Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
  • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
  • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics

Definitions

• the invention relates to the crystalline hydrates of a substituted diphenylazetidinone
• Amorphous diphenylazetidinones are already described in US Pat. No. 7,205,290. At this time, no hydrates of these diphenylazetidinones were known.
• n has a value of 0.5 to 1.8.
• n has a value of from 1.0 to 1.2.
• Crystalline agents are usually more stable than amorphous ones. This avoids problems with the degradation of the active ingredients and the breakdown products that occur.
• the amorphous form of a Wirkstoifs may still contain an undesirable content of solvents. These are usually difficult to remove because they can not be recrystallized.
• the amorphous form is more energetic than the crystalline form. This can lead to the random pattern of the molecular distribution of the amorphous form spontaneously rearranging with energy release and dissipating part of the energy. This can lead to a change in the effect of
• a further embodiment of the invention comprises crystalline hydrate of the formula I, characterized in that the XRPD measured with CuK ⁇ radiation has a main peak of 20.83 degrees 2 theta ⁇ 0.2 degrees 2 theta.
• a further embodiment of the invention comprises crystalline hydrate of the formula I, characterized characterized in that the XRPD measured with CuK ⁇ radiation has at least peaks of the following 2 theta values: 20.83 and 21.58 ⁇ 0.2 degrees 2 theta.
• a further embodiment of the invention comprises crystalline hydrate of the formula I, characterized in that the XRPD measured with CuK ⁇ radiation has at least peaks of the following 2 theta values: 12.19, 20.83 and 21.58 ⁇ 0.2 degrees 2 theta.
• a further embodiment of the invention comprises crystalline hydrate of the formula I, characterized in that the XRPD measured with CuK ⁇ radiation has at least peaks of the following 2 theta values: 20.43, 20.83, 21.58 ⁇ 0.2 degrees 2 theta.
• a further embodiment of the invention comprises crystalline hydrate of the formula I, characterized in that the XRPD measured with CuK ⁇ radiation has at least peaks of the following 2 theta values: 12.19, 17.31, 20.43, 20.83, 21.58 ⁇ 0.2 degrees 2 theta.
• a further embodiment of the invention comprises crystalline hydrate of the formula I, characterized in that the XRPD measured with CuK ⁇ radiation has at least peaks of the following 2 theta values: 7.33, 12.19, 16.05, 17.31, 20.83, 21.58 ⁇ 0.2 degrees 2 theta.
• a further embodiment of the invention comprises crystalline hydrate of the formula I, characterized in that the XRPD measured with CuK ⁇ radiation has at least peaks of the following 2 theta values:
• the amount of a compound of Formula I required to achieve the desired biological effect is dependent upon a number of factors, eg, the specific compound chosen, the intended use, the mode of administration, and the clinical condition of the patient. Generally, the daily dose ranges from 0.01 mg to 100 mg (typically 0.05 mg and 50 mg) per day per kilogram of body weight, eg, 0.05-10 mg / kg / day.
• Orally administrable unit dose formulations such as tablets or capsules, may contain, for example, from 1.0 to 1000 mg, more typically from 5 to 600 mg.
• the compounds according to formula I can themselves be used as compound, but they are preferably present with a compatible carrier in the form of a pharmaceutical composition.
• the carrier must of course be compatible in the sense that it is compatible with the other ingredients of the composition and is not harmful to the patient.
• the carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as a single dose, for example, as a tablet, which may contain from 0.05% to 95% by weight of the active ingredient.
• Other pharmaceutically active substances may also be present, including further compounds according to formula L.
• the pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods, which consist essentially in that the ingredients are mixed with pharmacologically acceptable carriers and / or excipients.
• compositions according to the invention are those which are suitable for oral and peroral (e.g., sublingual) administration, although the most suitable mode of administration in each individual case will depend on the nature and severity of the condition to be treated and on the nature of the particular compound of formula I used.
• coated formulations and coated slow release formulations are within the scope of the invention. Possible are acid and enteric formulations. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate,
• Hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and Methacrylate are examples of hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and Methacrylate.
• Suitable pharmaceutical compounds for oral administration may be in separate units, such as capsules, cachets, lozenges or tablets, each containing a certain amount of the compound of formula I; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
• these compositions may be prepared by any suitable pharmaceutical method comprising a step of contacting the active ingredient and the carrier (which may consist of one or more additional ingredients).
• the compositions are prepared by uniformly and homogeneously mixing the active ingredient with a liquid and / or finely divided solid carrier, after which the product is molded, if necessary.
• a tablet can be made by compressing or molding a powder or granules of the compound, optionally with one or more additional ingredients.
• Compressed tablets can be prepared by tableting the compound in free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent and / or surfactant / dispersant in a suitable machine.
• Molded tablets can be prepared by shaping the powdered compound moistened with an inert liquid diluent in a suitable machine.
• compositions suitable for peroral (sublingual) administration include lozenges containing a compound of formula I with a flavor, usually sucrose and gum arabic or tragacanth, and lozenges containing the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.
• the compound (s) of the formula (I) according to the invention can also be administered in combination with other active substances.
• Other active substances for the combined preparations are: All antidiabetics mentioned in the Red List 2007, Chapter 12; all weight loss / appetite suppressants listed in the Red List 2007, Chapter 1; all diuretics mentioned in the Red List 2007, chapter 36; all lipid lowering drugs mentioned in the Red List 2007, chapter 58. They can be combined with the compound of the formula I according to the invention in particular for the synergistic effect improvement.
• the administration of the active ingredient combination can be carried out either by separate administration of the active ingredients to the patient or in the form of combination preparations in which several active ingredients are present in a pharmaceutical preparation. If the administration of the active ingredients by separate administration of the active ingredients, so this can be done simultaneously or sequentially.
• Most of the drugs listed below are disclosed in the USP Dictionary of US and International Drug Names, US Pharmacopeia, Rockville, 2006.
• Antidiabetics include insulin and insulin derivatives, such as Lantus ® (see www.lantus.com) or HMR 1964 or Levemir® (insulin detemir), Humalog ⁇ (Lispro Insulin) Humulin ⁇ , VIAject TM, SuliXen ⁇ or those described in WO2005005477 (Novo Nordisk), fast-acting insulins (see US 6,221,633), inhalable insulins such.
• B. Exubera ®, Nasulin TM, or oral insulins such.
• GLP-I derivatives and GLP-I agonists such as exenatides or special preparations thereof, as described, for example, in WO2008061355, liraglutides, taspoglutides or those described in WO 98/08871, WO2005027978, WO2006037811, WO2006037810 by Novo Nordisk A / S, in WO 01/04156 of Zealand or in WO 00/34331 of Beaufour-Ipsen, Pramlintide acetate (Symlin; Amylin Pharmaceuticals), AVE-0010, BIM-51077 (R-1583, ITM-077), PC-DAC: Exendin-4 (an exendin-4 analogue covalently linked to recombinant human albumin), CVX-73, CVX-98 and CVx-96 (GLP-I analogs covalently linked to a monoclonal antibody, the specific binding sites for having GLP-I peptide), CNTO-736 (a GLP
• Antidiabetic agents also include agonists of the glucose-dependent insulinotropic polypeptide (GEP) receptor as described e.g. in WO2006121860 are described.
• GEP glucose-dependent insulinotropic polypeptide
• Antidiabetics also include the glucose-dependent insulinotropic polypeptide (GIP) as well as analogous compounds as described e.g. in WO2008021560 are described.
• GIP glucose-dependent insulinotropic polypeptide
• Antidiabetics also include analogs and derivatives of fibroblast growth factor 21 (FGF-21, fibroblast growth factor 21).
• the orally active hypoglycemic agents preferably comprise sulfonylureas
• Glucokinase activators inhibitors of fructose 1, 6-bisphosphatase
• Glucose Transporter 4 Modulators GLUT4
• Inhibitors of glutamine-fructose 6-phosphate amidotransferase GFAT
• Potassium channel opener such as Pinacidil, cromakalim, diazoxide or those as described by R. D.
• DPP-IV dipeptidyl peptidase-IV
• insulin sensitizer insulin sensitizer
• Modulators of sodium-dependent glucose transporters 1 or 2 (SGLT1, SGLT2), inhibitors of 11-beta-hydroxysteroid dehydrogenase-1 (11 ⁇ -HSD 1),
• PTP-IB protein tyrosine phosphatase IB
• Nicotinic receptor agonists
• Inhibitors of acetyl-CoA carboxylase ACCl and / or ACC2
• Inhibitors of GSK-3 beta ACCl and / or ACC2
• lipid metabolism-altering compounds such as antihyperlipidemic agents and antilipidemic agents.
• FXR Farnesoid X Receptor
• MTP inhibitors agonists of the estrogen receptor gamma (ERRD agonists)
• Sigma-1 receptor antagonists Antagonists of the somatostatin 5 receptor (SST5 receptor); Compounds that reduce food intake and compounds that increase thermogenesis.
• the compound of the formula I is administered in combination with insulin.
• the compound of the formula I is administered in combination with an active ingredient which acts on the ATP-dependent potassium channel of the beta cells, e.g. Sulfonylureas, e.g. Tolbutamide, glibenclamide, glipizide, gliclazide or glimepiride.
• an active ingredient which acts on the ATP-dependent potassium channel of the beta cells, e.g. Sulfonylureas, e.g. Tolbutamide, glibenclamide, glipizide, gliclazide or glimepiride.
• the compound of formula I is administered in combination with a tablet containing both glimepride which is rapidly released and contains metformin which is released over a prolonged period of time (as described, for example, in US2007264331, WO2008050987).
• the compound of formula I is used in combination with a biguanide, e.g. Metformin, administered.
• a biguanide e.g. Metformin
• the compound of formula I is used in combination with a meglitinide, e.g. Repaglinide, nateglinide or mitiglinide administered.
• a meglitinide e.g. Repaglinide, nateglinide or mitiglinide administered.
• the compound of formula I is combined with a combination of mitiglinides with a glitazone, e.g. Pioglitazone hydrochloride, administered.
• a glitazone e.g. Pioglitazone hydrochloride
• the compound of the formula I is administered with a combination of mitiglinides with an alpha-glucosidase inhibitor.
• the compound of the formula I is administered in combination with antidiabetic compounds, as described in WO2007095462, WO2007101060, WO2007105650. In a further embodiment, the compound of the formula I is administered in combination with antihypoglycemic compounds, as described in WO2007137008.
• the compound of formula I is used in combination with a thiazolidinedione, e.g. Troglitazone, ciglitazone, pioglitazone, rosiglitazone or those described in WO 97/41097 by Dr. med. Reddy's Research Foundation disclosed compounds, particularly 5 - [[4- [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinyhnethoxy) phenyl] methyl] -2,4-thiazolidinedione.
• a thiazolidinedione e.g. Troglitazone, ciglitazone, pioglitazone, rosiglitazone or those described in WO 97/41097 by Dr. med. Reddy's Research Foundation disclosed compounds, particularly 5 - [[4- [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinyhnethoxy) phenyl] methyl]
• the compound of formula I is used in combination with a PPAR gamma agonist, e.g. Rosiglitazone, pioglitazone, JTT-501, Gl 262570, R-483, CS-Ol 1 (rivoglitazone), DRL-17564, DRF-2593 (balaglitazone), INT-131, T-2384 or those as described in WO2005086904, WO2007060992 , WO2007100027, WO2007103252, WO2007122970, WO2007138485, WO2008006319, WO2008006969, WO2008010238, WO2008017398, WO2008028188.
• a PPAR gamma agonist e.g. Rosiglitazone, pioglitazone, JTT-501, Gl 262570, R-483, CS-Ol 1 (rivoglitazone), DRL-17564, DRF-2593 (balaglitazone), INT
• the compound of the formula I is administered in combination with Competact TM, a solid combination of pioglitazone hydrochloride with metformin hydrochloride.
• the compound of formula I is administered in combination with Tandemact TM, a solid combination of pioglitazone with glimepride.
• the compound of formula I in combination with a solid combination of pioglitazone hydrochloride with an angiotensin II agonist, e.g. TAK-536 administered.
• the compound of the formula I is administered in combination with a PPAR alpha agonist or mixed PPAR alpha / PPAR delta agonists, such as GW9578, GW-590735, K-111, LY-674, KRP-101, DRF 10945, LY-518674, CP-900691, BMS-687453, BMS-711939 or those as described in WO2001040207, WO2002096894, WO2005097076, WO2007056771, WO2007087448, WO2007089667, WO2007089557, WO2007102515, WO2007103252, JP2007246474, WO2007118963, WO2007118964, WO2007126043, WO2008006043, WO2008006044, WO2008012470, WO2008035359.
• a PPAR alpha agonist or mixed PPAR alpha / PPAR delta agonists such as GW9578, GW-5907
• the compound of formula I is used in combination with a mixed PPAR alpha / gamma agonist, e.g. Naveglitazar, LY-510929, ONO-5129, E-3030, AVE 8042, AVE 8134, AVE 0847, CKD-501 (Lobeglitazone Sulfate), MBX-213, KY-201 or as in WO 00/64888, WO 00/64876 , WO03 / 020269,
• a mixed PPAR alpha / gamma agonist e.g. Naveglitazar, LY-510929, ONO-5129, E-3030, AVE 8042, AVE 8134, AVE 0847, CKD-501 (Lobeglitazone Sulfate), MBX-213, KY-201 or as in WO 00/64888, WO 00/64876 , WO03 / 020269,
• the compound of formula I is used in combination with a PPAR delta agonist, e.g. GW-501516 or as described in WO2006059744, WO2006084176, WO2006029699, WO2007039172-WO2007039178, WO2007071766, WO2007101864, US2007244094, WO2007119887, WO2007141423, US2008004281, WO2008016175.
• a PPAR delta agonist e.g. GW-501516 or as described in WO2006059744, WO2006084176, WO2006029699, WO2007039172-WO2007039178, WO2007071766, WO2007101864, US2007244094, WO2007119887, WO2007141423, US2008004281, WO2008016175.
• the compound of the formula I is used in combination with a pan-SPPARM (selective PPAR modulator alpha, gamma, delta), such as e.g. GFT-505 or those as described in WO2008035359 administered.
• a pan-SPPARM selective PPAR modulator alpha, gamma, delta
• the compound of the formula I is administered in combination with metaglidases or with MBX-2044 or other partial PPAR gamma agonists / antagonists.
• the compound of the formula I is used in combination with an ⁇ -glucosidase inhibitor, such as, for example, miglitol or acarbose or those, as described, for example, in US Pat WO2007114532, WO2007140230, US2007287674, US2008103201.
• an ⁇ -glucosidase inhibitor such as, for example, miglitol or acarbose or those, as described, for example, in US Pat WO2007114532, WO2007140230, US2007287674, US2008103201.
• the compound of formula I is used in combination with a glycogen phosphorylase inhibitor, e.g. PSN-357 or FR-258900 or those as described in WO2003084922, WO2004007455, WO2005073229-31, WO2005067932.
• a glycogen phosphorylase inhibitor e.g. PSN-357 or FR-258900 or those as described in WO2003084922, WO2004007455, WO2005073229-31, WO2005067932.
• the compound of formula I is used in combination with glucagon receptor antagonists, such as e.g. A-770077 or NNC-25-2504 or as described in WO2004100875, WO2005065680, WO2006086488, WO2007047177, WO2007106181, WO2007111864, WO2007120270, WO2007120284, WO2007123581, WO2007136577, WO2008042223.
• glucagon receptor antagonists such as e.g. A-770077 or NNC-25-2504 or as described in WO2004100875, WO2005065680, WO2006086488, WO2007047177, WO2007106181, WO2007111864, WO2007120270, WO2007120284, WO2007123581, WO2007136577, WO2008042223.
• the compound of formula I is used in combination with an antisense compound, e.g. ISIS-325568, which inhibits the production of the glucagon receptor.
• an antisense compound e.g. ISIS-325568
• the compound of the formula I in combination with activators of glucokinase such as. LY-2121260 (WO2004063179), PSN-105, PSN-110, GKA-50, or those as described e.g. In WO2004072031, WO2004072066, WO2005080360, WO2005044801, WO2006016194, WO2006058923, WO2006112549, WO2006125972, WO2007017549,
• WO2007017649 WO2007007910, WO2007007040-42, WO2007006760-61, WO2007006814, WO2007007886, WO2007028135, WO2007031739, WO2007041365, WO2007041366, WO2007037534, WO2007043638, WO2007053345, WO2007051846, WO2007051845, WO2007053765, WO2007051847, WO2007061923, WO2007075847, WO2007089512, WO2007104034, WO2007117381, WO2007122482, WO2007125103, WO2007125105, US2007281942, WO2008005914, WO2008005964, WO2008043701, WO2008044777, WO2008047821, US2008096877, WO2008050101, WO2008059625.
• the compound of the formula I is used in combination with inhibitors of fructose-l, 6-bisphosphatase (FBPase), e.g. MB-07729, CS-917 (MB-06322) or MB-07803 or those as described in WO2006023515, WO2006104030, WO2007014619, WO2007137962, WO2008019309, WO2008037628.
• FBPase 6-bisphosphatase
• the compound of the formula I in combination with modulators of the glucose transporter-4 (GLUT4), such as. KST-48 (D.O. Lee et al .: Arzneim.-Forsch.drug Res. 54 (12), 835 (2004)).
• the compound of the formula I in combination with inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT), as z. As described in WO2004101528 administered.
• GFAT glutamine-fructose-6-phosphate amidotransferase
• the compound of the formula I in combination with inhibitors of dipeptidyl peptidase-rv in combination with inhibitors of dipeptidyl peptidase-rv (DPP-IV), such as. Vildagliptin (LAF-237), sitagliptin (MK-0431), sitagliptin phosphate, saxagliptin ((BMS-477118), GSK-823093, PSN-9301, SYR-322, SYR-619, TA-6666, TS-021 , GRC-8200 (melogliptin), GW-825964X, KRP-104, DP-893, ABT-341, ABT-279 or other salt thereof, S-40010, S-40755, PF-00734200, BI-1356, PHX -1149, Alogliptin or such compounds as described in WO2003074500, WO2003106456, WO2004037169, WO200450658, WO2005037828,
• the compound of formula I is administered in combination with Janumet TM, a solid combination of sitagliptin phosphate with metformin hydrochloride.
• the compound of formula I is administered in combination with Eucreas®, a solid combination of vildagliptin with metformin hydrochloride.
• the compound of formula I is administered in combination with a solid combination of a salt of sitagliptin with metformin hydrochloride.
• the compound of the formula I is used in combination with a
• the compound of formula I in combination with an insulin secretion enhancing substance, such as. KCP-265 (WO2003097064) or those as described in WO2007026761, WO2008045484.
• an insulin secretion enhancing substance such as. KCP-265 (WO2003097064) or those as described in WO2007026761, WO2008045484.
• the compound of the formula I in combination with agonists of the glucose-dependent insulinotropic receptor (GDIR) such.
• GDIR glucose-dependent insulinotropic receptor
• the compound of formula I is used in combination with an ATP citrate lyase inhibitor, e.g. SB-204990 administered.
• an ATP citrate lyase inhibitor e.g. SB-204990 administered.
• the compound of the formula I is used in combination with modulators of the sodium-dependent glucose transporter 1 or 2 (SGLT1, SGLT2), such as, for example, KGA-2727, T-1095, SGL-0010, AVE 2268, SAR 7226, SGL-5083 , SGL-5085, SGL-5094, ISIS-388626, sergliflozin or dapagliflozin or as such.
• modulators of the sodium-dependent glucose transporter 1 or 2 SGLT1, SGLT2
• modulators of the sodium-dependent glucose transporter 1 or 2 such as, for example, KGA-2727, T-1095, SGL-0010, AVE 2268, SAR 7226, SGL-5083 , SGL-5085, SGL-5094, ISIS-388626, sergliflozin or dapagliflozin or as such.
• the compound of formula I is used in combination with inhibitors of 11-beta-hydroxysteroid dehydrogenase-1 (II ⁇ -HSDl), such as.
• II ⁇ -HSDl 11-beta-hydroxysteroid dehydrogenase-1
• WO2007145835 WO2007146761, WO2008000950, WO2008000951, WO2008003611, WO2008005910, WO2008006702, WO2008006703, WO2008011453, WO2008012532, WO2008024497, WO2008024892, WO2008032164, WO2008034032, WO2008043544, WO2008044656, WO2008046758, WO2008052638, WO2008053194.
• the compound of formula I in combination with inhibitors of protein tyrosine phosphatase-1B (PTP-IB), as described, for.
• PTP-IB protein tyrosine phosphatase-1B
• the compound of formula I is used in combination with an agonist of GPR10A (HM74A receptor agonists; NAR agonists (nicotinic acid receptor agonists)), e.g. Nicotinic acid or "extended release niacin" in association with MK-0524A (laropiprant) or MK-0524 or such compounds as described in WO2004041274, WO2006045565, WO2006045564, WO2006069242, WO2006085108, WO2006085112, WO2006085113, WO2006124490, WO2006113150, WO2007017261, WO2007017262, WO2007017265 , WO2007015744, WO2007027532, WO2007092364, WO2007120575, WO2007134986, WO2007150025, WO2007150026, WO2008016968, WO2008051403.
• GPR10A HM74A receptor agonists
• the compound of formula I is administered in combination with a solid combination of niacin with simvastatin.
• the compound of formula I is administered in combination with nicotinic acid or extended release niacin in association with MK-0524A (laropiprant). In a further embodiment of the invention, the compound of the formula I is administered in combination with nicotinic acid or extended release niacin in conjunction with MK-0524A (laropiprant) and with simvastatin.
• the compound of formula I is administered in combination with nicotinic acid or another nicotinic acid receptor agonist and a prostaglandin DP receptor antagonist, e.g. such as those described in WO2008039882 administered.
• the compound of formula I is used in combination with an agonist of GPR16, as described, e.g. in WO2006067531, WO2006067532.
• the compound of formula I is used in combination with modulators of GPR40, as described, e.g. in WO2007013689, WO2007033002, WO2007106469,
• the compound of Formula I is used in combination with modulators of GPR19 (G protein-coupled glucose dependent insulinotropic receptor), such as e.g. PSN-119-1, MBX-2982 or such as z.
• GPR19 G protein-coupled glucose dependent insulinotropic receptor
• the compound of formula I is used in combination with modulators of GPRl 20, e.g. in EP168138.
• the compound of the formula I in combination with inhibitors of hormone-sensitive lipase (HSL) and / or phospholipases, such.
• HSL hormone-sensitive lipase
• WO2005073199, WO2006074957, WO2006087309, WO2006111321, WO2007042178, WO2007119837 In WO2005073199, WO2006074957, WO2006087309, WO2006111321, WO2007042178, WO2007119837.
• the compound of the formula I in combination with inhibitors of endothelial lipase, such as. As described in WO2007110216 administered.
• the compound of formula I is used in combination with a phospholipase A2 inhibitor, e.g. Darapladib or A-002 or those as described in WO2008048866, WO20080488867 administered.
• a phospholipase A2 inhibitor e.g. Darapladib or A-002 or those as described in WO2008048866, WO20080488867 administered.
• the compound of the formula I is administered in combination with myricitrin, a lipase inhibitor (WO2007119827).
• the compound of the formula I in combination with an inhibitor of glycogen synthase kinase-3 beta (GSK-3 beta), such as. B. in US2005222220, WO2005085230, WO2005111018, WO2003078403, WO2004022544, WO2003106410, WO2005058908, US2005038023, WO2005009997, US2005026984, WO2005000836, WO2004106343, EP1460075, WO2004014910, WO2003076442, WO2005087727, WO2004046117, WO2007073117, WO2007083978, WO2007120102, WO2007122634, WO2007125109, WO2007125110, US2007281949 , WO2008002244, WO2008002245, WO2008016123, WO2008023239, WO2008044700, WO2008056266, WO2008057940.
• GSK-3 beta glycogen synthase kin
• the compound of formula I is used in combination with an inhibitor of phosphoenolpyruvate carboxykinase (PEPCK), e.g. such as described in WO2004074288 administered.
• PPCK phosphoenolpyruvate carboxykinase
• the compound of formula I is administered in combination with an inhibitor of phosphoinositide kinase-3 (PI3K), such as those described in WO2008027584.
• PI3K phosphoinositide kinase-3
• the compound of the formula I in combination with an inhibitor of serum / glucocorticoid-regulated kinase (SGK), such as.
• SGK serum / glucocorticoid-regulated kinase
• the compound of formula I in combination with a modulator of the glucocorticoid receptor, such.
• a modulator of the glucocorticoid receptor such as described in WO2008057855, WO2008057856, WO2008057857, WO2008057859, WO2008057862.
• the compound of formula I in combination with an inhibitor of protein kinase C beta such as. B. Ruboxistaurin administered.
• PLC beta protein kinase C beta
• the compound of the formula I in combination with an activator of the AMP-activated protein kinase (AMPK), as described, for.
• AMPK AMP-activated protein kinase
• the compound of the formula I in combination with an inhibitor of ceramide kinase, as z.
• an inhibitor of ceramide kinase as described in WO2007112914, WO2007149865.
• the compound of formula I is used in combination with an inhibitor of MAPK-interacting kinase 1 or 2 (MNK1 or 2) as described e.g. in WO2007104053, WO2007115822, WO2008008547.
• MNK1 or 2 an inhibitor of MAPK-interacting kinase 1 or 2 as described e.g. in WO2007104053, WO2007115822, WO2008008547.
• the compound of the formula I is administered in combination with inhibitors of the "I-kappaB kinase" (IKK inhibitors), as described, for example, in WO2001000610, WO2001030774, WO2004022057, WO2004022553, WO2005097129, WO2005113544, US2007244140.
• IKK inhibitors inhibitors of the "I-kappaB kinase"
• the compound of the formula I in combination with inhibitors of NF-kappaB (NFKB) activation as z.
• NFKB NF-kappaB
• salsalates administered.
• ASK-I apoptosis signal-regulating kinase 1
• the compounds of the formula I are combined with an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin, L-659699, BMS-644950 or those described in US2007249583 administered.
• an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin, L-659699, BMS-644950 or those described in US2007249583 administered.
• the compound of the formula I is in
• FXR farnesoid X receptor
• the compound of the formula I is used in combination with a liver X receptor ligand (LXR), e.g. in WO2007092965, WO2008041003, WO2008049047.
• LXR liver X receptor ligand
• the compound of formula I is used in combination with a fibrate, e.g. Fenofibrate, clofibrate, bezafibrate.
• a fibrate e.g. Fenofibrate, clofibrate, bezafibrate.
• the compound of formula I is used in combination with fibrates, e.g. the choline salt of fenofibrate (SLV-348).
• fibrates e.g. the choline salt of fenofibrate (SLV-348).
• the compound of formula I is used in combination with fibrates, e.g. the choline salt of fenofibrate and a HMGCoA reductase inhibitor, e.g. Rosuvastatin, administered.
• fibrates e.g. the choline salt of fenofibrate and a HMGCoA reductase inhibitor, e.g. Rosuvastatin, administered.
• the compound of the formula I is administered in combination with bezafibrate and diflunisal. In a further embodiment of the invention, the compound of the formula I is administered in combination with a fixed combination of fenofibrate or a salt thereof with simvastatin, rosuvastatin, fluvastatin, lovastatin, cerivastatin, pravastatin or atorvastatin.
• the compound of the formula I is administered in combination with Synordia (R), a fixed combination of fenofibrate with metformin.
• the compound of formula I is administered in combination with a cholesterol reso ⁇ tion inhibitor, e.g. Ezetimibe, Tiqueside, Pamaqueside, FM-VP4 (sitostanol / campesterol ascorbyl phosphate, Forbes Medi-Tech, WO2005042692, WO2005005453), MD-0727 (Microbia Inc., WO2005021497, WO2005021495) or with compounds as described in WO2002066464, WO2005000353 (Kotobuki Pharmaceutical Co. Ltd.) or WO2005044256 or WO2005062824 (Merck & Co.) or WO2005061451 and
• a cholesterol reso ⁇ tion inhibitor e.g. Ezetimibe, Tiqueside, Pamaqueside, FM-VP4 (sitostanol / campesterol ascorbyl phosphate, Forbes Medi-Tech, WO2005042692, WO2005005453), MD-0727 (Microbia
• WO2005061452 (AstraZeneca AB) and WO2006017257 (Phenomix) or WO2005033100 (Lipideon Biotechnology AG) or as described in WO2002050060, WO2002050068, WO2004000803, WO2004000804, WO2004000805, WO2004087655, WO2004097655, WO2005047248, WO2006086562, WO2006102674, WO2006116499, WO2006121861, WO2006122186, WO2006122216, WO2006127893, WO2006137794, WO2006137796, WO2006137782, WO2006137793, WO2006137797, WO2006137795, WO2006137792, WO2006138163, WO2007059871, US2007232688, WO2007126358, WO2008033431, WO2008033465, WO2008052658, WO2008057336.
• the compound of formula I is administered in combination with an NPC ILl antagonist, e.g. those as described in WO2008033464, WO2008033465, administered.
• an NPC ILl antagonist e.g. those as described in WO2008033464, WO2008033465, administered.
• the compound of formula I is administered in combination with Vytorin TM, a fixed combination of ezetimibe with simvastatin. In one embodiment of the invention, the compound of formula I is administered in combination with a fixed combination of ezetimibe with atorvastatin.
• the compound of formula I is administered in combination with a fixed combination of ezetimibe with fenofibrate.
• the further active ingredient is a diphenylazetidinone derivative, e.g. in US 6,992,067 or US 7,205,290.
• the further active ingredient is a
• Diphenylazetidinone derivative e.g. in US 6,992,067 or US 7,205,290 combined with a statin such as e.g. Simvastatin, fluvastatin, pravastatin, lovastatin, cerivastatin, atorvastatin or rosuvastatin.
• a statin such as e.g. Simvastatin, fluvastatin, pravastatin, lovastatin, cerivastatin, atorvastatin or rosuvastatin.
• the compound of formula I is administered in combination with a solid combination of Lapaquistat, a squalene synthase inhibitor, with atorvastatin.
• the compound of formula I is used in combination with a CETP inhibitor, e.g. Torcetrapib, anacetrapib or JTT-705 (Dalcetrapib) or those described in WO2006002342, WO2006010422, WO2006012093, WO2006073973, WO2006072362, WO2007088996, WO2007088999, US2007185058, US2007185113, US2007185154, US2007185182, WO2006097169, WO2007041494, WO2007090752, WO2007107243, WO2007120621, US2007265252, US2007265304 , WO2007128568, WO2007132906, WO2008006257, WO2008009435, WO2008018529, WO2008058961, WO2008058967.
• a CETP inhibitor e.g. Torcetrapib, anacetrapib or JTT-705 (Dalcetrapib) or those described in WO
• the compound of the formula I is used in combination with bile acid resorption inhibitor (see, for example, US Pat. No. 6,245,744, US Pat. No. 6,221,897 or WO00 / 61568), for example HMR 1741 or DE 10 2005 033099.1 and DE 10 2005 033100.9, DE 10 2006 053635, DE 10 2006 053637, WO2007009655-56, WO2008058628, WO2008058629, WO2008058630, WO2008058631.
• bile acid resorption inhibitor see, for example, US Pat. No. 6,245,744, US Pat. No. 6,221,897 or WO00 / 61568
• the compound of the formula I is administered in combination with agonists of GPBAR1 (G-protein-coupled bile acid receptor-1; TGR5), as described, for example, in US Pat. in WO2007110237, WO2007127505, WO2008009407.
• GPBAR1 G-protein-coupled bile acid receptor-1
• the compound of formula I is used in combination with a polymeric bile acid adsorber, e.g. Cholestyramine, colesevelam hydrochloride.
• a polymeric bile acid adsorber e.g. Cholestyramine, colesevelam hydrochloride.
• the compound of the formula I is administered in combination with colesevelam hydrochloride and metformin or a sulfonylurea or insulin.
• the compound of the formula I is administered in combination with a phytosterol-containing chewing gum (Reductol TM).
• the compound of formula I is used in combination with an inhibitor of the microsomal triglyceride transfer protein (MTP inhibitor), e.g. Implitapide, BMS-201038, R-103757, AS-1552133, SLx-4090, AEGR-733 or those as described in WO2005085226, WO2005121091, WO2006010423, WO2006113910, WO2007143164, WO2008049806, WO2008049808.
• MTP inhibitor microsomal triglyceride transfer protein
• the compound of formula I is used in combination with a combination of a cholesterol absorption inhibitor, e.g.
• Ezetimibe and an inhibitor of the triglyceride transfer protein (MTP inhibitor), such as. Implitapide as described in WO2008030382 administered.
• MTP inhibitor an inhibitor of the triglyceride transfer protein
• the compound of formula I is administered in combination with an antihypertriglyceridemic agent, such as those described in WO2008032980.
• the compound of the formula I is administered in combination with an antagonist of the somatostatin 5 receptor (SST5 receptor), such as those described in WO2006094682.
• the compound of formula I is used in combination with an ACAT inhibitor, e.g. Avasimibe, SMP-797 or KY-382.
• ACAT inhibitor e.g. Avasimibe, SMP-797 or KY-382.
• the compound of the formula I in combination with an inhibitor of hepatic carnitine palmitoyltransferase-1 (L-CPTl), as described e.g. in WO2007063012, WO2007096251 (ST-3473), WO2008015081, US2008103182.
• L-CPTl hepatic carnitine palmitoyltransferase-1
• the compound of formula I is used in combination with a modulator of serine-palmitoyltransferase (SPT), as described e.g. in WO2008031032, WO2008046071.
• SPT serine-palmitoyltransferase
• the compound of formula I is used in combination with a squalene synthetase inhibitor, e.g. BMS-188494, TAK-475 (Lapaquistat acetate) or as described in WO2005077907, JP2007022943, WO2008003424.
• a squalene synthetase inhibitor e.g. BMS-188494, TAK-475 (Lapaquistat acetate) or as described in WO2005077907, JP2007022943, WO2008003424.
• the compound of the formula I is administered in combination with ISIS-301012 (mipomersen), an antisense oligonucleotide which is capable of regulating the apolipoprotein B gene.
• the compound of formula I is used in combination with an LDL receptor inducer (see US 6,342,512), e.g. HMRI 171, HMRI 586, or those described in WO2005097738, WO2008020607.
• an LDL receptor inducer see US 6,342,512
• the compound of the formula I is administered in combination with an HDL cholesterol-increasing agent, such as those described in WO2008040651.
• the compound of the formula I is administered in combination with an ABCA1 expression enhancer, as described, for example, in WO2006072393.
• the compound of the formula I is administered in combination with a lipoprotein-lipase modulator, e.g. Ibrolipim (NO-1886).
• a lipoprotein-lipase modulator e.g. Ibrolipim (NO-1886).
• the compound of formula I in combination with a lipoprotein (a) antagonist such as e.g. Gemcabene (CI-1027).
• the compound of formula I is administered in combination with a lipase inhibitor, e.g. Orlistat or cetilistat (ATL-962).
• a lipase inhibitor e.g. Orlistat or cetilistat (ATL-962).
• the compound of the formula I is administered in combination with an adenosine A1 receptor agonist (adenosine Al R), as described e.g. in EP1258247, EP 1375508, WO2008028590.
• an adenosine A1 receptor agonist as described e.g. in EP1258247, EP 1375508, WO2008028590.
• the compound of formula I is used in combination with adenosine A2B receptor agonist (adenosine A2B R), e.g. ATL-801 administered.
• adenosine A2B receptor agonist e.g. ATL-801 administered.
• the compound of the formula I in combination with a modulator of the adenosine A2A and / or adenosine A3 receptors such. in WO2007111954, WO2007121918, WO2007121921, WO2007121923.
• the compound of the formula I is administered in combination with an adenosine A2B receptor antagonist (adenosine A2B R), as described in US2007270433, WO2008027585.
• the compound of the formula I in combination with inhibitors of acetyl-CoA carboxylase (ACCl and / or ACC2) such.
• ACCl and / or ACC2 inhibitors of acetyl-CoA carboxylase
• the compound of the formula I is used in combination with modulators of the microsomal acyl-CoA: glycerol-3-phosphate acyltransferase 3 (GP AT3, described in WO2007100789) or with modulators of the microsomal acyl-CoA: glycerol-3-phosphate Acyltransferase 4 (GP AT4 described in WO2007100833).
• the compound of the formula I is administered in combination with modulators of xanthine oxidoreductase (XOR).
• the compound of formula I is used in combination with inhibitors of soluble epoxide hydrolase (sEH), as described e.g. in WO2008051873, WO2008051875.
• SEH soluble epoxide hydrolase
• the compound of the formula I is administered in combination with CART modulators (see “Cocaine-amphetamine-regulated transcriptinfluenza fl igransisportiv metabolism, anxiety and gastric emptying in mice” Asakawa, A. et al .: Hormone and Metabolism Research (2001 ), 33 (9), 554-558);
• NPY antagonists e.g. Naphthalene-1-sulfonic acid ⁇ 4 - [(4-amino-quinazolin-2-ylamino) -methyl] -cyclohexyl-methyl ⁇ -amide hydrochloride (CGP 71683A);
• NPY-5 receptor antagonists such as L-152804 or the compound "NPY-5-BY” from Banyu or as described, for example, in WO2006001318, WO2007103295, WO2007125952, WO2008026563, WO2008026564, WO2008052769; NPY-4 receptor antagonists as they are e.g. As described in WO2007038942;
• NPY-2 receptor antagonists such as. As described in WO2007038943;
• Peptide YY 3-36 PYY3-36 or analogous compounds such.
• CJC-1682 PYY3-36 conjugated to human serum albumin via Cys34
• CJC-1643 derivative of PYY3-36 conjugated to serum albumin in vivo
• CBIR Cannabinoid Receptor 1 antagonists such as rimonabant, surinabant (SRI 47778), SLV-319 (Ibipinabant), AVE-1625, taranabant (MK-0364) or salts thereof, Otenabant (CP-945,598), V-24343 or such Compounds as in z.
• Cannabinoid Receptor 1 / Cannabinoid Receptor 2 (CB1 / CB2) modulating compounds e.g. delta-9-tetrahydrocannabivarin or those as described e.g. in WO2007001939, WO2007044215, WO2007047737, WO2007095513, WO2007096764, WO2007112399, WO2007112402 are described;
• FAAH fatty acid amide hydrolase
• Vanilloid-1 receptor modulators modulators of the TRPVI
• Vanilloid-1 receptor modulators modulators of the TRPVI
• WO2007091948 WO2007129188, WO2007133637, WO2008007780, WO2008010061, WO2008007211, WO2008010061, WO2008015335, WO2008018827, WO2008024433, WO2008024438, WO2008032204, WO2008050199, WO2008059370 are described;
• Antagonists or inverse agonists of the opioid receptors as e.g. in WO2008021849, WO2008021851, WO2008032156 are described;
• Agonists of the prostaglandin receptor e.g. Bimatoprost or such compounds as described in WO2007111806;
• MC4 receptor agonists (melanocortin-4 receptor agonists, MC4R agonists such as 1 - Amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid [2- (3a-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo] 4 , 3-c] pyridin-5-yl) -l- (4-chloro-phenyl) -2-oxo-ethyl] -amide; (WO 01/91752)) or LB53280, LB53279, LB53278 or TfflQ, MB243, RY764, CHIR-785, PT-141, MK-0493 or those as described in WO2005060985, WO2005009950, WO2004087159, WO2004078717, WO2004078716, WO2004024720, US20050124652, WO2005051391,
• Orexin receptor 1 antagonists (OXlR antagonists), orexin receptor 2 antagonists (OX2R antagonists) or mixed OX1R / OX2R antagonists (eg l- (2-methylbenzoxazol-6-yl) -3- [l, 5] naphthyridine 4-yl-urea hydrochloride (SB-334867-A) or those as described, for example, in WO200196302, WO200185693, WO2004085403, WO2005075458, WO2006067224, WO2007085718, WO2007088276, WO2007116374, WO2007122591, WO2007126934, WO2007126935, WO2008008517, WO2008008518, WO2008008551 WO2008020405, WO2008026149, WO2008038251 are described);
• Histamine H3 receptor antagonists / inverse agonists eg 3-cyclohexyl-1- (4,4-dimethyl-1,4,6,7-tetrahydro-imidazo [4,5-c] pyridin-5-yl) - propan-1-one oxalic acid salt (WO 00/63208) or those as described in WO200064884, WO2005082893, US2005171181 (eg PF-00389027), WO2006107661, WO2007003804, WO2007016496, WO2007020213, WO2007049798, WO2007055418, WO2007057329, WO2007065820, WO2007068620, WO2007068641, WO2007075629, WO2007080140, WO2007082840, WO2007088450, WO2007088462, WO2007094962, WO2007099423, WO2007100990, WO2007105053, WO2007106349,
• Histamine Hl / histamine H3 modulators such as. B. Betahistine or its dihydrochloride;
• Histamine H4 modulators as described e.g. in WO2007117399 are described;
• CRF antagonists eg [2-methyl-9- (2,4,6-trimethyl-phenyl) -9H-l, 3,9-triaza-fluoren-4-yl] -dipropyl-amine (WO 00/66585) or those CRF1 antagonists, as described in WO2007105113, WO2007133756, WO2008036541, WO2008036579);
• CRF BP antagonists e.g., urocortin
• Agonists of the beta-3 adrenoceptor such as e.g. 1- (4-chloro-3-methanesulfonyhnethylphenyl) -2- [2- (2,3-dimethyl-1H-indol-6-yloxy) -ethylamino] -ethanol hydrochloride (WO 01/83451) or solabegron (GW -427,353) or N-5984 (KRP-204) or those as described in JP2006111553, WO2002038543, WO2002038544, WO2007048840-843;
• MSH melanocyte-stimulating hormone
• MCH (melanin-concentrating hormone) receptor antagonists such as NBI-845, A-761, A-665798, A-798, ATC-0175, T-226296, T-71 (AMG-071, AMG-076 ), GW-803430 or such compounds as described in WO2005085200, WO2005019240, WO2004011438, WO2004012648, WO2003015769, WO2004072025, WO2005070898, WO2005070925, WO2004039780, WO2004092181, WO2003033476, WO2002006245, WO2002089729, WO2002002744, WO2003004027, FR2868780, WO2006010446, WO2006038680, WO2006044293, WO2006044174, JP2006176443, WO2006018280, WO2006018279, WO2006118320, WO2006130075, WO2007018248, WO20070126
• WO2007093363-366 WO2007114902, WO2007114916, WO2007141200, WO2007142217, US2007299062, WO2007146758, WO2007146759, WO2008001160, WO2008015558, WO2008016811, WO2008020799, WO2008022979, WO2008038692, WO2008041090, WO2008044632, WO2008047544 are described);
• CCK-A (CCK-I) agonists such as ⁇ 2- [4- (4-chloro-2,5-dimethoxy-phenyl) -5- (2-cyclohexyl-ethyl) -thiazol-2-ylcarbamoyl] -5 , 7-dimethyl-indol-1-yl) -acetic acid trifluoroacetic acid salt (WO 99/15525) or SR-146131 (WO 0244150) or SSR-125180) or those as described in WO2005116034, WO2007120655, WO2007120688, WO2007120718;
• Serotonin reuptake inhibitors e.g., dexfenfluramines
• those as described in WO2007148341, WO2008034142 e.g., dexfenfluramines
• mixed serotonin / dopamine reuptake inhibitors e.g., bupropion
• mixed reuptake inhibitors such as e.g. DOV 21,947;
• mixed sertonine and noradrenergic compounds e.g., WO 00/71549
• 5-HT receptor agonists e.g. 1- (3-ethyl-benzofuran-7-yl) -piperazine oxalic acid salt (WO 01/09111);
• Dopa ⁇ uWNorepmephrin / acetylcholine reuptake inhibitors eg tesofensins
• acetylcholine reuptake inhibitors eg tesofensins
• Norepinephrine reuptake inhibitors as described, for example, in US2008076724;
• 5-HT2A receptor antagonists as described e.g. in WO2007138343 are described;
• 5-HT2C receptor agonists such as Lorcaserin hydrochloride (APD-356) or BVT-933 or those as described in WO200077010, WO200077001-02, WO2005019180, WO2003064423, WO200242304, WO2005035533, WO2005082859, WO2006004937, US2006025601, WO2006028961, WO2006077025, WO2006103511 , WO2007028132, WO2007084622, US2007249709, WO2007132841, WO2007140213, WO2008007661, WO2008007664, WO2008009125, WO2008010073);
• Lorcaserin hydrochloride APD-356
• BVT-933 those as described in WO200077010, WO200077001-02, WO2005019180, WO2003064423, WO200242304, WO2005035533, WO2005082859, WO2006004937
• 5-HT6 receptor modulators e.g. E-6837, BVT-74316 or PRX-07034 or such as e.g. in WO2005058858, WO2007054257, WO2007107373, WO2007108569, WO2007108742-744, WO2008003703, WO2008027073, WO2008034815, WO2008054288 are described;
• estrogen receptor gamma e.g. in WO2007131005, WO2008052709;
• Sigma-1 receptor antagonists as e.g. in WO2007098953, WO2007098961, WO2008015266, WO2008055932, WO2008055933 are described;
• Muscarinic 3 receptor (M3R) antagonists as described e.g. in WO2007110782, WO2008041184 are described;
• Bombesin receptor agonists (BRS-3 agonists), as described e.g. in WO2008051404, WO2008051405, WO2008051406 are described;
• Growth hormone eg, human growth hormone or AOD-9604
• Growth hormone releasing compounds (6-Benzyloxy-l- (2-diisopropylamino-ethylcarbamoyl) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (WO 01/85695));
• Growth Hormone Secretagogue Receptor Antagonists such as A-778193 or those as described in WO2005030734, WO2007127457, WO2008008286;
• Growth Hormone Secretagogue Receptor Modulators e.g. JMV-2959, JMV-3002, JMV-2810, JMV-2951 or those as described in WO2006012577 (e.g., YIL-781 or YIL-870), WO2007079239;
• TRH agonists see, e.g., EP 0462 884
• decoupling protein 2 or 3 modulators
• Leptin agonists see, eg, Lee, Daniel W, Leinung, Matthew C, Rozhavskaya Arena, Marina, Grasso, Patricia, Leptin agonists as a Potential Approach to the Treatment of Obesity, Drugs of the Future (2001), 26 (9), 873-881);
• DA agonists bromocriptine, doprexin
• Lipase / amylase inhibitors e.g., WO 00/40569
• DGATs diacylglycerol O-acyltransferases
• Inhibitors of fatty acid synthase e.g. C75 or those as described in WO2004005277, WO2008006113;
• Inhibitors of stearoyl-CoA delta9 desaturase as described e.g. in WO2007009236, WO2007044085, WO2007046867, WO2007046868, WO20070501124, WO2007056846, WO2007071023, WO2007130075, WO2007134457, WO2007136746, WO2007143597, WO2007143823, WO2007143824, WO2008003753, WO2008017161, WO2008024390, WO2008029266, WO2008036715, WO2008043087, WO2008044767, WO2008046226, WO2008056687 are described;
• hypoglycemic / hypertriglyceridemic indoline compounds as described in WO2008039087;
• thyroid hormone receptor agonists thyroid hormone receptor agonists
• B KB-2115 (Eprotirome), QRX-431 (Sobetirome) or DITPA or those as described in WO20058279, WO200172692, WO200194293, WO2003084915, WO2004018421, WO2005092316, WO2007003419, WO2007009913, WO2007039125, WO2007110225, WO2007110226, WO2007128492, WO2007132475, WO2007134864, WO2008001959 described or agonists of the thyroid hormone receptor beta (TR-beta) such.
• TR-beta thyroid hormone receptor beta
• the compound of the formula I is administered in combination with a combination of epotiromes with ezetimibe.
• the compound of formula I is used in combination with an inhibitor of Site-1 protease (SlP), e.g. PF-429242 administered.
• SlP Site-1 protease
• the compound of the formula I is in
• RNAi therapeutic which is directed against PCSK9 (Proprotein Convertase Subtilisin / Kexin Type 9) administered.
• the compound of formula I is administered in combination with Omacor® or Lovaza TM (omega-3 fatty acid esters, high-concentration ethyl esters of eicosapentaenoic acid and docosahexaenoic acid).
• Omacor® or Lovaza TM omega-3 fatty acid esters, high-concentration ethyl esters of eicosapentaenoic acid and docosahexaenoic acid.
• the compound of the formula I is administered in combination with lycopene.
• the compound of formula I is used in combination with an antioxidant, e.g. OPC-14117, AGI-1067 (succinobucol), probucol, tocopherol, ascorbic acid, beta-carotene or selenium.
• an antioxidant e.g. OPC-14117, AGI-1067 (succinobucol), probucol, tocopherol, ascorbic acid, beta-carotene or selenium.
• the compound of the formula I in combination with a vitamin, such as. As vitamin B6 or vitamin B 12 administered.
• the compound of the formula I is used in combination with more than one of the abovementioned compounds, for example in combination with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and Metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc. administered.
• the compound of formula I is used in combination with an inhibitor of carbonic anhydrase type 2, such as carbonic anhydrase type 2, e.g. such as described in WO2007065948 administered.
• an inhibitor of carbonic anhydrase type 2 such as carbonic anhydrase type 2, e.g. such as described in WO2007065948 administered.
• the compound of formula I is administered in combination with topiramate or a derivative thereof as described in WO2008027557.
• the compound of formula I is administered in combination with a solid combination of topiramate with phentermine (Qnexa TM).
• the compound of formula I is used in combination with an antisense compound, e.g. ISIS-377131, which inhibits the production of the glucocorticoid receptor.
• an antisense compound e.g. ISIS-377131
• the compound of formula I is administered in combination with an aldosterone synthase inhibitor and an antagonist of the glucocorticoid receptor, a cortisol synthesis inhibitor and / or an antagonist of the corticotropin releasing factor, such as corticotropin releasing factor, e.g. in EP-A-886695.
• the compound of the formula I in combination with an agonist of the RUP3 receptor, such as. As described in WO2007035355, WO2008005576.
• the compound of the formula I in combination with an activator of the gene coding for the Ataxia Telangiectasia Mutated (ATM) protein kinase such as. As chloroquine administered.
• ATM Ataxia Telangiectasia Mutated
• the compound of the formula I in combination with a tau protein kinase 1 inhibitor (TPKl inhibitor), such as. As described in WO2007119463, administered.
• TPKl inhibitor tau protein kinase 1 inhibitor
• the compound of the formula I is administered in combination with a "c-Jun N-terminal kinase” inhibitor (JNK inhibitor), as described, for example, in WO2007125405, WO2008028860.
• JNK inhibitor c-Jun N-terminal kinase inhibitor
• the compound of the formula I in combination with an endothelin A receptor antagonists, such as. B. avosentan (SPP-301).
• an endothelin A receptor antagonists such as. B. avosentan (SPP-301).
• the compound of formula I is used in combination with modulators of the glucocorticoid receptor (GR), e.g. KB-3305 or such compounds as e.g. As described in WO2005090336, WO2006071609, WO2006135826, WO2007105766.
• GR glucocorticoid receptor
• the other active ingredient is varenicline tartrate, a partial agonist of the alpha 4-beta 2 nicotinic acetylcholine receptor.
• the other active ingredient is trodusquemine.
• the further active ingredient is a modulator of the enzyme SIRTI (an NAD + -dependent protein deacetylase); this active ingredient may be, for example, resveratrol in suitable formulations, or such compounds as mentioned in WO2007019416 (eg SRT-1720).
• SIRTI an NAD + -dependent protein deacetylase
• the further active ingredient is DM-71 (N-acetyl-L-cysteine with bethanechol).
• the compound of the formula I is administered in combination with anti-hypercholesterolemic compounds, as described, for example, in WO2007107587, WO2007111994.
• the compound of the formula I is administered in combination with a cyclic peptide agonist of the VPAC2 receptor, as described, for example, in WO2007101146, WO2007133828.
• the compound of formula I is administered in combination with an agonist of the endothelin receptor, as described e.g. in WO2007112069 are administered.
• the compound of the formula I is administered in combination with AKP-020 (bis (ethylmaltolato) oxovanadium-IV).
• the compound of the formula I is administered in combination with tissue-selective androgen receptor modulators (SARMs), as described, for example, in WO2007099200, WO2007137874.
• SARMs tissue-selective androgen receptor modulators
• the compound of formula I is used in combination with an AGE (advanced glycation endproduct) inhibitor, e.g. in JP2008024673.
• an AGE advanced glycation endproduct
• the further active ingredient is leptin; see, e.g. "Perspectives in the therapeutic use of leptin", Salvador, Javier; Gomez-Ambrosi,
• the further active ingredient is metreleptin (recombinant methionyl-leptin) combined with pramlintide.
• the further active ingredient is the tetrapeptide ISF-402.
• the other active ingredient is dexamphetamine or amphetamine. In one embodiment, the other active ingredient is fenfluramine or dexfenfluramine.
• the further active ingredient is sibutramine or derivatives thereof as described in WO2008034142.
• the other active ingredient is mazindol or phentermine.
• the further active ingredient is geniposidic acid (geniposidic acid, WO2007100104) or derivatives thereof (JP2008106008).
• the further active ingredient is a nasally administered one
• Calcium channel blockers such as e.g. Diltiazem or those as described in US 7,138,107.
• the further active ingredient is an inhibitor of sodium-calcium ion exchange, e.g. those as described in WO2008028958.
• the further active ingredient is a blocker of calcium channels, e.g. of the CaV3.2 as described in WO2008033431, WO2008033447, WO2008033356, WO2008033460, WO2008033464, WO2008033465, WO2008033468.
• the further active ingredient is a blocker of the "T-type calcium channel" as described, for example, in WO2008033431.
• the further active ingredient is an inhibitor of KCNQ potassium channel-2 or -3, e.g. those as described in US2008027049, US2008027090.
• the further active ingredient is an inhibitor of the potassium Kv 1.3 ion channel such as those described in WO2008040057, WO2008040058, WO2008046065.
• the further active ingredient is a modulator of the MCP-1 receptor (monocyte chemoattractant protein-1 (MCP-I)) such as those described in WO2008014360, WO2008014381.
• MCP-1 receptor monocyte chemoattractant protein-1 (MCP-I)
• the additional active ingredient is a modulator of somatostatin receptor 5 (SSTR5), e.g. those as described in WO2008019967, US2008064697.
• SSTR5 somatostatin receptor 5
• the further active ingredient is a modulator of somatostatin receptor 2 (SSTR2), e.g. those as described in WO2008051272.
• SSTR2 somatostatin receptor 2
• the further active ingredient is an erythropoietin-mimetic peptide which acts as an erythropoietin (EPO) receptor agonist.
• EPO erythropoietin
• the further active ingredient is an anorectic / hypoglycemic compound, e.g. those as described in WO2008035305, WO2008035306, WO2008035686.
• the further active ingredient is an inducer of lipoic acid synthetase, e.g. those as described in WO2008036966, WO2008036967.
• the further active ingredient is a stimulator of endothelial nitric oxide synthase (eNOS), e.g. those as described in WO2008058641.
• eNOS endothelial nitric oxide synthase
• the further active ingredient is a modulator of carbohydrate and / or lipid metabolism, such as e.g. those as described in WO2008059023, WO2008059024, WO2008059025, WO2008059026.
• the further active ingredient is an angiotensin II receptor antagonist, for example those as described in WO2008062905.
• the further active ingredient is an agonist of the sphingosine-1 phosphate receptor (SLP), for example those as described in WO2008064315.
• the compound of formula I in combination with bulking agents preferably insoluble bulking agents
• bulking agents preferably insoluble bulking agents
• Caromax is a carob-containing product of the company Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark availability, 65926 Frankfurt / Main)) administered.
• Combination with Caromax ® is possible in one preparation or by separate administration of compounds of the formula I and Caromax ®.
• Caromax ® can also be administered in the form of food, such as in baked goods or muesli bars.
• the following active substances are suitable for combination preparations: All antiepileptic drugs, which are mentioned in the Red List 2007, chapter 15; all antihypertensive agents mentioned in the Red List 2007, chapter 17; all hypotensive agents mentioned in the Red List 2007, chapter 19; all anticoagulants mentioned in the Red List 2007, Chapter 20; all atherosclerosis agents listed in the Red List 2007, chapter 25; all beta-receptor, calcium channel blockers and inhibitors of the renin-angiotensin system mentioned in the Red List 2007, Chapter 27; all diuretics and circulation-promoting agents mentioned in the Red List 2007, Chapters 36 and 37; all weaning aids / means of treatment for addictions listed in the Red List 2007, chapter 39; all coronary and gastrointestinal agents mentioned in the Red List 2007, chapters 55 and 60; all migraine, neuropathic and Parkinson's remedies mentioned in the Red List 2007, Chapters 61, 66 and 70.
• the invention further relates to processes for the preparation of the compound of the formula I.
• ⁇ is purified by chromatography, for example on RP 18 silica gel with a suitable solvent system, for example, from water, acetonitrile and trifluoroacetic acid, and then converted by treatment with water in the crystalline hydrate of formula I.
• the compound of formula ⁇ is dissolved in an organic solvent.
• ethanol is used as the organic solvent.
• water can be added. This solution is added to a suspension of seed crystals in water.
• the required seed crystals can be prepared, for example, by Method A.
• the water may also contain a proportion of an organic solvent.
• the water content of the hydrate may be increased after drying under vacuum
• the amorphous compound of formula II (HPLC purity: 95.8%, water content: 0.3%) is purified by chromatography: Stationary phase: Kromasil C-18, 7 ⁇ m Columns volume: 1.7 L Column length: 22 cm Mobile phases:
• Substance application 8 g of compound II are dissolved in 770 ml of mobile phase B and diluted with 3500 ml of mobile phase A. The solution is filtered and added to the column at a flow rate of 200 mL / min. It is then eluted with the Gradienden given above. Fractions with a purity> 99% are combined. On a rotary evaporator, the acetonitrile is distilled off at a bath temperature ⁇ 40 0 C and the residue is freeze-dried. From 80 g, 60 g of the compound of formula II with an HPLC purity> 99% were obtained. The amorphous product contained 0.38% water and 3.1% trifluoroacetic acid. The compound of formula II shows the XRPD shown in Figure 3.
• the 2 Theata values of the peaks can be specified with an accuracy of +/- 0.2 degrees theta.
• amorphous compound II 100 g of the amorphous compound II (HPLC purity: 95.8%, water content: 0.3%) are dissolved in 400 ml of aqueous ethanol (denatured with methyl ethyl ketone, 80% (vol / vol)) by heating to 40 0 C. The solution is allowed to cool to 20-25 0 C. 2 g of the crystalline compound I from Example 1 are suspended at 10 ° -20 ° C. by stirring in 10 liters of distilled water. The solution of compound II in 80% ethanol is added to this suspension within 70 minutes. The addition vessel is subsequently rinsed with 40 ml of 80% ethanol. It forms a white precipitate. The mixture is then stirred for 20 h at 20 - 25 0 C.
• aqueous ethanol denatured with methyl ethyl ketone, 80% (vol / vol)
• Example 2 shows the XRPD shown in Figure 2.
• amorphous compound EL HPLC purity: 95.8%, water content: 0.3%) are dissolved in 100 ml of aqueous ethanol (denatured with methyl ethyl ketone, 80% (vol / vol)) by heating to 40 0 C
• Man lets the solution to 20 - 25 0 C cool.
• 500 mg of the crystalline compound I from Example 1 are suspended at 20-25 ° C. by stirring in 500 ml of distilled water.
• To this suspension is added the solution of compound H in 80% ethanol over the course of 60 minutes.
• the addition vessel is subsequently rinsed with 10 ml of 80% ethanol. It forms a white precipitate.
• the mixture is then stirred for 20 h at 20 - 25 0 C.
• the precipitate is filtered off with suction and washed with distilled water. After drying at 45 ° C in vacuo, 24.7 g of the crystalline hydrate.
• the XRPD shows peaks at the same 2Theta values
• Example 5 0.2 g of the crystalline compound of the formula I from Example 1 are suspended at 20-25 ° C. by stirring in 1000 ml of distilled water. To this suspension is added the solution of compound H in 80% ethanol within 10 minutes -. precipitate is filtered off and resuspended by pipes in 1 1 of water then the mixture is stirred for 1 hour at 20-25 0 C. the precipitate is filtered off with suction and washed with 20 ml of distilled water After drying at 50 0 C in vacuo. 7.87 g of the crystalline hydrate of the formula I are obtained. The XRPD shows peaks at the same 2Theta values as Example 2.
• Example 5 shows peaks at the same 2Theta values as Example 2.
• Example 2 The hydrate obtained in Example 2 was dried in vacuo at 50 0 C until a water content of 0.8% was reached. The crystalline product was stored at 23 0 C / 60% relative humidity.
• the compound of the hydrates of the formula I according to the invention was tested for its activity by the method described below: Influence of cholesterol absorption + 3 H-taurocholic acid excretion on the basis of fecal excretion in the mouse. Rat or hamster
• the animals are labeled with 3 H-TCA (taurocholic acid) sc 24 hours before the oral application of the test meal ( 14 C-cholesterol in Intralipid® 20, Pharmacia-Upjohn sc (eg 1 ⁇ Ci / mouse to 5 ⁇ Ci / rat)
• 3 H-TCA taurocholic acid
• sc eg 1 ⁇ Ci / mouse to 5 ⁇ Ci / rat
• Test substances are separated in 0.5% / (methylcellulose (Sigma) / 5% Solutol (BASF,
• the application volume of the test substance is 0.5 ml / mouse.
• the test substance is administered immediately before the test meal (intralipid with 14 C-cholesterol label) (cholesterol absorption test).
• the feces are collected over 24 h: the fecal elimination of 14 C-cholesterol and 3 H taurocholic acid (TCA) after 24 h is determined.
• the livers are harvested, homogenized and aliquots in oxime (Model 307,
• Kotproben Determine total weight, make up to defined volume with water, then homogenize, dry aliquot and in Oximat (Model 307, Packard for combustion of radioactively labeled samples): The amount of radioactive 3 H-H2O and 14 C-CO2 is extrapolated to the precipitated amount of 3 H-taurocholic acid or 14 C-cholesterol (dual-isotope technique).
• the ED 200 values are interpolated as a dose from a dose response curve than those doses that double the excretion of TCA and cholesterol, respectively, based on a control group treated simultaneously.
• the ingested amount of I4 C-cholesterol in the liver is related to the applied dose.
• the ED 5 0 values are interpolated from a dose-effect curve as the dose which bisects the uptake of 14 C-cholesterol in the liver (50%), based on a control group
• Example No. 2 shows an ED 2 oo value (fecal excretion [mg / mouse]) of 0.01 mg / mouse
• the measured ED 2 00 value confirms the activity of the compound of the formula I according to the invention and shows that the crystalline hydrates of the formula I have a very good absorption inhibiting effect on cholesterol.
• the dissolution rate is determined in a standard apparatus (paddle) according to US Pharmacopeia (USP) at 37 ° C.
• the stirrer speed is 75 rpm.
• the comparative solution is prepared as follows: 2-3 mg of the batch used are dissolved in a volumetric flask with 2 ml of dimethylformamide. It is then made up to 100.0 ml with 0.1% SDS solution.
• Example 2 The amorphous compound of the formula II used in Example 2 was compared with the crystalline compound of the formula I obtained in the same Example 2. The results are shown in the following table:
• the crystalline hydrates of the formula I have a significantly increased dissolution rate compared to the amorphous compound of the formula II from US Pat. No. 7,205,290.
• the invention thus relates to a crystalline hydrate of formula I, characterized in that in the measurement of the dissolution rate in a standard Paddle USP apparatus at 37 ° C and a stirrer speed of 75 rpm of 20mg of the crystalline hydrate of formula I in 1000ml a After 15 minutes, at least 50% of the crystalline hydrate of the formula I are already in solution in 0.1% aqueous sodium dodecyl sulfate solution.
• crystalline hydrate of the formula I 5 is characterized in that after 15 minutes at least 85% of the crystalline hydrate of the formula I are in solution.
• Solubility and dissolution rate in aqueous environments are two important factors. Solubilities of amorphous and crystalline
• the crystalline hydrate of the formula I shows a significantly higher dissolution rate than the amorphous compound II. After 15 minutes, a large part of the drug is in solution. This is almost three times the amount of the amorphous active ingredient. The effect of the crystalline hydrate of the formula I will thus begin faster than the action of the amorphous compound of the formula II

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