DE102010015123A1 - New benzylamidic diphenylazetidinone compounds, useful for treating lipid disorders, hyperlipidemia, atherosclerotic manifestations or insulin resistance, and for reducing serum cholesterol levels - Google Patents

Abstract

Benzylamidic diphenylazetidinone compounds (I) and their salts, are new. Benzylamidic diphenylazetidinone compounds of formula (I) and their salts, are new. X : 1-30C, preferably 2-10C alkylene, which is one or more times, preferably 1-3 times substituted by OH. An independent claim is included for a medicament comprising (I) and at least one further active substance. [Image] ACTIVITY : Antilipemic; Antiarteriosclerotic; Antidiabetic. MECHANISM OF ACTION : None given.

Description

The invention relates to benzylamidic Diphenylazetidinone, their physiologically acceptable salts and physiologically functional derivatives.

Diphenylazetidinones (such as ezetimibe) and their use for the treatment of hyperlipidemia and arteriosclerosis and hypercholesterolemia have already been described (US Pat. WO2002 / 050027 ). In US Pat. No. 7,205,290 B2 For example, a diphenylazetidinone is described which has improved solubility and improved stability in the stomach and small intestine.

The object of the invention was to provide further compounds which display a therapeutically utilizable hypolipidemic action. In particular, the task was to find new compounds that are only very slightly absorbable. Under very low resorbable compounds are understood, the in vitro permeability value in a Caco cell model is less than 10 × 10 ^-7 cm / sec.

With lower absorption, pharmaceutical active ingredients generally show significantly fewer side effects.

worin bedeuten
X -(C₁-C₃₀)-Alkylen-, wobei der Alkylenrest ein oder mehrfach durch -OH substituiert ist;
sowie deren pharmazeutisch verträglichen Salze.The invention therefore relates to compounds of the formula I,

in which mean
X - (C ₁ -C ₃₀ ) -alkylene-, wherein the alkylene radical is mono- or polysubstituted by -OH;
and their pharmaceutically acceptable salts.

Preference is given to compounds of the formula I in which
X - (C ₂ -C ₁₀ ) -alkylene-, wherein the alkylene radical is mono- or polysubstituted by -OH;
and their pharmaceutically acceptable salts.

Very particular preference is given to compounds of the formula I in which
X - (C ₂ -C ₁₀ ) -alkylene-, wherein the alkylene radical is substituted one to three times by -OH;
and their pharmaceutically acceptable salts.

An alkylene radical is understood to mean a straight-chain or branched hydrocarbon chain having two free valences, such as. As methylene, ethylene, iso-propylene, 1,1-dimethylethylene.

Pharmaceutically acceptable salts are particularly suitable for medical applications because of their higher water solubility compared to the starting or basic compounds. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds according to the invention are salts of inorganic acids, such as hydrochloric acid, hydrogen bromide, phosphoric, metaphosphoric, nitric, sulfonic and sulfuric acids and organic acids, such as. Acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic , Tartaric and trifluoroacetic acid. For medical purposes, the chloro salt is used in a particularly preferred manner. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth salts (such as magnesium and calcium salts).

Salts with a non-pharmaceutically acceptable anion are also within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and / or for use in non-therapeutic, for example, in vitro applications.

The term "physiologically functional derivative" as used herein refers to any physiologically acceptable derivative of a compound of the invention, e.g. For example, an ester which, when administered to a mammal, such as. Human, is able to form (directly or indirectly) such a compound or an active metabolite thereof.

Another aspect of this invention are prodrugs of the compounds of the invention. Such prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may or may not be effective.

The compounds of the invention may also be present in different polymorphic forms, for. B. as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the invention are within the scope of the invention and are a further aspect of the invention.

Hereinafter, all references to "compound (s) according to formula (I)" refer to compound (s) of formula (I) as described above, as well as their salts, solvates and physiologically functional derivatives as described herein.

The compounds of the formula I and their pharmaceutically acceptable salts and physiologically functional derivatives are ideal drugs for the treatment of lipid metabolism disorders, in particular hyperlipidemia. The compounds of the formula I are likewise suitable for influencing the serum cholesterol level and for the prevention and treatment of atherosclerotic phenomena.

The compound (s) of the formula (I) can also be administered in combination with other active substances.

The amount of a compound of formula (I) required to achieve the desired biological effect depends on a number of factors, e.g. The particular compound chosen, the intended use, the mode of administration and the clinical condition of the patient. In general, the daily dose is in the range of 0.1 mg to 100 mg (typically 0.1 mg and 50 mg) per day per kilogram of body weight, e.g. 0.1-10 mg / kg / day. For example, tablets or capsules may contain from 0.01 to 100 mg, typically from 0.02 to 50 mg. In the case of pharmaceutically acceptable salts, the abovementioned weights are based on the weight of the diphenylazetidinone ion derived from the salt. For the prophylaxis or therapy of the abovementioned conditions, the compounds according to formula (I) may themselves be used as compound, but they are preferably present with a tolerable 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 (I). 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.

Pharmaceutical compositions according to the invention are those suitable for oral and peroral (e.g., sublingual) administration, although the most suitable mode of administration in each individual case is the nature and severity of the condition being treated and the nature of the particular compound of formula (I) used ) is dependent. Also coated formulations and coated slow release formulations are within the scope of the invention. Preference is given to acid and enteric formulations. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and anionic polymers of methacrylic acid and methyl 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. As already mentioned, 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). In general, 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. For example, 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 may 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 / dispersing agent in a suitable machine. Molded tablets may be prepared by shaping the powdered compound moistened with an inert liquid diluent in a suitable machine.

Pharmaceutical compositions suitable for peroral (sublingual) administration include lozenges containing a compound of formula (I) having 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.

As further active substances for the combination preparations are suitable: All Antidiabetika, which in the Red List 2010, chapter 12 are called; all weight loss products / appetite suppressants used in the Red List 2007, Chapter 1 are called; all diuretics used in the Red List 2010, chapter 36 are called; all lipid lowering drugs used in the Red List 2010, chapter 58 are called. 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 active ingredients listed below are in USP Dictionary of US and International Drug Names, US Pharmacopeia, Rockville 2006 , disclosed.

Antidiabetics include insulin and insulin derivatives, such as. ^Lantus® (see www.lantus.com ) Or HMR 1964 or Levemir ^® (insulin detemir), Humalog ^® (insulin lispro), insulin Degludec, insulin aspart, poly-ethylene glycosidiertes (PEGylated) Insulin Lispro as in WO2009152128 described, Humulin ^®, VIAject ^TM, SuliXen ^®, VIAject ^TM or those described in WO2005005477 (Novo Nordisk), fast-acting insulins (see US 6,221,633 ), inhalable insulins, such as. B. Exubera ^®, Nasulin ^TM, or oral insulins such as. B. IN-105 (Nobex) or Oral-IYN ^™ (Generex Biotechnology) or Technosphere ^® Insulin (MannKind) or cobalamin ^TM oral insulin or ORMD-0801 or insulin precursors or insulin (insulin precursor) as in WO2007128815 . WO2007128817 . WO2008034881 . WO2008049711 . WO2008145721 . WO2009034117 . WO2009060071 . WO2009133099 or insulins that can be administered transdermally; In addition, such insulin derivatives which are bound by a bifunctional linker to albumin as they are z. In WO2009121884 are described;
GLP-1 derivatives and GLP-1 agonists such. As exenatides or special preparations thereof, as z. In WO2008061355 . WO2009080024 . WO2009080032 Liraglutide, Taspoglutide (R-1583), Albiglutide, Lixisenatide or those described in WO 98/08871 . WO2005027978 . WO2006037811 . WO2006037810 from Novo Nordisk A / S, in WO 01/04156 from Zealand or in WO 00/34331 by Beaufour-Ipsen, Pramlintide acetate (Symlin; Amylin Pharmaceuticals), inhalable GLP-1 (MKC-253 from MannKind), AVE-0010, BIM-51077 (R-1583, ITM-077), PC-DAC: Exendin-4 (an exendin-4 analogue covalently linked to recombinant human albumin), biotinylated exendin ( WO2009107900 ), a special formulation of exendin-4 as described in US2009238879 CVX-73, CVX-98 and CVx-96 (GLP-1 analogs covalently linked to a monoclonal antibody having specific binding sites for the GLP-1 peptide), CNTO-736 (a GLP-1 analog which is bound to a domain which includes the Fc portion of an antibody), PGC GLP-1 (GLP-1 bound to a nanocarrier), agonists or modulators as described e.g. B. at D. Chen et al., Proc. Natl. Acad. Sci. USA 104 (2007) 943 are described, such as those in WO2006124529 . WO2007124461 . WO2008062457 . WO2008082274 . WO2008101017 . WO2008081418 . WO2008112939 . WO2008112941 . WO2008113601 . WO2008116294 . WO2008116648 . WO2008119238 . WO2008148839 . US2008299096 . WO2008152403 . WO2009030738 . WO2009030771 . WO2009030774 . WO2009035540 . WO2009058734 . WO2009111700 . WO2009125424 . WO2009129696 . WO2009149148 are described, peptides such. , Obine epitides (TM-30338), orally active GLP-1 analogs (eg, NN9924 from Novo Nordisk), amylin receptor agonists, as described, for example, in US Pat. In WO2007104789 . WO2009034119 described analogs of human GLP-1, as they are in WO2007120899 . WO2008022015 . WO2008056726 chimeric pegylated peptides containing both GLP-1 and glucagon residues and as described e.g. In WO2008101017 . WO2009155257 . WO2009155258 described, glycosylated GLP-1 derivatives as described in WO2009153960 described as well as orally active hypoglycemic agents.

Antidiabetics also include gastrin analogs such as. Eg TT-223.

Furthermore, antidiabetics include poly- or monoclonal antibodies, which, for. B. against interleukin-1-beta (IL-1β), such as. XOMA-052.

Antidiabetics also include peptides which can bind to the human pro-island peptide receptor (HIP) receptor as described, for example, in US Pat. In WO2009049222 are described.

Antidiabetics also include agonists of the glucose-dependent insulinotropic polypeptide (GIP) receptor as described, for example, in US Pat. In WO2006121860 are described.

Antidiabetics also include the glucose-dependent insulinotropic polypeptide (GIP) as well as analogous compounds as described, for example, in US Pat. In WO2008021560 . WO2010016935 . WO2010016936 . WO2010016938 . WO2010016940 . WO2010016944 are described.

Also included are analogues and derivatives of the human pancreatic polypeptide as described, for example, in U.S. Pat. In WO2009007714 are described.

Antidiabetic agents further comprise encapsulated insulin-producing porcine cells such as e.g. B. DIABECELL ^®.

Antidiabetics also include analogs and derivatives of fibroblast growth factor 21 (FGF-21, fibroblast growth factor 21) as described, for example, in US Pat. In WO2009149171 . WO2010006214 are described.

The orally active hypoglycemic agents preferably comprise
sulfonylureas,
biguanides,
meglitinides,
oxadiazolidinediones,
thiazolidinediones,
PPAR and RXR modulators,
Glucosidase inhibitors,
Inhibitors of glycogen phosphorylase,
Glucagon receptor antagonists,
glucokinase
Inhibitors of fructose 1,6-bisphosphatase,
Glucose Transporter 4 Modulators (GLUT4),
Inhibitors of glutamine-fructose 6-phosphate amidotransferase (GFAT),
GLP-1 agonists,
Potassium channel opener, such as. As pinacidil, cromakalim, diazoxide, diazoxide choline salt or such as in RD Carr et al., Diabetes 52, 2003, 2513.2518 , at JB Hansen et al., Current Medicinal Chemistry 11, 2004, 1595-1615 , at Tagmose et al., J. Med. Chem. 47, 2004, 3202-3211 or at MJ Coghlan et al., J.Med.Chem. 44, 2001, 1627-1653 are described, or those that are in WO 97/26265 and WO 99/03861 disclosed by Novo Nordisk A / S,
Agents that act on the ATP-dependent potassium channel of beta cells,
Inhibitors of dipeptidyl peptidase-IV (DPP-IV),
Insulin sensitizers,
Inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and / or glycogenolysis,
Modulators of glucose uptake, glucose transport and glucose reabsorption,
Modulators of the Sodium-Dependent Glucose Transporter 1 or 2 (SGLT1, SGLT2),
Inhibitors of 11-beta-hydroxysteroid dehydrogenase-1 (11β-HSD1),
Inhibitors of protein tyrosine phosphatase-1B (PTP-1B),
Nicotinic receptor agonists,
Inhibitors of hormone-sensitive or endothelial lipases,
Inhibitors of acetyl-CoA carboxylase (ACC1 and / or ACC2) or inhibitors of GSK-3 beta.

Also included are lipid metabolism-altering compounds such as antihyperlipidemic agents and antilipidemic agents.
HMGCoA reductase inhibitors,
Farnesoid X Receptor (FXR) Modulators,
fibrates,
Cholesterinresreptionsinhibitoren,
CETP inhibitors,
bile acid,
MTP inhibitors
Agonists of the estrogen receptor gamma (ERRγ agonists),
Sigma-1 receptor antagonists,
Antagonists of the somatostatin 5 receptor (SST5 receptor);
Compounds that reduce food intake and
Compounds that increase thermogenesis.

In one embodiment of the invention, the compound of the formula I is administered in combination with insulin.

In another embodiment of the invention, the compound of the formula I in combination with an insulin sensitizer such. PN-2034 or ISIS-113715.

In one embodiment, the compound of Formula I is administered in combination with an agent that acts on the ATP-dependent potassium channel of beta cells, e.g. B. sulfonylureas, such as. As tolbutamide, glibenclamide, glipizide, gliclazides or glimepiride or such preparations as such. In EP2103302 described.

In one embodiment, the compound of formula I is administered in combination with a tablet containing both glimepride which is released rapidly and also contains metformin which is released over a prolonged period of time (such as in US Pat US2007264331 . WO2008050987 . WO2008062273 described).

In one embodiment, the compound of the formula I in combination with a biguanide, such. As metformin or one of its salts.

In a further embodiment, the compound of the formula I in combination with a guanidine, such as. B. benzylguanidine or one of its salts, or such guanidines as in WO2009087395 described.

In yet another embodiment, the compound of formula I in combination with a meglitinide, such as. B. repaglinide, nateglinide or mitiglinide administered.

In another embodiment, the compound of formula I is reacted with a combination of mitiglinides with a glitazone, e.g. As pioglitazone hydrochloride administered.

In another embodiment, the compound of formula I is administered with a combination of mitiglinides with an alpha-glucosidase inhibitor.

In a further embodiment, the compound of the formula I is used in combination with antidiabetic compounds, as described in WO2007095462 . WO2007101060 . WO2007105650 described.

In a further embodiment, the compound of the formula I is used in combination with antihypoglycemic compounds, as described in WO2007137008 . WO2008020607 described.

In one embodiment, the compound of formula I in combination with a thiazolidinedione, such as. Troglitazone, ciglitazone, pioglitazone, rosiglitazone or the in WO 97/41097 from dr. Reddy's Research Foundation disclosed compounds, especially 5 - [[4 - [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy) phenyl] methyl] -2,4-thiazolidinedione.

In one embodiment of the invention, the compound of the formula I in combination with a PPAR gamma agonist, such. Rosiglitazone, pioglitazone, JTT-501, GI 262570, R-483, CS-011 (rivoglitazone), DRL-17564, DRF-2593 (balaglitazone), INT-131, T-2384, or those as described in U.S. Pat WO2005086904 . WO2007060992 . WO2007100027 . WO2007103252 . WO2007122970 . WO2007138485 . WO2008006319 . WO2008006969 . WO2008010238 . WO2008017398 . WO2008028188 . WO2008066356 . WO2008084303 . WO2008089461 - WO2008089464 . WO2008093639 . WO2008096769 . WO2008096820 . WO2008096829 . US2008194617 . WO2008099944 . WO2008108602 . WO2008109334 . WO2008110062 . WO2008126731 . WO2008126732 . WO2008137105 . WO2009005672 . WO2009038681 . WO2009046606 . WO2009080821 . WO2009083526 . WO2009102226 . WO2009128558 . WO2009139340 described.

In one embodiment of the invention, the compound of formula I is administered in combination with Competact ^™ , a solid combination of pioglitazone hydrochloride with metformin hydrochloride.

In one embodiment of the invention, the compound of formula I is administered in combination with Tandemact ^™ , a solid combination of pioglitazone with glimepride.

In a further embodiment of the invention, the compound of the formula I in combination with a solid combination of pioglitazone hydrochloride with an angiotensin II agonist, such. TAK-536.

In one embodiment of the invention, the compound of the formula I in combination with a PPAR alpha agonist or mixed PPAR alpha / PPAR delta agonists, such. GW9578, GW-590735, K-111, LY-674, KRP-101, DRF-10945, LY-518674, CP-900691, BMS-687453, BMS-711939, or those as described in U.S. Pat WO2001040207 . WO2002096894 . WO2005097076 . WO2007056771 . WO2007087448 . WO2007089667 . WO2007089557 . WO2007102515 . WO2007103252 . JP2007246474 . WO2007118963 . WO2007118964 . WO2007126043 . WO2008006043 . WO2008006044 . WO2008012470 . WO2008035359 . WO2008087365 . WO2008087366 . WO2008087367 . WO2008117982 . JP2009023975 . WO2009033561 . WO2009047240 . WO2009072581 . WO2009080248 . WO2009080242 . WO2009149819 . WO2009149820 . WO2009147121 . WO2009153496 . WO2010008299 . WO2010014771 described.

In one embodiment of the invention, the compound of formula I in combination with a mixed PPAR alpha / gamma agonist, such as. Naveglitazar, aleglitazar, LY-510929, ONO-5129, E-3030, AVE 8042, AVE 8134, AVE 0847, CKD-501 (lobeglitazone sulfate), MBX-213, KY-201, BMS-759509, or as described in U.S. Pat WO 00/64888 . WO 00/64876 . WO03 / 020269 . WO2004024726 . WO2007099553 . US2007276041 . WO2007085135 . WO2007085136 . WO2007141423 . WO2008016175 . WO2008053331 . WO2008109697 . WO2008109700 . WO2008108735 . WO2009026657 . WO2009026658 . WO2009149819 . WO2009149820 or in JP Berger et al., TRENDS in Pharmacological Sciences 28 (5), 244-251, 2005 described, administered.

In one embodiment of the invention, the compound of the formula I in combination with a PPAR delta agonist, such. B. GW-501516 or as in WO2006059744 . WO2006084176 . WO2006029699 . WO2007039172 - WO2007039178 . WO2007071766 . WO2007101864 . US2007244094 . WO2007119887 . WO2007141423 . US2008004281 . WO2008016175 . WO2008066356 . WO2008071311 . WO2008084962 . US2008176861 . WO2009012650 . US2009137671 . WO2009080223 . WO2009149819 . WO2009149820 . WO2010000353 described.

In one embodiment of the invention, the compound of the formula I in combination with a pan-SPPARM (selective PPAR modulator alpha, gamma, delta), such. GFT-505, indeglitazar or such as those in WO2008035359 . WO2009072581 described.

In one embodiment, the compound of formula I is administered in combination with metaglidases or with MBX-2044 or other partial PPAR gamma agonist / antagonist.

In one embodiment, the compound of the formula I in combination with an α-glucosidase inhibitor, such as. As miglitol or acarbose or those, such as. In WO2007114532 . WO2007140230 . US2007287674 . US2008103201 . WO2008065796 . WO2008082017 . US2009076129 described.

In one embodiment, the compound of the formula I in combination with an inhibitor of glycogen phosphorylase, such. B. PSN-357 or FR-258900 or such as in WO2003084922 . WO2004007455 . WO2005073229 - 31 . WO2005067932 . WO2008062739 . WO2008099000 . WO2008113760 . WO2009016118 . WO2009016119 . WO2009030715 . WO2009045830 . WO2009045831 . WO2009127723 described, administered.

In another embodiment, the compound of the formula I in combination with an inhibitor of the interaction of the liver glycogen phosphorylase with the protein PPP1R3 (GL subunit of the glycogen-associated protein phosphatase 1 (PP1)), such. In WO2009030715 described, administered.

In one embodiment, the compound of the formula I in combination with glucagon receptor antagonists, such as. A-770077 or NNC-25-2504 or as in WO2004100875 . WO2005065680 . WO2006086488 . WO2007047177 . WO2007106181 . WO2007111864 . WO2007120270 . WO2007120284 . WO2007123581 . WO2007136577 . WO2008042223 . WO2008098244 . WO2009057784 . WO2009058662 . WO2009058734 . WO2009110520 . WO2009120530 . WO2009140342 . WO2010019828 described, administered.

In another embodiment, 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.

In one embodiment, the compound of the formula I in combination with activators of glucokinase, such as. B. LY-2121260 ( WO2004063179 ), PSN-105, PSN-110, GKA-50 or such as those 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 . WO2008050117 . WO2008050101 . WO2008059625 . US2008146625 . WO2008078674 . WO2008079787 . WO2008084043 . WO2008084044 . WO2008084872 . WO2008089892 . WO2008091770 . WO2008075073 . WO2008084043 . WO2008084044 . WO2008084872 . WO2008084873 . WO2008089892 . WO2008091770 . JP2008189659 . WO2008104994 . WO2008111473 . WO2008116107 . WO2008118718 . WO2008120754 . US2008280875 . WO2008136428 . WO2008136444 . WO2008149382 . WO2008154563 . WO2008156174 . WO2008156757 . US2009030046 . WO2009018065 . WO2009023718 . WO2009039944 . WO2009042435 . WO2009046784 . WO2009046802 . WO2009047798 . WO2009063821 . WO2009081782 . WO2009082152 . WO2009083553 . WO2009091014 . US2009181981 . WO2009092432 . WO2009099080 . WO2009106203 . WO2009106209 . WO2009109270 . WO2009125873 . WO2009127544 . WO2009127546 . WO2009128481 . WO2009133687 . WO2009140624 . WO2010013161 . WO2010015849 . WO2010018800 described.

In one embodiment, the compound of the formula I in combination with an inhibitor of gluconeogenesis, as z. In FR-225654 . WO2008053446 described.

In one embodiment, the compound of the formula I in combination with inhibitors of fructose 1,6-bisphosphatase (FBPase) such. MB-07729, CS-917 (MB-06322) or MB-07803 or such as those in WO2006023515 . WO2006104030 . WO2007014619 . WO2007137962 . WO2008019309 . WO2008037628 . WO2009012039 . EP2058308 . WO2009068467 . WO2009068468 described.

In one embodiment, the compound of the formula I in combination with modulators of the glucose transporter-4 (GLUT4), such as. B. KST-48 ( DO. Lee et al .: Arzneim.-Forsch. Drug Res. 54 (12), 835 (2004) ).

In one embodiment, the compound of formula I is used in combination with inhibitors of glutamine-fructose 6-phosphate amidotransferase (GFAT), as described e.g. In WO2004101528 described.

In one embodiment, the compound of formula I in combination with inhibitors of dipeptidyl peptidase-IV (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 another salt thereof, S-40010, S-40755, PF-00734200, BI-1356, PHX 1149, DSP-7238, alogliptin benzoate, linagliptin, melogliptin, carmegliptin, or such compounds as described in U.S. Pat WO2003074500 . WO2003106456 . WO2004037169 . WO200450658 . WO2005037828 . WO2005058901 . WO2005012312 . WO2005 / 012308 . WO2006039325 . WO2006058064 . WO2006015691 . WO2006015701 . WO2006015699 . WO2006015700 . WO2006018117 . WO2006099943 . WO2006099941 . JP2006160733 . WO2006071752 . WO2006065826 . WO2006078676 . WO2006073167 . WO2006068163 . WO2006085685 . WO2006090915 . WO2006104356 . WO2006127530 . WO2006111261 . US2006890898 . US2006803357 . US2006303661 . WO2007015767 (LY-2463665), WO2007024993 . WO2007029086 . WO2007063928 . WO2007070434 . WO2007071738 . WO2007071576 . WO2007077508 . WO2007087231 . WO2007097931 . WO2007099385 . WO2007100374 . WO2007112347 . WO2007112669 . WO2007113226 . WO2007113634 . WO2007115821 . WO2007116092 . US2007259900 . EP1852108 . US2007270492 . WO2007126745 . WO2007136603 . WO2007142253 . WO2007148185 . WO2008017670 . US2008051452 . WO2008027273 . WO2008028662 . WO2008029217 . JP2008031064 . JP2008063256 . WO2008033851 . WO2008040974 . WO2008040995 . WO2008060488 . WO2008064107 . WO2008066070 . WO2008077597 . JP2008156318 . WO2008087560 . WO2008089636 . WO2008093960 . WO2008096841 . WO2008101953 . WO2008118848 . WO2008119005 . WO2008119208 . WO2008120813 . WO2008121506 . WO2008130151 . WO2008131149 . WO2009003681 . WO2009014676 . WO2009025784 . WO2009027276 . WO2009037719 . WO2009068531 . WO2009070314 . WO2009065298 . WO2009082134 . WO2009082881 . WO2009084497 . WO2009093269 . WO2009099171 . WO2009099172 . WO2009111239 . WO2009113423 . WO2009116067 . US2009247532 . WO2010000469 . WO2010015664 described.

In one embodiment, the compound of formula I is administered in combination with Janumet ^™ , a solid combination of sitagliptin phosphate with metformin hydrochloride.

In one embodiment, the compound of formula I in combination with Eucreas ^®, a fixed combination of vildagliptin with metformin hydrochloride is administered.

In another embodiment, the compound of formula I is administered in combination with a solid combination of alogliptin benzoate with pioglitazone.

In one embodiment, the compound of formula I is administered in combination with a solid combination of a salt of sitagliptin with metformin hydrochloride.

In one embodiment, the compound of the formula I in combination with a combination of a DPP-IV inhibitor with omega-3 fatty acids or omega-3 fatty acid esters, such. In WO2007128801 described, administered.

In one embodiment, the compound of formula I in combination with a combination of a DPP-IV inhibitor with metformin hydrochloride, such as. In WO2009121945 described, administered.

In one embodiment, the compound of the formula I is administered in combination with a combination of a DPP-IV inhibitor with a GPR-119 agonist, such as e.g. In WO2009123992 described, administered.

In one embodiment, the compound of the formula I in combination with a combination of a DPP-IV inhibitor with miglitol, such. In WO2009139362 described, administered.

In one embodiment, the compound of formula I is administered in combination with a solid combination of a salt of sitagliptin with metformin hydrochloride.

In one embodiment, the compound of formula I is administered in combination with a fixed combination of alopliptin benzoate with pioglitazone hydrochloride.

In one embodiment, the compound of formula I in combination with an insulin secretion enhancing substance, such as. B. KCP-265 ( WO2003097064 ), or such as those in WO2007026761 . WO2008045484 . US2008194617 . WO2009109259 . WO2009109341 described.

In one embodiment, the compound of the formula I in combination with agonists of the glucose-dependent insulinotropic receptor (GDIR) such. B. APD-668 administered.

In one embodiment of the invention, the compound of the formula I in combination with an ATP citrate lyase inhibitor, such as. SB-204990.

In one embodiment, the compound of formula I in combination with modulators of the sodium-dependent glucose transporter 1 and / or 2 (SGLT1, SGLT2), such as. KGA-2727, T-1095, SGL-0010, AVE 2268, SAR 7226, SGL-5083, SGL-5085, SGL-5094, ISIS-388626, sergliflozin, dapagliflozin or remogliflozin etanobate, canagliflozin or as described e.g. In WO2004007517 . WO200452903 . WO200452902 . PCT / EP2005 / 005959 . WO2005085237 . JP2004359630 . WO2005121161 . WO2006018150 . WO2006035796 . WO2006062224 . WO2006058597 . WO2006073197 . WO2006080577 . WO2006087997 . WO2006108842 . WO2007000445 . WO2007014895 . WO2007080170 . WO2007093610 . WO2007126117 . WO2007128480 . WO2007129668 . US2007275907 . WO2007136116 . WO2007143316 . WO2007147478 . WO2008001864 . WO2008002824 . WO2008013277 . WO2008013280 . WO2008013321 . WO2008013322 . WO2008016132 . WO2008020011 . JP2008031161 . WO2008034859 . WO2008042688 . WO2008044762 . WO2008046497 . WO2008049923 . WO2008055870 . WO2008055940 . WO2008069327 . WO2008070609 . WO2008071288 . WO2008072726 . WO2008083200 . WO2008090209 . WO2008090210 . WO2008101586 . WO2008101939 . WO2008116179 . WO2008116195 . US2008242596 . US2008287529 . WO2009026537 . WO2009049731 . WO2009076550 . WO2009084531 . WO2009096503 . WO2009100936 . WO2009121939 . WO2009124638 . WO2009128421 . WO2009135673 . WO2010009197 . WO2010018435 . WO2010018438 or from AL Handlon in Expert Opinion. Ther. Patents (2005) 15 (11), 1531-1540 described.

In a further embodiment of the invention, the compound of the formula I is combined with a solid combination of a SGLT inhibitor with a DPP-IV inhibitor as described in U.S. Pat WO2009091082 described, administered.

In one embodiment, the compound of formula I in combination with a stimulator of glucose transport, such. In WO2008136392 . WO2008136393 described, administered.

In one embodiment, the compound of the formula I in combination with inhibitors of 11-beta-hydroxysteroid dehydrogenase-1 (11β-HSD1), such as. For example, BVT-2733, JNJ-25918646, INCB-13739, INCB-20817, DIO-92 ((-) - ketoconazole) or such. In WO200190090 - 94 . WO200343999 . WO2004112782 . WO200344000 . WO200344009 . WO2004112779 . WO2004113310 . WO2004103980 . WO2004112784 . WO2003065983 . WO2003104207 . WO2003104208 . WO2004106294 . WO2004011410 . WO2004033427 . WO2004041264 . WO2004037251 . WO2004056744 . WO2004058730 . WO2004065351 . WO2004089367 . WO2004089380 . WO2004089470 - 71 . WO2004089896 . WO2005016877 . WO2005063247 . WO2005097759 . WO2006010546 . WO2006012227 . WO2006012173 . WO2006017542 . WO2006034804 . WO2006040329 . WO2006051662 . WO2006048750 . WO2006049952 . WO2006048331 . WO2006050908 . WO2006024627 . WO2006040329 . WO2006066109 . WO2006074244 . WO2006078006 . WO2006106423 . WO2006132436 . WO2006134481 . WO2006134467 . WO2006135795 . WO2006136502 . WO2006138508 . WO2006138695 . WO2006133926 . WO2007003521 . WO2007007688 . US2007066584 . WO2007029021 . WO2007047625 . WO2007051811 . WO2007051810 . WO2007057768 . WO2007058346 . WO2007061661 . WO2007068330 . WO2007070506 . WO2007087150 . WO2007092435 . WO2007089683 . WO2007101270 . WO2007105753 . WO2007107470 . WO2007107550 . WO2007111921 . US2007207985 . US2007208001 . WO2007115935 . WO2007118185 . WO2007122411 . WO2007124329 . WO2007124337 . WO2007124254 . WO2007127688 . WO2007127693 . WO2007127704 . WO2007127726 . WO2007127763 . WO2007127765 . WO2007127901 . US2007270424 . JP2007291075 . WO2007130898 . WO2007135427 . WO2007139992 . WO2007144394 . WO2007145834 . WO2007145835 . WO2007146761 . WO2008000950 . WO2008000951 . WO2008003611 . WO2008005910 . WO2008006702 . WO2008006703 . WO2008011453 . WO2008012532 . WO2008024497 . WO2008024892 . WO2008032164 . WO2008034032 . WO2008043544 . WO2008044656 . WO2008046758 . WO2008052638 . WO2008053194 . WO2008071169 . WO2008074384 . WO2008076336 . WO2008076862 . WO2008078725 . WO2008087654 . WO2008088540 . WO2008099145 . WO2008101885 . WO2008101886 . WO2008101907 . WO2008101914 . WO2008106128 . WO2008110196 . WO2008119017 . WO2008120655 . WO2008127924 . WO2008130951 . WO2008134221 . WO2008142859 . WO2008142986 . WO2008157752 . WO2009001817 . WO2009010416 . WO2009017664 . WO2009020140 . WO2009023180 . WO2009023181 . WO2009023664 . WO2009026422 . WO2009038064 . WO2009045753 . WO2009056881 . WO2009059666 . WO2009061498 . WO2009063061 . WO2009070497 . WO2009074789 . WO2009075835 . WO2009088997 . WO2009090239 . WO2009094169 . WO2009098501 . WO2009100872 . WO2009102428 . WO2009102460 . WO2009102761 . WO2009106817 . WO2009108332 . WO2009112691 . WO2009112845 . WO2009114173 . WO2009117109 . US2009264401 . WO2009118473 . WO2009131669 . WO2009132986 . WO2009134384 . WO2009134387 . WO2009134392 . WO2009134400 . WO2009135581 . WO2009138386 . WO2010006940 . WO2010010157 . WO2010010174 . WO2010011917 described.

In one embodiment, the compound of the formula I is used in combination with inhibitors of protein tyrosine phosphatase-1B (PTP-1B), as described, for. In WO200119830 - 31 . WO200117516 . WO2004506446 . WO2005012295 . WO2005116003 . WO2005116003 . WO2006007959 . DE 10 2004 060 542.4 . WO2007009911 . WO2007028145 . WO2007067612 - 615 . WO2007081755 . WO2007115058 . US2008004325 . WO2008033455 . WO2008033931 . WO2008033932 . WO2008033934 . WO2008089581 . WO2008148744 . WO2009032321 . WO2009109999 . WO2009109998 described.

In another embodiment, the compound of formula I in combination with stimulators of tyrosine kinase B (Trk-B), as described, for. In WO2010014613 described.

In one embodiment of the invention, the compound of formula I is administered in combination with an agonist of GPR109A (HM74A receptor agonists; NAR agonists (nicotinic acid receptor agonists)), such as. B. nicotinic acid or "extended release niacin" in conjunction with MK-0524A (laropiprant) or MK-0524 or such compounds as described in WO2004041274 . WO2006045565 . WO2006045564 . WO2006069242 . WO2006085108 . WO2006085112 . WO2006085113 . WO2006124490 . WO2006113150 . WO2007002557 . WO2007017261 . WO2007017262 . WO2007017265 . WO2007015744 . WO2007027532 . WO2007092364 . WO2007120575 . WO2007134986 . WO2007150025 . WO2007150026 . WO2008016968 . WO2008051403 . WO2008086949 . WO2008091338 . WO2008097535 . WO2008099448 . US2008234277 . WO2008127591 described.

In another embodiment of the invention, the compound of formula I is administered in combination with a solid combination of niacin with simvastatin.

In another embodiment of the invention, 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.

In one embodiment of the invention, the compound of the formula I is administered in combination with nicotinic acid or another nicotinic acid receptor agonist and a prostaglandin DP receptor antagonist, such as e.g. Such as those in WO2008039882 described.

In another embodiment of the invention, the compound of formula I in combination with a solid combination of niacin with meloxicam, such as. In WO2009149056 described, administered.

In another embodiment of the invention, the compound of formula I in combination with an agonist of GPR116, as described, for. In WO2006067531 . WO2006067532 described.

In one embodiment, the compound of formula I is used in combination with modulators of the GPR40, as described, for. In WO2007013689 . WO2007033002 . WO2007106469 . US2007265332 . WO2007123225 . WO2007131619 . WO2007131620 . WO2007131621 . US2007265332 . WO2007131622 . WO2007136572 . WO2008001931 . WO2008030520 . WO2008030618 . WO2008054674 . WO2008054675 . WO2008066097 . US2008176912 . WO2008130514 . WO2009038204 . WO2009039942 . WO2009039943 . WO2009048527 . WO2009054479 . WO2009058237 . WO2009111056 . WO2010012650 described.

In one embodiment, the compound of formula I is used in combination with modulators of GPR119 (G protein-coupled glucose-dependent insulinotropic receptor), such as e.g. For example, PSN-119-1, PSN-821, PSN-119-2, MBX-2982 or such as z. In WO2004065380 . WO2005061489 (PSN-632408), WO2006083491 . WO2007003960 - 62 and WO2007003964 . WO2007035355 . WO2007116229 . WO2007116230 . WO2008005569 . WO2008005576 . WO2008008887 . WO2008008895 . WO2008025798 . WO2008025799 . WO2008025800 . WO2008070692 . WO2008076243 . WO200807692 . WO2008081204 . WO2008081205 . WO2008081206 . WO2008081207 . WO2008081208 . WO2008083238 . WO2008085316 . WO2008109702 . WO2008130581 . WO2008130584 . WO2008130615 . WO2008137435 . WO2008137436 . WO2009012275 . WO2009012277 . WO2009014910 . WO2009034388 . WO2009038974 . WO2009050522 . WO2009050523 . WO2009055331 . WO2009105715 . WO2009105717 . WO2009105722 . WO2009106561 . WO2009106565 . WO2009117421 . WO2009125434 . WO2009126535 . WO2009129036 . US2009286812 . WO2009143049 . WO2009150144 . WO2010001166 . WO2010004343 . WO2010004344 . WO2010004345 . WO2010004346 . WO2010004347 . WO2010004348 . WO2010008739 . WO2010006191 . WO2010009183 . WO2010009195 . WO2010009207 . WO2010009208 . WO2010014593 described.

In a further embodiment, the compound of formula I in combination with modulators of GPR120, as described, for. In EP1688138 . WO2008066131 . WO2008066131 . WO2008103500 . WO2008103501 . WO2008139879 . WO2009038204 . WO2009147990 . WO2010008831 described.

In another embodiment, the compound of the formula I in combination with antagonists of GPR105, as described, for. In WO2009000087 . WO2009070873 described.

In a further embodiment, the compound of formula I in combination with agonists of GPR43, such as. B. ESN-282 administered.

In one embodiment, the compound of the formula I in combination with inhibitors of hormone-sensitive lipase (HSL) and / or phospholipases, such. In WO2005073199 . WO2006074957 . WO2006087309 . WO2006111321 . WO2007042178 . WO2007119837 . WO2008122352 . WO2008122357 . WO2009009287 described, administered.

In one embodiment, the compound of the formula I in combination with inhibitors of endothelial lipase, such as. In WO2007110216 described, administered.

In one embodiment, the compound of the formula I in combination with a phospholipase A2 inhibitor such. B. Darapladib or A-002 or such, as in WO2008048866 . WO20080488867 . US2009062369 described.

In one embodiment, the compound of formula I is used in combination with myricitrin, a lipase inhibitor ( WO2007119827 ).

In one embodiment, the compound of the formula I in combination with an inhibitor of glycogen synthase kinase-3 beta (GSK-3 beta), such as. 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 . WO2008077138 . EP1939191 . EP1939192 . WO2008078196 . WO2008094992 . WO2008112642 . WO2008112651 . WO2008113469 . WO2008121063 . WO2008121064 . EP-1992620 . EP-1992621 . EP1992624 . EP-1992625 . WO2008130312 . WO2009007029 . EP2020232 . WO2009017452 . WO2009035634 . WO2009035684 . WO2009038385 . WO2009095787 . WO2009095788 . WO2009095789 . WO2009095792 . WO2009145814 . US2009291982 . WO2009154697 . WO2009156857 . WO2009156859 . WO2009156860 . WO2009156861 . WO2009156863 . WO2009156864 . WO2009156865 . WO2010013168 . WO2010014794 described.

In one embodiment, the compound of formula I in combination with an inhibitor of phosphoenolpyruvate carboxykinase (PEPCK), such as. B. such as in WO2004074288 described, administered.

In one embodiment, the compound of formula I in combination with an inhibitor of phosphoinositide kinase-3 (PI3K), such as. B. such as in WO2008027584 . WO2008070150 . WO2008125833 . WO2008125835 . WO2008125839 . WO2009010530 . WO2009026345 . WO2009071888 . WO2009071890 . WO2009071895 described, administered.

In one embodiment, the compound of the formula I is used in combination with a serum / glucocorticoid regulated kinase (SGK) inhibitor, such as, e.g. In WO2006072354 . WO2007093264 . WO2008009335 . WO2008086854 . WO2008138448 described, administered.

In one embodiment, the compound of formula I in combination with a modulator of the glucocorticoid receptor, such. In WO2008057855 . WO2008057856 . WO2008057857 . WO2008057859 . WO2008057862 . WO2008059867 . WO2008059866 . WO2008059865 . WO2008070507 . WO2008124665 . WO2008124745 . WO2008146871 . WO2009015067 . WO2009040288 . WO2009069736 . WO2009149139 described, administered.

In one embodiment, the compound of formula I in combination with a modulator of the mineralocorticoid receptor (MR), such as. Drospirenone, or such as those in WO2008104306 . WO2008119918 described.

In one embodiment, the compound of formula I in combination with an inhibitor of protein kinase C beta (PKC beta), such as. Ruboxistaurin, or such as in WO2008096260 . WO2008125945 described.

In one embodiment, the compound of formula I in combination with an inhibitor of protein kinase D, such as. B. doxazosin ( WO2008088006 ).

In a further embodiment, the compound of the formula I in combination with an activator / modulator of the AMP-activated protein kinase (AMPK), as described, for. In WO2007062568 . WO2008006432 . WO2008016278 . WO2008016730 . WO2008020607 . WO2008083124 . WO2008136642 . WO2009019445 . WO2009019446 . WO2009019600 . WO2009028891 . WO2009065131 . WO2009076631 . WO2009079921 . WO2009100130 . WO2009124636 . WO2009135580 . WO2009152909 described.

In one embodiment, the compound of the formula I in combination with an inhibitor of ceramide kinase, as z. In WO2007112914 . WO2007149865 described.

In another embodiment, the compound of formula I in combination with an inhibitor of MAPK-interacting kinase 1 or 2 (MNK1 or 2), as described, for. In WO2007104053 . WO2007115822 . WO2008008547 . WO2008075741 described.

In one embodiment, the compound of the formula I in combination with inhibitors of "I-kappaB kinase" (IKK inhibitors), as described, for. In WO2001000610 . WO2001030774 . WO2004022057 . WO2004022553 . WO2005097129 . WO2005113544 . US2007244140 . WO2008099072 . WO2008099073 . WO2008099073 . WO2008099074 . WO2008099075 . WO2009056693 . WO2009075277 . WO2009089042 . WO2009120801 described.

In another embodiment, the compound of formula I in combination with inhibitors of NF-kappaB (NFKB) activation, as described, for. As salsalates administered.

In a further embodiment, the compound of the formula I in combination with inhibitors of ASK-1 (apoptosis signal-regulating kinase 1), as described for. In WO2008016131 . WO2009123986 described.

In one embodiment of the invention, the compounds of the formula I are administered in combination with an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin, pitavastatin, L-659699, BMS-644950, NCX-6560 or those as they are in US2007249583 . WO2008083551 . WO2009054682 described.

In a further embodiment of the invention, the compound of the formula I in combination with a Farnesoid X receptor (FXR) modulators such. B. WAY-362450 or such as in WO2003099821 . WO2005056554 . WO2007052843 . WO2007070796 . WO2007092751 . JP2007230909 . WO2007095174 . WO2007140174 . WO2007140183 . WO2008000643 . WO2008002573 . WO2008025539 . WO2008025540 . JP2008214222 . JP2008273847 . WO2008157270 . US2008299118 . US2008300235 . WO2009005998 . WO2009012125 . WO2009027264 . WO2009062874 . US2009131409 . US2009137554 . US2009163552 . WO2009127321 . EP2128158 described, administered.

In another embodiment of the invention, the compound of the formula I in combination with a ligand of the liver X receptor (LXR), such. In WO2007092965 . WO2008041003 . WO2008049047 . WO2008065754 . WO2008073825 . US2008242677 . WO2009020683 . US2009030082 . WO2009021868 . US2009069373 . WO2009024550 . WO2009040289 . WO2009086123 . WO2009086129 . WO2009086130 . WO2009086138 . WO2009107387 . US2009247587 . WO2009133692 . WO2008138438 . WO2009144961 . WO2009150109 described, administered.

In one embodiment of the invention, the compound of the formula I in combination with a fibrate, such as. Fenofibrate, clofibrate, bezafibrate, or such as those in WO2008093655 described.

In one embodiment of the invention, the compound of the formula I in combination with fibrates, such as. The choline salt of fenofibrate (SLV-348, Trilipix ^™ ).

In one embodiment of the invention, the compound of the formula I in combination with fibrates, such as. As the choline salt of fenofibrate (Trilipix ^TM ) and a HMGCoA reductase inhibitor, such as. Rosuvastatin.

In a further embodiment of the invention, the compound of the formula I is administered in combination with bezafibrate and diflunisal.

In a further embodiment of the invention, the compound of formula I is administered in combination with a fixed combination of fenofibrate or a salt thereof with simvastatin, rosuvastatin, fluvastatin, lovastatin, cerivastatin, pravastatin, pitavastatin or atorvastatin.

In a further embodiment of the invention the compound of formula I in combination with Synordia ^®, a fixed combination of fenofibrate with metformin is administered.

In another embodiment of the invention, the compound of the formula I is used in combination with a solid combination of metformin with an MTP inhibitor, as in WO2009090210 described, administered.

In one embodiment of the invention, the compound of the formula I in combination with a cholesterol resorption inhibitor, such. Ezetimibe, tiqueside, pamaqueside, FM-VP4 (sitostanol / campesterol ascorbyl phosphate; Forbes Medi-Tech, WO2005042692 . WO2005005453 ), MD-0727 (Microbia Inc., WO2005021497 . WO2005021495 ) or with compounds as in WO2002066464 . WO2005000353 (Kotobuki Pharmaceutical Co. Ltd.) or WO2005044256 or WO2005062824 (Merck & Co.) or WO2005061451 and WO2005061452 (AstraZeneca AB) and WO2006017257 (Phenomix) or WO2005033100 (Lipideon Biotechnology AG) or as 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 . WO2008085300 . WO2008104875 . US2008280836 . WO2008108486 described, administered.

In one embodiment of the invention, the compound of the formula I in combination with an NPC1L1 antagonist, such. B. such as those in WO2008033464 . WO2008033465 described.

In one embodiment of the invention, the compound of formula I is administered in combination with Vytorin ^™ , 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.

In one embodiment of the invention, the compound of formula I is administered in combination with a fixed combination of ezetimibe with fenofibrate.

In one embodiment of the invention, the further active ingredient is a Diphenylazetidinonderivat such. In US 6,992,067 or US 7,205,290 described.

In a further embodiment of the invention, the further active ingredient is a Diphenylazetidinonderivativ such. In US 6,992,067 or US 7,205,290 described combined with a statin such. Simvastatin, fluvastatin, pravastatin, lovastatin, cerivastatin, atorvastatin, pitavastatin or rosuvastatin.

In one embodiment of the invention, the compound of formula I is administered in combination with a solid combination of Lapaquistat, a squalene synthase inhibitor, with atorvastatin.

In a further embodiment of the invention, the compound of the formula I is administered in combination with a conjugate consisting of the HMGCoA reductase inhibitor atorvastatin with the renin inhibitor aliskiren ( WO2009090158 ).

In one embodiment of the invention, the compound of the formula I in combination with a CETP inhibitor, such as. Torcetrapib, anacetrapib, or JTT-705 (dalcetrapib), or those as described in U.S. Pat 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 . WO2008059513 . WO2008070496 . WO2008115442 . WO2008111604 . WO2008129951 . WO2008141077 . US2009118287 . WO2009062371 . WO2009071509 described.

In one embodiment of the invention, the compound of the formula I is used in combination with bile acid absorption inhibitors (inhibitors of the intestinal bile acid transporter (IBAT)) (see, for example, US Pat. US 6,245,744 . US 6,221,897 or WO00 / 61568 ), such. HMR 1741 or such as in 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 described, administered.

In one embodiment, the compound of formula I is administered in combination with agonists of GPBAR1 (G-protein-coupled bile acid receptor-1; B. INT-777 or such as z. In US20060199795 . WO2007110237 . WO2007127505 . WO2008009407 . WO2008067219 . WO2008067222 . FR2908310 . WO2008091540 . WO2008097976 . US2009054304 . WO2009026241 . WO2009146772 . WO2010014739 . WO2010014836 described.

In one embodiment, the compound of formula I in combination with histone deacetylase modulators, such as. B. ursodeoxycholic acid as in WO2009011420 described, administered.

In one embodiment, the compound of formula I is used in combination with inhibitors / modulators of the TRPM5 channel (TRP cation channel M5), as described e.g. In WO2008097504 . WO2009038722 described.

In one embodiment, the compound of the formula I in combination with inhibitors / modulators of the TRPA1 channel (TRP cation channel A1), as described, for. In US2009176883 . WO2009089083 . WO2009144548 described.

In one embodiment, the compound of formula I is used in combination with inhibitors / modulators of the TRPV3 channel (TRP cation channel V3), as described e.g. In WO2009084034 . WO2009130560 described.

In one embodiment of the invention, the compound of the formula I in combination with a polymeric bile acid adsorber, such. Cholestyramine, colesevelam hydrochloride.

In one embodiment of the invention, the compound of the formula I is administered in combination with colesevelam hydrochloride and metformin or a sulfonylurea or insulin.

In one embodiment of the invention, the compound of the formula I is administered in combination with tocotrienol and insulin or an insulin derivative.

In one embodiment of the invention, the compound of formula I is administered in combination with a phytosterol-containing chewing gum (Reductol ^™ ).

In one embodiment of the invention, the compound of the formula I in combination with an inhibitor of the microsomal triglyceride transfer protein (MTTP inhibitor), such. Implitapide, BMS-201038, R-103757, AS-1552133, SLx-4090, AEGR-733, JTT-130 or those as in WO2005085226 . WO2005121091 . WO2006010423 . WO2006113910 . WO2007143164 . WO2008049806 . WO2008049808 . WO2008090198 . WO2008100423 . WO2009014674 described, administered.

In a further embodiment of the invention, the compound of the formula I is used in combination with a combination of a cholesterol absorption inhibitor, such as. Ezetimibe, and an inhibitor of Triglyceride transfer protein (MTP inhibitor), such as. Implitapide, as in WO2008030382 or in WO2008079398 described, administered.

In one embodiment of the invention, the compound of the formula I in combination with an antihypertriglyceridemic active substance, such as. Such as those in WO2008032980 described.

In another embodiment of the invention, the compound of the formula I in combination with an antagonist of the somatostatin 5 receptor (SST5 receptor), such. Such as those in WO2006094682 described.

In one embodiment of the invention, the compound of the formula I in combination with an ACAT inhibitor, such. As Avasimibe, SMP-797 or KY-382 or such, as in WO2008087029 . WO2008087030 . WO2008095189 . WO2009030746 . WO2009030747 . WO2009030750 . WO2009030752 . WO2009070130 . WO2009081957 . WO2009081957 described.

In a further embodiment of the invention, the compound of the formula I in combination with an inhibitor of hepatic carnitine palmitoyltransferase-1 (L-CPT1), as z. In WO2007063012 . WO2007096251 (ST-3473), WO2008015081 . US2008103182 . WO2008074692 . WO2008145596 . WO2009019199 . WO2009156479 . WO2010008473 described.

In another embodiment of the invention, the compound of the formula I in combination with an inhibitor of carnitine O-palmitoyltransferase II (CPT2), as z. In US2009270500 . US2009270505 . WO2009132978 . WO2009132979 described.

In a further embodiment of the invention, the compound of the formula I in combination with a modulator of serine palmitoyltransferase (SPT), as described, for. In WO2008031032 . WO2008046071 . WO2008083280 . WO2008084300 described.

In one embodiment of the invention, the compound of the formula I in combination with a squalene synthetase inhibitor, such as. BMS-188494, TAK-475 (Lapaquistat acetate) or as in WO 2005/077907 . JP2007022943 . WO2008003424 . WO2008132846 . WO2008133288 . WO2009136396 described, administered.

In one embodiment of the invention, the compound of formula I is administered in combination with ISIS-301012 (mipomersen), an antisense oligonucleotide capable of regulating the apolipoprotein B gene.

In one embodiment of the invention, the compound of formula I is administered in combination with apolipoprotein (ApoB) SNALP, a therapeutic product containing an siRNA (directed against the ApoB gene).

In one embodiment of the invention, the compound of the formula I in combination with a stimulator of the ApoA-1 gene, as z. In WO2008092231 described.

In one embodiment of the invention, the compound of the formula I in combination with a modulator of the synthesis of apolipoprotein C-III, such. B. ISIS-APOCIIIRx administered.

In one embodiment of the invention, the compound of the formula I in combination with an LDL receptor inducers (see US 6,342,512 ), such. HMR1171, HMR1586, or such as in WO2005097738 . WO2008020607 described, administered.

In another embodiment of the invention, the compound of the formula I in combination with an HDL cholesterol-increasing agent, such. Such as those in WO2008040651 . WO2008099278 . WO2009071099 . WO2009086096 . US2009247550 described.

In one embodiment of the invention, the compound of the formula I in combination with an ABCA1 expression enhancer, as described, for. In WO2006072393 . WO2008062830 . WO2009100326 described, administered.

In one embodiment of the invention, the compound of the formula I in combination with a lipoprotein-lipase modulator, such. Ibrolipim (NO-1886).

In one embodiment of the invention, the compound of the formula I in combination with a lipoprotein (a) antagonist, such as. G., Gemcabene (CI-1027).

In one embodiment of the invention, the compound of the formula I in combination with a lipase inhibitor, such as. Orlistat or cetilistat (ATL-962).

In one embodiment of the invention, the compound of the formula I in combination with an adenosine A1 receptor agonist (adenosine A1 R), such. B. CVT-3619 or such as they are for. In EP1258247 . EP1375508 . WO2008028590 . WO2008077050 . WO2009050199 . WO2009080197 . WO2009100827 . WO2009112155 described.

In one embodiment of the invention, the compound of the formula I in combination with an adenosine A2B receptor agonist (adenosine A2B R) such. B. ATL-801 administered.

In another embodiment of the invention, 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 . WO2008070661 . WO2009010871 described, administered.

In a further embodiment of the invention, the compound of the formula I in combination with a ligand of the adenosine A1 / A2B receptors, such. In WO2008064788 . WO2008064789 . WO2009080198 . WO2009100827 . WO2009143992 described, administered.

In one embodiment of the invention, the compound of the formula I is used in combination with an adenosine A2B receptor antagonist (adenosine A2B R) as described in US Pat US2007270433 . WO2008027585 . WO2008080461 . WO2009037463 . WO2009037467 . WO2009037468 . WO2009118759 described.

In one embodiment, the compound of the formula I in combination with inhibitors of acetyl-CoA carboxylase (ACC1 and / or ACC2) such. B. such as in WO199946262 . WO200372197 . WO2003072197 . WO2005044814 . WO2005108370 . JP2006131559 . WO2007011809 . WO2007011811 . WO2007013691 . WO2007095601 - 603 . WO2007119833 . WO2008065508 . WO2008069500 . WO2008070609 . WO2008072850 . WO2008079610 . WO2008088688 . WO2008088689 . WO2008088692 . US2008171761 . WO2008090944 . JP2008179621 . US2008200461 . WO2008102749 . WO2008103382 . WO2008121592 . WO2009082346 . US2009253725 . JP2009196966 . WO2009144554 . WO2009144555 . WO2010003624 . WO2010002010 described, administered.

In another embodiment, the compound of the formula I is used in combination with modulators of the microsomal acyl-CoA: glycerol-3-phosphate acyltransferase 3 (GPAT3, described in WO2007100789 ) or with modulators of microsomal acyl-CoA: glycerol-3-phosphate acyltransferase 4 (GPAT4, described in WO2007100833 ) or with mitochondrial glycerol-3-phosphate-O-acyltransferase modulators described in US Patent Nos. 4,314,231; WO2010005922 administered.

In a further embodiment, the compound of the formula I is administered in combination with modulators of xanthine oxidoreductase (XOR).

In another embodiment, the compound of the formula I in combination with inhibitors of soluble epoxide hydrolase (sEH), as z. In WO2008051873 . WO2008051875 . WO2008073623 . WO2008094869 . WO2008112022 . WO2009011872 . WO2009049154 . WO2009049157 . WO2009049165 . WO2009073772 . WO2009097476 . WO2009111207 . WO2009129508 . WO2009151800 described.

In another embodiment, the compound of formula I is used in combination with CART modulators (see "Cocaine-amphetamine-regulated transcript-influencing energy metabolism, anxiety and gastric emptying in mice" Asakawa, A. et al .: Hormone and Metabolic Research (2001), 33 (9), 554-558 );
NPY antagonists such. For example, naphthalene-1-sulfonic acid {4 - [(4-amino-quinazolin-2-ylamino) -methyl] -cyclohexylmethyl} -amide hydrochloride (CGP 71683A) or Velneperite or those as described in U.S. Pat WO2009110510 are described;
NPY-5 receptor antagonists / receptor modulators such as L-152804 or the compound "NPY-5-BY" of the company Banyu or as they are, for. In WO2006001318 . WO2007103295 . WO2007125952 . WO2008026563 . WO2008026564 . WO2008052769 . WO2008092887 . WO2008092888 . WO2008092891 . WO2008129007 . WO2008134228 . WO2009054434 . WO2009095377 . WO2009131096 are described;
NPY-4 receptor antagonists as they are e.g. In WO2007038942 are described;
NPY-2 receptor antagonists / modulators as described, for. In WO2007038943 . WO2009006185 . US2009099199 . US2009099243 . US2009099244 . WO2009079593 . WO2009079597 are described;
Peptide YY 3-36 (PYY3-36) or analogous compounds such. CJC-1682 (PYY3-36 conjugated to human serum albumin via Cys34) or CJC-1643 (derivative of PYY3-36 conjugated to serum albumin in vivo) or those as described in U.S. Pat WO2005080424 . WO2006095166 . WO2008003947 . WO2009080608 are described;
NPY-2 receptor agonists as described, for. In WO2009080608 are described;
Derivatives of the peptide obestatin like them WO2006096847 are described;
CB1R (cannabinoid receptor 1) antagonists / inverse agonists, such as. Rimonabant, Surinabant (SR147778), SLV-319 (Ibipinabant), AVE-1625, Taranabant (MK-0364) or salts thereof, Otenabant (CP-945,598), Rosonabant, V-24343, or such compounds as described in e.g. B. EP 0656354 . WO 00/15609 . WO2001 / 64632 - 64634 . WO 02/076949 . WO2005080345 . WO2005080328 . WO2005080343 . WO2005075450 . WO2005080357 . WO200170700 . WO2003026647 - 48 . WO200302776 . WO2003040107 . WO2003007887 . WO2003027069 . US6,509,367 . WO200132663 . WO2003086288 . WO2003087037 . WO2004048317 . WO2004058145 . WO2003084930 . WO2003084943 . WO2004058744 . WO2004013120 . WO2004029204 . WO2004035566 . WO2004058249 . WO2004058255 . WO2004058727 . WO2004069838 . US20040214837 . US20040214855 . US20040214856 . WO2004096209 . WO2004096763 . WO2004096794 . WO2005000809 . WO2004099157 . US20040266845 . WO2004110453 . WO2004108728 . WO2004000817 . WO2005000820 . US20050009870 . WO200500974 . WO2004111033 - 34 . WO200411038 - 39 . WO2005016286 . WO2005007111 . WO2005007628 . US20050054679 . WO2005027837 . WO2005028456 . WO2005063761 - 62 . WO2005061509 . WO2005077897 . WO2006018662 . WO2006047516 . WO2006060461 . WO2006067428 . WO2006067443 . WO2006087480 . WO2006087476 . WO2006100208 . WO2006106054 . WO2006111849 . WO2006113704 . WO2007009705 . WO2007017124 . WO2007017126 . WO2007018459 . WO2007018460 . WO2007016460 . WO2007020502 . WO2007026215 . WO2007028849 . WO2007031720 . WO2007031721 . WO2007036945 . WO2007038045 . WO2007039740 . US20070015810 . WO2007046548 . WO2007047737 . WO2007057687 . WO2007062193 . WO2007064272 . WO2007079681 . WO2007084319 . WO2007084450 . WO2007086080 . EP1816125 . US2007213302 . WO2007095513 . WO2007096764 . US2007254863 . WO2007119001 . WO2007120454 . WO2007121687 . WO2007123949 . US2007259934 . WO2007131219 . WO2007133820 . WO2007136571 . WO2007136607 . WO2007136571 . US7297710 . WO2007138050 . WO2007139464 . WO2007140385 . WO2007140439 . WO2007146761 . WO2007148061 . WO2007148062 . US2007293509 . WO2008004698 . WO2008017381 . US2008021031 . WO2008024284 . WO2008031734 . WO2008032164 . WO2008034032 . WO2008035356 . WO2008036021 . WO2008036022 . WO2008039023 . WO2998043544 . WO2008044111 . WO2008048648 . EP1921072-A1 . WO2008053341 . WO2008056377 . WO2008059207 . WO2008059335 . WO2008062424 . WO2008068423 . WO2008068424 . WO2008070305 . WO2008070306 . WO2008074816 . WO2008074982 . WO2008075012 . WO2008075013 . WO2008075019 . WO2008075118 . WO2008076754 . WO2008081009 . WO2008084057 . EP1944295 . US2008090809 . US2008090810 . WO2008092816 . WO2008094473 . WO2008094476 . WO2008099076 . WO2008099139 . WO2008101995 . US2008207704 . WO2008107179 . WO2008109027 . WO2008112674 . WO2008115705 . WO2008118414 . WO2008119999 . WO200812000 . WO2008121257 . WO2008127585 . WO2008129157 . WO2008130616 . WO2008134300 . US2008262066 . US2008287505 . WO2009005645 . WO2009005646 . WO2009005671 . WO2009023292 . WO2009023653 . WO2009024819 . WO2009033125 . EP2042175 . WO2009053548 - WO2009053553 . WO2009054923 . WO2009054929 . WO2009059264 . WO2009073138 . WO2009074782 . WO2009075691 . WO2009078498 . WO2009087285 . WO2009074782 . WO2009097590 . WO2009097995 . WO2009097996 . WO2009097998 . WO2009097999 . WO2009098000 . WO2009106708 . US2009239909 . WO2009118473 . US2009264436 . US2009264476 . WO2009130234 . WO2009131814 . WO2009131815 . US2009286758 . WO2009141532 . WO2009141533 . WO2009153569 . WO2010003760 . WO2010012437 . WO2010019762 are described;
Cannabinoid receptor 1 / cannabinoid receptor 2 (CB1 / CB2) modulating compounds such as. B. delta-9-Tetrahydrocannabivarin or such as z. In WO2007001939 . WO2007044215 . WO2007047737 . WO2007095513 . WO2007096764 . WO2007112399 . WO2007112402 . WO2008122618 . WO2009007697 . WO2009012227 . WO2009087564 . WO2009093018 . WO2009095752 . WO2009120660 . WO2010012964 are described;
Cannabinoid receptor 2 (CB2) modulating compounds such. B. such as z. In WO2008063625 . WO2008157500 . WO2009004171 . WO2009032754 . WO2009055357 . WO2009061652 . WO2009063495 . WO2009067613 . WO2009114566 are described;
Modulators of FAAH (fatty acid amide hydrolase) as z. In WO2007140005 . WO2008019357 . WO2008021625 . WO2008023720 . WO2008030532 . WO2008129129 . WO2008145839 . WO2008145843 . WO2008147553 . WO2008153752 . WO2009011904 . WO2009048101 . WO2009084970 . WO2009105220 . WO2009109504 . WO2009109743 . WO2009117444 . WO2009127944 . WO2009138416 . WO2009151991 . WO2009152025 . WO2009154785 . WO2010005572 . WO2010017079 are described;
Inhibitors of fatty acid synthase (FAS), as described, for. In WO2008057585 . WO2008059214 . WO2008075064 . WO2008075070 . WO2008075077 . WO2009079860 are described;
Long Chain Fatty Acid Elongase (LCE) inhibitors / Long Chain Fatty Acid CoA ligase, as described, for example, in US Pat. In WO2008120653 . WO2009038021 . WO2009044788 . WO2009081789 . WO2009099086 are described;
Vanilloid-1 receptor modulators (modulators of the TRPV1), as they are e.g. In WO2007091948 . WO2007129188 . WO2007133637 . WO2008007780 . WO2008010061 . WO2008007211 . WO2008010061 . WO2008015335 . WO2008018827 . WO2008024433 . WO2008024438 . WO2008032204 . WO2008050199 . WO2008059339 . WO2008059370 . WO2008066664 . WO2008075150 . WO2008090382 . WO2008090434 . WO2008093024 . WO2008107543 . WO2008107544 . WO2008110863 . WO2008125295 . WO2008125296 . WO2008125337 . WO2008125342 . WO2008132600 . WO2008133973 . WO2009010529 . WO2009010824 . WO2009016241 . WO2009023539 . WO2009038812 . WO2009050348 . WO2009055629 . WO2009055749 . WO2009064449 . WO2009081222 . WO2009089057 . WO2009109710 . WO2009112677 . WO2009112678 . WO2009112679 . WO2009121036 . WO2009124551 . WO2009136625 . WO2010002209 are described;
Modulators, ligands, antagonists or inverse agonists of the opioid receptors, such as. B. GSK-982 or such as z. In WO2007047397 . WO2008021849 . WO2008021851 . WO2008032156 . WO2008059335 . WO2008125348 . WO2008125349 . WO2008142454 . WO2009030962 . WO2009103552 . WO2009115257 are described;
Modulators of the "orphan opioid (ORL-1) receptor" as z. In US2008249122 . WO2008089201 are described;
Agonists of the prostaglandin receptor, such as. B. Bimatoprost or such compounds as in WO2007111806 are described;
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-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (4-chlorophenyl) -2-oxoethyl] -amide; WO 01/91752 )) or LB53280, LB53279, LB53278 or THIQ, MB243, RY764, CHIR-785, PT-141, MK-0493 or those as described in WO2005060985 . WO2005009950 . WO2004087159 . WO2004078717 . WO2004078716 . WO2004024720 . US20050124652 . WO2005051391 . WO2004112793 , WOUS20050222014, US20050176728 . US20050164914 . US20050124636 . US20050130988 . US20040167201 . WO2004005324 . WO2004037797 . WO2004089307 . WO2005042516 . WO2005040109 . WO2005030797 . US20040224901 . WO200501921 . WO200509184 . WO2005000339 . EP1460069 . WO2005047253 . WO2005047251 . WO2005118573 . EP1538159 . WO2004072076 . WO2004072077 . WO2006021655 - 57 . WO2007009894 . WO2007015162 . WO2007041061 . WO2007041052 . JP2007131570 . EP-1842846 . WO2007096186 . WO2007096763 . WO2007141343 . WO2008007930 . WO2008017852 . WO2008039418 . WO2008087186 . WO2008087187 . WO2008087189 . WO2008087186 - WO2008087190 . WO2008090357 . WO2008142319 . WO2009015867 . WO2009061411 . US2009076029 . US2009131465 . WO2009071101 . US2009305960 . WO2009144432 . WO2009151383 . WO2010015972 are described;
MC4 receptor modulators (melanocortin-4 receptor modulators) as they are e.g. In WO2009010299 . WO2009074157 are described;
Orexin receptor 1 antagonists (OX1R antagonists), orexin receptor 2 antagonists (OX2R antagonists), or mixed OX1R / OX2R antagonists (eg, 1- (2-methyl-benzoxazol-6-yl) -3- [1.5 ] naphthyridin-4-ylurea hydrochloride (SB-334867-A) or those as described, for example, in US Pat WO200196302 . WO200185693 . WO2004085403 . WO2005075458 . WO2006067224 . WO2007085718 . WO2007088276 . WO2007116374 . WO2007122591 . WO2007126934 . WO2007126935 . WO2008008517 . WO2008008518 . WO2008008551 . WO2008020405 . WO2008026149 . WO2008038251 . US2008132490 . WO2008065626 . WO2008078291 . WO2008087611 . WO2008081399 . WO2008108991 . WO2008107335 . US2008249125 . WO2008147518 . WO2008150364 . WO2009003993 . WO2009003997 . WO2009011775 . WO2009016087 . WO2009020642 . WO2009058238 . US2009186920 . US2009203736 . WO2009092642 . WO2009100994 . WO2009104155 . WO2009124956 . WO2009133522 . WO2009156951 . WO2010017260 described);
Histamine H3 receptor antagonist / 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 such as those in WO200064884 . WO2005082893 . WO2005123716 . US2005171181 (eg PF-00389027), WO2006107661 . WO2007003804 . WO2007016496 . WO2007020213 . WO2007049798 . WO2007055418 . WO2007057329 . WO2007062999 . WO2007065820 . WO2007068620 . WO2007068641 . WO2007075629 . WO2007080140 . WO2007082840 . WO2007088450 . WO2007088462 . WO2007094962 . WO2007099423 . WO2007100990 . WO2007105053 . WO2007106349 . WO2007110364 . WO2007115938 . WO2007131907 . WO2007133561 . US2007270440 . WO2007135111 . WO2007137955 . US2007281923 . WO2007137968 . WO2007138431 . WO2007146122 . WO2008005338 . WO2008012010 . WO2008015125 . WO2008045371 . EP1757594 . WO2008068173 . WO2008068174 . US20080171753 . WO2008072703 . WO2008072724 . US2008188484 . US2008188486 . US2008188487 . WO2008109333 . WO2008109336 . WO2008126886 . WO2008154126 . WO2008151957 . US2008318952 . WO2009003003 . WO2009013195 . WO2009036132 . WO2009039431 . WO2009045313 . WO2009058300 . WO2009063953 . WO2009067401 . WO2009067405 . WO2009067406 . US2009163464 . WO2009100120 . WO2009105206 . WO2009121812 . WO2009126782 . WO2010011653 . WO2010011657 described);
Histamine H1 / histamine H3 modulators, such as. B. Betahistine or its dihydrochloride;
Modulators of the histamine H3 transporter or the histamine H3 / serotonin transporter as described, for example, in US Pat. In WO2008002816 . WO2008002817 . WO2008002818 . WO2008002820 are described;
Modulators of vesicular monoamine transporter 2 (vesicular monoamine transporter 2 (VMAT2)) as described, for example, in US Pat. In WO2009126305 are described;
Histamine H4 modulators as they are eg. In WO2007117399 . US2009156613 are described;
CRF antagonists (eg, [2-methyl-9- (2,4,6-trimethyl-phenyl) -9H-1,3,9-triaza-fluoren-4-yl] -dipropyl-amine ( WO 00/66585 ) or those CRF1 antagonists as described in WO2007105113 . WO2007133756 . WO2008036541 . WO2008036579 . WO2008083070 . WO2010015628 . WO2010015655 described);
CRF BP antagonists (eg, urocortin);
Urocortin agonists;
Modulators of the beta-3 adrenoceptor such. B. 1- (4-chloro-3-methanesulfonylmethylphenyl) -2- [2- (2,3-dimethyl-1H-indol-6-yloxy) -ethylamino] -ethanol hydrochloride ( WO 01/83451 ) or Solabegron (GW-427353) or N-5984 (KRP-204) or those as described in JP2006111553 . WO2002038543 . WO2002038544 . WO2007048840 - 843 . WO2008015558 . EP1947103 . WO2008132162 are described;
MSH (melanocyte-stimulating hormone) agonists;
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-856464, NGD-4715, ATC-0453, ATC-0759, GW-803430, or such compounds as described in U.S. Pat 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 . WO2007012661 . WO2007029847 . WO2007024004 . WO2007039462 . WO2007042660 . WO2007042668 . WO2007042669 . US2007093508 . US2007093509 . WO2007048802 . JP2007091649 . WO2007092416 ; WO2007093363 - 366 . WO2007114902 . WO2007114916 . WO2007141200 . WO2007142217 . US2007299062 . WO2007146758 . WO2007146759 . WO2008001160 . WO2008016811 . WO2008020799 . WO2008022979 . WO2008038692 . WO2008041090 . WO2008044632 . WO2008047544 . WO2008061109 . WO2008065021 . WO2008068265 . WO2008071646 . WO2008076562 . JP2008088120 . WO2008086404 . WO2008086409 . US2008269110 . WO2008140239 . WO2009021740 . US2009011994 . US2009082359 . WO2009041567 . WO2009076387 . WO2009089482 . WO2009103478 . WO2009119726 . WO2009120655 . WO2009123194 . WO2009137270 . WO2009146365 . WO2009154132 described);
CCK-A (CCK-1) agonists / modulators (such as {2- [4- (4-chloro-2,5-dimethoxy-phenyl) -5- (2-cyclohexyl-ethyl) -thiazole-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 . WO2008091631 are described;
Serotonin reuptake inhibitors (eg, dexfenfluramines) or those as described in U.S. Pat WO2007148341 . WO2008034142 . WO2008081477 . WO2008120761 . WO2008141081 . WO2008141082 . WO2008145135 . WO2008150848 . WO2009043834 . WO2009077858 are described;
mixed serotonin / dopamine reuptake inhibitors (e.g., bupropion) or those as described in U.S. Pat WO2008063673 or fixed combinations of bupropion with naltrexone or bupropion with zonisamide;
mixed reuptake inhibitors such. DOV-21947 or such as in WO2009016214 . WO2009016215 . WO2009077584 . WO2009098208 . WO2009098209 . WO2009106769 . WO2009109517 . WO2009109518 . WO2009109519 . WO2009109608 . WO2009145357 . WO2009149258 are described;
mixed serotonin and noradrenergic compounds (e.g. WO 00/71549 );
5-HT receptor agonists z. B. 1- (3-ethyl-benzofuran-7-yl) -piperazine oxalic acid salt ( WO 01/09111 );
mixed dopamine / norepinephrine / acetylcholine reuptake inhibitors (e.g., tesofensins) or those as described e.g. In WO2006085118 . WO2008150480 are described;
Dopamine antagonists as z. In WO2008079838 . WO2008079839 . WO2008079847 . WO2008079848 are described;
Norepinephrine reuptake inhibitors as described, for. In US2008076724 . WO2009062318 are described;
5-HT1A receptor modulators as they are e.g. In WO2009006227 . WO2009137679 . WO2009137732 are described;
5-HT2A receptor antagonists as they are 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 . WO2008108445 . WO2009063991 . WO2009063992 . WO2009063993 . WO2009079765 described);
5-HT6 receptor modulators, such as For example, E-6837, BVT-74316, PF-3246799 or PRX-07034 or such as. In WO2005058858 . WO2007054257 . WO2007107373 . WO2007108569 . WO2007108742 - 744 . WO2008003703 . WO2008027073 . WO2008034815 . WO2008054288 . EP1947085 . WO2008084491 . WO2008084492 . WO2008092665 . WO2008092666 . WO2008101247 . WO2008110598 . WO2008116831 . WO2008116833 . WO2008117169 . WO2008136017 . WO2008147812 . EP2036888 . WO2009013010 . WO2009034581 . WO2009053997 . WO2009056632 . WO2009073118 . WO2009115515 . WO2009135925 . WO2009135927 . WO2010000456 . WO2010012806 . EP2145887 are described;
Agonists of the estrogen receptor gamma (ERRγ agonists), as described, for. In WO2007131005 . WO2008052709 are described;
Agonists of the estrogen receptor alpha (ERRα / ERR1 agonists), as described, for. In WO2008109727 are described;
Agonists of the estrogen receptor beta (ERRβ agonists), as described, for. In WO2009055734 . WO2009100335 . WO2009127686 are described;
Sigma-1 receptor antagonists, such as. In WO2007098953 . WO2007098961 . WO2008015266 . WO2008055932 . WO2008055933 . WO2009071657 are described;
Muscarinic 3 Receptor (M3R) Antagonists as They Are In WO2007110782 . WO2008041184 are described;
Bombesin receptor agonists (BRS-3 agonists), such as those described in US Pat. In WO2008051404 . WO2008051405 . WO2008051406 . WO2008073311 are described;
Galanin receptor antagonists;
Growth hormone (eg, human growth hormone or AOD-9604);
Growth Hormone Releasing Compounds (6-Benzyloxy-1- (2-diisopropylamino-ethylcarbamoyl) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester ( WO 01/85695 ));
Growth Hormone Secretagogue receptor antagonists (ghrelin antagonists) such as. B. A-778193 or those as described in WO2005030734 . WO2007127457 . WO2008008286 . WO2009056707 are described;
Growth Hormone Secretagogue Receptor Modulators (ghrelin modulators) such as: JMV-2959, JMV-3002, JMV-2810, JMV-2951, or those as described in U.S. Pat WO2006012577 (eg YIL-781 or YIL-870), WO2007079239 . WO2008092681 . WO2008145749 . WO2008148853 . WO2008148854 . WO2008148856 . WO2009047558 . WO2009071283 . WO2009115503 are described;
TRH agonists (see eg. EP 0 462 884 );
decoupling protein 2- or 3-modulators (such as in WO2009128583 described);
chemical decouplers (eg WO2008059023 . WO2008059024 . WO2008059025 . WO2008059026 );
Leptin receptor agonists (see, e.g. 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 );
Leptinrezeptormodulatoren as z. In WO2009019427 . WO2009071658 . WO2009071668 . WO2009071677 . WO2009071678 . WO2009147211 . WO2009147216 . WO2009147219 . WO2009147221 are described;
DA agonists (bromocriptine, bromocriptine mesylate, doprexin) or those like them in US2009143390 are described;
Lipase / amylase inhibitors (eg. WO 00/40569 . WO2008107184 . WO2009049428 . WO2009125819 );
Inhibitors of diacylglycerol O-acyltransferases (DGATs) such. B. BAY-74-4113 or such. In US2004 / 0224997 . WO2004094618 . WO200058491 . WO2005044250 . WO2005072740 . JP2005206492 . WO2005013907 . WO2006004200 . WO2006019020 . WO2006064189 . WO2006082952 . WO2006120125 . WO2006113919 . WO2006134317 . WO2007016538 . WO2007060140 . JP2007131584 . WO2007071966 . WO2007126957 . WO2007137103 . WO2007137107 . WO2007138304 . WO2007138311 . WO2007141502 . WO2007141517 . WO2007141538 . WO2007141545 . WO2007144571 . WO2008011130 . WO2008011131 . WO2008039007 . WO2008048991 . WO2008067257 . WO2008099221 . WO2008129319 . WO2008141976 . WO2008148840 . WO2008148849 . WO2008148851 . WO2008148868 . WO2009011285 . WO2009016462 . WO2009024821 . US2009076275 . WO2009040410 . WO2009071483 . WO2009081195 . WO2009119534 . WO2009126624 . WO2009126861 . WO2010007046 . WO2010017040 described;
Inhibitors of monoacylglycerol acyltransferase (2-acylglycerol-O-acyltransferase; MGAT) as described e.g. In WO2008038768 are described;
Inhibitors of fatty acid synthase (FAS) such. B. C75 or such, as in WO 2004/005277 . WO2008006113 described;
Inhibitors of stearoyl-CoA delta9 desaturase (SCD1) 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 . WO2008062276 . WO2008064474 . WO2008074824 . WO2008074832 . WO2008074833 . WO2008074834 . WO2008074835 . WO2008089580 . WO2008096746 . WO2008104524 . WO2008116898 . US2008249100 . WO2008120744 . WO2008120759 . WO2008123469 . WO2008127349 . WO2008128335 . WO2008135141 . WO2008139845 . WO2008141455 . US20080255130 . US2008255161 . WO2008141455 . WO2009010560 . WO2009016216 . WO2009012573 . WO2009024287 . JP2009019013 . WO2009037542 . WO2009056556 . WO2009060053 . WO2009060054 . WO2009070533 . WO2009073973 . WO2009103739 . WO2009117659 . WO2009117676 . US2009253693 . US2009253738 . WO2009124259 . WO2009126123 . WO2009126527 . WO2009129625 . WO2009137201 . WO2009150196 . WO2009156484 . WO2010006962 . WO2010007482 are described;
Inhibitors of fatty acid desaturase-1 (delta5 desaturase) as described, for. In WO2008089310 are described;
Inhibitors of monoglyceride lipase (MGL) as found in WO2008145842 are described;
hypoglycemic / hypertriglyceridemic indoline compounds as in WO2008039087 . WO2009051119 are described;
Inhibitors of "adipocyte fatty acid-binding protein aP2" such. BMS-309403 or such as in WO2009028248 are described;
Activators of adiponectin secretion, such. In WO2006082978 . WO2008105533 . WO2008136173 described;
Promoters of adiponectin production, such as. In WO2007125946 . WO2008038712 described;
modified adiponectins such. In WO2008121009 described;
Oxyntomodulin or analogs thereof (such as TKS-1225);
Oleoyl-estrone
or agonists or partial agonists of the thyroid hormone receptor agonists such as. B: KB-2115 (Eprotirome), QRX-431 (Sobetirome) or DITPA or those as in WO20058279 . WO200172692 . WO200194293 . WO2003084915 . WO2004018421 . WO2005092316 . WO2007003419 . WO2007009913 . WO2007039125 . WO2007110225 . WO2007110226 . WO2007128492 . WO2007132475 . WO2007134864 . WO2008001959 . WO2008106213 . JP2009155261 described
or agonists of the thyroid hormone receptor beta (TR-beta) such. MB-07811 or MB-07344, or such as in WO2008062469 described, administered.

In one embodiment of the invention, the compound of the formula I is administered in combination with a combination of Ezetimibe Eprotiromes.

In one embodiment of the invention, the compound of formula I in combination with an inhibitor of Site-1 protease (S1P), such as. PF-429242.

In a further embodiment of the invention, the compound of the formula I is used in combination with a modulator of the "Trace-Amine-Associated-Receptor-1" (TAAR1), as described, for. In US2008146523 . WO2008092785 described.

In one embodiment of the invention, the compound of the formula I in combination with an inhibitor of the growth factor receptor Bound protein 2 (GRB2), such. In WO2008067270 described, administered.

In a further embodiment of the invention, the compound of the formula I is administered in combination with an RNAi (siRNA) therapeutic which is directed against PCSK9 (proprotein convertase subtilisin / kexin type 9).

In one embodiment, the compound of formula I in combination with Omacor ^® or Lovaza ^™ (omega-3 fatty acid ester; highly concentrated ethyl esters of eicosapentaenoic acid and docosahexaenoic acid) is administered.

In one embodiment, the compound of the formula I is administered in combination with lycopene.

In one embodiment of the invention, the compound of the formula I in combination with an antioxidant, such as. OPC-14117, AGI-1067 (succinobucol), probucol, tocopherol, ascorbic acid, β-carotene or selenium, or those as described in U.S. Pat WO2009135918 described.

In one embodiment of the invention, the compound of the formula I in combination with a vitamin, such as. As vitamin B6 or vitamin B12 administered.

In one embodiment, the compound of formula I is used in combination with more than one of the aforementioned compounds, e.g. In combination with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin (PrandiMet ^(TM) ), insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.

In a further embodiment, the compound of the formula I is administered in combination with an activator of soluble guanylate cyclase (soluble guanylate cyclase (sGC)) as described, for example, in US Pat. In WO2009032249 are described.

In another embodiment, the compound of formula I in combination with an inhibitor of carbonic anhydrase type 2 (Carbonic anhydrase type 2), such as. B. such as in WO2007065948 . WO2009050252 described, administered.

In another embodiment, the compound of formula I is used in combination with topiramate or a derivative thereof as described in U.S. Pat WO2008027557 . US2009304789 described.

In another embodiment, the compound of formula I is administered in combination with a solid combination of topiramate with phentermine (Qnexa ^™ ).

In another embodiment, 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.

In another embodiment, the compound of the 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. In EP1886695 . WO2008119744 described, administered.

In one embodiment, the compound of formula I in combination with an agonist of the RUP3 receptor, such. In WO2007035355 . WO2008005576 described, administered.

In another embodiment, 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.

In one embodiment, the compound of the formula I in combination with a tau protein kinase 1 inhibitor (TPK1 inhibitor), such. In WO2007119463 . WO2009035159 . WO2009035162 described, administered.

In one embodiment, the compound of the formula I in combination with a "c-Jun N-terminal kinase" inhibitor (JNK inhibitor), such. B. BI-78D3 or such as in WO2007125405 . WO2008028860 . WO2008118626 described, administered.

In one embodiment, the compound of formula I in combination with an endothelin A receptor antagonist, such as. B. avosentan (SPP-301).

In one embodiment, the compound of formula I in combination with inhibitors of neutral endopeptidase (NEP inhibitors), such as. In WO2009138122 . WO2009135526 described.

In one embodiment, the compound of the formula I in combination with modulators of the glucocorticoid receptor (GR), such as. B. KB-3305 or such compounds as such. In WO 2005/090336 . WO2006071609 . WO2006135826 . WO2007105766 . WO2008120661 . WO2009040288 . WO2009058944 . WO2009108525 . WO2009111214 described.

In one embodiment, the other active ingredient is varenicline tartrate, a partial agonist of the alpha 4-beta 2 nicotinic acetylcholine receptor.

In one embodiment, the further active ingredient is an agonist of the alpha 7-nicotinic acetylcholine receptor, as described, for. In WO2009018551 . WO2009071519 . WO2009071576 . WO2009071577 are described.

In one embodiment, the other active ingredient is trodusquemine.

In one embodiment, the further active ingredient is a modulator of the enzyme SIRT1 and / or SIRT3 (an NAD ⁺ -dependent protein deacetylase); This active ingredient may, for. Resveratrol in suitable formulations, or such compounds as in WO2007019416 (eg SRT-1720), WO2008073451 . WO2008156866 . WO2008156869 . WO2009026701 . WO2009049018 . WO2009058348 . WO2009061453 . WO2009134973 . WO2009146358 . WO2010003048 are called.

In one embodiment of the invention, the further active ingredient is DM-71 (N-acetyl-L-cysteine with bethanechol).

In one embodiment, the compound of the formula I in combination with antihypercholesterolemisch acting compounds, as described, for. In WO2004000803 . WO2006000804 . WO2004000805 . WO2004087655 . WO2005113496 . WO2007059871 . WO2007107587 . WO2007111994 . WO2008052658 . WO2008106600 . WO2008113796 . US2008280836 . WO2009113952 . US2009312302 described.

In a further embodiment, the compound of the formula I in combination with inhibitors of SREBP (sterol regulatory element-binding protein), such. B. fatostatin or those as they are, for. In WO2008097835 described.

In another embodiment, the compound of formula I in combination with a cyclic peptide agonist of the VPAC2 receptor, as described, for. In WO2007101146 . WO2007133828 described.

In another embodiment, the compound of formula I in combination with an agonist of the endothelin receptor, as described, for. In WO2007112069 described.

In a further embodiment, the compound of the formula I is administered in combination with AKP-020 (bis (ethylmaltolato) oxovanadium-IV).

In another embodiment, the compound of the formula I is used in combination with tissue-selective androgen receptor modulators (SARM), as described, for example, in US Pat. In WO2007099200 . WO2007137874 described.

In a further embodiment, the compound of the formula I in combination with an AGE (advanced glycation endproduct) inhibitor, as z. In JP2008024673 described.

In one embodiment of the invention, the further active ingredient is leptin; see, for. B. "Perspectives in the therapeutic use of leptin", Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2 (10), 1615-1622 ,

In another embodiment of the invention, the further active ingredient is metreleptin (recombinant methionyl-leptin) combined with pramlintide.

In a further embodiment of the invention, the further active ingredient is the tetrapeptide ISF-402.

In one embodiment, the other active ingredient is dexamphetamine or amphetamine.

In one embodiment, the other active ingredient is fenfluramine or dexfenfluramine.

In yet another embodiment, the other active ingredient is sibutramine or such derivatives as described in U.S. Pat WO2008034142 are described.

In one embodiment, the other active ingredient is mazindol or phentermine.

In another embodiment, the further active ingredient geniposidic acid (geniposidic acid; WO2007100104 ) or derivatives thereof ( JP2008106008 ).

In another embodiment, the further active ingredient is an agonist of the neuropeptide FF2 as described, for. In WO2009038012 is described.

In one embodiment, the further active ingredient is a nasally administered calcium channel blocker such as. B. diltiazem or those as described in US 7,138,107 are described.

In one embodiment, the further active ingredient is an inhibitor of the sodium-calcium ion exchange such. For example, such as those in WO2008028958 . WO2008085711 are described.

In another embodiment, the further active ingredient is a blocker of calcium channels such as. As the CaV3.2 or CaV2.2 as in WO2008033431 . WO2008033447 . WO2008033356 . WO2008033460 . WO2008033464 . WO2008033465 . WO2008033468 . WO2008073461 are described.

In one embodiment, the further active ingredient is a modulator of a calcium channel such as. For example, such as those in WO2008073934 . WO2008073936 . WO2009107660 are described.

In one embodiment, the further active ingredient is an inhibitor of calcium metabolism, such as. For example, such as those in US2009124680 are described.

In one embodiment, the further active ingredient is a blocker of the "T-type calcium channel" as described, for. In WO2008033431 . WO2008110008 . US2008280900 . WO2008141446 . US2009270338 . WO2009146540 . US2009325979 . WO2009146539 are described.

In one embodiment, the further active ingredient is an inhibitor of KCNQ potassium channel 2 or -3 such as. For example, such as those in US2008027049 . US2008027090 are described.

In one embodiment, the further active ingredient is a modulator of KCNN potassium channel-1, -2 or -3 (modulators of the SK1, SK2 and / or SK3 channel), such as e.g. For example, such as those in US2009036475 are described.

In one embodiment, the further active ingredient is an inhibitor / blocker of the potassium Kv1.3 ion channel, such as e.g. B. such as those in WO2008040057 . WO2008040058 . WO2008046065 . WO2009043117 are described.

In one embodiment, the further active ingredient is a potassium channel modulator such as. For example, such as those in WO2008135447 . WO2008135448 . WO2008135591 . WO2009099820 are described.

In another embodiment, the further active ingredient is a hyperpolarization-activated and controlled by cyclic nucleotide potassium sodium channel inhibitor ("hyperpolarization-activated cyclic nucleotide-gated (HCN) potassium-sodium channel inhibitor") such. For example, such as those in US2009069296 are described.

In another embodiment, the further active ingredient is an inhibitor of the sodium-potassium-2-chloride (NKCCl) co-transporter such as. For example, such as those in WO2009130735 are described.

In another embodiment, the further active ingredient is a voltage-gated sodium channel inhibitor, such as a voltage-gated sodium channel inhibitor. For example, such as those in WO2009049180 . WO2009049181 are described.

In another embodiment, the further active ingredient is a modulator of the MCP-1 receptor (monocyte chemoattractant protein-1 (MCP-1)) such as. For example, such as those in WO2008014360 . WO2008014381 are described.

In one embodiment, the further active ingredient is a modulator of somatostatin receptor 3 (SSTR3), such as e.g. For example, such as those in WO2009011836 are described.

In one embodiment, the further active ingredient is a modulator of somatostatin receptor 5 (SSTR5), such as e.g. For example, such as those in WO2008019967 . US2008064697 . US2008249101 . WO2008000692 . US2008293756 . WO2008148710 are described.

In one embodiment, the further active ingredient is a modulator of somatostatin receptor 2 (SSTR2) such as, for example, For example, such as those in WO2008051272 are described.

In one embodiment, the further active ingredient is a compound capable of reducing the amount of retinol-binding protein 4 (RBP4), such as e.g. For example, such as those in WO2009051244 . WO2009145286 are.

In one embodiment, the further active ingredient is an erythropoietin-mimetic peptide which acts as an erythropoietin (EPO) receptor agonist. Such molecules are for. In WO2008042800 described.

In a further embodiment, the further active ingredient is an anorectic / a hypoglycemic compound such. For example, such as those in WO2008035305 . WO2008035306 . WO2008035686 are described.

In one embodiment, the further active ingredient is an inducer of lipoic acid synthetase, such as e.g. For example, such as those in WO2008036966 . WO2008036967 are described.

In one embodiment, the further active ingredient is a stimulator of endothelial nitric oxide synthase (eNOS), such as e.g. For example, such as those in WO2008058641 . WO2008074413 are described.

In one embodiment, the further active ingredient is a modulator of carbohydrate and / or lipid metabolism, such as e.g. For example, such as those in WO2008059023 . WO2008059024 . WO2008059025 . WO2008059026 are described.

In a further embodiment, the further active ingredient is an angiotensin II receptor antagonist, such as, for example, For example, such as those in WO2008062905 . WO2008067378 . WO2008062905 are described.

In one embodiment, the further active ingredient is an agonist of the sphingosine-1-phosphate receptor (S1P), such as e.g. For example, such as those in WO2008064315 . WO2008074820 , WO2008074821 . WO2008135522 . WO2009019167 . WO2009043013 . WO2009080663 . WO2009085847 . WO2009151529 . WO2009151621 . WO2009151626 . WO2009154737 are described.

In one embodiment, the further active ingredient is an agent which retards the gastric emptying such. B. 4-hydroxyisoleucine ( WO2008044770 ).

In one embodiment, the further active ingredient is a tryptophan 5-hydroxylase inhibitor-1 (TPH1 inhibitor) which modulates gastrointestinal motility, such as e.g. In WO2009014972 described.

In one embodiment, the further active ingredient is a muscle-relaxant substance such as, for. In WO2008090200 is described.

In another embodiment, the further active ingredient is an inhibitor of monoamine oxidase B (MAO-B) such as. For example, such as those in WO2008092091 . WO2009066152 are described.

In another embodiment, the further active ingredient is an inhibitor of monoamine oxidase A (MAO-A) such as. For example, such as those in WO2009030968 are described.

In another embodiment, the further active ingredient is an inhibitor of the binding of cholesterol and / or triglycerides to the SCP-2 protein (sterol carrier protein-2) such. For example, such as those in US2008194658 are described.

In another embodiment, the further active ingredient is a compound which binds to the β-subunit of the trimeric GTP-binding protein, e.g. Such as those in WO2008126920 are described.

In one embodiment, the further active ingredient is an inhibitor of the uric acid anion exchanger-1 (urate-anion-exchanger-inhibitor-1), as described, for. In WO2009070740 are described.

In one embodiment, the further active ingredient is a modulator of the ATP transporter, such as. In WO2009108657 described.

In another embodiment, the other active ingredient is lisofylline, which prevents autoimmune damage to insulin-producing cells.

In yet another embodiment, the further active ingredient is an extract of Bidens pilosa with the ingredient cytopiloin as in EP1955701 described.

In one embodiment, the further active ingredient is an inhibitor of glucosylceramide synthase such as. In WO2008150486 described.

In a further embodiment of the invention, the further active ingredient is a glycosidase inhibitor such as. In WO2009117829 . WO2009155753 described.

In another embodiment, the further active ingredient is an ingredient of the plant Hoodia gordonii as found in US2009042813 . EP2044852 is described.

In one embodiment, the further active ingredient is an antidiabetic such. B. D-tagatose.

In one embodiment, the further active ingredient is a zinc complex of curcumin as in WO2009079902 is described.

In one embodiment, the further active ingredient is an inhibitor of the cAMP response element binding protein (CREB) as described in US Pat WO2009143391 is described.

In another embodiment, the further active ingredient is an antagonist of the bradykinin B1 receptor as in WO2009124746 is described.

In another embodiment, the additional active ingredient is a compound capable of modulating diabetic peripheral neuropathy (DPN). Such modulators are z. FK-1706 or SB-509 or those as described in WO1989005304 . WO2009092129 . WO2010002956 are described.

In one embodiment, the additional active ingredient is a compound capable of modulating diabetic nephropathy. Such compounds are for. In WO2009089545 . WO2009153261 described.

In one embodiment, the further active ingredient is an inhibitor (eg, an anti-CD38 antibody) of CD38 as in US2009196825 described.

In one embodiment, the further active ingredient is an inhibitor of human fibroblast growth factor receptor 4 (FGFR4), such as human fibroblast growth factor receptor 4 (FGFR4). In WO2009046141 described.

In a further embodiment of the invention, the further active ingredient is a betazelle protective compound such as. B. 14-alpha-lipolyl-andrographolide (AL-1).

In yet another embodiment of the invention, the further active ingredient is the INGAP peptide (isletneogenesis associated protein), a peptide which restores insulin production in patients with diabetes mellitus.

In one embodiment of the invention, the further active ingredient is a modulator of the CFTR (cystic fibrosis transmembrane conductance regulator) as described, for. In US2009246137 . US2009264433 . US2009264441 . US2009264471 . US2009264481 . US2009264486 . WO2010019239 is described.

In one embodiment of the invention, the further active ingredient is a compound which stimulates / modulates insulin release, such as e.g. Eg those like them in WO2009109258 . WO2009132739 . US2009281057 . WO2009157418 are described.

In one embodiment of the invention, the further active ingredient is an extract of Hippophae rhamnoides, as described, for. In WO2009125071 is described.

In one embodiment of the invention, the further active ingredient is one of Huanglian and Ku Ding Cha, as he z. In WO2009133458 is described.

In another embodiment of the invention, the further active ingredient is a root extract of Cipadessa baccifera, as described in US2009238900 is described.

In one embodiment of the invention, the further active ingredients Borapetoside A and / or Borapetoside C, which can be isolated from the plant SDH-V, a species of Tinospora crispa, as described, for. In US2010016213 are described.

In one embodiment, the compound of formula I in combination with bulking agents, preferably insoluble bulking agents (see, e.g., B. (carob / Caromax ^® Guild HJ; et al., Carob pule preparation for the treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct), 18 (5), 230-6 .) Caromax is a carob-containing product of the company Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark Höchst, 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 used in the form of food, such as. B. in baked goods or cereal bars, administered.

It is understood that any suitable combination of the compounds of the present invention with one or more of the foregoing compounds and optionally one or more other pharmacologically active substances is considered to fall within the scope of the present invention.

Furthermore, the following active ingredients are suitable for combination preparations:
All antiepileptics used in the Red List 2010, chapter 15 are called;
all antihypertensive agents used in the Red List 2010, chapter 17 are called;
all hypotensives in the Red List 2010, chapter 19 are called;
all anticoagulants found in the Red List 2010, chapter 20 are called;
all arteriosclerotic agents used in the Red List 2010, chapter 25 are called;
all beta-receptors, calcium channel blockers and inhibitors of the renin-angiotensin system used in the Red List 2010, chapter 27 are called;
all diuretics and circulation-promoting agents used in the Red List 2010, chapters 36 and 37 are called;
all weaning aids / means of treatment for addictions found in the Red List 2010, chapter 39 are called;
all coronary and gastrointestinal agents used in the Red List 2010, chapters 55 and 60 are called;
all migraine medications, neuropathic preparations and Parkinson 's drugs used in the Red List 2010, chapters 61, 66 and 70 are called.

It is understood that any suitable combination of the compounds of the present invention with one or more of the foregoing compounds and optionally one or more other pharmacologically active substances is considered to fall within the scope of the present invention.

The invention furthermore relates to stereoisomer mixtures of the formula I as well as to the pure stereoisomers of the formula I and to diastereomer mixtures of the formula I and also to the pure diastereomers. The separation of the mixtures is carried out by chromatographic means.

Preference is given to racemic as well as enantiomerically pure compounds of formula I having the following structure:

Substantially the following protective groups are suitable for the hydroxy groups: benzyl, acetyl, benzoyl, pivaloyl, trityl, tert-butyldimethylsilyl, benzylidene, cyclohexylidene or isopropylidene protective groups.

Suitable protecting groups (see eg TW Greene, "Protective Groups in Organic Synthesis" ) for amino acids are primarily:
Arg (Tos), Arg (Mts), Arg (Mtr), Arg (PMV), Asp (OBzl), Asp (OBut), Cys (4-MeBzl), Cys (Acm), Cys (SBut), Glu (Obzl ), Glu (Obut), His (Tos), His (Fmoc), His (Dnp), His (Trt), Lys (Cl-Z), Lys (Boc), Met (O), Ser (Bzl), Ser (But), Thr (Bzl), Thr (But), Trp (Mts), Trp (CHO), Tyr (Br-Z), Tyr (Bzl) or Tyr (But).

Preferred amino-protecting groups are the benzyloxycarbonyl (Z) radical which can be split off by catalytic hydrogenation, the 2- (3,5-dimethyloxyphenyl) propyl (2) oxycarbonyl (Ddz) or trityl (Trt) radical which can be split off by weak acids t-butylcarbamate (BOC) radical which can be split off by acids, such as 3 M hydrochloric acid, and the 9-fluorenylmethyloxycarbonyl (Fmoc) radical cleavable by secondary amines.

wobei Y = CO ist;
W die Bedeuting -(C₁-C₁₀)-Alkylen- hat, wobei ein oder mehrere C-Atome des Alkylenrests durch -CH(OH)-, -CHF-, -CF₂-, -CH(NH₂)-, -C(Alkyl1)(Alkyl2)-, -CH(Alkyl1)-, -C[(C₂-C₆)-cycloalkylen], -CH(Aryl)-, -CH(Heteroaryl)-, -CH(CF₃)-, -C(OH)(Alkyl1)- ersetzt sein können, und wobei Alkyl1 und Alkyl2 unabhängig voneinander (C₁-C₅)-Alkyl sein können, und wobei der Aryl- und Heteroarylring bis zu dreifach mit F, Cl, CF₃, OCF₃, OCH₃, OC₂H₅, OCH(CH₃)₂, O-Phenyl, CN, SO₂-CH₃, SO₂NH₂, COOH substituiert sein kann.The invention furthermore relates to a process for the preparation of benzylamidic diphenylazetidinone derivatives of the formula I.

where Y = CO;
W is the meaning of - (C ₁ -C ₁₀ ) -alkylene, where one or more C atoms of the alkylene radical are represented by -CH (OH) -, -CHF-, -CF ₂ -, -CH (NH ₂ ) -, -C (Alkyl1) (alkyl 2) -, -CH (Alkyl1) -, -C [(C ₂ -C ₆₎ cycloalkylene], -CH (aryl) -, -CH (heteroaryl) -, -CH (CF ₃ ), -C (OH) (alkyl1) - may be replaced, and wherein alkyl1 and alkyl2 can be independently (C ₁ -C ₅ ) -alkyl, and wherein the aryl and heteroaryl ring up to three times with F, Cl, CF ₃ , OCF ₃ , OCH ₃ , OC ₂ H ₅ , OCH (CH ₃ ) ₂ , O-phenyl, CN, SO ₂ -CH ₃ , SO ₂ NH ₂ , COOH.

The process for the preparation of the compounds of formula I is z. Example, characterized in that reacting an amine of formula II with an acylating reagent, preferably in the omega position another functionality - possibly in protected form - carries. This is used (after deprotection) to attach the (LAG), for example, to form amide bonds.

General experimental procedures:

¹ H-NMR:

The ¹ H-NMR spectra were measured in deuterated dimethyl sulfoxide on a 500 MHz instrument (DRX 500, Bruker) at 300 ° K. Data: δ in ppm, multiplicity (s for singlet, d for doublet, t for triplet, q for quartet, m for multiplet, × H (number of hydrogen atoms)

HPLC / MS:

The HPLC-MS measurements were carried out on a Waters LCT device. Column: Waters XBridge C18 4.6 × 50 mm 4 μm;
Gradient [A]: (acetonitrile + 0.05% trifluoroacetic acid) :( water + 0.05% trifluoroacetic acid) 5:95 (0 minutes) at 95: 5 (3 minutes);
Gradient [B]: (acetonitrile + 0.05% trifluoroacetic acid) :( water + 0.05% trifluoroacetic acid) 5:95 (0 minutes) at 95: 5 (2.5 minutes) at 95: 5 (3.0 minutes);
Gradient [C]: (acetonitrile + 0.05% trifluoroacetic acid) :( water + 0.05% trifluoroacetic acid) 5:95 (0 minutes) at 95: 5 (3.4 minutes) at 95: 5 (4.4 minutes);
Gradient [C1]: (water + 0.05% trifluoroacetic acid) :( acetonitrile + 0.05% trifluoroacetic acid) 95: 5 (0 minutes) at 95: 5 (0.2 minutes) at 5:95 (2.4 minutes) at 5:95 (3.5 minutes ) after 95: 5 (3.6 minutes) after 95: 5 (4.5 minutes);
Gradient [D]: (water + 0.1% trifluoroacetic acid) :( acetonitrile + 0.1% trifluoroacetic acid) 97: 3 (0 minutes) after 40:60 (3.5 minutes) after 2:98 (5 minutes) after 97: 3 (5.2 minutes after 97: 3 (6.5 minutes);
Gradient [E]: (acetonitrile + 0.05% trifluoroacetic acid) :( water + 0.05% trifluoroacetic acid) 5:95 (0 minutes) to 5:95 (0.3 minutes) to 95: 5 (3.5 minutes) to 95: 5 (4 minutes );
Gradient [F]: column: YMC Jsphere ODS H80 20 × 2 mm, 4 μm; (Water + 0.05% trifluoroacetic acid) :( acetonitrile + 0.05% trifluoroacetic acid) 96: 4 (0 minutes) to 5:95 (2 minutes) to 96: 4 (2.4 minutes); Detector: Tecan LCT.

Chromatographic purification methods:

• [RP1]: flow: 30 ml / min; Gradient: acetonitrile / water + 0.1% trifluoroacetic acid; 30 min. Column: XTerra C18 5 μm 30 × 100 mm; Detection: MS (ESI), UV (DAD).
• [RP2]: flow: 150 ml / min; Gradient: acetonitrile / water + 0.1% trifluoroacetic acid; 20 min. Column: XTerra C18 10 μm 50 × 250 mm; Detection: MS (ESI), UV (DAD).

The following examples serve to illustrate the invention without restricting it to products and embodiments described in the examples.

Example I

4-Hydroxy-dodecanedioic acid-1- {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxy-propyl] -2- (4-methoxy-phenyl ) -4-oxo-azetidin-1-yl] -benzylamide} -12 - [((2S, 3R, 4R, 5R) -2,3,4,5,6-pentahydroxy-hexyl) -amide] (17) :

a) (3R, 4S) -1- (4-aminomethyl-phenyl) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxy-propyl] -4- (4-methoxyphenyl ) -azetidin-2-one (1):

The compound 1 is as in EP1345895 prepared from the corresponding aryl nitrile compound by hydrogenation with Raney nickel. Molecular weight (C ₂₆ H ₂₇ FNO ₃ ); MS (ESI): 418.2 (MH ⁺ NH ₃ ).

b) Pent-4-enyloxymethylbenzene (2):

11.5 ml of 4-pentenol are placed in 150 ml of tetrahydrofuran (tetrahydrofuran). 15.1 g of potassium tert-butoxide (KOtBu) are added in portions. The result is a clear, yellow solution that turns cloudy and slightly warm. It is stirred for 20 min at room temperature. Then a solution of 16.2 ml of benzyl bromide (BnBr) and 15 ml of tetrahydrofuran is added dropwise in 45 min. The internal temperature is kept at about 20 ° C (ice bath). It forms a bright solid. The suspension is stirred for a further 1 h at room temperature. The suspension is filtered off with suction and the solid washed twice with 10 ml of tetrahydrofuran. The yellow solution is completely concentrated at room temperature in vacuo. The yellow liquid residue (about 25 g) is taken up in 50 ml of dichloromethane (DCM), washed with 20 ml of water and dried with sodium sulfate. The resulting dichloromethane solution of compound 2 is reacted further directly.

c) 2- (3-Benzyloxypropyl) oxiranes (3)

The dichloromethane solution of the pentenobenzyl ether (compound 2) is diluted to a volume of 150 ml by the addition of DCM. With stirring at 0-5 ° C (ice bath), a solution of 26.5 g of m-chloroperbenzoic acid (mCPBA) in 200 ml DCM is added dropwise within 2 h. It forms a milky solution, the internal temperature during the dropping is never more than 3 ° C. It is stirred for 30 minutes in an ice bath and then at room temperature overnight. After a total of 19 hours of stirring the batch is worked up. The fluffy suspension is stirred for 30 minutes with 50 ml of saturated sodium sulfite solution; the phases are separated and the DCM phase washed with 30 ml of 2 N NaOH. After the phase separation, the DCM phase is extracted by shaking twice more with 20 ml of saturated sodium sulfite solution and once with 30 ml of 1 N NaOH and dried with sodium sulfate. The clear DCM solution is concentrated in vacuo. A colorless to pale yellow, slightly oily liquid is obtained; Crude yield: 25.2 g. The crude product 3 is further reacted directly.

d) 5-Benzyloxy-1-phenylsulfanylpentan-2-ol (4):

The crude product 3 is initially charged in 250 ml of 1,4-dioxane and stirred vigorously. Then a mixture of 14.2 ml of thiophenol (HSPh), 250 ml of NaOH and 100 ml of dioxane is added dropwise at room temperature in 30 min. It is stirred for 1 h at room temperature. The solution is then treated with abundant DCM, the phases are separated, and the organic phase is washed with 100 ml of half-concentrated ammonium chloride solution. The aqueous phase is washed with 20 ml DCM; The combined organic phases are dried with sodium sulfate and concentrated in vacuo. This gives 33.8 g of compound 4 as a colorless, slightly oily, still residues of thiophenol-containing liquid. Excess thiophenol can be separated by chromatography on silica gel (heptane / ethyl acetate 10: 1 to 3: 1).

e) (4-Benzyloxy-1-phenylsulfanylmethyl-butoxy) -tert-butyl-dimethyl-silane (5):

31.1 g of compound 4 are dissolved in 300 ml of DCM, treated with 18 ml of triethylamine and 75 mg of dimethylaminopyridine (DMAP) and cooled to about 10 ° C. Then a solution of 14.5 g of tert-butyldimethylsilyl chloride (TBDMS-Cl) and 40 ml of DCM is added over 5 minutes without the temperature rising appreciably. The reaction is stirred at room temperature for 19 h; Thereafter, the reaction mixture is diluted to 50 ml DCM to about 200 ml and a further 8.0 g of TBDMS-Cl, 12 ml of triethylamine and 150 mg of 4-dimethylaminopyridine are added. The batch is stirred at 40.degree. After 19 h at 40 ° C, the reactant is almost completely implemented. After cooling to room temperature, the batch is extracted by shaking with 150 ml of water. The organic phase is first with about 70 ml of 1 M HCL, then with 50 ml of semi-concentrated NaHCO ₃ - and finally with 20 ml of sat. Washed NaCl solution. Drying (Na ₂ SO ₄ ) and concentration in vacuo gives 45 g of a brown, oily crude product. The crude product is subjected to flash chromatography on silica gel (gradient heptane: ethyl acetate 25: 1 to 2: 1). 34.6 g of the silylated product 5 and 2.0 g of recovered educt 4 are obtained.

f) (1-Benzenesulfinylmethyl-4-benzyloxy-butoxy) -tert-butyl-dimethyl-silane (6):

16.1 g of the silylated compound 5 are initially charged in 100 ml of DCM. While stirring, 8.7 g mCPBA at 0-5 ° C (ice bath) are added in portions within 2 min. After 5 minutes, the ice bath is removed and the mixture is stirred at 25 ° C in a water bath. After about 6 h, the reaction mixture with 50 ml of sat. Na ₂ SO ₃ sol. (pH ~ 10) and stirred well for 30 minutes (test strips: peroxide-free). There are 30 ml of sat. Na ₂ CO ₃ sol. added, stirred for 15 min, the phases separated and the DCM phase first with 30 ml of semisaturated Na ₂ SO ₃ -Lsg. and then washed with 20 ml of water. The combined aqueous phases are extracted twice with 20 ml DCM. The combined organic phases are dried with Na ₂ SO ₄ , filtered and concentrated in vacuo; 17.8 g of crude product are obtained. Crystallization at 4-8 ° C (refrigerator) may remove an impurity; 16.9 g of sulfoxide 6 remain as an almost colorless, viscous oil.

g) Acetic acid 5-benzyloxy-2- (tert-butyl-dimethyl-silanyloxy) -1-phenylsulfanylpentyl ester (7):

16.0 g of sulfoxide 6 are initially charged in 100 ml of acetic anhydride, mixed with about 100 mg of potassium acetate and stirred at 140 ° C. The solution slowly turns brown. After 4.5 h, the oil bath temperature is increased to 155 ° C (reflux). After 8 hours, the heating is switched off and the batch is left overnight at room temperature. Concentration of the reaction mixture on a rotary evaporator gives 20 g of a brown oil. Digestion with heptane / diisopropyl ether 4: 1, washing the resulting heptane / diisopropyl ether solution with water and then with aqueous NaHCO ₃ solution and drying the organic phase with Na ₂ SO ₄ yields after concentration in vacuo 15.8 g of compound 7 as a brownish oil ,

h) 5-Benzyloxy-2- (tert-butyl-dimethyl-silanyloxy) -pentan-1-ol (8):

7.1 g of the oil 7 are dissolved in 40 ml of tetrahydrofuran, added under argon protective gas in portions with 0.75 g of LiBH ₄ and stirred at 23-35 ° C for 64 h. The reaction mixture is cautiously mixed with water (evolution of gas, H ₂ ) and stirred for 30 min. With heptane / ethyl acetate 9: 1 is extracted thoroughly. The water phases are washed again with ethyl acetate. Subsequently, the combined organic phases are dried with Na ₂ SO ₄ and concentrated in vacuo. This gives 5.29 g of a yellow, after thiophenol smelling oily crude product. The crude product is chromatographed on 10 g of silica gel (heptane / ethyl acetate 10: 1 to 3: 1). 3.93 g of the colorless oil 8 are obtained.

i) 5-Benzyloxy-2- (tert-butyl-dimethyl-silanyloxy) -pentanal (9):

0.91 g of the alcohol 8 are dissolved in 15 ml of dichloromethane and added in portions with 8.72 ml Dess-Martin periodinane (15% in methylene chloride) and stirred at room temperature. After about 2.5 h, 5 ml of saturated. Piped to NaHCO ₃ solution and then a total of 0.5 g of sodium thiosulfate are added in portions and the mixture is stirred for 15 min. The aqueous phase is separated, the organic phase washed with 5 ml of water and 5 ml of saturated NaCl solution. The DCM phase is dried with sodium sulfate and concentrated in vacuo. For final purification, the substance is chromatographed on silica gel (heptane / ethyl acetate 9: 1); 0.679 g of substance 9 are obtained.

k) (6-ethoxycarbonyl-hexyl) -triphenyl-phosphonium bromide (10):

4.7 g of triphenylphosphine are initially charged in about 10 ml of ethyl acetate, 4 ml of 7-bromo-heptanoic acid ethyl ester are added dropwise and the reaction mixture is heated with stirring in the microwave for 2 h at 160 ° C (5-6 bar). The dark reaction mixture is taken up in dichloromethane, on a rotary evaporator concentrated and the remaining resin on silica gel with dichloromethane / methanol 9: 1 to 5: 1 chromatographed. 5.7 g of the phosphonium bromide 10 are obtained.

1) Ethyl (E) -12-benzyloxy-9- (tert-butyl-dimethyl-silanyloxy) -dodec-7-enoate (11):

1.56 g of phosphonium bromide 10 are dissolved in 20 ml of dry tetrahydrofuran in an ultrasonic bath. At -73 ° C., 3.16 ml of a 1 M solution of KOtBu in tetrahydrofuran are added dropwise in the course of 15 minutes under argon blanketing gas. The reaction mixture turns yellow and orange into red-orange. The mixture is then stirred for 1 h at -70 to -30 ° C. It is then cooled to -70 ° C and the dissolved in 3 ml of dry tetrahydrofuran aldehyde 9 is added dropwise within 15 min. The color of the solution changes from orange red to pale yellow. The reaction temperature is raised in about 2.5 h from -70 ° C to room temperature, the reaction mixture is stirred for a further 2 h at room temperature. The reaction is stopped by adding saturated NH ₄ Cl solution. After adding a little water, the phases and the tetrahydrofuran phase are washed with saturated aqueous NaCl solution. The organic phase is dried with sodium sulfate and, after concentration in vacuo, purified on silica gel (mobile phase heptane / ethyl acetate 19: 1). 0.87 g of the olefin 11 are obtained.

m) ethyl 9- (tert-butyl-dimethyl-silanyloxy) -12-hydroxy-dodecanoate (12):

275 mg of the O-benzyl-protected olefin 11 are dissolved in 3 ml of ethyl acetate, mixed with 16 mg of 10% Pd / C and hydrogenated at normal pressure. 30 ml H ₂ be in about 25 min was added. The batch is aerated and centrifuged; the catalyst is washed with ethyl acetate and the combined organic solution is concentrated; 0.207 g of an oily crude product are obtained. Chromatography on silica gel with heptane / ethyl acetate 3: 1 gives 127 mg of compound 12 as a colorless oil.

n) 4- (tert-Butyl-dimethyl-silanyloxy) -dodecanedionic acid 12-ethyl ester (13):

The heterogeneous mixture of 104 mg of hydrogenated product 12, 1 ml of CCl ₄ , 1 ml of CH ₃ CN and 1.5 ml of H ₂ O is treated at room temperature with 237 mg NaIO ₄ and catalytic amounts RuCl ₃ and stirred at room temperature. After 2 h, dichloromethane and water are added, the phases are separated, the aqueous phase is washed with dichloromethane, the combined organic phases are dried (Na ₂ SO ₄ ) and concentrated in vacuo; Crude yield 130 mg. Compound 13 is reacted further without purification.

o) 9- (tert-Butyl-dimethyl-silanyloxy) -11- {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxy-propyl] - Ethyl 2- (4-methoxy-phenyl) -4-oxo-azetidin-1-yl] -benzylcarbamoyl-undecanoate (14):

130 mg of the Dodecandicarbonsäurederivat 13 are dissolved in 5 ml of dimethylformamide, mixed with 59.6 ul N-ethyl-morpholine, cooled to 0 ° C (ice / water), then treated with 36.3 ul ethyl chloroformate and stirred at 0 ° C for 1.5 h. Then, 174 mg of the benzylic amine 1 are added as a solid (immediate dissolution) and the cooling is removed. It is stirred for 2 h at room temperature. Thereafter, the reaction mixture is treated with aqueous KHSO ₄ solution. Extraction twice with DCM, washing the DCM phase with saturated NaCl solution, drying (Na ₂ SO ₄ ) and concentration in vacuo gives 275 mg of a clear, yellowish oil; Crude yield: 274 mg. Chromatography on silica gel (ethyl acetate / n-heptane 4: 3) gives 190 mg of compound 14.

p) 9- (tert-Butyl-dimethyl-silanyloxy) -11- {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxy-propyl] - 2- (4-methoxyphenyl) -4-oxo-azetidin-1-yl] benzylcarbamoyl} undecanoic acid (15):

300 mg of the ethyl ester 14 are taken up in 35 ml of acetonitrile and 25 ml of water, treated with 1 ml of 2N NaOH and stirred at room temperature for 65 h. Neutralization with aqueous saturated NH ₄ Cl solution and distilling off acetonitrile gives 300 mg of crude product. Chromatography on silica gel (methyl tert-butyl ether → methyl tert-butyl ether / ethyl acetate 4: 1 → MeOH) gives 104 mg of the pure carboxylic acid 15.

q) 11- {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxypropyl] -2- (4-methoxy-phenyl) -4- oxo-azetidin-1-yl] -benzylcarbamoyl} -9-hydroxy undecanoic acid (16):

100 mg of the protected silyl ether 15 are taken up in 30 ml of tetrahydrofuran and 15 ml of water, admixed with 1.7 ml of half-concentrated hydrochloric acid and stirred at room temperature. After about 30 minutes, aqueous Na ₂ CO ₃ solution is added. It is extracted with ethyl acetate, dried (Na ₂ SO ₄ ) and concentrated in vacuo; 141 mg of the crude product are obtained. Chromatography on silica gel (ethyl acetate → DCM / MeOH) gives 84 mg of the desilylated compound 16.

r) 4-Hydroxy-dodecanedioic acid 1- {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxy-propyl] -2- (4-methoxy -phenyl) -4-oxo-azetidin-1-yl] -benzylamide} -12 - [((2S, 3R, 4R, 5R) -2,3,4,5,6-pentahydroxy-hexyl) -amide] ( 17):

84 mg of the desilylated compound 16 are dissolved in 5-10 ml of dimethylformamide, mixed with 25 .mu.l of N-ethyl-morpholine, cooled to 0 ° C. (ice bath), treated with 14.6 .mu.l of ethyl chloroformate and 1.5 h at 0 ° C (ice / water ) touched. Then the cooling is removed and in the still cold solution 29.7 mg of D-glucamine are added in one portion. It formed after about 20 min, a solution. After about 2 h stirring at room temperature saturated aqueous NH ₄ Cl solution is added, the resulting suspension extracted three times with ethyl acetate. The collected ethyl acetate phases are dried (Na ₂ SO ₄ ) and concentrated in vacuo. There remain about 2 ml of a nearly colorless solution, which was further concentrated in a high vacuum; Crude yield 97 mg. After purification by preparative HPLC (YMC Pro C18RS, 5 μm, 150 × 20 mm, acetonitrile / water 47:53), 65 mg of the amide 17 with a purity of 98% are obtained. ¹ H-NMR (CH ₃ CN-D ₂ O): signal Shift [ppm] Number of protons 1 7.28 2 m 2 7.24 2 m 3 7.13 4 s 4 7.01 2 m 5 6.89 2 m 6 4.73 1 d 7 4.55 1 t 8th 4.17 H ₂ O 9 4.18 2 s 10 3.73 1 dd 11 3.72 3 s 12 3.66 1 dd 13 3.62 1 dd 14 3.62 1 dd 15 3.55 1 dd 16 3.52 1 dd 17 3.42 1 m 18 3.34 1 dd 19 3.12 1 dd 20 3.05 1 m 21 2.20 2 m 22 2.14 2 m 23 1.97 ACN-d ₆ 24 1.79 4 m 25 1.64 1 m 26 1.53 1 m 27 1.49 2 m 28 1.31 3 m 29 1.21 7 m

Example II

(S) -N * 4 * - {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxy-propyl] -2- (4-methoxy- phenyl) -4-oxo-azetidin-1-yl] -benzyl} -2-hydroxy-N * 1 * - ((2S, 3R, 4R, 5R) -2,3,4,5,6-pentahydroxy-hexyl ) -succinic acid amide (21):

a) (S) -N- {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxy-propyl] -2- (4-methoxy-phenyl ) -4-oxo-azetidin-1-yl] -benzyl} -2-hydroxy-succinic acid-hemiamide (18):

(Molekulargewicht 590,24 (C₃₃H₃₅FN₂O₇); Retentionszeit R_t = 3.15 min. [E]; MS (ESI): 591.24 (MH⁺)) und (S)-N*1*,N*4*-Bis-{4-[(2S,3R)-3-[(S)-3-(4-fluor-phenyl)-3-hydroxy-propyl]-2-(4-methoxy-phenyl)-4-oxo-azetidin-1-yl]-benzyl}-2-hydroxy-bernsteinsäureamid (20)

(Molekulargewicht 966,40 (C₅₆H₅₆F₂N₄O₉); Retentionszeit R_t = 3.31 min. [E]; MS (ESI): 967.37 (MH⁺)) isoliert.220 mg (1.27 mmol) of (S) - (+) - 2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid are dissolved in 10 ml of dry dimethylformamide, washed with 220 mg (1.44 mmol) of 1-hydroxybenzotriazole hydrate (HOBt), 276 mg (1.44 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and 223 mg (285 μL, 1.73 mmol) of N, N Diisopropylethylamine (DIPEA), and the mixture is stirred for 30 minutes at room temperature. Thereafter, 500 mg (1.15 mmol) of compound 1 are added and the mixture is stirred for 12 hours at room temperature. For workup, the reaction mixture is concentrated in vacuo, the residue is mixed with 20 ml of water and then extracted by shaking twice with 20 ml of ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatography over a reversed-phase column (method [RP1]). There are obtained (S) -N- {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxy-propyl] -2- (4-methoxyphenyl ) -4-oxo-azetidin-1-yl] benzyl} -2-hydroxy-succinic acid hemiamide (18); Molecular weight 550.21 (C ₃₀ H ₃₁ FN ₂ O ₇ ); Retention time R _t = 2.28 min. [E]; MS (ESI): 552.21 (MH ⁺ ). In addition, 2 - ((S) -2,2-dimethyl-5-oxo [1,3] dioxolan-4-yl) -N- {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxy-propyl] -2- (4-methoxyphenyl) -4-oxo-azetidin-1-yl] -benzyl} -acetamide (19)

(Molecular weight 590.24 (C ₃₃ H ₃₅ FN ₂ O ₇ ); retention time R _t = 3.15 min. [E]; MS (ESI): 591.24 (MH ⁺ )) and (S) -N * 1 *, N * * 4-bis {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxy-propyl] -2- (4-methoxy-phenyl) -4 -oxo-azetidin-1-yl] -benzyl} -2-hydroxy-succinic acid amide (20)

(Molecular weight 966.40 (C ₅₆ H ₅₆ F ₂ N ₄ O ₉ ); retention time R _t = 3.31 min. [E]; MS (ESI): 967.37 (MH ⁺ )) isolated.

b) (S) -N * 4 * - {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxy-propyl] -2- (4) methoxy-phenyl) -4-oxo-azetidin-1-yl] -benzyl} -2-hydroxy-N * 1 * - ((2S, 3R, 4R, 5R) -2,3,4,5,6-pentahydroxy -hexyl) -succinic acid amide (21):

300 mg (0.545 mmol) of compound 18 are dissolved in 6 ml of dry dimethylformamide and admixed successively with 104 mg of HOBt, 131 mg of EDC and 143 μl of DIPEA, and the mixture is stirred for 30 minutes at room temperature. Thereafter, the mixture is added to the mixture 109 mg of D-glucamine and stirred for a further 6 h at room temperature. The work-up is carried out as described for the compound 18. (S) -N * 4 * - {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxy-propyl] -2- (4) methoxy-phenyl) -4-oxo-azetidin-1-yl] -benzyl} -2-hydroxy-N * 1 * - ((2S, 3R, 4R, 5R) -2,3,4,5,6-pentahydroxy -hexyl) -succinic acid amide (21); Molecular weight 713.29 (C ₃₆ H ₄₄ FN ₃ O ₁₁ ); Retention time R _t = 3.44 min. [D]; MS (ESI): 714.57 (MH ⁺ ).

Example III

(R) -N * 4 * - {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxy-propyl] -2- (4-methoxy- phenyl) -4-oxo-azetidin-1-yl] -benzyl} -2-hydroxy-N * 1 * - ((2S, 3R, 4R, 5R) -2,3,4,5,6-pentahydroxy-hexyl ) -succinic acid amide (24):

Molekulargewicht 590,24 (C₃₃H₃₅FN₂O₇); Retentionszeit R_t = 3.15 min. [E]; MS (ESI): 591.24 (MH⁺) und als Hauptprodukt (R)-N-{4-[(2S,3R)-3-[(S)-3-(4-Fluor-phenyl)-3-hydroxy-propyl]-2-(4-methoxy-phenyl)-4-oxo-azetidin-1-yl]-benzyl}-2-hydroxy-bernsteinsäurehalbamid (23)

Die Verbindung 23 wird ohne weitere Reinigung wie für das Beispiel II beschrieben mit D-Glucamin weiter umgesetzt. Man erhält (R)-N*4*-{4-[(2S,3R)-3-[(S)-3-(4-Fluor-phenyl)-3-hydroxy-propyl]-2-(4-methoxy-phenyl)-4-oxo-azetidin-1-yl]-benzyl}-2-hydroxy-N*1*-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy-hexyl)-bernsteinsäureamid (24); Molekulargewicht 713,29 (C₃₆H₄₄FN₃O₁₁); Retentionszeit R_t = 3.45 min. [D]; MS (ESI): 714,57 (MH⁺).Analogously to the procedure for the preparation of the compound of Example II, the enantiomeric (R) - (-) - 2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid in a first step with the benzylamine 1 implemented. This gives 2 - ((R) -2,2-dimethyl-5-oxo [1,3] dioxolan-4-yl) -N- {4 - [(2S, 3R) -3 - [(S) - 3- (4-fluoro-phenyl) -3-hydroxy-propyl] -2- (4-methoxyphenyl) -4-oxo-azetidin-1-yl] -benzyl} -acetamide (22)

Molecular weight 590.24 (C ₃₃ H ₃₅ FN ₂ O ₇ ); Retention time R _t = 3.15 min. [E]; MS (ESI): 591.24 (MH ⁺ ) and as main product (R) -N- {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxy] propyl] -2- (4-methoxyphenyl) -4-oxo-azetidin-1-yl] benzyl} -2-hydroxy-succinic acid hemiamide (23)

The compound 23 is further reacted without further purification as described for Example II with D-glucamine. There are obtained (R) -N * 4 * - {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxy-propyl] -2- (4- methoxy-phenyl) -4-oxo-azetidin-1-yl] -benzyl} -2-hydroxy-N * 1 * - ((2S, 3R, 4R, 5R) -2,3,4,5,6-pentahydroxy -hexyl) -succinic acid amide (24); Molecular weight 713.29 (C ₃₆ H ₄₄ FN ₃ O ₁₁ ); Retention time R _t = 3.45 min. [D]; MS (ESI): 714.57 (MH ⁺ ).

Example XXIV

3-Hydroxy-3-methyl-pentanedioic acid 4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxy-propyl] -2- (4-methoxy-phenyl ) -4-oxo-azetidin-1-yl] -benzylamide ((2S, 3R, 4R, 5R) -2,3,4,5,6-pentahydroxy-hexyl) -amide (64):

gewonnen, welche ihrerseits durch Umsatz von 1 mit 3-Hydroxy-3-methylglutarsäure hergestellt wird.
63: Molekulargewicht 578,24 (C₃₂H₃₅FN₂O₇); Retentionszeit R_t = 3.93 min. [D]; MS (ESI): 561,08 (MH⁺-H₂O);
64: Molekulargewicht 741,32 (C₃₈H₄₈FN₃O₁₁); Retentionszeit R_t = 1.91 min. [C1]; MS (ESI): 742,53 (MH⁺).The amide 64 is prepared via the acid 63, 4- {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxypropyl] -2- (4- methoxy-phenyl) -4-oxo-azetidin-1-yl] -benzylcarbamoyl} -3-hydroxy-3-methyl-butyric acid,

which in turn is prepared by conversion of 1 with 3-hydroxy-3-methylglutaric acid.
63: molecular weight 578.24 (C ₃₂ H ₃₅ FN ₂ O ₇ ); Retention time R _t = 3.93 min. [D]; MS (ESI): 561.08 (MH ⁺ -H ₂ O);
64: molecular weight 741.32 (C ₃₈ H ₄₈ FN ₃ O ₁₁ ); Retention time R _t = 1.91 min. [C1]; MS (ESI): 742.53 (MH ⁺ ).

Example XXVI

4,5-Dihydroxy-dodecanedioic acid 1- {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxypropyl] -2- (4-methoxy) phenyl) -4-oxo-azetidin-1-yl] -benzylamide} 12 - [((2S, 3R, 4R, 5R) -2,3,4,5,6-pentahydroxy-hexyl) -amide] (76) :

a) Hept-6-methylic acid ester (67):

5 g of hept-6-acetic acid are added under argon protective gas to a mixture of 3.5 ml of acetyl chloride and 70-80 ml of methanol and stirred at room temperature. After standing overnight, concentration in vacuo, taking up the crude product in 5-10 ml of dichloromethane and filtration of the dichloromethane solution on silica gel to obtain 5.5 g of the methyl ester 67th

b) 7-Iodohept-6-methyl acetate (68):

6.6 g of the compound 67 are dissolved under argon protective gas in 100 ml of acetone, cooled to 0 ° C (ice / water) and treated with 11.7 g of NI-iodosuccinimide and 4.37 mg AgNO ₃ and stirred at 0 ° C. After 1.5 h, the reaction is stopped by adding saturated aqueous NH ₄ Cl and plenty of ethyl acetate. The organic phase is separated off; the aqueous phase is extracted by shaking with ethyl acetate and the organic phase is then washed with saturated aqueous common salt solution. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product (oil) is filtered through 100 ml of silica gel with ethyl acetate; after concentration in vacuo, 10.9 g of the DC-pure iodoalkyne 68 are obtained.

c) 12-Benzyloxy-9- (tert-butyldimethyl-silanyloxy) -8-hydroxy-dodec-6-methyl acetate (69):

A mixture of 4.1 g of CrCl ₂ and 5 mg of NiCl ₂ is mixed in a 100 ml 2Hals flask under argon gas with 30 ml of dry and degassed tetrahydrofuran, with 3.63 g of alkynyl iodide 68, dissolved in 7 ml of dry and degassed tetrahydrofuran and stirred at room temperature for 7-10 min. Then, at room temperature, a solution of 3 g of aldehyde 9 in 6 ml of degassed tetrahydrofuran is added dropwise (in ~ 5 min) and stirring is continued at room temperature. After 40 minutes, saturated aqueous NH ₄ Cl solution and methyl tert-butyl ether are added and stirred vigorously. The phases are separated, the green aqueous washed with methyl tert-butyl ether, the yellow organic with saturated aqueous NaCl solution. The organic phases are combined, dried (Na ₂ SO ₄ ) and concentrated in vacuo. This gives 3.9 g of an oily, yellow-orange crude product. Chromatography (silica gel, ethyl acetate / n-heptane 1: 3); gives 3 g of product 69.

d) Methyl 8,9-diacetoxy-12-benzyloxy-dodec-6-acidate (70):

1.5 g of product 69 are taken up in 20 ml of tetrahydrofuran and treated at room temperature with 2 g Bu ₄ NF × 3H ₂ O. The clear yellowish solution is stirred at room temperature. After 1 h, saturated aqueous NH ₄ Cl solution and methyl tert-butyl ether are added; after phase separation, the organic phase is washed with saturated aqueous NaCl solution and then with water. The combined water phases are washed with methyl tert-butyl ether; The combined organic phases are dried (MgSO ₄ ) and concentrated. The crude product is taken up in 10-15 ml of pyridine, treated with a catalytic amounts of dimethylaminopyridine and added in portions 2 ml of acetyl chloride. Thereafter, it is stirred for 1 h at room temperature. The reaction mixture is then partitioned between saturated KHSO ₄ solution and dichloromethane and between water and dichloromethane. Column chromatography on 100 g of silica gel (ethyl acetate / n-heptane 1: 2) gives 600 mg of diacetate 70.

e) Methyl 8,9-diacetoxy-12-hydroxy-dodecanoate (71):

390 mg of diacetate 70 are hydrogenated in a Büchi hydrogenation apparatus in 10 ml of methanol with 45 mg of 5% Pd / C (50% water-moist) for 3 h at 3 bar. The reaction solution is then centrifuged and the separated catalyst is washed with a few ml of ethyl acetate. The combined organic solutions are passed through a syringe filter and then concentrated; 316 mg of the colorless, oily compound 71 are obtained.

f) 12-methyl-4,5-diacetoxy-dodecanoic acid (72):

316 mg of the alcohol 71 are treated with 2 ml of CCl ₄ , 2 ml of CH ₃ CN and 3 ml of H ₂ O at room temperature. To this heterogeneous mixture are added 508 mg NaIO ₄ and 4 mg RuCl ₃ and stirred for 2 h at room temperature. Then dichloromethane and water are added, the phases are separated, the water phase is extracted twice with dichloromethane and once with ethyl acetate, the combined organic solutions are dried (Na ₂ SO ₄ ) and concentrated. 329 mg of compound 72 are obtained as a black-colored, clear oil.

g) 8,9-Diacetoxy-11- {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxy-propyl] -2- (4-methoxy -phenyl) -4-oxo-azetidin-1-yl] -benzylcarbamoyl} -undecanoic acid methyl ester (73):

350 mg of the crude product of compound 72 are dissolved in 10 ml of dimethylformamide, mixed with 200 .mu.l of N-ethyl-morpholine, cooled to 0 ° C. (ice / water), admixed after a few minutes with 120 .mu.l of ethyl chloroformate and 90 min at 0 ° C. touched. Subsequently, 520 mg of the benzylic amine 1 are added firmly and the cooling is removed. After a total of 2 h reaction time, water, then 3 M hydrochloric acid (to pH = 6) and ethyl acetate are added first. After phase separation, the aqueous phase is extracted twice with ethyl acetate. The combined ethyl acetate phase is washed with saturated NaCl solution, dried over sodium sulfate, filtered and then concentrated in vacuo. This gives a clear, dark oil; Crude yield: 870 mg. Chromatography on 180 g of silica gel (ethyl acetate / n-heptane 4: 1 to pure ethyl acetate) gives 550 mg of compound 73 as a white foam.

h) 11- {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxy-propyl] -2- (4-methoxy-phenyl) -4- oxo-azetidin-1-yl] -benzylcarbamoyl} -8,9-dihydroxy-undecanoic acid methyl ester 74:

300 mg of the coupling product 73 are mixed with 30 ml MeOH and 124 mg K ₂ CO ₃ and stirred at room temperature. After reaction for three hours, the reaction mixture is brought to pH 6-7 by addition of Amberlite IR120 H resin (previously briefly stirred with 5-6 M HCl, filtered and washed several times with methanol), the ion exchanger is filtered off and washed, and then the aqueous methanolic solution largely concentrated in vacuo; 240 mg of compound 74 are obtained in the form of a yellowish foam.

i) 11- {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxy-propyl] -2- (4-methoxy-phenyl) -4- oxo-azetidin-1-yl] -benzylcarbamoyl} -8,9-dihydroxy-undecanoic acid (75)

130 mg of the methyl ester 74 are clearly dissolved in 5 ml of CH ₃ CN and 1 ml of water, then treated with 300 .mu.l 2 M sodium hydroxide solution (pH 10) and the clear solution stirred at room temperature. After 3 h and the reaction is stopped by the addition of 2 ml of water and 63.5 μL 30% HCl (pH ~ 6). Addition of water and acetonitrile leads to a water-clear solution (Σ 60 ml). This is transferred to a 500 ml flask and freeze-dried overnight. The following day the substance is filtered to remove salts in dichloromethane / methanol: 8/2 on silica gel; Crude yield: 85 mg of the carboxylic acid (75).

k) 4,5-Dihydroxydodecanedioic acid 1- {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxy-propyl] -2- (4- methoxy-phenyl) -4-oxo-azetidin-1-yl] -benzylamides} 12 - [((2S, 3R, 4R, 5R) -2,3,4,5,6-pentahydroxy-hexyl) -amide] ( 76):

85 mg of the crude product of compound 75 are taken up in 10 ml of dimethylformamide, admixed with 63 μl of N-ethylmorpholine, cooled to 0 ° C. (ice / water), treated with 16 μl of ethyl chloroformate and ice for 1 h at 0 ° C. for 1 h. Water). Then the cooling is removed and in the still cold solution 34 mg of D-glucamine were added in one portion. The cloudy reaction mixture (glucamine was largely dissolved after 25 min) is stirred further at room temperature. The reaction is stopped after 1.5 h by addition of aqueous NaCl solution and 3 M HCl and brought to pH = 6. The turbid, slightly yellowish solution is extracted three times with n-butanol. The combined butanol phases are dried (Na ₂ SO ₄ ) and concentrated in vacuo as far as possible. Methanol is added twice and concentrated in vacuo; This gives 670 mg of a viscous, white-yellowish, still smelling of butanol residue. The material was purified by preparative HPLC (method [RP2]). 65 mg (97.5% purity) of compound (76) are obtained. ¹ H-NMR (δ, DMSO-d6): signal Shift [ppm] Number of protons waveform 1 8.18 1 t 2 7.67 1 t 3 7.30 4 t 4 7.12 4 s 5 7.10 2 t 6 6.97 2 d 7 5.27 1 d 8th 4.84 1 d 9 4.72 1 d 10 4.49 1 q 11 4.44 1 d 12 4.36 1 d 13 4.33 1 t 14 4.27 1 d 15 4.24 1 d 16 4.12 2 d 17 4.10 MeOH 18 3.72 3 s 19 3.56 3 m 20 3.48 3 m 21 3.37 H2O 22 3.23 3 m 23 3.16 MeOH 24 3.03 3 m 25 2.5 DMSO-d6 26 2.16 2 m 27 2.06 2 t 28 1.78 2 m 29 1.71 2 m 30 1.65 1 m 31 1.47 3 m 32 1.36 2 m 33 1.22 6 m

Example XXVII

4,5,6-Trihydroxy-dodecanedioic acid 1- {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxypropyl] -2- (4- methoxy-phenyl) -4-oxo-azetidin-1-yl] -benzylamide} 12 - [((2S, 3R, 4R, 5R) -2,3,4,5,6-pentahydroxy-hexyl) -amide] ( 85):

a) (E) -12-Benzyloxy-9-hydroxy-dodec-7-enoic Acid Ethyl Esters (77):

500 mg of the TBDMS-protected olefin 11 are taken up in 10 ml of tetrahydrofuran, admixed at room temperature with 1 g of NBu ₄ F × 3H ₂ O and stirred for 3 hours at room temperature. The reaction mixture is at room temperature overnight. The next day, the reaction mixture is mixed with 50-100 ml of water and extracted several times with ethyl acetate.

Drying of the organic phases with MgSO ₄ , filtration and concentration of the filtrate in vacuo gives 580 mg of compound 77 as a yellowish oil, which is reacted further without further purification.

b) 12-Benzyloxy-7,8,9-trihydroxy-dodecanoic acid ethyl ester (78):

580 mg of allyl alcohol 77 are taken up in 20 ml of acetone, mixed at 0-5 ° C (ice / water) with 339 mg of N-methylmorpholine-N-oxide (NMO) and a total of 4 ml of water. Then 1 ml of a 4% aqueous solution of OsO _{4 is} added. The cooling is removed and stirred for a further 2 h at room temperature. The clear, slightly yellowish reaction solution is left overnight. The following day, 10 ml of water and an excess of sodium thiosulphate are added and stirred for about 5 hours; after a further addition of water and saturated NaCl solution, the reaction mixture is extracted twice with ethyl acetate. The combined organic phases are washed with saturated NaCl solution, dried over MgSO ₄ , filtered and concentrated in vacuo. 650 mg of compound 78 are obtained as a brownish oil, which is reacted further directly.

c) 7,8,9-triacetoxy-12-benzyloxy-dodecanoic acid ethyl ester (79):

650 mg of the crude triol 78 are taken up in 15 ml of dichloromethane, admixed with 685 μl of pyridine, cooled to 0-5 ° C (ice / water), mixed with 506 μλ acetyl chloride and after brief stirring in the cold the cooling is removed and at room temperature stirred over the weekend. Additional dichloromethane is added and the reaction mixture is washed once with 2M HCl. The organic phase is then washed with saturated NaCl solution and with water, dried (MgSO ₄ ), concentrated in vacuo, taken up again with toluene, re-evaporated and chromatographed on silica gel (EA / n-heptane 1: 1); Yield: 440 mg of the yellowish oil 79.

d) 7,8,9-triacetoxy-12-hydroxy-dodecanoic acid ethyl ester (80):

415 mg of triacetate 79 are mixed with 41 mg of catalyst (5-10% Pd / C, 54% H ₂ O, Type 101 N / W 1, Degussa) and 10 ml of methanol and hydrogenated at 1.5 bar H ₂ . After 2 h, no starting material is detectable. The catalyst is separated and washed with 3 ml of methanol. After filtration, the pale green, methanolic filtrate is concentrated in vacuo; 425 mg of the pale green oil 80 are obtained.

e) 4,5,6-triacetoxy-dodecane-diacid 12-ethyl ester (81):

425 mg of the crude hydrogenation product 80 are mixed in 4 ml of CCl ₄ , 5 ml of CH ₃ CN and 5 ml of H ₂ O at room temperature with 1.03 g of NaIO ₄ and a catalytic amount of RuCl ₃ and stirred at room temperature. After 1.5 h, no starting material can be detected. Water and ethyl acetate are added, the phases are separated, the aqueous phase is washed with ethyl acetate, dried (Mg ₂ SO ₄ ) and concentrated in vacuo. A yellowish oil is obtained. For complete removal of solvent residues and water is added twice with toluene and concentrated in vacuo at 30-35 ° C; 381 mg of compound 81 are obtained in the form of a yellow-black oil, which is used without further purification in the next reaction.

f) 7,8,9-triacetoxy-11- {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxy-propyl] -2- (4 -methoxy-phenyl) -4-oxo-azetidin-1-yl] -benzylcarbamoyl} -undecanoic acid, ethyl ester (82):

Dissolve 381 mg of the carboxylic acid 81 in 10 ml of dimethylformamide, add 191 μL of N-ethylmorpholine, cool to 0-5 ° C (ice / water), add 113 μL ethyl chloroformate after a few minutes, and add 0-5 for 1.5 h ° C stirred. Subsequently, 536 mg of the benzylic amine 1 are added firmly and the cooling is removed. After 2.5 h, the work-up is carried out by adding water, a few drops of 3 M HCl and ethyl acetate. The aqueous phase is extracted twice with ethyl acetate, the organic phases are washed with saturated NaCl solution, dried over MgSO ₄ , filtered and concentrated in vacuo. This gives 1.04 g of a clear, dark oil; Chromatography (40 g SiO ₂ , ethyl acetate / n-heptane 3: 1 gives 550 mg of compound 82 as a white, slightly yellowish foam.

g) 11- {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxypropyl] -2- (4-methoxy-phenyl) -4- oxo-azetidin-1-yl] -benzylcarbamoyl} -7,8,9-trihydroxy-undecanoic acid methyl ester (83):

350 mg of the coupling product 82 are mixed with 20 ml of methanol and 167 mg K ₂ CO ₃ and stirred at room temperature for 6 h. The pH of the reaction mixture is then brought to 6-7 by addition of Amberlite IR120 H resin, the ion exchanger is filtered off and washed, then concentrated the methanolic solution of the product in vacuo, once concentrated pure with MeOH / toluene and once with MeOH. 326 mg of the deacetylated methyl ester 83 are obtained as a yellowish oil.

h) 11- {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxy-propyl] -2- (4-methoxy-phenyl) -4- oxo-azetidin-1-yl] -benzylcarbamoyl} -7,8,9-trihydroxy undecanoic acid (84):

218 mg of methyl ester 83 are mixed with 9 ml of CH ₃ CN, 3 ml of water and 400 .mu.l of 2 M NaOH (pH 9-10) and stirred at room temperature. The clear solution is stirred for about 3 h, then quenched by addition of 84 μL 30% HCl and the reaction mixture is concentrated several times in vacuo. The residue is chromatographed on silica gel in dichloromethane / methanol 8: 2; The crude product is taken up in a few ml of CH ₃ CN and dimethylformamide and concentrated in vacuo; Crude yield: 200 mg of compound 84.

i) 4,5,6-Trihydroxy-dodecane-diacid 1- {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxy-propyl] -2- ( 4-methoxy-phenyl) -4-oxo-azetidin-1-yl] -benzylamide} 12 - [((2S, 3R, 4R, 5R) -2,3,4,5,6-pentahydroxy-hexyl) -amide ] (85):

200 mg of compound 84 are dissolved in 10 ml of dimethylformamide, admixed with 74 μl of N-ethylmorpholine, cooled to 0 ° C. (ice / water), treated with 37 μl of ethyl chloroformate and incubated at 0 ° C. for 1 h 25 min. Water). Then the cooling is removed and in the still cold solution 79 mg of D-glucamine are added as a solid in one portion. The slightly turbid reaction mixture (glucamine was completely dissolved after 25 min) is stirred at room temperature for 110 min; the reaction is then stopped by the addition of 3 drops of 3 M HCl (→ pH 6-7) and aqueous saturated NaCl solution. The turbid solution is extracted three times with n-butanol. The combined butanol phases are washed once with saturated aqueous NaCl solution, dried (Na ₂ SO ₄ ) and concentrated in vacuo as far as possible. Methanol is added and concentrated again; Residue: 410 mg. The crude product is purified by preparative HPLC (YMC Pro C18RS, 5 μm, 150 × 20 mm, acetonitrile / water 47:53), the main fraction is dried overnight in (high) vacuum; Yield: 98 mg (purity 97.3%) 85. ¹ H-NMR (δ, DMSO-d6): signal Shift [ppm] Number of protons waveform 1 8.19 1 q 2 7.69 1 t 3 729 2 t 4 7.29 2 t 5 7.12 4 s 6 7.10 2 t 7 6.92 2 d 8th 5.30 1 d 9 4.83 1 d 10 4.74 1 d 11 4.49 1 t 12 4.47 1 d 13 4.39 1 d 14 4.23 2 t 15 4.26 1 d 16 4.22 2 d 17 4.16 MeOH 18 4.14 1 d 19 4.11 1 d 20 3.72 3 s 21 3.56 3 m 22 3.46 H2O 23 3.38 4 m 24 3.25 1 dt 25 3.16 MeOH 26 3.05 1 m 27 3.01 2 m 28 2.93 1 t 29 2.5 DMSO-d6 30 2.16 2 m 31 2.07 2 t 32 1.78 2 m 33 1.71 2 m 34 1.60 2 m 35 1.47 4 m 36 1.22 4 m

Example XXVIII

4,5-Dihydroxydodecanedioic acid 12- {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxy-propyl] -2- (4-methoxy) phenyl) -4-oxo-azetidin-1-yl] -benzylamide} 1 - [((2S, 3R, 4R, 5R) -2,3,4,5,6-pentahydroxy-hexyl) -amide] (88) :

a) Methyl 8,9-diacetoxy-11 - ((2S, 3R, 4R, 5R) -2,3,4,5,6-pentahydroxy-hexylcarbamoyl) -undecanoate (86):

376 mg of the black-colored, oily carboxylic acid 72 are taken up in 10 ml of dimethylformamide, admixed with 226 μl of N-ethylmorpholine, cooled to 0 ° C. (ice / water), then combined with 134 μl ethyl chloroformate and 1 h at 0 ° C. touched. Then 265 mg of D-glucamine are added firmly and the cooling is removed. It is stirred for 1.5 h at room temperature; the reaction mixture is at room temperature overnight and is quenched the next day by addition of water, n-butanol and 10% HCl and adjusted to pH ~ 2. After the phases have been separated, the water phase is shaken out with butanol; The organic phase is dried (Na ₂ SO ₄ ), filtered and concentrated. Subsequently, the crude product is taken up in a large amount of acetonitrile and filtered through a Chromabond C18 cartridge, then concentrated again; Crude yield: 650 mg of Compound 86 as black oil; The substance is used without further purification in the next stage.

b) 8,9-Dihydroxy-11 - ((2S, 3R, 4R, 5R) -2,3,4,5,6-pentahydroxy-hexylcarbamoyl) undecanoic acid (87):

650 mg of methyl ester 86 are taken up in 10 ml of CH ₃ CN; 9 ml of the solution are mixed with 1.67 ml of 2 M NaOH and stirred at room temperature. After 30 minutes, the heterogeneous reaction mixture is mixed with 4 ml of water and the resulting solid is dissolved. The reaction mixture is stirred for a further 2 h; then the addition of 600 μL 30% HCl. The acidic reaction mixture or the crude product is treated several times with CH ₃ CN and dimethylformamide (solvent of the next stage) and concentrated in vacuo to remove water and acetic acid; Crude product: 990 mg of a brownish-yellow oil (87).

c) 4,5-Dihydroxydodecanedioic acid 12- {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxypropyl] -2- (4- methoxy-phenyl) -4-oxo-azetidin-1-yl] -benzylamide} 1 - [((2S, 3R, 4R, 5R) -2,3,4,5,6-pentahydroxy-hexyl) -amide] ( 88):

990 mg of the yellow-brown crude product 87 are dissolved in 30 ml of dimethylformamide, mixed with 400 .mu.l of N-ethyl-morpholine, cooled to 0-5.degree. C. (ice / water), admixed with 144 .mu.l of ethyl chloroformate after a few minutes, for 80 min Stirred 0-5 ° C, finally 682 mg of amine 1 was added firmly and the cooling was removed. The reaction mixture is stirred for 105 min. at room temperature and is then stopped by the addition of 30% HCl, water, n-butanol and aqueous, saturated NaCl solution. After phase separation, the water phase is extracted twice with n-butanol; the butanol solution is concentrated in vacuo. Precipitated salts are separated and washed thoroughly with butanol. The combined butanol extracts are concentrated in vacuo; the residue is combined with methanol and concentrated again. The oily residue is purified on a preparative HPLC column. 157 mg of compound 88 are obtained. ¹ H-NMR (δ, DMSO-d6) signal Shift [ppm] Number of protons waveform 1 8.16 1 t 2 7.68 1 t 3 7.30 4 t 4 7.12 4 s 5 7.10 2 t 6 6.92 2 d 7 5.27 1 d 8th 4.84 1 d 9 4.73 1 d 10 4.49 1 q 11 4.45 1 dd 12 4.36 1 d 13 4.32 1 t 14 4.31 1 d 15 4.25 1 d 16 4.18 1 d 17 4.13 1 d 18 3.72 3 s 19 3.57 3 m 20 3.44 3 m 21 3.36 H2O 22 3.23 3 m 23 3.03 2 m 24 2.5 DMSO-d6 25 2.17 3 m 26 2.06 2 t 27 1.78 2 m 28 1.71 2 m 29 1.64 1 m 30 1.47 3 m 31 1.37 2 m 32 1.21 6 m

Example XXIX

4,6,7-trihydroxy-dodecanedioic acid 1- {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxy-propyl] -2- (4- methoxy-phenyl) -4-oxo-azetidin-1-yl] -benzylamide} 12 - [((2S, 3R, 4R, 5R) -2,3,4,5,6-pentahydroxy-hexyl) -amide] ( 100):

a) Trisisopropyl ester of hept-6-acid (89):

1.85 g of the colorless, clear heptinic acid are dissolved in 50 ml of dichloromethane, admixed with 4.5 g of NEt ₃ and combined with vigorous stirring with 4.72 ml of trisisopropylsilyl chloride (TIPS-Cl). The rapid portionwise addition of the silylating agent is accompanied by a slight warming and the formation of a vigorous white precipitate. The reaction mixture is stirred vigorously for 3 h at room temperature. The work-up is then carried out by addition of aqueous saturated NH ₄ Cl solution. The water phase is extracted with dichloromethane. The organic phase is washed with aqueous saturated NaCl solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Chromatographic purification (ethyl acetate / n-heptane 1: 17.5) gives 4.04 g of TIPS ester 89.

b) Trisisopropyl ester of 12-benzyloxy-9-hydroxy-dodec-6-acetic acid (90):

1 g of the colorless, clear heptinic acid TIPS ester 89 are dissolved in 10 ml of tetrahydrofuran, cooled to -95 ° C (liquid nitrogen / methanol), treated dropwise with 2.32 ml BuLi / hexane (5 min) and 30 min at this temperature touched. Then 0.981 ml of BF ₃ etherate are added and the mixture is stirred at -95 ° C. for a further 10 minutes. Subsequently, 750 mg of the freshly chromatographed epoxide 3, dissolved in 5 ml of tetrahydrofuran are added dropwise in 5 min and the mixture for 30 min at -95 ° C and then stirred at -80 ° C. 1.5 After addition of the epoxide, saturated aqueous NH ₄ Cl solution and methyl tert-butyl ether are added and the mixture is stirred vigorously. After phase separation, washing the aqueous phase again with methyl tert-butyl ether, drying the organic phase with Na ₂ SO ₄ , filtration and concentration in vacuo, the chromatographic purification is carried out on silica gel (ethyl acetate / n-heptane 1: 4). Product-containing fractions are concentrated in vacuo to give 775 mg of compound 90.

c) 12-Benzyloxy-9-hydroxy-dodec-6-methyl acetate (91):

1.2 g of the colorless, clear TIPS ester 90 from the Yamaguchi alkynylation are mixed with 28 ml of methanolic HCl - previously prepared from 3 ml of acetyl chloride and 25 ml of methanol - and stirred at room temperature. After 1.5 h, the reaction mixture is concentrated several times with methanol in vacuo; 850 mg of compound 91 are obtained. The crude product is reacted further without further purification.

d) 12-Benzyloxy-9-hydroxy-dodec-6-enoic acid methyl ester (92):

1.14 g of compound 91 are in a Büchi hydrogenator in 10 ml of n-heptane / ethyl acetate 2: 1 with 50 mg of quinoline and 200 mg Lindlar-Kat (5% Pd / CaCO ₃ , lead poisoned, ABCR 121386) and 16 h at 3.5 hydrogenated bar. The mixture is centrifuged, the catalyst is washed with ethyl acetate and the reaction solution is concentrated; 1.1 g of 92 are obtained as a brown oil.

e) 12-Benzyloxy-6,7,9-trihydroxy-dodecanoic acid methyl ester (93):

1 g of the crude product 92 from the hydrogenation under Lindlar conditions is taken up in 30 ml of acetone, at 0-5 ° C (ice / water) with 600 mg of N-methylmorpholine-N-oxide, 6 ml of water and 1.8 ml of a 4% wss. OsO ₄ solution added. The cooling is removed and the clear brownish solution is stirred for 7 h at room temperature. Then water and an excess of sodium thiosulfate are added. The clear reaction mixture is left overnight. Addition of NaCl solution, washing three times with ethyl acetate, washing the combined organic phases with saturated NaCl solution, drying over MgSO ₄ and concentration in vacuo gives 1.24 g of triol 93 as a brown oil.

f) methyl 6,7,9-triacetoxy-12-benzyloxy-dodecanoate (94):

1.24 g of triol 93 are taken up in 30 ml of dichloromethane, mixed with 2 ml of pyridine, cooled to 0-5 ° C (ice / water), in 3 portions with 1.5 ml of acetyl chloride. After brief stirring in the cold, the cooling is removed and stirred at room temperature. After 6 h, it is washed with 1-2 M HCl. It is then extracted with saturated NaCl solution and with water, the organic phase is dried (MgSO ₄ ), filtered, concentrated, taken up with toluene and concentrated under reduced pressure: 1.49 g of a dark brown oil are obtained. Chromatography on 150 g of silica gel (ethyl acetate / n-heptane 1: 3) gives 1.0 g of a slightly yellowish oil of compound 94.

g) Methyl 6,7,9-triacetoxy-12-hydroxy-dodecanoate (95):

1 g of benzyl ether 94 is hydrogenated in a Büchi hydrogenator with 75 mg of 5-10% Pd / C (54% water, type 101 N / W 1, Degussa) in 15 ml of methanol at room temperature and 3.5 bar H ₂ 3 h , Subsequently, the reaction solution is centrifuged and the catalyst washed with 2 ml of methanol. After complete concentration in vacuo, 809 mg of the colorless oily compound 95 are obtained. The compound is used without further purification in the next stage.

h) 4,6,7-triacetoxy-dodecanedioic acid 12-methyl ester (96):

824 mg of the alcohol 95 are mixed with 9 ml of CCl ₄ , 9 ml of CH ₃ CN and 12 ml of H ₂ O at room temperature. To this heterogeneous mixture are added 1.75 g NaIO ₄ and 21 mg RuCl ₃ and stirred for 1.5 h at room temperature. Then dichloromethane and water are added, the phases are separated, the water phase is extracted twice with dichloromethane and once with ethyl acetate; The combined organic phases are dried (Na ₂ SO ₄ ), filtered and concentrated. 950 mg of a black-colored, clear oil 96 are obtained.

i) 6,7,9-triacetoxy-11- {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxy-propyl] -2- (4 -methoxy-phenyl) -4-oxo-azetidin-1-yl] -benzylcarbamoyl} -undecanoic acid methyl ester (97):

950 mg of the crude product 96 are dissolved in 25 ml of dimethylformamide, distilled off a few ml in vacuo, treated with 442 μL N-ethyl-morpholine, cooled to 0-5 ° C (ice / water), after a few minutes with 262 μL ethyl chloroformate and Stirred at 0-5 ° C for 80 min. Subsequently, 1.24 g of the benzylic amine 1 are added as a solid and the cooling is removed. After a total reaction time of 2 h, plenty of water, 10 drops of 3 M HCl (pH ~ 6) and ethyl acetate are added. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with saturated NaCl solution, dried over Na ₂ SO ₄ and concentrated in vacuo. This gives a clear, dark oil; Crude yield: 2.1 g. Chromatography on 180 g of silica gel (ethyl acetate / n-heptane 2: 1 to pure ethyl acetate) gives after concentration in vacuo 1.12 g of compound 97 as a white-slightly yellowish foam and 305 mg of an approximately 80% material.

k) 11- {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxy-propyl] -2- (4-methoxy-phenyl) -4- oxo-azetidin-1-yl] -benzylcarbamoyl} -6,7,9-trihydroxy-undecanoic acid methyl ester (98):

1.12 g of the coupling product 97 are mixed with 50 ml of methanol and 556 mg K ₂ CO ₃ and stirred at room temperature. After reaction for four hours, the reaction mixture is brought to pH 5-6 by addition of Amberlite IR120 H resin (previously briefly stirred with 5-6 M HCl, filtered and washed several times with methanol), the ion exchanger is filtered off and washed, and then the aqueous methanolic solution of the compound 98 largely concentrated in vacuo, stored at about -4 ° C or used directly in the next stage.

l) 11- {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxy-propyl] -2- (4-methoxy-phenyl) -4- oxo-azetidin-1-yl] -benzylcarbamoyl} -6,7,9-trihydroxy undecanoic acid (99):

1 g of methyl ester 98 is clearly dissolved in 60 ml of acetonitrile and 25 ml of water, then treated with 1 ml of 2 M NaOH (pH 10) and the clear solution stirred at room temperature. After 2 h and 15 min, the reaction is stopped by the addition of 2.11 ml of 30% HCl (pH ~ 6) and the reaction mixture was first taken twice with methanol, then with 10 ml and again with 20 ml of dimethylformamide and concentrated in vacuo. 99 is obtained as a tough, yellowish oil which is used without further purification in the subsequent D-glucamine coupling.

m) 4,6,7-Trihydroxy-dodecane-diacid 1- {4 - [(2S, 3R) -3 - [(S) -3- (4-fluoro-phenyl) -3-hydroxy-propyl] -2- ( 4-methoxy-phenyl) -4-oxo-azetidin-1-yl] -benzylamide} 12 - [((2S, 3R, 4R, 5R) -2,3,4,5,6-pentahydroxy-hexyl) -amide ] (100):

2 g of the crude product 99 are taken up in 30 ml of dimethylformamide with 370 μL N-ethyl-morpholine, cooled to 0 ° C (ice / water), treated with 185 μL ethyl chloroformate and 1 h 25 min at 0 ° C (ice / water ) touched. The cooling is then removed and 395 mg of D-glucamine are added in one portion to the still cold solution. The cloudy reaction mixture (D-glucamine is largely dissolved after 25 min) is stirred further at room temperature. The reaction is stopped after 3 h by addition of aqueous NaCl solution and 3 M HCl and brought to pH = 6. The turbid, slightly yellowish solution is extracted three times with n-butanol. Combined butanol phases are dried (Na ₂ SO ₄ ) and concentrated in vacuo as far as possible. Methanol is added twice and concentrated in vacuo; This gives 1.8 g of a viscous, colorless, even after Butanolriechender residue. This material is purified on preparative HPLC. This gives 448 mg of compound 100. ¹ H-NMR (δ, DMSO-d6) signal Shift [ppm] Number of protons waveform 1 8.17 1 q 2 7.67 1 t 3 7.30 4 t 4 7.12 4 s 5 7.11 2 t 6 6.92 2 d 7 5.26 1 d 8th 4.84 1 d 9 4.72 1 d 10 4.49 1 t 11 4.40 1 d 12 4.36 2 d 13 4.31 2 t 14 4.24 1 d 15 4.17 1 d 16 4.13 2 d 17 3.72 3 s 18 3.57 4 m 19 3.47 1 m 20 3.40 3 m 21 3.32 H2O 22 3.25 1 dt 23 3.17 1 m 24 3.03 2 m 25 2.5 DMSO-d6 26 2.16 2 m 27 2.07 2 t 28 1.79 2 m 29 1.72 2 m 30 1.47 6 m 31 1.21 4 m

The compounds of the formula I according to the invention were tested for their 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

NMRI mice, Wistar rats, or Golden Syrian hamsters (in groups of n = 4-6) are kept in metabolic cages under standard diet (Altromin, Lage (Lippe)). On the afternoon before administration of radioactive tracers ( ¹⁴ C-cholesterol), the animals are fasted and adapted to grids.

In addition, the animals 24 hours before the oral administration of the test meal ⁽¹⁴ C-cholesterol in Intralipid ^® 20, Pharmacia-Upjohn) with ³ H-TCA (Taurocholic acid) sc labeled (eg., 1 uCi / mouse to 5 uCi /Rat)

Cholesterol absorption: orally administered 0.25 ml / mouse Intralipid ^® 20 (Pharmacia-Upjohn) ((spiked with 0.25 uCi ¹⁴ C-cholesterol in 0.1 mg of cholesterol) by gavage.

Test substances are prepared separately in 0.5% / (methylcellulose (Sigma) / 5% Solutol (BASF, Ludwigshafen) or suitable vehicle.

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.

Livers are harvested, homogenized and aliquots in oxime (Model 307, Packard) are burned to determine the ingested / absorbed amount of ¹⁴ C-cholesterol.

Evaluation:

Fecal samples:

Determine total weight, fill with water to defined volume, then homogenize, dry aliquot and incinerate in Oximat (Model 307, Packard for the 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.

Liver samples:

The amount of ¹⁴ C-cholesterol absorbed into the liver is related to the applied dose. The ED ₅₀ values are interpolated from a dose response curve as the dose that halves the uptake of ¹⁴ C-cholesterol into the liver (50%) relative to a control group

The following ED ₅₀ values confirm the activity of the compounds of the formula I according to the invention Example no. ED ₅₀ (liver) [mg / mouse] XXVI 0.3 XXVII 0.3 XXVIII 0.3 XXIX 0.1

From the table it can be seen that the compounds of formula I have a very good cholesterol lowering effect.

absorbability:

The absorbability of the compounds of the formula I was tested in a Caco cell model ( AR Hilgers et al., Caco-2 cell monolayers as a model for drug delivery across the intestinal mucosa, Pharm. Res. 1990, 7, 902 ).

Referenzstruktur 2:

Beispiel Nr. P_app.-Wert [cm/s] Referenzstruktur 1 5.68 × 10^–6 Referenzstruktur 2 0.1 × 10^–7 I 0.03 × 10^–7 II 0.02 × 10^–7 III 0.02 × 10^–7 XXIV 0.04 × 10^–7 XXVII 0.04 × 10^–7 XXVIII 0.09 × 10^–7 From the measured data can be read that the compounds of formula I according to the invention over the compounds described in the prior art ezetimibe (reference structure 1) and the compound of US Pat. No. 7,205,290 B2 (Reference structure 2) have a significantly lower absorption. Reference Structure 1:

Reference structure 2:

Example no. P _app. Value [cm / s] Reference structure 1 5.68 × 10 ^-6 Reference structure 2 0.1 × 10 ^-7 I 0.03 × 10 ^-7 II 0.02 × 10 ^-7 III 0.02 × 10 ^-7 XXIV 0.04 × 10 ^-7 XXVII 0.04 × 10 ^-7 XXVIII 0.09 × 10 ^-7

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• WO 2002/050027 [0002]
• US 7205290 B2 [0002, 0355]
• WO 2009152128 [0022]
• WO 2005005477 [0022]
• US 6221633 [0022]
• WO 2007128815 [0022]
• WO 2007128817 [0022]
• WO 2008034881 [0022]
• WO 2008049711 [0022]
• WO 2008145721 [0022]
• WO 2009034117 [0022]
• WO 2009060071 [0022]
• WO 2009133099 [0022]
• WO 2009121884 [0022]
• WO 2008061355 [0022]
• WO 2009080024 [0022]
• WO 2009080032 [0022]
• WO 98/08871 [0022]
• WO 2005027978 [0022]
• WO 2006037811 [0022]
• WO 2006037810 [0022]
• WO 01/04156 [0022]
• WO 00/34331 [0022]
• WO 2009107900 [0022]
• US 2009238879 [0022]
• WO 2006124529 [0022]
• WO 2007124461 [0022]
• WO 2008062457 [0022]
• WO 2008082274 [0022]
• WO 2008101017 [0022, 0022]
• WO 2008081418 [0022]
• WO 2008112939 [0022]
• WO 2008112941 [0022]
• WO 2008113601 [0022]
• WO 2008116294 [0022]
• WO 2008116648 [0022]
• WO 2008119238 [0022]
• WO 2008148839 [0022]
• US 2008299096 [0022]
• WO 2008152403 [0022]
• WO 2009030738 [0022]
• WO 2009030771 [0022]
• WO 2009030774 [0022]
• WO 2009035540 [0022]
• WO 2009058734 [0022, 0057]
• WO 2009111700 [0022]
• WO 2009125424 [0022]
• WO 2009129696 [0022]
• WO 2009149148 [0022]
• WO 2007104789 [0022]
• WO 2009034119 [0022]
• WO 2007120899 [0022]
• WO 2008022015 [0022]
• WO 2008056726 [0022]
• WO 2009155257 [0022]
• WO 2009155258 [0022]
• WO 2009153960 [0022]
• WO 2009049222 [0025]
• WO 2006121860 [0026]
• WO 2008021560 [0027]
• WO 2010016935 [0027]
• WO 2010016936 [0027]
• WO 2010016938 [0027]
• WO 2010016940 [0027]
• WO 2010016944 [0027]
• WO 2009007714 [0028]
• WO 2009149171 [0030]
• WO 2010006214 [0030]
• WO 97/26265 [0031]
• WO 99/03861 [0031]
• EP 2103302 [0035]
• US 2007264331 [0036]
• WO 2008050987 [0036]
• WO 2008062273 [0036]
• WO 2009087395 [0038]
• WO 2007095462 [0042]
• WO 2007101060 [0042]
• WO 2007105650 [0042]
• WO 2007137008 [0043]
• WO 2008020607 [0043, 0108, 0157]
• WO 97/41097 [0044]
• WO 2005086904 [0045]
• WO 2007060992 [0045]
• WO 2007100027 [0045]
• WO 2007103252 [0045, 0049]
• WO 2007122970 [0045]
• WO 2007138485 [0045]
• WO 2008006319 [0045]
• WO 2008006969 [0045]
• WO 2008010238 [0045]
• WO 2008017398 [0045]
• WO 2008028188 [0045]
• WO 2008066356 [0045, 0051]
• WO 2008084303 [0045]
• WO 2008089461 [0045]
• WO 2008089464 [0045]
• WO 2008093639 [0045]
• WO 2008096769 [0045]
• WO 2008096820 [0045]
• WO 2008096829 [0045]
• US 2008194617 [0045, 0075]
• WO 2008099944 [0045]
• WO 2008108602 [0045]
• WO 2008109334 [0045]
• WO 2008110062 [0045]
• WO 2008126731 [0045]
• WO 2008126732 [0045]
• WO 2008137105 [0045]
• WO 2009005672 [0045]
• WO 2009038681 [0045]
• WO 2009046606 [0045]
• WO 2009080821 [0045]
• WO 2009083526 [0045]
• WO 2009102226 [0045]
• WO 2009128558 [0045]
• WO 2009139430 [0045]
• WO 2001040207 [0049]
• WO 2002096894 [0049]
• WO 2005097076 [0049]
• WO 2007056771 [0049]
• WO 2007087448 [0049]
• WO 2007089667 [0049]
• WO 2007089557 [0049]
• WO 2007102515 [0049]
• JP 2007246474 [0049]
• WO 2007118963 [0049]
• WO 2007118964 [0049]
• WO 2007126043 [0049]
• WO 2008006043 [0049]
• WO 2008006044 [0049]
• WO 2008012470 [0049]
• WO 2008035359 [0049, 0052]
• WO 2008087365 [0049]
• WO 2008087366 [0049]
• WO 2008087367 [0049]
• WO 2008117982 [0049]
• JP 2009023975 [0049]
• WO 2009033561 [0049]
• WO 2009047240 [0049]
• WO 2009072581 [0049, 0052]
• WO 2009080248 [0049]
• WO 2009080242 [0049]
• WO 2009149819 [0049, 0050, 0050, 0051]
• WO 2009149820 [0049, 0050, 0051]
• WO 2009147121 [0049]
• WO 2009153496 [0049]
• WO 2010008299 [0049]
• WO 2010014771 [0049]
• WO 00/64888 [0050]
• WO 00/64876 [0050]
• WO 03/020269 [0050]
• WO 2004024726 [0050]
• WO 2007099553 [0050]
• US 2007276041 [0050]
• WO 2007085135 [0050]
• WO 2007085136 [0050]
• WO 2007141423 [0050, 0051]
• WO 2008016175 [0050, 0051]
• WO 2008053331 [0050]
• WO 2008109697 [0050]
• WO 2008108735 [0050]
• WO 2009026657 [0050]
• WO 2009026658 [0050]
• WO 2006059744 [0051]
• WO 2006084176 [0051]
• WO 2006029699 [0051]
• WO 2007039172 [0051]
• WO 2007039178 [0051]
• WO 2007071766 [0051]
• WO 2007101864 [0051]
• US 2007244094 [0051]
• WO 2007119887 [0051]
• US 2008004281 [0051]
• WO 2008071311 [0051]
• WO 2008084962 [0051]
• US 2008176861 [0051]
• WO 2009012650 [0051]
• US 2009137671 [0051]
• WO 2009080223 [0051]
• WO 2010000353 [0051]
• WO 2007114532 [0054]
• WO 2007140230 [0054]
• US 2007287674 [0054]
• US 2008103201 [0054]
• WO 2008065796 [0054]
• WO 2008082017 [0054]
• US 2009076129 [0054]
• FR 258900 [0055]
• WO 2003084922 [0055]
• WO 2004007455 [0055]
• WO 2005073229-31 [0055]
• WO 2005073231 [0055]
• WO 2005067932 [0055]
• WO 2008062739 [0055]
• WO 2008099000 [0055]
• WO 2008113760 [0055]
• WO 2009016118 [0055]
• WO 2009016119 [0055]
• WO 2009030715 [0055, 0056]
• WO 2009045830 [0055]
• WO 2009045831 [0055]
• WO 2009127723 [0055]
• WO 2004100875 [0057]
• WO 2005065680 [0057]
• WO 2006086488 [0057]
• WO 2007047177 [0057]
• WO 2007106181 [0057]
• WO 2007111864 [0057]
• WO 2007120270 [0057]
• WO 2007120284 [0057]
• WO 2007123581 [0057]
• WO 2007136577 [0057]
• WO 2008042223 [0057]
• WO 2008098244 [0057]
• WO 2009057784 [0057]
• WO 2009058662 [0057]
• WO 2009110520 [0057]
• WO 2009120530 [0057]
• WO 2009140342 [0057]
• WO 2010019828 [0057]
• WO 2004063179 [0059]
• WO 2004072031 [0059]
• WO 2004072066 [0059]
• WO 2005080360 [0059]
• WO 2005044801 [0059]
• WO 2006016194 [0059]
• WO 2006058923 [0059]
• WO 2006112549 [0059]
• WO 2006125972 [0059]
• WO 2007017549 [0059]
• WO 2007017649 [0059]
• WO 2007007910 [0059]
• WO 2007007040 [0059]
• WO 2007007042 [0059]
• WO 2007006760 [0059]
• WO 2007006761 [0059]
• WO 2007006814 [0059]
• WO 2007007886 [0059]
• WO 2007028135 [0059]
• WO 2007031739 [0059]
• WO 2007041365 [0059]
• WO 2007041366 [0059]
• WO 2007037534 [0059]
• WO 2007043638 [0059]
• WO 2007053345 [0059]
• WO 2007051846 [0059]
• WO 2007051845 [0059]
• WO 2007053765 [0059]
• WO 2007051847 [0059]
• WO 2007061923 [0059]
• WO 2007075847 [0059]
• WO 2007089512 [0059]
• WO 2007104034 [0059]
• WO 2007117381 [0059]
• WO 2007122482 [0059]
• WO 2007125103 [0059]
• WO 2007125105 [0059]
• US 2007281942 [0059]
• WO 2008005914 [0059]
• WO 2008005964 [0059]
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• FR 225654 [0060]
• WO 2008053446 [0060]
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• WO 2004007517 [0078]
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• EP 2005/005959 [0078]
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• WO 2008011453 [0081]
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• WO 2009061498 [0081]
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• WO 2009102460 [0081]
• WO 2009102761 [0081]
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• US 2009264401 [0081]
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• WO 2009134392 [0081]
• WO 2009134400 [0081]
• WO 2009135581 [0081]
• WO 2009138386 [0081]
• WO 2010006940 [0081]
• WO 2010010157 [0081]
• WO 2010010174 [0081]
• WO 2010011917 [0081]
• WO 200/19830 [0082]
• WO 200119831 [0082]
• WO 200/75166 [0082]
• WO 2004506446 [0082]
• WO 2005012295 [0082]
• WO 2005116003 [0082, 0082]
• WO 2006007959 [0082]
• DE 102004060542 [0082]
• WO 2007009911 [0082]
• WO 2007028145 [0082]
• WO 2007067612 [0082]
• WO 2007067615 [0082]
• WO 2007081755 [0082]
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• US 2008004325 [0082]
• WO 2008033455 [0082]
• WO 2008033931 [0082]
• WO 2008033932 [0082]
• WO 2008033934 [0082]
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• WO 2008148744 [0082]
• WO 2009032321 [0082]
• WO 2009109999 [0082]
• WO 2009109998 [0082]
• WO 2010014613 [0083]
• WO 2004041274 [0084]
• WO 2006045565 [0084]
• WO 2006045564 [0084]
• WO 2006069242 [0084]
• WO 2006085108 [0084]
• WO 2006085112 [0084]
• WO 2006085113 [0084]
• WO 2006124490 [0084]
• WO 2006113150 [0084]
• WO 2007002557 [0084]
• WO 2007017261 [0084, 0084]
• WO 2007017265 [0084]
• WO 2007015744 [0084]
• WO 2007027532 [0084]
• WO 2007092364 [0084]
• WO 2007120575 [0084]
• WO 2007134986 [0084]
• WO 2007150025 [0084]
• WO 2007150026 [0084]
• WO 2008016968 [0084]
• WO 2008051403 [0084]
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• US 2008234277 [0084]
• WO 2008127591 [0084]
• WO 2008039882 [0088]
• WO 2009149056 [0089]
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• WO 2007013689 [0091]
• WO 2007033002 [0091]
• WO 2007106469 [0091]
• US 2007265332 [0091, 0091]
• WO 2007123225 [0091]
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• WO 2007131620 [0091]
• WO 2007131621 [0091]
• WO 2007131622 [0091]
• WO 2007136572 [0091]
• WO 2008001931 [0091]
• WO 2008030520 [0091]
• WO 2008030618 [0091]
• WO 2008054674 [0091]
• WO 2008054675 [0091]
• WO 2008066097 [0091]
• US 2008176912 [0091]
• WO 2008130514 [0091]
• WO 2009038204 [0091, 0093]
• WO 2009039942 [0091]
• WO 2009039943 [0091]
• WO 2009048527 [0091]
• WO 2009054479 [0091]
• WO 2009058237 [0091]
• WO 2009111056 [0091]
• WO 2010012650 [0091]
• WO 2004065380 [0092]
• WO 2005061489 [0092]
• WO 2006083491 [0092]
• WO 2007003960-62 [0092]
• WO 2007003962 [0092]
• WO 2007003964 [0092]
• WO 2007035355 [0092, 0189]
• WO 2007116229 [0092]
• WO 2007116230 [0092]
• WO 2008005569 [0092]
• WO 2008005576 [0092, 0189]
• WO 2008008887 [0092]
• WO 2008008895 [0092]
• WO 2008025798 [0092]
• WO 2008025799 [0092]
• WO 2008025800 [0092]
• WO 2008070692 [0092]
• WO 2008076243 [0092]
• WO 200807692 [0092]
• WO 2008081204 [0092]
• WO 2008081205 [0092]
• WO 2008081206 [0092]
• WO 2008081207 [0092]
• WO 2008081208 [0092]
• WO 2008083238 [0092]
• WO 2008085316 [0092]
• WO 2008109702 [0092]
• WO 2008130581 [0092]
• WO 2008130584 [0092]
• WO 2008130615 [0092]
• WO 2008137435 [0092]
• WO 2008137436 [0092]
• WO 2009012275 [0092]
• WO 2009012277 [0092]
• WO 2009014910 [0092]
• WO 2009034388 [0092]
• WO 2009038974 [0092]
• WO 2009050522 [0092]
• WO 2009050523 [0092]
• WO 2009055331 [0092]
• WO 2009105715 [0092]
• WO 2009105717 [0092]
• WO 2009105722 [0092]
• WO 2009106561 [0092]
• WO 2009106565 [0092]
• WO 2009117421 [0092]
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• WO 2009126535 [0092]
• WO 2009129036 [0092]
• US 2009286812 [0092]
• WO 2009143049 [0092]
• WO 2009150144 [0092]
• WO 2010001166 [0092]
• WO 2010004343 [0092]
• WO 2010004344 [0092]
• WO 2010004345 [0092]
• WO 2010004346 [0092]
• WO 2010004347 [0092]
• WO 2010004348 [0092]
• WO 2010008739 [0092]
• WO 2010006191 [0092]
• WO 2010009183 [0092]
• WO 2010009195 [0092]
• WO 2010009207 [0092]
• WO 2010009208 [0092]
• WO 2010014593 [0092]
• EP 1688138 [0093]
• WO 2008066131 [0093, 0093]
• WO 2008103500 [0093]
• WO 2008103501 [0093]
• WO 2008139879 [0093]
• WO 2009147990 [0093]
• WO 2010008831 [0093]
• WO 2009000087 [0094]
• WO 2009070873 [0094]
• WO 2005073199 [0096]
• WO 2006074957 [0096]
• WO 2006087309 [0096]
• WO 2006111321 [0096]
• WO 2007042178 [0096]
• WO 2007119837 [0096]
• WO 2008122352 [0096]
• WO 2008122357 [0096]
• WO 2009009287 [0096]
• WO 2007110216 [0097]
• WO 2008048866 [0098]
• WO 20080488867 [0098]
• US 2009062369 [0098]
• WO 2007119827 [0099]
• US 2005222220 [0100]
• WO 2005085230 [0100]
• WO 2005111018 [0100]
• WO 2003078403 [0100]
• WO 2004022544 [0100]
• WO 2003106410 [0100]
• WO 2005058908 [0100]
• US 2005038023 [0100]
• WO 2005009997 [0100]
• US 2005026984 [0100]
• WO 2005000836 [0100]
• WO 2004106343 [0100]
• EP 1460075 [0100]
• WO 2004014910 [0100]
• WO 2003076442 [0100]
• WO 2005087727 [0100]
• WO 2004046117 [0100]
• WO 2007073117 [0100]
• WO 2007083978 [0100]
• WO 2007120102 [0100]
• WO 2007122634 [0100]
• WO 2007125109 [0100]
• WO 2007125110 [0100]
• US 2007281949 [0100]
• WO 2008002244 [0100]
• WO 2008002245 [0100]
• WO 2008016123 [0100]
• WO 2008023239 [0100]
• WO 2008044700 [0100]
• WO 2008056266 [0100]
• WO 2008057940 [0100]
• WO 2008077138 [0100]
• EP 1939191 [0100]
• EP 1939192 [0100]
• WO 2008078196 [0100]
• WO 2008094992 [0100]
• WO 2008112642 [0100]
• WO 2008112651 [0100]
• WO 2008113469 [0100]
• WO 2008121063 [0100]
• WO 2008121064 [0100]
• EP 1992620 [0100]
• EP 1992621 [0100]
• EP 1992624 [0100]
• EP 1992625 [0100]
• WO 2008130312 [0100]
• WO 2009007029 [0100]
• EP 2020232 [0100]
• WO 2009017452 [0100]
• WO 2009035634 [0100]
• WO 2009035684 [0100]
• WO 2009038385 [0100]
• WO 2009095787 [0100]
• WO 2009095788 [0100]
• WO 2009095789 [0100]
• WO 2009095792 [0100]
• WO 2009145814 [0100]
• US 2009291982 [0100]
• WO 2009154697 [0100]
• WO 2009156857 [0100]
• WO 2009156859 [0100]
• WO 2009156860 [0100]
• WO 2009156861 [0100]
• WO 2009156863 [0100]
• WO 2009156864 [0100]
• WO 2009156865 [0100]
• WO 2010013168 [0100]
• WO 2010014794 [0100]
• WO 2004074288 [0101]
• WO 2008027584 [0102]
• WO 2008070150 [0102]
• WO 2008125833 [0102]
• WO 2008125835 [0102]
• WO 2008125839 [0102]
• WO 2009010530 [0102]
• WO 2009026345 [0102]
• WO 2009071888 [0102]
• WO 2009071890 [0102]
• WO 2009071895 [0102]
• WO 2006072354 [0103]
• WO 2007093264 [0103]
• WO 2008009335 [0103]
• WO 2008086854 [0103]
• WO 2008138448 [0103]
• WO 2008057855 [0104]
• WO 2008057856 [0104]
• WO 2008057857 [0104]
• WO 2008057859 [0104]
• WO 2008057862 [0104]
• WO 2008059867 [0104]
• WO 2008059866 [0104]
• WO 2008059865 [0104]
• WO 2008070507 [0104]
• WO 2008124665 [0104]
• WO 2008124745 [0104]
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• WO 2009015067 [0104]
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• WO 2009152025 [0172]
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• WO 2010005572 [0172]
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• WO 2008057585 [0172]
• WO 2008059214 [0172]
• WO 2008075064 [0172]
• WO 2008075070 [0172]
• WO 2008075077 [0172]
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• WO 2008120653 [0172]
• WO 2009038021 [0172]
• WO 2009044788 [0172]
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• WO 2008125337 [0172]
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• WO 2009081222 [0172]
• WO 2009089057 [0172]
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• WO 2009112677 [0172]
• WO 2009112678 [0172]
• WO 2009112679 [0172]
• WO 2009121036 [0172]
• WO 2009124551 [0172]
• WO 2009136625 [0172]
• WO 2010002209 [0172]
• WO 2007047397 [0172]
• WO 2008021849 [0172]
• WO 2008021851 [0172]
• WO 2008032156 [0172]
• WO 2008125348 [0172]
• WO 2008125349 [0172]
• WO 2008142454 [0172]
• WO 2009030962 [0172]
• WO 2009103552 [0172]
• WO 2009115257 [0172]
• US 2008249122 [0172]
• WO 2008089201 [0172]
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• WO 2005060985 [0172]
• WO 2005009950 [0172]
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• WO 2004078716 [0172]
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• US 20050124652 [0172]
• WO2005051391 [0172]
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• US 20050176728 [0172]
• US 20050164914 [0172]
• US 20050124636 [0172]
• US 20050130988 [0172]
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• WO 2005030797 [0172]
• US 20040224901 [0172]
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• WO 2005000339 [0172]
• EP 1460069 [0172]
• WO 2005047253 [0172]
• WO 2005047251 [0172]
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• EP 1538159 [0172]
• WO 2004072076 [0172]
• WO 2004072077 [0172]
• WO 2006021655 [0172]
• WO 2006021657 [0172]
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• WO 2007015162 [0172]
• WO 2007041061 [0172]
• WO 2007041052 [0172]
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• WO 2008087187 [0172]
• WO 2008087189 [0172]
• WO 2008087190 [0172]
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• WO 2009010299 [0172]
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• WO 200196302 [0172]
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• WO 2004085403 [0172]
• WO 2005075458 [0172]
• WO 2006067224 [0172]
• WO 2007085718 [0172]
• WO 2007088276 [0172]
• WO 2007116374 [0172]
• WO 2007122591 [0172]
• WO 2007126934 [0172]
• WO 2007126935 [0172]
• WO 2008008517 [0172]
• WO 2008008518 [0172]
• WO 2008008551 [0172]
• WO 2008020405 [0172]
• WO 2008026149 [0172]
• WO 2008038251 [0172]
• US 2008132490 [0172]
• WO 2008065626 [0172]
• WO 2008078291 [0172]
• WO 2008087611 [0172]
• WO 2008081399 [0172]
• WO 2008108991 [0172]
• WO 2008107335 [0172]
• US 2008249125 [0172]
• WO 2008147518 [0172]
• WO 2008150364 [0172]
• WO 2009003993 [0172]
• WO 2009003997 [0172]
• WO 2009011775 [0172]
• WO 2009016087 [0172]
• WO 2009020642 [0172]
• WO 2009058238 [0172]
• US 2009186920 [0172]
• US 2009203736 [0172]
• WO 2009092642 [0172]
• WO 2009100994 [0172]
• WO 2009104155 [0172]
• WO 2009124956 [0172]
• WO 2009133522 [0172]
• WO 2009156951 [0172]
• WO 2010017260 [0172]
• WO 00/63208 [0172]
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• WO 2005082893 [0172]
• WO 2005123716 [0172]
• US 2005171181 [0172]
• WO 2006107661 [0172]
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• WO 2007016496 [0172]
• WO 2007020213 [0172]
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• WO 2007055418 [0172]
• WO 2007057329 [0172]
• WO 2007062999 [0172]
• WO 2007065820 [0172]
• WO 2007068620 [0172]
• WO 2007068641 [0172]
• WO 2007075629 [0172]
• WO 2007080140 [0172]
• WO 2007082840 [0172]
• WO 2007088450 [0172]
• WO 2007088462 [0172]
• WO 2007094962 [0172]
• WO 2007099423 [0172]
• WO 2007100990 [0172]
• WO 2007105053 [0172]
• WO 2007106349 [0172]
• WO 2007110364 [0172]
• WO 2007115938 [0172]
• WO 2007131907 [0172]
• WO 2007133561 [0172]
• US 2007270440 [0172]
• WO 2007135111 [0172]
• WO 2007137955 [0172]
• US 2007281923 [0172]
• WO 2007137968 [0172]
• WO 2007138431 [0172]
• WO 2007146122 [0172]
• WO 2008005338 [0172]
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• WO 2008015125 [0172]
• WO 2008045371 [0172]
• EP 1757594 [0172]
• WO 2008068173 [0172]
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• US 2008188484 [0172]
• US 2008188486 [0172]
• US 2008188487 [0172]
• WO 2008109333 [0172]
• WO 2008109336 [0172]
• WO 2008126886 [0172]
• WO 2008154126 [0172]
• WO 2008151957 [0172]
• US 2008318952 [0172]
• WO 2009003003 [0172]
• WO 2009013195 [0172]
• WO 2009036132 [0172]
• WO 2009039431 [0172]
• WO 2009045313 [0172]
• WO 2009058300 [0172]
• WO 2009063953 [0172]
• WO 2009067401 [0172]
• WO 2009067405 [0172]
• WO 2009067406 [0172]
• US 2009163464 [0172]
• WO 2009100120 [0172]
• WO 2009105206 [0172]
• WO 2009121812 [0172]
• WO 2009126782 [0172]
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• WO 2010011657 [0172]
• WO 2008002816 [0172]
• WO 2008002817 [0172]
• WO 2008002818 [0172]
• WO 2008002820 [0172]
• WO 2009126305 [0172]
• WO 2007117399 [0172]
• US 2009156613 [0172]
• WO 00/66585 [0172]
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• WO 2007133756 [0172]
• WO 2008036541 [0172]
• WO 2008036579 [0172]
• WO 2008083070 [0172]
• WO 2010015628 [0172]
• WO 2010015655 [0172]
• WO 01/83451 [0172]
• JP 2006111553 [0172]
• WO 2002038543 [0172]
• WO 2002038544 [0172]
• WO 2007048840 [0172]
• WO 2007048843 [0172]
• WO 2008015558 [0172]
• EP 1947103 [0172]
• WO 2008132162 [0172]
• WO 2005085200 [0172]
• WO 2005019240 [0172]
• WO 2004011438 [0172]
• WO 2004012648 [0172]
• WO 2003015769 [0172]
• WO 2004072025 [0172]
• WO 2005070898 [0172]
• WO 2005070925 [0172]
• WO 2004039780 [0172]
• WO 2004092181 [0172]
• WO 2003033476 [0172]
• WO 2002006245 [0172]
• WO 2002089729 [0172]
• WO 2002002744 [0172]
• WO 2003004027 [0172]
• FR 2868780 [0172]
• WO 2006010446 [0172]
• WO 2006038680 [0172]
• WO 2006044293 [0172]
• WO 2006044174 [0172]
• JP 2006176443 [0172]
• WO 2006018280 [0172]
• WO 2006018279 [0172]
• WO 2006118320 [0172]
• WO 2006130075 [0172]
• WO 2007018248 [0172]
• WO 2007012661 [0172]
• WO 2007029847 [0172]
• WO 2007024004 [0172]
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• WO 2007042660 [0172]
• WO 2007042668 [0172]
• WO 2007042669 [0172]
• US 2007093508 [0172]
• US 2007093509 [0172]
• WO 2007048802 [0172]
• JP 2007091649 [0172]
• WO 2007092416 [0172]
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• WO 2007093366 [0172]
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• WO 2007114916 [0172]
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• WO 2007142217 [0172]
• US 2007299062 [0172]
• WO 2007146758 [0172]
• WO 2007146759 [0172]
• WO 2008001160 [0172]
• WO 2008016811 [0172]
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• WO 2008022979 [0172]
• WO 2008038692 [0172]
• WO 2008041090 [0172]
• WO 2008044632 [0172]
• WO 2008047544 [0172]
• WO 2008061109 [0172]
• WO 2008065021 [0172]
• WO 2008068265 [0172]
• WO 2008071646 [0172]
• WO 2008076562 [0172]
• JP 2008088120 [0172]
• WO 2008086404 [0172]
• WO 2008086409 [0172]
• US 2008269110 [0172]
• WO 2008140239 [0172]
• WO 2009021740 [0172]
• US 2009011994 [0172]
• US 2009082359 [0172]
• WO 2009041567 [0172]
• WO 2009076387 [0172]
• WO 2009089482 [0172]
• WO 2009103478 [0172]
• WO 2009119726 [0172]
• WO 2009120655 [0172]
• WO 2009123194 [0172]
• WO 2009137270 [0172]
• WO 2009146365 [0172]
• WO 2009154132 [0172]
• WO 99/15525 [0172]
• WO 0244150 [0172]
• WO 2005116034 [0172]
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• WO 2007120688 [0172]
• WO 2007120718 [0172]
• WO 2008091631 [0172]
• WO 2007148341 [0172]
• WO 2008034142 [0172, 0213]
• WO 2008081477 [0172]
• WO 2008120761 [0172]
• WO 2008141081 [0172]
• WO 2008141082 [0172]
• WO 2008145135 [0172]
• WO 2008150848 [0172]
• WO 2009043834 [0172]
• WO 2009077858 [0172]
• WO 2008063673 [0172]
• WO 2009016214 [0172]
• WO 2009016215 [0172]
• WO 2009077584 [0172]
• WO 2009098208 [0172]
• WO 2009098209 [0172]
• WO 2009106769 [0172]
• WO 2009109517 [0172]
• WO 2009109518 [0172]
• WO 2009109519 [0172]
• WO 2009109608 [0172]
• WO 2009145357 [0172]
• WO 2009149258 [0172]
• WO 00/71549 [0172]
• WO 01/09111 [0172]
• WO 2006085118 [0172]
• WO 2008150480 [0172]
• WO 2008079838 [0172]
• WO 2008079839 [0172]
• WO 2008079847 [0172]
• WO 2008079848 [0172]
• US 2008076724 [0172]
• WO 2009062318 [0172]
• WO 2009006227 [0172]
• WO 2009137679 [0172]
• WO 2009137732 [0172]
• WO 2007138343 [0172]
• WO 200077010 [0172]
• WO 200077001 [0172]
• WO 200077002 [0172]
• WO 2005019180 [0172]
• WO 2003064423 [0172]
• WO 200242304 [0172]
• WO 2005035533 [0172]
• WO 2005082859 [0172]
• WO 2006004937 [0172]
• US 2006025601 [0172]
• WO 2006028961 [0172]
• WO 2006077025 [0172]
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• WO 2007084622 [0172]
• US 2007249709 [0172]
• WO 2007132841 [0172]
• WO 2007140213 [0172]
• WO 2008007661 [0172]
• WO 2008007664 [0172]
• WO 2008009125 [0172]
• WO 2008010073 [0172]
• WO 2008108445 [0172]
• WO 2009063991 [0172]
• WO 2009063992 [0172]
• WO 2009063993 [0172]
• WO 2009079765 [0172]
• WO 2005058858 [0172]
• WO 2007054257 [0172]
• WO 2007107373 [0172]
• WO 2007108569 [0172]
• WO 2007108742 [0172]
• WO 2007108744 [0172]
• WO 2008003703 [0172]
• WO 2008027073 [0172]
• WO 2008034815 [0172]
• WO 2008054288 [0172]
• EP 1947085 [0172]
• WO 2008084491 [0172]
• WO 2008084492 [0172]
• WO 2008092665 [0172]
• WO 2008092666 [0172]
• WO 2008101247 [0172]
• WO 2008110598 [0172]
• WO 2008116831 [0172]
• WO 2008116833 [0172]
• WO 2008117169 [0172]
• WO 2008136017 [0172]
• WO 2008147812 [0172]
• EP 2036888 [0172]
• WO 2009013010 [0172]
• WO 2009034581 [0172]
• WO 2009053997 [0172]
• WO 2009056632 [0172]
• WO 2009073118 [0172]
• WO 2009115515 [0172]
• WO 2009135925 [0172]
• WO 2009135927 [0172]
• WO 2010000456 [0172]
• WO 2010012806 [0172]
• EP 2145887 [0172]
• WO 2007131005 [0172]
• WO 2008052709 [0172]
• WO 2008109727 [0172]
• WO 2009055734 [0172]
• WO 2009100335 [0172]
• WO 2009127686 [0172]
• WO 2007098953 [0172]
• WO 2007098961 [0172]
• WO 2008015266 [0172]
• WO 2008055932 [0172]
• WO 2008055933 [0172]
• WO 2009071657 [0172]
• WO 2007110782 [0172]
• WO 2008041184 [0172]
• WO 2008051404 [0172]
• WO 2008051405 [0172]
• WO 2008051406 [0172]
• WO 2008073311 [0172]
• WO 01/85695 [0172]
• WO 2005030734 [0172]
• WO 2007127457 [0172]
• WO 2008008286 [0172]
• WO 2009056707 [0172]
• WO 2006012577 [0172]
• WO 2007079239 [0172]
• WO 2008092681 [0172]
• WO 2008145749 [0172]
• WO 2008148853 [0172]
• WO 2008148854 [0172]
• WO 2008148856 [0172]
• WO 2009047558 [0172]
• WO 2009071283 [0172]
• WO 2009115503 [0172]
• EP 0462884 [0172]
• WO 2009128583 [0172]
• WO 2008059023 [0172, 0239]
• WO 2008059024 [0172, 0239]
• WO 2008059025 [0172, 0239]
• WO 2008059026 [0172, 0239]
• WO 2009019427 [0172]
• WO 2009071658 [0172]
• WO 2009071668 [0172]
• WO 2009071677 [0172]
• WO 2009071678 [0172]
• WO 2009147211 [0172]
• WO 2009147216 [0172]
• WO 2009147219 [0172]
• WO 2009147221 [0172]
• US 2009143390 [0172]
• WO 00/40569 [0172]
• WO 2008107184 [0172]
• WO 2009049428 [0172]
• WO 2009125819 [0172]
• US 2004/0224997 [0172]
• WO 2004094618 [0172]
• WO 200058491 [0172]
• WO 2005044250 [0172]
• WO 2005072740 [0172]
• JP 2005206492 [0172]
• WO 2005013907 [0172]
• WO 2006004200 [0172]
• WO 2006019020 [0172]
• WO 2006064189 [0172]
• WO 2006082952 [0172]
• WO 2006120125 [0172]
• WO 2006113919 [0172]
• WO 2006134317 [0172]
• WO 2007016538 [0172]
• WO 2007060140 [0172]
• JP 2007131584 [0172]
• WO 2007071966 [0172]
• WO 2007126957 [0172]
• WO 2007137103 [0172]
• WO 2007137107 [0172]
• WO 2007138304 [0172]
• WO 2007138311 [0172]
• WO 2007141502 [0172]
• WO 2007141517 [0172]
• WO 2007141538 [0172]
• WO 2007141545 [0172]
• WO 2007144571 [0172]
• WO 2008011130 [0172]
• WO 2008011131 [0172]
• WO 2008039007 [0172]
• WO 2008048991 [0172]
• WO 2008067257 [0172]
• WO 2008099221 [0172]
• WO 2008129319 [0172]
• WO 2008141976 [0172]
• WO 2008148840 [0172]
• WO 2008148849 [0172]
• WO 2008148851 [0172]
• WO 2008148868 [0172]
• WO 2009011285 [0172]
• WO 2009016462 [0172]
• WO 2009024821 [0172]
• US 2009076275 [0172]
• WO 2009040410 [0172]
• WO 2009071483 [0172]
• WO 2009081195 [0172]
• WO 2009119534 [0172]
• WO 2009126624 [0172]
• WO 2009126861 [0172]
• WO 2010007046 [0172]
• WO 2010017040 [0172]
• WO 2008038768 [0172]
• WO 2004005277 [0172]
• WO 2008006113 [0172]
• WO 2007009236 [0172]
• WO 2007044085 [0172]
• WO 2007046867 [0172]
• WO 2007046868 [0172]
• WO 20070501124 [0172]
• WO 2007056846 [0172]
• WO 2007071023 [0172]
• WO 2007130075 [0172]
• WO 2007134457 [0172]
• WO 2007136746 [0172]
• WO 2007143597 [0172]
• WO 2007143823 [0172]
• WO 2007143824 [0172]
• WO 2008003753 [0172]
• WO 2008017161 [0172]
• WO 2008024390 [0172]
• WO 2008029266 [0172]
• WO 2008036715 [0172]
• WO 2008043087 [0172]
• WO 2008044767 [0172]
• WO 2008046226 [0172]
• WO 2008056687 [0172]
• WO 2008062276 [0172]
• WO 2008064474 [0172]
• WO 2008074824 [0172]
• WO 2008074832 [0172]
• WO 2008074833 [0172]
• WO 2008074834 [0172]
• WO 2008074835 [0172]
• WO 2008089580 [0172]
• WO 2008096746 [0172]
• WO 2008104524 [0172]
• WO 2008116898 [0172]
• US 2008249100 [0172]
• WO 2008120744 [0172]
• WO 2008120759 [0172]
• WO 2008123469 [0172]
• WO 2008127349 [0172]
• WO 2008128335 [0172]
• WO 2008135141 [0172]
• WO 2008139845 [0172]
• WO 2008141455 [0172, 0172]
• US 20080255130 [0172]
• US 2008255161 [0172]
• WO 2009010560 [0172]
• WO 2009016216 [0172]
• WO 2009012573 [0172]
• WO 2009024287 [0172]
• JP 2009019013 [0172]
• WO 2009037542 [0172]
• WO 2009056556 [0172]
• WO 2009060053 [0172]
• WO 2009060054 [0172]
• WO 2009070533 [0172]
• WO 2009073973 [0172]
• WO 2009103739 [0172]
• WO 2009117659 [0172]
• WO 2009117676 [0172]
• US 2009253693 [0172]
• US 2009253738 [0172]
• WO 2009124259 [0172]
• WO 2009126123 [0172]
• WO 2009126527 [0172]
• WO 2009129625 [0172]
• WO 2009137201 [0172]
• WO 2009150196 [0172]
• WO 2009156484 [0172]
• WO 2010006962 [0172]
• WO 2010007482 [0172]
• WO 2008089310 [0172]
• WO 2008145842 [0172]
• WO 2008039087 [0172]
• WO 2009051119 [0172]
• WO 2009028248 [0172]
• WO 2006082978 [0172]
• WO 2008105533 [0172]
• WO 2008136173 [0172]
• WO 2007125946 [0172]
• WO 2008038712 [0172]
• WO 2008121009 [0172]
• WO 20058279 [0172]
• WO 200172692 [0172]
• WO 200194293 [0172]
• WO 2003084915 [0172]
• WO 2004018421 [0172]
• WO 2005092316 [0172]
• WO 2007003419 [0172]
• WO 2007009913 [0172]
• WO 2007039125 [0172]
• WO 2007110225 [0172]
• WO 2007110226 [0172]
• WO 2007128492 [0172]
• WO 2007132475 [0172]
• WO 2007134864 [0172]
• WO 2008001959 [0172]
• WO 2008106213 [0172]
• JP 2009155261 [0172]
• WO 2008062469 [0172]
• US 2008146523 [0175]
• WO 2008092785 [0175]
• WO 2008067270 [0176]
• WO 2009135918 [0180]
• WO 2009032249 [0183]
• WO 2007065948 [0184]
• WO 2009050252 [0184]
• WO 2008027557 [0185]
• US 2009304789 [0185]
• EP 1886695 [0188]
• WO 2008119744 [0188]
• WO 2007119463 [0191]
• WO 2009035159 [0191]
• WO 2009035162 [0191]
• WO 2007125405 [0192]
• WO 2008028860 [0192]
• WO 2008118626 [0192]
• WO 2009138122 [0194]
• WO 2009135526 [0194]
• WO 2005090336 [0195]
• WO 2006071609 [0195]
• WO 2006135826 [0195]
• WO 2007105766 [0195]
• WO 2008120661 [0195]
• WO 2009058944 [0195]
• WO 2009108525 [0195]
• WO 2009111214 [0195]
• WO 2009018551 [0197]
• WO 2009071519 [0197]
• WO 2009071576 [0197]
• WO 2009071577 [0197]
• WO 2007019416 [0199]
• WO 2008073451 [0199]
• WO 2008156866 [0199]
• WO 2008156869 [0199]
• WO 2009026701 [0199]
• WO 2009049018 [0199]
• WO 2009058348 [0199]
• WO 2009061453 [0199]
• WO 2009134973 [0199]
• WO 2009146358 [0199]
• WO 2010003048 [0199]
• WO 2006000804 [0201]
• WO 2005113496 [0201]
• WO 2007107587 [0201]
• WO 2007111994 [0201]
• WO 2008106600 [0201]
• WO 2008113796 [0201]
• WO 2009113952 [0201]
• US 2009312302 [0201]
• WO 2008097835 [0202]
• WO 2007101146 [0203]
• WO 2007133828 [0203]
• WO 2007112069 [0204]
• WO 2007099200 [0206]
• WO 2007137874 [0206]
• JP 2008024673 [0207]
• WO 2007100104 [0215]
• JP 2008106008 [0215]
• WO 2009038012 [0216]
• US 7138107 [0217]
• WO 2008028958 [0218]
• WO 2008085711 [0218]
• WO 2008033447 [0219]
• WO 2008033356 [0219]
• WO 2008033460 [0219]
• WO 2008033468 [0219]
• WO 2008073461 [0219]
• WO 2008073934 [0220]
• WO 2008073936 [0220]
• WO 2009107660 [0220]
• US 2009124680 [0221]
• WO 2008110008 [0222]
• US 2008280900 [0222]
• WO 2008141446 [0222]
• US 2009270338 [0222]
• WO 2009146540 [0222]
• US 2009325979 [0222]
• WO 2009146539 [0222]
• US 2008027049 [0223]
• US 2008027090 [0223]
• US 2009036475 [0224]
• WO 2008040057 [0225]
• WO 2008040058 [0225]
• WO 2008046065 [0225]
• WO 2009043117 [0225]
• WO 2008135447 [0226]
• WO 2008135448 [0226]
• WO 2008135591 [0226]
• WO 2009099820 [0226]
• US 2009069296 [0227]
• WO 2009130735 [0228]
• WO 2009049180 [0229]
• WO 2009049181 [0229]
• WO 2008014360 [0230]
• WO 2008014381 [0230]
• WO 2009011836 [0231]
• WO 2008019967 [0232]
• US 2008064697 [0232]
• US 2008249101 [0232]
• WO 2008000692 [0232]
• US 2008293756 [0232]
• WO 2008148710 [0232]
• WO 2008051272 [0233]
• WO 2009051244 [0234]
• WO 2009145286 [0234]
• WO 2008042800 [0235]
• WO 2008035305 [0236]
• WO 2008035306 [0236]
• WO 2008035686 [0236]
• WO 2008036966 [0237]
• WO 2008036967 [0237]
• WO 2008058641 [0238]
• WO 2008074413 [0238]
• WO 2008062905 [0240, 0240]
• WO 2008067378 [0240]
• WO 2008064315 [0241]
• WO 2008074820 [0241]
• WO 2008074821 [0241]
• WO 2008135522 [0241]
• WO 2009019167 [0241]
• WO 2009043013 [0241]
• WO 2009080663 [0241]
• WO 2009085847 [0241]
• WO 2009151529 [0241]
• WO 2009151621 [0241]
• WO 2009151626 [0241]
• WO 2009154737 [0241]
• WO 2008044770 [0242]
• WO 2009014972 [0243]
• WO 2008090200 [0244]
• WO 2008092091 [0245]
• WO 2009066152 [0245]
• WO 2009030968 [0246]
• US 2008194658 [0247]
• WO 2008126920 [0248]
• WO 2009070740 [0249]
• WO 2009108657 [0250]
• EP 1955701 [0252]
• WO 2008150486 [0253]
• WO 2009117829 [0254]
• WO 2009155753 [0254]
• US 2009042813 [0255]
• EP 2044852 [0255]
• WO 2009079902 [0257]
• WO 2009143391 [0258]
• WO 2009124746 [0259]
• WO 1989005304 [0260]
• WO 2009092129 [0260]
• WO 2010002956 [0260]
• WO 2009089545 [0261]
• WO 2009153261 [0261]
• US 2009196825 [0262]
• WO 2009046141 [0263]
• US 2009246137 [0266]
• US 2009264433 [0266]
• US 2009264441 [0266]
• US 2009264471 [0266]
• US 2009264481 [0266]
• US 2009264486 [0266]
• WO 2010019239 [0266]
• WO 2009109258 [0267]
• WO 2009132739 [0267]
• US 2009281057 [0267]
• WO 2009157418 [0267]
• WO 2009125071 [0268]
• WO 2009133458 [0269]
• US 2009238900 [0270]
• US 2010016213 [0271]
• EP 1345895 [0286]

Cited non-patent literature

• Red List 2010, chapter 12 [0021]
• Red List 2007, Chapter 1 [0021]
• Red List 2010, chapter 36 [0021]
• Red List 2010, Chapter 58 [0021]
• USP Dictionary of US and International Drug Names, US Pharmacopeia, Rockville 2006 [0021]
• www.lantus.com [0022]
• D. Chen et al., Proc. Natl. Acad. Sci. USA 104 (2007) 943 [0022]
• RD Carr et al., Diabetes 52, 2003, 2513.2518 [0031]
• JB Hansen et al., Current Medicinal Chemistry 11, 2004, 1595-1615 [0031]
• Tagmose et al., J. Med. Chem. 47, 2004, 3202-3211 [0031]
• MJ Coghlan et al., J.Med.Chem. 44, 2001, 1627-1653 [0031]
• JP Berger et al., TRENDS in Pharmacological Sciences 28 (5), 244-251, 2005 [0050]
• DO. Lee et al .: Arzneim.-Forsch. Drug Res. 54 (12), 835 (2004) [0062]
• AL Handlon in Expert Opinion. Ther. Patents (2005) 15 (11), 1531-1540 [0078]
• "Cocaine-amphetamine-regulated transcript-influencing energy metabolism, anxiety and gastric emptying in mice" Asakawa, A. et al .: Hormones and Metabolic Research (2001), 33 (9), 554-558 [0172]
• 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 [0172]
• "Perspectives in the therapeutic use of leptin", Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2 (10), 1615-1622 [0208]
• Guild HJ; et al., Carob pule preparation for the treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct), 18 (5), 230-6 [0272]
• Red List 2010, Chapter 15 [0274]
• Red List 2010, Chapter 17 [0274]
• Red List 2010, Chapter 19 [0274]
• Red List 2010, Chapter 20 [0274]
• Red List 2010, Chapter 25 [0274]
• Red List 2010, Chapter 27 [0274]
• Red List 2010, chapters 36 and 37 [0274]
• Red List 2010, Chapter 39 [0274]
• Red List 2010, chapters 55 and 60 [0274]
• Red List 2010, Chapters 61, 66 and 70 [0274]
• TW Greene, "Protective Groups in Organic Synthesis" [0279]
• AR Hilgers et al., Caco-2 cell monolayers as a model for drug delivery across the intestinal mucosa, Pharm. Res. 1990, 7, 902 [0354]

Claims (13)

Compounds of the formula I,

wherein X is - (C ₁ -C ₃₀ ) -alkylene-, wherein the alkylene radical is mono- or polysubstituted by -OH; and their pharmaceutically acceptable salts; Compounds of the formula I as claimed in claim 1, wherein X is - (C ₂ -C ₁₀ ) -alkylene-, where the alkylene radical is mono- or polysubstituted by -OH; and their pharmaceutically acceptable salts. Compounds of formula I, according to claim 1 or 2, characterized in that X is - (C ₂ -C ₁₀ ) -alkylene-, wherein the alkylene radical is substituted one to three times by -OH; and their pharmaceutically acceptable salts. Medicament containing one or more of the compounds according to one or more of claims 1 to 3. Medicament containing one or more of the compounds according to one or more of claims 1 to 3 and at least one further active ingredient. Medicament according to Claim 6, characterized in that it contains as further active ingredient one or more compounds which normalize lipid metabolism. Medicament according to claim 4 or 5, characterized in that it contains as further active ingredient one or more statins from the group of simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin and pitavastatin. Compounds according to one or more of claims 1 to 3 for use as a medicament for the treatment of lipid metabolism disorders. A process for the preparation of a medicament comprising one or more of the compounds according to one or more of claims 1 to 3, characterized in that the active substance is mixed with a pharmaceutically suitable carrier and this mixture is brought into a form suitable for administration. Use of the compounds according to one or more of claims 1 to 3 for the manufacture of a medicament for the treatment of hyperlipidemia. Use of the compounds according to one or more of claims 1 to 3 for the preparation of a medicament for lowering the serum cholesterol level. Use of the compounds according to one or more of claims 1 to 3 for the manufacture of a medicament for the treatment of atherosclerotic phenomena. Use of the compounds according to one or more of claims 1 to 3 for the manufacture of a medicament for the treatment of insulin resistance.