# Patent

## Title
Derivatives of 2-arylimino-2,3-dihydrothiazoles, their preparation processes and their therapeutic use

## Abstract

The present invention is drawn to compounds of the formula




in racemic and enantiomeric form or all combinations of these forms wherein the various substituents are as defined in the application which compounds have a good affinity for certain subtypes of somatostatin receptors and have useful pharmacological properties.

## Background
This application is a Continuation-in-Part of U.S. patent application Ser. No. 10/031,429, now U.S. Pat. No. 6,727,269, filed Jan. 15, 2002 which is a 371 of PCT/FR02/00093, filed on Jan. 11, 2002.


A subject of the present Application is new derivatives of 2-arylimino-2,3-dihydrothiazoles and their preparation processes. These products have a good affinity with certain sub-types of somatostatin receptors and therefore have useful pharmacological properties. The invention also relates to these same products as medicaments, the pharmaceutical compositions containing them 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 lead 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, insensibility 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 ADS, 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 inflamatory 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 Zollin-gr-Ellison's syndrome, GRFoma as well as acute bleeding of oesophageal veins, gastroesophageal reflux, gastroduodenal reflux, pancreatitis, enterocutaneous and pancreatic fistulae but also diarrhoea, refractory diarrhoea of acquired immune deficiency 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 veins 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, leukemia, meningioma, cancerous cachexia, inhibition of H pylori, psoriasis, as well as 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 an amino(C7–C7)alkyl, aminoalkylarylalkyl, aminoalkylcycloalkylalkyl, (C1–C15)alkyl, (C3–C7)cycloalkyl, (C1–C6)alkyl(C3–C6)cycloalkyl, (C3–C6)cycloalkylalkyl, cyclohexenylalkyl, alkenyl, alkynyl, carbocyclic aryl radical containing at least two rings of which at least one is not aromatic, carbocyclic or heterocyclic aralkyl radical optionally substituted on the aryl group, bis-arylalkyl, alkoxyalkyl, furannylalkyl or tetrahydrofurannylalkyl, dialkylaminoalkyl, N-acetoamidoalkyl, cyanoalkyl, alkylthioalkyl, arylhydroxyalkyl, aralkoxyalkyl, morpholinoalkyl, pyrrolidinoalkyl, piperidinoalkyl, N-alkylpyrrolidinoalkyl, N-alkylpiperazinylalkyl or oxypyrrolidinoalkyl radical,

or R1 represents one of the radicals represented below:





or also R1 represents a —C(R11)(R12)-CO-R10 radical;

R2 represents an optionally substituted carbocyclic or heterocyclic aryl radical,

or R2 represents one of the radicals represented below:





R3 represents an alkyl, adamantyl, optionally substituted carbocyclic or heterocyclic aryl radical, carbocyclic or heterocyclic aralkyl optionally substituted on the aryl group,

or R3 represents one of the radicals represented below:





or also R3 represents a —CO-R5 radical;

R4 represents H, alkyl, carbocyclic or heterocyclic aralkyl optionally situated on the aryl radical;

or then the





radical represents a radical of general formula





in which i represents an integer from 1 to 3;

R5 represents the N(R6)(R7) radical;

R6 represents a (C1–C16)alkyl, cycloalkylalkyl, hydroxyalkyl, aryloxyalkyl radical, carbocyclic or heterocyclic aralkyl radical optionally substituted on the aryl group, aralkoxyalkykl, arylhydroxyalkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, alkynyl, cyclohexenyl, cyclohexenylalkyl, alkylthiohydroxyalkyl, cyanoalkyl, N-acetamidoalkyl radical, bis-arylalkyl radical optionally substituted on the aryl groups, di-arylalkyl radical optionally substituted on the aryl groups, morpholinoalkyl, pyrrolidinoalkyl, piperidinoalkyl, N-alkylpyrrolidinoalkyl, oxopyrrolidinoalkyl, tetrahydrofurannylalkyl, N-benzylpyrrolidinoalkyl, N-alkylpiperazinylalkyl, N-benzylpiperazinylalkyl, N-benzylpiperidinylalkyl or N-alkoxycarbonylpiperidinyl radical, or R6 represents a (C3–C8)cycloalkyl radical optionally substituted by a radical chosen from the group comprising the hydroxy radical and an alkyl radical,

or R6 represents one of the radicals represented below:





R7 represents H or an alkyl, hydroxyalkyl, mono- or di-aminoalkyl or aralkyl radical; or the —N(R6)(R7) radical represents the radical of the following general formula:





in which:

R8 represents H, alkyl, hydroxyalkyl, optionally substituted carbocyclic or heterocyclic aryl, aralkyl optionally substituted on the aryl group, alkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, bis-arylalkyl, piperidinyl, pyrrolidinyl, hydroxy, arylalkenyl,

or R8 represents —X—(CH2)b-R9;

R9 represents H or an alkyl, alkoxy, aryloxy, optionally substituted carbocyclic or heterocyclic aryl, morpholinyl, pyrrolidinyl, alkylamino or N,N′-(alkyl)(aryl)amino radical;

X represents CO, CO—NH or SO2;

Y represents CH or N;

a represents 1 or 2;

b represents an integer from 0 to 6;

or the N(R6)(R7) radical represents a radical of general formula





in which:

Z represents CH, O or S;

c represents an integer from 0 to 4;

or the N(R6)(R7) radical represents one of the radicals represented below:








R10 represents an amino(C2–C7)alkylamino, ((aminoalkyl)aryl)alkylamino, (aminoalkyl)cycloalkyl)alkylamino, piperazinyl, homopiperazinyl radical, or R10 represents the radical represented below:





R11 represents H;

R12 represents H or an alkyl, (C3–C7)cycloalkyl, optionally substituted carbocyclic or heterocyclic aralkyl, propargyl, allyl, hydroxyalkyl, alkylthioalkyl, arylalkylalkoxyalkyl, arylalkylthioalkoxyalkyl radical;

or the compounds of the invention are salts of the compounds of general formula (I).

When the compounds of general formula (I) contain the R1, R2, R3, R4, R6, R8, R9 or R12 radicals including a substituted aryl radical or an aralkyl substituted on the aryl group, said aryl or aralkyl radicals are preferably such that:
For R1, when the aryl group is substituted, it can be from 1 to 5 times (other than the bond which, links it with the remainder of the molecule) by radicals chosen independently from the group comprising a halogen atom and an alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, aryl, aralkoxy or SO2NH2 radical. Two substituents can, if appropriate, be linked together and form a ring, for example by representing together a methylenedioxy or propylene radical.
For R2, when the aryl group is substituted, it can be from 1 to 5 times (other than the bond which links it with the remainder of the molecule). The aryl radical can be substituted by radicals chosen independently from the group comprising a halogen atom and an alkyl, alkoxy, alkylthio, haloalkyl, alkenyl, haloalkoxy, nitro, cyano, azido, SO2N, mono- or di-alkylamino, aminoalkyl, aralkoxy, or aryl radical. Two substituents can, if appropriate, be linked together and form a ring, for example by representing together a methylenedioxy, ethylenedioxy or propylene radical.
For R3, when the aryl group or groups (originating from an aryl or aralkyl radical) are substituted, they can be, according to the case, from 1 to 5 times (other than the bond which links them with the remainder of the molecule). The carbocyclic aryl or aralkyl radicals can be substituted from 1 to 5 times on the aryl ring by radicals chosen independently from the group comprising a halogen atom and an alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, nitro, cyano, azido, mono- or di-alkylamino, pyrrolidinyl, morpholinyl, aralkoxy or aryl radical. Two substituents can, if appropriate, be linked together and form a ring, for example by representing together an alkylenedioxy radical containing 1 to 3 carbon atoms. The heterocyclic aryl or aralkyl radicals of R3 can be substituted 1 to 2 times on the ring by radicals chosen independently from the group comprising a halogen atom and an alkyl radical.
For R4, when the aryl group is substituted, it can be from 1 to 5 times (other than the bond which links it with the remainder of the molecule). The aryl radical can be substituted by the radicals chosen independently from the group comprising a halogen atom and an alkyl or alkoxy radical.
For R6, when the aryl group or groups are substituted, they can be from 1 to 5 times (other than the bond which links them with the remainder of the molecule). The optional substituents on the aryl groups are chosen independently from the group comprising a halogen atom and an alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, aryl, aryloxy or SO2NH2 radical.
For R8, when the aryl croup or groups are substituted, they can be from 1 to 5 times (other than the bond which links them with the remainder of the molecule). The optional substituents on the aryl groups are chosen independently from the group comprising a halogen atom and an alkyl, haloalkyl, alkoxy, hydroxy, cyano, nitro or alkylthio radical.
For R9, when the carbocyclic or heterocyclic aryl radical is substituted, it can be from 1 to 5 times (other than the bond which links it with the remainder of the molecule). The optional substituents on the aryl group are chosen independently from the group comprising a halogen atom and an alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, carbocyclic aryl, hydroxy, cyano or nitro radical.
For R12, when the carbocyclic or heterocyclic aryl radical is substituted, it can be from 1 to 5 times (other than the bond which links it with the remainder of the molecule). The optional substituents on the aryl group are chosen independently from the group comprising a halogen atom and an alkyl alkoxy, carbocyclic aryl, aralkoxy, hydroxy, cyano or nitro radical.
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 referred to as heterocyclic when at least one of the rings which comprise it contains a heteroatom (O, N or S). 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 alkylthio, alkoxy, haloalkyl, haloalkoxy, aminoalkyl, alkenyl, alkynyl and aralkyl radicals, is meant respectively the alkylthio, alkoxy, haloalkyl, haloalkoxy, aminoalkyl, alkenyl, alkynyl and aralkyl radicals the alkyl radical of which has the meaning indicated previously.
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, thiophenyl, indanyl, indolyl, imidazolyl, benzofurannyl, benzothiophehyl, phthalimidyl radicals. By carbocyclic or heterocyclic aralkyl, is meant in particular the benzyl, phenylethyl, phenylpropyl, phenylbutyl, indolylalkyl, phthalimidoalkyl, naphthylalkyl, furannylalkyl, thiophenylalkyl, benzothiophenylalkyl, pyridinylalkyl and imidazolylalkyl radicals.
When an arrow emanates from a chemical structure, said arrow indicates the point of attachment. For exemple:




represents the benzyl radical.

Preferably, the compounds of general formula (I) are such that:
R1 represents —C(R11)(R12)-CO-R10 or one of the following radicals:

























R2 represents one of the following radicals:








R3 represents CO-R5 or one of the following radicals:








R4 represents H, alkyl, carbocyclic or heterocyclic aralkyl optionally substituted on the aryl radical;

or then the





radical represents a radical of general formula





in which i represents an integer from 1 to 3;

R5 represents one of the following radicals:






































R10 represents one of the following radicals:









R11 represents H;

R12 represents one of the following radicals:








it being understood that for R4, when the aryl group is substituted, it can be from 1 to 5 times (other than the bond which links it with the remainder of the molecule) by radicals chosen independently from the group comprising a halogen atom and an alkyl or alkoxy radical.

The compounds of the invention are preferably such that R4 represents H.
More preferentially, the compounds according to the invention correspond to general formula (II)




in which:

    
    
        either R1 represents one of the radicals below
    
    






    
    
        R2 represents one of the radicals below
    
    






    
    
        R3 represents one of the radicals below
    
    






    
    
        and R4 represents H;
        or also R1 represents one of the radicals below
    
    






    
    
        R2 represents one of the radicals below
    
    






    
    
        R3 represents COR5,
        R4 represents H,
        and R5 represents one of the radicals below
    
    






    
    
        or finally R1 represents the —C(R11)(R12)-CO-R10 radical in which
        R10 represents the radical
    
    






    
    
        R11 represents H
        and R12 represents the radical
    
    






    
    
        R2 represents the radical
    
    






    
    
        R3 represents the radical
    
    






    
    
        and R4 represents H.
    
    


The invention also relates to a compound characterized in that it corresponds: to formula




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R2 represents





and R3 represents





to formula




R10 represents




R2 represents





and R3 represents





R10 represents




R2 represents





and R3 represents





R10 represents




R2 represents





and R3 represents





R10 represents




R2 represents





and R3 represents





R10 represents




R2 represents





and R3 represents





R10 represents




R2 represents





and R3 represents





R10 represents




R2 represents





and R3 represents





R10 represents




R2 represents





and R3 represents





or finally

R10 represents




R2 represents





and R3 represents





to formula




in which:

R10 represents




R2 represents





and R3 represents





R10 represents




R2 represents





and R3 represents





R10 represents




R2 represents





and R3 represents





R10 represents




R2 represents





and R3 represents





R10 represents




R2 represents





and R3 represents





R10 represents




R2 represents





and R3 represents





R10 represents




R2 represents





and R3 represents





R10 represents




R2 represents





and R3 represents





R10 represents




R2 represents





and R3 represents





R10 represents




R2 represents





and R3 represents





R10 represents




R2 represents





and R3 represents





R10 represents




R2 represents





and R3 represents





R10 represents




R2 represents





and R3 represents





R10 represents




R2 represents





and R3 represents





or finally

R10 represents




R2 represents





and R3 represents





or finally to formula




in which:

R1 represents




R2 represents





and R5 represents





R1 represents




R2 represents





R5 represents





R1 represents




R2 represents





and R5 represents





R1 represents




R2 represents





and R5 represents





R1 represents




R2 represents





and R5 represents





R1 represents




R2 represents





and R5 represents





R1 represents




R2 represents





and R5 represents





R1 represents




R2 represents





and R5 represents





R1 represents




R2 represents





and R5 represents





or finally

R1 represents




R2 represents





and R5 represents





or a salt of one of these compounds.

Even more preferentially, the invention relates to a compound characterized in that it corresponds to the formula




in which:

R1 represents




R2 represents





and R5 represents





R1 represents




R2 represents





and R5 represents





R1 represents




R2 represents





and R5 represents





R1 represents




R2 represents





and R5 represents





R1 represents




R2 represents





and R5 represents





R1 represents




R2 represents





and R5 represents





R1 represents




R2 represents





and R5 represents





R1 represents




R2 represents





and R5 represents





R1 represents




R2 represents





and R5 represents





or finally

R1 represents




R2 represents





and R5 represents





or a salt of one of these compounds.

In other words, the compounds described in Examples 1642 to 1654, 1656 to 1680, 2468 to 2502, 2525 to 2550, 2556 to 2582, 2605 to 2611, 2614, 2623 to 2630, 2632 to 2646, 2670 to 2678, 2680 to 2694, 2702 to 2710, 2712 to 2726 and 2827 to 2836 or a salt of one of these compounds will be preferred. The compounds of Examples 2827 to 2836 or their salts will be even more particularly preferred.
Moreover, the invention relates to preparation processes on a solid support for the compounds of general formula (I) described previously (also applicable to the corresponding compounds of general formula (II)).
According to the invention, the compounds of general formula (I)a




in which:

R1 represents a —CH2-A1-NH2 radical, in which A1 represents a —(CH2)n—, —(CH2)n—O—(CH2)p—, aralkylene or cycloalkylalkylene radical, n and p represent integers from 1 to 6;

R2 and R4 represent the same radicals as in general formula (I);

and R3 represents the same radicals as in general formula (I), with the exception of the —CO-R5 radicals;

can be prepared for example according to a process characterized in that it comprises the following successive stages:

1) treatment, in an aprotic solvent such as dichloromethane or dimethylformamide, of a p-nitrophenylcarbonate Wang resin with a large excess of R1-NH2 symmetrical diamine;

2) treatment, in an aprotic solvent such as dichloromethane or dimethylformamide, of the resin isolated after stage 1) with an aromatic isothiocyanate of general formula R2-N═C═S in which the R2 radical has the same meaning as in general formula (I)a;

3) treatment, in an aprotic solvent such as dioxane or dimethylformamide, of the resin obtained in Stage 2) with the compound of general formula (III)





in which the R3 and R4 radicals have the same meaning as in general formula (I)a;

4) cleavage of the resin under acid conditions;

5) treatment under basic conditions of the product obtained after Stage 4).

The preparation of the p-nitrophenylcarbonate Wang resin is described further on in the part entitled “PREPARATION OF THE COMPOUNDS OF THE INVENTION”.
Preferably, for the above process, in order to have the large excess in Stage 1), of the order of 10 to 20 equivalents of diamine R1-NH2 will be used Stage 1) is preferably carried out at ambient temperature. Stage 3) is carried out at a temperature greater than ambient temperature, for example at a temperature comprised between 60 and 90° C., using of the order of 2 to 5 equivalents of the compound of general formula (III). In Stage 4), the acid conditions can for example be created by using a dichloromethane/trifluroacetic acid mixture at 50%, said acid conditions being preferably maintained for a duration of the order of 1 to 2 hours. In Stage 5), the basic conditions can for example be created by using a saturated solution of sodium hydrogen carbonate or by elution on a basic alumina cartridge.
According to a variant of the invention, the compounds of general formula (I)b




in which:

R1 represents the same radicals as in general formula (1), with the exception of the —CH2-A1-NH2 type radicals, in which A1 represents a —(CH2)n—, —(CH2)n—O—(CH2)p—, aralkylene or cycloalkylalkylene radical, n and p representing integers from 1 to 6, and also with the exception of the —C(R11)(R12)-CO-R10 radicals;

R2 represents an aminoalkylphenyl radical;

R3 represents the same radicals as in general formula (I), with the exception of the —CO-R5 radicals;

can be prepared for example according to a process characterized in that it comprises the following successive stages:

1) treatment, in an aprotic solvent such as dichloromethane or dimethylformamide, of a Wang resin p-nitrophenylcarbonate with an excess of aminoalkylaniline of general formula R2-NH2 in which the R2 radical has the same meaning as in general formula (I)b;

2) treatment, in an aprotic solvent such as dichloromethane or dimethylformamide, of the resin isolated after Stage 1) with an isothiocyanate of general formula R1-N═C═S in which the R1 radical has the same meaning as in general formula (I)b;

3) treatment, in an aprotic solvent such as dioxane or dimethylformamide, of the resin obtained in Stage 2) with the compound of general formula (III)





in which the R3 and R4 radicals have the same meaning as in general formula (I)b;

4) cleavage of the resin under acid conditions;

5) treatment under basic conditions of the product obtained after Stage 4).

Preferably, for the above process, in order to have the excess in Stage 1), of the order of 5 to 10 equivalents of aminoalkylaniline will be used. Stage 1) is preferably carried out at ambient temperature. Stage 3) is carried out at a temperature greater than ambient temperature, for example at a temperature comprised between 60 and 90° C., using of the order of 2 to 5 equivalents of the compound of general formula (III). In Stage 4), the acid conditions can for example be created by using a dichloromethane/trifluoroacetic acid mixture at 50%, said acid conditions being preferably maintained for a duration of the order of 1 to 2 hours. In Stage 5), the basic conditions can for example be created by using a saturated solution of sodium hydrogen carbonate or by elution on a basic alumina cartridge.
According to another variant of the invention, the compounds of general formula (I)c




in which:

R1 represents a —CH2-A1-NH2 radical, in which A1 represents a —(CH2)n—, —(CH2)n—O—(CH2)p—, aralkylene or cycloalkylalkylene radical, n and p representing integers from 1 to 6;

R2 represents the same radicals as in general formula (I);

R3 represents a —CO-R5 radical;

and R4 and R5 represent the same radicals as in general formula (I);

can be prepared according to a process characterized in that it comprises the following successive stages:

1) treatment, in an aprotic solvent such as dichloromethane or dimethylformamide, of a Wang resin p-nitrophenylcarbonate with a large excess of symmetrical diamine of general formula R1-NH2 in which the R1 radical has the same meaning as in general formula (I)c;

2) treatment, in an aprotic solvent such as dichloromethane or dimethylformamide, of the resin isolated after Stage 1) with an aromatic isothiocyanate of general formula R2-N═C═S in which the R2 radical has the same meaning as in general formula (I)c;

3) treatment, in an aprotic solvent such as dioxane or dimethylformamide, of the resin obtained in Stage 2) with the acid of general formula (IV)





in which the R4 radical has the same meaning as in general formula (I)c;

4) peptide coupling;

5) cleavage of the resin under acid conditions;

6) treatment under basic conditions of the product obtained after Stage 5).

Preferably, for the above process, in order to have the large excess in Stage 1) of the order of 10 to 20 equivalents of symmetrical diamine will be used. Stage 1) is preferably carried out at ambient temperature. Stage 3) is carried out at, a temperature greater than ambient temperature, for example at a temperature comprised between 60 and 90° C., using of the order of 2 to 5 equivalents of the acid of general formula (IV). The peptide coupling of Stage 4) is carried out for example in DMF with coupling agents such as for example dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), a DIC/N-hydroxybenzotriazole (HOBt) mixture, benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (PyBOP), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) or 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) and aminated compounds. Preferably, the coupling agents are used in proportions of 4 to 5 equivalents, as with the aminated compounds, and the reaction will take place at a temperature of the order of ambient temperature for a duration of the order of 1 to 24 hours. In Stage 5), the acid conditions can for example be created by using a dichloromethane/trifluoroacetic acid mixture at 50%, said acid conditions being preferably maintained for a duration of the order of 1 to 2 hours. In Stage 6), the basic conditions can for example be created by using a saturated solution of sodium hydrogen carbonate or by elution on a basic alumina cartridge.
According to yet another variant, the compounds of general formula (I)d




in which:

R1 represents the same radicals as in general formula (I), with the exception of the —CH2-A1-NH2 type radicals, in which A1 represents a —(CH2)n—, —(CH2)n—O—(CH2)p—,

aralkylene or cycloalkylalkylene radical, n and p represent integers from 1 to 6, and also with the exception of the —C(R11)(R12)-CO-R10 radicals;

R2 represents an aminoalkylphenyl radical;

R3 represents a —CO-R5 radical;

and R4 and R5 represent the same radicals as in general formula (I);

can be prepared according to a process characterized in that it comprises the following successive stages:

1) treatment, in an aprotic solvent such as dichloromethane or dimethylformamide, of a Wang resin p-nitrophenylcarbonate with an excess of aminoalkylaniline of general formula R2-NH2 in which the R2 radical has the same meaning as in general formula (I)d;

2) treatment, in an aprotic solvent such as dichloromethane or dimethylformamide, of the resin isolated after Stage 1) with an isothiocyanate of general formula R1-N═C═S in which the R1 radical has the same meaning as in general formula (I)d;

3) treatment, in an aprotic solvent such as dioxane or dimethylformamide, of the resin obtained in Stage 2) with the acid of general formula (IV)





in which the R4 radical has the same meaning as in general formula (I)d;

4) peptide coupling;

5) cleavage of the resin under acid conditions;

6) treatment under basic conditions of the product obtained after Stage 5).

Preferably, for the above process, in order to have the excess in Stage 1), of the order of 5 to 10 equivalents of aminoalkylaniline will be used. Stage 1) is preferably carried out at ambient temperature. Stage 3) is carried out at a temperature greater than ambient temperature, for example at a temperature comprised between 60 and 90° C., using of the order of 2 to 5 equivalents of the acid of general formula (IV). The peptide coupling of Stage 4) is carried out for example in DMF with coupling agents such as for example dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), a DIC/N-hydroxybenzotriazole (HOBt) mixture, benzotriazolyloxytris(dim ethylamino) phosphonium hexafluorophosphate (PyBOP), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) or 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) and aminated compounds. Preferably, the coupling agents are used in proportions of 4 to 5 equivalents, as with the aminated compounds, and the reaction will take place at a temperature of the order of ambient temperature for a duration of the order of 1 to 24 hours. In Stage 5), the acid conditions can for example be created by using a dichloromethane/trifluoroacetic acid mixture at 50%, said acid conditions being preferably maintained for a duration of the order of 1 to 2 hours. In Stage 6), the basic conditions can for example be created by using a saturated solution of sodium hydrogen carbonate or by elution on a basic alumina cartridge.
According to another variant the compounds of general formula (I)e




in which:

R1 represents the same radicals as in general formula (I), with the exception of the —CH2-A1-NH2 type radicals, in which A1 represents a —(CH2)n—, —(CH2)n—O—(CH2)p—, aralkylene or cycloalkylalkylene radical, n and p representing integers from 1 to 6, and also with the exception of the —C(R11)(R12)CO-R10 radicals;

R2 represents the same radicals as in general formula (I);

R3 represents a —CO-R5 radical;

R4 represents H;

R5 represents an —NH—CH2-A1-NH2 radical, in which A1 represents a linear or branched alkylene radical containing 1 to 6 carbon atoms, —(CH2)n—O—(CH2)p—,

aralkylene or cycloalkylalkylene, n and p representing integers from 1 to 6, or also R5 represents the N(R6)(R7) radical corresponding to the following general formula:





in which:

R8 represents H;

Y represents N;

a represents 1 or 2;

can be prepared by a process characterized in that it comprises the following successive stages:

1) treatment, in an aprotic solvent such as dichloromethane or dimethylformamide, of a Wang resin p-nitrophenylcarbonate with a large excess of symmetrical diamine of general formula R5-H;

2) peptide coupling with the acid of general formula (IV) on the resin obtained in Stage 1)





in which the R4 radical has the same meaning as in general formula (I)e;

3) reaction of the primary amine of general formula R1-NH2 with the isothiocyanate of general formula R2-NCS in a solvent such as dimethylformamide or dioxane, R1 and R2 having the same meanings as in general formula (I)e;

4) addition of the thiourea obtained in Stage 3) to the resin obtained in Stage 2) and heating the mixture;

5) cleavage of the resin under acid conditions;

6) treatment under basic conditions of the product obtained after Stage 5).

Preferably, for the above process, in order to have the large excess in Stage 1), of the order of 10 to 20 equivalents of diamine R5-H will be used. Stage 1) is preferably carried out at ambient temperature. The peptide coupling of Stage 2) is carried out in DMF with a coupling agent such as for example the DIC/N-hydroxybenzotriazole (HOBt) mixture. Preferably, the reaction of Stage 3) is carried out in a solvent such as dimethylformamide or dioxane. During the addition of Stage 4), 2 to 5 equivalents of thiourea will preferably be used per equivalent of resin; preferably also, heating will be carried out at a temperature greater than ambient temperature, for example at a temperature from 40 to 100° C. (in particular at a temperature of approximately 80° C.) and for a duration of 2 to 24 hours. In Stage 5), the acid conditions can for example be created by using a dichloromethane/trifluoroacetic acid mixture at 50%, said acid conditions being preferably maintained for a duration of the order of 1 to 2 hours. In Stage 6), the basic conditions can for example be created by using a saturated solution of sodium hydrogen carbonate or by elution on a basic alumina cartridge.
According to yet another variant, the compounds of general formula (I)f




in which:

R1 represents a —C(R11)(R12)-CO-R10 radical;

R2, R3 and R4 represent the same radicals as in general formula (I);

R10 represents an amino(C2–C7)alkylamino, ((aminoalkyl)aryl)alkylamino, ((aminoalkyl)cycloalkyl)alkylamino, piperazinyl, homopiperazinyl radical,

or R10 represents the radical represented below:





R11 represents H;

R12 represents H or an alkyl, (C3–C7)cycloalkyl, optionally substituted carbocyclic or heterocyclic aralkyl, propargyl, allyl, hydroxyalkyl, alkylthioalkyl, arylalkyl alkoxyalkyl, arylalkylthioalkoxyalkyl radical;

can be prepared by a process characterized in that it comprises the following successive stages:

1) treatment, in an aprotic solvent such as dichloromethane or dimethylformamide, of a Wang resin p-nitrophenylcarbonate with a large excess of symmetrical diamine of general formula R10-H in which R10 has the same meaning as in general formula (I)f;

2) peptide coupling of the resin obtained in Stage 1) with an amino acid of general formula HOOC—C(R11)(R12)-NH-Fmoc in which R11 and R12 have the same meaning as in general formula (I)f;

3) cleavage of the Fmoc group from the resin obtained in Stage 2);

4) reaction of the resin obtained in Stage 3) with an isothiocyanate of general formula R2-NCS in which R2 has the same meaning as in general formula (I)f;

5) cleavage of the resin under acid conditions;

6) treatment under basic conditions of the product obtained after Stage 5).

Preferably, for the above process, in order to have the large excess in Stage 1), of the order of 10 to 20 equivalents of diamine R10-H will be used. Stage 1) is preferably carried out at ambient temperature. The peptide coupling of Stage 2) is carried out for example in DMF with coupling agents such as for example dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), a DIC/N-hydroxybenzotriazole (HOBt) mixture, benzotriazolyloxytris(dimethylamino) phosphonium hexafluorophosphate (PyBOP), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) or 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU). Preferably, the reaction of Stage 2) is carried out at ambient temperature and for a duration of 1 to 24 hours. The deprotection of Stage 3) can be carried out, for example, by a mixture of DMF containing 20% piperidine. Stage 4) will preferably be carried out in a solvent such as dimethylformamide or dichloromethane, the isothiocyanate preferably being added in a proportion of 5 to 10 equivalents per equivalent of the resin obtained in Stage 3). In Stage 5), the acid conditions can for example be created by using a dichloromethane/trifluoroacetic acid mixture at 50% said acid conditions being preferably maintained for a duration of the order of 1 to 2 hours. In Stage 6), the basic conditions can for example be created by using a saturated solution of sodium hydrogen carbonate or by elution on a basic alumina cartridge.
A subject of the invention is also, as medicaments, the compounds of general formulae (I) and (II) described previously or their pharmaceutically acceptable salts. It also relates to pharmaceutical compositions containing said compounds or their pharmaceutically acceptable salts, and their use for the preparation of a medicament intended to treat pathological states or diseases in which one (or more) of the somatostatin receptors are involved.
In particular, the compounds of general formulae (I) and (II) described previously or their pharmaceutically acceptable salts can be used for the preparation of a medicament intended to treat 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 phenomenon, angiopathy, angioplasty, hyperthyroidism, gigantism, endocrinic gastroenteropancreatic tumours including carcinoid syndrome, VIPoma, insulinoma, nesidioblastoma, hyperinsulinemia, glucagonoma, gastrinoma and Zollinsger-Ellison's syndrome, GRFoma as well as acute bleeding of the esophageal veins, ulcers, gastroesophageal reflux, gastroduodenal reflux, pancreatitis, enterocutaneous and pancreatic fistulae but also diarrhoea, refractory diarrhoea's of acquired immunodeficiency syndrome, chronic secretary diarrhoea, diarrhoea associated with irritable bowel syndrome, diarrhoea's induced by chemotherapy, disorders linked with gastrin releasing peptide, secondary pathologies with intestinal grafts, portal hypertension as well as haemorrhages of the veins 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 such as, for example, 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, leukemia, meningioma, cancerous cachexia, inhibition of H pylori, psoriasis, chronic rejection of allografts as well as Alzheimer's disease and finally osteoporisis.
Preferably, the compounds of general formulae (I) and (II) 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 tumors 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, tartrate, 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 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 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 glycols, as well as their mixtures, in varying proportions, in water.
The administration of a medicament according to the invention can be carried out 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 and 10 g according to the type of active compound used.
These compounds can be prepared according to the methods described below.
Preparation of the Compounds of the Invention
I) Preparation of α-bromoketones
First Method
This method is inspired by the protocols described in the following publications: Macholan, L.; Skursky, L. Chem. Listy 1955, 49, 1385–1388; Bestman, H. J.; Seng, F. Chem. Ber. 1963, 96, 465–469; Jones, R. G.; Kornfeld, E. C.; McLaughlin, K. C. J. Am. Chem. Soc. 1950, 72, 4526–4529; Nimgirawath, S.; Ritchie, E.; Taylor, W. C. Aust. J. Chem. 1973, 26, 183–193).




A carboxylic acid is firstly converted to an acid by using oxalyl or thionyl chloride, or by activating it in the form of an anhydride using an alkyl chloroformate (for example isobutyl chloroformate, cf. Krantz, A.; Copp, L. J. Biochemistry 1991, 30, 4678–4687; or ethyl chloroformate, cf. Podlech, J.; Seebach, D. Liebigs Ann. 1995, 1217–1228) in the presence of a base (triethylamine or N-methylmorpholine).
The activated carboxyl group is then converted to diazoketone using diazomethane in an ethereal solution or a commercial solution of trimethylsilyldiazomethane (Aoyama, T.; Shiori, T. Chem. Pharm. Bull. 1981, 29, 3249–3255) in an aprotic solvent such as diethyl ether, tetrahydrofuran (THF) or acetonitrile.
The bromination is then carried out using a bromination agent such as hydrobromic acid in acetic acid, aqueous hydrobromic acid in diethyl ether or dichloromethane.
Preparation 1
2-(4-bromo-3-oxobutyl)-1H-isoindole-1,3 (2H)-dione
(C12H10BrNO3, MM=296.12)




Oxalyl chloride (5.8 ml; 66.7 mmol) is added to Pht-β-Ala-OH (9.96 g; 44.5 mmol) dissolved in dichloromethane (120 ml) and 3 drops of dimethylformamide (DMF). The mixture is agitated for 3 hours at ambient temperature. After elimination of the solvent, the white solid is taken up in a 1:1 mixture of anhydrous tetrahydrofuran and acetonitrile (200 ml) then 49 ml of a 2M solution of (trimethylsilyl) diazomethane in hexane (97.9 mmol) is added dropwise at 0° C. The solvents are eliminated after agitation overnight at 0° C. The pale yellow solid is then dissolved in dichloromethane (60 ml) and 12 ml of aqueous hydrobromic acid (48%) is added dropwise at 0° C. The mixture is agitated until the temperature reaches 15° C. and 50 ml of a saturated solution of sodium bicarbonate is added. The organic phase is washed with salt water then dried over sodium sulphate. Crystallization from diethyl ether allows a white solid to be obtained (11.39 g; yield=86%).
NMR 1H (DMSO D6, 100 MHz, δ): 7.83 (s, 4H); 4.36 (s, 2H, CH2Br); 3.8 (t, 2H, J=7.1 Hz, NCH2); 2.98 (t, 2H, J=6.9 Hz, CH2CO).
Preparations 2–11
The following compounds were prepared in a similar fashion to the procedure described in Preparation 1:
















Prep.
R3
Yield (%)







2*




78


 


3*




60


 


4*




10


 


5*




69


 


6*




41


 


7 




67


 


8 




51


 


9 




38


 


10 




22


 


11 




67





*Compounds already described in the literature.






Second Method

The starting product is an arylmethylketone or a heteroarylmethylketone.




The starting arylmethylketone or heteroarylmethylketone is converted to the corresponding α-bromoketone by using different brominating agents:
CuBr2 (King, L. C.; Ostrum, G. K. J. Org. Chem. 1964, 29, 3459–3461) heated in ethyl acetate or dioxane;
N-bromosuccinimide in CCl4 or aqueous acetonitrile (Morton, H. E.; Leanna, M. R. Tetrahedron Lett. 1993, 34, 4481–4484);
bromine in glacial acetic acid or sulphuric acid;
phenyltrimethylammonium tribromide (Sanchez, J. P.; Parcell, R. P. J. Heterocyclic Chem, 1988, 25, 469–474) at 20–80° C. in an aprotic solvent such as THF or tetrabutylammonium tribromide (Kajigaeshi, S.; Kakinami, T.; Okamoto, T.; Fujisaki, S. Bull Chem. Soc. Jpn. 1987, 60, 1159–1160) in a dichloromethane/methanol mixture at ambient temperature;
brominating agent on a polymer support such as perbromide on an Amberlyst A-26 resin, poly(perbromide of vinylpyridinium hydrobromide) (Frechet, J. M. J.; Farrall, M. J. J. Macromol. Sci. Chem. 1977, 507–514) in a protic solvent such as methanol at approximately 20–35° C. for approximately 2–10 hours.
Preparation 12
1-(1-benzofuran-2-yl)-2-bromo-1-ethanone
(C10H7BrO2, MM=239.06)




A polymer of perbromide of pyridine hydrobromide (8.75 g; 17.5 mmol; 1.4 equivalent) is added to a solution of (benzofuran-2-yl)methylketone (2 g; 12.5 mmol) in methanol (40 ml). The resulting mixture is agitated at ambient temperature for 7 hours and the reaction is stopped by filtration. The methanol is eliminated under reduced pressure and an additional addition of diethyl ether allows crystallization of the expected product (3.6 g; yield=60%).
NMR 1H (DMSO D6, 100 MHz, δ): 8.09 (s, 1H); 7.98 (d, 1H, J=6.6 Hz); 7.75 (d, 1H, J=8.4 Hz); 7.58 (t, 1H, J=8.4 Hz); 7.4 (t, 1H, J=7 Hz); 4.83 (s, 2H, CH2Br).
Preparations 8–12
The following compounds were prepared in a similar fashion to the procedure described in Preparation 12:



















Duration



Prep.
R3
of reaction (hrs)
Yield (%)


















13*




8
78


 


14*




2
62


 


15*




10
56


 


16*




2
53


 


17*




3
95


 


18 




8
27





*Compound already described in the literature.






II) Synthesis of 2-arylimino-2,3-dihydrothiazoles via synthesis on solid phase
Preparation of Wang Resin p-nitrophenylcarbonate




This resin was prepared from Wang resin, acquired from Bachem or Novabiochem with a load greater than 0.89 mmol/g, by a well described general procedure (cf. Bunin, B. A. The Combinatorial Index, Academic Press, 1998, p. 62–63; Dressman, B. A.; Spangle, L. A.; Kaldor, S. W. Tetrahedron Lett. 1996, 37, 937–940; Hauske, J. R.; Dorff, P. Tetrahedron Lett. 1995, 36, 1589–1592; Cao, J.; Cuny, G. D.; Hauske, J. R. Molecular Diversity 1998, 3, 173–179): N-methylmorpholine or pyridine as base and 4-nitrophenylchloroformate are successively added to a Wang resin pre-swollen in dichloromethane (DCM) or tetrahydrofuran (THE) at ambient temperature. The mixture is agitated overnight. The resin is then washed successively with THF, diethyl ether and DCM then dried overnight under reduced pressure at 50° C.
Method A
Preparation of Monoprotected Symmetrical Diamines




General procedure: as already described in the literature (Dixit, D. M.; Leznoff, C. C. J. C. S. Chem. Comm. 1977, 798–799; Dixit, D. M.; Leznoff, C. C. Israel J. Chem. 1978, 17, 248–252; Kaljuste K.; Unden, A. Tetrahedron Lett. 1995, 36, 9211–9214; Munson, M. C.; Cook, A. W.; Josey, J. A.; Rao, C. Tetrahedron Lett. 1998, 39, 7223–7226), a Wang resin p-nitrophenylcarbonate is treated with a large excess of symmetrical diamine (10–20 equivalents), in an aprotic solvent such as DCM or DMF, in order to produce a monoprotected diamine resin after agitation overnight.
Preparation of Thiourea Resins




General procedure: aromatic and heteroaromatic isothiocyanates (5–10 equivalents) are added (Smith, J.; Liras, J. L.; Schneider, S. E.; Anslyn, E. V. J. Org. Chem. 1996, 61, 8811–8818) to monoprotected symmetrical diamines in a solvent such as DCM or DMF agitated overnight at ambient temperature. Washed successively with DMF and DCM, the thiourea resin is isolated then dried overnight under reduced pressure at 50° C.
Preparation 19
(phenylaminothioyl)ethyl Wang resin carbamate




Phenylisothiocyanate (1 ml; 8.5 mmol; 5 eq.) is added to an ethylene diamine Wang resin N-carbamate (2 g; 1.72 mmol; 0.86 mmol/g) swollen in DCM (50 ml). After agitation overnight at ambient temperature, the resin is washed successively with DMF (5×20 ml) and DCM (5×20 ml). The success of the coupling is monitored using the Kaiser ninhydrin test (Kaiser, E.; Colescott, R. L.; Bossinger, C. D.; Cook, P. I. Anal. Biochem. 1970, 34, 595–598). A pale yellow resin (1.79 g) is obtained with a load of 0.648 mmol/g calculated from the elemental analysis of sulphur.
Synthesis of 2-arylimino-2,3-dihydrothiazoles




General procedure: regioselective cyclization stage (Korohoda, M. J.; Bojarska, A. B. Polish J. Chem. 1984, 58, 447–453; Ragab, F. A.; Hussein, M. M.; Hanna, M. M.; Hassan, G. S.; Kenawy, S. A. Egypt. J. Pharm. Sci. 1993, 34, 387–400; Hassan, H. Y.; El-Koussi, N. A.; Farghaly, Z. S. Chem. Pharm. Bull. 1998, 46, 863–866) takes place in aprotic solvents such as dioxane or DMF at 80° C. for 2–3 hours between the thiourea resin and the α-bromoketone (2–5 equivalents). The resin is then washed successively with DMF, methanol and DCM then dried under reduced pressure. The 2-arylimino-2,3-dihydrothiazole resin is cleaved under acid conditions (DCM/trifluoroacetic acid at 50%) for 1–2 hours then rinsed with DCM. The solvent is evaporated off and the free base is isolated after treatment under basic conditions (saturated solution of sodium hydrogen carbonate), extraction with DCM or elution with methanol in a basic alumina cartridge (500 mg, Interchim).


EXAMPLE 1
N-[3-(2-aminoethyl)-4-(4-chlorophenyl)-1,3-thiazol-2(3H)-ylidene]aniline
(C17H16ClN3S, MM=29.86)




2-bromo-4′-chloroacetophenone (30.2 mg; 129 μmol; 2 eq.) dissolved in DMF (1 ml) is added to a thiourea resin prepared above (100 mg; 64.8 μmol; load of 0.648 mmol/g). The mixture is agitated for 2 hours at 80° C. The resin is then successively washed with DMF (3×2 ml), methanol (3×2 ml) and DCM (3×2 ml). The release stage, carried out in 1 ml of a mixture of DCM/trifluoroacetic acid at 50%, produces an oil after one hour 30 minutes of agitation which is eluted with methanol in a basic alumina cartridge (500 mg, Interchim). The free base is isolated in a quantitative fashion (21.3 mg) in the form of a yellow oil having a purity measured by UV spectrophotometry of 98% at 220 nm.
NMR 1H (DMSO D6, 100 MHz) δ: 7.55 (s, 5H); 7.3 (d, 2H, J=7.1 Hz); 6.99 (d, 2H, J=7.1 Hz); 6.21 (s, 1H, H azole); 3.74 (t, 2H, J=6.2 Hz, NCH2); 3.32 (broad s, 2H, NH2); 2.72 (t, 2H, J=6.2 Hz, NCH2). SM/LC: m/z=330 (M+H)+.
A series of 2-arylimino-2,3-dihydrothiazoles was synthesized according to method A using our robotic system (ACT MOS 496):
R1 groups:




R2 groups:














R4 represents H, alkyl, carbocyclic or heterocyclic aralkyl optionally situated on the aryl radical;

or then the





radical represents a radical of general formula





in which i represents an integer from 1 to 3;

it being understood that for R4, when the aryl group is substituted, it can be 1 to 5 times (other than the bond which links it to the remainder of the molecule) by radicals chosen independently from the group composed of a halogen atom and an alkyl or alkoxy radical.

Method B

Preparation of Wang Resin Carbamates from aminoalkylanilines




General procedure: as already described (Hulme, C.; Peng, J.; Morton, G.; Salvino, J. M.; Herpin, T.; Labaudiniere, R. Tetrahedron Lett. 1998, 39, 7227–7230), a p-nitrophenylcarbonate Wang resin is treated with an excess of aminoalkylaniline (5–10 eq.) in DCM or DMF and agitated at ambient temperature overnight. The resin is washed successively with DMF, methanol and DCM then dried overnight under reduced pressure at 50° C.
Preparation 20
4-aminophenylethyl Wang Resin Carbamate




A solution of 2-(4-aminophenyl)ethylamine (2.48 g; 17.3 mmol; 5 eq.) in 30 ml of anhydrous DMF is added to a Wang resin p-nitrophenylcarbonate (4.05 g; 3.47 mmol; load of 0.857 mmol/g) pre-swollen in 50 ml of anhydrous DMF. The mixture is agitated at ambient temperature overnight and filtered. The resin is washed successively with DMF (10×30 ml), methanol (5×30 ml) and DCM (5×30 ml). 3.7 g of yellow resin (load of 0.8 mmol/g calculated from the elemental analysis of the nitrogen), giving a positive Kaiser ninhydrin test, is isolated after drying overnight under reduced pressure at 50° C.
Preparation of Thiourea Resins with aliphatic isothiocyanates




General procedure: aliphatic isothiocyanates (5–10 equivalents) are added to an aminoalkylaniline resin in a solvent such as DCM or DMF and agitation is carried out overnight at ambient temperature. After washing Successively with DMF and DCM, the thiourea resin is isolated and dried overnight under reduced pressure at 50° C.
Preparation 21
4-{([(phenylethylamino)carbothioyi]amino}-phenylethyl Wang resin carbamate




10 ml of anhydrous DMF and phenylethylisothiocyanate (624 μl, 4 mmol, 10 eq.) are added under an argon atmosphere to the resin described previously (0.5 g; 0.4 mmol; load of 0.8 mmol/g). The reaction medium is agitated overnight at ambient temperature and produces a negative Kaiser ninhydrin test. The resin is then washed successively with DMF (5×20 ml) and DCM (5×20 ml). Drying under reduced pressure at 50° C. produces 488 mg of resin with a load of 0.629 mmol/g calculated from elemental analysis of the sulphur.
Synthesis of 2-arylimino-2,3-dihydrothiazoles




General procedure: the cyclization stage takes place in aprotic solvents such as dioxane or DMF at 80° C. for 2 hours between the thiourea resin and the α-bromoketone (2–5 equivalents). The resin is then washed successively with DMF, methanol and DCM then dried under reduced pressure. The iminothiazole resin is cleaved by treatment under acid conditions (DCM/trifluoroacetic acid at 50%) for 1–2 hours then rinsed with DCM. The solvent is evaporated off and the free base isolated after extraction under basic conditions (saturated solution of sodium hydrogen carbonate), extraction with DCM or elution with methanol in a basic alumina cartridge (500 mg, Interchim).
EXAMPLE 2
4-(2-aminoethyl)-N-[4-(4-chlorophenyl)-3-phenethyl-1,3-thiazol-2(3H)-ylidene]aniline
(C25H24ClN3S, MM=434.01)




100 mg (62.9 μmol, load of 0.629 mmol/g) of thiourea resin and 2-bromo-4′-chloroacetophenone (30 mg; 125.8 μmol; 2 eq.) are dissolved in 1 ml of DMF and heated to 80° C. for 2 hours. The resin is then washed successively with DMF (5×1 ml), methanol (5×1 ml) and DCM (5×1 ml). The resin is agitated in 1 ml of a DCM/trifluoroacetic acid mixture at 50% for one hour and 30 minutes at ambient temperature. The resin is rinsed with DCM (5×1 ml) and the filtrate evaporated under reduced pressure. The residue, dissolved in methanol, is eluted in a basic alumina cartridge (500 mg, Interchim) in order to quantitatively produce (27.3 mg) the expected product in the form of a solid (UV purity: 97% at 220 nm).
NMR 1H (DMSO D6, 100 MHz) δ: 7.9 (broad s, 2H, NH2); 7.53 (d, 2H, J=8.5 Hz); 7.32–7.15 (m, 7H); 7.08–6.9 (m, 4H); 6.37 (s, 1H, H azole); 4.07 (m, 2H; NCH2); 3.03 (m, 2H, NCH2); 2.88 (m, 4H). MS/LC: m/z=435 (M+H)+.
A series of 2-arylimino-2,3-dihydrothiazoles was synthesized according to method B with our robotic system (ACT MOS 496):
R1 groups










Method C

Synthesis of 2-arylimino-1,3-thiazole-4(3H)-carboxamides




General procedure: a regioselective cyclization stage using α-bromopyruvic acid (2–5 eq.) is carried out starting from the thiourea resin prepared in the method A in aprotic solvents such as dioxane or DMF at 80° C. for 2–3 hours. The resin is then washed successively with DMF, methanol and DCM then dried under reduced pressure. The peptide coupling (Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D. Tetrahedron Lett. 989, 30, 1927–1930) takes place in DMF at ambient temperature for 1–24 hours with different standard coupling agents (4–5 eq.) such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), a DIC/N-hydroxybenzotriazole (HOBt) mixture, benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (PyBOP), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) or 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) and aminated compounds (4–5 eq.). The 2-arylimino-1,3-thiazole-4 (3H)-carboxamide resin is cleaved by treatment under acid conditions (DCM/trifluoroacetic acid at 50%) for 1–2 hours then rinsed with DCM. The solvent is evaporated off and the free base is isolated after treatment under basic conditions (saturated solution of sodium hydrogen carbonate), extraction is carried out with DCM or elution with methanol in a basic alumina cartridge (500 mg, Interchim).
EXAMPLE 3
3-(4-aminobutyl)-N-benzhydryl-2-[(4-bromophenyl)imino]-1,3-thiazole-4(3H)-carboxamide
(C27H27BrN4OS, MM=535.51)




50 mg (27.5 μmol, load of 0.55 mmol/g) of carboxylic acid resin is activated for 15 minutes with 14.8 mg (0.11 mmol, 4 eq.) of N-hydroxybenzotriazole and 35.3 mg (0.11 mmol, 4 eq.) of TBTU in 800 μl of anhydrous DMF. 20.7 mg (0.11 mmol, 4 eq.) of aminodiphenylmethane dissolved in 200 μl of anhydrous DMF is then added and the resin is filtered after agitation overnight at ambient temperature. A sequential washing with DMF (5×1 ml), methanol (5×1 ml) and DCM (5×1 ml) produces a resin which is treated for one hour and 30 minutes under acid conditions (DCM/trifluoroacetic acid at 50%). The resin is rinsed with DCM (5×1 ml) and the filtrate evaporated under reduced pressure. The residue, taken up in methanol, is eluted in a basic alumina cartridge (500 mg, Interchim) in order to produce a pale yellow solid (8.2 mg; yield of 55.7%; UV purity of 94% at 220 nm).
NMR 1H (DMSO D6, 100 MHz, δ): 9.6 (d; 1H; J=8.6 Hz; NH); 7.49 (d; 2H; J=8.6 Hz); 7.35 (s; 10H); 6.92 (s; 1H; H azole); 6.91 (d; 2H; J=8.5 Hz); 6.27 (d; 1H; J=8.5 Hz; NHCH); 4.02 (m; 2H; NCH2); 3.45 (broad m; 2H+2H; NH2 and NCH2); 1.55–1.24 (broad m; 4H). MS/LC: m/z=535 (M+H).
A series of 2-arylimino-1,3-thiazole-4(3H)-carboxamides was synthesized according to method C using our robotic system (ACT MOS 496):
R1 and R2 groups already described in method A;
R3=—CO-R5;
R4=H;
R5 groups


































Method D

Synthesis of 2-arylimino-1,3-thiazole-4(3H)-carboxamides




General procedure: a regioselective cyclization stage using α-bromopyruvic acid (2–5 eq.) is carried out starting from the thiourea resin prepared in method B in aprotic solvents such as dioxane or DMF at 80° C. for 2–3 hours. The resin is then successively washed with DMF, methanol and DCM then dried under reduced pressure. The peptide coupling (Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D. Tetrahedron Lett. 1989, 30, 1927–1930) takes place in DMF at ambient temperature for 1–24 hours with different standard coupling agents (4–5 eq.) such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), a DIC/N-hydroxybenzotriazole (HOBt) mixture, benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (PyBOP), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) or 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) and aminated compounds (4–5 eq.). The 2-arylimino-1,3-thiazole-4(3H)-carboxamide resin is cleaved by treatment under acid conditions (DCM/trifluoroacetic acid at 50%) for 1–2 hours then rinsed with DCM. The solvent is evaporated off and the free base is isolated after treatment under basic conditions (saturated solution of sodium hydrogen carbonate) followed by an extraction with DCM or elution with methanol in a basic alumina cartridge (500 mg, Interchim).
EXAMPLE 4
(2Z)-2-{[4-(2-aminoethyl)phenyl]inlino}-N-(4-chlorobenzyl)-3-(2-phenylethyl)-2,3-dihydro-1,3-thiazole-4-carboxamide
(C27H27ClN4OS, MM=491.05)




Phenylethylisothiocyanate (310 mg; 1.9 mmol; 10 eq.) in 3 ml of dimethylformamide is added to 200 mg (190 μmol, load of 0.946 mmol/g) of aminated resin (see Preparation 20). Agitation overnight at ambient temperature produces a negative Kaiser ninhydrin test. The resin is then successively washed with DMF (5×3 ml) and DCM (5×3 ml) then dried under vacuum for one hour before adding bromopyruvic acid (63.4 mg; 380 μmol; 2 eq.) diluted beforehand in 3 ml of dimethylformamide. The mixture is agitated for 2.5 hours at 80° C. The resin is filtered and washed with DMF (5×3 ml), methanol (3×3 ml) then DCM (5×3 ml). The carboxylic acid resin is preactivated for 1 hour with 244 mg (0.76 mmol; 4 eq.) of TBTU diluted in 2 ml of anhydrous DMF. 110 mg (0.76 mmol; 4 eq.) of 4-chlorobenzylamine dissolved in 1 ml of anhydrous DMF is then added and the resin is filtered after agitation overnight at ambient temperature. Sequential washing with DMF (5×3 ml), methanol (3×3 ml) and DCM (3×3 ml) produces a resin which is treated for one hour and 30 minutes under acid conditions (DCM/trifluoroacetic acid at 50%). The resin is rinsed with DCM (5×1 ml) and the filtrate evaporated under reduced pressure. The residue, taken up in DCM, is neutralized with a saturated solution of sodium hydrogen carbonate in order to produce after evaporation a solid (38.2 mg; yield of 41%; UV purity of 90% at 210 nm). NMR 1H (DMSO D6, 400 MHz, δ): 9.1 (m, 1H); 7.39 (d, 2H, J=8.4 Hz); 7.33 (d, 2H, J=8.4 Hz); 7.25 (q, 2H, J=6.8 Hz); 7.19 (q, 1H, J=7.2 Hz); 7.11 (m, 4H); 6.8 (d, 2H, J=8 Hz); 6.75 (s, 1H, H azole); 4.34 (d, 2H, J=6 Hz); 4.27 (t, 2H, J=6.8 Hz); 3.14 (m, 1H); 2.89 (t, 2H, J=6.8 Hz); 2.73 (t, 1H, J=7.2 Hz); 2.62 (m, 2H). MS/LC: m/z=491.24 (M+H)+.
A series of 2-arylimino-1,3-thiazole-4(3H)-carboxamides was synthesized according to method D using our robotic system (ACT MOS 496):
R1 and R2 groups already described in method B
R3=—CO-R5
R4=H
R5 groups already described in method C.
Method E
Preparation of Monoprotected Diamine Resin Functionalized with α-bromopyruvic Acid




General procedure: the monoprotected symmetrical primary or secondary diamine resin (the preparation of which is already described in method A) is functionalized by peptide coupling with α-bromopyruvic acid (10 eq.), DIC (10 eq.) and HOBt (10 eq.) in a solvent such as DMF at ambient temperature. The resin is washed successively with DMF then with DCM after 2 to 24 hours of agitation before being dried under vacuum. The negative Kaiser ninhydrin test indicates a complete functionalization.
Preparation 22
N-carbamate of 2-[(3-bromo-2-oxopropanoyl)amino]ethyl Wang resin




HOBt (0.93 g, 6.88 mmol) and α-bromopyruvic acid (1.18 g, 6.88 mmol) are dissolved in 28 ml of DMF (0.5 M). DIC (1.07 ml; 6.88 mmol) is then added by syringe to activate the acid. The mixture is agitated for approximately 15 minutes at ambient temperature before adding it to the ethylene diamine Wang resin N-carbamate (0.8 g; 0.688 mmol; load rate 0.86 mmol/g). After agitation for 3 hours at ambient temperature, the Kaiser ninhydrin test being negative, the resin is filtered and washed successively with DMF (5×20 ml) then with DCM (5×20 ml) before being dried under vacuum. An ochre resin (0.812 g) is obtained with a load rate of 0.525 mmol/g calculated from elemental analysis of the bromine.
Synthesis of 2-arylimino-1,3-thiazole-4(3H)-carboxamides




General procedure: formation of the thiourea is carried out in a solvent such as DMF or dioxane by mixing an equimolar quantity of primary amine and aromatic or heteroaromatic isothiocyanate. After agitation for 2 to 24 hours at ambient temperature, the thiourea (2 to 5 eq.) is added to the functionalized resin then heated at 80° C. for 2 to 4 hours. The 2-arylimino-1,3-thiazole-4(3H)-carboxamide resin is cleaved by treatment under acid conditions (DCM/trifluoroacetic acid at 50%) for 1–2 hours then rinsing with DCM. The solvent is evaporated off and the free base isolated after treatment under basic conditions (saturated solution of sodium hydrogen carbonate), extraction with DCM or elution with methanol in a basic alumina cartridge (500 mg, Interchim).
EXAMPLE 5
(2Z)-N-(2-aminoethyl)-3-[2-(3,4-dimethoxyphenyl)ethyl]-2-(phenylimino)-2,3-dihydro-1,3-thiazole-4-carboxamide
(C22H26N4O3S, MM=426.54)




18 μl (105 μmol; 2 eq.) of β-(3,4-dimethoxyphenyl)ethylamine and 12.6 μl (105 μmol; 2 eq.) of phenylisothiocyanate are agitated in 1 ml of DMF for 18 hours. The thiourea is added to 100 mg (52.5 μmol; load rate of 0.525 mmol/g) of resin (Preparation 22) and the mixture heated at 80° C. for 3 hours. The resin is then filtered then washed successively with DMF (5×1 ml), methanol (5×1 ml) then DCM (5×1 ml). The resin is dried under vacuum before adding 1 ml of a 50% DCM/TFA mixture. Agitation is carried out for 1.5 hours at ambient temperature, the resin is filtered and rinsed with DCM. The residue recovered after evaporation is then eluted with methanol in a basic alumina cartridge in order to isolate 22.2 mg (quantitative yield; UV purity of 93.4% at 230 nm) of a brown solid corresponding to the free amine.
NMR 1H (DMSO D6, 100 MHz, δ): 8.42 (m, 1H, NH); 7.32 (t, 2H, J=7.1 Hz); 7.08–6.63 (m, 6H); 5.76 (s, 1H, H azole); 4.31 (t, 2H, J=6.6 Hz); 3.72 (s, 6H, OCH3); 3.32 (broad s, 2H); 3.17 (m, 2H); 2.89 (m, 2H); 2.62 (m, 2H). MS/LC: m/z=427.17 (M+H)+.
A series of 2-arylimino-1,3-thiazole-4(3H)-carboxamides was synthesized according to method E using our robotic system (ACT MOS 496):
R1 groups:






















R2 groups already described in method A
R3=—CO-R5
R4=H
R5 groups:




Method F

Preparation of monoprotected diamine resins functionalized with N-protected amino acids (Fmoc)




General procedure: the peptide coupling of the monoprotected diamine resins with N-Fmoc amino acids (4 to 10 eq.) which are commercially available (Bunin, B. A. The Combinatorial Index, Academic Press, 1998, p. 77–82) is carried out in DMF at ambient temperature for 1 to 24 hours with different standard coupling agents (4 to 10 eq.) such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), a DIC/N-hydroxybenzotriazole (HOBt) mixture, benzotriazolyloxytris(dimethylamino) phosphonium hexafluorophosphate (PyBOP), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) or 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU). The resin is then washed successively with DMF and DCM. The coupling sequence can be repeated (once or twice) until the Kaiser ninhydrin test is negative.
Preparation 23
4-[({[(9H-fluoren-9-ylmethoxy)carbonyl]amino}acetyl)amino]butyl N-carbamate




Fmoc-Gly-OH acid (2.36 g, 7.94 mmol) is activated with HOBt (1.07% g, 7.94 mmol) and DIC (1.25 ml, 7.94 mmol) in 22 ml of DMF for 5 minutes before adding the mixture to butylamine Wang resin N-carbamate (1 g, load rate of 0.794 mmol/g) preswollen in 10 ml of DMF. After agitation for 18 hours at ambient temperature, the resin is washed successively with DMF (5×20 ml) then with DCM (5×20 ml) before being dried under vacuum. 1.27 g of pale yellow resin is thus obtained presenting a negative Kaiser ninhydrin test.

    
    
        Preparation of the thiourea resins
    
    






General procedure: a resin described above is deprotected with a 20% DMF/piperidine mixture. After agitation for one hour at ambient temperature, the resin is filtered and washed successively with DMF then with DCM. The deprotection/washing sequence is repeated a second time and the resin is dried under vacuum. The latter is preswollen in a solvent such as DMF or DCM then an aromatic or heteroaromatic isothiocyanate (5 to 10 eq.) is added. The mixture is agitated for 2 to 24 hours at ambient temperature before the resin is filtered and washed successively with DMF then with DCM. The resin is then dried under vacuum and a negative Kaiser ninhydrin test confirms that the substitution reaction is complete.
Preparation 24
4-[({[(1-naphthylamino)carbothioyl]amino}acetyl)amino]butyl Wang resin N-carbamate




1.27 g of the above resin (see Preparation 23) is deprotected with 14 ml of DMF/piperidine at 20%. The mixture is agitated for one hour at ambient temperature. The resin is then filtered then washed with DMF (5×30 ml) then with DCM (5×30 ml). The deprotection/washing sequence is repeated once before the resin is dried under vacuum. 0.781 g of pale yellow resin was thus obtained with a load rate of 0.758 mmol/g calculated after elemental analysis of the sulphur. 416 mg (2.2 mmol, 10 eq.) of 1-naphthylisothiocyanate diluted in 6 ml of DMF is added to 0.3 g (0.22 mmol) of this thiourea resin. The mixture is agitated for 18 hours at ambient temperature. The resin is filtered then washed successively with DMF (5×20 ml) then with DCM (5×20 ml). 310 mg of a pale yellow resin is isolated after drying under vacuum with a load rate of 0.66 mmol/g calculated after elemental analysis of the nitrogen.
Synthesis of 2-arylimino-2,3-dihydrothiazoles




General procedure: the regioselective cyclization stage is carried out in aprotic solvents such as dioxane, DMF or N-methylpyrrolidinone at 80° C. for 2 to 3 hours between the thiourea resin and the α-bromoketone (2 to 5 eq.). The resin is then washed successively with DMF, methanol and DCM then dried under reduced pressure. The 2-arylimino-2,3-dihydrothiazole resin is cleaved under acid conditions (DCM/trifluoroacetic acid at 50%) for 1 to 2 hours then rinsed with DCM. The solvent is evaporated off and the free base isolated after treatment under basic conditions (saturated solution of sodium hydrogen carbonate) followed by an extraction with DCM or elution with methanol in a basic alumina cartridge (500 mg, Interchim).
EXAMPLE 6
N-(4-aminobutyl)-2-((2Z)-4-(4-chlorophenyl)-2-(1-naphthylimino)-1,3-thiazol-3(2H)-yl)acetamide
(C25H25ClN4OS, MM=465.02)




80 mg (52.8 μmol, load rate of 0.66 mmol/g) of thiourea resin (Preparation 24) and 25.1 mg (105.6 mmol, 2 eq.) of 2-bromo-4′-chloroacetophenone are diluted in 1 ml of DMF. The mixture is heated at 80° C. for 2 hours. The resin is filtered then washed with DMF (5×1 ml), methanol (5×1 ml) then DCM (5×1 ml) before being dried under vacuum. 1 ml of a 50% DCM/TFA mixture is added followed by agitation for 1 hour 30 minutes. The resin is filtered and rinsed with DCM. The filtrate is evaporated then rediluted in methanol for elution on basic alumina. 20.6 mg (yield of 84%; UV purity of 94.2% at 220 mm) of yellow solid is thus isolated after evaporation corresponding to the free base.
NMR 1H (DMSO D6, 100 MHz, δ): 8.36 (t, 1H, J=4.7 Hz, NH); 8.12 (dd, 1H, J=2.1 and 7.3 Hz); 7.87 (dd, 1H, J=2.7 and 6.3 Hz); 7.63–7.34 (m, 8H); 7.13 (dd, 1H, J=1.6 and 6.7 Hz); 6.33 (s, 1H, H azole); 4.44 (broad s, 2H); 3.14 (m, 2H); 2.7 (m, 2H); 1.5 (m, 4H). MS/LC: m/z=465.21 (M+H)+.
A series of 2-arylimino-2,3-dihydrothiazoles was synthesized according to method F using our robotic system (ACT MOS 496):
R1=—C(R11R12)-CO-R10
R2, R3 and R4 groups already described in method A
R10 groups:










EXAMPLES
Examples obtained according to methods A, B, C, D, E and F described above are shown below in the tables. These examples are shown to illustrate the above processes and must not in any circumstances be considered as limiting the scope of the invention.
The compounds obtained have been characterized by their retention times (rt) and by mass spectrometry (M+H)+.
The chromatograms are obtained from a high performance liquid chromatography device (Hewlett-Packard 1100) equipped with a scanning UV detector. The following conditions were used to measure the retention times by high performance liquid chromatography, it being understood that the extraction wavelength of each of the chromatograms is 220 nm:












t (min.)
A (%)
B (%)







0
90
10


6
15
85


8
15
85





Eluent A: water + 0.02% trifluoroacetic acid; eluent B: acetonitrile.


Flow rate: 1 ml/min; volume injected: 5 μl; temperature: 40° C.


Column: Uptisphere 3 μm ODS, 50 × 4.6 mm i.d. (Interchim)






The mass spectra are obtained from a single quadrupole mass spectrometer equipped with an electrospray source (Micromass, Platform II).


















 












Ex.
R2
R3
Purity (%)
rt (min.)
[M + H]+





  7








91.2
3.09
304.2


 


  8








93.1
3.38
338.2


 


  9








94
3.56
352.2


 


 10








93.3
3.42
338.2


 


 11








96.6
3.25
342.2


 


 12








96.4
3.46
365.2


 


 13








91.9
3.86
393.2


 


 14








96.4
3.44
358.2


 


 15








95.6
3.34
382.2


 


 16








94.5
3.7
408


 


 17








54.43
2.9
305.2


 


 18








50.4
3.14
339.2


 


 19








48.9
3.38
535.2


 


 20








39.3
3.26
339.2


 


 21








49.5
3.06
343.2


 


 22








42.3
3.29
366.2


 


 23








43.4
3.7
394.3


 


 24








56.7
3.16
359.2


 


 25








45.3
3.09
383.2


 


 26








45.7
3.3
409


 


 27








96.8
3.41
332.3


 


 28








92.8
3.7
366.3


 


 29








90.6
3.84
380.3


 


 30








93.7
3.76
366.3


 


 31








94.4
3.63
370.2


 


 32








89.1
3.82
393.2


 


 33








90.1
4.12
410.2


 


 34








96.7
3.83
386.2


 


 35








95.8
3.67
410.2


 


 36








93.4
4.17
436.1


 


 37








88.4
3.64
329.25


 


 38








91.8
4.03
363.2


 


 39








88.6
4.15
377.2


 


 40








94.1
4.22
363.2


 


 41








95.2
4.1
376.2


 


 42








92.8
4.35
390.2


 


 43








94.1
4.54
418.2


 


 44








95
4.34
383.1


 


 45








95.1
4.06
407.2


 


 46








93
4.7
433.1


 


 47








96.4
3.32
332.3


 


 48








92.9
3.62
366.3


 


 49








95.6
3.76
380.3


 


 50








95.6
3.64
366.33


 


 51








96
3.51
370.2


 


 52








87
3.69
390.2


 


 53








80.9
4.04
421.3


 


 54








97.1
3.7
436.1


 


 55








94.6
3.59
410.2


 


 56








95.6
3.92
436.1


 


 57








82.1
3.66
368.2


 


 58








90.7
3.94
402.2


 


 59








85.5
4.06
416.2


 


 60








94.4
4.09
402.2


 


 61








95.1
3.99
406.2


 


 62








93.6
4.21
429.2


 


 63








93.6
4.39
457.2


 


 64








96
4.22
422.1


 


 65








91.6
3.96
446.2


 


 66








94.5
4.65
472


 


 67








97
3.07
348.2


 


 68








93.6
3.36
382.2


 


 69








93.4
3.54
396.2


 


 70








94.7
3.41
382.1


 


 71








96.3
3.24
386.2


 


 72








94.5
3.44
409.1


 


 73








93.4
3.83
437.2


 


 74








95.4
3.41
402.1


 


 75








95.7
3.32
426.2


 


 76








92.4
3.64
452.2


 


 77








98.1
3.66
324.2


 


 78








91.2
3.98
388.2


 


 79








81.9
4.09
402.2


 


 80








96.1
4.12
388.2


 


 81








96.1
4.03
392.2


 


 82








94.2
4.24
415.2


 


 83








93.3
4.39
443.3


 


 84








96.3
4.28
408.1


 


 85








94.2
4.0
432.2


 


 86








95.6
4.7
458.1
















 












Ex.
R2
R3
Purity (%)
rt (min.)
[M + H]+





 87








97
3.35
338.2


 


 88








94
3.51
352.3


 


 89








94
3.58
352.3


 


 90








97
3.42
356.2


 


 91








86
4.01
422.2


 


 92








96
3.99
407.3


 


 93








7
3.65
391.3


 


 94








92
4.11
378.2


 


 95








95
3.43
435.2


 


 96








97
3.91
422.1


 


 97








43
3.19
339.2


 


 98








32
3.33
353.2


 


 99








39
3.45
353.2


 


 100








39
3.28
357.2


 


 101








42
3.8
423.2


 


 102








41
3.89
408.2


 


 103








14
3.43
392.2


 


 104








39
3.62
379.2


 


 105








28
3.2
436.2


 


 106








35
3.56
423.1


 


 107








95
4.65
464.1


 


 108








89
4.64
478.2


 


 109








82
4.88
478.1


 


 110








92
4.76
482.1


 


 111








90
5.41
548.1


 


 112








86
5.13
533.2


 


 113








9
4.5
517.1


 


 114








95
5.49
504.1


 


 115








80
4.4
561.1


 


 116








89
5.4
548.0


 


 117








96
4.85
422.2


 


 118








91
4.86
436.2


 


 119








88
5.08
436.2


 


 120








95
4.96
440.2


 


 121








81
5.56
506.2


 


 122








83
5.34
491.2


 


 123








3
4.7
475.3


 


 124








91
5.59
462.2


 


 125








92
4.61
519.2


 


 126








92
5.52
506.1


 


 127








98
3.63
366.3


 


 128








97
3.76
380.3


 


 129








98
3.82
380.3


 


 130








98
3.67
384.2


 


 131








97
4.16
450.2


 


 132








96
4.2
435.3


 


 133








21
3.9
419.3


 


 134








88
4.28
406.2


 


 135








97
3.68
463.3


 


 136








82
4.09
450.1


 


 137








93
3.44
417.2


 


 138








94
3.5
431.2


 


 139








95
3.71
431.2


 


 140








95
3.58
435.2


 


 141








94
4.27
501.2


 


 142








93
4.05
486.6


 


 143








94
4.28
457.2


 


 144








92
3.39
514.2


 


 145








85
4.16
501.1


 


 146








97
3.36
382.2


 


 147








94
3.53
396.2


 


 148








97
3.6
396.2


 


 149








97
3.43
400.2


 


 150








97
3.95
466.2


 


 151








95
4.01
451.3


 


 152








15
3.57
435.2


 


 153








94
4.0
422.2


 


 154








95
3.45
479.3


 


 155








95
3.84
466.1


 


 156








96
4.11
388.2


 


 157








90
4.14
402.2


 


 158








96
4.31
402.2


 


 159








96
4.21
406.2


 


 160








97
4.83
472.3


 


 161








95
4.57
457.3


 


 162








96
5.12
428.2


 


 163








88
4.01
485.3


 


 164








97
4.91
472.1
















 












Ex.
R2
R3
Purity (%)
rt (min.)
[M + H]+





 165








93
3.52
332.3


 


 166








99
3.76
370.3


 


 167








97
3.9
393.3


 


 168








98
4.25
436.2


 


 169








98
4.14
431.2


 


 170








99
4.79
488.2


 


 171








98
3.74
410.2


 


 172








98
4.28
410.3


 


 173








98
4.38
392.2


 


 174








98
4.73
456.2


 


 175








98
4.06
374.3


 


 176








98
4.37
412.3


 


 177








97
4.46
435.3


 


 178








98
4.8
478.3


 


 179








99
4.78
473.3


 


 180








94
5.43
530.3


 


 181








97
4.27
452.3


 


 182








85
4.73
452.4


 


 183








98
5.07
434.3


 


 184








93
5.33
498.3


 


 185








98
4.61
458.2


 


 186








97
5.23
496.1


 


 187








96
5.34
519.1


 


 188








97
5.72
562.1


 


 189








98
5.57
557.1


 


 190








96
6.16
614.1


 


 191








96
4.97
536.1


 


 192








85
5.67
536.2


 


 193








96
5.86
518.1


 


 194








97
6.32
582.1


 


 195








96
4.16
357.3


 


 196








98
4.74
395.2


 


 197








97
4.86
418.2


 


 198








98
5.26
461.2


 


 199








98
5.12
456.2


 


 200








97
5.72
513.2


 


 201








96
4.51
435.2


 


 202








98
5.18
435.3


 


 203








95
5.37
417.2


 


 204








95
5.84
481.2


 


 205








96
3.63
350.3


 


 206








98
3.95
388.2


 


 207








95
4.07
411.2


 


 208








98
4.44
454.2


 


 209








97
4.38
449.2


 


 210








89
5.03
506.2


 


 211








96
3.87
428.2


 


 212








97
4.4
428.3


 


 213








96
4.63
410.2


 


 214








96
4.96
474.2


 


 215








94
5.38
411.2


 


 216








98
5.63
449.2


 


 217








96
5.77
472.2


 


 218








98
6.04
515.2


 


 219








98
5.74
510.1


 


 220








91
6.29
567.2


 


 221








98
5.53
489.2


 


 222








96
6.38
489.3


 


 223








97
6.0
471.2


 


 224








98
6.49
535.1


 


 225








98
3.99
426.3


 


 226








98
4.34
464.2


 


 227








96
4.43
487.3


 


 228








97
4.78
530.2


 


 229








98
4.76
525.2


 


 230








96
5.36
582.2


 


 231








95
4.23
504.3


 


 232








97
4.7
504.3


 


 233








98
4.99
486.2


 


 234








97
5.3
550.2


 


 235








96
3.44
411.2


 


 236








95
3.94
449.2


 


 237








96
4.11
472.3


 


 238








95
4.52
515.2


 


 239








95
4.39
510.2


 


 240








94
5.01
567.2


 


 241








96
3.74
489.2


 


 242








96
4.41
489.3


 


 243








96
4.56
471.2


 


 244








97
5.01
535.2
















 












Ex.
R2
R3
Purity (%)
rt (min.)
[M + H]+





 245








98.1
3.2
290.2


 


 246








96.9
3.78
324.2


 


 247








69.3
3.88
355.2


 


 248








99.3
3.79
335.2


 


 249








99.4
3.86
324.2


 


 250








98
3.97
351.2


 


 251








98.7
4.14
388.1


 


 252








93.5
4.24
379.3


 


 253








82.4
5.16
446.2


 


 254








98.8
3.7
368.2


 


 255








98.5
3.9
332.3


 


 256








92.3
4.4
366.3


 


 257








82.3
4.55
397.2


 


 258








98.4
4.48
377.3


 


 259








97.3
4.49
366.3


 


 260








95.4
4.59
393.3


 


 261








98.7
4.77
430.2


 


 262








90.9
4.76
421.3


 


 263








98.7
5.72
488.2


 


 264








97.7
4.33
410.3


 


 265








98.5
3.42
369.2


 


 266








94.9
3.91
403.2


 


 267








98.1
3.81
434.2


 


 268








97.9
3.78
414.1


 


 269








98.1
4.06
403.2


 


 270








96.2
4.14
430.2


 


 271








98.3
4.28
467.1


 


 272








96.8
4.5
458.2


 


 273








98.3
4.92
525.2


 


 274








97.1
3.84
447.2


 


 275








96.5
4.28
354.2


 


 276








93.3
5.02
388.2


 


 277








68.7
4.96
419.2


 


 278








97.8
4.86
399.2


 


 279








96
5.13
388.2


 


 280








96.9
5.18
415.2


 


 281








98.6
5.31
452.1


 


 282








89.5
5.54
443.2


 


 283








65.5
5.89
510.2


 


 284








97.8
4.89
432.2


 


 285








93.2
5.08
369.2


 


 286








94.6
5.31
403.1


 


 287








97.6
5.07
434.1


 


 288








99.1
5.05
414.1


 


 289








99.1
5.39
403.1


 


 290








98.3
5.44
430.2


 


 291








99.4
5.47
467.1


 


 292








97.4
5.86
458.2


 


 293








99.5
5.87
525.1


 


 294








98.5
5.21
447.2


 


 295








95.7
4.41
396.3


 


 296








92.9
5.06
430.3


 


 297








54
5.19
461.2


 


 298








91.8
5.07
441.2


 


 299








95.8
5.18
430.3


 


 300








96
5.28
457.3


 


 301








96.9
5.45
494.2


 


 302








87
5.49
485.3


 


 303








35.6
6.18
552.2


 


 304








96.7
4.97
474.3


 


 305








83.9
5.24
380.2


 


 306








92.8
5.39
414.2


 


 307








92
5.14
445.2


 


 308








97.4
5.11
425.1


 


 309








98.1
5.47
414.2


 


 310








97.2
5.47
441.1


 


 311








97
5.52
478.1


 


 312








93.3
5.99
469.2


 


 313








98.3
5.91
536.1


 


 314








96.5
5.31
458.2


 


 315








98.7
4.12
340.3


 


 316








93.4
4.66
374.2


 


 317








98.9
4.78
405.2


 


 318








97.8
4.71
385.2


 


 319








98.1
4.78
374.2


 


 320








97.2
4.9
401.2


 


 321








98.8
5.09
438.1


 


 322








95.8
5.07
429.3


 


 323








98.5
5.82
496.2


 


 324








97.5
4.59
418.2
















 












Ex.
R2
R3
Purity (%)
rt (min.)
[M + H]+





 325








93
3.71
358.2


 


 326








68 + 30
4.0 + 4.1
396.2


 


 327








69 + 31
4.5 + 4.6
462.2


 


 328








66 + 27
4.7 + 4.8
484.3


 


 329








67 + 31
4.4 + 4.6
457.2


 


 330








67 + 30
4.3 + 4.5
541.2


 


 331








62 + 33
3.9 + 4.0
436.2


 


 332








64 + 30
3.5 + 3.6
447.3


 


 333








65 + 30
4.7 + 4.9
418.2


 


 334








68 + 29
3.8 + 3.9
372.3


 


 335








69 + 29
4.2 + 4.3
410.2


 


 336








68 + 30
4.6 + 4.8
476.2


 


 337








61 + 32
 4.8 + 4.89
498.3


 


 338








66 + 30
4.55 + 4.71
471.2


 


 339








68 + 29
4.46 + 4.58
555.2


 


 340








22 + 11
5.13 + 5.22
520.4


 


 341








67 + 24
4.09 + 4.14
450.3


 


 342








71 + 23
 3.7 + 3.74
461.3


 


 343








67 + 31
4.82 + 5.02
432.2


 


 344








66 + 31
4.14 + 4.39
404.3


 


 345








65 + 31
4.74 + 4.94
442.2


 


 346








65 + 31
5.25 + 5.47
508.2


 


 347








62 + 29
5.28 + 5.5 
530.3


 


 348








65 + 30
5.21 + 5.38
503.2


 


 349








63 + 30
5.03 + 5.24
587.2


 


 350








64 + 30
5.59 + 5.84
552.3


 


 351








58 + 28
4.49 + 4.66
482.3


 


 352








64 + 26
4.01 + 4.11
493.3


 


 353








65 + 31
5.54 + 5.71
464.2


 


 354








57 + 24
4.08 + 4.19
399.3


 


 355








62 + 28
4.52 + 4.7 
437.2


 


 356








62 + 28
  5 + 5.2
503.2


 


 357








58 + 26
5.08 + 5.25
525.3


 


 358








62 + 29
4.98 + 5.19
498.2


 


 359








62 + 29
4.82 + 4.99
582.2


 


 360








62 + 28
5.39 + 5.58
547.3


 


 361








56 + 26
4.37 + 4.49
477.3


 


 362








64 + 32
5.32 + 5.55
459.2


 


 363








94
6.36
505.2


 


 364








98
6.39
542.1


 


 365








25 + 72
6.74 + 6.77
608.1


 


 366








92
7.07
630.2


 


 367








23 + 73
6.38 + 6.42
603.1


 


 368








26 + 69
6.73 + 6.76
687.1


 


 369








60
7.55
652.3


 


 370








82
6.39
582.1


 


 371








94
5.74
593.2


 


 372








22 + 73
6.68 + 6.74
564.1


 


 373








59 + 27
4.88 + 5.13
403.3


 


 374








67 + 30
5.35 + 5.44
441.2


 


 375








64 + 34
5.84 + 5.92
507.2


 


 376








62 + 28
  6 + 6.13
529.3


 


 377








97
5.58
502.2


 


 378








65 + 32
5.71 + 5.8 
586.2


 


 379








49 + 23
6.45 + 6.58
551.3


 


 380








61 + 26
5.18 + 5.3 
481.2


 


 381








45 + 21
4.57 + 4.68
492.3


 


 382








84
5.9
463.2


 


 383








56 + 26
4.65 + 4.89
410.2


 


 384








64 + 30
5.29 + 5.47
448.2


 


 385








65 + 30
5.78 + 5.95
514.2


 


 386








63 + 27
 5.8 + 6.02
536.2


 


 387








65 + 31
5.71 + 5.81
509.1


 


 388








62 + 32
5.59 + 5.79
593.1


 


 389








30 + 14
6.22 + 6.45
558.3


 


 390








57 + 26
5.01 + 5.2 
488.2


 


 391








54 + 26
4.46 + 4.61
499.2


 


 392








27 + 11
6.09 + 6.18
470.2


 


 393








63 + 29
4.53 + 4.6 
464.3


 


 394








65 + 30
4.78 + 4.93
502.3


 


 395








61 + 28
5.16 + 5.35
568.2


 


 396








59 + 25
 5.3 + 5.42
590.3


 


 397








60 + 30
5.12 + 5.34
563.2


 


 398








63 + 32
5.01 + 5.17
647.2


 


 399








59 + 26
5.55 + 5.7 
612.4


 


 400








52 + 14
4.35 + 4.4 
553.3


 


 401








61 + 29
5.36 + 5.64
524.3
















 












Ex.
R2
R3
Purity (%)
rt (min.)
[M + H]+





 402








88.5
4.52
442.1


 


 403








94.6
4.72
432.15


 


 404








95
4.78
455.16


 


 405








98.6
5.19
493.12


 


 406








95.8
4.99
577.11


 


 407








95.1
4.44
472.19


 


 408








96.3
4.0
483.21


 


 409








94.5
5.35
498.04


 


 410








94.1
5.61
454.15


 


 411








83
5.43
526.03


 


 412








94.9
5.4
515.97


 


 413








93.4
5.52
539.00


 


 414








97.1
5.48
576.95


 


 415








92.7
5.69
660.99


 


 416








92.2
5.27
555.98


 


 417








92
4.7
567.00


 


 418








89.7
5.73
581.87


 


 419








87.8
5.77
538.00


 


 420








84.4
4.74
446.14


 


 421








92.6
4.9
436.08


 


 422








91.2
5.0
459.10


 


 423








72.4
5.0
487.16


 


 424








94.9
5.19
497.07


 


 425








91.7
5.18
581.05


 


 426








91.5
4.67
476.12


 


 427








89.6
4.16
487.13


 


 428








91.7
5.38
501.96


 


 429








89.9
5.48
458.10


 


 430








87.1
5.26
484.14


 


 431








95.7
5.41
474.10


 


 432








94.6
5.51
497.12


 


 433








97.4
5.64
535.01


 


 434








96.2
5.69
619.04


 


 435








94.4
5.21
514.10


 


 436








94.7
4.67
525.11


 


 437








92.7
5.84
539.94


 


 438








91
5.93
496.09


 


 439








82.4
4.82
492.18


 


 440








92.2
5.03
482.14


 


 441








90.4
5.08
505.15


 


 442








33.4
5.14
533.18


 


 443








97.6
5.45
543.07


 


 444








93.9
5.26
627.10


 


 445








93.6
4.78
522.14


 


 446








94
4.34
533.15


 


 447








91.6
5.6
547.98


 


 448








92.6
5.82
504.14


 


 449








84.9
5.76
468.08


 


 450








95.4
5.54
458.03


 


 451








93.3
5.74
481.03


 


 452








85.3
6.21
509.06


 


 453








97.4
5.62
518.97


 


 454








92
5.91
602.90


 


 455








91.4
5.54
498.06


 


 456








91.4
4.98
509.06


 


 457








88.7
5.9
523.88


 


 458








88.5
5.88
480.05


 


 459








88.2
4.69
506.18


 


 460








93.1
4.87
496.15


 


 461








91.2
4.92
519.15


 


 462








26.9
5.01
547.17


 


 463








93.9
5.26
557.08


 


 464








93.2
5.08
641.13


 


 465








95.7
4.64
536.15


 


 466








95.3
4.24
547.15


 


 467








92.3
5.39
562.00


 


 468








92
5.6
518.14


 


 469








75.3
4.59
494.13


 


 470








97.1
4.73
484.11


 


 471








95.4
4.81
507.11


 


 472








10.7
4.9
535.14


 


 473








96.4
5.07
545.02


 


 474








96.5
4.98
629.05


 


 475








95.2
4.5
524.08


 


 476








96
4.06
535.09


 


 477








95.3
5.22
549.95


 


 478








94.1
5.36
506.08
















 












Ex.
R2
R3
Purity (%)
rt (min.)
[M + H]+





 479








45.6
4.95
377.14


 


 480








79
5.17
431.07


 


 481








56.8
4.84
442.08


 


 482








79.2
5.04
415.07


 


 483








78.4
5.25
438.11


 


 484








82.6
5.47
481.10


 


 485








72.6
5.81
503.17


 


 486








79
5.36
560.04


 


 487








72.1
5.34
480.98


 


 488








76.9
5.0
441.09


 


 489








94.5
4.6
386.09


 


 490








95.4
5.34
440.04


 


 491








95.3
5.05
451.06


 


 492








95.2
5.23
424.07


 


 493








93.4
5.35
447.07


 


 494








96.1
5.67
490.07


 


 495








88.5
5.84
512.12


 


 496








92.9
5.55
569.00


 


 497








92.8
5.64
489.95


 


 498








92
5.03
450.08


 


 499








96.5
4.87
397.11


 


 500








96.1
5.26
451.06


 


 501








96.1
4.95
462.07


 


 502








96.3
5.15
435.08


 


 503








96.2
5.31
458.11


 


 504








96.5
5.57
501.08


 


 505








89.3
5.86
523.15


 


 506








95.8
5.46
580.03


 


 507








94.2
5.45
500.96


 


 508








93.5
5.07
461.08


 


 509








98.5
4.29
408.18


 


 510








97.2
4.98
462.13


 


 511








96.4
4.81
473.19


 


 512








96.3
4.9
446.17


 


 513








94.7
4.93
469.19


 


 514








96.9
5.29
512.17


 


 515








90.6
5.33
534.20


 


 516








96.3
5.15
591.13


 


 517








93.5
5.47
512.04


 


 518








95
4.65
472.19


 


 519








95.5
5.14
420.13


 


 520








95.6
5.63
474.07


 


 521








93.8
5.35
485.10


 


 522








95.1
5.53
458.09


 


 523








94.2
5.67
481.10


 


 524








94.6
5.9
524.09


 


 525








88.4
6.15
546.11


 


 526








92.6
5.83
603.07


 


 527








89.8
5.87
523.97


 


 528








92.3
5.41
484.11


 


 529








98.2
3.75
380.18


 


 530








96.4
4.35
434.11


 


 531








96.5
4.19
445.13


 


 532








95.7
4.25
418.14


 


 533








94.4
4.33
441.13


 


 534








95.5
4.69
484.14


 


 535








89.5
4.81
506.18


 


 536








95.5
4.54
563.08


 


 537








92.2
4.79
484.03


 


 538








93.7
4.07
444.14


 


 539








95.4
4.25
416.10


 


 540








95.7
5.05
470.07


 


 541








95.6
4.81
481.05


 


 542








95.4
4.96
454.07


 


 543








94.4
5.05
477.10


 


 544








95.9
5.4
520.04


 


 545








89.5
5.51
542.11


 


 546








94
5.26
599.02


 


 547








92.9
5.4
519.93


 


 548








92.3
4.72
480.08


 


 549








92
6.01
585.84


 


 550








96.7
6.18
639.79


 


 551








95.8
5.84
650.83


 


 552








96
6.04
623.81


 


 553








94.7
6.22
646.85


 


 554








95
6.39
689.82


 


 555








88.8
6.7
711.88


 


 556








94.9
6.4
768.76


 


 557








95
6.35
689.71


 


 558








93.7
6.01
649.83
















 












Ex.
R2
R3
Purity (%)
rt (min.)
[M + H]+





 559








87.5
4.07
408.18


 


 560








89.6
4.15
458.09


 


 561








89.5
4.04
421.17


 


 562








54.6
4.37
449.23


 


 563








92.7
4.85
516.14


 


 564








92.5
4.27
459.14


 


 565








94.2
3.87
438.18


 


 566








92.6
4.41
444.2


 


 567








92.2
3.5
449.21


 


 568








92.4
4.53
420.17


 


 569








86.7
4.23
422.21


 


 570








93.7
4.38
472.12


 


 571








88.7
4.27
435.19


 


 572








64.2
4.53
463.25


 


 573








93.8
5.15
530.18


 


 574








93.6
4.55
473.17


 


 575








86.8
4.07
452.21


 


 576








93.4
4.65
458.24


 


 577








91.8
3.71
463.23


 


 578








91.6
4.85
434.20


 


 579








83.1
4.38
436.23


 


 580








92.7
4.56
486.14


 


 581








88.9
4.43
449.24


 


 582








80.4
4.65
477.25


 


 583








93
5.34
544.19


 


 584








94.3
4.75
487.20


 


 585








93.2
4.23
466.23


 


 586








94
4.82
472.28


 


 587








92.1
3.88
477.28


 


 588








91.7
5.06
448.23


 


 589








83.1
4.62
419.20


 


 590








93
5.06
469.09


 


 591








88
4.89
432.18


 


 592








88.5
5.02
460.23


 


 593








93.2
5.69
527.16


 


 594








91.6
5.11
470.15


 


 595








90.2
4.53
449.19


 


 596








91.9
5.4
455.19


 


 597








90.2
3.99
460.20


 


 598








93
5.41
431.16


 


 599








86.1
4.05
424.22


 


 600








91.8
4.17
474.12


 


 601








90.2
4.04
437.19


 


 602








86.4
4.34
465.24


 


 603








93.5
4.91
532.19


 


 604








93.4
4.3
475.16


 


 605








87.9
3.86
454.20


 


 606








91.8
4.47
460.25


 


 607








90.7
3.48
465.21


 


 608








92
4.55
436.19


 


 609








85.9
5.19
541.25


 


 610








92.4
5.6
591.13


 


 611








89.7
5.45
554.23


 


 612








88.7
5.58
582.28


 


 613








93.2
6.06
649.24


 


 614








94.1
5.55
592.18


 


 615








90
5.09
571.23


 


 616








93.3
5.91
577.26


 


 617








91.4
4.53
582.24


 


 618








92.1
5.84
553.22


 


 619








76.6
5.06
490.15


 


 620








91.2
5.56
539.99


 


 621








86.7
5.39
503.12


 


 622








81
5.47
531.15


 


 623








92.2
6.13
598.06


 


 624








84.8
5.59
541.03


 


 625








88
5.04
520.11


 


 626








91.6
5.91
526.14


 


 627








89.4
4.49
531.11


 


 628








90.3
5.89
502.10


 


 629








83.3
4.41
458.20


 


 630








91.5
4.72
508.08


 


 631








87.8
4.57
471.18


 


 632








57.7
4.71
499.23


 


 633








92.8
5.54
566.12


 


 634








93.5
4.93
509.13


 


 635








89.3
4.29
488.19


 


 636








93.6
4.99
494.21


 


 637








91.7
3.88
499.21


 


 638








91.9
5.22
470.18
















 












Ex.
R2
R3
Purity (%)
rt (min.)
[M + H]+





 639








95
7.28
374.10


 


 640








87
7.62
364.24


 


 641








84
6.75
342.23


 


 642








79
6.6
321.24


 


 643








81
4.96
339.29


 


 644








82
6.44
324.28


 


 645








83
7.16
338.30


 


 646








59
6.6
356.25


 


 647








86
7.28
402.23


 


 648








84
7.29
346.26


 


 649








85
7.66
388.1


 


 650








84
7.96
378.21


 


 651








85
7.14
356.23


 


 652








73
7.02
335.26


 


 653








76
5.37
353.29


 


 654








83
6.84
338.30


 


 655








81
7.51
352.29


 


 656








75
6.99
370.27


 


 657








77
7.6
416.26


 


 658








80
7.65
360.25


 


 659








87
7.37
392.10


 


 660








71
7.7
382.16


 


 661








63
6.9
360.21


 


 662








59
6.7
339.23


 


 663








80
5.06
357.26


 


 664








63
6.61
342.26


 


 665








82
7.28
356.25


 


 666








39
6.74
374.22


 


 667








85
7.42
420.24


 


 668








81
7.39
364.26


 


 669








93
8.28
443.2


 


 670








88
8.61
433.2


 


 671








88
7.7
411.2


 


 672








80
7.76
390.26


 


 673








85
6.08
408.3


 


 674








89
7.36
393.3


 


 675








84
8.03
407.3


 


 676








81
7.59
425.3


 


 677








83
8.03
471.3


 


 678








91
8.24
415.2


 


 679








78
7.41
419.09


 


 680








75
6.98
369.23


 


 681








81
7.51
383.23


 


 682








85
7.46
391.20


 


 683








74
6.79
351.21


 


 684








81
5.18
369.26


 


 685








76
6.73
354.26


 


 686








87
7.39
368.27


 


 687








80
7.48
376.22


 


 688








83
8.14
424.11


 


 689








83
8.37
414.14


 


 690








78
7.48
371.21


 


 691








85
5.88
389.24


 


 692








79
7.53
374.24


 


 693








83
8.1
388.23


 


 694








77
8.18
452.23


 


 695








81
8.14
396.20


 


 696








76
7.94
413.16


 


 697








86
7.41
402.01


 


 698








93
7.57
360.16


 


 699








74
6.32
361.23


 


 700








88
7.75
344.19


 


 701








83
6.88
317.22


 


 702








93
8.33
509.9


 


 703








90
8.69
411.99


 


 704








72
8.16
382.21


 


 705








81
7.27
382.2


 


 706








82
7.7
436.05


 


 707








91
7.85
394.16


 


 708








80
6.59
395.19


 


 709








87
7.99
378.16


 


 710








83
7.3
351.2


 


 711








89
8.58
543.85


 


 712








89
8.9
446.01


 


 713








72
8.35
416.19


 


 714








82
7.62
416.19


 


 715








85
7.84
436.05


 


 716








88
7.97
394.14


 


 717








75
6.82
395.21


 


 718








88
8.13
378.13


 


 719








78
7.5
351.2


 


 720








91
8.65
543.86


 


 721








89
8.97
446.0


 


 722








75
8.55
416.19


 


 723








83
7.84
416.19


 


 724








90
8.24
506.01


 


 725








88
8.37
464.1


 


 726








76
7.43
465.17


 


 727








86
8.52
448.1


 


 728








84
8.11
421.11


 


 729








89
8.97
613.8


 


 730








90
9.24
515.94


 


 731








74
8.94
486.17


 


 732








81
8.51
486.16


 


 733








82
8.15
584.93


 


 734








81
8.26
543.05


 


 735








69
7.31
544.1


 


 736








80
8.43
527.07


 


 737








82
7.99
500.1


 


 738








88
8.92
692.79


 


 739








85
9.23
594.87


 


 740








71
8.84
565.1


 


 741








79
8.36
565.08


 


 742








82
7.77
475.06


 


 743








81
7.91
433.13


 


 744








86
6.72
434.21


 


 745








82
8.03
417.15


 


 746








74
7.32
390.17


 


 747








86
8.61
582.85


 


 748








76
8.94
485.01


 


 749








73
8.33
455.19


 


 750








84
7.59
455.2


 


 751








67
8.82
525.96


 


 752








75
8.93
484.08


 


 753








68
8.08
485.14


 


 754








75
9.08
468.06


 


 755








78
8.77
441.06


 


 756








81
9.56
633.79


 


 757








81
9.77
535.91


 


 758








70
9.55
506.12


 


 759








78
9.21
506.13
















 












Ex.
R2
R3
Purity (%)
rt (min.)
[M + H]+





 760








92.9
5.03
436.23


 


 761








90.4
5.56
422.33


 


 762








94.36
4.94
420.26


 


 763








88.08
5.09
428.30


 


 764








77.6
4.42
423.34


 


 765








92.4
5.52
480.38


 


 766








84.6
4.8
402.25


 


 767








89.8
5.79
462.37


 


 768








91.9
5.12
460.20


 


 769








91.4
5.14
476.21


 


 770








94.2
5.67
514.18


 


 771








93.0
5.37
464.18


 


 772








94.5
5.64
572.07


 


 773








87.9
5.76
522.21


 


 774








91.2
5.12
474.23


 


 775








78.1
5.82
530.27


 


 776








88.8
4.55
408.22


 


 777








90.7
5.13
394.34


 


 778








92.6
4.45
392.23


 


 779








88.8
4.65
400.30


 


 780








76.5
3.94
395.33


 


 781








90.8
5.11
452.38


 


 782








87.7
4.33
374.29


 


 783








91.5
5.35
434.38


 


 784








92.1
4.61
424.25


 


 785








89.3
5.28
410.33


 


 786








95
4.49
408.22


 


 787








82.4
4.74
416.27


 


 788








73.8
3.95
411.30


 


 789








92.9
5.27
468.36


 


 790








84.9
4.39
390.28


 


 791








91.5
5.53
450.37


 


 792








90
5.5
462.19


 


 793








93.9
6.25
448.31


 


 794








94.9
5.41
446.22


 


 795








93.5
5.76
454.26


 


 796








89.8
4.95
449.30


 


 797








92.4
6.22
506.34


 


 798








93
5.52
428.245


 


 799








92.8
6.39
488.34


 


 800








87.6
5.11
412.20


 


 801








92.5
5.9
398.30


 


 802








93.5
5
396.20


 


 803








92.2
5.35
404.26


 


 804








90.7
4.41
399.28


 


 805








94.2
5.87
456.34


 


 806








89.3
5.05
378.23


 


 807








90.9
6.07
438.33


 


 808








88.8
5.43
520.09


 


 809








94
6.19
506.19


 


 810








95.9
5.33
504.12


 


 811








92.9
5.68
512.15


 


 812








88.9
4.8
507.18


 


 813








92.3
6.17
564.20


 


 814








93.9
5.41
486.14


 


 815








93.5
6.35
546.18


 


 816








91.9
5.41
470.25


 


 817








93
5.98
456.34


 


 818








91.4
5.29
454.24


 


 819








90.4
5.49
462.29


 


 820








86.5
4.75
457.34


 


 821








90.5
5.94
514.34


 


 822








90.1
5.21
436.26


 


 823








89.7
6.18
496.37


 


 824








79.4
4.56
422.22


 


 825








92.5
5.08
408.32


 


 826








93
4.45
406.23


 


 827








90.2
4.63
414.26


 


 828








76.3
4.01
409.31


 


 829








94
5.08
466.36


 


 830








90.7
4.34
388.25


 


 831








92.9
5.29
448.36


 


 832








56
5.3
478.29


 


 833








83.9
5.7
464.38


 


 834








82.1
5.19
462.29


 


 835








80.5
5.31
470.35


 


 836








70.6
4.8
465.39


 


 837








82.9
5.67
522.41


 


 838








81
5.07
444.33


 


 839








83.5
5.91
504.41
















 












Ex.
R2
R3
Purity (%)
rt (min.)
[M + H]+





 840








35 + 64
3.68 + 3.78
423.2


 


 841








98
3.7
438.3


 


 842








35 + 63
4.3 + 4.4
446.2


 


 843








97
3.71
436.3


 


 844








32 + 65
3.28 + 3.34
447.3


 


 845








96
3.84
392.3


 


 846








96
4.18
447.3


 


 847








30 + 64
3.62 + 3.64
475.3


 


 848








36 + 61
4.46 + 4.61
418.3


 


 849








96
5.89
569.1


 


 850








94
6.09
584.2


 


 851








57 + 39
6.55 + 6.6 
592.1


 


 852








96
6.16
582.2


 


 853








28 + 59
5.53 + 5.61
593.2


 


 854








95
6.35
538.2


 


 855








54 + 41
 6.8 + 6.88
593.3


 


 856








94
5.96
621.2


 


 857








56 + 39
6.46 + 6.55
564.2


 


 858








34 + 63
4.09 + 4.2 
451.3


 


 859








96
4.03
466.4


 


 860








33 + 64
4.69 + 4.76
474.3


 


 861








27 + 70
4.04 + 4.07
464.4


 


 862








33 + 63
3.63 + 3.71
475.4


 


 863








95
4.18
420.4


 


 864








89
4.46
475.4


 


 865








22 + 68
3.94 + 3.98
503.4


 


 866








35 + 62
 4.9 + 5.01
446.4


 


 867








35 + 61
4.39 + 4.52
487.3


 


 868








33 + 63
4.22 + 4.29
502.3


 


 869








35 + 62
5.08 + 5.2 
510.2


 


 870








31 + 63
4.26 + 4.34
500.3


 


 871








33 + 62
3.82 + 3.91
511.3


 


 872








31 + 62
4.42 + 4.51
456.3


 


 873








29 + 64
4.66 + 4.72
511.4


 


 874








33 + 57
4.11 + 4.2 
539.3


 


 875








35 + 62
5.26 + 5.39
482.3


 


 876








32 + 65
3.63 + 3.7 
467.3


 


 877








97
3.69
482.4


 


 878








35 + 62
 4.2 + 4.28
490.3


 


 879








94
3.69
480.3


 


 880








28 + 68
 3.3 + 3.33
491.3


 


 881








96
3.8
436.3


 


 882








96
4.18
491.4


 


 883








94
3.63
519.3


 


 884








36 + 61
4.28 + 4.42
462.3


 


 885








36 + 62
4.24 + 4.36
517.3


 


 886








28 + 69
4.15 + 4.21
532.3


 


 887








35 + 62
4.84 + 4.96
540.2


 


 888








33 + 64
4.15 + 4.22
530.3


 


 889








32 + 63
3.76 + 3.84
541.3


 


 890








32 + 63
4.28 + 4.36
486.3


 


 891








24 + 73
4.56 + 4.6 
541.3


 


 892








31 + 59
4.05 + 4.11
569.3


 


 893








35 + 61
4.99 + 5.14
512.3


 


 894








33 + 64
5.59 + 5.7 
576.3


 


 895








35 + 61
5.29 + 5.39
591.3


 


 896








26 + 71
6.32 + 6.35
599.2


 


 897








34 + 63
5.41 + 5.5 
589.3


 


 898








35 + 61
4.88 + 4.99
600.3


 


 899








35 + 62
5.63 + 5.72
545.3


 


 900








34 + 61
5.76 + 5.86
600.3


 


 901








34 + 68
5.16 + 5.28
628.3


 


 902








98
6.45
571.3


 


 903








35 + 60
3.84 + 3.93
502.3


 


 904








32 + 62
3.72 + 3.79
517.3


 


 905








32 + 62
4.59 + 4.68
525.2


 


 906








33 + 61
3.75 + 3.82
515.3


 


 907








29 + 64
3.18 + 3.26
526.3


 


 908








32 + 59
  4 + 4.09
471.3


 


 909








32 + 60
4.28 + 4.38
526.3


 


 910








34 + 56
3.62 + 3.71
554.3


 


 911








31 + 63
4.58 + 4.66
497.3
















 












Ex.
R1
R3
Purity (%)
rt (min.)
[M + H]+





 912








 6.8 + 91.2
 3.6 + 3.76
332.22


 


 913








88.1
3.94
352.19


 


 914








89.6
4.22
380.22


 


 915








61.6
3.95
382.17


 


 916








83.5
3.8
377.19


 


 917








84.2
4.41
430.10


 


 918








70.9
4.24
393.18


 


 919








84.1
4.1
397.16


 


 920








82.2
4.55
436.05


 


 921








82.8
4.66
392.17


 


 922








98
4.25
380.22


 


 923








91.1
4.26
400.17


 


 924








92.4
4.46
428.21


 


 925








93.8
4.23
430.20


 


 926








86.4
4.14
425.17


 


 927








92.3
4.7
478.11


 


 928








82
4.56
441.18


 


 929








90.9
4.44
445.18


 


 930








89.8
4.9
484.07


 


 931








86.4
5.0
440.17


 


 932








97.2
4.38
394.22


 


 933








86.3
4.48
414.18


 


 934








92.6
4.68
442.22


 


 935








91
4.44
444.22


 


 936








85.9
4.34
439.18


 


 937








88.2
4.86
492.12


 


 938








83.6
4.71
455.2


 


 939








87.8
4.59
459.19


 


 940








89.8
5.0
498.09


 


 941








83.9
5.14
454.20


 


 942








87.7
4.26
384.17


 


 943








94.7
4.5
404.15


 


 944








18.6 + 76.4
 4.2 + 4.64
432.18


 


 945








95.2
4.32
434.16


 


 946








92
4.46
429.15


 


 947








94.4
5.08
482.06


 


 948








93
4.86
445.16


 


 949








94.2
4.82
449.13


 


 950








93.1
5.34
488.03


 


 951








93.7
5.47
444.16


 


 952








91.5
4.43
400.13


 


 953








95
4.82
420.12


 


 954








14.8 + 81.2
4.38 + 4.88
448.15


 


 955








95.8
4.64
450.13


 


 956








95
4.79
445.11


 


 957








95.4
5.4
498.06


 


 958








93.9
5.14
461.12


 


 959








94.5
5.12
465.10


 


 960








94.6
5.62
504.00


 


 961








96.4
5.74
460.13


 


 962








 6.5 + 87.5
 4.2 + 4.54
416.19


 


 963








92.9
4.76
436.17


 


 964








17.3 + 6.2 
4.5 + 4.9
464.21


 


 965








92.6
4.64
466.17


 


 966








89
4.76
461.16


 


 967








94.1
5.32
514.09


 


 968








92.1
5.09
477.19


 


 969








90.5
5.1
481.16


 


 970








92
5.56
520.02


 


 971








93
5.72
476.17


 


 972








91.6
4
410.16


 


 973








89.7
4.28
430.15


 


 974








83.4
4.46
458.19


 


 975








96.9
4.19
460.16


 


 976








58.2
4.29
455.12


 


 977








81.4
4.84
508.06


 


 978








85.8
4.64
471.15


 


 979








46.8
4.62
475.14


 


 980








77.4
5.06
514.02


 


 981








61.7
5.24
470.16


 


 982








4.8
3.54
356.15


 


 983








71.4
4.1
376.14


 


 984








79
4.3
404.17


 


 985








88.3
4.0
406.13


 


 986








12.2
5.32
401.11


 


 987








46.5
4.72
454.04


 


 988








56.3
4.49
417.15


 


 989








13.8
5.52
421.12


 


 990








35.3
4.95
460.02


 


 991








9.1
5.71
416.11
















 












Ex.
R1
R3
Purity (%)
rt (min.)
[M + H]+





 992








95.3
3.33
367.12


 


 993








91.9
3.97
400.03


 


 994








92.5
3.64
336.17


 


 995








83.7
3.75
363.13


 


 996








94.7
4.88
458.11


 


 997








93.1
4.03
372.14


 


 998








92.6
3.37
380.14


 


 999








92.1
4.36
362.12


 


1000








91
3.32
405.11


 


1001








87.8
3.9
397.14


 


1002








64.2
4.46
430.09


 


1003








61.6
4.18
366.23


 


1004








45.6
4.26
393.16


 


1005








72.4
5.28
488.17


 


1006








67
4.47
402.17


 


1007








51.1
3.86
410.16


 


1008








57.6
4.86
392.16


 


1009








75.1
3.92
435.16


 


1010








90.7
3.24
399.13


 


1011








79.6
3.79
432.06


 


1012








74.5
3.55
368.16


 


1013








58.8
3.62
395.15


 


1014








81
4.65
490.15


 


1015








86.8
3.88
404.17


 


1016








71.4
3.3
412.13


 


1017








73.7
4.13
394.15


 


1018








80.5
3.3
437.15


 


1019








94.6
4.19
417.10


 


1020








94.8
4.76
450.07


 


1021








92.9
4.42
386.13


 


1022








88.8
4.56
413.11


 


1023








94.1
5.48
508.13


 


1024








93.8
4.79
422.13


 


1025








92.3
4.04
430.15


 


1026








90
5.08
412.10


 


1027








93.2
3.95
455.13


 


1028








92.6
4.3
435.1


 


1029








92.8
4.9
470.1


 


1030








89.2
4.6
404.1


 


1031








89.2
4.76
431.1


 


1032








94.3
5.6
526.1


 


1033








93.5
5
440.2


 


1034








92.4
4.2
448.1


 


1035








87.9
5.2
430.1


 


1036








93.6
4.1
473.2


 


1037








80.4
4.16
447.14


 


1038








72.7
4.72
480.08


 


1039








77
4.39
416.14


 


1040








59.2
4.5
443.16


 


1041








16.8
5.98
538.12


 


1042








59.5
4.74
452.16


 


1043








74
4.02
460.16


 


1044








26.3
5.52
442.13


 


1045








91
3.82
485.17


 


1046








89.8
5.09
507.19


 


1047








84.5
5.52
540.09


 


1048








86
5.06
476.21


 


1049








75.6
5.22
503.21


 


1050








90.3
6.14
598.15


 


1051








85.9
5.38
512.22


 


1052








81.3
4.68
520.19


 


1053








83.3
5.66
502.20


 


1054








82
4.92
545.17


 


1055








93.1
4.34
445.16


 


1056








81.5
4.77
478.10


 


1057








79.9
4.46
414.17


 


1058








70.2
4.56
441.15


 


1059








85.8
5.56
536.11


 


1060








84.1
4.73
450.19


 


1061








78.4
4.12
458.20


 


1062








83.3
5.13
440.16


 


1063








83.1
4.22
















 












Ex.
R1
R3
Purity (%)
rt (min.)
[M + H]+





1064








86.6
3.52
338.12


 


1065








90.4
3.44
383.09


 


1066








87.3
4.25
422.10


 


1067








85.9
4.04
416.04


 


1068








70.5
4.4
444.18


 


1069








80.1
4.83
474.13


 


1070








80.6
4.34
402.16


 


1071








80.8
4.37
378.14


 


1072








86.5
4.77
442.06


 


1073








83.4
4.72
405.12


 


1074








90.5
3.02
340.15


 


1075








93.5
2.98
385.10


 


1076








91.7
3.9
424.12


 


1077








90.8
3.62
418.04


 


1078








80.8
4.09
446.18


 


1079








88.1
4.6
476.12


 


1080








91.5
3.98
404.16


 


1081








89.2
3.87
380.13


 


1082








87.3
4.36
444.10


 


1083








90.6
4.24
407.13


 


1084








86.4
4.24
414.15


 


1085








91.8
4.21
459.17


 


1086








88.2
4.89
498.19


 


1087








85.8
4.71
492.12


 


1088








76.1
4.9
520.21


 


1089








83.3
5.45
550.17


 


1090








84.9
4.9
478.24


 


1091








86.1
5.08
454.19


 


1092








78
5.38
518.14


 


1093








84.5
5.38
481.21


 


1094








37.5
3.36
386.14


 


1095








57.1
3.35
431.14


 


1096








44
3.78
470.17


 


1097








42
3.62
464.09


 


1098








38.8
4.14
492.21


 


1099








45.2
3.98
522.14


 


1100








33.4
3.99
450.20


 


1101








44.7
3.68
426.14


 


1102








33.4
4.08
490.12


 


1103








42.4
3.67
453.17


 


1104








92.6
4.23
390.14


 


1105








91.9
4.1
439.1


 


1106








92.1
5
474.13


 


1107








93
4.85
468.04


 


1108








86.5
5.04
496.18


 


1109








92.8
5.5
526.13


 


1110








92.8
5.1
454.17


 


1111








92
5.1
430.10


 


1112








92.8
5.48
494.08


 


1113








92.8
5.1
457.18


 


1114








93.8
4.6
406.10


 


1115








93.6
4.5
451.03


 


1116








93.1
5.2
490.10


 


1117








94.5
5.1
483.99


 


1118








89.54
5.29
512.13


 


1119








95.2
5.6
542.1


 


1120








92.8
5.38
470.15


 


1121








93.4
5.3
445.94


 


1122








94.7
5.7
510.05


 


1123








94.3
5.3
473.04


 


1124








89.5
4.06
400.12


 


1125








92.1
4.13
445.13


 


1126








88.9
4.81
484.15


 


1127








88.8
4.56
478.09


 


1128








82.4
4.76
506.20


 


1129








88.6
5.36
536.12


 


1130








85.7
4.78
464.18


 


1131








84
4.94
440.15


 


1132








64.3
5.38
504.10


 


1133








88.4
5.16
467.17


 


1134








82.7
3.76
446.16


 


1135








89
3.77
491.14


 


1136








87.1
4.4
530.13


 


1137








84.6
4.21
524.08


 


1138








76
4.52
552.19


 


1139








85.6
4.98
582.12


 


1140








83.1
4.44
510.21


 


1141








88.3
4.6
486.19


 


1142








1.5
5.07
550.12


 


1143








84
4.75
513.16
















 












Ex.
R1
R3
Purity (%)
rt (min.)
[M + H]+





1144








75
4.48
300.16


 


1145








82
4.89
348.16


 


1146








86.7
4.72
354.09


 


1147








89
4.96
398.01


 


1148








87
4.37
345.18


 


1149








90
5.4
396.1


 


1150








89
5.9
448.2


 


1151








85
5
404


 


1152








85
4.96
360.10


 


1153








91
4.39
417.14


 


1154








95
5.14
366.21


 


1155








92
5.52
414.17


 


1156








95
5.37
420.13


 


1157








93
5.6
464.08


 


1158








94
5
411.2


 


1159








91
6.04
462.19


 


1160








91.5
6.4
514.2


 


1161








92.6
5.7
470.1


 


1162








93.8
5.6
426.14


 


1163








91.4
5.02
483.21


 


1164








96.3
5.55
420.10


 


1165








78.2
5.81
468.10


 


1166








96.7
5.6
474.06


 


1167








96.9
5.8
517.97


 


1168








94.2
5.18
465.06


 


1169








94
6.25
516.10


 


1170








96.4
6.52
568.2


 


1171








94.6
5.9
524.0


 


1172








94.9
5.81
480.07


 


1173








91.9
5.25
537.09


 


1174








77.4
5.24
486.16


 


1175








96.8
5.36
402.15


 


1176








92.4
5.66
450.19


 


1177








93.3
5.48
456.12


 


1178








93.3
5.7
500.08


 


1179








90.7
5.12
447.15


 


1180








91.9
6.12
498.21


 


1181








95.1
6.5
550.3


 


1182








92.8
5.7
506.0


 


1183








94.9
5.74
462.15


 


1184








91.4
5.13
519.17


 


1185








73.6
3.52
346.19


 


1186








71.5
4.5
394.17


 


1187








82.2
4.58
400.10


 


1188








78.6
4.86
444.09


 


1189








70.5
5.3
442.17


 


1190








76.8
5
406.13


 


1191








80.5
4.1
463.19
















 












Ex.
R2
R5
Purity (%)
rt (min.)
[M + H]+





1192








28.3
3.61
373.15


 


1193








64.3
2.55
396.15


 


1194








66.8
3.58
425.13


 


1195








51.9
3.47
387.07


 


1196








75.8
4.43
471.21


 


1197








66.4
2.38
399.15


 


1198








42.6
3.11
474.14


 


1199








45.3
4.39
457.18


 


1200








64
4.62
485.21


 


1201








55.1
4.09
429.12


 


1202








75
4.22
449.13


 


1203








67.9
3.64
417.11


 


1204








31.7 + 17.3
4.65 + 4.8 
429.24


 


1205








41.8
3.86
407.14


 


1206








67.8
4.58
487.20


 


1207








33.2
4.31
415.20


 


1208








60.9
3.29
438.21


 


1209








58
4.29
467.18


 


1210








51.9
4.21
429.15


 


1211








70
5.03
513.24


 


1212








22.9
3.17
441.19


 


1213








71.8
3.81
516.16


 


1214








35.4
5.03
499.23


 


1215








64
5.18
527.25


 


1216








68.2
4.71
471.19


 


1217








76.5
4.84
491.18


 


1218








67.6
4.35
459.16


 


1219








28.7 + 14.2
5.27 + 5.4 
471.30


 


1220








66.9
4.52
449.21


 


1221








64.1
5.17
529.21


 


1222








49.7
4.55
423.19


 


1223








78.8
3.41
446.17


 


1224








76.2
4.48
475.15


 


1225








68.3
4.42
437.12


 


1226








79.6
5.24
521.17


 


1227








49.1
3.29
449.20


 


1228








72.2
4
524.15


 


1229








69.7
5.22
507.20


 


1230








75
5.42
535.20


 


1231








78
4.93
479.13


 


1232








79.1
5.04
499.16


 


1233








82.6
4.56
467.13


 


1234








  45 + 24.6
5.53 + 5.7 
479.26


 


1235








77
4.75
457.18


 


1236








70.4
5.41
537.18


 


1237








47.7
4.38
407.12


 


1238








71.3
3.27
430.12


 


1239








70.2
4.35
459.10


 


1240








68.1
4.27
421.06


 


1241








78.8
5.13
505.13


 


1242








24
3.17
433.11


 


1243








74.2
3.86
508.08


 


1244








43
5.16
491.08


 


1245








71.8
5.38
519.12


 


1246








69.9
4.85
463.05


 


1247








79.2
4.96
483.10


 


1248








77.9
4.45
451.07


 


1249








42.6 + 23.5
5.42 + 5.6 
463.20


 


1250








70
4.65
441.11


 


1251








72
5.36
521.12


 


1252








28.2
4.96
441.14


 


1253








65.8
3.69
464.14


 


1254








51
4.86
493.14


 


1255








64.5
4.79
455.08


 


1256








72.2
5.55
539.16


 


1257








27.2
3.59
467.16


 


1258








38.6
4.38
542.12


 


1259








49.4
5.53
525.16


 


1260








60.6
5.73
553.20


 


1261








67.7
5.27
497.13


 


1262








80.8
5.34
517.12


 


1263








78
4.92
485.13


 


1264








28.5 + 14.4
5.87 + 6.0 
497.26


 


1265








60.5
5.13
475.16


 


1266








65.7
5.73
555.14
















 












Ex.
R2
R5
Purity (%)
rt (min.)
[M + H]+





1267








60
3.86
439.18


 


1268








88.1
2.89
478.24


 


1269








89.1
3.83
389.20


 


1270








94.3
2.41
396.14


 


1271








94
2.33
418.20


 


1272








80.3
4.05
533.17


 


1273








93
4.33
485.23


 


1274








90.5
4.27
471.22


 


1275








82.4
3.94
423.20


 


1276








92.8
4.07
487.10


 


1277








92.3
4.09
463.16


 


1278








90.6
2.9
430.20


 


1279








94.7
3.69
431.14


 


1280








90.6
4.37
471.21


 


1281








86.4
4.51
501.20


 


1282








93.1
4.16
463.09


 


1283








63.6
5.58
541.11


 


1284








82.4
4.23
580.17


 


1285








87.6
5.63
491.16


 


1286








91.5
4.03
498.13


 


1287








89.5
3.91
520.13


 


1288








82.2
5.61
635.14


 


1289








92.3
5.9
587.14


 


1290








89.9
5.86
573.11


 


1291








90
5.66
525.14


 


1292








90.9
5.73
589.02


 


1293








91.2
5.69
565.07


 


1294








89.4
4.72
532.13


 


1295








93.3
5.44
533.08


 


1296








93.1
5.95
573.11


 


1297








90.1
6.06
603.16


 


1298








90.3
5.79
565.00


 


1299








63.6
4.65
515.20


 


1300








82.9
3.63
554.24


 


1301








85.9
4.67
465.23


 


1302








85.4
3.41
472.20


 


1303








83.7
3.31
494.23


 


1304








84.2
4.79
609.20


 


1305








86.5
5.11
561.20


 


1306








84.2
5.11
547.19


 


1307








84.8
4.75
499.23


 


1308








89
4.89
539.15


 


1309








85.9
3.76
506.23


 


1310








88.5
4.59
507.17


 


1311








87.8
5.16
547.20


 


1312








1.5
5.6
577.22


 


1313








89.7
4.99
539.10


 


1314








65.3
4.81
545.20


 


1315








86.7
3.82
584.25


 


1316








87.6
4.81
495.24


 


1317








91
3.63
502.20


 


1318








90.2
3.54
524.24


 


1319








85.4
4.91
639.22


 


1320








85.7
5.21
591.23


 


1321








90
5.19
577.22


 


1322








87.9
4.87
529.22


 


1323








86.4
5
593.12


 


1324








87.5
5.01
569.16


 


1325








89.7
4
536.23


 


1326








89.6
4.73
537.18


 


1327








89.6
5.24
577.24


 


1328








86.7
5.33
607.24


 


1329








90.6
5.1
569.10


 


1330








62.1
4.17
467.23


 


1331








92.8
3.23
506.28


 


1332








81.3
4.14
417.24


 


1333








91.9
2.95
424.19


 


1334








91.8
2.87
446.24


 


1335








78.7
4.31
561.19


 


1336








89.5
4.58
513.25


 


1337








91.3
4.54
499.24


 


1338








80.3
4.24
451.23


 


1339








77.6
4.37
515.12


 


1340








85.7
4.37
491.18


 


1341








92.3
3.34
458.25


 


1342








90.8
4.05
459.19


 


1343








79.9
4.63
499.25


 


1344








76.6
4.75
529.24


 


1345








91.9
4.45
491.13
















 












Ex.
R2
R5
Purity (%)
rt (min.)
[M + H]+





1346








56.9 + 24.5
4.07 + 4.2 
417.23


 


1347








64.6 + 24.4
4.98 + 5.1 
526.30


 


1348








62.4 + 25.1
3.96 + 4.1 
430.25


 


1349








80.5
3.44
490.37


 


1350








65.4 + 27.8
4.9 + 5.0
503.31


 


1351








64.5 + 25.5
5.6 + 5.7
536.35


 


1352








86.8
3.3
509.30


 


1353








64.1 + 29.8
5.02 + 5.1 
537.26


 


1354








60.8 + 32.2
5.37 + 5.5 
543.32


 


1355








59.6 + 31.5
5.24 + 5.3 
545.30


 


1356








61.6 + 24.8
4.69 + 4.8 
527.31


 


1357








88.7
3.8
536.36


 


1358








87.5
3.8
528.38


 


1359








  58 + 25.2
4.12 + 4.3 
417.27


 


1360








68.1 + 24.5
5.22 + 5.3 
529.31


 


1361








64.8 + 23.1
5.12 + 5.2 
535.19


 


1362








61.9 + 21.6
5.46 + 5.5 
535.23


 


1363








90.4
6.06
644.33


 


1364








89.7
5.31
548.24


 


1365








84.3
4.5
608.34


 


1366








95.2
6.06
621.27


 


1367








90.9
6.6
654.4


 


1368








84.2
4.41
627.29


 


1369








92.8
6.12
655.27


 


1370








91.9
6.4
661.33


 


1371








93.2
6.3
663.32


 


1372








87.3
5.9
645.32


 


1373








87.5
4.7
654.4


 


1374








84.8
4.7
646.38


 


1375








71.8
5.53
535.23


 


1376








94.2
6.28
647.32


 


1377








91.6
6.25
653.22


 


1378








  63 + 26.1
3.98 + 4.2 
441.30


 


1379








64.5 + 28  
4.8 + 5.0
550.36


 


1380








65.1 + 26.9
3.93 + 4.1 
454.30


 


1381








56.6 + 30.1
3.54 + 3.6 
514.40


 


1382








64.8 + 30.3
4.64 + 4.9 
527.34


 


1383








64.3 + 28.3
5.33 + 5.6 
560.39


 


1384








64.5 + 24.8
3.5 + 3.6
533.35


 


1385








62.9 + 27.5
4.77 + 5.0 
561.29


 


1386








48.5 + 20.8
5.08 + 5.3 
567.36


 


1387








61.2 + 27.5
4.98 + 5.2 
569.33


 


1388








58.4 + 22.7
4.5 + 4.7
551.36


 


1389








65.1 + 26.4
3.92 + 4.0 
560.38


 


1390








63.6 + 26.1
3.92 + 4.1 
552.43


 


1391








  64 + 27.3
4.01 + 4.2 
441.30


 


1392








66.2 + 28.9
4.96 + 5.2 
553.35


 


1393








62.8 + 26.6
4.84 + 5.0 
559.23


 


1394








59.4 + 26.3
3.95 + 4.1 
445.26


 


1395








63.7 + 28.7
4.89 + 5.1 
554.28


 


1396








  62 + 27.9
3.9 + 4.1
458.27


 


1397








58.9 + 28.7
3.48 + 3.5 
518.35


 


1398








62.9 + 29.3
4.75 + 5.0 
531.28


 


1399








63.2 + 28.4
5.46 + 5.7 
564.32


 


1400








58.3 + 30.4
3.39 + 3.5 
537.30


 


1401








61.8 + 28.3
4.88 + 5.0 
565.23


 


1402








61.5 + 27.9
5.2 + 5.4
571.28


 


1403








62.2 + 29.5
5.09 + 5.3 
573.28


 


1404








60.6 + 26.7
4.54 + 4.7 
555.30


 


1405








59.2 + 31.8
3.86 + 4.0 
564.32


 


1406








59.3 + 31.2
3.86 + 4.0 
556.37


 


1407








49.3 + 21.7
  4 + 4.2
445.26


 


1408








64.4 + 29.7
5.07 + 5.3 
557.28


 


1409








61.7 + 27.9
4.96 + 5.1 
563.20


 


1410








62.4 + 25.4
5.24 + 5.4 
552.27


 


1411








63.6 + 28.1
5.91 + 6.0 
661.33


 


1412








60.5 + 30.2
5.14 + 5.2 
565.25


 


1413








87.2
4.43
625.36


 


1414








60.9 + 31.9
5.88 + 6.0 
638.30


 


1415








61.1 + 31.2
6.47 + 6.6 
671.37


 


1416








89.3
4.34
644.35


 


1417








66.6 + 25.7
5.96 + 6.0 
672.28


 


1418








65.1 + 25.4
6.25 + 6.3 
678.35


 


1419








  63 + 27.5
6.13 + 6.2 
680.32


 


1420








54.7 + 29.8
5.75 + 5.8 
662.33


 


1421








91.7
4.71
671.38


 


1422








89.3
4.72
663.41


 


1423








  49 + 23.9
5.34 + 5.4 
552.26


 


1424








64.1 + 27.2
6.18 + 6.2 
664.34


 


1425








62.3 + 27.3
6.13 + 6.2 
670.25
















 












Ex.
R2
R5
Purity (%)
rt (min.)
[M + H]+





1426








78.4
4.58
463.27


 


1427








53.4
4.48
471.23


 


1428








86.2
3.67
526.29


 


1429








86
4.58
542.25


 


1430








84.9
4.98
546.21


 


1431








42.9
3.26
494.27


 


1432








84.4
4.14
522.26


 


1433








83.2
4.72
570.25


 


1434








87.1
4.04
530.22


 


1435








45.6
3.16
464.25


 


1436








85.6
4.4
475.20


 


1437








84.2
4.96
541.18


 


1438








87.2
3.88
554.28


 


1439








84.5
4.39
437.23


 


1440








33.8
5.34
593.17


 


1441








9.5
4.7
463.24


 


1442








78.8
5.11
499.20


 


1443








46.9
4.98
507.17


 


1444








87.9
3.88
562.19


 


1445








85.6
4.95
578.19


 


1446








84.9
5.3
582.14


 


1447








49
3.45
530.19


 


1448








81.4
4.62
558.18


 


1449








83
5.06
606.20


 


1450








84.9
4.42
566.15


 


1451








40.7
3.5
500.19


 


1452








85.1
4.87
511.13


 


1453








87.4
5.33
577.13


 


1454








85.6
4.08
590.24


 


1455








54.9
4.92
473.21


 


1456








43
5.66
629.13


 


1457








17.2
5.2
499.20


 


1458








77.6
4.3
479.20


 


1459








55.3
4.2
487.18


 


1460








85.2
3.32
542.22


 


1461








87
4.22
558.19


 


1462








85.9
4.64
562.14


 


1463








82.9
2.74
510.23


 


1464








81.6
3.84
538.20


 


1465








84.1
4.41
586.21


 


1466








85.5
3.65
546.16


 


1467








49.3
2.8
480.20


 


1468








81.7
4.11
491.15


 


1469








83.7
4.71
557.14


 


1470








82.2
3.59
570.24


 


1471








66.1
4.11
453.19


 


1472








29.5
5.12
609.14


 


1473








9.9
4.44
479.20


 


1474








82.8
5.36
491.28


 


1475








58.2
5.29
499.26


 


1476








86.5
4.37
554.27


 


1477








86.6
5.33
570.26


 


1478








84.1
5.67
574.20


 


1479








70.3
3.89
522.29


 


1480








84.2
4.94
550.28


 


1481








84.5
5.44
598.26


 


1482








86
4.84
558.24


 


1483








50.1
3.93
492.29


 


1484








82.5
5.23
503.25


 


1485








79.3
5.68
569.19


 


1486








87.3
4.51
582.31


 


1487








79.7
5.22
465.25


 


1488








26.1
6.06
621.20


 


1489








16.1
5.51
491.28


 


1490








77
5.02
453.22


 


1491








48.4
4.88
461.16


 


1492








83.3
3.74
516.22


 


1493








84.6
4.85
532.2


 


1494








84.4
5.23
536.15


 


1495








69.9
3.29
484.23


 


1496








79.5
4.51
512.22


 


1497








81.9
4.96
560.17


 


1498








85.5
4.29
520.16


 


1499








67.7
3.32
454.19


 


1500








82.7
4.78
465.14


 


1501








82.1
5.26
531.13


 


1502








84.8
3.95
544.22


 


1503








77.5
4.83
427.16


 


1504








24
5.6
583.11


 


1505








17.7
5.12
453.21
















 












Ex.
R2
R5
Purity (%)
rt (min.)
[M + H]+





1506








89.7
5.52
596.26


 


1507








87.2
5.37
562.23


 


1508








77
4.62
583.26


 


1509








89.1
3.7
579.25


 


1510








88.6
5.32
535.23


 


1511








87.6
4
570.27


 


1512








88
5.12
474.19


 


1513








90.5
5.09
519.14


 


1514








91.2
5.7
505.1


 


1515








88
3.74
475.17


 


1516








86.7
5.58
487.20


 


1517








88.3
3.88
532.18


 


1518








90.4
3
487.27


 


1519








92.8
4.86
443.21


 


1520








87.8
3.58
478.28


 


1521








90.4
5.2
478.28


 


1522








79.8
5.37
488.26


 


1523








90.3
5.13
523.27


 


1524








81.2
5.7
509.2


 


1525








91
3.88
479.26


 


1526








91.5
5.62
491.29


 


1527








91.1
4.1
536.28


 


1528








91.9
5.68
546.25


 


1529








92
5.54
512.24


 


1530








91.4
3.7
529.3


 


1531








92.4
5.49
485.23


 


1532








89.4
4.2
520.28
















 












Ex.
R2
R5
Purity (%)
rt (min.)
[M + H]+





1533








90.1
4.56
452.20


 


1534








76.8
4.76
462.18


 


1535








92.5
4.58
497.22


 


1536








93.4
3.21
453.21


 


1537








91.2
5.04
465.22


 


1538








92.7
3.44
510.22


 


1539








89.6
5.14
520.18


 


1540








90.2
4.93
486.17


 


1541








89.4
2.98
503.26


 


1542








90.9
4.84
459.18


 


1543








89.1
3.55
494.26
















 












Ex.
R2
R5
Purity (%)
rt (min.)
[M + H]+





1544








83.5
4.19
425.25


 


1545








78.8
5.1
535.25


 


1546








79.7
4.67
484.23


 


1547








88
5.46
537.27


 


1548








87.4
4.72
480.22


 


1549








82
4.94
494.23


 


1550








89.6
4.92
522.18


 


1551








86.9
5.03
599.27


 


1552








84.3
4.7
486.20


 


1553








82.7
3.36
455.18


 


1554








82
3.68
543.20


 


1555








86.7
3.91
557.20


 


1556








80.9
5.06
496.26


 


1557








83.1
4.35
420.21


 


1558








87.5
5.2
530.22


 


1559








76.7
4.62
495.27


 


1560








80.9
4.44
531.25


 


1561








85.7
5.16
584.30


 


1562








85.4
4.51
527.25


 


1563








82.1
4.66
541.25


 


1564








87.4
4.66
569.19


 


1565








82.9
5.03
646.34


 


1566








82.7
4.44
533.23


 


1567








85
3.46
502.24


 


1568








81.8
3.82
590.27


 


1569








84.5
4.03
604.26


 


1570








81.9
4.74
543.27


 


1571








84.3
4.13
467.25


 


1572








77.4
4.9
577.2


 


1573








77.7
5.15
550.3


 


1574








80.7
4.9
586.24


 


1575








86.4
5.6
639.34


 


1576








86.2
4.94
582.25


 


1577








82
5.17
596.28


 


1578








89.7
5.14
624.22


 


1579








86.1
5.22
701.35


 


1580








85.1
4.92
588.23


 


1581








81.7
3.67
557.23


 


1582








81
3.9
645.32


 


1583








85.2
4.12
659.31


 


1584








82.4
5.26
598.26


 


1585








83.6
4.62
522.25


 


1586








85.3
5.39
632.29


 


1587








82.8
4.94
481.16


 


1588








84.3
4.71
517.16


 


1589








89.6
5.54
570.16


 


1590








87.8
4.78
513.13


 


1591








85.2
4.99
527.15


 


1592








90.9
4.98
555.07


 


1593








88.1
5.21
632.22


 


1594








86.9
4.72
519.10


 


1595








87.4
3.47
488.12


 


1596








82.5
3.82
576.16


 


1597








86.1
4.06
590.12


 


1598








85.1
5.08
529.16


 


1599








84.8
4.34
453.13


 


1600








74.9
5.26
563.13
















 












Ex.
R2
R5
Purity (%)
rt (min.)
[M + H]+





1601








88.1
3.87
409.24


 


1602








90.1
4.0
423.26


 


1603








60.2
4.1
443.21


 


1604








91
3.9
427.24


 


1605








57.6
4.4
493.23


 


1606








48.1
4.12
423.27


 


1607








45.1
4.2
443.22


 


1608








60.8
4.49
493.24


 


1609








54.5
3.98
454.26


 


1610








84
4.19
443.23


 


1611








92.8
4.49
493.25


 


1612








86.2
4.51
477.21


 


1613








84.1
4.84
545.22


 


1614








77.7
4.34
459.30


 


1615








90.6
3.95
423.29


 


1616








91.8
4.6
499.35


 


1617








91.9
4.86 
519.27


 


1618








62
4.6
545.3


 


1619








91.7
4.28
449.32


 


1620








63.1
4.62
483.29


 


1621








83.8
4.41
431.26


 


1622








64.2
4.55
445.26


 


1623








48.9
4.66
465.21


 


1624








89
4.46
449.27


 


1625








56.7
4.94
515.24


 


1626








78.4
4.65
445.25


 


1627








44.5
4.72
465.21


 


1628








84.7
5.01
515.24


 


1629








73.9
4.5
476.27


 


1630








76.8
4.74
465.21


 


1631








88.6
5.02
515.24


 


1632








90.6
5.05
499.19


 


1633








89.4
5.35
567.21


 


1634








80.6
4.88
481.28


 


1635








90.6
4.49
445.26


 


1636








91.1
5.14
521.28


 


1637








91.2
5.38
541.23


 


1638








90
5.1
567.3


 


1639








92.9
4.84
471.28


 


1640








88.3
5.13
505.28
















 












Ex.
R2
R5
Purity (%)
rt (min.)
[M + H]+





1641








83.5
3.86
423.29


 


1642








81.9
4
437.30


 


1643








81.1
4.07
457.25


 


1644








89.9
3.89
441.27


 


1645








91.5
4.35
507.27


 


1646








70.6
4.08
437.31


 


1647








73.2
4.14
457.26


 


1648








91.7
4.42
507.27


 


1649








61.9
3.96
468.26


 


1650








82.6
41.6
457.25


 


1651








78.5
4.46
507.26


 


1652








80
4.46
491.21


 


1653








80.7
4.78
559.24


 


1654








90.3
4.28
473.33


 


1655








91.4
3.93
437.30


 


1656








93.5
4.55
513.33


 


1657








92.8
4.82
533.27


 


1658








58
4.5
559.3


 


1659








92.1
4.24
463.32


 


1660








92.2
4.53
497.29


 


1661








36.9
4.42
445.25


 


1662








31
4.56
459.28


 


1663








38.9
4.67
479.24


 


1664








43.4
4.47
463.27


 


1665








47.9
4.98
529.2


 


1666








32.1
4.66
459.28


 


1667








23
4.74
479.23


 


1668








38.1
5.02
529.25


 


1669








35.5
4.51
490.27


 


1670








47.1
4.74
479.23


 


1671








37.1
5.04
529.25


 


1672








60.9
5.07
513.19


 


1673








82.8
5.34
581.23


 


1674








20.5
4.91
495.27


 


1675








72
4.52
459.28


 


1676








91.1
5.14
535.30


 


1677








89.3
5.4
555.23


 


1678








52
5.1
581.3


 


1679








91.3
4.84
485.31


 


1680








71.7
5.14
519.29


 


1681








72.7
4.26
471.34


 


1682








76.3
4.36
485.34


 


1683








51.6
4.47
485.33


 


1684








33.6
4.39
501.32


 


1685








79.9
4.7
539.29


 


1686








76
4.77
555.28


 


1687








53.2
4.34
489.30


 


1688








59.2
4.51
505.27


 


1689








74.7
4.57
549.21


 


1690








82
4.84
547.34


 


1691








68.8
4.49
485.32


 


1692








73.4
4.25
510.37


 


1693








75.0
4.83
555.27


 


1694








44.5
4.39
489.30


 


1695








42.7
4.57
505.25


 


1696








79.8
4.97
547.32


 


1697








78.9
4.56
499.39


 


1698








70.8
4.27
531.36


 


1699








77.5
4.35
507.33


 


1700








78.9
4.34
507.33


 


1701








75.8
4.27
507.32


 


1702








74.9
4.41
507.32


 


1703








75.3
4.49
507.29


 


1704








73.5
4.75
539.22


 


1705








82.9
4.7
521.31
















 












Ex.
R1
R5
Purity (%)
rt (min.)
[M + H]+





1706








87.3
3.8
448.31


 


1707








86.0
4.3
482.24


 


1708








90.0
2.4
370.24


 


1709








76.6
3.88
387.26


 


1710








53.2
3.0
394.2


 


1711








91.2
2.3
449.29


 


1712








87.7
4.13
443.29


 


1713








88.3
3.7
419.28


 


1714








70.8
3.5
437.25


 


1715








87.0
4.4
469.30


 


1716








82.5
4.12
485.20


 


1717








88.1
2.59
428.29


 


1718








88.7
2.8
490.35


 


1719








79.0
4.68
529.23


 


1720








78.0
3.94
399.29


 


1721








87.4
3.7
480.32


 


1722








83.1
4.14
514.28


 


1723








89.1
2.44
402.24


 


1724








81.5
3.73
419.3


 


1725








56.1
3.0
416.2


 


1726








90.1
2.3
481.33


 


1727








87.3
3.96
475.31


 


1728








75.2
2.9
448.3


 


1729








85.7
3.61
451.29


 


1730








74.5
3.37
469.28


 


1731








83.7
4.22
501.32


 


1732








86.7
3.95
517.20


 


1733








80.6
2.61
460.32


 


1734








80.8
2.8
522.35


 


1735








74.0
4.48
561.23


 


1736








81.2
3.8
431.31


 


1737








87.1
4.76
546.27


 


1738








85.5
5.16
580.24


 


1739








85.5
3.72
468.24


 


1740








82.1
4.74
485.29


 


1741








80.7
3.04
492.24


 


1742








87.7
3.4
547.28


 


1743








81.9
4.96
541.23


 


1744








55.2
2.9
514.27


 


1745








87.2
4.7
517.25


 


1746








73.7
4.39
535.21


 


1747








84.3
5.22
567.25


 


1748








74.7
4.9
583.16


 


1749








76.8
3.53
526.28


 


1750








84.3
3.7
588.34


 


1751








74.4
5.41
627.20


 


1752








80.9
4.88
497.31


 


1753








83.4
4.53
516.2


 


1754








83.2
4.96
550.24


 


1755








84.1
3.39
438.25


 


1756








84.7
4.71
455.28


 


1757








56.6
2.8
462.24


 


1758








85.0
3.0
517.30


 


1759








84.6
4.9
511.26


 


1760








82.1
2.8
484.3


 


1761








84.4
4.44
487.27


 


1762








52.0
4.3
505.23


 


1763








84.5
5.12
537.28


 


1764








81.5
4.93
553.17


 


1765








80.2
3.34
496.29


 


1766








85.9
3.5
558.31


 


1767








53.4
5.39
597.22


 


1768








81.6
4.81
467.29


 


1769








83.5
3.5
540.32


 


1770








82.4
5.01
574.27


 


1771








80.9
3.72
462.30


 


1772








77.9
4.78
479.36


 


1773








79.3
3.11
486.32


 


1774








85.0
3.4
541.35


 


1775








85.3
4.9
535.31


 


1776








74.9
3.0
508.34


 


1777








83.9
4.58
511.33


 


1778








69.1
4.4
529.3


 


1779








83.1
5.1
561.3


 


1780








81.8
4.9
577.23


 


1781








83.6
3.64
520.34


 


1782








80.9
3.7
582.4


 


1783








68.0
5.34
621.28


 


1784








76.3
4.85
491.36
















 












Ex.
R1
R5
Purity (%)
rt (min.)
[M + H]+





1785








77.9
4.44
435.25


 


1786








78.8
4.83
437.30


 


1787








79.5
3.13
464.27


 


1788








80.3
3.28
526.38


 


1789








86.6
4.67
543.32


 


1790








74.8
2.9
458.32


 


1791








81.7
3.99
508.34


 


1792








86.9
5.41
526.38


 


1793








86.4
4.85
511.27


 


1794








82.2
5.07
533.35


 


1795








83.1
3.55
536.28


 


1796








82.3
4.66
471.3


 


1797








86.3
4.41
461.31


 


1798








85.1
4.95
505.33


 


1799








76.0
3.5
532.3


 


1800








81.1
4.87
483.34


 


1801








68.62
3.96
387.33


 


1802








73.4
4.39
389.33


 


1803








81.2
2.57
416.32


 


1804








79.2
2.9
478.3


 


1805








83.2
4.26
495.34


 


1806








70.2
2.5
410.3


 


1807








73.3
3.6
460.37


 


1808








75.0
5.01
478.39


 


1809








70.3
4.45
463.31


 


1810








83.9
4.73
485.37


 


1811








76.5
3.14
488.31


 


1812








79.1
4.28
423.35


 


1813








79.2
3.99
413.29


 


1814








75.5
4.55
457.33


 


1815








67.7
3.1
484.3


 


1816








62.7
4.44
435.33


 


1817








85.7
5.02
471.33


 


1818








70.2
5.31
473.37


 


1819








86.6
3.59
500.35


 


1820








83.8
3.7
562.4


 


1821








88.5
5.04
579.32


 


1822








39.8
3.3
494.3


 


1823








85.8
4.55
544.33


 


1824








86.4
5.78
562.36


 


1825








84.3
5.27
547.25


 


1826








69.7
5.58
569.32


 


1827








70.3
4.17
572.27


 


1828








85.4
5.17
507.34


 


1829








82.3
4.91
497.28


 


1830








82.4
5.41
541.29


 


1831








79.4
3.8
568.3


 


1832








86.9
5.31
519.33


 


1833








86.3
4.99
455.27


 


1834








84.5
5.3
457.30


 


1835








88.3
3.42
484.27


 


1836








83.6
3.65
546.29


 


1837








88.8
4.91
563.24


 


1838








65.2
3.3
478.24


 


1839








87.6
4.5
528.30


 


1840








90.4
5.68
546.30


 


1841








82.8
5.31
521.23


 


1842








68.2
5.57
553.28


 


1843








72.4
4.11
556.21


 


1844








83.9
5.15
491.29


 


1845








86.4
4.93
481.27


 


1846








86.3
5.29
525.25


 


1847








82.6
3.7
552.3


 


1848








88.1
5.3
503.29


 


1849








82.9
4.25
451.32


 


1850








82.1
4.64
453.35


 


1851








85.6
2.72
480.33


 


1852








82.9
3.16
542.35


 


1853








87.7
4.28
559.29


 


1854








75.3
2.82
474.33


 


1855








84.4
3.83
524.32


 


1856








87.0
5.0
542.36


 


1857








82.6
4.73
527.28


 


1858








65.8
5.01
549.31


 


1859








76.4
3.49
552.26


 


1860








80.4
4.54
487.35


 


1861








81.3
4.28
477.30


 


1862








79.9
4.59
521.29


 


1863








77.5
3.2
548.3


 


1864








86.5
4.65
499.32
















 












Ex.
R1
R5
Purity (%)
rt (min.)
[M + H]+





1865








84.7
4.94
435.29


 


1866








85.0
4.66
443.26


 


1867








26.2
4.82
494.26


 


1868








88.4
4.8
502.28


 


1869








83.6
5.48
519.28


 


1870








63.17
5.3
451.33


 


1871








91.1
3.4
542.3


 


1872








35.7
4.48
435.20


 


1873








88.8
3.8
502.26


 


1874








87.1
5.41
533.29


 


1875








89.5
5.14
513.22


 


1876








47.8
4.82
455.24


 


1877








77.1
5.32
521.24


 


1878








81.8
5.31
505.26


 


1879








19.7
4.37
395.24


 


1880








61.4
5.14
511.22


 


1881








82.7
4.95
463.31


 


1882








82.2
4.71
471.27


 


1883








67.2
4.84
522.26


 


1884








87.7
4.9
530.28


 


1885








79.4
5.54
547.28


 


1886








80.8
5.3
479.34


 


1887








88.9
3.6
570.24


 


1888








30.2
4.53
463.23


 


1889








88.9
3.98
530.26


 


1890








84.2
5.42
561.30


 


1891








75.8
5.17
541.22


 


1892








85.8
4.86
483.28


 


1893








71.7
5.33
549.26


 


1894








86.6
5.34
533.29


 


1895








54.1
4.43
423.28


 


1896








47.7
5.16
539.26


 


1897








74.6
4.44
509.30


 


1898








77.6
4.2
517.27


 


1899








38.8
4.53
568.26


 


1900








80.1
4.5
576.3


 


1901








72.3
5.17
593.30


 


1902








77.0
4.88
525.34


 


1903








80.5
3.3
616.3


 


1904








34.6
4.03
509.21


 


1905








81.3
3.6
576.2


 


1906








77.1
5.04
607.31


 


1907








79.6
4.76
587.24


 


1908








77.8
4.38
529.28


 


1909








78.0
4.95
595.28


 


1910








81.1
4.88
579.29


 


1911








32.4
3.89
469.29


 


1912








49.3
4.7
585.26


 


1913








87.0
5.59
503.20


 


1914








88.5
5.3
511.15


 


1915








69.5
5.28
562.16


 


1916








89.4
5.3
570.1


 


1917








79.1
5.98
587.17


 


1918








82.4
5.84
519.23


 


1919








89.5
3.9
610.1


 


1920








27.2
5.12
503.11


 


1921








88.6
4.41
570.13


 


1922








86.4
5.91
601.19


 


1923








84.9
5.66
581.11


 


1924








86.4
5.44
523.13


 


1925








61.9
5.81
589.16


 


1926








84.7
5.85
573.15


 


1927








36.8
5.1
463.16


 


1928








76.4
5.68
579.13


 


1929








79.4
4.65
415.30


 


1930








84.5
4.41
423.29


 


1931








44.0
4.62
474.29


 


1932








86.1
4.65
482.3


 


1933








78.5
5.33
499.31


 


1934








79.6
5.06
431.33


 


1935








84.6
3.4
522.30


 


1936








54.6
4.2
415.21


 


1937








85.4
3.7
482.29


 


1938








83.5
5.21
513.32


 


1939








85.7
4.92
493.24


 


1940








83.0
4.58
435.29


 


1941








75.1
5.1
501.31


 


1942








88.2
5.1
485.31


 


1943








76.1
4.08
375.28


 


1944








81.1
4.9
491.28
















 












Ex.
R1
R5
Purity (%)
rt (min.)
[M + H]+





1945








84.3
4.24
512.26


 


1946








85.4
3.63
514.25


 


1947








86.8
3.1
526.27


 


1948








87.7
4.32
530.23


 


1949








87.5
4.24
557.23


 


1950








88.8
2.9
513.26


 


1951








84.5
4.92
540.28


 


1952








87.7
4.49
526.27


 


1953








62.5
3.66
567.26


 


1954








89
4.08
542.26


 


1955








87.7
4.38
530.24


 


1956








82.4
2.7
513.28


 


1957








87.7
4.31
557.23


 


1958








91.0
4.44
556.27


 


1959








80.7
3.44
514.25


 


1960








68.6
4.67
535.24


 


1961








85.3
4.32
526.27


 


1962








83.0
3.75
528.25


 


1963








88.7
3.28
540.28


 


1964








86.8
4.37
544.25


 


1965








89.4
4.29
571.24


 


1966








86.9
3.1
527.25


 


1967








86.1
4.94
554.29


 


1968








87.6
4.54
540.27


 


1969








65.4
3.76
581.27


 


1970








86.3
4.16
556.28


 


1971








86.0
4.43
544.25


 


1972








83.2
2.8
527.3


 


1973








84.8
4.38
571.24


 


1974








87.8
4.5
570.28


 


1975








80.9
3.55
528.26


 


1976








62.7
4.71
549.27


 


1977








85.7
4.41
526.29


 


1978








84.2
3.82
528.27


 


1979








87.4
3.28
540.28


 


1980








86.6
4.47
544.24


 


1981








86.4
4.38
571.24


 


1982








85.9
3.1
527.27


 


1983








85.3
5.06
554.28


 


1984








85.3
4.66
540.28


 


1985








60.8
3.8
581.28


 


1986








86.1
4.25
556.28


 


1987








86.4
4.54
544.25


 


1988








75.9
2.86
527.28


 


1989








86.5
4.46
571.24


 


1990








88.4
4.6
570.29


 


1991








79.8
3.62
528.27


 


1992








63.2
4.82
549.26


 


1993








81.8
4.15
572.25


 


1994








81.0
3.58
574.25


 


1995








83.5
3.08
586.3


 


1996








84.3
4.2
590.27


 


1997








85.3
4.12
617.26


 


1998








86.1
2.91
573.28


 


1999








85.5
4.74
600.31


 


2000








87.3
4.37
586.28


 


2001








68.4
3.6
627.28


 


2002








85.4
3.98
602.28


 


2003








83.1
4.26
590.27


 


2004








84.5
2.7
573.26


 


2005








85.9
4.2
617.27


 


2006








86.9
4.32
616.31


 


2007








81.2
3.4
574.24


 


2008








69.0
4.54
595.29


 


2009








82.1
4.72
574.25


 


2010








80.1
4.15
576.27


 


2011








83.9
3.53
588.27


 


2012








80.8
4.78
592.26


 


2013








83.0
4.68
619.26


 


2014








85.6
3.35
575.25


 


2015








82.9
5.41
602.30


 


2016








81.9
4.96
588.26


 


2017








58.6
4.09
629.29


 


2018








81.7
4.53
604.27


 


2019








81.4
4.84
592.26


 


2020








78.7
3.06
575.31


 


2021








83.9
4.74
619.25


 


2022








82.6
4.89
618.29


 


2023








79.5
3.9
576.27


 


2024








64.2
5.15
597.27


 


2025








88.8
4.94
574.23


 


2026








88.4
4.96
592.25


 


2027








87.7
4.86
619.24


 


2028








89.7
3.61
575.2


 


2029








70.4
5.13
571.25


 


2030








88.0
5.58
602.28


 


2031








87.8
5.15
588.26


 


2032








76.5
4.24
629.28


 


2033








88.8
4.7
604.27


 


2034








88.3
5.04
592.25


 


2035








89.5
4.96
619.24


 


2036








87.5
5.41
642.26


 


2037








88.9
5.12
610.24


 


2038








89.4
5.07
618.27


 


2039








88.7
5.42
687.24


 


2040








87.7
3.68
580.30


 


2041








85.2
4.89
574.23


 


2042








84.4
4.9
592.25


 


2043








84.7
4.78
619.23


 


2044








89.0
3.58
575.25


 


2045








61.5
5.16
571.22


 


2046








83.2
5.57
602.28


 


2047








84.4
5.1
588.25


 


2048








73.2
4.25
629.27


 


2049








85.5
4.64
604.26


 


2050








85.6
4.99
592.2


 


2051








85.7
4.93
619.24


 


2052








86.2
5.34
642.25


 


2053








85.1
5.06
610.23


 


2054








84.6
5.06
618.27


 


2055








85.4
5.37
687.23


 


2056








85.8
3.68
580.30


 


2057








68.0
4.37
528.26


 


2058








86.3
4.41
546.22


 


2059








88.1
4.32
573.19


 


2060








86.1
3
529.25


 


2061








67.2
4.56
525.25


 


2062








91.2
4.98
556.26


 


2063








87.8
4.56
542.26


 


2064








75.6
3.73
583.23


 


2065








88.7
4.16
558.23


 


2066








88.4
4.46
546.22


 


2067








87.4
4.4
573.20


 


2068








87.7
4.88
596.21


 


2069








87.9
4.56
564.21


 


2070








87.5
4.51
572.26


 


2071








88.8
4.91
641.20


 


2072








86.2
3.08
534.27


 


2073








71.7
4.78
562.25


 


2074








82.1
4.8
580.23


 


2075








82.6
4.68
607.23


 


2076








79.5
3.4
563.21


 


2077








67.5
4.92
559.23


 


2078








83.0
5.39
590.27


 


2079








82.5
4.98
576.26


 


2080








42.5
4.1
617.23


 


2081








86.9
4.58
592.26


 


2082








82.5
4.88
580.23


 


2083








81.4
4.77
607.23


 


2084








82.3
5.24
630.26


 


2085








83.5
4.97
598.20


 


2086








81.6
4.93
606.28


 


2087








82.7
5.25
675.23


 


2088








84.4
3.4
568.26


 


2089








67.0
4.64
562.24


 


2090








83.0
4.66
580.23


 


2091








83.6
4.54
607.22


 


2092








82.5
3.3
563.25


 


2093








84.2
4.8
559.22


 


2094








86.2
5.21
590.29


 


2095








83.2
4.82
576.28


 


2096








62.8
3.99
617.26


 


2097








86.0
4.44
592.2


 


2098








85.8
4.72
580.25


 


2099








84.0
4.62
607.23


 


2100








83.4
5.09
630.26


 


2101








84.8
4.8
598.21


 


2102








83.7
4.78
606.29


 


2103








83.6
5.1
675.24


 


2104








5.6
3.05
568.28
















 

















Pur-








ity

[M +


Ex.
R5
R2
R1
(%)
rt (min.)
H]+





2105












81.5
4.9
468.27


 


2106












81.4
5.01
465.28


 


2107












77.3
5.34
505.31


 


2108












73.5
4.7
447.29


 


2109












70.5
5.28
499.26


 


2110












73.9
5.38
491.30


 


2111












72.0
4.5
489.31


 


2112












73.0
5.5
521.29


 


2113












90.0
4.23
381.29


 


2114












76.1
5.02
443.30


 


2115












56.9
4.2
434.32


 


2116












79.8
4.29
431.31


 


2117












79.1
4.45
471.35


 


2118












70.2
3.56
413.29


 


2119












72.4
4.68
465.27


 


2120












78.3
4.66
457.33


 


2121












90.1
3.41
455.33


 


2122












82.2
4.38
487.36


 


2123












68.8
2.99
347.34


 


2124












75.2
4.13
409.33


 


2125












56.9
4.01
513.30


 


2126












70.1
3.88
510.29


 


2127












77.8
4.16
550.29


 


2128












67.7
3.49
492.28


 


2129












71
4.27
536.28


 


2130












71.4
3.38
534.30


 


2131












67.7
4.29
566.30


 


2132












54.5
2.98
426.29


 


2133












70.1
3.85
488.31


 


2134












57.1
4.5
462.36


 


2135












83.2
4.61
459.35


 


2136












91.6
4.72
499.40


 


2137












80.7
3.94
441.32


 


2138












73.9
4.99
493.32


 


2139












77.5
4.95
485.37


 


2140












77.4
3.79
483.36


 


2141












66.1
4.62
515.38


 


2142












70.1
3.49
375.33


 


2143












74.1
4.46
437.35


 


2144












93.8
5.14
516.28


 


2145












90.0
5.27
513.28


 


2146












81.4
5.58
553.30


 


2147












78.6
5.02
495.27


 


2148












81.4
5.51
547.21


 


2149












85.5
5.62
539.29


 


2150












78.9
4.86
537.28


 


2151












83.2
5.76
569.28


 


2152












90.5
4.62
429.28


 


2153












91.8
5.31
491.31


 


2154












60.4
4.47
462.33


 


2155












83.6
4.62
479.31


 


2156












79.1
4.72
519.34


 


2157












72.6
3.96
461.31


 


2158












75.7
5.0
513.27


 


2159












79.3
4.99
505.34


 


2160












89.6
3.72
503.34


 


2161












89.6
4.7
535.32


 


2162












73.5
3.38
395.32


 


2163












80.1
4.5
457.32


 


2164












58.8
4.24
561.29


 


2165












77.9
4.16
558.27


 


2166












85.5
4.42
598.29


 


2167












82.8
3.87
540.27


 


2168












1.54
4.52
592.25


 


2169












56.0
4.54
584.25


 


2170












82.5
3.76
582.30


 


2171












71.8
4.58
614.31


 


2172












71.9
3.43
474.30


 


2173












80.9
4.16
536.28


 


2174












61.9
4.76
510.36


 


2175












83.1
4.93
507.35


 


2176












92.0
4.99
547.36


 


2177












88.3
4.27
489.35


 


2178












86.3
5.41
541.29


 


2179












79.7
5.36
533.36


 


2180












82.5
4.13
531.35


 


2181












74.0
4.99
563.34


 


2182












76
3.89
423.35


 


2183












79.8
4.89
485.38


 


2184












80.8
4.43
501.32


 


2185












66.2
4.18
545.31


 


2186












64.6
5.18
569.27


 


2187












57.2
4.78
589.30


 


2188












65.7
4.41
529.36


 


2189












65.4
4.52
549.28


 


2190












65.8
4.24
521.29


 


2191












71.4
4.19
481.37


 


2192












83.9
4.8
577.32


 


2193












76.5
4.54
583.24


 


2194












67.2
4.76
473.22


 


2195












66.6
4.69
517.20


 


2196












71
5.2
541.18


 


2197












69
4.73
561.15


 


2198












74.8
5.04
501.24


 


2199












69.5
5.18
521.16


 


2200












79.3
4.8
493.18


 


2201












74.9
4.79
453.24


 


2202












68.9
5.41
549.20


 


2203












68
5.2
555.11


 


2204












66
5.02
463.27


 


2205












62.2
4.83
507.28


 


2206












65.2
5.48
531.24


 


2207












66.3
4.99
551.22


 


2208












72.9
5.22
491.31


 


2209












77.2
5.31
511.24


 


2210












62.8
4.98
483.24


 


2211












62.4
4.98
443.31


 


2212












69.6
5.55
539.29


 


2213












63.5
5.41
545.19


 


2214












41.2
4.09
455.28


 


2215












58.5
3.73
499.35


 


2216












68.8
4.78
523.28


 


2217












36.2
4.37
543.28


 


2218












42.9
4.1
483.36


 


2219












46.1
4.24
503.30


 


2220












48.4
3.87
475.28


 


2221












39
3.8
435.34


 


2222












48.3
4.55
531.30


 


2223












47
4.33
537.20


 


2224












57.4
4.64
541.34


 


2225












69.1
4.34
585.37


 


2226












64.6
5.36
609.35


 


2227












40.2
4.94
629.34


 


2228












62.6
4.57
569.3


 


2229












68
4.72
589.31


 


2230












61.2
4.44
561.31


 


2231












61.2
4.37
521.36


 


2232












80.7
5.02
617.37


 


2233












74.2
4.77
623.28


 


2234












68.1
4.99
513.23


 


2235












66.1
4.98
557.22


 


2236












68.8
5.38
581.20


 


2237












69.7
4.9
601.19


 


2238












67.1
5.27
541.23


 


2239












72.6
5.45
561.16


 


2240












75.6
5.09
533.17


 


2241












74.6
5.08
493.26


 


2242












74.2
5.6
589.22


 


2243












70
5.48
595.14


 


2244












63.2
5.24
503.32


 


2245












61.1
5.1
547.30


 


2246












63.3
5.65
571.25


 


2247












63.7
5.15
591.28


 


2248












67.2
5.46
531.31


 


2249












76
5.58
551.24


 


2250












60.2
5.25
523.26


 


2251












58.8
5.24
483.3


 


2252












72.1
5.76
579.31


 


2253












65.2
5.66
585.20


 


2254












36
4.36
495.33


 


2255












58.6
3.97
539.36


 


2256












70
5.0
563.28


 


2257












50.2
4.55
583.28


 


2258












43.2
4.34
523.35


 


2259












52
4.53
543.29


 


2260












52.1
4.16
515.30


 


2261












46.2
4.07
475.38


 


2262












55.2
4.82
571.33


 


2263












51.5
4.63
577.22


 


2264












81.1
4.49
465.35


 


2265












84.1
4.7
481.36


 


2266












65.7
4.78
445.36


 


2267












63.0
4.51
399.29


 


2268












77.8
5.39
555.37


 


2269












78.5
5.21
485.32


 


2270












74.0
5.02
557.37


 


2271












78.1
4.38
525.37


 


2272












89.2
5.42
527.38


 


2273












83.0
5.75
537.30


 


2274












67.8
5.87
525.21


 


2275












83.2
5.75
541.16


 


2276












71.9
6.11
505.25


 


2277












70.5
5.14
459.15


 


2278












74.6
6.44
615.23


 


2279












71.5
5.88
545.10


 


2280












80.2
6.43
617.19


 


2281












93.4
5.82
585.18


 


2282












74.9
6.28
587.19


 


2283












68.3
6.24
597.14


 


2284












65.8
4.02
463.35


 


2285












75.8
4.22
479.33


 


2286












69.0
4.21
443.37


 


2287












4.2
4.36
397.33


 


2288












82.7
4.74
553.37


 


2289












89.8
4.62
483.29


 


2290












77.2
4.52
555.33


 


2291












69.3
3.98
523.35


 


2292












73.3
4.98
525.34


 


2293












73.1
5.44
535.29


 


2294












59.4
5.14
482.30


 


2295












76.0
5.09
498.28


 


2296












62.3
5.47
462.32


 


2297












58.6
4.55
416.22


 


2298












79.5
5.84
572.32


 


2299












74.9
5.3
502.25


 


2300












72.7
5.71
574.28


 


2301












71.1
5.06
542.32


 


2302












73.0
5.66
544.29


 


2303












64.6
5.62
554.24


 


2304












92.2
4.62
435.30


 


2305












90.1
4.67
451.29


 


2306












84.3
4.76
415.32


 


2307












43.7
4.34
369.27


 


2308












83.7
5.44
525.34


 


2309












80.3
4.96
455.25


 


2310












83.7
5.26
527.32


 


2311












82.8
4.64
495.34


 


2312












94.1
5.44
497.32


 


2313












90.1
5.55
507.29


 


2314












64.7
5.62
495.16


 


2315












50.7
5.54
511.15


 


2316












78.0
5.8
475.22


 


2317












20.9
4.86
429.14


 


2318












79.2
6.27
585.15


 


2319












46.3
5.58
515.12


 


2320












84.1
6.23
587.20


 


2321












91.1
5.64
555.18


 


2322












67.8
6.07
557.22


 


2323












23.9
5.96
567.17


 


2324












68.1
4.02
433.40


 


2325












65.6
4.2
449.38


 


2326












83.5
4.14
413.39


 


2327












36.4
3.94
367.35


 


2328












87.5
4.82
523.39


 


2329












65.1
4.42
453.33


 


2330












91.7
4.59
525.37


 


2331












81.5
4.01
493.40


 


2332












73.9
4.96
495.39


 


2333












72.7
5.3
505.33


 


2334












79.9
4.93
425.35


 


2335












81.8
4.88
468.33


 


2336












85.9
5.17
432.36


 


2337












36.2
4.25
386.28


 


2338












93.3
5.62
542.36


 


2339












76.5
4.96
472.3


 


2340












84.9
5.53
544.34


 


2341












80.6
4.96
512.34


 


2342












79.6
5.42
514.35


 


2343












64.9
5.34
524.27


 


2344












76.9
4.54
431.32


 


2345












80.7
5.47
457.38


 


2346












82.2
5.19
507.34


 


2347












82.1
5.38
491.35


 


2348












76.7
5.2
495.30


 


2349












83.1
5.42
531.30


 


2350












78.5
5.4
547.27


 


2351












86.8
5.58
539.33


 


2352












79.3
5.37
469.38


 


2353












83.1
5.18
499.31


 


2354












82.3
4.32
422.33


 


2355












78.2
5.26
448.39


 


2356












79.7
4.98
498.37


 


2357












80.0
5.2
482.38


 


2358












75.3
5.0
486.34


 


2359












81.9
5.26
522.30


 


2360












77.7
5.25
538.29


 


2361












83.9
5.4
530.35


 


2362












81.8
5.16
460.38


 


2363












79.3
5.03
490.31


 


2364












82.5
4.01
441.22


 


2365












80.6
4.98
467.28


 


2366












82.7
4.72
517.25


 


2367












83.6
5.0
501.26


 


2368












84.3
4.9
505.23


 


2369












82.5
5.48
541.19


 


2370












86.6
5.5
557.19


 


2371












85.4
5.53
549.24


 


2372












82.3
4.9
479.30


 


2373












81.5
5.26
509.21


 


2374












83.4
4.23
469.37


 


2375












82.3
4.94
495.40


 


2376












88.1
4.73
545.36


 


2377












90.4
4.99
529.39


 


2378












90.6
4.92
533.35


 


2379












85.2
5.62
569.33


 


2380












84.2
5.6
585.33


 


2381












85.0
5.54
577.38


 


2382












80.6
4.87
507.41


 


2383












85.9
5.42
537.34


 


2384












74.2
5.32
455.34


 


2385












92.3
5.1
505.32


 


2386












78.4
5.23
489.33


 


2387












71.3
5.12
493.32


 


2388












74.4
5.32
529.27


 


2389












68.8
5.29
545.25


 


2390












77.7
5.44
537.33


 


2391












80.7
5.24
467.36


 


2392












63.3
5.04
497.30


 


2393












87.4
4.16
420.33


 


2394












82.7
5.12
446.38


 


2395












82.4
4.88
496.35


 


2396












78.0
5.04
480.37


 


2397












75.9
4.9
484.33


 


2398












71.5
5.16
520.29


 


2399












65.4
5.12
536.30


 


2400












76.0
5.28
528.33


 


2401












93.8
5.03
458.38


 


2402












69.2
4.88
488.30


 


2403












68.3
3.88
439.23


 


2404












70.8
4.89
465.28


 


2405












76.2
4.72
515.23


 


2406












76.5
4.88
499.27


 


2407












90.1
4.88
503.26


 


2408












78.8
5.36
539.19


 


2409












76.1
5.31
555.17


 


2410












80.5
5.29
547.22


 


2411












68.2
4.86
477.30


 


2412












55.7
5.1
507.20


 


2413












69.2
4.12
467.36


 


2414












73.6
4.85
493.41


 


2415












73.9
4.72
543.36


 


2416












73.4
4.87
527.39


 


2417












90.6
4.92
531.36


 


2418












71.6
5.5
567.32


 


2419












60.5
5.4
583.32


 


2420












60.8
5.29
575.36


 


2421












58.8
4.82
505.39


 


2422












54.7
5.29
535.31
















 

















Pur-








ity

[M +


Ex.
R10
R2
R3
(%)
rt (min.)
H]+





2423












79.8
3.66
476.30


 


2424












59.3
3.68
496.26


 


2425












60.5
4.2
580.22


 


2426












52.7
3.68
554.24


 


2427












72.3
3.87
490.30


 


2428












63.8
3.85
510.26


 


2429












63.0
4.34
594.23


 


2430












54.1
3.82
568.25


 


2431












76.9
3.72
490.30


 


2432












70.7
3.73
510.26


 


2433












69.1
4.23
594.24


 


2434












52.7
3.72
568.24


 


2435












76.6
3.92
504.32


 


2436












64.8
3.9
524.28


 


2437












66.2
4.37
608.24


 


2438












59.3
3.86
582.27


 


2439












74.3
3.9
544.32


 


2440












65.4
3.91
564.29


 


2441












63.8
4.41
648.30


 


2442












57.6
3.92
622.31


 


2443












77.8
4.09
558.34


 


2444












65.5
4.08
578.30


 


2445












64.3
4.5
662.31


 


2446












47.6
4.04
636.36


 


2447












78.6
3.88
538.28


 


2448












61.2
3.9
558.24


 


2449












59.8
4.38
642.27


 


2450












48.4
3.88
616.30


 


2451












79.9
4.06
552.28


 


2452












59.4
4.04
572.25


 


2453












61.4
4.52
656.29


 


2454












50.0
4.02
630.31


 


2455












76.1
3.74
488.29


 


2456












88.3
3.72
508.25


 


2457












84.2
4.21
592.22


 


2458












82.1
3.71
566.24


 


2459












72.4
3.96
502.32


 


2460












88.5
3.89
522.27


 


2461












86.6
4.37
606.26


 


2462












77.2
3.8
580.26
















 

















Pur-








ity

[M +


Ex.
R10
R2
R3
(%)
rt (min.)
H]+





2463












86.6
3.96
487.31


 


2464












58.7
4
507.27


 


2465












64.9
4.48
591.22


 


2466












40.3
4
565.25


 


2467












91.3
4.12
501.31


 


2468












61.2
4.14
521.25


 


2469












62.4
4.62
605.25


 


2470












33.1
4.13
579.27


 


2471












87.3
4.01
501.31


 


2472












54.0
4.05
521.25


 


2473












69.1
4.51
605.26


 


2474












35.4
4.04
579.27


 


2475












88.4
4.18
515.31


 


2476












68.0
4.19
535.28


 


2477












72.9
4.64
619.25


 


2478












32.6
4.17
593.28


 


2479












92.7
4.18
555.33


 


2480












59.4
4.24
575.29


 


2481












71.8
4.72
659.33


 


2482












36.4
4.2
633.44


 


2483












92.4
4.36
569.34


 


2484












62.9
4.38
589.32


 


2485












71.9
4.82
673.33


 


2486












32.2
4.36
647.19


 


2487












90.2
4.14
549.28


 


2488












59.7
4.22
569.24


 


2489












66.6
4.7
653.25


 


2490












34.5
4.22
627.27


 


2491












91.3
4.32
563.30


 


2492












60.8
4.35
583.26


 


2493












73.3
4.8
667.27


 


2494












32.9
4.34
641.29


 


2495












60.4
3.94
499.30


 


2496












87.0
3.92
519.24


 


2497












84.4
4.41
603.24


 


2498












81.4
3.94
577.26


 


2499












73.9
4.12
513.31


 


2500












91.5
4.09
533.26


 


2501












89.6
4.54
617.26


 


2502












85.4
4.09
591.27
















 

















Pur-








ity

[M +


Ex.
R10
R2
R3
(%)
rt (min.)
H]+





2503












77.7
3.8
471.39


 


2504












37.7
3.82
491.34


 


2505












79.7
4.09
525.28


 


2506












58.5
4.23
541.33


 


2507












84.6
4.0
485.38


 


2508












73.2
4.0
505.34


 


2509












82.3
4.25
539.29


 


2510












74.2
4.37
555.34


 


2511












57.5
3.56
417.32


 


2512












66.9
3.56
437.27


 


2513












69.0
3.85
471.26


 


2514












71.1
4.0
487.33


 


2515












76.4
3.76
431.34


 


2516












67.8
3.75
451.30


 


2517












75.2
4.02
485.27


 


2518












70.4
4.16
501.32
















 

















Pur-








ity

[M +


Ex.
R10
R2
R3
(%)
rt (min.)
H]+





2519












76.4
3.73
471.38


 


2520












67.9
3.76
491.33


 


2521












75.0
4.04
525.28


 


2522












71.2
4.17
541.34


 


2523












87.9
3.94
485.39


 


2524












72.2
3.94
505.34


 


2525












82.1
4.2
539.30


 


2526












80.9
4.33
555.34


 


2527












70.7
3.51
417.32


 


2528












50.3
3.52
437.28


 


2529












72.4
3.8
471.26


 


2530












74.5
3.96
487.32


 


2531












84.4
3.72
431.32


 


2532












68
3.71
451.29


 


2533












89.6
3.98
485.26


 


2534












77.9
4.12
501.32
















 

















Pur-








ity

[M +


Ex.
R10
R2
R3
(%)
rt (min.)
H]+





2535












84.7
3.83
505.34


 


2536












75.2
3.89
525.30


 


2537












75.9
4.17
559.25


 


2538












70.4
4.29
575.30


 


2539












90.9
4.03
519.35


 


2540












71.5
4.04
539.31


 


2541












79.2
4.31
573.25


 


2542












80.6
4.43
589.33


 


2543












77.2
3.62
451.30


 


2544












69.9
3.65
471.27


 


2545












74.8
3.92
505.22


 


2546












66.7
4.06
521.26


 


2547












83.5
3.82
465.31


 


2548












72.9
3.82
485.28


 


2549












33.1
4.1
519.23


 


2550












51.2
4.22
535.28
















 

















Pur-








ity

[M +


Ex.
R10
R2
R3
(%)
rt (min.)
H]+





2551












79.8
3.45
521.33


 


2552












72.6
4.14
541.29


 


2553












63.7
3.79
575.24


 


2554












73.8
3.93
591.31


 


2555












91.2
3.65
535.35


 


2556












75.6
3.66
555.29


 


2557












78.3
3.94
589.26


 


2558












69.7
4.06
605.35


 


2559












69.1
3.22
467.29


 


2560












73.7
3.26
487.27


 


2561












79.6
3.56
521.20


 


2562












73.5
3.72
537.27


 


2563












86.1
3.42
481.31


 


2564












77.1
3.43
501.29


 


2565












83.0
3.73
535.22


 


2566












71.9
3.86
551.28
















 

















Pur-








ity

[M +


Ex.
R10
R2
R3
(%)
rt (min.)
H]+





2567












82.0
3.99
535.3


 


2568












40.6
4.04
555.31


 


2569












47.5
4.31
589.26


 


2570












37.4
4.43
605.33


 


2571












79.3
4.18
549.35


 


2572












38.8
4.19
569.30


 


2573












51.6
4.46
603.28


 


2574












36
4.55
619.35


 


2575












61.4
3.77
481.30


 


2576












37.9
3.81
501.28


 


2577












45.6
4.08
535.21


 


2578












34.9
4.2
551.27


 


2579












66.2
3.95
495.31


 


2580












44.8
3.96
515.25


 


2581












54.4
4.23
549.24


 


2582












36.5
4.34
565.28
















 

















Pur-








ity

[M +


Ex.
R10
R2
R3
(%)
rt (min.)
H]+





2583












52.2
3.91
465.24


 


2584












55.9
4
529.14


 


2585












51.3
3.9
445.29


 


2586












57.4
3.9
510.24


 


2587












54.3
4.04
479.28


 


2588












61.7
4.12
543.15


 


2589












80.0
3.82
465.25


 


2590












61.6
3.85
530.20


 


2591












61.1
3.97
499.25


 


2592












61.3
4.06
563.1


 


2593












84.2
3.96
479.29


 


2594












58.8
3.98
544.20


 


2595












61.5
4.1
513.26


 


2596












65.5
4.19
577.1
















 

















Pur-








ity

[M +


Ex.
R10
R2
R3
(%)
rt (min.)
H]+





2597












28.6
3.7
514.16


 


2598












39.0
3.83
483.24


 


2599












39.9
3.92
547.1


 


2600












53.5
3.8
463.26


 


2601












28.8
3.83
528.19


 


2602












31.0
3.96
497.24


 


2603












34.0
4.05
561.1


 


2604












64.5
3.72
483.24


 


2605












25.4
3.78
548.12


 


2606












36.8
3.9
517.20


 


2607












31.2
4
581.1


 


2608












72.8
3.86
497.24


 


2609












31.7
3.9
562.17


 


2610












40.1
4.02
531.21


 


2611












38.2
4.12
595.1
















 

















Pur-








ity

[M +


Ex.
R10
R2
R3
(%)
rt (min.)
H]+





2612












45.2
3.49
419.24


 


2613












56.6
3.39
439.21


 


2614












58.6
3.56
453.23
















 

















Pur-








ity

[M +


Ex.
R10
R2
R3
(%)
rt (min.)
H]+





2615












65.5
3.96
479.28


 


2616












50.5
4
544.19


 


2617












55.7
4.11
513.26


 


2618












55.5
4.2
577.13


 


2619












67.1
4.09
493.30


 


2620












53.7
4.11
558.20


 


2621












55.5
4.22
527.27


 


2622












72.1
4.3
591.13


 


2623












81.1
4.02
513.26


 


2624












51.0
4.08
578.18


 


2625












54.1
4.17
547.21


 


2626












65.2
4.26
611.11


 


2627












83.9
4.16
527.27


 


2628












60.2
4.18
592.21


 


2629












63
4.3
561.21


 


2630












74.0
4.36
625.11
















 

















Pur-








ity

[M +


Ex.
R10
R2
R3
(%)
rt (min.)
H]+





2631












83.1
4.06
515.26


 


2632












57.8
4.13
580.20


 


2633












37.4
4.22
549.23


 


2634












43.3
4.31
613.12


 


2635












86.7
4.18
529.27


 


2636












64.3
4.22
594.19


 


2637












37.0
4.32
563.25


 


2638












44.3
4.4
627.15


 


2639












86.9
4.14
549.23


 


2640












53.4
4.23
614.17


 


2641












37
4.3
583.21


 


2642












45.7
4.4
647.11


 


2643












88.9
4.24
563.25


 


2644












57.3
4.3
628.19


 


2645












39.4
4.39
597.22


 


2646












44.1
4.48
661.15
















 

















Pur-








ity

[M +


Ex.
R10
R2
R3
(%)
rt (min.)
H]+





2647












25.6
3.18
495.23


 


2648












33.1
3.59
533.15


 


2649












27.0
3
490.2


 


2650












33.6
3.14
562.16


 


2651












27.2
3.36
509.21


 


2652












32.5
3.76
547.16


 


2653












29.7
3.2
504.2


 


2654












34.8
3.32
576.21


 


2655












73.7
2.93
439.15


 


2656












60.6
3.37
477.14


 


2657












65.1
2.7
434.1


 


2658












69.3
2.92
506.14


 


2659












72.5
3.14
453.17


 


2660












77.2
3.55
491.14


 


2661












66.4
2.9
448.1


 


2662












65.9
3.14
520.15
















 

















Pur-








ity

[M +


Ex.
R10
R2
R3
(%)
rt (min.)
H]+





2663












63.3
3.82
555.21


 


2664












85.8
4.24
593.19


 


2665












87.5
3.8
550.2


 


2666












75.1
3.78
622.22


 


2667












66.1
3.98
569.21


 


2668












87.2
4.35
607.21


 


2669












82.9
3.9
564.2


 


2670












79.1
3.94
636.25


 


2671












82.0
3.55
499.18


 


2672












82.2
3.93
537.14


 


2673












86.4
3.4
494.2


 


2674












90.4
3.52
566.15


 


2675












88.0
3.72
513.19


 


2676












88.8
4.08
551.15


 


2677












88.9
3.6
508.2


 


2678












93.6
3.7
580.17
















 

















Pur-








ity

[M +


Ex.
R10
R2
R3
(%)
rt (min.)
H]+





2679












59.5
4
569.20


 


2680












82.6
4.37
607.21


 


2681












74.9
3.9
564.2
















 

















Pur-








ity

[M +


Ex.
R10
R2
R3
(%)
rt (min.)
H]+





2718












76.9
3.92
675.26


 


2719












75.5
3.63
538.18


 


2720












79.4
3.96
576.13


 


2721












73
3.5
533.2


 


2722












87.0
3.56
605.17


 


2723












81.8
3.8
552.18


 


2724












80.1
4.11
590.15


 


2725












79.4
3.6
547.2


 


2726












86.3
3.73
619.18
















 












Ex.
R2
R3
Purity (%)
rt (min.)
[M + H]+





2727








73.7
4.7
488.3


 


2728








87.1
4.2
508.2


 


2729








90.3
4.3
522.3


 


2730








78.2
4.5
586.1


 


2731








73
4.1
533.2


 


2732








86.4
4.5
542.2


 


2733








77.7
4.6
576.2


 


2734








80
4.7
592.2


 


2735








76.4
4.9
644.2


 


2736








81.4
4.6
558.2


 


2737








79.8
4.4
502.3


 


2738








87.5
4.4
522.3


 


2739








91.4
4.5
536.3


 


2740








83.3
4.6
600.1


 


2741








82
4.3
547.2


 


2742








83.9
4.6
556.2


 


2743








85.4
4.7
590.2


 


2744








85.2
4.8
606.2


 


2745








82
4.3
658.2


 


2746








86.7
4.7
572.2


 


2747








31.6
4.3
506.3


 


2748








71.1
4.3
526.2


 


2749








89.5
4.4
540.2


 


2750








59.6
4.5
604.1


 


2751








51.3
4.2
551.2


 


2752








62.2
4.5
560.2


 


2753








59.6
4.7
594.2


 


2754








63
4.7
610.2


 


2755








52.5
4.9
662.2


 


2756








67.8
4.6
576.1


 


2757








81.1
4.6
516.3


 


2758








85.8
4.5
536.3


 


2759








85.4
4.7
550.3


 


2760








76.6
4.7
614.1


 


2761








77.2
4.4
561.2


 


2762








85.4
4.7
570.2


 


2763








79.7
4.8
604.2


 


2764








81.1
4.9
620.2


 


2765








79.2
5.1
672.2


 


2766








82
4.8
586.3
















 

















Pur-








ity

[M +


Ex.
R10
R2
R3
(%)
rt (min.)
H]+





2767












64.3
3.91
530.20


 


2768












58.3
3.57
521.22


 


2769












66.7
4.03
564.20


 


2770












65.1
3.71
541.19


 


2771












56.1
3.58
521.21


 


2772












42.1
3.93
544.19


 


2773












34.6
3.59
535.22


 


2774












46.9
4.05
578.21


 


2775












33.3
3.73
555.19


 


2776












33.4
3.6
535.22


 


2777












39.6
3.97
558.22


 


2778












47.5
3.63
549.23


 


2779












50.3
4.09
592.23


 


2780












40.6
3.76
569.19


 


2781












42.7
3.63
549.25


 


2782












35.5
4.0
572.17


 


2783












33.2
3.69
563.26


 


2784












45
4.1
606.27


 


2785












36.0
3.82
583.23


 


2786












27.1
3.7
563.26


 


2787












73.6
3.98
530.19


 


2788












62.5
3.64
521.21


 


2789












74.8
4.09
564.2


 


2790












67.7
3.77
541.20


 


2791












71.3
3.65
521.21


 


2792












52.4
4.0
544.18


 


2793












47.0
3.65
535.22


 


2794












54.7
4.11
578.22


 


2795












43.7
3.79
555.20


 


2796












44.6
3.67
535.22


 


2797












53.7
4.03
558.20


 


2798












51.0
3.69
549.23


 


2799












56.5
4.15
592.23


 


2800












48.9
3.83
569.20


 


2801












46.0
3.7
549.24


 


2802












41.2
4.1
572.21


 


2803












36.7
3.76
563.26


 


2804












47.4
4.2
606.26


 


2805












37.0
3.89
583.22


 


2806












37.3
3.76
563.26
















 












Ex.
R3
R2
Purity (%)
rt (min.)
[M + H]+





2807








52.1
3.65
547.22


 


2808








61.7
3.61
563.24


 


2809








54.1
3.91
561.26


 


2810








56.7
3.69
563.23


 


2811








54.7
3.65
547.23


 


2812








63.6
3.96
561.25


 


2813








66.1
4.13
575.26


 


2814








34.9
4.29
589.29


 


2815








69.3
3.66
563.24


 


2816








47.6
3.66
547.23


 


2817








41.4
3.61
563.23


 


2818








28.5
3.97
561.24


 


2819








56.4
3.71
563.23


 


2820








45.6
3.65
547.22


 


2821








62.6
3.99
561.24


 


2822








42.0
4.17
575.26


 


2823








45.7
4.32
589.28


 


2824








23.5
3.65
551.21


 


2825








70.9
3.67
563.22









Some compounds according to the invention can be obtained according to method G described hereafter.
Method G
Synthesis in solution of 2-iminothiazole-4-carboxamide derivatives from monoprotected symmetrical diamines (Boc)




General Procedure:

The monoprotected symmetrical diamine (Boc) (1 equiv) is agitated overnight with an aromatic isothiocyanate (1 equiv) at ambient temperature in an anhydrous solvent such as dioxane, dimethylformamide or chloroform, 1 equivalent of an inorganic base such as sodium or potassium hydrogen carbonate and 1 equivalent of ethyl bromopyruvate dissolved beforehand in an anhydrous solvent such as dioxane or dimethylformamide is successively added to the crude isothiourea intermediate. The mixture is then heated at 80° C. for 1 to 3 hours and the inorganic salts are eliminated by filtration. The solvents are evaporated off under vacuum and the residue is purified by flash chromatography on silica gel using an ethyl acetate/heptane gradient. Saponification of the ester intermediate is carried out in a solvent such as tetrahydrofuran using a 1N solution of KOH, LiOH or NaOH. The mixture is agitated vigorously for 6 to 20 hours at ambient temperature then acidified with a 1N aqueous solution of hydrochloric acid to pH 2.5.
The organic phase is extracted several times with dichloromethane then the organic phase is washed with water until neutral pH and dried over sodium sulphate. A primary or secondary amine (1.1 to 2 equiv.) pre-dissolved in a anhydrous solvent such as dimethylformamide is added under argon to a solution of carboxylic acid intermediate (1 equiv.) and a peptide coupling agent such as DIC, DIC/HOBt, HATU or TBTU (1.1 to 2 equiv.), dissolved beforehand in an anhydrous solvent such as dimethylformamide. The mixture is agitated overnight at ambient temperature. The solvent is evaporated off under vacuum and the residue purified by flash chromatography on silica gel using an ethyl acetate/heptane gradient. The carboxamide intermediate is diluted in a solvent such as dichloromethane or ethyl acetate and deprotected after passage through the solution of a current of dry hydrogen chloride for 1 to 6 hours at ambient temperature. The corresponding dihydrochloride is isolated either by filtration of the precipitate or, after evaporation under vacuum of the solvent, by adding diethylether for better crystallisation.
Preparation 25
ethyl(2Z)-3-{5-[(tert-butoxycarbonyl)amino]pentyl}-2-[(3,5-dimethylphenyl)imino]-2,3-dihydro-1,3-thiazole-4-carboxylate
(C14H25N3O4S; MM=461.63)




N-Boc-1,5-diaminopentane (1.04 g; 5 mmol) is agitated with 3,5-dimethylisothiocyanate (824 mg; 5 mmol) in 10 ml anhydrous dioxane. 420 mg (5 mmol) of sodium hydrogen carbonate and 1.08 g (5 mmol) of ethyl bromopyruvate dissolved beforehand in 2 ml of anhydrous dioxane are successively added to the, crude isothiourea intermediate. The mixture is then heated at 80° C. for one hour and the inorganic salts are eliminated by filtration. The dioxane is evaporated off under vacuum and the yellow residue is purified by flash chromatography on silica gel (eluent:ethyl acetate/heptane 2:8 then 3:7). A yellow oil (1.8 g; yield of 77.9%) corresponding to the expected compound is then isolated.
NMR 1H (DMSO-d6, 400 MHz) δ: 7.23 (s, 1H); 6.71 (broad s, 1H); 6.65 (s, 1H); 6.54 (s, 2H); 4.26 (q, 2H, J=6.4 Hz); 4.13 (t, 2H, J=6.4 Hz); 2.9 (q, 2H, J=6 Hz); 2.22 (s, 6H); 1.63 (m, 2H); 1.4 (m, 2H); 1.36 (s, 9H); 1.29–1.23 (m, 2H+3H). MS/LC: m/z=462.3 (M+H)+.
Preparation 26
(2Z)-3-{5-[(ten-buroxycarbonyl)amino]pentyl}-2-[(3,5-dimethylphenyl)imino]=2,3-dihydro-1,3-thiazole-4-carboxylic acid
(C22H31N3O4S; MM=433.57)




The compound of Preparation 25 (1.77; 3.83 mmol) is dissolved in 20 ml of tetrahydrofuran and treated with 15 ml of a 1N aqueous solution of NaOH. The mixture is agitated vigorously for 6 hours at ambient temperature. The carboxylate is then acidified with a 1N aqueous solution of hydrochloric acid to pH 2.5. The aqueous phase is extracted with dichloromethane (4×50 ml) and the organic phases are washed with water until neutral pH and dried over sodium sulphate. A pale yellow solid is isolated (1.51 g; yield of 90.9%) after evaporation under vacuum of the solvents.
NMR 1H (DMSO-d6, 400 MHz) δ: 13.28 (broad s, 1H); 7.16 (s, 1H); 6.69 (broad s, 1H); 6.65 (s, 1H); 6.54 (s, 2H); 4.17 (t, 2H, J=7.2 Hz); 2.89 (q, 2H, J=6.4 Hz); 2.22 (s, 6H); 1.63 (q, 2H, J=6.8 Hz); 1.41 (m, 2H); 1.36 (s, 9H); 1.25 (m, 2H). MS/LC: m/z=434.27 (M+H)+
Preparation 27
tert-butyl 5-[(2Z)-2-[(3,5-dimethylphenyl)imino]-4-{[(1-phenylpropyl)amino]carbonyl}-1,3-thiazol-3(2H)-yl]pentylcarbamate
(C31H42N4O3S; MM=550.76)




600 mg (1.38 mmol) of carboxylic acid of Preparation 26 are activated beforehand with 888 mg (2.76 mmol; 2 equiv.) of TBTU in 10 ml of anhydrous dimethylformamide for one hour. 410 μl (2.76 mmol; 2 equiv.) of α-ethylbenzylamine is then added and the mixture is agitated at ambient temperature overnight. After evaporation of the dimethylformamide, the crude residue is purified by flash chromatography on silica gel (eluent: ethyl acetate/heptane 4:6) in order to produce a white solid (498 mg; yield of 65.5%).
NMR 1H (DMSO-d6, 400 MHz)*: 9.00 (d, 1H, J=8.4 Hz); 7.36–7.30 (m, 4H); 7.25–7.21 (m, 1H); 6.72 (t, 1H, J=5.4 Hz); 6.67 (s, 1H); 6.63 (s, 1H); 6.53 (s, 2H); 4.77 (q, 1H, J=8.8 Hz); 3.95 (m, 2H); 2.84 (q, 2H, J=6 Hz); 2.21 (s, 6H); 1.74 (m, 2H); 151 (m, 2H); 1.36 (s, 9H); 1.31 (q, 2H, J=7.2 Hz); 1.13 (m, 2H); 0.89 (t, 3H, J=7.2 Hz). MS/LC: m/z=551.44 (M+H)+.
EXAMPLE 2826
(2Z)-3-(5-aminopentyl)-2-[(3,5-dimethylphenyl)imino]-N-(1-phenylpropyl)-2,3-dihydro-1,3-thiazole-4-carboxamide dihydrochloride
(C26H34N4OS.2HCl; MM=523.57)




300 mg (0.54 mmol) of tert-butyl 5-[(2Z)-2-[(3,5-dimethylphenyl)imino]-4-{[(1-phenylpropyl)amino]carbonyl}-1,3-thiazol-3(2H)-yl]pentylcarbamate is dissolved in 15 ml of ethyl acetate. After bubbling anhydrous hydrogen chloride through the reaction medium for one hour at ambient temperature, the corresponding dihydrochloride salt precipitates. It is recovered by filtration and washed with diethyl ether in order to produce a white solid (268 mg; yield of 94.8%).
NMR 1H (DMSO-d6, 400 MHz)*: 9.48 (broad s, 1H); 8.03 (broad s, 3H); 7.39–7.32 (m, 5H); 7.25 (t, 1H, J=7.2 Hz); 7.00 (m, 3H); 4.80 (q, 1H, J=8.4 Hz); 4.33 (broad s, 2H); 2.70 (q, 2H, J=6.8 Hz); 2.29 (s, 6H); 1.77 (m, 2H); 1.65 (m, 2H); 1.52 (m, 2H); 1.27 (m, 2H); 0.89 (t, 3H, J=7.2 Hz).
MS/LC: m/z=451.35 (M+M)+.
According to method G, a series of compounds can be synthesized which include:
the R1 and R2 groups already described for method A; and
the R5 groups already described for method C.
In particular, the compounds shown in the table below have been synthesised using method G.
















 













Ex.
R1
R2
R5
Purity (%)
rt (min)
[M + H]+





2827












69 + 27
4.57 + 4.73
477.33


 


2828












98
4.36
437.29


 


2829












98
4.37
437.33


 


2830












98
3.72
423.37


 


2831












99
3.73
423.37


 


2832












99
4.07
455.32


 


2833












99
4.29
471.32


 


2834












98
4.33
515.24


 


2835












99
3.87
451.34


 


2836












99
3.88
451.34









Pharmacological Properties of the Products 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 on sub-types of human somatostatin receptors 1 to 5 (sst1, sst2, sst3, sst4 and sst5, respectively) is determined by measurement of the inhibition of the bond of [125I-Tyr11]SRIF-14 to transfected CHO-K1 cells.
The gene of the sst1 receptor of human somatostatin was 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 sst1 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 sst2 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 sst3 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 sst3 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 sst4 receptor, pCMV-HX, was provided by Dr. Graeme Bell (Univ. Chicago). This vector contains the genomic fragment coding for the human sst4 receptor of 1.4 Kb NheI—NheI, 456 bp of the non transcribed 5′ region, and 200 bp 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 sst4 receptor is obtained by transfection in CHO-K1 (ATCC) cells 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 gene corresponding to the human sst5 receptor, obtained by the PCR method using a genomic λ 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 transcribe 5′ region, the coding region in totality, and 55 bp 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 sst5 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 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 EDTA at 0.5 mM and centrifuged at 500 g for approximately 5 minutes at approximately 4° C. The pellet is resuspended in a Tris 50 mM buffer at pH 7.4 and centrifuged twice at 500 g for approximately 5 minutes at approximately 4° C. The cells are lysed by sonication then 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 experiments of the bond with [125I-Tyr11]SRIF-14 are carried out in duplicate in 96-well polypropylene plates. The cell membranes (10 μg protein/well) are incubated with [125I-Tyr11]SRIF-14 (0.05 nM) for approximately 60 min. at approximately 37° C. in a HEPES 50 mM buffer (pH 7.4) containing BSA 0.2%, MgCl2 5 mM, Trasylol '200 KIU/ml, bacitricin 0.02 mg/ml and phenylmethylsulphonyl fluoride 0.02 mg/ml.
The bound [125I-Tyr11]SRIF-14 is separated from the free [125-Tyr11]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 Filternate 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 is 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 105 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 minutes at approximately 37° C.
The production of cyclic AMP is stimulated by the addition of 1 mM of forskolin (ASK) for 15–30 minutes at approximately 37° C.,
The inhibitory 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 mM) 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 is 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 products 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 Ki being lower than micromolar for certain exemplified compounds, and in particular for the products shown in the table below.












Ki


Formula of compound
(nM)











<200


 






<200


 






<200


 






<200


 






<200


 






<200


 






<200


 






<200


 








 






<200









In addition to the compounds in the above tables, each of the compounds of Examples 2827 to 2836 also has a K, constant lower than 200 nM.

## Claims

1. A compound of the formula:




wherein




and R5 is























and or its stereoisomers or pharmaceutically acceptable salts thereof.

2. A compound of claim 1 wherein R2 is




and R5 is

3. A compound of claim 1 wherein R2 is




and R5 is

4. A composition comprising of a compound of claim 1 and a pharmaceutical carrier.