WO2010115736A2 - Dihydroorotate dehydrogenase inhibitors - Google Patents

Dihydroorotate dehydrogenase inhibitors Download PDF

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WO2010115736A2
WO2010115736A2 PCT/EP2010/054034 EP2010054034W WO2010115736A2 WO 2010115736 A2 WO2010115736 A2 WO 2010115736A2 EP 2010054034 W EP2010054034 W EP 2010054034W WO 2010115736 A2 WO2010115736 A2 WO 2010115736A2
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mmol
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carboxylic acid
het
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PCT/EP2010/054034
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French (fr)
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WO2010115736A3 (en
WO2010115736A9 (en
Inventor
Siva Sanjeeva Rao Thunuguntla
Hosahalli Subramanya
Satish Reddy Kunnam
Sekhar Reddy Sanivaru Vijay
Chakrapani Bingi
Raviraj Kusanur
Matthias Schwarz
Michael Arlt
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Merck Serono S.A.
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Priority to JP2012502605A priority Critical patent/JP5680054B2/en
Priority to US13/262,640 priority patent/US9006454B2/en
Priority to SG2011055167A priority patent/SG174125A1/en
Priority to CN2010800147415A priority patent/CN102574786A/en
Priority to EP10711665.9A priority patent/EP2414328B1/en
Priority to AU2010233917A priority patent/AU2010233917B2/en
Priority to ES10711665T priority patent/ES2882797T3/en
Priority to NZ595819A priority patent/NZ595819A/en
Publication of WO2010115736A2 publication Critical patent/WO2010115736A2/en
Publication of WO2010115736A3 publication Critical patent/WO2010115736A3/en
Publication of WO2010115736A9 publication Critical patent/WO2010115736A9/en

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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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    • 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 Dihydroorotate Dehydrogenase inhibitors, their use as medicament and their use for treating multiple sclerosis and other diseases such as inflammatory disorders, rheumatoid arthritis and cancer.
  • the invention relates to compounds of formula I:
  • R 1 denotes COOH, COOA, COA, CF 3 , acyl, cyano, Het, tetrazoyl, sulfonyl, or if Q is -C ⁇ C- or Hetarylene, or if Q is a tetrasubstituted Arylene, R 1 also denotes
  • R 2 denotes H, Hal, A, 0-A, Ar
  • R a denotes Ar, Het, O-Het, NH-Het, O-Ar, -O-(CH 2 ) m -Het, -NH-(CH 2 ) m -Het, NH-Ar,
  • X 1 , X 2 denote each independently of one another CR c R d , NR C , NR d , and when Y denote CR f , also O or S, provided that one of X 1 and X 2 is CR c R d or NR C ;
  • R b and R c together represent a chemical bond
  • R f and R e together represent a chemical bond, when Y is CR f
  • R e and R c in the definition of X 1 , together represent a chemical bond when Y is N, and
  • R b and R c in the definition of X 2 , together represent a chemical bond;
  • R d denotes H, A, -(CH 2 ) m -COOH;
  • Q denotes a group -C ⁇ C-, Arylene, Hetarylene, or the group Hal denotes F, Cl, Br or I;
  • Ar denotes a monocyclic or bicyclic, saturated, unsaturated or aromatic carbocyclic ring having 6 to 14 carbon atoms which may be unsubstituted or substituted by a group selected from (R 4 ) n and/or (R 5 ) n ;
  • Het denotes a monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic ring having 1 to 4 N, O and/or S atoms which may which may be unsubstituted or substituted by a group selected from (R 4 ) n and/or (R 5 ) n ;
  • Arylene denotes a divalent monocyclic or bicyclic, saturated, unsaturated or aromatic carbocyclic ring having 6 to 14 carbon atoms which may be unsubstituted or substituted by a group selected from (R 4 ) n and/or (R 5 ) n ;
  • Hetarylene denotes a divalent monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic ring having 1 to 4 N, O and/or S atoms which may which may be unsubstituted or substituted by a group selected from (R 4 ) n and/or (R 5 ) n ;
  • R 3 is H or alkyl
  • R 4 and R 5 are each independently selected from Hal, hydroxy, alkoxy, carboxy, carboxy- alkyl, perfluoro-alkyl, perfluoro-alkyloxy, acyl, alkylsulfonyl, sulfonyl, cyano, nitro, amino, amido, alkyl optionally substituted by a carboxy, or Het-alkyl optionally substituted by an acyl , alkylsulfonyl, -O(CH 2 ) n Ar, -O(CH 2 ) n Het, -(CH 2 ) m Het, OA, -NHCO(CH 2 ) m Ar, NHCO- (CH 2 ) m Het , CONHA, or alkyl; n denotes 0,1 ,2,3,4,5; and m denotes 0,1 ,2,3,4,5,6; and pharmaceutically acceptable derivatives, solvates, tautomers, salts and stereoiso- mers thereof
  • Formula I also includes all tautomeric forms.
  • Preferred tautomeric forms are represented by the following formulae for example wherein X 1 and X 2 are NR C or NR d , R d is H, R b and R c form a bond and R 1 is COOH , R 2 , Q, R a are as defined above, Y is CR f wherein R f is as defined above:
  • the invention relates to the use of compounds of formula I and pharmaceutically acceptable derivatives, solvates, tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios as a medicament, especially for treating multiple sclerosis and other diseases such as inflammatory disorders, rheumatoid arthritis and cancer.
  • the compounds of formula I and related formulae preferably are inhibitors of dihydroorotate dehydrogenase (DHODH or DHOD).
  • DHODH is a protein which catalyzes the fourth step in de novo pyrimidine nucleotide pathway. (Greene et al. Biochem Pharmacol 1995, 50:861-7; Davis J . P et al. FASEB J 1996, 10(6) : Abst C23). It catalyses 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.
  • I n hibitors of d ihyd roorotate dehydrogenase have found wider application as chemotherapeutic agents. Initially explored as anticancer drugs (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)).
  • the quinoline derivative Brequinar (6-Fluoro-2-(2'- fluoro[1 ,1 '-biphenyl]-4-yl)-3-methyl-4-quinolinecarboxylic Acid) exhibits an anticancer activity towards L1210 murine leukemia.
  • Edreson LW. Et al. Cancer Commun. 1989;1 (6):381-7 Chen SF. et al. Cancer Res. 1986 Oct;46(10):5014-9.
  • Brequinar potentiates 5-fluorouracil antitumor activity in a murine model colon 38 tumor by tissue-specific modulation of uridine nucleotide pools.
  • DHODH inhibitors have also been suggested as antibiotics, especially against Helicobacter Pylori (Marcinkeviciene et al. Biochem Pharmacol. 2000, 60, 339; Haque, T. S. et al. , J . Med . Chem. 2002, 45, 4669-4678), useful for treating Plasmodium falciparum related diseases (Heikkila, T. et al . J Med Chem . 50: 1 86 -91 (2007); Heikkila, T. et al. Bioorg Med Chem Lett. 16: 88 -92 (2006)), and as antifungal agents (Gustafson, G. et al. Curr. Genet. 1996, 30, 159).
  • DHODH inhibitors can also be useful for the treatment of viral mediated diseases (see US 6,841 ,561 ).
  • Leflunomide a well known DHODH inhibitor is a synthetic, low-molecular weight drug of the isoxazole class (see EP0527736, JP 1993506425, JP 1999322700, JP 1999343285, US 549491 1 , US5532259, WO19991017748). This drug is currently marketed 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.).
  • Oral treatment with Teriflunomide at 3 and 10mg/kg or with dexamethasone at 1 mg/kg began 10 days after inoculation with guinea pig spinal cord and Freund's adjuvant, when clonal expansion of inflammatory and immune cells had already occurred. Both compounds caused a significant delay in the onset of disease and in symptom severity (Styren, S. D. et al. Beneficial effects of Teriflunomide in experimental allergic encephalomyelitis. 34th Annu Meet Soc Neurosci (Oct 23-27, San Diego) 2004, Abst 344.5.).
  • autoimmune and related diseases require new d rugs th at can treat su ch d iseases .
  • 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 are also useful as part of chemotherapeutic regimens for the treatment of cancers, lymphomas and leukemias, alone or in combination with
  • a primary objective of the present invention is to provide novel compounds of formula I and related formulae which are inhibitors of dihydroorotate dehydrogenase.
  • the invention refers to novel compounds, which inhibits DHODH, to a process for their manufacture and pharmaceutical compositions containing them, and to their use for the treatment and prevention in diseases, in particular their use in diseases where there is an advantage in inhibiting DHODH.
  • the compounds of formula I and related formulae 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.
  • the present invention relates to compounds of formula I and related formulae for the treatment of multiple sclerosis and related diseases, rheumatoid arthritis and transplant rejection.
  • the inventions further relates to the use of compounds according to formula I and related formulae in combination with immunomodulating agents such as Fingolimod; cyclosporins, rapamycins or ascomycins, or their immunosuppressive analogs, e.g.
  • cyclosporin A cyclosporin G, FK-506, ABT-281 , ASM981 , rapamycin, 40-O-(2- hydroxy)ethyl-rapamycin etc.
  • corticosteroids cyclophosphamide; azathioprene; methotrexate; leflunomide; mizoribine; mycophenolic add; mycophenolate mofetil; 15- deoxyspergualine; diflucortolone valerate; difluprednate; Alclometasone dipropionate; amcinonide; amsacrine; asparaginase; azathioprine; basiliximab; beclometasone dipropionate; betamethasone; betamethasone acetate; betamethasone dipropionate; betamethasone phosphate sodique; betamethasone valerate; budesonide; captopril; chlormethine chlorhydrate; cladribine; clobet
  • CTLA41 g or other adhesion molecule inhibitors, e.g. mAbs or low molecular weight inhibitors including Selectin antagonists and VLA-4 antagonists.
  • a preferred composition is comprising a compound of formula I and Cyclosporin A, FK506, rapamycin, 40-(2-hydroxy)ethyl-rapamycin or Fingolimod.;
  • the dihydroorotate dehydrogenase inhibitors according to formula I and related formulae 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.
  • dihidroorotate dehydrogenase inhibitors according to formula I and related formulae of this invention may be prepared from readily available starting materials. If such starting materials are not commercially available they may be prepared by standard synthetic techniques. The following general methods and procedures described hereinafter in the examples may be employed to prepare compounds of formula I and related formulae.
  • Compound (C) will undergo cyclization for example in AcOH under reflux to give the corresponding compound of formula I, wherein X 1 and X 2 are NR C , NR d and R b and R c together represent a chemical bond, and wherein Y is CR f , R f and R e together represent a bond, according to scheme 1 ;
  • the pharmaceutically acceptable cationic salts of compounds of the present invention are readily prepared by reacting the acid forms with an appropriate base, usually one equivalent, in a co-solvent.
  • Typical bases are sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium hydroxide, potassium methoxide, magnesium hydroxide, calcium hydroxide, benzathine, choline, diethanolamine, ethylenediamine, meglumine, benethamine, diethylamine, piperazine, lysine, arginine, and tromethamine.
  • the salt is isolated by concentration to dryness or by addition of a non-solvent.
  • salts can be prepared by mixing a solution of the acid with a solution of the cation (sodium ethylhexanoate, magnesium oleate), employing a solvent in which the desired cationic salt precipitates, or can be otherwise isolated by concentration and addition of a non-solvent.
  • a solution of the acid with a solution of the cation (sodium ethylhexanoate, magnesium oleate)
  • a solvent in which the desired cationic salt precipitates or can be otherwise isolated by concentration and addition of a non-solvent.
  • compounds of formula I and related formulae (A), (B), (B'), (C), (D), (E) (F), (G) and (J) can be converted to alternative compounds of formula I and related formulae, employing suitable interconversion techniques well known by a person skilled in the art.
  • any individual compound of formula I and related formulae will depend on the specific substitutents 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 formula I and related formulae, 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.
  • Base addition salts may be obtained in an analogous manner by treating a solution of compound of formula I and related formulae , which contain an acid center, with a suitable base. Both types of salts may be formed or interconverted using ion-exchange resin techniques.
  • reaction times are generally between a few minutes and 14 days, and the reaction temperature is between about -30 0 C and 140 0 C, normally between -10°C and 90 0 C, in particular between about 0°C and about 70°C.
  • Compounds of the formula I and related formulae can furthermore be obtained by liberating compounds of the formula I from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent.
  • Preferred starting materials for the solvolysis or hydrogenolysis are those which conform to the formula I and related formulae, but contain corresponding protected amino and/or hydroxyl groups instead of one or more free amino and/or hydroxyl groups, preferably those which carry an amino-protecting group instead of an H atom bonded to an N atom, in particular those which carry an R'-N group, in which R' denotes an amino-protecting group, instead of an HN group, and/or those which carry a hydroxyl-protecting group instead of the H atom of a hydroxyl group, for example those which conform to the formula I, but carry a -COOR" group, in which R" denotes a hydroxyl-protecting group, instead of a -COOH group.
  • amino-protecting group is known in general terms and relates to groups which are suitable for protecting (blocking) an amino group against chemical reactions, but which are easy to remove after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino-protecting groups are removed after the desired reaction (or reaction sequence), their type and size are furthermore not crucial; however, preference is given to those having 1-20, in particular 1-8, carbon atoms.
  • acyl group is to be understood in the broadest sense in connection with the present process.
  • acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and, in particular, alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups.
  • acyl groups are alkanoyl, such as acetyl, propionyl and butyryl; aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl and tolyl; aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2- trichloroethoxycarbonyl, BOC (tert-butoxycarbonyl) and 2-iodoethoxycarbonyl; aralkoxycarbonyl, such as CBZ ("carbobenzoxy”), 4-methoxybenzyloxycarbonyl and FMOC; and arylsulfonyl, such as Mtr.
  • Preferred amino-protecting groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl and acetyl.
  • hydroxyl-protecting group is likewise known in general terms and relates to groups which are suitable for protecting a hydroxyl group against chemical reactions, but are easy to remove after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl or acyl groups, furthermore also alkyl groups.
  • the nature and size of the hydroxyl-protecting groups are not crucial since they are removed again after the desired chemical reaction or reaction sequence; preference is given to groups having 1-20, in particular 1-10, carbon atoms.
  • hydroxyl-protecting groups are, inter alia, benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, where benzyl and tert-butyl are particularly preferred.
  • the compounds of the formula I and related formulae are liberated from their functional derivatives - depending on the protecting group used - for example using strong acids, advantageously using TFA or perchloric acid, but also using other strong inorganic acids, such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids, such as trichloroacetic acid, or sulfonic acids, such as benzene- or p-toluenesulfonic acid.
  • strong acids advantageously using TFA or perchloric acid
  • other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids, such as trichloroacetic acid, or sulfonic acids, such as benzene- or p-toluenesulfonic acid.
  • strong acids advantageously using TFA or perchloric acid
  • other strong inorganic acids such as hydrochloric acid or sulfuric acid
  • strong organic carboxylic acids such as trichloroacetic acid
  • Suitable inert solvents are preferably organic, for example carboxylic acids, such as acetic acid, ethers, such as tetrahydrofuran or dioxane, amides, such as DMF, halogenated hydrocarbons, such as dichloromethane, furthermore also alcohols, such as methanol, ethanol or isopropanol, and water. Mixtures of the above-mentioned solvents are furthermore suitable. TFA is preferably used in excess without addition of a further solvent, and perchloric acid is preferably used in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9:1.
  • the reaction temperatures for the cleavage are advantageously between about 0 and about 50 0 C, preferably between 15 and 30 0 C (room temperature).
  • the BOC, OBut and Mtr groups can, for example, preferably be cleaved off using TFA in dichloromethane or using approximately 3 to 5N HCI in dioxane at 15-30°C, and the FMOC group can be cleaved off using an approximately 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30 0 C.
  • Protecting groups which can be removed hydrogenolytically can be cleaved off, for example, by treatment with hydrogen in the presence of a catalyst (for example a noble-metal catalyst, such as palladium, advantageously on a support, such as carbon).
  • a catalyst for example a noble-metal catalyst, such as palladium, advantageously on a support, such as carbon.
  • Suitable solvents are those indicated above, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as DMF.
  • the hydrogenolysis is generally carried out at temperatures between about 0 and 100 0 C and pressures between about 1 and 200 bar, preferably at 20-30 0 C and 1-10 bar. Hydrogenolysis of the CBZ group succeeds well, for example, on 5 to 10% Pd/C in methanol or using ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-30°C.
  • suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1 ,2- dichloroethane, tetrachloromethane, trifluoromethylbenzene, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n- butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, N-methylpyrrolidon
  • Esters can be saponified, for example, using acetic acid or using LiOH, NaOH or KOH in water, water/THF, water/THF/ethanol or water/dioxane, at temperatures between 0 and 100 0 C.
  • an inert solvent such as dichloromethane or THF
  • a base such as triethylamine or pyridine
  • leaving group preferably denotes Cl, Br, I or a reactively modified OH group, such as, for example, an activated ester, an imidazolide or alkylsulfonyloxy having 1-6 carbon atoms (preferably methylsulfonyloxy or trifluoro- methylsulfonyloxy) or arylsulfonyloxy having 6-10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy).
  • a reactively modified OH group such as, for example, an activated ester, an imidazolide or alkylsulfonyloxy having 1-6 carbon atoms (preferably methylsulfonyloxy or trifluoro- methylsulfonyloxy) or arylsulfonyloxy having 6-10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy).
  • Activated esters are advantageously formed in situ, for example through addition of HOBt or N-hydroxysuccinimide.
  • the formula I and related formulae also encompasses the optically active forms (stereoisomers), the enantiomers, the racemates, tautomers, the diastereomers and the hydrates and solvates of these compounds.
  • solvates of the compounds is taken to mean adductions of inert solvent molecules onto the compounds which form owing to their mutual attractive force. Solvates are, for example, mono- or dihydrates or alcoholates.
  • pharmaceutically usable derivatives is taken to mean, for example, the salts of the compounds of the formula I and so-called prodrug compounds.
  • prodrug derivatives is taken to mean compounds of the formula I which have been modified with, for example, alkyl or acyl groups, sugars or oligopeptides and which are rapidly cleaved in the organism to form the active compounds.
  • prodrug as of the compounds of formula I , refers to derivative compounds that are rapidly transformed in vivo to yield the parent compound of the formula I, as for example by hydrolysis in blood.
  • T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in "Pro-drugs as Novel Delivery Systems", VoI 14 of the A.C.S. Symposium Series, American Chemical Society (1975).
  • esters useful as prodrugs for compounds containing carboxyl groups can be found on pages 14-21 of "Bioreversible Carriers in Drug Design: Theory and Application", edited by E. B. Roche, Pergamon Press: New York (1987). It is intended that these references, and any others cited throughout this specification, are incorporated herein by reference.
  • the formula I and related formulae also encompasses mixtures of the compounds of the formula I, for example mixtures of two diastereomers, for example in the ratio 1 :1 , 1 :2, 1 :3, 1 :4, 1 :5, 1 :10, 1 :100 or 1 :1000. These are particularly preferably mixtures of stereoisomeric compounds.
  • X 1 preferably denotes NR C , NR d , or O, especially NR C .
  • X 2 preferably denotes NR C , NR d or CR c R d .
  • one of X 1 or X 2 denotes NR C or NR d
  • both X 1 and X 2 denote NR C or NR d
  • R 1 preferably denotes COOH, COOalkyl, A, COOA, COA, Het, CONHA, cyano, acyl, R 1 most preferably denotes one of the following groups:
  • R 3 is as defined above.
  • R 2 preferably denotes H, A, alkyl, Hal, O-alkyl, O-A, especially H, Me, OMe, F, Cl or Br.
  • R d preferably denotes H, A or alkyl, especially H.
  • R a preferably denotes Ar, Het, O-Ar, O-Het, especially Ar or Het.
  • R a more preferably denotes phenyl, pyridinyl, oxazolyl, thienyl, benzothiazolyl.
  • R a very most preferably denotes phenyl, pyridinyl, or pyrrole.
  • R a most preferably denotes one of the following groups:
  • A, R 3 , R d , m and Het are as defined above
  • Q preferably denotes Arylene, Hetarylene, especially Arylene or Hetarylene.
  • Q more preferably denotes divalent group derived from phenyl, pyridinyl, thienyl, or indolyl.
  • Q very most preferably denotes divalent group derived from phenyl or pyridinyl. Q most preferably denotes a single bond, a triple bond, or one of the following groups:
  • the group A very particularly preferably denotes alkyl having 1 , 2, 3, 4, 5 or 6 carbon atoms.
  • Alkyl preferably denotes methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1 ,1-, 1 ,2- or 2,2- dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1 ,1-, 1 ,2-, 1 ,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1 ,1 ,2- or 1 ,2,2-trimethylpropyl, furthermore preferably, for example, trifluoromethyl, pentafluoroethyl or 1 ,1 ,1 -trifluoroethyl.
  • Cycloalkyl preferably denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • Cycloalkylalkylene preferably denotes cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, cyclohexylmethylene or cycloheptylmethylene.
  • Alkylene is preferably methylene, ethylene, propylene, butylene, pentylene or hexylene, furthermore branched alkylene.
  • Perfluoroalkyl preferably denotes CF 3 .
  • Hal denotes Cl, Br, I, F and preferably F or Br.
  • Alkoxy is branched or linear and preferably denotes a group -O-(CH 2 ) n -CH 3 . Most preferablyalkoxy is Methoxy or Ethoxy. Carboxy denotes a group -COOH.
  • Carboxyalkyl denotes an ester group, preferably an alkyl ester, such as COOMe or COOEt.
  • Sulfonyl denotes a group -SO 2 -OH, -SO 2 -NH 2 , -SO 2 NHA.
  • Alkylsulfonyl denotes a group -SO 2 -alkyl, preferably Methylsulfonyl or Ethylsulfonyl.
  • Acyl denotes a group -C(O)R, wherein R can be A, Ar, Het as defined above.
  • R can be A, Ar, Het as defined above.
  • Acyl denotes acetyl (-C(O)CH 3 ).
  • Amino denotes the group -NRR'" where each R, R'" is independently hydrogen or alkyl or Ar or Het or A or Het-alkyl or Ar-alkyl, and where R and R'", together with the nitrogen atom to which they are attached, can optionally form a 3-8-membered Het ring.
  • Amido refers to the group -C(O)NRR'" where each R, R'" is independently hydrogen or alkyl or Ar or Het or A or Het-alkyl or Ar-alkyl, and where R and R'", together with the nitrogen atom to which they are attached, can optionally form a 3-8-membered Het ring.
  • Ar preferably denotes phenyl, which may be unsubstituted or monosubstituted, disubstituted or trisubstituted by a substitutent selected from R 4 and/or R 5 ;
  • Ar very particularly preferably denotes one of the following groups:
  • R 4 and R 3 are as defined above.
  • Ar is one of the following groups: wherein R , R is as defined above and preferably, wherein R is Hal and R is Hal, alkyl, O-alkyl or H.
  • Ar is unsubtituted or
  • Arylene is preferably a divalent group derived from Ar and more preferably denotes phenyl, which may be unsubstituted or monosubstituted, disubstituted or trisubstituted by a substitutent selected from R 4 and/or R 5 ;
  • Arylene very particularly preferably denotes one of the following groups:
  • R and R 5 are as defined above.
  • Arylene is one of the following groups:
  • R , R is as defined above and preferably, wherein R is Hal and R is Hal, alkyl, O-alkyl or H. Het preferably denotes a monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic ring having 1 to 3 N, O and/or S atoms which may which may be unsubstituted or substituted by a group selected from (R 4 ) n and/or (R 5 ) n ;
  • Het more preferably denotes a monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic ring having 1 to 3 N, O and/or S atoms which may which may be unsubstituted or substituted by a group selected from (R 4 ) n and/or (R 5 ) n ;
  • Het is preferably a 6 to 14 membered ring system and denotes, not withstanding further substitutions, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1 ,2,3-triazol-1-, -4- or -5-yl, 1 ,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1 , 2, 3-oxadiazol-4- or -5-yl, 1 , 2, 4-oxadiazol-3- or -5-yl, 1 ,3,4-thiadiazol-2
  • heterocyclic radicals may also be partially or fully hydrogenated.
  • Het can thus also denote, for example, 2,3-dihydro-2-, -3-, -A- or -5-furyl, 2,5-dihydro-2-, -3-, -A- or -5-furyl, tetrahydro-2- or -3-furyl, 1 ,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -A- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -A- or -5- pyrazolyl
  • Hetarylene is preferably derived from the group Het as defined above and is most preferably
  • R and R 5 are as defined above.
  • the invention provides compounds of formula I wherein R 1 denotes COOH, COOalkyl, CF 3 , acyl, cyano, preferably COOH;
  • the invention provides compounds of formula I wherein R 1 denotes COOH, COOMe, CF 3 , acetyl, cyano;
  • the invention provides compounds of formula I wherein R 1 denotes COOH, COOalkyl, CF 3 , acyl, cyano; R 2 denotes H, Hal, alkyl, O-alkyl;
  • the invention provides compounds of formula I wherein R 1 denotes COOH, COOMe, CF 3 , acetyl, cyano; R 2 denotes H, F, Cl or Br, Me, OMe;
  • the invention provides compounds of formula I wherein R 1 denotes COOH, COOalkyl, CF 3 , acyl, cyano; R 2 denotes H, Hal, alkyl, O-alkyl; X 1 and X 2 are as define above; In another specific embodiment, the invention provides compounds of formula I wherein R 1 denotes COOH, COOMe, CF 3 , acetyl, cyano; R 2 denotes H, F, Cl or Br, Me, OMe; X 1 and X 2 are as define above;
  • the invention provides compounds of formula I wherein R 1 denotes COOH, COOalkyl, CF 3 , acyl, cyano; R 2 denotes H, Hal, alkyl, O-alkyl; X 1 and X 2 are as define above; R d is H or alkyl;
  • the invention provides compounds of formula I wherein R 1 denotes COOH, COOMe, CF 3 , acetyl, cyano; R 2 denotes H, F, Cl or Br, Me, OMe; X 1 and X 2 are as define above; R d is H or Me;
  • the invention provides compounds of formula I wherein R 1 denotes COOH, COOalkyl, CF 3 , acyl, cyano; R 2 denotes H, Hal, alkyl, O-alkyl; X 1 and X 2 are as define above; R d is H or alkyl; Q denotes Arylene, Hetarylene;
  • the invention provides compounds of formula I wherein R 1 denotes COOH, COOMe, CF 3 , acetyl, cyano; R 2 denotes H, F, Cl or Br, Me, OMe; X 1 and X 2 are as define above; R d is H or Me; Q denotes Arylene, Hetarylene;
  • the invention provides compounds of formula I wherein R 1 denotes COOH, COOalkyl, CF 3 , acyl, cyano; R 2 denotes H, Hal, alkyl, O-alkyl; X 1 and X 2 are as define above; R d is H or alkyl; Q denotes Arylene, Hetarylene
  • the invention provides compounds of formula I wherein R 1 denotes COOH, COOMe, CF 3 , acetyl, cyano; R 2 denotes H, F, Cl or Br, Me, OMe; X 1 and X 2 are as define above; R d is H or Me; Q denotes Arylene, Hetarylene;
  • the invention provides compounds of formula I wherein R 1 denotes COOH, COOalkyl, CF 3 , acyl, cyano; R 2 denotes H, Hal, alkyl, O-alkyl; X 1 and X 2 are as define above; Rd is H or alkyl; Q denotes Arylene, Hetarylene; In another specific embodiment, the invention provides compounds of formula I wherein R 1 denotes COOH, COOMe, CF 3 , acetyl, cyano; R 2 denotes H, F, Cl or Br, Me, OMe; X 1 and X 2 are as define above; R d is H or Me; Q denotes Arylene, Hetarylene;
  • the invention provides compounds of formula I wherein R 1 denotes COOH, COOalkyl, CF 3 , acyl, cyano; R 2 denotes H, Hal, alkyl, O-alkyl; X 1 and X 2 are as define above; R d is H or alkyl; Q denotes -NH-, NHC(O)-; R a denotes Ar, O-Ar, 0-(CH 2 ) m -Ar, Het, O-Het, NH-Ar, SO 2 Ar; m denotes 0,1 ,2;
  • the invention provides compounds of formula I wherein R 1 denotes COOH, COOMe, CF 3 , acetyl, cyano; R 2 denotes H, F, Cl or Br, Me, OMe; X 1 and X 2 are as define above; R d is H or Me; Q denotes Arylene, Hetarylene ;R a denotes Ar, O-Ar, O-(CH 2 ) m -Ar, Het, O-Het, NH-Ar, SO 2 Ar; m denotes 0,1 ,2;
  • the invention provides compounds of formula I wherein R 1 denotes COOH, COOalkyl, CF 3 , acyl, cyano; R 2 denotes H, Hal, alkyl, O-alkyl; X 1 and X 2 are as define above; R d is H or alkyl; Q denotes Arylene, Hetarylene; R a denotes Ar, O-Ar, O-(CH 2 ) m -Ar, Het, O-Het, NH-Ar, SO 2 Ar; m denotes 0,1 ,2;
  • the invention provides compounds of formula I wherein R 1 denotes COOH, COOMe, CF 3 , acetyl, cyano; R 2 denotes H, F, Cl or Br, Me, OMe; X 1 and X 2 are as define above; R d is H or Me; Q denotes Arylene, Hetarylene; R a denotes Ar, O-Ar, O-(CH 2 ) m -Ar, Het, O-Het, NH-Ar, SO 2 Ar; m denotes 0,1 ,2;
  • the invention provides compounds of formula I wherein R 1 denotes COOH, COOalkyl, CF 3 , acyl, cyano; R 2 denotes H, Hal, alkyl, O-alkyl; X 1 and X 2 are as define above d; R d is H or alkyl; Q denotes -NH-, NHC(O)-; Ra denotes Ar, O- Ar, O-(CH 2 ) m -Ar, Het, O-Het, NH-Ar, SO 2 Ar; m denotes 0,1 ,2; wherein Ar is selected from phenyl or naphtyl and Het is selected from pyridinyl, thienyl, indolyl, benzothiazolyl, morpholino, pyridinyl-2-one, oxazolyl, azepan-2-one; wherein Ar and Het as defined are unsubstituted or substituted by a group selected from
  • the invention provides compounds of formula I wherein R 1 denotes COOH, COOalkyl, CF 3 , acyl, cyano; R 2 denotes H, Hal, alkyl, O-alkyl; X 1 and X 2 are as define above; R d is H or alkyl; Q denotes Arylene, Hetarylene; R a denotes Ar, O-Ar, 0-(CH 2 ) m -Ar, Het, O-Het, NH-Ar, SO 2 Ar; m denotes 0,1 ,2; wherein Ar is selected from Phenyl or Naphtyl and Het is selected from pyridinyl, thienyl, indolyl, benzothiazolyl, morpholino, pyridinyl-2-one, oxazolyl, azepan-2-one; wherein Ar and Het as defined are unsubstituted or substituted by a group selected from (
  • the invention provides compounds of formula I wherein R 1 denotes COOH, COOMe, CF 3 , acetyl, cyano; R 2 denotes H, F, Cl or Br, Me, OMe; X 1 and X 2 are as define above; R d is H or Me; Q denotes Arylene, Hetarylene; R a denotes Ar, O-Ar, O-(CH 2 ) m -Ar, Het, O-Het, NH-Ar, SO 2 Ar; m denotes 0,1 ,2; wherein Ar is selected from Phenyl or Naphtyl and Het is selected from pyridinyl, thienyl, indolyl, benzothiazolyl, morpholino, pyridinyl-2-one, oxazolyl, azepan-2-one; wherein Ar and Het as defined are unsubstituted or substituted by a group selected from (R 4
  • R 1 , R 2 , X 1 , X 2 , R a , R b , R 4 and n are as defined in formula I, and pharmaceutically acceptable derivatives, solvates, tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios;
  • R 1 , R 2 , X 2 ' R a , R 4 are as described in formula Il and pharmaceutically acceptable derivatives, solvates, tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios;
  • R 1 , R 2 , X 1 ' R a , R 4 are as described in formula Il and pharmaceutically acceptable derivatives, solvates, tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios;
  • R 1 , R 2 , X 1 , X 2 , R a , R b , R 4 , R 5 and n are as defined in formula I, and pharmaceutically acceptable derivatives, solvates, tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios;
  • R 1 , R 2 , X 2 , R 4 , R 5 , n are as described in formula III and pharmaceutically acceptable derivatives, solvates, tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios;
  • R 1 , R 2 , X 1 , R 4 , R 5 , m are as described in formula III and pharmaceutically acceptable derivatives, solvates, tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios;
  • the compounds of the formula I, II, Na, lib, III, Ilia, 1Mb and also the starting materials for the preparation thereof are, in addition, prepared by methods known per se, as described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme- Verlag, Stuttgart), under reaction conditions which are known and suitable for the said reactions.
  • Philip J see Philip J.
  • the starting materials can also be formed in situ so that they are not isolated from the reaction mixture, but instead are immediately converted further into the compounds of the formula I.
  • the reactions are preferably carried out in an inert solvent.
  • suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1 ,2- dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide or di
  • the invention relates, in particular, to the use of compounds of the formula I, II, Na, lib, III, Ilia, INb as defined above, wherein X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , R 5 , Q, R a and R b , R c , R d , Ar, Het and alkyl are as defined above as a medicament. Accordingly, the invention relates, in particular, to the use of compounds of the formula I,
  • the said compounds of the formula I, II, Na, lib, III, Ilia, INb can be used in their final non-salt form.
  • the present invention also relates to the use of these compounds in the form of their pharmaceutically acceptable salts, which can be derived from various organic and inorganic acids and bases by procedures known in the art.
  • Pharmaceutically acceptable salt forms of the compounds of the formula I are for the most part prepared by conventional methods. If the compound of the formula I, II, Na, lib,
  • Ilia, INb contains an acidic center, such as a carboxyl group
  • one of its suitable salts can be formed by reacting the compound with a suitable base to give the corresponding base-addition salt.
  • bases are, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; alkaline earth metal hydroxides, such as barium hydroxide and calcium hydroxide; alkali metal alkoxides, for example sodium- or potassium methoxide and sodium or potassiumpropoxide, alkalihydrides, such as sodium- or potassiumhydride; and various organic bases, such as piperidine, diethanolamine and N-methyl-glutamine, benzathine, choline, diethanolamine, ethylenediamine, meglumine, benethamine, diethylamine, piperazine and tromethamine.
  • aluminium salts of the compounds of the formula I, II, Na, lib, III, Ilia, INb are likewise included.
  • acid-addition salts can be formed by treating these compounds with pharmaceutically acceptable organic and inorganic acids, for example hydrogen halides, such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other mineral acids and corresponding salts thereof, such as sulfate, nitrate or phosphate and the like, and alkyl- and monoaryl-sulfonates, such as ethanesulfonate, toluenesulfonate and benzene-sulfonate, and other organic acids and corresponding salts thereof, such as acetate, trifluoro-acetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate and the like.
  • organic and inorganic acids for example hydrogen halides, such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other mineral acids and
  • pharmaceutically acceptable acid-addition salts of the compounds of the formula I and related formulae include the following: acetate, adipate, alginate, arginate, aspartate, benzoate, benzene-sulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphor-sulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclo-pentane-propionate, digluconate, dihydrogen-phosphate, dinitrobenzoate, dodecyl-sulfate, ethanesulfonate, fumarate, galacterate (from mucic acid), galacturonate, glucoheptanoate, gluco-nate, glutamate, glycerophosphate, hemi-succinate, hemisulfate, heptanoate, hexanoate, hippurate, hydro-chloride,
  • the base salts of the compounds of the formula I, II, Na, lib, III, Ilia, INb include aluminium, ammonium, calcium, copper, iron(lll), iron(ll), lithium, magne-sium, manganese(lll), manganese(ll), potassium, sodium and zink salts, but this is not intended to represent a restriction.
  • Salts of the compounds of the formula I which are derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, also including naturally occurring substituted amines, cyclic amines, and basic ion exchanger resins, for example arginine, betaine, caffeine, chloroprocaine, choline, N,N'-dibenzyl-ethylen-ediamine (benzathine), dicyclohexylamine, diethanol-amine, diethyl-amine, 2-diethyl-amino-ethanol, 2- dimethyl-amino-ethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N- ethyl-piperidine, glucamine, glucosamine, histidine, hydrabamine, isopropyl-amine, lido-caine, lysine, meglumine (N-methyl-D-glucamine), morpholine, pipe
  • Compounds of the formula I, II, Na, lib, III, Ilia, INb of the present invention which contain basic nitrogen-containing groups can be quaternised using agents such as (Ci-C 4 )-alkyl halides, for example methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; di(Ci-C 4 )alkyl sulfates, for example dimethyl, diethyl and diamyl sulfate; (Ci O -Ci 8 )alkyl halides, for example decyl, do-decyl, lauryl, myristyl and stearyl chloride, bromide and iodide; and aryl-(Ci-C 4 )alkyl halides, for example benzyl chloride and phenethyl bromide. Both water- and oil-soluble compounds of the formula I can be prepared using such salts.
  • the above-mentioned pharmaceutical salts which are preferred include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, me-glumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stea-rate, sulfate, subsalicylate, tartrate, thiomalate, tosylate and tro-meth-amine, but this is not intended to represent a restriction.
  • the acid-addition salts of basic compounds of the formula I, II, Na, lib, III, Ilia, INb are prepared by bringing the free base form into contact with a sufficient amount of the desired acid, causing the formation of the salt in a conventional manner.
  • the free base can be regenerated by bringing the salt form into contact with a base and isolating the free base in a conventional manner.
  • the free base forms differ in a certain respect from the corresponding salt forms thereof with respect to certain physical properties, such as solubility in polar solvents; for the purposes of the invention, however, the salts other-wise correspond to the respective free base forms thereof.
  • the pharmaceutically acceptable base-addition salts of the compounds of the formula I are formed with metals or amines, such as alkali metals and alkaline earth metals or organic amines.
  • metals are sodium, potassium, magnesium and calcium.
  • Preferred organic amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanol-amine, ethylenediamine, N-methyl-D-glucamine and procaine.
  • the base-addition salts of acidic compounds of the formula I, II, Na, lib, III, Ilia, INb are prepared by bringing the free acid form into contact with a sufficient amount of the desired base, causing the formation of the salt in a conventional manner.
  • the free acid can be regenerated by bringing the salt form into contact with an acid and isolating the free acid in a conventional manner.
  • the free acid forms differ in a certain respect from the corresponding salt forms thereof with respect to certain physical properties, such as solubility in polar solvents; for the purposes of the invention, however, the salts other-wise correspond to the respective free acid forms thereof.
  • a compound of the formula I, II, Na, lib, III, Ilia, 1Mb contains more than one group which is capable of forming pharmaceutically acceptable salts of this type, the formula I also encompasses multiple salts.
  • Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, di-phosphate, disodium and trihydrochloride, but this is not intended to represent a restriction.
  • the term "pharmaceutically acceptable salt” in the present connection is taken to mean an active ingredient which comprises a compound of the formula I, II, Na, lib, III, Ilia, INb 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.
  • the compounds of the formula I, II, Na, lib, III, Ilia, INb can be chiral and can accordingly occur in various enantiomeric forms. They can therefore exist in racemic or in optically active form. Since the pharmaceutical activity of the racemates or stereoisomers of the compounds according to the invention may differ, it may be desirable to use the enantiomers. In these cases, the end product or even the intermediates can be separated into enantiomeric compounds by chemical or physical measures known to the person skilled in the art or even employed as such in the synthesis.
  • diastereomers are formed from the mixture by reaction with an optically active resolving agent.
  • optically active acids such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (for example N-benzoylproline or N-benzenesulfonylproline), or the various optically active camphorsulfonic acids.
  • chromatographic enantiomer resolution with the aid of an optically active resolving agent (for example dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chirally derivatised methacrylate polymers immobilised on silica gel).
  • optically active resolving agent for example dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chirally derivatised methacrylate polymers immobilised on silica gel.
  • Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as, for example, hexane/isopropanol/ acetonitrile, for example in the ratio 82:15:3.
  • the invention furthermore relates to the use of compounds of formula I, II, Na, lib, III, Ilia,
  • medicaments used in the treatment of multiple sclerosis such as cladribine or another co-agent, such as interferon, e.g. pegylated or non-pegylated interferons, preferably interferon beta and/or with compounds improving vascular function or in combination with immunomodulating agents for example Fingolimod; cyclosporins, rapamycins or ascomycins, or their immunosuppressive analogs, e.g.
  • cyclosporin A cyclosporin G, FK- 506, ABT-281 , ASM981 , rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin etc.
  • corticosteroids cyclophosphamide; azathioprene; methotrexate; leflunomide; mizoribine; mycophenolic add; mycophenolate mofetil; 15-deoxyspergualine; diflucortolone valerate; difluprednate; Alclometasone dipropionate; amcinonide; amsacrine; asparaginase; azathioprine; basiliximab; beclometasone dipropionate; betamethasone; betamethasone acetate; betamethasone dipropionate; betamethasone phosphate sodique; betamethasone valerate; budesonide; captopril; chlormethine chlorhydrate; cladribine; clobet
  • CTLA41 g or other adhesion molecule inhibitors, e.g. mAbs or low molecular weight inhibitors including Selectin antagonists and VLA-4 antagonists.
  • a preferred composition is with Cyclosporin A, FK506, rapamycin or 40-(2- hydroxy)ethyl-rapamycin and Fingolimod.
  • further medicaments such as interferon beta, may be administered concomitantly or sequentially, e.g. by subcutaneous, intramuscular or oral routes.
  • the invention furthermore relates to the use of compounds of formula I, II, Na, lib, III, Ilia, INb in combination with at least one further medicament active ingredient, preferably medicaments used in the treatment of cancer wherein said antitumoral compounds are selected from those well know by the one skilled in the related art.
  • medicament active ingredient preferably medicaments used in the treatment of cancer wherein said antitumoral compounds are selected from those well know by the one skilled in the related art.
  • These compositions can be used as medicaments in human and veterinary medicine.
  • compositions can be administered in the form of dosage units, which comprise a predetermined amount of active ingredient per dosage unit.
  • a unit can comprise, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of a compound according to the invention, depending on the disease condition treated, the method of administration and the age, weight and condition of the patient, or pharmaceutical formulations can be administered in the form of dosage units which comprise a predetermined amount of active ingredient per dosage unit.
  • Preferred dosage unit formulations are those which comprise a daily dose or part-dose, as indicated above, or a corresponding fraction thereof of an active ingredient.
  • pharmaceutical formulations of this type can be prepared using a process, which is generally known in the pharmaceutical art.
  • 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 in the form of a 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.
  • the compounds of the formula I, II, Na, lib, III, Ilia, 1Mb and salts, solvates and physiologically functional derivatives thereof and the other active ingredients can also be administered in the form of liposome delivery systems, such as, for exam-pie, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from various phospholipids, such as, for example, cholesterol, stearylamine or phosphatidylcholines.
  • the compounds of the formula I, II, Na, lib, III, Ilia, 1Mb and the salts, solvates and physiologically functional derivatives thereof and the other active ingredients can also be delivered using monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds can also be coupled to soluble polymers as targeted medicament carriers.
  • Such polymers may encompass polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl-methacrylamidophenol, polyhydroxyethylaspartamido-phenol or polyethylene oxide polylysine, substituted by palmitoyl radicals.
  • the compounds may furthermore be coupled to a class of biodegradable polymers which are suitable for achieving controlled release of a medicament, for example polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, poly-orthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
  • a class of biodegradable polymers which are suitable for achieving controlled release of a medicament, for example polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, poly-orthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
  • compositions 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.
  • compositions 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.
  • 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.
  • the present invention provides the use of compounds according to formula (I) and related formulae, wherein R 1 denotes COOH, COOA, COA, CONHA, CON(R 3 ) 2 , CF 3 , acyl, cyano, Het, tetrazoyl, sulfonyl,; R 2 denotes H, Hal, A, O-alkyl, Ar; R a denotes H, A, Ar, Het, O-Het, NH-Het, O-Ar, -O-(CH 2 ) m -Ar, -O-(CH 2 ) m -Het, -NH-(CH 2 ) m - Het, NH-Ar, S(O) 2 Ar, S(O)Ar, -S-Ar, OCF 3 ,; Q denotes a single bond, a group -C ⁇ C -, Arylene or Hetarylene and pharmaceutically acceptable derivatives, solvates,
  • the present invention relates the use of compounds according to formula (I) and related formulae, and pharmaceutically usable derivatives, salts, tautomers, solvates and stereoisomers thereof, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment and/or prophylaxis of diseases in which the inhibition, activation , regulation , and/or modulation of dihydroorotate dehydrogenase plays a role.
  • the present invention relates to the use of compounds according to formula (I ) and related formulae, and pharmaceutically usable derivatives, salts, tautomers, solvates and stereoisomers thereof, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment and/or prophylaxis of a dihydroorotate dehydrogenase associated disorder.
  • the present invention relates to the use of compounds according to formula (I) and related formulae, wherein the dihydroorotate dehydrogenase associated disorder is an autoimmune disorder or condition associated with an overactive immune response.
  • the present invention related to the use of compounds according to formula (I) and related formulae, and pharmaceutically usable derivatives, salts, tautomers, solvates and stereoisomers thereof, including mixtures thereof in all ratios, for the preparation of a med icament for the treatment and/or prophylaxis of an immunerogulatory abnomality.
  • the present invention relates to the use according to the fifth aspect, wherein the immunoregulatory abnormality is an autoimmune or chronic inflammatory disease selected from the group consisting of: systemic lupus erythematosis, chronic rheumatoid arthritis, type I diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, amyotrophic lateral sclerosis (ALS), Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves ophthalmopathy and asthma.
  • autoimmune or chronic inflammatory disease selected from the group consisting of: systemic lupus erythematosis, chronic rheumatoid arthritis, type I diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, u
  • the present invention relates to the use according to the sixth aspect, wherein the immunoregulatory abnormality is bone marrow or organ transplant rejection or graft-versus-host disease.
  • the present invention relates to a kit or a set comprising at least one compound of Formula (I), preferably in combination with immunomodulating agents.
  • the kit consists of separate packs of : (a) an effective amount of a compound of the formula (I) and/or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and (b) an effective amount of a further medicament active ingredient.
  • a therapeutically effective amount of a compound of the formula I, II, Na, lib, III, Ilia, INb 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 furthermore relates to a method for treating a subject suffering from a Dihydroorate dehydrogenase related disorder, comprising administering to said subject an effective amount of a compound of formula I, II, Na, lib, III, Ilia, INb.
  • the present invention preferably relates to a method, wherein the Dihydroorate dehydrogenase associated disorder is an autoimmune disorder or condition associated with an overactive immune response or cancer.
  • the present invention furthermore relates to a method of treating a subject suffering from an immunerogulatory abnomality, comprising administering to said subject a compound of formula I, II, Na, lib, III, Ilia, INb in an amount that is effective for treating said immunoregulatory abnormality.
  • the present invention preferably relates to a method wherein the immunoregulatory abnormality is an autoimmune or chronic inflammatory disease selected from the group consisting of: amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus, chronic rheumatoid arthritis, type I diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarc
  • the present invention furthermore relates to a method wherein the immunoregulatory abnormality is bone marrow or organ transplant rejection or graft-versus-host disease.
  • the present invention furthermore relates to a method wherein the immunoregulatory abnormality is selected from the group consisting of: transplantation of organs or tissue, graft-versus-host diseases brought about by transplantation, autoimmune syndromes including rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, postinfectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborr
  • Preferred compounds of formula I and related formulae exhibit a IC 50 for the binding to the Dihydroorotate dehydrogenase of less than about 5 ⁇ M, preferably less than about 1 ⁇ M and even more preferred less than about 0,010 ⁇ M.
  • 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 formula I and related formulae 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 formula I and related formulae, which contain an acid center, with a suitable base. Both types of salts may be formed or interconverted using ion-exchange resin techniques.
  • Nomenclature of the compounds of this invention has been determined using ISIS/draw 2.5 SP1 software.
  • Method A HPLC columns: XbridgeTM C8 column 50 mm x 4.6 mm at a flow of 2 mL/ min; 8 min gradient from 0.1% TFA in H 2 O to 0.07% TFA in ACN.
  • Method B HPLC columns: XbridgeTM C8 column 50 mm x 4.6 mm at a flow of 1 mL/ min; 8 min gradient H 2 O ammonium acetate (10 ⁇ M, pH 9) - ACN from 95:5 to 0:100.
  • Method D HPLC columns: C18 BDS, 50X4.6mm, SCV307 at a flow of 0.8 mL/ min; A-
  • GC/MS GC Agilent 6890N & MS Agilent 5973.
  • the preparative HPLC purifications are performed with HPLC waters Prep LC 4000 System equipped with columns ®PrepMS C18 10 ⁇ m, 50x300mm, unless otherwise reported. All HPLC purifications were performed with a gradient of ACN/H 2 O or ACN/H 2 O/TFA (0.1 %).
  • Step 5 2,3-Diamino-benzoic acid methyl ester
  • 2-amino-3-nitro-benzoic acid methyl ester 2 g, 10 mmol
  • a suspension of 10% Pd/C 300 mg
  • methanol 5 ml. a suspension of 10% Pd/C (300 mg) in methanol 5 ml. was added and hydrogenated with a hydrogen balloon over a period of 8 h.
  • the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 1.5 g of the required compound as a brown coloured solid (88%).
  • Example 2 is obtained as described in example 1 but starting from 4-(benzyloxy)benzoic acid (procured commercially from aldrich).
  • Step 2 4-Bromomethyl-3-fluoro-3'-methoxy-biphenyl
  • 3-fluoro-3'-methoxy-4-methyl-bipheny 0.5 g, 1.7 mmol, 1.0 eq
  • chloroform 30 mL
  • N-bromo succinimide 0.3 g, 1 .7 mmol
  • the reaction mixture was refluxed by irradiating with a tungsten lamp for 3 hours. After the reaction was completed, it was cooled to room temperature and washed with water. The combined organic layers were dried over anhydrous sodium sulphate and concentrated.
  • Step 4 2-(3-Fluoro-3'-methoxy-biphenyl-4-yl)-1H-benzoimidazole-4-carboxylic acid
  • the precipitate was washed with water and dissolved in ethanol (5 ml.) containing 0.5 ml_ conc. HCI.
  • a solution of sodium sulphide (0.082 g, 1 .0512 mmol) in water was added.
  • the reaction mixture was kept acidic by adding 2-3 drops of cone HCI.
  • the reaction mixture was filtered hot to remove copper sulfide.
  • the pH of the solution adjusted to 4 and diluted with water.
  • the precipitate formed was filtered, washed with water and dried.
  • the residue obtained was purified by column chromatography using 5% methanol in dichloromethane to obtain the title compound.
  • Step 5 2, 3-Diamino-5-methoxy-benzoic acid methyl ester
  • Step 4 2-Amino-5-fluoro-3-nitro-benzoic acid To a slurry of 5-fluoro-7-nitro-1 H-indole-2, 3-dione (3 g, 14.2 mmol) in aqueous 5N NaOH solution (30 ml.) was added slowly an aq. solution of 33% hydrogen peroxide (3 ml.) at 0 0 C. After completion of the addition , the reaction mixture was stirred at room temperature for 4h. After completion of the reaction, the reaction mixture was acidified with 2N HCI and the resulting precipitate was filtered, washed with water (2-3 times) and dried under vacuum to obtain the title compound as yellow solid (2 g, 70.17%).
  • Step 1 N-(4- Bromo -phenyl)-2-hydroxyimino-acetamide
  • Step 3 5- Bromo-7-nitro-1H-indole-2, 3-dione
  • 5-bromo-1 H-indole-2,3-dione 5 g, 22.1 mmol
  • H 2 SO 4 22.5 ml.
  • fuming nitric acid 1.45 mL
  • the reaction mixture was stirred at the same temperature for one hour.
  • the reaction mixture was poured on to crushed ice and the resulting precipitate was filtered, washed with water (2-3 times) and dried under vacuum to obtain the title compound as yellow solid (5.5 g, 91.8%) which was used for the next step directly.
  • Step 4 2-Amino-5-bromo-3-nitro-benzoic acid To a slurry of 5-bromo-7-nitro-1 H-indole-2,3-dione (5.5 g, 20.3 mmol) in aqueous 5N NaOH solution (23.2 mL) was added an aq. solution of 33% hydrogen peroxide solution (4.96 mL) slowly at 0 0 C. After completion of the addition, the reaction mixture was stirred at room temperature for 4h. After completion of the reaction, the reaction mixture was acidified with 2N HCI and the solid the resulting precipitate was filtered, washed with water (2-3 times) and dried under vacuum to obtain the title compound as yellow solid (5 g, 94.5%).
  • Step 5 2-Amino-5-bromo-3-nitro-benzoic acid methyl ester
  • 2-amino-5-bromo -3-nitro-benzoic acid 5 g, 19.15 mmol
  • methanol 100 mL
  • diazomethane gas 75 mL
  • the reaction mixture was concentrated to dryness and the residue obtained was purified by column chromatography using 5% ethyl acetate in hexane as an eluent to obtain the title compound as yellow solid which was directly used for the next step (5 g, 94.3%).
  • Example 7 and 8 are obtained from example 1 by the following procedure.
  • 2-biphenyl-4-yl-1-methyl-1 H-benzoimidazole-4-carboxylic acid 400 mg, 1 .27 mmol
  • dry DMF(20 ml_) dry DMF(20 ml_)
  • potassium carbonate 800 mg, 5.79 mmol
  • methyl iodide 0.235 ml_, 3.77 mmol
  • the reaction mixture was then stirred overnight at room temperature. After the starting material was completely consumed, DMF was was removed under vacuum.
  • the resulting residue was directly purified by column chromatography and two compounds were isolated and characterized as methyl esters of 1 H- and 3H- isomers.
  • the corresponding carboxylic acids were prepared by hydrolysis with lithium hydroxide (aq. solution of 5 N, 10 ml.) at room temperature for 8 h in THF-Water mixture.
  • Example 9 is obtained as described in example 1 but starting from 3-phenoxybenzoic acid (prepared according to the literature method).
  • Example 10 is obtained as described in example 1 but starting from 3-phenoxybenzoic acid (procured commercially from aldrich).
  • Example 1 1 is obtained as described in example 1 but starting from 3'-methoxybiphenyl-
  • Example 12 is obtained as described in example 1 but starting from 4'-methylbiphenyl-4- carboxylic acid (prepared according to the literature method).
  • Step 1 2-Hydroxyimino-N-p-tolyl-acetamide
  • a solution of chloral hydrate (38 g, 0.223 mol), hydroxyl amine hydrochloride (41 g, 0.594 mol) and sodium sulphate (40 g, 0.281 mol) in water (800 mL) was heated to 9O 0 C.
  • To this mixture was added a solution of p-toluidine (20 g, 0.1866 mol) in cone. HCI (30 mL)
  • HCI (30 mL)
  • the resulting mixture was stirred for another 2 h.
  • the reaction mixture was cooled to room temperature, the precipitate was filtered and washed with water (100 mL). The solid was dried in a vacuum oven to get the required product as a grey coloured solid.
  • Example 14 is obtained as described in example 1 but starting from 2,3-diamino-5- methyl-benzoic acid methyl ester
  • Example 15 is obtained as described in example 1 but starting from 2'-fluorobiphenyl-4- carboxylic acid (prepared according to the literature method).
  • Step 2 4'-Trifluoromethoxy-biphenyl-4-carboxylic acid
  • acetone 10 ml.
  • the Jone's reagent was added slowly at O 0 C drop wise until reaction completes.
  • Acetone was removed completely and the residue was diluted with water, extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried over sodium sulphate and concentrated to obtain the title compound (0.7 g, 77%).
  • Example 17 is obtained as described in example 1 but starting from 3'-fluorobiphenyl-4- carboxylic acid (prepared according to the literature method Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), (1 ), 35-7; 1984).
  • Exam ple 1 8 is obtai n as d esc bed in 1 but starting from 3'- (trifluoromethoxy)biphenyl-4-carboxylic acid.
  • reaction mixture was warmed to room temperature and stirred for 4h. When the reaction is completed, the reaction mixture was poured into crushed ice. The precipitate was collected by filtration and washed several times with chilled water, then dried in a vaccum oven to the required product as a yellow coloured solid.
  • Step 4 3-[(Biphenyl-4-carbonyl)-amino]-2-hydroxy-benzoic acid methyl ester
  • Exam ple 20 is obta i ned as descri bed i n exa m ple 1 but starti n g from 2 ,6- dimethoxybiphenyl-4-carboxylic acid.
  • Step 2 2, ⁇ -Dimethoxy-biphenyM-carboxylic acid
  • Example 21 is obtained as described in example 1 but starting from 2,3 ,5,6- tetrafluorobiphenyl-4-carboxylic acid
  • Step 1 4-Bromo-2, 3, 5, 6-tetrafluoro-benzoic acid methyl ester
  • Step 2 2, 3, 5, ⁇ -Tetrafluoro-biphenyl- ⁇ carboxylic acid methyl ester
  • Step 3 2, 3, 5, ⁇ -Tetrafluoro-biphenyM-carboxylic acid
  • Step 4 2-(2, 3, 5, 6-Tetrafluoro-biphenyl-4-yl)-1H-benzoimidazole-4-carboxylic acid
  • Example 22 is obtained as described in example 1 but starting from 4-(3-thienyl)benzoic acid (prepared according to the literature method Tetrahedron letters 42(38), 6683-6686;
  • Example 23 is obtained as described in example 14 but starting from 4-(3- thienyl)benzoic acid .
  • Exam ple 24 is obtained as described in example 1 but starting from 2', 3- difluorobiphenyl-4-carboxylic acid (prepared as described in PCT lnt Appl. 2005009941 03 Feb 2005).
  • Example 25 is obtained as described in example 14 but starting from 2', 3- difluorobiphenyl-4-carboxylic acid.
  • Example 26 is obtained as described in example 14 but starting from 2'-fluorobiphenyl-4- carboxylic acid (prepared according to the literature method J Med Chem 47(2), 335-374, 2004).
  • Example 27 is obtained as described in example 1 but starting from 3-fluorobiphenyl-4- carboxylic acid (prepared according to the literature method
  • Example 28 is obtained as described in example 14 but starting from 3-fluorobiphenyl-4- carboxylic acid.
  • 1H NMR (300 MHz, DMSOd 6 ): ⁇ (ppm) 12.20(br.s, 1 H), 8.42-8.27(m, 1 H), 7.83- 7.25(m, 4H), 7.54-7.44(m, 5H), 2.50(s, 3H).
  • HPLC purity 93.70%.
  • Example 29 is obtained as described in example 5 but starting from 3-fluorobiphenyl-4- carboxylic acid (prepared according to the literature method Tetrahedron letter, 46(24), 4255-4259, 2005).
  • Example 30 is obtained as described in example 1 but starting from 2', 3, 4'- trifluorobiphenyl-4-carboxylic acid.
  • Step 1 3, 2', 4'-Trifluoro-biphenyl-4-carboxaldehyde
  • Step 2 3, 2', 4'-Trifluoro-biphenyl-4-carboxylic acid:
  • Example 31 is obtained as described in example 14 but starting from 2', 3,4'- trifluorobiphenyl-4-carboxylic acid.
  • Example 32 is obtained as described in example 1 but starting from 2',4'- difluorobiphenyl-4-carboxylic acid (prepared according to the literature method J Med Chem 47(2), 355-374; 2004).
  • Example 33 is obtained as described in example 14 but starting from 2', 4'- difluorobiphenyl-4-carboxylic acid.
  • Example 34 is obtained as described in example 5 but starting from 2', 3, 4'- trifluorobiphenyl-4-carboxylic acid.
  • Example 35 is obtained as described in example 1 but starting from methyl 2,3-diamino- 5-chlorobenzoate.
  • Example 36 is obtained as described in example 5 but starting from 1 H-indole-5- carboxylic acid (commercially procured from Aldrich).
  • Example 37 is obtained as described in example 5 but starting from 1 H-indole-6- carboxylic acid (commercially procured from Aldrich).
  • Example 39 is obtained as described in example 1 but starting from 1 -naphthoic acid (commercially procured from Aldrich).
  • Example 40 is obtained as described in example 14 but starting from 1 H-indole-2- carboxylic acid(commercially procured from Aldrich).
  • Example 41 is obtained as described in example 14 but starting from 2,3,5,6- tetrafluorobiphenyl-4-carboxylic acid.
  • Example 42 is obtained as described in example 14 but starting from 1H-indole-3- carboxylic acid(commercially procured from Aldrich).
  • Example 43 is obtained as described in example 1 but starting from 3- (trifluoromethyl)benzene-1,2-diamine
  • Step 1 N-(3-Trifluoromethyl-phenyl)-acetamide
  • 3-trifluoromethyl-phenylamine (4 g, 24.8 mmol), acetic anhydride (10.1 g, 99.3 mmol), DMAP (0.9 g, 7.4 mmol) and triethyl amine (2.5 g, 24.8 mmol) was heated to reflux 2h.
  • the reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the combined organic layers were dried over sodium sulphate and concentrated to dryness.
  • the obtained residue was purified by column chromatography using 30% ethylacetate in hexane to get the title compound as off-white solid.
  • N-(3-trifluoromethyl-phenyl)-acetamide (2.8 g, 13.7 mmol) was added in small portions to the cold fuming nitric acid (10 ml.) taken in a dry round bottom flask at -10 0 C. The reaction mixture was stirred for another 10 minutes at the same temperature then quenched with water (50 ml.) and extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated to dryness. The obtained residue was purified by column chromatography using 20% ethylacetate in hexane to get the title compound as yellow solid (0.9 g, 27.74%).
  • Example 44 is obtained as described in example 35 but starting from 3-fluorobiphenyl-4- carboxylic acid
  • Example 45 is obtained as described in example 35 but starting from 2'-fluorobiphenyl-4- carboxylic acid.
  • Example 46 is obtained as described in example 14 but starting from 3- methoxybiphenyl-4-carboxylic acid.
  • Example 47 is obtained as described in example 14 but starting from 4-(1 ,3- benzothiazol-2-yl)benzoic acid (synthesized using protocol described in U.S., 6251689, 26 Jun 2001 ).
  • Exam ple 48 is obtai ned as described in example 14 but starting from 3,5- difluorobiphenyl-4-carboxylic acid (prepared according to the literature method PCT Int. Appl., 2005009941 , 03 Feb 2005).
  • Example 49 is obtained as described in example 14 but starting from 4-phenylthiophene- 2-carboxylic acid (commercially procured from Aldrich).
  • Example 50 is obtained as described in example 1 but starting from 6-phenylnicotinic acid (Prepared according to the literature method Tetrahedron letter 45(29), 5661-5663; 2004).
  • Example 51 is obtained as described in example 61 but starting from a-Amino-5-chloro- 3-iodo-benzoic acid methyl ester (commercially procured from aldrich).
  • HPLC purity 94.90%.
  • Example 52 is obtained as described in example 14 but starting from 2', 3'- difluorobiphenyl-4-carboxylic acid. Step 1: 2', S'-Difluoro-biphenyl- ⁇ carboxylic acid methyl ester
  • Step 2 2', S'-Difluoro-biphenyl- ⁇ carboxylic acid
  • Step 3 2-(2 ', 3 '-Difluoro-biphenyl-4-yl)-6-methyl- 1 H-benzoimidazole-4-carboxylic acid
  • Example 53 is obtained as described in example 14 but starting from 5-phenylpyridine-2- carboxylic acid (prepared according to the literature method PCT Int. Appl., 2005020899, 10 Mar 2005).
  • Example 54 is obtained as described in example 1 but starting from 4- (phenylsulfonyl)benzoic acid.
  • Example 55 is obtained as described in example 1 but starting from 4-anilinobenzoic acid (prepared according to the literature method Zhurnal Obshchei Khimii, 30, 2693-8; 1960).
  • Example 56 is obtained as described in example 1 but starting from 4-(2,6- difluorophenoxy)benzoic acid.
  • Example 57 is obtained as described in example 1 but starting from 4-pyridin-4-ylbenzoic acid (prepared according to the literature method Synlett, (6), 829-831 ; 2000).
  • HPLC purity 93.93%.
  • Example 58 is obtained as described in example 5 but starting from 4-pyridin-3-ylbenzoic acid (prepared according to the literature method Synlett, (6), 829-831 ; 2000).
  • Example 59 is obtained as described in example 14 but starting from 4-pyridin-3- ylbenzoic acid.
  • Example 60 is obtained as described in example 1 but starting from 2', 3'- difluorobiphenyl-4-carboxylic acid.
  • Step 5 2-Biphenyl-4-yl-1H-indole-7-carboxylic acid To a solution of 2-amino-3-iodo-benzoic acid methyl ester (500 mg, 1.8 mmol), 4- ethynyl-biphenyl (416 mg, 2.3 mmol) in THF (20 ml_), CuI (17 mg, 0.09 mmol), bis- (triphenylphosphine)-palladium (ll)-chloride (64 mg, 0.09 mmol) and TEA (0.75 ml_, 5.4 mmol) were added. This mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC.
  • reaction mass was filtered through celite, and the collected filtrate was diluted with ethyl acetate (30 ml_), washed with water (2x20 ml.) and the combined organic layer was separated and dried over sodium sulphate and concentrated under reduced pressure to obtain brown mass which was purified by column chromatography using 5% ethyl acetate in hexane as an eluent to obtain 450 mg of 2-amino-3-biphenyl-4-ylethynyl-benzoic acid methyl ester as a pale yellow coloured solid (76%).
  • Example 62 is obtained as described in example 1 but starting from 4-morpholin-4- ylbenzoic (prepared according to the literature method: Bioorganic and medicinal chemistry letters 15(5), 1529-1534; 2005).
  • Example 63 is obtained as described in example 1 but starting from 4-(2-oxopyridin- 1 (2H)-yl)benzoic acid (prepared according to the literature method: Bioorganic and medicinal chemistry letters 17(16), 4419-4427; 2007).
  • Example 64 is obtained as described in example 14 but starting from 4-(2-oxopyridin- 1 (2H)-yl)benzoic acid.
  • HPLC purity 87.39%.
  • Exam ple 65 is obtain ed as descri bed in exam ple 1 but starti ng from 2', 6'- difluorobiphenyl-4-carboxylic acid (prepared according to the literature method:J Med Chem. 47(2), 355-374; 2004).
  • Example 66 is obtained as described in example 1 but starting from 4-(4,5-dimethyl-1 ,3- oxazol-2-yl)benzoic acid.
  • Step 1 Terephthalic acid 1 -methyl ester 4-(1-methyl-2-oxo-propyl) ester
  • Step 2 4-(4, 5-Dimethyl-oxazol-2-yl)-benzoic acid methyl ester
  • Step 3 4-(4, 5-Dimethyl-oxazol-2-yl)-benzoic acid.
  • Step 4 2-[4-(4, ⁇ -Dimethyl-oxazol ⁇ -y ⁇ -phenylJ-SH-benzoimidazole ⁇ -carboxylic acid
  • Example 67 is obtained as described in example 14 but starting from 4-phenoxybenzoic acid (commercially procured from aldrich).
  • Example 68 2-(3,5-Difluoro-biphenyl-4-yl)-6-fluoro-1 H-benzoimidazole-4- carboxylic acid
  • Example 68 is obtained as described in example 5 but starting from 3,5-difluorobiphenyl- 4-carboxylic acid (prepared according to the literature method: PCT Int. Appl., 2005009941, 03 Feb 2005).
  • Example 69 is obtained as described in example 1 , but from 1-(2,3- diaminophenyl)ethanone.
  • Step 4:1-(2,3-Diamino-phenyl)-ethanone A slurry of 1-(2-amino-3-nitro-phenyl)-ethanone (0.2 g, 1.1 1 mmol) and 10% palladium on carbon (0.020 g) in methanol (10 ml.) was hydrogenated with a hydrogen balloon for 2 h. After completion of the reaction, the reaction mixture was filtered and evaporated under vacuum to obtain the title compound as off white solid (0.120 g, 72.28%)
  • Example 70 is obtained as described in example 1 but starting from 4-(pyridin-2- yloxy)benzoic acid (prepared according to the literature method: Synlett, (2), 221-224; 2008).
  • Example 71 is obtained as described in example 14 but starting from 4-(pyridin-2- yloxy)benzoic acid.
  • Example 72 is obtained as described in example 14 but starting from 4- (pentafluorophenoxy)benzoic acid.
  • Example 73 is obtained as described in example 1 but starting from 4-pyridin-2-ylbenzoic acid (Prepared according to the literature method: Bioorganic and medicinal chemistry letters 15(3), 631-634; 2005).
  • Example 74 is obtained as described in example 14 but starting from 4-pyridin-2- ylbenzoic acid.
  • Example 75 is obtained as described in example 14 but starting from 6-phenylnicotinic acid (prepared according to the literature method: Tetrahedron letter 45(29), 5661 -5663;
  • Example 76 is obtained as described in example 14 but from 2',6'-difluorobiphenyl-4- carboxylic acid (prepared according to the literature method: J Med Chem. 47(2), 355-
  • Example 77 is obtained as described in example 1 but starting from 4-(4- cyanophenoxy)benzoic acid.
  • Example 78 is obtained as described in example 14 but starting from 4-(4- cyanophenoxy)benzoic acid.
  • Step 3 2-Amino-3-nitro-benzoic acid To a ice cold solution of 7-nitro-1 H-indole-2,3-dione (9 g, 47 mmol) in 2 M aqueous sodium hydroxide (50 mL), an aq. solution of 30% hydrogen peroxide (9 mL) was added drop wise. The mixture was warmed to room temperature and stirred overnight. The resulting mixture was carefully acidified by the addition of an aq. saturated citric acid solution. The solid precipitate was collected by filtration, washed with water and dried in a vacuum oven to get 6 g of the required product as a yellow coloured solid (70%).
  • Example 80 is obtained as described in example 14 but starting from 4-(2-oxoazepan-1- yl)benzoic acid (prepared according to the literature method: Bioorganic and medicinal chemistry letters 17(16), 4419-4427, 2007).
  • Example 81 is obtained as described in example 1 but starting from 4-(2-oxoazepan-1- yl)benzoic acid.
  • HPLC purity 90.10 %.
  • Example 82 2-[4-(2,5-Dimethyl-pyrrol-1 -yl)-2,3,5,6-tetrafluoro-phenyl]-6- methyl-1 H-benzoimidazole-4-carboxylic acid
  • Example 82 is obtained as described in example 1 but starting from 4-(2,5-Dimethyl- pyrrol-1-yl)-2,3,5,6-tetrafluoro-benzoic acid.
  • Step 1 4-Amino-2, 3, 5, 6-tetrafluoro-benzoic acid methyl ester
  • Step 2 4-(2, 5-Dimethyl-pyrrol-1-yl)-2, 3, 5, 6-tetrafluoro-benzoic acid methyl ester
  • Step 3 4-(2, 5-Dimethyl-pyrrol-1-yl)-2, 3, 5, 6-tetrafluoro-benzoic acid
  • Step 4 2-[4-(2,5-Dimethyl-pyrrol-1-yl)-2,3,5,6-tetrafluoro-phenyl]-6-methyl-1H- benzoimidazole-4-carboxylic acid
  • Step 1 2, 3, 5, 6-Tetrafluoro-4'-formyl-biphenyl-4-carboxylic acid methyl ester
  • a tolune / Water (175 mL+25 mL) mixture was degassed with nitrogen for 30 minutes.
  • Cesium carbonate (14.9 g, 43.55 mmol) was added followed by 4-bromo-2, 3,5,6- tetrafluoro-benzoic acid methyl ester (5.0 g, 17.42 mmol), 4-formyl boronic acid (3.4 g, 22.64 mmol) and dichlorobis(triphenylphosphine)-palladium(ll) catalyst (0.611 g, 0.87 mmol).
  • the reaction mixture was refluxed for 15 h. TLC shows completion of the reaction.
  • the reaction mixture was cooled to room temperature and was extracted with ethyl acetate.
  • Step 2 2, 3, 5, 6-Tetrafluoro-4'-hydroxymethyl-biphenyl-4-carboxylic acid methyl ester
  • Step 4 4'-(tert-Butyl-dimethyl-silanyloxymethyl)-2, 3, 5, 6-tetrafluoro-biphenyl-4- carboxylic acid
  • Step 5 2-Amino-3- ⁇ [4 '-(tert-butyl-dimethyl-silanyloxymethyl)-2, 3, 5, 6-tetrafluoro-biphenyl- 4-carbonyl]-amino ⁇ -5-methyl-benzoic acid methyl ester
  • Step 6 2-[4 '-(tert-Butyl-dimethyl-silanyloxymethyl)-2, 3, 5, 6-tetrafluoro-biphenyl-4-yl]-6- methyl-1H-benzoimidazole-4-carboxylic acid methyl ester
  • Step 7 6-Methyl-2-(2, 3, 5, 6-tetrafluoro-4 '-hydroxymethyl-biphenyl-4-yl)- 1 H- benzoimidazole-4-carboxylic acid methyl ester
  • Step 8 6-Methyl-2-(2, 3, 5, 6-tetrafluoro-4 '-formyl-biphenyl-4-yl)- 1 H-benzoimidazole-4- carboxylic acid methyl ester
  • Step 9 6-Methyl-2-(2, 3, 5, 6-tetrafluoro-4 '-piperidin-1 -ylmethyl-biphenyl-4-yl)- 1 H- benzoimidazole-4-carboxylic acid methyl ester
  • Step 10 6-Methyl-2-(2, 3, 5, 6-tetrafluoro-4 '-piperidin- 1 -ylmethyl-biphenyl-4-yl)- 1 H- benzoimidazole-4-carboxylic acid
  • Example 84 is obtained as described in example 14 but starting from phenyl-propynoic acid (procured commercially from aldrich).
  • 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 610nm.
  • Buffer Preparation 50 mM tris HCI, 150 mM KCI, and pH 8.0, 0.8% triton.
  • Percent inhibition is calculated as follows 100 * ⁇ (AbSfiin for reaction containing compound) - (Absgin for positive control) (Abs 6 io for no enzyme reaction)- (Abs 6 io 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 of the compound of formula I to be examined was prepared. 1/3rd dilutions were made as follows:
  • Example 194 Measurement of Cell Proliferation (Jurkat Cell) See also Roehm, N et al [1991] An improved colorimetric assay for cell proliferation and viability utilizing the tetrazolium salt XTT. J. Immunol. Methods 142:257-265.
  • Reagents Roswells park memorial institute's medium (RPMI-1640 complete media) pH-7.4 ⁇ 0.2 (Sigma R6504).
  • DMSO Dimethyl sulfoxide
  • Spectrochem purchased from Spectrochem, (cat no.0704209, B. no. - 3183650 MEM Cat. No. M0268, Sigma).
  • Fetal Bovine Serum Cat. No. F9665, Sigma Aldrich.
  • XTT sodium salt Sigma Cat. No. X4251 ).
  • PMS Sigma Cat. No. 68600).
  • RPMI media supplemented with antibiotics, 10% FBS, Sodium Pyruvate and NEA (non essential amino acids).
  • XTT - A freshly prepared solution of XTT is made in the growth medium , with a final concentration of 1 mg/ml.
  • PMS - Stock is prepared with 1x PBS at 0.383 mg/ml and stored in aliquots at -20 0 C.
  • Test solution Serially diluted DMSO solutions are further diluted with media to 2x the required concentration in well.
  • DMSO concentration should be kept constant at 0.25 - 0.5% for all wells.
  • compound concentration can start at 10 ⁇ M followed by half log dilutions for a total of 8-10 concentrations. Each concentration has to be tested in triplicate.
  • XTT assay to each well, add 50 ⁇ l_ of 1 mg/ml XTT solution with 20 ⁇ l of PMS/mL Read the plates after 2 hours at 465 nm using the spectrophotometer. XTT reading for media without cells is used as background reading.
  • Formulation 1 Tablets A compound of formula I and related formulae is admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg of active compound according to the invention per tablet) in a tablet press.
  • Formulation 2 Capsules
  • a compound of formula I and related formulae is admixed as a dry powder with a starch diluent in an approximate 1 :1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of active compound according to the invention per capsule).
  • Formulation 3 Liquid A compound of formula I and related formulae (1250 mg), sucrose (1 .75 g) and xanthan gum (4 mg) are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously prepared solution of microcrystalline cellulose and sodium carboxymethyl cellulose (1 1 :89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color are diluted with water and added with stirring. Sufficient water is then added to produce a total volume of 5 ml_.
  • Formulation 4 Tablets
  • a compound of formula I and related formulae is admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio.
  • a minor amount of magnesium stearate is added as a lubricant.
  • the mixture is formed into 450-900 mg tablets (150-300 mg of active compound according to the invention) in a tablet press.
  • a compound of formula I and related formulae is dissolved in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/mL.

Abstract

The invention relates to compounds of formula (I) wherein R1, R2, X1, X2, Y, Ra, Rb, Q have the meanings given in claim 1. The compounds are useful e.g. in the treatment of autoimmune disorders, such as multiple sclerosis and also in the treatment of cancer disorders.

Description

Dihydroorotate Dehydrogenase inhibitors.
The present invention relates to Dihydroorotate Dehydrogenase inhibitors, their use as medicament and their use for treating multiple sclerosis and other diseases such as inflammatory disorders, rheumatoid arthritis and cancer. In particular, the invention relates to compounds of formula I:
Figure imgf000003_0001
Wherein
R1 denotes COOH, COOA, COA, CF3, acyl, cyano, Het, tetrazoyl, sulfonyl, or if Q is -CΞC- or Hetarylene, or if Q is a tetrasubstituted Arylene, R1 also denotes
CON(R3)2 or CONHA. R2 denotes H, Hal, A, 0-A, Ar; Ra denotes Ar, Het, O-Het, NH-Het, O-Ar, -O-(CH2)m-Het, -NH-(CH2)m-Het, NH-Ar,
S(O)2Ar, S(O)Ar, -S-Ar, OCF3, Y denotes CRf or N
X1, X2 denote each independently of one another CRcRd, NRC, NRd, and when Y denote CRf, also O or S, provided that one of X1 and X2 is CRcRd or NRC;
Rb and Rc together represent a chemical bond;
Rf and Re together represent a chemical bond, when Y is CRf
Re and Rc, in the definition of X1, together represent a chemical bond when Y is N, and
Rb and Rc, in the definition of X2, together represent a chemical bond; Rd denotes H, A, -(CH2)m-COOH;
Q denotes a group -CΞC-, Arylene, Hetarylene, or the group
Figure imgf000004_0001
Hal denotes F, Cl, Br or I;
A is a branched or linear alkyl having 1 to 12 C-atoms, wherein one or more, preferably 1 to 7 H-atoms may be replaced by Hal, OR3, CN or N(R3)2 and wherein one or more, preferably 1 to 7 non-adjacent CH2-groups may be replaced by O, or S and/or by -CH=CH- or -C≡C- groups, or denotes cycloalkyl or cycloalkylalkylen having 3-7 ring C atoms;
Ar denotes a monocyclic or bicyclic, saturated, unsaturated or aromatic carbocyclic ring having 6 to 14 carbon atoms which may be unsubstituted or substituted by a group selected from (R4)n and/or (R5)n ;
Het denotes a monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic ring having 1 to 4 N, O and/or S atoms which may which may be unsubstituted or substituted by a group selected from (R4)n and/or (R5)n ;
Arylene denotes a divalent monocyclic or bicyclic, saturated, unsaturated or aromatic carbocyclic ring having 6 to 14 carbon atoms which may be unsubstituted or substituted by a group selected from (R4)n and/or (R5)n ;
Hetarylene denotes a divalent monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic ring having 1 to 4 N, O and/or S atoms which may which may be unsubstituted or substituted by a group selected from (R4)n and/or (R5)n ;
R3 is H or alkyl;
R4 and R5 are each independently selected from Hal, hydroxy, alkoxy, carboxy, carboxy- alkyl, perfluoro-alkyl, perfluoro-alkyloxy, acyl, alkylsulfonyl, sulfonyl, cyano, nitro, amino, amido, alkyl optionally substituted by a carboxy, or Het-alkyl optionally substituted by an acyl , alkylsulfonyl, -O(CH2)nAr, -O(CH2)nHet, -(CH2)mHet, OA, -NHCO(CH2)mAr, NHCO- (CH2)mHet , CONHA, or alkyl; n denotes 0,1 ,2,3,4,5; and m denotes 0,1 ,2,3,4,5,6; and pharmaceutically acceptable derivatives, solvates, tautomers, salts and stereoiso- mers thereof, including mixtures thereof in all ratios.
Formula I also includes all tautomeric forms. Preferred tautomeric forms are represented by the following formulae for example wherein X1 and X2 are NRC or NRd, Rd is H, Rb and Rc form a bond and R1 is COOH , R2, Q, Ra are as defined above, Y is CRf wherein Rf is as defined above:
Figure imgf000005_0001
More particularly, the invention relates to the use of compounds of formula I and pharmaceutically acceptable derivatives, solvates, tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios as a medicament, especially for treating multiple sclerosis and other diseases such as inflammatory disorders, rheumatoid arthritis and cancer.
The compounds of formula I and related formulae preferably are inhibitors of dihydroorotate dehydrogenase (DHODH or DHOD). DHODH is a protein which catalyzes the fourth step in de novo pyrimidine nucleotide pathway. (Greene et al. Biochem Pharmacol 1995, 50:861-7; Davis J . P et al. FASEB J 1996, 10(6) : Abst C23). It catalyses 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.
I n hibitors of d ihyd roorotate dehydrogenase have found wider application as chemotherapeutic agents. Initially explored as anticancer drugs (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[1 ,1 '-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 have also been suggested as antibiotics, especially against Helicobacter Pylori (Marcinkeviciene et al. Biochem Pharmacol. 2000, 60, 339; Haque, T. S. et al. , J . Med . Chem. 2002, 45, 4669-4678), useful for treating Plasmodium falciparum related diseases (Heikkila, T. et al . J Med Chem . 50: 1 86 -91 (2007); Heikkila, T. et al. Bioorg Med Chem Lett. 16: 88 -92 (2006)), and as antifungal agents (Gustafson, G. et al. Curr. Genet. 1996, 30, 159).
DHODH inhibitors can also be useful for the treatment of viral mediated diseases (see US 6,841 ,561 ).
Furthermore, inhibition of DHODH is a 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., lmmunolog Rev.(1993) 136, 51-70; Davis J. P et al. Biochemistry 1996, 35 :1270-3.).
Leflunomide, a well known DHODH inhibitor is a synthetic, low-molecular weight drug of the isoxazole class (see EP0527736, JP 1993506425, JP 1999322700, JP 1999343285, US 549491 1 , US5532259, WO19991017748). This drug is currently marketed 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.). Another study examined the activity of Teriflunomide on the proliferation of spleen colony-forming units (CFU) and shows that Teriflunomide in a dose-dependently manner inhibited CFU cycling (Milenkovic, P. et al. Exp Hematol 1995, 23: Abst 121.)- The effects of Teriflunomide on the behavioral consequences of experimental allergic encephalomyelitis (EAE) were assessed in female Lewis rats to determine the drug's potential utility in multiple sclerosis. Oral treatment with Teriflunomide at 3 and 10mg/kg or with dexamethasone at 1 mg/kg began 10 days after inoculation with guinea pig spinal cord and Freund's adjuvant, when clonal expansion of inflammatory and immune cells had already occurred. Both compounds caused a significant delay in the onset of disease and in symptom severity (Styren, S. D. et al. Beneficial effects of Teriflunomide in experimental allergic encephalomyelitis. 34th Annu Meet Soc Neurosci (Oct 23-27, San Diego) 2004, Abst 344.5.).
Teriflunomide was tested in a phase Il study in 179 patients with multiple sclerosis with relapses. Once-daily oral treatment with this drug (7 and 14mg) for 369 weeks led to a reduced number of unique active lesions as compared to placebo. (Li, D. K. B. et al. Multiple Scler 2004, 10(Suppl. 2) : Abst P685.)
An increasing number of patients affected by autoimmune and related diseases require new d rugs th at can treat su ch d iseases . There is sti l l a cru cial n eed 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 are 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.
A primary objective of the present invention is to provide novel compounds of formula I and related formulae which are inhibitors of dihydroorotate dehydrogenase. In particular, the invention refers to novel compounds, which inhibits DHODH, to a process for their manufacture and pharmaceutical compositions containing them, and to their use for the treatment and prevention in diseases, in particular their use in diseases where there is an advantage in inhibiting DHODH. The compounds of formula I and related formulae 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.
More particularly, the present invention relates to compounds of formula I and related formulae for the treatment of multiple sclerosis and related diseases, rheumatoid arthritis and transplant rejection.
The inventions further relates to the use of compounds according to formula I and related formulae in combination with immunomodulating agents such as Fingolimod; cyclosporins, rapamycins or ascomycins, or their immunosuppressive analogs, e.g. cyclosporin A, cyclosporin G, FK-506, ABT-281 , ASM981 , rapamycin, 40-O-(2- hydroxy)ethyl-rapamycin etc.; corticosteroids; cyclophosphamide; azathioprene; methotrexate; leflunomide; mizoribine; mycophenolic add; mycophenolate mofetil; 15- deoxyspergualine; diflucortolone valerate; difluprednate; Alclometasone dipropionate; amcinonide; amsacrine; asparaginase; azathioprine; basiliximab; beclometasone dipropionate; betamethasone; betamethasone acetate; betamethasone dipropionate; betamethasone phosphate sodique; betamethasone valerate; budesonide; captopril; chlormethine chlorhydrate; cladribine; clobetasol propionate; cortisone acetate; cortivazol; cyclophosphamide; cytarabine; daclizumab; dactinomycine; desonide; desoximetasone; dexamethasone; dexamethasone acetate; dexamethasone isonicotinate; dexamethasone metasulfobenzoate sodique; dexamethasone phosphate;dexamethasone tebutate;dichlorisone acetate; doxorubicine chlorhydrate; epirubicine chlorhydrate; fluclorolone acetonide; fludrocortisone acetate; fludroxycortide; flumetasone pivalate; flunisolide; fluocinolone acetonide; fluocinonide; fluocortolone; fluocortolone hexanoate; fluocortolone pivalate; fluorometholone; fluprednidene acetate; fluticasone propionate; gemcitabine chlorhydrate; halcinonide; hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone hemisuccinate melphalan; meprednisone; mercaptopurine; methylprednisolone; methylprednisolone acetate; methylprednisolone hemisuccinate; misoprostol; muromonab-cd3; mycophenolate mofetil; paramethasone acetate; prednazoline, prednisolone; prednisolone acetate; prednisolone caproate; prednisolone metasulfobenzoate sodique; prednisolone phosphate sodique; prednisone; prednylidene; rifampicine; rifampicine sodique; tacrolimus; thalidomide; thiotepa; tixocortol pivalate; triamcinolone; triamcinolone acetonide hemisuccinate; triamcinolone benetonide; triamcinolone diacetate; triamcinolone hexacetonide; immunosuppressive monoclonal antibodies, e.g., monoclonal antibodies to leukocyte receptors, e.g., MHC, CD2, CD3, CD4, CD7, CD25, CD28, B7, CD40, CD45 or CD58 or their ligands; or other immunomodulatory compounds, e.g. CTLA41 g, or other adhesion molecule inhibitors, e.g. mAbs or low molecular weight inhibitors including Selectin antagonists and VLA-4 antagonists. A preferred composition is comprising a compound of formula I and Cyclosporin A, FK506, rapamycin, 40-(2-hydroxy)ethyl-rapamycin or Fingolimod.;
The dihydroorotate dehydrogenase inhibitors according to formula I and related formulae 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.
The following abbreviations refer respectively to the definitions below: aq (aqueous), h (hour), g (gram), L (liter), mg (milligram), MHz (Megahertz), μM (micormolar) min. (minute), mm (millimeter), mmol (millimole), mM (millimolar), m.p. (melting point), eq (equivalent), ml. (milliliter), μl_ (microliter), ACN or MeCN (acetonitrile), BINAP (2,2'-bis(disphenylphosphino)-1 ,1 '-binaphthalene, BOC (tert- butoxy-carbonyl), CBZ (carbobenzoxy), CDCI3 (deuterated chloroform), CD3OD
(deuterated methanol), c-hex (cyclohexane), DCC (dicyclohexyl carbodiimide), DCM (dichloromethane), DIC (diisopropyl carbodiimide), DIEA (diisopropylethyl-amine), DMF (dimethylformamide), DMSO (dimethylsulfoxide), DMSO-d6 (deuterated dimethylsulfoxide), EDC (1-(3-dimethyl-amino-propyl)-3-ethylcarbodiimide), ESI (Electro- spray ionization), EtOAc (ethyl acetate), Et20 (diethyl ether), EtOH (ethanol), FMOC (fluorenylmethyloxycarbonyl), HATU (dimethylamino-([1 ,2,3]triazolo[4,5-b]pyridin-3- yloxy)-methylene]-dimethyl-ammonium hexafluorophosphate), HPLC (High Performance Liquid Chromatography), i-PrOH (2-propanol), K2CO3 (potassium carbonate), LC (Liquid Chromatography), MeOH (methanol), MgSO4 (magnesium sulfate), MS (mass spectrometry), MTBE (Methyl tert-butyl ether), Mtr. ( 4-Methoxy-2, 3, 6- trimethylbenzensulfonyl), MW(microwave), NaHCO3 (sodium bicarbonate), NaBH4 (sodium borohydride), NMM (N-methyl morpholine), NMR (Nuclear Magnetic Resonance), PPA (polyphosphoric acid), POA (phenoxyacetate), PyBOP® (benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate), RT (room temperature), Rt (retention time), SPE (solid phase extraction), TBTU (2-(1-H- benzotriazole-1-yl)-1 ,1 ,3,3-tetramethyluromium tetrafluoro borate), TEA (triethylamine), TFA (trifluoroacetic acid), THF (tetrahydrofuran), TLC (Thin Layer Chromatography), UV (Ultraviolet).
Depending on the nature of X1, X2, Ra, Rb, Rc, Rd, Re, R1, R2, Y, and Q, different synthetic strategies may be selected for the synthesis of compounds of formula I and related formulae. In the process illustrated in the following schemes, X1, X2, Ra, Rb, Rc, Rd, Re, R1, R2, Y and Q are as above defined in the description.
In general, the dihidroorotate dehydrogenase inhibitors according to formula I and related formulae of this invention may be prepared from readily available starting materials. If such starting materials are not commercially available they may be prepared by standard synthetic techniques. The following general methods and procedures described hereinafter in the examples may be employed to prepare compounds of formula I and related formulae.
The process for the preparation of compounds of formula I and related formulae, wherein X1, X2, Ra, Rb, Rc, Rd, Re, R1, R2, Y and Q are as defined above, and as outlined in the following schemes, is also object of the invention.
In Scheme 1 , coupling of aryl-1 ,2 diamine of formula (A) with an acid of formula (B) is achieved in the presence of a coupling agent such as HATU or from the corresponsding acid chloride (prepared from acid of formula B with a chorinating reagent such as thionyl chloride or oxalyl chloride) in a solvent such as DMF to form a compound of formula (C). Compound (C) will undergo cyclization for example in AcOH under reflux to give the corresponding compound of formula I, wherein X1 and X2 are NRC, NRd and Rb and Rc together represent a chemical bond, and wherein Y is CRf, Rf and Re together represent a bond, according to scheme 1 ;
Scheme1
Figure imgf000011_0001
An alternative route for compounds of formula (I), wherein X1 and X2 are NRC, NRd, wherein Y is CRf, Rf and Re together form a bond, and wherein Rb and Rc together represent a chemical bond and wherein Q represents a single bond, involves the reaction of aryl-1 ,2 diamine of formula (A) with an aldehyde of formula (G) to form the intermediate (H) which can undergo oxydation in the presence an oxydative reagent such as oxygen to form compounds of formula (I).
In case of formula I wherein X1 is O and X2 is NRC and Rb and Rc together represent a chemical bond, Y is CRf, Rf and Re together form a bond, the 2-Amino-Phenol derivatives (D) will react with the acyl-chloride (B') derived from the corresponding acid (B), in a solvent such as DCM in the presence of a base such as TEA. Compound (J) will undergo cyclization for example in the presence of PPA in an appropriate solvent to give the corresponding compound of formula I wherein X1 is O and X2 is NRd according to scheme 2.
Scheme 2
Figure imgf000012_0001
In case of formula I wherein X1 is NRd and X2 is CRcRd and Rb and Rc together represent a chemical bond, Y is CRf, Rf and Re together form a bond, the iodoaniline (E) will react with ethynyl derivatives (F) in the presence of a CuI, a palladium catalyst such as PdCI2(PPh3)2, a polar solvent such as THF and a suitable base to give the corresponding compound of formula Iwherein X1 is NRd and X2 is CH according to scheme 3.
Scheme 3
Figure imgf000012_0002
Alternative reaction conditions can be used as described in Naoyuki Suzuki, et al. Chem. Pharm. Bull., Vol. 51 , 1170-1 173 (2003), or Yashuhara et al. J. Chem. Soc, Perkin Trans. 1 , 1999, 529-534.
If the above set out general synthetic methods are not applicable for the obtention of compounds of formula I and related formulae, suitable methods of preparation known by a person skilled in the art should be used.
The pharmaceutically acceptable cationic salts of compounds of the present invention are readily prepared by reacting the acid forms with an appropriate base, usually one equivalent, in a co-solvent. Typical bases are sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium hydroxide, potassium methoxide, magnesium hydroxide, calcium hydroxide, benzathine, choline, diethanolamine, ethylenediamine, meglumine, benethamine, diethylamine, piperazine, lysine, arginine, and tromethamine. The salt is isolated by concentration to dryness or by addition of a non-solvent. In some cases, salts can be prepared by mixing a solution of the acid with a solution of the cation (sodium ethylhexanoate, magnesium oleate), employing a solvent in which the desired cationic salt precipitates, or can be otherwise isolated by concentration and addition of a non-solvent.
According to a further general process, compounds of formula I and related formulae, (A), (B), (B'), (C), (D), (E) (F), (G) and (J) can be converted to alternative compounds of formula I and related formulae, employing suitable interconversion techniques well known by a person skilled in the art.
In general, the synthesis pathways for any individual compound of formula I and related formulae will depend on the specific substitutents 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 formula I and related formulae, 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 formula I and related formulae , which contain an acid center, with a suitable base. Both types of salts may be formed or interconverted using ion-exchange resin techniques.
Depending on the conditions used, the reaction times are generally between a few minutes and 14 days, and the reaction temperature is between about -300C and 1400C, normally between -10°C and 900C, in particular between about 0°C and about 70°C.
Compounds of the formula I and related formulae can furthermore be obtained by liberating compounds of the formula I from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent.
Preferred starting materials for the solvolysis or hydrogenolysis are those which conform to the formula I and related formulae, but contain corresponding protected amino and/or hydroxyl groups instead of one or more free amino and/or hydroxyl groups, preferably those which carry an amino-protecting group instead of an H atom bonded to an N atom, in particular those which carry an R'-N group, in which R' denotes an amino-protecting group, instead of an HN group, and/or those which carry a hydroxyl-protecting group instead of the H atom of a hydroxyl group, for example those which conform to the formula I, but carry a -COOR" group, in which R" denotes a hydroxyl-protecting group, instead of a -COOH group.
It is also possible for a plurality of - identical or different - protected amino and/or hydroxyl groups to be present in the molecule of the starting material. If the protecting groups present are different from one another, they can in many cases be cleaved off selectively.
The term "amino-protecting group" is known in general terms and relates to groups which are suitable for protecting (blocking) an amino group against chemical reactions, but which are easy to remove after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino-protecting groups are removed after the desired reaction (or reaction sequence), their type and size are furthermore not crucial; however, preference is given to those having 1-20, in particular 1-8, carbon atoms. The term "acyl group" is to be understood in the broadest sense in connection with the present process. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and, in particular, alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl, such as acetyl, propionyl and butyryl; aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl and tolyl; aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2- trichloroethoxycarbonyl, BOC (tert-butoxycarbonyl) and 2-iodoethoxycarbonyl; aralkoxycarbonyl, such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl and FMOC; and arylsulfonyl, such as Mtr. Preferred amino-protecting groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl and acetyl.
The term "hydroxyl-protecting group" is likewise known in general terms and relates to groups which are suitable for protecting a hydroxyl group against chemical reactions, but are easy to remove after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl or acyl groups, furthermore also alkyl groups. The nature and size of the hydroxyl-protecting groups are not crucial since they are removed again after the desired chemical reaction or reaction sequence; preference is given to groups having 1-20, in particular 1-10, carbon atoms. Examples of hydroxyl-protecting groups are, inter alia, benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, where benzyl and tert-butyl are particularly preferred.
The compounds of the formula I and related formulae are liberated from their functional derivatives - depending on the protecting group used - for example using strong acids, advantageously using TFA or perchloric acid, but also using other strong inorganic acids, such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids, such as trichloroacetic acid, or sulfonic acids, such as benzene- or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but is not always necessary. Suitable inert solvents are preferably organic, for example carboxylic acids, such as acetic acid, ethers, such as tetrahydrofuran or dioxane, amides, such as DMF, halogenated hydrocarbons, such as dichloromethane, furthermore also alcohols, such as methanol, ethanol or isopropanol, and water. Mixtures of the above-mentioned solvents are furthermore suitable. TFA is preferably used in excess without addition of a further solvent, and perchloric acid is preferably used in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9:1. The reaction temperatures for the cleavage are advantageously between about 0 and about 500C, preferably between 15 and 300C (room temperature).
The BOC, OBut and Mtr groups can, for example, preferably be cleaved off using TFA in dichloromethane or using approximately 3 to 5N HCI in dioxane at 15-30°C, and the FMOC group can be cleaved off using an approximately 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-300C.
Protecting groups which can be removed hydrogenolytically (for example CBZ, benzyl or the liberation of the amidino group from the oxadiazole derivative thereof) can be cleaved off, for example, by treatment with hydrogen in the presence of a catalyst (for example a noble-metal catalyst, such as palladium, advantageously on a support, such as carbon). Suitable solvents here are those indicated above, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as DMF. The hydrogenolysis is generally carried out at temperatures between about 0 and 1000C and pressures between about 1 and 200 bar, preferably at 20-300C and 1-10 bar. Hydrogenolysis of the CBZ group succeeds well, for example, on 5 to 10% Pd/C in methanol or using ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-30°C.
Examples of suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1 ,2- dichloroethane, tetrachloromethane, trifluoromethylbenzene, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n- butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethyl- formamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids, such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of the said solvents.
Esters can be saponified, for example, using acetic acid or using LiOH, NaOH or KOH in water, water/THF, water/THF/ethanol or water/dioxane, at temperatures between 0 and 1000C.
Free amino groups can furthermore be acylated in a conventional manner using an acid chloride or anhydride or alkylated using an unsubstituted or substituted alkyl halide or reacted with CH3-C(=NH)-OEt, advantageously in an inert solvent, such as dichloromethane or THF and/or in the presence of a base, such as triethylamine or pyridine, at temperatures between -60°C and +30°C.
Throughout the specification, the term leaving group preferably denotes Cl, Br, I or a reactively modified OH group, such as, for example, an activated ester, an imidazolide or alkylsulfonyloxy having 1-6 carbon atoms (preferably methylsulfonyloxy or trifluoro- methylsulfonyloxy) or arylsulfonyloxy having 6-10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy).
Radicals of this type for activation of the carboxyl group in typical acylation reactions are described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme- Verlag, Stuttgart).
Activated esters are advantageously formed in situ, for example through addition of HOBt or N-hydroxysuccinimide.
The formula I and related formulae also encompasses the optically active forms (stereoisomers), the enantiomers, the racemates, tautomers, the diastereomers and the hydrates and solvates of these compounds. The term "solvates of the compounds" is taken to mean adductions of inert solvent molecules onto the compounds which form owing to their mutual attractive force. Solvates are, for example, mono- or dihydrates or alcoholates.
The term "pharmaceutically usable derivatives" is taken to mean, for example, the salts of the compounds of the formula I and so-called prodrug compounds.
The term "prodrug derivatives" is taken to mean compounds of the formula I which have been modified with, for example, alkyl or acyl groups, sugars or oligopeptides and which are rapidly cleaved in the organism to form the active compounds. Preferably "prodrug", as of the compounds of formula I , refers to derivative compounds that are rapidly transformed in vivo to yield the parent compound of the formula I, as for example by hydrolysis in blood. T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in "Pro-drugs as Novel Delivery Systems", VoI 14 of the A.C.S. Symposium Series, American Chemical Society (1975). Examples of esters useful as prodrugs for compounds containing carboxyl groups can be found on pages 14-21 of "Bioreversible Carriers in Drug Design: Theory and Application", edited by E. B. Roche, Pergamon Press: New York (1987). It is intended that these references, and any others cited throughout this specification, are incorporated herein by reference.
These also include biodegradable polymer derivatives of the compounds according to the invention, as described, for example, in Int. J. Pharm. 115, 61-67 (1995). The formula I and related formulae also encompasses mixtures of the compounds of the formula I, for example mixtures of two diastereomers, for example in the ratio 1 :1 , 1 :2, 1 :3, 1 :4, 1 :5, 1 :10, 1 :100 or 1 :1000. These are particularly preferably mixtures of stereoisomeric compounds.
Very particularly, prefered embodiments of formula I are the compounds of formula II, III:
Figure imgf000018_0001
wherein X1, X2, Rb, R1, R2, R4, R5, n are as defined above. Formula Il and formula wherein R1 is COOH, are especially prefered.
Preference is given to the compounds of the present invention selected from the following group 11 to 1192:
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
and pharmaceutically acceptable derivatives, solvates, tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios.
Alternatively, the present invention provides compounds of Formula (I) wherein R1 is CONHA, Ra is A or -O-(CH2)m-Ar, Q is a single bond, wherein A denotes a branched or linear alkyl having 1 to 12 C-atoms, wherein one or more, preferably 1 to 7 H-atoms may be replaced by Hal, OR3, CN or N(R3)2 and wherein one or more, preferably 1 to 7 non- adjacent CH2-groups may be replaced by O, NR3 or S and/or by -CH=CH- or -C≡C- groups, or denotes cycloalkyl or cycloalkylalkylen having 3-7 ring C atoms;
Above and below, all radicals, such as X1, X2, Q, R1, R2, R3, R4, R5, Ra, Rb, Rc,Rd, Re, A, Het, Ar, have the meaning indicated under the formula I, unless expressly stated otherwise.
Generally, compounds of formula I are the more preferred, the more preferred substiutents they carry.
X1 preferably denotes NRC, NRd, or O, especially NRC. X2 preferably denotes NRC, NRdor CRcRd.
In a preferred embodiment, one of X1 or X2 denotes NRC or NRd
In another preferred embodiment, both X1 and X2 denote NRC or NRd
R1 preferably denotes COOH, COOalkyl, A, COOA, COA, Het, CONHA, cyano, acyl, R1 most preferably denotes one of the following groups:
COOH, COOMe, COO(CH2)2OH, COO(CH2)2OR3, CN, COMe, CONH2, CONHOMe,
Figure imgf000031_0001
wherein R3 is as defined above. R2 preferably denotes H, A, alkyl, Hal, O-alkyl, O-A, especially H, Me, OMe, F, Cl or Br.
Rd preferably denotes H, A or alkyl, especially H.
Ra preferably denotes Ar, Het, O-Ar, O-Het, especially Ar or Het.
Ra more preferably denotes phenyl, pyridinyl, oxazolyl, thienyl, benzothiazolyl.
Ravery most preferably denotes phenyl, pyridinyl, or pyrrole.
Ra most preferably denotes one of the following groups:
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Wherein A, R3, Rd, m and Het are as defined above Q preferably denotes Arylene, Hetarylene, especially Arylene or Hetarylene. Q more preferably denotes divalent group derived from phenyl, pyridinyl, thienyl, or indolyl.
Q very most preferably denotes divalent group derived from phenyl or pyridinyl. Q most preferably denotes a single bond, a triple bond, or one of the following groups:
Figure imgf000035_0001
The group A very particularly preferably denotes alkyl having 1 , 2, 3, 4, 5 or 6 carbon atoms.
Alkyl preferably denotes methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1 ,1-, 1 ,2- or 2,2- dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1 ,1-, 1 ,2-, 1 ,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1 ,1 ,2- or 1 ,2,2-trimethylpropyl, furthermore preferably, for example, trifluoromethyl, pentafluoroethyl or 1 ,1 ,1 -trifluoroethyl.
Cycloalkyl preferably denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
Cycloalkylalkylene preferably denotes cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, cyclohexylmethylene or cycloheptylmethylene.
Alkylene is preferably methylene, ethylene, propylene, butylene, pentylene or hexylene, furthermore branched alkylene.
Perfluoroalkyl preferably denotes CF3.
Hal denotes Cl, Br, I, F and preferably F or Br.
Alkoxy is branched or linear and preferably denotes a group -O-(CH2)n-CH3. Most preferablyalkoxy is Methoxy or Ethoxy. Carboxy denotes a group -COOH.
Carboxyalkyl denotes an ester group, preferably an alkyl ester, such as COOMe or COOEt.
Sulfonyl denotes a group -SO2-OH, -SO2-NH2, -SO2NHA.
Alkylsulfonyl denotes a group -SO2-alkyl, preferably Methylsulfonyl or Ethylsulfonyl.
Acyl denotes a group -C(O)R, wherein R can be A, Ar, Het as defined above. Preferably Acyl denotes acetyl (-C(O)CH3).
Amino denotes the group -NRR'" where each R, R'" is independently hydrogen or alkyl or Ar or Het or A or Het-alkyl or Ar-alkyl, and where R and R'", together with the nitrogen atom to which they are attached, can optionally form a 3-8-membered Het ring.
Amido refers to the group -C(O)NRR'" where each R, R'" is independently hydrogen or alkyl or Ar or Het or A or Het-alkyl or Ar-alkyl, and where R and R'", together with the nitrogen atom to which they are attached, can optionally form a 3-8-membered Het ring.
Ar preferably denotes phenyl, which may be unsubstituted or monosubstituted, disubstituted or trisubstituted by a substitutent selected from R4 and/or R5;
Ar very particularly preferably denotes one of the following groups:
Figure imgf000036_0001
wherein R4 and R3 are as defined above.
More particulary, Ar is one of the following groups:
Figure imgf000037_0001
wherein R , R is as defined above and preferably, wherein R is Hal and R is Hal, alkyl, O-alkyl or H.
Most preferably, Ar is unsubtituted or
Figure imgf000037_0002
Arylene is preferably a divalent group derived from Ar and more preferably denotes phenyl, which may be unsubstituted or monosubstituted, disubstituted or trisubstituted by a substitutent selected from R4 and/or R5;
Arylene very particularly preferably denotes one of the following groups:
Figure imgf000037_0003
wherein R and R5 are as defined above.
More particulary, Arylene is one of the following groups:
Figure imgf000037_0004
wherein R , R is as defined above and preferably, wherein R is Hal and R is Hal, alkyl, O-alkyl or H. Het preferably denotes a monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic ring having 1 to 3 N, O and/or S atoms which may which may be unsubstituted or substituted by a group selected from (R4)n and/or (R5)n ;
Het more preferably denotes a monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic ring having 1 to 3 N, O and/or S atoms which may which may be unsubstituted or substituted by a group selected from (R4)n and/or (R5)n ;
Het is preferably a 6 to 14 membered ring system and denotes, not withstanding further substitutions, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1 ,2,3-triazol-1-, -4- or -5-yl, 1 ,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1 , 2, 3-oxadiazol-4- or -5-yl, 1 , 2, 4-oxadiazol-3- or -5-yl, 1 ,3,4-thiadiazol-2- or -5-yl, 1 ,2,4-thiadiazol-3- or -5-yl, 1 ,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, indazolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, A-, 5-, 6- or 7-benzothiazolyl, 2-, A-, 5-, 6- or 7-benzisothiazolyl, A-, 5-, 6- or 7-benz-2,1 ,3-oxadiazolyl, 2-, 3-, A-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, A-, 5-, 6-, 7- or 8-isoquinolyl, 3-, A-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or
6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1 ,4-oxazinyl, furthermore preferably 1 ,3- benzodioxol-5-yl, 1 ,4-benzodioxane-6-yl, 2,1 ,3-benzothiadiazol-4- or -5-yl or 2,1 ,3-benz- oxadiazol-5-yl.
The heterocyclic radicals may also be partially or fully hydrogenated. Het can thus also denote, for example, 2,3-dihydro-2-, -3-, -A- or -5-furyl, 2,5-dihydro-2-, -3-, -A- or -5-furyl, tetrahydro-2- or -3-furyl, 1 ,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -A- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -A- or -5- pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1 ,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1 ,2,3,4- tetrahydro-1-, -2-, -3-, -A-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or
4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1 ,4-dioxaneyl, 1 ,3-dioxane-2-, -A- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -A- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1 ,2,3,4-tetrahydro-1-, -2-, -3-, -A-, -5-, -6-, -7- or -8-quinolyl, 1 ,2,3,4- tetrahydro-1-, -2-, -3-, -A-, -5-, -6-, -7- or -8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or 8-3,4-dihydro- 2H-benzo-1 ,4-oxazinyl, furthermore preferably 2,3-methylenedioxyphenyl, 3,4- methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4-(difluoro- methylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or -6-yl, 2,3-(2-oxomethylenedioxy)- phenyl or also 3,4-dihydro-2H-1 ,5-benzodioxepin-6- or -7-yl, furthermore preferably 2,3- dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl.
Het very particularly denotes one of the following groups:
Figure imgf000039_0001
Hetarylene is preferably derived from the group Het as defined above and is most preferably
Figure imgf000040_0001
Wherein R and R5 are as defined above.
In another specific embodiment, the invention provides compounds of formula I wherein R1 denotes COOH, COOalkyl, CF3, acyl, cyano, preferably COOH;
In another specific embodiment, the invention provides compounds of formula I wherein R1 denotes COOH, COOMe, CF3, acetyl, cyano;
In another specific embodiment, the invention provides compounds of formula I wherein R1 denotes COOH, COOalkyl, CF3, acyl, cyano; R2 denotes H, Hal, alkyl, O-alkyl;
In another specific embodiment, the invention provides compounds of formula I wherein R1 denotes COOH, COOMe, CF3, acetyl, cyano; R2 denotes H, F, Cl or Br, Me, OMe;
In another specific embodiment, the invention provides compounds of formula I wherein R1 denotes COOH, COOalkyl, CF3, acyl, cyano; R2 denotes H, Hal, alkyl, O-alkyl; X1 and X2 are as define above; In another specific embodiment, the invention provides compounds of formula I wherein R1 denotes COOH, COOMe, CF3, acetyl, cyano; R2 denotes H, F, Cl or Br, Me, OMe; X1 and X2 are as define above;
In another specific embodiment, the invention provides compounds of formula I wherein R1 denotes COOH, COOalkyl, CF3, acyl, cyano; R2 denotes H, Hal, alkyl, O-alkyl; X1 and X2 are as define above; Rd is H or alkyl;
In another specific embodiment, the invention provides compounds of formula I wherein R1 denotes COOH, COOMe, CF3, acetyl, cyano; R2 denotes H, F, Cl or Br, Me, OMe; X1 and X2 are as define above; Rd is H or Me;
In another specific embodiment, the invention provides compounds of formula I wherein R1 denotes COOH, COOalkyl, CF3, acyl, cyano; R2 denotes H, Hal, alkyl, O-alkyl; X1 and X2 are as define above; Rd is H or alkyl; Q denotes Arylene, Hetarylene;
In another specific embodiment, the invention provides compounds of formula I wherein R1 denotes COOH, COOMe, CF3, acetyl, cyano; R2 denotes H, F, Cl or Br, Me, OMe; X1 and X2 are as define above; Rd is H or Me; Q denotes Arylene, Hetarylene;
In another specific embodiment, the invention provides compounds of formula I wherein R1 denotes COOH, COOalkyl, CF3, acyl, cyano; R2 denotes H, Hal, alkyl, O-alkyl; X1 and X2 are as define above; Rd is H or alkyl; Q denotes Arylene, Hetarylene
In another specific embodiment, the invention provides compounds of formula I wherein R1 denotes COOH, COOMe, CF3, acetyl, cyano; R2 denotes H, F, Cl or Br, Me, OMe; X1 and X2 are as define above; Rd is H or Me; Q denotes Arylene, Hetarylene;
In another specific embodiment, the invention provides compounds of formula I wherein R1 denotes COOH, COOalkyl, CF3, acyl, cyano; R2 denotes H, Hal, alkyl, O-alkyl; X1 and X2 are as define above; Rd is H or alkyl; Q denotes Arylene, Hetarylene; In another specific embodiment, the invention provides compounds of formula I wherein R1 denotes COOH, COOMe, CF3, acetyl, cyano; R2 denotes H, F, Cl or Br, Me, OMe; X1 and X2 are as define above; Rd is H or Me; Q denotes Arylene, Hetarylene;
In another specific embodiment, the invention provides compounds of formula I wherein R1 denotes COOH, COOalkyl, CF3, acyl, cyano; R2 denotes H, Hal, alkyl, O-alkyl; X1 and X2 are as define above; Rd is H or alkyl; Q denotes -NH-, NHC(O)-; Ra denotes Ar, O-Ar, 0-(CH2)m-Ar, Het, O-Het, NH-Ar, SO2Ar; m denotes 0,1 ,2;
In another specific embodiment, the invention provides compounds of formula I wherein R1 denotes COOH, COOMe, CF3, acetyl, cyano; R2 denotes H, F, Cl or Br, Me, OMe; X1 and X2 are as define above; Rd is H or Me; Q denotes Arylene, Hetarylene ;Ra denotes Ar, O-Ar, O-(CH2)m-Ar, Het, O-Het, NH-Ar, SO2Ar; m denotes 0,1 ,2;
In another specific embodiment, the invention provides compounds of formula I wherein R1 denotes COOH, COOalkyl, CF3, acyl, cyano; R2 denotes H, Hal, alkyl, O-alkyl; X1 and X2 are as define above; Rd is H or alkyl; Q denotes Arylene, Hetarylene; Ra denotes Ar, O-Ar, O-(CH2)m-Ar, Het, O-Het, NH-Ar, SO2Ar; m denotes 0,1 ,2;
In another specific embodiment, the invention provides compounds of formula I wherein R1 denotes COOH, COOMe, CF3, acetyl, cyano; R2 denotes H, F, Cl or Br, Me, OMe; X1 and X2 are as define above; Rd is H or Me; Q denotes Arylene, Hetarylene; Ra denotes Ar, O-Ar, O-(CH2)m-Ar, Het, O-Het, NH-Ar, SO2Ar; m denotes 0,1 ,2;
In another specific embodiment, the invention provides compounds of formula I wherein R1 denotes COOH, COOalkyl, CF3, acyl, cyano; R2 denotes H, Hal, alkyl, O-alkyl; X1 and X2 are as define above d; Rd is H or alkyl; Q denotes -NH-, NHC(O)-; Ra denotes Ar, O- Ar, O-(CH2)m-Ar, Het, O-Het, NH-Ar, SO2Ar; m denotes 0,1 ,2; wherein Ar is selected from phenyl or naphtyl and Het is selected from pyridinyl, thienyl, indolyl, benzothiazolyl, morpholino, pyridinyl-2-one, oxazolyl, azepan-2-one; wherein Ar and Het as defined are unsubstituted or substituted by a group selected from (R4)n and/or (R5)n; wherein R4 and/or R5 are each independently selected from Hal, alkoxy, perfluoroalkyl, perfluoroalkoxy, alkyl, cyano; n denotes 0,1 ,2,3,4,5; In another specific embodiment, the invention provides compounds of formula I wherein R1 denotes COOH, COOMe, CF3, acetyl, cyano; R2 denotes H, F, Cl or Br, Me, OMe; X1 and X2 are as define above; Rd is H or Me; Q denotes -NH-, NHC(O)-; Ra denotes Ar, O- Ar, 0-(CH2)m-Ar, Het, O-Het, NH-Ar, SO2Ar; m denotes 0,1 ,2; wherein Ar is selected from Phenyl or Naphtyl and Het is selected from pyridinyl, thienyl, indolyl, benzothiazolyl, morpholino, pyridinyl-2-one, oxazolyl, azepan-2-one; wherein Ar and Het as defined are unsubstituted or substituted by a group selected from (R4)n and/or (R5)n; wherein R4 and/or R5 are each independently selected from F, Cl or Br, OMe, CF3, OCF3, Me, cyano; n denotes 0,1 ,2,3,4,5;
In another specific embodiment, the invention provides compounds of formula I wherein R1 denotes COOH, COOalkyl, CF3, acyl, cyano; R2 denotes H, Hal, alkyl, O-alkyl; X1 and X2 are as define above; Rd is H or alkyl; Q denotes Arylene, Hetarylene; Ra denotes Ar, O-Ar, 0-(CH2)m-Ar, Het, O-Het, NH-Ar, SO2Ar; m denotes 0,1 ,2; wherein Ar is selected from Phenyl or Naphtyl and Het is selected from pyridinyl, thienyl, indolyl, benzothiazolyl, morpholino, pyridinyl-2-one, oxazolyl, azepan-2-one; wherein Ar and Het as defined are unsubstituted or substituted by a group selected from (R4)n and/or (R5)n; wherein R4 and/or R5 are each independently selected from Hal, alkoxy, Perfluoroalkyl, perfluoroalkoxy, alkyl, cyano; n denotes 0,1 ,2,3,4,5;
In another specific embodiment, the invention provides compounds of formula I wherein R1 denotes COOH, COOMe, CF3, acetyl, cyano; R2 denotes H, F, Cl or Br, Me, OMe; X1 and X2 are as define above; Rd is H or Me; Q denotes Arylene, Hetarylene; Ra denotes Ar, O-Ar, O-(CH2)m-Ar, Het, O-Het, NH-Ar, SO2Ar; m denotes 0,1 ,2; wherein Ar is selected from Phenyl or Naphtyl and Het is selected from pyridinyl, thienyl, indolyl, benzothiazolyl, morpholino, pyridinyl-2-one, oxazolyl, azepan-2-one; wherein Ar and Het as defined are unsubstituted or substituted by a group selected from (R4)n and/or (R5)n; wherein R4 and/or R5 are each independently selected from F, Cl or Br, OMe, CF3, OCF3, Me, cyano; n denotes 0,1 ,2,3,4,5;
In a very specific embodiment the invention provides compounds of formula Il
Figure imgf000044_0002
wherein
R1, R2, X1, X2, Ra, Rb, R4 and n are as defined in formula I, and pharmaceutically acceptable derivatives, solvates, tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios;
In a very specific prefered embodiment the invention provides compounds of formula Na
Figure imgf000044_0003
wherein R1, R2, X2' Ra, R4 are as described in formula Il and pharmaceutically acceptable derivatives, solvates, tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios;
In a very specific prefered embodiment the invention provides compounds of formula Nb
Figure imgf000044_0001
Wherein R1, R2, X1' Ra, R4 are as described in formula Il and pharmaceutically acceptable derivatives, solvates, tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios;
In a very specific embodiment the invention provides compounds of formula
Figure imgf000045_0001
wherein
R1, R2, X1, X2, Ra, Rb, R4, R5 and n are as defined in formula I, and pharmaceutically acceptable derivatives, solvates, tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios;
In a very specific embodiment the invention provides compounds of formula Ilia
Figure imgf000045_0002
wherein R1, R2, X2, R4, R5, n are as described in formula III and pharmaceutically acceptable derivatives, solvates, tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios;
In a very specific embodiment the invention provides compounds of formula INb
Figure imgf000045_0003
wherein R1, R2, X1, R4, R5, m are as described in formula III and pharmaceutically acceptable derivatives, solvates, tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios; The compounds of the formula I, II, Na, lib, III, Ilia, 1Mb and also the starting materials for the preparation thereof are, in addition, prepared by methods known per se, as described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme- Verlag, Stuttgart), under reaction conditions which are known and suitable for the said reactions. For all the protection and deprotection methods, see Philip J. Kocienski, in "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994 and, Theodora W. Greene and Peter G. M. Wuts in "Protective Groups in Organic Synthesis", Wiley Interscience, 3rd Edition 1999. Use can also be made here of variants which are known per se, but are not mentioned here in greater detail.
If desired, the starting materials can also be formed in situ so that they are not isolated from the reaction mixture, but instead are immediately converted further into the compounds of the formula I.
The starting compounds for the preparation of compounds of formula I are generally known. If they are novel, they can, however, be prepared by methods known per se.
The reactions are preferably carried out in an inert solvent. Examples of suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1 ,2- dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide or dimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids, such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of the said solvents.
Accordingly, the invention relates, in particular, to the use of compounds of the formula I, II, Na, lib, III, Ilia, INb as defined above, wherein X1, X2, R1, R2, R3, R4, R5, Q, Ra and Rb , Rc , Rd, Ar, Het and alkyl are as defined above as a medicament. Accordingly, the invention relates, in particular, to the use of compounds of the formula I,
II, Na, lib, III, Ilia, 1Mb as defined above, wherein X1, X2, R1, R2, R3, R4, R5, Q, Ra and Rb , Rc , Rd, Ar, Het and alkyl are as defined above for the preparation of pharmaceutical formulation for the prevention and/or the treatment of multiple sclerosis and related disorders.
The said compounds of the formula I, II, Na, lib, III, Ilia, INb can be used in their final non-salt form. On the other hand, the present invention also relates to the use of these compounds in the form of their pharmaceutically acceptable salts, which can be derived from various organic and inorganic acids and bases by procedures known in the art. Pharmaceutically acceptable salt forms of the compounds of the formula I are for the most part prepared by conventional methods. If the compound of the formula I, II, Na, lib,
III, Ilia, INb contains an acidic center, such as a carboxyl group, one of its suitable salts can be formed by reacting the compound with a suitable base to give the corresponding base-addition salt. Such bases are, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; alkaline earth metal hydroxides, such as barium hydroxide and calcium hydroxide; alkali metal alkoxides, for example sodium- or potassium methoxide and sodium or potassiumpropoxide, alkalihydrides, such as sodium- or potassiumhydride; and various organic bases, such as piperidine, diethanolamine and N-methyl-glutamine, benzathine, choline, diethanolamine, ethylenediamine, meglumine, benethamine, diethylamine, piperazine and tromethamine. The aluminium salts of the compounds of the formula I, II, Na, lib, III, Ilia, INb are likewise included. In the case of certain compounds of the formula I and related formulae, which contain a basic center, acid-addition salts can be formed by treating these compounds with pharmaceutically acceptable organic and inorganic acids, for example hydrogen halides, such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other mineral acids and corresponding salts thereof, such as sulfate, nitrate or phosphate and the like, and alkyl- and monoaryl-sulfonates, such as ethanesulfonate, toluenesulfonate and benzene-sulfonate, and other organic acids and corresponding salts thereof, such as acetate, trifluoro-acetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate and the like. Accordingly, pharmaceutically acceptable acid-addition salts of the compounds of the formula I and related formulae include the following: acetate, adipate, alginate, arginate, aspartate, benzoate, benzene-sulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphor-sulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclo-pentane-propionate, digluconate, dihydrogen-phosphate, dinitrobenzoate, dodecyl-sulfate, ethanesulfonate, fumarate, galacterate (from mucic acid), galacturonate, glucoheptanoate, gluco-nate, glutamate, glycerophosphate, hemi-succinate, hemisulfate, heptanoate, hexanoate, hippurate, hydro-chloride, hydrobromide, hydroiodide, 2- hydroxy-ethane-sulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, mono-hydrogen-phosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmo-ate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but this does not represent a restriction. Both types of salts may be formed or interconverted preferably using ion-exchange resin techniques.
Furthermore, the base salts of the compounds of the formula I, II, Na, lib, III, Ilia, INb include aluminium, ammonium, calcium, copper, iron(lll), iron(ll), lithium, magne-sium, manganese(lll), manganese(ll), potassium, sodium and zink salts, but this is not intended to represent a restriction. Of the above-mentioned salts, preference is given to ammonium; the alkali metal salts sodium and potassium, and the alkaline earth metal salts calcium and magnesium. Salts of the compounds of the formula I which are derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, also including naturally occurring substituted amines, cyclic amines, and basic ion exchanger resins, for example arginine, betaine, caffeine, chloroprocaine, choline, N,N'-dibenzyl-ethylen-ediamine (benzathine), dicyclohexylamine, diethanol-amine, diethyl-amine, 2-diethyl-amino-ethanol, 2- dimethyl-amino-ethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N- ethyl-piperidine, glucamine, glucosamine, histidine, hydrabamine, isopropyl-amine, lido-caine, lysine, meglumine (N-methyl-D-glucamine), morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanol-amine, triethylamine, trimethylamine, tripropyl-amine and tris(hydroxy-methyl)-methylamine (tromethamine), but this is not intended to represent a restriction.
Compounds of the formula I, II, Na, lib, III, Ilia, INb of the present invention which contain basic nitrogen-containing groups can be quaternised using agents such as (Ci-C4)-alkyl halides, for example methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; di(Ci-C4)alkyl sulfates, for example dimethyl, diethyl and diamyl sulfate; (CiO-Ci8)alkyl halides, for example decyl, do-decyl, lauryl, myristyl and stearyl chloride, bromide and iodide; and aryl-(Ci-C4)alkyl halides, for example benzyl chloride and phenethyl bromide. Both water- and oil-soluble compounds of the formula I can be prepared using such salts.
The above-mentioned pharmaceutical salts which are preferred include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, me-glumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stea-rate, sulfate, subsalicylate, tartrate, thiomalate, tosylate and tro-meth-amine, but this is not intended to represent a restriction.
The acid-addition salts of basic compounds of the formula I, II, Na, lib, III, Ilia, INb are prepared by bringing the free base form into contact with a sufficient amount of the desired acid, causing the formation of the salt in a conventional manner. The free base can be regenerated by bringing the salt form into contact with a base and isolating the free base in a conventional manner. The free base forms differ in a certain respect from the corresponding salt forms thereof with respect to certain physical properties, such as solubility in polar solvents; for the purposes of the invention, however, the salts other-wise correspond to the respective free base forms thereof.
As mentioned, the pharmaceutically acceptable base-addition salts of the compounds of the formula I are formed with metals or amines, such as alkali metals and alkaline earth metals or organic amines. Preferred metals are sodium, potassium, magnesium and calcium. Preferred organic amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanol-amine, ethylenediamine, N-methyl-D-glucamine and procaine.
The base-addition salts of acidic compounds of the formula I, II, Na, lib, III, Ilia, INb are prepared by bringing the free acid form into contact with a sufficient amount of the desired base, causing the formation of the salt in a conventional manner. The free acid can be regenerated by bringing the salt form into contact with an acid and isolating the free acid in a conventional manner. The free acid forms differ in a certain respect from the corresponding salt forms thereof with respect to certain physical properties, such as solubility in polar solvents; for the purposes of the invention, however, the salts other-wise correspond to the respective free acid forms thereof.
If a compound of the formula I, II, Na, lib, III, Ilia, 1Mb contains more than one group which is capable of forming pharmaceutically acceptable salts of this type, the formula I also encompasses multiple salts. Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, di-phosphate, disodium and trihydrochloride, but this is not intended to represent a restriction.
With regard to that stated above, it can be seen that the term "pharmaceutically acceptable salt" in the present connection is taken to mean an active ingredient which comprises a compound of the formula I, II, Na, lib, III, Ilia, INb 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.
Owing to their molecular structure, the compounds of the formula I, II, Na, lib, III, Ilia, INb can be chiral and can accordingly occur in various enantiomeric forms. They can therefore exist in racemic or in optically active form. Since the pharmaceutical activity of the racemates or stereoisomers of the compounds according to the invention may differ, it may be desirable to use the enantiomers. In these cases, the end product or even the intermediates can be separated into enantiomeric compounds by chemical or physical measures known to the person skilled in the art or even employed as such in the synthesis.
In the case of racemic amines, diastereomers are formed from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (for example N-benzoylproline or N-benzenesulfonylproline), or the various optically active camphorsulfonic acids. Also advantageous is chromatographic enantiomer resolution with the aid of an optically active resolving agent (for example dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chirally derivatised methacrylate polymers immobilised on silica gel). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as, for example, hexane/isopropanol/ acetonitrile, for example in the ratio 82:15:3.
The invention furthermore relates to the use of compounds of formula I, II, Na, lib, III, Ilia,
INb in combination with at least one further medicament active ingredient, preferably medicaments used in the treatment of multiple sclerosis such as cladribine or another co-agent, such as interferon, e.g. pegylated or non-pegylated interferons, preferably interferon beta and/or with compounds improving vascular function or in combination with immunomodulating agents for example Fingolimod; cyclosporins, rapamycins or ascomycins, or their immunosuppressive analogs, e.g. cyclosporin A, cyclosporin G, FK- 506, ABT-281 , ASM981 , rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin etc.; corticosteroids; cyclophosphamide; azathioprene; methotrexate; leflunomide; mizoribine; mycophenolic add; mycophenolate mofetil; 15-deoxyspergualine; diflucortolone valerate; difluprednate; Alclometasone dipropionate; amcinonide; amsacrine; asparaginase; azathioprine; basiliximab; beclometasone dipropionate; betamethasone; betamethasone acetate; betamethasone dipropionate; betamethasone phosphate sodique; betamethasone valerate; budesonide; captopril; chlormethine chlorhydrate; cladribine; clobetasol propionate; cortisone acetate; cortivazol; cyclophosphamide; cytarabine; daclizumab; dactinomycine; desonide; desoximetasone; dexamethasone; dexamethasone acetate; dexamethasone isonicotinate; dexamethasone metasulfobenzoate sodique; dexamethasone phosphate;dexamethasone tebutate;dichlorisone acetate; doxorubicine chlorhydrate; epirubicine chlorhydrate; fluclorolone acetonide; fludrocortisone acetate; fludroxycortide; flumetasone pivalate; flunisolide; fluocinolone acetonide; fluocinonide; fluocortolone; fluocortolone hexanoate; fluocortolone pivalate; fluorometholone; fluprednidene acetate; fluticasone propionate; gemcitabine chlorhydrate; halcinonide; hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone hemisuccinate; melphalan; meprednisone; mercaptopurine; methylprednisolone; methylprednisolone acetate; methylprednisolone hemisuccinate; misoprostol; muromonab-cd3; mycophenolate mofetil; paramethasone acetate; prednazoline, prednisolone; prednisolone acetate; prednisolone caproate; prednisolone metasulfobenzoate sodique; prednisolone phosphate sodique; prednisone; prednylidene; rifampicine; rifampicine sodique; tacrolimus; thalidomide; thiotepa; tixocortol pivalate; triamcinolone; triamcinolone acetonide hemisuccinate; triamcinolone benetonide; triamcinolone diacetate; triamcinolone hexacetonide; immunosuppressive monoclonal antibodies, e.g., monoclonal antibodies to leukocyte receptors, e.g., MHC, CD2, CD3, CD4, CD7, CD25, CD28, B7, CD40, CD45 or CD58 or their ligands; or other immunomodulatory compounds, e.g. CTLA41 g, or other adhesion molecule inhibitors, e.g. mAbs or low molecular weight inhibitors including Selectin antagonists and VLA-4 antagonists. A preferred composition is with Cyclosporin A, FK506, rapamycin or 40-(2- hydroxy)ethyl-rapamycin and Fingolimod. These further medicaments, such as interferon beta, may be administered concomitantly or sequentially, e.g. by subcutaneous, intramuscular or oral routes.
The invention furthermore relates to the use of compounds of formula I, II, Na, lib, III, Ilia, INb in combination with at least one further medicament active ingredient, preferably medicaments used in the treatment of cancer wherein said antitumoral compounds are selected from those well know by the one skilled in the related art. These compositions can be used as medicaments in human and veterinary medicine.
Pharmaceutical formulations can be administered in the form of dosage units, which comprise a predetermined amount of active ingredient per dosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of a compound according to the invention, depending on the disease condition treated, the method of administration and the age, weight and condition of the patient, or pharmaceutical formulations can be administered in the form of dosage units which comprise a predetermined amount of active ingredient per dosage unit. Preferred dosage unit formulations are those which comprise a daily dose or part-dose, as indicated above, or a corresponding fraction thereof of an active ingredient. Furthermore, pharmaceutical formulations of this type can be prepared using a process, which is generally known in the pharmaceutical art.
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.
Thus, for example, in the case of oral administration in the form of a 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. The compounds of the formula I, II, Na, lib, III, Ilia, 1Mb and salts, solvates and physiologically functional derivatives thereof and the other active ingredients can also be administered in the form of liposome delivery systems, such as, for exam-pie, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from various phospholipids, such as, for example, cholesterol, stearylamine or phosphatidylcholines.
The compounds of the formula I, II, Na, lib, III, Ilia, 1Mb and the salts, solvates and physiologically functional derivatives thereof and the other active ingredients can also be delivered using monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds can also be coupled to soluble polymers as targeted medicament carriers. Such polymers may encompass polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl-methacrylamidophenol, polyhydroxyethylaspartamido-phenol or polyethylene oxide polylysine, substituted by palmitoyl radicals. The compounds may furthermore be coupled to a class of biodegradable polymers which are suitable for achieving controlled release of a medicament, for example polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, poly-orthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
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.
In one aspect, the present invention provides the use of compounds according to formula (I) and related formulae, wherein R1 denotes COOH, COOA, COA, CONHA, CON(R3)2, CF3, acyl, cyano, Het, tetrazoyl, sulfonyl,; R2 denotes H, Hal, A, O-alkyl, Ar; Ra denotes H, A, Ar, Het, O-Het, NH-Het, O-Ar, -O-(CH2)m-Ar, -O-(CH2)m-Het, -NH-(CH2)m- Het, NH-Ar, S(O)2Ar, S(O)Ar, -S-Ar, OCF3,; Q denotes a single bond, a group -CΞC -, Arylene or Hetarylene and pharmaceutically acceptable derivatives, solvates, tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios as a medicament.
In a second aspect, the present invention relates the use of compounds according to formula (I) and related formulae, and pharmaceutically usable derivatives, salts, tautomers, solvates and stereoisomers thereof, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment and/or prophylaxis of diseases in which the inhibition, activation , regulation , and/or modulation of dihydroorotate dehydrogenase plays a role.
In a third aspect, the present invention relates to the use of compounds according to formula (I ) and related formulae, and pharmaceutically usable derivatives, salts, tautomers, solvates and stereoisomers thereof, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment and/or prophylaxis of a dihydroorotate dehydrogenase associated disorder.
In a fourth aspect, the present invention relates to the use of compounds according to formula (I) and related formulae, wherein the dihydroorotate dehydrogenase associated disorder is an autoimmune disorder or condition associated with an overactive immune response.
In a fifth aspect, the present invention related to the use of compounds according to formula (I) and related formulae, and pharmaceutically usable derivatives, salts, tautomers, solvates and stereoisomers thereof, including mixtures thereof in all ratios, for the preparation of a med icament for the treatment and/or prophylaxis of an immunerogulatory abnomality.
In a sixth aspect, the present invention relates to the use according to the fifth aspect, wherein the immunoregulatory abnormality is an autoimmune or chronic inflammatory disease selected from the group consisting of: systemic lupus erythematosis, chronic rheumatoid arthritis, type I diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, amyotrophic lateral sclerosis (ALS), Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves ophthalmopathy and asthma.
In a seventh aspect, the present invention relates to the use according to the sixth aspect, wherein the immunoregulatory abnormality is bone marrow or organ transplant rejection or graft-versus-host disease.
In a height aspect, the present invention relates to a kit or a set comprising at least one compound of Formula (I), preferably in combination with immunomodulating agents. Alternativelly, the kit consists of separate packs of : (a) an effective amount of a compound of the formula (I) and/or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and (b) an effective amount of a further medicament active ingredient.
A therapeutically effective amount of a compound of the formula I, II, Na, lib, III, Ilia, INb 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. The present invention furthermore relates to a method for treating a subject suffering from a Dihydroorate dehydrogenase related disorder, comprising administering to said subject an effective amount of a compound of formula I, II, Na, lib, III, Ilia, INb. The present invention preferably relates to a method, wherein the Dihydroorate dehydrogenase associated disorder is an autoimmune disorder or condition associated with an overactive immune response or cancer. The present invention furthermore relates to a method of treating a subject suffering from an immunerogulatory abnomality, comprising administering to said subject a compound of formula I, II, Na, lib, III, Ilia, INb in an amount that is effective for treating said immunoregulatory abnormality.The present invention preferably relates to a method wherein the immunoregulatory abnormality is an autoimmune or chronic inflammatory disease selected from the group consisting of: amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus, chronic rheumatoid arthritis, type I diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves ophthalmopathy and asthma. The present invention furthermore relates to a method wherein the immunoregulatory abnormality is bone marrow or organ transplant rejection or graft-versus-host disease. The present invention furthermore relates to a method wherein the immunoregulatory abnormality is selected from the group consisting of: transplantation of organs or tissue, graft-versus-host diseases brought about by transplantation, autoimmune syndromes including rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, postinfectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrhoeic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedemas, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus, Mooren's ulcer, scleritis, Graves' opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergies, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or inveterate asthma, late asthma and airway hyper- responsiveness, bronchitis, gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel diseases, inflammatory bowel diseases, necrotizing enterocolitis, intestinal lesions associated with thermal burns, coeliac diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture's syndrome, hemolytic-uremic syndrome, diabetic nephropathy, multiple myositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthyroidism, Basedow's disease, pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis, fibroid lung, idiopathic interstitial pneumonia, dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergy sensitivity, cutaneous T cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, myocardosis, scleroderma, Wegener's granuloma, Sjogren's syndrome, adiposis, eosinophilic fascitis, lesions of gingiva, periodontium, alveolar bone, substantia ossea dentis, glomerulonephritis, male pattern alopecia or alopecia senilis by preventing epilation or providing hair germination and/or promoting hair generation and hair growth, muscular dystrophy, pyoderma and Sezary's syndrome, Addison's disease, ischemia-reperfusion injury of organs which occurs upon preservation, transplantation or ischemic disease, endotoxin-shock, pseudomembranous colitis, colitis caused by drug or radiation, ischemic acute renal insufficiency, chronic renal insufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer, pulmonary emphysema, cataracta, siderosis, retinitis pigmentosa, senile macular degeneration, vitreal scarring, corneal alkali burn, dermatitis erythema multiforme, linear IgA ballous dermatitis and cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenesis, metastasis of carcinoma and hypobaropathy, disease caused by histamine or Ieukotriene-C4 release, Behcet's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial liver resection, acute liver necrosis, necrosis caused by toxin, viral hepatitis, shock, or anoxia, B-virus hepatitis, non-A/non-B hepatitis, cirrhosis, alcoholic cirrhosis, hepatic failure, fulminant hepatic failure, late-onset hepatic failure, "acute-on-chronic" liver failure, augmentation of chemotherapeutic effect, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, parkison diseases, trauma, and chronic bacterial infection.
Preferred compounds of formula I and related formulae exhibit a IC50 for the binding to the Dihydroorotate dehydrogenase of less than about 5 μM, preferably less than about 1 μM and even more preferred less than about 0,010 μM.
Compounds according to formula formula I and related formulae 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.
In general, the synthesis pathways for any individual compound of formula I and related formulae will depend on the specific substitutents 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 formula I and related formulae 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 formula I and related formulae, which contain an acid center, with a suitable base. Both types of salts may be formed or interconverted using ion-exchange resin techniques.
Nomenclature of the compounds of this invention has been determined using ISIS/draw 2.5 SP1 software.
In the following the present invention shall be illustrated by means of some examples, which are not construed to be viewed as limiting the scope of the invention.
Examples
The commercially available starting materials used in the following experimental description were purchased from Aldrich or Fluka unless otherwise reported.
The HPLC, NMR and MS data provided in the examples described below are obtained as followed:
The HPLC data:
Method A: HPLC columns: XbridgeTM C8 column 50 mm x 4.6 mm at a flow of 2 mL/ min; 8 min gradient from 0.1% TFA in H2O to 0.07% TFA in ACN.
Method B: HPLC columns: XbridgeTM C8 column 50 mm x 4.6 mm at a flow of 1 mL/ min; 8 min gradient H2O ammonium acetate (10 μM, pH 9) - ACN from 95:5 to 0:100.
Method C: HPLC columns: ATLANTIS C18 75x4.6mm 5U at a flow of 0.8 mL/ min; A-
0.1 %HCOOH B-ACN
Method D: HPLC columns: C18 BDS, 50X4.6mm, SCV307 at a flow of 0.8 mL/ min; A-
0.1 %TFA, B- ACN: Flow - 0.8mL/ min. UV detection (maxplot) for all methods. Mass spectrum data: LC/MS Waters ZMD (ESI);
GC/MS: GC Agilent 6890N & MS Agilent 5973.
1H-NMR data: Bruker DPX-300MHz unless otherwise reported.
The preparative HPLC purifications are performed with HPLC waters Prep LC 4000 System equipped with columns ®PrepMS C18 10μm, 50x300mm, unless otherwise reported. All HPLC purifications were performed with a gradient of ACN/H2O or ACN/H2O/TFA (0.1 %).
Example 1 : 2-Biphenyl-4-yl-1 H-benzoimidazole-4-carboxylic acid
Figure imgf000063_0001
Step 1: 2-Hydroxyimino-N-(2-nitro-phenyl)-acetamide
Figure imgf000063_0002
A solution of chloral hydrate (29 g, 175 mmol), hydroxyl amine hydrochloride (69.4 g, 1000 mmol) and anhydrous sodium sulphate (21 g, 149 mmol) in water (800 ml.) was heated to 650C. To this a suspension, 2-nitroaniline (20 g, 150 mmol) in 2 molar aqueous HCI (20 ml.) was added. This mixture was stirred overnight at the same temperature, then cooled to room temperature. The precipitated product was collected by filtration, washed with water dried in a vacuum oven to give 25 g of the required product as a yellow coloured solid (83%). 1H NMR (300 MHz, DMSOd6): δ (ppm) = 12.62 (s, 1 H), 10.94(s, 1 H), 8.29(d, 1 H, J= 8.4 Hz), 8.13(dd, 1 H, J=8.4 & 1.2 Hz), 7.77(m, 1 H), 7.62(s, 1 H), 7.36(m, 1 H). HPLC purity: 85%.
Step 2: 7-Nitro-1H-indole-2,3-dione
Figure imgf000063_0003
2-Hydroxyimino-N-(2-nitro-phenyl)-acetamide (15 g, 72 mmol) was carefully added in small portions to a stirred solution of preheated (9O0C) cone, sulphuric acid (45 ml.) over a period of 30 min and the resulting mixture was stirred for another 2 h at the same temperature. It was then cooled to room temperature, poured into crushed ice, the precipitated products was collected by filtrations. The collected precipitated products were washed with water and dried in a vacuum oven to get a brick red colour powder. 1H NMR (300 MHz, DMSO-d6): δ (ppm) = 11.68(s, 1 H), 8.31 (dd, 1 H, J= 8.4 & 0.9Hz), 7.92(dd, 1 H, J=8.4 & 0.9 Hz), 7.25(m, 1 H). HPLC purity: 93 %
Step 3: 2-Amino-3-nitro-benzoic acid
Figure imgf000064_0001
To a ice cold solution of 7-nitro-1 H-indole-2,3-dione (9 g, 47 mmol) in 2 M aqueous sodium hydroxide (50 ml_), 30% hydrogen peroxide (9 ml.) was added drop wise. The mixture was warmed to room temperature and stirred overnight. The mixture was carefully acidified by addition of a saturated citric acid solution. The solid precipitate was collected by filtration, washed with water and dried in a vacuum oven to get 6 g of the required product as a yellow coloured solid (70%).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.9(br.s, 1 H), 8.19(m, 2H), 6.63(m, 1 H). HPLC purity: 98 %. LCMC(-ive mode): 93% and m/z:181.9
Step 4: 2-Amino-3-nitro-benzoic acid methyl ester
Figure imgf000064_0002
To a solution of 2-amino-3-nitro-benzoic acid (6 g, 33 mmol) in methanol (20 mL), an ethereal solution of diazomethane gas was added until the staring material is completely consumed. The reaction mixture was then evaporated under reduced pressure. The crude sol id obtained was pu rified by flash column chromatography using 5% ethylacetate & hexane as an eluent, to obtain the required product as a yellow coloured solid. 1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.35(m, 3H), 8.22(m, 1 H), 6.75(m, 1 H), 3.86(s, 3H). HPLC purity: 99 %
Step 5: 2,3-Diamino-benzoic acid methyl ester
Figure imgf000064_0003
To a solution of 2-amino-3-nitro-benzoic acid methyl ester (2 g, 10 mmol) in methanol, a suspension of 10% Pd/C (300 mg) in methanol 5 ml. was added and hydrogenated with a hydrogen balloon over a period of 8 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 1.5 g of the required compound as a brown coloured solid (88%).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 7.09(dd, 1 H, J=8.1 & 1.2 Hz), 6.70(dd, 1 H, J=8.1 & 1.2 Hz), 6.3.8(m, 1 H), 6.199(s, 2H), 4.77(s, 2H), 3.76(s, 3H).
Step 6: 2-Amino-3-[(biphenyl-4-carbonyl)-amino]-benzoic acid methyl ester
Figure imgf000065_0001
To a stirred solution of 2,3-diamino-benzoic acid methyl ester (200 mg, 1.2 mmol, and biphenyl benzoic acid (238 mg, 1.2 mmol), HATU (1.14 g, 3 mmol) in dry DMF (5 ml.) was added diisopropylethyl amine (0.6 ml_, 3.6 mmol). The mixture was stirred at ambient temperature overnight and poured into water (50 ml_). The precipitated solid was filtered and dried in a vacuum oven to afford the required compound which was used directly for the next step without any purification (300 mg, 72%).
Step 7: 2-Biphenyl-4-yl-1H-benzoimidazole-4-carboxylic acid methyl ester
Figure imgf000065_0002
2-Amino-3-[(biphenyl-4-carbonyl)-amino]-benzoic acid methyl ester (300 mg, 0.86mmol) was dissolved in glacial acetic acid (20 ml.) and heated to 130 0C until the reaction was completed which was monitored by TLC (2 to 3 h). After the reaction is completed the solvent was removed and the solid residue was purified over silica gel using chloroform and methanol as an eluent to get the required product 9.
1H NMR (300 MHz, DMSOd6): δ (ppm) = 12.43 (s, 1 H), 8.42 (m, 2H), 8.01 (m, 1 H), 7.98-7.78(m, 5H), 7.55-7.33(m, 4H), 4.00 (s, 3H). Step 8: 2-Biphenyl-4-yl-1H-benzoimidazole-4-carboxylic acid
Figure imgf000066_0001
2-Biphenyl-4-yl-1 H-benzoimidazole-4-carboxylic acid methyl ester (180 mg, 0.54 mmol) was taken in THF (20 mL) and was refluxed with 5N NaOH (5 mL) solution for 14 h. It was then cooled to room temperature; THF was removed under reduced pressure to obtain a thick mass. This residue was diluted with water (10 mL) and adjusted pH to 2 with cone, hydrochloric acid. The precipitated solid was filtered, washed with water and dried in a vacuum oven to obtain compound the required compound as a pale yellow solid.
1H NMR (300 MHz, DMSOd6): δ (ppm) = 12.20 (m, 1 H) 8.41 (m, 2H) 8.02-7.76(m, 6H) 7.56(t, 2H) 7.44-7.34(m, 2H). HPLC purity: 90.37 %.
Example 2: 2-(4-Benzyloxy-phenyl)-1 H-benzoimidazole-4-carboxylic acid
Figure imgf000066_0002
Example 2 is obtained as described in example 1 but starting from 4-(benzyloxy)benzoic acid (procured commercially from aldrich).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.26(d,2H, J=8.7Hz), 7.94(dd,2H, J1=I -UHz, J2=1 1.1 Hz), 7.51-7.35(m, 6H), 7.26(d, 2H, J=9Hz), 5.25(s, 2H). HPLC purity: 92.44%.
Example 3: 2-(3-Fluoro-3'-methoxy-biphenyl-4-yl)-1 H-benzoimidazole-4-carboxylic acid
Figure imgf000066_0003
Step 1: 3-Fluoro-3'-methoxy-4-methyl-biphenyl
Figure imgf000067_0003
A mixture of toluene (22.7 mL) and water (22.7 mL+7.5 ml.) was degassed with nitrogen for 30 min. A mixture of cesium carbonate (3.3 g, 1 .04 mmol), 4-bromo-2-fluoro-1- methyl-benzene (1 .0 g, 5.2 mmol), 3-methoxyphenylboronic acid (0.8g, 5.2 mmol) and tetrakis triphenyl phosphene palladium (0.294 g, 0.26 mmol) was added to the above degassed aq. toluene and the resulting mixture was refluxed for 5 h. After the reaction was completed, it was cooled and extracted with ethyl acetate. The combined ethyl acetate layers were dried over sodium sulphate and concentrated. The residue was purified by column chromatography using 10% ethyl acetate in hexane to obtain the title compound (0.85 g, 74%).
1H NMR (300 MHz, CDCI3): δ (ppm) = 2.4 (s, 3H), 3.9(s, 3H), 6.9-7.4(m, 7H).
Step 2: 4-Bromomethyl-3-fluoro-3'-methoxy-biphenyl
Figure imgf000067_0001
To a solution of 3-fluoro-3'-methoxy-4-methyl-bipheny (0.5 g, 1.7 mmol, 1.0 eq) in chloroform (30 mL), was added N-bromo succinimide (0.3 g, 1 .7 mmol followed by catalytic amount of dibenzoyl peroxide. The reaction mixture was refluxed by irradiating with a tungsten lamp for 3 hours. After the reaction was completed, it was cooled to room temperature and washed with water. The combined organic layers were dried over anhydrous sodium sulphate and concentrated. The resulting residue was purified by column chromatography using 5% ethyl acetate in hexane to obtain the title compound (0.45 g, 89 %). 1H NMR (300 MHz, CDCI3): δ (ppm) = 3.9(s, 3H), 4.6(s, 2H), 6.9-7.4(m, 7H)
Step 3: S-FluoroS'-methoxy-biphenyl-^carbaldehyde
Figure imgf000067_0002
To a solution of 4-bromomethyl-3-fluoro-3'-methoxy-biphenyl (0.45 g, 1.5 mmol) in dimethyl sulfoxide (10 mL) was addedsodium bicarbonate (1.79 g, 21.3 mmol) and the resulting mixture was then stirred at 1000C for 2 h. After the reaction was completed, it was cooled to room temperature and quenched with brine solution. The mixture was extracted with diethylether (50 ml. x 2) and the combined ether layers were washed with water, dried over anhydrous sodium sulphate and concentrated. The resulting residue was purified by column chromatography using 4% ethyl acetate in hexane to obtain the title compound. 1H NMR (300 MHz, CDCI3): δ (ppm) = 3.9(s, 3H), 6.9-7.4(m, 7H), 10.4(s, 1 H)
Step 4: 2-(3-Fluoro-3'-methoxy-biphenyl-4-yl)-1H-benzoimidazole-4-carboxylic acid
Figure imgf000068_0001
A solution of 2, 3-diaminobenzoic acid (0.15 g, 0.824 mmol) in methanol (2 ml.) was acidified with acetic acid (0.5 ml.) To this mixture was added a solution of 3-fluoro-3'- methoxy-biphenyl-4-carbaldehyde (0.2466 g, 1 .0695 mmol) in methanol followed by a solution of cupric acetate (0.183 g, 0.919 mmol) in water (4 ml_). The resulting mixture was stirred vigorously and heated to 700C for 5 minutes and then filtered hot. The precipitate was washed with water and dissolved in ethanol (5 ml.) containing 0.5 ml_ conc. HCI. A solution of sodium sulphide (0.082 g, 1 .0512 mmol) in water was added. The reaction mixture was kept acidic by adding 2-3 drops of cone HCI. The reaction mixture was filtered hot to remove copper sulfide. The pH of the solution adjusted to 4 and diluted with water. The precipitate formed was filtered, washed with water and dried. The residue obtained was purified by column chromatography using 5% methanol in dichloromethane to obtain the title compound.
1H NMR (300 MHz, DMSOd6): δ (ppm) =13.20(br.s, 1 H), 12.00(br.s, 1 H), 8.27(t, 1 H, J=8.1 Hz), 7.98(d, 1 H, J=7.5Hz), 7.87-7.76(m, 4H), 7.47-7.35(m, 4H), 7.02(d,1 H, J=5.1 Hz), 3.80(s, 3H). HPLC purity: 86.60 %.
Example 4: 2-Biphenyl-4-yl-6-methoxy-1 H-benzoimidazole-4-carboxylic acid
Figure imgf000068_0002
Step 1 : 2-Hydroxyimino-N-(4-methoxy-2-nitro-phenyl)-acetamide
Figure imgf000069_0001
A slurry of 4-methoxy-2-nitro-phenylamine (5 g, 29.7 mmol), chloral hydrate (5.51 g, 33.3 mmol), sodium sulphate (21 g, 148.8 mmol), hydroxylamine hydrochloride (6.6 g, 95.2 mmol) and cone. HCI (5 ml.) in water (150 ml.) was heated for 2 h. After completion of the reaction, a solid separates out. The reaction mixture was then cooled to room temperature and the solids were filtered .washed with water (2-3 times) and dried under vacuum to obtain the title compound as off white solid (5 g, 70.40%) which was directly used for the next reaction .
Step-2; 5-Methoxy-7-nitro-1 H-indole-2, 3-dione
Figure imgf000069_0002
2-Hydroxyimino-N-(4-methoxy-2-nitro-phenyl)-acetamide (5g, 22 mmol) was added portion wise to a hot solution of cone. H2SO4 (20 ml_, 4 vol) at 600C. After completion of the addition, temperature was raised to 800C and maintained the same for one hour. After completion of the reaction, the reaction mixture was poured on to the crushed ice and the resulting precipitate separated was filtered, washed with water (2-3 times) and dried under vacuum to obtain the title compound as brick red colored solid which was used directly for the next reaction.
Step 3: 2-Amino-5-methoxy-3-nitro-benzoic acid
Figure imgf000069_0003
To a slurry of 5-methoxy-7-nitro-1 H-indole-2, 3-dione (3 g, 13.5 mmol) in aqueous 2N
NaOH solution (30 ml_), was added an aq. Solution of 33% hydrogen peroxide (3 ml.) slowly at 00C. After completion of the addition, the reaction mixture was stirred at room temperature for 4 h. After completion of the reaction, the reaction mixture was acidified with 2N HCI at 00C. The resulting precipitatewas filtered, washed with water (2-3 times) and dried under vacuum to obtain the title compound as yellow solid which was directly used for the next reaction.
Step 4: 2-Amino-5-methoxy-3-nitro-benzoic acid methyl ester
Figure imgf000070_0001
To a solution of 2-amino-5-methoxy-3-nitro-benzoic acid (2 g, 9.4 mmol) in methanol (100 ml.) was added slowly a saturated ethereal solution of diazomethane gas until the starting material was completely consumed (25 ml_). Ether was removed under vacuum and the resulting residue was purified by column chromatography using 5% ethyl acetate in hexane to obtain the title compound as a yellow solid which was used directly for the next reaction.
Step 5: 2, 3-Diamino-5-methoxy-benzoic acid methyl ester
Figure imgf000070_0002
A slurry of 2-amino-5-methoxy-3-nitro-benzoic acid methyl ester (1 g, 4.4 mmol) and 10% Pd/C (0.2 g, 20%) in methanol was hydrogenated with a hydrogen balloon for 6h.
After the reaction was completed, the mixture was filtered through a celite bed and the filtrates were evaporated to dryness . The obtained residue was purified over silica gel column using (30% ethyl acetate/hexane) as eluent to obtain the title compound as off white solid.
1H NMR (300 MHz, DMSOd6): δ (ppm) = 6.56-6.55(m, 1 H), 6.41-6.40(m, 1 H), 6.00-
5.80(bs, 2H), 5.20-4.80(bs, 2H), 3.76(s, 3H), 3.69(s, 3H)
Step 6: 2-Biphenyl-4-yl-6-methoxy-1H-benzoimidazole-4-carboxylic acid
Figure imgf000071_0001
The above title compound is obtained as described in example 1 but starting from methyl
2,3-diamino-5-methoxybenzoate.
1H NMR (300 MHz, DMSOd6): δ (ppm) =12.8(s, 1 H), 8.32- 8.19(m, 2H), 7.86(dd, 2H,
Ji=8.4Hz, J2=8.4Hz), 7.77(d, 2H, J=7.2Hz), 7.57-7.40(m, 3H), 7.21 (d, 1 H, J=2.4Hz),
7.00(d, 1 H, J=2.4Hz), 6.88-6.81 (m, 1 H), 3.8(s, 3H). HPLC purity: 90.40%.
Example 5: 2-Biphenyl-4-yl-6-fluoro-1 H-benzoimidazole-4-carboxylic acid
Figure imgf000071_0002
Step 1: N-(4-Fluoro-phenyl)-2-hydroxyimino-acetamide
Figure imgf000071_0003
To a slurry of 4-fluoro-phenylamine (5 g, 45.0 mmol) in water (150 ml_), was added chloral hydrate (1 1 .28 g, 67.56 mmol), sodium sulphate (31 .97 g, 225.2 mmol), hydroxylamine hydrochloride (6.21 , 90.0 mmol), cone. HCI (5 ml.) and the reaction mixture was heated to 85°C. It was stirred for another 2 h at the same temperature. After completion of the reaction, a solid separated out. The reaction mixture was cooled to room temperature and filtered .washed with water (2-3 times) and dried to obtain the title compound as off white solid.
Step 2: 5-Fluoro-1 H-indole-2,3-dione
Figure imgf000071_0004
To a hot solution of cone. H2SO4 (20 ml.) at 600C, (N-(4-Fluoro-phenyl)-2-hydroxyimino- acetamide (5g, 27.0 mmol) was added portion wise. After completion of the addition, the temperature was increased to 800C and maintained for one hour. After completion of the reaction, the reaction mixture was poured on to crushed ice and the resulting precipitate was filtered, washed with water (2-3 times) and dried to obtain the title compound as brick red solid.
Step 3: 5-Fluoro-7-nitro-1 H-indole-2, 3-dione
Figure imgf000072_0001
To a solution of 5-fluoro-1 H-indole-2, 3-dione (2.5 g, 15.0 mmol) in cone. H2SO4 (9 ml.) was added very slowly fuming nitric acid (1.5 ml.) at -5 to 00C. The reaction mixture was stirred at the same temperature for one hour. After completion of the reaction, the reaction mixture was poured onto crushed ice and the resulting precipitate was filtered, washed with water (2-3 times) and dried under vacuum to obtain the title compound as yellow solid (3 g, 94.30%) which was used for the next step directly.
Step 4: 2-Amino-5-fluoro-3-nitro-benzoic acid
Figure imgf000072_0002
To a slurry of 5-fluoro-7-nitro-1 H-indole-2, 3-dione (3 g, 14.2 mmol) in aqueous 5N NaOH solution (30 ml.) was added slowly an aq. solution of 33% hydrogen peroxide (3 ml.) at 00C. After completion of the addition , the reaction mixture was stirred at room temperature for 4h. After completion of the reaction, the reaction mixture was acidified with 2N HCI and the resulting precipitate was filtered, washed with water (2-3 times) and dried under vacuum to obtain the title compound as yellow solid (2 g, 70.17%).
Step 5: 2-Amino-5-methoxy-3-nitro-benzoic acid methyl ester
Figure imgf000073_0001
To a solution of 2-amino-5-fluoro-3-nitro-benzoic acid (2 g, 0.001 mol) in methanol (100 ml.) was added a saturated ethereal solution of diazomethane gas (50 mL) untill the starting material was consumed. The reaction mixture was concentrated to dryness and the residue obtained was purified by column chromatography using 5% ethyl acetate in hexane as an eluent to obtain the title compound as yellow solid which was directly used for the next step (1 .8 g, 84.1 1 %).
Step 6: 2, 3-Diamino-5-fluoro-benzoic acid methyl ester
Figure imgf000073_0002
A slurry of 2-amino-5-fluoro-3-nitro-benzoic acid methyl ester (1 .8 g, 84.0 mmol) and 10% Pd/C (0.5 g) in methanol (50 mL) was hydrogenated with a hydrogen balloon for 2 h. After completion of the reaction, the reaction mixture was filtered over celite bed, concentrated to dryness, the resulting residue was purified by column chromatography using 30% ethyl acetate in hexane to obtain the title compound as off white solid.
1H NMR (300 MHz, DMSOd6): δ (ppm) =6.72(m 1 H), 6.54(m, 1 H), 6.13(s, 2H) 5.21 (s, 2H), 3.77(s, 3H)
Step 7: 2-Biphenyl-4-yl-6-fluoro-1H-benzoimidazole-4-carboxylic acid
Figure imgf000073_0003
The above title compound was obtained as described in example 1 but starting from methyl 2,3-diamino-5-fluorobenzoate.
1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.43(d, 2H, J=8.4Hz), 7.94(d, 2H, J=8.4Hz),
7.88(dd, 1 H, J1=SJHz J2=8.4Hz), 7.81 (d, 2H, J=7.2Hz), 7.71 (dd, 1 H, J1=^Hz, J2=9.9Hz), 7.53(t, 2H, J=9Hz), 7.46(d,1 H, J=1.8Hz). HPLC purity:94.30 %.
Example 6: 2-Biphenyl-4-yl-6-bromo-1 H-benzoimidazole-4-carboxylic acid
Figure imgf000074_0001
Step 1: N-(4- Bromo -phenyl)-2-hydroxyimino-acetamide
Figure imgf000074_0002
To a slurry of 4-bromo-phenylamine (10 g, 58.13 mmol) in water (200 mL) was added chloral hydrate (1 1 .65 g, 69.76 mmol), sodium sulphate (50 g), hydroxylamine hydrochloride (12.8 g, 186 mmol) and cone. HCI (15 mL). The reaction mixture was then heated to 85°C and stirred for another 2 h. After completion of the reaction, a solid separated out. The mixture was cooled to room temperature, filtered and washed with water (2-3 times) and dried to obtain the title compound as off white solid (12 g, 84.9%).
Step 2: 5- Bromo -1 H-indole-2,3-dione
Figure imgf000074_0003
To a hot solution of cone. H2SO4 (48 mL) at 600C was added portion wise (N-(4-bromo- phenyl)-2-hydroxyimino-acetamide (12g, 41.1 mmol). After completion of the addition, the temperature was increased to 800C and maintained for one hour. After completion of the reaction, the reaction mixture was poured on to crushed ice and the resulting prcipitate was filtered, washed with water (2-3 times) and dried to obtain the title compound as brick red solid (10 g, 89%).
Step 3: 5- Bromo-7-nitro-1H-indole-2, 3-dione
Figure imgf000074_0004
To a solution of 5-bromo-1 H-indole-2,3-dione (5 g, 22.1 mmol) in cone. H2SO4 (22.5 ml.) was added fuming nitric acid (1.45 mL) very slowly at -5 to 00C. The reaction mixture was stirred at the same temperature for one hour. After completion of the reaction, the reaction mixture was poured on to crushed ice and the resulting precipitate was filtered, washed with water (2-3 times) and dried under vacuum to obtain the title compound as yellow solid (5.5 g, 91.8%) which was used for the next step directly.
Step 4: 2-Amino-5-bromo-3-nitro-benzoic acid
Figure imgf000075_0001
To a slurry of 5-bromo-7-nitro-1 H-indole-2,3-dione (5.5 g, 20.3 mmol) in aqueous 5N NaOH solution (23.2 mL) was added an aq. solution of 33% hydrogen peroxide solution (4.96 mL) slowly at 00C. After completion of the addition, the reaction mixture was stirred at room temperature for 4h. After completion of the reaction, the reaction mixture was acidified with 2N HCI and the solid the resulting precipitate was filtered, washed with water (2-3 times) and dried under vacuum to obtain the title compound as yellow solid (5 g, 94.5%).
Step 5: 2-Amino-5-bromo-3-nitro-benzoic acid methyl ester
Figure imgf000075_0002
To a solution of 2-amino-5-bromo -3-nitro-benzoic acid (5 g, 19.15 mmol) in methanol (100 mL) was added a saturated ethereal solution of diazomethane gas (75 mL) untill the starting material was consumed. The reaction mixture was concentrated to dryness and the residue obtained was purified by column chromatography using 5% ethyl acetate in hexane as an eluent to obtain the title compound as yellow solid which was directly used for the next step (5 g, 94.3%).
Step 6: 2, 3-Diamino-5-bromo-benzoic acid methyl ester
Figure imgf000076_0001
To a solution of 2-amino-5-bromo -3-nitro-benzoic acid methyl ester (5g, 18.18 mmol) in methanol (15 ml.) was added nickel chloride (10.8 g, 45.4 mmol) and was cooled to 00C. To this cold solution, sodiumborohydride (3.45 g, 90 mmol) was added in small portions. After the addition , the reaction mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were dried, concentrated and the resulting residue was purified by column chromatography using 30% ethyl acetate in hexane to obtain the title compound as grey coloured solid.
Step 7: 2-Biphenyl-4-yl-6-bromo-1H-benzoimidazole-4-carboxylic acid
Figure imgf000076_0002
The title compound is obtained as described in example 1 but starting from methyl 2,3- diamino-5-bromobenzoate.
1H NMR (300 MHz, DMSOd6): δ (ppm) = 12.20(br.s, 1 H), 12.4(br.s, 1 H), 8.43(d, 1 H, J=6.3Hz), 7.95-7.78(m, 5H), 7.54-7.34(m, 5H). HPLC purity: 89.69%.
Example 7 & 8: 2-Biphenyl-4-yl-1-methyl-1 H-benzoimidazole-4-carboxylic acid & 2-Biphenyl-4-yl-3-methyl-3H-benzoimidazole-4-carboxylic acid
Figure imgf000076_0003
Example 7 and 8 are obtained from example 1 by the following procedure. To a cold solution of 2-biphenyl-4-yl-1-methyl-1 H-benzoimidazole-4-carboxylic acid (400 mg, 1 .27 mmol) in dry DMF(20 ml_), potassium carbonate (800 mg, 5.79 mmol) and methyl iodide (0.235 ml_, 3.77 mmol) were added slowly at 5°C. The reaction mixture was then stirred overnight at room temperature. After the starting material was completely consumed, DMF was was removed under vacuum. The resulting residue was directly purified by column chromatography and two compounds were isolated and characterized as methyl esters of 1 H- and 3H- isomers. The corresponding carboxylic acids were prepared by hydrolysis with lithium hydroxide (aq. solution of 5 N, 10 ml.) at room temperature for 8 h in THF-Water mixture.
Example 7
1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.05(t, 3H) 7.96-7.86(m, 3H) 7.82-7.76(m, 2H),
7.58-7.42(m, 4H), 4.15(s, 3H). HPLC purity: 95.09%.
Example 8
1H NMR (300 MHz, DMSOd6): δ (ppm) = 12.40(br.s, 1 H), 7.95(m, 5H), 7.86-7.72(m, 3H), 7.60-7.30(m, 3H), 3.85(s, 3H). HPLC purity: 97.97%.
Example 9: 2-(3-Phenoxy-phenyl)-3H-benzoimidazole-4-carboxylic acid
Figure imgf000077_0001
Example 9 is obtained as described in example 1 but starting from 3-phenoxybenzoic acid (prepared according to the literature method
Synthetic communication 34(21 ), 3909-3914; 2004).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 13.2(br.s, 1 H), 12.45(br.s, 1 H), 8.23(d, 1 H), 8.20(s, 1 H), 7.90(d, 1 H), 7.82(d, 1 H), 7.56(t, 1 H), 7.44(t, 2H), 7.31 (t, 1 H) 7.24-7.08(m,
4H). HPLC purity: 95.18%.
Example 10: 2-(4-Phenoxy-phenyl)-3H-benzoimidazole-4-carboxylic acid
Figure imgf000077_0002
Example 10 is obtained as described in example 1 but starting from 3-phenoxybenzoic acid (procured commercially from aldrich).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 12.20(br.s, 1 H) 8.33(d, 2H, J=8.3Hz), 7.88(d, 1 H, J=8.1 Hz), 7.79(d, 1 H, J=7.5Hz), 7.46(t, 2H, J=7.5Hz), 7.30(t, 1 H, J=7.8Hz), 7.23(t, 1 H, J=7.5Hz), 7.13(m, 4H). HPLC purity: 94.79%. Example 11 : 2-(3'-Methoxy-biphenyl-4-yl)-3H-benzoimidazole-4-carboxylic acid
Figure imgf000078_0001
Example 1 1 is obtained as described in example 1 but starting from 3'-methoxybiphenyl-
4-carboxylic acid (prepared according to the literature method
Chemical Communications (Cambridge, United Kingdom), (5), 564-565; 2004).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 12.85(br.s, 1 H), 8.27(d, 2H), 7.89(d, 2H), 7.72-
7.66(m, 1 H), 7.58-7.52(m, 1 H), 7.46-7.20(m, 5H), 7.25-6.80(m, 1 H), 3.80(s, 3H). HPLC purity: 90.20%.
Exa m p l e 1 2 : 2-(4'-Methyl-biphenyl-4-yl)-3H-benzoimidazole-4-carboxylic acid
Figure imgf000078_0002
Example 12 is obtained as described in example 1 but starting from 4'-methylbiphenyl-4- carboxylic acid (prepared according to the literature method
Tetrahedron 2008, 64(35), 8164-8168).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 13.00(br.s, 1 H), 8.25(d, 2H), 7.85(d, 2H),
7.67(d, 3H), 7.33(d, 2H), 7.24-7.18(m, 3H), 2.40(s, 3H). HPLC purity: 96.34%.
Exam ple 1 3 : 2-(4'-Trifluoromethyl-biphenyl-4-yl)-3H-benzoimidazole-4-carboxylic acid
Figure imgf000078_0003
Exa m pl e 1 3 i s obta i n ed a s d escri bed i n exa m p l e 1 but starting from 4'- (trifluoromethyl)biphenyl-4-carboxylic acid (prepared according to the literature method Tetrahedron Letters, 46(34), 5751-5754; 2005).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 13.20(br.s, 1 H), 8.31 (m, 2H), 7.90(dd, 4H, J1 =16.5Hz, J2=15.6Hz), 7.86(d, 2H, J=8.1 Hz), 7.68-7.58(m, 2H), 7.30-7.20(m, 2H). HPLC purity: 91.51 %.
Example 14: 2-Biphenyl-4-yl-6-methyl-1H-benzoimidazole-4-carboxylic acid
Figure imgf000079_0001
Step 1: 2-Hydroxyimino-N-p-tolyl-acetamide
Figure imgf000079_0002
A solution of chloral hydrate (38 g, 0.223 mol), hydroxyl amine hydrochloride (41 g, 0.594 mol) and sodium sulphate (40 g, 0.281 mol) in water (800 mL) was heated to 9O0C. To this mixture was added a solution of p-toluidine (20 g, 0.1866 mol) in cone. HCI (30 mL) The resulting mixture was stirred for another 2 h. After the reaction is completed, the reaction mixture was cooled to room temperature, the precipitate was filtered and washed with water (100 mL). The solid was dried in a vacuum oven to get the required product as a grey coloured solid.
1H NMR (300 MHz, DMSOd6): δ (ppm) = 12.15(s, 1 H), 10.09(s, 1 H), 7.6(s, 1 H). 7.56(d, 2H, J=8.4), 7.12 (d, 2H, J=8.4), 2.26(s, 3H).
Step 2: 5-Methyl-1 H-indole-2,3-dione
Figure imgf000079_0003
2-Hydroxyimino-N-p-tolyl-acetamide (14 g, 0.0078 mol) was added portion wise to a preheated (6O0C) cone. H2SO4 (70 mL) over a period of 30 min. After the addition , the mixture was stirred at the same temperature for another 1 h. The reaction mixture was cooled to room temperature and was poured into crushed ice. The precipiate was collected by filtration and washed with chilled water several times. Finally it was dried in a vacuum oven to get the required product as brick red coloured solid. 1H NMR (300 MHz, DMSOd6): δ (ppm) = 10.94 (s,1 H), 7.42 (d, 1 H, J=1.2), 7.32 (s,1 H) 6.82(d, 1 H, J=8.1 ), 2.51 (s, 3H).
Step 3: 5-Methyl-7-nitro-1H-indole-2,3-dione
Figure imgf000080_0001
Fuming nitric acid (10 ml.) was added drop wise over a period of 30 min to a solution of 5-methyl-1 H-indole-2,3-dione (20 g, 0.124 mol) in in cone. H2SO4 (80 ml.) at -5 °C,utes. The reaction mass was stirred for another 5-10 min at the same temperature and was poured into crushed ice. The precipitate was filtered and washed with chilled water several times. Finally it was dried in a vacuum oven to get 6.5 g of the required product as a yellow coloured solid. 1H NMR (300 MHz, DMSOd6): δ (ppm) = 1 1.60(s, 1 H), 8.15 (m,1 H), 7.79 (m, 1 H), 2.51 (s, 3H).
Step 4: 2-Amino-5-methyl-3-nitro-benzoic acid
Figure imgf000080_0002
A solution of 5-methyl-7-nitro-1 H-indole-2,3-dione (6.5 g, 0.0315 mol) in 2N NaOH (35 ml.) was cooled to 2O0C and a 30% aq. solution of H2O2 (6.5 ml.) was added slowly over a period of 15 min. The reaction mixture was brought to room temperature and stirred for 12 h, then diluted with water (75 ml_). The pH was adjusted to 2 with cone. HCI. The formed precipitate was filtered and dried in a vacuum oven to get 5.3 g of the required product as a yellow coloured solid (85%).
1H NMR (300 MHz, DMSO-d6): δ (ppm) = 13.4 (br.s,1 H), 8.34(br.s, 2H), 8.14 (s, 1 H), 8.07 (s, 1 H), 2.24 (s, 3H).
Step 5: 2-Amino-5-methyl-3-nitro-benzoic acid methyl ester
Figure imgf000081_0001
To a solution of 2-amino-5-methyl-3-nitro-benzoic acid (5 g, 24 mmol) in a mixture of methanol & ether (8:2, 50 ml_), a freshly generated diazomethane gas collected in ether was added until the reaction completes. The reaction mixture was evaporated under reduced pressure and was purified by flash column chromatography using 5% ethyl acetate in hexane as an eluent to get 4.5 g (83%) of the required product as a yellow coloured solid.
1H NMR (300 MHz, CDCI3): δ (ppm) = 8.31 (br.s, 2H), 8.21 (s, 1 H), 8.08 (s, 1 H), 3.91 (s, 3H1) 2.29 (s, 3H).
Step 6: 2,3-Diamino-5-methyl-benzoic acid methyl ester
Figure imgf000081_0002
A solution of 2-amino-5-methyl-3-nitro-benzoic acid methyl ester (5.5 g, 26 mmol) in methanol (200 rtiL) was hydrogenated with hydrogen balloon in presence of 10% Palladium on charcoal (1.5 g) for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to get the required product as a brown coloured solid 4.5g (95%).
Example 14 is obtained as described in example 1 but starting from 2,3-diamino-5- methyl-benzoic acid methyl ester
1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.41 (d, 2H, J=8.1 Hz), 7.97(d, 2H, J=8.4Hz), 7.84-7.81 (m, 4H), 7.56-7.51 (m, 2H), 7.46(s,1 H), 2.54(s, 3H). HPLC purity: 97.77%.
Example 15: 2-(2'-Fluoro-biphenyl-4-yl)-3H-benzoimidazole-4-carboxylic acid
Figure imgf000081_0003
Example 15 is obtained as described in example 1 but starting from 2'-fluorobiphenyl-4- carboxylic acid (prepared according to the literature method
J Med Chem 47(2), 335-374, 2004).
1H NMR (300 MHz, CD3OD): δ (ppm) = 7.45(d, 2H, J=8.4Hz), 7.37(d, 1 H, J=7.5Hz),
7.24(d, 1 H, J=9Hz), 7.09(d, 2H, J=7.2Hz), 6.87-6.77(m, 2H), 6.67-6.63(m,1 H), 6.55-
6.43(m, 2H). HPLC purity: 96.85%.
Example 16: 2-(4'-Trif luoromethoxy-biphenyl-4-yl)-3H-benzoimidazole-4- carboxylic acid
Figure imgf000082_0001
Exam ple 1 6 is obtained as descri bed i n example 1 but starting from 4'-
(trifluoromethoxy)biphenyl-4-carboxylic acid
Step 1: 4'-Trifluoromethoxy-biphenyl-4-carbaldehyde
Figure imgf000082_0002
A mixture of toluene (70 ml.) and water (10 ml.) was degassed with nitrogen for 30 min. A mixture of sodium carbonate (3.2 g, 30.43 mmol), 4-bromobenzaldehyde (2.0 g, 10.6 mmol), 4-trifluoromethoxyphenylboronic acid (2.86 g, 13.95 mmol) and tetrakis triphenyl phosphene palladium(O) (1 .0g, 1 .562 mmol) were added to the above degassed water/toluene mixture. The reaction mixture refluxed overnight. After the reaction is completed, the reaction mixture was cooled to room temperature and extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated. The resulting residue was purified by column chromatography using 3% ethyl acetate in hexane to obtain the title compound. 1H NMR (300 MHz, CDCI3): δ (ppm) = 7.2-8.0(m, 8H), 10.0(s, 1 H).
Step 2: 4'-Trifluoromethoxy-biphenyl-4-carboxylic acid
Figure imgf000082_0003
To a cold solution of 4'-trifluoromethoxy-biphenyl-4-carbaldehyde (0.9 g, 3.38 mmol) in acetone (10 ml.) the Jone's reagent was added slowly at O0C drop wise until reaction completes. Acetone was removed completely and the residue was diluted with water, extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried over sodium sulphate and concentrated to obtain the title compound (0.7 g, 77%). 1H NMR (300 MHz, DMSOd6): δ (ppm) = 7.2-8.0(m, 8H), 13.0(bs, 1 H)
Step 3: 2-(4'-Trifluoromethoxy-biphenyl-4-yl)-3H-benzoimidazole-4-carboxylic acid
Figure imgf000083_0001
1H NMR (300 MHz, CD3OD): δ (ppm) = 7.48-7.40(m, 3H),7.27-7.19(m, 3H), 7.07(d, 2H,
J=8.7Hz), 6.92-6.87(m, 1 H), 6.63(d, 2H, J=8.4Hz). HPLC purity:98.94 %.
Example 17: 2-(3'-Fluoro-biphenyl-4-yl)-3H-benzoimidazole-4-carboxylic acid
Figure imgf000083_0002
Example 17 is obtained as described in example 1 but starting from 3'-fluorobiphenyl-4- carboxylic acid (prepared according to the literature method Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), (1 ), 35-7; 1984).
1H NMR (300 MHz, DMSO-d6): δ (ppm) = 8.42(d, 2H, J=8.4Hz) 7.96-7.87(m, 3H) 7.68- 7.65(m, 2H) 7.57-7.26(m, 4H). HPLC purity: 94.48%.
Example 18: 2-(3'-Trif luoromethoxy-biphenyl-4-yl)-3H-benzoimidazole-4- carboxylic acid
Figure imgf000084_0001
Exam ple 1 8 is obtai n as d esc bed in 1 but starting from 3'- (trifluoromethoxy)biphenyl-4-carboxylic acid.
Step 1: 3'-Tr\f\uoromethoxy-b\pheny\-4-carba\dehyde
Figure imgf000084_0002
A mixture of toluene (35 ml.) and water (5 ml.) was degassed with nitrogen for 30 minutes. A mixture of sodium carbonate (1.9 g, 18.09 mmol), 4-bromobenzaldehyde (0.7 g, 3.72 mmol), 3-trifluoromethoxyphenylboronic acid (2.86 g, 4.78 mmol) and tetrakis triphenyl phosphene palladium(O) (0.9 g, 0.75 mmol) was added to the above degassed water / toluene mixture. The reaction mixture was refluxed overnight. After the reaction is completed it was cooled to room temperature and extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated. The resulting residue was purified by column chromatography using 5% ethyl acetate in hexane to obtain the title compound (0.8 g, 80%). 1H NMR (300 MHz, CDCI3): δ (ppm) = 7.2-8.0(m, 8H), 10.0(s, 1 H)
Step 2: S'-Trifluoromethoxy-biphenyl-^carboxylic acid
Figure imgf000084_0003
To a cold solution of 3'-trifluoromethoxy-biphenyl-4-carbaldehyde (0.8 g, 3.0 mmol) in acetone(10 ml.) the Jone's reagent was added slowly at 00C until reaction completes. Acetone was removed completely and diluted with water. The mixture was extracted with ethyl acetateand the combined organic layers were washed with water and brine, dried over sodium sulphate and concentrated to obtain the title compound (0.7 g, 82%). 1H NMR (300 MHz, CDCI3): δ (ppm) = 7.4-8.2(m, 8H, Ar-H).
Step 3: 2-(3'-Trifluoromethoxy-biphenyl-4-yl)-3H-benzoimidazole-4-carboxylic acid
Figure imgf000085_0001
1H NMR (300 MHz, CD3OD): δ (ppm) = 7.49-7.44(m, 3H), 7.30-7.22(m, 3H), 7.01- 6.81 (m, 4H). 6.61-6.57(m, 1 H). HPLC purity: 98.64%.
Example 19: 2-Biphenyl-4-yl-benzooxazole-7-carboxylic acid
Figure imgf000085_0002
Step 1: Methyl 2-hydroxy-3-nitrobenzoate
Figure imgf000085_0003
To a ice cold solution of salicylic acid (10 g, 0.072 mol) in methanol (100 ml_), was added drop wise SOCb (12.8 g, 0.1 mol). After the addition, the mixture was warmed to room temperature and heated to reflux for 12 h. After reaction is completed the reaction mixture was cooled to room temperature and the excess methanol was evaporated under reduced pressure to obtain 9 g of methyl 2-hydroxybenzoate as a white solid. (81 %). A solution of methyl 2-hydroxybenzoate (9 g, 0.059 mol) in glacial acetic acid (90 ml.) was cooled to 15°C, fuming nitric acid (11.2 ml.) was added drop wise. The reaction mixture was warmed to room temperature and stirred for 4h. When the reaction is completed, the reaction mixture was poured into crushed ice. The precipitate was collected by filtration and washed several times with chilled water, then dried in a vaccum oven to the required product as a yellow coloured solid.
1H NMR (300 MHz, CDCI3): δ (ppm) = 12.0(s, 1 H), 8.2-8.1 (m, 2H), 7.01 (t, 1 H, J=8.1 Hz) 4.01 (s, 3H). Step 3: methyl 3-amino-2-hydroxybenzoate
Figure imgf000086_0001
A solution of methyl 2-hydroxy-3-nitrobenzoate (2 g, 0.010 mol) in methanol (30 ml_), was hydrogenated with a hydrogen balloon in the presence of 10% palladium on chacoal (600 mg) for 7h. After the reaction is completed, the reaction mixture was filtered through celite bed and the filtrate was concentrated under reduced pressure to obtain 1.6 g of the above required compound (72%) as a grey coloured solid. 1H NMR (300 MHz, CDCI3): δ (ppm) = 10.88(s, 1 H), 6.87 (d, 1 H, J=7.5Hz), 6.72 (d, 1 H, J= 7.8Hz), 3.88(s, 3H).
Step 4: 3-[(Biphenyl-4-carbonyl)-amino]-2-hydroxy-benzoic acid methyl ester
Figure imgf000086_0002
To an ice cold solution of 4-biphenyl benzoic acid (1.5 g, 23 mmol), triethyl amine (6.2 ml_, 46 mmol) in THF (50 ml_), SOCI2 (5 ml_, 46 mmol) was added drop wise and continued stirring for another 3h at the same temperature. After completion of the reaction, it was concentrated under reduced pressure to get the 4-bipehnyl benzoyl chloride which was used directly for the next reaction.
To an ice cold solution of methyl 3-amino-2-hydroxybenzoate (700 mg, 9.2 mmol) and pyridine (13 ml.) in DCM (100 ml.) was added slowly a solution of biphenyl benzoyl chloride (2.1 g, 9.7 mmol) in DCM. The reaction mixture was stirred for another 12 h at room temperature and diluted with another 200 ml. of DCM and washed with an aq. solution of 2N. HCI followed by water. The combined organic layers were dried over sodium sulphate and concentrated to dryness to get the 350 mg of the required product as a white coloured solid. 1H NMR (300 MHz, CDCI3): δ (ppm) = 1 1.40 (s, 1 H), 8.77(dd, 1 H, J=8.1 Hz, J=8.1 Hz), 8.66(br.s, 1 H), 8.00(m, 2H), 7.77(m, 2H), 7.66-7.58(m, 3H), 7.51-7.40(m, 3H), 6.97(t, 1 H, J=8.1 Hz), 3.99(s, 3H).
Step 5: 2-Biphenyl-4-yl-benzooxazole-7-carboxylic acid
Figure imgf000087_0001
3-[(biphenyl-4-carbonyl)-amino]-2-hydroxy-benzoic acid methyl ester (100 mg, 0.28mmol) was suspended in PPA (500 mg) and heated at 1700C for 4h. The reaction was monitored by TLC. After completion of the reaction, the crude mixture was cooled to room temperature and ice water was added. The pH was adjusted to 5 with an aq. solution of 5N NaOH and was extracted with ethyl acetate (3X50 ml_). The combined organic phases were dried over sodium sulphate and concentrated under reduced pressure. The crude mixture was purified by column chromatography to get 35 mg of the required product as a pale pink coloured solid.
1H NMR (300 MHz, CDCI3): δ (ppm) = 13.20(br.s, 1 H), 8.30(d, 2H, J=10.5Hz) 8.10- 7.90(m, 4H), 7.80(d, 2H, J=12Hz), 7.54(t, 3H, J=10.5Hz) 7.48-7.44(m, 1 H). HPLC purity: 85.64%.
Example 20: 2-(2,6-Dimethoxy-biphenyl-4-yl)-1 H-benzoimidazole-4- carboxylic acid
Figure imgf000087_0002
Exam ple 20 is obta i ned as descri bed i n exa m ple 1 but starti n g from 2 ,6- dimethoxybiphenyl-4-carboxylic acid.
Stepi; 2, β-Dimethoxy-biphenyl-^carboxylic acid methyl ester
Figure imgf000088_0001
A mixture of toluene (70 mL) and water (10 mL) was degassed with nitrogen for 30 min. A m i xtu re of ces i u m ca rbo n ate (2.3 g , 7.07 m m ol ) , 4-bromo-3,5-dimethoxy methylbenzoate (2.0 g, 7.2 mmol), phenylboronic acid (1.2 g, 9.9 mmol) and tetrakis triphenyl phosphene palladium(O) (1 .0 g, 0.8 mmol) was added to the above degassed water / toluene mixture. The reaction mixture was refluxed overnight. After the reaction is completed it was cooled to room temperature and extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated. The resulting residue was purified by column chromatography using 8% ethyl acetate in hexane to obtain the title compound. 1 H NMR (300 MHz, CDCI3): δ (ppm) = 3.8(s, 6H), 4.0(s, 3H,), 7.3-7.8(m, 7H).
Step 2: 2, β-Dimethoxy-biphenyM-carboxylic acid
Figure imgf000088_0002
To a solution of 2, θ-dimethoxy-biphenyl-4-carboxylic acid methyl ester (0.9 g, 3.3 mmol) in 10% aq. THF, an aq. solution of 5 N NaOH (5 mL) was added and the reaction mixture was refluxed for 5 h. After the reaction is completed, THF was removed completely under the vacuum and acidified with an aq . solution of 50% HCI. The resulting precipitate was filtered and washed thoroughly with water and dried to obtain the title compound (0.6 g, 70.5%). 1H NMR (300 MHz, DMSOd6): δ (ppm) = 3.8(s, 6H), 7.2-7.6(m, 7H), 13.0(bs, 1 H).
Step 3: 2-(2,6-Dimethoxy-biphenyl-4-yl)-1H-benzoimidazole-4-carboxylic acid
Figure imgf000089_0001
1H NMR (300 MHz, DMSO-d6): δ (ppm) = 8.08(d, 1 H, J=7.8Hz), 8.00(d, 1 H, J=7.5Hz), 7.80-7.76(m, 2H), 7.58-7.53(m, 1 H), 7.43-7.26(m, 5H), 3.84(s, 6H). HPLC purity: 90.23%.
Example 21 : 2-(2,3,5,6-Tetrafluoro-biphenyl-4-yl)-1 H-benzoimidazole-4- carboxylic acid
Figure imgf000089_0002
Example 21 is obtained as described in example 1 but starting from 2,3 ,5,6- tetrafluorobiphenyl-4-carboxylic acid
Step 1: 4-Bromo-2, 3, 5, 6-tetrafluoro-benzoic acid methyl ester
Figure imgf000089_0003
To a solution of 4-bromo-2, 3, 5, 6-tetrafluoro-benzoic acid (20 g, 73.49 mmol) in methanol (20 ml.) was added an ethereal solution of diazomethane gas until the starting material is completely consumed. Reaction mixture was then evaporated under reduced pressure. The crude solid obtained was purified by flash column chromatography using 5% ethyl acetate in hexane, to obtain title compound as colorless crystalline solid (18 g, 85%). 1H NMR (300 MHz, CDCI3): δ (ppm) = 4.0(s, 3H)
Step 2: 2, 3, 5, β-Tetrafluoro-biphenyl-^carboxylic acid methyl ester
Figure imgf000090_0001
A mixture of toluene (370 mL) and water (70 ml.) was degassed with nitrogen for 30 minutes. A mixture of cesium carbonate (102.6 g, 315 mmol), 4-bromo-2, 3, 5, 6- tetrafluoro-benzoic acid methyl ester (30.0 g, 105 mmol), phenyl boronic acid (19.26 g, 157 mmol) and tetrakis triphenyl phosphene palladium(O) (1 1.5 g, 9.9 mmol) were added to the above degassed water / toluene mixture. The reaction mixture was refluxed overnight. After the reaction is completed, it was cooled to room temperature and extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated. The resulting residue was purified by column chromatography using 5% ethyl acetate in hexane to obtain the title compound (26.5 g, 88.6%). 1H NMR (300 MHz, CDCI3): δ (ppm) = 4.0(s, 3H), 7.4-7.6(m, 5H)
Step 3: 2, 3, 5, β-Tetrafluoro-biphenyM-carboxylic acid
Figure imgf000090_0002
To a solution of 2, 3, 5, 6-tetrafluoro-biphenyl-4-carboxylic acid methyl ester (20 g, 70.4 mmol) in tetrahydrofuran (350 mL) was added an aq, solution of 5 N sodium hydroxide (150 mL). The reaction mixture refluxed with stirring for 4 hours. Progress of the reaction was monitored by TLC. The reaction mixture was then concentrated and the resulting residue was cooled to 10°C and acidified with an aq. Solution of 50% HCI. The formed precipitate was filtered, washed thoroughly with water and dried to obtain title compound as colorless solid (17 g, 89.4%). 1 H NMR (300 MHz, DMSO-D6): δ (ppm) = 7.6(s, 5H).
Step 4: 2-(2, 3, 5, 6-Tetrafluoro-biphenyl-4-yl)-1H-benzoimidazole-4-carboxylic acid
Figure imgf000091_0001
1H NMR (300 MHz, DMSO-d6): δ (ppm) = 13.2(br.s, 2H), 8.06(d, 1 H, J=8.1 Hz), 7.95- 7.88(m, 2H), 7.61-7.59(m, 4H), 7.44-7.39(m, 1 H). HPLC purity: 91.99%
Example 22: 2-(4-Thiophen-3-yl-phenyl)-1 H-benzoimidazole-4-carboxylic acid
Figure imgf000091_0002
Example 22 is obtained as described in example 1 but starting from 4-(3-thienyl)benzoic acid (prepared according to the literature method Tetrahedron letters 42(38), 6683-6686;
2001 ).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 13..6(br.s, 1 H),12.35(br.s, 1 H), 8.37-7.92(m,
6H), 7.82(d, 1 H, J=7.5Hz), 7.69 (s, 2H), 7.33(m, 1 H). HPLC purity: 88.42%.
Example 23: 6-Methyl-2-(4-thiophen-3-yl-phenyl)-1 H-benzoimidazole-4- carboxylic acid
Figure imgf000091_0003
Example 23 is obtained as described in example 14 but starting from 4-(3- thienyl)benzoic acid .
1H NMR (300 MHz, DMSOd6): δ (ppm) = 12.20(br.s, 2H), 8.40-8.20(m, 2H), 8.05- 7.89(m, 3H), 7.71-7.65(m, 4H), 2.2(s, 3H). HPLC purity: 87.17%.
Example 24: 2-(3,2'-Difluoro-biphenyl-4-yl)-3H-benzoimidazole-4-carboxylic acid
Figure imgf000092_0001
Exam ple 24 is obtained as described in example 1 but starting from 2', 3- difluorobiphenyl-4-carboxylic acid (prepared as described in PCT lnt Appl. 2005009941 03 Feb 2005).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.27(t, 1 H, J=8.1 Hz), 8.03(d, 1 H, J=8.1 Hz), 7.92(d, 1 H, J=7.5Hz), 7.68(dd, 3H, J^iθ.δHz, J2=16.5Hz), 7.53-7.36(m, 4H). HPLC purity: 94.41 %.
Example 25: 2-(3,2'-Difluoro-biphenyl-4-yl)-6-methyl-3H-benzoinnidazole-4- carboxylic acid
Figure imgf000092_0002
Example 25 is obtained as described in example 14 but starting from 2', 3- difluorobiphenyl-4-carboxylic acid.
1H NMR (300 MHz, DMSOd6): δ (ppm) = 1 1.80(br.s, 1 H), 8.27(t, 1 H, J=8.1 Hz), 7.80(s, 1 H), 7.71-7.61 (m, 4H), 7.55-7.48(m, 1 H), 7.38(dd, 2H, J1 = IS-SHz, J2=12.9Hz), 2.09(s, 3H). HPLC purity: 91.16%.
Example 26: 2-(2'-Fluoro-biphenyl-4-yl)-6-methyl-3H-benzoimidazole-4- carboxylic acid
Figure imgf000092_0003
Example 26 is obtained as described in example 14 but starting from 2'-fluorobiphenyl-4- carboxylic acid (prepared according to the literature method J Med Chem 47(2), 335-374, 2004).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.34(d, 2H, J=8.7Hz), 7.69-7.53(m, 5H), 7.46- 7.42(m, 1 H), 7.34(dd, 2H, ^12.9Hz, J2=12.9Hz), 2.43(s, 3H). HPLC purity: 92.24%. Example 27: 2-(3-Fluoro-biphenyl-4-yl)-3H-benzoimidazole-4-carboxylic acid
Figure imgf000093_0001
Example 27 is obtained as described in example 1 but starting from 3-fluorobiphenyl-4- carboxylic acid (prepared according to the literature method
Tetrahedron letter, 46(24), 4255-4259, 2005).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 13.4(br.s, 1 H), 12.20(br.s, 1 H), 8.28(t, 1 H,
J=8.1 Hz), 7.99(d, 1 H, J=7.8Hz), 7.88-7.75(m, 5H), 7.56-7.35(m, 4H). HPLC purity:
89.03%.
Example 28: 2-(3-Fluoro-biphenyl-4-yl)-6-methyl-3H-benzoimidazole-4- carboxylic acid
Figure imgf000093_0002
Example 28 is obtained as described in example 14 but starting from 3-fluorobiphenyl-4- carboxylic acid. 1H NMR (300 MHz, DMSOd6): δ (ppm) = 12.20(br.s, 1 H), 8.42-8.27(m, 1 H), 7.83- 7.25(m, 4H), 7.54-7.44(m, 5H), 2.50(s, 3H). HPLC purity: 93.70%.
Example 29: 6-Fluoro-2-(3-fluoro-biphenyl-4-yl)-3H-benzoimidazole-4- carboxylic acid
Figure imgf000093_0003
Example 29 is obtained as described in example 5 but starting from 3-fluorobiphenyl-4- carboxylic acid (prepared according to the literature method Tetrahedron letter, 46(24), 4255-4259, 2005).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 13.8(br.s, 1 H), 12.03(br.s, 1 H), 8.23(t, 1 H), 7.84-7.74(m, 5H), 7.63-7.60(m, 1 H), 7.55-7.43(m, 3H). HPLC purity: 89.90%.
Example 30: 2-(3,2',4'-Trifluoro-biphenyl-4-yl)-3H-benzoimidazole-4- carboxylic acid
Figure imgf000094_0001
Example 30 is obtained as described in example 1 but starting from 2', 3, 4'- trifluorobiphenyl-4-carboxylic acid.
Step 1: 3, 2', 4'-Trifluoro-biphenyl-4-carboxaldehyde
Figure imgf000094_0002
A mixture of toluene (40 ml.) and water (10 ml.) was degassed with nitrogen for 30 m i n u tes . A m ixtu re of sod i u m ca rbon ate ( 1 .04 g , 9.8 m m o l), 2-fluoro-4- bromobenzaldehyde (1 g, 4.9 mmol), 2,4-difluoro phenylboronic acid (0.78 g, 4.9 mmol) and dichloro bis(diphenylphosphine)ferrocene palladium (II) (0.18 g, 0.2 mmol) was added to the above degassed water / toluene mixture. The reaction mixture was refluxed overnight. After the reaction is completed it was cooled to room temperature and extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated. The resulting residue was purified by column chromatography using 2% ethyl acetate in hexane to obtain the title compound. 1H NMR (300 MHz, CDCI3): δ (ppm) = δ 7.0(m, 2H), 7.5(m, 3H), 8.0(t, 1 H), 10.5(s, 1 H).
Step 2: 3, 2', 4'-Trifluoro-biphenyl-4-carboxylic acid:
Figure imgf000094_0003
To a cold solution of 3, 2', 4'-trifluoro-biphenyl-4-carboxaldehyde (0.45 g, 1.9 mmol) in acetone (10 ml_), the Jone's reagent was added slowly drop wise at 00C until the reaction completes. Acetone was removed completely and the reaction mixture was diluted with water, extracted with ethyl acetateand the combined organic layers were washed with water and brine, dried over sodium sulphate and concentrated to get the title compound (0.410 g, 85%) 1H NMR (300 MHz, DMSOd6): δ (ppm) = 7.2(m, 6H), 13.0(bs, 1 H).
Step 3: 2-(3,2',4'-Trifluoro-biphenyl-4-yl)-3H-benzoimidazole-4-carboxylic acid
Figure imgf000095_0001
1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.27(t, 1 H, J=8.2Hz), 8.01 (d, 1 H, J=7.8Hz), 7.89(d, 1 H, J=7.5Hz), 7.80-7.59(m, 3H), 7.49(d, 1 H, J=2.7Hz), 7.47-7.38(m, 1 H), 7.30- 7.24(m, 1 H). HPLC purity: 93.78%.
Example 31 : 6-Methyl-2-(3,2\4'4rifluoroΦiphenyl-4-yl)-3H-benzoimidazole- 4-carboxylic acid
Figure imgf000095_0002
Example 31 is obtained as described in example 14 but starting from 2', 3,4'- trifluorobiphenyl-4-carboxylic acid.
1H NMR (300 MHz, DMSOd6): δ (ppm) = 7.48(t, 1 H, J=8.4Hz), 7.03(s, 1 H), 6.97(s, 1 H), 6.88-6.75(m, 3H), 6.35-6.28(m, 2H), 2.50(s, 3H). HPLC purity: 90.58%.
Example 32: 2-(2',4I-Difluoro-biphenyl-4-yl)-3H-benzoimidazole-4-carboxylic acid
Figure imgf000095_0003
Example 32 is obtained as described in example 1 but starting from 2',4'- difluorobiphenyl-4-carboxylic acid (prepared according to the literature method J Med Chem 47(2), 355-374; 2004).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.43(d, 2H, J=8.4Hz), 8.03(dd, 2H, J^iδ.θHz, J2=18.0Hz), 7.83-7.69(m, 3H), 7.55(t, 1 H, J=8.1 Hz), 7.49-7.41 (m, 1 H), 7.31-7.24(m,1 H). HPLC purity: 91.91 %.
Example 33: 2-(2I,4I-Difluoro-biphenyl-4-yl)-6-methyl-3H-benzoimidazole-4- carboxylic acid
Figure imgf000096_0001
Example 33 is obtained as described in example 14 but starting from 2', 4'- difluorobiphenyl-4-carboxylic acid.
1H NMR (300 MHz, CD3OD): δ (ppm) =7.42(d, 2H, J=8.4Hz), 7.20(s,1 H), 7.05-7.02(m,
3H), 6.83(dd, 1 H, J^i δ.θHz, J2=15Hz), 6.37-6.30(m, 2H), 2.49(s, 3H). HPLC purity: 90.00%.
Example 34: 6-Fluoro-2-(3,2',4'-trifluoro-biphenyl-4-yl)-3H-benzoimidazole-4- carboxylic acid
Figure imgf000096_0002
Example 34 is obtained as described in example 5 but starting from 2', 3, 4'- trifluorobiphenyl-4-carboxylic acid.
1H NMR (300 MHz, CD3OD): δ (ppm) = 7.47(t, 2H, J=8.7Hz), 6.98-6.79(m, 4H), 6.37- 6.30(m, 2H). HPLC purity: 87.73%.
Example 35: 2-Biphenyl-4-yl-6-chloro-3H-benzoimidazole-4-carboxylic acid
Figure imgf000097_0001
Example 35 is obtained as described in example 1 but starting from methyl 2,3-diamino- 5-chlorobenzoate.
Step 1: N-(4-Chlororo-phenyl)-2-hydroxyimino-acetamide
Figure imgf000097_0002
To a slurry of 4-chloro-phenylamine (5 g, 39.3 mmol) in water (150 ml.) was added chloral hydrate (9.86 g, 59.05 mmol), sodium sulphate (27.95 g, 196.8 mmol), hydroxylamine hydrochloride (5.46 g, 78.74 mmol) and cone. HCI (5 ml_). The reaction mixture was heated to 85°C. It was stirred for another 2 h at the same temperature. After completion of the reaction, solid separated out. The reaction mixture was cooled to room temperature, filtered, washed with water (2-3 times) and dried to obtain the title compound as off white solid (5.5 g, 71.42%).
Step 2: 5-Chloro-1 H-indole-2,3-dione
Figure imgf000097_0003
To a hot solution of cone. H2SO4 (20 ml.) at 600C was added portion wise N-(4-chloro- phenyl)-2-hydroxyimino-acetamide (5.5 g, 27.0 mmol). After the addition, the temperature was increased to 800C and maintained for one hour. After completion of the reaction , the reaction mixture was poured on to crushed ice and the resulting precipitated solid was separated, filtered, washed with water (2-3 times) and dried to obtain the title compound as brick red solid.
Step 3; 5-Chloro-7-nitro-1H-indole-2, 3-dione
Figure imgf000098_0001
To a solution of 5-chloro-1 H-indole-2,3-dione (2.8 g, 15.46 mmol) in cone. H2SO4 (9 ml.) was added fuming nitric acid (1.5 mL) very slowly at -5 to 00C. The reaction mixture was stirred at the same temperature for one hour. After completion of the reaction, the reaction mixture was poured on to crushed ice, and the resulting precipitate was filtered, washed with water (2-3 times) and dried under vacuum to obtain the title compound as yellow solid (3.2 g, 94.11 %) which was used for the next step directly.
Step 4: 2-Amino-5-chloro-3-nitro-benzoic acid
Figure imgf000098_0002
To a slurry of δ-chloro^-nitro-I H-indole^, 3-dione (3.2 g, 14.15 mmol) in aqueous 5N NaOH solution (30 mL) added an aq. solution of 33% hydrogen peroxide solution (3 mL) slowly at 00C. After the addition, the reaction mixture was stirred at room temperature for 4 h. After completion of the reaction, the reaction mixture was acidified with an aq. solution of 2N HCI and the resulting precipitated was filtered, washed with water (2-3 times) and dried under vacuum to obtain the title compound as yellow solid (2 g, 70.17%).
Step 6: 2-Amino-5-chloro-3-nitro-benzoic acid methyl ester
Figure imgf000098_0003
To a solution of 2-amino-5-chloro-3-nitro-benzoic acid (2 g, 1.0 mmol) in methanol (100 mL) was added a saturated ethereal solution of diazomethane gas (50 mL) till all the starting material was consumed. The reaction mixture was concentrated to dryness and the residue obtained was purified by column chromatography using 5% ethyl acetate in hexane as an eluent to obtain the title compound as yellow solid which was directly used for the next step (1.8 g, 84.1 1%).
Step 6: 2, 3-Diamino-5-chloro-benzoic acid methyl ester
Figure imgf000099_0001
A slurry of 2-amino-5-chloro-3-nitro-benzoic acid methyl ester (1 .8 g, 8.40 mmol) and 10% Pd/C (0.5 g) in methanol (50 ml.) was hydrogenated with a hydrogen balloon for 2 h. After completion of reaction, the reaction mixture was filtered over a celite bed and concentrated to dryness. The resulting residue was purified by column chromatography using 30% ethyl acetate in hexane to obtain the title compound as off white solid. 1H NMR (300 MHz, DMSOd6): δ (ppm) =7.01 (s, 1 H), 6.69(s, 1 H), 6.35(s, 2H) 5.19(s, 2H), 3.77(s,3H)
Step 7: 2-Biphenyl-4-yl-6-chloro-3H-benzoimidazole-4-carboxylic acid
Figure imgf000099_0002
1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.42(d, 2H, J=8.4Hz), 8.03(d, 1 H, J=1.8Hz), 7.89(d, 2H, J=8.4Hz), 7.81-7.77(s, 3H), 7.55-7.40(m, 3H). HPLC purity: 94.37%.
Example 36: 6-Fluoro-2-(1 H-indol-5-yl)-3H-benzoimidazole-4-carboxylic acid
Figure imgf000099_0003
Example 36 is obtained as described in example 5 but starting from 1 H-indole-5- carboxylic acid (commercially procured from Aldrich).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 13.4(br.s, 1 H), 12.2(br.s, 1 H), 11.39(br.s, 1 H), 8.58(s, 1 H), 8.31 (s, 2H), 7.88(d, 1 H), 7.71 (d, 1 H), 7.54-7.45(m, 2H). HPLC purity: 87.1 1%. Example 37: 6-Fluoro-2-(1 H-indol-6-yl)-3H-benzoimidazole-4-carboxylic acid
Figure imgf000100_0001
Example 37 is obtained as described in example 5 but starting from 1 H-indole-6- carboxylic acid (commercially procured from Aldrich).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 11.8(br.s, 1 H), 1 1.07(br.s, 1 H), 8.32(s, 1 H),
7.83(d, 1 H, J=8.4Hz), 7.67-7.60(m, 2H), 7.51 (s, 1 H), 7.37-7.34(m, 3H). HPLC purity:
88.98%.
Example 38: 2-Biphenyl-4-yl-3H-benzoimidazole-4-carbonitrile
Figure imgf000100_0002
Step 1: 2-Biphenyl-4-yl-1H-benzoimidazole-4-carboxylic acid amide
Figure imgf000100_0003
To the solution of 2-biphenyl-4-yl-1 H-benzoimidazole-4-carboxylic acid (0.35 g, 1.1 mmol) in THF (20 ml.) was added N-methyl morpholine (0.2 ml_, 1.6 mmol) and the mixture was cooled to -5O0C. lsobutyl chloroformate (0.22 ml_, 1.6 mmol) was then added drop wise, the reaction mixture was warmed to -1 O0C and stirred for 2 h. The reaction mixture was again cooled to -5O0C and purged with ammonia gas for 10 minutes. Reaction mixture warmed to room temperature and stirred for 1 hour. TLC showed completion of the reaction. The crude mixture was filtered and the filtrate concentrated. The resulting residue was stirred with hexane and the free solid formed filtered and dried to obtain title compound (0.24 g, 70%).
Step 2: 2-Biphenyl-4-yl-1H-benzoimidazole-4-carbonitrile
Figure imgf000101_0001
To the solution of 2-biphenyl-4-yl-1 H-benzoimidazole-4-carboxylic acid amide (0.24 g, 0.76 mmol) in pyridine (10 mL) was added imidazole (0.1 1 g, 1.53 mmol). The reaction mixture was cooled to -3O0C and phosphorous oxy chloride (0.3 mL, 3.1 mmol) was added drop wise. The reaction mixture was then stirred at -10°C for 4 h. Progress of the reaction was monitored by TLC. The reaction mixture was concentrated to dryness and water was added. This mixture was extracted with ethyl acetate and the combined organic layers were concentrated. The resulting residue was purified by column chromatography using 30% ethyl acetate in hexane to get the title compound. 1H NMR (300 MHz, DMSOd6): δ (ppm) = 13.57(br.s, 1 H), 8.34-8.31 (m, 2H), 7.94- 7.88(m, 3H), 7.81-7.79(m, 2H), 7.72-7.70(m, 1 H), 7.55-7.36(m, 4H). HPLC purity: 95.63%.
Example 39: 2-Naphthalen-1-yl-3H-benzoimidazole-4-carboxylic acid
Figure imgf000101_0002
Example 39 is obtained as described in example 1 but starting from 1 -naphthoic acid (commercially procured from Aldrich).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 13.80(br.s, 1 H), 8.27-8.24(m, 3H), 8.06(dd, 3H, J!=9Hz, J2=6.9Hz), 7.77-7.58(m, 5H). HPLC purity: 96.71%.
Example 40: 2-(1 H-lndol-2-yl)-6-methyl-3H-benzoimidazole-4-carboxylic acid
Figure imgf000101_0003
Example 40 is obtained as described in example 14 but starting from 1 H-indole-2- carboxylic acid(commercially procured from Aldrich).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 13.4(br.s, 1 H), 12.4(br.s, 1 H), 12.0(br.s, 1 H), 8.33(s, 1 H), 7.91-7.89(m, 4H), 7.71-7.65(m, 2H), 2.50(s, 3H). HPLC purity: 90.26%. Example 41: 6-Methyl-2-(2,3,5,6-tetrafluoro-biphenyl-4-yl)-3H- benzoimidazole-4-carboxylic acid
Figure imgf000102_0001
Example 41 is obtained as described in example 14 but starting from 2,3,5,6- tetrafluorobiphenyl-4-carboxylic acid.
1H NMR (300 MHz, CD3OD): δ (ppm) = 7.07(s, 1H), 6.99(s, 1H), 6.76(m, 5H), 2.53(s, 3H). HPLC purity: 97.64%.
Example 42: 2-(1H-lndol-3-yl)-6-methyl-3H-benzoimidazole-4-carboxylic acid
Figure imgf000102_0002
Example 42 is obtained as described in example 14 but starting from 1H-indole-3- carboxylic acid(commercially procured from Aldrich).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 12.0(br.s, 1H), 11.80(s, 2H), 8.01-7.98(m, 3H),
7.47-7.44(m, 2H), 7.20-7.11(m, 4H)HPLC purity: 86.94%.
Example 43: 2-Biphenyl-4-yl-4-trifluoromethyl-1H-benzoimidazole
Figure imgf000102_0003
Example 43 is obtained as described in example 1 but starting from 3- (trifluoromethyl)benzene-1,2-diamine
Step 1: N-(3-Trifluoromethyl-phenyl)-acetamide
Figure imgf000102_0004
A mixture of 3-trifluoromethyl-phenylamine (4 g, 24.8 mmol), acetic anhydride (10.1 g, 99.3 mmol), DMAP (0.9 g, 7.4 mmol) and triethyl amine (2.5 g, 24.8 mmol) was heated to reflux 2h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the combined organic layers were dried over sodium sulphate and concentrated to dryness. The obtained residue was purified by column chromatography using 30% ethylacetate in hexane to get the title compound as off-white solid.
Step 2: N-(2-Nitro-3-trifluoromethyl-phenyl)-acetamide
Figure imgf000103_0001
N-(3-trifluoromethyl-phenyl)-acetamide (2.8 g, 13.7 mmol) was added in small portions to the cold fuming nitric acid (10 ml.) taken in a dry round bottom flask at -100C. The reaction mixture was stirred for another 10 minutes at the same temperature then quenched with water (50 ml.) and extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated to dryness. The obtained residue was purified by column chromatography using 20% ethylacetate in hexane to get the title compound as yellow solid (0.9 g, 27.74%).
Step 3: 2-Nitro-3-trifluoromethyl-phenylamine
Figure imgf000103_0002
To a solution of N-(2-nitro-3-trifluoromethyl-phenyl)-acetamide (0.9 g, 3.6 mmol) in ethanol (23 ml.) was added an aq. solution of 20% aq. sodium hydroxide (4.5 ml.) and the mixture was heated to reflux for one hour. After completion of the the reaction, the reaction mixture was cooled to room temperature and the solvents were evaporated. The reaction mixture was then diluted with water (50 ml_), extracted with ethyl acetate (2X25 ml_). The combined organic layers were dried over sodium sulphate and concentrated to dryness to get the title compound as yellow solid (0.67 g, 95.54%). 1H NMR (300 MHz, DMSOd6): δ (ppm) =7.4-7.3(m,1 H) 7.3(d, J=12Hz,1 H) 7.4-6.8(m, 1 H) 5.00(bs,2H) Step 4: 3-Trifluoromethyl-benzene-1,2-diamine
Figure imgf000104_0001
A slurry of 2-nitro-3-trifluoromethyl-phenylamine (0.678 g, 3.2 mmol) and 10% palladium on carbon (0.067 g) in methanol (20 ml.) was hydrogenated with a hydrogen balloon for 2 h. After completion of the reaction, the reaction mixture was filtered and the solvent was evaporated under vacuum to obtain the title compound as off white solid (0.420 g, 73.17%).
Step 5: 2-Biphenyl-4-yl-4-trifluoromethyl-1H-benzoimidazole
Figure imgf000104_0002
1H NMR (300 MHz, CDCI3): δ (ppm) = 9.8(br.s, 1 H), 8.15(d, 2H, J=8.4Hz), 7.95(br.s, 1 H), 7.77(d, 2H, J=8.7Hz), 7.71-7.63(m, 2H), 7.56-7.46(m, 3H), 7.43-7.35(m, 2H). HPLC purity: 92.46%.
Example 44: 6-Chloro-2-(3-fluoro-biphenyl-4-yl)-1 H-benzoimidazole-4- carboxylic acid
Figure imgf000104_0003
Example 44 is obtained as described in example 35 but starting from 3-fluorobiphenyl-4- carboxylic acid
1H NMR (300 MHz, DMSOd6): δ (ppm) = 12.20(br.s, 2H), 8.25(br.s, 1 H), 8.05(br.s,1 H), 7.90-7.65(m, 5H), 7.60-7.40(m, 3H). HPLC purity: 89.68%.
Example 45: 6-Chloro-2-(2'-fluoro-biphenyl-4-yl)-1 H-benzoimidazole-4- carboxylic acid
Figure imgf000105_0001
Example 45 is obtained as described in example 35 but starting from 2'-fluorobiphenyl-4- carboxylic acid.
1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.43(d, 2H, J=7.8Hz), 8.02(br.s, 1 H), 7.75- 7.62(m, 4H), 7.49-7.33(m, 4H). HPLC purity: 92.60%.
Example 46: 2-(3-Methoxy-biphenyl-4-yl)-6-methyl-1 H-benzoimidazole-4- carboxylic acid
Figure imgf000105_0002
Example 46 is obtained as described in example 14 but starting from 3- methoxybiphenyl-4-carboxylic acid.
Step 1: 3-Methoxy-biphenyl-4-carboxaldehyde
Figure imgf000105_0003
A mixture of toluene (30 ml.) and water (5 ml.) was degassed with nitrogen for 30 min. A mixture of sodium carbonate (2.26 g, 6.9 mmol) was added followed by 2-methoxy-4- bromobenzaldehyde (0.5 g, 2.3 mmol), phenylboronic acid (0.337 g, 2.7 mmol) and tetrakis triphenyl phosphene palladium(O) (0.261 g, 0.022 mmol) to the above degassed water / toluene mixture. The reaction mixture was then refluxed overnight. After the reaction is completed, it was cooled to room temperature and extracted with ethyl acetate. The combined organic layers were dried over sodium su lphate and concentrated. The obtained residue was purified by column chromatography using 3% ethyl acetate in hexane to obtain the title compound. 1H NMR (300 MHz, CDCI3): δ (ppm) = 4.0(s, 3H), 7.2-7.9(m, 8H), 10.5(s, 1 H).
Step 2: S-Methoxy-biphenyl-^carboxylic acid
Figure imgf000106_0001
To a cold solution of 3-methoxy-biphenyl-4-carboxaldehyde (0.32 g, 1.5 mmol) in acetone (10 ml_), the Jone's reagent was added slowly drop wise at 0°C until the reaction completes. Acetone was removed completely and the resulting residue was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulphate and concentrated to obtain the title compound (0.25 g, 73.5%)
Step 3: 2-(3-Methoxy-biphenyl-4-yl)-6-methyl-1H-benzoimidazole-4-carboxylic acid
Figure imgf000106_0002
1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.33(d, 1 H, J=8.1 Hz), 7.87-7.81 (m, 4H), 7.59- 7.46(m, 5H), 4.17(s, 3H), 2.4(s, 3H). HPLC purity: 91.20 %.
Example 47: 2-(4-Benzothiazol-2-yl-phenyl)-6-methyl-1 H-benzoimidazole-4- carboxylic acid
Figure imgf000106_0003
Example 47 is obtained as described in example 14 but starting from 4-(1 ,3- benzothiazol-2-yl)benzoic acid (synthesized using protocol described in U.S., 6251689, 26 Jun 2001 ). 1H NMR (300 MHz, DMSO-d6): δ (ppm) = 8.5(d, 2H, J=7.5Hz), 8.27(d, 2H, J=8.1 Hz), 8.21 (d, 2H, J=7.8Hz), 8.12(d, 2H, J=7.8Hz), 7.76(s, 1 H), 7.69(s, 1 H), 7.59(t, 1 H, J=7.5Hz), 7.6(t, 1 H, J=6.9Hz), 2.4(s, 3H). HPLC purity: 92.66%.
Example 48: 2-(3,5-Difluoro-biphenyl-4-yl)-6-methyl-1 H-benzoimidazole-4- carboxylic acid
Figure imgf000107_0001
Exam ple 48 is obtai ned as described in example 14 but starting from 3,5- difluorobiphenyl-4-carboxylic acid (prepared according to the literature method PCT Int. Appl., 2005009941 , 03 Feb 2005).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 7.84(d, 2H, J=5.7Hz), 7.79-7.48(m, 7H), 2.4(s,3H). HPLC purity: 98.64%.
Example 49: 6-Methyl-2-(4-phenyl-thiophen-2-yl)-1 H-benzoimidazole-4- carboxylic acid
Figure imgf000107_0002
Example 49 is obtained as described in example 14 but starting from 4-phenylthiophene- 2-carboxylic acid (commercially procured from Aldrich).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.8(s, 1 H), 8.14(s, 1 H), 7.79(d, 2H, J=9Hz), 7.72(d, 2H, J=3Hz), 7.49(t, 2H, J=7.8Hz), 7.37(t, 1 H, J=7.2Hz), 2.4(s, 3H). HPLC purity: 99.44%.
Example 50: 2-(6-Phenyl-pyridin-3-yl)-1 H-benzoimidazole-4-carboxylic acid
Figure imgf000107_0003
Example 50 is obtained as described in example 1 but starting from 6-phenylnicotinic acid (Prepared according to the literature method Tetrahedron letter 45(29), 5661-5663; 2004).
1H NMR (300 MHz, DMSOd6): δ (ppm) =9.5(s, 1 H), 9.5(m, 1 H), 8.8-8.7(m, 1 H), 8.28- 8.22(m, 2H), 8.07(d, 2H, J=8.1 Hz), 7.98(d, 2H, J=7.5Hz), 7.59-7.49(m, 3H). HPLC purity: 94.90%.
Example 51 : 2-Biphenyl-4-yl-5-chloro-1 H-indole-7-carboxylic acid
Figure imgf000108_0001
Example 51 is obtained as described in example 61 but starting from a-Amino-5-chloro- 3-iodo-benzoic acid methyl ester (commercially procured from aldrich). 1H NMR (300 MHz, DMSOd6): δ (ppm) =9.5(s, 1 H), 9.5(m, 1 H), 8.8-8.7(m, 1 H), 8.28- 8.22(m, 2H), 8.07(d, 2H, J=8.1 Hz), 7.98(d, 2H, J=7.5Hz), 7.59-7.49(m, 3H). HPLC purity: 94.90%.
Example 52: 2-(2',3'-Difluoro-biphenyl-4-yl)-6-methyl-1 H-benzoimidazole-4- carboxylic acid
Figure imgf000108_0002
Example 52 is obtained as described in example 14 but starting from 2', 3'- difluorobiphenyl-4-carboxylic acid. Step 1: 2', S'-Difluoro-biphenyl-^carboxylic acid methyl ester
Figure imgf000108_0003
A mixture of toluene (16 mL) and water (4 mL) was degassed with nitrogen for 30 minutes. A mixture of sodium carbonate (1.4 g, 13.9 mmol), 4-bromomethylbenzoate (1 g, 4.6 mmol), 2,3-difluoro phenylboronic acid (0.726 g, 4.6 mmol) and dichloro bis(diphenylphosphine)ferrocene palladium (II) (0.18g, 0.22 mmol) was added to the above degassed water / toluene mixture. The reaction mixture was then refluxed overnight. After the reaction is completed it was cooled to room temperature and extracted with ethyl acetate. The combined organic layers were dried over sodium su l phate an d concentrated . The resu lti ng resid u e was pu rified by col u m n chromatography using 5% ethyl acetate in hexane to obtain the title compound. 1H NMR (300 MHz, CDCI3): δ (ppm) = 4.0(s, 3H), 7.2-7.9(m, 3H), 7.6(d, 2H), 8.1 (d, 2H).
Step 2: 2', S'-Difluoro-biphenyl-^carboxylic acid
Figure imgf000109_0001
To a solution of 2', S'-difluoro-biphenyM-carboxylic acid methyl ester (0.4 g, 1 .6 mmol) dissolved in 10% aq.TH F, an aq. solution of 5 N NaOH (5 ml.) was added and the reaction mixture refluxed for 5 h. THF was removed completely. The residue was cooled and acidified with an aq. solution of 50% aq. HCI solution. The resulting precipitate was filtered,washed thoroughly with water and dried to obtain the title compound (0.3g, 79%).
Step 3: 2-(2 ', 3 '-Difluoro-biphenyl-4-yl)-6-methyl- 1 H-benzoimidazole-4-carboxylic acid
Figure imgf000109_0002
1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.42(d, 2H, J=8.4Hz), 7.83-7.77(m, 4H), 7.54- 7.36(m, 3H), 2.43(s, 3H). HPLC purity: 96.10%.
Example 53: 6-Methyl-2-(5-phenyl-pyridin-2-yl)-1 H-benzoimidazole-4- carboxylic acid
Figure imgf000109_0003
Example 53 is obtained as described in example 14 but starting from 5-phenylpyridine-2- carboxylic acid (prepared according to the literature method PCT Int. Appl., 2005020899, 10 Mar 2005).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 9.16(s, 1 H), 8.6(d, 1 H, J=6Hz), 8.4(d, 1 H, J=9Hz), 7.9-7.81 (m, 4H), 7.61-7.51 (t, 3H, J=7.8Hz), 2.42(s, 3H). HPLC purity:95.23 %.
Example 54: 2-(4-Benzenesulfonyl-phenyl)-1 H-benzoimidazole-4-carboxylic acid
Figure imgf000110_0001
Example 54 is obtained as described in example 1 but starting from 4- (phenylsulfonyl)benzoic acid.
Step 1: 4-Phenylsulfanyl-benzaldehyde
Figure imgf000110_0002
To the solution of thiophenol (0.5 g, 0.463 ml_, 4.5 mmol) in DMF (6 ml.) was added potassium carbonate (0.94 g, 6.8 mmol) and the mixture was stirred at room temperature for 15 minutes. 4-fluoro benzaldehyde (0.675 g, 0.574 ml_, 5.4 mmol) was added and the reaction mixture stirred at 8O0C for 6 h. The progress of the reaction was monitored by TLC. The reaction mixture quenched with water (20 mL) and extracted with ethyl acetate (50 mL X 2). The combined organic layers were washed with water (25 mL X 2) then with brine (25 mL), dried over anhydrous sodium sulphate and concentrated. The obtained residue was purified by column chromatography using 5% ethyl acetate in hexane to obtain title compound (0.94 g, 96%). 1H NMR (300 MHz, DMSOd6): δ (ppm) = 7.3(d, 2H), 7.6(m, 5H), 7.8(d, 2H), 9.9(s, 1 H). Step 2: 4-Benzenesulfinyl-benzoic acid
Figure imgf000111_0001
The solution of 4-phenylsulfanyl-benzaldehyde (0.2 g, 0.93 mmol) in acetone (10 ml.) was cooled to O0C in an ice bath. A solution of sulfamic acid (0.272 g, 2.8 mmol) in water (1 ml.) was added and allowed to stir for 5 minutes at same temperature. An aq. solution of sodium chlorite (0.338 g, 3.7 mmol in 1 ml.) was added and thew reaction mixture was allowed to stir for 30 minutes. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with water and the resulting precipitate was filtered, washed with water and dried to get the title compound. 1 H NMR (300 MHz, DMSO-D6): δ (ppm) = 7.5(m, 3H), 7.8(m, 2H), 7.9(d, 2H), 8.1 (d, 2H), 13.3(s, 1 H).
Step 3: 4-Benzenesulfonyl-benzoic acid
Figure imgf000111_0002
4-Benzenesulfinyl-benzoic acid (0.14 g, 0.5 mmol) was suspended in sodium hypochlorite solution (10 rtiL) and the reaction mixture stirred for 24 h at room temperature. The progress of the reaction was monitored by TLC. The reaction mixture was acidified with an aq. solution of 10% HCI solution. The resulting precipitate was filtered and washed with water. The residue was then redissolved in methanol and concentrated to get the title compound (0.105 g, 70%).
Step 4: 2-(4-Benzenesulfonyl-phenyl)-1H-benzoimidazole-4-carboxylic acid
Figure imgf000112_0001
1H NMR (300 MHz, DMSO-d6): δ (ppm) = 8.3(d, 2H), 7.86-7.73(m, 6H), 7.65-7.52(m, 3H), 7.23(t, 2H). HPLC purity: 87.60%.
Example 55: 2-(4-Phenylamino-phenyl)-1 H-benzoimidazole-4-carboxylic acid
Figure imgf000112_0002
Example 55 is obtained as described in example 1 but starting from 4-anilinobenzoic acid (prepared according to the literature method Zhurnal Obshchei Khimii, 30, 2693-8; 1960).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.86(s, 1 H), 8.17(d, 2H), 7.89(m, 2H), 7.43(t, 1 H), 7.34(t, 2H), 7.2(t, 4H), 6.99(t, 1 H). HPLC purity: 89.90%.
Example 56: 2-[4-(2,6-Difluoro-phenoxy)-phenyl]-1H-benzoimidazole-4- carboxylic acid
Figure imgf000112_0003
Example 56 is obtained as described in example 1 but starting from 4-(2,6- difluorophenoxy)benzoic acid.
Step 1: 4-(2, 6-Difluoro-phenoxy)-benzaldehyde
Figure imgf000113_0001
A slurry of 2, 6-difluorophenol (1.0 g, 8 mmol), potassium carbonate (3.29 g, 24.2 mmol) and 4-fluoro benzaldehyde (1.36 g 10.4 mmol) in dry DMF (50 mL) was stirred at 1000C overnight under nitrogen atmosphere. After the reaction is completed it was cooled to room temperature and poured in to ice cold water. The mixture was extracted with ethyl acetate (100 mL X 2). The combined organic layers were washed with water (50 mL X 2), brine, then dried over anhydrous sodium sulphate and concentrated. The resulting residue was purified by column chromatography using 3% ethyl acetate in hexane to obtain the title compound.
Step 2: 4-(2, 6-Difluoro-phenoxy)-benzoic acid
Figure imgf000113_0002
To a cold solution of 4-(2, 6-difluoro-phenoxy)-benzaldehyde (1 g, 4.2 mmol) in acetone (10 mL) was added the Jone's reagent slowly drop wise at 00C until the reaction completes. The acetone was removed completely and the residue was diluted with water, extracted with ethyl acetateand the combined organic layers were washed with water and brine, then dried over sodium sulphate and concentrated to obtain the title compound (0.75 g, 70%) 1H NMR (300 MHz, DMSOd6): δ (ppm) = 7.0(d, 2H), 7.4(m, 3H), 8.0(d, 2H), 19.9(bs, 1 H).
Step 3: 2-[4-(2,6-Difluoro-phenoxy)-phenyl]-1H-benzoimidazole-4-carboxylic acid
Figure imgf000114_0001
1H NMR (300 MHz, DMSO-d6): δ (ppm) = 8.32(d, 2H, J=9Hz), 7.95(dd, 2H, J1=I ZJHz, J2=I 6.8Hz), 7.49-7.36(m, 4H), 7.2(d, 2H, J=8.7Hz). HPLC purity: 98.20%.
Example 57: 2-(4-Pyridin-4-yl-phenyl)-1H-benzoimidazole-4-carboxylic acid
Figure imgf000114_0002
Example 57 is obtained as described in example 1 but starting from 4-pyridin-4-ylbenzoic acid (prepared according to the literature method Synlett, (6), 829-831 ; 2000). 1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.85(d, 2H, J=5.1 Hz), 8.54(d, 2H, J=8.4Hz), 8.19-8.13(m, 4H), 7.98 (d, 1 H, J=7.8Hz), 7.87(d,1 H, J=6.9Hz), 7.39(t, 1 H, J=7.8Hz). HPLC purity: 93.93%.
Example 58: 6-Fluoro-2-(4-pyridin-3-yl-phenyl)-1 H-benzoimidazole-4- carboxylic acid
Figure imgf000114_0003
Example 58 is obtained as described in example 5 but starting from 4-pyridin-3-ylbenzoic acid (prepared according to the literature method Synlett, (6), 829-831 ; 2000).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.41 (d, 2H, J=8.4Hz), 7.88(d, 2H, J=8.4Hz),
7.83-7.78(m, 3H), 7.62-7.58(m, 1 H), 7.54-7.49(m, 2H), 7.45-7.40(m,1 H). HPLC purity:
93.73%.
Example 59: 6-Methyl-2-(4-pyridin-3-yl-phenyl)-1 H-benzoimidazole-4- carboxylic acid
Figure imgf000115_0001
Example 59 is obtained as described in example 14 but starting from 4-pyridin-3- ylbenzoic acid.
1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.29(d, 2H, J=8.4Hz), 7.97(d, 2H, J=8.7), 7.87- 7.8(m, 4H), 7.59-7.54(m, 2H), 2.45(s, 3H). HPLC purity: 98.93%.
Example 60: 2-(2',3'-Difluoro-biphenyl-4-yl)-1 H-benzoimidazole-4-carboxylic acid
Figure imgf000115_0002
Example 60 is obtained as described in example 1 but starting from 2', 3'- difluorobiphenyl-4-carboxylic acid.
1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.44(d, 2H, J=8.4Hz), 7.99(d, 1 H, J=8.1 Hz), 7.91 (d, 1 H, J=7.2Hz), 7.81 (d, 2H, J=6.9Hz), 7.53-7.35(m, 4H). HPLC purity: 86.73%.
Example 61 : 2-Biphenyl-4-yl-1 H-indole-7-carboxylic acid
Figure imgf000115_0003
Step 1: 2-(hydroxyimino)-N-(2-iodophenyl)acetamide
Figure imgf000115_0004
A mixture of 2-iodobenzenamine (4 g, 0.018 mol), chloral hydrate (3.1 g, 0.021 mol) hydroxylamine hydrochloride (4g, 0.057 mol), sodium sulphate (20 g,0.14 mol) and cone. HCI (5 mL) was dissolved in water (150 mL). This mixture was heated at 800C for 3h. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was cooled to room temperature and the precipitated product was collected by filtration. It was then washed with water and dried in a vaccum oven to get the 3.2 g of the required product as a yellow coloured solid.
Step 2: 7-iodoindoline-2,3-dione
Figure imgf000116_0001
2-(hydroxyimino)-N-(2-iodophenyl) acetamide (3.2 g, 0.01 1 mmol) was added to cone. H2SO4 (15 ml.) in small portions at 6O0C. The reaction mixture was further heated at 85 0C for 5 h. After the reaction completion, the reaction mixture was cooled to room temperature and poured into crushed ice. A brown color solid product precipitated. It was then filtered and washed with chilled water several times, then dried in a vacuum oven to get 2.9 g of the required product as a red coloured solid (87%).
Step 3: 2-Amino-3-iodo-benzoic acid
Figure imgf000116_0002
To a ice cold solution of 7-iodoindoline-2,3-dione (2.9 g, 0.0106 mol) in an aq. solution of 2 N NaOH (15 ml.) was added drop wise an aq. solution of 35% H2O2 (3 ml.) and then allowed to stir at room temperature over night. After the reaction is completed, the reaction mixture was diluted with water (50 ml_), adjusted the pH to 2 with cone. HCI. The precipitated solid was filtered, washed with water (10 ml.) and dried in a vacuum oven to get 2.5 g (89%) of the required product as a yellow coloured solid.
Step 4: 2-Amino-3-iodo-benzoic acid methyl ester
Figure imgf000116_0003
A solution of 2-amino-3-iodo-benzoic acid (2.5 g, 9.5 mmol) in methanol and diethyl ether mixture (15 ml_, 8:2) was added a freshly prepared solution of diazomethane gas in diethyl ether until all the starting material is consumed. Reaction mixture was then evaporated under reduced pressure to obtain a yellow solid which was purified by flash column using. 5% ethylacetate in hexane as an eluent.1.5 g of the required product was isolated as a yellow viscous liquid.
1H NMR (300 MHz, CDCI3): δ (ppm) = 7.81 (dd, 2H, J1=S.1 Hz. J2=8.1 Hz), 6.32-6.31 (m, 3H), 3.8(s, 3H).
Step 5: 2-Biphenyl-4-yl-1H-indole-7-carboxylic acid
Figure imgf000117_0001
To a solution of 2-amino-3-iodo-benzoic acid methyl ester (500 mg, 1.8 mmol), 4- ethynyl-biphenyl (416 mg, 2.3 mmol) in THF (20 ml_), CuI (17 mg, 0.09 mmol), bis- (triphenylphosphine)-palladium (ll)-chloride (64 mg, 0.09 mmol) and TEA (0.75 ml_, 5.4 mmol) were added. This mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion, the reaction mass was filtered through celite, and the collected filtrate was diluted with ethyl acetate (30 ml_), washed with water (2x20 ml.) and the combined organic layer was separated and dried over sodium sulphate and concentrated under reduced pressure to obtain brown mass which was purified by column chromatography using 5% ethyl acetate in hexane as an eluent to obtain 450 mg of 2-amino-3-biphenyl-4-ylethynyl-benzoic acid methyl ester as a pale yellow coloured solid (76%).
1H NMR (300 MHz, CDCI3): δ (ppm) = 7.81 (dd, 1 H, J1=S-I Hz, J2=8.1 Hz), 7.57-7.18(m, 10H), 6.56(t, 1 H, J=7.5Hz), 6.44(br.s, 2H), 3.81 (s, 3H).
To a cold solution of 2-amino-3-biphenyl-4-ylethynyl-benzoic acid methyl ester (300 mg, 0.91 mmol) in NMP (5 ml.) was added dropwise a solution of potassium t-butoxide (205 mg, 1 .83 mmol) in N MP (5 ml_). This reaction mixture was allowed to stir at room temperature for 5 h. After the reaction is completed it was poured into water and pH was adjusted to 2. The resulting precipitate was collected by filtration and was washed with water. Finally it was dried in a vacuum oven to get the 145 mg of 2-biphenyl-4-yl-1 H- indole-7-carboxylic acid as a pale yellow coloured solid. 1H NMR (300 MHz, DMSOd6): δ (ppm) = 13.05(s, 1 H) 10.75(s, 1 H) 8.00(d, 2H, J=8.4 Hz), 7.86-7.73(m, 5H) 7.50(t, 2H, J=7.28 Hz), 7.41-7.36(m, 1 H), 7.15(t, 1 H, J=7.8Hz), 7.09(d, 1 H, J=2.4Hz). HPLC purity: 84.78%
Example 62: 2-(4-Morpholin-4-yl-phenyl)-3H-benzoimidazole-4-carboxylic acid
Figure imgf000118_0001
Example 62 is obtained as described in example 1 but starting from 4-morpholin-4- ylbenzoic (prepared according to the literature method: Bioorganic and medicinal chemistry letters 15(5), 1529-1534; 2005).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.22(d, 2H, J=9Hz), 7.93(t, 2H, J=7.5Hz), 7.48(t, 1 H, J=7.8Hz), 7.15(d, 2H, J=9Hz), 3.76(m, 4H); 3.34(m, 4H). HPLC purity: 95.92%.
Example 63: 2-[4-(2-Oxo-2H-pyridin-1-yl)-phenyl]-3H-benzoimidazole-4- carboxylic acid
Figure imgf000118_0002
Example 63 is obtained as described in example 1 but starting from 4-(2-oxopyridin- 1 (2H)-yl)benzoic acid (prepared according to the literature method: Bioorganic and medicinal chemistry letters 17(16), 4419-4427; 2007).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.44(d, 2H), 8.07-7.98(m, 2H), 7.76-7.69(m, 3H), 7.59-7.51 (m, 2H), 6.53(d, 1 H, J=9.3Hz), 6.39(t, 1 H, J=6.6Hz). HPLC purity: 97.48%.
Example 64: 6-Methyl-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1 H- benzoimidazole-4-carboxylic acid
Figure imgf000119_0001
Example 64 is obtained as described in example 14 but starting from 4-(2-oxopyridin- 1 (2H)-yl)benzoic acid. 1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.41 (d, 2H, J=8.7Hz), 7.81-7.72(m, 3H), 7.66(d, 2H, J=8.4Hz), 7.55(t, 1 H, J=6.9Hz), 6.52(d, 1 H, J=9.3Hz). 6.37(t, 1 H, J=6.6Hz), 2.4(s, 3H). HPLC purity: 87.39%.
Example 65: 2-(2',6I-Difluoro-biphenyl-4-yl)-3H-benzoimidazole-4-carboxylic acid
Figure imgf000119_0002
Exam ple 65 is obtain ed as descri bed in exam ple 1 but starti ng from 2', 6'- difluorobiphenyl-4-carboxylic acid (prepared according to the literature method:J Med Chem. 47(2), 355-374; 2004).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.45(d, 2H, J=8.4Hz), 8.04(d, 1 H, J=8.1 Hz), 7.96(d, 1 H, J=7.5Hz), 7.72(d, 2H, J=8.1 Hz), 7.57-7.47(m, 2H), 7.29(d, 2H, J=8.1 Hz). HPLC purity: 96.80%.
Example 66: 2-[4-(4,5-Dimethyl-oxazol-2-yl)-phenyl]-3H-benzoimidazole-4- carboxylic acid
Figure imgf000119_0003
Example 66 is obtained as described in example 1 but starting from 4-(4,5-dimethyl-1 ,3- oxazol-2-yl)benzoic acid.
Step 1: Terephthalic acid 1 -methyl ester 4-(1-methyl-2-oxo-propyl) ester
Figure imgf000120_0001
A mixture of terphthalicacid monomethyl ester (1.0 g, 5 mmol), 3-hydroxy-butane-2-one (0.531 g, 6.8 mmol), 4-dimethylamino pyridine (1.27 g, 10 mmol), pyridine (0.79 g, 10 mmol) and EDCI. HCI (1.6 g, 8 mmol) was stirred in dry DMF (10 ml.) over night under nitrogen atmosphere. The reaction mixture was poured into ice cold water and extracted with ethyl acetate (100 ml. X 2). The combined organic layers were washed with water (50 m l. X 2) and with brine, then d ried over anhydrous sodium sulphate and concentrated, the obtained residue was purified by column chromatography using 3% ethyl acetate in hexane to obtain the title compound. 1H NMR (300 MHz, CDCI3): δ (ppm) = 2.2(s, 3H), 3.9(s, 3H), 5.1 (s, 2H), 8.1 (s, 4H).
Step 2: 4-(4, 5-Dimethyl-oxazol-2-yl)-benzoic acid methyl ester
Figure imgf000120_0002
To a solution of terephthalic acid 1 -methyl ester 4-(1-methyl-2-oxo-propyl) ester (0.5 g, 2 mmol) in acetic acid (20 ml.) was added ammonium acetate (0.308 g 4 mmol) and the mixture was stirred at 900C over night. Acetic acid was removed under reduced pressure and ice cold water (10 rtiL) was added to the residue. The resulting mixture was extracted with ethyl acetate (50 ml. X 2), the combined organic layers were washed with water (25 ml. X 2) and with brine, dried over anhydrous sodium sulphate and concentrated to obtain the title compound.
1H NMR (300 MHz, CDCI3): δ (ppm) = 2.2(s, 3H), 2.4(s, 3H), 4.0(s, 3H), 8.0(m, 4H). LCMS- M+H 232, 56.34%
Step 3: 4-(4, 5-Dimethyl-oxazol-2-yl)-benzoic acid.
Figure imgf000121_0001
To a solution of 4-(4, 5-dimethyl-oxazol-2-yl)-benzoic acid methyl ester (0.5 g, 2.1 mmol) in THF (20 ml_), an aq. solution of 5 N sodium hydroxide (10 ml.) was added. The reaction mixture refluxed at 900C over night. THF was removed completely under reduced pressure and the residue was acidified with cone. HCI, thenE extracted with ethyl acetate (50 ml. X 2). The combined organic layers werewashed with water (25 ml_ X 2) and with brine, then dried over anhydrous sodium sulphate and concentrated to get the title compound (0.3 g, 63.8 %). HPLC purity: 97.19%.
Step 4: 2-[4-(4, δ-Dimethyl-oxazol^-y^-phenylJ-SH-benzoimidazole^-carboxylic acid
Figure imgf000121_0002
1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.39(d, 2H, J=8.7Hz), 8.07(d, 2H, J=8.1 Hz), 7.92(d, 1 H, J=7.8Hz), 7.85(d, 1 H, J=7.5Hz), 7.37(t, 1 H, J=7.5Hz), 2.35(s,3H), 2.13(s, 3H). HPLC purity: 83.58%.
Example 67: 6-Methyl-2-(4-phenoxy-phenyl)-3H-benzoimidazole-4- carboxylic acid
Figure imgf000121_0003
Example 67 is obtained as described in example 14 but starting from 4-phenoxybenzoic acid (commercially procured from aldrich).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.3(d, 2H, J=8.4Hz), 7.71 (d, 2H, J=9.3Hz),
7.47(t, 2H, J=7.8Hz); 7.23(t, 1 H, J=7.5Hz); 7.16-7.12(m, 4H), 2.48(s, 3H). HPLC purity: 91.91%. Example 68: 2-(3,5-Difluoro-biphenyl-4-yl)-6-fluoro-1 H-benzoimidazole-4- carboxylic acid
Figure imgf000122_0001
Example 68 is obtained as described in example 5 but starting from 3,5-difluorobiphenyl- 4-carboxylic acid (prepared according to the literature method: PCT Int. Appl., 2005009941, 03 Feb 2005).
1H NMR (300 MHz, DMSOd6): δ (ppm) =12.95(br.s, 1H), 7.87-7.85(m, 3H), 7.72- 7.63(m,.3H), 7.56-7.48(m, 3H). HPLC purity: 89.25%.
Example 69: 1-(2-Biphenyl-4-yl-1H-benzoimidazol-4-yl)-ethanone
Figure imgf000122_0002
Example 69 is obtained as described in example 1 , but from 1-(2,3- diaminophenyl)ethanone.
Step 1: N-(2-Acetyl-phenyl)-acetamide
Figure imgf000122_0003
To an ice cold slurry of the 1-(2-amino-phenyl)-ethanone (2 g, 14.79 mmol) in dichloroethane (10 ml_), acetyl chloride (1.22 g, 16.2 mmol) was added slowly. The reaction mixture was warmed to room temperature and stirred for 2h. After completion of the reaction, the reaction mixture was quenched with water (10 ml.) and extracted with dichloromethane (2X25 ml_). The combined organic layers were washed with an aq. solution of 5% NaHCO3 followed by water and brine, then dried over anhydrous sodium sulphate and concentrated to dryness. The obtained residue was purified by column chromatography using 2% ethyl acetate in hexane to obtain the title compound as off- white solid which directly used for the next reaction. Step 2: N-(2-Acetyl-6-nitro-phenyl)-acetamide
Figure imgf000123_0001
A solution of N-(2-acetyl-phenyl)-acetamide (1 g, 5.65 mmol) in cone. H2SO4 (2.8 ml_, 45.2 mmol) was cooled to -200C and fuming nitric acid (2 ml_, 33 mmol) was slowly added. The reaction mixture was warmed to 00C and stirred for 7 h. After completion of the starting material, the reaction mixture was quenched with water and extracted with dichloromethane (2X25 ml_). The combined organic layers were washed with brine and water, then dried over anhydrous sodium sulphate and concontrated to dryness. The resulting residue was purified by column chromatography using 1 %methanol in chloroform to get the title compound as yellow solid
Step 3: 1-(2-Amino-3-nitro-phenyl)-ethanone
Figure imgf000123_0002
To a solution N-(2-acetyl-6-nitro-phenyl)-acetamide (0.3 g, 13.5 mmol) in ethanol (5 ml_), was added an aq. solution of 5 N HCI (4.5 ml.) and the reaction mixture was heated to reflux for one hour. After completion of the reaction, the reaction mixture was cooled to room temperature and evaporated under reduced pressure. The residue was diluted with water (25 ml.) and extracted with ethyl acetate (2X25 ml_). The combined organic layers were washed with a 10% aq. solution of sodium bicarbonate followed by water and dried over anhydrous sodium sulphate, then concentrated to dryness and purified by column chromatography using 15% ethyl acetate in hexane to get the title compound as yellow solid (0.20 g, 82.30%)
Step 4:1-(2,3-Diamino-phenyl)-ethanone
Figure imgf000123_0003
A slurry of 1-(2-amino-3-nitro-phenyl)-ethanone (0.2 g, 1.1 1 mmol) and 10% palladium on carbon (0.020 g) in methanol (10 ml.) was hydrogenated with a hydrogen balloon for 2 h. After completion of the reaction, the reaction mixture was filtered and evaporated under vacuum to obtain the title compound as off white solid (0.120 g, 72.28%)
1 H N MR (300 MHz, DMSO-d6): δ (ppm) = 7.12(d, J=12Hz,1 H) 6.80(bs,2H) 6.70(d, J=12Hz,1 H) 6.44-6.36(m,1 H) 4.80(s,2H) 2.45(s,3H).
Step 5: 1-(2-Biphenyl-4-yl-1H-benzoimidazol-4-yl)-ethanone
Figure imgf000124_0001
1H NMR (300 MHz, CDCI3): δ (ppm) = 1 1.2(br.s, 1 H), 8.2(d, 2H), 8.1 (d,1 H), 7.92- 7.6(m,3H), 7.7(d, 2H), 7.5(t, 2H), 7.44 (m, 2H), 2.9(s, 3H). HPLC purity: 96.25%.
Example 70: 2-[4-(Pyridin-2-yloxy)-phenyl]-1 H-benzoimidazole-4-carboxylic acid
Figure imgf000124_0002
Example 70 is obtained as described in example 1 but starting from 4-(pyridin-2- yloxy)benzoic acid (prepared according to the literature method: Synlett, (2), 221-224; 2008).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.27-7.90(m, 4H), 7.66-7.60(m, 2H), 7.23- 7.09(m, 5H). HPLC purity: 96.62%.
Example 71 : 6-Methyl-2-[4-(pyridin-2-yloxy)-phenyl]-1 H-benzoimidazole-4- carboxylic acid
Figure imgf000125_0001
Example 71 is obtained as described in example 14 but starting from 4-(pyridin-2- yloxy)benzoic acid.
1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.4(d, 2H, J=9Hz), 8.22(d, 1 H, J=4.8Hz), 7.97-
7.87(m, 3H), 7.41 (d, 2H, J=8.7Hz), 7.25-7.18(m, 2H), 2.54(s, 3H). HPLC purity: 92.02%.
Example 72: 6-Methyl-2-(4-pentafluorophenyloxy-phenyl)-1 H- benzoimidazole-4-carboxylic acid
Figure imgf000125_0002
Example 72 is obtained as described in example 14 but starting from 4- (pentafluorophenoxy)benzoic acid.
Step 1: 4-Pentafluorophenyloxy-benzaldehyde
Figure imgf000125_0003
A slurry of 2, 3, 4, 5, 6-pentafluorophenol (1.92 g, 10.4 mmol), potassium carbonate (3.3 g, 23.9 mmol) and 4-fluoro benzaldehyde (1.0 g, 8.0 mmol) in dry DMF (50 ml.) was stirred at 1000C overnight under nitrogen atmosphere. After the reaction is completed it was cooled to room temperature and poured in to ice cold water. The mixture was extracted with ethyl acetate (100 ml. X 2), the combined organic layers were washed with water (50 mL X 2), brine, then dried over anhydrous sodium sulphate and concentrated. The residue was purified by column chromatography using 3% ethyl acetate in hexane to obtain the title compound. 1H NMR (300 MHz, CDCI3): δ (ppm) = 7.2(dd, 2H), 7.9(dd, 2H), 10.0(s, 1 H).
Step 2: 4-Pentafluorophenyloxy-benzoic acid
Figure imgf000126_0001
To an ice cold solution of 4-pentafluorophenyloxy-benzaldehyde (0.6 g, 2.0 mmol) in acetone (10 mL), the Jone's reagent was added slowly drop wise until reaction the completed. Acetone was removed completely and diluted with water. The mixture was extracted with ethyl acetate, the combined organic layers were dried over anhydrous sodium sulphate and concentrated to get the title compound (0.45 g, 71 %). 1H NMR (300 MHz, CDCI3): δ (ppm) = 7.1 (m, 2H), 8.1 (m, 2H).
Step 3: 6-Methyl-2-(4-pentafluorophenyloxy-phenyl)-1H-benzoimidazole-4- carboxylic acid
Figure imgf000126_0002
1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.38-8.33(m, 2H), 7.72(d, 2H, J=12.6Hz), 7.44- 7.39(m, 2H), 2.49(s, 3H). HPLC purity: 94.98%.
Example 73: 2-(4-Pyridin-2-yl-phenyl)-3H-benzoimidazole-4-carboxylic acid
Figure imgf000127_0001
Example 73 is obtained as described in example 1 but starting from 4-pyridin-2-ylbenzoic acid (Prepared according to the literature method: Bioorganic and medicinal chemistry letters 15(3), 631-634; 2005).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.74(d, 1 H, J=4.2Hz), 8.46(d, 2H, J=8.4Hz), 8.33(s, 1 H), 8.3(d, 1 H, J=3Hz), 8.14(d, 1 H, J=7.8Hz), 8.01-7.90(m, 4H), 7.48-7.41 (m, 2H). HPLC purity: 95.53%.
Example 74: 6-Methyl-2-(4-pyridin-2-yl-phenyl)-3H-benzoimidazole-4- carboxylic acid
Figure imgf000127_0002
Example 74 is obtained as described in example 14 but starting from 4-pyridin-2- ylbenzoic acid.
1H NMR (300 MHz, CD3OD): δ (ppm) = 7.87(d, 1 H, J=4.2Hz), 7.48(d, 2H, J=8.4Hz),
7.39(d, 2H, J=8.4Hz), 7.18(t, 2H, J=7.5Hz), 7.05(s, 1 H), 6.95(s, 1 H), 6.64(d, 1 H,
J=4.8Hz), 2.48(s, 3H). HPLC purity: 88.93%.
Example 75: 6-Methyl-2-(6-phenyl-pyridin-3-yl)-3H-benzoimidazole-4- carboxylic acid
Figure imgf000127_0003
Example 75 is obtained as described in example 14 but starting from 6-phenylnicotinic acid (prepared according to the literature method: Tetrahedron letter 45(29), 5661 -5663;
2004).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 9.52(d, 1 H, J=2.1 Hz), 8.79(dd, 1 H, ^8.4Hz,
J2=8.7Hz), 8.31-8.22(m, 3H,), 7.89(d, 2H, J=6.3Hz), 7.6-7.54(m, 3H,), 2.55(s,3H,). HPLC purity: 96.55%. Example 76: 2-(2I,6I-Difluoro-biphenyl-4-yl)-6-methyl-3H-benzoimidazole-4- carboxylic acid
Figure imgf000128_0001
Example 76 is obtained as described in example 14 but from 2',6'-difluorobiphenyl-4- carboxylic acid (prepared according to the literature method: J Med Chem. 47(2), 355-
374; 2004).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.43(d, 2H, J=8.1 Hz), 7.87(d, 2H, J=4.5Hz),
7.75(d, 2H, J=8.4Hz), 7.59-7.51 (m, 1 H),7.32-7.27(m, 2H), 2.55(s, 3H). HPLC purity:
96.71%.
Example 77: 2-[4-(4-Cyano-phenoxy)-phenyl]-3H-benzoimidazole-4- carboxylic acid
Figure imgf000128_0002
Example 77 is obtained as described in example 1 but starting from 4-(4- cyanophenoxy)benzoic acid.
Step 1: 4-(4-Cyano-phenoxy)-benzaldehyde
Figure imgf000128_0003
A slurry of 4-cyanophenol (1.24 g, 10.4 mmol), potassium carbonate (3.3 g, 23.9 mmol), and 4-fluoro benzaldehyde (1.0 g, 8 mmol) in dry DMF (50 ml.) was stirred at 1000C overnight under nitrogen atmosphere. After the reaction is completed it was cooled to room temperature and poured in to ice cold water. The mixture was extracted with ethyl acetate (100 ml. X 2), the combined organic layers were washed with water (50 ml. X 2), and brine, then dried over anhydrous sodium sulphate and concentrated. The residue was purified by column chromatography using 3% ethyl acetate in hexane to obtain the title compound (2 g, 86%) 1H NMR (300 MHz, CDCI3): δ (ppm) = 7.0-8.0(m, 8H), 10.0(s, 1 H).
Step 2: 4-(4-Cyano-phenoxy)-benzoic acid
Figure imgf000129_0001
To an ice cold solution of 4-(4-cyano-phenoxy)-benzaldehyde (2.0 g, 8.9 mmol) in acetone (10 ml_), the Jone's reagent (7 ml.) was added slowly drop wise until reaction completes. Acetone was removed completely and diluted with water. The mixture was extracted with ethyl acetate, the combined organic layers were dried over anhydrous sodium sulphate and concentrated to get the title compound (1.5 g, 70%)
1 H NMR (300 MHz, DMSO-d6): δ (ppm) = 7.2(m, 4H), 7.8(d, 2H), 8.0(d, 2H).
Step 3: 2-[4-(4-Cyano-phenoxy)-phenyl]-3H-benzoimidazole-4-carboxylic acid
Figure imgf000129_0002
1H NMR (300 MHz, DMSOd6): δ (ppm; = 8.39-8.32(m, 2H), 8.2-7.9(m, 4H), 7.60- 7.45(m, 1 H), 7.40-7.15(m, 4H). HPLC purity: 72.20%.
Example 78: 2-[4-(4-Cyano-phenoxy)-phenyl]-6-methyl-3H-benzoimidazole- 4-carboxylic acid
Figure imgf000130_0001
Example 78 is obtained as described in example 14 but starting from 4-(4- cyanophenoxy)benzoic acid.
1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.39-8.32(m, 2H), 7.97-7.88(m, 2H), 7.646(d, 2H, J= 12Hz), 7.29-7.12(m, 5H); 2.50(s, 3H). HPLC purity: 78.7%.
Example 79: 2-Biphenyl-4-yl-1 H-benzoimidazole-4-carboxylic acid methyl ester
Figure imgf000130_0002
Step 1: 2-Hydroxyimino-N-(2-nitro-phenyl)-acetamide
Figure imgf000130_0003
A solution of chloral hydrate (29 g, 175 mmol), hydroxyl amine hydrochloride (69.4 g,1000 mmol) and anhydrous sodium sulphate (21 g, 149 mmol) in water (800 ml.) was heated to 650C. To this a suspension was added 2-nitroaniline (20 g,150 mmol) in 2 M aqueous HCI (20 ml_). This mixture was stirred overnight at the same temperature then was cooled to room temperature. The precipitated product was collected by filtration, washed with water dried in a vacuum oven to give 25 g of the required product as a yellow coloured solid (83%).
1 H NMR (300 MHz, DMSO-d6): δ (ppm) = 12.62 (s, 1 H), 10.94(s, 1 H), 8.29(d, 1 H, J= 8.4 Hz), 8.13(dd, 1 H, J=8.4 & 1 .2 Hz), 7.77(m, 1 H), 7.62(s, 1 H), 7.36(m, 1 H). HPLC purity: 85%. Step 2: 7-Nitro-1H-indole-2,3-dione
Figure imgf000131_0001
2-Hydroxyimino-N-(2-nitro-phenyl)-acetamide (15 g, 72 mmol) was carefully added in small portions over a period of 30 min to a stirred solution of cone, sulphuric acid (45 mL) which was preheated to 9O0C. The reaction mixture was stirred for another 2h at the same temperature then cooled to room temperature, poured into crushed ice. The precipitated products were collected by filtrations, washed with water and dried in a vacuum oven to get 9 g (65%) of brick red colour powder.
1H NMR (300 MHz, DMSOd6): δ (ppm) = 11.68(s, 1 H), 8.31 (dd, 1 H, J= 8.4 & 0.9Hz), 7.92(dd, 1 H, J=8.4 & 0.9 Hz), 7.25(m, 1 H). HPLC purity: 93 %
Step 3: 2-Amino-3-nitro-benzoic acid
Figure imgf000131_0002
To a ice cold solution of 7-nitro-1 H-indole-2,3-dione (9 g, 47 mmol) in 2 M aqueous sodium hydroxide (50 mL), an aq. solution of 30% hydrogen peroxide (9 mL) was added drop wise. The mixture was warmed to room temperature and stirred overnight. The resulting mixture was carefully acidified by the addition of an aq. saturated citric acid solution. The solid precipitate was collected by filtration, washed with water and dried in a vacuum oven to get 6 g of the required product as a yellow coloured solid (70%).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.9(br.s, 1 H), 8.19(m, 2H), 6.63(m, 1 H). HPLC purity: 98 %. LCMC(-ive mode): 93% and m/z:181.9
Step 4: 2-Amino-3-nitro-benzoic acid methyl ester
Figure imgf000131_0003
To a solution of 2-amino-3-nitro-benzoic acid (6 g, 33 mmol) in methanol (20 ml_), an ethereal solution of diazomethane gas was added until the staring material is completely consumed. The reaction mixture was then evaporated under reduced pressure and the crude resulting solid was purified by flash column chromatography using 5% ethylacetate & hexane as an eluent, to obtain 2g of the required product as a yellow coloured solid. 1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.35(m, 3H), 8.22(m, 1 H), 6.75(m, 1 H), 3.86(s, 3H). HPLC purity: 99 %
Step 5: 2,3-Diamino-benzoic acid methyl ester
Figure imgf000132_0001
To a solution of 2-amino-3-nitro-benzoic acid methyl ester (2 g, 10 mmol) in methanol, a suspension of 10% Pd/C (300 mg) in methanol 5 ml. was added and hydrogenated with a hydrogen balloon over a period of 8 h. The reaction mass was filtered and the filtrate was concentrated under reduced pressure to obtain 1.5 g of the required compound as a brown coloured solid (88%).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 7.09(dd, 1 H, J=8.1 & 1.2 Hz), 6.70(dd, 1 H, J=8.1 & 1.2 Hz), 6.3.8(m, 1 H), 6.199(s, 2H), 4.77(s, 2H), 3.76(s, 3H).
Step 6: 2-Amino-3-[(biphenyl-4-carbonyl)-amino]-benzoic acid methyl ester
Figure imgf000132_0002
To a stirred solution of 2,3-diamino-benzoic acid methyl ester (200 mg, 1.2 mmol), biphenyl benzoic acid (238 mg, 1.2 mmol), HATU (1.14g, 3mmol) in dry DMF (5 ml.) was added diisopropylethyl amine (0.6 ml_, 3.6 mmol). The mixture was stirred at ambient temperature overnight then poured into water (50 ml_). The precipitated solid was filtered and dried in a vacuum oven to afford the required compound, which was used directly for the next step without any purification (300 mg, 72%).
Step 7: 2-Biphenyl-4-yl-1H-benzoimidazole-4-carboxylic acid methyl ester
Figure imgf000133_0001
2-Amino-3-[(biphenyl-4-carbonyl)-amino]-benzoic acid methyl ester (300 mg, 0.86 mmol) was dissolved in glacial acetic acid (20 mL) and heated to 13O0C until the reaction was completed which was monitored by TLC (2 to 3 h). After the reaction is completed the solvent was removed and solid residue was purified over silica gel using chloroform and methanol as an eluent to get the required example 79.
1H NMR (300 MHz, DMSOd6): δ (ppm) = 12.43(br.s, 1 H), 8.42(d, 2H, J=8.7Hz), 7.99(d, 1 H, J=7.8Hz), 7.89-7.78(m, 5H), 7.54-7.33(m, 4H), 4.00(s, 3H). HPLC purity: 95.04 %.
Example 80: 6-Methyl-2-[4-(2-oxo-azepan-1-yl)-phenyl]-1 H-benzoimidazole- 4-carboxylic acid
Figure imgf000133_0002
Example 80 is obtained as described in example 14 but starting from 4-(2-oxoazepan-1- yl)benzoic acid (prepared according to the literature method: Bioorganic and medicinal chemistry letters 17(16), 4419-4427, 2007).
1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.27(d, 2H, J=8.1 Hz), 7.69(s, 1 H), 7.643(s, 1 H), 7.38(d, 2H, J=8.4Hz), 3.81 (m, 2H), 2.63-1.76(m, 8H), 2.55(s, 3H). HPLC purity: 88.20 %.
Example 81 : 2-[4-(2-Oxo-azepan-1 -yl)-phenyl]-1 H-benzoimidazole-4- carboxylic acid
Figure imgf000133_0003
Example 81 is obtained as described in example 1 but starting from 4-(2-oxoazepan-1- yl)benzoic acid. 1H NMR (300 MHz, DMSOd6): δ (ppm) = 8.25(d, 2H, J=7.2Hz), 7.79-7.72(m, 2H), 7.37(d, 2H, J=8.4Hz), 7.24(s, 1 H), 3.80(m, 2H), 2.65-1.75(m, 8H). HPLC purity: 90.10 %. Example 82: 2-[4-(2,5-Dimethyl-pyrrol-1 -yl)-2,3,5,6-tetrafluoro-phenyl]-6- methyl-1 H-benzoimidazole-4-carboxylic acid
Figure imgf000134_0001
Example 82 is obtained as described in example 1 but starting from 4-(2,5-Dimethyl- pyrrol-1-yl)-2,3,5,6-tetrafluoro-benzoic acid.
Step 1: 4-Amino-2, 3, 5, 6-tetrafluoro-benzoic acid methyl ester
Figure imgf000134_0002
To a solution of 4-amino -2, 3, 5, 6-tetrafluoro-benzoic acid (1 .0 g, 4.78 mmol) in ether (75 ml_), an ethereal solution of diazomethane gas was added until the starting material is completely consumed. The reaction mixture was then evaporated under reduced pressure. The crude solid obtained was purified by flash column chromatography using 0.5% ethyl acetate in hexane to obtain title compound (0.8 g, 75%).
Step 2: 4-(2, 5-Dimethyl-pyrrol-1-yl)-2, 3, 5, 6-tetrafluoro-benzoic acid methyl ester
Figure imgf000134_0003
To the solution of 4-amino-2, 3, 5, 6-tetrafluoro-benzoic acid methyl ester (0.5 g, 2.24 mmol) in absolute ethyl alcohol (20 ml.) containing 2 drops of cone. HCI was added followed by acetonyl acetone (0.233 g, 2.041 mmol). The reaction mixture was then refluxed at 950C for 18 hours. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated and the obtained residue was purified by column chromatography using 0.5% ethyl acetate in hexane to obtain the title compound. 1H NMR (300 MHz, CDCI3): δ (ppm) = 2.0(s, 6H), 4.0(s, 3H), 6.0(s, 2H). LCMS- m/z 302, 96%
Step 3: 4-(2, 5-Dimethyl-pyrrol-1-yl)-2, 3, 5, 6-tetrafluoro-benzoic acid
Figure imgf000135_0001
To the solution of 4-(2, 5-dimethyl-pyrrol-1-yl)-2, 3, 5, 6-tetrafluoro-benzoic acid methyl ester (0.6 g, 1.99 mmol) in THF (20 ml.) was added an aq. solution of 5 N NaOH (5 ml_). The reaction mixture was sirred under refluxed at 900C for 3 hours. TLC shows completion of the reaction. The reaction mixture was concentrated and the resulting residue was cooled, acidified with aq aq, solution of 2 N HCI, extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over anhydrous sodium sulphate then concentrated. The resulting residue was purified by washing with hot hexane to get the title compound (0.43 g, 75%). LCMS- m/z 288, 91 %
Step 4: 2-[4-(2,5-Dimethyl-pyrrol-1-yl)-2,3,5,6-tetrafluoro-phenyl]-6-methyl-1H- benzoimidazole-4-carboxylic acid
Figure imgf000135_0002
1H NMR (300 MHz, DMSOd6): δ (ppm) =2.10(s, 6H), 2.45(s, 3H), 5.97(s, 2H), 7.60(s, 2H). HPLC purity: 87.59%; LCMS m/e(M-1 ): 85.56%
Example 83: 6-Methyl-2-(2,3,5,6-tetrafluoro-4'-piperidin-1 -ylmethyl-biphenyl- 4-yl)-1 H-benzoimidazole-4-carboxylic acid
Figure imgf000135_0003
Step 1: 2, 3, 5, 6-Tetrafluoro-4'-formyl-biphenyl-4-carboxylic acid methyl ester
Figure imgf000136_0001
A tolune / Water (175 mL+25 mL) mixture was degassed with nitrogen for 30 minutes. Cesium carbonate (14.9 g, 43.55 mmol) was added followed by 4-bromo-2, 3,5,6- tetrafluoro-benzoic acid methyl ester (5.0 g, 17.42 mmol), 4-formyl boronic acid (3.4 g, 22.64 mmol) and dichlorobis(triphenylphosphine)-palladium(ll) catalyst (0.611 g, 0.87 mmol). The reaction mixture was refluxed for 15 h. TLC shows completion of the reaction. The reaction mixture was cooled to room temperature and was extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated. The obtained residue was purified by column chromatography using 5% ethyl acetate in hexane to get colorless solid (3.0 g, 55.24%). 1H NMR (300 MHz, CDCI3): δ (ppm) 4.0 (s, 3H), 7.6(d, 2H), 8.0(d, 2H), 10.0 (2, 1 H).
Step 2: 2, 3, 5, 6-Tetrafluoro-4'-hydroxymethyl-biphenyl-4-carboxylic acid methyl ester
Figure imgf000136_0002
2, 3, 5, 6-Tetrafluoro-4'-formyl-biphenyl-4-carboxylic acid methyl ester (1.26 g, 4.03 mmol) was dissolved in methanol (30 mL) and cooled to -1O0C. Sodium borohydride (0.76 g, 20.19 mmol) was added portion wise and reaction mixture stirred by maintaining the same temperature. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated to dryness. The obtained residue was redissolved in ethyl acetate (50 mL) and washed with water (20 mL X 2) followed by brine, dried over anhydrous sodium sulphate and concentrated to get colorless solid (1.1 g, 86.75%). 1H NMR (300 MHz, CDCI3): δ(ppm) 4.0 (s, 3H), 5.0 (s, 2H), 7.5(m, 4H). Step 3: 4 '-(tert-Butyl-dimethyl-silanyloxymethyl)-2, 3, 5, 6-tetrafluoro-biphenyl-4-carboxylic acid methyl ester
Figure imgf000137_0001
To a solution of 2, 3, 5, θ-tetrafluoro^'-hydroxymethyl-biphenyM-carboxylic acid methyl ester (1.6 g, 5.09 mmol) in dry dichloromethane (100 ml.) was added imidazole (0.7 g, 10.19 mmol) and TBDMS chloride (0.92 g, 6.1 1 mmol). The reaction mixture was stirred under nitrogen at room temperature for 15 h. The progression of the reaction was monitored by TLC. The reaction mixture was disovled in ethyl acetate, washed with water (50 ml. X 2) and with brine then dried over anhydrous sodium sulphate and concentrated to give colorless solid (2.0 g, 91.745).
1H NMR (300 MHz, CDCI3): δ (ppm) 0.2 (s, 6H), 1.0 (s, 9H), 4.0 (s, 3H), 4.8 (s, 2H), 7.4(m, 4H).
Step 4: 4'-(tert-Butyl-dimethyl-silanyloxymethyl)-2, 3, 5, 6-tetrafluoro-biphenyl-4- carboxylic acid
Figure imgf000137_0002
To a solution of 4'-(tert-butyl-dimethyl-silanyloxymethyl)-2, 3, 5, 6-tetrafluoro-biphenyl-4- carboxylic acid methyl ester (2.6 g, 6.0 mmol) in tetrahydrofuran (50 ml.) was added an aq. solution of 5 N sodium hydroxide (20 ml_). The reaction mixture was tirred and refluxed for 5 hours. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated. The resulting residue was cooled to 1 O0C and acidified with an aq. solutio of 50% HCI. The formed precipitate was filtered, washed thoroughly with water and dried to get colorless solid (2.2 g, 88.0%). 1H NMR (300 MHz, CDCI3): δ (ppm) 0.2 (s, 6H), 1.0 (s, 9H), 4.8 (s, 2H), 7.5(m, 4H).
Step 5: 2-Amino-3-{[4 '-(tert-butyl-dimethyl-silanyloxymethyl)-2, 3, 5, 6-tetrafluoro-biphenyl- 4-carbonyl]-amino}-5-methyl-benzoic acid methyl ester
Figure imgf000138_0001
To a solution of 4'-(tert-butyl-dimethyl-silanyloxymethyl)-2, 3, 5, 6-tetrafluoro-biphenyl-4- carboxylic acid (2.2 g, 5.3 mmol) in dry DMF (50 ml.) was added 2,3-diamino-5-methyl- benzoic acid methyl ester (0.95 g, 5.3 mmol) and HATU (3.03 g, 7.9 mmol) fallowed by N, N-diisopropylethylamine (1 ml_). The reaction mixture was stirred for 14 h at room temperature under nitrogen atmosphere. TLC shows completion of the reaction. The reaction mixture was quenched to crushed ice and the precipitate was filtered, washed with water and dried to get an off white solid (2.4 g, 80.80%) which was directly taken to the next step.
Step 6: 2-[4 '-(tert-Butyl-dimethyl-silanyloxymethyl)-2, 3, 5, 6-tetrafluoro-biphenyl-4-yl]-6- methyl-1H-benzoimidazole-4-carboxylic acid methyl ester
Figure imgf000138_0002
2-Amino-3-{[4'-(tert-butyl-dimethyl-silanyloxymethyl)-2,3,5,6-tetrafluoro-biphenyl-4- carbonyl]-amino}-5-methyl-benzoic acid methyl ester (2.4 g, 4.16 mmol) was dissolved in glacial acetic acid (75 ml.) and sirred and refluxed for 4 hours. Progress of the reaction was monitored by TLC. Acetic acid was distilled under vacuum and the resulting residue was quenched with ice cold water. The precipitate was washed with water and dried (2.0 g, 84.03%) which was directly taken to the next step.
Step 7: 6-Methyl-2-(2, 3, 5, 6-tetrafluoro-4 '-hydroxymethyl-biphenyl-4-yl)- 1 H- benzoimidazole-4-carboxylic acid methyl ester
Figure imgf000139_0001
2-[4'-(tert-butyl-dimethyl-silanyloxymethyl)-2!3!5,6-tetrafluoro-biphenyl-4-yl]-6-methyl-1 H- benzoimidazole-4-carboxylic acid methyl ester (2.0 g, 3.58 mmol) was suspended in an q. solution of 4 N HCI (100 ml.) and stirred at room temperature for 4 h. TLC shows completion of the reaction. The reaction mixture was diluted with water and extracted with ethyl acetate (100 mL X 3). Ethyl acetate layer washed with water (50 mL X 2) and brine. Dried over anhydrous sodium sulphate and concentrated to get off white solid (1.2 g, 75.9%) which was directly taken to next step.
Step 8: 6-Methyl-2-(2, 3, 5, 6-tetrafluoro-4 '-formyl-biphenyl-4-yl)- 1 H-benzoimidazole-4- carboxylic acid methyl ester
Figure imgf000139_0002
To a solution of 6-methyl-2-(2,3,5,6-tetrafluoro-4'-hydroxymethyl-biphenyl-4-yl)-1 H- benzoimidazole-4-carboxylic acid methyl ester (0.55 g, 1.22 mmol) in dry tetrahydrofuran (50 mL) was added pyridinium dichromate (0.2 g) portion wise. The reaction mixture was stirred at room temperature in nitrogen atmosphere for 14 hours. TLC shows completion of the reaction. The reaction mixture was filtered over celite bedand the filtrate was concentrated to dryness. The resulting residue was purified by column chromatography using 20% ethyl acetate in hexane to get to get the title compound as colorless solid (0.4 g, 74.07%). 1H NMR (300 MHz, DMSO-d6): δ (ppm) 2.6 (s, 3H), 4.0 (s, 3H), 7.6-8,2(m, 6H), 10.1 (s, 1 H), 13.0(bs, 1 H).
Step 9: 6-Methyl-2-(2, 3, 5, 6-tetrafluoro-4 '-piperidin-1 -ylmethyl-biphenyl-4-yl)- 1 H- benzoimidazole-4-carboxylic acid methyl ester
Figure imgf000140_0001
To a solution of 6-methyl-2-(2,3,5,6-tetrafluoro-4'-formyl-biphenyl-4-yl)-1 H- benzoimidazole-4-carboxylic acid methyl ester (0.13 g, 0.29 mmol) in tetrahydrofuran (100 mL) was added piperidine (0.03 g, 0.35 mmol). The reaction mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (0.374 g, 1.76 mmol) was added and stirring continued for another 1 hour. The progression of the reaction was monitored by TLC. The reaction mixture quenched with sodium bicarbonate solution (3 mL) and concentrated. The residue was then extracted with ethyl acetate and the combined organic layerd were washed with water and brine, dried over anhydrous sodium sulphate and concontrated to get the title compound (0.145 g, 96.66%) which was directly taken to next step.
Step 10: 6-Methyl-2-(2, 3, 5, 6-tetrafluoro-4 '-piperidin- 1 -ylmethyl-biphenyl-4-yl)- 1 H- benzoimidazole-4-carboxylic acid
Figure imgf000140_0002
To the solution of 6-methyl-2-(2,3,5,6-tetrafluoro-4'-piperidin-1-ylmethyl-biphenyl-4-yl)-
1 H-benzoimidazole-4-carboxylic acid methyl ester (0.145 g, 0.283 mmol) in tetrahydrofuran (50 mL) was added an aq. solution of 5 N sodium hydroxide (10 mL). The reaction mixture was stirred at 6O0C for 4 hours. TLC shows completion of the reaction. The reaction mixture was cooled to room temperature , then concentrated and the obtained residue was acidified with an aq. solution of 50% HCI. The resulting precipitate was filtered and purified by preparative HPLC.
1H NMR (300 MHz, DMSOd6): δ (ppm) =1.8 (m, 8H), 2.3(s, 3H), 3.0(s, 2H), 4.4(s, 2H), 7.8(s, 5H), 7.9(s, 1 H), 12.8(br.s, 1 H), 13.4(br.s, 1 H) HPLC: 96.83%
Example 84: 6-Methyl-2φhenylethynyl-1HΦenzoimidazole-4-carboxylic acid
Figure imgf000141_0001
Example 84 is obtained as described in example 14 but starting from phenyl-propynoic acid (procured commercially from aldrich).
1H NMR (300 MHz, DMSOd6): δ (ppm) =2.44(s, 3H), 7.51 (m, 3H), 7.66-7.61 (m, 4H). HPLC purity : 84.3%
The following examples I85 to 1192 have been prepared following similar procedures as described above.
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Example 193: Measurement of 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 610nm.
Reagents used:
L-Dihydroorotic acid, Sigma, D7128, 2,6-Dichloroindophenol sodium salt hydrate, sigma, D1878 Dimethyl sulfoxide (DMSO), spectroscopic grade purchased from Spectrochem, cat no.0704209, B. no. - 3183650 Decylubiquinone, Sigma, D791 1
Preparation of solutions/reagents:
Buffer Preparation: 50 mM tris HCI, 150 mM KCI, 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 2OmM in buffer
Decylubiquinone stock solution of 20 mM in buffer
DMSO used as vehicle
Procedure:
5 μl_ 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 μM. 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 μl_ of 20 mM solution of L-Dihydroorotic acid, 5 μL of 2 mM solution of Decylubiquinone and 3 μL of 2 mM solution of 2, 6-Dichloroindophenol sodium salt hydrate were added to the above solution (total assay volume 100 μL). 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*{(AbSfiin for reaction containing compound) - (Absgin 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 of the compound of formula I to be examined was prepared. 1/3rd dilutions were made as follows:
Figure imgf000150_0001
5 μl_ of each stock of compound of formula I (solution indicated in column 4 of table) was used for each 100 μl_ assay. Therefore, 5 μL of the 2 mM stock provided 100 μL of 100 μM 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.
Example 194: Measurement of Cell Proliferation (Jurkat Cell) See also Roehm, N et al [1991] An improved colorimetric assay for cell proliferation and viability utilizing the tetrazolium salt XTT. J. Immunol. Methods 142:257-265.
Reagents Roswells park memorial institute's medium , (RPMI-1640 complete media) pH-7.4 ± 0.2 (Sigma R6504).
Dimethyl sulfoxide (DMSO), spectroscopic grade purchased from Spectrochem, (cat no.0704209, B. no. - 3183650 MEM Cat. No. M0268, Sigma). Fetal Bovine Serum (Cat. No. F9665, Sigma Aldrich). XTT sodium salt (Sigma Cat. No. X4251 ). PMS (Sigma Cat. No. 68600).
Preparation of solutions/reagents
RPMI media supplemented with antibiotics, 10% FBS, Sodium Pyruvate and NEA (non essential amino acids).
XTT - A freshly prepared solution of XTT is made in the growth medium , with a final concentration of 1 mg/ml.
PMS - Stock is prepared with 1x PBS at 0.383 mg/ml and stored in aliquots at -200C.
The XTT solution at 20 μl/ml was added just before use. Test solution - Serially diluted DMSO solutions are further diluted with media to 2x the required concentration in well.
Procedure
Culture Jurkat cells in T-25 flasks at a density of 0.2x106 / ml 2-3 days before the day of experiment set up.
Centrifuge Jurkat T-cell suspension at 1200 rpm for 10 minutes and resuspend cells again in fresh RPMI medium with 10% FBS.
Count the cells and dilute suspension to a density of 2 x 106 cells/ml. Seed 50 μL of this suspension in each well of a 96 well plate (100,000 cells per well). Keep the edges of the plate empty to avoid evaporation.
Serially dilute DMSO stocks of compounds to get different concentrations for an EC50 curve. 50 μL of compound diluted in media (2x concentration required in well) is added to each well. DMSO concentration should be kept constant at 0.25 - 0.5% for all wells. Typically, for all compounds with IC50 < 1 μM, compound concentration can start at 10 μM followed by half log dilutions for a total of 8-10 concentrations. Each concentration has to be tested in triplicate.
Include controls such as cells without compound (with same DMSO concentration as compound wells), and media control
Incubate the 96 well plate in a CO2 incubator at 37°C for 72 hrs before determining cell viability using XTT assay
XTT assay: to each well, add 50 μl_ of 1 mg/ml XTT solution with 20 μl of PMS/mL Read the plates after 2 hours at 465 nm using the spectrophotometer. XTT reading for media without cells is used as background reading.
Calculate % cell viability assuming that the cells without compound are 100% viable.
Plot % cell viability as a function of concentration and determine EC50 by using software such as GraphPad Prism to fit the curve.
The following results have been obtained:
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Example 195: Preparation of a pharmaceutical formulation
Formulation 1 - Tablets A compound of formula I and related formulae is admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg of active compound according to the invention per tablet) in a tablet press. Formulation 2 - Capsules
A compound of formula I and related formulae is admixed as a dry powder with a starch diluent in an approximate 1 :1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of active compound according to the invention per capsule). Formulation 3 - Liquid A compound of formula I and related formulae (1250 mg), sucrose (1 .75 g) and xanthan gum (4 mg) are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously prepared solution of microcrystalline cellulose and sodium carboxymethyl cellulose (1 1 :89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color are diluted with water and added with stirring. Sufficient water is then added to produce a total volume of 5 ml_. Formulation 4 - Tablets
A compound of formula I and related formulae is admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of active compound according to the invention) in a tablet press.
Formulation 5 - Injection
A compound of formula I and related formulae is dissolved in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/mL.

Claims

Claims
1. A compound according to formula I:
Figure imgf000178_0001
Wherein
R1 denotes COOH, COOA, COA, CF3, acyl, cyano, Het, tetrazoyl, sulfonyl, or if Q is -CΞC- or Hetarylene, or if Q is a tetrasubstituted Arylene, R1 also denotes CON(R3)2 or CONHA
R2 denotes H, Hal, A, O-A, Ar;
Ra denotes Ar, Het, O-Het, NH-Het, O-Ar, -O-(CH2)m-Het, -NH-(CH2)m-Het, NH-Ar, S(O)2Ar, S(O)Ar, -S-Ar, OCF3,
Y denote CRf or N
X1, X2 denote each independently of one another CRcRd, NRC, NRd, and when Y denote CRf, also O or S, provided that one of X1 and X2 is CRcRd or NRC;
Rb and Rc together represent a chemical bond;
Rf and Re together represent a chemical bond, when Y is CRf Re and Rc, in the definition of X1, together represent a chemical bond when Y is N, and Rb and Rc, in the definition of X2, together represent a chemical bond;
Rd denotes H, A, -(CH2)m-C00H; Q denotes a group -CΞC-, Arylene, Hetarylene, or the group
Figure imgf000179_0001
Hal denotes F, Cl, Br or I;
A is a branched or linear alkyl having 1 to 12 C-atoms, wherein one or more, preferably 1 to 7 H-atoms may be replaced by Hal, OR3, CN or N(R3)2 and wherein one or more, preferably 1 to 7 non-adjacent CH2-groups may be replaced by O, or S and/or by -CH=CH- or -C≡C- groups, or denotes cycloalkyl or cycloalkylalkylen having 3-7 ring C atoms;
Ar denotes a monocyclic or bicyclic, saturated, unsaturated or aromatic carbocyclic ring having 6 to 14 carbon atoms which may be unsubstituted or substituted by a group selected from (R4)n and/or (R5)n ; Het denotes a monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic ring having 1 to 4 N, O and/or S atoms which may which may be unsubstituted or substituted by a group selected from (R4)n and/or (R5)n ;
Arylene denotes a divalent monocyclic or bicyclic, saturated, unsaturated or aromatic carbocyclic ring having 6 to 14 carbon atoms which may be unsubstituted or substituted by a group selected from (R4)n and/or (R5)n ;
Hetarylene denotes a divalent monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic ring having 1 to 4 N, O and/or S atoms which may which may be unsubstituted or substituted by a group selected from (R4)n and/or (R5)n ;
R3 is H or alkyl; R4 and R5 are each independently selected from Hal, hydroxy, alkoxy, carboxy, carboxy-alkyl, perfluoro-alkyl, perfluoro-alkyloxy, acyl, alkylsulfonyl, sulfonyl, cyano, nitro, amino, amido, alkyl optionally substituted by a carboxy, or Het-alkyl optionally substituted by an acyl , alkylsulfonyl, -O(CH2)nAr, -O(CH2)nHet, -(CH2)mHet, OA, -NHCO(CH2)mAr, NHCO-(CH2)mHet , CONHA, or alkyl;
n denotes 0,1 ,2,3,4,5;
and
m denotes 0,1 ,2,3,4,5,6; and pharmaceutically acceptable derivatives, solvates, tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios.
2. A compound according to formula Il or III:
Figure imgf000180_0001
wherein
R1 denotes COOH, COOA, CF3, acyl, cyano, R2, Ra, X1, X2, Rb, n R4 and R5 are as defined in claim 1 ; and pharmaceutically acceptable derivatives, solvates, tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios.
3. A compound according to formula I wherein Ra is one of the following group:
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Wherein A, R , R , m and Het are as defined in claim 1
A compound according to formula I wherein Q denotes a single bond, a triple bond or one of the following groups:
Figure imgf000184_0001
5. A compound according to any one of the preceding claims selected from the following group:
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
and pharmaceutically acceptable derivatives, solvates, tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios.
6. A pharmaceutical composition comprising at least one compound according to claims 1 to 5 and/or pharmaceutically usable derivatives, tautomers, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and/or adjuvants.
7. A pharmaceutical composition comprising at least one compound according to claims 1 to 5 and/or pharmaceutically usable derivatives, tautomers, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further active ingredient.
8. A kit consisting of separate packs of : (a) an effective amount of a compound of the formula (I) and/or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and (b) an effective amount of a further medicament active ingredient.
9. Use of compounds of formula I
Figure imgf000197_0001
wherein R1, R , X1, X , Ra, Rb, Re, Y and Q are as defined in claim 1 ; and pharmaceutically acceptable derivatives, solvates, tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios as a medicament.
10. Use of compounds according to one or more of claims 1 to 5, and pharmaceutically usable derivatives, salts, tautomers, solvates and stereoisomers thereof, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment and/or prophylaxis of a dihydroorotate dehydrogenase associated disorder.
11. Use of claim 10, wherein the dihydroorotate dehydrogenase associated disorder is an autoimmune disorder or condition associated with an overactive immune response.
12. Use of compounds according to one or more of claims 9 or 11 , and pharmaceutically usable derivatives, salts, tautomers, solvates and stereoisomers thereof, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment and/or prophylaxis of an immunerogulatory abnomality.
13. Use according to claim 12, wherein the immunoregulatory abnormality is multiple sclerosis or rheumatoid arthritis.
14. Use of the compounds according to claims 1 to 6 for the preparation of a medicament for the treatment and prophylaxis of cancer diseases, inflammatory bowel disease or rheumatoid arthritis.
15. A process for the preparation of compounds of Formula (I) wherein X1 and X2 are NRC or NRd and wherein Rb and Rc together represent a chemical bond, characterized in that : Compound (A)
Figure imgf000199_0001
wherein R1, R2 are as defined in claim 1 , Y is CRf, and Rf and Re together form a bond is reacted with compound (B)
Figure imgf000199_0002
wherein Q and Ra are as defined in claim 1
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