WO2011060036A1 - Composés bicycliques et leurs méthodes d'utilisation - Google Patents

Composés bicycliques et leurs méthodes d'utilisation Download PDF

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WO2011060036A1
WO2011060036A1 PCT/US2010/056181 US2010056181W WO2011060036A1 WO 2011060036 A1 WO2011060036 A1 WO 2011060036A1 US 2010056181 W US2010056181 W US 2010056181W WO 2011060036 A1 WO2011060036 A1 WO 2011060036A1
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treating
compounds
list
inhibitor
useful
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PCT/US2010/056181
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English (en)
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Xianhai Huang
Anandan Palani
Robert G. Aslanian
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Schering Corporation
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine

Definitions

  • the present invention relates to certain bicyclic compounds, compositions comprising such bicyclic compounds and methods for using the bicyclic compounds for treating or preventing a metabolic disorder, dyslipidemia, a cardiovascular disease, a neurological disorder, a hematological disease, cancer, inflammation, a respiratory disease, a gastroenterological disease, diabetes, a diabetic complicaton, obesity, an obesity-related disorder or non-alcoholic fatty liver disease.
  • Niacin commonly known as nicotinic acid, plays an important role in the production of several sex and stress-related hormones, particularly those made by the adrenal gland. It also plays a role in removing toxic and harmful chemicals from the body.
  • nicotinic acid When taken in large doses, nicotinic acid increases the level of high density lipoprotein (HDL) in blood, and is sometimes prescribed for patients with low HDL, and at high risk of heart attack. Nicotinic acid is also used in the treatment of
  • VLDL very low density lipoprotein
  • LDL low density lipoprotein
  • Nicotinic acid has also been used to treat metabolic syndrome, but there are problems with the clinical use of nicotinic acid, including skin flushing and diarrhea, even with moderate doses.
  • heterocyclic compounds as nicotinic acid receptor agonists is known in the art and such compounds are disclosed, for example, in M. Ridi, Gazzetta Chim. Ital. (1950) vol. 80, p. 121 and M. Ridi, Gazzetta Chim. itai. (1952) vol. 82, p. 23, which disclosse syntheses of barbituric acid derivatives useful as nicotinic acid receptor (NAR) agonists .
  • FR 2563223 discloses nucleoside analogs. T. Paterson et al., J. Chem. Soc, Perkins Trans. I (1972), vol. 8, pp.
  • Heterocyclic Chem. (1999), 36(1), pp. 225-235 discloses the synthesis of pyran-2- ones.
  • International Publication No. WO 04/1 10368 describes combination therapies for the treatment of hypertension comprising the combination of an anti-obesity agent and an anti-hypertensive agent.
  • WO 04/1 0375 describes combination therapies for the treatment of diabetes comprising the administration of a combination of an anti- obesity agent and an anti-diabetic agent.
  • U.S. Patent Publication No, 2004/0122033 describes combination therapies for the treatment of obesity comprising the administration of a combination of an appetite suppressant and/or metabolic rate enhancers and/or nutrient absorption inhibitors.
  • U.S. Patent Publication No. 2004/0229844 describes combination therapies for treating atherosclerosis comprising the administration of a combination of nicotinic acid or another nicotinic acid receptor agonist and a DP receptor antagonist
  • WO05/077950 describes xanthine derivatives which are agonists of the nicotinic acid receptor HM74A.
  • the present invention provides Compounds shown below in List
  • the compounds of List 1 are useful for treating or preventing a metabolic disorder, dyslipidemia, a cardiovascular disease, a neurological disorder, a
  • hematological disease cancer, inflammation, a respiratory disease, a
  • gastroenterological disease diabetes, a diabetic complicaton, obesity, an obesity-related disorder or non-alcoholic fatty liver disease (each being a "Condition") in a patient.
  • the invention provides methods for treating a Condition in a patient, comprising administering to the patient an effective amount of one or more compounds of List 1.
  • compositions comprising an effective amount of one or more compounds of List 1 and a pharmaceutically acceptable carrier.
  • a "patient” is a human or non-human mammal.
  • a patient is a human, in another embodiment, a patient is a non-human mammal, including, but not limited to, a monkey, dog, baboon, rhesus, mouse, rat, horse, cat or rabbit.
  • a patient is a companion animal, including but not limited to a dog, cat, rabbit, horse or ferret.
  • a patient is a dog.
  • a patient is a cat.
  • impaired glucose tolerance is defined as a two-hour glucose level of 140 to 199 mg per dL (7.8 to 11.0 mmol) as measured using the 75-g oral glucose tolerance test. A patient is said to be under the condition of impaired glucose tolerance when he/she has an intermediately raised glucose level after 2 hours, wherein the level is less than would qualify for type 2 diabetes mellitus.
  • paired fasting glucose is defined as a fasting plasma glucose level of 100 to 125 mg/dL; normal fasting glucose values are below lOO mg per dL.
  • an obese patient refers to a patient being overweight and having a body mass index (BMI) of 25 or greater, in one embodiment, an obese patient has a BMI of 25 or greater. In another embodiment, an obese patient has a B I from 25 to 30. In another embodiment, an obese patient has a BMI greater than 30. In still another embodiment, an obese patient has a BMI greater than 40.
  • BMI body mass index
  • obesity-related disorder refers to: (i) disorders which result from a patient having a BMI of 25 or greater; and (ii) eating disorders and other disorders associated with excessive food intake.
  • Non-limiting examples of an obesity- related disorder include edema, shortness of breath, sleep apnea, skin disorders and high blood pressure.
  • metabolic syndrome refers to a set of risk factors that make a patient more succeptib!e to cardiovascular disease and/or type 2 diabetes.
  • a patient is said to have metabolic syndrome if the patient simultaneously has three or more of the following five risk factors: 1) centrai/abdominal obesity as measured by a waist circumference of greater than 40 inches in a maie and greater than 35 inches in a femaie;
  • an effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount.
  • alkyi refers to an aliphatic hydrocarbon group which may be straight or branched and which contains from about 1 to about 20 carbon atoms. In one embodiment, an alkyi group contains from about 1 to about 12 carbon atoms. In another embodiment, an alkyi group contains from about 1 to about 6 carbon atoms.
  • Non-limiting examples of alkyi groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyf, n-pentyl, neopentyi, isopenty!, n-hexyl, isohexyl and neohexyl.
  • An a!kyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyi, aryl, cycloalkyl, -CN, - OH, -O-alkyi, -O-ary!, -alkylene-O-alkyl, alkylthio, -NH 2 , -NH(aikyl), -N(alkyl) 2 , - NH(cycloalkyl), -0-C(O)-alkyi, -O-C(0)-aryi, -O-C(O)-cycloalkyl, -C(O)OH and - C(0)0-alkyl.
  • an alkyi group is unsubstituted.
  • an alkyi group is linear, in another embodiment, an alkyi group is branched.
  • alkenyl refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and contains from about 2 to about 5 carbon atoms. In one embodiment, an alkenyl group contains from about 2 to about 12 carbon atoms. In another embodiment, an alkenyl group contains from about 2 to about 6 carbon atoms.
  • Non- limiting examples of alkenyl groups include ethenyl, propenyl, n-buteny!, 3-methylbut- 2-enyl, n-pentenyl, octenyl and decenyl.
  • An alkenyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independentiy selected from the group consisting of halo, alkyl, aryl, cycloalkyl, -CN, -O-alky! and -S(alkyl). In one embodiment, an alkenyl group is unsubstituted.
  • aikynyl refers to an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and contains from about 2 to about 15 carbon atoms. In one embodiment, an aikynyl group contains from about 2 to about 12 carbon atoms. In another embodiment, an aikynyl group contains from about 2 to about 6 carbon atoms.
  • Non- limiting examples of aikynyl groups include ethynyl, propynyl, 2-butynyl and 3- methylbutynyi.
  • An aikynyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being
  • an aikynyl group is unsubstituted.
  • alkylene refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a bond.
  • alkylene groups include - €3 ⁇ 4-, -CH2CH2-, - CH 2 CH 2 CH 2 -, -CH2CH2CH2CH2-, -CH(CH 3 )CH 2 CH 2 - and -CH 2 CH(CH 3 )CH 2 -.
  • an alkylene group has from 1 to about 6 carbon atoms.
  • an alkylene group is branched.
  • an alkylene group is linear.
  • Aryl means an aromatic monocyclic or multicyclic ring system comprising from about 6 to about 14 carbon atoms, in one embodiment, an aryl group contains from about 6 to about 10 carbon atoms.
  • An aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below.
  • Non-limiting examples of aryl groups include phenyl and naphthyl. In one embodiment, an aryl group is unsubstituted. In another embodiment, an aryl group is phenyl.
  • cycloalkyl refers to a non-aromatic mono- or muiticyclic ring system comprising from about 3 to about 10 ring carbon atoms, in one embodiment, a cycloalkyl contains from about 3 to about 7 ring carbon atoms, in another embodiment, a cycioaikyi contains from about 5 to about 7 ring atoms.
  • monocyclic cycloalkyls include cyciopropyl, cyclobutyl,
  • cyclopentyl cyclohexyl, cycloheptyl and cyclooctyl.
  • muiticyclic cycloalkyls include -decalinyl, norbornyl and adamantyl.
  • a cycloalkyl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below.
  • a cycloalkyl group may also have one of its ring carbon atoms substituted as a carbonyl group to form a cycloalkanoyl group (such as cyclobutanoyl, cyclopentanoyl, cyclohexanoyl, etc.).
  • a cycloalkyl group is unsubstituted.
  • heteroaryl refers to an aromatic monocyclic or muiticyclic ring system comprising about 5 to about 14 ring atoms, wherein from 1 to 4 of the ring atoms is independently O, N or S and the remaining ring atoms are carbon atoms.
  • a heteroaryl group has 5 to 10 ring atoms.
  • a heteroaryl group is monocyclic and has 5 or 6 ring atoms.
  • heteroaryl group can be optionally substituted by one or more "ring system
  • a heteroaryl group is joined via a ring carbon atom, and any nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide.
  • heteroaryl also encompasses a heteroaryl group, as defined above, which has been fused to a benzene ring.
  • Non-limiting examples of heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridonyl (including N-substituted pyridones), isoxazolyi, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl, 1 ,2,4- thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1 ,2- ajpyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindoiyi, benzimi
  • heteroaryl also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.
  • a heteroaryl group is unsubstituted.
  • a heteroaryl group is a 5-membered heteroaryl.
  • a heteroaryl group is a 6-membered heteroaryl.
  • heterocycloaikyi refers to a non-aromatic saturated monocyclic or multicyciic ring system comprising 3 to about 10 ring atoms, wherein from 1 to 4 of the ring atoms are independently O, S or N and the remainder of the ring atoms are carbon atoms.
  • a heterocycloaikyi group can be joined via a ring carbon or ring nitrogen atom.
  • a heterocycloaikyi group has from about 5 to about 10 ring atoms.
  • a heterocycloaikyi group has 5 or 6 ring atoms. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Any -NH group in a heterocycloaikyi ring may exist protected such as, for example, as an -N(BOC), -N ⁇ Cbz), -N(Tos) group and the like; such protected heterocycloaikyi groups are considered part of this invention.
  • a heterocycloaikyi group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below.
  • the nitrogen or sulfur atom of the heterocycloaikyi can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • Non-limiting examples of monocyclic heterocycloaikyi rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyi, oxetanyl, thiomorpholinyl, thiazoiidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyi, lactam, lactone, and the like.
  • a ring carbon atom of a heterocycloaikyi group may be functionalized as a carbonyl group.
  • An illustrative example of such a heterocycloaikyi group is pyrroiidonyl:
  • a heterocycloaikyi group is unsubstituted. In another embodiment, a heterocycloaikyi group is a 5-membered heterocycloaikyi. In another embodiment, a heterocycloaikyi group is a 6-membered heterocycloaikyi.
  • Ring system substituent refers to a substituent group attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system.
  • Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkyl-aryi, -aryl-alkyl, -alkylene-heteroaryl, - a!kenylene-heteroaryl, -alkynylene-heteroaryi, -OH, hydroxyaikyi, haioalkyl, -O-aikyl, - alkylene-O-alkyl, -O-aryl, -O-alkylene-aryl, acyl, aroyl, halo, nitro, -CN, -C(O)OH, - C(O)O-alkyi, -C(
  • Ring system substituenf may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system.
  • Examples of such moiety are methylenedioxy, ethylenedioxy, -C(CH 3 ) 2 - and the like which form moieties such as, for example:
  • Halo means -F, -CI, -Br or -I. In one embodiment, halo refers to -CI or -Br.
  • haioalkyl refers to an alkyl group as defined above, wherein one or more of the aikyl group's hydrogen atoms has been replaced with a halogen. In one embodiment, a haioalkyl group has from 1 to 6 carbon atoms. In another embodiment, a haioalkyl group is substituted with from 1 to 3 F atoms. Non- limiting examples of haioalkyl groups include --CH2F, -CHF 2 , -CF 3 , -CH 2 Ci and -CCI 3 .
  • hydroxyalkyl refers to an alky!
  • a hydroxyalkyl group has from 1 to 6 carbon atoms.
  • Non-limiting examples of hydroxyalkyl groups include -CH 2 OH, -CH 2 CH 2 OH, - CH 2 CH 2 CH 2 OH and -CH 2 CH(OH)CH 3 .
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • purified refers to the physical state of the compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof.
  • purified refers to the physical state of the compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like) , in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
  • protecting groups When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York.
  • any variable e.g., R 1 , R 2 , etc..
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • prodrugs means a compound (e.g, a drug precursor) that is transformed in vivo to yield a compound of List 1 or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood.
  • prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Ci-C 8 )alkyl, (C 2 - Ci 2 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 - methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,
  • alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyi having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyi having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4- crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N ⁇ (Ci-C 2 )alkylamino(C2-C 3 )alkyl (such as ⁇ -dimethylaminoethyi), carbamoyI-(Ci-C 2 )alkyl, ⁇ , ⁇ -di (Ci-C 2 )alkylcarbamoyl-(Ci- C 2 )
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (Ci-Cejalkanoyloxymethyl, 1-((Ci ⁇
  • a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (CrCio)alkyl, (C3-C7) cycloalkyi, benzyl, or R-carbonyl is a natural a-aminoacyl,— C(OH)C(0)OY 1 wherein Y 1 is H, (Ci-C 6 )alkyi or benzyl,— C(OY 2 )Y 3 wherein Y 2 is (C1-C4) alkyl and Y 3 is ⁇ C C 6 )aikyl, -C(0)0-(Ci-C e )alkyl, amino(C
  • One or more compounds of the invention may exist in unsolvated as well as soivated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both soivated and unsolvated forms.
  • “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H 2 O.
  • One or more compounds of the invention may optionally be converted to a solvate.
  • Preparation of solvates is generally known.
  • M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-61 1 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar
  • a typical, non-!imiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
  • Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
  • the compounds of List lean form salts which are also within the scope of this invention.
  • Reference to a compound of List 1 herein is understood to include reference to salts thereof, unless otherwise indicated.
  • the term "salt(s)" denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • zwitterions inner salts may be formed and are included within the term "salt(s)" as used herein.
  • the salt is a pharmaceutically acceptable (i.e., nontoxic, physiologically acceptable) salt.
  • the salt is other than a pharmaceutically acceptable salt. Salts of the compounds of the Formula I or II may be formed, for example, by reacting a compound of List 1 with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophiiization.
  • Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates,
  • camphorsulfonates fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates,
  • toluenesulfonates also known as tosylates,
  • acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et at, Cami!le G. (eds.) Handbook of Pharmaceutical Salts, Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson ef al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexyiamine, choline, t-butyl amine, and salts with amino acids such as arginine, lysine and the like.
  • Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialky! sulfates (e.g.
  • dimethyl, diethyl, and dibutyl sulfates dimethyl, diethyl, and dibutyl sulfates
  • long chain halides e.g. decyl, lauryl, and stearyi chlorides, bromides and iodides
  • aralkyl halides e.g. benzyl and phenethyl bromides
  • esters of the present compounds include the following groups: (1) carboxyiic acid esters obtained by esterification of the hydroxy group of a hydroxy! compound, in which the non-carbonyi moiety of the carboxyiic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, methyl, ethyl, n-propyl, isopropyl, t-butyl, sec-butyl or n-butyl), a!koxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halo, C 1-4 aikyl, or Ci -4 alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3)
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active
  • Sterochemically pure compounds may also be prepared by using chiral starting materials or by employing salt resolution techniques. Also, some of the compounds of List 1 may be
  • Atropisomers e.g., substituted biaryls
  • Enantiomers can also be separated by use of chiral HPLC column.
  • All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds including those of the salts, solvates, hydrates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4- pyridyl and 3-pyridyl).
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • the chiral centers of the present invention can have the S or configuration as defined by the lUPAC 1974 Recommendations.
  • the use of the terms "salt”, “solvate”, “ester”, “prodrug” and the like, is intended to apply equally to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
  • the present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 13 C, C, 5 N, 18 O, 17 0, 31 P, 32 P, 35 S, 8 F, and 36 CI, respectively.
  • Certain isotopically-labelled Compounds of Formulas (I) and (II) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Isotopically labelled compounds of List 1 can generally be prepared using synthetic chemical procedures analogous to those disclosed herein for making the compounds of List 1, by substituting an appropriate isotopically labelled starting material or reagent for a non-isotopically labelled starting material or reagent.
  • Polymorphic forms of the compounds of List 1, and of the salts, solvates, hydrates, esters and prodrugs of the compounds of List 1 are intended to be included in the present invention.
  • n-Bu is n-butyi
  • CDI is 1 ,1'-carbonyldiimidazole
  • dba is dibenzylideneacetone
  • D F is /V,A/ -dimethylformamide
  • DMSO is dimethylsulfoxide
  • EtOAc is ethyl acetate
  • EtOH is ethanol
  • HOAc is acetic acid
  • HPLC high performance liquid chromatography
  • Me is methyl
  • NiS is N-iodosuccinimide
  • PBS is phosphate-buffered saline
  • Ph is phenyl
  • PPh 3 is triphenylphoshpine
  • TFAA is trifluoroacetic acid.
  • the mixture of the ketoester (0.55g, 3 mmol) and 4-aminonitricacid methyl ester (0.47g, 3 mmoi) was heated to 150 °C for 2 hours.
  • Oxylyldiimidazole (0.141 g) was added to a solution of compound 28 (0.136 g) in benzene (3.0 mL) at room temperature. The mixture was heated at reflux for 2 hours. The reaction was cooled and diluted with EtOAc and HCI (0.5 M). Organic phase was washes with water, brine, dried (MgS0 4 ). Solvent was removed under reduced pressure and the residue was purified with Gilson reverse phase HPLC to give compound 46 and 47. .
  • the ketoester and aniline were mixed in a 1 :1 mole ratio and heated in a seal tube at 150°C over night.
  • the reaction mixture was cooled to room temperature and purified by prep-TLC and eluted with mixture of MeOH:DCM 1 :10; to give the desired product.
  • the cyanide compound was dissolved in 1 ,4-dioxane and water (1 :1) and treated with KOH (4 eq). The reaction mixture was heated to reflux. The mixture was cooled to room temperature and the aqueous layer was acidified with 1 HCI (aq), and the precipitation was collected to give the desired product.
  • the cyanide compound was dissolved in ethylene glycol and water (1 :1) and treated with KOH (4 eq). The resulting solution was heated at 50°C overnight. The mixture was cooled to room temperature and the aqueous layer was acidified with HCI (1 N, aq). The precipitation was collected to give the desired product.
  • the starting material (500 mg, 2.16 mmol) was dissolved in AC2O (2 ml_) and HOAc (2 mL). The mixture was cool with ice bath and fuming HN0 3 (0.15 mi_) was added. The resulting mixture was stirred at room temperature for 1 h. The volatile was removed. The residue was taken up with methanol, and filtered. The filtrate was concentrated and purified over silica gel column, eluted with MeOH:DCM (1 :40), to give 74A (371 mg, 25%), 74 (220 mg, 25%).
  • Step b
  • Step e To a solution of 68a (0.028g, 0.12mmol) in 3mi of 1 , 4-dioxane/H 2 0 (2:1) was added Na 3 (0.024g, 0.36mmoi) and ZnBr 2 (0.033g, 0.15mrnol). The mixture was heated at 120 °C in a sealed tube for 48h, and then extracted with CH2CI2 and 0.5N HCI, washed with H2O and brine, dried over Na 2 S0 4) filtered. The filtrate was concentrated and purified by reversal phase HPLC to give 0.012g of 68, yield: 36%. PREPARATIVE EXAMPLE 86-87
  • Step f
  • Step g
  • step a The same procedure as step a to give 97, yield: 30%; 98, yield: 3.7%; 99, yield: 3.9%; and 101, yield: 2%.
  • step b The same procedure as step b to give 1 4, yield: 66%; 108, yield: 53%; 109, yield: 47%; 111, yield: 44%; 112, yield: 16%; and 110, yield: 63%.
  • Step j
  • Step k
  • Step nr To a suspension of picolinic acid (4.74g, 38.39mmo! in 20ml of dry DMF was added CD! (6.60g, 40.70mmol). After stirring at r.t. under N 2 for 2h, 170b in 5m! of dry DMF (6.60g, 40.70mmoi) was added, and the mixture was stirred at 100°C for 24h. The mixture was cooled to r.t., extracted with EtOAc and saturated NH 4 CI (aq.), washed with H 2 O (3x) and brine, dried over Na 2 S0 4 , filtered. The filtrate was concentrated to give 7.4g of 170c, yield: 77%.
  • the compounds described in Table 1 are all HM74 agonists except the three which are also HM74A agonists.
  • HM74 agonist activity of the inventive compounds can be determined by following the inhibition of forskolin-stimulated cAMP accumulation in cells using the MesoScaie Discovery cAMP detection kit following the manufacturer's protocol. Briefly, Chinese Hamster Ovary (CHO) ceils expressing recombinant human HM74 are harvested enzymatically, washed 1X in phosphate buffered saline (PBS) and resuspended in PBS containing 0.5 mM IBMX at 3x10 6 cells/mL. Ten ⁇ . of cell suspension is added to each well of a 384-well plate, each well containing 10 ⁇ !_ of test compound. Test compounds are diluted with PBS containing 6 ⁇ of forskolin.
  • PBS phosphate buffered saline
  • the compounds of List 1 are useful in human and veterinary medicine for treating or preventing a Condition in a patient.
  • the compounds of List 1 can be administered to a patient in need of treatment or prevention of a Condition.
  • the compounds of List 1 are useful for treating or preventing pain in a patient. Accordingly, in one embodiment, the present invention provides a method for treating or preventing pain in a patient, comprising administering to the patient an effective amount of one or more compounds of List 1.
  • pain treatable or preventable using the present methods include, but are not limited to acute pain, chronic pain, neuropathic pain, nociceptive pain, cutaneous pain, somatic pain, visceral pain, phantom limb pain, cancer pain (including breakthrough pain), pain caused by drug therapy (such as cancer chemotherapy), headache (including migraine, tension headache, cluster headache, pain caused by arithntis, pain caused by injury, toothache, or pain caused by a medical procedure (such as surgery, physical therapy or radiation therapy).
  • the pain is neuropathic pain.
  • the pain is cancer pain.
  • the pain is headache.
  • the compounds of List 1 are useful for treating or preventing diabetes in a patient. Accordingly, in one embodiment, the present invention provides a method for treating diabetes in a patient, comprising administering to the patient an effective amount of one or more compounds of List 1.
  • Examples of diabetes treatable or preventable using the compounds of List 1 include, but are not limted to, type I diabetes (insulin-dependent diabetes mellitus), type II diabetes (non-insulin dependent diabetes meliitus), gestational diabetes, autoimmune diabetes, insulinopathies, idiopathic type I diabetes (Type 1b), latent autoimmumne diabetes in adults, early-onset type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition- related diabetes, diabetes due to pancreatic disease, diabetes associated with other endocrine diseases (such as Cushing's Syndrome, acromegaly, pheochromocytoma, glucagonoma, primary aldosteronism or somatostatinoma), type A insulin resistance syndrome, type B insulin resistance syndrome, Hpatrophic diabetes, diabetes induced by ⁇ -ceil toxins, and diabetes induced by drug therapy (such as diabetes induced by antipsychotic agents).
  • type I diabetes
  • the diabetes is type I diabetes.
  • the diabetes is type II diabetes.
  • the compounds of List 1 are useful for treating or preventing a diabetic complication in a patient. Accordingly, in one embodiment, the present invention provides a method for treating a diabetic complication in a patient, comprising administering to the patient an effective amount of one or more compounds of List 1.
  • diabetic complications treatable or preventable using the present methods include, but are not limted to, diabetic cataract, glaucoma, retinopathy, aneuropathy (such as diabetic neuropathy, polyneuropathy, mononeuropathy, autonomic neuropathy, microaluminuria and progressive diabetic neuropathyl), nephropathy, gangrene of the feet, immune-complex vasculitis, systemic lupsus erythematosus (SLE), atherosclerotic coronary arterial disease, peripheral arterial disease, nonketotic hyperglycemic-hyperosmolar coma, foot ulcers, joint problems, a skin or mucous membrane complication (such as an infection, a shin spot, a candidal infection or necrobiosis lipoidica diabeticorumobesity), hyperlipidemia, hypertension, syndrome of insulin resistance, coronary artery disease, a fungal infection, a bacterial infection, and cardiomyopathy.
  • aneuropathy such as diabetic neuropathy
  • the compounds of List 1 are useful for treating or preventing impaired glucose tolerance in a patient.
  • the present invention provides a method for treating impaired glucose tolerance in a patient, comprising administering to the patient an effective amount of one or more compounds of List 1.
  • the compounds of List 1 are useful for treating or preventing impaired fasting glucose in a patient.
  • the present invention provides a method for treating impaired fasting glucose in a patient, comprising administering to the patient an effective amount of one or more compounds of List 1.
  • the compounds of List 1 are useful for treating or preventing obesity or an obesity-related disorder in a patient.
  • the present invention provides a method for treating obesity or an obesity-related disorder in a patient, comprising administering to the patient an effective amount of one or more compounds of List 1.
  • the compounds of List 1 are useful for treating or preventing a hematological disorder in a patient.
  • the present invention provides a method for treating a hematological disorder in a patient, comprising administering to the patient an effective amount of one or more compounds of List 1.
  • hematological disorders treatable or preventable using the present methods include, but are not limted to, an anemia caused by hemolysis, an anemia caused by deficient erythropoiesis, a coagulation disorder, an eosinophilic disorder, hemostasis, a histiocytic syndrome, neutropenia, lymphocytopenia, thrombocytopenia, a thrombic disorder, a platelet disorder or a clotting disorder.
  • the compounds of List 1 are useful for treating or preventing a neurological disorder in a patient. Accordingly, in one embodiment, the present invention provides a method for treating a neuroiogica! disorder in a patient, comprising administering to the patient an effective amount of one or more compounds of List 1.
  • neurological disorders treatable or preventable using the present methods include, but are not limted to, meningitis, a movement disorder (such as Parkinson's disease or Huntington's disease) , delirium, dementia, a demyelinating disorder (such as multiple sclerosis or amyotrophic lateral sclerosis), aphasia, a peripheral nervous system disorder, a seizure disorder, a sleep disorder, a spinal cord disorder or stroke.
  • the compounds of List 1 are useful for treating or preventing a cardiovascular disease in a patient.
  • the present invention provides a method for treating a cardiovascular disease in a patient, comprising administering to the patient an effective amount of one or more compounds of List 1.
  • cardiovascular diseases treatable or preventable using the present methods include, but are not limited to atherosclerosis, congestive heart failure, cardiac arrhythmia, myocardial infarction, atrial fibrillation f atrial flutter, circulatory shock, ieft ventricular hypertrophy, ventricular tachycardia, supraventricular tachycardia, coronary artery disease, angina, infective endocarditis, non-infective endocarditis, cardiomyopathy, peripheral artery disease, Reynaud's phenomenon, deep venous thrombosis, aortic stenosis, mitral stenosis, pulmonic stenosis and tricuspid stenosis.
  • the cardiovascular disease is atherosclerosis.
  • the cardiovascular disease is congestive heart failure, in another embodiment, the cardiovascular disease is coronary artery disease.
  • the compounds of List 1 are useful for treating or preventing a respiratory disorder in a patient.
  • the present invention provides a method for treating a respiratory disorder in a patient, comprising administering to the patient an effective amount of one or more compounds of List 1.
  • respiratory disorders treatable or preventable using the present methods include, but are not limted to, asthma, bronchiectasis, chronic obstructive pulmonary disease, an interstitial !ung disease, a mediastai disorder, a pleural disorder, pneumonia or sarcoidosis.
  • the compounds of List 1 are useful for treating or preventing a
  • the present invention provides a method for treating a gastroenterological disorder in a patient, comprising administering to the patient an effective amount of one or more compounds of List 1.
  • gastroenterological disorders treatable or preventable using the present methods include, but are not limted to, an anorectal disorder, diarrhea, irritable bowel syndrome, dyspepsis, gastroesophageal reflux disease, diverticulitis, gastritis, peptic ulcer disease, gastroenteritis, inflammatory bowel disease, a malabsorption syndrome or pancreatitis.
  • the compounds of List 1 are useful for treating or preventing inflammation in a patient.
  • the present invention provides a method for treating inflammation in a patient, comprising administering to the patient an effective amount of one or more compounds of List 1.
  • the compounds of List 1 are useful for treating or preventing non-aicoholic fatty liver disease in a patient.
  • the present invention provides a method for treating non-alcoholic fatty liver disease in a patient, comprising administering to the patient an effective amount of one or more compounds of List 1.
  • the compounds of List 1 are useful for treating or preventing dyslipidemia in a patient.
  • the present invention provides a method for treating dyslipidemia in a patient, comprising administering to the patient an effective amount of one or more compounds of List 1.
  • the compounds of List 1 can also be useful for treating a metabolic disorder.
  • metabolic disorders treatable include, but are not limited to, metabolic syndrome (also known as "Syndrome X"), impaired glucose tolerance, impaired fasting glucose, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, low HDL levels, hypertension, phenylketonuria, post-prandial lipidemia, a glycogen-storage disease, Gaucher's Disease, Tay-Sachs Disease, Niemann-Pick Disease, ketosis and acidosis.
  • the invention provides methods for treating a metabolic disorder in a patient, wherein the method comprises administering to the patient an effective amount of one or more compounds of List 1 , or a
  • the metabolic disorder is hypercholesterolemia
  • the metabolic disorder is hyperlipidemia.
  • the metabolic disorder is hypertriglyceridemia.
  • the metabolic disorder is metabolic syndrome.
  • the metabolic disorder is low HDL levels.
  • the compounds of List 1 are useful for treating or preventing cancer in a patient.
  • the present invention provides a method for treating cancer in a patient, comprising administering to the patient an effective amount of one or more compounds of List 1.
  • Non-iimiting examples of cancers treatable or preventable using the present methods include the following cancers and metastases thereof: bladder cancer, breast cancer, colorectal cancer, kidney cancer, liver cancer, non-smali ceil lung cancer, small cell lung cancer, non-small cell lung cancer, head and neck cancer, esophageal cancer, gall bladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, skin cancer; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, chronic
  • lymphocytic leukemia acute lymphoblastic leukemia, B-cell lymphoma, T- cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma, and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias,
  • tumors of mesenchymal origin including fibrosarcoma and rhabdomyosarcoma
  • tumors of the central and peripheral nervous system including brain tumors (such as an astrocytoma, a neuroblastoma, a glioma or a schwannoma); and other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.
  • the compounds of List 1 are useful for treating primary tumors, metastatic tumors and tumors of unknown origin.
  • the cancer treated is lung cancer.
  • the cancer treated is breast cancer.
  • the cancer treated is colorectal cancer.
  • the cancer treated is prostate cancer.
  • the cancer treated is a leukemia.
  • the cancer treated is a lymphoma.
  • the cancer treated is a metastatic tumor.
  • the compounds of List 1 can be useful in the following
  • Chemoprevention is defined as inhibiting the
  • the compounds of List 1 can be useful in inhibiting tumor angiogenesis and metastasis.
  • the present invention provides methods for treating a Condition in a patient, the method comprising administering to the patient one or more compounds of List 1 , or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof and at least one additional therapeutic agent that is not a compound of List 1 , wherein the amounts administered are together effective to treat or prevent a Condition.
  • Non-limiting examples of additional therapeutic agents useful in the present methods for treating or preventing a Condition include an anti-obesity agent, an antidiabetic agent, an agent useful for treating metabolic syndrome, an agent useful for treating a cardiovascular disease, an agent useful for treating
  • hypercholesterolemia an agent useful for treating dyslipidemia, a cholesterol biosynthesis inhibitor, a cholesterol absorption inhibitor, a bile acid sequestrant, a probucol derivatives, an I BAT inhibitor, a nicotinic acid derivative, a nicotinic acid receptor (NAR) agonist, an ACAT inhibitors, a cholesteryl ester transfer proten (CETP) inhibitor, a low-denisity lipoprotein (LDL) activator, or any combination of two or more of these additional therapeutic agents.
  • a cholesterol biosynthesis inhibitor a cholesterol absorption inhibitor
  • a bile acid sequestrant a probucol derivatives
  • I BAT inhibitor a nicotinic acid derivative
  • a nicotinic acid receptor (NAR) agonist an ACAT inhibitors
  • CETP cholesteryl ester transfer proten
  • LDL low-denisity lipoprotein
  • additional therapeutic agents useful in the present methods for treating or preventing a condition include hydroxy-substituted azetidinone compounds, substituted ⁇ -iactam compounds, a-amylase inhibitors, o glucoside hydrolase inhibitors, fatty acid oxidation inhibitors, A2 antagonists, c-jun amino-terminal kinase inhibitors, glycogen phosphorylase inhibitors, VPAC2 receptor agonists, giucokinase activators, nicotinic acid receptor antagonists, bile acid sequestrants, inorganic cholesterol sequestrants, AcyiCoA:Cholesteroi O- acyltransferase inhibitors, cholesteryl ester transfer protein inhibitors, fish oils containing Omega 3 fatty acids, natural water soluble fibers, plant stanols and/or fatty acid esters of plant stanols, anti-oxidants, FXR receptor modulators, LXR receptor agonists, lipoprotein synthesis
  • agonists/antagonists include leptin agonists/modulators, leptin derivatives, opioid antagonists, orexin receptor antagonists, BRS3 agonists, CCK-A agonists, CNTF, CNTF
  • phytopharm compound 57 ghrelin antibodies, c3r agonists, ACC inhibitors, ⁇ 3 agonists, DGAT1 inhibitors, DGAT2 inhibitors, FAS inhibitors, PDE inhibitors, thyroid hormone ⁇ agonists, UCP-1 activators, UCP-2 activators, UCP-3 activators, acyl- estrogens, glucocorticoid agonists/antagonists, lipase inhibitors, fatty acid transporter inhibitors, dicarboxylate transporter inhibitors, glucose transporter inhibitors, phosphate transporter inhibitorsanti-hypertensive agents, anti-dyslipidemic agents, DP receptor antagonists, apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, sympathomimetic agonists, dopamine agonists, melanocyte-stimulating hormone receptor analogs, leptons, galanin receptor antagonists, bombesin agonists, thyrom
  • Examples of antidiabetic agents useful in the present methods for treating or preventing a Condition include, but are not limited to: a sulfonylurea, an insulin sensitizer, a glucosidase inhibitor, an insulin secretagogue, a hepatic glucose output lowering agent, an anti-obesity agent, an antihypertensive agent, a meglitinide, an agent that slows or blocks the breakdown of starches and sugars in vivo, a histamine H3 receptor antagonist, an antihypertensive agent, a sodium glucose uptake transporter 2 (SGLT-2) inhibitor, a peptide that increases insulin production, and insulin or any insulin-containing composition.
  • a sulfonylurea an insulin sensitizer, a glucosidase inhibitor, an insulin secretagogue, a hepatic glucose output lowering agent, an anti-obesity agent, an antihypertensive agent, a meglitinide, an agent
  • the antidiabetic agent is an insulin sensitizer.
  • Non-limiting examples of insulin sensitizers include PPAR activators, such as the glitazone and thiazoldinedione class of agents, which include rosiglitazone, rosiglitazone maleate (AVANDIATM from GlaxoSmithKline), pioglitazone, pioglitazone hydrochloride (ACTOSTM, from Takeda) ciglitazone and MCC-555 (Mitstubishi Chemical Co.), troglitazone and englitazone; biguanides, such as phenformin, metformin, metformin hydrochloride (such as GLUCOPHAGE® from Bristol-Myers Squibb), metformin hydrochloride with glyburide (such as GLUCOVANCETM from Bristol-Myers Squibb) and buformin; DPP-IV inhibitors, such as sitagliptin, saxagliptin (JanuviaTM, Merck), denagliptin, vild
  • sitagliptin/metformin HCI JanumetTM, Merck
  • PTP-1 B inhibitors such as A-401 ,674, KR 61639, OC-060062, OC-83839, OC-297962, MC52445, and MC52453
  • ⁇ - glucokinase activators such as acarbose, adipose, camiglibose, emiglitate, mig!itol, voglibose, pradimicin-Q, salbostatin, CDK-711 , MDL-25,637, MDL-73,945, and MOR 14.
  • the antidiabetic agent is a DPP-IV inhibitor.
  • the antidiabetic agent is a sulfonylurea.
  • Non-limiting examples of sulfonylureas include glipizide, tolbutamide, glyburide, glimepiride, chlorpropamide, acetohexamide, gliamilide, g!iclazide, glibenclamide and tolazamide.
  • the antidiabetic agent is a SGLT-2 inhibitor.
  • Non-limiting examples of SGLT-2 inhibitors useful in the present methods include dapagliflozin and sergliflozin, AVE2268 (Sanofi-Aventis) and T-1095 (Tanabe Seiyaku).
  • the antidiabetic agent is a hepatic glucose output lowering agent.
  • Non-limiting examples of hepatic glucose output lowering agents include Glucophage and Glucophage XR.
  • the antidiabetic agent is an insulin secretagogue.
  • Non-limiting examples of insulin secretagogues include GLP-1 , GLP-1 mimetics, exendin, GIP, secretin, glipizide, chlorpropamide, nategiinide, meglitinide, glibenclamide, repagiinide and glimepiride.
  • GLP-1 mimetics useful in the present methods include
  • the antidiabetic agent is insulin or an insulin-containing preparation.
  • insulin as used herein, includes all formualtions of insulin, including long acting and short acting forms of insulin.
  • Non-limiting examples of orally administrable insulin and insulin containing compositions include AL-401 from Autoimmune, and the compositions disclosed in U.S. Patent Nos. 4,579,730; 4,849,405; 4,963,526; 5,642,868; 5,763,396; 5,824,638; 5,843,866; 6,153,632; 6,191 ,105; and International Publication No. WO 85/05029, each of which is incorporated herein by reference.
  • the antidiabetic agent is anti-obesity agent, including, but not limited to those set forth below herein.
  • the antidiabetic agent is an antihypertensive agent.
  • Non-limiting examples of antihypertensive agents useful in the present methods for treating diabetes include ⁇ -blockers and calcium channel blockers (for example diltiazem, verapamil, nifedipine, amiopidine, and mybefradii), ACE inhibitors (for example captopri!, lisinopril, enalapril, spirapril, ceranopril, zefenopril, fosinoprii, cilazopril, and quinapril), AT-1 receptor antagonists (for example losartan, irbesartan, and vaisartan), renin inhibitors and endothelin receptor antagonists (for example sitaxsentan).
  • ⁇ -blockers and calcium channel blockers for example diltiazem, verapamil, nifedipine, amiopidine, and mybefradii
  • ACE inhibitors for example captopri!, lisinopril, en
  • the antidiabetic agent is a meglitinide.
  • Non-limiting examples of megiitinides useful in the present methods for treating diabetes include repaglinide and nateglinide.
  • the antidiabetic agent is an agent that slows or blocks the breakdown of starches and sugars in vivo.
  • Non-iimiting examples of antidiabetic agents that slow or block the breakdown of starches and sugars in vivo and are suitable for use in the compositions and methods of the present invention include alpha-glucosidase inhibitors and certain peptides for increasing insulin production.
  • Alpha-glucosidase inhibitors help the body to lower blood sugar by delaying the digestion of ingested carbohydrates, thereby resulting in a smaller rise in blood glucose concentration following meals.
  • suitable alpha-glucosidase inhibitors include acarbose; miglitol;
  • camiglibose certain polyamines as disclosed in WO 01/47528 (incorporated herein by reference); voglibose.
  • suitable peptides for increasing insulin production including amlintide (CAS Reg. No. 122384-88-7 from Amylin;
  • GLP-1 Glucagon-like peptide- 1
  • Non-limiting examples of orally administrable insulin and insulin containing compositions include AL-401 from Autoimmune, and the compositions disclosed in U.S. Patent Nos. 4,579,730; 4,849,405; 4,963,526; 5,642,868; 5,763,396; 5,824,638; 5,843,866; 6,153,632; 6,191 ,105; and International Publication No. WO 85/05029, each of which is incorporated herein by reference.
  • Non-limiting examples of anti-obesity agents useful in the present methods for treating a Condition include an appetite suppressant; a 5-HT2C agonist, such as !orcaserin; an AMP kinase activator; a histamine H 3 receptor antagonist or inverse agonist; a metabolic rate enhancer; or a nutrient absorption inhibitor.
  • Non-iimiting examples of appetite suppressant agents useful in the present methods for treating or preventing a Condition include cannabinoid receptor 1 (CB ⁇ antagonists or inverse agonists (e.g., rimonabant); Neuropeptide Y (NPY1 , NPY2, NPY4 and NPY5) antagonists; metabotropic giutamate subtype 5 receptor (mGluR5) antagonists (e.g., 2-methy
  • serotonin uptake inhibitors e.g. , dexfenfluramine and fluoxetine
  • serotonin (5HT) transport inhibitors e.g. , paroxetine, fluoxetine, fenfluramine, fluvoxamine, sertaline and imipramine
  • norepinephrine (NE) transporter inhibitors e.g. , desipramine, talsupram and nomifensine
  • ghrelin antagonists e.g. , leptin, adiponectin, or derivatives thereof
  • opioid antagonists e.g. , nalmefene, 3-methoxy naltrexone, naloxone and nalterxone
  • orexin antagonists e.in receptor subtype 3 (BRS3) agonists;
  • Cholecystokinin-A (CCK-A) agonists Cholecystokinin-A (CCK-A) agonists; ciliary neurotrophic factor (CNTF) or derivatives thereof (e.g. , butabindide and axokine); monoamine reuptake inhibitors (e.g. , sibutramine); glucagon-like peptide 1 (GLP-1 ) agonists; topiramate; and phytopharm compound 57.
  • CNTF ciliary neurotrophic factor
  • monoamine reuptake inhibitors e.g. , sibutramine
  • GLP-1 glucagon-like peptide 1
  • Non-limiting examples of metabolic rate enhancers useful in the present methods for treating or preventing a Condition include acetyl-CoA carboxylase-2 (ACC2) inhibitors; beta adrenergic receptor 3 ( ⁇ 3) agonists; diacylglycerol
  • DGAT1 and DGAT2 acyltransferase inhibitors
  • FAS fatty acid synthase
  • PDE phosphodiesterase
  • UCP-1 ,2 or 3 uncoupling protein activators (UCP-1 ,2 or 3) (e.g. , phytanic acid, 4-[(E)-2-(5,6,7,8-tetramethyl-2-naphtha!enyi)-1-propenyi]benzoic acid and retinoic acid); acyl-estrogens (e.g. , oleoyi-estrone); glucocorticoid
  • Non-limiting examples of nutrient absorption inhibitors useful in the present methods for treating or preventing a Condition include lipase inhibitors (e.g., orlistat, !ipstatin, tetrahydrolipstatin, teasaponin and diethylumbelliferyl phosphate); fatty acid transporter inhibitors; dicarboxylate transporter inhibitors; glucose transporter inhibitors; and phosphate transporter inhibitors.
  • lipase inhibitors e.g., orlistat, !ipstatin, tetrahydrolipstatin, teasaponin and diethylumbelliferyl phosphate
  • fatty acid transporter inhibitors e.g., dicarboxylate transporter inhibitors
  • glucose transporter inhibitors e transporter inhibitors
  • H 3 antagonists/inverse agonists useful in combination with the compounds of List 1 include thioperamide, 3-(1 H-imidazol-4-yI)propyl N-(4- pentenyl)carbamate, clobenpropit, iodophenpropit, imoproxifan, and GT2394
  • Non-limiting examples of cholesterol biosynthesis inhibitors useful in the present methods for treating or preventing a Condition include HMG-CoA reductase inhibitors, squaiene synthase inhibitors, squaiene epoxidase inhibitors, and mixtures thereof.
  • Non-limiting examples of cholesterol absorption inhibitors useful in the present methods for treating or preventing a Condition include ezetimibe.
  • the cholesterol absorption inhibitor is ezetimibe.
  • Non-limiting examples of squaiene synthesis inhibitors useful in the present methods for treating or preventing a Condition include, but are not limited to, squaiene synthetase inhibitors, such as squalestatin 1 ; and squalene epoxidase inhibitors, such as NB-598 ((EJ-N-ethyl-N-fe.e-dimethyl ⁇ hepten ⁇ -ynyiJ-S-p ⁇ '-bithiophen-S- yi)methoxy]benzene-methanamine hydrochloride).
  • squaiene synthetase inhibitors such as squalestatin 1
  • squalene epoxidase inhibitors such as NB-598 ((EJ-N-ethyl-N-fe.e-dimethyl ⁇ hepten ⁇ -ynyiJ-S-p ⁇ '-bithiophen-S- yi)methoxy]benzene-me
  • Non-limiting examples of bile acid sequestrants useful in the present methods for treating or preventing a Condition include, but are not limited to, cholestyramine (a styrene-divinylbenzene copolymer containing quaternary ammonium cationic groups capable of binding bile acids, such as QUESTRAN® or QUESTRAN LIGHT® cholestyramine which are available from Bristol-Myers Squibb), colestipol (a
  • COLESTID® tablets which are available from Pharmacia
  • coleseveiam hydrochloride such as WelChol® Tablets (poly(allylamine hydrochloride) cross-iinked with epichlorohydrin and alkylated with 1-bromodecane and (6-bromohexyI)- trimethylammonium bromide) which are available from Sankyo
  • water soluble derivatives such as 3,3-ioene, N-(cyc!oaikyl) alkylamines and poiiglusam
  • insoluble quaternized polystyrenes saponins and mixtures thereof.
  • Suitable inorganic cholesterol sequestrants include bismuth salicylate plus montmorillonite clay, aluminum hydroxide and calcium carbonate antacids.
  • Probucol derivatives useful in the present methods for treating or preventing a Condition include, but are not limited to, AGI-1067 and others disclosed in U.S.
  • IBAT inhibitors useful in the present methods for treating or preventing a Condition include, but are not limited to, benzothiepines such as therapeutic
  • Nicotinic acid derivatives useful in the present methods for treating or preventing a Condition include, but are not limited to, those having a pyridtne-3- carboxylate structure or a pyrazine-2-carboxylate structure, including acid forms, salts, esters, zwitterions and tautomers, where available.
  • Other examples of nicotinic acid derivatives useful in the present methods include nicotinic acid, niceritroi,
  • nicofuranose and acipimox (5-methy! pyrazine-2-carboxylic acid 4-oxide).
  • An example of a suitable nicotinic acid product is NIASPAN® (niacin extended-release tablets) which are available from Kos Pharmaceuticals, Inc. (Cranbury, NJ).
  • nicotinic acid derivatives useful in the present methods for treating or preventing a Condition include, but are not limited to, the compounds disclosed in U.S. Patent Publication Nos. 2006/0264489 and 2007/0066630, and U.S. Patent Application No 11/771538, each of which is incorporated herein by reference.
  • LDL-receptor activators useful in the present methods for treating or preventing a Condition include, but are not limited to, include HOE-402, an imidazolidinyl- pyrimidine derivative that directly stimulates LDL receptor activity. See M. Huettinger et al., "Hypolipidemic activity of HOE-402 is Mediated by Stimulation of the LDL Receptor Pathway", Arterioscler.T romfr. 1993; 13:1005-12.
  • Natural water-soluble fibers useful in the present methods for treating or preventing a Condition include, but are not limited to, psyllium, guar, oat and pectin.
  • Fatty acid esters of plant stands useful in the present methods for treating or preventing a Condition include, but are not limited to, the sitostanol ester used in BENECOL® margarine.
  • Non-limiting examples of hydroxy-substituted azetidinone compounds and substituted ⁇ -lactam compounds useful in the present methods for treating or preventing a Condition include those disclosed in U.S. Patents Nos. 5,767,1 15, 5,624,920, 5,668,990, 5,656,624 and 5,688,787, 5,756,470, U.S. Patent Application Nos. 2002/0137690 and 2002/0137689 and PCT Patent Application No. WO
  • a preferred azetidinone compound is ezetimibe (for exampie, ZETIA® which is available from Schering-Plough Corporation).
  • HMG-CoA reductase inhibitors useful in the present methods for treating or preventing a Condition include lovastatin (for example
  • MEVACOR ® which is available from Merck & Co.
  • simvastatin for example ZOCOR ® which is available from Merck & Co.
  • pravastatin for example PRAVACHOL ® which is available from Bristol Meyers Squibb
  • atorvastatin fluvastatin, cerivastatin, Ci-981 , rivastatin (sodium 7-(4-fluorophenyi)-2,6-diisopropyl-5-methoxymethylpyridin-3-yl)-3,5- dihydroxy-6-heptanoate), rosuvastatin calcium (CRESTOR® from AstraZeneca Pharmaceuticals), pravastatin (such as NK-104 of Negma Kowa of Japan).
  • Non-limiting examples of AcylCoA:Cholesterol O-acyltransferase (“ACAT”) inhibitors useful in the present methods for treating or preventing a Condition include avasimibe (P,4,6-tris(1-methylethyl)phenyl]acetyi]sulfamic acid, 2,6-bis(1- methylethyl)pheny[ ester, formerly known as CI-1011), HL-004, iecimibide (DuP-128) and CL-277082 (/V-(2,4-difluorophenyl)-/V-[I4-(2,2-dimethylpropyi)phenyi]methyl]-/ ⁇ /- heptylurea), and the compounds described in P. Chang et al., "Current, New and Future Treatments in Dyslipidaemia and Atherosclerosis", Drugs 2000 Jul; 60(1); 55- 93, which is incorporated by reference herein.
  • Non-limiting examples of cholesteryl ester transfer protein ("CETP") inhibitors useful in the present methods for treating or preventing a Condition include those disclosed in PCT Patent Application No. WO 00/38721 , U.S. Patent Nos. 6,147,090, 6,958,346, 6,924,313 6,906,082, 6,861 ,561 , 6,803,388, 6,794,396, 6,787,570, 6,753,346, 6,723,752, 6,723,753, 6,710,089, 6,699,898, 6,696,472, 6,696,435, 6,683,113, 5,519,001 , 5,512,548, 6,410,022, 6,426,365, 6,448,295, 6,387,929, 6,683,099, 6,677,382, 6,677,380, 6,677,379, 6,677,375, 6,677,353, 6,677,341 , 6,605,624, 6,586,433, 6,451 ,830, 6,451 ,823, 6,46
  • LDL low-density lipoprotein
  • HOE-402 an imidazolidinyl-pyrimidine derivative that directly stimulates LDL receptor activity, described in M. Huettinger et al., "Hypolipidemic activity of HOE-402 is Mediated by Stimulation of the LDL
  • HMG- CoA reductase inhibitors such as atorvastatin (WO 00/213797, WO 2004/056358, WO 2004/056359, and WO2005/011634).
  • a non-limiting example of a fish oil containing Omega 3 fatty acids useful in combination with the compounds of List 1 is 3-PUFA.
  • Non-limiting examples of natural water soluble fibers useful in the present methods for treating or preventing a Condition include psyllium, guar, oat and pectin.
  • a non-limiting example of a plant stanol and/or fatty acid ester of plant stanols useful in combination with the compounds of List 1 is the sitostanol ester used in BENECOL ® margarine.
  • a non-limiting example of an anti-oxidant useful in combination with the compounds of List 1 includes probucol.
  • Non-limiting examples of NE (norepinephrine) transport inhibitors useful in combination with the compounds of List 1 include GW 320659, despiramine, ta!supram, and nomifensine.
  • Non-limiting examples of ghrelin antagonists useful in combination with the compounds of List 1 include those described in WO 01/87335 and WO 02/08250 (each of the preceding references is herein incorporated by reference). Ghrelin antagonists are also known as GHS (growth hormone secretagogue receptor) antagonists. The pharmaceutical combinations and methods of the present invention therefore comprehend the use GHS antagonists in place of ghrelin antagonists (in combination with the nicotinic acid receptor agonists of the present invention).
  • MCH1 R melanin-concentrating hormone 1 receptor
  • MCH2R melanin-concentrating hormone 2 receptor
  • agonists/antagonists useful in combination with the compounds of List 1 include those described in WO 01/82925, WO 01/87834, WO 02/06245, WO 02/04433, WO
  • Non-limiting examples of NPY1 antagonists useful in combination with the compounds of List 1 include those described in US 6,001 ,836, WO 96/14307, WO 01/23387, WO 99/51600, WO 01/85690, WO 01/85098, WO 01/85173, and WO 01/89528 (each of the preceding references is herein incorporated by reference); and BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, and GI-264879A.
  • Non-limiting examples of NPY2 agonists useful in combination with the compounds of List 1 include PYY3-36 as described in Batterham, et ai., Nature, 418:650-654 (2003), NPY3-36, and other Y2 agonists such as N acetyl [Leu(28,31)] NPY 24-36 (White-Smith and Potter, Neuropeptides 33:526-33 (1999)), TASP-V (Malis et aL, Br. J. Pharmacol.
  • Non-limiting examples of NPY4 agonists useful in combination with the compounds of List 1 include pancreatic peptide (PP) as described in Batterham et a!., J. Ciin. Endocrinol. Metab. 88:3989-3992 (2003), and other Y4 agonists such as 1229U91 (Raposinho et al., Neuroendocrinology. 71 :2-7(2000) (both references are herein incorporated by reference).
  • PP pancreatic peptide
  • Non-limiting examples of NPY5 antagonists useful in combination with the compounds of List 1 include those described in US 6,140,354, US 6,191 ,160, US 6,258,837, US 6,313,298, US 6,337,332, US 6,329,395, US 6,340,683, US 6,326,375, US 6,335,345, EP-01010691 , EP-01044970, WO 97/19682, WO 97/20820, WO 97/20821 , WO 97/20822, WO 97/20823, WO 98/27063, WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO 01/02379, WO 01/23388, WO 01/23389, WO 01/44201 , WO 01/62737, WO 01/62738, WO 01/09
  • Non-limiting examples of mGluR5 (Metabotropic glutamate subtype 5 receptor) antagonists useful in combination with the compounds of List 1 include 2-methyl-6- (phenylethynyl)-pyridine (MPEP) and (3-[(2-methyl-1 ,3-thiazoi-4-yl)ethynyl]pyridine) (MTEP) and those compounds described in Anderson J. et a!., J, Eur J Pharmacol. Jul. 18, 2003;473(1):35-40; Cosford N. et al., Bioorg Med Chem Lett. Feb. 10,
  • leptins Non-limiting examples of leptins, leptin derivatives, and leptin
  • agonists/modulators useful in combination with the compounds of List 1 include recombinant human leptin (PEG-OB, Hoffman La Roche) and recombinant methionyl human leptin (Amgen).
  • Leptin derivatives (e.g., truncated forms of leptin) useful in the present invention include those described in US 5,552,524, US 5,552,523, US
  • Non-limiting examples of opioid antagonists useful in combination with the compounds of List 1 include nalmefene (RevexTM), 3-methoxynaitrexone, naloxone, and naltrexone, as well as opioid antagonists described in WO 00/21509 (herein incorporated by reference).
  • Non-iimiting examples of orexin receptor antagonists useful in combination with the compounds of List 1 include SB-334867-A, as well as those described in WO 01/96302, WO 01/68609, WO 02/51232, and WO 02/51838 (each of the preceding references is herein incorporated by reference).
  • Non-limiting examples of CNTF (specific ciliary neurotrophic factors) useful in combination with the compounds of List 1 include GI-181771 (Glaxo-SmithKline); SR146131 (Sanofi Aventis); butabindide; PD170.292, PD 149164 (Pfizer).
  • Non-limiting examples of CNTF derivatives and CNTF agonists/modulators useful in combination with the compounds of List 1 include axokine (Regeneron) and those described in WO 94/09134, WO 98/22128, and WO 99/43813 (each of which is herein incorporated by reference).
  • Non-limiting examples of 5HT2c agonists useful in combination with the compounds of List 1 include BVT933, DPCA37215, WAY161503, and R-1065, as well as those described in US 3,914,250, WO 02/36596, WO 02/48124, WO 02/10169, WO 01/66548, WO 02/44152, WO 02/51844, WO 02/40456, and WO 02/40457 (each of which is herein incorporated by reference).
  • Mc4r agonists useful in combination with the compounds of List 1 include CHIR86036 (Chiron); ME-10142, and ME-10145 (Melacure), as well as those described in WO 01/991752, WO 01/74844, WO
  • Non-limiting examples of monoamine reuptake inhibitors useful in combination with the compounds of List 1 include sibutramine (MeridiaTM/ReductilTM), as well as those described in WO 01/27068, WO 01/62341 , US 4,746,680, US 4,806,570, US 5,436,272, and US 2002/0006964 (each of which is herein incorporated by reference).
  • Non-limiting examples of serotonin reuptake inhibitors useful in combination with the compounds of List 1 include dexfenfluramine, fluoxetine, and those described in US 6,365,633, WO 01/27060, and WO 01/162341 (each of which is herein incorporated by reference).
  • Non-limiting examples of a-amylase inhibitors useful in combination with the compounds of List 1 include tendamistat, trestatin, and AI-3688.
  • Non-limiting examples of Ogiucokinase activators useful in combination with the compounds of List 1 include acarbose, adipose, camiglibose, emig!itate, miglitol, voglibose, pradimicin-Q, salbostatin, CDK-711 , MDL-25,637, MDL-73,945, and MOR 14.
  • Non-limiting examples of fatty acid oxidation inhibitors useful in combination with the compounds of List 1 include clomoxir and etomoxir.
  • Non-limiting examples of A2 antagonists useful in combination with the compounds of List 1 include midaglizole, isaglidole, deriglidole, idazoxan, earoxan, and fluparoxan.
  • Non-limiting examples of glycogen phosphorylase inhibitors useful in this specification include but not limited to, glycogen phosphorylase inhibitors, glycogen phosphorylase inhibitors, and others.
  • Non-limiting examples of additional analgesic agents useful in the present methods for treating or preventing pain include acetaminophen, an NSAID, an opiate or a tricyclic antidepressant.
  • the other analgesic agent is acetaminophen or an NSAID. In another embodiment, the other analgesic agent is an opiate.
  • the other analgesic agent is a tricyclic antidepressant.
  • nabumetone sulindac or tolmetin
  • a 2-arylpropionic acid such as ibuprofen, carprofen, fenoprofen, flurbiprofen, loxoprofen, naproxen, tiaprofenic acid or suprofen
  • a fenamic acid such as mefenamic acid or meclofenamic acid
  • a pyrazolidine derivative such as phenylbutazone, azapropazone, metamizole or oxyphenbutazone
  • a coxib such as DCecoxib, etoricoxib, iumiracoxib or parecoxib
  • an oxicam such as piroxicam, lornoxicam, meloxicam or tenoxicam
  • a oxicam such as piroxicam, lornoxicam, meloxicam or tenoxicam
  • suffonanilide such as nimesulide
  • Non-limiting examples of opiates useful in the present methods for treating or preventing pain include an anilidopiperidine, a phenylpiperidine, a
  • diphenylpropylamine derivative a benzomorphane derivative
  • an oripavine derivative a morphinane derivative
  • Additional illustrative examples of opiates include morphine, diamorphine, heroin, buprenorphine, dipipanone, pethidine,
  • dextromoramide alfentanil, fentanyl, remifentanil, methadone, codeine,
  • dihydrocodeine tramadol, pentazocine, vicodin, oxycodone, hydrocodone, percocet, percodan, norco, dilaudid, darvocet or lorcet.
  • Non-limiting examples of tricyclic antidepressants useful in the present methods for treating or preventing pain include amitryptyline, carbamazepine, gabapentin or pregabaiin.
  • the compounds of List 1 may also be useful in combination (administered together or sequentially in any order) with one or more separate anticancer treatments such as radiation therapy, and/or at least one anticancer agent different from the compound of List 1 .
  • the compounds of the present invention can be present in the same dosage unit as the anticancer agent or in separate dosage units.
  • Another aspect of the present invention is a method of treating one or more diseases associated with a cyclin dependent kinase, comprising administering to a patient in need of such treatment an amount of a first compound, which is a
  • Non-limiting examples of additional anticancer agents suitable for use in the present methods for treating cancer include cytostatic agents, cytotoxic agents (such as for example, but not limited to, DNA interactive agents (such as cisplatin or doxorubicin)); taxanes (e.g.
  • topoisomerase li inhibitors such as etoposide or teniposide
  • topoisomerase i inhibitors such as irinotecan (or CPT-11), camptostar, or topotecan
  • tubulin interacting agents such as paclitaxel, docetaxel or the epothiiones
  • hormonal agents such as tamoxifen
  • thymidilate synthase inhibitors such as 5-fluorouracil
  • anti-metabolites such as methoxtrexate
  • alkylating agents such as temozolomide (TEMODARTM from Schering-Plough Corporation, Kenilworth, New Jersey), cyclophosphamide
  • Farnesyl protein transferase inhibitors such as, SARASARTM(4-[2-[4-[(11 R)-3, 10-dibromo-8-chloro-6, 11 -dihydro ⁇ 5H ⁇
  • Additional anticancer agents include but are not limited to Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman,
  • Triethylenethiophosphoramine Busulfan, Carmustine, Lomustine, Streptozocin, dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, F!udarabine phosphate, oxalipiatin, leucovirin, oxaiiplatin (ELOXATINTM from Sanofi-Synthelabo Pharmaceuticals, France), Pentostatine, Vinblastine, Vincristine, Vindesine,
  • Medroxyprogesteroneacetate Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Oxaiiplatin, Aroplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine,
  • Droloxafine Droloxafine, Hexamethylmelamine, Avastin, Herceptin, Bexxar, Veicade, Zevalin, Trisenox, Xeloda, Vinorelbine, Profimer, Erbitux, Liposomal, Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane,
  • the CDC2 inhibitor olomucine has been found to act synergistically with known cytotoxic agents in inducing apoptosis (J. Cell Sci., (1995) 108, 2897.
  • the compounds of List 1 may also be administered sequentially with known anticancer or cytotoxic agents when a combination formulation is inappropriate.
  • the invention is not limited in the sequence of administration; the compounds of List 1 may be administered either prior to or after administration of the known anticancer or cytotoxic agent.
  • the cytotoxic activity of the cyclin-dependent kinase inhibitor flavopiridol is affected by the sequence of administration with anticancer agents. Cancer Research, ( 997) 57, 3375. Such techniques are within the skills of persons skilled in the art as well as attending physicians.
  • this invention includes methods for treating cancer in a patient, comprising administering to the patient an amount of at least one compound of List 1 , or a pharmaceutically acceptable salt, solvate, ester, prodrug or
  • the at least one compound of List land the one or more other treatment modalities act synergistically. In one embodiment, the at least one compound of List 1 and the one or more other treatment modalities act additively.
  • the other treatment modality is surgery.
  • the other treatment modality is radiation therapy.
  • the other treatment modality is biological therapy, such as hormonal therapy or anticancer vaccine therapy.
  • the present combination therapies for treating or preventing diabetes comprise administering a compound of List 1 , an antidiabetic agent and/or an antiobesity agent.
  • the present combination therapies for treating or preventing diabetes comprise administering a compound of List land an antidiabetic agent
  • the present combination therapies for treating or preventing diabetes comprise administering a compound of List 1 and an anti-obesity agent.
  • the present combination therapies for treating or preventing obesity comprise administering a compound of List 1 , an antidiabetic agent and/or an antiobesity agent.
  • the present combination therapies for treating or preventing obesity comprise administering a compound of List 1 and an antidiabetic agent.
  • the present combination therapies for treating or preventing obesity comprise administering a compound of List 1 and an anti-obesity agent.
  • the additional therapeutic agent is a cholesterol
  • the cholesterol biosynthesis inhibitor is a squalene synthetase inhibitor. In another embodiment, the cholesterol biosynthesis inhibitor is a squalene epoxidase inhibitor. In still another embodiment, the cholesterol biosynthesis inhibitor is an H G-CoA reductase inhibitor. In another embodiment, the HMG-CoA reductase inhibitor is a statin. In yet another embodiment, the statin is lovastatin, pravastatin, simvastatin or atorvastatin.
  • the additional therapeutic agent comprises a cholesterol absorption inhibitor and a cholesterol biosynthesis inhibitor. In another embodiment, the additional therapeutic agent comprises a cholesterol absorption inhibitor and a statin. In another embodiment, the additional therapeutic agent comprises ezetimibe and a statin. In another embodiment, the additional therapeutic agent comprises ezetimibe and simvastatin.
  • preventing metabolic syndrome comprise administering a compound of List 1 , an antidiabetic agent and/or an antiobesity agent.
  • the present combination therapies for treating or preventing metabolic syndrome comprise administering a compound of List 1 and an antidiabetic agent.
  • the present combination therapies for treating or preventing metabolic syndrome comprise administering a compound of List 1 and an anti-obesity agent.
  • preventing a cardiovascular disease comprise administering one or more compounds of List 1, and an additional agent useful for treating or preventing a cardiovascular disease.
  • the compounds of List 1 can also be used in combination with another therapeutic agent with comprises two or more active ingredients.
  • Another therapeutic agent with comprises two or more active ingredients is VYTORIN ® (a combination of simvastatin and ezetimibe).
  • compositions or compositions comprising therapeutic agents may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like.
  • the amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts).
  • the one or more compounds of List 1 are administered during a time when the additional therapeutic agent(s) exert their prophylactic or therapeutic effect, or vice versa.
  • the one or more compounds of List 1 and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating or preventing a Condition.
  • the one or more compounds of List 1 and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating or preventing a Condition.
  • the one or more compounds of List 1 and the additional therapeutic agent(s) act synergistically and are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating or preventing a Condition.
  • the one or more compounds of List 1 and the additional therapeutic agent(s) are present in the same composition.
  • this composition is suitable for oral administration. In another embodiment, this
  • composition is suitable for intravenous administration.
  • the one or more compounds of List 1 and the additional therapeutic agent(s) can act additively or synergistically.
  • a synergistic combination may allow the use of lower dosages of one or more agents and/or less frequent administration of one or more agents of a combination therapy.
  • a lower dosage or less frequent administration of one or more agents may lower toxicity of therapy without reducing the efficacy of therapy.
  • the administration of one or more compounds of List 1 and the additional therapeutic agent(s) may inhibit the resistance of a Condition to these agents.
  • the additional therapeutic agent when the patient is treated for diabetes or a diabetic complication, is an antidiabetic agent which is not a compound of List 1.
  • the additional therapeutic agent is an agent useful for reducing any potential side effect of a compound of List 1.
  • potential side effects include, but are not limited to, nausea, vomiting, headache, fever, lethargy, muscle aches, diarrhea, general pain, and pain at an injection site.
  • the additional therapeutic agent is used at its known therapeutically effective dose. In another embodiment, the additional therapeutic agent is used at its normally prescribed dosage. In another embodiment, the additional therapeutic agent is used at less than its normally prescribed dosage or its known therapeutically effective dose.
  • the doses and dosage regimen of the other agents used in the combination therapies of the present invention for the treatment or prevention of a Condition can be determined by the attending clinician, taking into consideration the approved doses and dosage regimen in the package insert; the age, sex and general health of the patient; and the type and severity of the viral infection or related disease or disorder.
  • the compound(s) of List 1 and the other agent(s) for treating or preventing diseases or conditions listed above can be administered simultaneously or sequentially. This particularly useful when the components of the combination are given on different dosing schedules, e.g., one component is administered once daily and another every six hours, or when the preferred
  • compositions are different, e.g. one is a tablet and one is a capsule.
  • a kit comprising the separate dosage forms is therefore advantageous.
  • a total daily dosage of the one or more compounds of List 1 and the additional therapeutic agent(s) can, when administered as combination therapy, range from about 0.1 to about 2000 mg per day, although variations will necessarily occur depending on the target of therapy, the patient and the route of administration.
  • the dosage is from about 0.2 to about 100 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 1 to about 500 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 1 to about 200 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 1 to about 100 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 1 to about 50 mg/day, administered in a single dose or in 2-4 divided doses, in a further embodiment, the dosage is from about 1 to about 20 mg/day, administered in a single dose or in 2-4 divided doses.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
  • the powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.
  • Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, PA.
  • Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propyiene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.
  • a pharmaceutically acceptable carrier such as an inert compressed gas, e.g. nitrogen.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral
  • transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • a compound of List 1 is administered orally.
  • a compound of List 1 is administered intravenously.
  • a compound of List 1 is administered intranasally.
  • a compound of List 1 is administered topically.
  • the pharmaceutical preparation is in a unit dosage form.
  • the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 150 mg, preferably from about 1 mg to about 75 mg, more preferably from about 1 mg to about 50 mg, according to the particular application.
  • the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
  • the amount and frequency of administration of the compounds of List 1 and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated.
  • recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 300 mg/day, preferably 1 mg/day to 75 mg/day, in two to four divided doses.
  • the two active components may be coadministered simultaneously or sequentially, or a single pharmaceutical composition comprising one or more compounds of List 1 and an additional therapeutic agent in a pharmaceutically acceptable carrier can be administered.
  • the components of the combination can be administered individually or together in any conventional dosage form such as capsule, tablet, powder, cachet, suspension, solution, suppository, nasal spray, etc.
  • the dosage of the additional therapeutic agent can be determined from published material, and may range from about 1 to about 1000 mg per dose. In one embodiment, when used in combination, the dosage levels of the individual
  • the components of a combination therapy regime are to be administered simultaneously, they can be administered in a single composition with a pharmaceutically acceptable carrier.
  • ком ⁇ онент when the components of a combination therapy regime are to be administered separately or sequentially, they can be administered in separate compositions, each containing a pharmaceutically acceptable carrier.
  • the components of the combination therapy can be administered individually or together in any conventional dosage form such as capsule, tablet, powder, cachet, suspension, solution, suppository, nasal spray, etc.
  • the present invention provides a kit comprising an effective amount of one or more compounds of List 1 , or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof, and a pharmaceutically acceptable carrier.
  • the present invention provides a kit comprising an amount of one or more compounds of List 1 , or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof, and an amount of at least one additional therapeutic agent listed above, wherein the combined amounts are effective for treating or preventing a Condition in a patient.
  • kits comprising a single package containing one or more containers, wherein one container contains one or more compounds of List 1 in a pharmaceutically acceptable carrier, and a second, separate container comprises an additional therapeutic agent in a pharmaceuticaily acceptable carrier, with the active components of each composition being present in amounts such that the combination is therapeutically effective.

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Abstract

La présente invention concerne certains nouveaux composés bicycliques, des compositions contenant ces composés bicycliques et des méthodes d'utilisation de ces derniers dans le traitement ou la prévention d'un trouble métabolique, d'une dyslipidémie, d'une maladie cardiovasculaire, d'un trouble neurologique, d'une maladie hématologique, d'un cancer, d'une inflammation, d'une maladie respiratoire, d'une maladie gastro-intestinale, du diabète, d'une complication diabétique, de l'obésité, d'un trouble associé à l'obésité ou d'une stéatopathie non alcoolique. Un composé bicyclique illustratif de l'invention est représenté ci-dessous :
PCT/US2010/056181 2009-11-16 2010-11-10 Composés bicycliques et leurs méthodes d'utilisation WO2011060036A1 (fr)

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CN105732494A (zh) * 2016-04-12 2016-07-06 叶芳 一种喹啉酮类衍生物的合成方法
WO2017019726A1 (fr) * 2015-07-29 2017-02-02 Merck Sharp & Dohme Corp. Oxy-cyanoquinolinone utilisée en tant qu'inhibiteur de pde9
KR101736387B1 (ko) * 2015-12-30 2017-05-16 한국해양과학기술원 티에노피리돈 유도체, 이의 제조방법 및 이를 포함하는 약학적 조성물
US10370336B2 (en) 2015-07-29 2019-08-06 Merck Sharp & Dohme Corp. Phenyl-cyanoquinolinone PDE9 inhibitors
US10376504B2 (en) 2015-07-29 2019-08-13 Merck, Sharp & Dohme Corp. Substituted quinolinones as PDE9 inhibitors
WO2021053046A1 (fr) * 2019-09-20 2021-03-25 Merck Patent Gmbh Composés hétérocycliques péri-condensés en tant que matériaux destinés à des dispositifs électroniques

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