WO2009056934A1 - Dérivés de 1,4-dihydronaphtyridine - Google Patents

Dérivés de 1,4-dihydronaphtyridine Download PDF

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Publication number
WO2009056934A1
WO2009056934A1 PCT/IB2008/002825 IB2008002825W WO2009056934A1 WO 2009056934 A1 WO2009056934 A1 WO 2009056934A1 IB 2008002825 W IB2008002825 W IB 2008002825W WO 2009056934 A1 WO2009056934 A1 WO 2009056934A1
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pain
compound
pharmaceutically acceptable
acceptable salt
compounds
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PCT/IB2008/002825
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English (en)
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Cuiman Cai
Fred Lawrence Ciske
Joseph Edward Duran
Kristina Sean Fors
Timothy Joseph Hagen
Daniel Dale Holsworth
Mehran Jalaie
Robert Michael Kennedy
Daniele Leonard
Toni-Jo Poel
John Quin Iii
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Pfizer Products Inc.
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Publication of WO2009056934A1 publication Critical patent/WO2009056934A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention relates to 1 ,4-dihydronaphthyridine derivatives ("DHN") that are calcium channel antagonists.
  • the derivatives of the invention modulate the L-type and T-type calcium channels and are useful as pharmaceutical agents in the treatment of a variety of disorders ranging from pain, hypertension, angina pectoris, Alzheimer disease, Parkinson disease and/or obesity.
  • Voltage-gated calcium channels are membrane-spanning, multi-subunit proteins that open in response to membrane depolarization, allowing calcium ion entry from the extracellular milieu. Calcium channels were initially classified based on the time and voltage-dependence of channel opening and on the sensitivity to pharmacological block.
  • the ⁇ i subunit is the primary determinant of the pharmacological properties and contains the channel pore and voltage sensor (Hockennan G H 1 Peterson B Z, Johnson B D, Catterall W A. 1997. Annu Rev Pharmacol Toxicol 37: 361-96; Striessnig J. 1999. Cell Physiol Biochem 9: 242-69).
  • Ten isoforms of the ⁇ i subunit are known, as indicated in Table 1.
  • the ⁇ 2 ⁇ subunit consists of two disulfide linked subunits, 0:2, which is primarily extracellular and a transmembrane ⁇ subunit.
  • the ⁇ subunit is a non-glycosylated cytoplasmic protein that binds to the ⁇ i subunit.
  • Four isoforms are known, termed ⁇ i to ⁇ 4 .
  • the y subunit is a transmembrane protein that has been biochemically isolated as a component of Ca v 1 and Ca v 2 channels.
  • the nomenclature for voltage-gated calcium channels is based upon the content of the ch subunit, as indicated in Table 1.
  • Each type of O 1 subunit can associate with a variety of ⁇ , ⁇ 2 ⁇ or v subunits, so that each Ca v type corresponds to many different combinations of subunits. TABLE 1 Classification of Neuronal Calcium Channels
  • Ca v 2 currents are found almost exclusively in the central and peripheral nervous system and in neuroendocrine cells and constitute the predominant forms of presynaptic voltage-gated calcium current. Presynaptic action potentials cause channel opening and neurotransmitter release is steeply dependent upon the subsequent calcium entry. Thus, Ca v 2 channels play a central role in mediating neurotransmitter release.
  • N-type calcium channels (Ca v 2.2) contain high-affinity binding sites for the peptide toxins ⁇ -conotoxin-MVIIC and ⁇ -conotoxin-GVIA, respectively, and these peptides have been used to determine the distribution and function of each channel type.
  • Ca v 2.2 is highly expressed at the presynaptic nerve terminals of neurons from the dorsal root ganglion and neurons of lamina I and Il of the dorsal horn (Westenbroek R E, Hoskins L, Catterall W A. 1998. J Neurosci 18: 6319-30; Cizkova D, Marsala J, Lukacova N, Marsala M, Jergova S, et al. 2002. Exp Brain Res 147: 456-63). Ca v 2.2 channels are also found in presynaptic terminals between second and third order interneurons in the spinal cord. Both sites of neurotransmission are very important in relaying pain information to the brain.
  • Pain, particularly neuropathic and intractable pain is a large unmet medical need. Millions of individuals suffer from severe pain that is not well controlled by current therapeutics.
  • the current drugs used to treat pain include non-steroidal antiinflammatory drugs (NSAIDs), cyclo-oxygenase 2 (COX-2) inhibitors, opioids, tricyclic antidepressants, and anticonvulsants.
  • NSAIDs non-steroidal antiinflammatory drugs
  • COX-2 cyclo-oxygenase 2
  • opioids opioids
  • tricyclic antidepressants tricyclic antidepressants
  • anticonvulsants anticonvulsants.
  • Neuropathic pain has been particularly difficult to treat as it does not respond well to opioids until high doses are reached.
  • Gabapentin is currently the most widely used therapeutic for the treatment of neuropathic pain, although additional therapeutic agents are desirable, particularly those with broader ranges of activities.
  • the T-type calcium channel (Ca v 3.1 , Ca v 3.2, and Ca v 3.3) may become over- expressed due to genetic or environmental causes, such as epilepsy (Tsakiridou, E. et al., J. Neurosci. 1995, 15, 3110-3117), high blood pressure (Self, D. A. et al., J. Vacs. Res. 1994, 31 , 359-366), ventricular hypertrophy (Nuss, H. B. et al., Circ. Res. 1995, 73, 777-7825), pain (Shin, H. S. et al., Science 2003, 302, 117-119), and angina pectoris (Van der Vring, J. A.
  • a representative drug for blocking the T-type calcium channel is mibefradil of Hoffman La Roche Ltd.
  • the drug was found to be effective in treating high blood pressure, angina pectoris and cerebral apoplexy. It was approved for treating high blood pressure in May, 1997.
  • a side effect caused by a drug-drug interaction due to inhibition of CYP 3A4 hepatic enzyme was discovered. As such, the drug was withdrawn from the market in June, 1999.
  • Dihydropyridine (DHP) antagonists of L-type calcium channels are widely used therapeutics in the treatment of hypertension, angina, arrhythmias, congestive heart failure, cardiomyopathy, atheriosclerosis, and cerebral and peripheral vascular disorders (Janis and Triggle, 1990 CRC Press, Cleveland).
  • DHPs Dihydropyridine
  • some of the DHPs are sensitive to T-type channel activity.
  • Bilateral edema of the lower limbs is one of the most common adverse effects of the DHPs. This is thought to be related to the profound vasodilatation caused by DHPs.
  • the peripheral edema is very uncomfortable, at times intolerable, and causes considerable distress and disfigurement.
  • the edema can lead to a misdiagnosis of heart failure; when in fact, this is not the case. Edema can result in the need for dose reduction or drug withdrawal which will negate the antihypertensive efficacy.
  • Noncompliance due to edema manifestation may contribute significantly to poor blood pressure control and to hypertension-related morbidity and mortality.
  • Vasodilator-induced edema is unresponsive to diuretics and somewhat relieved by angiotensin converting enzyme inhibition or angiotensin receptor antagonists.
  • angiotensin converting enzyme inhibition or angiotensin receptor antagonists the addition of a second drug leads to reduced patient compliance and possible exposure to side effects of a second drug.
  • a favorable drug tolerability profile is very important, since antihypertensive therapy requires long-term treatment and patient compliance.
  • Aldosterone is a circulating hormone known to regulate water and electrolyte excretion via effects on renal epithelial tissue. Aldosterone also contributes to the progression of end-organ damage associated with cardiovascular disease by promoting perivascular and interstitial myocardial fibrosis, endothelial dysfunction and vascular stiffening. Compounds that antagonize mineralocorticoid receptors or the secretion of aldosterone produce significant benefits in cardiovascular disease. T-type calcium channels have been characterized in adrenal cells and are integral for the secretion of aldosterone from adrenal glomerulosa cells.
  • dihydropyridines e.g., Nifedipine, Nicardipine, Nisoldipine, Isradipine, Folodipine, Nimodipine, AmLodipine, Aranidipine, Azelnidipine, Manidipine, Nilvadipine, Lercanidipine, Cilnidipine, Efonidipine, Lacidipine and Benedipine
  • benzothiazepines e.g., diltiazem
  • phenylalkylamines e.g., verapamil
  • diarylaminopropylamine ether e.g., bepridil
  • 1 ,6-naphthridine derivatives are disclosed in U.S. Patent No. 4,751 ,228 (EP0234516) that are described as calcium antagonists useful for combating heart circulation mortality such as cerebral, cardiac and peripheral blood vessel diseases.
  • the following compound is named: 2-[1-(4- diphenylmethylpiperazinyl)]-ethyl ( ⁇ )-1 ,4-dihydro-5-isopropoxy-2-methyl-4-(2- trifluoromethylphenyl)-1 ,6-naphthyridine-3-carboxylate.5 oxalate.
  • 1 ,6-naphthridine derivatives are also disclosed in U.S. 5,037,987 as calcium antagonists useful in the treatment of blood vessel diseases.
  • the present invention relates to a compound of formulae (I) or (II).
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formulae (I) or (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention also relates to pharmaceutical combination compositions comprising: a therapeutically effective amount of a composition comprising a first compound, the first compound being a selective T-type calcium channel antagonist compound of the compounds of the present invention, or a prodrug of the compound or a pharmaceutically acceptable salt of the compound or prodrug; a second compound, the second compound being a calcium channel antagonist with L-type calcium channel antagonist activity or a prodrug of the compound or a phar maceutically acceptable salt of the compound or prodrug; and a pharmaceutically acceptable carrier, vehicle or diluent.
  • the present invention further relates to a method of blocking calcium channels, the method comprising administering to a patient in need of calcium channel blocking a therapeutically effective amount of a compound of formulae (I) or (II) to block calcium channels.
  • Another embodiment of the invention relates to a method of treating pain, including chest pain, in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a compound of formulae (I) or (II), or a pharmaceutically acceptable salt thereof.
  • Another embodiment of the invention relates to a method of causing vasodilation in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a compound of formulae (I) or (II), or a pharmaceutically acceptable salt thereof.
  • a further embodiment of the invention relates to a method of treating a disease selected from hypertension, congestive heart failure, stroke, ischaemic heart disease, including myocardial ischemia angina pectoris and Printzmetal angina, reduction of food intake and obesity comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formulae (I) or (II) or a pharmaceutically acceptable salt thereof.
  • Another aspect of this invention is directed to methods of reducing myocardial tissue damage (e.g., substantially preventing tissue damage, inducing tissue protection) during surgery (e.g., coronary artery bypass grafting (CABG) surgeries, vascular surgeries, percutaneous transluminal coronary angioplasty (PTCA) or any percutaneous transluminal coronary intervention (PTCI), organ transplantation, or other non-cardiac surgeries) comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt of said compound.
  • a mammal e.g., a female or male human
  • Another aspect of the invention is directed to methods of treating Alzheimer and Parkinson disease comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt of said compound.
  • a mammal e.g., a female or male human
  • ⁇ vvW or " " refers to a bond for which the stereochemistry is not designated.
  • the designation " ' " refers to a bond that protrudes backward out of the plane of the page.
  • the compounds of the formula (I) and (II) exist as stereoisomers. Any reference in this application to one of the compounds of the formula (I) and (II) is meant to encompass either specific stereoisomers or a mixture of stereoisomers. Where indicated, the compounds follow the (+)- and (-)- designation or the Cahn-lngold-Prelog designation of (R)- and (S)- for the stereochemistry of compounds represented by formula (I) and (II) and intermediates thereof.
  • the specific stereoisomers can be prepared by stereospecific synthesis using enantiomerically pure or enantiomerically enriched starting materials.
  • the specific stereoisomers of either starting materials or products can be resolved and recovered by techniques known in the art, such as chromatography on chiral stationary phases, enzymatic resolution, or fractional recrystallization of addition salts formed by reagents used for that purpose.
  • Useful methods of resolving and recovering specific stereoisomers are known in the art and described in Stereochemistry of Organic Compounds, E. L. Eliel and S. H. Wilen, Wiley (1994) and Enantiomers, Racemates, and Resolutions, J. Jacques, A. Collet, and S. H. Wilen, Wiley (1981). Further details regarding the nomenclature may be found in M. B. Smith and J. March, Advanced Organic Chemistry, (2001).
  • a number of routes are available.
  • a mixture of enantiomers may be prepared, and then the two enantiomers may be separated.
  • a commonly employed method for the separation of a racemic mixture is the use of chiral high pressure liquid chromatography. Further details regarding resolution of enantiomeric mixtures may be found in J. Jacques, et al, Enantiomers, Racemates, and Resolutions, (1991).
  • suitable solvent refers to any solvent, or mixture of solvents, inert to the ongoing reaction that sufficiently solubilizes the reactions to afford a medium within which to effect the desired reaction.
  • Pharmaceutically acceptable salts of the compounds of formula (I) and (II) include the acid addition and base salts (including disalts) thereof. Suitable acid addition salts are formed from acids which form non-toxic salts.
  • Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • a pharmaceutically acceptable salt of a compound of formula (I) and (II) may be readily prepared by mixing together solutions of the compound of formula (I) and (II) and the desired acid or base, as appropriate.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionisation in the salt may vary from completely ionised to almost non-ionised.
  • Compounds of formula (I) and (II) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of formula (I) and (II) contains an alkenyl or alkenylene group, geometric cis/trans (or ZJE) isomers are possible. Where the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism ('tautomerism') can occur. It follows that a single compound may exhibit more than one type of isomerism.
  • racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) and (II) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound of formula (I) and (II) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
  • Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to
  • the present invention includes all pharmaceutically acceptable isotopically- labelled compounds of formula (I) and (II) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F 1 iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • isotopically-labelled compounds of formula (I) and (II), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier isotopes such as deuterium, i.e. 2 H may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Isotopically-labeled compounds of formula (I) and (II) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
  • the compounds of the present invention may be administered as prodrugs.
  • Prodrugs can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) and (II) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985).
  • prodrugs include:
  • Dialkyl 1 ,4-dihydropyridine-3,5-dicarboxylates of structure 1 wherein X is OMe or CF 3 and R is simple alkyl (e.g., Me or Et) are either commercially available or known in the literature and can be prepared by one skilled in the art via the Hantzsch synthesis (see Example 1 , Step 1A).
  • the alkyl esters 3 then undergo a transesterification reaction with 4-benzhydryl-1- piperazineethanol (or a salt form thereof) in the presence of a base such as sodium hydride or sodium t-butoxide in a solvent such as dimethylformamide or dimethylacetamide at a temperature typically in a range of 80-130 0 C to give the compounds 4 of this invention as the racemates.
  • a base such as sodium hydride or sodium t-butoxide
  • a solvent such as dimethylformamide or dimethylacetamide
  • DBU 1 ,8-diaza-7-bicyclo [5.4.0 ]undecene
  • DCC ⁇ /, ⁇ /'-dicyclohexylcarbodiimide
  • DCM dichloromethane
  • DIBAL-H diisobutylaluminum hydride
  • DIP-chloride B-chlorodiisopinocampheylborane
  • DIPEA diisopropylethylamine
  • DMAP 4-dimethylaminopyridine
  • DMF N,N -dimethylformamide
  • DMSO methyl sulfoxide
  • HMDS hexamethyldisilazane
  • IPA isopropyl alcohol
  • LDA lithium diisopropylamide
  • LAH lithium aluminum hydride
  • Step 1A Preparation of Example 1a: Diethyl 2.6-dimethyl-4-(2-(trifluoromethyl)phenyl)- 1 , 4-dih vdrop yridine-3, 5-dicarboxylate
  • Step 1B Preparation of Example 1b: racemic ethyl 5-hvdroxy-2-methyl-4-(2- thfluorometh vDphen yl)-1, 4-dih vdro- 1 , 6-naphthyridine-3-carboxylate
  • Step 1C Preparation of Example 1c: racemic ethyl 5-(cyclopentyloxy)-2-methyl-4-(2- (trifluoromethyl)phenyl)-1,4-dihvdro-1,6-naphthyhdine-3-carboxvlate
  • Crystals formed Filtered the slurry through a pad of ⁇ 200g of silica gel and eluted with 20% ethyl acetate 80% heptane. Collected in 500 mL fractions. The fractions containing pure product were combined and concentrated on the rotovap to an orange gum. 48.6 g, 51.5% yield resulted. Very pure by HPLC and TLC (1 :1 ethyl acetate:heptane).
  • Step 1D Preparation of Example 1d: racemic 2-(4-benzhydrylDiperazin-1-yl)ethyl 5- (cvclopentyloxy)-2-meth yl-4-(2-(trifluorometh vDohen yl)- 1 , 4-dih vdro- 1.6-naphth yridine-3- carboxylate
  • the combined organics were washed with 500 mL of water followed by 250 mL of water, followed by drying over sodium sulfate and concentrating to a red oil.
  • the oil was dissolved in 100 mL of heptane and 100 mL of ethyl acetate and filtered through a pad of about 50Og of silica gel.
  • the cake was washed with 500 mL portions of 1 :1 ethyl acetate:heptane. The portions containing the desired product were concentrated to an oil.
  • the oil was purified by chromatography over about 50Og of silica gel eluting with 2L of heptane, 2L of 10% ethyl acetate/heptane, 2L of 25% ethyl acetate/heptane and 2L of 50% ethyl acetate/heptane.
  • the fractions containing clean product were combined and concentrated to a light yellow foam to provide 54.3g of 1d.
  • the racemic product (Ex 1d) was separated into its enantiomers on a Berger Multigram with two connected OJ-H columns and using 30% methanol with 0.2% isopropylamine as the modifier and a flow of 70ml_/min, monitoring at 215nm.
  • Step 1F Preparation of Example 1f: (R)-Ethyl 5-hvdroxy-2-methyl-4-(2- trifluorometh vDphen yl)-1, 4-dih vdro- 1 , 6-naphthyridine-3-carboxylate
  • Chiral assays shows 0.81 % of the minor enantiomer.
  • the salt was carried forward without further purification.
  • the solids were slurried in 10% NaOH (250 mL) and ethyl acetate (500 mL).
  • the phases were separated the organics were dried over sodium sulfate and concentrated to provided 12.4 g of free base, 1f (>99% chiral purity by chiral SFC).
  • Chiral SFC conditions are as follows: Column: Chiralpak IC, 250x4.6
  • Modifier Methanol Gradient: 5% Methanol to 40% linear gradient in 8 minutes Wavelength: 220nm Outlet Pressure: 100 bar
  • Step 1G Preparation of Example 1Q: (R)-ethyl 5-(cvclopentyloxy)-2-methyl-4-(2- (trifluorometh vDphen yl)-1.4-dih vdro- 1 , 6-naphth yridine-3-carboxylate
  • Step 2a Preparation of methyl 4-(2-methoxyohenyl)-2-methyl-5-oxo-1.4.5.6-tetrahvdro- 1 ,6-naphthyridine-3-carboxylate
  • a 500 ml_ 3-neck flask was equipped with a mechanical stirrer and a condenser was charged with 2a (70.Og, 214.49 mmol, 1.0eq.) followed by DMF (15OmL, 2.1vol/g) while stirring under nitrogen.
  • the resulting mixture was charged with cesium carbonate (153.75g, 471.88 mmol, 2.2eq.), while heating to 60 0 C.
  • the reaction was then charged with cyclopentyl iodide (49.49mL, 428.99 mmol, 2.0eq.).
  • Step 2c Preparation of2-(4-benzhvdrylpiDerazin-1-yl)ethyl 5-(cvclopentyloxy)- 4-(2- methoxyphen yl)-2-meth W- 1.4-dih vdro- 1.6-naphth yridine-3-carboxvlate
  • a 1 L 3-neck flask was equipped with a mechanical stirrer, condenser and a nitrogen bubbler was charged with sodium hydride (60% in mineral oil, 6.65g, 166.25 mmol,
  • the resulting solution was heated to 120 0 C for 24h under a Nitrogen sweep to remove the methanol formed during the reaction.
  • the reaction was allowed to cool to 22 0 C and then charged with water (1000 ml_, 33.3vol/g) while stirring.
  • the resulting slurry was extracted to ethyl acetate (3x300 mL, 30vol/g).
  • the combined organic layers were washed with water (300 mL, 10vol/g) then brine (300 mL, 10 vol/g).
  • the resulting solution was concentrated to afford a very viscous oily product (69.78g, 79.1 % by HPLC), which was then purified by column chromatography (30% Acetone/heptane) to afford product 2 (> 95% by HPLC).
  • the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine activity or cytotoxicity using the standard tests described herein, or using other similar tests which are well known in the art.
  • Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
  • the present invention provides a method for causing vasodilation in a patient in need thereof comprising administering a compound of formulae (I) or (II).
  • the present invention provides a method of blocking calcium channels, the method comprising of administering to a patient in need of calcium channel blocking a therapeutically effective amount of a compound of formulae (I) or (II) to block calcium channels.
  • the calcium channels are T-type calcium channels.
  • the calcium channels are L-type calcium channels.
  • the calcium channels are both L- and T-type calcium channels.
  • the above compounds are consider to be L-type calcium channel antagonists, but may also have some T-type calcium channel antagonistic activity.
  • the present invention provides a method of treating a disease selected from hypertension, congestive heart failure, stroke, ischaemic heart disease, and angina pectoris comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formulae (I) or (II). It is also recognized that one skilled in the art may affect the associated diseases and conditions by treating a patient presently afflicted with the diseases or conditions or by prophylactically treating a patient afflicted with the diseases or conditions with a therapeutically effective amount of the compounds of formulae (I) or (II).
  • Another aspect of this invention is directed to methods of reducing myocardial tissue damage (e.g., substantially preventing tissue damage, inducing tissue protection) during surgery (e.g., coronary artery bypass grafting (CABG) surgeries, vascular surgeries, percutaneous transluminal coronary angioplasty (PTCA) or any percutaneous transluminal coronary intervention (PTCI), organ transplantation, or other non-cardiac surgeries) comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of a compound of formulae (I) or (II) or a pharmaceutically acceptable salt of said compound.
  • a mammal e.g., a female or male human
  • Another aspect of the invention is directed to reduction of food intake and methods of treating and/or preventing eating disorders and obesity.
  • eating disorders refer to illnesses in which the patient suffers disturbances in their eating behaviors and related thoughts and emotions.
  • Representative examples of obesity-related eating disorders include overeating, bulimia, binge-eating disorder, compulsive dieting, nocturnal sleep-related eating disorder, pica, Prader-Willi Syndrome, and night-eating syndrome.
  • Symptoms of night-eating syndrome include: little or no appetite for breakfast; eating more food after dinner than during the meal; eating more than half of daily food intake after the dinner hour; the pattern persists for at least two months; feeling tense, anxious, upset, or guilty while eating; difficulty falling asleep or staying asleep; unlike bingeing (which is done in relatively short episodes), continual eating throughout evening hours; and eating produces guilt and shame, not enjoyment .
  • a person suffering from nocturnal sleep-related eating disorder is somewhere between wakefulness and sleep, and may binge or consume strange combinations of food or non-food items. When awake, the person has little or no memory of the episodes.
  • Pica is a craving for non-food items, most commonly dirt, clay, chalk, paint chips, cornstarch, baking soda, coffee grounds, cigarette ashes, rust, plastic, etc. Pica is usually found in pregnant women, people whose diets are deficient in minerals contained in the consumed substances, people who have psychiatric disturbances, or people whose family or ethnic customs including eating certain non-food substances.
  • Prader-Willi syndrome is an uncommon inherited disorder characterized by mental retardation, decreased muscle tone, short stature, emotional lability and an insatiable appetite which can lead to life-threatening obesity.
  • the compounds of this invention may also be used in conjunction with other pharmaceutical agents for the treatment of the diseases/conditions described herein or as an adjunct therapy for treatment of related diseases/conditions (e.g., diabetes, metabolic syndrome, and arteriosclerosis). Therefore, methods of treatment that include administering compounds of the present invention in combination with other pharmaceutical agents are also provided.
  • other pharmaceutical agents for the treatment of the diseases/conditions described herein or as an adjunct therapy for treatment of related diseases/conditions (e.g., diabetes, metabolic syndrome, and arteriosclerosis). Therefore, methods of treatment that include administering compounds of the present invention in combination with other pharmaceutical agents are also provided.
  • anti-obesity agents selected from the group consisting of orlistat, cetilistat (ATL-962), sibutramine, bromocriptine, ephedrine, leptin, rimonabant, surinabant, taranabant, AVE1625 (CAS No. 358970-97-5), the hydrochloride salt of 1- [9-(4-chloro-phenyl)-8-(2-chloro-phenyl)-9H-purin-6-yl]-4-ethylamino-piperidine-4- carboxylic acid amide), or SLV319 (CAS No.
  • compounds of the present invention and combination therapies are administered in conjunction with exercise and a sensible diet.
  • obinepitide can be prepared as described in WO 05/089790
  • PYY 3 - 36 (including analogs thereof) can be prepared as described in US Publication No. 2002/0141985 and WO 03/027637
  • liraglutide can be prepared as described in U.S. Pat No. 6,268,343
  • the NPY Y5 receptor antagonist 2-oxo-N-(5- phenylpyrazinyl)spiro[isobenzofuran-1 (3H),4'-piperidine]-1 '-carboxamide can be prepared as described in US Publication No. 2002/0151456.
  • the CB-1 receptor antagonist is preferably selective to the CB-1 receptor.
  • CB-1 receptor selective means that the compound has little or no activity to antagonize the cannabinoid-2 receptor (CB-2). More preferably, the CB-1 antagonist is at least about 10 fold more selective for the CB-1 receptor in comparison to the CB-2 receptor.
  • the inhibitory concentration (IC 50 ) for antagonizing the CB-1 receptor is about 10 or more times lower than the IC 50 for antagonizing the CB-2 receptor.
  • Bioassay systems for determining the CB-1 and CB-2 binding properties and pharmacological activity of cannabinoid receptor ligands are described by Roger G.
  • CB-1 receptor antagonists include compounds disclosed in:
  • the MTP inhibitors are preferably intestinal selective.
  • intestinal selective means that the MTP inhibitor has a higher exposure to the MTP in the intestinal microsomes than the MTP in the liver.
  • Suitable intestinal-acting MTP inhibitors include compounds disclosed in U.S. Patent Nos. 4,453,913; 4,473,425;
  • a preferred CCKa agonist is ⁇ /-benzyl-2-[4-(1 H-indol-3-ylmethyl)-5-oxo-1-phenyl- 4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide which may be prepared as described in US Publication No. 2005/0267100 A1 , incorporated herein by reference.
  • Physiological pain is an important protective mechanism designed to warn of danger from potentially injurious stimuli from the external environment.
  • the system operates through a specific set of primary sensory neurons and is activated by noxious stimuli via peripheral transducing mechanisms (see Millan, 1999, Prog. Neurobiol., 57, 1-164 for a review).
  • These sensory fibers are known as nociceptors and are characteristically small diameter axons with slow conduction velocities. Nociceptors encode the intensity, duration and quality of noxious stimulus and by virtue of their topographically organised projection to the spinal cord, the location of the stimulus.
  • Pain may generally be classified as acute or chronic. Acute pain begins suddenly and is short-lived (usually twelve weeks or less). It is usually associated with a specific cause such as a specific injury and is often sharp and severe. It is the kind of pain that can occur after specific injuries resulting from surgery, dental work, a strain or a sprain. Acute pain does not generally result in any persistent psychological response. In contrast, chronic pain is long-term pain, typically persisting for more than three months and leading to significant psychological and emotional problems. Common examples of chronic pain are neuropathic pain (e.g. painful diabetic neuropathy, postherpetic neuralgia), carpal tunnel syndrome, back pain, headache, cancer pain, arthritic pain and chronic post-surgical pain.
  • neuropathic pain e.g. painful diabetic neuropathy, postherpetic neuralgia
  • carpal tunnel syndrome e.g. painful diabetic neuropathy, postherpetic neuralgia
  • back pain e.g. painful diabetic neuropathy, postherpetic neuralgia
  • Nociceptive pain is induced by tissue injury or by intense stimuli with the potential to cause injury. Pain afferents are activated by transduction of stimuli by nociceptors at the site of injury and activate neurons in the spinal cord at the level of their termination. This is then relayed up the spinal tracts to the brain where pain is perceived (Meyer et al., 1994, Textbook of Pain, 13-44). The activation of nociceptors activates two types of afferent nerve fibres. Myelinated A-delta fibres transmit rapidly and are responsible for sharp and stabbing pain sensations, whilst unmyelinated C fibres transmit at a slower rate and convey a dull or aching pain.
  • Moderate to severe acute nociceptive pain is a prominent feature of pain from central nervous system trauma, strains/sprains, burns, myocardial infarction and acute pancreatitis, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, renal colic, cancer pain and back pain.
  • Cancer pain may be chronic pain such as tumour related pain (e.g. bone pain, headache, facial pain or visceral pain) or pain associated with cancer therapy (e.g. postchemotherapy syndrome, chronic postsurgical pain syndrome or post radiation syndrome). Cancer pain may also occur in response to chemotherapy, immunotherapy, hormonal therapy or radiotherapy.
  • Back pain may be due to herniated or ruptured intervertebral discs or abnormalities of the lumber facet joints, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament. Back pain may resolve naturally but in some patients, where it lasts over 12 weeks, it becomes a chronic condition which can be particularly debilitating.
  • Neuropathic pain is currently defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system. Nerve damage can be caused by trauma and disease and thus the term 'neuropathic pain' encompasses many disorders with diverse aetiologies.
  • neuropathic pain The symptoms of neuropathic pain are difficult to treat, as they are often heterogeneous even between patients with the same disease (Woolf & Decosterd, 1999, Pain Supp., 6, S141-S147; Woolf and Mannion, 1999, Lancet, 353, 1959-1964). They include spontaneous pain, which can be continuous, and paroxysmal or abnormal evoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally innocuous stimulus).
  • Visceral pain is pain associated with the viscera, which encompass the organs of the abdominal cavity. These organs include the sex organs, spleen and part of the digestive system. Pain associated with the viscera can be divided into digestive visceral pain and non-digestive visceral pain.
  • Gl gastrointestinal
  • FBD functional bowel disorder
  • IBD inflammatory bowel disease
  • Gl disorders include a wide range of disease states that are currently only moderately controlled, including, in respect of FBD, gastro-esophageal reflux, dyspepsia, irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS), and, in respect of IBD, Crohn's disease, ileitis and ulcerative colitis, all of which regularly produce visceral pain.
  • Other types of visceral pain include the pain associated with dysmenorrhea, cystitis and pancreatitis and pelvic pain.
  • pain have multiple aetiologies and thus can be classified in more than one area, e.g. back pain and cancer pain have both nociceptive and neuropathic components.
  • Other types of pain include:
  • Parkinson disease may be related to age-related calcium signaling versus dopamine dysfunction. Nature (June 2007). Emerging evidence suggests that calcium toxicity contributes to cell death associated with Alzheimer disease and suggests that calcium channel blockade may be an effective treatment for Parkinson disease.
  • the basic physiology of SNc dopaminergic neurons shows a key difference from many other neurons - calcium ions are used to maintain autonomous activity.
  • rhythmic pacemaking activity ceased when cells were bathed in L-type calcium channel antagonists, such as isradipine, nimodipine, and other members of the dihydropyridine family.
  • mice with genetic deletions of the L-type channel subunit Cav1.3 which is highly expressed in the SNc neurons have been examined and it was determined that cells fired at a normal rate but were using sodium not calcium. Further experiments have shown that age determined whether pacemaking was governed by sodium or calcium. Recordings of SNc dopaminergic neurons from wild- type mice less than 3 weeks old showed a dependency on sodium that waned with age as calcium channels took over the pacemaking activity. Therefore, deleting the Cav1.3 calcium channel allowed the cells to retain their youthful ways. Consequently, another aspect of this invention is a method of treating Alzheimer and Parkinson diseases with the compounds of the invention.
  • the term "patient” refers to a warm-blooded animal such as a mammal which is (1) in need of vasodilation, (2) in need of blocking calcium channels, (3) afflicted with or at risk of developing hypertension, congestive heart failure, stroke, ischaemic heart disease, or angina pectoris, or (4) afflicted with pain or a sub-category of pain as described above. It is understood that guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep, and humans are examples of animals within the scope of the meaning of the term.
  • the term "therapeutically effective amount" of a compound of formulae (I) or (II) refers to an amount which is effective in (1) causing vasodilation in the patient in need thereof, (2) blocking calcium channels, (3) treating hypertension, congestive heart failure, stroke, ischaemic heart disease, or angina pectoris, or (4) treating pain.
  • treating is intended to refer to all processes wherein there may be a slowing, interrupting, arresting, or stopping of the progression of the diseases and conditions described herein, but does not necessarily indicate a total elimination of all disease and condition symptoms, and is intended to include prophylactic treatment of the hypertension, congestive heart failure, stroke, ischaemic heart disease, angina pectoris, or pain.
  • compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in 'Remington's Pharmaceutical Sciences', 19th Edition (Mack Publishing Company, 1995).
  • the compounds of the invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid formulations, such as tablets, capsules containing particulates, liquids, or powders; lozenges (including liquid- filled), chews; multi- and nano-particulates; gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays and liquid formulations.
  • Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
  • surface active agents such as sodium lauryl sulfate and polysorbate 80
  • glidants such as silicon dioxide and talc.
  • surface active agents may comprise from 0.2 weight % to 5 weight% of the tablet, and glidants may comprise from 0.2 weight% to 1 weight% of the tablet.
  • ingredients include anti-oxidants, colourants, flavoring agents, preservatives and taste-masking agents.
  • Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting.
  • the final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.
  • the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • solubility of compounds of formula (I) and (II) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release.
  • compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound.
  • examples of such formulations include drug- coated stents and PGLA microspheres.
  • the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated; see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999).
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • Capsules (made, for example, from gelatin or HPMC), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate.
  • a suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 ⁇ g to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 ⁇ l to 100 ⁇ l.
  • a typical formulation may comprise a compound of formula (I) or (II) propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
  • Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
  • Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, poly(DL-lactic-coglycolic acid (PGLA).
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled- , targeted and programmed release.
  • the compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema.
  • Cocoa butter is a traditional suppository base, but various well known alternatives may be used as appropriate.
  • the compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH- adjusted, sterile saline.
  • Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non- biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • the compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol- containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
  • soluble macromolecular entities such as cyclodextrin and suitable derivatives thereof or polyethylene glycol- containing polymers
  • a calcium channel blocker of the present invention may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of pain.
  • a compound of formulae (I) or (II), or a pharmaceutically acceptable salt thereof, as defined above may be administered simultaneously, sequentially or separately in combination with one or more agents selected from:
  • nonsteroidal antiinflammatory drugs e.g. aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, tolmetin, zomepirac, and their pharmaceutically acceptable salts;
  • NSAIDs nonsteroidal antiinflammatory drugs
  • barbiturate sedatives e.g. amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metharbital, methohexital, pentobarbital, phenobartital, secobarbital, talbutal, theamylal, thiopental and their pharmaceutically acceptable salts;
  • benzodiazepines having a sedative action e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, triazolam and their pharmaceutically acceptable salts,
  • Hi antagonists having a sedative action e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine, chlorcyclizine and their pharmaceutically acceptable salts
  • miscellaneous sedatives such as glutethimide, meprobamate, methaqualone, dichloralphenazone and their pharmaceutically acceptable salts
  • skeletal muscle relaxants e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, orphrenadine and their pharmaceutically acceptable salts,
  • NMDA receptor antagonists e.g. dextromethorphan ((+)-3-hydroxy-N- methylmorphinan) and its metabolite dextrorphan ((+)-3-hydroxy-N- methylmorphinan), ketamine, memantine, pyrroloquinoline quinone and cis-4-
  • tricyclic antidepressants e.g. desipramine, imipramine, amytriptiline and nortriptiline;
  • anticonvulsants e.g. carbamazepine and valproate
  • Tachykinin (NK) antagonists particularly Nk-3, NK-2 and NK-1 e.g. antagonists, ( ⁇ R,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9, 10,1 1 -tetrahydro-9- Jlnaphthridine-e-I S-dione (TAK-637), 5-[[(2R,3S)-2-[(1 R)-1 -[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4- fluorophenyl)-4-morpholinyl]methyl]-1 ,2-dihydro-3H-1 ,2,4-triazol-3-one (MK-869), lanepitant, dapitant and 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]methylamino]- 2-phenyl-piperidine (2S.3S)
  • Muscarinic antagonists e.g oxybutin, tolterodine, propiverine, tropsium chloride and darifenacin;
  • Non-selective COX inhibitors e.g. nitroflurbiprofen (HCT-1026);
  • Beta-adrenergic compounds such as propranolol
  • the compounds of the invention may be usefully combined with one or more agents for reducing the risk of a cardiovascular disorder including anti-inflammatory agents, such as alclofenac, algestone acetonide, alpha amylase, amcinafal, amcinafide, amfenac sodium, amiprilose hydrochloride, anakinra, anirolac, apazone, balsalazide disodium, bendazac, benoxaprofen, benzydamine hydrochloride, bromelains, broperamole, budesonide, carprofen, cicloprofen, cintazone, cliprofen, clobetasol propionate, clobetasone butyrate, clopirac, cloticasone propionate, cortodoxone, deflazacort, desonide, desoximetasone, dexamethasone dipropionate, diclofenac potassium, diclofenac sodium, diflumidone sodium, diflu
  • the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0.5 to about 75 ⁇ M, preferably, about 1 to 50 ⁇ M, most preferably, about 0.1 to about 5 ⁇ M. This may be achieved, for example, by the intravenous injection of a 0.05 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 10-500 mg of the active ingredient. Desirable blood levels may be maintained by multiple oral dosing, or continuous infusion to provide about 0.01-5.0 mg/kg/hr or by intermittent infusions containing about 0.4-15 mg/kg of the active ingredient(s).
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
  • a stable tetracycline-inducible TREx-293 cell line is generated expressing recombinant mouse ⁇ 1 H.
  • mouse ⁇ 1 H T-type calcium channel cDNA accession number NM_021415
  • cloning techniques e.g. Molecular Cloning Techniques
  • Cells are maintained at 37° C and 5% CO 2 in Dulbecco's Modified Eagle Media supplemented with 10% fetal bovine serum, 200 ⁇ g/mL Zeocin, and 5 ⁇ g/mL Blasticidin.
  • CeIIs are induced with 1 ⁇ g/mL tetracycline and plated onto black-sided 384 well PoIy-D Lysine coated plates at 12,000 cells/well for at least twenty-four hours.
  • the cells are incubated with the fluorescent Ca 2+ indicator Fluo-4 AM (50 ⁇ g, Molecular Devices, Sunnyvale, CA) dissolved in pluronic acid and DMEM supplemented with 2.6 mM probenecid for 1 hour at 37°C and 5% CO 2 .
  • Fluo-4 AM 50 ⁇ g, Molecular Devices, Sunnyvale, CA
  • Cells are then rinsed with assay buffer (consisting of 0.34 mM Na 2 HPO 4 , 4.2 mM NaHCO 3 , 0.44 mM KH 2 PO 4 , 0.41 mM MgSO 4 , 0.49 mM MgCI 2 , 20 mM HEPES, 5.5 mM d-Glucose, 0.1% BSA, 137 mM NaCI, and 2.6 mM probenecid) and incubated at 37 0 C and 5% CO 2 for 10 minutes. Cells are pretreated with putative antagonists for 5 minutes followed by a rapid increase of 4.8 mM extracellular Ca 2+ .
  • assay buffer consisting of 0.34 mM Na 2 HPO 4 , 4.2 mM NaHCO 3 , 0.44 mM KH 2 PO 4 , 0.41 mM MgSO 4 , 0.49 mM MgCI 2 , 20 mM HEPES, 5.5 mM d-Glucose, 0.1%
  • FLIPR fluorometric imaging plate reader
  • FLIPR fluorometric imaging plate reader
  • the basic principal involves illumination of 384-well microplate with the simultaneous measurement of emitted fluorescence using a CCD camera.
  • the cell plate wells contain cells that have been loaded with a fluorescent dye, whose emission characteristics change upon binding with a particular ion (Ca 2+ in this case).
  • Ca 2+ a particular ion
  • the growth media for A10 cells is Ham's F12/DME high glucose (Irvine Scientific, 9052), supplemented with 20% fetal bovine serum (HyClone Labs, SH30071.02), and 1% each of L-glutamine (Gibco BRL, 25030-032) and antibiotic-antimycotic (Gibco BRL, 15240-096).
  • Cells are grown to confluency and replated on black-sided 384-well plates (Falcon, 35 3962) at 12K cells/well for use in FLIPR. Forty-eight hours after replating, growth media is removed and cells are loaded at 37 0 C with 50 ⁇ l media containing 1 ⁇ M Fluo-4 dye (Molecular Probes, F-14201) for 1 hour. The dye-containing media Is then washed away six times with buffer (composition in mM: 1.25 CaCI 2 , 1.2 MgSO 4 , 11 glucose, 10 HEPES, 3.0 KCI, 137.0 NaCI, pH 7.4 with Tris base) in an Embla384 (Molecular Devices, 0200-3906). The residual buffer volume is adjusted to 20 ⁇ l and allowed to incubate at room temp for an additional hour.
  • FLIPR protocol A five minute drug-pre-incubation period at is initiated when 20 ⁇ l of drug-containing buffer is pipetted into the cell plate with the 384-well pipettor integrated in the FLIPR apparatus. Fluorescent counts are monitored at two second intervals for 960 seconds, beginning 60 seconds prior to the delivery of drug-containing buffer. Following drug addition, 20 ⁇ l aliquots of a high K+, depolarizing stimulus (composition in mM: 1.25 CaCI 2 , 1.2 MgSO 4 , 11 glucose, 10 HEPES, 140.0 KCI, pH 7.4 with Tris base) are added to each well and fluorescence is monitored at one second intervals for 120 secibds, beginning ten seconds prior to the stimulus addition. CCD camera exposure time is 0.4 seconds, laser excitation is at 488 nm with a power of 0.6W, and a 510 to 560nm bandpass interference filter preceded the camera.
  • Data are analyzed as a summation of fluorescent counts above basal during the stimulation period (an approximation of area under the curve), after normalizing the data with a spatial uniformity correction (for variations in laser illumination and cell density), a negative control correction and a bias subtraction (a bias subtraction subtracts the fluorescence value measured at a specific sample point from all the other time points in each well and allows for all data on the y-axis to be zeroed).
  • Drug effects are expressed as percent inhibition of fluorescence from an average of 8 K+-stimulated wells that were pre-treated in the drug incubation period with buffer only. Data are analyzed using FLIPR software, Microsoft Excel and Origin. The IC50 calculations are performed and graphed in Origin.
  • SHR Spontaneously hypertensive rats
  • Blood draws via Accusampler were done at 0.5, 1 , 2, 4, 7 and 20 hours post dose of compound and the plasma is tested for plasma exposure levels of the compound via mass spectrophotometry (PDM). After 48 hours post dose of compound, the rats were terminated.
  • animals were grouped by compound treatments and analyzed via the use of semi-automated Excel macros for data analysis efficiency. For each animal and parameter mean blood pressure, systolic blood pressure, diasystolic blood pressure and heart rate (MBP, SBP 1 DBP, and HR), values representing the median of fifteen one-minute values were calculated and plotted over a period of 20 hours post dose. Fifteen minutes prior to treatment, one 15-minute median value is calculated and designated as Time 0. The last 4 hours of the original data set were not utilized, as this is the period of time designated for animal husbandry. Group means and SEMs were calculated at each of these 15-minute time points and also plotted over the 20-hour post dose period.
  • BP blood pressure
  • a pneumatic transducer and a pressure transducer connected to an animal monitoring system. Temperature was measured with the rectal fluoroptic thermometer and maintained at 36 ⁇ 1o C.
  • a previous MRI technique was modified for the present studies. [15] Briefly, MRI was performed using a 7 Tesla Bruker MRI system. A 72 mm volume coil (Bruker Biospin, Billerica, MA) was used for RF excitation and reception. Preliminary experiments were performed on phantoms in order to optimize the sequence for T2 measurement. A vial with water titrated with Magnevist® to a known T2 (served as an imaging phantom) was placed between the hind paws.
  • a multi-slice spin-echo sequence was used to obtain axial multi-echo images to generate the T2 maps of the upper hindleg region.
  • Each T2 map acquisition took approximately 11 minutes.
  • Arterial blood pressure was allowed to stabilize for 30 minutes. The experiment was aborted if the predrug control blood pressure was less than 130 mm Hg.
  • Half of the drug dose was delivered as a bolus over 30 seconds, immediately followed by infusion of the other half of the dose over 60 minutes using a syringe infusion pump.
  • Two T2 scans, 10 minutes apart, were acquired, one at 30-40 minutes and the other at 50-60 minutes after the start of the infusion.
  • amLodipine an additional scan was done 50-80 minutes after the start of infusion.
  • T2 maps were calculated by monoexponential fitting of multi-echo images using the minimum mean squared error (MMSE) estimator. Percent increase in T2 during drug treatment was calculated voxel-by-voxel. To limit the number of false positives, all increases in T2 of less than 10% were set to zero.
  • Regions of interest (ROI) were drawn on the muscle tissue on the anatomical images using the tibial bone plateau as a fiducial mark.
  • the number of non-zero voxels (N) and the average change in T2 ( ⁇ T2) over these voxels in the ROI was calculated.
  • the percent increase in muscle volume was calculated from the pre-drug and post-drug scans.
  • Mean arterial blood pressure (“MABP") was measured at the time of the MRI scans.

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Abstract

L'invention concerne un composé de formule (I) (I) ou un promédicament du composé ou un sel pharmaceutiquement acceptable du composé ou du promédicament, les substituants étant tels que définis dans la description. L'invention concerne également des compositions pharmaceutiques contenant les composés utiles en tant qu'antagonistes des canaux calciques et des procédés de traitement de maladies cardiaques et de la douleur.
PCT/IB2008/002825 2007-10-31 2008-10-20 Dérivés de 1,4-dihydronaphtyridine WO2009056934A1 (fr)

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Cited By (10)

* Cited by examiner, † Cited by third party
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WO2012146067A1 (fr) 2011-04-29 2012-11-01 山东亨利医药科技有限责任公司 Dérivés de 1,4-dihydropyridine-3,5-dicarboxylate, procédés de préparation et utilisations
CN103214434A (zh) * 2013-05-14 2013-07-24 张家港威胜生物医药有限公司 1-二苯甲基-4-(2-羟乙基)哌嗪合成工艺的改进方法
WO2017070680A1 (fr) 2015-10-22 2017-04-27 Cavion Llc Procédés pour traiter le syndrome d'angelman et des troubles associés
WO2019223629A1 (fr) * 2018-05-22 2019-11-28 广东东阳光药业有限公司 Composé de dihydronaphtyridine substitué par phényle et son utilisation
US11130750B2 (en) 2017-02-15 2021-09-28 Cavion, Inc. Calcium channel inhibitors
CN113549066A (zh) * 2020-04-24 2021-10-26 广东东阳光药业有限公司 二氢萘啶类化合物的晶型及其用途
US11311522B1 (en) 2018-10-03 2022-04-26 Cavion, Inc. Treating essential tremor using (R)-2-(4-Isopropylphenyl)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetamide
US11324733B2 (en) 2017-04-26 2022-05-10 Cavion, Inc. Methods for improving memory and cognition and for treating memory and cognitive disorders
US11427540B2 (en) 2019-07-11 2022-08-30 Praxis Precision Medicines, Inc. Formulations of T-type calcium channel modulators and methods of use thereof

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Cited By (19)

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WO2012146067A1 (fr) 2011-04-29 2012-11-01 山东亨利医药科技有限责任公司 Dérivés de 1,4-dihydropyridine-3,5-dicarboxylate, procédés de préparation et utilisations
US9198902B2 (en) 2011-04-29 2015-12-01 Xuanzhu Pharma Co., Ltd. 1,4-dihydropyridine-3,5-dicarboxylate derivatives and preparation and use thereof
CN102416013A (zh) * 2011-12-30 2012-04-18 湖南九典制药有限公司 西尼地平的新用途
CN103214434A (zh) * 2013-05-14 2013-07-24 张家港威胜生物医药有限公司 1-二苯甲基-4-(2-羟乙基)哌嗪合成工艺的改进方法
WO2017070680A1 (fr) 2015-10-22 2017-04-27 Cavion Llc Procédés pour traiter le syndrome d'angelman et des troubles associés
EP3364993A4 (fr) * 2015-10-22 2019-08-28 Cavion, Inc. Procédés pour traiter le syndrome d'angelman et des troubles associés
AU2016341429B2 (en) * 2015-10-22 2023-09-21 Cavion, Inc. Methods for treating Angelman Syndrome and related disorders
US11273218B2 (en) 2015-10-22 2022-03-15 Cavion, Inc. Methods for treating Angelman syndrome and related disorders
US11130750B2 (en) 2017-02-15 2021-09-28 Cavion, Inc. Calcium channel inhibitors
US11324733B2 (en) 2017-04-26 2022-05-10 Cavion, Inc. Methods for improving memory and cognition and for treating memory and cognitive disorders
CN110511219A (zh) * 2018-05-22 2019-11-29 广东东阳光药业有限公司 苯基取代的二氢萘啶类化合物及其用途
CN110511219B (zh) * 2018-05-22 2022-06-03 年衍药业(珠海)有限公司 苯基取代的二氢萘啶类化合物及其用途
WO2019223629A1 (fr) * 2018-05-22 2019-11-28 广东东阳光药业有限公司 Composé de dihydronaphtyridine substitué par phényle et son utilisation
US11311522B1 (en) 2018-10-03 2022-04-26 Cavion, Inc. Treating essential tremor using (R)-2-(4-Isopropylphenyl)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetamide
US11427540B2 (en) 2019-07-11 2022-08-30 Praxis Precision Medicines, Inc. Formulations of T-type calcium channel modulators and methods of use thereof
US11649207B2 (en) 2019-07-11 2023-05-16 Praxis Precision Medicines, Inc. Formulations of T-type calcium channel modulators and methods of use thereof
CN113549066A (zh) * 2020-04-24 2021-10-26 广东东阳光药业有限公司 二氢萘啶类化合物的晶型及其用途
WO2021213486A1 (fr) * 2020-04-24 2021-10-28 东莞市东阳光新药研发有限公司 Forme cristalline de composé de dihydronaphtyridine et son utilisation
CN113549066B (zh) * 2020-04-24 2023-07-21 年衍药业(珠海)有限公司 二氢萘啶类化合物的晶型及其用途

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