WO2005108361A1 - Adamantyl pyrrolidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors - Google Patents
Adamantyl pyrrolidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors Download PDFInfo
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom
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- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
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Definitions
- the metabolic syndrome is a disease with increasing prevalence not only in the
- Glucocorticoids and ll ⁇ -HSDl are known to be important factors in differentiation of adipose stromal cells into mature adipocytes In the visceral stromal cells of obese patients, ll ⁇ -HSDl mRNA level is increased compared with subcutaneous tissue.
- adipose tissue over-expression of 1 l ⁇ -HSDl in transgenic mice is associated with increased corticosterone levels in the adipose tissue, visceral obesity, insulin sensitivity, Type 2 diabetes, hyperhpide ⁇ ua and hyperphagia (H. Masuzaki et al (2001), Science, 294, 2166-2170) Therefore, ll ⁇ -HSDl is most likely be involved in the development of visceral obesity and the metabolic syndrome.
- Obesity is also linked to cardiovascular risks There is a significant relationship between cortisol excreUon rate and HDL cholesterol in both men and women, suggesting that glucocorticoids regulate key components of cardiovascular ⁇ sk In analogy, aortic stiffness is also associated with visceral adiposity in older adults.
- Glucocorticoids increase the ⁇ sk of glaucoma by raising the intraocular pressure when administered exogenously and in certain conditions of increased production like in Cushing's syndrome
- Corticosteroid-induced elevation of intra ocular pressure is caused by increased resistance to aqueous outflow due to glucocorticoid induced changes in the trabecular meshwork and its intracellular matrix
- Zhou et al (Int J Mol Med (1998) 1, 339-346) also reported that corticosteroids increase the amounts of fibronectin as well as collagen type I and type IV in the trabecular meshwork of organ- cultured bovine antenor segments.
- ll ⁇ -HSDl is expressed in the basal cells of the corneal epithelium and the non- pigmenled epithelial cells Glucocorticoid receptor mRNA was only detected in the trabecular meshwork, whereas in the non-pigmented epithelial cells mRNA for the glucocorticoid-, mineralocorticoid receptor and 1 l ⁇ -HSDl was present.
- Carbenoxolone administration to patients resulted in a significant decrease in intra-ocular pressure (S. Rauz et al. (2001), Invest. Ophtalmol. Vis. Science, 42, 2037-2042), suggesting a role for HSD 1 -inhibitors in treating glaucoma.
- the underlying problem to be solved by the present invention was to identify potent ll ⁇ -HSD inhibitors, with a high selectivity for ll ⁇ -HSDl, and the use thereof in treating pathologies associated with excess cortisol forma ⁇ on such as obesity, diabetes, obesity related cardiovascular diseases, and glaucoma.
- the 3-subst ⁇ tuted 2-pyr ⁇ ol ⁇ d ⁇ none derivatives of formula (I) were found to be useful as a medicine, in particular m the manufacture of a medicament for the treatment of pathologies associated with excess cortisol formation.
- Blommaert A. et al. provides the preparation of pipe ⁇ dine- and pyrrolidinone-like polymer supported (R)-phenylglycinol-denvcd scaffolds and in particular discloses 2-Pyrrolid ⁇ none, l-[(lR)-2-hydroxy-l-phenyl- ethyl]-3-methyl-3-(phenylmethyl)- and 2-Pyrrol ⁇ dinone, l-[(lR)-2-hydroxy-l-phenyl- ethyl]-3-(phenylmethyl)-, (3R).
- Bausanne I. et al. provides the preparation of 3-subst ⁇ tuted pyrro dinones via ⁇ -alkylation of a chiral non-racemic ⁇ -lacton and in particular discloses l-(2-hydroxy-l-phenylethyl)-3-benzylpyrrol ⁇ d ⁇ n- 2-one.
- n 1 or 2;
- M represents a direct bond or a linker optionally substituted with one or two substituents selected from C ⁇ _4alkyl, C ⁇ . 3 alkyloxy-C ⁇ - alkyl-, hydroxy-C 1-4 alkyl-, hydroxy, R 1 and R 2 each independently represent hydrogen, halo, cyano, hydroxy, C]_ 4 alkyl optionally substituted with halo, Cj.
- R 3 represents hydrogen, halo, C ⁇ _ alkyloxy-, cyano or hydroxy
- R 4 represents hydrogen, halo, ⁇ alkyl, hydroxy, cyano or C ⁇ _ alkyloxy- optionally substituted with one or where possible two or three substituents selected from hydroxy and halo
- R 5 represents hydrogen, R 6 represents hydrogen, hydroxy, halo, Ci ⁇ alkyl or C 1-4 alkyoxy-
- R 7 represents hydrogen or R 7 and R 5 taken together with the carbon atom to which they are attached from a -C 2 -alkyl- linker
- Ar 1 and Ar 2 each independently represent phenyl or naphtyl wherein said phenyl and naphtyl are optionally substituted with Ci ⁇ alkyl, C ⁇ . 4 alkyloxy-, or phenyl-C ⁇ -4 alkyl.
- halo is generic to fluoro, chloro, bromo and iodo
- C ] 3 alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 3 carbon atoms such as, for example, methyl, ethyl, propyl, 1-methylethyl and the like
- C, .4 alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-d ⁇ methylethyl and the like
- C] 4 alkyloxy defines straight or branched saturated hydrocarbon radicalshaving form 1 to 3 carbon atoms such as methoxy, ethoxy, prop loxy, 1-methylethyloxy and the like
- the pharmaceutically acceptable addition salts as mentioned heremabove are meant to comprise the therapeutically active non-toxic acid addi ⁇ on salt forms, which the compounds of formula (I), are able to form
- the latter can conveniently be obtained by treating the base form with such approp ⁇ ate acid.
- Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e g hydrochloric or hydrobromic acid; sulfu ⁇ c, nitric, phospho ⁇ c and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succimc (l e butanedioic acid), maleic, fuma ⁇ c, malic, tartanc, citric, methanesulfonic, ethanesulfonic, benzenesulfomc, p-toluenesulfonic, cyclamic, salicylic, p-aminosahcylic, pamoic and the like acids.
- inorganic acids such as hydrohalic acids, e g hydrochloric or hydrobromic acid
- sulfu ⁇ c, nitric, phospho ⁇ c and the like acids or organic acids such as
- the pharmaceutically acceptable addition salts as mentioned heremabove are meant to comp ⁇ se the therapeutically active non-toxic base addition salt forms which the compounds of formula (I), are able to form
- Examples of such base addition salt forms are, foi example, the sodium, potassium, calcium salts, and also the salts with pharmaceutically acceptable amines such as, for example, ammonia, alkylamincs, benzathine, N-methyl-D-glucamine, hydrabamine, amino acids, e g arginine, lysine.
- salt forms can be converted by treatment with an appropriate base or acid into the free acid or base form
- addition salt as used heremabove also comprises the solvates which the compounds of formula (1), as well as the salts thereof, are able to form Such solvates are for example hydrates, alcoholates and the like
- stereochemically isome ⁇ c forms as used hereinbefore defines the possible different lsomenc as well as conformational forms which the compounds of formula (I), may possess Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically and conformationally isome ⁇ c forms, said mixtures containing all diastereomers, enantiomers and/or conformers of the basic molecular structure All stereochemically isome ⁇ c forms of the compounds of formula (I), both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.
- JV-oxide forms of the compounds of formula (I) are meant to comprise those compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called /V-oxide.
- An interesting group of compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply : (i) n is i or 2; (ii) M represents a direct bond or a -linker optionally substituted with C ⁇ . alkyl, hydroxy or hydroxy-C ⁇ _ alkyl; preferably M represents a Ci-linker optionally substituted with in particular M represents a Ci-linker; (iii) R 1 represents hydrogen, hydroxy, cyano, halo, C ⁇ profession 4 alkyl, Cj.
- R 1 represents substituted with halo
- R 2 represents hydrogen, halo, C ⁇ _ alkyl or C alkyloxy- optionally substituted with one or where possible two or three halo substituents
- R 3 represents hydrogen, halo, C ⁇ . 4 alkyl, C ⁇ _ 4 alkyloxy- or C M alkyl substituted with one or where possible two or three halo substituents
- R 4 represents hydrogen, halo or C ⁇ .
- R 5 represents hydrogen, C ]-4 alkyl or in particular hydrogen or methyl
- R 6 represents hydrogen or hydroxy, in particular hydrogen
- R represents hydrogen or R and R taken together with the carbon atom to which they are attached form a -C 2 -alkyl- linker
- Ar 2 represents phenyl optionally substituted with
- Another group of interesting compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply: (i) n is 1 or 2; (ii) M represents a Ci-linker; (iii) R 1 and R 2 represent hydrogen, Cj. alkyl or d ⁇ alkyloxy, in particular methyl or methoxy; (iv) R 3 represents hydrogen or C ⁇ _ alkyloxy, in particular hydrogen or methoxy; (v) R 4 represents hydrogen or halo; (vi) R 5 represents hydrogen or in particular hydrogen or methyl; (vii) R 6 represents hydrogen or hydroxy; (viii) R 7 represents hydrogen.
- n is 1 or 2;
- M represents a Ci -linker;
- R 1 represents hydrogen, C].
- R 2 represents hydrogen, or C ⁇ _ 4 alkyloxy, in particular hydrogen (v)
- R 3 represents hydrogen or C ⁇ _ 4 alkyloxy, in particular hydrogen or methoxy;
- R 4 represents hydrogen or halo;
- R 5 represents hydrogen or C].
- R 6 represents hydrogen or hydroxy;
- R 7 represents hydrogen.
- the compounds of formula (I) are selected from the group consisting of;
- the present invention provides compounds of formula
- M represents a direct bond or a C ⁇ -3 alkyl linker optionally substituted with one or two substituents selected from C ⁇ _ 3 alkyloxy-C ⁇ . alkyl-, hydroxy-Ci -4 alkyl-, hydroxy, or phenyl-C ⁇ _ 4 alkyl-;
- R 1 and R 2 each independently represent hydrogen, halo, cyano, hydroxy, C ⁇ .
- R 3 represents hydrogen, halo, C ⁇ -4 alkyl, C ⁇ - 4 alkyloxy-, cyano or hydroxy
- R 4 represents hydrogen, halo, Ci ⁇ alkyl, hydroxy, cyano or C].
- R 5 represents hydrogen, C ⁇ . 4 alkyl or A ⁇ -C ⁇ alky!-
- R 5 represents hydrogen, hydroxy, halo, C h alky] or C].
- Ar 1 and Ar 2 each independently represent phenyl or naphtyl wherein said phenyl and naphtyl are optionally substituted with C ⁇ alkyl, C ⁇ -4 alkyloxy-, or phenyl-C ⁇ _ 4 alkyl.
- Another group of interesting compounds consists of those compounds of formula (F) wherein one or more of the following restrictions apply: i. n is 1 or 2; ii. M represents a Ci-linker; iii. R 1 and R 2 represent hydrogen, C]. 4 alkyl or C]. alkyloxy, in particular methyl or methoxy; iv. R 3 represents hydrogen or in particular hydrogen or methoxy; v. R represents hydrogen or halo; vi. R 5 represents hydrogen or Cj. alkyl, in particular hydrogen or methyl; vii. R 6 represents hydrogen or hydroxy.
- the present invention provides any of the aforementioned group of compounds for use as a medicine.
- parthologies associated with excess cortisol formation such as obesity, diabetes, obesity related cardiovascular diseases and glaucoma.
- the 1,3-pyrrolidinine derivatives of the present invention are generally prepared by alkylation of the appropriate lactam (II) with an appropriate alkyl halide (III) in the presence of a base such as for example (diisopropylamino)lithium (LDA) or sec- butyllithium, optionally in the present of a co-solvent such as for example N,N',N"- Hexamethylphosphoramide (HMPA) or a salt such as for example LiBr (Scheme 1).
- HMPA N,N',N"- Hexamethylphosphoramide
- Scheme 1 LiBr
- reaction temperature and the reaction time may be altered depending on the starting material or reagents but is usually performed within a couple of hours at low temperatures (-50°C - -90°C). In some cases the coupling reaction is slow and the mixture has to be kept until completion. In these cases the temperature could be enhanced up to (-10°C - -30°C).
- Functional groups which it is desirable to protect include hydroxy, amino and carboxylic acid
- Suitable protecting groups for hydroxy include t ⁇ alkylsilyl groups (e g tert-butyldimethvlsilyl, tert-butyldiphenylsilyl or tnmethylsilyl), benzyl and tetrahydropyranyl
- Suitable protecting groups for amino include tcrt-butyloxycarbonyl or benzyloxycarbonyl
- Suitable protecting groups for carboxylic acid include C ( ⁇ 6>alkyl or benzyl esters
- the protection and deprotection of functional groups may take place before or after a reaction step
- N-atoms in compounds of formula (I) can be methylated by art- known methods using CH 3 -I in a suitable solvent such as, for example 2-propanone, tetrahydrofuran or dimethylformamide
- the compounds of formula (I) may also be converted to the corresponding N-oxide forms following art-known procedures for converting a bivalent nitrogen into its N-oxide form Said N-oxidation reaction may generally be earned out by reacting the starting matenal of formula (I) with 3-phenyl-2-(phenylsulfonyl)oxaz ⁇ d ⁇ ne or with an appropnate organic or inorganic peroxide.
- Appropnate inorganic peroxides compnse, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g.
- organic peroxides may compnse peroxy acids such as, for example, benze ⁇ ecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e g 3-chloroben enecarboperoxo ⁇ c acid, peroxoalkanoic acids, e g peroxoacetic acid, alkylhydroperoxides, e g t-butyl hydroperoxide
- Suitable solvents are, for example, water, lower alkanols, e g ethanol and the like, hydrocarbons, e g toluene, ketones, e.g 2-butanone, halogenated hydrocarbons, e g dichloromethane, and mixtures of such solvents
- Pure stereochemically isomenc forms of the compounds of formula (I) may be obtained by the application of art-known procedures Diastereomers may be separated by physical methods such as selective crystal
- stereochemically isomenc forms of said compounds and said intermediates can be obtained by the application of art-known procedures
- diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g counter current distnbution, liquid chromatography and the like methods
- Enan ⁇ omers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastereomenc salts or compounds, then physically separa ⁇ ng said mixtures of diastereomenc salts or compounds by, for example, selective crystallization or chromatographic techniques, e g liquid chromatography and the like methods, and finally converting said separated diastereomenc salts or compounds into the corresponding enantiomers.
- Pure stereochemically isomenc forms may also be obtained from the pure stereochemically is
- the compounds of the present invention are useful because they possess pharmacological properties. They can therefore be used as medicines, in particular to treat pathologies associated with excess cortisol formation such as for example, obesity, diabetes, obesity lelated cardiovascular diseases, and glaucoma
- the inhibitory effect of the present compounds on the 1 l ⁇ -HSDl-reductase activity has been demonstrated in vitro, in an enzymatic assay using the recombinant 11 ⁇ - HSD1 enzyme, by measuring the conversion of cortison into cortisol using HPLC purification and quantification methods.
- 1 l ⁇ -HSDl-reductase inhibition was also demonstrated in vitro, in a cell based assay comprising contacting the cells, expressing ll ⁇ -HSDl with die compounds to be tested and assessing the effect of said compounds on the formation of cortisol in the cellular medium of these cells.
- the cells preferably used in an assay of the present invention are selected from the group consisting of mouse fibroblast 3T3-L1 cells, HepG2 cells, pig kidney cell, in particular LCC-PK1 cells and rat hepatocytes.
- the present invention provides the compounds of formula (I) and their pharmaceutically acceptable N-oxides, addition salts, quaternary amines and stereochemically isomeric forms for use in therapy. More particular in the treatment or prevention of parthologies associated with excess cortisol formation such as obesity, diabetes, obesity related cardiovascular diseases and glaucoma.
- the compounds of formula (I) and their pharmaceutically acceptable N-oxides, addition salts, quaternary amines and the stereochemically isomeric forms may hereinafter be referred to as compounds according to the invention.
- a method for the treatment of an animal for example, a mammal including humans, suffering from a pathology associated with excess cortisol formation, which comprises administering an effective amount of a compound according to the present invention.
- Said method comprising the systemic or topical administration of an effective amount of a compound according to the invention, to warm-blooded animals, including humans.
- a compound according to the present invention for use as a medicine.
- the compound according to the present invention in the manufacture of a medicament for treating pathologies associated with excess cortisol formation such as for example, obesity, diabetes, obesity related cardiovascular diseases, and glaucoma.
- the amount of a compound according to the present invention, also referred to here as the active ingredient, which is required to achieve a therapeutical effect will be, of course, vary with the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated.
- a suitable daily dose would be from 0.001 mg kg to 500 mg/kg body weight, in particular from 0.005 mg/kg to 100 mg kg body weight.
- a method of treatment may also include administering the active ingredient on a regimen of between one and four intakes per day.
- the present invention further provides a pharmaceutical composition comprising a compound according to the present invention, together with a pharmaceutically acceptable carrier or diluent.
- a pharmaceutically acceptable carrier or diluent must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.
- compositions of this invention may be prepared by any methods well known in the art of pharmacy, for example, using methods such as those described in Gennaro et al. Remington's Pharmaceutical Sciences (18 lh ed., Mack Publishing Company, 1990, see especially Part 8 : Pharmaceutical preparations and their Manufacture).
- a therapeutically effective amount of the particular compound, in base form or addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration.
- compositions are desirably in unitary dosage form suitable, preferably, for systemic administration such as oral, percutaneous, or parenteral administration; or topical administration such as via inhalation, a nose spray, eye drops or via a cream, gel, shampoo or the like.
- systemic administration such as oral, percutaneous, or parenteral administration
- topical administration such as via inhalation, a nose spray, eye drops or via a cream, gel, shampoo or the like.
- any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions: or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets.
- tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.
- the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
- injectable solutions for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
- injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
- the carrier optionally comprises a penetration enhancing agent and or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
- These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment.
- compositions for topical application there may be cited all compositions usually employed for topically administering drugs e.g. creams, gellies, dressings, shampoos, tinctures, pastes, ointments, salves, powders and the like.
- compositions may be by aerosol, e.g. with a propellant such as nitrogen, carbon dioxide, a freon, or without a propellant such as a pump spray, drops, lotions, or a semisolid such as a thickened composition which can be applied by a swab.
- a propellant such as nitrogen, carbon dioxide, a freon
- a propellant such as a pump spray
- drops lotions
- a semisolid such as a thickened composition which can be applied by a swab.
- semisolid compositions such as salves, creams, gellies, ointments and the like will conveniently be used.
- Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
- dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
- 'DCM dichloromethane
- DIPE diisopropyl ether
- DMF diisopropyl ether
- EtOAc diethylether
- 'LDA' means (diisopropylamino)lithium
- 'THF' means tetrahydrofuran.
- 1,2-ethaned ⁇ ol (15 ml) was stirred and refluxed over the weekend The reaction mixture was cooled, poured out into water and extracted with DCM. The aqueous layer was acidified with citnc acid (pH 5) and extracted with DCM The oiganic layer was separated, dned, filtered and the solvent was evaporated, yielding 1.8 g of intermediate
- intermediate 14 A mixture of intermediate 13 (0.0064 mol) in methanol (150 ml) was stirred and hydrogenated overnight with palladium on activated carbon 10% (0.5 g) as a catalyst. After uptake of hydrogen (1 equiv), the catalyst was filtered off and the filtrate was evaporated, yielding 1.2 g of intermediate 14.
- Example B2 Preparation of compound 2 Tn a flame dned Schlenk-flask 0.16 g (0.47 mmol) of compound 1 in 10 ml THF were cooled to -80°C.
- LDA 1.3 equivalent, 0.31 ml, ca. 2M commercial solution in THF heptane /ethylbenzene
- Methyl iodide 0.09 g, 0.66 mmol
- Table 1 lists the compounds that were prepared according to the above Examples. Table 1
- Example C 1 Enzymatic assays to test the effect of compounds on llb-hydroxysteroid dehydrogenase type 1 and type 2
- the effect on the 11 ⁇ -HSD1 -dehydrogenase activity was measured in a reaction mixture containing 0 1M sodium phosphate buffer pH 9 0, 300 ⁇ M NADP, 25 ⁇ M cortisol, 1 ⁇ l drug and or solvent and 3 5 ⁇ g recombinant protein in a final volume of 100 ⁇ l.
- the effects on the 11 ⁇ -HSD2 dependent dehydrogenase activity was studied in a reaction mixture containing 0 1M sodium phosphate buffer pH 7 5, 300 ⁇ M NAD, 100 nM cortisol (of which 2 nM is 3H-rad ⁇ o labelled), 1 ⁇ l drug and/or solvent and 2 5 ⁇ g recombinant protein in a final volume of 100 ⁇ l All incubations were performed for 45 minutes at 37 ⁇ C in a water bath. The reaction was stopped by adding 100 ⁇ l acetonitrile containing 20 ⁇ g corticosterone as internal standard.
- Example C2 Cellular assays to test the effect of compounds on 1 lb-hydroxysteroid dehydrogenase type 1 and type 2
- Mouse fibroblast 3T3-L1 cells (ATCC-CL-173) were seeded at a density of 16500 cells / ml in 12 well plates and grown for 7 days in DMEM medium (supplemented with 10 % heat inactivated foetal calf serum, 2mM glutamine and 25 mg gentamycin) at 37°C in a humidified 5% C0 2 atmosphere. Medium was refreshed twice a week. Fibroblasts were differentiated into adipocytes at 37°C in a 5% C0 2 humidified atmosphere in growth medium containing 2 ⁇ g ml insulin, 55 ⁇ g/ml D3MX and 39.2 ⁇ g/ml dexamethasone.
- hepatocytes from male rats were seeded on BD-Biocoat Matrigel matrix multiwell plates at a density of 250000 cells /well and incubated for 10 days at 37°C in a 5% C0 2 humidified atmosphere in DMEM-HAM's F12 medium containing 5% Nu- serum, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin , 0.25 ⁇ g ml amphotericin B, 50 ⁇ g/ml gentamycin sulfate, 5 ⁇ g/ml insulin and 392 ng/ml dexamethasone. Medium was refreshed 3 times a week.
- HepG2-cells (ATCC HB-8065) were seeded in 12 well plates at a density of 100,000 cells/ml and grown at 37°C in a humidified 5% C0 atmosphere in MEM-Rcga-3 mcdium supplemented with 10% heat inactivated foetal calf serum, 2 mM L-glutamine and sodium bicarbonate). Medium was refreshed twice a week.
- Pig kidney cells (LCC-PK1, ATCC CRL-1392) were seeded at a density of 150,000 cells /ml in 12 well plates and grown at 37°C in a humidified 5% C0 2 atmosphere in Medium 199 supplemented with Earls modified salt solution, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin and 10 % foetal calf serum. Medium was refreshed twice a week. Twenty four hours prior to the onset of the experiment, medium was changed by medium containing 10% charcoal stripped foetal calf serum. Following a 4 hour pre-incubation with test compound, 0.5 ⁇ Ci 3 H-cortisol or corticosterone, was added to the cultures. One hour later, the medium was extracted on Extrelut 3 -columns with 15 ml diethyl ether and the extract was analysed by HPLC as described above.
- compositions suitable for systemic or topical administration to animal and human subjects in accordance with the present invention.
- Active ingredient as used throughout these examples relates to a compound of formula (I) or a pharmaceutically acceptable addition salt thereof.
- Example D.l film-coated tablets Prparation , of ab et . core
- a mixture of A.I. (100 g), lactose (570 g) and starch (200 g) was mixed well and thereafter humidified with a solution of sodium dodecyl sulfate (5 g) and polyvinylpyrrolidone (10 g) in about 200 ml of water.
- the wet powder mixture was sieved, dried and sieved again. Then there was added microcrystalline cellulose (100 g) and hydrogenated vegetable oil (15 g). The whole was mixed well and compressed into tablets, giving 10.000 tablets, each comprising 10 mg of the active ingredient.
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Abstract
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Priority Applications (15)
Application Number | Priority Date | Filing Date | Title |
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NZ551076A NZ551076A (en) | 2004-05-07 | 2005-04-29 | Adamantyl pyrrolidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors |
US11/632,195 US7687644B2 (en) | 2004-05-07 | 2005-04-29 | Adamantyl pyrrolidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors |
EA200602058A EA011021B1 (en) | 2004-05-07 | 2005-04-29 | Adamantyl pyrrolidin -2-one derivatives as 11 beta hydroxysteroid dehydrogenase inhibitors |
EP05738030A EP1747198B1 (en) | 2004-05-07 | 2005-04-29 | Adamantyl pyrrolidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors |
CA2565632A CA2565632C (en) | 2004-05-07 | 2005-04-29 | Adamantyl pyrrolidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors |
PL05738030T PL1747198T3 (en) | 2004-05-07 | 2005-04-29 | Adamantyl pyrrolidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors |
MXPA06012929A MXPA06012929A (en) | 2004-05-07 | 2005-04-29 | Adamantyl pyrrolidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors. |
JP2007512176A JP4898664B2 (en) | 2004-05-07 | 2005-04-29 | Adamantylpyrrolidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors |
DE602005007344T DE602005007344D1 (en) | 2004-05-07 | 2005-04-29 | ADAMANTYL PYRROLIDIN-2-ON DERIVATIVES AS 11-BETA HYDROXYSTEROID DEHYDROGENAS INHIBITORS |
AU2005240785A AU2005240785B2 (en) | 2004-05-07 | 2005-04-29 | Adamantyl pyrrolidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors |
KR1020067024229A KR101193464B1 (en) | 2004-05-07 | 2005-04-29 | Adamantyl pyrrolidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors |
CN2005800225945A CN1980889B (en) | 2004-05-07 | 2005-04-29 | Adamantyl pyrrolidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors |
IL179064A IL179064A (en) | 2004-05-07 | 2006-11-06 | Adamantyl pyrrolidin-2-one and piperidine-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors |
NO20065615A NO338504B1 (en) | 2004-05-07 | 2006-12-06 | Adamantyl-pyrrolidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors |
HK07112354.8A HK1106765A1 (en) | 2004-05-07 | 2007-11-12 | ADAMANTYL PYRROLIDIN-2-ONE DERIVATIVES AS 11-BETA HYDROXYSTEROID DEHYDROGENASE INHIBITORS 11-ß |
Applications Claiming Priority (2)
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EP04101993.6 | 2004-05-07 | ||
EP04101993 | 2004-05-07 |
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PCT/EP2005/051970 WO2005108361A1 (en) | 2004-05-07 | 2005-04-29 | Adamantyl pyrrolidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors |
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US (1) | US7687644B2 (en) |
EP (1) | EP1747198B1 (en) |
JP (1) | JP4898664B2 (en) |
KR (1) | KR101193464B1 (en) |
CN (1) | CN1980889B (en) |
AR (1) | AR049089A1 (en) |
AT (1) | ATE397586T1 (en) |
AU (1) | AU2005240785B2 (en) |
CA (1) | CA2565632C (en) |
DE (1) | DE602005007344D1 (en) |
EA (1) | EA011021B1 (en) |
ES (1) | ES2307175T3 (en) |
HK (1) | HK1106765A1 (en) |
IL (1) | IL179064A (en) |
MX (1) | MXPA06012929A (en) |
MY (1) | MY137469A (en) |
NO (1) | NO338504B1 (en) |
NZ (1) | NZ551076A (en) |
PL (1) | PL1747198T3 (en) |
TW (1) | TWI357896B (en) |
WO (1) | WO2005108361A1 (en) |
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---|---|---|---|---|
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WO2008106128A2 (en) | 2007-02-26 | 2008-09-04 | Vitae Pharmaceuticals, Inc. | CYCLIC UREA AND CARBAMATE INHIBITORS OF 11β -HYDROXYSTEROID DEHYDROGENASE 1 |
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Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003065983A2 (en) * | 2002-02-01 | 2003-08-14 | Merck & Co., Inc. | 11-beta-hydroxysteroid dehydrogenase 1 inhibitors useful for the treatment of diabetes, obesity and dyslipidemia |
WO2003104207A2 (en) * | 2002-06-10 | 2003-12-18 | Merck & Co., Inc. | 11-beta-hydroxysteroid dehydrogenase 1 inhibitors useful for the treatment of diabetes, obesity and dyslipidemia |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997019074A1 (en) | 1995-11-17 | 1997-05-29 | Hoechst Marion Roussel, Inc. | Substituted 4-(1h-benzimidazol-2-yl-amino)piperidines useful for the treatment of allergic diseases |
US6211199B1 (en) * | 1995-11-17 | 2001-04-03 | Aventis Pharmaceuticals Inc. | Substituted 4-(1H-benzimidazol-2-yl-amino)piperidines useful for the treatment of allergic diseases |
US6194406B1 (en) * | 1995-12-20 | 2001-02-27 | Aventis Pharmaceuticals Inc. | Substituted 4-(1H-benzimidazol-2-yl)[1,4]diazepanes useful for the treatment of allergic disease |
IL125002A0 (en) | 1995-12-20 | 1999-01-26 | Hoechst Marion Roussel Inc | Novel substituted 4-(1H-benzimidazol-2-yl) [1,4] diazepanes useful for the treatment of allergic diseases |
US6423704B2 (en) * | 1995-12-20 | 2002-07-23 | Aventis Pharmaceuticals Inc. | Substituted 4-(1H-benzimidazol-2-yl)[1,4]diazepanes useful for the treatment of allergic diseases |
US6784167B2 (en) * | 2000-09-29 | 2004-08-31 | Bayer Pharmaceuticals Corporation | 17-beta-hydroxysteroid dehydrogenase-II inhibitors |
US6612055B2 (en) | 2001-10-23 | 2003-09-02 | World Lit Corporaion | Sign panel using ambient or artificial light |
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- 2005-04-29 DE DE602005007344T patent/DE602005007344D1/en active Active
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003065983A2 (en) * | 2002-02-01 | 2003-08-14 | Merck & Co., Inc. | 11-beta-hydroxysteroid dehydrogenase 1 inhibitors useful for the treatment of diabetes, obesity and dyslipidemia |
WO2003104207A2 (en) * | 2002-06-10 | 2003-12-18 | Merck & Co., Inc. | 11-beta-hydroxysteroid dehydrogenase 1 inhibitors useful for the treatment of diabetes, obesity and dyslipidemia |
Cited By (129)
Publication number | Priority date | Publication date | Assignee | Title |
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US7507860B2 (en) | 2004-04-13 | 2009-03-24 | Pfizer Inc. | Androgen modulators |
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US8372841B2 (en) | 2004-04-29 | 2013-02-12 | Abbott Laboratories | Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme |
US9133145B2 (en) | 2004-04-29 | 2015-09-15 | Abbvie Inc. | Methods of use of inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme |
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WO2006100502A1 (en) * | 2005-03-24 | 2006-09-28 | Sterix Limited | 11-beta-hydroxysteroid dehydrogenase inhibitors |
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WO2007124337A1 (en) | 2006-04-21 | 2007-11-01 | Eli Lilly And Company | Biphenyl amide lactam derivatives as inhibitors of 11- beta-hydroxysteroid dehydrogenase 1 |
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WO2007127765A1 (en) | 2006-04-25 | 2007-11-08 | Eli Lilly And Company | Inhibitors of 11-beta-hydroxysteroid dehydrogenase 1 |
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US7829582B2 (en) | 2006-04-28 | 2010-11-09 | Eli Lilly And Company | Piperidinyl substituted pyrrolidinones as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1 |
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EP2351568A2 (en) | 2006-05-04 | 2011-08-03 | Boehringer Ingelheim International GmbH | Uses of dpp-iv inhibitors |
WO2007128761A2 (en) | 2006-05-04 | 2007-11-15 | Boehringer Ingelheim International Gmbh | Uses of dpp-iv inhibitors |
WO2008044656A1 (en) * | 2006-10-06 | 2008-04-17 | Taisho Pharmaceutical Co., Ltd. | Imidazolidinone derivative |
JP2010506876A (en) * | 2006-10-19 | 2010-03-04 | エフ.ホフマン−ラ ロシュ アーゲー | Imidazolone and imidazolidinone derivatives as 11β-HSD1 inhibitors for diabetes |
WO2008046758A3 (en) * | 2006-10-19 | 2009-06-11 | Hoffmann La Roche | Imidazolone and imidazolidinone derivatives as 11b-hsd1 inhibitors for diabetes |
WO2008046758A2 (en) * | 2006-10-19 | 2008-04-24 | F. Hoffmann-La Roche Ag | Imidazolone and imidazolidinone derivatives as 11b-hsd1 inhibitors for diabetes |
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US8129423B2 (en) | 2006-10-19 | 2012-03-06 | Hoffman-La Roche Inc. | Imidazolone and imidazoloidinone derivatives as 11b-HSD1 inhibitors |
WO2008074384A1 (en) | 2006-12-21 | 2008-06-26 | Merck Patent Gmbh | 2-ADAMANTYL-BUTYRAMIDE DERIVATIVES AS SELECTIVE 11βETA-HSD1 INHIBITORS |
WO2008106128A3 (en) * | 2007-02-26 | 2009-02-19 | Vitae Pharmaceuticals Inc | CYCLIC UREA AND CARBAMATE INHIBITORS OF 11β -HYDROXYSTEROID DEHYDROGENASE 1 |
US8835426B2 (en) | 2007-02-26 | 2014-09-16 | Vitae Pharmaceuticals, Inc. | Cyclic urea and carbamate inhibitors of 11β-hydroxysteroid dehydrogenase 1 |
WO2008106128A2 (en) | 2007-02-26 | 2008-09-04 | Vitae Pharmaceuticals, Inc. | CYCLIC UREA AND CARBAMATE INHIBITORS OF 11β -HYDROXYSTEROID DEHYDROGENASE 1 |
JP2010519304A (en) * | 2007-02-26 | 2010-06-03 | ヴァイティー ファーマシューティカルズ,インコーポレイテッド | Cyclic urea and carbamate inhibitors of 11β-hydroxysteroid dehydrogenase 1 |
WO2008120655A1 (en) * | 2007-03-30 | 2008-10-09 | Institute Of Medicinal Molecular Design, Inc. | Oxazolidinone derivative having inhibitory activity on 11β-hydroxysteroid dehydrogenase type i |
US7998992B2 (en) | 2007-03-30 | 2011-08-16 | Institute Of Medicinal Molecular Design, Inc. | Oxazolidinone derivative having inhibitory activity on 11β-hydroxysteroid dehydrogenase type 1 |
US8383622B2 (en) | 2007-05-18 | 2013-02-26 | Shionogi & Co., Ltd. | Nitrogen-containing heterocyclic derivative having 11β-hydroxysteroid dehydrogenase type I inhibitory activity |
US7790711B2 (en) | 2007-07-17 | 2010-09-07 | Hoffmann-La Roche Inc. | Inhibitors of 11β-Hydroxysteroid Dehydrogenase |
US9079861B2 (en) | 2007-11-07 | 2015-07-14 | Vitae Pharmaceuticals, Inc. | Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1 |
US8859580B2 (en) | 2007-11-16 | 2014-10-14 | Boehringer Ingelheim International Gmbh | Aryl- and heteroarylcarbonyl derivatives of benzomorphanes and related scaffolds, medicaments containing such compounds and their use |
US8748444B2 (en) | 2007-12-11 | 2014-06-10 | Vitae Pharmaceuticals, Inc. | Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1 |
US8673899B2 (en) | 2008-05-01 | 2014-03-18 | Vitae Pharmaceuticals, Inc. | Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
WO2009138386A3 (en) * | 2008-05-13 | 2010-02-11 | Boehringer Ingelheim International Gmbh | Alicyclic carboxylic acid derivatives of benzomorphans and related scaffolds, medicaments containing such compounds and their use |
US9073870B2 (en) | 2008-05-13 | 2015-07-07 | Boehringer Ingelheim International Gmbh | Alicyclic carboxylic acid derivatives of benzomorphans and related scaffolds, medicaments containing such compounds and their use |
US8765780B2 (en) | 2008-05-13 | 2014-07-01 | Boehringer Ingelheim International Gmbh | Alicyclic carboxylic acid derivatives of benzomorphans and related scaffolds, medicaments containing such compounds and their use |
WO2009138386A2 (en) * | 2008-05-13 | 2009-11-19 | Boehringer Ingelheim International Gmbh | Alicyclic carboxylic acid derivatives of benzomorphans and related scaffolds, medicaments containing such compounds and their use |
US8487094B2 (en) | 2008-07-25 | 2013-07-16 | Boehringer Ingelheim International Gmbh | Synthesis of inhibitors of 11β-hydroxysteroid dehydrogenase type 1 |
US8754076B2 (en) | 2008-07-25 | 2014-06-17 | Vitae Pharmaceuticals, Inc./Boehringer-Ingelheim | Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
US8846668B2 (en) | 2008-07-25 | 2014-09-30 | Vitae Pharmaceuticals, Inc. | Inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
US8829027B2 (en) | 2008-10-23 | 2014-09-09 | Boehringer Ingelheim International Gmbh | Urea derivatives of substituted nortropanes, medicaments containing such compounds and their use |
US8637505B2 (en) | 2009-02-04 | 2014-01-28 | Boehringer Ingelheim International Gmbh | Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
US8680093B2 (en) | 2009-04-30 | 2014-03-25 | Vitae Pharmaceuticals, Inc. | Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
US8703765B2 (en) | 2009-06-02 | 2014-04-22 | Boehringer Ingelheim International Gmbh | Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1 |
US8822452B2 (en) | 2009-06-04 | 2014-09-02 | Laboratorios Salvat, S.A. | Inhibitor compounds of 11-beta-hydroxysteroid dehydrogenase type 1 |
US8524894B2 (en) | 2009-06-04 | 2013-09-03 | Laboratorios Salvat, S.A. | Inhibitor compounds of 11-beta-hydroxysteroid dehydrogenase type 1 |
US8927539B2 (en) | 2009-06-11 | 2015-01-06 | Vitae Pharmaceuticals, Inc. | Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1 based on the 1,3-oxazinan-2-one structure |
US8883778B2 (en) | 2009-07-01 | 2014-11-11 | Vitae Pharmaceuticals, Inc. | Cyclic inhibitors of 11 beta-hydroxysteroid dehydrogenase 1 |
US8552212B2 (en) | 2009-11-05 | 2013-10-08 | Boehringer Ingelheim International Gmbh | Chiral phosphorus ligands |
US9663470B2 (en) | 2009-11-06 | 2017-05-30 | Vitae Pharmaceuticals, Inc. | Aryl- and heteroarylcarbonyl derivatives of hexahydroindenopyridine and octahydrobenzoquinoline |
US9328072B2 (en) | 2009-11-06 | 2016-05-03 | Vitae Pharmaceuticals, Inc. | Aryl-and heteroarylcarbonyl derivatives of hexahydroindenopyridine and octahydrobenzoquinoline |
US8497281B2 (en) | 2009-11-06 | 2013-07-30 | Vitae Pharmaceuticals, Inc. | Aryl- and heteroarylcarbonyl derivatives of hexahydroindenopyridine and octahydrobenzoquinoline |
US8648192B2 (en) | 2010-05-26 | 2014-02-11 | Boehringer Ingelheim International Gmbh | 2-oxo-1,2-dihydropyridin-4-ylboronic acid derivatives |
US8933072B2 (en) | 2010-06-16 | 2015-01-13 | Vitae Pharmaceuticals, Inc. | Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use |
US9090605B2 (en) | 2010-06-16 | 2015-07-28 | Vitae Pharmaceuticals, Inc. | Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use |
US8765744B2 (en) | 2010-06-25 | 2014-07-01 | Boehringer Ingelheim International Gmbh | Azaspirohexanones |
US8846613B2 (en) | 2010-11-02 | 2014-09-30 | Boehringer Ingelheim International Gmbh | Pharmaceutical combinations for the treatment of metabolic disorders |
US8686149B2 (en) | 2010-11-05 | 2014-04-01 | Boehringer-Ingelheim International Gmbh | Aryl- and heteroarylcarbonyl derivatives of hexahydroindenopyridine and octahydrobenzoquinoline |
US9120769B2 (en) | 2010-11-05 | 2015-09-01 | Boehringer-Ingelheim International Gmbh | Aryl-and heteroarylcarbonyl derivatives of hexahydroindenopyridine and octahydrobenzoquinoline |
US9073906B2 (en) | 2011-03-31 | 2015-07-07 | Korea Research Institute Of Chemical Technology | Sulfamide derivative having an adamantyl group and its pharmaceutically acceptable salt |
WO2012134233A2 (en) | 2011-03-31 | 2012-10-04 | 한국화학연구원 | Sulphamide derivative having an adamantyl group and a pharmaceutically acceptable salt thereof |
US8975405B2 (en) | 2011-08-17 | 2015-03-10 | Boehringer Ingelheim International Gmbh | Indenopyridine derivatives |
US8735585B2 (en) | 2011-08-17 | 2014-05-27 | Boehringer Ingelheim International Gmbh | Indenopyridine derivatives |
WO2020210922A1 (en) * | 2019-04-17 | 2020-10-22 | Pontificia Universidad Católica De Chile | Derivatives of adamantyl oxadiazoles and pharmaceutically acceptable solvates, hydrates and salts thereof, pharmaceutical composition comprising same, synthesis method, suitable for use as effective and selective inhibitors of the reductase activity of the enzyme 11-beta dehydrogenase type 1 (11β-hsd1) |
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JP4898664B2 (en) | 2012-03-21 |
IL179064A (en) | 2010-12-30 |
PL1747198T3 (en) | 2008-11-28 |
AR049089A1 (en) | 2006-06-28 |
NO20065615L (en) | 2006-12-06 |
KR101193464B1 (en) | 2012-10-24 |
EP1747198B1 (en) | 2008-06-04 |
NO338504B1 (en) | 2016-08-29 |
US20070287743A1 (en) | 2007-12-13 |
MY137469A (en) | 2009-01-30 |
IL179064A0 (en) | 2007-03-08 |
AU2005240785A1 (en) | 2005-11-17 |
TWI357896B (en) | 2012-02-11 |
CN1980889A (en) | 2007-06-13 |
ATE397586T1 (en) | 2008-06-15 |
DE602005007344D1 (en) | 2008-07-17 |
KR20070008699A (en) | 2007-01-17 |
NZ551076A (en) | 2009-05-31 |
CA2565632A1 (en) | 2005-11-17 |
MXPA06012929A (en) | 2007-01-26 |
HK1106765A1 (en) | 2008-03-20 |
TW200606143A (en) | 2006-02-16 |
ES2307175T3 (en) | 2008-11-16 |
CN1980889B (en) | 2010-11-10 |
US7687644B2 (en) | 2010-03-30 |
EA200602058A1 (en) | 2007-04-27 |
CA2565632C (en) | 2013-04-23 |
JP2007536337A (en) | 2007-12-13 |
EA011021B1 (en) | 2008-12-30 |
EP1747198A1 (en) | 2007-01-31 |
AU2005240785B2 (en) | 2011-02-03 |
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