US20060287374A1 - Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1 - Google Patents

Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1 Download PDF

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US20060287374A1
US20060287374A1 US11/511,224 US51122406A US2006287374A1 US 20060287374 A1 US20060287374 A1 US 20060287374A1 US 51122406 A US51122406 A US 51122406A US 2006287374 A1 US2006287374 A1 US 2006287374A1
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methyl
thiazol
chloro
ethyl
acetyl
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Tjeerd Barf
Marianne Nilsson
Jerk Vallgarda
Guido Kurz
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Swedish Orphan Biovitrum AB
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Biovitrum AB
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    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
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    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to processes for their preparation, as well as to the use of the compounds in medicine and for the preparation of a medicament which acts on the human 11- ⁇ -hydroxysteroid dehydrogenase type 1 enzyme (11 ⁇ HSD1).
  • 11 ⁇ HSD1 human 11- ⁇ -hydroxysteroid dehydrogenase type 1 enzyme
  • glucocorticoids have a central role in diabetes, e.g. the removal of the pituitary or the adrenal gland from a diabetic animal alleviates the most severe symptoms of diabetes and lowers the concentration of glucose in the blood (Long, C. D. and F. D. W. Leukins (1936) J. Exp. Med. 63: 465-490; Houssay, B. A. (1942) Endocrinology 30: 884-892). It is also well established that glucocorticoids enable the effect of glucagon on the liver.
  • 11 ⁇ HSD1 as an iimportant regulator of local glucocorticoid effect and thus of hepatic glucose production is well substantiated (see e.g. Jamieson et al. (2000) J. Endocrinol. 165: p. 685-692).
  • the hepatic insulin sensitivity was improved in healthy human volunteers treated with the non-specific 11 ⁇ HSD1 inhibitor carbenoxolone (Walker, B. R. et al. (1995) J. Clin Endocrinol. Metab. 80: 3155-3159). Furthermore, the expected mechanism has been established by different experiments with mice and rats.
  • Obesity is an important factor in syndrome X as well as in the majority (>80%) of type 2 diabetic, and omental fat appears to be of central importance.
  • Abdominal obesity is closely associated with glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and other factors of the so-called syndrome X (e.g. raised blood pressure, decreased levels of HDL and increased levels of VLDL) (Montague & O'Rahilly, Diabetes 49: 883-888, 2000).
  • inhibition of the enzyme in pre-adipocytes (stromal cells) has been shown to decrease the rate of differentiation into adipocytes. This is predicted to result in diminished expansion (possibly reduction) of the omental fat depot, i.e. reduced central obesity (Bujalska, I. J., S. Kunmar, and P. M. Stewart (1997) Lancet 349: 1210-1213).
  • Adrenalectomy attenuates the effect of fasting to increase both food intake and hypothalamic neuropeptide Y expression. This supports the role of glucocorticoids in promoting food intake and suggests that inhibition of 11 ⁇ HSD1 in the brain might increase satiety and therefore reduce food intake (Woods, S. C. et al. (1998) Science, 280: 1378-1383).
  • glucocorticoids suppress the immune system. But in fact there is a dynamic interaction between the immune system and the HPA (hypothalamo-pituitary-adrenal) axis (Rook, G. A. W. (1999) Baillièr's Clin. Endocrinol. Metab. 13: 576-581).
  • HPA hypothalamo-pituitary-adrenal
  • the balance between the cell-mediated response and humoral responses is modulated by glucocorticoids.
  • a high glucocorticoid activity such as at a state of stress, is associated with a humoral response.
  • inhibition of the enzyme 11 ⁇ HSD1 has been suggested as a means of shifting the response towards a cell-based reaction.
  • 11 ⁇ HSD1 In the eye, expression of 11 ⁇ HSD1 is confined to basal cells of the corneal epithelium and the non-pigmented epithelialium of the cornea (the site of aqueous production), to ciliary muscle and to the sphincter and dilator muscles of the iris.
  • the distant isoenzyme 11 ⁇ HSD2 is highly expressed in the non-pigmented ciliary epithelium and corneal endothelium. None of the enzymes is found at the trabecular meshwork, the site of drainage.
  • FR 2384498 discloses thiazolo-benzenesulfonamides which show antibacterial, antifungal and hypoglycaemic properties.
  • WO99/28306 and EP 0 819 681 A2 relate to thiazolobenzenesulfonamides which can be used for treating neurodegenerative pathologies, such as Alzheimer's disease.
  • JP 7149745 A2 and JP 7149746 A2 both describe 2-aminothiazole derivatives as esterase inhibitors. None is disclosed about inhibiting 11 ⁇ HSD1.
  • JP 7309757 A2 relates to treating Alzheimer's disease using N-(5-nitro-2-thiazolyl)benzenesulfonamides.
  • JP 3173876 A2 presents preparation of diphenylthiazoles. These compounds are used as anti-inflammatories, analgesics, anti-allergy agents, uric acid accelerators and blood platelet aggregation inhibitors.
  • EP 0 790 057 A1 discloses an antibacterial or bactericide comprising a 2-aminothiazole derivative.
  • U.S. Pat. No. 2,362,087 describes the preparation of thiazolobenzenesulfonamides, such as 2-bromobenzenesulfonamido-4-methylthiazole. Nothing is disclosed about inhibiting 11 ⁇ HSD1 and no therapeutic use of such substances is disclosed.
  • the compounds according to the present invention solve the above problems and embraces a novel class of compounds which has been developed and which inhibit the human 11- ⁇ -hydroxysteroid dehydrogenase type 1 enzyme (11- ⁇ -HSD 1 ), and may therefore be of use in the treating disorders such as diabetes, obesity, glaucoma, osteoporosis, cognitive disorders, immune disorders, and depression.
  • 11- ⁇ -HSD 1 human 11- ⁇ -hydroxysteroid dehydrogenase type 1 enzyme
  • One object of the present invention is a compound of the formula (I) wherein
  • T is a monocyclic aryl ring or monocyclic heteroaryl ring, optionally independently substituted by [R] n , wherein n is an integer 0-5, and R is hydrogen, C 1-6 -alkyl, halogen, aryl or aryloxy, wherein the aryloxy residue can further be optionally substituted in one or more positions independently of each other by cyano and halogen;
  • T is not 4-methylphenyl
  • T is not 4-chlorophenyl
  • T is not 4-chlorophenyl
  • T is not 4-methylphenyl.
  • A is C 1-6 -alkyl, vinyl or 3-(ethyl 3-methylbutanoate);
  • B is hydrogen, methyl, ethyl, n-propyl, n-butyl, halogenated C 1-6 -allyl, C 1-6 -acyl or C 1-6 -aloxycarbonyl;
  • T is selected from 4-bromo-5-chloro-2-thienyl and phenyl substituted with one or more of bromo, chloro, 3-chloro-2-cyanophenoxy, fluoro, methyl, phenyl, n-propyl;
  • T is not phenyl
  • T is not 4-methylphenyl
  • T is not 4-bromophenyl
  • T is not 4-chlorophenyl
  • T is not 4-methylphenyl
  • T is not 4-chlorophenyl
  • T is not 4-methylphenyl.
  • A is selected from methyl, ethyl, n-propyl, isopropyl, i-butyl, tert-butyl, n-pentyl, vinyl or 3-(ethyl 3-methylbutanoate);
  • B is selected from hydrogen, methyl, ethyl, n-propyl, n-butyl, 2,2,2-trichloroethyl, acetyl and carbethoxy.
  • T is a substituted phenyl group
  • phenyl ring is substituted as follows:
  • Another object of the present invention is a compound as described above for medical use.
  • Another object of the present invention is a process for the preparation of a compound as described above comprising at least one of the following steps:
  • Another object of the present invention is a method for the treatment or prevention of diabetes, syndrome X, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, osteoporosis, tuberculosis, dementia, depression, virus diseases and inflammatory disorders, said method comprising administering to a mammal, including man, in need of such treatment an effective amount of a compound of the formula (I) wherein
  • T is an aryl ring or heteroaryl ring, optionally independently substituted by [R] n , wherein n is an integer 0-5, and R is hydrogen, C 1-6 -alkyl, halogen, aryl or axyloxy, wherein the aryloxy residue can further be optionally substituted in one or more positions independently of each other by cyano and halogen;
  • A is C 1-6 -alkyl, vinyl or 3-(ethyl 3-methylbutanoate);
  • B is hydrogen, halogen, C 1-6 -alkyl, halogenated C 1-6 -alkyl, C 1-6 -acyl or C 1-6 -alkoxycarbonyl;
  • These compounds may also be used in the manufacture of a medicament for the prevention, management or treatment of diabetes, syndrome X, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, osteoporosis, tuberculosis, dementia, depression, virus diseases and inflammatory disorders.
  • T is selected from 4-bromo-5-chloro-2-thienyl and phenyl substituted with one or more of bromo, chloro, 3-chloro-2-cyanophenoxy, fluoro, methyl phenyl n-propyl;
  • A is selected from methyl ethyl, n-propyl, isopropyl, n-butyl tert-butyl n-pentyl, vinyl or 3-(ethyl 3-methylbutanoate);
  • B is selected from hydrogen, bromo, methyl, ethyl n-propyl, n-butyl, 2,2,2-trichloroethyl, acetyl and carbethoxy.
  • Another object of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of the formula (I) as defined above, and a pharmaceutically acceptable carrier.
  • the compounds according to the present invention may be used in several indications which involve 11- ⁇ -hydroxysteroid dehydrogenase type 1 enzyme.
  • the compounds according to the present invention may be used against dementia (see WO97/07789), osteoporosis (see Canalis E 1996, Mechanisms of glucocorticoid action in bone: implications to glucocorticoid-induced osteoporosis, Journal of Clinical Endocrinology and Metabolism, 81, 3441-3447) and may also be used disorders in the immune system (see Franchimont et al., “Inhibition of Th1 immune response by glucocorticoids: dexamethasone selectively inhibits IL-12-induced Stat 4 phosphorylation in T lymphocytes”, The journal of Immunology 2000, Feb. 15, vol 164 (4), pages 1768-74) and also in the above listed indications.
  • aryl in the present description is intended to include aromatic rings (monocyclic or bicyclic) having from 6 to 10 ring carbon atoms, such as phenyl (Ph; a monocyclic ring) and naphthyl (a bicyclic ring), which optionally may be substituted by C 1-6 -alkyl.
  • substituted aryl groups are benzyl and 2-methylphenyl
  • heteroaryl means in the present description a monocyclic, bi- or tricyclic aromatic ring system (only one ring need to be aromatic) having from 5 to 14, preferably 5 to 10 ring atoms such as 5, 6, 7, 8, 9 or 10 ring atoms (mono- or bicyclic), in which one or more of the ring atoms are other than carbon, such as nitrogen, sulfur, oxygen and selenium.
  • heteroaryl rings examples include pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, tetrazole, chroman, isochroman, quinoline, quinoxaline, isoquinoline, phthalazine, cinnoline, quinazoline, indole, isoindole, indoline, isoindoline, benzothiophene, benzofuran, isobenzofuran, benzoxazole, 2,1,3-benzoxadiazole, benzothiazole, 2,1,3-benzothiazole, 2,1,3-benzoselenadiazole, benzimidazole, indazole, benzodioxane, indan
  • Examples of monocyclic heteroaryl rings are pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, and tetrazole.
  • C 1-6 -alkyl in the compound of formula (I) according to the present application is preferably C 1-4 -alkyl.
  • Exemplary alkyl groups include methyl, ethyl, n-propyl isopropyl butyl sec-butyl tert-butyl, n-pentyl, isopentyl hexyl, and isohexyl.
  • C 1-6 -alkoxy in the compound of formula (I) according to the present application may be straight or branched, is preferably C 1-4 -alkoxy.
  • Exemplary alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, hexyloxy, and isohexyloxy.
  • C 1-6 -acyl in the compound of formula (1) according to the present application may be saturated or unsaturated and is preferably C 1-4 -acyl.
  • exemplary acyl groups include formyl, acetyl, propionyl butyryl, isobutyryl, valeryl, isovaleryl, butenoyl (e.g. 3-butenoyl); hexenoyl (e.g. 5-hexenoyl).
  • halogen in the present description is intended to include fluorine, chlorine, bromine and iodine.
  • prodrug forms in the present description means a pharmacologically acceptable derivative, such as an ester or an amide, which derivative is biotransformed in the body to form the active drug (see Goodman and Gilman's, The Pharmacological basis of Therapeutics, 8 th ed., McGraw-Hill, Int. Ed. 1992, “Biotransformation of Drugs, p. 13-15).
  • “Pharmaceutically acceptable” means in the present description being useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use.
  • “Pharmaceutically acceptable salts” mean in the present description salts which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with organic and inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, methanesulfonic acid, triluoroacetic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid and the like. Base addition salts may be formed with organic and inorganic bases, such as sodium, ammonia, potassium, calcium, ethanolamine, diethanolamine, N-methylglucamine, choline and the like.
  • compositions according to the present invention contain a pharmaceutically acceptable carrier together with at least one of the compounds comprising the formula (I) as described herein above, dissolved or dispersed therein as an active, antimicrobial, ingredient.
  • the therapeutic composition is not immunogenic when administered to a human patient for therapeutic purposes, unless that purpose is to induce an immune response.
  • compositions that contains active ingredients dissolved or dispersed therein are well understood in the art.
  • compositions are prepared as sterile in injectables either as liquid solutions or suspensions, aqueous or non-aqueous, however, solid forms suitable for solution, or suspensions, in liquid prior to use can also be prepared.
  • the preparation can also be emulsified.
  • the active ingredient may be mixed with excipients, which are pharmaceutically acceptable and compatible with the active ingredient and in amounts suitable for use in the therapeutic methods described herein.
  • Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like and combinations thereof.
  • the composition may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like which enhance the effectiveness of the active ingredient.
  • Adjuvants may also be present in the composition.
  • aqueous carriers are well known in the art.
  • exemplary of liquid carriers are sterile aqueous solutions that contain no materials in addition to the active ingredients and water, or contain a buffer such as sodium phosphate at physiological pH value, physiological saline or both, such as phosphate-buffered saline.
  • aqueous carriers can contain more than one buffer salt, as well as salts such as sodium and potassium chlorides, dextrose, propylene glycol polyethylene glycol and other solutes.
  • Liquid compositions can also contain liquid phases in addition to and to the exclusion of water.
  • additional liquid phases are glycerine, vegetable oils such as cottonseed oil, organic esters such as ethyl oleate, and water-oil emulsions.
  • compositions comprising compounds comprising the formula (I), may include pharmaceutically acceptable salts of that component therein as set out above.
  • Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the polypeptide) that are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic acid, tartaric acid, mandelic acid and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine and the like.
  • the preparations according to the preferred embodiments may be administered orally, topically, intraperitoneally, intraarticularly, intracranially, intradermally, intramuscularly, intraocularly, intrathecally, intravenously, subcutaneously.
  • Other routes which are known for the skilled person in the art are thinkable.
  • compositions according to the present invention may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations; such as oral, topical or sterile parenteral solutions or suspensions.
  • Tablets and capsules for oral administration may be in unit dose presentation form and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol traganath or polyvinyl-pyrrolidone; fillers e.g. lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant e.g.
  • Oral liquid preparations may be in the form of e.g. aqueous or oily suspensions, solutions, emulsions, syrups or elixirs or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, e.g. sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents e.g.
  • non-aqueous vehicles which may include edible oils, e.g. almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives e.g. methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • edible oils e.g. almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol
  • preservatives e.g. methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • a pharmaceutical composition according to the present invention may comprise typically an amount of at least 0.1 weight percent of compound comprising the formula (I) per weight of total therapeutic composition.
  • a weight percent is a ratio by weight of total composition.
  • 0.1 weight percent is 0.1 grams of compound comprising the formula (I) per 100 grams of total composition.
  • a suitable daily oral dose for a mammal, preferably a human being may vary widely depending on the condition of the patient. However a dose of compound comprising the formula (I) of about 0.1 to 300 mg/kg body weight may be appropriate.
  • compositions according to the present invention may also be used veterinarily and thus they may comprise a veterinarily acceptable excipient or carrier.
  • the compounds of the present invention in labelled form may be used as a diagnostic agent.
  • the compounds of the formula (I) above may be prepared by, or in analogy with, conventional methods, and especially according to or in analogy with the following methods. Further, the pharmacology in-vitro was studied using the following reagents and methods.
  • [1,2(n)- 3 H]-cortisone was purchased from Amersham Pharmacia Biotech Anti-cortisol monoclonal mouse antibody, clone 6D6.7 was obtained from Immunotech and Scintillation proximity assay (SPA) beads coated with monoclonal antimouse antibodies were from Amersham Pharmacia Biotech. NADPH, tetrasodium salt was from Calbiochem and glucose-6-phosphate (G-6-P) was supplied by Sigma. The human 11- ⁇ -hydroxysteroid dehydrogenase type-1 enzyme (11- ⁇ -HSD 1 ) was expressed in Pichia pastoris. 18- ⁇ -glycyrrhetinic acid (GA) was obtained from Sigma.
  • the 11- ⁇ -HSD 1 enzyme assay was carried out in 96 well microtiter plates (Packard, Optiplate) in a total well volume of 220 ⁇ L and contained 30 mM Tris-HCl, pH 7.2 with 1 mM EDTA, a substrate mixture tritiated Cortisone/NADPH (175 nM/181 ⁇ M), G-6-P (1 mM) and inhibitors in serial dilutions (9 to 0.15 ⁇ M. Reactions were initiated by the addition of human 11- ⁇ -HSD 1 , either as Pichia pastoris cell homogenate or microsomes prepared from Pichia pastoris (the final amount of enzyme used was varied between 0.057 to 0.11 mg/mL).
  • the plates were covered with plastic film and incubated on a shaker for 30 minutes, at room temperature, before counting.
  • the amount of [ 3 H]-cortisol, bound to the beads was determined in a microplate liquid scintillation counter.
  • the calculation of the K i values for the inhibitors was performed by use of Activity Base.
  • the IC 50 is measured experimentally in an assay wherein the decrease of the turnover of cortisone to cortisol is dependent on the inhibition potential of each substance.
  • the K i values of the compounds of the present invention for the 11- ⁇ -HSD1 enzyme lie typically between about 10 nM and about 10 ⁇ M.
  • K i values have been determined in the human 11- ⁇ -HSD1 enzyme assay (see Table 1): TABLE 1 Ki values determined in the human 11- ⁇ -HSD1 enzyme assay.
  • Reverse phase preparative HPLC was carried out on a 100 ⁇ 21.2 mm, 5 ⁇ Hypersil Elite column eluting with a gradient of 5% ACN in 95% water to 95% ACN in 5% water (0.2% TFA buffer) over 10 mins at a flow rate of 20 mL/mm with the UV detector set at 254 nm.
  • Thin layer chromatography was carried out using pre-coated silica gel F-254 plates (thickness 0.25 mm). Electrospray MS spectra were obtained on a Micromass platform LCMS spectrometer.
  • the carboxylic acid was suspended in DCM (0.05M) followed by the addition of EDCI (1.1 eq), triethylamine (3 eq), DMAP (0.5 eq) and the amine of choice (1.2 eq). DMF was added when the staring materials did not dissolve properly. The reaction mixture was stirred at ambient temperature over night. The organic phase was washed with aqueous HCl (1 M), dried over sodium sulfate, filtered and evaporated in vacuo. The crude product amide was purified by flash column chromatography on silica gel, eluting with methanol (1 ⁇ 3 ⁇ 6%) in: DCM or ethyl acetate.
  • the title compound was prepared similar to EXAMPLE 6 according to METHOD A from 4-methyl-5-(2,2,2-trichloroethyl)-1,3-thiazol-2-ylamine (123 mg, 0.5 mmol) and 3-chloro-2-methylbenzenesulfonyl chloride (112.5 mg, 0.5 mmol). The solution was allowed to stand at r.t. overnight. Water (5 mL) was added and the resulted solution was made acidic with conc. HCl. The precipitate was filtered, washed with water and dried.
  • the title compound was prepared according to METHOD A from 4-methyl-5-(2,2,2-trichloroethyl)-1,3-thiazol-2-ylamine (123 mg, 0.5 mmol, prepared according to Dodinoy, A. A et al (1993) Chem. Heterocycl. Comp (Eng. Transl.) 29(8): 955-958) and 2,4,6-trichlorobenzenesulfonyl chloride (140 mg, 0.5 mmol). The solution was allowed to stand at room temperature overnight.
  • Ethyl 2-(2- ⁇ [(3-chloro-2-methylphenyl)sulfonyl]amino ⁇ -1,3-thiazol-4-yl)acetate was prepared according to METHOD A at 30° C., using a Quest 210 apparatus. This procedure gave 2.05 g (34%) of an off-white solid.
  • the title compound was prepared from 5-acetyl-2-amino-4-methylthiazole (42 mg) and 2,4,5-trichlorobenzenesulfonyl chloride (76 mg) as described in the synthetic METHOD B to give a white solid (23.7 mg) with purity >90%: MS (pos) m/z 399.2, 401.2; HRMS m/z 397.9103 (calc. of monoisotopic mass for C 12 H 9 Cl 3 N 2 O 3 S 2 gives 397.9120).
  • the title compound was prepared from 5-acetyl-2-amino-4-methylthiazole (42 mg) and 4-bromo-2,5-difluorobenzenesulfonyl chloride (79 mg) as described in the synthetic METHOD B to give a white solid (21.0 mg) with purity >90%: MS pos) m/z 411.2, 413.2.
  • This compound was prepared from ethyl 2-amino methylthiazole-5-carboxylate and 4-biphenylsulfonyl chloride as described for EXAMPLE 30 with the exception that it was not recrystallized. Yield 96 mg, 24%: 1 H NMR (DMSO) ⁇ 7.8-7.95 (m, 4H), 7.65-7.75 (m, 2H), 7.35-7.55 (m, 3H), 4.23 (q, 2H), 2.39 (s, 3H), 1.26 (t, 3H), MS-ES (neg) m/z 401.2.
  • This compound was prepared from ethyl 2-amino-4-methylthiazole-5-carboxylate and 2,4,6-trichlorobenzenesulfonyl chloride as described for EXAMPLE 30 with the exception that it was purified by recrystallization only. Yield 249 mg, 58%: 1 H NMR (DMSO) ⁇ 7.84 (s 2H), 4.23 (q, 2H), 2.42 (s, 3H), 1.25 (t, 3H); MS-ES (neg) m/z 429.1.

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Abstract

The present invention relates to compounds with the formula (I) and also to pharmaceutical compositions comprising the compounds, to processes for their preparation, as well as to the use of the compounds in medicine and for the preparation of a medicament which acts on the human 11-β-hydroxysteroid dehydrogenase type 1 enzyme.
Figure US20060287374A1-20061221-C00001

Description

    TECHNICAL FIELD
  • The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to processes for their preparation, as well as to the use of the compounds in medicine and for the preparation of a medicament which acts on the human 11-β-hydroxysteroid dehydrogenase type 1 enzyme (11βHSD1).
    • BACKGROUND ART
  • 1. Glucorticoids, Diabetes and Hepatic Glucose Production
  • It has been known for more than half a century that glucocorticoids have a central role in diabetes, e.g. the removal of the pituitary or the adrenal gland from a diabetic animal alleviates the most severe symptoms of diabetes and lowers the concentration of glucose in the blood (Long, C. D. and F. D. W. Leukins (1936) J. Exp. Med. 63: 465-490; Houssay, B. A. (1942) Endocrinology 30: 884-892). It is also well established that glucocorticoids enable the effect of glucagon on the liver.
  • The role of 11βHSD1 as an iimportant regulator of local glucocorticoid effect and thus of hepatic glucose production is well substantiated (see e.g. Jamieson et al. (2000) J. Endocrinol. 165: p. 685-692). The hepatic insulin sensitivity was improved in healthy human volunteers treated with the non-specific 11βHSD1 inhibitor carbenoxolone (Walker, B. R. et al. (1995) J. Clin Endocrinol. Metab. 80: 3155-3159). Furthermore, the expected mechanism has been established by different experiments with mice and rats. These studies showed that the mRNA levels and activities of two key enzymes in hepatic glucose production were reduced, namely: the rate-limiting enzyme in gluconeogenesis, phosphoenolpynivate carboxyliinase (PEPCK), and glucose-6-phosphatase (G6Pase) catalyzing the last common step of gluconeogenesis and glycogenolysis. Finally, the blood glucose level and hepatic glucose production is reduced in mice having the 11βHSD1 gene knocked-out. Data from this model also confirm that inhibition of 11βHSD1 will not cause hypoglycemia, as predicted since the basal levels of PEPCK and G6Pase are regulated independently of glucocorticoids (Kotelevtsev, Y. et al., (1997) Proc. Natl. Acad. Sci. USA 94: 14924-14929).
  • 2. Possible Reduction of Obesity and Obesity Related Cardiovascular Risk Factors
  • Obesity is an important factor in syndrome X as well as in the majority (>80%) of type 2 diabetic, and omental fat appears to be of central importance. Abdominal obesity is closely associated with glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and other factors of the so-called syndrome X (e.g. raised blood pressure, decreased levels of HDL and increased levels of VLDL) (Montague & O'Rahilly, Diabetes 49: 883-888, 2000). inhibition of the enzyme in pre-adipocytes (stromal cells) has been shown to decrease the rate of differentiation into adipocytes. This is predicted to result in diminished expansion (possibly reduction) of the omental fat depot, i.e. reduced central obesity (Bujalska, I. J., S. Kunmar, and P. M. Stewart (1997) Lancet 349: 1210-1213).
  • Inhibition of 11βHSD1 in mature adipocytes is expected to attenuate secretion of the plasminogen activator inhibitor 1(PAI-1)—an independent cardiovascular risk factor (Halleux, C. M. et al. (1999) J. Clin. Endocrinol. Metab. 84: 4097-4105). Furthermore, there is a clear correlation between glucocorticoid “activity” and cardiovascular risk factore suggesting that a reduction of the glucocorticoid effects would be beneficial (Walker, B. R. et al. (1998) Hypertension 31: 891-895; Fraser, R. et al. (1999) Hypertension 33: 1364-1368).
  • Adrenalectomy attenuates the effect of fasting to increase both food intake and hypothalamic neuropeptide Y expression. This supports the role of glucocorticoids in promoting food intake and suggests that inhibition of 11βHSD1 in the brain might increase satiety and therefore reduce food intake (Woods, S. C. et al. (1998) Science, 280: 1378-1383).
  • 3. Possible Beneficial Effect on the Pancreas
  • Inhibition of 11βHSD1 in isolated murine pancreatic β-cells improves the glucose-stimulated insulin secretion (Davani, B. et al. (2000) J. Biol. Chem 2000 Nov. 10; 275(45): 34841-4). Glucocorticoids were previously known to reduce pancreatic insulin release in vivo (Billaudel, B. and B. C. J. Sutter (1979) Horm. Metab. Res. 11: 555-560). Thus, inhibition of 11βHSD1 is predicted to yield other beneficial effects for diabetes treatment, besides effects on liver and fat.
  • 4. Possible Beneficial Effects on Cognition and Dementia Stress and glucocorticoids influence cognitive function (de Quervain, D. J.-F., B. Roozendaal, and J. L. McGaugh (1998) Nature 394: 787-790). The enzyme 11βHSD1 controls the level of glucocorticoid action in the brain and thus contributes to neurotoxicity (Rajan, V., C. R. W. Edwards, and J. R. Seckl, J. (1996) Neuroscience 16: 65-70; Seckl, J. R., Front. (2000) Neuroendocrinol. 18: 49-99). Unpublished results indicate significant memory improvement in rats treated with a non-specific 11βHSD1 inhibitor (J. Seckl, personal communication). Based the above and on the known effects of glucocorticoids in the brain, it may also be suggested that inhibiting 11βHSD1 in the brain may result in reduced anxiety Tronche, F. et al. (1999) Nature Genetics 23:-99-103). Thus, taken together, the hypothesis is that inhibition of 11βHSD1 in the human brain would prevent reactivation of cortisone into cortisol and protect against deleterious glucocorticoid-mediated effects on neuronal survival and other aspects of neuronal function, including cognitive impairment, depression, and increased appetite (previous section).
  • 5. Possible Use of Immuno-Modulation using 11βHSD1 Inhibitors
  • The general perception is that glucocorticoids suppress the immune system. But in fact there is a dynamic interaction between the immune system and the HPA (hypothalamo-pituitary-adrenal) axis (Rook, G. A. W. (1999) Baillièr's Clin. Endocrinol. Metab. 13: 576-581). The balance between the cell-mediated response and humoral responses is modulated by glucocorticoids. A high glucocorticoid activity, such as at a state of stress, is associated with a humoral response. Thus, inhibition of the enzyme 11βHSD1 has been suggested as a means of shifting the response towards a cell-based reaction.
  • In certain disease states, including tuberculosis, lepra and psoriasis the immune reaction is normaly biased towards a humoral response when in fact the appropriate response would be cell based. Temporal inhibition of 11βHSD1, local or systemic, might be used to push the immune system into the appropriate response (Mason, D. (1991) Immunology Today 12: 57-60; Rook et al., supra).
  • An analogous use of 11βHSD1 inhibition, in this case temporal, would be to booster the immune response in association with immunization to ensure that a cell based response would be obtained, when desired.
  • 6. Reduction of Intraocular Pressure
  • Recent data suggest that the levels of the glucocorticoid target receptors and the 11βHSD enzymes determines the susceptibility to glaucoma (Stokes, J. et al. (2000) Invest. Ophthalmol. 41: 1629-1638). Further, inhibition of 11βHSD1 was recently presented as a novel approach to lower the intraocular pressure (Walker E. A. et al, poster P3-698 at the Endocrine society meeting Jun. 12-15, 1999, San Diego). Ingestion of carbenoxolone, a non-specific inhibitor of 11βHSD1, was shown to reduce the intraocular pressure by 20% in normal subjects. In the eye, expression of 11βHSD1 is confined to basal cells of the corneal epithelium and the non-pigmented epithelialium of the cornea (the site of aqueous production), to ciliary muscle and to the sphincter and dilator muscles of the iris. In contrast, the distant isoenzyme 11βHSD2 is highly expressed in the non-pigmented ciliary epithelium and corneal endothelium. None of the enzymes is found at the trabecular meshwork, the site of drainage. Thus, 11βHSD1 is suggested to have a role in aqueous production, rather than drainage, but it is presently unknown if this is by interfering with activation of the glucocorticoid or the mineralocorticoid receptor, or both.
  • 7. Reduced Osteoporosis
  • Glucocorticoids have an essential role in skeletal development and function but are detrimental in excess. Glucocorticoid-induced bone loss is derived, at least in part, via inhibition of bone formation, which includes suppression of osteoblast proliferation and collagen synthesis (Kim, C. H., S. L. Cheng, and G. S. Kim (1999) J. Endocrinol. 162: 371-379). The negative effect on bone nodule formation could be blocked by the non-specific inhibitor carbenoxolone suggesting an important role of 11βHSD1 in the glucocorticoid effect (Bellows, C-. G., A. Ciaccia, and J. N. M. Heersche, (1998) Bone 23: 119-125). Other data suggest a role of 11βHSD1 in providing sufficiently high levels of active glucocorticoid in osteoclasts, and thus in augmenting bone resorption (Cooper, M. S. et al (2000) Bone 27: 375-381). Taken together, these different data suggest that inhibition of 11βHSD1 may have beneficial effects against osteoporosis by more than one mechanism working in parallel.
  • WO 99/65884 discloses carbon substituted aminothiazole inhibitors of cyclin dependent kinases. These compounds may e.g. be used against cancer, inflammation and arthritis. U.S. Pat. No. 5,856,347 discloses an antibacterial preparation or bactericide comprising 2-aminothiazole derivative and/or salt thereof. Further, U.S. Pat. No. 5,403,857 discloses benzenesulfonamide derivatives having 5-lipoxygenase inhibitory activity. Additionally, tetrahydrothiazolo[5,4-c]pyridines are disclosed in: Analgesic tetrahydrothiazolo[5,4-c]pyridines. Fr. Addn (1969), 18 pp, Addn. to Fr. 1498465. CODEN: FAXXA3; FR 94123 19690704 CAN 72:100685 AN 1970:100685 CAPLUS and 4,5,6,7-Tetrthydrothiazolo[5,4-c]pyridines. Neth. Appl. (1967), 39 pp. CODEN: NAXXAN NL 6610324 19670124 CAN 68:49593, AN 1968: 49593 CAPLUS.
  • FR 2384498 discloses thiazolo-benzenesulfonamides which show antibacterial, antifungal and hypoglycaemic properties. WO99/28306 and EP 0 819 681 A2 relate to thiazolobenzenesulfonamides which can be used for treating neurodegenerative pathologies, such as Alzheimer's disease. JP 7149745 A2 and JP 7149746 A2 both describe 2-aminothiazole derivatives as esterase inhibitors. Nothing is disclosed about inhibiting 11βHSD1. JP 7309757 A2 relates to treating Alzheimer's disease using N-(5-nitro-2-thiazolyl)benzenesulfonamides. JP 3173876 A2 presents preparation of diphenylthiazoles. These compounds are used as anti-inflammatories, analgesics, anti-allergy agents, uric acid accelerators and blood platelet aggregation inhibitors. EP 0 790 057 A1 discloses an antibacterial or bactericide comprising a 2-aminothiazole derivative. U.S. Pat. No. 2,362,087 describes the preparation of thiazolobenzenesulfonamides, such as 2-bromobenzenesulfonamido-4-methylthiazole. Nothing is disclosed about inhibiting 11βHSD1 and no therapeutic use of such substances is disclosed.
  • However, none of the above disclosures discloses the compounds according to the present invention, or their use for the treatment of diabetes, obesity, glaucoma, osteoporosis, cognitive disorders, immune disorders, and depression.
  • Consequently, there is a need of new compounds that are useful in the treatment of diabetes, obesity, glaucoma, osteoporosis, cognitive disorders, immune disorders, and depression.
    • DISCLOSURE OF THE INVENTION
  • The compounds according to the present invention solve the above problems and embraces a novel class of compounds which has been developed and which inhibit the human 11-β-hydroxysteroid dehydrogenase type 1 enzyme (11-β-HSD1), and may therefore be of use in the treating disorders such as diabetes, obesity, glaucoma, osteoporosis, cognitive disorders, immune disorders, and depression.
  • One object of the present invention is a compound of the formula (I)
    Figure US20060287374A1-20061221-C00002
    wherein
  • T is a monocyclic aryl ring or monocyclic heteroaryl ring, optionally independently substituted by [R]n, wherein n is an integer 0-5, and R is hydrogen, C1-6-alkyl, halogen, aryl or aryloxy, wherein the aryloxy residue can further be optionally substituted in one or more positions independently of each other by cyano and halogen;
  • with the proviso:
  • that when A is methyl and B is hydrogen, then T is not phenyl;
  • that when A is methyl and B is 2,2,2-trichloroethyl, then T is not 4-methylphenyl;
  • that when A is methyl and B is hydrogen, then T is not 4-bromophenyl;
  • that when A is tert-butyl and B is bromo, then T is not 4-chlorophenyl;
  • optionally also when A is methyl and B is hydrogen, then T is not 4-methylphenyl;
  • optionally also when A is methyl and B is hydrogen, then T is not 4-chlorophenyl; and
  • optionally also when A is methyl and B is 2,2,2-trichloroethyl, then T is not 4-methylphenyl.
  • A is C1-6-alkyl, vinyl or 3-(ethyl 3-methylbutanoate);
  • B is hydrogen, methyl, ethyl, n-propyl, n-butyl, halogenated C1-6-allyl, C1-6-acyl or C1-6-aloxycarbonyl;
  • as well as pharmaceutically acceptable salts, hydrates and solvates thereof.
  • It is preferred that:
  • T is selected from 4-bromo-5-chloro-2-thienyl and phenyl substituted with one or more of bromo, chloro, 3-chloro-2-cyanophenoxy, fluoro, methyl, phenyl, n-propyl;
  • with the proviso:
  • that when A is methyl and B is hydrogen, then T is not phenyl;
  • that when A is methyl and B is 2,2,2-trichloroethyl, then T is not 4-methylphenyl;
  • that when A is methyl and B is hydrogen, then T is not 4-bromophenyl;
  • that when A is tert-butyl and B is bromo, then T is not 4-chlorophenyl;
  • optionally also when A is methyl and B is hydrogen, then T is not 4-methylphenyl;
  • optionally also when A is methyl and B is hydrogen, then T is not 4-chlorophenyl; and
  • optionally also when A is methyl and B is 2,2,2-trichloroethyl, then T is not 4-methylphenyl.
  • A is selected from methyl, ethyl, n-propyl, isopropyl, i-butyl, tert-butyl, n-pentyl, vinyl or 3-(ethyl 3-methylbutanoate);
  • B is selected from hydrogen, methyl, ethyl, n-propyl, n-butyl, 2,2,2-trichloroethyl, acetyl and carbethoxy.
  • When T is a substituted phenyl group, it is preferred that the phenyl ring is substituted as follows:
    • a) either T is phenyl, wherein the phenyl is substituted with one or more of 3-chloro-2-cyanophenoxy, fluoro, phenyl, n-propyl and, in o- or m-position, bromo, chloro, methyl;
    • b) T is phenyl substituted with at least two chloro and optionally one or more methyl; or
    • c) T is phenyl substituted with one bromo and 2 fluoro.
  • Specific examples of compounds according to the invention are:
      • 4-chloro-N-(4-methyl-1,3-thiazol-2-yl)benzenesulfonamide,
      • 3-chloro-2-methyl-N-(4-methyl-1,3-thiazol-2-yl)benzenesulfonamide,
      • 3-chloro-2-methyl-N-[4-methyl-5-(2,2,2-trichloroethyl)-1,3-thiazol-2-yl]benzenesulfonamide,
      • N-[4-methyl-5-(2,2,2-trichloroethyl)-1,3-thiazol-2-yl]-2,4,6-trichlorobenzene-sulfonamide,
      • 3-chloro-N-(5-ethyl4-methyl-1,3-thiazol-2-yl)-2-methylbenzenesulfonamide,
      • 3-chloro-2-methyl-N-(4-methyl-5-propyl-1,3-thiazol-2-yl)benzenesulfonamide,
      • 3-chloro-N-(4-ethyl-1,3-thiazol-2-yl)-2-methylbenzenesulfonamide,
      • 3-chloro-N-(4-ethyl-5-methyl-1,3-thiazol-2-yl)-2-methylbenzenesulfonamide,
      • 3-chloro-2-methyl-N-(4-propyl-1,3-thiazol-2-yl)benzenesulfonamide,
      • 3-chloro-N-(4-isopropyl-1,3-thiazol-2-yl)-2-methylbenzenesulfonamide,
      • N-(4-butyl-1,3-thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide,
      • N-(5-butyl-4-methyl-1,3-thiazol-2-yl)-2,4-dichloro-6-methylbenzenesulfonamide,
      • N-(4-tert-butyl-1,3-thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide,
      • ethyl 3-(2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,3-thiazol-4-yl)-3-methylbutanoate,
      • 2,4-dichloro-6-methyl-N-(4-pentyl-1,3-thiazol-2-yl)benzenesulfonamide,
      • 3-chloro-2-methyl-N-(4-vinyl-1,3-thiazol-2-yl)benzenesulfonamide,
      • N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-4-chlorobenzenesulfonamide,
      • N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide,
      • N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)[1,1′-biphenyl]-4-sulfonamide,
      • N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-4-(3-chloro-2-cyanophenoxy)benzenesulfonamide,
      • N-5-acetyl-4-methyl-1,3-thiazol-2-yl)-4-propylbenzenesulfonamide,
      • N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-2,4,6-trichlorobenzenesulfonamide,
      • N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-2,4-dichloro-methylbenzenesulfonamide,
      • N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-2,4,5-trichlorobenzenesulfonamide,
      • N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-4-bromo-5-chloro-2-thienylsulfonamide,
      • N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-4-bromo-2,5-difluoro-2-benzenesulfonamide,
      • N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-2,6-dichlorobenzenesulfonamide,
      • N-(5-carbethoxy-4-methyl-1,3-thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide,
      • N-(5-carbethoxy-4-methyl-1,3-thiazol-2-yl)[1,1′-biphenyl]-4-sulfonamide,
      • N-(5-carbethoxy-4-methyl-1,3-thiazol-2-yl)-4-propylbenzenesulfonamide,
      • N-(5-carbethoxy-4-methyl-1,3-thiazol-2-yl)-2,4-dichloro-6-methylbenzenesulfonamide,
      • N-(5-carbethoxy-4-methyl-1,3-thiazol-2-yl)-2,4,6-trichlorobenzenesulfonamide.
  • Another object of the present invention is a compound as described above for medical use.
  • Another object of the present invention is a process for the preparation of a compound as described above comprising at least one of the following steps:
    • a) sulfonamide coupling by reacting a 2-aminothiazole with a sulfonylchloride in the presence of a base,
    • b) sulfonamide coupling by reacting a 2-aminothiazole derivative with a sulfonylchloride in the presence of a base,
      • c) saponification by treatment of a carboxylic acid ester with aqueous hydroxide,
      • d) amide coupling by reacting a carboxylic acid with an amine in the presence of EDCI,
      • e) formation of a thiazole ring by reacting an optionally substituted thiourea with an α-haloketone,
      • f) formation of a thiazole ring by reacting a thiourea with a ketone,
      • g) reduction of an ester with lithium aluminium hydride,
      • h) conversion of an alcohol to a bromide with triphenylphosphine and carbon tetrabromide,
      • i) elimination of a bromide with a base to an alkene.
  • Another object of the present invention is a method for the treatment or prevention of diabetes, syndrome X, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, osteoporosis, tuberculosis, dementia, depression, virus diseases and inflammatory disorders, said method comprising administering to a mammal, including man, in need of such treatment an effective amount of a compound of the formula (I)
    Figure US20060287374A1-20061221-C00003
    wherein
  • T is an aryl ring or heteroaryl ring, optionally independently substituted by [R]n, wherein n is an integer 0-5, and R is hydrogen, C1-6-alkyl, halogen, aryl or axyloxy, wherein the aryloxy residue can further be optionally substituted in one or more positions independently of each other by cyano and halogen;
  • A is C1-6-alkyl, vinyl or 3-(ethyl 3-methylbutanoate);
  • B is hydrogen, halogen, C1-6-alkyl, halogenated C1-6-alkyl, C1-6-acyl or C1-6-alkoxycarbonyl;
  • as well as pharmaceutically acceptable salts, hydrates and solvates thereof
  • These compounds may also be used in the manufacture of a medicament for the prevention, management or treatment of diabetes, syndrome X, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, osteoporosis, tuberculosis, dementia, depression, virus diseases and inflammatory disorders.
  • It is preferred that:
  • T is selected from 4-bromo-5-chloro-2-thienyl and phenyl substituted with one or more of bromo, chloro, 3-chloro-2-cyanophenoxy, fluoro, methyl phenyl n-propyl;
  • A is selected from methyl ethyl, n-propyl, isopropyl, n-butyl tert-butyl n-pentyl, vinyl or 3-(ethyl 3-methylbutanoate);
  • B is selected from hydrogen, bromo, methyl, ethyl n-propyl, n-butyl, 2,2,2-trichloroethyl, acetyl and carbethoxy.
  • Specific examples of compounds according to the invention are:
      • 4-chloro-N-(4-methyl-1,3-thiazol-2-yl)benzenesulfonamide,
      • N-(4-methyl-1,3-thiazol-2-yl)benzenesulfonamide,
      • 3-chloro-2-methyl-N-(4-methyl-1,3-thiazol-2-yl)benzenesulfonamide,
      • 4-chloro-N-[4-methyl-5-(2,2,2-trichloroethyl)-1,3-thiazol-2-yl]benzenesulfonamide,
      • 3-chloro-2-methyl-N-[4-methyl-5-(2,2,2-trichloroethyl)-1,3-thiazol-2-yl]benzenesulfonamide,
      • N-[4methyl-5-(2,2,2-trichloroethyl)-1,3-thiazol-2-yl]-2,4,6-trichlorobenzene-sulfonamide,
      • 3-chloro-N-(5-ethyl-4-methyl-1,3-thiazol-2-yl)-2-methylbenzenesulfonamide,
      • 3-chloro-2-methyl-N-(4methyl-5-propyl-1,3-thiazol-2-yl)benzenesulfonamide,
      • 3-chloro-N-(4-methyl-1,3-thiazol-2-yl)-2-methylbenzenesulfonamide,
      • 3-chloro-N-(4-ethyl-5-methyl-1,3-thiazol-2-yl)-2-methylbenzenesulfonamide,
      • 3-chloro-2-methyl-N-(4propyl-1,3-thiazol-2-yl)benzenesulfonamide,
      • 3-chloro-N-(isopropyl-1,3-thiazol-2-yl)-2-methylbenzenesulfonamide,
      • N-(4-butyl-1,3-thiazol-2-yl-3-chloro-2-methylbenzenesulfonamide,
      • N-(5-butyl-4-methyl-1,3-thiazol-2-yl)-2,4-dichloro-6-methylbenzenesulfonamide,
      • N-(4-tert-butyl-1,3-thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide,
      • ethyl 3-(2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,3-thiazol-4-yl)-3-methylbutanoate,
      • 2,4-dichloro-6-methyl-N-(4-pentyl-1,3-thiazol-2-yl)benzenesulfonamide,
      • 3-chloro-2-methyl-N-(4-vinyl-1,3-thiazol-2-yl)benzenesulfonamide,
      • N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-4-chlorobenzenesulfonamide,
      • N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide,
      • N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)[1,1′-biphenyl]-4-sulfonamide,
      • N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-4-(3-chloro-2-cyanophenoxy)benzenesulfonamide,
      • N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-4-propylbenzenesulfonamide,
      • N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-2,4,6-trichlorobenzenesulfonamide,
      • N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-2,4-dichloro-6-methylbenzenesulfonamide,
      • N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-2,4,5-trichlorobenzenesulfonamide,
      • N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-4-bromo-5-chloro-2-thienylsulfonamide,
      • N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-4-bromo-2,5-difluoro-2-benzenesulfonamide,
      • N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-2,6-dichlorobenzenesulfonamide,
      • N-(5-carbethoxy-4-methyl-1,3-thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide,
      • N-(5-carbethoxy-4-methyl-1,3-thiazol-2-yl)[1,1′-biphenyl]-4-sulfonamide,
      • N-(5-carbethoxy-4-methyl-1,3-thiazol-2-yl)-4-propylbenzenesulfonamide,
      • N-(5-carbethoxy-4-methyl-1,3-thiazol-2-yl)-2,4-dichloro-6-methylbenzenesulfonamide,
      • N-(5-carbethoxy-4-methyl-1,3-thiazol-2-yl)-2,4,6-trichlorobenzenesulfonamide,
      • N-[5-bromo-4-(tert-butyl)-1,3-thiazol-2-yl]-4-chlorobenzenesulfonamide.
  • Another object of the present invention is a pharmaceutical composition comprising at least one compound of the formula (I) as defined above, and a pharmaceutically acceptable carrier.
  • The compounds according to the present invention may be used in several indications which involve 11-β-hydroxysteroid dehydrogenase type 1 enzyme. Thus the compounds according to the present invention may be used against dementia (see WO97/07789), osteoporosis (see Canalis E 1996, Mechanisms of glucocorticoid action in bone: implications to glucocorticoid-induced osteoporosis, Journal of Clinical Endocrinology and Metabolism, 81, 3441-3447) and may also be used disorders in the immune system (see Franchimont et al., “Inhibition of Th1 immune response by glucocorticoids: dexamethasone selectively inhibits IL-12-induced Stat 4 phosphorylation in T lymphocytes”, The journal of Immunology 2000, Feb. 15, vol 164 (4), pages 1768-74) and also in the above listed indications.
  • The various terms used, separately and in combinations, in the above definition of the compounds having the formula (I) will be explained.
  • The term “aryl” in the present description is intended to include aromatic rings (monocyclic or bicyclic) having from 6 to 10 ring carbon atoms, such as phenyl (Ph; a monocyclic ring) and naphthyl (a bicyclic ring), which optionally may be substituted by C1-6-alkyl. Examples of substituted aryl groups are benzyl and 2-methylphenyl
  • The term “eteroaryl” means in the present description a monocyclic, bi- or tricyclic aromatic ring system (only one ring need to be aromatic) having from 5 to 14, preferably 5 to 10 ring atoms such as 5, 6, 7, 8, 9 or 10 ring atoms (mono- or bicyclic), in which one or more of the ring atoms are other than carbon, such as nitrogen, sulfur, oxygen and selenium. Examples of such heteroaryl rings are pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, tetrazole, chroman, isochroman, quinoline, quinoxaline, isoquinoline, phthalazine, cinnoline, quinazoline, indole, isoindole, indoline, isoindoline, benzothiophene, benzofuran, isobenzofuran, benzoxazole, 2,1,3-benzoxadiazole, benzothiazole, 2,1,3-benzothiazole, 2,1,3-benzoselenadiazole, benzimidazole, indazole, benzodioxane, indane, 1,2,3,4-tetrahydroquinoline, 3,4-dihydro-2H-1,4-benzoxazine, 1,5-naphthyridine, 1,8-naphthyridine, acridine, fenazine and xanthene. Examples of monocyclic heteroaryl rings are pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, and tetrazole.
  • C1-6-alkyl in the compound of formula (I) according to the present application, which may be straight or branched, is preferably C1-4-alkyl. Exemplary alkyl groups include methyl, ethyl, n-propyl isopropyl butyl sec-butyl tert-butyl, n-pentyl, isopentyl hexyl, and isohexyl.
  • C1-6-alkoxy, in the compound of formula (I) according to the present application may be straight or branched, is preferably C1-4-alkoxy. Exemplary alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, hexyloxy, and isohexyloxy.
  • C1-6-acyl, in the compound of formula (1) according to the present application may be saturated or unsaturated and is preferably C1-4-acyl. Exemplary acyl groups include formyl, acetyl, propionyl butyryl, isobutyryl, valeryl, isovaleryl, butenoyl (e.g. 3-butenoyl); hexenoyl (e.g. 5-hexenoyl).
  • The term “halogen” in the present description is intended to include fluorine, chlorine, bromine and iodine.
  • The term “prodrug forms” in the present description means a pharmacologically acceptable derivative, such as an ester or an amide, which derivative is biotransformed in the body to form the active drug (see Goodman and Gilman's, The Pharmacological basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992, “Biotransformation of Drugs, p. 13-15).
  • “Pharmaceutically acceptable” means in the present description being useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use.
  • “Pharmaceutically acceptable salts” mean in the present description salts which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with organic and inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, methanesulfonic acid, triluoroacetic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid and the like. Base addition salts may be formed with organic and inorganic bases, such as sodium, ammonia, potassium, calcium, ethanolamine, diethanolamine, N-methylglucamine, choline and the like.
  • Pharmaceutical compositions according to the present invention contain a pharmaceutically acceptable carrier together with at least one of the compounds comprising the formula (I) as described herein above, dissolved or dispersed therein as an active, antimicrobial, ingredient. In a preferred embodiment the therapeutic composition is not immunogenic when administered to a human patient for therapeutic purposes, unless that purpose is to induce an immune response.
  • The preparation of a pharmacological composition that contains active ingredients dissolved or dispersed therein is well understood in the art. Typically such compositions are prepared as sterile in injectables either as liquid solutions or suspensions, aqueous or non-aqueous, however, solid forms suitable for solution, or suspensions, in liquid prior to use can also be prepared. The preparation can also be emulsified.
  • The active ingredient may be mixed with excipients, which are pharmaceutically acceptable and compatible with the active ingredient and in amounts suitable for use in the therapeutic methods described herein. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like and combinations thereof. In addition, if desired, the composition may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like which enhance the effectiveness of the active ingredient. Adjuvants may also be present in the composition.
  • Pharmaceutically acceptable carriers are well known in the art. Exemplary of liquid carriers are sterile aqueous solutions that contain no materials in addition to the active ingredients and water, or contain a buffer such as sodium phosphate at physiological pH value, physiological saline or both, such as phosphate-buffered saline. Still further, aqueous carriers can contain more than one buffer salt, as well as salts such as sodium and potassium chlorides, dextrose, propylene glycol polyethylene glycol and other solutes.
  • Liquid compositions can also contain liquid phases in addition to and to the exclusion of water. Exemplary of such additional liquid phases are glycerine, vegetable oils such as cottonseed oil, organic esters such as ethyl oleate, and water-oil emulsions.
  • The pharmaceutical composition according to one of the preferred embodiments of the present invention comprising compounds comprising the formula (I), may include pharmaceutically acceptable salts of that component therein as set out above. Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the polypeptide) that are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic acid, tartaric acid, mandelic acid and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine and the like.
  • The preparations according to the preferred embodiments may be administered orally, topically, intraperitoneally, intraarticularly, intracranially, intradermally, intramuscularly, intraocularly, intrathecally, intravenously, subcutaneously. Other routes which are known for the skilled person in the art are thinkable.
  • The orally administrable compositions according to the present invention may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations; such as oral, topical or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in unit dose presentation form and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol traganath or polyvinyl-pyrrolidone; fillers e.g. lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant e.g. magnesium stearate, talc, polyethylene glycol or silica; disintegrants e.g. potato starch, or acceptable wetting agents such as sodium lauryl sulfate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of e.g. aqueous or oily suspensions, solutions, emulsions, syrups or elixirs or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, e.g. sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents e.g. lecithin, sorbitan monooleate or acacia, non-aqueous vehicles (which may include edible oils), e.g. almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives e.g. methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • A pharmaceutical composition according to the present invention, may comprise typically an amount of at least 0.1 weight percent of compound comprising the formula (I) per weight of total therapeutic composition. A weight percent is a ratio by weight of total composition. Thus, for example, 0.1 weight percent is 0.1 grams of compound comprising the formula (I) per 100 grams of total composition. A suitable daily oral dose for a mammal, preferably a human being, may vary widely depending on the condition of the patient. However a dose of compound comprising the formula (I) of about 0.1 to 300 mg/kg body weight may be appropriate.
  • The compositions according to the present invention may also be used veterinarily and thus they may comprise a veterinarily acceptable excipient or carrier.
  • The compounds of the present invention in labelled form, e.g. isotopically labelled, may be used as a diagnostic agent.
  • The compounds of the formula (I) above may be prepared by, or in analogy with, conventional methods, and especially according to or in analogy with the following methods. Further, the pharmacology in-vitro was studied using the following reagents and methods.
  • All publications mentioned herein are hereby incorporated by reference. By the expression “comprising” we understand including but not limited to. Thus, other non-mentioned substances, additives or carriers may be present.
  • The invention will now be described in reference to the following Figures and Examples. These Figures and Examples are not to be regarded as limiting the scope of the present invention, but shall only serve in an illustrative manner.
    • EXPERIMENTAL METHODS Scintillation Proximity Assay
  • [1,2(n)-3H]-cortisone was purchased from Amersham Pharmacia Biotech Anti-cortisol monoclonal mouse antibody, clone 6D6.7 was obtained from Immunotech and Scintillation proximity assay (SPA) beads coated with monoclonal antimouse antibodies were from Amersham Pharmacia Biotech. NADPH, tetrasodium salt was from Calbiochem and glucose-6-phosphate (G-6-P) was supplied by Sigma. The human 11-β-hydroxysteroid dehydrogenase type-1 enzyme (11-β-HSD1) was expressed in Pichia pastoris. 18-β-glycyrrhetinic acid (GA) was obtained from Sigma. The serial dilutions of the compounds were performed on a Tecan Genesis RSP 150. Compounds to be tested were dissolved in DMSO (1 mM) and diluted in 50 mM Tris-HCl, pH 7.2 containing 1 mM EDTA.
  • The multiplication of plates was done on a WallacQuadra. The amount of the product [3H]-cortisol, bound to the beads was determined in a Packard, Top Count microplate liquid scintillation counter.
  • The 11-β-HSD1 enzyme assay was carried out in 96 well microtiter plates (Packard, Optiplate) in a total well volume of 220 μL and contained 30 mM Tris-HCl, pH 7.2 with 1 mM EDTA, a substrate mixture tritiated Cortisone/NADPH (175 nM/181 μM), G-6-P (1 mM) and inhibitors in serial dilutions (9 to 0.15 μM. Reactions were initiated by the addition of human 11-β-HSD1, either as Pichia pastoris cell homogenate or microsomes prepared from Pichia pastoris (the final amount of enzyme used was varied between 0.057 to 0.11 mg/mL). Following mixing, the plates were shaken for 30 to 45 minutes at room temperature. The reactions were terminated with 10 μL 1 mM GA stop solution. Monoclonal mouse antibody was then added (10 μL of 4 μM) followed by 100 μL of SPA beads (suspended according to the manufacturers instructions). Appropriate controls were set up by omitting the 11-β-HSD1 to obtain the non-specific binding (NSB) value.
  • The plates were covered with plastic film and incubated on a shaker for 30 minutes, at room temperature, before counting. The amount of [3H]-cortisol, bound to the beads was determined in a microplate liquid scintillation counter.
  • The calculation of the Ki values for the inhibitors was performed by use of Activity Base. The Ki value is calculated from IC50 and the Km value is calculated using the Cheng Prushoff equation (with reversible inhibition that follows the Michaelis-Menten equation): Ki=IC50(1+[S]/Km) [Cheng, Y. C.; Prushoff, W. H. Biochem. Pharmacol. 1973, 22, 3099-3108]. The IC50 is measured experimentally in an assay wherein the decrease of the turnover of cortisone to cortisol is dependent on the inhibition potential of each substance. The Ki values of the compounds of the present invention for the 11-β-HSD1 enzyme lie typically between about 10 nM and about 10 μM. Illustrative of the invention, the following Ki values have been determined in the human 11-β-HSD1 enzyme assay (see Table 1):
    TABLE 1
    Ki values determined in the human 11-β-HSD1 enzyme assay.
    Compound of Example Ki (nM)
    3 122
    6 123
    18 90
    22 108
    • COMPOUND PREPARATION
  • General:
  • For preparative straight phase HPLC purification a Phenomenex column (250×21.1 mm, 10 μm) was used on a Gilson system eluting with ethanol in chloroform (gradient from 0 -10% in 10 min) with a flow of 20 mL/min. Column chromatography was performed on silica using Silica gel 60 (230-400 mesh), Merck Melting points were determined on a Gallenkamp apparatus. Elemental analyses were recorded using a Vario EL instrument. HPLC analyses were performed using a Hypersil Elite column (150×4.6 mm, 3μ) with a flow of 3 mL/min on a Waters 600E system with monitoring at 254 nm. Reverse phase preparative HPLC was carried out on a 100×21.2 mm, 5μ Hypersil Elite column eluting with a gradient of 5% ACN in 95% water to 95% ACN in 5% water (0.2% TFA buffer) over 10 mins at a flow rate of 20 mL/mm with the UV detector set at 254 nm. Thin layer chromatography was carried out using pre-coated silica gel F-254 plates (thickness 0.25 mm). Electrospray MS spectra were obtained on a Micromass platform LCMS spectrometer. Crude, worked up compounds were purified by flash column chromatography using pre packed silica SPE columns (10 g silica) on an Isco Foxy 200 Combiflash system, and a gradient of 16.67% ethyl acetate in hexane increasing incrementally to 100% ethyl acetate.
    • List of Abbreviations
    • DCM=dichloromethane
    • DIEA=N,N-diisopropylethylamine
    • DMAP=4-diethylaminopyridine
    • DME=ethyleneglycol dimethyl ether
    • DMF=dimethylformamide
    • DMSO=dimethyl sulfoxide
    • EDCI=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
    • EDTA=ethylenediaminetetraacetic acid
    • HCOOH=formic acid
    • HOAT=1-hydroxy-7-azabenzotiazole
    • HOBT=1-hydroxybenzotriazole hydrate
    • MTBE=tert-butyl methyl ether
    • TEA=trethylamine
    • THF=tetrahydrofuran
      Sulfonamide Couplings:
      Method A:
  • 1 Eq of the 2-aminothiazole was dissolved in pyridine (0.5 M solution). The sulfonyl chloride (1.2 eq) was added and the reaction mixture was stirred at ambient temperature under nitrogen atmosphere for 15 h. The reaction mixture was poured into aqueous HCl (1 M). If the product precipitated it was collected on a filter and washed with aqueous HCl (1 M) and recrystallised from ethanol. In case an oil was obtained, the crude was extracted with DCM and worked up and purified using standard procedures.
  • Method B:
  • A solution of the 2-aminothiazole derivative (1 eq), triethylamine (2 eq) and DMAP (1 eq) in DMF (1 M) and DCM (0.225 M) was dispensed into a reaction vial. The sulfonyl chloride (1.2 eq) was dissolved in DCM (0.33 W and added. The reaction mixtures were kept at room temperature over night. The mixture was then added to petroleum ether (10 times reaction volume). After some hours in refrigerator the supernatants were decanted and (a portion of) the residual materials were dissolved in DMSO-methanol-acetic acid (300 μL+500 μL+50 μL) and purified by preparative LCMS (acetonitrile-water gradients). The purest fractions were collected and lyophlihzed. Alternatively, the crude was isolated using extractive work-up and purified using standard procedures.
  • Saponifications:
  • Method C:
  • 1 Eq of the ester was suspended in 95% ethanol (0.1 M) and treated with KOH (aqueous, 6 eq). Water was added until a clear solution was achieved. The reaction mixture was stirred for 2-3 h at ambient temperature. The solvent was removed under reduced pressure and the crude was redissolved in water. Addition of conc. HCl until pH 2 gave a precipitate which was collected on a filter and washed with cold water and dried.
  • Amide Couplings:
  • Method E:
  • The carboxylic acid was suspended in DCM (0.05M) followed by the addition of EDCI (1.1 eq), triethylamine (3 eq), DMAP (0.5 eq) and the amine of choice (1.2 eq). DMF was added when the staring materials did not dissolve properly. The reaction mixture was stirred at ambient temperature over night. The organic phase was washed with aqueous HCl (1 M), dried over sodium sulfate, filtered and evaporated in vacuo. The crude product amide was purified by flash column chromatography on silica gel, eluting with methanol (1→3→6%) in: DCM or ethyl acetate.
  • Formation of Thiazole Ring:
  • Method H:
  • To a solution or suspension of an optionally substituted thiourea in ethanol (0.5 M), 1 equivalent of α-haloketone was added at room temperature. The reaction mixture was stirred in a sealed tube at 95° C. for 4 h, cooled, concentrated, redissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate and chromatographed on silica gel using petroleum-ether and ethyl acetate as eluents.
  • Method I:
  • To a 0.5 M solution of ketone (1 eq) and thiourea (2 eq) in ethanol at 60° C., 1 eq of iodine was added in one portion. The reaction tube was sealed and the reaction mixture was stirred at 100° C. for 16 hours. After evaporation of the solvent the residue was taken up in DCM, washed with saturated aqueous sodium hydrogen carbonate, dried with magnesium sulfate. Products were purified by chromatography on silica gel using a gradient of petroleum-ether/ethyl acetate from 8:1 to 2:1 for elution.
    • KNOWN EXAMPLES
  • The compounds of the following Examples 2, 4 and 35 are commercially available and could e g be purchased from Maybridge.
    • 2 [216A] N-(4-Methyl-1,3-thiazol-2-yl)benzenesulfonamide
    • 4 [218A] 4-methyl-N-[4-methyl-5-(2,2,2-trichloroethyl)-1,3-thiazol-2-yl]benzenesulfonamide
    • 35 [341A] N-[5-bromo-4-(tert-butyl)-1,3-thiazol-2-yl]-4-chlorobenzenesulfonamide
    NOVEL EXAMPLES
  • The following specific compounds were synthesized. The commercially available compounds thus only form embodiments, as indicated earlier in the description, as pharmaceutical compositions and use of said compounds as set out in the appended set of claims.
    • Example 1 [215A]
  • 4-Chloro-N-(4-methyl-1,3-thiazol-2-yl)benzenesulfonamide
  • The title compound was prepared according to METHOD A, giving 143 mg (41%) after recrystallization from DCM: MS (Ionspray, [M+H]+) m/z 288; Anal. Calcd. (found) for C10H9ClN2O2S2: C 41.6 (41.5) % H 3.1 (2.7) % N 9.7 (9.3) %.
    • Example 3 [217A]
  • 3-Chloro-2-methyl-N-(4-methyl-1,3-thiazol-2-yl)benzenesulfonamide
  • The title compound was prepared from 2-amino-4-methylthiazole (285 mg) and 3-chloro-2-methylbenzenesulfonyl chloride (619 mg) according to METHOD A. This afforded 167 mg (22%) of a yellow solid after purification: 1H NMR (DMSO-d6) δ 2.1 (s, 3H), 2.6 (s, 3H), 6.35 (s, 1H), 7.35 (t, 1H), 7.65 (d, 1H), 7.85 (d, 1H), 12.7 (br s, 1H).
    • Example 5 [219A]
  • 3-Chloro-2-methyl-N-[4-methyl-5(2,2,2-trichloroethyl)-1,3-thiazol-2-yl]benzenesulfonamide
  • The title compound was prepared similar to EXAMPLE 6 according to METHOD A from 4-methyl-5-(2,2,2-trichloroethyl)-1,3-thiazol-2-ylamine (123 mg, 0.5 mmol) and 3-chloro-2-methylbenzenesulfonyl chloride (112.5 mg, 0.5 mmol). The solution was allowed to stand at r.t. overnight. Water (5 mL) was added and the resulted solution was made acidic with conc. HCl. The precipitate was filtered, washed with water and dried. Flash column chromatography of the precipitate on silica gel, eluted with a mixed solvents of ethyl ether and hexane (2:1) gave the title compound as a solid (165 mg, 76% yield). The product can be recrystallized from ethyl acetate and hexane: MS m/e: 439, 437, 435, 433.
    • Example 6 [220A]
  • 2,4,6-trichloro-N-[4-methyl-5-(2,2,2-trichloroethyl)-1,3-thiazol-2-yl]benzenesulfonamide
  • The title compound was prepared according to METHOD A from 4-methyl-5-(2,2,2-trichloroethyl)-1,3-thiazol-2-ylamine (123 mg, 0.5 mmol, prepared according to Dodinoy, A. A et al (1993) Chem. Heterocycl. Comp (Eng. Transl.) 29(8): 955-958) and 2,4,6-trichlorobenzenesulfonyl chloride (140 mg, 0.5 mmol). The solution was allowed to stand at room temperature overnight. The solution was directly loaded on a silica gel column for flash column chromatography, eluted with a mixed solvent of ethyl acetate and hexane (up to 40% v/v) to give a solid product. Crystallization of the product from ethyl acetate and hexane gave the title compound as a white solid (112 mg, 46% yield): mp 228-229° C.; MS m/e 487, 489, 491, 493, Anal. Calcd (found) for C12H8Cl6N2O2: C 29.5 (29.7) % H 1.7 (2.1) % N 5.7 (5.8) %.
    • Example 7 [221A]
  • 3-Chloro-N-(5-ethyl-4-methyl-1,3-thiazol-2-yl)-2-methylbenzenesulfonamide
  • The title compound was prepared from 5-ethyl-4-methyl-1,3-thiazol-2-ylamine (METHOD I) and 3-chloro-2-methylbenzenesulfonyl chloride according to METHOD A, yellow solid, 42 mg (25% yield): HRMS Calcd (found) for C13H15ClN2O2S2 m/z 330.0263 (330.0250).
    • Example 8 [222A ]
  • 3-Chloro-2-methyl-N-(4-methyl-5-propyl-1,3-thiazol-2-yl)benzenesulfonamide
  • The title compound was prepared from 4-methyl-5-propyl-1,3-thiazol-2-ylamine (METHOD I) and 3-chloro-2-methylbenzenesulfonyl chloride according to METHOD A, yellow solid, 110 mg (46% yield): HRMS Calcd (found) for C14H17ClN2O2S2 m/z 344.0420 (344.0403).
    • Example 9 [224A]
  • 3-Chloro-N-(4-ethyl-1,3-thiazol-2-yl)-2-methylbenzenesulfonamide
  • The title compound was prepared from 4-ethyl-1,3-thiazol-2-ylamine (METHOD H) and 3-chloro-2-methylbenzenesulfonyl chloride according to METHOD A, yellowish solid, 53 mg (17% yield): HRMS Calcd (found) for C12H13ClN2O2S2 m/z 316.0107 (316.0120).
    • Example 10 [225A]
  • 3-Chloro-N-(4-ethyl-5-methyl-1,3-thiazol-2-yl)-2-methylbenzenesulfonamide
  • The title compound was prepared from 4-ethyl-5-methyl-1,3,-thiazol-2-ylamine (METHOD I) and 3-chloro-2-methylbenzenesulfonyl chloride according to METHOD A, yellowish foam, 40 mg (12% yield): HRMS Calcd (found) for C13H15ClN2O2S2 m/z 330.0263 (330.0271).
    • Example 11 [226A]
  • 3-Chloro-2-methyl-N-(4-propyl-1,3-thiazol-2-yl)benzenesulfonamide
  • The title compound was prepared from 4-propyl-1,3-thiazol-2-ylamine (METHOD 1) and 3-chloro-2-methylbenzenesulfonyl chloride according to METHOD A, yellow solid, 90 mg (39% yield): mp 169° C.; HRMS Calcd (found) for C13H15ClN2O2S2 m/z 330.0263 (330.0251).
    • Example 12 [227A]
  • 3-Chloro-N-(4-isopropyl-1,3-thiazol-2-yl)-2-methylbenzenesulfonamide
  • The title compound was prepared from 4-isopropyl-1,3-thiazol-2-ylamine (METHOD I) and 3-chloro-2-methylbenzenesulfonyl chloride according to METHOD A, white foam, 80 mg (48% yield): HRMS Calcd (found) for C13H15ClN2O2S2 m/z 330.0263 (330.0257).
    • Example 13 [228A]
  • N-(4-Butyl-1,3-thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide
  • The title compound was prepared from 4-butyl-1,3-thiazol-2-ylamime (METHOD H) and 3-chloro-2-methylbenzenesulfonyl chloride according to METHOD A, yellow solid, 52 mg (22% yield): HRMS Calcd (found) for C14H17ClN2O2S2 m/z 344.0420 (334.0414).
    • Example 14 [229A]
  • N-(5-butyl-4-methyl-1,3-thiazol-2-yl)-2,4-dichloro-6-methylbenzenesulfonamide
  • The title compound was prepared from 5-butyl-4-methyl-1,3-thiazol-2-ylamine (METHOD I) and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (41 mg) with purity >90%. MS (pos) m/z 393.2, 395.2.
    • Example 15 [230A]
  • N-(4-Tert-butyl-1,3-thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide
  • The title compound was prepared from 4-tert-butyl-1,3-thiazol-2-ylamine (METHOD H) and 3-chloro-2-methylbenzenesulfonyl chloride according to METHOD A, white foam 273 mg (40% yield). mp 178° C.; HRMS Calcd (found) for C14H17ClN2O2S2 m/z 344.0420 (344.0408).
    • Example 16 [231A]
  • Ethyl 3-(2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,3-thiazol-4-yl)-3-methylbutanoate
  • The title compound was prepared from ethyl 3-(2-amino-1,3-thiazol-4-yl)-3-methylbutanoate (METHOD I) and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic method to give a white solid (55.0 mg) with purity >90%. MS (pos) m/z 451.2, 453.2.
    • Example 17 [232A]
  • 2,4-Dichloro-6-methyl-N-(4-pentyl-1,3-thiazol-2-yl)benzenesulfonamide
  • The title compound was prepared from 4-pentyl-1,3-thiazol-2-ylamine (METHOD I) and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (28.6 mg) with purity >90%. MS (pos) m/z 393.1, 395.1.
    • Example 18 [233A]
  • 3-Chloro-2-methyl-N-(4-vinyl-1,3-thiazol-2-yl)benzenesulfonamide
  • The title compound was prepared in the following steps 1-4:
  • Step 1
  • Ethyl 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-4-yl)acetate was prepared according to METHOD A at 30° C., using a Quest 210 apparatus. This procedure gave 2.05 g (34%) of an off-white solid.
  • Step 2
  • To a solution of the product from Step 1 (5.00 g, 13.34 mmol) in tetrahydrofuran (200 mL) was added litium aluminum hydride (1.06 g, 28.02 mmol) in small portions. The temperature was kept below 0° C. during the addition, and the mixture was stirred for 45 min. at 0° C., treated with water (1 mL), conc. HCl(1 mL) and water (1 mL). Sodium sulfate was added and the solid was filtered off. The solvent was evaporated and the crude product was purified by flash column chromatography on silica gel eluting with 20% acetone in dichloromethane to yield the product (2.41 g, 7.24 mmol, 54%).
  • Step 3
  • An ice-cold mixture of the product from Step 2 (2.03 g, 6.10 mmol), triphenylphosphine (4.80 g, 18.31 mmol) and carbon tetrabromide (6.07 g, 18.31 mmol) in DMF (30 mL) was stirred for 1.5 h, and was then poured into water. The mixture was extracted with dichloromethane, dried (sodium sulfate) and the solvent was evaporated. The crude material was twice purified by flash chromatography on silica gel gradient eluting with 0-4% acetone in dichloromethane giving N-[4-(2-bromoethyl)-1,3-thiazol-2-yl]-3-chloro-2-methylbenzenesulfonamide as a solid (990 mg, 41%).
  • Step 4
  • Sodium hydride (95% dry, 32 mg, 1.27 mmol) was added to a stirred solution of the product from Step 3 (240 mg, 0.61 mmol) and 3-hydroxypyridine (63 mg, 0.67 mmol) in tetrahydrofuran (10 mL) at 0° C. After 2 h at reflux temperature the reaction was neutralized by adding 2 M HCl and the product mixture was extracted with dichloromethane. The organic phase was dried (Na2SO4) and the solvent was evaporated. The crude material was purified by flash chromatography on silica gel gradient eluting with 2-5% acetone in dichloromethane giving the title compound as a solid (33 mg, 17%). MS (Ionspray, [M+H]+) m/z 314; Anal. Calcd (found) for C12H11ClN2O2S2: C 45.8(45.0) % H 3.5(3.9) % N 8.9(9.1) %.
    • Example 19 [237A]
  • N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-4-chlorobenzenesulfonamide
  • The title compound was prepared from 5-acetyl-2-amino-4-methylthiazole and 4-chlorobenzenesulfonyl chloride as described in the'synthetic METHOD B to give a white solid (12.2 mg) with purity >90%. LCMS (pos) m/z 331.2.
    • Example 20 [238A]
  • N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide
  • The title compound was prepared from 5-acetyl-2-amino-4-methylthiazole and 3-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (10.8 mg) with purity >90%. LCMS (pos) m/z 345.0.
    • Example 21 [239A]
  • N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)[1,1′-biphenyl]-4-sulfonamide
  • The title compound was prepared from 5-acetyl-2-amino-4-methylthiazole and 4-biphenylsulfonyl chloride as described in the synthetic METHOD B to give a white solid (5.5 mg) with purity >90%. LCMS (pos) m/z 372.8.
    • Example 22 [240A]
  • N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-4-(3-chloro-2-cyanophenoxy)benzenesulfonamide
  • The title compound was prepared from 5-acetyl-2-amino-4-methylthiazole and 4-(3-chloro-2-cyanophenoxy)benzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (9.9 mg) with purity >90%. LCMS (pos) m/z 448.0; LCMS (neg) m/z 446.0.
    • Example 23 [241A]
  • N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-4-propylbenzenesulfonamide
  • The title compound was prepared from 5-acetyl-2-amino-4-methylthiazole and 4-n-propylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (11.6 mg) with purity >90%: MS (pos) m/z 339.2; HRMS m/z 338.0748 (calc. of monoisotopic mass for C15H18N2O3S2 gives 338.0759).
    • Example 24 [242A]
  • N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-2,4,6-trichlorobenzenesulfonamide
  • The title compound was prepared from 5-acetyl-2-amino-4-methylthiazole and 2,4,6-trichlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white-yellow solid (15.5 mg) with purity >90%. MS (pos) m/z 399.1, 401.1, 403.1.
    • Example 25 [243A]
  • N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-2,4-dichloro-6-methylbenzenesulfonamide
  • The title compound was prepared from 5-acetyl-2-amino-4-methylthiazole and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white-yellow solid (28.4 mg) with purity >90%. MS (pos) m/z 379.1, 381.1.
    • Example 26 [243B]
  • N-(5-Acetyl-4-methyl-1,3-thiazol-2-yl)-2,4,5-trichlorobenzenesulfonamide
  • The title compound was prepared from 5-acetyl-2-amino-4-methylthiazole (42 mg) and 2,4,5-trichlorobenzenesulfonyl chloride (76 mg) as described in the synthetic METHOD B to give a white solid (23.7 mg) with purity >90%: MS (pos) m/z 399.2, 401.2; HRMS m/z 397.9103 (calc. of monoisotopic mass for C12H9Cl3N2O3S2 gives 397.9120).
    • Example 27 [243C]
  • N-(5-Acetyl-4-methyl-1,3-thiazol-2-yl)-4-bromo-5-chloro-2-thiophenesulfonamide
  • The title compound was prepared from 5-acetyl-2-amino-4-methylthiazole (42 mg) and 4-bromo-5-chlorothiophene-2-sulfonyl chloride (80 mg) as described in the synthetic METHOD B to give a white solid (11.7 mg) with purity >90%: MS (pos) m/z 415.3, 417.3.
    • Example 28 [243D]
  • N-(5-Acetyl-4-methyl-1,3-thiazol-2-yl)bromo-2,5-difluorobenzenesulfonamide
  • The title compound was prepared from 5-acetyl-2-amino-4-methylthiazole (42 mg) and 4-bromo-2,5-difluorobenzenesulfonyl chloride (79 mg) as described in the synthetic METHOD B to give a white solid (21.0 mg) with purity >90%: MS pos) m/z 411.2, 413.2.
    • Example 29 [243E]
  • N-(5-Acetyl-4-methyl-1,3-thiazol-2-yl)-2,6-dichlorobenzenesulfonamide
  • The title compound was prepared from 5-acetyl-2-amino-4-methylthiazole (42 mg) and 2,6-dichlorobenzenesulfonyl chloride (66 mg) as described in the synthetic METHOD B to give a white solid (21.4 mg) with purity >90%: MS (pos) m/z 365.3, 367.3.
    • Example 30 [243F]
  • Ethyl 2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-4-methyl-1,3-thiazole-5-carboxylate
  • Ethyl 2-amino4-methylthiazole-5-carboxylate (186 mg, 1.0 mmol) and DMAP (122 mg, 1.0 mmol) was mixed with DCM (4 mL) and Et3N (0.28 mL, 2.0 mmol). The mixture was cooled in ice. 3-Chloro-2-methylbenzenesulfonyl chloride (236 mg, 1.05 mmol) was added in two portions. After ½ h the mixture was stirred at room temperature and left overnight. More DCM was added and the solution was washed with aqueous HCl (0.2 M), water and aqueous sodium bicarbonate (0.1 M). A precipitate was separated from the solution. The solution was passed through a silica gel column, eluting with 2% methanol/DCM to give a product (73 mg after recryst. from methanol). The precipitate was combined with the 73 mg and recrystallized from methanol. Yield 266 mg, 71%: 1H NMR (DMSO) δ 13.3 (bs, 1H), 7.91 (d, 1H), 7.70 (d, 1H), 7.41 (s, 1H), 4.20 (q, 2H), 2.62 (s, 3H), 2.39 (s, 3H), 1.24 (q, 3H); MS ES (neg) m/z 373.1.
    • Example 31 [243G]
  • Ethyl 2-[([1,1′-biphenyl]-4-ylsulfonyl)amino]-4-methyl-1,3-thiazole-5-carboxylate
  • This compound was prepared from ethyl 2-amino methylthiazole-5-carboxylate and 4-biphenylsulfonyl chloride as described for EXAMPLE 30 with the exception that it was not recrystallized. Yield 96 mg, 24%: 1H NMR (DMSO) δ 7.8-7.95 (m, 4H), 7.65-7.75 (m, 2H), 7.35-7.55 (m, 3H), 4.23 (q, 2H), 2.39 (s, 3H), 1.26 (t, 3H), MS-ES (neg) m/z 401.2.
    • Example 32 [243H]
  • Ethyl 4-methyl-2-{[(4-propylphenyl)sulfonyl]amino}-1,3-thiazole-5-carboylate
  • This compound was prepared from ethyl 2-amino-4-methylthiazole-5-carboxylate and 4-n-propylbenzenesulfonyl chloride as described for EXAMPLE 30 with the exception that it was not recrystallized. Yield 315 mg, 85%: 1H NMR (DMSO) δ 7.70 (d, 2H), 7.37 (d, 2H), 4.21 (q, 2H), 2.60 (t, 2H) 2.38 (s, 3H), 1.58 (m, 2H), 1.25 (t, 3H), 0.87 (t, 3H); MS-ES (neg) m/z 367.2.
    • Example 33 [243I]
  • Ethyl 2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-4-methyl-1,3-thiazole-5-carboxylate
  • This compound was prepared from ethyl 2-amino-4-methylthiazole-5-carboxylate and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described for EXAMPLE 30. Yield 254 mg, 62%: 1H NMR (DMSO) δ 7.64 (d, 1H), 7.53 (d, 1H), 4.22 (q, 2H), 2.67 (s, 3H), 2.41 (s, 3H), 1.25 (t, 3H); MS-ES (neg) m/z 407.1.
    • Example 34 [243J]
  • Ethyl 4-methyl-2-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-1,3-thiazole-5-carboxylate
  • This compound was prepared from ethyl 2-amino-4-methylthiazole-5-carboxylate and 2,4,6-trichlorobenzenesulfonyl chloride as described for EXAMPLE 30 with the exception that it was purified by recrystallization only. Yield 249 mg, 58%: 1H NMR (DMSO) δ 7.84 (s 2H), 4.23 (q, 2H), 2.42 (s, 3H), 1.25 (t, 3H); MS-ES (neg) m/z 429.1.
  • Various embodiments of the present invention have been described above but a person skilled in the art realizes further minor alterations which would fall into the scope of the present invention. The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

Claims (10)

1-12. (canceled)
13. A compound of the formula (I)
Figure US20060287374A1-20061221-C00004
wherein
T is a monocyclic heteroaryl ring, optionally independently substituted by [R]n, wherein n is an integer 0-5, and R is hydrogen, C1-6-alkyl, halogen, aryl or aryloxy, wherein the aryloxy residue can further be optionally substituted in one or more positions independently of each other by cyano and halogen;
A is C1-6-alkyl, vinyl or 3-(ethyl 3-methylbutanoate);
B is hydrogen, methyl, ethyl, n-propyl, n-butyl, halogenated C1-6-alkyl, C1-6-acyl or C1-6-alkoxycarbonyl;
as well as pharmaceutically acceptable salts, hydrates and solvates thereof.
14. A compound according to claim 13, wherein
T is 4-bromo-5-chloro-2-thienyl
A is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, vinyl or 3-(ethyl 3-methylbutanoate);
B is selected from hydrogen, methyl, ethyl, n-propyl, n-butyl, 2,2,2-trichloroethyl, acetyl and carbethoxy.
15. A compound of claim 13 that is
N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-4-bromo-5-chloro-2-thienylsulfonamide,
16. A process for the preparation of a compound according to claim 13 comprising at least one of the following steps:
a) sulfonamide coupling by reacting a 2-aminothiazole with a sulfonylchloride in the presence of a base,
b) sulfonamide coupling by reacting a 2-aminothiazole derivative with a sulfonylchloride in the presence of a base,
c) saponification by treatment of a carboxylic acid ester with aqueous hydroxide,
d) amide coupling by reacting a carboxylic acid with an amine in the presence of EDCI,
e) formation of a thiazole ring by reacting an optionally substituted thiourea with an α-haloketone,
f) formation of a thiazole ring by reacting a thiourea with a ketone,
g) reduction of an ester with lithium aluminium hydride,
h) conversion of an alcohol to a bromide with triphenylphosphine and carbon tetrabromide,
i) elimination of a bromide with a base to an alkene.
17. A method for the treatment or prevention of diabetes, syndrome X, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, osteoporosis, cognitive impairment, depression, virus diseases and inflammatory disorders and to achieve immuno-modulation, said method comprising administering to a mammal, including man, in need of such treatment an effective amount of a compound of the formula (I)
Figure US20060287374A1-20061221-C00005
wherein
T is an aryl ring or heteroaryl ring, optionally independently substituted by [R]n, wherein n is an integer 0-5, and R is hydrogen, C1-6-alkyl, halogen, aryl or aryloxy, wherein the aryloxy residue can further be optionally substituted in one or more positions independently of each other by cyano and halogen;
A is C1-6-alkyl, vinyl or 3-(ethyl 3-methylbutanoate);
B is hydrogen, halogen, C1-6-alkyl, halogenated C1-6-alkyl, C1-6-acyl or C1-6-alkoxycarbonyl;
as well as pharmaceutically acceptable salts, hydrates and solvates thereof.
18. A method according to claim 17, wherein the immuno-modulation is achieved by the treatment or prevention of tuberculosis, lepra and psoriasis.
19. A method according to claim 17, wherein
T is selected from 4-bromo-5-chloro-2-thienyl and phenyl substituted with one or more of bromo, chloro, 3-chloro-2-cyanophenoxy, fluoro, methyl, phenyl, n-propyl;
A is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, vinyl or 3-(ethyl 3-methylbutanoate);
B is selected from hydrogen, bromo, methyl, ethyl, n-propyl, n-butyl, 2,2,2-trichloroethyl, acetyl and carbethoxy.
20. A method according to claim 17, wherein the compound is selected from:
4-chloro-N-(4-methyl-1,3-thiazol-2-yl)benzenesulfonamide,
N-(4-methyl-1,3-thiazol-2-yl)benzenesulfonamide,
3-chloro-2-methyl-N-(4-methyl-1,3-thiazol-2-yl)benzenesulfonamide,
4-chloro-N-[4-methyl-5-(2,2,2-trichloroethyl)-1,3-thiazol-2-yl]benzenesulfonamide,
3-chloro-2-methyl-N-[4-methyl-5-(2,2,2-trichloroethyl)-1,3-thiazol-2-yl]benzenesulfonamide,
N-[4-methyl-5-(2,2,2-trichloroethyl )-1,3-thiazol-2-yl]-2,4,6-trichlorobenzene sulfonamide,
3-chloro-N-(5-ethyl-4-methyl-1,3-thiazol-2-yl)-2-methylbenzenesulfonamide,
3-chloro-2-methyl-N-(4-methyl-5-propyl-1,3-thiazol-2-yl)benzenesulfonamide,
3-chloro-N-(4-ethyl-1,3-thiazol-2-yl )-2-methylbenzenesulfonamide,
3-chloro-N-(4-ethyl-5-methyl-1,3-thiazol-2-yl)-2-methylbenzenesulfonamide,
3-chloro-2-methyl-N-(4-propyl-1,3-thiazol-2-yl)benzenesulfonamide,
3-chloro-N-(4-isopropyl-1,3-thiazol-2-yl)-2-methylbenzenesulfonamide,
N-(4-butyl-1,3-thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide,
N-(5-butyl-4-methyl-1,3-thiazol-2-yl)-2,4-dichloro-6-methylbenzenesulfonamide,
N-(4-tert-butyl-1,3-thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide,
ethyl 3-(2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,3-thiazol-4-yl )-3-methylbutanoate,
2,4-dichloro-6-methyl-N-(4-pentyl-1,3-thiazol-2-yl)benzenesulfonamide,
3-chloro-2-methyl-N-(4-vinyl-1,3-thiazol-2-yl)benzenesulfonamide,
N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-4-chlorobenzenesulfonamide,
N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide,
N-(5-acetyl-4-methyl-1,3-thiazol-2-yl) [1,1′-biphenyl]-4-sulfonamide,
N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-4-(3-chloro-2-cyanophenoxy)benzene sulfonamide,
N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-2,4,5-trichlorobenzenesulfonamide,
N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-4-bromo-5-chloro-2-thienylsulfonamide,
N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-4-bromo-2,5-difluoro-2-benzenesulfonamide,
N-(5-acetyl-4-methyl-1,3 -thiazol-2-yl)-2,6-dichlorobenzenesulfonamide,
N-(5-carbethoxy-4-methyl-1,3-thiazol-2-yl)-3-chloro-2-methylbenzene sulfonamide,
N-(5-carbethoxy-4-methyl-1,3-thiazol-2-yl)[1,1′-biphenyl]-4-sulfonamide,
N-(5-carbethoxy-4-methyl-1,3-thiazol-2-yl )-4-propylbenzenesulfonamide,
N-(5-carbethoxy-4-methyl-1,3-thiazol-2-yl)-2,4-dichloro-6-methylbenzene sulfonamide,
N-(5-carbethoxy-4-methyl-1,3-thiazol-2-yl)-2,4,6-trichlorobenzenesulfonamide,
N-[5-bromo-4-(tert-butyl )-1,3-thiazol-2-yl]-4-chlorobenzenesulfonamide.
21. A pharmaceutical composition comprising at least one compound of the formula (I) as defined in claim 13, and a pharmaceutically acceptable carrier.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023023310A1 (en) * 2021-08-20 2023-02-23 Enanta Pharmaceuticals, Inc. 17-beta-hydroxysteroid dehydrogenase type 13 inhibitors and methods of use thereof

Families Citing this family (184)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE0001899D0 (en) 2000-05-22 2000-05-22 Pharmacia & Upjohn Ab New compounds
EP1309697A2 (en) * 2000-07-05 2003-05-14 Bayer Aktiengesellschaft Regulation of human 11 beta-hydroxysteroid dehydrogenase 1-like enzyme
GB0107383D0 (en) * 2001-03-23 2001-05-16 Univ Edinburgh Lipid profile modulation
US7074788B2 (en) * 2001-11-22 2006-07-11 Biovitrum Ab Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1
US20030130279A1 (en) * 2001-11-22 2003-07-10 Guido Kurz Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1
IL161154A0 (en) * 2001-11-22 2004-08-31 Biovitrum Ab Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1
IL160630A0 (en) * 2001-11-22 2004-07-25 Biovitrum Ab Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1
AU2007205749B2 (en) * 2001-11-22 2009-04-23 Biovitrum Ab Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1
ES2346961T3 (en) * 2001-11-22 2010-10-22 Biovitrum Ab INHIBITORS OF 11-BETA-HYDROXIESTEROID DEHYDROGENASE TYPE 1.
US7485655B2 (en) 2002-01-16 2009-02-03 University Of Virginia Patent Foundation 2-Aminothiazole allosteric enhancers of A1 adenosine receptors
EP1474139B1 (en) * 2002-02-01 2007-11-21 Merck & Co., Inc. 11-beta-hydroxysteroid dehydrogenase 1 inhibitors useful for the treatment of diabetes, obesity and dyslipidemia
US7338969B2 (en) * 2002-03-08 2008-03-04 Quonova, Llc Modulation of pathogenicity
ES2335488T3 (en) * 2002-03-29 2010-03-29 Schering Corporation STEREOSELECTIVE RENTAL OF CHIRAL PIPERAZINS 2-METHYL-4-PROTECTED.
SE0201194D0 (en) * 2002-04-19 2002-04-19 Astrazeneca Ab New compounds
US20030198965A1 (en) 2002-04-19 2003-10-23 Isis Pharmaceuticals Inc. Antisense modulation of hydroxysteroid 11-beta dehydrogenase 1 expression
AR040241A1 (en) 2002-06-10 2005-03-23 Merck & Co Inc INHIBITORS OF 11-BETA-HYDROXIESTEROID DEHYDROGRENASE 1 FOR THE TREATMENT OF DIABETES OBESITY AND DISLIPIDEMIA
US7105526B2 (en) 2002-06-28 2006-09-12 Banyu Pharmaceuticals Co., Ltd. Benzimidazole derivatives
US20040138258A1 (en) * 2002-09-18 2004-07-15 Hanauske-Abel Hartmut M. Inhibitors of 11beta-hydroxysteroid dehydrogenase and uses therefor
BR0315166A (en) * 2002-10-11 2005-08-16 Astrazeneca Ab Use of a compound or a pharmaceutically acceptable salt thereof, a compound or a pharmaceutically acceptable salt thereof, pharmaceutical composition, and method for producing an inhibitory effect of 11betahsd1 on a warm-blooded animal such as man needing treatment
GB0224830D0 (en) 2002-10-24 2002-12-04 Sterix Ltd Compound
WO2004037251A1 (en) 2002-10-24 2004-05-06 Sterix Limited Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1 and type 2
EP1562574A1 (en) * 2002-11-07 2005-08-17 Astrazeneca AB 2-oxo-ethanesulfonamide derivates
AR041952A1 (en) * 2002-11-14 2005-06-01 Novartis Ag N-SULFONYLAMINOTIAZOL
GB0226602D0 (en) * 2002-11-14 2002-12-24 Novartis Ag Organic compounds
JO2397B1 (en) 2002-12-20 2007-06-17 ميرك شارب اند دوم كوربوريشن Triazole Derivatives As Inhibitors Of 11-Beta -Hydroxysteriod Dehydrogenase-1
WO2004056744A1 (en) 2002-12-23 2004-07-08 Janssen Pharmaceutica N.V. Adamantyl acetamides as hydroxysteroid dehydrogenase inhibitors
FR2849599B1 (en) * 2003-01-07 2006-12-29 Merck Sante Sas USE OF KYNURENINE-3-HYDROXYLASE INHIBITORS FOR THE TREATMENT OF DIABETES
FR2849598B1 (en) * 2003-01-07 2006-09-22 Merck Sante Sas USE OF KYNURENINE-3-HYDROXYLASE INHIBITORS FOR THE TREATMENT OF DIABETES BY INCREASING THE NUMBER OF CELLS OF THE LANGERHANS ISLANDS
TW200503994A (en) * 2003-01-24 2005-02-01 Novartis Ag Organic compounds
US7772188B2 (en) 2003-01-28 2010-08-10 Ironwood Pharmaceuticals, Inc. Methods and compositions for the treatment of gastrointestinal disorders
DE10314610A1 (en) 2003-04-01 2004-11-04 Aventis Pharma Deutschland Gmbh New diphenylazetidinone with improved physiological properties, process for its preparation, medicaments containing these compounds and its use
WO2004089896A1 (en) * 2003-04-11 2004-10-21 Novo Nordisk A/S 11β-HYDROXYSTEROID DEHYDROGENASE TYPE 1 ACTIVE COMPOUNDS
JP2006522747A (en) 2003-04-11 2006-10-05 ノボ　ノルディスク　アクティーゼルスカブ Pharmaceutical use of condensed 1,2,4-triazole
US7700583B2 (en) 2003-04-11 2010-04-20 High Point Pharmaceuticals, Llc 11β-hydroxysteroid dehydrogenase type 1 active compounds
EP1785424A3 (en) * 2003-04-11 2009-12-23 High Point Pharmaceuticals, LLC Fused 1,2,4-triazoles and pharmaceutical uses thereof
US7501405B2 (en) 2003-04-11 2009-03-10 High Point Pharmaceuticals, Llc Combination therapy using an 11β-hydroxysteroid dehydrogenase type 1 inhibitor and an antihypertensive agent for the treatment of metabolic syndrome and related diseases and disorders
US7173030B2 (en) 2003-05-21 2007-02-06 Biovitrum Ab Inhibitors of 11-β-hydroxy steroid dehydrogenase type 1
AU2004240885A1 (en) * 2003-05-21 2004-12-02 Biovitrum Ab Inhibitors of 11-beta-hydroxy steroid dehydrogenase type I
CA2526712A1 (en) * 2003-05-29 2004-12-09 Merck & Co., Inc. Triazole derivatives as inhibitors of 11-beta hydroxysteroid dehydrogenase-1
SE0301885D0 (en) * 2003-06-25 2003-06-25 Biovitrum Ab New use IV
WO2004113310A1 (en) * 2003-06-25 2004-12-29 Biovitrum Ab Use of an inhibitor of 11-b-hydroxysteroid dehydrogenase type 1 compounds for promoting wound healing
SE0301884D0 (en) * 2003-06-25 2003-06-25 Biovitrum Ab New use III
SE0301882D0 (en) * 2003-06-25 2003-06-25 Biovitrum Ab New use I
SE0301883D0 (en) * 2003-06-25 2003-06-25 Biovitrum Ab New use II
JP4765627B2 (en) 2003-09-22 2011-09-07 Ｍｓｄ株式会社 Novel piperidine derivatives
GB0324792D0 (en) 2003-10-23 2003-11-26 Sterix Ltd Compound
GB0325745D0 (en) * 2003-11-05 2003-12-10 Astrazeneca Ab Chemical compounds
JP2007514731A (en) * 2003-12-19 2007-06-07 ファイザー インコーポレイテッド Benzenesulfonylamino-pyridin-2-yl derivatives and related compounds as inhibitors of 11-beta-hydroxysteroid dehydrogenase type 1 (11-β-hsd-1) for the treatment of diabetes and obesity
WO2005063247A1 (en) 2003-12-22 2005-07-14 Amgen Inc. Aryl sulfonamide compounds and uses related thereto
AU2005207925B2 (en) 2004-01-26 2008-09-04 Merck Sharp & Dohme Corp. Novel crystalline forms of an inhibitor of 11-beta-hydroxysteroid dehydrogenase Type 1
US20080125403A1 (en) 2004-04-02 2008-05-29 Merck & Co., Inc. Method of Treating Men with Metabolic and Anthropometric Disorders
JP2007261945A (en) * 2004-04-07 2007-10-11 Taisho Pharmaceut Co Ltd Thiazole derivative
MXPA06011868A (en) 2004-04-14 2007-03-21 Amgen Inc Aryl sulfones and uses related thereto.
GB0408771D0 (en) * 2004-04-20 2004-05-26 Sterix Ltd Compound
CA2561858A1 (en) 2004-04-20 2005-12-15 Amgen Inc. Arylsulfonamides and uses related thereto
US9012494B2 (en) 2004-05-07 2015-04-21 Janssen Pharmaceutica N.V. Pyrrolidin-2-one and piperidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
US8686011B2 (en) 2004-05-24 2014-04-01 Amgen Inc. Inhibitors of 11-β-hydroxy steroid dehydrogenase type 1
EA014419B1 (en) 2004-05-24 2010-12-30 Эмджен Инк. 5,5-disubstituted-2-amino-4-thiazolidinone and process for preparation thereof, pharmaceutical composition and method for treatment
AU2005256442B2 (en) 2004-06-28 2009-02-12 F. Hoffmann-La Roche Ag Pyrimidine derivatives as 11beta-HSD1 inhibitors
MX2007001271A (en) * 2004-08-05 2007-03-21 Hoffmann La Roche Substituted n-acyl-2-aminothiazoles.
RU2386617C2 (en) 2004-08-30 2010-04-20 Янссен Фармацевтика Н.В. TRICYCLIC LACTAM DERIVATIVES AS 11-β-HYDROXYSTEROID DEHYDROGENASE INHIBITORS
DE602005017159D1 (en) 2004-08-30 2009-11-26 Janssen Pharmaceutica Nv OXYSTEROID DEHYDROGENASE INHIBITORS
NZ553159A (en) 2004-08-30 2010-05-28 Janssen Pharmaceutica Nv N-Adamantan-2-yl-2-phenoxy-acetamide derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
DE602005012292D1 (en) * 2004-09-29 2009-02-26 Hoffmann La Roche INDOZONE DERIVATIVES AS 11B-HSD1 INHIBITORS
CN101035762B (en) * 2004-10-04 2010-09-29 霍夫曼-拉罗奇有限公司 Alkil-pyridines as 11-beta inhibitors for diabetes
ES2436178T3 (en) * 2004-10-14 2013-12-27 Abbvie Deutschland Gmbh & Co Kg Aromatic compounds substituted with arylsulfonylmethyl or arylsulfonamide suitable for treating disorders that respond to dopamine D3 receptor modulation
JP2008517930A (en) 2004-10-21 2008-05-29 トランス テック ファーマ，インコーポレイテッド Bissulfonamide compounds, compositions, and methods of use as agonists of GalR1
EP1659113A1 (en) * 2004-11-08 2006-05-24 Evotec AG Inhibitors of 11beta-hydroxy steroid dehydrogenase type 1 (11beta-HSD1)
EP1666467A1 (en) * 2004-11-08 2006-06-07 Evotec AG 11Beta-HSD1 Inhibitors
WO2006051662A1 (en) * 2004-11-09 2006-05-18 Taisho Pharmaceutical Co., Ltd. Thiazole derivative
WO2006059507A1 (en) * 2004-11-30 2006-06-08 Sankyo Company, Limited 11β-HSD1 ANTISENSE COMPOUND
EP1888544A2 (en) * 2004-12-17 2008-02-20 Takeda San Diego, Inc. Hydroxysteroid dehydrogenase inhibitors
GB0506133D0 (en) * 2005-03-24 2005-05-04 Sterix Ltd Compound
WO2006105127A2 (en) 2005-03-31 2006-10-05 Takeda San Diego, Inc. Hydroxysteroid dehydrogenase inhibitors
CA2602781C (en) 2005-04-05 2011-02-08 F. Hoffmann-La Roche Ag 1h-pyrazole 4-carboxylamides, their preparation and their use as 11beta-hydroxysteroid dehydrogenase
AU2006253312B2 (en) 2005-05-30 2011-08-18 Msd K.K. Novel piperidine derivative
BRPI0611853A2 (en) * 2005-06-16 2010-10-05 Pfizer n- (pyridin-2-yl) sulfonamide derivatives
WO2006134481A1 (en) * 2005-06-16 2006-12-21 Pfizer Inc. Inhibitors of 11-beta hydroxysteroid dehydrogenase type 1
US20100216758A1 (en) 2005-08-10 2010-08-26 Makoto Ando Pyridone Compounds
CA2619770A1 (en) 2005-08-24 2007-03-01 Banyu Pharmaceutical Co., Ltd. Phenylpyridone derivative
US7622492B2 (en) 2005-08-31 2009-11-24 Hoffmann-La Roche Inc. Pyrazolones as inhibitors of 11β-hydroxysteroid dehydrogenase
WO2007029847A1 (en) 2005-09-07 2007-03-15 Banyu Pharmaceutical Co., Ltd. Bicyclic aromatic substituted pyridone derivative
JP4879988B2 (en) 2005-09-29 2012-02-22 メルク・シャープ・エンド・ドーム・コーポレイション Acylated spiropiperidine derivatives as melanocortin-4 receptor modulators
JP2007099659A (en) * 2005-10-03 2007-04-19 Toray Fine Chemicals Co Ltd Method for producing piperazinecarboxylic acid ester
JP2009511599A (en) * 2005-10-12 2009-03-19 バーテックス ファーマシューティカルズ インコーポレイテッド Biphenyl derivatives as regulators of voltage-gated ion channels
CN101291662A (en) 2005-10-21 2008-10-22 诺瓦提斯公司 Combination of a renin-inhibitor and an anti-dyslipidemic agent and/or an antiobesity agent
JPWO2007049798A1 (en) 2005-10-27 2009-04-30 萬有製薬株式会社 New benzooxathiin derivatives
AU2006312557B2 (en) 2005-11-10 2011-12-08 Msd K.K. Aza-substituted spiro derivative
US20070110802A1 (en) * 2005-11-15 2007-05-17 Janan Jona Wet granulation process
CA2630718A1 (en) 2005-11-22 2007-05-31 Amgen Inc. Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1
KR20080081178A (en) 2005-12-21 2008-09-08 버텍스 파마슈티칼스 인코포레이티드 Heterocyclic derivatives as modulators of ion channels
WO2007076875A2 (en) * 2006-01-06 2007-07-12 Aarhus Universitet Compounds acting on the serotonin transporter
JP5068768B2 (en) 2006-01-18 2012-11-07 エフ．ホフマン−ラ ロシュ アーゲー Thiazole as an 11 beta-HSD1 inhibitor
AU2007244971B2 (en) * 2006-04-24 2012-01-19 Eli Lilly And Company Cyclohexyl substituted pyrrolidinones as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1
ATE473210T1 (en) * 2006-04-24 2010-07-15 Lilly Co Eli SUBSTITUTED PYRROLIDINONES AS INHIBITORS OF 11-BETA-HYDROXYSTEROIDDEHYDROGENASE 1
PE20110235A1 (en) 2006-05-04 2011-04-14 Boehringer Ingelheim Int PHARMACEUTICAL COMBINATIONS INCLUDING LINAGLIPTIN AND METMORPHINE
CN101096363B (en) * 2006-06-27 2011-05-11 中国人民解放军军事医学科学院毒物药物研究所 2,4,5-three-substituted thiazole compound, preparation method, medicament composition and pharmacy use thereof
EP2061767B1 (en) 2006-08-08 2014-12-17 Sanofi Arylaminoaryl-alkyl-substituted imidazolidine-2,4-diones, processes for preparing them, medicaments comprising these compounds, and their use
EP2083831B1 (en) 2006-09-22 2013-12-25 Merck Sharp & Dohme Corp. Method of treatment using fatty acid synthesis inhibitors
CA2664358A1 (en) 2006-09-28 2008-04-03 Banyu Pharmaceutical Co., Ltd. Diarylketimine derivative
DE102007005045B4 (en) 2007-01-26 2008-12-18 Sanofi-Aventis Phenothiazine derivatives, process for their preparation and their use as medicines
CN101668524B (en) * 2007-02-12 2012-10-24 阿斯利康(瑞典)有限公司 Pyrazole derivatives as 11-beta-hsd1 inhibitors
ZA200904916B (en) 2007-02-23 2010-09-29 High Point Pharmaceuticals Llc N-adamantyl benzamides as inhibitors of 11-beta-hydroxysteroid dehydrogenase
US20110003856A1 (en) 2007-02-23 2011-01-06 Soren Ebdrup N-adamantyl benzamides as inhibitors of 11-beta-hydroxysteroid dehydrogenase
US20110003852A1 (en) 2007-02-23 2011-01-06 Soren Ebdrup N-adamantyl benzamides as inhibitors of 11-beta-hydroxysteroid dehydrogenase
WO2008118758A1 (en) 2007-03-23 2008-10-02 Icagen, Inc. Inhibitors of ion channels
EP2145884B1 (en) 2007-04-02 2014-08-06 Msd K.K. Indoledione derivative
US20100137377A1 (en) * 2007-04-11 2010-06-03 Soren Ebdrup Et Al Novel compounds
US20100120694A1 (en) 2008-06-04 2010-05-13 Synergy Pharmaceuticals, Inc. Agonists of Guanylate Cyclase Useful for the Treatment of Gastrointestinal Disorders, Inflammation, Cancer and Other Disorders
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
US7879802B2 (en) 2007-06-04 2011-02-01 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
US8222417B2 (en) 2007-06-27 2012-07-17 Taisho Pharmaceutical Co., Ltd Compound having 11β-HSD1 inhibitory activity
EP2025674A1 (en) 2007-08-15 2009-02-18 sanofi-aventis Substituted tetra hydro naphthalines, method for their manufacture and their use as drugs
DE102007054497B3 (en) 2007-11-13 2009-07-23 Sanofi-Aventis Deutschland Gmbh New crystalline hydrate form of dodecanedioic acid 4-((2S,3R)-3-((S)-3-(4-fluoro-phenyl)-3-hydroxy-propyl)-2-(4-methoxy-phenyl)-4-oxo-azetidin-1-yl)-benzylamide ((2S,3R,4R,5R)-pentahydroxy-hexyl)-amide useful e.g. to treat hyperlipidemia
JPWO2009110510A1 (en) 2008-03-06 2011-07-14 Ｍｓｄ株式会社 Alkylaminopyridine derivatives
JPWO2009119726A1 (en) 2008-03-28 2011-07-28 Ｍｓｄ株式会社 Diarylmethylamide derivatives having melanin-concentrating hormone receptor antagonistic activity
US20110071129A1 (en) 2008-06-19 2011-03-24 Makoto Ando Spirodiamine-diaryl ketoxime derivative
TW201014822A (en) 2008-07-09 2010-04-16 Sanofi Aventis Heterocyclic compounds, processes for their preparation, medicaments comprising these compounds, and the use thereof
EP2321341B1 (en) 2008-07-16 2017-02-22 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders
WO2010013595A1 (en) 2008-07-30 2010-02-04 萬有製薬株式会社 (5-membered)-(5-membered) or (5-membered)-(6-membered) fused ring cycloalkylamine derivative
EP2348857B1 (en) 2008-10-22 2016-02-24 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
EP2350010B1 (en) 2008-10-30 2014-03-26 Merck Sharp & Dohme Corp. Isonicotinamide orexin receptor antagonists
CA2741672A1 (en) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
KR200452117Y1 (en) * 2008-11-10 2011-02-08 대성공업주식회사 Brake wire holder wheel chair
EP2362730A4 (en) 2008-11-21 2012-08-29 High Point Pharmaceuticals Llc Adamantyl benzamide compounds
WO2010068601A1 (en) 2008-12-08 2010-06-17 Sanofi-Aventis A crystalline heteroaromatic fluoroglycoside hydrate, processes for making, methods of use and pharmaceutical compositions thereof
ES2350077B1 (en) 2009-06-04 2011-11-04 Laboratorios Salvat, S.A. INHIBITING COMPOUNDS OF 11BETA-HYDROXIESTEROID DEHYDROGENASE TYPE 1.
DK2470552T3 (en) 2009-08-26 2014-02-17 Sanofi Sa NOVEL, CRYSTALLINE, heteroaromatic FLUORGLYCOSIDHYDRATER, MEDICINES COVERING THESE COMPOUNDS AND THEIR USE
US8895596B2 (en) 2010-02-25 2014-11-25 Merck Sharp & Dohme Corp Cyclic benzimidazole derivatives useful as anti-diabetic agents
US8933024B2 (en) 2010-06-18 2015-01-13 Sanofi Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases
US8530413B2 (en) 2010-06-21 2013-09-10 Sanofi Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments
TW201215388A (en) 2010-07-05 2012-04-16 Sanofi Sa (2-aryloxyacetylamino)phenylpropionic acid derivatives, processes for preparation thereof and use thereof as medicaments
TW201215387A (en) 2010-07-05 2012-04-16 Sanofi Aventis Spirocyclically substituted 1,3-propane dioxide derivatives, processes for preparation thereof and use thereof as a medicament
WO2012015715A1 (en) * 2010-07-27 2012-02-02 High Point Pharmaceuticals, Llc Substituted thiazol-2-ylamine derivatives, pharmaceutical compositions, and methods of use as 11-beta hsd1 modulators
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
MX348131B (en) 2011-02-25 2017-05-26 Merck Sharp & Dohme Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents.
MX357121B (en) 2011-03-01 2018-06-27 Synergy Pharmaceuticals Inc Star Process of preparing guanylate cyclase c agonists.
WO2012120051A1 (en) 2011-03-08 2012-09-13 Sanofi Benzyl-oxathiazine derivates substituted with adamantane or noradamantane, medicaments containing said compounds and use thereof
WO2012120057A1 (en) 2011-03-08 2012-09-13 Sanofi Novel substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof
WO2012120053A1 (en) 2011-03-08 2012-09-13 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120055A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120056A1 (en) 2011-03-08 2012-09-13 Sanofi Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120058A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives which are substituted with benzyl or heteromethylene groups, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120050A1 (en) 2011-03-08 2012-09-13 Sanofi Novel substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof
US8901114B2 (en) 2011-03-08 2014-12-02 Sanofi Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof
US8828994B2 (en) 2011-03-08 2014-09-09 Sanofi Di- and tri-substituted oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2013037390A1 (en) 2011-09-12 2013-03-21 Sanofi 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
EP2567959B1 (en) 2011-09-12 2014-04-16 Sanofi 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
EP2760862B1 (en) 2011-09-27 2015-10-21 Sanofi 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
AR088352A1 (en) 2011-10-19 2014-05-28 Merck Sharp & Dohme ANTAGONISTS OF THE RECEIVER OF 2-PIRIDILOXI-4-NITRILE OREXINE
CN103204824B (en) * 2012-01-12 2015-04-08 清华大学深圳研究生院 2-aminothiazole-4-amide derivative, its preparation method and application
US20140045746A1 (en) 2012-08-02 2014-02-13 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
US9840512B2 (en) 2013-02-22 2017-12-12 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
WO2014139388A1 (en) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Novel indole derivatives useful as anti-diabetic agents
CA2905435A1 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions useful for the treatment of gastrointestinal disorders
EP2970384A1 (en) 2013-03-15 2016-01-20 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
TW201512171A (en) 2013-04-19 2015-04-01 Pfizer Ltd Chemical compounds
BR112015030326A2 (en) 2013-06-05 2017-08-29 Synergy Pharmaceuticals Inc ULTRAPURE GUANYLATE CYCLASE C AGONISTS, METHOD OF MANUFACTURING AND USING THEM
WO2015051496A1 (en) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
ES2901114T3 (en) 2014-08-29 2022-03-21 Tes Pharma S R L Alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase inhibitors
CN105017135A (en) * 2015-07-19 2015-11-04 佛山市赛维斯医药科技有限公司 11 beta-HSD1 inhibitor with dipyridyl-tert-alcohol structure and its preparation method and use
CN105001152A (en) * 2015-07-19 2015-10-28 佛山市赛维斯医药科技有限公司 11 beta-HSD1 inhibitor of dimethylamino bipyridine tertiary alcohol structure and application thereof
EP3235813A1 (en) 2016-04-19 2017-10-25 Cidqo 2012, S.L. Aza-tetra-cyclo derivatives
KR20190065312A (en) 2016-10-14 2019-06-11 테스 파마 에스.알.엘. Inhibitors of alpha-amino-beta-carboxy-muconic acid semialdehyde decarboxylase
CN107663204A (en) * 2016-10-19 2018-02-06 首都医科大学附属北京世纪坛医院 A kind for the treatment of tuberculosis application of compound
WO2018106518A1 (en) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Antidiabetic heterocyclic compounds
WO2018118670A1 (en) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Antidiabetic spirochroman compounds
US11655246B2 (en) * 2017-11-30 2023-05-23 Step Pharma S.A.S. Aminothiazole compounds as inhibitors of CTPS1
EP3717465A1 (en) 2017-11-30 2020-10-07 Step Pharma S.A.S. Compounds
MA51828B1 (en) 2018-02-15 2022-11-30 Vertex Pharma Macrocycles used as modulators of the cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions thereof, their use in the treatment of cystic fibrosis and method of making the same
CN108358869B (en) * 2018-03-27 2019-09-10 河北师范大学 A kind of N- benzothiazolyl benzsulfamide analog derivative, Preparation method and use
CN108659219B (en) * 2018-06-08 2021-02-09 扬州大学 Preparation method of polyaniline
WO2020104456A1 (en) 2018-11-20 2020-05-28 Tes Pharma S.R.L INHIBITORS OF α-AMINO-β-CARBOXYMUCONIC ACID SEMIALDEHYDE DECARBOXYLASE
CN109748831A (en) * 2018-12-17 2019-05-14 南通正达农化有限公司 A kind of preparation method of trifluoromethanesulfonic acid trifluoro ethyl ester
WO2020167706A1 (en) 2019-02-13 2020-08-20 Merck Sharp & Dohme Corp. 5-alkyl pyrrolidine orexin receptor agonists
US20230018413A1 (en) 2019-08-08 2023-01-19 Merck Sharp & Dohme Corp. Heteroaryl pyrrolidine and piperidine orexin receptor agonists
TW202115092A (en) 2019-08-14 2021-04-16 美商維泰克斯製藥公司 Modulators of cystic fibrosis transmembrane conductance regulator
EP4013760A1 (en) 2019-08-14 2022-06-22 Vertex Pharmaceuticals Incorporated Crystalline forms of cftr modulators
TW202120517A (en) 2019-08-14 2021-06-01 美商維泰克斯製藥公司 Process of making cftr modulators
CN111620837B (en) * 2020-06-29 2022-02-15 郑州大学 Cedar ketone thiazole amide compound, and preparation method and application thereof
WO2022040070A1 (en) 2020-08-18 2022-02-24 Merck Sharp & Dohme Corp. Bicycloheptane pyrrolidine orexin receptor agonists
US20230373974A1 (en) * 2020-10-07 2023-11-23 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
CN112451514A (en) * 2020-11-26 2021-03-09 江西农业大学 Dihydromyricetin nano-selenium and preparation method and application thereof
CN113461635A (en) * 2021-07-07 2021-10-01 上海毕得医药科技股份有限公司 4- (2-chloroethyl) thiazole-2-carboxylic acid ethyl ester and preparation method and application thereof

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2362087A (en) * 1938-06-03 1944-11-07 May & Baker Ltd Sulphanilamido-thiazoles
US2611770A (en) * 1949-04-16 1952-09-23 American Cyanamid Co N-(2-thiazolyl)-2-hydroxypyridine-5-sulfonamides
US4254260A (en) * 1975-03-06 1981-03-03 Fujisawa Pharmaceutical Co., Ltd. 3-Substituted-7-substituted alkanamido-3-cephem-4-carboxylic acid compounds
US4889553A (en) * 1986-05-17 1989-12-26 Schering Agrochemicals Herbicides
US5403857A (en) * 1991-09-10 1995-04-04 Imperial Chemical Industries Plc Benzenesulphonamide derivatives having 5-lipoxygenase inhibitory activity
US5783597A (en) * 1997-03-04 1998-07-21 Ortho Pharmaceutical Corporation 2,5-disubstituted thiophenes: inhibitors of 5-lipoxygenase and inducible cyclooxygenase (COX-2) enzymes, composition and use
US5856347A (en) * 1994-11-29 1999-01-05 Hisamitsu Pharmaceutical Co., Inc. Antibacterial preparation or bactericide comprising 2-aminothiazole derivative and/or salt thereof
US5962490A (en) * 1987-09-25 1999-10-05 Texas Biotechnology Corporation Thienyl-, furyl- and pyrrolyl-sulfonamides and derivatives thereof that modulate the activity of endothelin
US20030130258A1 (en) * 2001-11-22 2003-07-10 Guido Kurz Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1
US20030130279A1 (en) * 2001-11-22 2003-07-10 Guido Kurz Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1
US20030130318A1 (en) * 2001-11-22 2003-07-10 Tjeerd Barf Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1
US20030166689A1 (en) * 2000-05-22 2003-09-04 Guido Kurz Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1

Family Cites Families (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB620654A (en) * 1939-10-03 1949-03-29 Chinoin Gyogyszer Es Vegyeszet A process for the preparation of sulphonamide derivatives of 2-amino-thiazole
GB822947A (en) 1957-01-25 1959-11-04 Smith & Nephew Improvements in and relating to sulphonamides
DE1620508A1 (en) 1965-07-23 1969-09-18 Thomae Gmbh Dr K Process for the preparation of new 4,5,6,7-tetrahydrothiazolo- [5,4-c] -pyridines
FR2384498A1 (en) 1975-11-26 1978-10-20 Parcor Antibacterial, antifungal and hypoglycaemic sulphonamido thiazole(s) - prepd. from a phenyl sulphonamide and an isothiocyanato butyne
US5591761A (en) 1993-05-20 1997-01-07 Texas Biotechnology Corporation Thiophenyl-, furyl-and pyrrolyl-sulfonamides and derivatives thereof that modulate the activity of endothelin
US5594021A (en) 1993-05-20 1997-01-14 Texas Biotechnology Corporation Thienyl-, furyl- and pyrrolyl sulfonamides and derivatives thereof that modulate the activity of endothelin
JPH021483A (en) 1988-03-10 1990-01-05 Nippon Tokushu Noyaku Seizo Kk Agricultural fungicide
JPH078863B2 (en) 1989-09-21 1995-02-01 久光製薬株式会社 Novel diphenylthiazole derivative
JPH0670024B2 (en) 1993-04-13 1994-09-07 塩野義製薬株式会社 Method for producing glutaconate derivative
US6030991A (en) 1993-05-20 2000-02-29 Texas Biotechnology Corp. Benzenesulfonamides and the use thereof to modulate the activity of endothelin
JPH07149745A (en) * 1993-11-30 1995-06-13 Hisamitsu Pharmaceut Co Inc New 2-aminothiazole derivative
JPH07149746A (en) * 1993-11-30 1995-06-13 Hisamitsu Pharmaceut Co Inc New 2-substituted aminothiazole derivative
JPH07309757A (en) * 1994-05-18 1995-11-28 Asahi Chem Ind Co Ltd Beta-amyloid protein neurocyte toxicity reducing agent
CZ285290B6 (en) 1994-08-09 1999-06-16 Cortendo Ab Application of ketokonazole
SE505391C2 (en) 1995-05-30 1997-08-18 Cortendo Ab Use of cortisol agonists to prepare a system for diagnosing the metabolic syndrome
GB9512697D0 (en) 1995-06-22 1995-08-23 Zeneca Ltd Heterocyclic compounds
GB9517622D0 (en) 1995-08-29 1995-11-01 Univ Edinburgh Regulation of intracellular glucocorticoid concentrations
WO1997047299A1 (en) * 1996-06-12 1997-12-18 3-Dimensional Pharmaceuticals, Inc. Amidino and guanidino heterocyclic protease inhibitors
US5877193A (en) * 1996-07-19 1999-03-02 Hoffmann-La Roche Inc. Use of N-(4-aryl-thiazol-2-yl)-sulfonamides
ATE229949T1 (en) 1996-10-16 2003-01-15 American Cyanamid Co PRODUCTION AND USE OF ORTHO-SULFONAMIDO-HETEROARYLHYDROXAMIC ACIDS AS MATRIX METALLOPROTEINASE AND TACE INHIBITORS
DZ2376A1 (en) 1996-12-19 2002-12-28 Smithkline Beecham Plc New sulfonamide derivatives process for their preparation and pharmaceutical compositions containing them.
SE9700642D0 (en) 1997-02-24 1997-02-24 Kronvall Stefan Med Ab Means and ways of preventing and treating the metabolic syndrome
US6316450B1 (en) 1997-07-11 2001-11-13 Smithkline Beecham P.L.C. Compounds
GB9725141D0 (en) * 1997-11-27 1998-01-28 Pharmacia & Upjohn Spa Benzenesulfonamide compounds
ATE288904T1 (en) 1998-06-18 2005-02-15 Bristol Myers Squibb Co AMINOTHIAZOLES SUBSTITUTED BY CARBON AS INHIBITORS OF CYCLINE-DEPENDENT KINASES
CZ302691B6 (en) 1998-07-08 2011-09-07 Sanofi - Aventis Deutschland GmbH N-arylamide compound, process for its preparation, pharmaceutical composition containing thereof, the compound for use as activator and for use in therapy or prophylaxis
GB9915625D0 (en) 1999-07-02 1999-09-01 Cortendo Ab Method
GB0001449D0 (en) 2000-01-21 2000-03-08 Cortendo Ab Compositions
IT1317735B1 (en) 2000-01-26 2003-07-15 Nicox Sa SALTS OF ANTIMICROBIAL AGENTS.
AU2002213048A1 (en) 2000-10-05 2002-04-15 Smith Kline Beecham Corporation Phosphate transport inhibitors
GB0118300D0 (en) 2001-07-26 2001-09-19 Cortendo Ab Formulations
IL161154A0 (en) 2001-11-22 2004-08-31 Biovitrum Ab Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2362087A (en) * 1938-06-03 1944-11-07 May & Baker Ltd Sulphanilamido-thiazoles
US2611770A (en) * 1949-04-16 1952-09-23 American Cyanamid Co N-(2-thiazolyl)-2-hydroxypyridine-5-sulfonamides
US4254260A (en) * 1975-03-06 1981-03-03 Fujisawa Pharmaceutical Co., Ltd. 3-Substituted-7-substituted alkanamido-3-cephem-4-carboxylic acid compounds
US4889553A (en) * 1986-05-17 1989-12-26 Schering Agrochemicals Herbicides
US5962490A (en) * 1987-09-25 1999-10-05 Texas Biotechnology Corporation Thienyl-, furyl- and pyrrolyl-sulfonamides and derivatives thereof that modulate the activity of endothelin
US5403857A (en) * 1991-09-10 1995-04-04 Imperial Chemical Industries Plc Benzenesulphonamide derivatives having 5-lipoxygenase inhibitory activity
US5856347A (en) * 1994-11-29 1999-01-05 Hisamitsu Pharmaceutical Co., Inc. Antibacterial preparation or bactericide comprising 2-aminothiazole derivative and/or salt thereof
US5783597A (en) * 1997-03-04 1998-07-21 Ortho Pharmaceutical Corporation 2,5-disubstituted thiophenes: inhibitors of 5-lipoxygenase and inducible cyclooxygenase (COX-2) enzymes, composition and use
US20030166689A1 (en) * 2000-05-22 2003-09-04 Guido Kurz Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1
US20030199501A1 (en) * 2000-05-22 2003-10-23 Marianne Nilsson Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1
US20030130258A1 (en) * 2001-11-22 2003-07-10 Guido Kurz Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1
US20030130279A1 (en) * 2001-11-22 2003-07-10 Guido Kurz Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1
US20030130318A1 (en) * 2001-11-22 2003-07-10 Tjeerd Barf Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023023310A1 (en) * 2021-08-20 2023-02-23 Enanta Pharmaceuticals, Inc. 17-beta-hydroxysteroid dehydrogenase type 13 inhibitors and methods of use thereof

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