WO2004037778A1 - Tetralines et indanes substitues - Google Patents

Tetralines et indanes substitues Download PDF

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Publication number
WO2004037778A1
WO2004037778A1 PCT/US2003/033090 US0333090W WO2004037778A1 WO 2004037778 A1 WO2004037778 A1 WO 2004037778A1 US 0333090 W US0333090 W US 0333090W WO 2004037778 A1 WO2004037778 A1 WO 2004037778A1
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WIPO (PCT)
Prior art keywords
compound
ureido
ylsulfanyl
ethyl
trifluoromethoxyphenyl
Prior art date
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PCT/US2003/033090
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English (en)
Inventor
Xiaoli Chen
Jay M. Matthews
Keith T. Demarest
Jung Lee
Philip Rybczynski
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Janssen Pharmaceutica, N.V.
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Priority to JP2005501629A priority Critical patent/JP2006503916A/ja
Priority to MXPA05004191A priority patent/MXPA05004191A/es
Priority to BR0315596-0A priority patent/BR0315596A/pt
Priority to AU2003277441A priority patent/AU2003277441B2/en
Priority to EP03809577A priority patent/EP1569897A1/fr
Priority to UAA200503452A priority patent/UA80297C2/uk
Priority to CA002502661A priority patent/CA2502661A1/fr
Priority to NZ539510A priority patent/NZ539510A/en
Application filed by Janssen Pharmaceutica, N.V. filed Critical Janssen Pharmaceutica, N.V.
Priority to YUP-2005/0318A priority patent/RS20050318A/sr
Priority to EA200500515A priority patent/EA009553B1/ru
Publication of WO2004037778A1 publication Critical patent/WO2004037778A1/fr
Priority to HR20050335A priority patent/HRP20050335A2/hr
Priority to EGNA2005000152 priority patent/EG24842A/xx
Priority to NO20052199A priority patent/NO20052199L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C07C323/43—Y being a hetero atom
    • C07C323/44—X or Y being nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the invention features substituted tetralin and indane derivatives, compositions containing them, and methods of using them.
  • a member of the nuclear receptor family a group of ligand-activated transcription factors, the peroxisome proliferator-activated receptor alpha (PPAR alpha) is a necessary transcription factor regulating genes relating to fatty acid metabolism and insulin action.
  • PPAR alpha peroxisome proliferator-activated receptor alpha
  • PPAR alpha receptors are found predominantly in the liver.
  • the genes regulated by PPAR alpha include enzymes involved in the beta-oxidation of fatty acids, the liver fatty acid transport protein, and apo A1 , an important component of high density lipoproteins (HDL).
  • Selective, high affinity PPAR alpha agonists increase hepatic fatty acid oxidation, which in turn decreases circulating triglycerides and free fatty acids.
  • the reduction of circulating triglycerides may mediate the observed decrease, or improvement, in insulin resistance in insulin resistant or diabetic animals when treated with PPAR alpha agonists.
  • Such treatment in animal obesity models is associated with weight loss.
  • fibrates are weak PPAR alpha agonists.
  • Examples of known PPAR alpha agonists variously useful for hyperlipidemia, diabetes, or atherosclerosis include fibrates such as fenofibrate (Fournier), gemfibrozil (Parke-Davis/Pfizer, Mylan, Watson), clofibrate (Wyeth- Ayerst, Novopharm), bezafibrate, and ciprofibrate and ureidofibrates such as GW 7647, GW 9578, and GW 9820 (GiaxoSmithKline).
  • fibrates such as fenofibrate (Fournier), gemfibrozil (Parke-Davis/Pfizer, Mylan, Watson), clofibrate (Wyeth- Ayerst, Novopharm), bezafibrate, and ciprofibrate and ureidofibrates such as GW 7647, GW 9578, and GW 9820 (GiaxoSmithKline).
  • the invention features compounds of formula (I) below:
  • each of R ⁇ and R 2 is independently H, C ⁇ -6 alkyl, (CH 2 ) m NR a R b , (CH 2 ) m OR 8 , (CH 2 )mNH(CO)R 8 , or (CH 2 ) m CO 2 R8, where each of R a , Rb, and R 8 is independently H or C 1 - 6 alkyl, or R ⁇ and R 2 taken together with the carbon atom to which they are attached are a C 3-7 cycloalkyl;
  • n 1 and 6;
  • n 1 or 2;
  • X is O or S; wherein X is at the 5 or 6 position when n is 1 ; and wherein X is at the 6 or 7 position when n is 2;
  • R 3 is H, phenyl, C ⁇ -3 alkoxy, C ⁇ -3 alkylthio, halo, cyano, C 1 - 6 alkyl, nitro, NR9R 1 0, NHCOR10, CONHR 1 0; and COOR 1 0; and R 3 is ortho or meta to X;
  • R 4 is H or -(C 1-5 alkylene)R ⁇ s, where R15 is H, C ⁇ _ 7 alkyl, [di(C ⁇ -2 alkyl)amino](C 1-6 alkylene), (C ⁇ -3 alkoxyacyl)(C 1 - 6 alkylene), C 1-6 alkoxy, C 3 .
  • R 4 has no more than 9 carbon atoms
  • R can also be -(C ⁇ -5 aIkylene)Ri 5 wherein R 15 is C 3-6 cycloalkyl, phenyl, phenyl-O-, phenyl-S-, or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
  • Y is NH, NH-CH 2 , or O
  • each of R 5 and R 7 is independently selected from H, C ⁇ -6 alkyl, halo, cyano, nitro, COR 11 , COOR 11 , C ⁇ - 4 alkoxy, C ⁇ - alkylthio, hydroxy, phenyl, NRnR- ⁇ 2 and 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
  • Re is selected from C ⁇ -6 alkyl, halo, cyano, nitro, COR ⁇ 3 , COOR ⁇ 3 , C ⁇ -4 alkoxy, C ⁇ - alkylthio, hydroxy, phenyl, NRi 3 R-i and 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
  • R 5 and Re or Re and R 7 may be taken together to be a bivalent moiety, saturated or unsaturated, selected from -(CH 2 ) 3 - -(CH 2 ) -, and (CH 1-2 ) P N(CH 1-2 ) q ,
  • p is 0-2 and q is 1-3, where the sum (p + q) is at least 2;
  • each of R 9 and R 10 is independently C ⁇ -6 alkyl; each of R 11 , R ⁇ 2 , R ⁇ 3 and R ⁇ is independently H or C 1 - 6 alkyl;
  • compositions that include one or more compounds of formula (I) and a pharmaceutical carrier or excipient.
  • compositions and the methods below may further include additional pharmaceutically active agents, such as lipid-lowering agents or blood-pressure lowering agents, or both.
  • Another aspect of the invention includes methods of using the disclosed compounds or compositions in various methods for preventing, treating, or inhibiting the progression of, a disease mediated by PPAR alpha.
  • PPAR alpha-mediated diseases include dyslipidemia and atherosclerosis.
  • Dyslipidemia includes hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, and hypo-HDL-cholesterolemia.
  • dyslipidemia may be one or more of the following: low HDL ( ⁇ 35 or 40 mg/dl), high triglycerides ( > 200 mg/dl), and high LDL (> 150 mg/dl).
  • Alkyl includes optionally substituted straight chain and branched hydrocarbons with at least one hydrogen removed to form a radical group.
  • Alkyl groups include methyl, ethyl, propyl, isoprdpyl, butyl, isobutyl, t-butyl, 1- methylpropyl, pentyl, isopentyl, sec-pentyl, hexyl, heptyl, octyl, and so on.
  • Alkyl includes cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • Alkenyl includes optionally substituted straight chain and branched hydrocarbon radicals as above with at least one carbon-carbon double bond (sp 2 ).
  • Alkenyls include ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), isopropenyl (or 1-methylvinyI), but-1-enyl, but-2-enyl, butadienyls, pentenyls, hexa-2,4-dienyl, and so on.
  • Hydrocarbon radicals having a mixture of double bonds and triple bonds, such as 2-penten-4-ynyl, are grouped as alkynyls herein.
  • Alkenyl includes cycloalkenyl. Cis and trans or (E) and (Z) forms are included within the invention.
  • Alkynyl includes optionally substituted straight chain and branched hydrocarbon radicals as above with at least one carbon-carbon triple bond (sp).
  • Alkynyls include ethynyl, propynyls, butynyls, and pentynyls.
  • Hydrocarbon radicals having a mixture of double bonds and triple bonds, such as 2-penten-4- ynyl, are grouped as alkynyls herein.
  • Alkynyl does not include cycloalkynyl.
  • Alkoxy includes an optionally substituted straight chain or branched alkyl group with a terminal oxygen linking the alkyl group to the rest of the molecule.
  • Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and so on.
  • Aminoalkyl”, “thioalkyl”, and “sulfonylalkyl” are analogous to alkoxy, replacing the terminal oxygen atom of alkoxy with, respectively, NH (or NR), S, and SO 2 .
  • Heteroalkyl includes alkoxy, aminoalkyl, thioalkyl, and so on.
  • Aryl includes phenyl, naphthyl, biphenylyl, tetrahydronaphthyl, indenyl, and so on, any of which may be optionally substituted.
  • Aryl also includes arylalkyl groups such as benzyl, phenethyl, and phenylpropyl.
  • Aryl includes a ring system containing an optionally substituted 6-membered carbocyclic aromatic ring, said system may be bicyclic, bridge, and/or fused. The system may include rings that are aromatic, or partially or completely saturated.
  • ring systems include indenyl, pentalenyl, 1-4-dihydronaphthyl, indanyl, benzimidazolyl, benzothiophenyl, indolyl, benzofuranyl, isoquinolinyl, and so on.
  • Heterocyclyl includes optionally substituted aromatic and nonaromatic rings having carbon atoms and at least one heteroatom (O, S, N) or heteroatom moiety (SO 2 , CO, CONH, COO) in the ring.
  • a heterocyclic radical may have a valence connecting it to the rest of the molecule through a carbon atom, such as 3-furyl or 2-imidazolyl, or through a heteroatom, such as N-piperidyl or 1-pyrazolyI.
  • a monocyclic heterocyclyl has between 5 and 7 ring atoms, or between 5 and 6 ring atoms; there may be between 1 and 5 heteroatoms or heteroatom moieties in the ring, and preferably between 1 and 3, or between 1 and 2.
  • a heterocyclyl may be saturated, unsaturated, aromatic (e.g., heteroaryl), nonaromatic, or fused.
  • Heterocyclyl also includes fused, e.g., bicyclic, rings, such as those optionally condensed with an optionally substituted carbocyclic or heterocyclic five- or six-membered aromatic ring.
  • heteroaryl includes an optionally substituted six-membered heteroaromatic ring containing 1 , 2 or 3 nitrogen atoms condensed with an optionally substituted five- or six-membered carbocyclic or heterocyclic aromatic ring.
  • Said heterocyclic five- or six- membered aromatic ring condensed with the said five- or six-membered aromatic ring may contain 1 , 2 or 3 nitrogen atoms where it is a six-membered ring, or 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur where it is a five- membered ring.
  • heterocyclyls include thiazoylyl, furyl, thienyl, pyranyl, isobenzofuranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolyl, furazanyl, pyrrolidinyl, pyrrolinyl, imdazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, and morpholinyl.
  • heterocyclyls or heterocyclic radicals include morpholinyl, piperazinyl, pyrrolidinyl, pyridyl, cyclohexylimino, thienyl.and more preferably, piperidyl or morpholinyl.
  • heteroaryl examples include thienyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, benzothienyl, benzofuranyl, benzimidazolyl, benz ⁇ xazolyl, benzothiazolyl.
  • Acyl refers to a carbonyl moiety attached to either a hydrogen atom (i.e., a formyl group) or to an optionally substituted alkyl or alkenyl chain, or heterocyclyl.
  • Halo or “halogen” includes fluoro, chloro, bromo, and iodo, and preferably fluoro or chloro as a substituent on an alkyl group, with one or more halo atoms, such as trifluoromethyl, trifluoromethoxy, trifluoromethylthio, difluoromethoxy, or fluoromethylthio.
  • Alkanediyl or "alkylene” represents straight or branched chain optionally substituted bivalent alkane radicals such as, for example, methylene, ethylene, propylene, butylene, pentylene or hexylene.
  • Alkenediyl represents, analogous to the above, straight or branched chain optionally substituted bivalent alkene radicals such as, for example, propenylene, butenylene, pentenylene or hexenylene. In such radicals, the carbon atom linking a nitrogen preferably should not be unsaturated.
  • Aroyl refers to a carbonyl moiety attached to an optionally substituted aryl or heteroaryl group, wherein aryl and heteroaryl have the definitions provided above.
  • benzoyl is phenylcarbonyl.
  • two radicals, together with the atom(s) to which they are attached may form an optionally substituted 4- to 7-, 5 - to 7-, or a 5- to 6- membered ring carbocyclic or heterocyclic ring, which ring may be saturated, unsaturated or aromatic.
  • Said rings may be as defined above in the Summary of the Invention section. Particular examples of such rings are as follows in the next section.
  • “Pharmaceutically acceptable salts, esters, and amides” include carboxylate salts, amino acid addition salts, esters, and amides which are within a reasonable benefit/risk ratio, pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. These salts, esters, and amides may be, for example, C ⁇ - ⁇ alkyl, C 3- s cycloalkyl, aryl, C 2-10 heteroaryl, or C 2 - 1 0 non-aromatic heterocyclic salts, esters, and amides. Salts, free acids, and esters are more preferable than amides on the terminal carboxylate/carboxylic acid group on the left of formula (I).
  • Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, and laurylsulfonate.
  • alkali metal and alkali earth cations such as sodium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethylamine.
  • alkali metal and alkali earth cations such as sodium, potassium, calcium, and magnesium
  • non-toxic ammonium, quaternary ammonium, and amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethylamine.
  • amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethylamine.
  • Representative pharmaceutically acceptable amides of the invention include those derived from ammonia, primary C ⁇ - ⁇ alkyl amines and secondary di (C ⁇ - 6 alkyl) amines.
  • Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic ring moieties containing at least one nitrogen atom and optionally between 1 and 2 additional heteroatoms.
  • Preferred amides are derived from ammonia, C ⁇ -3 alkyl primary amines, and di (C ⁇ -2 alkyl)amines.
  • Representative pharmaceutically acceptable esters of the invention include C ⁇ _ 7 alkyl, C 5-7 cycloalkyl, phenyl, and phenyl(C ⁇ -6 )alkyl esters.
  • Preferred esters include methyl and ethyl esters.
  • Patient or subject includes mammals such as humans and animals (dogs, cats, horses, rats, rabbits, mice, non-human primates) in need of observation, experiment, treatment or prevention in connection with the relevant disease or condition.
  • the patient or subject is a human.
  • Composition includes a product comprising the specified ingredients in the specified amounts as well as any product which results from combinations of the specified ingredients in the specified amounts.
  • “Therapeutically effective amount” or “effective amount” means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the condition or disorder being treated.
  • each radical includes substituted radicals of that type and monovalent, bivalent, and multivalent radicals as indicated by the context of the claims.
  • the context will indicate that the substituent is an alkylene or hydrocarbon radical with at least two hydrogen atoms removed (bivalent) or more hydrogen atoms removed (multivalent).
  • An example of a bivalent radical linking two parts of the molecule is Y in formula (I) which links a phenyl substituted with R 5 , Re, and R to the rest of the molecule.
  • radicals or structure fragments as defined herein are understood to include substituted radicals or structure fragments.
  • Hydrocarbyls include monovalent radicals containing carbon and hydrogen such as alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl (whether aromatic or unsaturated), as well as corresponding divalent (or multi-valent) radicals such as alkylene, alkenylene, phenylene, and so on.
  • Heterocarbyls include monovalent and divalent (or multivalent) radicals containing carbon, optionally hydrogen, and at least one heteroatom.
  • Examples of monovalent heterocarbyls include acyl, acyloxy, alkoxyacyl, heterocyclyl, heteroaryl, aroyl, benzoyl, dialkylamino, hydroxyalkyl, and so on.
  • alkyl should be understood to include substituted alkyl having one or more substitutions, such as between 1 and 5, 1 and 3, or 2 and 4 substituents.
  • the substituents may be the same (dihydroxy, dimethyl), similar (chlorofluoro), or different (chlorobenzyl- or aminomethyl- substituted).
  • substituted alkyl examples include haloalkyl (such as fluoromethyl, chloromethyl, difluoromethyl, perchloromethyl, 2-bromoethyl, trifluoromethyl, and 3-iodocyclopentyl), hydroxyalkyl (such as hydroxymethyl, hydroxyethyl, 2-hydroxypropyl, aminoalkyl (such as aminomethyl, 2-aminoethyl, 3-aminopropyl, and 2-aminopropyl), nitroalkyl, alkylalkyl, and so on.
  • haloalkyl such as fluoromethyl, chloromethyl, difluoromethyl, perchloromethyl, 2-bromoethyl, trifluoromethyl, and 3-iodocyclopentyl
  • hydroxyalkyl such as hydroxymethyl, hydroxyethyl, 2-hydroxypropyl
  • aminoalkyl such as aminomethyl, 2-aminoethyl, 3-aminopropyl, and 2-
  • a di(C ⁇ - 6 alkyl)amino group includes independently selected alkyl groups, to form, for example, methylpropylamino and isopropylmethylamino, in addition dialkylamino groups having two of the same alkyl group such as dimethyl amino or diethylamino.
  • dialkylamino groups having two of the same alkyl group such as dimethyl amino or diethylamino.
  • first, only stable compounds are intended. For example, where there is an NRnR ⁇ 2 group, and R can be an alkenyl group, the double bond is at least one carbon removed from the nitrogen to avoid enamine formation.
  • compositions containing and methods of using compounds of formula (I) as described in the Summary section above include those compounds wherein: (a) one of Ri and R 2 is methyl or ethyl; (b) wherein each of Ri and R 2 is methyl; (c) Ri and R 2 taken together are cyclobutyl or cyclopentyl; (d) R 3 is H; (e) R 4 is H or C 2- alkyl; (e) R is H or C 2-5 alkyl; (f) R 4 is ethyl; (g) R is H; (h) n is 1 ; (i) n is 2; 0) Y is NHCH 2 ; (k) Y is NH; (I) X is S; (m) X is O; (n) at least one of R 5 and R 7 is H; (o) Re is C ⁇ - alkyl, halomethoxy, or halothiomethoxy; (p) Re is t-butyl,
  • Additional preferred compounds include:
  • the most preferred compounds are selected from:
  • the invention provides the disclosed compounds and closely related, pharmaceutically acceptable forms of the disclosed compounds, such as salts, esters, amides, acids, hydrates or solvated forms thereof; masked or protected forms; and racemic mixtures, or enantiomerically or optically pure forms.
  • Related compounds also include compounds of the invention that have been modified to be detectable, e.g., isotopically labelled with 18 F for use as a probe in positron emission tomography (PET) or single-photon emission computed tomography (SPECT).
  • the invention also includes disclosed compounds having one or more functional groups (e.g., hydroxyl, amino, or carboxyl) masked by a protecting group. See, e.g., Greene and Wuts, Protective Groups in Organic Synthesis. 3 rd ed., (1999) John Wiley & Sons, NY. Some of these masked or protected compounds are pharmaceutically acceptable; others will be useful as intermediates. Synthetic intermediates and processes disclosed herein, and minor modifications thereof, are also within the scope of the invention.
  • Protection for the hydroxyl group includes methyl ethers, substituted methyl ethers, substituted ethyl ethers, substitute benzyl ethers, and silyl ethers.
  • substituted methyl ethers examples include methyoxymethyl, methylthiomethyl, t-butylthiomethyl, benzyloxymethyl, p- methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl, t-butoxymethyl.
  • substituted ethyl ethers include 1-ethoxyethyl, 1-methyl-1- methoxyethyl, 1 -methyl- 1-benzyloxyethyl, 2,2,2-trichloroethyl, t-butyl, allyl, p- chlorophenyl, p-methoxyphenyl, and benzyl. Substituted Benzyl Ethers
  • substituted benzyl ethers include p-methoxybenzyl, 3,4- dimethoxybenzyl, p-halobenzyl, 2,6-dichIorobenzyl, p-cyanobenzyl, p- phenylbenzyl, diphenylmethyl.
  • esters include formate, benzoylformate, acetate, trichloroacetate, trifluoroacetate, methoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, benzoate.
  • sulfonates include sulfate, methanesulfonate(mesylate), benzylsulfonate, and tosylate.
  • Protection for the amino group includes carbamates, amides, and special -NH protective groups.
  • carbamates examples include methyl and ethyl carbamates, substituted ethyl carbamates, assisted cleavage carbamates, photolytic cleavage carbamates, urea-type derivatives, and miscellaneous carbamates.
  • methyl and ethyl carbamates examples include methyl and ethyl, 9- fluorenylmethyl, and 4-methoxyphenacyl.
  • substituted ethyl carbamates include 2,2,2-trichloroethyl, 2- phenylethyl, t-butyl, vinyl, allyl, 1-isopropylallyl , benzyl, p-methoxybenzyl, p- nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl and diphenylmethyl.
  • photolytic cleavage examples include m-nitrophenyl, 3,5- dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, and phenyI(o- nitrophenyl)methyl.
  • amides include N-formyl, N-acetyl, N-trichloroacetyl, N- trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl, N-3- pyridylcarboxamide, N-benzoyl, N-p-phenylbenzoyl, and phthaloyl.
  • cyclic acetals and ketals examples include 1 ,3-dioxanes and 5- methylene-1 ,3-dioxane.
  • substituted methyl esters examples include 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, methoxyethoxymethyl, 2- (trimethylsilyl)ethoxymethyl, benzyl oxymethyl, phenacyl, p-bromophenacyl, ⁇ - methylphenacyl, and p-methoxyphenacyl.
  • esters also include straight chain or branched alkyl esters such as tert-butyl, ethyl, propyl, isopropyl, and butyl.
  • substituted benzyl esters include triphenylmethyl, diphenylmethyl, 9-anthrylmethyl, 2,4,6-trimethylbenzyl, p-bromobenzyl, o- nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl, 2,6-dimethoxybenzyl, piperonyl, 4- picolyl and p-P-benzyl.
  • silyl esters examples include trimethylsilyl, triethylsilyl, f-butyldimethylsilyl, / ' -propyldimethylsilyl, phenyldimethylsilyl and di-f- butylmethylsilyl.
  • the invention provides methods of making the disclosed compounds according to traditional organic synthetic methods as well as matrix or combinatorial synthetic methods.
  • Schemes 1 through 10 describe suggested synthetic routes. Using these Schemes, the guidelines below, and the examples, a person of skill in the art may develop analogous or similar methods for a given compound that are within the invention.
  • synthesis of the compounds of the present invention may be effected by purchasing an intermediate or protected intermediate compounds described in any of the schemes disclosed herein.
  • One skilled in the art will further recognize that during any of the processes for preparation of the compounds in the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in "Protective Groups in Organic Synthesis", John Wiley & Sons, 1991. These protecting groups may be removed at a convenient stage using methods known from the art.
  • Examples of the described synthetic routes include Synthetic Examples 1 through 57. Compounds analogous to the target compounds of these examples can be, and in many cases, have been, made according to similar routes. The disclosed compounds are useful in basic research and as pharmaceutical agents as described in the next section.
  • Abbreviations or acronyms used herein include: AcOH (glacial acetic acid); DCC (1 ,3-dicycIohexylcarbodiimide); DCE (1 ,2-dichloroethane); DIG (2-dimethylaminoisopropyl chloride hydrochloride); DIEA (diisopropylethylamine); DMF (dimethylformamide); EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide); EtOAc (ethyl acetate); mCPBA (3-chloroperoxybenzoic acid); NMI (1-methylimidazole); TEA (triethylamine);TFA (trifluoroacetic acid); THF (tetrahydrofuran);TMEDA (N, N, N', N'-tetramethyl- ethylenediamine).
  • the tetralins can be made by conversion of compound 1 to compound 2.
  • a methoxy-2-tetralone such as 6- methoxy-2-tetralone
  • a reagent such as ammonium acetate or ammonia, or hydroxyl amine.
  • the corresponding imine can be reduced with an appropriate reducing agent, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride and the resulting oxime can be reduced catalytically using palladium or platinum in a polar protic solvent, such as methanol, ethanol or ethyl acetate, to obtain a racemic compound 2.
  • a polar protic solvent such as methanol, ethanol or ethyl acetate
  • the indanes can be prepared by conversion of a compound 3 to a compound 5.
  • a methoxy indanone such as 5-methoxy-1 -indanone
  • an acylating agent such as butyl nitrite or isoamyl nitrite in the presence of a catalytic amount of acid, such as hydrochloric acid or hydrobromic acid in a polar solvent, such as methanol or ether
  • a keto-oxime 4 is obtained.
  • Reduction of a compound 4 can be achieved by using the appropriate reducing agent(s), such as lithium aluminum hydride or hydrogen and a catalyst, such as palladium or platinum, in an appropriate solvent, such as acetic acid-sulfuric acid, THF, or methanol at an appropriate temperature.
  • reducing agent(s) such as lithium aluminum hydride or hydrogen and a catalyst, such as palladium or platinum
  • an appropriate solvent such as acetic acid-sulfuric acid, THF, or methanol at an appropriate temperature.
  • a compound 2 or 5 can be converted to a compound 12.
  • a racemic amine hydrochloride is treated with a base, such as sodium hydride or lithium hydride in a polar aprotic solvent, such as DMF or THF and consequently reacted with an anhydride, such as phthalic anhydride at elevated temperatures, a cyclic imide 6 can be furnished.
  • Cleavage of methyl aryl ethers of Formula 6 to a compound of the Formula 7 can be accomplished using a Lewis acid such as boron tribromide, boron trichloride, aluminum chloride or trimethylsilyliodide in nonpolar, aprotic solvents such as toluene, dichloromethane, or dichloroethane with or without cooling.
  • a Lewis acid such as boron tribromide, boron trichloride, aluminum chloride or trimethylsilyliodide in nonpolar, aprotic solvents such as toluene, dichloromethane, or dichloroethane with or without cooling.
  • Acylation of phenols of Formula 7 to a compound of Formula 8 can be achieved using thiocarbamoyl chlorides, such as dimethylaminothiocarbamoyl chloride or diethylthiocarbamoyl chloride and a non-reactive, tertiary
  • Compounds of Formula 8 can be rearranged thermally to compounds of Formula 9 at temperatures between 180 °C to 350 °C, either neat as a melt or using high-boiling solvents such as DOWTHERM ® A (a mixture of biphenyl and biphenyl ether sold by, for example, Fluka Chemical Corp., Milwaukee, Wl USA), N,N-dimethylaniline, diphenyl ether or decalin.
  • Compounds of Formula 10 can be prepared from compounds of Formula 9 by treating with a suitable nucleophile, such as hydrazine, disodium sulfide or methylamine in appropriate polar solvent such as ethanol or THF at elevated temperatures.
  • Conversion of Formula 10 to compounds of Formula 11 can be achieved using an appropriate reagent, such as potassium hydroxide in an alchoholic solvent, such as ethanol or methanol, or lithium aluminum hydride in THF or ether, followed by alkylation using an appropriately substituted alkyl halide, such as terf-butyl 2-bromoisobutyrate, ethyl bromoacetate, or ethyl 2- bromobutyrate and a reducing agent, such as lithium borohydride or sodium borohydride.
  • an appropriate reagent such as potassium hydroxide in an alchoholic solvent, such as ethanol or methanol, or lithium aluminum hydride in THF or ether
  • an appropriately substituted alkyl halide such as terf-butyl 2-bromoisobutyrate, ethyl bromoacetate, or ethyl 2- bromobutyrate
  • a reducing agent such as lithium borohydride or sodium borohydride.
  • Compounds of Formula 11 can be substituted to provide compounds of Formula 12 using a carboxylic acid or an acid chloride and an appropriate reducing agent such as borane-THF or borane-dimethylsulfide, using aprotic solvents such as THF, dichloromethane, or hexanes.
  • substitution can be accomplished using an aldehyde and a reducing agent, such as sodium cyanoborohydride or sodium triacetoxyborohydride, in appropriate aprotic solvents, such as THF, dichloromethane or dichloroethane.
  • compounds of Formula 13 can be prepared from compounds of Formula 12 by acylating a secondary amine with an aryl acetic acid, using thionyl chloride or oxalyl chloride neat or in toluene or dichloromethane with or without catalytic DMF.
  • the coupling can be achieved using standard peptide conditions, such as EDC, DCC, or DIG in dichloromethane.
  • EDC EDC
  • DCC e.
  • DIG dichloromethane
  • Y NH or O
  • an aryl isocyanate or aryl chloroformate, respectively, in a non-polar aprotic solvent, such as THF, dichloromethane or hexanes can be used to provide compounds of Formula 13.
  • a non-polar aprotic solvent such as THF
  • dichloromethane or hexanes can be used to provide compounds of Formula 13.
  • the choice of deprotection methods may be easily determined by one skilled in the art to provide compounds
  • compounds of Formula 16 can be prepared from compounds of
  • a compound of Formula 18 can be prepared from a compound of Formula
  • compound of Formula 10 can be treated with ethyl formate or ammonium formate either neat or in the presence of a suitable solvent, such as dichloromethane or dichloroethane with or without heating to provide a compound of Formula 17.
  • a suitable solvent such as dichloromethane or dichloroethane
  • Compounds of Formula 17 can be converted to compounds of Formula 18 by using an appropriate reagent, such as lithium aluminum hydride in a suitable solvent, such as THF or ether followed by alkylation using an appropriately substituted alkyl halide, such as terf-butyl 2- bromoisobutyrate, ethyl bromoacetate, or ethyl 2-bromobutyrate and a reducing agent, such as lithium borohydride or sodium borohydride.
  • an appropriate reagent such as lithium aluminum hydride in a suitable solvent, such as THF or ether
  • an appropriately substituted alkyl halide such as terf-butyl 2- bromoi
  • Compounds of Formula 20 can be converted to compounds of Formula 21 by treating with an appropriate base, such as potassium carbonate, cesium carbonate or potassium hydroxide and an appropriately substituted alkyl halide, such as terf-butyl 2- bromoisobutyrate, ethyl bromoacetate, or ethyl 2-bromobutyrate in a suitable solvent, such as DMF or methanol.
  • an appropriate base such as potassium carbonate, cesium carbonate or potassium hydroxide
  • an appropriately substituted alkyl halide such as terf-butyl 2- bromoisobutyrate, ethyl bromoacetate, or ethyl 2-bromobutyrate in a suitable solvent, such as DMF or methanol.
  • compound of Formula 22 can be treated with an appropriate base, such as butyl lithium or sec-butyl lithium in an appropriate solvent, such as ether or THF, with or without TMEDA and cooling, and the appropriate electrophile, such as alkyl halides, aldehydes, or disulfides to provide compounds of Formula 23.
  • an appropriate base such as butyl lithium or sec-butyl lithium
  • an appropriate solvent such as ether or THF
  • TMEDA and cooling the appropriate electrophile, such as alkyl halides, aldehydes, or disulfides
  • Compounds of Formula 29 can be substituted to provide compounds of Formula 30 using a carboxylic acid under coupling conditions outlined previously or an acid chloride with a tertiary amine, such as diisopropylethylamine or triethylamine in a suitable solvent, such as dichloromethane or dichloroethane.
  • a tertiary amine such as diisopropylethylamine or triethylamine in a suitable solvent, such as dichloromethane or dichloroethane.
  • a compound of Formula 30 can converted to a compound of Formula 31 using with an oxidizing agent, such as mCPBA or hydrogen peroxide in a suitable solvent, such as methylene chloride, followed by subsequent treatment of compounds of Formula 30 with trifluoroacetic anhydride with or without a solvent, such as chloroform, followed by treatment with a tertiary amine, such as triethylamine or diisopropylethylamine in a suitable solvent, such as methanol affords compounds of Formula 31.
  • an oxidizing agent such as mCPBA or hydrogen peroxide in a suitable solvent, such as methylene chloride
  • trifluoroacetic anhydride with or without a solvent, such as chloroform
  • a tertiary amine such as triethylamine or diisopropylethylamine in a suitable solvent, such as methanol affords compounds of Formula 31.
  • deprotection of the thio ether in compounds of Formula 30 can be achieved using a base, such as tert-butyl sodium sulfide, sodium, sodium methyl thiol in a suitable solvent, such as DMF, N-methyl-2-pyrrolidone or ammonia to provide compounds of Formula 31.
  • a base such as tert-butyl sodium sulfide, sodium, sodium methyl thiol in a suitable solvent, such as DMF, N-methyl-2-pyrrolidone or ammonia
  • a suitable solvent such as DMF, N-methyl-2-pyrrolidone or ammonia
  • compounds of Formula 22 can be treated with an appropriate base, such as butyl lithium or sec-butyl lithium in an appropriate solvent, such as ether or THF, with or without TMEDA and cooling, and the appropriate disulfide, such as dimethyl disulfide or dibenzyl disulfide provide compounds of Formula 33.
  • an appropriate base such as butyl lithium or sec-butyl lithium
  • an appropriate solvent such as ether or THF
  • TMEDA and cooling such as TMEDA and cooling
  • disulfide such as dimethyl disulfide or dibenzyl disulfide
  • Removal of the dimethylamino thiocarbamate from compounds of Formula 33 is achieved using potassium or sodium hydroxide in an appropriate solvent, such as water, methanol, or ethanol with or without heating, to afford compounds of Formula 34.
  • Compounds of Formula 34 can be methylated to provide compounds of Formula 19a by using methyl iodide, dimethylsulfate, or diazomethane in an appropriate solvent, such as DMF, methanol, or dichloromethane, with or without base, such as cesium carbonate or potassium carbonate.
  • an appropriate solvent such as DMF, methanol, or dichloromethane
  • base such as cesium carbonate or potassium carbonate.
  • the crude residue is purified by flash chromatography (Si ⁇ 2 ) eluting with a hexanes-EtOAc gradient to provide 3.1 g (58%) of dimethylthiocarbamic acid S-[6-(1 ,3-dioxo-1 ,3-dihydroisoindol-2-yl)- 5,6,7,8-tetrahydronaphthalen-2-yl] ester as a white solid.
  • the aqueous phase is extracted extensively with CHCI 3 several times and the extracts are combined, washed with H 2 O, brine, dried over Na 2 SO 4 , filtered and evaporated under reduced pressure to provide 77.3 g (66%) of a crude oil.
  • the oil was subjected to flash chromatography (SiO 2 ) eluting with 40 : 2.2 : 0.2 CHCI3 : MeOH : NH 4 OH to provide 43.8 g (37%) of a dark oil.
  • the oil is dissolved in ether (1 L), cooled to 0 °C, and the solution is saturated with HCI (g). The solvent was removed under reduced pressure and the solid triturated with ether, filtered, and washed with ether to provide 43.8 g (30%) of 5-methoxyindan-2-ylamine hydrochloride as a white solid.
  • reaction mixture was diluted with CH2CI2, washed with H 2 O, brine, dried over Na 2 SO 4 , filtered and the solvent evaporated under reduced pressure to afford 2-methyl-2-(2-pent-4- enylaminoindan-5-ylsulfanyl)propionic acid tert-butyl ester as a crude oil.
  • Compound 2.26 (20 mg; 56% for 2 steps; white solid) was prepared following Route 2 and Compound 2.14 by replacing 4-trifluoromethoxyphenyl isocyanate with 4-trifluoromethylphenyl isocyanate.
  • Compound 1.6 (10 mg; oil) can be prepared by replacing 4- trifluoromethoxyphenyl isocyanate with 4-tert-butyl phenyl isocyanate and using Route 1 , steps I, J, and K and Schemes 4 and 10.
  • Compound 5.2 can be prepared prepared following Route 5, substituting carbonic acid 1 -chloro-ethyl ester 4-trifluoromethoxy phenyl ester for p-tolyl chlroroformate and Step M of Route 2.
  • compound 5.2 can be prepared using the following procedure:
  • This oil was added to a solution of carbonic acid 1- chloro-ethyl ester 4-trifluoromethoxy-phenyl ester (1.23g; 4.31 mmol) in toluene(8 mL), and the reaction mixture was stirred for 1 h at RT followed by 1 h at 90 °C. The reaction was allowed to cool to RT, diluted with Et 2 O and washed with 1 N of aqueous HCI and saturated NaHCO 3 . The organic extract was dried over Na 2 SO 4 , and the solvent was removed under reduced pressure.
  • the compounds of the present invention may be formulated into various pharmaceutical forms for administration purposes.
  • an effective amount of a particular compound, in base or acid addition salt form, as the active ingredient is intimately mixed with a pharmaceutically acceptable carrier.
  • a carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for oral administration or parenteral injection.
  • any of the usual pharmaceutical media may be employed. These include water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets.
  • tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are generally employed.
  • the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
  • injectable solutions for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
  • injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause a significant deleterious effect to the skin. Such additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
  • compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.
  • Acid addition salts of the compounds of formula I due to their increased water solubility over the corresponding base form, are more suitable in the preparation of aqueous compositions.
  • Posage unit form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
  • Pharmaceutically acceptable acid addition salts include the therapeutically active non-toxic acid addition salt forms which the disclosed compounds are able to form. The latter can conveniently be obtained by treating the base form with an appropriate acid.
  • Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g.
  • hydrochloric or hydrobromic acid sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, palmoic and the like acids.
  • the term addition salt also comprises the solvates which the disclosed componds, as well as the salts thereof, are able to form.
  • Stereoisomeric forms define all the possible isomeric forms which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More in particular, stereogenic centers may have the (R)- or (S)-configuration; substituents on bivalent cyclic saturated radicals may have either the cis- or trans-configuration.
  • the invention encompasses stereochemically isomeric forms including diastereoisomers, as well as mixtures thereof in any proportion of the disclosed compounds.
  • the disclosed compounds may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above and following formulae are intended to be included within the scope of the present invention.
  • compound 2.1 or Example 3 there is a chiral center on the C-2 of the indane ring.
  • the (S) isomer is more active than the (R) isomer.
  • a therapeutically effective dose would be from 0.001 mg/kg to 5 mg/kg body weight, more preferably from 0.01 mg/kg to 0.5 mg/kg body weight. It may be appropriate to administer the therapeutically effective dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 0.05 mg to 250 mg or 750 mg, and in particular 0.5 to 50 mg of active ingredient per unit dosage form. Examples include 2 mg, 4 mg, 7 mg, 10 mg, 15 mg, 25 mg, and 35 mg dosage forms.
  • Compounds of the invention may also be prepared in time- release or subcutaneous or transdermal patch formulations. Pisclosed compound may also be formulated as a spray or other topical or inhalable formulations.
  • the exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient as well as other medication the patient may be taking, as is well known to those skilled in the art.
  • said effective daily amount may be lowered or increased depending on the response of the treated patient and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.
  • the effective daily amount ranges mentioned herein are therefore only guidelines.
  • the compounds of the present invention are pharmaceutically active, for example, as PPAR alpha agonists.
  • the compounds are preferably selective PPAR alpha agonists, having an activity index (e.g., PPAR alpha potency over PPAR gamma potency) of 10 or more, and preferably 15, 25, 30, 50 or 100 or more.
  • PPAR alpha agonists are useful for the treatment, prevention, or inhibiting the progression of one or more of the following conditions or diseases: phase I hyperlipidemia, pre-clinical hyperlipidemia, phase II hyperlipidemia, hypertension, CAP (coronary artery disease), coronary heart disease, and hypertriglyceridemia.
  • Preferred compounds of the invention are useful in lowering serum levels of low-density lipoproteins (LPL), IPL, and/or small-density LPL and other atherogenic molecules, or molecules that cause atherosclerotic complications, thereby reducing cardiovascular complications.
  • Preferred compounds also are useful in elevating serum levels of high-density lipoproteins (HPL), in lowering serum levels of triglycerides, LPL, and/or free fatty acids. It is also desirable to lower FPG/HbA1c.
  • HPL high-density lipoproteins
  • the compounds of the present invention may be used in combination with other pharmaceutically active agents. These agents include lipid lowering agents, and blood pressure lowering agents.
  • compositions or the disclosed drug combinations are known in the art for determining effective doses for therapeutic and prophylactic purposes for the disclosed pharmaceutical compositions or the disclosed drug combinations, whether or not formulated in the same composition.
  • joint effective amount means that amount of each active compound or pharmaceutical agent, alone or in combination, that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • the term "jointly effective amount” refers to that amount of each active compound or pharmaceutical agent, alone or in combination, that treats or inhibits in a subject the onset or progression of a disorder as being sought by a researcher, veterinarian, medical doctor or other clinician.
  • the present invention provides combinations of two or more drugs wherein, for example, (a) each drug is administered in an independently therapeutically or prophylactically effective amount; (b) at least one drug in the combination is administered in an amount that is sub-therapeutic or sub-prophylactic if administered alone, but is therapeutic or prophylactic when administered in combination with the second or additional drugs according to the invention; or (c) both (or more) drugs are administered in an amount that is sub-therapeutic or sub-prophylactic if administered alone, but are therapeutic or prophylactic when administered together.
  • the compounds of the invention may be more potent and efficacious for lowering triglycerides than known fibrates.
  • the present compounds also may increase fat and/or lipid metabolism, providing a method for losing weight, losing fat weight, lowering body mass index, lowering lipids (such as lowering triglycerides), or treating obesity or the condition of being overweight.
  • lipid lowering agents include bile acid sequestrants, fibric acid derivatives, nicotinic acid, and HMGCoA reductase inhibitors.
  • statins such as LIPITORTM, ZOCORTM, PRAVACHOLTM, LESCOLTM, and MEVACORTM
  • pitavastatin nisvastatin
  • APX-159 extended release lovastatin
  • Colestid Locholest, Questran, Atromid, Lopid, and Tricor.
  • blood pressure lowering agents include anti-hypertensive agents, such as angiotensin-converting enzyme (ACE) inhibitors (Accupril, Altace, Captopril, Lotensin ,Mavik, Monopril, Prinivil, Univasc, Vasotec, and Zestril), adrenergic blockers (such as Cardura, Pibenzyline, Hylorel, Hytrin, Minipress, and Minizide) alpha/beta adrenergic blockers (such as Coreg, Normodyne, and Trandate), calcium channel blockers (such as Adalat, Calan, Cardene, Cardizem, Covera-HS, Pilacor, PynaCirc, Isoptin, Nimotop, Norvace, Plendil, Procardia, Procardia XL, Sula, Tiazac, Vascor, and Verelan), diuretics, angiotensin II receptor antagonists (such as Atacand, Avapro, Coza
  • Example 60 - ⁇ 6-[Ethyl-(4-trifluoromethoxy-phenoxycarbonyl)-amino]-5,6,7,8-tetrahydro- naphthalen-2-ylsulfanyl ⁇ -2-methyl-propionic acid
  • HP bPNA Assay H4IIE rat hepatoma cell line was obtained from ATCC. Cells were cultured in 175cm 2 tissue culture flask or seeded in 96-welI plate with (high serum content, 10% fetal bovine serum and 10% calf serum) culture medium and maintained at 37°C and 5% CO2 throughout study. Twenty-four hours after the initial seeding of the 96-well plate by hand (approximate 100,000/well), the HP gene induction assay was initiated. Media was removed and replaced with 100ul of low serum culture media (5% charcoal/dextran treated calf serum) containing vehicle (PMSO) or test compounds or standard. Cells returned to incubator for 24 hours culture.
  • low serum culture media 5% charcoal/dextran treated calf serum
  • PMSO vehicle
  • lysis buffer with HO gene specific CE, LE, BL probes was added directly into each well to initiate the bPNA HP mRNA assay.
  • the branched PNA assay was performed according to the manufacturer's protocol (Bayer Piagnostics; Emeryville. CA.).
  • the luminescence was quantitated in Pynex MLX microtiter plate luminometer. ECso's were determined by non-linear regression with a sigmoidal fit utilizing Graphpad Prism.
  • HEK293 cells were grown in PMEM/F-12 Media supplemented with 10% FBS and glutamine (GIBCOBRL). The cells were co-transfected with PNA for PPAR-Gal4 receptor and Gal4-Luciferase Reporter using the PMRIE-C Reagent. On the following day, the PNA-containing medium were replaced with 5% Charcoal treated FBS growth medium. After six hours, cells were seeded in 96well plate and incubated at 37 °C in CO2 incubator overnight. Cells were challenged by test compounds and incubated for 24 hours at 37°C in 5%CO 2 incubator. Luciferase activity was assayed using the Steady-Glo Luciferase Assay Kit from Promega.
  • PMRIE-C Reagent was purchased from GIBCO Cat. No.10459-014.
  • OPTI-MEM I Reduced Serum Medium was purchased from GIBCO Cat. No. 31985.
  • Steady-Glo Luciferase Assay Kit was obtained from Promega Part# E254B.
  • the differentiation assay may be initiated.
  • Medium may be removed and replaced with 150 ⁇ l of differentiation medium containing vehicle (PMSO) or test compounds. Cells may be returned to incubator for 24 hours culture.
  • PMSO differentiation medium containing vehicle
  • 100 ul of lysis buffer may be added to initiate the bPNA aP2 mRNA assay.
  • the branched PNA assay may be performed according to the manufacturer's protocol (Bayer Piagnostics; Emeryville, CA). Result may be expressed as the fold increase of aP2 mRNA production activated over vehicle controls.
  • EC 50 's and Emax may be determined by non-linear regression with a sigmoidal fit curve.
  • cells may be lysed with lysis buffer (Bayer Piagnostics) containing the aP2 oligonucleotides.
  • 70 ul of the lysis buffer from each well may be added to a corresponding capture well (preincubated with 70 ul of blocking buffer (Bayer Piagnostics)).
  • the capture plate may be incubated overnight at 53°C in a plate incubator (Bayer Piagnostics).
  • the bPNA and labeled probes may be annealed as directed by the manufacturer. Following a 30-minute incubation with the luminescent alkaline phosphatase substrate, dioxitane, the luminescence may be quantitated in a Pynex MLX microtiter plate luminometer.
  • Oligonucleotide probes designed to anneal to the aP2 mRNA and function in the bPNA mRNA detection system are designed with ProbePesigner software (Bayer Piagnostics). This software package analyzes a target sequence of interest with a series of algorithms in order to determine which regions of the sequence can perform as locations for capture, label, or spacer probe annealing.
  • the sequences of the oligonucleotides are as follows:
  • mice Male db/db mice (C57 BLK S/J-m+/+Lepr db , Jackson Labs, Bar Harbor, ME), 6-7 weeks of age, were housed four per cage in solid-bottomed shoe box cages. Room temperature was maintained at 68-72 °F and humidity at 50-65%. Room lighting was on a 12-hour light/12-hour dark cycle. Mice were fed a certified NIH Rat and Mouse/Auto 6F reduced fat diet #5K52 (P M I Nutrition Int'I, St. Louis, MO, via W. F. Fisher and Son, Inc., Bound Brook, NJ). Food and water were supplied ad libitum.
  • the compound was prepared as suspensions in 0.5% hydroxypropyl- methylcellulose (Pow Chemical, Midland, Ml). The dosing volume was 10 mL/kg of body weight.
  • mice 18-24 hours after the final dose for each group, the mice were anesthetized with CO 2 /O 2 (70:30) and bled by retro-orbital sinus puncture into micro-tubes containing clog activator and then put in ice.
  • the serum samples were prepared by centrifugation.
  • Serum glucose and triglycerides were determined by using COBAS Mira Plus blood chemistry analyzer (Roche Piagnostics, NJ). Serum insulin was measured by using ALPCO insulin ELISA kit.
  • Statistical analysis was performed using the program Prism (Graphpad, Monrovia, CA) and performing one-way ANOVA with a Punnett's multiple comparison test.
  • mice Male ob/ob mice (C57 BL/6J-Lep ob , Jackson Labs, Bar Harbor, ME), 7 weeks of age, were housed two per cage in solid-bottomed shoe box cages. Room temperature was maintained at 68-72 °F and humidity at 50-65%. Room lighting was on a 12-hour light/12-hour dark cycle. Mice were fed a certified NIH Rat and Mouse diet #5K50 (P M I Nutrition Int'I, St. Louis, MO, via W. F. Fisher and Son, Inc., Bound Brook, NJ). Food and water were supplied ad libitum.
  • the compound was prepared as suspensions in 0.5% hydroxypropyl- methylcellulose (Pow Chemical, Midland, Ml). The dosing volume was 10 mL/kg of body weight.
  • mice 18 hours after the final dose for each group, the mice were anesthetized with CO 2 /O 2 (70%:30%) and bled by retro-orbital sinus puncture into micro-tubes containing clog activator and then put in ice.
  • the serum samples were prepared by centrifugation.
  • Serum glucose and triglycerides were determined by using COBAS Mira Plus blood chemistry analyzer (Roche Piagnostics, NJ). Serum insulin and free fatty acids were measured by using ALPCO insulin ELISA kit and Wako NEFA kit, respectively.

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  • Chemical & Material Sciences (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Diabetes (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des composés à base de tétralines et d'indanes représentés par la formule générale (I), des compositions contenant ces composés, et leurs méthodes d'utilisation. Ces composés et ces compositions sont utilisés comme modulateurs des PPAR alpha pour traiter ou stopper la progression de la dyslipidémie, par exemple.
PCT/US2003/033090 2002-10-21 2003-10-17 Tetralines et indanes substitues WO2004037778A1 (fr)

Priority Applications (13)

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CA002502661A CA2502661A1 (fr) 2002-10-21 2003-10-17 Tetralines et indanes substitues
BR0315596-0A BR0315596A (pt) 2002-10-21 2003-10-17 Tetralinas e indanos substituìdos
AU2003277441A AU2003277441B2 (en) 2002-10-21 2003-10-17 Substituted tetralins and indanes
EP03809577A EP1569897A1 (fr) 2002-10-21 2003-10-17 Tetralines et indanes substitues
UAA200503452A UA80297C2 (en) 2002-10-21 2003-10-17 Substituted tetralins and indanes
JP2005501629A JP2006503916A (ja) 2002-10-21 2003-10-17 置換テトラリンおよびインダン
NZ539510A NZ539510A (en) 2002-10-21 2003-10-17 Substituted tetralin and indane derivatives
MXPA05004191A MXPA05004191A (es) 2002-10-21 2003-10-17 Tetralinas e indanos sustituidos.
YUP-2005/0318A RS20050318A (en) 2002-10-21 2003-10-17 Substituted tetralins and indanes
EA200500515A EA009553B1 (ru) 2002-10-21 2003-10-17 Замещённые тетралины и инданы
HR20050335A HRP20050335A2 (en) 2002-10-21 2005-04-14 Substituted tetralins and indanes
EGNA2005000152 EG24842A (en) 2002-10-21 2005-04-20 Substituted tetralins and indanes
NO20052199A NO20052199L (no) 2002-10-21 2005-05-04 Substituerte tetraliner og indaner

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US41993502P 2002-10-21 2002-10-21
US60/419,935 2002-10-21
US49527003P 2003-08-15 2003-08-15
US60/495,270 2003-08-15

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005105737A1 (fr) * 2004-04-21 2005-11-10 Janssen Pharmaceutica, N.V. Procedes de preparation de derives de tetraline substituee et d'indane substitue
WO2006049941A2 (fr) * 2004-10-27 2006-05-11 Neurogen Corporation Diaryl urees, antagonistes du cb1
US10471066B2 (en) 2005-12-22 2019-11-12 Vtv Therapeutics Llc Phenoxy acetic acids and phenyl propionic acids as PPAR delta agonists

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT1554240E (pt) * 2002-10-21 2009-06-17 Janssen Pharmaceutica Nv Tetralinas e indanos substituídos e sua utilização
JP2006503915A (ja) * 2002-10-21 2006-02-02 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ 置換テトラリンおよびインダンを用いたｘ症候群の治療

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997036579A1 (fr) * 1996-03-30 1997-10-09 Glaxo Group Limited Utilisation d'agonistes du recepteur alpha active par un proliferateur de peroxysome pour traiter l'obesite
WO2000023407A2 (fr) * 1998-10-16 2000-04-27 Glaxo Group Limited Composes chimiques
WO2002064130A1 (fr) * 2001-02-15 2002-08-22 Pfizer Products Inc. Composes de recepteurs actives de la proliferation des peroxysomes (ppar)

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2400021A1 (fr) * 2000-02-18 2001-08-23 Merck & Co., Inc. Acides aryloxyacetiques utilises en cas de diabete et de troubles lipidiques
PL361162A1 (en) * 2000-10-05 2004-09-20 Bayer Aktiengesellschaft Propionic acid derivatives with ppar-alpha activating properties
WO2002044129A1 (fr) * 2000-11-29 2002-06-06 Kyorin Pharmaceutical Co., Ltd. Dérivés d'acide carboxylique substitués
JPWO2002046146A1 (ja) * 2000-12-05 2004-04-08 杏林製薬株式会社 置換カルボン酸誘導体
WO2002050047A1 (fr) * 2000-12-20 2002-06-27 Glaxo Group Limited Oxazoles et thiazoles substitues utiles en tant qu'agonistes de hppar alpha
UA82835C2 (en) * 2001-12-03 2008-05-26 Reddys Lab Ltd Dr ?-aryl-?-oxysubstituted propionuc acid derivatives and pharmaceutical composition based thereon
PT1554240E (pt) * 2002-10-21 2009-06-17 Janssen Pharmaceutica Nv Tetralinas e indanos substituídos e sua utilização
JP2006503915A (ja) * 2002-10-21 2006-02-02 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ 置換テトラリンおよびインダンを用いたｘ症候群の治療

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997036579A1 (fr) * 1996-03-30 1997-10-09 Glaxo Group Limited Utilisation d'agonistes du recepteur alpha active par un proliferateur de peroxysome pour traiter l'obesite
WO2000023407A2 (fr) * 1998-10-16 2000-04-27 Glaxo Group Limited Composes chimiques
WO2002064130A1 (fr) * 2001-02-15 2002-08-22 Pfizer Products Inc. Composes de recepteurs actives de la proliferation des peroxysomes (ppar)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005105737A1 (fr) * 2004-04-21 2005-11-10 Janssen Pharmaceutica, N.V. Procedes de preparation de derives de tetraline substituee et d'indane substitue
US7576238B2 (en) 2004-04-21 2009-08-18 Janssen Pharmaceutica N.V. Process for the preparation of substituted tetralin and substituted indane derivatives
WO2006049941A2 (fr) * 2004-10-27 2006-05-11 Neurogen Corporation Diaryl urees, antagonistes du cb1
WO2006049941A3 (fr) * 2004-10-27 2006-12-28 Neurogen Corp Diaryl urees, antagonistes du cb1
US10471066B2 (en) 2005-12-22 2019-11-12 Vtv Therapeutics Llc Phenoxy acetic acids and phenyl propionic acids as PPAR delta agonists

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HRP20050335A2 (en) 2006-05-31
AU2003277441B2 (en) 2009-05-07
EA009553B1 (ru) 2008-02-28
TW200418773A (en) 2004-10-01
RS20050318A (en) 2007-09-21
JP2006503916A (ja) 2006-02-02
EP1569897A1 (fr) 2005-09-07
AU2003277441A1 (en) 2004-05-13
NZ539510A (en) 2008-01-31
NO20052199L (no) 2005-06-24
EG24842A (en) 2010-10-13
KR20050055773A (ko) 2005-06-13
BR0315596A (pt) 2005-09-06
CR7795A (es) 2012-10-25
PL376325A1 (en) 2005-12-27
CA2502661A1 (fr) 2004-05-06
EA200500515A1 (ru) 2005-10-27
MXPA05004191A (es) 2006-01-27

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