USOO890 1114B2

(12) United States Patent (10) Patent No.: US 8,901,114 B2 B0ehme et al. (45) Date of Patent: Dec. 2, 2014

(54) OXATHIAZINE DERIVATIVES SUBSTITUTED 3 I/55 (2013.01); A61 K3I/69 (2013.01); A61 K WITH CARBOCYCLES OR HETEROCYCLES, 45/06 (2013.01); C07D 419/12 (2013.01); METHOD FOR PRODUCING SAME, DRUGS C07F 5/027 (2013.01) CONTAINING SAID COMPOUNDS, AND USE USPC ...... 514/222.5: 514/222.2:544/2 THEREOF (58) Field of Classification Search None (75) Inventors: Thomas Boehme, Frankfurt am Main See application file for complete search history. (DE); Christian Engel, Frankfurt am (56) References Cited Main (DE); Stefan Guessregen, Frankfurt am Main (DE); Torsten U.S. PATENT DOCUMENTS Haack, Frankfurt am Main (DE); Gerhard Kretzschmar, Frankfurt am 2013/0345125 A1 12/2013 Boehme et al...... 5.14?6.5 Main (DE); Kurt Ritter, Frankfurt am 2014/0024584 A1 1/2014 Boehme et al...... 5.14?6.5 Main (DE); Georg Tschank, Frankfurt FOREIGN PATENT DOCUMENTS am Main (DE) WO WOO2f1 1722 A1 2, 2002 (73) Assignee: Sanofi, Paris (FR) WO WO 2008/073956 A2 6, 2008 (*) Notice: Subject to any disclaimer, the term of this OTHER PUBLICATIONS patent is extended or adjusted under 35 Seigo Suzue et al., Studies on Hypoglycemic Agents. IV. 1) Synthesis U.S.C. 154(b) by 0 days. of 14,3-Benzoxathiazine-4,4-dioxides, Chemical and Pharmaceuti cal Bulletin, (May 25, 1968), vol. 16, No. 5, pp. 806-813. (21) Appl. No.: 14/003,499 Tsuneo Iwakawa et al., Cycloaddition in Synthesis of Sulfonamide Derivatives. IV. One-Pot Synthesis of 3-Dimethylamino-4, 1.2- (22) PCT Filed: Mar. 7, 2012 benzoxathiazine 1,1-Dioxides,3-Methoxy-4-methyl-1,2,4- benzothiadizine 1,1-Dioxiade and 3-Dimethylamino-1.4.2- (86). PCT No.: PCT/EP2012/053935 benzodithiazine 1,1-Dioxides, Chemical and Pharmaceutical Bulletin, (Aug. 25, 1991), vol.39, No. 8, pp. 1939-1943. S371 (c)(1), International Search Report dated Aug. 7, 2012 issued in PCT/ (2), (4) Date: Sep. 6, 2013 EP2012,053935. (87) PCT Pub. No.: WO2012/120052 * cited by examiner PCT Pub. Date: Sep. 13, 2012 Primary Examiner — James H Alstrum Acevedo Assistant Examiner — Fred Reynolds (65) Prior Publication Data (74) Attorney, Agent, or Firm — Scully, Scott, Murphy & US 2013/0345128A1 Dec. 26, 2013 Presser, P.C. (30) Foreign Application Priority Data (57) ABSTRACT The invention relates to the compounds of formula (I) and Mar. 8, 2011 (EP) ...... 11305,240 physiologically acceptable salts thereof. The compounds are Suitable, e.g., for treating hyperglycemia. (51) Int. Cl. A6 IK3I/SI (2006.01) C07D 291/08 (2006.01) (I) H CO7D 55/04 (2006.01) R2 A6 IK3I/545 (2006.01) O NS -Rl A6 IK3I/55 (2006.01) L A6 IK3I/69 (2006.01) A6 IK 45/06 (2006.01) A 1N CO7D 49/12 (2006.01) R3 / V C07F 5/02 (2006.01) /\, (52) U.S. Cl. CPC ...... C07D 291/08 (2013.01); C07D515/04 (2013.01); A61K 3.1/5415 (2013.01); A61 K 11 Claims, No Drawings US 8,901,114 B2 1. 2 OXATHAZINEDERVATIVES SUBSTITUTED Preference is given to compounds of the formula I in WITH CARBOCYCLES OR HETEROCYCLES, which: METHOD FOR PRODUCING SAME, DRUGS A is a bond, CH, CF; CONTAINING SAID COMPOUNDS, AND USE L is a bond, C(R5)(R6), N(R5); THEREOF 5 R1 (C-C)-carbocycle, where the carbocycle radical may be mono- to trisubsti Oxathiazine derivatives substituted with carbocycles or tuted by F, Cl, Br, I, OH, -(C-C)-alkylene-OH, CF, heterocycles, method for producing same, drugs containing CHF CHF, NO, CN, OCF, OCHF, O (C-C)- said compounds, and use thereof. alkyl, (C-C)-alkyl, NH, NH(C-C)-alkyl, N(C- The invention relates to oxathiazine derivatives substituted 10 by carbocycles or heterocycles, and to the physiologically C)-alkyl), SO CH, SO. NH, SO. NH(C- compatible salts thereof. C)-alkyl, SO. NH(C-C)-alkyl). COOH, COO– It was an object of the invention to provide compounds (C-C)-alkyl, CONH CONH(C-C)-alkyl, CON which display a therapeutically utilizable action. More par ((C-C)-alkyl). SFs, ticularly, it was a further object to find novel compounds 15 phenyl, Suitable for treatment of diabetes, hyperglycemia, insulin where the phenyl radical may be mono- to trisubstituted by resistance, obesity, lipid metabolism disorders or other dis F, Cl, Br, I, OH, CF, CHF, CHF, NO, CN, OCF, CaSCS. OCHF, O (C-C)-alkyl, (C-C)-alkyl, NH, The invention therefore relates to the compound of the NH(C-C)-alkyl, N(C-C)-alkyl), SO CH, formula I SO. NH, SO. NH(C-C)-alkyl, SO N((C- C)-alkyl). COOH, COO (C-C)-alkyl, CONH, CONHCC-C)-alkyl, CONC(C-C)-alkyl). SFs: (I) H a heterocycle selected from the group of thiophene, R2 pyran, tetrahydropyran, piperidine, thiopyran, tetrahy O N-N-Rl 25 drothiopyran, pyrrole, tetrahydropyrrole, azepane or L 2,3,4,5,6,7,8,9,10,11-decabora-bicyclo8.1.1 dode Cane, A 1N where the heterocyclyl radical may be mono- to trisubsti R3 / V O O tuted by F, Cl, Br, I, OH, CF, CHF, CHF, NO, CN, 30 OCF, OCHF (C-C)-alkyl, NH, NH(C-C)-alkyl, N((C-C)-alkyl), SO CH, SO. NH, SO. NH in which (C-C)-alkyl, SO NO(C-C)-alkyl), COOH, A is a bond, CH, CF. O; COO (C-C)-alkyl, CONH CONHC-C)-alkyl, L is a bond, C(R5)(R6), N(R5): CONC(C-C)-alkyl). SFs: R1 (C-C)-carbocycle, 35 and where the heterocycle may be fused to a further ring or where the carbocycle radical may be mono- to trisubsti ring system; tuted by F, Cl, Br, I, OH, -(C-C)-alkylene-OH, CF, R2, R3 are each independently H, (C-C)-alkyl: CHF CHF, NO, CN, OCF, OCHF, O (C-C)- R5, R6 are each independently H, (C-C)-cycloalkyl, (C- alkyl, (C-C)-alkyl, NH, NH(C-C)-alkyl, N(C- C)-alkylene-(C-C)-cycloalkylene, (C(R7)(R8)), O— C)-alkyl). SO, CH, SO. NH, SO. NH(C- 40 (CO) N(R7)(R8); C)-alkyl, SO N((C-C)-alkyl). COOH, COO R7, R8 are each independently H, (C-C)-alkyl: (C-C)-alkyl, CONH, CONH(C-C)-alkyl, CON n is 0, 1, 2: ((C-C)-alkyl). SFs, and pharmaceutically acceptable salts thereof. (Co-Co)-aryl, Particular preference is given to compounds of the formula where the aryl radical may be mono- to trisubstituted by F. 45 I in which Cl, Br, I, OH, CF, CHF, CHF, NO, CN, OCF, A is a bond, CH, CF; OCHF, O (C-C)-alkyl, (C-C)-alkyl, NH, L is a bond, C(R5)(R6), N(R5); NH(C-C)-alkyl, N(C-C)-alkyl), SO CH, R1 (C-Cs)-carbocycle, SO. NH, SO. NH(C-C)-alkyl, SO, N((C- where the carbocycle radical may be mono- to trisubsti C)-alkyl). COOH, COO (C-C)-alkyl, CONH2, 50 tuted by F, Cl, Br, I, OH, -(C-C)-alkylene-OH, CF, CONHCC-C)-alkyl, CONC(C-C)-alkyl). SFs: NO, CN, OCF (C-C)-alkyl, CONH CONH(C- 4-12-membered heterocycle, C)-alkyl, CONC(C-C)-alkyl); where the heterocyclyl radical may be mono- to trisubsti phenyl, tuted by F, Cl, Br, I, OH, CF, CHF, CHF, NO, CN, where the phenyl radical may be mono- to trisubstituted by OCF, OCHF, O (C-C)-alkyl, (C-C)-alkyl, NH, 55 F, Cl, Br, I, OH, -(C-C)-alkylene-OH, CF, NO, NH(C-C)-alkyl, N(C-C)-alkyl). SO, CH, CN, OCF, (C-C)-alkyl, CONH, CONH(C-C)- SO. NH, SO. NH(C-C)-alkyl, SO N((C- alkyl, CONC(C-C)-alkyl); C)-alkyl). COOH, COO (C-C)-alkyl, CONH2, a heterocycle selected from the group of carborane, CONHCC-C)-alkyl, CONC(C-C)-alkyl). SFs: thiophene, tetrahydropyran, piperidine, thiochromane, and where the heterocycle may be fused to a further ring or 60 hexahydrocyclopentacpyrrole, azepane and 2,3,4,5,6, ring System; 7,8,9,10,11-decaborabicyclo8.1.1 dodecane, where R2, R3 are each independently H, (C-C)-alkyl: the heterocycle radical may be mono- to trisubstituted R5, R6 are each independently H, (C-C)-alkyl, (C-C)- by F, Cl, Br, I, OH, —(C-C)-alkylene-OH, CF, NO, cycloalkyl, (C(R7)(R8))-O-(CO) N(R7)(R8); CN, OCF (C-C)-alkyl, CONH CONH(C-C)- R7, R8 are each independently H, (C-C)-alkyl: 65 alkyl, CONC(C-C)-alkyl); n is 0, 1, 2: R2, R3 are each independently H, (C-C)-alkyl: and pharmaceutically acceptable salts thereof. R5, R6 are each independently H, (C-C)-alkyl: US 8,901,114 B2 3 4 and pharmaceutically acceptable salts thereof. An aryl radical is understood to mean a phenyl, naphthyl, In one embodiment, preference is given to compounds of biphenyl, tetrahydronaphthyl, alpha- or beta-tetralonyl, inda the formula I in which A is a bond. nyl or indan-1-onyl radical. In one embodiment, preference is given to compounds of The aryl radicals may be mono- or polysubstituted by the formula I in which A is CH. Suitable groups as described above. In one embodiment, preference is given to compounds of Heterocycle and heterocyclic radical are understood to the formula I in which A is CF. mean rings and ring systems which, apart from carbon, also In one embodiment, preference is given to compounds of contain heteroatoms, for example nitrogen, oxygen or Sulfur. the formula I in which A is O. In addition, this definition also includes ring systems in which In one embodiment, preference is given to compounds of 10 the heterocycle or the heterocyclic radical is fused to a further the formula I in which L is a bond. ring or ring system. The heterocycle or the heterocyclic radi In one embodiment, preference is given to compounds of cal may be saturated, partly saturated or aromatic. the formula I in which L is C(R5)(R6). Suitable “heterocycles” or "heterocyclic radicals' are In one embodiment, preference is given to compounds of acridinyl, azepanyl, azocinyl, benzimidazolyl, benzofuryl, the formula I in which L is N(R5). 15 benzothienyl, benzothiophenyl, benzoxazolyl, benzothiaz In one embodiment, preference is given to compounds of olyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, ben the formula I in which R1 is (C-C)-carbocycle. Zisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl, In one embodiment, preference is given to compounds of carbolinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, qui the formula I in which R1 is (C-C)-aryl. noxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, In one embodiment, preference is given to compounds of decahydroquinolinyl, 2H,6H-1.5.2-dithiazinyl, dihydrofuro the formula I in which R1 is 4-12-membered heterocycle. 2,3-b-tetrahydrofuran, 5,6-dihydro-4H-cyclopentathiazol If radicals or Substituents occur more than once in the 2-yl 4,5-dihydrothiazol-2-yl, furyl, furazanyl, imidazolidi compounds of the formula I (for example R7), they may each nyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, independently be defined as specified and be the same or indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochro different. 25 manyl, isolindazolyl, isoindolinyl, isoindolyl, isoquinolinyl The invention relates to compounds of the formula I in the (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, form of their tautomers, racemates, racemic mixtures, Stere naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1.2.3- oisomer mixtures, pure stereoisomers, diastereoisomer mix oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1.3,4-oxa tures and pure diastereoisomers. The mixtures are separated, diazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, for example, by a chromatographic route. 30 phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazi Because of their higher water solubility compared to the nyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, starting or base compounds, pharmaceutically acceptable piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyroazo salts are particularly Suitable for medical applications. These lidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, salts must have a pharmaceutically acceptable anion or cat pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrim ion. Suitable pharmaceutically acceptable acid addition salts 35 idinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl pyrrolyl. 4,5,6, of the compounds of the invention are salts of inorganic acids 7-tetrahydrobenzooxazol-2-yl, 4,5,6,7-tetrahydro-ben Such as hydrochloric acid, hydrobromic acid, phosphoric Zothiazol-2-yl 4,5,6,7-tetrahydrobenzoimidazol-2-yl 4,5,6, acid, metaphosphoric acid, nitric acid and Sulfuric acid, and 7-tetrahydro-pyrazolo 1.5-alpyridin-2-yl, tetrahydrofuranyl, of organic acids, for example acetic acid, benzenesulfonic tetrahydropyranyl, tetrahydroisoquinolinyl, tetrahydro acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric 40 quinolinyl, 6H-1,2,5-thiadazinyl, thiazolyl, 1,2,3-thiadiaz acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, olyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiaz lactobionic acid, maleic acid, malic acid, methanesulfonic olyl, thienyl, triazinyl, triazolyl, tetrazolyl, thiazolo 4,5-b] acid, Succinic acid, p-toluenesulfonic acid and tartaric acid. pyridinyl, thieno 2,3-dthiazol-2-yl, tropanyl and Xanthenyl. Suitable pharmaceutically acceptable basic salts are ammo The heterocycles or heterocyclic radicals may be mono- or nium salts, alkali metal salts (such as Sodium and potassium 45 polysubstituted by suitable groups as described above. salts), alkaline earth metal salts (such as magnesium and The compound(s) of the formula I can also be administered calcium salts), trometamol (2-amino-2-hydroxymethyl-1,3- in combination with further active ingredients. propanediol), diethanolamine, lysine or ethylenediamine. The amount of a compound of the formula I required to Salts with a pharmaceutically unacceptable anion, for achieve the desired biological effect depends on a number of example trifluoroacetate, likewise belong within the frame 50 factors, for example the specific compound chosen, the work of the invention as useful intermediates for the prepa intended use, the mode of administration and the clinical ration or purification of pharmaceutically acceptable salts condition of the patient. The daily dose is generally in the and/or for use in nontherapeutic, for example in vitro, appli range from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) cations. per day and per kilogram of body weight, for example 3-10 The inventive compounds may also be in various polymor 55 mg/kg/day. An intravenous dose may be, for example, in the phic forms, for example as amorphousand crystalline poly range from 0.3 mg to 1.0 mg/kg, which can Suitably be admin morphic forms. All polymorphic forms of the inventive com istered as infusion of 10ng to 100ng perkilogram perminute. pounds are within the scope of the invention and are a further Suitable infusion solutions for these purposes may contain, aspect of the invention. for example, 0.1 ng to 10 mg. typically 1 ng to 10 mg, per All references to “compound(s) of formula I hereinafter 60 milliliter. Single doses may contain, for example, 1 mg to 10 refer to compound(s) of the formula I as described above, and g of the active ingredient. Thus, ampoules for injections may the salts and solvates thereofas described herein. contain, for example, from 1 mg to 100 mg, and orally admin An alkyl radical is understood to mean a straight-chain or istrable single-dose formulations, for example tablets or cap branched hydrocarbyl chain having one to eight carbons, for Sules, may contain, for example, from 1.0 to 1000 mg. typi example methyl, ethyl, isopropyl, tert-butyl, hexyl, heptyl, 65 cally from 10 to 600 mg. For treatment of the abovementioned octyl. The alkyl radicals may be mono- or polysubstituted as conditions, the compounds of the formula I themselves may described above. be used as the compound, but they are preferably present with US 8,901,114 B2 5 6 a compatible carrier in the form of a pharmaceutical compo Pharmaceutical compositions suitable for rectal adminis sition. The carrier must of course be acceptable in the sense tration are preferably in the form of single-dose Suppositories. that it is compatible with the other constituents of the com These can be produced by mixing a compound of formula I position and is not harmful to the patient’s health. The carrier with one or more conventional Solid carriers, for example may be a solid or a liquid or both and is preferably formulated cocoa butter, and shaping the resulting mixture. with the compound as a single dose, for example as a tablet, Pharmaceutical compositions Suitable for topical use on which may contain from 0.05% to 95% by weight of the the skin are preferably in the form of ointment, cream, lotion, active ingredient. Other pharmaceutically active substances paste, spray, aerosol or oil. Carriers which can be used are may likewise be present, including other compounds of for petrolatum, lanolin, polyethylene glycols, alcohols and com mula I. The pharmaceutical compositions of the invention can 10 binations of two or more of these substances. The active be produced by one of the known pharmaceutical methods, ingredient is generally present in a concentration of 0.1 to which essentially consist of mixing the ingredients with phar 15% by weight of the composition, for example 0.5 to 2%. macologically acceptable carriers and/or excipients. Transdermal administration is also possible. Pharmaceuti Inventive pharmaceutical compositions are those Suitable cal compositions Suitable for transdermal uses may be in the for oral, rectal, topical, peroral (for example Sublingual) and 15 form of single patches which are suitable for long-term close parenteral (for example Subcutaneous, intramuscular, intrad contact with the patient’s epidermis. Such patches suitably ermal or intravenous) administration, although the most Suit contain the active ingredient in an aqueous Solution which is able mode of administration depends in each individual case buffered where appropriate, dissolved and/or dispersed in an on the nature and severity of the condition to be treated and on adhesive or dispersed in a polymer. A Suitable active ingredi the nature of the compound of formula I used in each case. ent concentration is about 1% to 35%, preferably about 3% to Coated formulations and coated slow-release formulations 15%. A particular option is for the active ingredient to be are also within the scope of the invention. Preference is given released by electrotransport or iontophoresis as described, for to acid- and gastric juice-resistant formulations. Suitable gas example, in Pharmaceutical Research, 206): 318 (1986). tric juice-resistant coatings comprise cellulose acetate phtha Further suitable active ingredients for the combination late, polyvinyl acetate phthalate, hydroxypropylmethylcellu 25 products are: lose phthalate and anionic polymers of methacrylic acid and Allantidiabetics mentioned in the Rote Liste 2009, chapter methyl methacrylate. 12; all weight-reducing agents/appetite Suppressants men Suitable pharmaceutical compounds for oral administra tioned in the Rote Liste 2009, chapter 1; all diuretics men tion may be in the form of separate units, for example cap tioned in the Rote Liste 2009, chapter 36; all lipid-lowering Sules, cachets, lozenges or tablets, each of which contains a 30 agents mentioned in the Rote Liste 2009, chapter 58. They defined amount of the compound of formula I; as powders or can be combined with the inventive compound of the formula granules; as solution or Suspension in an aqueous or nonaque I, especially for a synergistic improvement in action. The ous liquid; or as an oil-in-water or water-in-oil emulsion. active ingredient combination can be administered either by These compositions may, as already mentioned, be prepared separate administration of the active ingredients to the patient by any suitable pharmaceutical method which includes a step 35 or in the form of combination products in which a plurality of in which the active ingredient and the carrier (which may active ingredients are present in one pharmaceutical prepara consist of one or more additional ingredients) are brought into tion. When the active ingredients are administered by sepa contact. The compositions are generally produced by uniform rate administration of the active ingredients, this can be done and homogeneous mixing of the active ingredient with a simultaneously or Successively. Most of the active ingredients liquid and/or finely divided solid carrier, after which the prod 40 mentioned hereinafter are disclosed in the USP Dictionary of uct is shaped if necessary. For example, a tablet can be pro USAN and International Drug Names, US Pharmacopeia, duced by compressing or molding a powder or granules of the Rockville 2006. compound, where appropriate with one or more additional Antidiabetics include insulin and insulin derivatives, for ingredients. Compressed tablets can be produced by tableting example Lantus(R (see www.lantus.com) or HMR 1964 or the compound in free-flowing form such as, for example, a 45 Levemir R (insulin detemir), Humalog R (Insulin Lispro), powder or granules, where appropriate mixed with a binder, Humulin(R), VIAjectTM, or those as described in glidant, inert diluent and/or one (or more) Surfactant(s)/dis WO2005005477 (Novo Nordisk), fast-acting insulins (see persant(s) in a suitable machine. Molded tablets can be pro U.S. Pat. No. 6,221,633), inhalable insulins, for example duced by molding the pulverulent compound moistened with Exubera R, NasulinTM, or oral insulins, for example IN-105 an inert liquid diluent in a suitable machine. 50 (Nobex) or Oral-lynTM (Generex Biotechnology), or Techno Pharmaceutical compositions suitable for peroral (sublin sphere(RInsulin (MannKind) or CobalaminTM oral insulin, or gual) administration include lozenges which contain a com insulins as described in WO2007128815, WO2007128817, pound of formula I with a flavoring, typically Sucrose, and or insulins which can be administered transdermally; GLP-1 gum arabic or tragacanth, and pastilles which comprise the derivatives and GLP-1 agonists, for example exenatide, lira compound in an inert base such as gelatin and glycerol or 55 glutide, or those which have been disclosed in WO98/08871, Sucrose and gum arabic. WO2005027978, WO2006037811, WO2006037810 by Pharmaceutical compositions suitable for parenteral Novo Nordisk A/S, in WO 01/04156 by Zealand or in WO administration comprise preferably sterile aqueous prepara 00/34331 by Beaufour-Ipsen, pramlintide acetate (Symlin; tions of a compound of formula I, which are preferably iso Amylin Pharmaceuticals), AVE-0010, BIM-51077 (R-1583, tonic with the blood of the intended recipient. These prepa 60 ITM-077), PC-DAC:Exendin-4 (an exendin-4 analog which rations are preferably administered intravenously, although is bonded covalently to recombinant human albumin), CVX administration may also take place by Subcutaneous, intra 73, CVX-98 and CVx-96 (GLP-1 analogs which are bonded muscular or intradermal injection. These preparations can covalently to a monoclonal antibody which has specific bind preferably be produced by mixing the compound with water ing sites for the GLP-1 peptide), CNTO-736 (a GLP-1 analog and making the resulting solution sterile and isotonic with 65 which is bonded to a domain which includes the Fc portion of blood. Injectable inventive compositions generally contain an antibody), PGC-GLP-1 (GLP-1 bonded to a nanocarrier), from 0.1 to 5% by weight of the active compound. agonists, as described, for example, in D. Chen et al., Proc. US 8,901,114 B2 7 8 Natl. Acad. Sci. USA 104 (2007) 943, those as described in compounds which reduce food intake, and WO2006124529, WO2007 124461, peptides, for example compounds which increase thermogenesis. obinepitide (TM-30338), amylin receptor agonists, as In one embodiment of the invention, the compound of the described, for example, in WO2007104789, analogs of the formula I is administered in combination with insulin. In one embodiment, the compound of the formula I is human GLP-1, as described in WO2007120899, and orally 5 administered in combination with an active ingredient which active hypoglycemic ingredients. acts on the ATP-dependent potassium channel of the beta Antidiabetics also include agonists of the glucose-depen cells, for example Sulfonylureas, for example tolbutamide, dent insulinotropic polypeptide (GIP) receptor, as described, glibenclamide, glipizide, gliclaZide or glimepiride. for example, in WO2006121860. In one embodiment, the compound of the formula I is Antidiabetics also include analogs and derivatives offibro 10 administered in combination with a tablet which comprises blast growth factor 21 (FGF-21). both glimepiride, which is released rapidly, and metformin, The orally active hypoglycemic ingredients preferably which is released over a longer period (as described, for include Sulfonylureas, example, in US2007264331). biguanidines, In one embodiment, the compound of the formula I is 15 administered in combination with a biguanide, for example meglitinides, metformin. oxadiazolidinediones, In another embodiment, the compound of the formula I is thiazolidinediones, administered in combination with a meglitinide, for example PPAR and RXR modulators, repaglinide, nateglinide or mitiglinide. glucosidase inhibitors, 2O In a further embodiment, the compound of the formula I is inhibitors of glycogen phosphorylase, administered with a combination of mitiglinide with a glita glucagon receptor antagonists, Zone, e.g. pioglitaZone hydrochloride. glucokinase activators, In a further embodiment, the compound of the formula I is inhibitors of fructose 1,6-bisphosphatase, administered with a combination of mitiglinide with an modulators of glucose transporter 4 (GLUT4), 25 alpha-glucosidase inhibitor. inhibitors of glutamine:fructose-6-phosphate amidotrans In a further embodiment, the compound of the formula I is ferase (GFAT), administered in combination with antidiabetic compounds, as GLP-1 agonists, described in WO2007095462, WO2007101060, potassium channel openers, for example pinacidil, cro WO2007 105650. makalim, diazoxide, or those as described in R. D. Carret al., 30 In a further embodiment, the compound of the formula I is Diabetes 52, 2003, 2513-2518, in J. B. Hansen et al., Current administered in combination with antihypoglycemic com Medicinal Chemistry 11, 2004, 1595-1615, in T. M. Tagmose pounds, as described in WO2007 137008. et al., J. Med. Chem. 47, 2004,3202-3211 or in M.J. Coghlan In one embodiment, the compound of the formula I is et al., J. Med. Chem. 44, 2001, 1627-1653, or those which administered in combination with a thiazolidinedione, for have been disclosed in WO97/26265 and WO99/03861 by 35 exampletroglitaZone, ciglitaZone, pioglitaZone, rosiglitaZone Novo Nordisk A/S, or the compounds disclosed in WO 97/41097 to Dr. Reddy’s active ingredients which act on the ATP-dependent potas Research Foundation, especially 5-4-(3,4-dihydro-3-me sium channel of the beta cells, thyl-4-oxo-2-quinazolinylmethoxyphenylmethyl-2,4- inhibitors of dipeptidyl peptidase-IV (DPP-IV), thiazolidinedione. insulin sensitizers, 40 In one embodiment of the invention, the compound of the inhibitors of liver enzymes involved in stimulating gluco formula I is administered in combination with a PPAR neogenesis and/or glycogenolysis, gamma agonist, for examplerosiglitaZone, pioglitaZone, JTT modulators of glucose uptake, of glucose transport and of 501, G1 262570, R-483, CS-011 (rivoglitazone), DRL glucose reabsorption, 17564, DRF-2593 (balaglitaZone), or those as described in modulators of sodium-dependent glucose transporter 1 or 2 45 WO2007060992, WO2007 100027, WO2007103252, (SGLT1, SGLT2), WO2007 122970. inhibitors of 11-beta-hydroxysteroid dehydrogenase-1 In one embodiment of the invention, the compound of the (11 B-HSD1), formula I is administered in combination with CompetactTM, inhibitors of protein tyrosine phosphatase-1B (PTP-1B), a solid combination of pioglitazone hydrochloride with met nicotinic acid receptor agonists, 50 formin hydrochloride. inhibitors of hormone-sensitive or endothelial lipases, In one embodiment of the invention, the compound of the inhibitors of acetyl-CoA carboxylase (ACC1 and/or formula I is administered in combination with TandemactTM, ACC2) or a solid combination of pioglitaZone with glimepiride. inhibitors of GSK-3beta. In a further embodiment of the invention, the compound of Also included are compounds which modify the lipid 55 the formula I is administered in combination with a solid metabolism, Such as active antihyperlipidemic ingredients combination of pioglitaZone hydrochloride with an angio and active antilipidemic ingredients, tensin II agonist, for example TAK-536. HMG-CoA reductase inhibitors, In one embodiment of the invention, the compound of the farnesoid X receptor (FXR) antagonists, formula I is administered in combination with a PPAR alpha fibrates, 60 agonist or mixed PPAR alpha/PPAR delta agonist, for cholesterol reabsorption inhibitors, example GW9578, GW-590735, K-1 11, LY-674, KRP-101, CETP inhibitors, DRF-10945, LY-518674, CP-900691, BMS-687453, BMS bile acid absorption inhibitors, 711939, or those as described in WO2001040207, MTP inhibitors, WO2002096894, WO2005097076, WO2007056771, estrogen receptor gamma agonists (ERR agonists), 65 WO2007087448, WO2007089667, WO2007089557, sigma-1 receptor antagonists, WO2007 102515, WO2007103252, JP2007246474, antagonists of the somatostatin 5 receptor (SSTS receptor); WO2007 118963, WO2007118964, WO2007 126043. US 8,901,114 B2 10 In one embodiment of the invention, the compound of the In one embodiment, the compound of the formula I is formula I is administered in combination with a mixed PPAR administered in combination with modulators of glucose alpha/gamma agonist, for example naveglitazar, LY-510929, transporter 4 (GLUT4), for example KST-48 (D.-O. Lee et ONO-5129, E-3030, AVE 8042, AVE 8134, AVE 0847, CKD al.: Arzneim.-Forsch. Drug Res. 54 (12), 835 (2004)). 501 (lobeglitazone sulfate), MBX-213, or as described in WO In one embodiment, the compound of the formula I is 00/64888, WO 00/64876, WO03/020269, WO2007099553, administered in combination with inhibitors of glutamine: US2007276041, WO2007085135, WO2007085136, or in J. fructose-6-phosphate amidotransferase (GFAT), as P. Berger et al., TRENDS in Pharmacological Sciences 28(5), described, for example, in WO2004 101528. 244-251, 2005. In one embodiment, the compound of the formula I is 10 administered in combination with inhibitors of dipeptidyl In one embodiment of the invention, the compound of the peptidase IV (DPP-IV), for example vildagliptin (LAF-237), formula I is administered in combination with a PPAR delta Sitagliptin (MK-0431), Sitagliptin phosphate, saxagliptin agonist, for example GW-501516, or as described in ((BMS-477118), GSK-823093, PSN-9301, SYR-322, SYR WO2006059744, WO2006084176, WO2006029699, 619, TA-6666, TS-021, GRC-8200, GW-825964X, KRP WO2007039172, WO200703.9178, WO200707 1766, 15 104, DP-893, ABT-341, ABT-279 or another salt thereof, WO2007101864, US2007244094, WO2007 119887. S-40010, S-40755, PF-00734200, BI-1356, PHX-1149, In one embodiment of the invention, the compound of the alogliptin, or those compounds described in formula I is administered in combination with a pan-SP WO2003074500, WO2003106456, WO2004037169, PARM (selective PPAR modulator alpha, gamma, delta), for WO200450658, WO2005037828, WO2005058901, example GFT-505. WO2005012312, WO2005/012308, WO2006039325, In one embodiment, the compound of the formula I is WO2006058.064, WO2006015691, WO2006015701, administered in combination with metaglidasen or with WO2006015699, WO2006015700, WO2006018117, MBX-2044 or other partial PPARgamma agonists/antago WO2006099.943, WO20060.99941, JP2006160733, nists. WO200607 1752, WO2006065826, WO2006078676, In one embodiment, the compound of the formula I is 25 WO2006073167, WO2006068163, WO2006085685, administered in combination with an O-glucosidase inhibitor, WO2006090915, WO2006104356, WO2006127530, for example miglitol or acarbose, or those as described, for WO2006111261, WO2007O15767 (LY-2463665), example, in WO2007 114532, WO2007 140230. WO2007024993, WO2007029086, WO2007063928, In one embodiment, the compound of the formula I is WO2007070434, WO2007071738, WO2007077508, administered in combination with an inhibitor of glycogen 30 WO2007087231, WO2007097931, WO2007099385, phosphorylase, for example PSN-357 or FR-258900, or those WO2007100374, WO2007 112347, WO2007 112669, as described in WO2003084922, WO2004007455, WO2007 113226, WO2007 113634, WO2007115821, WO2005073229-31, WO2005067932. WO2007 116092, US2007259900, EP1852108, In one embodiment, the compound of the formula I is US2007270492, WO2007126745, WO2007136603. administered in combination with glucagon receptor antago 35 In one embodiment, the compound of the formula I is nists, for example A-770077 or NNC-25-2504 or as described administered in combination with JanumetTM, a solid combi in WO2004100875, WO2005065680, WO2006086488, nation of Sitagliptin phosphate with metformin hydrochlo WO2007 106181, WO2007 111864, WO2007 120270, ride. WO2007 120284, WO2007 123581, WO2007136577. In one embodiment, the compound of the formula I is In a further embodiment, the compound of the formula I is 40 administered in combination with Eucreas(R), a solid combi administered in combination with an antisense compound, nation of Vildagliptin with metformin hydrochloride. e.g. ISIS-325568, which inhibits the production of the gluca In one embodiment, the compound of the formula I is gon receptor. administered in combination with a combination of a DPP-IV In one embodiment, the compound of the formula I is inhibitor with omega-3 fatty acids or omega-3 fatty acid administered in combination with activators of glucokinase, 45 esters, as described, for example, in WO2007 128801. for example LY-2121260 (WO2004063179), PSN-105, PSN In one embodiment, the compound of the formula I is 110, GKA-50, or those as described, for example, in administered in combination with a substance which WO2004072031, WO2004072066, WO2005080360, enhances insulin secretion, for example KCP-265 WO2005044801, WO2006016194, WO2006058923, (WO2003097064), or those as described in WO2007026761. WO2006112549, WO2006125972, WO2007017549, 50 In one embodiment, the compound of the formula I is WO2007017649, WO2007007910, WO2007007040-42, administered in combination with agonists of the glucose WO2007006760-61, WO2007006814, WO2007007886, dependent insulinotropic receptor (GDIR), for example WO2007028135, WO2007031739, WO2007041365, APD-668. WO2007041366, WO2007037534, WO2007043638, In one embodiment of the invention, the compound of the WO2007053345, WO2007051846, WO2007051845, 55 formula I is administered in combination with an ATP citrate WO2007053765, WO2007051847, WO2007061923, lyase inhibitor, for example SB-204990. WO2007075847, WO2007089512, WO2007104034, In one embodiment, the compound of the formula I is WO2007 117381, WO2007122482, WO2007125103, administered in combination with modulators of the sodium WO2007125105, US2007281942. dependent glucose transporter 1 or 2 (SGLT1, SGLT2), for In one embodiment, the compound of the formula I is 60 example KGA-2727, T-1095, SGL-0010, AVE 2268, SAR administered in combination with an inhibitor of gluconeo 7226, SGL-5083, SGL-5085, SGL-5094, ISIS-388626, ser genesis, for example FR-225654. gliflozin or dapagliflozin, or as described, for example, in In one embodiment, the compound of the formula I is WO2004.007517, WO200452903, WO200452902, PCT/ administered in combination with inhibitors of fructose 1,6- EP2005/005.959, WO2005085237, JP2004359630, bisphosphatase (FBPase), for example CS-917 (MB-06322) 65 WO2005121161, WO2006018150, WO2006035796, or MB-07803, or those as described in WO2006023515, WO2006062224, WO2006058597, WO2006073197, WO2006104030, WO2007014619, WO2007 137962. WO2006080577, WO2006087997, WO2006108842, US 8,901,114 B2 11 12 WO2007000445, WO2007014895, WO2007080170, In another embodiment of the invention, the compound of WO2007093610, WO2007 126117, WO2007 128480, the formula I is administered in combination with nicotinic WO2007129668, US2007275907, WO2007136116, or by A. acid or extended release niacin in conjunction with L. Handlon in Expert Opin. Ther. Patents (2005) 15(11), MK-0524A (laropiprant). 1531-1540. In a further embodiment of the invention, the compound of In one embodiment, the compound of the formula I is the formula I is administered in combination with nicotinic administered in combination with inhibitors of 11-beta-hy acid or extended release niacin in conjunction with droxysteroid dehydrogenase 1 (113-HSD1), for example MK-0524A (laropiprant) and with simvastatin. BVT-2733, NJ-25918646, INCB-13739, D10-92 ((-)-keto In another embodiment of the invention, the compound of conazole) or those as described, for example, in 10 the formula I is administered in combination with an agonist WO200190090-94, WO200343999, WO2004112782, of GPR116, as described, for example, in WO2006067531, WO200344000, WO200344009, WO2004112779, WO2OO6067532. WO2004 113310, WO2004103980, WO2004112784, In one embodiment, the compound of the formula I is WO2003065983, WO2003104207, WO2003104208, 15 administered in combination with modulators of GPR40, as WO2004 106294, WO2004011410, WO2004033427, described, for example, in WO2007013.689, WO2004041264, WO2004037251, WO2004.056744, WO2007033002, WO2007 106469, US2007265332, WO2004058730, WO2004065351, WO2004089367, WO2007 123225, WO2007 131619, WO2007131620, WO2004089380, WO2004089470-71, WO2004089896, WO2007 131621, US2007265332, WO2007 131622, WO2005016877, WO2005063247, WO2005097759, WO2007136572. WO2006010546, WO2006012227, WO2006012173, In one embodiment, the compound of the formula I is WO2006017542, WO2006034804, WO2006040329, administered in combination with GPR119b modulators, as WO2006051662, WO2006048750, WO2006049952, described, for example, in WO2004041274. WO2006048331, WO2006050908, WO2006024627, In one embodiment, the compound of the formula I is WO2006040329, WO2006066109, WO2006074244, 25 administered in combination with modulators of GPR119 (G WO2006078006, WO2006106423, WO2006132436, protein-coupled glucose-dependent insulinotropic receptor), WO2006134481, WO2006134467, WO2006135795, for example PSN-119-1, or those as described, for example, WO2006136502, WO2006138508, WO2006138695, in WO2005061489 (PSN-632408), WO2004065380, WO2006133926, WO2007003521, WO2007007688, WO2006018662, WO2007003960-62 and WO2007003964, 30 WO2007 116229, WO2007.116230. US2007066584, WO2007029021, WO2007047625, In a further embodiment, the compound of the formula I is WO2007051811, WO2007051810, WO2007057768, administered in combination with modulators of GPR120, as WO2007058346, WO2007061661, WO2007068330, described, for example, in EP1688.138. WO2007070506, WO2007087150, WO2007092435, In one embodiment, the compound of the formula I is WO2007089683, WO2007101270, WO2007 105753, 35 administered in combination with inhibitors of hormone-sen WO2007107470, WO2007107550, WO2007 111921, sitive lipase (HSL) and/or phospholipases, as described, for US2007207985, US2007208001, WO2007 115935, example, in WO2005073199. WO2006074957, WO2007 118185, WO2007122411, WO2007 124329, WO20060873.09, WO2006111321, WO2007042178, WO2007 124337, WO2007 124254, WO2007127688, WO2007 119837. WO2007127693, WO2007 127704, WO2007 127726, 40 In one embodiment, the compound of the formula I is WO2007 127763, WO2007 127765, WO2007 127901, administered in combination with inhibitors of endothelial US2007270424, JP2007291075, WO2007 130898, lipase, as described, for example, in WO2007110216. WO2007135427. In one embodiment, the compound of the formula I is In one embodiment, the compound of the formula I is administered in combination with a phospholipase A2 inhibi administered in combination with inhibitors of protein 45 tor, for example darapladib or A-002. tyrosine phosphatase 1B (PTP-1B), as described, for In one embodiment, the compound of the formula I is example, in WO2001 19830-31, WO200117516, administered in combination with myricitrin, a lipase inhibi WO2004506446, WO2005012295, WO2005116003, tor (WO2007119827). WO2005116003, WO2006007959, DE 10 2004 060542.4, In one embodiment, the compound of the formula I is WO2007009911, WO2007028145, WO2007067612-615, 50 administered in combination with an inhibitor of glycogen WO2007081755, WO2007 115058. synthase kinase-3 beta (GSK-3 beta), as described, for example, in US2005222220, WO2005085230, In one embodiment of the invention, the compound of the WO2005111018, WO2003078.403, WO2004022544, formula I is administered in combination with an agonist of WO2003106410, WO2005058908, US2005038023, GPR109A (HM74A receptor agonists; NAR agonists (nico WO2005.009997, US2005026984, WO2005000836, tinic acid receptor agonists)), for example nicotinic acid or WO2004 106343, EP1460075, WO2004014910, “extended release niacin’ in conjunction with MK-0524A WO2003076442, WO2005087727, WO2004.046117, (laropiprant) or MK-0524, or those compounds as described WO2007073117, WO2007083978, WO2007120102, in WO2006045565, WO2006045564, WO2006069242, WO2007 122634, WO2007125109, WO20071251.10. WO2006085108, WO20060851 12, WO2006085113, 60 In one embodiment, the compound of the formula I is WO2006124490, WO2006113150, WO2007017261, administered in combination with an inhibitor of phospho WO2007017262, WO2007017265, WO2007015744, enolpyruvate carboxykinase (PEPCK), for example those as WO2007027532, WO2007092364, WO2007120575, described in WO2004074288. WO2OO7134986. In one embodiment, the compound of the formula I is In another embodiment of the invention, the compound of 65 administered in combination with an inhibitor of serum/glu the formula I is administered in combination with a solid cocorticoid-regulated kinase (SGK), as described, for combination of niacin with simvastatin. example, in WO2006072354, WO2007093264. US 8,901,114 B2 13 14 In one embodiment, the compound of the formula I is (Phenomix) or WO2005033100 (Lipideon Biotechnology administered in combination with an inhibitor of protein AG), or as described in WO2002050060, WO2002050068, kinase C beta (PKC beta), for example ruboxistaurin. WO2004000803, WO2004000804, WO2004000805, In a further embodiment, the compound of the formula I is WO2004087655, WO2004097655, WO2005047248, administered in combination with an activator of the AMP WO2006086562, WO2006102674, WO2006116499, activated protein kinase (AMPK), as described, for example, WO2006121861, WO2006122186, WO2006122216, in WO2OO7O62.568. WO2006127893, WO2006137794, WO2006137796, In one embodiment, the compound of the formula I is WO2006137782, WO2006137793, WO2006137797, administered in combination with an inhibitor of ceramide WO2006137795, WO2006137792, WO2006138163, kinase, as described, for example, in WO2007 112914. 10 In a further embodiment, the compound of the formula I is WO2007059871, US2007232688, WO2007 126358. administered in combination with an inhibitor of MAPK In one embodiment of the invention, the compound of the interacting kinase 2 (MNK2), as described, for example, in formula I is administered in combination with VytorinTM, a WO2007 104053, WO2007 115822. solid combination of eZetimibe with simvastatin. In one embodiment, the compound of the formula I is 15 In one embodiment of the invention, the compound of the administered in combination with inhibitors of “I-kappaB formula I is administered in combination with a solid combi kinase” (IKK inhibitors), as described, for example, in nation of eZetimibe with atorvastatin. WO2001000610, WO2001030774, WO2004022057, In one embodiment of the invention, the compound of the WO2004022553, WO2005097 129, WO2005113544, formula I is administered in combination with a solid combi US2OO7244140. nation of eZetimibe with fenofibrate. In one embodiment of the invention, the compound of the In one embodiment of the invention, the further active formula I is administered in combination with an HMG-CoA ingredient is a diphenylaZetidinone derivative, as described, reductase inhibitor Such as simvastatin, fluvastatin, pravasta for example, in U.S. Pat. Nos. 6,992,067 or 7.205.290. tin, lovastatin, atorvastatin, cerivastatin, rosuvastatin, In a further embodiment of the invention, the further active L-659699, or those as described in US2007249583. 25 ingredient is a diphenylaZetidinone derivative, as described, In a further embodiment of the invention, the compound of for example, in U.S. Pat. Nos. 6,992,067 or 7.205.290, com the formula I is administered in combination with a farnesoid bined with a statin, for example simvastatin, fluvastatin, prav X receptor (FXR) antagonist, as described, for example, in astatin, lovastatin, cerivastatin, atorvastatin or rosuvastatin. WO2007052843, WO2007070796, WO2007092751, In one embodiment of the invention, the compound of the JP2007230909, WO2007095174, WO2007 140174, 30 formula I is administered in combination with a solid combi WO2OO714O183. nation of lapaquistat, a squalene synthase inhibitor, with ator In another embodiment of the invention, the compound of vastatin. the formula I is administered in combination with a ligand of In one embodiment of the invention, the compound of the the liver X receptor (LXR), as described, for example, in formula I is administered in combination with a CETP inhibi WO2007092965. 35 tor, for example torcetrapib, anacetrapib or JTT-705, or those In one embodiment of the invention, the compound of the as described in WO2006002342, WO2006010422, formula I is administered in combination with a fibrate, for WO2006012093, WO2006073973, WO2006072362, example fenofibrate, clofibrate, bezafibrate. WO2007088996, WO2007088999, US2007185058, In one embodiment of the invention, the compound of the US2007 185113, US2007 185154, US2007 185182, formula I is administered in combination with fibrates, for 40 WO2006097169, WO2007041494, WO2007090752, example the choline salt offenofibrate (SLV-348). WO2007 107243, WO2007 120621, US2007265252, In one embodiment of the invention, the compound of the US2007265304, WO2007128568, WO2007 132906. formula I is administered in combination with fibrates, for In one embodiment of the invention, the compound of the example the choline salt of fenofibrate and an HMG-CoA formula I is administered in combination with bile acid reab reductase inhibitor, for example rosuvastatin. 45 sorption inhibitor (see, for example, U.S. Pat. No. 6.245,744, In a further embodiment of the invention, the compound of U.S. Pat. No. 6,221,897 or WO00/61568), for example HMR the formula I is administered in combination with bezafibrate 1741, or those as described in DE 10 2005 033099.1 and DE and diflunisal. 10 2005 033100.9, WO200700.9655-56. In a further embodiment of the invention, the compound of In one embodiment, the compound of the formula I is the formula I is administered in combination with a solid 50 administered in combination with agonists of GPBAR1 combination offenofibrate or a salt thereof with simvastatin, (G-protein-coupled bile acid receptor-1; TGR5), as rosuvastatin, fluvastatin, lovastatin, cerivastatin, pravastatin described, for example, in WO2007110237, oratorvastatin. WO2007 127505. In a further embodiment of the invention, the compound of In one embodiment of the invention, the compound of the the formula I is administered in combination with Synordia 55 formula I is administered in combination with a polymeric (R), a solid combination offenofibrate with metformin. bile acid adsorber, for example cholestyramine, colesevelam In one embodiment of the invention, the compound of the hydrochloride. formula I is administered in combination with a cholesterol In one embodiment of the invention, the compound of the absorption inhibitor, for example eZetimibe, tiqueside, pam formula I is administered in combination with a chewing gum aqueside, FM-VP4 (sitostanol/campesterol ascorbyl phos 60 comprising phytosterols (ReductolTM) phate; Forbes Medi-Tech, WO2005042692, In one embodiment of the invention, the compound of the WO2005005453), MD-O727 (Microbia Inc., formula I is administered in combination with an inhibitor of WO2005021497, WO2005021495) or with compounds as the microsomal triglyceride transfer protein (MTP inhibitor), described in WO2002066464, WO2005000353 (Kotobuki for example implitapide, BMS-201038, R-103757, Pharmaceutical Co. Ltd.) or WO2005044256 or 65 AS-1552133, SLX-4090, AEGR-733, or those as described in WO2005062824 (Merck & Co.) or WO2005061451 and WO2005085226, WO2005121091, WO2006010423, WO2005061452 (AstraZeneca AB) and WO2006017257 WO2OO611391O. US 8,901,114 B2 15 16 In another embodiment of the invention, the compound of In a further embodiment, the compound of the formula I is the formula I is administered in combination with an antago administered in combination with modulators of Xanthine nist of the somatostatin 5 receptor (SSTS receptor), for oxidoreductase (XOR). example those as described in WO2006094682. In a further embodiment, the compound of the formula I is In one embodiment of the invention, the compound of the administered in combination with CART modulators (see formula I is administered in combination with an ACAT 'Cocaine-amphetamine-regulated transcript influences inhibitor, for example avasimibe, SMP-797 or KY-382. energy metabolism, anxiety and gastric emptying in mice’ In a further embodiment of the invention, the compound of Asakawa, A. et al.: Hormone and Metabolic Research (2001), the formula I is administered in combination with an inhibitor 33(9), 554-558); of liver carnitine palmitoyltransferase 1 (L-CPT1), as 10 NPY antagonists, for example 4-(4-aminoquinazolin-2- described, for example, in WO2007063012, WO2007096251 ylamino)methyl-cyclohexylmethylnaphthalene-1-sulfona (ST-3473). mide hydrochloride (CGP 71683A); In one embodiment of the invention, the compound of the NPY-5 receptor antagonists, such as L-152804 or the com formula I is administered in combination with a squalene 15 pound “NPY-5-BY” from Banyu, or as described, for synthetase inhibitor, for example BMS-188494, TAK-475 example, in WO2006001318, WO2007103295, (lapaquistat acetate), or as described in WO2005077907, WO2007125952; JP2007022943. NPY-4 receptor antagonists, as described, for example, in In one embodiment of the invention, the compound of the WO2007038942: formula I is administered in combination with ISIS-301012 NPY-2 receptor antagonists, as described, for example, in (mipomersen), an antisense oligonucleotide which is capable WO2007038943: of regulating the apolipoprotein B gene. peptide YY 3-36 (PYY3-36) or analogous compounds, for In one embodiment of the invention, the compound of the example CJC-1682 (PYY3-36 conjugated with human serum formula I is administered in combination with an LDL recep albumin via Cys34) or CJC-1643 (derivative of PYY3-36, tor inducer (see U.S. Pat. No. 6,342.512), for example 25 which is conjugated in vivo to serum albumin), or those as HMR1171, HMR1586, or those as described in described in WO2005080424, WO2006095166; WO2005097738. derivatives of the peptide obestatin, as described by In one embodiment of the invention, the compound of the WO2006096847: formula I is administered in combination with an ABCA1 CB1R (cannabinoid receptor 1) antagonists, for example expression enhancer, as described, for example, in 30 rimonabant, Surinabant (SR 147778), WO2O06O72393. SLV-319, AVE-1625, taranabant (MK-0364) or salts In one embodiment of the invention, the compound of the thereof, V-24343 or those compounds as described in, for formula I is administered in combination with a lipoprotein example, EP 0656354, WO 00/15609, WO2001/64.632 lipase modulator, for example ibrolipim (NO-1886). 35 64634, WO 02/076949, WO2005080345, WO2005080328, In one embodiment of the invention, the compound of the WO2005080343, WO2005075450, WO2005080357, formula I is administered in combination with a lipoprotein WO200170700, WO2003026647-48, WO2003.02776, (a) antagonist, for example gemcabene (CI-1027). WO2003040 107, WO2003007887, WO2003027069, U.S. In one embodiment of the invention, the compound of the Pat. No. 6,509,367, WO200132663, WO200308.6288, formula I is administered in combination with a lipase inhibi 40 WO2003087037, WO2004.048317, WO2004058145, tor, for example orlistat or cetilistat (ATL-962). WO2003084930, WO2003084943, WO2004058744, In one embodiment of the invention, the compound of the WO2004013 120, WO2004029204, WO2004035566, formula I is administered in combination with an adenosine WO2004058249, WO2004058255, WO2004058727, A2B receptor agonist (adenosine A2B R), for example ATL WO2004069838, US20040214837, US20040214855, 8O1. 45 US20040214856, WO2004096209, WO2004096763, In another embodiment of the invention, the compound of WO2004096794, WO2005000809, WO2004.099157, the formula I is administered in combination with a modula US20040266845, WO2004110453, WO2004108728, tor of adenosine A2A and/or adenosine A3 receptors, as WO2004000817, WO2005000820, US20050009870, described, for example, in WO2007 111954, WO200500.974, WO2004111033-34, WO2004.11038-39, WO2007 121918, WO2007 121921, WO2007 121923. 50 WO2005016286, WO2005007111, WO2005.007628, In one embodiment of the invention, the compound of the US2005.0054679, WO2005027837, WO2005028456, formula I is administered in combination with an adenosine WO2005063761-62, WO2005061509, WO2005077897, A2B receptor antagonist (adenosine A2B R), as described in WO2006047516, WO2006060461, WO2006067428, US2OO727O433. WO2006067443, WO2006087480, WO2006087476, In one embodiment, the compound of the formula I is 55 WO2006100208, WO2006106054, WO200611 1849, administered in combination with inhibitors of acetyl-CoA WO2006113704, WO200700.9705, WO2007017124, carboxylase (ACC1 and/or ACC2), for example those as WO2007017126, WO2007018459, WO2007018460, described in WO1999.46262, WO200372197, WO2007016460, WO2007020502, WO2007026215, WO2003072197, WO2005044814, WO2005108370, WO2007028849, WO2007031720, WO2007031721, JP2006131559, WO200701 1809, WO200701 1811, 60 WO2007036945, WO2007038.045, WO2007039740, WO2007013691, WO2007095601-603, WO2007 119833. US20070015810, WO2007046548, WO2007047737, In another embodiment, the compound of the formula I is WO2007057687, WO2007062193, WO2007064272, administered in combination with modulators of microsomal WO2007079681, WO2007084319, WO2007084450, acyl-CoA:glycerol-3-phosphate acyltransferase 3 (GPAT3, WO200708.6080, EP1816125, US2007213302, described in WO2007.100789) or with modulators of 65 WO2007095513, WO2007096764, US2007254.863, microsomal acyl-CoA:glycerol-3-phosphate acyltransferase WO2007 119001, WO2007120454, WO2007121687, 4 (GPAT4, described in WO2007 100833). WO2007 123949, US2007259934, WO2007 131219, US 8,901,114 B2 17 18 WO2007133820, WO2007136607, WO2007136571, CRF antagonists (e.g. 2-methyl-9-(2,4,6-trimethylphe US7297710, WO2007138050, WO2007 140385, nyl)-9H-13.9-triazafluoren-4-yldipropylamine (WO WO2007 140439; 00/66585) or those CRF1 antagonists as described in cannabinoid receptor 1/cannabinoid receptor 2 (CB1/CB2) WO2007 105113, WO2007133756); modulating compounds, for example delta-9-tetrahydrocan CRF BP antagonists (e.g. urocortin): nabivarin, or those as described, for example, in urocortin agonists; WO2007001939, WO2007044215, WO2007047737, agonists of the beta-3 adrenoceptor, for example 1-(4- WO2007095513, WO2007096764, WO2007 112399, chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dim WO2007 112402; 10 ethyl-1H-indol-6-yloxy)ethylamino-ethanol hydrochloride modulators of FAAH (fatty acid amide hydrolase), as (WO 01/83451) or solabegron (GW-427353) or N-5984 described, for example, in WO2007 14.0005; (KRP-204), or those as described in JP2006111553, vanilloid 1 receptor modulators (modulators of TRPV 1), WO2002038543, WO2002038544, WO2007048840-843; as described, for example, in WO2007091948, MSH (melanocyte-stimulating hormone) agonists; WO2007 1291.88, WO2007133637; 15 MCH (melanine-concentrating hormone) receptor antago activators of the capsaicin receptor, as described, for nists (for example NBI-845, A-761, A-665798, A-798, ATC example, in JP2007210969; 0175, T-226296, T-71, GW-803430, or those compounds as agonists of the prostaglandin receptor, for example bimato described in WO2005085200, WO2005019240, prost or those compounds as described in WO2007 111806; WO2004011438, WO2004012648, WO2003015769, MC4 receptoragonists (melanocortin-4 receptor agonists, WO2004.072025, WO2005070898, WO2005070925, MC4R agonists, for example N-2-(3a-benzyl-2-methyl-3- WO2004039780, WO2004.09218.1, WO2003.033476, oxo-2.3.3a,4,6,7-hexahydropyrazolo 4.3-c-pyridin-5-yl)-1- WO2002006245, WO2002089729, WO2002002744, (4-chlorophenyl)-2-oxoethyl-1-amino-1,2,3,4-tetrahy WO2003004027, FR2868780, WO2006010446, dronaphthalene-2-carboxamide: (WO 01/91752)) or WO2006038680, WO2006044293, WO2006044174, LB53280, LB53279, LB53278 or THIQ, MB243, RY764, 25 JP2006176443, WO2006018280, WO2006018279, CHIR-785, PT-141, MK-0493, or those as described in WO2006118320, WO2006130075, WO2007018248, WO2005060985, WO2005.009950, WO2004087.159, WO2007012661, WO200702.9847, WO2007024004, WO2004078717, WO2004078716, WO2004024720, WO2007039462, WO2007042660, WO2007042668, US20050124652, WO2005051391, WO2004.112793, WO2007042669, US2007093508, US2007093509, WOUS20050222014, US20050176728, US20050164914, 30 WO2007048802, JP2007091649, WO2007092416; US20050124636, US20050130988, US2004.01672.01, WO2007093363-366, WO2007 114902, WO2007 114916); WO2004.005324, WO2004.037797, WO2005042516, CCK-A (CCK-1) agonists (for example {2-4-(4-chloro-2, WO2005040109, WO2005030797, US20040224901, 5-dimethoxyphenyl)-5-(2-cyclohexylethyl)thiazol-2-ylcar WO200501921, WO200509184, WO2005000339, 35 bamoyl-5,7-dimethylindol-1-yl)acetic acid trifluoroacetic EP1460069, WO2005047253, WO2005047251, acid salt (WO 99/15525) or SR-146131 (WO 0244150) or WO2005118573, EP1538159, WO2004072076, SSR-125180), or those as described in WO2005116034, WO2004072077, WO2006021655-57, WO200700.9894, WO2007 120655, WO2007120688, WO2007120718; WO2007015162, WO2007041061, WO2007041052, serotonin reuptake inhibitors (for example dexfenflu JP2007 131570, EP-1842846, WO2007096186, 40 ramine); WO2007096763; mixed serotonin/dopamine reuptake inhibitors (e.g. bupro orexin receptor 1 antagonists (OX1R antagonists), orexin pion), or Solid combinations of bupropion with naltrexone or receptor 2 antagonists (OX2R antagonists) or mixed OX1 R/ bupropion with Zonisamide; OX2R antagonists (e.g. 1-(2-methyl-benzoxazol-6-yl)-3-1, mixed reuptake inhibitors, for example DOV-2 1947; 5 naphthyridin-4-ylurea hydrochloride (SB-334867-A), or 45 mixed serotoninergic and noradrenergic compounds (e.g. those as described, for example, in WO200196302, WO 00/71549): WO200185693, WO200408.5403, WO2005075458, WO2006067224, WO2007085718, WO2007088276, 5-HT receptor agonists, for example 1-(3-ethylbenzofu WO2007 116374; WO2007122591, WO2007 126934, ran-7-yl)piperazine oxalic acid salt (WO 01/09111): WO2007126935); 50 mixed dopamine/norepinephrine/acetylcholine reuptake histamine H3 receptor antagonists/inverse agonists (e.g. inhibitors (e.g. tesofensine), or those as described, for 3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4, example, in WO20060851 18; 5-cpyridin-5-yl)propan-1-one oxalic acid salt (WO 5-HT2C receptoragonists (for example lorcaserine hydro 00/63208), or those as described in WO200064884, chloride (APD-356) or BVT-933, or those as described in WO2005082893, US2005171181 (e.g. PF-00389027), 55 WO200077010, WO200077001-02, WO2005019180, WO2006 107661, WO2007003.804, WO2007016496, WO2003064423, WO200242304, WO2005035533, WO2007020213, WO2007049798, WO2007055418, WO2005082859, WO2006004937, US2006025601, WO2007057329, WO2007065820, WO2007068620, WO2006028961, WO2006077025, WO2006103511, WO2007028132, WO2007084622, US2007249709; WO2007068641, WO2007075629, WO2007080140, 60 WO2007082840, WO2007088450, WO2007088462, WO2007 132841, WO2007 140213): WO2007094962, WO2007099423, WO2007 100990, 5-HT6 receptor modulators, for example E-6837, BVT WO2007 105053, WO2007106349, WO2007 110364, 74316 or PRX-07034, or those as described, for example, in WO2007 115938, WO2007 131907, WO2007133561, WO2005058858, WO2007054257, WO2007107373, US2007270440, WO2007135111): 65 WO2007 10.8569, WO2007108742-744; histamine H1/histamine H3 modulators, for example beta agonists of estrogen receptor gamma (ERR agonists), as histine or its dihydrochloride; described, for example, in WO2007 131005; US 8,901,114 B2 19 20 sigma-1 receptor antagonists, as described, for example, in In a further embodiment of the invention, the compound of WO2007098953, WO2007098.961; the formula I is administered in combination with an RNAi muscarin 3 receptor (M3R) antagonists, as described, for therapeutic agent directed against PCSK9 (proprotein con example, in WO2007110782; bombesin receptor agonists vertase subtilisin/kexin type 9). (BRS-3 agonists); In one embodiment, the compound of the formula I is galanin receptor antagonists; administered in combination with Omacor R or Lovaza TM growth hormone (e.g. human growth hormone or AOD (omega-3 fatty acid ester, highly concentrated ethyl ester of 9604): eicosapentaenoic acid and of docosahexaenoic acid). growth hormone releasing compounds (tert-butyl 6-benzy In one embodiment, the compound of the formula I is loxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro 10 administered in combination with lycopene. 1H-isoquinoline-2-carboxylate (WO 01/85695)); In one embodiment of the invention, the compound of the growth hormone secretagogue receptor antagonists (ghre formula I is administered in combination with an antioxidant, lin antagonists), for example A-778193, or those as described for example OPC-14117, succinobucol, probucol, toco in WO2005030734, WO2007 127457; 15 pherol, ascorbic acid, B-carotene or selenium. growth hormone secretagogue receptor modulators, for In one embodiment of the invention, the compound of the example JMV-2959, JMV-3002, JMV-2810, JMV-2951, or formula I is administered in combination with a vitamin, for those as described in WO2006.012577 (e.g. YIL-781 or YIL example vitamin B6 or vitamin B12. 870), WO2007079239; In one embodiment, the compound of the formula I is TRH agonists (see, for example, EP 0462884): administered in combination with more than one of the afore decoupling protein 2 or 3 modulators; mentioned compounds, for example in combination with a leptin agonists (see, for example, Lee, Daniel W.; Leinung, Sulfonylurea and metformin, a Sulfonylurea and acarbose, Matthew C.; Rozhayskaya-Arena, Marina; Grasso, Patricia. repaglinide and metformin, insulin and a Sulfonylurea, insu Leptin agonists as a potential approach to the treatment of lin and metformin, insulin and troglitaZone, insulin and lov obesity. Drugs of the Future (2001), 26(9), 873-881); 25 astatin, etc. dopamine agonists (DA agonists, for example bromocrip In another embodiment, the compound of the formula I is tine, Doprexin); administered in combination with an inhibitor of carboanhy lipase/amylase inhibitors (e.g. WO 00/40569); drase type 2 (carbonic anhydrase type 2), for example those as inhibitors of diacylglycerol O-acyltransferases (DGATs), described in WO2007065948. 30 for example BAY-74-41 13, or as described, for example, in In another embodiment, the compound of the formula I is US2004/0224997, WO2004094618, WO200058491, administered in combination with topiramat. WO2005044250, WO2005072740, JP2005206492, In a further embodiment, the compound of the formula I is WO2005013907, WO2006004200, WO2006019020, administered in combination with a solid combination of WO2006064189, WO2006082952, WO2006120125, 35 topiramat with phentermine (QnexatM) WO2006113919, WO2006134317, WO2007016538, In a further embodiment, the compound of the formula I is WO2007060140, JP2007 131584, WO200707 1966, administered in combination with an antisense compound, WO2007 126957, WO2007137103, WO2007137107, e.g. ISIS-377131, which inhibits the production of the gluco WO2007138304, WO2007138311; corticoid receptor. inhibitors offatty acid synthase (FAS), for example C75, or 40 those as described in WO2004.005277; In one embodiment, the compound of the formula I is inhibitors of stearoyl-CoA delta9 desaturase (SCD1), as administered in combination with an agonist of the RUP3 described, for example in WO2007009236, WO2007044085, receptor, as described, for example, in WO2007035355. WO2007046867, WO2007046868, WO20070501124, In another embodiment, the compound of the formula I is WO2007056846, WO2007071023, WO2007 130075, 45 administered in combination with an activator of the gene WO2007 134457, WO2007136746; which codes for ataxia telangiectasia mutated (ATM) protein inhibitors of “adipocyte fatty acid-binding protein aP2. kinase, for example chloroquine. for example BMS-309403; activators of adiponectin secre In one embodiment, the compound of the formula I is tion, as described, for example, in WO2006082978; promot administered in combination with a tau protein kinase 1 ers of adiponectin production, as described, for example, in 50 inhibitor (TPK1 inhibitor), as described, for example, in WO2007125946; WO2O07119.463. Oxyntomodulin; In one embodiment, the compound of the formula I is oleoyl-estrone administered in combination with a “c-Jun N-terminal or agonists or partial agonists of the thyroid hormone kinase' inhibitor (JNK inhibitor), as described, for example, receptor (thyroid hormone receptor agonists), for example: 55 in WO2OO71254.05. KB-2115, or those as described in WO20058279, In one embodiment, the compound of the formula I is WO200172692, WO200194293, WO2003084915, administered in combination with an endothelin A receptor WO2004018421, WO2005092316, WO2007003419, antagonist, for example avosentan (SPP-301). WO2007009913, WO2007039 125, WO2007110225, 60 In one embodiment, the compound of the formula I is WO2007110226, WO2007 128492, WO2007 132475, administered in combination with modulators of the gluco WO2007 134864; corticoid receptor (GR), for example KB-3305 or those com or agonists of the thyroid hormone receptor beta (TR-beta), pounds as described, for example, in WO2005090336, for example MB-07811 or MB-07344. WO200607 1609, WO2006135826, WO2007 105766. In one embodiment of the invention, the compound of the 65 In one embodiment, the further active ingredient is Vareni formula I is administered in combination with an inhibitor of cline tartrate, a partial agonist of the alpha 4-beta 2 nicotinic site-1 protease (S1P), for example PF-429242. acetylcholine receptor. US 8,901,114 B2 21 22 In one embodiment, the further active ingredient is tro In another embodiment of the invention, the further active dusquemine. ingredient is meterleptin (recombinant methionyl-leptin) In one embodiment, the further active ingredientis a modu combined with pramlintide. lator of the enzyme SIRT1 (an NAD"-dependent protein In a further embodiment of the invention, the further active deacetylase); this active ingredient may, for example, be res 5 ingredient is the tetrapeptide ISF-402. In one embodiment, the further active ingredient is dexam Veratrol in Suitable formulations, or those compounds as phetamine or amphetamine. specified in WO2007019416 (e.g. SRT1720). In one embodiment, the further active ingredient is fenflu In one embodiment of the invention, the further active ramine or dexfenfluramine. ingredient is DM-71 (N-acetyl-L-cysteine with bethanechol). In another embodiment, the further active ingredient is In one embodiment, the compound of the formula I is 10 Sibutramine. administered in combination with antihypercholesterolemic In one embodiment, the further active ingredient is mazin compounds, as described, for example, in WO2007107587, dol or phentermin. WO2OO711 1994. In a further embodiment, the further active ingredient is In another embodiment, the compound of the formula I is geniposidic acid (WO2007 100104). 15 In one embodiment, the compound of the formula I is administered in combination with a cyclic peptide agonist of administered in combination with bulking agents, preferably the VPAC2 receptor, as described, for example, in insoluble bulking agents (see, for example, Carob/Caromax(R) WO2007101146, WO2007133828. (Zunft H J et al., Carob pulp preparation for treatment of In a further embodiment, the compound of the formula I is hypercholesterolemia, ADVANCES IN THERAPY (2001 administered in combination with an agonist of the endothe September-October), 18(5), 230-6). Caromax is a carob-con lin receptor, as described, for example, in WO2007 112069. taining product from Nutrinova, Nutrition Specialties & Food In a further embodiment, the compound of the formula I is Ingredients GmbH, Industriepark Höchst, 65926 Frankfurt/ administered in combination with AKP-020 (bis(ethylmalto Main)). Combination with Caromax(R) is possible in one lato)oxovanadium(IV)). preparation or by separate administration of compounds of In another embodiment, the compound of the formula I is 25 the formula I and Caromax(R). Caromax(R) can also be admin administered in combination with tissue-selective androgen istered in the form of food products Such as, for example, in receptor modulators (SARM), as described, for example, in bakery products or muesli bars. WO20070992.00. It will be appreciated that every suitable combination of the In one embodiment of the invention, the further active compounds of the invention with one or more of the afore ingredient is leptin; see, for example, “Perspectives in the 30 mentioned compounds and optionally one or more other therapeutic use of leptin', Salvador, Javier; Gomez-Ambrosi, pharmacologically active Substances is considered to be cov Javier; Fruhbeck, Gema, Expert Opinion on Pharmaco ered by the scope of protection conferred by the present therapy (2001), 2(10), 1615-1622. invention.

HO O O O

HO l o1 No O O Na" Na" R= CH3: CH-CH

GI262570 O

M Ceroy N O HN O

US 8,901,114 B2

-continued PSN-119-1 S-4O755 O F O F F O S OH

1. O -O O

LY-2463665 BMS-512148

dapagliflozin BI-1356 PT-429242

O N N N O

N NH2 SLV-348 S

N X= O N O O N Nr.N VH N

O balaglotazpme

NPY-5-BY BMS-711939

NO -O O N N o1 O C F

O

BMS-687453 ST-3473 cror couldNo

US 8,901,114 B2 43 44 -continued KB-3305 ISF-4O2 N= O S. N s O O O O

N N H O O 1N 'O

SRT-1720 O O/ \, l F F O O ?u O N. O O 11a-N

darapladib

A-002 DITPA I

O

HO I Ol OH

O

50 EXAMPLES -continued C R1-NH2, The examples and preparation methods adduced below DIPEA, CHCl2, serve to illustrate the invention, but without limiting it. A N 0° C. 1 h The inventive compounds of the formula I can be prepared 55 s1's with the aid of reactions known in- principle.- - For example, the OAV O so compounds were prepared according to the general reaction schemes which follow. trans C 60 NaOH, H H Dioxane, 100°C., 2h He O O A S se -- \/ 2 TSTAIBN, CC14, 85°C.,T- 6h / \, O 1“n 2 65 "trans' US 8,901,114 B2 45 46 -continued -continued o, R O N NR1 D N R5 A S -N R. 7\ / \, O O 'cis' 10 4-Tolylamide is reacted with thionyl chloride and pyridine to give N-sulfinyl-4-tolylamide. The latter reacts in a hetero A cyclic alkene can be used to prepare a corresponding Diels-Alder reaction with an alkene to give 2-tolyl-4-oxathi chlorosulfonyl isocyanate in a free-radical reaction. This 15 azine. In the case of cyclic alkenes, exclusively the cis con gives exclusively the cis configuration. Subsequently, reac figuration is obtained. After oxidation to give 2-tolyl-4.4- dioxathiazine with 3-chloroperbenzoic acid, hydrolysis is tion is effected with primary amines to give chlorosulfony effected with sodium hydroxide solution to give 1,2-dim lureas. The corresponding sodium salts cyclize when heated ethyl-2-hydroxycyclohexylsulfonamide. Further treatment to give cis-4.4-dioxooxathiazines. with base and an isothiocyanate, and Subsequent oxidative In the cases in which diastereomers or racemates form ring closure with NBS gives the desired 4,4-dioxooxathiaz during the synthesis, these can be separated from one another 1CS by preparative HPLC. In the cases in which diastereomers or racemates form during the synthesis, these can be separated from one another Other inventive compounds can be obtained in other ways 25 by preparative HPLC. outlined by way of example in the scheme which follows. Other examples again were obtained as indicated in the following scheme:

30 SOCl, Pyridine, Et2O, -e- ON H 35 PhMe, riflx., 5 h He O NH2 R1 R1 R3 R2

R2 R4 40 CISONH2, DIPEA, O CH2Cl2, rt, 16 h THF, -40°C. tort -e- N) -- N ss S. no 45 r R2 O R3 R1 O \/ NaBH4, MeOH, 1 d mCPBA, DCM, rt 16 h R1 NN He H N 50 R2 R2 s1 1. KOtBu, DMF, rt, 5 min R4 OH OV/ O 2. R3-N=C=S, rt, 5 min O S 3. NBS, rt, 5 min n R1 NH2 R3 55 R1 O R2 NaOH, MeOH, rflx., 1 d -- R1 O N DC YR3 R7 W ( N O O 60 R2 7\ R OH 1. KOtBu, DMF, rt,5 min / O 2. R5-N=C=S, rt, 5 min 3. NBS, rt, 5 min He NH2 W 65 R7CO O A ketone is reacted with morpholine to give the enamine. The latter is then treated with sulfamoyl chloride. The result US 8,901,114 B2 47 48 ing ketosulfonamide can be reduced with a Suitable reducing -continued agent, for example sodium borohydride, to give the hydrox F ySulfonamide. This forms diastereomers and, in the case of R3 cyclic ketones, cis/trans isomers, which can be separated Rs-NH, DCM from one another. The ratio of the diastereomers or cis/trans R1 s’ isomers depends on the nature of the R1 and R2 radicals and R2 -N on the choice of reducing agent. The treatment of the hydrox R4 ySulfonamide with base and an isothiocyanate, and Subse O O quent oxidative ring closure with NBS, gives the desired 10 Riv O 4,4-dioxooxathiazines. In the cases in which diastereomers or racemates form N during the synthesis, these can be separated from one another R2 s1 by preparative HPLC. Other examples again were obtained as indicated in the 15 following scheme: Chlorosulfonyl isocyanate is first reacted with 2-fluo rophenol to give the corresponding chlorosulfonyl carbam V / 2O 2-Fluorophenol, DCM, 1 h ate. The latter reacts in a 2+4 cycloaddition with an alkene to 1NN2S 2 C give the corresponding 2-(2-fluorophenoxy)-4,4-dioxothiaz R1 R2 ine. In the case of cyclic alkenes, exclusively the cis configu ration is obtained. The reaction with amines affords the O O 9 desired 4.4-dioxooxathiazines.

\/ ls -e-NaH, R3 R4 25 In the cases in which diastereomers or racemates form C1 NN O H during the synthesis, these can be separated from one another F by preparative HPLC. Revise from here onwards and delete examples with >Cs.

Reten- Molar tion 3.SS Example CHEMISTRY Method time (g/mol) Name

1 O O A. 1.244 286.4 Cyclohexyl-(1,1-dioxo-4a,5,6,7,8,8a hexahydro-1H-1 lambda6 \/ benzo14,3oxathiazin-3-yl)-amine OC -- H

2 C 4.648 286.4 (-)-Cyclohexyl-((4aR,8aS)-1,1-dioxo 4a,5,6,7,8,8a-hexahydro-1H-1 lambda6 benzo(14.3oxathiazin-3-yl)-amine *

3 C 6.145 286.4 (+)-Cyclohexyl-((4aS,8aR)-1,1-dioxo 4a,5,6,7,8,8a-hexahydro-1H-1 lambda6 benzo(14.3oxathiazin-3-yl)-amine *

5 B 9.494 326.5 ((4aR,8aS)-1,1-Dioxo-4a,5,6,7,8,8a hexahydro-1H-1 lambda6 benzo(14.3oxathiazin-3-yl)-(4-methyl bicyclo[2.2.2]oct-1-yl)-amine *

US 8,901,114 B2

-continued

Reten- Molar tion 8SS Example CHEMISTRY Method time (g/mol) Name Eluent; 0 min 93% H2O (0.05% TFA) - 1.2 min 95% acetonitrile - 1.4 min 95% acetonitrile - 1.45 min 7% acetonitrile (30°C., flow rate 1.1 ml/min) Method O Column: Mercury MS, Luna C18(2), S-3 um, 10 x 2.0 mm Eluent: 0 min 93% H2O (0.05%TFA) - 1.0 min 95% acetonitrile - 1.45 min 95% acetonitrile - 1.5 min 7% acetonitrile (30°C., flow rate 1.1 ml/min) Method P Column: Chiralpak IA 103 Eluent; heptane:ethanol:methanol 40:1:1 + 0.1% trifluoroacetic acid (30°C., flow rate 1 ml/min)

The efficacy of the compounds was tested as follows: TABLE 2-continued Enzymatic 11beta-HSD1 test: 15 To measure the activity of the compounds, an SPA-based Biological activity in nanomolar (nM) detection method (Solly et al. 2005) was employed. First of all, 2011 of the human 113-HSD1 microsome fraction (0.2 ug of protein), prepared in 50 mM HEPES, 0.1% BSA (w/v), ICso were applied to a plate with 384 wells. The test compounds Example (nM) (0.09 ul) were applied to the assay plate in 100% DMSO. The reaction was started by addition of 20 Jul of 1.2-H-cortisone 38 570 (0.1 uCi/100 mM) in assay buffer comprising 25 mM HEPES, 39 440 100 mM KC1, 5 mM NaCl, 2 mM MgCl, and 0.25 mM 41 497 47 16S NADPH. The plate was agitated at 37° C. for 1 hour. At the 25 same time, a stop solution comprising 20 mg/ml SPA-PVT 48 93 beads, 1.6 mg/ml monoclonal cortisol antibody and 0.01 mM 50 24 SSR110887 (inhibitor from the Biovitrium patent) in 50 mM 51 3OO HEPES, 1 MNaCl and 1 M KCl was stirred at room tempera 53 S4 ture. To stop the reaction, 25 ul of the stop solution were 30 S4 29 added to each well. The plate was agitated gently at room 55 670 temperature for 1 further hour and then centrifuged at 500g, 56 16 for 1 mM, in order that the SPA beads could settle out. The 57 40S plate was then read in a Wallac-1450-Microbeta unit with a 59 658 standard SPA program (counting time 1 min/well). The com 35 parative compound was glycyrrhetinic acid. 61 64 Protein and radioactive substrate were dispensed with a 62 43 Biomek FX unit (Beckman Coulter) for handling liquids. The 64 38 test compounds were added with a Cybi-Well equipped with 65 3O8 a 90 ml pin tool (CyBio). 40 66 148 Lit.: Solly S, Mundt SS, Zokian HJ, Juy-Fang Ding G, 68 23 Hermanowski-Vosatka A, Strulovici B and Zheng W. High 72 74 throughput Screening of 118-Hydroxysteroid dehydrogenase 73 13 type 1 in Scintillation proximity format. Assay Drug Dev 74 18 Technol 2005; 3:377-384. 45 75 11 TABLE 2 76 49 78 2 Biological activity in nanomolar (nM 8O 98 ICso 50 81 355 Example (nM) 82 9 83 18 1 31 2 575 84 779 3 24 86 655 5 8 55 9 5 87 197 10 104 88 234 13 5 89 49 14 236 2O 13 23 2O 24 215 60 25 121 It can be inferred from the test data that the compounds of 26 425 the formula I inhibit 11beta-HSD1 (11beta-hydroxysteroid 27 671 dehydrogenase type 1), and are thus of good Suitability for 28 22 29 275 treatment of hyperglycemia, insulin resistance, diabetes, obe 35 11 65 sity, lipid metabolism disorders, high blood pressure, cogni 36 59 tive improvement, elevated intraocular pressure, promotion of wound healing, and other diseases.

US 8,901,114 B2 75 76 1-Isopropyl-2-methyl-propylamine 5.00 g of 3-acetyloxazolidin-2-one were initially charged in 25 ml of carbon tetrachloride and heated to 70° C. under an argon atmosphere. Then, alternately, a solution of 3.46 ml of sulfuryl chloride in 5 ml of carbon tetrachloride and 0.10 g of 2,2'-azobis(2-methylpropionitrile) were added, and then the mixture was stirred at the same temperature for 2 hours. After N cooling to room temperature, the clear Solution was decanted off from the solid residues, and the solvent was removed under reduced pressure. This gave the product (6.80 g) with a 2,4-Dimethyl-3-pentanone (5 g) and titanium(IV) isopro 10 poxide (24 g) were stirred in 7 N methanolic ammonia solu molecular weight of 163.6 g/mol (CHCINO). tion (30 ml) at room temperature for 5 hours. Sodium boro 3-Acetyl-3H-oxazol-2-one hydride (2.5 g) was added while cooling the solution, and the mixture was stirred at room temperature for a further 2 hours. Subsequently, 10 N ammonium hydroxide solution (5 ml) 15 was added, the mixture was filtered, and then 2 N hydrochlo ric acid (pH~2) was added to the solution. The solution was washed with ethyl acetate and then concentrated to dryness. This gave the hydrochloride of the product with a molecular weight of 115.2 g/mol (CHN), MS (ESI): m/e=116 (M+H+) 6.80 g of 3-acetyl-5-chlorooxazolidin-2-one were distilled 4-Pentylbicyclo[2.2.2]oct-1-ylamine in a Kugelrohr distillation under reduced pressure (50 mbar) at a temperature of 180°C. This gave the product (3.80g) with 25 a molecular weight of 127.1 g/mol (CHNO). 5-Acetyl-10-spirocyclopropyl-3-oxa-5-azatricyclo HN 5 .2.1 0<2,6>dec-8-en-4-one

30 1.00 g of 4-pentylbicyclo[2.2.2]octane-1-carboxylic acid was dissolved in a mixture of 20 ml of toluen and 0.81 ml of N,N-diisopropylamine under an argon atmosphere, and then 1.06 ml of diphenylphosphoryl azide were added dropwise. After stirring at 100° C. for 2 hours and cooling to room 35 temperature, the solvent was removed under reduced pres s Sure. The residue was taken up in dichloromethane and washed with 5% aqueous citric acid and Saturated aqueous Sodium hydrogencarbonate Solution, the organic phase was > dried and the solvent was removed under reduced pressure. 40 The crude product was purified by means of normal phase A vial containing 3.00 g of 3-acetyl-3H-oxazol-2-one and chromatography using a Flashmaster with an n-heptane/ethyl 2.89 ml of spiro[2.4]hepta-4,6-diene in 6 ml of 1,2-dichloro acetate gradient. The product-containing fractions were com ethane was closed with a Teflon septum and stirred at 200° C. bined and concentrated by rotary evaporation. This gave the in a microwave (Emrys Optimizer, Personal Chemistry) for product (406 mg) with a molecular weight of 221.4 g/mol 45 90 minutes. Subsequently, the solvent was removed under (CHNO). reduced pressure and the residue was purified twice by means 390 mg of 1-isocyanato-4-pentylbicyclo[2.2.2]octane of normal phase chromatography using a Flashmaster with an were suspended in 10 ml of aqueous 6 N hydrochloric acid n-heptane/ethyl acetate gradient. The product-containing and stirred at 100° C. over the course of 16 h. After cooling to fractions were combined and concentrated by rotary evapo room temperature, the precipitate was filtered off with suction 50 ration. This gave the product (3.27 g) with a molecular weight and then dried by coevaporation with toluene under reduced of 219.2 g/mol (CHNO); MS (ESI): m/e=220 (M+H+). pressure. The product (305 mg) with a molecular weight of 195.4 g/mol (CHN); MS (ESI); m/e=196 (M+H+) was 5-Acetyl-10-spirocyclopropyl-3-oxa-5-azatricyclo obtained in the form of a hydrochloride salt. 55 5.2.1.0<2,6>decan-4-one 3-Acetyl-5-chlorooxazolidin-2-one

60

65 US 8,901,114 B2 77 78 1.50 g of 5-acetyl-10-spirocyclopropyl-3-oxa-5-azatricy 3-Amino-7,7-dimethylcyclopropylbicyclo[2.2.1 cloS.2.1.0<2,6>dec-8-en-4-one were dissolved in 30 ml of heptan-2-ol ethanol and, with addition of 0.15g of 5% Pd/C, stirred under a gauge hydrogen pressure of 0.5 bar for 1 hour. After filtra tion to remove the solid residues, the filtrate was freed of the 5 Solvent under reduced pressure. This gave the product (1.47 g) with a molecular weight of 221.3 g/mol (CHNO); MS (ESI): m/e=222 (M--H+). 10 3-Amino-7-spiro-cyclopropylbicyclo2.2.1]heptan-2- O ol N In a microwave vial. 2.04 g of potassium hydroxide were 15 dissolved in 4 ml of water, and a solution of 1.62g of 5-acetyl 10, 10-dimethyl-3-oxa-5-azatricyclo[5.2.1.0*2.6*decan-4- one in 2ml of ethanol was added. After closure of the vial with a Teflon septum, the reaction mixture was stirred at 120°C. in a microwave (Emrys Optimizer, Personal Chemistry) for 90 minutes. Subsequently, the solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The aqueous phase was washed twice with 50 ml of ethyl acetate and the combined organic phases In a microwave vial, 1.86 g of potassium hydroxide were 25 were dried with sodium sulfate and the solvent was removed dissolved in 4 ml of water, and a solution of 1.47 g of 5-acetyl under reduced pressure. 10-spirocyclopropyl-3-oxa-5-azatricyclo5.2.1.0<2.6>de This gave the product (920 mg) with a molecular weight of can-4-one in 2 ml of ethanol was added. After closure of the 155.2 g/mol (CHNO); MS (ESI); m/e=156 (M+H+). vial with a Teflon septum, the reaction mixture was stirred at 30 Adamantan-1-ylhydrazine 120° C. in a microwave (Emrys Optimizer, Personal Chem istry) for 90 minutes. Subsequently, the solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The aqueous phase was washed twice with 50 ml of ethyl acetate and the combined 35 organic phases were dried with sodium Sulfate and the solvent was removed under reduced pressure. This gave the product (930 mg) with a molecular weight of 153.2 g/mol (CHNO); MS (ESI): m/e=154 (M+H+). 40

5-Acetyl-10,10-dimethyl-3-oxa-5-azatricyclo Helvetica Chimica Acta 1967, 50(7), 2008-2010 5.2.1.0*2.6* decan-4-one 45 Amino-p-carborane

50

55 Inorganic Chemistry 1999, 38(12), 2936-2940 Sulfamoyl chloride 1.75 g of 5-acetyl-10-spiro-cyclopropyl-3-oxa-5-azatricy 60 cloS.2.1.0<2,6>decan-4-one were dissolved in 20 ml of glacial acetic acid and, with addition of 0.33 g of platinum O O dioxide, stirred under a gauge hydrogen pressure of 0.5 bar V/ for 16 hours. After filtration to remove the solid residues, the HN1 S Nc filtrate was freed of the solvent under reduced pressure. This 65 gave the product (1.62 g) with a molecular weight of 223.3 g/mol (CH7NO.); MS (ESI): m/e=224 (M+H+). Journal of the American Chemical Society 1962, 94, 1994 US 8,901,114 B2 79 80 N-Sulfinyl-4-toluamide product (128 mg) with a molecular weight of 307.4 g/mol (CHNOS); MS (ESI): m/e=308 (M+H+) 2-Hydroxy-1,2-dimethylcyclohexanesulfonamide

10 N 10g of p-toluamide were suspended in 100 ml of ether and 12.5 ml of pyridine under argon. The 5.8 ml of thionyl chlo ride dissolved in 10 ml of ether were added dropwise at 5°C. and the mixture was stirred for a further 5 minutes. Subse 15 137 mg of 4a.8a-dimethyl-3-p-tolyl-4-a,5,6,7,8,8a quently, the cooling was removed and the mixture was stirred hexahydrobenzo. 14.3oxathiazine 1,1-dioxide were dis at room temperature for a further 16 hours. Under argon, the solved in methanol, 1.5 ml of 6 N NaOH were added and the solid pyridinium hydrochloride was then filtered off, and then mixture was boiled overnight. After cooling, the mixture was the solution was concentrated. The residue was used without acidified with concentrated hydrochloric acid and the metha further workup. nol was evaporated off under reduced pressure. The residue 4a.8a-Dimethyl-3-p-tolyl-4-a,5,6,7,8,8a-hexahy was then admixed with 10 ml of water and extracted twice with 10 ml of n-butanol. The n-butanol was evaporated under drobenzo. 14.3oxathiazine 1-oxide reduced pressure and the residue (96 mg) was used without 25 further workup. 4-(3,6-Dihydro-2H-pyran-4-yl)morpholine

30

s1 N

O 35 The 3.17 g of N-sulfinyl-4-toluamide were dissolved in 20 ml of dry dichloromethane, and 3.85g of 1,2-dimethylcyclo 650 mg of tetrahydro-4H-pyran-4-one together with 950 hexene were slowly added dropwise at 5° C. After 16 hours, mg of morpholine were dissolved in 10 ml of toluene and the the mixture was concentrated under reduced pressure and 40 mixture was heated under reflux in a light water separator for chromatographed using silica gel. This gave the product (1.57 5 hours. Subsequently, the mixture was concentrated under g) with a molecular weight of 291.4 g/mol (CHNOS); reduced pressure, and residue (1.3 g) was used further without MS (ESI): m/e=292 (M+H+) further workup. 4a.8a-Dimethyl-3-p-tolyl-4-a,5,6,7,8,8a-hexahy 45 4-Oxotetrahydropyran-3-sulfonamide drobenzo 1.4.3oxathiazine 1,1-dioxide

50 O -NH2

N 55 1.3 g of 4-(3,6-dihydro-2H-pyran-4-yl)morpholine were dissolved under argon in 12 ml of THF, the mixture was cooled to -40°C., and then 1.3 g of sulfamoyl chloride were 228 mg of 4a,8a-dimethyl-3-p-tolyl-4-a,5,6,7,8,8a added, followed by 6 ml of diisopropylamine. The cooling hexahydrobenzo. 14.3oxathiazine 1-oxide were dissolved in 60 was removed and, after the mixture had come to room tem 4 ml of dichloromethane, and 190 mg of m-chloroperbenzoic perature, it was stirred for another 2 hours. An oil separated acid were added at 5° C. and the mixture was stirred for 16 out. The THF was decanted off, and the residue was taken up hours. The m-chlorobenzoic acid formed was filtered off and in methanol and filtered through silica gel. The filtrate was the filtrate was washed twice with 0.1 N aqueous NaOH concentrated under reduced pressure and the residue, bound solution and once with saturated NaCl solution, dried with 65 to 12g of Celite, was purified by means of a silica gel column sodium sulfate, filtered and concentrated. The residue was (50 g): solvent A: dichloromethane, B: methanol, gradient:0 recrystallized from n-pentane/diethyl, ether. This gave the min 2% B, 3 min 2% B, 5 min 5% B, 35 min 10% B, 45 min US 8,901,114 B2 81 82 10% B; flow rate 20 ml/min: detection: 220 nm, fraction size: 20 ml. After removal of the solvent under reduced pressure, the product was thus obtained with impurities. The residue (1.09 g) was used further without further workup. 4-Hydroxytetrahydropyran-3-sulfonamide Cro /V O O

OH 10 Cyclohexyl-(1,1-dioxo-4-a,5,6,7,8,8a-hexahydro-1H 1 lambda 6-benzo 1.4.3oxathiazin-3-yl)amine O -NH2

15 1.09 g of 4-oxotetrahydropyran-3-sulfonamide were dis solved in THF, 0.23g of sodium borohydride was added and CrO the mixture was stirred at room temperature for 18 hours. The mixture was then adjusted to pH-2 with hydrochloric acid and concentrated under reduced pressure. The residue, bound to 8 g of Celite, was purified by means of a silica gel column The trans-cyclohexyl-(1,1-dioxo-5,6,8.8a-tetrahydro-1H, (50 g): solvent A: dichloromethane, B: methanol, gradient:0 4aH-4,7-dioxa-1 lambda 6*-thia-2-azanaphthalen-3-yl) min 3% B, 3 min 3% B, 5 min 5% B, 35 min 10% B, 44 min amines were obtained by separation on a chiral column (see 10% B; flow rate 20 ml/min: detection: 220 nm, fraction size: 25 table 1). 20 ml. After removal of the solvent under reduced pressure, the product was thus obtained with impurities. The residue Cyclohexyl-(7,7-difluoro-1,1-dioxo-4-a,5,6,7,8,8a (615 mg) was used further without further workup. hexahydro-1H-1 lambda 6*-benzo 1.4.3oxathiazin Cyclohexyl-(4a,8a-dimethyl-1,1-dioxo-4-a,5,6,7,8, 30 3-yl)amine 8a-hexahydro-1H-1 lambda6-benzo. 14.3oxathiazin 3-yl)amine

35 O N CrO s1r / \, 40 90 mg of 2-hydroxy-1,2-dimethylcyclohexanesulfona 3-(2-Fluorophenoxy)-4-a-methyl-4-a,5,6,7,8,8a hexahydrobenzo. 14.3oxathiazine 1,1-dioxide mide were suspended in DMF and then treated with 54 mg of 45 potassium tert-butoxide in an ultrasound bath for 5 minutes. Then 67 mg of cyclohexyl isothiocyanate were added. After stirring for 3 minutes, 68 mg of N-bromosuccinimide were then added and the mixture was stirred for a further 5 minutes. The solution was then concentrated under reduced pressure and purified by preparative HPLC. This gave the product (3.4 50 mg) with a molecular weight of 314.4 g/mol; MS (ESI) m/e=315 (M+H+). CO MV The following products were prepared in the same way: O O trans-Cyclohexyl-(1,1-dioxo-5,6,8.8a-tetrahydro-1H4aH-4, 7-dioxa-1 lambda 6*-thia-2-azanaphthalen-3-yl)amine 55 6.42g of chlorosulfonyl isocyanate were dissolved in 65 ml of methylene chloride, and 6.7 g of 2-fluorophenol were added at room temperature. After 1 hour, the mixture was 60 concentrated under reduced pressure, and the residue was dissolved in 30 ml of THF and cooled to -78° C. 1.95g of 60% sodium hydride were added to this solution and the CrO cooling was removed. Subsequently, the mixture was heated gradually to 35° C. and then 1-methyl-1-cyclohexene was 65 added. The mixture was stirred at 35° C. for another 2 hours cis-Cyclohexyl-(1,1-dioxo-5,6,8.8a-tetrahydro-1H4aH-4,7- and then poured onto 100g of ice. The mixture was extracted dioxa-1 lambda 6*-thia-2-azanaphthalen-3-yl)amine with ethyl acetate, dried with sodium sulfate, filtered and

US 8,901,114 B2 85 86 a heterocycle selected from the group of carborane, the sodium-dependent glucose transporter 1 or 2, GPR40 thiophene, tetrahydropyran, piperidine, thiochromane, modulators, inhibitors of hormone-sensitive lipase, inhibitors hexahydrocyclopentacpyrrole, azepane and 2,3,4,5,6, of acetyl-CoA carboxylase, inhibitors of phosphoenolpyru 7,8,9,10,11-decaborabicyclo8.1.1 dodecane, vate carboxykinase, inhibitors of glycogen synthase kinase-3 where the heterocycle radical may be mono- to trisub beta, inhibitors of protein kinase C beta, endothelin-A recep stituted by F, Cl, Br, I, OH, -(C-C)-alkylene-OH, tor antagonists, inhibitors of IkappaB kinase, modulators of CF, NO, CN, OCF, (C-C)-alkyl, CONH, the glucocorticoid receptor, CART agonists, NPY agonists, CONHCC-C)-alkyl, CONC(C-C)-alkyl); MC4 agonists, orexin agonists, H3 agonists, TNF agonists, R2, R3 are each independently H, (C-C)-alkyl; CRF agonists, CRF BP antagonists, urocortin agonists, B3 R5, R6 are each independently H, (C-C)-alkyl: 10 and pharmaceutically acceptable salts thereof. agonists, CB1 receptor antagonists, MSH (melanocyte 4. A pharmaceutical composition comprising the com stimulating hormone) agonists, CCK agonists, serotonin pound of claim 1, or pharmaceutically acceptable salts reuptake inhibitors, mixed serotoninergic and noradrenergic thereof, and a pharmaceutically acceptable carrier and/or compounds, 5HT agonists, bombesin agonists, galanin excipient. 15 antagonists, growth hormones, growth hormone-releasing 5. The pharmaceutical composition of claim 4, further compounds, TRH agonists, decoupling protein 2 or 3 modu comprising at least one further active ingredient. lators, leptin agonists, DA agonists, lipase/amylase inhibi 6. The pharmaceutical composition of claim 5, wherein tors, PPAR modulators, RXR modulators or TRB agonists or said active ingredient is one or more antidiabetics, active amphetamines. hypoglycemic ingredients, HMG-CoA reductase inhibitors, 7. A process for preparing a pharmaceutical composition cholesterol absorption inhibitors, PPARgamma agonists, comprising mixing the compound of claim 1 with a pharma PPAR alpha agonists, PPAR alpha/gamma agonists, PPAR ceutically suitable carrier and converting said mixture to a form suitable for administration. delta agonists, fibrates, MTP inhibitors, bile acid absorption 8. A method of treating hyperglycemia comprising admin inhibitors, CETP inhibitors, polymeric bile acid adsorbers, istering to a patient in need thereofatherapeutically effective LDL receptor inducers, ACAT inhibitors, antioxidants, lipo 25 protein lipase inhibitors, ATP citrate lyase inhibitors, amount of the pharmaceutical composition of claim 4. squalene synthetase inhibitors, lipoprotein(a) antagonists, 9. A method of treating diabetes comprising administering HM74A receptor agonists, lipase inhibitors, insulins, sulfo to a patient in need thereofatherapeutically effective amount nylureas, biguanides, meglitinides, thiazolidinediones, of the pharmaceutical composition of claim 4. C-glucosidase inhibitors, active ingredients which act on the 30 10. A method of treating insulin resistance comprising ATP-dependent potassium channel of the beta cells, glycogen administering to a patient in need thereof a therapeutically phosphorylase inhibitors, glucagon receptor antagonists, effective amount of the pharmaceutical composition of claim activators of glucokinase, inhibitors of gluconeogenesis, 4. inhibitors of fructose 1,6-biphosphatase, modulators of glu 11. A kit consisting of separate packages of cose transporter 4, inhibitors of glutamine-fructose-6-phos 35 a) an effective amount the compound of claim 1 and phate amidotransferase, inhibitors of dipeptidylpeptidase IV. b) an effective amount of a further active medicament inhibitors of 11-beta-hydroxysteroid dehydrogenase 1, ingredient. inhibitors of protein tyrosine phosphatase 1B, modulators of