# Patent

## Title
4-aminopiperidine and their use as a medicine

## Abstract

A subject of the present application is new derivatives of 4-aminopiperidines of formula 




in which R1, R2 and R3 represent various radical, 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.

## Background
This application is a 371 of PCT/FR00/03497 filed Dec. 13, 2000.
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.
Somatostatin (SST) is a cyclic tetradecapeptide which was isolated for the first time from the hypothalamus as a substance which inhibits the growth hormone (Brazeau P. et al., Science 1973, 179, 77-79). It also operates as a neurotransmitter in the brain (Reisine T. et al., Neuroscience 1995, 67, 777-790; Reisine T. et al., Endocrinology 1995, 16, 427-442). Molecular cloning has allowed it to be shown that the bioactivity of somatostatin depends directly on a family of five receptors linked to the membrane.
The heterogeneity of the biological functions of somatostatin has led to studies which try to identify the structure-activity relationships of peptide analogues on somatostatin receptors, which has led to the discovery of 5 sub-types of receptors (Yamada et al., Proc. Natl. Acad. Sci. U.S.A, 89, 251-255, 1992; Raynor, K. et al, Mol. Pharmacol., 44, 385-392, 1993). The functional roles of these receptors are currently being actively studied. The affinities with different sub-types of somatostatin receptors have been associated with the treatment of the following disorders/diseases. Activation of sub-types 2 and 5 has been associated with suppression of the growth hormone (GH) and more particularly with that of adenomas secreting GH (acromegalia) and those secreting hormone TSH. Activation of sub-type 2 but not sub-type 5 has been associated with the treatment of adenomas secreting prolactin. Other indications associated with the activation of sub-types of somatostatin receptors are the recurrence of stenosis, inhibition of the secretion of insulin and/or of glucagon and in particular diabetes mellitus, hyperlipidemia, insensiblity to insulin, Syndrome X, angiopathy, proliferative retinopathy, Dawn phenomenon and nephropathy; inhibition of the secretion of gastric acid and in particular peptic ulcers, enterocutaneous and pancreaticocutaneous fistulae, irritable colon syndrome, dumping syndrome, aqueous diarrhea syndrome, diarrhea associated with AIDS, diarrhea induced by chemotherapy, acute or chronic pancreatitis and secretory gastrointestinal tumors; the treatment of cancer such as hepatomas; the inhibition of angiogenesis, the treatment of inflammatory disorders such as arthritis; chronic rejection of allografts; angioplasty; the prevention of bleeding of grafted vessels and gastrointestinal bleeding. The agonists of somatostatin can also be used to reduce the weight of a patient.
Among the pathological disorders associated with somatostatin (Moreau J. P. et al., Life Sciences 1987, 40, 419; Harris A. G. et al., The European Journal of Medicine, 1993, 2, 97-105), there can be mentioned for example: acromegalia, hypophyseal adenomas, Cushing's disease, gonadotrophinomas and prolactinomas, catabolic side-effects of glucocorticoids, insulin dependent diabetes, diabetic retinopathy, diabetic nephropathy, hyperthyroidism, gigantism, endocrinic gastroenteropancreatic tumors including carcinoid syndrome, VIPoma, insulinoma, nesidioblastoma, hyperinsulinemia, glucagonoma, gastrinoma and Zollinger-Ellison's syndrome, GRFoma as well as acute bleeding of the esophageal varices, gastroesophageal reflux, gastroduodenal reflux, pancreatitis, enterocutaneous and pancreatic fistulae but also diarrheas, refractory diarrheas of acquired immunodeficiency syndrome, chronic secretary diarrhea, diarrhea associated with irritable bowel syndrome, disorders linked with gastrin releasing peptide, secondary pathologies with intestinal grafts, portal hypertension as well as hemorrhages of the varices in patients with cirrhosis, gastro-intestinal hemorrhage, hemorrhage of the gastroduodenal ulcer, Crohn's disease, systemic scleroses, dumping syndrome, small intestine syndrome, hypotension, scleroderma and medullar thyroid carcinoma, illnesses linked with cell hyperproliferation such as cancers and more particularly breast cancer, prostate cancer, thyroid cancer as well as pancreatic cancer and colorectal cancer, fibroses and more particularly fibrosis of the kidney, fibrosis of the liver, fibrosis of the lung, fibrosis of the skin, also fibrosis of the central nervous system as well as that of the nose and fibrosis induced by chemotherapy, and other therapeutic fields such as, for example, cephaleas including cephalea associated with hypophyseal tumors, pain, panic attacks, chemotherapy, cicatrization of wounds, renal insufficiency resulting from delayed development, obesity and delayed development linked with obesity, delayed uterine development, dysplasia of the skeleton, Noonan's syndrome, sleep apnea syndrome, Graves' disease, polycystic disease of the ovaries, pancreatic pseudocysts and ascites, leukemia, meningioma, cancerous cachexia, inhibition of H pylori, psoriasis, as well as Alzheimer's disease. Osteoporisis can also be mentioned.
The 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.
Therefore a subject of the present invention is the compounds of general formula 




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

    R1 represents a linear or branched (C1-C16)alkyl, alkenyl, alkynyl, —(CH2)m—Y-Z11 or —(CH2)m-Z12 radical in which
    
        Z11 represents a (C1-C6)alkyl or aryl optionally substituted,
        Z12 represents cyano, cyclohexenyl, bis-phenyl, (C3-C7)cycloalkyl, optionally substituted (C3-C7) heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl,
        or Z12 represents a radical of formula 




or R1 represents a radical of formula 




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




    X1 represents a linear or branched (C1-C15)alkyl, alkenyl, alkynyl, —(CH2)m—Y-Z21 or —(CH2)pZ22 radical in which
    
        Z21 represents a (C1-C6)alkyl
        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,
        or Z22 represents a radical of formula 




    
    
    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
    
        Z23 represents a (C1-C6)alkyl or aryl optionally substituted;
        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,
        or Z24 represents a radical of formula 




or X2 represents a radical represented below: 




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

    
    
    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
    
        Z25 represents aryl or heteroaryl optionally substituted,

or X3 represents a radical of formula 




Optionally substituted by one or more halo radicals identical or different;

    
    
    Y represents an oxygen or sulphur atom;
    W represents an oxygen or sulphur atom, or SO2;
    U represents a covalent bond or the oxygen atom;
    n is an integer from 0 to 4;
    m is an integer from 1 to 6;
    p is an integer from 0 to 6;
    q is an integer from 0 to 2,
    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.


A more particularly subject of the invention is the products of general formula I as defined above, 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.


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.
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.
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.
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.
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.
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.
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.
A more particular subject of the present invention is the compounds of general formula I as defined above 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 




        Y represents the oxygen atom,

or R1 represents a radical of formula 




    
    
    R2 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 




        
        
        X2 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 




        
        
        or X2 represents 




        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,
    
    
    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 




        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
        
            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.
        
        
    
    


Preferentially, 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 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;
        or Z12 represents 




        Y represents the oxygen atom,

or R1 represents a radical of formula given below: 




    
    


Preferentially, 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 




        
        
        X2 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 




or X2 represents 




        
        
        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,
    
    


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

    
    
        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 




        X3 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;
        
        
    
    


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.
Very preferentially, 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.
        
        
    
    


Very preferentially, R3 represents the hydrogen atom or the methyl radical.
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
It is carried out according to the following stage: 




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

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




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




A2) Functionalization of Piperidines

A2a) Syntheses of Ureas and Thioureas

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: 




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.

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





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.
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).
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: 










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: 
















A2b) Synthesis of Amides from Carboxylic Acids

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




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.

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





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
















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

A3) Syntheses of 4-aminodisubstituted Piperidines

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: 




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





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.
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).
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) Syntheses in Solid Phase of 4-aminopiperidines
4-aminopiperidines were prepared by synthesis in solid phase starting with Wang resin.
B1) Preparation of the Resin
B1a) Preparation of the p-nitrophenyl Carbonate Wang Resin
It is carried out according to the following diagram 




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.
B1b) Preparation of the Piperidone Carbamate Resin
It is carried out according to the following diagram 




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
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, 6.7 g (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
It is carried out according to the diagram 




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).

Preparation 3 




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
B3a) Functionalization with Isocyanates or Isothiocyanates
It is carried out according to the diagram 




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





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.
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).
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: 



















The X1 radicals which can be envisaged are those illustrated in point A above.
B3b) Functionalization with Sulphonyl Chlorides
It is carried out according to the following diagram 




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





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.
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).
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: 










B3c) Functionalization with Acid Chlorides

It is carried out according to the following diagram 




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





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%).
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).
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. 
















B3d) Functionalization with Carboxylic Acids

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: 




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





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%).
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).
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 
It is carried out according to the diagram 




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





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.
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).
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
It is carried out according to the following diagram 




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





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.
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).
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
It is carried out according to the following diagram 




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





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.
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).
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
It is carried out starting from vinyl sulphone resin (Kroll, F. E. K.; Morphy, R.; Rees, D.: Gani. 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
It is carried out according to the following diagram: 




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
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
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: 




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.

Preparation 5 




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
D3a) Functionalization with Isocyanates 




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.

Preparation 6 




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.
D3b) Functionalization with Sulphonyl Chlorides
The Functionalization operating method is identical to that stated in point B3b.
D3c) Functionalization with Acid Chlorides
The functionalization operating method is identical to that stated in point B3c.
D3d) Functionalization with Carboxylic Acids
The functionalization operating method is identical to that stated in point B3d.
D4) Cleavage Stage
The cleavage stage described below is valid whatever the functionalization carried out beforehand on the secondary amine: 




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





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.
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).
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: 













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.
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 the reducing amination of the following N-substituted piperidone 




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 




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 above, in order to obtain a compound of formula (2) 




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 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;

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




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,

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.



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

the reducing amination of the ketonic resin 




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) 




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 above, in order to obtain a compound of formula (5) 




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 above, in order to obtain a compound of formula (6) 




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 above, in order to obtain a compound of formula (7) 




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 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.


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

the reducing amination of the ketonic resin 




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) 




which compound of formula (8) is reacted with

    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) 




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);

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




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);

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




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);

    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,

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).



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.
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.
An illustration of the pharmacological properties of the compounds of the invention will be found hereafter in the experimental part.
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.
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.
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.
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.
A subject of the present invention is also the use of compounds of general formula Ia 




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

    R1a represents a linear or branched (C1-C16)alkyl, alkenyl, alkynyl, —(CH2)m—Y-Z11 or —(CH2)m-Z12 radical in which
    
        Z11 represents a (C1-C6)alkyl or aryl optionally substituted,
        Z12 represents cyano, cyclohexenyl, bis-phenyl, (C3-C7)cycloalkyl, optionally substituted (C3-C7) heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl,
        or Z12 represents a radical of formula 




or R1a represents a radical of formula 




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




    X1 represents a linear or branched (C1-C15)alkyl, alkenyl, alkynyl, —(CH2)m—Y-Z21 or —(CH2)pZ22 radical in which
    
        Z21 represents a (C1-C6)alkyl
        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,
        or Z22 represents a radical of formula 




    
    
    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
    
        Z23 represents a (C1-C6)alkyl or aryl optionally substituted;
        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,
        or Z24 represents a radical of formula 




or X2 represents a radical represented below: 




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

    
    
    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
    
        Z25 represents aryl or heteroaryl optionally substituted,

or X3 represents a radical of formula 




optionally substituted by one or more halo radicals identical or different;

    
    
    Y represents an oxygen or sulphur atom;
    W represents an oxygen or sulphur atom, or SO2;
    U represents a covalent bond or the oxygen atom;
    n is an integer from 0 to 4;
    m is an integer from 1 to 6;
    p is an integer from 0 to 6;
    q is an integer from 0 to 2,

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.



A more particulary subject of the invention is the use of products of general formula Ia as defined above, 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.


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

    
    
        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 




        Y represents the oxygen atom,

or R1a represents a radical of formula 




    
    


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

    
    
        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 




        
        
        X2 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 




        
        
        or X2 represents 




        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.
    
    


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

    
    
        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 




        
        
        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
        
            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.
        
        
    
    


Preferentially, 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 




        Y represents the oxygen atom,

or R1a represents a radical of formula given below: 




    
    


Preferentially, 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 




        
        
        X2 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 




        
        
        or X2 represents 




        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,
    
    


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

    
    
        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 




        X3 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, 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;
        
        
    
    


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.
Very preferentially, R2a 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.
        
        
    
    


Very preferentially, R3a represents the hydrogen atom or the methyl radical.
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:
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.
The compounds are characterized by their retention time (rt), expressed in minutes, and their molecular peak (M+H+) determined by mass spectroscopy (MS).
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:
Conditions C1 and C2


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














T (min)
A %
B %

















0
100
0


1
100
0


10
15
85


12
15
85




















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









Conditions C3

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














T (min)
A %
B %

















0
90
10


6
15
85


10
15
85









    Flow rate: 1 ml/min
    Injection: 5 μl
    Column: Uptisphere ODS 3 μm 50*4.6 mm i.d
    Temp: 40° C.
    Wavelength (% UV): 220 nm


The conditions depending on the examples, are as follows:














Examples
Conditions









 1 to 29 
C2



 30 to 263
C1



264 to 425
C3



426 to 456
C2



457 to 503
C3



504 to 586
C1



587 to 778
C3










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
















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





















1















66
7.6
523.3


2















94
7.7
543.2


3















96
8.1
557.2


4















98
8.5
593.2


5















95
7.8
557.2


6















97
8.1
623.1


7















95
8.1
588.2


8















19
8.1
535.2


9















99
8.5
622.2


10















80
8.4
611.2


11















99
8.2
569.2


12















93
8.9
656.2


13















85
9.1
697.0


14















95
8.7
611.2


15















87
7.8
573.2


16















100
8.4
653.2


17















97
8.6
611.1


18















99
8.7
636.3


19















83
7.2
621.2


20















98
7.4
595.2


21















84
7.4
536.3


22















99
8.4
614.3


23















63
8.2
570.2


24















92
7.5
572.3


25















93
8.4
606.4


26















96
7.4
582.3


27















93
8.1
624.2


28















93
7.8
602.2


29















95
7.4
585.2


30















87.39
4.0
516.4


31















92
5.5
560.3


32















90
5.7
563.3


33















87.73
5.6
625.4


34















85.41
6.0
565.4


35















98.4
6.4
671.1


36















86
4.9
542.3


37















89
6.1
572.3


38















77.61
6.8
555.4


39















89.16
4.2
545.4


40















93.32
5.3
599.3


41















83
6.0
589.2


42















36.3
5.9
531.2


43















83.27
5.9
555.3


44















82
4.5
564.4


45















86.75
6.0
577.3


46















91.95
4.7
501.4


47















88.94
4.5
475.3


48















73
5.3
542.3


49















90.96
4.4
486.4


50















95.5
5.9
530.4


51















94.51
6.1
533.4


52















93.64
6.0
595.4


53















96.05
6.5
535.4


54















84.68
6.9
641.1


55















86
5.5
512.3


56















92
6.5
542.4


57















91.29
7.2
525.5


58















94.7
4.7
515.4


59















94
5.8
569.3


60















89.43
6.6
559.3


61















32
6.9
501.5


62















93.53
6.4
525.4


63















94.7
4.9
534.4


64















94.32
6.4
547.3


65















91.71
5.2
471.4


66















92.47
5.0
445.4


67















58
5.9
512.3


68















84.55
3.6
559.4


69















87.7
4.7
603.4


70















90.77
4.8
606.4


71















72.34
4.8
668.4


72















87.18
5.1
608.4


73















69.52
5.4
714.1


74















63.39
4.2
585.3


75















54.46
5.1
615.4


76















87.3
5.7
598.4


77















96.1
3.8
588.4


78















89.9
4.5
642.3


79















61.5
5.1
632.3


80















43.65
5.0
574.3


81















88.18
5.0
598.3


82















88.6
4.0
607.4


83















90.08
5.1
620.3


84















85.57
4.0
544.3


85















48.41
4.5
585.3


86















82.68
6.1
589.3


87















79.99
6.5
611.4


88















86.07
4.8
503.4


89















82
5.1
551.4


90















19.44
4.4
502.4


91















86.48
5.1
550.4


92















80
6.3
567.3


93















94.62
6.6
559.3


94















57.01
6.9
581.4


95















92
5.2
473.4


96















87.4
5.6
521.4


97















20.99
5.0
472.4


98















88.63
5.7
520.4


99















84
6.7
537.3


100















89.71
5.2
632.2


101















90.25
5.5
654.4


102















90.09
4.0
546.4


103















71
4.4
594.3


104















37.19
3.8
545.3


105















76.55
4.5
593.4


106















69.62
5.9
405.2


107















98
7.1
493.2


108















80
6.0
467.3


109















88
6.5
471.2


110















60.04
5.7
427.3


111















78
6.5
515.2


112















97
6.2
455.2


113















70
5.7
489.3


114















90
6.2
493.3


115















62.88
3.6
305.3


116















82.99
4.7
393.2


117















74.42
5.0
393.1


118















10.53
5.4
367.3


119















74.79
4.3
371.2


120















50.14
3.4
327.3


121















70
4.3
415.2


122















84
3.9
355.3


123















66
3.5
389.3


124















94.61
3.9
393.2


125















71
5.5
462.3


126















52
6.6
550.2


127















57
6.8
550.1


128















60
5.6
524.2


129















64
6.1
528.2

























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





















130















27
5.4
484.3


131















51
6.2
572.2


132















73
5.7
512.2


133















61
5.4
546.2


134















43
5.8
550.2


135















76
5.3
483.3


136















49
6.4
571.2


137















63
6.6
571.1


138















79
5.4
545.2


139















57
5.9
549.2


140















66.58
5.2
505.3


141















61
6.0
593.2


142















67
5.5
533.2


143















61
5.2
567.3


144















51
5.6
571.2


145















56
7.0
457.3


146















64
8.1
545.2


147















52
8.3
545.2


148















69
7.1
519.3


149















70
7.6
523.3


150















63.77
6.7
479.4


151















50
7.3
567.3


152















46
7.3
507.3


153















78
6.7
541.3


154















66
7.0
545.3


155















68
6.0
457.2


156















65
7.1
545.2


157















67
7.3
545.1


158















66
6.1
519.2


159















77
6.6
523.2


160















60.49
5.8
479.3


161















60
6.6
567.3


162















69
6.2
507.2


163















50
5.8
541.2


164















49
6.2
545.2


165















67
4.4
466.3


166















45
5.5
554.2


167















65.89
5.7
554.1


168















5
5.4
528.2


169















64.08
5.0
532.2


170















62.51
4.3
488.3


171















55
5.2
576.3


172















50.35
4.7
516.3


173















7
5.2
550.3


174















48.63
4.8
554.3


175















53
5.7
459.2


176















49
6.9
547.2


177















61
7.1
547.1


178















57
5.9
521.2


179















65
6.4
525.2


180















88.99
5.6
481.3


181















58
6.4
569.2


182















64
6.0
509.2


183















63
6.0
547.2


184















67.83
10.1
516.3


185















61.66
6.7
525.3


186















40.48
9.9
537.3


187















50
6.4
546.3


188















42.57
7.4
478.4


189















29
4.8
487.3


190















55
10.3
499.3


191















19.39
6.7
508.3


192















67
11.1
567.3


193















64.73
7.9
576.3


194















92
10.6
586.3


195















85
7.3
595.3


196















96
10.5
607.3


197















89.25
7.2
616.3


198















98.24
7.9
548.3


199















94
5.6
557.3


200















98
10.8
569.2


201















93.17
7.3
578.2


202















97.82
11.7
637.3


203















88.11
8.5
646.3


204















73
11.2
690.0


205















60.44
7.9
699.0


206















76
11.1
711.0


207















72.2
7.8
720.0


208















89.42
8.5
652


209















48
6.2
659.0


210















78.2
11.6
673.0


211















66.1
7.9
682.0


212















78
12.6
739.1


213















88.77
9.1
750.0


214















73
10.6
604.3


215















67
7.5
613.2


216















73
10.5
625.3


217















83
7.3
634.2


218















87.32
7.9
566.3


219















79
5.7
575.2


220















89
10.7
587.2


221















78.75
7.4
596.2


222















95
11.6
655.3


223















79
8.6
664.3


224















58
9.4
614.2


225















78
6.4
623.2


226















75
9.2
635.3


227















88
6.1
644.3


228















86
6.7
576.3


229















80
4.6
585.2


230















73
9.5
597.2


231















66
6.2
606.2


232















62
10.5
665.3


233















81
7.5
674.3


234















92
8.9
540.3


235















86
5.6
549.2


236















91
8.7
561.3


237















94.51
5.4
570.2


238















93.36
6.2
502.3


239















97
3.8
511.3


240















98.13
9.0
523.3


241















82
5.4
532.2


242















99
10.1
591.3


243















94.74
6.8
600.3


244















89
9.8
596.3


245















81
6.6
605.3


246















96
9.7
617.3


247















85.68
6.4
626.3


248















98.65
7.1
558.3


249















92
4.8
567.2


250















96
10.0
579.2


251















88.12
6.5
588.2

























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





















252















97
10.9
647.3


253















86
7.8
656.3


254















79
10.1
572.2


255















79
7.0
581.2


256















71
10.0
593.3


257















72.74
6.6
602.2


258















79.1
7.4
534.3


259















74
4.9
543.2


260















84.17
10.3
555.2


261















76.16
6.7
564.2


262















95
11.1
623.3


263















78.91
8.0
632.3


264















75.26
5.1
430.2


265















90.43
5.0
430.3


266















74.93
4.3
452.3


267















79.62
4.9
390.3


268















92.82
5.6
490.4


269















68.87
3.6
421.3


270















79.07
4.9
440.2


271















84.22
3.0
392.3


272















67.34
4.9
418.2


273















81.63
4.4
352.3


274















90.11
4.7
342.3


275















54.36
4.3
438.3


276















81.69
4.9
432.2


277















85.62
5.2
382.3


278















86.19
3.2
377.3


279















94.76
4.9
451.2


280















99.42
4.7
451.3


281















90.55
4.0
473.3


282















93.80
4.6
411.3


283















82.71
5.4
511.4


284















90.85
3.4
442.3


285















98.65
4.6
461.2


286















98.80
2.8
404.3


287















86.02
4.6
439.3


288















97.47
4.1
373.3


289















99.31
4.4
363.3


290















45.77
4.1
459.3


291















94.07
4.6
453.3


292















95.65
5.0
403.4


293















94.30
2.9
398.3


294















80.64
5.9
481.2


295















98.05
5.7
481.3


296















94.93
5.0
503.4


297















96.81
5.6
441.3


298















95.00
6.3
541.4


299















95.13
4.2
472.4


300















52.68
3.2
452.4


301















98.03
5.6
491.2


302















96.44
3.7
217.9


303















97.22
5.6
469.3


304















96.97
5.2
403.3


305















99.05
5.4
393.4


306















32.67
5.1
489.3


307















84.51
5.6
483.3


308















98.44
6.0
433.4


309















97.78
4.0
428.3


310















79.54
5.0
460.2


311















78.59
4.9
460.3


312















66.24
4.2
482.3


313















70.15
4.8
420.3


314















57.87
5.5
520.4


315















71.26
3.6
451.3


316















81.16
4.8
470.2


317















74.96
2.9
413.3


318















53.47
4.8
448.3


319















87.88
4.3
382.3


320















91.41
4.6
372.3


321















1.59
5.0
468.3


322















77.81
4.8
462.3


323















76.59
5.1
412.3


324















83.35
3.1
407.3


325















87.42
5.2
444.2


326















98.89
5.1
444.3


327















95.68
4.3
466.3


328















97.27
4.9
404.3


329















95.73
5.7
504.4


330















83.37
3.7
435.3


331















71.88
3.2
413.3


332















98.33
5.0
454.2


333















83.73
3.0
397.3


334















94.77
5.0
432.3


335















95.88
4.5
366.3


336















98.9
4.7
356.3


337















50.74
4.4
452.3


338















95.39
5.0
446.3


339















98.2
5.3
396.3


340















92.35
3.2
391.3


341















90.41
5.1
444.2


342















87.41
5.0
444.3


343















87.37
4.3
466.3


344















83.01
4.9
404.3


345















89.47
5.6
504.4


346















77.55
3.6
435.3


347















49.49
2.4
414.3


348















85.63
4.9
454.2


349















88.12
2.9
397.3


350















87.73
4.9
432.3


351















84.48
4.4
366.3


352















82.03
4.7
356.3


353















82.93
4.9
446.3


354















72.6
5.3
396.3


355















86.75
3.2
391.3


356















93.75
4.7
413.1


357















96.13
4.6
413.2


358















98.3
3.8
435.2


359















96.45
4.5
373.2


360















97.9
5.3
473.4


361















97.57
3.0
404.3


362















78.0
2.5
383.2


363















98.96
4.5
423.1


364















93.98
2.4
366.3


365















97.98
4.5
401.2


366















93.33
4.0
335.2


367















95.73
4.3
325.3


368















1.21
3.9
421.3

























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





















369















88.55
4.6
415.2


370















95.93
4.9
365.3


371















99.1
2.6
360.2


372















90.59
3.4
392.1


373















93.57
3.3
392.2


374















97.23
2.6
414.2


375















93.83
3.1
352.3


376















96.81
4.0
452.4


377















97.7
2.2
383.3


378















53.69
2.3
362.2


379















97.2
3.1
402.1


380















70.3
2.5
345.3


381















97.59
3.1
380.2


382















86.74
2.4
314.2


383















87.28
2.6
304.3


384















10.27
3.1
400.2


385















93.38
3.1
394.2


386















88.99
3.4
344.3


387















89.43
2.5
339.3


388















86.18
4.2
458.3


389















37.01
3.9
404.3


390















57.02
2.7
437.4


391















78.70
4.3
441.3


392















67.94
4.6
490.3


393















39.75
4.5
479.3


394















94.48
2.8
435.4


395















83.7
3.4
432.3


396















96.5
4.7
464.4


397















43.75
4.5
547.3


398















86.87
3.3
399.3


399















47.77
2.9
345.3


400















82
3.4
382.3


401















97.10
3.8
431.2


402















76.92
3.8
420.2


403















97.3
2.8
373.3


404















95.9
4.0
405.3


405















69.50
3.7
488.3


406















90.79
4.1
420.3


407















86.38
2.5
399.3


408















67.52
4.6
452.2


409















99.8
2.7
397.3


410















97.7
3.3
394.3


411















87.97
5.0
488.3


412















97.23
3.6
467.4


413















99.29
3.7
465.4


414















96.2
4.2
462.4


415















72.0
5.5
494.3


416















85.09
4.3
467.3


417















68.52
4.1
413.3


418















98.76
2.8
446.4


419















73.21
4.4
450.3


420















76.94
4.7
499.2


421















85.12
4.6
488.2


422















98.15
2.9
444.4


423















58
5.1
477.3


424















25
3.6
410.3


425















69.90
4.6
556.3


426















90.11
8.2
556.3


427















95.30
9.7
552.3


428















89.35
9.6
573.3


429















97.48
11.8
547.4


430















91.35
9.6
591.3


431















66.60
9.7
557.3


432















97.25
10.5
547.3


433















98.20
10.2
549.3


434















88.28
4.7
489.3


435















94.30
5.8
485.3


436















92.92
5.6
506.3


437















95.73
7.1
480.4


438















89.80
5.6
524.3


439















69.38
5.6
490.3


440















95.21
6.2
480.3


441















96.98
6.0
482.3


442















85.00
5.4
456.3


443















94.40
6.5
452.3


444















91.10
6.3
473.3


445















96.60
7.7
447.3


446















92.80
6.3
491.2


447















85.40
6.3
457.2


448















96.70
6.9
447.2


449















98
6.7
449.2


450















38.17
3.6
385.2


451















92.70
3.4
406.2


452















89.50
4.7
380.3


453















86.24
3.4
424.2


454















71.20
3.3
390.2


455















88.60
3.8
380.2


456















89.26
3.5
382.2


457















96.55
4.9
445.3


458















94.46
4.8
455.2


459















95.6
4.7
411.3


460















98.1
5.0
461.3


461















93.31
5.1
419.4


462















97.08
4.2
402.3


463















94.61
4.4
395.3


464















97.05
4.9
503.2


465















95.13
5.1
453.4


466















93.21
4.8
475.3


467















94.08
4.7
485.2


468















93.08
4.6
441.3


469















95.17
4.9
491.3


470















89.99
5.0
449.4


471















92
4.1
432.3


472















94.71
4.3
425.3


473















95.3
4.8
533.2


474















94.13
5.0
483.4


475















95
5.1
459.3


476















94.69
5.0
469.2


477















94.44
4.9
425.3


478















98
5.2
475.3


479















96.2
5.3
433.4


480















93
4.4
416.3


481















94.59
4.6
409.3


482















95.22
5.1
517.2


483















95.7
5.3
467.4


484















94.8
4.6
457.2


485















86.7
4.5
420.3


486















88.5
4.8
447.3


487















96.9
5.1
483.4


488















92.3
4.7
505.2


489















65.4
4.9
471.2


490















62.6
4.7
434.3


491















57.9
5.0
461.3


492















94.2
5.3
497.4


493















54.0
5.0
519.2


494















54.6
4.8
501.3

























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





















495















64.9
4.7
464.3


496















70.4
4.9
491.3


497















96.5
5.2
527.4


498















55.7
4.9
549.2


499















57.4
5.1
485.3


500















59.3
4.9
448.4


501















53.6
5.2
475.3


502















97.8
5.4
511.4


503















10 + 36.87
5.2
533.2


504















96.33
11.2
646.3


505















92.67
9.4
690.1


506















41.11
9.5
656.2


507















97.65
10.1
646.2


508















96.29
9.9
648.2


509















90.89
8.5
501.3


510















61.04
5.8
401.2


511















99.16
10.5
496.4


512















95.73
7.1
396.3


513















66
9.3
496.3


514















95.00
8.9
396.2


515















96.61
9.5
530.3


516















94.05
6.4
430.3


517















87
8.6
536.3


518















91.59
5.6
436.3


519















86.84
8.4
522.3


520















94.18
5.4
422.3


521















99.75
10.4
517.4


522















96.8
6.8
417.4


523















70.34
9.1
517.3


524















93.49
5.8
417.3


525















93.03
9.3
551.3


526















97.13
6.1
451.3


527















74.37
8.4
557.3


528















92.92
5.3
457.3


529















92.92
8.8
484.3


530















92.68
5.5
384.2


531















98.29
10.8
479.3


532















96.39
7.0
379.3


533















99
9.5
479.2


534















99.76
6.0
379.2


535















99.17
9.7
513.2


536















99.74
6.3
413.2


537















68.71
8.7
519.3


538















90.09
5.4
419.3


539















91.37
9.8
552.3


540















95.39
6.6
452.3


541















98.71
11.7
547.4


542















99.02
7.9
447.4


543















79.38
10.5
547.3


544















95.46
7.1
447.3


545















95.3
10.6
581.3


546















95.45
7.3
481.3


547















80.92
9.8
587.3


548















92.06
6.5
487.3


549















63
7.7
529.4


550















79
7.1
495.4


551















70
6.7
529.3


552















77
6.3
495.3


553















61
6.9
563.3


554















69
6.5
529.3


555















69
6.1
569.3


556















76
5.8
535.3


557















79
5.9
555.3


558















88
5.6
521.3


559















90.81
7.4
550.4


560















95.6
6.9
516.4


561















80.85
6.4
550.3


562









 





85.8
6.0
516.3


563















92.92
6.6
584.3


564















97.26
6.3
550.3


565















82.91
5.8
590.3


566















87.77
5.5
556.3


567















86
6.0
517.3


568















83.41
5.7
483.3


569















95
7.6
512.3


570















94.08
7.1
478.4


571















87.39
6.5
512.3


572















90.06
6.1
478.3


573















85.61
6.8
546.2


574















83.51
6.4
512.3


575















78.63
5.9
552.3


576















79.58
5.6
518.3


577















84
7.1
585.3


578















91
6.7
551.3


579















89.59
8.6
580.4


580















97.13
7.9
546.4


581















83
7.6
580.3


582















92.05
7.1
546.3


583















86
7.8
614.3


584















95.49
7.3
580.3


585















77
7.0
620.3


586















91.1
6.6
586.4


587















95
4.6
435


588















90
4.4
391.3


589















88
5.1
435.3


590















92
4.9
447.3


591















20.32
5.1
399.4


592















85
5.3
486.3


593















97
5.1
442.3


594















92
5.7
486.4


595















79
5.5
498.3


596















93.4
4.68
451.29


597















94.9
4.86
425.27


598















97.9
5.37
475.22


599















97.1
5.20
457.32


600















95.1
5.10
441.24


601















91.1
4.61
481.29


602















97.5
4.78
455.29


603















98.0
5.28
505.22


604















95.4
5.12
487.33


605















94.0
5.03
471.27


606















89.8
4.86
465.29


607















98.2
5.03
439.29


608















97.6
5.53
489.24


609















93.3
5.36
471.34


610















91.4
5.27
455.26


611















94
4.9
459.3


612















92.95
4.8
469.2


613















91.61
4.7
425.3


614















92
5.0
475.3


615















85.2
5.1
433.4


616















83
4.2
416.3


617















94.11
4.4
409.3


618















93.85
5.0
517.2


619















92.74
5.1
467.4


620















91
4.8
489.3


621















91.9
4.7
499.3


622















89.71
4.6
455.3


623















90
4.9
505.3


624















83.96
5.0
463.4


625















87
4.1
446.3


626















93.1
4.3
439.3


627















93.21
4.8
547.2

























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





















628















90.67
5.0
497.4


629















79.6
4.9
485.2


630















72.8
4.8
448.3


631















78.7
5.1
475.3


632















97.3
5.4
511.4


633















51.5
5.1
533.2


634















76.1
4.9
515.3


635















74.2
4.7
478.3


636















76.5
5.0
505.3


637















97.7
5.3
541.4


638















71.4
5.0
563.2


639















82.54
4.4
451.3


640















93.42
4.2
397.3


641















98.93
2.9
430.4


642















81.46
4.5
434.3


643















96.41
4.9
483.3


644















91.55
4.7
472.3


645















97.96
2.9
428.4


646















96.9
5.0
425.3


647















95.8
4.9
457.3


648















91.41
4.6
540.3


649















88.0
4.75
465.3


650















99.0
4.89
439.3


651















98.5
5.42
489.2


652















93.3
5.24
471.3


653















87.6
5.14
455.3


654















88.3
4.66
495.3


655















98.1
4.82
469.3


656















98.4
5.34
519.2


657















95.4
5.16
501.3


658















89.8
5.08
485.3


659















80.76
4.84
410.2


660















61.69
4.97
426.2


661















90.93
4.79
454.1


662















91.55
4.58
394.2


663















91.99
4.88
454.1


664















92.79
5.55
526.2


665















93.78
5.02
502.1


666















96.3
4.75
408.2


667















81.2
5.02
408.2


668















90.79
4.74
440.2


669















78.93
4.88
456.3


670















91.87
4.69
484.2


671















91.19
4.51
424.2


672















95.27
4.79
484.2


673















89.5
5.46
542.2


674















90.77
4.92
532.1


675















95.1
4.66
438.2


676















88.7
4.92
524.2


677















81.65
4.99
424.2


678















70.32
5.11
440.3


679















90.06
4.96
468.2


680















94.11
4.74
408.2


681















93.96
5.04
468.2


682















93.3
5.66
540.2


683















94.79
5.16
516.1


684















96.5
4.9
422.3


685















88.2
5.19
438.2


686















87.93
4.86
424.2


687















84.74
5
440.2


688















95.34
4.82
468.2


689















89.78
4.6
408.2


690















95.16
4.9
468.1633


691















95.6
5.56
540.2


692















95.24
5.05
516.3


693















96.6
4.8
422.2


694















90.4
5.04
438.2


695















93.12
4.78
454.2


696















86.11
4.92
470.3


697















94.89
4.73
498.2


698















94.1
4.54
438.3


699















95.66
4.81
498.2


700















94.8
5.48
570.2


701















93.63
4.96
546.1


702















96.7
4.7
452.3


703















85.6
4.96
468.2


704















78.36
3.14
359.1


705















47.4
3.9
367.1


706















69.72
4.28
385.2


707















34.86
4.96
393.2


708















37.54
4.91
449.2


709















81.57
4.46
483.1


710















55.98
5.12
491.1


711















73.74
3.09
441.2


712















40.19
2.85
449.2


713















90.07
3.18
426.2


714















74.98
3.84
434.2


715















78.14
4.24
397.2


716















39.87
4.92
405.2


717















57.34
4.45
477.2


718















37.75
5.01
485.1


719















70.3
5.2
412.1


720















70.7
5.0
386.1


721















61.9
6.3
600.3


722















49.3
6.1
538.4


723















65.0
5.1
412.2


724















44.3
4.9
386.2


725















49.2
6.2
600.3


726















37.5
6.0
538.4


727















87.1
5.1
468.1


728















84.4
4.9
442.1


729















82.3
6.2
656.3


730















93.8
4.7
406.3


731















80.7
4.6
380.3


732















84.1
5.9
594.3


733















67.9
4.7
462.1


734















66.9
4.6
436.1


735















56.8
5.9
650.2


736















88.1
4.3
400.3


737















82.8
4.1
374.3


738















51.4
5.6
588.3


739















77.7
5.1
446.2


740















76.1
4.9
420.2


741















67.1
6.2
634.3


742















88.9
4.7
384.3


743















79.3
4.5
358.3


744















65.1
5.9
572.4


745















80.0
4.0
398.3


746















76.9
3.8
372.3


747















42.7
5.8
586.4


748















64.6
4.4
483.3


749















87.4
5.3
409.3


750















71.0
5.1
383.3


751















59.8
6.7
597.4


752















84.4
5.6
494.3


753















80.1
3.9
398.3


754















63.1
3.7
372.3


755















64.4
4.3
483.3


756















84.6
5.3
409.3


757















59.6
5.0
383.3


758















52.9
6.6
597.4


759















81.6
5.5
494.3


760















75.3
5.3
465.3


761















60.3
5.1
439.3


762















61.8
6.6
653.4


763















74.4
5.6
550.3


764















74.5
3.6
448.2


765















51.3
3.4
422.2


766















58.8
3.9
533.2


767















86.2
4.8
459.3


768















63.2
4.6
433.3


769















60.1
6.2
647.4


770















83.5
5.1
544.2


771















68.1
4.1
432.3


772















63.8
3.9
406.2


773















41.1
5.8
620.4


774















62.8
4.4
517.2


775















85.5
5.4
443.3


776















62.5
5.2
417.3


777















66.0
6.7
631.4


778















87.7
5.6
528.3









Pharmacological Study

The compounds of the present invention can and have been tested as regards their affinity for different sub-types of somatostatin receptors according to the procedures described below.
Study of the Affinity for the Sub-types of Human Somatostatin Receptors:
The affinity of a compound of the invention for sub-types of human somatostatin receptors 1 to 5 (sst1, sst2, sst3, sst4 and sst5, respectively) is determined by measurement of the inhibition of the bond of [125I-Tyr11]SRIF-14 to transfected CHO-K1 cells.
The gene of the sst1 receptor of human somatostatin has been cloned in the form of a genomic fragment. A segment PstI-XmnI of 1.5 Kb containing 100 bp of the non transcribed 5′ region, 1.17 Kb of the coding region in totality, and 230 bp of the non transcribed 3′ region is modified by the addition of the linker BglII. The resulting DNA fragment is subcloned in the BamHI site of a pCMV-81 in order to produce the expression plasmid in mammals (provided by Dr. Graeme Bell, Univ. Chicago). A cloned cell line expressing in a stable fashion the sst1 receptor is obtained by transfection in CHO-K1 cells (ATCC) using the calcium phosphate co-precipitation method. The plasmid pRSV-neo (ATCC) is included as selection marker. Cloned cell lines were selected in an RPMI 1640 medium containing 0.5 mg/ml of G418 (Gibco), followed by circular cloning and multiplication in culture.
The gene of the sst2 receptor of human somatostatin, isolated in the form of a genomic fragment of DNA of 1.7 Kb BamHI-HindIII and subcloned in a plasmid vector pGEM3Z (Promega), was provided by Dr. G. Bell (Univ. of Chicago). The expression vector of the mammalian cells is constructed by inserting the BamH1-HindII fragment of 1.7 Kb in endonuclease restriction sites compatible with the plasmid pCMV5. A cloned cell line is obtained by transfection in CHO-K1 cells using the calcium phosphate co-precipitation method. The plasmid pRSV-neo is included as selection marker.
The 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.
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.
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.
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.
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.
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).
The specific bond is obtained by subtracting the non-specific bond (determined in the presence of 0.1 μM of SRIF-14) from the total bond. The data relative to the bond are analyzed by computer-aided non-linear regression analysis (MDL) and the values of the inhibition constants (Ki) are determined.
Determination of the agonist or antagonist character of a compound of the present invention is carried out using the test described below.
Functional Test Inhibition of Production of Intracellular cAMP:
CHO-K1 cells expressing the sub-types of human somatostatin receptors (SRIF-14) are cultured in 24-well plates in an RPMI 1640 medium with 10% of foetal calf serum and 0.4 mg/ml of geneticin. The medium is changed the day preceding the experiment.
The cells at a rate of 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.

    the production of cyclic AMP is stimulated by the addition of 1 mM of forskolin (FSK) for 15-30 minutes at approximately 37° C.
    the inhibitory effect of the somatostatin of an agonist compound is measured by the simultaneous addition of FSK (1 μM), SRIF-14 (10−12 M to 10−6 M) and of the compound to be tested (10−10 M to 10−5 M).
    the antagonist effect of a compound is measured by the simultaneous addition of FSK (1 μM), SRIF-14 (1 to 10 nM) and of the compound to be tested (10−10 M to 10−5 M).


The reaction medium is eliminated and 200 ml of 0.1 N HCl are added. The quantity of cAMP is measured by a radioimmunological test (FlashPlate SMP001A kit, New England Nuclear).
Results:
The tests carried out according to the protocols described above have demonstrated that the products of general formula (I) defined in the present Application have a good affinity for at least one of the sub-types of somatostatin receptors, the inhibition constant K1 being lower than micromolar for certain exemplified compounds.

## Claims

1. A compound of the formula 




in racemic, enantiomeric form or all combinations of these forms, wherein
R1 is —(CH2)m-Y-Z11 or 
—(CH2)m-Z12, 
Z11 is (C1-C6)alkyl or optionally substituted aryl, 
Z12 is bis-phenyl optionally substituted aryl or -optionally substituted heteroaryl, 
R2 is selected from the group consisting of —C(Y)NHX1, —C(O)X2 and SO2X3; 

R3 is selected from the group consisting of hydrogen, an optionally substituted alkyl, alkenyl and alkynyl, 
X1 is selected from the group consisting of (C1-C15)alkyl, alkenyl, alkynyl, —(CH2)m-Y-Z21 and —(CH2)pZ22, 
Z21 is (C1-C6)alkyl 
Z22 is selected from the group consisting of cyclohexenyl, indanyl, bis-phenyl, (C3-C7)cycloalkyl and (C3-C7)heterocycloalkyl, aryl and heteroaryl optionally substituted 

X2 is selected from the group consisting of alkenyl optionally substituted by phenyl optionally substituted, alkynyl, —(CH2)m-W-(CH2)q-Z23 and —(CH2)p-U-Z24 wherein 
Z23 is (C1-C6)alkyl or aryl optionally substituted; 
Z24 is selected from the group consisting of cyclohexenyl, bis-phenyl, (C3-C7)cycloalkyl optionally substituted, (C3-C7)heterocycloalkyl, cyano, amino, mono and di-alkylamino, aryl and heteroaryl optionally substituted, 

X3 is selected from the group consisting of (C1-C10)alkyl, alkenyl optionally substituted by phenyl optionally substituted, —CF3, and 
—(CH2)pZ25, 
Z25 is aryl optionally substituted, 

Y is oxygen or sulfur, 
W is oxygen or sulfur or SO2; 
U is a covalent bond or oxygen; 
n is an integer from 0 to 4; 
m is an integer from 1 to 6; 
p is an integer from 0 to 6; 
q is an integer from 0 to 2, 

and their addition salts with pharmaceutically acceptable acids.

2. A compound of claim 1 wherein
i) the substituents carried by aryl represented by Z11 and Z12 and heteroaryl represented by Z12 are independently selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, —CF3, —OCF3, phenyl, phenoxy and aminosulfonyl; 
iii) the substituents carried by aryl and heteroaryl represented by Z22 are independently selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl, alkenyl, alkoxy, alkylthio, —CF3, —OCF3, nitro, cyano, azido, aminosulfonyl, piperidinosulfonyl, mono- or di-alkylamino, —C(O)—O-alkyl, —C(O)-alkyl, phenyl, phenoxy, phenylthio and benzyloxy, the phenyl optionally substituted; 
iv) the substituents carried by aryl represented by Z23 and Z24, cycloalkyl and heteroaryl represented by Z24 are selected independently from the group consisting of 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, alkylsulfonyl, mono- or di-alkylamino, amino, aminoalkyl, pyrrolyl, pyrrolidinyl, phenyl, phenoxy, phenylthio, benzyl and benzyloxy, the aryl is optionally substituted by at least one member selected from the group consisting of alkyl, CF3 and halo; 
v) the substituents carried by aryl and heteroaryl represented by Z25 are independently selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl, alkoxy, —CF3, —OCF3, nitro, cyano, —NH—C(O)-alkyl, alkylsulfonyl, amino, mono- and di-alkylamino, phenyl and pyridino; 
vi) the substituents carried by alkyl represented by R3 is cyano;

3. A compound of claim 1 wherein
R1 is selected from the group consisting of —(CH2)m-Y-Z11 and —(CH2)m-Z12, 
Z11 is (C1-C6)alkyl, 
Z12 is selected from the group consisting of bis-phenyl, optionally substituted aryl and heteroaryl optionally substituted by at least one member selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl and alkoxy, 
Y is oxygen, 


R2 is selected from the group consisting of —C(Y)NHX1, —C(O)X2 and SO2X3 wherein 
X1 is (C1-C15)alkyl, or —(CH2)pZ22, 
Z22 is selected from the group consisting of cyclohexenyl, bis-phenyl, (C3-C7)cycloalkyl, and (C3-C7)heterocycloalkyl, aryl and heteroaryl-unsubstituted or substituted by at least one member selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, —CF3, OCF3, nitro, cyano, azido, piperidinosulfonyl, —C(O)—O-alkyl, —C(O)-alkyl, or phenyl, 
X2 is selected from the group consisting of alkynyl, —(CH2)m-W-(CH2)q-U-Z23 and —(CH2)p-U-Z24, 
W is SO2, 
U is a covalent bond, 
Z23 is aryl; 
Z24 is selected from the group consisting of cyclohexenyl, bis-phenyl, (C3-C7)cycloalkyl optionally substituted by an aminoalkyl, aryl and heteroaryl unsubstituted or substituted by at least one member selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl, alkoxy, —CF3, —OCF3, —SCF3, hydroxy, —O—C(O)-alkyl, mono- or di-alkylamino, amino 
X3 is —(CH2)pZ25, Z25 is aryl optionally substituted by at least one member selected from the group consisting of alkoxy and —CF3, 

R3 is selected from the group consisting of hydrogen, alkyl, alkenyl.

4. A compound of claim 1 wherein R1 is [(C1-C6)alkyl,] —(CH2)m-Y-Z11 and —(CH2)m-Z12,
Z11 is (C1-C6)alkyl, 
Z12 is selected from the group consisting of morpholino, bis-phenyl, pyrrolidinyl substituted by oxy, phenyl, piperazinyl, pyridinyl and indolyl, all unsubstituted or substituted by at least one member selected from the group consisting of bromo, fluoro, chloro, alkyl, alkoxy, —CF3 and —OCF3; 
Y is oxygen.

5. A compound of claim 1 wherein R2 is selected from the group consisting of —C(Y)NHX1, —C(O)X2 and SO2X3 
X1 is (C1-C10)alkyl, or —(CH2)pZ22, 
Z22 is selected from the group consisting of cyclohexyl, cyclohexenyl and bis-phenyl, morpholino, piperidino, and phenyl, naphthyl and furyl unsubstituted or substituted by at least one member selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, —CF3, —OCF3, nitro, cyano, azido, piperidinosulfonyl, —C(O)—O-alkyl, —C(O)-alkyl, —C(O)-alkyl and phenyl, 
or Z22 is 





X2 is selected from the group consisting of alkyl, alkynyl, —(CH2)m-W-(CH2)q-Z23 and —(CH2)pZ24, 
W is SO2; 
Z21 is phenyl; 
Z24 is selected from the group consisting of cyclohexenyl, bis-phenyl, cyclohexyl optionally substituted by an aminoalkyl, and phenyl, naphthyl, benzothienyl, thienyl and indolyl unsubstituted or substituted by at least one member selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl, alkoxy, —CF3, —OCF3, —SCF3, hydroxy, —O—C(O)-alkyl, —NH—C(O)-alkyl, mono- or di-alkylamino and amino, or 

X3 is —(CH2)pZ25, Z25 is phenyl unsubstituted or substituted by at least one alkoxy or —CF3.

6. A compound of claim 1 wherein R3 is selected from the group consisting of hydrogen, alkyl, alkenyl.

7. A compound of claim 1 wherein R1 is —(CH2)mZ12 in which m=2 and Z12 is bis-phenyl or indolyl substituted by at least one member selected from the group consisting of alkyl and alkoxy.

8. A compound of claim 1 wherein R2 is —C(Y)NHX1 or —C(O)X2,
Y is S; 
X1 is phenyl optionally substituted by at least one azido, 
X2 is —(CH2)pZ24, 
p is 1, 2 or 3, 
Z24 is cyclohexyl, or phenyl or benzothienyl optionally substituted by at least one member selected from the group consisting of fluoro, chloro, bromo, iodo, —CF3.

9. A compound of claim 1 wherein R3 is hydrogen or methyl.

10. A pharmaceutical composition having an affinity for somatostatin receptors comprising an effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.