HRP980462A2 - Small molecules useful in the treatment of inflammatory disease - Google Patents

Description

Field of invention

The proposed invention generally relates to new small molecules, their synthesis and their use in the treatment of inflammatory diseases. The invention further relates to the use of similar, but known, compounds in the treatment of inflammatory diseases.

State of the art

A body of research in the last decade has helped to elucidate the molecular events that target cell-cell interactions in the body, particularly those events involved in the movement and activation of cells in the immune system. See generally, Sringer, T. Nature, 1990, 346, 425-434. Proteins on the cell surface, especially cellular adhesion molecules (e. Cellular Adhesion Molecules, CAMs) and "leukointegrins", including LFA-1, MAC-1, and gp150.95 (in the WHO nomenclature, they are referred to as CD18/CD11a, CD18/CD11b , and CD18/CD11c) were appropriately subjected to pharmaceutical research as well as their targeted intervention in the processes of leukocyte extravasation on the side of the injury and leukocyte migration towards certain targets. For example, it is now believed that prior to leukocyte extravasation, which is a mandatory component of the inflammatory response, there is an activation of integrins constitutively multiplied on leukocytes, followed by a close ligand-receptor interaction between integrins (eg LFA-1) and one or several specific intracellular adhesion molecules (ICAMs) labeled as ICAM-1, ICAM-2, ICAM-3 or ICAM-4 that multiply on the surfaces of endothelial cells of blood vessels and on other leukocytes. The interaction of CAM molecules with leukointegrins is a vital step in the normal functioning of the immune system. All immune processes, such as antigen presentation, T-cell-mediated cytotoxicity and leukocyte extravasation, require cell adhesion mediated by ICAM molecules that interact with leukointegrins. See generally Kishimoto, T.K.; Rothlein, R.R. Adv. Pharmacol. 1994, 25: 117-138 and Diamond, M.; Springer, T. Current Biology, 1994, 4, 506-532.

A group of individuals has been identified who lack adequate leukointegrin expression, a condition termed “E. Leukocyte Adhesion Deficiency” (Anderson, D. C., et al., Fed. Proc. 1985, 44, 2671-2677 and Anderson, D. C. , et al., J. Infect. Dis. 1985, 152, 668-689). These individuals are unable to mount normal inflammatory and/or immune responses due to the inability of their cells to adhere to cellular substrates. These data show that immune reactions are attenuated when lymphocytes cannot stick together in a normal way due to the lack of functional adhesion molecules from the CD18 family. Based on the fact that LAD patients, who lack CD18, cannot mount inflammatory responses, it is believed that antagonism of the CD18, CD11/ICAM-1 interaction will also inhibit the inflammatory response.

It has been shown that the antagonism of the interaction between CAM molecules and leukointegrin can be achieved by means directed towards any component. In particular, blocking CAM molecules, such as for example ICAM-1, or leukointegrins, such as for example LFA-1, by antibodies directed against one or both of these molecules effectively inhibits inflammatory responses. In vitro models of inflammation and immune responses inhibited with antibodies to CAM or leukointegrins include antigen- or mitogen-induced lymphocyte proliferation, homotypic lymphocyte aggregation, T cell-mediated cytolysis, and antigen-specific induced tolerance. The respective in vitro studies were supported by in vivo studies with antibodies directed against ICAM-1 or LFA-1. For example, antibodies directed against LFA-1 can prevent thyroid graft rejection and prolong the survival of heart allograft mice (Gorski, A., Immunology Today, 1994, 15, 251-255). More significantly, antibodies directed against ICAM-1 have shown efficacy in vivo as anti-inflammatory agents in human diseases such as renal allograft rejection and rheumatoid arthritis (Rothlein, R.R.; Scharschmidt, L., in Adhesion Molecules; Wegner, C.D. Ed ., 1994, 1-38, Cosimi, C.B., et al., J. Immunol. 1990, 144, 4604-4612 and Kavanaugh, A., et al., Arthritis Rheum. 1994, 37, 992-1004), and antibodies directed against LFA-1 have shown immunosuppressive effects in bone marrow transplantation and in the prevention of early rejection of renal allografts (Fischer, A., et al., Lancet, 1989, 2, 1058-1060 and Le Mauff, B., et al., Transplantation, 1991, 52, 291-295).

It was also shown that the recombinant soluble form of ICAM-1 can act as an inhibitor of the interaction of ICAM-1 with LFA-1. Soluble ICAM-1 acts as a direct antagonist of CD18, CD11/ICAM-1 molecules interactions on cells and shows inhibitory activity in in vitro models of immune response such as human mixed lymphocyte response, cytotoxic T cell response and T cell proliferation in diabetic patients as islet cell response (Becker, J. C., et al., J. Immunol. 1993, 151, 7224 and Roep, B. O., et al., Lancet, 1994, 343, 1590).

Thus, according to the state of the art, it has been shown that numerous protein molecules that antagonize the binding of CAM molecules to leukointegrins have therapeutic possibilities in mitigating inflammatory and immune responses that are often associated with the pathogenesis of many autoimmune and inflammatory diseases. However, proteins have significant drawbacks as therapeutic agents, including the inability to administer them orally and possible immune reactivity that limits the utility of these molecules for chronic administration. Furthermore, the production of protein-based therapeutics is generally expensive.

It follows that small molecules, which have a similar ability to antagonize the binding of CAM molecules to leukointegrins as large protein molecules, would provide advantageous therapeutic agents. To date, however, no activity of small molecules as direct antagonists has been reported.

Several small molecules that interfere with the interaction of CAM molecules and leukointegrins have been described in the literature. A natural product isolated from the roots of Trichilia rubra was found to be an inhibitor in an in vitro cell attachment assay (Musza, L.L., et al., Tetrahedron, 1994, 50, 11369-11378). A number of molecules were also found (Boschelli, D. H., et al., J. Med. Chem. 1994, 37, 717 and Boschelli, D. H., et al., J. Med. Chem. 1995, 38, 4597-4614) which orally active in the reverse passive Arthus reaction, a model of induced inflammation characterized by neutrophil accumulation (Chang, Y. H., et al., Eur. J. Pharmacol. 1992, 69, 155-164). Another set of molecules has also been found to be orally active in a type of delayed hypersensitivity reaction in rats (Sanfilippo, P. J., et al., J. Med. Chem. 1995, 38, 1057-1059). All these molecules appear to act nonspecifically, either by inhibiting ICAM-1 transcription only with other proteins or by acting intracellularly to inhibit leukointegrin activation by an unknown mechanism. None of these molecules directly antagonize the interaction of CAM molecules with leukointegrins. Due to lack of potency, lack of selectivity and lack of a specific mechanism of action, the described small molecules seem unsatisfactory for therapeutic use.

Based on the state of the art, there remains a clear need for therapeutically usable small molecules that have the ability to antagonize the interaction of CAM molecules and leukointegrins.

Brief description of the invention

In a first aspect, the invention includes a method for treating or preventing cell-mediated inflammatory and immune diseases by administering certain novel and known small molecules. These compounds act by inhibiting the interaction of cellular adhesion molecules, specifically by antagonizing the binding of human intercellular adhesion molecules (including, for example, ICAM-1, ICAM-2, and ICAM-3) to leukointegrins (including, for example, CD18/CD11a and CD18/ CD11b). Another aspect of the invention involves novel small molecules having the above-mentioned therapeutic activities. A third aspect of the invention involves methods for producing these novel compounds. A final aspect of the invention includes pharmaceutical compositions containing the aforementioned compounds suitable for the prevention or treatment of cell-mediated inflammatory and immune conditions.

Description of the invention in detail

In a first aspect, the invention includes a method for treating or preventing cell-mediated inflammatory and immune diseases by administering certain novel and known small molecules of formula I

[image]

where

Y is an oxygen or sulfur atom;

Z is an oxygen or sulfur atom;

X is a divalent group of the formula >CHR1, >NR1, >CHSO2R1, or >NSO2R1, or an oxygen or sulfur atom, where

R1 is:

(A) hydrogen atom,

(B) a branched or unbranched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group may be mono- or polysubstituted with:

(i) halogen,

(ii) oxo,

(iii) aryl, which is selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolizinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, quinolinyl, phthalaninyl, quinoxalinyl, naphthyridinyl, pteridinyl and quinazolinyl, wherein one or more hydrogens atom of the mentioned aryl residue can be, if necessary, independently replaced with:

(a) alkyl having 1 to 3 carbon atoms,

(b) -COOH,

(c) -SO2OH,

(d) -PO(OH)2,

(e) a group of the formula -COOR7, where R7 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms,

(f) a group of the formula -NR8R9, where each of R8 and R9 independently represents a hydrogen atom, alkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms, or in which R8 and R9 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which, together with the nitrogen atom between them, form a heterocyclic ring,

(g) a group of the formula -CONR10R11, where each of R10 and R11 independently represents a hydrogen atom, an alkyl having from 1 to 6 carbon atoms or a cycloalkyl having from 3 to 6 carbon atoms, or in which R10 and R11 form a saturated hydrocarbon bridge that has from 3 to 5 carbon atoms which, together with the nitrogen atom between them, form a heterocyclic ring,

(h) a group of the formula -OR12a, where R12a represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms,

(i) a group of the formula -SR12b, where R12b represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms,

(j) cyano, or

(k) amidino group of the formula

[image]

in which each of R13, R14 and R15 independently represents a hydrogen atom or alkyl having from 1 to 3 carbon atoms and in which two of R13, R14 and R15 can additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with nitrogen atom(s) between them to form a heterocyclic ring,

(iv) a group of the formula -COOR16, where R16 represents straight or branched alkyl having from 1 to 7 carbon atoms or cycloalkyl having from 3 to 6 carbon atoms,

(v) cyano,

(vi) a group of the formula -CONR17R18, where each of R17 and R18 independently represents a hydrogen atom, an alkyl having from 1 to 6 carbon atoms or a cycloalkyl having from 3 to 6 carbon atoms, or in which R17 and R18 form a saturated hydrocarbon bridge that has from 3 to 5 carbon atoms which, together with the nitrogen atom between them, form a heterocyclic ring,

(vii) a group of the formula -OR19, where R19 represents a hydrogen atom or an alkyl or acyl group having from 1 to 7 carbon atoms,

(viii) a group of the formula -SR20, where R20 represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms,

(ix) a group of the formula -NR21R22, where each of R21 and R22 independently represents

(a) hydrogen atom,

(b) alkyl or acyl having from 1 to 7 carbon atoms or cycloalkyl having from 3 to 7 carbon atoms,

(c) a group of the formula -(CH2)mCOOH, where m is 0, 1 or 2, or

(d) a group of the formula -(CH2)nCOOR23, where n is 0, 1 or 2, and R23 is straight or branched alkyl having from 1 to 6 carbon atoms,

or where R21 and R22 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, or

(x) by the quaternary group of the formula

[image]

in which each of R24, R25 and R26 independently represents a branched or unbranched alkyl group having from 1 to 7 carbon atoms and Q- is a chlorine, bromine or iodine ion of the opposite charge,

(C) branched or unbranched carboxylic acid group having from 3 to 6 carbon atoms,

(D) branched or unbranched phosphonic acid group having from 2 to 6 carbon atoms,

(E) a branched or unbranched sulfonic acid group having from 2 to 6 carbon atoms,

(F) amidino group of the formula

[image]

in which r is 2, 3, 4, 5 or 6, and

each of R27, R28 and R29 independently represents a hydrogen atom or alkyl having from 1 to 3 carbon atoms, and in which two of R27, R28 and R29 can additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with a nitrogen atom (atoms) between them form a heterocyclic ring,

(G) guanidino group of the formula

[image]

in which s is 2, 3, 4, 5 or 6, i

each of R30, R31, R32 and R33 independently represents a hydrogen atom or alkyl having from 1 to 3 carbon atoms, and in which two of R30, R31, R32 and R33 may additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms that together with the nitrogen atom(s) between them form a heterocyclic ring,

(H) piperidyl, in which the nitrogen atom of the mentioned group is optionally substituted with:

(i) alkyl having 1 to 3 carbon atoms,

(ii) a carboxyl ester group having 2 to 7 carbon atoms,

(iii) a carboxylic acid group that has from 2 to 5 carbon atoms,

(iv) a phosphonic acid group having from 1 to 6 carbon atoms, or

(v) a sulfonic acid group having from 1 to 6 carbon atoms, or

(I) aryl which is selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl , indolizinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, quinolinyl, phthalaninyl, quinoxalinyl, naphthyridinyl, pteridinyl and quinazolinyl, wherein one or more hydrogen atoms the mentioned aryl groups can be independently replaced with:

(i) alkyl having 1 to 3 carbon atoms,

(ii) -COOH,

(iii) -SO2OH,

(iv) -PO(OH)2,

(v) a group of the formula -COOR7, where R7 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms,

(vi) a group of the formula -NR8R9, where each of R8 and R9 independently represents a hydrogen atom, an alkyl having from 1 to 6 carbon atoms, a cycloalkyl having from 3 to 6 carbon atoms or an acyl having from 1 to 7 carbon atoms, or in which R8 and R9 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which, together with the nitrogen atom between them, form a heterocyclic ring,

(vii) a group of the formula -CONR10R11, where each of R10 and R11 independently represents a hydrogen atom, an alkyl having from 1 to 6 carbon atoms or a cycloalkyl having from 3 to 6 carbon atoms, or in which R10 and R11 form a saturated hydrocarbon bridge that has from 3 to 5 carbon atoms which, together with the nitrogen atom between them, form a heterocyclic ring,

(viii) a group of the formula -OR12a, where R12a represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms,

(ix) a group of the formula -SR12b, where R12b represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms,

(x) cyano, or

(xi) amidino group of the formula

[image]

in which each of R13, R14 and R15 independently represents a hydrogen atom or alkyl having from 1 to 3 carbon atoms, and in which two of R13, R14 and R15 can additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with with nitrogen atom(s) between them they form a heterocyclic ring;

R2 is:

(A) hydrogen atom, or

(B) a branched or unbranched alkyl group having from 1 to 3 carbon atoms or a cycloalkyl group having from 3 to 5 carbon atoms, wherein said alkyl or cycloalkyl group can be optionally substituted with:

(i) a group of the formula -OR34, where R34 represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms or

(ii) a group of the formula -NR35R36, where each of R35 and R36 independently represents a hydrogen atom, an alkyl having from 1 to 2 carbon atoms, or an acyl having from 1 to 2 carbon atoms;

R3 is a group of the formula -(CR37R38)x(CR39R40)yR41, in which

each of x and y independently represents 0 or 1,

each of R37, R38 and R39 independently represents:

(A) hydrogen atom,

(B) a group of the formula -OR42, where R42 represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms,

(C) branched or unbranched alkyl having from 1 to 3 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms,

R40 is:

(A) hydrogen atom,

(B) a group of the formula -OR42, where R42 represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms,

(C) branched or unbranched alkyl having from 1 to 3 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms, or

(D) aryl which is selected from the class consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, 3-, 6- or 7-indolizinyl, 2-, 3-, 5- or 6- isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5 - or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3 -, 7- or 8-quinolizinyl, 3-, 6- or 7-quinolinyl, 6- or 7-phthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7- naphthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl, whereby one or more hydrogen atoms of the mentioned aryl group can to be independently replaced with:

(i) R43, which is selected from the class consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2- , 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3- , 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1- , 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, 3-, 6- or 7-indolizinyl, 2-, 3-, 5- or 6 -isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-quinolinyl, 6- or 7-phthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7 -naphthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl, whereby one or more hydrogen atoms of the mentioned aryl group can to be independently replaced with:

(a) a branched or unbranched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or polysubstituted with halogen or oxo,

(b) -COOH,

(c) -SO2OH,

(d) -PO(OH)2,

(e) a group of the formula -COOR44, where R44 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms,

(f) a group of the formula -NR45R46, where each of R45 and R46 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms , or in which R45 and R46 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,

(g) a group of the formula -CONR47R48, where each of R47 and R48 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms or cycloalkyl having from 3 to 6 carbon atoms, or in which R47 and R48 form a saturated hydrocarbon a bridge that has from 3 to 5 carbon atoms that, together with the nitrogen atom between them, form a heterocyclic ring,

(h) a group of the formula -OR49, where R49 represents a hydrogen atom, or an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms,

(i) a group of the formula -SR50, where R50 represents a hydrogen atom, or an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms,

(j) cyano,

(k) nitro,

(l) amidino group of the formula

[image]

in which each of R51, R52 and R53 independently represents a hydrogen atom or alkyl having from 1 to 3 carbon atoms, and in which two of R51, R52 and R53 may additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with nitrogen atom(s) between them to form a heterocyclic ring, or

(m) halogen,

(ii) methyl, which can be mono- or polysubstituted with fluorine atoms and can additionally be monosubstituted with R43,

(iii) a branched or unbranched alkyl group having from 2 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or polysubstituted with oxo,

(iv) a group of the formula -COOR54, where R54 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms,

(v) a group of the formula -NR55R56, where each of R55 and R56 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms , or in which R55 and R56 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and where one of R55 and R56 may additionally be the group R43,

(vi) a group of the formula -CONR57R56, where each of R57 and R58 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, or cycloalkyl having from 3 to 6 carbon atoms, or in which R57 and R58 form saturated a hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and where one of R57 and R58 can additionally be the group R43,

(vii) a group of the formula -COR59, where R59 represents a hydrogen atom, straight or branched or alkyl having from 1 to 5 carbon atoms, cycloalkyl having from 3 to 5 carbon atoms, or R43,

(viii) a group of the formula -OR60, where R60 represents a hydrogen atom, an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, or R43,

(ix) a group of the formula -SR61, where R61 represents a hydrogen atom, an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, or R43,

(x) cyano,

(xi) nitro, or

(xii) halogen,

R41 is:

aryl selected from the group consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5- pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5- pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5- triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, 3-, 6- or 7-indolizinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or 6-benzthiazolyl , 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolisinyl, 3-, 6- or 7-quinolinyl, 6- or 7-phthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-naphthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl, whereby one or more hydrogen atoms of the mentioned aryl group can be rebi and independently substituted with:

(A) R 62 , which is aryl selected from the group consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2 -, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3 -, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1 -, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, 3-, 6- or 7-indolizinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2- , 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2- , 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-quinolinyl, 6- or 7-phthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-naphthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl,

where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with:

(i) a branched or unbranched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or polysubstituted with halogen or oxo,

(ii) -COOH,

(iii) -SO2OH,

(iv) -PO(OH)2,

(v) a group of the formula -COOR63, where R63 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms,

(vi) a group of the formula -NR64R65, where each of R64 and R65 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms , or in which R64 and R65 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,

(vii) a group of the formula -CONR66R67, where each of R66 and R67 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms or cycloalkyl having from 3 to 6 carbon atoms, or in which R66 and R67 form a saturated hydrocarbon a bridge that has from 3 to 5 carbon atoms that, together with the nitrogen atom between them, form a heterocyclic ring,

(viii) a group of the formula -OR68, where R68 represents a hydrogen atom, or an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms,

(ix) a group of the formula -SR69, where R69 represents a hydrogen atom, or an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms,

(x) cyano,

(xi) nitro, or

(xii) amidino group of the formula

[image]

in which each of R70, R71 and R72 independently represents a hydrogen atom or alkyl having from 1 to 3 carbon atoms, and in which two of R70, R71 and R72 may additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with nitrogen atom(s) between them to form a heterocyclic ring, or

(xiii) halogen,

(B) methyl, which can be mono- or polysubstituted with fluorine atoms and can additionally be monosubstituted with R62,

(C) a branched or unbranched alkyl group having from 2 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or polysubstituted with halogen or oxo,

(D) a group of the formula -COOR73, where R73 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms,

(E) a group of the formula -NR74R75, where each of R74 and R75 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms , or in which R74 and R75 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and where one of R74 and R75 may additionally be the group R62,

(F) a group of the formula -CONR76R77, where each of R76 and R77 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, or cycloalkyl having from 3 to 6 carbon atoms, or in which R76 and R77 form saturated a hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and where one of R76 and R77 may additionally be the group R62,

(G) a group of the formula -COR78, where R78 represents a hydrogen atom, straight or branched or alkyl having from 1 to 5 carbon atoms, cycloalkyl having from 3 to 5 carbon atoms, or R62,

(H) a group of the formula -OR79, where R79 represents a hydrogen atom, an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, or R62,

(I) a group of the formula -SR80, where R80 represents a hydrogen atom, an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, or R62,

(J) cyano,

(K) nitro, or

(L) halogen,

R 4 is Cl or trifluoromethyl; and

each of R5 and R6 independently represents hydrogen, a fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl;

or pharmaceutically acceptable salts thereof.

As mentioned above, some of the compounds included in the class of compounds described above are known and described in U.S. Pat. patent 3,668,217; LOUSE. patent 4,944,791; LOUSE. patent number 3,741,981; Li, W.-Y., et al., J. Pharm. Sci. 1984, 73, 553-558 and Abd El Halim, M.S., et al., Monatshefte für Chemie, 1994, 125, 1437-1442.

In another aspect, the invention includes novel compounds of formula I

[image]

wherein X, Y, Z, R 2 , R 3 , R 4 , R 5 and R 6 are as defined above except that in the group R 3 at least one of the hydrogen atoms in the aryl group R 41 is necessarily, rather than necessarily, replaced by:

(A) R 62 , which is aryl selected from the group consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2 -, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3 -, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1 -, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, 3-, 6- or 7-indolizinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2- , 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2- , 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-quinolinyl, 6- or 7-phthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-naphthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl,

wherein one or more hydrogen atoms of the mentioned aryl group can be independently substituted with

(i) a branched or unbranched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or polysubstituted with halogen or oxo,

(ii) -COOH,

(iii) -SO2OH,

(iv) -PO(OH)2,

(v) a group of the formula -COOR63, where R63 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms,

(vi) a group of the formula -NR64R65, where each of R64 and R65 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms , or in which R64 and R65 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,

(vii) a group of the formula -CONR66R67, where each of R66 and R67 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms, or in which R66 and R67 form a saturated hydrocarbon a bridge that has from 3 to 5 carbon atoms that, together with the nitrogen atom between them, form a heterocyclic ring,

(viii) a group of the formula -OR68, where R68 represents a hydrogen atom, or an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms,

(ix) a group of the formula -SR69, where R69 represents a hydrogen atom, or an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms,

(x) cyano,

(xi) nitro,

(xii) amidino group of the formula

[image]

in which each of R70, R71 and R72 independently represents a hydrogen atom or alkyl having from 1 to 3 carbon atoms, and in which two of R70, R71 and R72 may additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with nitrogen atom(s) between them to form a heterocyclic ring, or

(xiii) halogen,

(B) methyl, which can be mono- or polysubstituted with fluorine atoms and can additionally be monosubstituted with R62,

(C) a branched or unbranched alkyl group having from 2 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or polysubstituted with halogen or oxo,

(D) a group of the formula -COOR73, where R73 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms,

(E) a group of the formula -NR74R75, where each of R74 and R75 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms , or in which R74 and R75 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and where one of R74 and R75 may additionally be the group R62,

(F) a group of the formula -CONR76R77, where each of R76 and R77 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms, or in which R76 and R77 form a saturated hydrocarbon a bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and where one of R76 and R77 can additionally be the group R62,

(G) a group of the formula -COR78, where R78 represents a hydrogen atom, straight or branched or alkyl having from 1 to 5 carbon atoms, cycloalkyl having from 3 to 5 carbon atoms, or R62,

(H) a group of the formula -OR79, where R79 represents a hydrogen atom, an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, or R62,

(I) a group of the formula -SR80, where R80 represents a hydrogen atom, an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, or R62,

(J) cyano,

(K) nitro, or

(L) halogenim;

or pharmaceutically acceptable salts thereof.

Preferred compounds of formula I are those in which:

Y is an oxygen or sulfur atom;

Z is an oxygen or sulfur atom;

X is a divalent group of the formula >CHR1, >NR1, >CHSO2R1, or >NSO2R1, or an oxygen or sulfur atom, where

R1 is:

(A) hydrogen atom,

(B) a branched or unbranched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group may be mono- or polysubstituted with:

(i) halogen,

(ii) oxo,

(iii) aryl selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolizinyl , isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, quinolinyl, phthalaninyl, quinoxalinyl, naphthyridinyl, pteridinyl and quinazolinyl,

whereby one or more hydrogen atoms of the mentioned aryl group can be independently replaced with:

(a) alkyl having 1 to 3 carbon atoms,

(b) -COOH,

(c) -SO2OH,

(d) -PO(OH)2,

(e) a group of the formula -COOR7, where R7 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms,

(f) a group of the formula -NR8R9, where each of R8 and R9 independently represents a hydrogen atom, alkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms, or in which R8 and R9 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which, together with the nitrogen atom between them, form a heterocyclic ring,

(g) a group of the formula -CONR10R11, where each of R10 and R11 independently represents a hydrogen atom, an alkyl having from 1 to 6 carbon atoms or a cycloalkyl having from 3 to 6 carbon atoms, or in which R10 and R11 form a saturated hydrocarbon bridge that has from 3 to 5 carbon atoms which, together with the nitrogen atom between them, form a heterocyclic ring,

(h) a group of the formula -OR12a, where R12a represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms,

(i) a group of the formula -SR12b, where R12b represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms,

(j) cyano, or

(k) amidino group of the formula

[image]

in which each of R13, R14 and R15 independently represents a hydrogen atom or alkyl having from 1 to 3 carbon atoms and in which two of R13, R14 and R15 can additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with nitrogen atom(s) between them to form a heterocyclic ring,

(iv) a group of the formula -COOR16, where R16 represents straight or branched alkyl having from 1 to 7 carbon atoms or cycloalkyl having from 3 to 6 carbon atoms,

(v) cyano,

(vi) a group of the formula -CONR17R18, where each of R17 and R18 independently represents a hydrogen atom, an alkyl having from 1 to 6 carbon atoms or a cycloalkyl having from 3 to 6 carbon atoms, or in which R17 and R18 form a saturated hydrocarbon bridge that has from 3 to 5 carbon atoms which, together with the nitrogen atom between them, form a heterocyclic ring,

(vii) a group of the formula -OR19, where R19 represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms,

(viii) a group of the formula -SR20, where R20 represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms,

(ix) a group of the formula -NR21R22, where each of R21 and R22 independently represents:

(a) hydrogen atom,

(b) alkyl or acyl having from 1 to 7 carbon atoms or cycloalkyl having from 3 to 7 carbon atoms,

(c) a group of the formula -(CH2)mCOOH, where m is 0, 1 or 2, or

(d) a group of the formula -(CH2)nCOOR23, where n is 0, 1 or 2, and R23 is straight or branched alkyl having from 1 to 6 carbon atoms,

or where R21 and R22 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, or

(x) by the quaternary group of the formula

[image]

in which each of R24, R25 and R26 independently represents a branched or unbranched alkyl group having from 1 to 7 carbon atoms and Q- is a chlorine, bromine or iodine ion of the opposite charge,

(C) branched or unbranched carboxylic acid group having from 3 to 6 carbon atoms,

(D) branched or unbranched phosphonic acid group having from 2 to 6 carbon atoms,

(E) a branched or unbranched sulfonic acid group having from 2 to 6 carbon atoms,

(F) amidino group of the formula

[image]

in which r is 2, 3, 4, 5 or 6, and

each of R27, R28 and R29 independently represents a hydrogen atom or alkyl having from 1 to 3 carbon atoms and in which two of R27, R28 and R29 can additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with a nitrogen atom ( atoms) between them form a heterocyclic ring,

(G) guanidino group of the formula

[image]

in which s is 2, 3, 4, 5 or 6, i

each of R30, R31, R32 and R33 independently represents a hydrogen atom or alkyl having from 1 to 3 carbon atoms and in which two of R30, R31, R32 and R33 can additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with nitrogen atom(s) between them form a heterocyclic ring, or

(H) piperidyl, in which the nitrogen atom of the mentioned group is optionally substituted with:

(i) alkyl having 1 to 3 carbon atoms,

(ii) a carboxyl ester group having 2 to 7 carbon atoms,

(iii) a carboxylic acid group that has from 2 to 5 carbon atoms,

(iv) a phosphonic acid group having from 1 to 6 carbon atoms, or

(v) a sulfonic acid group having from 1 to 6 carbon atoms;

R2 is:

(A) hydrogen atom, or

(B) methyl;

R3 is a group of the formula -CH2R41, in which:

R41 is:

aryl selected from the group consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5- pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5- pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5- triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, 3-, 6- or 7-indolizinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or 6-benzthiazolyl , 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolisinyl, 3-, 6- or 7-quinolinyl, 6- or 7-phthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-naphthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl,

whereby one or more hydrogen atoms of the mentioned aryl group are necessarily and independently substituted with:

(A) R 62 , which is aryl selected from the group consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2 -, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3 -, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1 -, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, 3-, 6- or 7-indolizinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 3- , 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2- , 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-quinolinyl, 6- or 7-phthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-naphthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl,

where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with:

(i) a branched or unbranched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or polysubstituted with halogen or with oxo,

(ii) -COOH,

(iii) -SO2OH,

(iv) -PO(OH)2,

(v) a group of the formula -COOR63, where R63 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms,

(vi) a group of the formula -NR64R65, where each of R64 and R65 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms , or in which R64 and R65 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,

(vii) a group of the formula -CONR66R67, where each of R66 and R67 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms or cycloalkyl having from 3 to 6 carbon atoms, or in which R66 and R67 form a saturated hydrocarbon a bridge that has from 3 to 5 carbon atoms that, together with the nitrogen atom between them, form a heterocyclic ring,

(viii) a group of the formula -OR68, where R68 represents a hydrogen atom, or an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms,

(ix) a group of the formula -SR69, where R69 represents a hydrogen atom, or an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms,

(x) cyano,

(xi) nitro,

(xii) amidino group of the formula

[image]

in which each of R70, R71 and R72 independently represents a hydrogen atom or alkyl or fluoroalkyl having from 1 to 3 carbon atoms, and in which two of R70, R71 and R72 may additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,

(xiii) halogen,

(B) methyl, which can be mono- or polysubstituted with fluorine atoms and can additionally be monosubstituted with R62,

(C) a branched or unbranched alkyl group having from 2 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or polysubstituted with halogen or with oxo,

(D) a group of the formula -COOR73, where R73 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms,

(E) a group of the formula -NR74R75, where each of R74 and R75 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms , or in which R74 and R75 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and where one of R74 and R75 may additionally be the group R62,

(F) a group of the formula -CONR76R77, where each of R76 and R77 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, or cycloalkyl having from 3 to 6 carbon atoms, or in which R76 and R77 form saturated a hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and where one of R76 and R77 may additionally be the group R62,

G) the group of the formula -COR78, where R78 represents a hydrogen atom, straight or branched alkyl having from 1 to 5 carbon atoms, cycloalkyl having from 3 to 5 carbon atoms, or R62,

(H) a group of the formula -OR79, where R79 represents a hydrogen atom, an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, or R62,

(I) a group of the formula -SR80, where R80 represents a hydrogen atom, an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, or R62,

(J) cyano,

(K) nitro, or

(L) halogen,

R 4 is Cl or trifluoromethyl; and

each of R5 and R6 independently represents hydrogen, a fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl;

or pharmaceutically acceptable salts thereof.

Even more advantageous are those new compounds of formula I in which:

Y is an oxygen atom;

Z is an oxygen atom;

X is a divalent group of the formula >CHR1 or >NR1, where

R1 is:

(A) hydrogen atom,

(B) a branched or unbranched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group may be mono- or polysubstituted with:

(i) oxo,

(ii) aryl selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl and triazinyl,

where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with:

(a) alkyl having 1 to 3 carbon atoms,

(b) -COOH,

(c) -SO2OH,

(d) -PO(OH)2,

(e) a group of the formula -COOR7, where R7 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms,

(f) group of the formula -NH2,

(g) group of the formula -CONH2,

(h) a group of the formula -OR12a, where R12a represents a hydrogen atom or methyl,

(i) amidino group of the formula

[image]

in which each of R13, R14 and R15 independently represents hydrogen atoms,

(iii) a group of the formula -COOR16, where R16 represents straight or branched alkyl having from 1 to 7 carbon atoms or cycloalkyl having from 3 to 6 carbon atoms,

(iv) a group of the formula -OR19, where R19 represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms, or

(v) quaternary group of the formula

[image]

in which each of R24, R25 and R26 independently represents methyl and Q- is an oppositely charged chlorine, bromine or iodine ion,

(C) branched or unbranched carboxylic acid group having from 3 to 6 carbon atoms,

(D) branched or unbranched phosphonic acid group having from 2 to 6 carbon atoms,

(E) a branched or unbranched sulfonic acid group having from 2 to 6 carbon atoms,

(F) amidino group of the formula

[image]

in which r is 2, 3, 4, 5 or 6, and

each of R27, R28 and R29 independently represents hydrogen atoms,

(G) guanidino group of the formula

[image]

where s is 2, 3, 4, 5 or 6,

each of R30, R31, R32 and R33 independently represents hydrogen atoms, or

(H) piperidyl, in which the nitrogen atom of the mentioned group is optionally substituted with:

(i) alkyl having 1 to 3 carbon atoms,

(ii) a carboxyl ester group having 2 to 7 carbon atoms,

(iii) a carboxylic acid group that has from 2 to 5 carbon atoms,

(iv) a phosphonic acid group having from 1 to 6 carbon atoms, or

(v) a sulfonic acid group having from 1 to 6 carbon atoms;

R2 is:

(A) hydrogen atom, or

(B) methyl;

R3 is a group of the formula -CH2R41, in which

R41 is aryl selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl and triazinyl,

whereby one or more hydrogen atoms of the mentioned aryl group are necessarily and independently substituted with:

(A) R 62 , which is aryl selected from the group consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl and triazinyl,

where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with:

(i) methyl,

(ii) -COOH,

(iii) -SO2OH,

(iv) -PO(OH)2,

(v) a group of the formula -COOR63, where R63 represents methyl,

(vi) a group of the formula -NR64R65, where each of R64 and R65 independently represents a hydrogen atom or methyl,

(vii) a group of the formula -CONR66R67, where each of R66 and R67 independently represents a hydrogen atom or methyl,

(viii) a group of the formula -OR68, where R68 represents a hydrogen atom or methyl,

(ix) a group of the formula -SR69, where R69 represents a hydrogen atom or methyl,

(x) cyano,

(xi) nitro, or

(xii) halogen,

(B) methyl, which can be mono- or polysubstituted with fluorine atoms and which can additionally be monosubstituted with R62,

(C) a branched or unbranched alkyl group having from 2 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or polysubstituted with halogen or oxo,

(D) a group of the formula -COOR73, where R73 represents methyl,

(E) a group of the formula -NR74R75, where each of R74 and R75 independently represents a hydrogen atom or methyl, and in which one of R74 and R75 can additionally be the group R62,

(F) a group of the formula -CONR76R77, where each of R76 and R77 independently represents a hydrogen atom or methyl, and in which one of R76 and R77 can additionally be a group R62,

(G) a group of the formula -COR78, where R78 represents a hydrogen atom or methyl, or R62,

(H) a group of the formula -OR79, where R79 represents a hydrogen atom, methyl, or R62,

(I) a group of the formula -SR80, where R80 represents a hydrogen atom, methyl, or R62,

(J) cyano,

(K) nitro, or

(L) halogenim;

R 4 is Cl or trifluoromethyl;

R5 is a hydrogen atom; and

R 6 is Cl, or trifluoromethyl;

or pharmaceutically acceptable salts thereof.

Even more preferable are those new compounds of formula I in which:

Y is an oxygen atom;

Z is an oxygen atom;

X is a divalent group of the formula >CHR1 or >NR1, where

R1 is:

(A) hydrogen atom,

(B) a branched or unbranched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group may be mono- or polysubstituted with:

(i) oxo,

(ii) aryl selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl and triazinyl,

where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with:

(a) alkyl having 1 to 3 carbon atoms,

(b) -COOH,

(c) -SO2OH,

(d) -PO(OH)2,

(e) a group of the formula -COOR7, where R7 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms,

(f) group of the formula -NH2,

(g) group of the formula -CONH2,

(h) a group of the formula -OR12a, where R12a represents a hydrogen atom or methyl,

(i) amidino group of the formula

[image]

in which each of R13, R14 and R15 independently represents hydrogen atoms,

(iii) a group of the formula -COOR16, where R16 represents straight or branched alkyl having from 1 to 7 carbon atoms or cycloalkyl having from 3 to 6 carbon atoms,

(iv) a group of the formula -OR19, where R19 represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms, or

(v) quaternary group of the formula

[image]

in which each of R24, R25 and R26 independently represents methyl and Q- is an oppositely charged chlorine, bromine or iodine ion,

(C) branched or unbranched carboxylic acid group having from 3 to 6 carbon atoms,

(D) branched or unbranched phosphonic acid group having from 2 to 6 carbon atoms,

(E) a branched or unbranched sulfonic acid group having from 2 to 6 carbon atoms,

(F) amidino group of the formula

[image]

in which r is 2, 3, 4, 5 or 6, and

each of R27, R28 and R29 independently represents hydrogen atoms,

(G) guanidino group of the formula

[image]

in which s is 2, 3, 4, 5 or 6, i

each of R30, R31, R32 and R33 independently represents hydrogen atoms, or

(H) piperidyl, in which the nitrogen atom of the mentioned group is optionally substituted with:

(i) alkyl having 1 to 3 carbon atoms,

(ii) a carboxyl ester group having 2 to 7 carbon atoms,

(iii) a carboxylic acid group that has from 2 to 5 carbon atoms,

(iv) a phosphonic acid group having from 1 to 6 carbon atoms,

(v) a sulfonic acid group having from 1 to 6 carbon atoms;

R2 is:

(A) hydrogen atom, or

(B) methyl;

R3 is a group of the formula -CH2R41, in which

R41 is aryl selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl and pyrazinyl,

whereby one or more hydrogen atoms of the mentioned aryl group are necessarily and independently substituted with:

(A) R 62 , which is aryl selected from the group consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl and pyrazinyl,

where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with:

(i) methyl,

(ii) -COOH,

(iii) the group of the formula -COOR63, where R63 represents methyl,

(iv) a group of the formula -OR68, where R68 represents a hydrogen atom or methyl, or

(v) halogen,

(B) methyl, which can be mono- or polysubstituted with fluorine atoms or which can be monosubstituted with R62,

(C) a branched or unbranched alkyl group having from 2 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or polysubstituted with halogen or oxo,

(D) a group of the formula -COOR73, where R73 represents methyl,

(E) a group of the formula -CONR76R77, where each of R76 and R77 represents methyl, and in which one of R76 and R77 can additionally be a group R62,

(F) a group of the formula -COR78, where R78 represents a hydrogen atom, methyl or R62,

(G) a group of the formula -OR79, where R79 represents a hydrogen atom, methyl or R62,

(H) cyano,

(I) nitro, or

(J) halogen,

R 4 is Cl or trifluoromethyl;

R5 is a hydrogen atom; and

R 6 is Cl or trifluoromethyl;

or pharmaceutically acceptable salts thereof.

Also, new compounds of formula I in which:

Y is an oxygen atom;

Z is an oxygen atom;

X is a divalent group of the formula >CHR1 or >NR1, where

R1 is:

(A) hydrogen atom,

(B) a branched or unbranched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group may be mono- or polysubstituted with:

(i) oxo,

(ii) aryl selected from the class consisting of phenyl or pyridyl,

where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with:

(a) alkyl having 1 to 3 carbon atoms,

(b) -COOH,

(c) -SO2OH,

(d) -PO(OH)2,

(e) a group of the formula -OR12a, where R12a represents a hydrogen atom or methyl,

(f) amidino group of the formula

[image]

in which each of R13, R14 and R15 independently represents hydrogen atoms,

(iii) a group of the formula -OR19, where R19 represents a hydrogen atom, or

(iv) an alkyl or acyl group having from 1 to 7 carbon atoms, or

(v) quaternary group of the formula

[image]

in which each of R24, R25 and R26 independently represents methyl and Q- is an oppositely charged chlorine, bromine or iodine ion,

(C) branched or unbranched carboxylic acid group having from 3 to 6 carbon atoms,

(D) branched or unbranched phosphonic acid group having from 2 to 6 carbon atoms,

(E) a branched or unbranched sulfonic acid group having from 2 to 6 carbon atoms,

(F) amidino group of the formula

[image]

in which r is 2, 3, 4, 5 or 6, and

each of R27, R28 and R29 independently represents hydrogen atoms,

(G) guanidino group of the formula

[image]

where s is 2, 3, 4, 5 or 6,

each of R30, R31, R32 and R33 independently represents hydrogen atoms, or

(H) piperidyl, in which the nitrogen atom of the mentioned group is optionally substituted with:

(i) alkyl having 1 to 3 carbon atoms,

(ii) a carboxyl ester group having 2 to 7 carbon atoms,

(iii) a carboxylic acid group that has from 2 to 5 carbon atoms,

(iv) a phosphonic acid group having from 1 to 6 carbon atoms, or

(v) a sulfonic acid group having from 1 to 6 carbon atoms;

R2 is:

(A) hydrogen atom, or

(B) methyl;

R3 is a group of the formula -CH2R41, in which

R41 is aryl selected from the class consisting of phenyl or pyridyl,

whereby one or more hydrogen atoms of the mentioned aryl group are necessarily and independently substituted with:

(A) R62, which is aryl selected from the group consisting of phenyl, or pyridyl,

where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with:

(i) methyl,

(ii) -COOH,

(iii) the group of the formula -COOR63, where R63 represents methyl,

(iv) a group of the formula -OR68, where R68 represents a hydrogen atom or methyl, or

(vi) halogen,

(B) methyl, which can be mono- or polysubstituted with fluorine atoms or which can additionally be monosubstituted with R62,

(C) a branched or unbranched alkyl group having from 2 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or polysubstituted with fluorine or with oxo,

(D) a group of the formula -COOR73, where R73 represents methyl,

(E) a group of the formula -CONR76R77, where each of R76 and R77 represents methyl, in which one of R76 and R77 is methyl and the other is the group R62,

(F) a group of the formula -COR78, where R78 represents a hydrogen atom, methyl or R62,

(G) a group of the formula -OR79, where R79 represents a hydrogen atom, methyl or R62,

(K) cyano,

(L) nitro, or

(M) halogen;

R4 is a chlorine atom or trifluoromethyl;

R5 is a hydrogen atom; and

R 6 is a chlorine atom or trifluoromethyl;

or pharmaceutically acceptable salts thereof.

Especially preferred new compounds of formula I are those in which:

Y is an oxygen atom;

Z is an oxygen atom;

X is a divalent group of the formula >CHR1 or >NR1, where

R1 is:

(A) hydrogen atom,

(B) alkyl having from 1 to 2 carbon atoms which may be monosubstituted with:

(i) oxo,

(ii) aryl selected from the class consisting of phenyl or pyridyl,

where one hydrogen atom of the mentioned aryl group can be replaced by:

(a) alkyl having 1 to 3 carbon atoms,

(b) -COOH,

(c) -SO2OH,

(d) -PO(OH)2,

(e) a group of the formula -OR12a, where R12a represents a hydrogen atom or methyl, or

(f) amidino group of the formula

[image]

wherein each of R13, R14 and R15 represents hydrogen atoms, or

(iii) a group of the formula -OR19, where R19 represents a hydrogen atom or methyl,

(C) branched or unbranched carboxylic acid group having from 3 to 6 carbon atoms,

(D) branched or unbranched phosphonic acid group having from 2 to 6 carbon atoms,

(E) a branched or unbranched sulfonic acid group having from 2 to 6 carbon atoms,

(F) amidino group of the formula

[image]

in which r is 2, 3, 4, 5 or 6, and

each of R27, R28 and R29 represents hydrogen atoms, or

(G) guanidino group of the formula

[image]

where s is 2, 3, 4, 5 or 6,

each of R30, R31, R32 and R33 independently represents hydrogen atoms,

R2 is:

(A) hydrogen atom, or

(B) methyl;

R3 is a group of the formula -CH2R41, in which

R41 is phenyl,

whereby one or more hydrogen atoms of the mentioned phenyl group are necessarily and independently replaced by:

(A) R 62 , which is aryl selected from the group consisting of phenyl or, pyridyl,

where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with:

(i) methyl,

(ii) a group of the formula -COOR63, where R63 represents methyl,

(iii) a group of the formula -OR68, where R68 represents a hydrogen atom or methyl, or

(iv) halogen,

(B) methyl, which can be mono- or polysubstituted with fluorine atoms or which can be monosubstituted with R62,

(C) a group of the formula -COOR73, where R73 represents methyl,

(D) a group of the formula -COR78, where R78 represents methyl or R62,

(E) a group of the formula -OR79, where R79 represents a hydrogen atom, methyl, or R62,

(F) cyano,

(G) nitro, or

(H) halogen,

R4 is a chlorine atom or trifluoromethyl;

R5 is a hydrogen atom; and

R 6 is a chlorine atom or trifluoromethyl;

or pharmaceutically acceptable salts thereof.

However, even more special preferred novel compounds of formula I are those in which:

Y is an oxygen atom;

Z is an oxygen atom;

X is a divalent group of the formula >NR1, where

R1 is:

(A) hydrogen atom,

(B) methyl or ethyl, or

(C) -COCH3;

R2 is:

(A) hydrogen atom, or

(B) methyl;

R3 is a group of the formula -CH2R41, in which

R41 is phenyl,

whereby one or more hydrogen atoms of the mentioned phenyl group are necessarily and independently replaced by:

(A) R62, which is aryl selected from the group consisting of phenyl, or pyridyl,

where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with:

(i) methyl,

(ii) a group of the formula -COOR63, where R63 represents methyl,

(iii) a group of the formula -OR68, where R68 represents a hydrogen atom or methyl, or

(vi) halogen,

(B) methyl, which can be mono- or polysubstituted with fluorine atoms or which can be monosubstituted with R62,

(C) a group of the formula -COOR73, where R73 represents methyl,

(D) a group of the formula -COR78, where R78 represents methyl or R62,

(E) a group of the formula -OR79, where R79 represents a hydrogen atom, methyl, or R62,

(F) cyano,

(G) nitro, or

(H) halogen,

R4 is a chlorine atom or trifluoromethyl;

R5 is a hydrogen atom; and

R 6 is a chlorine atom or trifluoromethyl;

or pharmaceutically acceptable salts thereof.

The penultimate preferred novel compounds of formula I are those in which:

Y is an oxygen atom;

Z is an oxygen atom;

X is a divalent group of the formula >NR1, where

R1 is:

(A) hydrogen atom,

(B) methyl or ethyl, or

(C) -COCH3;

R2 is:

(A) hydrogen atom, or

(B) methyl;

R3 is a group of the formula -CH2R41, in which

R41 is phenyl,

whereby one or more hydrogen atoms of the mentioned phenyl group are necessarily and independently replaced by:

(A) R62, which is aryl selected from the group consisting of phenyl, or pyridyl,

where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with:

(i) methyl,

(ii) halogen,

(B) methyl, which can be mono- or polysubstituted with fluorine atoms,

(C) a group of the formula -COR78, where R78 represents methyl, or R62,

(D) halogen,

R4 is a chlorine atom;

R5 is a hydrogen atom; and

R 6 is a chlorine atom;

or pharmaceutically acceptable salts thereof.

Finally, preferred new compounds of formula I are especially compounds having the following structures:

[image]

or pharmaceutically acceptable salts thereof.

Synthesis of the compounds of the invention

The synthesis of compounds similar to the compounds of the invention is well known in the art. Depending on the purpose, some routes may be better for obtaining small amounts of different compounds, while other routes may be much more suitable for synthesizing a large amount of a particular compound. Several routes to these compounds and examples of compounds that were synthesized by the respective routes are presented below.

The starting amino acids and their derivatives required for the synthesis of hydanthion and thio-hydantoin structures are commercially available or can be produced by obvious modifications of procedures known from the literature (see, for example, Williams, R.W. Synthesis of Optically Active α-Amino Acids; Pergamon: Oxford, 1989, α-Amino Acid Synthesis; O'Donnell, M.J., Ed.; Tetrahedron Symposium, in press; Pergamon: London, 1988: Vol. 44, 17th ed., Jung, M.J. Chemistry and Biochemistry of Amio Acids; Barrett, G. C., Ed. .; Chapman and Hall: New York, 1985; p. 227 and Spero, D. M.; Kapadia, S. R. J. Org. Chem. 1996, 61: 7398-7401). As an example, the synthesis and decomposition of ethyl 2-amino-2-(4-bromobenzyl)-propanoate (starting material for example 39) is given.

A solution of alanine ethyl ester hydrochloride (15.3 g, 99.3 mmol) in 60 ml of water was stirred for 30 minutes at room temperature with triethylamine (14.6 ml, 104.8 mmol). The mixture is then extracted twice with 100 ml of methylene chloride. The organic layers are combined, dried over sodium sulfate and concentrated in vacuo to give 10.0% free amino ester base (86% yield). The residue is redissolved in methylene chloride and cooled in an ice bath. Magnesium sulfate (11.3 g, 93.9 mmol) was added followed by trimethyl acetaldehyde (9.3 mL, 85.6 mmol). The ice bath was removed and the mixture was stirred overnight. The magnesium sulfate is removed by filtration and the filtrate is concentrated in vacuo to give 11.8 g of the imine intermediate (74.6% yield).

The above imine (11.8 g, 63.7 mmol) was dissolved in toluene (90 mL), 4-bromobenzyl bromide (17.5 g, 70.1 mmol) was added and the reaction mixture was cooled to approx. -10oC. Potassium tert.butoxide (8.6 g, 76.5 mmol) is added at such a rate that the temperature does not exceed 0°C. The reaction mixture was stirred in a cold bath for two hours, then diluted with ether and washed with water (150 ml). The organic layer is dried (sodium sulfate), filtered and concentrated in vacuo to give a clear yellow oil. This was mixed with 1N HCl (100 mL, 100 mmol) and stirred overnight. The reaction mixture was extracted with ethyl acetate (100 ml) and 14.1 g of racemic amino ester hydrochloride was obtained from the aqueous layer (yield 68.7%).

Racemic compounds can be separated into their component enantiomers by a number of known methods. Ethyl 2-(R)-amino-2-(4-bromobenzyl)-propanoate (starting material for Example 29) was prepared from racemic ethyl 2-amino-2-(4-bromobenzyl)-propanoate by the following procedure. To 1.3 L of buffer prepared from 13.69 g of KH 2 PO 4 and 2 L of water was added 20 g of commercially available enzyme lipase L10 (Amano Enzyme USA Co., Ltd, Lombardi, IL) followed by 12 g of the HCl salt of the racemic amino ester. The pH is observed and 1N KOH is added as needed to maintain the pH of the mixture at 6.4. The course of the reaction is monitored using reverse phase HPLC and after 2 days HPLC analysis shows that 50.4% of the starting material has hydrolyzed. At this point, sufficient solid NaHCO 3 is added and the pH is adjusted to 8.1 and the mixture is extracted twice with toluene, ether and EtOAc. The combined organic layers were dried and concentrated and the crude product was purified by chromatography on silica gel (EtOAc:hexane) to give 5.21 g (87%) of ethyl 2-(R)-amino-2-(4-bromobenzyl)-propanoate .

Method A.

Starting material amino acid and phenylisocyanate.

Cyclization with acid.

The releasing amino acid is dissolved in an aqueous base (such as, for example, NaOH, KOH, Na2CO3, NaHCO3, K2CO3 or KHCO3) and heated to a temperature between 20 and 90oC. The appropriate isocyanate is added to the mixture and the resulting solution is stirred mostly until the reaction is complete. When cooled, the mixture is acidified and the resulting ureido-acetic acid is isolated by filtration or extraction into an organic solvent. By removing the solvent, the ureido-acetic acid intermediate is obtained. In the manner described by Sauli (US Patent 4,099,008) the ureido-acetic acid intermediate is cyclized by heating in the presence of a catalytic amount of acid (such as, for example, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, or hydrochloric acid) in organic or aqueous solvent, which gives the desired hydantoin. The processing consists in the collection of hydantoin by filtration and purification, for example, by silica gel chromatography or recrystallization.

The compounds listed in Table 1 were produced by this general method.

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Method A is illustrated by the synthesis of the compound of Example 12 (see Table 1), which was carried out as follows. Homophenylalanine (1.00 g, 5.58 mmol) was dissolved in a solution of NaOH (0.28 g, 6.69 mmol) in water (10.0 ml) and heated at 45°C. When the solution becomes homogeneous, 3,5-dichlorophenyl isocyanate (1.05 g, 5.58 mmol) is added and the mixture is heated for another 2 hours at 45oC. The reaction mixture was cooled and then acidified with concentrated HCl to pH 2-3. The precipitate is collected by filtration, washed with water and dried in a vacuum at 50oC, which gives 0.85 g of intermediate ureido-acetic acid (crude yield 42%). The intermediate is then taken up in a solution of concentrated HCl (5.0 ml) and water (5.0 ml) and heated under reflux for 5 hours. The reaction mixture was cooled to room temperature and the white solid was collected by suction filtration, washed with water and dried in vacuo at 50°C, yielding 0.52 g of crude hydantoin. This material was purified by recrystallization from EtOH to give 0.37 g (45%) of the compound from Example 12.

Method B.

Starting materials amino acid and phenylisocyanate.

Cyclization with EDC.

The releasing amino acid is dissolved in an aqueous base (such as NaOH, KOH, Na2CO3, NaHCO3, K2CO3 or KHCO3) and heated to a temperature between 20 and 90oC. The appropriate isocyanate is added to this mixture and the resulting solution is stirred mostly until the reaction is complete. When it cools, the mixture is acidified and the resulting ureido-acetic acid is isolated by filtration or extraction into an organic solvent. By removing the solvent, the ureido-acetic acid intermediate is obtained. The ureido-acetic acid intermediate is then cyclized to the desired hydantoin in an organic solvent (such as, for example, DMF, NMP, or THF) using any of a number of dehydrating agents (such as, for example, dicyclohexylcarbodiimide (DCC) or 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (EDC) in the presence of an ester activating agent (such as 1-hydroxybenzotriazole hydrate (HOBT)) and a non-nucleophilic base (such as, for example, triethylamine or N,N-diisopropyl -ethylamine).The treatment consists in extraction into an organic solvent and then purification, for example, by silica gel chromatography or recrystallization.

The compounds listed in Table 2 were produced by this general method.

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Method B is illustrated by the synthesis of the compound of Example 15 (see Table 2), which was carried out as follows. 3,5-dichlorophenyl isocyanate (0.38 g, 2 mmol) is added to a solution of (R)-phenylalanine (0.33 g, 2 mmol) in 1 l of 2N NaOH solution and 10 ml of water at 50°C. The resulting mixture is then stirred for another 1 hour. The solution is cooled and mixed with concentrated HCl until a precipitate is obtained and the solution remains acidic. The precipitate was collected by filtration and dried in vacuo to give the desired ureidoacetic acid (0.60 g, 85%). Ureidoacetic acid (0.35 g, 1 mmol) was dissolved in 20 ml of DMF and stirred for 1 hour at room temperature with EDC (0.19 g, 1 mmol) and HOBT (0.14 g, 1 mmol). After this period, N,N-diisopropylethylamine (0.35 ml, 2 mmol) was added and the mixture was stirred overnight. Processing consists of trituration with water, collection of hydantoins by filtration and purification by silica gel chromatography. The yield in this example was 0.20 g (60%).

Method C.

Starting materials amino ester or hydroxy ester and phenylisocyanate. Cyclization with base or acid.

The releasing amino ester and the corresponding isocyanate are dissolved in an organic solvent (such as, for example, DMF, THF, or DMSO) in the presence of a base (such as, for example, NaOH, KOH, Na2CO3, NaHCO3, K2CO3, or KHCO3) and heated at a temperature between room temperature and 60oC. After 1 hour, the temperature of the reaction mixture is raised to between 50 and 100oC until it is seen that the reaction is complete. The solution is then cooled and diluted with an organic solvent (such as, for example, EtOAc or CH 2 Cl 2 ). The organic phase is then washed successively with dilute aqueous acid (eg 1N HCl) and water, dried (eg over MgSO4) and concentrated. The desired hydantoin is purified, for example, by silica gel chromatography or recrystallization. (Alternatively, the ureido-acetic ester can be cyclized to hydantoin by heating at a temperature between about 50 and 100oC in the presence of an acid such as, for example, aqueous HCl while observing that the reaction is complete).

The compounds listed in Table 3 were produced by this general method.

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Method C is illustrated by the synthesis of the compound of Example 30 in Table 3, which was carried out as follows. Methyl 2-amino-2-benzylbutyric acid (0.21 g, 1 mmol) and 3,5-dichlorophenyl isocyanate (0.19 g, 1 mmol) were dissolved in DMSO (5 mL) in the presence of approximately 0.2 g Na2CO3 and let them mix for 1 hour at 50oC. At the end of that period, the solution is heated for 2 hours at 90oC. The solution was then cooled, diluted with EtOAc and washed with 0.1 N HCl and water. The organic layer was dried over MgSO4 and concentrated to give the crude product which was further purified by silica gel chromatography to give 0.12 g (33%) of the compound from Example 30.

Method D.

Solid phase synthesis.

There are several examples in the literature showing that the synthesis of hydantoins and their precursor amino acid derivatives can be carried out on a solid phase, which can produce a large number of these compounds suitable for an automated approach. Primers for the synthesis of precursor derivatives of amino acids are presented in the following journals: J. American Chemical Society, 1996, 118, 6070-1, Tetrahedron Letters, 1997, 38, 7163-7166, Tetrahedron Letters, 1997, 38, 8821. Article in which conversion of an amino acid derivative to hydantoin was reported in J. Organic Chemistry 1997, 62, 6060-2.

An amino acid attached to the solid-phase resin by its carboxylic acid group, through a suitable linker (for example Wang's resin: 4-benzyloxy-benzyl polystyrene) is protected on its nitrogen with a reagent that will allow alkylation of the alpha-carbon (for example, derivatives of benzaldehyde that forms an imine with an amino acid nitrogen). The protected compound is further treated with a base and an alkylating agent, resulting in an amino acid derivative with a new protective group. The protecting group is removed using standard conditions (in the case of imines, for example, with aqueous HCl) and the free amino group reacts with the isocyanate, yielding the urea intermediate. This intermediate is mixed with a reagent that catalyzes the cyclization of the urea moiety at the carboxylate end of the molecule forming the desired hydantoin and the product is cleaved from the resin. Purification is done by chromatography on silica gel, reverse-phase HLPC or recrystallization.

The compounds listed in Table 4 were produced by this general method.

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Method D is illustrated by the synthesis of the compound of Example 67, which was carried out as follows. The reaction vessel was charged with commercially available Fmoc-Ala-Wang (300 mg, 0.150 mmol) and 3 ml of a 20% solution of piperidine in N-methyl pyrrolidinone (NMP). The reaction vessel is shaken for 45 minutes at room temperature on an orbital shaker. The resin is filtered off and washed with NMP (3x1 ml). The resin reaction vessel was sealed with a rubber stopper, placed under argon, and 3,4-dichlorobenzaldehyde (394 mg, 2.25 mmol) and trimethyl orthoformate (3.5 mL) and NMP (1.5 mL) were added. The resulting mixture is shaken for 15 hours at room temperature. The solid resin was isolated by filtration and washed successively with NMP (3x3 ml), tetrahydrofuran (3x3 ml) and CH2Cl2 (3x3 ml). The resin is then dried under vacuum for approximately one hour to obtain a resin with an imine intermediate.

The resin with the imine intermediate is alkylated with 2,3-difluoro-4-trifluoromethylbenzyl bromide (123.8 mg, 0.45 mmol) by mixing the two reagents, 2-tert.butylimino-2-diethylamino-1,3-dimethylperhydro-1 ,3,2-diazaphosphorine (BEMP, 0.217 ml, 0.75 mmol) and NMP (3.5 ml) and the mixture was shaken for 15 hours at room temperature on an orbital shaker. The solid substance is isolated by filtration and washed successively with NMP (3x3 ml), THF (3x3 ml) and CH2Cl2 (3x3 ml), which after drying gives the alkylated imine intermediate on the resin.

The imine was cleaved from the previous intermediate by treatment with aqueous 1N HCl (1.8 ml) and THF (3.6 ml) and shaking approx. 15 hours at room temperature. The amino ester bound to the resin was isolated by filtration and washed successively with NMP (3x3 ml), THF (3x3 ml) and CH2Cl2 (3x3 ml) and dried in vacuo.

The resin-bound amino ester is converted to hydantoin using a process that cleaves the final product from the resin. The intermediate amino ester was placed in a reaction vessel and mixed with 3 ml of a 20% solution of N,N-diisopropylethylamine in NMP. After shaking at room temperature, it is washed with NMP (3x3 ml) and with methanol (3x3 ml) and placed under vacuum. The vessel was then opened under argon and filled with 2.5 ml of a 1.75 M solution of 3,5-dichlorophenylisocyanate in dimethylformamide (DMF, 0.45 mmol). The mixture is shaken overnight under argon at room temperature and the product is separated by filtration. After washing the resin with ethyl acetate (6x2 ml), the combined organic layers are diluted with water and then washed with water (3x3 ml) and with saturated aqueous NaCl solution (2x3 ml), dried over sodium sulfate, filtered and concentrated under a stream of nitrogen . The purification ends with the application of HPLC reverse phases (gradient of acetonitrile and water).

Method E.

Starting materials isocyanate-ester and aniline.

Cyclization with base or acid.

To the appropriate isocyanate ester dissolved in an organic solvent (such as, for example, methylene chloride) is added the appropriate aniline and the mixture is stirred for between 1 and 24 hours at room temperature under an inert atmosphere such as argon. Then the organic solvent was removed in vacuo. Excess aniline is removed (by boiling the crude solid in hexane and decanting the liquid, or by vacuum chromatography over silica gel), leaving a solid ureido-acetic ester. The ureido-acetic ester is cyclized to the desired hydantoin by treatment with a base (such as, for example, NaH, NaHMDS, Na2CO3, NaHCO3, K2CO3 or KHCO3) in an organic solvent (such as THF or DMF) and then heating at approx. . 60-90oC. The solution is first cooled and diluted with an organic solvent (such as EtOAc). The organic solution is washed successively with dilute aqueous acid (such as 1N HCl) and then with water, dried (with MgSO4) and concentrated. The desired hydanthion is purified by silica gel chromatography or recrystallization. (Alternatively, the ureido-acetic ester intermediate can be cyclized to hydantoin by heating at approx. 90°C in the presence of an acid such as aqueous HCl, as mentioned in Method C).

The compounds listed in Table 5 were produced by this method.

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Method E is illustrated by the synthesis of the compound of Example 70 shown in Table 5, which was carried out as follows. To a solution of ethyl 2-isocyanato-3-phenylpropionate (99.0 mL, 0.110 g, 0.501 mmol) in dry CH2Cl2 (5.0 mL) was added 3,4,5-trichloroaniline (0.1952 g, 0.994 mmol) as solid substance. The mixture is stirred for 20 hours at room temperature in an argon atmosphere. The solution was then concentrated in vacuo and the residue was recrystallized twice from ethyl acetate/hexane to give 0.14 g (65%) of pure intermediate urea as a white solid. A suspension of sodium hydride (0.06 g of a 60% dispersion in mineral oil, 1.52 mmol) in dry THF (4.0 mL) was mixed with a solution of the above urea (0.108 g, 0.260 mmol) in dry THF- in (4.0 ml). The mixture is stirred for 1 hour at room temperature in an argon atmosphere. The mixture is then poured into 100 ml of 1N aqueous HCl. The THF was removed under reduced pressure and the mixture was filtered. The solid was purified by preparative thin layer chromatography (SiO2, 1:1 hexane/ethyl acetate) to give a solid which was further purified by recrystallization from absolute EtOH to give 0.027 g of the pure compound (28%).

Method F. Synthesis of succinimide.

Equimolar amounts of the appropriate starting diacids or anhydrides and the appropriate starting aniline are refluxed in a solvent (such as xylene) in the presence of a catalytic amount of base (such as triethylamine) between approx. 2 and 24 hours. The solvent is removed in vacuo and the residue is dissolved in an organic solvent (such as EtOAc), washed successively with aqueous dilute base (such as NaHCO3) and aqueous dilute acid (such as HCl), dried (eg over MgSO4) and thickens. Purification is done, for example, by recrystallization or chromatography over silica gel.

Starting diacids and anhydrides are commercially available or can be produced by methods known from the literature. As an example, the procedure for the synthesis of 2-benzyl-3-carboxy-2-methylbutanoic acid (starting material for example 74) is given.

A solution of 2.0 g of 2-methyl-3-phenylpropionic acid (12.2 mmol), 2.2 g of carbonyldiimidazole (CDI, 13.56 mmol) in 20 ml of THF was refluxed for 1 hour under nitrogen. The temperature was lowered to 50°C and 1.2 ml of crotyl alcohol (14.1 mmol) and then 20 mg of 4-(N,N-dimethylamino)-pyridine (DMAP) were added. The mixture is heated for 3 hours at 50oC, concentrated and purified by chromatography on silica gel, which gives 1.7 g of the intermediate ester: trans-2-butenyl-2-benzyl-3-carboxy-2-methylbutanoate (64%).

The ester undergoes a [3,3] sigmatropic rearrangement to give the following intermediate. In argon at -78oC to a solution of lithium diisopropylamide (LDA, 3.25 mmol, obtained from 1.3 ml of 2.5 M n-BuLi and 0.54 ml of Pr2NH in 3 ml of THF, -10oC, 15 min), containing 500 microliters of DMPU, was added to a solution of 560 mg of the intermediate ester (2.57 mmol) in THF (1 ml). The mixture was stirred for 30 minutes and then a solution of 480 mg of TBSCl (3.1 mmol) in 1 ml of THF was added. The mixture is stirred for 30 minutes at -78oC, 20 minutes at room temperature and then heated for 10 hours at 60oC. The mixture is cooled to 0°C, quenched with 2N HCl (5 ml) and stirred for 10 hours at room temperature. The mixture was basified to pH 10 with 2N NaOH, and extracted with ether (5 ml). The aqueous layer was separated, acidified to pH 1 with concentrated HCl, extracted with EtOAc and concentrated to give 500 mg (89%) of the intermediate: 2-benzyl-2,3-dimethyl-4-pentenoic acid.

The mono-acid is converted into the desired diacid by oxidation of the terminal alkene with ozone and the resulting intermediate is further oxidized with a chromium reagent. Through a solution of 500 mg of 2-benzyl-2,3-dimethyl-4-pentenoic acid (2.29 mmol) in MeOH (20 ml) and methylene chloride (10 ml) containing 120 microliters of pyridine, a sufficient stream of O3 is passed rapidly at -78oC, so that the solution returns to a slightly blue color. The mixture was mixed with 1 ml of methyl sulfide and stirred for 5 minutes at -78oC. The mixture is then warmed to room temperature, concentrated and passed through a silica gel column (with 10% MeOH in CH2Cl2 as eluent) and concentrated. The crude material is dissolved in 5 ml of acetone and mixed with Jones reagent (16 g CrO3, 16 g conc. H2SO4 in 100 ml water) at room temperature until the orange color becomes permanent. After the addition of water (10 ml), the mixture was stirred for 1 hour, washed with EtOAc and concentrated. The mixture was purified on silica gel by chromatography with 3% AcOH-EtOAc to give 300 mg of the desired di-acid (55%).

The compounds listed in Table 6 were produced by this method.

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Method F is illustrated by the synthesis of compounds from Examples 92 and 93 (see Table 6) which was carried out as follows. A mixture of isomers of the starting di-acid from Example 92 (0.58 g, 1.8 mmol, 3:1 mixture of isomers), 3,5-dichloroaniline (0.35 g, 2.2 mmol), Et3N (10 ml, 0 .07 mmol) in xylene (5 mL) was refluxed for 24 h under argon in a Deark-Stark stoppered flask. The mixture is cooled, concentrated and purified by chromatography on silica gel (eluting with 10% then 15% ethyl acetate in hexane), which gives 0.45 g (52%) of the trans-methyl isomer (example 73, melting point 139-140oC) and 15 mg (2%) of the cis-methyl isomer (Example 72, melting point: oil).

Method G.

Conversion of carbonyls to thio-carbonyls

Several reagents known from the literature convert carbonyls into thiocarbonyls. A typical sequence involves heating the substrate with a reagent such as P2S3 in a high-boiling solvent such as tetralin for 1 to 48 hours. Isolation of the product is done under relatively standard conditions, such as diluting the mixture in an organic solvent, such as EtOAc, and washing the mixture with water and saturated aqueous NaCl, followed by drying and concentration. Purification, by which the desired product is obtained, is performed by chromatography on silica gel or by recrystallization.

The compounds listed in Table 7 were produced by this method.

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Method G is illustrated by the synthesis of the compound of Example 78, which was carried out as follows. The starting substrate (1.5 g, 3.5 mmol) was dissolved in 5 ml of tetralin, mixed with P2S3 (0.9 g, 5.7 mmol) and heated for 2 hours at 225°C. When cooled, the mixture was diluted with water and the product was extracted into EtOAc. The organic layer is washed with saturated aqueous NaCl solution, dried and concentrated. The resulting oil is triturated with hexane to give a yellow solid which is isolated by filtration. This material was purified by vacuum chromatography (1:4 EtOAc:hexane) to give 1.13 g (70%) of the desired compound.

Method H.

Selective hydrolysis of thio-carbonyl to carbonyls

Compounds containing dithio-carbonyl, produced by method G, can, depending on the choice of conditions, be selectively hydrolyzed into each of the two monothio-carbonyl compounds. In general, the thio-carbonyl in the 4-position of the ring is much more sensitive to nucleophilic conditions. As seen in Example 81, it can be converted to the 4-oxo compound by treatment with aqueous ethanolamine followed by acid hydrolysis. The thio-carbonyl in the 2-position of the ring is more nucleophilic on sulfur and can be alkylated with methyl sulfate. This intermediate can then be hydrolyzed with a mild acid. This gives the compound from example 80. Purification of compounds of any class is easily carried out by silica gel chromatography or recrystallization.

The compounds listed in Table 8 were produced by this method.

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Example 80 was prepared by mixing a solution of the starting material (0.23 g, 0.49 mmol) in 3 ml of THF with 10 ml of 50% aqueous ethanolamine and heating under reflux for 2 hours. After cooling, the mixture was extracted with EtOAc and the organic layer was washed with water and saturated aqueous NaCl, dried and concentrated to give a brown solid. This solid is then mixed with 20 ml of 6N HCl and heated under reflux for 72 hours. When cooled, the mixture was extracted with EtOAc and the organic layer was washed with saturated aqueous NaCl, dried and concentrated. The product was purified by preparative TLC over silica gel using 1:1 EtOAc:hexanes as solvent to give the product in 34% yield.

Example 81 was prepared by preparing a solution of the starting material (0.5 g, 1.09 mmol) in 1.6 ml of 2N NaOH. As the compound does not immediately dissolve, 1 ml of water and 1 ml of THF are added to aid dissolution. The mixture was then cooled in an ice bath and Me2SO4 (0.12 ml, 1.3 mmol) was added dropwise over 5 minutes. The mixture is stirred for another 3 hours at 0oC and then 45 minutes at room temperature. The reaction was quenched by the addition of 1N HCl sufficient to obtain a pH of the solution below 2. The mixture was extracted with EtOAc and the organic layer was washed with saturated aqueous NaCl, dried and concentrated to give a yellow oil. This oil is then mixed with 10 ml of 6N HCl and heated under reflux for 3 hours. When cooled, the mixture was extracted with EtOAc and the organic layer was washed with saturated aqueous NaCl, dried and concentrated. The product was purified by silica gel column chromatography using 1:1 EtOAc:hexanes as the solvent to give the product in 5% yield.

Method I.

N-alkylation of hydantoin

The appropriate hydantion is dissolved in a suitable solvent (such as, for example, DMF, THF, or DMSO) and mixed with one equivalent of a base (such as, for example, NaH, LDA, LiHMDS, KHMDS, KH, or NaHMDS). After approximately 10 minutes to 1 hour, the appropriate alkylating agent is added and the mixture is stirred for approx. 24 hours at a temperature between room temperature and 90oC. (The progress of the reaction can be observed using TLC). The solution is then cooled and diluted with an organic solvent (such as, for example, EtOAc or CH 2 Cl 2 ). The organic phase is washed successively with dilute acid (such as 1N HCl) and water, dried (eg over MgSO4) and concentrated. The desired hydantoin is purified by silica gel chromatography or recrystallization.

The compounds listed in Table 9 were produced by this general method.

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Method I is illustrated by the synthesis of the compound of Example 97 (see Table 9) which is carried out by dissolving the starting material (0.21 g, 0.5 mmol) in DMF (5 ml) and mixing successively with a solution of 1 M NaHMDS ( 0.5 ml, 0.5 mmol) and EtJ (0.04 ml, 0.5 mmol). After 1 hour, the reaction mixture was partitioned between EtOAc and water and the organic phase was washed with water and dried over MgSO4. Chromatography over a silica gel column produced 0.17 g (72%) of the desired product.

Method J.

C-alkylation of heterocycles

The appropriate heterocycle is dissolved in an aprotic solvent (such as DMF, THF or DMSO) and mixed with one equivalent of a base (such as Et3N, LDA, KHMDS, LiMDS or NaHMDS) at a temperature between approx. -78oC to room temperature. After approximately 10 minutes to 2 hours, a suitable acylating agent is added and the mixture is stirred for 24 hours at a temperature between approx. 0 and 90oC. (Reaction progress can be monitored by TLC). The solution is then cooled and diluted with an organic solvent (such as, for example, EtOAc). The organic phase is washed successively with dilute aqueous acid (such as 1N HCl) and water, dried (for example, over MgSO 4 ) and concentrated. The desired hydantoin is purified, for example, by silica gel chromatography or recrystallization.

The compounds listed in Table 10 were produced by this general method.

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Method J is illustrated by the synthesis of Example 148 (see Table 10) which was carried out as follows. The starting material (0.11 g, 040 mmol) was dissolved in THF (5.0 mL) and cooled in a dry ice/acetone bath (approximately -78°C). Lithium bis(trimethylsilyl)amide (LiHMDS, 405.0 μl, 0.40 mmol) was added dropwise. The resulting yellow solution was stirred for 15 minutes in a cold bath, after which 2-fluorobenzyl bromide was added to it. The mixture is stirred for another 30 minutes at that temperature and then another 30 minutes at 0oC. The reaction mixture was then poured into 1N HCl (40 mL) and extracted into EtOAc (50 mL). The organic layer was washed with saturated aqueous NaCl solution (35 ml), dried (Na2SO4), filtered and concentrated in vacuo to give 0.16 g of crude product. This material was purified by vacuum chromatography over silica gel (1:3 EtOAc/hexane) to give 0.87 g (57.0%) of the compound from Example 148.

Method K. C-alkylation of hydantoin using methyl magnesium carbonate

As described by Finkbeiner (J. Org. Chem. 1965, 30, 3414), hydantoins can be alkylated with an alkyl halide using magnesium methyl carbonate (MMC). A solution of MMC in an organic solvent (such as DMF) is saturated at approx. 80oC with CO2 during a period of approx. 1 hour. The appropriate hydantion is then added and heated with MMC approx. 1 to 2 hours, after which the appropriate alkyl halide is added. The reaction mixture is then heated for approx. 2 to 3 hours at approx. 100oC, then cool down to approx. room temperature. The mixture is then poured into a concentrated aqueous acid (such as HCl) over ice and cooled. The resulting solid is collected by filtration and purified by silica gel chromatography and/or recrystallization of the desired product.

The compounds listed in Table 11 were produced by this method.

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Method K is illustrated by the synthesis of Example 181 (see Table 11) which was carried out as follows. A dry double-necked round bottom flask is evacuated and filled with a CO2 atmosphere. Magnesium methyl carbonate in DMF (860 μl, 2.0 M) was placed in the flask and the solution was heated to 80oC. CO2 is introduced from the vessel with dry ice through the cannula connected to the reaction vessel and is passed through the solution for 1 hour, after which the argon tube is connected and the cannula is removed. The starting material (0.21 g, 0.86 mmol) in DMF (4.0 ml) was added and the reaction mixture was heated for 1.5 hours at 80°C. A solution of 3-picolyl chloride (0.12 g, 0.94 mmol - the HCl salt was first the free base prepared with NaOH) in DMF (1.0 ml) was then added dropwise. The temperature of the oil bath is raised to 110oC and the mixture is heated for 4 hours at that temperature. When it has cooled to room temperature, the mixture is poured into a mixture of 5 ml of concentrated HCl and 10 g of ice and stored overnight in the refrigerator. Then the solution is neutralized to pH 7-8 with 6N NaOH and the resulting solid is collected by filtration with suction and washed with ice water. By drying the compound at 50oC in a vacuum, 0.20 g of crude product is obtained. It was purified by vacuum chromatography (5% MeOH/CH2Cl2) to give 0.06 g of material which was further purified by recrystallization from ETOH to give 0.04 g (14.9%) of the compound of Example 181.

Method L.

Synthesis of compounds using cross-linking with Pd as a catalyst

An appropriately substituted arylboronic acid, or arylstannate, is mixed with an aryl halide or aryl triflate and a catalytic amount of tetrakis(triphenylphosphine)palladium in an appropriate solvent system (such as benzene containing ethanol and aqueous Na2CO3, DMF, NMP, or THF) under an inert atmosphere. If necessary, other components such as LiCl and triethylamine can be added. The mixture is heated between approx. 2 and 48 hours at a temperature between approx. 50 and 150oC. The mixture is then cooled and diluted with an organic solvent (such as EtOAC). The organic phase is washed successively with water and saturated aqueous NaCl solution. It is dried (for example with Na2SO4) and concentrated, which gives an impure mixture, from which the desired material is isolated by chromatography on silica gel.

The compounds listed in Table 12 were produced by this method.

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Method L is illustrated by the synthesis of Example 182 (see Table 12) which was carried out as follows. In the manner described by Miyaura, M., Yanagy, T., Suzuki, A. Synth. Commun. 1981, 11, 513, starting material (0.24 g, 0.54 mmol) was mixed with phenylboronic acid (0.73 g, 0.60 mmol), tetrakis(triphenylphosphine)palladium(0) (0.31 g, 0.03 mmol), sodium carbonate (0.19 g, 1.79 mmol), benzene (3.0 ml), water (1.0 ml) and ethanol (1.0 ml) and stirred for 12 hours under reflux . The reaction mixture was then poured into EtOAc (70 ml) and washed successively with water and saturated aqueous NaCl. The organic layer is dried (Na2SO4), filtered and concentrated in vacuo to give 0.25 g of crude product. This material was purified by two successive silica gel column chromatographies (1:3 then 1:1 EtOAc/hexane) to give 0.11 g (48%) of the compound of Example 183.

Method M.

Synthesis of compounds using cross-linking with carbonylation Pd as a catalyst

An appropriately substituted arylboronic acid or arylstannate is mixed with an aryl halide or aryl triflate and a catalytic amount of tetrakis(triphenylphosphine)palladium in an appropriate solvent system (such as benzene containing ethanol and aqueous Na2CO3, DMF, NMP, or THF) under an inert atmosphere of carbon monoxide. If necessary, other components can be added, such as LiCl and triethylamine. The mixture is heated between approx. 2 and 48 hours at a temperature between approx. 50 and 150oC. The mixture is then cooled and diluted with an organic solvent (such as EtOAC). The organic phase is washed successively with water and saturated aqueous NaCl, dried (for example with Na2SO4) and concentrated, thereby obtaining an impure mixture from which the desired material is isolated by chromatography on silica gel.

The compounds listed in Table 13 were produced by this method.

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Method M is illustrated by the synthesis of Example 215 (see Table 13) which was carried out as follows. The starting material (0.23 g, 0.53 mmol) was mixed with phenyltributylstannane (0.86 ml, 2.64 mmol), bis(triphenylphosphine)-palladium(II) chloride (0.037 g, 0.05 mmol) , DMF (10.0 ml) and LiCl (5.1 mg, 1.6 mmol), the reaction mixture was then purged with argon, saturated with CO and stirred for 12 hours at 115oC. The reaction mixture is then poured into 1M tetrabutylammonium fluoride (10 ml), then diluted with 95 ml of EtOAc and washed successively with water and saturated aqueous NaCl solution. The organic layer is dried (Na2SO4), filtered and concentrated in vacuo to give 1.2 g of crude product. This material was purified by silica gel chromatography (1:3 EtOAc/hexane) to give 0.14 g (48%) of the compound from Example 215.

Method N.

Electrophilic aromatic substitution

Compounds containing aromatic rings can be modified with a number of reagents using electrophilic aromatic substitution. It includes the processes of acylation, nitration, sulfonation and halogenation of these rings.

The compounds listed in Table 14 were produced by this method.

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Such a case is represented by the compound of the example which was produced as follows. A solution of the starting material (0.4 g, 1.1 mmol) in 1 mL of HOAc and 0.1 mL of H2SO4 was mixed with NaJO3 (0.05 g, 0.2 mmol) and J2 (0.06 g, 0.5 mmol). The mixture is then heated for 19 hours at 70oC and then cooled to room temperature, extracted several times in EtOAc. The EtOAc was concentrated and the product was isolated after purification by silica gel chromatography. Yield: 33 mg (30%).

Method Q.

Deprotection of compounds protected with acid-labile groups

Compounds that have acid-labile protecting groups can be deprotected in a known manner by treatment under acidic conditions. This generally involves treatment of the substrate with TFA, resin cation exchange (H+), HCl or HCr in AcOH with or without heating. The thus obtained compound is collected by filtration or extraction and purified by silica gel chromatography or recrystallization.

The compounds listed in Table 15 were produced by this general method.

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Method Q is illustrated by the synthesis of the compound of Example 219 which was carried out as follows. A mixed solution of the starting material (0.10 g, 0.19 mmol) in 10 ml of methylene chloride was first cooled to 0°C and then 2.0 ml of trifluoroacetic acid was added. Stirring is continued for another 20 minutes and then the solution is allowed to slowly warm to room temperature. The solution is stirred for another 6 hours and then thickened to give a white solid which is further dried for another 16 hours under vacuum. The crude solid is then triturated with 10 ml of boiling hexane and the mixture is allowed to cool to room temperature. The resulting white precipitate was collected by filtration, washed with 5 ml of hexane and dried for 4 hours under high vacuum to give 0.06 g (68% yield) of the compound from Example 219.

Method P.

Acid saponification of esters with hydroxide

Certain compounds containing a carboxylic ester group can be converted into carboxylic acids in a known manner by treatment with saponification agents. This generally involves treating the substrate with NaOH, KOH or LiOH in a solvent such as water which sometimes contains a solubilizing agent such as THF. Purification generally involves extracting the unreacted starting material with an organic solvent, such as EtOAc or CH2Cl2, acidifying the aqueous layer, and purifying the acid by filtration or extraction into an organic solvent, such as EtOAc or CH2Cl2. Further purification can be carried out by recrystallization, chromatography on silica gel or reverse phase HPLC to obtain the desired compound.

The compounds listed in Table 16 were produced by this general method.

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Example 239 (Table 16) was prepared by dissolving the starting material (0.38 gm, 0.65 mmol) in 4 ml of water and 8 ml of MeOH containing LiOH (0.08 g, 1.95 mmol) and heating the mixture 2.5 hours at 60oC. The MeOH was removed by concentration and the aqueous residue was mixed with 1N HCl. The product is extracted into EtOAc from which it crystallizes after cooling. Yield: 262 mg (72%).

Method Q.

Cleavage of the phthalimide protecting group

Primary amines can be protected as their phthalimide derivatives. These derivatives are rapidly synthesized by method U using the potassium salt of phthalimide as a nucleophile. The amine can be liberated from the phthalimide protecting group using nucleophilic reagents, such as hydrazine or methyl amine, in a solvent such as EtOH. Purification generally involves acidifying the aqueous layer and extracting the unreacted starting material with an organic solvent such as EtOAc or CH2Cl2. Basifying the aqueous layer gives the free amine base, which is purified by filtration or extraction into an organic solvent such as EtOAc or CH2Cl2. Further purification can be carried out by recrystallization, chromatography on silica gel or reverse-phase HPLC to obtain the desired compound.

The compounds listed in Table 17 were produced by this general method.

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The compound of Example 240 was prepared by dissolving the starting material (prepared by method U, 0.72 g, 1.2 mmol) in 73 ml of EtOH and mixing with 19.5 ml of a 33% solution of MeNH 2 in EtOH. The mixture is heated for 2.5 hours under reflux and then cooled to room temperature. The reaction mixture is concentrated and the residue is dissolved in CH2Cl2, which is further washed with water and saturated aqueous NaCl solution. The organic layer is dried (Na2SO4) and concentrated. The yellow oil was dissolved in EtOH and treated with HCl gas. The amine hydrochloride of the compound from Example 240 was obtained with a yield of 69% (0.49 g).

Method R.

Conversion of nitriles to amidines

Aromatic nitriles can be converted to amidine groups in several ways. Generally two steps are required for this conversion, with the first step involving treatment with an acid (such as, for example, HCl) and with an alcohol (such as, for example, MeOH or EtOH) to give the intermediate imino ether. This derivative is then converted into an amidine by treatment with an amine. Purification is usually done by recrystallization of amidine derivative salts. Further purification can be carried out by recrystallization, chromatography on silica gel or reverse-phase HPLC, which gives the desired product.

The compounds listed in Table 18 were produced by this general method.

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The compound from example 243 was prepared by dissolving the starting material (0.2 g, 0.4 mmol) in 7 ml of EtOH, cooling the mixture in an ice bath and treating the mixture with dry gaseous HCl for 15 minutes. The mixture is then stirred for 1 hour at room temperature and thickened, thereby obtaining the crude imino ether hydrochloride. The intermediate was dissolved in EtOH (10 mL), cooled in an ice bath, and treated with anhydrous NH 3 gas for 20 min. After 5 hours, the reaction mixture is concentrated, thus obtaining crude amidine hydrochloride. This material was purified by chromatography on silica gel (1:9 MeOH:CH2Cl2), yielding 0.08 g (38%) of the product.

Method S.

Reduction of carboxylic acids into alcohols

Certain compounds having a carboxylic acid group can be converted into alcohols in a known manner by treatment with reducing reagents. This generally involves treating the substrate with LiAlH4 or a BH3-based reagent in a solvent such as THF or ether. After careful quenching with an aqueous system, purification typically involves extraction of the product into an organic solvent such as EtOAC or CH2Cl2 and purification using recrystallization, silica gel chromatography, or reverse phase HPLC to yield the desired product.

The compounds listed in Table 19 were produced by this general method.

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The compound of Example 244 was prepared by dissolving the starting material (prepared by methods J and O, 0.16 g, 0.32 mmol) in 1 ml of THF, cooling the mixture in an ice bath and mixing the mixture with 0.65 ml of 1M of BH3-THF solution (0.65 mmol). Let the mixture warm to room temperature and stir for 15 hours. The reaction mixture was quenched by slowly and cautiously adding water and the organic component was extracted into EtOAc. The EtOAc layer was washed with water, saturated aqueous NaCl and dried over Na2SO4. Concentration and chromatography on silica gel (1:1 EtOAc:hexane) gave the desired compound (0.06 g, 42%).

Method T.

Deprotection of compounds with nucleophilic reagents

Certain compounds having methoxy protecting groups can be deprotected in a known manner into hydroxy derivatives by treatment with certain nucleophilic reagents. This generally involves treating the substrate with BBr3 or TMSI in a solvent such as CH2Cl2, generally by cooling in an ice bath and then with or without heating. After between 10 minutes and 8 hours, the reaction is quenched with a weak base such as aqueous NaHCO3 and the organic component is extracted into a solvent such as EtOAc and after concentration is purified by silica gel chromatography or recrystallization to give the desired product.

The compounds listed in Table 20 were produced by this general method.

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Method T is illustrated by the synthesis of the compound of Example 246 which was carried out as follows. A stirred solution of the starting material (0.35 g, 0.64 mmol) in 9 mL of CH2Cl2 was cooled to 0°C before the addition of 1.0 mL of BBr3 (1.07 mmol, 1M CH2Cl2). Stirring is continued and then the solution is allowed to slowly warm to room temperature. The solution is stirred for another 4 hours and then a saturated aqueous solution of NaHCO3 is added, the organic layer is removed and concentrated to obtain the crude product. Purification is carried out by chromatography on silica gel (1:4 EtOAc/hexane), which gives 0.16 g (48% yield) of the desired compound.

Method U.

Nucleophilic displacement

The appropriate nucleophilic agent is dissolved in an aprotic solvent (such as DMF, THF, or DMSO) and mixed with one to three equivalents of nucleophile (such as Me3N, Na imidazole salt, Na2SO3, NaCN, P(OEt)3, or K salt phthalimide at a temperature between about room temperature and 100°C. The mixture is stirred for about 24 hours at a temperature between about 0 and 100°C. (Progress of the reaction can be monitored using TLC.) The solution is then cooled and diluted with an organic solvent (such as eg EtOAc).The organic phase is washed successively with dilute aqueous acid (such as 1N HCl) and water, dried (eg over MgSO4) and concentrated.The desired compound is purified by silica gel chromatography, reverse phase HPLC or recrystallization.

The compounds listed in Table 21 were produced by this general method.

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Method U is illustrated by the synthesis of the compound of Example 262 which was carried out as follows. 1-H-pyrazolecarboxamide (0.08 g, 0.54 mmol) was added to the starting material (0.28 g, 0.54 mmol) followed by 7 ml of DMF and 0.2 ml of N,N-diisopropyl- ethylamine. The resulting mixture is then stirred for 15 hours at room temperature. Ether is then added causing the mixture to become cloudy. If no crystals form, MeOH is added to redissolve the reaction components and the product is precipitated as its HCl salt by addition of 1N HCl. The solid was collected and washed with ether to give 0.11 g (20%) of guanidine hydrochloride.

Method V.

Separation of a mixture of enantiomers.

There are several ways to resolve the compounds of the invention into their enantiomerically pure forms. One such method is chiral HPLC. One example of a column packing is Chiracel-OD (Diacel Chemistry Industries). An example of a solvent system is 9:1 hexane:isopropyl alcohol. In general, the R-enantiomer is washed out first, but this should not be taken as the sole criterion for determining stereochemistry.

The compounds listed in Table 22 were resolved by this method.

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Description of biological properties

The biological properties of typical compounds of formula I were investigated using the experimental protocols described below. The results of such tests are shown in table 23 below.

An attempt to determine the inhibition of LFA-1 binding to ICAM-1

Purpose of the test:

This test protocol was designed to study the direct antagonism, by the test compound, of the interaction of CAM, ICAM-1 with leukointegrin CD18/CD11a (LFA-1).

Description of the test protocol:

LFA-1 was immunopurified with TS2/4 antibody from 20 g pellet of human JY or SKW3 cells, using a previously described protocol (Dustin, M.J., et al., J. Immunol. 1992, 148, 2654-2660). LFA-1 was purified from SKW3 lysates by immunoaffinity chromatography on TS2/4 LFA-1 mAb Sepharose and washed at pH 11.5 in the presence of 2 mM MgCl2 and 1% octylglucoside. After collection and neutralization of the fractions from the TS2/4 column, the samples were collected and pre-cleared with protein G agarose.

A soluble form of ICAM-1 was constructed, expressed, purified and characterized as previously described (Marlin, S., et al., Nature, 1990, 344, 70-72 and see Arruda, A. et al., Antimicrob. Agents Chemother 1992, 36, 1186-1192). Briefly, isoleucine 454, which is localized at the so-called boundary between domain 5 of the ectodomain and the transmembrane domain, was changed toward a stop codon using standard oligonucleotide-directed mutagenesis. This construction yields a molecule identical to the first 453 amino acids of the membrane boundary of ICAM-1. An expression vector was created with the hamster dihydrofolate reductase gene, the neomycin-resistant marker, and the sICAM-1 coding region of the construct described above, with only the promoter, splice signals, and SV40 early region polyadenylation signal. The recombinant plasmid was transfected into HCO DUX cells using standard calcium phosphate methods. Cells were passaged in selective medium (G418) and colonies secreting sICAM-1 were expanded using methotrexate. sICAM-1 were purified from serum-free media using conventional non-affinity chromatography procedures, including ion exchange and size exclusion chromatography.

Binding of LFA-1 to ICAM-1 was observed first by incubating sICAM-1 at 40 μg/ml in Dulbecco's phosphate-buffered saline with calcium and magnesium, supplemented with 2 mM MgCl2 and 0.1 mM PMSF (dilution buffer) in a plate with 96 wells for 30 minutes at room temperature. Plates were then blocked by the addition of 2% (w/v) bovine serum albumin in dilution buffer for 1 hour at 37oC. The blocking solution was removed from the wells and test compounds were diluted and added followed by the addition of approximately 25 ng of immunoaffinity purified LFA-1. LFA-1 was incubated in the presence of the test compound and ICAM-1 for 1 hour at 37°C. Wells were washed with dilution buffer. LFA-1 binding was detected by addition of a polyclonal antibody directed against a peptide corresponding to the cytoplasmic end of CD18 at a 1:100 dilution with dilution buffer and 1% BSA and incubation for 45 minutes at 37oC. Wells were washed 3 times with wash buffer and polyclonal antibody binding was detected by addition of 1:4000 diluted horseradish peroxidase conjugated to goat immunoglobulin directed against rabbit immunoglobulin. This reagent was incubated for 20 minutes at 37oC, the dishes were washed as above and horseradish peroxidase substrate was added to each well to develop a quantitative colorimetric signal proportional to the amount of LFA-1 bound to sICAM-1. Soluble ICAM-1 (60 μg/ml) was used as a positive control to inhibit the LFA-1/ICAM-1 interaction. The absence of LFA-1 addition in the binding experiment was used as a basic control for all samples. Dose-response curves were obtained for all tested compounds.

The results of these tests are reported as Kd's in μM.

MMT test to determine cytotoxicity

The purpose of the examination

In order to obtain meaningful data from cellular experiments, the compounds must first be tested in an experiment measuring cellular toxicity. For this purpose, the MTT test can be applied.

Description of the test protocol:

MTT, (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide), is a yellow substrate that is cleaved by cells with active mitochondria, yielding a deep blue/purple formazan product. This precipitate can be solubilized and the amount of material can be quantified by spectrophotometric procedures (Gerlier, D., Thomaset, N., J. Immunol. Methods, 1986, 94, 57-63). The amount of dye is proportional to the number of viable cells. This test system was applied to evaluate the effect of test compounds on the ability of cells to live in vitro.

SKW3 cells, which express LFA-1, were used. Cells used in each experiment were seeded at 1.25x10 6 cells/ml and 100 μl of this stock was dispersed into each well of a 96-well flat bottom microtiter plate. Three wells were determined for each condition in an individual experiment. Serial dilutions of each test compound or vehicle alone were added to each well. Before assessing cell viability, cells were incubated with the compound for 4-24 hours at 37oC. Then, 10 μl of filter-sterilized MMT was added to each well. The stock of MTT was made in phosphate-buffered saline at a concentration of 5 mg/ml. Then the plates were incubated for 1 hour at 37oC in an atmosphere with 5% CO2. The plates were periodically examined for the development of formazon crystals.

At the end of the incubation period, formazon crystals were dissolved by adding 100 μl of 0.04 N HCl in iso-propyl alcohol to each well. Each well was thoroughly mixed by repeated pipetting with a multichannel pipettor. The plates were left to reach room temperature for 15-20 minutes and then read with a spectrophotometer. Absorbance was measured at a test wavelength of 570 nm. Data are presented as the concentration range (in μM) in which 50% of cells are no longer viable.

An attempt to determine the inhibition of binding of SKW3 cells to ICAM-1 vs. binding to fibronectin

Purpose of the experiment:

This experiment was applied to examine the selective ability of a test compound to antagonize the interaction of the cell border form LFA-1 with ICAM-1. The experiment uses the human T cell line, SKW3 cells that express CD18, CD11a and other integrins that are not related to CD18, CD11a and that cannot be "activated" with phorbol esters. Phorbol esters enhance the affinity of CD18, CD11a for ICAM-1.

The same lymphocyte line, SKW3, also adheres to fibronectin in the presence of phorbol ester. This adhesion is mediated by membrane proteins independently of the LFA-1/ICAM-1 interaction. SKW3 cells express another integrin, VLA4, which is a receptor for fibronectin. Therefore, as a preliminary indication of the selectivity of the test compounds to interfere with leukointegrin/CAM interactions, but not other cases of integrin-ligand binding, the compound can be tested for its ability to antagonize cellular binding of the fibronectin receptor in its interaction with purified fibronectin. Compounds that inhibit this fibronectin adhesion are not specific antagonists of CD18, CD11a/ICAM-1 binding.

Description of the test protocol:

96-well plates were coated with sICAM-1 (40 μg/ml) or fibronectin (100 μg/ml) in dilution buffer for 1 hour at room temperature. 100 μl of appropriately diluted test compound or 100 μl of RPMI with 15% fetal bovine serum as a control was added to the wells. SKW3 cells, which express CD18, CD11a and VLA-4 (Dustin, M. et al., J. Exp. Med. 1987, 165, 672-692) were washed and suspended at a concentration of 10 6 cells/ml in RPMI with 15 % fetal bovine serum. Immediately before adding cells to the wells, cells were stimulated with phorbol ester 12-myristate 13-acetate (PMA) to a final concentration of 100 μg/ml. 100 μl cells were then added to the wells, giving a final concentration of 50 μg/ml PMA and 2 cells/well. The plates were incubated for 2 hours at 37oC. Unbound and weakly bound cells were gently washed with RPMI. Cells retained and therefore bound to ICAM-1 or to fibronectin were quantified using the same reagent used in the MTT experiment above.

Data are presented as the concentration or concentration range (in μM) at which 50% binding was inhibited.

Compounds that inhibit JY cell aggregation

The purpose of the examination

This is an in vitro cell-to-cell adhesion assay that can be applied to test the ability of a test compound to directly inhibit LFA-1-dependent aggregation at the cellular level.

Many cells transformed with Epstein Barr virus show aggregation. This aggregation can be enhanced by the addition of phorbol ester. It has been found that such homotypic aggregation (ie, aggregation involving only one cell type) can be blocked with anti-LFA-1 antibodies (Rothlein, R.R. et al., J. Exp. Med. 1986, 163, 1132-1149). Therefore, the extent of LFA-1-dependent binding can be determined by assessing the extent of spontaneous or phorbol ester-dependent aggregation.

An agent that interferes with LFA-1-dependent aggregation can be identified by using an experiment to determine whether the agent interferes with spontaneous or phorbol ester-dependent aggregation of Epstein-Barr virus-transformed cells. Cells of the JY cell line (Terhost, L. et al., Proc. Natl. Acad. Sci. USA, 1976, 73, 910) are used primarily for the homotypic aggregation experiment. This assay, which can measure LFA-1-dependent aggregation, can be used to identify agents that act as antagonists of LFA-1-dependent aggregation. Such agents may act to attenuate the ability of LFA-1 or ICAM-1 to mediate aggregation. Therefore, these agents can be tested to directly determine whether they are antagonists of LFA-1 aggregation.

Description of the test protocol:

JY cells were grown in RPMI 1640 culture medium supplemented with 10% fetal calf serum and 50 μg/ml gentamicin. Cells were grown at 37oC in an atmosphere with 5% CO2 at a relative humidity of 95%. The JY cells used in this study were washed twice with RPMI 1640 medium containing 5 mM HEPES buffer and resuspended to a concentration of 2x10 6 cells/ml. 50 μl of the test compound diluted in complete medium, 50 μl of complete medium with or without purified monoclonal antibodies (negative and positive inhibition control), 50 μl of complete medium containing 200 ng/ml phorbol ester were added to 96 flat-bottom wells of the microtiter plate. myristate acetate (PMA) and 100 μl of cells with a concentration of 2x106 cells/ml in the complete medium. This resulted in a final concentration of 50 ng/ml PMA and 2x105 cells/well. Cells were allowed to settle spontaneously and the degree of aggregation was counted at various time points. The results are graded from 0 to 4, where 0 means that the cells are mostly not in clusters; 1 means <25% of cells are in clusters; 2 means that <50% of cells are in clusters; 3 means that <75% of cells are in clusters and 4 means that 100% of cells are aggregated. This procedure is described by Rothlein, R.R., et al., J. Exp. Honey. 1986, 163, 1132-1149. The article also states that antibodies to LFA-1 are able to inhibit the formation of aggregates. While 100% of cells form aggregates in the absence of LFS-1 antibody, the same article states that less than 20% of cells are found in aggregates when anti-LFA-1 antibody is added.

Data are presented as the concentration or concentration range (in μM) at which 50% binding was inhibited.

An experiment to determine the inhibition of the reaction of mixed lymphocytes

The purpose of the examination

As discussed earlier, ICAM-1 is necessary for effective cell-cell interactions during the immune response mediated by LFA-1-dependent cell adhesion. When lymphocytes from two unrelated individuals are cultured together, lethal transformation and cellular proliferation of the lymphocytes is observed. This response is known as the mixed lymphocyte response (MLR) and is analogous to the response of lymphocytes to the addition of antigen or mitogen (Immunology: The Science of Self-Nonself Discrimination; Klein, J., Ed. John Wiley & Sons, NY, 1982, p. 453-458). Monoclonal antibodies directed against ICAM-1 and LFA-1 were used as controls to determine inhibition of cell adhesion-dependent stimulation and proliferation of lymphocytes.

This experimental protocol was applied to determine the effect of the test compound on human MLRs. The ability of the test compound to inhibit MLR and antigen-specific mononuclear cell responses indicates that it has therapeutic utility in acute graft rejection as well as in related immune-mediated disorders dependent on CD18, CD11a/ICAM interactions.

Description of the test protocol

Peripheral blood was obtained from normal, healthy donors by venipuncture. Blood was collected in heparinized tubes and diluted 1:1 at room temperature with Puck's (GIBCO) balanced salt solution (BSS). The blood mixture (20 ml) was placed on a 15 ml Ficoll/Hypaque density gradient (Pharmacia, density = 1.078, room temperature) and centrifuged for 20 minutes at 1000 x g. Then the contact area was collected and washed 3 times in Puck's G. The cells were pooled on a hemocytometer and resuspended in RPMI 1640 culture medium (GIBCO) containing 0.5% gentamicin, 1 mM L-glutamine (GIBCO) and 5% heat-inactivated (56oC, 30 minutes) human AB sera (Flow Laboratories) (referred to below as RPMI culture medium).

Peripheral blood mononuclear cells (PBMC) were cultured in medium at 6.25x10 5 cells/ml in a Linbro round-bottom microtiter plate. Stimulator cells (cells that have been irradiated so that they are unable to proliferate) from specific donors were cultured with cells expected to respond at the same concentration. The test compound was added to the wells in various concentrations. The total volume per culture was 0.2 ml. Controls included compound only in vehicle (DMSO), only responsive cells, and only stimulatory cells. Plates with cultures were incubated for 5 days at 37oC in an atmosphere of humid air with 5% CO2. Wells were pulsed with 0.5 μCi tritiated thymidine (3HT) (New England Nuclear) for the last 18 hours. In some cases, two-way MLR can be performed. The protocol is the same except that the other donor cells are not inactivated by irradiation.

Cells were collected on glass fiber filters using a multiple sample collector (Skatron, Norway) and washed with water and methanol. Filters were dried in a desiccator and counted in Aquasol in a Beckman (LS-3801) liquid scintillation counter.

Data are reported as “+” or “-” at the given concentration (in μM).

In vivo: an allogeneic cell transplant model

The purpose of the experiment

The ability of cells to recognize other cells of their own or cells from another genetically different individual (non-self) is an important property for maintaining the integrity of tissue and organ structure. Allogeneic cell transplant response is an important model for studying graft rejection and immunocompetence. This T-cell-mediated immune response can be induced in adult mice by injection of lymphocytes from a histologically incompatible mouse strain into the paw pad. This response is characterized by T-cell proliferation that is restricted to the popliteal lymph node that receives drainage from the injected area of the paw pad. No in vitro system can completely duplicate that in vivo response. Therefore, this model can be used to test the ability of a test compound to suppress graft rejection.

Description of the test protocol

Experiments were conducted on male or female mice (20 - 26 grams). Any histologically incompatible mouse species can be used as donor and recipient populations. Typical DBA mice were used as donors, and C57b1/6 mice were used as recipients. A minimum of 1 week of stabilization and conditioning period is required prior to experiments, during which time animals are maintained in accordance with Animal Resource Center S.O.P. For each study, 36 recipient mice were used, divided into groups of 6. The studies lasted approximately 4 days. Donor mice were sacrificed by CO2 asphyxiation and their spleens were removed and processed into a cell suspension. Cells (1.0x107/metatarsal in 0.05 ml) were injected intradermally (according to standard protocol) into the dorsal metatarsal skin of recipient mice. Four days later the animals were sacrificed by CO2 inhalation and the popliteal nodes were removed and weighed. Groups of mice receiving sham immunosuppressive agents were dosed subcutaneously, intraperitoneally, or orally one hour before cell injection and daily thereafter according to a standard protocol. To determine significant differences between the popliteal lymph nodes of the group of untreated mice and those of mice treated with sham immunosuppressive agents, the Student's T test was applied (see: Kroczek, R.A., Black, C.D., Barbet. J., Shevach, E.M., Immunology, 1987, 139, 3597).

Data are presented as the dose at which 50% inhibition was observed and the route in which the compound was administered.

In table 23, the following symbols apply:

and = not determined, bpercent inhibition at 160 μg/ml, no inhibition observed up to the highest dose. Accurate quantification is not always possible due to the intrinsic toxicity of the compound (see MTT results). dinhibition percentage (concentration in μM). approximated from an incomplete dose response curve. More specific; the compound is an intermediate of synthesis.

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Description of therapeutic use

New and known small molecules are used in this method according to the invention to inhibit ICAM-1/LFA-1 dependent homotypic aggregation of human lymphocytes, adhesion of human lymphocytes to ICAM-1 and response of human lymphocytes to antigen. These compounds have therapeutic utility in modulating immune cell activation/proliferation, eg as competitive inhibitors of intracellular ligand/receptor binding reactions involving CAMs and leukointegrins. Inflammatory conditions treatable with the compounds of the invention include conditions resulting from non-specific immune system responses in mammals (eg, adult respiratory distress syndrome, shock, oxygen toxicity, secondary multiple organ injury syndrome in septicemia, secondary multiple organ injuries in trauma, tissue reperfusion injury due to cardiopulmonary bypass, myocardial infarction or use with thrombolytic agents, acute glomerulonephritis, vasculitis, reactive arthritis, dermatosis with acute inflammatory components, stroke, thermal injury, hemodialysis, leukopheresis, ulcerative colitis, necrotizing enterocolitis and associated granulocyte transfusion syndrome) and conditions resulting from a specific immune system response in mammals (eg psoriasis, organ/tissue transplant rejection, graft vs. host reactions and autoimmune diseases including Raynaud's syndrome, autoimmune thyroiditis, dermatitis, multiple sclerosis, re rheumatoid arthritis, insulin-dependent diabetes mellitus, uveitis, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, and systemic lupus erythematosus). In accordance with the invention, the new and known compounds can also be used to treat asthma or as an adjunct to minimize the toxicity of cytokine therapy in the treatment of cancer. In general, these compounds can be used to treat those diseases that are now treated with steroids.

In accordance with the method provided by the present invention, these new and known compounds can be administered for prophylactic or therapeutic purposes alone or together with other immunosuppressive or anti-inflammatory agents. If administered prophylactically, the immunosuppressive compound(s) is administered prior to any inflammatory response or symptoms (for example prior to transplantation or shortly after organ or tissue transplantation but prior to any symptoms of organ rejection). Prophylactic administration of a compound of formula I serves to prevent or alleviate any subsequent inflammatory response (such as, for example, rejection of a transplanted organ or tissue, etc.). Therapeutic administration of a compound of formula I serves to alleviate any acute inflammation (such as rejection of a transplanted organ or tissue). Therefore, in accordance with the invention, the compound of formula I can be given before the onset of inflammation (so as to suppress the expected inflammation) or after the onset of inflammation.

New and known compounds of formula I according to the invention are given in single or divided doses orally, parenterally or topically. A suitable oral dosage for a compound of formula I ranges from approx. 0.5 mg to 1 g per day. In parenteral formulations, a suitable dosage unit may contain from 0.1 to 250 mg of the mentioned compound, whereby formulations containing 0.01 to 1% of the active compound are preferred for topical administration. It is understood, however, that the prescribed dosage may vary from patient to patient and the dosage for each individual patient will depend on the clinical judgment of one who applies the size and condition of the patient as a criterion for determining the proper dosage, as well as on the patient's response to the drug.

When the compounds of the present invention are administered orally, they may be administered as medicaments in the form of pharmaceutical compositions containing them together with a compatible pharmaceutical carrier. Such carrier material may be an inert organic or inorganic carrier material suitable for oral administration. Examples of such materials are water, gelatin, talc, starch, magnesium stearate, gum arabic, vegetable oils, polyalkylene glycols, petroleum gel and the like.

Pharmaceutical preparations can be produced in a conventional manner, and the finished dosage forms can be solid dosage forms, for example tablets, dragees, capsules and the like, or liquid dosage forms, for example solutions, suspensions, emulsions and the like. Pharmaceutical preparations may be subjected to conventional pharmaceutical procedures such as sterilization. Furthermore, pharmaceutical preparations may contain conventional pharmaceutical auxiliaries such as preservatives, stabilizers, emulsifiers, flavor enhancers, wetting agents, buffers, salts for adjusting osmotic pressure, and the like. Solid carrier material that can be used includes, for example, starch, lactose, mannitol, methyl cellulose, microcrystalline cellulose, talc, silicon oxide, dibasic calcium phosphate, and high molecular weight polymers (such as polyethylene glycol).

For parenteral use, the compound of formula I may be administered in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable oil or mixture of liquids, which may contain bacteriostatic agents, antioxidants, preservatives, buffers or other solutions, so as to obtain a solution which is isotonic with blood, thickening agents, suspending agents or other pharmaceutically acceptable additives. Additives of this type include, for example, tartrate, citrate, and acetate buffers, ethanol, propylene glycol, polyethylene glycol, complexing agents (such as EDTA), antioxidants (such as sodium bisulfite, sodium metabisulfite, and ascorbic acid), polymers of high molecular weight (such as liquid polyethylene oxides) for viscosity regulation and polyethylene derivatives of sorbitol anhydride. If necessary, preservatives such as benzoic acid, methyl or propyl paraben, benzalkonium chloride and other quaternary ammonium compounds can also be added.

The compounds of this invention can be given as solutions for nasal application which, in addition to the compounds of this invention, can additionally contain suitable buffers, agents for tonicity adjustment, microbiological preservatives, antioxidants and agents for increasing viscosity in the aqueous vehicle. Examples of agents used to increase viscosity are polyvinyl alcohol, cellulose derivatives, polyvinylpyrrolidinone, polysorbates or glycerin. Added microbiological preservatives may include benzalkonium chloride, thimerosal, chlorobutanol or phenylethyl alcohol.

In addition, the compounds of this invention may be administered as suppositories.

Formulations

Compounds of formula I can be formulated for therapeutic administration in a number of ways. Below are descriptions of several example formulations.

Example A

Capsules or tablets

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The compound of formula I is mixed into a powder mixture with premixed auxiliary materials, as indicated above with the exception of the lubricant. Then the lubricant is mixed in and the resulting mixture is pressed into tablets or filled into hard gelatin capsules.

Example B

Parenteral solutions:

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The auxiliary materials are mixed and then added to one of the compounds of formula I in the volume required for dissolution. Stirring is continued until a clear solution is obtained. The solution is filtered into appropriate vials or ampoules and sterilized in an autoclave.

Example C

Suspension:

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The auxiliary materials are mixed with water and then one of the compounds of formula I is added and mixing is continued until a homogeneous suspension is obtained. Then the suspension is transferred into appropriate vials or ampoules.

Claims (17)

1. A method for treating or preventing inflammatory and cell-mediated immune diseases or conditions, comprising administering a prophylactic or therapeutic amount of a compound of formula I [image] wherein Y is an oxygen or sulfur atom; Z is an oxygen or sulfur atom; X is a divalent group of the formula >CHR1, >NR1, >CHSO2R1, or >NSO2R1, or an oxygen or sulfur atom, where R1 is: (C) a hydrogen atom, (D) a branched or unbranched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group may be mono- or polysubstituted with: (iv) halogen, (v) oxo, (vi) aryl, which is selected from the class consisting of phenyl, naphthyl , indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolizinyl, isoindolyl, benzo[b]furanyl, benzo[b ]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, quinolinyl, phthalaninyl, quinoxalinyl, naphthyridinyl, pteridinyl and quinazolinyl, whereby one or more hydrogen atoms of the mentioned aryl residue can be optionally and independently substituted with: (l ) by alkyl which has 1 to 3 carbon atoms, (m) -COOH, (n) -SO2OH, (o) -PO(OH)2, (p) a group of the formula -COOR7, where R7 represents straight or branched alkyl having from 1 to 5 of carbon atoms or cycloalkyl having from 3 to 5 carbon atoms, (q) a group of the formula -NR8R9, where each of R8 and R9 independently represents a hydrogen atom, alkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms atom or acyl having from 1 to 7 carbon atoms, or in which R8 and R9 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms that together with the nitrogen atom between them form a heterocyclic ring, (r) a group of the formula -CONR10R11, where each of R10 and R11 independently represents a hydrogen atom, an alkyl having from 1 to 6 carbon atoms or a cycloalkyl having from 3 to 6 carbon atoms, or in which R10 and R11 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with a nitrogen atom between them they form a heterocyclic ring, (with) a group of the formula -OR12a, gdj e R12a represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms, (t) a group of the formula -SR12b, where R12b represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms, (in ) cyano, or (v) amidino group of the formula [image] in which each of R13, R14 and R15 independently represents a hydrogen atom or alkyl having from 1 to 3 carbon atoms and in which two of R13, R14 and R15 can additionally form a saturated hydrocarbon a bridge that has from 3 to 5 carbon atoms that together with the nitrogen atom(s) between them form a heterocyclic ring, (iv) a group of the formula -COOR16, where R16 represents a straight or branched alkyl that has from 1 to 7 carbon atoms or a cycloalkyl that has from 3 to 6 carbon atoms, (v) cyano, (vi) a group of the formula -CONR17R18, where each of R17 and R18 independently represents a hydrogen atom, an alkyl having from 1 to 6 carbon atoms or a cycloalkyl having from 3 to 6 carbon atoms , or in which R17 and R18 form zasi a hydrocarbon bridge that has from 3 to 5 carbon atoms that together with the nitrogen atom between them form a heterocyclic ring, (vii) a group of the formula -OR19, where R19 represents a hydrogen atom or an alkyl or acyl group that has from 1 to 7 carbon atoms, ( viii) a group of the formula -SR20, where R20 represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms, (ix) a group of the formula -NR21R22, where each of R21 and R22 independently represents (e) a hydrogen atom, ( f) alkyl or acyl having from 1 to 7 carbon atoms or cycloalkyl having from 3 to 7 carbon atoms, (g) a group of the formula -(CH2)mCOOH, where m is 0, 1 or 2, or (h) a group of the formula -(CH2)nCOOR23, where n is 0, 1 or 2, and R23 is straight or branched alkyl having from 1 to 6 carbon atoms, or where R21 and R22 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with a nitrogen atom between them they form a heterocyclic ring, or (x) a quaternary group of the formula [image] in k where each of R24, R25 and R26 independently represents a branched or unbranched alkyl group having from 1 to 7 carbon atoms and Q- is a chlorine, bromine or iodine ion of the opposite charge, (C) a branched or unbranched carboxylic acid group having from 3 to 6 carbon atoms, (D) branched or unbranched phosphonic acid group having from 2 to 6 carbon atoms, (E) branched or unbranched sulfonic acid group having from 2 to 6 carbon atoms, (F) amidino group of the formula [image] in wherein r is 2, 3, 4, 5 or 6, and each of R27, R28 and R29 independently represents a hydrogen atom or an alkyl having from 1 to 3 carbon atoms, and in which two of R27, R28 and R29 may additionally form a saturated hydrocarbon a bridge having from 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, (G) a guanidino group of the formula [image] in which s is 2, 3, 4, 5 or 6, and each of R30 , R31, R32 and R33 independently represent a hydrogen atom or alkyl which im and from 1 to 3 carbon atoms, and in which two of R30, R31, R32 and R33 can additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms that together with the nitrogen atom(s) between them form a heterocyclic ring, (H) piperidyl, in which the nitrogen atom of the mentioned group is optionally substituted with: (vi) an alkyl having 1 to 3 carbon atoms, (vii) a carboxylic ester group having 2 to 7 carbon atoms, (viii) a carboxylic acid group having from 2 up to 5 carbon atoms, (ix) a phosphonic acid group having from 1 to 6 carbon atoms, or (x) a sulfonic acid group having from 1 to 6 carbon atoms, or (I) an aryl selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolizinyl, isoindolyl, benzo[b]furanyl, benzo[ b]thiophenyl, indazolyl, benzthiazo lyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolisinyl, quinolinyl, phthalaninyl, quinoxalinyl, naphthyridinyl, pteridinyl and quinazolinyl, wherein one or more hydrogen atoms of the mentioned aryl group can be optionally and independently substituted with: (i) alkyl having 1 up to 3 carbon atoms, (ii) -COOH, (iii) -SO2OH, (iv) -PO(OH)2, (v) a group of the formula -COOR7, where R7 represents a straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms, (vi) a group of the formula -NR8R9, where each of R8 and R9 independently represents a hydrogen atom, alkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms, or in which R8 and R9 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms that together with the nitrogen atom between them form a heterocyclic ring, (vii) a group of the formula -CONR10R11, where each of R10 and R11 independently represent a hydrogen atom, an alkyl which has from 1 to 6 carbon atoms or cycloalkyl having from 3 to 6 carbon atoms, or in which R10 and R11 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms that together with the nitrogen atom between them form a heterocyclic ring, (viii) a group of the formula -OR12a, where R12a represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms, (ix) a group of the formula -SR12b, where R12b represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 of carbon atoms, (x) cyano, or (xi) amidino group of the formula [image] in which each of R13, R14 and R15 independently represents a hydrogen atom or alkyl having from 1 to 3 carbon atoms, and in which two of R13, R14 and R15 can additionally form a saturated hydrocarbon bridge that has from 3 to 5 carbon atoms that together with the nitrogen atom(s) between them form a heterocyclic ring; R2 is: (A) a hydrogen atom, or (B) a branched or unbranched alkyl group having from 1 to 3 carbon atoms or a cycloalkyl group having from 3 to 5 carbon atoms, wherein said alkyl or cycloalkyl group can be substituted if necessary with : (i) a group of the formula -OR34, where R34 represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms, or (ii) a group of the formula -NR35R36, where each of R35 and R36 independently represents a hydrogen atom, alkyl which has from 1 to 2 carbon atoms, or acyl having from 1 to 2 carbon atoms; R3 is a group of the formula -(CR37R38)x(CR39R40)yR41, in which each of x and y independently represents 0 or 1, each of R37, R38 and R39 independently represents: (A) a hydrogen atom, (B) a group of the formula -OR42, where R42 represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms, (C) a branched or unbranched alkyl having from 1 to 3 carbon atoms or a cycloalkyl having from 3 to 5 carbon atoms, R40 is: (A ) a hydrogen atom, (B) a group of the formula -OR42, where R42 represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms, (C) a branched or unbranched alkyl having from 1 to 3 carbon atoms or a cycloalkyl which has from 3 to 5 carbon atoms, or (D) aryl which is selected from the class consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3 - or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5 -thiazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl , 2-pyrazinyl, 2-triazinyl, 2-, 3-, 6- or 7-indolizinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b] furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2 -, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolizinyl, 3-, 6- or 7- quinolinyl, 6- or 7-phthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-naphthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl, wherein one or more hydrogen atoms of said aryl group may be optionally and independently substituted with: (i) R43, which is selected from the class consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2 -, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4 - or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4 - or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, 3-, 6- or 7-indolizinyl, 2-, 3-, 5- or 6-isoindolyl , 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3- , 7- or 8-quinolizinyl, 3-, 6- or 7-quinolinyl, 6- or 7-phthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-naphthyridinyl . from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- and or polysubstituted with halogen or oxo, (b) -COOH, (c) -SO2OH, (d) -PO(OH)2, (e) a group of the formula -COOR44, where R44 represents straight or branched alkyl having from 1 to 5 of carbon atoms or cycloalkyl having from 3 to 5 carbon atoms, (f) a group of the formula -NR45R46, where each of R45 and R46 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms, or in which R45 and R46 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms that together with the nitrogen atom between them form a heterocyclic ring, (g) a group of the formula -CONR47R48 , where each of R47 and R48 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms or cycloalkyl having from 3 to 6 carbon atoms, or in which R47 and R48 form a saturated hydrocarbon bridge having from 3 to 5 of carbon atoms which, together with the nitrogen atom between them, form het erocyclic ring, (h) a group of the formula -OR49, where R49 represents a hydrogen atom, or an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, (i) a group of the formula -SR50, where R50 represents a hydrogen atom, or an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, (j) cyano, (k) nitro, (l) amidino group of the formula [image] in which each of R51, R52 and R53 independently represents a hydrogen atom or alkyl having from 1 to 3 carbon atoms, and in which two of R51, R52 and R53 can additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, or (m) halogen, ( ii) methyl, which can be mono- or polysubstituted with fluorine atoms and can additionally be monosubstituted with R43, (iii) a branched or unbranched alkyl group having from 2 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalc yl group can be mono- or polysubstituted with oxo, (iv) a group of the formula -COOR54, where R54 represents a straight or branched alkyl having from 1 to 5 carbon atoms or a cycloalkyl having from 3 to 5 carbon atoms, (v) a group of the formula -NR55R56, where each of R55 and R56 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms, or in which R55 and R56 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and where one of R55 and R56 may additionally be a group R43, (vi) a group of the formula -CONR57R56, where each of R57 and R58 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, or cycloalkyl having from 3 to 6 carbon atoms, or in which R57 and R58 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with with a nitrogen atom between them, they form a heterocyclic ring, and where one of R57 and R58 can additionally be a group R43, (vii) a group of the formula -COR59, where R59 represents a hydrogen atom, straight or branched or alkyl having from 1 to 5 carbon atoms, cycloalkyl which has from 3 to 5 carbon atoms, or R43, viii) a group of the formula -OR60, where R60 represents a hydrogen atom, an alkyl, fluoroalkyl or acyl group that has from 1 to 7 carbon atoms, or R43, (ix) a group of the formula -SR61 , where R61 represents a hydrogen atom, an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, or R43, (x) cyano, (xi) nitro, or (xii) halogen, R41 is: aryl selected from the class consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3 -furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4 - or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl , 4- or 5-oxadiazolyl, 1-, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, 3-, 6- or 7-indolizinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolisinyl, 3-, 6- or 7-quinolinyl, 6- or 7-phthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-naphthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl, whereby one or more hydrogen atoms of the mentioned aryl group can be independently substituted as needed with: (A) R 62 , which is aryl selected from the group consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl , 2-, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1- , 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2- pyrazinyl, 2-triazinyl, 2-, 3-, 6- or 7-indolizinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2 -, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3 -, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-quinolinyl, 6 - or 7-phthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-naphthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7- quinazolinyl, whereby one or more hydrogen atoms of the mentioned aryl group can be, if necessary, independently replaced with: i) a branched or unbranched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or the cycloalkyl group may be mono- or polysubstituted with halogen or oxo, (ii) -C OOH, (iii) -SO2OH, (iv) -PO(OH)2, (v) a group of the formula -COOR63, where R63 represents a straight or branched alkyl having from 1 to 5 carbon atoms or a cycloalkyl having from 3 to 5 carbon atoms atoms, (vi) a group of the formula -NR64R65, where each of R64 and R65 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 of carbon atoms, or in which R64 and R65 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which, together with the nitrogen atom between them, form a heterocyclic ring, (vii) a group of the formula -CONR66R67, where each of R66 and R67 independently represents a hydrogen atom , alkyl or fluoroalkyl having from 1 to 6 carbon atoms or cycloalkyl having from 3 to 6 carbon atoms, or in which R66 and R67 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms that together with the nitrogen atom between them form a heterocyclic ring, (viii) group of the formula -OR68, where R68 represents a hydrogen atom, or an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, (ix) a group of the formula -SR69, where R69 represents a hydrogen atom, or an alkyl, fluoroalkyl or acyl group having from 1 up to 7 carbon atoms, (x) cyano, (xi) nitro, or (xii) amidino group of the formula [image] in which each of R70, R71 and R72 independently represents a hydrogen atom or an alkyl having from 1 to 3 carbon atoms, and in in which two of R70, R71 and R72 can additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, or (xiii) halogen, (B) methyl, which can be mono- or polysubstituted with fluorine atoms and may additionally be monosubstituted with R62, (C) a branched or unbranched alkyl group having from 2 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono-il and polysubstituted with halogen or oxo, (D) a group of the formula -COOR73, where R73 represents a straight or branched alkyl having from 1 to 5 carbon atoms or a cycloalkyl having from 3 to 5 carbon atoms, (E) a group of the formula -NR74R75, where each of R74 and R75 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms, or in which R74 and R75 form saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and where one of R74 and R75 may additionally be the group R62, (F) a group of the formula -CONR76R77, where each of R76 and R77 independently represents hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, or cycloalkyl having from 3 to 6 carbon atoms, or in which R76 and R77 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom and between them they form a heterocyclic ring, and where one of R76 and R77 can additionally be a group R62, (G) a group of the formula -COR78, where R78 represents a hydrogen atom, straight or branched or alkyl having from 1 to 5 carbon atoms, cycloalkyl having from 3 to 5 carbon atoms, or R62, (H) a group of the formula -OR79, where R79 represents a hydrogen atom, an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, or R62, I) a group of the formula -SR80, where R80 represents a hydrogen atom, an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, or R62, (J) cyano, (K) nitro, or (L) halogen, R4 is Cl or trifluoromethyl; and each of R 5 and R 6 independently represents hydrogen, a fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl; or pharmaceutically acceptable salts thereof. 2. A compound of formula I [image] characterized in that Y is an oxygen or sulfur atom; Z is an oxygen or sulfur atom; X is a divalent group of the formula >CHR1, >NR1, >CHSO2R1, or >NSO2R1, or an oxygen or sulfur atom; where R1 is: (A) a hydrogen atom, (B) a branched or unbranched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group may be mono- or polysubstituted with : (i) halogen, (ii) oxo, (iii) aryl selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolizinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolisinyl, quinolinyl, phthalaninyl, quinoxalinyl, naphthyridinyl, pteridinyl and quinazolinyl, whereby one or more hydrogen atoms of the mentioned aryl residue can be replaced as necessary and independently with: (a) alkyl having 1 to 3 carbon atoms, (b) -COOH, (c) -SO2OH, (d) -PO(OH)2, (e) group of formula -COOR7, gdj e R7 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms, (f) a group of the formula -NR8R9, where each of R8 and R9 independently represents a hydrogen atom, alkyl having from 1 up to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms, or in which R8 and R9 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (g) a group of the formula -CONR10R11, where each of R10 and R11 independently represents a hydrogen atom, an alkyl having from 1 to 6 carbon atoms or a cycloalkyl having from 3 to 6 carbon atoms, or in which R10 and R11 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (h) a group of the formula -OR12a, where R12a represents a hydrogen atom or an alkyl or acyl group having from 1 to 7 carbon atoms , (i) a group of the formula -SR12b, where R12b represents a hydrogen atom or an alkyl or acyl group having from 1 to 7 carbon atoms, (j) cyano, or (k) an amidino group of the formula [image] in which each of R13, R14 and R15 independently represents a hydrogen atom or alkyl having from 1 to 3 carbon atoms and in which two of R13, R14 and R15 can additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms that together with the nitrogen atom(s) between them form a heterocyclic ring, (iv) a group of the formula -COOR16, where R16 represents a straight or branched alkyl having from 1 to 7 carbon atoms or a cycloalkyl having from 3 to 6 carbon atoms, (v) cyano, (vi) a group of the formula -CONR17R18, where each of R17 and R18 independently represents a hydrogen atom, an alkyl having from 1 to 6 carbon atoms, a cycloalkyl having from 3 to 6 carbon atoms, or in which R17 and R18 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms that along with the nitrogen atom between them h form a heterocyclic ring, (vii) a group of the formula -OR19, where R19 represents a hydrogen atom or an alkyl or acyl group having from 1 to 7 carbon atoms, (viii) a group of the formula -SR20, where R20 represents a hydrogen atom, or an alkyl or acyl group a group having from 1 to 7 carbon atoms, (ix) a group of the formula -NR21R22, where each of R21 and R22 independently represents (a) a hydrogen atom, (b) alkyl or acyl having from 1 to 7 carbon atoms or cycloalkyl having from 3 to 7 carbon atoms, (c) a group of the formula -(CH2)mCOOH, where m is 0, 1 or 2, or (d) a group of the formula -(CH2)nCOOR23, where n is 0, 1 or 2, and R23 is a straight or branched alkyl having from 1 to 6 carbon atoms, or where R21 and R22 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms that together with the nitrogen atom between them form a heterocyclic ring, or (x) a quaternary group of the formula [ image] in which each of R24, R25 and R26 independently represents a branched or unbranched alkyl group having from 1 to 7 carbon atoms and Q- is a chlorine, bromine or iodine ion of the opposite charge, (C) a branched or unbranched carboxylic acid group having from 3 to 6 carbon atoms, (D) a branched or unbranched phosphonic acid group having from 2 up to 6 carbon atoms, (E) a branched or unbranched sulfonic acid group having from 2 to 6 carbon atoms, (F) an amidino group of the formula [image] in which r is 2, 3, 4, 5 or 6, and each of R27 , R28 and R29 independently represent a hydrogen atom or alkyl having from 1 to 3 carbon atoms, and in which two of R27, R28 and R29 can additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, (G) a guanidino group of the formula [image] in which s is 2, 3, 4, 5 or 6, and each of R30, R31, R32 and R33 independently represents a hydrogen atom or an alkyl having from 1 to 3 carbon atoms, and in which two of R30, R31, R32 and R33 can additionally form a saturated carbon isohydrogen bridge having from 3 to 5 carbon atoms which, together with the nitrogen atom(s) between them form a heterocyclic ring, (H) piperidyl, in which the nitrogen atom of the mentioned group is, if necessary, substituted with: (i) alkyl having 1 to 3 carbon atoms, (ii) a carboxylic ester group having 2 to 7 carbon atoms, (iii) a carboxylic acid group having 2 to 5 carbon atoms, (iv) a phosphonic acid group having 1 to 6 carbon atoms, or (v) ) by a sulfonic acid group having from 1 to 6 carbon atoms, or (I) an aryl selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl . , n aftiridinyl, pteridinyl and quinazolinyl, whereby one or more hydrogen atoms of the mentioned aryl group can be independently substituted with (i) alkyl having 1 to 3 carbon atoms, (ii) -COOH, (iii) -SO2OH, (iv) ) -PO(OH)2, (v) a group of the formula -COOR7, where R7 represents a straight or branched alkyl having from 1 to 5 carbon atoms or a cycloalkyl having from 3 to 5 carbon atoms, (vi) a group of the formula -NR8R9, where each of R8 and R9 independently represents a hydrogen atom, an alkyl having from 1 to 6 carbon atoms, a cycloalkyl having from 3 to 6 carbon atoms or an acyl having from 1 to 7 carbon atoms, or in which R8 and R9 form a saturated hydrocarbon a bridge that has from 3 to 5 carbon atoms that together with the nitrogen atom between them form a heterocyclic ring, (vii) a group of the formula -CONR10R11, where each of R10 and R11 independently represents a hydrogen atom, an alkyl that has from 1 to 6 carbon atoms or a cycloalkyl which has from 3 to 6 carbon atoms, or in which R10 and R11 tv or a saturated hydrocarbon bridge that has from 3 to 5 carbon atoms that together with the nitrogen atom between them form a heterocyclic ring, (viii) a group of the formula -OR12a, where R12a represents a hydrogen atom or an alkyl or acyl group that has from 1 to 7 carbon atoms, (ix) a group of the formula -SR12b, where R12b represents a hydrogen atom or an alkyl or acyl group having from 1 to 7 carbon atoms, (x) cyano, or (xi) an amidino group of the formula [image] in which each of R13, R14 and R15 independently represents a hydrogen atom or an alkyl having from 1 to 3 carbon atoms, and in which two of R13, R14 and R15 can additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms that together with the nitrogen atom(s) between them form heterocyclic ring; R2 is: (A) a hydrogen atom, or (B) a branched or unbranched alkyl group having from 1 to 3 carbon atoms or a cycloalkyl group having from 3 to 5 carbon atoms, wherein said alkyl or cycloalkyl group can be substituted if necessary with : (i) a group of the formula -OR34, where R34 represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms, or (ii) a group of the formula -NR35R36, where each of R35 and R36 independently represents a hydrogen atom, alkyl which has from 1 to alkyl or fluoroalkyl atoms, or acyl having from 1 to 2 carbon atoms; R3 is a group of the formula -(CR37R38)x(CR39R40)yR41, in which each of x and y independently represents 0 or 1, each of R37, R38 and R39 independently represents: (A) a hydrogen atom, (B) a group of the formula -OR42, where R42 represents a hydrogen atom or an alkyl or acyl group having from 1 to 7 carbon atoms, or (C) a branched or unbranched alkyl having from 1 to 3 carbon atoms or a cycloalkyl having from 3 to 5 carbon atoms, R40 is: (A ) a hydrogen atom, (B) a group of the formula -OR42, where R42 represents a hydrogen atom or an alkyl or acyl group having from 1 to 7 carbon atoms, (C) a branched or unbranched alkyl having from 1 to 3 carbon atoms or a cycloalkyl having of 3 to 5 carbon atoms, or (D) aryl selected from the group consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5- thiazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazoles 1, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4 -pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, 3-, 6- or 7-indolizinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[ b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 3-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl , 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-quinolinyl, 6- or 7-phthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-naphthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl, wherein one or more hydrogen atoms of said aryl group may be optionally and independently substituted with: (i) R43, which is aryl selected from the class consisting of phenyl, 2-naphthyl, 2-, 3- , 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3- pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1- , 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl , 1-, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, 3-, 6- or 7-indolizinyl, 2-, 3-, 5 - or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-quinolinyl, 6- or 7-phthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6 - or 7-naphthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl, whereby one or more hydrogen atoms of the mentioned aryl group can be optionally and independently substituted with: (a) branched or an unbranched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or polysubstituted with halogen or oxo, (b) -COOH, (c) -SO2OH, (d) -PO(OH)2, (e) a group of the formula -COOR44, where R44 represents straight or branched alkyl having from 1 up to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms, (f) a group of the formula -NR45R46, where each of R45 and R46 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms, or in which R45 and R46 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms that together with the nitrogen atom between them form a heterocyclic ring, (g) a group of the formula -CONR47R48, where each of R47 and R48 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms or cycloalkyl having from 3 to 6 carbon atoms, or in which R47 and R48 form a saturated hydrocarbon bridge having from 3 up to 5 carbon atoms which together with the nitrogen atom between them tv ore heterocyclic ring, (h) a group of the formula -OR49, where R49 represents a hydrogen atom or an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, (i) a group of the formula -SR50, where R50 represents a hydrogen atom or an alkyl, fluoroalkyl or an acyl group having from 1 to 7 carbon atoms, (j) cyano, (k) nitro, (l) amidino group of the formula [image] in which each of R51, R52 and R53 independently represents a hydrogen atom or alkyl having from 1 up to 3 carbon atoms, and in which two of R51, R52 and R53 can additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, or (m) halogen, (ii) ) methyl, which can be mono- or polysubstituted with fluorine atoms and can additionally be monosubstituted with R43, (iii) branched or unbranched alkyl having from 2 to 6 carbon atoms or cycloalkyl having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group m it must be mono- or polysubstituted with halogen or oxo, (iv) a group of the formula -COOR54, where R54 represents a straight or branched alkyl having from 1 to 5 carbon atoms or a cycloalkyl having from 3 to 5 carbon atoms, (v) a group of the formula -NR55R56, where each of R55 and R56 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms, or in which R55 and R56 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and where one of R55 and R56 may additionally be a group R43, (vi) a group of the formula -CONR57R56, where each of R57 and R58 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, or cycloalkyl having from 3 to 6 carbon atoms, or in which R57 and R58 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with with a nitrogen atom between them, they form a heterocyclic ring, and where one of R57 and R58 can additionally be a group R43, (vii) a group of the formula -COR59, where R59 represents a hydrogen atom, straight or branched or alkyl having from 1 to 5 carbon atoms, cycloalkyl which has from 3 to 5 carbon atoms, or R43, (viii) a group of the formula -OR60, where R60 represents a hydrogen atom, an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, or R43, (ix) a group of the formula - SR61, where R61 represents a hydrogen atom, an alkyl, fluoroalkyl, or acyl group having from 1 to 7 carbon atoms, or R43, (x) cyano, (xi) nitro, or (xii) halogen, R41 is: aryl selected from class consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2 - or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3 -, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-iz otiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, 3-, 6- or 7-indolizinyl , 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3- , 5- or 6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl , 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-quinolinyl, 6- or 7-phthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl , 2-, 3-, 6- or 7-naphthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl, whereby at least one of the hydrogen atoms of the mentioned aryl group can be replaced by: ( A) R62, which is aryl selected from the group consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2- , 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3- , 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, 3-, 6- or 7-indolizinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5 - or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7 -quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-quinolinyl, 6- or 7-phthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-naphthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl, wherein one or several hydrogen atoms of the mentioned aryl group can be independently replaced as necessary with: (i) a branched or unbranched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or polysubstituted with halogen or oxo, (ii) -COOH, (iii) -SO2OH, (iv) -PO(OH)2, (v) a group of the formula -COOR63, where R63 represents a straight or branched alkyl having from 1 to 5 carbon atoms or a cycloalkyl having from 3 to 5 carbon atoms, (vi) by a group of the formula -NR64R65, where each of R64 and R65 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms, or in in which R64 and R65 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (vii) a group of the formula -CONR66R67, where each of R66 and R67 independently represents a hydrogen atom, alkyl or fluoroalkyl which has from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms, or in which R66 and R67 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms that together with the nitrogen atom between them form a heterocyclic ring, (viii) by the formula group -OR68, where R68 represents a hydrogen atom, or an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, (ix) a group of the formula -SR69, where R69 represents a hydrogen atom or an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, (x) cyano, (xi) nitro, or (xii) amidino group of the formula [image] in which each of R70, R71 and R72 independently represents a hydrogen atom or an alkyl having from 1 to 3 carbon atoms and in which two of R70, R71 and R72 can additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, or (xiii) halogen, (B) methyl, which can be mono- or polysubstituted with atoms fluorine and can additionally be monosubstituted with R62, (C) a branched or unbranched alkyl group having from 2 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or polysubstituted wound with halogen or oxo, (D) a group of the formula -COOR73, where R73 represents a straight or branched alkyl having from 1 to 5 carbon atoms or a cycloalkyl having from 3 to 5 carbon atoms, (E) a group of the formula -NR74R75, where each of R74 and R75 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms, or in which R74 and R75 form a saturated hydrocarbon a bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and where one of R74 and R75 can additionally be a group R62, (F) a group of the formula -CONR76R77, where each of R76 and R77 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms or cycloalkyl having from 3 to 6 carbon atoms, or in which R76 and R77 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form heterocyclic ring, and where one of R76 and R77 can additionally be a group R62, (G) a group of the formula -COR78, where R78 represents a hydrogen atom, straight or branched or alkyl having from 1 to 5 carbon atoms, cycloalkyl having from 3 to 5 carbon atoms, or R62, (H) a group of the formula -OR79, where R79 represents a hydrogen atom, an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, or R62, (I) a group of the formula -SR80, where R80 represents a hydrogen atom, an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, or R62, (J) cyano, (K) nitro, or (L) halogen, R4 is Cl or trifluoromethyl; and each of R 5 and R 6 independently represents hydrogen, a fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl; or a pharmaceutically acceptable salt thereof. 3. Compound of formula I, according to claim 2, characterized in that Y is an oxygen or sulfur atom; Z is an oxygen or sulfur atom; X is a divalent group of the formula >CHR1, >NR1, >CHSO2R1, or >NSO2R1, or an oxygen or sulfur atom; where R1 is: (A) hydrogen atom, (B) a branched or unbranched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group may be mono- or polysubstituted with: (i) halogen, (ii) oxo, (iii) aryl selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolizinyl , isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, quinolinyl, phthalaninyl, quinoxalinyl, naphthyridinyl, pteridinyl and quinazolinyl, whereby one or more hydrogen atoms of the mentioned aryl group can be independently replaced with: (a) alkyl having 1 to 3 carbon atoms, (b) -COOH, (c) -SO2OH, (d) -PO(OH)2, (e) a group of the formula -COOR7, where R7 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms, (f) a group of the formula -NR8R9, where each of R8 and R9 independently represents a hydrogen atom, alkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms, or in which R8 and R9 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which, together with the nitrogen atom between them, form a heterocyclic ring, (g) a group of the formula -CONR10R11, where each of R10 and R11 independently represents a hydrogen atom, an alkyl having from 1 to 6 carbon atoms or a cycloalkyl having from 3 to 6 carbon atoms, or in which R10 and R11 form a saturated hydrocarbon bridge that has from 3 to 5 carbon atoms which, together with the nitrogen atom between them, form a heterocyclic ring, (h) a group of the formula -OR12a, where R12a represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms, (i) a group of the formula -SR12b, where R12b represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms, (j) cyano, or (k) amidino group of the formula [image] in which each of R13, R14 and R15 independently represents a hydrogen atom or alkyl having from 1 to 3 carbon atoms and in which two of R13, R14 and R15 can additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with nitrogen atom(s) between them to form a heterocyclic ring, (iv) a group of the formula -COOR16, where R16 represents straight or branched alkyl having from 1 to 7 carbon atoms or cycloalkyl having from 3 to 6 carbon atoms, (v) cyano, (vi) a group of the formula -CONR17R18, where each of R17 and R18 independently represents a hydrogen atom, an alkyl having from 1 to 6 carbon atoms or a cycloalkyl having from 3 to 6 carbon atoms, or in which R17 and R18 form a saturated hydrocarbon bridge that has from 3 to 5 carbon atoms which, together with the nitrogen atom between them, form a heterocyclic ring, (vii) a group of the formula -OR19, where R19 represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms, (viii) a group of the formula -SR20, where R20 represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms, (ix) a group of the formula -NR21R22, where each of R21 and R22 independently represents: (a) hydrogen atom, (b) alkyl or acyl having from 1 to 7 carbon atoms or cycloalkyl having from 3 to 7 carbon atoms, (c) a group of the formula -(CH2)mCOOH, where m is 0, 1 or 2, or (d) a group of the formula -(CH2)nCOOR23, where n is 0, 1 or 2, and R23 is straight or branched alkyl having from 1 to 6 carbon atoms, or where R21 and R22 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, or (x) by the quaternary group of the formula [image] in which each of R24, R25 and R26 independently represents a branched or unbranched alkyl group having from 1 to 7 carbon atoms and Q- is a chlorine, bromine or iodine ion of the opposite charge, (C) branched or unbranched carboxylic acid group having from 3 to 6 carbon atoms, (D) branched or unbranched phosphonic acid group having from 2 to 6 carbon atoms, (E) a branched or unbranched sulfonic acid group having from 2 to 6 carbon atoms, (F) amidino group of the formula [image] in which r is 2, 3, 4, 5 or 6, and each of R27, R28 and R29 independently represents a hydrogen atom or alkyl having from 1 to 3 carbon atoms and in which two of R27, R28 and R29 can additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with a nitrogen atom ( atoms) between them form a heterocyclic ring, (G) guanidino group of the formula [image] in which s is 2, 3, 4, 5 or 6, i each of R30, R31, R32 and R33 independently represents a hydrogen atom or alkyl having from 1 to 3 carbon atoms and in which two of R30, R31, R32 and R33 can additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with nitrogen atom(s) between them form a heterocyclic ring, or (H) piperidyl, in which the nitrogen atom of the mentioned group is optionally substituted with: (i) alkyl having 1 to 3 carbon atoms, (ii) a carboxyl ester group having 2 to 7 carbon atoms, (iii) a carboxylic acid group that has from 2 to 5 carbon atoms, (iv) a phosphonic acid group having from 1 to 6 carbon atoms, or (v) a sulfonic acid group having from 1 to 6 carbon atoms; R2 is: (A) hydrogen atom, or (B) methyl; R3 is a group of the formula -CH2R41, in which: R41 is: aryl selected from the group consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5- pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5- pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5- triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, 3-, 6- or 7-indolizinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or 6-benzthiazolyl , 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolisinyl, 3-, 6- or 7-quinolinyl, 6- or 7-phthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-naphthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl, whereby one or more hydrogen atoms of the mentioned aryl group are necessarily and independently substituted with: (A) R 62 , which is aryl selected from the group consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2 -, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3 -, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1 -, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, 3-, 6- or 7-indolizinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 3- , 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2- , 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-quinolinyl, 6- or 7-phthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-naphthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl, where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with: (i) a branched or unbranched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or polysubstituted with halogen or with oxo, (ii) -COOH, (iii) -SO2OH, (iv) -PO(OH)2, (v) a group of the formula -COOR63, where R63 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms, (vi) a group of the formula -NR64R65, where each of R64 and R65 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms , or in which R64 and R65 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (vii) a group of the formula -CONR66R67, where each of R66 and R67 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms or cycloalkyl having from 3 to 6 carbon atoms, or in which R66 and R67 form a saturated hydrocarbon a bridge that has from 3 to 5 carbon atoms that, together with the nitrogen atom between them, form a heterocyclic ring, (viii) a group of the formula -OR68, where R68 represents a hydrogen atom, or an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, (ix) a group of the formula -SR69, where R69 represents a hydrogen atom, or an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, (x) cyano, (xi) nitro, (xii) amidino group of the formula [image] in which each of R70, R71 and R72 independently represents a hydrogen atom or alkyl or fluoroalkyl having from 1 to 3 carbon atoms, and in which two of R70, R71 and R72 may additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, (xiii) halogen, (B) methyl, which can be mono- or polysubstituted with fluorine atoms and can additionally be monosubstituted with R62, (C) a branched or unbranched alkyl group having from 2 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or polysubstituted with halogen or with oxo, (D) a group of the formula -COOR73, where R73 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms, (E) a group of the formula -NR74R75, where each of R74 and R75 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms , or in which R74 and R75 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and where one of R74 and R75 may additionally be the group R62, (F) a group of the formula -CONR76R77, where each of R76 and R77 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, or cycloalkyl having from 3 to 6 carbon atoms, or in which R76 and R77 form saturated a hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and where one of R76 and R77 may additionally be the group R62, (G) a group of the formula -COR78, where R78 represents a hydrogen atom, straight or branched alkyl having from 1 to 5 carbon atoms, cycloalkyl having from 3 to 5 carbon atoms, or R62, (H) a group of the formula -OR79, where R79 represents a hydrogen atom, an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, or R62, (I) a group of the formula -SR80, where R80 represents a hydrogen atom, an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, or R62, (J) cyano, (K) nitro, or (L) halogen, R 4 is Cl or trifluoromethyl; and each of R5 and R6 independently represents hydrogen, a fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl; or a pharmaceutically acceptable salt thereof. 4. Compound of formula I, according to claim 3, characterized in that Y is an oxygen atom; Z is an oxygen atom; X is a divalent group of the formula >CHR1 or >NR1, where R1 is: (A) hydrogen atom, (B) a branched or unbranched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group may be mono- or polysubstituted with: (i) oxo, (ii) aryl selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl and triazinyl, where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with: (a) alkyl having 1 to 3 carbon atoms, (b) -COOH, (c) -SO2OH, (d) -PO(OH)2, (e) a group of the formula -COOR7, where R7 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms, (f) group of the formula -NH2, (g) group of the formula -CONH2, (h) a group of the formula -OR12a, where R12a represents a hydrogen atom or methyl, (i) amidino group of the formula [image] in which each of R13, R14 and R15 independently represents hydrogen atoms, (iii) a group of the formula -COOR16, where R16 represents straight or branched alkyl having from 1 to 7 carbon atoms or cycloalkyl having from 3 to 6 carbon atoms, (iv) a group of the formula -OR19, where R19 represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms, or (v) quaternary group of the formula [image] in which each of R24, R25 and R26 independently represents methyl and Q- is an oppositely charged chlorine, bromine or iodine ion, (C) branched or unbranched carboxylic acid group having from 3 to 6 carbon atoms, (D) branched or unbranched phosphonic acid group having from 2 to 6 carbon atoms, (E) a branched or unbranched sulfonic acid group having from 2 to 6 carbon atoms, (F) amidino group of the formula [image] in which r is 2, 3, 4, 5 or 6, and each of R27, R28 and R29 independently represents hydrogen atoms, (G) guanidino group of the formula [image] where s is 2, 3, 4, 5 or 6, each of R30, R31, R32 and R33 independently represents hydrogen atoms, or (H) piperidyl, in which the nitrogen atom of the mentioned group is optionally substituted with: (i) alkyl having 1 to 3 carbon atoms, (ii) a carboxyl ester group having 2 to 7 carbon atoms, (iii) a carboxylic acid group that has from 2 to 5 carbon atoms, (iv) a phosphonic acid group having from 1 to 6 carbon atoms, or (v) a sulfonic acid group having from 1 to 6 carbon atoms; R2 is: (A) hydrogen atom, or (B) methyl; R3 is a group of the formula -CH2R41, in which R41 is aryl selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl and triazinyl, wherein one or more of hydrogen atoms of the mentioned aryl group necessarily and independently substituted with: (A) R 62 , which is aryl selected from the group consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl and triazinyl, where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with: (i) methyl, (ii) -COOH, (iii) -SO2OH, (iv) -PO(OH)2, (v) a group of the formula -COOR63, where R63 represents methyl, (vi) a group of the formula -NR64R65, where each of R64 and R65 independently represents a hydrogen atom or methyl, (vii) a group of the formula -CONR66R67, where each of R66 and R67 independently represents a hydrogen atom or methyl, (viii) a group of the formula -OR68, where R68 represents a hydrogen atom or methyl, (ix) a group of the formula -SR69, where R69 represents a hydrogen atom or methyl, (x) cyano, (xi) nitro, or (xii) halogen, (B) methyl, which can be mono- or polysubstituted with fluorine atoms and which can additionally be monosubstituted with R62, (C) a branched or unbranched alkyl group having from 2 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or polysubstituted with halogen or oxo, (D) a group of the formula -COOR73, where R73 represents methyl, (E) a group of the formula -NR74R75, where each of R74 and R75 independently represents a hydrogen atom or methyl, and in which one of R74 and R75 can additionally be the group R62, (F) a group of the formula -CONR76R77, where each of R76 and R77 independently represents a hydrogen atom or methyl, and in which one of R76 and R77 can additionally be a group R62, (G) a group of the formula -COR78, where R78 represents a hydrogen atom or methyl, or R62, (H) a group of the formula -OR79, where R79 represents a hydrogen atom, methyl, or R62, (I) a group of the formula -SR80, where R80 represents a hydrogen atom, methyl, or R62, (J) cyano, (K) nitro, or (L) halogenim; R 4 is Cl or trifluoromethyl; R5 is a hydrogen atom; and R 6 is Cl, or trifluoromethyl; or a pharmaceutically acceptable salt thereof. 5. Compound of formula I, according to claim 4, characterized in that Y is an oxygen atom; Z is an oxygen atom; X is a divalent group of the formula >CHR1 or >NR1, where R1 is: (A) hydrogen atom, (B) a branched or unbranched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group may be mono- or polysubstituted with: (i) oxo, (ii) aryl selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl and triazinyl, where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with: (a) alkyl having 1 to 3 carbon atoms, (b) -COOH, (c) -SO2OH, (d) -PO(OH)2, (e) a group of the formula -COOR7, where R7 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms, (f) group of the formula -NH2, (g) group of the formula -CONH2, (h) a group of the formula -OR12a, where R12a represents a hydrogen atom or methyl, (i) amidino group of the formula [image] in which each of R13, R14 and R15 independently represents hydrogen atoms, (iii) a group of the formula -COOR16, where R16 represents straight or branched alkyl having from 1 to 7 carbon atoms or cycloalkyl having from 3 to 6 carbon atoms, (iv) a group of the formula -OR19, where R19 represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms, or (v) quaternary group of the formula [image] in which each of R24, R25 and R26 independently represents methyl and Q- is an oppositely charged chlorine, bromine or iodine ion, (C) branched or unbranched carboxylic acid group having from 3 to 6 carbon atoms, (D) branched or unbranched phosphonic acid group having from 2 to 6 carbon atoms, (E) a branched or unbranched sulfonic acid group having from 2 to 6 carbon atoms, (F) amidino group of the formula [image] in which r is 2, 3, 4, 5 or 6, and each of R27, R28 and R29 independently represents hydrogen atoms, (G) guanidino group of the formula [image] in which s is 2, 3, 4, 5 or 6, i each of R30, R31, R32 and R33 independently represents hydrogen atoms, or (H) piperidyl, in which the nitrogen atom of the mentioned group is optionally substituted with: (i) alkyl having 1 to 3 carbon atoms, (ii) a carboxyl ester group having 2 to 7 carbon atoms, (iii) a carboxylic acid group that has from 2 to 5 carbon atoms, (iv) a phosphonic acid group having from 1 to 6 carbon atoms, (v) a sulfonic acid group having from 1 to 6 carbon atoms; R2 is: (A) hydrogen atom, or (B) methyl; R3 is a group of the formula -CH2R41, in which R41 is aryl selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl and pyrazinyl, whereby one or more hydrogen atoms of the mentioned aryl group are necessarily and independently substituted with: (A) R 62 , which is aryl selected from the group consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl and pyrazinyl, where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with: (i) methyl, (ii) -COOH, (iii) the group of the formula -COOR63, where R63 represents methyl, (iv) a group of the formula -OR68, where R68 represents a hydrogen atom or methyl, or (v) halogen, (B) methyl, which can be mono- or polysubstituted with fluorine atoms or which can be monosubstituted with R62, (C) a branched or unbranched alkyl group having from 2 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or polysubstituted with halogen or oxo, (D) a group of the formula -COOR73, where R73 represents methyl, (E) a group of the formula -CONR76R77, where each of R76 and R77 represents methyl, and in which one of R76 and R77 can additionally be a group R62, (F) a group of the formula -COR78, where R78 represents a hydrogen atom, methyl or R62, (G) a group of the formula -OR79, where R79 represents a hydrogen atom, methyl or R62, (H) cyano, (I) nitro, or (J) halogen, R 4 is Cl or trifluoromethyl; R5 is a hydrogen atom; and R 6 is Cl or trifluoromethyl; or a pharmaceutically acceptable salt thereof. 6. Compound of formula I, according to claim 5, characterized in that Y is an oxygen atom; Z is an oxygen atom; X is a divalent group of the formula >CHR1 or >NR1, where R1 is: (A) hydrogen atom, (B) a branched or unbranched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group may be mono- or polysubstituted with: (i) oxo, (ii) aryl selected from the class consisting of phenyl or pyridyl, where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with: (a) alkyl having 1 to 3 carbon atoms, (b) -COOH, (c) -SO2OH, (d) -PO(OH)2, (e) a group of the formula -OR12a, where R12a represents a hydrogen atom or methyl, (f) amidino group of the formula [image] in which each of R13, R14 and R15 independently represents hydrogen atoms, (iii) a group of the formula -OR19, where R19 represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms, or (v) quaternary group of the formula [image] in which each of R24, R25 and R26 independently represents methyl and Q- is an oppositely charged chlorine, bromine or iodine ion, (C) branched or unbranched carboxylic acid group having from 3 to 6 carbon atoms, (D) branched or unbranched phosphonic acid group having from 2 to 6 carbon atoms, (E) a branched or unbranched sulfonic acid group having from 2 to 6 carbon atoms, (F) amidino group of the formula [image] in which r is 2, 3, 4, 5 or 6, and each of R27, R28 and R29 independently represents hydrogen atoms, (G) guanidino group of the formula [image] where s is 2, 3, 4, 5 or 6, each of R30, R31, R32 and R33 independently represents hydrogen atoms, or (H) piperidyl, in which the nitrogen atom of the mentioned group is optionally substituted with: (i) alkyl having 1 to 3 carbon atoms, (ii) a carboxyl ester group having 2 to 7 carbon atoms, (iii) a carboxylic acid group that has from 2 to 5 carbon atoms, (iv) a phosphonic acid group having from 1 to 6 carbon atoms, or (v) a sulfonic acid group having from 1 to 6 carbon atoms; R2 is: (A) hydrogen atom, or (B) methyl; R3 is a group of the formula -CH2R41, in which R41 is aryl selected from the class consisting of phenyl or pyridyl, whereby one or more hydrogen atoms of the mentioned aryl group are necessarily and independently substituted with: (A) R62, which is aryl selected from the group consisting of phenyl, or pyridyl, where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with: (i) methyl, (ii) -COOH, (iii) the group of the formula -COOR63, where R63 represents methyl, (iv) a group of the formula -OR68, where R68 represents a hydrogen atom or methyl, or (vi) halogen, (B) methyl, which can be mono- or polysubstituted with fluorine atoms or which can additionally be monosubstituted with R62, (C) a branched or unbranched alkyl group having from 2 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or polysubstituted with fluorine or with oxo, (D) a group of the formula -COOR73, where R73 represents methyl, (E) a group of the formula -CONR76R77, where each of R76 and R77 represents methyl, in which one of R76 and R77 is methyl and the other is the group R62, (F) a group of the formula -COR78, where R78 represents a hydrogen atom, methyl or R62, (G) a group of the formula -OR79, where R79 represents a hydrogen atom, methyl or R62, (H) cyano, (I) nitro, or (J) halogen; R4 is a chlorine atom or trifluoromethyl; R5 is a hydrogen atom; and R 6 is a chlorine atom or trifluoromethyl; or a pharmaceutically acceptable salt thereof. 7. Compound of formula I, according to claim 6, characterized in that Y is an oxygen atom; Z is an oxygen atom; X is a divalent group of the formula >CHR1 or >NR1, where R1 is: (A) hydrogen atom, (B) alkyl having from 1 to 2 carbon atoms which may be monosubstituted with: (i) oxo, (ii) aryl selected from the class consisting of phenyl or pyridyl, where one hydrogen atom of the mentioned aryl group can be replaced by: (a) alkyl having 1 to 3 carbon atoms, (b) -COOH, (c) -SO2OH, (d) -PO(OH)2, (e) a group of the formula -OR12a, where R12a represents a hydrogen atom or methyl, or (f) amidino group of the formula [image] wherein each of R13, R14 and R15 represents hydrogen atoms, or (iii) a group of the formula -OR19, where R19 represents a hydrogen atom or methyl, (C) branched or unbranched carboxylic acid group having from 3 to 6 carbon atoms, (D) branched or unbranched phosphonic acid group having from 2 to 6 carbon atoms, (E) a branched or unbranched sulfonic acid group having from 2 to 6 carbon atoms, (F) amidino group of the formula [image] in which r is 2, 3, 4, 5 or 6, and each of R27, R28 and R29 represents hydrogen atoms, or (G) guanidino group of the formula [image] where s is 2, 3, 4, 5 or 6, each of R30, R31, R32 and R33 independently represents hydrogen atoms, R2 is: (A) hydrogen atom, or (B) methyl; R3 is a group of the formula -CH2R41, in which R41 is phenyl, whereby one or more hydrogen atoms of the mentioned phenyl group are necessarily and independently replaced by: (A) R 62 , which is aryl selected from the group consisting of phenyl or, pyridyl, where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with: (i) methyl, (ii) a group of the formula -COOR63, where R63 represents methyl, (iii) a group of the formula -OR68, where R68 represents a hydrogen atom or methyl, or (vi) halogen, (B) methyl, which can be mono- or polysubstituted with fluorine atoms or which can be monosubstituted with R62, (C) a group of the formula -COOR73, where R73 represents methyl, (D) a group of the formula -COR78, where R78 represents methyl or R62, (E) a group of the formula -OR79, where R79 represents a hydrogen atom, methyl, or R62, (F) cyano, (G) nitro, or (H) halogen, R4 is a chlorine atom or trifluoromethyl; R5 is a hydrogen atom; and R 6 is a chlorine atom or trifluoromethyl; or a pharmaceutically acceptable salt thereof. 8. Compound of formula I, according to claim 7, characterized in that Y is an oxygen atom; Z is an oxygen atom; X is a divalent group of the formula >NR1, where R1 is: (A) hydrogen atom, (B) methyl or ethyl, or (C) -COCH3; R2 is: (A) hydrogen atom, or (B) methyl; R3 is a group of the formula -CH2R41, in which R41 is phenyl, whereby one or more hydrogen atoms of the mentioned phenyl group are necessarily and independently replaced by: (A) R62, which is aryl selected from the group consisting of phenyl, or pyridyl, where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with: (i) methyl, (ii) a group of the formula -COOR63, where R63 represents methyl, (iii) a group of the formula -OR68, where R68 represents a hydrogen atom or methyl, or (vi) halogen, (B) methyl, which can be mono- or polysubstituted with fluorine atoms and which can be monosubstituted with R62, (C) a group of the formula -COOR73, where R73 represents methyl, (D) a group of the formula -COR78, where R78 represents methyl or R62, (E) a group of the formula -OR79, where R79 represents a hydrogen atom, methyl, or R62, (F) cyano, (G) nitro, or (H) halogen, R4 is a chlorine atom or trifluoromethyl; R5 is a hydrogen atom; and R 6 is a chlorine atom or trifluoromethyl; or a pharmaceutically acceptable salt thereof. 9. Compound of formula I, according to claim 8, characterized in that Y is an oxygen atom; Z is an oxygen atom; X is a divalent group of the formula >NR1, where R1 is: (A) hydrogen atom, (B) methyl or ethyl, or (C) -COCH3; R2 is: (A) hydrogen atom, or (B) methyl; R3 is a group of the formula -CH2R41, in which R41 is phenyl, whereby one or more hydrogen atoms of the mentioned phenyl group are necessarily and independently replaced by: (A) R62, which is aryl selected from the group consisting of phenyl, or pyridyl, where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with: (i) methyl, (ii) halogen, (B) methyl, which can be mono- or polysubstituted with fluorine atoms, (C) a group of the formula -COR78, where R78 represents methyl, or R62, (D) halogen, R4 is a chlorine atom; R5 is a hydrogen atom; and R 6 is a chlorine atom; or a pharmaceutically acceptable salt thereof. 10. A compound, indicated by the fact that it is selected from the group consisting of: [image] or pharmaceutically acceptable salts thereof. 11. A method for the treatment or prevention of inflammatory, immune diseases or conditions, mediated by cells, characterized in that it includes the administration of a prophylactic or therapeutic amount of the compound according to claim 2, 3, 4, 5, 6, 7, 8, 9 or 10. 12. The method according to claim 1 or 11, characterized in that the disease or condition is selected from the group consisting of adult respiratory distress syndrome, shock, oxygen toxicity, secondary multiple organ injury syndrome after blood poisoning, secondary multiple organ injury syndrome after trauma, reperfusion tissue injury due to cardiopulmonary bypass, myocardial infarction or use with thrombolysis agents, acute glomerulonephritis, vasculitis, reactive arthritis, dermatosis with acute inflammatory components, stroke, burn, hemodialysis, leukopheresis, ulcerative colitis, necrotizing enterocolitis, and granulocyte transfusion-related syndrome . 13. The method according to claim 1 or 11, characterized in that the disease or condition is selected from the group consisting of psoriasis, transplanted organ/tissue rejection, host reactions to the graft and autoimmune diseases including Raynaud's syndrome, autoimmune thyroiditis, dermatitis, multiple sclerosis, rheumatoid arthritis, insulin-dependent diabetes mellitus, uveitis, inflammatory bowel diseases including Crohn's disease and ulcerative colitis; and systemic lupus erythematosus. 14. The method according to claim 1 or 11, characterized in that the disease or condition is asthma. 15. The method according to claim 1 or 11, characterized in that the condition is toxicity associated with cytokine therapy. 16. A pharmaceutical composition, characterized in that it contains a pharmaceutically acceptable carrier and a compound of formula I [image] in which Y is an oxygen or sulfur atom; Z is an oxygen or sulfur atom; X is a divalent group of the formula >CHR1, >NR1, >CHSO2R1, or >NSO2R1, or an oxygen or sulfur atom, where R1 is: (A) a hydrogen atom, (B) a branched or unbranched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group may be mono- or polysubstituted with: (i) halogen, (ii) oxo, (iii) aryl selected from the group consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolizinyl, isoindolyl, benzo[b]furanyl, benzo[b] thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolisinyl, quinolinyl, phthalaninyl, quinoxalinyl, naphthyridinyl, pteridinyl and quinazolinyl, whereby one or more hydrogen atoms of the mentioned aryl residue can be optionally and independently substituted with: (a) by alkyl which has 1 to 3 carbon atoms, (b) -COOH, (c) -SO2OH, (d) -PO(OH)2, (e) a group of the formula -COOR7, where R7 represents straight or branched alkyl having from 1 to 5 of carbon atoms or cycloalkyl having from 3 to 5 carbon atoms, (f) a group of the formula -NR8R9, where each of R8 and R9 independently represents a hydrogen atom, alkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms atoms or acyl having from 1 to 7 carbon atoms, or in which R8 and R9 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms that together with the nitrogen atom between them form a heterocyclic ring, (g) a group of the formula -CONR10R11, where each of R10 and R11 independently represents a hydrogen atom, an alkyl having from 1 to 6 carbon atoms or a cycloalkyl having from 3 to 6 carbon atoms, or in which R10 and R11 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with a nitrogen atom between them they form a heterocyclic ring, (h) a group of the formula -OR12a, gdj e R12a represents a hydrogen atom or an alkyl or acyl group having from 1 to 7 carbon atoms, (i) a group of the formula -SR12b, where R12b represents a hydrogen atom or an alkyl or acyl group having from 1 to 7 carbon atoms, (j) cyano , or (k) an amidino group of the formula [image] in which each of R13, R14 and R15 independently represents a hydrogen atom or an alkyl having from 1 to 3 carbon atoms and in which two of R13, R14 and R15 can additionally form a saturated hydrocarbon bridge which has from 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, (iv) a group of the formula -COOR16, where R16 represents a straight or branched alkyl having from 1 to 7 carbon atoms or a cycloalkyl having from 3 up to 6 carbon atoms, (v) cyano, (vi) a group of the formula -CONR17R18, where each of R17 and R18 independently represents a hydrogen atom, alkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms, or in which R17 and R18 form saturated a hydrocarbon bridge that has from 3 to 5 carbon atoms that together with the nitrogen atom between them form a heterocyclic ring, (vii) a group of the formula -OR19, where R19 represents a hydrogen atom or an alkyl or acyl group that has from 1 to 7 carbon atoms, (viii ) a group of the formula -SR20, where R20 represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms, (ix) a group of the formula -NR21R22, where each of R21 and R22 independently represents (a) a hydrogen atom, (b) ) alkyl or acyl having from 1 to 7 carbon atoms or cycloalkyl having from 3 to 7 carbon atoms, (c) a group of the formula -(CH2)mCOOH, where m is 0, 1 or 2, or (d) a group of the formula - (CH2)nCOOR23, where n is 0, 1 or 2, and R23 is straight or branched alkyl having from 1 to 6 carbon atoms, or where R21 and R22 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with with a nitrogen atom between them to form a heterocyclic ring, or (x) with a quaternary group of the formula [image] in which each of R24, R25 and R26 independently represents a branched or unbranched alkyl group having from 1 to 7 carbon atoms and Q- is a chlorine, bromine or iodine ion of the opposite charge, (C) a branched or unbranched carboxylic acid group having from 3 to 6 of carbon atoms, (D) a branched or unbranched phosphonic acid group having from 2 to 6 carbon atoms, (E) a branched or unbranched sulfonic acid group having from 2 to 6 carbon atoms, (F) an amidino group of the formula [image] in which r is 2, 3, 4, 5 or 6, and each of R27, R28 and R29 independently represents a hydrogen atom or an alkyl having from 1 to 3 carbon atoms, and in which two of R27, R28 and R29 may additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, (G) a guanidino group of the formula [image] in which s is 2, 3, 4, 5 or 6, and each of R30, R31, R32 and R33 independently represent a hydrogen atom or an alkyl having from 1 to 3 carbon atoms, and in which two of R30, R31, R32 and R33 can additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, (H) piperidyl, in which the nitrogen atom of the mentioned group is optionally substituted with: (i) an alkyl having 1 to 3 carbon atoms, (ii) a carboxylic ester group having 2 to 7 carbon atoms, (iii) a carboxylic acid group having from 2 to 5 of carbon atoms, (iv) a phosphonic acid group having from 1 to 6 carbon atoms, or (v) a sulfonic acid group having from 1 to 6 carbon atoms, or (I) an aryl selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolizinyl, isoindolyl, benzo[b]furanyl, benzo[b] thiophenyl, indazolyl, benzthiazolyl, ben zimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolisinyl, quinolinyl, phthalaninyl, quinoxalinyl, naphthyridinyl, pteridinyl and quinazolinyl, whereby one or more hydrogen atoms of the mentioned aryl group can be optionally and independently substituted with (i) alkyl having 1 to 3 carbon atoms atoms, (ii) -COOH, (iii) -SO2OH, (iv) -PO(OH)2, (v) a group of the formula -COOR7, where R7 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl which has from 3 to 5 carbon atoms, (vi) a group of the formula -NR8R9, where each of R8 and R9 independently represents a hydrogen atom, alkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms, or in which R8 and R9 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms that together with the nitrogen atom between them form a heterocyclic ring, (vii) a group of the formula -CONR10R11, where each of R10 and R11 independently represents a hydrogen atom, an alkyl having from 1 up to 6 carbon atoms, or cycloalkyl having from 3 to 6 carbon atoms, or in which R10 and R11 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms that together with the nitrogen atom between them form a heterocyclic ring, (viii) a group of the formula -OR12a, where R12a represents a hydrogen atom or an alkyl or acyl group having from 1 to 7 carbon atoms, (ix) a group of the formula -SR12b, where R12b represents a hydrogen atom or an alkyl or acyl group having from 1 to 7 carbon atoms, ( x) cyano, or (xi) amidino group of the formula [image] in which each of R13, R14 and R15 independently represents a hydrogen atom or alkyl having from 1 to 3 carbon atoms, and in which two of R13, R14 and R15 can additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring; R2 is: (A) a hydrogen atom, or (B) a branched or unbranched alkyl group having from 1 to 3 carbon atoms or a cycloalkyl group having from 3 to 5 carbon atoms, wherein said alkyl or cycloalkyl group can be substituted if necessary with : (i) a group of the formula -OR34, where R34 represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms, or (ii) a group of the formula -NR35R36, where each of R35 and R36 independently represents a hydrogen atom, alkyl which has from 1 to 2 carbon atoms, or acyl having from 1 to 2 carbon atoms; R3 is a group of the formula -(CR37R38)x(CR39R40)yR41, in which each of x and y independently represents 0 or 1, each of R37, R38 and R39 independently represents: (A) a hydrogen atom, (B) a group of the formula -OR42, where R42 represents a hydrogen atom or an alkyl or acyl group having from 1 to 7 carbon atoms, (C) a branched or unbranched alkyl having from 1 to 3 carbon atoms or a cycloalkyl having from 3 to 5 carbon atoms, R40 is: (A) a hydrogen atom, (B) a group of the formula -OR42, where R42 represents a hydrogen atom or an alkyl or acyl group having from 1 to 7 carbon atoms, (C) a branched or unbranched alkyl having from 1 to 3 carbon atoms or a cycloalkyl having from 3 to 5 carbon atoms, or (D) aryl selected from the group consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl , 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1 -, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, 3-, 6- or 7-indolizinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl , 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 3-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2- , 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-quinolinyl , 6- or 7-phthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-naphthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl, wherein one or more hydrogen atoms of said aryl group may be optionally and independently substituted with: (i) R43, which is an aryl selected from the class consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2 -, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3- , 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1- , 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, 3-, 6- or 7-indolizinyl, 2-, 3-, 5- or 6 -isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-quinolinyl, 6- or 7-phthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7 -naphthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl, whereby one or more hydrogen atoms of the mentioned aryl group can be optionally and independently substituted with: (a) a branched or unbranched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono - or polysubstituted with halogen or oxo, (b) -COOH, (c) -SO2OH, (d) -PO(OH)2, (e) a group of the formula -COOR44, where R44 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms, (f) a group of the formula -NR45R46, where each of R45 and R46 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 up to 6 carbon atoms or acyl having from 1 to 7 carbon atoms, or in which R45 and R46 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms that together with the nitrogen atom between them form a heterocyclic ring, (g) a group of the formula - CONR47R48, wherein each of R47 and R48 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms or cycloalkyl having from 3 to 6 carbon atoms, or wherein R47 and R48 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms that together with the nitrogen atom between them form heterocyclic ring, (h) a group of the formula -OR49, where R49 represents a hydrogen atom or an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, (i) a group of the formula -SR50, where R50 represents a hydrogen atom or an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, (j) cyano, (k) nitro, (l) amidino group of the formula [image] in which each of R51, R52 and R53 independently represents a hydrogen atom or alkyl having from 1 to 3 carbon atoms, and in which two of R51, R52 and R53 can additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, or (m) halogen, (ii) methyl, which can be mono- or polysubstituted with fluorine atoms and can additionally be monosubstituted with R43, (iii) branched or unbranched alkyl having from 2 to 6 carbon atoms or cycloalkyl having from 3 to 6 carbon atoms, which alkyl or cycloalkyl the group can be mono- or polysubstituted with halogen or oxo, (iv) a group of the formula -COOR54, where R54 represents a straight or branched alkyl having from 1 to 5 carbon atoms or a cycloalkyl having from 3 to 5 carbon atoms, (v) a group of the formula - NR55R56, where each of R55 and R56 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms, or in which R55 and R56 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and where one of R55 and R56 may additionally be a group R43, (vi) a group of the formula -CONR57R56, where each of R57 and R58 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, or cycloalkyl having from 3 to 6 carbon atoms, or in which R57 and R58 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with shower with any atom between them forming a heterocyclic ring, and where one of R57 and R58 can additionally be the group R43, (vii) the group of the formula -COR59, where R59 represents a hydrogen atom, straight or branched or alkyl having from 1 to 5 carbon atoms, cycloalkyl which has from 3 to 5 carbon atoms, or R43, (viii) a group of the formula -OR60, where R60 represents a hydrogen atom, an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, or R43, (ix) a group of the formula - SR61, where R61 represents a hydrogen atom, an alkyl, fluoroalkyl, or acyl group having from 1 to 7 carbon atoms, or R43, (x) cyano, (xi) nitro, or (xii) halogen, R41 is: aryl selected from the class of consist of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4 - or 5-oxadiazolyl, 1-, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, 3-, 6- or 7-indolizinyl, 2- , 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-quinolinyl, 6- or 7-phthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2- . (A) R 62 , which is aryl selected from the group consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2 -, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3 -, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2 -triazinyl, 2-, 3-, 6- or 7-indolizinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3 -, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6 - or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-quinolinyl, 6- or 7 -phthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-naphthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl, at whereby one or more hydrogen atoms of the mentioned aryl group can be, if necessary, independently replaced with: (i) a branched or unbranched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or polysubstituted with halogen or oxo, (ii) -COO H, (iii) -SO2OH, (iv) -PO(OH)2, (v) a group of the formula -COOR63, where R63 represents a straight or branched alkyl having from 1 to 5 carbon atoms or a cycloalkyl having from 3 to 5 carbon atoms atoms, (vi) a group of the formula -NR64R65, where each of R64 and R65 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 of carbon atoms, or in which R64 and R65 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (vii) a group of the formula -CONR66R67, where each of R66 and R67 independently represents a hydrogen atom , alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms, or in which R66 and R67 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms that together with the nitrogen atom between them form a heterocyclic ring, (viii) a group of the formula -OR6 8, where R68 represents a hydrogen atom, or an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, (ix) a group of the formula -SR69, where R69 represents a hydrogen atom, or an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, (x) cyano, (xi) nitro, or (xii) amidino group of the formula [image] in which each of R70, R71 and R72 independently represents a hydrogen atom or an alkyl having from 1 to 3 carbon atoms and in which two of R70, R71 and R72 can additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, or (xiii) halogen, (B) methyl, which can be mono- or polysubstituted with fluorine atoms and may additionally be monosubstituted with R62, (C) a branched or unbranched alkyl group having from 2 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or poly substituted with halogen or oxo, (D) a group of the formula -COOR73, where R73 represents a straight or branched alkyl having from 1 to 5 carbon atoms or a cycloalkyl having from 3 to 5 carbon atoms, (E) a group of the formula -NR74R75, where each of R74 and R75 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms, or in which R74 and R75 form a saturated hydrocarbon a bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and where one of R74 and R75 can additionally be a group R62, (F) a group of the formula -CONR76R77, where each of R76 and R77 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, or cycloalkyl having from 3 to 6 carbon atoms, or in which R76 and R77 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between they form a heterocyclic ring, and where one of R76 and R77 can additionally be a group R62, (G) a group of the formula -COR78, where R78 represents a hydrogen atom, straight or branched or alkyl having from 1 to 5 carbon atoms, cycloalkyl having from 3 to 5 carbon atoms, or R62, (H) a group of the formula -OR79, where R79 represents a hydrogen atom, an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, or R62, (I) a group of the formula -SR80, where R80 represents a hydrogen atom, an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, or R62, (J) cyano, (K) nitro, or (L) halogen, R4 is Cl or trifluoromethyl; and each of R 5 and R 6 independently represents hydrogen, a fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl. 17. Pharmaceutical composition, characterized in that it contains a pharmaceutically acceptable carrier and a compound according to claim 2, 3, 4, 5, 6, 7, 8, 9 or 10.