EP1202980A1 - 2-arylimino-2,3-dihydrothiazoles et leur utilisation comme ligands des recepteurs de la somatostatine - Google Patents

2-arylimino-2,3-dihydrothiazoles et leur utilisation comme ligands des recepteurs de la somatostatine

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Publication number
EP1202980A1
EP1202980A1 EP00958575A EP00958575A EP1202980A1 EP 1202980 A1 EP1202980 A1 EP 1202980A1 EP 00958575 A EP00958575 A EP 00958575A EP 00958575 A EP00958575 A EP 00958575A EP 1202980 A1 EP1202980 A1 EP 1202980A1
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EP
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Prior art keywords
radical
general formula
radicals
aryl
resin
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.)
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Application number
EP00958575A
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German (de)
English (en)
French (fr)
Inventor
Christophe Moinet
Carole Sackur
Christophe Thurieau
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.)
Ipsen Pharma SAS
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Societe de Conseils de Recherches et dApplications Scientifiques SCRAS SAS
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Publication of EP1202980A1 publication Critical patent/EP1202980A1/fr
Withdrawn legal-status Critical Current

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Definitions

  • the present application relates to new derivatives of 2-arylimino-2,3-dihydrothiazoles and their preparation methods. These products have a good affinity with certain subtypes of somatostatin receptors and therefore have interesting pharmacological properties.
  • the invention also relates to these same products as medicaments, pharmaceutical compositions containing them and their use for the preparation of a medicament intended for treating pathological conditions or diseases in which one (or more) of the somatostatin receptors is (are involved).
  • Somatostatin is a cyclic tetradecapeptide that was first isolated from the hypothalamus as a growth hormone inhibitor (Brazeau P. et al., Science 1973, 179, 77-79). It also acts as a neurotransmitter in the brain (Reisine T. et al., Neuroscience 1995, 67, 777-790; Reisine et al., Endocrinology 1995, 16, 427-442). Molecular cloning has shown that the bioactivity of somatostatin depends directly on a family of five receptors linked to the membrane.
  • Activation of subtypes 2 and 5 has been associated with the suppression of growth hormone (GH) and more particularly that of adenomas secreting GH (acromegaly) and those secreting the hormone TSH.
  • Activation of subtype 2 but not subtype 5 has been associated with the treatment of prolactin-secreting adenomas.
  • somatostatin receptor subtypes Other indications associated with activation of somatostatin receptor subtypes are restenosis, inhibition of insulin and / or glucagon secretion and in particular diabetes mellitus, hyperlipidemia, insulin insensitivity, Syndrome X, angiopathy, proliferative retinopathy, Dawn phenomenon and nephropathy; inhibition of gastric acid secretion and in particular peptic ulcers, enterocutaneous and pancreatocutaneous fistulas, irritable bowel syndrome, Dumping syndrome, watery diarrhea syndrome, AIDS-related diarrhea, diarrhea induced by chemotherapy, acute or chronic pancreatitis and secreting gastrointestinal tumors; treating cancer like hepatomas; inhibition of angiogenesis, treatment of inflammatory disorders such as arthritis; chronic rejection of allografts; angioplasty; prevention of bleeding from transplanted vessels and gastrointestinal bleeding.
  • Somatostatin agonists can also be used to reduce the weight of a patient.
  • the compounds of general formula (I) described below have an affinity and a selectivity for somatostatin receptors.
  • somatostatin and its peptide analogs often have poor oral bioavailability and low selectivity (Robinson, C, Drugs of the Future, 1994, 19, 992; Reubi, JC et al., TIPS, 1995, 16, 110)
  • said compounds, non-peptide somatostatin agonists or antagonists can be advantageously used to treat pathological conditions or diseases as presented above and in which one (or more) of somatostatin receptors is (are) involved (s).
  • said compounds can be used for the treatment of acromegaly, pituitary adenomas or endocrine gastroenteropancreatic tumors including carcinoid syndrome.
  • RI represents an amino (C -C) alkyl, aminoalkylarylalkyl, aminoalkylcycloalkylalkyl, (C] -Ci 5 ) alkyl, (C 3 -C) cycloalkyl radical,
  • RI represents one of the radicals represented below:
  • RI represents a radical -C (R11) (R12) -CO-Rl 0;
  • R2 represents an optionally substituted carbocyclic or heterocyclic aryl radical
  • R2 represents one of the radicals represented below:
  • R3 represents an alkyl, adamantyl, optionally substituted carbocyclic or heterocyclic aryl, carbocyclic or heterocyclic aralkyl group optionally substituted on the aryl group,
  • R3 represents one of the radicals represented below:
  • R3 represents a radical -CO-R5
  • R4 represents H, alkyl, carbocyclic or heterocyclic aralkyl optionally located on the aryl radical; or the radical represents a radical of general formula
  • i represents an integer of 1 to 3;
  • R5 represents the radical N (R6) (R7);
  • R6 represents a radical (C] -C ⁇ 6 ) alkyl, cycloalkylalkyl, hydroxyalkyl, aryloxyalkyl, carbocyclic or heterocyclic aralkyl optionally substituted on the aryl, aralkoxyalkylke, arylhydroxyalkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, alkynyl, cyclohexylalkylalkylalkylalkylalkylalkylalkylalkylalkyl, hydroxyalkyl, cyclohexenyl, cyclohexenyl, cyclohexenyl, hydroxyalkyl N-acetamidoalkyl, bis-arylalkyl optionally substituted on the aryl groups, di-arylalkyl optionally substituted on the aryl, morpholinoalkyl, pyrrolidinoalkyl, piperidinoal
  • R6 represents one of the radicals represented below:
  • R7 represents H or an alkyl, hydroxyalkyl, mono- or di-aminoalkyl or aralkyl radical
  • radical -N (R6) (R7) represents the radical of the following general formula:
  • R8 represents H, alkyl, hydroxyalkyl, optionally substituted carbocyclic or heterocyclic aryl, optionally substituted aralkyl on the aryl, alkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, bis-arylalkyl, piperidinyl, pyrrolidinyl, hydroxy, arylalkenyl group.
  • R8 represents -X- (CH 2 ) b -R9;
  • R9 represents H or an alkyl, alkoxy, aryloxy, optionally substituted carbocyclic or heterocyclic aryl, morpholinyl, pyrrolidinyl, alkylamino or N, N '- (alky ⁇ ) (aryl) amino radical;
  • X represents CO, CO-NH or SO 2 ;
  • Y represents CH or N
  • a 1 or 2;
  • b represents an integer from 0 to 6;
  • radical N (R6) (R7) represents a radical of general formula
  • Z represents CH, O or S
  • c represents an integer from 0 to 4.
  • radical N (R6) (R7) represents one of the radicals represented below:
  • RIO represents an amino (C 2 -C) alkylamino, ((aminoalkyl) aryl) alkylamino, (((aminoalkyl) cycloalkyl) alkylamino, piperazinyl, homopiperazinyl) radical, or RIO represents the radical represented below:
  • RI 1 represents H
  • R12 represents H or an alkyl radical, (C 3 -C) cycloalkyl, optionally substituted carbocyclic or heterocyclic aralkyl, propargyl, allyl, hydroxyalkyl, alkylthioalkyl, arylalkylalkoxyalkyl, arylalkylthioalkoxyalkyl; or the compounds of the invention will be salts of the compounds of general formula (I).
  • radicals RI, R2, R3, R4, R6, R8, R9 or RI 2 including a substituted aryl radical or aralkyl substituted on the aryl group
  • said aryl or aralkyl radicals will preferably be such than :
  • aryl group when substituted, it can be substituted from 1 to 5 times (in addition to the bond which connects it to the rest of the molecule) by radicals independently chosen from the group consisting of a halogen atom and d '' an alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, aryl, aralkoxy or SO 2 NH 2 radical. If necessary, two substituents can be linked together and form a ring, for example by representing together a methylenedioxy or propylene radical.
  • the aryl radical can be substituted by radicals independently selected from the group consisting of a halogen atom and an alkyl, alkoxy, alkylthio, haloalkyl, alkenyl, haloalkoxy, nitro, cyano, azido, SO 2 N, mono- or di-alkylamino, aminoalkyl, aralkoxy or aryl. If necessary, two substituents can be linked together and form a ring, for example by representing together a methylenedioxy, ethylenedioxy or propylene radical.
  • the aryl or carbocyclic aralkyl radicals can be substituted from 1 to 5 times on the aryl ring by radicals independently selected from the group consisting of a halogen atom and an alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, nitro, cyano radical , azido, mono- or di-alkylamino, pyrrolidinyl, morpholinyl, aralkoxy or aryl. If necessary, two substituents can be linked together and form a ring, for example by representing together an alkylenedioxy radical containing from 1 to 3 carbon atoms.
  • the heterocyclic aryl or aralkyl radicals of R3 can be substituted from 1 to 2 times on the nucleus by radicals independently chosen from the group consisting of a halogen atom and an alkyl radical.
  • aryl group when substituted, it can be substituted 1 to 5 times (in addition to the bond which connects it to the rest of the molecule).
  • the aryl radical can be substituted by radicals independently selected from the group consisting of a halogen atom and an alkyl or alkoxy radical.
  • aryl group (s) when the aryl group (s) is (are) substituted (s), it (s) can (s) be 1 to 5 times (in addition to the bond which ( s) connects to the rest of the molecule).
  • the optional substituents on the aryl groups are independently chosen from the group consisting of a halogen atom and an alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, aryl, aryloxy or SO 2 NH radical.
  • aryl group (s) when the aryl group (s) is (are) substituted (s), it (s) can (be) it from 1 to 5 times (in addition to the bond which ( s) connects to the rest of the molecule).
  • the optional substituents on the aryl groups are independently chosen from the group consisting of a halogen atom and an alkyl, haloalkyl, alkoxy, hydroxy, cyano, nitro or alkylthio radical.
  • the carbocyclic or heterocyclic aryl radical when substituted, it can be substituted 1 to 5 times (in addition to the bond which connects it to the rest of the molecule).
  • the optional substituents on the aryl group are independently chosen from the group consisting of a halogen atom and an alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, carbocyclic aryl, hydroxy, cyano or nitro radical.
  • RI 2 when the carbocyclic or heterocyclic aryl radical is substituted, it can be substituted 1 to 5 times (in addition to the bond which connects it to the rest of the molecule).
  • the optional substituents on the aryl group are independently chosen from the group consisting of a halogen atom and an alkyl, alkoxy, carbocyclic aryl, aralkoxy, hydroxy, cyano or nitro radical.
  • alkyl when no further details are given, is meant a linear or branched alkyl radical containing from 1 to 6 carbon atoms.
  • cycloalkyl when it is not given more precision, is meant a carbon monocyclic system containing from 3 to 7 carbon atoms.
  • alkenyl when it is not given more precision, is meant a linear or branched alkyl radical having from 1 to 6 carbon atoms and having at least one unsaturation (double bond).
  • alkynyl when no further details are given, is meant a linear or branched alkyl radical containing from 1 to 6 carbon atoms and having at least one double unsaturation (triple bond).
  • carbocyclic or heterocyclic aryl is intended to mean a carbocyclic or heterocyclic system comprising at least one aromatic ring, a system being said to be heterocyclic when at least one of the rings which compose it comprises a heteroatom (O, N or S).
  • haloalkyl is meant an alkyl radical in which at least one of the hydrogen atoms (and possibly all) is replaced by a halogen atom.
  • alkylthio, alkoxy, haloalkyl, haloalkoxy, aminoalkyl, alkenyl, alkynyl and aralkyl radicals are meant respectively the alkylthio, alkoxy, haloalkyl, haloalkoxy, aminoalkyl, alkenyl, alkynyl and aralkyl radicals whose alkyl radical has the meaning indicated above.
  • linear or branched alkyl having from 1 to 6 carbon atoms is meant in particular the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl radicals.
  • cycloalkyl is understood to mean in particular the cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexyl and cycloheptanyl radicals.
  • carbocyclic or heterocyclic aryl is meant in particular the phenyl, naphthyl, pyridinyl, furannyl, thiophenyl, indanyl, indolyl, imidazolyl, benzofurannyl, benzothiophenyl, phthalimidyl radicals.
  • Carbocyclic or heterocyclic aralkyl is understood to mean in particular the benzyl, phenylethyl, phenylpropyl, phenylbutyl, indolylalkyl, phthalimidoalkyl, naphthylalkyl, furannylalkyl, thiophenylalkyl, benzothiophenylalkyl, pyridinylalkyl and imidazolylalkyl radicals.
  • the compounds of general formula (I) will be such that:
  • RI represents -C (R11) (R12) -CO-R10 or one of the following radicals
  • R3 represents CO-R5 or one of the following radicals
  • R4 represents H, alkyl, carbocyclic or heterocyclic aralkyl optionally substituted on the aryl radical;
  • i represents an integer of 1 to 3;
  • R5 represents one of the following radicals
  • RIO represents one of the following radicals
  • Rl l represents H
  • R12 represents one of the following radicals
  • R4 when the aryl group is substituted, it can be substituted from 1 to 5 times (in addition to the bond which connects it to the rest of the molecule) by radicals independently chosen from the group consisting of a halogen atom and an alkyl or alkoxy radical.
  • the compounds of the invention will preferably be such that R4 represents H.
  • R3 represents one of the following radicals
  • R4 represents H
  • RI represents one of the radicals below
  • R2 represents one of the following radicals
  • R3 represents COR5
  • R4 represents H
  • R5 represents one of the following radicals
  • RI represents the radical -C (R11) (R12) -CO-R10 in which
  • RIO represents the radical
  • RI 1 represents H
  • RI 2 represents the radical
  • R2 represents the radical
  • R3 represents the radical
  • R4 represents H.
  • the invention further relates to processes for the preparation on a solid support of the compounds of general formula (I) described above (also applicable to the corresponding compounds of general formula (II)).
  • RI represents a radical -CH 2 -A1-NH, in which Al represents a radical - (CH) n -, - (CH 2 ) n -O- (CH) p -, aralkylene or cycloalkylalkylene, n and p representing integers from 1 to 6;
  • R2 and R4 represent the same radicals as in the general formula (I);
  • R3 represents the same radicals as in the general formula (I) except the radicals -CO-R5;
  • step 1) of the order of 10 to 20 equivalents of diamine R1-NH.
  • Step 1) will preferably be carried out at room temperature.
  • Step 3) is carried out at a temperature above room temperature, for example at a temperature between 60 and 90 ° C, using on the order of 2 to 5 equivalents of compound of general formula (III).
  • the acid conditions can for example be created using a dichloromethane / trifluoroacetic acid mixture at 50%, said acid conditions being preferably maintained for a period of the order of 1 to 2 hours.
  • step 5 the basic conditions can for example be created using a saturated solution of sodium hydrogencarbonate or by elution on a basic alumina cartridge.
  • RI represents the same radicals as in the general formula (I), except the radicals of the type -CH -A1-NH 2 , in which Al represents a radical - (CH 2 ) n -, - (CH 2 ) nO- (CH 2 ) p -, aralkylene or cycloalkylalkylene, n and p representing integers from 1 to 6, and also excepting the radicals -C (R11) (R12) -CO-R10;
  • R2 represents an aminoalkylphenyl radical
  • R3 represents the same radicals as in the general formula (I) except the radicals -CO-R5;
  • R4 represents the same radicals as in the general formula (I);
  • the excess from step 1) will be used in the order of 5 to 10 equivalents of aminoalkylaniline.
  • Step 1) will preferably be carried out at room temperature.
  • Step 3) takes place at a temperature above the room temperature, for example at a temperature between 60 and 90 ° C, using of the order of 2 to 5 equivalents of compound of general formula (III).
  • the acid conditions can for example be created using a dichloromethane / trifluoroacetic acid mixture at 50%, said acid conditions being preferably maintained for a period of the order of 1 to 2 hours.
  • the basic conditions can for example be created using a saturated solution of sodium hydrogencarbonate or by elution on a basic alumina cartridge.
  • RI represents a radical -CH 2 -A1-NH 2 , in which Al represents a radical - (CH) n -, - (CH 2 ) n -O- (CH) p -, aralkylene or cycloalkylalkylene, n and p representing integers from 1 to 6;
  • R2 represents the same radicals as in the general formula (I);
  • R3 represents a radical -CO-R5
  • R4 and R5 represent the same radicals as in the general formula (I);
  • step 1) of the order of 10 to 20 equivalents of symmetrical diamine.
  • Step 1) will preferably be carried out at room temperature.
  • Step 3) is carried out at a temperature above room temperature, for example at a temperature between 60 and 90 ° C, using about 2 to 5 equivalents of acid of general formula (IV) .
  • the peptide coupling of step 4) is carried out for example in DMF with coupling agents such as for example dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), a DIC / N-hydroxybenzotriazole mixture (HOBt), hexafluorophosphate benzotriazolyloxytris (dimethylamino) phosphonium (PyBOP), 2- (1H-benzotriazol-l-yl) -l, l, 3,3-tetramethyluronium ( ⁇ BTU) hexafluorophosphate or 2- (1H-benzotriazol-l tetrafluoroborate -yl) -l, l, 3,3-tetramethyluronium (TBTU) and amino compounds.
  • DCC dicyclohexylcarbodiimide
  • DIC diisopropylcarbodiimide
  • HOBt DIC / N-hydroxybenzotri
  • the coupling agents will be used in proportions of 4 to 5 equivalents, like the amino compounds, and the reaction will take place at a temperature of the order of room temperature for a period of the order of 1 to 24 hours.
  • the acid conditions can for example be created using a dichloromethane / trifluoroacetic acid mixture at 50%, said acid conditions being preferably maintained for a period of the order of 1 to 2 hours.
  • the basic conditions can for example be created by using a saturated solution of sodium hydrogencarbonate or by elution on a basic alumina cartridge.
  • the compounds of general formula (I) d the compounds of general formula (I) d
  • RI represents the same radicals as in the general formula (I), except the radicals of the type -CH 2 -A1-NH, in which Al represents a radical - (CH 2 ) n - :> - (CH) n -O- (CH 2 ) p -, aralkylene or cycloalkylalkylene, n and p representing integers from 1 to 6, and also excepting the radicals -C (R11) (R12) -CO-R10;
  • R2 represents an aminoalkylphenyl radical
  • R3 represents a radical -CO-R5
  • R4 and R5 represent the same radicals as in the general formula (I);
  • the excess from step 1) will be used in the order of 5 to 10 equivalents of aminoalkylaniline.
  • Step 1) will preferably be carried out at room temperature.
  • Step 3) is carried out at a temperature above room temperature, for example at a temperature between 60 and 90 ° C, using about 2 to 5 equivalents of acid of general formula (IV) .
  • the peptide coupling of step 4) is carried out for example in DMF with coupling agents such as for example dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), a DIC / N-hydroxybenzotriazole mixture (HOBt), hexafluorophosphate benzotriazolyloxytris (dimethylamino) phosphonium (PyBOP), 2- (1H-benzotriazol-l-yl) -l, l, 3,3-tetramethyluronium ( ⁇ BTU) hexafluorophosphate or 2- (1H-benzotriazol-l tetrafluoroborate -yl) -l, l, 3,3-tetramethyluronium (TBTU) and amino compounds.
  • DCC dicyclohexylcarbodiimide
  • DIC diisopropylcarbodiimide
  • HOBt DIC / N-hydroxybenzotri
  • the coupling agents will be used in proportions of 4 to 5 equivalents, like the amino compounds, and the reaction will take place at a temperature of the order of room temperature for a period of the order of 1 to 24 hours.
  • the acid conditions can for example be created using a dichloromethane / trifluoroacetic acid mixture at 50%, said acid conditions being preferably maintained for a period of the order of 1 to 2 hours.
  • the basic conditions can for example be created by using a saturated solution of sodium hydrogencarbonate or by elution on a basic alumina cartridge.
  • RI represents the same radicals as in the general formula (I), except the radicals of the type -CH 2 -A1-NH 2 , in which Al represents a radical - (CH 2 ) n -, - (CH 2 ) nO- ( CH 2 ) p -, aralkylene or cycloalkylalkylene, n and p representing integers from 1 to 6, and also excepting the radicals -C (R11) (R12) -CO-R10;
  • R2 represents the same radicals as in the general formula (I);
  • R3 represents a radical -CO-R5
  • R4 represents H
  • R5 represents a radical -NH-CH 2 -A1-NH 2 , in which Al represents a linear or branched alkylene radical having 1 to 6 carbon atoms, - (CH 2 ) n -O- (CH) p -, aralkylene or cycloalkylalkylene, n and p representing integers from 1 to 6, or alternatively R5 represents the radical N (R6) (R7) corresponding to the following general formula:
  • R8 represents H
  • Y represents N
  • a 1 or 2;
  • step 4 adding the thiourea obtained in step 3) to the resin obtained in step 2) and heating the mixture;
  • step 1) of the order of 10 to 20 equivalents of diamine R5-H.
  • Step 1) will preferably be carried out at room temperature.
  • the peptide coupling of step 2) is carried out in DMF with a coupling agent such as for example the mixture DIC / N-hydroxybenzotriazole (HOBt).
  • the reaction of step 3) is preferably carried out in a solvent such as dimethylformamide or dioxane.
  • step 4 use will preferably be made of 2 to 5 equivalents of thiourea per equivalent of resin; more preferably, it will be heated to a temperature above room temperature, for example to a temperature of 40 to 100 ° C (in particular to a temperature of about 80 ° C) and for a period of 2 to 24 hours.
  • the acid conditions can for example be created using a dichloromethane / trifluoroacetic acid mixture at 50%, said acid conditions being preferably maintained for a period of the order of 1 to 2 hours.
  • step 6 the basic conditions can for example be created by using a saturated solution of sodium hydrogencarbonate or by elution on a basic alumina cartridge.
  • RI represents a radical -C (R11) (R12) -CO-R10;
  • R2, R3 and R4 represent the same radicals as in the general formula (I);
  • RIO represents an amino radical (C 2 -C) alkylamino, ((aminoalkyl) aryl) alkylamino, ((aminoalkyl) cycloalkyl) alkylamino, piperazinyl, homopiperazinyl, or RIO represents the radical represented below:
  • RI 1 represents H
  • RI 2 represents H or an alkyl radical, (C 3 -C) cycloalkyl, carbocyclic or heterocyclic aralkyl optionally substituted, propargyl, allyl, hydroxyalkyl, alkylthioalkyl, arylalkylalkoxyalkyle, arylalkylthioalkoxyalkyl;
  • Step 1) of the order of 10 to 20 equivalents of diamine R10-H.
  • Step 2) will preferably be carried out at room temperature.
  • the peptide coupling of step 2) is carried out for example in DMF with coupling agents such as for example dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), a DIC / N-hydroxybenzotriazole mixture (HOBt), hexafluorophosphate benzotriazolyloxytris (dimethylamino) phosphonium (PyBOP), 2- (1H-benzotriazol-l-yl) -l, l, 3,3-tetramethyluronium ( ⁇ BTU) hexafluorophosphate or 2- (1H-benzotriazol-l tetrafluoroborate -yl) -1,3,3-tetramethyluronium (TBTU).
  • DCC dicyclohexylcarbodiimide
  • DIC
  • step 2) is preferably carried out at room temperature and for a period of 1 to 24 hours.
  • the deprotection of step 3) can be carried out, for example, by a mixture of DMF containing 20% of piperidine.
  • Step 4) will preferably be carried out in a solvent such as dimethylformamide or dichloromethane, the isothiocyanate preferably being added in a proportion of 5 to 10 equivalents per equivalent of resin obtained in step 3).
  • the acid conditions can for example be created using a dichloromethane / trifluoroacetic acid mixture at 50%, said acid conditions being preferably maintained for a period of the order of 1 to 2 hours.
  • the basic conditions can for example be created by using a saturated solution of sodium hydrogencarbonate or by elution on a basic alumina cartridge.
  • a subject of the invention is also, as medicaments, the compounds of general formulas (I) and (II) described above or their pharmaceutically acceptable salts. It also relates to pharmaceutical compositions comprising said compounds or their pharmaceutically acceptable salts, and their use for the preparation of a medicament intended to treat pathological conditions or diseases in which one (or more) of the somatostatin receptors is (are) (s) involved.
  • the compounds of general formulas (I) and (II) described above or their pharmaceutically acceptable salts may be used for the preparation of a medicament intended to treat the pathological conditions or the diseases chosen from the group composed of the pathological states or of the following diseases: acromegaly, pituitary adenomas, Cushing's disease, gonadotrophinomas and prolactinomas, catabolic side effects of glucocorticoids, insulin-dependent diabetes, diabetic retinopathy, diabetic nephropathy, syndrome X, Dawn phenomenon, angiopathy, angioplasty, hyperthyroidism, gigantism, endocrine gastroenteropancreatic tumors including carcinoid syndrome, VIPome, insulinoma, neidioblastosis, hyperinsulinemia, glucagonoma, gastrinoma and Zollinger-Ellison syndrome, GRFome as well as acute bleeding from esophageal varices, ulcers, gastroesophageal reflux, gastroduo
  • the compounds of general formulas (I) and (II) described above or their pharmaceutically acceptable salts can be used for the preparation of a medicament intended to treat the pathological conditions or the diseases chosen from the group composed of the pathological states or the following diseases: acromegaly, pituitary adenomas or gastroenteropancreatic endocrine tumors including carcinoid syndrome, and gastrointestinal bleeding.
  • pharmaceutically acceptable salt is intended to mean in particular addition salts of inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide and nitrate or of organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate , methane sulfonate, p-toluenesulfonate, pamoate, oxalate and stearate.
  • the salts formed from bases such as sodium or potassium hydroxide.
  • the pharmaceutical composition can be in the form of a solid, for example powders, granules, tablets, capsules, liposomes or suppositories.
  • Suitable solid carriers can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, carboxymethyl cellulose sodium, polyvinylpyrrolidine and wax.
  • the suspensions will in particular include the suspensions of microparticles with prolonged release charged with active principle (in particular microparticles in polylactide-co-glycolide or PLGA - cf. for example the patents US 3,773,919, EP 52 510 or EP 58 481 or the patent application PCT WO 98/47489), which allow the administration of a determined daily dose over a period of several days to several weeks.
  • compositions containing a compound of the invention can also be presented in liquid form, for example, solutions, emulsions, suspensions or syrups.
  • suitable liquid carriers can be, for example, water, organic solvents such as glycerol or glycols, as well as their mixtures, in varying proportions, in water.
  • the administration of a medicament according to the invention can be done by topical, oral, parenteral route, by intramuscular injection, etc.
  • the administration dose envisaged for a medicament according to the invention is between 0.1 mg to 10 g depending on the type of active compound used.
  • a carboxylic acid is first converted to an acid chloride using oxalyl or thionyl chloride, or by activating it in the form of an anhydride using an alkyl chloroformate (by example isobutyl chloroformate, cf. Krantz, A.; Copp, LJ Biochemistry 1991, 30, 4678-4687; or ethyl chloroformate, cf. Podlech, J.; Seebach, D. Liebigs Ann. 1995, 1217 -1228) in the presence of a base (triethylamine or N-methylmorpholine).
  • alkyl chloroformate by example isobutyl chloroformate, cf. Krantz, A.; Copp, LJ Biochemistry 1991, 30, 4678-4687; or ethyl chloroformate, cf. Podlech, J.; Seebach, D. Liebigs Ann. 1995, 1217 -1228
  • the activated carboxyl group is then transformed into diazoketone using diazomethane in ethereal solution or a commercial solution of trimethylsilyldiazomethane (Aoyama, T.; Shiori, T. Chem. Pharm. Bull. 1981, 29, 3249-3255) in an aprotic solvent such as diethyl ether, tetrahydrofuran (THF) or acetonitrile.
  • diazomethane in ethereal solution or a commercial solution of trimethylsilyldiazomethane (Aoyama, T.; Shiori, T. Chem. Pharm. Bull. 1981, 29, 3249-3255) in an aprotic solvent such as diethyl ether, tetrahydrofuran (THF) or acetonitrile.
  • THF tetrahydrofuran
  • bromination is then carried out using a brominating agent such as hydrobromic acid in acetic acid, aqueous hydrobromic acid in diethyl ether or dichloromethane.
  • a brominating agent such as hydrobromic acid in acetic acid, aqueous hydrobromic acid in diethyl ether or dichloromethane.
  • Oxalyl chloride (5.8 ml; 66.7 mmol) is added to Pht- ⁇ -Ala-OH (9.96 g; 44.5 mmol) dissolved in dichloromethane (120 ml) and 3 drops of dimethylformamide (DMF ). The mixture is stirred for 3 hours at room temperature. After removing the solvent, the white solid is taken up in a 1: 1 mixture of anhydrous tetrahydrofuran and acetonitrile (200 ml) then 49 ml of 2M solution of (trimethylsilyl) diazomethane in hexane (97.9 mmol) are added. drip at 0 ° C. The solvents are removed after stirring overnight at 0 ° C.
  • the starting material is an arylmethyl ketone or a heteroarylmethyl ketone.
  • the starting arylmethylketone or heteroarylmethylketone is converted into the corresponding ⁇ -bromoketone using different brominating agents:
  • a brominating agent on a polymer support such as perbromide on a resin Amberlyst A-26, poly (perbromide of vinylpyridinium hydrobromide) (Frechet, JMJ; Farrall, M. j. J. Macromol. Sci. Chem. 1977, 507- 514) in a protic solvent such as methanol at about 20-35 ° C for about 2-10 h.
  • a protic solvent such as methanol
  • This resin was prepared from Wang resin, acquired from Bachem or Novabiochem with a load greater than 0.89 mmol / g, by a general procedure well described (cf. Bunin, BA The Combinatorial Index, Académie Press, 1998 p. 62-63; Dressman, BA; Spangle, LA; Kaldor, SW Tetrahedron Lett. 1996, 37, 937-940; Hauske, JR; Dorff, P. Tetrahedron Lett.
  • N-methylmorpholine or pyridine as base and 4-nitrophenylchloroformate are successively added to a Wang resin pre-swollen in dichloromethane (DCM) or tetrahydrofuran (THF) at room temperature. The mixture is stirred overnight. The resin is then washed successively with THF, diethyl ether and DCM and then dried under reduced pressure at 50 ° C overnight.
  • DCM dichloromethane
  • THF tetrahydrofuran
  • the resin is then washed successively with DMF, methanol and DCM and then dried under reduced pressure.
  • the 2-arylimino-2,3-dihydrothiazole resin is cleaved under acidic conditions (DCM / 50% trifluoroacetic acid) for 1-2 hours and then rinsed with DCM.
  • the solvent is evaporated and the free base isolated after treatment under basic conditions (saturated solution of sodium hydrogencarbonate), extraction with DCM or elution with methanol in a basic alumina cartridge (500 mg, Interchim).
  • the release stage carried out in 1 ml of DCM / 50% trifluoroacetic acid mixture, gives, after one and a half hours of stirring, an oil which is eluted with methanol in a basic alumina cartridge (500 mg, Interchim) .
  • the free base is quantitatively isolated (21.3 mg) in the form of a yellow oil having a purity measured by UV spectrophotometry of 98% at 220 nm.
  • n 1-6
  • R4 represents H, alkyl, carbocyclic or heterocyclic aralkyl optionally located on the aryl radical;
  • i represents an integer of 1 to 3;
  • R4 when the aryl group is substituted, it can be substituted from 1 to 5 times (in addition to the bond which connects it to the rest of the molecule) by radicals independently chosen from the group consisting of a halogen atom and an alkyl or alkoxy radical.
  • the cyclization step takes place in aprotic solvents such as dioxane or DMF at 80 ° C for 2 hours between the thiourea resin and the ⁇ -bromoketone (2-5 equivalents).
  • the resin is then successively washed with DMF, methanol and DCM and then dried under reduced pressure.
  • the iminothiazole resin is cleaved by treatment under acidic conditions (DCM / 50% trifluoroacetic acid) for 1-2 hours and then rinsed with DCM.
  • the solvent is evaporated and the free base isolated after extraction under basic conditions (saturated solution of sodium hydrogencarbonate), extraction with DCM or elution with methanol in a basic alumina cartridge (500 mg, Interchim).
  • Example 2 Example 2
  • the 2-arylimino-1,3-thiazole-4 (3H) -carboxamide resin is cleaved by treatment under acidic conditions (DCM / trifluoroacetic acid 50%) for 1-2 hours then rinsing with DCM.
  • the solvent is evaporated and the free base isolated after treatment under basic conditions (saturated solution of sodium hydrogencarbonate), extraction with DCM or elution with methanol in a basic alumina cartridge (500 mg, Interchim).
  • the 2-arylimino-1,3-thiazole-4 (3H) - carboxamide resin is cleaved by treatment under acid conditions (DCM / 50% trifluoroacetic acid) for 1-2 hours then rinsing with DCM.
  • the solvent is evaporated and the free base isolated after treatment under basic conditions (saturated solution of sodium hydrogen carbonate) followed by extraction with DCM or elution with methanol in a basic alumina cartridge (500 mg, Interchim).
  • thiourea is carried out in a solvent such as DMF or dioxane by mixing an equimolar amount of primary amine and aromatic or heteroaromatic isothiocyanate. After 2 to 24 hours of stirring at room temperature, the thiourea (2 to 5 eq.) Is added to the functionalized resin and then heated to 80 ° C. for 2 to 4 hours.
  • the 2-arylimino-1,3-thiazole-4 (3H) -carboxamide resin is cleaved by treatment under acidic conditions (DCM / trifluoroacetic acid 50%) for 1-2 hours then rinsing with DCM.
  • the solvent is evaporated and the free base isolated after treatment under basic conditions (saturated solution of sodium hydrogencarbonate), extraction with DCM or elution with methanol in a basic alumina cartridge (500 mg, Interchim).
  • Fmoc-Gly-O ⁇ acid (2.36 g, 7.94 mmol) is activated with HOBt (1.07 g, 7.94 mmol) and DIC (1.25 ml, 7.94 mmol ) in 22 ml of DMF for 5 minutes before adding the mixture to the Wang N-butylamine carbamate resin (1 g, loading rate of 0.794 mmol / g) pre-swollen in 10 ml of DMF. After 18 hours of stirring at room temperature, the resin is washed successively with DMF (5 x 20 ml) then with DCM (5 x 20 ml) before being dried under vacuum. 1.27 g of pale yellow resin is thus obtained having a negative Kaiser ninhydrin test.
  • the regioselective cyclization stage is carried out in aprotic solvents such as dioxane, DMF or N-methylpyrrolidinone at 80 ° C for 2 to 3 hours between the thiourea resin and the ⁇ -bromoketone (2 to 5 eq.).
  • the resin is then washed successively with DMF, methanol and DCM and then dried under reduced pressure.
  • the 2-arylimino-2,3-dihydrothiazole resin is cleaved under acidic conditions (DCM / 50% trifluoroacetic acid) for 1 to 2 hours then rinsed with DCM.
  • the solvent is evaporated and the free base isolated after treatment under basic conditions (saturated solution of sodium hydrogencarbonate) followed by extraction with DCM or elution with methanol in a basic alumina cartridge (500 mg, Interchim).
  • R1 -C (R11R12) -CO-R10
  • R11 H Groups RI 2:
  • the compounds obtained were characterized by their retention time (tr) and mass spectrometry (M + H) + .
  • the chromatograms are obtained from a high performance liquid chromatography device (Hewlett-Packard 1100) equipped with a UV scanning detector. The following conditions were used for the measurement of the retention times by high performance liquid chromatography, knowing that the extraction wavelength of each of the chromatograms is 220 nm:
  • Eluent A water + 0.02% trifluoroacetic acid
  • eluent B acetonitrile
  • Mass spectra are obtained from a simple quadrupole mass spectrometer equipped with an electrospray source (Micromass, Platforme II).
  • the compounds of the present invention can and have been tested for their affinity for different subtypes of somatostatin receptors according to the procedures described below.
  • the affinity of a compound of the invention for the somatostatin receptor 1 to 5 subtypes is determined by measuring the inhibition of the binding of [I-Tyr JSRIF-14 to transfected cells CHO-K1.
  • the human somatostatin ssti receptor gene has been cloned as a genomic fragment.
  • a 1.5 Kb Pstl-Xmnl segment containing 100 bp of the non-transcribed 5 'region, 1.17 Kb of the entire coding region, and 230 bp of the non-transcribed 3' region is modified by the addition of the linker BglII.
  • the resulting DNA fragment is subcloned into the BamHI site of a pCMV-81 to give the expression plasmid in mammals (supplied by Dr. Graeme Bell, Univ. Chicago).
  • a cloned cell line stably expressing the ssti receptor is obtained by transfection into CHO-K1 cells (ATCC) using the calcium phosphate co-precipitation method.
  • the plasmid pRSV-neo (ATCC) is included as a selection marker.
  • Cloned cell lines were selected in RPMI 1640 medium containing 0.5 mg / ml of G418 (Gibco), cloned in a circle, and multiplied in culture.
  • the human somatostatin sst receptor gene isolated in the form of a 1.7 Kb BamHI-HindIII genomic DNA fragment and subcloned in a plasmid vector pGEM3Z (Promega), was supplied by Dr. G. Bell (Univ . of Chicago).
  • the mammalian cell expression vector is constructed by inserting the 1.7 Kb BamHI-Hindlll fragment into compatible endonuclease restriction sites of the plasmid pCMV5.
  • a cloned cell line is obtained by transfection into CHO-K1 cells using the calcium phosphate co-precipitation method.
  • the plasmid pRSV-neo is included as a selection marker.
  • the sst 3 receptor is isolated as a genomic fragment, and the complete coding sequence is contained in a 2.4 Kb BamRVHindlII fragment.
  • the mammalian expression plasmid, pCMV-h3 is constructed by inserting the 2.0 Kb Ncol-Hindlll fragment into the EcoRI site of the pCMV vector after modification of the terminations and addition of EcoRI linkers.
  • a cloned cell line stably expressing the sst3 receptor is obtained by transfection into CHO-K1 cells (ATCC) by the calcium phosphate co-precipitation method.
  • the plasmid pRSV-neo (ATCC) is included as a selection marker. Cloned cell lines were selected in RPMI 1640 medium containing 0.5 mg / ml of G418 (Gibco), cloned in a circle, and multiplied in culture.
  • the human sst 4 receptor expression plasmid, pCMV-HX, was supplied by the
  • This vector contains the genomic fragment coding for the human sst4 receptor of 1.4 Kb Nhel-Nhe ⁇ , 456 bp of the 5 'non-transcribed region, and 200 bp of the 3' non-transcribed region, cloned in the XballEc ⁇ R ⁇ sites of PCMV- HX.
  • a cloned cell line stably expressing the sst 4 receptor is obtained by transfection into CHO-K1 cells (ATCC) by the calcium phosphate co-precipitation method.
  • the plasmid pRSV-neo is included as a selection marker. Cloned cell lines were selected in RPMI 1640 medium containing 0.5 mg / ml of G418 (Gibco), cloned in a circle, and multiplied in culture.
  • the gene corresponding to the human ssts receptor obtained by the PCR method using a ⁇ genomic clone as probe, was supplied by Dr. Graeme Bell (Univ. Chicago).
  • the resulting PCR fragment of 1.2 Kb contains 21 base pairs of the 5 'non-transcribed region, the entire coding region, and 55 bp of the 3' non-transcribed region.
  • the clone is inserted into an EcoRl site of the plasmid pBSSK (+).
  • the insert is recovered in the form of a 1.2 kb HindIII-Xbal fragment for subcloning in an expression vector in mammals, pCVM5.
  • a cloned cell line stably expressing the ssts receptor is obtained by transfection into CHO-K1 cells
  • ATCC by the calcium phosphate co-precipitation method.
  • the plasmid pRSV-neo (ATCC) is included as a selection marker. Cloned cell lines were selected in RPMI 1640 medium containing 0.5 mg / ml of G418 (Gibco), cloned in a circle, and multiplied in culture.
  • CHO-K1 cells stably expressing one of the human sst receptors are cultured in RPMI 1640 medium containing 10% fetal calf serum and 0.4 mg / ml of geneticin.
  • the cells are collected with 0.5 mM EDTA and centrifuged at 500 g for about 5 min at about 4 ° C.
  • the centrifuge is re- suspended in a 50 mM Tris buffer medium at pH 7.4 and centrifuged twice at 500 g for approximately 5 min at approximately 4 ° C.
  • the cells are lysed by sonication and centrifuged at 39,000 g for approximately 10 min at 4 ° C.
  • the centrifugate is re-suspended in the same buffer medium and centrifuged at 50,000 g for 10 min at approximately 4 ° C and the membranes in the centrifugate obtained are stored at - 80 ° C.
  • the bound [ 125 I-Tyr ⁇ ] SRIF-14 is separated from the free [ 125 I-Tyr ⁇ ] SRIF-14 by immediate filtration through fiberglass filter plates GF / C (Unifilter, Packard) prepreg with 0 , 1% polyethylenimine (PEI), using a Filtermate 196 (Packard).
  • the filters are washed with 50 mM HEPES buffer at approximately 0-4 ° C for approximately 4 seconds and their radioactivity is determined using a counter (Packard Top Count).
  • the specific binding is obtained by subtracting the non-specific binding (determined in the presence of 0.1 ⁇ M SRIF-14) from the total binding.
  • the data relating to the link are analyzed by computer-assisted non-linear regression analysis (MDL) and the values of the inhibition constants (Ki) values are determined.
  • CHO-K1 cells expressing the human somatostatin receptor subtypes are cultured in 24-well plates in RPMI 1640 medium with 10% fetal calf serum and 0.4 mg / ml of geneticin. The environment is changed the day before the experiment.
  • the cells at a rate of 10 cells / well are washed twice with 0.5 ml of new RPMI medium comprising 0.2% BSA supplemented with 0.5 mM of 3-isobutyl-1-methylxanthine (IBMX) and incubated for approximately 5 min at around 37 ° C.
  • new RPMI medium comprising 0.2% BSA supplemented with 0.5 mM of 3-isobutyl-1-methylxanthine (IBMX) and incubated for approximately 5 min at around 37 ° C.
  • IBMX 3-isobutyl-1-methylxanthine
  • cyclic AMP is stimulated by the addition of 1 mM forskolin (FSK) for 15-30 minutes at about 37 ° C.
  • FSK forskolin
  • the somatostatin inhibitory effect of an agonist compound is measured by the simultaneous addition of FSK (1 ⁇ M), SRIF-14 (10 "12 M to 10 “ 6 M) and the test compound (10 "10 M to 10 "5 M).
  • the antagonistic effect of a compound is measured by the simultaneous addition of FSK (1 ⁇ M), SRIF-14 (1 to 10 nM) and of the test compound (10 "10 M to 10 " 5 M).
  • the reaction medium is eliminated and 200 ml of 0.1 N HCl are added.
  • the amount of cAMP is measured by a radioimmunological test (Kit FlashPlate SMP001A, New England Nuclear).

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EP00958575A 1999-07-22 2000-07-21 2-arylimino-2,3-dihydrothiazoles et leur utilisation comme ligands des recepteurs de la somatostatine Withdrawn EP1202980A1 (fr)

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BRPI0712720A2 (pt) 2006-05-31 2012-11-20 Abbott Lab compostos tiazàis como ligantes do receptor canabinàide e usos dos mesmos
US8841334B2 (en) 2006-05-31 2014-09-23 Abbvie Inc. Compounds as cannabinoid receptor ligands and uses thereof
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JP2010522760A (ja) 2007-03-28 2010-07-08 アボット・ラボラトリーズ カンナビノイド受容体リガンドとしての１，３−チアゾール−２（３ｈ）−イリデン化合物
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