TREA

Hydantoin thiohydantoin pyrimidinedione and thioxopyrimidinone derivatives preparation method and use as medicines

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Information

  • Patent Grant
  • 6759415
  • Patent Number
    6,759,415
  • Date Filed
    Wednesday, January 23, 2002
    22 years ago
  • Date Issued
    Tuesday, July 6, 2004
    20 years ago
Information
Abstract
The invention concerns compounds for treating pathological conditions or diseases wherein one (or several) somatostatin receptors is (are) involved, corresponding to general formula (I) wherein: R1 represents in particular a carbocyclic or heterocyclic aryl radical optionally substituted or a non-aromatic heterocyclic radical optionally substituted; R2 represents H, alkyl or aryl optionally substituted; R3 represents H or —(CH2)p—Z3, Z3 representing in particular alkyl, cycloalkyl, bis-arylalkyl or di-aryalkyl, —Y1—(CH2)p-phenyl-(X1)n, carbocyclic or heterocyclic aryl optionally substituted, a non-aromatic heterocyclic radical optionally substituted, X1, every time it is present, being independently selected in particular among the radicals H, Cl, F, Br, I, CF3, NO2, OH, NH2, CN, N3, —OCF3, alkyl, alkoxy, —S-alkyl, —(CH2)p—NH2, —(CH2)p—NH-alkyl, —(CH2)p—N-alkyl; Y1 represents O, S, NH or is not present; R4 represents —(CH2)p—Z4, Z4 representing in particular amino, alkylamino, N,N-dialkylamino; R5 represents in particular H or alkyl; X represents O or S; p each time it is present is independently 0 or an integer ranging between 1 and 6; q each time it is present is independently an integer between 1 and 5; n represents 0 or 1; provided that when n represents 0, m represents 1, 2 or 3, and when n represents 1, m represents 0 or 1.
Description




The invention relates to new derivatives of hydantoins, thiohydantoins, pyrimidinediones and thioxopyrimidinones of general formula (I) represented below, their preparation processes and their use as medicaments. These compounds have a good affinity with certain sub-types of somatostatin receptors and therefore have useful pharmacological properties. The invention also relates to the pharmaceutical compositions containing said compounds and their use for the preparation of a medicament intended to treat pathological states or diseases in which one (or more) somatostatin receptors are involved.




Somatostatin (SST) is a cyclic tetradecapeptide which was isolated for the first time from the hypothalamus as a substance which inhibits the growth hormone (Brazeau P. et al.,


Science


1973, 179, 77-79). It also operates as a neurotransmitter in the brain (Reisine T. et al.,


Neuroscience


1995, 67, 777-790; Reisine T. et al.,


Endocrinology


1995, 16, 427-442). Molecular cloning has allowed it to be shown that the bioactivity of somatostatin depends directly on a family of five receptors linked to the membrane.




The heterogeneity of the biological functions of somatostatin has led to studies which try to identify the structure-activity relationships of peptide analogues on somatostatin receptors, which has led to the discovery of 5 sub-types of receptors (Yamada et al.,


Proc. Natl. Acad. Sci. U.S.A


, 89, 251-255, 1992; Raynor, K. et al,


Mol. Pharmacol


., 44, 385-392, 1993). The functional roles of these receptors are currently being actively studied. The affinities with different sub-types of somatostatin receptors have been associated with the treatment of the following disorders/diseases. Activation of sub-types 2 and 5 has been associated with suppression of the growth hormone (GH) and more particularly with that of adenomas secreting GH (acromegalia) and those secreting hormone TSH. Activation of sub-type 2 but not sub-type 5 has been associated with the treatment of adenomas secreting prolactin. Other indications associated with the activation of sub-types of somatostatin receptors are the recurrence of stenosis, inhibition of the secretion of insulin and/or of glucagon and in particular diabetes mellitus, hyperlipidemia, insensiblity to insulin, Syndrome X, angiopathy, proliferative retinopathy, dawn phenomenon and nephropathy; inhibition of the secretion of gastric acid and in particular peptic ulcers, enterocutaneous and pancreaticocutaneous fistulae, irritable colon syndrome, dumping syndrome, aqueous diarrhoea syndrome, diarrhoea associated with AIDS, diarrhoea induced by chemotherapy, acute or chronic pancreatitis and secretory gastrointestinal tumours; the treatment of cancer such as hepatomas; the inhibition of angiogenesis, the treatment of inflammatory disorders such as arthritis; chronic rejection of allografts; angioplasty; the prevention of bleeding of grafted vessels and gastrointestinal bleeding. The agonists of somatostatin can also be used to reduce the weight of a patient.




Among the pathological disorders associated with somatostatin (Moreau J. P. et al., Life Sciences 1987, 40, 419; Harris A. G. et al.,


The European Journal of Medicine


, 1993, 2, 97-105), there can be mentioned for example: acromegalia, hypophyseal adenomas, Cushing's disease, gonadotrophinomas and prolactinomas, catabolic side-effects of glucocorticoids, insulin dependent diabetes, diabetic retinopathy, diabetic nephropathy, hyperthyroidism, gigantism, endocrinic gastroenteropancreatic tumours including carcinoid syndrome, VIPoma, insulinoma, nesidioblastoma, hyperinsulinemia, glucagonoma, gastrinoma and Zollinger-Ellison's syndrome, GRFoma as well as acute bleeding of the esophageal varices, gastroesophageal reflux, gastroduodenal reflux, pancreatitis, enterocutaneous and pancreatic fistulae but also diarrhoeas, refractory diarrhoeas of acquired immunodeficiency syndrome, chronic secretary diarrhoea, diarrhoea associated with irritable bowel syndrome, disorders linked with gastrin releasing peptide, secondary pathologies with intestinal grafts, portal hypertension as well as haemorrhages of the varices in patients with cirrhosis, gastro-intestinal haemorrhage, haemorrhage of the gastroduodenal ulcer, Crohn's disease, systemic scleroses, dumping syndrome, small intestine syndrome, hypotension, scleroderma and medullar thyroid carcinoma, illnesses linked with cell hyperproliferation such as cancers and more particularly breast cancer, prostate cancer, thyroid cancer as well as pancreatic cancer and colorectal cancer, fibroses and more particularly fibrosis of the kidney, fibrosis of the liver, fibrosis of the lung, fibrosis of the skin, also fibrosis of the central nervous system as well as that of the nose and fibrosis induced by chemotherapy, and other therapeutic fields such as, for example, cephaleas including cephalea associated with hypophyseal tumours, pain, panic attacks, chemotherapy, cicatrization of wounds, renal insufficiency resulting from delayed development, obesity and delayed development linked with obesity, delayed uterine development, dysplasia of the skeleton, Noonan's syndrome, sleep apnea syndrome, Graves' disease, polycystic disease of the ovaries, pancreatic pseudocysts and ascites, leukaemia, meningioma, cancerous cachexia, inhibition of


H pylori


, psoriasis, as well as Alzheimer's disease. Osteoporosis can also be mentioned.




The Applicant found that the compounds of general formula (I) described hereafter have an affinity and a selectivity for the somatostatin receptors. As somatostatin and its peptide analogues often have a poor bioavailability by oral route and a low selectivity (Robinson, C.,


Drugs of the Future


, 1994, 19, 992; Reubi, J. C. et al.,


TIPS


, 1995, 16, 110), said compounds, non-peptide agonists or antagonists of somatostatin, can be advantageously used to treat pathological states or illnesses as presented above and in which one (or more) somatostatin receptors are involved. Preferably, said compounds can be used for the treatment of acromegalia, hypophyseal adenomas or endocrine gastroenteropancreatic tumours including carcinoid syndrome.




The compounds of the present invention correspond to general formula (I)











in racemic, enantiomeric form or all combinations of these forms, in which:




R1 represents a (C


1


-C


12


)alkyl, (C


0


-C


6


)alkyl-C(O)—O—Z1, (C


0


-C


6


)alkyl-C(O)—NH—(CH


2


)


p


—Z2 or aryl radical optionally substituted,




Z1 represents H, a (C


1


-C


6


)alkyl, —(CH


2


)


p


-aryl radical;




Z2 represents an amino, (C


1


-C


12


)alkylamino, (C


3


-C


8


)cycloalkylamino, N,N-di-(C


1


-C


12


)alkylamino, NH—C(O)—O—(CH


2


)


p


-phenyl, NH—C(O)—O—(CH


2


)


p


—(C


1


-C


6


)alkyl radical, an optionally substituted carbocyclic or heterocyclic aryl radical or an optionally substituted heterocyclic non aromatic radical;




R2 represents H, (C


1


-C


12


)alkyl or aryl optionally substituted;




R3 represents H or (CH


2


)


p


—Z3;




Z3 represents (C


1


-C


12


)alkyl, (C


1


-C


12


)alkenyl, (C


3


-C


8


)cycloalkyl, —Y1—(CH


2


)


p


-phenyl-(X1)


n


, —S—(C


1


-C


12


)alkyl, S—(C


1


-C


12


)alkyl-S—S—(C


1


-C


12


)alkyl, an optionally substituted carbocyclic or heterocyclic aryl radical, and in particular one of the radicals represented below











 an optionally substituted heterocyclic non aromatic radical, a bis-arylalkyl or di-arylalkyl radical or also the radical











Y1 represents O, S, NH or is absent;




R4 represents (CH


2


)


p


—Z4;




Z4 represents amino, (C


1


-C


12


)alkyl, (C


3


-C


8


)cycloalkyl, (C


1


-C


12


)alkylamino, N,N-di-(C


1


-C


12


)alkylamino, amino(C


3


-C


6


)cycloalkyl, amino(C


1


-C


6


)alkyl(C


3


-C


6


)cycloalkyl(C


1


-C


6


)alkyl, carboxylic or heterocyclic aminoaryl, (C


1


-C


12


)alkoxy, (C


1


-C


12


)alkenyl, N—C(O)O(C


1


-C


6


)alkyl, an optionally substituted carbocyclic or heterocyclic aryl radical, an optionally substituted heterocyclic non aromatic radical, bis-arylalkyl, di-arylalkyl or one of the radicals represented below











 or also Z4 represents an N(R6)(R7) radical in which R6 and R7 taken together with the nitrogen atom which they carry form together a heterocycle with 5 to 7 members;




R5 represents H, —(CH


2


)


p


—C(O)—(CH


2


)


p


—Z5, —(CH


2


)


p


—Z5, —(CH


2


)


p


—OZ5 or —(C


0


-C


6


)alkyl-C(O)—NH—(CH


2


)


p


—Z5,




Z5 representing an optionally substituted radical chosen from the group constituted by the —(C


1


-C


12


)alkyl, benzo[b]thiophene, phenyl, naphthyl, benzo[b]furannyl, thiophene, isoxazolyl, indolyl radicals, and











 it being understood that an optionally substituted radical or an optionally substituted phenyl is optionally substituted by one or more substituent, each preferably chosen independently from the group constituted by the Cl, F, Br, I, CF


3


, NO


2


, OH, NH


2


, CN, N


3


, —OCF


3


, (C


1


-C


12


)alkyl, (C


1


-C


12


)alkoxy, —(CH


2


)


p


-phenyl-(X1)


q


, —NH—CO—(C


1


-C


6


)alkyl, —NH—C(O)O—(C


1


-C


6


)alkyl, —S—(C


1


-C


6


)alkyl, —S-phenyl-(X1)


q


, —O—(CH


2


)


p


-phenyl-(X1)


q


, —(CH


2


)


p


—C(O)—O—(C


1


-C


6


)alkyl, —(CH


2


)


p


—C(O)—(C


1


-C


6


)alkyl, —O—(CH


2


)


p


—NH


2


, —O—(CH


2


)


p


—NH—(C


1


-C


6


)alkyl, —O—(CH


2


)


p


—N-di-((C


1


-C


6


)alkyl) and —((C


0


-C


12


))alkyl-(X1)


q


radicals;




X1, each time that it occurs, is independently chosen from the group constituted by the H, Cl, F, Br, I, CF


3


, NO


2


, OH, NH


2


, CN, N


3


, —OCF


3


, (C


1


-C


12


)alkyl, (C


1


-C


12


)alkoxy, —S—(C


1


-C


6


)alkyl, —(CH


2


)


p


-amino, —(CH


2


)


p


—NH—(C


1


-C


6


)alkyl, —(CH


2


)


p


—N-di-((C


1


-C


6


)alkyl), —(CH


2


)


p


—phenyl and —(CH


2


)


p


—NH—(C


3


-C


6


)cycloalkyl radicals;




p each time that it occurs is independently 0 or an integer from 1 to 6;




q each time that it occurs is independently an integer from 1 to 5.




X represents O or S;




n represents 0 or 1; and finally




when n represents 0, m represents 1, 2 or 3, and when n represents 1, m represents 0 or 1.




According to a preferred variant of the invention, the compounds of general formula (I) are such that R5 represents H.




The compounds of general formula (I) can, if appropriate, contain more than one asymmetrical centre. If this happens, the diastereomers or any mixture of diastereomers are also included in the invention. For example, when the compound of general formula (I) has two asymmetrical centres, the invention will include the compounds of general formula (I) of “R,S”, “S,R”, “R,R” and “S,S” configurations, as well as a mixture in whatever proportions of the latter.




In the present invention, the alkyl radicals can be linear or branched. By alkyl, unless specified otherwise, is meant a linear or branched alkyl radical containing 1 to 6 carbon atoms. By cycloalkyl, unless specified otherwise, is meant a monocyclic carbon system containing 3 to 7 carbon atoms. By alkenyl, unless specified otherwise, is meant a linear or branched alkyl radical containing 1 to 6 carbon atoms and having at least one unsaturation (double bond). By alkynyl, unless specified otherwise, is meant a linear or branched alkyl radical containing 1 to 6 carbon atoms and having at least one double unsaturation (triple bond). By carbocyclic or heterocyclic aryl, is meant a carbocyclic or heterocyclic system containing at least one aromatic ring, a system being called heterocyclic when at least one of the rings which comprise it contains a heteroatom (O, N or S). By aryl, unless specified otherwise, is meant a carbocyclic system comprising at least one aromatic ring. By haloalkyl, is meant an alkyl radical of which at least one of the hydrogen atoms (and optionally all) is replaced by a halogen atom. By heterocyclic non aromatic radical, is meant a heterocyclic system containing no aromatic ring, at least one of the rings comprising said system containing at least one heteroatom (O, N or S).




By alkylthio, alkoxy, haloalkyl, haloalkoxy, aminoalkyl, alkylamino, alkenyl, alkynyl and aralkyl radicals, is meant respectively the alkylthio, alkoxy, haloalkyl, haloalkoxy, aminoalkyl, alkylmino, alkenyl, alkynyl and aralkyl radicals the alkyl radical of which has the meaning indicated previously.




By N,N-di-(C


1


-C


12


)alkylamino radical, is meant a dialkylamino radical of which the two alkyl radicals substituting the nitrogen atom can have independently 1 to 12 carbon atoms.




By linear or branched alkyl having 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. By cycloalkyl, is meant in particular the cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexyl and cycloheptanyl radicals. By carbocyclic or heterocyclic aryl, is meant in particular the phenyl, naphthyl, pyridinyl, furannyl, pyrrolyl, thiophenyl, thiazolyl, indanyl, indolyl, imidazolyl, benzofurannyl, benzothiophenyl, phthalimidyl radicals. By carbocyclic or heterocyclic aralkyl, is meant in particular the benzyl, phenylethyl, phenylpropyl, phenylbutyl, indolylalkyl, phthalimidoalkyl radicals.




When an arrow emanates from a chemical structure, said arrow indicates the attachment point. For example:











represents the aminoethyl radical.




When an arrow is drawn through a bi- or tricyclic group, said arrow indicates that said bi- or tricyclic group can be attached by any of the available attachment points on any aromatic ring of said group. For example:











represents a radical which is attached at any position on the benzene ring.




In particular, the compounds of general formula (I) according to the invention can be chosen such that:




R1 represents an optionally substituted aryl radical;




R2 represents H or an alkyl radical;




R3 represents one of the following radicals:



























R1 represents one of the following radicals:



































R5 represents H or an alkyl radical.




Preferably, the compounds of general formula (I) are such that:




R1 represents the phenyl radical optionally substituted by a halogen atom or a (C


1


-C


12


)alkyl, (C


1


-C


12


)alkoxy or nitro radical;




R2 and R5 represent H or alkyl;




R3 represents H or (CH


2


)


p


—Z3;




Z3 represents (C


1


-C


12


)alkyl, (C


3


-C


8


)cycloalkyl, Y1—(CH


2


)


p


-phenyl-(X1)


n


, an optionally substituted carbocyclic or heterocyclic aryl radical, an optionally substituted heterocyclic non aromatic radical, bis-arylalkyl, di-arylalkyl or one of the radicals represented below











Y1 represents O, S, NH or is absent;




R4 represents (CH


2


)


p


—Z4;




Z4 represents amino, (C


3


-C


8


)cycloalkyl, (C


1


-C


12


)alkylamino, N,N-di-(C


1


-C


12


)alkylamino, amino(C


3


-C


6


)cycloalkyl, amino(C


1


-C


6


)alkyl(C


3


-C


6


)cycloalkyl(C


1


-C


6


)alkyl, carbocyclic or heterocyclic aminoaryl, an optionally substituted carbocyclic or heterocyclic aryl radical, an optionally substituted heterocyclic non aromatic radical, bis-arylalkyl, di-arylalkyl or one of the radicals represented below











 it being understood that an optionally substituted radical or an optionally substituted phenyl is optionally substituted by one or more substituent, each preferably chosen independently from the group constituted by the Cl, F, Br, I, CF


3


, NO


2


, OH, NH


2


, CN, N


3


, —OCF


3


, (C


1


-C


12


)alkyl, (C


1


-C


12


)alkoxy, —(CH


2


)


p


-phenyl-(X1)


q


, —NH—CO—(C


1


-C


6


)alkyl, —NH—C(O)O—(C


1


-C


6


)alkyl, —S—(C


1


-C


6


)alkyl, —S-phenyl-(X1)


q


, —O—(CH


2


)


p


-phenyl-(X1)


q


, —(CH


2


)


p


—C(O)—O—(C


1


-C


6


)alkyl, —(CH


2


)


p


—C(O)—(C


1


-C


6


)alkyl, —O—(CH


2


)


p


—NH


2


, —O—(CH


2


)


p


—NH—(C


1


-C


6


)alkyl, —O—(CH


2


)


p


—N-di-((C


1


-C


6


)alkyl) and —((C


0


-C


12


))alkyl-(X1)


q


radicals;




X1, each time that it occurs, is independently chosen from the group constituted by the H, Cl, F, Br, I, CF


3


, NO


2


, OH, NH


2


, CN, N


3


, —OCF


3


, (C


1


-C


12


)alkyl, (C


1


-C


12


)alkoxy, —S—(C


1


-C


6


)alkyl, —(CH


2


)


p


-amino, —(CH


2


)


p


—NH—(C


1


-C


6


)alkyl, —(CH


2


)


p


—N-di-((C


1


-C


6


)alkyl), —(CH


2


)


p


-phenyl and —(CH


2


)


p


—NH—(C


3


-C


6


)cycloalkyl radicals;




p each time that it occurs is independently 0 or an integer from 1 to 6;




q each time that it occurs is independently an integer from 1 to 5.




X represents O or S;




n represents 0 or 1; and finally




when n represents 0, m represents 1, 2 or 3, and when n represents 1, m represents 0 or 1.




More preferentially, the compounds of general formula (I) are such that:




R1 represents the phenyl radical optionally substituted by a halogen atom or a (C


1


-C


12


)alkyl, (C


1


-C


12


)alkoxy or nitro radical;




R2 and R5 represent H or alkyl;




R3 represents (CH


2


)


p


—Z3,




Z3 representing a (C


3


-C


8


)cycloalkyl radical or an optionally substituted radical chosen from the phenyl, naphthyl, furannyl, thiophene, indolyl, pyrrolyl and benzothiophene radicals;




R4 represents (CH


2


)


p


—Z4;




Z4 representing amino, (C


1


-C


2


)alkylamino, N,N-di-(C


1


-C


12


)alkylamino or amino(C


1


-C


6


)alkyl(C


3


-C


6


)cycloalkyl-(C


1


-C


6


)alkyl;




X represents S;




p each time that it occurs is independently 0 or an integer from 1 to 6;




m represents 0, 1 or 2; and finally




n represents 0 or 1.




Yet more preferentially, the compounds of the present invention are of the compounds:




of general sub-formula (I)a represented below:











in which:




R′3 represents one of the radicals represented below:











and R′4 represents one of the radicals represented below:











of general sub-formula (I)b represented below:











in which:




R′3 represents one of the radicals represented below:











and R′4 represents one of the radicals represented below:











of general sub-formula (I)c represented below:











in which:




R′3 represents one of the radicals represented below:











and R′4 represents one of the radicals represented below:











The invention relates moreover to the preparation processes for the compounds of general formula (I) described previously (also applicable to the corresponding compounds of general sub-formulae (I)a, (I)b and (I)c).




The compounds of general formula (I) described previously for which n represents 0 and X represents O or S can be prepared by the reaction in an aprotic solvent of the compound of general formula (II) represented below











in which m, R1, R2, R3 and R5 have the same meaning as in general formula (I), and the O—GP radical is a parting protective group derived from an alcohol and in particular benzyloxy, methoxy or tert-butoxy,




with an isocyanate or isothiocyanate of general formula (III)




 R4—N═C═X,  (III)




 in which R4 and X have the same meaning as in general formula (I),




preferably in the presence of a tertiary base for a duration of approximately 1 to 24 hours and at a temperature preferably comprised between 20 and 60° C.




The compounds of general formula (I) described previously for which n represents 1 and X represents O or S can be prepared by the reaction in an aprotic solvent of the compound of general formula (IV) represented below











in which m, R1, R2, R3 and R5 have the same meaning as in general formula (I), and the O—GP radical is a parting protective group derived from an alcohol and in particular benzyloxy, methoxy or tert-butoxy,




with an isocyanate or isothiocyanate of general formula (III)






R4—N═C═X  (III)






 in which R4 and X have the same meaning as in general formula (I),




preferably in the presence of a tertiary base for a duration of approximately 1 to 48 hours and at a temperature preferably comprised between 20 and 70° C.




For the above processes, the aprotic solvent is preferably polar and can in particular be THF or dichloromethane. The tertiary base will be for example triethylamine or N,N-diisopropylethylamine.




Moreover the invention offers new synthesis intermediates which are useful for the preparation of the compounds of general formula (I). These compounds, precursors of the compounds of general formula (II) and (IV), correspond to general formula (V):











in which




R1, R2, R5, m and n have the same meaning as in general formula (I);




and the O—GP radical is a parting protective group derived from an alcohol and in particular benzyloxy, methoxy or tert-butoxy.




The following compounds corresponding to general formula (V) are the preferred intermediates:




benzyl (2S)-2-amino-3-[(4-phenyl)-1H-imidazol-2-yl]propanoate;




benzyl (2R)-2-amino-3-[(4-phenyl)-1H-imidazol-2-yl]propanoate;




benzyl (2S)-2-amino-4-[(4-phenyl)-1H-imidazol-2-yl]butanoate;




benzyl (2R)-2-amino-4-[(4-phenyl)-1H-imidazol-2-yl]butanoate;




benzyl (3R)-3-amino-4-[(4-phenyl)-1H-imidazol-2-yl]propanoate;




benzyl (3S)-3-amino-4-[(4-phenyl)-1H-imidazol-2-yl]propanoate.




A subject of the invention is also, as medicaments, the compounds of general formulae (I), (I)a, (I)b and (I)c described previously or their pharmaceutically acceptable salts. It also relates to the pharmaceutical compositions containing said compounds or their pharmaceutically acceptable salts, and their use for the preparation of a medicament intended to treat the pathological states or diseases in which one (or more) of the somatostatin receptors are involved.




In particular, the compounds of general formulae (I), (I)a, (I)b and (I)c described previously or their pharmaceutically acceptable salts can be used for the preparation of a medicament intended to treat the pathological states or diseases chosen from the group comprising the following pathological states or diseases: acromegalia, hypophyseal adenomas, Cushing's disease, gonadotrophinomas and prolactinomas, catabolic side-effects of glucocorticoids, insulin dependent diabetes, diabetic retinopathy, diabetic nephropathy, syndrome X, dawn phenomena, angiopathy, angioplasty, hyperthyroidism, gigantism, endocrinic gastroenteropancreatic tumours including carcinoid syndrome, VIPoma, insulinoma, nesidioblastoma, hyperinsulinemia, glucagonoma, gastrinoma and Zollinger-Ellison's syndrome, GRFoma as well as acute bleeding of the esophageal varices, ulcers, gastroesophageal reflux, gastroduodenal reflux, pancreatitis, enterocutaneous and pancreatic fistulae but also diarrhoeas, refractory diarrhoeas of acquired immunodeficiency syndrome, chronic secretary diarrhoea, diarrhoea associated with irritable bowel syndrome, diarrhoeas induced by chemotherapy, disorders linked with gastrin releasing peptide, secondary pathologies with intestinal grafts, portal hypertension as well as haemorrhages of the varices in patients with cirrhosis, gastro-intestinal haemorrhage, haemorrhage of the gastroduodenal ulcer, bleeding of grafted vessels, Crohn's disease, systemic scleroses, dumping syndrome, small intestine syndrome, hypotension, scleroderma and medullar thyroid carcinoma, illnesses linked with cell hyperproliferation such as cancers and more particularly breast cancer, prostate cancer, thyroid cancer as well as pancreatic cancer and colorectal cancer, fibroses and more particularly fibrosis of the kidney, fibrosis of the liver, fibrosis of the lung, fibrosis of the skin, also fibrosis of the central nervous system as well as that of the nose and fibrosis induced by chemotherapy, and in other therapeutic fields, cephaleas including cephalea associated with hypophyseal tumours, pain, inflammatory disorders such as arthritis, panic attacks, chemotherapy, cicatrization of wounds, renal insufficiency resulting from delayed development, hyperlipidemia, obesity and delayed development linked with obesity, delayed uterine development, dysplasia of the skeleton, Noonan's syndrome, sleep apnea syndrome, Graves' disease, polycystic disease of the ovaries, pancreatic pseudocysts and ascites, leukaemia, meningioma, cancerous cachexia, inhibition of


H pylori


, psoriasis, chronic rejection of allografts as well as Alzheimer's disease and finally osteoporosis.




Preferably, the compounds of general formulae (I), (I)a, (I)b and (I)c described previously or their pharmaceutically acceptable salts can be used for the preparation of a medicament intended to treat the pathological states or diseases chosen from the group comprising the following pathological states or diseases: acromegalia, hypophyseal adenomas or endocrinic gastroenteropancreatic tumours including carcinoid syndrome, and gastrointestinal bleeding.




By pharmaceutically acceptable salt is meant in particular addition salts of inorganic acids such as hydrochloride, sulphate, phosphate, diphosphate, hydrobromide and nitrate, or of organic acids, such as acetate, maleate, fumarate, tartarate, succinate, citrate, lactate, methanesulphonate, p-toluenesulphonate, pamoate, oxalate and stearate.




The salts formed from bases such as sodium or potassium hydroxide also fall within the scope of the present invention, when they can be used. For other examples of pharmaceutically acceptable salts, reference can be made to “Pharmaceutical salts”,


J. Pharm. Sci


. 66:1 (1977).




The pharmaceutical composition can be in the form of a solid, for example powders, granules, tablets, capsules, liposomes or suppositories. Appropriate solid supports can be for example calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.




The pharmaceutical compositions containing a compound of the invention can also be presented in the form of a liquid, for example, solutions, emulsions, suspensions or syrups. Appropriate liquid supports can be, for example, water, organic solvents such as glycerol or the glycols, as well as their mixtures, in varying proportions, in water. The suspensions contain in particular suspensions of sustained release microparticles loaded with active ingredient (in particular microparticles of polylactide-co-glycolide or PLGA—cf. for example the Patents U.S. Pat. No. 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.




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 comprised between 0.1 mg to 10 g according to the type of active compound used.




These compounds are prepared according to the following procedures.




PREPARATION OF THE COMPOUNDS OF THE INVENTION




Preparation of Imidazolyl Derivatives




General Procedure:




i) Cyclization in Order to Obtain the Imidazole Group:




An amino acid is converted to its cesium salt using cesium carbonate in a polar solvent such as a DMF/H


2


O (1:1) or EtOH/H


2


O (1:1) mixture. An ester is then obtained using an appropriate bromoketone in an aprotic polar solvent such as anhydrous DMF. The cesium bromide formed is eliminated by filtration and ammonium acetate is added in an aprotic solvent having a high boiling temperature such as xylene or toluene or in an acidic aprotic solvent such as acetic acid. The mixture is maintained under reflux using a Dean-Stark trap for 30 minutes to one hour. In the diagram directly below, PG1 is a protective group, preferably a carbamate, such as t-Boc or benzylcarbamate, and PG2 is also a protective group, preferably a benzyl group.











ii) N-Substitution on the Imidazole Group:




If appropriate, the N-substitution on the imidazole group is carried out by the reaction described hereafter for the compounds of general formula (I) for which R5 does not represent H.




A solution of the intermediate obtained in the preceding stage, an alkylating agent such as an -bromoketone, an -bromoester, an alkyl or aryl bromide, is heated to a temperature of 20 to 80° C. for a duration of 2 to 48 hours in the presence of an organic or inorganic base (optionally supported on a resin such as polystyrene resin), in an aprotic solvent such as THF, acetonitrile or DMF.




Preparation of Benzyl (2S)-2-[(tert-Butoxycarbonyl)amino]-3-(4-phenyl-1H-imidazol-2-yl)propanoate











A solution of Boc-L-Asp-OBn (12 g; 37.1 mmol) and cesium carbonate (6.05 g; 0.5 eq.) is stirred for approximately 30 minutes at approximately 20° C. in EtOH/H


2


O (1:1, 7 ml), then concentrated under reduced pressure at approximately 40° C.




25 ml of a solution of 2-bromoacetophenone (7.38 g; 1 eq.) in dry DMF is added to the resulting salt dissolved in 130 ml of dry DMF. The mixture is stirred for approximately 1 hour at approximately 20° C. under an argon atmosphere then concentrated under reduced pressure. Ethyl acetate is added (100 ml) and the mixture filtered, CsBr being washed with ethyl acetate. The filtrate is then concentrated under reduced pressure.




A solution of the residue obtained and ammonium acetate (58 g; 20 eq.) in xylene (280 ml) is maintained under reflux for approximately 30 minutes at approximately 140° C. The excess NH


4


OAc and water are eliminated using a Dean-Stark trap. The progress of the reaction is monitored by thin layer chromatography (TLC; eluent:ethyl acetate/heptane 1:1). The mixture is then taken to approximately 20° C. then washed successively with water, a saturated solution of NAHCO


3


solution until a basic pH is obtained then with salt water until a neutral pH is obtained. The organic phase is then dried over Na


2


SO


4


and concentrated under reduced pressure.




Purification of the resulting residue by flash chromatography on silica gel (eluent:ethyl acetate/heptane 1:1) yields the expected compound (8.2 g; 52%).




NMR (


1


H, 400 MHz, CDCl


3


): 7.64-7.14 (m, 11H, arom H); 5.95 (d, 1H, NHBoc); 5.21-5.13 (AB, 2H, OCH


2


Ph, J


AB


=12Hz); 4.73 (m, 1H, CH); 3.30 (m, 2H, CH


2


); 1.42 (s, 9H, (CH


3


)


3


C). MS/LC: calculated MM=421.2; m/z=422.2 (M+H).




The following compounds are prepared in an analogous fashion to the procedure described for benzyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-phenyl-1H-imidazol-2-yl)propanoate:











Deprotection Stage
















General procedure: the imidazolyl derivatives protected by N-Boc are treated with a organic or inorganic acid such as trifluoroacetic acid or hydrogen chloride (aqueous or in gaseous form) in an aprotic solvent such as dichloromethane or ethyl acetate at a temperature comprised between 0° C. and 25° C. for 0.5 to 5 hours.




Preparation of the Dihydrochloride of Benzyl (3S)-3-(4-Phenyl-1H-imidazol-2-yl)-3-amino-propanoate











A flow of dry HCl is passed through a solution of benzyl (3S)-3-(4-phenyl-1H-imidazol-2-yl)-3-[(tert-butoxycarbonyl)amino propanoate (5 g) in ethyl acetate (120 ml) at 0° C. until the TLC (eluent: 100% ethyl acetate) shows that the starting compound has completely disappeared. The resulting mixture is then evaporated under reduced pressure. Diethylether is added to the solid obtained and the mixture is filtered. The hydrochloride is washed several times with dichloromethane then diethylether and dried under reduced pressure to produce 4.6 g of expected compound (98% yield).




NMR (


1


H, 400 MHz, DMSOd6): 9.21 (broad s, 2H, NH); 8.03-7.28 (m, arom. H, 11H); 5.10 (s, 1H, OCH


2


Ph); 5.04 (m, 1H, CH); 3.61 (dd, 1H, CH


2


, 3J=9 Hz, 2J=17.0 Hz); 3.39 (dd, 1H, CH


2


′, 3J=5.5 Hz, 2J=17.0 Hz). MS/LC: Calculated MM=321.2; m/z=322.1 (M+H).




The following compounds are prepared in an analogous fashion to the procedure described for the dihydrochloride of benzyl (3S)-3-(4-phenyl-1H-imidazol-2-yl)-3-amino-propanoate.











N-Alkylation Reaction
















General procedure: A free amine of formula (a) or (b) is treated with an aldehyde in a protic or aprotic solvent, preferably dichloromethane or tetrahydrofuran, for a duration of 1 to 15 hours at 20-50° C. The resulting imine is then reduced using a reducing agent, preferably sodium triacetoxyborohydride or sodium cyanoborohydride with or without the presence of an acid such as acetic acid, at a temperature comprised between 20 and 50° C. for a duration of 0.2 to 5 hours. The N-alkylated compound is isolated by adding water and extraction followed by flash chromatography on silica gel or by crystallization.




Preparation of Benzyl (2S)-4-(4-Phenyl-1H-imidazol-2-yl)-2-[(3-thienylmethyl)amino]butanoate











Thiophene-3-carboxaldehyde (1 ml; 1 eq.) is added to a solution of benzyl (2S)-2-amino-4-(4-phenyl-1H-imidazol-2-yl)butanoate in the form of a free base (3.6 g; 1 eq.) in tetrahydrofuran (hereafter THF, 40 ml). The mixture is stirred for 15 hours at approximately 20° C. and diluted by adding 50 ml of tetrahydrofuran. NaBH(OAc)


3


(4.73 g; 2 eq.) is then added. After 1 hour of stirring at approximately 20° C., the reaction is stopped by adding water (40 ml) and ethyl acetate is then added (100 ml). After decantation and extraction, the combined organic phases are washed with salt water, dried over Na


2


SO


4


then evaporated under reduced pressure at 40° C. Flash chromatography purification on silica gel (eluent: ethyl acetate/heptane 9:1) yields the expected compound in the form of a yellow oil (3.08 g; 66% yield).




NMR (


1


H, 400 MHz, CDCl


3


): 7.62-7.04 (m, 15H, arom. H, NH); 5.18 (s, 2H, OCH


2


); 3.87-3.69 (AB, 2H, CH


2


NH, 2J


AB


=13 Hz); 3.38 (dd, 1H, CHNH, 3J=4.5 Hz, 2J=8.5 Hz); 2.98 (m, 1H, CH


2


CH); 2.88 (m, 1H, CH


2


CH); 2.17 (m, 1H, CH


2


); 1.97 (m, 1H, CH


2


). MS/LC: Calculated MM=431.2; m/z=432.2 (M+H); m/z=430.8 (M−H).




The following compounds (in their two enantiomer forms) are prepared in an analogous fashion to the procedure described for benzyl (2S)-4-(4-phenyl-1H-imidazol-2-yl)-2-[(3-thienylmethyl)amino]butanoate:











In the above formulae, R3 represents one of the following radicals:



























Preparation of Hydantoins and Thiohydantoins
















General Procedure:




An amine of formula (II), in which m, R1, R2, R3 and R5 have the same meanings as in general formula (I) and the O—GP radical is a parting protective group derived from an alcohol and in particular benzyloxy, methoxy or tert-butoxy, is treated with an isocyanate or a isothiocyanate of general formula R4—NCX in which R4 has the same meaning as in general formula (I), in the presence or in the absence of a tertiary base such as triethylamine or N,N-diisopropylethylamine, in an aprotic solvent, preferably tetrahydrofuran or dichloromethane, at a temperature comprised between approximately 20 and 60° C. and for 1 to 24 hours. The resulting hydantoin or thiohydandoin can be isolated with a yield of 60 to 95%, either by flash chromatography on silica gel or by addition to the reaction mixture of a nucleophilic reagent carried by a polymer such as for example an aminomethylpolystyrene resin (acquired from Novabiochem) followed by filtration and evaporation of the filtrate.




When R4 represents a radical comprising a primary amino termination (for example R4 represents aminoethyl, aminopropyl, etc.), the reagent is not R4—NCX but the corresponding compound the amino group of which is protected by a suitable protective group, for example a tert-butoxycarbonyl group. A subsequent deprotection stage (carried out under standard conditions, namely an acid treatment) must therefore be carried out in order to obtain the compound of general formula (I).




Preparation of Certain Non-commercial Isothiocyanates of General Formula (III):











These compounds are prepared as follows: a primary amine of general formula R4—NH


2


is treated with a mixture of carbon disulphide and N-cyclohexylcarbodiimide N-methyl polystyrene resin, in an aprotic solvent, preferably tetrahydrofuran or dichloromethane, for a duration of 1 hour to 18 hours at 20-50° C. The resulting isothiocyanate is isolated after filtration on frit and evaporation of the filtrate.




Preparation of 6-Isothiocyanato-N,N-dimethyl-1-hexanamine











Carbon disulphide (8.3 mL, 10 eq) and a solution of N,N-dimethyl-1,6-hexanediamine (2g, 1 eq) in THF (10 mL) are added successively dropwise to a suspension of N-cyclohexylcarbodiimide N-methyl polystyrene resin (7.8 g, 1.1 eq; acquired from Novabiochem, load 1.95 mmol/g) in anhydrous THF (120 mL). The suspension is stirred for 2 hours at approximately 20° C. then filtered on frit. The filtrate is then concentrated to dryness under reduced pressure at 40° C. in order to produce the expected isothiocyanate derivative (2.6 g, 93% yield).




NMR


1


H, 400 MHz, CDCl


3


,): 3.50 (t, 2H); 2.24 (t, 2H), 2.20 (s, 6H), 1.68 (q, 2H), 1.50-1.31 (m, 6H).




The following compounds are prepared in an analogous fashion to the procedure described for 6-isothiocyanato-N,N-dimethyl-1-hexanamine:











Preparation of (5S)-1-(1H-Indol-3-ylmethyl)-3-(4-nitrophenyl)-5-[2-(4-phenyl-1H-imidazol-2-yl)ethyl]-2-thioxo-4-imidazolidinone











4-nitro-phenylisothiocyanate (43 mg; 1.2 eq.) is added to a solution of benzyl (2S)-2-[(1H-indol-3-ylmethyl)amino]-4-(4-phenyl-1H-imidazol-2-yl)butanoate (93 mg; 1 eq.) in THF (2 ml). The mixture is stirred for 2 hours at approximately 20° C. then diluted with 4 ml of THF. Aminomethylpolystyrene resin (acquired from Novabiochem, load 3.2 mmol/g, 125 mg, 2 eq.) is added, then triethylamine (200 μl). The mixture is stirred for 15 hours at approximately 20° C. then filtered on frit. The filtrate is concentrated to dryness under reduced pressure at 40° C. (a co-evaporation with dichloromethane is necessary to eliminate the excess triethylamine). Purification of the residue by flash chromatography on silica gel (eluent: ethyl acetate/heptane 9:1) yields the expected compound (90 mg; 84% yield).




NMR (


1


H, 400 MHz, CDCl


3


): 8.24-7.09 (m, 17H, arom H, NH); 5.88, 4.64 (AB, 2H, CH


2


N, 2J


AB


=15 Hz); 3.38 (dd, 1H, CH, 3J=3.0 Hz, 2J=8.5 Hz); 2.92 (m, 2H, CH


2


CH); 2.74 (m, 1H, CH


2


); 2.24 (m, 1H, CH


2


). MS/LC: Calculated MM=536.2; m/z=537.1 (M+H).




The following compounds (in their two enantiomer forms) are prepared in an analogous fashion to the procedure described for (5S)-1-(1H-indol-3-ylmethyl)-3-(4-nitrophenyl)-5-[2-(4-phenyl-1H-imidazol-2-yl)ethyl]-2-thioxo-4-imidazolidinone (apart from the final purification by flash chromatography on silica gel which is optional):











In the above formulae, R3 represents one of the following radicals:











and R4 represents one of the following radicals:



































Preparation of (5S)-1-(1H-Indol-3-ylmethyl)-5-[2-(4-phenyl-1H-imidazol-2-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]-2,4-imidazolidinedione











3-trifluoromethyl-phenylisocyanate (11 mg, 1.2 eq.) is added to a solution of benzyl (2S)-2-[(1H-indol-3-ylmethyl)amino]-4-(4-phenyl-1H-imidazol-2-yl)butanoate (23 mg, 1 eq.) in 2 ml of THF. The mixture is stirred for 2 hours at approximately 20° C. then diluted with 2 ml of THF. Aminomethylpolystyrene resin (acquired from Novabiochem, load 3.2 mmol/g, 125 mg, 2 eq.) is added, then triethylamine (200 μl). The mixture is stirred for 15 hours at approximately 20° C. then filtered on frit. The filtrate is then concentrated to dryness under reduced pressure at 40° C. (a co-evaporation with dichloromethane is necessary to eliminate the excess triethylamine) in order to produce the expected compound (25 mg, 92% yield).




NMR (


1


H, 400 MHz, CDCl


3


): 7.75-6.99 (m, 17H, arom H, NH); 5.25, 4.44 (AB, 2H, CH


2


N, J


AB


=15 Hz); 3.77 (m, 1H, CH); 2.92 (m, 1H, CH


2


CH); 2.88 (m, 1H, CH


2


CH); 2.72 (m, 1H, CH


2


); 2.17 (m, 1H, CH


2


). MS/LC: Calculated MM=543.2; m/z=544.2 (M+H).




The following compounds (in their two enantiomer forms) are prepared in an analogous fashion to the procedure described for (5S)-1-(1H-indol-3-ylmethyl)-5-[2-(4-phenyl-1H-imidazol-2-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]-2,4-imidazolidinedione:











In the above formulae, R3 represents one of the following radicals:











and R4 represents one of the following radicals:



















Preparation of Dihydropyrimidine-2,4-diones and 2-Thioxotetrahydro-4-pyrimidinones
















General Procedure:




An amine of general formula (IV), in which m, R1, R2, R3 and R5 have the same meanings as in general formula (I) and the O—GP radical is a parting protective group derived from alcohol and in particular benzyloxy, methoxy or tert-butoxy, is treated with an isocyanate or isothiocyanate R4—NCX in the presence of a tertiary base such as triethylamine or N,N-diisopropylethylamine in an aprotic solvent, preferably THF or dichloromethane, at a temperature comprised between 20 and 70° C. for 1 to 48 hours. The compound obtained can be isolated with a yield of 40 to 90%, either by flash chromatography on silica gel or by addition to the reaction mixture of a nucleophilic reagent carried by a polymer such as for example an aminomethylpolystyrene resin (acquired from Novabiochem) followed by filtration and evaporation of the filtrate.




When R4 represents a radical comprising a primary amino termination (for example: R4 represents aminoethyl, aminopropyl, etc.), the reagent is not R4—NCX but the corresponding compound the amino group of which is protected by a suitable protective group, for example a tert-butoxycarbonyl group. A subsequent deprotection stage (carried out under standard conditions, namely an acid treatment) must therefore be carried out in order to obtain the compound of general formula (I).




Preparation of (6S)-1-(1H-Indol-3-ylmethyl)-3-propyl-6-(4-phenyl-1H-imidazol-2-yl)-2-thioxotetrahydro-4(1H)-pyrimidinone











Propylisothiocyanate (25 μl, 1.2 eq.) is added to a solution of benzyl (3S)-3-[(1H-indol-3-ylmethyl)amino]-3-(4-phenyl-1H-imidazol-2-yl)propanoate (90 mg, 1 eq.) in 2 ml of THF. The mixture is stirred for 15 hours at a temperature of approximately 40° C. then diluted with 2 ml of THF. An aminomethylpolystyrene resin (acquired from Novabiochem, load 3.2 mmol/g, 125 mg, 2 eq.) is added. The mixture is stirred for 5 hours at a temperature of approximately 20° C. then filtered on frit. The filtrate is concentrated under reduced pressure at 40° C. 1 ml of THF and 1 ml of triethylamine are added to the residue. The mixture is stirred for 15 hours at a temperature of approximately 40° C. then concentrated under reduced pressure. Purification by flash chromatography on silica gel (eluent: ethyl acetate/heptane 8:2) yields the expected compound (72 mg, yield 82%).




NMR (


1


H, 400 MHz, CDCl


3


): mixture of 2 atropisomers: 8.69-6.45 (m, 12H, H arom, NH); 6.42, 4.89 (AB, 1H, CH


2


, J


AB


=14.5 Hz); 5.78, 5.42 (AB, 1H, CH


2


, J


AB


=14.5 Hz); 4.99 (m, 1H, CH); 4.41-4.36 (m, 1H, CH


2


); 4.20-4.11 (m, 1H, CH


2


); 3.49, 2.94 (AB, 1H, CH


2


CO, J


AB


=16 Hz); 3.28, 2.80 (AB, 1H, CH


2


CO, JAB=16 Hz); 1.52 (m, 1H, CH


2


); 1.40 (m, 1H, CH


2


); 0.76, 0.62 (2m, 3H, CH


3


). MS/LC: Calculated MM=443.2; m/z=444.2 (M+H).




The following compounds (in their two enantiomer forms) are prepared in an analogous fashion to the procedure described for (6S)-1-(1H-indol-3-ylmethyl)-3-propyl-6-(4-phenyl-1H-imidazol-2-yl)-2-thioxotetrahydro-4(1H)-pyrimidinone (except for the final purification by flash chromatography on silica gel which is optional):











In the above formula, R3 represents one of the following radicals:



























and R4 represents one of the following radicals:



























Preparation of (6S)-1-(1H-Indol-3-ylmethyl)-3-(4-methoxyphenyl)-6-(4-phenyl-1H-imidazol-2-yl)dihydro-2.4(1H,3H)-pyrimidinedione











4-methoxyphenylisocyanate (40 μl, 1.2 eq.) is added to a solution of benzyl (3S-3-[(1H-indol-3-ylmethyl)amino]-3-(4-phenyl-1H-imidazol-2-yl)propanoate (100 mg, 1 eq.) in THF (2 ml). The mixture is stirred for 5 hours at a temperature of approximately 20° C. then diluted with 2 ml of THF. An aminomethylpolystyrene resin (acquired from Novabiochem, load 3.2 mmol/g, 138 mg, 2 eq.) is added. The mixture is stirred for 3 hours at a temperature of approximately 20° C. then filtered on frit. The filtrate is concentrated under reduced pressure at 40° C. 2 ml of THF and 2 ml of triethylamine are added to the residue. The mixture is taken to reflux for 24 hours then concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: ethyl acetate/heptane 8:2) yields the expected compound (80 mg, yield 74%.




NMR (


1


H, 400 MHz, CDCl


3


): mixture of 2 atropisomers: 9.67-8.96 (2s, 1H, NH); 8.49 (s, 1H, NH); 5.15, 4.36 (AB, 1H, CH


2


, J


AB


=15 Hz); 5.08, 4.69 (AB, 1H, CH


2


, J


AB


=15 Hz); 4.67, 4.57 (2m, 1H, CH); 3.72 (s, 3H, OCH


3


); 3.29-2.79 (m, 2H, CH


2


CO). MS/LC: Calculated MM=491.2; m/z=492.3 (M+H).




The following compounds (in their two enantiomer forms) are prepared in an analogous fashion to the procedure described for (6S)-1-(1H-indol-3-ylmethyl)-3-(4-methoxyphenyl)-6-(4-phenyl-1H-imidazol-2-yl)dihydro-2.4(1H,3H)-pyrimidinedione (except for the final purification by flash chromatography on silica gel which is optional):











In the above formula, R3 represents one of the following radicals:











and R4 represents one of the following radicals:


























EXAMPLES




The examples prepared according to the synthesis methods described above are shown in tables below. These examples are presented to illustrate the above procedures and should in no case be considered as limiting the scope of the invention.




Analytical Methods Used for the Characterization of the Compounds




The compounds obtained have been characterized according to their retention time (rt) and to their mass spectrometry (MH+).




Mass Spectrometry




For the mass spectrometry, a single quadrupole mass spectrometer (Micromass, platform model) equipped with an electrospray source is used with a resolution of 0.8 Da at 50% valley.




Calibration is carried out monthly between the masses 80 and 1000 Da using a calibration mixture of sodium and rubidium iodide in solution in an isopropanol/water mixture (1/1 Vol.).




High Performance Liquid Chromatography (HPLC)




For the liquid chromatography, an HPLC HP1100 system (Hewlett-Packard) including an in-line degasser, a quaternary pump, a column oven and a diode array UV detector is used.




Different elution conditions are used according to the examples:















Conditions (i):



























Eluants:




A




water + 0.04% trifluoroacetic acid








B




acetonitrile

















T(min)




A %




B %









 0




100




 0






 1




100




 0






 8




 30




70






10




 30




70

















Flow rate:




1.1 ml/min







Injection:




5 μl







Column:




Uptisphere ODS 3 μm 33*4.6 mm i.d.







Temperature:




40° C.


























Conditions (ii):



























Eluants:




A




water + 0.04% trifluoroacetic acid








B




acetonitrile

















T(min)




A %




B %









 0




90




10






 6




15




85






10




15




85

















Flow rate:




1 ml/min







Injection:




5 μl







Column:




Uptisphere ODS 3 μm 50*4.6 mm i.d.







Temperature:




40° C.















Elution conditions (i) are used for the characterization of Examples 1 to 479, 560 to 572 and 733 to 1040. As regards conditions (ii) they are used for Examples 480 to 559, 573 to 732 and 1041 to 1234. The UV detection is carried out at a wavelength of 220 nm for all the examples.




















Analyses

















Ex. No.




Formula




R1




R2




Purity




rt (min)




[M + H]+














































1




C29H25N5O2




























89.6%




6.2




476.2













2




C30H27N5O2




























91.0%




6.4




490.3













3




C30H27N5O3




























90.1%




6.2




506.3













4




C30H27N5O2S




























91.0%




6.6




522.2













5




C30H24F3N5O3




























83.1%




7.0




560.2













6




C32H31N5O2




























84.9%




7.0




518.3













7




C29H24BrN5O2




























81.9%




6.7




556.1













8




C29H24ClN5O2




























79.1%




6.6




510.2













9




C29H24N6O4




























87.3%




6.4




521.2













10




C35H37N5O2




























94.1%




7.3




560.3













11




C29H23F2N5O2




























96.9%




6.3




512.2













12




C30H27N5O2




























96.3%




6.4




490.2













13




C31H29N5O2




























92.0%




6.5




504.2













14




C29H31N5O2




























85.7%




6.6




482.3













15




C26H27N5O2




























94.2%




5.9




442.3













16




C27H29N5O2




























91.7%




6.3




456.3













17




C26H25N5O2




























96.6%




5.8




440.2













18




C28H31N5O2




























87.2%




6.6




470.3













19




C26H27N5O2




























89.1%




6.0




442.2













20




C32H31N5O5




























80.5%




6.1




566.2













21




C25H22N4O2S




























92.3%




5.9




443.2













22




C26H24N4O2S




























90.2%




6.2




457.2













23




C26H24N4O3S




























92.1%




6.0




473.2













24




C26H24N4O2S2




























92.8%




6.4




489.2













25




C26H21F3N4O3S




























87.7%




6.8




527.2













26




C28H28N4O2S




























87.8%




6.8




485.3













27




C25H21BrN4O2S




























84.3%




6.5




523.1













28




C25H21ClN4O2S




























84.9%




6.4




477.2













29




C25H21N5O4S




























94.0%




6.2




488.2













30




C31H34N4O2S




























97.2%




7.2




527.3













31




C25H20F2N4O2S




























96.7%




6.1




479.2













32




C26H24N4O2S




























95.3%




6.2




457.2













33




C27H26N4O2S




























93.0%




6.4




471.2













34




C25H28N4O2S




























88.3%




6.4




449.2













35




C22H24N4O2S




























90.8%




5.7




409.2













36




C23H26N4O2S




























91.8%




6.1




423.2













37




C22H22N4O2S




























97.9%




5.6




407.2













38




C24H28N4O2S




























84.3%




6.4




437.2













39




C22H24N4O2S




























87.2%




5.7




409.2













40




C28H28N4O5S




























92.2%




5.9




533.2













41




C28H26N4O3




























93.9%




6.1




467.2













42




C29H28N4O3




























95.8%




6.3




481.3













43




C29H28N4O4




























93.0%




6.1




497.3













44




C29H28N4O3S




























94.5%




6.5




513.2













45




C29H25F3N4O4




























90.4%




6.9




551.2













46




C31H32N4O3




























87.7%




6.9




509.3













47




C28H25BrN4O3




























84.2%




6.6




547.1













48




C28H25ClN4O3




























86.6%




6.5




501.2













49




C28H25N5O5




























93.9%




6.3




512.2













50




C34H38N4O3




























98.3%




7.2




551.3













51




C28H24F2N4O3




























98.0%




6.2




503.2













52




C29H28N4O3




























94.6%




6.4




481.2













53




C30H30N4O3




























91.5%




6.4




495.3













54




C28H32N4O3




























85.8%




6.5




473.3













55




C25H28N4O3




























89.7%




5.8




433.3













56




C26H30N4O3




























90.6%




6.2




447.3













57




C25H26N4O3




























97.1%




5.7




431.2













58




C27H32N4O3




























75.3%




6.5




461.3













59




C25H28N4O3




























86.1%




5.9




433.3













60




C31H32N4O6




























83.5%




6.0




557.2













61




C29H29N5O2




























92.62%*




5.3




480.3













62




C30H31N5O2




























93.25%*




5.6




494.3













63




C30H31N5O3




























94.39%*




5.4




510.3













64




C30H31N5O2S




























95.36%*




5.8




526.3













65




C30H28F3N5O3




























89.2%




6.3




564.2













66




C32H35N5O2




























86.35%*




6.3




522.3













67




C29H28BrN5O2




























84.14%*




5.9




560.1













68




C29H28ClN5O2




























85.8%




5.8




514.2













69




C29H28N6O4




























94.4%




5.6




525.3













70




C35H41N5O2




























95.76%*




6.8




564.3













71




C29H27F2N5O2




























96.29%*




5.5




516.3













72




C30H31N5O2




























97.59%*




5.6




494.3













73




C31H33N5O2




























94.87%*




5.7




508.3













74




C29H35N5O2




























87.63%*




5.8




486.3













75




C26H31N5O2




























87.69%*




5.0




446.3













76




C27H33N5O2




























86.66%*




5.4




460.3













77




C26H29N5O2




























93.78%*




4.9




444.3













78




C28H35N5O2




























85%*




5.8




474.3













79




C26H31N5O2




























87.49%*




5.0




446.3













80




C32H35N5O5




























87.6%




5.3




570.3


















































81




C28H23N5O2




























92%




6.2




462.2













82




C29H25N5O2




























93%




6.5




476.2













83




C29H25N5O3




























94%




6.2




492.2













84




C29H25N5O2S




























92%




6.6




508.2













85




C29H22F3N5O3




























92%




7.0




546.2













86




C31H29N5O2




























92%




7.1




504.3













87




C28H22BrN5O2




























92%




6.8




542.1













88




C28H22ClN5O2




























92%




6.7




496.2













89




C28H22N6O4




























82%




6.5




507.2













90




C34H35N5O2




























92%




7.3




546.3













91




C28H21F2N5O2




























90%




6.2




498.2













92




C31H29N5O5




























82%




6.2




552.2













93




C29H22F3N5O2




























92%




6.9




530.2













94




C30H25N5O3




























89%




6.1




504.2













95




C29H25N5O2




























92%




6.4




476.2













96




C30H27N5O2




























93%




6.6




490.3













97




C25H25N5O2




























95%




5.9




428.2













98




C26H27N5O2




























95%




6.3




442.3













99




C25H23N5O2




























95%




5.8




426.2













100




C27H29N5O2




























94%




6.6




456.3













101




C24H20N4O2S




























92%




5.9




429.2













102




C25H22N4O2S




























91%




6.2




443.2













103




C25H22N4O3S




























90%




6.0




459.2













104




C25H22N4O2S2




























87%




6.4




475.2













105




C25H19F3N4O3S




























89%




6.8




513.2













106




C27H26N4O2S




























89%




6.9




471.2













107




C24H19BrN4O2S




























91%




6.5




509.1













108




C24H19ClN4O2S




























90%




6.4




463.1













109




C24H19N5O4S




























76%




6.3




474.2













110




C30H32N4O2S




























90%




7.1




513.3













111




C24H18F2N4O2S




























82%




6.0




465.2













112




C27H26N4O5S




























77%




5.8




519.2













113




C25H19F3N4O2S




























89%




6.7




497.2













114




C26H22N4O3S




























86%




5.8




471.2













115




C25H22N4O2S




























85%




6.1




443.2













116




C26H24N4O2S




























82%




6.3




457.2













117




C21H22N4O2S




























84%




5.6




395.2













118




C22H24N4O2S




























93%




5.9




409.2













119




C21H20N4O2S




























89%




5.4




393.2













120




C23H26N4O2S




























81%




6.3




423.2













121




C27H24N4O3




























91%




6.0




453.2













122




C28H26N4O3




























92%




6.3




467.2













123




C28H26N4O4




























91%




6.0




483.3













124




C28H26N4O3S




























88%




6.4




499.2













125




C28H23F3N4O4




























91%




6.9




537.2













126




C30H30N4O3




























90%




6.9




495.2













127




C27H23BrN4O3




























89%




6.6




533.1













128




C27H23ClN4O3




























91%




6.5




487.2













129




C27H23N5O5




























75%




6.4




498.2













130




C33H36N4O3




























90%




7.2




537.3













131




C27H22F2N4O3




























82%




6.1




489.2













132




C30H30N4O6




























79%




6.0




543.2













133




C28H23F3N4O3




























90%




6.8




521.2













134




C29H26N4O4




























85%




5.9




495.2













135




C28H26N4O3




























89%




6.2




467.2













136




C29H28N4O3




























89%




6.4




481.2













137




C24H26N4O3




























88%




5.7




419.3













138




C25H28N4O3




























90%




6.1




433.3













139




C24H24N4O3




























92%




5.6




417.3













140




C26H30N4O3




























87%




6.4




447.3













141




C28H27N5O2




























89%




5.1




466.2













142




C29H29N5O2




























89%




5.5




480.3













143




C29H29N5O3




























90%




5.2




496.3













144




C29H29N5O2S




























86%




5.7




512.2













145




C29H26F3N5O3




























87%




6.2




550.2













146




C31H33N5O2




























87%




6.2




508.3













147




C28H26BrN5O2




























88%




5.8




546.1













148




C28H26ClN5O2




























88%




5.7




500.2













149




C28H26N6O4




























74.76%*




5.6




511.2













150




C34H39N5O2




























85%




6.7




550.3













151




C28H25F2N5O2




























81%




5.3




502.2













152




C31H33N5O5




























79%




5.2




556.3













153




C29H26F3N5O2




























88%




6.1




534.2













154




C30H29N5O3




























85%




5.1




508.3













155




C29H29N5O2




























86%




5.4




480.3













156




C30H31N5O2




























86%




5.6




494.3













157




C25H29N5O2




























85%




4.8




432.3













158




C26H31N5O2




























84%




5.2




446.3













159




C25H27N5O2




























86%




4.7




430.3













160




C27H33N5O2




























88%




5.6




460.3


















































161




C30H27N5OS




























80%




7.1




506.2













162




C30H26ClN5OS




























83%




7.3




540.2













163




C30H25Cl2N5OS




























81%




7.7




574.1













164




C31H27N5O3S




























81%




7.0




550.2













165




C30H26FN5OS




























82%




7.1




524.3













166




C31H29N5OS




























81%




7.3




520.3













167




C31H28ClN5OS




























83%




7.6




554.2













168




C33H33N5O3S




























80%




7.0




580.3













169




C32H31N5OS




























78%




7.4




534.3













170




C28H25N5O2S




























85%




6.7




496.3













171




C28H29N5O2S




























81%




6.6




500.3













172




C28H29N5OS




























71%




7.1




484.3













173




C29H31N5OS




























61%




7.3




498.3













174




C30H33N5OS




























64%




7.6




512.3













175




C29H32N6O2S




























84%




5.0




529.3













176




C30H34N6O2S




























86%




5.0




543.3













177




C30H36N6OS




























83%




5.2




529.3













178




C26H27N5O2S




























82%




6.3




474.3













179




C27H29N5O2S




























80%




6.4




488.3













180




C27H29N5OS




























74%




7.0




472.3













181




C26H24N4OS2




























77%




6.9




473.2













182




C26H23ClN4OS2




























78%




7.1




507.2













183




C26H22Cl2N4OS2




























84%




7.6




541.1













184




C27H24N4O3S2




























80%




6.9




517.2













185




C26H23FN4OS2




























75%




7.0




491.2













186




C27H26N4OS2




























80%




7.1




487.2













187




C27H25ClN4OS2




























85%




7.4




521.2













188




C29H30N4O3S2




























87%




6.8




547.2













189




C28H28N4OS2




























77%




7.3




501.2













190




C24H22N4O2S2




























86%




6.5




463.2













191




C24H26N4O2S2




























58.9% + 19.6%




6.4




467.2













192




C24H26N4OS2




























75%




6.9




451.2













193




C25H28N4OS2




























77%




7.2




465.2













194




C26H30N4OS2




























76%




7.5




479.3













195




C25H29N5O2S2




























81%




4.8




496.3













196




C26H31N5O2S2




























82%




4.9




510.3













197




C26H33N5OS2




























71%




5.0




496.3













198




C22H24N4O2S2




























81%




6.1




441.2













199




C23H26N4O2S2




























78%




6.2




455.2













200




C23H26N4OS2




























79%




6.8




551.2













201




C29H28N4O2S




























80%




7.0




497.3













202




C29H27ClN4O2S




























81%




7.2




643.2













203




C29H26Cl2N4O2S




























86%




7.6




677.2













204




C30H28N4O4S




























82%




7.0




653.2













205




C29H27FN4O2S




























72%




7.1




627.2













206




C30H30N4O2S




























83%




7.2




511.3













207




C30H29ClN4O2S




























87%




7.5




657.2













208




C32H34N4O4S




























87%




6.9




571.3













209




C31H32N4O2S




























83%




7.4




637.3













210




C27H26N4O3S




























87%




6.6




599.2













211




C27H30N4O3S




























59% + 20%




6.5 + 6.6




491.2













212




C27H30N4O2S




























81%




7.0




475.5













213




C28H32N4O2S




























82%




7.2




601.2













214




C29H34N4O2S




























83%




7.5




615.3













215




C28H33N5O3S




























86%




5.0




520.3













216




C29H35N5O3S




























86%




5.0




646.3













217




C29H37N5O2S




























78%




5.1




632.3













218




C25H28N4O3S




























87%




6.2




577.2













219




C26H30N4O3S




























80%




6.4




591.3













220




C26H30N4O2S




























85%




6.9




575.2













221




C30H31N5OS




























77%




6.5




510.3













222




C30H30ClN5OS




























66%




6.8




544.3













223




C30H29Cl2N5OS




























69%




7.3




690.2













224




C31H31N5O3S




























75%




6.4




666.3













225




C30H30FN5OS




























52%




6.6




528.5













226




C31H33N5OS




























82%




6.7




636.3













227




C31H32ClN5OS




























85%




7.1




670.3













228




C33H37N5O3S




























82%




6.4




696.3













229




C32H35N5OS




























66%




7.0




650.3













230




C28H29N5O2S




























77%




6.1




612.2













231




C28H33N5O2S




























26% + 48




5.8 + 5.9




616.3













232




C28H33N5OS




























76%




6.4




600.3













233




C29H35N5OS




























78%




6.7




614.3













234




C30H37N5OS




























77%




4.6




645.3













235




C29H36N6O2S




























85%




4.6




659.4













236




C30H38N6O2S




























84%




4.8




532.3













237




C30H40N6OS




























36%




5.5




590.3













238




C26H31N5O2S




























79%




5.7




492.3













239




C27H33N5O2S




























69%




6.3




588.3













240




C27H33N5OS




























78%




6.3




476.3
















Analyses


















Ex. No.




Formula




m




R1




R2




Purity




rt (min)




[M + H]+















































241




C29H25N5OS




2




























93%




6.7




492.2













242




C31H27N5O2S




2




























87%




6.6




534.2













243




C35H37N5OS




2




























68%




7.9




576.3













244




C32H31N5OS




2




























88%




7.5




534.2













245




C29H23F2N5OS




2




























92%




6.9




528.2













246




C29H24FN5OS




2




























92%




6.8




510.2













247




C29H22Cl3N5OS




2




























82%




7.6




594.1













248




C29H23Cl2N5OS




2




























86%




7.5




560.1













249




C29H22Br3N5OS




2




























76%




7.8




725.9













250




C31H29N5OS




2




























47%




7.1




520.2













251




C31H23F6N5OS




2




























88%




7.8




628.2













252




C30H24F3N5OS




2




























90%




7.3




560.2













253




C31H29N5O3S




2




























86%




6.9




552.2













254




C30H27N5O2S




2




























93%




6.8




522.2













255




C30H27N5OS2




2




























88%




7.1




538.2













256




C29H24N6O3S




2




























92%




6.9




537.2













257




C29H24N8OS




2




























92%




7.1




533.2













258




C31H30N6OS




2




























67%




6.7




268.2













259




C30H24N6OS




2




























82%




6.7




517.2













260




C36H31N5O2S




2




























86%




7.6




598.2













261




C29H29N5OS




2




























78%




6.1




248.7













262




C31H31N5O2S




2




























65%




6.0




269.7













263




C35H41N5OS




2




























53%




7.5




290.8













264




C32H35N5OS




2




























82%




7.0




269.8













265




C29H27F2N5OS




2




























79%




6.4




266.7













266




C29H28FN5OS




2




























73%




6.2




257.7













267




C29H26Cl3N5OS




2




























87%




7.2




299.6













268




C29H27Cl2N5OS




2




























70%




7.1




282.6













269




C29H26Br3N5OS




2




























78%




7.3




365.5













270




C31H33N5OS




2




























3%




6.6




262.7













271




C31H27F6N5OS




2




























39%




7.5




316.8













272




C30H28F3N5OS




2




























64%




6.9




282.7













273




C31H33N5O3S




2




























78%




6.3




278.7













274




C30H31N5O2S




2




























45%




6.2




263.7













275




C30H31N5OS2




2




























66%




6.5




271.7













276




C29H28N6O3S




2




























67%




6.4




271.2













277




C29H28N8OS




2




























62%




6.5




269.2













278




C31H34N6OS




2




























37%




6.1




270.2













279




C30H28N6OS




2




























49%




6.1




261.3













280




C36H35N5O2S




2




























73%




7.2




301.8













281




C24H20N4OS2




1




























89%




6.6




445.1













282




C26H22N4O2S2




1




























88%




6.6




487.2













283




C30H32N4OS2




1




























86%




7.9




529.2













284




C27H26N4OS2




1




























96%




7.5




487.2













285




C24H18F2N4OS2




1




























93%




6.7




481.1













286




C24H19FN4OS2




1




























90%




6.8




463.1













287




C24H17Cl3N4OS2




1




























97%




7.5




547.0













288




C24H18Cl2N4OS2




1




























90%




7.8




513.1













289




C24H17Br3N4OS2




1




























92%




7.7




678.9













290




C26H24N4OS2




1




























87%




7.0




473.2













291




C26H18F6N4OS2




1




























91%




8.2




581.1













292




C25H19F3N4OS2




1




























87%




7.5




513.1













293




C26H24N4O3S2




1




























95%




6.8




505.2













294




C25H22N4O2S2




1




























92%




6.7




475.1













295




C25H22N4OS3




1




























89%




7.1




491.1













296




C24H19N5O3S2




1




























88%




7.0




490.1













297




C24H19N7OS2




1




























90%




7.1




486.2













298




C26H25N5OS2




1




























86%




6.6




244.7













299




C25H19N5OS2




1




























89%




6.8




470.1













300




C31H26N4O2S2




1




























88%




7.7




551.2













301




C27H24N4O2S




1




























92%




6.7




469.2













302




C29H26N4O3S




1




























91%




6.7




511.2













303




C33H36N4O2S




1




























89%




8.0




553.3













304




C30H30N4O2S




1




























95%




7.6




511.2













305




C27H22F2N4O2S




1




























95%




6.8




505.2













306




C27H23FN4O2S




1




























93%




6.9




487.2













307




C27H21Cl3N4O2S




1




























93%




7.6




571.1













308




C27H22Cl2N4O2S




1




























85%




7.9




537.1













309




C27H21Br3N4O2S




1




























93%




7.8




702.9













310




C29H28N4O2S




1




























86%




7.1




497.2













311




C29H22F6N4O2S




1




























93%




8.3




605.2













312




C28H23F3N4O2S




1




























93%




7.5




537.1













313




C29H28N4O4S




1




























96%




6.9




529.2













314




C28H26N4O3S




1




























97%




6.8




499.2













315




C28H26N4O2S2




1




























84%




7.2




515.2













316




C27H23N5O4S




1




























88%




7.1




514.2













317




C27H23N7O2S




1




























94%




7.2




510.2













318




C29H29N5O2S




1




























89%




6.7




256.7













319




C28H23N5O2S




1




























90%




6.8




494.2













320




C34H30N4O3S




1




























89%




7.7




575.2
















Analyses

















Ex. No.




Formula




R1




R2




Purity




rt (min)




[M + H]+














































321




C29H25N5OS




























91




7.2




492.2













322




C29H24ClN5OS




























91




7.5




526.2













323




C29H23Cl2N5OS




























91




7.9




560.1













324




C30H25N5O3S




























92




7.0




536.2













325




C29H24FN5OS




























93




7.3




510.2













326




C30H27N5OS




























92




7.4




506.2













327




C30H26ClN5OS




























91




7.8




540.2













328




C32H31N5O3S




























90




7.1




566.2













329




C31H29N5OS




























91




7.6




520.2













330




C27H23N5O2S




























92




6.8




482.2













331




C27H27N5O2S




























35 + 51




6.64 + 6.76




486.2













332




C27H27N5OS




























90




7.2




470.2













333




C28H29N5OS




























89




7.4




484.3













334




C29H31N5OS




























90




7.7




498.3













335




C28H30N6O2S




























94




5.2




258.3













336




C29H32N6O2S




























93




5.1




265.3













337




C29H34N6OS




























85




5.3




258.3













338




C25H25N5O2S




























92




6.4




460.2













339




C26H27N5O2S




























92




6.5




474.2













340




C26H27N5OS




























91




7.1




458.2













341




C25H22N4OS2




























90




7.0




459.2













342




C25H21ClN4OS2




























89




7.4




493.1













343




C25H20Cl2N4OS2




























92




7.7




527.1













344




C26H22N4O3S2




























88




6.9




503.2













345




C25H21FN4OS2




























91




7.1




477.2













346




C26H24N4OS2




























89




7.3




473.2













347




C26H23ClN4OS2




























91




7.7




507.1













348




C28H28N4O3S2




























88




6.9




533.2













349




C27H26N4OS2




























85




7.5




487.2













350




C23H20N4O2S2




























93




6.6




449.1













351




C23H24N4O2S2




























36 + 50




6.34 + 6.46




453.2













352




C23H24N4OS2




























87




7.0




437.2













353




C24H26N4OS2




























84




7.3




451.2













354




C25H28N4OS2




























86




7.5




465.2













355




C24H27N5O2S2




























91




5.0




241.7













356




C25H29N5O2S2




























88




5.0




248.8













357




C25H31N5OS2




























61




5.1




241.8













358




C21H22N4O2S2




























88




6.1




427.1













359




C22H24N4O2S2




























87




6.3




441.1













360




C22H24N4OS2




























84




6.9




425.2













361




C28H26N4O2S




























89




7.1




483.2













362




C28H25ClN4O2S




























89




7.5




517.2













363




C28H24Cl2N4O2S




























91




7.8




551.1













364




C29H26N4O4S




























89




7.0




527.2













365




C28H25FN4O2S




























95




7.2




501.2













366




C29H28N4O2S




























90




7.3




497.2













367




C29H27ClN4O2S




























89




7.7




531.2













368




C31H32N4O4S




























90




7.0




557.2













369




C30H30N4O2S




























91




7.5




511.2













370




C26H24N4O3S




























92




6.7




473.2













371




C26H28N4O3S




























39 + 45




6.44 + 6.56




477.2













372




C26H28N4O2S




























89




7.1




461.2













373




C27H30N4O2S




























90




7.3




475.2













374




C28H32N4O2S




























90




7.6




489.3













375




C27H31N5O3S




























93




5.1




253.7













376




C28H33N5O3S




























90




5.1




260.8













377




C28H35N5O2S




























73




5.3




253.8













378




C24H26N4O3S




























91




6.2




451.2













379




C25H28N4O3S




























91




6.4




465.2













380




C25H28N4O2S




























90




7.0




449.2













381




C29H29N5OS




























85




6.4




248.7













382




C29H28ClN5OS




























85




6.9




265.7













383




C29H27Cl2N5OS




























84




7.3




282.6













384




C30H29N5O3S




























85




6.3




270.7













385




C29H28FN5OS




























88




6.5




257.7













386




C30H31N5OS




























84




6.7




255.6













387




C30H30ClN5OS




























87




7.2




272.7













388




C32H35N5O3S




























82




6.4




285.8













389




C31H33N5OS




























81




6.9




262.7













390




C27H27N5O2S




























89




5.9




243.7













391




C27H31N5O2S




























43 + 43




5.68 + 5.86




245.7













392




C27H31N5OS




























83




6.4




237.7













393




C28H33N5OS




























83




6.7




244.7













394




C29H35N5OS




























85




7.0




251.7













395




C28H34N6O2S




























87




4.6




259.8













396




C29H36N6O2S




























84




4.6




267.2













397




C25H29N5O2S




























74




5.4




232.7













398




C26H31N5O2S




























83




5.6




239.7













399




C26H31N5OS




























87




6.3




231.8
















Analyses


















Ex. No.




Formula




m




R1




R2




Purity




rt (min)




[M + H]+















































400




C30H34N6O3S




2




























83%




7.8




559.2













401




C31H36N6O3S




2




























82%




7.9




573.2













402




C32H38N6O3S




2




























82%




8.0




587.3













403




C33H40N6O3S




2




























81%




8.3




601.3













404




C34H42N6O3S




2




























80%




8.5




615.3













405




C26H31N5O3S2




2




























81%




7.6




526.2













406




C27H33N5O3S2




2




























83%




7.8




540.2













407




C28H35N5O3S2




2




























88%




7.9




554.2













408




C29H37N5O3S2




2




























86%




8.2




568.2













409




C30H39N5O3S2




2




























86%




8.4




582.3













410




C29H35N5O4S




2




























87%




7.7




550.3













411




C30H37N5O4S




2




























87%




7.9




564.3













412




C31H39N5O4S




2




























92%




8.0




578.3













413




C32H41N5O4S




2




























89%




8.3




592.3













414




C33H43N5O4S




2




























88%




8.5




606.3













415




C30H38N6O3S




2




























83%




7.0




563.3













416




C31H40N6O3S




2




























85%




7.2




577.3













417




C32H42N6O3S




2




























88%




7.4




591.3













418




C33H44N6O3S




2




























88%




7.7




303.3













419




C34H46N6O3S




2




























88%




7.9




310.4













420




C29H32N6O3S




2




























78%




7.9




545.2













421




C30H34N6O3S




2




























81%




8.0




559.2













422




C31H36N6O3S




2




























84%




8.1




573.3













423




C32H38N6O3S




2




























82%




8.3




587.3













424




C33H40N6O3S




2




























86%




8.5




601.3













425




C25H29N5O3S2




2




























80%




7.7




512.2













426




C26H31N5O3S2




2




























82%




7.8




526.2













427




C27H33N5O3S2




2




























87%




7.9




540.2













428




C28H35N5O3S2




2




























86%




8.2




554.2













429




C29H37N5O3S2




2




























84%




8.4




568.2













430




C28H33N5O4S




2




























86%




7.8




536.3













431




C29H35N5O4S




2




























85%




7.9




550.3













432




C30H37N5O4S




2




























92%




8.0




564.3













433




C31H39N5O4S




2




























90%




8.2




578.3













434




C32H41N5O4S




2




























90%




8.5




592.3













435




C29H36N6O3S




2




























80%




6.9




549.3













436




C30H38N6O3S




2




























78%




7.1




563.3













437




C31H40N6O3S




2




























84%




7.3




577.3













438




C32H42N6O3S




2




























83%




7.5




296.3













439




C33H44N6O3S




2




























85%




7.8




303.3













440




C25H26N6OS




1




























76%




5.4




459.2













441




C26H28N6OS




1




























61%




5.4




473.3













442




C27H30N6OS




1




























75%




5.6




244.2













443




C28H32N6OS




1




























32%




5.7




251.1













444




C29H34N6OS




1




























59%




5.9




258.3













445




C21H23N5OS2




1




























78%




5.1




426.2













446




C22H25N5OS2




1




























79%




5.2




440.2













447




C23H27N5OS2




1




























84%




5.4




227.6













448




C24H29N5OS2




1




























84%




5.5




234.7













449




C25H31N5OS2




1




























83%




5.7




241.7













450




C24H27N5O2S




1




























88%




5.3




450.2













451




C25H29N5O2S




1




























96%




5.4




464.2













452




C26H31N5O2S




1




























90%




5.6




239.7













453




C27H33N5O2S




1




























90%




5.7




246.7













454




C28H35N5O2S




1




























91%




5.9




253.7













455




C25H30N6OS




1




























84%




4.8




232.2













456




C26H32N6OS




1




























89%




4.9




238.8













457




C27H34N6OS




1




























86%




5.0




246.1













458




C28H36N6OS




1




























93%




5.2




252.9













459




C29H38N6OS




1




























93%




5.4




260.1













460




C24H24N6OS




1




























68%




5.6




445.2













461




C25H26N6OS




1




























55%




5.5




459.2













462




C26H28N6OS




1




























55%




5.6




473.3













463




C27H30N6OS




1




























48%




5.7




487.3













464




C28H32N6OS




1




























44%




5.9




501.2













465




C20H21N5OS2




1




























84%




5.3




412.1













466




C21H23N5OS2




1




























86%




5.2




426.2













467




C22H25N5OS2




1




























90%




5.3




440.2













468




C23H27N5OS2




1




























79%




5.5




227.7













469




C24H29N5OS2




1




























91%




5.7




234.8













470




C23H25N5O2S




1




























92%




5.5




436.2













471




C24H27N5O2S




1




























88%




5.4




450.2













472




C25H29N5O2S




1




























93%




5.5




464.3













473




C26H31N5O2S




1




























92%




5.6




478.3













474




C27H33N5O2S




1




























95%




5.8




246.7













475




C24H28N6OS




1




























87%




4.9




224.7













476




C25H30N6OS




1




























80%




4.8




231.9













477




C26H32N6OS




1




























84%




4.9




238.9













478




C27H34N6OS




1




























90%




5.0




245.7













479




C28H36N6OS




1




























91%




5.2




505.3
















Analyses


















Ex. No.




Formula




X




R1




R2




Purity




rt (min)




[M + H]+















































480




C30H34N6O3S




S




























86%




5.4




559.2













481




C31H36N6O3S




S




























88%




5.5




573.2













482




C32H38N6O3S




S




























88%




5.5




587.3













483




C33H40N6O3S




S




























89%




5.7




601.3













484




C34H42N6O3S




S




























91%




5.8




615.3













485




C35H36N6O3S




S




























91%




5.6




621.3













486




C31H34N6O4S




S




























56%




5.6




587.2













487




C32H36N6O4S




S




























73%




5.6




601.2













488




C33H38N6O4S




S




























79%




5.7




615.3













489




C34H40N6O4S




S




























71%




5.9




629.3













490




C35H42N6O4S




S




























81%




6.0




643.3













491




C36H36N6O4S




S




























60%




5.8




649.3













492




C30H34N6O3S




S




























83%




5.4




559.2













493




C31H36N6O3S




S




























87%




5.5




573.2













494




C32H38N6O3S




S




























87%




5.5




587.3













495




C33H40N6O3S




S




























87%




5.7




601.3













496




C34H42N6O3S




S




























88%




5.8




615.3













497




C35H36N6O3S




S




























89%




5.6




621.3













498




C31H34N6O4S




S




























71%




5.6




587.2













499




C32H36N6O4S




S




























45%




5.6




601.2













500




C33H38N6O4S




S




























75%




5.7




615.3













501




C34H40N6O4S




S




























68%




5.9




629.3













502




C35H42N6O4S




S




























76%




6.0




643.3













503




C36H36N6O4S




S




























55%




5.8




649.3













504




C30H34N6O4




O




























88%




4.9




543.3













505




C31H36N6O4




O




























88%




5.0




557.3













506




C32H38N6O4




O




























85%




5.0




571.3













507




C33H40N6O4




O




























86%




5.2




585.3













508




C31H34N6O5




O




























79%




4.9




571.2













509




C32H36N6O5




O




























56%




5.0




585.3













510




C33H38N6O5




O




























77%




5.1




599.3













511




C34H40N6O5




O




























74%




5.2




613.3













512




C30H34N6O4




O




























90%




4.9




543.3













513




C31H36N6O4




O




























90%




5.0




557.3













514




C32H38N6O4




O




























89%




5.0




571.3













515




C33H40N6O4




O




























91%




5.2




585.3













516




C31H34N6O5




O




























76%




4.9




571.2













517




C32H36N6O5




O




























81%




5.0




585.3













518




C33H38N6O5




O




























74%




5.1




599.3













519




C34H40N6O5




O




























75%




5.2




613.3













520




C25H26N6OS




S




























93%




6.8




459.2













521




C26H28N6OS




S




























93%




6.6




473.2













522




C27H30N6OS




S




























90%




6.7




487.2













523




C28H32N6OS




S




























92%




6.8




501.2













524




C29H34N6OS




S




























92.%




6.9




515.2













525




C30H28N6OS




S




























89%




6.8




521.2













526




C26H26N6O2S




S




























63%




7.1




487.2













527




C27H28N6O2S




S




























87%




6.8




501.2













528




C28H30N6O2S




S




























85%




6.9




515.2













529




C29H32N6O2S




S




























79%




7.0




529.2













530




C30H34N6O2S




S




























91%




7.2




543.2













531




C31H28N6O2S




S




























80%




7.1




549.2













532




C25H26N6OS




S




























91%




6.8




459.2













533




C26H28N6OS




S




























89%




6.6




473.2













534




C27H30N6OS




S




























93%




6.7




487.2













535




C28H32N6OS




S




























91%




6.8




501.2













536




C29H34N6OS




S




























91%




6.9




515.2













537




C30H28N6OS




S




























87%




6.8




521.2













538




C26H26N6O2S




S




























90%




7.0




487.2













539




C27H28N6O2S




S




























61%




6.8




501.2













540




C28H30N6O2S




S




























87%




6.9




515.2













541




C29H32N6O2S




S




























83%




7.0




529.2













542




C30H34N6O2S




S




























93%




7.2




543.2













543




C31H28N6O2S




S




























76%




7.1




549.2













544




C25H26N6O2




O




























91%




6.1




443.2













545




C26H28N6O2




O




























90%




6.1




457.2













546




C27H30N6O2




O




























87%




6.1




471.2













547




C28H32N6O2




O




























88%




6.2




485.2













548




C26H26N6O3




O




























93%




6.2




471.2













549




C27H28N6O3




O




























91%




6.1




485.2













550




C28H30N6O3




O




























81%




6.2




499.2













551




C29H32N6O3




O




























82%




6.3




513.2













552




C25H26N6O2




O




























91%




6.1




443.2













553




C26H28N6O2




O




























91%




6.1




457.2













554




C27H30N6O2




O




























89%




6.1




471.2













555




C28H32N6O2




O




























91%




6.1




485.2













556




C26H26N6O3




O




























93%




6.2




471.2













557




C27H28N6O3




O




























95%




6.1




485.2













558




C28H30N6O3




O




























85%




6.2




499.2













559




C29H32N6O3




O




























85%




6.3




513.2













560




C24H24N6OS




S




























84%




3.6




445.2













561




C26H28N6OS




S




























92%




3.5




473.3













562




C27H30N6OS




S




























83%




3.6




487.3













563




C28H32N6OS




S




























88%




3.7




501.3













564




C29H26N6OS




S




























59%




3.7




507.2













565




C24H24N6O2




O




























87%




3.2




429.2













566




C25H26N6O2




O




























92%




3.1




443.3













567




C26H28N6O2




O




























97%




3.1




457.3













568




C27H30N6O2




O




























90%




3.1




471.3













569




C24H24N6O2




O




























91%




3.1




429.2













570




C25H26N6O2




O




























97%




3.1




443.3













571




C26H28N6O2




O




























95%




3.1




457.3













572




C27H30N6O2




O




























95%




3.2




471.3
















Analyses

















Ex. No.




Formula




R1




R2




Purity




rt (min)




[M + H]+














































573




C29H25N5OS




























93%




6.7




492.2













574




C29H24ClN5OS




























93%




7.2




526.2













575




C29H23Cl2N5OS




























93%




7.6




560.1













576




C30H27N5OS




























94%




7.0




506.2













577




C29H24FN5OS




























95%




6.9




510.3













578




C30H27N5OS




























90%




6.9




506.3













579




C30H26ClN5OS




























92%




7.4




540.2













580




C32H31N5O3S




























88%




6.4




566.3













581




C31H29N5OS




























87%




7.1




520.2













582




C27H23N5O2S




























93%




6.2




482.2













583




C27H27N5O2S




























38 + 45%




5.6 + 5.71




486.3













584




C28H30N6O2S




























87%




4.6




515.3













585




C29H32N6O2S




























84%




4.5




529.3













586




C29H34N6OS




























89%




4.7




515.3













587




C25H25N5O2S




























90%




5.18 m




460.3













588




C26H27N5O2S




























87%




5.6




474.3













589




C25H22N4OS2




























89%




6.7




459.2













590




C25H21ClN4OS2




























87%




7.2




493.2













591




C25H20Cl2N4OS2




























90%




7.6




527.1













592




C26H24N4OS2




























83%




7.0




473.2













593




C25H21FN4OS2




























88%




6.9




477.2













594




C26H24N4OS2




























80%




7.0




473.2













595




C26H23ClN4OS2




























79%




7.4




507.2













596




C28H28N4O3S2




























82%




6.4




533.2













597




C27H26N4OS2




























79%




7.2




487.2













598




C23H20N4O2S2




























80%




6.2




449.2













599




C23H24N4O2S2




























31 + 32%




5.7 + 5.86




453.2













600




C24H27N5O2S2




























80%




4.3




241.7













601




C25H29N5O2S2




























81%




4.3




248.8













602




C25H31N5OS2




























81%




4.5




482.3













603




C21H22N4O2S2




























79%




5.6




427.1













604




C22H24N4O2S2




























78%




5.9




441.2













605




C28H26N4O2S




























89%




6.8




483.2













606




C28H25ClN4O2S




























90%




7.2




517.2













607




C28H24Cl2N4O2S




























91%




7.7




551.1













608




C29H28N4O2S




























88%




7.0




497.3













609




C28H25FN4O2S




























89%




6.9




501.2













610




C29H28N4O2S




























87%




7.0




497.3













611




C29H27ClN4O2S




























90%




7.5




531.2













612




C31H32N4O4S




























91%




6.5




557.2













613




C30H30N4O2S




























87%




7.2




511.3













614




C26H24N4O3S




























89%




6.3




473.2













615




C26H28N4O3S




























39 + 43%




5.7 + 5.85




477.2













616




C27H31N5O3S




























34%




4.5




506.3













617




C28H33N5O3S




























79%




4.4




520.3













618




C28H35N5O2S




























76%




4.6




506.3













619




C24H26N4O3S




























85%




5.7




451.2













620




C25H28N4O3S




























84%




5.9




465.2













621




C29H29N5OS




























89%




5.9




248.8













622




C29H28ClN5OS




























89%




6.4




265.7













623




C29H27Cl2N5OS




























93%




6.9




282.7













624




C30H31N5OS




























90%




6.2




255.8













625




C29H28FN5OS




























92%




6.1




257.8













626




C30H31N5OS




























87%




6.2




255.8













627




C30H30ClN5OS




























90%




6.8




272.7













628




C32H35N5O3S




























87%




5.6




285.8













629




C31H33N5OS




























88%




6.4




262.8













630




C27H27N5O2S




























89%




5.4




243.7













631




C27H31N5O2S




























31 + 37%




5.26 + 5.33




245.6













632




C28H34N6O2S




























79%




3.7




260.3













633




C29H36N6O2S




























77%




3.7




267.3













634




C29H38N6OS




























78%




3.9




260.2













635




C25H29N5O2S




























80%




4.9




232.7













636




C26H31N5O2S




























79%




5.0




239.7













637




C28H23F3N4O2S




























88%




7.4




537.2













638




C28H22ClF3N4O2S




























90%




7.8




571.1













639




C28H21Cl2F3N4O2S




























92%




8.3




605.1













640




C29H25F3N4O2S




























89%




7.6




551.2













641




C28H22F4N4O2S




























89%




7.5




555.2













642




C29H25F3N4O2S




























88%




7.7




551.2













643




C29H24ClF3N4O2S




























90%




8.1




585.1













644




C31H29F3N4O4S




























92%




7.2




611.2













645




C30H27F3N4O2S




























86%




7.8




565.2













646




C26H21F3N4O3S




























88%




7.0




527.2













647




C26H25F3N4O3S




























44 + 42%




6.59 + 6.7




531.2













648




C27H28F3N5O3S




























81%




5.0




280.8













649




C28H30F3N5O3S




























82%




5.0




287.8













650




C28H32F3N5O2S




























86%




5.2




280.8













651




C24H23F3N4O3S




























90%




6.6




505.2













652




C25H25F3N4O3S




























88%




6.8




519.2


















































653




C29H32N6O3S




























88%




6.4




545.3













654




C30H34N6O3S




























90%




6.3




559.3













655




C31H36N6O3S




























89%




6.3




573.3













656




C32H38N6O3S




























91%




6.5




587.3













657




C33H40N6O3S




























91%




6.8




601.3













658




C25H29N5O3S2




























78%




6.7




512.3













659




C26H31N5O3S2




























87%




6.5




526.3













660




C27H33N5O3S2




























86%




6.6




540.3













661




C28H35N5O3S2




























84%




6.8




554.3













662




C29H37N5O3S2




























83%




7.0




568.3













663




C28H33N5O4S




























83%




6.7




536.3













664




C29H35N5O4S




























88%




6.6




550.3













665




C30H37N5O4S




























84%




6.6




564.3













666




C31H39N5O4S




























86%




6.8




578.3













667




C32H41N5O4S




























86%




7.0




592.3













668




C29H36N6O3S




























82%




5.8




549.3













669




C30H38N6O3S




























80%




5.7




563.3













670




C31H40N6O3S




























84%




5.8




577.3













671




C32H42N6O3S




























84%




6.0




591.4













672




C33H44N6O3S




























84%




6.3




605.4













673




C28H30F3N5O4S




























82%




7.5




590.3













674




C29H32F3N5O4S




























81%




7.3




604.3













675




C30H34F3N5O4S




























84%




7.4




618.3













676




C31H36F3N5O4S




























86%




7.5




632.3













677




C32H38F3N5O4S




























88%




7.7




646.3













678




C29H34N6O4S




























81%




5.8




563.3













679




C30H36N6O4S




























81%




5.8




577.3













680




C31H38N6O4S




























82%




5.8




591.3













681




C32H40N6O4S




























82%




6.0




605.3













682




C33H42N6O4S




























83%




6.2




619.4













683




C27H30N6O5S




























77%




6.9




551.3













684




C28H32N6O5S




























75%




6.8




585.3













685




C29H34N6O5S




























81%




6.9




579.3













686




C30H36N6O5S




























82%




7.0




593.3













687




C31H38N6O5S




























82%




7.3




607.3













688




C27H37N5O3S




























77%




7.5




512.3













689




C28H39N5O3S




























71%




7.3




526.4













690




C29H41N5O3S




























76%




7.3




540.3













691




C30H43N5O3S




























74%




7.5




554.4













692




C31H45N5O3S




























74%




7.7




568.4













693




C24H24N6OS




























47%




4.2




445.3













694




C25H26N6OS




























45%




3.9




459.3













695




C26H28N6OS




























52%




4.0




473.3













696




C27H30N6OS




























43%




4.1




487.3













697




C28H32N6OS




























38%




4.3




501.3













698




C20H21N5OS2




























78%




4.1




412.2













699




C21H23N5OS2




























81%




4.0




426.3













700




C22H25N5OS2




























84%




4.1




440.2













701




C23H27N5OS2




























86%




4.2




454.3













702




C24H29N5OS2




























85%




4.3




468.3













703




C23H25N5O2S




























82%




4.2




436.3













704




C24H27N5O2S




























84%




4.1




450.3













705




C25H29N5O2S




























88%




4.2




464.3













706




C26H31N5O2S




























88%




4.3




478.3













707




C27H33N5O2S




























87%




4.4




492.3













708




C24H28N6OS




























80%




3.5




449.3













709




C25H30N6OS




























83%




3.4




436.3













710




C26H32N6OS




























84%




3.5




477.3













711




C27H34N6OS




























84%




3.6




491.3













712




C28H36N6OS




























85%




3.8




505.3













713




C23H22F3N5O2S




























83%




4.8




490.3













714




C24H24F3N5O2S




























84%




4.8




504.2













715




C25H26F3N5O2S




























88%




4.8




518.2













716




C26H28F3N5O2S




























91%




4.9




532.2













717




C27H30F3N5O2S




























90%




5.0




546.2













718




C24H26N6O2S




























70%




3.6




463.3













719




C25H28N6O2S




























82%




3.5




477.3













720




C26H30N6O2S




























83%




3.5




491.3













721




C27H32N6O2S




























89%




3.7




505.3













722




C28H34N6O2S




























89%




3.8




519.3













723




C22H22N6O3S




























81%




4.3




451.2













724




C23H24N6O3S




























80%




4.3




465.2













725




C24H26N6O3S




























89%




4.3




479.2













726




C25H28N6O3S




























86%




4.4




493.3













727




C26H30N6O3S




























86%




4.5




507.3













728




C22H29N5OS




























79%




4.8




412.3













729




C23H31N5OS




























75%




4.6




426.3













730




C24H33N5OS




























78%




4.6




440.3













731




C25H35N5OS




























78%




4.7




454.3













732




C26H37N5OS




























83.8%




5.0




468.2


















































733




C28H24N6OS




























45%




4.7




493.2













734




C29H26N6OS




























57%




4.2




507.3













735




C24H21N5OS2




























69%




4.7




460.2













736




C25H23N5OS2




























77%




4.2




474.2













737




C27H25N5O2S




























73%




4.8




484.3













738




C28H27N5O2S




























76%




4.3




497.3













739




C28H28N6OS




























67%




3.9




497.3













740




C29H30N6OS




























62%




3.6




511.3













741




C27H22F3N5O2S




























61%




5.7




538.2













742




C28H24F3N5O2S




























75%




4.9




552.2













743




C28H26N6O2S




























57%




4.0




511.2













744




C29H28N6O2S




























60%




3.7




525.3













745




C26H22N6O3S




























70%




5.0




499.2













746




C27H24N6O3S




























65%




4.4




513.2













747




C26H29N5OS




























78%




5.4




460.3













748




C27H31N5OS




























80%




4.7




474.3













749




C34H34N6O3S




























86%




6.6




593.3













750




C33H32N6O3S




























82%




6.5




607.3













751




C30H31N5O3S2




























77%




6.7




560.2













752




C29H29N5O3S2




























77%




6.7




574.2













753




C33H35N5O4S




























81%




6.8




584.3













754




C32H33N5O4S




























76%




6.7




598.3













755




C34H38N6O3S




























77%




5.9




597.3













756




C33H36N6O3S




























74%




5.8




611.3













757




C33H32F3N5O4S




























76%




7.4




638.3













758




C32H30F3N5O4S




























74%




7.3




652.3













759




C34H36N6O4S




























78%




6.1




611.3













760




C33H34N6O4S




























76%




6.0




625.3













761




C32H32N6O5S




























74%




6.9




599.2













762




C31H30N6O5S




























69%




6.8




613.3













763




C32H39N5O3S




























78%




7.3




560.3













764




C31H37N5O3S




























74%




7.5




574.3













765




C31H34N6O4S




























76%




6.9




587.2













766




C32H36N6O4S




























86%




6.8




601.3













767




C33H38N6O4S




























81%




6.8




615.3













768




C34H40N6O4S




























84%




7.0




629.3













769




C35H42N6O4S




























78%




7.2




643.4













770




C36H36N6O4S




























83%




6.8




649.3













771




C31H34N6O4S




























81%




6.9




587.2













772




C32H36N6O4S




























76%




6.8




601.3













773




C33H38N6O4S




























82%




6.8




615.3













774




C34H40N6O4S




























84%




7.0




629.3













775




C35H42N6O4S




























73%




7.2




643.3













776




C36H36N6O4S




























71%




6.8




649.3













777




C26H26N6O2S




























84%




4.4




487.3













778




C27H28N6O2S




























85%




4.4




501.3













779




C28H30N6O2S




























65%




4.4




515.3













780




C29H32N6O2S




























75%




4.6




529.3













781




C30H34N6O2S




























84%




4.7




543.3













782




C31H28N6O2S




























82%




4.5




549.3













783




C26H26N6O2S




























87%




4.4




487.3













784




C27H28N6O2S




























87%




4.4




501.3













785




C28H30N6O2S




























83%




4.4




515.3













786




C29H32N6O2S




























91%




4.5




529.3













787




C30H34N6O2S




























84%




4.7




543.3













788




C31H28N6O2S




























79%




4.5




549.3













789




C24H24N6OS




























42%




4.3




445.3













790




C25H26N6OS




























72%




4.1




459.3













791




C26H28N6OS




























87%




4.1




473.4













792




C27H30N6OS




























88%




4.3




487.4













793




C28H32N6OS




























92%




4.4




501.4













794




C29H26N6OS




























78%




4.3




507.3













795




C24H24N6OS




























46%




4.3




445.3













796




C25H26N6OS




























71%




4.1




459.3













797




C26H28N6OS




























93%




4.1




473.4













798




C27H30N6OS




























94%




4.3




487.4













799




C28H32N6OS




























86%




4.5




501.4













800




C29H26N6OS




























77%





507.3


















































801




C30H30N4OS




























96%




7.7




495.3













802




C30H29ClN4OS




























97%




8.1




529.3













803




C30H28Cl2N4OS




























99%




8.6




563.2













804




C31H32N4OS




























95%




7.9




509.3













805




C30H29FN4OS




























96%




7.8




513.3













806




C31H32N4OS




























93%




7.9




509.3













807




C31H31ClN4OS




























95%




8.4




543.3













808




C33H36N4O3S




























93%




7.4




569.3













809




C32H34N4OS




























94%




8.1




523.3













810




C28H28N4O2S




























96%




7.2




485.3













811




C28H32N4O2S




























37 + 44%




6.7 + 6.84




489.3













812




C29H35N5O2S




























88%




5.3




518.3













813




C30H37N5O2S




























94%




5.3




532.4













814




C30H39N5OS




























89%




5.4




518.4













815




C26H30N4O2S




























92%




6.7




463.3













816




C27H32N4O2S




























91%




6.9




477.3













817




C29H27N5O2S




























93%




6.0




510.3













818




C29H26ClN5O2S




























87%




6.5




544.2













819




C29H25Cl2N5O2S




























74%




6.9




578.2













820




C30H29N5O2S




























94%




6.2




524.3













821




C29H26FN5O2S




























94%




6.2




528.3













822




C30H29N5O2S




























93%




6.3




524.3













823




C30H28ClN5O2S




























93%




6.7




558.2













824




C32H33N5O4S




























91%




5.7




584.3













825




C31H31N5O2S




























89%




6.5




538.3













826




C27H25N5O3S




























90%




5.5




500.3













827




C27H29N5O3S




























27% + 24




4.99 + 5.1




504.3













828




C28H32N6O3S




























85%




3.9




533.3













829




C29H34N6O3S




























87%




3.9




547.3













830




C29H36N6O2S




























88%




4.1




533.3













831




C25H27N5O3S




























92%




4.9




478.3













832




C26H29N5O3S




























93%




5.1




492.3













833




C27H23N5O3S




























93%




7.0




498.3













834




C27H22ClN5O3S




























85%




7.4




532.2













835




C27H21Cl2N5O3S




























88%




7.8




566.1













836




C28H25N5O3S




























90%




7.3




512.3













837




C27H22FN5O3S




























88%




7.1




516.2













838




C28H25N5O3S




























90%




7.3




512.3













839




C28H24ClN5O3S




























91%




7.8




546.2













840




C30H29N5O5S




























92%




6.8




572.2













841




C29H27N5O3S




























94%




7.5




526.3













842




C25H21N5O4S




























89%




6.6




488.2













843




C25H25N5O4S




























46% + 46




6.24 + 6.4




492.3













844




C26H28N6O4S




























82%




4.6




521.3













845




C27H30N6O4S




























84%




4.6




535.3













846




C27H32N6O3S




























76%




4.8




521.3













847




C23H23N5O4S




























90%




6.1




466.2













848




C24H25N5O4S




























90%




6.3




480.3













849




C24H21N5OS2




























87%




6.1




460.2













850




C24H20ClN5OS2




























53%




6.6




494.1













851




C24H19Cl2N5OS2




























85%




7.0




528.0













852




C25H23N5OS2




























79%




6.2




474.1













853




C24H20FN5OS2




























76%




6.2




478.1













854




C25H23N5OS2




























74%




6.4




474.1













855




C25H22ClN5OS2




























82%




6.9




508.1













856




C27H27N5O3S2




























73%




5.8




534.1













857




C26H25N5OS2




























74%




6.6




488.1













858




C22H19N5O2S2




























77%




5.5




450.1













859




C22H23N5O2S2




























23 + 25%




5.2 + 5.33




454.1













860




C23H26N6O2S2




























78%




3.9




483.2













861




C24H28N6O2S2




























68%




3.9




497.2













862




C24H30N6OS2




























59%




4.1




483.2













863




C20H21N5O2S2




























68%




5.0




428.1













864




C21H23N5O2S2




























65%




5.3




442.1













865




C27H30N4OS




























97%




7.4




459.2













866




C27H29ClN4OS




























98%




7.9




493.2













867




C27H28Cl2N4OS




























97%




8.4




527.1













868




C28H32N4OS




























98%




7.6




473.2













869




C27H29FN4OS




























96%




7.6




477.2













870




C28H32N4OS




























94%




7.7




473.2













871




C28H31ClN4OS




























96%




8.3




507.2













872




C30H36N4O3S




























94%




7.2




533.2













873




C29H34N4OS




























91%




7.9




487.2













874




C25H28N4O2S




























95%




6.9




449.2













875




C25H32N4O2S




























38 + 8%




6.9 + 7.04




453.2













876




C26H35N5O2S




























94%




5.0




482.2













877




C27H37N5O2S




























93%




5.0




496.3













878




C27H39N5OS




























94%




5.2




482.3













879




C23H30N4O2S




























95%




6.5




427.2













880




C24H32N4O2S




























97%




6.7




441.2













881




C29H27ClN4OS




























78%




7.7




515.2













882




C29H28N4OS




























59%




7.2




481.2













883




C31H32N4OS




























63%




8.6




617.2













884




C31H30N4O2S




























61%




7.1




523.2













885




C32H34N4OS




























60%




7.9




523.3













886




C31H33N5OS




























28%




6.7




524.2













887




C29H27N5O3S




























53%




7.6




526.2













888




C29H27BrN4OS




























68%




7.8




559.1













889




C29H26F2N4OS




























62%




7.3




517.2













890




C29H27N7OS




























64%




7.6




522.2













891




C30H27N5OS




























66%




7.3




506.2













892




C30H28N4O3S




























62%




7.1




525.2













893




C29H26ClN5O3S




























55%




7.9




560.1













894




C33H36N4OS




























59%




8.1




537.3













895




C30H30N4OS




























67%




7.9




565.2













896




C31H32N4OS




























57%




7.7




509.2













897




C28H24ClN5O2S




























64%




6.2




530.1













898




C28H25N5O2S




























64%




5.6




496.2













899




C30H29N5O2S




























52%




7.1




632.2













900




C30H27N5O3S




























57%




5.5




538.2













901




C31H31N5O2S




























65%




6.4




538.2













902




C30H30N6O2S




























29%




5.0




539.2













903




C28H24N6O4S




























51%




6.0




541.2













904




C28H24BrN5O2S




























72%




6.3




574.0













905




C28H23F2N5O2S




























66%




5.7




532.2













906




C28H24N8O2S




























52%




6.1




537.2













907




C29H24N6O2S




























65%




5.7




521.1













908




C29H25N5O4S




























66%




5.5




540.1













909




C28H23ClN6O4S




























55%




6.4




575.1













910




C32H33N5O2S




























64%




6.6




552.2













911




C29H27N5O2S




























68%




6.5




580.1













912




C30H29N5O2S




























68%




6.1




524.2













913




C26H20ClN5O3S




























60%




7.0




518.1













914




C26H21N5O3S




























63%




6.6




484.2













915




C28H25N5O3S




























41%




7.8




620.1













916




C28H23N5O4S




























51%




6.4




526.1













917




C29H27N5O3S




























64%




7.3




526.2













918




C28H26N6O3S




























21%




6.2




527.2













919




C26H20N6O5S




























27%




6.8




529.1













920




C26H20BrN5O3S




























61%




7.2




562.0













921




C26H19F2N5O3S




























55%




6.6




520.1













922




C26H20N8O3S




























61%




7.0




525.1













923




C27H20N6O3S




























50%




6.6




509.1













924




C27H21N5O5S




























68%




6.5




528.1













925




C26H19ClN6O5S




























44%




7.2




563.1













926




C30H29N5O3S




























60%




7.5




540.2













927




C27H23N5O3S




























62%




7.3




568.1













928




C28H25N5O3S




























60%




7.0




512.2













929




C23H18ClN5OS2




























28%




6.4




480.1













930




C23H19N5OS2




























22%




5.8




446.1













931




C25H23N5OS2




























34%




7.3




582.1













932




C25H21N5O2S2




























25%




5.7




488.1













933




C26H25N5OS2




























21%




6.6




488.1













934




C25H24N6OS2




























13%




5.3




489.1













935




C23H18N6O3S2




























23%




6.2




491.1













936




C23H18BrN5OS2




























38%




6.5




524.0













937




C23H17F2N5OS2




























58%




5.8




482.1













938




C23H18N8OS2




























28%




6.3




487.1













939




C24H18N6OS2




























32%




5.9




471.1













940




C24H19N5O3S2




























23%




5.7




490.1













941




C23H17ClN6O3S2




























33%




6.7




525.0













942




C27H27N5OS2




























29%




6.8




502.2













943




C24H21N5OS2




























35%




6.7




530.1













944




C25H23N5OS2




























16%




6.3




474.1













945




C26H27ClN4OS




























61%




7.5




479.2













946




C26H28N4OS




























54%




7.0




445.2













947




C28H32N4OS




























61%




8.4




581.1













948




C28H30N4O2S




























49%




6.9




487.2













949




C29H34N4OS




























57%




7.7




487.2













950




C28H33N5OS




























16%




6.4




488.2













951




C26H27N5O3S




























44%




7.4




490.2













952




C26H27BrN4OS




























70%




7.6




523.1













953




C26H26F2N4OS




























61%




7.0




481.2













954




C26H27N7OS




























66%




7.4




486.2













955




C27H27N5OS




























68%




7.1




470.2













956




C27H28N4O3S




























63%




6.9




489.2













957




C26H26ClN5O3S




























66%




7.7




524.1













958




C30H36N4OS




























58%




7.9




501.3













959




C27H30N4OS




























64%




7.7




529.2













960




C28H32N4OS




























46%




7.5




473.2













961




C30H30N4O3




























57%




10.5




495.2













962




C30H27F3N4O2




























69%




11.6




533.2













963




C29H28N4O2




























69%




10.4




465.2













964




C29H27N5O4




























61%




11.0




510.2













965




C30H29ClN4O2




























74%




11.6




513.2













966




C32H32N4O4




























52%




11.0




537.2













967




C29H27BrN4O2




























76%




11.2




543.1













968




C29H27FN4O2




























60%




10.7




483.2













969




C29H26Cl2N4O2




























68%




11.9




533.1













970




C31H30N4O3




























71%




10.3




507.2













971




C30H30N4O2S




























72%




10.9




511.2













972




C30H27F3N4O3




























77%




11.6




549.2













973




C29H27BrN4O2




























66%




11.3




543.1













974




C32H34N4O2




























85%




11.5




507.3













975




C29H26F2N4O2




























72%




10.8




501.2













976




C32H34N4O5




























71%




10.3




555.2













977




C29H27N5O4




























72%




8.0




510.2













978




C29H24F3N5O3




























70%




9.3




548.2













979




C28H25N5O3




























79%




7.8




480.2













980




C28H24N6O5




























62%




8.6




525.2













981




C29H26ClN5O3




























71%




9.1




528.2













982




C31H29N5O5




























65%




8.6




552.2













983




C28H24BrN5O3




























82%




8.8




558.1













984




C28H24FN5O3




























73%




8.2




498.2













985




C28H23Cl2N5O3




























66%




9.5




548.1













986




C30H27N5O4




























81%




7.7




522.2













987




C29H27N5O3S




























79%




8.4




526.2













988




C29H24F3N5O4




























83%




9.3




564.2













989




C28H24BrN5O3




























69%




8.8




558.1













990




C31H31N5O3




























84%




9.2




522.3













991




C28H23F2N5O3




























86%




8.1




516.2













992




C31H31N5O6




























60%




7.7




570.2













993




C27H23N5O5




























76%




9.5




498.2













994




C27H20F3N5O4




























71%




10.7




536.1













995




C26H21N5O4




























85%




9.4




468.2













996




C26H20N6O6




























56%




10.0




513.2













997




C27H22ClN5O4




























77%




10.7




516.1













998




C29H25N5O6




























64%




10.2




540.2













999




C26H20BrN5O4




























83%




10.4




546.0













1000




C26H20FN5O4




























74%




9.8




486.2













1001




C26H19Cl2N5O4




























69%




11.0




536.1













1002




C28H23N5O5




























81%




9.3




510.2













1003




C27H23N5O4S




























79%




10.1




514.1













1004




C27H20F3N5O5




























74%




10.8




552.1













1005




C26H20BrN5O4




























66%




10.4




546.0













1006




C29H27N5O4




























84%




10.8




510.2













1007




C26H19F2N5O4




























76%




9.8




504.1













1008




C29H27N5O7




























74%




9.3




558.2













1009




C24H21N5O3S




























60%




8.2




460.1













1010




C24H18F3N5O2S




























65%




9.5




498.1













1011




C23H19N5O2S




























77%




8.0




430.1













1012




C23H18N6O4S




























60%




8.7




475.1













1013




C24H20ClN5O2S




























62%




9.4




478.1













1014




C26H23N5O4S




























63%




8.9




502.2













1015




C23H18BrN5O2S




























79%




9.1




508.0













1016




C23H18FN5O2S




























63%




8.4




448.1













1017




C23H17Cl2N5O2S




























54%




9.8




498.1













1018




C25H21N5O3S




























82%




8.0




472.1













1019




C24H21N5O2S2




























73%




8.8




476.1













1020




C24H18F3N5O3S




























70%




9.6




514.1













1021




C23H18BrN5O2S




























60%




9.2




508.0













1022




C26H25N5O2S




























74%




9.6




472.2













1023




C23H17F2N5O2S




























62%




8.3




466.1













1024




C26H25N5O5S




























64%




8.0




520.1













1025




C27H22F2N4O3




























76%




9.4




489.2













1026




C27H19F5N4O2




























77%




10.6




527.1













1027




C26H20F2N4O2




























87%




9.2




459.2













1028




C26H19F2N5O4




























79%




9.9




504.1













1029




C27H21ClF2N4O2




























74%




10.6




507.1













1030




C29H24F2N4O4




























59%




10.1




531.2













1031




C26H19BrF2N4O2




























82%




10.3




537.1













1032




C26H19F3N4O2




























79%




9.7




477.1













1033




C26H18Cl2F2N4O2




























69%




11.0




527.1













1034




C28H22F2N4O3




























82%




9.2




501.2













1035




C27H22F2N4O2S




























76%




9.9




505.1













1036




C27H19F5N4O3




























83%




10.7




543.1













1037




C26H19BrF2N4O2




























68%




10.4




537.1













1038




C29H26F2N4O2




























86%




10.7




501.2













1039




C26H18F4N4O2




























80%




9.6




495.1













1040




C29H26F2N4O5




























43%




9.2




549.2
















Analyses

















Ex. No.




Formula




R′3




R4




Purity




rt (min)




[M + H]+














































1041




C26 H33 N5 O S2




























56




3.69




496.3













1042




C29 H37 N5 O2 S




























74




3.78




520.3













1043




C30 H36 N6 O S




























76




3.77




529.3













1044




C31 H38 N6 O S




























73




3.85




543.3













1045




C30 H39 N5 O S




























63




4.19




518.3













1046




C30 H36 N6 O S




























71




4.01




529.3


















































1047




C27 H35 N5 O S2




























69




3.65




510.3













1048




C30 H39 N5 O2 S




























75




3.75




534.3













1049




C31 H42 N6 O S




























71




3.49




547.3













1050




C31 H38 N6 O S




























66




3.74




543.3













1051




C31 H38 N6 O S




























87




3.89




543.3


















































1052




C30 H36 N6 O S




























83.38




4.71




529.3













1053




C26 H33 N5 O S2




























72.31




4.41




496.3













1054




C29 H37 N5 O2 S




























71.47




4.5




520.3













1055




C30 H40 N6 O S




























62.38




3.86




533.3













1056




C25 H32 N6 O S2




























25.6




3.9




497.2













1057




C28 H33 F2 N5 O S




























63.2




4.5




526.3













1058




C31 H41 N5 O S




























69.01




5.17




532.4













1059




C28 H34 N6 O3 S




























73.01




4.58




535.3













1060




C28 H41 N5 O S




























44.6




4.9




496.4













1061




C29 H34 F3 N5 O2 S




























80.9




5.1




574.2













1062




C30 H39 N5 O S




























58.64




4.91




518.3













1063




C36 H42 N6 O S




























54.23




5.3




607.3













1064




C28 H34 Br N5 O S




























76.51




4.86




568.2













1065




C28 H33 Cl2 N5 O S




























74.91




5.03




558.2













1066




C29 H34 F3 N5 O S




























66.26




4.93




558.2













1067




C28 H34 N6 O3 S




























40




4.6




535.2













1068




C32 H37 N5 O S




























73.1




4.9




540.3













1069




C29 H34 N6 O5 S




























55.8




4.58




579.2













1070




C34 H39 N5 O S




























64.6




5.2




566.3













1071




C29 H34 N6 O S




























70.75




4.38




515.3













1072




C29 H37 N5 O S




























64.36




4.68




504.3













1073




C35 H41 N5 O2 S




























40.5




5




596.3













1074




C31 H38 N6 O S




























80.4




4




543.3


















































1075




C26H32N6O3S2




























45.2%




6.1




541.3













1076




C27H34N6O3S2




























35.3%




6.3




555.3













1077




C28H36N6O3S2




























39.9%




6.5




569.3













1078




C30H38N6O3S2




























14.9 + 22.82%




6.7 + 6.76




595.3













1079




C32H41N5O3S




























70.3%




7.5




576.4













1080




C33H43N5O3S




























71.9%




7.7




590.4













1081




C34H45N5O3S




























72.7%




7.9




604.4













1082




C36H47N5O3S




























34.6 + 34.7%




8.1 + 8.28




630.4













1083




C29H33F2N5O3S




























60.6%




6.9




570.3













1084




C30H35F2N5O3S




























62.7%




7.1




584.3













1085




C31H37F2N5O3S




























65.5%




7.3




598.3













1086




C33H39F2N5O3S




























33.92% + 32.4%




7.5 + 4.6




624.3













1087




C29H34BrN5O3S




























65.6%




7.3




612.2













1088




C30H36BrN5O3S




























68.6%




7.5




626.2













1089




C31H38BrN5O3S




























75.2%




7.7




640.3













1090




C33H40BrN5O3S




























37.14% + 37.1%




7.88 + 8.0




666.3













1091




C29H34BrN5O3S




























71.9%




7.3




612.2













1092




C30H36BrN5O3S




























76.2%




7.4




626.2













1093




C31H38BrN5O3S




























77.0%




7.6




640.3













1094




C33H40BrN5O3S




























39.4 + 39.64% m




7.8 + 8.0




666.3













1095




C29H33Cl2N5O3S




























72.1%




7.6




602.2













1096




C30H35Cl2N5O3S




























74.9%




7.7




616.3













1097




C31H37Cl2N5O3S




























76.4%




7.9




630.3













1098




C33H39Cl2N5O3S




























39.6% + 39.16%




8.1 + 8.4




656.3













1099




C30H34F3N5O3S




























64.3%




7.3




602.3













1100




C31H36F3N5O3S




























71.3%




7.5




616.3













1101




C32H38F3N5O3S




























71.6%




7.6




630.3













1102




C34H40F3N5O3S




























34.8 + 34.91%




8.0 + 7.8




656.4













1103




C29H34N6O5S




























63.2%




6.9




579.3













1104




C30H36N6O5S




























66.1%




7.1




593.3













1105




C31H38N6O5S




























66.1%




7.3




607.3













1106




C33H40N6O5S




























33.7% + 24.4%




7.5 + 7.6




633.4













1107




C33H37N5O3S




























84.0%




7.2




584.4













1108




C34H39N5O3S




























86.3%




7.4




598.4













1109




C35H41N5O3S




























86.2%




7.6




612.4













1110




C37H43N5O3S




























43.1% + 43.4%




7.9 + 8.12




638.4













1111




C36H41N5O4S




























58.2%




7.3




640.4













1112




C37H43N5O4S




























61.1%




7.5




654.4













1113




C38H45N5O4S




























67.6%




7.7




668.4













1114




C40H47N5O4S




























38.1% + 38.5%




7.9 + 8.1




694.4













1115




C21H24N6OS2




























74.0%




3.9




441.2













1116




C22H26N6OS2




























80.2%




4.0




455.3













1117




C23H28N6OS2




























47.3%




4.2




469.3













1118




C25H30N6OS2




























18.31% + 14%




4.2 + 4.3




495.3













1119




C27H33N5OS




























76.8%




5.1




476.4













1120




C28H35N5OS




























77.9%




5.3




490.4













1121




C29H37N5OS




























75.6%




5.4




504.4













1122




C31H39N5OS




























38.42% + 26.7% m




5.5 + 5.7




530.4













1123




C24H25F2N5OS




























68.1%




4.5




470.3













1124




C25H27F2N5OS




























66.9%




4.7




484.3













1125




C26H29F2N5OS




























70.0%




4.8




498.3













1126




C28H31F2N5OS




























25.0%




4.9




524.3













1127




C24H26BrN5OS




























72.7%




4.9




512.2













1128




C25H28BrN5OS




























78.5%




5.0




526.2













1129




C26H30BrN5OS




























80.2%




5.1




540.2













1130




C28H32BrN5OS




























39.21% + 27%




5.3 + 5.4




566.2













1131




C24H26BrN5OS




























77.9%




4.9




512.2













1132




C25H28BrN5OS




























81.4%




5.0




526.2













1133




C26H30BrN5OS




























78.25%*




5.1




540.2













1134




C28H32BrN5OS




























31.02% + 27.9




5.2 + 5.4




566.2













1135




C24H25Cl2N5OS




























79.9%




5.1




502.2













1136




C25H27Cl2N5OS




























81.2%




5.2




516.2













1137




C26H29Cl2N5OS




























80.1%




5.3




530.2













1138




C28H31Cl2N5OS




























33.63% + 28.8%




5.4 + 5.6




556.2













1139




C25H26F3N5OS




























73.7%




4.9




502.3













1140




C26H28F3N5OS




























80.8%




5.1




516.2













1141




C27H30F3N5OS




























76.86%*




5.2




530.3













1142




C29H32F3N5OS




























27.7% + 27.3




5.3 + 5.4




556.3













1143




C24H26N6O3S




























70.7%




4.6




479.3













1144




C25H28N6O3S




























72.3%




4.7




493.3













1145




C26H30N6O3S




























72.4%




4.8




507.3













1146




C28H32N6O3S




























27.5% + 26.5%




4.9 + 5.3




533.3













1147




C28H29N5OS




























88.2%




4.8




484.3













1148




C29H31N5OS




























89.1%




5.0




498.3













1149




C30H33N5OS




























89.9%




5.1




512.3













1150




C32H35N5OS




























46.67% + 31.0




5.3 + 5.5




538.3













1151




C31H33N5O2S




























46.0%




5.0




540.3













1152




C32H35N5O2S




























46.6%




5.1




554.2













1153




C33H37N5O2S




























54.2%




5.2




568.3













1154




C35H39N5O2S




























28 + 21%




5.3 + 5.5




594.3


















































1155




C29H34N6O5S




























82%




6.5




579.3













1156




C30H36N6O5S




























85%




6.7




593.3













1157




C31H38N6O5S




























84%




6.9




607.4













1158




C33H40N6O5S




























42 + 42%




7.1 + 7.28




633.4













1159




C30H34N6O7S




























78%




6.5




623.3













1160




C30H36N6O7S




























82%




6.7




637.3













1161




C32H38N6O7S




























80%




6.9




651.3













1162




C34H40N6O7S




























34 + 41%




7.1 + 7.2




677.4













1163




C35H39N5O3S




























83%




7.1




610.4













1164




C36H41N5O3S




























84%




7.3




624.4













1165




C37H43N5O3S




























85%




7.5




638.4













1166




C39H45N5O3S




























41 + 42%




7.7 + 7.9




664.4













1167




C33H37N5O3S




























91%




6.9




584.4













1168




C34H39N5O3S




























90%




7.1




598.4













1169




C35H41N5O3S




























89%




7.3




612.4













1170




C37H43N5O3S




























41 + 42%




7.5 + 7.7




638.4













1171




C30H34N6O3S




























85%




6.4




559.3













1172




C31H36N6O3S




























87%




6.5




573.3













1173




C32H38N6O3S




























81%




6.8




587.4













1174




C34H40N6O3S




























42 + 43%




6.9 + 7.1




613.4













1175




C37H43N5O5S




























86%




6.9




670.4













1176




C38H45N5O5S




























82%




7.1




684.5













1177




C39H47N5O5S




























86%




7.3




698.5













1178




C41H49N5O5S




























38.3 + 38.4%




7.5 + 7.62




724.4













1179




C31H39N5O3S




























86%




6.9




562.4













1180




C32H41N5O3S




























87%




7.1




576.4













1181




C33H43N5O3S




























86%




7.3




590.4













1182




C35H45N5O3S




























38 + 39%




7.5 + 7.64




616.4













1183




C37H42N6O3S




























85%




7.2




651.4













1184




C38H44N6O3S




























88%




7.3




665.4













1185




C39H46N6O3S




























88%




7.5




679.4













1186




C41H48N6O3S




























38.4 + 38.5%




7.8 + 7.98




705.4













1187




C36H39N5O3S




























86%




7.2




622.4













1188




C37H41N5O3S




























87%




7.4




636.4













1189




C38H43N5O3S




























82%




7.6




650.4













1190




C40H45N5O3S




























40.6 + 40.9%




7.8 + 8.01




676.4













1191




C31H36N6O3S




























85.41%*




6.6




573.3













1192




C32H38N6O3S




























89%




6.8




587.4













1193




C33H40N6O3S




























90%




7.0




601.4













1194




C35H42N6O3S




























43.1 + 44.5%




7.3 + 7.45




627.4













1195




C24H26N6O3S




























87%




4.3




479.3













1196




C25H28N6O3S




























92%




4.4




493.3













1197




C26H30N6O3S




























92%




4.6




507.3













1198




C28H32N6O3S




























35 + 33.9%




4.7 + 4.8




533.3













1199




C25H26N6O5S




























82%




4.3




523.2













1200




C26H28N6O5S




























86%




4.5




537.3













1201




C27H30N6O5S




























83%




4.6




551.3













1202




C29H32N6O5S




























35 + 33.9%




4.7 + 4.8




577.3













1203




C30H31N5OS




























88%




4.9




510.3













1204




C31H33N5OS




























90%




5.0




524.3













1205




C32H35N5OS




























89%




5.2




538.3













1206




C34H37N5OS




























43 + 31%




5.3 + 5.4




564.3













1207




C28H29N5OS




























92%




4.7




484.3













1208




C29H31N5OS




























93%




4.8




498.3













1209




C30H33N5OS




























92%




4.9




512.3













1210




C32H35N5OS




























43 + 30.1%




5.1




538.3













1211




C25H26N6OS




























87%




4.1




459.3













1212




C26H28N6OS




























86%




4.2




473.3













1213




C27H30N6OS




























82%




4.4




487.3













1214




C29H32N6OS




























40 + 36%




4.5 + 4.6




513.3













1215




C32H35N5O3S




























87%




4.8




570.3













1216




C33H37N5O3S




























84%




4.9




584.3













1217




C34H39N5O3S




























86%




5.0




598.3













1218




C36H41N5O3S




























32% + 29%




5.2 + 5.3




624.4













1219




C26H31N5OS




























90%




4.6




462.3













1220




C27H33N5OS




























92%




4.7




476.4













1221




C28H35N5OS




























91%




4.9




490.4













1222




C30H37N5OS




























42 + 29.9%




5.0 + 5.2




516.3













1223




C32H34N6OS




























80%




5.0




551.3













1224




C33H36N6OS




























90%




5.1




565.3













1225




C34H38N6OS




























85%




5.3




579.4













1226




C36H40N6OS




























37% + 27




5.45.6




605.4













1227




C31H31N5OS




























90%




5.0




522.3













1228




C32H33N5OS




























91%




5.1




536.3













1229




C33H35N5OS




























90%




5.2




550.3













1230




C35H37N5OS




























42% + 30.8




5.4 + 5.5




576.3













1231




C26H28N6OS




























68%




4.4




473.4













1232




C27H30N6OS




























56%




4.5




487.4













1233




C28H32N6OS




























40%




4.7




613.2













1234




C30H34N6OS




























40%




4.8




527.4














Pharmacological Properties of the Compounds of the Invention




The compounds of the present invention can and have been tested as regards their affinity for different sub-types of somatostatin receptors according to the procedures described below.




Study of the Affinity for the Sub-types of Human Somatostatin Receptors:




The affinity of a compound of the invention for sub-types of somatostatin receptors 1 to 5 (sst


1


, sst


2


, sst


3


, sst


4


and sst


5


, respectively) is determined by measurement of the inhibition of the bond of [


125


I-Tyr


11


]SRIF-14 to transfected CHO-K1 cells. The gene of the sst


1


receptor of human somatostatin has been cloned in the form of a genomic fragment. A segment PstI-XmnI of 1.5 Kb containing 100 bp of the non transcribed 5′ region, 1.17 Kb of the coding region in totality, and 230 bp of the non transcribed 3′ region is modified by the addition of the linker BglII. The resulting DNA fragment is subcloned in the BamHI site of a pCMV-81 in order to produce the expression plasmid in mammals (provided by Dr. Graeme Bell, Univ. Chicago). A cloned cell line expressing in a stable fashion the sst


1


receptor is obtained by transfection in CHO-K1 cells (ATCC) using the calcium phosphate co-precipitation method. The plasmid pRSV-neo (ATCC) is included as selection marker. Cloned cell lines were selected in an RPMI 1640 medium containing 0.5 mg/ml of G418 (Gibco), followed by circular cloning and multiplication in culture.




The gene of the sst


2


receptor of human somatostatin, isolated in the form of a genomic fragment of DNA of 1.7 Kb BamHI-HindIII and subcloned in a plasmid vector pGEM3Z (Promega), was provided by Dr. G. Bell (Univ. of Chicago). The expression vector of the mammalian cells is constructed by inserting the BamHI-HindII fragment of 1.7 Kb in endonuclease restriction sites compatible with the plasmid pCMV5. A cloned cell line is obtained by transfection in CHO-K1 cells using the calcium phosphate co-precipitation method. The plasmid pRSV-neo is included as selection marker.




The sst


3


receptor is isolated as a genomic fragment, and the complete coding sequence is contained in a BamHI/HindIII fragment of 2.4 Kb. The expression plasmid in mammals, pCMV-h3, is constructed by insertion of the NcoI-HindIII fragment of 2.0 Kb in the EcoRI site of the vector pCMV after modification of the terminations and addition of EcoRI linkers. A cloned cell line expressing in a stable fashion the sst


3


receptor is obtained by transfection in CHO-K1 cells (ATCC) by the calcium phosphate co-precipitation method. The plasmid pRSV-neo (ATCC) is included as selection marker. Cloned cell lines were selected in an RPMI 1640 medium containing 0.5 mg/ml of G418 (Gibco), followed by circular cloning and multiplication in culture.




The expression plasmid of the human sst


4


receptor, pCMV-HX, was provided by Dr. Graeme Bell (Univ. Chicago). This vector contains the genomic fragment coding for the human sst


4


receptor of 1.4 Kb NheI-NheI, 456 pb of the non transcribed 5′ region, and 200 pb of the non transcribed 3′ region, cloned in the XbaI/EcoRI sites of PCMV-HX. A cloned cell line expressing in a stable fashion the sst


4


receptor is obtained by transfection in CHO-K1 cells (ATCC) by the calcium phosphate co-precipitation method. The plasmid pRSV-neo (ATCC) is included as selection marker. The cloned cell lines were selected in an RPMI 1640 medium containing 0.5 mg/ml of G418 (Gibco), followed by circular cloning and multiplication in culture.




The gene corresponding to the human sst


5


receptor, obtained by the PCR method using a genomic clone as probe, was provided by Dr. Graeme Bell (Univ. Chicago). The resulting PCR fragment of 1.2 Kb contains 21 base pairs of the non transcribed 5′ region, the coding region in totality, and 55 pb of the non transcribed 3′ region. The clone is inserted in an EcoRI site of the plasmid pBSSK(+). The insert is recovered in the form of a HindIII-XbaI fragment of 1.2 Kb for subcloning in an expression vector in mammals, pCVM5. A cloned cell line expressing in a stable fashion the sst


5


receptor is obtained by transfection in CHO-K1 cells (ATCC) by the calcium phosphate co-precipitation method. The plasmid pRSV-neo (ATCC) is included as selection marker. The cloned cell lines were selected in an RPMI 1640 medium containing 0.5 mg/ml of G418 (Gibco), followed by circular cloning and multiplication in culture.




The CHO-K1 cells which express in a stable fashion the human sst receptors are cultured in an RPMI 1640 medium containing 10% of foetal calf serum and 0.4 mg/ml of geneticin. The cells are collected with 0.5 mM EDTA and centrifuged at 500 g for approximately 5 minutes at approximately 4° C. The pellet is resuspended in Tris 50 mM at pH 7.4 and centrifuged twice at 500 g for approximately 5 minutes at approximately 4° C. The cells are lysed by sonication and centrifuged at 39000 g for approximately 10 minutes at 4° C. The pellet is resuspended in the same buffer and centrifuged at 50000 g for approximately 10 minutes at approximately 4° C. and the membranes in the pellet obtained are stored at −80° C.




The competitive inhibition tests of the bond with [


125


I-Tyr


11


]SRIF-14 are carried out in duplicate using 96-well polypropylene plates. The cell membranes (10 μg protein/well) are incubated with [


125


I-Tyr


11


]SRIF-14 (0.05 nM) for approximately 60 min. at approximately 37° C. in a 50 mM HEPES buffer (pH 7.4) containing BSA 0.2%, MgCl


2


5 mM, Trasylol 200 KIU/ml, bacitricin 0.02 mg/ml, phenylmethylsulphonyl fluoride 0.02 mg/ml.




The bound [


125


I-Tyr


11


]SRIF-14 is separated from the free [


125


I-Tyr


11


]SRIF-14 by immediate filtration through GF/C glass fibre filter plates (Unifilter, Packard) pre-impregnated with 0.1% of polyethylenimine (P.E.I.), 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 bond is obtained by subtracting the non-specific bond (determined in the presence of 0.1 μM of SRIF-14) from the total bond. The data relative to the bond are analyzed by computer-aided non-linear regression analysis (MDL) and the values of the inhibition constants (Ki) are determined.




Determination of the agonist or antagonist character of a compound of the present invention is carried out using the test described below.




Functional Test: Inhibition of Production of Intracellular cAMP:




CHO-K1 cells expressing the sub-types of human somatostatin receptors (SRIF-14) are cultured in 24-well plates in an RPMI 1640 medium with 10% of foetal calf serum and 0.4 mg/ml of geneticin. The medium is changed the day preceding the experiment.




The cells at a rate of 10


5


cells/well are washed twice with 0.5 ml of new RPMI medium comprising 0.2% BSA completed by 0.5 mM of 3-isobutyl-1-methylxanthine (IBMX) and incubated for approximately 5 min at approximately 37° C.




The production of cyclic AMP is stimulated by the addition of 1 mM of forskolin (FSK) for 15-30 minutes at approximately 37° C.




The inhibitor effect of the somatostatin of an agonist compound is measured by the simultaneous addition of FSK (1 μM), SRIF-14 (10


−12


M to 10


−6


M) and of the compound to be tested (10


−10


M to 10


−5


M).




The antagonist effect of a compound is measured by the simultaneous addition of FSK (1 μM), SRIF-14 (1 to 10 nM) and of the compound to be tested (10


−10


M to 10


−5


M).




The reaction medium is eliminated and 200 ml of 0.1 N HCl are added. The quantity of cAMP is measured by a radioimmunological test (FlashPlate SMP001A kit, New England Nuclear).




Results:




The tests carried out according to the protocols described above have demonstrated that the compounds of general formula (I) defined in the present Application have a good affinity for at least one of the sub-types of somatostatin receptors, the inhibition constant K


i


being lower than micromolar for certain exemplified compounds, and in particular for the compounds shown in the Tables I and II below.












TABLE I







































R′3




R′4




K


i























(CH


2


)


3


NH


2


(CH


2


)


4


NH


2


(CH


2


)


5


NH


2


(CH


2


)


6


NH


2






<1 μM <1 μM <1 μM <1 μM

























(CH


2


)


3


NH


2


(CH


2


)


4


NH


2


(CH


2


)


5


NH


2


(CH


2


)


6


NH


2






<1 μM <1 μM <1 μM <1 μM






















TABLE II







































R′3




R′4




K


i























(CH


2


)


4


NH


2


(CH


2


)


5


NH


2


(CH


2


)


6


NH


2


(CH


2


)


6


NMe


2






<1 μM <1 μM <1 μM

























(CH


2


)


5


NH


2


(CH


2


)


6


NH


2


(CH


2


)


6


NMe


2






<1 μM <1 μM <1 μM

























(CH


2


)


5


NH


2


(CH


2


)


6


NH


2


(CH


2


)


6


NMe


2






<1 μM <1 μM <1 μM

























(CH


2


)


5


NH


2


(CH


2


)


6


NH


2


(CH


2


)


6


NMe


2






<1 μM <1 μM <1 μM

























(CH


2


)


5


NH


2


(CH


2


)


6


NH


2


(CH


2


)


6


NMe


2






<1 μM <1 μM <1 μM

























(CH


2


)


6


NMe


2






<1 μM













Claims
  • 1. A compound of the formula in racemic, enantiomeric form or all combinations of these forms,R1 is selected from the group consisting of (C1-C12)alkyl, (C0-C6)alkyl-C(O)—O—Z1, (C0-C6)alkyl-C(O)—NH—(CH2)p—Z2 and unsubstituted or substituted aryl, Z1 is selected from the group consisting of H, (C1-C6)alkyl and —(CH2)p-aryl; Z2 is selected from the group consisting of amino, (C1-C12)alkylamino, (C3-C8)cycloalkylamino, N,N-di-(C1-C12)alkylamino, NH—C—(O)—O—(CH2)p-phenyl, NH—C(O)—O—(CH2)p—(C1-C6)alkyl, an unsubstituted or substituted carbocyclic or heterocyclic aryl and unsubstituted or substituted heterocyclic non-aromatic; R2 is selected from the group consisting of H, (C1-C12)alkyl and aryl optionally substituted; R3 is H or (CH2)p—Z3; Z3 is selected from the group consisting of (C1-C12)alkyl, (C1-C12)alkenyl, (C3-C8)cycloalkyl, Y1—(CH2)p-phenyl-(X1)n, —S—(C1-C12)alkyl, S—(C1-C12)alkyl-S—S—(C1-C12) alkyl, and unsubstituted or substituted carbocyclic or heterocyclic aryl; Y1 is O, S, NH or is absent; R4 is (CH2)p—Z4; Z4 is selected from the group consisting of amino, (C1-C12)alkyl, (C3-C8)cycloalkyl, (C1-C12)alkylamino, N,N-di-(C1-C12)alkylamino, amino(C3-C6)cycloalkyl, amino(C1-C6)alkyl(C3-C8)cycloalkyl(C1-C6)alkyl, carbocyclic or heterocyclic aminoaryl, (C1-C12)alkoxy, (C1-C12)alkenyl, N—C(O)O(C1-C6)alkyl, unsubstituted or substituted carbocyclic or heterocyclic aryl, unsubstituted or substituted heterocyclic non-aromatic radical, bis-arylalkyl, di-arylalkyl,  and N(R6)(R7), R6 and R7 taken together with the nitrogen atom which they carry form together a heterocycle of 5 to 7 ring members; R5 is selected from the group consisting of H, —(CH2)p—C(O)—(CH2)p—Z5, —(CH2)p—Z5, —(CH2)p—OZ5 or —(C0-C6)alkyl-C(O)—NH—(CH2)p—Z5, Z5 is unsubstituted or substituted member selected from the group consisting of —(C1-C12)alkyl, benzo[b]thiophene, phenyl, naphthyl, benzo[b]furannyl, thiophene, isoxazolyl, indolyl,  it being understood that a substituted radical is substituted by at least one member of the group consisting of Cl, F, Br, I, CF3, NO2, OH, NH2, CN, N3, —OCF3, (C1-C12)alkyl, (C1-C12)alkoxy, —(CH2)p-phenyl-(XI)q, —NH—CO—(C1-C6)alkyl, —NH—C(O)O—(C1-C6)alkyl, —S—(C1-C6)alkyl, —S-phenyl-(X1)q, —O—(CH2)p-phenyl-(X1)q, —(CH2)p—C(O)—O—(C1-C6)alkyl, —(CH2)p—C(O)—(C1-C6)alkyl, —O—(CH2)p—NH2, —O—(CH2)p—NH—(C1-C6)alkyl, —O—(CH2)p—N-di((C1-C6)alkyl) and ((C0-C12)alkyl-(X1)q; X1, each time that it occurs, is independently selected from the group consisting of H, Cl, F, Br, I, CF3, NO2, OH, NH2, CN, N3, —OCF3, (C1-C12)alkyl, (C1-C12)alkoxy, —S—(C1-C6)alkyl, —(CH2)p-amino, —(CH2)p—NH—(C1-C6)alkyl, —(CH2)p—N-di-((C1-C6)alkyl), —(CH2)p-phenyl and —(CH2)p—NH—(C3-C6)-cycloalkyl; p each time that it occurs is independently an integer from 0 to 6; q each time that it occurs is independently an integer from 1 to 5; X is O or S; n is 1; and m is 0 or 1 and its pharmaceutical salts.
  • 2. A compound of claim 1, whereinR1 is unsubstituted or substituted aryl; R2 is H or alkyl; R3 is selected from the group consisting of R4 is selected from the group consisting of R5 is H or alkyl.
  • 3. A compound of claim 1, whereinR1 is unsubstituted phenyl or phenyl substituted with a member of the group consisting of halogen or (C1-C12)alkyl, (C1-C12)alkoxy and nitro; R2 and R5 are H or alkyl; R3 is H or (CH2)p—Z3; Z3 is selected from the group consisting of (C1-C12)alkyl, (C3-C8)cycloalkyl, Y1—(CH2)p-phenyl-(X1)n, unsubstituted or substituted carbocyclic or heterocyclic aryl, unsubstituted or substituted non-aromatic heterocyclic, bis-arylalkyl, di-arylalkyl, Y1 is O, S, NY or is absent; R4 is (CH2)p—Z4; Z4 is selected from the group consisting of amino, (C1-C12)alkyl, (C3-C8)cycloalkyl, (C1-C12)alkylamino, N,N-di-(C1-C12)alkylamino, amino(C3-C6)cycloalkyl, amino(C1-C6)alkyl(C3-C8)cycloalkyl(C1-C6)alkyl, carbocyclic or heterocyclic aminoaryl, an unsubstituted or substituted carbocyclic and heterocyclic aryl, unsubstituted or substituted non-aromatic heterocyclic, bis-arylalkyl, di-arylalkyl,  it being understood that the substituents or substituted phenyl is at least one member of the group consisting of Cl, F, Br, I, CF3, NO2, OH, NH2, CN, N3, —OCF3, (C1-C12)alkoxy, —(CH2)p-phenyl-(X1)q, —NH—CO—(C1-C6)alkyl, —NH—C(O)o-(C1-C6)alkyl, —S—(C1-C6)alkyl, —S-phenyl-(X1)q, —O—(CH2)p-phenyl-(X1)q, —(CH2)p—C(O)—O—(C1-C6)alkyl, —(CH2)p—C(O)—(C1-C6)alkyl, —O—(CH2)p—NH2, —O0(CH2)p—NH—(C1-C6)alkyl, —O—(CH2)p—N-di-((C1-C6)alkyl and (C0-C12)alkyl-(X1)q; X1, each time that it occurs, is selected from the group consisting of H, Cl, F, Br, I, CF3, NO2, OH, NH2, CN, N3, —OCF3, (C1-C12)alkyl, (C1-C12)alkoxy, —S—(C1-C6)alkyl, —(CH2)p-amino, —(CH2)p—NH—(C1-C6)alkyl, —(CH2)p—N-di-((C1-C6)alkyl), —(CH2)p-phenyl and —(CH2)p—NH—(C3-C6)cycloalkyl; p each time that it occurs is independently an integer from 0 to 6; and 1 each time that it occurs is independently an integer from 1 to 5.
  • 4. A compound of claim 3, whereinR1 is phenyl or phenyl substituted by a member selected from the group consisting of halogen, (C1-C12)alkyl, (C1-C12)alkoxy and nitro; R2 and R5 are H or alkyl; R3 is (CH2)p—Z3, Z3 is selected from the group consisting of (C3-C8)cycloalkyl, unsubstituted or substituted phenyl, naphthyl, furannyl, thiophene, indolyl, pyrrolyl and benzothiophene; R4 is (CH2)p—Z4; Z4 is selected from the group consisting of amino, (C1-C12)alkylamino, N,N-di-(C1-C12)alkylamino and amino (C1-C6)alkyl(C3-C6)cycloalkyl-(C1-C6)alkyl; X is S; p each time that it occurs is independently an integer from 0 to 6; m is 0, 1 or 2; and n is 1.
  • 5. A compound of claim 4 of the formula:
  • 6. A compound of claim 1, wherein Z3, is selected from the group consisting of unsubstituted or substituted non-aromatic heterocyclic, bis-arylalkyl, diarylalkyl and
  • 7. A compound of claim 1 wherein carbocyclic aryl and heterocyclic are selected from the group consisting of phenyl, naphthyl, pyridinyl, furannyl, pyrrolyl, thiophenyl, thiazolyl, indanyl, indolyl, imidazolyl, benzofurannyl, benzothiophenyl and phthalimidyl and carbocyclic aralkyl and heterocyclic aralkyl are selected from the group consisting of benzyl, phenylethyl, phenylpropyl, phenylbutyl, indolylalkyl and phthalimidoalkyl.
  • 8. A process for the preparation of a compound of claim 1 in which n is 1, comprising reacting in an aprotic solvent a compound of the formula in which m, R1, R2, R3 and R5 have the same meaning as in claim 1, and the O-GP radical is a parting protective group derived from an alcohol and with an isocyanate of the formulaR4N═C═X  (III) in which R4 and X have the same meaning as claim 1, in the presence of a tertiary base for the duration of approximately 1 to 48 hours and at a temperature between 20 and 70° C.
  • 9. The process of claim 8 wherein the protective parting group is an alcohol derived from the group consisting of benzyl alcohol, methanol and tert.-butanol.
  • 10. A composition for inhibiting tumors comprising a tumor inhibitorily effective amount of a compound of claim 1 and a pharmaceutical carrier.
  • 11. A method of inhibiting tumors in warm-blooded animals comprising administering to warm-blooded animals in need thereof an amount of a compound of claim 1 sufficient to inhibit tumors.
Priority Claims (1)
Number Date Country Kind
99 09886 Jul 1999 FR
Parent Case Info

This application is a 371 of PCT/FR00/02164 filed Jul. 28, 2000.

PCT Information
Filing Document Filing Date Country Kind
PCT/FR00/02164 WO 00
Publishing Document Publishing Date Country Kind
WO01/09090 2/8/2001 WO A
Foreign Referenced Citations (7)
Number Date Country
9743278 Nov 1997 WO
9813045 Apr 1998 WO
9845285 Oct 1998 WO
9858646 Dec 1998 WO
9964401 Dec 1999 WO
9964420 Dec 1999 WO
9965942 Dec 1999 WO