EP1379495A2 - Ligands de l'integrine alpha-v-beta 6 - Google Patents

Ligands de l'integrine alpha-v-beta 6

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Publication number
EP1379495A2
EP1379495A2 EP02747260A EP02747260A EP1379495A2 EP 1379495 A2 EP1379495 A2 EP 1379495A2 EP 02747260 A EP02747260 A EP 02747260A EP 02747260 A EP02747260 A EP 02747260A EP 1379495 A2 EP1379495 A2 EP 1379495A2
Authority
EP
European Patent Office
Prior art keywords
biphenyl
propionic acid
ethanoylamino
ureido
butanoylamino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02747260A
Other languages
German (de)
English (en)
Inventor
Oliver Schadt
Alfred Jonczyk
Wolfgang Stähle
Simon Goodman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1379495A2 publication Critical patent/EP1379495A2/fr
Withdrawn legal-status Critical Current

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Definitions

  • the invention relates to new compounds of formula I.
  • R 2 H, A alkenyl with 1 to 8 C atoms and 1 to 2
  • Double bonds (CH ⁇ r, (CH 2 ) m Het, (CH 2 ) m cycloalkyl, (CH 2 ) m CHAAr, (CH 2 ) m CHAHet, (CH 2 ) m CHACycloalkyl,
  • WO96 / 22966 A1 WO 97/08145 A1
  • WO 00/48996 A2 all compounds being active as integrin inhibitors.
  • Integrins are membrane-bound, heterodimeric glycoproteins that consist of an ⁇ subunit and a smaller ⁇ subunit. The relative affinity and specificity for ligand binding is determined by combining the different ⁇ and ⁇ subunits.
  • the compounds of WO 96/22966 A1 selectively inhibit the ⁇ 4 ⁇ r integrin receptor and the compounds of WO 97/08145 A1 selectively inhibit the ⁇ v ⁇ 3 integrin receptor.
  • the compounds of WO 00/48996 A2 primarily inhibit ⁇ v ⁇ 3 and ⁇ v ⁇ 5 integrin receptors.
  • the object of the invention was to find new compounds with valuable properties, in particular those which are used for the production of medicaments.
  • the compounds of the formula I and their salts have very valuable pharmacological properties with good tolerability.
  • the new compounds according to the invention are preferred ligands of the ⁇ v ⁇ 6 integrin receptor.
  • the compounds act in particular as antagonists, but can also act as agonists. While agonists have both affinity and intrinsic activity and stimulate receptors, antagonists inhibit the stimulatory effects of agonists.
  • the integrins have different physiological and pathological functions, which can be found in detail, for example, in the following reviews: 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.
  • the ⁇ v integrins play an important role, such as in The role of alpha v integrins in tumor progression and metastasis. Marshall JF; Hard 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).
  • ⁇ v ß 6 epithelial integrins there are also ⁇ v ß 6 epithelial integrins. Sheppard-D bioessays. 1996 Aug; 18 (8): 655-60 and the two integrins ⁇ v ß 3 and represent the known adhesion receptors, the biological meaning of which, for example, in JA Varner et al. Cell Adhesion and Communication 3, 367-374 (1995) and in J. Samanen et al. Curr. Pharmaceutical Design, 3, 545-584 (1997).
  • ⁇ v ß 6 is a relatively rare integrin (Busk et al., 1992 J. Biol. Chem. 267 (9), 5790), which is increasingly formed in repair processes in epithelial tissue and the natural matrix molecules fibronectin and tenascin preferably binds (Wang et al., 1996, Am. J. Respir. Cell Mol. Biol. 15 (5), 664). Vitronectin also binds to ⁇ v ß 6 (Characterization of the integrin alpha v beta 6 as a fibronectin-binding protein. Busk-M; Pytela-R; Sheppard-D. J-Biol-Chem.
  • the integrin alphavbeta ⁇ is c tical for keratinocyte migration on both its known ligand, fibronectin, and on vitronectin.
  • ⁇ v ß 6 The physiological and pathological functions of ⁇ v ß 6 are not yet exactly known, but it is believed that this integrin is important in physiological processes and diseases (e.g. inflammation, wound healing, tumors) in which epithelial cells are involved Role plays (Expression of the beta 6 integrin subunit in development, neoplasia and tissue repair suggests a role in epithelial remodeling. Breuss, -JM; Gallo, -J; Deüsser, -HM; Klimanskaya, -IV; Folkesson, -HG; Pittet , -JF; Nishimura, -SL; Aldape, -K; Landers, -DV; Carpenter, -W; et-al. J-Cell-Sci. 1995 Jun; 108 (Pt 6) 2241-51).
  • ⁇ v ß 6 is expressed on keratinocytes in wounds (keratinocytes in human wounds express alpha v beta 6 integrin.
  • Epidermal integrin expression is upregulated rapidly in human fetal wound repair.
  • ⁇ v ß 6 is expressed more strongly than normal control tissue.
  • the frequency and level of expression increases from the leukoplakia, via borrowed planus, to squamous cell carcinoma (squamous cell carcinoma), so that a connection between expression of ⁇ v ß 6 and the malignant transformation of leukplacia can be assumed: expression of alpha (v) beta6 integ ⁇ n in oral leukoplakia.
  • ⁇ v ß 6 plays a role in the respiratory 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 beta ⁇ knockout mice.
  • fibrosis can also occur in other organs, such as the skin, the liver (up to cirrhosis), the kidneys and the bladder, the heart and the pancreas (cystic fibrosis). It can be assumed that the integrin ⁇ v ß 6 also plays a role in these pathological increases in connective tissue and the course of the disease is therefore due to agonists / antagonists of the integrin ⁇ v ß 6 . (Mechanisms of tissue repair: from wound healing to fibrosis, Mutsaers SE, Bishop JE, Mcgrouther G, Laurent G, J Int. J. Biochem. Cell Biol.
  • ⁇ v ß 6 also plays a role in the intestinal epithelium, so that corresponding integrin agonists / antagonists could be used in the treatment of inflammation, tumors and wounds of the gastrointestinal tract.
  • MMP-9 matrix metalloproteases
  • 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 Rl, Pytela R, Sheppard D, J Cell Biol (1994) 127 (2): 547-56; Integhn-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.
  • alpha v beta 6 integrin regulates its own expression with cell crowding: Implications for tumor 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, Hau IR, Speight PM, Marshall JF, JOURNAL OF INVESTIGATIVE DERMATOLOGY (2001
  • the regulation of MMP activity could be a mechanism which enables the cells, as the tumor mass grows, to make room for themselves again by proliferating and migrating through the proteolysis of the surrounding matrix.
  • integrin c ⁇ ß Due to the role of integrin c ⁇ ß in infection processes, it can be assumed that its agonists / antagonists can also be used in microbial infections (protozoa, microphytes; bacteria, viruses, yeasts, fungi).
  • microbial infections protozoa, microphytes; bacteria, viruses, yeasts, fungi.
  • the relationship with the ⁇ v ß 6 integrin is described, for example, for the Coxsackievirus or for the infection of host cells with the foot and mouth disease virus (FMDV), which is dependent on the ⁇ v ß 3 , but also ⁇ v ß 6 - dependent (Integrin alpha v beta 6 enhances coxsackievirus B1 lytic infection of human colon cancer cells.
  • FMDV foot and mouth disease virus
  • the epithelial integrin alphavbeta ⁇ 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, AtakilitA, 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
  • HIV HIV-induced infection with HIV (AIDS) is also dependent on ⁇ v ß integrins, so that the agonists / antagonists of integrin ⁇ v ß 6 could also be used here
  • HIV human immunodeficiency virus
  • the bacterium Bacillus anthracis secretes a toxin that consists of 3 proteins, one of which, the so-called PA or protective antigen, binds to cell membrane-bound receptors (Anthrax Toxin Receptor, ATR).
  • ATR is a type I membrane protein with an extracellular domain of the Willebrandt Factor (vWF A) type. Integrins also contain such vWF A domains.
  • ⁇ v ß 6 For integrin ⁇ v ß 6 , this can be traced via a homology analysis in the Swiss Prot database (http://www.expasy.ch/cgi-bin/niceprot.pl7P18564; here sequence ß 6 (131-371)), as well for ⁇ v ß 3 (http://www.expasy.ch/cgi- bin / niceprot.pl? P05106; ß 3 (135-377)). It can therefore be assumed that ⁇ v ß 6 agonists / antagonists can also be used for anthrax (anthrax of the lungs, skin and intestine) (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).
  • anthrax anth
  • the integrin ⁇ v ß 6 interacts with TGF-ß and thereby leads to its activation (avb6 Integrin mediates latent TGFß activation: Implications for cutaneous fibrosis, Dalton SL, J Am Acad Dermatol (1999) 41: 457-463; The integrin avb6 binds and activates latent TGFbl: a mechanism for regulating pulmonary inflammation and fibrosis, Munger JS et al. Cell (1999) 96: 319-328).
  • Latent TGFß ! (one of the pro forms) binds to the integrin ⁇ v ß 6 and is thereby activated proteolytically.
  • the agonists / antagonists of the integrin ⁇ v ⁇ 6 according to the invention could thus prevent the activation of TGF- ⁇ and other subtypes by inhibiting the binding of TGF- ⁇ (pro-form, LAP peptide, LAP-TGFß, latent TGF) and thereby modulate the effect of TGFß.
  • the compounds also act as inhibitors of the ⁇ v ß 3 or ⁇ v ß 5 integrin receptors and as inhibitors of the glycoprotein llb / llla.
  • the ⁇ v ß 3 integrin for example, is expressed on a number of cells, for example endothelial cells, cells of the smooth vascular muscles, for example the aorta, cells for breaking down bone matrix (osteoclasts) or tumor cells.
  • the effect of the compounds according to the invention on the various integrin receptors can be demonstrated, for example, by the method described by JW Smith et al. in J. Biol. Chem. 1990, 265, 12267-12271.
  • the compounds of the formula I can inhibit the binding of metalloproteinases to integrins and thus prevent the cells from being able to use the enzymatic activity of the proteinase.
  • An example is the inhibibility of the binding of MMP-2- (matrix metallo-proteinase-2) to find the vitronectin receptor ⁇ v ß 3 by a cyclo-RGD peptide, as described in PC Brooks et al., Cell 1996, 85, 683-693.
  • micro-aggregates microthrombi
  • the tumor cells are shielded by the protection in the micro-aggregate and are not recognized by the cells of the immune system.
  • the micro-aggregates can attach themselves to the vessel walls, which facilitates further penetration of tumor cells into the tissue. Since the formation of the microthrombi by ligand binding to the corresponding integrin receptors, eg ot v ß 3 or c.
  • the corresponding antagonists can be regarded as effective metastasis inhibitors.
  • a measure of the absorption of an active pharmaceutical ingredient into an organism is its bioavailability. If the active pharmaceutical ingredient is added intravenously to the organism in the form of a solution for injection, its absolute bioavailability, ie the proportion of the drug that remains unchanged in the systemic blood, ie in the large circulation, is 100%.
  • the agent When a therapeutic agent is administered orally, the agent is usually present as a solid in the formulation and must therefore first dissolve so that it can overcome the entry barriers, for example the gastrointestinal tract, the oral mucosa, nasal membranes or the skin, in particular the stratum corneum or can be absorbed by the body.
  • Pharmacokinetic data i.e. bioavailability can be obtained analogously to the method of J. Shaffer et al, J. Pharm. Sciences, 1999, 88, 313-318.
  • Another measure of the resorbability of a therapeutic agent is the logD value, because this value is a measure of the lipophilicity of a molecule.
  • the compounds of formula I have at least one chiral center and can therefore occur in several stereoisomeric forms. All of these forms (e.g. D and L forms) and their mixtures (e.g. the DL forms) are included in the formula.
  • prodrug derivatives are also included in the compounds according to the invention, i.e. with e.g. Alkyl or acyl groups, sugars or oligopeptides modified compounds of formula I, which are quickly cleaved in the organism to the active compounds of the invention.
  • Solvates of the compounds of the formula I are understood to mean the addition of inert solvent molecules to the compounds of the formula I, which are formed on account of their mutual attraction. Solvates are, for example, mono- or dihydrates or addition compounds with alcohols, such as with methanol or ethanol.
  • the invention relates to the compounds of the formula I and their salts and solvates and to a process for the preparation of compounds of the formula I and their salts and solvates, characterized in that
  • R is a protective group and R 1 , R 1 ' , R 1 "has the meanings given in formula I and in the case that R 1 , R 1 and / or R 1" have free hydroxyl or amino groups, these each protected by a protective group,
  • R 2 and n have the meanings given in formula I and wherein for the case that R 2 is free hydroxyl and / or
  • R is a protective group and R 1 , R r and R 1 "have the meanings given in formula I and in the case that R ⁇ R r and / or R 1" contain free hydroxyl and / or amino groups, these each protected by protective groups,
  • n and R 2 have the meanings given in formula I and wherein for the case that R 2 is free hydroxyl and / or Contains amino groups, these are each protected by protective groups, and the protective group R and optionally the protective groups on R 1 , R 1 ' , R 1 " and / or R 2 are split off, or
  • R r and / or R 1 "contains free hydroxyl and / or amino groups, these are each protected by protective groups, reacted, the protective group on the amino group is split off, then the compound of formula IV according to (b) with a
  • A means alkyl, is linear or branched, and has 1 to 8, preferably 1, 2, 3, 4, 5 or 6 carbon atoms.
  • A means preferably methyl, furthermore ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, furthermore 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.
  • alkyl groups mentioned which can be substituted one or more times by shark or NO 2 , preferably trifluoromethyl, 2,2,2-trifluoroethyl or 2-nitroethyl, or alkyl groups whose carbon chain is interrupted by -O- can be, preferably -CH 2 -O-CH 3 , -CH 2 -O-CH 2 -CH 3 or -CH 2 -CH 2 -O-CH 3 .
  • A is particularly preferably methyl or ethyl.
  • Alkenyl is linear or branched and has 2 to 8, preferably 2, 3, 4, 5 or 6, carbon atoms.
  • R 1 is aryl. Particularly preferred is R 1 thereby unsubstituiert.es or mono- or polysubstituted phenyl, in particular unsubstituted phenyl.
  • Ar is unsubstituted or mono- or polysubstituted by shark, A, OA, OH, CO-A, CN, COOA, COOH, CONH 2 , CONHA, CONA 2 , CF 3 , OCF 3 or NO 2 , naphthyl, anthranyl, Flourenyl, Indenyl, Anthracenyl or Biphenyl.
  • Multiply substituted means two, three or four times, preferably two or three times substituted. Is preferred unsubstituted, preferably - as indicated - monosubstituted phenyl, naphthy, fluorine or biphenyl.
  • Naphthyl, phenyl, flourenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl are particularly preferred.
  • Cycloalkyl has 3 to 15 carbon atoms and is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, particularly preferably cyclohexyl. Cycloalkyl also means mono- or bicyclic terpenes, preferably p-menthan, menthol, pinan, bornan or camphor, including any known stereoisomeric form or adamantyl. For campers, this means both L-campers and D-campers.
  • Shark is preferably F, Cl or Br. Shark F or Cl is particularly preferred.
  • Amino protecting group preferably means formyl, acetyl, propionyl, butyryl, phenylacetyl, benzoyl, toluyl, POA, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl, CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC, Mtr or benzyl.
  • Het is an unsubstituted, mono-, di-, tri- or tetrasubstituted heterocycle having 1, 2, 3 and / or 4 N, O and / or S atoms, preferably unsubstituted or mono- or disubstituted by A, NHA and / or NH 2 substituted 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, further preferably 1, 2,3-triazol-1-, -4- or -5-yl, 1, 2,4-triazol-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-
  • Het 2 can, for. B. also mean 2,3-dihydro-1-, -2-, -3-, -4- or - 5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 4,5-dihydro-imidazol-2-yl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -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
  • n is preferably 1, 2, 3 or 4, very particularly preferably n is 2 or 3.
  • m is preferably 0, 1 or 2, very particularly preferably m is 0 or 1.
  • Multiple substituted means one, two, three or four times substituted.
  • Pol means a solid phase without a terminal functional group, as explained in more detail below.
  • the term solid phase and resin is used synonymously in the following.
  • the second phenyl radical is preferably coupled in the 3- or 4-position to the first phenyl radical, particularly preferably to the 4-position of the first phenyl ring.
  • the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above.
  • Some preferred groups of compounds can be expressed by the following sub-formulas la to li, which is the Formula I correspond and in which the radicals not specified have the meaning given for the formula I, but in
  • (CH 2 ) m is cycloalkyl, CHAAr;
  • R 1 Ar wherein Ar is an unsubstituted or mono- or disubstituted phenyl radical substituted by A, OA, OH, Hai, CF 3 in ig) R 1 Ar wherein
  • R 1 ' , R 1 " each denotes H
  • Y independently of one another NH or O
  • Heterocycle with 1 to 4 N, O and / or S atoms, which is unsubstituted or mono- or disubstituted by shark, A, OA, OCF 3 , -CO-A, COOA, CONH 2 , CONHA, CONA 2 , NH 2 , NHA, or NA 2 may be substituted m denotes 0, 1 or 2 n 2 or 3, in ii) XO, p
  • Y independently of one another NH or O
  • R r , R 1 each denotes H
  • R 2 H, A (CH ⁇ r 2 , (CH 2 ) m cycloalkyl, alkenyl with
  • CHA'Ar 2 in which A 'is alkyl with 1, 2 or 3 carbon atoms, A alkyl with 1 to 6 carbon atoms,
  • Naphthyl or Flourenyl m 0, 1 or 2 n 1, 2 or 3 means.
  • the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I according to claim 1.
  • amino protecting group is generally known and refers to groups which are suitable for protecting (blocking) an amino group against chemical reactions. Unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups are particularly typical of such groups. Since the amino protective groups are removed after the desired reaction (or reaction sequence), their type and size is otherwise not critical; however, preference is given to those having 1-20, in particular 1-8, carbon atoms.
  • acyl group is in the broadest sense in connection with the present process specific.
  • acyl groups derived from aliphatic, araliphatic, alicyclic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular alkoxycarbonyl, alkenyloxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups.
  • acyl groups are alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluyl; Aryloxyalkanoyl such as phenoxyacetyl; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl; Alkenyloxycarbonyl such as allyloxycarbonyl (aloe), aralkyloxycarbonyl such as CBZ (synonymous with Z), 4-methoxybenzyloxycarbonyl (MOZ), 4-nitrobenzyloxycarbonyl or 9-fluorenylmethoxycarbonyl (Fmoc); 2- (phenylsulfonyl) ethoxycarbonyl; Trimethylsilylethoxycarbonyl (Teo
  • hydroxyl protecting group is also generally known and refers to groups which are suitable for protecting a hydroxyl group against chemical reactions. Typical of such groups are the unsubstituted or substituted aryl, aralkyl, aroyl or acyl groups mentioned above, furthermore also alkyl groups, alkyl, aryl or aralkylsilyl groups or O, O or O, S-acetals.
  • the nature and size of the hydroxyl protective groups is not critical since they are removed again after the desired chemical reaction or reaction sequence; groups with 1-20, in particular 1-10, carbon atoms are preferred.
  • hydroxy protecting groups include aralkyl groups such as benzyl, 4-methoxybenzyl or 2,4-dimethoxybenzyl, aroyl groups such as benzoyl or p-nitrobenzoyl, acyl groups such as acetyl or pivaloyl, p-toluenesulfonyl, alkyl groups such as methyl or tert-butyl, but also allyl, alkylsilyl such as trimethylsilyl (TMS), triisopropylsilyl (TIPS), tert.-butyldimethylsilyl (TBS) or triethylsilyl, trimethylsilylethyl, aralkylsilyl groups such as tert-butyldiphenylsilyl (TBDPS), cyclic acetals such as isopropylidene, cyclohexylidene, p -Methoxybenzyliden- or o
  • the groups BOC and O-tert-butyl can e.g. preferably with TFA in dichloromethane or with about 3 to 5 N HCl in dioxane at 15-30 ° C, the Fmoc group with an about 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30 ° C.
  • the aloe group can be split gently under precious metal catalysis in chloroform at 20-30 ° C.
  • a preferred catalyst is tetrakis (triphenyl-phosphine) palladium (0).
  • the starting compounds of the formulas II to VI and 1 to 3 are generally known. If they are new, they can be manufactured according to methods known per se.
  • the compounds of the formula I can also be synthesized on a solid phase, the binding to the solid phase being effected via OH of the carboxyl group.
  • the carboxyl group is substituted with OPol, where Pol means a solid phase without a terminal functional group.
  • Pol stands for the polymeric carrier material as well as for all atoms of the anchor group of a solid phase, except for the terminal functional group.
  • the anchor groups of a solid phase also called linkers, are necessary for the connection of the connection to be functionalized to the solid phase.
  • a summary of solid phase syntheses and the solid phases and / or linkers that can be used for this purpose is given, for example, in Novabiochem - The Combinatorial Chemistry Catalog, March 99, pages S1-S72.
  • Solid phases which are particularly suitable for the synthesis of the compounds according to the invention are solid phases with a hydroxyl group as terminal functionality, for example the Wang resin or polystyrene A OH.
  • the bromophenyl-substituted carboxylic acid 1 is activated in situ by known methods, for example by reaction with diisopropylcarbodiimide, and reacted with the alcohol HO-L, where L has the meaning given above.
  • Subsequent coupling of compound 2 with an unsubstituted or substituted arylboronic acid under Suzuki compounds produces derivative 3. Elimination of the protective group SG, under known conditions, releases a compound of the formula II.
  • the Suzuki reaction is advantageously carried out in a palladium-mediated manner, preferably by adding Pd (PPh 3 ) 4 , in the presence of a base such as potassium carbonate in an inert solvent or solvent mixture, for example DMF, at temperatures between 0 ° and 150 °, preferably between 60 ° and 120 °.
  • a base such as potassium carbonate
  • the reaction time is between a few minutes and several days depending on the conditions used.
  • the boronic acid derivatives can be prepared by conventional methods or are commercially available.
  • the reactions can be carried out analogously to those described in Suzuki et al., J. Am. Chem. Soc. 1989, 111, 314ff. and in Suzuki et al. Chem. Rev. 1995, 95, 2457ff. specified methods are carried out.
  • Compounds of the formula I are obtained by peptide-analogous coupling of the compounds of the formula II with a compound of the formula III or by peptide-analogous coupling of the compounds of the formula IV with a compound of the formula V under standard conditions.
  • Compounds of the formula III are obtained by peptide-analogous coupling of a compound of the formula V with an amino compound H 2 N-CH 2 -COOSG 2 under standard conditions, where SG 2 denotes a hydroxyl protective group as described above, which is split off after the coupling.
  • the coupling reaction is preferably carried out in the presence of a dehydrating agent, for example a carbodiimide such as Dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDC) or diisopropylcarbodiimide (DIC), furthermore, for example, propanephosphonic anhydride (cf. Angew. Chem.
  • a dehydrating agent for example a carbodiimide such as Dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDC) or diisopropylcarbodiimide (DIC), furthermore, for example, propanephosphonic anhydride (cf. Angew. Chem.
  • diphenylphosphoryl azide or 2 -Ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline in an inert solvent, for example a halogenated hydrocarbon such as dichloromethane, an ether such as tetrahydrofuran or dioxane, an amide such as DMF or dimethylacetamide, a nitrile such as acetonitrile, in dimethyl sulfoxide or in the presence thereof Solvents, at temperatures between about -10 and 40, preferably between 0 and 30 °. The reaction time is between a few minutes and several days depending on the conditions used.
  • a halogenated hydrocarbon such as dichloromethane
  • an ether such as tetrahydrofuran or dioxane
  • an amide such as DMF or dimethylacetamide
  • a nitrile such as acetonitrile
  • alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali metal or alkaline earth metal preferably of potassium, sodium, calcium or cesium, can also be favorable.
  • a base of the formula I can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation.
  • acids that provide physiologically acceptable salts are suitable for this implementation.
  • inorganic acids can be used, for example sulfuric acid, sulfurous acid, dithionic acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or poly-based carbon.
  • sulfonic 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 , Isonicotinic acid, methane or ethanesulfonic acid, benzenesulfonic acid, trimethoxybenzoic acid, adamantane carboxylic acid, p-toluenesulfonic acid, glycolic acid, embonic acid, chlorophenoxyacetic acid, aspartic acid, glutamic acid, proline, Glyoxylic acid, palmitic acid, parachlorophen
  • Salts with physiologically unacceptable acids for example picrates, can be used for the isolation and / or purification of the compounds of the formula I.
  • compounds of the formula I with bases for example sodium or potassium hydroxide or carbonate
  • bases for example sodium or potassium hydroxide or carbonate
  • compounds of the formula I with bases can be converted into the corresponding metal, in particular alkali metal or alkaline earth metal or into the corresponding ammonium salts.
  • the invention also relates to the compounds of the formula I according to claim 1, their stereoisomers and / or their physiologically acceptable salts or solvates as active pharmaceutical ingredients.
  • the invention furthermore relates to compounds of the formula I according to claim 1, their stereoisomers and / or their physiologically acceptable salts or solvates as integrin agonists and / or antagonists.
  • the invention also relates to the compounds of the formula I as claimed in claim 1, their stereoisomers and / or their physiologically acceptable salts or solvates for use in combating diseases.
  • the use of the compounds for combating diseases includes their use for therapy and / or prophylaxis.
  • the invention further relates to pharmaceutical preparations containing at least one compound of the formula I according to claim 1 or 2, its stereoisomers and / or one of its physiologically acceptable salts or solvates.
  • the compounds of formula I brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and optionally in combination with one or more further active ingredients.
  • Suitable carriers are organic or inorganic substances which are suitable for enteral (e.g. oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly.
  • Tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used for oral use, suppositories for rectal use, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for topical use for parenteral use Ointments, creams or powder.
  • the new compounds can also be lyophilized and the resulting lyophilisates e.g. can be used for the production of injectables.
  • the specified preparations can be sterilized and / or contain auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, taste and / or several other active substances, e.g. one or more vitamins.
  • auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, taste and / or several other active substances, e.g. one or more vitamins.
  • sprays can be used which contain the active ingredient either dissolved or suspended in a propellant gas or propellant gas mixture (for example CO 2 or chlorofluorocarbons).
  • a propellant gas or propellant gas mixture for example CO 2 or chlorofluorocarbons.
  • the active ingredient is expediently used in micronized form, it being possible for one or more additional physiologically compatible solvents to be present, for example ethanol.
  • Inhalation solutions can be administered using standard inhalers.
  • the compounds of formula I, their stereoisomers and / or their physiologically acceptable salts or solvates can be used as active pharmaceutical ingredients in human and veterinary medicine, in particular for the prophylaxis and / or therapy of diseases of the circulatory system, pulmonary fibrosis, pulmonary embolism, thrombosis, in particular deep vein thrombosis , myocardial infarction, arteriosclerosis, dissecting aneurysm, transient ischemic attacks, stroke, angina pectoris, in particular unstable angina pectoris, pathological connecting tissue proliferation in organs or fibrosis, in particular pulmonary fibrosis, but also cystic fibrosis, skin fibrosis, liver fibrosis, liver cirrhosis, bladder outlet fibrosis, kidney fibrosis, cardiac fibrosis, infantile endocardial Fibrosis, pancreatic fibrosis, cornification disorders of the skin, in particular leukoplakia, lying planus and squamous cell carcinoma,
  • osteolytic diseases such as osteoporosis, hyperparathyroidism, Paget's disease, malignant hypercalcaemia, incompatible blood transfusion, pathologically angiogenic diseases such as inflammation, ophthalmic diseases, diabetic retinopathy, macular degeneration, myopia , Corneal transplantation, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis, Crohn's disease, atherosclerosis, psohasis, restenosis, especially after angioplasty, multiple sclerosis, pregnancy, absumptio placentaris, viral infection, bacterial infection, fungal infection, mucosal
  • the compounds according to the invention act in particular by inhibiting or cleaving viral bonds between cell-mediated integrin-binding proteins and the virus envelope or indirectly by preventing the uptake of the viruses which are bound to extracellular matrix constituents which have been recognized as integrins, or by cleavage of mechanisms mediated by integrins which are associated with the viral infection (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): 192-202. (FMDV), Virus Res. 2001 Jul; 76 (1): 1-8 (Echovirus), J Biol Chem.
  • RTX Leukotoxins In the case of parasitic infestation, the effect takes place in particular by inhibiting the binding and / or absorption of the parasitic or parasite-derived or induced toxins to cells via mechanisms directed at integrins (Infect Immun. 1999 Sep; 67 (9): 4477-84. (Leishmania) ).
  • the substances according to the invention are generally preferably administered in doses between about 0.05 and 500 mg, in particular between 0.5 and 100 mg per dosage unit.
  • the daily dosage is preferably between about 0.01 and 2 mg / kg body weight.
  • the specific dose for each patient depends on a variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, gender, on the diet, on the time and route of administration, on which
  • Elimination rate, drug combination and severity of the disease to which the therapy applies are preferred.
  • the compounds of the formula I can be used as integrin ligands for the preparation of columns for affinity chromatography for the purification of integrins.
  • the ligand i.e. a compound of formula I is activated via an anchor function, e.g. the carboxy group, covalently coupled to a polymeric support.
  • Suitable polymeric carrier materials are the polymeric solid phases known per se in peptide chemistry with preferably hydrophilic properties, for example cross-linked poly sugars such as cellulose, MISSING AT THE TIME OF PUBLICATION
  • Ethyl acetate or dichloromethane is separated off, the organic phase is dried over sodium sulfate, evaporated and purified by chromatography on silica gel, by preparative HPLC and / or by crystallization. The purified compounds are optionally freeze-dried.
  • HPLC analyzes (retention time RT) were carried out in the following
  • MS- FAB MS- FAB (M + H) + .
  • Example 2 Analogously to Example 1, the resin "BC” is reacted with FMOC-protected 4-amino-butanoic acid and 4-methoxy-phenyl isocyanate. You get 3- Biphenyl-4-yl-3- ⁇ 2- [4- (3- (4-methoxyphenyl) urido) butanoylamino] ethanoylaminoj propionic acid.
  • Example 2 Analogously to Example 1, the resin "BC” is reacted with FMOC-protected 5-aminopentanoic acid and 3-methoxyphenyl isocyanate. You get 3- Biphenyl-4-yl-3- ⁇ 2- [5- (3- (3-methoxyphenyl) urido) pentanoylamino] ethanoylamino ⁇ propionic acid.
  • Example 2 Analogously to Example 1, the resin "BC” is reacted with FMOC-protected 3-aminopropanoic acid and ethyl formate. 3-biphenyl-4-yl 3- [2- (3-ethoxycarbonylamino-propanoylamino) ethanoylamino] propionic acid.
  • Example 2 Analogously to Example 1, the resin "BC” is reacted with FMOC-protected 3-aminopropanoic acid and benzyl formate.
  • Example A Injection glasses
  • a solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Each injection jar contains 5 mg of active ingredient.
  • Example B Suppositories A mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
  • a solution of 1 g of an active ingredient is prepared of the formula I, 9.38 g of NaH 2 PO 4 • 2H 2 O, 28.48 g Na 2 HPO 4 12 ⁇ H 2 O and 0.1 g of benzalkonium chloride in 940 ml of double- distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This solution can be used in the form of eye drops.
  • Example D ointment
  • 500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
  • a mixture of 1 kg of active ingredient of the 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 compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient.
  • Example F coated tablets
  • Example E tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
  • Example G capsules
  • each capsule contains 20 mg of the active ingredient.
  • Example H ampoules A solution of 1 kg of active ingredient of the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.

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Abstract

L'invention concerne de nouveaux dérivés de biphényle correspondant à la formule générale (I), dans laquelle R?1, R1', R1'', R2¿ et n correspondent aux définitions données dans la revendication 1, ainsi que leurs stéréoisomères et leurs sels ou solvates physiologiquement acceptables, lesquels sont de nouveaux ligands de l'intégrine, en particulier du récepteur d'intégrine α¿V?β6. Ces nouveaux composés peuvent être utilisés comme médicaments.
EP02747260A 2001-04-14 2002-03-13 Ligands de l'integrine alpha-v-beta 6 Withdrawn EP1379495A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10118550A DE10118550A1 (de) 2001-04-14 2001-04-14 Liganden des Integrins alpha¶nu¶beta¶6¶
DE10118550 2001-04-14
PCT/EP2002/002728 WO2002083627A2 (fr) 2001-04-14 2002-03-13 Ligands de l'integrine $g(a)v$g(b)¿6 ?

Publications (1)

Publication Number Publication Date
EP1379495A2 true EP1379495A2 (fr) 2004-01-14

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US (1) US20040142877A1 (fr)
EP (1) EP1379495A2 (fr)
JP (1) JP2004528325A (fr)
KR (1) KR20030090739A (fr)
CN (1) CN1501827A (fr)
BR (1) BR0208885A (fr)
CA (1) CA2444247A1 (fr)
CZ (1) CZ20033000A3 (fr)
DE (1) DE10118550A1 (fr)
HU (1) HUP0303804A3 (fr)
MX (1) MXPA03009318A (fr)
PL (1) PL363328A1 (fr)
RU (1) RU2003130639A (fr)
SK (1) SK13732003A3 (fr)
WO (1) WO2002083627A2 (fr)
ZA (1) ZA200308857B (fr)

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NZ535425A (en) 2002-03-13 2008-05-30 Biogen Idec Inc Anti-alphavbeta6 antibodies
US20090028853A1 (en) * 2006-10-19 2009-01-29 The Regents Of The University Of California, A California Corporation TREATMENT AND PREVENTION OF CHRONIC ASTHMA USING ANTAGONISTS OF INTEGRIN ALPHAvBETA6
US7838252B2 (en) * 2005-02-17 2010-11-23 The Board Of Trustees Of The Leland Stanford Junior University Methods and compositions for treating a subject having an anthrax toxin mediated condition
CN102875681A (zh) 2005-07-08 2013-01-16 拜奥根Idec马萨诸塞公司 抗-αvβ6抗体及其用途
AU2007272995B2 (en) 2006-07-10 2013-02-07 Biogen Idec Ma Inc. Compositions and methods for inhibiting growth of smad4-deficient cancers
WO2014018913A2 (fr) * 2012-07-27 2014-01-30 University Of Connecticut Compositions de santacruzamate a et analogues et procédés d'utilisation
WO2014144466A1 (fr) 2013-03-15 2014-09-18 Biogen Idec Ma Inc. Anticorps anti-alpha ν bêta 6 et leurs utilisations
WO2014143739A2 (fr) 2013-03-15 2014-09-18 Biogen Idec Ma Inc. Anticorps anti-alpha ν bêta 6 et leurs utilisations
KR102634762B1 (ko) * 2016-11-01 2024-02-06 애로우헤드 파마슈티컬스 인코포레이티드 알파-v 베타-6 인테그린 리간드 및 그의 용도

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EP0378167B1 (fr) * 1989-01-10 1994-12-28 Sumitomo Chemical Company Limited Composition de colorants dispersés utile pour la teinture ou l'impression de matériaux en fibres hydrophobes
DE3927069A1 (de) * 1989-08-16 1991-02-21 Basf Ag Phenonazofarbstoffe und verfahren zum thermischen transfer dieser farbstoffe
US5550098A (en) * 1991-11-14 1996-08-27 Dai Nippon Printing Co., Ltd. Thermal transfer sheet
CN1146541C (zh) * 1999-02-20 2004-04-21 默克专利股份有限公司 β-丙氨酸衍生物
DE19933173A1 (de) * 1999-07-15 2001-01-18 Merck Patent Gmbh Cyclische Peptidderivate als Inhibitoren des Integrins alpha¶v¶beta¶6¶

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Title
See references of WO02083627A2 *

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Publication number Publication date
BR0208885A (pt) 2004-06-29
WO2002083627A3 (fr) 2003-10-09
HUP0303804A2 (hu) 2004-03-29
CA2444247A1 (fr) 2002-10-24
MXPA03009318A (es) 2004-02-12
RU2003130639A (ru) 2005-04-10
CN1501827A (zh) 2004-06-02
DE10118550A1 (de) 2002-10-17
CZ20033000A3 (cs) 2004-02-18
ZA200308857B (en) 2004-09-13
PL363328A1 (en) 2004-11-15
JP2004528325A (ja) 2004-09-16
HUP0303804A3 (en) 2005-09-28
SK13732003A3 (sk) 2004-02-03
WO2002083627A2 (fr) 2002-10-24
KR20030090739A (ko) 2003-11-28
US20040142877A1 (en) 2004-07-22

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