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    • 专利摘要:
    The present invention relates to novel biphenyl derivatives of the general formula (I) [Formula I] [Wherein, R 1 , R 1 ′ , R 1 ″ , R 2 and n are defined in claim 1]. The present invention also relates to novel integrin ligands, in particular stereoisomers and physiologically acceptable salts thereof, which exhibit the α ｖ β 6 integrin receptor. Such novel compounds are suitable for use as medicaments.
    公开号:KR20030090739A
    申请号:KR10-2003-7013447
    申请日:2002-03-13
    公开日:2003-11-28
    发明作者:샤트올리버；욘크직알프레트；슈탈레볼프강；굿맨시몬
    申请人:메르크 파텐트 게엠베하；
    IPC主号:
    专利说明:

    Ligands of the αｖβ6 INTEGRIN
    [12] Compounds with partially similar structures are disclosed in WO 96/22966 A1, WO 97/08145 A1 and WO 00/48996 A2, and all compounds are effective as integrin inhibitors. Integrins are membrane-bound heterodimeric glycoproteins that consist of α-subunits and smaller β-subunits. Relative affinity and specificity for ligand binding are determined by the combination of different α- and β- subunits. According to the disclosure of said patent application, the compounds of WO 96/22966 A1 are α 4 β 1 integrin to selectively inhibit the receptor, the compounds of WO 97/08145 A1 are selectively inhibiting the α v β 3 integrin receptor. The compounds of WO 00/48996 A2 is mainly inhibition of α v β 3 and α v β 5 integrin receptor.
    [1] The present invention relates to novel compounds of formula (I), their stereoisomers and their physiologically acceptable salts and solvates:
    [2]
    [3] [In the meal,
    [4] X is O or S,
    [5] Y is independently of each other NH, O or S,
    [6] R 1 , R 1 ′ and R 1 ″ are H, A, Ar, Het, Hal, NO 2 , CN, OH, OA, NH 2 , NHA, NA 2 , COOH, COOA, CONH 2 , CONHA or CONA 2 ,
    [7] R 2 is H, A, alkenyl having 1 to 8 carbon atoms and having 1 to 2 double bonds, (CH 2 ) m Ar, (CH 2 ) m Het, (CH 2 ) m cycloalkyl, (CH 2 ) m CHAAr, (CH 2 ) m CHAHet or (CH 2 ) m CHA-cycloalkyl,
    [8] A is alkyl having 1 to 8 carbons,
    [9] Het is unsubstituted or Hal, A, OH, OA, SA, OCF 3 , -CO-A, CN, COOA, COOH, CONH 2 , CONHA, CONA 2 , NH 2 , NHA, NA 2 and / or NO 2 An aromatic monocyclic or bicyclic heterocyclic radical having 1 to 4 N, O and / or S atoms, which may be monosubstituted or disubstituted,
    [10] m is 0, 1 or 2,
    [11] n is 1, 2, 3 or 4;
    [13] The present invention aimed to find novel compounds having useful properties, in particular compounds used in the preparation of medicaments.
    [14] It has been found that the compounds of formula (I) and salts thereof have very useful pharmacological properties and are highly adaptable to drug administration. Surprisingly, the preferred ligand of the novel compounds is α v β 6 integrin receptors according to the invention.
    [15] The compounds in particular act as antagonists as well as agonists. On the other hand, the agent has both affinity and intrinsic activity, stimulates receptors, and antagonists inhibit the stimulatory action of the agent.
    [16] Integrins are believed to be responsible for various physiological and pathological actions, for example, as shown in the following review paper:
    [17] Integrins and signal transduction. Dedhar-S, Curr-Opin-Hematol. 1999 Jan; 6 (1): 37-43, Integrins take partners: cross-talk between integrins and other membrane receptors. Porter-JC; Hogg-N, Trends-Cell-Biol. 1998 Oct; 8 (10): 390-6, Regulation of integrin-mediated adhesion during cell migration. Cox-EA; Huttenlocher-A, Microsc-Res-Tech. 1998 Dec 1; 43 (5): 412-9, The role of integrins in the malignant phenotype of gliomas. Uhm-JH; Gladson-CL; Rao-JS, Front-Biosci. 1999 Feb 15; 4: D188-99], or [Sperm disintegrins, egg integrins, and other cell adhesion molecules of mammalian gamete plasma membrane interactions. Evans-JP Front-Biosci. 1999 Jan 15; 4: D114-31.
    [18] Important roles here are described, for example, in The role of alpha v-integrins in tumor progression and metastasis. Marshall-JF; Hart-IR Semin-Cancer-Biol. 1996 Jun; 7 (3): 129-38] or The role of alpha v-integrins during angiogenesis. Eliceiri-BP and Cheresh-DA Molecular Medicine 4: 741-750 (1998) are believed to be responsible for α ｖ .
    [19] These integrins are also known as α ｖ β 6 [Epithelial integrins, Sheppard-D Bioessays. 1996 Aug; 18 (8): 655-60], and two integrins α ｖ β 3 and α ｖ β 5 , which are known as adhesion receptors, and their biological significance is described, for example, in JA Varner et al. Cell Adhesion and Communication 3, 367-374 (1995) and J. Chem. Samanen et al. Curr. Pharmaceutical Design, 3, 545-584 (1997).
    [20] α ｖ β 6 is a relatively rare integrin (Busk et al., 1992 J. Biol. Chem. 267 (9), 5790), which is progressively formed in epithelial tissue during the repair process and is a natural matrix molecule fibronectin Predominantly binds to and tenasin (Wang et al., 1996, Am. J. Respir. Cell Mol. Biol. 15 (5), 664). Vibronectin also binds to α ｖ β 6 (Characterization of the integrin alpha v beta 6 as afibronectin-binding protein.Busk-M; Pytela-R; Sheppard-D. J-Biol-Chem. 1992 Mar 25 ; 267 (9): 5790-6] Restricted distribution of integrin beta 6 mRNA in primate epithelial tissues.Breuss, -JM; Gillett, -N; Lu, -L; Sheppard, -D; Pytela, -R J- Histochem-Cytochem. 1993 Oct; 41 (10): 1521-7; [Differential regulation of airway epithelial integrins by growth factors.Wang-A; Yokosaki-Y; Ferrando-R; Balmes-J; Sheppard-D. Am- J-Respir-Cell-Mol-Biol. 1996 Nov; 15 (5): 664-72); [The integrin alphavbeta6 is critical for keratinocyte migration on both its known ligand, fibronectin, and on vitronectin. Huang, -X; Wu, -J; Spong, -S; Sheppard, -D J-Cell-Sci. 1998 Aug; 111 (Pt 15) 2189-95].
    [21] Although the physiological and pathological effects of α ｖ β 6 are still not exactly known, the integrins are believed to play a role in the physiological processes and disorders (e.g., inflammation, wound healing and tumors) involving epithelial cells ([ Expression of the beta 6 integrin subunit in development, neoplasia and tissue repair suggests a role in epithelial remodeling.Breuss, -JM; Gallo, -J; DeLisser, -HM; Klimanskaya, -IV; Folkesson, -HG; Pittet, Nishimura, -SL; Aldape, -K; Landers, -DV; Carpenter, -W; et-al. J-Cell-Sci. 1995 Jun; 108 (Pt 6) 2241-51].
    [22] Thus, α ｖ β 6 is expressed in keratinocytes of wounds (Keratinocytes in human wounds express alpha v beta 6 integrin.Haapasalmi-K, Zhang-K, Tonnesen-M, Olerud-J, Sheppard-D, Salo-T , Kramer-R, Clark-RA, Uitto-VJ, Larjava-H. J-Invest-Dermatol. 1996 Jan, 106 (1): 42-8; Epidermal integrin expression is upregulated rapidly in human fetal wound repair.Cas -DL, Bullard-KM, Sylvester-KG, Yang-EY, Sheppard-D, Herlyn-M, Adzick-NS J-Pediatr-Surg. 1998 Feb, 33 (2): 312-6]), from which wound healing In addition to processes and inflammation, other pathological developments in the skin, such as, for example, psoriasis, can be affected by the agonists or antagonists of the integrins.
    [23] In addition, in the disturbed hornification of the skin (called oral white matter), α ｖ β 6 is expressed to a more severe extent than in normal comparative tissues. The incidence and level of leukemia increase through squamous cell lines to squamous cell carcinoma, suggesting a correlation between the expression of α ｖ β 6 and malignant cell turnover of leukemia.
    [24] (Expression of alpha (v) beta6 integrin in oral leukoplakia. Hamidi-S, Salo-T, Kainulainen-T, Epstein-J, Lerner-K, Larjava-H Br-J-Cancer. 2000 Apr, 82 (8) : Stromal fibroblasts influence oral squamous-cell carcinoma cell interactions with tenascin-C.Ramos-DM, Chen-BL, Boylen-K, Stern-M, Kramer-RH, heppard-D, Nishimura-SL, Greenspan-D, Zardi-L, Pytela-R Int-J-Cancer. 1997 Jul 17, 72 (2): 369-76]; Expression of the alpha v beta 6 integrin promotes migration and invasion in squamous carcinoma cells Thomas- GJ, Lewis-MP, Whawell-SA, Russell-A, Sheppard-D, Hart-IR, Speight-PM, Marshall-JF JOURNAL-OF-INVESTIGATIVE-DERMATOLOGY.JUL 2001; 117 (1): 67-73]; Integrins alpha5beta1, alphavbeta1, and alphavbeta6 collaborate in squamous carcinoma cell spreading and migration on fibronectin.Koivisto, -L, Grenman-R, Heino-J, Larjava-H Exp-Cell-Res. 2000 Feb 25, 255 (1): 10-7]).
    [25] In addition, α ｖ β 6 plays a role in circulatory epithelium (Weinacker et al., 1995, Am. J. Respir. Cell Mol. Biol. 12 (5), 547-56); [Expression of the human integrin beta6 subunit in alveolar type II cells and bronchiolar epithelial cells reverses lung inflammation in beta6 knockout mice.Huang X, Wu J, Zhu W, Pytela R, Sheppard D, Am-J-Respir-Cell-Moi-Biol. 1998 Oct, 19 (4): 636-42]; Expression of integrin cell adhesion receptors during human airway epithelial repair in vivo. Pilewski JM, Latoche JD, Arcasoy SM, Albelda-SM Am-J-Physiol. 1997 Jul, 273 (1 Pt 1 ): L256-63]; [Global analysis of gene expression in pulmonary fibrosis reveals distinct programs regulating lung inflammation and fibrosis.Kaminski, -N; Allard JD, Pittet JF, Zuo F, Griffiths MJ, Morris D, Huang X, Sheppard D , Heller RA, Proc-Natl-Acad-Sci-USA.2000.Feb 15, 97 (4): 1778-83]), the corresponding agonists / antagonists of the integrins, such as bronchitis, asthma, pulmonary fibrosis and circulatory tumors. cycle It can be used successfully with disabilities.
    [26] Fibrosis can occur in addition to the lungs (bronchi), and in other organs such as, for example, skin, liver (deepening to sclerosis), kidneys and bladder, heart and pancreas (gallbladder fibrosis). Since integrin α ｖ β 6 plays a role in pathological connective tissue proliferation, disease progression may be affected by agonists / antagonists of integrin α ｖ β 6 (Mechanisms of tissue repair: from wound healing to fibrosis, Mutsaers SE, Bishop JE, Mcgrouther G, Laurent G, J Int. J. Biochem.Cell Biol. (1997) 29 (1): 5-17]; avb6 Integrin mediates latent TGFßactivation: Implications for cutaneous fibrosis.Datlton SL, J. Am. Acad. Dermatol (1999) 41: 457-463; Clinical significance of blood serum connective tissue components in organ fibrosis, Kropf J, Gressner AM, Z. Med. Laboratoriums diagn. (1991) 32 (3/4) Angiotensin II, adhesion, and cardiac fibrosis, Schnee JM, Hsueh WA, Cardiovasc. Res. (2000) 46 (2): 264-268; Pulmonary fibrosis and its treatment: today and in the next millennium.Sime P, J. Curr.Opin.Anti-Inflammatory Immunomodulatory Invest.Drugs (1999) 1 (5): 423-432]; Hepatic fibrosis: pathophysiology and laboratory diagnosis, H ousset C, Guechot J, Pathol. Biol. (1999) 47 (9): 886-894; Progressive renal disease.Fibroblasts, extracellular matrix, and integrins, Norman JT, Fine LG, Exp. Nephrol. (1999) 7 (2): 167-177; Renal fibrosis: insights into pathogenesis and treatment, Nahas AM EI, Muchaneta-Kubara EC, Essawy M, Soylemezoglu O, Int. J. Biochem. Cell Biol. (1997) 29 (1): 55-62).
    [27] In addition, since α ｖ β 6 also plays a role in the intestinal epithelium, it is known that the integrin agonist / antagonist can also be used for the treatment of inflammation, tumors and wounds of the gastrointestinal / intestinal tract. It is shown here that integrin α ｖ β 6 also affects the secretion of matrix metalloproteases such as gelatinase B (MMP-9): (The alpha v beta 6 integrin promotes proliferation of colon carcinoma cells through a unique region of the beta 6 cytoplasmic domain, Agrez M, Chen A, Cone RI, Pytela R, Sheppard D, J Cell Biol (1994) 127 (2): 547-56]; Integrin-mediated signaling of gelatinase B secretion in colon cancer cells, Niu J, Gu X, Turton J, Meldrum C, Howard EW, Agrez M, Biochem Biophys Res Commun (1998) 249 (1): 287-91].
    [28] It is known that the expression of α ｖ β 6 is accompanied by changes in cell density and MMP activity ([The alpha v beta 6 integrin regulates its own expression with cell crowding: Implications for tumour progression, Niu J, Gu X, Ahmed N, Andrews S, Turton J, Bates R, Agrez M, INTERNATIONAL JOURNAL OF CANCER, (2001) 92 (1): 40-48]; The alpha v beta 6 integrin induces gelatinase B secretion in colon cancer cells, Agrez M, Gu X, Turton J, Meldrum C, Niu J, Antalis T, Howard EW, Int J Cancer (1999) 81 (1): 90-7], [alpha v beta 6 integrin upregulates matrix metalloproteinase 9 and promotes migration of normal oral keratinocytes , Thomas GJ, Poomsawat S, Lewis MP, Hart IR, Speight PM, Marshall JF, JOURNAL OF INVESTIGATIVE DERMATOLOGY (2001) 116 (6): 898-904]; alpha V beta 6 integrin promotes invasion of squamous carcinoma cells through up -regulation of matrix metalloproteinase-9, Thomas GJ, Lewis MP, Hart IR, Marshall JF, Speight PM, INTERNATIONAL JOURNAL OF CANCER (2001) 92 (5): 641-6 50]). Regulation of MMP activity (differentially different MMPs) by tumor cells, a function of cell density, may be a mechanism that allows cells to recreate space for proliferation and movement by proteolysis of the surrounding matrix during growth of tumor masses. .
    [29] Because of the role of integrin α ｖ β 6 in the infection process, it is assumed that its agonists / antagonists may also be used in microbial infections (protozoa, microphyte, bacteria, viruses, yeast and fungi). The relationship with integrin α ｖ β 6 has been described for coxsackievirus or infection of host cells of foot and mouth virus (FMDV), which not only occurs dependent on α ｖ β 6 but also depends on α ｖ β 3 . . (Integrin alpha v beta 6 enhances coxsackievirus B1 lytic infection of human colon cancer cells.Agrez MV, Shafren DR, Gu X, Cox K, Sheppard D, Barry RD, Virology (1997) 239 (1): 71-7); The epithelial integrin alphavbeta6 is a receptor for foot-and-mouth disease virus, Jackson T, Sheppard D, Denyer M, Blakemore W, King AM, J Virol (2000) 11: 4949-56; Role of the cytoplasmic domain of the beta-subunit of integrin alpha (v) beta6 in infection by foot-and-mouth disease virus, Miller LC, Blakemore W, Sheppard D, Atakilit A, King AM, Jackson T, J Virol (2001) 75 (9): 4158- 64]; The ability of integrin avb3 to function as a receptor for foot-and-mouth disease virus is not dependent on the presence of complete subunit cytoplasmic domains, Neff S, Baxt B, J Virol (2001) 75 (1): 527-532]; Foot-and-mouth disease virus virulent for cattle utilizes the integrin avb3 as its receptor, Neff S, Sa-Carvalho D, Rieder E, Mason, PW, Blystone SD, Brown EJ, Baxt B, J Virol (1998) 72 (5): 3587-3594; Arginine- glycine-aspartic acid-specific binding by foot-and-mouth disease viruses to the purified integrin avb3 in vitro, Jackson T, Sharma A, Ghazaleh RA, Blakemore WE, Ellard FM, Simmons DL, Newman JWI, Stuart DI, King AMQ, J Virol (1997) 71 (11): 8357-8361].
    [30] Since HIV (AIDS) infection is also α ｖ β integrin dependent, agonists / antagonists of integrin α ｖ β 6 can likewise be used (A novel integrin specificity for the human immunodeficiency virus (HIV) Tat protein, Ruoslahti EI, Vogel BE, Wong-Staal FY, PCT Int. Appl (1992) WO 9214755].
    [31] According to more recent knowledge, the bacterium Bacillus anthracis secretes a toxin consisting of three proteins, one of which is a so-called PA or protective antigen, which binds to a receptor on the cell membrane (anthrax toxin receptor, ATR). ATR is a type I membrane protein with extracellular regions of Willebrandt genotype (vWF A). Integrins also include vWF A regions of this type. This is α ｖ β 6 ( http://www.expasy.ch/cgi-bin/niceprot.pl P18564 ; sequence β 6 (131-371)), and α ｖ β 3 ( http: //www.expasy. ch / cgi-bin / niceprot.pl P05106 ; β 3 (135-377)) is understandable through homology analysis to the Swiss Prot database for both integrins. Thus, it is assumed that α ｖ β 6 agonists / antagonists may also be used for anthrax in the lungs, skin and intestines (Identification of the cellular receptor for anthrax toxin. KA Bradley et al. Nature 414, 225-229 (2001) [ and accompanying articles]; [Evolution of von Willebrand factor A (vWA) domains, Tuckwell D, Biochem Soc Trans (1999) 27 (6): 835-840].
    [32] Cell adhesion molecules in the pathogenesis of and host defence against microbial infection, Kerr JR, Medical Microbiology, Manchester Royal Infirmary, UK, MOLECULAR on adhesion receptors for bacteria and yeasts (germ fungi, Candida) PATHOLOGY (1999) 52 (4): 220-30]; Vitronectin-dependent invasion of epithelial cells by Neisseria gonorrhoeae involves alpha (v) integrin receptors, Dehio M, Gomez-Duarte OG, Dehio C, Meyer TF, FEBS LETTERS ( 1998) 424 (1-2): 84-8]; [A natural variant of the cysteine protease virulence factor of group A Streptococcus with an arginine-glycine-aspartic acid (RGD) motif preferentially binds human integrins alphavbeta3 and alphaIIbbeta3, Stockbauer KE , Magoun L, Liu M, Burns EH Jr, Gubba S, Renish S, Pan X, Bodary SC, Baker E, Coburn J, Leong JM, Musser JM, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (1999 ), 96 (1): 242-7; [Involvement of alpha (v) beta3 integrin-like receptor and glycosaminoglycans in Candida albicans germ tube adhesion to vitronectin and to a human endothelial cell line, Santoni G, Spreghini E, Lucciarini R, Amantini Q Piccoli M, MICROBIAL PATHOGENESIS (2001) 31 (4): 159-72]) The possibility of using an agonist / antagonist of integrin α ｖ β 6 in.
    [33] Integrin α ｖ β 6 interacts with and activates TGF-β (avb6 Integrin mediates latent TGFß activation: Implications for cutaneous fibrosis, Dalton SL, J Am Acad Dermatol (1999) 41: 457-463); integrin avb6 binds and activates latent TGFb1: a mechanism for regulating pulmonary inflammation and fibrosis, Munger JS et al. Cell (1999) 96: 319-328]). Latent TGFβ 1 (one of its preforms) binds to integrin α ｖ β 6 and is proteolytically activated. Thus, integrin α ｖ β 6 agonists / antagonists according to the present invention inhibit the binding of TGF-β (formers, LAP peptides, LAP-TGFβ, latent TGF), thereby activating TGF-β 1 and other subunits. Can be prevented to modulate the effect of TGFβ.
    [34] Three human TGFβ isoenzymes have recently been found to play a role in the multiplicity of growth and differentiation processes, particularly inflammatory processes, fibrosis, wound healing, bone growth, modulation of immune function, angiogenesis and tumor metastasis (Rifkin DB et al., Thrombosis and Haemostasis (1993) 70: 177-179; Hata A et al., Molecular Medicine Today (June 1998) 257-262]; integrin-mediated activation of transforming growth factor-beta (1) in pulmonary fibrosis, Sheppard DC, (2001) 120 (1 Suppl): 49S-53S, Wickstom P et al., Prostate (1998) 37: 19-29). Α ｖ β 6 agonists / antagonists according to the invention may also be used in the process.
    [35] An additional article highlighting the degradation of α ｖ β 6 in the immunological process describes the influx of neutrophils after chemical injury to the lungs (Expression of the beta6 integrin subunit is associated with sites of neutrophil influx in lung) epithelium, Miller LA, Barnett NL, Sheppard D, Hyde DM, J Histochem Cytochem (2001) 49 (1): 41-8]).
    [36] The effect of a compound on the α ｖ β 6 integrin receptor, and therefore as an inhibitor, is described, for example, in JW Smith et al. in J. Biol. Chem. 1990, 265, 12267-12271].
    [37] In addition to the inhibition of α v β 6 integrin receptors desired, the compounds also act as inhibitors of α v β 3 or α v β 5 integrin receptor protein inhibitor and each of the IIb / IIIa. Integrin α ｖ β 3 is expressed on a number of cells, for example endothelial cells, vascular smooth muscle cells, for example aorta, cells for destruction of the bone matrix (osteoblasts) or tumor cells.
    [38] The action of the cells according to the invention is described, for example, in J.W. Smith et al. in J. Biol. Chem. 1990, 265, 12267-12271].
    [39] Angiogenesis dependence on the interaction between vascular integrins and extracellular matrix proteins is described in P.C. Brooks, R. A. Clark and D.A. Cheresh in Science 1994, 264, 569-571.
    [40] The possibility of inhibiting this interaction to initiate apoptosis of angiogenic vascular cells by the cyclic peptide is [P.C. Brooks, A.M. Montgomery, M. Rosenfeld, R.A. Reisfeld, T. Hu, G. Klier and D.A. Cheresh in Cell 1994, 79, 1157-1164. It describes, for example, an αvβ3 antagonist or antibody against αvβ3 which causes tumor contraction due to the onset of apoptosis.
    [41] Experimental evidence also shows that the compounds according to the invention also prevent the attachment of live cells to the matrix protein of interest, and thus prevent the attachment of tumor cells to the matrix protein. Mitjans et al., J. Cell Science 1995, 108, 2825-2838].
    [42] Compounds of formula (I) can inhibit the binding of metalloproteinases to integrins, thereby preventing cells from utilizing the enzymatic activity of proteinases. An example is given in [P.C. Cyclo RGD, which inhibits the binding of αｖβ3 MMP-2 (matrix-metallo-proteinase-2) to the bibronectin receptor, as described in Brooks et al., Cell 1996, 85, 683-693. It can be observed in the ability of the peptide.
    [43] Compounds of formula (I) that block the interaction of ligands with integrin receptors, such as, for example, the interaction of fibrinogen with fibrinogen receptors (glycoprotein IIb / IIIa), prevent the spread of tumor cells by metastasis as antagonists, It can be used as an anti-substance during surgery to surgically remove or attack.
    [44] Diffusion of tumor cells from local tumors into the vascular system occurs through the formation of microaggregates (microthrombosis) due to the interaction of tumor cells with platelets. Tumor cells are masked by the protection of microaggregates and are not recognized by immune system cells. Microaggregates adhere to the vessel wall, making it easier to further penetrate tumor cells into tissue. Since the formation of microthrombosis is promoted by ligands that bind to the corresponding integrin receptors, such as αvβ3 or αIIbβ3 on activated platelets, the antagonists can be considered as effective metastasis inhibitors.
    [45] The action of compounds on αvβ5 integrin receptors and thus activity as inhibitors is described, for example, in J.W. Smith et al. in J. Biol. Chem. 1990, 265, 12267-12271].
    [46] The measure of absorption of a pharmaceutically active ingredient in an organism is its bioavailability.
    [47] When a drug active ingredient is administered intravenously to an organism in the form of an injection, its absolute bioavailability, i.e., the proportion of drug species that is invariant in systemic blood, ie, enters the systemic circulation, is 100%.
    [48] Upon oral administration of a therapeutically active ingredient, the active ingredient is generally in the form of a solid dosage form, so that it may be absorbed by the body by overcoming barriers of entry such as the gastrointestinal tract, oral mucosa, nasal mucosa or skin, especially the stratum corneum. To be able to, it must first be dissolved. In other words, pharmacokinetic data on bioavailability is described in [J. Shaffer et al., J. Pharm. Sciences, 1999, 88, 313-318 can be obtained similarly.
    [49] Another measure of therapeutically active ingredient absorption is the logD value, since that value is a measure of the fat solubility of the molecule.
    [50] Compounds of formula (I) have one or more chiral centers and can therefore lead to many stereoisomeric forms. All such forms (eg D and L forms) and mixtures thereof (eg DL forms) are included in the above formula.
    [51] The compounds of the invention according to claim 1 are also modified by so-called prodrug derivatives, for example alkyl or acyl groups, sugars or oligopeptides, which are rapidly degraded in an organism to give an effective compound according to the invention. It includes a compound of.
    [52] In addition, a free amino group or free hydroxyl group may be provided as a substituent of the compound of formula (I) having the corresponding protecting group.
    [53] The term solvate of a compound of formula (I) means an addition of an inert solvent molecule to the compound of formula (I) that is formed due to mutual attraction. Solvates are, for example, monohydrates or dihydrates, or addition compounds with alcohols, for example methanol or ethanol.
    [54] The present invention relates to compounds of formula (I) and salts and solvates thereof, and to processes for preparing compounds of formula (I) and salts and solvates thereof characterized by
    [55] (a) reacting a compound of formula II with a compound of formula III:
    [56]
    [57] [Wherein R is a protecting group and R 1 , R 1 ′ and R 1 ″ are as defined in Formula I, wherein R 1 , R 1 ′ and / or R 1 ″ have free hydroxyl or amino groups In each case protected by a protector],
    [58]
    [59] [Wherein R 2 and n are as defined in formula I, wherein if R 2 contains free hydroxyl and / or amino groups, they are in each case protected with a protecting group],
    [60] Removing the protecting groups R and any protecting groups present on R 1 , R 1 ′ , R 1 ″ and / or R 2 ;
    [61] or
    [62] (b) reacting a compound of formula IV with a compound of formula V:
    [63]
    [64] [Wherein R is a protecting group and R 1 , R 1 ′ and R 1 ″ are as defined in Formula I, wherein R 1 , R 1 ′ and / or R 1 ″ are free hydroxyl and / or amino groups , In each case protected by a protecting group],
    [65]
    [66] Wherein n and R 2 are as defined in formula (I), wherein if R 2 has free hydroxyl and / or amino groups, they are in each case protected with a protecting group],
    [67] Removing the protecting groups R and any protecting groups present on R 1 , R 1 ′ , R 1 ″ and / or R 2 ;
    [68] or
    [69] (c) one or more radicals R 1 , R 1 ′ , R 1 ″ and / or R 2 in the compound of formula I, for example, by one or more radicals R 1 , R 1 ′ , R 1 ″ and / or Convert to R 2 :
    [70] i) alkylating hydroxyl groups,
    [71] ii) hydrolyzing ester groups to carboxyl groups,
    [72] iii) esterifying a carboxyl group,
    [73] iv) alkylating amino groups,
    [74] v) reacting the aryl bromide or iodide with boric acid by Suzuki coupling to obtain the corresponding coupling product, or
    [75] vi) acylating amino groups,
    [76] or
    [77] (d) a compound of formula VI:
    [78]
    [79] Wherein the free amino group is protected by a protecting group
    [80] Is a compound of Formula II wherein R is a protecting group and R 1 , R 1 ′ and R 1 ″ are as defined in Formula I, wherein R 1 , R 1 ′ and / or R 1 ″ are free hydroxide In the case of having a hydroxyl or amino group, they are in each case protected with a protecting group] so that the compound of formula IV wherein R is a protecting group and R 1 , R 1 ′ and R 1 ″ are defined as Wherein, where R 1 , R 1 ′ and / or R 1 ″ have free hydroxyl or amino groups, they are in each case protected with a protecting group],
    [81] Remove the protecting group on the amino group,
    [82] Subsequently, as described in (b), the compound of formula IV is converted to a compound of formula V, wherein n and R 2 are as defined in formula I, wherein R 2 is a free hydroxyl and / or amino group If contained, they are in each case protected with a protecting group]
    [83] Removing the protecting groups R and any protecting groups present in R 1 , R 1 ′ , R 1 ″ and / or R 2 ,
    [84] And / or
    [85] Converting a basic or acidic compound of formula (I) to one of its salts or solvates by acid or base treatment.
    [86] Throughout the present invention, all radicals that appear more than once, for example A, may be the same or different, ie independent of one another.
    [87] In the above formula, A is alkyl, linear or branched, having 1 to 8 carbon atoms, preferably 1, 2, 3, 4, 5 or 6 carbon atoms. A is preferably methyl, more preferably ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, also pentyl, 1-, 2- or 3-methylbutyl, 1,1- , 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2 , 2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1 , 2,2-trimethylpropyl, heptyl or octyl. Further preferred embodiments of A are, on the one hand, said alkyl groups, preferably trifluoromethyl, 2,2,2-trifluoroethyl or 2-nitroethyl, which may be mono- or polysubstituted by Hal or NO 2 . Or an alkyl group into which -O- can be inserted in the carbon chain, preferably -CH 2 -O-CH 3 , -CH 2 -O-CH 2 -CH 3 or -CH 2 -CH 2 -O-CH 3 to be. A is particularly preferably methyl or ethyl.
    [88] Alkenyl is linear or branched and has 2 to 8 carbon atoms, preferably 2, 3, 4, 5 or 6 carbon atoms. Alkenyl is preferably ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, isobutenyl, 1,4-butadienyl, 1-pentenyl, 2-pentenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-1-butenyl, 1,4-pentadienyl or 1,5-pentadienyl. Particular preference is given to allyl having the formula H 2 C═CH—CH 2 —.
    [89] The meanings of the substituents R 1 , R 1 ′ and R 1 ″ are in each case independent of each other. R 1 is preferably aryl. R 1 is particularly preferably unsubstituted, mono- or disubstituted phenyl, in particular non- Ring phenyl.
    [90] Ar is phenyl, naph unsubstituted or mono-substituted or disubstituted with Hal, A, OA, OH, CO-A, CN, COOA, COOH, CONH 2 , CONHA, CONA 2 , CF 3 , OCF 3 or NO 2 , respectively Til, anthranyl, fluorenyl, indenyl, anthracenyl or biphenyl. Multisubstituted means di-, tri- or tetra-substituted, preferably di- or tri-substituted. Preference is given to phenyl, naphthyl, fluorenyl or biphenyl, each unsubstituted or preferably monosubstituted as indicated. Particularly preferably naphthyl, phenyl, fluorenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- Or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-cyanophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p-methyl Thiophenyl, o-, m- or p-methylsulfinylphenyl, o-, m- or p-methylsulfonylphenyl, o-, m- or p-aminophenyl, o-, m- or p-methylamino Phenyl, o-, m- or p-dimethylaminophenyl, o-, m- or p-nitrophenyl, o-, m- or p-acetylphenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- or p-aminocarbonylphenyl, even more preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl , 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2, 6-, 3,4- or 3,5- Dibromophenyl, 2-chloro-3-methyl-, 2-chloro-4-methyl-, 2-chloro-5-methyl-, 2-chloro-6-methyl-, 2-methyl-3-chloro-, 2-methyl-4-chloro-, 2-methyl-5-chloro-, 2-methyl-6-chloro-, 3-chloro-4-methyl-, 3-chloro-5-methyl- or 3-methyl-4 -Chlorophenyl, 2-bromo-3-methyl-, 2-bromo-4-methyl-, 2-bromo-5-methyl-, 2-bromo-6-methyl-, 2-methyl-3- Bromo-, 2-methyl-4-bromo-, 2-methyl-5-bromo-, 2-methyl-6-bromo-, 3-bromo-4-methyl-, 3-bromo-5 -Methyl- or 3-methyl-4-bromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 2,3,4-, 2,3 , 5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-tri-tert-butylphenyl, 2,5-dimethylphenyl, p- Iodophenyl, 4-fluoro-3-chlorophenyl, 4-fluoro-3,5-dimethylphenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl , 2,4-dichloro-5-methylphenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 2- Ethoxy-5-methylphenyl or 2,4,6-tri-isopropylphenyl.
    [91] Cycloalkyl has 3 to 15 carbon atoms, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, particularly preferably cyclohexyl. Cycloalkyl is likewise a monocyclic or bicyclic terpene, preferably p-mentan, menthol, pinane, bornan or camphor, or adamantyl, in which each known stereoisomeric form is included. In the case of camphor, it is both L-camphor and D-camphor.
    [92] Hal is preferably F, Cl or Br. Hal is particularly preferably F or Cl.
    [93] Amino protecting groups are preferably formyl, acetyl, propionyl, butyryl, phenylacetyl, benzoyl, tolyl, POA, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC , 2-iodoethoxycarbonyl, CBZ ("carbenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC, Mtr or benzyl.
    [94] Het is an unsubstituted, monosubstituted, disubstituted, trisubstituted or tetrasubstituted heterocyclic radical having 1, 2, 3 and / or 4 N, O and / or S atoms, preferably 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 3- or 4-pyridyl, 2-, 4- , 5- or 6-pyrimidinyl, even more preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazole-1-, -3 Or 5-yl, 1- or 5-tetrazolyl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1 -, 2-, 4- or 5- benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 3-, 4-, 5-, 6- , 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8- Cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 1H-imidazo [4,5-b] pyridin-2-yl or 1,8-naphthyridine-7 -yl, and each of which is unsubstituted or substituted, with the proviso that substituted back by a, NHA and / or NH 2 Or it is disubstituted. 4-pyridyl is particularly preferred.
    [95] Heterocyclic radicals may also be partially or fully hydrogenated. Het 2 is thus for example 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-l, -2-,- 3-,-4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 4,5-dihydroimidazole -2-yl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-l, -3- or -4-pyrazolyl, 1 , 4-dihydro-1-,-2-,-3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-,-2-,-3-,-4-,- 5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, morpholinyl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1- , -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5 -, -6-, -7- or -8-isoquinolyl, 1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl. Hydrogenated or partially hydrogenated Het 2 radicals may be additionally substituted by = NH or carbonyl oxygen.
    [96] n is preferably 1, 2, 3 or 4, and n is very particularly preferably 2 or 3.
    [97] "Multi" substituted means 1-, 2-, 3- or 4-substituted.
    [98] Pol means a solid phase having no terminal functional groups, as described in more detail below. The terms solid phase and resin are used synonymously below.
    [99] If the compound of the formula (I) comprises biphenyl, the second phenyl radical is preferably coupled with the first phenyl radical at the 3- or 4-position, particularly preferably the 4-position of the first phenyl ring.
    [100] The present invention therefore relates in particular to compounds of formula (I), in which one or more of said radicals has one of the preferred meanings indicated above. Some preferred groups of compounds may be represented by the following subformulas (Ia) to (Ii), in which the radicals conforming to formula (I) and not defined in detail have the meanings given under formula (I)
    [101] In Ia),
    [102] R 2 is H, A, alkenyl, (CH 2 ) m Ar, (CH 2 ) m Het, (CH 2 ) m cycloalkyl, (CH 2 ) m CHAAr, (CH 2 ) m CHAHet or (CH 2 ) m CHA-cycloalkyl;
    [103] In Ib)
    [104] R 2 is H, A, alkenyl, (CH 2 ) m Ar, (CH 2 ) m Het, (CH 2 ) m cycloalkyl, (CH 2 ) m CHAAr, (CH 2 ) m CHAHet or (CH 2 ) m CHA-cycloalkyl,
    [105] Where Ar is phenyl unsubstituted or mono- or polysubstituted, respectively, with Hal, A, OA, OH, CO-A, CN, COOA, COOH, CONH 2 , CONHA, CONA 2 , CF 3 , OCF 3 or NO 2 , Naphthyl, anthranyl or fluorenyl,
    [106] In the presence of (CH 2 ) m CHAAr, (CH 2 ) m CHAHet or (CH 2 ) m CHA-cycloalkyl, m = 0;
    [107] In Ic)
    [108] R 2 is H, A, alkenyl, (CH 2 ) m Ar, (CH 2 ) m Het, (CH 2 ) m cycloalkyl or CHAAr;
    [109] In Id)
    [110] R 1 , R 1 ′ and R 1 ″ are H, Ar, Het, Hal, OH, NHA, NA 2 , COOA, CONH 2 , CONHA and / or CONA 2 ;
    [111] Ie),
    [112] R 1 is Ar;
    [113] In),
    [114] R 1 is Ar,
    [115] Wherein Ar is phenyl radical unsubstituted or mono- or di-substituted with A, OA, OH, Hal or CF 3 ;
    [116] Ig),
    [117] R 1 is Ar,
    [118] Where Ar is phenyl,
    [119] R 1 ' and R 1'' are each H;
    [120] Ih),
    [121] X is O or S,
    [122] Y is independently of each other NH or O,
    [123] R 1 , R 1 ′ and R 1 ″ are H, A, Ar, Het, Hal, OA, NH 2 , NHA, NA 2 , COOA, CONH 2 , CONHA, CONA 2 and / or 1 to 4 carbon atoms and one Alkenyl having a double bond,
    [124] R 2 is H, A, (CH 2 ) m Ar, (CH 2 ) m Het, (CH 2 ) m cycloalkyl or CHAAr,
    [125] A is alkyl having 1 to 6 carbon atoms,
    [126] Ar is phenyl, naphthyl or biphenyl, unsubstituted or mono- or di-substituted with Hal, A, OA, COOA, COOH, CONH 2 , CONHA, CONA 2 , CF 3 or OCF 3 , respectively,
    [127] Het is one to four, unsubstituted or mono- or disubstituted with Hal, A, OA, OCF 3 , -CO-A, COOA, CONH 2 , CONHA, CONA 2 , NH 2 , NHA or NA 2 Aromatic monocyclic or bicyclic heterocyclic radicals having N, O and / or S atoms,
    [128] m is 0, 1 or 2,
    [129] n is 2 or 3;
    [130] Ii),
    [131] X is O or S,
    [132] Y is independently of each other NH or O,
    [133] R 1 is Ar 1 ,
    [134] R 1 and R 1 '' are each H,
    [135] R 2 is H, A, (CH 2 ) m Ar 2 , (CH 2 ) m cycloalkyl, alkenyl having 1 to 4 carbon atoms and having 1 double bond, or CHA'Ar 2 ,
    [136] here,
    [137] A 'is alkyl having 1, 2 or 3 carbon atoms,
    [138] A is alkyl having 1 to 6 carbon atoms,
    [139] Ar 1 is phenyl,
    [140] Ar 2 is phenyl, naphthyl or fluorenyl, each unsubstituted or mono- or di-substituted with Hal, A, OA, COOA, CONH 2 , CONHA, CONA 2 , CF 3 or OCF 3 ,
    [141] m is 0, 1 or 2,
    [142] n is 1, 2 or 3.
    [143] Particular preference is given to compounds of the general formula I mentioned below:
    [144] 3-biphenyl-4-yl-3- {2- [3- (3-benzylthioureido) propanoylamino] ethanoaminoamino} propionic acid,
    [145] 3-biphenyl-4-yl-3- {2- [4- (3-benzylureido) butanoylamino] ethanoylamino} propionic acid,
    [146] 3-biphenyl-4-yl-3- [2- (4-ureidobutanoylamino) ethanoylamino} propionic acid,
    [147] 3-biphenyl-4-yl-3- {2- [4- (3-ethylureido) butanoylamino] ethanoylamino} propionic acid,
    [148] 3-biphenyl-4-yl-3- {2- [4- (3-cyclohexylureido) butanoylamino] ethanoaminoamino} propionic acid,
    [149] 3-biphenyl-4-yl-3- {2- [4- (3-isoproylureido) butanoylamino] ethanoylamino} propionic acid,
    [150] 3-biphenyl-4-yl-3- {2- [4- (3-butylureido) butanoylamino] ethanoylamino} propionic acid,
    [151] 3-biphenyl-4-yl-3- {2- [4- (3-tert-butylureido) butanoylamino] ethanoylamino} propionic acid,
    [152] 3-biphenyl-4-yl-3- {2- [4- (3-methylthioureido) butanoylamino] ethanoaminoamino} propionic acid,
    [153] 3-biphenyl-4-yl-3- {2- [4- (3-methylthioureido) butanoylamino] ethanoaminoamino} propionic acid,
    [154] 3-biphenyl-4-yl-3- {2- [4- (3-phenylureido) butanoylamino] ethanoylamino} propionic acid,
    [155] 3-biphenyl-4-yl-3- {2- [4- (3-phenylethylureido) butanoylamino] ethanoylamino} propionic acid,
    [156] 3-biphenyl-4-yl-3- {2- [4- (3- (2-chlorophenyl) ureido) butanoylamino] ethanoylamino} propionic acid,
    [157] 3-biphenyl-4-yl-3- {2- [4- (3- (3-chlorophenyl) ureido) butanoylamino] ethanoylamino} propionic acid,
    [158] 3-biphenyl-4-yl-3- {2- [4- (3- (4-chlorophenyl) ureido) butanoylamino] ethanoylamino} propionic acid,
    [159] 3-biphenyl-4-yl-3- {2- [4- (3- (2-methoxyphenyl) ureido) butanoylamino] ethanoylamino} propionic acid,
    [160] 3-biphenyl-4-yl-3- {2- [4- (3- (4-methoxyphenyl) ureido) butanoylamino] ethanoylamino} propionic acid,
    [161] 3-biphenyl-4-yl-3- [2- (3-ureidopropanoylamino) ethanoylamino] propionic acid,
    [162] 3-biphenyl-4-yl-3- {2- [3- (3-ethylureido) propanoylamino] ethanoylamino} propionic acid,
    [163] 3-biphenyl-4-yl-3- {2- [3- (3-cyclohexylureido) propanoylamino] ethanoylamino} propionic acid,
    [164] 3-biphenyl-4-yl-3- {2- [3- (3-butylureido) propanoylamino] ethanoylamino} propionic acid,
    [165] 3-biphenyl-4-yl-3- {2- [3- (3-tert-butylureido) propanoylamino] ethanoylamino} propionic acid,
    [166] 3-biphenyl-4-yl-3- {2- [3- (3-methylthioureido) propanoylamino] ethanoylamino} propionic acid,
    [167] 3-biphenyl-4-yl-3- {2- [3- (3-phenylureido) propanoylamino] ethanoylamino} propionic acid,
    [168] 3-biphenyl-4-yl-3- {2- [3- (3-phenylethylureido) propanoylamino] ethanoylamino} propionic acid,
    [169] 3-biphenyl-4-yl-3- {2- [3- (3- (2-chlorophenylethyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    [170] 3-biphenyl-4-yl-3- {2- [3- (3- (3-chlorophenylethyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    [171] 3-biphenyl-4-yl-3- {2- [3- (3- (4-chlorophenylethyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    [172] 3-biphenyl-4-yl-3- {2- [3- (3- (2-methoxyphenyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    [173] 3-biphenyl-4-yl-3- {2- [3- (3- (4-methoxyphenyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    [174] 3-biphenyl-4-yl-3- {2- [3- (3- (3-methoxyphenyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    [175] 3-biphenyl-4-yl-3- {2- [3- (3-((R) -1-phenylethyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    [176] 3-biphenyl-4-yl-3- {2- [3- (3-((S) -1-phenylethyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    [177] 3-biphenyl-4-yl-3- {2- [3- (3-((R) -1-naphthalen-1-ylethyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    [178] 3-biphenyl-4-yl-3- {2- [3- (3-((S) -1-naphthalen-1-ylethyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    [179] 3-biphenyl-4-yl-3- {2- [3- (3-naphthalen-1-ylureido) propanoylamino] ethanoylamino} propionic acid,
    [180] 3-biphenyl-4-yl-3- {2- [3- (3-naphthalen-2-ylureido) propanoylamino] ethanoylamino} propionic acid,
    [181] 3-biphenyl-4-yl-3- {2- [3- (3-benzylthioureido) propanoylamino] ethanoaminoamino} propionic acid,
    [182] 3-biphenyl-4-yl-3- {2- [3- (3- (4-methylbenzyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    [183] 3-biphenyl-4-yl-3- {2- [3- (3- (2,4-dichlorobenzyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    [184] 3-biphenyl-4-yl-3- {2- [3- (3- (4-fluorobenzyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    [185] 3-biphenyl-4-yl-3- {2- [3- (3- (3,4-dichlorobenzyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    [186] 3-biphenyl-4-yl-3- {2- [3- (3- (2-chlorobenzyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    [187] 3-biphenyl-4-yl-3- {2- [3- (3- (3-propyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    [188] 3-biphenyl-4-yl-3- {2- [3- (3-allylureido) propanoylamino] ethanoylamino} propionic acid,
    [189] 3-biphenyl-4-yl-3- [2- (5-ureidopentanoylamino) ethanoylamino] propionic acid,
    [190] 3-biphenyl-4-yl-3- {2- [5- (3-ethylureido) pentanoylamino] ethanoylamino} propionic acid,
    [191] 3-biphenyl-4-yl-3- {2- [5- (3-cyclohexylureido) pentanoylamino] ethanoylamino} propionic acid,
    [192] 3-biphenyl-4-yl-3- {2- [5- (3-isopropylureido) pentanoylamino] ethanoylamino} propionic acid,
    [193] 3-biphenyl-4-yl-3- {2- [5- (3-butylureido) pentanoylamino] ethanoylamino} propionic acid,
    [194] 3-biphenyl-4-yl-3- {2- [5- (3-tert-butylureido) pentanoylamino] ethanoylamino} propionic acid,
    [195] 3-biphenyl-4-yl-3- {2- [5- (3-methylthioureido) pentanoylamino] ethanoylamino} propionic acid,
    [196] 3-biphenyl-4-yl-3- {2- [5- (3-phenylureido) pentanoylamino] ethanoylamino} propionic acid,
    [197] 3-biphenyl-4-yl-3- {2- [5- (3-phenylethylureido) pentanoylamino] ethanoylamino} propionic acid,
    [198] 3-biphenyl-4-yl-3- {2- [5- (3- (2-chlorophenyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    [199] 3-biphenyl-4-yl-3- {2- [5- (3- (3-chlorophenyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    [200] 3-biphenyl-4-yl-3- {2- [5- (3- (4-chlorophenyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    [201] 3-biphenyl-4-yl-3- {2- [5- (3- (2-methoxyphenyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    [202] 3-biphenyl-4-yl-3- {2- [5- (3- (4-methoxyphenyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    [203] 3-biphenyl-4-yl-3- {2- [5- (3- (3-methoxyphenyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    [204] 3-biphenyl-4-yl-3- {2- [4- (3-((R) -1-phenylethyl) ureido) butanoylamino] ethanoylamino} propionic acid,
    [205] 3-biphenyl-4-yl-3- {2- [4- (3-((S) -1-phenylethyl) ureido) butanoylamino] ethanoylamino} propionic acid,
    [206] 3-biphenyl-4-yl-3- {2- [4- (3-naphthalen-1-ylureido) butanoylamino] ethanoylamino} propionic acid,
    [207] 3-biphenyl-4-yl-3- {2- [4- (3-benzylthioureido) butanoylamino] ethanoylamino} propionic acid,
    [208] 3-biphenyl-4-yl-3- {2- [4- (3-naphthalen-2-ylureido) butanoylamino] ethanoylamino} propionic acid,
    [209] 3-biphenyl-4-yl-3- {2- [4- (3- (4-methylbenzyl) ureido) butanoylamino] ethanoylamino} propionic acid,
    [210] 3-biphenyl-4-yl-3- {2- [4- (3- (3-methylbenzyl) ureido) butanoylamino] ethanoylamino} propionic acid,
    [211] 3-biphenyl-4-yl-3- {2- [4- (3- (2-methylbenzyl) ureido) butanoylamino] ethanoylamino} propionic acid,
    [212] 3-biphenyl-4-yl-3- {2- [4- (3- (2,4-dichlorobenzyl) ureido) butanoylamino] ethanoylamino} propionic acid,
    [213] 3-biphenyl-4-yl-3- {2- [4- (3- (4-fluorobenzyl) ureido) butanoylamino] ethanoylamino} propionic acid,
    [214] 3-biphenyl-4-yl-3- {2- [4- (3- (3,4-dichlorobenzyl) ureido) butanoylamino] ethanoylamino} propionic acid,
    [215] 3-biphenyl-4-yl-3- {2- [4- (3- (2-chlorobenzyl) ureido) butanoylamino] ethanoylamino} propionic acid,
    [216] 3-biphenyl-4-yl-3- {2- [4- (3- (4-methoxybenzyl) ureido) butanoylamino] ethanoylamino} propionic acid,
    [217] 3-biphenyl-4-yl-3- {2- [4- (3-propylureido) butanoylamino] ethanoylamino} propionic acid,
    [218] 3-biphenyl-4-yl-3- {2- [4- (3-allylureido) butanoylamino] ethanoylamino} propionic acid,
    [219] 3-biphenyl-4-yl-3- {2- [5- (3-((R) -1-phenylethyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    [220] 3-biphenyl-4-yl-3- {2- [5- (3-((S) -1-phenylethyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    [221] 3-biphenyl-4-yl-3- {2- [5- (3-naphthalen-1-ylureido) pentanoylamino] ethanoylamino} propionic acid,
    [222] 3-biphenyl-4-yl-3- {2- [5- (3-benzylthioureido) pentanoylamino] ethanoylamino} propionic acid,
    [223] 3-biphenyl-4-yl-3- {2- [5- (3-naphthalen-2-ylureido) pentanoylamino] ethanoylamino} propionic acid,
    [224] 3-biphenyl-4-yl-3- {2- [5- (3- (4-methylbenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    [225] 3-biphenyl-4-yl-3- {2- [5- (3- (3-methylbenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    [226] 3-biphenyl-4-yl-3- {2- [5- (3- (2-methylbenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    [227] 3-biphenyl-4-yl-3- {2- [5- (3- (2,4-dichlorobenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    [228] 3-biphenyl-4-yl-3- {2- [5- (3- (4-fluorobenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    [229] 3-biphenyl-4-yl-3- {2- [5- (3- (3,4-dichlorobenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    [230] 3-biphenyl-4-yl-3- {2- [5- (3- (2-chlorobenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    [231] 3-biphenyl-4-yl-3- {2- [5- (3- (4-methoxybenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    [232] 3-biphenyl-4-yl-3- {2- [5- (3-propylureido) pentanoylamino] ethanoylamino} propionic acid,
    [233] 3-biphenyl-4-yl-3- {2- [3- (9H-fluoren-9-yl-methoxycarbonylamino) propanoylamino] ethanoylamino} propionic acid,
    [234] 3-biphenyl-4-yl-3- {2- [4- (9H-fluoren-9-yl-methoxycarbonylamino) butanoylamino] ethanoylamino} propionic acid,
    [235] 3-biphenyl-4-yl-3- {2- [5- (9H-fluoren-9-yl-methoxycarbonylamino) pentanoylamino] ethanoylamino} propionic acid,
    [236] 3-biphenyl-4-yl-3- {2- [5- (3-allylureido) pentanoylamino] ethanoylamino} propionic acid,
    [237] 3-biphenyl-4-yl-3- {2- [3- (3-ethoxycarbonylamino) propanoylamino] ethanoylamino} propionic acid,
    [238] 3-biphenyl-4-yl-3- {2- [3- (3-benzyloxycarbonylamino) propanoylamino] ethanoylamino} propionic acid,
    [239] 3-biphenyl-4-yl-3- {2- [3- (3- (2,2-dimethylpropoxycarbonylamino) propanoylamino] ethanoylamino} propionic acid,
    [240] 3-biphenyl-4-yl-3- {2- [3- (4-ethoxycarbonylaminobutanoylamino) ethanoylamino] propionic acid,
    [241] 3-biphenyl-4-yl-3- {2- [3- (4-benzyloxycarbonylaminobutanoylamino) ethanoaminoamino] propionic acid,
    [242] 3-biphenyl-4-yl-3- {2- [3- (4- (2,2-dimethylpropoxycarbonylamino) butanoylamino] ethanoylamino} propionic acid,
    [243] 3-biphenyl-4-yl-3- {2- [3- (9H-fluoren-9-yl-methoxycarbonylamino) propanoylamino] ethanoylamino} propionic acid,
    [244] 3-biphenyl-4-yl-3- {2- [4- (9H-fluoren-9-yl-methoxycarbonylamino) butanoylamino] ethanoylamino} propionic acid,
    [245] 3-biphenyl-4-yl-3- {2- [5- (9H-fluorene-9-ylmethoxycarbonylamino) pentanoylamino] ethanoylamino} propionic acid,
    [246] 3-biphenyl-4-yl-3- [2- (3-ethoxycarbonylaminopropanoylamino) ethanoylamino] propionic acid,
    [247] 3-biphenyl-4-yl-3- [2- (3-benzyloxycarbonylaminopropanoylamino) ethanoylamino] propionic acid,
    [248] 3-biphenyl-4-yl-3- {2- [3- (2,2-dimethylpropoxycarbonylamino) propanoylamino] ethanoylamino} propionic acid,
    [249] 3-biphenyl-4-yl-3- [2- (4-ethoxycarbonylaminobutanoylamino) ethanoylamino] propionic acid,
    [250] 3-biphenyl-4-yl-3- [2- (4-benzyloxycarbonylaminobutanoylamino) ethanoylamino] propionic acid, or
    [251] 3-biphenyl-4-yl-3- {2- [4- (2,2-dimethylpropoxycarbonylamino) butanoylamino] ethanoylamino} propionic acid.
    [252] The compounds of formula (I) according to claim 1, and also starting materials for their preparation, are also prepared by methods known per se, as known and clearly described in the literature under reaction conditions suitable for the reaction. (For example, standard books such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart). Modifications known per se can also be used, but are not mentioned here in detail.
    [253] If desired, the starting materials can also be formed in situ so that they are not isolated from the reaction mixture but instead are immediately converted further to the compounds of formula I according to claim 1.
    [254] It is also possible for a plurality of -identical or different -protecting amino and / or hydroxyl groups to be present in the molecule of the starting material. If the protecting groups present differ from one another, in many cases they can be selectively removed (see in this respect: TW Greene, PGM Wuts, Protective Groups in Organic Chemistry, 2nd Edn., Wiley, New York 1991 or PJ Kocienski, Protecting Groups, 1st Edn., Georg Thieme Verlag, Stuttgart-New-York, 1994).
    [255] The term "amino protecting group" is generally known and relates to groups suitable for protecting (shielding) the amino group against chemical reactions. Representative such groups are especially unsubstituted or substituted acyl, aryl, alkoxymethyl or aralkyl groups. Because amino protecting groups are removed after the desired reaction (or a series of synthesis), the type and size of the protecting groups is not more critical; Preferred are protecting groups having 1 to 20 carbon atoms, especially 1 to 8 carbon atoms. The term "acyl group" is understood in a broad sense with respect to the method. These include aliphatic, araliphatic, cycloaliphatic, aromatic and heterocyclic carboxylic or sulfonic acids derived from acyl groups, and in particular, alkoxycarbonyl, alkenyloxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Include. Examples of such acyl groups include alkanoyls such as acetyl, propionyl and butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl and tolyl; Aryloxyalkanoyl such as phenoxyacetyl; Alkoxycarbonyls such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC and 2-iodoethoxycarbonyl; Alkenyloxycarbonyl such as allyloxycarbonyl (Aloc), aralkoxycarbonyl such as CBZ (synonymous with Z), 4-methoxybenzyloxycarbonyl (MOZ), 4-nitrobenzyl-oxycarbonyl and 9 Fluorenylmethoxycarbonyl (Fmoc); 2- (phenylsulfonyl) -ethoxycarbonyl; Trimethylsilylethoxycarbonyl (Teoc), and arylsulfonyl such as 4-methoxy-2,3,6-trimethylphenylsulfonyl (Mtr). Preferred amino protecting groups are BOC, Fmoc and Aloc, also CBZ, benzyl and acetyl. Particularly preferred protecting groups are BOC and Fmoc.
    [256] Likewise the term "hydroxyl protecting group" is generally known and relates to a group suitable for protecting the hydroxyl group against chemical reactions. Representative such groups are the aforementioned unsubstituted or substituted aryl, aralkyl, aroyl or acyl groups, also alkyl groups, alkyl-, aryl- and aralkylsilyl groups, and O, O- and O, S-acetals. Because hydroxylprotecting groups are removed again after the desired chemical reaction or series of synthesis, their nature and size are not critical; Preference is given to protecting groups having 1 to 20 carbon atoms, in particular 1 to 10 carbon atoms. Among others, examples of hydroxyl protecting groups include aralkyl groups such as benzyl, 4-methoxybenzyl and 2,4-dimethoxybenzyl, aroyl groups such as benzoyl and p-nitrobenzoyl, acyl groups such as acetyl and pivaloyl, p-toluenesulfonyl, alkyl groups such as methyl and tert-butyl as well as allyl, alkylsilyl groups such as trimethylsilyl (TMS), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS) and triethylsilyl, Trimethylsilylethyl, aralkylsilyl groups such as tert-butyldiphenylsilyl (TBDPS), cyclic acetals such as isopropylidene acetal, cyclopentylidene acetal, cyclohexylidene acetal, benzylidene acetal, p-methoxy Benzylidene acetal and o, p-dimethoxybenzylidene acetal, noncyclic acetals such as tetrahydropyranyl (Thp), methoxymethyl (MOM), methoxyethoxymethyl (MEM), benzyloxymethyl (BOM) and methylthiomethyl (MTM). Particularly preferred hydroxyl protecting groups are benzyl, acetyl, tert-butyl and TBS.
    [257] The release of the compounds of formula (I) from the functional derivatives of formula (I) is known from the literature for protecting groups used in each case (see, eg, TW Greene, PGM Wuts, Protective Groups in Organic Chemistry, 2nd Edn., Wiley, New York 1991 or PJ Kocienski, Protecting Groups, 1st Edn., Georg Thieme Verlag, Stuttgart-New York, 1994]. Modifications known per se may be used but are not mentioned here in detail.
    [258] For example, BOC and O-tert-butyl groups are predominantly using, for example, TFA in dichloromethane, or approximately 3 to 5N HCl in dioxane at 15 to 30 ° C., so that the Fmoc group is approximately 5 to 50% of dimethyl A DMF solution of amine, diethylamine or piperidine is removed using 15-30 ° C. Aloc groups can be removed under mild conditions using a noble metal catalyst in chloroform at 20-30 ° C. Preferred catalyst is tetrakis (triphenylphosphine) palladium (0).
    [259] Starting compounds of the formulas (II) to (VI) and (1) to (3) are generally known. However, if they are new they can be prepared by methods known per se.
    [260] In addition, compounds of formula (I) can be synthesized in the solid phase, and the bonding to the solid phase takes place via the OH of the carboxyl group. In the case of synthesis in the solid phase, the carboxyl group is substituted by OPol in which Pol is a solid phase having no terminal functional group. Pol stands for the polymeric support material and all atoms of the anchor group in the solid phase are separated from the terminal functional group. Solid phase anchor groups, also known as linkers, are necessary to allow the bonding of compounds to be functionalized into the solid phase. Synthesis in the solid phase, and a schematic description of the solid phase and / or linking groups that can be used for this purpose are described, for example, in Novabiochem-The Combinational Chemistry Catalog, March 99, pp. S1-S72].
    [261] Particularly suitable solid phases for the synthesis of the compounds according to the invention are solid phases having hydroxyl groups as terminal functional groups, for example Wang resins or polystyrene A OH.
    [262] Compounds of formula II wherein R1 = Ar and R = OL (L is Pol) are prepared, for example, according to Scheme 1 wherein SG 1 refers to an amino protecting group as described above:
    [263] Scheme 1:
    [264]
    [265] Bromophenyl substituted carboxylic acid 1 is activated by known methods, for example by reaction with diisopropylcarbodiimide, and with alcohol HO-L (L is as defined above). Continuous coupling of compound 2 to unsubstituted or substituted arylboric acid under Suzuki conditions results in derivative 3. Removal of the protecting group SG 1 under known conditions liberates the compound of formula II.
    [266] The Suzuki reaction is carried out at the temperature of 0 ° to 150 °, preferably 60 ° to 120 ° in an inert solvent or solvent mixture, for example DMF, in the presence of a base such as potassium carbonate, with palladium control, preferably Pd ( It is advantageously carried out by the addition of PPh 3 ) 4 . Depending on the conditions used, the reaction time is from several seconds to several days. Boric acid derivatives may be prepared by conventional methods, and may be commercially available. The reaction is described in Suzuki et al., J. Am. Chem. Soc. 1989, 111, 314ff and Suzuki et al. Chem. Rev. 1995, 957 2457ff.
    [267] Compounds of formula (I) are obtained under standard conditions by peptide-like coupling of a compound of formula (II) with a compound of formula (III) or by peptide-like coupling of a compound of formula (IV) with a compound of formula (V). The compound of formula III is a peptide-like coupling of a compound of formula V with an amino compound H 2 N-CH 2 -COOSG 2 (SG 2 means a hydroxyl protecting group as described above, which is removed after coupling) under standard conditions Obtained by. Compounds of formula IV are prepared under standard conditions by peptide-like coupling of a compound of formula II with a carboxyl compound HOOC-CH 2 -NHSG 1 (SG 1 means an amino protecting group as described above, which is separated after coupling). Obtained. Conventional methods of peptide synthesis are described, for example, in Houben-Weyl, 1.c., Volume 15 / II, 1974, pp.1-806.
    [268] The coupling reaction is preferably a dehydrating agent, for example carbodiimide, such as dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDC) or Diisopropylcarbodiimide (DIC), also for example propanephosphonic anhydride (see Angew. Chem. 1980, 92, 129), diphenylphosphoryl azide or 2-ethoxy-N-ethoxycarbide In the presence of carbonyl-1,2-dihydroquinoline, inert solvents such as halogenated hydrocarbons such as dichloromethane, ethers such as tetrahydrofuran or dioxane, amides such as DMF or dimethylacetamide, nitriles such as acetonitrile Medium, in dimethyl sulfoxide or in the presence of a solvent, it proceeds at a temperature of about -10 to 40 °, preferably 0 to 30 °. The reaction time is from several minutes to several days depending on the conditions used. Coupling Reagent TBTU (O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate) or O- (benzotriazol-1-yl) -N In the presence of one of the compounds of, N, N ', N'-tetramethyluronium hexafluorophosphate, only a slight racemic reaction occurs and no cytotoxic by-products are formed, so the coupling reagent TBTU (O- (Benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate) or O- (benzotriazol-1-yl) -N, N, N', N It has proved particularly advantageous to add '-tetramethyluronium hexafluorophosphate.
    [269] Instead of compounds of formula III, V and / or VI, derivatives of compounds of formula III, V and / or VI, preferably preactivated carboxylic acids or carboxylic acid halides, symmetrical or mixed anhydrides or active esters Can be used. Radicals of this type for activation of carboxyl groups in representative acylation reactions are described in the literature (for example, Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart) Standard book). The activated ester is advantageously formed in situ, for example by the addition of HOBt (1-hydroxybenzotriazole) or N-hydroxysuccinimide.
    [270] The reaction is generally carried out in an inert solvent; If a carboxylic acid halide is used, it is carried out in the presence of an acid binder, preferably an organic base such as triethylamine, dimethylaniline, pyridine or quinoline.
    [271] It is also advantageous to add alkali or alkaline earth metal hydroxides, carbonates or bicarbonates or another salt of an alkali or alkaline earth metal, preferably potassium, sodium, calcium or cesium.
    [272] Bases of formula (I) can be converted to associative acid addition salts using acids, for example by reacting an equivalent amount of base with an acid in an inert solvent such as ethanol and then evaporating. Suitable acids for this reaction are those which in particular produce physiologically acceptable salts. Thus, inorganic acids, for example sulfuric acid, sulfurous acid, dithiic acid, nitric acid, hydrohalic acid such as hydrochloric acid or hydrobromic acid, phosphoric acid such as orthophosphoric acid, sulfamic acid, also organic acids, especially aliphatic, cycloaliphatic, aliphatic , Aromatic or heterocyclic monobasic or polybasic carboxylic acids, sulfonic acids or sulfuric acids, for example formic acid, acetic acid, propionic acid, hexanoic acid, octanoic acid, decanoic acid, hexadecanoic acid, octadecanoic acid, pivalic acid, Diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isnicotinic acid, methane or ethanesulfonic acid, benzenesulfonic acid, trimethoxybenzoic acid, acetic acid Monocarboxylic acid, p-toluenesulfonic acid, glycolic acid, embonic acid, chlorophenoxyacetic acid, aspartic acid, glutamic acid, proline, glycolic acid, palmitic acid, para-chlorophenoxy Small acid, cyclohexanecarboxylic acid, glucose 1-phosphate, naphthalene mono- and disulfonic acid, or La is possible to use lauryl sulfate. Salts with physiologically acceptable acids, such as picrates, can be used to isolate and / or purify the compound of formula (I).
    [273] On the other hand, the compounds of formula (I) can be converted to the corresponding metal salts, in particular alkali metal or alkaline earth metal salts, or corresponding ammonium salts, using bases (e.g. sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate). have.
    [274] The invention also relates to a compound of formula (I) according to claim 1, a stereoisomer thereof and / or a physiologically acceptable salt or solvate thereof, which is a pharmaceutically active ingredient.
    [275] The invention also relates to a compound of formula (I) according to claim 1, stereoisomers thereof and / or physiologically acceptable salts or solvates thereof according to claim 1 which are integrin agonists and / or antagonists.
    [276] The invention also relates to a compound of formula (I), stereoisomers thereof and / or physiologically acceptable salts or solvates thereof according to claim 1 for use in the fight against disease. The use of the compounds used to fight disease encompasses their use for the treatment and / or prophylaxis.
    [277] The invention also relates to a pharmaceutical formulation containing at least one of the compounds of formula (I), stereoisomers and / or physiologically acceptable salts or solvates thereof according to claim 1 or 2. The compounds of formula (I) may be combined with one or more solid, liquid and / or semi-liquid excipients or adjuvants, if necessary, with one or more additional active ingredients to form a suitable dosage form.
    [278] These agents can be used as medicaments in human or livestock medicine. Suitable excipients are organic or inorganic ingredients suitable for enteric (eg oral), parenteral or topical administration and which do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol Triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc or petrolatum. In particular, tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops are suitable for oral administration, suppositories are suitable for rectal administration, solutions, preferably oily or aqueous solutions, also suspensions, Emulsions or implants are suitable for parenteral administration, and ointments, creams or powders are suitable for topical application. The novel compounds can also be lyophilized and the resulting lyophilisates are used for the preparation of injectable preparations, for example. The formulations presented may be sterilized and / or adjuvants such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for osmotic modification, buffers, dyes, perfumes and / or a plurality of further active ingredients, for example 1 It may contain more than one vitamin.
    [279] For administration as an inhalation spray, it is possible to use sprays in which the active ingredient is dissolved or suspended in propellant gas or propellant gas mixture (eg, CO 2 or chlorofluorocarbons). The active ingredient is used herein in micronized form, in which case there may be one or more additional physiologically acceptable solvents such as ethanol. Inhalation solutions can be administered with the aid of a conventional inhaler.
    [280] Compounds of formula (I), stereoisomers thereof and / or physiologically acceptable salts or solvates thereof are pharmaceutically active ingredients in medicaments of humans and livestock, in particular circulatory disorders, pulmonary fibrosis, pulmonary embolism, thrombosis, especially cardiac vein thrombosis, myocardium Infarctions, atherosclerosis, aneurysms, transient ischemic attacks, strokes, angina pectoris, especially unstable angina pectoris, pathologically related tissue proliferation or fibrosis in organs, especially pulmonary fibrosis, but also cystic fibrosis, skin fibrosis, liver fibrosis, liver cirrhosis, Urethral fibrosis, renal fibrosis, cardiac fibrosis, infantile endocardial fibrosis, pancreatic fibrosis, disturbed hornification of the skin, in particular white valve, squamous and squamous cell carcinoma, tumor diseases such as tumor development of solid tumors , Tumor angiogenesis or tumor metastasis, and tumor diseases of the blood or immune system such as skin tumors, squamous cell carcinoma, blood Ducts, gastrointestinal tract, lungs, chest, liver, kidneys, spleen, pancreas, brain, testicles, ovaries, uterus, vagina, muscles, bone tumors, and tumors of the throat and head, osteolytic diseases such as osteoporosis, parathyroidism, Paget's disease, malignant calcium, inadequate transfusion, pathological angiogenesis disorders such as, for example, inflammation, eye disease, diabetic retinopathy, macular degeneration, myopia, corneal transplantation, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, Neovascular glaucoma, ulcerative colitis, Crohn's disease, atherosclerosis, psoriasis, restenosis, especially restenosis after angioplasty, multiple sclerosis, pregnancy, absumptio placentaris, viral infections, bacterial infections, fungal infections, foot and mouth disease (FMD) , HIV, anthrax, Candida albicans, parasitic infections, acute renal seizures, and healing methods supplemental wound healing, can be used for their prophylaxis and / or treatment.
    [281] In the case of a viral infection, the compounds according to the invention are in particular bound to extracellular matrix constructs, which are recognized as integrins or by inhibiting or breaking viral binding between cell-mediated integrin binding proteins and viral shells. Acts indirectly by preventing uptake of proteins or by destroying the integrin-promoted mechanisms associated with viral infections (J Virol 2000 Jun; 74 (11): 4949-56, J Virol 2000 Aug; 74 (16). ): 7298-306, J Virol 2001 May; 75 (9): 4158-64, Virology.2001 Sep 30; 288 (2): 192 (FMDV), Virus Res. 2001 Jul; 76 (1): l-8 (echovirus), J Biol Chem. 2001 Jul 13; 276 (28): 26204-10 (HIV), Biochem Biophys Res Commun. 2001 May 11; 283 (3): 668-73 (papillomavirus), Proc Natl Acad Sci US A. 2000 Dec 19; 97 (26): 14644-9 (rotavirus).
    [282] In the case of bacterial infections, in particular, they act by inhibiting toxin products caused by or by cellular infection by or through cells by binding and / or uptake of bacterial or bacterial toxins, or by integrin-promoted mechanisms (Nature 2001 Nov 8: 225-229 (Anthrax), J Exp Med. 2001 May 7; 193 (9): 1035-44 (Pertussis), Proc Natl Acad Sci US A. 2000 Feb 29; 97 (5): 2235-40 (group A streptococcus), Infect Immun. 2000 Jan; 68 (1): 72-9 (Pasteurella Haemolytica Leucotoxin), J Biol Chem. 1997 Nov 28; 272 (48): 30463-9 (RTX Leucotoxine).
    [283] In the case of parasitic infections, in particular, it acts by inhibiting parasites or parasite-derived or induced toxins on or by cells through the integrin-directed mechanism (Infect Immun. 1999 Sep; 67 (9): 4477 (leishmania)).
    [284] The substance according to the invention is generally preferably administered in a dosage of about 0.05 to 500 mg, in particular 0.5 to 100 mg, per dosage unit. The daily dosage is preferably about 0.01 to 2 mg / 1 kg (body weight). However, the specific dosage for each patient can vary greatly depending on a variety of factors, including the efficacy, age, weight, general health, sex, diet, time and method of administration, rate of secretion, drug combination and treatment of the specific compound used. It depends on the severity of the particular disease to be applied. Parenteral administration is preferred.
    [285] In addition, the compounds of formula (I) can be used as integrin ligands for the preparation of columns for affinity chromatography, for purification of integrins.
    [286] In this process, the ligand, ie the compound of formula I, is covalently coupled to the polymeric support via an anchor functional group, for example a carboxyl group.
    [287] Suitable polymeric support materials are polymeric solid phases, preferably crosslinked polysaccharides such as cellulose, sepharose or Sephadex, which are preferably hydrophilic, known in peptide chemistry. ), Acrylamide, polyethylene glycol based polymer or Tentakel Polymer.
    [288] Integrin preparative affinity chromatography materials are prepared under conditions conventional and known per se for condensation of amino acids.
    [289] Since the compounds of formula (I) have one or more chiral centers, they may exist in racemic or optically active forms. The racemates obtained can be separated into enantiomers mechanically or chemically by methods known per se. Diastereomers are preferably formed from racemic mixtures by reaction with optically active separating agents. Examples of suitable separating agents are D and L forms of optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid and various optically active camphorsulfonic acids such as β-camphorsulfonic acid. to be. It is also advantageous to separate diastereoisomers with the aid of a column packed with an optically active separating agent (eg dinitrobenzoylphenylglycine); Examples of suitable eluents are mixtures of hexane / isopropanol / acetonitrile, for example, by volume ratio 82: 15: 3.
    [290] It is of course also possible to obtain optically active compounds of the formula (I) by the process described above using already optically active starting materials.
    [291] Above and below, all temperatures are in degrees Celsius. In the examples below, "traditional work-up" means adding water if necessary, adjusting the pH to a value from 2 to 10 if necessary depending on the composition of the final product, and adjusting the mixture to ethyl acetate or dichloro Extraction with methane, phase separation, drying the organic phase with sodium sulfate and evaporation, and purification of the product by silica gel column chromatography by preparative HPLC and / or crystallization. If necessary, the purified compound is lyophilized.
    [292] The eluent used is a gradient of acetonitrile (B) with 0.08% TFA (trifluoroacetic acid) and water (A) with 0.1% TFA. Gradients are expressed in% by volume of acetonitrile.
    [293] HPLC analysis (ret. Time RT) was performed on the following systems:
    [294] 3 μm silica-rod column with 210 sec gradient of 20-100% water / acetonitrile / 0.01% trifluoroacetic acid, with detection at 220 nm at a flow rate of 2.2 ml / min.
    [295] Compounds purified by preparative HPLC are isolated as trifluoroacetate.
    [296] Mass spectrometry (MS) by FAB (High Speed Atomic Impact): MS-FAB (M + H) + .
    [297] The examples illustrate the invention without restricting it.
    [298] The compounds described by way of example can exist as various stereoisomers, and if stereochemical data are not given, in each case a mixture of stereoisomers is present.
    [299] Example 1
    [300] Synthesis of 3-biphenyl-4-yl-3- {2- [3- (3-isopropylureido) propanoylamino] ethanoylamino} propionic acid
    [301]
    [302] a. 7.36 g of trityl resin (Rapp) was suspended with 50 mL of dichloromethane, and then 3.6 mL of diisopropylethylamine was added. To the suspension was added 6.50 g of dichloromethane solution of Fmoc-diphenylaminopropionic acid, and the mixture was then shaken at RT for 4 hours. For work up, the solid phase was filtered off, washed three times with each of dichloromethane, DMF, dichloromethane and methanol and dried in a vacuum drying cabinet.
    [303] b. The solid phase was suspended with DMF, then a DMF solution of 50% piperidine was added and the mixture was shaken at RT for 30 minutes. The solid phase was then filtered off and the same procedure was repeated twice. The solid phase was then washed three times with each of DMF, dichloromethane and methanol and dried overnight in a vacuum drying cabinet to give a resin bound 3-biphenyl-4-yl-3-aminopropionic acid “AB”.
    [304] c. 14.098 g of solid phase was suspended in 80 ml of DMF, and 13.83 ml of diisopropylethylamine was added. Subsequently, 21.28 g of Fmoc-glycine, 14.00 g of HOBt and 13.84 mL of diisopropylcarbodiimide were added as 130 mL of DMF solution and the reaction batch was shaken at RT overnight. For work up, the solid phase is filtered off, washed three times with respective DMF, dichloromethane and methanol and dried overnight in a vacuum drying cabinet to give resin bound 3-biphenyl-4-yl-3- (2- Aminoethanoylamino) propionic acid "BC" was obtained.
    [305] d. 5.25 g of polymer was suspended in 30 mL of DMF, 5.33 mL of diisopropylethylamine was added, and a solution of 5.90 g of Fmoc-β-alanine, 5.4 g of HOBt and 5.36 mL of diisopropylcarbodiimide Was added. The suspension was shaken overnight at RT. 622 μl of diethyl azadicarboxylate was added dropwise. The suspension was stirred overnight at RT. For work up, the solid phase is filtered off, washed three times with respective DMF, dichloromethane and methanol and dried overnight in a vacuum drying cabinet to give resin bound 3-biphenyl-4-yl-3- [2- (3-aminopropanoylamino) ethanoaminoamino] propionic acid "CD" was obtained.
    [306] e. 150 mg of the polymer was suspended in 2 ml of dichloromethane, and 187 µl of diisopropylethylamine was added. To the suspension was added 93 mg of dichloromethane solution of isopropyl isocyanate and the reaction batch was shaken at RT overnight. For work up, the solid phase is filtered off, washed three times with respective DMF, dichloromethane and methanol and dried overnight in a vacuum drying cabinet to give 3-biphenyl-4-yl-3- {2- [3- (3-isopropylureido) -propanoylamino] ethanoylamino} propionic acid "DE" was obtained.
    [307] f. 164 mg of polymer was suspended in 1 ml of dichloromethane, 3 ml of 50% TFA's dichloromethane solution was added and the mixture was shaken at RT for 1 hour. The solid phase was filtered off and the solution was evaporated to dryness at Speedvac to give 34 mg of the desired product (3-biphenyl-4-yl-3- {2- [3- (3-isopropylureido) propanoylamino] Ethanoylamino} propionic acid; (EMD 388100)) was obtained as a pale brown oil.
    [308] Example 2:
    [309] Similar to Example 1, the resin "BC" is reacted with FMOC protected β-alanine and benzyl isothiocyanate to give 3-biphenyl-4-yl-3- {2- [3- (3-benzyl Thioureido) propanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [3- (3-benzylthioureido) propanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.887 min, FAB- MS (M + H) + 519.15 (EMD 388118) was obtained.
    [310] Similar to Example 1, the resin "BC" is reacted with FMOC protected 4-aminobutanoic acid and benzyl isocyanate to give 3-biphenyl-4-yl-3- {2- [4- (3-benzylurei Butanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (3-benzylureido) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.627 min, FAB-MS (M + H) + 517.2 (EMD 387143) was obtained.
    [311] Similar to Example 1, the resin "BC" was reacted with FMOC protected 4-aminobutanoic acid and isocyanic acid to yield 3-biphenyl-4-yl-3- [2- (4-ureidobutanoyl Amino) ethanoaminoamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- [2- (4-ureidobutanoylamino) ethanoylamino} propionic acid trifluoroacetate, RT 1.232 min, FAB-MS (M + H) + 427.1 (EMD 387505) was obtained.
    [312] Similar to Example 1, the resin "BC" was reacted with FMOC protected 4-aminobutanoic acid and ethyl isocyanate to give 3-biphenyl-4-yl-3- {2- [4- (3-ethylurea Butanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (3-ethylureido) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.363 min, FAB-MS (M + H) + 455.2 (EMD 387506) was obtained.
    [313] Similar to Example 1, the resin "BC" is reacted with FMOC protected 4-aminobutanoic acid and cyclohexyl isocyanate to give 3-biphenyl-4-yl-3- {2- [4- (3-cyclo Hexyl ureido) butanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (3-cyclohexylureido) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.688 min, FAB-MS ( M + H) + 508.2 (EMD 387507) was obtained.
    [314] Similar to Example 1, the resin "BC" is reacted with FMOC protected 4-aminobutanoic acid and isopropyl isocyanate to give 3-biphenyl-4-yl-3- {2- [4- (3-iso Proylureido) butanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (3-isoproylureido) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.454 min, FAB-MS (M + H) + 462.2 (EMD 387508) was obtained.
    [315] Similar to Example 1, the resin "BC" is reacted with FMOC protected 4-aminobutanoic acid and n-butyl isocyanate to give 3-biphenyl-4-yl-3- {2- [4- (3- Butylureido) butanoylamino] ethanoaminoamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (3-butylureido) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.588 min, FAB-MS (M + H) + 483.2 (EMD 387509) was obtained.
    [316] Similar to Example 1, the resin "BC" is reacted with FMOC protected 4-aminobutanoic acid and tert-butyl isocyanate to give 3-biphenyl-4-yl-3- {2- [4- (3- tert-butylureido) butanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (3-tert-butylureido) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.6 min, FAB-MS (M + H) + 483.2 (EMD 387510) was obtained.
    [317] Similar to Example 1, the resin "BC" was reacted with FMOC protected 4-aminobutanoic acid and methyl isothiocyanate to give 3-biphenyl-4-yl-3- {2- [4- (3 -Methylthioureido) butanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (3-methylthioureido) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.399 min, FAB-MS (M + H) + 457.2 (EMD 387511) was obtained.
    [318] Similar to Example 1, the resin "BC" was reacted with FMOC protected 4-aminobutanoic acid and methyl isothiocyanate to give 3-biphenyl-4-yl-3- {2- [4- (3 -Methylthioureido) butanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (3-methylthioureido) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.399 min, FAB-MS (M + H) + 457.2 (EMD 387511) was obtained.
    [319] Similar to Example 1, the resin "BC" is reacted with FMOC protected 4-aminobutanoic acid and phenyl isocyanate to give 3-biphenyl-4-yl-3- {2- [4- (3-phenylurei Butanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (3-phenylureido) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.66 min, FAB-MS (M + H) + 503.2 (EMD 387512) was obtained.
    [320] Similar to Example 1, the resin "BC" was reacted with FMOC protected 4-aminobutanoic acid and phenylethyl isocyanate to give 3-biphenyl-4-yl-3- {2- [4- (3-phenyl Ethyl ureido) butanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (3-phenylethylureido) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.717 min, FAB-MS ( M + H) + 531.2 (EMD 387513) was obtained.
    [321] Similar to Example 1, the resin "BC" was reacted with FMOC protected 4-aminobutanoic acid and 2-chlorophenyl isocyanate to give 3-biphenyl-4-yl-3- {2- [4- (3 -(2-chlorophenyl) ureido) butanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (3- (2-chlorophenyl) ureido) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.778 min, FAB-MS (M + H) + 537.2 / 539 (EMD 387514) were obtained.
    [322] Similar to Example 1, the resin "BC" was reacted with FMOC protected 4-aminobutanoic acid and 3-chlorophenyl isocyanate to give 3-biphenyl-4-yl-3- {2- [4- (3 -(3-chlorophenyl) ureido) butanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (3- (3-chlorophenyl) ureido) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.883 min, FAB-MS (M + H) + 537.2 / 539 (EMD 387515) were obtained.
    [323] Similar to Example 1, the resin "BC" was reacted with FMOC protected 4-aminobutanoic acid and 4-chlorophenyl isocyanate to give 3-biphenyl-4-yl-3- {2- [4- (3 -(4-chlorophenyl) ureido) butanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (3- (4-chlorophenyl) ureido) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.834 min, FAB-MS (M + H) + 537.2 / 539 (EMD 387516) were obtained.
    [324] Similar to Example 1, the resin "BC" was reacted with FMOC protected 4-aminobutanoic acid and 2-methoxyphenyl isocyanate to give 3-biphenyl-4-yl-3- {2- [4- ( 3- (2-methoxyphenyl) ureido) butanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (3- (2-methoxyphenyl) ureido) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.709 min , FAB-MS (M + H) + 533.2 (EMD 387517) was obtained.
    [325] Similar to Example 1, the resin "BC" was reacted with FMOC protected 4-aminobutanoic acid and 4-methoxyphenyl isocyanate to give 3-biphenyl-4-yl-3- {2- [4- ( 3- (4-methoxyphenyl) ureido) butanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (3- (4-methoxyphenyl) ureido) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.622 min , FAB-MS (M + H) + 533.2 (EMD 387518) was obtained.
    [326] Similar to Example 1, the resin "BC" was reacted with FMOC protected β-alanine and isocyanic acid to yield 3-biphenyl-4-yl-3- [2- (3-ureidopropanoylamino ) Ethanoylamino] propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- [2- (3-ureidopropanoylamino) ethanoylamino] propionic acid trifluoroacetate, RT 1.197 min, FAB-MS (M + H) + 413.2 (EMD 388097) was obtained.
    [327] Similar to Example 1, the resin "BC" was reacted with FMOC protected β-alanine and ethyl isocyanate to give 3-biphenyl-4-yl-3- {2- [3- (3-ethylureido) Propanoylamino] ethanoaminoamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [3- (3-ethylureido) propanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.32 min, FAB-MS ( M + H) + 441.2 (EMD 388098) was obtained.
    [328] Similar to Example 1, the resin "BC" is reacted with FMOC protected β-alanine and cyclohexyl isocyanate to give 3-biphenyl-4-yl-3- {2- [3- (3-cyclohexylurei) Fig. 6) Propanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [3- (3-cyclohexylureido) propanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.634 min, FAB-MS (M + H) + 495.2 (EMD 388099) were obtained.
    [329] Similar to Example 1, the resin "BC" is reacted with FMOC protected β-alanine and n-butyl isocyanate to give 3-biphenyl-4-yl-3- {2- [3- (3-butylurey Fig. 6) Propanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [3- (3-butylureido) propanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.536 min, FAB-MS ( M + H) + 469.2 (EMD 388101).
    [330] Similar to Example 1, the resin "BC" is reacted with FMOC protected β-alanine and tert-butyl isocyanate to give 3-biphenyl-4-yl-3- {2- [3- (3-tert- Butylureido) propanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [3- (3-tert-butylureido) propanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.543 min, FAB- MS (M + H) + 469.2 (EMD 388102) was obtained.
    [331] Similar to Example 1, the resin "BC" is reacted with FMOC protected β-alanine and methyl isothiocyanate to give 3-biphenyl-4-yl-3- {2- [3- (3-methyl Thioureido) propanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [3- (3-methylthioureido) propanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.363 min, FAB- MS (M + H) + 443.2 (EMD 388103) was obtained.
    [332] Similar to Example 1, the resin "BC" is reacted with FMOC protected β-alanine and phenyl isocyanate to give 3-biphenyl-4-yl-3- {2- [3- (3-phenylureido) Propanoylamino] ethanoaminoamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [3- (3-phenylureido) propanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.615 min, FAB-MS ( M + H) + 489.2 (EMD 388104) was obtained.
    [333] Similar to Example 1, the resin "BC" is reacted with FMOC protected β-alanine and phenylethyl isocyanate to give 3-biphenyl-4-yl-3- {2- [3- (3-phenylethylurei Fig. 6) Propanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [3- (3-phenylethylureido) propanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.662 min, FAB-MS (M + H) + 517.2 (EMD 388105) was obtained.
    [334] Similar to Example 1, the resin "BC" was reacted with FMOC protected β-alanine and 2-chlorophenyl isocyanate to give 3-biphenyl-4-yl-3- {2- [3- (3- ( 2-chlorophenylethyl) ureido) propanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [3- (3- (2-chlorophenylethyl) ureido) propanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.772 Min, FAB-MS (M + H) + 523.2 / 525 (EMD 388106) were obtained.
    [335] Similar to Example 1, the resin "BC" was reacted with FMOC protected β-alanine and 3-chlorophenyl isocyanate to give 3-biphenyl-4-yl-3- {2- [3- (3- ( 3-chlorophenylethyl) ureido) propanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [3- (3- (3-chlorophenylethyl) ureido) propanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.782 Min, FAB-MS (M + H) + 523.2 / 525 (EMD 388107) were obtained.
    [336] Similar to Example 1, the resin "BC" was reacted with FMOC protected β-alanine and 4-chlorophenyl isocyanate to give 3-biphenyl-4-yl-3- {2- [3- (3- ( 4-chlorophenylethyl) ureido) propanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [3- (3- (4-chlorophenylethyl) ureido) propanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.779 Min, FAB-MS (M + H) + 523.2 / 525 (EMD 388108) were obtained.
    [337] Similar to Example 1, the resin "BC" is reacted with FMOC protected β-alanine and 2-methoxyphenyl isocyanate to give 3-biphenyl-4-yl-3- {2- [3- (3- (2-methoxyphenyl) ureido) propanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [3- (3- (2-methoxyphenyl) ureido) propanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.65 Min, FAB-MS (M + H) + 519.2 (EMD 388109) were obtained.
    [338] Similar to Example 1, the resin "BC" was reacted with FMOC protected β-alanine and 4-methoxyphenyl isocyanate to give 3-biphenyl-4-yl-3- {2- [3- (3- (4-methoxyphenyl) ureido) propanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [3- (3- (4-methoxyphenyl) ureido) propanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.572 Min, FAB-MS (M + H) + 519.2 (EMD 388110) were obtained.
    [339] Similar to Example 1, the resin "BC" is reacted with FMOC protected β-alanine and 3-methoxyphenyl isocyanate to give 3-biphenyl-4-yl-3- {2- [3- (3- (3-methoxyphenyl) ureido) propanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [3- (3- (3-methoxyphenyl) ureido) propanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.624 Minutes, FAB-MS (M + H) + 519.2 (EMD 388111) were obtained.
    [340] Similar to Example 1, the resin "BC" is reacted with FMOC protected β-alanine and (R) -1-phenylethyl isocyanate to give 3-biphenyl-4-yl-3- {2- [3- (3-((R) -1-phenylethyl) ureido) propanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [3- (3-((R) -1-phenylethyl) ureido) propanoylamino] ethanoylamino} propionic acid trifluoroacetate , RT 1.653 min, FAB-MS (M + H) + 517.2 (EMD 388112) was obtained.
    [341] Similar to Example 1, the resin "BC" is reacted with FMOC protected β-alanine and (S) -1-phenylethyl isocyanate to give 3-biphenyl-4-yl-3- {2- [3- (3-((S) -1-phenylethyl) ureido) propanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [3- (3-((S) -1-phenylethyl) ureido) propanoylamino] ethanoylamino} propionic acid trifluoroacetate , RT 1.656 min, FAB-MS (M + H) + 517.2 (EMD 388113) was obtained.
    [342] Similar to Example 1, the resin "BC" is reacted with FMOC protected β-alanine and (R) -1-naphthalen-1-ylethyl isocyanate to give 3-biphenyl-4-yl-3- {2 -[3- (3-((R) -1-naphthalen-1-ylethyl) ureido) propanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [3- (3-((R) -1-naphthalen-1-ylethyl) ureido) propanoylamino] ethanoylamino} propionic acid Trifluoroacetate, RT 1.854 min, FAB-MS (M + H) + 567.2 (EMD 388114) was obtained.
    [343] Similar to Example 1, the resin "BC" was reacted with FMOC protected β-alanine and (S) -1-naphthalen-1-ylethyl isocyanate to give 3-biphenyl-4-yl-3- {2 -[3- (3-((S) -1-naphthalen-1-ylethyl) ureido) propanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [3- (3-((S) -1-naphthalen-1-ylethyl) ureido) propanoylamino] ethanoylamino} propionic acid Trifluoroacetate, RT 1.851 min, FAB-MS (M + H) + 567.2 (EMD 388115) was obtained.
    [344] Similar to Example 1, the resin "BC" is reacted with FMOC protected β-alanine and naphthalen-1-yl isocyanate to give 3-biphenyl-4-yl-3- {2- [3- (3- Naphthalen-1-ylureido) propanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [3- (3-naphthalen-1-ylureido) propanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.742 min, FAB-MS (M + H) + 539.2 (EMD 388116) were obtained.
    [345] Similar to Example 1, the resin "BC" is reacted with FMOC protected β-alanine and naphthalen-2-yl isocyanate to give 3-biphenyl-4-yl-3- {2- [3- (3- Naphthalen-2-ylureido) propanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [3- (3-naphthalen-2-ylureido) propanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.829 min, FAB-MS (M + H) + 539.2 (EMD388117) was obtained.
    [346] Similar to Example 1, the resin "BC" is reacted with FMOC protected β-alanine and benzyl isothiocyanate to give 3-biphenyl-4-yl-3- {2- [3- (3-benzyl Thioureido) propanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [3- (3-benzylthioureido) propanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.77 min, FAB- MS (M + H) + 519.2 (EMD 388118) was obtained.
    [347] Similar to Example 1, the resin "BC" was reacted with FMOC protected β-alanine and 4-methylbenzyl isocyanate to give 3-biphenyl-4-yl-3- {2- [3- (3- ( 4-methylbenzyl) ureido) propanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [3- (3- (4-methylbenzyl) ureido) propanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.696 min , FAB-MS (M + H) + 517.2 (EMD 388119) was obtained.
    [348] Similar to Example 1, the resin "BC" was reacted with FMOC protected β-alanine and 2,4-dichlorobenzyl isocyanate to give 3-biphenyl-4-yl-3- {2- [3- (3 -(2,4-dichlorobenzyl) ureido) propanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [3- (3- (2,4-dichlorobenzyl) ureido) propanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.852 min, FAB-MS (M + H) + 572.1 (EMD 388120) was obtained.
    [349] Similar to Example 1, the resin "BC" is reacted with FMOC protected β-alanine and 4-fluorobenzyl isocyanate to give 3-biphenyl-4-yl-3- {2- [3- (3- (4-fluorobenzyl) ureido) propanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [3- (3- (4-fluorobenzyl) ureido) propanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.632 Min, FAB-MS (M + H) + 521.2 (EMD 388121) was obtained.
    [350] Similar to Example 1, the resin "BC" was reacted with FMOC protected β-alanine and 3,4-dichlorobenzyl isocyanate to give 3-biphenyl-4-yl-3- {2- [3- (3 -(3,4-dichlorobenzyl) ureido) propanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [3- (3- (3,4-dichlorobenzyl) ureido) propanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.833 min, FAB-MS (M + H) + 572.2 (EMD 388122) were obtained.
    [351] Similar to Example 1, the resin "BC" was reacted with FMOC protected β-alanine and 2-chlorobenzyl isocyanate to give 3-biphenyl-4-yl-3- {2- [3- (3- ( 2-chlorobenzyl) ureido) propanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [3- (3- (2-chlorobenzyl) ureido) propanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.694 min , FAB-MS (M + H) + 537.2 / 539 (EMD 388123) was obtained.
    [352] Similar to Example 1, the resin "BC" was reacted with FMOC protected β-alanine and n-propyl isocyanate to give 3-biphenyl-4-yl-3- {2- [3- (3- (3 -Propyl) ureido) propanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [3- (3- (3-propyl) ureido) propanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.418 min, FAB-MS (M + H) + 455.2 (EMD 388124) were obtained.
    [353] Similar to Example 1, the resin "BC" is reacted with FMOC protected β-alanine and allyl isocyanate to give 3-biphenyl-4-yl-3- {2- [3- (3-allylureido) Propanoylamino] ethanoaminoamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [3- (3-allylureido) propanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.376 min, FAB-MS ( M + H) + 453.2 (EMD 388125) was obtained.
    [354] Similar to Example 1, the resin "BC" was reacted with FMOC protected 5-aminopentanoic acid and isocyanic acid to yield 3-biphenyl-4-yl-3- [2- (5-ureidopentanoylamino ) Ethanoylamino] propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- [2- (5-ureidopentanoylamino) ethanoylamino] propionic acid trifluoroacetate, RT 1.225 min, FAB-MS (M + H) + 441.2 (EMD 388126) was obtained.
    [355] Similar to Example 1, the resin "BC" was reacted with FMOC protected 5-aminopentanoic acid and ethylisocyanic acid to yield 3-biphenyl-4-yl-3- {2- [5- (3-ethyl Ureido) pentanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [5- (3-ethylureido) pentanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.354 min, FAB-MS (M + H) + 496.2 (EMD 388127) were obtained.
    [356] Similar to Example 1, the resin "BC" is reacted with FMOC protected 5-aminopentanoic acid and cyclohexyl isocyanate to give 3-biphenyl-4-yl-3- {2- [5- (3-cyclohexyl Ureido) pentanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [5- (3-cyclohexylureido) pentanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.678 min, FAB-MS ( M + H) + 523.2 (EMD 388128).
    [357] Similar to Example 1, the resin "BC" was reacted with FMOC protected 5-aminopentanoic acid and isopropyl isocyanate to give 3-biphenyl-4-yl-3- {2- [5- (3-isopropyl Ureido) pentanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [5- (3-isopropylureido) pentanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.447 min, FAB-MS ( M + H) + 483.2 (EMD 388129) was obtained.
    [358] Similar to Example 1, the resin "BC" is reacted with FMOC protected 5-aminopentanoic acid and n-butyl isocyanate to give 3-biphenyl-4-yl-3- {2- [5- (3-butyl Ureido) pentanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [5- (3-butylureido) pentanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.572 min, FAB-MS (M + H) + 497.2 (EMD 388130) were obtained.
    [359] Similar to Example 1, the resin "BC" is reacted with FMOC protected 5-aminopentanoic acid and tert-butyl isocyanate to give 3-biphenyl-4-yl-3- {2- [5- (3-tert -Butylureido) pentanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [5- (3-tert-butylureido) pentanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.588 min, FAB-MS (M + H) + 497.2 (EMD 388131) were obtained.
    [360] Similar to Example 1, the resin "BC" was reacted with FMOC protected 5-aminopentanoic acid and methylisothiocyanate to give 3-biphenyl-4-yl-3- {2- [5- (3- Methylthioureido) pentanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [5- (3-methylthioureido) pentanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.393 min, FAB-MS (M + H) + 471.2 (EMD 388132) was obtained.
    [361] Similar to Example 1, the resin "BC" was reacted with FMOC protected 5-aminopentanoic acid and phenyl isocyanate to give 3-biphenyl-4-yl-3- {2- [5- (3-phenylureido ) Pentanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [5- (3-phenylureido) pentanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.645 min, FAB-MS (M + H) + 517.2 (EMD 388133) was obtained.
    [362] Similar to Example 1, the resin "BC" was reacted with FMOC protected 5-aminopentanoic acid and phenylethyl isocyanate to give 3-biphenyl-4-yl-3- {2- [5- (3-phenylethyl Ureido) pentanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [5- (3-phenylethylureido) pentanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.698 min, FAB-MS ( M + H) + 545.2 (EMD 388134) was obtained.
    [363] Similar to Example 1, the resin "BC" was reacted with FMOC protected 5-aminopentanoic acid and 2-chlorophenyl isocyanate to give 3-biphenyl-4-yl-3- {2- [5- (3- (2-Chlorophenyl) ureido) pentanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [5- (3- (2-chlorophenyl) ureido) pentanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.768 min, FAB-MS (M + H) + 551.2 / 553 (EMD 388135) were obtained.
    [364] Similar to Example 1, the resin "BC" was reacted with FMOC protected 5-aminopentanoic acid and 3-chlorophenyl isocyanate to give 3-biphenyl-4-yl-3- {2- [5- (3- (3-chlorophenyl) ureido) pentanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [5- (3- (3-chlorophenyl) ureido) pentanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.823 min, FAB-MS (M + H) + 551.2 / 553 (EMD 388136) were obtained.
    [365] Similar to Example 1, the resin "BC" was reacted with FMOC protected 5-aminopentanoic acid and 4-chlorophenyl isocyanate to give 3-biphenyl-4-yl-3- {2- [5- (3- (4-Chlorophenyl) ureido) pentanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [5- (3- (4-chlorophenyl) ureido) pentanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.816 min, FAB-MS (M + H) + 551.04 / 553 (EMD 388137) were obtained.
    [366] Similar to Example 1, the resin "BC" was reacted with FMOC protected 5-aminopentanoic acid and 2-methoxyphenyl isocyanate to give 3-biphenyl-4-yl-3- {2- [5- (3 -(2-methoxyphenyl) ureido) pentanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [5- (3- (2-methoxyphenyl) ureido) pentanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.693 min , FAB-MS (M + H) + 547.2 (EMD 388138) was obtained.
    [367] Similar to Example 1, the resin "BC" was reacted with FMOC protected 5-aminopentanoic acid and 4-methoxyphenyl isocyanate to give 3-biphenyl-4-yl-3- {2- [5- (3 -(4-methoxyphenyl) ureido) pentanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [5- (3- (4-methoxyphenyl) ureido) pentanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.602 min , FAB-MS (M + H) + 547.2 (EMD 388139) was obtained.
    [368] Similar to Example 1, the resin "BC" was reacted with FMOC protected 5-aminopentanoic acid and 3-methoxyphenyl isocyanate to give 3-biphenyl-4-yl-3- {2- [5- (3 -(3-methoxyphenyl) ureido) pentanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [5- (3- (3-methoxyphenyl) ureido) pentanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.660 min , FAB-MS (M + H) + 547.2 (EMD 388140) was obtained.
    [369] Similar to Example 1, the resin "BC" was reacted with FMOC protected 3-amino-propanoic acid and (9H-fluoren-9-yl) methyl formate, resulting in 3-biphenyl-4-yl-3 -{2- [3- (9H-Fluoren-9-yl-methoxycarbonylamino) propanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [3- (9H-fluoren-9-yl-methoxycarbonylamino) propanoylamino] ethanoaminoamino} propionic acid trifluoroacetate , RT 2.089 min, FAB-MS (M + H) + 529.2 (EMD 388141) were obtained.
    [370] Similar to Example 1, the resin "BC" is reacted with FMOC protected 4-aminobutanoic acid and (9H-fluoren-9-yl) methyl formate to yield 3-biphenyl-4-yl-3- {2- [4- (9H-Fluoren-9-yl-methoxycarbonylamino) butanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (9H-fluoren-9-yl-methoxycarbonylamino) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 2.120 min, FAB-MS (M + H) + 606.2 (EMD 388142) were obtained.
    [371] Similar to Example 1, the resin "BC" was reacted with FMOC protected 5-aminopentanoic acid and (9H-fluoren-9-yl) methyl formate, yielding 3-biphenyl-4-yl-3- { 2- [5- (9H-Fluoren-9-yl-methoxycarbonylamino) pentanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [5- (9H-fluoren-9-yl-methoxycarbonylamino) pentanoylamino] ethanoaminoamino} propionic acid trifluoroacetate, RT2.142 min, FAB-MS (M + H) + 620.2 (EMD 388143) was obtained.
    [372] Similar to Example 1, the resin "BC" is reacted with FMOC protected 4-aminobutanoic acid and (R) -1-phenylethyl isocyanate to give 3-biphenyl-4-yl-3- {2- [ 4- (3-((R) -1-phenylethyl) ureido) butanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (3-((R) -1-phenylethyl) ureido) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.677 min, FAB-MS (M + H) + 531.2 (EMD 388181) were obtained.
    [373] Similar to Example 1, the resin "BC" was reacted with FMOC protected 4-aminobutanoic acid and (S) -1-phenylethyl isocyanate to give 3-biphenyl-4-yl-3- {2- [ 4- (3-((S) -1-phenylethyl) ureido) butanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (3-((S) -1-phenylethyl) ureido) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.674 min, FAB-MS (M + H) + 531.2 (EMD 388182) were obtained.
    [374] Similar to Example 1, the resin "BC" was reacted with FMOC protected 4-aminobutanoic acid and naphthalen-1-yl isocyanate to give 3-biphenyl-4-yl-3- {2- [4- ( 3-naphthalen-1-ylureido) butanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (3-naphthalen-1-ylureido) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.756 min, FAB -MS (M + H) + 553.2 (EMD388183) were obtained.
    [375] Similar to Example 1, the resin "BC" was reacted with FMOC protected 4-aminobutanoic acid and benzyl isothiocyanate to give 3-biphenyl-4-yl-3- {2- [4- (3 -Benzylthioureido) butanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (3-benzylthioureido) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.765 min, FAB-MS (M + H) + 533.2 (EMD 388185) were obtained.
    [376] Similar to Example 1, the resin "BC" was reacted with FMOC protected 4-aminobutanoic acid and naphthalen-2-yl isocyanate to give 3-biphenyl-4-yl-3- {2- [4- ( 3-naphthalen-2-ylureido) butanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (3-naphthalen-2-ylureido) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.842 min, FAB -MS (M + H) + 553.2 (EMD 388186) were obtained.
    [377] Similar to Example 1, the resin "BC" is reacted with FMOC protected 4-aminobutanoic acid and 4-methylbenzyl isocyanate to give 3-biphenyl-4-yl-3- {2- [4- (3 -(4-methylbenzyl) ureido) butanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (3- (4-methylbenzyl) ureido) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.706 min, FAB-MS (M + H) + 531.2 (EMD 388187) were obtained.
    [378] Similar to Example 1, the resin "BC" was reacted with FMOC protected 4-aminobutanoic acid and 3-methylbenzyl isocyanate to give 3-biphenyl-4-yl-3- {2- [4- (3 -(3-methylbenzyl) ureido) butanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (3- (3-methylbenzyl) ureido) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.705 min, FAB-MS (M + H) + 531.2 (EMD 388188) were obtained.
    [379] Similar to Example 1, the resin "BC" is reacted with FMOC protected 4-aminobutanoic acid and 2-methylbenzyl isocyanate to give 3-biphenyl-4-yl-3- {2- [4- (3 -(2-methylbenzyl) ureido) butanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (3- (2-methylbenzyl) ureido) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.691 min, FAB-MS (M + H) + 531.2 (EMD 388189) were obtained.
    [380] Similar to Example 1, the resin "BC" is reacted with FMOC protected 4-aminobutanoic acid and 2,4-dichlorobenzyl isocyanate to give 3-biphenyl-4-yl-3- {2- [4- (3- (2,4-dichlorobenzyl) ureido) butanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (3- (2,4-dichlorobenzyl) ureido) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.864 Minutes, FAB-MS (M + H) + 585.2 / 587 (EMD 388190) were obtained.
    [381] Similar to Example 1, the resin "BC" was reacted with FMOC protected 4-aminobutanoic acid and 4-fluorobenzyl isocyanate to give 3-biphenyl-4-yl-3- {2- [4- ( 3- (4-fluorobenzyl) ureido) butanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (3- (4-fluorobenzyl) ureido) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.646 min , FAB-MS (M + H) + 535.2 (EMD 388191) was obtained.
    [382] Similar to Example 1, the resin "BC" is reacted with FMOC protected 4-aminobutanoic acid and 3,4-dichlorobenzyl isocyanate to give 3-biphenyl-4-yl-3- {2- [4- (3- (3,4-dichlorobenzyl) ureido) butanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (3- (3,4-dichlorobenzyl) ureido) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.851 Minutes, FAB-MS (M + H) + 585.2 / 587 (EMD 388192) were obtained.
    [383] Similar to Example 1, the resin "BC" was reacted with FMOC protected 4-aminobutanoic acid and 2-chlorobenzyl isocyanate to give 3-biphenyl-4-yl-3- {2- [4- (3 -(2-chlorobenzyl) ureido) butanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (3- (2-chlorobenzyl) ureido) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.713 min, FAB-MS (M + H) + 551.2 / 553 (EMD 388193) were obtained.
    [384] Similar to Example 1, the resin "BC" was reacted with FMOC protected 4-aminobutanoic acid and 4-methoxybenzyl isocyanate to give 3-biphenyl-4-yl-3- {2- [4- ( 3- (4-methoxybenzyl) ureido) butanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (3- (4-methoxybenzyl) ureido) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.598 min , FAB-MS (M + H) + 547.2 (EMD 388194) was obtained.
    [385] Similar to Example 1, the resin "BC" was reacted with FMOC protected 4-aminobutanoic acid and n-propyl isocyanate to give 3-biphenyl-4-yl-3- {2- [4- (3- Propylureido) butanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (3-propylureido) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.432 min, FAB-MS (M + H) + 469.2 (EMD 388195) was obtained.
    [386] Similar to Example 1, the resin "BC" was reacted with FMOC protected 4-aminobutanoic acid and allyl isocyanate to give 3-biphenyl-4-yl-3- {2- [4- (3-allylureiure Butanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (3-allylureido) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.393 min, FAB-MS (M + H) + 467.2 (EMD 388196) was obtained.
    [387] Similar to Example 1, the resin "BC" was reacted with FMOC protected 5-aminopentanoic acid and (R) -1-phenylethyl isocyanate to give 3-biphenyl-4-yl-3- {2- [5 -(3-((R) -1-phenylethyl) ureido) pentanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [5- (3-((R) -1-phenylethyl) ureido) pentanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.694 min, FAB-MS (M + H) + 545.2 (EMD 388197) was obtained.
    [388] Similar to Example 1, the resin "BC" was reacted with FMOC protected 5-aminopentanoic acid and (S) -1-phenylethyl isocyanate to give 3-biphenyl-4-yl-3- {2- [5 -(3-((S) -1-phenylethyl) ureido) pentanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [5- (3-((S) -1-phenylethyl) ureido) pentanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.698 min, FAB-MS (M + H) + 545.2 (EMD 388198) was obtained.
    [389] Similar to Example 1, the resin "BC" was reacted with FMOC protected 5-aminopentanoic acid and naphthalen-1-yl isocyanate to give 3-biphenyl-4-yl-3- {2- [5- (3 -Naphthalen-1-ylureido) pentanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [5- (3-naphthalen-1-ylureido) pentanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.780 min, FAB -MS (M + H) + 567.2 (EMD 388199) were obtained.
    [390] Similar to Example 1, the resin "BC" was reacted with FMOC protected 5-aminopentanoic acid and benzyl isothiocyanate to give 3-biphenyl-4-yl-3- {2- [5- (3- Benzylthioureido) pentanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [5- (3-benzylthioureido) pentanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.788 min, FAB-MS (M + H) + 547.3 (EMD 388200) were obtained.
    [391] Similar to Example 1, the resin "BC" was reacted with FMOC protected 5-aminopentanoic acid and naphthalen-2-yl isocyanate to give 3-biphenyl-4-yl-3- {2- [5- (3 Naphthalen-2-ylureido) pentanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [5- (3-naphthalen-2-ylureido) pentanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.862 min, FAB -MS (M + H) + 567.2 (EMD 388201) was obtained.
    [392] Similar to Example 1, the resin "BC" was reacted with FMOC protected 5-aminopentanoic acid and 4-methylbenzyl isocyanate to give 3-biphenyl-4-yl-3- {2- [5- (3- (4-methylbenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [5- (3- (4-methylbenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.729 min, FAB-MS (M + H) + 545.2 (EMD 388202) were obtained.
    [393] Similar to Example 1, the resin "BC" is reacted with FMOC protected 5-aminopentanoic acid and 3-methylbenzyl isocyanate to give 3-biphenyl-4-yl-3- {2- [5- (3- (3-methylbenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [5- (3- (3-methylbenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.724 min, FAB-MS (M + H) + 545.2 (EMD 388203) were obtained.
    [394] Similar to Example 1, the resin "BC" is reacted with FMOC protected 5-aminopentanoic acid and 2-methylbenzyl isocyanate to give 3-biphenyl-4-yl-3- {2- [5- (3- (2-methylbenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [5- (3- (2-methylbenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.708 min, FAB-MS (M + H) + 545.2 (EMD 388204) were obtained.
    [395] Similar to Example 1, the resin "BC" was reacted with FMOC protected 5-aminopentanoic acid and 2,4-dichlorobenzyl isocyanate to give 3-biphenyl-4-yl-3- {2- [5- ( 3- (2,4-dichlorobenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [5- (3- (2,4-dichlorobenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.891 Min, FAB-MS (M + H) + 600.2 (EMD 388205) were obtained.
    [396] Similar to Example 1, the resin "BC" was reacted with FMOC protected 5-aminopentanoic acid and 4-fluorobenzyl isocyanate to give 3-biphenyl-4-yl-3- {2- [5- (3 -(4-fluorobenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [5- (3- (4-fluorobenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.669 min , FAB-MS (M + H) + 549.2 (EMD 388206) was obtained.
    [397] Similar to Example 1, the resin "BC" was reacted with FMOC protected 5-aminopentanoic acid and 3,4-dichlorobenzyl isocyanate to give 3-biphenyl-4-yl-3- {2- [5- ( 3- (3,4-dichlorobenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [5- (3- (3,4-dichlorobenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.875 Min, FAB-MS (M + H) + 600.2 (EMD 388207) were obtained.
    [398] Similar to Example 1, the resin "BC" is reacted with FMOC protected 5-aminopentanoic acid and 2-chlorobenzyl isocyanate to give 3-biphenyl-4-yl-3- {2- [5- (3- (2-chlorobenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [5- (3- (2-chlorobenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.735 min, FAB-MS (M + H) + 565.2 / 567.2 (EMD 388208) were obtained.
    [399] Similar to Example 1, the resin "BC" was reacted with FMOC protected 5-aminopentanoic acid and 4-methoxybenzyl isocyanate to give 3-biphenyl-4-yl-3- {2- [5- (3 -(4-methoxybenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [5- (3- (4-methoxybenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.622 min , FAB-MS (M + H) + 561.2 (EMD 388209) was obtained.
    [400] Similar to Example 1, the resin "BC" is reacted with FMOC protected 5-aminopentanoic acid and n-propyl isocyanate to give 3-biphenyl-4-yl-3- {2- [5- (3-propyl Ureido) pentanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [5- (3-propylureido) pentanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.451 min, FAB-MS (M + H) + 483.2 (EMD 388210) was obtained.
    [401] Similar to Example 1, the resin "BC" is reacted with FMOC protected 5-aminopentanoic acid and allyl isocyanate to give 3-biphenyl-4-yl-3- {2- [5- (3-allylureido ) Pentanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [5- (3-allylureido) pentanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.414 min, FAB-MS (M + H) + 481.2 (EMD 388211) was obtained.
    [402] Similar to Example 1, the resin "BC" was reacted with FMOC protected 3-aminopropanoic acid and ethyl formate to yield 3-biphenyl-4-yl-3- [2- (3-ethoxycarbonyl Aminopropanoylamino) ethanoaminoamino] propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- [2- (3-ethoxycarbonylaminopropanoylamino) ethanoylamino] propionic acid trifluoroacetate, RT 1.467 min, FAB-MS (M + H) + 442.2 (EMD 391898) was obtained.
    [403] Similar to Example 1, the resin "BC" is reacted with FMOC protected 3-aminopropanoic acid and benzyl formate to yield 3-biphenyl-4-yl-3- [2- (3-benzyloxycarbonyl Aminopropanoylamino) ethanoaminoamino] propionic acid was obtained. Preparative HPLC -biphenyl-4-yl-3- [2- (3-benzyloxycarbonylaminopropanoylamino) ethanoylamino] propionic acid trifluoroacetate, RT 1.758 min, FAB-MS (M + H ) + 504.2 (EMD 391899) was obtained.
    [404] Similar to Example 1, the resin "BC" was reacted with FMOC protected 3-aminopropanoic acid and 2,2-dimethylpropyl formate to yield 3-biphenyl-4-yl-3- {2- [3 -(2,2-dimethyl-propoxycarbonylamino) propanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [3- (2,2-dimethyl-propoxycarbonylamino) propanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.801 Min, FAB-MS (M + H) + 484.2 (EMD 391900) were obtained.
    [405] Similar to Example 1, the resin "BC" was reacted with FMOC protected 4-aminobutanoic acid and ethyl formate, yielding 3-biphenyl-4-yl-3-[-2- (4-ethoxycarbine. Bonylaminobutanoylamino) ethanoaminoamino] propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3-[-2- (4-ethoxycarbonylaminobutanoylamino) ethanoylamino] propionic acid trifluoroacetate, RT 1.501 min, FAB-MS (M + H) + 456.2 (EMD 391901) were obtained.
    [406] Similar to Example 1, the resin "BC" is reacted with FMOC protected 4-aminobutanoic acid and benzyl formate to give 3-biphenyl-4-yl-3- [2- (4-benzyloxycarbonyl Aminobutanoylamino) ethanoylamino] propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- [2- (4-benzyloxycarbonylaminobutanoylamino) ethanoylamino] propionic acid trifluoroacetate, RT 1.789 min, FAB-MS (M + H ) + 518.2 (EMD 391902) was obtained.
    [407] Similar to Example 1, the resin "BC" was reacted with FMOC protected 4-aminobutanoic acid and 2,2-dimethyl propyl formate to yield 3-biphenyl-4-yl-3- {2- [4 -(2,2-dimethyl-propoxycarbonylamino) butanoylamino] ethanoylamino} propionic acid was obtained. Preparative HPLC 3-biphenyl-4-yl-3- {2- [4- (2,2-dimethyl-propoxycarbonylamino) butanoylamino] ethanoylamino} propionic acid trifluoroacetate, RT 1.842 min , FAB-MS (M + H) + 498.2 (EMD 391903) was obtained.
    [408] The following examples relate to pharmaceutical formulations:
    [409] Example A: Injection Vials
    [410] A solution of 3 g bidistilled water of 100 g of active ingredient of formula (I) and 5 g of disodium hydrogen phosphate was adjusted to pH 6.5 with 2N hydrochloric acid, sterile filtered, transferred to an injection vial, and sterilized conditions. Lyophilized and sealed under sterile conditions. Each injection vial contains 5 mg of active ingredient.
    [411] Example B: Suppositories
    [412] 20 g of a mixture of the active ingredient of formula I were melted with 100 g soy lecithin and 1400 g cocoa butter, poured into a mold and cooled. Each suppository contains 20 mg of active ingredient.
    [413] Example C: Solution
    [414] The solution was prepared from 1 g of active ingredient of formula I, 9.38 g of NaH 2 PO 4 .2H 2 O, 28.48 g of Na 2 HPO 4 .12H 2 O and 0.1 g of benzalkonium chloride in 940 mL distilled water. The pH was adjusted to 6.8 and the solution made to 1 L and then sterilized by irradiation. The solution may be used in the form of eye drops.
    [415] Example D: Ointment
    [416] 500 mg of the active ingredient of formula (I) were mixed with 99.5 g of petrolatum under aseptic conditions.
    [417] Example E: Tablets
    [418] A mixture of 1 Kg of active ingredient of Formula I, 4 Kg of lactose, 1.2 Kg of potato starch, 0.2 Kg of talc, and 0.1 Kg of magnesium stearate is prepared in a conventional manner such that each tablet contains 10 mg of active ingredient. It was pressed to obtain a tablet.
    [419] Example F: Coated Tablets
    [420] Similar to Example E, the tablets were compressed and then coated in a conventional manner using sucrose, potato starch, talc, tragacanth and dyes.
    [421] Example G: Capsule
    [422] 2 Kg of the active ingredient of formula (I) was introduced in a conventional manner into the hard gelatin capsules such that each capsule contained 20 mg of the active ingredient.
    [423] Example H: Ampoules
    [424] A solution of 60 L of distilled water of 1 Kg of active ingredient of formula I was sterile filtered, delivered in ampoules, lyophilized under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.
    [425] Example I: Inhalation Spray
    [426] 14 g of the active ingredient of formula (I) were dissolved in 10 L of an isotonic NaCl solution and the solution was delivered to a commercial spray vessel by a pump mechanism. The solution can be sprayed into the mouth or nose. One spray shot (about 0.1 mL) corresponds to a dosage of about 0.14 mg.
    权利要求:
    Claims (9)
    [1" claim-type="Currently amended] Compounds of formula I, stereoisomers thereof and physiologically acceptable salts and solvates thereof:
    [Formula I]
    [In the meal,
    X is O or S,
    Y is independently of each other NH, O or S,
    R 1 , R 1 ′ and R 1 ″ are H, A, Ar, Het, Hal, NO 2 , CN, OH, OA, NH 2 , NHA, NA 2 , COOH, COOA, CONH 2 , CONHA or CONA 2 ,
    R 2 is H, A, alkenyl having 1 to 8 carbon atoms and having 1 to 2 double bonds, (CH 2 ) m Ar, (CH 2 ) m Het, (CH 2 ) m cycloalkyl, (CH 2 ) m CHAAr, (CH 2 ) m CHAHet or (CH 2 ) m CHA-cycloalkyl,
    A is alkyl having 1 to 8 carbons,
    Het is unsubstituted or Hal, A, OH, OA, SA, OCF 3 , -CO-A, CN, COOA, COOH, CONH 2 , CONHA, CONA 2 , NH 2 , NHA, NA 2 and / or NO 2 An aromatic monocyclic or bicyclic heterocyclic radical having 1 to 4 N, O and / or S atoms, which may be monosubstituted or disubstituted,
    m is 0, 1 or 2,
    n is 1, 2, 3 or 4;
    [2" claim-type="Currently amended] A compound according to claim 1 which is:
    3-biphenyl-4-yl-3- {2- [3- (3-benzylthioureido) propanoylamino] ethanoaminoamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (3-benzylureido) butanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- [2- (4-ureidobutanoylamino) ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (3-ethylureido) butanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (3-cyclohexylureido) butanoylamino] ethanoaminoamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (3-isoproylureido) butanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (3-butylureido) butanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (3-tert-butylureido) butanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (3-methylthioureido) butanoylamino] ethanoaminoamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (3-methylthioureido) butanoylamino] ethanoaminoamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (3-phenylureido) butanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (3-phenylethylureido) butanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (3- (2-chlorophenyl) ureido) butanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (3- (3-chlorophenyl) ureido) butanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (3- (4-chlorophenyl) ureido) butanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (3- (2-methoxyphenyl) ureido) butanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (3- (4-methoxyphenyl) ureido) butanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- [2- (3-ureidopropanoylamino) ethanoylamino] propionic acid,
    3-biphenyl-4-yl-3- {2- [3- (3-ethylureido) propanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [3- (3-cyclohexylureido) propanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [3- (3-butylureido) propanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [3- (3-tert-butylureido) propanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [3- (3-methylthioureido) propanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [3- (3-phenylureido) propanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [3- (3-phenylethylureido) propanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [3- (3- (2-chlorophenylethyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [3- (3- (3-chlorophenylethyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [3- (3- (4-chlorophenylethyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [3- (3- (2-methoxyphenyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [3- (3- (4-methoxyphenyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [3- (3- (3-methoxyphenyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [3- (3-((R) -1-phenylethyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [3- (3-((S) -1-phenylethyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [3- (3-((R) -1-naphthalen-1-ylethyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [3- (3-((S) -1-naphthalen-1-ylethyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [3- (3-naphthalen-1-ylureido) propanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [3- (3-naphthalen-2-ylureido) propanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [3- (3-benzylthioureido) propanoylamino] ethanoaminoamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [3- (3- (4-methylbenzyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [3- (3- (2,4-dichlorobenzyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [3- (3- (4-fluorobenzyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [3- (3- (3,4-dichlorobenzyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [3- (3- (2-chlorobenzyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [3- (3- (3-propyl) ureido) propanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [3- (3-allylureido) propanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- [2- (5-ureidopentanoylamino) ethanoylamino] propionic acid,
    3-biphenyl-4-yl-3- {2- [5- (3-ethylureido) pentanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [5- (3-cyclohexylureido) pentanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [5- (3-isopropylureido) pentanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [5- (3-butylureido) pentanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [5- (3-tert-butylureido) pentanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [5- (3-methylthioureido) pentanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [5- (3-phenylureido) pentanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [5- (3-phenylethylureido) pentanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [5- (3- (2-chlorophenyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [5- (3- (3-chlorophenyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [5- (3- (4-chlorophenyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [5- (3- (2-methoxyphenyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [5- (3- (4-methoxyphenyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [5- (3- (3-methoxyphenyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (3-((R) -1-phenylethyl) ureido) butanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (3-((S) -1-phenylethyl) ureido) butanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (3-naphthalen-1-ylureido) butanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (3-benzylthioureido) butanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (3-naphthalen-2-ylureido) butanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (3- (4-methylbenzyl) ureido) butanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (3- (3-methylbenzyl) ureido) butanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (3- (2-methylbenzyl) ureido) butanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (3- (2,4-dichlorobenzyl) ureido) butanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (3- (4-fluorobenzyl) ureido) butanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (3- (3,4-dichlorobenzyl) ureido) butanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (3- (2-chlorobenzyl) ureido) butanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (3- (4-methoxybenzyl) ureido) butanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (3-propylureido) butanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (3-allylureido) butanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [5- (3-((R) -1-phenylethyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [5- (3-((S) -1-phenylethyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [5- (3-naphthalen-1-ylureido) pentanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [5- (3-benzylthioureido) pentanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [5- (3-naphthalen-2-ylureido) pentanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [5- (3- (4-methylbenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [5- (3- (3-methylbenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [5- (3- (2-methylbenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [5- (3- (2,4-dichlorobenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [5- (3- (4-fluorobenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [5- (3- (3,4-dichlorobenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [5- (3- (2-chlorobenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [5- (3- (4-methoxybenzyl) ureido) pentanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [5- (3-propylureido) pentanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [5- (3-allylureido) pentanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [3- (9H-fluoren-9-yl-methoxycarbonylamino) propanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (9H-fluoren-9-yl-methoxycarbonylamino) butanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [5- (9H-fluoren-9-yl-methoxycarbonylamino) pentanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- [2- (3-ethoxycarbonylaminopropanoylamino) ethanoylamino] propionic acid,
    3-biphenyl-4-yl-3- [2- (3-benzyloxycarbonylaminopropanoylamino) ethanoylamino] propionic acid,
    3-biphenyl-4-yl-3- {2- [3- (2,2-dimethylpropoxycarbonylamino) propanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- [2- (4-ethoxycarbonylaminobutanoylamino) ethanoylamino] propionic acid,
    3-biphenyl-4-yl-3- [2- (4-benzyloxycarbonylaminobutanoylamino) ethanoaminoamino] propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (2,2-dimethylpropoxycarbonylamino) butanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [3- (9H-fluoren-9-yl-methoxycarbonylamino) propanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [4- (9H-fluoren-9-yl-methoxycarbonylamino) butanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- {2- [5- (9H-fluorene-9-ylmethoxycarbonylamino) pentanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- [2- (3-ethoxycarbonylaminopropanoylamino) ethanoylamino] propionic acid,
    3-biphenyl-4-yl-3- [2- (3-benzyloxycarbonylaminopropanoylamino) ethanoylamino] propionic acid,
    3-biphenyl-4-yl-3- {2- [3- (2,2-dimethylpropoxycarbonylamino) propanoylamino] ethanoylamino} propionic acid,
    3-biphenyl-4-yl-3- [2- (4-ethoxycarbonylaminobutanoylamino) ethanoylamino] propionic acid,
    3-biphenyl-4-yl-3- [2- (4-benzyloxycarbonylaminobutanoylamino) ethanoylamino] propionic acid, or
    3-biphenyl-4-yl-3- {2- [4- (2,2-dimethylpropoxycarbonylamino) butanoylamino] ethanoylamino} propionic acid.
    [3" claim-type="Currently amended] A process for preparing the compound of formula (I), stereoisomers thereof and salts and solvates thereof according to claim 1, characterized by the following:
    (a) reacting a compound of formula II with a compound of formula III:
    [Formula II]
    [Wherein R is a protecting group and R 1 , R 1 ′ and R 1 ″ are as defined in Formula I, wherein R 1 , R 1 ′ and / or R 1 ″ have free hydroxyl or amino groups In each case protected by a protector],
    [Formula III]
    [Wherein R 2 and n are as defined in formula I, wherein if R 2 contains free hydroxyl and / or amino groups, they are in each case protected with a protecting group],
    Removing the protecting groups R and any protecting groups present on R 1 , R 1 ′ , R 1 ″ and / or R 2 ;
    or
    (b) reacting a compound of formula IV with a compound of formula V:
    [Formula IV]
    [Wherein R is a protecting group and R 1 , R 1 ′ and R 1 ″ are as defined in Formula I, wherein R 1 , R 1 ′ and / or R 1 ″ are free hydroxyl and / or amino groups , In each case protected by a protecting group],
    [Formula V]
    Wherein n and R 2 are as defined in formula (I), wherein if R 2 has free hydroxyl and / or amino groups, they are in each case protected with a protecting group],
    Removing the protecting groups R and any protecting groups present on R 1 , R 1 ′ , R 1 ″ and / or R 2 ;
    or
    (c) Conversion from the compounds of formula (I) by one or more radicals R 1, R 1 ', R 1 " and / or R 2 of one or more radicals for the R 1, R 1', R 1" and / or R 2 Sikkim:
    i) alkylating hydroxyl groups,
    ii) hydrolyzing ester groups to carboxyl groups,
    iii) esterifying a carboxyl group,
    iv) alkylating amino groups,
    v) reacting the aryl bromide or iodide with boric acid by Suzuki coupling to obtain the corresponding coupling product, or
    vi) acylating amino groups,
    or
    (d) a compound of formula VI:
    [Formula VI]
    Wherein the free amino group is protected by a protecting group
    Is a compound of Formula II wherein R is a protecting group and R 1 , R 1 ′ and R 1 ″ are as defined in Formula I, wherein R 1 , R 1 ′ and / or R 1 ″ are free hydroxide In the case of having a hydroxyl or amino group, they are in each case protected with a protecting group] so that the compound of formula IV wherein R is a protecting group and R 1 , R 1 ′ and R 1 ″ are defined as Wherein, where R 1 , R 1 ′ and / or R 1 ″ have free hydroxyl or amino groups, they are in each case protected with a protecting group],
    Remove the protecting group on the amino group,
    Subsequently, as described in (b), the compound of formula IV is converted to a compound of formula V, wherein n and R 2 are as defined in formula I, wherein R 2 is a free hydroxyl and / or amino group If contained, they are in each case protected with a protecting group] Removing the protecting groups R and any protecting groups present in R 1 , R 1 ′ , R 1 ″ and / or R 2 ,
    And / or
    Converting a basic or acidic compound of formula (I) to one of its salts or solvates by acid or base treatment.
    [4" claim-type="Currently amended] The compound of formula (I), its stereoisomers and physiologically acceptable salts or solvates thereof as claimed in claim 1 or 2 as a pharmaceutically active ingredient.
    [5" claim-type="Currently amended] 3. Compounds of formula (I), stereoisomers thereof and physiologically acceptable salts or solvates thereof according to claims 1 or 2 as integrin agonists and / or antagonists.
    [6" claim-type="Currently amended] The compound of formula (I), its stereoisomers and physiologically acceptable salts or solvates thereof according to claim 1 or 2, for use in the fight against disease.
    [7" claim-type="Currently amended] A pharmaceutical formulation containing at least one of a compound of formula (I), a stereoisomer thereof and / or a physiologically acceptable salt or solvate thereof according to claim 1.
    [8" claim-type="Currently amended] Use of a compound of formula (I), a stereoisomer thereof and / or a physiologically acceptable salt or solvate thereof according to claim 1 for the manufacture of a medicament.
    [9" claim-type="Currently amended] Circulatory disorders, pulmonary fibrosis, pulmonary embolism, thrombosis, in particular, deep vein thrombosis, myocardial infarction, arteriosclerosis, dissecting aneurysms, transient ischemic attack, stroke, angina, especially unstable angina, pathologically related tissue proliferation or fibrosis in the organs , Especially pulmonary fibrosis, also gallbladder fibrosis, skin fibrosis, liver fibrosis, liver cirrhosis, urethral fibrosis, kidney fibrosis, cardiac fibrosis, infantile endocardial fibrosis, pancreatic fibrosis, disturbed hornification of the skin, especially white plate , Squamous and squamous cell carcinoma, tumor diseases such as tumor development of solid tumors, tumor angiogenesis or tumor metastasis, and tumor diseases of the blood or immune system such as skin tumors, squamous cell carcinoma, blood vessels, gastrointestinal tract, lungs, chest, Liver, kidney, spleen, pancreas, brain, testes, ovaries, uterus, vagina, muscle, bone tumors, and tumors of the throat and head, bone soluble diseases such as osteoporosis, Hyperparathyroidism, Paget's disease, malignant calcium, inadequate transfusion, pathological angiogenesis disorders such as inflammation, ocular disease, diabetic retinopathy, macular degeneration, myopia, corneal transplantation, ocular histoplasmosis, rheumatoid Arthritis, osteoarthritis, neovascular glaucoma, ulcerative colitis, Crohn's disease, atherosclerosis, psoriasis, restenosis, in particular restenosis after angioplasty, multiple sclerosis, pregnancy, absumptio placentaris, viral infections, bacterial infections, fungal infections, Paragraph 1 or 2 for the prevention and / or treatment of foot and mouth disease (FMD), HIV, anthrax, Candida albicans, parasitic infections, acute kidney attacks and wound healing aids. Use of the compounds of the formula (I) described, stereoisomers thereof and / or physiologically acceptable salts or solvates thereof.
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    同族专利:
    公开号 | 公开日
    CN1501827A|2004-06-02|
    CA2444247A1|2002-10-24|
    US20040142877A1|2004-07-22|
    ZA200308857B|2004-09-13|
    DE10118550A1|2002-10-17|
    SK13732003A3|2004-02-03|
    PL363328A1|2004-11-15|
    JP2004528325A|2004-09-16|
    WO2002083627A2|2002-10-24|
    CZ20033000A3|2004-02-18|
    RU2003130639A|2005-04-10|
    EP1379495A2|2004-01-14|
    WO2002083627A3|2003-10-09|
    HU0303804A3|2005-09-28|
    BR0208885A|2004-06-29|
    MXPA03009318A|2004-02-12|
    HU0303804A2|2004-03-29|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2001-04-14|Priority to DE10118550.2
    2001-04-14|Priority to DE10118550A
    2002-03-13|Application filed by 메르크 파텐트 게엠베하
    2002-03-13|Priority to PCT/EP2002/002728
    2003-11-28|Publication of KR20030090739A
    优先权:
    申请号 | 申请日 | 专利标题
    DE10118550.2|2001-04-14|
    DE10118550A|DE10118550A1|2001-04-14|2001-04-14|New 3-ethanoylamino-3-phenyl-propionic acid derivatives, are integrin agonists or antagonists useful e.g. for treating angiogenic, cardiovascular, inflammatory, osteolytic or tumor diseases or infections|
    PCT/EP2002/002728|WO2002083627A2|2001-04-14|2002-03-13|Ligands des integrins avss6|
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