MXPA06010410A - Tetrahydroisoquinoline-and tetrahydrobenzazepine derivatives as igf-1r inhibitors - Google Patents

Abstract

where R2, R5, R6 have the meanings as given in the description, and U, V and W, respectively, may be CR2', CR4'and CR6', respectively (with the definitions of R2', R4'and R6'again as in the description), or may be N, were io synthesized. They were found to down-regulate or inhibit the expression or function of the IGF-1 receptor.

Description

DERIVATIVES OF TETRAHYDROISOQUINOLINE AND TETRAHYDROBENZAZEPINE AS INHIBITORS OF THE INSULIN-TYPE GROWTH RECEIVER FACTOR -1 (IGF-IR) FIELD OF THE INVENTION The present invention relates to new compounds capable of down-regulation or inhibition of the expression or function of the factor receptor. -1 of insulin-like growth (IGF-1R). The invention is also directed to methods for the down regulation or inhibition of the expression or function of IGF-IR in order to prevent and / or treat cancer and other abnormal cell developments, and metabolic disorders, as well as proliferation. of blood vessels, in which an uncontrolled expression of this receptor is observed. BACKGROUND OF THE INVENTION The insulin-like growth factor receptor (IGF-1 R) is one of 58 transmembrane tyrosinase receptors in humans (Review: Structure and function of the insulin-like growth factor receptor Type 1 TEAdams et al., Cell, Mol.Life Sci. 57 (2000) 1050-1093.] Genetic evidence and studies on cells lacking the IGF-1 receptor have shown that it is required for optimal growth but is not an absolute condition for growth [R. Baserga et al., Biochim Biophys, Acta 1332 (1997) 105-126.] An expression Ref. No.: 174960 of the IGF-1 receptor protects cells against apoptosis and appears to be a requirement for establishment and maintenance of the transformed phenotype both in vitro and in vivo [R. Baserga et al., Biochim, Biophys, Acta 1332 (1997) 105-126] Several in vitro and in vivo studies have shown that the inhibition of the expression or function of the receiver IGF-1 reverses the transformed phenotype and inhibits the growth of tumor cells. The techniques used in these studies include neutralizing antibodies [Kalebic et al. Cancer Res. 5 4 (1994) 5531-5534], the antisense oligonucleotides [Resnicoff et al. Cancer Res. 54 (1994) 2218-2222], the dominant negative receptors [D1 mbrosio et al. Cancer Res. 56 (1996) 4013-4020], oligonucleotides forming triple helix [Rinninsland et al. Proc.Nati. Acad. Sci. 94 (1997) 5854-5859], antisense mRNA [Nakamura et al. Cancer Res. 60 (2000) 760-765] and RNA interference using a double-stranded RNA (V.M. M acaulay et al., WO-A-03/100059). The use of antisense oligonucleotides to inhibit the expression of the IGF-1 receptor in keratinocytes has been shown to reverse epidermal hyperproliferation in psoriasis lesions [C.J. Wraight et al. Nat. Biotechnol. 18 (2000) 521-526]. Diminishing regulation of the IGF-1 receptor would also, possibly, have a beneficial effect with respect to diseases such as diabetic retinopathy [L.K. Shawver et al. DDT 2 (1997) 50-63] as well as in atherosclerosis and restenosis [A. Bayes-Genis et al. Circ. Res. 86 (2000) 125-130]. The IGF-1 receptor system is considered an attractive target for the prevention and / or treatment of diseases that depend on the expression or overexpression of the IGF-1 receptor for its proliferation [L. Long et al. Cancer Research 55 (1995) 1006-1009, R. Baserga TIBTECH 14 (1996) 150-152; R. Baserga et al. Endocrine 7 (August 1997) 99-102; V.M. Macaulay et al. Annals of Oncogene 20 (2001) 4029-4040]. It has been shown that a series of substances, termed tyrphostins, down regulate or inhibit the expression of the IGF-1 receptor [M. Parrizas et al. Endocrinology 138 (1997) 1427-1433; G. Blum et al. Biochemistry 39 (2000) 15705-15712; G. Blum et al. J. Biol. Chem. 278 (2003) 40442-40454]. The drawback of tyrphostins is their low activity in cellular systems and the fact that they cross-react with the insulin receptor. It has been shown [L. Kanter-Lewensohn et al. Mol. Cell. Endocrinology 165 (2000) 131-137] that tamoxifen, at a high concentration, has the ability to regulate the decrease or inhibit the tyrosine phosphorylation of the R subunit of IGF-IR, thereby blocking downstream signaling . In US Patent 6337338 Bl, a variety of heteroaryl aryl urea substances have been described as antagonists of the IGF-1 receptor. In studies of inhibition of cell growth on cell lines MCF-7 and MCF-10 Aas substances show low activities. In the patent publication WO 02/102804 it has been shown that podophyllotoxin, deoxipodophyllotoxin, picropodophyllin and deoxypicropodophyllin are selective and effective inhibitors of the IGF-1 receptor. Deoxypicropodophylline has previously been shown [A. Akahori et al. Chem. Pharm. Bull. 20 (1972) 1150-1155] which is superior to deoxipodophyllotoxin in delaying the death of mice inoculated with L1210 lymphatic leukemia. However, no mechanism of action has been proposed. In patent publication WO 02/102805 it has been shown that also acetylpodophyllotoxin, epipodophyllotoxin, podophyllotoxone and 4 '-desmethylpodophyllotoxin are potent inhibitors of phosphorylation of IGF-IR. In the patent publication WO 03/048133 a variety of pyrimidine derivatives have been described as modulators of the IGF-1 receptor. The present invention aims to provide compounds with better down regulation activity of IGF-1R.

BRIEF DESCRIPTION OF THE INVENTION The object indicated is achieved by the compounds of the following formula (I): wherein (I) R2 designates hydrogen, Me, Et, CHO, CN, OH, OMe, COR9, COOR9, CONHRg or CSNHRg, wherein R9 denotes alkyl (C? -C); R5 designates hydrogen, (C? -C4) alkyl, OH, alkoxy (Ci-C), OCF3, trifluoromethyl or halogen; R6 designates Me, alkoxy (C? -C4), OCF3, SMe or SEt; n is 1 or 2; R3 'and 5' each independently designate OH, Me, Et, OMe, OCF3, trifluoromethyl or halogen; U designates N or CR 2, where R 2 'denotes hydrogen, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, trifluoromethyl or halogen; V designates N or CR4 ', wherein R41 denotes hydrogen, alkoxy (Ci-Cß), alkyl (C? ~ C6), OH, trifluoromethyl or halogen; designates N or CRß ', where Re denotes hydrogen, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, trifluoromethyl or halogen; and the pharmaceutically acceptable salts thereof, when applicable (see below).

The preferred embodiments of the compound (I) are derived from the dependent claims. The most preferred examples of the compounds of formula (I) are those of claim 13. Other objects of the invention are the use of the compounds (I) as a medicament, particularly for the prevention or treatment of diseases in which the regulation by decreasing or inhibiting the expression or function of the IGF-1 receptor is considered beneficial, and pharmaceutical compositions containing a compound (I). DETAILED DESCRIPTION OF THE INVENTION The compounds of formula (I) which contain a tetrahydroisoquinoline (n = 1) or a tetrahydrobenzazepine (n = 2) moiety. In the above formula (I) preferably R2 is Me, OH, CN, CHO, COR9 or COOR9, CONHR9 or CSNHR9; Particularly preferred examples of R2 are Me (methyl), CHO (formyl), COMe (acetyl) and CN (cyano). Preferably R5 is hydrogen, Me, OMe or halogen; and preferably Rs is OMe or OEt. Particularly, preferably R5 is hydrogen or OMe and R6 is OMe. The most preferred substituent pattern for R5 and Rs is R5 = hydrogen and R6 = OMe. In the formula (I) the substituent at the 1-position of the 1, 2, 3, 4-tetrahydroisoquinoline or 2,3,4,5-tetrahydro-1 H-2-benzazepine portions can be a phenyl substituent (U = CR2 '; V = CR4 '; W = CRe',), a 4-pyridyl substituent (U = CR2; V = N; W = CR6 '), a 2-pyridyl substituent (V = CR4'; U = N, W = CR6 ', or U = CR2', W = N), a 2-pyrimidyl substituent (U, W = N; V = CR41), a 4-pyrimidyl substituent (V = N; U = CR2 ', W = N, or U = N, W = CRS '), or a triazinyl substituent (U, V, W = N) .- A preferred substitution pattern in said substituent at position 1 is R3', R5 '= each independently chlorine, bromine, Me or OMe. In a more preferred embodiment, R3 'and R5 They are Adénticos. In another preferred embodiment, both are chlorine, both are bromine, both are Me or both are OMe; in another preferred embodiment R3 'is chloro or bromo, and R5' is O Me. More preferably, both R3 'and R5' are chlorine or bromine. When the 1-substituent is phenyl, then R2 'and Rs' are preferably hydrogen. R4 'is then preferably hydrogen, chlorine, bromine, Me or OMe. Three more preferred substitution patterns in phenyl as 1-substituents are a) R3 ', R4', R5 '= OMe; b) R3 '= chlorine, R4', Rs' = OMe; and c) R4 '= hydrogen and R3' and R5 '= both chlorine or both bromine. Due to the rotational freedom of phenyl, b) the definitions for R3 'and R5' are interchangeable. The alkyl residue in the (C1-C4) alkyl or alkoxy (d.-C), as used in the definitions of the substituent of formula (I), may be branched, unbranched or cyclic and may contain double or triple bonds . It is, for example, methyl, ethyl, n-propyl, n-butyl, isopropyl, sec-butyl, t-butyl, cyclopropyl, cyclobutyl, ethenyl, prop-2-enyl or prop-3-enyl, but-1-enyl, but-2-enyl, but-3-enyl or propargyl. Preferably it is methyl, ethyl or isopropyl; methyl is particularly preferred. The alkyl residue in the alkyl (C? -C6) or (C? -C6) alkoxy can be unbranched, unbranched or cyclic and can contain double or triple bonds. Examples of unbranched alkyls are methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl. Examples of branched alkyl are isopropyl, sec-butyl, t-butyl, 1- (1,1-diethyl) methyl, (1-propyl-1-methyl) methyl, (1-isopropyl-1-methyl) methyl, (1, 1-dimethyl-1-ethyl) methyl, (1-t-butyl) methyl, (1-propyl-1-ethyl) methyl, (1-isopropyl-1-ethyl) methyl, (1,1-diethyl-1-methyl) methyl) methyl and (1-t-butyl-1-methyl) methyl. Examples of cyclic alkyls are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or (2- or 3-methyl) cyclopentyl. Examples of unsaturated alkyls are ethenyl, prop-2-enyl, prop-3-enyl, but-1-enyl, but-2-enyl, but-3-enyl, pent-1-enyl, pent-2-enyl, pent 3-enyl, pent-4-enyl, penta-1,3-dienyl, penta-1,4-dienyl, penta-2,4-dienyl or propargyl. The term "halogen" means in the context of the present application, fluorine, chlorine or bromine.

In the context of the present application, the term "IGF-1 receptor" encompasses the human IGF-1 receptor, whose known amino acid sequence [see for example, T.E. Adams et al. Cellular and Molecular Life Sciences 2000, 57, p. 1050-1093], but also encompasses other IGF-1 R, such as mammalian IGF-IR in general. The pharmaceutically acceptable salts of the compounds of Formula (I) are acid addition salts with pharmaceutically acceptable acids which are possible in the case in which R2 is hydrogen, Me or Et; and / or at least of U, V and W is nitrogen. Examples of pharmaceutically acceptable acids are hydrochloric, hydrobromic, methanesulfonic, acetic, propionic, benzoic, citric, tartaric, malic, maleic, fumaric, lactic, nitric, phosphoric or succinic. The compounds (I) of the present invention can be prepared using the methods described below with reference to reaction schemes la and Ib. Preferably, the compounds (I) of the present invention are synthesized through the imine (II) pathway, which is a 3,4-dihydroisoquinoline (n = 1) or a 4,5-dihydro-3H-2- benzazepine (n = 2). The imine (II) can then be converted by reduction to a secondary amino compound (I) of the invention, where R2 = hydrogen. Sodium borohydride in methane can be used with reducing agent) or other reducing agents such as DIBAL, B2H6, LiAIH4, or catalytic hydrogenation using a catalyst, which can be chiral, suitable for reducing imine, but which will not influence other parts of the compound (I , R2 = hydrogen). The compounds (I) in which R2 = Me or Et and the 1-substituent is phenyl, can be prepared by alkylation of (II) with a corresponding alkyl halide R2X, where X is a leaving group, such as bromine, iodine, mesylate, tosylate or triflate, to form an intermediate imine salt (III) (reaction scheme la). This alkylation is preferably carried out at room temperature to reflux temperature, in an aprotic solvent such as acetone, DMF, CH 3 CN, DMSO or 1,2-dimethoxyethane. The iminium salt (III) is then reduced under similar conditions to the above for the reduction of the imine (II) itself, to form the compounds (I) of the invention, in which R2 = Me or Et. The compounds (I) in which R2 = Me or Et, respectively, and the 1-substituent are different from phenyl, (ie, at least one of U, V or W is nitrogen) can be prepared by acylation of (I), where R 2 = hydrogen, with XCOOEt or XCOMe, respectively, where X is a leaving group such as chlorine (in XCOMe X may also be acetoxy), to form a compound (I) in which R2 is COOEt or COMe, respectively, which is then reduced for example, with LiAIH4 or B2H6 / to compound (I) with R2 = Me or Et, respectively (reaction scheme Ib).

For all compounds (I), in which R2 = methyl, the conventional Eschweiler-Clarke reaction can also be used, to directly form its derivatives from the corresponding secondary amino compound (I) wherein R 2 = hydrogen (reaction scheme or lb). All compounds (I) in which R2 = COR9, COOR9 or cyano can be prepared from the above secondary amino compound (I) in which R2 = hydrogen by acylation with an appropriate alkyl halide R9COX, (in particular for R9 = I can also be used acetic anhydride), haloformic acid ester R9OCOX, or cyanogen halide XCN (X = chlorine or bromine); by the use of an appropriate auxiliary base such as NEt3 or pyridine and, optionally, a catalyst such as 4-dimethylaminopyridine (reaction schemes or lb). The reaction temperature can be from room temperature to the boiling temperature of the solvent, where the solvent can be an ether such as THF or 1,2-dimethoxyethane; CH3CN; N-methylpyrrolidone or CH2C12. In the case where a cyanogen halide is used, anhydrous potassium carbonate can be used to neutralize the hydrogen halide formed. The acetylations (R2 = COMe) are preferably carried out in net acetic anhydride, ie, without catalyst solvents, to facilitate the isolation of the N-acetyl derivative.

All compounds (I) where R2 = formyl, can be prepared from the previous secondary amino compound (I), in which R2 = hydrogen, by the use of formic acid in refluxing toluene (reaction schemes la and lb). All compounds (I) in which R2 = CONHR9 or CSNHR9 can be prepared from the secondary amino compound (I) in which: R2 = hydrogen, under conventional conditions of reaction thereof with an isocyanate OCNR9 or an isothiocyanate SCNHR9 at room temperature in an inert solvent such as an ether, DMF or acetonitrile (Reaction diagrams L a and lb). The imine (II) itself can be prepared from an appropriately substituted phenethylamine (VIII) or a 3-phenylpropylamine (IX) (scheme, reaction 2), by acylation of any of these with an appropriately substituted acyl chloride (X) , for example, under conventional Schotten-Baumann conditions, which provides an amide (IV). This amide (IV) can then be cyclized to the imine (II) under conditions of dehydration with dehydrating agent such as zinc chloride or P0C13 (of type Bischler-Napieralski) or P205 (Pictet-Ga s type). Any of the amines (VIII) or (IX) can be prepared by techniques known in the art from appropriately substituted benzaldehydes (V). For sequence (V) to (VI) to (VIII) reference is made for example to Ko no et al. , Bull. Chem. Soc. Jpn., 1990, 63 (4), 1252-1254. In some cases, phenethylamine (VIII) is still commercially available, as in the case of Reaction Scheme Reaction scheme lb (|), R2 «MßOtEt (0 (IV), p »1,2 (II), n- 1,8 for 3-methoxyphenylethylamine, which inter alia was used in Examples 31-38 (see below). Sequence (V) to (VII) is easily achieved according to the procedure designed for the corresponding 4-methoxy derivative (DiBiase, S.A. et al J. Org Chem. 44 (1979) 4640-4649). The compound (VII) is then reduced to the amine (IX) by catalytic hydrogenation. The appropriately substituted benzaldehyde (V) of reaction scheme II in turn is either commercially available or unknown in the literature. Some examples of known benzaldehydes (V) that can be used to synthesize some preferred compounds (I) are the following: 2-C 1 -C 4 alkyl-3-alkoxybenzaldehyde (C 1 -C 4) (ie, with R 5 = C 1 -C 4 alkyl), R 6 = (C 1 -C 4) alkoxy, and 2-alkyl (C 1 -C 4) ) -3-trifluoromethoxy-benzaldehydes (ie with R5 = alkyl) (Q-GJ), R6 = OCF3), respectively, can be synthesized from 2-alkyl (C? -C4) -3-hydroxy-benzaldehydes by etherification of Williamson with a corresponding alkyl bromide (C? -C4) and trifluoromethyl iodide respectively. 2-alkoxy (C? -C4) -3- (C? -C4) alkoxybenzaldehydes (ie, with R5 = (Cx-C4) alkoxy, R6 = (C? -C4) alkoxy) and 2-alkoxy (Cx-) C) -3-trifluoromethoxy-benzaldehydes (ie, with Rs = (C 1 -C 4) alkoxy, R 6 = OCF 3), respectively, can be synthesized from 2-(C 1 -C 4) alkoxy-3-hydroxy-benzaldehydes by Williamson etherification with a corresponding alkyl bromide (C? ~ C4) and trifluoromethyl iodide respectively. Alternatively, all of these compounds are available from 3-benzyloxy-2-hydroxybenzaldehyde by etherification, followed by debenzylation and etherification of the 3-hydroxy group. 2-alkyl (Ci-C4) -3-methylthio-benzaldehydes (ie, with R5 = (C1-C4) alkyl, R6 = SMe) and 2-alkyl (Cx-C4) -3-ethylthiobenzaldehydes (ie, with R5 = (C? -C4) alkyl, Rs = SEt), respectively, can be synthesized from 2-alkyl (C? -C4) -3-bromo-benzaldehydes diethyl acetals by reaction of their Grignard reagent with dimethyl sulfide or diethyl sulfide, respectively (for a similar reaction see M. Euerby et al., Synthetic Communications 11 (1981) , 849-851). 2-alkoxy (O.-G -3-methylthio-benzaldehydes (ie, with R5 = (C4-alkoxy), Rs = SMe) and 2-alkoxy (CX-C4) -3-ethylthio-benzaldehydes (i.e., with Rs = alkoxy (Ci-C4), Rs = SEt), respectively, can be synthesized from 2-alkoxy (Ci-C4) -3-bromo-benzaldehydes by reacting their Grignard reagent with dimethyl sulfide or sulfide of diethyl, respectively (for a similar reaction see, M. Euerby et al., Synthetic Communications 11 (1981), 849-851). Another route for these starting materials is by etherification of 2-hydroxy-3- (methylthio) enzaldehyde or 2-hydroxy-3- (ethylthio) benzaldehyde (A. Makoto et al., Bull. Chem. Soc. Jpn. 1978) 2435-2436).

The appropriately substituted acyl chloride (X) for the synthesis of the amide (IV) are benzoyl chlorides, in which U = CR2 ', V = CR' and W = CR6 '; and they are known or can be synthesized under conventional conditions from the corresponding benzoic acids with thionyl chloride or oxalyl chloride. Some examples of known benzoyl chlorides (X) and benzoic acids which can synthesize some preferred compounds (I) are the following: benzoyl chloride (X) CAS No. 3, 5-difluorobenzoyl chloride 129714-97-2 3,5-dichlorobenzoyl chloride 2905-62-6 3,5-dibromobenzoyl chloride 23950-59-6 3, 5-chloride -diethylbenzoyl 57664-62-7 3,5-dimethoxybenzoyl chloride 17213-57-9 3,5-dimethylbenzoyl chloride 6613-44-1 3,5-bis (trifluoromethyl) benzoyl chloride 785-56-8 3-chloro chloride -bromo-5-chlorobenzoyl 21900-27-6 3-chloro-5-methylbenzoyl chloride 21900-22-1 3-methoxy-5-methylbenzoyl chloride 96227-40-6 3-bromo-5-methoxybenzoyl chloride 157893- 14-6 3-chloro-5-methoxybenzoyl chloride 89106-53-6 3-fluoro-5- (trifluoromethyl) benzoyl chloride 171243-30-4 3,4,5-trimethoxybenzoyl chloride 4521-61-3 3,4,5-trifluorobenzoyl 177787-26-7 3,4,5-trichlorobenzoyl chloride 42221-50-1 3,4,5-trimethylbenzoyl chloride 57498-46-1 4-bromo-3,5- chloride dimethoxybenzoyl 56518-43-5 Appropriately substituted benzoic acids are known or can be easily synthesized by the use of conventional procedures known to those skilled in the art. Those skilled in the art will appreciate that in the methods of the present invention it is necessary to protect certain functional groups by protecting groups, such as hydroxyl groups, in the starting reagents or intermediates. Therefore, the preparation of the compounds (I) may involve the addition and removal of one or more protecting groups. Therefore, the preparation of the compounds (I) may involve the addition and removal of one or more protecting groups. The protection and deprotection of the functional groups is described in "Protective Groups in Organic Chemistry", edited by J.W.F. McOmie, Plenum Press (1973) and "Protective Groups in Organic Synthesis", 2nd edition, T.W. Greene and P.G.M. Wuts, Wiley-lnterscience (1991). Suitable protecting groups for aromatic hydroxyl groups in the present invention are for example benzyl or isopropyl groups. The removal of the benzyl group and the isopropyl group is easily effected by catalytic hydrogenation (Pd / carbon catalyst) and by treatment with BC13, respectively. Appropriately substituted acyl chlorides (X), in which U = CR2 ', V = N and W = CRs, can be synthesized under conventional conditions from isonicotinic acids appropriately substituted with thionyl chloride. Appropriately substituted acyl chlorides (X), in which U = N, V = CR4 'and W = CR6' can be synthesized under conventional conditions from substituted pyridine 2-carboxylic acid. The appropriately substituted acyl chlorides (X), in which U = N, V = CR4 'and W = CRs, or in which U = CR2', V = CR4 'and W = N; they can be synthesized under conventional conditions from appropriate substituted 2-carboxylic acid pyridines. Appropriately substituted acyl chlorides (X) in which U = CR2 'and V, W = N, can be synthesized under conventional conditions from appropriate substituted 4-carboxylic acid pyrimidines. Appropriately substituted acyl chlorides (X), in which U, W = N and V = CR4 'can be synthesized under conventional conditions from appropriate substituted 2-carboxylic acid pyrimidines. Appropriately substituted acyl chlorides (X), in which U, V, W = N, can be substituted under conventional conditions from substituted 2-carboxylic acid triazines. Some examples of suitable starting materials for the production of nitrogen-containing acid chlorides (X) are the following known compounds: The transformation of amides, ethyl esters and aldehydes to their corresponding carboxylic acid derivatives are reactions well known to those skilled in the art. The compounds of the present invention contain a chiral center and therefore can exist in different enantiomeric forms. Although the particularly preferred compounds (I) are enantiomerically pure, the scope of the present invention covers both the enantiomers per se and the mixtures thereof in any ratio, such as in racemic mixtures. The compounds (I) of the present invention can be obtained in their enantiomerically pure forms by crystallization of their addition salts with chiral acids [see for example, D.L. Minor et al. J. Med. Chem. 37 (1994) 4317-4328; US Patent 4349472], or alternatively, can be isolated by preparative HPLC using commercially available chiral phases. Other routes for obtaining pure enantiomers of the products of the present invention are the use of asymmetric synthesis [M.J. Munchhof et al. J. Org. Chem. 60 (1995) 7086-7087; R.P. Polniaszek et al. Tetrahedron Letters 28 (1987) 4511-4514], by hydrogenation by asymmetric transfer of the intermediate imines (II) or the iminium (III) salts [N. Uematsu et al. J. Am. Chem. Soc. 118 (1996) 4916-4917; G. Meuzelaar et al. Eur. J. Org. Chem. 1999 ,. 2315-2321], or by resolution of the chiral diastereomeric derivatives thereof as known to those skilled in the art. The compounds of the formula (I) and their pharmaceutically acceptable salts when applicable, may be administered in the form of a pharmaceutical composition in which they are associated with a pharmaceutically acceptable additive, diluent or carrier, to prevent or treat any disease in which the Those skilled in the art consider that inhibition of the IGF-1 receptor would be considered beneficial. The present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof as defined above, in association with a pharmaceutically acceptable additive, diluent or carrier. As for the appropriate excipients, diluents and additives, reference can be made to the conventional literature describing them, for example, to chapter 25.2 of Vol. 5 of "Comprehensive Medicinal Chemistry", Pergamon Press 1990, and to "Lexikon der Hilfsstoffe" für Pharmazie, Kosmetik und angrenzende Gebiete ", by HP Fiedler, Editio Cantor, 2002 (in Germany). Compounds (I) of the examples of the present invention have IC50 activities in intact cell systems ranging from 8 micrograms / ml to 150 picograms / ml. Due to the large difference in activities, the pharmaceutical compositions of the invention preferably comprise from 0.001 to 50% by weight of the compound (I). The daily dose of compounds (I) will necessarily vary depending on the host treated, the particular route of administration and the severity of the class of disease treated. Therefore, the optimal doses can be determined by the professional who is treating any particular patient. The pharmaceutical compositions of the invention can be formulated in the form of creams, gels, solutions, ointments, suspensions or plasters, etc., when they are intended for topical administration; for administration by inhalation, for example, aerosols or dry powders; for oral administration, for example, in the form of tablets, capsules, gels, syrups, suspensions, solutions, powders or granules; for rectal or vaginal administration, for example, as suppositories; or for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) in the form of a sterile solution, suspension or emulsion. It was found that the compounds of the present invention down regulated or inhibited the expression or function of the human IGF-1 receptor, without inhibiting the structurally intimately related insulin receptor. They were found to promote apoptosis of malignant cells and to interfere with cell division by blocking cells in the pro-phase of the mitotic cycle. The compounds (I) are useful for the prevention and / or treatment of downregulated IGF-IR expression diseases, including cell proliferation diseases such as cancer, atherosclerosis, restenosis, inflammatory diseases, e.g., psoriasis, autoimmune diseases , rheumatoid arthritis, and rejection of transplants. Some examples of cancers in which I and IGF-IR are down-regulated or over-expressed, and which can be prevented and / or treated by the compounds (I) of the invention, include, but are not limited to, breast, prostate, colon, lung, brain, pancreatic and melanoma, multiple myeloma, lymphoma and leukemia. Under the paragraph "Biological Data", some techniques are described to evaluate the sensitivity of the cancer cells with respect to the compounds (I) of the invention, and the presence of the IGF-1 receptor. Optionally the compounds (I) can be used against cell proliferation diseases in combination with conventional treatments such as irradiation and / or one or more chemotherapeutic agents- such as, for example, Actinomycin, Altretamine, Bleomycin, Busulfan, Capecitabine, Carboplatin, Carmustine. , Chlorambucil, Cisplatin, Cladribine, Crisantaspase, Cyclophosphamide, Cytarabine, Dacarbazine, Daunorubicin, Doxorubicin, Epirubicin, Etoposide, Fludarabine, Fluoruracil, Gemcitabine, Idarubicin, Ifosfamide, Irinotecan, Lomustine, Melphalan, Mercaptopurine, Methotrexate, Mitomycin, Mitoxantrone, Oxaliplati, Pentostatin , Procarbazine, Streptozocin, Taxol, Temozolomide, Thiotepa, Thioguanine / Thioguanine, Topotecan, Treosulfan, Vinblastine, Vincristine, Vindesine or Vinorelbine. When a chemotherapeutic agent is used in combination with the compound of formula (I), it may be used in the form of a medicament containing a combination of its two agents, for simultaneous administration or may be used in the form of separate dosage forms, each of them containing one of the agents, and in the latter case, individual dosage forms can be used, for example, consecutively, ie a dosage form with the compound (I), followed by a dosage form containing the chemotherapeutic agent (or vice versa). This embodiment of the two separate dosage forms can be conceived and provided in the form of a kit. In addition to their use in therapeutic medicine, the compounds (I) and their pharmaceutically acceptable salts are also useful as pharmacological tools for the development and standardization of the in vitro and in vivo assay systems for the evaluation of the effects of the inhibitors of the activity of the cell cycle in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the investigation to discover new therapeutic agents. EXAMPLES The products described in the Examples have data of nuclear magnetic resonance spectra and / or mass spectrum. The melting points are not corrected. The substances described in the examples are racemates, unless marked with (-), which denotes the levogyrative enantiomer. Examples 1 to 30: Synthesis of Racemic Compounds (I) In Examples 1 to 30 the following general synthetic procedures were used: 1. Production of amides (Reaction Scheme 2, IV): The appropriate amine (VIII or IX) was added , 0.1 mol) to an aqueous solution of sodium hydroxide (200 ml, 2M) and dichloromethane (200 ml). To the vigorously stirred mixture containing the amine, the appropriate acyl chloride was added (X, 0.1 mol) dissolved in dichloromethane (200 ml) for 30 minutes at room temperature. After the addition, the mixture was stirred for a further 60 minutes. The dichloromethane phase was separated, washed with hydrochloric acid (200 ml, 2M), dried (sodium sulfate) and concentrated to dryness. The residual amide (IV) is suitable without further purification as a starting material for the production of imines. All the produced amides that were obtained in crystalline state could be recrystallized from methanol. 2. Production of imines (Reaction Scheme 2, II): A mixture of the appropriate amide (IV, 0.05-0.1 mol), toluene (200 ml) and phosphorus oxychloride (80 ml) was refluxed for 1.5-24 hours. The progress of the reaction was followed by TLC (silica gel / ethyl acetate or methanol). The reaction mixture was concentrated to dryness and partitioned between ethyl acetate (500 ml) and aqueous sodium hydroxide. (400 ml, 2 M). The formed imine (II) was transferred to an aqueous phase by extraction of the organic phase with hydrochloride acid (3 x 200 ml, 2 M), which was made basic (pH 11-12) and extracted with dichloromethane. The organic phase was dried and concentrated to dryness to provide the imine. If necessary, most of the imines (II) could be purified by crystallization from diethyl ether or ethanol, or by crystallization of the corresponding hydrochlorides from ethanol. 3.-production of secondary amino compounds (I) by reduction of imines (Reaction Schemes la and Ib): A solution of the appropriate imine (II, 0.01-0.05 mol) in methane was treated (200 ml) with an excess of sodium borohydride (300 ml, 2M) at room temperature until no starting material remained. The mixture was concentrated to dryness and partitioned between aqueous sodium hydroxide (300 ml, 2M) and dichloromethane (400 ml). The organic phase was separated, dried and concentrated to dryness to leave the pure secondary amine. The amino compound (I, R2 = hydrogen) could be crystallized from diethyl ether or ethanol, or by crystallization of the corresponding hydrochloride from ethanol or ethanol / diethyl ether. 4. Production of N-alkyl compounds (Reaction scheme la, III and I, R2 = Me or Et): The appropriate imine (II, 0.005-0.01 mol) was dissolved in acetone (25-50 ml) and the alkyl halide selected MeX or EtX (1.2 equivalents). The mixture was stirred at room temperature or at room temperature or at reflux temperature for 1-24 hours, depending on the nature of the alkyl halide. After cooling to room temperature, the iminium salt formed (III) was separated by filtration and dried. The iminium salt thus obtained was treated in the manner described for the reduction of imine in paragraph 3 above. The compounds (I), wherein R2 = Me or Et, crystallized from diethyl ether or ethanol, or by crystallization of the corresponding hydrochlorides from ethanol or ethanol / diethyl ether. N-methyl compounds (I) could also be produced by the Eschweiler-Clarke reaction. A mixture of the appropriate secondary amino compound (I, R2 = hydrogen, 0.005-0.01 mol), 1,2-dimethoxyethane (10 ml), formaldehyde (37% in water, 5 ml) and formic acid (5 ml) were heated to 80 ° C for 5 hours. The reaction mixture was concentrated to dryness and then the N-methyl compound (I) was isolated as described for the secondary amino compounds (I) in paragraph 3. 5. Production of the N-acetyl compounds (Reaction scheme lb, I; R2 = COMe): The appropriate secondary amino compound (I, 0.005-0.01 mol) was treated with acetic anhydride (150 ml) at room temperature for 24 hours. The mixture was concentrated to dryness leaving the N-acetyl compound (I) which crystallized from methanol (except the products of Examples 6, 8, and 51 which were obtained in the form of gums, and from Examples 43, 44 and 47, which were isolated in the form of amorphous solids). 6. Production of N-formyl compounds (I, Reaction Schemes la and lb): A mixture of the appropriate secondary amino compound (I, 0.005-0.01 mol), formic acid. (10 equivalents) and toluene (100 ml) were heated under reflux for 18 hours using a Dean-Stark trap. The reaction mixture was concentrated to dryness and the residue was dissolved in ethyl acetate. The organic phase was washed with 2N hydrochloric acid, dried and concentrated to dryness leaving the N-formyl compound (I). 7. Production of N-acyl compounds (I, Reaction Schemes la and lb): A mixture of the appropriate secondary amino compound (I, 0. 005-0.01 mol), pyridine (25 ml) and the selected acyl chloride R9C0C1 (1.2 equivalents) was heated at 80 ° C for two hours. The reaction mixture was concentrated to dryness and partitioned between ethyl acetate and 2M sodium hydroxide. The organic phase was washed with 2M hydrochloric acid, dried and concentrated to dryness, leaving the N-acyl compound (I). 8. Production of N-carboxylic acid ester compounds (I, Reaction Schemes la and lb): A mixture of the appropriate secondary amino compound (I, 0.005-0.01 mol), anhydrous potassium carbonate (5 equivalents), acetone ( 100 ml) and the selected chloroformate RgOCOCl (2 equivalents) was refluxed for 24 hours. The reaction mixture was concentrated to dryness, and the residue was partitioned between hydrochloric acid (100 ml, 2 M) and dichloromethane (300 ml). The organic phase was dried and concentrated to dryness to provide the N-carboxylic acid ester compound (I). 9. Production of the N-carboxylic acid amide compounds (I) and N-carbothioic acid amide compounds (I) (I, Reaction schemes la and lb): The appropriate secondary amino compound was dissolved (I, 0.005 -0.01 mol) in acetonitrile (25 ml) and treated with the selected isocyanate OCNR9 or the isothiocyanate SCNR9 (2 equivalents) at room temperature for 24 hours. The mixture was concentrated to dryness and the residue crystallized from methanol to give the title compound (I) • 10. Production of N-cyano compounds (I) (I, Reaction schemes la and Ib): A mixture of the appropriate secondary amino compound (I, 0.005-0.01 mol), 1,2-dimethoxyethane (10 ml) ), dry sodium carbonate (5 equivalents) and cyanogen halide such as cyanogen bromide (2 equivalents) was heated at 50 ° C for three hours. The reaction mixture was partitioned between dichloromethane (200 ml) and 2M hydrochloric acid (100 ml). The organic phase was dried and concentrated to dryness, which afforded the N-cyano compound (I), which crystallized from methanol. By appropriate use of the general synthesis steps 1-10 outlined above, the racemic compounds (I) were prepared according to Table 1 below. The melting points given in the table are not corrected. fifteen fifteen UJ 00 15 UJ Example 33-40: Synthesis of enantiomerically pure compounds (I) Example 33: (-) -1- (3,4,5-trimethoxyphenyl) -2-cyano-6-methoxy-1,2,3,4-tetrahydroisoquinoline 1 3-Methoxyphenylethylamine (25.0 g) was added to an aqueous solution of sodium hydroxide (200 ml, 2M) and dichloromethane (200 ml). To the vigorously stirred amine-containing mixture was added 3,4,5-trimethoxybenzoyl chloride (38.1 g) dissolved in dichloromethane (200 ml) for 30 minutes at room temperature. After the addition, the mixture was stirred for a further 60 minutes. The dichloromethane phase was separated, washed with hydrochloric acid (200 ml, 2M), dried (sodium sulfate) and concentrated to dryness. The residual amide (57.2 g) is suitable as a starting material without further purification for the production of the corresponding imine. An analytical mixture was obtained by crystallization from methanol, which gave a white solid, m.p. 115-117 ° C. 2. A mixture of the amide from step 1 (52.0 g), toluene (350 ml) and phosphorus oxychloride (140 ml) was heated under reflux for 1.5 hours. The reaction mixture was concentrated to dryness and partitioned between ethyl acetate (500 ml) and aqueous sodium hydroxide (400 ml, 2M). The formed imine was transferred to an aqueous phase by extraction of the organic phase with hydrochloric acid (3 x 300 ml, 2M), which was made alkaline (pH 11-12) and extracted with dichloromethane. The organic phase was dried and concentrated to dryness to give the imine (48.2 g). An analytical sample was obtained by crystallization from methanol, which yielded a white solid m.p. 141-143 ° C. 3. The imine produced in step 2 (69.3 g) was dissolved in a methane mixture (500 ml) and 1, 2- dimethoxyethane (300 ml) and treated with sodium borohydride at room temperature until no starting material remained (TLC: silica gel / methanol). The mixture was concentrated to dryness and partitioned between aqueous sodium hydroxide (500 ml, 2M) and dichloromethane (500 ml). The organic phase was separated, dried and concentrated to dryness, which gave the secondary amine "(67.8 g). An analytical sample was obtained by crystallization from ethyl acetate which gave a white solid, mp 118-120. C. The secondary amine (48.3 g) produced according to step 3 was dissolved in hot ethanol (600 ml) and the solution was added to N-acetyl-D-leucine (25.0 g) dissolved in hot ethanol, (200 ml) The mixture was allowed to settle to room temperature for 24 hours, after which it was filtered in. The retained crystals were washed with ethanol (200 ml) and dried which gave a white solid (60.0 g, 10.9%). ee) A second crystallization (59.7 g) from ethanol (1400 ml) gave a white solid (39.2 g, 37.9% ee) A third crystallization (39.0 g) from ethanol (1150 ml) gave a white solid (26.0 g, 77.2% ee) A fourth crystallization (25.7 g) from ethanol (900 m) l) provided a white solid (21.6 g, 99.9% ee). The product of the last crystallization was partitioned between dichloromethane (400 ml) and aqueous sodium hydroxide (400 ml, 2M). The organic phase was dried and concentrated to dryness, which left the enantiomer. (-) (13.9 g). Crystallization from ethanol gave the pure (-) enantiomer (12.4 g, 100.0% ee). The corresponding hydrochloride, crystallized from methanol, was used for characterization purposes, m.p. 270-275 ° C (dec), [a] D20 -46.8 ° (c = 0.051, DMF). 5. A mixture of the pure enantiomer (0.50 g) from step 4, 1, 2-dimethoxyethane (20 ml), sodium carbonate (0.30 g) and cyanogen bromide (0.35 g) was heated at 50 ° C for three hours. The reaction mixture was partitioned between dichloromethane (200 ml) and hydrochloric acid (100 ml, 2M). The organic phase was dried and concentrated to dryness. The residue crystallized from methanol, which afforded the title compound as a white solid (0.36 g), m.p.122-134 ° C, [a] D20-93.2 ° (c = 1.0, CHC13). Example 34: (-) -1- (3,5-dichlorophenyl) -2-acetyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline 1. 3-Methoxyphenylethylamine (18.1 g) was added to an aqueous solution of sodium hydroxide (200 ml, 2M) and dichloromethane (200 ml). To the vigorously stirred mixture containing the amine, 3,5-dichlorobenzoyl chloride was added (25.0 g) dissolved in dichloromethane (200 ml) for 30 minutes at room temperature. After the addition the mixture was stirred for a further 60 minutes. The dichloromethane phase was separated, washed with hydrochloric acid (200 ml, 2M), dried (sodium sulfate), and concentrated to dryness. The residual amide (40.6 g) is suitable without further purification as a starting material for the production of the corresponding imine. An analytical sample was obtained by crystallization from methanol, which yielded a white solid, m.p. 111-113 ° C. 2. A mixture of the amide from step 1 (35.8 g), toluene (200 ml) and phosphorus oxychloride (80 ml) was heated under reflux for 6 hours. The reaction mixture was concentrated to dryness and partitioned between ethyl acetate (500 ml) and aqueous sodium hydroxide (400 ml, 2M). The ethyl acetate phase was dried and concentrated to dryness. The residue crystallized from methanol which gave the imine (24.0 g), m.p. 110-113 ° C. 3. The imine from step 2 (18.2 g) was dissolved in methanol (300 ml) containing 1.05 equivalents of acetic acid and treated with an excess of sodium cyanoborohydride at room temperature until no starting material remained (TLC: silica gel-ethyl acetate). The mixture was concentrated to dryness and partitioned between aqueous sodium hydroxide (300 ml, 2M) and dichloromethane (400 ml). The organic phase was separated, dried, and concentrated to dryness, which afforded a secondary amine (17.7 g). An analytical sample was obtained by crystallization from ethanol p.p .. 122-124 ° C. 4. The secondary amine (46.0 g) produced according to step 3 was dissolved in hot ethanol (800 ml) and the solution was added to N-acetyl-D-leucine (25.84 g) dissolved in hot ethanol (650 ml). . The mixture was allowed to come to room temperature overnight, after which it was filtered. The retained crystals were washed with ethanol (150 ml) and then partitioned between dichloromethane (500 ml) and aqueous sodium hydroxide (400 ml, 2M). The organic phase was dried and concentrated to dryness, which afforded the levogylator enantiomer (6.9 g, 99.3% ee). Crystallization from ethanol gave the pure (-) - enantiomer (5.2 g), m.p. 94-95 ° C, [a] D20 -24.8 ° (c = 1.5, CHC13). 5. The (-) enantiomer of step 4 (1.6 g) was treated with acetic anhydride (100 ml) at 100 ml at room temperature for 24 hours. The mixture was then concentrated to dryness and the residue was partitioned between dichloromethane (200 ml) and hydrochloric acid (2M, 100 ml). The organic phase was dried and concentrated to dryness, which afforded the title compound as a white amorphous solid, [α] D20 -154.9 ° (c = 1.52, CHC13). Example 35: (-) -1- (2,6-dichloro-4-pyridyl) -2-formyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline 1. A mixture of 2,6-dichloroisonicotinic acid ( 26.1 g), thionyl chloride (140 ml) and 1,2-dimethoxyethane (70 ml) were refluxed for 6 hours. The excess thionyl chloride and the solvent were evaporated and an acid chloride remained. 3-Methoxyphenylethylamine (20.6 g) was added to an aqueous solution of sodium hydroxide (300 ml, 2M) and dichloromethane (400 ml).

To the vigorously stirred mixture containing the amine, the above acid chloride, dissolved in 1,2-dimethoxyethane (50 ml), was added for 30 minutes at room temperature. After the addition, the mixture was stirred for a further 60 minutes. The dichloromethane phase was separated, dried and concentrated to dryness. The residual amide crystallized from methanol, which gave a white solid, (31.6 g), p.f. 105-108 ° C. 2. A mixture of the amide produced according to step 1 (38.0 g), toluene (300 ml) and phosphorus oxychloride (80 ml) was heated under reflux for 5 hours. The reaction mixture was concentrated to dryness and partitioned between ethyl acetate (500 ml) and aqueous sodium hydroxide (400 ml, 2M). The formed imine was transferred to an aqueous phase by extraction of the organic phase with hydrochloric acid (5 x 300 ml., 2M), which was basified (pH 11-12) and extracted with dichloromethane. The organic phase was dried and concentrated to dryness, which gave the crude imine (27.3 g). Crystallization from methanol gave the imine (22.8 g). An analytical sample was obtained by recrystallization from acetone, which gave a white solid m.p. 130-133 ° C. 3. A mixture of a dimer of benzenethrhenium (II) chloride (19 mg), (-) - (SS, 2S) -N- (naphthalene-1-sulfonyl) -1,2-diphenylethylenediamine (31 mg) [G.J. Meuzelaar et al. Eur. J. Org. Chem. (1999) 2315-2321], triethylamine (0.5 ml) and acetonitrile was heated with stirring under nitrogen at 80 ° C for one hour. After cooling to room temperature, the imine from step II (4.0 g) dissolved in acetonitrile (10 ml) and an azeotropic mixture of formic acid and triethylamine (10 ml, 5: 2) were added to the mixture containing the catalyst. After 20 hours of reaction, the same amount of catalyst and the azeotropic mixture were added to the reaction mixture. After a total reaction time of 47 hours, the reaction mixture was partitioned between aqueous sodium hydroxide (250 ml, IM) and ethyl acetate.The organic phase was dried and concentrated to dryness. chromatography on silica gel (40-63 μM, 6x21 cm) using ethyl acetate as eluent The fraction containing the secondary amine was concentrated to dryness.

The residual amine was transferred to its hydrochloric salt by treatment with hydrogen chloride in methanol (1.25 M, 15 ml). crystallization from methanol gave the amine hydrochloride (0.72 g, 99.8% ee), m.p. 221-260 ° C (dec), [a] D20-28.9 ° (c = 0.72, DMF). 4. A mixture of the free amine from step 3 (0.60 g), formic acid (2 1) and toluene (100 ml) was heated under reflux for 18 hours using a Dean-Stark trap. The reaction mixture was concentrated to dryness and the residue was dissolved in ethyl acetate (200 ml), which was washed with aqueous sodium hydroxide (100 ml, 2M), dried and concentrated to dryness which gave the derivative formyl in the form of a solid. Crystallization from methanol gave the title compound as a white solid (0.52 g, 100.0% ee), m.p. 156-158 ° C, [a] D20 -213.1 ° (c = 1.05, CHC13). Examples 36-40: synthesis of five additional enantiomerically pure compounds (I) Enantiomerically pure compounds 34, 36 and 37 were synthesized from the enantiomerically pure secondary amine described in example 32, step 4, by using the steps described and generals noted above, 4-10. Compound 38 was synthesized from the enantiomerically pure secondary amine described in Example 31, step 4, by the use of the general synthesis step. Compound 35 was synthesized by reduction of l- (3,5- < ± i? Retaxyphenyl) -6-methaxy-3,4 ^ asymmetric transfer hydrogenation according to layer 33, step 3, followed by crystallization of the secondary amine hydrochloride formed from ethanol. The enantiomerically pure secondary amine was transferred to its formyl derivative by application of step 6 of the general synthesis description. The properties of compounds 34-38 are described in Lab 2 below: BIOLOGICAL DATA Study of the inhibition of cell growth in breast cancer cell lines Jurkat, MCF-7 and SK-MEL 28 28 MCF-7 and SK-MEL 28 cells (5000 cells / 100 μl) 96-well plates were transferred, and cultured, with or without test compounds, for 48 hours at 37 ° C in RPMI medium (Gibco) supplemented with 10% fetal calf serum containing penicillin and streptomycin (Gibco). The same procedure was followed for Jurkat cells, except for the cell density (-50000 cells / 100 μl) and the incubation time was limited to 24 hours. At the end of the incubation times, inhibition of cell growth of the Jurkat and SK-MEL 28 cell lines was determined by using CellTiter 96 (Promega) and MCF-7 with a methylene blue assay. It was found that the compounds of the examples had in the above assays a Cl50 of from 8 micrograms 8 / ml to 150 picogram / ml in at least one cell line. Cell death by apoptosis Jurkat and SK-MEL 28 cells were incubated with the compound (I) of the example, 3 during 6, 24 and 48 hours, after which the percentage of apoptotic cells was determined by staining with Annexin V. The results are described in Table 3 below.

The numbers that are described in the Table represent the percentage of Annexin-V positive cells. From the results of Table 3 above it is obvious that the compound of Example 3 induces apoptosis in the cell lines tested, but with a slower kinetics than that of SuperFasL. Interaction with cell division The mitotic index was determined after incubation of SK-Mel-28 cells with vehicle, compound (I) of example 3 and nocodazole for 4 hours (essentially as described by CL Rieder et al.: Current Biology 10 (2000) 1067-1070] The results are given in Table 4 below.

The substances tested blocked the cells in the prophase stage of mitosis. Inhibition of phosphorylation of IGF-IR and insulin receptor (IR) in SK-MEL-28 IGF-1R: Test without treatment with compounds (I). (Essentially as described by M. Rubini et al., Exp. Cell Res. 230 (1997) 284-292). Cells SK-MEL-28 (density 60000 / cm2; disc with a diameter of 100 mm containing 10 ml of RPMI 1640) were left in starvation for 24 hours at 37 ° C and then treated for 5 minutes at 37 ° C. ° C with IGF-1 (200 ng, Sigma). The untreated cells served as control. The cells were used and subjected to immunoprecipitation using a specific antibody against IGF-IR (alpha-IR3, Oncogene Science). The immunoprecipitates were separated by electrophoresis with polyacrylamide gel and transferred to nitrocellulose membrane (Amersham Bioscience). The immunoprecipitated IGF-1 receptor was placed on the nitrocellulose membrane using an antibody against the alpha subunit of IGF-1R (N-20: sc-712, Santa Cruz Biotech.). The detection of tyrosine phosphorylation of the IGF-1 receptor was carried out by incubating the nitrocellulose membranes with an anti-phosphotyrosine antibody (4G10, Upstate Biotechnology Ltd., UK). To reveal rabbit polyclonal anti-IGF-1R antibody and anti-phosphotyrosine mouse monoclonal antibody, the membranes were incubated with anti-mouse IgG antibody and anti-mouse IgG coupled to HRP, respectively, and visualized by the use of a detection system by increased chemilumincency (ECL) (Pierce). IGF-IR: Test with treatment with compounds (I) Starved SK-MEL-28 cells (60000 cells / cm2; disk plate 100 mm in diameter, containing 10 ml RPMI 1640) were treated for two hours with 10 micrograms of compound 31. After two hours of treatment the cells were stimulated for 5 minutes at 37 ° C with 200 mg of IGF-1, and then treated as described above. Table 5: Percentage of phosphorylation 'IGF-IR in SK-MER-28 cells IR: Test with and without treatment with the compounds (I). SK-MEL-28 cells (density 60000 / cm2) were grown in 100 mm diameter dishes containing 10 ml RPMI 1640 supplemented with 10% fetal bovine serum (FBS) for 24 hours. After 24 hours fresh medium supplemented with 10% FBS was added together with or without 1 microgram / ml of compound 33. The plates were incubated at 37 ° C for 2 hours, after which the cells were lysed and subjected to immunoprecipitation using 2 microliths and an anti-IR monoclonal antibody (18-44, ABCAM) and 20 microliters of G protein conjugated with agarose. Antibody-antigen complexes were left to form for 4 h at 4 ° C and then harvested by c-centrifugation at 4 ° C for 1 minute at 5000 rpm. The immunoprecipitated complexes were separated by electrophoresis on an 8% polyacrylamide gel by electroblotting on a nitrocellulose membrane (Amersham Bioscience). The efficiency of immunoprecipitation was determined by the use of a polyclonal antibody against the beta-subunit of the insulin receptor (C-19, Santa Cruz Biotech.). Detection of tyrosine phosphorylation of the insulin receptor was carried out by incubating the nitrocellulose membranes with an anti-phosphotyrosine antibody (4G10, Upstate Biotechnology Ltd., UK). To reveal the anti-IR rabbit polyclonal antibody and the antiphosphotyrosine mouse monoclonal antibody, the membranes were incubated with anti-mouse anti-IgG and anti-mouse IgG antibodies, respectively, and visualized by the use of an enhanced chemiluminescence detection system ( ECL) (Pierce). No difference was detected in the phosphorylation of the insulin receptor between the untreated cells and the cells treated with 1 microgram / ml of the compound 33. It is noted that in relation to this date, the best method known by the applicant to carry the practice said invention is that which is clear from the present description of the invention.

Claims (20)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. Compound having the following general formula (I): characterized in that R2 designates hydrogen, Me, Et, CHO, CN, OH, OMe, COR9, COOR9, CONHR9 or CSNHR9, where R9 denotes (C1-C4) alkyl; R5 denotes hydrogen, alkyl (C? -C), OH, alkoxy (d.-C4), OCF3, trifluoromethyl or halogen; R6 designates Me, alkoxy (Ca-C4), OCF3, SMe or SEt; n is 1 or 2; R3"and Rs' each independently denote OH, Me, Et, OMe, OCF3, trifluoromethyl or halogen, U designates N or CR2 ', where R2' denotes hydrogen, (C? -C4) alkyl, (C? -C4) alkoxy ), trifluoromethyl or halogen, V denotes N or CR4, where R4"denotes hydrogen, (C-C6) alkoxy, (C? -Ce) alkyl, OH, trifluoromethyl or halogen; W designates N or CRs, where R6"denotes hydrogen, (C1-C4) alkyl, (C1-C4) alkoxy, trifluoromethyl or halogen, and the pharmaceutically acceptable salts thereof ..
2. 2. Compound according to claim 1, characterized in that R2 designates Me, OH, CN, CHO, COR9, COOR9, CONHR9 or CSNHR9.
3. Compound according to claim 1, characterized in that R2 designates Me, CN, CHO or COMe.
4. 4. Compound according to any of claims 1 to 3, characterized in that R5 designates hydrogen, Me, OMe or halogen.
5. Compound according to any of claims 1 to 4, characterized in that Re designates OMe or OEt.
6. 6. Compound according to any of claims 1 to 3, characterized in that R5 designates hydrogen or OMe, preferably hydrogen; and Rs designates OMe.
7. 7. Compound according to any of claims 1 to 6, characterized in that R3 'and R5' each independently designate chlorine, bromine, Me or OMe.
8. Compound according to claims 1 to 7, characterized in that R3"and R5 'are identical, or R3" designates chlorine or bromine, and R5' designates OMe.
9. Compound according to claim 7, characterized in that R3 'and R5"designate both chlorine or both bromine
10. 10. Compound according to any of claims 1 to 9, characterized in that U and W designate CH and V designates CR'
11. 11. Compound according to claim 10, characterized in that R4 'designates hydrogen, chlorine, bromine, Me or OMe
12. 12. Compound according to claim 10, characterized in that R3', R4 'and Rs' designate OMe; R3 'designates chloro and R4' and R5 'denote OMe; or R4' designates hydrogen and R3 'and R5' denote both chlorine or both bromine
13. 13. Compound according to claim 1, characterized by consisting of: 1- (3 , 5-dichlorophenyl) -2-formyl-6-methoxy-l, 2,3,4-tetrahydroisoquinoline, 1- (3,5-dichlorophenyl) -2-acetyl-6-methoxy-1, 2,3,4- tetrahydroisoquinoline, 1- (3,5-dichlorophenyl) -2-cyano-6-methoxy-l, 2,3,4-tetrahydroisoquinoline, 1- (3, 5-dibro ofenyl) -2-formyl-6-methoxy-1 , 2,3,4-tetrahydroisoquinoli Na, 1- (3,5-dibromophenyl) -2-acetyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline, 1- (3,5-dibromophenyl) -2-cyano-β-methoxy-1, 2,3,4-tetrahydroisoquinoline, 1- (3,5-dimethoxyphenyl) -2-formyl-6-methoxy-l, 2,3,4-tetrahydroisoquinoline, 1- (3,5-dimethoxyphenyl) -2-acetyl- 6-methoxy-1,2,3,4-tetrahydroisoquinoline, 1- (3,5-dimethoxyphenyl) -2-cyano-6-methoxy-1,2,4,4-tetrahydroisoquinoline, 1- (3,4,5 -trimetoxifenii) -2-formyl-6-methoxy-l, 2,3,4-tetrahydroisoquinoline, 1- (3,4,5-trimethoxyphenyl) -2-acetyl-6-methoxy-1, 2,3, 4- tetrahydroisoquinoline, 1- (3,4,5-trimethoxyphenyl) -2-cyano-6-methoxy-l, 2,3,4-tetrahydroisoquinoline, 1- (3-chloro-4,5-dimethoxyphenyl) -2-formyl- 6-methoxy-1,2,3,4-tetrahydroisoquinoline, 1- (3-chloro-4,5-dimethoxyphenyl) -2-acetyl-6-methoxy-l, 2,3,4-tetrahydroisoquinoline, 1- (3 -chloro-4,5-dimethoxyphenyl) -2- cyano-6-methoxy-1,2,3,4-tetrahydroisoquinoline, 1- (3,5-dichlorophenyl) -2-formyl-6-ethoxy-1,2, 3,4-tetra idioisoquinoline, 1- (3,5-dichlorophenyl) -2-ac ethyl-6-ethoxy-1,2,3,4-tetrahydroisoquinoline1- (3, 5-dicyclophenyl) -2-cyano-6-ethoxy-l, 2,3,4-tetrahydroisoquinoline, 1- (3,5-dibromophenyl) -2-formyl-6-ethoxy-2, , 3,4-tetrahydroisoquinoline, 1- (3,5-dibromophenyl) -2-acetyl-6-ethoxy-1, 2,3,4-tetrahydroisoquinoline, 1- (3,5-dibromophenyl) -2-cyano-6 -ethoxy-l, 2,3,4-tetrahydroisoquinoline, 1- (3,5-dimethoxyphenyl) -2-formyl-6-ethoxy-l, 2,3,4-tetrahydroisoquinoline, 1- (3,5-dimethoxyphenyl) -2-acetyl-6-ethoxy-1,2,3,4-tetrahydroisoquinoline, 1- (3,5-dimethoxyphenyl) -2-cyano-6-ethoxy-l, 2,3,4-tetrahydroisoquinoline, 1- ( 3, 4, 5-trimethoxyphenyl) -2-formyl-6-ethoxy-1, 2,3,4-tetrahydroisoquinoline, 1- (- (3, 4, 5-trimethoxyphenyl) -2-acetyl-6-ethoxy-1 , 2, 3, 4-tetrahydroisoquinoline, 1- (3,4,5-trimethoxyphenyl) -2-cyano-6-ethoxy-1, 2,3,4-tetrahydroisoquinoline, 1- (3-chloro-4,5) dimethoxyphenyl) -2- formyl-6-ethoxy-l, 2,3,4-tetrahydroisoquinoline, 1- (3-chloro-4,5-dimethoxyphenyl) -2-acetyl-6-ethoxy-l, 2,3,4 - tetrahydroisoquinoline p 1- (3-chloro-4,5-dimethoxyphenyl) -2- cyano-6-ethoxy-1, 2, 3, 4-tetrahydroisoquinoline, l- (3,5-dichlorophenyl) -2-formyl-5,6-dimethoxy-l, 2,3,4-tetrahydroisoquinoline, 1- (3,5-dichlorophenyl) -2- acetyl-5,6-dimethoxy-1, 2,3,4-tetrahydroisoquinoline, 1- (3,5-dichlorophenyl) -2-cyano-5,6-dimethoxy-1,3,4-tetrahydroisoquinoline 1- (3, 5-dibromophenyl) -2-formyl-5,6-dimethoxy-1, 2,3,4-tetrahydroisoquinoline, 1- (3,5-dibromophenyl) -2-acetyl-5,6-dimethoxy-1, 2,3,4-tetrahydroisoquinoline, 1- (3,5-dibromophenyl) -2-cyano-5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline, 1- (3,5-dimethoxyphenyl) -2- formyl-5,6-dimethoxy-1,2,4-tetrahydroisoquinoline, 1- (3,5-dimethoxyphenyl) -2-acetyl-5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline 1- (3, 5-dimethoxyphenyl) -2-cyano-5,6-dimethoxy-l, 2,3,4-tetrahydroisoquinoline, 1- (3,4,5-trimethoxyphenyl) -2-formyl-5,6-dimethoxy- 1, 2,3,4-tetrahydroisoquinoline, 1- (3,4,5-trimethoxyphenyl) -2-acetyl-5,6-dimethoxy-1,2,4,4-tetrahydroisoquinoline, 1- (3, 4, 5 -trimethoxyphenyl) -2-cyano-5,6-dimethoxy-1, 2,3, 4-tetr ahydroisoquinoline, 1- (3-chloro-4,5-dimethoxyphenyl) -2-formyl-5,6-dimethoxy-l, 2,3,4-tetrahydroisoquinoline, 1- (3-chloro-4,5-dimethoxyphenyl) - 2- acetyl-5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline or 1- (3-chloro-, 5-dimethoxyphenyl) -2-cyano-5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline , or a pharmaceutically acceptable salt thereof.
14. 14. Compound according to any of claims 1 to 13, characterized in that it consists of the (R) - or (S) - enantiomer.
15. 15. Compound according to any of claims 1 to 14, characterized in that it is used as a medicine.
16. 16. Use of a compound according to any of claims 1 to 14, for the preparation of a medicament for the prophylaxis or treatment of a disease in which the down regulation or the inhibition of the expression or function of the IGF- receptor 1 is beneficial.
17. 17. Use according to claim 16, wherein the disease is selected from cell proliferation diseases such as cancer, atherosclerosis, restenosis, inflammatory diseases such as psoriasis, autoimmune diseases such as rheumatoid arthritis and rejection of transplants.
18. 18. A pharmaceutical composition characterized in that it comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof as defined in any of claims 1 to 14, and a pharmaceutically acceptable additive, diluent or carrier.
19. 19. Items characterized in that they contain a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to any of claims 1 to 14, and a chemotherapeutic agent, in the form of a combination for simultaneous, separate or successive administration in the therapy of a disease in which the down regulation or the inhibition of the expression or function of the IGF-1 receptor is beneficial.
20. 20. Use of a compound of the formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 14, as a pharmacological tool in the development and standardization of in vitro and in vivo assay systems for the evaluation of the effects of inhibitors of cell cycle activity in laboratory animals.