HK1099291B - Pyrimidine derivatives antagonists of vitronectin receptor - Google Patents

Description

The present invention relates to novel vitronectin receptor antagonist derivatives, their preparation process, their use as medicinal products and the pharmaceutical compositions containing them.

The invention relates to pyrimidine derivatives of general formula (I): - What? wherein R, R1, R2, R3 and R4 have the meanings given below, as well as their isomeric forms and their physiologically acceptable mixtures and salts. Formula (I) compounds are compounds with pharmacological activity and are therefore usable as medicines. They are vitrectin receptor antagonists and cell adhesion inhibitors and they inhibit bone resorption by osteoclasts. They are therefore useful for the therapeutic or prophylactic treatment of diseases that are caused at least in part by an unwanted increase in bone resorption, e.g. osteoporosis.

Bone formation is the result of the deposition of a mineral matrix by osteoblasts and bone resorption is the result of the dissolution of this bone matrix by osteoclasts. The majority of disorders at the bone level are based on a disturbed balance between bone formation and bone resorption. Osteoporosis is characterized by a dry loss of this bone matrix. A mature osteoclast activates bone after adhesion to the bone matrix via enzyme secretion, and proteolytic proteases break down inside the bone, or at the time of osteoclast depression, which occur at the surface of the bone.

Studies have shown that the binding of osteoclasts to bone is mediated by receptors: integrins. Integrins are a superfamily of receptors mediating cell/cell adhesion processes and more specifically cell/matrix, including αIIbβ3 as a platelet receptor (fibrinogen) and αvβ3 as a vitronectin receptor. Peptides containing the RGD motif as well as anti-αvβ3 antibodies are known for their ability to inhibit dentin absorption and to prevent osteoclasts from binding to mineralized matrices (Horton et al. Resolutions (1991, 195, 368). Echinolesterol, a receptor of isocyanate and isocyanate, is also a potent inhibitor of the absorption of dentin in vivo in rats and rats (Rocan et al. Resolutions (1992, 1711, 1913, 1711), and in vitro in the tissue of J. and J. Fischer (1993, 1993).

The αvβ3 receptor is a transmembrane glycoprotein that is expressed in a large number of cells including endothelial cells, smooth muscle cells, osteoclasts and cancer cells, resulting in pluripotentiality of the compounds of formula (I) according to the invention.

The αvβ3 receptors expressed at the membrane level of osteoclasts underlie the adhesion/resorption process, contribute to the organization of the cell cytoskeleton, and are involved in osteoporosis. The αvβ3 receptors expressed at the level of the smooth muscle cells of the aorta stimulate their migration to the neointima, which leads to the formation of arteriosclerosis and the occurrence of postangioplastic restenosis (Brown et al., cardiovascular Res. (1994), 28, 1815).

Integrin αvβ3 antagonists may thus cause cancer tumours to regress by inducing the apoptosis of angiogenic blood vessels (Brook et al. Cell (1994) 79, 1157).

Cheresh et al (Science 1995, 270, 1500) described anti-αvβ3 antibodies or αvβ3 receptor antagonists that inhibit the bFGF-induced angiogenesis process in the rat eye, a property that may be used for the treatment of retinopathies, particularly diabetic retinopathy.

The patent application WO-A-94/12181 describes substituted aromatic or non-aromatic systems and WO-A-94/08577 describes substituted heterocycles as fibrinogen receptor antagonists and platelet aggregation inhibitors. EP-A-528586 and EP-A-528587 describe phenylalanine derivatives substituted by an aminoalcohol or heterocycle and WO-A-95/32710 describes arylic derivatives as inhibitors of bone resorption by osteoclasts. WO-A-96/00574 describes benzodiazines and WO-A-96/00730 describes compounds in the fibrinogen receptor, in particular benzodiazepine as a receptor antagonist of cyclohexanone, which are antagonists of the cyclohexanine receptor. WO-A-92499 and WO-A-9379 describe antagonists of the cyclohexanine receptor, in particular azothiazide.

Further investigations have shown that formula (I) derivatives exhibit strong activity as antagonists of the vitronectin receptor and osteoclast-mediated bone resorption. WO 2004048375 describes compounds based on formula (I) where R is a nitrogen-bound piperidine, and substituted at position 4; which compounds are excluded from the present invention, and complementary to those described below.

The invention relates to compounds of formula (I): in their pure stereoisomeric forms and mixtures of these stereoisomers, and, where appropriate, pure E isomers, pure Z isomers and mixtures of E/Z, and their physiologically acceptable additive salts and solvates of these compounds, of which: (i) the R is ■ a radical - What? where G is: - What? and G itself may be substituted by a radical (C1-C8) alcoylamino, the alcoholic part of which in the straight or branched chain may be substituted by a phenyl or heterocyclic radical with 5 or 6 chains containing 1 to 4 heteroatoms chosen from nitrogen,The following is a list of the substances which are to be classified as 'n' in the Annex to this Regulation: where G is: - What? and G is substituted by an alcohol radical ((C1-C6) amino whose alcoholic radical can itself be substituted by a 5- or 6-chain aromatic phenyl or monocyclic heterocyclic radical, containing a heteroatom chosen from nitrogen, oxygen or sulphur;R1 represents a hydrogen atom; a (C5-C14) -aryl group; (C5-C14) -aryl- (C1-C4) -alcoyl-; an unsubstituted amino radical, monosubstituted or dissubstituted by an alcoholic radical and/or an acyl radical containing 1 to 4 carbon atoms;R2 represents a hydrogen atom; a carbon atom; a substitution radical; a radical containing 1 or 4 carbon atoms; or a radical containing 1 or 4 acyl groups;CHOR represents a substitution radical containing 1 or 4 carbon atoms; or -R2 represents a substitution radical containing 1 or 4 acyl groups; or -R2 represents a substitution radical containing 1 or 2 carbon atoms; or -R2 represents a substitution radical containing 1 or 2 carbon atoms; or -R2 represents a substitution radical containing 1 or 4 carbon atoms; or -R2 represents a substitution radical containing 1 or 4 acyl groups; or -R2 represents a substitution radical containing 1 or -R2 -R2 represents a substitution radical containing 1 or -R2 atoms; or -R2 represents a substitution radical containing 1 or -R2 atoms; or -R2 represents a substitution radical containing 1 or -R2 atoms; or -R2 represents a substitution radical containing 1 or -R2 -R2 represents a substitution radical containing 1 or -R2 atoms; or -R2 represents a substitution radical containing 1 or -R2 -R2 represents a substitution radical containing -R2 or -R2 or -R2 or -R2 -R2 represents a substitution of -R2 or -R2); ■ one hydrogen atom ■ one radical - CO2R5,■ a radical -SO2R5 or■ a monocyclic or polycyclic system, each cycle consisting of 4 to 10 aromatic or non-aromatic chains, the cycle or at least one of the cycles containing 1 to 4 heteroatoms selected from N, O or S, whether or not substituted by one or more radicals R°,R4 represents OH; (C1-C8) -alkoxy-; (C5-C14) -aryl-(C1-C4) -alkoxy-; (C5-C14) -aryloxy-; (C3-C12) -cycloalcoyloxy; (C3-C12) -cycloalcoyl-C1-C1-C4-alcoyloxy; (C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C4-C1-C1-C1-C1-C1-C1-C1-C1-C1-C4-C1-C1-C1-C1-C1-C1-C1-C1-C1-C4-C1-C1-C1-C1-C1-C1-C1-C1-C4-C1-C1-C1-C1-C1-C1-C1-C1-C1-C4-C1-C1-C1-C1-C1-C1-C1-C1-C4-C1-C1-C1-C1-C1-C1-C4-C1-C1-C1-C1-C1-C1-C4-C1-C1-C1-C1-C1-C4-C1-C1-C1-C1-C1-C1-C4-C1-C1-C1-C4-C1-C1-C1-C1-C1-C4-C1-C1-C1-C1-C1-C4-C1-C1-C1-C1-C4-C1-C1-C1-C1-C4-C1-C1-C1-C1-C4-C1-C1-C1-C4-C1-C1-C1-C4-C1-C1-C1-C4-C1-C1-C1-C4-C1-C1-C4-C1-C1-C1-C1-C1-C4-C4-C1-C1-C4-C1-C1-C4-C1-C4-Cycloalcoyl- ((C1-C4) -alcoyl-, tricycloalcoyl- ((C1-C4) -alcoyl-, the so-called arylic radicals, alcohols, cycloalcoyles, bicycloalcoyles and tricycloalcoyles, not substituted or replaced by one or more groups Ro;Ro is a halogen; amino; nitro; hydroxyl, (C1-C4) -alcoyloxy-; (C1-C4) -alcoylthio; (C1-C4) -alcoylsulfonyl-; carboxy; (C1-C4) -alcoyloxycarbonyl-; (C1-C8) -alcoyl not substituted or replaced by one or more hydrogen atoms, (C5-C14) -Caryle (C1-C1-C1-C1-C1-C4-C1-C1-C1-C1-C1-C4-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C4-C5-C5-C5-C5-C1-C1-C1-C1-C1-C4-C1-C1-C1-C1-C1-C1-C1-C1-C1-C4-C5-C5-C5-C5-C5-C4-C5-C5-C5-C4-C5-C5-C5-C5-C5-C4-C5-C5-C5-C5-C4-C5-C5-C5-C5-C5-C5-C4-C5-C5-C5-C4-C5-C5-C5-C5-C5-C4-C5-C5-C5-C4-C5-C5-C5-C5-C5-C5-C4-C5-C5-C5-C5-C5-C4-C5-C5-C5-C5-C4-C5-C5-C5-C5-C5-C5-C5-C4-C5-C5-C5-C5-C4-C5-C5-C5-C5-C5-C5-C5-C5-C5-C4-C5-C5-C5-C5-C5-C4-C5-C5-C5-C5-C4-C5-C5-C5-C5-C5-C5-C5-C4-C5-C5-C5-C5-C5-C5-C5-C4-C5-C5-C5-C5-C-C5-C or II) R is a radical - What? where G is: - What? and G which may or may not be itself substituted by one or more Ro groups;R1 is an alcoholic radical containing 1 to 4 carbon atoms in a straight or branched chain; a cycloalcoholic radical containing 3 to 6 carbon atoms; or an alkoxy or alkoxy-thionic radical with the alcoholic part containing 1 to 4 carbon atoms in a straight or branched chain;R2R3, R4 and R5 are defined as previously in I;Ro is defined as previously in I; or (III) R is defined as previously in II;R1, R3, R4 and R5 are defined as previously in I;R2 is a hydroxymethyl radical, a formal radical, or a disubstituted amino radical whose substituents together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocycle containing 4 to 6 chains; andRo is defined as previously in I; orIV) R is defined as previously in II);R1, R2, R4 and are defined as previously in I);R3 is ■ a straight or branched alcoholic (C1-C4) or alkenyl (C2-C4) radical,Err1:Expecting ',' delimiter: line 1 column 969 (char 968)Err1:Expecting ',' delimiter: line 1 column 748 (char 747)with the nitrogen atom to which they are attached, an arylamine radical, aralcoyl ((C1-C4) amino or heteroaralcoyl ((C1-C4) amino whose aryl or heteroaryl radical is monocyclic or polycyclic and comprises 5 to 10 chains, the heteroaryl radical may comprise 1 to 4 heteroatoms chosen from nitrogen, oxygen or sulphur; andRo is defined as I above; or V) R, R2, R3 and R4 are defined as previously in I); R1 is defined as previously in II); or (VI) R, R1, R3 and R4 are defined as previously in II; orVII) R, R1 and R2 are defined as previously in I) ;R4 is defined as previously in I); andR3 is defined as previously in IV); or VIII) R,R1 and R2 are defined as previously in II; R4 is defined as previously in I; andR3 is defined as previously in IV); orIX) R and R3 are defined as previously in I);R4 is defined as previously in I);R1 is defined as previously in II) ; andR2 is defined as previously in III) ; or X) R and R2 are defined as previously in I);R4 is defined as previously in I);R1 is defined as previously in II); andR3 is defined as previously in IV); or XI) R and R1 are defined as previously in II);R4 is defined as previously in I);R2 is defined as previously in III); andR3 is defined as previously in IV) orXII) R and R4 are defined as previously in I;R1 is defined as previously in II;R2 is defined as previously in III;R3 is defined as previously in IV; provided that the radicals according to definitions I to XII above cannot have the meaning simultaneously R is a radical (Ib) where G is 1,2,3,4-tetrahydro-1,8-naphtyridin-7-yl,R1 is methyl,R2 is methyl,R3 is benzyloxycarbonyl andR4 is OH or t.butoxy.

All radicals that can occur multiple times in compounds of formula (I), such as the radical Ro, are independent of each other and can be identical or different.

It is understood that the radicals or alcoholic portions may be straight or branched.

Cycloalcoyl radicals may be monocyclic, bicyclic or tricyclic. For example, monocyclic radicals may be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyyl, cyclotetracycyl or cycloctadecyyl which may be substituted, for example, by an alcohol containing 1 to 4 carbon atoms in a straight or branched chain.

The bicycloalcoholic and tricycloalcoholic radicals may be unsubstituted or substituted in any position, for example by one or more oxo radicals and/or 1 or more identical or different alcohol radicals such as methyl, ethyl or isopropyl, preferably methyl. The junction bond of the bicyclic or tricyclic radical may be at any position in the molecule. The bond may be at the level of a bridged carbon atom or one of the other carbon atoms. This bond may also have any position from the point of view of stereochemistry, for example exoboryls.

Halogen is fluorine, chlorine, bromine or iodine.

The term (C5-C14) -aryle means: or (C5-C14) -heterocyclic (or (C5-C14) -heterocyclic) aryl radicals, in which one or more carbon atoms in the cycle are replaced by a heteroatom such as nitrogen, oxygen or sulphur,or (C6-C14) -carbocyclic aryl radicals.

Carbocyclic C6-C14-aryl radicals include phenyl, naphthyl, anthryl or fluorenyl and particularly 1-naphthyl, 2-naphthyl and phenyl.

Unless otherwise specified, the arylic radicals, in particular phenyl, may be unsubstituted or substituted by one or more identical or different radicals selected from among (C1-C8) -alcoyl, in particular (C1-C4) -alcoyl, hydroxyl, (C1-C8) -alcoyl, (C1-C8) -alcoyl, halogen, fluorine, chlorine and bromine, nitro, amino, (C1-C4) -alcoylamino, di-(C1-C4) -alcoylamino, trifluoethyl, methyldioxy, cyano, carbamoyl, (C1-C4) -alcoyl, di-C1-C4-alcoyl, carboxy, (C1-C4) -alcoyl, benzyl, phenylexy, benzyl, benzyl, benzyl.

In the case of a monosubstituted phenyl radical, the position of the substituents is indifferent, preferably it is substituted in position 3 or 4. In the case of the phenyl being di-substituted, the position of the substituents is indifferent. Preferably the 2 substituents are in position 3.4. When the phenyl is tri-substituted the position of the substituents is indifferent. Similarly, naphthyl radicals or other arylic radicals can be substituted in any position.

When the (C5-C14) -aryl group represents a monocyclic or polycyclic aromatic system in which 1 to 4 carbon atoms in the cycle are replaced by heteroatoms, identical or different from nitrogen, oxygen and sulphur, or when the heteroaryl meaning is used, the pyridyl, pyrrolyl, furyl, thienyl, imidazoleyl, pyrazolyl, oxazoleyl, isoxazoleyl, thiazoleyl, isothiazoleyl, tetrazolyl, pyridyl, pyrazol, pyrimidyl, indoxy, isocinyl, indoxy, phenylethyl, indazole, quinol, quine, naphyr, cyclohexal, quinopyrazole, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone

Heterocyclic radicals are, unless otherwise specified, monocyclic or polycyclic aromatic or not, and may be selected, inter alia, but not limited to, from pyrrolyl, pyrazolyl, imidazolyl, triazinyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazolyl, pyrannyl, thiopyrannyl, indolyl, isozinyl, benzofurannyl, isobenzofurannyl, benzopropenyl, indazolyl, indozinyl, tinyl, benzozinyl, iminyl, iminyl, benzopropenyl, quinzoid, quinzoid, quinzoid, quinzoid, quinzoid, quinzoid, quinzoid, quinzoid, quinzoid, quinzoid, quinzoid, quinzoid, quinzoid, quinzoid, quinzoid, quinzoid, quinzoid, quinzoid, quinzoid, quinzoid, quinzoid, quinzoid, quinzoid, quinzoid, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo, quinzo

The optically active carbon atoms contained in the compounds of formula (I) may independently of each other have the R or S configuration.

The compounds of formula (I) may be in the form of pure enantiomers or diastereoisomers or in the form of a mixture of enantiomers, e.g. in the form of racemates or diastereoisomer mixtures.

The present invention therefore covers pure enantiomers, mixtures of these enantiomers, pure diastereoisomers and mixtures of these diastereoisomers.

The invention includes mixtures of two or more stereoisomers of formula (I) and all ratios of these stereoisomers within the said mixtures.

The compounds of formula (I) may be present as isomers E or Z, as appropriate. The invention therefore concerns pure E isomers, pure Z isomers and mixtures E/Z according to any ratio.

Stereoisomers as well as E and Z isomers can be separated into pure forms by known methods, e.g. by chromatography, chiral phase chromatography or crystallization.

Physiologically acceptable salts of formula (I) compounds are in particular pharmaceutically usable or non-toxic or physiologically usable salts.

When compounds of formula (I) contain an acid group such as carboxylic acid, the salts may be e.g. salts of alkaline or alkaline earth metals such as sodium, potassium, magnesium, calcium salts, addition salts with physiologically acceptable amines such as triethylamine, ethanolamine or tris- (((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((())))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))

When compounds of formula (I) contain a base group, they may form addition salts with acids e.g. with mineral acids such as hydrochloric, sulphuric, phosphoric or with carboxylic acids such as acetic, trifluoroacetic, citric, benzoic, maleic, fumaric, tartaric, methanesulfonic or p-toluenesulfonic acids.

Compounds of formula (I) containing a base group and an acid group may be present as zwiterions (betaines), which are also included in the present invention.

Where appropriate, a physiologically acceptable Q- anion may be contained in compounds of formula (I) containing a charged ammonium group. This is preferably a monovalent anion or a polyvalent anion equivalent of a non-toxic, physiologically acceptable and particularly pharmaceutically acceptable organic or mineral acid, e.g. the anion or an anion equivalent of one of the above acids useful for the formation of addition salts.

Q- may be, for example, one of the anions (or anion equivalent) of a group selected from chlorine, sulphate, phosphate, acetate, trifluoroacetate, citrate, benzoate, maleate, fumarate, tartrate, methanesulfonate and p-toluenesulfonate.

Salts of formula (I) compounds may be obtained by ordinary methods known to the professional, for example by combining a formula (I) compound with an organic or inorganic acid or base in a suitable solvent or dispersant or from another salt by cation or anion exchange.

The invention also includes all salts of formula (I) compounds which, because of their low physiological acceptability, are not directly usable as medicinal products but are usable as intermediates for purification, or to implement further chemical modifications at the level of formula (I) compounds or as starting products for the preparation of physiologically acceptable salts.

The present invention also includes all solvates of formula (I) compounds e.g. hydrates, solvates formed with alcohols, and all derivatives of formula (I) compounds e.g. esters, prodrugs and other physiologically acceptable derivatives, as well as metabolites of formula (I) compounds.

The prodrugs of formula (I) compounds, i.e. derivatives of formula (I) compounds chemically modified to obtain desired improved properties, are known to the trade.

For further information on the type of prodrug envisaged in the present invention, reference may be made to the following works: Fleicher et al., Advanced Drug Delivery Review 19 (1996) 115-130; Design of prodrugs, H. Bundgaard, Ed., Elsevier, 1985; H. Bungaard, Drugs of the Future 16 (1991) 443; Saulnier et al. Bioorg. Med. Chem. Lett. 4 (1994) 1985; Safadi et al. Pharmaceutical Res. 10 (1993) 1350. prodrugs in the form of esters of carboxylic groups, prodrugs in the form of acyl and carbamate for groups containing an acylable nitrogen such as amino groups.

In acylated prodrugs or in the form of a carbamate, once or more, for example twice, a hydrogen atom on the nitrogen atom is replaced by an acyl or carbamate group. Preferred acyl or carbamate groups include the groups R6CO-, R7OCO-, in which R6 is a hydrogen or a radical (C1-C18) -alkyl, (C3-C14) -cycloalkyl, (C3-C14) -cycloalkyl-(C1-C8) -alkyl, (C5-C14) -aryl, in which 1 to 5 carbon atoms can be replaced by heteroatoms such as N, O, Sky or (C5-C14) -aryle-C1-Calkyl, in which 5 carbon atoms can be replaced by the same heteroatoms, such as R6 and S7 in the aryl, except that the heteroatoms can be replaced by the same atoms, such as R6 and S7 in the aryl.

The invention relates in particular to compounds of formula (I) where G is: - What?

The invention relates in particular to compounds of formula (I) as defined above in which R3 is a benzyloxycarbonyl group, or in which R3NH- forms an amide or urea function and their pharmaceutically acceptable additive salts.

The invention relates in particular to compounds of formula (I) as defined above in which R2 is a hydrogen, an alcoholic radical containing 1 to 4 carbon atoms, particularly methyl and ethyl, a hydroxymethyl radical or a fluorine atom and their pharmaceutically acceptable additive salts.

The invention relates in particular to compounds of formula (I) as defined above in which R1 is an alcoholic radical containing 1 to 4 carbon atoms in a straight or branched chain, or a cycloalcool containing 3 to 6 carbon atoms.

The present invention also concerns a process for the preparation of compounds of formula (I). Compounds may generally be prepared, for example by convergent synthesis by coupling of two or more fragments which can be derived by retrosynthesis of compounds of formula (I). To prevent the functional groups from leading to adverse or secondary reactions during each synthesis step, it may be advantageous or necessary prior to some phases of synthesis of compounds of formula (I) to introduce the functional groups as precursors which are subsequently converted into desired temporary groups or to protect these functional groups according to methods for the establishment and elimination of protective radicals which are not known to remain in the protective molecule; in particular, Wiley, Greene Organic Synthesis Group (1991).

According to the invention, products of general formula (I) can be prepared as follows: wherein R1, R2, R3, R4 and R are defined as above in I) to XII) and Hal represents a halogen atom, preferably chlorine or bromine.

According to the invention, the process of preparation of formula (I) products consists in: (a) the action of a pyrimidine derivative of formula (II) - What? in which R1, R2, R and Hal are as defined above on an amine of formula (III) - What? where R3 and R4 are defined as before, either in the presence of a strong base or by catalysis with palladium, (b) then, when a product is desired for which the radical R is saturated or partially saturated, the product of general formula (I) is hydrogenated, as appropriate, (c) then, if desired, for which a pyrimidine derivative of general formula (I) for which R2 is hydroxymethyl,Err1:Expecting ',' delimiter: line 1 column 526 (char 525)

The reaction of pyrimidine of formula (II) with amine of formula (III) is usually carried out in the presence of a heavy base such as diisopropylethylamine under reactive conditions known to the professional in the implementation of nucleophilic substitution.Preferably in the presence of an amide (e.g. dimethylacetamide, dimethylformamide) at a temperature between 90°C and the reflux temperature of the reaction mixture.Moreover, the COR4 grouping is preferably chosen from the heavy groups such as tertbutoxycarbonyl.It is also possible to catalyze the reaction with palladium (e.g. trisodifluorobenzene) in the presence of a fluorinated acid.These functions are not understood to be related to the reaction with the usual reaction protecting molecules, but to the reaction with the fluorinated acid.

When a product is desired for which the radical R is saturated or partially saturated, the hydrogenation reaction is carried out in the presence of platinum oxide in a solvent such as an alcohol (e.g. ethanol, methanol) at atmospheric pressure.

When a pyrimidine derivative of general formula (I) is desired for which R2 is hydroxymethyl, the reduction of the corresponding derivative for which R2 is a formal radical is preferably by means of an alkaline borohydride (sodium borohydride) in a solvent such as an alcohol (e.g. ethanol, methanol) at a temperature of 10 to 40 °C, preferably at room temperature.

When a pyrimidine derivative of general formula (I) is desired for which G (in R) represents a heterocyclic radical with a substituted amino radical, the substitution of the corresponding product with a primary amine function on the heterocyclic radical is carried out by action of the corresponding aldehyde in a reducing medium, in particular in the presence of a borohydride such as an alkaline metal triacetotoxyborohydride.

Err1:Expecting ',' delimiter: line 1 column 122 (char 121)

The condensation of R3 radicals of possibly substituted alcohol structure is carried out by action of the corresponding aldehyde in a reducing medium, in particular in the presence of a borohydride such as an alkaline metal triacethoxyborohydride.

The reaction of hydrolysis to obtain an acid derivative (COR4=CO2H), esterification to obtain an ester or prodrug (particularly COR4=alcoyloxycarbonyl or aryloxycarbonyl from the corresponding acid) or amidification (COR4=aminocarbonyl mono or disubstituted from the corresponding acid) is carried out according to the usual methods known to the professional.

In particular, hydrolysis is carried out in an acidic medium, e.g. in the presence of trifluoroacetic acid, in an organic solvent such as dichloromethane.

If necessary, the conversion to physiologically acceptable salts is carried out by processes known to the professional.

Pyrimidine derivatives of formula (II) may be prepared by the action of a product of formula (IV) in which R is defined as above on a dihalogenated derivative of pyrimidine of general formula: - What? wherein R1, R2 and Hal are defined as before.

The reaction is advantageously carried out in the presence of a strong, congested base at the reflux temperature of the reaction mixture. The conditions described in the examples below are used, in particular in the presence of a congested amine such as diisopropylethylamine, in an amide such as dimethylacetamide. It is understood that the functions that may interfere with the reaction are previously protected. The protection and release of these functions is carried out by the usual methods that do not alter the rest of the molecule.

The preparation of dihalogenated pyrimidines of general formula (V) may be carried out by or by analogy with the methods described below in the examples.

The compounds of formula (I) are compounds with pharmacological activity and can therefore be used as medicinal products, in particular in the treatment or prevention of bone diseases, tumour diseases and cardiovascular disorders.

The present invention therefore concerns the physiologically acceptable compounds of formula (I) and/or their salts as medicinal products.

The compounds of formula (I) and their physiologically acceptable salts and prodrugs may be administered to animals, preferably mammals and in particular to humans as medicinal products for therapeutic or prophylactic purposes.

They may be administered on their own or in combination with one or more other formula (I) compounds or in the form of a pharmaceutical preparation (pharmaceutical formulation) which allows enteral or parenteral administration and which contains as active substance an effective dose of at least one physiologically acceptable formula (I) compound and/or its salts and commonly used and pharmaceutically inert media and/or additives.

The pharmaceutical formulations of the invention allow enteral or parenteral administration and contain as active ingredient an effective dose of at least one physiologically acceptable formula (I) compound and/or its salts and one or more pharmaceutically inert media and/or one or more common additives.

The invention therefore relates to pharmaceutical compositions containing a compound of general formula (I) in its pure form or in the presence of one or more excipients.

Medicines may be taken orally, for example as pills, tablets, coated tablets, film-coated tablets, granules, soft capsules and capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures.

However, administration may be by rectal route, e. g. as a suppositories, parenterally, e. g. as solutions for injection or infusions, microcapsules or implants, percutaneously, e. g. as ointments, solutions, pigments or dyes, transdermally as patches or by other routes such as aerosol or nasal spray.

The pharmaceutical formulations of the invention are prepared by methods known in themselves, from organic or inorganic, pharmaceutically inert media which can be added to the physiologically acceptable formula (I) compounds and/or their salts.

The suitable media for soft gelatin capsules or for suppositories are e.g. fats, waxes, semi-solid or liquid polyols, natural or modified oils, etc. The suitable vehicles for preparing solutions, e.g. injectable solutions, emulsions or syrups are e.g. water, alcohols, glycol, For formulations, polyols, sucrose, inverse sugars, glucose, vegetable fats, etc. The suitable pharmaceutical preparations for suppositories are for example micro-acids or polyols containing 0.5% (i.e. 90%) of glyoxylic acid and their pharmaceutical formulations are physically acceptable.

In addition to active substances and media, pharmaceutical preparations may contain additives such as diluents, disintegrators, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, flavour or flavour tinting agents, thickeners, buffering agents, solvents or solubilisers or agents to achieve a delaying effect and also salts to modify osmotic pressure, coating agents or antioxidants.

They may also contain two or more general formula (I) compounds and/or their physiologically acceptable salts; in addition, in addition to at least one or more general formula (I) compounds and/or their physiologically acceptable salts, they may contain at least one or more other active substances which may be used for therapeutic or prophylactic purposes.

Pharmaceutical preparations (pharmaceutical formulations) normally contain 0.2 to 500 mg, and preferably 1 to 200 mg of the compound formula (I) and/or their physiologically acceptable salts and/or prodrugs.

The compounds of formula (I) are particularly antagonists of Vitronectin receptors and are thus able to inhibit, for example, the adhesion of osteoclasts to the surface of bone and thus bone resorption by osteoclasts.

The action of formula (I) compounds can be demonstrated, for example, in a test in which the inhibition of vitronectin binding to cells containing the vitronectin receptor is determined. Details on this test are given below. As vitronectin receptor antagonists, formula (I) compounds and their physiologically acceptable salts are generally suitable for the treatment or prevention of diseases related to interactions between vitronectin receptors and their ligands, in cell-cell or stem cell-cell interaction processes or that can be influenced by the inhibition of such interactions, to ease or heal when an inhibition of such interactions is desired. As explained earlier, such interaction plays an important role in the proliferation of vascular or bone marrow, muscle or vascular proliferation.

Bone diseases requiring the use of formula (I) compounds for treatment or prevention include osteoporosis, hypercalcemia, osteopenia, e.g. caused by bone metastases, dental disorders such as periodontitis, hyperparathyroidism, periarticular erosion in rheumatoid arthritis, and Paget' s disease.

All of these disorders are characterized by bone loss, which is based on a disequilibrium between bone formation and bone destruction and which can be favorably influenced by the inhibition of bone resorption by osteoclasts. In addition to this use as an inhibitor of osteoclast-mediated bone resorption, the physiologically acceptable formula (I) compounds and their salts are used as inhibitors of tumor growth or cancerous metastases, in the treatment of inflammatory disorders, for the treatment or prevention of cardiovascular disorders, such as atherosclerosis or restenosis, or the treatment or prevention of retinopathy or nephropathy such as retinopathy.

The compounds of the invention may also have activity towards other integrins that interact with their ligand via the RGD tripeptide sequence (αvβ1, αvβ5, αIIbβ3), giving them pharmacological properties that can be used to treat pathologies associated with these receptors.

This activity with respect to integrins thus makes formula (I) compounds usable in the prevention or treatment of many diseases such as those mentioned above or in Dermot Cox's journal DN§P 8(4) May 1995, 197-205 the contents of which are incorporated in this application as a reference.

The present invention therefore relates in particular to a physiologically acceptable compound of formula (I) and/or its salts as defined above as a drug having inhibitory activity of bone resorption or for the treatment or prevention of osteoporosis.

The present invention therefore relates more particularly to a physiologically acceptable compound of formula (I) and/or its salts as defined above as a drug having inhibitory activity against tumour growth or cancer metastases.

The present invention therefore relates in particular to a physiologically acceptable compound of formula (I) and/or its salts as defined above as a drug having anti-inflammatory activity or for the treatment or prevention of cardiovascular disorders, restenosis, arteriosclerosis, nephropathies or retinopathies.

The present invention also concerns the use of physiologically acceptable formula (I) compounds and/or their salts as defined above for the preparation of drugs for the prevention or treatment of osteoporosis.

The present invention also concerns the use of physiologically acceptable formula (I) compounds and/or their salts as defined above for the preparation of drugs intended to inhibit tumor growth or cancer metastases.

The present invention also concerns the use of physiologically acceptable compounds of formula (I) and/or their salts as defined above for the preparation of medicinal products for the prevention or treatment of cardiovascular disorders, restenosis, arteriosclerosis, nephropathies or retinopathies.

When formula (I) compounds are used, doses may vary within wide limits and should be set according to the person to be treated, for example, depending on the compound used or the nature and severity of the disease to be treated and whether one is in serious or chronic conditions or whether prophylactic treatment is being used.

For oral administration, the daily dose is generally between 0.1 and 100 mg/kg and preferably between 0.1 and 50 mg/kg.

In the case of intravenous administration, the daily dose ranges from approximately 0.01 to 100 mg/ kg and preferably from 0.1 to 10 mg/ kg.

The daily dose may be divided, especially in the case of large amounts of active ingredient, into several, e.g. 2, 3 or 4 servings. If appropriate, depending on individual behaviour, it may be necessary to administer the different doses in increasing or decreasing ways. Apart from using formula (I) compounds as medicines, their use as a vehicle or carrier of active compounds may also be considered in order to specifically transport these active compounds to a site of action (Drug targeting, Targeted Drug Delivery, see R. C. Juliano, Handbook of Experimental Pharmacology, Vol 100, Ed. Born, G. V. R. et al., Springer).

Formula (I) compounds and their salts may also be used as diagnostic agents, e.g. for in vitro methods, or as an adjuvant in biochemical studies where the vitronectin receptor is to be blocked or cell-cell or stem-cell interactions are to be influenced.

Examples

Compounds, which have been chromatographically purified using an electrolyte containing e.g. acetic or trifluoroacetic acid, and which are then dried or in which in the last step of synthesis, e.g. trifluoroacetic acid was used to remove a tert-butyl protective group, sometimes contain, depending on how the product has been dried, the acid from the electrolyte or the last step of synthesis and thus appear partially or completely as the salt of the acid, e.g. in the form of acetic or trifluoroacetic acid or less hydrated.

Abbreviations/chemical names used where appropriate:

The following is a list of the substances which are to be used in the preparation of the product: acetoacetate of ethyl; EDCI: 1- (3-dimethylaminopropyl) 3-ethyl-carbodiimide hydrochloride; DMF: dimethylformamide; DIPEA: diisopropylethylamine; MeOH: methanol; TEA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; MCPBA: meta-chloroperoxybenzoic acid; DBU: 1,8-diazabicyclo[5.4.0] undec-7-ene; APTS: parsilolufosulfonic acid; DPPA: diphenylethylphosphate; DMSO: dimethyl sulphosphate; Pd/Cladium on carbon; Boxycyl carbonyl: benzyl carbonyl: palladium; TBC: 1,3-bromethyl iodyl; TBC: trimethyl carbonyl; TBC: trimethyl bromethyl carbonyl; TBC: trimethyl bromethyl carbonyl; TBC: trimethyl bromethyl bromethyl carbonyl; TBC: trimethyl bromethyl bromethyl bromethyl iod; TBC: trimethyl bromethyl bromethyl bromethyl iod; TBC: trimethyl bromethyl bromethyl bromethyl bromethyl iod;

Infrared: IR; NMR: Nuclear Magnetic Resonance; SM: Mass Spectrum; ESP: Electrospray positive mode; ep.: Shoulder; F: strong; s: singlet; d: double; t: triple; q: quadruplet; quint: quintuple; 1: wide; m: multiple or massive; J: coupling constant; Rf: retention factor (chromatography).

Example 1 Synthesis of the (6-bromo-5-ethyl-pyrimidine-4-yl) -[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl) -propyl]amine

A mixture of 0.20 g (1 mmole) of 3-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-ylpropylamine [prepared according to J. Org. Chem. 2004, 69, (1959-1966) ] and 0.30 g (1.1 mmoles) of 4.6-dibromo-5-ethylpyrimidine in 20 ml dimethylacetamide and 1 ml diisopropylethylamine is carried at 120 °C for 6 hours. The reaction mixture is evaporated dry under reduced pressure (2 kPa) and the residue is taken up by ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried on 100% silicon sulfate and evaporated as a reducing residue (2 kPa). The residue is obtained by evaporating on a chromatograph with a gradient of up to 0.21 g of magnesium sulphate. The following is the list of active substances: The following substances are considered to be toxic if they are used in the manufacture of the active substance: The number of employees is: SM 378,379 (MH+).

The following is a list of the active substances that may be used in the preparation of the active substance:

A mixture of 105 mg (0.28 mmole) of (6-bromo-5-ethyl-pyrimidine-4-yl) -[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl) -propyl]amine, 150 mg (0.5 mmole) of 3-amino-2-benzyloxycarbonylamino tert-butyl propionate (prepared according to J. Med. Chem.2001), 448), 1158-1176), 140 mg (0.92 mmole) of ceonium fluoride, 40 mg (0.044 mmole) of trisdibenzylidene acetone (dipalladium 2,2-0), and 60 mg (0.7 mmole) of'-diphenyl-bisphosphate-1,1'-propyl is heated at the reflux stage for 20 hours. The mixture is evaporated for 4 ml and then reduced to a solution of sodium dioxide (2 kPa) and sodium dioxide (2 kPa) separated by a pressure reducing agent and reduced to a solution of bicarbonate of sulphate.The residue is chromatographed on alumina by electrolysis with a heptane acetate ethyl gradient of 100-0 to 0-100. The following is the list of active substances in the active substance: The following substances are considered to be toxic if they are used in the manufacture of the active substance: 1H-RMN (CDCl3): δ 1,11 (t, 3H, CH2-CH3); 1,47 (s, 9H, tBu); 1,96 and 2,16 (2m, 2X2H, CH2-CH2-CH2) ; 2,41 (q, 2H, CH2-CH3) ; 2,77 and 2,84 (2t, 2X2H, CH2-CH2-CH2-NH) ; 3,44 and 3,52 (2m, 2X2H, CH2-CH2-CH2-NH); 3,86 (m, 2H, NH-CH2-CH-NH); 4,39 (m, 1H, NH-CH2-CH-NH) ; 5,16 (s, 2H, CH2-Ph); 6,43 and 7,35 (masked) (2d, 2H, H naphthyridine); 7,35 (m, 5H, Ph) 8,15 ppm (s),The following shall be reported: The following are the types of the test: SM 590 (MH+); 534 (MH-tBu+); 400 (MH-COOCH2Ph+).

The chemical composition of the compound is determined by the following equation:

65 mg (0.11 mmole) of 2-benzyloxycarbonylamino-3-[5-ethyl-6-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl) propylamino]-pyrimidine-4-ylamino]-tert-butyl propionate is stirred in 5 ml of dichloromethane with 0.5 ml of trifluoroacetic acid at room temperature for 16 hours. Toluene is added and the reaction mixture is evaporated at reduced pressure (2 kPa). The residue is dissolved in the minimum of dichloromethane with a little methanol poured over diisopropyl ether. The precipitate is filtered. 45 mg of the expected product is obtained in the form of a beige solid. The following is the list of active substances in the active substance: The following substances are to be used:

Example 2 Synthesis of (6-chloro-5-methyl-pyrimidine-4-yl) -[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl) -propyl]amine

A mixture of 774.3 mg (4.05 mmoles) of 3-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-ylpropylamine (prepared according to J. Org. Chem. 2004, 69, 1959-1966) and 600 mg (3.68 mmoles) of 4.6-dichloro-5-methyl-pyrimidine in 6 ml dimethylacetamide and 1.2 ml diisopropylethylamine is carried at 120°C for 9 hours. The reaction mixture is evaporated dry under reduced pressure (2 kPa) and the residue is taken up by ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried on 100% magnesium sulfate and evaporated under reduced pressure (2 kPa). The residue is then evaporated on 100% magnesium sulfate (R=58%) and then produced on a 100% magnesium sulfate (R=80%) chromatograph. The following is the list of active substances: The following substances are considered to be toxic if they are used in the manufacture of chemicals: The following is the list of the Member States which have adopted the measures:

The following two methods are used:

A mixture of 680 mg (2,14 mmole) of (6-Chloro-5-methyl-pyrimidine-4-yl) -[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl) -propyl]amine, 755 mg (2,57 mmole) of tert-butyl 3-amino-2-benzyloxycarbonylamino propionate (prepared according to J. Med. Chem.(2001), 44(8), 1158-1176), 455 mg (3 mmole) of cesium fluoride, 133 mg (0,214 mmole) of trisodiamine (dibenzylideneacetone) 2,2 dipalladium0), and 98 mg (0,107 mmole) of dibisphenylephospholipino-1--1-apyl) is heated at the reflux, in 20 ml of dimethoxyphetane for 24 hours.

The reaction mixture is evaporated dry at reduced pressure (2 kPa) and the residue is taken up by ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried on magnesium sulfate and the evaporated solvent at reduced pressure (2 kPa). The residue is chromatographed 2 times on alumina by eluting with an isopropyl ethyl ether acetate gradient (50/50) with 10% of a dichloromethane-methanol mixture (9/1). 220 mg of the expected product is obtained. The following is the list of active substances in the active substance: The following substances are considered to be toxic if they are used in the manufacture of chemicals containing chemicals other than those mentioned in the Annex to this Regulation: The following are the main components of the test: SM 576 (MH+); 520 ((MH - tbu+); 386 ((MH - tbu-COOCH2Ph+).

Synthesis of 2-benzyloxycarbonylamino-3-[5-methyl-6-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)propylamino]-pyrimidine-4-ylamino]-propionic acid, which is a bis (trifluoroacetate).

40 mg (0.069 mmole) of 2-benzyloxycarbonylamino-3-[5-methyl-6-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl) propylamino]-pyrimidine-4-ylamino]-tert-butyl propionate is stirred in 1 ml of dichloromethane with 0.2 ml of trifluoroacetic acid at room temperature for 16 hours. Toluene is added and the reaction mixture is evaporated at reduced pressure (2 kPa). The residue is dissolved in the minimum of dichloromethane poured over diisopropyl ether. The precipitate is filtered. 43 mg of the product is obtained in the form of a broken white solid. The following is the list of active substances in the active substance: The following substances are considered to be toxic if they are used as a starting material in the manufacture of chemicals: The test chemical is used to determine the concentration of the active substance in the test chemical.

Example 3 Preparation of 3-[1,8]naphthyridin-2-yl-propan-1-ol:

In a cylinder containing 1 g (8.19 mmoles) of 2-amino-pyridine-3-carbaldehyde in solution in 5 ml of ethanol, add 914 μl (9 mmoles) of 5-Hydroxypentan-2-one, 750 μl (9 mmoles) of pyrrolidine and 11.5 μl (0.2 mmoles) of concentrated sulphuric acid at room temperature and bring the reaction mixture to the reflux (78°C) for 3 hours and 30 minutes.

After cooling, the solution is dried at reduced pressure (2 kPa) and the resulting residue is taken up by a mixture of water, ethyl acetate and a saturated sodium bicarbonate solution. The organic phase is separated and the aqueous phase is extracted to ethyl acetate and then to n-butanol. The aggregated organic phases are dried on magnesium sulfate. The filtrate is dried and then chromatographed on silicagel by eluting with an ethyl acetate gradient (100%) of ethyl methane acetate (98-2) to methane methanol acetate (90-10).

We get 990 milligrams of the expected product. The following is the list of active substances in the active substance: The following substances are considered to be toxic if they are used in the manufacture of the active substance: The following is the list of the Member States:

Synthesis of 2-[3-(6-chloro-5-methyl-pyrimidine-4-yloxy) -propyl]-[1,8]naphthyridine:

In a monocol containing 102 mg (2,12 mmoles) of sodium hydride and 7 ml of dioxane, 800 mg (4.24 mmoles) of 3-[1,8]naphthyridin-2-yl-propan-1-ol in solution in 5 ml of dioxane is added at room temperature and nitrogen, drop by drop.

The mixture is agitated and kept in an inert atmosphere at room temperature for 2 hours.

346.4 mg (2.12 mmoles) of 4,6-dichloro-5-methylpyrimidine in solution in 5 ml of dioxane is then added.

The resulting residue is then taken up by a mixture of water, ethyl acetate and a saturated sodium bicarbonate solution. The organic phase is separated and the aqueous phase is re-extracted by ethyl acetate. The grouped organic phases are dried on magnesium sulfate. The filtrate is dried and then chromatographed on silicagel by eluting with an ethyl acetate (100%) gradient of ethyl methanol acetate (98-2).

We get 300 mg of the expected product. The following is the list of active substances: The following substances are considered to be toxic if they are used as a starting material in the manufacture of the active substance:

Synthesis of 7-[3-(6-chloro-5-methyl-pyrimidine-4-yloxy) -propyl]-1,2,3,4-tetrahydro-[1,8]naphthyridine:

The reaction mixture is then vacuum-surged and topped with a hydrogen-containing belt balloon. The reaction mixture is then stirred and left at room temperature for 6 hours and then overnight. The reaction mixture is filtered on clarcel and concentrated dry under reduced pressure (2 kPa). The result is 300 mg of the expected product. CCM: Rf = 0.6 [Sagel, electrolyte: methyl ethanol acetate (95-5) ] The following substances are considered to be toxic if they are used as a starting material in the manufacture of the active substance: The following is added:

The following is added to the list of active substances:

A mixture of 2 g (6,27 mmoles) of 7-[3-(6-chloro-5-methyl-pyrimidine-4-yloxy) -propyl]-1,2,3,4-tetrahydro-[1,8]naphthyridine and 2,2 g (7,52 mmoles) of tert-butyl 3-amino-2-benzyloxycarbonylamino propionate in the presence of 1,3 g (8,78 mmoles) of caesium fluoride, 390 mg (62,7 μmol) of (2,2'-bis (diphenylphosphino) -1,1'-binthyl) and 290 mg (31,3 μmol) of tris-diphenyl acetate dipholipid dihydro) in 35 ml of 1,2-dimethoxyfluoride is refilled for 24 hours.

After cooling the solution is concentrated dry and then taken up by a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is settled and the aqueous phase is extracted to ethyl acetate. The organic phases are dried on magnesium sulfate and evaporated dry in vacuum. The residue is chromatographed on silica with a gradient of ethyl dichloromethane acetate (50-50) to ethyl dichloromethane acetate (80-20). 772 mg of the expected product is obtained. The following substances are to be classified as substances with a potential for the degradation of the chemical composition of the feed additive: The following is added:

Example 4 Formation of the acid corresponding to the ester in example 3: Synthesis of 2-Benzyloxycarbonylamino-3-{5-methyl-6-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -propoxy]-pyrimidine-4-ylamino}-propionic acid, bis ((trifluoroacetate) which is a precursor to the active substance.

A mixture of 65 mg (0.11 mmoles) of 2-benzyloxycarbonylamino-3-{5-methyl-6-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -propoxy]-pyrimidine-4-ylamino}-tert-butyl propionate is stirred at room temperature in 1 ml of dichloromethane and 50 μl of trifluoroacetic acid for 25 hours. Toluene is added and evaporated into the mixture. The residue is then solubilised in a minimum of dichloromethane poured over a mixture of diisopropyl ether and dichloromethane. The precipitate is filtered.

We get 21 mg of the expected product. The following information is provided for the purpose of the analysis: The following substances are considered to be toxic if they are used in the manufacture of the active substance: 1H-RMN (CDCl3): δ 1,72 and 1,95 (m, 5H, -CH3, NH-CH2-CH2-CH2); 2,15 (m, 2H, O-CH2-CH2-CH2); 2,63 and 2,85 (m, 4H, NH-CH2-CH2, O-CH2-CH2); 3,45 (m, 2H, NH-CH2-CH2-CH2); 3,7 and 4,0 (m, 2H, NH-CH2-CH-NH); 4,3 (m, 3H, O-CH2-CH2, NH-CH2-CH-NH); 5,1 (m, 2H, O-CH2-Ph) ; 5,78 and 6,10m, 2H, NH); 6,33 and 7,25 (2d, 2H, CH=naphidine); 7,28 and 7,45 (m, 5H, CH); 8,13 (s, N=N, N). The following is added:

Example 5 1°) Synthesis of N-t-butoxycarbonyl-3- ((methoxy-methyl-carbamoyl) -azetidin.

Dissolve 2 g (10 mmol) of N-t.butoxycarbonyl-azetidin-3-carboxylic acid) in 20 ml of dimethylformamide with argon.

This solution is cooled to 0°C with an ice bath and 5.46 g (12.3 mmol) of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, 1.4 g (14.3 mmol) of N,O-dimethylhydroxylamine chloride and 6 ml of diisopropylethylamine are added, the reaction mixture is allowed to return to room temperature and stirred for 18 hours at room temperature.

Dimethylformamide and diisopropylethilamine are evaporated at reduced pressure (2 kPa).

Purify by chromatography on Silicagel by eluting with a 50:50 heptane/ ethyl acetate mixture.

We're picking up 2.1 grams of colorless oil. The following is the list of active substances which are to be classified in the additive:

2°) Synthesis of N-t.butoxycarbonyl-3-acetyl-azetidin

110 mg (0.45 mmol) of N-t.butoxycarbonyl-3- ((methoxy-methyl-carbamoyl) -azetidin is solubilised in 2 ml of argon ether.

Cool this solution to 0°C using an ice bath and add 1 ml of 1.6M methyllythium solution to the ether drop by drop.

Stir for 2 hours at this temperature and then treat with an aqueous solution of 1M hydrochloric acid.

The aqueous and ether phases are decanted and separated, this process is repeated three times, then the ether phases are collected and dried on MgSO4, and after filtration the ether is evaporated at reduced pressure.

We're getting 40 milligrams of a colorless oil. The following is the list of active substances which are to be classified in the Annex to Regulation (EC) No 1907/2006 as substances with a specific chemical composition:

N-t.butoxycarbonyl-3-[1,8]naphthyridin-2-yl-azetidin: whether or not chemically defined

30 mg of N-t.butoxycarbonyl-3-acetyl-azetidin (0.150 mmol) is dissolved in 2 ml of ethanol to which are added 18 mg (0.150 mmol) of 2-aminopyridine-3-carboxyaldehyde and 25 mg of potassium carbonate (0.18 mmol).

This mixture is allowed to reflux for 24 hours and then allowed to return to room temperature and evaporates the ethanol at reduced pressure (2 kPa).

The resulting residue is purified by silica gel chromatography by elution with a dichloromethane/MeOH 95:5 mixture.

30 mg of the expected product is recovered as a beige solid. The following is the list of active substances: The following information is provided for the purpose of this Regulation: The following are the main characteristics of the test chemical:

3-[1,8]Naphthyridin-2-yl-azetidin is a substance that is used in the manufacture of pharmaceutical products.

50 mg (0.175 mmol) of N-t.butoxycarbonyl-3-[1,8]Naphthyridin-2-yl-azetidin is solubilised in 2 ml of CH2Cl2 to which is added 0.2 ml of trifluoroacetic acid and agitated for 18 hours at room temperature.

Evaporate trifluoroacetic acid and dichloromethane at reduced pressure (2 kPa).

Isolate 40 mg of the raw product in the form of yellow oil. The following is the list of active substances: The following is the list of the Member States:

The following is added to the list of active substances:

40 mg of 3-[1,8]naphthyridin-2-yl-azetidin is dissolved in 2 ml of ethanol to which 10 mg of platinum oxide is added.

We filter the catalyst and evaporate the ethanol at reduced pressure.

The crude residue is purified by silica gel filtration by eluting with a dichloromethane/MeOH 95:5 and 85:15 mixture

25 mg (61%) of a colourless oil is recovered The following is the list of substances that are to be classified as 'metals' in the Annex to Regulation (EC) No 1907/2006 of the European Parliament and of the Council: The following is the list of the substances which are to be used:

Synthesis of 2,5-dimethyl-4,6-dihydroxy-pyrimidine:

A monocol containing 40 ml of methanol, placed under a nitrogen atmosphere, is cooled to 0 °C by an ice bath, 9.72 g of sodium methyllate (i.e. a solution of concentration c=3 mol.l-1) is added to the reaction mixture and then 5 g (53 mmoles) of acetaminophen hydrochloride is added at 0 °C and in small quantities (53 mmoles) of acetaminophen hydrochloride. It is stirred at room temperature for about twenty minutes, then 8.3 ml of diethyl methylmalonate is added drop by drop. The stirring is maintained for 3 hours. The chemical composition of the product is determined by the following equation: The test chemical is a chemical that is used to treat the effects of the chemical on the body.

Synthesis of 2,5-dimethyl-4,6-dichloro pyrimidine

A 3.3 g (23.5 mmoles) mixture of 2.5-dimethyl-4,6-dihydroxy-pyrimidine and 15 ml of phosphorus oxychloride is brought to the reflux for 8 hours. After returning to room temperature, the reaction mixture is slowly poured over a mixture of ice and water. This aqueous phase is extracted to ethyl acetate. The organic phase is washed with a saturated solution of sodium bicarbonate and then dried on magnesium sulfate and evaporated dry under reduced pressure (2 kPa). The following is the list of active substances in the active substance: The Commission has not yet adopted a decision on the application of Article 108 (3) TFEU.

Synthesis of 7-[1-(6-Chloro-2,5-dimethyl-pyrimidine-4-yl) -azetidin-3-yl]-1,2,3,4-tetrahydro-[1,8]naphthyridine:

90 mg (0.47 mmol) of 7-azetidin-3-yl-1,2,3,4-tetrahydro-[1,8]naphthyridine is dissolved in 2 ml of dimethylacetamide to which 90 mg (0.51 mmol) 2,5-dimethyl-4,6-dichloro-pyrimidine is added.

This mixture is heated to 100°C for 18 hours.

Evaporate the solvent at reduced pressure ((2 kPa).

The crude residue is purified by silica gel chromatography by elution with a dichloromethane/MeOH 95:5 mixture

50 mg (32%) of expected product is recovered. The following is the list of active substances and their active substances: The following is the list of the Member States which have adopted the new rules:

2-benzyloxycarbonylamino-3-{2,5-dimethyl-6-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -azetidin-1-yl]-pyrimidin-4-ylamino}-propionate of tert-butyl:

The solution is in 2 ml of dioxane 50 mg ((0,150 mmol) of 7-[1-(6-Chloro-2,5-dimethyl-pyrimidine-4-yl) -azetidin-3-yl]-1,2,3,4-tetrahydro-[1,8] naphthyridine, 53 mg of tert-butyl 3-amino-2-benzyloxycarbonylamino propionate and 70 mg (0.460 mmol) of cesium fluoride.

This mixture is heated for 5 minutes at 90°C and then 6 mg (0.01 mmol) of rac-2,2'-Bis ((diphenylphosphino)-1,1'-Binaphtyl and 9 mg (0.01 mmol) of tris (dibenzylideneacetone) dipalladium are added. This mixture is heated at 110°C for 2 hours under magnetic agitation. The same quantities of catalyst and cesium fluoride are added again and heated for 2 hours at 140°C. The dioxane is evaporated at reduced pressure (2 kPa).

The resulting residue is purified by silicagel chromatography by eluting with a 1:1 Heptane/Ethyl Acetate mixture.

25 mg of the expected product is recovered as a yellow solid. The following is the list of active substances and their active substances: The following is a list of the active substances in the active substance:

It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5 and boiling in the range of approximately -15 oC to -15 oC (- 372oF to -157oF).]

20 mg 2-benzyloxycarbonylamino-3-{2,5-dimethyl-6-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -azetidin-1-yl]-pyrimidine-4-ylamino}-propionate of tert-butyl is solubilised in 1 ml of CH2Cl2 and 0,1 ml of trifluoroacetic acid is added.

The solution is agitated for 24 hours at room temperature and diluted with toluene.

Evaporate the solvents and trifluoroacetic acid at reduced pressure (2 kPa) and take the resulting residue with a minimum of CH2Cl2 and pour this solution on isopropyl ether.

The insoluble is thus isolated by filtration and 15 mg of the expected product is recovered as a white powder. The following is the list of active substances: H-RMN (MeOD) : δ from 1,95 to 2,00 (m, 5H, H1 and H11) ; 2,50 (s, 3H, H3); 3,35 ((dd, 2H, H10); 3,52 ((dd, 2H, H12); 3,30 ((m, 1H, H7) 3,97 and 4,15 ((2m, 2H, H4) ; 4,53 ((m, 3H, H5 + H2 or H2') ; 4,80 ((dd); partially masked by H2O, 2H, H2 or H2') ; 5,10 ((m, 2H, -O-CH2-C6H5) ; 6,82 ((d, 1H, H8) ; 7,30 ((m, 5H, -O-CH2-C65) 7,62 ((d, 1H, H9) ; 53 ((MH) ; 39 ((MH, H2 or H2') ; 39 ((MH-CH2-C6H5) ; 6 ((H, H8)); 7,30 ((m, 5H, -O-CH2-C6H5)); 7,62 ((d, 1H, H2) ; 53 ((MH) ; 39 ((MH) ; 39 ((MH) ; 39 ((M-CH2-C6H-C6H-C6H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-

Example 6 Synthesis of 2-benzyloxycarbonylamino-3-[6-(6-amino-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-1'-yl)-5-methyl-pyrimidine-4-ylamino]-propionate from tert-butyl 1°) Synthesis of N-t-butoxycarbonyl-4-hydroxypipperidine:

1 g (5 mmol) of N-t-butoxycarbonyl-4-oxo-1-pipperidine (marketed by Aldrich) is dissolved in 5 ml of ethanol. This solution is cooled to 0 °C with an ice bath and 200 mg (7.56 mmol) of sodium tetraborohydride is added per serving and stirred for 4 hours at room temperature. An aqueous solution saturated with ammonium chloride is added to the reaction mixture. The ethanol oil is evaporated at reduced pressure (2 kPa) and the reaction mixture is resumed with ethyl acetate. The organic phase is separated from the aqueous phase. This extraction is repeated once and then the organic phases are collected and dried on a base of ammonium chloride. The following is the list of active substances: The following equation is used for the determination of the concentration of the test chemical in the test chemical:

The following is a list of the active substances in the active substance:

2,15 g of triphenylphosphine (8,2 mmole) and 2,08 g of iodine (8,2 mmole) are dissolved in 30 ml of acetonitrile.

The reaction is treated by adding an aqueous solution of sodium thiosulfate and evaporating acetonite then at reduced pressure (2 kPa). The reaction is resumed with ethyl acetate, extracted and washed with an aqueous solution of sodium thiosulfate. The organic phases are filtered and evaporated on MgSO4, and the aqueous phase of silicon thiosulfate is reduced to 90 kPa (2 kPa).

The oil is then extracted from the oil. The following is the list of active substances: The following equation is used for the determination of the concentration of the substance in the test chemical:

3°) Synthesis of 2-bromo-6 (2,5-dimethyl-pyrol-1-yl) pyridine (3):

In a 100 ml balloon topped with a Dean Stark mount, 1 g (5.78 mmol) of 2-amino-6-bromopyridine is placed in 30 ml of toluene. 0.3 ml of acetic acid and 0.8 ml (6.78 mmol) of acetonylacetone are added. Toluene is heated at the reflux for 5 hours. It is allowed to return to room temperature and the toluene is evaporated at reduced pressure (2 kPa). Water is added and extracted to ethyl acetate. Organic phases are collected and reduced to magnesium sulfate.

We're getting 1 g of the product we're waiting for as a yellow powder. The following is the list of active substances: The following are the active substances which are to be used in the manufacture of the test chemical:

4°) Synthesis of 6- (2,5-dimethyl-pyrrol-1-yl) -3,4,5,6'-tetrahydro-2'H-[2,4']bipyridinyl-1'-carboxylic acid tert-butyl ester:

Suspend 284 mg (4,34 mmol) of electrolytic zinc in an argon atmosphere, to which 0,033 ml of 1,2-dibromoethane and 1 ml of tetrahydrofuran are added.

The reaction mixture is agitated for 45 minutes at room temperature and added to a solution containing 30 mg (0.032 mmol) of aldrich-commercialised trisdibenzylideneacetone dipalladium and 30 mg (0.13 mmol) of tris2-furylphosphine. 1 g (4.2 mmol) of 2--62-bromoxybutyric acid dipyrrhophyr-1-dipropyl-1-dipropyl is then added to the soluble solution for 2 hours at 60°C.The water phase is extracted twice with ethyl acetate, then the organic phases are collected and dried on magnesium sulfate. The ethyl acetate is evaporated at reduced pressure (2 kPa) and the crude residue is purified by silicone gel chromatography by eluting with a 4:1 heptane/ethyl acetate mixture. 350 mg of the expected product is recovered in the form of yellow oil. The following is the list of active substances: The test chemical is a chemical that is used to test the concentration of a substance in a sample.The following substances are to be classified as 'metals' in the Annex to Regulation (EC) No 1272/2008 of the European Parliament and of the Council:

5°) Synthesis of 6- (2,5-dimethyl-pyrrol-1-yl) -1,2,3,4,5,6'-hexahydro-[2,4']bipyridinyl

330 mg (0.928 mmol) 6-(2,5-dimethyl-pyrrol-1-yl)-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-1'-carboxylic acid tert-butyl ester is added to 3 ml of dichloromethane and 0.3 ml of trifluoroacetic acid is added to 330 mg (0.928 mmol) of dichloromethane tert-butyl ester. The solution is stirred at room temperature for 2 hours. The dichloromethane is evaporated at reduced pressure (2 kPa). The resulting residue is taken back to water, dipped to pH = 10 with concentrated ammonia and the product is extracted with dichloromethane. The organic phase is dried on magnesium sulfate and the dichloromethane is evaporated at reduced pressure (2 kPa). The following is the list of active substances: The following substances are to be classified as substances with a specific chemical composition: The following is the list of the Member States which have adopted the new rules:

6°) Synthesis of 1'- ((6-chloro-5-methyl-pyrimidine-4-yl) -6- ((2,5-dimethyl-pyrrol-1-yl) -1,2,3,4,5,6'-hexahydro-[2,4']bipyridinyl:

220 mg (0.860 mmol) of 6-(2,5-dimethyl-pyrrol-1-yl)-1',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl is dissolved in 2 ml of dimethylacetamide, to which 140 mg (0.860 mmol) of 4,6-dichloro-5-methyl-pyrimidine marketed by and 0,2 ml of diisopropylethylamine are added. The mixture is heated to 110 °C under magnetic agitation for one hour. The mixture is allowed to return at room temperature and dimethylacetamide is evaporated under reduced pressure (0.2 kPa). The raw residue is taken to the acetate of ethyl ether and washed in water. The following is the list of active substances: The following substances are to be classified as substances with a specific chemical composition, in accordance with the provisions of Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 16 February 2006 on the approximation of the laws of the Member States relating to the permissible sound power level of compressed air (OJ L 345, 20.12.2006, p.

The following is added to the list of active substances:

330 mg (0.866 mmol) of 1'-(6-chloro-5-methyl-pyrimidine-4-yl) -6-(2,5-dimethyl-pyrrol-1-yl) -1,2,2,3,4,4,5,6'-hexahydro-[2,4']bipyridinyl is dissolved in 5 ml of dimethoxyethane. 286 mg (1 mmol) 3-amino-2-benzyloxycarbonylamino tert-butyl propionate is added successively to 184 mg (1.21 mmol) of cesium fluoride, 54 mg (10 mol) of 2,2'-bisphenylephosphino) -1,5,5-dimethyl-pyrrol-1-yl, and 40 mg (5%) of trisodium dihydroacetate. This mixture is mixed at 100 °C for 18 hours. It is then washed at room temperature and re-heated with sodium dimethoxy acetate and then removed from the water.The resulting residue is purified by chromatography on silicagel by eluting with a 1:1 mixture of heptane/ethyl acetate. 200 mg of yellow solid is recovered. CCM: Rf=0.2 (silicagel, eluting: Heptane/ethyl acetate 1:1) 1H-RMN (CD3): δ 1,50 (s,9H, tBu); 1,97sBuH, CH3); 2,02 to 2,10m, 4H, -2-CH2-N-CH2-CH2-); 2,18sBuH, 6P, -CH3-CH=CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-The following substances are to be classified in the same heading as the active substance: The following information is provided for the purpose of this Regulation:

Synthesis of 3-[6-(6-amino-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-1'-yl) -5-methylpyrimidine-4-ylamino]-2-benzyloxycarbonylamino-propionate from tert-butyl:

100 mg (0.15 mmol) 2-benzyloxycarbonylamino-3-{6-[6-(2,5-dimethyl-pyrrol-1-yl)-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-1'-yl]-5-methyl-pyrimidine-4-ylamino}-tert-butyl propionate is dissolved in 3 ml of ethanol and 0.3 ml of water. 50 mg (0.75 mmol) hydroxylamine hydrochloride is added and heated for 18 hours at 90°C. The solvents are evaporated at reduced pressure (2 kPa) and the crude residue is purified by silicon chromatography by eluting with a mixture of CH22/ClOH. 90:10. The following is the list of active substances: The chemical composition of the compound is determined by the following equation: The following is a list of the active substances in the active substance:

The following is added to the list of active substances:

50 mg (0.09 mmol) of 2-benzyloxycarbonylamino-3-[6-(6-amino-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-1'-yl)-5-methyl-pyrimidine-4-ylamino]-propionate tert-butyl is solubilised in 2 ml of dichloromethane. The set is placed under argon atmosphere and cooled to 0 °C using an ice bath.

0,01 ml (0,18 mmol) of acetaldehyde and 30 mg (0,14 mmol) of sodium triacetatoxyborohydride are added.

Stir the mixture for 1 hour at room temperature and add again the same amounts of acetaldehyde and sodium triacetatoxyborohydride.

The agitation at room temperature is maintained for 2 hours and then an additional 30 mg sodium triacetatoxyborohydride is added.

The dichloromethane is agitated at room temperature for 15 minutes and then evaporated at reduced pressure (2 kPa).

The crude residue is purified by Silicagel chromatography by elevating to dichloromethane/methanol 95:5 and then 90:10.

We're picking up 40 milligrams of product we're waiting for. The following is the list of active substances: The following are the main components of the HCl-RMN (CDCl3): δ 1,30 (t, 3H, H1) ; 1,45 (s, 9H, tBu) ; 1,95 (s, 3H, H9) ; 1,85 to 2,05 ((m, 4H, H7 and H7') ; 2,72 ((m, 1H, H6) ; 2,95 ((m, 2H, H8 or H8') ; 3,30 ((m, 2H, H2) ; 3,68 (m, 2H, H8 or H8') ; 3,90 ((m, 2H, H11) ; 4,45 ((m, 1H, H12)); 4,95 ((m, 1H, H mobile) ; 5,12 ((m, 2H, -O-CH2-C6H5) ; 6,19 ((m, 1H, H6) ; 6,30 ((d), 1H, H6,50 (d), 6,50 (d), 7,35 ((m, H5) ; 7,35 ((c), 5 ((m, H6) ; 8,35 ((c), 5 ((m, H6) ; 1,46 ((c), 1,6) ; 1,60 (d), 1,60 (d), 1,60 (d), 1,60 (d), 1,60 (d), 1,60 (d), 1,60 (d), 1,60 (d), 1,60 (d), 1,60 (d), 1,60 (d), 1,60 (d), 1,60 (d), 1,60 (d), 1,60 (d), 1,60 (d), 1,60 (d), 1,60 (d), 1,60 (d), 1,60 (d), 1,60 (d), 1,60 (d), 1,60 (d), 1,60 (d), 1,60 (d), 1,0,1,2,5, (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), ( The following is the list of substances which are to be used in the preparation of the product:

The following shall be indicated in the column for the product:

300 mg (0,51 mmol) of 2-benzyloxycarbonylamino-3-[6-(6-ethylamino-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-1'-yl) -5-methyl-pyrimidine-4-ylamino]-propionate of tert-butyl is solubilised in 5 ml of dichloromethane to which 0,5 ml of trifluoroacetic acid is added.

Stir the mixture at room temperature for 4 hours.

Dilute with toluene and evaporate trifluoroacetic acid, dichloromethane and toluene at reduced pressure (2 kPa).

The resulting residue is taken with a minimum of CH2Cl2 and the solution is poured on isopropyl ether.

The precipitate is filtered and 220 mg of the expected product is recovered as a beige solid. The following is the list of active substances: The following are the main components of the H-RMN (MeOD): δ 1,32 (t, 3H, H1) ; 2.00 (s, 3H, H9) ; 1,90 to 2,10 ((m, 4H, H7 and H7') ; 2,95 to 3,15 ((m, 3H, H6 and H8 or H8') ; 3,45 (m, 2H, H2) ; 3,75 (m, 2H, H8 or H8') ; 3,80 and 4,00 (2m, 2H, H11) ; 4,50 (m, 1H, H12) ; 5,10 ((m, 2H, -O-CH2-C6H5) ; 6,80d, 1H, H3) ; 6,90 (d, 1H, H5); 7,35 to 7,40 ((m, 3H, H6 and H8 or H8') ; 7,86 ((m, 2H, H8 or H8') ; 8,20 ((s, H80) ; 1,400 ((s, H4H) = 53 ((MH-O-CO-O-5)); 1,60 ((m, 2H), -O-CH2-C6H5)); 6,80d, 1H, H3) ; 6,90 (d, 1H, 1H, H2-C65); 7,35 ((MH-CH2-C65) ; 7,86 ((H, H20 ((s, H80) ; 8,20 ((s, H4H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-H-

Examples 7 to 11

By operating in a manner analogous to the method described in Example 6, the following products are prepared: - What?

Exemple		Rf	SM(MH+)	Acide formé	FW	SM (MH+)	Rf
7		0,3	646		589	590	0,25
8		0,3	659		601	602	0,25
9		0,3	659		601	602	0,25
10		0,3	653		595	598	0,25
11		0,3	604		547	548	0,25

Example 12 Synthesis of 2-methyl-4,6-dihydroxy-5-methoxy-pyrimidine.

Add 10.8 g (200 mO) of sodium methyllate to a 5.5 g (58 mO) solution of acetamide hydrochloride in 100 ml of ethanol cooled to 0 °C and stir for 15 minutes; then add 7.2 mO (52 mO) of dimethyl methoxy malonate to 50 mO of ethanol and stir overnight at room temperature. Evaporate the reaction mixture at reduced dry pressure (2 kPa). The residue is taken up by 100 ml of a sodium chloride saturated solution and extracted by 800 and 200 n-butanol. The organic phases are dried on sodium sulphate, filtered and evaporated at pressure (2 kPa). The resulting white solid is reduced to 2.4 g. The test chemical is a chemical that is used to determine the concentration of a substance in a sample. The following is a list of the Member States of the European Union:

Synthesis of 4,6-dichloro-2-methyl-5-methoxy-pyrimidine.

A 1.9 g (12.2 mmoles) mixture of 2-methyl-4,6-dihydroxy-5-methoxy-pyrimidine in 60 ml of phosphorus oxychloride is brought to the backflow for 2 hours. After returning to room temperature, the reaction mixture is poured over a mixture of ice and water and then baking soda is added gently to the base pH. The following is the list of active substances in the active substance: The following is the list of active substances in the active substance: The Commission has also published a report on the implementation of the new rules.

Synthesis of 2-piperin-4-yl-[1,8]naphthyridine:

51 g (300 mmoles) of 4- ((2-methyl-[1,3]dioxolan-2-yl) piperidine ((prepared according to J. Org. chem. 29; 1964; 2898-2903) are dissolved in 550 ml of ethanol.

This mixture is cooled to 0 °C using an ice bath.

Add 85 ml of 6N hydrochloric acid (510 mO).

The mixture is heated at the ethanol backflow for 24 hours.

Then add 20.4 g (510 mmoles) of baking soda to neutralize the pH and 32.13 g (260 mmoles) of 2-aminopyridine-3-carboxyaldehyde and 200 ml of ethanol.

Finally, 40.8 g (295 mmoles) of potassium carbonate is added.

Stir this mixture at 100°C for 8 hours and then at room temperature for 18 hours.

You evaporate the ethanol at low pressure, you dilute it with water and butanol, you separate the two phases, and you extract the product to butanol.

The organic phase is dried on sodium sulphate and then filtered and evaporated under reduced pressure.

We recover a solid 65 g brown which we use without purification for further use. The following is the list of active substances: 1H-RMN (MeOD): δ from 1.90 to 2.10 m, 4H, H7 and H7') ; from 2.8 to 2.90 m, 2H, H8 or H8') ; from 3.12 to 3.28 m, 3H, H6 + H8 or H8') ; from 7.58 to 7.68 m, 2H, H2 and H5) ; from 8.38 to 8.45 m, 2H, H3 and H4) ; 9.03 m, 1H, H1). The following is the list of the products covered by the exemption:

Synthesis of 2-[1-(6-Chloro-5-methoxy-2-methyl-pyrimidine-4-yl) -pipéridine-4-yl]-[1,8]naphthyridine from the following:

The resulting residue is then taken up by a mixture of water, ethyl acetate and a solution of saturated sodium bicarbonate. The organic phase is separated and the solid phase is re-extracted from the silicon acetate. The organic phases are regurgitated in the form of magnesium sulfate on the surface of the water, avoiding the evaporation of 0-0 kPa. The resulting residue is then reduced to a solid form of 0-170 mg of chromethyl acetate. The following information is provided for the purpose of the analysis: The following substances are to be classified as substances with a potential for the degradation of the chemical composition of the feed additive: The following is a list of the Member States of the European Union:

Synthesis of 2-benzyloxycarbonylamino-3-[5-methoxy-2-methyl-6-(4-[1,8]naphthyridin-2-yl-pipéridin-1-yl) -pyrimidin-4-ylamino]-propionate from tert-butyl

A mixture of 870 mg (2.36 mmoles) of 2-[1-(6-Chloro-5-methoxy-2-methyl-pyrimidine-4-yl) -pipéridine-4-yl]-[1,8]naphthyridine, 766 mg (2.59 mmoles) of 3-amino-2-benzyloxycarbonylamino propionate tert-butyl, 540 mg (3.57 mmoles) of caesium fluoride, 120 mg (0.124 mmoles) of trisdibenzylideneacetone (dipalladium) 0, and 70 mg (0.108 mmoles) of 2,2'-bisphenylephosphino) -1,1'-binaphtyl is heated at the back-flow. The mixture is evaporated to 2 kPa during the 6 hour period and the residual phase is evaporated by sodium bicarbonate and sodium bicarbonate separated on a solution of magnesium (2 kPa) at reduced pressure.The residue is chromatographed first on alumina by eluting with ethyl ethyl acetate 50-50 and then on silica by eluting with ethyl heptane acetate 50-50. The following is the list of active substances: The following substances are to be classified as substances with a potential for the production of chlorine, including those that are not chemically defined:The following are the main characteristics of the product: The following information is provided for the purpose of the assessment:

Synthesis of 2-benzyloxycarbonylamino-3-{5-methoxy-2-methyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino}-propionate from tert-butyl

A mixture of 820 mg (1.3 mmoles) of 2-benzyloxycarbonylamino-3-[5-methoxy-2-methyl-6-(4-[1,8]naphthyridin-2-yl-pipéridin-1-yl) -pyrimidine-4-ylamino]propionate of tert-butyl and 30 mg of platinum oxide is stirred in 50 ml of ethanol for 2 hours under atmospheric hydrogen pressure. The reaction mixture is filtered on a clarinet and then evaporated at reduced pressure (2 kPa). The residue is crystallized in diisopropyl ether. 570 mg of the product is obtained as an amorphous white solid. The following is the list of active substances: The following substances are considered to be toxic if they are used in the manufacture of the active substance: 1H-RMN (CDCl3): δ 1,48 ppm (s, 1H, tBu); 1,67 and 1,97 (m, 6H, CH2-CH2-NH and CH2-CH-CH2) ; 2,35 (s, 3H, C-CH3) ; 2,65 (tt, 1H, CH2-CH-CH2) ; 2,71 (t, 2H, CH2-CH2-CH2-NH); 2,87 and 4,47 (tl and dl, 4H, CH2-CH2-N-CH2-CH2) ; 3,41 (m, 2H, CH2-CH2-NH) 3,57 (s, 3H, C-O3) ; 3,84 (m, 2H, NH-CH2-NH-); 4,36 (m, 1H, NH-CH2-CH-NH) 5,12 (d, 2H, CH2-CH2-Ph) ; 6,11 and CH-CHd; 7,11 and CH-CH2; 2,11 and CH= 5,75 (m, 2,75 and CH= 7,12; 2,11 and CH-CH-CH2-CH2 = 5,75; 2,75 and CH= 5,75 (m, 2,75 and CH-CH-CH2); 2,12 (d, 2,11 and CH-CH2-CH2-CH2-CH2-CH2-CH2) ; 2,11 and CH= 5,12 (m, 2,75 and CH-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2) ; 2,75 (m, 2,75 and CH= 5,12 (m, 2,75 and CH-CH2-CH2-CH2-CH2-CH2-CH2); 2,75 and CH-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2) ; 2,11 and CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2) ; 2,11; 2,11 and CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH The following are the main components of the test:

Example 13 The following is a list of the active substances in the active substance:

280 mg (0.443 mmole) of 2-benzyloxycarbonylamino-3-{5-methoxy-2-methyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino}-tert-butyl propionate is agitated in 15 ml of dichloromethane with 3 ml of trifluoroacetic acid at room temperature for 18 hours. Toluene is added and the reaction mixture is evaporated at reduced pressure (2 kPa). The residue is dissolved in the minimum of dichloromethane poured over diisopropyl ether. 210 mg of the product is obtained by filtration as a white solid. The chemical composition of the product is determined by the following equation: The following substances are considered to be toxic if they are used in the manufacture of chemicals containing chemicals which are not classified as chemicals: The following are the types of substances: SM 576 ((MH+); 442 ((MH-COOCH2Ph+) ; 574 ((MH-); 466 ((574-OCH2Ph-) ; 1150 ((2M-).

Example 14 Synthesis of 2-tert-butyl-5-methyl-4,6-dihydroxy-pyrimidine:

A monocol containing 80 ml of ethanol is cooled to 0 °C by an ice bath, 4 g (55.6 mmoles) of sodium ethyllate and 3.8 g (27.8 mmoles) of tert-butylcarbamide hydrochloride are added. The reaction mixture is allowed to return to room temperature, then 5 ml (27.8 mmoles) of methyl diethyl ester methylmalonate is added by drip. The stirring is then maintained at room temperature for one night. The ethanol is condensed at reduced pressure (2 kPa). The resulting crude is dissolved in a minimum of water (about 40 ml), then acidified at 0 °C with acetic acid to a pH between 4 and 5.2 g. The white precipitate is filtered, then produced by rinsing and reducing the white ether to a pH of 2.4 kPa. The following is the list of active substances: The following is a list of the most commonly used methods: The following is the list of active substances in the active substance:

Synthesis of 2-tert-butyl-4,6-dichloro-5-methylpyrimidine

A 2.91 g (15.9 mmoles) mixture of 2-tert-Butyl-5-methyl-4,6-dihydroxy-pyrimidine and 15 ml of phosphorus oxychloride is brought to the backflow for 1 hour 30 minutes. After returning to room temperature, the reaction mixture is slowly poured over a mixture of ice, water and solid sodium carbonate. This aqueous phase is extracted to ethyl acetate. The following is the list of active substances in the active substance: The following is a list of the substances that are considered to be toxic to humans:

Synthesis of 2-[1-(2-tert-butyl-6-chloro-5-methyl-pyrimidine-4-yl) -pipéridine-4-yl]-[1,8]naphthyridine:

In a monocol containing 1.5 g (6.84 mmoles) of 2-tert-Butyl-4,6-dichloro-5-methyl-pyrimidine and 1.46 g (6.84 mmoles) of 2-Piperidin-4-yl-[1,8]naphthyridine, 20 ml of dimethylacetamide and 5 ml (17.8 mmoles) of diisopropylethylamine are added to a monocol and heated to 100 °C for one night. The next day, 0.2 equivalent of naphthyridine is added and heated for another 6 hours, the reaction mixture is brought back to room temperature before concentration to dry. The remainder is taken up by a mixture of water, silicon acetate and saturated sodium bicarbonate. The following is the list of active substances and their active substances: The substance is classified as a substance of very high concern for the protection of human health and the environment. The following is a list of the Member States of the European Union:

Synthesis of 2-benzyloxycarbonylamino-3-[2-tert-butyl-5-methyl-6-(4-[1,8]naphthyridin-2-yl-pipéridin-1-yl) -pyrimidin-4-ylamino]-propionate from tert-butyl

A mixture of 1.7 g (4.2 mmoles) of 2-[1-(2-tert-Butyl-6-chloro-5-methyl-pyrimidine-4-yl) -pipéridine-4-yl]-[1,8]naphthyridine and 1.51 g (5.04 mmoles) of 3-amino-2-benzyloxycarbonylamino propionate tert-butyl, in the presence of 1.95 g (12.6 mmoles) of cesium fluoride, 266 mg (0.42 mmoles) of (2,2'-bis-diphenylphosphino) -1,1'-binthyl in 20 ml of dioxane is brought to the reflux, 230 mg (0.21 mmoles) of tris-diphenylbenzylidene is added to the heat, sodium dihydipalladium is added to 5 ml of dioxane solution, and refluxed for 15 hours. The mixture is then mixed with water at a temperature of 26 °C (2 °C) and then reduced to a concentrated solution of sodium bicarbonate, then reduced to a saturated solution of 2 kPa.The organic phase is decanted and the aqueous phase is extracted to ethyl acetate. The organic phases are dried on magnesium sulfate and evaporated dry at reduced pressure (2 kPa). The residue is chromatographed on silica with a dichloromethane-ethyl acetate gradient (95-5) to (70-30). 1.91 g of expected product is obtained. The following is the list of active substances: The following substances are to be classified in the same category as the product:The active substance is a substance that is used in the manufacture of foodstuffs for human consumption. The following is added:

Synthesis of 2-benzyloxycarbonylamino-3-[2-tert-butyl-5-methyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl-pipéridin-1-yl) -pyrimidin-4-ylamino]-propionate from tert-butyl

A 1.8 g (2.75 mmoles) 2-benzyloxycarbonylamino-3-[2-tert-butyl-5-methyl-6-(4-[1,8]naphthyridin-2-yl-pipéridin-1-yl) -pyrimidine-4-ylamino]-propionate tert-butyl is dissolved in 80 ml of ethanol, 120 mg of platinum oxide (IV) is added. The reaction mixture is then vacuum cleaned and topped with a hydrogen-containing bolt-action balloon. The reaction mixture is agitated and left to stand at room temperature for 6 hours. The reaction mixture is concentrated on clarcel and dried under reduced pressure (2 kPa). The residue is chromatographed on silica with a dichloromethane gradient (98-2 g). The following is the list of active substances and their active substances: The following substances are to be classified as substances with a potential for the degradation of the chemical composition of the feed additive: The following is the text of the communication:

Example 15 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

A 350 mg (0.53 mmoles) mixture of 2-benzyloxycarbonylamino-3-[2-tert-butyl-5-methyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl-pipéridin-1-yl) -pyrimidine-4-ylamino]-tert-butyl propionate is stirred at room temperature in a solution of 6 ml of dichloromethane and 2.2 ml of trifluoroacetic acid for up to 24 hours. Toluene is added and purified into the mixture. The residue is dissolved in a minimum of dichloromethane and then poured over a mixture of pentane and diisopropyl ether. The precipitate is filtered.

We get 390 mg of the expected product. The following is the list of active substances in the active substance: The following substances are to be classified as substances with a potential for the degradation of the chemical composition of the feed additive: The following is a list of the types of vehicles:

Example 16 Synthesis of 2-methyl-5-cyclopropyl-4,6-dihydroxypyrimidine:

A monocol containing 80 ml of ethanol is cooled to 0 °C by an ice bath, 4.5 g (66.4 mmoles) of sodium ethyllate and 4 g (33.2 mmoles) of cyclopropylcarbamidine hydrochloride are added. The reaction mixture is allowed to return to room temperature, then 5.7 ml (33.2 mmoles) of methyl methylmalonate of diethyl ester is added drop by drop. The agitation is then maintained at room temperature for one night. The ethanol is condensed at reduced pressure (2 kPa). The resulting crude is dissolved in a minimum of water (about 40 ml), then acidified at 0 °C with acetic acid to a pH between 4 and 5. The following table shows the number of samples of the test chemical: The following substances are considered to be toxic if they are used in the manufacture of the active substance:

Synthesis of 2-cyclopropyl-4,6-dichloro-5-methylpyrimidine:

A 3.68 g (22 mmoles) mixture of 2-cyclopropyl-5-methyl-4,6-dihydroxy-pyrimidine and 20 ml of phosphorus oxychloride is brought to the backflow for 1 hour and 30 minutes. After returning to room temperature, the reaction mixture is slowly poured over a mixture of ice, water and solid sodium carbonate. This aqueous phase is extracted to ethyl acetate. The organic phase is washed several times with a saturated sodium bicarbonate solution until the acid is completely neutralized and then dried on magnesium sulfate and evaporated dry at reduced pressure (2 kPa). The following is the list of active substances and their active substances: The following substances are to be classified as substances with a specific chemical composition: SM: (MH+) = 204

Synthesis of 2-[1-(2-cyclopropyl-6-chloro-5-methyl-pyrimidine-4-yl) -pipéridine-4-yl]-[1,8]naphthyridine from the following:

In a monocol containing 1.5 g (7.39 mmoles) of 2-cyclopropyl-4,6-dichloro-5-methylpyrimidine and 1.58 g (7.39 mmoles) of 2-Piperidin-4-yl[1,8]naphthyridine, 20 ml of dimethylacetamide and 3.36 ml (19.2 mmoles) of diisopropylethylamine are added to a monocol and heated to 100 °C overnight. The next day, 0.2 equivalent of naphthyridine is added and heated for 6 hours. The reaction mixture is then brought to room temperature at a dry concentration. The resulting residue is mixed by a re-mixing of water, silicon acetate and a 100% sodium bicarbonate solution. The organic phase and the saturated sodium acetate are separated. The substance is classified as a substance of very high concern for the protection of human health and the environment. The following is a list of the Member States which have adopted the new rules:

Synthesis of 2-benzyloxycarbonylamino-3-[2-cyclopropyl-5-methyl-6-(4-[1,8]naphthyridin-2-yl-pipéridin-1-yl) -pyrimidin-4-ylamino]-propionate from tert-butyl

A mixture of 1.4 g (3.68 mo) of 2-[1-(2-tert-Butyl-6-chloro-5-methyl-pyrimidine-4-yl) -pipéridin-4-yl]-[1,8]naphthyridine and 1.3 g (4.42 mo) of 3-amino-2-benzyloxycarbonylamino propionate tert-butyl), in the presence of 1.68 g (11 mo) of cesium fluoride, 230 mg (0.37 mo) and (2,2'-bisdiphenylphosphino) then-1,1'-binaphthyl in 20 ml of dioxane is brought to the reflux. 200 mg (0.19 mo) of tris-dibenzylidine-acetone) is added to hot water, leaving sodium dihydride (dihydride) in 5 ml of dioxane, is refluxed for 15 hours. The mixture is then mixed at room temperature and reduced to a saturated solution of sodium bicarbonate, then reduced to a concentrated solution of sodium bicarbonate (2 kPa) and then reduced to a dry solution of water.The organic phase is decanted and the aqueous phase is extracted to ethyl acetate. The organic phases are dried on magnesium sulfate and evaporated dry at reduced pressure (2 kPa). The residue is chromatographed on Alumina and then on silica with a dichloromethane-ethyl acetate gradient (95-5) to (70-30). 1.5 g of expected product is obtained. The following is the list of active substances: The following substances are considered to be toxic if they are used in the manufacture of the active substance:The active substance is a substance that is capable of being used as a solvent for the production of alcohols, ethers, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, esters, etc. The following is added:

Synthesis of 2-benzyloxycarbonylamino-3- [2-cyclopropyl-5-methyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl-pipéridin-1-yl) -pyrimidin-4-ylamino]-propionate from tert-butyl

The reaction mixture is then vacuum-swept and topped with a hydrogen-containing bolt-on balloon. It is stirred and left at room temperature for 6 hours. The reaction mixture is filtered on clarinets and concentrated at reduced dry pressure (2 kPa). The residue is chromatographed on silica with a dichloromethane gradient (98-223 g). The expected result is 1. The total number of samples of the test chemical is calculated by adding the number of samples of the test chemical to the total number of samples of the test chemical. The following is a list of the Member States which have adopted the new rules:

Example 17 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C4.]

A 300 mg (0.47 mmoles) mixture of 2-benzyloxycarbonylamino-3- [2-cyclopropyl-5-methyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl-pipéridin-1-yl) -pyrimidine-4-ylamino]-tert-butyl propionate is stirred at room temperature in a solution of 5 ml of dichloromethane and 2 ml of trifluoroacetic acid for 24 hours. Toluene is then added and the mixture is purified dry. The residue is dissolved in a minimum of dichloromethane poured over a mixture of pentane and diisopropyl ether. The precipitate is filtered.

We get 320 mg of the expected product. The following is the list of active substances in the active substance: The following substances are to be classified as substances with a potential for toxic effects on human health and the environment: 1H-RMN (CDCl3): δ 1,05 (m, 4H, cyclopropyl); 1,95 (m, 9H, CH3, CH2-CH2-CH2-NH, N-CH2-CH2-CH2-CH2-CH2); 2,3 (m, 1H, cyclopropyl); 2,77 (t, 2H, CH2-CH2-CH2-NH); 2,85 to 3,2 and 3,95 (3m, 7H, CH2-CH2-N-CH2-CH2, N-CH2-CH2-CH-CH2-CH2, NH-CH2-CH-NH); 3,5 (m, 2H, CH2-CH2-CH2-NH); 4,25 (m, 1H, NH-CH2-CH-NH); 5,1 (s, 2H, O-CH2-Ph); 6,07 (m, 1H, NH); 6,35 (d, 1H, naph, naph); 7,2 (m, 6H, naph, naph and naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, naph, The following are the main components of the test:

Example 18 Synthesis of 2-methoxy-4,6-dihydroxy-5-methylpyrimidine.

The solution of 10 g (58 mmoles) of methoxyformamide sulfate in 100 ml of ethanol cooled to 0 °C is then added to 13.8 g (200 mmoles) of sodium ethylethate and stirred for 15 minutes; then a solution of 9 ml (52 mmoles) of methyl diethyl malonate is added to 50 ml of ethanol and stirred overnight at room temperature. The mixture is evaporated in a dry reaction at reduced pressure (2 kPa). The residue is taken up by 100 ml of a saturated sodium chloride solution and extracted by 800 and 200 ml of n-Pa butanol. The organic phases are dried on sodium sulfate, filtered and evaporated at reduced pressure (2 kPa). The test chemical is a chemical that is used to determine the concentration of a substance in a sample. The following are the main components of the test:

Synthesis of 4,6-dichloro-2-methoxy 5-methyl pyrimidine.

A 0.9 g (5.77 mmoles) mixture of 2-methoxy-4,6-dihydroxy-5-methyl-pyrimidine in 30 ml of phosphorus oxychloride is brought to the backflow for 2 hours. After returning to room temperature, the reaction mixture is poured over a mixture of ice and water and then baking soda is added gently to the base pH. The following is the list of active substances in the active substance: The following is a list of the active substances in the active substance: The Commission has also published a report on the implementation of the new rules.

Synthesis of 2-[1-(6-Chloro-2-methoxy-5-methyl-pyrimidine-4-yl) -pipéridine-4-yl]-[1,8]naphthyridine from the following:

In a monocol containing 0.48 g (2.2 mmol) 4-(1,8-naphthyridin-7-yl)-1-pipéridine, 30 ml of dimethylacetamide, 0.4 g of 4.6-dichloro-2-methoxy5-methyl-pyrimidine (2 mmol) and 3 ml of diisopropylethylamine are added to a monocol. This mixture is heated to 120 °C for 4 hours and then dried under reduced pressure (2 kPa). The residue is obtained by a mixture of water, ethyl acetate and a saturated sodium bicarbonate solution. The organic phase is separated and the solid phase is re-extracted from the ethyl acetate. The organic phases are grouped together as magnesium sulfate residues on the surface of the soil to avoid evaporation. The residue is obtained by a reaction with a solution of sodium bicarbonate at a pressure of 0-100 mg (260 kPa). The organic phase is then extracted as silicon acetate. The following information is provided for the purpose of the analysis: The following substances are to be classified as substances with a potential for the degradation of the chemical composition of the feed additive: The following is a list of the Member States of the European Union:

The following substances are to be classified in the same category as the active substance:

A mixture of 460 mg (1.25 mmoles) 2-[1-(6-chloro-2-methoxy-5-methyl-pyrimidine-4-yl) -pipéridine-4-yl]-[1,8]naphthyridine, 405 mg (1.37 mmoles) tert-butyl 3-amino-2-benzyloxycarbonylamino propionate, 250 mg (1.65 mmoles) caesium fluoride, 57 mg (0.062 mmoles) trisodium dibenzylidene acetate ((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((The residue is chromatographed on alumina by electrolysis with a heptane-ethyl acetate gradient of 100-0 to 0-100. The following is the list of active substances: The following substances are to be classified as substances with a potential for the production of lead in the form of lead compounds:The number of units of measurement is calculated as follows: The following information is provided for the purpose of the assessment:

Synthesis of 2-benzyloxycarbonylamino-3-{2-methoxy-5-methyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidin-4-ylamino}-propionate from tert-butyl

A mixture of 300 mg (0.477 mmole) of -2-benzyloxycarbonylamino-3-[2-methoxy-5-methyl-6-(4-[1,8]naphthyridin-2-yl-pipéridin-1-yl) -pyrimidine-4-ylamino]propionate of tert-butyl and 30 mg of platinum oxide is stirred in 30 ml of ethanol for 1 hour under atmospheric hydrogen pressure. The reaction mixture is filtered on clarcel and then evaporated dry under reduced pressure (2 kPa). 170 mg of the product is obtained as an orange amine oil.

The amine is reacted with 120 mg benzyloxycarbonyl-succinimide in 40 ml dimethoxyethane for 3 hours at room temperature. The reaction mixture is taken up by ethyl acetate, water and a saturated sodium bicarbonate solution. The organic phase is separated, dried on magnesium sulfate and the evaporated solvent at reduced pressure (2 kPa). The residue is chromatographed on gel by eluting with a heptane-ethyl acetate gradient of 100-0 to 0-100. 200 mg (Rdt=93%; 67% for both steps) of expected product is obtained in the form of a yellow oil. The following is the list of active substances: The following substances are considered to be toxic if they are used in the manufacture of the active substance: 1H-RMN (CDCl3): δ 1,46 ppm (s, 1H, tBu); 1,77 and 1,97 (m, 6H, CH2-CH2-NH and CH2-CH-CH2); 1,90 (s, 3H, C-CH3); 2,61 (tt, 1H, CH2-CH-CH2) ; 2,71 (tl, 2H, CH2-CH2-CH2-NH) ; 2,91 and 3,72 (tl and dl, 4H, CH2-CH2-N-CH2-CH2); 3,41 (m, 2H, CH2-CH2-CH2-NH) ; 3,84 and 3,95 (2m, 2H, CH2-CH2-NH); 3,89 (s, 3H, C-O3); 4,43 (m, 1H, CH2-CH-NH); 5,11 (dH, 2Ph, CH2-CH2-CH2) ; 6,41 and 7,12 (dH, CH= 2,12 and 2,12; 7,12 and CH= 4,7); 5,21 and 5,21 (dH, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH2, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, The following are the main components of the test:

Synthesis of 2-benzyloxycarbonylamino-3-{2-methoxy-5-methyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino}-propionic acid with a bis-trifluoroacetate content of less than 0,5% by weight

200 mg (0.317 mmole) of 2-benzyloxycarbonylamino-3-{2-methoxy-5-methyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino}-tert-butyl propionate is agitated in 10 ml of dichloromethane with 2 ml of trifluoroacetic acid at room temperature until the starting product disappears into CCM (silicone, emulsifying: CH2Cl2-OHMe-H2O-OHAc-10-1-90-1). Toluene is added and the mixture is evaporated under dry pressure (2 kPa). The residue is reduced to the minimum in dichloromethane diethyl diethyl. The resulting product is obtained in the form of a beige 170 mg solid. The chemical composition of the product is determined by the following equation: The test chemical is used to determine the concentration of the active substance in the test chemical and to determine the concentration of the active substance in the test chemical. The following are the types of medicinal products: SM 576 ((MH+); 442 ((MH-COOCH2Ph+); 574 ((MH-); 466 ((574-OCH2Ph-); 1150 ((2M-).

Example 19 Synthesis of 2,5-dimethoxy-4,6-dihydroxy-pyrimidine

The solution of 9 g (52 mL) of methoxyformamide sulfate in 100 ml of ethanol cooled to 0 °C is then added to 9.7 g (180 mL) of sodium methyllate and stirred for 15 minutes; then a 6.5 ml (46.8 mL) solution of methyl methoxy malonate is added to 50 ml of ethanol and stirred overnight at room temperature. The mixture is evaporated in a dry reaction under reduced pressure (2 kPa). The residue is taken up by 100 ml of a saturated solution of sodium chloride and extracted by 800 and 200 ml of n-Pa butanol. The organic phases are dried on sodium sulfate, filtered and evaporated under pressure (2 kPa). 7 g of the expected white product is obtained in the form of a solid. The following is a list of the most commonly used methods for the analysis of the data: The following are the main components of the test:

Synthesis of 4,6-dichloro-2,5-dimethoxy-pyrimidine.

A 1.7 g (10 mmoles) mixture of 2.5-dimethoxy-4,6-dihydroxy-pyrimidine in 30 ml of phosphorus oxychloride is brought to the reflux for 5 hours. After returning to room temperature, the reaction mixture is poured over a mixture of ice and water and then sodium bicarbonate is added gently to base pH. It is extracted with butanol, dried on sodium sulfate and evaporated dry under reduced pressure (2 kPa). 0.50 g of brown oil is obtained. The following is the list of active substances in the active substance: The following is the list of substances that are to be classified as chemicals:

The following is added to the list of active substances:

In a monocol containing 1.3 g (7.8 mmoles) of 4-(1,8-naphthyridin-7-yl)-1-pipéridine, 40 ml of dimethylacetamide, 1.25 g of 4.6-dichloro-2,5-dimethoxy-pyrimidine (5.6 mmoles) and 5 ml of diisopropylethilamine are added to the mixture. This mixture is heated to 120 °C for 5 hours and then dried at reduced pressure (2 kPa). The resulting residue is then taken up by a mixture of water, ethyl acetate and a saturated sodium bicarbonate solution. The organic phase is separated and the solid phase is re-extracted as silicon acetate. The organic phases are regrouped as magnesium sulfate on the surface of the evaporative solvent. The resulting residue is obtained by reducing the chloride chloride to a temperature of 0.0 to 0.0 kPa. The resulting residue is obtained by a chromatographic reaction with a chloride chloride chloride solution. The following information is provided for the purpose of the analysis: The following substances are considered to be toxic if they are used in the manufacture of the active substance: The number of employees is:

Synthesis of 2-benzyloxycarbonylamino-3-[2,5-dimethoxy-6-(4-[1,8]naphthyridin-2-yl-pipéridin-1-yl) -pyrimidin-4-ylamino]-propionate from tert-butyl

A mixture of 1.2 g (3.1 moles) 2-[1-(6-Chloro-2,5-dimethoxy-pyrimidine-4-yl) -pipéridine-4-yl]-[1,8]naphthyridine, 1.3 g (4.40 moles) tert-butyl 3-amino-2-benzyloxycarbonylamino propionate, 750 mg (4.95 moles) caesium fluoride, 200 mg (0.217 moles) tris (dibenzylidene acetone) -dipalladium, and 120 mg (0.186 moles) 2,2'-dibisphenyl-phosphino) --1,1'-binaphtyl is heated at the back-flow. The reaction mixture is evaporated at a pressure of 2 kPa and the residue is reduced to saturated sodium acetate, separated from the sodium and magnesium sulphate phase by a solution of 2,2 kPa of organic solvent.The residue is chromatographed first on alumina by eluting with ethyl ethyl acetate 50-50 and then a second time on silica with a heptane-ethyl acetate gradient of 100-0 to 0-100. The following is the list of active substances: The following substances are considered to be toxic if they are used in the manufacture of the active substance:The following are the main components of the test method: CH2Ph); 7.48 and 8.16 (2d, 2H, C-CH=CH-C(CH) =N); 7.48 (dd,1H, N-CH=CH-CH=C); 8.19 (dd,1H N-CH=CH-CH=C); 9.11 (dd,1H N-CH=CH-CH=C); 5.37 and 6.29 (tl and dl H mobile). The following information is provided for the purpose of the assessment:

Synthesis of 2-benzyloxycarbonylamino-3-{2,5-dimethoxy-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino}-propionate from tert-butyl

A mixture of 85 mg (1.32mmol) of 2-benzyloxycarbonylamino-3-[2,5-dimethoxy-6-(4-[1,8]naphthyridin-2-yl-pipéridin-1-yl) -pyrimidine-4-ylamino]propionate of tert-butyl and 30 mg of platinum oxide is stirred in 50 ml of ethanol for 2 hours under atmospheric hydrogen pressure. The reaction mixture is filtered on clarcel and then evaporated dry under reduced pressure (2 kPa). The residue is chromatographed on silica with a heptane-acetate gradient of ethylene-thanol of 100-0-0 to 0-100-0-0-0 and then 0-95-5. The following is the list of active substances: The following substances are considered to be toxic if they are used in the manufacture of the active substance: 1H-RMN (CDCl3): δ 1,46 ppm (s, 1H, tBu); 1,79 and 1,97 (dt and m, 6H, CH2-CH2-CH2-NH and CH2-CH-CH2); 2,72 (tl, 3H, CH2-CH-CH2 and CH2-CH2-CH2-NH); 2,92 and 4,57 (tl and dl, 4H, CH2-CH2-N-CH2-CH2); 3,43 (m, 2H, CH2-CH2-CH2-NH); 3,56 and 3,87 (2s, 6H, C-OCH3) ; 3,85 (masked m, 2H, NH-CH2-NH); 4,41 (m, 1H, NH-CH2-NH-CH); 5,12 (s, 2H, CH2-CH2-); 6,37 and 7,16 (2Phd, CH=CH=CH=C); 7,35 (m, 5H, CH2-CH2-CH2); 5,35 and 5,28 (m, 5,33 and H-CH-CH-NH); 6,28 (m, 2H, CH-CH2-NH-CH2-NH-NH-); 6,37 and 7,16 (2Phd, 2H, C=CH=C); 6,35 (m, CH=C=C); 5,35 and 5,28 (m, CH2 and H-CH2-CH2-CH2-NH); 6,33 and 6,28 (m, 6,28 (m, CH-CH-CH-CH-NH-CH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-CH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH-NH- The following information is provided for the purpose of the assessment:

Example 20 The following is the list of active substances in the active substance:

350 mg (0.54 mmole) of 2-benzyloxycarbonylamino-3-{2,5-dimethoxy-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylaminol-propionate tert-butyl is agitated in 10 ml of dichloromethane with 2 ml of trifluoroacetic acid at room temperature until the starting product disappears into CCM (silicon, eluting: CH2Cl2-MeOH-H2O-OHAc 90-10-1-1. The following is the list of active substances in the active substance: The following substances are considered to be toxic if they are used in the manufacture of the active substance: 1H-RMN (CD3OD): δ 1,79 and 1,96ppm (q and m, 6H, CH2-CH2-CH2-NH and CH2-CH2-NH2); 2,82 (tl, 2H, CH2-CH2-CH2-NH); 2,91 (t1, 1H, CH2-CH-CH2); 3,50 and 4,58 (tl and dl, 4H, CH2-CH2-N-CH2-CH2); 3,50 (tl, 2H, CH2-CH2-CH2-NH); 3,67 and 3,87 masked, 2H NH-CH2-CH-NH); 3,52 and 3,85 (2s, 6H, C-CH3-O3); 4,39 (m, 1H, NH-CH2-CH-NH); 5,07 (q, 2H, CH2-CH2-Ph); 6,62 and 7,58 (2d, 2H, CCH=CHC); 7,31 (Ph, 2H, CH2-CH2m). The following are included in the list of substances: SM 592 (MH+); 458 (MH-COOCH2Ph+); 590 (MH-); 482 (590-OCH2Ph-); 1182 (2M-).

Example 21 The following is added to the list of active substances:

In a monocol containing 3.9 g (17 mmoles) of 7-Piperidin-4-yl-1,2,3,4-tetrahydro[1,8]naphthyridine, 80 ml of dimethylacetamide, 3.9 g (22 mmoles) of 4.6-dichloro-5-formyl-pyrimidine [prepared according to Liebigs Annalen der Chemie (1972) 766 73-88] and 8 ml of diisopropylethylamine are added to a monocol. This mixture is heated to 120 °C for 3 hours and then concentrated at reduced pressure (2 kPa). The resulting residue is taken up by a mixture of water, ethyl acetate and a saturated sodium bicarbonate solution.

2.3 g of the expected product is obtained as a yellow powder. The total number of samples of the test chemical is calculated by adding the following data: The following is a list of the Member States of the European Union:

The following is the list of active substances and their chemical names:

A mixture of 180 mg (0.5 mmole) of 4-Chloro-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidine-5-carbaldehyde, 150 mg (0.5 mmole) of 3-amino-2-benzyloxycarbonylamino propionate tert-butyl, 117 mg (0.77 mmole) of caesium fluoride, 23 mg (0.025 mmole) of trisdibenzylideneacetone dipalladium and 32 mg (0.51 mmole) of 2,2'-bisdibenzylidene-phosphino) -1,1'-binaphtyl is heated at the back of the tank in 30 ml of dimethox for 2 hours. The mixture is cooled again for 23 mg (0.025 mmole) of trisdibenzyloxycarbonylamineacetane and then cooled in a solution of sodium bicarbonate and dissolved in water for 2 hours. The remainder is then reduced to a solution of sodium bicarbonate and cooled by heating.The organic phase is separated, dried on magnesium sulfate and the solvent evaporated at reduced pressure (2 kPa). The residue is chromatographed on silicagel by eluting with a mixture of ethyl chloride acetate and methylene methanol 50-45-5. 120 mg of the expected product is obtained as a white amorphous solid. The following is the list of active substances: The following substances are to be classified as substances of very high concern in accordance with the provisions of Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 16 December 2006 on the approximation of the laws of the Member States relating to the permissible sound power level of compressed air (OJ L 345, 20.12.2006, p.The following is a list of the active substances that may be used in the preparation of the active substance: 13 (s, 2H, CH2-Ph); 6.37 and 7.19 (2d, 2H, CH=CH naphthyridine); 7.36 (m, 5H, Ph)); 8.35 (s, 1H, N=CH-N); 9.77 (s, 1H, C-CH=O); 6.17 and 9.16 (dl and tl, 2H, NH). SM: 616 (MH+); 560 (MH-tBu+); 426 (MH-COOCH2Ph+).

The following is the list of active substances and their chemical names:

120 mg (0.195 mmole) of 2-benzyloxycarbonylamino-3-{5-formyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino}-tert-butyl propionate is stirred in 10 ml of dichloromethane with 1 ml of trifluoroacetic acid at room temperature for 24 hours. Toluene is added and the reaction mixture is evaporated at reduced pressure (2 kPa). The residue is dissolved in the minimum of dichloromethane with a little methanol poured over diisopropyl ether. The precipitate is filtered. 60 mg of the expected white solid is obtained. The following is the list of active substances in the active substance: The following are the active substances: SM 560 (MH+); 426 (MH-COOCH2Ph+); 558- (M-H-); 450- (558-OCH2Ph-); 1117- (2M-H-).

Example 22 Synthesis of 2-benzyloxycarbonylamino-3-{5-hydroxymethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino}-propionate from tert-butyl

340 mg (0.55 mmole) of 2-benzyloxycarbonylamino-3-{5-formyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipperidin-1-yl]-pyrimidine-4-ylamino}-propionate tert-butyl is stirred in 50 ml of methanol with 350 mg (9.2 mmole) of sodium borohydride at room temperature for 2 hours. 100 ml of a saturated solution of ammonium chloride is then added and the reaction mixture is evaporated dry at reduced pressure (2 kPa). The resulting residue is then re-mixed with water and methyl chloride acetate. The organic phase is evaporated on silicon sulfate of the evaporated sodium chloride in the form of 0 kPa (2 kPa). The following is added to the list of substances: The following substances are considered to be toxic if they are used in the manufacture of the active substance: 1H-RMN (CDCl3): δ 1,48 (s, 9H, tBu); 1,80 to 2,05 (m, 6H, CH2-CH2-CH2-NH and CH2-CH2-CH2-NH2); 2,72 (t,2H, CH2-CH2-CH2-NH) ; 2,87 (tl, 1H, CH2-CH-CH2); 2,99 and 3,81 (tl and dl, 4H, CH2-CH2-N-CH2-CH2) ; 3,42 (m, 2H, CH2-CH2-CH2-NH) ; 3,90 (m, 2H, NH-CH2-CH-NH); 4,44 (m, 1H, NH-CH2-NH); 5,09 (m, 2H, CH2-CH2-NH); 6,40 and 7,14 (2d, 2H, CH=naphidine); 7,32 (m, 5H, Ph)); 8,27 (s, 1,8,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,2,1,1,1,1,1,1,1,1,2,1,1,1,2,1,1,2,1,2,1,2,1,2,1,2,1,2,1,2,1,2,1,2,2,2,2,2,2,2,2,2,2,3,2,3,2,3,2,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,4,4,4,4,4,4,4,4,4,4,5,4,5,5,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,8,

The following is a list of the active substances in the active substance:

150 mg (0.24 mmole) of 2-benzyloxycarbonylamino-3-{5-hydroxymethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino}-tert-butyl propionate is agitated in 15 ml of dichloromethane with 0.8 ml of trifluoroacetic acid at room temperature for 24 hours. Toluene is added and the reaction mixture is evaporated at reduced pressure (2 kPa). The residue is then dissolved in the minimum of dichloromethane poured over diisopropyl ether. The precipitate is filtered. 100 mg of the expected product is obtained in the form of a white solid. The following is the list of active substances in the active substance: The following are the types of the test: SM 562 (MH+); 560- (M-H-); 452- (560-OCH2Ph-); 1121- (2M-H-).

Example 23

By working as described in the previous examples, by means of 5-amino-4,6-dichloro-pyrimidine and 2,5-dimethoxy-tetrahydrofuran, 2-benzyloxycarbonylamino-3-{5-pyrrol-1-yl-6-[4-(5,6,7,8-tetra-hydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino}-propionate of tert-butyl The following is the list of active substances: The following is added to the list of active substances: SM 653 (MH+); 463 (MH-(tBu and CO-O-CH2-C6H5) + then 2-benzyloxycarbonylamino-3-{5-pyrrol-1-yl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino}-propionic acid The following is the list of active substances: The following is added to the list of substances: The following are the main components of the test method: 1H-RMN (MeOD): δ from 1,60 to 2,00 (3m, 6H, H2, H7 and H7') ; from 2,70 to 2,85 ((m, 3H, H6 and H3)); 3,5 ((m, 2H, H1); 3,62 and 3,92 ((2m, 2H, H12); 4,35 ((m, 1H, H13); 5,10 ((m, 2H, -O-CH2-C6H5); 6,32 ((m, 2H, H11); 6,55 ((d, 1H, H5)); 6,67 ((m, 2H, H10); 7,25 ((m, 5H, -O-CH2-C6H5)); 7,55 ((d, 1H, H4); 8,12 ((m, 1H, H9)).

Examples 24 to 37 General method of preparation of amines Stage a)

The reaction is slower, so a 100 mg (0.208 mmoles) mixture of 2-amino-3-{5-ethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) piperidin-1-yl]-pyrimidine-4-ylamino] tert-butyl propionate and 0.228 mmoles of aldehyde is added to the solution for 10 minutes in 3 ml of tetrahydrofuran. For some aldehydes the reaction is slower, so the reaction mixture is heated at room temperature for 4 hours or cooled in silicon for 4 hours. The reaction is then resumed: after being saturated with sodium acetylate, the mixture is washed with a concentrated solution of magnesium sulphate (Pa/methyl chloride) at a dry pressure of 50 kPa. The following is the list of active substances in the active substance:

Stage b)

A mi-mass of 3-{5-ethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino}-2-alkylamino-propionate tert-butyl is stirred in 5 ml of dichloromethane with 850 μl of trifluoroacetic acid at room temperature until the starting product disappears into CCM (silicagel, eluting: CH2ClMe2-OH-H2O-OH Acute 90-10-1-1). Toluene is rained and the reaction mixture is evaporated at reduced pressure (2 kPa). The residue is soaked in a solution of dichloromethane on top of the diethyl ether. The resulting mi-mass is filtered. The following is the list of active substances in the active substance:

Example 24 Stage a) Synthesis of 2-(2-Ethyl-butylamino)-3-{5-ethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino}-propionate from tert-butyl.

The solution of 75 mg (0.35 mmoles) of sodium triacethoxyborohydride in 6 ml of tetrahydrofuran is allowed to agitate for 10 minutes at TA. Then a mixture of 100 mg (0.208 mmoles) of 2-amino-3-{5-ethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino-propionate tert-butyl and 0.228 mmoles of 2-ethyl-butyldehyde in solution in 3 ml of tetrahydrofuran is added. The following mixture is agitated at room temperature for 4 hours. The silicate is then extracted from the ethanol after washing with a sodium bicarbonate solution. The saturated phase is then obtained by drying the sulphate with the organic solvent magnesium/Pa/ethyl chloride at 50 kPa (20.50 kPa/m3) of chromatophane.We get a my mass of expected product. The following is the list of active substances which are to be used in the preparation of the additive: The following substances are to be classified as substances with a potential for the degradation of the chemical composition of the feed additive: The following are the main categories of products:

Stage b) Synthesis of 2-(2-Ethyl-butylamino)-3-{5-ethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidin-4-ylamino}-propionic acid, Bis (trifluoroacetate)

80 mg (0.141 mmoles) of 3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-(4-methoxybenzoyl) alaninate of (1,1-dimethyl) ethyl is agitated in 5 ml of dichloromethane with 400 μl of trifluoroacetic acid at room temperature for 9 hours.

The residual is then dissolved in the minimum of dichloromethane and then poured over diisopropyl ether. The precipitate is filtered. 90 mg of the expected product is obtained.

The following is the list of active substances which are to be used in the preparation of the additive: The following substances are to be classified as substances with a potential for the degradation of the chemical composition of the feed additive: The following is a list of the Member States of the European Union: Mx: mass of aldehyde introduced My: mass of ester obtained. Mz: mass of acid obtained.

Exemple	Acide obtenu	FW (Base libre)	FW (Base libre + 2 TFA)	Mz (mg)
25		543,72	771,72	90
26		516,65	744,65	25
27		591,76	819,76	30
28		571,77	799,77	35
29		559,67	787,67	46
30		566,71	794,71	34
31		521,69	749,69	14
32		558,73	786,73	38
33		554,70	782,70	13
34		582,71	810,71	14
35		509,70	737,70	90
36		592,75	820,75	10
37		646,80	876,80	40

The products obtained above are prepared from the following raw materials:

Exemple	Aldéhyde	FW	Mx (mg)	produit attendu	FW		Rdt
25		138,18	28		599.83	100	94
26		107,11	25		572,76	37	31
27		182,22	42		647,87	20	15
28		106,12	24		571,77	36	30
29		150,13	34		615,78	40	31
30		157,17	36		622,82	79	61
31		112,15	26		577,8	26	21
34		173,17	40		638,82	30	23
35		100,16	22		565,81	89	38
36		183,21	42		648,86	32	24
37		237,26	54		702,91	42	29

Example 38 Synthesis of 3-[5-methyl-6-[4-(5,6,7,8-tetrahydro-(1,8)naphty-ridin-2-yl) -pipéridin-1-yl]-pyrimidin-4-ylamino]-2-(4-methoxy benzoyl) -propionate from tert-butyl

A mixture of 109 mg (0.233 mo) 2-amino-3-{5-methyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino}-propionate of tert-butyl in solution in 6 ml of dichloromethane and 650 μl of pyridine is mixed with 40 mg (0.233 mo) 4-methoxybenzoyl chloride in solution in 3 ml of dichloromethane. The reaction mixture is agitated at room temperature for 1 hour. Then the evaporated solvent is reduced to pressure (2 kPa) and the following residue is chromatographed on silicomagel with the electrolyte: 50-55 mg (95/50/50/50/5) of acetylated ethyl acetate of ethyl acetate is obtained by an electrolyte of ethyl acetate of ethyl acetate. The following is the list of active substances in the active substance: The following substances are to be classified as substances with a potential for toxic effects on human health and the environment: 1H-RMN (CDCl3): δ 1,54ppm (s, 9H, tBu); 1,20 (t, 3H, CCH3); 1,78 to 2,05 ((m, 6H, CH2-CH-CH2 and CH2-CH2-CH2-NH); 2,66 (tt, 1H, CH2-CH-CH2); 2,72 (t, 2H, CH2-CH2-CH2-NH); 2,92 and 3,68 (ql and m, 4H, CH2-CH2-N-CH2-CH2); 3,42 (m, 2H, CH2-CH2-CH2-NH); 3,86 (s, 3H, COCH3); 3,97 (t, 2H, NH-CH2-CH-NH); 4,78 (q, 1H, NH-CH2-CH-NH); 5,17 (t, 1H, 1H, CH2-CH2-NH) ; 6,41 (d, 2,4H, naph, and m, 4H, CH2-CH2-NH2); 8,13 (d, 2,8H, NH-CH2-NH); 8,23 (d, NH, 8,13 (d, NH, NH, 8,23; 2,8H, NH, NH, NH, 2,82, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH)); 2,13 (d, 6,13 (d, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH, NH The following information is provided for the purpose of the assessment:

Synthesis of 3-[5-methyl-6-[4-(5,6,7,8-tetrahydro-(1,8)naphtyridin-2-yl) -pipéridin-1-yl]-pyrimidin-4-ylamino]-2- ((4-methoxy benzoyl) -propionic acid, bis (trifluoroacetate)

20 mg (0.033 mmole) of 3-[5-methyl-6-[4-(5,6,7,8-tetrahydro-(1,8)naphtyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino]-2-(4-methoxy benzoyl) -propinate tert-butyl is stirred in 2 ml of dichloromethane with 0.3 ml of trifluoroacetic acid at room temperature for 3 hours. Toluene is added and the reaction mixture is evaporated at reduced pressure (2 kPa). The residue is dissolved in the minimum of dichloromethane poured over diisopropyl ether. The precipitate is filtered. 20 mg of the product is obtained in the form of a beige solid. The following substances are considered to be toxic if they are used in the manufacture of the active substance: 1H-RMN (CDCl3): δ 1,77 to 2,15 (m, 6H, CH2-CH-CH2 and CH2-CH2-CH2-NH); 2,37 (s, 3H, CCH3); 2,77 (tl, 2H, CH2-CH2-CH2-NH); 2,99 (tl, 1H, CH2-CH-CH2); 3,22 and 3,97 (tl and dl, 4H, CH2-CH2-N-CH2-CH2); 3,52 (m, 2H, CH2-CH2-CH2-NH); 3,91 and 4,14 (2m, 2H, NH-CH2-CH-NH); 4,82 (m, 1H, NH-CH2-CH-NH); 6,89 and 7,82 (2d, 2H, H naphthyridine); 7,19 and 7,38 (2d, 4H, Hbenzoyl); 8,25 (ppm), 1H, N= 7,79; 6,01 and 9,09 N; 9,09; 9,09; 9,09; 9,09; 9,09; 9,09; The following is added:

Examples 39 to 51 General method of preparation of amides Stage a)

112,5 mg (0.23 mmoles) 2-amino-3-{5-ethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino}-propionate of tert-butyl in solution in 6 ml of dichloromethane is added to 650 μl of pyridine, after agitation for 15 minutes in TA, 0.23 mmoles (mass mx) of acid chloride in solution in 3 ml of dichloromethane is added. The reaction mixture is agitated at room temperature for 1 to 3 hours depending on the acid chloride used. The following solvent is then reduced to 50 kPa by evaporation (2 kPa) and the residue is agglomerated with the chloride: acetylated methyl chloride and acetylated methyl chloride (Pa) 50/90/50/50/50/0.50. The following is the list of active substances in the active substance:

Stage b)

A mi of tert-butyl ester of step (a) is agitated in 5 ml of dichloromethane with 850 μl of trifluoroacetic acid at room temperature until the starting product disappears into CCM (silicagel, electrolyte: CH2Cl2-MeOH-H2O-AcOH 90-10-1-1). Toluene is added and the reaction mixture is evaporated at reduced pressure (2 kPa). The residue is solubilised in the minimum of dichloromethane and then poured over diethyl isopropyl ether. The precipitate is filtered. The following is the list of active substances:

Example 39 Stage a) Synthesis of 3-[5-ethyl-6-[4-(5,6,7,8-tetrahydro-(1,8)naphtyri-din-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino]-2-(4-methoxy benzoyl) -propionate from tert-butyl

A mixture of 112,5 mg (0.233 moles) 2-amino-3-{5-ethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino}-tert-butyl propionate in solution in 6 ml of dichloromethane and 650 μl of pyridine is mixed with 40 mg (0.233 moles) 4-methhoxybenzoyl chloride in solution in 3 ml of dichloromethane. The reaction mixture is agitated at room temperature for 1 hour. The solvent is then evaporated at reduced pressure (2 kPa) and the residue is chromatographed on silicon with the following acetylated acetylated acetylated acetylated acetylated acetylated acetylated (50-50/50/50/501) (9/50/50/50/505) acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated acetylated ac The following is the list of active substances in the active substance: The following substances are to be classified as substances with a specific chemical composition, in accordance with the provisions of Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 16 February 2006 on the approximation of the laws of the Member States relating to the permissible sound power level of compressed air (OJ L 345, 20.12.2006, p. 1). The following are the main components of the test:

Stage b) Synthesis of 3-[5-ethyl-6-[4-(5,6,7,8-tetrahydro-(1,8)naphtyridin-2-yl) -pipéridin-1-yl]-pyrimidin-4-ylamino]-2- ((4-methoxy benzoyl) -propionic acid, bis (trifluoroacetate)

90 mg (0.146 mmoles) of 3-[5-ethyl-6-[4-(5,6,7,8-tetrahydro-(1,8)naphtyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino]-2-(4-methoxy benzoyl) - tert-butyl propionate is agitated in 5 ml of dichloromethane with 850 μl of trifluoroacetic acid at room temperature for 7 hours.

The residual is dissolved in the minimum of dichloromethane and then poured over diisopropyl ether. The precipitate is filtered. 85 mg of the expected product is obtained. The following is the list of active substances in the active substance: The following substances are to be classified as substances with a specific chemical composition, in accordance with the provisions of Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 16 February 2006 on the approximation of the laws of the Member States relating to the permissible sound power level of compressed air (OJ L 345, 20.12.2006, p. 1). The following is a list of the Member States of the European Union: Mx: mass of acid chloride introduced. My: mass of ester obtained. Mz: mass of acid obtained. - What?

Exemple	Acide obtenu	FW (Base libre)	FW (Base libre + 2TFA)	Mz (mg)	SM (MH+)
39		559,67	787,67	85	560
40		555,69	783,69	50	556
41		543,67	771,67	62	544
42		549,72	777,72	70	550
43		535,70	763,7	66	536
44		529,65	757,65	84	530
45		573,66	801,66	89	574
46		579,71	807,71	95	580
47		597,64	825,64	64	598
48		559,67	787,67	80	560
49		557,70	785,7	75	558
50		605,75	833,75	123	605
51		573,70	801,7	155	574

The products obtained above are prepared from the following raw materials:

Exemple	Chlorure d'acide	mx (mg)	ester formé	FW		Rdt	SM (MH+)	Rf
39		40		615,78	98	68	616	0,53
40		30		611,79	50	46	612
41		36,2		599,78	81	58	600	0,50
42		37,4		605,83	81	57	606	0,53
43		34,2		591,8	74	53,5	592	0,53
44		33		585,76	86	63	586	0,47
45		43		629,77	92	62,5	630	0,50
46		44,5		635,82	94	63	636	0,53
47		48,7		653,75	94	61,5	654	0,53
48		40		615,78	92	64	616	0,58
49		39,4		613,81	85	59	614	0,58
50		46		661,85	63	38	662	0,20
51		36		629,81	90	57	630	0,16

Example 52 Synthesis of 3-[5-ethyl-6-[4-(5,6,7,8-tetrahydro-(1,8)naphtyridin-2-yl) -pipéridin-1-yl]-pyrimidin-4-ylamino]-2-[3-(2-nitrophenyl) -ureido]-propionate from tert-butyl

A mixture of 240 mg (0.50 mmole) 2-amino-3-{5-ethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino}-propionate tert-butyl and 82 mg (0.50 mmole) 2-nitrophenylisocynate in 15 ml of tetrahydrofuran is agitated for 3 hours at room temperature. The reaction mixture is evaporated at reduced pressure (2 kPa) and the residue is taken up by ethyl acetate and water. The organic phase is separated, dried on magnesium sulfate and evaporates in solvent under pressure (2 kPa). The residue is reduced to alumina by reducing the chromate gradient with a 50-50 mg on-methyl chloride of on-methyl acetate to a product of 50-50 mg on-methyl chloride.- What? The following is the list of active substances which are to be used in the preparation of the additive: The following substances are considered to be toxic if they are used in the manufacture of the active substance: 1H-RMN (CDCl3): δ 1,20 (t, 3H, CH2CH3); 1,45 (s, 9H, tBu); 1,80 to 2,02 (m, 6H, CH2-CH-CH2 and CH2-CH2-CH2-NH); 2,50 (q, 2H, CH2-CH3); 2,66 (t1, 1H, CH2-CH-CH2); 2,73 (t, 2H, CH2-CH2-CH2-NH); 2,97 and 3,62 (tl and m, 4H, CH2-CH2-N-CH2-CH2); 3,43 (m, 2H, CH2-CH2-CH2-NH); 3,95 (m, 2H, NH-CH2-CH2-NH); 4,57 (m, 1H, NH-CH2-CH2-NH); 5,03 (t, 1H, 1H, CH2-CH2-CHCH-NH); 6,42 and 7,15 (d), 2,56 and 2,56 (d), 2,68 and 8,8 (d); 2,38 and 7,8 (d); 2,38 and 2,38 (d); 2,38 and 2,38 (d); 2,38 and 2,38 (d); 2,38 and 7,38 (d); 2,38 and 2,38 (d); 2,38 and 2,38 (d; 2,38 and 2,38 (d); 2,38 and 2,38 (d; 2,38 and 2,38 and 8,8 (d); 2,38 and 2,38 and 2,38 (d; 2,38 and 2,38 and 2,38 (d; 2,38 and 2,8 and 2,38 and 2,38 (d; 2,38 and 2,8 and 2,8 and 2,8 and 2,8 = 2,8 and 2,8 (d); 2,8 and 2,8 and 2,8 and 2,8 and 2,8 (d; 2,8 and 2,8 and 2,8 and 2,8 and 2,8 and 2,8 and 2,8 and 2,9 and 2,8 and 2,8 (d; 2,8 and 2,8 and 2,8 and 2,8 and 2,9 and 2,8 and 2,8 and 2,9 and 2,8 and 2,8 and 2,8 and 2,9 and 2,8 and 2,8 and 2,8 and 2,8 and 2,8 and 2,8 and 2,8 and 2, and 2,8 and 2, and 2, and 2, and 2, and 2, and 2, and 2, and The following are the types of the test: SM 646 (MH+); 590 (MH-tBu+); 644- (MH-).

Synthesis of 3-[5-ethyl-6-[4-(5,6,7,8-tetrahydro-(1,8)naphtyridin-2-yl) -pipéridin-1-yl]-pyrimidin-4-ylamino]-2-[3-(4-methoxy-2-aminophenyl) -ureido]-propionic acid, bis (trifluoroacetate)

110 mg (0.17 mmole) of 3-[5-ethyl-6-[4-(5,6,7,8-tetrahydro-(1,8)naphtyridin-2-yl) piperidin-1-yl]-pyrimidine-4-ylamino]-2-[3-(4-methoxy-2-nitro-phenyle) -reido]-tert-butyl propionate and 70 mg of zinc are shaken in 5 ml of acetic acid at room temperature until the starting product disappears into CCM (silicagel, emitting: CH2Cl2-MeOH-H2O-Ac 90-10-1). The mixture is filtered on clarinette, cyclohexane and evaporated under dry pressure (2 kPa). The residue is recovered by the acetylated phase of 90 kPa. The residue is separated from the raw aluminium chloride and evaporated on a chromatographic scale, reducing the chloride to 90 kPa. The solution is dissolved in aluminium sulphate and dissolved in an organic solution with methanol and magnesium sulphate (2 kPa).

The resulting product is agitated in 4 ml of dichloromethane with 0.5 ml of trifluoroacetic acid at room temperature until the starting product disappears into CCM (silicagel, eluent: CH2Cl2-MeOH-H2O-AcOH 90-10-1-1). Toluene is added and the dry reaction mixture is evaporated at reduced pressure (2 kPa). The residue is solubilised in the minimum of dichloromethane with a little methanol and then precipitated on to diisopropyl ether. The precipitate is filtered. 40 mg of the expected product is obtained as a beige solid. The following is the list of active substances in the active substance: The following are the active substances: The following substances are considered to be toxic if they are used in the manufacture of the active substance: 1H-RMN (DMSO d6): δ 1,07 (m, 3H, CH2CH3); 1,65 to 2,05 (m, 6H, CH2-CH-CH2 and CH2-CH2-CH2-NH); 2,50 (masked, 2H, CH2-CH3); 2,77 (t, 2H, CH2-CH2-CH2-NH); 2,87 (m, 1H, CH2-CH-CH2); 3,01 and 3,55 (tl and dl, 4H, CH2-CH2-N-CH2-CH2); 3,45 (m, 2H, CH2-CH2-CH2-NH) ; 3,72 and 3,84 (2m, 2H, CH2-CH2-CH-NH); 4,53 (m, 1H, NH-CH2-CH-NH); 6,68 and 7,56 (2d, 2H, CH2-CH2-CH2-NH); 7,65 to 7,00 (CH=CH, 2H, CCH-CH=C, 2, CCH=C, 2,CH=N; 8,12 to 8,50; 1H, CH=C, 2H, CH=N); and 1H, CH=C, 2,CH=C, 2,CH=C, 2,CH=C, 2,CH=C, 2,CH=C, 2,CH=C, 2,CH=C, 2,CH=C, 2,CH=C, 2,CH=C, 2,CH=C, 2,CH=C, 2,CH=C, 2,CH; 8,28 to 1,CH=C,CH=C,CH,CH,CH,CH,CH=C,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH,CH The following is a list of the types of products:

Examples 54 to 62 General method of preparation of urea: Stage a)

The reaction mixture is agitated at room temperature for 3 hours and 30 minutes. The solvent is then evaporated at reduced pressure (2 kPa) and the residue is chromatographed on gel with the following solvent: 100% ethylene silicate, acetylated ethylene chloride (50-methyl methalamide) and acetylated ethylene chloride (50-methyl methalamide) (950-55-methyl methalamide) (50-methyl methalamide) (950-55-methyl methalamide) (550-55-methyl methalamide).

We get a my mass of expected product. The following is the list of active substances:

Stage b)

A my mass of tert-butyl ester of step a) is agitated in 5 ml of dichloromethane with 500 μl of trifluoroacetic acid at room temperature until the starting product disappears into CCM (silicagel, electrolyte: CH2Cl2-MeOH-H2O-AcOH 90-10-1-1). Toluene is added and the reaction mixture is evaporated dry under reduced pressure (2 kPa). The residue is solubilised in the minimum of dichloromethane and then poured over ethyl ether. The precipitate is filtered. This is a mixture of the expected product and the cycling subproduct. This is purified over silica to give a expected product mzange mass. The following is the list of active substances in the active substance:

Example 53 Synthesis of 3-[5-ethyl-6-[4-(5,6,7,8-tetrahydro-(1,8)naphtyridin-2-yl) -pipéridin-1-yl]-pyrimidin-4-ylamino]-2-[3-(2-nitrophenyl) -ureido]-propionic acid, bis (trifluoroacetate)

30 mg (0.046 mmole) of 3-[5-ethyl-6-[4-(5,6,7,8-tetrahydro-(1,8)naphtyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino]-2-[3-(2-nitrophenyl) -ureaido]-tert-butyl propinate is agitated in 3 ml of dichloromethane with 0.5 ml of trifluoroacetic acid at room temperature until the starting product disappears into CCM (silicagel, eluting: CH2Cl2-MeOH-H2O-OH 90-10-1-1). Toluene is added and the mixture evaporates at reduced pressure (2 kPa). The residue is then precipitated into the soil of dichloromethane coiled on diethyl diethyl. The product is obtained in the form of a 35 mg minimum filtered solution. The following is the list of active substances in the active substance: The following information is provided for the purpose of the application: The following substances are considered to be toxic if they are used in the manufacture of the active substance: 1H-RMN (CDCl3): δ 1,19 (t, 3H, CH2CH3); 1,82 to 2,05 (m, 6H, CH2-CH-CH2 and CH2-CH2-CH2-NH) ; 2,50 (t, 2H, CH2-CH3) ; 2,76 (t, 2H, CH2-CH2-CH2-NH); 2,98 (tl, 1H, CH2-CH-CH2); 3,25 and 3,84 (tl and dl, 4H, CH2-CH2-N-CH2-CH2); 3,49 (m, 2H, CH2-CH2-CH2-NH); 3,87 and 4,06 (2m, 2H, CH2-CH2-NH); 4,63 (m, 1H, NH-CH2-CH2-NH); 6,41 and 7,37 (2d, 2H, CH2-CH2-NH); naphthyrin); 7,54 and 7,7 (tCH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=CH=

Example 54 Stage a) Synthesis of 2-(3-benzo[1,3]dioxol-5-yl-ureaedo)-3-{5-ethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino}-propionate from tert-butyl

The reaction mixture is agitated at room temperature for 3 hours and 30 minutes. The solvent is then evaporated at reduced pressure (2-10) kPa and the following residue is chromatised on silicone with the electrolyte: 100% acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acetylated, acety, acety, acety, acety, acety, acety, acety, acety, acety, The following is the list of active substances: The following substances are to be classified as substances with a potential for the degradation of the chemical composition of the feed additive: The following are the types of the test: SM 645 (MH+), 588 (MH-tBu).

Stage b) Synthesis of 2-(3-benzo[1,3]dioxol-5-yl-urea)-3-{5-ethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridine-1-yl]-pyrimidine-4-ylamino}-propionic acid, bis-trifluoroacetate

55 mg (0.085 mmoles) of 2-(3-benzo[1,3]dioxol-5-yl-ureido)-3-{5-ethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino}-tert-butyl propionate is agitated in 5 ml of dichloromethane with 500 μl of trifluoroacetic acid at room temperature for 13 hours.

Toluene is then added and the dry reaction mixture is evaporated under reduced pressure (2 kPa). The residue is dissolved in the minimum of dichloromethane and then poured on ethyl ether.

We get 39 mg of the expected product. The following is the list of active substances: The following substances are considered to be toxic if they are used in the manufacture of the active substance: 1H-RMN (MeOD): δ 1,17 (t, 3H, CH2-CH3) ; 1,85 and 2 (m, 6H, N-CH2-CH2-CH2-CH2, CH2-CH2-CH2-NH) ; 2,55 (q, 2H, CH2-CH3); 2,8 (m, 2H, N-CH2-CH2-CH2-CH2, CH2-CH2-CH2-NH) ; 2,95 and 3,5 (2m, 4H, N-CH2-CH2-CH2-CH2) ; 3,33 (m, 2H, CH2-CH2-CH2-NH) ; 3,65 and 3,95 (m, 2H, NH-CH2-CH2) ; 4,47 (m, 1H, NH-CH2-CH2-NH) ; 5,32 (t, 1H, NH); 5,5 (s, 1H, NH); 5,9 (s, 2H, NH-CH2) ; 7,5 (m, 4H, N-CH2-CH2-CH2-CH2-CH2-CH2) ; naphyl, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1 The following is a list of the Member States which have adopted the new rules: Mx: mass of isocyanate introduced My: mass of ester obtained. Mz: mass of acid obtained

Exemple	Acide obtenu	FW (Base libre)	FW (Base libre + 2 TFA)	Mz (mg)	SM (MH+)
55		558,69	786,69	48	559
56		604,71	832,71	51	605
57		550,71	778,71	51	551
58		644,78	872,78	49	645
59		579,11	807,11	48	579
60		562,65	790,65	50	563
61		602,70	830,70	43	603
62		572,71	800,71	29	573

The products obtained above may be prepared from the following raw materials: - What?

Exemple	Isocyanate	Mx (mg)	produit attendu		Rdt	SM (MH+)
55		28,0		56,5	44	615
56		37,0		51,7	38	661
57		26,0		80	63	607
58		45,5		56	38	701
59		31,7		54,4	41	635
60		29,0		57,6	45	619

Example 63 Synthesis of 2-{N-[(dimethylamino) sulfonylamino]}-3-{5-ethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino}-propionate from tert-butyl

A 2 g (4.27 moles) solution of 2-amino-3-{5-ethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino}-propionate tert-butyl in 200 ml of anhydrous tetrahydrofuran is added to 16 ml of triethylamine and then a 700 μl (6.4 moles) solution of dimethylaminosulfonyl chloride in 40 ml of anhydrous tetrahydrofuran. The addition is done by drip drops, at room temperature, under nitrogen flow pressure. The mixture is kept under agitation.The residue is chromatographed on silica gel by eluting with 100% ethyl acetate to obtain 1.1 g (of expected product). The following is the list of active substances: The following substances are considered to be toxic if they are used in the manufacture of the active substance: 1H-RMN (CDCl3): δ 1,48 (s, 9H, tBu); 1,93 and 2,02 (2m, 6H, N-CH2-CH2-CH-CH2-CH2, CH2-CH2-CH2-NH); 2,01 (s, 3H, CH3); 2,73 (m, 3H, N-CH2-CH2-CH2-CH2, CH2-CH2-CH3), 2,81 (s, 6H, N(CH3)2); 2,95 and 3,70 (2m, 4H, N-CH2-CH2-CH2-CH2); 3,44 (m, 2H, CH2-CH2-CH2-NH); 3,81 and 3,91 and 4,11 (3m, 3H, NH-CH2-CH2-NH); 4,87 (t, 1H, NH); 5,86 (dl, 1H, NH41); 6,17 and 7,dCH=2H, naphthine, CH=8,28 (n, 1H, NH-CH1, NH=1H); The following is a list of the Member States of the European Union:

Example 64 The following is the list of active substances that may be used in the preparation of the active substance:

290 mg (0.5 mmoles) of 2-{N-[(dimethyl-amino) sulfonylamino]}-3-{5-ethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino}-tert-butyl propionate is agitated in 30 ml of dichloromethane with 3 ml of trifluoroacetic acid at room temperature until the starting product disappears into CCM (silicagel, eluting: CH2Cl2-MeOH-H2O-AcOH 90-10-1-1). The toluene is then mixed and evaporated in the reduced pressure reaction (2 kPa). The residue is evaporated to the minimum with a little dichloromethane and then the etheric product is filtered to 197,3 mg of ethylene. The following is the list of active substances in the active substance: The following substances are considered to be toxic if they are used as a starting material in the manufacture of the active substance: The following is a list of the Member States of the European Union:

Example 65 Synthesis of 3-[5-methyl-6-[4-(5,6,7,8-tetrahydro-(1,8)naphtyri-din-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino]-N-[1,1-dimethylthyloxycarbonyl) aminosulfonyl]-propionate from tert-butyl.

0.13 ml (1.5 mL) of chlorosulfonyl isocyanate in solution in 30 ml of dichloromethane is dripped with 111 mg (1.5 mL) of terbutanol in solution in 30 ml of dichloromethane and stirred at room temperature for 45 minutes. This solution is then dripped on a 700 mg (1.5 mL) mixture of 2-amino-3-{5-ethyl-6-[4-5,(6,7,8-tetrahydro-[1,8]naphimidyl-2-thyr) -pipéridinyl]-pyridinine-4-ylamino{}-propionate of tert-butyl and 0.35 ml (2 mL) of diisopropyllamine 400 mL of dichloromethane. The mixture is agitated at room temperature for 2 mL. The residue is then reduced by evaporation, and the solution is re-pressurized for 2 mL.The organic phase is separated and the aqueous phase is re-extracted by ethyl acetate. The organic phases are dried on magnesium sulphate and the solvent is evaporated at reduced pressure (2 kPa). 830 mg of the expected product is obtained in the form of a yellow oil. The following is the list of active substances in the active substance: The following equation is used for the determination of the concentration of the test chemical in the test chemical:The total number of samples of the active substance shall be calculated by adding the following data: 74 (tl and dl, 4H, CH2-CH2-N-CH2-CH2); 3,52 (m, 2H, CH2-CH2-CH2-NH); 3,89 and 3,99 (2dt, 2H, NH-CH2-CH-NH); 4,32 (dt, 1H, NH-CH2-CH-NH); 4,88 (tl, 1H, 1H, NH-CH2-CH-NH); 6,42 and 7,36 (2d, 2H, H naphthyridine); 8,28 ppm (s, 1H, N=CH-N). The following are the types of the test: SM 647 (MH+); 645 (MH-).

Synthesis of 3-[5-methyl-6-[4-(5,6,7,8-tetrahydro-(1,8)naphty-ridin-2-yl) -pipéridin-1-yl]-pyrimidin-4-ylamino]-N-[N,N-(1,1-dimethylethylloxycarbonyl) (phenylmethyl) aminosulfonyl]propionate of tert-butyl

A mixture of 130 mg (0.2 mmole) of 3-[5-methyl-6-(4-(5,6,7,8-tetrahydro-(1,8)naphtyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino]-N-[1,1-dimethyl-ethyl-carbonyl) amino-sulfonyl]-propionate tert-butyl and 60 mg (0.3 mmole) triphenylphosphine in solution in 10 ml of dichloromethane is added to 0,047 ml of diethyl azodicarboxylate and then 0,041 ml (0.4 mmole) of benzene alcohol is dripped in solution in 5 ml of dichloromethane and agitated at room temperature for 1 hour. Then 0,047 ml of azodicarboxylate is added again in a drop of 0,047 ml (0,41 mmole) of dichloromethane and then the remaining solution is reduced to 1 ml of dichloromethane, then the solution is agitated at room temperature for 1 hour.The organic phase is separated and the aqueous phase is re-extracted by ethyl acetate. The organic phases are dried on magnesium sulfate and the solvent is evaporated at reduced pressure (2 kPa). The crude is purified by silica chromatography by elevating with a methylene-methanol chloride elution gradient of 100-0 to 90-10. 80 mg of the expected product is obtained in the form of a beige solid. The following is the list of active substances in the active substance: 1H-RMN (CDCl3): δ 1,38 and 1,53 ppm (2s, 18H, tBu); 1,85 to 2,15 (m, 6H, tBu)The following substances are to be classified as chemicals with a specific active substance, in accordance with the provisions of the relevant national legislation: The following information is provided for the purpose of this Decision:

Synthesis of 3-[5-methyl-6-[4-(5,6,7,8-tetrahydro-(1,8)naphtyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino]-N-[N,N-(1,1-dimethylethyloxycarbonyl) (phenylmethyl) aminosulfonyl]-propionic acid, bis (trifluoroacetate)

73 mg (0.1 mmole) of 3-[5-methyl-6-[4-(5,6,7,8-tetrahydro-(1,8)naphtyridin-2-yl) piperidin-1-yl]-pyrimidine-4-ylamino]-N-[N,N-(1,1dimethylethylloxycarbonyl) ((phenylmethyl) aminosulfonyl) tert-butyl propionate is stirred in 5 ml of dichloromethane with 1 ml of trifluoroacetic acid at room temperature for 3 hours. The toluene is stirred and the reaction mixture is evaporated at reduced pressure (2 kPa). The residue is ground in the dichloromethane solid onto the diethyl ether. The minimum is filtered. A 35 mg solid product is obtained. The following is a list of the Member States of the European Union:

Example 66 Synthesis of the hydrochloride of 2- ((4-methoxybenzenesulfonylamino) -3-{2-methoxy-5-methyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -piperidin-1-yl]-pyrimidine-4-ylamino}-propionic acid:

2 g (2.99 moles) of tert-butyl ester of 2-(4-methoxy-benzenesulfonylamino)-3-acid 2-{2-methoxy-5-methyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -piperidin-1-yl]-pyrimidine-4-ylamino}-propionic is stirred in 20 ml of a 6N hydrochloric acid solution in water, the reaction mixture is heterogeneous, the hydrochloride taken from the ester is rapidly massed, then 20 ml of distilled water is added to improve solubility.

Stir at room temperature for 20 hours before adding 5 ml of 6N hydrochloric acid to the water twice.

The reaction mixture is agitated for a total of 60 hours and then concentrated dry at reduced pressure (2 kPa) in the presence of toluene and isopropanol successively.

The resulting residue is solubilised in the minimum of dichloromethane and methanol and then poured on ethyl ether twice. The precipitate formed is filtered, washed with ether and then with pentane and vacuum dried. The following is the list of active substances: The following substances are to be classified as substances with a specific chemical composition, in accordance with the provisions of the Annex to Regulation (EC) No 1907/2006 of the European Parliament and of the Council: The following information is provided for the purpose of this Decision:

Synthesis of the tert-butyl ester of 2- ((4-methoxy-benzenesulfonylamino) -3-{2-methoxy-5-methyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -piperidin-1-yl]-pyrimidine-4-ylamino}-propionic acid: Stage 1 Synthesis of the tert-butyl ester of 2-amino-3-{2-methyl,5-methoxy-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino}-propionic acid:

In a mono-collection containing 5.4 g (8.5 mmoles) of 2-benzyloxycarbonylamino-3-{2-methyl,5-methoxy-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -piperidin-1-yl]-pyrimidine-4-ylamino}-propionic acid ter-butyl ester, 500 ml of 100% acetic acid and 500 mg of platinum oxide are added. This mixture is vacuum purged and left to agitate at TA pressure and atmospheric hydrogen for 20 hours.

The resulting heterogeneous medium is filtered on clarcel. The filtrate is concentrated dry in the presence of cyclohexane. It is then taken up by a mixture of ethyl acetate and a solution of saturated sodium bicarbonate. The organic phase is extracted and dried on magnesium sulfate and the solvent is evaporated in a vacuum. The resulting residue is chromatographed on silica gel with the following eluting agent: dichloromethane-heptane 50-50 to (dichloromethane-methanol 90-10 / ethyl acetate) (50-50). CCM: Rf=0.32, electrolyte: (dichloromethane-methanol 90-10 / ethyl acetate) (50-50) on silica The following substances are to be classified as chemicals with a specific chemical composition: 1H-RMN (CDCl3): δ 1,47 (s, 9H, tBu); 1,93 (m, 9H, N-CH2-CH2-CH-CH2-CH2, CH2-CH2-CH2-NH, CH3-) ; 2,7 (m, 3H, N-CH2-CH2-CH2-CH2-CH2, CH2-CH2-CH2-NH); 2,92 and 3,72 (2m, 4H, CH2-CH2-CH2-CH2-CH2-CH); 3,42 (m, 2H, CH2-CH2-CH2-NH) ; 3,5 (m, 2H, NH-CH2-CH-NH) ; 3,65 (m, 1H, NH-CH2-CH-NH) 3; 3,9 (s, 3H, -N=N-CH-O3) 5,0 and 5,65 (m, 2H, NH-CH2-CH2-CH2-CH2-CH2-CH2); 6,4 and 7,13 (2dH, CH2-CH2-CH-TH, CH-naphine); The following is the list of the Member States:

Stage 2

A mixture of 2.2 g (4.43 mmoles) of 2-amino-3-[2-methoxy-5-methyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)piperidin-1-yl) -pyrimidine-4-ylamino]-propionic acid tert-butyl ester in solution in 800 ml of tetrahydrofuran and 950 μl of triethylamine is added to a 2.2 g (4.43 mmoles) mixture of 915 mg (4.43 mmoles) of 4-methoxy-benzenesulfonyl chloride in solution in 200 ml of tetrahydrofuran. The temperature reaction is agitated at room temperature for one night. The soil is then evaporated (2 k) and the residue is chromatographed with alumina: (Pa-diethyl-acetyl-acetyl-acetyl-acetyl-acetyl-acetyl) 50/50/100.

This results in 2.02 g (Rdt=68%) of expected product. The following is the list of active substances: The following substances are to be classified as substances with a specific chemical composition, in accordance with the provisions of Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 16 February 2006 on the approximation of the laws of the Member States relating to the permissible sound power level of compressed air (OJ L 345, 20.12.2006, p. 1). The number of persons who have been subjected to the same treatment shall be as follows:

Example 67 Synthesis of the hydrochloride of 2- ((4-methoxybenzenesulfonylamino) -3-{2,5-dimethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino}-propionic acid:

3 g (4.6 moles) of tert-butyl ester of 2-(4-methoxy-benzenesulfonylamino) acid-3-{(2,5)-dimethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino}-propionic acid is stirred in 30 ml of a 6N hydrochloric acid solution in water, the reaction mixture remains heterogeneous, then rapidly taken in mass of the hydrochloride of the ester formed, 20 ml of 6N hydrochloric acid is added to water, the mixture becomes clear again.

Stir at room temperature for four hours, the mixture turns milky again.

The substance is then dried at reduced pressure (2 kPa) in the presence of toluene and isopropanol successively.

The resulting residue is solubilised in a minimum of dichloromethane and methanol and then poured over ethyl ether. The following is the list of active substances in the active substance: The following substances are to be classified as substances with a specific chemical composition, in accordance with the provisions of the Annex to Regulation (EC) No 1907/2006 of the European Parliament and of the Council: The following is added to the list of products:

Synthesis of the tert-butyl ester of 2- ((4-methoxy-benzenesulfonylamino) -3-{(2,5) -dimethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -piperidin-1-yl]-pyrimidine-4-ylamino}-propionic acid: Stage 1 Synthesis of the tert-butyl ester of 2-amino-3-{2,5-dimethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino}-propionic acid

In a mono-collection containing 13 g (21.1 mmoles) of 2-benzyloxycarbonylamino-3-{2,5-dimethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino}-propionic acid ter-butyl ester, prepared according to the international requirement (WO 2004 048375(A1)), 1 litre of 100% acetic acid and 1 g of platinum oxide (5-10%) is filled. This mixture is purged under vacuum and left to agitate at room temperature and atmospheric pressure with hydrogen for 20 hours.

The resulting heterogeneous medium is filtered on clarcel. The filtrate is concentrated dry in the presence of cyclohexane. It is then taken up by a mixture of ethyl acetate and a solution of saturated sodium bicarbonate. The organic phase is extracted and dried on magnesium sulfate and the solvent is evaporated in a vacuum. The resulting residue is chromatographed on silica gel with the following eluent: dichloromethane 100% to dichloromethane-ethanol 95-5. The following substances are to be classified as 'methanol' and 'methanol' in the Annex to Regulation (EC) No 1907/2006 of the European Parliament and of the Council [2]: The following information is provided for the purpose of the calculation of the MRL:

Stage 2

A mixture of 750 mg (1.56 mL) 2-Amino-3-[(2,5)-dimethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pyrimidine-4-ylamino]-propionic acid tert-butyl ester in solution in 350 ml of tetrahydrofuran and 7 ml of triethylamine is mixed with 322 mg (1.56 mL) 4-methoxybenzeneulfonyl chloride in solution in 35 ml of tetrahydrofuran, added by drip. The reaction medium is agitated at room temperature for one night. The solvent is then evaporated at reduced pressure (2 kPa) and the chromatograph is chromatographed with the following evaporator: acetyl alumina: acetyl-diethyl chloride (50-diethyl-methyl-methyl-acetyl) 50-98/92).

This results in 2.02 g (Rdt=68%) of expected product. The following is the list of active substances: The following substances are to be classified as substances with a specific chemical composition, in accordance with the provisions of the Annex to Regulation (EC) No 1907/2006 of the European Parliament and of the Council: The following shall be added to the list of products:

Examples 68 to 80 Stage A: activation of the alcohol

1,5 equivalents of di-N-succinimidyl) carbonate is dissolved in 4 ml of methylene chloride. At room temperature, one equivalent of alcohol dissolved in methylene chloride and 2 equivalents of triethylamine are added. The reaction mixture is agitated for 6 hours.

Then, if the activated alcohol formed is stable, it can be isolated by extraction with ethyl acetate and washing with sodium bicarbonate before addition to the amine.

Step B: addition of the amine

The activated alcohol is to be treated with a 0,8 ter-butyl ester equivalent of 2-amino-3-{2,5-dimethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridine-1-yl]-pyrimidine-4-ylamino}-propionic acid, and a triethylamine equivalent.

The mixture is left to agitate overnight at room temperature.

The reaction mixture is then extracted to ethyl acetate after washing with a solution of saturated sodium bicarbonate. The resulting organic phase is dried on magnesium sulfate before being concentrated dry under reduced pressure (2 kPa). The residue is then chromatographed on alumina with the following eluent: ethyl acetate/isopropyl ether to ethyl acetate 100%. The expected ester is obtained with an efficiency of 38 to 90%.

Step C: hydrolysis of the ester

A mc mass of 3-[[2,5-dimethyl-6-[4-]] (1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N- (((alkyl) alaninate of (1,1-dimethyl) is stirred in 5 ml of dichloromethane and 500 μl of trifluoroacetic acid at room temperature until the starting product disappears into CCM (silicagel, eluting: CH2Cl2-MeOH-H2O-AcOH 90-10-1-1). Toluene is then added to the evaporative reaction mixture at reduced pressure (2 kPa). The resulting residue is pre-filtered into a dichloromethane powder onto diethyl diopropane. The resulting mass is then filtered into a pentacyclic acid and then precipitated to a low pressure (2 kPa) solution.

Exemple	alcool utilisé	Produit attendu		FW	Rendement	SM [M/Z+H]
68				631,8	38	632
69				673,91	51	674
70				650,23	49	650
71				694,68	59	694
72				635,86	46	636
73				679,87	59	680

exemples	Alcool utilisé	Produit attendu		FW	Rendement	SM [M/Z+H]
74				579,75	64	580
75				607,8	66	608
76				625,82	54	626
77				659,84	48	660
78				616,77	90	617
79				644,82	46	645
80				691,88	50	692

Exemple	Ester de départ		Acide attendu	FW (base libre)
68		250		575,69	210	576
69		320		617,84	320	618
70		320		594,12	420	594, 596
71		430		638,57	480	639
72		330		579,75	450	580
73		410		623,76	510	624
74		390		523,64	610	524
75		500		551,69	720	552
76		400		569,71	610	570
77		310		603,73	490	604
78		300		588,72	243	294 (Z=2)
79		400		560,66	400	561
80		260		635,77	220	636

Example 81 Synthesis of tert-butyl ester from 2-cyclohexylmethoxycarbonylamino-3-{2,5-dimethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino}-propionic acid Step A: Synthesis of the activated alcohol N-succinimidyl carbonic acid cyclohexylmethyl ester

5.38 g (10.5 mo) of di-N-succinimidyl) carbonate is dissolved in 60 ml of methylene chloride. 2.16 ml (17.55 mo) of cyclohexyl methanol dissolved in 10 ml of methylene chloride and 4.92 ml (35.1 mo) of triethylamine are added at room temperature. The reaction mixture is agitated for 1 night.

The reaction mixture is then dried before extraction to ethyl acetate and washed with a solution of saturated sodium bicarbonate. The resulting organic phase is dried on magnesium sulphate before being dried at reduced pressure (2 kPa). 4.4 g of activated alcohol is obtained which is used as is in the next step (quantitative yield). The following is the list of active substances: The following equation is used for the calculation of the concentration of the test chemical in the test chemical: The following substances are to be classified as 'methanol' and 'methanol' in the respective CN codes:

Step B: the

The test chemical is to be used in the manufacture of the test chemical, and the test chemical is to be used in the manufacture of the test chemical.

The mixture is left to agitate overnight at room temperature.

The reaction mixture is then extracted to ethyl acetate after washing with a solution of saturated sodium bicarbonate. The organic phase obtained is dried on magnesium sulphate before being concentrated dry under reduced pressure (2 kPa). The resulting residue is then chromatographed on silica gel with the electrolyte: following ethyl acetate/heptane to 100% ethyl acetate, 6.9 g of expected product is obtained (efficiency = 65%). CCM: (eluting agent: ethyl dichloromethane acetate 50-50 on alumina and ethyl heptane acetate 80-20 on silica). The following is the list of active substances: The following substances are to be classified as substances with a potential for the production of lead in the feed additive: The following information is provided for the purpose of the assessment:

Example 82 Synthesis of the hydrochloride of 2-Cyclohexylmethoxycarbonylamino-3-{2,5-dimethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -piperidin-1-yl]-pyrimidine-4-ylamino}-propionic acid:

28 g (0.045 moles) of tert-butyl ester of 2-cyclohexylmethoxycarbonylamino-3-{2,5-dimethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino-propionic acid is agitated in 76 ml of a solution of 6N hydrochloric acid in water at room temperature for 20 hours.

The reaction mixture is concentrated dry at reduced pressure (2 kPa) in the presence of toluene and isopropanol successively.

The resulting residue is solubilised in the minimum of dichloromethane and then poured over ethyl ether. The following is the list of active substances in the active substance: The following substances are to be classified as chemicals with a specific chemical composition, which are to be classified as chemicals with a specific chemical composition, which are to be classified as chemicals with a specific chemical composition, which are to be classified as chemicals with a specific chemical composition, which are to be classified as chemicals with a specific chemical composition, which are to be classified as chemicals with a specific chemical composition, which are to be classified as chemicals with a specific chemical composition, which are to be classified as chemicals with a specific chemical composition, which are to be classified as chemicals with a specific chemical composition, which are to be classified as chemicals with a specific chemical composition, which are to be classified as chemicals with a specific chemical composition, which are to be classified as chemicals with a specific chemical composition, which are to be classified as chemicals with a specific chemical composition, which are to be classified as chemicals with a specific chemical composition, which are to be classified as chemicals with a specific chemical composition, which are to be classified as chemicals with a specific chemical composition, which are to be classified as chemicals with a specific chemical composition, which are to be classified as chemicals with a specific chemical composition, which are to be classified as chemicals with a specific chemical composition, which are to be classified as chemicals with a specific chemical composition, which are to be classified as chemicals with a chemical composition, which are to be classified as chemicals with a chemical composition, which are to be classified as chemicals with a chemical composition, which are to be classified as chemicals with a chemical composition, which are to be classified as chemicals with a chemical composition, which are to be classified as chemicals with a chemical composition, which are to be classified as chemicals with a chemical composition, which are chemicals with a chemical composition, which are to be classified as chemicals with a chemical composition, which are to be classified as chemicals with a chemical composition, which are to be classified as chemicals with a chemical composition, which are chemicals with a chemical composition, which are to which are to which are to be classified as chemicals with a chemical The Commission has received a request from the United Kingdom to provide additional information on the information contained in the request.

Example 83 Synthesis of the hydrochloride from 2-cyclohexylmethoxycarbonylamino-3-{2,5-dimethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -piperidin-1-yl]-pyrimidin-4-ylamino acid}-propionic tert-butyl ester

Shake 27.2 g (43.8 mmoles) of 2-cyclohexylmethoxycarbonylamino-3-{2,5-dimethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) -piperidin-1-yl]-pyrimidine-4-ylamino}-propionic acid tert-butyl ester in 240 ml of a 50/50 mixture of dichloromethane and ethyl ether, and then slowly add a mixture consisting of 21.9 ml of hydrochloric acid 2N in the ether and 20 ml of ethyl ether.

The reaction mixture must have remained clear during addition.

The solvent is then partially evaporated at reduced pressure (2 kPa), the solution containing a minimum of solvent is poured on 1 litre of isopropyl ether and then on 500 ml of pentane, the precipitate formed is filtered and vacuum dried.

You get 28.5 grams of white powder. The following substances are to be classified as chemicals with a specific chemical composition, in accordance with the provisions of the Annex to Regulation (EC) No 1907/2006 of the European Parliament and of the Council: The following information is provided for the purpose of this Decision:

The following information is provided in the Annex to Regulation (EC) No 1831/2003: Protocol:

96 MaxiSorp well plates are coated overnight at 40°C with 100 μl of Kistrine at 1 μg/ml (coating buffer dilution: carbonate 0.05 M/NaOH pH 9.6). The next day the wells are emptied and the ligands (kistrine) are then fixed (fixing buffers: PBS containing 0.5% BSA (pH = 7.4)) for 1 hour at room temperature with a gentle agitation of 125 rpm. The wells are washed six times (washing buffer: PBS containing 0.05% Tween 20 (pH 7.7)), then adding per well in this order: 40 μl of incubation buffer10 μl of dilution of the test product (products are diluted in a 50:50 DMSO/Water mixture)50 μl of human αvβ3 receptor (cf. Pytella et al. Methods Enzymol. (1987) 144 (Incubation buffer dilution, to be adjusted according to the receptor batch and according to the ligand).

The wells are washed again six times and then incubated for 2 hours at room temperature with a gentle agitation of 125 rpm, in the presence of 100 μl of anti-receptor antibody coupled with peroxidase (The 4B12-HRP antibody is diluted in an incubation buffer (50 mM TRIS pH 7.4; 0.5% BSA; 0.05% Tween 20; 1 mM MnCl2; 50 film CaCl2; 50 film MgCl2; 100 film NaCl).

The wells are then washed six times before the ligand-receptor binding is measured by a peroxidase detector kit (TBM Microwell Peroxidase Substrate System Kirkegaard; Ref cat 50-76-00).

This kit contains a substrate A vial (3,3',5,5'-tetramethylebenzidine at 0,4 g/l) and a B vial (H2O2 at 0,02% buffer Citrate/citric acid).

The enzymatic reaction develops for Kistrine/αvβ3 for 6 to 10 minutes and is then stopped by the addition of 100 μl of phosphoric acid 1M. The optical density is determined at 450 nm.

Expression of results

The following curve is plotted: the percentage of binding as a function of the logarithm of each concentration of the test product.

For each product, the IC50 is determined by the following formula: IC50= (B0+ Bmin)/2

B0=Maximum bonding in the absence of any product

Bmin = Minimum binding in the presence of the highest product concentration. - What?

1 à 65	2 à 10000

Activity in vivo Parathyroid hormone (PTH) induced hypercalcaemia in a model of thyropathyroid-dectomised rats (TPXT)

Stimulation of bone resorption is induced in TPXT rats by infusion of PTH and variations in bone resorption are followed by serum calcium concentration.

Male Sprague Dawley rats weighing 150-200 g are thyroparathyroid-ectomised. The rats are subjected to a standard diet containing 7 g Ca/kg (UAR) and Volvic water. The effectiveness of thyroparathyroid-ectomy is tested by measuring serum Ca concentrations 8 days after surgery in animals on an empty stomach since the day before. The rats are considered thyroparathyroid-ectomised when serum Ca levels are below 80 mg/l. Rat PTH (1-34) (Bachem) is dissolved in 0.15M NaCl Cys.HCl 2% and delivered by mini osmotic pumps (ALZET 2001PD) at a dose of 200 mg/mL/kg. The mini pumps are introduced into the veins under intravenous anesthesia and the rats are administered TXT-filled TP (75 mg/kg) -TXT-filled Pamps (TXT-filled Pamps) at a dose of 200 mg/kg.

Either the test product or the vehicle (controls and PTH-treated rats) is administered 2 times subcutaneously (2 ml/kg body weight) at 0 and 3 h after the start of the PTH infusion. The test is continued for the next 6 hours. At the end of the treatment, all blood is collected after decapitation. Blood samples are centrifuged at 3000 rpm for 15 min (CR422 Jouan) to obtain serum.

Total serum Ca concentrations are measured by colorimetry (Ciba-Corning) using an IEMS Labsystems microplate reading system, at 540 nm.

The difference between the mean calcium values of the treated rats and the controls is analysed in variance and by the Dunnett test.

The activity of a product is calculated by the following formula: $\mathrm{Effet}\%=\frac{\mathrm{Calcémie}\left(\mathrm{produit}\right)-\mathrm{calcémie}\left(\mathrm{PTH}\right)}{\mathrm{Calcémie}\left(\mathrm{PTH}\right)-\mathrm{calcémie}\left(\mathrm{contrôle}\right)}x100$

The products of the invention tested in this method described were active in rats at doses ranging from 2 times 1 mg/kg to 2 times 10 mg/kg subcutaneously and at doses ranging from 2 times 3 mg/kg to 2 times 30 mg/kg orally.

Claims (13)

1. Pyrimidine derivatives of general formula (I): in their stereoisomeric forms in the pure state and mixtures of these stereoisomers, and if appropriate, pure E isomers, pure Z isomers and E/Z mixtures, as well as their physiologically acceptable addition salts and the solvates of these compounds, in which

   I)

   - R represents:

   • a radical for which G represents: and G may be itself optionally substituted by a (C₁-C₈) alkylamino radical, the alkyl part of which in straight or branched chain may be substituted by a phenyl or heterocyclyl radical with 5 or 6 members containing 1 to 4 heteroatoms chosen from nitrogen, oxygen or sulphur, and n represents 1 or 2, or

   • a radical for which G represents: and G is substituted by an alkyl(C₁-C₆) amino radical, the alkyl radical of which may itself be substituted by a phenyl or aromatic monocyclic heterocyclyl radical with 5 or 6 members, containing a heteroatom chosen from nitrogen, oxygen or sulphur;

   - R¹ represents a hydrogen atom; a (C₅-C₁₄)-aryl; (C₅- C₁₄) -aryl- (C₁-C₄) -alkyl- group; an amino radical non-substituted, monosubstituted or disubstituted by an alkyl radical and/or an acyl radical containing 1 to 4 carbon atoms;

   - R² represents a hydrogen atom; a halogen atom; a nitro group; an alkyl radical containing 1 to 4 carbon atoms; an amino radical non-substituted or monosubstituted or disubstituted by an alkyl radical and/or an acyl radical containing 1 to 4 carbon atoms; a -(CH₂)_0-2-CO₂R⁵ group; or a -(CH₂)_0-2-OR⁵ group;

   - R³ represents:

   • a hydrogen atom,

   • a -CO₂R⁵ radical,

   • an -SO₂R⁵ radical, or

   • a monocyclic or polycyclic system, each ring being constituted of 4 to 10 aromatic or non-aromatic members, the ring or at least one of the rings containing 1 to 4 heteroatoms chosen from N, 0 or S, substituted or non-substituted by one or more R° radicals,

   - R⁴ represents OH; (C₁-C₈)-alkoxy-; (C₅-C₁₄) -aryl-(C₁-C₄) -alkyloxy-; (C₅-C₁₄) -aryloxy-; (C₃-C₁₂)-cycloalkyloxy; (C₃- C₁₂)-cycloalkyl-(C₁-C₄)-alkyloxy-; (C₁-C₈)-alkylcarbonyloxy-(C₁-C₄)-alkyloxy-; (C₅-C₁₄) -aryl- (C₁-C₄) -alkylcarbonyloxy-(C₁-C₄) -alkyloxy-; (C₁-C₈)dialkylaminocarbonylmethyloxy-; (C₅-C₁₄)-aryl-(C₁-C₄)-dialkylaminocarbonylmethyloxy-; an amino radical non-substituted or monosubstituted or disubstituted by a (C₁-C₄)-alkyl and/or (C₅-C₁₄)-aryl and/or (C₅-C₁₄) -aryl- (C₁-C₄) -alkyl-radical and/or a (C₁-C₅)-acyl radical; or the radical of a D or L amino acid;

   - R⁵ represents (C₁-C₈)-alkyl; (C₅-C₁₄) -aryl; (C₅-C₁₄) -aryl- (C₁-C₄) -alkyl-; (C₃-C₁₂) -cycloalkyl or (C₃-C₁₂) -cycloalkyl- (C₁-C₄) -alkyl-, bicycloalkyl-(C₁-C₄)-alkyl-, tricycloalkyl-(C₁-C₄)-alkyl-, said aryl, alkyl, cycloalkyl, bicycloalkyl and tricycloalkyl radicals being non-substituted or substituted by one or more R° groups;

   - R° represents halogen; amino; nitro; hydroxyl, (C₁-C₄) -alkyloxy-; (C₁-C₄) -alkylthio-; (C₁-C₄)-alkylsulfonyl-; carboxy; (C₁-C₄)-alkyloxycarbonyl-; (C₁-C₈)-alkyl non-substituted or substituted by one or more halogen atoms, (C₅-C₁₄)-aryl, (C₅-C₁₄) -aryl- (C₁-C₄) -alkyl-; (C₅-C₁₄)-aryl-(C₁-C₄)-alkyloxy- or (C₅-C₁₄)-heterocyclyl, or

   II)

   - R represents a radical: for which G represents: and G may be itself substituted or non-substituted by one or more R° groups;

   - R¹ represents an alkyl radical containing 1 to 4 carbon atoms in straight or branched chain; a cycloalkyl radical containing 3 to 6 carbon atoms; or an alkyloxy or alkylthio radical, the alkyl part of which contains 1 to 4 carbon atoms in straight or branched chain;

   - R², R³, R⁴, and R⁵ are defined as previously in I) ;

   - R° is defined as previously in I);

   or

   III)

   - R is defined as previously in II);

   - R¹, R³, R⁴, and R⁵ are defined as previously in I) ;

   - R² represents a hydroxymethyl radical, a formyl radical or a disubstituted amino radical, the substituents of which form together with the nitrogen atom to which they are attached, a saturated or unsaturated heterocycle containing 4 to 6 members; and

   - R° is defined as previously in I);

   or

   IV)

   - R is defined as previously in II);

   - R¹, R², and R⁴ are defined as previously in I);

   - R³ represents:

   • a straight or branched (C₁-C₄) alkyl or (C₂-C₄) alkenyl radical, optionally substituted by an aryl or mono or polycyclic heterocyclyl radical with 4 to 10 members, themselves being able to be substituted by one or more radicals chosen from hydroxy, (C₁-C₄) alkyloxy, amino, (C₁-C₄) alkylamino, (C₁-C₄)-dialkylamino, phenyl, cyanophenyl or monocyclic heterocyclyl containing 1 to 4 heteroatoms chosen from nitrogen, oxygen or sulphur;

   • a -CO₂R⁵ radical, in which

   - R⁵ represents (C₁-C₈)-alkyl; (C₅-C₁₄) -aryl; (C₅-C₁₄) -aryl- (C₁-C₄) -alkyl-; (C₃-C₁₂) -cycloalkyl or (C₃-C₁₂) -cycloalkyl- (C₁-C₄) -alkyl-, bicycloalkyl-(C₁-C₄)-alkyl-, tricycloalkyl-(C₁-C₄)-alkyl-, said aryl, alkyl, cycloalkyl, bicycloalkyl and tricycloalkyl radicals being substituted by one or more R° groups chosen from (C₁-C₄)-alkylsulfonyl-; (C₅-C₁₄) -aryl- (C₁-C₄) -alkyloxy- or (C₅-C₁₄)-heterocyclyl, or

   • a -COR'⁵ radical,

   • an -SO₂R''⁵ radical,

   - R'5 represents: (C₁-C₈)-alkyl substituted by a radical as defined for R⁵ or by a (C₅-C₁₄) aryloxy radical, the aryl or cycloalkyl radicals themselves being able to be substituted by one or more R° radicals; or

   R'5 represents a cycloalkyl, aryl or mono or polycyclic heterocyclyl radical optionally substituted by trifluoromethylalkyloxy or (C₁-C₁₀)-aryl radicals; or

   R'5 represents (C₁-C₄) alkylamino; (C₃-C₈) cycloalkylamino; arylamino or heterocyclylamino, the aryl or heterocyclyl part of which are mono or polycyclic, these R'5 radicals being able themselves to be substituted by a halogen atom, a nitro, amino, (C₁-C₄) alkyloxy, (C₁-C₄) alkyloxycarbonyl, aryl or arylalkyl radical, the alkyl part of which contains 1 to 4 carbon atoms in straight or branched chain; and

   R"5 represents a (C₁-C₄) alkylamino or di(C₁-C₄) alkylamino radical, the alkyl parts of which can together form a heterocycle with 5 to 7 members, with the nitrogen atom to which they are linked, an arylamino, aralkyl(C₁-C₄) amino or heteroaralkyl(C₁-C₄) amino radical, the aryl or heteroaryl radical of which is mono or polycyclic and comprises 5 to 10 members, the heteroaryl radical being able to comprise 1 to 4 heteroatoms chosen from nitrogen, oxygen or sulphur; and

   - R° is defined as previously in I);

   or

   V)

   - R, R², R³ and R⁴ are defined as previously in I);

   - R¹ is defined as previously in II);

   or

   VI)

   - R, R¹, R³ and R⁴ are defined as previously in II) ;

   - R² is defined as previously in III);

   or

   VII)

   - R, R¹ and R² are defined as previously in I);

   - R⁴ is defined as previously in I); and

   - R³ is defined as previously in IV);

   or

   VIII)

   - R, R¹ and R² are defined as previously in II);

   - R⁴ is defined as previously in I); and

   - R³ is defined as previously in IV);

   or

   IX)

   - R and R³ are defined as previously in I);

   - R⁴ is defined as previously in I);

   - R¹ is defined as previously in II); and

   - R² is defined as previously in III);

   or

   X)

   - R and R² are defined as previously in I);

   - R⁴ is defined as previously in I);

   - R¹ is defined as previously in II); and

   - R³ is defined as previously in IV);

   or

   XI)

   - R and R¹ are defined as previously in II);

   - R⁴ is defined as previously in I);

   - R² is defined as previously in III); and

   - R³ is defined as previously in IV);

   or

   XII)

   - R and R⁴ are defined as previously in I);

   - R¹ is defined as previously in II);

   - R² is defined as previously in III);

   - R³ is defined as previously in IV); provided that the radicals according to definitions I-XII above cannot simultaneously have the meaning:

   - R represents a radical (Ib) in which G is 1, 2, 3, 4-tetrahydro-1,8-naphthyridin-7-yl,

   - R¹ represents methyl,

   - R² represents methyl,

   - R³ represents benzyloxycarbonyl, and

   - R⁴ represents OH or t-butoxy.
2. The compounds of formula (I) according to claim 1 in which R³ is a benzyloxycarbonyl group or in which R³NH- forms an amide or urea function, as well as their stereoisomeric forms, their mixtures and their pharmaceutically acceptable addition salts.
3. The compound of formula (I) according to any one of claims 1 or 2 in which R² is a hydrogen, an alkyl radical containing 1 to 4 carbon atoms, a hydroxymethyl radical or a fluorine atom as well as their stereoisomeric forms, their mixtures and their pharmaceutically acceptable addition salts.
4. The compounds of formula (I) according to claim 3 in which R² is methyl or ethyl.
5. A process for the preparation of compounds of formula (I) according to one of claims 1 to 4, characterized in that

   a) reacting a pyrimidine derivative of formula (II): in which R¹, R² and R are as defined previously in claim 1 and Hal represents a halogen atom, with an amine of formula (III): in which R³ and R⁴ are defined as previously, either in the presence of a strong base, or by catalysis with palladium,

   b) then when one wishes to obtain a product for which the R radical is saturated or partially saturated, the product of general formula (I) is, if appropriate, subjected to a hydrogenation step,

   c) then, if appropriate, when one wishes to obtain a pyrimidine derivative of general formula (I) for which R² is hydroxymethyl, reduction of the corresponding derivative for which R² represents a formyl radical,

   d) and/or if appropriate, when G represents a heterocyclyl radical carrying a substituted amino radical, substitution of the corresponding product carrying a primary amine function on the heterocyclyl radical,

   e) then, if appropriate, cleavage of the R³-NH-function of the product of general formula (I) in order to regenerate the free amine, and condense an R³ radical of -CO₂-R⁵, -CO-R'⁵, -SO₂-R⁵ or -SO₂-R''⁵ structure or optionally substituted alkyl,

   f) and/or optionally hydrolysis and/or esterification or amidification and/or salification of the pyrimidine derivative obtained.
6. As a medication, the compounds of formula (I) and/or their physiologically acceptable salts as defined according to any one of claims 1 to 4.
7. A pharmaceutical composition comprising a medication as defined in claim 6 in the pure state or in the presence of one or more excipients.
8. As a medication, according to claim 6 having an inhibitory activity on bone resorption or for the treatment or prevention of osteoporosis, a compound of formula (I) and/or its physiologically acceptable salts as defined according to any one of claims 1 to 4.
9. As a medication, according to claim 6, having an inhibitory activity on tumour growth or cancer metastasis, a compound of formula (I) and/or its physiologically acceptable salts as defined according to any one of claims 1 to 4.
10. As a medication, according to claim 6, having an anti-inflammatory activity or for the treatment or prevention of cardiovascular disorders, restenosis, arteriosclerosis, nephropathy or retinopathy, a compound of formula (I) and/or its physiologically acceptable salts as defined according to any one of claims 1 to 4.
11. The utilization of compounds of formula (I) and/or their physiologically acceptable salts as defined according to any one of claims 1 to 4 for the preparation of medications intended for the prevention or treatment of osteoporosis.
12. The utilization of compounds of formula (I) and/or their physiologically acceptable salts as defined according to any one of claims 1 to 4 for the preparation of medications intended to inhibit tumour growth or cancer metastasis.
13. The utilization of compounds of formula (I) and/or their physiologically acceptable salts as defined according to any one of claims 1 to 4 for the preparation of medications intended for the prevention or treatment of cardiovascular disorders, restenosis, arteriosclerosis, nephropathy or retinopathy.