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HK1076277B - Novel vitronectin receptor antagonist derivatives, method for preparing same, use thereof as medicines and pharmaceutical compositions containing same - Google Patents

Novel vitronectin receptor antagonist derivatives, method for preparing same, use thereof as medicines and pharmaceutical compositions containing same Download PDF

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Publication number
HK1076277B
HK1076277B HK05109816.8A HK05109816A HK1076277B HK 1076277 B HK1076277 B HK 1076277B HK 05109816 A HK05109816 A HK 05109816A HK 1076277 B HK1076277 B HK 1076277B
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HK
Hong Kong
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formula
amino
following
pyrimidinyl
compounds
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HK05109816.8A
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German (de)
French (fr)
Chinese (zh)
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HK1076277A1 (en
Inventor
Jean-Marie Ruxer
Jean-Michel Lefrancois
Bertrand Heckmann
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Galapagos Nv
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Priority claimed from FR0214429A external-priority patent/FR2847254B1/en
Application filed by Galapagos Nv filed Critical Galapagos Nv
Publication of HK1076277A1 publication Critical patent/HK1076277A1/en
Publication of HK1076277B publication Critical patent/HK1076277B/en

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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 compounds of formula (I): - What? where R1, R2, R3, R4 and G have the meanings shown below and their physiologically acceptable salts. Formula (I) compounds are compounds with pharmacological activity and are therefore usable as medicines. They are antagonists of the vitronectin receptor and inhibitors of cell adhesion and they inhibit osteoclast-mediated bone resorption. They are therefore useful for 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 actively adheres to the bone matrix via the secretion of proteolytic enzyme, and detaches proteins from the inside of the bone, or at the time of osteoclast depression, which appears 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 aminoalkyl 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. WO-A-9993/3999 describes antagonists of the cyclohexanine receptor, specifically azothiazide, which are antagonists of the cyclohexanine receptor. WO-A-9993/3999 describes antagonists of the cyclohexanine receptor.
Further investigations have shown that formula (I) derivatives exhibit strong activity as antagonists of the vitronectin receptor and osteoclast-mediated bone resorption.
The invention relates to compounds of formula (I): - What? in all their isomeric forms, whether or not in mixtures, and their physiologically acceptable additive salts, in which: G is: The following substances are to be classified as 'metals' in the Annex to Regulation (EC) No 1907/2006 of the European Parliament and of the Council: Het representing a monocyclic or polycyclic system, each cycle being composed of 4 to 10 aromatic or non-aromatic chains, the cycle or at least one of the cycles containing 1 to 4 nitrogen atoms, whether or not substituted by one or more groups R9;R1 represents a hydrogen atom; a (C5-C14) -aryl group; (C5-C14) -aryl- (C1-C4) -alkyl group; an unsubstituted or monosubstituted amino acid or dissubstituted by an alkyl radical and/or an acyl radical containing 1 to 4 carbon atoms;R2 represents a hydrogen atom; a carbon atom; a substitution radical; an alkylated radical containing 1 or more carbon atoms; or a radical -CH2 or a radical -R2 - substitution of 1 or more carbon atoms; or an amino radical containing 4 or more carbon atoms; or a radical -R2 - substitution of 1 or more carbon atoms; or one hydrogen atom, one radical -CO2R5,-SO2R5 radical 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 R9,R4 represents OH; (C1-C8) -alkoxy- (C5-C14) -aryl- (C1-C4) -alkyloxy- (C5-C14) -aryloxy- (C3-C12) -aryloxy- (C3-C12) -alkylocyclic- (C1-C4) -alkyloxy- (C1-C7) -alkyloxy- (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-C1-C1-C1-C4-C1-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-C4-C1-C1-C1-C1-C4-C1-C1-C1-C4-C1-C1-C4-C1-C4-C1-C4-C1-C1-C4-C4-C1-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-The so-called aryl, alkyl, cycloalkyl, bicycloalkyl and tricycloalkyl radicals, being unsubstituted or substituted by one or more of the groups chosen R9;R6 represents one hydrogen atom; a hydroxyl group; nitro, (C1-C6) -alkyl-O-CO-; or (C1-C6) -alkyl-O-CO-;R7 and R8, independently of each other, represent one hydrogen atom or one radical (C1-C6) -alkyl not substituted or substituted by halogen; R9 represents an amino carboxylate; nitro, (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-C1-C1-C1-C4-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C4-C1-C1-C1-C1-C1-C1-C4-C1-C1-C1-C1-C1-C4-C5-C5-C8-C5-C4-C5-C4-C5-C4-C5-C4-C4-C5-C8-C5-C5-C8-C5-C8-C8-C5-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C8-C
All radicals that can occur repeatedly in compounds of formula (I), such as the radical R9, are independent of each other and can be identical or different.
Alkyl radicals can be linear or branched, and this also applies when they carry a substituent or when they are included in groups such as alkoxy, alkoxycarbonyl or aralkyl.
(C1-C8) -alkylate is the radical methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, n-isomers of these radicals, isopropyl, isobutyl, isopentyl, neopentyl, isohexyl, 3-methylepentyl, 2,3,4-trimethylhexyl, dry-butyl, methyl-tert-butyl, tert-pentyl.
Cycloalkyl radicals may be monocyclic, bicyclic or tricyclic. These include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyle, cycloundecyle, cyclodecyle, cyclotetracycyl or cycloctadecyle radicals, which may be substituted for example by an alkyl containing 1 to 4 carbon atoms.
The bicycloalkyl and tricycloalkyl radicals may be unsubstituted or substituted at any position, e.g. by one or more oxo groups and/or 1 or more identical or different alkyl groups such as methyl or isopropyl and 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 bridged carbon atom or one of the other carbon atoms. This bond may also have any position from a stereochemical point of view, e.g. exo or endo.
Halogen is fluorine, chlorine, bromine or iodine.
The term (C5-C14) -aryle means: or the heterocyclic (C5-C14) -aryl radicals (= (C5-C14) -heteroaryl), in which one or more carbon atoms in the cycle are replaced by a heteroatom such as nitrogen, oxygen or sulphur, or the carbocyclic (C6-C14) -aryl radicals.
Carbocyclic C6-C14-aryl radicals include phenyl, naphthyl, biphenyl, 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) -alkylyl, in particular (C1-C4) -alkylyl, hydroxyl, (C1-C8) -alkyloxy, (C1-C8) -alkylthio, halogen such as fluorine, chlorine and bromine, nitro, amino, (C1-C4) -alkylamino, di-(C1-C4) -alkylamino, trifluoromethyl, methyldioxy, cyano, aminocarbonyl, (C1-C4) -alkylaminocarbonyl, di-(C1-C4) -alkylaminocarbonyl, carboxy, (C1-C4) -alkylaminocarbonyl, phenyl, benzyl, benzyl and benzyl.
In the case of monosubstituted phenyl, the substituent may be in position 2, 3 or 4, and preferably in position 3 or 4. In the case of phenyl di-substituted, the substituents may be in position 2, 3 or 2, 4 or 2, 5 or 2, 6 or 3, 4 or 3, 5. Preferably, in di-substituted phenyls, the two substituents are in position 3.4. When this phenyl is tri-substituted the positions are: 2, 3, 4 or 2, 3, 5 or 2, 3, 6 or 2, 4, 5 or 2, 4, 6 or 2, 4, 6 or 3, 4, 5.
The (C5-C14) -aryl group can also represent a monocyclic or polycyclic aromatic system in which 1, 2, 3, or 4 carbon atoms in the cycle are replaced by heteroatoms, especially identical or different from the group consisting of nitrogen, oxygen and sulfur. Heterocyclic (C5-C14) -aryl groups (= (C5-C14) -heteroaryl) include the 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, furyl, imidazolyl, pyrazinyl, oxazol, isoxazol, thioxinyl, carothiazol, isothiazol, hetrazol, pyridoxal, pyrazol, cycloheptamine, indolyl, phenylethyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzoyl, quinzo
The optically active carbon atoms contained in the compounds of formula (I) may be independently of each other in 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.
The invention also includes all tautomeric forms of compounds of formula (I), e.g. with respect to the form represented by formula (I), with G = R7R8N-C(=NR6) -NH-CO- the form in which acylguanidine is present as a group -CO-N=C(NR6) -NR7R8 is considered, and all other forms which differ by the different position of the hydrogen atom.
Diastereoisomers, including E/Z isomers, can be separated into individual isomers, e.g. by chromatography. Racetams can be separated into two enantiomers by common methods such as chiral phase chromatography or by resolution methods.
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, these are for example salts of alkaline or alkaline earth metals such as sodium, potassium, magnesium, calcium salts, as well as salts formed with physiologically acceptable quaternary ammonium ions and addition salts with acids such as ammonia and physiologically acceptable organic amines such as triethylamine, ethanolamine or tris- (((2-hydroxyethylamine).
When compounds of formula (I) contain a base group, they may form an addition salt with acids e.g. with inorganic acids such as hydrochloric, sulphuric, phosphoric or with carboxylic organic acids such as acetic, trifluoroacetic, citric, benzoic, maleic, fumaric, tartaric, methanesulfonic or para-sulfonic toluene.
Compounds of formula (I) containing a base group and an acid group, such as guanidine and carboxylic acid, 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 polyvalent anion equivalent of a non-toxic, physiologically acceptable and particularly pharmaceutically acceptable organic or inorganic acid, e.g. the anion or an anion equivalent of one of the above mentioned 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, acetone, trifluoroacetate, citrate, malezoate, fumarate, benzoate, methane, trifluoroethane, and para-methanol.
Salts of formula (I) compounds may be obtained by ordinary methods known to the trade, for example by combining a formula (I) compound with an organic or inorganic acid or base in a 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 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 compounds of formula (I) e.g. hydrates, solvates formed with alcohols, and all derivatives of compounds of formula (I), e.g. esters, prodrugs and other physiologically acceptable derivatives, as well as metabolites of compounds of formula (I).
The invention relates in particular to compounds of formula (I) in which G represents a group Het, Het-NHCO-, or Het-NH-CH2- in which Het represents: - What?
The invention relates in particular to compounds of formula (I) as defined above in which R3 is: - What? and their pharmaceutically acceptable additive salts.
The invention relates in particular to compounds of formula (I) as defined above in which R3 is a benzyloxycarbonyl group, 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 alkyl radical containing 1 to 4 carbon atoms, and particularly methyl and ethyl, 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: G is: - What? and their pharmaceutically acceptable additive salts.
The invention relates in particular to compounds of formula (I) as defined above in which the - G is for: - What? R1 is a hydrogen atom. R2 is a hydrogen atom, a fluorine atom, a methyl radical or an ethyl radical, R3 is a benzyloxycarbonyl group R4 is a hydroxy or (C1-C4) -alkyloxy group,
As well as pharmaceutically acceptable additive salts.
The invention relates in particular to compounds of formula (I) whose names are: 3-[ethyl-6-[4-]]1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[[phenylemethoxy) carbonyl]alanine3-[phenylemethoxy]alanine4-[1,2,3,4-pyrimidinyl]-1-[pyrimidinyl-1-]-1-[pyrimidinyl-1-]-1-[pyrimidinyl-1-]-1-[pyrimidinyl-1-]-1-[pyrimidinyl-1-]-1-[pyrimidinyl-1-]-1-[pyrimidinyl-1-]-1-[pyrimidinyl-1-]-1-[pyrimidinyl-1-]-1-[pyrimidinyl-1-]-1-[pyrimidinyl-1-]-1-[pyrimidinyl-1-]-1-[pyrimidinyl-1-]-1-[pyrimidinyl-1-]-1-[pyrimidinyl-1-]-1-[pyrimidinyl-1-]-1-[pyrimidinyl-1-]-1-[pyrimidinyl-1-]-1-[pyrimidinyl-1-]-1-[pyrimidinyl-1-]-1-[pyrimidinyl-1-]-1-[pyrimidinyl-1-]-1-[pyrimidinyl-1-[pyrimidinyl-1-]-1-[pyrimidinyl-1-]-1-[pyrimidinyl-1-]-1-[pyrimidinyl-1-]-1-[pyrimidinyl-1-[pyrimidinyl-1-]-1],[pyrimid-1-[pyrimid-1-]-1],[pyramid-1-[pyramid-1-],[pyramid-1-], and other[pyramid-1-pyr-1-]-pyramid-1-[pyramid-2-]-pyramid-pyramid-pyramid-pyramid-pyramid-pyramid-pyramid-pyramid-pyramid-pyramid-pyramid-pyramid-pyramid-pyramid-pyramid-pyramid-pyramid-pyramid-pyramid-pyramid-pyramid-pyramid-pyramid-pyramid-pyramid-pyramid-pyramid-pyramid-pyr in the R or S configuration or mixtures thereof, and their additive salts.
The present invention also concerns a process for the preparation of compounds of formula (I). Compounds may generally be prepared, for example, during convergent synthesis by coupling 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 during the synthesis of compounds of formula (I) to introduce functional groups as precursors which are then blocked into desired temporary groups or to convert these functional groups appropriately by implementing a protective group strategy appropriate to the synthesis of the organism known as human synthesis (Greene, Wiley, Organic Synthesis Group in 1991).
Thus, compounds of formula (I) can be prepared as follows:
The invention therefore concerns a process for the preparation of compounds of formula (I) in which: a compound of formula (II) is reacted - What? wherein R1, R2, R3 and R4 are as defined above, (a) with a compound of formula (III) - What? where G is as defined above in the presence of a base or a transition metal coupling reagent (b) and then the compound of formula (I) is subjected, where appropriate, to cleavage of the R3-NH- function to regenerate the free amine, followed by the condensation of radical R3 of structure -CO2-R5 or -SO2-R5, and/or hydrolysis and where appropriate esterification or amidification and/or salification.
As a variant, the invention also concerns a process for preparing compounds of formula (I) in which the (a) a compound of formula (II) as defined above is reacted with a compound of formula (IIIa): - What? to obtain the intermediate compound of formula (IV): (b) then a compound of formula Het-NH2 is reacted to obtain the compounds of formula (I) with G representing a Het-NHCO-group, (c) then the compound of formula (I) obtained is subjected, possibly to cleavage of the R3-NH- function to regenerate the free amine, followed by the condensation of radicals R3 of structure -CO2-R5 or -SO2-R5, and/or, where appropriate, esterification or amidification and/or salification.
The coupling of a compound of formula (II) with a piperidine derivative of formula (III) or (IIIa) may be performed in the presence of a strong base congested at the reflux.
At the formula (IV) compound level, when OR is a hydroxyl, so if a guanidine of formula (Het-NH2) reacts with a carboxylic acid of formula (IV), then the carboxylic acid is first activated.
Activation may be carried out for example with dicyclohexylcarbodiimide (DCCI) or with O- (((cyano (ethoxycarbonyl) -methylene) amino)-1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU; Kônig et al, Proc. 21st Europ. Peptide Symp. 1990 (Eds Giralt, Andreu, Escom, Leiden 1991, p. 243) or other common activating agents in peptide synthesis.
In addition to the free-form guanidins (Het-NH2), guanidine salts can also be used in the reaction with the compounds of formula (IV), the free guanidins being formed in situ or by a separate step by means of a base.
The reaction of an activated carboxylic acid derivative of formula (IV) with guanidine (or derivative) of formula (Het-NH2) is preferably carried out in a known-in-itself manner in a protic or aprotic but inert organic solvent, using solvents such as methanol, isopropanol, tert-butanol, dimethylformamide, dichloromethane or tetrahydrofuran at temperatures ranging from 0 °C to the reflux temperature of these solvents, notably when the methyl or ethyl esters (ORflux is a methoxy or anhoxy) react with guanines.
The reactions of formula (IV) compounds with free guanidins are advantageously implemented in an inert aprotic solvent such as dimethylformamide, dichloromethane, tetrahydrofuran, dimethoxyethane, or dioxane, if appropriate by adding a base such as potassium tert-butoxide, sodium methoxide or an organic base such as N-methylmorpholine. However, water can also be used as a solvent in the reactions of formula (IV) compounds with formula (NH-Het2) guanidins, for example by using a base such as sodium hydroxide.
The reaction mixture is then treated and if desired the reaction product is purified by methods known to the professional.
The protectors which may be present in formula (I) compounds obtained from formula (IV) compounds with Het-NH2 amines or guanidins or from formula (II) compounds with formula (III) compounds are then removed by conventional processes; for example, tert-butyl ester groups are converted to carboxylic acid by treatment with trifluoroacetic acid, benzyl groups are removed by hydrogenation or fluorenylmethhoxycarbonyl groups are removed in the presence of a secondary amine and other reactions are carried out by standard processes, e.g. acylation reactions.
The reactions of hydrolysis to obtain an acid derivative (COR4 = CO2H), esterification to obtain an ester or prodrug (particularly COR4 = alkyloxycarbonyl or aryloxycarbonyl from the corresponding acid) or amidification (COR4 = aminocarbonyl mono or disubstituted from the corresponding acid) are 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.
The preparation of formula (II) starting compounds may be prepared by processes described in the literature or may be obtained by analogy. The preparation of formula (II) starting compounds is illustrated in the diagram above, it being understood that the present invention is not restricted to these starting compounds or products. There is no major difficulty for the professional to foresee modifications of the syntheses described in our application for the preparation of other formula (II) starting compounds according to the invention.
The invention therefore relates to the process of preparation of compounds of formula (II) characterized by the reaction of a compound of formula (V): where R1 and R2 are as defined above, and X is a halogen, preferably chlorine with a compound formula (VI): - What? wherein R3 and R4 are as defined above, in the presence of a strong base.
In general, a strongly congested base such as diisopropylethylamine is used under reactive conditions known to the professional in the implementation of nucleophilic substitution.
According to another variant of the invention, products of formula (I) may also be prepared as follows:
According to the invention, the process of preparation of formula (I) products consists in: (a) the reaction of a product of formula (IIa) - What? wherein R1, R2, G and X are as defined above, with a product of formula (VI) - What? where R3 and R4 are defined as before, either in the presence of a strong base or by catalysis with palladium, (b) then the product of formula (I) is subjected, where appropriate, to cleavage of the R3-NH- function to regenerate the free amine, followed by the condensation of R3 radicals of structure -CO2-R5 or -SO2-R5, and/or where appropriate hydrolysis and possibly esterification or amidification and/or salification.
The reaction of pyrimidine formula (IIa) with the general formula (VI) amine takes place under conditions analogous to those described above for the reaction of a pyrimidine formula (V) with the general formula (VI) amine. In particular, it is possible to operate in diisopropylethilamine in an organic solvent such as an amide (e.g. dimethylacetamide, dimethylformamide), at a temperature between 90°C and the reflux temperature of the reaction mixture. It is also possible to operate by catalysis with palladium (e.g. trisodiethylidene acetone) dipalladium in the presence of fluoride, at the reflux temperature of the mixture.
The free amine is condensed into R3 radicals with a structure of -CO2-R5 or -SO2-R5 and hydrolysed as described above.
Pyrimidine derivatives of formula (IIa) may be prepared by the action of a product of formula (III) - What? where G is defined as above, on a dihalogenated pyrimidine derivative of formula (V) - What? wherein R1, R2 and X are defined as before.
The reaction is advantageously carried out in the presence of a strong, clogged 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 clogged amine such as diisopropylethylamine, in an amide such as dimethylacetamide. It is understood that the functions that may interfere with the reaction are 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 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 containing 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 formula (I) as defined above and 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, e. g. as aerosols or nasal sprays.
The pharmaceutical formulations of the invention are prepared by methods known in themselves, organic or inorganic media, pharmaceutically inert, being added to the physiologically acceptable formula (I) compounds and/or their salts.
The suitable media for soft gelatin capsules or for suppositories are for example 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 for example water, alcohols, glycol, For formulations, polyols, sucrose, inverse sugars, glucose, vegetable fats, etc. The suitable medium for pharmaceutical preparations or implants is for example 90% (i.e. 0,5%) of their physical and chemical content of glyoxylic acid and their chemical formulations are normally 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 physiologically acceptable formula (I) compounds and/or their salts, and in addition to at least one physiologically acceptable formula (I) compound and/or their salts, they may contain at least one or more other active substances for therapeutic or prophylactic use.
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 an imbalance 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, 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 nephropathy or retinopathy 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.
The present invention therefore relates more particularly to a physiologically acceptable compound of formula (I) and/or its salts as defined above as a medicinal product having vitronectin receptor antagonist activity.
The present invention therefore relates in particular to a compound of formula (I) and/or its physiologically acceptable salts and/or prodrugs 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 0.01 and 100 mg/kg and preferably between 0.1 and 50 mg/kg, in particular between 0.1 and 5 mg/kg. For example, for an adult of 75 kg, a daily dose of 0.3 to 0.5 mg/kg may be considered.
In the case of intravenous administration, the daily dose ranges from approximately 0.01 to 100 mg/ kg and preferably from 0.05 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 doses. 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: methachloroperoxybenzoic acid; DBU: 1,8-diazabicyclo[5.4.0] undec-7-ene; APTS: paratolu sulfonic acid; DPPA: diphosphyl sulphate; DMSO: dimethyl sulphate; Pd/C Pd on carbon; Boccal: benzoyl: benzoyl: trimethyl sulphate; CBM: trimethyl sulphate; TMSO: trimethyl sulphate; CBM: trimethyl sulphate; CBM: trimethyl sulphate: trimethyl sulphate; CBM: trimethyl sulphate; TMSO: trimethyl sulphate;
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).
It is understood that in the following examples the products of examples 1 to 5 are racemic, the products of examples 6 to 9, 11 and 13 to 41 and their precursor esters are of form (S) on the asymmetrical centre of the 3-amino alanine and examples 10 and 12 and where applicable their precursor esters are of form (R) on the asymmetrical centre of the 3-amino alanine.
Preparation 1 Synthesis of 4,6-dichloro-5-ethylpyrimidine (Compound with formula (V).
A 5 g (35.7 mO) mixture of 5-ethyl-4,6-dihydroxypyrimidine (marketed by Aldrich) in 30 ml of phosphorus oxychloride is brought to the reflux for 1 hour. After returning to room temperature, a 4 ml N,N-diethylaniline mixture is added to 10 ml of phosphorus oxychloride and brought to the reflux for 4 hours. After returning to room temperature, the reaction medium is placed on a mixture of ice and water.
The following is the list of active substances:
Example 1 3-[5-ethyl-6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[phenylmethoxy) carbonyl]alanine, bis (trifluoroacetate) Stage a) Synthesis of 3-[(6-chloro-5-ethyl-4-pyrimidinyl) amino]-N-[(phenylmethoxy) carbonyl] alanine from (1,1-dimethylethyl).
A mixture of 3.8 g (21 mmoles) of 4.6-dichloro-5-ethylpyrimidine and 4.4 g (15 mmoles) of 3-amino-N-[(phenylmethoxy) carbonyl]alaninate of (1,1-dimethylethyl) (1,1-dimethylethyl) alanate) (prepared according to J. Med. Chem.((2001),(448), 1158-1176) is added to 50 ml of dimethylformamide, 10 ml of diisopropylethylamine is added and then heated to 120 °C for 6 hours. Dimethylformamide is then removed in a vacuum and the residue is taken up by a mixture of ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is decanted in the form of magnesium sulfate and removed by a vacuum. The residue is obtained in the form of heptane (heptane) with a gradient of 0.0 to 0.0 g. The resulting solution is obtained by heptane (heptane) with a gradient of 0.0 to 0.0%.
The following is the list of active substances in the active substance:
The following is the list of active substances and mixtures:
The following equation is used for the determination of the concentration of the test chemical in the test chemical:
The test chemical is used to determine the concentration of the test chemical in the test medium.
Stage b) The chemical formula is based on the chemical formula of 3-[5-ethyl-6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[[phenylmethhoxy) carbonyl]alaninate of (1,1-dimethylethyl).
A mixture of 1.68 g (3 moles) of 1,2,3,4-tetrahydro-7-(4-pipperidinyl)-1,8-naphthyridine, tris ((trifluoroacetate) (prepared under patents EP1065207 or WO 0078317) and 7.5 g (14.1 moles base equivalents) of polystyrene aminomethyl (Polymer Labs 1.88 moles/g) in 200 ml dichloromethane-ethanol 50-50 solution is agitated at separate temperature for 1 hour. The mixture is filtered, the resin washed with methanol and dichloromethane and the concentrated sodium chloride filtered in water under vacuum giving 630 ml of free sodium chloride. The mixture also contains 65 mg (11.5 mg) of residual sodium chloride (1-1.5-0.1-0.1-0.6-dimethyl-methyl-methyl-acetyl-methyl-methyl-methyl) (10.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.1-0.
The following is the list of active substances which are to be used in the preparation of the active substance:
The following is the list of active substances which are to be classified in the additive:
The following equation is used for the determination of the concentration of the active substance in the feed additive:
The test chemical is used to determine the concentration of the test chemical in the test medium.
Stage c) Synthesis of 3-[5-ethyl-6-[4-], 1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[phenylmethoxy) carbonyl]alanine, bis (trifluoroacetate) is also known as the trifluoroacetate.
110 mg (0.18 mmoles) of 3-[[5-ethyl-6-[4-]], 1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[[[[phenylmethoxy) carbonyl]alanate of (1,1-dimethyl) alanate is agitated in 5 ml of dichloromethane with 1 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 drawn out and evaporated in a vacuum drying reaction. The residue is precipitated into the soil in the form of dichloromethane with a minimum of a small amount of diethyl methacrylate. The resulting product is a thin film of 78 mg (R) of diethyl methacrylate.
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 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 (t, 3H, CH2-CH3); 1,77 and 1,94 (2m, 4H, N-CH2-CH2-CH-); 1,84 (m, 2H, NH-CH2-CH2-CH2-); 2,45 (q, 2H, CH2-CH3); 2,75 (t, 2H, NH-CH2-CH2-CH2-); 2,85 (t, 1H, N-CH2-CH2-CH-); 2,98 and 3,53 (2m, 4H, N-CH2-CH2-CH-); 3,43 (m, 2H, N-CH2-CH2-CH2-); 3,61 and 3,85 (2m, 2H, NH-CH2-CH2-CH-d); 4,32 (q, 1H, NH-CH2-CH2-); 4,99 and 5,04 (q, 2H, NH-CH2-CH2-CH2-); 2,64 (t, 2H, NH-CH2-CH2-CH2-); 6,2H, NH-CH2-CH2-phd (p, 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 information shall be provided for the purpose of the assessment of the toxicity of the active substance:
Microanalysis is the following:
Théorie C=51,84 %; H=4,99 %; N=12,45 %;
Trouvé C=52,0 %; H=5,2 %; N=12,4 %;
Example 2 The chemical formula is based on the formula of the product, which is the 3-[5-ethyl-6-[4-[1,2,3,4,5,6-hexahydro-2-pyrimidinyl) iminocarbonyl]-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[[phenylmethoxy) carbonyl] alanine. Stage a) The chemical formula is 3-[5-ethyl-6-[4-methylocarbonyl]-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[[[phenylmethoxy]carbonyl]alaninate of (1,1-dimethylethyl).
A mixture of 1.2 g (2.8 mmoles) of 3-[(6-chloro-5-ethyl-4-pyrimidinyl) amino]-N-[(phenyl methoxy) carbonyl]alaninate of (1,1-dimethyl ethyl), 5 ml of 4-methyl piperidinylcarboxylate and 1 ml of isopropylethylamine is heated at 110-120 °C for 4 hours. After cooling at room temperature, the reaction medium is taken up by ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, then dried under vacuum heated magnesium sulfate. The residual chromate is cremated on a chromograph with a gradient of pure acetate to a desired concentration of 17 mg (RdT) of pure sodium.
The following is the list of active substances and their active substances:
The following is the list of active substances which are to be classified in the additive:
The following equation is used for the determination of the concentration of the test chemical in the test chemical:
The test chemical is used to determine the concentration of the active substance in the test chemical.
Stage b) The chemical formula is based on the chemical formula of 3-[5-ethyl-6-[4-[1,2,3,4,5,6-hexahydro-2-pyrimidinyl) iminocarbonyl]-1-pipéridinyl]-4-pyrimidinyl] amino]-N-[phenylmethoxy) carbonyl] alanine.
- What? A mixture of 250 mg (0.46 mole) 3-[5-ethyl-6-[4-[methoxycarbonyl]-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[[[phenylmethylmethoxycarbonyl]alanate of (1,1-dimethyl) and 200 mg (2.0 mole) 2-amino-1,4,5,6-tetrahydropyrimidine (prepared according to R. F. Evans J. Chem. Soc. 1964, 2450-2455) in 15 ml of dichloromethane is agitated for 24 hours at room temperature. After dry evaporation, the residue is pre-filtered under vacuum under a chromagel by mixing with a silicomethane gradient until a dichloromethane-amorpho-acid-acid dichloromethane mixture is obtained. After the purification of the residue, the resulting product is a solution of approximately 18 to 50-50 mg of dichloromethane and a minimum of 85 to 250 mg of acetic acid.
The following is the list of active substances in the active substance:
The following is the list of active substances which are to be classified in the additive:
The following equation is used for the determination of the concentration of the test chemical in the test chemical: δ 1,05 (t, 3H, CH2-CH3); 1,67 and 1,86 (2m,4H, N-CH2-CH2-CH-NH); 1,80 (m, 2H, NH-CH2-CH2-CH2-NH); 2,26 (m, 1H, N-CH2-CH2-CH-); 2,38 (m, 2H, CH2-CH3); 2,78 and 3,33 (2m, 4H, N-CH2-CH2-CH-); 3,24 (m, 4H, NH-CH2-CH2-NH); 3,42 and 3,75 (2m, 2H, NH-CH2-NH); 4,08 (m, 1H, NH-CH2-CH2-NH); 4,95 and 5,00 (system ABtl, 2H, NH-CH2-CH-); 6,10 (m, 1H, CH2-CH-CH); 6,74 and 3,33 (m, 4H, NH-CH2-CH2-CH2-CH-); 8,05 and 5,05 (m, 2H, NH-CH2-NH); 8,05 (m, 2H, NH-CH2-CH2-NH); 8,05 (m, 2H, NH-CH2-CH2-CH2-NH); 5,05 (m, 2H, NH-CH2-CH2-CH2-CH2-NH; 8,05 (m, NH-CH2-CH2-CH2-CH2-CH2-NH); 5,05 (m, NH-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-); 6,10 (m; 8,05 (m, NH-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-CH
The test chemical is used to determine the concentration of the active substance in the test chemical.
Example 3 3-[6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-5-methyl-4-pyrimidinyl]amino]-N-[phenylmethoxy) carbonyl]alanine Stage a) Synthesis of 3-[(6-chloro-5-methyl-4-pyrimidinyl) amino]-N-[(phenylmethoxy) carbonyl] alanine from (1,1-dimethylethyl).
A mixture of 325 mg (2 mmoles) of 4.6-dichloro-5-methylpyrimidine (marketed by SPECS), 600 mg (2 mmoles) of 3-amino-N-[phenylmethyl) carbonyl] alanine (1,1-dimethylethyl) alanine (prepared according to J. Med. Chem. (2001), 44 (((8), 1158-1176) is heated at 120°C overnight in 3 ml of dimethylformamide and 3 ml of diisopropylamine. The reaction medium is vacuum-dried and the residue is then taken up by a mixture of water, Lesethyl acetate (50 mg) and a saturated organic silicate bicarbonate solution. The mixture is re-heated and the aqueous phase of acetyl acetate is re-heated. The residues are then separated by a mixture of hydrated organic acetyl acetate (100 mg) and magnesium sulphate (50-50 mg) in the form of a solution of phenol acetate.
The following is the list of active substances in the active substance:
The test chemical is used to determine the concentration of the test chemical in the test medium and to determine the concentration of the test chemical in the test medium.
The following information is provided for the purpose of this Annex:
Stage b) The chemical formula is based on the chemical formula of 3-[6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-5-methyl-4-pyrimidinyl]amino]-N-[phenylmethoxy) carbonyl]alanate of (1,1-dimethylethyl).
A mixture of 370 mg (0.88 mmoles) of 3-[(6-chloro-5-methyl-4-pyrimidinyl) amino]-N-[(phenylmethyoxy) carbonyl] alanine (1,1-dimethylethyl) and 1.0 g (1.79 mmoles) of 1,2,3,4-tetrahydro-7-(4-pipéridinyl)-1,8-naphthyridine, tris (trifluoroacetate) (prepared according to EP1065207 or WO 0078317) in 1 ml of diisopropylethylamine is heated to 120 °C = 2 hours. 10 ml of xylenol is then added and the reaction is repeated in the reflux phase for 4 hours. The reaction is decomposed by a mixture of water, saturated acetylamine and a solution of sodium acetylamine and bicarbonate of sodium. The product is recovered on a dry medium of 200 mg (10-104 mg) of dichloromethyl chloride and sulphate of ethyl chloride.
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 1,49 (s, 9H, tBu); 1,97 (m, 2H, NH-CH2-CH2-CH2); 2,01 (s, 3H, CH3); 2,18 (m, 4H, N-CH2-CH2-CH3); 2,79 (m, 2H, NH-CH2-CH2-CH2); 2,98 (m, 1H, N-CH2-CH2-CH2); 3,39 and 3,89 (2m, 4H, N-CH2-CH2-CH2); 3,52 (m, 2H, NH-CH2-CH2-CH2); 3,77 and 4,09 (2m, 2H, NH-CH2-CH2); 4,47 (m, 1H, NH-CH2-CH2-CH3); 5,13 (m, 2H, O-CH2-Ph); 5,92 (m, 2H, NH-CH2-CH2); 6,47 (m, 1H, NH-CH2-CH2-CH2); 1,38 (m, 1, 7, 3, 3, 3, 4, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 9, 8, 9, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15,
The following are the main components of the test:
Stage c) The chemical formula is based on the chemical formula of 3-[6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-5-methyl-4-pyrimidinyl]amino]-N-[phenylmethoxy) carbonyl]alanine.
A mixture of 38 mg (0.06 mmoles) of 3-[6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-5-methyl-4-pyrimidinyl]amino]-N-[[1,2-phenyl methoxy) carbonyl]alaninate and 2 ml of trifluoroacetic acid is stirred at room temperature in 10 ml of dichloromethane for 3 hours. 5 ml of toluene is then added and evaporated to dry the mixture. 26 mg (Rdt = 76%) of the expected product is obtained from an amorphous solid.
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 active substance in the feed additive:
HPLC/SM: (tr = 7min) 546 (MH+); 273 (M+2H++) The mean of the two samples is:
Example 4 3-[6-[4-[1,2,3,4,5,6-hexahydro-2-pyrimidinyl) iminocarbonyl] -1-pipéridinyl]-5-methyl-4-pyrimidinyl]amino]-N-[phenylmethhoxy) carbonyl]alanine Stage a) The chemical formula is 3-[6-[4-[methoxycarbonyl)-1-pipéridinyl]-5-methyl-4-pyrimidinyl]amino]-N-[[phenylmethoxy) carbonyl]alaninate of (1,1-dimethylethyl).
A mixture of 80 mg (0.19 mmoles) of 3-[(6-chloro-5-methyl-4-pyrimidinyl) amino]-N-[(phenylmethylamethoxy) carbonyl] alanine (1,1-dimethylethyl) and 3 ml of 4-pipyridinylcarboxylate methyl is heated at reflux for 3 hours. The reaction medium is then recovered after cooling by water, ethyl acetate and a saturated sodium bicarbonate solution. The organic phase is separated and the aqueous phase is then re-extracted by ethyl acetate. The organic phases are then sub-grouped and dried on magnesium sulfate in the emulsifying solvent. The residual chromate is removed on the emulsifying gradient with a concentration of silicate (50-50 mg) of ethyl acetate (100 to 25 mg) 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 in the additive:
The following substances are considered to be toxic if they are used in the manufacture of the active substance: 1H-RMN (DMSO-d6): δ 1,31 (s, 9H, tBu); 1,68 (ql, 2H, CH2-CH(C=O)); 1,87 (m, 2H, CH2-CH(C=O)); 1,87 (s, 3H, CH3-C=); 2,51 (masked, 1H, -CH2-CH-CH2-); 2,80 (tl, 2H, -N-CH2-CH2-(CH2) 2-); 3,44 (dl, 2H, -N-CH2-(CH2-(2) 2-); 3,62 (s, 3H, CH3-O); 3,71 (m, 2H, NH-CH2-CH-NH-); 4,22 (m, 1H, NH-CH2-CH2-CH-); 5,03 (sl, 2H, O-CH2-Ph35); 6,1H, CH2-CH3-); 7,34 (ppm, NH-CH2-H, -N-CH2-); 7,03 (ppm, NH2-CH2-CH2-); 8,03 (ppm, NH-CH2-CH2-); 1,03 (ppm, NH2-CH2-CH2-); 1,08 (ppm, NH-CH2-CH2-); 1,03 (ppm, NH2-CH2-CH2-CH2-); 1,03 (ppm, NH2-CH2-CH2-CH2-); 8,03 (ppm, NH2-CH2-CH2-CH2-); 1,03 (ppm, NH2-CH2-CH2-CH2-); 1,08 (ppm, NH2-CH2-CH2-CH2-); 1, 1, Ph-CH2-CH2- (s; 1,03 (ppm, NH2-CH2-CH2-CH2-CH2-); 1, N-CH2-CH2-; 1, N-CH2-CH2-; 1, N-CH2-CH2-; 1, N-CH2-CH2-; 1, N-CH2-CH2-; 1, N-CH2-CH2-CH2-; 1, N-CH2-CH2-CH2-; 1, N-CH2-CH2-CH2-; 1, N-CH2-CH2-CH2-; 1, N-CH2-CH2-CH2-CH2-CH2-; 1, N; 1, CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-
The test chemical is used to determine the concentration of the active substance in the test chemical.
Stage b) The chemical formula is based on the chemical formula of 3-[6-[4-[1,2,3,4,5,6-hexahydro-2-pyrimidinyl) iminocarbonyl]-1-pipéridinyl]-5-methyl-4-pyrimidinyl]amino]-N-[phenylmethoxy) carbonyl]alanine.
A mixture of 100 mg (0.19 moles) of 3-[6-[4-[methoxycarbonyl)-1-pipéridinyl]-5-methyl-4-pyrimidinyl]amino]-N-[phenylemethoxy) carbonyl]alaninate (1,1-dimethylethyl) and 150 mg (1.5 moles) of 2-amino-1,4,5,6-tetrahydropyrimidine (prepared according to R. F. Evans J. Chem. Soc. 1964, 2450-2455) is stirred at room temperature in 10 ml of dichloromethane for 5 hours. The residue is evaporated under vacuum and chromatographed on a gel by ejecting a mixture of dichloromethane-methyl methanol-acetic acid 85-15-2-2.
10 mg (Rdt = 10%) of the expected product is obtained as an amorphous solid.
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:
HPLC/SM: (tr = 1,9 min) 1077 (2MH+); 539 (MH+); 440 (MH-aminotetrahydro pyrimidine+)
Example 5 3-[5-ethyl-6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]axnino]-N-[phenylmethoxy]carbonyl]ethyl alanate, dichlorohydrate, whether or not chemically defined
A solution of 354 mg (0.45 mmoles) of 3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-([phenylmethhoxy) carbonyl]alanine, bis (trifluoroacetate) is added to 160 μl (2,19 mmoles) of thionyl chloride cooled at -12 °C in 13 ml of ethanol. The filter is stirred for 30 minutes at -12 °C and then allowed to return to room temperature and finally heated at 40 °C for 4 hours. The ammonia solution is evaporated in a vacuum and dissolved in a dry crystalline medium and a solid form of pentropyl esterol (R) is obtained.
The following is the list of active substances in the active substance:
The following is added to 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 (DMSO-d6): δ 1,09 (t, 3H, CH2-CH3); 1,14 (t, 3H, O-CH2-CH3); 1,85 (m, 2H, NH-CH2-CH2-CH2); 1,85 and 2,00 (2m, 4H, N-CH2-CH2-CH2); 2,48 (m, 2H, CH2-CH3); 2,75 (t, 2H, NH-CH2-CH2-CH2); 2,92 (m, 1H, N-CH2-CH2-CH2); 3,03 and 3,57 (2m, 4H, N-CH2-CH2-CH3); 3,44 (t, 2H, N-CH2-CH2-CH2); 3,76 and 3,87 (2m, 2H, NH-CH2-CH2-CH2); 4,07 (q, 2H, O-CH2-CH3); 4,39 (CH-CH2, 1p, NH-CH2-CH2-CH2-CH2); 7,03 (NH-CH2-CH2-CH2-CH2-CH2-CH2-CH2); 7,03 (NH-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2); 4,03 (NH-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH3); 1,38 (NH-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2); 7,02, 1,5, 1,5, 1,5, 1, 2,3, 1, 2, 3, 2, 3, 5, 2, 3, 4, 1, 2, 2, 3, 2, 3, 4, 1, 2, 3, 4, 2, 3, 4, 1, 2, 4, 1, 2, 2, 2, 2, 2, 2, 2, 3, 4, 1, 2, 2, 2, 4, 1, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 4, 5, 4, 5, 4, 5, (NH-H-H-H-H-H-H-H), 1, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2,
The test chemical is used to determine the concentration of the active substance in the test chemical.
Example 6 Synthesis of 4,6-dihydroxy-5-methyl pyrimidine.
To a 7.5 g (94 mo) solution of formamide hydrochloride in 250 ml of ethanol cooled to 0 °C, add 102 ml (282 mo) of a 21% sodium ethyl solution in ethanol and stir for 30 minutes; then add 13 ml (94 mo) of methyl diethyl malonate solution in 50 ml of ethanol and stir overnight at room temperature. Evaporate the reaction mixture at reduced dry pressure (2 kPa) and then take the residue by ethyl acetate, water and acetic acid to bring it to a pH below 6.
The following is the list of active substances which are to be used in the preparation of the active substance:
The test chemical is a chemical that is used to treat the effects of the chemical on the human body.
The following are the main components of the test:
Synthesis of 4,6-dibromo-5-methyl pyrimidine.
A mixture of 6 g (47.6 mmoles) of 5-methyl-4,6-dihydroxypyrimidine in 18 g of phosphorus oxybromide is heated to 200 °C for 3 hours. After returning to room temperature, the reaction mixture is taken up by a mixture of sodium bicarbonate ice water and extracted to ethyl acetate, washed the organic phases with water, dried on magnesium sulfate and evaporated dry under reduced pressure (2 kPa). 9 g (Rdt = 75%) of a beige solid is obtained.
The following is the list of active substances:
The test chemical is a chemical that is used to determine the concentration of a substance in a solution.
The Commission has not yet adopted a decision on the application of Article 108 (3) TFEU.
The following is added to the list of active substances:
In a monocol containing 8 g (36.8 mmoles) of 4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridine released from its salt, 70 ml of dimethylacetamide, 7.56 g (30 mmoles) of 4.6-dibromo-5-methylpyrimidine dissolved in 40 ml of dimethylacetamide and 14 ml of diisopropylethylamine are added to a monocol containing 8 g (36.8 mmoles) of 4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridine, heated to 140 °C and then concentrated for 4 hours and then dried at reduced pressure (2 kPa). The resulting residue is obtained by mixing water, ethyl acetate and a solution of saturated sodium bicarbonate. The organic phase is separated into a clear powder and re-agglomerated with the organic grade of diethyl acetate. The resulting organic phase is obtained by concentrating the sodium chloride in the form of phenylethyl acetate (a phenylethyl acetate) (93 g/mol) and then reducing the total amount of the product to 53 g/mol (7.5 mg/mol) of sulphate. The resulting organic resinates are obtained in the form of a mixture of ethyl acetate of methyl acetate (a phenylethyl acetate) (a phenylethyl acetate) (a) obtained by reducing the total amount of the product in the form of phenylate of methyl acetate of methyl acetate (a) is obtained in the form of a mixture of methyl acetate of methyl acetate (a) (a) (a mixture of methyl acetate) is obtained by reducing the product in the form of ethyl acetate of ethyl acetate of methyl acetate of sodium (a) to 70 mg/methyl acetate of sodium chloride (a) at reduced to 70 mg/methyl acetate (a) and a mixture of sodium chloride (a) (a) (a) (a) (a) (a) (a) (a) (a) (b
Preparation of naphthyridine as free amine:
22 g of naphthyridine is removed from its salt by 6 mass equivalents of amberlyst A21 basic resin (R-NMe2 resin) in a mixture of CH2Cl2/MeOH/AcOEt 1/1/1 stirred for 30 minutes. The resin is washed and allowed to inflate for 20 minutes in this solvent mixture. This operation must be repeated 3 times to achieve total salt displacement. After filtration of the resin and evaporation of the solvents, 8 g (36.8 mmoles) of free naphthyridine 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 naphthyridine:
The number of employees shall be determined by the number of employees.
The chemical formula is based on the chemical formula of 3-[5-methyl-6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[[phenylmethhoxy) carbonyl]alaninate of (1,1-dimethylethyl).
A mixture of 620 mg (1.6 moles) of 4-bromo-5-methyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipeninyl]pyrimidine, 565 mg (1.92 moles) of 3-amino-N-[(phenylmethyl) carbonyl]alanate of (1,1-dimethyl) alanate (prepared according to J. Med. Chem. (2001), 44(8), 1158-1176), 340 mg (2.25 moles) of fluoride of fluoride, 73 mg (0.08 moles) of trisethylphosphenylethyl) mmozydium dipalladium, 100 mmo (0.16 moles) of S-dioxyphenyl (1,1,2-dioxyphenyl) diphaladium for 340 hours (0.25 moles) in 50 ml of trisethyldioxyphenyl (CAS RN 804-84-0) and 280 mg (0.08 moles) of difluorophenyldioxyphenyl) is added to the reflux, and then a new solution of 3-dioxyphenylphosphenylethyl (1,1,3-dioxyphenyl) is added to the reflux.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 first chromatographed on silicagel by eluting with a 50-50-0-0-methylene-triethylamine-ethanol acetate gradient of 50-50-2-2. The resulting product is then chromatographed a second time on alumina by mixing with a 50-50-methylene-heptchloride ammonium to methyl-ethyl-diethyl-diethyl-diethyl acetate 50-50.
The following is the list of active substances in the active substance:
The following is the list of active substances which are to be classified in 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 1,47 (s, 9H, tBu); 1,94 (s, 3H, C-CH3); 1,75 to 2,05 (m, 6H, CH2-CH2-CH2-NH and CH2-CH-CH2); 2,60 to 2,77 (m, 3H, CH2-CH-CH2 and CH2-CH2-CH2-CH2-NH); 2,93 and 3,90 (2m, 4H, CH2-CH2-N-CH2-CH2); 3,42 (m, 2H, CH2-CH2-CH2-NH); 3,66 (m, 2H, NH-CH2-CH-NH); 4,45 (m, 1H, NH-CH2-NH); 4,95, 5,25 and 6,20 (3m, 3H2-CH2-CH2-NH-CH2-NH, NH-CH2-CH2-NH); 5,12 (Phs), 2,7 (Phs), 2,2 (Phs), 7,2 (phm, CH2-CH2-N), 5,35 (pN), 8,29 (Phs);
The following are the active substances: SM 602 (MH+); 546 (MH-tBu+); 412 (MH-COOCH2Ph+).
[αD] (0,625 % EtOH) is -4,5°
The chemical formula is based on the chemical formula of 3-[5-methyl-6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[phenylmethoxy) carbonyl]alanine, bis-trifluoroacetate.
350 mg (0.58 mmoles) of 3-[5-methyl-6-[4-],1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[[[[phenylmethoxy) carbonyl]alaninate of (1,1-dimethyl) alanate is shaken in 15 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 mixture is evaporated and the solid evaporates under pressure in a dry reaction (2 kPa). The residue is solubilised to a minimum of white chloride with a little bit of diethyl methacrylate on the surface. The product is then expressed in a pure soluble form (PaR = 73 mg).
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 introduction of a substance into the food chain: δ 1,96 (s, 3H, C-CH3); 1,80 to 2,05 (m, 6H, CH2-CH2-CH2-NH and CH2-CH2-CH2); 2,76 (t, 2H, NH-CH2-CH2-CH2-CH2-); 2,96 (t, 1H, N-CH2-CH2-CH-); 3,21 and 3,83 (2m, 4H, N-CH2-CH2-CH-); 3,50 (m, 2H, N-CH2-CH2-CH2-); 3,83 and 4,05 (2m, 2H, NH-CH2-CH-NH); 4,54 (q, 1H, NH-CH2-CH-NH); 5,50 (s, 2H, O-CH2-CH2-); 6,40 (d, 1H, naphidine); 6,55 (d, 1H, 1H, 1H); 7,28 (mH, 7, 5pm, 1H, 1H, 1H, naphidine); 8,22 (p, 1H, 1H, 1H), 1H, 1H (ph), 1H, 1H, 1H, 1H (ph), 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 are the active substances:
The test chemical is used to determine the concentration of the test chemical in the test medium.
Example 7
Preparation of naphthyridine as free amine:
22 g of naphthyridine is removed from its salt by 6 mass equivalents of amberlyst A21 basic resin (R-NMe2 resin) in a mixture of CH2Cl2/MeOH/AcOEt 1/1/1 stirred for 30 minutes. The resin is washed and allowed to inflate for 20 minutes in this solvent mixture. This operation must be repeated 3 times to achieve total salt displacement. After filtration of the resin and evaporation of the solvents, 8 g (36.8 mmoles) of free naphthyridine is obtained.
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 naphthyridine:
The following information is provided for the purpose of the assessment:
Synthesis of N-(alpha) -Z-L,2-3-diaminopropionate of ethyl.
In a mono-collection containing 26 ml of absolute ethanol, 12 ml (168 mO) of thionyl chloride is added at 0 °C, stirred for about 20 minutes at TA and then 2 g (8.4 mO) of N-(alpha) -Z-L,2-3-diaminopropioic acid is added in small quantities, resulting in a white discoloration.
The reaction mixture is then brought to reflux (78°C) for 2 hours (after a few minutes of heating, the solution becomes clear).
After cooling the solution is concentrated dry, a yellow liquid is obtained to which isopropyl ether is added. The expected product is taken in bulk, the surfactant is removed and the 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 again to ethyl acetate. The organic phases are dried on magnesium sulfate and the evaporated solvent in vacuum.
CCM: Rf = 0.41 [ Silica gel, electrolyte: methylene-methanol chloride (85-15) and 2% acetic acid water ((1-1).
The following substances are to be classified as substances of very high concern:
The test chemical is used to determine the concentration of the substance in the test medium.
The chemical formula is based on the chemical formula of 3-[6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-5-methyl-4-pyrimidinyl]amino]-N-[phenylmethhoxy) carbonyl]alanate of ethyl.
A mixture of 1.9 g (4.9 mmoles) of 6-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-5-methyl-4-bromopyrimidine and 1.62 g (6.08 mols) of 3-amino-N-[phenylmethoxy) carbonyl]ethyl alanine, in the presence of 1.06 g (6.86 mmoles) of cesium fluoride, 310 mg (490 μmol) of (2,2 bis-bis-diphenyl'-phosphino) -1.1 binaphthyl and 230 mg (245 μmol) of trisdibenzyliddiacetone) dipalladium is refluxed into the mixture for 40 hours. The reaction is then brought to a temperature of 230 mg (245 μmol) of trisdibenzyliddiacetone, which is then brought back to the temperature of 230 mg (245 μmol).
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 grouped organic phases are dried on magnesium sulfate and vacuum-dried evaporated. The residue is chromatographed on silicagel by 100% ethyl acetate.
CCM: Rf = 0.16 (electrolytic silica gel: 100% ethyl acetate)
The test chemical is a chemical that is used to determine the concentration of a substance in a solution. - What? The total number of samples of the test chemical is calculated by adding the following data: 9H, NH-CH2-CH2-CH2-CH2, N-CH2-CH2-CH2, CH3-C=C-); 2,72 (m, 3H, CH2-CH-CH2, NH-CH2-CH2-CH2); 2,95 and 3,93 (2m, 4H, CH2-CH2-N-CH2-CH2); 3,45 (m, 2H, NH-CH2-CH2-CH2); 3,68 (d, 2H, NH-CH2-CH-NH) 4,23 (t, 2H, CH3-CH2-CH2); 4,45 (m, 1H, NH-CH2-CH-NH); 5,10 and 5,17 (system AB, 2H, O-CH2-Ph); -6,41 and 7,18 (2d, 2H, CH= naphthyridine); 7,35 (m, 5H, Ph); 8,27 (s, 1H, N-CH-NH).
The test chemical is used to determine the concentration of the test chemical in the test medium.
The following formulae are used:
Formation of the hydrochloride:
1,15 g of 3-[[6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-5-methyl-4-pyrimidinyl]amino]-N-[[[phenylmethoxy) carbonyl]ethyl alanate are solubilised in a minimum of methylene chloride. This solution is poured over ethyl ether, the solution should remain clear.
Example 8
Preparation of naphthyridine as free amine:
22 g of naphthyridine is removed from its salt by 6 mass equivalents of amberlyst A21 basic resin (R-NMe2 resin) in a mixture of CH2Cl2/MeOH/AcOEt 1/1/1 stirred for 30 minutes. The resin is washed and allowed to inflate for 20 minutes in this solvent mixture. This operation must be repeated 3 times to achieve total salt displacement. After filtration of the resin and evaporation of the solvents, 8 g (36.8 mmoles) of free naphthyridine is obtained.
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 naphthyridine:
SM (FAB): (tr=0.50 min and 2.80 min): 388 ((M); 389 ((MH+)
The chemical composition of the product is determined by the following equation:
In a monocol containing 125 ml of isopropanol, 46 ml (840 mO) of thionyl chloride is added at 0 °C, stirred for about 20 minutes at TA and then 10 g (42 mO) of N-(alpha) -Z-L,2-3-diamino-propionic acid is added in small quantities, resulting in a white discoloration.
The reaction mixture is then brought to reflux (78°C) for 2 hours (after a few minutes of heating, the solution becomes clear).
After cooling the solution is concentrated dry, a yellow liquid is obtained to which isopropyl ether is added. The expected product is taken in bulk, the surfactant is removed and the 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 again to ethyl acetate. The organic phases are dried on magnesium sulfate and the solvent evaporated under vacuum.
CCM: Rf = 0.5 Silica gel, electrolyte: methylene-methanol chloride (85-15) and 2% acetic acid water
The following substances are to be classified as substances with a specific chemical composition:
The following information shall be provided in the following order:
[α]D (CHCl3) = +15,02 The following equation is used:
The chemical formula is based on the chemical formula of 3-[6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-5-methyl-4-pyrimidinyl]amino]-N-[phenylmethoxy) carbonyl]alanate from isopropyl.
A mixture of 1.5 g (3.86 mmoles) of 6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-5-methyl-4-bromo-pyrimidine and 1.30 g (4.63 mols) of 3-amino-N-[phenylmethyl) carbonyl] isopropyl alanineate, in the presence of 825 mg (5.41 mmoles) of cesium fluoride, 241 mg (386 μmol) of (2,2 bisdiphenylphosphophino) -1-piperidinyl) and 180 (193 μmol) of trisdibenzylidallaacone (dibenzylidallaacone) dipdioxy) is refluxed into the 40 ml of 1,2-dimethoxane for 5 hours and 30 minutes. The reaction is then brought to 180 mg (245 μmol) of trisdibenzylidalaacetone.
The following day, 180 mg (193 μmol) of tris (dibenzylideneacetone) dipalladium (Tris) is added and heated for another 9 hours. After cooling, the solution is concentrated dry and then re-mixed with a mixture of water, ethyl acetate and a saturated sodium bicarbonate solution. 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 underneath.
CCM: Rf = 0.18 (electrolytic silica gel: 100% ethyl acetate)
The following substances are to be classified as substances with a potential for the degradation of the chemical composition of the feed additive:
The test chemical is used to determine the concentration of the test chemical in the test medium.
The following formulae are used:
Formation of the hydrochloride: - What?
3.8 g of 3-[[6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-5-methyl-4-pyrimidinyl]amino]-N-[[[phenylmethoxy) carbonyl]alaninate isopropyl is solublelized in 20 ml of methylene chloride. This solution is poured over ethyl ether, the solution should remain clear. Then 3.23 ml of HCl 2N diluted in a little ethyl ether is added drop by drop, then stirred.
Example 9 Synthesis of 4,6-dibromo-5-ethylpyrimidine
A mixture of 2.8 g (20 mmoles) of 5-ethyl-4,6-dihydroxypyrimidine (marketed by Aldrich) and 8.85 g (31 mmoles) of phosphorus oxybromide is heated to 160 °C for 1 hour. After return to room temperature, the reaction mixture is poured over a mixture of ice, sodium bicarbonate saturated solution and ethyl acetate. The organic phase is settled, washed with sodium bicarbonate saturated solution, dried on magnesium sulfate, and the solvent is removed by evaporation under solid pressure (2 kPa). The residual chromate is cleared on silicone by evaporation with a heptane gradient of up to 100 per cent.
The following is the list of active substances:
The following is the list of substances that are to be classified in the additive:
The test chemical is used to determine the concentration of the test chemical in the test medium.
The following are the main components of the test chemical: SM 266 (mu+); 249 (MH-CH3+); 184 (MH-HBr+).
The following is added to the list of active substances:
A mixture of 3,67 g (6,45 mmoles) of 1,2,3,4-tetrahydro-7-(4-pipéridinyl)-1,8-naphthyridine, tris ((trifluoroacetate) (prepared according to the patents EP1065207 or WO 0078317) and 25 g of Amberlyst A-21 resin (Fluka 06424 original previously washed with dichloromethane acetate solution of ethylene methanol 1-1-1) in 150 ml of dichloromethane acetate solution of ethylene methanol 1-1-1 is agitated at room temperature for 1 hour. The mixture is filtered, the soil washed with the dry solution. The filtrate is agitated at room temperature for 1 hour in the presence of 25 g of Amberlyst A-21 resin as previously; the filtrate is then re-filtered once (2 kPa) to obtain a third concentrated solution.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 magnesium sulfate and the evaporated solvent under reduced pressure (2 kPa). The residue is chromatographically chromatographically on a silicate gel by eluting with a heptane gradient up to 100 percent heptane acetate 50-50.5 g (Rdt = 58%) of the product expected as a beige solid.
The following is the list of active substances in the active substance:
The following is the list of active substances and mixtures:
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 the list of the Member States which have adopted the measures:
The chemical formula is based on the chemical formula of 3-[5-ethyl-6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[[phenylmethhoxy) carbonyl]alaninate of (1,1-dimethylethyl).
A mixture of 317 mg (0.79 moles) of 4-bromo-5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipperidinyl]pyrimidine, 279 mg (0.95 moles) of 3-amino-N-[(phenylmethylmethoxy) carbonyl]alanate of (1,1-dimethylethyl) alanate (prepared according to J. Med. Chem. (2001), 44(8), 1158-1176), 168 mg (1.11 moles) of fluoride of magnesium, 36 mg (0.04 moles) of trisodioxybenzyl) mmoxide of chlorophyll (0,0 kPa), 49 mg (0.08 moles) of S-dioxybenzyl) for 50 to 50 hours (0.01 to 0.02 to 0.01 to 0.04 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.01 to 0.0 to 0.0 to 0.0 to 0.0 to 0.0 to 0.0 to 0.0 to 0.0 to 0.0 to 0.0 to 0.0 to 0.0 to 0.0 to 0.0 to 0.0 to 0.0 to 0.0 to 0.0 to 0.0 to 0.0 to 0.0 to 0.0 to 0.0 to
The following is a list of the active substances in the active substance:
The following equation is used for the determination of the concentration of the active substance in the feed additive:
The following are the main components of the test: SM 616 (MH+); 560 (MH-tBu+); 426 (MH-COOCH2Ph+).
[αD] (1% CHCl3): +2.4° The concentration of the substance in the solution is calculated as follows:
[αD] (1,05% EtOH) is -6,1°
Synthesis of 3-[5-ethyl-6-[4-], 1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[phenylmethoxy) carbonyl]alanine, bis (trifluoroacetate) is also known as the trifluoroacetate.
475 mg (0.77 mmoles) of 3-[5-ethyl-6-[4-],1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]aminol-N-[[[1,1-phenylmethylmethoxy]carbonyl]alanate is agitated in 15 ml of dichloromethane with 3.5 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 mixture is evaporated and the solid evaporates under pressure in a dry reaction (2 kPa). The residue is solubilised to the minimum in the form of amorphous dichloromethane with a little bit of diethyl methacrylate. The product is then expressed in a 368 mg (Pa) of diethyl methacrylate.
The following is the list of active substances in the active substance:
The following is a list of the chemical compounds of the compound:
The following equation is used for the determination of the concentration of the active substance in the feed additive: δ 1,04 (t, 3H, N-CH2-CH2-CH-); 1,77 and 1,90 (2m, 4H, N-CH2-CH2-CH-); 1,81 (m, 2H, NH-CH2-CH2-CH2-); 2,45 (q, 2H, CH2-CH3-); 2,73 (t, 2H, NH-CH2-CH2-CH2-); 2,78 (t, 1H, N-CH2-CH2-CH-); 2,87 and 3,48 (2m, 4H, N-CH2-CH2-CH-); 3,23 (m, 2H, N-CH2-CH2-); 3,58 and 3,83 (2m, 2H, NH-CH2-CH2-CH2-); 4,28 (q, 1H, NH-CH2-CH1-); 5,01 (q, 2H, NH-CH2-CH2-CH2-); 5,02 (AB, 2H, 2H-CH2-CH2-); 6,65 (t, 1H, 1H, 1H, 1, 2, 2, 2, 2, 2, 3, 2, 2, 3, 4, 5, 6, 2, 2, 2, 2, 2, 5, 5, 6, 2, 5, 6, 2, 5, 6, 6, 6, 6, 6, 6, 7, 2, 5, 6, 6, 6, 6, 7, 5, 6, 6, 6, 7, 5, 6, 6, 6, 7, 8, 6, 6, 6, 7, 8, 8, 8, 15, 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
The following are the active substances: SM 560 (MH+); 426 (MH-COOCH2Ph+); 558- (MH-); 450- (558-OCH2Ph-); 1117 - (2M-H-)
[αD] (1% CHCl3): +2,4° The concentration of the substance in the solution is calculated as follows:
Example 10 N-[phenylmethoxy]carbonyl]alanate of (1,1 dimethylethyl)
The mixture is then mixed with 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 silicagel by eluting with a heptane sub-acetate gradient of 100-0-0, 000-0, 000-0, and 0-5-05. Finally, 50 mg (dt) = 10 % of the expected oil product is obtained.
The following is the list of active substances in the active substance:
[αD] (1,25% CHCl3): -9,0° The concentration of the substance in the solution is calculated as follows:
Synthesis of 3-[5-ethyl-6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[[phenylmethhoxy) carbonyl]alanate from 1,1-dimethyl.
A mixture of 200 mg (0.5 mmole) of 4-bromo-5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]pyrimidine, 50 mg (0.17 mmole) of (D) 3-amino-N-[(phenylmethylamethoxy) carbonyl]alanate of (1,1) dimethylethyl), 40 mg (0.26 mmole) of caesium fluoride, 15 mg (0.016 mmole) of trisdibenzylidene mmodipedione (mmodipedium) 0, 20 mg (0.032 mmole) of 2,2'-dibenzylidene diphosphenoxide) 1,1-dipediamine 20 mg (0.17 mmole) of (D) 3-amino-N-[ (phenylmethylamethoxy) carbonyl]alanate of (1,1) dimethylethylethyl), 40 mg (0.26 mmole) of caesium fluoride, 15 mg (0.016 mmole) of trisdibenzylidene (mmodipedium) fluoride), 10 mg (0.016 mmol) of dibenzylidene (mmodipedium) 20 mg (0.01-dipedium) of dihydrogen dioxide for 5 hours, 10 mg (0.01-dimethylphenylmethylmethyl) dihydrogen (methyl) carbonyl) for 5 mg (0.01-dimethyl) carbonyl) of (1,0 and 10 mg (0.01-dimethyl) is added once again to the refrigerant for 5 hours, and then the mixture is reduced to a solid solution of sodium and sodium (250 mg (0.0−0,0−0,0−0,0−0) of sodium dihydrogen sulphenol by a second step, and then the remaining solution is dissoluble in the aqueous solution of sodium chloride and alumina and sodium (250 mg (250−hydrogen sulphate and sodium) is disulfide (250 kPa is disulfide and acetyl sulphate.
The following is the list of active substances:
The following is a list of the types of products:
[αD] (1,0 % CHCl3): -2,4
Synthesis of 3-[5-ethyl-6-[4-], 1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[phenylmethoxy) carbonyl]alanine, bis (trifluoroacetate) is also known as the trifluoroacetate.
40 mg (0.77 mmoles) of 3-[[5-ethyl-6-[4-]], 1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[[[[phenylmethoxy) carbonyl]alanate of (1,1-dimethylethyl) is agitated in 10 ml of dichloromethane with 1 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 mixture is evaporated and the solution evaporates under dry pressure (2 kPa). The residue is agitated on silicate by mixing with a CH2OH2-OH2-H2O-acetyl chloride. The resulting product is expressed as 48 mg of chromate (Radiol) -acetyl-10.
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- (MH-); 450- (558-OCH2Ph-); 1117- (2M-H-)
[αD] (1,75 % CHCl3): -6,0 The following is the total amount of CHCl in the solution:
Example 11 3-[5-ethyl-6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[phenylmethoxy) carbonyl]ethyl alanate, dichlorohydrate, whether or not chemically defined
A solution of 354 mg (0.45 mmoles) of 3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-([phenylmethhoxy) carbonyl]alanine, bis (trifluoroacetate) is added to 5 ml of ethanol cooled to -12 °C in a nitrogen atmosphere and stirred for 30 minutes. The filter is stirred for 30 minutes at -12 °C and then allowed to return to room temperature and finally to 40 °C for 4 hours. The ammonia mixture is mixed in a dry form and reduced to a solid form (2 kPa) of pentopropyl diethylamide and obtained in the form of a crystalline solution (R) of 95 mg (24%).
The following is the list of active substances in the active substance:
It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]
The following substances are considered to be toxic if they are used in the manufacture of the active substance: 1H-RMN (DMSO-d6): δ 1,09 (t, 3H, CH2-CH3); 1,14 (t, 3H, O-CH2-CH3); 1,85 (m, 2H, NH-CH2-CH2-CH2); 1,85 and 2,00 (2m, 4H, N-CH2-CH2-CH2); 2,48 (m, 2H, CH2-CH3); 2,75 (t, 2H, NH-CH2-CH2-CH2); 2,92 (m, 1H, N-CH2-CH2-CH2); 3,03 and 3,57 (2m, 4H, N-CH2-CH2-CH3); 3,44 (t, 2H, N-CH2-CH2-CH2); 3,76 and 3,87 (2m, 2H, NH-CH2-CH2-CH2); 4,07 (q, 2H, O-CH2-CH3); 4,39 (CH1, 1, 2, NH-CH2-CH2-CH2-CH2); 7,03 (NH2, 1, 1, 1, 1, 1, 1, 2, 2, 2, 2, 2, 2, 2, 2, 3, 2, 3, 4, 5, 2, 2, 2, 2, 3, 4, 5, 2, 2, 2, 3, 4, 5, 2, 5, 2, 2, 2, 2, 3, 4, 5, 2, 5, 2, 5, 2, 5, 2, 5, 2, 5, 2, 5, 2, 5, 2, 2, 5, 2, 5, 2, 5, 2, 5, 6, 2, 5, 6, 2, 2, 2, 5, 6, 2, 2, 5, 6, 2, 2, 5, 6, 2, 2, 2, 5, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 1, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2,
The following are the active substances: SM 588 (MH+); 454 (MH-COOCH2Ph+); 426 (454-C2H4+).
[αD] (1% CHCl3): +4
Example 12 N-[phenylmethoxy) carbonyl]ethyl alanate
The reaction mixture is evaporated at reduced pressure (2 kPa) and the residue crystallized in a mixture of diisopropyl ether and pentane and the solid is filtered. The solid is obtained from ethyl acetate, water and a saturated sodium bicarbonate solution. 535 mg (Rdt) = 50 percent by weight of the product obtained by hydrolysis.
The following is the list of active substances in the active substance:
HPLC/SM: (tr = 0,5 and 1,4 min) 267 (MH+).
[αD] (1,0 % CHCl3): -11,2
The chemical formula is based on the chemical formula of 3-[5-ethyl-6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[phenylmethhoxy) carbonyl]alanate of ethyl.
A mixture of 320 mg (0.8 mmole) of 4-bromo-5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]pyrimidine, 215 mg (1.04 mmole) of (D) 3-amino-N-[(phenylmethy) carbonyl]alanate ethyl, 190 mg (1.25 mmole) of cesium fluoride, 37 mg (0.04 mmole) of tris (dibenzylidene acetate) didipodium (0), 50 mg (0.08 mmole) of S-) di-bisylphosphenyle-hydrin), is heated at the back of the tank, under 15'-dihydro-1,1'-dihydroxydioxane for 5 hours. The mixture is cooled again by adding 37 mg (0.04 mmol) of tris (dibenzylidene acetate) for 10 hours. The residue is then cooled to a temperature of 10-20 °C. The product is then reduced to a solution of sodium dihydroxy and di-hydroxydioxycyl sulphate and then dissolved in a solution of sodium dihydroxy and di-hydroxydioxylated in the tank, and then reduced to a solution of sodium dihydroxydioxylate and di-hydroxydioxylated in the tank.
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 total number of samples of the active substance shall be calculated by adding the total number of samples of the active substance to the total number of samples of the active substance.
The following information is provided for the purpose of the assessment:
[αD] (1,3 % CHCl3): -6,0
Example 13 The following is added to the list of active substances:
In a monocol containing 12.5 g (57.5 mmoles) of 4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridine released from its salt, 80 ml of dimethylacetamide, 11.8 g (30 mmoles) of 4.6-dichloro-5-ethyl-pyrimidine dissolved in 40 ml of dimethylacetamide and 24 ml of diisopropylalamine are added to a monocol containing 12.5 g (57.5 mmoles) of 4-(1,2,3,3-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridine. This mixture is heated to 140 °C for 5 hours and then concentrated in vacuum oil. The resulting residue is then taken up by a mixture of water, ethyl acetate (50-50) and sodium bicarbonate solution. The organic phase is separated and re-extracted by the hydrolysis of the silicate acetone. The organic phylloxane is then obtained in the form of a concentrated solution of hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hydrolysed hyd
3 g of the expected product is obtained as a pale yellow powder (RdT total = 58%)
Preparation of naphthyridine as free amine:
28,5 g of naphthyridine is removed from its salt by 6 mass equivalents of amberlyst A21 basic resin (R-NMe2 resin) in a mixture of CH2Cl2/MeOH/AcOEt 1/1/1 agitated for 30 minutes.
This operation must be repeated 3 times for the salt to be completely displaced.
After filtration of the resin and evaporation of the solvents, 12.5 g (57.5 mmoles) of free naphthyridine is obtained.
The following is the list of active substances and their active substances:
The total number of samples of the active substance shall be calculated from the total number of samples of the active substance.
HPLC / SM: (tr = 0.51 min and 2.93 min): 358 (MH+)
The chemical formula is based on the chemical formula of 3-[6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-5-ethyl-4-pyrimidinyl]amino]-N-[phenylmethoxy) carbonyl]alanate from isopropyl.
A mixture of 1 g (2.79 mmoles) of 6-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-5-ethyl-4-chloro-pyrimidine and 940 mg (3.35.mols) of 3-amino-N-[phenylmethoxy) carbonyl] isopropyl alanineate, in the presence of 594 mg (3.91 mmoles) of cesium fluoride, 174 mg (279 μmol) of (2,2 bis-diphenyl'-phosphino)-1,1,1 μmol) of diphenyl-phenyl-phenyl and 130 mg (140 μmol) of trisdibenzyliddiacetone) diphenyl is refluxed into the mixture for 5 hours. The reaction is then repeated for another 180 mg (140 μmol) of trisdibenzyliddiacetone (140 μmol) of diphenyl-phenyl.
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 grouped organic phases are dried on magnesium sulfate and evaporated dry in vacuum. The residue is chromatographed on silicagel by 100% ethyl acetate.
CCM: Rf = 0.20 (electrolytic silica gel: 100% ethyl acetate)
The following substances are to be classified as substances with a potential for the degradation of the chemical composition of the feed additive:
The test chemical is used to determine the concentration of the test chemical in the test medium.
[α]D (CHCl3) = + 2,175 The following equation is used:
Formation of the hydrochloride:
3,2 g (5.3 mmoles) of 3-[[6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-5-ethyl-4-pyrimidinyl]amino]-N-[(phenylmethhoxy) carbonyl]alanate isopropyl is solublelized in a minimum of methylene chloride. This solution is poured over ethylene ether, the solution should remain clear. Then, drop by drop, stirring, 2.65 ml of HCl 2N is added to the ethylene ether. The hydrochloride is taken in bulk, the overfloat is oiled, then the residue is recalculated in the isopropyl ether.
Example 14 The following is a list of the active substances in the active substance:
80 mg (0.15 mmole) of 3-[5-ethyl-6-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[[phenylmethoxy) carbonyl]alanine, 45 mg (0.20 mmole) of terbutyl L-leucinate hydrochloride, 22 mg (0.16 mmole) of 1-hydroxy benzotriazole, 30 mg (0.16 mmole) of 1-[3-dimethylmetholamino) propyl]-3-ethyl carbodiimide, 0,050 ml (0.45 mmole) of N-methylmoroline and 0,070 ml (0.50 mmole) of silicon triamethyl in 5 ml of dimethylmetholamine at ambient temperature for 24 hours The mixture is evaporated and dissolved in a semi-solid solution of sodium dimethyl chloride and sodium methylamide (PaPa) at a temperature of between 60 and 55 kPa. The product is reduced to a solid state by a 60 to 50 mg of sodium dimethyl chloride and a 50-50 kPa of sodium chloride.
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 introduction of chemicals into the environment: (i) chemicals which are not classified as chemicals in accordance with the relevant provisions of this Regulation; (ii) chemicals which are not classified as chemicals in accordance with the relevant provisions of this Regulation; (iii) chemicals which are not classified as chemicals in accordance with this Regulation; (iv) chemicals which are classified as chemicals in accordance with this Regulation; (v) chemicals which are classified as chemicals in accordance with this Regulation; (v) chemicals which are classified as chemicals in accordance with this Regulation; (v) chemicals which are classified as chemicals in accordance with this Regulation; (v) chemicals which are classified as chemicals in accordance with this Regulation; (v) chemicals which are classified as chemicals in accordance with this Regulation; (v) chemicals which are classified as chemicals in accordance with this Regulation; (v) chemicals which are classified as chemicals in accordance with this Regulation; (v) chemicals which are classified as chemicals in accordance with this Regulation; (v) chemicals which are classified as chemicals in accordance with this Regulation; (v) chemicals which are classified as chemicals in accordance with this Regulation; (v) chemicals which are not in accordance with this Regulation; (v) chemicals which are not in accordance with this Regulation; (v) chemicals which are not in accordance with this Regulation; (v) with the provisions of this Regulation; (v) and (v) of this Regulation (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v
The following is the list of the Member States:
The chemical composition of the compound is determined by the following equation:
60 mg (0.083 mmoles) 2-(2-benzyloxycarbonylamino-3-{5-ethyl-6-[4-(5,6,7,8-tetrahydro-[1,8] naphtyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino}-propinylamino) -4-methylpentanoate of terbutyl is agitated in 5 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-AcOH 90-10-1-1). The toluene is pre-mixed and evaporated under reduced pressure (2 kdt). The residue is then evaporated to a minimum of white chloride with a little dichloromethane diethylamide. The product is then expressed as a pure solvent (PaPa) of 74 mg/l.
The following is the list of active substances in the active substance:
The following is a list of the Member States which have adopted the new rules:
Example 15 Synthesis of 4,6-dihydroxy-5-propyl pyrimidine.
To a 7.5 g (94 moles) solution of formamide hydrochloride in 200 ml of ethanol cooled to 0 °C, add 102 ml (282 moles) of a 21% sodium ethyllate solution in ethanol and stir the mixture for 30 minutes; then add 19.5 ml (94 moles) of propyl diethyl malonate solution in 50 ml of ethanol and stir overnight at room temperature. The reaction mixture is evaporated dry under reduced pressure (2 kPa). The residue is taken up by 100 ml of a solution saturated with sodium chloride and extracted by 800 ml and 200 ml of n-butanol. The organic phases are dried on sodium sulphate, filtered and evaporated under reduced pressure. The result is a dry product of 7.3 g (Pa) = 50 kPa.
The test chemical is a chemical that is used to determine the concentration of a substance in a solution.
The following are the main components of the test:
Synthesis of 4,6-dichloro-5-propyl pyrimidine
A 3 g (19.5 mo) mixture of 5-propyl-4,6-dihydroxy-pyrimidine in 20 ml of phosphorus oxychloride is brought to the reflux for 1 hour. After returning to room temperature, a 3 ml mixture of N,N-diethylaniline is dripped into 10 ml of phosphorus oxychloride and brought to the reflux for 4 hours. After returning to room temperature, the reaction mixture is poured over a mixture of ice and water and then the sodium bicarbonate is added gently to the basic pH.
The following is the list of active substances in the active substance:
The following is added to the list of active substances:
In a monocol containing 1.6 g (7.4 mmoles) of 4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridine released from its salt, add 50 ml dimethylacetamide, 2 g (10.5 mmoles) of 4.6-dichloro-5-propyl-pyrimidine and 4 ml diisopropylethylamine. This mixture is heated at 140 °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 solution of saturated sodium bicarbonate. The organic phase is separated in solid form and the aqueous phase is re-extracted from the acetylated acetylated acetylate. The organic resins are dissolved in ammonia and dissolved in sulphuric acid. The resulting residue is then obtained by reducing the sodium chloride in the form of silicon chloride (RH) to a concentration of 50 - 800 kPa.
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 number of employees is: SM 372,374 (MH+).
The chemical formula is based on the chemical formula of 3-[5-propyl-6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[[phenylmethhoxy) carbonyl]alaninate of (1,1-dimethylethyl).
A mixture of 600 mg (1.62 mmoles) of 4-chloro-5-propyl-6-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]pyrimidine, 590 mg (2 mmoles) of 3-amino-N-[1,2-phenylmethylphosphotoxy) carbonyl]alanate of (1,1-dimethylethyl) (1,1-dimethylethyl) (1,1-dimethylethyl) alanate (prepared according to J. Med. Chem. (2001), 448), 1158-1176), 380 mg (2,51 mmoles) of caesium fluoride, 76 mg (0.083 mmoles) of trisethylbenzylidene of 7−50−90−0), 102 mg (0.016−3 mmoles) of 2-diethylbenzylidene of 0−10−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1−1
The following is the list of active substances:
The following substances are to be classified in the additive: - 1H-RMN (CDCl3): δ 0,90(t, 2H, C-CH2-CH2-CH3); 1,01(t, 3H, C-CH2-CH2-CH3); 1,48 (s, 9H, tBu); 1,81 to 2,07 (m, 6H, NH-CH2-CH2-CH2, N-CH2-CH2-CH2); 2,39(t, 2H, C-CH2-CH3-CH3); 2,65 (tl, 1H, CH2-CH-CH2); 2,73 (t, 2H, NH-CH2-CH2-CH2); 2,97 and 3,55 (tl and dl, 4H, CH2-N-CH2-CH2); 3,44 (m, 2H, NH-CH2-CH2-CH2); 3,85 and 3,93m (2, 2H, CH2-CH2-CH2); 4,46 (m, 1H, CH2-CH2-CH2); naphthyridine (NH, 1, 2, 2, 1, 6, 2, 1, 2, 2, 2, 2, 2, 2, 2, 3, 2, 4, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 4, 2, 2, 2, 4, 2, 4, 2, 2, 4, 2, 4, 2, 4, 5, 2, 2, 2, 2, 2, 2, 4, 2, 4, 2, 4, 2, 4, 2, 4, 5, 2, 2, 4, 2, 4, 2, 4, 5, 2, 4, 2, 4, 5, 2, 2, 4, 5, 2, 2, 4, 5, 2, 2, 4, 5, 2, 2, 2, 5, 2, 2, 1, 2, 1, 2, 2, 2, 1, 2, 1, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2,
The following are the active substances: SM 630 (MH+); 574 (MH-tBu+); 440 (MH-COOCH2Ph+).
Synthesis of 3-[5-propyl-6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[phenylmethoxy) carbonyl]alanine, bis (trifluoroacetate) is also known as the 3-[5-propyl-6-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino.
610 mg (0.97 mmole) of 3-[[5-propyl-6-[4-]], (1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[[[[[phenylmethoxy) carbonyl]alaninate of (1,1-dimethyl) alanate is agitated in 50 ml of dichloromethane with 5 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 mixture is evaporated and the mixture evaporates under dry pressure (2 kPa) in a reaction with a solvent. The residue is dissolved into a minimum of dichloromethane with a little bit of diethyl methacrylate on top. The product is then expressed as a beige (Radiophenol) diethyl nitrate.
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 introduction of a substance into the food chain: 1H-RMN (DMSO d6): δ 0,93(t, 3H,C-CH2-CH2-CH3-CH3); 1,48(m, 2H, C-CH2-CH2-CH3-CH3); 1,67 to 2,00(m, 6H, CH2-CH2-CH2-NH and CH2-CH-CH2); 2,40(t, 2H, C-CH2-CH2-CH3); 2,65 to 2,96 (m, 5H, NH-CH2-CH2-CH2-CH2, N-CH2-CH2-CH-, N-CH2-CH2-CH2-CH-); 3,32 to 3,51 (m, 4H, N-CH2-CH2-CH- and NH-CH2-CH2-CH2-CH3); 3,56 and 3,84 (2m, 2H, NH-CH2-CH2-CH-NH); 4,31 (q, 1H, CH2-CH2-CH2-NH); 5,02 (CH2, 2H, Ph-CH2-CH2-CH3); 6,02 (m, 2H, 2H, naph, 1H, naph, 1H, 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 active substances:
The following is the total number of samples of the test chemical:
Example 16 Synthesis of 4,6-dihydroxy-5-isobutyl-pyrimidine.
To a 7.5 g (94 moles) solution of formamide hydrochloride in 200 ml of ethanol cooled to 0 °C, add 102 ml (282 moles) of a 21% sodium ethyllate solution in ethanol and stir the mixture for 30 minutes; then add 20.6 ml (94 moles) of propyl diethyl malonate solution in 50 ml of ethanol and stir overnight at room temperature. The reaction mixture is evaporated dry under reduced pressure (2 kPa). The residue is taken up by 100 ml of a solution saturated with sodium chloride and extracted by 800 ml and 200 ml of n-butanol. The organic phases are dried on sodium sulphate, filtered and evaporated under reduced pressure.
The following is the list of active substances in the active substance:
The test chemical is used to determine the concentration of the active substance in the test medium.
The following is a list of the main components of the system:
Synthesis of 4,6-dichloro-5-isobutyl-pyrimidine
A 3 g (17.9 mmoles) mixture of 5-isobutyl-4,6-dihydroxy-pyrimidine in 20 ml of phosphorus oxychloride is brought to the reflux for 1 hour. After returning to room temperature, a 3 ml mixture of N,N-diethylaniline is dripped into 10 ml of phosphorus oxychloride and brought to the reflux for 4 hours. After returning to room temperature, the reaction mixture is poured over a mixture of ice and water and then the sodium bicarbonate is added gently to basic pH.
The following is the list of active substances and their active substances:
The following is added to the list of active substances:
In a monocol containing 0.95 g (4.4 mmoles) of 4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridine released from its salt, add 25 ml dimethylacetamide, 0.9 g (4.4 mmoles) of 4.6-dichloro-5-isobutyl-pyrimidine and 2 ml diisopropylethylamine to a monocol. This mixture is heated to 120 °C for 5 hours and then concentrated at reduced pressure (2 kPa). The resulting residue is taken up by a mixture of water, ethyl acetate and a solution of saturated sodium bicarbonate. The organic phase is separated and the organic phase is re-extracted from the acetic acid of ethyl acetate. The organic phosphatases are obtained by reducing the concentration of the residual sulphate to 60 - 0 kPa. The resulting residue is obtained by reducing the concentration of ethyl chloride in the sodium chloride solution (Rg) to 50 - 100 kPa.
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 number of employees is:
The chemical formula is based on the chemical formula of 3-[5-isobutyl-6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[[phenylmethhoxy) carbonyl]alaninate of (1,1-dimethylethyl).
A mixture of 450 mg (1.17 mmoles) of 4-chloro-5-isobutyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]pyrimidine, 413 mg (1.4 mmoles) of 3-amino-N-[(phenylmethylphosphoroxy) carbonyl]alanate of (1,1-dimethylethyl) alanate (prepared according to J. Med. Chem. (2001), 448), 1158-1176), 275 mg (1.81 mmoles) of fluoride of magnesium, 55 mg (0.060-mmol) of tris (dibenzylidene-7-yl)-1-pipéridinyl]pyrimidine, 75 mg (0.0-mmol) of 0'-dibenzylidene-dibenzylidene under sodium chloride, 0.0-0.0-0.0 mmol) of 0'-dibenzylidene-dibenzylidene, 0.1 mmol, 0.0-0.1 mmol, 0.0-0.0 mmol, 0.0-0.0 mmol, 0.0-0.0 mmol, 0.0-0.0 mmol, 0.0-0.0 mmol, 0.0-0.0 mmol, 0.0-0.0 mmol, 0.0-0.0 mmol, 0.0-0.0 mmol, 0.0-0.0 mmol, 0.0-0.0 mmol, 0.0-0.0 mmol, 0.0-0.0 mmol, 0.0-0.0 mmol, 0.0-0.0 mmol, 0.0-0.0 mmol, 0.0-0.0 mmol, 0.0-0.0 mmol, 0.0-0.0 mmol, 0.0-0.0 mmol, 0.0-0.0 mmol, 0.0-0.0 mmol, 0.0-0.0 mmol, 0.0-0.0 mmol. The mixtra is then heated in a saturated phase of 35 ml of water. The residue is then reduced to a solid solution of ammonium oxalicyl chloride and the remaining sodium oxide is reduced to a solution of chloride and the remaining sodium oxide is then reduced to a solution of chloride and a solution of chloride (2-methyl chlor
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 following are the active substances: SM 644 (MH+); 588 (MH-tBu+); 454 (MH-COOCH2Ph+).
The chemical formula is based on the chemical formula of 3-[5-isobutyl-6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[phenylmethoxy) carbonyl]alanine, bis-trifluoroacetate.
620 mg (0.96 mmole) of 3-[[5-isobutyl-6-[4-]], 1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[[[phenylemethoxy) carbonyl]alanate of (1,1-dimethyl) is agitated in 50 ml of dichloromethane with 5 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 pre-mixed and evaporated under reduced pressure (2 kPa). The residue is then agitated to the minimum in the form of dichloromethane with a small amount of diethyl methacrylate. The resulting product is expressed as a 67 mg (Pa) of diethyl methacrylate (R) expressed as a percentage of the net net net net net heat output.
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 introduction of a substance into the food chain: 1H-RMN (DMSO d6): 0,83 ((d, 6H, CH2-CH-CH-CH3) 2); 1,60 to 2,05 (m, 7H, -CH2-CH-CH-CH3)); 3,57 to 3,84 (2m, 7H, -CH2-CH-CH2-CH2); 2,35 ((m, 2H, -CH2-CH-CH-CH3)2); 2,65 to 2,87 (m, 3H, CH2-CH-CH2 and NH-CH2-CH2-CH2); 2,91 (tl, 2H CH2-CH2-N-CH2-CH2); 3,42 (m 4H, CH2-CH2-N-CH2-CH2 and NH-CH2-CH2-CH2); 3,57 and 3,84 (2m, 2H, NH-CH2-CH-CH2); 4,32 (m, 1H, CH2-CH2-CH-CH); 5,0 (Ph, CH2-CH2-CH2-CH2); 6,0 (Ph, CH2-H2, CH2-H2, CH2-N-CH2-CH2-CH2); 7,0 (Ph, CH2-H2, CH2-H2, CH2-CH2-CH2-CH2-CH2); 7,0 (Ph, 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 are the active substances:
The test chemical is used to determine the concentration of the substance in the test medium.
Example 17 Synthesis of 5-methoxy-4,6-dihydroxy-pyrimidine:
In a monocol containing 30 ml of absolute ethanol and 90 ml of sodium ethyllate solution at 1.7 mol/l in ethanol, 5 g (6.2 mmoles) of formamide hydrochloride is added at 0 °C in small quantities. It is agitated at room temperature for about 20 minutes, then 8.5 ml of dimethyl methoxymalonate is added by drip. The agitation is maintained for 16 hours. The reaction mixture is then acidified with pure acetic acid to a pH of 4 to 5, concentrated dry in the presence of cyclohexane. The raw material is chromatographically obtained on silicone after emptying with a mixture of methyl chloride-acetylene (g-185-15% g-acetylene) and water, resulting in a low amount of sodium acetate.
CCM: Rf = 0 [Silicagel, electrolyte: methylene-methanol chloride (85-15) and 2% acetic acid water ((1-1).
The test chemical is a chemical that is used to determine the concentration of a substance in a solution.
The following information shall be provided for each test chemical:
The test shall be performed in accordance with the following procedure:
Synthesis of 4,6-dichloro-5-methoxy-pyrimidine:
A mixture of 5 g (35.2 mmoles) of 5-methoxy-4,6-dihydroxypyrimidine and 40 ml of phosphorus oxychloride is brought to the backflow for one hour.
The reaction mixture is then slowly poured over a mixture of ice and water and then neutralized by a saturated solution of sodium bicarbonate. This aqueous phase is extracted to ethyl acetate. The organic phases are dried on magnesium sulfate and vacuum-dried.
The resulting residue is purified on silica by eluting with a mixture of cyclohexane and acetate (95-5).
2.5 g (Rdt = 40%) of the expected product is obtained as a white powder.
The following information is provided for the purpose of the analysis:
The test chemical is used to determine the concentration of the test chemical in the test medium.
HPLC/SM: tr = 1.3 min
Synthesis of 6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-5-methoxy-4-chloro-pyrimidine with the following:
In a monocol containing 800 mg (3.68 mmoles) of 4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridine released from its salt, 2.2 g (12.3 mmoles) of 4.6-dichloro-5-methoxy-pyrimidine dissolved in 25 ml dimethylacetamide and 3640 μl diisopropylethylamine is added to a monocol, heated to 130 °C for 2 hours and then concentrated in a vacuum. The resulting residue is then re-heated by a mixture of water, ethyl acetate and a saturated sodium bicarbonate solution. The organic phase is separated and the acute phase is re-extracted from the organic phase of acetate. The organic phosphatases are re-mixed on a vacuum with a solution of aluminum sulphate (R) and are then evaporated in a solution of aluminum chloride (R) of about 68% (80-20%) and the residue is then obtained by evaporating the solution of aluminum chloride (R) in a vacuum.
Preparation of naphthyridine as free amine:
2.4 g of naphthyridine is removed from its salt by 6 mass equivalents of amberlyst A21 basic resin (R-NMe2 type resin) in a mixture of CH2Cl2/MeOH/AcOEt 1/1/1 stirred for 30 minutes. The resin is washed and allowed to inflate for 20 minutes in this solvent mixture. This operation must be repeated 3 times for the total salt displacement.
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:
HPLC / SM: (tr = 0.53 min and 2.56 min): 359 ((M); 360 ((MH+); 361 (M+2H++).
The chemical formula is based on the chemical formula of 3-[6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-5-methoxy-4-pyrimidinyl]amino]-N-[phenylmethoxy) carbonyl]alaninate of (1,1-dimethylethyl).
A mixture of 300 mg (0.83 mmoles) of 6-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-5-methoxy-4-chloro-pyrimidine and 295 mg (1 mmole) of 3-amino-N-[phenylmethoxy) carbonyl] alanine (1,1-dimethyl) alanine (prepared according to J. Med. Chem. (2001), 44(8), 1158-1176), (in the presence of 177 mg (1.17 mmoles) of caesium fluoride, 52 mg (83 μmoles) of (2,2'-bisdihydrophosphenoyl) -mono-1,1-bisdihydroxyethyl) -mono-1,3-methyl and 40 μmoles (42 μmoles) of dihydroxybenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylben
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 grouped organic phases are dried on magnesium sulfate and vacuum-dried to evaporate. The residue is chromatographed on alumina with a gradient of isopropyl ether and ethyl acetate (70-30, 60-40, 50-50) ending in 100% ethyl acetate. The fractions containing the desired product are collected for a second purification in silicone gel with a gradient of 100% acetate.
CCM: Rf = 0.3 (electrolyte alumina: ethyl isopropyl acetate ether 60-40)
The following substances are considered to be toxic if they are used in the manufacture of the active substance: 1H-RMN (MeOD): δ 1,46 (s, 9H, tBu); 1,80 (m, 2H, NH-CH2-CH2-CH2); 1,90 (m, 4H, N-CH2-CH2-CH-CH2); 2,65 (m, 1H, CH2-CH2-CH2); 2,69 (t, 2H, NH-CH2-CH2-CH2); 2,95 and 3,78 (2m, 4H, CH2-CH2-N-CH2-CH2); 3,38 (t, 2H, NH-CH2-CH2-CH2); 3,59 (s, CH3-O); 4,35 (m, 1H, NH-CH2-CH2-NH); 4,45 (d, 2H, NH-CH2-CH2-CH2); 5,03 and 5,12 (system, 2H, O-CH2-CH38); 6,38 and 7,15 (2d, CH= 2H, CH= 7,4H, naph; AB, 5H, CH= 5H, naph; N, PH= 7,32 (N, CH= 5H, PH); 1 (s, N= 1,90).
The test chemical is used to determine the concentration of the test chemical in the test medium.
Synthesis of the corresponding acid:
A 200 mg (0.32 mmoles) mixture of 3-[5-methoxy-6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-5-methyl-4-pyrimidinyl]amino]-N-[[1,1-methylmethylphenyl]carbonyl]alaninate and 1.5 ml of trifluoroacetic acid is stirred at room temperature in 15 ml of dichloromethane for 8 hours. Toluene is then added and evaporated to dry the mixture. 350 mg of toluene oil is obtained from a yellow oil, this hd is taken up in a minimum of methylen chloride and precipitated into isopyl isopyl salt, thus obtaining trifluoroacetate impurity.
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 test chemical is used to determine the concentration of the test chemical in the test medium.
Example 18 Synthesis of 4,6-dibromo-5-fluoro-pyrimidine.
1/ To a solution of 5.83 g (56 moles) of formamidine acetate in 300 ml of ethanol cooled to 0°C, add 60.7 ml (168 moles) of a 21% sodium ethyl solution in ethanol and stir the mixture for 30 minutes; then add a solution of 10 g (56 moles) of diethyl fluoride malonate in 25 ml of ethanol and stir overnight at room temperature. The mixture is cooled to 0°C, then 17.85 ml of concentrated hydrochloric acid is added to bring the pH to 6. Finally, the filtered precipitate is washed successively with water, isopropanol, diethyl ether and pentane.The reaction mixture is then taken up by a mixture of sodium bicarbonate ice water and extracted to ethyl acetate, washed with water, dried on magnesium sulfate and dried at reduced pressure (2 kPa). The residue is chromatographically evaporated on silicone gel with a chlorophyll-methylheptane gradient of 0-1000.850 mg (Rdt = 06%) of the expected product is obtained as a beige solid used as is.
The following is the list of active substances:
The following is added to the list of active substances:
A mixture of 840 mg (1.5 mmoles) of 1,2,3,4-tetrahydro-7-(4-pipéridinyl)-1,8-naphthyridine, tris ((trifluoroacetate) (prepared according to EP1065207 or WO 0078317) patents) and 5 g of Amberlyst A-21 resin (Fluka 06424 original previously washed with ethyl-methanol 1-1-1 dichloromethane acetate solution) in 100 ml of ethyl-methanol 1-1-1 dichloromethane acetate solution is agitated at room temperature for 1 hour. The mixture is filtered, the lavender is resinated with the soil solvent. The filtrate is agitated at room temperature for 1 hour in the presence of 5 g of Amberlyst resin as previously removed. The filtrate is thus reduced to 320 mg (2 kPa) of free-flowing concentrated solution.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 solvent evaporated at reduced pressure (2 kPa). The chromatographic residue is evaporated on silicone by heptane-acetate of ethyl 50-50. 300 mg (R = 52%) of the expected product is obtained as a solid.
The test chemical is a chemical that is used to produce a mixture of two or more substances.
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 a list of the Member States of the European Union:
The chemical formula is based on the chemical formula of 3-[5-fluoro-6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[[phenylmethroxy) carbonyl]alaninate of (1,1-dimethylethyl).
A mixture of 280 mg (0.72 mmole) of 4-bromo-5-fluoro-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]pyrimidine, 253 mg (0.86 mmole) of 3-amino-N-[(phenylmethylphosphoryl) carbonyl]alaninate of (1,1-dimethylethyl) (1,1-dimethyl) alaninate (prepared according to J. Med. Chem.(2001), 44(8), then 1158-1176), 152 mg (1.00 mmole) of caesium fluoride, 33 mg (0.036 mmole) of trisethyldibenzyl acetate) mmoladium (0,02-pipéridinyl) pyrimidine, 45 mg (0.072 mmole) of 2,2'-dibenzylphosphoryl fluoridine for one hour (0.1⁄2 hour) in 50 mg (0.06-dibenzylphosphoryl) (1,1⁄2 hour) of trisethyldibenzyl acetate and 45 mg (0.03-dibenzylphosphoryl) (1,1⁄2 hour) of ondibenzyl-dibenzyl-dibenzyl-dibenzyl-methyl (1,1⁄2 hour) and one hundred and twenty-five mg (0.03-dibenzyl-dibenzyl-dibenzyl-dibenzyl-dibenzyl-dibenzyl-dibenzyl) (1,1⁄2), and another 45 mg (1,31-dibenzyl-dibenzyl-dibenzyl-dibenzyl-dibenzyl-dibenzyl-dibenzyl-dibenzyl-dioxide) is added to the reflux, and then added to the reflux.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 on silicagel by eluting with an ethyl methanol heptane acetate gradient of 100-0-0 to 0-100-0 and finally 0-95-5. The resulting product is then chromatographed a second time on alumina by eluting with a methyl chloride heptane mixture 50-50 to ethyl diethyl acetate 50-50.
The following is the list of active substances:
The following is the list of active substances which are to be classified in 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 1,47 (s, 9H, tBu); 1,70 to 2,05 ((m, 6H, CH2-CH2-CH2-NH and CH2-CH2-NH2); 2,73 (t, 2H, CH2-CH2-CH2-NH); 2,80 (tl, 1H, CH2-CH-CH2); 3,01 and 3,90 (tl and m, 4H, CH2-CH2-N-CH2-CH2); 3,43 (m, 2H, CH2-CH2-CH2-NH); 4,42 (m, 1H, NH-CH2-CH-NH); 4,51 (dl, 2H, NH-CH2-NH); 5,11 (m, 1H NH); 5,14 (s, 2H, CH2-CH2-NH); 6,12 (m, 1H2-CH2-CH2-NH); 6,37 (dH, CH1, CH1, CH1, CH1, CH1, CH1, 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, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH3, CH
The following substances are to be classified in the same category as the active substance: SM 606 (MH+); 550 (MH-tBu+); 416 (550-COOCH2Ph+), 604-[(M-H) ]-, 650- [(604+HCOOH) ]-, 496- [(604-OCH2Ph) ]-.
[αD] (1,0 % CHCl3): +4,4
The chemical formula is based on the chemical formula of 3-[5-fluoro-6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[phenylmethoxy) carbonyl]alanine, bis (trifluoroacetate).
290 mg (0.48 mmole) of 3-[[5-fluoro-6-[4-]], 1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[[[phenylmethoxy) carbonyl] alanine (1,1-dimethyl) alanine is shaken in 40 ml of dichloromethane with 4 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 mixture is evaporated and the solid evaporates under pressure in a dry reaction (2 kPa). The residue is solubilised to a minimum of white chloride with a little dichloromethane diethylamide. The product is then expressed in a pure form (PaR = 310%).
The following is the list of active substances in the active substance:
The following are the active substances:
The following is the total number of samples of the test chemical:
Example 19 Synthesis of 3-[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]alanate from (1,1-dimethylethyl).
In a monocol containing 3 g (4.87 mmoles) of 3-[[6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-5-ethyl-4-pyrimidinyl]amino]-N-[phenylmethyl) carbonyl]alanine, 150 ml of 100% acetic acid is added and
300 mg of activated palladium on charcoal (5-10%) This mixture is purged under reduced pressure (2 kPa) and then allowed to agitate at room temperature and atmospheric hydrogen pressure for 22 hours.
The heterogeneous medium is filtered on clarcel. The filtrate is concentrated dry and then taken up by a mixture of water, ethyl acetate and a solution of saturated sodium bicarbonate. The organic phase is extracted from ethyl acetate and dried on magnesium sulfate and then the solvent is evaporated under reduced pressure (2 kPa). 1.95 g of a pale yellow oil 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 the active substance: 1H-RMN (CDCl3): δ 1,09 (t, 3H, CH2-CH3); 1,35 (s, 9H, tBu); 1,75 (m, 6H, CH2-CH-CH2 and CH2-CH2-CH2-NH); 2,44 (m, 2H, CH2-CH3); 2,60 (t, 2H, CH2-CH2-CH2-NH); 2,81 (m, 2H, CH2-CH-CH2 and NH-CH2-CH-NH); 3,23 (m, 2H, CH2-CH2-CH2-NH); 3,41 (m, 4H, CH2-CH2-N-CH2-NH2); 3,42 and 3,57 (2m, 2H, NH-CH2-CH2-NH); 6,25 (m, 2H, CH2-CH2-CH2-NH and NH-CH2-CH2-NH); 6,30 (2d, 7,04 and 2H, naphthyrine); 8,08 (ppm, N=CH-NH, N=N).
The following is the list of the active substances in the active substance:
The following is the list of substances that are to be used in the preparation of the test chemical:
[αD] : -3 (1% CHCl3)
The chemical formula is based on the chemical formula of 3-[5-ethyl-6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[adamantylmethoxy) carbonyl]alaninate of (1,1-dimethylethyl).
A mixture of 239 mg (0.49 mo) of 3-[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]alaninate of (1,1-dimethylethyl), 152 mg (0.49 mo) of N-adamantylmethoxycarbonyloxysuccinimide and 0.104 ml (0.75 mo) of triethylamine in 50 ml of methyl chloride is agitated for 5 hours at room temperature. The reaction mixture is evaporated at reduced dry pressure (2 kPa) and the residue is recovered by silicon chloride, water and a saturated bicarbonate solution. The separated phase is sodium chloride, dissolved in organic solvent and evaporated with up to 90 mg of magnesium sulphate (Radiol-methyl chloride) at a temperature of 17-10 kPa. The residue is obtained by dissolving the sodium chloride in a solvent with a concentration of up to 90%.
The following is the list of active substances in the active substance:
The following is the list of active substances and mixtures:
The following substances are to be classified as substances with a potential for the production of adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, adsorbent, and adsorbent are to be used when the test chemical is used in the test, and the test is performed in accordance with the following equation:
The following are the active substances: SM 674 (MH+); 618 (MH-tBu+); 426 (618-COOCH2adam+); 337,7 (M2H++); 718- (M-H-HCOOH); 672- (M-H).
[α]D: +2,5 (1% CHCl3)
Synthesis of 3-[[5-ethyl-6-[4-]]1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[[adamantylmethoxy) carbonyl]alanine
130 mg (0.19 mmoles) of 3-[5-ethyl-6-[4-],1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[[[[adamantylmethoxy) carbonyl]alanate of (1,1-dimethyl) alanate is agitated in 20 ml of dichloromethane with 2 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 pre-mixed and evaporated to dry under pressure (2 kPa). The residue is then reduced to the minimum in the form of ammonium chloride with a little dichloromethane diethylamide. The product is then expressed in a 368 mg (Pa) of diethyl methacrylate.
The following is the list of active substances in the active substance:
The following is the list of substances that are to be classified in the product:
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 active substances:
The following is the total number of vehicles:
Example 20 Synthesis of 3-[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]alanate from (1,1-dimethylethyl).
In a monocol containing 3 g (4.87 mmoles) of 3-[[6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-5-ethyl-4-pyrimidinyl]amino]-N-[phenylmethyoxy) carbonyl]alanine, 150 ml of 100% acetic acid is added and
300 mg of activated palladium on charcoal (5-10%) This mixture is purged under reduced pressure (2 kPa) and then allowed to agitate at TA under atmospheric hydrogen pressure for 22 hours.
The heterogeneous medium obtained is filtered on clarcel. The filtrate is concentrated dry under reduced pressure (2 kPa) and then taken up by a mixture of water, ethyl acetate and a saturated sodium bicarbonate solution. The organic phase is extracted to ethyl acetate and dried on magnesium sulfate and then the solvent is evaporated under reduced pressure (2 kPa). 1.95 g of a pale yellow oil is obtained.
The following information shall be provided for the purpose of the assessment:
The following formulae are used:
The following substances are considered to be toxic if they are used in the manufacture of the active substance: 1H-RMN (CDCl3): δ 1,09 (t, 3H, CH2-CH3); 1,35 (s, 9H, tBu); 1,75 (m, 6H, CH2-CH-CH2 and CH2-CH2-CH2-NH); 2,44 (m, 2H, CH2-CH3); 2,60 (t, 2H, CH2-CH2-CH2-NH); 2,81 (m, 2H, CH2-CH-CH2 and NH-CH2-CH-NH); 3,23 (m, 2H, CH2-CH2-CH2-NH); 3,41 (m, 4H, CH2-CH2-N-CH2-NH2); 3,42 and 3,57 (2m, 2H, NH-CH2-CH2-NH); 6,25 (m, 2H, CH2-CH2-CH2-NH and NH-CH2-CH2-NH); 6,30 (2d, 7,04 and 2H, naphthyrine); 8,08 (ppm, N=CH-NH, N=N).
The following is added to the list of active substances:
The following substances are to be classified as 'metals' in the Annex to Regulation (EC) No 1907/2006 of the European Parliament and of the Council:
Examples 21 to 31 Example 28 Stage a) The chemical formula is based on the chemical formula of 3-[5-ethyl-6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[4-methoxy-benzenesulfonyl) alanate of (1,1-dimethylethyl).
To a 150 mg (0.31 mo) mixture of 3-[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphtiridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]alanate of (1,1-dimethylethyl) in solution in 6 ml of dichloromethane and 650 μl of pyridine, add 64.3 mg (0.31 mo) of 4-methoxybenzenesulfonyl chloride in solution in 3 ml of dichloromethane. The reaction mixture is agitated at room temperature for 5 hours. Then the solvent is evaporated at reduced pressure (2 kPa) and the remainder is chromatographed on silicone gel with the following: acetylated methyl methyl methyl acetate (RMethyl methyl acetate) (50 mg/RMethyl methyl acetate) (50-50 mg/RMethyl acetate) = 28 mg/RMethyl acetate (RMethyl acetate) = 90 mg/RMethyl acetate) obtained at 90 °C.
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 the text of the communication:
Stage b) The chemical formula is based on the chemical formula of 3-[5-ethyl-6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[4-methoxy-benzenesulfonyl) alanine.
55.8 mg (0.086 mmoles) of 3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-(4-methoxybenzenesulfonyl) alaninate of (1,1-dimethyl) is agitated in 5 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-Acrylate 85-15-2-2). The toluene is mixed and the reaction is evaporated at pressure (2 kdt). The residue is dissolved into the minimum solution with a little dichloromethane diethylamide (PaPa) on a 5% solution of methanol. The resulting product is expressed as 85 mg of diethyl methanol (PaPa) in the filtered solution.
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 which have adopted the measures:
General method of preparation of sulphonamides
Stage a)
A 150 mg (0.31 mmol) mixture of 3-[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphtiridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]alanate of (1,1-dimethylethyl) in solution in 6 ml of dichloromethane and 650 μl of pyridine is mixed with 0.31 mmol (mass mx) of sulphonyl chloride in solution in 3 ml of dichloromethane. The reaction mixture is agitated at room temperature for 5 hours. The solvent is then evaporated at reduced pressure (2 kPa) and the following residue is chromatised on silicate with the electrolyte: acetyl-methyl-methyl-methyl-acetate/methyl-methyl-methyl-methyl-methyl-acetate 50-50/95/50/5). The result is a mass of 90-10.5 mO.
The following is the list of active substances in the active substance:
Stage b)
A mi-mass of 3-[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-(R-sulfonyl) alaninate of (1,1-dimethyl) is stirred in 5 ml of dichloromethane with 0.5 ml of trifluoroacetic acid at room temperature until the starting product disappears into CCM (silica gel, eluting: CH2Cl2-MeOH-H2O-OHAc 85-15-2). Toluene is added and the mixture is evaporated at reduced pressure (2 kPa). The residue is evaporated in dichloromethane soil with a minimum mass of diethyl methanol. The product is then filtered to obtain a small amount of mz.
The following is the list of active substances in the active substance:
Exemple 21 47,1 30 22 672 0,61
Exemple 22 40,4 38,7 29 640 0,63
Exemple 23 59,3 48 24 636 0,69
Exemple 24 55,1 18,4 10 622-624 0,65
Exemple 25 65,6 57,6 28 656-658 0,67
Exemple 26 78,6 70 32 698 0,67
Exemple 27 73,0 49,3 23 680 0,67
Exemple 29 76,1 63,4 30 690 0,63
Exemple 30 81,7 21,4 10 708 0,63
Exemple 31 62,7 56,3 28 647 0,65
Exemple 21 615,76 843,76 20,8 616 0,4
Exemple 22 583,69 811,69 31,2 584 0,33
Exemple 23 579,73 807,73 45,4 580 0,3
Exemple 24 566,13 794,13 11,6 566-568 0,26
Exemple 25 600,14 828,14 58,3 600-601 0,3
Exemple 26 641,8 869,8 56,6 642 0,37
Exemple 27 623,74 851,74 41,2 624 0,37
Exemple 29 633,7 861,7 59,8 634 0,33
Exemple 30 651,79 879,79 48,5 652 0,35
Exemple 31 590,71 818,71 28 591 0,26
Example 32 The chemical formula is based on the chemical formula of 3-[5-ethyl-6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[1-naphthalenesulfonyl) alaninate of (1,1-dimethylethyl).
A mixture of 239 mg (0.49 mmoles) of 3-[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino] (1,1-dimethylethyl) alanine, 113 mg (0.5 mmoles) of 1-naphthalamenesulfonyl chloride and 0.104 ml (0.75 mmoles) of trielamine in 50 ml of tetrahydrofuran is agitated at room temperature for 5 hours. The reaction mixture is evaporated dry under reduced pressure (2 kPa) and the residue is re-evaporated by ethyl acetate, water and a saturated sodium bicarbonate solution. The phase is separated in the form of white, organic sulfate and evaporated with aluminum sulfate. The residue is evaporated at a temperature of 220 to 75 mg (R) at a temperature of 0 to 100 kPa.
The following is the list of active substances in the active substance:
The following is the list of active substances which are to be classified in the additive:
The following substances are to be classified as substances with a potential for the introduction of a substance into the food chain: 1H-RMN (CDCl3): δ 1,02 (t, 3H, CH2CH3); 1,15 (s, 9H, tBu); 1,81 to 2,03 ((m, 6H, CH2-CH-CH2 and_CH2-CH2-CH2-NH); 2,23 and 2,31 (2q, 2H, CH2-CH3); 2,67 (t, 1H, CH2-CH-CH2); 2,72 (t, 2H, CH2-CH2-CH2-NH); 2,93 and 3,56 (tl and dl, 4H, CH2-CH2-N-CH2-CH2); 3,43 (m, 2H, CH2-CH2-CH2-NH); 3,66 and 3,76 (2m, 2H, NH-CH2-CH2-NH-nap); 3,97 (m, 1H, CH2-CH2-SO); 4,73 (t, 1H, 1H, CH2-CH2-NH2); 6,2 (t, 1H, 1H, CH2-CH2-CH2-NH2); 1,1, 2,1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 1, 2, 1, 1, 2, 1, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 2, 2, 2, 2, 1, 2, 2, 2, 2, 2, 1, 2, 2, 1, 2, 2, 2, 2, 1, 2, 2, 2, 2, 1, 2, 2, 2, 2, 1, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2,
The following are the active substances: SM 672 (MH+); 426 (616-SOOnapht+); 670- (M-H).
[α]D: +3,3 (1% CHCl3)
The chemical formula is based on the following formula:
220 mg (0.33 mmoles) of 3-[[5-ethyl-6-[4-]], 1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N- ((1-naphthalenesulfonyl) alaninate of (1,1-dimethyl) is agitated in 20 ml of dichloromethane with 2 ml of trifluoroacetic acid at room temperature until the starting product disappears into CCM (silicone, emitting CH2Cl2-OHMe-H2O-OHAc-10-1-90-1). Toluene is precipitated and the mixture evaporates under dry pressure (2 kPa). The residue is reduced to the solid form of dichloromethane with a minimum of a small amount of diethyl methacrylate. The product is then expressed in a pure white solution (R = 82 mg) of methacrylate.
The following is the list of active substances in the active substance:
It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]
The following substances are considered to be toxic if they are used in the manufacture of the active substance: 1H-RMN (DMSO-d6): δ 0,87 (t, 3H, CH2-CH3); 1,77 (m, 6H, CH2-CH-CH2, CH2-CH2-CH2-NH); 2,05 (q, 1H, CH2-CH3); 2,16 (q, 1H, CH2-CH3); 2,62 (t, 2H, CH2-CH2-CH2-NH); 2,73 and 3,50 (2m, 4H, CH2-CH2-N-CH2-CH2); 2,80 (m, 1H, CH2-CH2-CH2); 3,20 (m, 2H, CH2-CH2-CH2-NH); 3,50 (m, 2H, CH2-CH2-CH2-NH); 3,66 and 3,76 (2m, 2H, CH2-CH2-CH2-NH); 3,97 (t, 1H, CH2-CH2-NH); 6,26 (m, 1H2-CH2-CH2-CH2-CH2-CH2-NH); 1,28 (m, 1H2-CH2-CH2-N-CH2-CH2-CH2-CH2-CH2-CH2-CH2); 1,28 (m, 1H2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2); 1,8, 1H1-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-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-
The following are the active substances:
[αD] : (0,4 % CH3OH) : +7,0
Example 33 The chemical formula is based on the chemical formula of 3-[5-ethyl-6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-(2-pyridinyl) alaninate of (1,1-dimethylethyl).
A 240 mg (0.50 mmole) mixture of 3-[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]alaninate (1,1-dimethylethyl) and 3 ml of 2-fluoropyridine is agitated for 24 hours at reflux. 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 under soil vaporization (2 kPa). The residue is evaporated on alumina by mixing with ethyl chloride acetate at reduced pressure (2 kPa). The resulting product is 13 mg of methyl chloride-methyl-ethanol (R-methyl) - 80 mg of oncholate (R-methyl) = 13-14%.
The following is the list of active substances in the active substance:
The following is the list of the Member States which have adopted the new rules:
The chemical formula is based on the following formula:
13 mg (0.023 mmole) of 3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-(2-pyridinyl) alaninate of (1,1-dimethyl) is agitated in 2 ml of dichloromethane with 0.2 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 then agitated and the mixture evaporates in a dry reaction at reduced pressure (2 kPa). The residue is dissolved in soil of dichloromethane to a minimum of diethyl diethyl. The product is expressed as a dry powder (Radiol) of 76 mg/L. The product is expressed as a solid.
The following is the list of active substances in the active substance:
The following is a list of the categories of products:
Example 34 The chemical formula is based on the chemical formula of 3-[5-ethyl-6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[2-benzothiazolyl) alaninate of (1,1-dimethylethyl).
A 200 mg (0.42 mmole) mixture of 3-[5-ethyl-6-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]alaninate (1,1-dimethylethyl) and 90 mg (0.6 mmole) 2-fluorobenzothiazol in 5 ml of pyridine is agitated for 2 hours at 100 °C. The reaction mixture is evaporated dry and then separated 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 dried under water, dried on magnesium sulfate and evaporated with solvent (2 kPa) with the pressure inverse. The residue is reduced once on the chromate gradient to a 100 - 80 mg/L by a second step of 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 - 0 -
The following is the list of active substances:
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 1,06 (t, 3H, CH2CH3); 1,49 (s, 9H, tBu); 1,77 to 2,01 ((m, 6H, CH2-CH-CH2 and CH2-CH2-CH2-NH); 2,41 (q, 2H, CH2-CH3); 2,61 (t, 1H, CH2-CH-CH2); 2,72 (t, 2H, CH2-CH2-CH2-NH); 2,92 and 3,51 (ql and tl, 4H, CH2-CH2-N-CH2-CH2); 3,42 (m, 2H, CH2-CH2-CH2-NH); 3,95 and 4,09 (2m, 2H, NH-CH2-CH2-NH); 4,88 (m, 1H, NH-CH2-CH2-NH); 4,98 and 5,63 (m, t, 2H, NH-CH2-CH2-NH and NH-CH2-CH2-NH); 6,41 and 4,2 (m, 1, 2, 2, 2, 2, 2, 3, 7, 12, 7, 12, 12, 12, 12, 13, 13, 13, 13, 13, 13, 13, 13, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 14, 15, 14, 15, 15, 15, 16, 16, 16, 16, 16, 16, 16, 16, 16, 16, 16, 16, 16, 16, 16, 16, 16, 17, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, and 22, 22, 22, 22, 23, 23, 23, 23, 23, 23, 23, 23, 23, 23, 23, 23, 23, 23, 23, 23, 23, 23, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25,
The following are the types of the test: SM 615 (MH+); 559 (MH-tBu+); 613- (MH-).
The following is a list of the active substances that may be used in the preparation of the active substance:
45 mg (0.073 mmole) of 3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-(2-benzothiazolyl) alaninate of (1,1-dimethyl) is agitated in 10 ml of dichloromethane with 1 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 pre-filtered and the mixture evaporates at reduced pressure (2 kPa). The residue is then dissolved in the dichloromethane soil with a minimum of a small amount of diethyl methacrylate. The product is expressed as a white solid (Radiopropyl) of 60 mg.
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 1,15 (t, 3H, CH2-CH3); 1,75 to 2,07 ((m, 6H, CH2-CH-CH2, CH2-CH2-CH2-NH); 2,51 (q, 1H, CH2-CH3); 2,76 (tl, 2H, CH2-CH2-CH2); 2,96 (m, 1H, CH2-CH2-CH2); 3,20 and 3,73 (2m, 4H, CH2-CH2-CH2-CH2); 3,51 (m, 2H, CH2-CH2-CH2-NH); 4,23 (m, 2H, NH-CH2-CH-NH); 4,67 (m, 1H, NH-CH2-CH2-NH); 6,38 and 7,352d, H, 2H, naphidine); 7,20, 7,35, 7,47 and 7,54 (t, masked, H, dl, 7,35, and 7,34 dl, dl, and dl, 2,05, and dl, 2,05, and dl, 2,05, and dl, 2,05, and dl, 2,05, and dl, 2,05, and dl, 2,05, and dl, 2,05, and dl, 2,05, and dl, 2,05, and dl, 2,05, and dl, 2,05, and dl, 2,05, and dl, 2,05, and dl, 2,05, and dl, 2,05, and dl, 2,05, and dl, 2,05, and dl, 2,05, and dl, and dl, and dl, and dl, respectively; 2,05, and dl, and dl, and dl, and dl, and dl, and dl, respectively; 2,05, and dl, and dl, and dl, and dl, and dl, respectively; 2,0 and dl, and dl, and dl, and dl, respectively, and dl, and dl, and dl, and dl, respectively, and dl, and dl, respectively, and dl, and dl, and dl, respectively, and dl, and dl, respectively, and dl, and dl, and dl, respectively, and dl, and dl, and dl, and dl, and dl, respectivly, and dl, and dl, and dl, respectivly, and dl
The following is a list of the types of products:
Example 35
By operating by analogy with example 34, 3-[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]alanine of (1,1-dimethylethyl) is prepared to form 3-[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[2-(4-methoxybenzymidazolyl]alanine 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 classified as substances with a potential for the introduction of chemicals into the environment: 1H-RMN (CDCl3): δ 1,12 (m, 3H, CH2CH3); 1,65 to 2,07 (m, 6H, CH2-CH-CH2 and _CH2-CH2-CH2-NH); 2,47 (m, 2H, CH2-CH2-NH3); 2,74 (m, 2H, CH2-CH2-CH2-NH); 2,92 (m, 1H, CH2-CH-CH2); 3,17 and 3,73 (2m, 4H, CH2-CH2-CH2-N-CH2-CH2); 3,52 (m, 2H, CH2-CH2-CH2-NH); 3,79 (s, 1H, OCH3); 4,18 (m, 1H, 2H, NH-CH2-CH-NH); 4,81 (m, 1H, NH-CH2-CH-NH); 6,35 and 7,36 (cd, 2H, naphthyridine); 6,72 and 7,18 (d, 2,CH-CH2-CH2-CH2-CH2); 2,72 (cd, 2,CH-CH2-CH2-CH2-CH2-CH2-CH2); 2,73 (cd, 2,CH-CH2-CH2-CH2-CH2-CH2-CH3); 2,84 (cd, 2,78 and 2,78 (cd, 1,CH-CH3-CH3-CH3-CH3)); 3,8 (cd, 1,78 (cd, 1,78 and 2,CH-CH3-CH3-CH3-CH3-CH3-CH3-CH3-CH3-CH3); 3,8 (c)); 3,8 (cd, 7,84 (cd, 1,78 and 2,78 (cd, CH-CH3-CH3-CH3-CH3-CH3-CH3-CH3-CH3-CH3-CH3-CH3-CH3); 7,78 (c)); 3,8 (cd, 7,8 (cd, 1,78 (cd, CH3-CH3-CH3-CH3-CH3-CH3-CH3-CH3-CH3-CH3); 7,83); 7,83); 7,8 (c) 3,8 (c) 3,8 (c) 3,8 (c) 3,8 (c) 3,8 (c) 3,8 (c) 3,8 (c) 3,8 (c) 3,8 (
The following is a list of the types of products:
Example 36 The following two methods are used to determine the concentration of terbutyl-propinylamino-propylate in the feed additive:
170 mg (0.30 mmole) of 3-[5-methyl-6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[[[phenylmethylmethoxy) carbonyl]alanine, 150 mg (1.0 mmole) of terbutyl L-alanate, 66 mg (0.48 mmole) of 1-hydroxybenzotriazole, 90 mg (0.48 mmole) of 1-[3-dimethylmetholamino) propyl chloride, 0.015 ml (0.135 mmole) of N-methylmormormorpholine and 0.2 ml (0.10 mmole) of triethylmetholamine are agitated for 24 hours at room temperature. The reaction is carried out in a saturated phase with a white solution of sodium bicarbonate and a solution of sodium methylamide (260 mg) is reduced to a dry solution of sodium chloride and sodium chloride (250 kPa) in a saturated phase.
The following is the list of active substances in the active substance:
The following is a list of the Member States which have adopted the new rules:
The chemical composition of the compound is determined by the following equation:
120 mg (0.179 mmoles) of 2-(2-benzyloxycarbonylamino-3-{5-methyl-6-[4-(5,6,7,8-tetrahydro-[1,8] naphtyridin-2-yl) -pipéridin-1-y1]-pyrimidine-4-ylamino}-propinylamino) -terbutyl propionate is agitated in 5 ml of dichloromethane with 1 ml of trifluoroacetic acid at room temperature until the starting product disappears into CCM (silica gel, emitting CH2Cl2-OHMe-H2O-AcOH-10 90-1-1). The toluene is evaporated and the mixture is reduced to dry (2 kPa) in a pressure reaction. The residue is then reduced to the solid form of dichloromethane with a minimum of white diethyl methacrylate. The product is then expressed in 63 mg of thiophenol (PaPa) and then reduced to a 95% thiophenol (Pa) The product is expressed in a solid form.
The following is the list of active substances in the active substance:
The following is the list of the Member States which have adopted the new rules:
Example 37 The following two methods are used to determine the concentration of terbutyl-propinylamino-propylate in the feed additive:
80 mg (0.15 mmole) of 3-[5-ethyl-6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-4-pyrimidinyl]amino]-N-[[[phenylmethylmethoxy) carbonyl]alanine, 32 mg (0.20 mmole) of terbutyl L-alanate, 22 mg (0.16 mmole) of 1-hydroxybenzotriazole, 30 mg (0.16 mmole) of 1-[3-dimethylmethyl) propyl chloride, 0.050 ml (0.45 mmole) of N-methylmorpholine, 0.070 ml (0.50 mmole) of dimethyl silicamide triformate for 24 hours at room temperature, 22 mg (0.16 mmole) of 1-hydroxybenzotriazole, 30 mg (0.16 mmole) of 1-[3-dimethylmethyl) propyl chloride, 3-methyl carbodilimide, 0.050 ml (0.45 mmole) of N-methylphyrimidinyl-N- (0.070 mmol) and 50 ml (0.50 mmole) of dimethyl silicamide triformate are mixed together for 24 hours at room temperature. The product is evaporated in a saturated phase with a white solution of sodium chloride and reduced to a 50-50 mg (25-50 mmol) sodium chloride by a solution of sodium chloride and sodium methyde (Pa-methyl-methyl) is reduced to a solid solution of sodium chloride and sodium sulphate (25-methyl-methyl-methyl-methyl-methyl chloride) at a solution of sodium (25.0-5-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl) is reduced to a solution of sodium (25.0 and reduced to a sodium chloride of sodium-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-meth
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 introduction of chemicals into the environment: 1H-RMN (CDCl3): δ 0,91 (t, 3H, CH2-CH3); 1,38 (d, 3H, CONH-CH(CH3)-CO); 1,48 (s, 9H, tBu); 1,79 to 2,07 (m, 6H, CH2-CH2-NH, CH2-CH-CH2); 2,49 (m, 2H, CH2-CH3); 2,66 (m, 1H, CH2-CH-CH2); 2,73 (t, 2H, CH2-CH2-CH2-NH); 2,97 and 3,63 (2m, 4H, CH2-CH2-N-CH2-CH2); 3,42 (m, 2H, CH2-CH2-CH2-NH); 3,73 and 4,14 (2m, 2H, CH2-CH2-NH); 4,31 (m, 1H, CH2-CH2-NH); 4,44 (m, 1H, CH2-CH2-CH2); 4,14 (m, 1H, CH2-CH2-CH2-CH2); 5,14 (m, 1H, CH2-CH2-CH2-CH2); 7,29 (m, 2, 5, 2, 2, 2, 3, 5, 2, 5, 2, 5, 2, 5, 2, 5, 2, 5, 2, 5, 2, 5, 2, 5, 2, 5, 2, 5, 2, 5, 2, 5, 2, 5, 2, 5, 2, 5, 2, 5, 2, 5, 2, 5, 5, 5, 2, 7, 2, 5, 2, 5, 2, 5, 5, 2, 5, 5, 5, 5, 5, 2, 5, 5, 5, 5, 5, 5, 6, 7, 2, 2, 2, 5, 5, 2, 5, 5, 5, 5, 5, 6, 7, 2, 2, 2, 2, 5, 5, 5, 5, 5, 5, 6, 7, 2, 2, 2, 2, 2, 5, 5, 5, 5, 5, 5, 5, 6, 7, 2, 2, 2, 2, 5, 5, 5, 5, 5, 5, 6, 7, 2, 5, 5, 6, 2, 2, 2, 5, 5, 5, 5, 5, 6, 7, 2, 2, 2, 2, 5, 5, 5, 5, 5, 5, 5, 5, 5, 6, 7, 2, 2, 2, 2, 5, 5, 5, 5, 5, 5, 6, 7, 2, 2, 2, 2, 2, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 6, 5, 6, 7, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 6, 5, 6, 5, 6, 7, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2,
The following is a list of the Member States which have adopted the new rules:
The chemical composition of the compound is determined by the following equation:
50 mg (0.073 mmoles) of 2-(2-benzyloxycarbonylamino-3-{5-ethyl-6-[4-(5,6,7,8-tetrahydro-[1,8] naphtyridin-2-yl) -pipéridin-1-yl]-pyrimidine-4-ylamino}-propinylamino) -terbutyl propionate is agitated in 5 ml of dichloromethane with 0.5 ml of trifluoroacetic acid at room temperature until the starting product disappears into CCM (silica gel, emitting CH2Cl2-OHMe-H2O-AcOH-10 90-1-1). The toluene is evaporated and the mixture evaporates under pressure at a pressure of 2 kPa. The residue is reduced to the ground in the form of dichloromethane with a minimum of a small amount of diethyl methacrylate. The product is then expressed as 53 mg of thiophenol (Pa) and then reduced to a solid form of 85 mg of diethyl methacrylate.
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 introduction of chemicals into the food chain: 1H-RMN (CDCl3): δ 1,16 (t, 3H, CH2-CH3); 1,41 (d, 3H, CONH-CH2-CH(CH3)-CO); 1,80 to 2,10 (m, 6H, CH2-CH2-CH2-NH, CH2-CH2-CH2); 2,48 (m, 2H, CH2-CH2-CH3); 2,79 (m, 2H, CH2-CH2-CH2-NH); 3,00 (tl, 1H, CH2-CH-CH2); 3,28 and 3,84 (2m, 4H, CH2-CH2-N-CH2-CH2); 3,52 (m, 2H, CH2-CH2-CH2-NH); 3,78 and 4,13 (2m, 2H, NH-CH2-NH); 4,46 (m, 1H, CH2-CH2-NH); 4,59 (m, 1H, CH2-CH2-CH3); 5,05 (m, 2H, CH2-CH2-CH2-CH2-NH); 7,38 (m, 2, 4, 8, 8, 9, 10, 8, 9, 10, 9, 10, 10, 10, 11, 12, 12, 12, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 14, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 16, 16, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, 21, and 22, 22, 22, 22, 22, 22, 22, 22, 22, 22, 22, 22, 22, 23, 23, 23, 23, 23, 23, 23, 23, 23, 23, 23, 23, 23, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 24, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, and 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25,
The following is the list of the Member States which have adopted the new rules:
Example 38 1°) Synthesis of tert-butyl 4-hydroxy-1-pipéridinecarboxylate 1:
1 g (5 mmol) of tert-butyl 4-oxo-1-pipéridinecarboxylate (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 is evaporated at reduced pressure (2 kPa) and then the reaction mixture is mixed with ethyl acetate. The organic phase of the aqueous phase is mixed. This extraction is repeated and then the organic phases are collected to reduce the water to dry.
The following is the list of active substances:
The test chemical is used to determine the concentration of the active substance in the test chemical.
2°) Synthesis of tert-butyl 4-iodo-1-pipéridine carboxylate 2:
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 on MgSO4, and the aqueous phase of silicon thiosulfate is filtered and evaporated (2 kPa). On chromatography on acetonite, the diethyl ethanol dichloromethane is reduced to 90 kPa.
1.1 g (rdt = 70%) of colourless oil is recovered.
The following is the list of active substances:
The following equation is used for the determination of the concentration of 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 marketed by Aldrich is placed in 30 ml of toluene. 0.3 ml of acetic acid and 0.8 ml (6.78 mmol) of acetonylacetone marketed by Aldrich are added. Toluene is heated at the reflux for 5 hours.
1 g (Rdt = 90%) of yellow powder is obtained.
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:
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 4:
Suspend 284 mg (4.34 mmol) of electrolytic zinc in an argon atmosphere and add 0.033 ml of 1-2-dibromoethane and 1 ml of tetrahydrofuran.
This reaction mixture is stirred for 45 minutes at room temperature and added to a solution containing 30 mg (0.032 mmol) of trisdibenzylidene dipalladium acetone (purified by Aldrich) and 30 mg (0.13 mmol) of trisylphosphatylphosphate (purified by LANTERCAS). 1 g (4.2 mmol) of 3 solubilis solubilis is then added to 10 ml of tetrahydrofuran. The reaction mixture is left in the saturated phase for 60 minutes. The product is then recovered in a liquid solution of sodium acetate and clarinethyl acetate (PaCl) at a temperature of between 350 °C and 2 °C. The product is then reduced to a saturated phase with a liquid solution of sodium acetate and clarinethyl acetate (PaCl) in the presence of water.
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:
5°) Synthesis of 6- (2,5-dimethyl-pyrrol-1-yl) -1,2,3,4,5,6'-hexahydro-[2,4']bipyridinyl
The first dichloromethane is evaporated at reduced pressure (2 kPa). The resulting residue is taken back to water, basified to pH = 10 with concentrated ammonia and the product is extracted to dichloromethane. The organic phase is dried on magnesium sulfate and the dichloromethane is evaporated at reduced pressure (2 kPa). 220 mg (Rdt = 92%) of yellow oil is recovered.
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:
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 5 is dissolved in 2 ml of dimethylacetamide, to which 140 mg (0.860 mmol) of SPECS-marketed 4,6-dichloro-5-methyl-pyrimidine 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 to room temperature and dimethylacetamide is evaporated under reduced pressure (0.2 kPa). The residue is re-converted to ethyl acetate and washed with water. The aqueous phase is extracted 2 times with ethyl acetate, the organic phases are collected and dried on magnesium sulfate.
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:
7°) Synthesis of 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}-propionic acid tert-butyl ester 7:
The 330 mg (0.866 mmol) of the previous stage is soluble in 5 ml of dimethoxyethane. 286 mg (1 mmol) of 3-amino-N-[phenylemethoxy) carbonyl] alanine (1,1-dimethylethyl) (1,1-dimethylethyl) alanine (prepared according to J. Med. Chem. (2001), 44 (((8), 1158-1176), 184 mg (1.21 mmol) of cesium fluoride, 54 mg (10% mol) of rac-2'-bisphenylphosphino-1,2'-Brichthylethyl obtained by aqueous purification, and 40 mg (1 mmol) of trisodium ondiphenyl sulphate (Alddiphenyl sulphate) (1,5%) obtained by heating the water, are added successively. This is mixed with sodium ondiphenyl sulphate under a saturated heating heater. This is washed at 100°C for 18 hours. The remaining residue is further washed with 54 mg (10%) of trisodium ondiphenyl sulphate (2,2-bisphenylphenylenyl sulphate) and ondiphenyl sulphate (1,2-Brichthylethylethyl sulphate) (1,2-Brichthylethylethyl sulphate) and ondiphenyl sulphate of magnesium is recovered at a temperature of 200°C. This is obtained by adding ondiphenyl sulphate of sulphate and dimethyl sulphate to the aqueous solution of the sodium ondiphenyl sulphate.
The following is the list of active substances:
The following substances are to be classified as aromatic substances: -H-RMN (CDCl3): δ 1,50 (s,9H, tBu); 1,97 (s,3H, CH3); 2,02 to 2,10 (m, 4H, -CH2-CH2-N-CH2-CH2-CH2-CH2-); 2,18 (s, 6H, -CH3C=CH-CH-CH=CCH3-); 3,20 and 3,78 (m, 4H, -CH2-CH2-N-CH2-CH2-); 3,00 (m, 1H, CH2-CH2-N-CH2-); 3,85 to 4,00 (m,2H, NH-CH2-CHCOOtBuNH); 4,47 (m, 1,H, NH-CH2Ot-COBuNH); 5,122 (m, 2H, -CH3-CH=CH3-CH2-); 5,92 (m, 2H, -CH3C=CH3-CH3-); 6,12 (m, 7,1d); 7,13 (m, 7,1d); or 7,13 (m, 7,1d); or 7,13 (m, 7,1d); or 7,13 (m, 7,1d); HH, 7,13 (m, 7,1d; 7,13 (m, 1,13; 7,13; 7,13; 7,13; 7,13; 7,13; 7,13; 8,13; 8,13; 8,13; 8,13; 8,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,13; 13,14; 13,14; 13,14; 13,
The following information is provided for the purpose of this Decision:
8°) Synthesis of 3-[6-(6-Amino-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-1'-yl)-5-methyl-pyrimidine-4-ylamino]-2-benzyloxycarbonylamino-propionic acid tert-butyl ester 8:
100 mg (0.15 mmol) of 7 is dissolved in 3 ml of ethanol and 0.3 ml of water. 50 mg (0.75 mmol) of hydroxylamine hydrochloride marketed as ACROS is added and heated for 18 h at 90°C. The solvents are evaporated at reduced pressure (2 kPa) and the crude residue is purified by silicagel chromatography by eluting with a mixture of CH2Cl2/MeOH 90:10. 30 mg (36%) of the expected product is obtained as a colourless resin.
The following is the list of active substances:
The chemical composition of the compound is determined by the following equation:
The following is added to the list of substances:
9°) Synthesis of 3-[6-(6-Amino-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-1'-yl)-5-methyl-pyrimidine-4-ylamino]-2-benzyloxycarbonylamino-propionic acid 9':
30 mg (0.053 mmol) of 8 prepared beforehand are dissolved in 2 ml of dichloromethane and 0.2 ml of trifluoroacetic acid. The product is agitated for 9 h at room temperature. Toluene is added and evaporated dry under reduced pressure (((2 kPa).
10 mg (Rdt = 37%) of the expected product is recovered as a beige solid in a mixture of CH2Cl2/isopropyl ether.
The following is the list of active substances:
The following substances are considered to be toxic if they are present in the food: 1H-RMN (DMSO): δ 1,90 s,3H, CH3); 1,80 to 1,85 (m, 4H, -CH2-CH2-N-CH2-CH2-CH2-); partially water-masked DMSO: (((4H, -CH2-CH2-N-CH2-CH2-) and (2H, NH-CH2-CHCOBuNH-); 2,80,(m, 1H, CH-CH2-CH2-N-CH2-); 4,15 m, CH1-CH2-CH-COBuNH-); 5,02 H, O-CH2-Phenyl); 6,27 (d, 1H, H3 or H5); 6,40 (d, 1H, H3 or H5); 6,52 m, 1H, H4); 7,5 m, CH-CH2-CH2-N-H; 8,10 s, CH2-CH-N=;
The following are the active substances: SM 506 (MH+), 372 (MH-CO-O-Benzyl+).
Example 39 The active substance is a substance that is capable of being used as a solvent for the production of organic compounds. Stage a) Synthesis of the acid ((4-aminomethylpipperidine)-1-carboxylate of ((1,1-dimethylethyl).
A 10 g (87.5 mmoles) solution of 4-aminomethylpipperidine (marketed by Aldrich) is added to 110 ml of toluene in a nitrogen stream, 9 mL of benzaldehyde (87.5 mmoles) is added, and the mixture is heated to 120 °C (in the presence of a dean-stark) for 8 hours. The reaction mixture is allowed to return to room temperature and then 21 g (96.25 mmoles) of Di-tert-butyl dicarbonate is added at 0 °C for 1⁄4 hour. The mixture is agitated in the presence of nitrogen overnight. The mixture is then mixed in a dry reaction at reduced pressure (2 kPa) and the oil is re-heated by 115 mL of KOHOHO once every two hours and is re-heated twice during the 1 kN phase, and is then re-activated. The resulting NaCl is then reduced to water by the addition of hydrated chlorophyll chloride (NaCl) and 7 g/m3 of sodium chloride.
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 is a list of the substances which are to be used:
Stage b) Synthesis of the acid ((4- ((2-aminomethylpyridinyl) -pipperidine)-1-carboxylate of (1,1-dimethylethyl).
A mixture of 2.18 g (10.19 mmoles) of 4-aminomethylpipperidine-1-carboxylate of acid in 5 ml of 2-fluoropyridine is brought to the reflux for 6 hours. After returning to room temperature, the solvent is evaporated at reduced pressure (2 kPa) and the yellow solid residue is taken up by a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is decanted, washed with a saturated solution of sodium chloride dried on magnesium sulphate and then dried at pressure (1,3 kPa) in silicon chromite. The residue is evaporated with the evaporator: ethyl acetate-acetate.
CCM: Rf = 0,4 (silicagel, electrolyte: ethylcyclohexane acetate 70-30)
The following substances are to be classified as substances with a specific chemical composition:
The following is a list of the active substances:
Stage c) Synthesis of 2- (4-methylpipperidinyl) aminopyridine.
1.09 g (3.74 mmoles) of 4- ((2-aminomethylpyridinyl) -pipperidine) -acid-1-carboxylate of (1,1-dimethylethyl) is agitated in 25 ml of dichloromethane with 6 ml of trifluoroacetic acid at room temperature until the starting product disappears into CCM (silicagel, eluting: ethyl acetate 100). 20 ml of toluene is added and the mixture is drawn at reduced dry pressure (2 kPa). The residue is taken up with a mixture of methyl chloride and a solid aqueous solution of sodium hydroxide at 2 N. The organic phase is washed, decanted with a saturated solution of sodium chloride, sodium sulphate and possibly magnesium diopropane. The product is reduced to a slightly condensed dry pressure (2 kPa) and reduced to a slightly condensed solution of pentropyl (2 kPa) (2 kPa).
The following is the list of active substances in the active substance:
The method of analysis is based on the following equations:
The following is a list of the Member States of the European Union:
Stage (d) The chemical formula is based on the chemical formula of 4-bromo-5-ethyl-6-[4-aminomethyl-2-pyridinyl)-1-pipéridinyl]pyrimidine.
Add 1.8 ml of diisopropylethilamine to a mixture of 657 mg (2.47 mmoles) of 4.6-dibromo-5-ethylpyrimidine and 450 mg (2.35 mmoles) of 2-(4-methylpipperidinyl) aminopyridine in 55 ml N,N-dimethylacetamide. Heat this mixture at 110°C for 4 hours. Then remove the solvent at reduced pressure (0.2 kPa) and take up the residue by a mixture of ethyl acetate, water and a saturated sodium bicarbonate solution. The next organic phase is decantation, dried on magnesium sulphate at high pressure (2 747 kPa). The martinised chromate is condensed on aluminium acetate with a gradient of 84 kPa. The resulting beethanol is obtained at a concentration of 80 mg/L.
The test chemical is a chemical that is used to produce a specific chemical.
The following substances are considered to be toxic if they are used as a source of toxicity: 1H-RMN (CDCl3): δ 1,29 (t, 3H, CH2-CH3); 1,42 and 1,9 (2m, 5H, N-CH2-CH2-CH2-CH2); 2,70 (q, 2H, CH2-CH3); 2,95 and 3,88 (2m, 4H, N-CH2-CH2-CH2-CH2); 3,27 (m, 2H, CH-CH2-NH); 4,81 (m, 1H, NH mobile); 6,42 (m, 1H, CH=CH pyridine); 6,60 (m, 1H, CH=CH pyridine); 7,46 (m, 1H, CH=CH pyridine); 8,09 (m, 1H, N-CH=CH); 8,31 (s, 1H, N=CH-N).
The following is the list of the Member States which have adopted the measures:
Stage e) Synthesis of 3-[5-ethyl-6-[4-aminomethyl-2-pyridinyl)-1-pipéridinyl]-4-pyrimidinylamino]-N-[[(phenylmethoxy) carbonyl]alanate from (1,1-dimethylethyl).
A mixture of 300 mg (0.79 mmoles) of 4-bromo-5-ethyl-6-[4-aminomethyl-2-pyridinyl)-1-pipperidinyl]pyrimidine, 282.5 mg (0.96 mmoles) of 3-amino-N-[phenylemethoxy) carbonyl]alaninate (1,1-dimethylethyl), 168.6 mg (1.11 mmoles) of cesium fluoride, 49.8 mg (0.08 mmoles) of trisdibenzyleneacetone (dipalladium) and 49.8 mg (0.08 mmoles) of 2-bisdiphenyl-phosphino) --1,1'-pinidine is cooled in water under 8 kPa of 1,4-dioxane for 7 hours. The mixture is then returned to the ambient temperature for a saturated phase of sodium bifluoride (0.08 mmol) and then reduced to a concentrated solution of magnesium (2 kPa) by means of a refrigerant.
The residue is first chromatographed on aluminium by electrolysis with the following gradient: 80-20% diisopropyl ethyl acetate ether to 100% ethyl acetate.
272 mg (Rdt = 58%) of expected product is obtained.
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 chemical composition of the compound is determined by the following equation:
The following is the list of substances which are to be classified in the Annex to this Regulation:
Stage f) Synthesis of 3-[5-ethyl-6-[4-aminomethyl-2-pyridinyl)-1-pipéridinyl]-4-pyrimidinylamino]-N-[phenylmethoxy) carbonyl]alanine, bis (trifluoroacetate) is also known as the 3-[5-ethyl-6-[4-aminomethyl-2-pyridinyl)-1-pipéridinyl]-4-pyrimidinylamino]-N-[[[[phenylmethoxy) carbonyl]alanine.
229 mg (0.39 mmoles) of 3-[5-ethyl-6-4- ((aminomethyl-2-pyridinyl) --1-pipéridinyl) -4-pyrimidinylamino]-N-[n-phenyl-dimethyl) carbonyl]alaninate of (1,1-dimethyl) is agitated in 7,5 ml of dichloromethane with 0.9 ml of trifluoroacetic acid at room temperature until the starting product disappears into CCM (silicagel, eluting: dichloromethane-methanol-water-acetic acid 90-10-1-1). At the end of the reaction, toluene is added to the reaction mixture under pressure in a dry onapomite solution (2 kPa). The residue is then reduced to a minimum of 38 kPa.
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 the list of the Member States which have adopted the new rules:
[α]D (CHCl3) = +1,88
Example 40 Stage a) Synthesis of the acid 4-[3-(4-methoxy-2-nitro-phenyl) -thioureidomethyl]-pipéridine-1-carboxylate of (1,1-dimethyl ethyl).
A mixture of 1 g (4.67 mo) of 4-aminomethylpipperidine (1,1-dimethylethyl) acid-1-carboxylate and 1.08 g (6.06 mo) of 4-methoxy-2-nitrophenyl isothiocyanate in 70 ml of tetrahydrofuran is agitated at room temperature with a nitrogen stream for 5 hours. The solvent is then evaporated at reduced pressure (2 kPa) and the residue is chromatographed on silicagel with the following eluting agent: ethylheptane acetate from 20-80 to 30-70 g. The result is 1.66 g (Rdt = 84%) of 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 as a source of pesticides:
The following is a list of the Member States that have adopted the new rules:
Stage b) Synthesis of 4-[(6-methoxy-2-aminomethylbenzimidazole) ]-pipéridine-1-carboxylate of (1,1-dimethylethyl).
A solution of 1.12 g (2.64 mmoles) of 4-[3-(4-methoxy-2-nitro-phenyl) -thioureidomethyl]-pipéridine-1-carboxylate (1,1-dimethylethyl) acid in 100 ml of acetic acid is mixed with a mixture of 2 g of activated zinc in a little acetic acid (the zinc is activated by heating with the heating gun).
The reaction mixture is agitated at room temperature for 15 hours. The solvent is then evaporated at reduced pressure (0.2 kPa) and the residue is taken up with a mixture of water, a saturated solution of sodium bicarbonate and ethyl acetate. The organic phase is settled, dried on magnesium sulfate and the solvent is eliminated by evaporation at reduced pressure (2 kPa). The residue is chromatographically treated on aluminum by graduating with the following gradient: 50-50% CH2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2OH/Cl2Cl2Cl2Cl2Cl2Cl2Cl2Cl2Cl2Cl2Cl2Cl2Cl2Cl2Cl2Cl2Cl2Cl2Cl2Cl2Cl2Cl2Cl2Cl
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 are the types of products: SM 361 (MH+); 305 (MH-tBu+); 261 (MH-COOtBu+).
Stage c) Synthesis of 4-methylbenzimidazole piperidine, trifluoroacetate.
918 mg (2.55 mmoles) of 4-[(6-methoxy-2-aminomethylbenzimidazole) ]-pipéridine-1-carboxylate (1,1-dimethylethyl) acid is agitated in 35 ml of dichloromethane with 6 ml of trifluoroacetic acid at room temperature until the starting product disappears into CCM (silicagel, eluting: dichloromethane-thanol-water-acetic acid 90-10-1-1). Toluene is then added and the mixture is evaporated at reduced pressure (2 kPa). 1.15 g of the expected product is obtained as a trifluoroacetic salt.
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 which have adopted the new rules:
Stage (d) The chemical composition of the compound is determined by the following equation:
In a monocol containing 356 mg (1.37 mmoles) of 4- ((methoxy-2-aminomethylbenzimidazole) piperidine, released from its salt, 35 ml of N,N-dimethylacetamide, 381.84 mg (1.43 mmoles) of 4.6-dibromo-5-ethylpyrimidine in solution are added to a monocol containing 356 mg (1.37 mmoles) of 4- ((methoxy-2-aminomethylbenzimidazole) piperidine, heated to 110 °C for 3 hours and then concentrated at reduced pressure (0.2 kPa). The resulting residue is taken up by a mixture of water, ethyl acetate from a saturated sodium bicarbonate solution. The organic phase is separated and re-extracted by silicomethyl acetate. The organic phenol-methyl acetate is evaporated on a 90-10 kPa solvent, which is produced by dissolving dichloromethane in magnesium sulphate (2-10 kPa) and chloromethane (2-10 kPa) in a solvent.
383 mg (Rdt = 63%) of expected product is obtained.
Preparation of 4- ((6-Methoxy-2-aminomethyl benzimidazole) piperidine in the form of free amine:
700 mg of 4- ((6-methoxy-2-aminomethylbenzimidazole) piperidine is removed from its salt by 6 mass equivalents of amberlyst A21 basic resin (R-NMe2 resin) in a mixture of CH2Cl2-MeOH-AcOEt 1-1-1 stirred for 30 minutes. The resin is washed and allowed to inflate for 20 minutes in this solvent mixture. This operation must be repeated 3 times for the total salt displacement. After filtration of the resin and evaporation of the solvents, 356 mg (1.37 moles) of 4- ((6-methoxy-2-aminomethylbenzimidazole) piperidine is obtained free.
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:
The following is the list of the Member States which have adopted the new rules:
Stage e) Synthesis of 4-bromo-5-ethyl-6-[4-(6-methoxy-2-aminomethyl-1-carboxylate from (1,1-dimethylethyl) benzimidazole)-1-pipéridinyl]pyrimidine.
The residue is then mixed with a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is siliconized, decanted on magnesium sulfate in the form of magnesium sulfate in the form of magnesium sulfate (2 kPa): the product is obtained by reacting with a 60-60% heptanol (RMN) heptanol (RN) at a pressure of 60-60 kPa. The product is obtained by separating the heptanol from the heptanol by a 60-60% heptanol (RN) heptanol (RN) heptanol (RN) at a pressure of 60-66 kPa.
The following is the list of active substances:
The following substances are considered to be toxic if they are administered as a single administration to a single patient: 1H-RMN (CDCL3): δ 1,30 (t, 6H, CH2-CH3); 1,47 and 1,96 (2m, 8H, N-CH2-CH2-CH2-CH2-CH2); 1,72 (2sl, 20H, tBu, N-CH2-CH2-CH2-CH2 ); 2,70 (q, 4H, CH2-CH3); 2,97 and 3,89(2m, 8H, N-CH2-CH2-CH2-CH2); 3,52 (m, 4H, CH-CH2-NH); 3,82 (s, 6H, OCH3); 6,62 and 6,82 and 7,31 and 7,46 (4d, 4H, CH=CH benzimidazole); 7,00 and 7,26 (2s, 2H, NH-C=CH-C-CH-O3); 8,31 (s, 2H, N-CH=N).
The Commission has not yet adopted a decision on the application of Article 5 of Regulation (EC) No 1224/2009.
Stage f) Synthesis of 3-[5-ethyl-6-[4-(6-methoxy-2-aminomethylbenzimidazole-1-carboxylate of (1,1-dimethylethyl))-1-pipéridinyl]-4-pyrimidinylamino]-N-[(phenylmethyoxy) carbonyl]alanate of (1,1-dimethylethyl).
A mixture of 136 mg (0.25 mmoles) of 4-Bromo-5-ethyl-6-[4-(6-methoxy-2-aminomethyl-1-carboxylate of (1,1-dimethyl) benzimidazole)-1-pipéridinyl]pyrimidine, 88,5 mg (0.30 mmoles) of 3-amino-N-[(phenylmethoxy) carbonyl]alaninate of (1,1-dimethyl), 53,2 mg (0.35 mmoles) of celium fluoride, 11,4 mg (0.012 mmoles) of trisodiethylbenzylidene acetone, 50-bisodiethylbenzylidene acetone) and 15,6 mg (0.025 mmoles) of 2-diphenyl-diphenylbenzylidene-1,1'-phosphospholates decomposes in 6 times the water: the residue is saturated for 1,2-diphenylbenzylidene during the first phase. The residue is reduced to a 50-50 mg (24-50 mg) kPa by the addition of sodium sulphate, followed by a 50-50 mg (24-50 kPa) sodium sulphate solution. The mixture is then cooled to a 50-50 kPa by the addition of sodium sulphate.
58 mg (Rdt = 30%) of expected product (as 2 regiosomers distinguished by NMR with a 50/50 ratio) is obtained.
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, as defined in the Annex to Regulation (EC) No 1907/2006, and as defined in 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 the assessment:
Stage g) Synthesis of 3-[5-ethyl-6-[4-(6-methoxy-2-aminomethyl benzimidazole)-1-pipéridinyl]-4-pyrimidinylamino]-N-[(phenylmethoxy) carbonyl]alanine, bis (trifluoroacetate) from the chemical compound is carried out.
58 mg (0.08 mmoles) of 3-[5-ethyl-6-[4-(6-methoxy-2-aminomethylbenzimidazole-1-carboxylate of (1,1-dimethyl))-1-pipéridinyl]-4-pyrimidinylamino]-N-[[[[phenylmethyl) carbonyl]alaninate of (1,1-dimethyl) is agitated in 2 ml of dichloromethane with 0,2 ml of trifluoroacetic acid at room temperature until the starting product disappears into CCM (silicagel, prefiltering: dichloromethane-methyl-ethyl-fluoroacetic acid under 90-10-1-1). At the end of the reaction, toluene is added to the solid reaction mixture and the remaining amorphous solution is reduced to dry powder in the form of a solution of diethyl (2 kPa). The product is then dissolved in a thin layer of dichloromethane (R) with a minimum of 16 mg of diethyl methacrylate (R) per cent.
The following is the list of active substances in the active substance:
The total number of samples of the test chemical is calculated by adding the following data: δ 1,12 (t, 3H, CH2-CH3); 1,49 and 1,95 (2m, 5H, N-CH2-CH2-CH2-CH2); 2,51 (q, 2H, CH2-CH3); 3,00 and 3,52 (2m, 4H, N-CH2-CH2-CH2-CH2); 3,39 (d, 2H, CH-CH2-NH); 3,77 and 4,01 (2m, 2H, NH-CH2-CH-NH) ;3,86 (s, 3H, OCH3); 4,56 (m, 1H, NH-CH2-CH-NH); 5,07 (m, 2H, O-CH2-Ph); 6,91 (d, 1H, CH=benzimidazole); 6,96 (s, 1H-CH-CH=C-CH-CH; 7,32 (m, 2H, CH=CH2, CH2-CH-NH); 6,20 (s, 6H=NH, 8, NH-CH); N-CH=N.
The following information shall be provided for the purpose of the assessment:
Example 41 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 agitated at room temperature for about 20 minutes, then 8.3 ml of diethyl methylmalonate is added drop by drop. The agitation is maintained for 3 hours. The methanol is then condensed under reduced pressure (2 kPa). The resulting crude is taken with water, cooled to 0 °C with white acid between pH 0.2 and 4.3 g (0.2 and 0.3 g) and left to dry. The product is then reduced to 3,2 kPa (Pa) and filtered in water.
The chemical composition of the product is determined by the following equation:
The test chemical is a chemical that is used to determine the concentration of a substance in a solution.
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 medium 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).
CCM: Rf = 0,9 (Silicagel, electrolyte: 100% ethyl acetate)
The following equation is used for the calculation of the concentration of the test chemical:
The Commission has not yet adopted a decision on the application of Article 108 (3) TFEU.
Synthesis of 6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-2,5-dimethyl-4-chloropyrimidine from the following:
In a monocol containing 2.95 g (13.5 mmoles) of 4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperin released from its salt, add 2 g (11.3 mmoles) of 4.6-dichloro-2,5-dimethylpyrimidine dissolved in 25 ml dimethylacetamide and 5 ml diisopropylethylamine. This mixture is heated to 130 °C for 4 hours and then concentrated in a dry vacuum. 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 acute phase is re-extracted from the saturated silicate. The residues are then regurgitated on a graduated basis with a solution of phenylacetate (95% sodium acetate) and obtained by reducing the concentration of the sodium sulphate (R2-55%) by a reducing step.
Preparation of naphthyridine as free amine:
8.3 g of naphthyridine is removed from its salt by 6 mass equivalents of amberlyst A21 basic resin (R-NMe2 resin) in a mixture of CH2Cl2/MeOH/AcOEt 1/1/1 and stirred for 30 minutes. The resin is washed and allowed to inflate for 20 minutes in this solvent mixture. This operation must be repeated 3 times to achieve total salt displacement.
After filtration of the resin and evaporation of the solvents, 2,95 g (13,5 mmoles) of free naphthyridine is obtained.
The following information is provided for the purpose of the analysis:
The substance is classified as a substance of very high concern in the Union for the assessment of the safety of the use of the active substance.
The following is a list of the Member States of the European Union:
The chemical formula is based on the chemical formula of 3-[6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-2,5-dimethyl-4-pyrimidinyl]amino]-N-[phenylmethhoxy) carbonyl]alaninate of (1,1-dimethylethyl).
A mixture of 2.2 g (6.15 mmoles) of 6-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-2,5-dimethyl-4-chloro-pyrimidine and 2.17 g (7.38 mmoles) of 3-amino-N[(phenylmethyl) carbonyl] alanine (1,1-dimethyl) alanine (prepared according to J. Med. Chem. (2001), 44(8), then 1158-1176), in the presence of 1.31 g (8.61 mmoles) of caesium fluoride, 383 mg (2,615 mmoles) of caesium fluoride,2'-phosphenol-2-chloro-pyrimidine)-1,1'-difluoride and 281 kdifluoride (0,730 mg) of ambien tribenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenzylbenThe organic phase is decanted and the aqueous phase is extracted to ethyl acetate. The organic phases are dried on magnesium sulphate and evaporated dry at reduced pressure (2 kPa). The residue is chromatographed on alumina with a gradient of isopropyl ether/ethyl acetate (50/50) - dichloromethane (50-50). The fractions containing the expected product are combined for a second purification on silicate acetate with an acetone gradient of ethyl-heptane-methenol 50-50-0 at 90-0-10. 550 mg (R = 15%) of the expected product is obtained.
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:
The following is a list of the Member States of the European Union:
Synthesis of the corresponding acid:
A mixture of 500 mg (0.81 mmoles) of 3-[6-[4-[1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-pipéridinyl]-2,5-dimethyl-4-pyrimidinyl]amino]-N-[[[1,2-phenylmethoxy) carbonyl]alanate and 5 ml of trifluoroacetic acid is stirred at room temperature in 30 ml of dichloromethane for 24 hours. Toluene is added and evaporated to dry the mixture. The residue is dissolved in the minimum of dichloromethane with a little methanol and then poured over diopropyl ether. The precipitate is filtered.
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 source of toxicity: 1H-RMN (CDCl3): δ 1,97 (m, 9H, NH-CH2-CH2-CH2, N-CH2-CH2-CH2, C=C-CH3); 2,54 (s, 3H, N=C-CH3); 2,78 (m, 2H, NH-CH2-CH2-CH2); 2,98 (m, 1H, N-CH2-CH2-CH2-CH2); 3,22 and 3,80 to 4,07 (2m, 6H, N-CH2-CH2-CH2, NH-CH2-CH-NH); 3,51 (m, 2H, NH-CH2-CH2-CH2); 4,45 (m, 1H, NH-CH2-CH-NH); 5,10 (s, 2H, O-CH2-CH2); 6,42 and 7,37 (2m, 3H, CH-CH2-CH2, naphthyridine; CH-CH2, NH-CH2-CH2-CH2); 7,32 (m, 5H, Ph, CH, PH, PH)
The following information is provided for the purpose of the assessment:
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 added per well and 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 (Antibody 4B12-HRP is diluted in an incubation buffer (50 mM TRIS pH 7.4; 0.5 % BSA; 0.05 % Tween 20; 1 mM MnCl2; 50 μM CaCl2; 50 μM MgCl2; 100 mM 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 = (BO+ Bmin)/2
BO = Maximum bonding in the absence of any product
Bmin = Minimum binding in the presence of the highest product concentration. - What?
1 3
2 160
3 3,1
4 5,1
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 to be thyroparathyroid-ectomised when serum Ca levels are below 80 mg/l. The PTH (1-34) of the rat (Bachem) is dissolved in 0.15M NaCl Cys.HCl 2 % and delivered by mini osmotic pumps (ALPET 2001ZD) at a dose of 200 mg/kg/mol. The pumps are introduced into the veins and the rats are administered intravenous TXT-filled TXT-filled Phthalamine at 2.5 mg/kg/l.
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: effet % = Calcémie produit - Calcémie PTH Calcémie PTH - Calcémie contrôle × 100
Products from examples 6, 9, 13 and 15 to 19 tested in the above method were active at doses ranging from 2x1 mg/kg to 2x10 mg/kg subcutaneously in rats.

Claims (21)

  1. The compounds of formula (I) in all their isomeric forms, alone or in mixture, as well as their physiologically acceptable addition salts, and their solvates, in which G represents R7R8N-C (=NR6)-NH-CO- Het-NH-CO-; Het-NH-CH2-; Het-, Het representing a monocyclic or polycyclic system, each ring being constituted by 4 to 10 aromatic or non aromatic members, the ring or at least one of the rings containing 1 to 4 nitrogen atoms, substituted or non substituted by one or more R9 groups R1 represents a hydrogen atom; a (C5-C14)-aryl; (C5-C14)-aryl-(C1-C4)-alkyl-group; an amino radical non substituted or 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)0-2OR5 group; R3 represents a hydrogen atom a -CO2R5 radical, a -SO2R5 radical or a monocyclic or polycyclic system, each ring being constituted by 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, O or S, substituted or non substituted by one or more R9 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- and/or a (C1-C5)-acyl radical; or the remainder of an amino acid D or L; 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-, the said aryl, alkyl, cycloalkyl, bicycloalkyl and tricycloalkyl radicals being non substituted or substituted by one or more chosen R9 groups; R6 represents a hydrogen atom; a hydroxyl; nitro, (C1-C6)-alkyl-O-CO-; or (C1-C6)-alkyl-O-CO-O-group: and R7 and R8, independently of one another represent a hydrogen atom or a (C1-C6)-alkyl radical non substituted or substituted by R9; R9 represents halogen; amino; nitro; hydroxyl, (C1-C4)-alkyloxy-; (C1-C4)-alkylthio-; 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; it being understood that the aryl radicals can be non substituted or substituted by one or more identical or different radicals chosen from (C1-C8)-alkyl, in particular (C1-C4)-alkyl, hydroxyl, (C1-C8)-alkylox, (C1-C8)-alkylthio, halogen chosen from fluorine, chlorine and bromine, nitro, amino, (C1-C4)-alkylamino, di-(C1-C4)-alkylamino, trifluoromethyl, methylenedioxy, cyano, aminocarbonyl, (C1-C4)-alkylaminocarbonyl, di-(C1-C4)-alkylaminocarbonyl, carboxy, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl and benzyloxy.
  2. The compounds of formula (I) according to claim 1 in which G represents a Het, Het-NHCO-, or Het-NH-CH2-group with Het representing the following heterocycles:
  3. The compounds of formula (I) according to any one of claims I to 2 in which R3 is:
    a heterocycle chosen from
    as well as their pharmaceutically acceptable addition salts.
  4. The compounds of formula (I) according to any one of claims 1 to 2 in which R3 is a benzyloxycarbonyl group, as well as their pharmaceutically acceptable addition salts.
  5. The compounds of formula (I) according to any one of claims 1 to 4 in which R2 is a hydrogen, an alkyl radical containing 1 to 4 carbon atoms or a fluorine atom as well as their pharmaceutically acceptable addition salts.
  6. The compounds of formula (I) according to claim 5 in which R2 is a methyl or ethyl.
  7. The compounds of formula (I) according to any one of claims 1 to 6 in which:
    G represents as well as their pharmaceutically acceptable addition salts.
  8. The compounds of formula (I) according to any one of claims 1 to 7 in which:
    G represents R1 represents a hydrogen atom R2 represents a hydrogen atom, a fluorine atom, a methyl radical or an ethyl radical, R3 represents a benzyloxycarbonyloxy group R4 represents a hydroxy group as well as the pharmaceutically acceptable addition salts
  9. The compounds of formula (I) according to any one of claims 1 to 8 the names of which follow:
    3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine,
    3-[[5-ethyl-6-[4-[(1,2,3,4,5,6-hexahydro-2-pyrimidinyl)iminocarbonyl]-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine,
    3-[[6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-5-methyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine,
    3-[[6-[4-[(1,2,3,4,5,6-hexahydro-2-pyrimidinyl)iminocarbonyl]-1-piperidinyl]-5-methyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine,
    ethyl 3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate
    isopropyl 3-[[6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-5-methyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate
    (1,1-dimethylethyl)-3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate
    (1,1-dimethylethyl)-3-[[5-methyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate
    (1,1-dimethylethyl)-3-[[6-[4-1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-2,5-dimethyl-4-pyrimidinyl]amino]-N-[phenylmethoxy)carbonyl] alaninate
    (1,1-dimethylethyl)-3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-(1-naphtalenesulfonyl)alaninate
    in (R) configuration or (S) configuration or their mixtures, as well as their addition salts.
  10. A process for the preparation of the compounds of formula (I) in which
    a) a compound of formula (II) in which R1, R2, R3 and R4 are as defined in claim 1 is reacted, with a compound of formula (III) in which G is as defmed in claim 1 in the presence of a base or a transition metal coupling reagent
    b) the compound of formula (I) thus obtained is subjected, optionally to cleavage of the R3-NH-function in order to regenerate the free amine, followed by condensation of the R3 radicals of -CO2-R5 or -SO2-R5 structure, and/or if appropriate to hydrolysis and optionally to esterification or to amidification and/or to salification.
  11. A process for the preparation of the compounds of formula (I) in which
    a) a compound of formula (II) as defined in claim 10 is reacted with a compound of formula (IIIa) in order to obtain the intermediate compound of formula (IV)
    b) the compound of formula (IV) is reacted with a formula of Het-NH2 in order to obtain the compounds of formula (I) with G representing a Het-NHCO-group,
    c) the compound of formula (I) obtained is subjected, optionally to cleavage of the function R3-NH- in order to regenerate the free amine, followed by condensation of the R3 radicals of -CO2-R5 or - SO2-R5 structure, and/or if appropriate to hydrolysis and optionally to esterification or to amidification and/or to salification.
  12. A process for the preparation of the compounds of formula (I) according to one of claims 1 to 9, characterized in that
    a) a product of general formula (IIa) in which R1, R2, G and X are as defined previously, is reacted with a product of formula (VI) in which R3 and R4 are as defined previously, either in the presence of a strong base, or by catalysis with palladium,
    b) then the product of formula (I) is subjected, optionally to cleavage of the function R3-NH- in order to regenerate the free amine, followed by condensation of the R3 radicals of -CO2-R5 or -SO2-R5 structure, and/or if appropriate to hydrolysis and optionally to esterification or to amidification and/or to salification.
  13. As a medicament, the compounds of formula (I) and/or their physiologically acceptable salts as defined according to any one of claims 1 to 9.
  14. A pharmaceutical composition comprising a medicament as defined in claim 13 as well as one or more excipients.
  15. As a medicament, according to claim 13, having a antagonist activity on the vitronectin receptor, a compound of formula (I) and/or its physiologically acceptable salts as defined according to any one of claims 1 to 9.
  16. As a medicament, according to claim 13, 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 9.
  17. As a medicament, according to claim 13, having an inhibitory activity on tumorous growth or cancerous metastases, a compound of formula (I) and/or its physiologically acceptable salts as defined according to any one of claims 1 to 9.
  18. As a medicament, according to claim 13, having an anti-inflammatory activity or for the treatment or prevention of cardiovascular disorders, restenosis, arteriosclerosis, nephropathies or retinopathies, a compound of formula (I) and/or its physiologically acceptable salts and/or its prodrugs as defined according to any one of claims 1 to 9.
  19. Use of the compounds of formula (I) and/or their physiologically acceptable salts as defined according to any one of claims 1 to 9 for the preparation of medicaments intended for the prevention or treatment of osteoporosis.
  20. Use of the compounds of formula (I) and/or their physiologically acceptable salts as defined according to any one of claims 1 to 9 for the preparation of medicaments intended to inhibit tumorous growth or cancerous metastases.
  21. Use of the compounds of formula (I) and/or their physiologically acceptable salts as defined according to any one of claims 1 to 9 for the preparation of medicaments for the prevention or treatment of cardiovascular disorders, restenosis, arteriosclerosis, nephropathies or retinopathies.
HK05109816.8A 2002-11-19 2003-11-12 Novel vitronectin receptor antagonist derivatives, method for preparing same, use thereof as medicines and pharmaceutical compositions containing same HK1076277B (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR02/14429 2002-11-19
FR0214429A FR2847254B1 (en) 2002-11-19 2002-11-19 NOVEL VITRONECTIN RECEPTOR ANTAGONIST DERIVATIVES, PROCESS FOR PREPARING THEM, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS REFLECTING THEM
PCT/FR2003/003349 WO2004048375A1 (en) 2002-11-19 2003-11-12 Novel vitronectin receptor antagonist derivatives, method for preparing same, use thereof as medicines and pharmaceutical compositions containing same

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HK1076277B true HK1076277B (en) 2009-12-31

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