[go: up one dir, main page]

WO2009056881A1 - Composés chimiques 313 - Google Patents

Composés chimiques 313 Download PDF

Info

Publication number
WO2009056881A1
WO2009056881A1 PCT/GB2008/051012 GB2008051012W WO2009056881A1 WO 2009056881 A1 WO2009056881 A1 WO 2009056881A1 GB 2008051012 W GB2008051012 W GB 2008051012W WO 2009056881 A1 WO2009056881 A1 WO 2009056881A1
Authority
WO
WIPO (PCT)
Prior art keywords
lβhsdl
agents
pharmaceutically
compound
treatment
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB2008/051012
Other languages
English (en)
Inventor
William Mccoull
Martin Packer
James Stewart Scott
Paul Robert Owen Whittamore
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca UK Ltd
AstraZeneca AB
Original Assignee
AstraZeneca UK Ltd
AstraZeneca AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from TW096140633A external-priority patent/TW200827346A/zh
Application filed by AstraZeneca UK Ltd, AstraZeneca AB filed Critical AstraZeneca UK Ltd
Publication of WO2009056881A1 publication Critical patent/WO2009056881A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention relates to (lR,5S,6r)-3-[5-(adamantan-2-ylcarbamoyl)-6- (methylthio)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid and pharmaceutically-acceptable salts thereof.
  • the compound possesses human
  • 11- ⁇ -hydroxysteroid dehydrogenase type 1 enzyme (1 l ⁇ HSDl) inhibitory activity and accordingly have value in the treatment of disease states including metabolic syndrome and are useful in methods of treatment of a warm-blooded animal, such as man.
  • the invention also relates to processes for the manufacture of said compound, to pharmaceutical compositions containing it and to its use in the manufacture of medicaments to inhibit 1 l ⁇ HSDl in a warm-blooded animal, such as man.
  • Glucocorticoids are counter regulatory hormones i.e. they oppose the actions of insulin (Dallman MF, Strack AM, Akana SF et al. 1993; Front Neuroendocrinol 14, 303-347). They regulate the expression of hepatic enzymes involved in gluconeogenesis and increase substrate supply by releasing glycerol from adipose tissue (increased lipolysis) and amino acids from muscle (decreased protein synthesis and increased protein degradation). Glucocorticoids are also important in the differentiation of pre-adipocytes into mature adipocytes which are able to store triglycerides (Bujalska IJ et al.
  • 1 l ⁇ HSDl may well be regulating the effects of insulin by decreasing tissue levels of active glucocorticoids (Walker BR et al. 1995; J. Clin. Endocrinol. Metab. 80, 3155-3159).
  • Cushing's syndrome is associated with Cortisol excess which in turn is associated with glucose intolerance, central obesity (caused by stimulation of pre-adipocyte differentiation in this depot), dyslipidaemia and hypertension.
  • Cushing's syndrome shows a number of clear parallels with metabolic syndrome. Even though the metabolic syndrome is not generally associated with excess circulating Cortisol levels (Jessop DS et al. 2001; J. Clin. Endocrinol. Metab.
  • 1 l ⁇ HSDl knock-out mice show attenuated glucocorticoid- induced activation of gluconeogenic enzymes in response to fasting and lower plasma glucose levels in response to stress or obesity (Kotelevtsev Y et al. 1997; Proc. Natl. Acad. Sci USA 94, 14924-14929) indicating the utility of inhibition of 1 l ⁇ HSDl in lowering of plasma glucose and hepatic glucose output in type 2 diabetes. Furthermore, these mice express an anti-atherogenic lipoprotein profile, having low triglycerides, increased HDL cholesterol and increased apo-lipoprotein AI levels. (Morton NM et al. 2001; J. Biol. Chem. 276,
  • This phenotype is due to an increased hepatic expression of enzymes of fat catabolism and PP ARa. Again this indicates the utility of 1 l ⁇ HSDl inhibition in treatment of the dyslipidaemia of the metabolic syndrome.
  • 1 l ⁇ HSDl transgenic mice When expressed under the control of an adipose specific promoter, 1 l ⁇ HSDl transgenic mice have high adipose levels of corticosterone, central obesity, insulin resistant diabetes, hyperlipidaemia and hyperphagia. Most importantly, the increased levels of 1 l ⁇ HSDl activity in the fat of these mice are similar to those seen in obese subjects. Hepatic 1 l ⁇ HSDl activity and plasma corticosterone levels were normal, however, hepatic portal vein levels of corticosterone were increased 3 fold and it is thought that this is the cause of the metabolic effects in liver.
  • 1 l ⁇ HSDl tissue distribution is widespread and overlapping with that of the glucocorticoid receptor.
  • 1 l ⁇ HSDl inhibition could potentially oppose the effects of glucocorticoids in a number of physiological/pathological roles.
  • 1 l ⁇ HSDl is present in human skeletal muscle and glucocorticoid opposition to the anabolic effects of insulin on protein turnover and glucose metabolism are well documented (Whorwood CB et al. 2001; J. Clin. Endocrinol. Metab. 86, 2296-2308). Skeletal muscle must therefore be an important target for 1 l ⁇ HSDl based therapy.
  • Glucocorticoids also decrease insulin secretion and this could exacerbate the effects of glucocorticoid induced insulin resistance.
  • Pancreatic islets express 1 l ⁇ HSDl and carbenoxolone can inhibit the effects of 11-dehydocorticosterone on insulin release
  • Skeletal development and bone function is also regulated by glucocorticoid action.
  • 1 l ⁇ HSDl is present in human bone osteoclasts and osteoblasts and treatment of healthy volunteers with carbenoxolone showed a decrease in bone resorption markers with no change in bone formation markers (Cooper MS et al 2000; Bone 27, 375-381). Inhibition of 1 l ⁇ HSDl activity in bone could be used as a protective mechanism in treatment of osteoporosis.
  • Glucocorticoids may also be involved in diseases of the eye such as glaucoma.
  • 1 l ⁇ HSDl has been shown to affect intraocular pressure in man and inhibition of 1 l ⁇ HSDl may be expected to alleviate the increased intraocular pressure associated with glaucoma (Rauz S et al. 2001; Investigative Opthalmology & Visual Science 42, 2037-2042).
  • Evidence suggests that a drug which specifically inhibits 1 l ⁇ HSDl in type 2 obese diabetic patients will lower blood glucose by reducing hepatic gluconeogenesis, reduce central obesity, improve the atherogenic lipoprotein phenotype, lower blood pressure and reduce insulin resistance. Insulin effects in muscle will be enhanced and insulin secretion from the beta cells of the islet may also be increased.
  • metabolic syndrome There are two main recognised definitions of metabolic syndrome.
  • the Adult Treatment Panel (ATP III 2001 JMA) definition of metabolic syndrome indicates that it is present if the patient has three or more of the following symptoms: Waist measuring at least 40 inches (102 cm) for men, 35 inches (88 cm) for women; Serum triglyceride levels of at least 150 mg/dl (1.69 mmol/1); HDL cholesterol levels of less than 40 mg/dl (1.04 mmol/1) in men, less than 50 mg/dl (1.29 mmol/1) in women;
  • Blood pressure of at least 135/80 mm Hg; and / or Blood sugar (serum glucose) of at least 110 mg/dl (6.1 mmol/1).
  • the patient has at least one of the following conditions: glucose intolerance, impaired glucose tolerance (IGT) or diabetes mellitus and/or insulin resistance; together with two or more of the following: Raised Arterial Pressure;
  • (lR,5S,6r)-3-[5-(Adamantan-2-ylcarbamoyl)-6-(methylthio)pyridin-2-yl]-3- azabicyclo[3.1.0]hexane-6-carboxylic acid may hereinafter be referred to as 'the Agent' .
  • a suitable pharmaceutically-acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifiuoroacetic, citric or maleic acid.
  • a suitable pharmaceutically-acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, tert- butylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • the invention also relates to in- vivo hydro lysable esters of the Agent.
  • a pharmaceutically-acceptable ester is hydrolysed in the human or animal body to produce the parent acid.
  • Possible pharmaceutically-acceptable esters for the carboxy in the Agent include Ci to C ⁇ alkoxymethyl esters for example methoxymethyl, Ci- 6 alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C 3 -scycloalkoxycarbonyloxyCi- ⁇ alkyl esters for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters, for example 5-methyl-l,3-dioxolen-2-onylmethyl; and Ci- ⁇ alkoxycarbonyloxyethyl esters.
  • the invention relates to any and all tautomeric forms of the compound that possess 1 l ⁇ HSDl inhibitory activity.
  • the compound may 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 possess 1 l ⁇ HSDl inhibitory activity.
  • the invention relates to a compound: (lR,5S,6r)-3-[5-(adamantan-2-ylcarbamoyl)-6-(methylthio)pyridin-2-yl]-3- azabicyclo[3.1.0]hexane-6-carboxylic acid; and pharmaceutically-acceptable salts thereof.
  • Another aspect of the present invention provides a process for preparing the Agent or a pharmaceutically acceptable salt thereof which process comprises: a) reacting a compound of the formula:
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
  • cortisone to the active steroid Cortisol by 1 l ⁇ HSDl oxo- reductase activity can be measured using a competitive homogeneous time resolved fluorescence assay (HTRF) (CisBio International, R&D, Administration and Europe Office, In Vitro Technologies — HTRF® / Bioassays BP 84175, 30204 Bagnols/Ceze Cedex, France.
  • HTRF time resolved fluorescence assay
  • DMSO dimethyl sulphoxide
  • the assay was carried out in a total volume of 20 ⁇ l consisting of cortisone (Sigma, Poole, Dorset, UK, 16OnM), glucose-6-phosphate (Roche Diagnostics, ImM), NADPH (Sigma, Poole, Dorset, lOO ⁇ M), glucose-6-phosphate dehydrogenase (Roche Diagnostics, 12.5 ⁇ g/ml), EDTA (Sigma, Poole, Dorset, UK, ImM), assay buffer (K 2 HPO 4 ZKH 2 PO 4 , 10OmM) pH 7.5, recombinant 1 l ⁇ HSDl [using an appropriate dilution to give a viable assay window - an example of a suitable dilution may be 1 in 1000 dilution of stock enzyme] plus test compound.
  • the assay plates were incubated for 25 minutes at 37°C after which time the reaction was stopped by the addition of lO ⁇ l of 0.5mM glycerrhetinic acid plus conjugated cortisol(XL665 or D2). lO ⁇ l of anti-cortisol Cryptate was then added and the plates sealed and incubated for 6 hours at room temperature. Fluorescence at 665nm and 620nm was measured and the 665nm:620nm ratio calculated using an Envision plate reader.
  • adipose tissue was washed with Phosphate buffered saline (PBS) and digest buffer (30ml) (0.6 mg/ml collagenase (Roche) in digestion medium (Medium M 199 + 1% penicillin and streptomycin + 4% BSA) was added for 1 hour.
  • PBS Phosphate buffered saline
  • digest buffer 30ml
  • collagenase Gibcos
  • Mature adipocytes were isolated following filtration using 250 ⁇ M gauze and washed four times with 1% wash medium (Medium M 199 + 1% penicillin and streptomycin + 1% BSA). Cells were resuspended in assay medium Dulbecco's Modified Eagles Medium (DMEM) (6% glucose) + 1% penicillin and streptomycin + 10% FCS) prior to assay.
  • DMEM Dulbecco's Modified Eagles Medium
  • % conversion of 3H-cortisone to 3H-cortisol was calculated using the AUC of the cortisone and Cortisol peaks.
  • Example 1 was tested twice in this assay giving IC50S of 4.3nM, and 3.OnM.
  • the oral bioavailability of the compound of the invention may be tested as follows:
  • Compounds are dosed intravenously at 2mg/kg (2ml/kg) and orally at 5mg/kg (5ml/kg) in a 25% HPBCD in sorrensons buffer pH 5.5 formulation.
  • Blood samples (20OuI) are taken Predose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8 and 24 h post dose for both routes and plasma prepared by centrifugation. Plasma samples are analysed as below.
  • PK parameters (clearance, volume of distribution, bioavailability, fraction absorbed etc.) are calculated by standard
  • Bioanalvsis of plasma samples The guidelines described are for the manual preparation of plasma samples following single compound or cassette dosing of project compounds to all PK species used within discovery DMPK. Analysis by open access (LC-MS/MS) or manual approaches (LC-MS) is described.
  • Solubilise compound(s) to lmg/ml using DMSO taking into account salt factors if any.
  • the DMSO stock(s) may be used to make all calibration & quality control (QC) samples:
  • IV and PO oral dose formulations of expected concentration to lOug/ml in methanol.
  • IV and PO oral dose formulations of expected concentration to lOug/ml in methanol.
  • a formulation made to an expected concentration of 2 mg/ml would be diluted 1:200 to give 10ug/ml solution).
  • a pharmaceutical composition which comprises the Agent, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent 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).
  • compositions in a form suitable for oral use are preferred.
  • 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
  • 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.
  • 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-accep table 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.
  • the amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
  • 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.
  • the Agent or a pharmaceutically-acceptable salt thereof, is an effective 1 l ⁇ HSDl inhibitor, and accordingly have value in the treatment of disease states associated with metabolic syndrome.
  • metabolic syndrome relates to metabolic syndrome as defined in 1) and/or 2) or any other recognised definition of this syndrome.
  • Synonyms for "metabolic syndrome” used in the art include Reaven's Syndrome, Insulin Resistance Syndrome and Syndrome X. It is to be understood that where the term “metabolic syndrome” is used herein it also refers to Reaven's Syndrome, Insulin Resistance Syndrome and Syndrome X.
  • the Agent or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use in a method of prophylactic or therapeutic treatment of a warm-blooded animal, such as man.
  • the Agent or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use as a medicament.
  • the Agent or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use in the treatment of type II diabetes.
  • the Agent, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use in the treatment of obesity is provided.
  • the Agent or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use in the production of an inhibitory effect in a warm- blooded animal, such as man.
  • the Agent or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the production of an 1 l ⁇ HSDl inhibitory effect in a warm-blooded animal, such as man.
  • production of or producing an 1 l ⁇ HSDl inhibitory effect is referred to suitably this refers to the treatment of metabolic syndrome.
  • production of an 1 l ⁇ HSDl inhibitory effect is referred to this refers to the treatment of diabetes, obesity, hyperlipidaemia, hyperglycaemia, hyperinsulinemia or hypertension, particularly diabetes and obesity.
  • an 1 l ⁇ HSDl inhibitory effect refers to the treatment of glaucoma, osteoporosis, tuberculosis, dementia, cognitive disorders or depression.
  • production of an 1 l ⁇ HSDl inhibitory effect refers to the treatment of cognitive disorders, such as improving the cognitive ability of an individual, for example by improvement of verbal fluency, verbal memory or logical memory, or for treatment of mild cognitive disorders. See for example WO03/086410 and references contained therein, and Proceedings of National Academy of Sciences (PNAS), 2001, 98(8), 4717-4721.
  • a method for producing an 1 l ⁇ HSDl inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of the Agent, or a pharmaceutically-acceptable salt thereof.
  • the Agent, or a pharmaceutically- salt thereof is also useful as pharmacological tool in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of 1 l ⁇ HSDl in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
  • the inhibition of 1 l ⁇ HSDl described herein may be applied as a sole therapy or may involve, in addition to the subject of the present invention, one or more other substances and/or treatments. 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.
  • agents than might be co-administered with 1 l ⁇ HSDl inhibitors, particularly those of the present invention may include the following main categories of treatment: 1) Insulin and insulin analogues;
  • Insulin secretagogues including sulphonylureas (for example glibenclamide, glipizide), prandial glucose regulators (for example repaglinide, nateglinide), glucagon- like peptide 1 agonist (GLPl agonist) (for example exenatide, liraglutide) and dipeptidyl peptidase IV inhibitors (DPP-IV inhibitors);
  • sulphonylureas for example glibenclamide, glipizide
  • prandial glucose regulators for example repaglinide, nateglinide
  • GLPl agonist glucagon- like peptide 1 agonist
  • DPP-IV inhibitors dipeptidyl peptidase IV inhibitors
  • Insulin sensitising agents including PPAR ⁇ agonists (for example pioglitazone and rosiglitazone);
  • anti-diabetic agents including phosotyrosine phosphatase inhibitors, glucose 6 - phosphatase inhibitors, glucagon receptor antagonists, glucokinase activators, glycogen phosphorylase inhibitors, fructose 1,6 bisphosphastase inhibitors, glutamine:fructose -6-phosphate amidotransferase inhibitors
  • Anti-obesity agents for example sibutramine and orlistat
  • Anti- dyslipidaemia agents such as, HMG-CoA reductase inhibitors (statins, eg pravastatin); PPAR ⁇ agonists (fibrates, eg gemfibrozil); bile acid sequestrants (cholestyramine); cholesterol absorption inhibitors (plant stanols, synthetic inhibitors); ileal bile acid absorption inhibitors (IBATi), cholesterol ester transfer protein inhibitors and nicotinic acid and analogues (niacin and slow release formulations);
  • 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);
  • ⁇ blockers eg atenolol, inderal
  • ACE inhibitors eg lisinopril
  • calcium antagonists eg. nifedipine
  • angiotensin receptor antagonists eg candesartan
  • ⁇ 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; 12) Anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (eg. aspirin) and steroidal anti-inflammatory agents (eg. cortisone); and 13) Agents that prevent the reabsorption of glucose by the kidney (SGLT inhibitors).
  • SGLT inhibitors the alternative and preferred embodiments of the compounds of the invention described herein also apply.
  • 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;
  • evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pa; 4.5-30 mmHg) with a bath temperature of up to 60 0 C;
  • chromatography means flash chromatography on silica gel
  • 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
  • (x) relative volume (rel vol) is the relative volume compared to the amount of the key intermediate. Relative volume is usually used to refer to the amount of solvent. For example if the key intermediate is lOOg and 1000ml of solvent is used, then this is referred to as 10 rel vol of solvent;
  • Lithium hydroxide monohydrate (0.735 g, 17.51 mmol) was added in one portion to ethyl (lR,5S)-3-[5-(2-adamantylcarbamoyl)-6-methylsulfanylpyridin-2-yl]-3- azabicyclo[3.1.0]hexane-6-carboxylate (Intermediate 3, 3.99 g, 8.76 mmol) in THF (45 mL) and methanol (15 mL). Water (9 mL) was then added dropwise with vigorous stirring. The resulting suspension was stirred at room-temperature for 16 hours. The reaction mixture was evaporated to dryness and redissolved in water (50 mL) and acidified with 2M HCl.
  • Example 1 may be prepared as follows:
  • Aqueous potassium hydroxide solution (2M) (5 mol eq.) was added to intermediate 3 (1 mol eq.) in ethanol (20 relative vol.) and stirred at ambient temperature overnight. The mixture was carefully brought to pH5 with aqueous HCl and diluted with water and stirred for 1 hour. The resulting solid was filtered off, washed with water and dried under vacuum at 5O 0 C for 24 hours.
  • Oxalyl chloride (8.72 ml, 100.00 mmol) was added dropwise to 2,6-dichloronicotinic acid ([Helvetica Chim. Acta, 1976, 59(1), 222], 60 g, 50 mmol) and N,N-dimethylformamide (0.039 ml, 0.50 mmol) in DCM at 20 0 C over a period of 10 minutes under nitrogen. The resulting suspension was stirred at 20 0 C for 2 hours.
  • 2,6-dichloronicotinic acid [Helvetica Chim. Acta, 1976, 59(1), 222], 60 g, 50 mmol
  • N,N-dimethylformamide 0.039 ml, 0.50 mmol
  • Intermediate 1 may be prepared as follows:
  • Oxalyl chloride (2 mol eq.) was added dropwise to 2,6-dichloronicotinic acid (1 mol eq.) and DMF (0.01 mol eq.) in DCM (23 mol eq) at 2O 0 C over 10 minutes under nitrogen. The resulting suspension was stirred at 2O 0 C for 2 hours to form a clear solution and then evaporated to dryness. The residue was azeotroped with toluene (2X) to afford the crude acid chloride as an oil.
  • intermediate 2 may be prepared as follows:
  • intermediate 3 may be prepared as follows: Intermediate 2 (1 mol eq.), (lR,5S,6r)-ethyl 3-azabicyclo[3.1.0]hexane-6-carboxylate hydrochloride (1.2 mol eq.) and potassium carbonate (3 mol eq.) were suspended in butyronitrile (10 relative vol.) and sealed in a Parr pressure bomb. The reaction was heated to 16O 0 C for 37 hours. The crude reaction mixture was filtered and resulting solid washed butyronitrile. The solvent was evaporated off to give a solid, which was stirred in DCM for 15minutes. The solid was then filtered off and the filtrate was evaporated to give a solid. The solid was purified on a column (Redisep 75Og silica cartridge) eluting with DCM to 10% EtOAc.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne l'acide (1R,5S,6r)-3-[5-(adamantan-2-ylcarbamoyl)-6-(méthylthio)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane-6-carboxylique et ses sels acceptables sur le plan pharmaceutique ; ainsi que son utilisation dans l'inhibition de la 11β-HSD1, ses procédés de fabrication et des compositions pharmaceutiques le renfermant.
PCT/GB2008/051012 2007-10-29 2008-10-29 Composés chimiques 313 Ceased WO2009056881A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
TW096140633A TW200827346A (en) 2006-11-03 2007-10-29 Chemical compounds
TW96140633 2007-10-29
US11/928,744 US7964618B2 (en) 2006-11-03 2007-10-30 Chemical compounds
US11/928,744 2007-10-30
US4825808P 2008-04-28 2008-04-28
US61/048,258 2008-04-28

Publications (1)

Publication Number Publication Date
WO2009056881A1 true WO2009056881A1 (fr) 2009-05-07

Family

ID=40266981

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2008/051012 Ceased WO2009056881A1 (fr) 2007-10-29 2008-10-29 Composés chimiques 313

Country Status (1)

Country Link
WO (1) WO2009056881A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
US8324265B2 (en) 2005-11-21 2012-12-04 Shionogi & Co., Ltd. Heterocyclic compounds having type I 11β hydroxysteroid dehydrogenase inhibitory activity
US8383622B2 (en) 2007-05-18 2013-02-26 Shionogi & Co., Ltd. Nitrogen-containing heterocyclic derivative having 11β-hydroxysteroid dehydrogenase type I inhibitory activity
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
EP3235813A1 (fr) 2016-04-19 2017-10-25 Cidqo 2012, S.L. Dérivés aza-tétra-cycliques

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004089896A1 (fr) * 2003-04-11 2004-10-21 Novo Nordisk A/S Composes actifs de la 11?-hydroxysteroide deshydrogenase de type 1
WO2005054200A1 (fr) * 2003-11-29 2005-06-16 Astrazeneca Ab Derives d'acide benzoyl-amino-pyridyl-carboxylique utilises en tant qu'activateurs de la glucokinase (glk)
WO2008053194A2 (fr) * 2006-11-03 2008-05-08 Astrazeneca Ab Composés chimiques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004089896A1 (fr) * 2003-04-11 2004-10-21 Novo Nordisk A/S Composes actifs de la 11?-hydroxysteroide deshydrogenase de type 1
WO2005054200A1 (fr) * 2003-11-29 2005-06-16 Astrazeneca Ab Derives d'acide benzoyl-amino-pyridyl-carboxylique utilises en tant qu'activateurs de la glucokinase (glk)
WO2008053194A2 (fr) * 2006-11-03 2008-05-08 Astrazeneca Ab Composés chimiques

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8324265B2 (en) 2005-11-21 2012-12-04 Shionogi & Co., Ltd. Heterocyclic compounds having type I 11β hydroxysteroid dehydrogenase inhibitory activity
US8383622B2 (en) 2007-05-18 2013-02-26 Shionogi & Co., Ltd. Nitrogen-containing heterocyclic derivative having 11β-hydroxysteroid dehydrogenase type I inhibitory activity
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
EP3235813A1 (fr) 2016-04-19 2017-10-25 Cidqo 2012, S.L. Dérivés aza-tétra-cycliques
WO2017182464A1 (fr) 2016-04-19 2017-10-26 Cidqo 2012, S.L. Nouveaux dérivés d'aza-tétracyclo

Similar Documents

Publication Publication Date Title
WO2009056881A1 (fr) Composés chimiques 313
US7951833B2 (en) Crystalline forms of 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]Benzoic acid 471
US20100022589A1 (en) Pyridine-3-carboxamide compounds and their use for inhibiting 11-beta-hydroxysteroid dehydrogenase
US8344016B2 (en) Pyrazole derivatives as 11-beta-HSD1 inhibitors
CA2668006C (fr) Pyridin-3-yl amides substitues sous forme d'inhibiteurs 1 ss hsd1
WO2007122411A1 (fr) Derives de diazepan-1-yl-sulfonyle pour le traitement du syndrome metabolique
AU2008326226B2 (en) 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid - 465
US20110092526A1 (en) Adamantyl Iminocarbonyl-Substituted Pyrimidines As Inhibitors Of 11-Beta-HSD1 826
HK1135090B (en) Pyridine carboxamides as 11-beta-hsd1 inhibitors

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08845625

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08845625

Country of ref document: EP

Kind code of ref document: A1