WO2007144571A1 - Forme cristalline de l'acide (trans-4-{4- [({5-[(3,4-difluorophényl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]phényl}cyclohexyl)acétique - Google Patents

Forme cristalline de l'acide (trans-4-{4- [({5-[(3,4-difluorophényl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]phényl}cyclohexyl)acétique Download PDF

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WO2007144571A1
WO2007144571A1 PCT/GB2007/002097 GB2007002097W WO2007144571A1 WO 2007144571 A1 WO2007144571 A1 WO 2007144571A1 GB 2007002097 W GB2007002097 W GB 2007002097W WO 2007144571 A1 WO2007144571 A1 WO 2007144571A1
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Prior art keywords
amino
acetic acid
cyclohexyl
carbonyl
crystalline form
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PCT/GB2007/002097
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English (en)
Inventor
Andrew Hornby Dobson
Walter Grundy
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Astrazeneca Ab
Astrazeneca Uk Limited
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Application filed by Astrazeneca Ab, Astrazeneca Uk Limited filed Critical Astrazeneca Ab
Priority to EP07733109A priority Critical patent/EP2041101A1/fr
Priority to MX2008015762A priority patent/MX2008015762A/es
Priority to BRPI0712354-0A priority patent/BRPI0712354A2/pt
Priority to CA002653550A priority patent/CA2653550A1/fr
Priority to AU2007259031A priority patent/AU2007259031A1/en
Priority to JP2009514875A priority patent/JP2009539954A/ja
Publication of WO2007144571A1 publication Critical patent/WO2007144571A1/fr
Priority to IL195348A priority patent/IL195348A0/en
Priority to NO20084963A priority patent/NO20084963L/no

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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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    • A—HUMAN NECESSITIES
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    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A61P3/00—Drugs for disorders of the metabolism
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    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a novel crystalline chemical compound and more particularly to novel crystalline forms of (tr ⁇ «s-4- ⁇ 4-[( ⁇ 5-[(3,4-difluorophenyl)amino]- l,3,4-oxadiazol-2-yl ⁇ carbonyl)amino]phenyl ⁇ cyclohexyi)acetic acid illustrated in Formula (I) hereinafter, which compound is an inhibitor of acetyl Co A(acetyl coenzyme A):diacylglycerol acyltransferase (DGATl) activity.
  • the invention also relates to processes for the manufacture of the crystalline forms, pharmaceutical compositions comprising the crystalline forms and the use of the crystalline forms in medical treatment.
  • the Agent of formula (I) can be prepared in other crystalline forms, hereinafter referred to as Form 2 and Form 3.
  • Such polymorphic forms may have different solubilities and/or stabilities and/or bioavailabilities and/or different impurity profiles (minor impurities which arise for example because of the process of manufacture and/or isolation) and/or crystal forms which are easier to handle, micronise and/or form into tablets.
  • the X-Ray powder diffraction pattern for Form 2 is shown in Figure 1.
  • a comparison between Forms 1 and 2 is shown in Figure 3 and thermal data for Form 2 is shown in Figure 4 (Form 2 in anhydrous form).
  • Tables 1, 2 and 3 show, respectively, major peaks for Forms 2, 1 and 3.
  • Forms 2 and 3 obtained according to the present invention are respectively substantially free from other crystal and non-crystal forms of compound (I).
  • the term "substantially free from other crystal and non-crystal forms" shall be understood to mean that the desired crystal form contains less than 50%, preferably less than 20%, more preferably less than 10%, more preferably less than 5% of any other forms of compound
  • the X-ray powder diffraction patterns were determined by mounting a sample of the crystalline material on Siemens single silicon crystal (SSC) wafer mounts and spreading out the sample into a thin layer with the aid of a microscope slide. The sample was spun at 30 revolutions per minute (to improve counting statistics) and irradiated with X-rays generated by a copper long-fine focus tube operated at 40 kV and 40 niA with a wavelength of 1.5406 Angstroms using a Bruker D5000 powder X-ray diffractometer (Bruker AXS, Banner Lane Coventry CV4 9GH).
  • SSC Siemens single silicon crystal
  • the collimated X-ray source was passed through an automatic variable divergence slit set at V20 and the reflected radiation directed through a 2 mm antiscatter slit and a 0.2 mm detector slit.
  • the sample was exposed for 1 second per 0.02 degree 2-theta increment (continuous scan mode) over the range 2 degrees to 40 degrees 2-theta in theta-theta mode.
  • the instrument was equipped with a scintillation counter as detector. Control and data capture was by means of a Dell Optiplex 686 NT 4.0 Workstation operating with Diffrac ⁇ software.
  • an X-ray powder diffraction pattern may be obtained which has one or more measurement errors depending on measurement conditions (such as equipment, sample preparation or machine used).
  • intensities in an X-ray powder diffraction pattern may fluctuate depending on measurement conditions and sample preparation.
  • the skilled person will realize that the relative intensity of peaks can be affected by, for example, grains above 30 microns in size and non-unitary aspect ratios, which may affect analysis of samples.
  • the position of reflections can be affected by the precise height at which the sample sits in the diffractometer and the zero calibration of the diffractometer.
  • the surface planarity of the sample may also have a small effect.
  • the crystalline forms of compound (I) are not limited to the crystals that provide X-ray powder diffraction patterns identical to the X-ray powder diffraction patterns respectively shown in Figures 1 and 5 and any crystals providing X-ray powder diffraction patterns substantially the same as that shown respectively in Figures 1 and 5 fall within the scope of the present invention.
  • Forms 2 and 3 may also be characterised by other analytical techniques known in the art such as Differential scanning calorimetry (DSC) and Thermogravimetric analysis (TGA) according to standard methods, such as, for example those described in Hohne, G. W. H. et al (1996), Differential Scanning Calorimetry, Springer, Berlin.
  • DSC Differential scanning calorimetry
  • TGA Thermogravimetric analysis
  • onset/peak temperature values of the DSC and the weight loss values for TGA may vary slightly from one machine to another or from one sample to another, and so the values quoted in the thermal trace figures are not to be construed as absolute. The techniques used are described in more detail below.
  • Differential Scanning Calorimetry was performed using analytical instrument Mettler DSC820e. Typically less than 5mg of material contained in a 40 ⁇ l aluminium pan fitted with a pierced lid was heated over the temperature range 25°C to 325°C at a constant heating rate of 10 0 C per minute. A purge gas using nitrogen was used - flow rate 100ml per minute.
  • Thermogravimetric Analysis was performed using analytical instrument: Mettler TG851. Typically between 3 and 12 mg of material contained in a 70 ⁇ l alox (aluminium oxide) crucible was heated over the temperature range 25°C to 325 0 C at a constant heating rate of 1O 0 C per minute. A purge gas using helium was used - flow rate 50ml per minute. Form 2 and Form 3 may be crystallised as illustrated in the accompanying examples.
  • a process for the manufacture of crystalline Form 2 of a compound of formula (I) which comprises preparation and isolation of compound (I) from water and methanol, then stirring a suspension of the obtained solid in water (for example for 1-5 days, such as 3 days), and isolation of the obtained solid (for example by filtration, optionally washing with water, and drying).
  • a process for the manufacture of crystalline Form 3 of a compound of formula (I) which comprises stirring a mixture in acetonitrile of compound (I) Forms 1 and 2 (for example stirred for 1-5 days, such as 3 days) at elevated temeprature (for example, 30°C to 70 0 C, particularly at, or about, 50°C), and isolation of the obtained solid (for example by filtration, optionally washing with a suitable solvent, and drying).
  • elevated temeprature for example, 30°C to 70 0 C, particularly at, or about, 50°C
  • isolation of the obtained solid for example by filtration, optionally washing with a suitable solvent, and drying.
  • a pharmaceutical composition which comprises Form 2 or Form 3, as defined hereinbefore or hereinafter, in association with a pharmaceutically-acceptable excipient or carrier.
  • 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 g-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.
  • 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
  • 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.
  • 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, poly vinyl-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
  • the aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p_-hydroxybenzoate, anti-oxidants (such as ascorbic
  • flavouring agents such as sucrose, saccharine or aspartame.
  • 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).
  • a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil
  • a mineral oil such as liquid paraffin
  • the oily suspensions may also contain a thickening agent such as
  • compositions may 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
  • 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.
  • the pharmaceutical 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.
  • Form 2 or Form 3 as defined hereinbefore or hereinafter for use in a method of treatment of the human or animal body by therapy.
  • a further feature of the present invention is Form 2 or Form 3 for use as a medicament.
  • this is Form 2 or Form 3 for use as a medicament for producing an inhibition of DGATl activity in a warm-blooded animal such as a human being.
  • Form 2 or Form 3 for use as a medicament for treating diabetes mellitus and/or obesity in a warm-blooded animal such as a human being.
  • Form 2 or Form 3 in the manufacture of a medicament for use in the production of an inhibition of DGATl activity in a warm-blooded animal such as a human being.
  • Form 2 or Form 3 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 Form 2 or Form 3 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 Form 2 or Form 3 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 Form 2 or Form 3 defined hereinbefore or hereinafter.
  • 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 Form 2 or Form 3 as defined hereinbefore or hereinafter.
  • the size of the dose required for the therapeutic or prophylactic treatment of a particular disease state will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated.
  • 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.
  • compounds defined in the present invention are of interest for their ability to inhibit the activity of
  • 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 inflammatory bowel disease such as Crohn's disease and ulcerative colitis.
  • T2DM type 2
  • 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.
  • 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. 2) 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; 5) Agents that modulate hepatic glucose balance (for example metformin, fructose 1 , 6 bisphosphatase inhibitors, glycogen phopsphorylase inhibitors, glycogen synthase kinase inhibitors, glucokinase activators);
  • Anti- dyslipidaemia agents such as, HMG-CoA reductase inhibitors (eg statins); PPAR alpha-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);
  • Antihypertensive agents such as beta-blockers (eg atenolol, inderal); ACE inhibitors (eg lisinopril); Calcium antagonists (eg. nifedipine); Angiotensin receptor antagonists (eg candesartan), alpha-antagonists and diuretic agents (eg. furosemide, benzthiazide);
  • beta-blockers eg atenolol, inderal
  • ACE inhibitors eg lisinopril
  • Calcium antagonists eg. nifedipine
  • Angiotensin receptor antagonists eg candesartan
  • alpha-antagonists and diuretic agents eg. furosemide, benzthiazide
  • 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
  • the in vitro assay to identify DGATl inhibitors uses human DGATl expressed in insect cell membranes as the enzyme source (Proc. Natl. Acad. Sci. 1998, 95, 13018-13023). Briefly, sf9 cells were infected with recombinant baculovirus containing human DGATl coding sequences and harvested after 48 h. Cells were lysed by sonication and membranes isolated by centrifuging at 28000 rpm for 1 h at 4 °C on a 41% sucrose gradient. The membrane fraction at the interphase was collected, washed, and stored in liquid nitrogen.
  • 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-,s#-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. In this test the compound of formula (I) has an IC 50 of 2.5 nM.
  • 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.
  • chromatography means flash chromatography on silica gel; where a Biotage cartridge is referred to this means a cartridge containing KP-SILTM silica, 60A, particle size 32-63 mM, supplied by Biotage, a division of Dyax Corp., 1500 Avon Street Extended, Charlottesville, VA 22902, USA; (iv) in general, the course of reactions was followed by TLC and reaction times are given for illustration only;
  • 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- 6 ) 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 SiliCycle cartridge where a SiliCycle cartridge is referred to this means a cartridge containing Ultra Pure Silica Gel particle size 230-400 mesh, 40 -63 um pore size, supplied by SiliCycle Chemical
  • xiv 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,
  • the GC column was a DB-5MS of length 25 m, 0.32 mm i.d. with a film thickness of 0.52 ⁇ m supplied by J & W Scientific, Folsom, CA, USA;
  • Example 1 Form 2 (/m/ ⁇ -4-f4-f( ⁇ 5-[(3,4-Difluorophenyl)amino1-l,3.,4-oxadiazoI-2- vIlcarbonvDaminolphenvUcvclohexyDacetic acid
  • Lithium hydroxide monohydrate (10 equivalents) in water (2.23 L per mole of Intermediate 1) was added to a stirred suspension of methyl (trans-4- ⁇ 4-[( ⁇ 5-[(3,4- difluorophenyl)amino] - 1 ,3 ,4-oxadiazol-2-yl ⁇ carbonyl)amino]phenyl ⁇ cyclohexyl)acetate (Intermediate 1; 1 equivalent) in methanol (9.38 L per mole of Intermediate 1).
  • the reaction mixture was stirred at 3O 0 C for 2 hours then cooled to O 0 C and acidified to pH2 with concentrated hydrochloric acid (keeping the temperature below 1O 0 C).
  • 3,4-Difluoroisothiocyanate (1.2 equivalent), was added to a stirred suspension of methyl [tr ⁇ r ⁇ -4-(4- ⁇ [hydrazino(oxo)acetyl]amino ⁇ phenyl)cyclohexyl]acetate (Intermediate 2, 1 equivalent) in DMA (approximately 5.3 litres per mole of Intermediate 2) and the mixture was heated to 45 0 C and stirred for 2 hours. EDAC (1.2 equivalent) was added and the resulting mixture was heated to 85°C and stirred for 3 hours. Water (approximately 4.3 litres per mole of Intermediate 2) was added.
  • Trimethyl phosphonoacetate (170 niL, 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 o ambient temperature and stirred for I h. In a separate vessel, N,N-tetramethyl guanidine (144 niL, 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 s 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 0 leave an off-white solid.
  • the solid was slurried in a mixture of ether and hexane (2:1 ; 470 niL), filtered and washed with a mixture of ether and isohexane (2:1; 240 mL) to give the product as a white solid (285 g, 94%).
  • reaction mixture was heated at 3O 0 C under a hydrogen atmosphere (2 bar).
  • the mixture was filtered over Celite to leave a solid, which was washed with THF (50 mL).
  • the THF solution was concentrated in vacuo to leave a residue, which was washed with ethyl acetate.
  • the crude mixture was dissolved in hot ethyl acetate (100 mL) and then cooled to ambient temperature. After chilling with ice water, the precipitate was filtered and washed io with ethyl acetate (50 mL) to give the title compound as a solid (42 g, 42%).
  • the intermediate triflate (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 0 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.
  • Example 2 Form 3 (;raws-4-f4-[( ⁇ 54(3,4-Difluorophenyl)amino1-l,,3,4-oxadiazoI-2- yl ⁇ carbonyl)aminolphenyl ⁇ cvclohexyl)acetic acid
  • Form 2 (as prepared in Example 1 ; approximately 20mg) was placed in a small vial containing a magnetic stirrer. A small amount of Form 1 was added as seed and acetonitrile (approximately ImI) added. The vial was sealed with a lid, and placed on a hotplate stirrer at 50°C for 3 days, stirring throughout. After 3 days, the vial was removed from the stirrer, the lid taken off and any remaining solvent allowed to evaporate. The resulting Form 3 solid was analysed (see Figures 5 & 6 and Table 3).
  • the Form 1 material was prepared as follows...
  • Methyl 2-[4-[4-[[5-[(3,4-difluorophenyl)amino] 1 ,3,4-oxadiazole-2-carbonyl]amino]- phenyl]cyclohexyl]acetate was suspended, with stirring under nitrogen, in methanol/tetrahydrofuran (14 vol/7vol) and a solution of lithium hydroxide (10eq) in water (5 vol) added. A yellow solution was formed which was heated to 30°C (complete by (lc/ms) after 2 hours). The mixture was then cooled to O 0 C and acidified to pH2 with concentrated hydrochloric acid, keeping the temperature below 10°C.

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Abstract

L'invention concerne de nouvelles formes cristallines du composé d'acide (trans-4-{4-[({5-[(3,4-difluorophényl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]phényl}cyclohexyl)acétique ainsi que des procédés de production de ces formes, des compositions pharmaceutiques les comprenant et l'utilisation de ces formes dans un traitement médical. Formule (I)
PCT/GB2007/002097 2006-06-12 2007-06-08 Forme cristalline de l'acide (trans-4-{4- [({5-[(3,4-difluorophényl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]phényl}cyclohexyl)acétique WO2007144571A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
EP07733109A EP2041101A1 (fr) 2006-06-12 2007-06-08 Forme cristalline de l'acide (trans-4-{4- [({5-[(3,4-difluorophényl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]phényl}cyclohexyl)acétique
MX2008015762A MX2008015762A (es) 2006-06-12 2007-06-08 Forma cristalina de acido (trans-4-[({5-[(3,4-difluorofe-nil)amino ]-1,3,4,-oxadiazol-2-il}carbonil)amino]fenil}ciclohexil)acetico.
BRPI0712354-0A BRPI0712354A2 (pt) 2006-06-12 2007-06-08 forma cristalina de um composto,formulação farmacêutica,uso do composto,e,métado de tratamento de uma condição.
CA002653550A CA2653550A1 (fr) 2006-06-12 2007-06-08 Forme cristalline de l'acide (trans-4-{4- [({5-[(3,4-difluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]phenyl}cyclohexyl)acetique
AU2007259031A AU2007259031A1 (en) 2006-06-12 2007-06-08 Crystalline form of (trans-4- [ ( { 5- [ (3, 4 -di fluorophenyl) amino] -1,3, 4-oxadiazol-2-yl}carbonyl) amino) phenyl } cyclohexyl) acetic acid
JP2009514875A JP2009539954A (ja) 2006-06-12 2007-06-08 （ｔｒａｎｓ−４−｛４−［（｛５−［（３，４−ジフルオロフェニル）アミノ］−１，３，４−オキサジアゾール−２−イル｝カルボニル）アミノ］フェニル｝シクロヘキシル）酢酸の結晶形
IL195348A IL195348A0 (en) 2006-06-12 2008-11-17 Crystalline form of (trans-4-[({5-[(3,4-difluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]phenyl}cyclohexyl)acetic acid
NO20084963A NO20084963L (no) 2006-06-12 2008-11-26 Krystallinske former av (trans-4-[({5-[3,4-difluorofenyl)amino]-1,3,4-oksadiazol-2-yl}karbonyl)amino]fenyl}cykloheksyl)eddiksyre

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GBGB0611552.1A GB0611552D0 (en) 2006-06-12 2006-06-12 Chemical compounds
GB0611552.1 2006-06-12

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AU (1) AU2007259031A1 (fr)
BR (1) BRPI0712354A2 (fr)
CA (1) CA2653550A1 (fr)
CL (1) CL2007001700A1 (fr)
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IL (1) IL195348A0 (fr)
MX (1) MX2008015762A (fr)
NO (1) NO20084963L (fr)
TW (1) TW200815378A (fr)
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008099221A1 (fr) * 2007-02-15 2008-08-21 Prosidion Limited Dérivés d'amide et d'urée pour le traitement de maladies métaboliques
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
US8188092B2 (en) 2009-06-19 2012-05-29 Astrazeneca Ab Substituted pyrazines as DGAT-1 inhibitors
US8835451B2 (en) 2006-03-31 2014-09-16 Novartis Ag Compounds

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2963005B1 (fr) * 2010-07-23 2012-08-17 Sanofi Aventis Derives d'oxadiazoles et de pyridazines, leur preparation et leur application en therapeutique

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004100881A2 (fr) * 2003-05-09 2004-11-25 Bayer Pharmaceuticals Corporation Preparation et utilisation de derives d'aryl alkyl acide pour le traitement de l'obesite
WO2006064189A1 (fr) * 2004-12-14 2006-06-22 Astrazeneca Ab Dérivés d'oxadiazole en tant qu'inhibiteurs de dgat

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004100881A2 (fr) * 2003-05-09 2004-11-25 Bayer Pharmaceuticals Corporation Preparation et utilisation de derives d'aryl alkyl acide pour le traitement de l'obesite
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
US7749997B2 (en) 2005-12-22 2010-07-06 Astrazeneca Ab Pyrimido [4,5-B] -Oxazines for use as DGAT inhibitors
US8017603B2 (en) 2005-12-22 2011-09-13 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
WO2008099221A1 (fr) * 2007-02-15 2008-08-21 Prosidion Limited Dérivés d'amide et d'urée pour le traitement de maladies métaboliques
US7879850B2 (en) 2007-09-28 2011-02-01 Novartis Ag Organic compounds
US8217065B2 (en) 2007-09-28 2012-07-10 Novartis Ag Organic compounds
US7994179B2 (en) 2007-12-20 2011-08-09 Astrazeneca Ab Carbamoyl compounds as DGAT1 inhibitors 190
EP2805951A2 (fr) 2009-03-20 2014-11-26 Metabasis Therapeutics, Inc. Inhibiteurs de diacylglycérol o-acétyltransférase 1 (dgat-1) et leurs utilisations
WO2010108051A2 (fr) 2009-03-20 2010-09-23 Ligand Pharmaceuticals 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
US8188092B2 (en) 2009-06-19 2012-05-29 Astrazeneca Ab Substituted pyrazines as DGAT-1 inhibitors

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CA2653550A1 (fr) 2007-12-21
EP2041101A1 (fr) 2009-04-01
MX2008015762A (es) 2009-03-16
NO20084963L (no) 2009-01-07
UY30404A1 (es) 2008-01-31
JP2009539954A (ja) 2009-11-19
BRPI0712354A2 (pt) 2012-06-05
TW200815378A (en) 2008-04-01
KR20090015980A (ko) 2009-02-12
GB0611552D0 (en) 2006-07-19
AR061332A1 (es) 2008-08-20
CN101466690A (zh) 2009-06-24
IL195348A0 (en) 2009-08-03
CL2007001700A1 (es) 2008-01-18
AU2007259031A1 (en) 2007-12-21

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