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WO2007096251A1 - Inhibiteurs de cpt dans le système nerveux central en tant que médicaments antidiabétiques et/ou anti-obésité - Google Patents

Inhibiteurs de cpt dans le système nerveux central en tant que médicaments antidiabétiques et/ou anti-obésité Download PDF

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Publication number
WO2007096251A1
WO2007096251A1 PCT/EP2007/051197 EP2007051197W WO2007096251A1 WO 2007096251 A1 WO2007096251 A1 WO 2007096251A1 EP 2007051197 W EP2007051197 W EP 2007051197W WO 2007096251 A1 WO2007096251 A1 WO 2007096251A1
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WO
WIPO (PCT)
Prior art keywords
piperazine
carboxyamide
carboxamide
trimethoxybenzyl
methyl
Prior art date
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Ceased
Application number
PCT/EP2007/051197
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English (en)
Inventor
Emanuela Tassoni
Fabio Giannessi
Natalina Dell' Uomo
Grazia Gallo
Roberto Conti
Maria Ornella Tinti
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sigma Tau Industrie Farmaceutiche Riunite SpA
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Sigma Tau Industrie Farmaceutiche Riunite SpA
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Publication of WO2007096251A1 publication Critical patent/WO2007096251A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

  • the present invention describes a new class of compounds with inhibitory action on carnitine palmitoyl transferase (CPT) in the central nervous system (CNS). BACKGROUND OF THE INVENTION
  • the object of the present invention therefore relates to new inhibitors of CPT1 , derivatives of trimetazidine and perhexiline, preferentially selective for the hepatic form of CPT1 (CPT1 L) also abundantly expressed in the brain, with different structural characteristics from those of the inhibitors which are the object of the earlier application WO99/59957.
  • A is a monovalent group selected from the group comprising
  • n is selected among 0, 1 , 2 and 3; R and R', the same or different, are selected from the group comprising H, alkyl
  • R1 is selected between H and the group -CH 2 -CH(cycloalkyl (C 5 -C 6 )) 2
  • X is selected between CH 2 and NR2;
  • R2 is selected from the group comprising CH-(PhR3,R4,R5) 2 , -CH 2 PhR3,R4,R5, - COPhR3,R4,R5, - (CH 2 ) q -S-PhR3,R4,R5, -CH 2 COheterocyclo(C 5 -Ci 0 ), -
  • Z is either absent or is selected from the group comprising CO, CH 2 ; r is selected between 0 and 1
  • R3, R4 and R5, the same or different, are selected from the group including H, OH, halogen, alkoxy (CrC 4 ), straight or branched alkyl (CrC 4 ); or R3 and R4 together form an alkylidene(CrC 4 )-dioxy group;
  • Y is selected between (CH 2 ) q -O and (CH 2 ) q NH; q is selected among 1 , 2 and 3; m is selected between 0 and 1 ; and its pharmaceutically acceptable salts.
  • each of the products of formula (I) may exist both as a ramie mixture R/S and as separate isomeric forms
  • the compounds of formula (I) can also be salified with pharmaceutically acceptable acids.
  • Preferred pharmaceutically acceptable salts of the compounds of formula (I) according to the present invention are, for example, the salts obtained by adding pharmaceutically acceptable acids, such as hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or acid phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methane sulphonate, benzene sulphonate and paratoluene sulphonate. It is expected that the compounds of formula (I), which do not contain a clear positive or negative charge, are more efficient at crossing the blood-brain barrier.
  • A is preferably equal to the group
  • R1 is preferably H and R2 is preferably the group CH 2 PhR3,R4,R5 with R3, R4 and R5 being preferably methoxy.
  • R1 is preferably the group -CH 2 -CH(cycloalkyl(C 5 -C 6 ))2; m is preferably equal to 0.
  • Y is preferably the group (CH 2 ) q -0 and q is 2.
  • the compounds of general formula (I) can be prepared using known reactions in the state of the art and can also be prepared with parallel chemistry using a suitable reactor consisting of several reaction tubes in each of which a reaction is set up with various reagents but under the same conditions of temperature and inert atmosphere.
  • Diagram A An example of synthesis is given in Diagram A below.
  • Step 2 When m is 0, the isocyanate attacks the amine; the solvents which are preferably used have low boiling points and are chlorided like dichloromethane.
  • the reaction temperature is between 20 and 40 0 C preferably 25 0 C.
  • the reaction time is between 1 and 18 hours, preferably 2 hours.
  • the reaction temperature is between 50 and 140 0 C, preferably 120 0 C.
  • the reaction time is between 5 and 30 hours, preferably 24 hours. All the reactions are conducted in a stream of inert gas, preferably argon. In each reaction one of the two reagents is present in excess quantities equal to 0.5 mols compared with the defective reagent, the excess reagent is removed by using polystyrene "scavenger" resins.
  • the isocyanate is preferably used in excess quantities compared with the amine and/or alcohol, and the aminomethyl polystyrene resin allows the excess to be removed.
  • the compounds of formula (I) are also used in the prevention and/or treatment of heart disorders such as CHF (congestive heart failure).
  • CHF congestive heart failure
  • a further object of the present invention are pharmaceutical compounds containing one or more compounds of formula (I) described first in combination with excipients and/or pharmaceutically acceptable diluents.
  • the compounds in question may, together with the compounds of formula (I), contain known active ingredients.
  • the pharmaceutical compounds according to the present invention can be adapted for oral, parenteral, rectal, transdermal and intranasal administration.
  • the oral form includes capsules, tablets, granules, powders, syrups and elixirs.
  • the parenteral forms include solutions or emulsions.
  • the dosage of the compounds of the present invention varies according to the type of compound used, the route of administration and the extent to which the disease to be treated has developed. In general an effective dosage is between 0.1 and
  • the invention also includes the use of formula (I) compounds for preparing medicaments having hypoglycaemic and anti-obesity action.
  • a further aspect of the invention is a process for preparing pharmaceutical compounds characterised by mixing one or more compounds of formula (I) with suitable, stabilising and/or pharmaceutically-acceptable diluents.
  • Another object of the present invention is the method for treating a mammal suffering from hyperglycaemia, diabetes, obesity and associated disorders, as reported above, including the administration of a therapeutically-effective quantity of the compound of formula (I).
  • Kl is added in catalytic quantities (0.22 g) and bromoethanol (0.056 g; 0.45 mmols). The reaction is left at 40 0 C for 24 hours under magnetic stirring. The reaction mixture is then filtered and evaporated under reduced pressure.
  • the phenylethyl isocyanate (0.026 g; 0.179 mmols) is added to the intermediate 1- (2-hydroxyethyl)-4-(2,3,4 trimethoxybenzyl)piperazine prepared as described above (0.037 g; 0.119 mmols) dissolved in 2.5 ml of toluene.
  • the reaction mixture is left at 130 0 C at reflux for 24 hours under continuous magnetic stirring.
  • the raw reaction product is purified with sulphuryl chloride polystyrene resin (0.032 g; capacity 1.52 mmols/g) in the presence of triethylamine (4.9 mg, 5 ⁇ l_, 0.048 mmols).
  • the reaction was left for one hour at room temperature under slow magnetic stirring.
  • the aminomethyl resin (0.056 g; 2.7 mmols/g) was then added to the filtrate and the mixture left for 2 hours at room temperature under slow magnetic stirring.
  • Example 4 Synthesis of 4-benzyl-N-(4-fluorobenzyl)-1-carboxyamide-piperazine ST3344
  • the compound of example 4 was prepared as described in example 3 from 4- benzyl piperazine and 4-fluorobenzyl isocyanate to give 0.048 g of product (yield 79%)
  • Example 7 Synthesis of 4-benzoyl-N-(2-phenylethyl)-1 -carboxamide-piperazine ST3341
  • the compound of example 7 was prepared as described in example 3 from A- benzoyl piperazine and 2- phenylethyl isocyanate to give 0.040 g of product (yield 75.2%)
  • the compound of example 11 was prepared as described in example 3 from 2- (2,2-dicycloesylethyl)piperidine and 4-fluorophenyl isocyanate to give 0.035 g of product (yield 91 %)
  • the compound of example 17 was prepared as described in example 3 from 2- (2,2-dicycloesylethyl)piperidine and 4-methoxybenzyl isocyanate to give 0.025g of product (yield 34%).
  • the compound of example 20 was prepared as described in example 3 from A-
  • the compound of example 22 was prepared as described in example 3 from A- (bis(4-fluorophenyl)methyl)piperazine and 4-chlorophenyl isocyanate to give 0.025g of product (yield 34%)
  • the compound of example 23 was prepared as described in example 3 from A- (bis(4-fluorophenyl)methyl)piperazine and 4-methoxybenzyl isocyanate to give 0.039g of product (yield 52%)
  • the compound of example 24 was prepared as described in example 3 from A- (1 ,3-benzodioxol-5-methyl)piperazine and 2-phenylethyl isocyanate to give 0.053g of product (yield 86%)
  • the compound of example 25 was prepared as described in example 3 from A- (1 ,3-benzodioxol-5-methyl)piperazine and 4-ethylphenyl isocyanate to give 0.053g of product (yield 86%)
  • the compound of example 26 was prepared as described in example 3 from A- (1 ,3-benzodioxol-5-methyl)piperazine and 4-heptyloxyphenyl isocyanate to give 0.062g of product (yield 82%)
  • the compound of example 28 was prepared as described in example 3 from A- (1 ,3-benzodioxol-5-methyl)piperazine and 4-chlorophenyl isocyanate to give 0.052g of product (yield 83%)
  • the compound of example 30 was prepared as described in example 3 from A- (2,3,4-trimethoxybenzyl)piperazine and 4-heptyloxyphenyl isocyanate to give 0.082g of product (yield 75%)
  • the compound of example 31 was prepared as described in example 3 from A- (2,3,4-trimethoxybenzyl)piperazine and 2-phenylethyl isocyanate to give 0.030 g of product (yield 90%)
  • the compound of example 34 was prepared as described in example 3 from A- (2,3,4-trimethoxybenzyl)piperazine and 4-methoxybenzyl isocyanate to give 0.033g of product (yield 85%) ESI-MS m/z 430 [M+H] ⁇ 452 [M+Na] + .
  • Example 35 Synthesis of 4-(2,3,4-trimethoxybenzyl)-N-(4-chlorophenyl)-1 -carboxyamide- piperazine ST3414
  • the compound of example 36 was prepared as described in example 3 from A- (2,3,4-trimethoxybenzyl)piperazine and 4-metylthiophenyl isocyanate to give 0.040 g of product (yield 93 %)
  • the compound of example 38 was prepared as described in example 3 from A-
  • the compound of example 39 was prepared as described in example 3 from A- (2,3,4-trimethoxybenzyl)piperazine and 2,4-(dichlorophenyl)isocyanate to give
  • the compound of example 40 was prepared as described in example 3 from 2- (2,2-dicycloesylethyl)piperidine and 4-methylthiophenyl isocyanate to give 0.049 g of product (yield 98%)
  • the compound was prepared as described in example 3 from 1-(2-aminoetyl)-4- (2,3,4-trymethoxybenzyil)piperazine prepared as described in example 41 and 2,4 dichlorophenylisocyanate.
  • the raw product obtained was purified by SPE (SCX) to give 0.028 g of product (yield of 85%).
  • Test 1 Evaluation of the inhibitory activity on CPT
  • the inhibition of CPT has been evaluated on fresh mitochondrial preparations obtained from the liver or heart of the normally fed Fischer rat; the mitochondria taken from the liver or heart are suspended in 75 mM sucrose, EGTA 1 mM, pH 7.5. 100 ⁇ l of a mitochondrial suspension, containing 50 ⁇ M of [ 14 C] palmitoyl-CoA (spec. act. 10000 dpm/mole) and 10 mM of L-carnitine, are incubated at 37 0 C in the presence of scalar concentrations (0-3 mM) of the product under examination. Reaction time: 1 minute. The IC50 is then evaluated.
  • Test 2 Evaluation of the production of ⁇ -hvdroxybutyrate stimulated by oleate The synthesis of ⁇ -hydroxybutyrate is an indicator of the activity of CPT. In fact the production of ketone bodies, end-products of mitochondrial beta-oxidation, is linked to the activity of CPT.
  • hepatocytes obtained according to the technique described by Venerando R. et al. (1994) Am. J. Physiol. 266: C455-C461] are used.
  • the hepatocytes are incubated at 37°C in KRB bicarbonate buffer at pH 7.4, 6 mM glucose, 1 % BSA in O2/CO2 95/5 % atmosphere at a concentration of 2.5 x 10 6 cells/ml.
  • the first series of samples is taken (T 0 mm ) and the oleate added (1 final mM in KRB + BSA 1.4%). After 20 mins the second sample is taken
  • Test 3 ⁇ -hydroxybutyrate in the serum of treated rats
  • Normally-fed Fischer rats is left to fast for 24 hours and is then treated with the compounds under examination. One hour after the treatment the animals is sacrificed and the serum concentrations of ⁇ -hydroxybutyrate are evaluated.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Obesity (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une nouvelle classe de composés à activité inhibitrice vis-à-vis de la carnitine palmitoyltransférase (CPT) dans le système nerveux central (SNC), lesdits composés étant dérivés de la trimétazidine et de la perhexiline, et étant de préférence sélectifs vis-à-vis de la forme hépatique de CPT1 (CPT1L). La présente invention concerne également les composés pharmaceutiques contenant au moins un nouveau composé selon l'invention, ainsi que leur utilisation thérapeutique dans le traitement prophylactique et/ou thérapeutique de l'obésité, de l'hyperglycémie, du diabète et des troubles associés, par exemple la rétinopathie diabétique, la neuropathie diabétique et les troubles cardio-vasculaires. Les composés selon la présente invention sont également employés dans le traitement prophylactique et/ou thérapeutique de troubles cardiaques tels que l'insuffisance cardiaque congestive (ICC).
PCT/EP2007/051197 2006-02-22 2007-02-08 Inhibiteurs de cpt dans le système nerveux central en tant que médicaments antidiabétiques et/ou anti-obésité Ceased WO2007096251A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITRM2006A000090 2006-02-22
IT000090A ITRM20060090A1 (it) 2006-02-22 2006-02-22 Nuovi composti inibitori cpt a livello del snc come farmaci antidiabetici e o antiobesita

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Cited By (27)

* Cited by examiner, † Cited by third party
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WO2008122787A1 (fr) * 2007-04-05 2008-10-16 Evotec Ag Composés de pipérazine pour l'inhibition de prostaglandine synthase d hématopoïétique
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2010068453A1 (fr) 2008-11-25 2010-06-17 Janssen Pharmaceutica Nv Modulateurs d'urée substitués par hétéroaryle d'amide d'acide gras hydrolase
WO2010141809A1 (fr) 2009-06-05 2010-12-09 Janssen Pharmaceutica Nv Modulateurs heterocycliques a base d'uree a substitution aryle de l'hydrolase des amides d'acides gras (faah)
WO2010141817A1 (fr) 2009-06-05 2010-12-09 Janssen Pharmaceutica Nv Modulateurs d'amide d'acide gras hydrolase de type diamine urée spirocyclique substituée par un groupe hétéroaryle
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
EP2567959A1 (fr) 2011-09-12 2013-03-13 Sanofi Dérivés d'amide d'acide 6-(4-Hydroxy-phényl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs
US8598356B2 (en) 2008-11-25 2013-12-03 Janssen Pharmaceutica Nv Heteroaryl-substituted urea modulators of fatty acid amide hydrolase
WO2014036603A1 (fr) * 2012-09-05 2014-03-13 Adelaide Research & Innovation Pty Ltd Utilisations de (-)-perhexiline
US8940745B2 (en) 2010-05-03 2015-01-27 Janssen Pharmaceutica Nv Modulators of fatty acid amide hydrolase
WO2015131231A1 (fr) * 2014-03-03 2015-09-11 Adelaide Research & Innovation Pty Ltd Procédés d'utilisation de (-)-perhexiline
US9169224B2 (en) 2004-12-30 2015-10-27 Janssen Pharmaceutica Nv Piperazinyl and piperidinyl ureas as modulators of fatty acid amide hydrolase
US9393221B2 (en) 2011-07-20 2016-07-19 The General Hospital Corporation Methods and compounds for reducing intracellular lipid storage
US9457017B2 (en) 2007-11-23 2016-10-04 Heart Metabolics Limited Treatment of heart failure
WO2017031330A1 (fr) * 2015-08-20 2017-02-23 The Regents Of The University Of Californa Procédés de réduction de la protéotoxicité
JP2019509338A (ja) * 2016-02-23 2019-04-04 セルビシオ アンダルーサ デ サルー 治療活性が増加した抗ウイルス剤としてのピペラジン誘導体
US10556013B2 (en) 2017-06-20 2020-02-11 Imbria Pharmaceuticals, Inc. Compositions and methods for increasing efficiency of cardiac metabolism
WO2020081361A1 (fr) 2018-10-17 2020-04-23 Imbria Pharmaceuticals, Inc. Procédés de traitement de maladies rhumatismales à l'aide de composés à base de trimétazidine
US20220249463A1 (en) * 2019-05-31 2022-08-11 Imbria Pharmaceuticals, Inc. Methods of altering cardiac remodeling using compounds that promote glucose oxidation
US11530184B2 (en) 2020-06-30 2022-12-20 Imbria Pharmaceuticals, Inc. Crystal forms of 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate
US11780811B2 (en) 2020-06-30 2023-10-10 Imbria Pharmaceuticals, Inc. Methods of synthesizing 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate
US11883396B2 (en) 2021-05-03 2024-01-30 Imbria Pharmaceuticals, Inc. Methods of treating kidney conditions using modified forms of trimetazidine

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