New derivatives of imidazolidine, receipt, use and containing pharmaceuticals

 

The invention relates to new derivatives of imidazolidine formula (I), where W denotes the R1-A-C(R13), Z denotes oxygen, And represents a simple bond or alkylene, denotes a bivalent residue of group (C1-C6-alkylene, phenylene, and divalent alkalinity residue may be substituted or unsubstituted, E denotes R10CO, R denotes hydrogen or (C1-C8)-alkyl, R0denotes hydrogen, (C1-C8)-alkyl, if necessary substituted (C6-C14)-aryl, substituted heteroaryl, R1indicates, if necessary, replaced the rest of the series phenyl, thienyl or pyridyl, R2denotes hydrogen or alkyl, R3denotes hydrogen, alkyl, substituted aryl, substituted heteroaryl, R11NH, CONHR4, CONHR15, R4denotes hydrogen, alkyl, which can be repeatedly replaced, R5denotes a substituted aryl, R10represents hydroxy or alkoxy, R11denotes hydrogen, R12a-CO, R12a-O-CO, R12b-CO, R12adenotes alkyl, alkenyl, cycloalkyl, substituted aryl, R12bmeans R12a-NH, R13denotes hydrogen or alkyl, R15means R16-Alki the m or partially saturated and which may be substituted by one or more alkyl. In addition, the compounds of formula (I) have inhibitory adhesion in the cells U937/VCAM-1, and due to this property can be used as active substances in pharmaceuticals, for the treatment or prevention of various diseases. The invention relates to a method for producing compounds of formula (I), which consists in condensing the compounds of formula (II) with the compound of the formula (III). 3 S. and 14 C.p. f-crystals, 3 PL.

Description text in facsimile form (see graphic part).

Claims

1. Derivatives of imidazolidine formula Iwhere W stands for R1-A-C(R13); Z means oxygen; a represents a simple bond or (C1-C2-alkylen; means the divalent residue of group (C1-C6-alkylene, (C2-C6-albaniles, phenylene, phenylene-(C1-C3)-alkyl, (C1-C3-alkylen-phenyl, and divalent (C1-C6)-alkilinity the residue is unsubstituted or substituted by a residue from the group (C1-C8)-alkyl, (C2-C8)-alkenyl, if necessary>4)-aryl-(C1-C6)-alkyl; E mean R10CO; R is hydrogen, (C1-C8)-alkyl; R0means hydrogen, (C1-C8)-alkyl, if necessary substituted (C6-C14)-aryl, substituted if necessary in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl; if necessary substituted heteroaryl, substituted if necessary in the heteroaryl residue heteroaryl-(C1-C8)-alkyl; R1means, if necessary, replaced the rest of the series phenyl, thienyl and pyridyl; R2means hydrogen or (C1-C8)-alkyl; R3means hydrogen, (C1-C8)-alkyl, if necessary substituted (C6-C14)-aryl, substituted if necessary in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl; if necessary substituted heteroaryl: R11NH, CONHR4, CONHR15; R4means hydrogen or (C1-C10)-alkyl, which if necessary can be one or multi-substituted by identical or different residues from the group hydroxy, (C1-C8-alkoxygroup, R5hydroxycarbonyl, mono - or di-((C1-C185means, if necessary, substituted (C6-C14)-aryl, substituted if necessary in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl; R10means hydroxy, (C1-C8)-alkoxy; R11means hydrogen, R12a-CO, R12a-O-CO, R12b-CO; R12ameans(C1-C18)-alkyl, (C2-C8)-alkenyl, (C3-C12-cycloalkyl, if necessary substituted (C6-C14)-aryl, substituted if necessary in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, or R15; R12bmeans R12a-NH; R13means hydrogen or (C1-C6)-alkyl; R15means R16-(C1-C6)-alkyl, or R16; R16means a 6-membered to 24-membered tricyclic residue, which is saturated or partially unsaturated and which may be substituted by one or more substituents from the group (C1-C4)-alkyl; heteroaryl is a monocyclic or polycyclic aromatic residue with 5 to 14 members in the ring, containing 1 or 2 heteroatoms from the group O or N in the ring; Het is a residue linked through a nitrogen atom which may contain in the ring one or two identical or different additional heteroatoms from the group oxygen or nitrogen; e and h are independently from each other 0 or 1;
in all their stereoisomeric forms and their physiologically acceptable salts.

2. The compounds of formula I on p. 1, where W means R1-A-C(R13); Z means oxygen; a represents a simple bond or methylene; means a divalent methylene or ethylene residues, which can be unsubstituted or substituted by one residue from the group (C1-C8)-alkyl, (C2-C8)-alkenyl, if necessary substituted (C6-C14)-aryl, substituted if necessary in the aryl residue (C6-C14)-aryl-(C1-C6)-alkyl; E mean R10CO; R is hydrogen, (C1-C8)-alkyl; R0means hydrogen, (C1-C8)-alkyl, if necessary substituted (C6-C14)-aryl, substituted if necessary in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl; if necessary substituted heteroaryl, substituted if necessary in the heteroaryl residue heteroaryl-(C1-C8)-alkyl; R1means, if necessary, replaced the rest of the series phenyl, thienyl and pyridyl; R2means hydrogen or (C1-C8)-alkyl; R3oznacza is necessary aryl residue (C6-C14)-aryl-(C1-C8)-alkyl; if necessary substituted heteroaryl, R11NH, CONHR4, CONHR15; R4means (C1-C8)-alkyl, which if necessary may be single - or multi-substituted by identical or different residues from the group hydroxy, (C1-C8-alkoxygroup, R5hydroxycarbonyl, mono - or di-((C1-C18)-alkyl)-aminocarbonyl, (C6-C14)-aryl-(C1-C8-alkoxycarbonyl, (C1-C8-alkoxycarbonyl, Het-CO; R5means, if necessary, substituted (C6-C14)-aryl, substituted if necessary in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl; R10means hydroxy, (C1-C8)-alkoxy; R11means hydrogen, R12A-CO, R12A-O-CO, R12b-CO; R12Ameans (C1-C18)-alkyl, (C2-C8)-alkenyl, (C3-C12-cycloalkyl, if necessary substituted (C6-C14)-aryl, substituted if necessary in the aryl residue (C6-C14)-aryl-(C1-C8)-Akil, or R15; R12bmeans R12A-NH; R13means hydrogen or (C1-C6)- the nogo tricyclic residue, which is saturated or partially unsaturated and which may be substituted by one or more substituents from the group (C1-C4)-alkyl; Het is a residue linked through a nitrogen atom in the ring is 5-membered to 10-membered, saturated monocyclic or polycyclic heterocycle, which may contain in the ring one or two identical or different additional heteroatoms from the group oxygen or nitrogen; e and h are independently from each other 0 or 1; in all their stereoisomeric forms and their physiologically acceptable salts.

3. The compounds of formula I on PP.1 and/or 2, where W means R1-A-C(R13); Z means oxygen; a represents a simple bond or methylene; means a divalent methylene or ethylene residues, which can be unsubstituted or substituted by one residue from the group (C1-C8)-alkyl, (C2-C8)-alkenyl, if necessary substituted (C6-C14)-aryl, substituted if necessary in the aryl residue (C6-C14)-aryl-(C1-C6)-alkyl; E mean R10CO; R is hydrogen, (C1-C4)-alkyl; R0means (C1-C8)-alkyl, if necessary substituted (C6-C14)-and, if necessary, substituted heteroaryl, replaced if necessary in the heteroaryl residue - heteroaryl-(C1-C8)-alkyl; R1means, if necessary, replaced the rest of the series phenyl, thienyl and pyridyl; R2means hydrogen or (C1-C4)-alkyl; R3means (C1-C8)-alkyl, if necessary substituted (C6-C14)-aryl, substituted if necessary in the aryl residue (C6-C14)-aryl-(C1-C4)-alkyl; if necessary substituted heteroaryl, R11NH, CONHR4, CONHR15; R4means (C1-C8)-alkyl, which if necessary may be single - or multi-substituted by identical or different residues from the group hydroxy, (C1-C8-alkoxygroup, R5hydroxycarbonyl, mono - or di-((C1-C8)-alkyl)-aminocarbonyl, (C6-C14)-aryl-(C1-C8-alkoxycarbonyl, (C1-C8-alkoxycarbonyl, Het-CO; R5means, if necessary, substituted (C6-C14)-aryl, substituted if necessary in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl; R10means hydroxy, (C1-C8)-alkoxy; R11means R3-C12-cycloalkyl, if necessary substituted (C6-C14)-aryl, substituted if necessary in the aryl residue (C6-C14)-aryl-(C1-C8)alkyl, or R15; R12bmeans R12a-NH; R13means hydrogen or (C1-C4)-alkyl; R15means R16-(C1-C3)-alkyl, or R16; R16mean 7-membered to 12-membered tricyclic residue, which is saturated or partially unsaturated and which may be substituted by one or more substituents from the group (C1-C4)-alkyl; Het is a residue linked through a nitrogen atom in the ring is 5-membered to 10-membered, saturated monocyclic or polycyclic heterocycle, which may contain in the ring one or two identical or different additional heteroatoms from the group oxygen or nitrogen; e and h are independently from each other 0 or 1; in all their stereoisomeric forms and their physiologically acceptable salts.

4. The compounds of formula I according to one or more paragraphs.1-3, in which W stands for R1-A-C(R13); Z means oxygen; a represents a simple bond or methylene; means unsubstituted methylene residue or substituted by a residue from the group (C is, replaced if necessary in the aryl residue (C6-C10)-aryl-(C1-C4)-alkyl; E mean R10CO; R is hydrogen, (C1-C4)-alkyl; R0means replaced if necessary in the aryl residue (C6-C14)-aryl-(C1-C4)-alkyl; substituted, if necessary, in the heteroaryl residue heteroaryl-(C1-C4)-alkyl; R1means, if necessary, replaced the rest of the series phenyl, thienyl and pyridyl; R2means hydrogen, (C1-C4)-alkyl; R3means unsubstituted phenyl or naphthyl or phenyl or naphthyl substituted by one, two or three identical or different residues from the group (C1-C4)-alkyl, or R3means pyridyl, R11NH, CONHR4, CONHR15; R4means (C1-C8)-alkyl, which if necessary may be single - or multi-substituted by identical or different residues from the group hydroxy, (C1-C8-alkoxygroup, R5hydroxycarbonyl, (C6-C10)-aryl-(C1-C4-alkoxycarbonyl, (C1-C6-alkoxycarbonyl, Het-CO; R5means, if necessary, substituted (C6-C10)-and R10means hydroxy, (C1-C8)-alkoxy; R11means R12a-CO, R12a-O-CO, R12b-CO; R12bmeans (C1-C10)-alkyl, (C2-C8)-alkenyl, (C3-C12-cycloalkyl, if necessary substituted (C6-C14)-aryl, substituted if necessary in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, or R; R12bmeans R12a-NH; R13means hydrogen or (C1-C4)-alkyl; R15means R16-(C1-C3)-alkyl, or R16; R16mean 7-membered to 12-membered tricyclic residue, which is saturated or partially unsaturated and which may be substituted by one or two substituents from the group (C1-C4)-alkyl; Het is a residue linked through a nitrogen atom in the ring is 5-membered to 7-membered, saturated monocyclic or polycyclic heterocycle, which may contain in the ring one or two identical or different additional heteroatoms from the group oxygen or nitrogen; e and h are independently from each other 0 or 1; in all their stereoisomeric forms and their physiologically acceptable salts.

5. The compounds of formula I according to one or more paragraphs.1-4, deareating forms and their physiologically acceptable salts.

6. The compounds of formula I according to one or more paragraphs.1-5, where R1means the rest of the series phenyl, thienyl or pyridyl, which is unsubstituted or substituted one, two or three identical or different substituents from the group (C1-C4)-alkyl, (C1-C4-alkoxygroup, halogen, amino, trifluoromethyl, hydroxy-group, hydroxy-(C1-C4)-alkyl, methylenedioxy, atlantoxerus, phenyl, fenoxaprop, benzyl and benzyloxy all stereoisomeric forms and their physiologically acceptable salts.

7. The compounds of formula I according to one or more paragraphs.1-6, where R1means the rest of the series phenyl, 2-thienyl, 3-thienyl, 3-pyridyl, 4-pyridyl, and phenyl unsubstituted or substituted by one or two identical or different substituents from the group (C1-C4)-alkyl, (C1-C4-alkoxygroup, halogen, trifluoromethyl, hydroxy-group, hydroxy-(C1-C4)-alkyl, methylenedioxy, atlantoxerus, phenyl, fenoxaprop, benzyl and benzyloxy, and all heteroaromatic residues unsubstituted or substituted by one or two identical or different substituents from the group (C1-C4)-alkyl, (C1-C4-alkoxygroup, halogen, amino, cryptograph, benzyl and benzyloxy, all stereoisomeric forms and their physiologically acceptable salts.

8. The compounds of formula I according to one or more paragraphs.1-7, where R1means unsubstituted residue of the number of phenyl, 2-thienyl, 3-thienyl, 3-pyridyl and 4-pyridyl all stereoisomeric forms and their physiologically acceptable salts.

9. The compounds of formula I according to one or more paragraphs.1-8, where R1means unsubstituted residue of the number of phenyl, 2-thienyl, 3-thienyl, 4-pyridyl, all stereoisomeric forms and their physiologically acceptable salts.

10. The compounds of formula I according to one or more paragraphs.1-9 and/or their physiologically acceptable salts for use as pharmaceuticals.

11. The compounds of formula I according to one or more paragraphs.1-9 and/or their physiologically acceptable salts for use as anti-inflammatory drugs.

12. The compounds of formula I according to one or more paragraphs.1-9 and/or their physiologically acceptable salts for use in the treatment or prevention of rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus or inflammatory diseases of the Central nervous system.

13. The compounds of formula I according to one or more paragraphs.1-9 and/or their physiologically acceptable salts for primei their physiologically acceptable salts for use in the treatment or prevention of cardiovascular diseases, atherosclerosis, restenosis or diabetes, to prevent rejection of transplants, for inhibiting tumor growth or treatment of malaria.

15. The compounds of formula I according to one or more paragraphs.1-9 and/or their physiologically acceptable salts for use as inhibitors of the adhesion and/or migration of leukocytes or as inhibitors of VLA-4 receptor.

16. Method of producing compounds of the formula I according to one or more paragraphs.1-9, characterized in that conduct the condensation of fragments of the compounds of formula II

with the compound of the formula III

in formulas II and III group W, Z, b, E, R, R0, R2and R3and e and h have the meanings as defined in the PP.1-9 or functional groups can be present in protected form or in the form of precursors and G means hydroxycarbonyl, (C1-C6-alkoxycarbonyl or activated carboxylic acid derivative.

17. Pharmaceutical drug, possessing inhibiting adhesion to cells U937/VCAM-1, containing the active ingredient and pharmaceutically acceptable carriers and/or additives, characterized in that the active substance contains a compound of the formula is

 

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