METHODS AND MOLECULES USEFUL FOR IDENTIFYING MOLECULES THAT BIND LFA-1 AND FOR DETERMINING RECEPTOR OCCUPANCY

Abstract: The present invention relates generally to a method for identifying molecules that bind the R7.1 epitope of LFA-1 or bind LFA-1 such that the R7.1 epitope is modified. The present invention further relates to a method for determining occupancy of the LFA-1 receptor by molecules that bind to the R7.1 epitope or bind LFA-1 such that the R7.1 epitope is modified after administration to a subject. The present invention further relates to molecules useful in the methods of the invention.

Description: METHODS AND MOLECULES USEFUL FOR IDENTIFYING MOLECULES THAT BIND LFA-1 AND FOR DETERMINING RECEPTOR OCCUPANCY RELATED APPLICATIONS This application claims benefit to US Provisional Application serial no. 60/225,327 filed August 14, 2000. FIELD OF THE INVENTION The present invention relates generally to a method for identifying molecules that bind or modify the R7.1 epitope of LFA-1. R7.1 is an anti-CDl la monoclonal antibody (mAb). The present invention further relates to a method for determining occupancy of the LFA-1 receptor by molecules that bind to the R7.1 epitope after administration to a subject. The invention further relates to molecules useful in such methods. BACKGROUND OF THE INVENTION Research spanning the last decade has helped to elucidate the molecular events attending cell-cell interactions in the body, especially those events involved in the movement and activation of cells in the immune system. See generally, Springer, T., 1990, Nature 346:425-434. Cell surface proteins, and especially the Cellular Adhesion Molecules ("CAMs") and "Leukointegrins", including LFA-1, MAC-1 and gp 150.95 (referred to in WHO nomenclature as CD18/CDl la, CD18/CDl lb, and CD18/CDl lc, respectively) have correspondingly been the subject of pharmaceutical research and development having as its goal the intervention in the processes of leukocyte extravasation to sites of injury and leukocyte movement to distinct targets. For example, it is presently believed that prior to the leukocyte extravasation, which is a mandatory component of the inflammatory response, activation of integrins constituitively expressed on leukocytes occurs and is followed by a tight ligand/receptor interaction between integrins (e.g., LFA- 1) and one or several distinct intercellular adhesion molecules (ICAMs) designated ICAM-1, ICAM-2, ICAM-3 or ICAM-4 which are expressed on leukocytes. ICAM-1, ICAM-2, and ICAM-3 are expressed on blood vessel endothelial cell surfaces, as well. The interaction of the CAMs with the Leukointegrins is a vital step in the normal functioning of the immune system. Immune processes such as antigen presentation, T-cell mediated cytotoxicity and leukocyte extravasation all require cellular adhesion mediated by ICAMs interacting with the Leukointegrins. See generally, Kishimoto, T. K.and R.R. Rothlein, 1994, Adv. Pharmacol 25:117-138. A group of individuals has been identified which lack the appropriate expression of Leukointegrins, a condition termed "Leukocyte Adhesion Deficiency" (Anderson, D. C. et al, 1985, Fed. Proc, 44:611-2611 and Anderson, D. C. et al, 1985, J. Infect. Dis., i 52:668-689). These individuals are unable to mount a normal inflammatory and/or immune response(s) due to an inability of their cells to adhere to cellular substrates. These data show that immune reactions are mitigated when lymphocytes are unable to adhere in a normal fashion due to the lack of functional adhesion molecules of the CD 18 family. By virtue of the fact that LAD patients who lack CD 18 cannot mount an inflammatory response, it is believed that antagonism of CD18,CD11/ICAM-l interactions will also inhibit an inflammatory response. It has been demonstrated that the antagonism of the interaction between the CAMs and the Leukointegrins can be realized by agents directed against either component. Specifically, blocking of the CAMs, such as for example ICAM-1, or the Leukointegrins, such as for example LFA-1, by antibodies directed against either or both of these molecules effectively inhibits inflammatory responses. In vitro models of inflammation and immune response inhibited by antibodies to CAMs or Leukointegrins include antigen or mitogen- induced lymphocyte proliferation, homotypic aggregation of lymphocytes, T-cell mediated cytolysis and antigen-specific induced tolerance. See generally, Kishimoto, T.K. and R.R. Rothlein, 1994, Adv. Pharmacol 25:117-138. The relevance of the in vitro studies are supported by in vivo studies with antibodies directed against ICAM-1 or LFA- 1. See generally, Rothlein, R. and J.R. Jaeger, 1996, In Therapeutic Immunology (eds) Austen et al. Blackwell Science, Cambridge Mass., p. 347. For example, antibodies directed against LFA-1 can prevent thyroid graft rejection and prolong heart allograft survival in mice (Gorski, A., 1994, Immunology Today 15:251-255). Of greater significance, 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 demonstrated 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 has also been demonstrated that a recombinant soluble form of ICAM-1 can act as an inhibitor of the ICAM-1 interaction with LFA-1. Soluble ICAM-1 acts as a direct antagonist of CD18,CD11 /ICAM-1 interactions on cells and shows inhibitory activity in in vitro models of immune response such as the human mixed lymphocyte response, cytotoxic T cell responses and T cell proliferation from diabetic patients in response to islet cells (Becker, J. C; et al, J. Immunol. 1993, 151:1224 and Roep, B. O.; et al, Lancet, 1994, 343:1590). In addition, several small molecules have been described in the literature which affect the interaction of CAMs and Leukointegrins. A natural product isolated from the root of Trichilia rubra was found to be inhibitory in an in vitro cell binding assay (Musza, L. L.; et al, Tetrahedron, 1994, 50:11369-11378). One series of molecules (Boschelli, D. H.; et al, J. Med. Chem. 1994, 37: 111 and Boschelli, D. H.; et al, J. Med. Chem. 1995, 38: 4597-4614) was found to be orally active in a reverse passive Arthus reaction, an induced model of inflammation that is characterized by neutrophil accumulation (Chang, Y. H.; et al, Eur. J. Pharmacol. 1992, 69: 155-164). Another series of molecules was also found to be orally active in a delayed type hypersensitivity reaction in rats (Sanfilippo, P. J.; et al, J. Med. Chem. 1995, 38: 1057-1059). All of these molecules appear to act nonspecifically, either by inhibiting the transcription of ICAM-1 along with other proteins or act intracellularly to inhibit the activation of the Leukointegrins by an unknown mechanism. None of the molecules directly antagonize the interaction of the CAMs with the Leukointegrins. Thus, the prior art has demonstrated that molecules which antagonize the binding of the CAMs to the Leukointegrins have therapeutic potential in mitigating inflammatory and immunological responses often associated with the pathogenesis of many autoimmune or inflammatory diseases. Recently, a small molecule, (R)-5-(4-bromobenzyl)-3-(3,5-dichlorophenyl)-l,5- dimethylimidazolidine-2,4-dione (referred to herein as Compound 1), has been shown to interact specifically with LFA-1 via noncovalent binding to the CD1 la chain and prevent LFA-1 from binding to ICAM-1. (Kelly et al, 1999, J. Immunol. 163:5173-5177). Based on the status of the prior art, there remains a clear need for a method of identifying molecules that specifically bind or modify LFA-1. In addition, there is a need in the clinic for a method for determining LFA-1 receptor occupancy on target cells of a subject treated with such molecules for determining, wter alia: how much compound has reached target cells after treatment; the amount of compound necessary to saturate LFA-1 receptors; and how much receptor occupancy is needed for efficacy. SUMMARY OF THE INVENTION A first aspect of the invention comprises a method for identifying a molecule that specifically binds the R7.1 epitope of LFA-1 or binds LFA-1 such that the R7.1 epitope is modified wherein the LFA-1 is either purified or cell surface LFA-1. A second aspect of the invention comprises a method for determining LFA-1 receptor occupancy on target cells of a subject treated with a molecule that specifically binds the R7.1 epitope of LFA-1 or binds LFA-1 such that the R7.1 epitope is modified. A third aspect comprises molecules useful in the methods of the invention. In specific embodiments, the target cells are peripheral blood mononuclear cells and polymorphonuclear leukocytes. One advantage of the cellular assays is the abrogation of the need to purify LFA-1 thereby providing a system that more closely resembles that found in nature. The methods for determining receptor occupancy described herein can provide invaluable information in the clinic for determining, inter alia: how much compound has reached target cells after treatment; the amount of compound necessary to saturate LFA-1 receptors; and how much receptor occupancy is needed for efficacy. The invention provides methods for identifying a molecule that binds or modifies the R7.1 epitope of LFA-1 comprising incubating purified LFA-1 or a cell that expresses LFA-1 with a first test molecule and a second labeled molecule that specifically binds the R7.1 epitope of LFA-1 or binds LFA-1 such that the R7.1 epitope is modified; and detecting the second labeled molecule; wherein a decrease in binding of the second molecule indicates binding of the first test molecule. The invention further provides methods for identifying a molecule that binds or modifies the R7.1 epitope of LFA-1 comprising incubating purified LFA-1 or a cell that expresses LFA-1 with (i) a first test molecule, (ii) a second molecule that specifically binds the R7.1 epitope of LFA-1 or binds LFA-1 such that the R7.1 epitope is modified, and (iii) a third labeled molecule, wherein the third labeled molecule binds the second molecule; and detecting the third labeled molecule bound to the second molecule; wherein a decrease in binding of the second molecule indicates binding of the first test molecule. Another aspect of the invention provides methods for determining LFA-1 receptor occupancy comprising administering a first test molecule to a subject; withdrawing a sample of blood from the subject; incubating the sample with a second labeled molecule that specifically binds the R7.1 epitope of LFA-1 or binds LFA-1 such that the R7.1 epitope is modified; and detecting the amount of the second labeled molecule, wherein a decrease in the amount of binding of the second labeled molecule indicates binding of the first test molecule. The invention further provides methods for determining LFA-1 receptor occupancy comprising administering a first test molecule to a subject; withdrawing a sample of blood from the subject; incubating the sample with a second molecule that specifically binds the R7.1 epitope of LFA-1 or binds LFA-1 such that the R7.1 epitope is modified and a third labeled molecule that binds the second molecule; and detecting the amount of the second molecule, wherein a decrease in the amount of binding of the second molecule indicates binding of the first test molecule. In a specific embodiment, the molecule that specifically binds or modifies the R7.1 epitope of LFA-1 is a monoclonal antibody or fragment thereof. In another embodiment, the molecule that specifically binds or modifies the R7.1 epitope of LFA-1 is R7.1 (Bender MedSystems Diagnostics GmBH; Vienna, Austria). The invention further relates to equivalents of R7.1 (for example, molecules that bind or modify the R7.1 epitope of LFA-1) including but not limited to small molecules as described in: U.S. patent application No. 09/375,010 by Kelly et al, filed August 16, 1999; U.S. patent application No. 09/604,312 by Kelly et al, filed June 27, 2000; U.S. patent application No. 09/605,584 by Kelly et al, filed June 28, 2000, which are incorporated herein in their entireties. In another embodiment, the molecule that specifically binds or modifies the R7.1 epitope of LFA-1 is labeled with a fluorescent compound. BRIEF DESCRIPTION OF FIGURES Figure 1. Inhibition of monoclonal antibody (mAb) binding to Immobilized LFA-1 by Compound 1 (5μM)((R)-5-(4-bromobenzyl)-3-(3,5-dichlorophenyl)-l,5- dimethylimidazolidine-2,4-dione). Immobilized LFA-1 was incubated with various anti- LFA-1 mAbs (CLB-LFA-1, R7.1, R3.1, MHM 24, TS 2/4, T/S 1/22, and mAb38) in the presence of Compound 1 (5μM) or its enantiomer, Compound 2 (5μM), or a dimethyl sulfoxide (DMSO) control. Absorbance at 405 nm is shown. Results are the mean of duplicate wells ± SE. Figure 2. Inhibition of mAb binding to SKW-3 cells by Compound 1. SKW-3 cells were incubated with an anti-LFA-1 mAb (mAb38 or R3.1; 13.3 nM) or an anti-CD18 mAb (mAb 15.7, 13.3 nM) in the presence of Compound 1 (10 μM) or a DMSO control (0.09%). Median fluorescence was assessed using flow cytometry. Figure 3. Dose dependent inhibition of mAb binding to human leukocytes by Compound 1. Human whole blood was incubated with a mAb (R3.1or R15.7; 3.3 nM) and Compound 1 (10 μM or 2μM) or a DMSO control (0.2%). Median fluorescence was assessed using flow cytometry. DETAILED DESCRIPTION OF THE INVENTION The present invention provides useful screening methods and compositions for identifying molecules that specifically bind or modify the R7.1 epitope of LFA-1. The molecules thus identified may be useful therapeutic agents for treating or preventing inflammatory and immune cell mediated diseases. Another aspect of the invention relates to methods and molecules for determining LFA-1 receptor occupancy on target cells of a subject treated with a molecule that specifically binds or modifies the R7.1 epitope of LFA-1. The methods for determining receptor occupancy described herein can provide invaluable information in the clinic for determining, wter alia: how much compound has reached target cells after treatment; the amount of compound necessary to saturate LFA-1 receptors; and how much receptor occupancy is needed for efficacy. A third aspect provides molecules useful in the methods of the invention. The invention provides methods for identifying a molecule that binds or modifies the R7.1 epitope of LFA-1 comprising incubating purified LFA-1 or a cell that expresses LFA-1 with a first test molecule and a second labeled molecule that specifically binds the R7.1 epitope of LFA-1 or binds LFA-1 such that the R7.1 epitope is modified; and detecting the second labeled molecule; wherein a decrease in binding of the second molecule indicates binding of the first test molecule. The invention further provides methods for identifying a molecule that binds or modifies the R7.1 epitope of LFA-1 comprising incubating purified LFA-1 or a cell that expresses LFA-1 with (i) a first test molecule, (ii) a second molecule that specifically binds the R7.1 epitope of LFA-1 or binds LFA-1 such that the R7.1 epitope is modified, and (iii) a third labeled molecule, wherein the third labeled molecule binds the second molecule; and detecting the third labeled molecule bound to the second molecule; wherein a decrease in binding of the second molecule to the R7.1 epitope indicates binding of the first test molecule. Another aspect of the invention provides methods for determining LFA-1 receptor occupancy comprising administering a first test molecule to a subject; withdrawing a sample of blood from the subject; incubating the sample with a second labeled molecule that specifically binds the R7.1 epitope of LFA-1 or binds LFA-1 such that the R7.1 epitope is modified; and detecting the amount of the second labeled molecule, wherein a decrease in the amount of binding of the second labeled molecule indicates binding of the first test molecule. The invention further provides methods for determining LFA-1 receptor occupancy comprising administering a first test molecule to a subject; withdrawing a sample of blood from the subject; incubating the sample with a second molecule that specifically binds the R7.1 epitope of LFA-1 or binds LFA-1 such that the R7.1 epitope is modified and a third labeled molecule that binds the second molecule; and detecting the amount of the second molecule, wherein a decrease in the amount of binding of the second molecule indicates binding of the first test molecule. The molecules of the invention that specifically bind or modify the R7.1 epitope of LFA-1 include but are not limited to: antibodies, preferably monoclonal antibodies (for example, R3.1 (Ma et al., 1992, Circulation 86:937), R7.1 (Bender MedSystems Diagnostics GmBH; Viemia, Austria)), derivatives or fragments thereof (for example, Fab fragments, F(ab') 2 fragments, fragments produced by a Fab expression library) and epitope-binding fragments of any of the above. In a specific embodiment, the molecule that specifically binds or modifies the R7.1 epitope of LFA-1 is mAb R7.1. In another embodiment, the molecule that specifically binds or modifies the R7.1 epitope of LFA-1 is a Fab fragment. For preparation of monoclonal antibodies that specifically bind or modify the R7.1 epitope of LFA-1, any technique which provides for the production of antibody molecules by continuous cell lines in culture may be used. For example, the hybridoma technique originally developed by Kohler and Milstein (1975, Nature 256:495-497), as well as the trioma technique, the human B-cell hybridoma technique (Kozbor et al., 1983, Immunology Today 4:72), and the EBV-hybridoma technique to produce human monoclonal antibodies (Cole et al., 1985 in "Monoclonal Antibodies and Cancer Therapy", Alan R. Liss, Inc., pp. 77-96). Antibody fragments that recognize the R7.1 epitope may be generated by known techniques. For example, such fragments include but are not limited to: the F(ab') 2 fragments which can be produced by pepsin digestion of the antibody molecule and the Fab fragments, which can be generated by reducing the disulfide bridges of the F(ab') 2 fragments. Alternatively, Fab expression libraries may be constructed (Huse et al., 1989, Science, 246:1275-1281) to allow rapid and easy identification of monoclonal Fab fragments with the desired specificity. The molecules of the invention that specifically bind or modify the R7.1 epitope of LFA-1 may also include chemical compounds, including but not limited to small molecules such as those described in: U.S. patent application No. 09/375,010 by Kelly et al, filed August 16, 1999; U.S. patent application No. 09/604,312 by Kelly et al, filed June 27, 2000; U.S. patent application No. 09/605,584 by Kelly et al, filed June 28, 2000. Such compounds include but are not limited to those compounds of the formula I, formula II, and formula III shown below: wherein: Y is an oxygen or sulfur atom; Z is an oxygen or sulfur atom; X is a divalent group of the formula X3HR 1 , >NR 1 , >CHSθ2R 1 , or >NSO2R 1 , or an oxygen or sulfur atom, wherein R is: (A) a hydrogen atom, (B) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl 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, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]fhiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein one or more hydrogen atoms of said aryl group may be optionally and independently replaced with: (a) alkyl of 1 to 3 carbon atoms, (b) -COOH, (c) -SO 2 OH, (d) -PO(OH)2, (e) a group of the formula -COOR^, wherein R^ is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (f) a group of the formula -NR8R9, wherein R^ and R^ are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R and R^ constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (g) a group of the formula -CONRl ORI 1 , wherein R**- 0 and R! 1 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein RlO and R constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (h) a group of the formula -OR^a, wherein R^ a is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, (i) a group of the formula -SR^b 5 wherein R^^° is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, 0) cyano, or (k) an amidino group of the formula wherein R**--*- 1 , R χ 4 and R i: 5 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms and wherein two of R 1 ^. Rl4 and R^ may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, (iv) a group of the formula -COOR 1 ^, wherein R 1 ^ is straight or branched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, (v) cyano, (vi) a group of the formula -CONRl 7R1 S wherein Rl 7 and R**- 8 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein 7 and R**-° constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (vii) a group of the formula -ORl9. wherein R 1 *^ is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, (viii) a group of the formula -SR^O, wherein R-20 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, (ix) a group of the formula --NR21R22. wherein R21 and R^2 are each, independently, (a) a hydrogen atom, (b) alkyl or acyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, (c) a group of the formula -(CH2) m COOH, wherein m is 0, 1 or 2, or (d) a group of the formula -(CH2) n COOR23, wherein n is 0, 1 or 2, wherein R23 is straight or branched alkyl of 1 to 6 carbon atoms, or wherein R-21 and R^2 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, or (x) a quaternary group of the formula wherein R^, R-25 and R-^6 are each, independently, a branched or unbranched alkyl group of 1 to 7 carbon atoms and Q" is a chlorine, bromine or iodine counterion, (C) a branched or unbranched carboxylic acid group of 3 to 6 carbon atoms, (D) a branched or unbranched phosphonic acid group of 2 to 6 carbon atoms, (E) a branched or unbranched sulfonic acid group of 2 to 6 carbon atoms, (F) an amidino group of the formula wherein r is 2, 3, 4, 5 or 6, and 27 5 R28 an R2 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of ^ , R^8 and R-29 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, (G) an guanidino group of the formula wherein s is 2, 3, 4, 5 or 6, and 30 ? R31 } R32 an( j R33 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of , R31, R32 anc ι R33 ma y additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, (H) piperidyl, wherein the nitrogen atom of said group is optionally substituted with: (i) alkyl of 1 to 3 carbon atoms, (ii) a carboxylic ester group of 2 to 7 carbon atoms, (iii) a carboxylic acid group of 2 to 5 carbon atoms, (iv) a phosphonic acid group of 1 to 6 carbon atoms, or (v) a sulfonic acid groups of 1 to 6 carbon atoms, or 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, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein one or more hydrogen atoms of said aryl group may be optionally and independently replaced with: (i) alkyl of 1 to 3 carbon atoms, (ii) -COOH, (iii) -SO 2 OH, (iv) -PO(OH) 2 , (v) a group of the formula -COOR^, wherein R is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (vi) a group of the formula -NR8R9, wherein R^ and R^ are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R and R^ constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (vii) a group of the formula -CONRl ORI 1. wherein R**- 0 and R * *- * are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein RlO and RU constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (viii) a group of the formula -OR^a wherein R^ a is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, (ix) a group of the formula -SR^D, wherein Rl2b is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, (x) cyano, or (xi) an amidino group of the formula wherein Rl3, R14 an d Rl5 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R13, Rl4 and Rf$ may additionally constitute a saturated hydrocarbon bridge of 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) branched or unbranched alkyl of 1 to 3 carbon atoms or cycloalkyl of 3 to 5 carbon atoms wherein said alkyl or cycloalkyl group may optionally be substituted with: (i) a group of the formula -0R34 } wherein R34 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, or (ii) a group of the formula -NR35R36 5 wherein R35 and R36 are each, independently, a hydrogen atom, alkyl of 1 to 2 carbon atoms, or acyl of 1 to 2 carbon atoms; group of the fomiula -(CR 3 7R38) χ (CR39 R 40) yR 41 5 wherein; x and y are each independently 0 or 1, R 7 } R38 an d R 39 are each, independently: (A) a hydrogen atom, (B) a group of the formula -0R42. wherein R42 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, or (C) branched or unbranched alkyl of 1 to 3 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, R40 is: (A) a hydrogen atom, (B) a group of the formula -OR42. wherein R4 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, (C) branched or unbranched alkyl of 1 to 3 carbon atoms or cycloalkyl of 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-pyιτolyl, 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-indolyzinyl, 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-cinnolinyl, 6- or 7-pthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl, wherein one or more of the hydrogen atoms of said aryl group may be optionally and independently replaced with: (i) R . 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- indolyzinyl, 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-cinnolinyl, 6- or 7-pthalaninyl, 2-, 3-, 6- or 7- quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or 7- pteridinyl and 2-, 6- or 7-quinazolinyl, wherein one or more of the hydrogen atoms of said aryl group may be optionally and independently replaced with: (a) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with halogen or oxo, (b) -COOH, (c) -SO 2 OH, (d) -PO(OH) 2 , (e) a group of the formula -COOR44. wherein R 4 4 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (f) a group of the formula -NR45R46 ) wherein R45 and R46 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R45 and R 6 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (g) a group of the formula -CONR 4 7R48 } wherein R 7 and R48 are each independently a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R47 and R 8 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (h) a group of the formula -OR49. wherein R49is a hydrogen atom, or an alkyl , fluoroalkyl or acyl group of 1 to 7 carbon atoms, (i) a group of the formula -SR^O, wherein R-50 is a hydrogen atom, or an alkyl , fluoroalkyl or acyl group of 1 to 7 carbon atoms, 0 ' ) cyano, (k) nitro, (1) an amidino group of the formula wherein R^ 1 , R-^2 and R->3 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R-^ 1 , R52 and R53 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, or (m) halogen, (ii) methyl, which may be mono- or polysubstituted with fluorine atoms and additionally may be monosubstituted with R43, (iii) branched or unbranched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with halogen or oxo, (iv) a group of the formula -COOR54, wherein R-5 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (v) a group of the formula -NR*55R56 } wherein R-^and R-^6 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R-^and R^6 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one of R-^and R^° may additioanlly be the group R4 , (vi) a group of the formula -CONR57R58 5 wherein R57 and R-58 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R$7 and R$ constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one of R57 and R^ may additionally be the group R 3, (vii) a group of the formula -COR^9. wherein R5 is a hydrogen atom, straight or branched alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms or R43, (viii) a group of the formula -OR^O, wherein R^O is a hydrogen atom, an alkyl , fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R4 . (ix) a group of the formula -SR^ 1 , wherein R^ 1 is a hydrogen atom, an alkyl , fluoroalkyl or acyl group of 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-indolyzinyl, 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-cinnolinyl, 6- or 7-pthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or 7- pteridinyl and 2-, 6- or 7-quinazolinyl, wherein one or more of the hydrogen atoms of said aryl group may be optionally and independently replaced with: (A) R°2. 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- indolyzinyl, 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-cinnolinyl, 6- or 7-pthalaninyl, 2-, 3-, 6- or 7- quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or 7- pteridinyl and 2-, 6- or 7-quinazolinyl, wherein one or more of the hydrogen atoms of said aryl group may be optionally and independently replaced with: (i) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with halogen or oxo, (ii) -COOH, (iii) -SO2OH, (iv) -PO(OH)2, (v) a group of the formula -COOR63. wherein R^3 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (vi) a group of the formula -NR6 R65 5 wherein R^4 and R65 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R^4 and R^5 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (vii) a group of the formula -CONR66R67 5 ^erein R66 and R"7 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R^6 and R67 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (viii) a group of the formula -OR"°, wherein R° o is a hydrogen atom, or an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms, (ix) a group of the formula -SR6 . wherein R^ is a hydrogen atom, or an alkyl , fluoroalkyl or acyl group of 1 to 7 carbon atoms, (x) cyano, (xi) nitro, or (xii) an amidino group of the formula wherein R70, R71 and R72 are each, independently, a hydrogen atom or alkyl or fluoroalkyl of 1 to 3 carbon atoms, and wherein two of R70 ; R71 anc ι 72 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, or (xiii) halogen, (B) methyl, which may be mono- or polysubstituted with fluorine atoms and additionally may be monosubstituted with R 62 , (C) branched or unbranched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with halogen or oxo, (D) a group of the formula -COOR73. wherein R73 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (E) a group of the formula -NR7 R75 5 wherein R 74 and R 75 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R74 and R75 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one of R7 and R75 may additionally be the group R6 . (F) a group of the formula -CONR 7 6R77 5 wherein R 7 6 and R77 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R76 anc l R77 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one of R76 and R77 may additionally be the group R^2. (G) a group of the formula -COR78, wherein R78 is a hydrogen atom, straight or branched alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms or R62 ? (H) a group of the formula -OR79. wherein R79 is a hydrogen atom, an alkyl , fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R6 . (I) a group of the formula -SR^O, wherein R^O is a hydrogen atom, an alkyl , fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R62 ? (J) cyano, (K) nitro, or (L) halogen; R4 is Cl or trifluoromethyl; and, R5 and R° are each, independently, a hydrogen, fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl; or a pharmaceutically acceptable salt thereof; wherein: A 1 is =N- or =C(H)-; A 2 is =N-, =C(H)-, or =C(R')- wherein R' is halogen, -CN, -Oalkyl, -CO 2 alkyl or -SO 2 alkyl, wherein the foregoing alkyl moieties are of 1 to 3 carbon atoms; D is =N-, =C(R!)-, =C(H)-, =C(SO 2 R 1 )-, =C(S(O)R 1 )-, =C(C(O)R!)-, =C(C(O)H)-, =C(SR l )-, =C(OR la )- or =C(NHR la )-, wherein R is selected from the class consisting of: (A) -RlOO, W hich is: branched or unbranched alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or cycloalkyl or cycloalkenyl of 3 to 6 carbon atoms, in which alkyl, alkenyl, cycloalkyl or cycloalkenyl group one or more hydrogen atoms are optionally and independently replaced with: (i) halogen, (ii) oxo, (iii) aryl or heteroaryl 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, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein one or more hydrogen atoms of said aryl or heteroaryl group are optionally and independently replaced with: (a) alkyl of 1 to 3 carbon atoms, (b) -COOH, (c) -SO 2 OH, (d) -PO(OH) 2 , (e) a group of the formula -COOR^, wherein R^ is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (f) a group of the formula -NR R10 5 wherein R9 and RlO are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R9 and RlO constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (g) a group of the formula -CONR RI2. wherein RI and R 2 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein RI and R 2 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by -O-, -S-, S(O)-, SO 2 -, -NH-. or -NMe-, (h) a group of the formula -OR 3, wherein Rl3 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, (i) a group of the formula -SR1 , wherein R 4 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, (j) -CN, or (k) an amidino group of the formula wherein Rl5, Rl6 and Rl are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms and wherein two of R^, R**- 0" and R 7 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, (1) halogen, (m) a group of the formula -NHCONHalkyl, wherein the alkyl moiety contains 1 to 3 carbon atoms, (n) a group of the formula -NHCOOalkyl, wherein the alkyl moiety contains 1 to 3 carbon atoms, (iv) a group of the formula -COORl , wherein R 8 is straight or branched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, (v) -CN, (vi) a group of the formula -CONRI9R20 ? wherein R 9 and R20 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R 9 and R 0 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by -O-, -S-, S(O)-, SO 2 -, -NH-, or-NMe-, (vii) a group of the formula -OR21, wherein R21 is a hydrogen atom, or a straight or branched alkyl or acyl group of 1 to 7 carbon atoms, wherein one or more hydrogen atoms of said alkyl or acyl group are optionally replaced with a group independently selected from the class consisting of -OH, -Oalkyl (wherein the alkyl moiety contains 1 to 6 carbon atoms), -NH 2 , -NHMe and -NMe 2, (viii) a group of the formula -SR2 , wherein R22 1S a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, wherein one or more hydrogen atoms of said alkyl or acyl group are optionally replaced with a group independently selected from the class consisting of -OH, -Oalkyl ( wherein the alkyl moiety is 1 to 6 carbon atoms), -NH 2 , -NHMe and -NMe 2> (ix) a group of the formula -NR23R 4 ; wherein R23 and R2 are each, independently, (a) a hydrogen atom, (b) straight or branched alkyl or acyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, wherein said one or more hydrogen atoms of said alkyl or acyl group are optionally replaced with a group independently selected from the class consisting of -OH, -Oalkyl (wherein the alkyl moiety is 1 to 6 carbon atoms), -NH 2 , -NHMe and -NMe 2] (c) a group of the formula -(CH 2 ) m COOH, wherein m is 0, 1 or 2, (d) a group of the formula -(CH 2 ) n COOR25, wherein n is 0, 1 or 2, and wherein R25 is straight or branched alkyl of 1 to 6 carbon atoms, or (e) a group of the formula -(CH 2 ) n CONHR25, wherein n is 0, 1 or 2, and wherein R25 is straight or branched alkyl of 1 to 6 carbon atoms, (x) a quaternary group of the formula wherein R26 } R27 an( j R 28 are each, independently, a branched or unbranched alkyl group of 1 to 7 carbon atoms and Q" is a pharmaceutically acceptable counter ion, (xi) a saturated, or partially unsaturated heterocyclic group consisting of 3 to 7 ring atoms selected from N, O, C and S, including but not limited to imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclic group is optionally mono- or polysubstituted with oxo, and (xii) a cycloalkyl group of 3 to 7 carbon atoms, (B) branched or unbranched carboxylic acid groups of 3 to 6 carbon atoms, (C) branched or unbranched phosphonic acid groups of 2 to 6 carbon atoms, (D) branched or unbranched sulfonic acid groups of 2 to 6 carbon atoms, (E) amidino groups of the formula wherein r is 2, 3, 4, 5 or 6, and R29 5 R30 an( j R 31 are ea ch, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R . R30 and R31 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, (F) guanidino groups of the formula wherein s is 2, 3, 4, 5 or 6, and R ? R33 5 R 34 an d R 35 are eacn . independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R32. R33 5 R34 m( R35 ma y additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, (G) aryl or heteroaryl 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, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein one or more hydrogen atoms of said aryl or heteroaryl group are optionally and independently replaced with: (i) alkyl of 1 to 3 carbon atoms, (ii) -COOH, (iii) -SO 2 OH, (iv) -PO(OH)2, (v) a group of the formula -C00R36 ? wherein R36 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (vi) a group of the formula -NR37R38 } wherein R37 and R38 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R37 and R38 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (vii) a group of the formula -CONR39 40 5 wherein R39 and R 0 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R39 and R40 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by -O-, -S-, S(O)-, SO 2 -, -NH-, or -NMe-, (viii) a group of the formula -0R41, wherein R41 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, (ix) a group of the formula -SR42. wherein R42 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, (x) -CN, or (xi) an amidino group of the formula wherein R43, R44 an( j R 45 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R43 5 R44 anc ι R 45 ma y additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, (H) groups of the formula -NR46R47 wherein 6 an d R47 are eac h independently a hydrogen atom, phenyl which is optionally mono-or polysubstituted with halogen, or Rl ^ wherein RlOO is as hereinbefore defined, (I) saturated or unsaturated heterocyclic groups consisting of 3 to 7 ring atoms selected from N, O, C and S, or bicyclic heterocyclic groups consisting of 8 to 11 atoms selected from N, O, C and S, including but not limited to imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclic group is optionally mono- or poly-substituted with moieties selected from the class consisting of: (i) oxo, (ii) -OR 101 , wherein R 101 is: (a) a hydrogen atom, (b) alkyl of 1 to 7 carbons, wherein any hydrogen atom of said alkyl group is optionally replaced with -OH, -OR! 10 (wherein RI 10 is an alkyl moiety of 1 to 6 carbon atoms), -NH 2 , -NHMe or -NMe 2 (c) acyl of 1 to 7 carbons, wherein any hydrogen atom of said acyl group is optionally replaced with -OH, -0R111 (wherein RI 11 is an alkyl moiety of 1 to 6 carbon atoms), -NH 2 , -NHMe or -NMe 2 , (d) -CONR1° 2 R103 J wherein R 102 and Rl° 3 are each independently a hydrogen atom or alkyl of 1 to 7 atoms, or wherein Rl 2 and R!0 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by -O-, -S-, S(O)-, SO 2 -, -NH-, or -NMe-, or (e) -COORl°4, wherein Rl 4 i s a lkyl of 1 to 7 atoms, (iii) -CONRl 05 R1 06 , wherein RI 05 a nd RI 06 are each independently: (a) a hydrogen atom, (b) straight or branched alkyl of 1 to 7 atoms or cycloalkyl of 3 to 7 atoms, (c) benzoyl, (d) benzyl or (e) phenyl, wherein said phenyl ring is optionally mono- or polysubstituted with -OR! 12,wherein RI 12 is alkyl of 1 to 6 carbon atoms, or, wherein Rl 5 and R! ° constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by -O-, -S-, S(O)-, SO 2 -, -NH-, or-NMe-, (iv) -COOR107 J wherein Rl07 i s a hydrogen atom, or straight or branched alkyl of 1 to 7 carbon atoms , (v) straight or branched alkyl of 1 to 7 carbon atoms, alkenyl or alkynyl of 2 to 7 carbon atoms, or cycloalkyl of 3 to 7 carbons, wherein one or more hydrogen atoms of said alkyl, alkenyl, alkynyl or cycloalkyl group is optionally replaced with a moiety independently selected from the class consisting of: (a) oxo, (b) -OH, (c) -OR! 13, wherein RI 13 is alkyl of 1 to 6 carbon atoms, (d) -OCOCH 3 , (e) -NH 2 , (f) -NHMe, (g) -NMe 2 , (h) -CO 2 H, and (i) -CO 2 RI 14 wherein RI 14 is alkyl of 1 to 3 carbon atoms, or cycloalkyl of 3 to 7 carbons, (vi) acyl of 1 to 7 carbon atoms, which may be straight, branched or cyclic, and wherein one or more hydrogen atoms of said acyl group is optionally replaced with a moiety independently selected from the class consisting of: (a) -OH, (b) -OR! 1 --Wherein RI 15 is alkyl of 1 to 6 carbon atoms, (c) -NH 2 , (d) -NHMe, (e) -NMe 2 , (f) -NHCOMe, (g) oxo, (h) -CO 2 RI 16, wherein RI 1^ is alkyl of 1 to 3 carbon atoms, (i) -CN, (j) the halogen atoms, (k) heterocycles selected from the class consisting of imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanyl, and (1) aryl or heteroaryl 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, indolyzinyl, isoindolyl, benzo[b]flιranyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, (vii) -SO 2 R 108 , wherein R 108 is: (a) aryl or heteroaryl which is 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, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein said aryl or heteroaryl moiety is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and -OR! 17 (wherein RI 17 is hydrogen or alkyl of 1 to 6 carbon atoms), (b) a heterocyclic group selected from the class consisting of imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclic group is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and -OR! 18 (wherein RI 18 is hydrogen or alkyl of 1 to 6 carbon atoms), or (c) straight or branched alkyl of 1 to 7 atoms, wherein said alkyl moiety is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and -OR! 19 (wherein RI 1 is hydrogen or alkyl of 1 to 6 carbon atoms), (viii) -COR 109 , wherein R 109 is: (a) aryl or heteroaryl 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, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein said aryl or heteroaryl moiety is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and -OR120 (wherein Rl 0 is hydrogen or alkyl of 1 to 6 carbon atoms), (b) a heterocyclic group selected from the class consisting of imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclyl is optionally substituted with one or more halogen, straight or branched alkyl of 1 to 6 carbons, or -OR121 (wherein Rl21 is hydrogen or alkyl of 1 to 6 carbon atoms), or (c) straight or branched alkyl of 1 to 7 atoms, wherein said alkyl moiety is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and -OR122 (wherein Rl2 i s hydrogen or alkyl of 1 to 6 carbon atoms), (ix) -CHO, (x) the halogen atoms, and (xi) aryl or heteroaryl 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, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, (J) the halogen atoms, and (K) -CN, and wherein R i a is RI ; X is an oxygen or sulfur atom; R is: (A) a hydrogen atom, or (B) branched or unbranched alkyl of 1 to 3 carbon atoms or cycloalkyl of 3 to 5 carbon atoms wherein said alkyl or cycloalkyl group is optionally substituted with: (i) a group of the formula -OR , wherein R48 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, or (ii) a group of the formula -NR49R50 5 wherein R49 and R^ are each, independently, a hydrogen atom, alkyl of 1 to 2 carbon atoms, or acyl of 1 to 2 carbon atoms; is a group of the formula -(CR 5 lR 52 ) x (CR 53 R*54) y R55 ; wherein, x is 0 or 1, y is O or l, R.51, R 52 an( j R 53 are each, independently: (A) a hydrogen atom, (B) a group of the formula -OR*^, wherein R-^6 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, or (C) branched or unbranched alkyl of 1 to 3 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, R5 1S: (A) a group of the formula R$7, wherein R-57 is independently selected from the same class as is Rl, or (B) a group of the formula -OR-58. wherein R-58 is independently selected from the same class as is Rl; R 55 is: aryl or heteroaryl 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, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein one or more of the hydrogen atoms of said aryl or heteroaryl group is optionally and independently replaced with: (A) R5 5 which is aryl or heteroaryl 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, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein one or more of the hydrogen atoms of said aryl or heteroaryl group is optionally and independently replaced with: (i) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group is optionally mono- or polysubstituted with halogen or oxo, (ii) a group of the formula -COOR^O, wherein R^O is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (iii) a group of the formula -NR61R62 5 wherein R 0" ! and R^2 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R^l and R62 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (iv) a group of the formula -CONR 63 R 6 4, wherein R 63 and R 64 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R"3 and R^4 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (v) a group of the formula -OR65. wherein R^5 is a hydrogen atom, or an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms, (vi) a group of the formula -SR66, wherein R^6 is a hydrogen atom, or an alkyl , fluoroalkyl or acyl group of 1 to 7 carbon atoms, (vii) -CN, (viii) nitro, or (ix) halogen, (B) methyl, which is optionally mono- or polysubstituted with fluorine atoms and additionally is optionally monosubstituted with R5 , (C) branched or unbranched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group is optionally mono- or polysubstituted with halogen or oxo, (D) a group of the formula -COOR67. wherein R^7 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (E) a group of the formula -NR6SR69 ? wherein R^8 and R^ are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R68 and R^9 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one of R^8 and R^ m y additionally be the group R59. (F) a group of the formula -CONR70R71 J wherein R70 and R 1 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R70 and R71 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one of R7 and R71 may additionally be the group R-59. (G) a group of the formula -COR72. wherein R72 is a hydrogen atom, straight or branched alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms or R$9, (H) a group of the formula -OR73. wherein R73 is a hydrogen atom, an alkyl , fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R-5 . (I) a group of the formula -SR74. wherein R74 is a hydrogen atom, an alkyl , fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R-59. (J) -CN, (K) nitro, or (L) halogen; r trifluoromethyl; Z is =N- or =C(R6)- wherein R6 is a hydrogen, fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl; and, 7 is a hydrogen, fluorine, chlorine, bromine or iodine atom, methyl, -CN, nitro or trifluoromethyl, with the condition that when Z is =N- or =C(H)-, R7 is chlorine, trifluoromethyl, -CN or nitro; and pharmaceutically acceptable salts thereof; wherein: Al, A and A3 are each, independently, =N- or =CH-; D is =N-, =CRl-, =CSO 2 R 1 -, =CS0R1-, =CSR1-, ^OR 1 -, =CC0R!-, or =CNHR1-, wherein Rl is: (A) a hydrogen atom, (B) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl 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, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein one or more hydrogen atoms of said aryl group may be optionally and independently replaced with: (a) alkyl of 1 to 3 carbon atoms, (b) -COOH, (c) -SO 2 OH, (d) -PO(OH) 2 . (e) a group of the formula -COOR^, wherein R^ is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (f) a group of the formula -NR9R10 ? wherein R9 and Rl 0 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R and Rl constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (g) a group of the formula -CONRI 1R12, wherein Rl 1 and Rl2 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein Rl 1 and Rl constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (h) a group of the formula -ORl3, wherein Rl3 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, (i) a group of the formula -SRl , wherein Rl4 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, (j) cyano, or (k) an amidino group of the formula wherein Rl5, R16 and Rl7 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms and wherein two of Rl5, R16 and Rl7 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, (iv) a group of the formula -COORl 8, wherein Rl § is straight or branched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, (v) cyano, (vi) a group of the formula -CONRI 9R20 } wherein Rl 9 and R20 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein Rl9 and R20 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (vii) a group of the formula -OR21, wherein R21 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, (viii) a group of the formula -SR22. wherein R22 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, (ix) a group of the formula -NR 3R24 ; wherein R23 and R2 are each, independently, (a) a hydrogen atom, (b) alkyl or acyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, (c) a group of the formula -(CH 2 ) m COOH, wherein m is 0, 1 or 2, or (d) a group of the formula -(CH 2 ) n COOR25, wherein n is 0, 1 or 2, wherein R25 is straight or branched alkyl of 1 to 6 carbon atoms, or wherein R23 and R24 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, or (x) a quaternary group of the formula wherein R26 ? R27 an d R28 are each, independently, a branched or unbranched alkyl group of 1 to 7 carbon atoms and Q" is a chlorine, bromine or iodine counterion, (C) a branched or unbranched carboxylic acid group of 3 to 6 carbon atoms, (D) a branched or unbranched phosphonic acid group of 2 to 6 carbon atoms, (E) a branched or unbranched sulfonic acid group of 2 to 6 carbon atoms, (F) an amidino group of the formula wherein r is 2, 3, 4, 5 or 6, and R2 . R30 an d R31 are eac h. independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R29. R30 an d R31 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, (G) an guanidino group of the formula wherein s is 2, 3, 4, 5 or 6, and R 2. 33 ; R 34 an R35 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R32, R33 ? R 34 an R35 m ay additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, (H) 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, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein one or more hydrogen atoms of said aryl group may be optionally and independently replaced with: (i) alkyl of 1 to 3 carbon atoms, (ii) -COOH, (iii) -SO OH, (iv) -PO(OH)2. (v) a group of the formula -COOR3", wherein R 6 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (vi) a group of the formula -NR37 38 5 wherein R37 and R are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R37 and R38 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (vii) a group of the formula -CONR39R40 5 wherein R39 and R40 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R3 and R constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (viii) a group of the formula -OR41, wherein R41 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, (ix) a group of the formula -SR42, wherein R 2 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, (x) cyano, or (xi) an amidino group of the formula wherein R43. R44 an d R45 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R43, R44 and R45 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, (I) a group of the formula -NR 6R47 ? wherein R46 an d R47 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R ° a nd R47 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (J) a morpholinyl moiety, or, (K) halogen; X is an oxygen or sulfur atom; R 3 is: (A) a hydrogen atom, or (B) branched or unbranched alkyl of 1 to 3 carbon atoms or cycloalkyl of 3 to 5 carbon atoms wherein said alkyl or cycloalkyl group may optionally be substituted with: (i) a group of the formula -OR48, wherein R48 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, or (ii) a group of the formula -NR 9R50 5 wherein R49 a nd R50 are each, independently, a hydrogen atom, alkyl of 1 to 2 carbon atoms, or acyl of 1 to 2 carbon atoms; R 4 is a group of the formula -(CR 5 lR 52 ) χ (CR 53 R54) y R55 5 wherein; x and y are each independently 0 or 1, R51, R-52 an R53 are each, independently: (A) a hydrogen atom, (B) a group of the formula -OR56. wherein R^6 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, or (C) branched or unbranched alkyl of 1 to 3 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, R54 is: (A) a group of the formula R^, wherein R57 is defined similarly to Rl above, or (B) a group of the formula -OR^S. wherein R^8 is defined similarly to Rl above; 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-indolyzinyl, 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-cinnolinyl, 6- or 7-pthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7- quinazolinyl, wherein one or more of the hydrogen atoms of said aryl group may be optionally and independently replaced with: (A) R5 , 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- indolyzinyl, 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-cinnolinyl, 6- or 7-pthalaninyl, 2-, 3-, 6- or 7- quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or 7- pteridinyl and 2-, 6- or 7-quinazolinyl, wherein one or more of the hydrogen atoms of said aryl group may be optionally and independently replaced with: (i) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with halogen or oxo, (ii) a group of the formula -COOR^O. wherein R^ is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (iii) a group of the formula -NR°1R62 5 wherein R^l and R62 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R°l and R^2 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (iv) a group of the formula -CONR63R64 5 wherein R^3 and R64 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R63 and R64 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (v) a group of the formula -OR^- 5 , wherein R65 i s a hydrogen atom, or an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms, (vi) a group of the formula -SR66, wherein R 6o~ i s a hydrogen atom, or an alkyl , fluoroalkyl or acyl group of 1 to 7 carbon atoms, (vii) cyano, (viii) nitro, or (ix) halogen, (B) methyl, which may be mono- or polysubstituted with fluorine atoms and additionally may be monosubstituted with R 5 9, (C) branched or unbranched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with halogen or oxo, (D) a group of the formula -COOR67, wherein R^7 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (E) a group of the formula -NR 68 R 69 , wherein R 68 and R 69 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R^8 and R6 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one of R°° and R69 may additionally be the group R-^ . (F) a group of the formula -CONR70R71 s wherein R7 and R71 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R7 and R71 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one of R7 and R71 may additionally be the group R^9. (G) a group of the formula -COR 72 , wherein R72 i s a hydrogen atom, straight or branched alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms or R$9, (H) a group of the formula -OR73. wherein R 3 is a hydrogen atom, an alkyl , fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R-5 . (I) a group of the formula -SR74 } wherein R74 is a hydrogen atom, an alkyl , fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R5 , (J) cyano, (K) nitro, or (L) halogen; R5 is Cl or trifluoromethyl; Z is -=N- or =CR 6 - wherein R" is a hydrogen, fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl; and, R7 is a hydrogen, fluorine, chlorine, bromine or iodine atom, methyl, cyano, nitro or trifluoromethyl, with the condition that when Z is N or =CH-, R7 is chlorine or trufluoromethyl; and pharmaceutically acceptable salts thereof. As the term is used herein, a "pharmaceutically acceptable counter ion" is any counter ion generally regarded by those skilled in the pharmaceutical art as being pharmaceutically acceptable. For a discussion of what are pharmaceutically acceptable counter ions, reference may be had to Stephen M. Bergle, Lyle D. Bighley and Donald C. Monkhouse, "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, 66 (1977), 1-19. By way of non-limiting example, the chloride, bromide, acetate, and sulphate ions are pharmaceutically acceptable counter ions. Preferred compounds of formula I are those wherein: Y is an oxygen atom; Z is an oxygen atom; X is a divalent group of the formula >NRl, wherein Rl is: (A) a hydrogen atom, (B) methyl or ethyl, or (C) -COCH3 R is: (A) a hydrogen atom, or (B) methyl; R3 is a group of the formula -GH^ ^l, wherein R41 is phenyl wherein one or more of the hydrogen atoms of said phenyl group are necessarily and independently replaced with: (A) R62 5 which is aryl selected from the class consisting of phenyl, or pyridyl, wherein one or more of the hydrogen atoms of said aryl group may be optionally and independently replaced with: (i) methyl, or (ii) halogen, (B) methyl, which may be mono- or polysubstituted with fluorine atoms, (C) a group of the formula -COR78, wherein R78 is methyl or R62, (D) halogen; R4 is a chlorine atom; R5 is a hydrogen atom; and, R6 is a chlorine atom; or a pharmaceutically acceptable salt thereof. Preferred compounds of formula II are those wherein: Al is =N-; A2 is =C(H)-; D is wherein Rl is selected from the class consisting of: (A) methyl, and (B) saturated heterocyclic groups selected from the class consisting of pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl wherein said heterocyclic groups are optionally mono- or di-substituted with moieties independently selected from the class consisting of: (i) oxo, (ii) -ORlOl, wherein R!°1 is: (a) a hydrogen atom, (b) alkyl of 1 to 7 carbons, wherein one hydrogen atom of said alkyl group is optionally replaced with -OH, -OR! 10 (wherein Rl 10 is an alkyl moiety of 1 to 6 carbon atoms), -NH 2 , -NHMe or -NMe 2ι or (c) acyl of 1 to 7 carbons, wherein one hydrogen atom of said acyl group is optionally replaced with -OH, -OR! 11 (wherein Rl 11 is an alkyl moiety of 1 to 6 carbon atoms), -NH 2 , -NHMe or -NMe 2 , (iii) -CONRl °5R106 ; wherein Rl ° 5 and Rl 06 are each independently: (a) a hydrogen atom, or (b) straight or branched alkyl of 1 to 7 atoms or cycloalkyl of 3 to 7 atoms, wherein said alkyl or cycloalkyl group is optionally monosubstituted with -OH, -OR123 (wherein Rl23 1S an alkyl moiety of 1 to 6 carbon atoms), -NH 2 , -NHMe, -NMe 2 , pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, or, wherein Rl05 and Rl06 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by -O-, -NH-, or -NMe-, (iv) -COOR1 7. wherein Rl07 i s a hydrogen atom, or straight or branched alkyl of 1 to 7 carbon atoms , (v) straight or branched alkyl of 1 to 7 carbon atoms wherein one or two hydrogen atoms of said alkyl group are optionally replaced with moieties independently selected from the class consisting of: (a) oxo, (b) -OH, (c) -0R113, wherein RH-3 is alkyl of 1 to 6 carbon atoms, (d) -OCOCH 3 , (e) -NH 2 , (f) -NHMe, (g) -NMe 2 , (h) -CO,H, and (i) -CO 2 Rl 14 wherein Rl 14 is alkyl of 1 to 3 carbon atoms, or cycloalkyl of 3 to 7 carbons, (vi) acyl of 1 to 7 carbon atoms, which may be straight, branched or cyclic, and wherein one or two hydrogen atoms of said acyl group is optionally replaced with a moiety selected from the class consisting of: (a) -OH, (b) -OR! 15>wherein Rl 15 is alkyl of 1 to 6 carbon atoms, (c) -NH 2 , (d) -NHMe, (e) -NMe 2 , (f) -NHCOMe, (g) oxo, (h) -CO 2 Rl 1 6 , wherein Rl 1 6 is alkyl of 1 to 3 carbon atoms, (i) -CN, (j) the halogen atoms, (k) heterocycles selected from the class consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, and (1) aryl or heteroaryl selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl and oxazolyl, (vii) -SO 2 R 108 , wherein R 108 is: (a) a heterocyclic group selected from the class consisting of pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl wherein said heterocyclic group is optionally substituted with one moiety selected from the class consisting of straight or branched alkyl of 1 to 6 carbons, and -OR! 18 (wherein Rl 1^ is hydrogen or alkyl of 1 to 6 carbon atoms), (viii) -COR 109 , wherein R 109 is: (a) a heterocyclic group selected from the class consisting of pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl wherein said heterocyclyl is optionally substituted with one halogen, straight or branched alkyl of 1 to 6 carbons, or -OR121 (wherein Rl21 is hydrogen or alkyl of 1 to 6 carbon atoms), and (ix) -CHO; X is an oxygen atom; R3 is methyl; R is a group of the formula -CH2R55, wherein, R55 is: phenyl, which is optionally substituted at the 4-position with: (A) R e ; which is aryl or heteroaryl selected from the class consisting of phenyl, pyridyl, and pyrimidinyl (B) -CN, (B) nitro, or (C) halogen; R 5 is Cl; Z is =C(H)-; and, R7 is Cl; and pharmaceutically acceptable salts thereof. Preferred compounds of formula III are those wherein: Al, A and A3 are each, independently, =N- or =CH-; D is *=N-, =€Rl-, =CSO 2 Rl-, =CS0R1-, =CSR 1 -, =C0R1-, =CC0R1-, or =CNHRl-, wherein Rl is: (A) a hydrogen atom, (B) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl 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, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein one or more hydrogen atoms of said aryl group may be optionally and independently replaced with: (a) alkyl of 1 to 3 carbon atoms, (b) -COOH, (c) -SO 2 OH, (d) -PO(OH) 2 , (e) a group of the formula -COOR 8 , wherein R 8 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (f) a group of the formula -NR9R10. wherein R9 and Rl 0 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R and Rl constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (g) a group of the formula -CONRl 1R12, wherein Rl 1 and Rl2 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein Rl 1 and Rl2 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (h) a group of the formula -ORl3, wherein Rl is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, (i) a group of the formula -SRl4, wherein Rl4 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, (j) cyano, or (k) an amidino group of the formula wherein Rl , R!6 and Rl7 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms and wherein two of Rl5, R16 and Rl7 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, (iv) a group of the formula -COORl 8 , wherein Rl 8 is straight or branched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, (v) cyano, (vi) a group of the formula -CONR19R20 5 wherein Rl and R 2 0 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein Rl9 and R2 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (vii) a group of the formula -OR21, wherein R21 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, (viii) a group of the formula -SR 2, wherein R22 i s a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, (ix) a group of the formula -NR23R24 3 wherein R23 and R24 are each, independently, (a) a hydrogen atom, (b) alkyl or acyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, (c) a group of the formula -(CH 2 ) m COOH, wherein m is 0, 1 or 2, or (d) a group of the formula -(CH 2 ) I1 COOR25 ) wherein n is 0, 1 or 2, wherein R25 is straight or branched alkyl of 1 to 6 carbon atoms, or wherein R23 and R24 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, or 00 a quaternary group of the formula wherein R2° 5 R27 an d R28 are each, independently, a branched or unbranched alkyl group of 1 to 7 carbon atoms and Q" is a chlorine, bromine or iodine counterion, (C) a branched or unbranched carboxylic acid group of 3 to 6 carbon atoms, (D) a branched or unbranched phosphonic acid group of 2 to 6 carbon atoms, (E) a branched or unbranched sulfonic acid group of 2 to 6 carbon atoms, (F) an amidino group of the formula wherein r is 2, 3, 4, 5 or 6, and R29. R30 an d R31 are e ach, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R29, R30 an R31 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, (G) an guanidino group of the formula wherein s is 2, 3, 4, 5 or 6, and R32, 33 5 R 34 an d R35 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R32, R 3 ; R34 an d R 5 ma y additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, (H) 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, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein one or more hydrogen atoms of said aryl group may be optionally and independently replaced with: (i) alkyl of 1 to 3 carbon atoms, (ii) -COOH, (iii) -SO 2 OH, (iv) -PO(OH) 2 , (v) a group of the formula -COOR36. wherein R36 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (vi) a group of the formula -NR37R38 ? wherein R 7 and R 8 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R37 and R38 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (vii) a group of the formula -CONR39R40 5 wherein R and R are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R39 and R4 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (viii) a group of the formula -OR41 , wherein R41 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, (ix) a group of the formula -SR42, wherein 42 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, (x) cyano, or (xi) an amidino group of the formula wherein R , R44 an d R45 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R 3, R44 and R45 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, (I) a group of the formula -NR 6R47. wherein R46 and R 7 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R46 and R47 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (J) a morpholinyl moiety, or, (K) halogen; X is an oxygen or sulfur atom; R 3 is: (A) a hydrogen atom, or (B) branched or unbranched alkyl of 1 to 3 carbon atoms or cycloalkyl of 3 to 5 carbon atoms wherein said alkyl or cycloalkyl group may optionally be substituted with: (i) a group of the formula -OR48, wherein R48 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, or (ii) a group of the formula -NR4 R50 5 wherein R49 and R50 are each, independently, a hydrogen atom, alkyl of 1 to 2 carbon atoms, or acyl of 1 to 2 carbon atoms; R4 is a group of the formula -CH 2 R5 . wherein: R 5 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-indolyzinyl, 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-cinnolinyl, 6- or 7-pthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7- quinazolinyl, wherein one or more of the hydrogen atoms of said aryl group may be optionally and independently replaced with: (A) R59 5 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- indolyzinyl, 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-cinnolinyl, 6- or 7-pthalaninyl, 2-, 3-, 6- or 7- quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or 7- pteridinyl and 2-, 6- or 7-quinazolinyl, wherein one or more of the hydrogen atoms of said aryl group may be optionally and independently replaced with: (i) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with halogen or oxo, (ii) cyano, (iii) nitro, or (iv) halogen, (B) methyl, which may be mono- or polysubstituted with fluorine atoms and additionally may be monosubstituted with R59, (C) branched or unbranched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with halogen or oxo, (D) a group of the formula -COOR67, wherein R^7 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (E) a group of the formula -NR 68 R 69 , wherein R 68 and R 69 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R^ 8 and R°9 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one of R68 and R^9 may additionally be the group R5 5 (F) a group of the formula -CONR70R71 } wherein R 0 and R71 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R7 and R71 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the mtrogen atom between them form a heterocyclic ring, and wherein one of R70 and R71 may additionally be the group R59 ? (G) a group of the formula -COR72. wherein R72 is a hydrogen atom, straight or branched alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms or R59 ? (H) a group of the formula -OR73. wherein R73 is a hydrogen atom, an alkyl , fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R 9 5 (I) a group of the formula -SR74 ? wherein R74 i s a hydrogen atom, an alkyl , fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R 5 9. (J) cyano, (K) nitro, or (L) halogen; R5 is Cl or trifluoromethyl; Z is =N- or =CR 6 - wherein R° is a hydrogen, fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl; and, R7 is a hydrogen, fluorine, chlorine, bromine or iodine atom, methyl, cyano, nitro or trifluoromethyl, with the condition that when Z is N or =CH-, R is chlorine or trufluoromethyl; and pharmaceutically acceptable salts thereof. The molecules of the invention can be screened for ability to bind or modify the R7.1 epitope of LFA-1 using techniques known in the art, including but not limited to competitive binding and non-competitive assay systems such as radioimmunoassays, ELISA, immunofluorescence assays, etc. For example, a test molecule can be screened against mAb R7.1 in a competitive immunofluorescence assay. One molecule that cross- competes with R7.1 (i.e., binds to the same to similar epitope) is R3.1 (data not shown). The molecules that specifically bind or modify the R7.1 epitope of LFA-1 may be labeled with various compounds known in the art, including but not limited to: enzymes, radioisotopes, fluorescent compounds. The labeling and detection methods employed herein may, for example, be such as those described in Harlow and Lane (Harlow and Lane, 1988, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York). Enzymes which can be used to label the molecules described herein include, z ' nter alia, biotin, horseradish peroxidase, alkaline phosphatase. The detection can be accomplished by colorimetric methods which employ a chromogenic substrate for the enzyme. Detection may also be accomplished by visual comparison of the extent of enzymatic reaction of a substrate in comparison with similarly prepared standards. Radioisotopes which can be used to label the molecules described herein include, znter alia, 125 1, 131 1, 3 H. Such labeled molecules can be detected in in vitro assays using a radioimmunoassay (RIA) or radioprobe by means such as the use of a gamma counter or a scintillation counter or by autoradiography. For use in the detection methods of the invention, the molecules are preferably labeled with a fluorescent compound, for example, Oregon Green ® 488-X, succinimidyl ester 6- isomer (Molecular Probes, Inc., Eugene OR). When the fluorescently labeled molecule is exposed to light of the proper wavelength, its presence can then be detected due to fluorescence by means such as a fluorescence microscope or flow activated cell sorting system (e.g., FACScan). Among the most commonly used fluorescent labeling compounds are fluorescein isothiocyanate (FITC), rhodamine, phycoerythrin (PE), phycocyanin, allophycocyanin, o-phthaldehyde, and fluorescamine. In another aspect, the molecules of the invention may be detected using a labeled molecule that binds such molecules. The label may be selected from those described above. For example, R7.1 may be detected using a goat-anti-mouse IgG-PE conjugate. For the receptor occupancy methods of the invention, a test molecule is administered to a subject. The subject is an animal, including but not limited to a mammal (e.g., cats, dogs, old and new world monkeys, humans). In a preferred embodiment, the subject is a human. The methods of the invention can be used in formulating a range of dosage of the test compound for use in humans. The invention also provides kits comprising one or more containers filled with one or more of the molecules of the invention. The invention is further described in the following examples which are in no way intended to limit the scope of the invention. EXAMPLES In its first aspect, the invention comprises a method for identifying a molecule that specifically binds or modifies the R7.1 epitope of LFA-1. Molecular Assay to Identify Molecules that Bind LFA-1 Purpose of Assay: This assay protocol was designed to develop a method for identifying molecules that inhibit the binding of purified LFA-1 to a molecule that specifically binds or modifies the R7.1 epitope of LFA-1. EXAMPLE 1 LFA-1 was purified using the TS2/4 mAb (American Type Culture Collection; Manassas, VA) from a 20 g pellet of human JY or SKW3 cells, utilizing a protocol previously described (Dustin, M.J. et al, 1992, J. Immunol. 148:2654-2660). The LFA-1 was purified from SKW3 lysates by immunoaffinity chromatography on TS2/4 LFA-1 mAb Sepharose and eluted at pH 11.5 in the presence of 2 mM MgCl 2 and 1% octylglucoside. After collection and neutralization of fractions from the TS2/4 column, samples were pooled and precleared with Protein G agarose. Micellar LFA-1 (50 μl) was immobilized onto a microtiter plate by adsorption at approximately 3 μg/ml in assay buffer (AB: dPBS + 2 mM Mg* ) for 1 hr at room temperature. Non-specific sites were then blocked for 30 min with 2% BSA-AB. Various purified mAbs (50 μl at 10 μg/ml) (CLB-LFA-1, Research Diagnostics Inc., Flanders, NJ; R7.1 and R3.1, generated at Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI), Ridgefield, CT; MHM 24, Biomedia, Foster City, CA; TS 2/4 and T/S 1/22, American Type Culture Collection, Manassas, VA; and mAb38, Research Diagnostics Inc., Flanders, NJ) and 50 μl of Compound 1 ((R)-5-(4-bromobenzyl)-3-(3,5-dichlorophenyl)- l,5-dimethylimidazolidine-2,4-dione) or its enantiomer (Compound 2; 5 μM in AB) or dimethyl sulfoxide (DMSO) were then added and allowed to bind for 1 hour at 37°C. The plate was then washed 4 times and 50 μl of a goat anti-mouse-horseradish peroxidase (HRP) conjugate (Zymed, South San Francisco, California) was added at a 1/4000 dilution in 1% BSA-AB. After 20 min at 37°C, the plate was washed as above and 200 μl of azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) reagent (Zymed, South San Francisco, California) was added to visualize binding. After approximately 15 min, absorbance was measured at 405 nm. Bars represent the mean of duplicate wells ± the standard error. Results: Figure 1 shows that Compound 1, but not its enantiomer or a DMSO control, significantly inhibited the binding of R3.1 and R7.1 to purified LFA-1. As discussed above, R3.1 and R7.1 cross-compete, i.e., bind to the same or similar epitope (data not shown). Compound 1 did not inhibit the binding of the other anti-LFA mAbs. Cellular Assays to Identify Molecules that Bind LFA-1 Purpose of Assays: This assay protocol (exemplified in Examples 2-4) was designed to identify molecules that inhibit the binding of cell surface LFA-1 to a molecule that specifically binds or modifies LFA-1. This assay may also be used to determine LFA-1 receptor occupancy on target cells treated with a molecule that specifically binds LFA-1 as described below in Example 5. EXAMPLE 2: SKW-3 Cells Using flow cytometry, the binding of R3.1 to SKW-3 cells, a T-cell lymphoma that expresses high amounts of LFA-1, was assessed. After washing and counting, 100 μl of SKW-3 cells (1X10 7 cells/ml) were incubated with 13.3 nM mAb38 or R3.1 or R15.7 (generated at BIPI, Ridgefield, CT) and 10 μM Compound 1 or DMSO (0.09%) (negative control) for 30 minutes at 37°C. After centrifugation and 2 washes in HBSS (GIBCO, Grand Island, NY), cells were incubated with a goat anti-mouse IgG-PE conjugate (Biosource International, Camarillo, CA) (diluted 1:50 in dPBS) for 20 minutes at 4°C. After 2 washes in dPBS, cells were fixed with 500 μl 1% paraformaldehyde and analyzed on a FACScan (Becton Dickinson, San Jose, CA). Results: Figure 2 shows that Compound 1 but not DMSO inhibited the binding of R3.1 to the cell- bound LFA-1. Similar to the molecular assay described in Example 1, Compound 1 did not inhibit the binding of mAb38, another I domain binding mAb) or the anti-CD 18 mAb, R15.7 (Smith et al, 1989, J. Clin. Invest. 83(6):2008-2017). EXAMPLE 3: Human Whole Blood Cells Using flow cytometry, the binding of R3.1 to human whole blood cells was assessed. Peripheral blood was obtained from normal healthy donors by venipuncture. R3.1 (3.3 nM) or R7.1 (3.3 nM) and various dilutions of Compound 1 or DMSO (0.2%) were incubated with 100 μl of human whole blood for 20 minutes at 4°C. After centrifugation and 1 wash in dPBS, the cells were then incubated with a goat anti-mouse IgG-PE conjugate (Biosource International, Camarillo, CA) diluted 1:50 in dPBS. After incubation in secondary reagent for 15 minutes at 4°C, cells were lysed and fixed in 100 μl of lysis buffer (Immunotech, Westbrook, Maine) for 10 min at room temperature and then 1 ml of water was added to each sample before analysis on a FACScan (Becton Dickinson, San Jose, CA). Results: Figure 3 shows that Compound 1, but not DMSO, inhibited the binding of R3.1 to leukocytes in a dose dependent manner. The same concentrations of compound did not inhibit the binding of the anti-CD18 mAb R15.7. EXAMPLE 4: Inhibition of Binding of Fab Fragments Using flow cytometry, the inhibition of binding of R3.1 Fab fragments to human whole blood cells by a small molecule (Compound) such as that described in: U.S. patent application No. 09/375,010 by Kelly et al, filed August 16, 1999; U.S. patent application No. 09/604,312 by Kelly et al, filed June 27, 2000; and U.S. patent application No. 09/605,584 by Kelly et al, filed June 28, 2000 is assessed. R3.1 Fab fragments are generated by papain digestion: R3.1 is dialyzed into 0.1M sodium phosphate (EM Sciences), 50mM sodium chloride (EM Sciences), pH 7.2 buffer (PBS). The concentration of the antibody is adjusted to between l-5mg/ml and 5 mM L-cysteine (Sigma, St. Louis, MO) is added to the antibody solution. Papain (Sigma, St. Louis, MO) is added immediately afterwards in 1 :40 w/w (Ab:papain). After mixing well, the solution is incubated in a 37°C water bath for 2-3 hours. 0.2 mM iodoacetamide in 5-10 ml of PBS is added to the AB solution which is then incubated for 30 min. The fragments are analyzed under reduced and non-reduced SDS-PAGE (polyacrylamide gel electrophoresis). The Fab fragments are separated from the Fc portion using Protein A affinity chromatography (ProSepA, Bioprocessing, Inc., Scarborough, ME) followed by anion exchange chromatography (DEAE Sepharose Fast Flow resin, Pharmacia). Following anion exchange, the Fab fragment solution is concentrated using the Amicon Filtron system (Millipore) with lOKd Diaflo ultrafiltration membranes. Amino acid analysis is performed to determine the concentration of Fab (Yale Biotechnology Center, New Haven, CT). The R3.1 Fab fragments are labeled with Alexa 488® according to manufacturer's instructions (Molecular Probes, Inc., Eugene, OR). Peripheral blood is obtained from normal healthy donors by venipuncture. R3.1 Fab fragments labeled with Alexa 488® (10 nM) and various dilutions of Compound or Fab fragments (10 nM) in the absence of compound are incubated with 100 μl of human whole blood for 20 minutes at 4°C. After centrifugation and 1 wash in dPBS, the cells are lysed and fixed in 100 μl of lysis buffer (Immunotech, Westbrook, Maine) for 10 min at room temperature and then 1 ml of water is added to each sample before analysis on a FACScan (Becton Dickinson, San Jose, CA). EXAMPLE 5: A test compound is administered orally, intramucosally or parenterally to a subject. Peripheral blood is withdrawn from the subject at various time points post-administration of the test compound. A molecule that specifically binds or modifies the R7.1 epitope of LFA-1 is added to the blood and incubated for 20 minutes at 4°C. After centrifugation and one wash in dPBS, the cells are then incubated with a goat anti-mouse IgG-PE conjugate (Biosource International, Camarillo, CA) diluted 1:50 in dPBS. After incubation in secondary reagent for 15 minutes at 4°C, cells are lysed and fixed in 100 μl of lysis buffer (Immunotech, Westbrook, Maine) for 10 min at room temperature and then 1 ml of water is added to each sample before analysis on a FACScan (Becton Dickinson, San Jose, CA). The present invention is not to be limited in scope by the specific embodiments described herein, which are intended as single illustrations of individual aspects of the invention, and functionally equivalent methods and components are within the scope of the invention. Indeed, various modifications of the invention, in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims. Various patent applications and publications are cited herein, the disclosures of which are incorporated by reference in their entireties.

Claims: What is claimed is: 1. A method for identifying a molecule that binds or modifies the R7.1 epitope of LFA-1 comprising: (a) incubating a cell that expresses LFA-1 with a first test molecule and a second molecule that specifically binds the R7.1 epitope of LFA-1 or binds LFA-1 such that the R7.1 epitope is modified; and (b) detecting the second molecule; wherein a decrease in binding of the second molecule indicates binding of the first test molecule. 2. A method for identifying a molecule that binds or modifies the R7.1 epitope of LFA-1 comprising: (a) incubating purified LFA-1 that expresses LFA-1 with a first test molecule and a second molecule that specifically binds the R7.1 epitope of LFA-1 or binds LFA-1 such that the R7.1 epitope is modified; and (b) detecting the second molecule, wherein a decrease in binding of the second molecule indicates binding of the first test molecule. The method according to claim 1 wherein the second molecule is a compound of the formula I. The method according to claim 2 wherein the second molecule is a compound of the formula I. 5. The method according to claim 1 wherein the second molecule is a compound of the formula II. The method according to claim 2 wherein the second molecule is a compound of the formula II. 7. The method according to claim 1 wherein the second molecule is a compound of the formula III. The method according to claim 2 wherein the second molecule is a compound of the formula III. A method for identifying a molecule that specifically binds or modifies the R7.1 epitope of LFA-1 comprising: (a) incubating a cell that expresses LFA-1 (i) a first test molecule, (ii) a second molecule that specifically binds the R7.1 epitope of LFA-1 or binds LFA-1 such that the R7.1 epitope is modified, and (iii) a third labeled molecule, wherein the third labeled molecule binds the second molecule; and (b) detecting the third labeled molecule bound to the second molecule; wherein a decrease in binding of the second molecule indicates binding of the first test molecule. 10. A method for identifying a molecule that specifically binds or modifies the R7.1 epitope of LFA-1 comprising: (a) incubating purified LFA-1 that expresses LFA-1 with (i) a first test molecule, (ii) a second molecule that specifically binds the R7.1 epitope of LFA-1 or binds LFA-1 such that the R7.1 epitope is modified, and (iii) a third labeled molecule, wherein the third labeled molecule binds the second molecule; and (b) detecting the third labeled molecule bound to the second molecule; wherein a decrease in binding of the second molecule indicates binding of the first test molecule. 11. The method according to any of claims 1 ,2, 9, or 10 wherein the molecule that specifically binds or modifies the R7.1 epitope is a monoclonal antibody or a fragment thereof. 12. The method according to claim 11 wherein the monoclonal antibody is R7.1. 13. The method according to any one of claims 1-10 wherein the labeled molecule is labeled with a fluorescent compound. 14. A method for determining LFA-1 receptor occupancy comprising: (a) administering a first test molecule to a subject; (b) withdrawing a sample of blood from the subject; (c) incubating the sample with a second labeled molecule that specifically binds the R7.1 epitope of LFA-1 or binds LFA-1 such that the R7.1 epitope is modified; and (d) detecting the amount of the second molecule, wherein a decrease in the amount of binding of the second labeled molecule indicates binding of the first test molecule. 15. A method for determining LFA- 1 receptor occupancy comprising: (a) administering a first test molecule to a subject; (b) withdrawing a sample of blood from the subject; (c) incubating the sample with a second molecule that specifically binds the R7.1 epitope of LFA-1 or binds LFA-1 such that the R7.1 epitope is modified; (d) incubating the sample with a third labeled molecule, wherein the third labeled molecule binds the second molecule; and (e) detecting the third labeled molecule bound to the second molecule, wherein a decrease in the amount of binding of the second molecule indicates binding of the first test molecule. 16. The method according to claim 14 or 15 wherein the second molecule is a monoclonal antibody or a fragment thereof. 17. The method according to claim 16 wherein the monoclonal antibody is R7.1. 18. The method according to claim 14 or 15 wherein the second molecule is a compound of the formula I. 19. The method according to claim 14 or 15 wherein the second molecule is a compound of the formula II. 20. The method according to claim 14 or 15 wherein the second molecule is a compound of the formula III. 21. The method according to claim 14 or 15 wherein the subject is a human. 22. The method of claim 14 or 15 wherein the labeled molecule is labeled with a fluorescent compound.

Inventors: CAVINESS GARY O, KISHIMOTO TAKASHI, LEMIEUX RENE M, MAGOLDA RONALD L, REISER HANS C, ROTHLEIN ROBERT, WOSKA JOSEPH R, CAVINESS, GARY, O., KISHIMOTO, TAKASHI, LEMIEUX, RENE, M., MAGOLDA, RONALD, L., REISER, HANS, C., ROTHLEIN, ROBERT, WOSKA, JOSEPH, R.
Applicants: BOEHRINGER INGELHEIM PHARMA, BOEHRINGER INGELHEIM PHARMACEUTICALS, INC.
Application year: 2001
Main classification: G01N33
IPC codes: C12Q1, G01N33