60- 120 mesh) using 50% ethyl acetate in hexane to get the afford ethyl 2-(4'-(cyclopropanecarboxamido)-[l, - biphenyl]-4-yl)-3H-imidazo[4,5-b]pyridine-7-carboxylate as a pale yellow solid (0.3 g, 93%). lH NMR (400 MHz, DMSO-d6): δ 13.9 (s, 1H), 10.35 (s, 1H), 8.51-8.32 (m, 3H), 7.90-7.86 (d, 7=8.4 Hz, 2H), 7.78-7.72 (m, 4H), 7.65 (m, 1H), 4.51-4.46 (m, 2H), 1.8 (m, 1H) 1.44- 1.40 (m, 3H), 0.8 (m, 4H); MS m/z = 427.2 (M+H)+.
General Procedure-C: Formation of an Acid from Ethyl ester.
To a flask containing an appropriate aryl ester (General procedure B) in an aqueous organic solvents (such as THF or ethanol, 1,4-dioxane preferably THF and ethanol) is added 5 equiv. of aqueous LiOH solution and the reaction mixture is stirred at RT for l-8h (preferably 4h). The progress of the reaction is monitored by TLC. Excess solvent is removed under vacuum and the solution is acidified with 10% HC1 solution. The separated solid is collected by filtration and dried under vacuum to obtain the target carboxylic acid derivative. Illustrative example of General Procedure-C:
Example-I: Synthesis of 2-(4'-(cyclopropanecarboxamido)-rU'-biphenyll-4-yl)-3H-imidazo r4,5-blpyridine-7-carboxylic acid (Com ound- 1).
Figure imgf000024_0001
To a stirred solution of ethyl 2-(4'-(cyclopropanecarboxamido)-[l, -biphenyl]-4-yl)- 3H-imidazo[4,5-b]pyridine-7-carboxylate (0.3 g, 0.70 mmol, preparation-B. l) in a mixture of THF (10 mL) and ethanol (2 mL) was added an aq. 2N LiOH (2 mL). The reaction mixture was stirred at RT for 4h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated, and the aq. layer was cooled and acidified with an aq. 2N HC1 to pH~2 and the separated solid was filtered and dried under vacuum to afford the title compound as an off white solid (0.2 g, 71%). lH NMR (400 MHz, DMSO-i¾: δ 13.90 (bs, 1H), 12.82 (s, 1H), 10.34 (s, 1H), 8.53-8.35 (m, 2H), 7.88-7.64 (m, 8H), 1.81 (m, 1H), 0.83 (m, 4H); and LC-MS m/z = 397 (M-H)".
General Procedure-D: Amide formation.
To a flask containing appropriate carboxylic acid derivative (1.0 equiv) (General procedure C) in an organic solvent (such as DMF, THF or CH2CI2) is added EDCI.HC1 (1.5 equiv), HOBT (1.5 equiv) and N-ethyl-N-isopropylpropan-2-amine (3 equiv). After stirring for about 10-15 min at approximately 25°C-35°C, the appropriate amine (1.5 equiv) is added and the reaction is stirred for an additional 8-12h, preferably 12h. The separated solid upon addition of water is collected by filtration and dried under vacuum to obtain the amide derivative.
Illustrative example of General Procedure-D:
Example-II: Synthesis of 2-(4'-(cvclopropanecarboxamido)-riJ'-biphenyll-4-yl)-3H-imidazo r4,5-bl yridine-7-carboxamide (Compound-2).
Figure imgf000025_0001
To a flask containing a 2-(4'-(cyclopropanecarboxamido)-[l, -biphenyl]-4-yl)-3H- imidazo[4,5-b]pyridine-7 -carboxylic acid (0.130 g, 0.32 mmol, Compound-1) in DMF (5 mL) was added EDCI.HC1 (0.094 g, 0.48 mmol), HOBT (0.066 g, 0.48 mmol) and N-ethyl- N-isopropylpropan-2-amine (0.126 g, 0.96 mmol). The mixture was stirred at about 25°C for 10 min followed by addition of ammonium chloride (0.051 g, 0.96 mmol). The reaction mixture was then stirred at about 25°C for 12h and the progress of the reaction was monitored by TLC. The reaction mixture was quenched with water (50 mL). The separated solid was collected by filtration and dried under vacuum to obtain the desired compound as brown solid (0.09 g, 70%). lU NMR (400 MHz, DMSO-ifc): δ 14.0 (bs, 1H), 10.34 (s, 1H), 9.02 (s, 1H), 8.48 -8.38 (m, 3H), 8.170 (bs, 1H), 7.90-7.88 (d, 7=8.4 Hz, 2H), 7.77-7.72 (m, 5H), 1.84 (m, 1H), 0.83 (m, 4H); and LC-MS m/z = 398.2 (M+H)+.
General Procedure-E: Oxidation of methyl to Acid.
To a flask containing appropriate methyl benzimidazole derivative (1.0 equiv) in organic solvent (such as methanol, ethanol, isopropanol, ie/ -Butyl alcohol preferably tert- Butyl alcohol) is added KMn04 (1 to 10 equiv preferably 5 equiv) and water. The reaction mixture was stirred at reflux temperature for 10 to 30h (preferably 20h) under nitrogen. The progress of the reaction was monitored by TLC. The hot reaction mixture was filtered through Celite pad, and was washed thoroughly with hot water. The resulting filtrate was acidified. The precipitated solids were collected by filtration and dried. The product is purified by crystallization or trituration from an appropriate solvent or solvents or by preparative HPLC or flash chromatography.
Illustrative example of General Procedure-E:
Example-Ill: Synthesis of 2-(rU'-biphenyll-4-yl)-3H-imidazor4,5-blpyridine-7-carboxylic acid (Compound-3 .
Figure imgf000026_0001
2-([l,r-biphenyl]-4-yl)-7-methyl-3H-imidazo[4,5-b]pyridine (0.2 g, 0.7 mmol) (General procedure A) was taken in ieri-butyl alcohol (15 mL) and the resulting mixture was heated to 80°C. Aqueous KMn04 (0.55 g, 3.5 mmol) in water (15 mL) was added to the above reaction mixture and stirred at 100°C for 20h. The progress of the reaction was monitored by TLC. The reaction mixture was filtered through Celite® pad, and was washed thoroughly with hot water. The resulting filtrate was acidified with 6N HC1. The precipitated solids were collected by filtration and dried to afford compound 3 as a pale yellow solid (0.1 g, 45%). lH NMR (400 MHz, DMSO-d6): δ 14 (s, 1H), 12.3 (s, 1H), 8.49-8.42 (m, 3H), 7.87 (d, 7=8.8 Hz, 2H), 7.77 (d, 7=1.2 Hz, 2H), 7.52 (m, 1H), 7.50-7.40 (m, 3H); and LC-MS m/z = 316.1 (M+H)+.
The below compounds were prepared by procedure similar to the one described in General procedures-A, B, C, D and E with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table.
Figure imgf000026_0002
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Example-IV: Synthesis of 2-(4-(6-oxo-3 A5,6-tetrahydro-lH-azepinor5 A3-cdlindol-2-yl) phenyl) - 3 H-imidazo Γ4 ,5 -bl pyridine-7 -carboxylic acid . 2,2,2-trifluoroacetic acid (Compound- 181
Figure imgf000029_0002
Step-i: Synthesis of N-(3-amino-4-methylpyridin-2-yl)-4-bromobenzamide.
To a stirred solution of 4-methylpyridine-2,3 -diamine (2 g, 16.2 mmol) and 4- bromobenzoic acid (3.5 g, 17.8 mmol), HATU (9.83, 24.3 mmol) in dry DMF (20 mL) was added diisopropylethyl amine (5.7 mL, 32.4 mmol). The mixture was stirred at ambient temperature for 12h. The progress of the reaction was monitored by TLC and after the completion of the reaction water (100 mL) was added. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The obtained crude compound was purified by column chromatography over silica gel (60-120 mesh) using 30% ethyl acetate in hexane to get the desired compound as an off white solid (0.95 g, 40%). XH NMR (400 MHz, DMSO-d6): δ 10.314 (s, 1H), 7.96-7.943 (d, 7=8.4 Hz, 2H), 7.736-7.622 (m, 3H), 6.99-6.98 (m, 1H), 4.795 (bs, 2H), 2.17 (s, 3H); and LC-MS m/z = 308 (M+3H)3+.
Step-ii: Synthesis of 2-(4-bromophenyl)-7-methyl-3H-imidazo Γ4, 5-bl pyridine. N-(3-amino-4-methylpyridin-2-yl)-4-bromobenzamide (0.95 g, 3.1 mmol) was dissolved in acetic acid (20 mL) and heated 130°C for 12h. The progress of the reaction was monitored by TLC and after the completion of the reaction solvent was removed added water (100 mL). The separated solid was collected by filtration and dried under vacuum to obtain the get the desired compound as brown solid (0.7 g, 78%). lU NMR (400 MHz, DMSO-ifc): δ 13.6 (bs, 1H), 8.27-8.16 (m, 3H), 7.83-7.76 (m, 2H), 7.09-7.06 (m, 1H), 2.209 (m, 3H); and LC-MS m/z = 290 (M+3H)3+.
Step-iii: Synthesis of 2-(4-bromophenyl)-3H-imidazor4,5-blpyridine-7-carboxylic acid.
The process of this step adopted from compound-3 of example-Ill. The compound obtained as an off white solid (0.6 g, 75%). lH NMR (400 MHz, DMSO-d6): δ 13.6 (bs, 1H), 8.273-8.167 (m, 3H), 7.833-7.763 (m, 2H), 7.099-7.066 (m, 1H), 2.209 (m, 3H); and LC-MS m/z = 290 (M+3H)3+.
Step-iv: Synthesis of methyl 2-(4-bromophenyl)-3H-imidazo Γ4, 5-bl pyridine-7-carboxylate.
To a solution of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-7-carboxylic acid (0.6 g, 1.89 mmol) in methanol (25 mL) at 0°C was added cone. H2S04 (2 mL) during 5 min. The reaction mixture was stirred at 90°C for 12h. The progress of the reaction was monitored by TLC. Reaction mixture was concentrated under vacuum and the resulting crude product was added to ice water. The separated solid was filtered and dried under vacuum to get the title compound as a pale yellow solid (0.45 g, 71 %). lH NMR (400 MHz, DMSO-ifc): δ = 8.55 (m, 1H), 8.33-8.28 (m, 2H), 7.83-7.79 (m, 2H), 7.69-7 '.66 (m,lH), 4.01 (s, 3H); and LC-MS m/z = 332 (M+H)+.
Step-v: Synthesis of methyl 2-(4-(4, 4, 5, 5-tetramethyl- 3, 2-dioxaborolan-2-yl) phenyl)- 3H-imidazo Γ4, 5-bl pyridine-7-carboxylate:
The slurry of potassium acetate (0.264 g, 2.69 mmol) in 1,4-dioxane was degassed with nitrogen for 15 minutes then methyl 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-7- carboxylate (0.450 g, 1.35 mmol) was added followed by bis(pinacalato)diboron (0.411 g, 1.62 mmol) and degassed again for 15 minutes. Finally [l, l-bis(diphenylphosphino)- ferrocene]dichloropalladium(II) (0.029 g, 0.06 mmol) was added. The reaction mixture was stirred at 80°C for 8h under nitrogen. The progress of the reaction was monitored by TLC. 1,4-dioxane was removed under vacuum and the obtained residue was dissolved in ethyl acetate, washed with water. The combined organic layers were dried over sodium sulphate and concentrated under vacuum to get the title compound as black oily liquid (0.270 g, crude). The obtained crude compound was directly used for the next step without purification. LC-MS m/z = 380 (M+H)+. Step-vi: Synthesis of 2-(4-(6-oxo-3,4,5,6-tetrahydro- lH-azepinor5,4,3-cdlindol-2-yl)phenyl)- 3H-imidazor4,5-blpyridine-7-carboxylic acid.
A mixture of 1,4 dioxane (10 mL) and water (5 mL) was degassed with nitrogen for 10 minutes Na2C03 (0.188 g, 1.77 mmol) was added followed by 2-bromo-4,5-dihydro- lH- azepino[5,4,3-cd]indol-6(3H)-one (0.188 g, 0.71 mmol) and methyl 2-(4-(4,4,5,5-tetramethyl -l,3,2-dioxaborolan-2-yl)phenyl)-3H-imidazo[4,5-b]pyridine-7-carboxylate (0.270 g, 0.71 mmol). The reaction mixture was again degassed for 15 min. Finally bis(triphenylphosphine)palladium(II) dichloride (0.049 g, 0.07 mmol) was added and then the reaction mixture was stirred at reflux temperature for 12h under nitrogen. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to RT and evaporated to dryness under reduced pressure. The obtained residue was dissolved in EtOAc, washed with water and brine solution, dried over sodium sulphate and concentrated. The crude compound was purified by column chromatography over silica gel (100-200 mesh) using 10% methanol in DCM to get the desired compound as an off white solid (0.030 g, 10%). lU NMR (400 MHz, DMSO-d6): δ 11.73 (s, 1H), 8.51-8.39 (m, 3H), 8.11 (s, 1H), 7.84 (d, =8.0 Hz, 2H), 7.69-7.51 (m, 3H), 7.27-7.25 (m, 2H), 3.62-3.21 (m, 4H); and LC-MS m/z = 424.1 (M+H)+. PHARMACOLOGICAL ACTIVITY:
Measurement of DHQDH inhibitory enzyme activity (in vitro assays):
The DHODH activity assay is a coupled enzyme assay in which oxidation of DHO and subsequent reduction of ubiquinone are stoichiometrically equivalent to the reduction of DCIP (2,6-dichlorophenol). The reduction of DCIP is accompanied by a loss of absorbance at 610 nm.
Preparation of solutions/reagents:
Buffer Preparation: 50 mM tris HC1, 150 mM KC1, and pH 8.0, 0.8% triton.
L-Dihydroorotic acid stock solution of 20 mM in buffer.
2, 6-Dichloroindophenol Sodium salt hydrate stock solution of 20 mM in buffer. Decylubiquinone stock solution of 20 mM in buffer.
DMSO used as vehicle.
Procedure:
5 μΐ^ of Dimethyl sulfoxide or a compound of formula (I) in DMSO solution was added to the wells of a 96 well plate. Compounds of formula (I) were measured at 10 μΜ.
Protein along with buffer was added, so that the total volume including the DMSO was 87 μL·. Compound and protein were incubated for half an hour at room temperature after mixing. 5 μΐ^ of 20 mM solution of L-Dihydroorotic acid, 5 μΐ^ of 2 mM solution of Decylubiquinone and 3 μΐ^ of 2 mM solution of 2, 6-Dichloroindophenol sodium salt hydrate were added to the above solution (total assay volume 100 μί). The mixture was stirred for 2 min and absorbance was recorded at every 10 min at 610 nanometers.
Percent inhibition is calculated as follows:
100* { (Abs6io for reaction containing compound) - (Abs6io for positive control).
(Abs6io for no enzyme reaction) - (Abs6io for positive control).
Reaction containing compound has compound, buffer, enzyme and substrates.
Positive control contains DMSO, buffer, enzyme and substrates.
No Enzyme reaction contains DMSO, buffer and substrates.
IC50 determination:
A 2 mM DMSO stock solution of the selected compound of formula (I) of the present invention to be examined was prepared. Subsequent l/3rd dilutions were made.
5 μΐ^ of each stock of compound of formula (I) was used for each 100 μΐ^ assay. Therefore, 5 μΐ^ of the 2 mM stock provided 100 μΐ^ of 100 μΜ solution of compound of formula (I), when made up with buffer, protein and substrate. See also: Ulrich et al. (2001) Eur. J. Biochem.268, 1861-1868.
IC50 values of the selected compounds of present invention were provided in below table. Compounds exhibiting IC50 values < 300 nM were grouped as 'a' and the compounds exhibiting IC50 value >300 nM were grouped as 'b' .
Table: DHODH inhibition activity of the selected compounds.
Group Compound No's
a 1, 2, 3, 5, 7, 8, 9 and 10
b 13

Claims

We claim:
1. A compound of formula (I
Figure imgf000033_0001
or a pharmaceutically acceptable salt thereof,
wherein,
Ri is hydroxy or amino;
R2 is optionally substituted aryl, optionally substituted heterocyclyl or -0-(CH2)i_2 aryl; wherein the substituent at each occurrence is one to four R4;
R3 is hydrogen, halogen, alkyl, alkoxy, amino, amide, cyano, carboxy, or hydroxyl;
R4 is halogen or -NHC(0)cycloalkyl;
'n' is an integer ranging from 1 to 4, both inclusive.
2. The compound according to claim 1, wherein aryl is phenyl.
3. The compound according to claim 1 is a compound of formula (la)
Figure imgf000033_0002
(la)
or a pharmaceutically acceptable salt thereof,
wherein,
Ri, R3 and R4 are same and are as defined in claim 1.
4. A compound selected from the group consisting of:
2-(4'-(cyclopropanecarboxamido)-[l, -biphenyl]-4-yl)-3H-imidazo[4,5-b]pyridine-7- carboxylic acid (Compound- 1);
2-(4'-(cyclopropanecarboxamido)-[l, -biphenyl]-4-yl)-3H-imidazo[4,5-b]pyridine-7- carboxamide (Compound-2);
2-([l, -biphenyl]-4-yl)-3H-imidazo[4,5-b]pyridine-7-carboxylic acid (Compound-3);
2-([l, -biphenyl]-4-yl)-3H-imidazo[4,5-b]pyridine-7-carboxamide (Compound-4);
2-(3-fluoro-[l, -biphenyl]-4-yl)-3H-imidazo[4,5-b]pyridine-7-carboxylic acid (Compound-5);
2-(3-fluoro-[l, -biphenyl]-4-yl)-3H-imidazo[4,5-b]pyridine-7-carboxamide
(Compound-6); 2-(4'-(cyclopropanecarboxamido)-3-fluoro-[l, -biphenyl]-4-yl)-3H-imidazo[4,5- b]pyridine-7-carboxylic acid (Compound-7);
2-(2^3-difluoro-[l, -biphenyl]-4-yl)-3H-imidazo[4,5-b]pyridine-7-carboxylic acid (Compound-8);
2-(4'-(cyclopropanecarboxamido)-2',3-difluoro-[l, -biphenyl]-4-yl)-3H-imidazo[4,5- b]pyridine-7-carboxylic acid (Compound-9);
2-(4'-(cyclopropanecarboxamido)-2',3-difluoro-[l, -biphenyl]-4-yl)-3H-imidazo[4,5- b]pyridine-7-carboxamide (Compound- 10);
2-(2'-(cyclopropanecarboxamido)-3-fluoro-[l, -biphenyl]-4-yl)-3H-imidazo[4,5- b]pyridine-7-carboxylic acid (Compound- 11);
2-(2'-(cyclopropanecarboxamido)-3-fluoro-[l, -biphenyl]-4-yl)-3H-imidazo[4,5- b]pyridine-7-carboxamide (Compound- 12);
2-(3'-(cyclopropanecarboxamido)-3-fluoro-[l, -biphenyl]-4-yl)-3H-imidazo[4,5- b]pyridine-7-carboxylic acid (Compound- 13);
2-(3'-(cyclopropanecarboxamido)-3-fluoro-[l, -biphenyl]-4-yl)-3H-imidazo[4,5- b]pyridine-7-carboxamide (Compound- 14);
2-(2-fluoro-4-(2-oxo-l,2,3,4-tetrahydroquinolin-7-yl)phenyl)-3H-imidazo[4,5- b]pyridine-7-carboxylic acid (Compound- 15);
2-(4-(benzyloxy)phenyl)-3H-imidazo[4,5-b]pyridine-7-carboxylic acid (Compound-
16);
2-(4-(benzyloxy)phenyl)-3H-imidazo[4,5-b]pyridine-7-carboxamide (Compound- 17); and
2-(4-(6-oxo-3,4,5,6-tetrahydro-lH-azepino[5,4,3-cd]indol-2-yl)phenyl)-3H- imidazo[4,5-b]pyridine-7-carboxylic acid (Compound- 18);
or a pharmaceutically acceptable salt thereof.
5. A pharmaceutical composition comprising at least one compound according to any one of claims 1-4 or a pharmaceutically acceptable salt, in admixture with at least one pharmaceutically acceptable carrier or excipient including mixtures thereof in all ratios, for use as a medicament.
6. A pharmaceutical composition comprising at least one compound according to any one of claims 1-4 or a pharmaceutically acceptable salt thereof, and at least one further active ingredient.
7. Use of a compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prophylaxis of a dihydroorotate dehydrogenase associated diseases or disorder.
8. Use according to claim 7, wherein the dihydroorotate dehydrogenase associated disorder is an autoimmune disorder or condition associated with an overactive immune response.
9. Use according to claim 8, and pharmaceutically acceptable salts thereof, for the preparation of a medicament for the treatment and/or prophylaxis of an immunerogulatory abnormality.
10. Use according to claim 9, wherein the immunoregulatory abnormality is multiple sclerosis or rheumatoid arthritis.
11. Use of the compound according to claim 1, for the preparation of a medicament for the treatment and prophylaxis of cancer diseases, inflammatory bowel disease, multiple sclerosis or rheumatoid arthritis.
12. Compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, for use in the treatment and prophylaxis of cancer diseases, inflammatory bowel disease, multiple sclerosis or rheumatoid arthritis.
13. A method of treating dihydroorotate dehydrogenase associated disease or disorder in a subject comprising administering a therapeutically effective amount of a compound according to any one of claims 1-4 or a pharmaceutically acceptable salt thereof.
14. The method according to claim 13, wherein the dihydroorotate dehydrogenase associated disorder is an autoimmune disorder or condition associated with an overactive immune response.
PCT/IB2015/053051 2014-04-30 2015-04-27 3h-imidazo[4,5-b]pyridine derivatives as dihydroorotate dehydrogenase inhibitors WO2015166398A1 (en)

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CN110294751A (en) * 2018-03-21 2019-10-01 湖南化工研究院有限公司 Have the imidazoles [4,5-b] of bioactivity and pyridine compounds and their and its preparation method and application
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CN107286166A (en) * 2016-04-11 2017-10-24 上海勋和医药科技有限公司 Replace 1,3,4,5- tetrahydrochysene -6H- pyrrolo-es [4,3,2-EF] [2] benzo-aza -6- ketone derivatives
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