WO2007096251A1 - Inhibitors of cpt in the central nervous system as antidiabetic and/or anti-obesity drugs - Google Patents

Inhibitors of cpt in the central nervous system as antidiabetic and/or anti-obesity drugs Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
piperazine
carboxyamide
carboxamide
trimethoxybenzyl
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2007/051197
Other languages
French (fr)
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
Original Assignee
Sigma Tau Industrie Farmaceutiche Riunite SpA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sigma Tau Industrie Farmaceutiche Riunite SpA filed Critical Sigma Tau Industrie Farmaceutiche Riunite SpA
Publication of WO2007096251A1 publication Critical patent/WO2007096251A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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.

Landscapes

  • 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

The invention relates to a new class of compounds with inhibitory action on carnitine palmitoyl transferase (CPT) in the central nervous system (SNC), derived from trimetazidine and perhexiline, preferentially selective for the hepatic form of CPT1 (CPT1L), pharmaceutical compounds which contain at least one new compound according to the invention, and their therapeutic use in the treatment and/or in the prevention of obesity, hyperglycaemia, diabetes and disorders associated with them, such as, for example, diabetic retinopathy, diabetic neuropathy and cardiovascular disorders. The compounds of the present invention are also used in the prevention and/or treatment of heart disorders such as CHF (congestive heart failure).

Description

Inhibitors of CPT in the central nervous system as antidiabetic and/or anti- obesity drugs FIELD OF THE INVENTION
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
International patent application WO99/59957 describes and claims a class of butyric acid derivatives with inhibitory action on CPT1. One example of these compounds is R-4-trimethylammonium-3-(tetradecylcarbamoyl)-aminobutyrate (ST1326).
It has recently been demonstrated that the inhibition of the hepatic isoform of CPT1 (CPT1 L) in the hypothalamus, experimentally produced by ICV administration, is capable of significantly and consistently reducing, in terms of extent and duration of effect, food intake and gluconeogenesis (Nature Medicine, 2003, 9(6), 756-761 ). As confirmation of these data, a brain-liver circuit has recently been demonstrated to be involved in the homeostasis of glucose (Cell Metabolism 2005, vol 1 , 53-61 ). This property has also been reported using the compound ST1326. International patent application WO2004/071458 demonstrates that food intake and glucose production can be regulated by modulating the levels of the enzyme LC-Co-A (long-chain fatty acyl-Co-A) in the hypothalamus. In particular it demonstrates that the intracerebroventricular injection (ICV) of ST1326 significantly inhibits food intake and the production of glucose in the treated animals (rats). In the literature there is data on weak activity on CPT1 , more marked for the muscular form, of antianginal agents such as trimetazidine, perhexiline and amiodarone (Pharmacol. Research vol. 44, No. 2, 2001 ; Biochem. Pharmacol, vol.52, 2, 1996). The action of these drugs seems to take place, at least in part, by promoting a shift in the cellular metabolism in the myocardium which leads to the preferential use of glucose reducing the oxidation of the fatty acids by inhibiting the activity of CPT1. DESCRIPTION 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.
These compounds are capable of inhibiting CPT1 in the hypothalamus and therefore reducing food intake and gluconeogenesis and as drugs are therefore useful for the treatment of obesity and/or diabetes. The present invention meets with this requirement and relates to new inhibitors having the general formula (I):
Figure imgf000004_0001
(I) where:
A is a monovalent group selected from the group comprising
Figure imgf000004_0002
straight or branched, saturated or unsaturated alkyl (C1-C15), unsubstituted or substituted with an aryloxy (C5-C10) unsubstituted or in turn substituted with a halogen or alkyl (C1-C10) or alkoxy (C1-C10); n is selected among 0, 1 , 2 and 3; R and R', the same or different, are selected from the group comprising H, alkyl
(CrC8), alkoxy (Ci-C8), nitro and halogen;
R1 is selected between H and the group -CH2-CH(cycloalkyl (C5-C6))2
X is selected between CH2 and NR2;
R2 is selected from the group comprising CH-(PhR3,R4,R5)2, -CH2PhR3,R4,R5, - COPhR3,R4,R5, - (CH2)q-S-PhR3,R4,R5, -CH2COheterocyclo(C5-Ci0), -
COheterocycloC5-Cio, -(CH2)SCH3, -CH2 cycloalkyl; and the group (CH2)q-(NH-Z)r- heterocyclo (C5-C10) with one or more heteroatoms;
Z is either absent or is selected from the group comprising CO, CH2; 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 (CrC4), straight or branched alkyl (CrC4); or R3 and R4 together form an alkylidene(CrC4)-dioxy group; Y is selected between (CH2)q-O and (CH2)qNH; q is selected among 1 , 2 and 3; m is selected between 0 and 1 ; and its pharmaceutically acceptable salts.
Depending on the meaning of the radicals A, R, R', R1 , R2, R3, R4, R5, and Y the compounds of formula (I) may have one or more chiral centres. In these cases for the purposes of the present invention it is specified that each of the products of formula (I) may exist both as a ramie mixture R/S and as separate isomeric forms
R and S.
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
Figure imgf000006_0001
and R and R' are preferably different with R = H and R' = alkyloxy group; n is preferably 0.
When X is NR2, R1 is preferably H and R2 is preferably the group CH2PhR3,R4,R5 with R3, R4 and R5 being preferably methoxy.
When X is CH2, R1 is preferably the group -CH2-CH(cycloalkyl(C5-C6))2; m is preferably equal to 0.
When m is different from 0, Y is preferably the group (CH2)q-0 and q is 2.
The following compounds are particularly preferred: 2-[4-(2,3,4 trimethoxybenzyl)piperazine-1 -yl]ethyl-(2-phenylethyl)carbamate
(ST3473);
2-[2-(2,2dicycloesylethylpiperidine-1-yl]ethyl(4-butylphenyl)carbamate (ST3348);
4-benzyl-N-(2-phenylethyl)-1 -carboxamide-piperazine (ST3340);
4-benzyl-N-(4-fluorobenzyl)-1 -carboxamide-piperazine (ST3344); 4-benzyl-N-(2,4-dichlorophenyl)-1 -carboxamide-piperazine (ST3342);
4-benzoyl-N-(4-ethylphenyl)-1 -carboxamide-piperazine (ST3343); 4-benzoyl-N-(2-phenylethyl)-1 -carboxamide-piperazine (ST3341 );
4-benzoyl-N-(4-fluorobenzyl)-1-carboxamide-piperazine (ST3345);
2-(2,2-dicycloesylethyl)- N-(4-chlorophenyl)-1 -carboxamide-piperidine (ST3346);
2-(2,2-dicycloesylethyl)- N-(4-butylphenyl)-1 -carboxamide-piperidine (ST3347); 2-(2,2-dicycloesylethyl)- N-(4-fluorobenzyl)-1 -carboxamide-piperidine (ST3349);
4-benzoyl-N-(4-chlorophenyl)-1 -carboxamide-piperazine (ST3350);
4-benzoyl-N-(2,4-dichlorophenyl)-1 -carboxamide-piperazine (ST3351 );
2-(2,2-dicycloesylethyl)- N-(2-phenylethyl)-1 -carboxamide-piperidine (ST3410);
2-(2,2-dicycloesylethyl)- N-(4-ethylphenyl)-1 -carboxamide-piperidine (ST3411 );. 2-(2,2-dicycloesylethyl)- N-(4-heptyloxyphenyl)-1 -carboxamide-piperidine
(ST3412);
2-(2,2-dicycloesylethyl)- N-(4-methoxybenzyl)-1 -carboxamide-piperidine (ST3413);
2-(2,2-dicycloesylethyl)- N-(4-nitrophenyl)-1 -carboxamide-piperidine (ST3415);
4-[bis(4-fluorophenyl)methyl]-N-(2-phenylethyl)-1-carboxyamide-piperazine (ST3416);
4-[bis(4-fluorophenyl)methyl]-N-(2-ethylphenyl)-1-carboxyamide-piperazine
(ST3417);
4-[bis(4-fluorophenyl)methyl]-N-(4-heptyloxyphenyl)-1-carboxyamide-piperazine
(ST3418); 4-[bis(4-fluorophenyl)methyl]-N-(4-chlorophenyl)-1-carboxyamide-piperazine
(ST3419); 4-[bis(4-fluorophenyl)methyl]-N-(4-methoxybenzyl)-1-carboxyamide-piperazine
(ST3420);
4-(1 ,3-benzodioxol-5-methyl)-N-(2-phenylethyl)-1-carboxyamide-piperazine
(ST3421 ); 4-(1 ,3-benzodioxol-5-methyl)-N-(4-ethylphenyl)-1 -carboxyamide-piperazine
(ST3422);
4-(1 ,3-benzodioxol-5-methyl)-N-(4-heptyloxyphenyl)-1 -carboxyamide-piperazine
(ST3423);
4-(1 ,3-benzodioxol-5-methyl)-N-(4-methoxybenzyl)-1 -carboxyamide-piperazine (ST3424);
4-(1 ,3-benzodioxol-5-methyl)-N-(4-chlorophenyl)-1 -carboxyamide-piperazine
(ST3425);
4-(1 ,3-benzodioxol-5-methyl)-N-(4-nitrophenyl)-1 -carboxyamide-piperazine
(ST3426); 4-(2, 3, 4-trimethoxybenzyl)-N-(4-heptyloxyphenyl)-1 -carboxyamide-piperazine
(ST3428);
4-(2,3,4-trimethoxybenzyl)-N-(2-phenylethyl)-1 -carboxyamide-piperazine (ST3519);
4-(2,3,4-trimethoxybenzyl)-N-(4-ethylphenyl)-1 -carboxyamide-piperazine (ST3520);
4-(2,3,4-trimethoxybenzyl)-N-(4-nitrophenyl)-1 -carboxyamide-piperazine (ST3521 ); 4-(2,3,4-trimethoxybenzyl)-N-(4-methoxybenzyl)-1 -carboxyamide-piperazine
(ST3522); 4-(2,3,4-trimethoxybenzyl)-N-(4-chlorophenyl)-1-carboxyamide-piperazine
(ST3414).
4-(2,3,4-trimethoxybenzyl)-N- (4-methyltiophenyl)1-carboxyamide-piperazine
(ST3821 ); 4-(2,3,4-trimethoxybenzyl)-N-2-(tert-butylphenyl)- 1 -carboxyamide-piperazine
(ST3822);
4-(2, 3, 4-trimethoxybenzyl)-N-benzyl-1 -carboxyamide-piperazine (ST3823);
4-(2, 3, 4-trimethoxybenzyl)-N-(2,4-dichlorophenyl)-1 -carboxyamide-piperazine
(ST3824); 2-(2,2-dicycloesylethyl)- N-(4-methylthiophenyl)-1 -carboxyamide-piperidine
(ST3825);
N-(2-[4-(2,3,4-trymethoxybenzyl)piperazin-1-il]etyl)-N'benzylurea dichlorydrate
(ST3933); and
N-(2-[4-(2,3,4-trymethoxybenzyl)piperazin-1-il]etyl)-N'-(2,4 dichlorophenyl)urea monochlorydrate (ST3934).
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.
An example of synthesis is given in Diagram A below. Diagram A
Figure imgf000010_0001
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 0C preferably 25 0C. The reaction time is between 1 and 18 hours, preferably 2 hours.
When m is different from O and Y = (Chyq-O the isocyanate attacks the oxydrylic group; the solvents which are preferably used have high boiling points like toluene. The reaction temperature is between 50 and 140 0C, preferably 120 0C. 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.
When m is different from 0 and Y = (CH2)q-NH in step 1 is used as reagent CHO-
(Y)m to obtain (G. W. Gribble, C. F. Nutaitis Org. Prep. & Procedures Int. 1985, 17, 317-384) the intermediate for step 2 where 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 0C preferably 25 0C. The reaction time is between 1 and 18 hours, preferably 2 hours. The compounds of formula (I) have inhibitory activity on CPT1. This activity makes it possible to use them in the treatment and/or in the prevention of obesity, hyperglycaemia, diabetes and disorders associated with them, such as, for example, diabetic retinopathy, diabetic neuropathy and cardiovascular disorders.
The compounds of formula (I) are also used in the prevention and/or treatment of heart disorders such as CHF (congestive heart failure).
The inhibitory action of the compounds of formula (I) is exerted mainly on the hepatic isoform of CPT1 and, in particular, also in the hypothalamus. 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
100 mg/kg.
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).
The present invention is illustrated by means of the following non-limiting examples. EXAMPLES
Example 1
Synthesis of 2-[4-(2,3,4 trimethoxybenzyl)piperazine-1-yllethyl-(2- phenylethyltearbamate (ST3473)
Figure imgf000013_0001
Synthesis of the intermediate 1 -(2-hydroxyethyl)-4-(2,3,4 trimethoxybenzvDpiperazine
K2CO3 (0.376 g; 2,72 mmols) is added to 0.151 g (0.45 mmols) of 1 -(2,3,4 trimethoxybenzyl)piperazine dichloride in 10 ml of anhydrous acetonitrile and 5 ml of anhydrous CHCI3, and the reaction mixture is left at T = 50 0C for 24 hours. After cooling, Kl is added in catalytic quantities (0.22 g) and bromoethanol (0.056 g; 0.45 mmols). The reaction is left at 400C for 24 hours under magnetic stirring. The reaction mixture is then filtered and evaporated under reduced pressure. The raw product obtained is purified by silica gel chromatography using as eluent chloroform/methanol 97/3. 0.087g of product with a yield of 60% will be obtained. Silica gel TLC with eluent CH2CI2/Me0H 8/2 Rf = 0.38. ESI-MS m/z 350 [M+K]+ 1H-NMR (CD2CI2, 300 MHz) δ 7.00 (1 H, d), 6.70 (1 H, d), 3.85 (3H, s), 3.80 (6H, s), 3.50 (2H, t), 3.40 (2H,s), 2.65 (2H, m), 2.50 (8H, m).
Synthesis of 2-[4-(2,3,4 trimethoxybenzyl )piperazine-1-yl1ethyl-(2- phenylethvDcarbamate ST3473
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 0C 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 μl_, 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.
The mixture was then filtered and the solvent evaporated under reduced pressure. The solid was treated with ethyl acetate and the solution separated from the precipitate. The collected solution was evaporated under reduced pressure and 0.042 g of the product will be obtained as oil, with a yield of 77.2 %. 1H-NMR (CD2CI2, 300 MHz) δ 7.3(5H1 m), 7.0(1 H, d), 6.6(1 H, d), 4.1 (2H, t), 3.85(3H1S)1 3.84(6H1S)1 3.4(4H,s+t), 2.8(2H,t), 2.5(2H,t), 2.4 (8H, brt+brs). HPLC Column Symmetry C-18 (3.5μm) 4.6χ75mm, T = room temperature, mobile phase
CH3CN/H2O in a linear gradient of 20 mins. from 10/90 to 80/20 (v/v), pH = unchanged, flow=0.7ml /min, U.V. detector 220nm, retention time: 5.3mins, ESI-
MS m/z 458 [M+H]+ , 480 [M+Na]+ , 496 [M+K]+
Example 2
Synthesis of 2-[2-(2,2dicycloesylethylpiperidine-1 -yl1ethyl(4-butylphenyl)carbamate
(ST3348)
Figure imgf000015_0001
Synthesis of the intermediate 2-(2,2dicvcloesylethyl)-1-(2-hvdroxyethyl)piperidine N(Et)3 (0.075 g; 0.733 mmols, 0.103 ml), Kl in catalytic quantities (0.020g;0.120 mmols) and bromoethanol (0.110g;0.880 mmols, 0.057 ml) was added to 0.203 g of 2-(2,2 dicycloesylethyl)piperidine (0.733 mmols) dissolved in 8 ml of anhydrous acetonitrile. The reaction was left at T = 500C for 24 hours under magnetic stirring. The reaction mixture was then filtered and evaporated under reduced pressure. Having observed the continuing presence of the starting product 2-(2,2 dicycloesylethyl)piperidine the methylisocyanate polystyrene resin (80 mg ;1.84 mmols/g) in 5 ml of anhydrous dichloromethane was added to the raw reaction product, the suspension was left for 2 hours at room temperature, the mixture was then filtered and evaporated under reduced pressure. 0.100 g of the solid product with a yield of 43% will be obtained. P.f. 134.5°C-135.5°C. 1H-NMR (CDCI3, 300 MHz) δ 4.2(1 H,t), 3.80(2H,m), 3.00(2H,m), 2.70(3H,m), 2.00-1.00 (31 H, m).Silica gel TLC with eluent CH3OH/CH2CI2 90/10, Rf =0.24. ESI-MS m/z: 322 [M+H]+ Synthesis of 2-[2-(2,2dicvcloesylethylpiperidine-1 -yl1ethyl(4-butylphenyl)carbamate ST3348
4-butylphenylisocyanate (0.131 g; 0.752 mmols) was added to 0.161 g (0.501 mmols) of 2 (2,2dicycloesylethyl)-1-(2-hydroxyethyl)piperidine dissolved in 5 ml of toluene. The reaction mixture was brought to 1300C and left at reflux for 24 hours under magnetic stirring. The aminomethyl polystyrene resin (0.186g, 2.7mmols/g) was then added to the reaction mixture, the mixture was left for two hours at room temperature under slow magnetic stirring. At the end of this time the mixture was filtered and evaporated under reduced pressure. 0.234 g of oily product will be obtained with a yield of 94%. TLC silica gel with eluent CH3OH/CH2CL2 90/10, Rf =0.74;1H-NMR (CDCI3 300 MHz) δ 7.35 (2H, d), 7.15 (2H, d), 4.30 (2H, brs), 3.20 (2H, brm), 2.8-2.6 (3H, m), 2.50 (2H, t),1.90-0.90 (38 H, m); HPLC Column Symmetry C-18 (3.5μm) 4.6χ75mm,T = room temperature, mobile phase CH3CN/H2O +0.1 % formic acid in linear gradient of 20 mins from 10/90 to 80/20 (v/v), pH = unchanged, flow=1 ml/min, U. V. detector 220nm, retention time 11.2 min. EI-MS m/z 497 [M+H]+ Example 3 Synthesis of 4-benzyl-N-(2-phenylethyl)-1-carboxyamide-piperazine ST3340 The product was obtained from 0.030 g (0.185 mmols) of 4-benzyl piperazine and 2-phenylethyl isocyanate 0.041 g (0.277 mmols) in 2 ml of anhydrous CH2CI2. The reaction mixture was left for 2 hours under stirring at room temperature under a stream of Argon. 0.068 g of methylamine polystyrene resin (2.7 mmols/g) was then added to the solution and the mixture was left for 2 hours under gentle stirring at room temperature and under a stream of Argon. The mixture was then filtered and the solution evaporated under a stream of nitrogen. 0.048g of product (yield 80 %) will be obtained ESI-MS m/z 346 [M+Na]+ , + HPLC Column Symmetry C-18 (3.5μm) 4.6χ75mm, T = room temperature, mobile phase CH3CN/H2O in linear gradient of 20 mins. from 10/90 to 80/20 (v/v), pH = unchanged, flow=1 ml /min, U.V. detector 220nm, retention time: 9.1 mins. 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%)
ESI-MS m/z 328 [M+H]+ , . HPLC Column Luna C-18 (3.5μm) 4.6x250mm,T = room temperature, mobile phase CH3CN/H2O in linear gradient of 20 mins from 10/90 to 80/20 (v/v), pH = unchanged, flow=0.7 ml/min, U.V. detector 220 nm, retention time:8.77 mins. Example 5
Synthesis of 4-benzyl-N-(2,4-dichlorophenyl)-1 -carboxamide-piperazine ST3342 The compound of example 5 was prepared as described in example 3 from A- benzyl piperazine and 2,4-dichlorophenyl isocyanate to give 0.060 g of product (yield 88%)
ESI-MS m/z 364 [M+H]+, +. HPLC Column Symmetry C-18 (3.5μm) 4.6x75mm, T = room temperature, mobile phase CH3CN/H2O in linear gradient of 20 mins from 10/90 to 80/20 (v/v), pH = unchanged, flow=1ml/min, U.V. detector 220 nm, retention time: 7.1 mins. Example 6
Synthesis of 4-benzoyl-N-(4-ethylphenyl)-1 -carboxamide-piperazine ST3343 The compound of example 6 was prepared as described in example 3 from A- benzoyl piperazine and 4-ethylphenyl isocyanate to give 0.032 g of product (yield 60%) ESI-MS m/z 360 [M+Na]+, . HPLC Column Luna C-18 (3.5μm) 4.6x250 mm, T = room temperature, mobile phase CH3CN/H2O in linear gradient of 20 mins from 10/90 to 80/20 (v/v), pH = unchanged, flow=0.7 ml/min, U.V. detector 220 nm, retention time:8.79mins. 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%)
ESI-MS m/z 360 [M+Na]+ ,. HPLC Column Symmetry C-18 (3.5μm) 4.6x75mm, T = room temperature, mobile phase CH3CN/H2O in linear gradient of 20 mins. from 10/90 to 80/20 (v/v), pH = unchanged, flow=0.7ml/min, U. V. detector 220nm, retention time: 7.1 min,.
Example 8 Synthesis of 4-benzoyl-N-(4-fluorobenzyl)-1-carboxamide-piperazine ST3345
The compound of example 8 was prepared as described in example 3 from A- benzoyl piperazine and 4-fluorobenzyl isocyanate to give 0.044 g of product (yield
82%)
ESI-MS m/z 363 [M+Na]+, . HPLC Column Luna C-18 (3.5μm) 4.6x250mm, T = room temperature, mobile phase CH3CN/H2O in linear gradient of 20 mins. from
10/90 to 80/20 (v/v), pH = unchanged, flow=0.7 ml/min, U.V. detector 220 nm, retention time: 6.8mins.
Example 9
Synthesis of 2-(2,2-dicvcloesylethyl)- N-(4-chlorophenyl)-1-carboxamide-piperidine ST3346 The compound of example 9 was prepared as described in example 3 from 2-(2,2- dicycloesylethyl)piperidine and 4-chlorophenyl isocyanate to give 0.040 g of product (yield 46%)
ESI-MS m/z 453 [M+Na]+,. HPLC Column Symmetry C-18 (3.5μm) 4.6x75mm, T =room temperature, mobile phase CH3CN/H2O + 0.1 % formic acid in linear gradient of 20 mins. from 10/90 to 80/20 (v/v), pH = unchanged, flow=1 ml/min, U.V. detector 220nm, retention time: 23,6min,
1H-NMR (CDCI3 200 MHz) δ 7.4-7.2 (4H, d+d), 6.3 (1 H, brs), 4.2 (1 H, m), 3.9 (1 H, m), 3,0 (1 H, t), 1.90-0.90 (31 H, m). Example 10
Synthesis of 2-(2,2-dicvcloesylethyl)- N-(4-butylphenyl)-1-carboxamide-piperidine
ST3347
The compound of example 10 was prepared as described in example 3 from 2-
(2,2-dicycloesylethyl)piperidine and 4-butylphenyl isocyanate to give 0.065 g of product (yield 80%)
ESI-MS m/z 453 [M+H]+, 475 [M+Na]+, HPLC Column Symmetry C-18 (3.5μm)
4.6χ75mm, T = room temperature, mobile phase CH3CN/H2O + 0.1 % formic acid in linear gradient of 20 mins. from 10/90 to 80/20 (v/v), pH = unchanged, flow=1 ml/min, U.V. detector 220nm, retention time: 30.2min,. 1H-NMR (CDCI3 200 MHz) δ 7.4-7.2 (4H, d+d), 6.3 (1 H, brs), 4.2 (1 H, m), 3.9 (1 H, m), 3.0 (1 H, t), 2.5 (2 H, t), 1.90-0.90 (38 H, m). Example 11
Synthesis of 2-(2,2-dicycloesylethyl)- N-(4-fluorobenzyl)-1-carboxamide-piperidine ST3349
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 %)
ESI-MS m/z 451 [M+Na]+ .HPLC Column Symmetry C-18 (3.5μm) 4.6x75mm, T = room temperature, mobile phase CH3CN/H2O + 0.1% TFA in linear gradient of 20 mins. from 10/90 to 80/20 (v/v), pH = unchanged, flow=1 ml/min, U.V. detector 220nm, retention time: 13.4mins. 1H-NMR (CDCI3 200 MHz) δ 7.3 (2H, d) 7.0 (2H, t), 4.4 (2H, brs), 1.90-0.90 (31 H, m). Example 12
Synthesis of 4-benzoyl-N-(4-chlorophenyl)-1-carboxamide-piperazine ST3350 The compound of example 12 was prepared as described in example 3 from 4- benzoyl piperazine and 4-chlorophenyl isocyanate to give 0.054g of product (yield 100%). ESI-MS m/z 366 [M+Na]+, +. HPLC Column Symmetry C-18 (3.5μm) 4.6χ75mm, T = room temperature, mobile phase CH3CN/H2O + 0.1 % formic acid in linear gradient of 20 mins. from 10/90 to 80/20 (v/v), pH = unchanged, flow=1 ml/min, U.V. detector 220 nm, retention time: 7.9 mins. 1H-NMR (CDCI3 200 MHz) δ 7.4 (5H, m) 7.3 (4H, m), 3.9-3.4 (8H, m). Example 13
Synthesis of 4-benzoyl-N-(2,4-dichlorophenyl)-1 -carboxamide-piperazine ST3351. The compound of example 13 was prepared as described in example 3 from 4- benzoyl piperazine and 2,4-dichlorophenyl isocyanate to give 0.063 g of product (yield 90%)
ESI-MS m/z 400 [M+Na]+, HPLC Column Symmetry C-18 (3.5μm) 4.6x75mm, T = room temperature, mobile phase CH3CN/H2O in linear gradient of 20 mins. from 10/90 to 80/20 (v/v), pH = unchanged, flow=0.7ml/min, U.V. detector 220nm, retention time: 9.7 mins. Example 14
Synthesis of 2-(2,2-dicvcloesylethyl)- N-(2-phenylethyl)-1-carboxamide-piperidine
ST3410
The compound of example 14 was prepared as described in example 3 from 2-
(2,2-dicycloesylethyl)piperidine and 2-phenylethyl isocyanate to give 0.060 g of product (yield 85%)
ESI-MS m/z 453 [M+H]+, 447 [M+Na]+, HPLC Column Symmetry C-18 (3.5μm) 4.6χ75mm, T = room temperature, mobile phase CH3CN/H2O 90/10 (v/v), pH = unchanged, flow=1 ml/min, U.V. detector 220nm, retention time: 6.24 mins. Example 15 Synthesis of 2-(2,2-dicycloesylethyl)- N-(4-ethylphenyl)-1 -carboxamide-piperidine ST3411 The compound of example 15 was prepared as described in example 3 from 2-
(2,2-dicycloesylethyl)piperidine and 4-ethylphenyl isocyanate to give 0.061 g of product (yield 86%)
ESI-MS m/z 447 [M+Na]+.HPLC Column Symmetry C-18 (3.5μm) 4.6x75mm,T = room temperature, mobile phase CH3CN/H2O 90/10 (v/v), pH = unchanged, flow=1 ml/min, U.V. detector 220nm, retention time: 7.34 mins.
Example 16
Synthesis of 2-(2,2-dicvcloesylethyl)- N-(4-heptyloxyphenyl)-1-carboxamide- piperidine ST3412 The compound of example 16 was prepared as described in example 3 from 2-
(2,2-dicycloesylethyl)piperidine and 4-heptyloxyphenyl isocyanate to give 0.052g
(yield 61 %).
ESI-MS m/z 533 [M+Na]+. HPLC Column Symmetry C-18 (3.5μm) 4.6x75mm,T = room temperature, mobile phase CH3CN/H2O 90/10 (v/v), pH = unchanged, flow=1 ml/min, U.V. detector 220nm, retention time: 18.15mins.
Example 17
Synthesis of 2-(2,2-dicvcloesylethyl)- N-(4-methoxybenzyl)-1-carboxamide- piperidine ST3413
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%). ESI-MS m/z 463 [M+Na]+.HPLC Column Symmetry C-18 (3.5μm) 4.6x75mm,T = room temperature, mobile phase CH3CN/H2O 90/10 (v/v), pH = unchanged, flow=1 ml/min, U.V. detector 220 nm, retention time: 4.6mins,
Example 18 Synthesis of 2-(2,2-dicvcloesylethyl)- N-(4-nitrophenyl)-1 -carboxamide-piperidine
ST3415
The compound of example 18 was prepared as described in example 3 from 2-
(2,2-dicycloesylethyl)piperidine and 4-nitrophenyl isocyanate to give 0.032g of product (yield 43%). ESI-MS m/z, 442 [M+H]+, HPLC Column Symmetry C-18 (3.5μm) 4.6x75mm,T = room temperature, mobile phase CH3CN/H2O 90/10 (v/v), pH = unchanged, flow=1 ml/min, U.V. detector 220 nm, retention time: 5.1 mins.
Example 19
Synthesis of 4-[bis(4-fluorophenyl)methyl1-N-(2-phenylethyl)-1 -carboxyamide- piperazine ST3416
The compound of example 19 was prepared as described in example 3 from 4-
(bis(4-fluorophenyl)methyl)piperazine and 2-phenylethyl isocyanate to give 0.066g of product (yield 91 %)
ESI-MS m/z 436 [M+H]+, 458 [M+Na]+, HPLC Column Symmetry C-18 (3.5μm) 4.6χ75mm, T = room temperature, mobile phase CH3CN/H2O in linear gradient of 20 mins. from 10/90 to 80/20 (v/v), pH = unchanged, flow=1 ml/min, U.V. detector
220 nm, retention time: 17.5 mins.
Example 20
Synthesis of 4-[bis(4-fluorophenyl)methyl1-N-(2-ethylphenyl)-1 -carboxyamide- piperazine ST3417
The compound of example 20 was prepared as described in example 3 from A-
(bis(4-fluorophenyl)methyl)piperazine and 2-ethylphenyl isocyanate to give 0.063g of product (yield 87%)
LC-MS: ES I -MS m/z 436 [M+H]+.HPLC Column Luna C-18 (3.5μm) 4.6x250mm, T = room temperature, mobile phase CH3CN/H2O in linear gradient of 20 mins. from
10/90 to 80/20 (v/v), pH = unchanged, flow=1 ml/min, U.V. detector 205-380nm, retention time: 19.2 mins.
Example 21
Synthesis of 4-[bis(4-fluorophenyl)methyl1-N-(4-heptyloxyphenyl)-1 -carboxyamide- piperazine ST3418
The compound of example 21 was prepared as described in example 3 from A-
(bis(4-fluorophenyl)methyl)piperazine and 4-heptyloxyphenyl isocyanate to give
0.061 g of product (yield 70%)
LC-MS:ESI-MS m/z 522 [M+H]+.HPLC Column Luna C-18 (3.5μm) 4.6x250mm, T = room temperature, mobile phase CH3CN/H2O in linear gradient of 20 mins. from 10/90 to 80/20 (v/v), pH = unchanged, flow=1 ml/min, U.V. detector 205-380nm, retention time: 24.07 mins.
Example 22
Synthesis of 4-[bis(4-fluorophenyl)methyl1-N-(4-chlorophenyl)-1 -carboxyamide- piperazine ST3419
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%)
ESI-MS m/z 442 [M+H]+. HPLC Column Luna C-18 (3.5μm) 4.6x250mm, T = room temperature, mobile phase CH3CN/H2O 70/30(v/v), pH = unchanged, flow=0.7ml/min, U.V. detector 254nm, retention time: 22.4 mins. Example 23
Synthesis of 4-[bis(4-fluorophenyl)methyl1-N-(4-methoxybenzyl)-1 -carboxyamide- piperazine ST3420
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%)
LC-MS: ESI-MS m/z 452 [M+H]+.HPLC Column Luna C-18 (3.5μm) 4.6x250mm, T = room temperature, mobile phase CH3CN/H2O in linear gradient of 20 mins. from 10/90 to 80/20 (v/v), pH = unchanged, flow=1 ml/min, U.V. detector 205-380nm, retention time: 16.2 mins. Example 24 Synthesis of 4-(1 ,3-benzodioxol-5-methyl)-N-(2-phenylethyl)-1 -carboxyamide- piperazine ST3421
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%)
ESI-MS m/z 368 [M+H]+, 390 [M+Na]+. HPLC Column Symmetry C-18 (3.5μm) 4.6χ75mm, T = room temperature, mobile phase CH3CN/H2O in linear gradient of 20 mins. from 10/90 to 80/20 (v/v), pH = unchanged, flow=1 ml/min, U.V. detector 220nm, retention time: 15.4 mins. Example 25
Synthesis of 4-(1 ,3-benzodioxol-5-methyl)-N-(4-ethylphenyl)-1 -carboxyamide- piperazine ST3422
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%)
ESI-MS m/z 368 [M+H]+, 390 [M+Na]+. HPLC Column Symmetry C-18 (3.5μm) 4.6χ75mm, T = room temperature, mobile phase CH3CN/H2O in linear gradient of 20 mins. from 10/90 to 80/20 (v/v), pH = unchanged, flow=1 ml/min, U.V. detector 220nm, retention time: 17.3 mins. Example 26 Synthesis of 4-(1 ,3-benzodioxol-5-methyl)-N-(4-heptyloxyphenyl)-1-carboxyamide- piperazine ST3423
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%)
ESI-MS m/z 454 [M+H]+, 476 [M+Na]+. HPLC Column Symmetry C-18 (3.5μm) 4.6χ75mm, T = room temperature, mobile phase CH3CN/H2O in linear gradient of 20 min. from 10/90 to 80/20 (v/v), pH = unchanged, flow=1 ml/min, U.V. detector 220nm, retention time: 23.9 mins. Example 27
Synthesis of 4-(1 ,3-benzodioxol-5-methyl)-N-(4-methoxybenzyl)-1-carboxyamide- piperazine ST3424
The compound of example 27 was prepared as described in example 3 from A- (1 ,3-benzodioxol-5-methyl)piperazine and 4-methoxybenzyl isocyanate to give 0.05Og of product (yield 78%)
LC-MS: ES I -MS m/z 384 [M+H]+.HPLC Column Luna C-18 (3.5μm) 4.6x250mm, T = room temperature, mobile phase CH3CN/H2O in linear gradient of 20 mins. from 10/90 to 80/20 (v/v) , pH = unchanged, flow=1 ml/min, U.V. detector 205-380nm, retention time: 10.35 mins. Example 28 Synthesis of 4-(1 ,3-benzodioxol-5-methyl)-N-(4-chlorophenyl)-1 -carboxyamide- piperazine ST3425
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%)
ESI-MS m/z 374 [M+H]+ HPLC Column Symmetry C-18 (3.5μm) 4.6x75mm, T =room temperature, mobile phase CH3CN/H2O in linear gradient of 20 mins. from 10/90 to 80/20 (v/v), pH = unchanged, flow=1 ml/min, U.V. detector 220nm, retention time: 17 mins. Example 29
Synthesis of 4-(1 ,3-benzodioxol-5-methyl)-N-(4-nitrophenyl)-1 -carboxyamide- piperazine ST3426
The compound of example 29 was prepared as described in example 3 from A- (1 ,3-benzodioxol-5-methyl)piperazine and 4-nitrophenyl isocyanate to give 0.041 g of product (yield 64%)
ESI-MS m/z 385 [M+H]+ HPLC Column Symmetry C-18 (3.5μm) 4.6x75mm, T =room temperature, mobile phase CH3CN/H2O in linear gradient of 20 mins. from 10/90 to 80/20 (v/v), pH = unchanged, flow=1ml/min, U.V. detector 220 nm, retention time: 16.2 mins. Example 30 Synthesis of 4-(2,3,4-trimethoxybenzyl)-N-(4-heptyloxyphenyl)-1 -carboxyamide- piperazine ST3428
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%)
ESI-MS m/z 500 [M+H]+ HPLC Column Symmetry C-18 (3.5μm) 4.6x75mm, T = room temperature, mobile phase CH3CN/H2O 70/30(v/v), pH = unchanged, flow=1 ml/min, U. V. detector 220nm, retention time: 5.06 mins, TLC silica gel with eluent CHCL3/CH3OH 99/1 ,Rf =0,22 Example 31
Synthesis of 4-(2,3,4-trimethoxybenzyl)-N-(2-phenylethyl)-1 -carboxyamide- piperazine ST3519
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%)
ESI-MS m/z 414 [M+H]+ , 436 [M+Na]+. HPLC Column Symmetry C-18 (3.5μm) 4.6χ75mm, T = room temperature, mobile phase CH3CN/H2O 60/40(v/v), pH = unchanged, flow=0.75ml/min, U.V. detector 220nm, retention time: 2.7 mins. Example 32 Synthesis of 4-(2,3,4-trimethoxybenzyl)-N-(4-ethylphenyl)-1 -carboxyamide- piperazine ST3520 The compound of example 32 was prepared as described in example 3 from A-
(2,3,4-trimethoxybenzyl)piperazine and 4-ethylphenyl isocyanate to give 0.032g of product (yield 96%)
ESI-MS m/z 414 [M+H]+, 436 [M+Na]+. HPLC Column Symmetry C-18 (3.5μm) 4.6χ75mm, T = room temperature, mobile phase CH3CN/H2O 60/40(v/v), pH = unchanged, flow=0.6ml/min, U.V. detector 220nm, retention time: 3.6 mins.
Example 33
Synthesis of 4-(2,3,4-trimethoxybenzyl)-N-(4-nitrophenyl)-1 -carboxyamide- piperazine ST3521 The compound of example 33 was prepared as described in example 3 from A-
(2,3,4-trimethoxybenzyl)piperazine and 4-nitrophenyl isocyanate to give 0.03Og;
0.074mmols of product (yield 91 %). ESI-MS m/z 430 [M+Na]+. HPLC Column
Symmetry C-18 (3.5μm) 4.6χ75mm, T = room temperature, mobile phase
CH3CN/H2O 60/40(v/v), pH = unchanged, flow=0.6ml/min, U.V. detector 220nm, retention time: 3.0 mins.
Example 34
Synthesis of 4-(2,3,4-trimethoxybenzyl)-N-(4-methoxybenzyl)-1 -carboxyamide- piperazine ST3522
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]+. HPLC Column Symmetry C-18 (3.5μm) 4.6χ75mm, T = room temperature, mobile phase CH3CN/H2O 60/40(v/v), pH = unchanged, flow=0.6ml/min, U.V. detector 220 nm, retention time: 2.4 mins. Example 35 Synthesis of 4-(2,3,4-trimethoxybenzyl)-N-(4-chlorophenyl)-1 -carboxyamide- piperazine ST3414
The compound of example 35 was prepared as described in example 3 from A- (2,3,4-trimethoxybenzyl)piperazine and 4-chlorophenyl isocyanate to give 0.033 g of product (yield 83%) ESI-MS m/z 420 [M+H]+, 442 [M+Na]+. HPLC Column Symmetry C-18 (3.5μm)
4.6χ75mm, T = room temperature, mobile phase CH3CN/H2O 60/40(v/v), pH = unchanged, flow=0.75ml/min, U.V. detector 220 nm, retention time: 2.7 mins. Example 36
Synthesis of 4-(2,3,4-trimethoxybenzyl)-N- (4-methyltiophenyl)1-carboxyamide- piperazine ST3821
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 %)
ESI-MS m/z 432 [M+H]+, 454 [M+Na]+, 470 [M+K]+.HPLC Column Luna Phenyl 1- Hexil (5μm) 4,6x150mm,T = room temperature, mobil phase CH3CN/H2O 70/30 (v/v), pH =unchanged, flow=1 ml/min, U. V. detector 220 nm, retention time: 3.82 min, 91.7%.
Example 37 Synthesis of 4-(2,3,4-trimethoxybenzyl)-N-2-(tert-butylphenyl)- 1-carboxyamide- piperazine ST3822
The compound of example 37 was prepared as described in example 3 from A-
(2,3,4-trimethoxybenzyl)piperazine and 2-(tert-butylphenvD- isocvanate to give
0.045 g of product (yield 90 %) ESI-MS m/z 442 [M+H]+, 464 [M+Na]+, 480 [M+K]+.HPLC Column Luna Phenyl 1-
Hexil (5μm) 4,6x150mm,T = room temperature, mobil phase CH3CN/H2O 70/30
(v/v), pH =unchanged, flow=1 ml/min, U.V. detector 220 nm, retention time: 3.46 min, 95.6%.
Example 38 Synthesis of 4-(2,3,4-trimethoxybenzyl)-N-benzyl-1 -carboxyamide-piperazine
ST3823
The compound of example 38 was prepared as described in example 3 from A-
(2,3,4-trimethoxybenzyl)piperazine and benzyl jsocyanate to give 0.042 g of product (yield 93%). LC-MS: ESI-MS m/z 400 [M+H]+, 422 [M+Na]+.HPLC Column Luna Phenyl 1-Hexil (5μm) 4,6x150mm, T = room temperature, mobil phase
CH3CN/H2O 70/30 (v/v), pH unchanged, flow=1 ml/min, U.V. detector 205-308 nm, retention time: 3.47 min, 94.1 %. Example 39
Synthesis of 4-(2,3,4-trimethoxybenzyl)-N-(2,4-dichlorophenyl)-1 -carboxyamide- piperazine ST3824
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
0.045 g of product (yield 88%)
LC-MS:ESI-MS m/z 454 [M+H]+, 476 [M+Na]+.HPLC Column Luna Phenyl 1-Hexil
(5μm) 4,6x150mm,T = room temperature, mobil phase CH3CN/H2O 70/30 (v/v), pH
=unchanged, flow=1 ml/min, U.V. detector 205-308 nm, retention time: 4.47 min, 86.5%.
Example 40
Synthesis di 2-(2,2-dicycloesylethyl)- N-(4-methylthiophenyl)-1-carboxyamide- piperidine ST3825
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%)
ESI-MS m/z 443 [M+H]+, 465 [M+Na]+.HPLC Column Gemini C-18, 4.6x150mm, T
=room temperature, mobile phase CH3CN/H2O=90/10 (v/v), pH = unchanged, flow=1 ml/min, U.V. detector 254nm, retention time: 11.41 min, 92.8%. Example 41
Synthesis of N-(2-[4-(2,3,4-trymethoxybenzyl)piperazin-1 -ilietyiD-N'benzylurea dichlorhvdrate ST3933 Synthesis of the intermediate 1 -(2-aminoethyl)-4-(2,3,4-trimethoxybenzyl) piperazine
0,226 g (0.85 mmoli) of 4-(2,3,4-trymethoxybenzyl)piperazine was added to N-BOC- 2-aminoacetaldehyde (0,135 g; 0,85 mmoli), acetic acid (0,486 ml; 8,50 mmoli) and MP-CN-BH3 (1 ,104 g; 2,550 mmoli) in 36 ml of anhydrous CH2CI2.The reaction was left at T = room temperature for 24 hours under slow magnetic stirring. The reaction mixture was then evaporated under reduced pressure. The raw product obtained is purified by silica gel chromatography using chloroform/methanol=97/3 as eluent. 0.179 g of product with a yield of 51 % will be obtained. Silica gel TLC with eluent CHCIs/MeOH 2/8 Rf = 0.7. ESI-MS m/z 410 [M+H]+, 432 [M+Na]+ .
The intermediate 1 -(N-Boc-2-aminoetyl)-4-(2,3,4-trymethoxybenzyl)piperazine prepared as described above (0,179 g; 0,438 mmoli) was dissolved in 4 ml di CH2CI2 anhydrous and is added to TFA (3,37 ml; 43,76 mmoli). The reaction is left at T= room temperature for 2 hours under magnetic stirring. The reaction mixture was then evaporated under reduced pressure and precipitated from ether solution. The salt was extracted with basic water/ CH2CI2, 0.080 g of product with yield of 59% will be obtained. TLC with eluent (chloroform=42, methanol=28, isopropyl alcohol=7, acetic acid=10,5, H2O=10,5) Rf = 0.38. ESI-MS m/z 310 [M+H]+. 1H- NMR (CD3OD 300 MHz) δ 7.0 (1 H, d),6.8 (1 H, d), 3.8 (9H, s+s+s), 3.5 (2H, s), 2.8 (2H, t), 3.0 (1 H, t), 2.6-2.3 (10 H, m).
Synthesis of N-(2-[4-(2,3,4-trymethoxybenzyl)piperazin-1 -ilietyiD-N'benzylurea dichlorhvdrate ST3933 The compound was prepared as described in example 3 from 1-(2-aminoetyl)-4- (2,3,4-trymethoxybenzyil)piperazine prepared as described above and benzyl isocyanate. The raw product obtained was purified by SPE (SCX) to give 0.022 g of product (yield of 76%). ESI-MS m/z 443 [M+H]+, 465 [M+Na]+. The product was then converted in dichlorohydrate with HCI 1 ,25 M in CH3OH (0.080 ml).TLC with eluent CH3OH/CHCI3=8=2 Rf=0.54. 1H-NMR (CDCI3 300 MHz) δ 7.4-7.2 (5H, m), 7 (1 H, d), 6.6 (1 H, d), 4.4 (2H, d), 3.8 (9H, s+s+s), 3.5 (2H, s), 3.3 (2H1 d), 2.6-2.4 (lO H. m) Example 42 Synthesis of N-(2-r4-(2.3.4-trvmethoxybenzvnpiperazin-1 -illetvn-N'-(2.4 dichlorophenvDurea monochlorhvdrate ST3934
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%). ESI-MS m/z 497-499 [M+H]+, 519-521 [M+Na]+.HPLC Column Gemini C-18, 4.6x150mm, T= room temperature, mobile phase CH3CN+0.1 %TFA/H2O+0.1 %TFA=gradient, pH = unchanged, flow=1 ml/min, U.V. detector 254nm, retention time: 14.83 min, 96%. 10 mg of the product was converted in monochlorohydrate with HCI 1.25 M in CH3OH (0.020 ml). TLC with eluent CH3OH/CHCI3=8=2 Rf=0.69. 1H-NMR (CDCI3 300 MHz) δ 8.1 (1 H. d), 7.35 (1 H, d), 7.2 (1 H, d), 7 (1 H, d), 6.6 (1 H, d), 6.3 (1 H, brs), 3.8 (9H, s+s+s), 3.6 (2H, s), 3.4 (2H, d), 3.0-2.6 (10 H, m) EVALUATION OF THE PHARMACOLOGICAL ACTIVITY OF THE COMPOUNDS
OF FORMULA (I)
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 μl of a mitochondrial suspension, containing 50 μM of [14C] palmitoyl-CoA (spec. act. 10000 dpm/mole) and 10 mM of L-carnitine, are incubated at 37 0C 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 β-hvdroxybutyrate stimulated by oleate The synthesis of β-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.
Preparations of 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 106 cells/ml. After a preincubation time of 40 mins. with the compound to be assayed at various concentrations, the first series of samples is taken (T0 mm ) and the oleate added (1 final mM in KRB + BSA 1.4%). After 20 mins the second sample is taken
Test 3: β-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 β-hydroxybutyrate are evaluated.
Other tests
The ability of these compounds to cross the blood-brain barrier in rats or mice after oral or intravenous administration is measured on brain homogenates using HPLC- MS techniques.
In addition, the evaluation of food intake after oral or intravenous intranasal administration is determined on rats with access to food ad libitum, at timed intervals or fasting, via acute or subchronic administration.
Finally the lowering of glycaemia via oral or intracerebroventricular administration in diabetic mice, for example db/db mice, is measured.

Claims

1. A compound in the racemic form (R1S) or in its enantiomeric forms R and S, or its pharmacologically-acceptable salt, having the structure described by formula (I):
Figure imgf000040_0001
(I) where:
A is a monovalent group selected from the group comprising
Figure imgf000040_0002
straight or branched, saturated or unsaturated alkyl (CrCi5), unsubstituted or substituted with an aryloxy (C5-Ci0) unsubstituted or in turn substituted with a halogen or alkyl (C1-C10) or alkoxy (C1-C10); n is selected among 0, 1 , 2 and 3; R and R', the same or different, are selected from the group comprising H, alkyl (Ci-
C8), alkoxy (CrC8), nitro and halogen;
R1 is selected between H and the group -CH2-CH(cycloalkyl (C5-C6))2
X is selected between CH2 and NR2;
R2 is selected from the group comprising CH-(PhR3,R4,R5)2, -CH2PhR3,R4,R5, - COPhR3,R4,R5, - (CH2)q-S-PhR3,R4,R5, -CH2COheterocyclo(C5-Ci0), COheterocycloC5-Cio, -(CH2)SCH3, -CH2 cycloalkyl; and the group (CH2)q-(NH-Z)r- heterocyclo (C5-Ci0) with one or more heteroatoms; Z is either absent or is selected from the group comprising CO, CH2; 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 (CrC4), straight or branched alkyl (CrC4); or R3 and R4 together form an alkylidene(CrC4)-dioxy group; Y is selected between (CH2)q-O and (CH2)qNH; q is selected among 1 , 2 and 3; m is selected between 0 and 1.
2. The compound according to claim 1 , where A is the group
Figure imgf000041_0001
in which R is H, R' is methoxy and n is 0.
3. The compound according to claim 1 , where X is NR2, R2 and the group - CH2PhR3,R4,R5 and R3,R4,R5, which are the same, are methoxy.
4. The compound according to claim 3, where X is CH2, R1 is the group -CH2- CH(cycloalkyl(C5-C6))2 and m is 0.
5. The compound according to claims 3 or 4, where m is 1 , Y is the group (CH2)q- O and q is 2.
6. The compound according to claim 1 which is selected from the group comprising: 2-[4-(2,3,4 trimethoxybenzyl)piperazine-1-yl]ethyl-(2-phenylethyl)carbamate; 2-[2-(2,2dicycloesylethylpiperidine-1-yl]ethyl(4-butylphenyl)carbamate;
4-benzyl-N-(2-phenylethyl)-1-carboxamide-piperazine;
4-benzyl-N-(4-fluorobenzyl)-1-carboxamide-piperazine;
4-benzyl-N-(2,4-diclorophenyl)-1-carboxamide-piperazine; 4-benzyl-N-(4-ethylphenyl)-1 -carboxamide-piperazine;
4-benzoyl-N-(2-phenylethyl)-1-carboxamide-piperazine;
4-benzoyl-N-(4-fluorobenzyl)-1 -carboxamide-piperazine;
2-(2,2-dicycloesylethyl)- N-(4-chlorophenyl)-1-carboxamide-piperidine;
2-(2,2-dicycloesylethyl)- N-(4-butylphenyl)-1-carboxamide-piperidine; 2-(2,2-dicycloesylethyl)- N-(4-fluorobenzyl)-1 -carboxamide-piperidine;
4-benzoyl-N-(4-chlorophenyl)-1 -carboxamide-piperazine;
4-benzoyl-N-(2,4-dichlorophenyl)-1 -carboxamide-piperazine;
2-(2,2-dicycloesylethyl)- N-(2-phenylethyl)-1 -carboxamide-piperidine;
2-(2,2-dicycloesylethyl)- N-(4-ethylphenyl)-1 -carboxamide-piperidine; 2-(2,2-dicycloesylethyl)- N-(4-heptyloxyphenyl)-1 -carboxamide-piperidine;
2-(2,2-dicycloesylethyl)- N-(4-methoxybenzyl)-1 -carboxamide-piperidine;
2-(2,2-dicycloesylethyl)- N-(4-nitrophenyl)-1 -carboxamide-piperidine;
4-[bis(4-fluorophenyl)methyl]-N-(2-phenylethyl)-1-carboxyamide-piperazine;
4-[bis(4-fluorophenyl)methyl]-N-(2-ethylphenyl)-1-carboxyamide-piperazine; 4-[bis(4-fluorophenyl)methyl]-N-(4-heptyloxyphenyl)-1-carboxyamide-piperazine;
4-[bis(4-fluorophenyl)methyl]-N-(4-chlorophenyl)-1-carboxyamide-piperazine;
4-[bis(4-fluorophenyl)methyl]-N-(4-methoxybenzyl)-1-carboxyamide-piperazine;
4-(1 ,3-benzodioxol-5-methyl)-N-(2-phenylethyl)-1-carboxyamide-piperazine; 4-(1 ,3-benzodioxol-5-methyl)-N-(4-ethylphenyl)-1-carboxyamide-piperazine;
4-(1 ,3-benzodioxol-5-methyl)-N-(4-heptyloxyphenyl)-1-carboxyamide-piperazine;
4-(1 ,3-benzodioxol-5-methyl)-N-(4-methoxybenzyl)-1-carboxyamide-piperazine;
4-(1 ,3-benzodioxol-5-methyl)-N-(4-chlorophenyl)-1-carboxyamide-piperazine; 4-(1 ,3-benzodioxol-5-methyl)-N-(4-nitrophenyl)-1 -carboxyamide-piperazine;
4-(2,3,4-trimethoxybenzyl)-N-(4-heptyloxyphenyl)-1-carboxyamide-piperazine;
4-(2, 3, 4-trimethoxybenzyl)-N-(2-phenylethyl)-1 -carboxyamide-piperazine.;
4-(2, 3, 4-trimethoxybenzyl)-N-(4-ethylphenyl)-1 -carboxyamide-piperazine;
4-(2,3,4-trimethoxybenzyl)-N-(4-nitrophenyl)-1 -carboxyamide-piperazine; 4-(2,3,4-trimethoxybenzyl)-N-(4-methoxybenzyl)-1 -carboxyamide-piperazine;
4-(2, 3, 4-trimethoxybenzyl)-N-(4-chlorophenyl)-1 -carboxyamide-piperazine;
4-(2,3,4-trimethoxybenzyl)-N- (4-methyltiophenyl)1 -carboxyamide-piperazine;
4-(2,3,4-trimethoxybenzyl)-N-2-(tert-butylphenyl)- 1 -carboxyamide-piperazine;
4-(2,3,4-trimethoxybenzyl)-N-benzyl-1 -carboxyamide-piperazine; 4-(2, 3, 4-trimethoxybenzyl)-N-(2,4-dichlorophenyl)-1 -carboxyamide-piperazine;
2-(2,2-dicycloesylethyl)- N-(4-methylthiophenyl)-1-carboxyamide-piperidine;
N-(2-[4-(2,3,4-trymethoxybenzyl)piperazin-1 -il]etyl)-N'benzylurea dichlorydrate; and
N-(2-[4-(2,3,4-trymethoxybenzyl)piperazin-1-il]etyl)-N'-(2,4 dichlorophenyl)urea monochlorydrate.
7. The compound according to claims 1 to 6, for use in therapy.
8. A pharmaceutical composition containing as active principle one or more of the compounds according to claims 1 to 6 in association with excipients and/or pharmaceutically-acceptable diluents.
9. Use of the compounds according claims 1 to 6 for the preparation of a medicament for the treatment of conditions connected with hyperactivity of carnitine palmitoyl transferase.
10. The use according to claim 9, for the prevention and treatment of obesity, hyperglycaemia, diabetes and the conditions connected with them and congestive heart failure.
11. Process for the preparation of compounds according to claims 1 to 6.
12. The process according to claim 11 according to the Diagram below:
R1
1. OHC(CH2)qNHB Ioc Step 1 /
Br(CH2)qOH
2. CF3COOH I I / / CH3CN dry
1. 1,5 ιsocyanate 2. scavenger resin
Figure imgf000044_0002
Figure imgf000044_0001
Step 2
13. The process for the preparation of the pharmaceutical compition according to claim 8 including the mixing of one or more compounds according to claims 1 to 6 with pharmaceutically-acceptable excipients and/or diluents.
14. Method of treating a mammal suffering from hyperglycaemia, diabetes, obesity and associated disorders, as reported above, including the administration of a therapeutically-effective quantity of the compounds according to claims from 1 to 6.
PCT/EP2007/051197 2006-02-22 2007-02-08 Inhibitors of cpt in the central nervous system as antidiabetic and/or anti-obesity drugs Ceased WO2007096251A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITRM2006A000090 2006-02-22
IT000090A ITRM20060090A1 (en) 2006-02-22 2006-02-22 NEW COMPOUNDS CPT INHIBITORS AT LEVEL OF THE SNC AS ANTI-DIABETIC AND OR ANTI-BESIDE DRUGS

Publications (1)

Publication Number Publication Date
WO2007096251A1 true WO2007096251A1 (en) 2007-08-30

Family

ID=37903503

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2007/051197 Ceased WO2007096251A1 (en) 2006-02-22 2007-02-08 Inhibitors of cpt in the central nervous system as antidiabetic and/or anti-obesity drugs

Country Status (2)

Country Link
IT (1) ITRM20060090A1 (en)
WO (1) WO2007096251A1 (en)

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008122787A1 (en) * 2007-04-05 2008-10-16 Evotec Ag Piperazine compounds for the inhibition of haematopoietic prostaglandin d synthase
WO2009021740A2 (en) 2007-08-15 2009-02-19 Sanofis-Aventis Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments
WO2010068453A1 (en) 2008-11-25 2010-06-17 Janssen Pharmaceutica Nv Heteroaryl-substituted urea modulators of fatty acid amide hydrolase
WO2010141809A1 (en) 2009-06-05 2010-12-09 Janssen Pharmaceutica Nv Aryl-substituted heterocyclic urea modulators of fatty acid amide hydrolase
WO2010141817A1 (en) 2009-06-05 2010-12-09 Janssen Pharmaceutica Nv Heteroaryl-substituted spirocyclic diamine urea modulators of fatty acid amide hydrolase
WO2011157827A1 (en) 2010-06-18 2011-12-22 Sanofi Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases
WO2012120053A1 (en) 2011-03-08 2012-09-13 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120054A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120052A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof
WO2012120055A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120056A1 (en) 2011-03-08 2012-09-13 Sanofi Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
EP2567959A1 (en) 2011-09-12 2013-03-13 Sanofi 6-(4-Hydroxy-phenyl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
US8598356B2 (en) 2008-11-25 2013-12-03 Janssen Pharmaceutica Nv Heteroaryl-substituted urea modulators of fatty acid amide hydrolase
WO2014036603A1 (en) * 2012-09-05 2014-03-13 Adelaide Research & Innovation Pty Ltd Uses of (-)-perhexiline
US8940745B2 (en) 2010-05-03 2015-01-27 Janssen Pharmaceutica Nv Modulators of fatty acid amide hydrolase
WO2015131231A1 (en) * 2014-03-03 2015-09-11 Adelaide Research & Innovation Pty Ltd Methods for using (-)-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 (en) * 2015-08-20 2017-02-23 The Regents Of The University Of Californa Methods for reducing proteotoxicity
JP2019509338A (en) * 2016-02-23 2019-04-04 セルビシオ アンダルーサ デ サルー Piperazine derivatives as antiviral agents with increased therapeutic activity
US10556013B2 (en) 2017-06-20 2020-02-11 Imbria Pharmaceuticals, Inc. Compositions and methods for increasing efficiency of cardiac metabolism
WO2020081361A1 (en) 2018-10-17 2020-04-23 Imbria Pharmaceuticals, Inc. Methods of treating rheumatic diseases using trimetazidine-based compounds
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
US12569480B2 (en) 2019-05-31 2026-03-10 Imbria Pharmaceuticals, Inc. Methods of treating fibrosis using compounds that promote glucose oxidation

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3721674A (en) * 1970-03-02 1973-03-20 Upjohn Co Piperazinyl ethyl carbamates
US3823006A (en) * 1970-10-30 1974-07-09 Bayer Ag Method for selective weed control in beets
US4122090A (en) * 1976-06-05 1978-10-24 Basf Aktiengesellschaft Cyclic esters of 3,4-dihydroxy-thiophene-1,1-dioxide compounds and 3,4-dihydroxy-cyclopentadienone compounds
EP0129207A2 (en) * 1983-06-16 1984-12-27 Boehringer Ingelheim Pharmaceuticals Inc. Substituted phenylalkyl(piperazinyl or homopiperazinyl)-propyl-(ureas or thioureas)
WO1997026252A1 (en) * 1996-01-19 1997-07-24 Fmc Corporation Insecticidal n-heterocyclylalkyl- or n-[(polycyclyl)-alkyl]-n'-substituted piperazines
WO1997042230A1 (en) * 1996-05-03 1997-11-13 Warner-Lambert Company Rapid purification by polymer supported quench
WO2006074025A1 (en) * 2004-12-30 2006-07-13 Janssen Pharmaceutica N.V. Piperazinyl and piperidinyl ureas as modulators of fatty acid amide hydrolase

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3721674A (en) * 1970-03-02 1973-03-20 Upjohn Co Piperazinyl ethyl carbamates
US3823006A (en) * 1970-10-30 1974-07-09 Bayer Ag Method for selective weed control in beets
US4122090A (en) * 1976-06-05 1978-10-24 Basf Aktiengesellschaft Cyclic esters of 3,4-dihydroxy-thiophene-1,1-dioxide compounds and 3,4-dihydroxy-cyclopentadienone compounds
EP0129207A2 (en) * 1983-06-16 1984-12-27 Boehringer Ingelheim Pharmaceuticals Inc. Substituted phenylalkyl(piperazinyl or homopiperazinyl)-propyl-(ureas or thioureas)
WO1997026252A1 (en) * 1996-01-19 1997-07-24 Fmc Corporation Insecticidal n-heterocyclylalkyl- or n-[(polycyclyl)-alkyl]-n'-substituted piperazines
WO1997042230A1 (en) * 1996-05-03 1997-11-13 Warner-Lambert Company Rapid purification by polymer supported quench
WO2006074025A1 (en) * 2004-12-30 2006-07-13 Janssen Pharmaceutica N.V. Piperazinyl and piperidinyl ureas as modulators of fatty acid amide hydrolase

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
"AKos Screening Library", 7 January 1006, AKOS-CONSULTING AND SOLUTIONS GMBH, BASEL, CH *
CHO J K; WHITE P D; KLUTE W; DEAN T W; BRADLEY M: "Self-indicating amine scavenger resins", CHEMICAL COMMUNICATIONS, 2004, pages 502 - 503, XP002429172 *
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; SILVERMAN, IAN R. ET AL: "Preparation of N-heterocyclylalkyl- or N-[(polycyclyl)-alkyl]-N'- substituted piperazines as insecticides.", XP002429176, retrieved from STN Database accession no. 1997:499179 *
DATABASE CHEMCATS CHEMICAL ABSTRACT SERVICES, COLUMBUS, OHOI, US; XP002429175 *
EIDEN, FRITZ ET AL: "Analysis of calcium antagonists. III. Verapamil, diltiazem, and perhexiline (1)", PHARMAZEUTISCHE ZEITUNG , 129(12), 678-85 CODEN: PHZIAP; ISSN: 0031-7136, 1984, XP001245693 *
GIANNESSI F: "CARNITINE PALMITOYLTRANSFERASE INHIBITORS IN THE MANAGEMENT OF TYPE 2 DIABETES: AN OLD PROMISE TO BE MAINTAINED", DRUGS OF THE FUTURE, BARCELONA, ES, vol. 28, no. 4, 1 April 2003 (2003-04-01), pages 371 - 381, XP009047902, ISSN: 0377-8282 *
LEE, S-H; MATSUSHITA H; CLAPHAM B; JANDA K D: "The direct conversion of carbamates tu ureas using aluminium hydrides", TETRAHEDRON, vol. 60, 2004, pages 3439 - 3443, XP002429171 *
MINH D N ET AL: "Study of local anaesthetics. Part 98(3): Preparation and local anaesthetic activity of 4-alkylpiperazinoethyl esters of o-heptyloxyphenylcarbamic acid.", DIE PHARMAZIE FEB 1992, vol. 47, no. 2, February 1992 (1992-02-01), pages 94 - 96, XP001249083, ISSN: 0031-7144 *
SCHWEIM H G ET AL: "N-ACYL- UND N-ARYL-N'-ALKYLIDENHARNSTOFFE ALS VORSTUFEN VON ISOCYANATEN ODER ACYLISOCYANATEN N-ACYL- AND N-ARYL-N'-AKYLIDENUREAS AS PRECURSORS OF ISOCYANATES ORACYLISOCYANATES", ARCHIV DER PHARMAZIE, VCH VERLAGSGESELLSCHAFT MBH, WEINHEIM, DE, vol. 320, no. 9, 1987, pages 844 - 850, XP001002079, ISSN: 0365-6233 *

Cited By (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9169224B2 (en) 2004-12-30 2015-10-27 Janssen Pharmaceutica Nv Piperazinyl and piperidinyl ureas as modulators of fatty acid amide hydrolase
WO2008122787A1 (en) * 2007-04-05 2008-10-16 Evotec Ag Piperazine compounds for the inhibition of haematopoietic prostaglandin d synthase
WO2009021740A2 (en) 2007-08-15 2009-02-19 Sanofis-Aventis Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments
US9457017B2 (en) 2007-11-23 2016-10-04 Heart Metabolics Limited Treatment of heart failure
US9468634B2 (en) 2007-11-23 2016-10-18 Heart Metabolics Limited Treatment of heart failure
US8877769B2 (en) 2008-11-25 2014-11-04 Janseen Pharmaceutica Nv Heteroaryl-substituted urea modulators of fatty acid amide hydrolase
WO2010068453A1 (en) 2008-11-25 2010-06-17 Janssen Pharmaceutica Nv Heteroaryl-substituted urea modulators of fatty acid amide hydrolase
US8598356B2 (en) 2008-11-25 2013-12-03 Janssen Pharmaceutica Nv Heteroaryl-substituted urea modulators of fatty acid amide hydrolase
US8461159B2 (en) 2008-11-25 2013-06-11 Jannsen Pharmaceutica BV Heteroaryl-substituted urea modulators of fatty acid amide hydrolase
WO2010141809A1 (en) 2009-06-05 2010-12-09 Janssen Pharmaceutica Nv Aryl-substituted heterocyclic urea modulators of fatty acid amide hydrolase
US8901111B2 (en) 2009-06-05 2014-12-02 Janssen Pharmaceutica Nv Aryl-substituted heterocyclic urea modulators of fatty acid amide hydrolase
WO2010141817A1 (en) 2009-06-05 2010-12-09 Janssen Pharmaceutica Nv Heteroaryl-substituted spirocyclic diamine urea modulators of fatty acid amide hydrolase
US8940745B2 (en) 2010-05-03 2015-01-27 Janssen Pharmaceutica Nv Modulators of fatty acid amide hydrolase
US9688664B2 (en) 2010-05-03 2017-06-27 Janssen Pharmaceutica Nv Modulators of fatty acid amide hydrolase
WO2011157827A1 (en) 2010-06-18 2011-12-22 Sanofi Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases
WO2012120056A1 (en) 2011-03-08 2012-09-13 Sanofi Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120055A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120052A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof
WO2012120054A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120053A1 (en) 2011-03-08 2012-09-13 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
US9393221B2 (en) 2011-07-20 2016-07-19 The General Hospital Corporation Methods and compounds for reducing intracellular lipid storage
EP2567959A1 (en) 2011-09-12 2013-03-13 Sanofi 6-(4-Hydroxy-phenyl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
WO2014036603A1 (en) * 2012-09-05 2014-03-13 Adelaide Research & Innovation Pty Ltd Uses of (-)-perhexiline
WO2015131231A1 (en) * 2014-03-03 2015-09-11 Adelaide Research & Innovation Pty Ltd Methods for using (-)-perhexiline
WO2017031330A1 (en) * 2015-08-20 2017-02-23 The Regents Of The University Of Californa Methods for reducing proteotoxicity
JP2019509338A (en) * 2016-02-23 2019-04-04 セルビシオ アンダルーサ デ サルー Piperazine derivatives as antiviral agents with increased therapeutic activity
US10556013B2 (en) 2017-06-20 2020-02-11 Imbria Pharmaceuticals, Inc. Compositions and methods for increasing efficiency of cardiac metabolism
US11844840B2 (en) 2017-06-20 2023-12-19 Imbria Pharmaceuticals, Inc. Compositions and methods for increasing efficiency of cardiac metabolism
US10918728B2 (en) 2017-06-20 2021-02-16 Imbria Pharmaceuticals, Inc. Compositions and methods for increasing efficiency of cardiac metabolism
US10953102B2 (en) 2017-06-20 2021-03-23 Imbria Pharmaceuticals, Inc. Compositions and methods for increasing efficiency of cardiac metabolism
US11376330B2 (en) 2017-06-20 2022-07-05 Imbria Pharmaceuticals, Inc. Compositions and methods for increasing efficiency of cardiac metabolism
JP2024133410A (en) * 2017-06-20 2024-10-01 インブリア ファーマシューティカルズ， インコーポレイテッド Compositions and methods for increasing cardiac metabolic efficiency - Patents.com
US12318453B2 (en) 2017-06-20 2025-06-03 Imbria Pharmaceuticals, Inc. Compositions and methods for increasing efficiency of cardiac metabolism
JP7761717B2 (en) 2017-06-20 2025-10-28 インブリア ファーマシューティカルズ， インコーポレイテッド Compositions and methods for increasing cardiac metabolic efficiency
EP4497474A3 (en) * 2018-10-17 2025-04-23 Imbria Pharmaceuticals, Inc. Methods of treating rheumatic diseases using trimetazidine-based compounds
WO2020081361A1 (en) 2018-10-17 2020-04-23 Imbria Pharmaceuticals, Inc. Methods of treating rheumatic diseases using trimetazidine-based compounds
US12318382B2 (en) 2018-10-17 2025-06-03 Imbria Pharmaceuticals, Inc. Methods of treating rheumatic diseases using trimetazidine-based compounds
EP3866794A4 (en) * 2018-10-17 2022-07-20 Imbria Pharmaceuticals, Inc. METHODS OF TREATING RHEUMATIC DISEASES USING TRIMETAZIDINE COMPOUNDS
US12569480B2 (en) 2019-05-31 2026-03-10 Imbria Pharmaceuticals, Inc. Methods of treating fibrosis using compounds that promote glucose oxidation
US20220249463A1 (en) * 2019-05-31 2022-08-11 Imbria Pharmaceuticals, Inc. Methods of altering cardiac remodeling using compounds that promote glucose oxidation
US11746090B2 (en) 2020-06-30 2023-09-05 Imbria Pharmaceuticals, Inc. Crystal forms of 2-[4-[(2,3,4- trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate
US12110275B2 (en) 2020-06-30 2024-10-08 Imbria Pharmaceuticals, Inc. Methods of synthesizing 2-[4-[(2,3,4-trimethoxyphenyl)methyl] piperazin-1-yl]ethyl pyridine-3-carboxylate
US12065410B2 (en) 2020-06-30 2024-08-20 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
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
US12285428B2 (en) 2021-05-03 2025-04-29 Imbria Pharmaceuticals, Inc. Methods of treating kidney conditions using modified forms of trimetazidine
US11883396B2 (en) 2021-05-03 2024-01-30 Imbria Pharmaceuticals, Inc. Methods of treating kidney conditions using modified forms of trimetazidine

Also Published As

Publication number Publication date
ITRM20060090A1 (en) 2007-08-23

Similar Documents

Publication Publication Date Title
WO2007096251A1 (en) Inhibitors of cpt in the central nervous system as antidiabetic and/or anti-obesity drugs
Titus et al. Resolution and absolute configuration of an ergoline-related dopamine agonist, trans-4, 4a, 5, 6, 7, 8, 8a, 9-octahydro-5-propyl-1H (or 2H)-pyrazolo [3, 4-g] quinoline
US7531685B2 (en) Deuterium-enriched oxybutynin
EP1140836B1 (en) Amide compounds
RS20060318A (en) Derivatives of n-/phenyl(piperidine-2-yl)methyl/benzamide, preparation method thereof and application of same in therapeutics
EP0343961A2 (en) Aryl- and heteroaryl piperazinyl carboxamides having central nervous system activity
EP0581167B1 (en) Novel arylglycinamide derivatives and preparative processes therefor and their use for treatment of dysuria
US5486526A (en) Histamine H3 -receptor antagonists and therapeutic uses thereof
SK118794A3 (en) 4(4'-piperidinyl or 3'- pyrrolidinyl) substitutes imidazoles as h3-receptor
JPH04217663A (en) 4-aminomethylpiperidine derivative
Larson et al. Stereochemical studies on medicinal agents. 12. Distinction of enantiotopic groups in the interaction of 1-methyl-4-phenyl-4-propionoxypiperidine with analgetic receptors
DE60015732T2 (en) AMID COMPOUNDS FOR STRENGTHENING THE CHOLINERGIC EFFECT
US5965734A (en) Processes and intermediates for preparing 2-substituted piperidine stereoisomers
US5106849A (en) Use of aryl- and heteroaryl piperazinyl carboxamides in the treatment of various central nervous system disorders
JPH02167279A (en) Apovincamic acid derivative
US5482940A (en) Use of aryl- and heteroaryl piperazinyl carboxamides in the treatment of various central nervous system disorders
CN101855200B (en) New polymorphic forms of N-[4-(trifluoromethyl)benzyl]-4-methoxybutyramide
JP3041834B2 (en) N-aminoalkyl-2-anthraquinone carboxamides; new ligands specific for dopamine receptor subtype
FI91398C (en) Process for the preparation of therapeutically useful sulfonanilides
US5278160A (en) Use of aryl- and heteroaryl piperazinyl carboxamides in the treatment of various central nervous system disorders
US5639775A (en) 4-[4'-piperodinyl or 3'-pirrolidinyl] substituted imidazoles as H3 -receptor antagonists and therapeutic uses thereof
WO2006092204A1 (en) Derivatives of aminobutanoic acid inhibiting cpt
JP3091233B2 (en) New N-aminoalkyl-1-biphenylenyl-2-carboxamides, new dopamine receptor / subtype specific ligands
EA003613B1 (en) Ureidopiperidine derivatives as selective human nk3 receptor antagonists
EP0522914A1 (en) 2-Piperidinylpyrimidin-4-carboxamide derivatives, their preparation and their application in therapy

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07704450

Country of ref document: EP

Kind code of ref document: A1