MXPA06008295A - Combination of organic compounds - Google Patents

Abstract

The invention relates to a combination, such as a combined preparation or pharmaceutical composition, respectively, comprising the renin inhibitor of formula (I) or a pharmaceutically acceptable salt thereof and at least one PDGF receptor tyrosine kinase inhibitor.

Description

COMBINATION OF ORGANIC COMPOUNDS The invention relates to a combination, such as a combined preparation or a pharmaceutical composition, respectively, which comprises a renin inhibitor or a pharmaceutically acceptable salt thereof, and at least one tyrosine kinase inhibitor of the derived growth factor. of platelets, preferably N-. { 5- [4- (4-methyl-pi perazi non-methyl) -benzoi I-a mido] -2-methylene-f eni l} -4- (3-pyridyl) -2-pyrimidine-amine, or a pharmaceutically acceptable salt thereof. Accordingly, in a first aspect, the present invention relates to a combination, such as a combined preparation or a pharmaceutical composition, respectively, which comprises, as active ingredients: (i) a renin inhibitor or a pharmaceutically acceptable salt of the same; and (ii) at least one tyrosine kinase inhibitor that receives the platelet-derived growth factor, or a pharmaceutically acceptable salt thereof. The class of renin inhibitors comprises compounds that have different structural characteristics. For example, mention may be made of the compounds that are selected from the group consisting of ditequirene (chemical name: [1 S- [1 R *, 2R *, 4R * (1 R *, 2R *)]] - 1 - [(1,1-dimethyl-ethoxy) -carbonyl] -L-prolyl-L-phenyl-alanyl-N- [2-hydroxy-5-methyl-1- (2-methyl-propyl) -4- [ [[2-methyl-1 - [[(2-pyridyl-methyl) -amino] -carbonyl] -butyl] -amino] -carbonyl] -hexyl] -N-alpha-methyl-Lh! n- amide); Terlaquirene (chemical name: [R- (R *, S *)] - N- (4-morpholinyl-carbonyl) - L-phen I-alan il-N- [1 - (cyclohexyl-methyl) -2-h id roxy-3- (1-methyl-ethoxy) -3-oxopropyl] - S-methyl-L-cysteinamide); zanquirene (chemical name: [1 S- [1 R * [R * (R *)], 2S *, 3R *]] - N- [1- (cyclohexyl-methyl) -2,3-dihydroxy-5- methyl-hexyl] - alpha - [[2 - [[(4-methyl-1-piperazinyl) -sulfonyl] -methyl] -1 -oxo-3-phenyl-propyl-amino] -4-thiazole-propanamide), in special its hydrochloride; RO 66-1 132 and RO-66-1 168, respectively, of Formulas (A) and (B): The compound of the formula (I) is especially preferred: chemically defined as 2 (S), 4 (S), 5 (S), 7 (S) -N- (3-amino-2,2-dimethyl-3-oxopropyl) -2,7-di- ( 1-methyl-ethyl) -4-hydroxy-5-amino-8- [4-methoxy-3- (3-methoxy-propoxy) -phenyl] -octanamide (hereinafter: "aliskyrene" [International Unregistered Name ]), which is released from a specific way in European Patent Number EP 678503 A. The hemi-fumarate salt thereof is especially preferred. The term "at least one" will mean that, in addition to the renin inhibitor, one or more, for example two, and further three, active ingredients, as specified in accordance with the present invention, may be combined. The tyrosine kinase inhibitors of platelet-derived growth factor-used according to the present invention are preferably selected from the group comprising the following compounds: 4- (4-methyl-piperazin-1-ylmethyl) -N - [4-methyl-3- (4-pyridin-3-yl) -pyrimidin-2-ylamino) -phenyl] -benzamide, 4-methyl-N- [3- (4-methyl-imidazol-1 - il) -5-trifluoro-methyl-phenyl] -3- (4-pyridin-3-yl-pyrimidin-2-ylamino) -benzamide, an inhibitor of the isoforms of the factor receptor of platelet-derived growth, compounds as described in Mahboobi S. et al., J. Med. Chem. 2002, 45: 1002-1018, and incorporated herein by reference; the platelet-derived growth factor receptor-binding kinase blocker AG 1295, which has CAS Number 71897-07-9; AG1295 / 96 as described by Kovalenko M. et al., Cancer Res. 1994, 54: 6106-61 14 and Ludewig D. et al., Cell Tissue Res. 2000, 299: 97-103, and incorporated herein by reference; CT52923 (4- (6,7-dimethoxy-4-quinazolinyl) -N- (3,4-methylenedioxy-benzyl) -1-piperazine-thiocarboxamide); RP-1776; GFB-1 1 1; pyrrolo- [3,4-c] -beta-carboline-diones, SU 102 (developed by SUGEN); AG1296 having the CAS Number 146535-1 1 -7; RPR10151 1 A developed by Aventis Pharma; CDP 860 and Zvegf3 developed by ZymoGenetics; CP 673451 and PD 170262 from Pfizer; Kl 6783, which has CAS Number 190726-45-5, a platelet-derived growth factor receptor inhibitor developed by Kirin Brewery, Japan; KN 1022 developed by Kyowa Hakko in Japan and by Millenium Pharmaceuticals in the United States; AG 13736 developed by Pfizer; CH I R 258 developed by Chiron Corporation; M LN 518 from Millenium Pharmaceuticals and SU 1 1248 from SUGEN-Pfizer; Leflunomide; or pharmaceutically acceptable salts thereof. CT52923 has been described by Matsuno K. et al., "Synthesis and structure activity of PDGF receptor phosphorylation inhibitor-1", at the 18th Symposium on Medicinal Chemistry; November 25-27, 1998; Kyoto, Japan, Pharmaceutical Society of Japan, Division of Medicinal Chemistry, Tokyo, Japan: Extract 2-P-05. RP-1776, a cyclic peptide, was isolated from the culture broth of Streptomyces sp. KY1 1784. It is described, for example, by Toki S. Agatsuma T. et al., J. Antibiot. (Tokyo) May 2001; 54 (5): 405-14. GFB-1 1 1 is described, for example, in Blaskovich M. A. et al., Nat. Biotechnol. October 2000; 18 (1 0): 1065-70, and in Delarue F. et al., 91st Annual Meeting of the American Association for Cancer Research, 41: 458, 2000. Pyrrolo- [3,4-c] -beta-carboline-diones are described, for example, by Teller S. Eur. J. Med. Chem. April-2000; 35 (4): 413-27. CDP 860 is a fragment of pegylated antibody derived to from anti-platelet-derived growth factor receptor-beta antibody. PD 170262 or 2- [4- (2-diethyl-amino-ethoxy) -phenyl-amino] -8-methyl-6- (3-thienyl) -pyrido- [2,3-d] -pyrimidin-7 ( 8H) -one, is a potent inhibitor of tyrosine kinase with selectivity for the tyrosine kinase of platelet-derived growth factor. The synthesis and inhibitory activity of tyrosine kinase of a series of 2-amino-8H-pyrido- [2,3-d] -pyrimidines are described, for example, in Klutchko S. et al., 213th American Chemical Society National meeting : abstr. MEDÍ 201 (poster), 1997, USA. Kl 6783 or 4- (3,4-dimethoxy-phenoxy) -6,7-dimethoxy-quinoline is described, for example, in Kubo K. et al., Bioorganic and Medicinal Chemistry Letters 7: 2935-2940, 1997 and Yagi M. et al., Exp. Cell Research 234: 285-92, 1997. KN 1 022 or 6,7-dimethoxy-4- [4- (4-nitro-phenyl) -amino-carbonyl-piperazin-1-yl. ] -quinazoline, which inhibits phosphorylation of the platelet-derived growth factor receptor, is described, for example, in 217th American Chemical Society National meeting abstr. MEDÍ 061, Part 1, 1999, Japan. AG 013736 or N-methyl-2- [3- [2- (2-pyridyl) -vinyl] -1 H -ndazol-6-ylsulfanyl] -benzamide is disclosed, for example, in Heller et al. Pharmacological activities of AG 013736, a small molecule inhibitor of VEGF / PDGFR tyrosine kinases, 93rd Annual Meeting of the American Association for Cancer research 43: 1082, 2002, USA. CHIR 258 is a growth factor kinase inhibitor of orally active amino-benzimidazole-quinoline that demonstrated a spectrum of inhibitory activity against receptor tyrosine kinases, for example from the family of platelet-derived growth factor receptors. CHIR 258 is disclosed, for example, in Steigewalt R. et al. And in Lee S. H. et al., At the 94th Annual Meeting of the American Association for Cancer Research 753 (more poster) abstr. 3783 and 934 (more poster) abstr. R4702, respectively, 2003, USA. SU 1 1248 or 5- [3-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidene-methyl] -2- diethyl-amino) -amine dimethyl-1 H-pyrrol-3-carboxylic acid, is a multi-target kinase inhibitor with selectivity, for example, for the platelet-derived growth factor receptor. SU 1 1248 is disclosed, for example, in Xin L. et al., 93rd Annual Meeting of the American Association for Cancer Research 43: 1081 (more poster), 2002, USA. M NL 51 8 is a piperazinyl derivative of quinazoline of the Formula 4- [4- (N-para-iso-propoxy-phenyl-carbamoyl) -1-piperazinyl] -6-methoxy-7- (piperidino-propyloxy) -quinazoline, which inhibits, for example, the phosphorylation of the platelet-derived growth factor in the binding assays, and is described, for example, by Stone RM et al., Blood 102: 65-66, 2003, Kelly LM et al., Cancer Cell 1: 421-23, 2002. leflunomide (SU 101) or 4-oxazole-carboxamide, 5-methyl-N- [4- (trifluoromethyl) -phenyl] is an inhibitor of tyrosine kinase. Preferred platelet derived growth factor-receptor tyrosine kinase inhibitors are N-phenyl derivatives. 2-pyrimidine-amine of Formula I I: as described in Patent Applications Numbers EP 0,564,409 A1 and WO 99/03854, incorporated in the present application by reference. Preference is especially given especially to the compound of Formula (I I), which is CGP 57148B. { N- [5- [4- (4-methyl-piperazino-methyl) -benzoyl-amido] -2-methyl-phenyl} -4- (3-pyridyl) -2-pyrimidine-amine} . CGP 57148B (hereinafter: "Imatinib" [Non-Registered International Name]), and the use thereof, especially as an anti-tumor agent, are described in Example 21 of the European Patent Application Number EP -A-0,564,409, which was published on October 6, 1993, and in the equivalent applications and patents in numerous other countries, for example in U.S. Patent Number 5,521, 184, and in Japanese Patent Number 2706682. Another preference is given to the β-crystal form of the methanesulfonate of 4- (4-methyl-piperazin-1-methylmethyl) -N- [4-methyl-3- (4-pyridin-3-yl) -p Rimidin-2-ylamino) -phenyl] -benzamide, as described in European Patent Application Number 998,473, published May 10, 2000. The term "4- (4-methyl-piperazin-1-ylmethyl)" ) -N- [4-methyl-3- (4-pyridin-3-yl) -pyrimidin-2-yl-amino) -phenyl] -benzamide "includes all forms of crystal, especially the crystal form -β, as described in European Patent Application Number 998,473. Most preferably, an N-phenyl-2-pyrimidine-amine derivative of the Formula (I I) is used, in the form of its monomesylate salt. The compounds of Formula II are disclosed in a generic and specific manner in Patent Applications Nos. EP 0 564 409 A1 and WO 99/03854, in particular in the claims of compounds and in the final products of the processing examples, and the subject matter of the final products, pharmaceutical preparations, and claims is incorporated in the present application by reference to these publications. In the same way, the corresponding stereoisomers are included, as well as the corresponding polymorphs, for example the crystal modifications, which are disclosed therein. In European Patent Number EP 0,564,409 A1, the compounds I I are described as useful for the therapy of cancer, thrombosis, psoriasis, fibrosis, dermatosclerosis, and atherosclerosis. For the purposes of isolation or purification, as well as in the case of compounds that are used additionally as intermediates, it is also possible to use pharmaceutically unacceptable salts. However, for therapeutic purposes, only pharmaceutically acceptable non-toxic salts are used, and therefore, these salts are preferred. Other suitable tyrosine kinase inhibitors of platelet derived growth factor are disclosed in the International Publication Number WO 98/35958, especially the compound of Example 62, and in U.S. Patent No. US 5,093,330, in each particular case in the claims of the compound and in the final products of the examples of processing, whose subject matter is incorporated in the present application by reference to these publications. Other preferred compounds are described in Patent Application Number WO 04/005281, especially in the examples, more preferably the compound of Example 92 of the Formula: which is also known as 4-methyl-N- [3- (4-methyl-imidazol-1-yl) -5-trifluoromethyl-phenyl] -3- (4-pyridin-3-yl-pyrimidin-2) -ylamino) -benzamide. Preferred platelet derived growth factor receptor tyrosine kinase inhibitors are selected from 4- (4-methyl-piperazin-1-ylmethyl) -N- [4-methyl-3- (4-pyridin-3-) il) -pyridin-2-ylamino) -phenyl] -benzamide (imatinib), 4- (4-methyl-piperazin-1-ylmethyl) -N- [4-methyl-3- ( 4-pyridin-3-yl) -pyrimidin-2-ylamino) -phenyl] -benzamide, 4-methyl-N- [3- (4-methyl-imidazol-1-yl) -5- trifluoro-methyl-phenyl] -3- (4-pyridin-3-yl-pyrimidin-2-ylamino) -benzamide, CT52923 (4- (6,7-dimethoxy-4-quinazolinyl) - N- (3,4-methylenedioxy-benzyl) -1-piperazine-thiocarboxamide), RP-1776, GFB-1 1 1, pyrrolo- [3,4-c] -beta-carboline-diones, SU 102 (developed by SUGEN), AG 1296 (CAS number 146535-1 1 -7), AG 1296 (CAS number 71897-07-9), and RPR10151 1A, or in each case, a pharmaceutically acceptable salt thereof. In each case, where appropriate, for example, if the compound is not present as a pharmaceutically acceptable salt by itself, in the case of hydrochlorothiazide, these compounds also include their pharmaceutically acceptable salts. The corresponding active ingredients, or the pharmaceutically acceptable salts thereof, may also be used in the form of a solvate, such as a hydrate, or including other solvents, used for crystallization. The most preferred platelet-derived growth factor receptor tyrosine kinase inhibitors are N-. { 5- [4- (4-methyl-piperazino-methyl) -benzoyl-amido] -2-methyl-phenyl) -4- (3-pyridyl) -2-pyrimidine-amine (imatinib), and 4-methyl -N- [3- (4-methyl-imidazol-1 -yl) -5-trifluoromethyl-phenyl] -3- (4-pyridin-3-yl-pyrimidin-2-ylamino) -benzamide, or in each in the case of a pharmaceutically acceptable salt thereof, such as the mono-hydrochloride. Combinations, such as combined preparations or pharmaceutical compositions, respectively, comprising a DPP-IV inhibitor, preferably LAF237, or a pharmaceutically acceptable salt thereof, and, as the second active agent, a selected active agent are preferred. from the group consisting of 4- (4-methyl-piperazin-1-methylmethyl) -N- [4-methyl-3- (4-pyridin-3-yl) -pyridin-2-ylammon) -phenyl] -benzam ida (imatinib), 4- (4-methyl-piperazin-1-ylmethyl) -N- [4-methyl-3- (4-pyridin-3-yl) -pyrimidin-2-ylamino) -phenyl] - methanesulfonate benzamide, CT529.23 (4- (6,7-dimethoxy-4-quinazolinyl) -N- (3,4-methylenedioxy-benzyl) -1- pi perazi n-thiocarboxamido), 4-methyl-N- [3 - (4-methyl-imidazol-1-l) -5-trifluoromethyl-phenyl] -3- (4-pyridin-3-yl-pyrimidin-2-ylamino) -benzamide, RP-1776, GFB-1 1 1, pyrrolo- [3,4-c] -beta-carboline-diones, SU 102 (developed by S UGEN), AG 1296 (CAS number 146535-1 1 -7), AG 1296 (CAS number 71897-07- 9), and RPR10151 1A, or in each case, a pharmaceutically acceptable salt thereof. The corresponding active ingredients, or a pharmaceutically acceptable salt thereof, can also be used in the form of a solvate, such as a hydrate, or including other solvents, used for crystallization. The compounds to be combined may be present as pharmaceutically acceptable salts. If these compounds have, for example, at least one basic center, they can form acid addition salts. If desired, the corresponding acid addition salts having a basic center additionally present can also be formed. Compounds having an acidic group (e.g., COOH) can also form salts with bases. All these traded products can be used as such for the combination therapy according to the present invention. The structure of the active agents identified by names generic or commercial, can be taken from the current edition of the standard compendium "The Merck Index", or databases, for example Patents International (for example, I MS World Publications). The corresponding content thereof is incorporated herein by reference. The subject matter of the aforementioned references, especially the compounds specifically described, for example in the claims or in the examples, are incorporated by reference in this specification. Any person skilled in the art is absolutely qualified to identify the active agents, and, based on these references, in the same way is able to manufacture and test the pharmaceutical indications and the properties in conventional test models, both in vitro and in vivo. . A preferred tyrosine kinase inhibitor of the preferred platelet-derived growth factor is selected from N-. { 5- [4- (4-methyl-piperazin-methyl) -benzoyl-amido] -2-methyl-phenyl} -4- (3-pyridyl) -2-pyrimidine-amine (imatinib), and 4-methyl-N- [3- (4-methyl-imidazol-1-yl) -5-trifluoromethyl-phenyl] -3 - (4-pyridin-3-yl-pyrimidin-2-ylammon) -benzamide, or in each case a pharmaceutically acceptable salt thereof, such as the mono-hydrochloride. A preferred renin inhibitor is 2 (S), 4 (S), 5 (S), 7 (S) -N- (3-amino-2,2-dimethyl-3-oxopropyl) -2,7-di. - (1-methyl-ethyl) -4-hydroxy-5-amino-8- [4-methoxy-3- (3-methoxy-propoxy) -phenyl] -octanamide (alkykyrene), or a pharmaceutically acceptable salt thereof the same, such as a hemi-fumarate salt thereof.

Accordingly, the present invention preferably relates to a combination, such as a combined preparation or a pharmaceutical composition, respectively, which comprises, as active ingredients: (i) 2 (S), 4 (S), 5 (S) ), 7 (S) -N- (3-am ino-2,2-dimethyl-3-oxopropyl) -2,7-di- (1-methyl-ethyl) -4-hydroxy-5-amino-8- [4-methoxy-3- (3-methoxy-propoxy) -phenyl] -octanamide or a pharmaceutically acceptable salt thereof; and (i) an inhibitor of the tyrosine kinase receptor of the platelet-derived growth factor selected from N-. { 5- [4- (4-methyl-pi-perazi non-m-ethyl) -benzoyl-l-amido] -2-m-ethyl-phen-yl} -4- (3-pyridyl) -2-pyrimidine-amine and 4-methyl-N- [3- (4-methyl-imidazol-1-yl) -5-trifluoromethyl-phenyl] -3- (4- pyridin-3-yl-pyrimidin-2-ylamino) -benzamide, or in each case a pharmaceutically acceptable salt thereof. The corresponding active ingredients, or pharmaceutically acceptable salts thereof, may also be used in the form of a solvate, such as a hydrate, or including other solvents used for crystallization. The compounds to be combined may be present as pharmaceutically acceptable salts. If these compounds have, for example, at least one basic center, they can form acid addition salts. If desired, corresponding acid addition salts having a basic center additionally present can also be formed. Compounds that have an acid group (eg, COOH) can also form salts with bases. The pharmaceutical activities carried out through the administration of the renin inhibitor, especially the aliskirene of the Formula (I), or of the combination of the active agents used according to the present invention, can be demonstrated, for example, by the use of the corresponding pharmacological models known in the art. relevant technique. The person skilled in the relevant field is absolutely qualified to select a relevant animal test model to test the therapeutic indications and beneficial effects indicated hereinafter and later herein. In order to evaluate the anti-hypertensive activity of the combination according to the invention, for example, the methodology described by Lovenberg W: Animal models for hypertension research, Prog. Clin. Biol. Ras. 1987, 229, 225-240. For the evaluation that the combination according to the present invention can be used for the treatment of congestive heart failure, for example, the methods disclosed by Smith H.J. Nuthall A can be applied: Experimental models of heart failure. Cardiovasc. Res. 1985, 19, 181-186. Molecular approaches, such as transgenic methods, are also described, for example, in Luft et al: Hypertension-induced end-organ damage. "A new transgemic approach for an old problem" Hypertension 1999, 33, 212-218. The evaluation of the cardiovascular beneficial effects, especially in diabetes, of the agents given alone or in combination, can be carried out using models such as the Zucker fat rat, as described in the Nawano et al. Publication, Metabolism 48: 1248-1255, 1999. Also, studies using spontaneously hypertensive diabetic rats are described in Sato et al. Publication, Metabolism 45: 457-462, 1 996. The subject subject matter of these references is incorporated by reference into this descriptive memory. The combinations of the invention can also be determined by other test models known as such for the person skilled in the relevant field, or by clinical studies. The person skilled in the relevant art is absolutely qualified to select a relevant test model to test the therapeutic indications and the beneficial effects indicated herein (ie, good therapeutic margin, better therapeutic efficacy, no action on hypertension, and other benefits). For example, the pharmacological activity can be demonstrated in a clinical study or in the test procedure essentially as described hereinafter, in a manner known to the skilled person. According to the foregoing, the combination according to the present invention can be used, for example, for the prevention, delay of progress, or treatment of diseases or disorders that can be inhibited by renin inhibitors, especially of Formula (I), or that can be inhibited by tyrosine kinase inhibitors that receive platelet-derived growth factor. In particular, the combination according to the present invention can be used, for example, for the prevention, delay of progress, or treatment of diseases or disorders selected from the group consisting of cancer, thrombosis, psoriasis, fibrosis, dermatosclerosis, atherosclerosis, restenosis, cardiovascular hypertrophy or cardiovascular hypertrophic remodeling, or cardiovascular diseases induced by hypertension, cardiac hypertrophy, cardiac remodeling after myocardial infarction, pulmonary congestion and cardiac fibrosis in dilated or hypertrophic cardiomyopathy, left or right ventricular hypertrophy, diabetic myopathy, prevention of embolism in congestive heart failure, hypertrophic medial thickening in arteries and / or large vessels, vascular diseases induced by hypertension, hypertrophy of the mesenteric vasculature, renal hyperfiltration such as after portal renal ablation, proteinuria in chronic kidney disease, renal arteriopathy as a consequence of hypertension, nephrosclerosis or nephrosclerosis hypertensive, mesanglial hypertrophy, hypertension, congestive heart failure, diabetes, especially type 2 diabetes mellitus, diabetic retinopathy, macular degeneration, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, syndrome X, premenstrual syndrome, coronary heart disease, angina chest, myocardial infarction, embolism, vascular restenosis, macular degeneration, cataracts, premenstrual syndrome, skin and connective tissue disorders, endothelial dysfunction, and impaired vascular compliance. Cardiac, vascular or kidney hypertrophy, or hypertrophic remodeling, is characterized by an increase in the mass of the heart, arteries, large vessels, or kidney.

The combination of the invention is particularly useful for the treatment and / or prevention of injuries in relation to hypertension. Hypertension, a condition of high blood pressure, affects a substantial number of the human population. The consequences of persistent hypertension include vascular damage to the ocular, renal, cardiac, and cerebral systems, and the risk of these complications increases as blood pressure increases. The basic factors that control blood pressure are heart rate and peripheral vascular resistance, the latter being the predominant common mechanism that is controlled by different influences. Injuries related to hypertension, according to the invention, are preferably, but not limited to, heart failure, cardiac hypertrophy such as right or left ventricular hypertrophy (LVH), renal arteriopathy, and vascular diseases, for example thickening medial hypertrophic arteries and / or large vessels, hypertrophy of the mesenteric vasculature, restenosis, or atherosclerosis. Preferably, this combination can be used for the treatment of hypertension, especially ISH, congestive heart failure, endothelial dysfunction, impaired vascular compliance, vascular restenosis. Preferably, this combination can be used for the treatment of cardiovascular diseases induced by hypertension, or vascular diseases induced by hypertension. A "disease or condition that can be inhibited by the renin inhibitor of Formula (I)", as defined in this application, includes, but is not limited to, hypertension, congestive heart failure, diabetes, especially type 2 diabetes mellitus, diabetic retinopathy, macular degeneration, diabetic nephropathy, glomerulosclerosis, renal failure, especially chronic renal failure, diabetic neuropathy, syndrome X, syndrome premenstrual, coronary heart failure, angina pectoris, myocardial infarction, embolism, vascular restenosis, endothelial dysfunction, and the like. Hypertension, in connection with injuries related to hypertension, includes and is not limited to, mild hypertension, moderate, and severe, as defined in Journal of Hypertension 1999, 17: 151-183, especially on page 162. "Isolated systolic hypertension" (ISH) is especially preferred. Preferably, the therapeutically co-effective amounts of the active agents according to the combination of the present invention can be administered in a single or sequential manner in any order, for example separately or in a fixed combination. Under certain circumstances, drugs with different mechanisms of action can be combined. However, only considering any combination of drugs that have different modes of action, but that act in a similar field, does not necessarily lead to combinations with suitable effects. Most surprising is the experimental discovery that the combined administration of the renin inhibitor, preferably aliskiren, and at least one receptor tyrosine kinase inhibitor of the platelet derived growth factor, preferably imatinib, or in each case, a pharmaceutically acceptable form thereof, results not only in a beneficial, especially enhancing or synergistic therapeutic effect. Regardless of the same, additional benefits resulting from combined treatment can be achieved, such as a surprising prolongation of efficacy, a wider variety of therapeutic treatment, and surprising beneficial effects on the diseases and conditions associated with hypertension, for example fewer cardiovascular side effects. . A further and preferred aspect of the present invention is the prevention, delay of progress, or treatment of the condition of isolated systolic hypertension and impaired vascular compliance, which means a lower vascular elasticity. The term "potentiation" will mean an increase in the corresponding pharmacological activity or therapeutic effect, respectively. The enhancement of a component of the combination according to the present invention by the co-administration of another component according to the present invention means that an effect is being achieved that is greater than that achieved with a single component. The term "synergistic" will mean that the drugs, when taken together, produce a total joint effect that is greater than the sum of the effects of each drug when taken alone. Isolated systolic hypertension is the most common form of hypertension in people over 50 years of age. is defined as high systolic blood pressure (above 140 mmHg) in conjunction with normal diastolic blood pressure (below 90 mmHg). High systolic blood pressure is an independent risk factor for cardiovascular diseases, and can lead, for example, to myocardial hypertrophy and heart failure. Isolated systolic hypertension is further characterized by an increased pulse pressure, defined as the difference between systolic and diastolic blood pressures. High pulse pressure is being recognized as the type of hypertension with the least chance of controlling well. A reduction of the high systolic blood pressure and correspondingly of the pulse pressure, is associated with a significant risk reduction of cardiovascular death. Surprisingly, it has been found that the combination of the renin inhibitor of Formula (I) and a tyrosine kinase inhibitor of platelet-derived growth factor leads to a decrease in isolated systolic hypertension and pulse rate. , both in hypertensive patients with type 2 diabetes mellitus, and in hypertensive patients without type 2 diabetes mellitus. In addition, chronic co-administration of a tyrosine kinase inhibitor receptor of the derived growth factor has been found. of platelets imparts the beneficial effect on the morphology and function of the blood vessel, and results in a decrease in vascular rigidity, and, in a corresponding manner, maintenance and improvement of vascular compliance. It has also been found that chronic co-administration of a receptor tyrosine kinase inhibitor of the platelet-derived growth factor and a renin inhibitor, imparts the beneficial effect on morphology and cardiac function. In accordance with the foregoing, it has been found that the addition of a tyrosine kinase inhibitor receiving the platelet-derived growth factor to that of the renin inhibitors, preferably of Formula (I), would enhance the effect on the pressure systolic blood flow, and also improve vascular compliance / stiffness, and also reduce cardiovascular side effects. In an inverse manner, the proven anti-hypertensive effects of renin inhibitors on systolic and diastolic blood pressure, can be enhanced by the addition of a tyrosine kinase inhibitor that receives the platelet-derived growth factor. The benefit of these combinations can also be extended to an additional or enhanced effect on endothelial function, and vascular function and structure is improved in different organs / tissues, including the kidney, heart, eye, and brain. Through the use of this combination, an anti-thrombotic and anti-atherosclerotic effect can also be demonstrated. This effect is highly beneficial in causing an additive or synergistic effect on cardiovascular function / structure, when administered with the renin inhibitor of Formula (I), which only improves cardiovascular function and structure through a different mechanism. The combined administration of a renin inhibitor with a tyrosine kinase inhibitor that receives platelet-derived growth factor will cause additional anti-hypertensive effects, improve vascular dynamics in hypertensive patients to a greater extent. degree than after the administration of another given agent alone. Other benefits are that lower doses of the individual drugs to be combined according to the present invention can be used to reduce the dosage, for example, that dosages not only need to be often smaller, but also that they apply less frequently, or they can be used in order to decrease the incidence of side effects. This is in accordance with the wishes and requirements of the patients to be treated. For example, it has turned out that the combination according to the present invention provides benefits, especially in the treatment of modest hypertension or isolated systolic hypertension, which are beneficial for all diabetic patients, regardless of their state of hypertension, for example by reducing the risk of negative cardiovascular events through two different modes of action. Renin inhibitors, especially of Formula (I), have also proven useful in the treatment of type 2 diabetes mellitus beyond the reduction of blood pressure, for example, by improving microalbuminuria. In sub-therapeutic doses, with respect to the treatment of hypertension, the combination according to the invention can be used merely for the treatment of diabetes, especially diabetes mellitus type 2. In view of the reduced dose of the renin inhibitor of the Formula (I), there is a considerable safety profile of the combination, making it suitable for better therapy.

Therefore, the present invention further relates to: 1) A combination according to the present invention, to be used as a medicament. 2) The use of a renin inhibitor, preferably of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with at least one tyrosine kinase inhibitor of platelet-derived growth factor receptor, or a salt thereof. pharmaceutically acceptable thereof, or for the manufacture of a medicament for the prevention, delay of progress, or treatment of a disease and disorder selected from cancer, thrombosis, psoriasis, fibrosis, dermatosclerosis, atherosclerosis, restenosis, cardiovascular hypertrophy or hypertrophic remodeling cardiovascular disease, or cardiovascular diseases 5 induced by hypertension, cardiac hypertrophy, cardiac remodeling after myocardial infarction, pulmonary congestion and cardiac fibrosis in dilated or hypertrophic cardiomyopathy, left or right ventricular hypertrophy, diabetic myopathy, prevention of embolism in congestive heart failure, medial thickening hi pertrophic in the arteries and / or in the large vessels, vascular lesions induced by hypertension, hypertrophy of the mesenteric vasculature, renal hyperfiltration such as after portal renal ablation, proteinuria in chronic renal disease, renal arteriopathy as a consequence of hypertension, nephrosclerosis or hypertensive nephrosclerosis, mesanglial hypertrophy, hypertension, congestive heart failure, diabetes, especially type 2 diabetes mellitus, diabetic retinopathy, macular degeneration, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, myocardial infarction, embolism, vascular restenosis, macular degeneration, cataracts, premenstrual syndrome, skin and connective tissue disorders, endothelial dysfunction, and impaired vascular compliance. 3) A method for the prevention, delay of progress, or treatment of a disease and disorder selected from cancer, thrombosis, psoriasis, fibrosis, dermatosclerosis, atherosclerosis, restenosis, cardiovascular hypertrophy or cardiovascular hypertrophic remodeling, or cardiovascular diseases induced by hypertension, cardiac hypertrophy, cardiac remodeling after myocardial infarction, pulmonary congestion and cardiac fibrosis in dilated or hypertrophic cardiomyopathy, left or right ventricular hypertrophy, diabetic myopathy, prevention of embolism in congestive heart failure, hypertrophic medial thickening in the arteries and / or in large vessels, vascular lesions induced by hypertension, hypertrophy of the mesenteric vasculature, renal hyperfiltration such as after portal renal ablation, proteinuria in chronic kidney disease, renal arteriopathy as a consequence of hypertension, nephrosclerosis or hypertensive nephrosclerosis, mesanglial hypertrophy, hypertension, congestive heart failure, diabetes, especially diabetes mellitus type 2, diabetic retinopathy, macular degeneration, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, myocardial infarction, embolism, vascular restenosis, macular degeneration, cataracts, premenstrual syndrome, skin and connective tissue disorders, endothelial dysfunction , and impaired vascular compliance, which comprises administering to a warm-blooded animal, including man, in need thereof, therapeutically co-effective amounts of: (i) a renin inhibitor, preferably of Formula (I), or a pharmaceutically acceptable salt thereof; (ii) at least one tyrosine kinase inhibitor receiving the platelet-derived growth factor, or a pharmaceutically acceptable salt thereof. 4) A pharmaceutical composition for the prevention, delay of progress, or treatment of a disease or condition selected from the group consisting of cancer, thrombosis, psoriasis, fibrosis, dermatosclerosis, atherosclerosis, restenosis, cardiovascular hypertrophy or cardiovascular hypertrophic remodeling, or Cardiovascular diseases induced by hypertension, cardiac hypertrophy, cardiac remodeling after myocardial infarction, pulmonary congestion and cardiac fibrosis in dilated or hypertrophic cardiomyopathy, left or right ventricular hypertrophy, diabetic myopathy, prevention of embolism in congestive heart failure, hypertrophic medial thickening in arteries and / or large vessels, vascular lesions induced by hypertension, hypertension of the mesenteric vasculature, renal hyperfiltration such as after portal renal ablation, proteinuria in chronic kidney disease, renal arteriopathy as a consequence of hypertension, nephrosclerosis or hypertensive nephrosclerosis, mesanglial hypertrophy, hypertension, congestive heart failure, diabetes, especially diabetes mellitus type 2, diabetic retinopathy, macular degeneration, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, myocardial infarction, embolism, vascular restenosis, degeneration macular, cataracts, premenstrual syndrome, skin and connective tissue disorders, endothelial dysfunction, and impaired vascular compliance; which comprises, as active ingredients: (i) a renin inhibitor, preferably of Formula (I), or a pharmaceutically acceptable salt thereof; (ii) at least one tyrosine kinase inhibitor receiving the platelet-derived growth factor, or a pharmaceutically acceptable salt thereof; and at least one additional pharmaceutically acceptable vehicle.

The method or use as described above, wherein the renin inhibitor is administered in a simultaneous manner with the inhibitor of tyrosine kinase receptor growth factor platelet derivative, or in sequence over time with the tyrosine kinase inhibitor receptor for platelet-derived growth factor. The method or use as described above, wherein the renin inhibitor and the tyrosine kinase inhibitor receptor platelet-derived growth factor, are administered in the form of a combination of the present invention, such as a fixed combination or a combined preparation or a kit of parts. The method or use as described above, for the treatment and / or prevention of injuries in relation to hypertension. The method or use as described above, for the treatment and / or prevention of injuries in relation to hypertension, where the patient is suffering from hypertension, or in hypertensive patients having type 2 diabetes mellitus. The method or use as described in described above, for the treatment and / or prevention of heart failure, cardiac hypertrophy, such as hypertrophy of the right or left ventricle (LVH), renal arteriopathy, and vascular diseases, for example hypertrophic medial thickening in the arteries and / or large vessels, hypertrophy of the mesenteric vasculature, restenosis or atherosclerosis, where the patient is suffering from diabetes, preferably diabetes mellitus type 2. The pharmaceutical compositions according to the present invention, as described hereinabove and hereinafter, can be used for simultaneous use or use in sequence in any order, for separate use, or as a fixed combination. Combinations, such as combined preparations or pharmaceutical compositions, respectively, which comprise the renin inhibitor of Formula (I) or a pharmaceutically acceptable salt thereof, and, as the second active agent, an active agent are preferred. selected from the group consisting of imatinib, CT52923, RP-1776, GFB-1 1, pyrrolo- [3,4-c] -beta-carboline-diones, SU 102, AG 1296, AG 1296, and RPR10151 1 A. The pharmaceutical composition according to the present invention comprises a "kit of parts", in the sense that the components can be dosed independently, or by using different fixed combinations with distinguished amounts of the components at different points of the weather. The parts of the "case of parts", for example, can then be administered in a simultaneous or chronologically staggered manner, that is, at different points of time, and with equal or different time intervals for any part of the "parts case". " Preferably, the time intervals are selected in such a way that the effect on the disease or condition treated in the combined use of the parts is greater than the effect that would be obtained by using only any of the components. Preferably, there is at least one beneficial effect, for example a mutual improvement of the effect of: (i) a renin inhibitor, preferably of Formula (I), or a pharmaceutically acceptable salt thereof; (ii) at least one tyrosine kinase inhibitor receiving the platelet-derived growth factor, or a pharmaceutically acceptable salt thereof; in particular an enhancement or a synergism, for example an effect rather than additive, additional convenient effects, fewer side effects, a combined therapeutic effect in an ineffective dosage of one or each of the components, especially an enhancement or a strong synergism The invention further relates to a commercial package comprising the combination according to the present invention, together with instructions for simultaneous, separate, or sequential use. These pharmaceutical preparations are for enteral administration, such as orally, and also rectally or parenterally, to homeotherms, the preparations comprising the pharmacologically active compound either alone or together with the customary pharmaceutical auxiliaries. For example, the pharmaceutical preparations consist of from about 0.1 percent to 90 percent, preferably from about 1 percent to about 80 percent of the active compound. Pharmaceutical preparations for enteral or parenteral administration, and also ocular, are, for example, in unit dose forms, such as coated tablets, tablets, capsules, or suppositories, and also ampoules. These are prepared in a manner that is known per se, for example using conventional mixing, granulating, coating, solubilizing, or lyophilizing processes. Accordingly, pharmaceutical preparations for use Oral can be obtained by combining the active compound with solid excipients, if desired a mixture that has been obtained is granulated, and if required or necessary, the mixture or granulate is processed into tablets or cores of coated tablets after of having added the appropriate auxiliary substances. The dosage of the active compound may depend on a variety of factors, such as the mode of administration, the homeothermic species, the age, and / or the individual condition. Preferred dosages for the active ingredients of the pharmaceutical combination according to the present invention are therapeutically effective dosages, especially those which are commercially available. Usually, in the case of oral administration, an approximate daily dose of about 1 milligram to about 360 milligrams should be estimated, for example, for a patient weighing approximately 75 kilograms. The dosage of the active compound may depend on a variety of factors, such as the mode of administration, the homeothermic species, the age, and / or the individual condition. The renin inhibitor of Formula (I) will be supplied in the form of a suitable dosage unit, for example, a capsule or tablet, and comprising a therapeutically effective amount, for example, from about 10 to about 500 milligrams. of the renin inhibitor of Formula (I), which can be applied to patients. The corresponding doses can be taken, for example, in the tomorrow, at noon, or at night. Administration twice a day is preferred. The monomesylate of N-. { 5- [4- (4-methyl-piperazino-methyl) -benzoyl-amido] -2-methyl-phenyl} -4- (3-pyridyl) -2-pyrimidine-amine is preferably administered to a human in a dosage in the range of about 2.5 to 850 milligrams / day, more preferably 5 to 600 milligrams / day, and a very preferable way from 20 to 300 milligrams / day. Unless otherwise reported herein, the compound is preferably administered 1 to 4 times per day.

Galenic Formulation - Example 1: Film-Coated Tablets The following constituents are processed for the preparation of 1,000 tablets, each containing 1000 milligrams of active ingredient: Hemi-fumarate of the compound of Formula (I) 1,000 grams Corn starch 680 grams Colloidal silicic acid 200 grams Magnesium stearate 20 grams Stearic acid 50 grams Sodium carboxymethyl starch 250 grams Water Sufficient Amount A mixture of one of the compounds of Formula I mentioned in the previous examples as active ingredient, 50 grams of corn starch, and colloidal silicic acid, is processed to obtain a wet mass with the starch paste prepared from 250 grams of corn starch and 2.2 kilograms of demineralized water. The mass is forced through a sieve having a mesh size of 3 millimeters, and dried at 45 ° C for 30 minutes in a fluidized bed dryer. The dried granules are compressed through a sieve having a mesh size of 1 millimeter, mixed with a previously sieved mixture (1 millimeter sieve) of 330 grams of corn starch, magnesium stearate, stearic acid, and the sodium carboxymethyl starch, and compress to form slightly biconvex tablets.

Galenic Formulation - Example 2: Capsules with 4-r (4-methyl-1-piperazin-1-methyl) -N-r4-methyl-3-rr4- (3-p) methanesulfonate capsules (1) -2- pyrimic din-amol-phenol-benzamide (optionally in its crlstal-b form). Capsules containing 1 19.5 milligrams of the mentioned compound are prepared. in the title (= mesilate of COM POSITION I), corresponding to 100 milligrams of COMPOUND I (free base) as active substance, in the following composition: Composition COMPOSITE mesylate I 1 19.5 milligrams MK cellulose GR 92 milligrams Crospovidone XL 15 milligrams Aerosil 200 2 milligrams Magnesium Stearate 1.5 milligrams The capsules are prepared by mixing the components, and filling the mixture into hard gelatin capsules, size 1.

These Examples illustrate the invention without limiting its scope in any way.

Claims (12)

1. CLAIMS 1 . A combination, which comprises, as active ingredients: (i) a renin inhibitor or a pharmaceutically acceptable salt thereof; (ii) at least one tyrosine kinase inhibitor receiving the platelet-derived growth factor, or a pharmaceutically acceptable salt thereof.
2. 2. The combination according to claim 1, wherein the tyrosine kinase inhibitors of the platelet derived growth factor receptor are selected from 4- (4-methyl-piperazin-1-methylmethyl) -N- [4 -methyl-3- (4-pyridin-3-yl) -pyrimidin-2-ylamino) -phenyl] -benzamide, 4- (4-methyl-piperazin-1-ylmethyl) -N- [4-methyl- methanesulfonate] 3- (4-pyridin-3-yl) -pyrimidin-2-ylamino) -phenyl] -benzamide, 4-methyl-N- [3- (4-methyl-imidazol-1-yl) -5- trifluoro-methyl-phenyl] -3- (4-pyridin-3-yl-pyrimidin-2-ylamino) -benza ida, CT52923 (4- (6,7-dimethoxy-4-quinazolinyl) -N- (3,4 -methylenediox-benzyl) -1-piperazin-thiocarboxamide), RP-1776, GFB-1 1, pyrrolo- [3,4-c] -beta-carboline-diones, SU 102, AG1296, AG 1296 and RPR10151 1A , or in each case, a pharmaceutically acceptable salt thereof.
3. 3. The combination according to claim 1 or claim 2, wherein the renin inhibitor is selected from 2 (S), 4 (S), 5 (S), 7 (S) -N- ( 3-amino-2,2-dimethyl-3-oxopropyl) -2,7-di- (1-methyl-ethyl) -4-hydroxy-5-amino-8- [4-methoxy-3- (3-methoxy -propoxy) -phenyl] -octanamide, detiquirene, tervachirene, and zanquirene, or a pharmaceutically salt acceptable of them.
4. 4. The combination according to claim 1 or claim 2, wherein the renin inhibitor is 2 (S), 4 (S), 5 (S), 7 (S) -N- (3-amin or -2, 2-dim eti-l-3-oxopropyl) -2,7-di- (1-methyl-ethyl) -4-hydroxy-5-amino-8- [4-methoxy-3- (3- methoxy-propoxy) -phenyl] -octanamide, or a pharmaceutically acceptable salt thereof.
5. 5. A combination, which comprises, as active ingredients: (i) 2 (S), 4 (S), 5 (S), 7 (S) -N- (3-amino-2,2-dimethyl-3 -oxopropyl) -2,7-di- (1-methyl-ethyl) -4-hydroxy-5-amino-8- [4-methoxy-3- (3-methoxy-propoxy) -phenyl] -octanamide or a salt pharmaceutically acceptable thereof; and (ii) an inhibitor of the tyrosine kinase receptor of the platelet-derived growth factor selected from N-. { 5- [4- (4-methyl-pi-perazi non-methyl) -benzoyl-amido] -2-methylene-phenol} -4- (3-pyridyl) -2-pyrimidine-amine and 4-methyl-N- [3- (4-methyl-imidazol-1-yl) -5-trifluoromethyl-phenyl] -3- ( 4-pyridin-3-yl-pyrimidin-2-ylamino) -benzamide, or in each case a pharmaceutically acceptable salt thereof.
6. The combination according to claim 4 or claim 5, wherein the active ingredient (i) is in the form of its hemi-fumarate salt, and the active ingredient (ii) is in the form of its salt of monomesilato.
7. The combination according to any of claims 1 to 6, in the form of a combined preparation or a pharmaceutical composition.
8. 8. The present invention also relates to a method for the prevention, delay of progress, or treatment of a disease or disorder selected from cancer, thrombosis, psoriasis, fibrosis, dermatosclerosis, atherosclerosis, restenosis, cardiovascular hypertrophy or cardiovascular hypertrophic remodeling, or cardiovascular diseases induced by hypertension, cardiac hypertrophy, cardiac remodeling after myocardial infarction, pulmonary congestion and cardiac fibrosis in dilated or hypertrophic cardiomyopathy, left or right ventricular hypertrophy, diabetic myopathy, prevention of embolism in congestive heart failure, hypertrophic medial thickening in the arteries and / or large vessels , vascular lesions induced by hypertension, hypertrophy of the mesenteric vasculature, renal hyperfiltration such as after portal renal ablation, proteinuria in chronic kidney disease, renal arteriopathy as a consequence of hypertension, nephrosclerosis or nephrosclerosis hypertensive erosis, mesanglial hypertrophy, hypertension, congestive heart failure, diabetes, especially diabetes mellitus type 2, diabetic retinopathy, macular degeneration, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, myocardial infarction, embolism, vascular restenosis, macular degeneration, cataracts, premenstrual syndrome, skin and connective tissue disorders, endothelial dysfunction, and impaired vascular compliance, which comprises administering a warm-blooded animal, including man, in need thereof, together therapeutically effective amounts of a combination according to any of claims 1 to 7.
9. 9. The present invention relates to the use of a renin inhibitor, preferably of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with at least one tyrosine kinase inhibitor that receives platelet-derived growth factor, or a pharmaceutically acceptable salt thereof; for the manufacture of a medicament for the prevention, delay of progress, or treatment of a disease or disorder selected from cancer, thrombosis, psoriasis, fibrosis, dermatosclerosis, atherosclerosis, restenosis, cardiovascular hypertrophy or cardiovascular hypertrophic remodeling, or diseases cardiovascular events induced by hypertension, cardiac hypertrophy, cardiac remodeling after myocardial infarction, pulmonary congestion and cardiac fibrosis in dilated or hypertrophic cardiomyopathy, left or right ventricular hypertrophy, diabetic myopathy, prevention of embolism in 5 congestive heart failure, hypertrophic medial thickening in the arteries and / or in the large vessels, vascular lesions induced by hypertension, hypertrophy of the mesenteric vasculature, renal hyperfiltration such as after renal portal ablation, proteinuria in chronic kidney disease, renal arteriopathy as a consequence of and hypertension, or nephrosclerosis or hypertensive nephrosclerosis, mesanglial hypertrophy, hypertension, congestive heart failure, diabetes, especially diabetes mellitus type 2, diabetic retinopathy, macular degeneration, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, syndrome X, premenstrual syndrome , heart disease, coronary heart disease, angina pectoris, myocardial infarction, embolism, restenosis vascular, macular degeneration, cataracts, premenstrual syndrome, skin and connective tissue disorders, endothelial dysfunction, and impaired vascular compliance.
10. 10. A kit of parts, which comprises: (i) an amount of a renin inhibitor in a first unit dosage form; (ii) an amount of at least one tyrosine kinase inhibitor receiving the platelet-derived growth factor, or, in each case, where appropriate, a pharmaceutically acceptable salt thereof, in the form of two or three or more separate units of components (i) to (ii). eleven .
11. The use according to claim 9, a kit of parts according to claim 10, wherein the renin inhibitor is selected from the group consisting of aliskirene, dethyrin, terlaquirene, and zanquirene.
12. 12. The use according to claim 9 or 1, the kit of parts according to claim 10 or 1, wherein the tyrosine kinase inhibitors of the platelet derived growth factor are selected from - (4-Methyl-piperazin-1-ylmethyl) -N- [4-methyl-3- (4-pyridin-3-yl) -pyrimidin-2-ylamino) -phenyl] -benzamide, methansulfonide of 4- ( 4-methyl-piperazin-1-ylmethyl) -N- [4-methyl-3- (4-pyridin-3-yl) -pyrimidin-2-ylamino) -phenyl] -benzamide, 4-methyl- N- [3- (4-Methyl-imidazol-1-yl) -5-trifluoromethyl-phenyl] -3- (4-pyridin-3-yl-pyrimidin-2-ylamino) -benzamide, CT52923 (4- (6,7-dimethoxy-4-quinazolinyl) -N- (3,4-methylenedioxy-benzyl) -1-piperazine-thiocarboxamide), RP-1776, GFB-1 1, pyrrolo- [3,4-c] -beta- carbolina-diones, SU 1 02, AG 1296, AG 1296 and RPR 10151 1 A, or in each case, a pharmaceutically acceptable salt thereof. The use according to claim 9, or the kit of parts according to claim 10, wherein the ingredient 5 active: (i) is 2 (S), 4 (S), 5 (S), 7 (S) -N- (3-amino-2,2-dimethyl-3-oxo-propyl) -2.7 -di- (1-methyl-ethyl) -4-hydroxy-5-amino-8- [4-methoxy-3- (3-methoxy-propoxy) -phenyl] -octanamide or a pharmaceutically acceptable salt thereof; and / or O (ii) is an inhibitor of the tyrosine kinase receptor of the platelet-derived growth factor selected from N-. { 5- [4- (4-methyl-piperazino-methyl) -benzoyl-amido] -2-methyl-phenyl} -4- (3-pyridyl) -2- pyrimidine-amine and 4-methyl-N- [3- (4-methyl-imidazol-1-yl) -5-trifluoromethyl-phenyl] -3- (4- pyridin-3-yl-pyrimidin-2-ylamino) -benzamide, or in each case a pharmaceutically acceptable salt thereof. The use or kit of parts according to claim 13, wherein the active ingredient (i) is in the form of its hemi-fumarate salt, and the active ingredient (ii) is in the form of its salt of monomesilato.