MXPA06009696A - Isothiourea derivatives - Google Patents

Abstract

The present invention relates to isothiourea derivatives, processes for their production, their uses, in particular in transplantation, autoimmune or infectious diseases, and pharmaceutical compositions containing them.

Description

DERIVATIVES OF ISOTIOU REA The present invention relates to isothiourea derivatives, to processes for their production, to their uses, and to pharmaceutical compositions containing them. More particularly, the present invention provides a compound of the formula I: RG "\ R * where: Rt is a residue of the formula (a), (b), or (c): (a) (b) (c) R2 is - (CR22R23) 1 -3- or -C (O) -; each of R3 and Rs is independently S; OR; or NR2; each and every one of R 4 and R 5 is independently cycloalkyl of 3 to 1 2 carbon atoms optionally substituted by R 25, alkyl of 1 to 12 carbon atoms, or a polycyclic residue of 8 to 12 carbon atoms saturated; or aryl optionally substituted by R26 and / or R27, aryl-alkyl of 1 to 4 carbon atoms, or heteroaryl; wherein up to 4 carbon atoms of R and / or R5 are optionally substituted by S, O, or N R24; R6 is H; alkyl of 1 to 6 carbon atoms; cycloalkyl of 3 to 6 carbon atoms; or aryl optionally substituted by R26 and / or R27, aryl-alkyl of 1 to 4 carbon atoms, or heteroaryl; R7 is CR28 or N; R9 is a direct link; - (CR22R23)? 2-; or NR2; each of R1 0-23 and 2s is independently H; F; Cl; Br; alkyl of 1 to 6 carbon atoms; alkoxy of 2 to 6 carbon atoms-alkyl; haloalkyl of 1 to 6 carbon atoms; cycloalkyl of 3 to 6 carbon atoms; aryl optionally substituted by R26 and / or R27, or heteroaryl; WITH R29R30; COOR29; CN; NO2; OR OR3?; or two of R-? o-19, which are attached to the same carbon atom, together with the carbon atom to which they are attached, form a non-aromatic 3 to 7 membered ring that optionally contains up to two heteroatoms independently selected from N, O , and S; or R17 and R? s, together with the carbon atoms with which they are attached, form a non-aromatic 4- to 7-membered ring optionally containing up to two heteroatoms independently selected from N, O, and S; or R2o and R2-? , together with the carbon atoms with which they are attached, form an aryl optionally substituted by R26 and / or R27, or heteroaryl; each of R24, R29, and R30 is independently H; alkyl of 1 to 6 carbon atoms, alkoxy of 2 to 6 carbon atoms-alkyl; haloalkyl of 1 to 6 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; or aryl optionally substituted by R26 and / or R27, aryl-alkyl of 1 to 4 carbon atoms, or heteroaryl; R25 represents from 1 to 4 substituents, each independently having one of the meanings given for R10-23 above; R26 represents from 1 to 4 substituents, each independently selected from alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 1 to 6 carbon atoms; alkoxy of 2 to 6 carbon atoms-alkyl; haloalkyl of 1 to 6 carbon atoms; cycloalkyl of 3 to 6 carbon atoms; alkenyl of 2 to 6 carbon atoms; cycloalkenyl of 3 to 6 carbon atoms; alkynyl of 2 to 6 carbon atoms; aril; heteroaryl; Heteroaryl N-oxide; F; Cl; Br; I; OH; OR4; CONH2; CONHR4; CONR4R4; OC (0) R4; OC (O) OR4; OC (0) NHR4; OC (O) NR4R4; OS02R4; COOH; COOR4; CF3; CHF2; CH2F; CN; N02; NH2; NHR4; NR4R4; NHC (0) R4; NR4C (0) R4; NHC (0) NHR4; NHC (0) NH2; NR4C (0) NHR4; NR4C (O) NR4R4; NHC (0) OR4; NR4C (0) OR4; NHSOzR4; N (S02R4) 2; NR4SO2R4; SR4; S (0) R4; SOzR4; Yes (CH3) 3, and B (OC (CH3) 2) 2; R27 represents two adjacent substituents that form a non-aromatic 4-7 membered null ring optionally containing up to two heteroatoms independently selected from N, O, and S; R31 is alkyl of 1 to 6 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; aryl optionally substituted by R26 and / or R27, aryl-alkyl of 1 to 4 carbon atoms, or heteroaryl; or CF3. Any alkyl, alkenyl, or alkynyl can be linear or branched. Halogen is F, Cl, Br, or I. Aryl means phenyl or naphthyl. The polycyclic residue can be, for example, adamantyl optionally substituted by R25, bicyclo [3.2.1] octyl, or wherein n is 1 or 2. Heteroaryl means an aromatic ring system comprising mono-, bi-, or tri-cyclic systems containing up to 4 heteroatoms independently selected from N, O, and S. Examples of heteroaryl include , for example, pyridyl, indolyl, benzothiazolyl, thiazolyl, imidazolyl, benzimidazolyl. Examples of 3 to 7-membered non-aromatic rings containing 1 or 2 heteroatoms include, for example, morpholinyl, piperazinyl, piperidyl. The compounds of the formula I can exist in the form of several tautomers and E / Z isomers which interconvert, for example: These can exist in free form or in salt form, for example addition salts with, for example, organic or inorganic acids, for example hydrochloric acid, acetic acid. When the compounds of the formula I have one or more asymmetric centers in the molecule, it should be understood that the present invention encompasses the different optical isomers, as well as the racemates, diastereoisomers, and mixtures thereof. In the compounds of the formula I, the following meanings are preferred individually or in any sub-combination: 1. (a) Each of R? O-23 and 2s is independently H; or alkyl of 1 to 6 carbon atoms; (b) two of R10-19, which are attached to the same carbon atom, together with the carbon atom to which they are attached, form a non-aromatic ring of 3 to 6 members which optionally contains up to two heteroatoms independently selected from from N, O, and S; or (c) R? 7 and R-is, together with the carbon atoms with which they are attached, form a non-aromatic 4- to 7-membered ring optionally containing up to two heteroatoms independently selected from N, O, and S; or 2. R9 is a direct link; or -CR22R23-; 3. each of R24, R29, and R30 is independently H; alkyl of 1 to 6 carbon atoms; or cycloalkyl of 3 to 7 carbon atoms; 4. R7 is R28; . R2 is -CR22R23-; 6. each of R 4 and R 5 is independently cycloalkyl of 5 to 9 carbon atoms or alkyl of 6 to 1 2 carbon atoms optionally substituted by R 25; or adamantyl; wherein optionally up to 4 carbon atoms of R4 and / or R5 are substituted by S, O, or N R2; 7. R6 is H; or alkyl of 1 to 6 carbon atoms; 8. each of R3 and R8 is independently S; 9. aryl-alkyl of 1 to 4 carbon atoms is benzyl. The invention also covers a process for the preparation of a compound of the formula I, which comprises reacting a compound of the formula I I: with a compound of the formula ll: R «\ R? -R32 ni wherein R -,. 6 are as defined above, and R32 is a leaving group; and optionally converting a resulting compound of formula I obtained in free form to a salt form, or vice versa. Preferably, R32 is halogen, more preferably chloro. The compounds of the formula I are known or can be prepared by the reaction of a compound of the formula IV (a), (b), or (c): (a) (b) (c) where R8-2? they are as defined above, with 1, 3-dichloro-acetone, and recovering the compound of the formula III in free or salt form. The compounds of formulas II and IV are known and can be prepared according to methods well established in the art.

The following examples illustrate the invention without limitation. Example 1 1,3-dicyclohexyl-2- (5,6-dihydro-imidazo [2,1-b] thiazol-3-ylmethyl) -iso-thiourea. A mixture of N, N'-dicyclohexyl thiourea (0.21 grams, 1.0 mmol), 3-chloro-methyl-5,6-dihydro-midazo [2,1-b] thiazole (0.72 grams, 3.0 mmol), and acetonitrile (10 milliliters), reflux for 4 hours. The precipitate is filtered and crystallized from methanol / ether to give the 1,3-dicyclohexyl-2- (5,6-dihydro-imidazo [2,1-b] thiazol-3-ylmethyl) -isothiourea dihydrochloride . MS / ESI 379 [M + H +].

Example 2 1,3-dicyclohexyl-2- (3-methyl-2-methyl-imino-2,3-dihydro-thiazol-4-ylmethyl) -sothiourea. 1,3-Dicyclohexyl-2- (3-methyl-2-methyl-imino-2,3-dihydro-thiazol-4-ylmethyl) -isothiourea is prepared from 4-chloro-methyl-3-methyl-3H - thiazol-2-ylidene-methyl-amine, using a procedure analogous to that described in Example 1, with the exception that the latter compound is used in place of 3-chloro-methyl-5,6-dihydro-imidazo [2] , 1-b] thiazole.

MS / ESI 381 [M + H +]. The (4-chloromethyl-3-methyl-3H-thiazol-2-ylidene) -methyl-amine used as a starting material is prepared according to the following procedure: A mixture of N, N'-dimethyl-thiourea (1. 04 grams, 0.01 mmol), 1,3-dichloro-acetone (1.27 grams, 1.0 mmol), and normal butanol (25 milliliters), is heated at 140 ° C for 1 hour. The solvent is removed, and the residue is crystallized from methanol / ether, to give (4-chloro-methyl-3-methyl-3H-thiazole-2-liden) -methyl-amine hydrochloride. MS / ES I 177 [M + H +]. Example 3 1,3-dicyclohexyl-2- (6,6-dimethyl-5,6-dihydro-imidazo [2, 1-b] thiazol-3-methyl) -isothiourea. 1,3-Dicyclohexyl-2- (6,6-dimethyl-5,6-dihydro-imidazo [2, 1-b] -thiazol-3-ylmethyl) -isothiourea is prepared from 3-chloro-methyl- 6,6-dimethyl-5,6-dihydro-imidazo [2, 1-b] thiazole, employing a procedure analogous to that described in Example 1, with the exception that the latter compound is used in place of 3-chloro- methyl-5,6-dihydro-imidazo [2,1-b] thiazole. MS / ESI 407 [M + H +]. The 3-chloro-methyl-6,6-dimethyl-5,6-dihydro-imidazo [2,1-b] thiazole used as the starting material is prepared according to the following procedure: A mixture of 4,4- dimethyl-imidazolidine-2-thione (1.0 grams, 7.5 mmol), 1,3-dichloro-acetone (1.00 grams, 7.5 mmol), and acetonitrile (15 milliliters), is refluxed for 2 hours. The colorless precipitate is filtered, dried, suspended in 1-methoxy-2- (2-methoxy-ethoxy) -ethane, and subsequently heated at 140 ° C for 2 hours. The precipitate is filtered and washed with ether to give 3-chloro-methyl-6,6-dimethyl-5,6-dihydro-midazo [2,1-b] -thiazole hydrochloride. MS / ESI 203 [M + H +]. The following examples of the formula V: they are prepared by applying similar procedures.

Compounds of the formula I in free form or in the form of pharmaceutically acceptable salt exh, have valuable pharmacological properties, for example as antagonists of CXCR4, for example as indicated in the in vitro tests, and by consequently, they are indicated for therapy. CXCR4 is a G-protein coupled receptor (GPCR) of the chemokine receptor, which is expressed in a variety of normal tissues, including monocytes. SDF-1 (CXCL12) is the ligand cognate of this receptor, and is known to act as a chemoattractant that drives the chemotaxis of cells expressing CXCR4. a) CXCR4 membrane binding assay. Membranes are prepared from the T lymphoblast cell line, CEM, which endogenously expresses CXCR4. Like the radioligand, SDF-1 is used to be labeled with 125-1. The membranes, the radioligand, and a compound of the formula I are incubated, and the amount of bound radioligand is determined. The data is reported as the IC50, that is, the concentration of the compound required to achieve a 50 percent inhibition of the [l-125] S DF-1 binding. In this test, the compounds of the formula I have an IC5o of < 50 pM. b) Functional assay of CXCR4 - mobilization of Ca2 +. The mobilization of Ca2 + induced by SDF-1 is measured from the intracellular stores in CEM cells loaded with the fluorochrome Fluo-4 Ca2 + detector. The cells loaded with Fluo-4 are incubated with the compounds of the formula I, and then the increase in fluorescence induced by S DF-1 is recorded in a fluorescence imaging plate reader. The inhibitory effects of the compounds are expressed as IC50 values, which represent the concentration of the compound that reduces the SDF-1 response by 50 percent. In this test, the compounds of formula I have IC50 values of < 50 pM. c) Functional assay of CXCR4 - chemotaxis. Cell migration (chemotaxis) stimulated by SDF-1 is evaluated in transwell tissue culture inserts with porous polycarbonate membranes. Objective cells (eg, Jurkat T cells, CEM cells, or lymphocytes) are added to the upper compartment, and the chemokine / S DF-1 to the lower compartment. The compounds of formula I are added to both compartments in the same concentration. The compounds of the formula I inhibit the chemotaxis induced by SDF-1 with IC50 values <50 μM. Accordingly, the compounds of the formula I are useful in the prevention and / or treatment of diseases or disorders mediated by the interactions between the chemokine receptors, for example CXCR4, and their ligands, for example in the transplantation, such as acute or chronic rejection of allo- or xenografts of organs, tissues, or cells or delayed function of the graft, autoimmune diseases, for example rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I or II diabetes and the disorders associated with it, vasculitis, pernicious anemia, Sjoegren's syndrome, uveitis, psoriasis, alopecia areata and others, allergic diseases, for example allergic asthma, atopic dermatitis, rhinitis / allergic conjunctivitis, allergic dermatitis contact, inflammatory diseases optionally with underlying aberrant reactions, for example inflammatory bowel disease, Crohn or ulcerative colitis, intrinsic asthma, inflammatory lesion of the lung, inflammatory lesion of the liver, inflammatory glomerular lesion, atherosclerosis, osteoarthritis, irritant contact dermatitis and other eczematous dermatitis, seborrheic dermatitis, cutaneous manifestations of immunologically mediated disorders, inflammatory disease of the eyes, keratoconjunctivitis, myocarditis or hepatitis, ischemia / reperfusion injury, for example myocardial infarction, embolism, ischemia of the intestine, renal failure or hemorrhagic shock, traumatic shock and others, infectious diseases, for example toxic shock (for example, induced by super-antigen), septic shock, adult respiratory distress syndrome or viral infections, for example linkage or entry of HIV virus into cells expressing CXCR4, or progress of AIDS. Transplantation means allo- or xenografts of, for example, cells, tissues, or solid organs, e.g., pancreatic islets, totipotent cells, bone marrow, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver , intestine, pancreas, trachea, or esophagus. Chronic rejection is also referred to as graft vessel disease. CXCR4 signaling is involved in the progress, invasion, or metastasis of tumors, for example solid tumors. It has been observed that stromal or epithelial cells associated with primary tumors frequently express SDF-1. The interactions of CXCR4 / SDF-1 are involved in the establishment, growth, angiogenesis, or localized invasion of the tumor at the primary site, for example development of blood vessels, or promotion of the entry of tumor cells into the blood or lymphatic circulation by means of the expression of SDF-1 by cells associated with blood vessels, for example in the first steps of metastasis. In addition, the expression of SDF-1 by bone marrow cells promotes the recruitment, adherence, or proliferation of tumor cells that express CXCR4 in bone. The expression of SDF-1 in other sites or tissues has a similar role in the metastasis or in the establishment of tumors in these sites. Multiple myeloma is an example of a cancer in which the recruitment of cells to the bone marrow has an initiating, environmental and proliferative role critical in the establishment and progress. Accordingly, the compounds of the invention are also useful in the prevention or treatment of proliferative diseases, especially malignant or neoplastic proliferative diseases, for example tumors, for example brain tumors and other tumors of the central nervous system (e.g. of the meninges, the brain, the spinal cord, the cranial nerves and other parts of the central nervous system, for example glioblastomas or marrow blastomas); cancer of the head and / or neck; breast tumors; tumors of the circulatory system (eg, heart, mediastinum and pleura, and other intrathoracic organs, vascular tumors, and vascular tissue associated with tumor); excretory system tumors (eg, kidney, renal pelvis, ureter, bladder, and other urinary organs not specified); tumors of the gastrointestinal tract (eg, esophagus, stomach, small intestine, colon, colorectal, rectosigmoid junction, rectum, anus, and anal canal), tumors involving the liver and intrahepatic bile ducts, vesicle, other unspecified parts of the biliary tract, pancreas, other digestive organs); head and neck; oral cavity (lip, tongue, gums, floor of the mouth, palate, and other parts of the mouth, parotid gland, and other parts of the salivary glands, angina, oropharynx, nasopharynx, piriform sinus, hypopharynx, and other sites of the lip , of the oral cavity, and of the pharynx); reproductive system tumors (eg, vulva, vagina, Cervix uteri, Corpus uteri, uterus, ovary, and other sites associated with the female genital organs, placenta, penis, prostate, testes, and other sites associated with the male genital organs); respiratory tract tumors (e.g., nasal cavity and middle ear, accessory sinuses, larynx, trachea, bronchi and lungs, e.g., small cell lung cancer or non-small cell lung cancer); tumors of the skeletal system (e.g., bone and articular cartilage of the limbs, articular cartilage of bones, and other sites); skin tumors (eg, malignant melanoma of the skin, non-melanoma skin cancer, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, mesothelioma, Kaposi's sarcoma); and tumors that involve other tissues, including peripheral nerves and the autonomic nervous system, connective and soft tissue, retroperitoneum and peritoneum, eyes and adnexa, thyroid gland, adrenal gland and other endocrine glands and related structures, secondary malignant neoplasm and unspecified lymph nodes, secondary malignant neoplasm of the respiratory and digestive systems, and secondary malignant neoplasm of other sites, tumors of the blood and lymphatic circulatory system (eg, Hodgkin's disease, non-Hodgkin's lymphoma, lymphoma of the Burkitt, lymphomas related to SI DA, malignant immunoproliferative diseases, multiple myeloma and malignant neoplasms of plasma cells, lymphoid leukemia, acute or chronic myeloid leukemia, acute or chronic lymphocytic leukemia, monocytic leukemia, other leukemias of specified cell type, leukemia of unspecified cell type, other malignant neoplasms is not of lymphoid, hematopoietic and related tissues, for example, diffuse large cell lymphoma, T-cell lymphoma, or cutaneous T-cell lymphoma). Myeloid cancer includes, for example, acute or chronic myeloid leukemia. Previously in the present and subsequently, when a tumor, a tumor disease, a carcinoma, or a cancer is mentioned, metastasis in the original organ or tissue, and / or in any other location, is also alternatively or in addition involved, whatever be the location or locations of the tumor and / or metastasis. The compounds of the formula I are particularly indicated for the treatment of tumor invasiveness or symptoms associated with this tumor growth, for preventing the metastatic spread of tumors, or for preventing or inhibiting the growth of micrometastases in a subject in need thereof, especially for the treatment or prevention of the metastatic extension of bone tumors, for example bone marrow. In one embodiment, the compounds of formula I are indicated to prevent or treat metastasis, tumor invasiveness, or tumor growth mted by CXCR4 receptors and / or SDF-1 expression. In a further embodiment, the compounds of the formula I are indicated to inhibit or control misregulated angiogenesis, eg angiogenesis mted by CXCR4 and / or SDF-1, in a subject in need thereof. For previous uses, the required dosage, of course, will vary depending on the mode of administration, the particular condition to be treated, and the desired effect. In general, it is indicated that satisfactory results are obtained systemically with daily dosages of approximately 0.01 to 10 milligrams / kilogram of body weight. An indicated daily dosage in the higher mammal, for example in humans, is in the range of about 0.5 milligrams to about 1,000 milligrams, conveniently administered, for example, in divided doses up to four times a day, or in a delayed form. Unit dosage forms suitable for oral administration comprise from 0.1 to 500 milligrams, for example from approximately 0.5 to 4 milligrams of I? active ingredient. The compounds of the formula I can be administered by any conventional route, in particular enterally, for example orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injectable solutions or suspensions; topically, for example in the form of lotions, gels, ointments or creams, or in a nasal or suppository form. Pharmaceutical compositions comprising a compound of formula I in free form or in pharmaceutically acceptable salt form can be manufactured in association with at least one pharmaceutically acceptable carrier or diluent, in a conventional manner, by mixing it with a pharmaceutically acceptable carrier or diluent. The compounds of formula I can be administered in free form or in pharmaceutically acceptable salt form, for example as indicated above. These salts can be prepared in a conventional manner, and exhibit the same order of activity as the free compounds. In accordance with the foregoing, the present invention further provides: 1.1 A method for preventing or treating disorders or diseases mediated by interactions between chemokine receptors, for example CXCR4 receptors, and their ligands, for example, such as indicated above, in a subject in need of such treatment, which method comprises administering to this subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof; 1.2 A method for preventing or treating rejection of acute or chronic transplantation or inflammatory or autoimmune diseases, for example as indicated above, in a subject in need of such treatment, which method comprises administering to this subject an effective amount of a compound of the formula I or a pharmaceutically acceptable salt thereof; 1.3 A method for preventing or treating a proliferative disease, for example as indicated above, in a subject in need of such treatment, which method comprises administering to this subject an effective amount of a compound of the formula I or a pharmaceutically acceptable salt thereof; 1.4 A method for treating tumor progression, invasiveness, or symptoms associated with said tumor growth, for preventing the metastatic spread of tumors, or for preventing or inhibiting the growth of micrometastases, or for preventing tumor-associated angiogenesis, for example as indicated above, in a subject in need of such treatment, which method comprises administering to this subject an effective amount of a compound of the formula I or a pharmaceutically acceptable salt thereof; 1.5 A method for preventing or combating infectious diseases, for example viral infection, in particular to prevent or combat the binding or entry of a virus into cells expressing the chemokine receptor, for example the binding or the. entry of the HIV virus, such as HIV-1 or HIV-2, into cells expressing CXCR4, or the progress of AIDS. 2. A compound of the formula I, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical product, for example in any of the methods indicated in 1.1 to 1.4 above. 3. A pharmaceutical composition, for example for use in any of the methods 1.1 to 1.4 above, which comprises a compound of the formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier therefor. . 4. A compound of the formula I, or a pharmaceutically acceptable salt thereof, for use in the preparation of a pharmaceutical composition for use in the method of 1.4 above. The compounds of formula I can be administered as the sole active ingredient, or in conjunction with, for example as an adjuvant for, other drugs, for example in immunosuppressive or immunomodulatory regimens or with other anti-inflammatory agents, for example for the treatment or the prevention of acute or chronic rejection of allo-or xenograft or of inflammatory or autoimmune disorders, or as an anti-infective agent, for example an anti-viral agent such as, for example, an anti-retroviral agent, or an antibiotic For example, the compounds of the formula I can be used with a calcineurin inhibitor, for example cyclosporin A or FK 506; an mTOR inhibitor, for example rapamycin, 40-O- (2-hydroxy-ethyl) -rapamycin, CCI779, ABT578, AP23573, AP23464, AP23675, AP23841, or TAFA-93; a disgust that has immunosuppressive properties, for example ABT-281, ASM981, etc .; corticosteroids; cyclophosphamide; azathioprine; methotrexate; leflunomide; _mizoribin; ichophenic acid; mycophenolate-mofetil; 15-deoxy-spergualin or a homolog, analog or immunosuppressive derivative thereof; a sphingosine-1-phosphate receptor agonist, for example FTY720; monoclonal antibodies to the leukocyte receptors, for example MHC, CD2, CD3, CD4, CD7, CD8, CD11a / CD18, CD25, CD27, CD28, CD45, CD45, CD58, CD80, CD86, CD137, ICOS, CD50 (SLAM) , OX40, 4-1BB or its ligands, for example CD154, or antagonists thereof; other immunomodulatory compounds, for example a recombinant binding molecule having at least a portion of the extracellular domain of CLTA4 or a mutant thereof, for example at least an extracellular portion of CTLA4 or a mutant thereof, bound to a sequence that is not CTLA4 protein, for example CTLA4lg (for example, designated as ATCC 68629) or a mutant thereof, for example LEA29Y; inhibitors of adhesion molecules, for example LFA-1 antagonists, ICAM-1 or -3 antagonists, VCAM-4 antagonists, or VLA-4 antagonists; or anti-chemokine antibodies or anti-chemokine receptor antibodies or low molecular weight chemokine receptor antagonists, for example anti-MCP-1 antibodies. The term "anti-viral agent", as used herein, includes, but is not limited to, an anti-retroviral agent; an antibody against virus; for example an anti-HIV antibody; a reverse transcriptase inhibitor; for example an inhibitor of HIV reverse transcriptase, especially nucleoside analogs, such as Retrovir® (3'-azido-3'-deoxy-pyrimidine, Zidovudine) and 3'-azido-3'-deoxy-thymidine (AZT) ) from GlaxoSmithKIine, HIVID® (2 ', 3'-dideoxy-cytidine, Zalcitabine) from Hoffmann-LaRoche, Videx® or VidexEC® (2', 3'-dideoxy-inosine, Didanosine) from Bristol-Myers-Squibb , Epivir® (Lamivudine) from GlaxoSmithKIine, Zerit® (stavudine) from Bristol-Myers-Squibb, Viread® (tenofovir DF) from Gilead, Ziagen® (abacavir) from GlaxoSmithKIine, Emtriva® (E tricitabine, FTC) from Gilead Sciences; or non-nucleoside analogs, such as, for example, Rescriptor® (delavirdine) from Pfizer, Sustiva® (Efavirenz) from Bristol-Meyer-Squibb, Viramune® (nevirapine) from Boehringer-Ingelheim; 11-cyclopropyl-5,11-dihydro-4-methyl- (6H) -dipyrido [3,2-b; 2 ', 3'-e] - [1,4] diazepin-6-one, tri-sodium phosphonoformate, ammonium-21-tugstenate-9-antimonate, 1-β-D-ribofuranoxyl-1, 2,4- triazole-3-carboxamide; a viral or retroviral protease inhibitor, for example a viral aspartate protease inhibitor, for example an HIV protease inhibitor, such as Aganerase® (amprenavir) from GlaxoSmithKine, Reyataz® (atazanavir) from Bristol-Myers-Squibb, Lexiva ® (fosamprenavir) from GSK, Crixivan® (Indinavir) from Merck & Co.; Viracept® (nelfinavir) from Agouron, Norvir® (ritonavir) from Abbott; Fortovas.e® and Invirase® (saquinavir) from Hoffmann-LaRoche; and other compounds, such as lasinavir (5 (S) - (terbutoxy-carbonyl-amino) -4 (S) -hydroxy-6-phenyl-2 (R) (2,3,4-trimethoxy-phenyl-methyl) - hexanoyl- (L) -valyl-N- (2-methoxy-ethyl) -amide), Adriamycin, KVX-478 from GlaxoWeIlcome; VX-478 of Vértex; 141W94 from Kissei Pharmaceuticals; AG-1343 of Agouron; KNÍ-272 of Nippon Mining; U-96988 of Upjohn; BILA-2011BS (Palinavir) from Boehringer-lngelheim; compounds that prevent the penetration of viruses, such as, for example, poly-monoacetate; fusion inhibitors, such as, for example, Fuzeon® (enfuvirtide, T-20) from Hoffmann-LaRoche; or any combination thereof, such as Epzicom® (Abacavir and Lamivudine) from GlaxoSmithKine, Trizivir® (Abacavir, Lamivudine and Zidovudine) from GlaxoSmithKine, Truvada® (Emtricitabine and Tenofir DF) from Gilead Sciences, Combivir® (Lamivudine and Zidovudine) of GlaxoSmithKIine, Kaletra® (Lopinavir and Ritonavir) from Abbott. The term "anti-viral agent" further includes an agent that treats opportunistic infections that are caused by immunosuppression resulting from viral infection, for example HIV infection. The term "HIV", as used herein, includes, but is not limited to, HIV-1 and HIV-2. A compound of the formula I can also be used with advantage in combination with other anti-proliferative agents. These anti-proliferative agents include, but are not limited to, aromatase inhibitors, anti-estrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule-active agents, alkylating agents, histone deacetylase inhibitors, farnesyl transferase inhibitors. , COX-2 inhibitors, MMP inhibitors, mTOR inhibitors, anti-neoplastic anti-metabolites, platinum compounds, compounds that decrease the activity of protein kinase and other anti-angiogenic compounds, gonadorelin agonists, anti-androgens , bengamides, bisphosphonates, anti-proliferative antibodies, and temozolomide (TEMODAL®). The term "aromatase inhibitors", as used herein, refers to compounds that inhibit the production of estrogen, ie, the conversion of the substrates of androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to, steroid, especially exemestane and formestane, and in particular non-steroids, especially amoglutathione, vorozole, fadrozole, anastrozole, and most especially letrozole. The exemestane can be administered, for example, in the form as it is traded, for example under the registered trademark AROMAS IN M R. Formestane can be administered, for example, in the manner in which it is used. trade, for example under the registered trademark LENTARONMR. Fadrozole can be administered, for example, in the form as it is traded, for example under the registered trademark AFEMAM R. Anastrozole can be administered, for example, in the form as it is traded, for example under the registered trademark ARIM I DEXMR. The letrozole can be administered, for example, in the form as it is traded, for example under the registered trademark FEMARAM R or FEMARMR. The aminoglutethimide can be administered, for example, in the form as it is traded, for example under the registered trademark ORIMETEN ™. A combination of the invention comprising an anti-neoplastic agent that is an aromatase inhibitor, is particularly useful for the treatment of breast tumors positive for the hormone receptor. The term "anti-estrogen" as used herein, refers to compounds that antagonize the effect of estrogens at the level of the estrogen receptor. The term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen can be admired, for example, in the form in which it is traded, for example under the registered trademark NO LVADEX R. Raloxifene hydrochloride can be administered, for example, in the form in which it is traded, for example. under the registered trademark EVISTAMR. The fulvestrant can be formulated as disclosed in US Pat. No. 4,659,516, or it can be administered, for example, in the form as it is traded, for example under the registered trademark FASLODEXM R. The term "topoisomerase I inhibitors", as used herein, includes, but is not limited to, topotecan, irinotecan, 9-nitro-camptothecin, and the macromolecular camptothecin conjugate PNU-166148 (compound A1 of International Publication Number WO) 99/17804). The irinotecan can be administered, for example, in the way it is traded, for example under the registered trademark CAMPTOSARMR. The topotecan can be administered, for example, in the form as it is traded, for example under the registered trademark HYCAMTI NM R. The term "topoisomerase I I inhibitors", as used in v >; present, including, but not limited to, the anthracyclines doxorubicin (including liposomal formulation, eg, CAELYXMR), epirubicin, idarubicin, and nemorubicin; the anthraquinones mitoxantrone and losoxantrone, and the podophyllotoxins etoposide and teniposide. The etoposide can be admired, for example, in the way it is traded, for example under the registered trademark - ETO PO PH OSMR. The teniposide can be administered, for example, in the form as it is traded, for example under the registered trademark VM 26-BRISTOLM R. Doxorubicin can be administered, for example, in the form as it is traded, for example under the trademark commercial registered ADRI BLASTI NMR. Epirubicin can be administered, for example, in the form as it is traded, for example under the registered trademark FARMORUBICINMR. Idarubicin can be administered, for example, in the form as it is traded, for example under the registered trademark ZAVEDOSM R. Mitoxantrone can be administered, for example, in the form as it is traded, for example under the registered trademark NOVANTRONMR . The term "microtubule-active agents" refers to microtubule stabilizing and microtubule-destabilizing agents, including, but not limited to, taxanes paclitaxel and docetaxel, vinca alkaloids, for example vinblastine, especially vinblastine sulfate, vincristine , especially vincristine sulfate, and vinorelbine, discodermolide and epothilones, such as epothilones B and D. Docetaxel can be administered, for example, in the form as it is traded, for example under the registered trademark TAXOTEREMR. The vinblastine sulfate can be administered, for example, in the form as it is traded, for example under the commercial label recorded at VI N B LASTIN R. P .MR. The vincristine sulfate can be administered, for example, in the form as it is traded, for example under the registered trademark FARMISTI NM R. Discodermolide can be obtained, for example, as disclosed in the United States Patent North America No. 5,010,099. The term "alkylating agents," as used herein, includes, but is not limited to, cyclophosphamide, ifosfamide, and melphalan.

Cyclophosphamide can be administered, for example, in the form as it is traded, for example under the registered trademark CYCLOSTINMR. The phosphamide can be administered, for example, in the form as it is traded, for example under the registered trademark HOLOXAN ™. The term "histone deacetylase inhibitors" refers to compounds that inhibit histone deacetylase, and which possess anti-proliferative activity. The term. "farnesyl transferase inhibitors" refers to compounds that inhibit farnesyl transferase, and that possess anti-proliferative activity. The term "COX-2 inhibitors" refers to compounds that inhibit the enzyme cyclo-oxygenase type 2 (COX-2), and which possess an anti-proliferative activity, such as celecoxib (Celebrex®), rofecoxib (Vioxx® ), and lumiracoxib (COX189). The term "MMP inhibitors" refers to compounds that inhibit matrix metalloproteinase (MMP), and which possess anti-proliferative activity. The term "mTO R inhibitors" refers to compounds that inhibit the mammalian target of rapamycin (mTOR), and that possess an anti-proliferative activity, such as sirolimus (Rapam une®). , everolim us (CerticanM R), CCl-779, and ABT578. The term "anti-neoplastic anti-metabolites" includes, but is not limited to, 5-fluorouracil, tegafur, capecitabine, cladribine, cytarabine, fludarabine phosphate, fluorouridine, gemcitabine, 6-mercapto-purine, hydroxy urea, methotrexate, edatrexate, and the salts of these compounds, and in addition ZD 1 694 (RALTITREXEDM R), LY231514 (ALIMTA R), LY264618 (LOMOTREXOL R), and OGT719. The term "platinum compounds," as used herein, includes, but is not limited to, carboplatin, cs-platin, and oxaliplatin. Carboplatin can be administered, for example, in the form as it is traded, for example under the registered trademark CARBOPLAT ™. Oxaliplatin can be administered, for example, in the form as it is traded, for example under the registered trademark ELOXATI NMR. The term "compounds that decrease the activity of the protein kinase and other anti-angiogenic compounds", as used herein, includes, but is not limited to, compounds that decrease the activity of, for example, the Vascular Endothelial Growth (VEGF), Epidermal Growth Factor (EGF), c-Src, protein kinase C, platelet-derived growth factor (PDGF), tyrosine kinase Bcr-Abl, c-kit, Flt -3, and the Insulin Type I Growth Factor Receptor (IGF-IR), and the cyclin-dependent kinases (CDKs), and the anti-angiogenic compounds that have another mechanism of action different from decreasing the activity of the kinase of protein. Compounds that decrease endothelial vascular growth factor activity are especially compounds that inhibit vascular endothelial growth factor receptor, especially the activity of vascular endothelial growth factor receptor tyrosine kinase, and compounds that are link to the vascular endothelial growth factor, and are in particular the compounds, proteins, and generic monoclonal antibodies and specifically disclosed in Patent Numbers WO 98/35958 (which describes the compounds of the formula I), WO 00/09495, WO 00/27820, WO 00/59509, WO 98/11223, WO 00/27819, WO 01/55114, WO 01/58899, and EP 0,769,947; those described by M. Prewett et al. in Cancer Research 5_9 (1999) 5209-5218, by F. Yuan et al in Proc. Nati Acad. Sci. USA, Volume 93, pages 14765-14770, December 1996, by Z. Zhu et al. In Cancer Res.58, 1998, 3209-3214, and by J. Mordenti et al. In Toxicologic Pathology, Volume 27, Number 1 , pages 14-21, 1999; in International Publications Nos. WO 00/37502 and WO 94/10202; Angiostatin ™, described by M .. S. O'Reilly et al., Cell 79, 1994, 315-328; and EndostatinIUR, described by M. S. O'Reilly et al., Cell 88, 1977, 277-285; the compounds that decrease the epidermal growth factor activity are in particular the compounds that inhibit the epidermal growth factor receptor, especially the tyrosine kinase activity of the epidermal growth factor receptor, and the compounds that bind to the epidermal growth factor receptor. the epidermal growth factor, and are in particular the generic compounds and specifically disclosed in Patent Numbers WO 97/02266 (which describes the compounds of the formula IV), EP 0,564,409, WO 99/03854, EP 0520722, EP 0,566,226 , EP 0 787,722, EP 0,837,063, WO 98/10767, WO 97/30034, WO 97/49688, WO 97/38983, and in particular WO 96/33980; Compounds that decrease the activity of c-Src include, but are not limited to, compounds that inhibit the activity of protein tyrosine c-Src kinase, as defined below, and inhibitors of interaction with SH2, such such as those disclosed in International Publications Nos. WO 97/07131 and WO 97/08193; compounds that inhibit the tyrosine c-Src protein kinase activity include, but are not limited to, compounds belonging to the structural classes of the pyrrolo-pyrimidines, especially pyrrolo- [2,3-d] - pyrimidines, purines, pyrazo-pyrimidines, especially pyrazo- [3,4-d] -pipmidines, pyrazo-pyrimidines, especially pyrazo- [3,4-d] -pyrimidines, and pyrido-pyrimidines, especially pyrido- [ 2,3-d] -pyrimidines. Preferably, the term refers to the compounds disclosed in International Publications Nos. WO 96/10028, WO 97/28161, WO 97/32879, and WO 97/49706; the compounds that decrease the activity of protein kinase C are in particular the staurosporine derivatives disclosed in European Patent Number EP 0,296,110 (the pharmaceutical preparation is described in International Publication Number WO 00/48571), whose compounds they are inhibitors of protein kinase C; other specific compounds that decrease the activity of the protein kinase and that can also be used in combination with the compounds of the present invention are Imatinib (Gleevec® / Glivec®), midostaurin, lressawl® (ZD1839), PKI166, Vatalanib, ZD6474, GW2016, CHIR-200131, CEP-7055 / CEP5214, CP-547632 and KRN-633; Anti-angiogenic compounds that have another mechanism of action other than decreasing protein kinase activity include, but are not limited to, for example, thalidomide (THALOMID), celecoxib (Celebrex), SU5416 and ZD6126. The term "gonadorelin agonist", as used herein, includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin is disclosed in US Pat. No. 4,100,274, and may be administered, for example, in the form as it is traded, for example under the registered trademark ZOLADEX ™. Abarelix can be formulated, for example, as disclosed in U.S. Patent No. 4,843,901. The term "anti-androgen", as used herein, includes, but is not limited to, bicalutam ida (CAS OR DEXM R), which may be formulated, for example, as disclosed in Patent of the United States of North America Number US 4,636,505. The term "bengamides" refers to bengamides and their derivatives that have anti-proliferative properties. The term "bisphosphonates", as used herein, includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. The "etridonic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark DI DRON ELM R. The "clodronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark BONEFOSM R. The "tiludronic acid" can be administered, for example, in the way it is traded, for example under the registered trademark SKELIDM R. The "pamidronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark AREDIAMR. The "alendronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark FOSAMAXM R. The "ibandronic acid" can be administered, for example in the form as it is traded, for example under the registered trademark B ON DRANATM R. The "risedronic acid" can be administered, for example, in the form in which it is traded, for example under the registered trademark ACTONELMR. The "zoledronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark ZOMETA R. The term "anti-proliferative antibodies", as used herein, includes, but is not limits to, trastuzumab (Herceptin ™), Trastuzumab-DM t, erlotinib (Tarceva® R), bevacizumab (Avastin® R), rituximab (Rituxan®), PR064553 (anti-CD40), and the 2C4 antibody. For the treatment of acute myeloid leukemia (AML), the compounds of the formula I can be used in combination with conventional therapies for leukemia, especially in combination with the therapies employed for the treatment of acute myeloid leukemia. In particular, the compounds of the formula I can be administered in combination, for example, with the farnesyl transferase inhibitors and / or other drugs useful for the treatment of acute myeloid leukemia, such as Daunorubicin, Adriamycin, Ara-C, VP -1,6, Teniposide, Mitoxantrone, Idarubicin, Carboplatin, and midostaurin. The structure of the active agents identified by code numbers, generic or commercial names, can be taken from the current edition of the standard compendium "The Merck I ndex", or from the databases, for example Patents International (for example, IMS World Publications). The above-mentioned compounds, which can be used in combination with a compound of the formula I, can be prepared and administered as described in the art, such as in the documents cited above. When the compounds of the formula I are administered, in conjunction with another immunosuppressive / immunomodulatory, anti-inflammatory, anti-proliferative, anti-infection, anti-viral, or chemotherapeutic therapy, the dosages of the immunosuppressant, immunomodulatory, anti-inflammatory compound , anti-proliferative, anti-infective, anti-viral, or chemotherapeutic co-administered, of course, will vary depending on the type of co-drug used, for example whether it is a steroid or a calcineurin inhibitor, the specific drug employed, the condition what is being treated, etc. In accordance with the foregoing, the present invention provides, in a still further aspect: A method as defined above, which comprises the co-administration, for example in a concomitant or sequential manner, of a non-toxic amount and Therapeutically effective of a compound of the formula I, and a second drug substance, for example an immunosuppressive, immunomodulatory, anti-inflammatory, anti-proliferative, anti-neoplastic, anti-infectious, anti-viral, antibiotic, or chemotherapeutic drug, for example as indicated above. 6. A pharmaceutical combination, for example a therapeutic kit, which comprises: a) a first agent that is a CSCR4 antagonist, for example a compound of formula I as disclosed herein, in free form or pharmaceutically acceptable salt form, and b) at least one co-agent, for example an immunosuppressant, immunomodulatory, anti-inflammatory, anti-proliferative, anti-infectious, or chemotherapeutic drug. The therapeutic kit may comprise instructions for its administration. The terms "co-administration" or "combined administration" or similar, as used herein, are intended to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens wherein the agents are not necessarily administered by the same route of administration or at the same time. The term "pharmaceutical combination", as used herein, means a product resulting from the mixture or combination of more than one active ingredient, and includes both the fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, for example a compound of the formula I and a co-agent, for example a viral agent, are both administered to a patient in a simultaneous manner in the form of a single entity. or dosage. The term "non-fixed combination" means that the active ingredients, for example a compound of the formula I and a co-agent, for example a viral agent, are both administered to a patient as separate entities either simultaneously, concurrently or in combination. sequence without specific time limits, wherein this administration provides therapeutically effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, for example the administration of three or more active ingredients.

Claims (11)

1 . A compound of the formula I: where: Ri is a residue of formula (a), (b), or (c): (a) () (c) R2 is - (CR22R23)? - 3- or -C (O) -; each of R3 and R8 is independently S; OR; or NR2; each of R and R5 is independently cycloalkyl of 3 to 1 2 carbon atoms optionally substituted by R25, alkyl of 1 to 12 carbon atoms, or a polycyclic residue of 8 to 12 carbon atoms saturated; or aryl optionally substituted by R26 and / or R27, aryl-alkyl of 1 to 4 carbon atoms, or heteroaryl; wherein up to 4 carbon atoms of R4 and / or R5 are optionally substituted by S, O, or NR24; R6 is H; alkyl of 1 to 6 carbon atoms; cycloalkyl of 3 to 6 carbon atoms; or aryl optionally substituted by R26 and / or R27, aryl-alkyl of 1 to 4 carbon atoms, or heteroaryl; R7 is CR28 or N; . R9 is a direct link; - (CR22R23)? 2-; or N R24; each of R? 0-23 and 2ß is independently H; F; Cl; Br; alkyl of 1 to 6 carbon atoms; alkoxy of 2 to 6 carbon atoms-alkyl; haloalkyl of 1 to 6 carbon atoms; cycloalkyl of 3 to 6 carbon atoms; aryl optionally substituted by R26 and / or R27, or heteroaryl; WITH R29R30; COOR29; CN; NO2; or OR31; or two of R-? o-19, which are attached to the same carbon atom, together with the carbon atom to which they are attached, form a non-aromatic 3 to 7 membered ring that optionally contains up to two heteroatoms independently selected from N, O , and S; or R17 and R1, together with the carbon atoms with which they are attached, form a non-aromatic 4- to 7-membered ring optionally containing up to two heteroatoms independently selected from N, O, and S; or R20 and R2? , together with the carbon atoms with which they are attached, form an aryl optionally substituted by R26 and / or R27, or heteroaryl; each of R24, R29, and R30 is independently H; alkyl of 1 to 6 carbon atoms, alkoxy of 2 to 6 carbon atoms-alkyl; haloalkyl of 1 to 6 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; or aryl optionally substituted by R2e and / or R27, aryl-alkyl of 1 to 4 carbon atoms, or heteroaryl; R25 represents from 1 to 4 substituents, each independently having one of the meanings given for R? O-23 above; R26 represents from 1 to 4 substituents, each independently selected from alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 1 to 6 carbon atoms; alkoxy of 2 to 6 carbon atoms-alkyl; haloalkyl of 1 to 6 carbon atoms; cycloalkyl of 3 to 6 carbon atoms; alkenyl of 2 to 6 carbon atoms; cycloalkenyl of 3 to 6 carbon atoms; alkynyl of 2 to 6 carbon atoms; aril; heteroaryl; Heteroaryl N-oxide; F; Cl; Br; I; OH; OR4; CONH2; CONHR4; CONR4R4; OC (0) R4; OC (0) OR4; OC (0) NHR4; OC (0) NR4R4; OS02R4; COOH; COOR4; CF3; CHF2; CH2F; CN; N02; NH2; NHR4; NR4R4; NHC (0) R4; NR4C (0) R4; NHC (0) NHR4; NHC (0) NH2; NR4C (0) NHR4; NR4C (0) NR4R4; NHC (0) OR4; NR4C (0) OR4; NHS02R4; N (S02R4) 2; NR4S02R4; SR4; S (0) R4; S02R4; Yes (CH3) 3, and B (OC (CH3) 2) 2; R27 represents two adjacent substituents that form a non-aromatic 4-7 membered null ring optionally containing up to two heteroatoms independently selected from N, O, and S; R3? it is alkyl of 1 to 6 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; aryl optionally substituted by R26 and / or R27, aryl-alkyl of 1 to 4 carbon atoms, or heteroaryl; or CF3; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, which is selected from 1,3-dicyclo-hexyl-2- (5,6-dihydro-imydazo [2,1- b] thiazol-3-ylmethyl) ) -isothiourea, 1-cyclohexyl-3-cyclopentyl-2- (5,6-dihydro-imidazo [2,1-b] thiazol-3-ylmethyl) -isothiourea, 1 -cyclohexate til-3-cyclohexyl-2- (5,6-dihydro-lmidazo [2,1-b] thiazol-3-ylmethyl) -isothiourea, 1,3-dicyclo-heptyl-2- (5,6-dihydro) -imidazo [2, 1-b] thiazol-3-ylmethyl) -isothiourea, 1-cyclohexyl-3-cyclo-octyl-2- (5,6-dihydro-imidazo [2,1- b] thiazol-3-ylmethyl) - isothiourea, 1,3-dicyclohexyl-2- (6,6-dimethyl-5,6-dihydro-imidazo [2,1-b] thiazol-3-ylmethyl) -isothiourea, 1,3-dicyclo- octyl-2- (5,6-dihydro-imidazo [2,1-b] thiazol-3-ylmethyl) -sothiourea, and 1,3-di-cycloheptyl-2- (6,6-dimethyl-5,6- dihydro-imydazo [2,1-b] thiazol-3-ylmethyl) -is? thiourea.

3. A pharmaceutical composition, which comprises a compound according to claim 1, in free form or in a pharmaceutically acceptable salt form, in association with a pharmaceutically acceptable diluent or carrier therefor.

4. The use of a compound as claimed in claim 1, in free form or in a pharmaceutically acceptable salt form, for the manufacture of a medicament for preventing or treating disorders or diseases mediated by the interactions between the receptors of chemokine, rejection of chronic acute transplantation, inflammatory diseases, autoimmune diseases, or proliferative diseases.

5. The use of a compound as claimed in claim 1, in free form or in a pharmaceutically acceptable salt form, for the manufacture of a medicament for preventing or inhibiting tumor invasiveness, symptoms associated with tumor growth, metastatic spread of tumors, angiogenesis associated with tumor, or growth of micrometastasis.

6. The use of a compound as claimed in claim 1 or claim 2,. or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for preventing or combating infectious diseases, in particular viral infections or progress of AIDS.

7. A process for the preparation of a compound of the formula I, which comprises reacting a compound of the formula II: with a compound of the formula lll: wherein R1-6 are as defined in claim 1, and R32 is a leaving group; and optionally converting a resulting compound of formula I obtained in free form to a salt form, or vice versa.

8. A pharmaceutical combination, which comprises a compound according to claim 1 or claim. 2, in free form or in a pharmaceutically acceptable salt form, and an additional agent selected from immunosuppressive, immunomodulatory, anti-inflammatory, anti-proliferative, anti-neoplastic, chemotherapeutic, anti-infectious, anti-viral agents, and antibiotics, and agents for the treatment of acute myeloid leukemia.

9. A combination according to claim 8, which comprises an anti-retroviral agent, in particular an anti-HIV agent. The use of a combination according to claim 9, for the manufacture of a medicament for preventing or combating an infectious disease, in particular a viral infection or the progress of AIDS. 11. A method for the treatment or prevention of any of the following conditions: i) disorders or diseases mediated by interactions between chemokine receptors, i) rejection of acute or chronic transplants, ii) inflammatory or autoimmune diseases, V) proliferative diseases, v) symptoms associated with tumor invasiveness or tumor growth, vi) metastatic tumor extensions, angiogenesis associated with tumor, and growths of micrometastases, v) infectious diseases, in particular viral infections, in particular viral or HIV virus entry, or progression of AIDS, which comprises administering to this subject a therapeutically effective amount of a compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of according to claim 3. RESU MEN The present invention relates to isothiourea derivatives, to processes for their production, to their uses, in particular in transplantation, autoimmune or infectious diseases, and pharmaceutical compositions containing them. * * * * *