Patent Application
20110112097
The invention relates to imidazolidine-2,4-diones which are substituted by an aralkyl radical and to the physiologically compatible salts thereof.
Structurally similar imidazoline-2,4-diones have already been described (see U.S. Pat. No. 5,411,981).
It was an object of the invention to provide compounds which display a therapeutically utilizable action. In particular, it was an object of the invention to find novel compounds which are suitable for the treatment of metabolic syndrome, of type II diabetes and of obesity.
The invention therefore relates to compounds of the formula I
in which
Preference is given to compounds of the formula I in which one or more radicals are each defined as follows:
Particular preference is given to compounds of the formula I in which one or more radicals are each defined as follows:
R4, R5 substituents when they are defined as N, or R2−D=E−R3 or R4−G=L−R5 are defined as S or O and where the five-membered or six-membered ring may be fused to —(CH2)3— or —(CH2)4— to form a bicyclic system;
Very particular preference is given to compounds of the formula I in which one or more radicals are each defined as follows:
Preference is further given to compounds of the formula Ia
in which
Preference is further given to compounds of the formula Ia in which
In one embodiment, preference is given to compounds of the formula I in which p is 1.
In one embodiment, preference is given to compounds of the formula I in which R6 is CH2-aryl, where aryl may be substituted.
In one embodiment, preference is given to compounds of the formula I in which R6 is (C═O)-aryl, where aryl may be substituted.
In one embodiment, preference is given to compounds of the formula I in which R and R′ are each methyl.
In one embodiment, preference is given to compounds of the formula I in which A is CH.
In one embodiment, preference is given to compounds of the formula I in which A is N.
In one embodiment, preference is given to compounds of the formula I in which D is CH.
In one embodiment, preference is given to compounds of the formula I in which D is N.
In one embodiment, preference is given to compounds of the formula I in which E is CH.
In one embodiment, preference is given to compounds of the formula I in which E is N.
In one embodiment, preference is given to compounds of the formula I in which one of the R1, R2, R3, R4 and R5 radicals is not H.
In one embodiment, preference is given to compounds of the formula I in which two of the R1, R2, R3, R4 and R5 radicals are not H.
When radicals or substituents (for example R12) can occur more than once in the compounds of the formula I, they may all each independently be defined as specified and be the same or different.
The invention further provides both stereoisomer mixtures of the formula I and the pure stereoisomers of the formula I, and also diastereoisomer mixtures of the formula I and the pure diastereoisomers. The mixtures are separated, for example, by a chromatographic route.
The invention relates to compounds of the formula I in the form of their tautomers, racemates, racemic mixtures, stereoisomer mixtures, pure stereoisomers, diastereoisomer mixtures, pure diastereoisomers. The mixtures are separated, for example, by a chromatographic route.
The alkyl radicals in the substituents R1 to R18 and R and R′ may be either straight-chain or branched.
Owing to their high water solubility, pharmaceutically acceptable salts are particularly suitable for medical applications compared to the starting or base compounds. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the inventive compounds are salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, and also organic acids, for example acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid and tartaric acid. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts), trometamol (2-amino-2-hydroxymethyl-1,3-propanediol), diethanolamine, lysine or ethylenediamine.
Salts with a pharmaceutically unacceptable anion, for example trifluoroacetate, are also included 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 applications, for example in vitro applications.
The inventive compounds may also be present in different polymorphic forms, for example as amorphous and crystalline polymorphic forms. All polymorphic forms of the inventive compounds are included within the scope of the invention and are a further aspect of the invention.
Hereinafter, all references to “compound(s) of the formula I” relate to compound(s) of the formula I as described above, and to their salts and solvates as described herein.
An alkyl radical is understood to mean a straight-chain or branched hydrocarbon chain having from one to eight carbons, for example methyl, ethyl, isopropyl, tert-butyl, hexyl, heptyl, octyl. The alkyl radicals may be mono- or polysubstituted as described above.
A cycloalkyl radical is understood to mean a ring system which comprises one or more rings, is present in saturated or partially unsaturated form (with one or two double bonds) and is formed exclusively from carbon atoms, for example cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl or adamantyl.
The cycloalkyl radicals may be mono- or polysubstituted by suitable groups as described above.
An aryl radical is understood to mean a phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha- or beta-tetralonyl, indanyl or indan-1-onyl radical.
The aryl radicals may be mono- or polysubstituted by suitable groups as described above.
A heteroaryl radical is understood to mean aromatic rings and ring systems which, apart from carbon, also contain heteroatoms, for example nitrogen, oxygen or sulfur. This definition also includes ring systems in which the heteroaryl radical is fused to benzene rings. This likewise includes systems in which one or more CH group(s) has/have been replaced by C═O or C═S, preferably C═O.
Suitable heteroaryl radicals are, for example, furyl, imidazolyl, benzimidazolyl, benzothiazolyl, indolyl, indolinyl, pyrimidinyl, pyridyl, pyrazinyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, isoxazolyl, pyridazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl; the 2H-pyridazin-3-one, dihydropyridazine-3,6-dione, imidazolidin-2-one, 1,3-dihydroimidazol-2-one, imidazolidin-2,5-dione, quinoline, isoquinoline, quinoxaline, quinazoline, benzol[1,3]-dioxole, 2,3-dihydrobenzo[1,4]dioxin, 4-H-benzo[1,3]dioxin or 3,4-dihydro-2H-benzo[b][1,4] system.
The linkage to the heteroaryl radicals may be at any of the possible atoms; for example, pyridyl may be 2-, 3- or 4-pyridyl; thienyl may be 2- or 3-thienyl; furyl may be 2- or 3-furyl.
Also included are the corresponding N-oxides of these compounds, i.e., for example, 1-oxy-2-, -3- or -4-pyridyl.
The heteroaryl radicals may be mono- or polysubstituted by suitable groups as described above.
The invention also encompasses solvates or hydrates of the compounds of the formula I.
The compounds of the formula I are cannabinoid 1 receptor (CB1R) modulators and are, as such, suitable in humans and in animals for the treatment or for the prevention of diseases which are based on disruption of the endocannabinoid system.
For example, and without restriction, the compounds of the formula I are useful as psychotropic medicaments, especially for the treatment of psychiatric disorders including states of anxiety, depressions, disorders of the mind, insomnia, deliria, obsessive-compulsive neuroses, general psychoses, schizophrenia, attention deficit hyperactivity disorder (ADHD) in hyperkinetic children, and for the treatment of disorders in connection with the use of psychotropic substances, especially in the case of abuse of a substance and/or dependence on such a substance, including alcohol dependence and nicotine dependence, but also dependence on cocaine, methamphetamine and heroin (see, for example, Behavioural Pharmacology 2005, 16:275-296). Reviews of CBR1-mediated means of therapeutic intervention can be found, for example, in Ken Mackie: Annu. Rev. Pharmacol. Toxicol. 46, 101-122 (2006), S. C. Black: Curr. Opin. Investig. Drugs 5, 389-394 (2004), V. Di Marzio et al.: Nat. Rev. Drug Discov. 3, 771-784 (2004), B. Le Foll et al.: J. Pharmacol. Exp. Ther. 312, 875-883 (2005) or L. Walter et al.: Br. J. Pharmacol. 141, 775-785 (2004).
The inventive compounds of the formula I may be used as medicaments for the treatment of migraine, stress, disorders of psychosomatic origin, panic attacks, epilepsy, disrupted movement, especially dyskinesias or Parkinson's disease, trembling and dystonia.
The inventive compounds of the formula I can also be used as medicaments for the treatment of disorders of memory, mental defects, especially for the treatment of age-related dementia, of Alzheimer's disease and for the treatment of reduced alertness or wakefulness.
In addition, it is also possible to use the compounds of the formula I as neuroprotectors, for the treatment of ischemia, cranial injuries and the treatment of neurodegenerative disorders, including chorea, Huntington's chorea, Tourette's syndrome.
The inventive compounds of the formula I can also be used as medicaments in the treatment of pain; this includes neuropathic pain, acute peripheral pain, chronic pain of inflammatory origin.
The inventive compounds of the formula I may also serve as medicaments for the treatment of eating disorders (for example binge eating disorders, anorexia and bulimia), for the treatment of addiction to confectionery, carbohydrates, drugs, alcohol or other addictive substances.
The inventive compounds of the formula I are particularly suitable for the treatment of obesity or of bulimia, and for the treatment of type II diabetes and also for the treatment of dyslipidemias and of metabolic syndrome. The inventive compounds of the formula I are therefore useful for the treatment of obesity and of the risks associated with obesity, especially the cardiovascular risks.
Moreover, the inventive compounds may be used as medicaments for the treatment of gastrointestinal disorders, for the treatment of diarrhea, of gastric and intestinal ulcers, of vomiting, of bladder trouble and disorders of urination, of disorders of endocrine origin, of cardiovascular problems, of low blood pressure, of hemmorrhagic shock, of septic shock, chronic liver cirrhosis, liver steatosis, of nonalcoholic steatohepatitis, of asthma, of Raynaud's syndrome, of glaucoma, of fertility problems, termination of pregnancy, early birth, inflammatory symptoms, disorders of the immune system, especially autoimmune and neuroinflammatory disorders, for example rheumatic inflammation of joints, reactive arthritis, of disorders which lead to demyelinization, of multiple sclerosis, of infection disorders and viral disorders, for example encephalitis, ischemic stroke, and as medicaments for chemotherapy of cancer, for the treatment of Guillain-Barré syndrome and for the treatment of osteoporosis.
The inventive compounds of the formula I may also find use as medicaments for the treatment of polycystic ovary syndrome (PCOS).
According to the present invention, the compounds of the formula I are particularly useful for the treatment of psychotic complaints, especially of schizophrenia, reduced alertness and hyperactivity (ADHD) in hyperkinetic children, for the treatment of eating disorders and of obesity, for the treatment of type II diabetes, for the treatment of deficits of memory and cognitive deficits, for the treatment of alcohol addiction, of nicotine addiction, i.e. for alcohol and tobacco withdrawal.
The inventive compounds of the formula I are very particularly useful for the treatment and prevention of eating disorders, appetite disorders, metabolic disorders, gastrointestinal disorders, inflammation symptoms, disorders of the immune system, psychotic disorders, alcohol addiction and nicotine addiction.
According to one of its aspects, the invention relates to the use of a compound of the formula I, the pharmaceutically acceptable salts thereof and the solvates or hydrates thereof for the treatment of the above-specified disorders and diseases.
The compound(s) of the formula I may also be administered in combination with further active ingredients.
The amount of a compound of the formula I which is required in order to achieve the desired biological effect is dependent upon a series of factors, for example the specific compound selected, the intended use, the mode of administration and the clinical condition of the patient. The daily dose is generally in the range from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day per kilogram of bodyweight, for example 3-10 mg/kg/day. An intravenous dose may, for example, be in the range from 0.3 mg to 1.0 mg/kg and may suitably be administered as an infusion of from 10 ng to 100 ng per kilogram per minute. Suitable infusion solutions for these purposes may, for example, contain from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter. Single doses may contain, for example, from 1 mg to 10 g of the active ingredient. Ampoules for injections may therefore contain, for example, from 1 mg to 100 mg, and single dose formulations which can be administered orally, for example tablets or capsules, may contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. The compounds of the formula I may be used for therapy of the above-mentioned conditions as the compounds themselves, although they are preferably in the form of a pharmaceutical composition with an acceptable carrier. The carrier of course has to be acceptable, in the sense that it is compatible with the other constituents of the composition and is not damaging to the health of 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. Further pharmaceutically active substances may likewise be present, including further compounds of the formula I. The inventive pharmaceutical compositions may be produced by one of the known pharmaceutical methods which consist essentially in mixing the constituents with pharmacologically acceptable carriers and/or excipients.
Inventive pharmaceutical compositions are those which are suitable for oral, rectal, topical, peroral (for example sublingual) and parenteral (for example subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration depends in each individual case on the nature and severity of the condition to be treated and on the type of the compound of the formula I used in each case. Coated formulations and coated slow-release formulations are also encompassed by the scope of the invention. Preference is given to acid- and gastric fluid-resistant formulations. Suitable gastric fluid-resistant coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.
Suitable pharmaceutical preparations for oral administration may be in the form of separate units, for example capsules, cachets, lozenges or tablets, each of which contains a certain amount of the compound of the formula I; as powder or granules; as solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. These compositions may, as already mentioned, be prepared by any suitable pharmaceutical method which includes a step in which the active ingredient and the carrier (which may consist of one or more additional constituents) are brought into contact. In general, the compositions are prepared by uniform and homogeneous mixing of the active ingredient with a liquid carrier and/or finely divided solid carrier, after which the product is shaped if necessary. For example, a tablet can thus be produced by compressing or shaping a powder or granules of the compound, optionally with one or more additional constituents. Compressed tablets can be prepared by tableting the compound in free-flowing form, for example a powder or granules, optionally mixed with a binder, lubricant, inert diluent and/or one (or more) surfactants/dispersants in a suitable machine. Shaped tablets can be prepared by shaping the pulverulent compound moistened with an inert liquid diluent in a suitable machine.
Pharmaceutical compositions which are suitable for peroral (sublingual) administration include lozenges which contain a compound of the formula I with a flavoring, customarily sucrose, and gum arabic or tragacanth, and pastilles which include the compound in an inert base, such as gelatin and glycerol or sucrose and gum arabic.
Suitable pharmaceutical compositions for parenteral administration include preferably sterile aqueous preparations of a compound of the formula I which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although the administration may also be subcutaneous, intramuscular or intradermal as an injection. These preparations can preferably be produced by mixing the compound with water and making the solution obtained sterile and isotonic with the blood. Injectable compositions according to the invention generally contain from 0.1 to 5% by weight of the active compound.
Suitable pharmaceutical compositions for rectal administration are preferably in the form of single dose suppositories. These can be prepared by mixing a compound of the formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.
Suitable pharmaceutical compositions for topical application on the skin are preferably in the form of an ointment, cream, lotion, paste, spray, aerosol or oil. Useful carriers include petroleum jelly, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. The active ingredient is generally present in a concentration of from 0.1 to 15% by weight of the composition, preferably from 0.5 to 2%.
Transdermal administration is also possible. Suitable pharmaceutical compositions for transdermal applications may be in the form of single plasters which are suitable for long-term close contact with the epidermis of the patient. Such plasters suitably contain the active ingredient in an optionally buffered aqueous solution, dissolved and/or dispersed in an adhesive or dispersed in a polymer. A suitable active ingredient concentration is from approx. 1% to 35%, preferably from approx. 3% to 15%. A particular means of releasing the active ingredient may be by electrotransport or iontophoresis, as described, for example, in Pharmaceutical Research, 2(6): 318 (1986).
Suitable further active ingredients for the combination products are:
All antidiabetics which are mentioned in the Rote Liste 2007, chapter 12; all weight-reducing agents/appetite suppressants which are mentioned in the Rote Liste 2007, chapter 1; all diuretics which are mentioned in the Rote Liste 2007, chapter 36; all lipid-lowering agents which are mentioned in the Rote Liste 2007, chapter 58. They can be combined with the compound of the invention of the formula I in particular for a synergistic improvement in action. The active ingredient combination can be administered either by separate administration of the active ingredients to the patient or in the form of combination products in which a plurality of active ingredients are present in one pharmaceutical preparation. If the active ingredients are administered separately, this can be done simultaneously or successively. Most of the active ingredients mentioned hereinafter are disclosed in the USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2006.
Antidiabetics include insulin and insulin derivatives, for example Lantus® (see www.lantus.com) or HMR 1964 or Levemir® (insulin detemir), Humalog® (Insulin Lispro), Humulie)®, VIAject™, SuliXen® or those as described in WO2005005477 (Novo Nordisk), fast-acting insulins (see U.S. Pat. No. 6,221,633), inhalable insulins, for example Exubera®, Nasulin™ or oral insulins, for example IN-105 (Nobex) or Oral-lyn™ (Generex Biotechnology), or Technosphere® Insulin (MannKind) or Cobalamin™ oral insulin, or insulins as described in WO2007128815, WO2007128817, WO2008034881, WO2008049711, or insulins which can be administered transdermally;
GLP-1 derivatives and GLP-1 agonists, for example exenatide or specific formulations thereof, as described, for example, in WO2008061355, liraglutide, taspoglutide (R-1583), albiglutide, lixisenatide or those which have been disclosed in WO 98/08871, WO2005027978, WO2006037811, WO2006037810 by Novo Nordisk A/S, in WO 01/04156 by Zealand or in WO 00/34331 by Beaufour-Ipsen, pramlintide acetate (Symlin; Amylin Pharmaceuticals), AVE-0010, BIM-51077 (R-1583, ITM-077), PC-DAC:Exendin-4 (an exendin-4 analog which is bonded covalently to recombinant human albumin), CVX-73, CVX-98 and CVx-96 (GLP-1 analog which is bonded covalently to a monoclonal antibody which has specific binding sites for the GLP-1 peptide), CNTO-736 (a GLP-1 analog which is bonded to a domain which includes the Fc portion of an antibody), PGC-GLP-1 (GLP-1 bonded to a nanocarrier), agonists, as described, for example, in D. Chen et al., Proc. Natl. Acad. Sci. USA 104 (2007) 943, those as described in WO2006124529, WO2007124461, WO2008062457, WO2008082274, WO2008101017, WO2008081418, WO2008112939, WO2008112941, WO2008113601, WO2008116294, WO2008116648, WO2008119238, peptides, for example obinepitide (TM-30338), amylin receptor agonists, as described, for example, in WO2007104789, analogs of the human GLP-1, as described in WO2007120899, WO2008022015, WO2008056726, and orally active hypoglycemic ingredients.
Antidiabetics also include agonists of the glucose-dependent insulinotropic polypeptide (GIP) receptor, as described, for example, in WO2006121860.
Antidiabetics also include the glucose-dependent insulinotropic polypeptide (GIP), and also analogous compounds, as described, for example, in WO2008021560.
Antidiabetics also include analogs and derivatives of fibroblast growth factor 21 (FGF-21).
The orally active hypoglycemic ingredients preferably include
sulfonylureas,
biguanidines,
meglitinides,
oxadiazolidinediones,
thiazolidinediones,
PPAR and RXR modulators,
glucosidase inhibitors,
inhibitors of glycogen phosphorylase,
glucagon receptor antagonists,
glucokinase activators,
inhibitors of fructose 1,6-bisphosphatase
modulators of glucose transporter 4 (GLUT4),
inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT),
GLP-1 agonists,
potassium channel openers, for example pinacidil, cromakalim, diazoxide, or those as described in R. D. Can et al., Diabetes 52, 2003, 2513.2518, in J. B. Hansen et al., Current Medicinal Chemistry 11, 2004, 1595-1615, in T. M. Tagmose et al., J. Med. Chem. 47, 2004, 3202-3211 or in M. J. Coghlan et al., J. Med. Chem. 44, 2001, 1627-1653, or those which have been disclosed in WO 97/26265 and WO 99/03861 by Novo Nordisk A/S, active ingredients which act on the ATP-dependent potassium channel of the beta cells, inhibitors of dipeptidylpeptidase IV (DPP-IV),
insulin sensitizers,
inhibitors of liver enzymes involved in stimulating gluconeogenesis and/or glycogenolysis,
modulators of glucose uptake, of glucose transport and of glucose reabsorption,
modulators of 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 acid 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 compounds which modify the metabolism, such as active
antihyperlipidemic ingredients and active antilipidemic ingredients,
HMGCoA reductase inhibitors,
farnesoid X receptor (FXR) modulators,
fibrates,
P cholesterol reabsorption inhibitors,
CETP inhibitors,
bile acid reabsorption inhibitors,
MTP inhibitors,
agonists of estrogen receptor gamma (ERRγ agonists),
sigma-1 receptor antagonists,
antagonists of the somatostatin 5 receptor (SST5 receptor);
compounds which reduce food intake, and
compounds which increase thermogenesis.
In one embodiment of the invention, the compound of the formula I is administered in combination with insulin.
In one embodiment, the compound of the formula I is administered in combination with an active ingredient which acts on the ATP-dependent potassium channel of the beta cells, for example sulfonylureas, for example tolbutamide, glibenclamide, glipizide, gliclazide or glimepiride.
In one embodiment, the compound of the formula I is administered in combination with a tablet which comprises both glimepiride, which is released rapidly, and metformin, which is released over a longer period (as described, for example, in US2007264331, WO2008050987, WO2008062273).
In one embodiment, the compound of the formula I is administered in combination with a biguanide, for example metformin.
In another embodiment, the compound of the formula I is administered in combination with a meglitinide, for example repaglinide, nateglinide or mitiglinide.
In a further embodiment, the compound of the formula I is administered with a combination of mitiglinide with a glitazone, e.g. pioglitazone hydrochloride.
In a further embodiment, the compound of the formula I is administered with a combination of mitiglinide with an alpha-glucosidase inhibitor.
In a further embodiment, the compound of the formula I is administered in combination with antidiabetic compounds, as described in WO2007095462, WO2007101060, WO2007105650.
In a further embodiment, the compound of the formula I is administered in combination with antihypoglycemic compounds, as described in WO2007137008, WO2008020607.
In one embodiment, the compound of the formula I is administered in combination with a thiazolidinedione, for example troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 by Dr. Reddy's Research Foundation, 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 is administered in combination with a PPAR gamma agonist, for example rosiglitazone, pioglitazone, JTT-501, Gl 262570, R-483, CS-011 (rivoglitazone), DRL-17564, DRF-2593 (balaglitazone), INT-131, T-2384, or those as described in WO2005086904, WO2007060992, WO2007100027, WO2007103252, WO2007122970, WO2007138485, WO2008006319, WO2008006969, WO2008010238, WO2008017398, WO2008028188, WO2008066356, WO2008084303, WO2008089461-WO2008089464, WO2008093639, WO2008096769, WO2008096820, WO2008096829, US2008194617, WO2008099944, WO2008108602, WO2008109334, WO2008126731, WO2008126732.
In one embodiment of the invention, the compound of the 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 the formula I is administered in combination with Tandemact™, a solid combination of pioglitazone with glimepiride.
In a further embodiment of the invention, the compound of the formula I is administered in combination with a solid combination of pioglitazone hydrochloride with an angiotensin II agonist, for example TAK-536.
In one embodiment of the invention, the compound of the formula I is administered in combination with a PPAR alpha agonist or mixed PPAR alpha/PPAR delta agonist, for example GW9578, GW-590735, K-111, LY-674, KRP-101, DRF-10945, LY-518674, CP-900691, BMS-687453, BMS-711939, or those as described in WO2001040207, WO2002096894, WO2005097076, WO2007056771, WO2007087448, WO2007089667, WO2007089557, WO2007102515, WO2007103252, JP2007246474, WO2007118963, WO2007118964, WO2007126043, WO2008006043, WO2008006044, WO2008012470, WO2008035359, WO2008087365, WO2008087366, WO2008087367, WO2008117982.
In one embodiment of the invention, the compound of the formula I is administered in combination with a mixed PPAR alpha/gamma agonist, for example naveglitazar, LY-510929, ONO-5129, E-3030, AVE 8042, AVE 8134, AVE 0847, CKD-501 (lobeglitazone sulfate), MBX-213, KY-201 or as described in WO 00/64888, WO 00/64876, WO03/020269, WO2004024726, WO2007099553, US2007276041, WO2007085135, WO2007085136, WO2007141423, WO2008016175, WO2008053331, WO2008109697, WO2008109700, WO2008108735 or in J. P. Berger et al., TRENDS in Pharmacological Sciences 28(5), 244-251, 2005.
In one embodiment of the invention, the compound of the formula I is administered in combination with a PPAR delta agonist, for example GW-501516, or as described in WO2006059744, WO2006084176, WO2006029699, WO2007039172-WO2007039178, WO2007071766, WO2007101864, US2007244094, WO2007119887, WO2007141423, US2008004281, WO2008016175, WO2008066356, WO2008071311, WO2008084962, US2008176861.
In one embodiment of the invention, the compound of the formula I is administered in combination with a pan-SPPARM (selective PPAR modulator alpha, gamma, delta), for example GFT-505, or those as described in WO2008035359.
In one embodiment, the compound of the formula I is administered in combination with metaglidasen or with MBX-2044 or other partial PPAR gamma agonists/antagonists.
In one embodiment, the compound of the formula I is administered in combination with an α-glucosidase inhibitor, for example miglitol or acarbose, or those as described, for example, in WO2007114532, WO2007140230, US2007287674, US2008103201, WO2008065796, WO2008082017.
In one embodiment, the compound of the formula I is administered in combination with an inhibitor of glycogen phosphorylase, for example PSN-357 or FR-258900, or those as described in WO2003084922, WO2004007455, WO2005073229-31, WO2005067932, WO2008062739, WO2008099000, WO2008113760.
In one embodiment, the compound of the formula I is administered in combination with glucagon receptor antagonists, for example A-770077 or NNC-25-2504 or as described in WO2004100875, WO2005065680, WO2006086488, WO2007047177, WO2007106181, WO2007111864, WO2007120270, WO2007120284, WO2007123581, WO2007136577, WO2008042223, WO2008098244.
In a further embodiment, the compound of the formula I is administered 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 is administered in combination with activators of glucokinase, for example LY-2121260 (WO2004063179), PSN-105, PSN-110, GKA-50, or those as described, for example, 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.
In one embodiment, the compound of the formula I is administered in combination with an inhibitor of gluconeogenesis, as described, for example, in ER-225654, WO2008053446.
In one embodiment, the compound of the formula I is administered in combination with inhibitors of fructose 1,6-bisphosphatase (FBPase), for example MB-07729, CS-917 (MB-06322) or MB-07803, or those as described in WO2006023515, WO2006104030, WO2007014619, WO2007137962, WO2008019309, WO2008037628.
In one embodiment, the compound of the formula I is administered in combination with modulators of glucose transporters 4 (GLUT4), for example KST-48 (D.-O. Lee et al.: Arzneim.-Forsch. Drug Res. 54 (12), 835 (2004)).
In one embodiment, the compound of the formula I is administered in combination with inhibitors of glutamine:fructose-6-phosphate amidotransferase (GFAT), as described, for example, in WO2004101528.
In one embodiment, the compound of the formula I is administered in combination with inhibitors of dipeptidyl peptidase IV (DPP-IV), for example 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, alogliptin benzoate, linagliptin, melogliptin, or those compounds as described in 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.
In one embodiment, the compound of the formula I is administered in combination with Janumet™, a solid combination of sitagliptin phosphate with metformin hydrochloride.
In one embodiment, the compound of the formula I is administered in combination with Eucreas®, a solid combination of vildagliptin with metformin hydrochloride.
In a further embodiment, the compound of the formula I is administered in combination with a solid combination of alogliptin benzoate with pioglitazone.
In one embodiment, the compound of the 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 is administered in combination with a combination of a DPP-IV inhibitor with omega-3 fatty acids or omega-3 fatty acid esters, as described, for example, in WO2007128801.
In one embodiment, the compound of the 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 is administered in combination with a substance which enhances insulin secretion, for example KCP-265 (WO2003097064), or those as described in WO2007026761, WO2008045484, US2008194617.
In one embodiment, the compound of the formula I is administered in combination with agonists of the glucose-dependent insulinotropic receptor (GDIR), for example APD-668.
In one embodiment of the invention, the compound of the formula I is administered in combination with an ATP citrate lyase inhibitor, for example SB-204990.
In one embodiment, the compound of the formula I is administered in combination with modulators of the sodium-dependent glucose transporter 1 or 2 (SGLT1, SGLT2), for example KGA-2727, T-1095, SGL-0010, AVE 2268, SAR 7226, SGL-5083, SGL-5085, SGL-5094, ISIS-388626, sergliflozin or dapagliflozin, or as described, for example, 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 or by A. L. Handlon in Expert Opin. Ther. Patents (2005) 15(11), 1531-1540.
In one embodiment, the compound of the formula I is administered in combination with inhibitors of 11-beta-hydroxysteroid dehydrogenase 1 (11β-HSD1), for example BVT-2733, JNJ-25918646, INCB-13739, INCB-20817, DIO-92 ((−)-ketoconazole) or those as described, for example, 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.
In one embodiment, the compound of the formula I is administered in combination with inhibitors of protein tyrosine phosphatase 1B (PTP-1B), as described, for example, in WO200119830-31, WO200117516, WO2004506446, WO2005012295, WO2005116003, WO2005116003, WO2006007959, DE 10 2004 060542.4, WO2007009911, WO2007028145, WO2007067612-615, WO2007081755, WO2007115058, US2008004325, WO2008033455, WO2008033931, WO2008033932, WO2008033934, WO2008089581.
In one embodiment of the invention, the compound of the formula I is administered in combination with an agonist of GPR109A (HM74A receptor agonists; NAR agonists (nicotinic acid receptor agonists)), for example nicotinic acid or “extended release niacin” in conjunction with MK-0524A (laropiprant) or MK-0524, or those compounds as described in WO2004041274, WO2006045565, WO2006045564, WO2006069242, WO2006085108, WO2006085112, WO2006085113, WO2006124490, WO2006113150, WO2007017261, WO2007017262, WO2007017265, WO2007015744, WO2007027532, WO2007092364, WO2007120575, WO2007134986, WO2007150025, WO2007150026, WO2008016968, WO2008051403, WO2008086949, WO2008091338, WO2008097535, WO2008099448, US2008234277, WO2008127591.
In another embodiment of the invention, the compound of the formula I is administered in combination with a solid combination of niacin with simvastatin.
In another 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).
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, for example those as described in WO2008039882.
In another embodiment of the invention, the compound of the formula I is administered in combination with an agonist of GPR116, as described, for example, in WO2006067531, WO2006067532.
In one embodiment, the compound of the formula I is administered in combination with modulators of GPR40, as described, for example, in WO2007013689, WO2007033002, WO2007106469, US2007265332, WO2007123225, WO2007131619, WO2007131620, WO2007131621, US2007265332, WO2007131622, WO2007136572, WO2008001931, WO2008030520, WO2008030618, WO2008054674, WO2008054675, WO2008066097, US2008176912.
In one embodiment, the compound of the formula I is administered in combination with modulators of GPR119 (G-protein-coupled glucose-dependent insulinotropic receptor), for example PSN-119-1, PSN-821, PSN-119-2, MBX-2982 or those as described, for example, 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.
In a further embodiment, the compound of the formula I is administered in combination with modulators of GPR120, as described, for example, in EP1688138, WO2008066131, WO2008066131, WO2008103500, WO2008103501.
In one embodiment, the compound of the formula I is administered in combination with inhibitors of hormone-sensitive lipase (HSL) and/or phospholipases, as described, for example, in WO2005073199, WO2006074957, WO2006087309, WO2006111321, WO2007042178, WO2007119837, WO2008122352, WO2008122357.
In one embodiment, the compound of the formula I is administered in combination with inhibitors of endothelial lipase, as described, for example, in WO2007110216.
In one embodiment, the compound of the formula I is administered in combination with a phospholipase A2 inhibitor, for example darapladib or A-002, or those as described in WO2008048866, WO20080488867.
In one embodiment, the compound of the formula I is administered in combination with myricitrin, a lipase inhibitor (WO2007119827).
In one embodiment, the compound of the formula I is administered in combination with an inhibitor of glycogen synthase kinase-3 beta (GSK-3 beta), as described, for example, 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.
In one embodiment, the compound of the formula I is administered in combination with an inhibitor of phosphoenolpyruvate carboxykinase (PEPCK), for example those as described in WO2004074288.
In one embodiment, the compound of the formula I is administered in combination with an inhibitor of phosphoinositide kinase-3 (PI3K), for example those as described in WO2008027584, WO2008070150, WO2008125833, WO2008125835, WO2008125839.
In one embodiment, the compound of the formula I is administered in combination with an inhibitor of serum/glucocorticoid-regulated kinase (SGK), as described, for example, in WO2006072354, WO2007093264, WO2008009335, WO2008086854.
In one embodiment, the compound of the formula I is administered in combination with a modulator of the glucocorticoid receptor, as described, for example, in WO2008057855, WO2008057856, WO2008057857, WO2008057859, WO2008057862, WO2008059867, WO2008059866, WO2008059865, WO2008070507, WO2008124665, WO2008124745.
In one embodiment, the compound of the formula I is administered in combination with a modulator of the mineralocorticoid receptor (MR), for example drospirenone, or those as described in WO2008104306, WO2008119918.
In one embodiment, the compound of the formula I is administered in combination with an inhibitor of protein kinase C beta (PKC beta), for example ruboxistaurin, or those as described in WO2008096260, WO2008125945.
In one embodiment, the compound of the formula I is administered in combination with an inhibitor of protein kinase D, for example doxazosin (WO2008088006).
In a further embodiment, the compound of the formula I is administered in combination with an activator of the AMP-activated protein kinase (AMPK), as described, for example, in WO2007062568, WO2008006432, WO2008016278, WO2008016730, WO2008083124.
In one embodiment, the compound of the formula I is administered in combination with an inhibitor of ceramide kinase, as described, for example, in WO2007112914, WO2007149865.
In a further embodiment, the compound of the formula I is administered in combination with an inhibitor of MAPK-interacting kinase 1 or 2 (MNK1 or 2), as described, for example, in WO2007104053, WO2007115822, WO2008008547, WO2008075741.
In one embodiment, the compound of the formula I is administered in combination with inhibitors of “I-kappaB kinase” (IKK inhibitors), as described, for example, in WO2001000610, WO2001030774, WO2004022057, WO2004022553, WO2005097129, WO2005113544, US2007244140, WO2008099072, WO2008099073, WO2008099073, WO2008099074, WO2008099075.
In another embodiment, the compound of the formula I is administered in combination with inhibitors of NF-kappaB (NFKB) activation, for example salsalate.
In a further embodiment, the compound of the formula I is administered in combination with inhibitors of ASK-1 (apoptosis signal-regulating kinase 1), as described, for example, in WO2008016131.
In one embodiment of the invention, the compound of the formula I is administered in combination with an HMG-CoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin, pitavastatin, L-659699, BMS-644950, or those as described in US2007249583, WO2008083551.
In a further embodiment of the invention, the compound of the formula I is administered in combination with a farnesoid X receptor (FXR) modulator, for example WAY-362450 or those as described in WO2003099821, WO2005056554, WO2007052843, WO2007070796, WO2007092751, JP2007230909, WO2007095174, WO2007140174, WO2007140183, WO2008000643, WO2008002573, WO2008025539, WO2008025540, JP2008214222.
In another embodiment of the invention, the compound of the formula I is administered in combination with a ligand of the liver X receptor (LXR), as described, for example, in WO2007092965, WO2008041003, WO2008049047, WO2008065754, WO2008073825, US2008242677.
In one embodiment of the invention, the compound of the formula I is administered in combination with a fibrate, for example fenofibrate, clofibrate, bezafibrate, or those as described in WO2008093655.
In one embodiment of the invention, the compound of the formula I is administered in combination with fibrates, for example the choline salt of fenofibrate (SLV-348).
In one embodiment of the invention, the compound of the formula I is administered in combination with fibrates, for example the choline salt of fenofibrate and an HMG-CoA reductase inhibitor, for example 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 the formula I is administered in combination with a solid 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 the formula I is administered in combination with Synordia (R), a solid combination of fenofibrate with metformin
In one embodiment of the invention, the compound of the formula I is administered in combination with a cholesterol reabsorption inhibitor, for example ezetimibe, tiqueside, pamaqueside, FM-VP4 (sitostanol/campesterol ascorbyl phosphate; Forbes Medi-Tech, WO2005042692, WO2005005453), MD-0727 (Microbia Inc., WO2005021497, WO2005021495) or with compounds as described in WO2002066464, WO2005000353 (Kotobuki Pharmaceutical Co. Ltd.) or WO2005044256 or WO2005062824 (Merck & Co.) or WO2005061451 and WO2005061452 (AstraZeneca AB) and WO2006017257 (Phenomix) or WO2005033100 (Lipideon Biotechnology AG), or as described in WO2002050060, WO2002050068, WO2004000803, WO2004000804, WO2004000805, WO2004087655, WO2004097655, WO2005047248, WO2006086562, WO2006102674, WO2006116499, WO2006121861, WO2006122186, WO2006122216, WO2006127893, WO2006137794, WO2006137796, WO2006137782, WO2006137793, WO2006137797, WO2006137795, WO2006137792, WO2006138163, WO2007059871, US2007232688, WO2007126358, WO2008033431, WO2008033465, WO2008052658, WO2008057336, WO2008085300.
In one embodiment of the invention, the compound of the formula I is administered in combination with an NPC1L1 antagonist, for example those as described in WO2008033464, WO2008033465.
In one embodiment of the invention, the compound of the formula I is administered in combination with Vytorin™, a solid combination of ezetimibe with simvastatin.
In one embodiment of the invention, the compound of the formula I is administered in combination with a solid combination of ezetimibe with atorvastatin.
In one embodiment of the invention, the compound of the formula I is administered in combination with a solid combination of ezetimibe with fenofibrate.
In one embodiment of the invention, the further active ingredient is a diphenylazetidinone derivative, as described, for example, in U.S. Pat. No. 6,992,067 or U.S. Pat. No. 7,205,290.
In a further embodiment of the invention, the further active ingredient is a diphenylazetidinone derivative, as described, for example, in U.S. Pat. No. 6,992,067 or U.S. Pat. No. 7,205,290, combined with a statin, for example simvastatin, fluvastatin, pravastatin, lovastatin, cerivastatin, atorvastatin, pitavastatin or rosuvastatin.
In one embodiment of the invention, the compound of the formula I is administered in combination with a solid combination of lapaquistat, a squalene synthase inhibitor, with atorvastatin.
In one embodiment of the invention, the compound of the formula I is administered in combination with a CETP inhibitor, for example torcetrapib, anacetrapib or JTT-705 (dalcetrapib), or those as described in WO2006002342, WO2006010422, WO2006012093, WO2006073973, WO2006072362, WO2007088996, WO2007088999, US2007185058, US2007185113, US2007185154, US2007185182, WO2006097169, WO2007041494, WO2007090752, WO2007107243, WO2007120621, US2007265252, US2007265304, WO2007128568, WO2007132906, WO2008006257, WO2008009435, WO2008018529, WO2008058961, WO2008058967, WO2008059513, WO2008070496, WO2008115442, WO2008111604.
In one embodiment of the invention, the compound of the formula I is administered in combination with bile acid reabsorption inhibitors (inhibitors of the intestinal bile acid transporter (IBAT)) (see, for example, U.S. Pat. No. 6,245,744, U.S. Pat. No. 6,221,897 or WO00/61568), for example HMR 1741, or those as described 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.
In one embodiment, the compound of the formula I is administered in combination with agonists of GPBAR1 (G-protein-coupled bile acid receptor-1; TGR5), as described, for example, in US20060199795, WO2007110237, WO2007127505, WO2008009407, WO2008067219, WO2008067222, FR2908310, WO2008091540, WO2008097976.
In one embodiment of the invention, the compound of the formula I is administered in combination with inhibitors of the TRPM5 channel (TRP cation channel M5), as described, for example, in WO2008097504.
In one embodiment of the invention, the compound of the formula I is administered in combination with a polymeric bile acid adsorber, for example 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 a chewing gum comprising phytosterols (Reductol™).
In one embodiment of the invention, the compound of the formula I is administered in combination with an inhibitor of the microsomal triglyceride transfer protein (MTP inhibitor), for example implitapide, BMS-201038, R-103757, AS-1552133, SLx-4090, AEGR-733, or those as described in WO2005085226, WO2005121091, WO2006010423, WO2006113910, WO2007143164, WO2008049806, WO2008049808, WO2008090198, WO2008100423.
In a further embodiment of the invention, the compound of the formula I is administered in combination with a combination of a cholesterol absorption inhibitor, for example ezetimibe, and an inhibitor of the triglyceride transfer protein (MTP inhibitor), for example implitapide, as described in WO2008030382 or in WO2008079398.
In one embodiment of the invention, the compound of the formula I is administered in combination with an active antihypertriglyceridemic ingredient, for example those as described in WO2008032980.
In another embodiment of the invention, the compound of the formula I is administered in combination with an antagonist of the somatostatin 5 receptor (SST5 receptor), for example those as described in WO2006094682.
In one embodiment of the invention, the compound of the formula I is administered in combination with an ACAT inhibitor, for example avasimibe, SMP-797 or KY-382, or those as described in WO2008087029, WO2008087030, WO2008095189.
In a further embodiment of the invention, the compound of the formula I is administered in combination with an inhibitor of liver carnitine palmitoyltransferase 1 (L-CPT1), as described, for example, in WO2007063012, WO2007096251 (ST-3473), WO2008015081, US2008103182, WO2008074692.
In a further embodiment of the invention, the compound of the formula I is administered in combination with a modulator of serine palmitoyltransferase (SPT), as described, for example, in WO2008031032, WO2008046071, WO2008083280, WO2008084300.
In one embodiment of the invention, the compound of the formula I is administered in combination with a squalene synthetase inhibitor, for example BMS-188494, TAK-475 (lapaquistat acetate), or as described in WO2005077907, JP2007022943, WO2008003424.
In one embodiment of the invention, the compound of the formula I is administered in combination with ISIS-301012 (mipomersen), an antisense oligonucleotide which is capable of regulating the apolipoprotein B gene.
In one embodiment of the invention, the compound of the formula I is administered in combination with a stimulator of the ApoA-1 gene, as described, for example in WO2008092231.
In one embodiment of the invention, the compound of the formula I is administered in combination with an LDL receptor inducer (see U.S. Pat. No. 6,342,512), for example HMR1171, HMR1586, or those as described in WO2005097738, WO2008020607.
In another embodiment of the invention, the compound of the formula I is administered in combination with an HDL cholesterol-elevating agent, for example those as described in WO2008040651, WO2008099278.
In one embodiment of the invention, the compound of the formula I is administered in combination with an ABCA1 expression enhancer, as described, for example, in WO2006072393, WO2008062830.
In one embodiment of the invention, the compound of the formula I is administered in combination with a lipoprotein lipase modulator, for example ibrolipim (NO-1886).
In one embodiment of the invention, the compound of the formula I is administered in combination with a lipoprotein(a) antagonist, for example gemcabene (CI-1027).
In one embodiment of the invention, the compound of the formula I is administered in combination with a lipase inhibitor, for example orlistat or cetilistat (ATL-962).
In one embodiment of the invention, the compound of the formula I is administered in combination with an adenosine A1 receptor agonist (adenosine A1 R), as described, for example, in EP1258247, EP1375508, WO2008028590, WO2008077050.
In one embodiment of the invention, the compound of the formula I is administered in combination with an adenosine A2B receptor agonist (adenosine A2B R), for example ATL-801.
In another embodiment of the invention, the compound of the formula I is administered in combination with a modulator of adenosine A2A and/or adenosine A3 receptors, as described, for example, in WO2007111954, WO2007121918, WO2007121921, WO2007121923, WO2008070661.
In a further embodiment of the invention, the compound of the formula I is administered in combination with an agonist of the adenosine A1/A2B receptors, as described, for example, in WO2008064788, WO2008064789.
In one embodiment of the invention, the compound of the formula I is administered in combination with an adenosine A2B receptor antagonist (adenosine A2B R), as described in US2007270433, WO2008027585, WO2008080461.
In one embodiment, the compound of the formula I is administered in combination with inhibitors of acetyl-CoA carboxylase (ACC1 and/or ACC2), for example those as described 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.
In another embodiment, the compound of the formula I is administered in combination with modulators of 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).
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 is administered in combination with inhibitors of soluble epoxide hydrolase (sEH), as described, for example, in WO2008051873, WO2008051875, WO2008073623, WO2008094869, WO2008112022.
In a further embodiment, the compound of the formula I is administered in combination with CART modulators (see “Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice” Asakawa, A. et al.: Hormone and Metabolic Research (2001), 33(9), 554-558);
NPY antagonists, for example N-{4-[(4-aminoquinazolin-2-ylamino)methyl]-cyclohexylmethyl}naphthalene-1-sulfonamide hydrochloride (CGP 71683A) or velneperit;
NPY-5 receptor antagonists, such as L-152804 or the compound “NPY-5-BY” from Banyu, or as described, for example, in WO2006001318, WO2007103295, WO2007125952, WO2008026563, WO2008026564, WO2008052769, WO2008092887, WO2008092888, WO2008092891;
NPY-4 receptor antagonists, as described, for example, in WO2007038942;
NPY-2 receptor antagonists, as described, for example, in WO2007038943;
peptide YY 3-36 (PYY3-36) or analogous compounds, for example CJC-1682 (PYY3-36 conjugated with human serum albumin via Cys34) or CJC-1643 (derivative of PYY3-36, which is conjugated in vivo to serum albumin), or those as described in WO2005080424, WO2006095166, WO2008003947;
derivatives of the peptide obestatin, as described by WO2006096847;
CB1R (cannabinoid receptor 1) antagonists, for example rimonabant, surinabant (SR147778), SLV-319 (ibipinabant), AVE-1625, taranabant (MK-0364) or salts thereof, otenabant (CP-945,598), rosonabant, V-24343 or those compounds as described in, for example, EP 0656354, WO 00/15609, WO2001/64632-64634, WO 02/076949, WO2005080345, WO2005080328, WO2005080343, WO2005075450, WO2005080357, WO200170700, WO2003026647-48, WO200302776, WO2003040107, WO2003007887, WO2003027069, U.S. Pat. No. 6,509,367, 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, U.S. Pat. No. 7,297,710, 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;
cannabinoid receptor 1/cannabinoid receptor 2 (CB1/CB2) modulating compounds, for example delta-9-tetrahydrocannabivarin, or those as described, for example, in WO2007001939, WO2007044215, WO2007047737, WO2007095513, WO2007096764, WO2007112399, WO2007112402, WO2008122618;
modulators of FAAH (fatty acid amide hydrolase), as described, for example, in WO2007140005, WO2008019357, WO2008021625, WO2008023720, WO2008030532;
inhibitors of fatty acid synthase (FAS), as described, for example, in WO2008057585, WO2008059214, WO2008075064, WO2008075070, WO2008075077;
inhibitors of LCE (long chain fatty acid elongase), as described, for example, in WO2008120653;
vanilloid-1 receptor modulators (modulators of TRPV1), as described, for example, in WO2007091948, WO2007129188, WO2007133637, WO2008007780, WO2008010061, WO2008007211, WO2008010061, WO2008015335, WO2008018827, WO2008024433, WO2008024438, WO2008032204, WO2008050199, WO2008059339, WO2008059370, WO2008066664, WO2008075150, WO2008090382, WO2008090434, WO2008093024, WO2008107543, WO2008107544, WO2008110863;
modulators, antagonists or inverse agonists of the opioid receptors, for example GSK-982 or those as described, for example, in WO2007047397, WO2008021849, WO2008021851, WO2008032156, WO2008059335;
modulators of the “orphan opioid (ORL-1) receptor”, as described, for example, in US2008249122, WO2008089201;
agonists of the prostaglandin receptor, for example bimatoprost or those compounds as described in WO2007111806;
MC4 receptor agonists (melanocortin-4 receptor agonists, MC4R agonists, for example N-[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-5-yl)-1-(4-chlorophenyl)-2-oxoethyl]-1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxamide; (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, 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;
orexin receptor 1 antagonists (OX1R antagonists), orexin receptor 2 antagonists (OX2R antagonists) or mixed OX1R/OX2R antagonists (e.g. 142-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea hydrochloride (SB-334867-A), or those as described, for example, in WO200196302, WO200185693, WO2004085403, WO2005075458, WO2006067224, WO2007085718, WO2007088276, WO2007116374; WO2007122591, WO2007126934, WO2007126935, WO2008008517, WO2008008518, WO2008008551, WO2008020405, WO2008026149, WO2008038251, US2008132490, WO2008065626, WO2008078291, WO2008087611, WO2008081399, WO2008108991, WO2008107335, US2008249125);
histamine H3 receptor antagonists/inverse agonists (e.g. 3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazol[4,5-c]pyridin-5-yl)propan-1-one oxalic acid salt (WO 00/63208), or those as described in WO200064884, WO2005082893, US2005171181 (e.g. PF-00389027), WO2006107661, WO2007003804, WO2007016496, WO2007020213, WO2007049798, WO2007055418, WO2007057329, 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);
histamine H1/histamine H3 modulators, for example betahistine or its dihydrochloride;
modulators of the histamine H3 transporter or of the histamine H3/serotonin transporter, as described, for example, in WO2008002816, WO2008002817, WO2008002818, WO2008002820;
histamine H4 modulators, as described, for example, in WO2007117399;
CRF antagonists (e.g. [2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine (WO 00/66585) or those CRF1 antagonists as described in WO2007105113, WO2007133756, WO2008036541, WO2008036579, WO2008083070);
CRF BP antagonists (e.g. urocortin);
urocortin agonists;
modulators of the beta-3 adrenoceptor, for example 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;
MSH (melanocyte-stimulating hormone) agonists;
MCH (melanine-concentrating hormone) receptor antagonists (for example 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 those compounds as described in WO2005085200, WO2005019240, WO2004011438, WO2004012648, WO2003015769, WO2004072025, WO2005070898, WO2005070925, WO2004039780, WO2004092181, WO2003033476, WO2002006245, WO2002089729, WO2002002744, WO2003004027, FR2868780, WO2006010446, WO2006038680, WO2006044293, WO2006044174, JP2006176443, WO2006018280, WO2006018279, WO2006118320, WO2006130075, WO2007018248, 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);
CCK-A (CCK-1) agonists/modulators (for example {2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)thiazol-2-ylcarbamoyl]-5,7-dimethylindol-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;
serotonin reuptake inhibitors (e.g. dexfenfluramine), or those as described in WO2007148341, WO2008034142, WO2008081477, WO2008120761;
mixed serotonin/dopamine reuptake inhibitors (e.g. bupropion), or those as described in WO2008063673, or solid combinations of bupropion with naltrexone or bupropion with zonisamide;
mixed reuptake inhibitors, for example DOV-21947;
mixed serotoninergic and noradrenergic compounds (e.g. WO 00/71549);
5-HT receptor agonists, for example 1-(3-ethylbenzofuran-7-yl)piperazine oxalic acid salt (WO 01/09111);
mixed dopamine/norepinephrine/acetylcholine reuptake inhibitors (e.g. tesofensine), or those as described, for example, in WO2006085118;
dopamine antagonists, as described, for example, in WO2008079838, WO2008079839, WO2008079847, WO2008079848;
norepinephrine reuptake inhibitors, as described, for example, in US2008076724;
5-HT2A receptor antagonists, as described, for example, in WO2007138343;
5-HT2C receptor agonists (for example lorcaserine 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);
5-HT6 receptor modulators, for example E-6837, BVT-74316 or PRX-07034, or those as described, for example, in WO2005058858, WO2007054257, WO2007107373, WO2007108569, WO2007108742-744, WO2008003703, WO2008027073, WO2008034815, WO2008054288, EP1947085, WO2008084491, WO2008084492, WO2008092665, WO2008092666, WO2008101247, WO2008110598, WO2008116831, WO2008116833;
agonists of estrogen receptor gamma (ERRγ agonists), as described, for example, in WO2007131005, WO2008052709;
agonists of estrogen receptor alpha (ERRα/ERR1 agonists), as described, for example, in WO2008109727;
sigma-1 receptor antagonists, as described, for example, in WO2007098953, WO2007098961, WO2008015266, WO2008055932, WO2008055933;
muscarin 3 receptor (M3R) antagonists, as described, for example, in WO2007110782, WO2008041184;
bombesin receptor agonists (BRS-3 agonists), as described, for example, in WO2008051404, WO2008051405, WO2008051406, WO2008073311;
galanin receptor antagonists;
growth hormone (e.g. human growth hormone or AOD-9604);
growth hormone releasing compounds (tert-butyl 6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (WO 01/85695));
growth hormone secretagogue receptor antagonists (ghrelin antagonists), for example A-778193, or those as described in WO2005030734, WO2007127457, WO2008008286;
growth hormone secretagogue receptor modulators (ghrelin modulators), for example JMV-2959, JMV-3002, JMV-2810, JMV-2951, or those as described in WO2006012577 (e.g. YIL-781 or YIL-870), WO2007079239, WO2008092681;
TRH agonists (see, for example, EP 0 462 884);
decoupling protein 2 or 3 modulators;
chemical decouplers (e.g. WO2008059023, WO2008059024, WO2008059025, WO2008059026);
leptin agonists (see, for example, Lee, Daniel W.; Leinung, Matthew C.; Rozhayskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as a potential approach to the treatment of obesity. Drugs of the Future (2001), 26(9), 873-881);
DA agonists (bromocriptin, doprexin);
lipase/amylase inhibitors (e.g. WO 00/40569, WO2008107184);
inhibitors of diacylglycerol O-acyltransferases (DGATs), for example BAY-74-4113, or as described, for example, 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;
inhibitors of monoacylglycerol acyltransferase (2-acylglycerol O-acyltransferase; MGAT), as described, for example, in WO2008038768;
inhibitors of fatty acid synthase (FAS), for example C75, or those as described in WO2004005277, WO2008006113;
inhibitors of stearoyl-CoA delta9 desaturase (SCD1), as described, for example, 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;
inhibitors of fatty acid desaturase 1 (delta5 desaturase), as described, for example, in WO2008089310;
hypoglycemic/hypertriglyceridemic indoline compounds, as described in WO2008039087;
inhibitors of “adipocyte fatty acid-binding protein aP2”, for example BMS-309403;
activators of adiponectin secretion, as described, for example, in WO2006082978, WO2008105533;
promoters of adiponectin secretion, as described, for example, in WO2007125946, WO2008038712;
modified adiponectins, as described, for example, in WO2008121009;
oxyntomodulin or analogs thereof;
oleoyl-estrone
or agonists or partial agonists of the thyroid hormone receptor (thyroid hormone receptor agonists), for example: KB-2115 (eprotirome), QRX-431 (sobetirome) or DITPA, or those as described in WO20058279, WO200172692, WO200194293, WO2003084915, WO2004018421, WO2005092316, WO2007003419, WO2007009913, WO2007039125, WO2007110225, WO2007110226, WO2007128492, WO2007132475, WO2007134864, WO2008001959, WO2008106213;
or agonists of the thyroid hormone receptor beta (TR-beta), for example MB-07811 or MB-07344, or those as described in WO2008062469.
In one embodiment of the invention, the compound of the formula I is administered in combination with a combination of eprotirome with ezetimibe.
In one embodiment of the invention, the compound of the formula I is administered in combination with an inhibitor of site-1 protease (SIP), for example PF-429242.
In a further embodiment of the invention, the compound of the formula I is administered in combination with a modulator of the “trace amine associated receptor 1” (TAAR1), as described, for example, in US2008146523, WO2008092785.
In one embodiment of the invention, the compound of the formula I is administered in combination with an inhibitor of growth factor receptor bound protein 2 (GRB2), as described, for example, in WO2008067270.
In a further embodiment of the invention, the compound of the formula I is administered in combination with an RNAi (siRNA) therapeutic agent directed against PCSK9 (proprotein convertase subtilisin/kexin type 9).
In one embodiment, the compound of the formula I is administered in combination with Omacor® or Lovaza™ (omega-3 fatty acid ester; highly concentrated ethyl ester of eicosapentaenoic acid and of docosahexaenoic acid).
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 is administered in combination with an antioxidant, for example OPC-14117, AGI-1067 (succinobucol), probucol, tocopherol, ascorbic acid, β-carotene or selenium.
In one embodiment of the invention, the compound of the formula I is administered in combination with a vitamin, for example vitamin B6 or vitamin B12.
In one embodiment, the compound of the formula I is administered in combination with more than one of the aforementioned compounds, for example in combination with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin (PrandiMet™), insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.
In another embodiment, the compound of the formula I is administered in combination with an inhibitor of carboanhydrase type 2 (carbonic anhydrase type 2), for example those as described in WO2007065948.
In another embodiment, the compound of the formula I is administered in combination with topiramat or a derivative thereof, as described in WO2008027557.
In a further embodiment, the compound of the formula I is administered in combination with a solid combination of topiramat with phentermin (Qnexa™).
In a further embodiment, the compound of the formula I is administered 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, as described, for example, in EP1886695, WO2008119744.
In one embodiment, the compound of the formula I is administered in combination with an agonist of the RUP3 receptor, as described, for example, in WO2007035355, WO2008005576.
In another embodiment, the compound of the formula I is administered in combination with an activator of the gene which codes for ataxia telangiectasia mutated (ATM) protein kinase, for example chloroquine.
In one embodiment, the compound of the formula I is administered in combination with a tau protein kinase 1 inhibitor (TPK1 inhibitor), as described, for example, in WO2007119463.
In one embodiment, the compound of the formula I is administered in combination with a “c-Jun N-terminal kinase” inhibitor (JNK inhibitor), as described, for example, in WO2007125405, WO2008028860, WO2008118626.
In one embodiment, the compound of the formula I is administered in combination with an endothelin A receptor antagonist, for example avosentan (SPP-301).
In one embodiment, the compound of the formula I is administered in combination with modulators of the glucocorticoid receptor (GR), for example KB-3305 or those compounds as described, for example, in WO2005090336, WO2006071609, WO2006135826, WO2007105766, WO2008120661.
In one embodiment, the further 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 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 example, be resveratrol in suitable formulations, or those compounds as specified in WO2007019416 (e.g. SRT-1720), WO2008073451.
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 is administered in combination with antihypercholesterolemic compounds, as described, for example, in WO2007107587, WO2007111994, WO2008106600, WO2008113796.
In a further embodiment, the compound of the formula I is administered in combination with inhibitors of SREBP (sterol regulatory element-binding protein), as described, for example, in WO2008097835.
In another embodiment, the compound of the formula I is administered in combination with a cyclic peptide agonist of the VPAC2 receptor, as described, for example, in WO2007101146, WO2007133828.
In a further embodiment, the compound of the formula I is administered in combination with an agonist of the endothelin receptor, as described, for example, in WO2007112069.
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 administered in combination with tissue-selective androgen receptor modulators (SARM), as described, for example, in WO2007099200, WO2007137874.
In a further embodiment, the compound of the formula I is administered in combination with an AGE (advanced glycation endproduct) inhibitor, as described, for example, in JP2008024673.
In one embodiment of the invention, the further active ingredient is leptin; see, for example, “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 further active ingredient is dexamphetamine or amphetamine.
In one embodiment, the further active ingredient is fenfluramine or dexfenfluramine.
In another embodiment, the further active ingredient is sibutramine or those derivatives as described in WO2008034142.
In one embodiment, the further active ingredient is mazindol or phentermin
In a further embodiment, the further active ingredient is geniposidic acid (WO2007100104) or derivatives thereof (JP2008106008).
In one embodiment, the further active ingredient is a nasal calcium channel blocker, for example diltiazem, or those as described in U.S. Pat. No. 7,138,107.
In one embodiment, the further active ingredient is an inhibitor of sodium-calcium ion exchange, for example those as described in WO2008028958, WO2008085711.
In a further embodiment, the further active ingredient is a blocker of calcium channels, for example of CaV3.2 or CaV2.2, as described in WO2008033431, WO2008033447, WO2008033356, WO2008033460, WO2008033464, WO2008033465, WO2008033468, WO2008073461.
In one embodiment, the further active ingredient is a modulator of a calcium channel, for example those as described in WO2008073934, WO2008073936.
In one embodiment, the further active ingredient is a blocker of the “T-type calcium channel”, as described, for example, in WO2008033431, WO2008110008.
In one embodiment, the further active ingredient is an inhibitor of KCNQ potassium channel 2 or 3, for example those as described in US2008027049, US2008027090.
In one embodiment, the further active ingredient is an inhibitor of the potassium Kv1.3 ion channel, for example those as described in WO2008040057, WO2008040058, WO2008046065.
In another embodiment, the further active ingredient is a modulator of the MCP-1 receptor (monocyte chemoattractant protein-1 (MCP-1)), for example those as described in WO2008014360, WO2008014381.
In one embodiment, the further active ingredient is a modulator of somatostatin receptor 5 (SSTR5), for example those as described in WO2008019967, US2008064697, US2008249101, WO2008000692.
In one embodiment, the further active ingredient is a modulator of somatostatin receptor 2 (SSTR2), for example those as described in WO2008051272.
In one embodiment, the further active ingredient is an erythropoietin-mimetic peptide which acts as an erythropoietin (EPO) receptor agonist. Such molecules are described, for example, in WO2008042800.
In a further embodiment, the further active ingredient is an anorectic/a hypoglycemic compound, for example those as described in WO2008035305, WO2008035306, WO2008035686.
In one embodiment, the further active ingredient is an inductor of lipoic acid synthetase, for example those as described in WO2008036966, WO2008036967.
In one embodiment, the further active ingredient is a stimulator of endothelial nitric oxide synthase (eNOS), for example those as described in WO2008058641, WO2008074413.
In one embodiment, the further active ingredient is a modulator of carbohydrate and/or lipid metabolism, for example those as described in WO2008059023, WO2008059024, WO2008059025, WO2008059026.
In a further embodiment, the further active ingredient is an angiotensin II receptor antagonist, for example those as described in WO2008062905, WO2008067378.
In one embodiment, the further active ingredient is an agonist of the sphingosine-1-phosphate receptor (SIP), for example those as described in WO2008064315, WO2008074820, WO2008074821.
In one embodiment, the further active ingredient is an agent which retards gastric emptying, for example 4-hydroxyisoleucine (WO2008044770).
In one embodiment, the further active ingredient is a muscle-relaxing substance, as described, for example, in WO2008090200.
In a further embodiment, the further active ingredient is an inhibitor of monoamine oxidase B (MAO-B), for example those as described in WO2008092091.
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), for example those as described in US2008194658.
In another embodiment, the further active ingredient is lisofylline, which prevents autoimmune damage to insulin-producing cells.
In one embodiment, the compound of the formula I is administered in combination with bulking agents, preferably insoluble bulking agents (see, for example, Carob/Caromax® (Zunft H J; et al., Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 September-October), 18(5), 230-6). Caromax is a carob-containing product from Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark Höchst, 65926 Frankfurt/Main)). Combination with Caromax® is possible in one preparation or by separate administration of compounds of the formula I and Caromax®. Caromax® can in this connection also be administered in the form of food products such as, for example, in bakery products or muesli bars.
It will be appreciated that every suitable combination of the compounds of the invention with one or more of the aforementioned compounds and optionally one or more other pharmacologically active substances is considered to be covered within the scope of protection conferred by the present invention.
Also suitable are the following active ingredients for combination preparations:
The invention further provides processes for preparing the compounds of the general formula I, wherein the compounds of the formula I are obtained in a procedure analogous to the reaction schemes which follow. The scheme shown here describes the special case, without being restricted thereto, in which Y″═CH2, i.e. Q1 and Q2 in the description of the R6-R10 radicals are each hydrogen and the R19 radical is an optionally substituted aryl or heteroaryl radical.
In a first method “A”, the procedure is to convert a suitably substituted aniline of the formula A in which the R1 to R5 radicals are in some circumstances present in protected form to an isocyanate of the formula B. This reaction can be carried out, for example, with phosgene in toluene or with diphosgene or triphosgene. The isocyanate B is subsequently reacted with the methyl ester or another ester (e.g. tert-butyl) of the amino acid J in which R and R′ are each as defined in formula I, or a salt of an ester of the amino acid J, with addition of base (e.g. triethylamine), to give a urea of the formula K. This urea can be ring-closed under basic or acidic conditions, preferably acidic conditions, to give the imidazolidine-2,4-dione of the formula L. The further conversion to a compound of the formula H, which constitutes the ortho-substituted special case of a compound of the formula I, can, for example, be effected by alkylating a suitably substituted compound Q, where Z may be one or more substituents as described above in formula I, and Y is either a carboxylic ester radical —COOR where R is, for example, methyl, an aldehyde radical —CHO or a protected hydroxymethyl radical —CH—OR where R is, for example, acetyl or benzyl, and V is either a halogen atom, preferably a chlorine or bromine atom, or else, for example, an O—SO2—C6H4-4-CH3 radical or an O—SO2—CH3 radical or an O—SO2—CF3 radical, to obtain the compound M. After conversion by means of standard reactions of the Y radical to a Y′ radical defined as —CH2—O—P(O)(Oethyl)2 or —CH2-halogen, preferably —CH2—Br, M can be reacted further under Suzuki conditions (e.g.: S. M. Nobre et al.: Tetrahedron Letters 45 (2004) 8225-8228; S. Langle et al.: Tetrahedron Letters 44 (2003) 9255-9258; S. Chowdhury et al.: Tetrahedron Letters 40 (1999) 7599-7603; L. Chahen et al.: Synlett (2003), 1668-1672; M. McLaughlin: Organic Letters 7 (2005) 4875-4878) with arylboronic acids or arylboronic esters to give compounds of the formula H. W in R19-W of the formula O is, for example, defined as —B(OH)2. This reaction can alternatively also be carried out in such a way that Y in the compound Q is a halogen atom (e.g. bromine or iodine) and, in the compound of the formula M, is converted to a Y′ radical defined as 4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl. This can be achieved, for example, by means of copper-catalyzed coupling of the iodide with pinacolborane (W. Zhu et al.: Organic Letters 8 (2006) 261-263) or palladium acetate-catalyzed reaction of the bromine compound with bis(pinacolato)diboron (T. Ishiyama et al.: Tetrahedron 57 (2001) 9813-16). The arylboronic ester of the formula M thus formed can then be reacted in a next step with a compound of the formula R19-W in which W is defined as —CH2—Hal, preferably —CH2—Br, or —CH2—O—P(O)(Oethyl)2, to give a compound of the formula H.
The compound L can also be further converted to the compound H by reacting L under alkylating conditions with a compound of the formula N where V may be defined as outlined above, and where Y2 may be defined as, for example, —CH2— (methylene). The compound N in turn can be obtained by reaction of P in which V′ is a carboxylic ester function —COOalkyl, which can be converted by means of standard reactions to a suitably protected hydroxyalkyl function, and where Y1 is —CH2—Br or —B(OH)2 or 4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl, with a possibly substituted R19-W compound O under Suzuki conditions. W is defined as —B(OH)2 or 4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl when Y1 is defined as —CH2—Br, and as —CH2—Br when Y1 is defined as —B(OH)2 or 4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl. The protected hydroxyl function V′ can be converted by standard reactions to the function V with the definitions described above.
Any protecting groups present in the compound H can be removed at the end.
The formula H shown here constitutes a special case of the formula I in which the Y″—R19 radical in formula I is in the ortho position; this radical may correspondingly also be in the meta or para position.
Compounds in which Q1/Q2 is not H can be prepared in an analogous manner.
In another method “B”,
the isocyanate B is reacted with a suitably substituted amino acid ester derivative C in which the particular substituents may be provided with protecting groups, and where the methyl ester shown in the scheme is a nonlimiting example of an ester, and where Y is either a carboxylic ester radical —COOR where R is, for example, methyl, an aldehyde radical —CHO or a protected hydroxymethyl radical —CH—OR where R is, for example, acetyl or benzyl, or a boronic acid radical —B(OH)2 or a boronic ester radical, for example 4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl, with addition of a base (e.g. triethylamine), to give a urea of the formula F. The amino acid ester derivative C can be prepared from the compound D in which Z may be one or more substituents as described above in formula I, and where Y is a carboxylic ester radical —COOR where R is, for example, methyl, an aldehyde radical —CHO or a protected hydroxymethyl radical —CH—OR where R is, for example, acetyl or benzyl, or a boronic acid radical —B(OH)2 or a boronic ester radical, for example 4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl, and X is a (CH2)p-U moiety in which U may be defined as Cl, Br, I, O—SO2—C6H4-4-CH3, O—SO2—CH3 or O—SO2—CF3, with an amino acid ester of the formula E in which R and R′ are each as defined in formula I, under alkylating conditions. Alternatively, the compound of the formula C can be obtained by reductive amination of the aldehyde D (Z and Y as described above, but with the proviso that the aldehyde function there is protected as, for example, the acetal and X═(CH2)p—CHO) with the amino acid derivative E. The urea F can be ring-closed under basic or acidic conditions, preferably acidic conditions, to give the imidazolidine-2,4-dione of the formula G. A carboxylic ester radical —COOR where R is, for example, methyl, an aldehyde radical —CHO or a protected hydroxymethyl radical —CH—OR where R is, for example, acetyl or benzyl, in the compounds of the formula G, can be converted by standard reactions to a —CH2-halogen function, preferably —CH2—Br function. According to whether Y in the compound of the formula G is —CH2—Br or boronic acid (boronic ester), reaction with compounds of the formula O in which W is either boronic acid (boronic ester) or —CH2—Br, under Suzuki conditions, can prepare compounds of the formula H.
Any protecting groups present in the compound H can be removed at the end.
The formula H shown here constitutes a special case of the formula I in which the Y″—R19 radical in formula I is in the ortho position; this radical may correspondingly also be in the meta or para position.
Compounds in which Q1/Q2 is not H can be prepared in an analogous manner.
In a further method (method “C”),
p-methoxybenzyl isocyanate B′ is reacted with an amino acid ester, for example E in which R and R′ are each as defined in formula I, under basic conditions to give the urea K′. The urea K′ can be ring-closed under basic or acidic conditions, preferably acidic conditions, to give the imidazolidine-2,4-dione of the formula L′. The compounds M′ are obtained by reacting the compounds L′ with the compounds Q under alkylating conditions. Z, V and Y of the compounds Q are each defined as specified in method “A”. The p-methoxybenzyl group in the compounds M′ can be eliminated oxidatively to obtain the compounds T. The N-arylation of the imide nitrogen atom in compounds of the formula T using arylboronic acids of the formula S by processes as described, for example, in J.-B. Lan et al.: SYNLETT 2004, 1095-1097 or D. M. T. Chan et al.: Tetrahedron Lett. 1998, 39, 2933-2936, affords compounds of the formula G′. After conversion by means of standard reactions of the Y radical to a Y′ radical defined as —CH2—O—P(O)(Oethyl)2 or —CH2-halogen, preferably —CH2—Br, the compounds of the formula H can be obtained by reaction with compounds of the formula O in which W is either a boronic acid radical —B(OH)2 or a boronic ester radical, for example 4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl.
Any protecting groups present in the compound H can be removed at the end.
The formula H shown here constitutes a special case of the formula I in which the Y″—R19 radical in formula I is in the ortho position; this radical may correspondingly also be in the meta or para position.
Compounds in which Q1/Q2 is not H can be prepared in an analogous manner.
A further method (“method D”) is especially, but not exclusively, suitable for the preparation of compounds in which Y″ is C═O, i.e. Q1 and Q2 in the description of the R6-R10 radicals together are a double-bonded oxygen atom (═O):
In method “D”, the procedure may be to alkylate a suitably substituted imidazolidine-2,4-dione of the formula L with a suitably substituted compound Q′ where Z may be one or more substituents as described above in formula I, and Y is either a carboxylic ester radical —COOR where R is, for example, methyl or a halogen atom (e.g. bromine or iodine), and V is either a halogen atom, preferably a chlorine or bromine atom, or else, for example, an O—SO2—C6H4-4-CH3 radical or an O—SO2—CH3 radical or an O—SO2—CF3 radical, to obtain the compound M′. After conversion by means of standard reactions of the Y radical to a Y′ radical defined as —COCl (carbonyl chloride, prepared from the ester) or 4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl (prepared, for example, from the halide), M′ can be reacted further under Suzuki cross-coupling conditions (e.g.: M. Haddach et al.: Tetrahedron Letters 44 (2003) 271-273) with (hetero)arylboronic acids or (hetero)arylboronic esters or with (hetero)arylcarbonyl chlorides to give compounds of the formula H′. W in R19-W of the formula O, for example, is defined, respectively, as —B(OH)2 or 4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl, and —COCl.
The compound L can also be converted to the compound H′ in such a way that L is reacted under alkylating conditions with a compound of the formula N′ where V may be defined as outlined above, and where Y2 is defined as C═O (carbonyl). The compound N′ in turn can be obtained by reaction of P′ in which V′ is either a carboxylic ester function —COOalkyl, which can be converted by means of standard reactions to a suitably protected hydroxyalkyl function and further to a —CH2-halogen, preferably —CH2—Br, function, or in which V′ is a hydrogen atom and the methyl group can be converted by means of standard reactions, for example, to a —CH2—Br function, and where Y1 is —B(OH)2 or 4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl, with a possibly substituted R19-W compound O under Suzuki cross-coupling conditions. W here is defined as —COCl when Y1 is defined as —B(OH)2 or 4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl. Or else W is defined as —B(OH)2 or 4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl when Y1 is defined as —COCl. The protected hydroxyl function V′ can be converted by standard reactions to the function V with the definitions described above. Any protecting groups present in the compound H can be removed at the end of the reaction sequence.
The formula H shown here constitutes a special case of the formula I in which the Y″—R19 radical where Y″ is C═O in formula I is in the ortho position; this radical may correspondingly also be in the meta or para position.
Compounds of the formula N′ in which Y2 is C═O can also be obtained by Friedel-Crafts acylation of the compounds of the formula P′ in which Y1 is hydrogen with a compound of the formula R19-W in which W is carbonyl chloride (COCl). The reaction can also be conducted in such a way that compounds of the formula P′ in which Y1 is COCl are reacted with compounds of the formula R19-W in which W is hydrogen.
Compounds of the formula H′ in which Y″ is CHOH, i.e. Q1 and Q2 in the description of the R6-R10 radicals are each hydrogen (H) and hydroxyl (OH), can be obtained, for example, by reduction of the keto function of the compounds prepared, for example, by method “D”. Compounds of this kind can also be prepared by reacting compounds of the formula L under alkylating conditions with a compound of the formula N′ where V may be defined as outlined above, and where Y2 is defined as CHOQ3. Q3 here is a protecting group for the alcohol function. Suitable protecting groups are, for example, acyl groups such as acetyl or benzoyl, or alkyl groups such as methyl, isopropyl or tert-butyl, or benzyl groups such as p-methoxybenzyl. These protecting groups can be eliminated again on completion of reaction to obtain the hydroxyl function.
Compounds of the formula H′ in which Y″ is CHOR18, CHO—CO—OR18 or CHO—CO—R18, i.e. Q1 and Q2 in the description of the R6-R10 radicals are each hydrogen (H) and OR18, O—CO—OR18 or O—CO—R18, can be obtained, for example, by alkylation, alkoxyacylation or acylation of the corresponding alcohol, or constitute an intermediate, as described above, in the preparation of the alcohols.
Compounds of the formula H′ in which Y″ is COHR18, i.e. Q1 and Q2 in the description of the R6-R10 radicals are each hydroxyl (OH) and R18, can be obtained, for example, by reaction of the ketone by means of standard reactions, for example with a Grignard reagent such as methylmagnesium bromide.
Compounds of the formula H′ in which Y″ is CHF or CFR18, i.e. Q1 and Q2 in the description of the R6-R10 radicals are each hydrogen (H) and fluorine (F) or fluorine (F) and R18, can be obtained, for example, by reaction of the corresponding alcohols with DAST (diethylaminosulfur trifluoride) or BAST ([bis(2-methoxyethyl)amino]sulfur trifluoride).
Compounds of the formula H′ in which Y″ is CF2, i.e. Q1 and Q2 in the description of the R6-R10 radicals are both fluorine (F), can be obtained, for example, by reaction of the corresponding ketones with DAST (diethylaminosulfur trifluoride) or BAST ([bis(2-methoxyethyl)amino]sulfur trifluoride).
Compounds of the formula H′ in which Y″ is C(R18)2, i.e. Q1 and Q2 in the description of the R6-R10 radicals are both an R18 radical, e.g. methyl (CH3), can be obtained, for example, by reaction of the corresponding ketones with trimethylaluminum (J. Furukawa et al.: J. Chem. Soc. Chem. Commun. 1974, 77) or with dimethyltitanium dichloride.
Compounds of the formula H′ in which Y″ is CHNH2, CHNR18 or CHN(R18)2, i.e. Q1 and Q2 in the description of the R6-R10 radicals are hydrogen (H) and amino (NH2), substituted amino (NHR18) or disubstituted amino (N(R18)2), can be obtained, for example, by reductive amination of the corresponding ketones with ammonia, primary or secondary amines under standard conditions.
Compounds of the formula H′ in which Y″ is CHNHCOR18, i.e. Q1 and Q2 in the description of the R6-R10 radicals are hydrogen (H) and acylamino (NHCOR18), can be obtained by means of standard methods by acylating the corresponding amines.
Compounds of the formula H′ in which Q1 and Q2 in the description of the R6-R10 radicals, together with the carbon atom to which they are bonded form a carbocycle, can be obtained from the corresponding ketones, for example, by means of a Wittig reaction (three-membered ring) or by means of reaction with N,N-diisopropyl-N-benzylamine and titanium tetrachloride (four-membered ring).
The examples which follow serve to illustrate the invention in detail, without limiting it to the products and embodiments described in the examples.
The 1H NMR spectra were measured in deuterated dimethyl sulfoxide on a 500 MHz instrument (Bruker DRX 500) or on a 400 MHz instrument (Bruker DRX 400) at 300 K. Data: δ in ppm, multiplicity (s for singlet, d for doublet, t for triplet, q for quartet, m for multiplet, x H (number of hydrogen atoms))
The HPLC-MS analyses were carried out on an LCT instrument from Waters. Column: YMC Jshere 33×2 4 μm; gradient [A]: (acetonitrile+0.05% trifluoroacetic acid):(water+0.05% trifluoroacetic acid) 5:95 (0 minutes) to 95:5 (3 minutes); gradient [B]: (acetonitrile+0.05% trifluoroacetic acid):(water+0.05% trifluoroacetic acid) 5:95 (0 minutes) to 95:5 (2.5 minutes) to 95:5 (3.0 minutes); gradient [C]: (acetonitrile+0.05% trifluoroacetic acid):(water+0.05% trifluoroacetic acid) 5:95 (0 minutes) to 95:5 (3.4 minutes) to 95:5 (4.4 minutes); detector: Tecan-LCT.
[RP1]: flow rate: 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 rate: 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).
Compound 1.2 can be prepared by method “B”. To this end, 9 g (45.99 mmol) of tert-butyl 2-amino-2-methylpropionate hydrochloride were suspended at room temperature in 120 ml of dichloroethane and admixed while stiffing with 6.41 ml (45.99 mmol) of triethylamine. The mixture was stirred for 15 min. Thereafter, 11.07 g of magnesium sulfate and 9.026 g (45.99 mmol) of 2-benzylbenzaldehyde were added and the mixture was stirred under reflux for 8 h; subsequently, the mixture stood at room temperature overnight. For workup, the reaction mixture was filtered and the filtrate was extracted by shaking first with water and then with saturated sodium chloride solution. The organic phase was removed, dried over magnesium sulfate, filtered and concentrated under reduced pressure. This afforded 15.5 g (quantitative) of tert-butyl 2-{[1-(2-benzylphenyl)methylidene]amino}-2-methylpropionate 1.2. 1H NMR: 8.55, s, 1H, 7.8, d, 1H, 7.4-7.1, m, 8H, 4.28, s, 2H, 1.35, s, 9H, 1.3, s, 6H. Molecular weight 337.20 (C22H27NO2); retention time Rt=1.76 min. [B]; MS(ESI): 338.31 (MH+).
15.5 g (45.93 mmol) of the imine 1.2 were dissolved in a mixture of 80 ml of dichloromethane and 80 ml of methanol at room temperature and admixed with 244 mg of palladium on carbon (10% Pd/C) and hydrogenated at 5 bar of hydrogen pressure. For workup, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (silica gel, n-heptane/ethyl acetate=5/1). The product-containing fractions were concentrated under reduced pressure. This afforded 13.76 g (88% yield) of compound 1.1. 1H NMR: 7.35-7.1, m, 9H, 4.08, s, 2H, 3.6, d, 2H, 2.0, s (broad), 1H, 1.4, s, 9H, 1.2, s, 6H. Molecular weight 339.21 (C22H29NO2); retention time Rt=1.53 min. [B]; MS(ESI): 340.23 (MH+).
To 0.15 mmol of the amino ester 1.1 in 2 ml of dry acetonitrile was added 0.165 mmol of 1-ethyl-3-isocyanatobenzene. The mixture was stirred with exclusion of moisture at room temperature overnight. Thereafter, 0.1 ml of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for a further 3 h until completion of conversion (ring closure). The solvent was removed under reduced pressure; the residue was dissolved in 2 ml of dimethylformamide, filtered through a syringe filter and purified by means of preparative HPLC. This afforded the compound of example 1 in a yield of 78%. 1H NMR: 7.4-7.15, m, 13H, 4.55, s, 2H, 4.1, s, 2H; 2.65, q, 2H, 1.22, t, 3H, 1.18, s, 6H. Molecular weight 412.21 (C27H28N2O2); retention time Rt=2.30 min. [B]; MS(ESI): 413.19 (MH+).
The compounds of examples 2-87 (see table 1) were prepared in an analogous manner, by reacting compound 1.1 with the appropriate isocyanates.
For obtaining the compound of example 2 1-(3-isocyanatophenyl)ethanone was used,
1H NMR
Alternatively, compound 88 can be prepared by in situ generation of the isocyanate required from 4-amino-2-trifluoromethylbenzonitrile:
1.47 g (7.9 mmol) of 4-amino-2-trifluoromethylbenzonitrile were dissolved in 20 ml of dry acetonitrile. This solution was added dropwise with stiffing to a 20% solution, heated to 70° C., of phosgene in toluene and then the mixture was stirred for 1 h. The cooled reaction solution was concentrated under reduced pressure, and the residue was taken up with toluene and concentrated again under reduced pressure. Finally, the residue was dissolved in acetonitrile and reacted with the amino acid ester 1.1 as described in example 1, step 3, to give 4-[3-(2-benzylbenzyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-trifluoro-methylbenzonitrile.
The compound of example 88 can be prepared by a further method, by alkylation of the previously prepared imidazolidine-2,4-dione 88.1:
Compound 88.1 can be prepared by method “A”. To this end, 1.47 g (7.92 mmol) of 4-amino-2-trifluoromethylbenzonitrile were dissolved in 20 ml of dry acetonitrile. This solution was added dropwise with stirring to a 20% solution, heated to 70° C., of phosgene in toluene and then stirred for 1 h. The cooled reaction solution was concentrated under reduced pressure, and the residue was taken up with toluene and concentrated again under reduced pressure. Finally, the residue was dissolved in 15 ml of dry acetonitrile and the solution was admixed while stirring with 1.55 g (7.92 mmol) of tert-butyl 2-amino-2-methylpropionate hydrochloride. To this reaction mixture were slowly added dropwise 1.20 g (11.88 mmol) of triethylamine, and the mixture was then stirred at room temperature for 45 min. Thereafter, the mixture was admixed cautiously with 5 ml of concentrated hydrochloric acid and stirred at 70° C. for 1 h. The cooled reaction mixture was concentrated under reduced pressure and the residue was admixed with ethyl acetate and water. The organic phase was removed, washed with saturated sodium hydrogencarbonate solution and then with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography using silica gel with 2:1 heptane/ethyl acetate. This afforded 2.12 g (90% yield) of 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-trifluoromethylbenzonitrile 88.1 with melting point 208-211° C.
2.84 g (10.86 mmol) of triphenylphosphine and 0.88 g (12.93 mmol) of imidazole were dissolved in 25 ml of dichloromethane and admixed dropwise at 5° C. with a solution of 1.736 g (0.558 ml; 10.86 mmol) of bromine in 5 ml of dichloromethane. After the reaction mixture had been stirred at 5° C. for 10 min, a solution of 2.05 g (10.34 mmol) of 2-benzylbenzyl alcohol in 20 ml of dichloromethane was added dropwise. The mixture was stirred at 5° C. for 2 h and stood at room temperature overnight. The mixture was admixed with 25 ml of 1 N hydrochloric acid; the organic phase was removed; dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel; 3:1 n-heptane/ethyl acetate). This afforded 1-benzyl-2-bromomethylbenzene in 71% yield. 1H NMR: 7.42-7.1, m, 9H, 4.7, s, 2H, 4.1, s, 2H.
0.75 g (2.52 mmol) of compound 88.1 are dissolved with 0.791 g (3.02 mmol) of compound 88.2 in 20 ml of dry acetonitrile, admixed with 0.822 g of cesium carbonate and stirred at room temperature for 4 h. For workup, the reaction mixture is admixed with ethyl acetate and water; the organic phase is removed, dried over magnesium sulfate, filtered and dried under reduced pressure. The purification was effected by method [RP1]. The product-containing fractions were combined, and the acetonitrile was removed under reduced pressure. The aqueous residue was neutralized by addition of sodium hydrogencarbonate solution and extracted twice with dichloromethane. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. This afforded 1.13 g (94% yield) of 4-[3-(2-benzylbenzyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-trifluoromethyl-benzonitrile 88. Molecular weight 477.16 (C24H22F3N3O2); retention time Rt=2.68 min. [B]; MS(ESI): 478.41 (MH+). 1H NMR: 8.32, d, 2H, 8.2, s, 1H, 8.08, d, 2H, 7.6, d, 1H, 7.31-7.16, m, 8H, 4.55, s, 2H, 4.1, s, 2H, 1.2, s, 6H.
Compound 89.1 was prepared like compound 88.1, with the difference that 1,3-difluoro-2-isocyanatobenzene was used in place of the 4-isocyanato-2-trifluoromethylbenzonitrile obtained in situ. This afforded 3-(2,6-difluorophenyl)-5,5-dimethylimidazolidine-2,4-dione; 1H NMR: 8.85, s, 1H, 7.63, p, 1H, 7.35, t, 2H, 1.42, s, 6H.
Analogously to the procedure as described in the preparation of 88, step 3, compound 89.1 was reacted with 1-benzyl-2-bromomethylbenzene. This afforded 1-(2-benzylbenzyl)-3-(2,6-difluorophenyl)-5,5-dimethylimidazolidine-2,4-dione 89 in a yield of 86%. Molecular weight 420.16 (C25H22F3N2O2); retention time Rt=2.73 min [C]; MS(ESI): 421.29 (MH+).
Reaction of 2,6-dichloro-4-isocyanatopyridine with tert-butyl 2-amino-2-methylpropionate hydrochloride with triethylamine in tetrahydrofuran by method “A” afforded 3-(2,6-dichloropyridin-4-yl)-5,5-dimethylimidazolidine-2,4-dione. Molecular weight 273.00 (C10H9ClN3O2); retention time Rt=1.48 min. [B]; MS(ESI): 274.03 (MH+).
Analogously to the procedure as described in the preparation of 88, step 3, compound 90.1 was reacted with 1-benzyl-2-bromomethylbenzene. This afforded 1-(2-benzylbenzyl)-3-(2,6-dichloropyridin-4-yl)-5,5-dimethylimidazolidine-2,4-dione 90 in a yield of 88%. Molecular weight 453.10 (C24H21Cl2N3O2); retention time Rt=2.43 min. [B]; MS(ESI): 454.14 (MH+).
1H NMR: 8.73, s, 1H; 7.8, d, 2H; 7.7, d, 2H; 7.3-6.9, m, 18H; 4.27, s, 4H; 3.85, s, 4H; 1.45, s, 6H
1H NMR: 7.5-7.08, m, 17H; 4.55, s, 2H; 4.1, s, 2H; 1.18, s, 6H
1H NMR: 8.41, s, 1H; 8.35, d, 1H; 8.09, d, 1H; 7.41, d, 1H; 7.31-7.16, m, 8H; 4.55, s, 2H; 4.1, s, 2H; 1.2, s, 6H
1H NMR: 8.3, d, 1H; 8.22, s, 1H; 8.08, d, 1H; 7.4-7.15, m, 9H; 4.52, s, 2H; 4.1, s, 2H; 2.0, m, 2H; 1.61, m, 4H; 1.35, m, 2H
1H NMR: 8.3, d, 1H; 8.2, s, 1H; 8.02, d, 1H; 7.35-7.15, m, 9H; 4.7, s, 2H; 4.15, s, 2H; 2.2, m, 4H; 1.85, m, 1H; 1.4, m, 1H
1H NMR: 8.3, d, 1H; 7.62, d, 1H; 7.58, s, 1H; 7.4-7.2, m, 11H; 4.5, dd, 2H; 4.2, t, 2H; 3.0, dd, 2H; 1.3, s, 6H
1H NMR: 8.3, d, 1H; 8.22, s, 1H; 8.08, d, 1H; 7.4-7.15, m, 9H; 4.5, s, 2H; 4.1, s, 2H; 1.8, m, 4H; 1.5, m, 3H; 1.25, m, 2H; 0.9, m, 1H
The compounds of the examples in table 2 were prepared in an analogous procedure by method “A” by reaction of 1-benzyl-2-bromomethylbenzene 88.1 with the appropriate imidazolidine-2,4-diones;
The imidazolidine-2,4-diones were, as described for the preparation of 88.1, prepared from the correspondingly substituted anilines.
Thus, for the preparation of 91.1 4-aminobenzenesulfonamide was used,
2 g (8 mmol) of 3-nitropentafluorosulfanylbenzene (CAS # 2613-26-5) were dissolved in 20 ml of ethanol, admixed with 0.1 g of palladium on carbon (10%) and hydrogenated at 5.5 bar until the uptake of hydrogen had ended. Subsequently, the reaction mixture was filtered and concentrated under reduced pressure. Molecular weight 219.01 (C6H6F5NS); retention time Rt=1.74 min [C]; MS(ESI): 261.07 (MH++CH3CN).
1.5 g (6.84 mmol) of 3-pentafluorosulfanylphenylamine 102.8 were suspended with 1.01 g (6.84 mmol) of phthalic anhydride in 4 ml of acetic acid and boiled under reflux for 2 h. The cooled reaction mixture was admixed with 40 ml of water, treated in an ultrasound bath for 30 min and filtered. The residue was washed with water and then with a little ethanol and dried under reduced pressure. This afforded 2-(3-pentafluorosulfanylphenyl)isoindole-1,3-dione 102.7 with melting point 188-190° C.
1 g (2.863 mmol) of 2-(3-pentafluorosulfanylphenyl)isoindole-1,3-dione 102.7 was dissolved at 0° C. in 3.29 ml of concentrated nitric acid, and the mixture was stirred at 0° C. for 2 h. Thereafter, the mixture was left to stand at room temperature overnight. The reaction solution was added to 50 g of ice-water and the mixture was stirred for 1 h; then the precipitate was filtered off with suction, washed with water, dried and purified by chromatography using silica gel with toluene as the eluent. This afforded 2-(4-nitro-3-pentafluorosulfanylphenyl)isoindole-1,3-dione 102.5 with melting point 200-203° C. and 2-(2-nitro-5-pentafluorosulfanylphenyl)isoindole-1,3-dione 102.6 with melting point 175-177° C. in a ratio of 1:2.
1.94 g (4.92 mmol) of 2-(4-nitro-3-pentafluorosulfanylphenyl)-isoindole-1,3-dione 102.5 were dissolved in 20 ml of methanol, admixed with 53 mg of 10% palladium on activated carbon and hydrogenated at room temperature at a hydrogen pressure of 5 bar. After the reaction had ended, the catalyst was filtered off and the filtrate was concentrated. The residue was stirred in a mixture of dichloromethane and n-heptane, filtered off with suction and dried under reduced pressure. This afforded 2-(4-amino-3-pentafluorosulfanylphenyl)isoindole-1,3-dione 102.4 with melting point 176-178° C.
To a solution of 1 g (2.74 mmol) of 2-(4-amino-3-pentafluorosulfanyl-phenyl)isoindole-1,3-dione 102.4 in acetic acid was slowly added dropwise at 0° C. 0.46 ml (8.24 mmol) of semiconcentrated sulfuric acid. The mixture was stirred at 0° C. for 10 min; then a solution of 189.4 mg of sodium nitrite in 2 ml of water was slowly added dropwise with stirring, and the resulting solution was stirred at 0° C. for 30 min. This solution was finally added dropwise to a solution, cooled to 0° C., of 246 mg (2.74 mmol) of copper(I) cyanide and 536 mg (8.23 mmol) of potassium cyanide in 5 ml of water. The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for another 3 h. After the reaction had ended, the mixture was added to water and the aqueous phase was extracted by shaking twice with ethyl acetate. The organic phase was dried over magnesium sulfate and filtered, the filtrate was concentrated and the residue was purified by chromatography using silica gel, first with toluene and then with 20/1 toluene/ethyl acetate. This afforded 4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-pentafluorosulfanylbenzonitrile 102.3. 1H NMR: 8.4, m, 2H, 8.1-7.95, m, 5H.
610 mg (1.63 mmol) of 4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-pentafluorosulfanylbenzonitrile 102.3 were dissolved in 30 ml of ethanol and admixed with 100 mg (1.956 mmol) of hydrazine hydrate (100%). The mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography (preparative HPLC; Purospher STAR RP-18e (10 μm); eluent: acetonitrile/water (0.5% trifluoroacetic acid) 5/95→95/5 145 min 1). This afforded 4-amino-2-pentafluorosulfanylbenzonitrile 102.2 (1H NMR: 7.65, s, 1H, 7.2, s, 1H, 6.8, m, 3H) and N-(4-cyano-3-pentafluorosulfanylphenyl)-phthalamide ethyl ester 102.2a (1H NMR: 11.3, s, 1H, 8.6, s, 1H, 8.2, d, 1H, 8.1, d, 1H, 7.95, d, 1H, 7.75, m, 1H, 7.7, m, 2H, 4.2, q, 2H, 1.15, t, 3H).
505 mg of the amine 102.2 and 227.1 mg of triphosgene were dissolved in 15 ml of dry tetrahydrofuran. At 0° C., 0.864 ml of triethylamine in 2.5 ml of tetrahydrofuran was added dropwise over 30 minutes and then the mixture was stirred at 5° C. for a further 10 minutes. 404.7 mg of the hydrochloride of tert-butyl 2-amino-2-methylpropionate were added, and the mixture was allowed to warm to room temperature and was stirred at room temperature for 2 h. The reaction mixture was admixed with 2.5 ml of concentrated hydrochloric acid and stirred at room temperature for a further 2 h. For workup, the mixture was admixed with water and ethyl acetate, and the organic phase was removed, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The chromatographic purification was effected by method [RP1]. The product-containing fractions were concentrated under reduced pressure, the residue was extracted by shaking repeatedly with dichloromethane, and the organic phase was dried over magnesium sulfate and concentrated under reduced pressure. This afforded 102.1 in 41% yield. 1H NMR: 8.85, s, 1H, 8.4, s, 1H, 8.3, d, 1H, 8.02, d, 1H, 1.4, s, 6H.
5.3 ml of phosgene solution (20% in toluene) were initially charged under an argon atmosphere. At 75° C., a solution of 4-cyano-3-trifluoromethylaniline in 15 ml of dry acetonitrile was slowly added dropwise. After the addition had ended, the mixture was stirred at 75° C. for another 90 min. The mixture was concentrated under reduced pressure. The residue was then repeatedly taken up in toluene and concentrated again under reduced pressure. Finally, the residue was dissolved in 15 ml of dry tetrahydrofuran and admixed with 0.72 g of 1-amino-1-cyclohexanecarboxylic acid and dropwise with 1.05 ml of triethylamine, and the mixture was stirred at room temperature for 2 h. After standing at room temperature overnight, the reaction mixture was admixed with 5 ml of concentrated hydrochloric acid and stirred under reflux for 2 h. The cooled reaction mixture was admixed with saturated sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. This afforded 0.62 g of 4-(2,4-dioxo-1,3-diazaspiro[4.5]dec-3-yl)-2-trifluoromethylbenzonitrile (114.1). 1H NMR: 9.21, s, 1H, 8.30, d, 1H, 8.19, s, 1H, 8.02, d, 1H, 1.8-1.5, m, 9H, 1.4-1.25, m, 1H.
Converted in the same way, methyl 1-amino-1-cyclopentanecarboxylate afforded compound 106.1; methyl 1-amino-1-cyclobutanecarboxylate afforded compound 107.1; methyl 1-amino-1-cycloheptanecarboxylate afforded compound 116.1; ethyl 2-amino-3-(4-chlorophenyl)-2-methylpropionate afforded compound 109.1.
The reaction of mono-tert-butyl 4-aminopiperidine-1,4-dicarboxylate with phosgene and 4-cyano-3-trifluoromethylaniline, as described above for the preparation of 114.1, afforded 4-(2,4-dioxo-1,3,8-triazaspiro[4.5]dec-3-yl)-2-trifluoromethylbenzonitrile 112.1. Molecular weight 338.09 (C15H13F3N4O2); retention time Rt=1.22 min. [B]; MS(ESI): 339.45 (MH+).
112.1 was reacted by standard methods with tert-butoxycarbonyloxysuccinimide to obtain 112.2. 1H NMR: 9.31, s, 1H, 8.30, d, 1H, 8.19, s, 1H, 8.02, d, 1H, 3.82, d (broad), 2H, 3.2, s (broad), 2H, 1.8, m, 4H, 1.4, s, 9H.
The reaction of 112.1 with methyl iodide and cesium carbonate in dimethylformamide afforded, in addition to the bismethyl derivative 4-(1,8-dimethyl-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-3-yl)-2-trifluoro-methylbenzonitrile 111.2 (1H NMR: 8.35, d, 1H, 8.19, s, 1H, 8.02, d, 1H, 3.7, m, 4H, 3.22, s, 3H, 3.18, s, 3H, 2.28, m, 4H), the desired monomethyl derivative 4-(8-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-3-yl)-2-trifluoromethylbenzonitrile 111.1. Molecular weight 352.11 (C16H15F3N4O2); retention time Rt=1.17 min. [B]; MS(ESI): 353.42 (MH+).
0.93 g of 4-cyano-3-trifluoromethylaniline was dissolved at room temperature in 25 ml of dry dichloromethane and admixed dropwise with 0.44 ml of chloroacetyl chloride. Thereafter, the mixture was admixed dropwise while stirring with 0.77 ml of triethylamine. After stirring at room temperature for 4 h, the reaction mixture was diluted with dichloromethane and washed successively with water and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was stirred with diisopropyl ether, filtered off with suction, washed with diisopropyl ether and dried. This afforded 115.3 in 70% yield. 1H NMR: 11.1, s, 1H, 8.25, s, 1H, 8.12, d, 1H, 8.0, d, 1H, 4.35, s, 2H.
0.96 g of compound 115.3 was admixed at room temperature with 10.4 ml of a 7 molar solution of ammonia in methanol and left to stand for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in dichloromethane, filtered off with suction, washed with dichloromethane and dried. For further purification, the mixture was stirred with ethyl acetate, filtered off with suction and dried again. Molecular weight 243.06 (C10H8F3N3O); retention time Rt=0.93 min. [B]; MS(ESI): 244.28 (MH+).
0.11 g of compound 115.2 was dissolved in 10 ml of dry tetrahydrofuran, admixed with 1-benzyl-2-bromomethylbenzene and 0.18 ml of diisopropylethylamine and left to stand at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure; the residue was taken up in water and the aqueous phase was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The purification was effected by chromatography by method [RP1]. Molecular weight 423.15 (C24H20F3N3O); retention time Rt=1.72 min. [B]; MS(ESI): 424.49 (MH+).
The reaction of compound 115.1 with phosgene (20% in toluene) in dichloromethane afforded 115. 1H NMR: 8.31, d, 1H, 8.08, s, 1H, 7.93, s, 1H, 4.59, s, 2H, 4.1, s, 2H, 3.85, s, 2H.
5.3 ml of a 20% solution of phosgene in toluene were initially charged under an argon atmosphere and admixed dropwise at 75° C. with a solution of 1 g of 4-amino-2-trifluoromethylbenzonitrile in 25 ml of dry acetonitrile; then the mixture was stirred at 75° C. for 2 h. The reaction mixture was concentrated under reduced pressure, taken up in toluene and concentrated again. The residue was dissolved in 20 ml of tetrahydrofuran and admixed with 1 g of methyl 2-aminophenylacetate hydrochloride. To this mixture were slowly added dropwise 1.05 ml of triethylamine with stirring and the reaction mixture was then stirred at room temperature for 8 h. Finally, 5 ml of concentrated hydrochloric acid were added and the mixture was heated under reflux for 8 h. Thereafter, the cooled reaction mixture was admixed cautiously with saturated sodium hydrogencarbonate solution. The mixture was extracted with ethyl acetate; the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography (method [RP1]). This afforded 120.1; molecular weight 345.07 (C17H10F3N3O2); retention time Rt=2.04 min. [B]; MS(ES−): 344.51 (M-H+).
2) Analogously to the procedure as described in the preparation of 88, step 3, compound 120.1 was reacted with 1-benzyl-2-bromomethylbenzene 88.2. This afforded 4-[3-(2-benzylbenzyl)-2,5-dioxo-4-phenylimidazolidin-1-yl]-2-trifluoromethylbenzonitrile 120 (see table 2).
Under an argon atmosphere, 1 g of 5,5-dimethylhydantoin, 1.343 g of 4-methoxybenzyl chloride and 1.618 g of potassium carbonate were combined and admixed with 10 ml of dry acetonitrile. The mixture was stirred at room temperature for 8 h. For workup, the reaction mixture was admixed with ethyl acetate and water; the organic phase was removed, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The chromatographic purification was effected with method [RP1]. This afforded 3-(4-methoxybenzyl)-5,5-dimethylimidazolidine-2,4-dione 122.3 in a yield of 93%. Molecular weight 248.11 (C13H16N2O3); retention time Rt=1.58 min. [B]; MS (ES): 247.47 (M-FE).
700 mg of compound 122.3 were dissolved in 7 ml of dry acetonitrile, admixed with 1.148 g of cesium carbonate and 773 mg of compound 88.2 and stirred at 75° C. for 6 h. For workup, the cooled reaction mixture was admixed with ethyl acetate and water. The organic phase was removed, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography using silica gel with 3/1 n-heptane/ethyl acetate. This afforded 122.2 in 67% yield. Molecular weight 428.21 (C27H28N2O3); retention time Rt=2.21 min. [B]; MS(ESI): 429.26 (MH+).
810 mg of compound 122.2 were dissolved in 50 ml of acetonitrile and admixed with 4.145 g of cerium(IV) ammonium nitrate and 12 ml of water. The mixture was stirred at room temperature for 3 h. Subsequently, the acetonitrile was removed by distillation, and the residue was admixed with 50 ml of saturated sodium chloride solution and then extracted three times with 50 ml each time of ethyl acetate. The organic phase was washed successively with saturated sodium hydrogencarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The chromatographic purification was effected using silica gel with 3/1 n-heptane/ethyl acetate. This afforded 122.1 in a yield of 79%. Molecular weight 308.15 (C19H20N2O2); retention time Rt=1.72 min. [B]; MS (ESI): 309.19 (MH+).
Under an argon atmosphere, 200 mg of compound 122.1 were combined with 260 mg of [(4-methylsulfonyl)phenyl]boronic acid, 177 mg of copper(II) acetate, 0.106 ml of pyridine and 6 ml of dichloromethane, admixed with a little 4A molecular sieve and stirred at room temperature for 24 h. Thereafter, the reaction mixture was admixed with ammoniacal ammonium chloride solution; the organic phase was removed, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography (method [RP1]). This afforded 1-(2-benzylbenzyl)-3-(4-methanesulfonylphenyl)-5,5-dimethylimidazolidine-2,4-dione 122. Molecular weight 462.16 (C26H26N2O4S); retention time Rt=2.58 min. [B]; MS(ESI): 463.23 (MH+).
The compounds of the examples in table 3
were prepared in an analogous procedure by reaction of 1-(2-benzylbenzyl)-5,5-dimethylimidazolidine-2,4-dione 122.1 with the appropriate boronic acids or boronic esters;
The carboxylic acid of example 130 was obtained by hydrolysis of the ester 128 by means of hydrobromic acid in glacial acetic acid (33%):
74 mg of compound 88.1 were dissolved at room temperature in 2 ml of dry dimethylformamide, admixed with 76 mg of 4-(bromomethyl)-benzophenone and 90 mg of cesium carbonate and stirred at 80° C. for 4 h. The reaction mixture was filtered and purified by chromatography (method [RP1]). This afforded 4-[3-(4-benzoylbenzyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile 132. Molecular weight: 491.14 (C27H20F3N3O3); retention time Rt=2.63 min. [C]; MS(ESI): 492.28 (MH+).
0.2 g of methyl terephthaloyl chloride and 0.14 g of o-tolylboronic acid were admixed at room temperature with 29 mg of tetrakis-(triphenylphosphine)palladium(0), Pd(PPh3)4, and 0.98 g of cesium carbonate. Under an argon atmosphere, 10 ml of dry toluene were added and the mixture was stirred at 100° C. for 8 h. The cooled reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was taken up in diisopropyl ether, stirred, filtered and concentrated again under reduced pressure. This afforded methyl 4-(2-methylbenzoyl)benzoate 133.3. The compound was used in the next stage without any further purification.
0.18 g of compound 133.3 were dissolved at room temperature in 10 ml of dry tetrachloromethane, admixed with 0.14 g of N-bromosuccinimide and 12 mg of azodiisobutyronitrile and stirred at 80° C. for 2 h. The cooled reaction mixture was filtered; the filtrate was diluted with dichloromethane and then washed with water, 1 molar sodium sulfite solution and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Chromatographic purification (silica gel; 85/15 n-heptane/ethyl acetate) afforded methyl 4-(2-bromomethylbenzoyl)benzoate 133.2, which was used in the next stage.
Compound 133.1 can be prepared by method “A”. To this end, 1.5 g (9.76 mmol) of methyl 2-amino-2-methylpropionate hydrochloride were suspended in 20 ml of dry tetrahydrofuran, and admixed with 1.38 ml (9.76 mmol) of triethylamine and 2 g (9.76 mmol) of 1-fluoro-4-isocyanato-2-trifluoromethylbenzene. The mixture was stirred at 70° C. for 1 h; then the mixture was allowed to cool somewhat, 10 ml of concentrated hydrochloric acid were added and the mixture was stirred at 70° C. for 2 h. The cooled reaction mixture was admixed with ethyl acetate and water; the organic phase was removed, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography (method [RP2]) and, after dissolution in ethyl acetate, drying of the solution, concentration under reduced pressure and redissolution in dichloromethane, was crystallized with n-heptane. This afforded 2.8 g of 3-(4-fluoro-3-trifluoromethylphenyl)-5,5-dimethylimidazolidine-2,4-dione (133.1) with melting point 111-114° C. Molecular weight 290.06 (C12H10F4N2O2); retention time Rt=1.55 min. [B]; MS(ESI): 291.27 (MH+).
0.1 g of compound 133.1 in 10 ml of dry acetonitrile was admixed at room temperature with 0.14 g of compound 133.2 and 0.11 g of cesium carbonate and stirred at room temperature for 4 h and then left to stand overnight. The reaction mixture was filtered and concentrated under reduced pressure: The residue was taken up in water and the aqueous phase was extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Chromatographic purification (method [RP1]) afforded methyl 4-{2-[3-(4-fluoro-3-trifluoromethylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-ylmethyl]benzoyl}benzoate 133. Molecular weight 542.14 (C28H22F4N3O5); retention time Rt=2.26 min. [B]; MS(ESI): 543.27 (MH+).
The compounds of examples 134, 137, 139-142, 146-151, 155 and 158 were prepared in an analogous manner:
Thus, methyl 4-(5-fluoro-2-methylbenzoyl)benzoate (134.3; 1H NMR: 8.12, d, 2H, 7.85, d, 2H, 7.44, m, 1H, 7.35, m, 1H, 7.25, m, 1H, 3.9, s, 3H, 2.18, s, 3H) was obtained by reaction of methyl terephthaloyl chloride with 5-fluoro-2-methylphenylboronic acid; this was converted further as described above for 133.2 to methyl 4-(2-bromomethyl-5-fluorobenzoyl)benzoate (134.2; 1H NMR: 8.15, d, 2H, 7.9, d, 2H, 7.74, m, 1H, 7.48, m, 1H, 7.35, m, 1H, 4.74, s, 2H, 3.9, s, 3H), which was then processed further with 133.1 to give 134.
The preparation of the compound of example 137 passed, in an analogous manner, through the sequence of methyl 4-(4-chloro-2-methylbenzoyl)benzoate (137.3, prepared by reaction of methyl terephthaloyl chloride with 4-chloro-2-methylphenylboronic acid; 1H NMR: 8.1, d, 2H, 7.83, d, 2H, 7.51, s, 1H, 6.9, m, 2H, 3.9, s, 3H, 2.27, s, 3H) methyl 4-(2-bromomethyl-4-chlorobenzoyl)benzoate (137.2; was used in the next stage without any further purification)→methyl 4-{4-chloro-2-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-ylmethyl]benzoyl}benzoate (137; by reaction of 137.2 with 88.1).
The compound of example 139 was obtained via the sequence of (4-chlorophenyl)(5-fluoro-2-methylphenyl)methanone (139.3, prepared by reaction of 4-chlorobenzoyl chloride with 5-fluoro-2-methylphenylboronic acid; 1H NMR: 7.74, d, 2H, 7.62, d, 2H, 7.4, m, 1H, 7.32, m, 1H, 7.2, m, 1H, 2.16, s, 3H)→(2-bromomethyl-5-fluorophenyl)(4-chlorophenyl)methanone (139.2; was used in the next stage without any further purification)→4-{3-[2-(4-chlorobenzoyl)-4-fluorobenzyl]-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl}-2-trifluoromethylbenzonitrile (139; by reaction of 139.2 with 88.1).
The compound of example 140 was obtained via the sequence of (4-butoxyphenyl)-(5-fluoro-2-methylphenyl)methanone (140.3, prepared by reaction of 4-butoxybenzoyl chloride with 5-fluoro-2-methylphenylboronic acid; 1H NMR: 7.69, d, 2H, 7.4, m, 1H, 7.3, m, 1H, 7.18, m, 1H, 7.08, d, 2H, 4.1, t, 2H, 2.13, s, 3H, 1.72, m, 2H, 1.42, m, 2H, 0.92, t, 3H)→(2-bromomethyl-5-fluorophenyl)(4-butoxyphenyl)-methanone (140.2; was used in the next stage without any further purification)→4-{3-[2-(4-butoxybenzoyl)-4-fluorobenzyl]-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl}-2-trifluoromethylbenzonitrile (140; by reaction of 140.2 with 88.1).
The compound of example 141 was obtained via the sequence of (4-tert-butylphenyl)-(5-fluoro-2-methylphenyl)methanone (141.3, prepared by reaction of 4-tert-butylbenzoyl chloride with 5-fluoro-2-methylphenylboronic acid; 1H NMR: 7.68, d, 2H, 7.6, d, 2H, 7.4, m, 1H, 7.3, m, 1H, 7.19, m, 1H, 2.15, s, 3H, 1.3, s, 9H)→(2-bromomethyl-5-fluorophenyl)(4-tert-butylphenyl)methanone (141.2; was used in the next stage without any further purification)→4-{3-[2-(4-tert-butylbenzoyl)-4-fluorobenzyl]-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl}-2-trifluoromethylbenzonitrile (141; by reaction of 141.2 with 88.1).
The compound of example 142 was obtained via the sequence of methyl 4-(3-fluoro-2-methylbenzoyl)benzoate (142.3, prepared by reaction of methyl terephthaloyl chloride with 3-fluoro-2-methylphenylboronic acid; 1H NMR: 8.11, d, 2H, 7.86, d, 2H, 7.4, m, 2H, 7.21, m, 1H, 3.9, s, 3H, 2.15, s, 3H)→methyl 4-(2-bromomethyl-3-fluorobenzoyl)benzoate (142.2; was used in the next stage without any further purification)→methyl 4-{2-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-ylmethyl]-3-fluorobenzoyl}benzoate (142; by reaction of 142.2 with 88.1).
The compound of example 146 was obtained via the sequence of biphenyl-4-yl(5-fluoro-2-methylphenyl)methanone (146.3, prepared by reaction of 4-biphenylcarbonyl chloride with 5-fluoro-2-methylphenylboronic acid; 1H NMR: 7.9-7.72, m, 6H, 7.56-7.21, m, 6H, 2.2, s, 3H)→biphenyl-4-yl-(2-bromomethyl-5-fluorophenyl)-methanone (146.2; was used in the next stage without any further purification)→4-{3-[2-(biphenyl-4-carbonyl)-4-fluorobenzyl]-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl}-2-trifluoromethylbenzonitrile (146; by reaction of 146.2 with 88.1).
The compound of example 147 was obtained via the sequence of (5-fluoro-2-methylphenyl)(3-methoxyphenyl)methanone (147.3, prepared by reaction of 3-methoxybenzoyl chloride with 5-fluoro-2-methylphenylboronic acid; 1H NMR: 7.48, m, 2H, 7.4, m, 1H, 7.3, m, 2H, 7.2, m, 2H, 3.8, s, 3H, 2.15, s, 3H) (2-bromomethyl-5-fluorophenyl)(3-methoxyphenyl)methanone (147.2; was used in the next stage without any further purification)→4-{3-[4-fluoro-2-(3-methoxybenzoyl)-benzyl]-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl}-2-trifluoromethylbenzonitrile (147; by reaction of 147.2 with 88.1).
The compound of example 148 was obtained via the sequence of (5-fluoro-2-methylphenyl)(3-trifluoromethylphenyl)methanone (148.3, prepared by reaction of 3-(trifluoromethyl)benzoyl chloride with 5-fluoro-2-methylphenylboronic acid; 1H NMR: 8.09, d, 1H, 8.01, s, 1H, 7.95, d, 1H, 7.8, t, 1H, 7.45, m, 1H, 7.35, m, 1H, 7.28, m, 1H, 2.2, s, 3H)→(2-bromomethyl-5-fluorophenyl)(3-trifluoromethylphenyl)methanone (148.2; was used in the next stage without any further purification)→4-{3-[4-fluoro-2-(3-trifluoromethylbenzoyl)benzyl]-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl}-2-trifluoromethylbenzonitrile (148; by reaction of 148.2 with 88.1).
The compound of example 149 was obtained via the sequence of methyl 4-(3-methyl-benzoyl)benzoate (149.3, prepared by reaction of methyl terephthaloyl chloride with m-tolylboronic acid; 1H NMR: 8.11, d, 2H, 7.83, d, 2H, 7.59, s, 1H, 7.54, m, 2H, 7.48, m, 1H, 3.9, s, 3H, 2.4, s, 3H)→methyl 4-(3-bromomethylbenzoyl)benzoate (149.2; was used in the next stage without any further purification)→4-{3-[4-fluoro-2-(3-trifluoromethylbenzoyl)benzyl]-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl}-2-trifluoromethylbenzonitrile (149; by reaction of 149.2 with 133.1).
The compound of example 150 was obtained via the sequence of 4-(5-fluoro-2-methylbenzoyl)benzonitrile (150.3, prepared by reaction of 4-cyanobenzoyl chloride with 5-fluoro-2-methylphenylboronic acid; 1H NMR: 8.05, d, 2H, 7.87, d, 2H, 7.45, m, 1H, 7.38, m, 1H, 7.27, m, 1H, 2.2, s, 3H)→4-(2-bromomethyl-5-fluorobenzoyl)-benzonitrile (150.2; was used in the next stage without any further purification)→4-{3-[2-(4-cyanobenzoyl)-4-fluorobenzyl]-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl}-2-trifluoromethylbenzonitrile (150; by reaction of 150.2 with 88.1).
The compound of example 151 was obtained via the sequence of methyl 4-(4-methyl-benzoyl)benzoate (151.3, prepared by reaction of methyl terephthaloyl chloride with 4-methylphenylboronic acid; 1H NMR: 8.11, d, 2H, 7.83, d, 2H, 7.68, d, 2H, 7.4, d, 2H, 3.91, s, 3H, 2.41, s, 3H)→methyl 4-(4-bromomethylbenzoyl)benzoate (151.2; was used in the next stage without any further purification)→methyl 4-{4-[3-(4-fluoro-3-trifluoromethylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-ylmethyl]-benzoyl}benzoate (151; by reaction of 151.2 with 133.1).
The compound of example 155 was obtained via the sequence of (5-fluoro-2-methylphenyl)(4-trifluoromethylphenyl)methanone (155.3, prepared by reaction of 4-(trifluoromethyl)benzoyl chloride with 5-fluoro-2-methylphenylboronic acid; 1H NMR: 7.96, m, 4H, 7.45, m, 1H, 7.37, m, 1H, 7.28, m, 1H, 2.2, s, 3H)→(2-bromomethyl-5-fluorophenyl)(4-trifluoromethylphenyl)methanone (155.2; was used in the next stage without any further purification)→4-{3-[4-fluoro-2-(3-methoxybenzoyl)benzyl]-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl}-2-trifluoromethylbenzonitrile (155; by reaction of 155.2 with 88.1).
The compound of example 158 was obtained via the sequence of methyl (4-(5-chloro-2-methylbenzoyl)benzoate (158.3, prepared by reaction of methyl terephthaloyl chloride with 5-chloro-2-methylphenylboronic acid; 1H NMR: 8.11, d, 2H, 7.82, d, 2H, 7.58, m, 1H, 7.42, m, 2H, 3.9, s, 3H, 2.2, s, 3H)→methyl (4-(2-bromomethyl-5-chlorobenzoyl)benzoate (158.2; was used in the next stage without any further purification)→methyl 4-{5-chloro-2-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-ylmethyl]benzoyl}benzoate (158; by reaction of 158.2 with 88.1).
Under an argon atmosphere, 2 g of methyl 4-(bromomethyl)benzoate, 1.8 g of 2-(tert-butoxymethyl)phenylboronic acid, 39 mg of palladium(II) acetate, 151 mg of 9,9-dimethyl-4,5-bis(diphenyl-phosphino)xanthene and 8.5 g of cesium carbonate were suspended in 20 ml of dry dioxane and stirred at 100° C. for 6 h. The cooled reaction mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by chromatography (silica gel; 95/5 to 85/85 n-heptane/ethyl acetate). This afforded methyl 4-(2-tert-butoxymethylbenzyl)benzoate 143.3. 1H NMR: 7.89, d, 2H, 7.38, d, 1H, 7.8, d, 2H, 7.22, m, 2H, 7.12, d, 1H, 4.33, s, 2H, 4.1, s, 2H, 3.81, s, 3H, 1.16, s, 9H.
1.82 g of compound 143.3 were dissolved at room temperature in 20 ml of dry dichloromethane, admixed at 5° C. with 111.6 μl of trimethylsilyl trifluoromethanesulfonate and stirred at room temperature overnight. Thereafter, another 0.1 equivalent of trimethylsilyl trifluoromethanesulfonate was added and the mixture was stirred for a further 24 h. The reaction mixture was admixed with saturated sodium hydrogencarbonate solution, and the organic phase was removed and dried over magnesium sulfate, filtered and concentrated under reduced pressure. Chromatographic purification (silica gel; 9/1 n-heptane/ethyl acetate) afforded methyl 4-(2-hydroxymethylbenzyl)benzoate 143.2. The compound was used as such in the next reaction.
750 mg of compound 143.2 were dissolved at room temperature in 10 ml of dry dichloromethane, admixed dropwise at 5° C. with a solution of 792 mg of phosphorus tribromide in 5 ml of dry dichloromethane and stirred at 5° C. for 30 minutes and at room temperature for a further 4 h. For workup, the reaction mixture was admixed with solid sodium hydrogencarbonate and 0.5 ml of water, filtered through a short silica gel cartridge and concentrated under reduced pressure. This afforded methyl 4-(2-bromomethylbenzyl)benzoate 143.1. 1H NMR: 7.9, d, 2H, 7.48, d, 1H, 7.38-7.2, m, 4H, 7.12, d, 1H, 4.7, s, 2H, 4.2, s, 2H, 3.84, s, 3H.
250 mg of compound 88.1 in 5 ml of dry acetonitrile were admixed at room temperature with 282 mg of compound 143.1 and 343 mg of cesium carbonate. The mixture was stirred at 75° C. for 5 h. The cooled reaction mixture was admixed with water and then extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Chromatographic purification (silica gel; 9/1 n-heptane/ethyl acetate) afforded methyl 4-{2-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-ylmethyl]benzyl}benzoate 143. 1H NMR: 8.32, d, 1H, 8.2, s, 1H, 8.08, d, 1H, 7.9, d, 2H, 7.45, d, 1H, 7.32, d, 2H, 7.28, m, 2H, 7.22, d, 1H, 4.54, s, 2H, 4.21, s, 2H, 3.83, s, 3H, 1.22, s, 6H.
The compound of example 144 was obtained in an analogous manner by reaction of 143.1 with 133.1. Molecular weight 528.16 (C28H24F4N2O4); retention time Rt=2.27 min. [B]; MS(ESI): 529.17 (MH+).
0.46 g of compound 133 were dissolved at room temperature in 15 ml of dry tetrahydrofuran, admixed with 1.1 g of potassium trimethylsilanolate and stirred at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure and purified by chromatography (method [RP1]). Molecular weight 528.13 (C27H20F4N2O5); retention time Rt=1.93 min. [B]; MS(ESI): 529.15 (MH+).
In an analogous manner, compound 136 was prepared from 134, 138 from 137, 145 from 142, 152 from 149, 154 from 151, 153 from 158, 154 from 151, 156 from 143 and 157 from 144:
1H NMR: 13.3, s, broad, 1H; 8.1, d, 2H; 8.0, d, 1H; 7.88, m, 1H; 7.82, d, 2H; 7.78, d, 2H; 7.7, m, 1H; 7.62, d, 2H; 4.72, s, 2H; 1.4, s, 6H
In vitro functional assays with recombinant cells:
Function-testing assays were performed by means of the FLIPR technique (“Fluorometric Imaging Plate Reader”, Molecular Devices Corp.).
To this end, ligand-induced changes in the intracellular concentration of Ca2+ in recombinant HEK293 cells, which expressed both a cannabinoid receptor (CB1 or CB2) and G-protein Galpha16, were determined. For the studies, cells were sown into 96-well microtiter plates (60 000 cells/well) and left to grow overnight. The medium was removed and the cells were incubated in buffer which contained the fluorescent dye Fluo-4. After this loading with dye, the cells were washed, test substance was added dissolved in buffer, the mixture was incubated for 20 minutes, a known cannabinoid receptor agonist as a reference agonist was added in buffer and, finally, the changes in the intracellular Ca2+ concentration were measured in the FLIPR unit.
Results were presented as the percentage change relative to the control (0%: analogous experiment without test substance and without reference agonist, i.e. only with buffer; 100%: analogous experiment without test substance, but with reference agonist in excess), and used to calculate dose/action curves, and IC50 values were determined
Results:
The values of the functional assay compared to the cannabinoid 1 receptor including illustrative selectivities compared to the cannabinoid 2 receptor can be taken from table 1 which follows.
Test compounds: The compounds (3 μl, 10 mM, 100% DMSO), pipetted into 96-well PP microtiter plates, were diluted with 27 μl of 100% DMSO (dimethyl sulfoxide). Proceeding from this solution, further 3-fold dilution steps were undertaken by transferring 10 μl in each case to a new PP microtiter plate and adding a further 20 μl of 100% DMSO. In each case 6 μl of these solutions were transferred into new 96-well PP microtiter plates and made up with 144 μl of assay buffer. The end concentrations ranged from 10 μM to 0.005 μM.
Negative control: AM 251, dissolved in assay buffer with 1% DMSO, was added to the dilution series in the microtiter plates as a control. The end concentration was 1 μM.
Blank control: assay buffer with 1% DMSO was added to the dilution series of the microtiter plates as a blank control.
High control: 3H binding without addition of the compound
Low control: 3H binding in the presence of 1 μM AM 251
The values were calculated using the corrected raw data.
The values reported were obtained as average values of a double determination. The IC50 values were calculated from the measurements with the program Xlfit, formula 205. Ki values were obtained from the IC50 and Kd values utilizing the Cheng-Prusoff equation:
Results: Ki values of example compounds: Table 5:
It can be seen from the test data that the inventive compounds of the formula I act as CB1R antagonists and are therefore very suitable for treating metabolic syndrome, type II diabetes and obesity.
The test is used to study the anorexigenic potency of the test substances. Female NMRI mice, 25-35 g in weight, are used. The mice are accustomed to the housing conditions for at least one week and to the condensed milk supplied for 2 days.
The feed is removed from the mice for 24 hours, but they have constant access to water. On the day of the experiment, the animals are put in individual cages; the cage lids can accommodate the pipettes filled with milk. The test substances are administered orally, intraperitoneally or subcutaneously. After the administration, the mice are put in their cages and receive access to the milk 30 min later. The milk consumption is read off every 30 min over 7 hours; at the same time, obvious changes in behavior of the animals are noted.
“Antagonization of CB1-Mediated Hypothermia”
The test is used to measure the potency of cannabinoid CB1 receptor (CB1) antagonists. What is measured is the extent to which the CB1 antagonists to be tested are capable of preventing or of antagonizing hypothermia induced by a CB1 agonist.
Female NMRI mice, 25-35 g in weight, are used. The mice are accustomed to the housing conditions for at least one week.
At time 0 min, the animals are treated orally, intravenously or intraperitoneally with the CB1 antagonist to be tested. 30 min later, the CB1 agonist CP55.940, 1.25 mg/kg, is administered to the mice intraperitoneally. This brings about a fall in the body temperature by 5-6° C. within 30 min. The body temperature is measured rectally for the first time 30 min before the test substance administration and then every 30 min after this administration, if appropriate immediately before a substance administration, over 4 hours.
The potency of the test substances is reported as the percentage decrease in the area under the temperature-time curve which is formed firstly by the average basal temperature, and secondly by the temperature-time curve, of the animals treated exclusively with the CB1 antagonist.
The method serves firstly to study the influence of test substances themselves on the small intestinal motility, and secondly to study to what extent specifically induced effects on the small intestinal motility can be prevented or antagonized, for example the delay in the intestinal passage by the cannabinoid CB1 agonist CP55.940.
Female NMRI mice with a weight of 25-35 g are used. The mice are accustomed to the housing conditions for at least one week.
The feed is removed from the mice for 24 hours, but they have constant access to water. The test substances are administered orally, intravenously, subcutaneously, but not intraperitoneally. If a specific effect is to be antagonized, the test substance is administered 30-120 min before the specific effector. 30 min after this administration, a defined amount of a dyed, non-caloric filler is introduced into the stomach by gavage. After a further 30 min (the dyed filler has about 80% filled the small intestine at this point), the animals are sacrificed and the small intestine is dissected. The intestinal motility is reported as the passage of the dyed filler compared to the total length of the small intestine in percent. A treatment effect is reported as the difference of this passage to the vehicle control, likewise in percent.
| Number | Date | Country | Kind |
|---|---|---|---|
| 08290135.6 | Feb 2008 | EP | regional |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/EP2009/000590 | Jan 2009 | US |
| Child | 12852084 | US |
