2-Arylimino-2,3-dihydrothiazoles, and their use thereof as somatostatin receptor ligands

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, insensiblity to insulin, Syndrome X, angiopathy, proliferative retinopathy, dawn phenomenon and nephropathy; inhibition of the secretion of gastric acid and in particular peptic ulcers, enterocutaneous and pancreaticocutaneous fistulae, irritable colon syndrome, dumping syndrome, aqueous diarrhea syndrome, diarrhea associated with AIDS, diarrhea induced by chemotherapy, acute or chronic pancreatitis and secretory gastrointestinal tumors; the treatment of cancer such as hepatomas; the inhibition of angiogenesis, the treatment of inflammatory disorders such as arthritis; chronic rejection of allografts; angioplasty; the prevention of bleeding of grafted vessels and gastrointestinal bleeding. The agonists of somatostatin can also be used to reduce the weight of a patient.

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

The European Journal of Medicine,

1993, 2, 97-105), there can be mentioned for example: acromegalia, hypophyseal adenomas, Cushing's disease, gonadotrophinomas and prolactinomas, catabolic side-effects of glucocorticoids, insulin dependent diabetes, diabetic retinopathy, diabetic nephropathy, hyperthyroidism, gigantism, endocrinic gastroenteropancreatic tumors including carcinoid syndrome, VIPoma, insulinoma, nesidioblastoma, hyperinsulinemia, glucagonoma, gastrinoma and Zollinger-Ellison's syndrome, GRFoma as well as acute bleeding of the esophageal varices, gastroesophageal reflux, gastroduodenal reflux, pancreatitis, enterocutaneous and pancreatic fistulae but also diarrheas, refractory diarrheas of acquired immunodeficiency syndrome, chronic secretary diarrhea, diarrhea associated with irritable bowel syndrome, disorders linked with gastrin releasing peptide, secondary pathologies with intestinal grafts, portal hypertension as well as hemorrhages of the varices in patients with cirrhosis, gastro-intestinal hemorrhage, hemorrhage 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 tumors, 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 Alzheimer's disease. Osteoporisis can also be mentioned. The Applicant found that the compounds of general formula (I) described hereafter have an affinity and a selectivity for the somatostatin receptors. As somatostatin and its peptide analogues often have a poor bioavailability by oral route and a low selectivity (Robinson, C., Drugs of the Future, 1994, 19, 992; Reubi, J. C. et al., TIPS, 1995, 16, 110), said compounds, non-peptide agonists or antagonists of somatostatin, can be advantageously used to treat pathological states or illnesses as presented above and in which one (or more) somatostatin receptors are involved. Preferably, said compounds can be used for the treatment of acromegalia, hypophyseal adenomas or endocrine gastroenteropancreatic tumors 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(C

2

-C

7

)alkyl, aminoalkylarylalkyl, aminoalkylcycloalkylalkyl, (C

1

-C

15

)alkyl, (C

3

-C

7

)cycloalkyl, (C

1

-C

6

)alkyl(C

3

-C

6

)cycloalkyl, (C

3

-C

6

)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, tetrahydrofurannylalkyl, dialkylaminoalkyl, N-acetamidoalkyl, cyanoalkyl, alkylthioalkyl, arylhydroxyalkyl, aralkoxyalkyl, morpholinoalkyl, pyrrolidinoalkyl, piperidinoalkyl, N-alkylpyrrolidinoalkyl, N-alkylpiperazinylalkyl or oxopyrrolidinoalkyl 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,

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 (C

1

-C

16

)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 (C

3

-C

8

)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—(CH

2

)

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 SO

2;

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(C

2

-C

7

)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, (C

3

-C

7

)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 or R9 radicals including an 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 the radicals chosen independently from the group comprising a halogen atom and an alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, aryl, aralkoxy or SO

2

NH

2

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) by the radicals chosen independently from the group comprising a halogen atom and an alkyl, alkoxy, alkylthio, haloalkyl, alkenyl, haloalkoxy, nitro, cyano, azido, SO

2

N, mono- or di-alkylamino, aminoalkyl, aralkoxy or aryl 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 the 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 the 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 SO

2

NH

2

radical.

For R8, 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, 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 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, benzothiophenyl, 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 attachment point. For example:

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 the 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.

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 —CH

2

—Al—NH

2

radical, in which Al represents a —(CH

2

)

n

—, —(CH

2

)

n

—O—(CH

2

)

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—NH

2

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—NH

2

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 a variant of the invention, the compounds of general formula (I)b

in which:

R1 represents the same radicals as in general formula (I), with the exception of the —CH

2

—Al—NH

2

type radicals, in which Al represents a —(CH

2

)

n

—, —(CH

2

)

n

—O—(CH

2

)

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;

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

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 an excess of aminoalkylaniline of general formula R2—NH

2

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 —CH

2

—Al—NH

2

radical, in which Al represents a —(CH

2

)

n

—, —(CH

2

)

n

—O—(CH

2

)

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 p-nitrophenylcarbonate Wang resin with a large excess of symmetrical diamine of formula R1—NH

2

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 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 the 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) as defined in claim

1

, with the exception of the —CH

2

—Al—NH

2

type radicals, in which Al represents a —(CH

2

)

n

—, —(CH

2

)

n

—O—(CH

2

)

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 p-nitrophenylcarbonate Wang resin with an excess of aminoalkylaniline of general formula R2—NH

2

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(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 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 —CH

2

—Al —NH

2

radicals, in which Al represents a —(CH

2

)

n

—, —(CH

2

)

n

—O—(CH

2

)

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 a —CH

2

—Al—NH

2

radical, in which Al represents a linear or branched alkylene radical containing 1 to 6 carbon atoms, —(CH

2

)

n

—O—(CH

2

)

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 p-nitrophenylcarbonate Wang resin 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 that in the general formula (I)e;

3) reaction of the primary amine of general formula R1—NH

2

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—NH

2

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 a 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 be used per equivalent of resin; preferably, heating will be carried out at a 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 the order 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(R11R12)—CO—R10 radical;

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

R10 represents an amino(C

2

-C

7

)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, (C

3

-C

7

)cycloalkyl, optionally substituted carbocyclic or heterocyclic aralkyl, propargyl, allyl, hydroxyalkyl, alkylthioalkyl, arylalkylalkoxyalkyl, 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 p-nitrophenylcarbonate Wang resin 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 of 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 means of 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 the pharmaceutical compositions containing said compounds or their pharmaceutically acceptable salts, and their use for the preparation of a medicament intended to treat the pathological states or the 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 the pathological states or the diseases chosen from the group comprising the following pathological states or diseases: acromegalia, hypophyseal adenomas, Cushing's disease, gonadotrophinomas and prolactinomas, catabolic side-effects of glucocorticoids, insulin dependent diabetes, diabetic retinopathy, diabetic nephropathy, syndrome X, dawn phenomena, angiopathy, angioplasty, hyperthyroidism, gigantism, endocrinic gastroenteropancreatic tumors including carcinoid syndrome, VIPoma, insulinoma, nesidioblastoma, hyperinsulinemia, glucagonoma, gastrinoma and Zollinger-Ellison's syndrome, GRFoma as well as acute bleeding of the esophageal varices, ulcers, gastroesophageal reflux, gastroduodenal reflux, pancreatitis, enterocutaneous and pancreatic fistulae but also diarrheas, refractory diarrheas of acquired immunodeficiency syndrome, chronic secretary diarrhea, diarrhea associated with irritable bowel syndrome, diarrheas induced by chemotherapy, disorders linked with gastrin releasing peptide, secondary pathologies with intestinal grafts, portal hypertension as well as hemorrhages of the varices in patients with cirrhosis, gastro-intestinal hemorrhage, hemorrhage 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 tumors, 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 the glycols, as well as their mixtures, in varying proportions, in water.

The administration of a medicament according to the invention can be done by topical, oral, parenteral route, by intramuscular injection, etc.

The administration dose envisaged for a medicament according to the invention is comprised between 0.1 mg to 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

(C

12

H

10

BrNO

3

, 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 stirred 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 2 M solution of (trimethylsilyl) diazomethane in hexane (97.9 mmol) are added dropwise at 0° C. The solvents are eliminated after one night of stirring 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 stirred 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

1

H (DMSO D6, 100 MHz, δ): 7.83 (s, 4H); 4.36 (s, 2H, CH

2

Br); 3.8 (t, 2H, J=7.1 Hz, NCH

2

); 2.98 (t, 2H, J=6.9 Hz, CH

2

CO).

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:

CuBr

2

(King, L. C.; Ostrum, G. K.

J. Org. Chem.

1964, 29, 3459-3461) heated in ethyl acetate or dioxane;

the N-bromosuccinimide in CCl

4

or aqueous acetonitrile,(Morton, H. E.; Leanna, M. R.

Tetrahedron Lett.

1993, 34, 4481-4484);

the 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

(C

10

H

7

BrO

2

, 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 stirred 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

1

H (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, CH

2

Br).

Preparations 8-12

The following compounds have been prepared in 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 p-nitrophenylcarbonate Wang Resin

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 (THF) at ambient temperature. The mixture is stirred 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 p-nitrophenylcarbonate Wang resin 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 stirring 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 stirred 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 Carbamate Wang Resin

Phenylisothiocyanate (1 ml; 8.5 mmol; 5 eq.) is added to an ethylene diamine N-carbamate Wang resin (2 g; 1.72 mmol; 0.86 mmol/g) swollen in DCM (50 ml). After stirring 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

(C

17

H

16

ClN

3

S, MM=329.86):

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 stirred 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 mixture of DCM/trifluoroacetic acid at 50%, produces an oil after one hour 30 minutes of stirring 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

1

H (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, NCH

2

); 3.32 (broad s, 2H, NH

2

); 2.72 (t, 2H, J=6.2 Hz, NCH

2

). 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 carbamate Wang resins 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 stirred 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 Carbamate Wang Resin

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 p-nitrophenylcarbonate Wang resin (4.05 g; 3.47 mmol; load of 0.857 mmol/g) pre-swollen in 50 ml of anhydrous DMF. The mixture is stirred 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 stirring 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)carbothioyl]amino}-phenylethyl Carbamate Wang Resin

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 stirred 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

(C

25

H

24

ClN

3

S, 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 stirred 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%).

NMR

1

H (DMSO D6, 100 MHz) δ: 7.9 (broad s, 2H, NH

2

); 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, NCH

2

); 3.03 (m, 2H, NCH

2

); 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

R2 groups

R3 and R4 groups such as those of method A

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 to 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

(C

27

H

27

BrN

4

OS, 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 stirring 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

1

H (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; NCH

2

); 3.45 (broad m; 2H+2H; NH

2

and NCH

2

); 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]imino}-N-(4-chlorobenzyl)-3-(2-phenylethyl)-2,3-dihydro-1,3-thiazole-4-carboxamide

(C

27

H

27

ClN

4

OS, 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). Stirring 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 stirred 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 stirring 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 % to).

NMR

1

H (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)

30

.

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 stirring 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 stirred for approximately 15 minutes at ambient temperature before adding it to the N-carbamate of ethylene diamine Wang resin (0.8 g; 0.688 mmol; load rate 0.86 mmol/g). After stirring 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 stirring 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

(C

22

H

26

N

4

O

3

S, 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 stirred 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. Stirring 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

1

H (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, OCH

3

); 3.32 (broad s, 2H); 3.17 (mn, 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 Conmbinatorial 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 (1 to two times) until the Kaiser ninhydrin test is negative.

Preparation 23

N-carbamate of 4-[({[(9H-fluoren-9-ylmethoxy)carbonyl]amino}acetyl)amino]butyl Wang Resin

The Fmoc-Gly-OH acid (2.36 g, 7.94 mmol) is activated with HOBt (1.07 g, 7.94 mmol) and of the DIC (1.25 ml, 7.94 mmol) in 22 ml of DMF for 5 minutes before adding the mixture to butylamine N-carbamate Wang resin (1 g, load rate of 0.794 mmol/g) preswollen in 10 ml of DMF. After stirring 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 stirring 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 stirred 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 N-carbamate Wang Resin

1.27 g of the above resin (see Preparation 23) is deprotected with 14 ml of DMF/piperidine at 20%. The mixture is stirred 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 stirred 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 resin yellow 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-chlorophenl)-2-(1-naphthylimino)-1,3-thiazol-3-thiazol-3(2H)-yl)acetamide

(C

25

H

25

ClN

4

OS, 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 stirring 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 nm) of yellow solid is thus isolated after evaporation corresponding to the free base.

NMR

1

H (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=1.61 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:

R11=H

R12 groups:

EXAMPLES

Examples obtained according to methods A, B, C, D, E and F described above are shown below. These examples are presented to illustrate the above procedures and must in no case be considered as a limit to the scope of the invention.

The compounds obtained have been characterized by their retention times (rt) and by mass spectrometry (M+H)

+

.

Ex.

R2

R3

Purity (%)

rt (min.)

[M + H]

+

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

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

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

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

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

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

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

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

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

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

840

35 + 64

3.68 + 3.73

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

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

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

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

67.8

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

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

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

38

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

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

3.66

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

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

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

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

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

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

4.16

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

501.37

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

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

531.23

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

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

83.0

4.66

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

Ex.

R5

R2

R1

Purity (%)

rt (min.)

[M + 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

482.33

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

58.0

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

499

647.36

2177

88.3

4.27

489.35

2178

86.3

541

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

436

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

643

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

452.35

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

412

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

Ex.

R10

R2

R3

Purity (%)

rt (min.)

[M + 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

586.24

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

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

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

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

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

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

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

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

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

2612

45.2

3.49

419.24

2613

56.6

3.39

439.21

2614

58.6

3.56

453.23

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

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

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

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

2679

59.5

4

569.20

2680

82.6

4.37

607.21

2681

74.9

3.9

564.2

2682

70.6

3.94

636.26

2683

55.3

4.14

583.24

2684

85.3

4.49

621.22

2685

86.1

4.1

578.2

2686

72.7

4.09

650.26

2687

87.5

3.74

513.20

2688

86.1

4.1

551.16

2689

87.4

3.6

508.2

2690

87.9

3.73

580.18

2691

87.2

3.89

527.21

2692

88.3

4.24

565.15

2693

89.8

3.8

522.2

2694

92.5

3.86

594.17

2695

69.9

4.14

605.25

2696

81.8

4.55

643.21

2697

65.3

4.1

600.2

2698

69.2

4.11

672.25

2699

74.0

4.28

619.24

2700

69.3

4.67

657.24

2701

75.9

4.3

614.2

2702

84.8

4.27

686.27

2703

86.6

3.91

549.16

2704

77.7

4.26

587.13

2705

69.4

3.8

544.1

2706

88.0

3.9

616.19

2707

79.9

4.06

563.18

2708

75.9

4.38

601.14

2709

62

3.9

603.2

2710

87.7

4.05

630.21

2711

56.8

3.85

594.20

2712

69.7

4.18

632.22

2713

62.2

3.7

589.2

2714

79.2

3.76

661.23

2715

56.8

4

608.23

2716

70.5

4.31

646.23

2717

62

3.9

603.2

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

Ex.

R2

R10

R3

Purity (%)

rt (min.)

[M + 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

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 (sst

1

, sst

2

, sst

3

, sst

4

and sst

5

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

125

I-Tyr

11

]SRIF-14 to transfected CHO-K1 cells.

The gene of the sst

1

receptor of human somatostatin has been cloned in the form of a genomic fragment. A segment PstI-XmnI of 1.5 Kb containing 100 bp of the non transcribed 5′ region, 1.17 Kb of the coding region in totality, and 230 bp of the non transcribed 3′ region is modified by the addition of the linker Bg1II. The resulting DNA fragment is subcloned in the BamHI site of a pCMV-81 in order to produce the expression plasmid in mammals (provided by Dr. Graeme Bell, Univ. Chicago). A cloned cell line expressing in a stable fashion the sst

1

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

The gene of the sst

2

receptor of human somatostatin, isolated in the form of a genomic fragment of DNA of 1.7 Kb BamHI-HindIII and subdcloned 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 BamH1-HindII fragment of 1.7 Kb in endonuclease restriction sites compatible with the plasmid pCMV5. A cloned cell line is obtained by transfection in CHO-K1 cells using the calcium phosphate co-precipitation method. The plasmid pRSV-neo is included as selection marker.

The sst

3

receptor is isolated as a genomic fragment, and the complete coding sequence is contained in a BamHI/HindIII fragment of 2.4 Kb. The expression plasmid in mammals, pCMV-h3, is constructed by insertion of the NcoI-HindIII fragment of 2.0 Kb in the EcoR1 site of the vector pCMV after modification of the terminations and addition of EcoR1 linkers. A cloned cell line expressing in a stable fashion the sst

3

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

The expression plasmid of the human sst

4

receptor, pCMV-HX, was provided by Dr. Graeme Bell (Univ. Chicago). This vector contains the genomic fragment coding for the human sst4 receptor of 1.4 Kb NheI-NheI, 456 pb of the non transcribed 5′ region, and 200 pb of the non transcribed 3′ region, cloned in the XbaI/EcoR1 sites of PCMV-HX. A cloned cell line expressing in a stable fashion the sst

4

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. The cloned cell lines were selected in an RPMI 1640 medium containing 0.5 mg/ml of G418 (Gibco), followed by circular cloning and multiplication in culture.

The gene corresponding to the human sst

5

receptor, obtained by the PCR method using a genomic 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 transcribed 5′ region, the coding region in totality, and 55 pb of the non transcribed 3′ region. The clone is inserted in an EcoR1 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 lines expressing in a stable fashion the sst

5

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

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

The competitive inhibition experiments of the bond with [

125

I-Tyr

11

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

125

I-Tyr

11

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

2

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

The bound [

125

I-Tyr

11

]SRIF-14 is separated from the free [125I-Tyr

11

]SRIF-14 by immediate filtration through GF/C glass fibre filter plates (Unifilter, Packard) pre-impregnated with 0.1% of polyethylenimine (P.E.I.), using a Filtermate 196 (Packard). The filters are washed with 50 mM HEPES buffer at approximately 0-4° C. for approximately 4 seconds and their radioactivity is determined using a counter (Packard Top Count).

The specific bond is obtained by subtracting the non-specific bond (determined in the presence of 0.1 μM of SRIF-14) from the total bond. The data relative to the bond are analyzed by computer-aided non-linear regression analysis (MDL) and the values of the inhibition constants (Ki) are determined.

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

Functional test: Inhibition of production of intracellular cAMP:

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

The cells at a rate of 10

5

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

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

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

−12

M to 10

−6

M) and of the compound to be tested (10

−10

M to 10

−5

M).

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

−10

M to 10

−5

M).

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

Results:

The tests carried out according to the protocols described above have demonstrated that the 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 K

i

being lower than micromolar for certain exemplified compounds, and in particular for the products shown in the table below.

Formula of compound

K

i

(nM)

<200

2-Arylimino-2,3-dihydrothiazoles, and their use thereof as somatostatin receptor ligands

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