WO2008129319A1 - Sel de dérivés d'oxadiazole comme inhibiteurs de dgat - Google Patents

Sel de dérivés d'oxadiazole comme inhibiteurs de dgat Download PDF

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Publication number
WO2008129319A1
WO2008129319A1 PCT/GB2008/050270 GB2008050270W WO2008129319A1 WO 2008129319 A1 WO2008129319 A1 WO 2008129319A1 GB 2008050270 W GB2008050270 W GB 2008050270W WO 2008129319 A1 WO2008129319 A1 WO 2008129319A1
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amino
phenyl
oxadiazol
cyclohexyl
trans
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PCT/GB2008/050270
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English (en)
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Kevin Richard Back
David Paul Whalley
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Astrazeneca Ab
Astrazeneca Uk Limited
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Publication of WO2008129319A1 publication Critical patent/WO2008129319A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to certain novel salts of compounds which inhibit acetyl CoA(acetyl coenzyme A):diacylglycerol acyltransferase (DGATl) activity, to processes for preparing such compounds, to their utility in treating clinical conditions associated with obesity, to methods for their therapeutic use and to pharmaceutical compositions containing them.
  • DGATl diacylglycerol acyltransferase
  • DGAT Acyl CoA:diacylglycerol acyltransferase
  • DGAT genes have been cloned and characterised. Both of the encoded proteins catalyse the same reaction although they share no sequence homology.
  • the DGATl gene was identified from sequence database searches because of its similarity to acyl CoAxholesterol acyltransferase (ACAT) genes. [Cases et al (1998) Identification of a gene encoding an acyl CoA: diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis. Proc. Natl. Acad. Sci. USA 95: 13018-13023].
  • DGATl activity has been found in many mammalian tissues, including adipocytes.
  • DGATl is known to be significantly up-regulated during adipocyte differentiation. Studies in gene knockout mice has indicated that modulators of the activity of
  • DGATl would be of value in the treatment of type II diabetes and obesity.
  • DGATl knockout (Dgatl '1' ) mice are viable and capable of synthesizing triglycerides, as evidenced by normal fasting serum triglyceride levels and normal adipose tissue composition.
  • Dgatl '1' mice have less adipose tissue than wild-type mice at baseline and are resistant to diet-induced obesity. Metabolic rate is -20% higher in Dgatl '1' mice than in wild-type mice on both regular and high-fat diets [Smith et al (2000) Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking DGAT. Nature Genetics 25: 87-90].
  • Dgatl '1' mice Increased physical activity in Dgatl '1' mice partially accounts for their increased energy expenditure.
  • the Dgatl '1' mice also exhibit increased insulin sensitivity and a 20% increase in glucose disposal rate.
  • Leptin levels are 50% decreased in the Dgatl '1' mice in line with the 50% decrease in fat mass.
  • Dgatl '1' mice are crossed with ob/ob mice, these mice exhibit the ob/ob phenotype [Chen et al (2002) Increased insulin and leptin sensitivity in mice lacking acyl CoA:diacylglycerol acyltransferase J. Clin. Invest. 109:1049-1055] indicating that the Dgatl '1' phenotype requires an intact leptin pathway.
  • Dgatl '1' mice are crossed with Agouti mice a decrease in body weight is seen with normal glucose levels and 70% reduced insulin levels compared to wild type, agouti or ob/ob
  • R 1 is phenyl optionally substituted with 1, 2 or 3 substituents independently selected from fiuoro, chloro, bromo, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, cyano, methyl and ethyl; R A is hydrogen or methyl; p is 0 or 1.
  • substituents independently selected from fiuoro, chloro, bromo, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, cyano, methyl and ethyl
  • R A is hydrogen or methyl
  • p is 0 or 1.
  • the drug substance In the formulation of drug compositions, it is important for the drug substance to be in a form in which it can be conveniently handled and processed. This is of importance, not only from the point of view of obtaining a commercially viable manufacturing process, but also from the point of view of subsequent manufacture of pharmaceutical formulations comprising the active compound.
  • the drug substance, and compositions containing it should preferably be capable of being effectively stored over appreciable periods of time, without exhibiting a significant change in the active component's physico-chemical characteristics (e.g. its chemical composition, density, hygroscopicity and solubility).
  • the present invention provides a sodium, magnesium, tert-butylammonium salt, tris(hydroxymethyl)methylammonium, triethanolammonium, diethanolammonium, ethanolammonium, methylethanolammonium, diethylammonium, or nicotinamide salt of a compound of formula (I):
  • R 1 is phenyl optionally substituted with 1, 2 or 3 substituents independently selected from fiuoro, chloro, bromo, trifiuoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, cyano, methyl and ethyl;
  • R A is hydrogen or methyl;
  • p is 0 or 1 ; with the proviso that the salt of formula (I) is not sodium ⁇ trans -4- ⁇ 4-[( ⁇ 5-[(2,4,5- trifluorophenyl) amino]- l,3,4-oxadiazol-2-yl ⁇ carbonyl)amino]phenyl ⁇ cyclohexyl)acetate.
  • R 1 is phenyl, optionally substituted with 1 , 2 or 3 substituents independently selected from fiuoro, chloro, trifiuoromethyl, trifluoromethoxy, cyano, methyl and ethyl.
  • R 1 is phenyl substituted with 1, 2 or 3 fiuoro. In another embodiment, R 1 is phenyl substituted with 1 or 2 fiuoro.
  • R 1 is phenyl substituted with 1 fiuoro. In another embodiment, R 1 is phenyl substituted with 2 fiuoro. In another embodiment, R 1 is phenyl substituted with 3 fiuoro. In another embodiment, R 1 is phenyl substituted with 1 methyl group. In another embodiment, R 1 is phenyl substituted with 1 ethyl group.
  • R 1 is phenyl substituted with 1 methoxy group. In another embodiment, R 1 is phenyl substituted with 1 cyano group. In another embodiment, R 1 is phenyl substituted with 1 trifiuoromethyl group. In another embodiment, R 1 is phenyl substituted with 1 trifluoromethoxy group. In one embodiment, R A is methyl. In another embodiment, R A is hydrogen.
  • p is 0. In another embodiment p is 1. In one embodiment p is 1 and R A is hydrogen.
  • the sodium, magnesium, fe/t-butylammonium salt tris(hydroxymethyl)methylammonium, triethanolammonium, diethanolammonium, ethanolammonium, methylethanolammonium, diethylammonium, or nicotinamide salt of(trans-4- ⁇ 4-[( ⁇ 5-[(4-ethylphenyl)amino]-l,3,4-oxadiazol-2- yl ⁇ carbonyl)amino]phenyl ⁇ cyclohexyl)acetic acid.
  • the sodium, magnesium, t ⁇ t-butylammonium salt tris(hydroxymethyl)methylammonium, triethanolammonium, diethanolammonium, ethanolammonium, methylethanolammonium, diethylammonium, or nicotinamide salt of(trans-4- ⁇ 4-[( ⁇ 5-[(3-cyanophenyl)amino]-l,3,4-oxadiazol-2- yl ⁇ carbonyl)amino]phenyl ⁇ cyclohexyl)acetic acid.
  • the sodium, magnesium, t ⁇ t-butylammonium salt tris(hydroxymethyl)methylammonium, triethanolammonium, diethanolammonium, ethanolammonium, methylethanolammonium, diethylammonium, or nicotinamide salt of(trans-4- ⁇ 4-[( ⁇ 5-[(3-methylphenyl)amino]-l,3,4-oxadiazol-2- yl ⁇ carbonyl)amino]phenyl ⁇ cyclohexyl)acetic acid.
  • the sodium, magnesium, t ⁇ t-butylammonium salt tris(hydroxymethyl)methylammonium, triethanolammonium, diethanolammonium, ethanolammonium, methylethanolammonium, diethylammonium, or nicotinamide salt of (trans-4- ⁇ 4-[( ⁇ 5-[(4-fluorophenyl)amino]-l,3,4-oxadiazol-2- yl ⁇ carbonyl)amino]phenyl ⁇ cyclohexyl)acetic acid.
  • the sodium, magnesium, t ⁇ t-butylammonium salt tris(hydroxymethyl)methylammonium, triethanolammonium, diethanolammonium, ethanolammonium, methylethanolammonium, diethylammonium, or nicotinamide salt of (trans-4- ⁇ 4-[( ⁇ 5-[(2,4-difluorophenyl)amino]-l,3,4-oxadiazol-2- yl ⁇ carbonyl)amino]phenyl ⁇ cyclohexyl)acetic acid.
  • the sodium, magnesium, t ⁇ t-butylammonium salt tris(hydroxymethyl)methylammonium, triethanolammonium, diethanolammonium, ethanolammonium, methylethanolammonium, diethylammonium, or nicotinamide salt of (trans-4- ⁇ 4-[( ⁇ 5-[(2,6-difluorophenyl)amino]-l,3,4-oxadiazol-2- yl ⁇ carbonyl)amino]phenyl ⁇ cyclohexyl)acetic acid.
  • the sodium, magnesium, t ⁇ t-butylammonium salt tris(hydroxymethyl)methylammonium, triethanolammonium, diethanolammonium, ethanolammonium, methylethanolammonium, diethylammonium, or nicotinamide salt of(trans-4- ⁇ 4-[( ⁇ 5-[(3-fluorophenyl)amino]-l,3,4-oxadiazol-2- yl ⁇ carbonyl)amino]phenyl ⁇ cyclohexyl)acetic acid.
  • the sodium, magnesium, t ⁇ t-butylammonium salt tris(hydroxymethyl)methylammonium, triethanolammonium, diethanolammonium, ethanolammonium, methylethanolammonium, diethylammonium, or nicotinamide salt of (trans-4- ⁇ 4-[( ⁇ 5-[(2,5-difluorophenyl)amino]-l,3,4-oxadiazol-2- yl ⁇ carbonyl)amino]phenyl ⁇ cyclohexyl)acetic acid.
  • the sodium, magnesium, t ⁇ t-butylammonium salt tris(hydroxymethyl)methylammonium, triethanolammonium, diethanolammonium, ethanolammonium, methylethanolammonium, diethylammonium, or nicotinamide salt of2- (trans-4- ⁇ 4-[( ⁇ 5-[(2,4,5-trifluorophenyl)amino]-l,3,4-oxadiazol-2- yl ⁇ carbonyl)amino]phenyl ⁇ cyclohexyl)propanoic acid.
  • the sodium, magnesium, tert-butylammonium salt tris(hydroxymethyl)methylammonium, triethanolammonium, diethanolammonium, ethanolammonium, methylethanolammonium, diethylammonium, or nicotinamide salt of tr ⁇ n5-2-(4- ⁇ 4-[( ⁇ 5-[(3,4-difluorophenyl)amino]-l,3,4-oxadiazol-2-yl ⁇ carbonyl)amino]- phenyl ⁇ cyclohexyl)propanoic acid.
  • the sodium, magnesium, t ⁇ t-butylammonium salt tris(hydroxymethyl)methylammonium, triethanolammonium, diethanolammonium, ethanolammonium, methylethanolammonium, diethylammonium, or nicotinamide salt of(trans-4- ⁇ 4-[( ⁇ 5-[(3,4-difluorophenyl)amino]-l,3,4-oxadiazol-2- yl ⁇ carbonyl)amino]phenyl ⁇ cyclohexyl)acetic acid.
  • the salts of the invention are crystalline solids.
  • Compounds of the present invention exist as cis/trans isomers across the cycloalkyl ring. It is to be understood that the present invention encompasses all such isomers. It is also to be understood that certain compounds of the formula (I) and salts thereof can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which inhibit DGATl activity.
  • the compound of the invention can be prepared as outlined below. However, the invention is not limited to these methods.
  • Suitable protecting groups P are (l-6C)alkyl groups, which may be removed by any suitable known process known, such as by hydrolysis under acidic or basic conditions.
  • Certain compounds of formula (2) may also have chiral centres or can exist in different isomeric forms such as cis/trans isomers, and may be prepared as individual isomers, as illustrated below in Schemes 1 and 2 and in the accompanying examples.
  • Intermediate (5) may be prepared by palladium catalysed amination of intermediate (6), for example using benzophenone imine in the presence of palladium acetate, followed by removal of the protecting group, for example by hydrogeno lysis in the presence of palladium on carbon.
  • Intermediate (6) may be prepared by reaction of intermediate (7) with a trifluoromethanesulfonylating agent such as N-phenyltrifluoromethanesufonimide.
  • Intermediate (7) may be prepared by reaction of intermediate (8) with ethyl 2- (diethoxyphosphoryl)propanoate, followed by hydrogenation of the double bond, for example using palladium on carbon catalyst.
  • the pure trans isomer may be obtained by recrystallisation, for example from a mixture of isohexane and ethyl acetate.
  • Ester (9a) may be made by alkaline hydrolysis of ester (9a) as prepared using a published procedure (J. Het. Chem. 1977, 14, 1385-1388). Ester (9a) may be made by cyclisation of a compound of formula (9b) (where X is O or S) in a similar manner as described in process b) for compounds of formula (4).
  • Compounds of formula (2) may be coupled with compounds of formula (3) under standard conditions for formation of amide bonds.
  • an appropriate coupling reaction such as a carbodiimide coupling reaction performed with EDAC, optionally in the presence of DMAP, in a suitable solvent such as DCM, chloroform or DMF at room temperature.
  • a suitable solvent such as DCM, chloroform or DMF at room temperature.
  • Compounds of formula (4) and (9b) where X is S may be made by reaction of an aminocarbonyl acylhydrazine or ethoxycarbonyl acylhydrazine with a thioisocyanate or thioisocyanate equivalent such as aminothiocarbonylimidazole in a suitable solvent such as DMF or MeCN at a temperature between 0 and 100 0 C.
  • a suitable solvent such as DMF or MeCN
  • reaction of an aniline with methyl chlorooxoacetate in the presence of pyridine in a suitable solvent such as DCM followed by reaction with hydrazine in a suitable solvent such as ethanol at a temperature between 0 and 100 0 C .
  • the compound of formula (4) may then be cyclised using, for example agents such as carbonyldiimidazole, or tosyl chloride and a suitable base (such as triethylamine), under conditions known in the art.
  • Iso(thio)cyanates R 1 - NCX are commercially available or may be made by reaction of the acid chlorides R ⁇ -NH 2 with for example (thio)phosgene or a (thio)phosgene equivalent followed by a suitable base (such as triethylamine).
  • the amine salts of compounds of formula (I) may be prepared by reacting an acid of formula (I) with the appropriate amine in an inert solvent, for example ethanol, methanol, propan-2-ol, ethyl acetate, dichloromethane, toluene or mixtures thereof or a mixture of ethanol or methanol or propan-2-ol and water, at a temperature in the range of 0-100 0 C and isolating the solid salt.
  • the salt may be isolated by cooling the reaction solution and optionally seeding the solution with the desired product and/or concentrating the solution.
  • the product may be isolated by adding an antisolvent to a solution of the product in an inert solvent.
  • the solid may be collected by methods known to those skilled in the art for example filtration or centrifugation.
  • the alkali metal salts of formula (I), such as the sodium salts may be prepared by reacting an acid of formula (I) with an alkali metal alkoxide, for example sodium methoxide, or hydroxide, for example sodium hydroxide, in an appropriate alcohol solvent such as methanol, or water at a temperature in the range of 0-100 0 C and isolating the solid salt.
  • the salt may be isolated by cooling the reaction solution and optionally seeding the solution with the desired product and/or concentrating the solution.
  • the product may be isolated by adding an antisolvent to a solution of the product in an inert solvent.
  • the solid may be collected by methods known to those skilled in the art for example filtration or centrifugation.
  • the mono- or di- alkali salts may be prepared by this method, requiring the addition of one or two equivalents of alkali metal alkoxide or hydroxide as appropriate.
  • the magnesium salts of formula (I) may be prepared by an analogous method to the sodium salts above.
  • the acid was suspended in methanol and 1 equivalent of tert- butylamine in methanol was added at room temperature. A transient solution was observed followed by precipitation of the product t ⁇ t-butylammonium salt, which was collected by filtration and dried under vacuum at room temperature.
  • the acid was suspended in methanol and 1 equivalent of a solution of sodium methoxide in methanol was added.
  • the solvents were evaporated at room temperature and the residual mono- sodium salt was collected by filtration and dried under vacuum at room temperature.
  • the acid was suspended in methanol and 1 equivalent of a solution of 2-amino-2-(hydroxymethyl)propane-l,3-diol in methanol was added. A transient solution was observed followed by precipitation of the product tris(hydroxymethyl)methylammonium (that is, l,3-dihydroxy-2-(hydroxymethyl)prop-2- ylammonium salt), which was collected by filtration and dried under vacuum at room temperature.
  • inert solvent refers to a liquid in which the acid and the amine are both soluble that does not react with either of these starting materials.
  • in one aspect of the invention there is provided a salt of a compound of formula (I) obtainable by a process as described above.
  • the compounds of the invention are conveniently presented as a pharmaceutical composition.
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixir
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p_-hydroxybenzoate, and anti-oxidants, such as ascorbic acid.
  • Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
  • Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol
  • the aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p_-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
  • preservatives such as ethyl or propyl p_-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin).
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
  • Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavouring and preservative agents.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
  • sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
  • compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above.
  • a sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets.
  • Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
  • this is a compound of formula (I) for use as a medicament for producing an inhibition of DGATl activity in a warm-blooded animal such as a human being.
  • this is a compound of formula (I) for use as a medicament for treating diabetes mellitus and/or obesity in a warm-blooded animal such as a human being.
  • a compound of formula (I) in the manufacture of a medicament for use in the treatment of diabetes mellitus and/or obesity in a warm-blooded animal such as a human being.
  • a pharmaceutical composition which comprises a compound of formula (I) as defined hereinbefore in association with a pharmaceutically-acceptable excipient or carrier for use in producing an inhibition of DGATl activity in an warm-blooded animal, such as a human being.
  • a pharmaceutical composition which comprises a compound of formula (I) as defined hereinbefore, in association with a pharmaceutically-acceptable excipient or carrier for use in the treatment of diabetes mellitus and/or obesity in an warm-blooded animal, such as a human being.
  • a method for producing an inhibition of DGATl activity in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) as defined hereinbefore.
  • a method of treating diabetes mellitus and/or obesity in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) as defined hereinbefore.
  • a daily dose in the range of 1-50 mg/kg is employed.
  • the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
  • a compound of the invention may therefore be useful for the prevention, delay or treatment of a range of disease states including diabetes mellitus, more specifically type 2 diabetes mellitus (T2DM) and complications arising there from (for example retinopathy, neuropathy and nephropathy), impaired glucose tolerance (IGT), conditions of impaired fasting glucose, metabolic acidosis, ketosis, dysmetabolic syndrome, arthritis, osteoporosis, obesity and obesity related disorders, (which include peripheral vascular disease, (including intermittent claudication), cardiac failure and certain cardiac myopathies, myocardial ischaemia, cerebral ischaemia and reperfusion, hyperlipidaemias, atherosclerosis, infertility and polycystic ovary syndrome); the compounds of the invention may also be useful for muscle weakness, diseases of the skin such as acne, Alzheimer's disease, various immunomodulatory diseases (such as psoriasis), HIV infection, inflammatory bowel syndrome and
  • the compounds of the present invention are of interest for the prevention, delay or treatment of diabetes mellitus and/or obesity and/or obesity related disorders.
  • the compounds of the invention are used for prevention, delay or treatment of diabetes mellitus.
  • the compounds of the invention are used for prevention, delay or treatment of obesity.
  • the compounds of the invention are used for prevention, delay or treatment of obesity related disorders.
  • compounds of the invention are used for treatment of
  • Alzheimer's disease and/or dementia are associated with Alzheimer's disease and/or dementia.
  • the inhibition of DGATl activity described herein may be applied as a sole therapy or in combination with one or more other substances and/or treatments for the indication being treated. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment. Simultaneous treatment may be in a single tablet or in separate tablets.
  • such conjoint treatment may be beneficial in the treatment of metabolic syndrome [defined as abdominal obesity (as measured by waist circumference against ethnic and gender specific cut-points) plus any two of the following: hypertriglyceridemia (> 150 mg/dl; 1.7mmol/l); low HDLc ( ⁇ 40 mg/dl or ⁇ 1.03mmol/l for men and ⁇ 50 mg/dl or 1.29 mmol/1 for women) or on treatment for low HDL (high density lipoprotein); hypertension (SBP > 130 mmHg DBP > 85 mmHg) or on treatment for hypertension; and hyperglycemia (fasting plasma glucose > 100 mg/dl or 5.6 mmol/1 or impaired glucose tolerance or pre-existing diabetes mellitus) - International Diabetes Federation & input from IAS/NCEP].
  • hypertriglyceridemia > 150 mg/dl; 1.7mmol/l
  • low HDLc ⁇ 40 mg/dl or ⁇ 1.03mmol/l for men and ⁇ 50 mg/dl or
  • Such conjoint treatments may include the following main categories: 1) Anti-obesity therapies such as those that cause weight loss by effects on food intake, nutrient absorption or energy expenditure, such as orlistat, sibutramine and the like.
  • Insulin secretagogues including sulphonylureas (for example glibenclamide, glipizide), prandial glucose regulators (for example repaglinide, nateglinide);
  • Agents that improve incretin action for example dipeptidyl peptidase IV inhibitors, and GLP-I agonists;
  • Insulin sensitising agents including PPARgamma agonists (for example pioglitazone and rosiglitazone), and agents with combined PPARalpha and gamma activity;
  • Agents that modulate hepatic glucose balance for example metformin, fructose 1, 6 bisphosphatase inhibitors, glycogen phopsphorylase inhibitors, glycogen synthase kinase inhibitors, glucokinase activators;
  • SGLT inhibitors Agents that prevent the reabsorption of glucose by the kidney (SGLT inhibitors); 8) Agents designed to treat the complications of prolonged hyperglycaemia (for example aldose reductase inhibitors);
  • Anti- dyslipidaemia agents such as, HMG-CoA reductase inhibitors (eg statins); PPAR ⁇ -agonists (fibrates, eg gemfibrozil); bile acid sequestrants (cholestyramine); cholesterol absorption inhibitors (plant stanols, synthetic inhibitors); bile acid absorption inhibitors (IBATi) and nicotinic acid and analogues (niacin and slow release formulations); 10) Antihypertensive agents such as, ⁇ -blockers (eg atenolol, inderal); ACE inhibitors (eg lisinopril); Calcium antagonists (eg. nifedipine); Angiotensin receptor antagonists (eg candesartan), ⁇ antagonists and diuretic agents (eg. furosemide, benzthiazide);
  • HMG-CoA reductase inhibitors eg statins
  • PPAR ⁇ -agonists fibra
  • Haemostasis modulators such as, antithrombotics, activators of fibrinolysis and antiplatelet agents; thrombin antagonists; factor Xa inhibitors; factor Vila inhibitors); antiplatelet agents (eg. aspirin, clopidogrel); anticoagulants (heparin and Low molecular weight analogues, hirudin) and warfarin;
  • Anti-inflammatory agents such as non-steroidal anti-inflammatory drugs (eg. aspirin) and steroidal anti-inflammatory agents (eg. cortisone).
  • non-steroidal anti-inflammatory drugs eg. aspirin
  • steroidal anti-inflammatory agents eg. cortisone
  • compounds of formula (I) are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of DGATl activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
  • DGATl activity was assayed by a modification of the method described by Coleman (Methods in Enzymology 1992, 209, 98-102).
  • Compound at 1-10 ⁇ M was incubated with 0.4 ⁇ g membrane protein, 5 mM MgCl 2 , and 10 O ⁇ M 1,2 dioleoyl-sft-glycerol in a total assay volume of 200 ⁇ l in plastic tubes.
  • the reaction was started by adding 14 C oleoyl coenzyme A (30 ⁇ M final concentration) and incubated at room temperature for 30 minutes.
  • the reaction was stopped by adding 1.5 mL 2-propanol:heptane:water (80:20:2).
  • Radioactive triolein product was separated into the organic phase by adding ImL heptane and 0.5 mL 0.1 M carbonate buffer pH 9.5.
  • DGATl activity was quantified by counting aliquots of the upper heptane layer by liquid scintillography.
  • the compounds generally show activity with IC 50 ⁇ 10 ⁇ M, particularly ⁇ 1 ⁇ M.
  • Mouse adipocyte 3T3 cells were cultured to confluency in 6 well plates in new born calf serum containing media. Differentiation of the cells was induced by incubating in medium containing 10% foetal calf serum, 1 ⁇ g/mL insulin, 0.25 ⁇ M dexamethasone and 0.5 mM isobutylmethyl xanthine. After 48 h the cells were maintained in medium containing 10% foetal calf serum and 1 ⁇ g/mL insulin for a further 4-6 days. For the experiment, the medium was changed to serum- free medium and the cells pre-incubated with compound solubilised in DMSO (final concentration 0.1%) for 30 minutes.
  • DMSO final concentration 0.15%
  • the lipids were extracted into the organic phase using a heptane:propan-2-ol:water (80:20:2) mixture followed by aliquots of water and heptane according to the method of Coleman (Methods in Enzymology, 1992, 209, 98-104).
  • the organic phase was collected and the solvent evaporated under a stream of nitrogen.
  • MCF7 Human mammary epithelial (MCF7) cells were cultured to confluency in 6 well plates in foetal calf serum containing media. For the experiment, the medium was changed to serum-free medium and the cells pre-incubated with compound solubilised in DMSO (final concentration 0.1%) for 30 minutes. De novo lipogenesis was measured by the addition of 50 ⁇ M sodium acetate plus 3 ⁇ Ci/mL 14 C-sodium acetate to each well for a further 3 h (J. Biol. Chem., 1976, 251, 6462-6464).
  • the cells were washed in phosphate buffered saline and solubilised in 1% sodium dodecyl sulfate. An aliquot was removed for protein determination using a protein estimation kit (Perbio) based on the method of Lowry (J. Biol. Chem., 1951, 193, 265-275).
  • the lipids were extracted into the organic phase using a heptane:propan-2-ol:water (80:20:2) mixture followed by aliquots of water and heptane according to the method of Coleman (Methods in Enzymology, 1992, 209, 98-104). The organic phase was collected and the solvent evaporated under a stream of nitrogen.
  • temperatures are given in degrees Celsius ( 0 C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25 0 C and under an atmosphere of an inert gas such as argon;
  • chromatography means flash chromatography on silica gel; where a Biotage cartridge is referred to this means a cartridge containing KP-SILTM silica, 6OA, particle size 32-63 mM, supplied by Biotage, a division of Dyax Corp., 1500 Avon Street Extended, Charlottesville, VA 22902, USA;
  • NMR data ( 1 H) is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS), determined at 300 or 400 MHz (unless otherwise stated) using perdeuterio dimethyl sulfoxide (DMSO-d ⁇ ) as solvent, unless otherwise stated; peak multiplicities are shown thus: s, singlet; d, doublet; dd, doublet of doublets; dt, doublet of triplets; dm, doublet of multiplets; t, triplet, q, quartet; m, multiplet; br, broad;
  • a microwave where a microwave is referred to this means a Biotage Initiator sixty or Smith Creator microwave, supplied by Biotage, a division of Dyax Corp., 1500 Avon Street Extended, Charlottesville, VA 22902, USA;
  • Boc tert-butoxycarbonyl AIl compound names were derived using ACD NAME computer package.
  • Example 1 (?mns-4- ⁇ 4-[( ⁇ 5-[(4-Ethylphenyr)aminol-l,3.,4-oxadiazol-2- vUcarbonvDaminol phenyl ⁇ cyclohexyDacetic acid
  • Example 14 ⁇ m «5-4- ⁇ 4-[( ⁇ 5-[(3,4-Difluorophenyl)aminol-l,3,4-oxadiazol-2- vUcarbonvDaminol phenyl ⁇ cyclohexyDacetic acid
  • the resulting white precipitate was filtered, washed with water and methanol and then dried under vacuum at 5O 0 C to give the title compound as a solid (82% yield). This solid was then suspended in water (approximately 28ml per g of compound) with stirring, the suspension was then stirred for 3 days. The solid was then filtered off and washed with fresh water (slow filtration). The resulting white solid was dried to constant weight at 50 0 C in a high vacuum drying oven.
  • Example 15 2-(trans-4- ⁇ 4- [( ⁇ 5- [(2,4.,5-trifluor ophenvDaminol - 1 ,3,4-oxadiazol-2- vUcarbonvDaminolphenvUcyclohexyDpropanoic acid
  • Example 16 trans-2-(4- ⁇ 4- [( ⁇ 5- [(3,4-Difluorophenyl)aminol - 1 ,3,4-oxadiazol-2- yl ⁇ carbonvDaminol -phenyl ⁇ cvclohexyDpr opanoic acid
  • This oil was purified by flash chromatography on a 80 g BiotageTM silica column, using a gradient of 0-20% EtOAc in hexane as the eluent to give crude methyl [tr ⁇ n5-4-(4-nitrophenyl)cyclohexyl]acetate which was dissolved in ethyl acetate (30 mL). 10% palladium on carbon (0.400 g) was added and the resulting suspension was stirred at ambient temperature for 16 hours under an atmosphere of hydrogen. The suspension was filtered through diatomaceous earth and concentrated in vacuo to give a solid.
  • methyl [/r ⁇ fts-4-(4-aminophenyl)cyclohexyl] acetate can be made by the following method: a) Methyl 2-r4-(4-hvdroxyphenyl)cvclohexylidenelacetate
  • Trimethyl phosphonoacetate (170 mL, 1.05 mol) was added dropwise to a stirred suspension of sodium hydride (60 % in mineral oil, 27.5 g, 1.14 mol) in THF (3.5 L) cooled to 12°C. After completion of addition, the reaction mixture was allowed to warm to ambient temperature and stirred for I h. In a separate vessel, N,N-tetramethyl guanidine (144 mL, 1.14 mol) was added to a suspension of 4-(4-hydroxyphenyl)cyclohexan-l-one (235 g, 0.95 mol) in THF (1.2 L) and the reaction mixture was stirred for 1 h at ambient temperature.
  • the phosphonoacetate mixture was cooled to 10 0 C and the guanidine solution added slowly, controlling the temperature between 8 and 12 0 C until no residual exotherm was observed. The temperature was allowed to rise to ambient temperature and the reaction mixture was stirred for 16 h. The mixture was partitioned between a dilute aqueous solution of ammonium chloride (2.4 L) and ethyl acetate (2.4 L). The aqueous phase was separated and extracted with ethyl acetate (1.2 L). The organic phases were combined and washed with brine (2.4 L), dried (MgSO 4 ) and concentrated in vacuo to leave an off- white solid.
  • a dilute aqueous solution of ammonium chloride 2.4 L
  • ethyl acetate 2.4 L
  • the aqueous phase was separated and extracted with ethyl acetate (1.2 L).
  • the organic phases were combined and washed with brine (2.4 L), dried (MgSO 4 ) and concentrated in va
  • the intermediate trifiate (12 g, 32 mmol) was added to a mixture of cesium carbonate (14.4 g, 44 mmol), palladium acetate (0.43 g, 1.9 mmol), BINAP (1.2 g, 1.9 mmol), and benzophenone imine (7.9 mL, 47 mmol) in THF (200 mL). Stirring was started and the vessel was evacuated and purged with nitrogen 5 times. The stirred mixture was heated to reflux for 16 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to leave a residue. The residue was partitioned between ether (360 mL) and water (210 mL) and the layers were separated.
  • the aqueous layer was extracted with ether (3 x 360 mL) and the combined organic layers were dried (MgSO 4 ) and concentrated in vacuo to leave a crude yellow oil which was used with no further purification.
  • the crude imine (21 g, 51 mmol) was dissolved in methanol (300 mL) and the solution cooled to 4°C.
  • a I M solution of hydrochloric acid (100 mL) was added slowly, maintaining the temperature below 7°C. The suspension was warmed to ambient temperature over 16 h. The methanol was removed in vacuo and the resulting mixture diluted with water (100 mL).
  • the aqueous mixture was washed with ether (2 x 30 mL) and the combined organic layer washed with a 1 M solution of hydrochloric acid (2 x 30 mL).
  • the combined aqueous layers were basified to pH9 with a 10% aqueous solution of sodium carbonate to give a precipitate.
  • Ethyl acetate (3 x 200 mL) was added and the layers were separated.
  • the combined organic layers were dried (MgSO 4 ) and concentrated in vacuo until a precipitate formed.
  • the mixture was cooled, filtered and washed with hexane (20 mL) to give the product as a pale yellow solid.
  • Methyl chloro(oxo)acetate (0.842 mL) was added to a stirred solution of methyl [trans -4- (4-aminophenyl)cyclohexyl]acetate (1740 mg) and pyridine (0.689 mL) in DCM (50 mL) at 0 0 C. After the addition was complete the mixture was allowed to warm to ambient temperature and stirred for 64 hours.
  • This intermediate was made by the method used for Intermediates 9-13 using 3,4- difluoroisothiocyanate as starting material.
  • 2,4,5-Trifluorophenyl isothiocyanate (252 mg, 1.33 mmol) was added in one portion to a suspension of trans-ethyl 2-[4-(4- ⁇ [hydrazino(oxo)acetyl]amino ⁇ phenyl)cyclo- hexyl]propanoate (Intermediate 17, 400 mg, 1.11 mmol) in DMA (6 mL) and the reaction mixture was stirred at room temperature for 2 h.
  • EDCI (319 mg, 1.66 mmol) was added in one portion and the reaction mixture was heated to 90 0 C for 10 mins in the microwave. The mixture was then cooled to room temperature and H 2 O (20 mL) was added.
  • tetramethylguanidine (6.61 g, 57.4 mmol) was added in one portion to a solution of 4-(4-hydroxyphenyl)cyclohexanone (9.1 g, 47.8 mmol) in THF (40 mL) at 10 0 C under an argon atmosphere and the stirred mixture was warmed to room temperature over 1 h.
  • This mixture was added in one portion to the ethyl 2-(diethoxyphosphoryl)propanoate mixture at 10 0 C and the combined reaction mixture was warmed to ambient temperature and stirred for 18 h under an argon atmosphere.
  • a saturated aqueous solution of ammonium chloride (75 mL) and EtOAc (100 mL) were added.

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Abstract

L'invention porte sur un sel de l'activité tert-butylammonium, des sels de tris(hydroxyméthyl)méthylammonium, triéthanolammonium, diéthanolammonium, éthanolammonium, méthyléthanolammonium, diéthylammonium et nicotinamide d'un composé de formule (I), lesquels composés inhibent le sodium, magnésium, acétyl CoA(acétyle coenzyme A) : diacylglycérol acyltransférase (GDAT1) activité : Formule (I) dans laquelle R1 représente un phényle facultativement substitué par 1, 2 ou 3 substituants choisis indépendamment parmi fluoro, chloro, bromo, trifluorométhyle, méthoxy, difluorométhoxy, trifluorométhoxy, cyano, méthyle et éthyle ; R A représente hydrogène ou méthyle ; p vaut 0 ou 1 ; à la condition que le sel de formule (I) ne soit pas le (trans-4-{4-[({5-[(2,4,5-trifluorophényl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]phényl}cyclohexyl)acétate de sodium. L'invention porte également sur des procédés de préparation de tels composés, sur leur utilisation dans le traitement de conditions cliniques associées à l'obésité, sur des procédés pour leur utilisation thérapeutique et sur des compositions pharmaceutiques les contenant.
PCT/GB2008/050270 2007-04-20 2008-04-18 Sel de dérivés d'oxadiazole comme inhibiteurs de dgat WO2008129319A1 (fr)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010070343A1 (fr) * 2008-12-19 2010-06-24 Astrazeneca Ab Dérivés de 1,3,4-oxadiazole et leurs utilisations dans le traitement du diabète
US7749997B2 (en) 2005-12-22 2010-07-06 Astrazeneca Ab Pyrimido [4,5-B] -Oxazines for use as DGAT inhibitors
US7795283B2 (en) 2004-12-14 2010-09-14 Astrazeneca Ab Oxadiazole derivative as DGAT inhibitors
WO2010108051A2 (fr) 2009-03-20 2010-09-23 Ligand Pharmaceuticals Inhibiteurs de diacylglycérol o-acétyltransférase 1 (dgat-1) et leurs utilisations
US7879850B2 (en) 2007-09-28 2011-02-01 Novartis Ag Organic compounds
US7994179B2 (en) 2007-12-20 2011-08-09 Astrazeneca Ab Carbamoyl compounds as DGAT1 inhibitors 190
US8003676B2 (en) 2006-05-30 2011-08-23 Astrazeneca Ab 1,3,4-oxadiazole derivatives as DGAT1 inhibitors
US8084478B2 (en) 2006-05-30 2011-12-27 Asstrazeneca Ab Substituted 5- phenylamino- 1, 3, 4-oxadiazol-2-ylcarbonylamino-4-phenoxy-cyclohexane carboxylic acid as inhibitors of acetyl coenzyme A diacylglycerol acyltransferase
US8835451B2 (en) 2006-03-31 2014-09-16 Novartis Ag Compounds
CN112153979A (zh) * 2018-05-07 2020-12-29 诺和诺德股份有限公司 包含glp-1激动剂和n-(8-(2-羟基苯甲酰基)氨基)辛酸的盐的固体组合物

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006064189A1 (fr) * 2004-12-14 2006-06-22 Astrazeneca Ab Dérivés d'oxadiazole en tant qu'inhibiteurs de dgat

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006064189A1 (fr) * 2004-12-14 2006-06-22 Astrazeneca Ab Dérivés d'oxadiazole en tant qu'inhibiteurs de dgat

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7795283B2 (en) 2004-12-14 2010-09-14 Astrazeneca Ab Oxadiazole derivative as DGAT inhibitors
US8017603B2 (en) 2005-12-22 2011-09-13 Astrazeneca Ab Pyrimido [4,5-B]-oxazines for use as DGAT inhibitors
US7749997B2 (en) 2005-12-22 2010-07-06 Astrazeneca Ab Pyrimido [4,5-B] -Oxazines for use as DGAT inhibitors
US8912208B2 (en) 2006-03-31 2014-12-16 Novartis Ag (4-{4-[5-(benzooxazol-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid useful for treating or preventing conditions or disorders associated with DGAT1 activity
US8835451B2 (en) 2006-03-31 2014-09-16 Novartis Ag Compounds
US8084478B2 (en) 2006-05-30 2011-12-27 Asstrazeneca Ab Substituted 5- phenylamino- 1, 3, 4-oxadiazol-2-ylcarbonylamino-4-phenoxy-cyclohexane carboxylic acid as inhibitors of acetyl coenzyme A diacylglycerol acyltransferase
US8003676B2 (en) 2006-05-30 2011-08-23 Astrazeneca Ab 1,3,4-oxadiazole derivatives as DGAT1 inhibitors
US8217065B2 (en) 2007-09-28 2012-07-10 Novartis Ag Organic compounds
US7879850B2 (en) 2007-09-28 2011-02-01 Novartis Ag Organic compounds
US7994179B2 (en) 2007-12-20 2011-08-09 Astrazeneca Ab Carbamoyl compounds as DGAT1 inhibitors 190
WO2010070343A1 (fr) * 2008-12-19 2010-06-24 Astrazeneca Ab Dérivés de 1,3,4-oxadiazole et leurs utilisations dans le traitement du diabète
WO2010108051A2 (fr) 2009-03-20 2010-09-23 Ligand Pharmaceuticals Inhibiteurs de diacylglycérol o-acétyltransférase 1 (dgat-1) et leurs utilisations
EP2805951A2 (fr) 2009-03-20 2014-11-26 Metabasis Therapeutics, Inc. Inhibiteurs de diacylglycérol o-acétyltransférase 1 (dgat-1) et leurs utilisations
US8962618B2 (en) 2009-03-20 2015-02-24 Metabasis Therapeutics, Inc. Inhibitors of diacylglycerol O-acyltransferase 1 (DGAT-1) and uses thereof
US9340566B2 (en) 2009-03-20 2016-05-17 Metabasis Therapeutics, Inc. Inhibitors of diacylglycerol O-acyltransferase 1 (DGAT-1) and uses thereof
US10034891B2 (en) 2009-03-20 2018-07-31 Metabasis Therapeutics, Inc. Inhibitors of diacylglycerol O-acyltransferase 1 (DGAT-1) and uses thereof
EP3366686A2 (fr) 2009-03-20 2018-08-29 Metabasis Therapeutics, Inc. Inhibiteurs de diacylglycérol o-acétyltransférase 1 (dgat-1) et leurs utilisations
US10709718B2 (en) 2009-03-20 2020-07-14 Metabasis Therapeutics, Inc. Inhibitors of diacylglycerol O-acyltransferase 1 (DGAT-1) and uses thereof
CN112153979A (zh) * 2018-05-07 2020-12-29 诺和诺德股份有限公司 包含glp-1激动剂和n-(8-(2-羟基苯甲酰基)氨基)辛酸的盐的固体组合物

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