4-Aminopiperidine and their use as a medicine

Description

[0001] A subject of the present application is new derivatives of 4-aminopiperidines and their preparation processes by synthetic methods in parallel in liquid and solid phase. These products having a good affinity with certain sub-types of somatostatin receptors, they are particularly useful for treating the pathological states or diseases in which one (or more) somatostatin receptors are involved.

[0002] 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.

[0003] The heterogeneity of the biological functions of somatostatin has led to studies which try to identify the structure-activity relationships of peptide analogues on somatostatin receptors, which has led to the discovery of 5 sub-types of receptors (Yamada et al., Proc. Natl. Acad. Sci. U.S.A, 89, 251-255, 1992; Raynor, K. et al, Mol. Pharmacol., 44, 385-392, 1993). The functional roles of these receptors are currently being actively studied. The affinities with different sub-types of somatostatin receptors have been associated with the treatment of the following disorders/diseases. Activation of sub-types 2 and 5 has been associated with suppression of the growth hormone (GH) and more particularly with that of adenomas secreting GH (acromegalia) and those secreting hormone TSH. Activation of sub-type 2 but not sub-type 5 has been associated with the treatment of adenomas secreting prolactin. Other indications associated with the activation of sub-types of somatostatin receptors are the recurrence of stenosis, inhibition of the secretion of insulin and/or of glucagon and in particular diabetes mellitus, hyperlipidemia, insensiblity to insulin, Syndrome X, angiopathy, proliferative retinopathy, Dawn phenomenon and nephropathy; inhibition of the secretion of gastric acid and in particular peptic ulcers, enterocutaneous and pancreaticocutaneous fistulae, irritable colon syndrome, dumping syndrome, aqueous 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.

[0004] 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.

[0005] The applicants found that the compounds of general formula 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.

[0006] Therefore a subject of the present invention is the compounds of general formula

[0007] in racemic, enantiomeric form or all combinations of these forms, in which:

[0008] R1 represents a linear or branched (C1-C16)alkyl, alkenyl, alkynyl, —(CH2)m—Y—Z11 or —(CH2)m—Z12 radical in which

[0009] Z11 represents a (C1-C6)alkyl or aryl optionally substituted,

[0010] Z12 represents cyano, cyclohexenyl, bis-phenyl, (C3-C7)cycloalkyl, optionally substituted (C3-C7) heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl,

[0011] or Z12 represents a radical of formula

[0012] or R1 represents a radical of formula

[0013] R2 represents a radical of formula —C(Y)NHX1, —C(O)X2 or SO2X3;

[0014] R3 represents the hydrogen atom, an optionally substituted alkyl, alkenyl, alkynyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl radical, or a radical of formula —C(Y)—NHX1, —(CH2)n—C(O)X2, SO2X3 or

[0015] X1 represents a linear or branched (C1-C15)alkyl, alkenyl, alkynyl, —(CH2)m—Y—Z21 or —(CH2)pZ22 radical in which

[0016] Z21 represents a (C1-C6)alkyl

[0017] Z22 represents cyclohexenyl, indanyl, bis-phenyl, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl, mono- or di-alkylamino, —C(O)—O-alkyl, or aryl or heteroaryl optionally substituted,

[0018] or Z22 represents a radical of formula

[0019] X2 represents a linear or branched (C1-C10)alkyl radical, an alkenyl radical optionally substituted by a phenyl radical (the phenyl radical being itself optionally substituted), an alkynyl radical, or a radical of formula —(CH2)m, —W—(CH2)q—Z23 or —(CH2)p—U—Z24 in which

[0020] Z23 represents a (C1-C6)alkyl or aryl optionally substituted;

[0021] Z24 represents alkyl, cyclohexenyl, bis-phenyl, (C3-C7)cycloalkyl optionally substituted, (C3-C7)heterocycloalkyl, cyano, amino, mono or di-alkylamino, or aryl or heteroaryl optionally substituted,

[0022] or Z24 represents a radical of formula

[0023] or X2 represents a radical represented below:

[0024] where the protective group (PG) represents H or tert-butyloxycarbonyl;

[0025] X3 represents a linear or branched (C1-C10)alkyl radical, an alkenyl radical optionally substituted by a phenyl radical (the phenyl radical being itself optionally substituted), CF3, or —(CH2)pZ25 in which

[0026] Z25 represents aryl or heteroaryl optionally substituted,

[0027] or X3 represents a radical of formula

[0028] Optionally substituted by one or more halo radicals identical or different;

[0029] Y represents an oxygen or sulphur atom;

[0030] W represents an oxygen or sulphur atom, or SO2;

[0031] U represents a covalent bond or the oxygen atom;

[0032] n is an integer from 0 to 4;

[0033] m is an integer from 1 to 6;

[0034] p is an integer from 0 to 6;

[0035] q is an integer from 0 to 2,

[0036] or their addition salts with pharmaceutically acceptable mineral or organic acids, with the exclusion of compounds of general formula I wherein R1 represents the radical alkyle, alkenyle or benzyle. R2 an optionally substituted benzyloxy and R3 aralkyle.

[0037] A more particularly subject of the invention is the products of general formula I as defined above, characterized in that

[0038] i) the substituent or substituents which can be carried by the aryl radicals represented by Z11 and Z12 and heteroaryl represented by Z12 are chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, —CF3, —OCF3, phenyl, phenoxy, aminosulphonyl radicals;

[0039] ii) the substituent or substituents which can be carried by the heterocycloalkyl radical represented by Z12 are chosen independently from the oxy and alkyl radicals;

[0040] iii) the substituent or substituents which can be carried by the aryl and heteroaryl radicals represented by Z22 are chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkenyl, alkoxy, alkylthio, CF3, OCF3, nitro, cyano, azido, aminosulphonyl, piperidinosulphonyl, mono- or di-alkylamino, —C(O)—O-alkyl, —C(O)-alkyl, or phenyl, phenoxy, phenylthio, benzyloxy radicals, the phenyl radical being able to be substituted;

[0041] iv) the substituent or substituents which can be carried by the aryl radicals represented by Z23 and Z24, cycloalkyl and heteroaryl represented by Z24 are chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, CF3, OCF3, OCHF2, SCF3, nitro, cyano, azido, hydroxy, —C(O)O-alkyl, —O—C(O)-alkyl, —NH—C(O)-alkyl, alkylsulphonyl, mono- or di-alkylamino, amino, aminoalkyl, pyrrolyl, pyrrolydinyl or the radicals phenyl, phenoxy, phenylthio, benzyl, benzyloxy radicals the aryl radical of which is optionally substituted by one or more alkyl, CF3 or halo radicals;

[0042] v) the substituent or substituents which can be carried by the aryl and heteroaryl radicals represented by Z25 are chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, OCF3, nitro, cyano, —NH—C(O)-alkyl, alkylsulphonyl, amino, mono- and di-alkylamino, phenyl, pyridino radicals;

[0043] vi) the substituent which can be carried by the alkyl radical represented by R3 is the cyano radical;

[0044] vii) the substituent or substituents which can be carried by the aralkyl radical represented by R3 are chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, OCF3, OCHF2, SCF3, SCHF2, nitro, cyano, —C(O)O-alkyl, alkylsulphonyl, thiadiazolyl radicals, or the phenyl and phenoxy radicals the phenyl radical of which is optionally substituted by one or more halo radicals;

[0045] viii) the substituent or substituents which can be carried by the heteroarylalkyl radical represented by R3 are chosen independently from the fluoro, chloro, bromo or nitro radicals.

[0046] In the definitions indicated above, the expression halo represents the fluoro, chloro, bromo or iodo radical, preferably chloro, fluoro or bromo. The expression alkyl (when it is not specified otherwise), preferably represents a linear or branched alkyl radical having 1 to 6 carbon atoms, such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl or amyl, isopentyl, neopentyl, hexyl or isohexyl radicals. Among the alkyl radicals containing 1 to 15 carbon atoms, there can be mentioned the alkyls as defined above but also the heptyl, octyl, nonyl, decyl, dodecyl, tridecyl or pentadecyl radicals.

[0047] By alkenyl, when it is not specified otherwise, is understood a linear or branched alkyl radical containing 1 to 6 carbon atoms and having at least one unsaturation (double bond), such as for example vinyl, allyl, propenyl, butenyl or pentenyl. By alkynyl, when it is not specified otherwise, is understood a linear or branched alkyl radical containing 1 to 6 carbon atoms and having at least one double unsaturation (triple bond) such as for example an ethynyl, propargyl, butynyl or pentynyl radical.

[0048] The term cycloalkyl designates a monocyclic carbon system comprising 3 to 7 carbon atoms, and preferably the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl rings. The expression heterocycloalkyl designates a saturated cycloalkyl containing 2 to 7 carbon atoms and at least one heteroatom. This radical can contain several identical or different heteroatoms. Preferably, the heteroatoms are chosen from oxygen, sulphur or nitrogen. As examples of a heterocycloalkyl, there can be mentioned the pyrrolidine, pyrrolidinone, imidazolidine, pyrrazolidine, isothiazolidine. thiazolidine, isoxazolidine, piperidine, piperazine or morpholine ring.

[0049] The alkoxy radicals can correspond to the alkyl radicals indicated above such as for example the methoxy, ethoxy, propyloxy or isopropyloxy radicals but also linear, secondary or tertiary butoxy, pentyloxy. The term lower alkylthio preferably designates the radicals in which the alkyl radical is as defined above such as for example methylthio, ethylthio, The term alkylsulphonyl preferably designates the radicals in which the alkyl radical is as defined above.

[0050] The expression aryl represents an aromatic radical, constituted by a condensed ring or rings, such as for example the phenyl or naphthyl radical. The expression heteroaryl designates an aromatic radical, constituted by a ring or condensed rings, with at least one ring containing one or more identical or different heteroatoms chosen from sulphur, nitrogen or oxygen. As an example of a heteroaryl radical, there can be mentioned the thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, thiazolyl, isoxazolyl, oxazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, quinoxalinyl, benzothienyl, benzofuryl, indolyl, benzoxadiazoyl radicals.

[0051] The terms mono- and di-alkylamino preferably designate the radicals in which the alkyl radicals are as defined above, such as for example methylamino, ethylamino, dimethylamino, diethylamino or (methyl)(ethyl)amino.

[0052] The symbol -> * corresponds to the attachment point of the radical. When the attachment site is not specified on the radical, this signifies that the attachment is carried out on one of the sites which are available to this radical for such an attachment.

[0053] A more particular subject of the present invention is the compounds of general formula I as defined above in which:

[0054] R1 represents a linear or branched (C1-C6)alkyl radical, the —(CH2)m—Y—Z11 or —(CH2)m—Z12 radical in which

[0055] Z11 represents a (C1-C6)alkyl,

[0056] Z12 represents bis-phenyl, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl optionally substituted, or aryl or heteroaryl optionally substituted by one or more substituents chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy radicals,

[0057] or Z12 represents

[0058] Y represents the oxygen atom,

[0059] or R1 represents a radical of formula

[0060] R2 represents a radical of formula —C(Y)NHX1, —C(O)X2 or SO2X3 in which

[0061] X1 represents a linear or branched (C1-C15)alkyl radical, or —(CH2)pZ22 in which

[0062] Z22 represents cyclohexenyl, bis-phenyl, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl, mono- or di-alkylamino, —C(O)—O-alkyl, or aryl or heteroaryl optionally substituted by one or more radicals chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, CF3, OCF3, nitro, cyano, azido, piperidinosulphonyl, —C(O)—O-alkyl, —C(O)-alkyl, or phenyl radicals,

[0063] or Z22 represents a radical of formula

[0064] X2 represents a linear or branched (C1-C10)alkyl, alkynyl, —(CH2)m—W—(CH2)q—Z23 or —(CP2)p—U—Z24 radical in which

[0065] W represents SO2,

[0066] U represents a covalent bond,

[0067] Z23 represents an aryl radical;

[0068] Z24 represents cyclohexenyl, bis-phenyl, (C3-C7)cycloalkyl optionally substituted by an aminoalkyl, or aryl or heteroaryl radical optionally substituted by one or more radicals chosen from fluoro, chloro, bromo, iodo, alkyl, alkoxy, —CF3, —OCF3, SCF3, hydroxy, —O—C(O)-alkyl, mono- or di-alkylamino, amino

[0069] or Z24 represents a radical of formula

[0070] or X2 represents

[0071] X3 represents a —(CH2)pZ25 radical in which Z25 represents an aryl radical optionally substituted by one or more identical or different radicals chosen from alkoxy and CF3,

[0072] R3 represents the hydrogen atom, an alkyl, alkenyl, heteroarylalkyl radical optionally substituted or a radical of formula —C(Y)—NHX1, —C(O)X2 or SO2X3 in which

[0073] X1 represents a —(CH2)pZ22 radical in which

[0074] Z22 represents an aryl radical optionally substituted by one or more radicals chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, phenoxy radicals;

[0075] X2 represents the vinyl radical substituted by a phenyl, the phenyl radical being itself optionally substituted by one or more halo, or —(CH2)p—U—Z24 radicals in which

[0076] Z24 represents alkyl, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl, bis-phenyl, amino, mono or di-alkylamino, or aryl or heteroaryl optionally substituted by one or more radicals chosen from alkoxy, bromo, chloro, fluoro, hydroxy, CF3, nitro, amino, mono- and di-alkylamino, pyrrolyl,

[0077] or X2 represents a radical of formula

[0078] X3 represents a linear or branched (C1-C10)alkyl radical, the vinyl radical substituted by a radical (the phenyl radical being itself optionally substituted). CF3, or —(CH2)pZ25 in which

[0079] Z25 represents aryl or heteroaryl optionally substituted by one or more substituents chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, —NH—C(O)-alkyl, mono- and di-alkylamino radicals.

[0080] Preferentially, R1 represents a linear or branched (C1-C6)alkyl radical, the —(CH2)m—Y—Z11 or —(CH2)m—Z12 radical in which

[0081] Z11 represents a (C1-C6)alkyl,

[0082] Z12 represents naphthyl, morpholino, bis-phenyl, pyrrolidinyl substituted by the oxy radical, or the phenyl, piperazinyl, pyridinyl and indolyl radicals which are optionally substituted by one or more substituents chosen independently from the bromo, fluoro, chloro, alkyl, alkoxy, —CF4, —OCF3 radicals;

[0083] or Z12 represents

[0084] Y represents the oxygen atom,

[0085] or R1 represents a radical of formula given below:

[0086] Preferentially, R2 represents a radical of formula —C(Y)NHX1, —C(O)X2 or SO2X3 in which

[0087] X1 represents a linear or branched (C1-C10)alkyl, or —(CH2)pZ22 radical in which

[0088] Z22 represents cyclohexyl, cyclohexenyl, bis-phenyl, morpholino, piperidino, mono- or di-alkylamino, —C(O)—O-alkyl, or phenyl, naphthyl or furyl optionally substituted by one or more radicals chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, CF3, OCF3, nitro, cyano, azido, piperidinosulphonyl, —C(O)—O-alkyl, —C(O)-alkyl or phenyl radicals,

[0089] or Z22 represents a radical of formula

[0090] X2 represents an alkyl, alkynyl, —(CH2)m—W—(CH2)q—Z23 or —(CH2)pZ24 radical in which

[0091] W represents SO2;

[0092] Z23 represents the phenyl radical

[0093] Z24 represents cyclohexenyl, bis-phenyl, cyclohexyl optionally substituted by an aminoalkyl, or phenyl, naphthyl, benzothienyl, thienyl or indolyl radical optionally substituted by one or more radicals chosen from fluoro, chloro, bromo, iodo, alkyl, alkoxy, —CF3, —OCF3, SCF3, hydroxy, —O—C(O)-alkyl, —NH—C(O)-alkyl, mono- or di-alkylamino, amino, or

[0094] Z24 represents a radical of formula

[0095] or X2 represents

[0096] X3 represents a —(CH2)pZ25 radical in which Z25 represents the phenyl radical optionally substituted by one or more identical or different radicals chosen from alkoxy and CF3,

[0097] Preferentially, R3 represents the hydrogen atom, an alkyl, alkenyl or furyl-methyl radical substituted by one or more nitro radicals, or a radical of formula —C(Y)—NHX1, —C(O)X2 or SO2X3 in which

[0098] X1 represents a —(CH2)pZ2 radical in which

[0099] Z22 represents the phenyl or naphthyl radical optionally substituted by one or more radicals chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, phenoxy radicals,

[0100] X2 represents the vinyl radical substituted by a phenyl radical itself optionally substituted by one or more halo, or —(CH2)p—U—Z24 radicals in which

[0101] Z24 represents alkyl, cyclohexyl, tetrahydrofuryl, bis-phenyl, amino, mono or di-alkylamino, or phenyl, indolyl, thienyl, pyridinyl, benzothienyl and furyl optionally substituted by one or more radicals chosen from alkoxy, bromo, chloro, fluoro, amino, mono- and di-alkylamino, nitro, hydroxy, pyrrolyl

[0102] or X2 represents a radical of formula

[0103] X3 represents a linear or branched (C1-C10)alkyl radical, the vinyl radical substituted by a phenyl, CF3, or —(CH2)pZ25 radical in which

[0104] Z25 represents a phenyl, naphthyl, thienyl, pyrazolyl or thiazolyl radical optionally substituted by one or more substituents chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, —NH—C(O)-alkyl, mono- and di-alkylamino radicals;

[0105] Very preferentially, R1 represents the —CH2)mZ12 radical in which m=2 and Z12 represents bis-phenyl or the radical indolyl substituted by one or more substituents chosen independently from the alkyl and alkoxy radicals.

[0106] Very preferentially, R2 represents the radicals of formula —C(Y)NHX1 and —C(O)X2 in which

[0107] Y represents S

[0108] X1 represents a phenyl radical optionally substituted by one or more azido radicals,

[0109] X2 represents —(CH2)pZ24 in which

[0110] p is equal to 1, 2 or 3,

[0111] Z24 represents cyclohexyl, or phenyl or benzothienyl optionally substituted by one or more radicals chosen from fluoro, chloro, bromo, iodo or —CF3.

[0112] Very preferentially, R3 represents the hydrogen atom or the methyl radical.

[0113] The compounds according to the invention can be prepared in solid or liquid phase.

A) SYNTHESES IN LIQUID PHASE VIA THE N-SUBSTITUTED PIPERIDONE

A1) Reducing Amination

[0114] It is carried out according to the following stage:

[0115] in which R represents methyl or Boc and R1 has the meaning indicated above.

[0116] The general procedure is as follows: the reducing amination (Abdel-Magid, A. F. Maryanoff, C. A.; Carson, K. G. Tetrahedron Lett. 1990, 31, 5595-5598 Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D., J. Org. Chem. 1996, 61, 3849-3862) of the N-substituted piperidone is carried out in anhydrous chlorinated solvents such as dichloroethane in the presence of a primary amine (1.1 to 1.5 eq.), a reducing agent such as sodium triacetoxyborohydride (1.1 to 1.5 eq.) and acetic acid (10% by mass relative to the N-substituted piperidone). The reaction mixture is agitated for 1 to 4 hours at ambient temperature. In certain cases, a solution of soda (0.1 M) is added and the mixture is agitated for 20 to 90 minutes. If not, the reaction mixture is washed with a saturated solution of sodium bicarbonate, with sodium chloride, dried over magnesium sulphate, filtered and concentrated. The desired product is purified by flash chromatography on silica gel.

Preparation 1

[0117] tert-butyl 4-[(3,3-diphenylpropyl)amino]-1-piperidine carboxylate(C25H34N2O2, M=394.56)

[0118] 3,3-diphenylpropylamine (5.8 g, 27.5 mmol), sodium triacetoxyborohydride (6.36 g, 30 mmol) and 0.5 ml of acetic acid are added to 5 g (25 mmol) of N-Boc-piperidone in 100 ml of dry dichloroethane. The turbid yellow solution is agitated at ambient temperature after 1 hour. 50 ml of a soda solution (0.1 M) is then added and the mixture is agitated for 30 minutes. The organic phase is washed with a saturated solution of sodium bicarbonate, with sodium chloride, dried over magnesium sulphate, filtered and concentrated in order to produce 10 g of a yellow solid. This solid is purified by flash chromatography on silica gel eluting with a heptane/ethyl acetate mixture (4/1, 3/1, 2/1 then 1/1) then with pure ethyl acetate. The fractions are concentrated under vacuum in order to produce 5.6 g (yield=57%) of a pale yellow solid.

[0119] NMR 1H (CD3OD, 400 MHz) δ: 7.27 (m, 8H); 7.16 (m, 2H); 4 (dd, J=6.4 and 14 Hz, 3H); 2.73 (m, 2H); 2.55 (m, 3H); 2.26 (q, J=7.6 Hz, 2H); 1.78 (d, J=12 Hz, 2H); 1.45 (s, 9H); 1.15 (qd, J=4.4 and 12.8 Hz, 2H). MS/LC: m/z=395.2 (M+H).

[0120] A series of 4-aminosubstituted-1-piperidine was prepared according to this procedure with the following other R1 groups:

A2) Functionalization of piperidines

[0121] A2a) Syntheses of ureas and thioureas

[0122] The syntheses of ureas and thioureas are implemented according to the procedure described in the literature (Kaldor, S. W.; Siegel, M. G. Fritz, J. E. Dressman. B. A.; Hahn, P. J. Tetrahedron Lett. 1996, 37, 7193-7196; Kaldor, S. W. Fritz, J. E.; Tang, J.; McKinney, E. R. Bioorg. Med. Chem. Lett. 1996, 6, 3041-3044 Booth, R. J.; Hodges, J. C. J Am. Chem. Soc. 1997, 119, 4882-4886 ; Flynn, D. L. Crich, J. Z.; Devraj, R. V.; Hockerman, S. L.; Parlow, J. J.; South, M. S. Woodard, S.; J. Am. Chem. Soc. 1997, 119, 4874-4881) following the following diagram:

[0123] in which R represents methyl or Boc and X1 and Y have the meaning indicated above. It should be noted that in the case where R represents Boc, the product thus obtained is a final product corresponding to formula I according to the invention but can also be used as a synthesis intermediate.

[0124] The general procedure is as follows: the isocyanate or the isothiocyanate (1.1 to 1.5 eq.) is added to the 4-aminosubstituted-1-piperidine in aprotic solvents such as dichloromethane, tetrahydrofuran or dimethylformamide and the mixture is agitated for 45 minutes to 18 hours at ambient temperature. The aminomethyl resin (Novabiochem, 1.33 mmol/g, 0.2 to 1 eq.) is added and the mixture is agitated for 45 minutes to 18 hours. In certain cases, the basic ion exchange resin such as IRA-68 (Gayo, L. M.; Suto, M. J. Tetrahedron Lett. 1997, 38, 513-516) can be added.

[0125] The resins are filtered and the filtrate is concentrated. Other purifications on silica gel or basic alumina cartridges (500 mg, Interchim) can optionally be carried out.

Example A2a

[0126] tert-butyl-4-((3,3-diphenylpropyl){[3-(trifluoromethyl)anilino]carbonyl}amino)-1-piperidine carboxylate (C33H38F3N3O3, M=581.68)

[0127] 246 mg (1.32 mmol) of 3-(trifluoromethyl)phenyl isocyanate is added to a solution of tert-butyl 4-[(3,3-diphenylpropyl)amino]-1-piperidine carboxylate (470 mg, 1.2 mmol) in 5 ml of dichloromethane. The solution is agitated for 45 minutes, and the aminomethyl resin (180 mg, 0.36 mmol) is added and the reaction medium is again placed on an orbital shaker for 45 minutes. The resin is filtered and washed with dichloromethane. The filtrate is concentrated in vacuo in order to produce 610 mg (yield=87%) of a white foam.

[0128] NMR 1H (CD3OD, 400 MHz) δ: 7.71 (s, 1H); 7.57 (d, 1H); 7.43 (t, 1H); 7.26 (m, 10H); 7.15 (m, 1H); 4.1 (m, 3H); 3.97 (dd, J=7.6 and 10 Hz, 1H); 3.17 (m, 2H); 2.75 (m, 2H); 2.35 (m, 2H); 1.65 (d, J=12 Hz, 2H); 1.46 (s, 9H, tbutyl group); 1.39 (dd, J=2.4 and 10.8 Hz, 2H); 1.29 (s, 1H). MS/LC: m/z=582 (M+H).

[0129] For the R1 groups as illustrated in point A1 above, the X1 groups which can be envisaged for the synthesis of ureas (Y=O) according to the above procedure, are the following:

[0130] For the R1 groups as illustrated in point A1 above, the X1 groups which can be envisaged for the synthesis of thioureas (Y=S) according to the above procedure, are the following:

[0131] A2b) Synthesis of amides from carboxylic Acids

[0132] The syntheses of amides from carboxylic acids are implemented according to the following reaction diagram:

[0133] in which R represents methyl or Boc and X2 has the meaning indicated above. It should be noted that in the case where R represents Boc, the product thus obtained is a final product corresponding to formula I according to the invention but can also be used such as a synthesis intermediate.

[0134] The general procedure is as follows: carboxylic acid (1.1 to 2.5 eq.) dissolved in an anhydrous aprotic solvent such as dichloromethane, dimethylformamide or tetrahydrofuran is activated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide bonded on resin (P-EDC, Novabiochem, 2.33 mmol/g, 1.3 to 3 eq.) (Desai, M. C.; Stephens Stramiello, L. M. Tetrahedron Lett. 1993, 34, 7685-7688). This mixture is agitated for 5 to 30 minutes at ambient temperature. 4-aminosubstituted-1-piperidine dissolved beforehand in an anhydrous aprotic solvent such as dichloromethane, dimethylformamide or tetrahydrofuran is then added and the reaction mixture is agitated at ambient temperature for 1 to 18 hours. In certain cases, basic ion exchange resin (IRA-68, SAX) is added and the mixture is again agitated at ambient temperature for 1 to 18 hours. The resins are filtered on frit or on a basic ion exchange resin cartridge (IRA-68, SAX) or on an alumina cartridge (500 mg, Interchim).

Example A2b

[0135] tert-butyl 4-{(3,4-dimethoxyphenethyl)[2-(1H-indol-3-yl)acetyl]amino}-1-piperidine carboxylate (C35H41N3O3, M=551.74)

[0136] 512 mg (1.12 mmol, 1.4 eq.) of P-EDC resin is preswollen in dichloromethane. 2-(1H)-indol-3-yl)acetic acid (153 mg, 0.875 mmol, 1.1 eq.) is added and the mixture is agitated for 10 minutes. Tert-butyl 4-[(3,3-diphenylpropyl)amino]-1-piperidine carboxylate (292 mg, 0.8 mmol) in tetrahydrofuran is added and the reaction medium is agitated overnight. 2 spatulas of basic ion exchange resin IRA-68 are added and the reaction medium is again agitated overnight. The resins are filtered and the filtrate is concentrated under vacuum in order to produce 250 mg (yield=86%) of a pale yellow foam.

[0137] NMR 1H (CD3OD, 400 MHz) 67 : 7.63 (d, J=8 Hz, 1H); 7.44 (d, J=8 Hz, 1H); 7.36 (d, J=8 Hz, 1H); 7.26 (d, J=8 Hz, 1H); 7.2 (m, 6H); 7.13 (m, 3H); 7.1 (m, 2H); 6.68 (s, 1H); 4-3.75 (m, 4H); 3.65 (s, 1H); 3.2 (m, 1H); 3 (m, 1H), 2.75 (m, 1H); 2.26 (m, 3H); 1.6 (m, 2H); 1.44 (s, 9H); 1.13 (m, 2H). MS/LC: m/z=552.4 (M+H).

[0138] A series of amides was synthesized according to this procedure. The X2 radicals which can be envisaged are the following:

[0139] where the protective group (PG) represents H or tert-butyloxycarbonyl.

A3) Syntheses of 4-aminodisubstituted piperidines

[0140] The synthesis of 4-aminodisubstitueted piperidines according to the invention, can be carried out by acid treatment of the N-Boc compounds described previously, following the following reaction diagram:

[0141] General procedure: two methods were used to carry out the deprotection in acid media of the ureas, thioureas and amides described previously. The first consists in dissolving the compound in dichloromethane and adding trifluoroacetic acid (5 to 20 eq.) whilst in the second a solution of dilute hydrochloric acid in solvents such as ethyl acetate, dioxane or diethylether (5 to 20 eq.) is used. The reaction medium is agitated for 1 to 4 hours at ambient temperature. In certain cases, dichloromethane is added and the organic phase is washed with a saturated solution of sodium bicarbonate, dried over magnesium sulphate, filtered and concentrated under vacuum in order to isolate the free base.

Example A3

[0142] N-(3,3-diphenylpropyl)-N-(4-piperidinyl)-N′-[3-(trifluoromethyl) phenyl]urea (C28H30F3N30, M=481.57)

[0143] 1.6 ml (21 mmol, 20 eq.) of trifluoroacetic acid is added to a solution of tert-butyl 4-((3,3-diphenylpropyl) {[3-(trifluoromethyl)anilino]carbonyl}amino)-1-piperidine carboxylate (600 mg, 1.04 mmol) in dichloromethane. The reaction medium is agitated for 90 minutes then concentrated. Dichloromethane is added and the organic phase is washed with a saturated solution of sodium bicarbonate, dried over magnesium sulphate, filtered and concentrated under vacuum in order to isolate 490 mg (yield=98%) of a white foam.

[0144] NMR 1H (CD3OD, 400 MHz) δ: 7.7 (s, 1H); 7.55 (d, 1H); 7.44 (t, 1H); 7.28 (m, 9H); 7.18 (m, 2H); 4.05 (m, 2H); 3.26 (m, 2H); 3.11 (d, J=10.8 Hz, 2H); 2.7 (td, J=2.4 and 12.4 Hz, 2H); 2.38 (q, J=8 Hz, 2H); 1.76 (d, J=10 Hz, 2H); 1.63 (qd, J=4 and 12.4 Hz, 2H). MS/LC: m/z=482.2 (M+H).

[0145] A series of 4-aminopiperidines was synthesized according to this procedure. The R1, X1 and X2 radicals which can be envisaged are those already illustrated in points A1 and A2 above.

B) SYNTHESIS IN SOLID PHASE OF 4-AMINOPIPERIDINES

[0146] 4-aminopiperidines were prepared by synthesis in solid phase starting with Wang resin.

B1) Preparation of the resin

[0147] B1a) Preparation of the p-nitrophenyl carbonate Wang resin

[0148] It is carried out according to the following diagram

[0149] This resin was prepared from Wang resin (supplied by Bachem or Novabiochem) with a load rate greater than 0.89 mmol/g, following the procedure described in the literature (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 and 4-nitrophenyl chloroformate are added successively to the Wang resin preswollen in dichloromethane or tetrahydrofuran at ambient temperature. The mixture is agitated overnight. The resin is washed with tetrahydrofuran, with diethylether and with dichloromethane then dried in vacuo at 50° C. overnight.

[0150] B1b) Preparation of the piperidone carbamate resin

[0151] It is carried out according to the following diagram

[0152] Triethylamine (1 eq.) and the molecular sieve are added to the hydrated piperidone hydrochloride diluted in dimethylformamide. The mixture is heated until complete dissolution of the ketone. This solution is added to the p-nitrophenyl carbonate Wang resin (0.05 eq.) preswollen in dimethylformamide. After agitation for 24 to 72 hours at ambient temperature, the resin is filtered then washed several times with dimethylformamide, tetrahydrofuran, diethylether and dichloromethane.

Preparation 2

[0153] 2.5 g of p-nitrophenyl carbonate Wang resin (load rate of 0.88 mmol/g, 2.2 mmol) is preswollen in 100 ml of dimethylformamide. At the same time, 6.7g (44 mmol, 20 eq.) of hydrated piperidone hydrochloride, 4.45 g (44 mmol, 20 eq.) of triethylamine and three spatulas of molecular sieve are heated in 100 ml of dimethylformamide until complete dissolution. The yellowish solution is poured warm onto the resin and the mixture is agitated for 40 hours at ambient temperature. The resin is filtered then washed with dimethylformamide, tetrahydrofuran, diethylether and dichloromethane (3 times with each solvent) then dried under vacuum. 2.4 g of pale yellow resin is isolated with a load rate of 0.88 mmol/g calculated after elementary analysis of the nitrogen.

B2) Reducing Amination on Solid Support

[0154] It is carried out according to the diagram

[0155] The general procedure is the following: the primary amine (5 to 10 eq.) is added to the ketonic resin preswollen in trimethylorthoformate (TMOF) then the mixture is sonicated. Then, the borane pyridine complex (8M, 5 to 10 eq.) is added and the mixture is agitated for 12 to 72 hours. The resin is filtered, washed with solvents such as dichloromethane, dimethylformamide and tetrahydrofuran then dried under vacuum (Pelter, A.; Rosser, R. M. J. Chem. Soc. Perkin Trans I 1984, 717-720; Bomann, M. D.; Guch, I. C.; DiMare, M. J. Org. Chem. 1995, 60, 5995-5996 ; Khan, N. M.; Arumugam, V.; Balasubramanian, S. Tetrahedron Lett. 1996, 37, 4819-4822).

[0156] 300 mg (load rate of 0.88 mmol/g, 0.27 mmol) of ketonic resin is preswollen in TMOF. Then 4-bromophenethylamine (540 mg, 420 μl, 2.7 mmol, 10 eq.) then the borane pyridine complex (8 M, 338 μl, 2.7 mmol, 10 eq.) are added. The mixture is agitated for 56 hours at ambient temperature. The resin is filtered, rinsed successively with dichloromethane, dimethylformamide, tetrahydrofuran and dichloromethane then dried under vacuum. 340 mg of pale yellow resin is thus obtained with a load rate of 0.81 mmol/g calculated after elementary analysis of the nitrogen.

B3) Functionalization

[0157] B3a) Functionalization with isocyanates or isothiocyanates

[0158] It is carried out according to the diagram

[0159] The general procedure is the following: the “secondary amine” resin is preswollen in a solvent such as dichloromethane or dimethylformamide before the addition of isocyanate or isothiocyanate (3 to 10 eq.). The mixture is agitated for 1 to 24 hours at ambient temperature. The resin is then filtered, washed with solvents such as dichloromethane, dimethylformamide and tetrahydrofuran then dried under vacuum. Cleavage of the resin is carried out in the presence of an equimolar mixture of dichloromethane and trifluoroacetic acid and agitation is carried out for 30 minutes to 4 hours. The resin is rinsed with dichloromethane then the filtrate is concentrated under vacuum. In certain cases the filtrate is redissolved in dichloromethane then desalified with a saturated solution of sodium carbonate. The organic phase is evaporated under vacuum in order to produce the free base.

Example B3a

[0160] N-(4-bromophenethyl)-N-(4-piperidinyl)-N′-[4-(trifluoromethyl)phenyl]urea (C21H23BrF3N3O, M=470.3)

[0161] 55 mg (50 μmol) of resin (see Preparation 3) is preswollen in anhydrous dichloromethane. Then 4-trifluorophenylisocyanate (28 mg, 150 μmol, 3 eq.) is added and the whole is agitated overnight. The resin is filtered, rinsed with tetrahydrofuran, with dimethylformamide, with tetrahydrofuran then with dichloromethane before being dried under vacuum. Then agitation is carried out for 1.5 hour in the presence of 800 μl of an equimolar mixture of dichloromethane and trifluoroacetic acid. The resin is filtered and rinsed with dichloromethane, the filtrate is concentrated, rediluted in dichloromethane and washed with a saturated solution of sodium bicarbonate. 6 mg of a brown oil (yield=25%) is thus isolated.

[0162] NMR 1H (CD3OD, 400 MHz) δ: 7.53 (m, 4H); 7.44 (d, J=6.8 Hz, 2H); 7.21 (d, J=8.4 Hz, 2H); 4.1 (m, 1H); 3.53 (t, J=7.2 Hz, 2H); 3.12 (d, J=12.8 Hz, 2H); 2.89 (t, J=8 Hz, 2H); 2.7 (m, 2H); 1.73 (m, 4H). MS/LC: m/z=472.2 (M+H).

[0163] A series of ureas (Y=O) and thioureas (Y=S) was synthesized according to this procedure. The R1 radicals which can be envisaged are the following:

[0164] The X1 radicals which can be envisaged are those illustrated in point A above.

[0165] B3b) Functionalization with sulphonyl chlorides

[0166] It is carried out according to the following diagram

[0167] General procedure: the “secondary amine” resin is preswollen in solvents such as dichloromethane, dimethylformamide or tetrahydrofuran. Then sulphonyl chloride (5 to 10 eq.) and triethylamine (6 to 12 eq.) are added and the mixture is agitated for 12 to 24 hours at ambient temperature. The resin is filtered, washed with solvents such as dichloromethane, dimethylformamide and tetrahydrofuran, then dried under vacuum. Then the resin is agitated for 1 to 4 hours in the presence of an equimolar mixture of dichloromethane and trifluoroacetic acid. The resin is rinsed with dichloromethane then the filtrate is concentrated under vacuum. In certain cases the filtrate is redissolved in dichloromethane then desalified with a saturated solution of sodium carbonate. The organic phase is evaporated under vacuum in order to produce the free base.

Example B3b

[0168] N-(4-bromophenethyl)-4-methoxy-N-(4-piperidinyl)phenyl sulphonamide (C20H25BrN2O3S, M=453.4)

[0169] 55 mg (50 μmol) of resin (see Preparation 3) is preswollen in anhydrous dichloromethane. Then triethylamine (42 μl, 300 μmol, 6 eq.) then 4-methoxybenzene sulphonyl chloride (51.5 mg, 250 μmol, 5 eq.) are added and the whole is agitated overnight. The resin is filtered, rinsed with tetrahydrofuran, with dimethylformamide, with tetrahydrofuran then with dichloromethane before being dried under vacuum. The reaction is repeated a second time in order to have a complete substitution. 800 μl of an equimolar mixture of dichloromethane and trifluoroacetic acid is added and agitation is carried out for 1.5 hour at ambient temperature. The resin is filtered and rinsed with dichloromethane. The filtrate is concentrated, rediluted in dichloromethane and washed with a saturated solution of sodium bicarbonate. 14 mg of a brown oil (yield=63%) were thus isolated.

[0170] NMR 1H (CD3OD, 400 MHz) δ: 7.8 (dd, J=2.8 and 10 Hz, 2H); 7.44 (dd, J=1.2 and 6.8 Hz, 2H); 7.17 (d, J=8.4 Hz, 2H); 7.07 (dd, J=3.2 and 10Hz, 2H); 3.87 (s, 3H, OCH3); 3.72 (m, 1H); 3.3 (m, 2H); 3.04 (d, J=12.8 Hz, 2H); 2.92 (t, J=8.4 Hz, 2H); 2.6 (t, J=12.4 Hz, 2H); 1.58 (m, 2H); 1.47 (broad d, J=10 Hz, 2H). MS/LC: m/z=455 (M+H).

[0171] A series of sulphonamides was synthesized according to this procedure. The R1 radicals which can be envisaged are those illustrated in points A and B3a above. The X3 radicals which can be envisaged are the following:

[0172] B3c) Functionalization with Acid chlorides

[0173] It is carried out according to the following diagram

[0174] General procedure: the “secondary amine” resin is preswollen in solvents such as dichloromethane, dimethylformamide or tetrahydrofuran. Then the acid chloride (5 to 10 eq.) and triethylamine (6 to 12 eq.) are added and the mixture is agitated for 12 to 24 hours at ambient temperature. The resin is filtered, washed with solvents such as dichloromethane, dimethylformamide and tetrahydrofuran, then dried under vacuum. The resin is then agitated for 1 to 4 hours in the presence of an equimolar mixture of dichloromethane and trifluoroacetic acid. The resin is rinsed with dichloromethane then the filtrate is concentrated under vacuum. In certain cases the filtrate is redissolved in dichloromethane then desalified with a saturated solution of sodium carbonate. The organic phase is evaporated under vacuum in order to produce the free base.

Example B33c

[0175] N-(4-bromophenethyl)-N-(4-piperidinyl)-2-thiophene carboxamide (C18H21BrN2OS, M=393.3)

[0176] 55 mg (50 μl) of resin (see Preparation 3) is preswollen in anhydrous tetrahydrofuran. Then triethylamine (42 μl, 300 μmol, 6 eq.) then 2-thiophene carbonyl chloride (37 mg, 250 μmol, 5 eq.) are added and the whole is agitated overnight. The resin is filtered, rinsed with tetrahydrofuran, with dimethylformamide. with tetrahydrofuran then with dichloromethane before being dried under vacuum. 800 μl of an equimolar mixture of dichloromethane and trifluoroacetic acid is added and agitation is carried out for 1.5 hour at ambient temperature. The resin is filtered and rinsed with dichloromethane. The filtrate is concentrated, rediluted in dichloromethane and washed with a saturated solution of sodium bicarbonate in order to obtain 10 mg of a brown oil (yield=50%).

[0177] NMR 1H (CD3OD, 400 MHz) δ: 7.64 (dd, J=0.8 and 4.8 Hz, 1H); 7.44 (d, J=8.4 Hz, 2H); 7.36 (d, J=3.6 Hz, 1H); 7.14 (m, 3H); 4.11 (m, 1H); 3.61 (t, J=8 Hz, 2H)); 3.09 (d, J=12Hz, 2H); 2.92 (m, 2H); 2.54 (mn, 2H); 1.82 (m, 2H); 1.7 (m, 2H). MS/LC: m/z=393.1 (M+H).

[0178] A series of amides was synthesized according to this procedure. The R1 groups envisaged are those illustrated in points A and B3 above. The X2 groups are illustrated below.

[0179] B3d) Functionalization with carboxylic Acids

[0180] It is carried out according to the procedure described in the literature (Kobayashi, S; Aoki, Y., J. Comb. Chem. 1999, 1, 371-372) following the diagram:

[0181] General procedure: the “secondary amine” resin is preswollen in solvents such as dichloromethane, dimethylformamide or tetrahydrofuran. Then the carboxylic acid (3 to 5 eq.), benzo-triazol-1-yl-oxy-tris-pyrrolidino phosphonium hexafluorophosphate (PyBoP, 3 to 5 eq.) and diisopropylethylamine (6 to 10 eq.) are added and the mixture is agitated for 24 hours at ambient temperature. The resin is filtered, washed with solvents such as dichloromethane, dimethylformamide and tetrahydrofuran, then dried under vacuum. Then the resin is agitated for 1 to 4 hours in the presence of an equimolar mixture of dichloromethane and trifluoroacetic acid. The resin is rinsed with dichloromethane then the filtrate is concentrated under vacuum. In certain cases the filtrate is redissolved in dichloromethane then desalified with a saturated solution of sodium carbonate. The organic phase is evaporated under vacuum in order to produce the free base.

Example B3d

[0182] N-[2-(4-bromophenyl)ethyl]-N-(4-piperidinyl)acetamide (C15H21BrN2O, M=325.25)

[0183] 55 mg (50 μmol) of resin (see Preparation 3) is preswollen in anhydrous dimethylformamide. Then acetic acid (8.8 mg, 150 μmol, 3 eq.) PyBoP (76 mg, 150 μmol, 3 eq.) then diisopropylethylamine (38 mg, 300 μmol, 6 eq.) are added and the whole is agitated overnight. The resin is filtered, rinsed with dimethylformamide, with tetrahydrofuran then with dichloromethane before being dried under vacuum. 800 μl of an equimolar mixture of dichloromethane and trifluoroacetic acid is added and agitation is carried out for 1.5 hour at ambient temperature. The resin is filtered and rinsed with dichloromethane. The filtrate is concentrated, rediluted in dichloromethane and washed with a saturated solution of sodium bicarbonate in order to obtain 11 mg of a brown oil (yield=68%).

[0184] NMR 1H (CD3OD, 400 MHz) δ: 7.44 (m, 2H); 7.20 (m, 2H); 4.05 (m, 1H)) 3.45 (m, 2H); 3.10 (m, 2H); 2.83 (m, 2H); 2.64 (m, 2H); 2.13 (s,3H); 1.73 (m, 4H). MS/LC: m/z=325.2 (M+H).

[0185] A series of amides was synthesized according to this procedure. The R1 groups envisaged are those illustrated in points A and B3a above. The X2 groups are illustrated in point A above.

C) FUNCTIONALIZATION OF THE PIPERIDINE PART IN SOLUTION

C1) Obtaining piperidine with R3=—C(Y)NHX1

[0186] It is carried out according to the diagram

[0187] General procedure: an isocyanate or isothiocyanate (1.1 to 1.5 eq.) is added to piperidine in the form of the free base diluted in dichloromethane. The mixture is agitated for one to 18 hours at ambient temperature. The aminomethyl resin (0.2 to 1 eq.) is added and the mixture is again agitated for 2 to 18 hours. In certain cases, ion exchange resin such as IRA68 or SAX is added. The resins are filtered and the filtrate is concentrated. In certain cases, the product is dissolved in dichloromethane or ethyl acetate then filtered on a silica gel or basic alumina cartridge (500 mg, Interchim).

Example C1

[0188] 4-((3,3-diphenylpropyl){[3-(trifluoromethyl)anilino]carbonyl}amino)-N-phenyl-1-piperidine carboxamide (C35H35F3N4O2, M=600.68)

[0189] N-(3,3-diphenylpropyl)-N-(4-piperidinyl)-N′-[3-(trifluoromethyl)phenyl]urea (24 mg, 0.05 mmol) is dissolved in dichloromethane. Phenylisocyanate (9 mg, 0.075 mmol, 1.5 eq.) is added and the mixture is agitated for 2.5 hours. The aminomethyl resin (0.02 mmol) is added and the reaction is again agitated overnight. The resin is filtered, rinsed with dichloromethane and the filtrate is concentrated. The oil obtained is passed through a silica gel cartridge eluting with an equimolar mixture of heptane and ethyl acetate in order to obtain 12 mg (yield=40%) of a yellow oil after concentration.

[0190] NMR 1H (CD3OD, 400 MHz) δ: 7.72 (s, 1H); 7.58 (d, 1H); 7.44 (m, 1H); 7.38 (m, 2H); 7.29 (m, 12H); 7.12 (m, 2H); 7.07 (m, 1H); 4.2 (d, J=12.4Hz, 3H); 3.21 (t, J=8 Hz, 2H); 2.9 (t, J=12.4 Hz, 2H); 2.38 (q, J=8 Hz, 2H); 1.73 (d, J=10 Hz, 2H); 1.54 (qd, J=3.6 and 12 Hz, 2H). MS/LC: m/z=601.4 (M+H).

[0191] A series of ureas (Y=O) and thioureas (Y=S) was synthesized according to this procedure. The R1, X1 and X2 groups which can be envisaged, are those illustrated in the above points (A and B3a), A, and (A and B3c) respectively.

C2) Functionalization with carboxylic acids

[0192] It is carried out according to the following diagram

[0193] General procedure: the P-EDC resin (1.3 to 3 eq.) is preswollen in anhydrous dichloromethane. Carboxylic acid (1.1 to 2.5 eq.) is dissolved in an anhydrous solvent such as dichloromethane, dimethylformamide or tetrahydrofuran and is added to the resin. This mixture is agitated for 5 to 30 minutes at ambient temperature. The 4-aminodisubstituted piperidine, in the form of the free base, in solution in an anhydrous solvent such as dichloromethane, dimethylformamide or tetrahydrofuran is then added to this mixture and the whole is agitated for 1 to 18 hours at ambient temperature. In certain cases, ion exchange resin such as IRA68 or SAX is added and the mixture is again agitated at ambient temperature for 1 to 18 hours. The resins are filtered on frit, on a SAX ion exchange resin cartridge (500 mg, Interchim) or on a basic alumina cartridge (500 mg, Interchim).

Example C2

[0194] N-(1-acetyl-4-piperidinyl)-N-(3,3-diphenylpropyl)-N′-[3-(trifluoromethyl)phenyl]urea (C30H32F3N3O2, M=523.60)

[0195] 117 mg (175 μmol, 3.5 eq.) of P-EDC resin is preswollen in 1.5 ml of anhydrous dichloromethane. Acetic acid (7.5 mg, 125 μmol, 2.5 eq.) is added and the mixture is agitated for 10 minutes. Then N-(3,3-diphenylpropyl)-N-(4-piperidinyl)-N′-[3-(trifluoromethyl)phenyl]urea (24.3 mg, 50 μmol) is added in its turn and the mixture is agitated overnight. The resin is filtered and the filtrate is concentrated. The oil obtained is passed through a silica gel cartridge eluting with an equimolar mixture of heptane and ethyl acetate in order to obtain 16 mg (yield=62%) of a white foam after concentration.

[0196] NMR 1H (CD3OD, 400 MHz) δ: 7.71 (s, 1H); 7.58 (d, J=8.4 Hz, 1H); 7.43 (t, J=8 Hz, 1H); 7.28 (m, 9H); 7.17 (m, 2H); 4.56 (dd, J=2 and 11.2 Hz, 1H); 4.17 (m, 1H); 3.96 (t, J=7.6 Hz, 1H); 3.88 (d, J=12 Hz, 1H); 3.19 (q, J=4 and 8 Hz, 2H); 3.1 (t, J=12 Hz, 1H); 2.58 (t, J=12 Hz, 1H); 2.37 (m, 2H); 2.06 (s, 3H, CH3); 1.72 (t, J=14.4 Hz, 2H); 1.43 (qd, J=4 and 12.4 Hz, 2H). MS/LC: m/z=524.3 (M+H).

[0197] A series of amides was synthesized according to this procedure. The R1, X1 and X2 groups which can be envisaged, are those illustrated in points (A and B3a), A, (A and B3c) respectively.

C3) Functionalization with sulphonyl chlorides

[0198] It is carried out according to the following diagram

[0199] General procedure: the morpholinomethyl resin (Novabiochem, 2 to 3 eq.) is preswollen in anhydrous solvents such as dichloromethane, dimethylformamide or tetrahydrofuran. Sulphonyl chloride (1.1 to 2 eq.) dissolved in anhydrous solvents such as dichloromethane, dimethylformamide or tetrahydrofuran is added, followed by 4-aminodisubstituted piperidine. The mixture is agitated for 16 to 48 hours. The aminomethyl resin (0.1 to 1.5 eq.) is added and the reaction medium is agitated overnight. In certain cases, ion exchange resin such as IRA68 or SAX is added and the mixture is agitated at ambient temperature for 1 to 18 hours. The resins are filtered on frit, on a SAX ion exchange resin cartridge (500 mg, Interchim) or on a basic alumina cartridge (500 mg, Interchim).

Example C3

[0200] N-(3,3-diphenylpropyl)-N-{1-[(4-methoxyphenyl)sulphonyl]-4-piperidinyl}-N′-[3-(trifluoromethyl)phenyl]urea (C35H36F3N3O4S, M=651.75)

[0201] 27.5 mg (100 μmol, 2 eq.) of morpholinomethyl resin is preswollen in anhydrous tetrahydrofuran, then 4-methoxyphenylsulphonyl chloride (15.5 mg, 0.075 mmol, 1.5 eq.) then N-(3,3-diphenylpropyl)-N-(4-piperidinyl)-N′-[3-(trifluoromethyl)phenyl]urea (24.3 mg, 0.05 mmol) are added. The mixture is agitated overnight. The aminomethyl (20 mg) and SAX ion exchange resins are added and the mixture is agitated overnight. The resins are filtered and rinsed with dichloromethane. The oil obtained after evaporation is passed through a silica gel cartridge (500 mg, Interchim) eluting with ethyl acetate in order to obtain 18 mg (yield=56%) of a white solid after concentration.

[0202] NMR 1H (CD3OD, 400 MHz) δ: 7.71 (d, J=9.2 Hz, 2H); 7.65 (s, 1H); 7.51 (d, 1H); 7.41 (t, J=7.6 Hz, 1H); 7.29 (m, 9H); 7.20 (m, 2H); 7.11 (dd, J=1.6 and 6.8 Hz, 2H); 3.88 (s, 31H, OCH3); 3.77 (d, J=12.4 Hz, 2H); 3.16 (t, J=8 Hz, 2H); 2.33 (m, 4H): 1.71 (d, J=10 Hz, 2H); 1.62 (qd, J=4 and 12 Hz, 2H); 1.3 (m, 2H). MS/LC: m/z=652.4 (M+H).

[0203] A series of sulphonamides was synthesized according to this procedure. The R1, X1, X2 and X3 groups which can be envisaged are those illustrated in points (A and B3a), A, (A and B3c) and B3b respectively.

D) SYNTHESIS OF TRI-SUBSTITUTED PIPERIDINES IN SOLID PHASE

[0204] It is carried out starting from vinyl sulphone resin (Kroll, F. E. K.; Morphy, R. Rees, D.: Gam. I) Tetrahedron Lett. 1997, 38, 8573-8576; Brown, A. R. J Comb Chem 1999. 1. 283-285) according to the following diagram:

D1) Preparation of the resin

[0205] It is carried out according to the following diagram:

[0206] Triethylamine (1 eq.) is added to hydrated piperidone hydrochloride diluted in dimethylformamide. The mixture is heated until complete dissolution of the ketone. This solution is added to the vinyl sulphone resin (0.05 eq.) preswollen in dimethylformamide. After agitation for 24 to 72 hours at ambient temperature, the resin is filtered then washed several times with dimethylformamide, tetrahydrofuran, diethylether and dichloromethane.

Preparation 4

[0207] 1.5 g of vinyl sulphone resin (Novabiochem, load rate of 1 mmol/g, 1.5 mmol) is preswollen in 50 ml of dimethylformamide. At the same time, 2.3 g (15 mmol, 10 eq.) of hydrated piperidone hydrochloride and 1.8 g (15 mmol, 10 eq.) of triethylamine are heated in 100 ml of dimethylformamide until complete dissolution. The yellowish solution is poured warm onto the resin and the mixture is agitated for 24 hours at ambient temperature. The resin is filtered then washed with dimethylformamide, tetrahydrofuran, diethylether and dichloromethane (3 times with each solvent) then dried under vacuum. 1.7 g of pale yellow resin is isolated with a load rate of 1 mmol/g calculated after elementary analysis of the nitrogen.

D2) Reducing Amination on Solid Support

[0208] It is carried out according to the procedure described in the literature (Pelter, A. Rosser, R. M.; J. Chem. Soc. Perkin Trans I 1984, 717-720 ; Bomann, M. D. Guch, I. C.; DiMare, M.; J. Org. Chem. 1995, 60, 5995-5996 ; Khan, N. M. Arumugam, V.; Balasubramanian, S.; Tetrahedron Lett. 1996, 37, 4819-4822) following the diagram:

[0209] General procedure: The primary amine (5 to 10 eq.) is added to the ketonic resin preswollen in trimethylorthoformate (TMOF) then the mixture is sonicated. Then the borane pyridine complex (8 M, 5 to 10 eq.) is added and the mixture is agitated for 12 to 72 hours. The resin is filtered, washed with solvents such as dichloromethane, dimethylformamide, methanol and tetrahydrofuran then dried under vacuum.

[0210] 1 g (load rate of 1 mmol/g, 1 mmol) of ketonic resin is preswollen in TMOF. Then 2-(1-methyl-1H)-indol-3-yl)ethylamine (1.01 g, 10 mmol, 10 eq.) then the borane pyridine complex (8M, 1.25 ml, 10 mmol, 10 eq.) are added. The mixture is agitated for 48 hours at ambient temperature. The resin is filtered, rinsed successively with dichloromethane, dimethylformamide, methanol, tetrahydrofuran and dichloromethane then dried under vacuum. 1.05 g of pale yellow resin is thus obtained with a load rate of 0.91 mmol/g calculated after elementary analysis of the nitrogen.

D3) Functionalization of the Secondary amine

[0211] D3a) Functionalization with isocyanates

[0212] General procedure: the “secondary amine” resin is preswollen in a solvent such as dichloromethane or dimethylformamide before the addition of isocyanate (3 to 10 eq.). The mixture is agitated for 1 to 24 hours at ambient temperature. The resin is then filtered, washed with solvents such as dichloromethane, dimethylformamide and tetrahydrofuran then dried under vacuum.

[0213] 55 mg (50 μmol) of resin (see Preparation 5) is preswollen in anhydrous dichloromethane. Then 4-trifluorophenylisocyanate (28 mg, 150 μmol, 3 eq.) is added and the whole is agitated for 2 hours at ambient temperature. The resin is filtered, rinsed with tetrahydrofuran, with dimethylformamide, with tetrahydrofuran then with dichloromethane before being dried under vacuum.

[0214] D3b) Functionalization with sulphonyl chlorides

[0215] The Functionalization operating method is identical to that stated in point B3b.

[0216] D3c) Functionalization with Acid chlorides

[0217] The functionalization operating method is identical to that stated in point B3c.

[0218] D3d) Functionalization with carboxylic Acids

[0219] The functionalization operating method is identical to that stated in point B3d.

D4) Cleavage Stage

[0220] The cleavage stage described below is valid whatever the functionalization carried out beforehand on the secondary amine:

[0221] General procedure: The disubstituted resin is swollen in solvents such as dichloromethane, dimethylformamide or tetrahydrofuran then the halide R3X is added in which R3 has the meaning indicated previously and X represents a halogen atom (5 eq.) and the mixture agitated overnight at a temperature comprised between 20 and 60° C. The resin is filtered, rinsed with solvents such as dimethylformamide, tetrahydrofuran, methanol and dichloromethane then dried under vacuum. The resin is swollen again in dichloromethane and basic ion exchange resin (Ouyang, X. Armstrong, R. W.; Murphy, M. M. J. Org. Chem. 1998, 63, 1027-1032) is added. The whole is agitated for 48 hours at ambient temperature. The resins are filtered, rinsed with dichloromethane and the filtrate is concentrated under vacuum.

Example D4

[0222] N-[2-(1-methyl-1H-indol-3-yl)ethyl]-N-(1-methyl-4-piperidinyl)-N′-[4-(trifluoromethyl)phenyl]urea (C25H29F3N4O, M=458.5)

[0223] 55 mg (50 μmol) of the urea resin is swollen in dimethylformamide then 35 mg (250 μmol, 5 eq.) of iodomethane is added and the mixture is agitated for 18 hours at ambient temperature. The resin is filtered, rinsed with dimethylformamide, tetrahydrofuran, methanol and dichloromethane then dried under vacuum. The resin is swollen again in dichloromethane then approximately 100 mg of amberlite IRA68 resin is added and the mixture is agitated for 48 hours. The resins are filtered, rinsed with dichloromethane and the filtrate is concentrated in order to produce 18 mg (yield=78%) of a colourless oil.

[0224] NMR 1H (CD3OD, 400 MHz) δ: 7.65 (m, 2H); 7.40 (m, 2H); 7.31 (m, 1H) 7.20 (t, 1H); 7.10 (m, 1H); 7.06 (m, 2H); 4.04 (m, 1H); 3.68 (s, 3H); 3.60 (t, 2H); 3.04 (t, 2); 2.94 (m, 2H); 2.29 (s, 3H); 2.14 (m, 2H); 1.91 (m, 2H); 1.76 (m, 2H). MS/LC: m/z=459.3 (M+H).

[0225] For the R1, X1, X2 and X3 groups as illustrated in points A and B above, the R3 groups which can be envisaged for the synthesis of trisubstituted 4-aminopiperidines according to the above procedure, are the following:

[0226] A subject of the invention is also the process for the preparation of compounds I according to the invention, in solid or liquid phase, as described previously.

[0227] A more particular subject of the invention is a process for the preparation, in liquid phase, of compounds of formula I as defined above, characterized in that it comprises

[0228] the reducing amination of the following N-substituted piperidone

[0229] in which R represents the methyl or Boc radical, in the presence of an amine of formula R1NH2 in which R1 has the meaning indicated above, in order to obtain the compound of formula 1

[0230] which compound of formula (1) is reacted with

[0231] A) either a compound of formula X1NC(Y) in which X1 and Y have the meaning indicated above, in order to obtain a compound of formula (2)

[0232] which compound of formula (2) represents the corresponding compound of formula (I) in which R3 represents Me or Boc and which, when R3 represents Boc, can be subjected to an acid treatment in order to obtain the corresponding compound of formula (I) in which R3 represents the hydrogen atom,

[0233] which compound of formula (I) thus obtained can be reacted with a compound of formula X1NC(Y), X2CO2H or X3SO2Cl in which X1, Y, X2 and X3 have the meaning indicated above, in order to obtain the corresponding compound of formula I in which R2 represents a radical of formula —C(Y)NHX1 and R3 the —C(Y)—NHX1, —C(O)X2 or SO2X3 radical respectively;

[0234] B) or a compound of formula X2CO2H in which X2 has the meaning indicated above, in order to obtain a compound of formula (3)

[0235] which compound of formula (3) represents the corresponding compound of formula (I) in which R3 represents Me or Boc and which, when R3 represents Boc, can be subjected to an acid treatment in order to obtain the corresponding compound of formula (I) in which R3 represents the hydrogen atom,

[0236] which compound of formula (I) thus obtained can be reacted with a compound of formula X1NC(Y), X2CO2H or X3SO2Cl in which X1, Y, X2 and X3 have the meaning indicated above, in order to obtain the corresponding compound of formula I in which R2 represents a radical of formula —C(O)X2 and R3 the —C(Y)—NHX1, —C(O)X2 or SO2X3 radical respectively.

[0237] A more particular subject of the invention is also a preparation process, in solid phase, for compounds of formula I as defined above, characterized in that it comprises

[0238] the reducing amination of the ketonic resin

[0239] in the presence of an amine of formula R1NH2 in which R1 has the meaning indicated above, in order to obtain the compound of formula (4)

[0240] which compound of formula (4) is reacted with

[0241] A) either a compound of formula X1NC(Y) in which X1 and Y have the meaning indicated above, in order to obtain a compound of formula (5)

[0242] followed by cleavage of the resin in order to obtain the corresponding compound of formula (I) in which R3 represents the hydrogen atom,

[0243] B) or a compound of formula X3SO2Cl in which X3 has the meaning indicated above, in order to obtain a compound of formula (6)

[0244] followed by cleavage of the resin in order to obtain the corresponding compound of formula (I) in which R3 represents the hydrogen atom,

[0245] C) or a compound of formula X2CO2Cl in which X2 has the meaning indicated above, in order to obtain a compound of formula (7)

[0246] followed by cleavage of the resin in order to obtain the corresponding compound of formula (I) in which R3 represents the hydrogen atom;

[0247] D) or a compound of formula X2CO2H in which X2 has the meaning indicated above, in order to obtain a compound of formula (7) as defined above, followed by cleavage of the resin in order to obtain the corresponding compound of formula (I) in which R3 represents the hydrogen atom.

[0248] Finally a more particular subject of the invention is a preparation process, in solid phase, for compounds of formula I as defined above, characterized in that it comprises

[0249] the reducing amination of the ketonic resin

[0250] in the presence of an amine of formula R1NH2 in which R1 has the meaning indicated above, in order to obtain the compound of formula (8)

[0251] which compound of formula (8) is reacted with

[0252] A) either a compound of formula X1NC(O) in which X1 has the meaning indicated above, in order to obtain a compound of formula (9)

[0253] which compound (9) thus formed is reacted with a compound of formula R3X in which R3 is as defined above and X represents Br or I, followed by cleavage of the resin in order to obtain the corresponding compound of formula (I);

[0254] B) or a compound of formula X3SO2Cl in which X3 has the meaning indicated above, in order to obtain a compound of formula (10)

[0255] which compound (10) thus formed is reacted with a compound of formula R3X in which R3 is as defined above and X represents Br or I, followed by cleavage of the resin in order to obtain the corresponding compound of formula (I);

[0256] C) or a compound of formula X2CO2Cl in which X2 has the meaning indicated above, in order to obtain a compound of formula (11)

100

[0257] which compound (11) thus formed is reacted with a compound of formula R3X in which R3 is as defined above and X represents Br or I, followed by cleavage of the resin in order to obtain the corresponding compound of formula (I)

[0258] D) or a compound of formula X2CO2H in which X2 has the meaning indicated above, in order to obtain a compound of formula (11) as defined above,

[0259] which compound (11) thus formed is reacted with a compound of formula R3X in which R3 is as defined above and X represents Br or I, followed by cleavage of the resin in order to obtain the corresponding compound of formula (I).

[0260] Compounds I of the present invention have useful pharmacological properties. Thus it has been discovered that compounds I of the present invention have a high affinity for one (or more) of the somatostatin receptors. They can be used as non-peptide agonists or antagonists of somatostatin in a selective or non-selective manner.

[0261] The compounds of the present invention can therefore be used in different therapeutic applications. They can advantageously be used to treat the pathological states or the diseases as presented above and in which one (or more) of the somatostatin receptors are involved.

[0262] An illustration of the pharmacological properties of the compounds of the invention will be found hereafter in the experimental part.

[0263] A subject of the present Application is also, as medicaments, the products of formula I as defined above, as well as the addition salts with pharmaceutically acceptable mineral or organic acids of said products of formula I, as well as the pharmaceutical compositions containing, as active ingredient, at least one of the medicaments as defined above, in combination with a pharmaceutically acceptable support.

[0264] The pharmaceutical composition can be in the form of a solid, for example, powders, granules, tablets, gelatin capsules 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.

[0265] The pharmaceutical compositions containing a compound of the invention can also be presented in liquid form, for example, solutions, emulsions, suspensions or syrups. Appropriate liquid supports can be, for example, water, organic solvents such as glycerol or glycols, similarly their mixtures, in varying proportions, in water, with added pharmaceutically acceptable oils or fats. The sterile liquid compositions can be used for intramuscular, intraperitoneal or subcutaneous injections and the sterile compositions can also be administered intravenously.

[0266] Some compounds of the general formula I as defined above, are covered by the patent application DE 2751138. This DE patent application described compounds which antagonise the effects of dopamine and endogenous or exogenous dopaminergic agents, and stimulate serotoninergic mechanism, activity which is far different from the activity of the compounds of the present invention.

[0267] A subject of the present invention is also the use of compounds of general formula Ia

101

[0268] in racemic, enantiomeric form or all combinations of these forms, in which:

[0269] R1a represents a linear or branched (C1-C16)alkyl, alkenyl, alkynyl, —(CH2)m—Y—Z11 or —(CH2)m—Z12 radical in which

[0270] Z11 represents a (C1-C6)alkyl or aryl optionally substituted,

[0271] Z12 represents cyano, cyclohexenyl, bis-phenyl, (C3-C7)cycloalkyl, optionally substituted (C3-C7) heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl,

[0272] or Z12 represents a radical of formula

102

[0273] or R1a represents a radical of formula

103

[0274] R2a represents a radical of formula —C(Y)NHX1, —C(O)X2 or SO2X3;

[0275] R3a represents the hydrogen atom, an optionally substituted alkyl, alkenyl, alkynyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl radical, or a radical of formula —C(Y)—NHX1, —(CH2)n—C(O)X2, SO2X3 or

104

[0276] X1 represents a linear or branched (C1-C15)alkyl, alkenyl, alkynyl, —(CH2)m—Y—Z21 or —(CH2)pZ22 radical in which

[0277] Z21 represents a (C1-C6)alkyl

[0278] Z22 represents cyclohexenyl, indanyl, bis-phenyl, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl, mono- or di-alkylamino, —C(O)—O-alkyl, or aryl or heteroaryl optionally substituted,

[0279] or Z22 represents a radical of formula

105

[0280] X2 represents a linear or branched (C1-C10)alkyl radical, an alkenyl radical optionally substituted by a phenyl radical (the phenyl radical being itself optionally substituted), an alkynyl radical, or a radical of formula —(CH2)m—W—(CH2)q—Z23 or —(CH2)p—U—Z24 in which

[0281] Z23 represents a (C1-C6)alkyl or aryl optionally substituted

[0282] Z24 represents alkyl, cyclohexenyl, bis-phenyl, (C3-C7)cycloalkyl optionally substituted, (C3-C7)heterocycloalkyl, cyano, amino, mono or di-alkylamino, or aryl or heteroaryl optionally substituted,

[0283] or Z24 represents a radical of formula

106

[0284] or X2 represents a radical represented below:

107

[0285] where the protective group (PG) represents H or tert-butyloxycarbonyl

[0286] X3 represents a linear or branched (C1-C10)alkyl radical, an alkenyl radical optionally substituted by a phenyl radical (the phenyl radical being itself optionally substituted), CF3, or —(CH2)pZ25 in which

[0287] Z25 represents aryl or heteroaryl optionally substituted,

[0288] or X3 represents a radical of formula

108

[0289] optionally substituted by one or more halo radicals identical or different;

[0290] Y represents an oxygen or sulphur atom;

[0291] W represents an oxygen or sulphur atom, or SO2;

[0292] U represents a covalent bond or the oxygen atom;

[0293] n is an integer from 0 to 4;

[0294] m is an integer from 1 to 6;

[0295] p is an integer from 0 to 6;

[0296] q is an integer from 0 to 2,

[0297] or their addition salts with pharmaceutically acceptable mineral or organic acids, for the preparation of a medicament intended to treat pathological states or diseases in which one (or more receptor(s) of somatostatin is (are) involved.

[0298] A more particulary subject of the invention is the use of products of general formula Ia as defined above, characterized in that

[0299] i) the substituent or substituents which can be carried by the aryl radicals represented by Z11 and Z12 and heteroaryl represented by Z12 are chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, —CF3, —OCF3, phenyl, phenoxy, aminosulphonyl radicals

[0300] ii) the substituent or substituents which can be carried by the heterocycloalkyl radical represented by Z12 are chosen independently from the oxy and alkyl radicals;

[0301] iii) the substituent or substituents which can be carried by the aryl and heteroaryl radicals represented by Z22 are chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkenyl, alkoxy, alkylthio, CF3, OCF3, nitro, cyano, azido, aminosulphonyl, piperidinosulphonyl, mono- or di-alkylamino, —C(O)—O-alkyl, —C(O)-alkyl, or phenyl, phenoxy, phenylthio, benzyloxy radicals, the phenyl radical being able to be substituted;

[0302] iv) the substituent or substituents which can be carried by the aryl radicals represented by Z23 and Z24, cycloalkyl and heteroaryl represented by Z24 are chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, CF3, OCF3, OCHF2, SCF3, nitro, cyano, azido, hydroxy, —C(O)O-alkyl, —O—C(O)-alkyl, —NH—C(O)-alkyl, alkylsulphonyl, mono- or di-alkylamino, amino, aminoalkyl, pyrrolyl, pyrrolydinyl or the radicals phenyl, phenoxy, phenylthio, benzyl, benzyloxy radicals the aryl radical of which is optionally substituted by one or more alkyl, CF3 or halo radicals;

[0303] v) the substituent or substituents which can be carried by the aryl and heteroaryl radicals represented by Z25 are chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, OCF3, nitro, cyano, —NH—C(O)-alkyl, alkylsulphonyl, amino, mono- and di-alkylamino, phenyl, pyridino radicals

[0304] vi) the substituent which can be carried by the alkyl radical represented by R3 is the cyano radical.

[0305] vii) the substituent or substituents which can be carried by the aralkyl radical represented by R3 are chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, OCF3, OCHF2, SCF3, SCHF2, nitro, cyano, —C(O)O-alkyl, alkylsulphonyl, thiadiazolyl radicals, or the phenyl and phenoxy radicals the phenyl radical of which is optionally substituted by one or more halo radicals.

[0306] viii) the substituent or substituents which can be carried by the heteroarylalkyl radical represented by R3 are chosen independently from the fluoro, chloro, bromo or nitro radicals.

[0307] A more particular subject of the present invention is the use of compounds of general formula Ia as defined above in which R1a represents a linear or branched (C1-C6)alkyl radical, the —(CH2)m—Y—Z11 or —(CH2)m—Z12 radical in which

[0308] Z11 represents a (C1-C6)alkyl,

[0309] Z12 represents bis-phenyl, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl optionally substituted, or aryl or heteroaryl optionally substituted by one or more substituents chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy radicals,

[0310] or Z12 represents

109

[0311] Y represents the oxygen atom,

[0312] or R1a represents a radical of formula

110

[0313] A more particular subject of the present invention is the use of compounds of general formula Ia as defined above in which R2a represents a radical of formula —C(Y)NHX1, —C(O)X2 or SO2X3 in which

[0314] X1 represents a linear or branched (C1-C15)alkyl radical, or —(CH2)pZ22 in which

[0315] Z22 represents cyclohexenyl, bis-phenyl, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl, mono- or di-alkylamino, —C(O)—O-alkyl, or aryl or heteroaryl optionally substituted by one or more radicals chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, CF3, OCF3, nitro, cyano, azido, piperidinosulphonyl, —C(O)—O-alkyl, —C(O)-alkyl, or phenyl radicals,

[0316] or Z22 represents a radical of formula

111

[0317] X2 represents a linear or branched (C1-C10)alkyl, alkynyl, —(CH2)m—W—(CH2)q—Z23 or —(CH2)p—U—Z24 radical in which

[0318] W represents SO2,

[0319] U represents a covalent bond,

[0320] Z23 represents an aryl radical

[0321] Z24 represents cyclohexenyl, bis-phenyl, (C3-C7)cycloalkyl optionally substituted by an aminoalkyl, or aryl or heteroaryl radical optionally substituted by one or more radicals chosen from fluoro, chloro, bromo, iodo, alkyl, alkoxy, —CF3, —OCF3, SCF3, hydroxy, —O—C(O)-alkyl, mono- or di-alkylamino, amino

[0322] or Z24 represents a radical of formula

112

[0323] or X2 represents

113

[0324] X3 represents a —(CH2)pZ25 radical in which Z25 represents an aryl radical optionally Substituted by one or more identical or different radicals chosen from alkoxy and CF3.

[0325] A more particular subject of the present invention is the use of compounds of general formula Ia as defined above in which R3a represents the hydrogen atom, an alkyl. alkenyl. heteroarylalkyl radical optionally substituted or a radical of formula —C(Y)—NHX1, —C(O)X2 or SO2X3 in which

[0326] X1 represents a —(CH2)pZ22 radical in which

[0327] Z22 represents an aryl radical optionally substituted by one or more radicals chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, phenoxy radicals;

[0328] X2 represents the vinyl radical substituted by a phenyl, the phenyl radical being itself optionally substituted by one or more halo, or —(CH2)p—U—Z24 radicals in which

[0329] Z24 represents alkyl, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl, bis-phenyl, amino, mono or di-alkylamino, or aryl or heteroaryl optionally substituted by one or more radicals chosen from alkoxy, bromo, chloro, fluoro, hydroxy, CF3, nitro, amino, mono- and di-alkylamino, pyrrolyl,

[0330] or X2 represents a radical of formula

114

[0331] X3 represents a linear or branched (C1-C10)alkyl radical, the vinyl radical substituted by a radical (the phenyl radical being itself optionally substituted), CF3, or —(CH2)pZ25 in which

[0332] Z25 represents aryl or heteroaryl optionally substituted by one or more substituents chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, —NH—C(O)-alkyl, mono- and di-alkylamino radicals.

[0333] Preferentially, R1a represents a linear or branched (C1-C6)alkyl radical, the —(CH2)m—Y—Z11 or —(CH2)m—Z12 radical in which

[0334] Z11 represents a (C1-C6)alkyl,

[0335] Z12 represents naphthyl, morpholino, bis-phenyl, pyrrolidinyl substituted by the oxy radical, or the phenyl, piperazinyl, pyridinyl and indolyl radicals which are optionally substituted by one or more substituents chosen independently from the bromo, fluoro, chloro, alkyl, alkoxy, —CF3, —OCF3 radicals

[0336] or Z12 represents

115

[0337] Y represents the oxygen atom,

[0338] or R1a represents a radical of formula given below:

116

[0339] Preferentially, R2a represents a radical of formula —C(Y)NHX1, —C(O)X2 or SO2X3 in which

[0340] X1 represents a linear or branched (C1-C10)alkyl, or —(CH2)pZ22 radical in which

[0341] Z22 represents cyclohexyl, cyclohexenyl, bis-phenyl, morpholino, piperidino, mono- or di-alkylamino, —C(O)—O-alkyl, or phenyl, naphthyl or furyl optionally substituted by one or more radicals chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, CF3, OCF3, nitro, cyano, azido, piperidinosulphonyl, —C(O)—O-alkyl, —C(O)-alkyl or phenyl radicals,

[0342] or Z22 represents a radical of formula

117

[0343] X2 represents an alkyl, alkynyl, —(CH2)m—W—(CH2)q—Z23 or —(CH2)pZ24 radical in which

[0344] W represents SO2;

[0345] Z23 represents the phenyl radical;

[0346] Z24 represents cyclohexenyl, bis-phenyl, cyclohexyl optionally substituted by an aminoalkyl, or phenyl, naphthyl, benzothienyl, thienyl or indolyl radical optionally substituted by one or more radicals chosen from fluoro, chloro, bromo, iodo, alkyl, alkoxy, —CF3, —OCF3, SCF3, hydroxy, —O—C(O)-alkyl, —NH—C(O)-alkyl, mono- or di-alkylamino, amino, or

[0347] Z24 represents a radical of formula

118

[0348] or X2 represents

119

[0349] X3 represents a —(CH2)pZ25 radical in which Z25 represents the phenyl radical optionally substituted by one or more identical or different radicals chosen from alkoxy and CF3,

[0350] Preferentially, R3a represents the hydrogen atom, an alkyl, alkenyl or furyl-methyl radical substituted by one or more nitro radicals, or a radical of formula —C(Y)—NHX1, —C(O)X2 or SO2X3 in which

[0351] X1 represents a —(CH2)pZ22 radical in which

[0352] Z22 represents the phenyl or naphthyl radical optionally substituted by one or more radicals chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, phenoxy radicals,

[0353] X2 represents the vinyl radical substituted by a phenyl radical itself optionally substituted by one or more halo, or —(CH2)p—U—Z24 radicals in which

[0354] Z24 represents alkyl, cyclohexyl, tetrahydrofuryl, bis-phenyl, amino, mono or di-alkylamino, or phenyl, indolyl, thienyl, pyridinyl, benzothienyl and furyl optionally substituted by one or more radicals chosen from alkoxy, bromo, chloro, fluoro, amino, mono- and di-alkylamino, nitro, hydroxy, pyrrolyl

[0355] or X2 represents a radical of formula

120

[0356] X3 represents a linear or branched (C1-C10)alkyl radical, the vinyl radical substituted by a phenyl, CF3, or —(CH2)pZ25 radical in which

[0357] Z25 represents a phenyl, naphtyl, thienyl, pyrazolyl or thiazolyl radical optionally substituted by one or more substituents chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, —NH—C(O)-alkyl, mono- and di-alkylamino radicals;

[0358] Very preferentially, R1a represents the —(CH2)mZ12 radical in which m=2 and Z12 represents bis-phenyl or the radical indolyl substituted by one or more substituents chosen independently from the alkyl and alkoxy radicals.

[0359] Very preferentially, R2a represents the radicals of formula —C(Y)NHX1 and —C(O)X2 in which

[0360] Y represents S;

[0361] X1 represents a phenyl radical optionally substituted by one or more azido radicals,

[0362] X2 represents —(CH2)pZ24 in which

[0363] p is equal to 1, 2 or3,

[0364] Z24 represents cyclohexyl, or phenyl or benzothienyl optionally substituted by one or more radicals chosen from fluoro, chloro, bromo, iodo or —CF3.

[0365] Very preferentially, R3a represents the hydrogen atom or the methyl radical.

[0366] All the technical and scientific terms used in the present text have the meaning known to a person skilled in the art. Furthermore, all patents (or patent applications) as well as other bibligraphical references are incorporated by way of reference.

Experimental Part

[0367] Other compounds according to the invention obtained according to the procedures of Examples A, B, C and D described previously, are set out in the table below.

[0368] The compounds are characterized by their retention time (rt), expressed in minutes, and their molecular peak (M+H+) determined by mass spectroscopy (MS).

[0369] For the mass spectroscopy, a single quadripole mass spectrometer (Micromass, Platform model) equipped with an electrospray source is used with a resolution of 0.8 Da at 50% valley. The conditions for Examples 1 to 778 below, are as follows:

[0370] Conditions C1 and C2

[0371] Eluent:A:Water+0.02% trifluoracetic acid; B:acetonitrile

1T (min)A %B %0100011000101585121585

[0372]

2

Condition C1
Condition C2

Flow rate: 1.1 ml/min
Flow rate: 1.1 ml/min

Injection: 5 μl
Injection: 20 μl

Temp: 40° C.
Temp :40° C.

Wavelength (% UV): 210 nm
Wavelength (% UV): 210 nm

Column: Uptisphere ODS 3 μm
Column: Kromasyl ODS 3.5 μm

33 * 46 mm i.d
50 * 4.6 mm i.d

[0373] Conditions C3

[0374] Eluent:A:Water+0.02% trifluoracetic acid; B:acetonitrile

3T (min)A %B %0901061585101585

[0375] Flow rate: 1 ml/min

[0376] Injection: 5 μl

[0377] Column:Uptisphere ODS 3 μm 50*4.6 mm i.d

[0378] Temp: 40° C.

[0379] Wavelength (% UV): 220 nm

[0380] The conditions depending on the examples, are as follows:

4ExamplesConditions 1 to 29 C2 30 to 263C1264 to 425C3426 to 456C2457 to 503C3504 to 586C1587 to 778C3

[0381] These examples are presented to illustrate the above procedures and should in no considered as limiting the scope of the invention.

5ExR1R2R3Purity (%)rtM + H +1

121

122

123

667.6523.32

124

125

126

947.7543.23

127

128

129

968.1557.24

130

131

132

988.5593.25

133

134

135

957.8557.26

136

137

138

978.1623.17

139

140

141

958.1588.28

142

143

144

198.1535.29

145

146

147

998.5622.210

148

149

150

808.4611.211

151

152

153

998.2569.212

154

155

156

938.9656.213

157

158

159

859.1697.014

160

161

162

958.7611.215

163

164

165

877.8573.216

166

167

168

1008.4653.217

169

170

171

978.6611.118

172

173

174

998.7636.319

175

176

177

837.2621.220

178

179

180

987.4595.221

181

182

183

847.4536.322

184

185

186

998.4614.323

187

188

189

638.2570.224

190

191

192

927.5572.325

193

194

195

938.4606.426

196

197

198

967.4582.327

199

200

201

938.1624.228

202

203

204

937.8602.229

205

206

207

957.4585.230

208

209

210

87.394.0516.431

211

212

213

925.5560.332

214

215

216

905.7563.333

217

218

219

87.735.6625.434

220

221

222

85.416.0565.435

223

224

225

98.46.4671.136

226

227

228

864.9542.337

229

230

231

896.1572.338

232

233

234

77.616.8555.439

235

236

237

89.164.2545.440

238

239

240

93.325.3599.341

241

242

243

836.0589.242

244

245

246

36.35.9531.243

247

248

249

83.275.9555.344

250

251

252

824.5564.445

253

254

255

86.756.0577.346

256

257

258

91.954.7501.447

259

260

261

88.944.5475.348

262

263

264

735.3542.349

265

266

267

90.964.4486.450

268

269

270

95.55.9530.451

271

272

273

94.516.1533.452

274

275

276

93.646.0595.453

277

278

279

96.056.5535.454

280

281

282

84.686.9641.155

283

284

285

865.5512.356

286

287

288

926.5542.457

289

290

291

91.297.2525.558

292

293

294

94.74.7515.459

295

296

297

945.8569.360

298

299

300

89.436.6559.361

301

302

303

326.9501.562

304

305

306

93.536.4525.463

307

308

309

94.74.9534.464

310

311

312

94.326.4547.365

313

314

315

91.715.2471.466

316

317

318

92.475.0445.467

319

320

321

585.9512.368

322

323

324

84.553.6559.469

325

326

327

87.74.7603.470

328

329

330

90.774.8606.471

331

332

333

72.344.8668.472

334

335

336

87.185.1608.473

337

338

339

69.525.4714.174

340

341

342

63.394.2585.375

343

344

345

54.465.1615.476

346

347

348

87.35.7598.477

349

350

351

96.13.8588.478

352

353

354

89.94.5642.379

355

356

357

61.55.1632.380

358

359

360

43.655.0574.381

361

362

363

88.185.0598.382

364

365

366

88.64.0607.483

367

368

369

90.085.1620.384

370

371

372

85.574.0544.385

373

374

375

48.414.5585.386

376

377

378

82.686.1589.387

379

380

381

79.996.5611.488

382

383

384

86.074.8503.489

385

386

387

825.1551.490

388

389

390

19.444.4502.491

391

392

393

86.485.1550.492

394

395

396

806.3567.393

397

398

399

94.626.6559.394

400

401

402

57.016.9581.495

403

404

405

925.2473.496

406

407

408

87.45.6521.497

409

410

411

20.995.0472.498

412

413

414

88.635.7520.499

415

416

417

846.7537.3100

418

419

420

89.715.2632.2101

421

422

423

90.255.5654.4102

424

425

426

90.094.0546.4103

427

428

429

714.4594.3104

430

431

432

37.193.8545.3105

433

434

435

76.554.5593.4106

436

437

438

69.625.9405.2107

439

440

441

987.1493.2108

442

443

444

806.0467.3109

445

446

447

886.5471.2110

448

449

450

60.045.7427.3111

451

452

453

786.5515.2112

454

455

456

976.2455.2113

457

458

459

705.7489.3114

460

461

462

906.2493.3115

463

464

465

62.883.6305.3116

466

467

468

82.994.7393.2117

469

470

471

74.425.0393.1118

472

473

474

10.535.4367.3119

475

476

477

74.794.3371.2120

478

479

480

50.143.4327.3121

481

482

483

704.3415.2122

484

485

486

843.9355.3123

487

488

489

663.5389.3124

490

491

492

94.613.9393.2125

493

494

495

715.5462.3126

496

497

498

526.6550.2127

499

500

501

576.8550.1128

502

503

504

605.6524.2129

505

506

507

646.1528.2

[0382]

6

Ex
R1
R2
R3
Purity (%)
rt
M + H +

130

508

509

510

27
5.4
484.3

131

511

512

513

51
6.2
572.2

132

514

515

516

73
5.7
512.2

133

517

518

519

61
5.4
546.2

134

520

521

522

43
5.8
550.2

135

523

524

525

76
5.3
483.3

136

526

527

528

49
6.4
571.2

137

529

530

531

63
6.6
571.1

138

532

533

534

79
5.4
545.2

139

535

536

537

57
5.9
549.2

140

538

539

540

66.58
5.2
505.3

141

541

542

543

61
6.0
593.2

142

544

545

546

67
5.5
533.2

143

547

548

549

61
5.2
567.3

144

550

551

552

51
5.6
571.2

145

553

554

555

56
7.0
457.3

146

556

557

558

64
8.1
545.2

147

559

560

561

52
8.3
545.2

148

562

563

564

69
7.1
519.3

149

565

566

567

70
7.6
523.3

150

568

569

570

63.77
6.7
479.4

151

571

572

573

50
7.3
567.3

152

574

575

576

46
7.3
507.3

153

577

578

579

78
6.7
541.3

154

580

581

582

66
7.0
545.3

155

583

584

585

68
6.0
457.2

156

586

587

588

65
7.1
545.2

157

589

590

591

67
7.3
545.1

158

592

593

594

66
6.1
519.2

159

595

596

597

77
6.6
523.2

160

598

599

600

60.49
5.8
479.3

161

601

602

603

60
6.6
567.3

162

604

605

606

69
6.2
507.2

163

607

608

609

50
5.8
541.2

164

610

611

612

49
6.2
545.2

165

613

614

615

67
4.4
466.3

166

616

617

618

45
5.5
554.2

167

619

620

621

65.89
5.7
554.1

168

622

623

624

5
5.4
528.2

169

625

626

627

64.08
5.0
532.2

170

628

629

630

62.51
4.3
488.3

171

631

632

633

55
5.2
576.3

172

634

635

636

50.35
4.7
516.3

173

637

638

639

7
5.2
550.3

174

640

641

642

48.63
4.8
554.3

175

643

644

645

53
5.7
459.2

176

646

647

648

49
6.9
547.2

177

649

650

651

61
7.1
547.1

178

652

653

654

57
5.9
521.2

179

655

656

657

65
6.4
525.2

180

658

659

660

88.99
5.6
481.3

181

661

662

663

58
6.4
569.2

182

664

665

666

643
6.0
509.2

183

667

668

669

63
6.0
547.2

184

670

671

672

67.83
10.1
516.3

185

673

674

675

61.66
6.7
525.3

186

676

677

678

40.48
9.9
537.3

187

679

680

681

50
6.4
546.3

188

682

683

684

42.57
7.4
478.4

189

685

686

687

29
4.8
487.3

190

688

689

690

55
10.3
499.3

191

691

692

693

19.39
6.7
508.3

192

694

695

696

67
11.1
567.3

193

697

698

699

64.73
7.9
576.3

194

700

701

702

92
10.6
586.3

195

703

704

705

85
7.3
595.3

196

706

707

708

96
10.5
607.3

197

709

710

711

89.25
7.2
616.3

198

712

713

714

98.24
7.9
548.3

199

715

716

717

94
5.6
557.3

200

718

719

720

98
10.8
569.2

201

721

722

723

93.17
7.3
578.2

202

724

725

726

97.82
11.7
637.3

203

727

728

729

88.11
8.5
646.3

204

730

731

732

73
11.2
690.0

205

733

734

735

60.44
7.9
699.0

206

736

737

738

76
11.1
711.0

207

739

740

741

72.2
7.8
720.0

208

742

743

744

89.42
8.5
652

209

745

746

747

48
6.2
659.0

210

748

749

750

78.2
11.6
673.0

211

751

752

753

66.1
7.9
682.0

212

754

755

756

78
12.6
739.1

213

757

758

759

88.77
9.1
750.0

214

760

761

762

73
10.6
604.3

215

763

764

765

67
7.5
613.2

216

766

767

768

73
10.5
625.3

217

769

770

771

83
7.3
634.2

218

772

773

774

87.32
7.9
566.3

219

775

776

777

79
5.7
575.2

220

778

779

780

89
10.7
587.2

221

781

782

783

78.75
7.4
596.2

222

784

785

786

95
11.6
655.3

223

787

788

789

79
8.6
664.3

224

790

791

792

58
9.4
614.2

225

793

794

795

78
6.4
623.2

226

796

797

798

75
9.2
635.3

227

799

800

801

88
6.1
644.3

228

802

803

804

86
6.7
576.3

229

805

806

807

80
4.6
585.2

230

808

809

810

73
9.5
597.2

231

811

812

813

66
6.2
606.2

232

814

815

816

62
10.5
665.3

233

817

818

819

81
7.5
674.3

234

820

821

822

92
8.9
540.3

235

823

824

825

86
5.6
549.2

236

826

827

828

91
8.7
561.3

237

829

830

831

94.51
5.4
570.2

238

832

833

834

93.36
6.2
502.3

239

835

836

837

97
3.8
511.3

240

838

839

840

98.13
9.0
523.3

241

841

842

843

82
5.4
532.2

242

844

845

846

99
10.1
591.3

243

847

848

849

94.74
6.8
600.3

244

850

851

852

89
9.8
596.3

245

853

854

855

81
6.6
605.3

246

856

857

858

96
9.7
617.3

247

859

860

861

85.68
6.4
626.3

248

862

863

864

98.65
7.1
558.3

249

865

866

867

92
4.8
567.2

250

868

869

870

96
10.0
579.2

251

871

872

873

88.12
6.5
588.2

[0383]

7

Ex
R1
R2
R3
Purity (%)
rt
M + H +

252

874

875

876

97
10.9
647.3

253

877

878

879

86
7.8
656.3

254

880

881

882

79
10.1
572.2

255

883

884

885

79
7.0
581.2

256

886

887

888

71
10.0
593.3

257

889

890

891

72.74
6.6
602.2

258

892

893

894

79.1
7.4
534.3

259

895

896

897

74
4.9
543.2

260

898

899

900

84.17
10.3
555.2

261

901

902

903

76.16
6.7
564.2

262

904

905

906

95
11.1
623.3

263

907

908

909

78.91
8.0
632.3

264

910

911

912

75.26
5.1
430.2

265

913

914

915

90.43
5.0
430.3

266

916

917

918

74.93
4.3
452.3

267

919

920

921

79.62
4.9
390.3

268

922

923

924

92.82
5.6
490.4

269

925

926

927

68.87
3.6
421.3

270

928

929

930

79.07
4.9
440.2

271

931

932

933

84.22
3.0
392.3

272

934

935

936

67.34
4.9
418.2

273

937

938

939

81.63
4.4
352.3

274

940

941

942

90.11
4.7
342.3

275

943

944

945

54.36
4.3
438.3

276

946

947

948

81.69
4.9
432.2

277

949

950

951

85.62
5.2
382.3

278

952

953

954

86.19
3.2
377.3

279

955

956

957

94.76
4.9
451.2

280

958

959

960

99.42
4.7
451.3

281

961

962

963

90.55
4.0
473.3

282

964

965

966

93.80
4.6
411.3

283

967

968

969

82.71
5.4
511.4

284

970

971

972

90.85
3.4
442.3

285

973

974

975

98.65
4.6
461.2

286

976

977

978

98.80
2.8
404.3

287

979

980

981

86.02
4.6
439.3

288

982

983

984

97.47
4.1
373.3

289

985

986

987

99.31
4.4
363.3

290

988

989

990

45.77
4.1
459.3

291

991

992

993

94.07
4.6
453.3

292

994

995

996

95.65
5.0
403.4

293

997

998

999

94.30
2.9
398.3

294

1000

1001

1002

80.64
5.9
481.2

295

1003

1004

1005

98.05
5.7
481.3

296

1006

1007

1008

94.93
5.0
503.4

297

1009

1010

1011

96.81
5.6
441.3

298

1012

1013

1014

95.00
6.3
541.4

299

1015

1016

1017

95.13
4.2
472.4

300

1018

1019

1020

52.68
3.2
452.4

301

1021

1022

1023

98.03
5.6
491.2

302

1024

1025

1026

96.44
3.7
217.9

303

1027

1028

1029

97.22
5.6
469.3

304

1030

1031

1032

96.97
5.2
403.3

305

1033

1034

1035

99.05
5.4
393.4

306

1036

1037

1038

32.67
5.1
489.3

307

1039

1040

1041

84.51
5.6
483.3

308

1042

1043

1044

98.44
6.0
433.4

309

1045

1046

1047

97.78
4.0
428.3

310

1048

1049

1050

79.54
5.0
460.2

311

1051

1052

1053

78.59
4.9
460.3

312

1054

1055

1056

66.24
4.2
482.3

313

1057

1058

1059

70.15
4.8
420.3

314

1060

1061

1062

57.87
5.5
520.4

315

1063

1064

1065

71.26
3.6
451.3

316

1066

1067

1068

81.16
4.8
470.2

317

1069

1070

1071

74.96
2.9
413.3

318

1072

1073

1074

53.47
4.8
448.3

319

1075

1076

1077

87.88
4.3
382.3

320

1078

1079

1080

91.41
4.6
372.3

321

1081

1082

1083

1.59
5.0
468.3

322

1084

1085

1086

77.81
4.8
462.3

323

1087

1088

1089

76.59
5.1
412.3

324

1090

1091

1092

83.35
3.1
407.3

325

1093

1094

1095

87.42
5.2
444.2

326

1096

1097

1098

98.89
5.1
444.3

327

1099

1100

1101

95.68
4.3
466.3

328

1102

1103

1104

97.27
4.9
404.3

329

1105

1106

1107

95.73
5.7
504.4

330

1108

1109

1110

83.37
3.7
435.3

331

1111

1112

1113

71.88
3.2
413.3

332

1114

1115

1116

98.33
5.0
454.2

333

1117

1118

1119

83.73
3.0
397.3

334

1120

1121

1122

94.77
5.0
432.3

335

1123

1124

1125

95.88
4.5
366.3

336

1126

1127

1128

98.9
4.7
356.3

337

1129

1130

1131

50.74
4.4
452.3

338

1132

1133

1134

95.39
5.0
446.3

339

1135

1136

1137

98.2
5.3
396.3

340

1138

1139

1140

92.35
3.2
391.3

341

1141

1142

1143

90.41
5.1
444.2

342

1144

1145

1146

87.41
5.0
444.3

343

1147

1148

1149

87.37
4.3
466.3

344

1150

1151

1152

83.01
4.9
404.3

345

1153

1154

1155

89.47
5.6
504.4

346

1156

1157

1158

77.55
3.6
435.3

347

1159

1160

1161

49.49
2.4
414.3

348

1162

1163

1164

85.63
4.9
454.2

349

1165

1166

1167

88.12
2.9
397.3

350

1168

1169

1170

87.73
4.9
432.3

351

1171

1172

1173

84.48
4.4
366.3

352

1174

1175

1176

82.03
4.7
356.3

353

1177

1178

1179

82.93
4.9
446.3

354

1180

1181

1182

72.6
5.3
396.3

355

1183

1184

1185

86.75
3.2
391.3

356

1186

1187

1188

93.75
4.7
413.1

357

1189

1190

1191

96.13
4.6
413.2

358

1192

1193

1194

98.3
3.8
435.2

359

1195

1196

1197

96.45
4.5
373.2

360

1198

1199

1200

97.9
5.3
473.4

361

1201

1202

1203

97.57
3.0
404.3

362

1204

1205

1206

78.0
2.5
383.2

363

1207

1208

1209

98.96
4.5
423.1

364

1210

1211

1212

93.98
2.4
366.3

365

1213

1214

1215

97.98
4.5
401.2

366

1216

1217

1218

93.33
4.0
335.2

367

1219

1220

1221

95.73
4.3
325.3

368

1222

1223

1224

1.21
3.9
421.3

[0384]

8

Ex
R1
R2
R3
Purity (%)
rt
M + H +

369

1225

1226

1227

88.55
4.6
415.2

370

1228

1229

1230

95.93
4.9
365.3

371

1231

1232

1233

99.1
2.6
360.2

372

1234

1235

1236

90.59
3.4
392.1

373

1237

1238

1239

93.57
3.3
392.2

374

1240

1241

1242

97.23
2.6
414.2

375

1243

1244

1245

93.83
3.1
352.3

376

1246

1247

1248

96.81
4.0
452.4

377

1249

1250

1251

97.7
2.2
383.3

378

1252

1253

1254

53.69
2.3
362.2

379

1255

1256

1257

97.2
3.1
402.1

380

1258

1259

1260

70.3
2.5
345.3

381

1261

1262

1263

97.59
3.1
380.2

382

1264

1265

1266

86.74
2.4
314.2

383

1267

1268

1269

87.28
2.6
304.3

384

1270

1271

1272

10.27
3.1
400.2

385

1273

1274

1275

93.38
3.1
394.2

386

1276

1277

1278

88.99
3.4
344.3

387

1279

1280

1281

89.43
2.5
339.3

388

1282

1283

1284

86.18
4.2
458.3

389

1285

1286

1287

37.01
3.9
404.3

390

1288

1289

1290

57.02
2.7
437.4

391

1291

1292

1293

78.70
4.3
441.3

392

1294

1295

1296

67.94
4.6
490.3

393

1297

1298

1299

39.75
4.5
479.3

394

1300

1301

1302

94.48
2.8
435.4

395

1303

1304

1305

83.7
3.4
432.3

396

1306

1307

1308

96.5
4.7
464.4

397

1309

1310

1311

43.75
4.5
547.3

398

1312

1313

1314

86.87
3.3
399.3

399

1315

1316

1317

47.77
2.9
345.3

400

1318

1319

1320

82
3.4
382.3

401

1321

1322

1323

97.10
3.8
431.2

402

1324

1325

1326

76.92
3.8
420.2

403

1327

1328

1329

97.3
2.8
373.3

404

1330

1331

1332

95.9
4.0
405.3

405

1333

1334

1335

69.50
3.7
488.3

406

1336

1337

1338

90.79
4.1
420.3

407

1339

1340

1341

86.38
2.5
399.3

408

1342

1343

1344

67.52
4.6
452.2

409

1345

1346

1347

99.8
2.7
397.3

410

1348

1349

1350

97.7
3.3
394.3

411

1351

1352

1353

87.97
5.0
488.3

412

1354

1355

1356

97.23
3.6
467.4

413

1357

1358

1359

99.29
3.7
465.4

414

1360

1361

1362

96.2
4.2
462.4

415

1363

1364

1365

72.0
5.5
494.3

416

1366

1367

1368

85.09
4.3
467.3

417

1369

1370

1371

68.52
4.1
413.3

418

1372

1373

1374

98.76
2.8
446.4

419

1375

1376

1377

73.21
4.4
450.3

420

1378

1379

1380

76.94
4.7
499.2

421

1381

1382

1383

85.12
4.6
488.2

422

1384

1385

1386

98.15
2.9
444.4

423

1387

1388

1389

58
5.1
477.3

424

1390

1391

1392

25
3.6
410.3

425

1393

1394

1395

69.90
4.6
556.3

426

1396

1397

1398

90.11
8.2
556.3

427

1399

1400

1401

95.30
9.7
552.3

428

1402

1403

1404

89.35
9.6
573.3

429

1405

1406

1407

97.48
11.8
547.4

430

1408

1409

1410

91.35
9.6
591.3

431

1411

1412

1413

66.60
9.7
557.3

432

1414

1415

1416

97.25
10.5
547.3

433

1417

1418

1419

98.20
10.2
549.3

434

1420

1421

1422

88.28
4.7
489.3

435

1423

1424

1425

94.30
5.8
485.3

436

1426

1427

1428

92.92
5.6
506.3

437

1429

1430

1431

95.73
7.1
480.4

438

1432

1433

1434

89.80
5.6
524.3

439

1435

1436

1437

69.38
5.6
490.3

440

1438

1439

1440

95.21
6.2
480.3

441

1441

1442

1443

96.98
6.0
482.3

442

1444

1445

1446

85.00
5.4
456.3

443

1447

1448

1449

94.40
6.5
452.3

444

1450

1451

1452

91.10
6.3
473.3

445

1453

1454

1455

96.60
7.7
447.3

446

1456

1457

1458

92.80
6.3
491.2

447

1459

1460

1461

85.40
6.3
457.2

448

1462

1463

1464

96.70
6.9
447.2

449

1465

1466

1467

98
6.7
449.2

450

1468

1469

1470

38.17
3.6
385.2

451

1471

1472

1473

92.70
3.4
406.2

452

1474

1475

1476

89.50
4.7
380.3

453

1477

1478

1479

86.24
3.4
424.2

454

1480

1481

1482

71.20
3.3
390.2

455

1483

1484

1485

88.60
3.8
380.2

456

1486

1487

1488

89.26
3.5
382.2

457

1489

1490

1491

96.55
4.9
445.3

458

1492

1493

1494

94.46
4.8
455.2

459

1495

1496

1497

95.6
4.7
411.3

460

1498

1499

1500

98.1
5.0
461.3

461

1501

1502

1503

93.31
5.1
419.4

462

1504

1505

1506

97.08
4.2
402.3

463

1507

1508

1509

94.61
4.4
395.3

464

1510

1511

1512

97.05
4.9
503.2

465

1513

1514

1515

95.13
5.1
453.4

466

1516

1517

1518

93.21
4.8
475.3

467

1519

1520

1521

94.08
4.7
485.2

468

1522

1523

1524

93.08
4.6
441.3

469

1525

1526

1527

95.17
4.9
491.3

470

1528

1529

1530

89.99
5.0
449.4

471

1531

1532

1533

92
4.1
432.3

472

1534

1535

1536

94.71
4.3
425.3

473

1537

1538

1539

95.3
4.8
533.2

474

1540

1541

1542

94.13
5.0
483.4

475

1543

1544

1545

95
5.1
459.3

476

1546

1547

1548

94.69
5.0
469.2

477

1549

1550

1551

94.44
4.9
425.3

478

1552

1553

1554

98
5.2
475.3

479

1555

1556

1557

96.2
5.3
433.4

480

1558

1559

1560

93
4.4
416.3

481

1561

1562

1563

94.59
4.6
409.3

482

1564

1565

1566

95.22
5.1
517.2

483

1567

1568

1569

95.7
5.3
467.4

484

1570

1571

1572

94.8
4.6
457.2

485

1573

1574

1575

86.7
4.5
420.3

486

1576

1577

1578

88.5
4.8
447.3

487

1579

1580

1581

96.9
5.1
483.4

488

1582

1583

1584

92.3
4.7
505.2

489

1585

1586

1587

65.4
4.9
471.2

490

1588

1589

1590

62.6
4.7
434.3

491

1591

1592

1593

57.9
5.0
461.3

492

1594

1595

1596

94.2
5.3
497.4

493

1597

1598

1599

54.0
5.0
519.2

494

1600

1601

1602

54.6
4.8
501.3

[0385]

9

Ex
R1
R2
R3
Purity (%)
rt
M + H +

495

1603

1604

1605

64.9
4.7
464.3

496

1606

1607

1608

70.4
4.9
491.3

497

1609

1610

1611

96.5
5.2
527.4

498

1612

1613

1614

55.7
4.9
549.2

499

1615

1616

1617

57.4
5.1
485.3

500

1618

1619

1620

59.3
4.9
448.4

501

1621

1622

1623

53.6
5.2
475.3

502

1624

1625

1626

97.8
5.4
511.4

503

1627

1628

1629

10 +36.87
5.2
533.2

504

1630

1631

1632

96.33
11.2
646.3

505

1633

1634

1635

92.67
9.4
690.1

506

1636

1637

1638

41.11
9.5
656.2

507

1639

1640

1641

97.65
10.1
646.2

508

1642

1643

1644

96.29
9.9
648.2

509

1645

1646

1647

90.89
8.5
501.3

510

1648

1649

1650

61.04
5.8
401.2

511

1651

1652

1653

99.16
10.5
496.4

512

1654

1655

1656

95.73
7.1
396.3

513

1657

1658

1659

66
9.3
496.3

514

1660

1661

1662

95.00
8.9
396.2

515

1663

1664

1665

96.61
9.5
530.3

516

1666

1667

1668

94.05
6.4
430.3

517

1669

1670

1671

87
8.6
536.3

518

1672

1673

1674

91.59
5.6
436.3

519

1675

1676

1677

86.84
8.4
522.3

520

1678

1679

1680

94.18
5.4
422.3

521

1681

1682

1683

99.75
10.4
517.4

522

1684

1685

1686

96.8
6.8
417.4

523

1687

1688

1689

70.34
9.1
517.3

524

1690

1691

1692

93.49
5.8
417.3

525

1693

1694

1695

93.03
9.3
551.3

526

1696

1697

1698

97.13
6.1
451.3

527

1699

1700

1701

74.37
8.4
557.3

528

1702

1703

1704

92.92
5.3
457.3

529

1705

1706

1707

92.92
8.8
484.3

530

1708

1709

1710

92.68
5.5
384.2

531

1711

1712

1713

98.29
10.8
479.3

532

1714

1715

1716

96.39
7.0
379.3

533

1717

1718

1719

99
9.5
479.2

534

1720

1721

1722

99.76
6.0
379.2

535

1723

1724

1725

99.17
9.7
513.2

536

1726

1727

1728

99.74
6.3
413.2

537

1729

1730

1731

68.71
8.7
519.3

538

1732

1733

1734

90.09
5.4
419.3

539

1735

1736

1737

91.37
9.8
552.3

540

1738

1739

1740

95.39
6.6
452.3

541

1741

1742

1743

98.71
11.7
547.4

542

1744

1745

1746

99.02
7.9
447.4

543

1747

1748

1749

79.38
10.5
547.3

544

1750

1751

1752

95.46
7.1
447.3

545

1753

1754

1755

95.3
10.6
581.3

546

1756

1757

1758

95.45
7.3
481.3

547

1759

1760

1761

80.92
9.8
587.3

548

1762

1763

1764

92.06
6.5
487.3

549

1765

1766

1767

63
7.7
529.4

550

1768

1769

1770

79
7.1
495.4

551

1771

1772

1773

70
6.7
529.3

552

1774

1775

1776

77
6.3
495.3

553

1777

1778

1779

61
6.9
563.3

554

1780

1781

1782

69
6.5
529.3

555

1783

1784

1785

69
6.1
569.3

556

1786

1787

1788

76
5.8
535.3

557

1789

1790

1791

79
5.9
555.3

558

1792

1793

1794

88
5.6
521.3

559

1795

1796

1797

90.81
7.4
550.4

560

1798

1799

1800

95.6
6.9
516.4

561

1801

1802

1803

80.85
6.4
550.3

562

1804

1805

1806

85.8
6.0
516.3

563

1807

1808

1809

92.92
6.6
584.3

564

1810

1811

1812

97.26
6.3
550.3

565

1813

1814

1815

82.91
5.8
590.3

566

1816

1817

1818

87.77
5.5
556.3

567

1819

1820

1821

86
6.0
517.3

568

1822

1823

1824

83.41
5.7
483.3

569

1825

1826

1827

95
7.6
512.3

570

1828

1829

1830

94.08
7.1
478.4

571

1831

1832

1833

87.39
6.5
512.3

572

1834

1835

1836

90.06
6.1
478.3

573

1837

1838

1839

85.61
6.8
546.2

574

1840

1841

1842

83.51
6.4
512.3

575

1843

1844

1845

78.63
5.9
552.3

576

1846

1847

1848

79.58
5.6
518.3

577

1849

1850

1851

84
7.1
585.3

578

1852

1853

1854

91
6.7
551.3

579

1855

1856

1857

89.59
8.6
580.4

580

1858

1859

1860

97.13
7.9
546.4

581

1861

1862

1863

83
7.6
580.3

582

1864

1865

1866

92.05
7.1
546.3

583

1867

1868

1869

86
7.8
614.3

584

1870

1871

1872

95.49
7.3
580.3

585

1873

1874

1875

77
7.0
620.3

586

1876

1877

1878

91.1
6.6
586.4

587

1879

1880

1881

95
4.6
435

588

1882

1883

1884

90
4.4
391.3

589

1885

1886

1887

88
5.1
435.3

590

1888

1889

1890

92
4.9
447.3

591

1891

1892

1893

20.32
5.1
399.4

592

1894

1895

1896

85
5.3
486.3

593

1897

1898

1899

97
5.1
442.3

594

1900

1901

1902

92
5.7
486.4

595

1903

1904

1905

79
5.5
498.3

596

1906

1907

1908

93.4
4.68
451.29

597

1909

1910

1911

94.9
4.86
425.27

598

1912

1913

1914

97.9
5.37
475.22

599

1915

1916

1917

97.1
5.20
457.32

600

1918

1919

1920

95.1
5.10
441.24

601

1921

1922

1923

91.1
4.61
481.29

602

1924

1925

1926

97.5
4.78
455.29

603

1927

1928

1929

98.0
5.28
505.22

604

1930

1931

1932

95.4
5.12
487.33

605

1933

1934

1935

94.0
5.03
471.27

606

1936

1937

1938

89.8
4.86
465.29

607

1939

1940

1941

98.2
5.03
439.29

608

1942

1943

1944

97.6
5.53
489.24

609

1945

1946

1947

93.3
5.36
471.34

610

1948

1949

1950

91.4
5.27
455.26

611

1951

1952

1953

94
4.9
459.3

612

1954

1955

1956

92.95
4.8
469.2

613

1957

1958

1959

91.61
4.7
425.3

614

1960

1961

1962

92
5.0
475.3

615

1963

1964

1965

85.2
5.1
433.4

616

1966

1967

1968

83
4.2
416.3

617

1969

1970

1971

94.11
4.4
409.3

618

1972

1973

1974

93.85
5.0
517.2

619

1975

1976

1977

92.74
5.1
467.4

620

1978

1979

1980

91
4.8
489.3

621

1981

1982

1983

91.9
4.7
499.3

622

1984

1985

1986

89.71
4.6
455.3

623

1987

1988

1989

90
4.9
505.3

624

1990

1991

1992

83.96
5.0
463.4

625

1993

1994

1995

87
4.1
446.3

626

1996

1997

1998

93.1
4.3
439.3

627

1999

2000

2001

93.21
4.8
547.2

[0386]

10

Ex
R1
R2
R3
Purity (%)
rt
M + H +

628

2002

2003

2004

90.67
5.0
497.4

629

2005

2006

2007

79.6
4.9
485.2

630

2008

2009

2010

72.8
4.8
448.3

631

2011

2012

2013

78.7
5.1
475.3

632

2014

2015

2016

97.3
5.4
511.4

633

2017

2018

2019

51.5
5.1
533.2

634

2020

2021

2022

76.1
4.9
515.3

635

2023

2024

2025

74.2
4.7
478.3

636

2026

2027

2028

76.5
5.0
505.3

637

2029

2030

2031

97.7
5.3
541.4

638

2032

2033

2034

71.4
5.0
563.2

639

2035

2036

2037

82.54
4.4
451.3

640

2038

2039

2040

93.42
4.2
397.3

641

2041

2042

2043

98.93
2.9
430.4

642

2044

2045

2046

81.46
4.5
434.3

643

2047

2048

2049

96.41
4.9
483.3

644

2050

2051

2052

91.55
4.7
472.3

645

2053

2054

2055

97.96
2.9
428.4

646

2056

2057

2058

96.9
5.0
425.3

647

2059

2060

2061

95.8
4.9
457.3

648

2062

2063

2064

91.41
4.6
540.3

649

2065

2066

2067

88.0
4.75
465.3

650

2068

2069

2070

99.0
4.89
439.3

651

2071

2072

2073

98.5
5.42
489.2

652

2074

2075

2076

93.3
5.24
471.3

653

2077

2078

2079

87.6
5.14
455.3

654

2080

2081

2082

88.3
4.66
495.3

655

2083

2084

2085

98.1
4.82
469.3

656

2086

2087

2088

98.4
5.34
519.2

657

2089

2090

2091

95.4
5.16
501.3

658

2092

2093

2094

89.8
5.08
485.3

659

2095

2096

2097

80.76
4.84
410.2

660

2098

2099

2100

61.69
4.97
426.2

661

2101

2102

2103

90.93
4.79
454.1

662

2104

2105

2106

91.55
4.58
394.2

663

2107

2108

2109

91.99
4.88
454.1

664

2110

2111

2112

92.79
5.55
526.2

665

2113

2114

2115

93.78
5.02
502.1

666

2116

2117

2118

96.3
4.75
408.2

667

2119

2120

2121

81.2
5.02
408.2

668

2122

2123

2124

90.79
4.74
440.2

669

2125

2126

2127

78.93
4.88
456.3

670

2128

2129

2130

91.87
4.69
484.2

671

2131

2132

2133

91.19
4.51
424.2

672

2134

2135

2136

95.27
4.79
484.2

673

2137

2138

2139

89.5
5.46
542.2

674

2140

2141

2142

90.77
4.92
532.1

675

2143

2144

2145

95.1
4.66
438.2

676

2146

2147

2148

88.7
4.92
524.2

677

2149

2150

2151

81.65
4.99
424.2

678

2152

2153

2154

70.32
5.11
440.3

679

2155

2156

2157

90.06
4.96
468.2

680

2158

2159

2160

94.11
4.74
408.2

681

2161

2162

2163

93.96
5.04
468.2

682

2164

2165

2166

93.3
5.66
540.2

683

2167

2168

2169

94.79
5.16
516.1

684

2170

2171

2172

96.5
4.9
422.3

685

2173

2174

2175

88.2
5.19
438.2

686

2176

2177

2178

87.93
4.86
424.2

687

2179

2180

2181

84.74
5
440.2

688

2182

2183

2184

95.34
4.82
468.2

689

2185

2186

2187

89.78
4.6
408.2

690

2188

2189

2190

95.16
4.9
468.1633

691

2191

2192

2193

95.6
5.56
540.2

692

2194

2195

2196

95.24
5.05
516.3

693

2197

2198

2199

96.6
4.8
422.2

694

2200

2201

2202

90.4
5.04
438.2

695

2203

2204

2205

93.12
4.78
454.2

696

2206

2207

2208

86.11
4.92
470.3

697

2209

2210

2211

94.89
4.73
498.2

698

2212

2213

2214

94.1
4.54
438.3

699

2215

2216

2217

95.66
4.81
498.2

700

2218

2219

2220

94.8
5.48
570.2

701

2221

2222

2223

93.63
4.96
546.1

702

2224

2225

2226

96.7
4.7
452.3

703

2227

2228

2229

85.6
4.96
468.2

704

2230

2231

2232

78.36
3.14
359.1

705

2233

2234

2235

47.4
3.9
367.1

706

2236

2237

2238

69.72
4.28
385.2

707

2239

2240

2241

34.86
4.96
393.2

708

2242

2243

2244

37.54
4.91
449.2

709

2245

2246

2247

81.57
4.46
483.1

710

2248

2249

2250

55.98
5.12
491.1

711

2251

2252

2253

73.74
3.09
441.2

712

2254

2255

2256

40.19
2.85
449.2

713

2257

2258

2259

90.07
3.18
426.2

714

2260

2261

2262

74.98
3.84
434.2

715

2263

2264

2265

78.14
4.24
397.2

716

2266

2267

2268

39.87
4.92
405.2

717

2269

2270

2271

57.34
4.45
477.2

718

2272

2273

2274

37.75
5.01
485.1

719

2275

2276

2277

70.3
5.2
412.1

720

2278

2279

2280

70.7
5.0
386.1

721

2281

2282

2283

61.9
6.3
600.3

722

2284

2285

2286

49.3
6.1
538.4

723

2287

2288

2289

65.0
5.1
412.2

724

2290

2291

2292

44.3
4.9
386.2

725

2293

2294

2295

49.2
6.2
600.3

726

2296

2297

2298

37.5
6.0
538.4

727

2299

2300

2301

87.1
5.1
468.1

728

2302

2303

2304

84.4
4.9
442.1

729

2305

2306

2307

82.3
6.2
656.3

730

2308

2309

2310

93.8
4.7
406.3

731

2311

2312

2313

80.7
4.6
380.3

732

2314

2315

2316

84.1
5.9
594.3

733

2317

2318

2319

67.9
4.7
462.1

734

2320

2321

2322

66.9
4.6
436.1

735

2323

2324

2325

56.8
5.9
650.2

736

2326

2327

2328

88.1
4.3
400.3

737

2329

2330

2331

82.8
4.1
374.3

738

2332

2333

2334

51.4
5.6
588.3

739

2335

2336

2337

77.7
5.1
446.2

740

2338

2339

2340

76.1
4.9
420.2

741

2341

2342

2343

67.1
6.2
634.3

742

2344

2345

2346

88.9
4.7
384.3

743

2347

2348

2349

79.3
4.5
358.3

744

2350

2351

2352

65.1
5.9
572.4

745

2353

2354

2355

80.0
4.0
398.3

746

2356

2357

2358

76.9
3.8
372.3

747

2359

2360

2361

42.7
5.8
586.4

748

2362

2363

2364

64.6
4.4
483.3

749

2365

2366

2367

87.4
5.3
409.3

750

2368

2369

2370

71.0
5.1
383.3

751

2371

2372

2373

59.8
6.7
597.4

752

2374

2375

2376

84.4
5.6
494.3

753

2377

2378

2379

80.1
3.9
398.3

754

2380

2381

2382

63.1
3.7
372.3

755

2383

2384

2385

64.4
4.3
483.3

756

2386

2387

2388

84.6
5.3
409.3

757

2389

2390

2391

59.6
5.0
383.3

758

2392

2393

2394

52.9
6.6
597.4

759

2395

2396

2397

81.6
5.5
494.3

760

2398

2399

2400

75.3
5.3
465.3

761

2401

2402

2403

60.3
5.1
439.3

762

2404

2405

2406

61.8
6.6
653.4

763

2407

2408

2409

74.4
5.6
550.3

764

2410

2411

2412

74.5
3.6
448.2

765

2413

2414

2415

51.3
3.4
422.2

766

2416

2417

2418

58.8
3.9
533.2

767

2419

2420

2421

86.2
4.8
459.3

768

2422

2423

2424

63.2
4.6
433.3

769

2425

2426

2427

60.1
6.2
647.4

770

2428

2429

2430

83.5
5.1
544.2

771

2431

2432

2433

68.1
4.1
432.3

772

2434

2435

2436

63.8
3.9
406.2

773

2437

2438

2439

41.1
5.8
620.4

774

2440

2441

2442

62.8
4.4
517.2

775

2443

2444

2445

85.5
5.4
443.3

776

2446

2447

2448

62.5
5.2
417.3

777

2449

2450

2451

66.0
6.7
631.4

778

2452

2453

2454

87.7
5.6
528.3

[0387] Pharmacological Study

[0388] 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.

[0389] Study of the Affinity for the Sub-types of Human Somatostatin Receptors.

[0390] The affinity of a compound of the invention for sub-types of human somatostatin receptors 1 to 5 (sst1, sst2, sst3, sst4 and sst5, respectively) is determined by measurement of the inhibition of the bond of [125I-Tyr11]SRIF-14 to transfected CHO-K1 cells.

[0391] The gene of the sst1 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 sst1 receptor is obtained by transfection in CHO-K1 cells (ATCC) using the calcium phosphate co-precipitation method. The plasmid pRSV-neo (ATCC) is included as selection marker. Cloned cell lines were selected in an RPMI 1640 medium containing 0.5 mg/ml of G418 (Gibco), followed by circular cloning and multiplication in culture.

[0392] The gene of the sst2 receptor of human somatostatin, isolated in the form of a genomic fragment of DNA of 1.7 Kb BamHI-HindIII and subcloned in a plasmid vector pGEM3Z (Promega), was provided by Dr. G. Bell (Univ. of Chicago). The expression vector of the mammalian cells is constructed by inserting the 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.

[0393] The sst3 receptor is isolated as a genomic fragment, and the complete coding sequence is contained in a BamHI/HindIII fragment of 2.4 Kb. The expression plasmid in mammals, pCMV-h3, is constructed by insertion of the NcoI-HindIII fragment of 2.0 Kb in the 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 sst3 receptor is obtained by transfection in CHO-K1 cells (ATCC) by the calcium phosphate co-precipitation method. The plasmid pRSV-neo (ATCC) is included as selection marker. Cloned cell lines were selected in an RPMI 1640 medium containing 0.5 mg/ml of G418 (Gibco), followed by circular cloning and multiplication in culture.

[0394] The expression plasmid of the human sst4 receptor, pCMV-HX, was provided by Dr. Graeme Bell (Univ. Chicago). This vector contains the genomic fragment coding for the human sst4 receptor of 1.4 Kb NheI-NheI, 456 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 sst4 receptor is obtained by transfection in CHO-K1 (ATCC) cells by the calcium phosphate co-precipitation method. The plasmid pRSV-neo (ATCC) is included as selection marker. 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.

[0395] The gene corresponding to the human sst5 receptor, obtained by the PCR method using a genomic λ clone as probe, was provided by Dr. Graeme Bell (Univ. Chicago). The resulting PCR fragment of 1.2 Kb contains 21 base pairs of the non 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 sst5 receptor is obtained by transfection in CHO-K1 cells (ATCC) by the calcium phosphate co-precipitation method. The plasmid pRSV-neo (ATCC) is included as selection marker. 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.

[0396] The CHO-K1 cells which express in a stable fashion one of 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 buffer medium 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.

[0397] The competitive inhibition tests of the bond with [125I-Tyr11]SRIF-14 are carried out in duplicate in 96-well polypropylene plates. The cell membranes (10 μg protein/well) are incubated with [125I-Tyr11]SRIF-14 (0.05 nM) for approximately 60 min. at approximately 37° C. in a HEPES 50 mM buffer (pH 7.4) containing BSA 0.2%, MgCl2 5 mM, Trasylol 200 KIU/ml, bacitricin 0.02 mg/ml and phenylmethylsulphonyl fluoride 0.02 mg/ml.

[0398] The bound [125I-Tyr11]SRIF-14 is separated from the free [125I-Tyr11]SRIF-14 by immediate filtration through GF/C glass fibre filter plates (Unifilter, Packard) pre-impregnated with 0.1% of polyethylenimine (P.E.I.), using a 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).

[0399] 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.

[0400] Determination of the agonist or antagonist character of a compound of the present invention is carried out using the test described below.

[0401] Functional test Inhibition of production of intracellular cAMP:

[0402] 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.

[0403] The cells at a rate of 105 cells/well are washed twice with 0.5 ml of new RPMI medium comprising 0.2% BSA completed by 0.5 mM of 3-isobutyl-1-methylxanthine (IBMX) and incubated for approximately 5 min at approximately 37° C.

[0404] the production of cyclic AMP is stimulated by the addition of 1 mM of forskolin (FSK) for 15-30 minutes at approximately 37° C.

[0405] the inhibitory effect of the somatostatin of an agonist compound is measured by the simultaneous addition of FSK (1 μM), SRIF-14 (10−12 M to 10−6 M) and of the compound to be tested (10−10 M to 10−5 M).

[0406] 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).

[0407] 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).

[0408] Results:

[0409] 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 K1 being lower than micromolar for certain exemplified compounds.

Claims

1. Compounds of general formula
2. Compounds of general formula I according to claim 1, characterized in that i) the substituent or substituents which can be carried by the aryl radicals represented by Z11, and Z12 and heteroaryl represented by Z12 are chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, —CF3, —OCF3, phenyl, phenoxy, aminosulphonyl radicals; ii) the substituent or substituents which can be carried by the heterocycloalkyl radical represented by Z12 are chosen independently from the oxy and alkyl radicals; iii) the substituent or substituents which can be carried by the aryl and heteroaryl radicals represented by Z22 are chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkenyl, alkoxy, alkylthio, CF3, OCF3, nitro, cyano, azido, aminosulphonyl, piperidinosulphonyl, mono- or di-alkylamino, —C(O)—O-alkyl, —C(O)-alkyl, or phenyl, phenoxy, phenylthio, benzyloxy radicals, the phenyl radical being able to be substituted; iv) the substituent or substituents which can be carried by the aryl radicals represented by Z23 and Z24, cycloalkyl and heteroaryl represented by Z24 are chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, CF3, OCF3, OCHF2, SCF3, nitro, cyano, azido, hydroxy, —C(O)O-alkyl, —O—C(O)-alkyl, —NH—C(O)-alkyl, alkylsulphonyl, mono- or di-alkylamino, amino, aminoalkyl, pyrrolyl, pyrrolydinyl or the phenyl, phenoxy, phenylthio, benzyl, benzyloxy radicals the aryl radical of which is optionally substituted by one or more alkyl, CF3 or halo radicals; v) the substituent or substituents which can be carried by the aryl and heteroaryl radicals represented by Z25 are chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, OCF3, nitro, cyano, —NH—C(O)-alkyl, alkylsulphonyl, amino, mono- and di-alkylamino, phenyl, pyridino radicals; vi) the substituent which can be carried by the alkyl radical represented by R3 is the cyano radical. vii) the substituent or substituents which can be carried by the aralkyl radical represented by R3 are chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, OCF3, OCHF2, SCF3, SCHF2, nitro, cyano, —C(O)O-alkyl, alkylsulphonyl, thiadiazolyl radicals, or the phenyl and phenoxy radicals the phenyl radical of which is optionally substituted by one or more halo radicals. viii) the substituent or substituents which can be carried by the heteroarylalkyl radical represented by R3 are chosen independently from the fluoro, chloro, bromo or nitro radicals.
3. Compounds of general formula I according to claim 1 or 2 in which: R1 represents a linear or branched (C1-C6)alkyl radical, the —CH2)m—Y—Z11 or —(CH2)m—Z12 radical in which Z11 represents a (C1-C6)alkyl, Z12 represents bis-phenyl, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl optionally substituted, or aryl or heteroaryl optionally substituted by one or more substituents chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy radicals, or Z12 represents 2463Y represents the oxygen atom, or R1 represents a radical of formula 2464R2 represents a radical of formula —C(Y)NHX1, —C(O)X2 or SO2X3 in which X1 represents a linear or branched (C1-C15)alkyl radical, or —(CH2)pZ22 in which Z22 represents cyclohexenyl, bis-phenyl, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl, mono- or di-alkylamino, —C(O)—O-alkyl, or aryl or heteroaryl optionally substituted by one or more radicals chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, CF3, OCF3, nitro, cyano, azido, piperidinosulphonyl, —C(O)—O-alkyl, —C(O)-alkyl, or phenyl radicals, or Z22 represents a radical of formula 2465X2 represents a linear or branched (C1-C10)alkyl, alkynyl, —(CH2)m—W—(CH2)q—Z23 or —(CH2)p—U—Z24 radical in which W represents SO2, U represents a covalent bond, Z23 represents an aryl radical; Z24 represents cyclohexenyl, bis-phenyl, (C3-C7)cycloalkyl optionally substituted by an aminoalkyl, or aryl or heteroaryl radical optionally substituted by one or more radicals chosen from fluoro, chloro, bromo, iodo, alkyl, alkoxy, —CF3, —OCF3, SCF3, hydroxy, —O—C(O)-alkyl, mono- or di-alkylamino, amino or Z24 represents a radical of formula 2466or X2 represents 2467X3 represents a —(CH2)pZ25 radical in which Z25 represents an aryl radical optionally substituted by one or more identical or different radicals chosen from alkoxy and CF3, R3 represents the hydrogen atom, an alkyl, alkenyl, heteroarylalkyl radical optionally substituted or a radical of formula —C(Y)—NHX1, —C(O)X2 or SO2X3 in which X1 represents a —(CH2)pZ22 radical in which Z22 represents an aryl radical optionally substituted by one or more radicals chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, phenoxy radicals; X2 represents the vinyl radical substituted by a phenyl, the phenyl radical being itself optionally substituted by one or more halo, or —CH2)p—U—Z24 radicals in which Z24 represents alkyl, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl, bis-phenyl, amino, mono or di-alkylamino, or aryl or heteroaryl optionally substituted by one or more radicals chosen from alkoxy, bromo, chloro, fluoro, hydroxy, CF3, nitro, amino, mono- and di-alkylamino, pyrrolyl, or X2 represents a radical of formula 2468X3 represents a linear or branched (C1-C10)alkyl radical, the vinyl radical substituted by a radical (the phenyl radical being itself optionally substituted), CF3, or —(CH2)pZ25 in which Z25 represents aryl or heteroaryl optionally substituted by one or more substituents chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, —NH—C(O)-alkyl, mono- and di-alkylamino radicals.
4. Compounds of general formula I according to any of the preceding claims, wherein R1 represents a linear or branched (C1-C6)alkyl radical, the —(CH2)m—Y—Z11 or —(CH2)m—Z12 radical in which Z11represents a (C1-C6)alkyl, Z12 represents naphthyl, morpholino, bis-phenyl, pyrrolidinyl substituted by the oxy radical, or the phenyl, piperazinyl, pyridinyl and indolyl radicals which are optionally substituted by one or more substituents chosen independently from the bromo, fluoro, chloro, alkyl, alkoxy, —CF3, —OCF3 radicals; or Z12 represents 2469Y represents the oxygen atom, or R1 represents a radical of formula given below: 2470
5. Compounds of general formula I according to any of the preceding claims, wherein R2 represents a radical of formula —C(Y)NHX1, —C(O)X2 or SO2X3 in which X1 represents a linear or branched (C1-C10)alkyl, or —(CH2)pZ22 radical in which Z22 represents cyclohexyl, cyclohexenyl, bis-phenyl, morpholino, piperidino, mono- or di-alkylamino, —C(O)—O-alkyl, or phenyl, naphthyl or furyl optionally substituted by one or more radicals chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, CF3, —OCF3, nitro, cyano, azido, piperidinosulphonyl, —C(O)—O-alkyl, —C(O)-alkyl or phenyl radicals, or Z22 represents a radical of formula 2471X2 represents an alkyl, alkynyl, —(CH2)m—W—(CH2)q—Z23 or —(CH2)pZ24 radical in which W represents SO2; Z23 represents the phenyl radical; Z24 represents cyclohexenyl, bis-phenyl, cyclohexyl optionally substituted by an aminoalkyl, or phenyl, naphthyl, benzothienyl, thienyl or indolyl radical optionally substituted by one or more radicals chosen from fluoro, chloro, bromo, iodo, alkyl, alkoxy, —CF3, —OCF3, —SCF3, hydroxy, —O—C(O)-alkyl, —NH—C(O)-alkyl, mono- or di-alkylamino, amino, or Z24 represents a radical of formula 2472or X2 represents 2473X3 represents a —(CH2)pZ25 radical in which Z25 represents the phenyl radical optionally substituted by one or more identical or different radicals chosen from alkoxy and CF3,
6. Compounds of general formula I according to any of the preceding claims, wherein R3 represents the hydrogen atom, an alkyl, alkenyl or furyl-methyl radical substituted by one or more nitro radicals, or a radical of formula —C(Y)—NHX1, —C(O)X2 or SO2X3 in which X1 represents a —(CH2)pZ22 radical in which Z22 represents the phenyl or naphthyl radical optionally substituted by one or more radicals chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, phenoxy radicals, X2 represents the vinyl radical substituted by a phenyl radical itself optionally substituted by one or more halo, or —(CH2)p—U—Z24 radicals in which Z24 represents alkyl, cyclohexyl, tetrahydrofuryl, bis-phenyl, amino, mono or di-alkylamino, or phenyl, indolyl, thienyl, pyridinyl, benzothienyl and furyl optionally substituted by one or more radicals chosen from alkoxy, bromo, chloro, fluoro, amino, mono- and di-alkylamino, nitro, hydroxy, pyrrolyl or X2 represents a radical of formula 2474X3 represents a linear or branched (C1-C10)alkyl radical, the vinyl radical substituted by a phenyl, CF3, or —(CH2)pZ25 radical in which Z25 represents a phenyl, naphthyl, thienyl, pyrazolyl or thiazolyl radical optionally substituted by one or more substituents chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, —NH—C(O)-alkyl, mono- and di-alkylamino radicals;
7. Compounds of general formula I according to any of the preceding claims, wherein R1 represents the —(CH2)mZ12 radical in which m=2 and Z12 represents bis-phenyl or the radical indolyl substituted by one or more substituents chosen independently from the alkyl and alkoxy radicals.
8. Compounds of general formula I according to any of the preceding claims, wherein R2 represents the radicals of formula —C(Y)NHX1 and —C(O)X2 in which Y represents S; X1 represents a phenyl radical optionally substituted by one or more azido radicals, X2 represents —(CH2)pZ24 in which p is equal to 1, 2 or 3, Z24 represents cyclohexyl, or phenyl or benzothienyl optionally substituted by one or more radicals chosen from fluoro, chloro, bromo, iodo or —CF3.
9. Compounds of general formula I according to any of the preceding claims, wherein R3 represents the hydrogen atom or the methyl radical.
10. Process for the preparation, in liquid phase, of compounds of formula I according to claim 1, characterized in that it comprises the reducing amination of the following N-substituted piperidone 2475 in which R represents the methyl or Boc radical, in the presence of an amine of formula R1NH2 in which R1 has the meaning indicated in claim 1, in order to obtain the compound of formula 1 2476 which compound of formula (1) is reacted with A) either a compound of formula X1NC(Y) in which X1 and Y have the meaning indicated in claim 1, in order to obtain a compound of formula (2) 2477 which compound of formula (2) represents the corresponding compound of formula (I) in which R3 represents Me or Boc and which, when R3 represents Boc, can be subjected to an acid treatment in order to obtain the corresponding compound of formula (I) in which R3 represents the hydrogen atom, which compound of formula (I) thus obtained can be reacted with a compound of formula X1NC(Y), X2CO2H or X3SO2Cl in which X1, Y, X2 and X3 have the meaning indicated in claim 1, in order to obtain the corresponding compound of formula I in which R2 represents a radical of formula —C(Y)NHX1 and R3 the —C(Y)—NHX1, —C(O)X2 or SO2X3 radical respectively; B) or a compound of formula X2CO2H in which X2 has the meaning indicated in claim 1, in order to obtain a compound of formula (3) 2478which compound of formula (3) represents the corresponding compound of formula (I) in which R3 represents Me or Boc and which, when R3 represents Boc, can be subjected to an acid treatment in order to obtain the corresponding compound of formula (I) in which R3 represents the hydrogen atom, which compound of formula (I) thus obtained can be reacted with a compound of formula X1NC(Y), X2CO2H or X3SO2Cl in which X1, Y, X2 and X3 have the meaning indicated in claim 1, in order to obtain the corresponding compound of formula I in which R2 represents a radical of formula —C(O)X2 and R3 the —C(Y)—NHX1, —C(O)X2 or SO2X3 radical respectively.
11. Preparation process, in solid phase, for compounds of formula I according to claim 1, characterized in that it comprises the reducing amination of the ketonic resin 2479 in the presence of an amine of formula R1NH2 in which R1 has the meaning indicated in claim 1, in order to obtain the compound of formula (4) 2480 which compound of formula (4) is reacted with A) either a compound of formula X1NC(Y) in which X1 and Y have the meaning indicated in claim 1, in order to obtain a compound of formula (5) 2481 followed by cleavage of the resin in order to obtain the corresponding compound of formula (I) in which R3 represents the hydrogen atom, B) or a compound of formula X3SO2Cl in which X3 has the meaning indicated in claim 1, in order to obtain a compound of formula (6) 2482 followed by cleavage of the resin in order to obtain the corresponding compound of formula (I) in which R3 represents the hydrogen atom, C) or a compound of formula X2CO2Cl in which X2 has the meaning indicated in claim 1, in order to obtain a compound of formula (7) 2483 followed by cleavage of the resin in order to obtain the corresponding compound of formula (I) in which R3 represents the hydrogen atom; D) or a compound of formula X2CO2H in which X2 has the meaning indicated in claim 1, in order to obtain a compound of formula (7) as defined above, followed by cleavage of the resin in order to obtain the corresponding compound of formula (I) in which R3 represents the hydrogen atom.
12. Preparation process, in solid phase, for compounds of formula I according to claim 1, characterized in that it comprises the reducing amination of the ketonic resin 2484 in the presence of an amine of formula R1NH2 in which R1 has the meaning indicated in claim 1, in order to obtain the compound of formula (8) 2485 which compound of formula (8) is reacted with A) either a compound of formula X1NC(O) in which X1 has the meaning indicated in claim 1, in order to obtain a compound of formula (9) 2486 which compound (9) thus formed is reacted with a compound of formula R3X in which R3 is as defined in claim 1 and X represents Br or I, followed by cleavage of the resin in order to obtain the corresponding compound of formula (I); B) or a compound of formula X3SO2Cl in which X3 has the meaning indicated in claim 1, in order to obtain a compound of formula (10) 2487 which compound (10) thus formed is reacted with a compound of formula R3X in which R3 is as defined in claim 1 and X represents Br or I, followed by cleavage of the resin in order to obtain the corresponding compound of formula (I); C) or a compound of formula X2CO2Cl in which X2 has the meaning indicated in claim 1, in order to obtain a compound of formula (11) 2488 which compound (11) thus formed is reacted with a compound of formula R3X in which R3 is as defined in claim 1 and X represents Br or I, followed by cleavage of the resin in order to obtain the corresponding compound of formula (I); D) or a compound of formula X2CO2H in which X2 has the meaning indicated in claim 1, in order to obtain a compound of formula (11) as defined above, which compound (11) thus formed is reacted with a compound of formula R3X in which R3 is as defined in claim 1 and X represents Br or I, followed by cleavage of the resin in order to obtain the corresponding compound of formula (I).
13. As medicaments, the products of formula I according to claims 1 to 9, as well as the addition salts with pharmaceutically acceptable mineral or organic acids of said products of formula I.
14. Pharmaceutical compositions containing, as active ingredient, at least one of the medicaments according to claim 13, in combination with a pharmaceutically acceptable support.
15. Use of compounds of general formula Ia
16. Use of products of general formula Ia according to claim 15, characterized in that i) the substituent or substituents which can be carried by the aryl radicals represented by Z11 and Z12 and heteroaryl represented by Z12 are chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, —CF3, —OCF3, phenyl, phenoxy, aminosulphonyl radicals; ii) the substituent or substituents which can be carried by the heterocycloalkyl radical represented by Z12 are chosen independently from the oxy and alkyl radicals; iii) the substituent or substituents which can be carried by the aryl and heteroaryl radicals represented by Z22 are chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkenyl, alkoxy, alkylthio, CF3, OCF3, nitro, cyano, azido, aminosulphonyl, piperidinosulphonyl, mono- or di-alkylamino, —C(O)—O-alkyl, —C(O)-alkyl, or phenyl, phenoxy, phenylthio, benzyloxy radicals, the phenyl radical being able to be substituted; iv) the substituent or substituents which can be carried by the aryl radicals represented by Z23 and Z24, cycloalkyl and heteroaryl represented by Z24 are chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, CF3, OCF3, OCHF2, SCF3, nitro, cyano, azido, hydroxy, —C(O)O-alkyl, —O—C(O)-alkyl, —NH—C(O)-alkyl, alkylsulphonyl, mono- or di-alkylamino, amino, aminoalkyl, pyrrolyl, pyrrolydinyl or the radicals phenyl, phenoxy, phenylthio, benzyl, benzyloxy radicals the aryl radical of which is optionally substituted by one or more alkyl, CF3 or halo radicals; v) the substituent or substituents which can be carried by the aryl and heteroaryl radicals represented by Z25 are chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, OCF3, nitro, cyano, —NH—C(O)-alkyl, alkylsulphonyl, amino, mono- and di-alkylamino, phenyl, pyridino radicals; vi) the substituent which can be carried by the alkyl radical represented by R3 is the cyano radical. vii) the substituent or substituents which can be carried by the aralkyl radical represented by R3 are chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, OCF3, OCHF2, SCF3, SCHF2, nitro, cyano, —C(O)O-alkyl, alkylsulphonyl, thiadiazolyl radicals, or the phenyl and phenoxy radicals the phenyl radical of which is optionally substituted by one or more halo radicals. viii) the substituent or substituents which can be carried by the heteroarylalkyl radical represented by R3 are chosen independently from the fluoro, chloro, bromo or nitro radicals.
17. Use of compounds of general formula Ia according to any of claims 15 to 16 in which R1a represents a linear or branched (C1-C6)alkyl radical, the —(CH2)m—Y—Z11 or —(CH2)m—Z12 radical in which Z11 represents a (C1-C6)alkyl, Z12 represents bis-phenyl, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl optionally substituted, or aryl or heteroaryl optionally substituted by one or more substituents chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy radicals, or Z12 represents 2497Y represents the oxygen atom, or R1a represents a radical of formula 2498
18. Use of compounds of general formula Ia according to any of claims 15 to 17 in which R2a represents a radical of formula —C(Y)NHX1, —C(O)X2 or SO2X3 in which X1 represents a linear or branched (C1-C15)alkyl radical, or CH2)pZ22 in which Z22 represents cyclohexenyl, bis-phenyl, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl, mono- or di-alkylamino, —C(O)—O-alkyl, or aryl or heteroaryl optionally substituted by one or more radicals chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, CF3, OCF3, nitro, cyano, azido, piperidinosulphonyl, —C(O)—O-alkyl, —C(O)-alkyl, or phenyl radicals, or Z22 represents a radical of formula 2499X2 represents a linear or branched (C1-C10)alkyl, alkynyl, —(CH2)m—W—(CH2)q—Z23 or —(CH2)p—U—Z24 radical in which W represents SO2, U represents a covalent bond, Z23 represents an aryl radical; Z24 represents cyclohexenyl, bis-phenyl, (C3-C7)cycloalkyl optionally substituted by an aminoalkyl, or aryl or heteroaryl radical optionally substituted by one or more radicals chosen from fluoro, chloro, bromo, iodo, alkyl, alkoxy, —CF3, —OCF3, SCF3, hydroxy, —O—C(O)-alkyl, mono- or di-alkylamino, amino or Z24 represents a radical of formula 2500or X2 represents 2501X3 represents a —(CH2)pZ25 radical in which Z25 represents an aryl radical optionally substituted by one or more identical or different radicals chosen from alkoxy and CF3,
19. Use of compounds of general formula Ia according to any of claims 15 to 18 in which R3a represents the hydrogen atom, an alkyl, alkenyl, heteroarylalkyl radical optionally substituted or a radical of formula —C(Y)—NHX1, —C(O)X2 or SO2X3 in which X1 represents a —(CH2)pZ22 radical in which Z22 represents an aryl radical optionally substituted by one or more radicals chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, phenoxy radicals; X2 represents the vinyl radical substituted by a phenyl, the phenyl radical being itself optionally substituted by one or more halo, or —(CH2)p—U—Z24 radicals in which Z24 represents alkyl, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl, bis-phenyl, amino, mono or di-alkylamino, or aryl or heteroaryl optionally substituted by one or more radicals chosen from alkoxy, bromo, chloro, fluoro, hydroxy, CF3, nitro, amino, mono- and di-alkylamino, pyrrolyl, or X2 represents a radical of formula 2502X3 represents a linear or branched (C1-C10)alkyl radical, the vinyl radical substituted by a radical (the phenyl radical being itself optionally substituted), CF3, or —(CH2)pZ25 in which Z25 represents aryl or heteroaryl optionally substituted by one or more substituents chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, —NH-C(O)-alkyl, mono- and di-alkylamino radicals.
20. Use of compounds of general formula Ia according to any of claims 15 to 19 in which R1a represents a linear or branched (C1-C6)alkyl radical, the —(CH2)m—Y—Z11 or —(CH2)m—Z12 radical in which Z11 represents a (C1-C6)alkyl, Z12 represents naphthyl, morpholino, bis-phenyl, pyrrolidinyl substituted by the oxy radical, or the phenyl, piperazinyl, pyridinyl and indolyl radicals which are optionally substituted by one or more substituents chosen independently from the bromo, fluoro, chloro, alkyl, alkoxy, —CF3, —OCF3 radicals; or Z12 represents 2503Y represents the oxygen atom, or R1a represents a radical of formula given below: 2504
21. Use of compounds of general formula Ia according to any of claims 15 to 20 in which R2a represents a radical of formula —C(Y)NHX1, —C(O)X2 or SO2X3 in which X1 represents a linear or branched (C1-C10)alkyl, or —(CH2)pZ22 radical in which Z22 represents cyclohexyl, cyclohexenyl, bis-phenyl, morpholino, piperidino, mono- or di-alkylamino, —C(O)—O-alkyl, or phenyl, naphthyl or furyl optionally substituted by one or more radicals chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, CF3, OCF3, nitro, cyano, azido, piperidinosulphonyl, —C(O)—O-alkyl, —C(O)-alkyl or phenyl radicals, or Z22 represents a radical of formula 2505X2 represents an alkyl, alkynyl, —(CH2)m—W—(CH2)q—Z23 or —(CH2)pZ24 radical in which W represents SO2; Z23 represents the phenyl radical; Z24 represents cyclohexenyl, bis-phenyl, cyclohexyl optionally substituted by an aminoalkyl, or phenyl, naphthyl, benzothienyl, thienyl or indolyl radical optionally substituted by one or more radicals chosen from fluoro, chloro, bromo, iodo, alkyl, alkoxy, —CF3, —OCF3, SCF3, hydroxy, —O—C(O)-alkyl, —NH—C(O)-alkyl, mono- or di-alkylamino, amino, or Z24 represents a radical of formula 2506or X2 represents 2507X3 represents a —(CH2)pZ25 radical in which Z25 represents the phenyl radical optionally substituted by one or more identical or different radicals chosen from alkoxy and CF3,
22. Use of compounds of general formula Ia according to any of claims 15 to 21 in which R3a represents the hydrogen atom, an alkyl, alkenyl or furyl-methyl radical substituted by one or more nitro radicals, or a radical of formula —C(Y)—NHX1, —C(O)X2 or SO2X3 in which X1 represents a —(CH2)pZ22 radical in which Z22 represents the phenyl or naphthyl radical optionally substituted by one or more radicals chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, phenoxy radicals, X2 represents the vinyl radical substituted by a phenyl radical itself optionally substituted by one or more halo, or —(CH2)p—U—Z24 radicals in which Z24 represents alkyl, cyclohexyl, tetrahydrofuryl, bis-phenyl, amino, mono or di-alkylamino, or phenyl, indolyl, thienyl, pyridinyl, benzothienyl and furyl optionally substituted by one or more radicals chosen from alkoxy, bromo, chloro, fluoro, amino, mono- and di-alkylamino, nitro, hydroxy, pyrrolyl or X2 represents a radical of formula 2508X3 represents a linear or branched (C1-C10)alkyl radical, the vinyl radical substituted by a phenyl, CF3, or —(CH2)pZ25 radical in which Z25 represents a phenyl, naphthyl, thienyl, pyrazolyl or thiazolyl radical optionally substituted by one or more substituents chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, —NH—C(O)-alkyl, mono- and di-alkylamino radicals;
23. Use of compounds of general formula Ia according to any of claims 15 to 22 in which R1a represents the —(CH2)mZ12 radical in which m=2 and Z12 represents bis-phenyl or the radical indolyl substituted by one or more substituents chosen independently from the alkyl and alkoxy radicals.
24. Use of compounds of general formula Ia according to any of claims 15 to 23 in which R2a represents the radicals of formula —C(Y)NHX, and —C(O)X2 in which Y represents S; X1 represents a phenyl radical optionally substituted by one or more azido radicals, X2 represents —(CH2)pZ24 in which p is equal to 1, 2 or 3, Z24 represents cyclohexyl, or phenyl or benzothienyl optionally substituted by one or more radicals chosen from fluoro, chloro, bromo, iodo or —CF3.
25. Use of compounds of general formula Ia according to any of claims 15 to 24 in which R3a represents the hydrogen atom or the methyl radical.
26. Use according to claims 15 to 25 for the preparation of a medicament intended to treat acromegalia, hypophyseal adenomas or endocrine gastroenteropancreatic tumors including carcinoid syndrome.

Priority Claims (1)

Number	Date	Country	Kind
99/15724	Dec 1999	FR

PCT Information

Filing Document	Filing Date	Country	Kind
PCT/FR00/03497	12/13/2000	WO

4-Aminopiperidine and their use as a medicine

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CPC

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Abstract

Description

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Priority Claims (1)

PCT Information