Patent Application
20100048536
The present invention relates to novel compounds which bind to integrin receptors, their use as ligands of integrin receptors, in particular as ligands of the αvβ3 integrin receptor, and pharmaceutical preparations comprising these compounds.
Integrins are cell surface glycoprotein receptors which mediate interactions between identical and different cells as well as between cells and extracellular matrix proteins. They are involved in physiological processes, such as embryogenesis, hemostasis, wound healing, immune response and formation/maintenance of the tissue architecture.
Disturbances in the gene expression of cell adhesion molecules and functional disorders of the receptors can contribute to the pathogenesis of many disorders, such as tumors, thromboembolic events, cardiovascular disorders, lung diseases, disorders of the CNS, the kidney, the gastrointestinal tract or inflammations.
Integrins are heterodimers of an α- and a β-transmembrane subunit in each case, which are noncovalently bonded. Up to now, 16 different α- and 8 different β-subunits and 22 different combinations have been identified.
Integrin αvβ3 also called the vitronectin receptor, mediates adhesions to a multiplicity of ligands—plasma proteins, extracellular matrix proteins, cell surface proteins-, of which the majority contain the amino acid sequence RGD (Cell, 1986, 44, 517-581; Science 1987, 238, 491-497), such as vitronectin, fibrinogen, fibronectin, von Willebrand factor, thrombospondin, osteopontin, laminin, collagen, thrombin, tenascin, MMP-2, bone sialoprotein II, various viral fungal, such as the surface molecules of Candida albicans, parasitic and bacterial proteins, natural integrin antagonists such as disintegrins, neurotoxins—mambin—and blood fluke proteins—decorsin, ornatin—and also some non—RGD ligands, such as Cyr-61 and PECAM-1 (L. Piali, J. Cell Biol. 1995, 130, 451-460; Buckley, J. Cell Science 1996, 109, 437-445, J. Biol. Chem. 1998, 273, 3090-3096).
A number of integrin receptors show cross-reactivity with ligands which contain the RGD motif. Thus integrin αIIbβ3, also called the platelet fibrinogen receptor, recognizes fibronectin, vitronectin, thrombospondin, von Willebrand factor and fibrinogen.
Integrin αvβ3 is expressed, inter alia, on endothelial cells, blood platelets, monocytes/macrophages, smooth muscle cells, some B cells, fibroblasts, osteoclasts and various tumor cells, such as melanomas, glioblastomas, lung, breast, prostate and bladder carcinomas, osteosarcomas or neuroblastomas.
Increased expression is observed under various pathological conditions, such as in the prothrombotic state, in vascular injury, tumor growth or metastasis or reperfusion and on activated cells, in particular on endothelial cells, smooth muscle cells, or macrophages.
An involvement of integrin αvβ3 has been demonstrated, inter alia, in the following syndromes:
cardiovascular disorders such as atherosclerosis, restenosis after vascular injury, and angioplasty (neointima formation, smooth muscle cell migration and proliferation) (J. Vasc. Surg. 1994, 19, 125-134; Circulation 1994, 90, 2203-2206),
acute kidney failure (Kidney Int. 1994, 46, 1050-1058; Proc. Natl. Acad. Sci. 1993, 90, 5700-5704; Kidney Int. 1995, 48, 1375-1385),
angiogenesis-associated microangiopathies such as diabetic retinopathy or rheumatoid arthritis (Ann. Rev. Physiol 1987, 49, 453-464; Int. Opthalmol. 1987, 11, 41-50; Cell 1994, 79, 1157-1164; J. Biol. Chem. 1992, 267, 10931-10934),
arterial thrombosis,
stroke (phase II studies with ReoPro, Centocor Inc., 8th annual European Stroke Meeting), carcinomatous disorders, such as in tumor metastasis or in tumor growth (tumor-induced angiogenesis) (Cell 1991, 64, 327-336; Nature 1989, 339, 58-61; Science 1995, 270, 1500-1502),
osteoporosis (bone resorption after proliferation, chemotaxis and adhesion of osteoclasts to bone matrix) (FASEB J. 1993, 7, 1475-1482; Exp. Cell Res. 1991, 195, 368-375, Cell 1991, 64, 327-336),
high blood pressure (Am. J. Physiol. 1998, 275, H1449-H1454),
psoriasis (Am. J. Pathol. 1995, 147, 1661-1667),
hyperparathyroidism,
Paget's disease (J. Clin. Endocrinol. Metab. 1996, 81, 1810-1820),
malignant hypercalcemia (Cancer Res. 1998, 58, 1930-1935),
metastatic osteolytic lesions (Am. J. Pathol. 1997, 150, 1383-1393),
pathogenic protein (e.g. HIV-1 tat)-induced processes (e.g. angiogenesis, Kaposi's sarcoma) (Blood 1999, 94, 663-672)
inflammation (J. Allergy Clin. Immunol. 1998, 102, 376-381),
cardiac insufficiency, CHF, and also in
antiviral, antiparasitic, antifungal or antibacterial therapy and prophylaxis (adhesion and internalization) (J. Infect. Dis. 1999, 180, 156-166; J. Virology 1995, 69, 2664-2666; Cell 1993, 73, 309-319).
On account of their key role, pharmaceutical preparations which contain low-molecular weight integrin αvβ3 ligands are of high therapeutic or diagnostic benefit, inter alia, in the indications mentioned.
Advantageous αvβ3 integrin receptor ligands bind to the integrin αvβ3 receptor with an increased affinity.
In contrast to integrin αvβ3, particularly advantageous αvβ3 integrin receptor ligands additionally have an increased selectivity and are less active with respect to the integrin αIIbβ3 by at least a factor of 10, preferably at least a factor of 100.
For multiplicity of compounds, such as anti-αvβ3 monoclonal antibodies, peptides which contain the RGD binding sequence, natural, RGD-containing proteins (e.g. disintegrins) and low-molecular weight compounds, an integrin αvβ3 antagonistic action has been shown and a positive in vivo effect demonstrated (FEBS Letts 1991, 291, 50-54; J. Biol. Chem. 1990, 265, 12267-12271; J. Biol. Chem. 1994, 269, 20233-20238; J. Cell Biol 1993, 51, 206-218; J. Biol. Chem. 1987, 262, 17703-17711; Bioorg. Med. Chem. 1998, 6, 1185-1208).
Antagonists of the αvβ3 integrin receptor based on a tricyclic structural element having a heptacycle are described in WO 9906049, WO 9911626 and WO 9701540.
EP 889037 describes tricyclic allergy inhibitors.
U.S. Pat. No. 5,429,0123 describes tricyclic antagonists of the endothelin receptor.
It is an object of the present invention to make available novel integrin receptor ligands having advantageous properties.
Accordingly, we have found that this object is achieved by compounds of the formula I
B-G-L I
U-T IL
In the structural element L, T is understood as meaning a group COOH, a radical hydrolyzable to COOH or a radical bioisosteric to COOH.
A radical hydrolyzable to COOH is understood as meaning a radical which changes into a group COOH after hydrolysis.
A group which may be mentioned by way of example as a radical T hydrolyzable to COOH is
in which RT1 has the following meanings:
A radical bioisosteric to COOH is understood as meaning radicals which can replace the function of a group COOH in active compounds by equivalent bond donor/acceptor capabilities or by equivalent charge distribution.
Radicals which may be mentioned by way of example as radicals bioisosteric to —COOH are those such as described in “The Practice of Medicinal Chemistry”, Editor: C. G. Wermuth, Academic Press 1996, pages 125 and 216, in particular the radicals —P═O(OH)2, —SO3H, tetrazole or acylsulfonamides.
Preferred radicals T are —COOH, —CO—O—C1-C8alkyl or —CO-o-benzyl.
The radical —U— in the structural element L is a spacer selected from the group consisting of —(XL)a—(CRL1RL2)b-, —CRL1═CRL2-, ethynylene and ═CRL1-. In the case of the radical ═CRL1-, the structural element L is linked to the structural element G via a double bond.
XL is a radical CRL3RL4, NRL5, oxygen or sulfur.
Preferred radicals —U— are the radicals —CRL1═CRL2-, ethynylene or —(XL)a(CRL1RL2)b-, where XL is preferably CLL3RL4 (a=0 or 1) or oxygen (a=1).
Particularly preferred radicals —U— are the radicals —(XL)a—(CRL1RL2)b-, where XL is preferably CRL3RL4 (a=0 or 1) or oxygen (a=1).
Under RL1, RL2, RL3 or RL4 in structural element L, a halogen radical is understood as meaning, for example, F, Cl, Br or I, preferably F.
Under RL1, RL2, RL3 or RL4 in structural element L, a branched or unbranched C1-C6-alkyl radical is understood as meaning, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl or 1-ethyl-2-methylpropyl, preferably branched or unbranched C1-C4-alkyl radicals such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl, particularly preferably methyl.
Under RL1, RL2, RL3 or RL4 in structural element L, a branched or unbranched C2-C6-alkenyl radical is understood as meaning, for example, vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl and 1-ethyl-2-methyl-2-propenyl, in particular 2-propenyl, 2-butenyl, 3-methyl-2-butenyl or 3-methyl-2-pentenyl.
Under RL1, RL2, RL3 or RL4 in structural element L, a branched or unbranches C2-C6-alkynyl radical is understood as meaning, for example, ethynyl, 2-propynal, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl, preferably ethynyl, 2-propynyl, 2-butynyl, 1-methyl-2-propynyl or 1-methyl-2-butynyl.
Under RL1, RL2, RL3 or RL4 in structural element L, a branched or unbranched C3-C7-cycloalkyl radical is understood as meaning, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
Under RL1, RL2, RL3 or RL4 in structural element L, a branched or unbranched C1-C4-alkoxy radical is understood as meaning, for example, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy.
The radicals —CO—NH(C1-C6-alkyl), —CO—N(C1-C6-alkyl)2 are secondary or tertiary amides and are composed of the amide bond and the corresponding C1-C6-alkyl radicals such as described above for RL1, RL2, RL3 or RL4.
The radicals RL1, RL2, RL3 or RL4 can furthermore be a radical
C1-C2-alkylene-T, such as methylene-T or ethylene-T, C2-alkenylene-T, such as ethenylene-T or C2-alkynylene-T, such as ethynylene-T,
an aryl radical, such as phenyl, 1-naphthyl or 2-naphthyl or
an arylalkyl radical, such as benzyl or ethylenephenyl (homobenzyl),
where the radicals can optionally be substituted.
Furthermore, two radicals RL1 and RL2 or RL3 and RL4 or optionally RL1 and RL3 can in each case independently of one another together be an optionally substituted 3- to 7-membered saturated or unsaturated carbocycle or heterocycle, which can contain up to three different or identical heteroatoms O, N, S.
All radicals for RL1, RL2, RL3 or RL4 can be optionally substituted. For the radicals RL1, RL2, RL3 or RL4 and all further substituted radicals of the description below, suitable substituents, if the substituents are not specified in greater detail, are independently of one another up to 5 substituents, for example selected from the following group:
—NO2, —NH2, —OH, —CN, —COOH, —O—CH2—COOH, halogen, a branched or unbranched, optionally substituted C1-C4-alkyl radical, such as methyl, CF3, C2F5 or CH2Fm—CO—O—C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-alkoxy, C1-C4-thioalkyl, —NH—CO—O—C1-C4-alkyl, —O—CH2—COO—C1-C4-alkyl, —NH—CO—C1-C4-alkyl, —CO—NH—C1-C4-alkyl, —NH—SO2—C1-C4-alkyl, —SO2NH—C1-C4-alkyl, —N(C1-C4-alkyl)2, —NH—C1-C4-alkyl, or —SO2—C1-C4-alkyl radical, such as —SO2—CF3, an optionally substituted —NH—CO-aryl, —CO—NH-aryl, —NH—CO—O-aryl, —NH—CO—O-alkylenearyl, —NH—SO2-aryl, —SO2—NH-aryl, —CO—NH-benzyl, —NH—SO2-benzyl or —SO2—NH-benzyl radical, an optionally substituted radical —SO2—NR5 2R5 or —CO—NR52R53 where the radicals R52 and R53 independently of one another can have the meaning RL5 as below or both radicals R52 and R53 together can be a 3- to 6-membered, optionally substituted, saturated, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to three further different or identical heteroatoms O, N, S, and optionally two radicals substituted on this heterocycle can together be a fused, saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and the cycle can be optionally substituted or a further, optionally substituted cycle can be fused to this cycle.
If not specified in greater detail, in all terminally bonded, substituted hetaryl radicals of the description, two substituents can form a fused 5- to 7-membered, unsaturated or aromatic carbocycle.
Preferred radicals RL1, or RL2, RL3 or RL4 are independently of one another hydrogen, halogen, a branched or unbranched, optionally substituted C1-C4-alkyl, C1-C4-alkoxy or C3-C7-cycloalkyl radical or the radical —NRL6RL7.
Particularly preferred radicals RL1, RL2, RL3 or R14 are independently of one another hydrogen, fluorine or a branched or unbranched, optionally substituted C1-C4-alkyl radical, preferably methyl.
The radicals RL5, RL6, RL7 in structural element L are independently of one another hydrogen, a branched or unbranches, optionally substituted.
C1-C6-alkyl radical, for example as described above for RL1,
C3-C7-cycloalkyl radical, for example as described above for RL1,
CO—O—C1-C6-alkyl, SO2—C1-C6-alkyl or CO—C1-C6-alkyl radical, which is composed of the group CO—O, SO2 or CO and, for example, of the C1-C6-alkyl radicals described above for RL1,
or an optionally substituted CO—O-alkylenearyl, SO2-aryl, SO2-alkylenearyl or CO-alkylenearyl radical, which is composed of the group CO—O, SO2 or CO and, for example, of the aryl or arylalkyl radicals described above for RL1.
Preferred radicals for RL6 in structural element L are hydrogen, a branched or unbranched, optionally substituted C1-C4-alkyl, CO—O—C1-C4-alkyl, CO—C1-C4-alkyl or SO2—C1-C4-alkyl radical or an optionally substituted CO—O-benzyl, SO2-aryl, SO2-alkylenearyl or CO-aryl radical.
Preferred radicals for RL7 in structural element L are hydrogen or a branched or unbranched; optionally substituted C1-C4-alkyl radical.
Preferred structural elements L are composed of the preferred radicals of the structural element.
Particularly preferred structural elements L are composed of the particularly preferred radicals of the structural element.
G is a structural element of the formula IG
where the structural element B is bonded via Ar and the structural element L is bonded via XG to the structural element G by means of a single bond or a double bond.
Ar in structural element G is a fused aromatic 3- to 10-membered carbocycle or heterocycle which can contain up to 4 different or identical heteroatoms O, N, S and is optionally substituted by up to 4 substituents.
Preferably, Ar is a fused aromatic 3- to 6-membered carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and is optionally substituted by up to two substituents.
Particularly preferably, Ar is an aromatic 3- to 6-membered carbocycle or heterocycle optionally substituted by up to two substituents and selected from one of the following doubly bonded structural formulae:
In particular selected from one of the following, doubly bonded structural formulae:
The substitution pattern on Ar relative to the structural element B is not critical. Preferably, the substitution takes place, in particular in the case of 5- and 6-membered cycles, ortho or meta to WG, when this position is not occupied by a heteroatom.
DG in structural element G is an optionally substituted, fused, unsaturated or aromatic 3- to 10-membered carbocycle or heterocycle which can contain up to 4 different or identical heteroatoms O, N, S.
Preferably, DG is a fused, aromatic or unsaturated 3- to 6-membered carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and is optionally substituted by up to two substituents.
Particularly preferably, DG is an optionally substituted, fused, unsaturated or aromatic 3- to 6-membered carbocycle or heterocycle, for example selected from one of the following doubly bonded structural formulae:
In particular selected from one of the following, doubly bonded structural formulae:
XG in structural element G is CRG2 or nitrogen in the case of a single bond to structural element L, or carbon in the case of a double bond to structural element L.
Preferably, XG is CRG1 in the case of a single bond or carbon in the case of a double bond to structural element L.
Particularly preferably, XG is CRG1 and is bonded to the structural element L via a single bond.
WG in structural element G is the doubly bonded radical —YG—N(RG5)— or —N(RG5)—YG—.
YG in structural element G is CO, CS, C═NRG2 or CRG3RG4, preferably CO, C═NRG2 or CRG3RG4, particularly preferably CO or CRG3RG4.
RG1 in structural element WG is hydrogen, halogen, such as Cl, F, Br or I, a hydroxyl group or a branched or unbranched, optionally substituted C1-C6-alkyl radical, preferably C1-C4-alkyl or C1-C4-alkoxy radical, for example as in each case described above for RL1.
Preferred radicals for RG1 are hydrogen, hydroxyl and optionally substituted C1-C4-alkyl or C1-C4-alkoxy radicals.
Particularly preferred radicals for RG1 are hydrogen and carboxyl-substituted C1-C4-alkyl or C1-C4-alkoxy radicals, in particular the radicals —CH2COOH or —O—CH2COOH.
RG2 in structural element G is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy or C3-C7-cycloalkyl radical, for example as in each case described above for RL1,
an optionally substituted —O—C3-C7-cycloalkyl radical, which is composed of an ether group and, for example, of the C3-C7-cycloalkyl radical described above for RL1,
an optionally substituted aryl or arylalkyl radical, for example as in each case described above for RL1 or
an optionally substituted —O-aryl or —O-alkylenearyl radical, which is composed of a group —O— and, for example, of the aryl or arylalkyl radicals described above for RL1.
Preferred radicals RG2 in structural element G are hydrogen, hydroxyl or a branched or unbranched, optionally substituted C1-C6-alkyl radical, in particular methyl or C1-C4-alkoxy radical, in particular methoxy.
Possible substituents are, for example, the above mentioned substituents.
RG3 and RG4 are, independently of one another, hydrogen or a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C4-alkoxy radical or both radicals RG3 and RG4 together are a cyclic acetal —O_CH2—CH2—O— or —O—CH2—O_ or both radicals RG3 and RG4 together are an optionally substituted C3-C7-cycloalkyl radical,
with the proviso that, as substituents of the C1-C6-alkyl radicals, the groups COOH and carboxylic acid ester are excluded.
In a preferred embodiment, the groups COOH and carbocyclic acid ester are excluded as substituents for all radicals RG3 and RG4.
Branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C4-alkoxy radicals for RG3 or RG4 in structural element G independently of one another are understood as meaning, for example, the corresponding radicals in each case described above for RL1.
Further, both radicals RG3 and RG4 can together form a cyclic acetal, such as —O—CH2—CH2—O— or —O—CH2—O—.
Furthermore, both radicals RG3 and RG4 can together form an optionally substituted C3-C7-cycloalkyl radical.
Preferred radicals for RG3 or RG4 are independently of one another hydrogen, C1-C6-alkyl or C1-C4-alkoxy, and both radicals RG3 and RG4 together form a cyclic acetal, such as —O—CH2—CH2—O— or —O—CH2—O—.
Particularly preferred radicals for RG3 or RG4 are independently of one another hydrogen and both radicals RG3 and RG4 together form a cyclic acetal, in particular —O—CH2—CH2—O— or —O—CH2—O—.
RG5 is a radical RG5A or a radical C0-C6-alkylene—RG5B, C2-C4-alkenylene—RG5B, C2-C4-alkynylene—RG5B, C1-C6-oxoalkylene—RG5B, C2-C4-oxoalkenylene—RG5B, C2-C4-oxoalkynylene—RG5B, C1-C4-aminoalkylene—RG5B, C2-C4-aminoalkenylene—RG5B, C2-C4-aminoalkynylene—RG5B, C2-C4-alkylene—RG5B, optionally substituted by one or more radicals selected from the group consisting of RG5A and RG5C, where
RG5A is a radical CORG5G, COC(RG5E)2(RG5H), CSRG5G, S(O)g1—ORG5E)(RG5F), PO(ORG5E), PO(ORG5E)2, B(ORG5E)2, NO2 or tetrazolyl,
RG5B is hydrogen or an optionally substituted C3-C7-cycloalkyl, C3-C7-cycloheteroalkyl, aryl or hetaryl radical,
RG5C is hydrogen, halogen, CN, NO2, ORG5DCF3, or a radical N(RG5E)RG5D), CF3S(O)g2, CO2RG5E)2, Co—C6-alkylene—RG5B, C1-C6-oxoalkylene—RG5B, C2-C4-alkenylene—RG5B or C2-C4-alkynylene—RG5B,
RG5D is a radical RG5E, —CO—RG5E, CO—ORG5J, CO—N(RG5E)2, S(O)g1—RG5E or S(O)g1—N(RGE)2,
RGE5 is hydrogen, an optionally substituted C1-C6-alkyl, aryl-Co—C6-alkylene, C3-C7-cycloalkyl-Co—C6-alkylene, hetaryl or hetarylalkyl radical,
RG5F is a radical RG5E, CO—RG5E or CO—ORG5E,
RG5G is a radical ORG5E, N(RG5E)(RG5F), N(RG5E)—SO2RG5E, N(RG5E) (ORG5E), O—C (RG5E)2-CO—ORG5E, O—C(RG5E)2-O—CO—RG5E, O—C (RG5E)2-CO—N(RG5E)2 or CF3,
RG5H is a radical ORG5E, CN, S(O)g2—RG5E, S(O)g1—N(RG5E)2, CO—RG5E, C(O)N(RG5E)2 or CO2—RG5E,
RG5J is hydrogen or an optionally substituted C1-C6-alkyl or aryl-Co—C6-alkylene radical,
g1 is 1 or 2 and
g2 is 0, 1 or 2
with the proviso that if WG=—YG—N(RG5)—the radical —(CH2)m—CORG6 is excluded for RG5, where
In a preferred embodiment of RG5, if WG=—N(RG5)—YG- the radical —(CH2)m—CORG6 is also excluded for RG5.
Further preferred radicals for RG5 are hydrogen,
C1-C6-alkyl, C3-C7-cycloalkyl, aryl or arylalkyl such as described above for RL1,
a radical COO—C1-C6-alkyl, SO2—C1-C6-alkyl or CO—C1-C6-alkyl which is composed of the group consisting of COO, SO2 or CO and the C1-C6-alkyl radicals described above,
a radical COO—C1-C4-alkylene aryl, SO2-aryl, CO-aryl, CO-hetaryl, SO2—C1-C4-alkylene-aryl or CO—C1-C4-alkylene-aryl.
Particularly preferred radicals for RG5 are hydrogen, methyl, ethyl, CH2CF3, benzyl or homobenzyl, where the phenyl group can optionally be substituted by a C1-C4-alkyl, C1-C4-alkoxy or C1-C4-alkylthio radical, CF3, or OH or halogen.
Very particularly preferred radicals for RG5 are hydrogen, methyl, ethyl or CH2CF3.
Preferred structural elements G are composed of at least one preferred radical of the structural element G, while the remaining radicals are widely variable.
Particularly preferred structural elements G are composed of the preferred radicals of the structural element G.
Very particularly preferred structural elements G are composed of the particularly preferred radicals of the structural element G.
Structural element B is understood as meaning a structural element containing at least one atom which, under physiological conditions, can form hydrogen bridges as a hydrogen acceptor, at least one hydrogen acceptor atom having a distance of 4 to 15 atom bonds from structural element G along the shortest possible route along the structural element skeleton. The arrangement of the structural skeleton of structural element B is widely variable.
Suitable atoms which, under physiological conditions, can form hydrogen bridges as hydrogen acceptors are, for example, atoms having Lewis base properties, such as the heteroatoms nitrogen, oxygen or sulfur.
Physiological conditions are understood as meaning a pH which prevails at the site in a body at which the ligands interact with the receptors. In the present case, the physiological conditions have a pH of, for example, 5 to 9.
In a preferred embodiment, structural element B is a structural element of the formula IB
A-E IB
In a particularly preferred embodiment, the structural element A is a structural element selected from the group consisting of structural elements of the formulae IA1 to IA18,
In a further very particularly preferred embodiment, the structural element A is a structural element of the formula IA1, IA4, IA8, or IA17.
A branched or unbranched, optionally substituted C1-C6-alkyl radical for RA1 or RA2 independently of one another is understood as meaning, for example, the corresponding radicals described above for RG1, preferably methyl or trifluoromethyl.
For RA1 or RA2 in the structural elements IA1, IA2, IA3 and IA17, the branched or unbranched, optionally substituted radical CO—C1-C6-alkyl is composed, for example, of the group CO and the branch d or unbranched, optionally substituted C1-C6-alkyl radicals described above for RA1 or RA2.
Optionally substituted hetaryl, hetarylalkyl, aryl, arylalkyl or C3-C7-cycloalkyl radicals for RA1 or RA2 independently of one another are understood as meaning, for example, the corresponding radicals described above for RG7.
For RA1 or RA2, the optionally substituted radicals CO—O—RA14, O—RA14, S—RA14, NRA15RA16 or SO2NRA16RA16 are composed, for example, of the groups CO—O, O, S, N, CO—N or SO2—N and the radicals RA14, RA15 or RA16 described in greater detail below.
Further, both radicals RA1 and RA2 can together form a fused, optionally substituted 5- or 6-membered, unsaturated or aromatic carbocycle or heterocycle which can contain up to three heteroatoms selected from the group consisting of O, N and S.
RA13 and RA13* are independently of one another hydrogen, CN,
halogen, such as fluorine, chlorine, bromine or iodine,
a branched or unbranched, optionally substituted C1-C6-alkyl radical, such as described above for RG1, preferably methyl or trifluoromethyl or
an optionally substituted aryl, arylalkyl, hetaryl or C3-C7-cycloalkyl radical or a radical CO—O—RA14, O—RA14, S—RA14, NRA15RA16, SO2NRA15RA16 or CO—NRA15RA16 as in each case described above for RA1.
Preferred radicals for RA13 and RA13* are the radicals hydrogen, F, Cl, a branched or unbranched, optionally substituted C1-C6-alkyl radical, optionally substituted aryl or arylalkyl or a radical CO—O—RA14, O—RA14, NRA15RA16, SO2—NRA15RA16 or CO—NRA15RA16.
A branched or unbranched, optionally substituted C1-C6-alkyl, C3-C7-cycloalkyl, alkylenecycloalkyl, alkylene-C1-C4-alkoxy, C2-C6-alkenyl or C2-C6-alkynyl radical for RA14 in structural element A is understood as meaning, for example, the corresponding radicals described above for RG7.
Optionally substituted aryl, arylalkyl, hetaryl or alkylhetaryl radicals for RA14 in structural element A are understood as meaning, for example, the corresponding radicals described above for RG7.
Preferred radicals for RA14 are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical and optionally substituted benzyl.
A branched or unbranched, optionally substituted C1-C6-alkyl or arylalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, hetaryl or hetarylalkyl radical for RA15 or RA16 independently of one another is understood as meaning, for example, the corresponding radicals described above for RA14.
The branched or unbranched, optionally substituted CO—C1-C6-alkyl, SO2—C1-C6-alkyl, COO—C1-C6-alkyl, CO—NH—C1-C6-alkyl, COO-alkylenearyl, CO—NH-alkylenearyl, CO—NH-alkylenehetaryl or SO2-alkylenearyl radicals or the optionally substituted CO-aryl, SO2-aryl, CO—NH-aryl, CO—NH-hetaryl or CO-hetaryl radicals for RA15 or RA16 are composed, for example, of the corresponding groups —CO—, —SO2—, —CO—O—, —CO—NH— and the corresponding branched or unbranched, optionally substituted C1-C6-alkyl, hetarylalkyl or arylalkyl radicals or the corresponding optionally substituted aryl or hetaryl radicals described above.
A radical —(CH2)n—(XA)j—RA12 for RA3 or RA4 independently of one another is understood as meaning a radical which is composed of the corresponding radicals —(CH2)n—, (XA)j and RA12. Here, n can be: 0, 1, 2 or 3 and j can be: 0 or 1.
XA is a doubly bonded radical selected from the group consisting of —CO—, —CO—N(Rx1)—, —N(Rx1)—CO—, —N(Rx1)—CO—N(Rx1*)-, —N(Rx1)—CO—O—, —O—, —S—, —SO2—, —SO2—N(RX1)—, —SO2—O—, —CO—O—, —O—CO—, —O—CO—N(RX1)—, —NRX1)— or —N(RX1)—SO2—.
RA12 is hydrogen,
a branched or unbranched, optionally substituted C1-C6-alkyl radical, as described above for RG7,
a C2-C6-alkynyl or C2-C6-alkenyl radical optionally substituted by C1-C4-alkyl or aryl,
or a 3- to 6-membered, saturated or unsaturated heterocycle which is substituted by up to three identical or different radicals and can contain up to three different or identical heteroatoms O, N, S, such as optionally substituted 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 6-pyrimidyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-(1,3,4-thiadiazolyl), 2-(1,3,4)-oxadiazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, triazinyl.
Further, RA12 and RX1 or Rx1* can together form a saturated or unsaturated C3-C7-heterocycle which can optionally contain up to two further heteroatoms selected from the group consisting of O, S and N.
Preferably, the radical RA12 together with the radical RX1 or RX1* forms a cyclic amine as the C3-C7-heterocycle in the case where the radicals are bonded to the same nitrogen atom, such as N-pyrrolidinyl, N-piperidinyl, N-hexahydroazepinyl, N-morpholinyl or N-piperazinyl, where in heterocycles which carry free amine protons, such as N-piperazinyl, the free amine protons can be replaced by customary amine protective groups, such as methyl, benzyl, Boc (tert-butoxycarbonyl), z (benzyloxycarbonyl), tosyl, —SO2—C1-C4-alkyl, —SO2-phenyl or —SO2-benzyl.
A branched or unbranched, optionally substituted C1-C6-alkyl, C2-C12-alkynyl, preferably C2-C6-alkynyl or C2-C6-alkenyl radical, an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl or hetaryl radical for RX1 and RX1* independently of one another is understood as meaning, for example, the corresponding radicals described above for RG7.
Preferred branched or unbranched, optionally substituted C1-C6-alkoxyalkyl for RX1 and RX1* are independently of one another methoxymethylene, ethoxymethylene, t-butoxymethylene, methoxyethylene or ethoxyethylene.
Preferred branched or unbranched, optionally substituted radicals CO—C1-C6-alkyl, CO—O—C1-C6-alkyl, SO2—C1-C6-alkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, CO-hetaryl or SO2-alkylenearyl are preferably composed of the C1-C6-alkyl, arylalkyl, aryl or hetaryl radicals and the radicals —CO—, —O—, —SO2— described above.
Preferred radicals for RX1 and Rx1* are independently of one another hydrogen, methyl, cyclopropyl, alkyl and propargyl.
RA3 and RA4 can further together form a 3- to 8-membered saturated, unsaturated or aromatic N heterocycle which can additionally contain two further, identical or different heteroatoms O, N or S, where the cycle can be optionally substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle.
RA5 is a branched or unbranched, optionally substituted C1-C6-alkyl, arylalkyl, C1-C4-alkyl-C3-C7-cycloalkyl or C3-C7-cycloalkyl radical or an optionally substituted aryl, hetaryl, heterocycloalkyl or heterocycloalkenyl radical, such as described above for RG7.
RA6 and RA6* are independently of one another hydrogen, a branched or unbranched, optionally substituted
C1-C4-alkyl radical, such as optionally substituted methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl,
—CO—O—C1-C4-alkyl or —CO—C1-C4-alkyl radical such as composed of the group —CO—O— or —CO— and the C1-C4-alkyl radicals described above,
arylalkyl radical, as described above for RG7,
—CO—O-alkylenearyl or —CO-alkylenearyl radical such as composed of the group —CO—O— or —CO— and the arylalkyl radicals described above,
—CO—O-allyl or —CO-allyl radical,
or C3-C7-cycloalkyl radical, such as described above for RG7.
Further, both radicals RA6 and RA6* in structural element IA7 can together form an optionally substituted, saturated, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to two further different or identical heteroatoms O, N, S.
RA7 is hydrogen, —OH, —CN, —CONH2, a branched or unbranched, optionally substituted C1-C4-alkyl radical, for example as described above for RA6, C1-C4-alkoxy, arylalkyl or C3-C7-cycloalkyl radical, for example as described above for RL14, a branched or unbranched, optionally substituted —O—CO—C1-C4-alkyl radical, which is composed of the group —O—CO— and, for example, of the C1-C4-alkyl radicals mentioned above or an optionally substituted —O-alkylenearyl, —O—CO-aryl, —O—CO-alkylenearyl or —O—CO-allyl radical which is composed of the groups —O— or —O—CO— and, for example, of the corresponding radicals described above for RG7.
Further, both radicals RA6 and RA7 can together form an optionally substituted unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to two further different or identical heteroatoms O, N, S.
For RA8 in structural element A, a branched or unbranched, optionally substituted C1-C4-alkyl radical or an optionally substituted aryl or arylalkyl radical is understood as meaning, for example, the corresponding radicals described above for RA15, where the radicals C0-Ca—C4-alkyl, SO2—C1-C4-alkyl, CO—O—C1-C4-alkyl, CO-aryl, SO2-aryl, CO—O-aryl, CO-alkylenearyl, SO2-alkylenearyl or CO—O-alkylenearyl are composed analogously to the other composed radicals of the group consisting of CO, SO2 and COO and, for example, of the corresponding C1-C4-alkyl, aryl or arylalkyl radicals described above for RA15, and these radicals can be optionally substituted.
In each case, for RA9 or RA10, a branched or unbranched, optionally substituted C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl or C3-C7-cycloalkyl radical independently of one another is understood as meaning, for example, the corresponding radicals described above for RA14, preferably methyl or trifluoromethyl.
In each case, for RA9 or RA10, a radical CO—O—RA14, S—RA14, SO2—NRA15RA16 or CO—NRA15RA16 independently of one another is understood as meaning, for example, the corresponding radicals described above for RA13.
Further, both radicals RA9 and RA10 together in structural element IA14 can form a 5- to 7-membered saturated, unsaturated or aromatic carbocycle or heterocycle, which can contain up to three different or identical heteroatoms O, N, S and is optionally substituted by up to three identical or different radicals.
Substituents in this case are in particular understood as meaning halogen, CN, a branched or unbranched, optionally substituted C1-C4-alkyl radical, such as methyl or trifluoromethyl, or the radicals O—RA14, S—RA14, NRA15RA16 or ((RA8)HN)C═N—RA7.
A branched or unbranched, optionally substituted C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C3-C7-cycloalkyl radical or a radical CO—O—RA14, O—RA14, S—RA14, NRA15RA16, SO2—NRA15RA16 or CO—NRA15RA16 for RA11 is understood, for example, as meaning the corresponding radicals described above for RA9.
Further, in structural element IA16, both radicals RA9 and RA17 together can form a 5- to 7-membered saturated, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to three different or identical heteroatoms O, N, S and is optionally substituted by up to three identical or different radicals.
A branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- or bisalkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical —SO2—RG11, —CO—ORG11, —CO—NRG11RG11 for —CO—RG11RG11 for RA18 and RA19 independently of one another is understood as meaning, for example, the radicals described above for RG12, preferably hydrogen or a branched or unbranched, optionally substituted C1-C8-alkyl radical.
Z1, Z2, Z3, Z4 are independently of one another nitrogen, C—H, C-halogen, such as C—F, C—Cl, C-Br or C—I or a branched or unbranched, optionally substituted C—C1-C4-alkyl radical which is composed of a carbon radical and, for example, a C1-C4-alkyl radical described above for RA6 or a branched or unbranched optionally substituted C—C1-C4-alkoxy radical which is composed of a carbon radical and, for example, a C1-C4-alkoxy radical described above for RA7.
Z5 is oxygen, sulfur or a radical NRA8.
Preferred structural elements A are composed of at least one preferred radical of the radicals belonging to the structural element A, while the remaining radicals are widely variable.
Particularly preferred structural elements A are composed of the preferred radicals of the structural element A.
In a preferred embodiment, the spacer structural element E is understood as meaning a structural element that consists of a branched or unbranched aliphatic C2-C30-hydrocarbon radical which is optionally substituted and contains heteroatoms and/or of a 4- to 20-membered aliphatic or aromatic mono- or polycyclic hydrocarbon radical which is optionally substituted and contains heteroatoms.
In a further preferred embodiment, the spacer structural element E is composed of two to four substructural elements, selected from the group consisting of E1 and E2, where the sequence of linkage of the substructural elements is arbitrary and E1 and E2 have the following meanings:
-(YE)k1—(CRE1RE2)c-(QE)k2-(CRE3RE4)d- IE1
-(NRE11)k3-(CRE5RE6)f-(ZE)k4-(CRE7RE8)g-(XE)k5—(CRE9RE10)h-(NRE11*)k6- IE2,
The coefficient c is preferably 0 or 1, the coefficient d is preferably 1 or 2, the coefficients f, g, h independently of one another are preferably 0 or 1 and k6 is preferably 0.
An optionally substituted 4- to 11-membered mono- or polycyclic aliphatic or aromatic hydrocarbon which can contain up to 6 double bonds and up to 6 identical or different heteroatoms selected from the group consisting of N, O, S, where the ring carbons or ring nitrogens can optionally be substituted, for QE and XE independently of one another is preferably understood as meaning optionally substituted arylene, such as optionally substituted phenylene or naphthylene, or optionally substituted hetarylene such as the radicals.
and their substituted or fused derivatives, or radicals of the formulae IE1 to IE11,
where the incorporation of the radicals can take place in both orientations. Aliphatic hydrocarbons are understood as meaning, for example, saturated and unsaturated hydrocarbons.
Z6 and Z7 are independently of one another CH or nitrogen.
Z8 is oxygen, sulfur or NH,
Z9 is oxygen, sulfur or NRE20.
r1, r2, r3 and t are independently of one another 0, 1, 2 or 3.
s and u are independently of one another 0, 1 or 2.
Particularly preferably XE and QE independently of one another are optionally substituted phenylene, a radical
and their substituted or fused derivatives, or radicals of the formulae IE1, IE2, IE3, IE4 and IE7, where the incorporation of the radicals can take place in both orientations.
RE18 and RE19 are independently of one another hydrogen, —NO2, —NH2, —CN, —COOH, a hydroxyl group, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, as in each case described above.
RE20 is, independently of one another, hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C6-alkoxyalkyl, C3-C12-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, hetaryl, CO-hetaryl or SO2-alkylenearyl radical, preferably hydrogen or a branched or unbranched, optionally substituted C1-C6-alkyl radical.
YE and ZE are independently of one another CO, —N(RE11)-, CO—NRE12, NRE12-CO, sulfur, SO, SO2, SO2—NRE12, NRE12-SO2, CS, CS—NRE12, NRE12-CS, CS—O, O—CS, CO—O, O—CO, oxygen, ethynylene, C(RE13) (CRE14) CRE13-O—CRE14, C(═CRE13RE14), CRE13═CRE14, —CRE13 (ORE15)—CHRE14- or —CHRE13-CRE14 (ORE15)-,
preferably oxygen, —N(RE11)—, —C(RE13) (CRE14)-, CO—NRE12, NRE12-CO, SO2—NRE12, NRE12-SO2 or CRE13CRE14
particularly preferably oxygen, —N(RE11)-, —C(RE13) (CRE14)-, CO—NRE12 or NRE12-CO.
RE12 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl or C2-C8-alkynyl radical or an optionally substituted C3-C7-cycloalkyl, hetaryl, arylalkyl or hetarylalkyl radical, such as correspondingly described above for RG or a radical CO—RE16, COORE16 or SO2—RE16, preferably hydrogen, methyl, allyl, propargyl and cyclopropyl.
A branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical for RE13, RE14 or RE15 independently of one another is understood as meaning, for example, the corresponding radicals described above for RG7.
A branched or unbranched, optionally substituted C1-C4-alkoxy radical for RE13 or RE14 independently of one another is understood as meaning, for example, the C1-C4-alkoxy radicals described above for RA14.
Preferred alkylenecycloalkyl radicals for RE13, RE14 or RE15 independently of one another are, for example, the C1-C4-alkylene-C3-C7-cycloalkyl radicals described above for RG7.
A branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C5-alkylene-C1-C4-alkoxy radical, or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkylene-C3-C7-heterocycloalkyl, C1-C4-alkylene-C3-C7-heterocycloalkenyl or hetarylalkyl radical for RE16 is understood as meaning, for example, the corresponding radicals described above for RG11.
A branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl, or hetarylalkyl radical for RE1, RE2, RE3, RE4, RE5, RE6, RE7, RE8, RE9, or RE10 independently of one another is understood as meaning, for example, the corresponding radicals mentioned above for RG7.
Further, two radicals RE3 and RE4 or RE5 and RE6 or RE7 and RE8 or RE9 and RE10 can in each case independently of one another together form a 3- to 7-membered, optionally substituted, saturated or unsaturated carbo- or heterocycle which can contain up to three heteroatoms from the group consisting of O, N and S.
The radical —(CH2)x—(WE)z—RE17 is composed of a C0-C4-alkylene radical, optionally a bonding element WE selected from the group consisting of
—CO—, —CO—N(Rw2)—, N(Rw2)—CO—, —N(Rw2)—CO—N(Rw2*)-, N(R12)—CO—O—, —O—, —S—, —SO2—, —SO2—N(Rw2)—, —SO2—O—, —CO—O—, —O—CO—, —O—CO—N(Rw2)—, —N(Rw2)—SO2—, preferably selected from the group consisting of —CO—N(Rw2)-, —N(Rw2)—CO—, —O—, —SO2—N(RW2)—, —N(RW2)— and —N(Rw2)—SO2—, and the radical RE17, where
independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C8-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted hetaryl, hetarylalkyl, arylalkyl, C3-C7-cycloalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, CO-hetaryl or SO2-alklenearyl radical, preferably independently of on another are hydrogen, methyl, cyclopropyl, allyl, propargyl, and
is hydrogen, a hydroxyl group, CN, halogen, a branched or unbranched, optionally substituted C1—C6-alkyl radical, an optionally substituted C3-C7-cycloalkyl, aryl, hetaryl or arylalkyl radical, a C2-C6-alkynyl or C2-C6-alkenyl radical optionally substituted by C1-C4-alkyl or aryl, an optionally substituted C6-C12-bicycloalkyl, C1-C6-alkylene-C6-C12-bicycloalkyl, C7-C20-tricycloalkyl or C1-C6-alkylene-C7-C20-tricycloalkyl radical, or a 3- to 8-membered, saturated or unsaturated heterocycle substituted by up to three identical or different radicals, which can contain up to three different or identical heteroatoms O, N, S, where two radicals can together be a fused, saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S, and the cycle can optionally be substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, such as optionally substituted 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 6-pyrimidyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-(1,3,4-thiadiazolyl), 2-(1,3,4)-oxadiazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl or triazinyl.
Further, RE17 and Rw2 or Rw2* can together form a saturated or unsaturated C3-C7-heterocycle which can optionally contain up to two further heteroatoms selected from the group consisting of O, S and N.
Preferably, the radicals RE17 and Rw2 or Rw2* together form a cyclic amine as the C3-C7-heterocycle in the case where the radicals are bonded to the same nitrogen atom, such as N-pyrrolidinyl, N-piperidinyl, N-hexahydroazepinyl, N-morpholinyl or N-piperazinyl where in heterocycles which carry free amine protons, such as N-piperazinyl, the free amino protons can be replaced by customary amine protective groups, such as methyl, benzyl, Boc (tert-butoxycarbonyl), Z (benzyloxycarbonyl), tosyl, —SO2—C1-C4-alkyl, —SO2-phenyl or —SO2-benzyl.
Preferred radicals for RE1, RE2, RE3, RE4, RE5, RE6, RE7, RE8, RE9 or RE10 are independently of one another hydrogen, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, 17 optionally substituted aryl or the radical —(CH2)x—(WE)z—RE17.
Particularly preferred radicals for RE1, RE2, RE3, RE4, RE5, RE6, RE7, RE8, RE9 or RE10 are independently of one another hydrogen, F, a branched or unbranched, optionally substituted C1-C4-alkyl radical, in particular methyl.
A branched or unbranched, optionally substituted C1-C6-alkyl, C1-C6-alkoxyalkyl, C2-C6-alkenyl, C2-C12-alkynyl or arylalkyl radical or an optionally substituted aryl, hetaryl or C3-C7-cycloalkyl for RE11 and RE11* in structural element E independently of one another is understood as meaning, for example, the corresponding radicals described above for RG7.
The branched or unbranched, optionally substituted radicals CO—C1-C6-alkyl, CO—O—C1-C6-alkyl, CO—NH—C1-C6-alkoxyalkyl, CO—NH—C1-C6-alkyl or SO2—C1-C6-alkyl, radical or the optionally substituted radicals CO—O-alkylenearyl, CO—NH-alkylenearyl, CO-alkylenearyl, CO-aryl, CO—NH-aryl, SO2-aryl, CO-hetaryl, SO2-alkylenehetaryl for RE11 and RE11* independently of one another are composed, for example, of the corresponding groups CO, COO, CONH, or SO2 and the corresponding radicals mentioned above.
Preferred radicals for RE11 or RE11* are independently of one another hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C6-alkoxy, C2-C6,-alkenyl, C2-C12-alkynyl or arylalkyl radical, or an optionally substituted hetaryl or C3-C7-cycloalkyl radical.
Particularly preferred radicals for RE11 or RE11* are hydrogen, methyl, cyclopropyl, allyl or propargyl.
In a particularly preferred embodiment of structural element E1, structural element E1 is a radical —CH2—CH2—CO—, —CH2—CH2—CH2—CO— or a C1-C5-alkylene radical.
In a particularly preferred embodiment of structural element E, the spacer structural element E used is a structural element of the formula IE1E2
-E2-E1- IE1E2
where the structural elements E2 and E1 have the meanings described above.
Preferred structural elements E are composed of at least one preferred radical of the radicals belonging to structural element E, while the remaining radicals are widely variable.
Particularly preferred structural elements E are composed of the preferred radicals of structural element E.
Preferred structural elements B are composed either of the preferred structural element A, while E is widely variable or of the preferred structural element E, while A is widely variable.
The compounds of the formula I, and also the intermediates for their preparation, can have one or more asymmetric substituted carbon atoms. The compounds can be present as pure enantiomers or pure diastereomers or as a mixture thereof. The use of an enantiomerically pure compound as the active compound is preferred.
The compounds of the formula I can also be present in other tautomeric forms.
The compounds of the formula I can also be present in the form of physiologically tolerable salts.
The compounds of the formula I can also be present as prodrugs in a form in which the compounds of the formula I are liberated under physiological conditions. By way of example, reference may be made to the group T in structural element L, which in some cases contains groups which are hydrolyzable to the free carboxylic acid group under physiological conditions. Also suitable are derivatized structural elements B or A which liberate the structural element B or A respectively under physiological conditions.
In preferred compounds of the formula I, in each case one of the three structural elements B, G or L has the preferred range, while the remaining structural elements are widely variable.
In particularly preferred compounds of the formula I, in each case two of the three structural elements B, G or L have the preferred range, while the remaining structural elements are widely variable.
In very particularly preferred compounds of the formula I, in each case all three structural elements B, G or L have the preferred range, while the remaining structural element is widely variable.
Preferred compounds of the formula I contain, for example, the preferred structural element G, while the structural elements B and L are widely variable.
In particularly preferred compounds of the formula I, for example, B is replaced by the structural element A-E- and the compounds contain, for example, the preferred structural element G and the preferred structural element A, while the structural elements E and L are widely variable.
Further particularly preferred compounds of the formula I contain, for example, the preferred structural element G and preferred structural element A, while the structural elements E and L are widely variable.
Very particular preferred compounds of the formula I in which A-E- is B- re listed below, the number before the text block being the number of an individualized compound of the formula I, and in the text block A-E-G-L the abbreviations being separated by a bonding dash in each case for an individual structural element A, E, G or L and the meaning of the abbreviates of the structural elements being explained after the table.
In the above list, the following abbreviations are used for the structural units A, E, G, and L.
The bond to the structural unit L=as should be understood as meaning a single or double bond for X═C.
The compounds of the formula I and the starting substances used for their preparation can generally be prepared by methods of organic chemistry known to the person skilled in the art, such as are described in standard works such as Houben-Weyl, “Methoden der Organischen Chemie” (Methods of Organic Chemistry), Thieme-Verlag, Stuttgart, or March “Advanced Organic Chemistry”, 4th Edition, Wiley & Sons. Further preparation methods are also described in R. Larock, “Comprehensive Organic Transformations”, Weinheim 1989, in particular the preparation of alkenes, alkynes, halides, amines, ethers, alcohols, phenols, aldehydes, ketones, nitriles, carboxylic acids, esters, amides and acid chlorides. The selection of suitable protective groups for functional groups and the introduction or removal of the protective groups is described, for example, in Greene and Wats in “Protective Groups in Organic Synthesis”, 2nd Edition, Wiley & Sons, 1991. The synthesis of compounds of the formula I can either be carried out in solution or on a polymer support, in each case reaction conditions being used as are known and are suitable for the respective reactions. Use can also be made in this case of variants which are known per se, but not mentioned here.
The general synthesis of compounds of the formula I, where, as described above, A-E- can be the structural element B- and —U-T can be the structural element -L, is described in Schemes 1-10. If not stated otherwise, all starting materials and reagents are commercially available, or can be prepared from commercially obtainable precursors according to customary methods.
Structural units of the formula III (for XG=carbon) are either known or can be used by known methods starting from appropriately fused 1H-azepine-2,5-diones (II), as is described in an exemplary manner, for example, in J. Med. Chem. 1986, 29, 1877-1888 or DE 1568217. 1H-Azepnie-2,5-diones (II), which are used for the preparation of compounds of the formula I, are either commercially available or can be prepared according to the following publications:
5H-dibenzo[b,e]azepine-6,11-dione or substituted variants according to J. Med. Chem. 1965, 8, 74, or Gazz. Chim. Ital. 1953, 83, 533, and 1954, 84, 1135; 5H-pyridol [3,2-c][1] benzazepine-5,11(6H)-dione according to Liebigs Ann. Chem. 1989, 469-476; 4H-thienol [3,2-c][1] benzazepine-4,10(5H)-dione according to Eur. J. Med. Chem. Ther. 1981, 16, 391-398.
Further examples and their access are described in the following references: J. Heterocycl. Chem. 1981, 28, 379-384; Eur. J. Med. 1993, 28, 439-445; J. Med. Chem. 1965, 8, 74; J. Med. Chem. 1989, 32, 1033-1038; Synth. Commun. 1996, 26, 1839-1847; Indian J. Chem. Sect. B 1984, 23, 163-164; J. Heterocycl. Chem. 1982, 19, 689-690; J. Chem. Soc. Perkin Trans. 11976, 1279-1285; J. Chem. Res. 1984, 350-351; Synth. Commun. 1990, 20, 1379-1385; J. Chem. Soc. C 1969, 1321; J. Pharm. Soc. 1994, 83, 137-142; Arch. Pharm. 1979, 312, 662-669; J. Heterocycl. Chem. 1998, 35, 675-686; J. Med. Chem. 1981, 24, 1097-1099.
The conversion into compounds of the formula III is generally carried out by methods known to the person skilled in the art, such as are described in Larock, “Comprehensive Organic Transformations”, Weinheim 1989, p. 167 ff, where methods which are not mentioned can also be used here. Preferably, compounds of the general formula III are prepared by reaction of the ketones II with a phosphonic ester of the general formula (EtO)2P(═O)—(XL)a—CRL1RL2)b-COO-PG1 in the presence of a base. PG1 is understood as meaning an acid protective group.
The reaction preferably takes place in a polar aprotic solvent, such as tetrahydrofuran, dioxane; dimethylformamide (DMF), dimethylacetamide or acetamide; dimethyl sulfoxide, sulfolane; N-methylpyrrolidone, 1,3-dimethyltetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone; in a temperature range—depending on the nature of the solvent used—from −40° C. up to the boiling point of the corresponding solvent.
The base used can be an alkali metal or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as alkali metal carbonate, e.g. sodium or potassium carbonate, an alkali metal or alkaline earth metal hydroxide such as sodium or potassium hydroxide, an alkoxide such as sodium methoxide, potassium tert-butixidem an organometallic compound such as butyllithium or alkali metal amides such as lithium diisopropylamide and lithium, sodium or potassium bis(trimethylsilyl)amide.
The reaction to give IV is carried out by hydrogenation of the double bond under standard conditions. Here too, use can be made of variants known per se which are not mentioned. Preferably, the hydrogenation is carried out in the presence of a noble metal catalyst, such as Pd on active carbon, Pt, PtO2, Rh on AI2O3 in an inert solvent at a temperature of 0-150° C. and a pressure of 1-200 bar; the addition of an acid such as acetic acid or hydrochloric acid can be advantageous. The hydrogenation is particularly preferably carried out in the presence of 5-10% Pd on active carbon.
Solvents which can be used are all customary inert solvents, such as hydrocarbons such as hexane, heptane, petroleum ether, toluene, benzene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform, dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, dioxane; glycol ethers such as ethylene glycol monomethyl ether or monoethyl ether, ethylene glycol dimethyl ether; ketones such as acetone, butanone; amides such as dimethylformamide (DMF), dimethylacetamide or acetamide; sulfoxides such as dimethyl sulfoxide, sulfolane; pyridine, N-methylpyrrolidone, 1,3-dimethyltetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone; water or mixtures—of the solvents mentioned.
Compounds of type V are prepared by reaction with compounds of the general formula A-E′-UE (VI), where the radical UE is OH, COOH, NH2 or a customary leaving group, for example halogen such as chlorine, bromine, iodine or aryl- or alkylsulfonyl optionally substituted by halogen, alkyl or haloalkyl, such as toluenesulfonyl, trifluoroethanesulfonyl and methylsulfonyl or another equivalent leaving group, and MR, for example, is Br, Cl, I, OH, COOPG2, NHPG3 and E′ is a subfragment of E defined such that M-E′ is equal to E or E′ is equal to E if MR═Hal.
The introduction of the side chain in compounds of the formula V depends on the radical M on the aromatic ring Ar (formulae II to IV). The following description of the preparation of the compounds of the formula V is by way of example and is non-limiting for the possible synthesis. In this case, use can also be made of methods for the preparation of substituted aromatic rings, which are known per se, but not mentioned here.
If MR═OR, a method for the formation of carbon-oxygen bonds can be used for the ether bond to be produced. Analogous methods can be used in the synthesis of amine or sulfide linkages. Phenol (1) in scheme2 is reacted with an alcohol HO-E′-A in a Mitsunobu-like coupling (Organic Reactions 1992, 42, 335-656; 35 Synthesis 198.1, 1-28) to give the product (2). The reaction proceeds via the adduct of DEAD and triphenylphosphine and is carried out in an aprotic solvent such as THF, CH2Cl2 or DMF.
Compounds of the formula V can also be prepared by other methods known to the person skilled in the art. Ether bonding in formula V can be obtained, for example, by the reaction of the hydroxyl function with compounds which contain a leaving group such as chloride, bromide or iodide.
If MR═OMe, the methoxy group in (3) can be converted into the hydroxy function by the action of BBr3 in an inert solvent such as CH2Cl2 or alternatively by reaction with ethanethiol and AlCl3 in an inert solvent, preferably CH2Cl2. Other methods for the cleavage of the methoxy function are described in Greene's “Protective Groups in Organic Synthesis” (Wiley).
The phenol (1) can be converted into the corresponding triflate (4) by reacting it with trifluoromethanesulfonic anhydride (Tf2O) in the presence of a suitable base such as 2,6-lutidine in an inert solvent such as CH2Cl2. The triflate (4) can in turn be converted into the carboxylic acid (5, MR═COOH) in the presence of potassium acetate, 1,1′-bis(diphenylphosphino) ferrocene (dppf) and a palladium catalyst such as palladium-I1 acetate (Pd(OAc)2) in a solvent such as DMSO according to the general method of Cacchi and Lupi (Tetrahedron Lett. 33 (1992) 3939) using CO. Alternatively, the same reaction is possible starting from the bromide (6) or the corresponding iodide, or any functional group which can be converted into the triflate, the bromide or the iodide.
Derivatives such as (5) can be coupled, for example, with amines to give compounds of the formula V. Such coupling methods are generally known, as described in the following, for example in Bodansky's “The Practice of Peptide Synthesis” (Springer, Berlin 1984).
Further methods for the reaction of carboxylic acids to give amides can also be read up in standard reference works such as “Compendium of Organic Synthetic Methods”, Vol I-VI (Wiley). If the amine component employed for the reaction contains a protective group, this can be removed before or alternatively after the hydrolysis of the ester. Cleavage methods are described in Greeners “Protective Groups in Organic Synthesis”. When using the Boc protective group, this can be removed under acidic conditions, e.g. by the action of 4N HCl in dioxane or trifluoroacetic acid.
For MR═Br, Cl or I, an acetylene unit can be introduced by means of a coupling method for the formation of carbon-carbon bonds, e.g. a Stille coupling of aromatic triflates or organostannanes with palladium catalysis, preferably (PPh3)2PdCl2, in the presence of LiCl in an inert solvent such as DMF or dioxane (J. Am. Chem. Soc. 1987, 109, 5478-86). The triple bond can be converted into the double or single bond according to known methods by the choice of suitable reduction conditions.
Removal of the protective group PG1 according to standard conditions (see below) leads to the compounds of the general formula I. If PG1 is equal to C1-C4-alkyl or benzyl, the compounds of the general formula V correspond directly to the compounds of the type I.
Alternatively to this synthesis strategy, compounds of type I can also be prepared via VII as an intermediate, where here too reaction conditions are used such as are known to the person skilled in the art and described in standard works.
Compound V is prepared by reaction of compounds of the type IV with radicals of the general formula DE-E′-XE (VIII) under reaction conditions such as have already been described above for the preparation of V (from IV+VI). XE is a suitable leaving group, such as has likewise already been described, and DE is CN, or a protected amino or acid function of the general formula NHPG3 or COOPG2. The synthesis of the fragments DE-E′ or A-E′ is carried out—depending on the actual structure of E—by removal of the protective groups and coupling of the residual fragments according to standard methods, e.g. amide couplings.
The introduction of A is then carried out analogously to the reactions described in Schemes 6-10.
Generally, however, syntheses of the compounds of the formula II are possible in all sorts of ways.
An alkylation of the nitrogen (WG′ corresponds to WG, if RG5 is equal to hydrogen) can take place either after the cyclization (IX to II, Scheme 3) or before the cyclization (X to XI, Scheme 3). The cyclization of XI to II can be carried out, for example, by use of polyphosphoric acid (Procter et al., J. Chem. Soc. (C) 1969, 1000). Alternatively, XI can be converted by methods known to the person skilled in the art into the acid chloride XII, which is then cyclized to II by activators such as AlCl3 or SnCl4 according to Friedel-Craft.
Use can also be made of other preactivated carboxylic acid derivatives XII: symmetrical or mixed anhydrides or “active esters” which are customarily used for the acrylation of amines. These activated carboxylic acid derivatives (COQ) can also be prepared in situ. It is to be taken into account in this connection that, for example, when using AlCl3 a methoxy group (M—R′=OMe, X) is converted into the hydroxy function. (M—R′═OH, II), which is why it can be the case that R is not equal to R′.
In many cases (e-g. if MR═OH), the hydrogenation of the compounds III to IV (Scheme 1) is carried out after protection of the function (Scheme 4). One possibility is acetylation. The protective group (PG in compound XIII) is introduced by known methods and removed by known methods after the hydrogenation (see Greene “Protective Groups in Organic Synthesis”, Wiley).
Another possibility consists in carrying out the hydrogenation only after the introduction of the side chain (XV to VII, Scheme 4), according to methods such as have already been described for compounds of the formula V.
Compounds of the formula I in which XG is equal to N can be prepared according to Scheme 5.
The starting point of the synthesis are compounds of the type XVI, which are either known or are accessible by methods known to the person skilled in the art, such as are described, for example, in Pharmazie 45(8), 1990, 555-559.
Alkylation with a compound of the general formula XIX (UL=customary leaving group) under customary reaction conditions leads to XVII. The further reactions to give I then proceed via XVIII analogously to Scheme 1.
The coupling of the individual fragments and the removal of the protective groups can be carried out according to known processes (see Larock, “Comprehensive Organic Transformations”; protective groups: Greene, T., “Protective Groups in Organic Synthesis”, New York 1991), in the case of amide bonds also analogously to the methods of peptide synthesis, such as are described in standard works, e.g. in Bodanszky “The Practice of Peptide Synthesis”, 2nd Edition, Springer-Verlag 1994, and Bodanszky “Principles of Peptide Synthesis”, Springer-Verlag 1984. A general survey of the customary methods for peptide synthesis and a listing of suitable reagents is furthermore to be found in NOVABIOCHEM 1999 “Catalog 40 and Peptide Synthesis Handbook”.
The amide couplings mentioned can be carried out with the aid of customary coupling reagents using suitably protected amino and carboxylic acid derivatives. Another method consists in the use of preactivated carboxylic acid derivatives, preferably of carboxylic acid halides, symmetrical or mixed anhydrides or “active esters”, which are customarily used for the aceylation of mines. These activated carboxylic acid derivatives can also be prepared in situ. As a rule, the couplings can be carried out in inert solvents in the presence of an acid-binding agent, preferably of an organic base such as triethylamine, pyridine, diisopropylethylamine, N-methylmorpholine, quinoline; the addition of an alkali metal or alkaline earth metal hydroxide, carbonate or hydrogencarbonate or of another salt of a weak acid of the alkali metals or alkaline earth metals, preferably of potassium, sodium, calcium or cesium, can also be favorable.
Depending on the conditions used, the reaction time is between [lacuna] minutes and 14 days; the reaction temperature between −40° C. and 140° C., preferably between −20° C. and 100° C.
Suitable inert solvents are, for example, hydrocarbons such as hexane, heptane, petroleum ether, toluene, benzene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform; dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, dioxane; glycol ethers such as ethylene glycol monomethyl ether or monoethyl ether, ethylene glycol dimethyl ether; ketones such as acetone, butanone; amides such as dimethylformamide (DMF), dimethylacetamide or acetamide; nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide, sulfolane; N-methylpyrrolidone, 1,3-dimethyltetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone, nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate; water; or mixtures of the solvents mentioned.
Protective groups PG which can be used are all protective groups known and customary from peptide synthesis to the person skilled in the art, such as are also described in the abovementioned standard works. The removal of the protective groups in the compounds of the formulae V, VII and XVIII is likewise carried out according to conditions such as are known to the person skilled in the art and are described, for example, by Greene and Wuts in “Protective Groups in Organic Synthesis”, 2nd Edition, Wiley & Sons, 1991.
Protective groups such as PG3 are “N-terminal amino protective groups”; Boc, Fmoc, benzyloxycarbonyl (Z), acetyl and Mtr are preferred here.
PG1 and PG2 are “C-terminal hydroxy protective groups”; C1-4-alkyl such as methyl, ethyl, tert-butyl, or alternatively benzyl or trityl, or polymer-bound protective groups in the form of the commercially available polystyrene resins such as 2-chlorotrityl chloride resin or Wang resin (Bachem, Novabiochem) are preferred here.
The removal of acid-labile protective groups (e.g. Boc, tert-butyl, Mtr, trityl) can be carried out, depending on the protective group used, using organic acids such as trifluoroacetic acid (TFA), trichloroacetic acid, perchloric acid, trifluoroethanol, sulfonic acids such as benzene- or p-toluenesulfonic acid but also inorganic acids such as hydrochloric acid or sulfuric acid, the acids generally being employed in an excess.
In the case of trityl, the addition of thiols such as thioanisole or thiophenol can be advantageous. The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents are preferably organic solvents, for example carboxylic acids such as acetic acid, ethers such as THF or dioxane, amides such as DMF or dimethylacetamide, halogenated hydrocarbons such as dichloromethane, alcohols such as methanol, isopropanol or water. Mixtures of the solvents mentioned are also suitable. The reaction temperature for these reactions is between 10° C. and 50° C., preferably the reactions are carried out in a range between 0° C. and 30° C.
Base-labile protective groups such as Fmoc are cleaved by treatment with organic amines such as dimethylamine, diethylamine, morpholine, piperidine as 5-50% solutions in CH2Cl2 or DMF. The reaction temperature for these reactions is between 110° C. and 50° C. and the reactions are preferably carried out in a range between 0° C. and 30° C.
Acid protective groups such as methyl or ethyl are preferably cleaved by basic hydrolysis in an inert solvent. The bases used are preferably alkali metal or alkaline earth metal hydroxides, preferably NaOH, KOH or LiOH. The solvents used are all customary inert solvents such as hydrocarbons such as hexane, heptane, petroleum ether, toluene, benzene or xylene, chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform, dichloromethane, alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol, ethers such as diethyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, dioxane, glycol ethers such as ethylene glycol monomethyl ether or monoethyl ether, ethylene glycol dimethyl ether, ketones such as ac tone, butanone, amides such as dimethylformamide (DMF), dimethylacetamide or acetamide, nitriles such as acetonitrile, sulfoxides such as dimethyl sulfoxide, sulfolane, N-methylpyrrolidone, 1,3-dimethyltetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone, nitro compounds such as nitromethane or nitrobenzene, water or mixtures of the solvents mentioned. The addition of a phase-transfer catalyst can be advantageous depending on the solvent or solvent mixture used. The reaction temperature for these reactions is generally between −10° C. and 100° C.
Hydrogenolytically removable protective groups such as benzyloxycarbonyl (z) or benzyl can be removed, for example, by hydrogenolysis in the presence of a catalyst (e.g. of a noble metal catalyst on active carbon as a support). Suitable solvents are those indicated above, in particular alcohols such as methanol or ethanol, amides such as DMF or dimethylacetamide, esters such as ethyl acetate. As a rule, the hydrogenolysis is carried out at a pressure of 1-200 bar and at temperatures between 0 and 100° C.; the addition of an acid such as acetic acid or hydrochloric acid may be advantageous. The catalyst used is preferably 5 to 10% Pd on active carbon.
The synthesis of structural units of Type E (or E′) is generally carried out by methods known to the person skilled in the art. The structural units used are either commercially available or accessible by methods known from the literature. The synthesis of some of these structural units is described by way of example in the example section.
In the case in which the fragments QE or XE contained in the compounds of the type VI and VIII are a hetaryl radical, the structural units used are either commercially available or accessible by methods known to the person skilled in the art. A large number of preparation methods are described in detail in Houben-Weyl's “Methoden der organischen Chemie” [Methods of Organic Chemistry (Vol. E6: furans, thiophenes, pyrroles, indoles, benzothiophenes, benzofurans, benzopyrroles; Vol. E7: quinolines, pyridines; Vol. E8: isoxazoles, oxazoles, thiazoles, pyrazoles, imidazoles and their benzo-fused representatives, and also oxadiazoles, thiadiazoles and triazoles; Vol. E9: pyridazines, pyrimidines, triazines, azepines and their benzo-fused representatives, and purines). The linkage of these fragments to E can also take place, depending on the structure of E, via the amino or acid function by methods which are known to the person skill d in the art.
The synthesis of structures of the general formula A-E′-DE is carried out by methods known to the person skilled in the art, such as are described in WO 97/08145. Examples of these are the conversion of compounds of the general formula:
HNRE12-EA1-DE (XX)
NC-EA2-DE (XXI)
into compounds of the general formula:
A-NRE12-EA1-DE (XXII)
A-E′-DE (XXIII)
The groups EA1 and EA2 in the formulae XX-XXII are structural fragments which after the appropriate modification, e.g. the reaction with suitable reagents or coupling with appropriate structural units, form the structural fragment A-E in totality. These structural units can then be reacted either directly—in the case of the corresponding free amines or carboxylic acids—or after removal of the protective groups—to give compounds of the general formula I (Schemes 1 and 5). In principle, A, however, can also be introduced, as described in Scheme 1, into compounds of type IV, where the reaction conditions mentioned can be used exactly as variants not described here.
In Schemes 6-10, a number of the methods for the introduction of A are described by way of example, where in each case reaction conditions were used such as are known and suitable for the respective reactions. Use can also be made in this case of variants which are known per se, but not mentioned here.
Ureas and thioureas (AE-1 to AE-3) can be prepared by customary methods of organic chemistry, e.g. by reaction of an isocyanate or of an thioisocyanate with an amine, if appropriate in an inert solvent, with warming (Houben-Weyl Volume VIII, 157ff.) (Scheme 6)
Scheme 7 shows, by way of example, the preparation of compounds of the type AE-4, such as is described, for example, by Blakemoore et al. in Eur. J. Med. Chem. 1987 (22) 2, 91-100, or von Misra et al. in Bioorg. Med. Chem. Lett. 1994 4 (18), 2165-2170. The pyridine N-oxide can be converted into the corresponding pyridines under the conditions of a transfer hydrogenation (e.g. Pd catalyst such as Pd/active carbon; inert solvent such as methanol, ethanol, isopropanol) using, for example, cyclohexene, 1,4-cyclohexadiene, formic acid or formates.
Unsubstituted or cyclic guanidine derivatives of the general formula AE-5 and AE-6 can be prepared by means of commercially available or readily accessible reagents, such as are described, for example, in Synlett 1990, 745, J. Org. Chem. 1992, 57, 2497, Bioorg. Med. Chem. 1996, 6, 1185-1208; Bioorg. Med. Chem. 1998, 1185, or Synth. Comm. 1998, 28, 741-746.
The preparation of compounds of the general formula AE-7 can be carried out analogously to U.S. Pat. No. 3,202,660, compounds of the formula AE-9, AE-10, AE-11 and AE-12 analogously to WO 97/08145. Compounds of the formula AE-8 can be prepared, as shown in Scheme 5, for example, according to the method described by Perkins et al., Tetrahedron Lett. 1999, 40, 1103-1106. Scheme 8 gives a general survey of the synthesis of the compounds mentioned.
Compounds of the general formula AE-13 can be prepared analogously to Froeyen et al., Phosphorus Sulfur Silicon Relat. Elem. 1991, 63, 283-293, AE-14 analogously to Yoneda et al., Heterocycles 1998, 15 N′-1, Spec. Issue, 341-344 (Scheme 9). The preparation of corresponding compounds can also be carried out analogously to WO 97/36859:
Compounds of the general formula AE-15 can be prepared as in Synthesis 1981, 963-965 and Synth. Comm. 1997, 27 (15), 2701-2707, AE-16 analogously to J. Org. Chem. 1991, 56 (6), 2260-2262 (Scheme 10).
Structural units of the type IA17 (see sketch on p. 24, naphthyridine derivatives) can be prepared analogously to WO 00/09503.
The invention further relates to the use of the structural element of the formula IGL
G-L IGL
for the preparation of compounds which bind to integrin receptors.
The invention further relates to drugs comprising the structural element of the formula IGL.
The invention further relates to pharmaceutical preparations, comprising at least one compound of the formula I in addition to the customary pharmaceutical excipients.
The compounds according to the invention can be administered, orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) in the customary manner. Administration can also be carried out through the nasopharynx using vapors or sprays. Further, the compounds according to the invention can be introduced by direct contact with the affected tissue.
The dose depends on the age, condition and weight of the patient and on the manner of administration. As a rule, the daily dose of active compound is between approximately 0.5 and 50 mg/kg of body weight in the case of oral administration and between approximately 0.1 and 10 mg/kg of body weight in the case of parenteral administration.
The novel compounds can be administered in solid or liquid form in the customary pharmaceutical administration forms, e.g. as tablets, film-coated tablets, capsules, powders, granules, coated tablets, suppositories, solutions, ointments, creams or sprays. These are prepared in a customary manner. The active compounds can in this case be processed using the customary pharmaceutical excipients such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-delaying agents, antioxidants and/or propellants (cf. H. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991). The administration forms thus obtained normally contain the active compound in an amount from 0.1 to 90% by weight.
The invention further relates to the use of the compounds of the formula I for the production of drugs for the treatment of diseases. The compounds of the formula I can be used for treating human and animal diseases. The compounds of the formula I bind to integrin receptors. They are therefore preferably suitable as integrin receptor ligands and for the production of drugs for treating diseases in which an integrin receptor is involved, in particular for the treatment of diseases in which the interaction between integrins and their natural ligands is dysregulated, i.e. excessive or reduced.
Integrin receptor ligands are understood as meaning agonists and antagonists.
An excessive or decreased interaction is understood as meaning either an excessive or decreased expression of the natural ligand and/or of the integrin receptor and thus an excessive or decreased amount of natural ligand and/or integrin receptor or an increased or decreased affinity of the natural ligand for the integrin receptor.
The interaction between integrins and their natural ligands is dysregulated compared with the normal stat, i. excessive or decreased, if this dysregulation does not correspond to the physiological state. An increased or decreased interaction can lead to pathophysiological situations.
The level of dysregulation which leads to a pathophysiological situation is dependent on the individual organism and on the site and nature of the disorder.
Preferred integrin receptors for which the compounds of the formula I according to the invention can be used are the α5β1, α4β1, gpIIbβ3, αvβ5 and αvβ3 integrin receptors.
The compounds of the formula I particularly preferably, bind to the αvβ3 integrin receptor and can thus be particularly preferably used as ligands of the αvβ3 integrin receptor and for the treatment of diseases in which the interaction between αvβ3 integrin receptor and its natural ligands is excessive or decreased.
The compounds of the formula I are preferably used for the treatment of the following diseases:
cardiovascular disorders such as atherosclerosis, restenosis after vascular injury or stent implantation, and angioplasty (neointima formation, smooth muscle cell migration and proliferation),
acute kidney failure,
angiogenesis-associated microangiopathies such as diabetic antipathies or retinopathy or rheumatoid arthritis,
blood platelet-mediated vascular occlusion, arterial thrombosis,
stroke, reperfusion damage after myocardial infarct or stroke,
carcinomatous disorders, such as in tumor metastasis or in tumor growth (tumor-induced angiogenesis),
osteoporosis (bone resorption after chemotaxis and adhesion of osteoclasts to the bone matrix),
high blood pressure, psoriasis, hyperparathyroidism, Paget's disease, malignant hypercalcemia, metastatic osteolytic lesions, inflammation, wound healing, cardiac insufficiency, congestive heart failure CHF, as well as in
antiviral, antimycotic, antiparasitic or antibacterial therapy and prophylaxis (adhesion and internalization), in particular in mycotically mediated disorders, in particular infections by Candida albicans.
Advantageously, the compounds of the formula I can be administered in combination with at least one further compound in order to achieve an improved curative action in a number of indications. These further compounds can have the same or a different mechanism of action as/from the compounds of the formula I.
In addition to the compounds of the formula I and the customary pharmaceutical excipients, the pharmaceutical preparations can therefore contain at least one further compound, depending on the indication, in each case selected from one of the 10 groups below.
Group 1:
inhibitors of blood platelet adhesion, activation or aggregation, such as acetylsalicylic acid, lysine acetylsalicylate, piracetam, dipyridamol, abciximab, thromboxane antagonists, fibrinogen antagonists, such as tirofiban, or inhibitors of ADP-induced aggregation such as ticlopidine or clopidogrel, anticoagulants which prevent thrombin activity or formation, such as inhibitors of IIa, Xa, XIa, IXa or VIIa, antagonists of blood platelet-activating compounds and selectin antagonists
for the treatment of blood platelet-mediated vascular occlusion or thrombosis, or
Group 2:
inhibitors of blood platelet activation or aggregation, such as GPIIb/IIIa antagonists, thrombin or factor Xa inhibitors or ADP receptor antagonists,
serine protease inhibitors,
fibrinogen-lowering compounds,
selectin antagonists,
antagonists of ICAM-1 or VCAM-1
inhibitors of leukocyte adhesion
inhibitors of vascular wall transmigration,
fibrinolysis-modulating compounds, such as streptokinase, tPA, plasminogen-activating stimulants, TAFI inhibitors, XIa inhibitors or PAI-1 antagonists,
inhibitors of complement factors,
endothelin-receptor antagonists,
tyrosine kinase inhibitors,
antioxidants and
interleukin 8 antagonists
for the treatment of myocardial infarct or stroke, or
Group 3:
endothelin antagonists,
ACE inhibitors,
angiotensin receptor antagonists,
endopeptidase inhibitors,
beta-blockers,
calcium channel antagonists,
phosphodiesterase inhibitors and
caspase inhibitors
for the treatment of congestive heart failure, or
Group 4:
thrombin inhibitors,
inhibitors of factor Xa,
inhibitors of the coagulation pathway which leads to thrombin formation, such as heparin or low-molecular weight heparins, inhibitors of blood platelet adhesion, activation or aggregation, such as GPIIb-IIIa antagonists or antagonists of the blood platelet adhesion and activation mediated by vWF or GPIb, endothelin receptor antagonists,
nitrogen oxide synthase inhibitors,
CD44 antagonists,
selectin antagonists,
MCP-1 antagonists,
inhibitors of signal transduction in proliferating cells, antagonists of the cell response mediated by EGF, PDGF, VEGF or bFGF and
antioxidants
for the treatment of restenosis after vascular injury or stent implantation, or
Group 5:
antagonists of the cell response mediated by EGF, PDGF, VEGF or bFGF,
heparin or low-molecular weight heparins or further GAGS,
inhibitors of MMPs,
selectin antagonists,
endothelin antagonists,
ACE inhibitors,
angiotensin receptor antagonists and
glycosylation inhibitors or AGE formation inhibitors or AGE breakers and antagonists of their receptors, such as RAGE,
for the treatment of diabetic angiopathies or
Group 6:
lipid-lowering compounds,
selectin antagonists,
antagonists of ICAM-1 or VCAM-1
heparin or low-molecular weight heparins or further GAGs,
inhibitors of MMPs,
endothelin antagonists,
apolipoprotein A1 antagonists,
cholesterol antagonists,
HHG CoA reductase inhibitors,
ACAT inhibitors,
ACE inhibitors,
angiotensin receptor antagonists,
tyrosine kinase inhibitors,
protein kinase C inhibitors,
calcium channel antagonists,
LDL receptor function stimulants,
antioxidants
LCAT mimetics and
free radical scavengers
for the treatment of atherosclerosis or
Group 7:
cytostatic or antineoplastic compounds,
compounds which inhibit proliferation, such as kinase inhibitors and
heparin or low-molecular weight heparins or further GAGs
for the treatment of cancer, preferably for the inhibition of tumor growth or metastasis, or
Group 8:
compounds for antiresorptive therapy,
compounds for hormone exchange therapy, such as estrogen or progesterone antagonists, recombinant human growth hormone,
bisphosphonates, such as alendronates
compounds for calcitonin therapy,
calcitonin stimulants,
calcium channel antagonists,
bone formation stimulants, such as growth factor agonists,
interleukin-6 antagonists and
Src tyrosine kinase inhibitors
for the treatment of osteoporosis or
Group 9:
TNF inhibitors, such as TNF antibodies, in particular the human antibody D2E7,
antagonists of VLA-4 or VCAM-1,
antagonists of LFA-1, Mac-1 or ICAMs,
complement inhibitors,
immunosuppressants,
interleukin-1, -5 or -8 antagonists and
dihydrofolate reductase inhibitors
for the treatment of rheumatoid arthritis or
Group 10:
collagenase,
PDGF antagonists and
for improved wound healing.
A pharmaceutical preparation comprising at least one compound of the formula I, if appropriate pharmaceutical excipients and at least one further compound, depending on the indication, in each case selected from one of the above groups, is understood as meaning a combined administration of at least one of the compounds of the formula I with at least one further compound in each case selected from one of the groups described above and, if appropriate, pharmaceutical excipients.
Combined administration can be carried out by means of a substance mixture comprising at least one compound of the formula I, if appropriate pharmaceutical excipients and at least one further compound, depending on the indication, in each case selected from one of the above groups, but also spatially and/or chronologically separate.
In the case of the spatially and/or chronologically separate administration, the administration of the components of the pharmaceutical preparation, the compounds of the formula I and the compounds selected from one of the abovementioned groups takes place spatially and/or chronologically separately.
For the treatment of restenosis after vascular injury or stenting, the administrations of the compounds of the formula I can be carried out locally at the affected sites, on their own or in combination with at least one compound selected from group 4. It may also be advantageous to coat the stents with these compounds.
For the treatment of osteoporosis, it may be advantageous to carry out the administration of the compounds of the formula I in combination with antiresorptive or hormone replacement therapy.
The invention accordingly relates to the use of the abovementioned pharmaceutical preparations for the production of drugs for the treatment of diseases.
In a preferred embodiment, the invention relates to the use of the abovementioned combined pharmaceutical preparations for the production of drugs for treating
blood platelet-mediated vascular occlusion or thrombosis
when using compounds of group 1,
myocardial infarct or, stroke
when using compounds of group 2,
congestive heart failure
when using compounds of group 3,
restenosis after vascular injury or stent implantation
when using compounds of group 4,
diabetic angiopathies
when using compounds of group-5,
atherosclerosis
when using compounds of group 6,
cancer
when using compounds of group 7,
osteoporosis
when using compounds of group 8,
rheumatoid arthritis
when using compounds of group 9,
wound healing
when using compounds of group 10.
The following examples illustrate the invention, the selection of these examples being non-limiting.
A mixture of 2-chloropyridine N-oxide (70.0 mmol, 11.0 g), 4-aminobutanol (130 mmol, 11.5 g) and NaHC03 (340.0 mol, 28.9 g) in tert-amyl alcohol (500 ml) was heated under reflux for 24 h. After dilution with CH2Cl2, the suspension was filtered and the filtrate was concentrated in a rotary evaporator. Chromatography on silica gel (CH2Cl2/MeOH 0 to 20%) afforded 6.9 g of target product; ESI-MS [2M+H+]=365.1, [M+H+]=183.05, 83.2; 1H-NMR (270 MHz, CDCl3) δ ppm: 8.11 (d, 1H), 7.23 (t, 1H), 6.86 (s br., 1H), 6.66-6.47 (m, 2H), 3.69 (t, 2H), 3.32 (q, 2H), 2.53 (s br., 1H), 1.90-1.54 (m, 4H).
A mixture of 2-chloropyridine N-oxide (7.70 mmol, 997.5 mg), 3-aminopropanol (15.0 mmol, 1.1 g) and NaHCO3 (40.0 mmol, 3.4 g) in tert-amyl alcohol (80 ml) was heated under reflux for 21 h. After dilution with CH2Cl2, the suspension was filtered and the filtrate was concentrated in a rotary evaporator. Chromatography on silica gel (CH2Cl2/MeOH 0 to 20%) afforded 1 g of target product; ESI-MS [2M+H+]=337.1, [M+H+]=169.15; 1H-NMR (270 MHz, DMSO) δ ppm: 8.07 (d, 1H), 7.26-7.08 (m, 1H), 6.78 (d, 1H), 6.56 (t, 1H), 4.61 (s br., 1H), 3.60-3.13 (m, incl. DMSO), 1.69 (quint., 2H).
1H-NMR (360 MHz, DMSO) δ ppm: 9.5 and 9.05 (each s, 1H), 7.45 (d, 2H), 7.35 (m, 1H), 7.20 (d, 1H), 7.15, 6.95, 6.75, 6.60 (each m, 1H), 4.85 (s, 2H), 4.10 (d, 2H), 1.35 (s, 9H).
2-Bromopyridine (100 g; 0.633 mol) and 1,3-diaminopropane (234.5 g; 3.16 mol) were heated to reflux for 7 h. After reaction was complete, the mixture was evaporated. Distillation in an oil pump vacuum of the residue which remained afforded 43 g of the desired product; ESI-MS [M+H+]=152.15;
1H-NMR (360 MHz, CDCl3) δ (ppm): 8.05 (d, 1H), 7.36 (t, 1H), 6.51 (t, 1H), 6.36 (d, 1H), 4.98 (s, 1H), 3.35 (s, 2H), 2.82 (t, 2H), 1.73 (m, 1H), 1.32 (s, 2H).
A solution of 3-methoxyaniline (80.0 mmol, 9.9 g) was added dropwise at 10° C. to a solution of phthalic anhydride (80.0 mmol, 11.9 g) in THF (80 ml). The mixture was stirred overnight and treated with water (1.2 l). The precipitate was filtered off with suction, washed with ice-cold water and also with acetone and pentane and then dried in vacuo. Yield: 19.5 g; mp 168.4 to 168.9° C.; ESI-MS: [2M+Na+]=565.2, [M+K+]=310.0, [M+H+]=272.05;
1H-NMR (400 MHz; DMSO-d6): δ (ppm) 13.01 (s br., 1H), 10.31 (s br., 1H), 7.87 (d, 1H), 7.69-7.49 (m, 3E), 7.39 (s, 1H), 7.26-7.19 (m, 2H), 6.69-6.62 (m, 1H), 3.73 (s, 3H).
2-[(3-Methoxyanilino)carbonyl]benzoic acid (5, 36.9 mmol 10.0 g) was introduced at 10° C. into a suspension of 5.3 g of NaH (60%; freed from oil using pentane) in DM50 (110.0 ml). The mixture was stirred at RT for 1 h until the evolution of H2 was complete. Methyl iodide (169.6 mmol, 24.1 g) was added dropwise and the mixture was stirred further overnight. For the work-up, water (100 ml) was added dropwise and the solution was extracted with ethyl acetate. The combined organic phases were washed with an aq. saturated NaCl solution. Drying and concentration of the organic phase afforded 11.2 g of yellow residue; ESI-MS: [2M+N+]=621.3, [M+K+]=338.0, [M+H+]=300.15;
1H-NMR (400 MHz; CDCl3;): d (ppm) 7.78 (d, 1H), 7.32 (t, 1H), 7.28-7.21 (m, 1H), 7.17 (d, 1H), 7.04 (t, 1H), 6.74-6.64 (m, 2H), 6.61 (d, 1H), 3.92 (s, 3H), 3.63 (s, 3H), 3.51 (s, 3H).
LiOH (73.5 mmol, 1.8 g) in water (250 ml) was added dropwise to a solution of methyl 2-{[3-methoxy(methyl)anilino]carbonyl}benzoate (6, 36.8 mmol, 11.0 g) in methanol (250 ml). The mixture was stirred at 40° C. overnight. The mixture was acidified to pH 4.1 (using 2 N HCl) at 0° C. and the suspension was concentrated. The residue was dissolved using CH2Cl2 and extracted by shaking with water. Drying and concentration of the organic phase afforded 9.8 g of foam; ESI-MS: [2M+Na+]=593.3, [M+K+] 324.0, [M+H+]=286.15; 1H-NMR (270 MHz; DMSO-d6): d (ppm) 13.13 (s br., 1H), 7.68 (d, 1H), 7.42-7.24 (m, 2H), 7.18 (d, 1H), 7.07 (t, 1H), 6.92-6.73 (m, 2H), 6.64 (d, 1H), 3.59 (s, 3H).
Thionyl chloride (56.6 mmol, 6.7 g) was added at 5° C. to a solution of 2-{[3-ethoxy(methyl)anilino]carbonyl}benzoic acid (7, 33.3 mmol, 9.5 g) in THF (180 ml). The mixture was warmed to 40° C. for 2 h and then codistilled a number of times with toluene. It was possible to react the residual brown oil (10.4 g) further without purification.
2-{[3-Methoxy(methyl)anilino]carbonyl)benzoyl chloride (8, 10.4 g) was heated to 180° C. with a mixture of AlCl3 (701.9 mmol, 93.6 g) and NaCl (391.0 mmol, 23.0 g) and the black melt was stirred for 15 min. For the work-up, the cooled melt was poured onto ice/water and the, deposited precipitate was filtered off with suction. The precipitate was washed by stirring with heptane and filtered and purified by means of chromatography on silica gel (eluent: gradient of hexane/CH2Cl2 50 to 100% to CH2Cl2/MeOH 0 to 5%): 2.8 g; ESI-MS: [M+K+]=292.0, [M+H+]=254.1;
1H-NMR (270 MHz; DMSO-d6): d (ppm) 10.59 (s br., 1H), 8.08-7.99 (m, 1H), 7.81-7.69 (m, 2H), 7.69-7.59 (m, 1H), 7.41 (d, 1H), 6.86 (d, 1H), 6.73 (dd, 1H), 3.50 (s, 3H).
A solution of methyl diethylphosphonoacetate (23.7 mmol, 5.0 g) and lithium methoxide (23.7 mmol, 0.9 g) in DMF (50 ml) was added dropwise at 0° C. under N2 to 3-hydroxy-5-methyl-5H—dibenzo[b,e]jazepine-6,11-dione (9, 7.9 mmol, 2.0 g) and lithium methoxide (7.9 mmol, 0.3 g) in DMF (50 ml). The mixture was warmed to 60° C. overnight. The solution was treated at 0° C. with 2 N HCl and extracted with ethyl acetate. The combined organic phases were extracted by shaking with aq. saturated NaCl solution. Drying, concentration and chromatography on silica gel (CH2Cl2/MeOH 0 to 100%) afforded 2.0 g as a cis:trans mixture; ESI-MS: [M+K+]=348.0, [M+H+]=310.05.
Acetyl chloride (2.23 mmol, 0.18 g) and then pyridine (4.46 mmol, 0.35 g) were injected at 0° C. into a solution of methyl (2 E, Z)-(3-hydroxy-5-methyl-6-oxo-5,6-dihydro-11H-dibenzo[b,] azepin-11-ylidene)ethanoate (10, 0.74 mmol, 0.23 g) in DMF (10 ml). The mixture was stirred overnight at RT and, for the work-up, poured onto 20 ml of ice/water. The mixture was acidified and extracted with diethyl ether. Drying and concentration of the organic phase afforded 0.26 g; ESI-MS: [M+K+]=390.0, [M+H+]=352.0.
Methyl [2 E,Z)-(3-acetyloxy-5-methyl-6-oxo-5,6-dihydro-1H-dibenzo-[b,e]azepin-11-ylidene)ethanoate (11, 0.68 mmol, 0.24 g) and Pd/carbon (40 mg) in MeOH (24 ml)/ethyl acetate (24 ml) were treated with H2 gas at 50° C., 120 bar for 21 h. Filtering through Celite and concentration afforded 0.25 g; ESI-MS: [M+K+]=392.0, [M+H+]=354.15.
K2CO3 was added at 5° C. to a solution of methyl [3-acetyloxy-5-methyl-6-oxo-6,11-dihydro-5H-djbenzo[b,e]azepin-11-yl)acetate (12, 0.71 mmol, 0.25 g) in MeOH (9 ml). The mixture was stirred at RT for 5 h. The solution was neutralized using aq. NH4Cl and extracted with CH2Cl2. Drying and concentration afforded 0.18 g of white residue; ESI-MS: [2M+Na+]=645.2, [M+K+]=350.0, [M+H+]=312.05.
A solution of 4-[(1-oxido-2-pyridinyl)amino]-1-butanol (1) (0.40 30 mmol, 0.07 g) and diethyl azodicarboxylate (0.40 mmol, 0.08 g) in DMF (2 ml) was added dropwise to methyl [3-Hydroxy-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetate (13, 0.16 mmol, 0.05 g) and triphenylphosphine (0.43 mmol, 0.11 g) in DMF (5 ml) under argon. The mixture was stirred overnight at 40° C. Concentration, codistillation with xylene and chromatography on silica gel (heptane/CH2Cl2 0 to 100% to CH2Cl2/MeOH 0 to 100%) afforded 24.00 mg (purity 90%).
The suspension of methyl (5-methyl-3-{4-[[1-oxido-2-pyridinyl)amino]-butoxy)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]-azepin-11-yl)acetate (14, 0.05 mmol, 24.0 mg), cyclohexene (4.93 mmol, 0.50 ml) and Pd/carbon (30.0 mg) was stirred under reflux overnight. After filtration through Celite and concentration, the residue was taken up in water and the mixture was extracted with diethyl ether. Concentration afforded 6.70 mg.
A solution of 3-[(1-oxido-2-pyridinyl)amino]-1-propanol (2, 0.81 mmol, 0.14 g) and diethyl azodicarboxylate (0.81 mmol, 0.17 g) was added dropwise to a solution of methyl (2E,Z)-(3-hydroxy-5-methyl-6-oxo-5,6-dihydro-11H-dibenzo[b,e]azepin-11-yl idene)ethanoate (10, 0.32 mmol, 0.10 g) and triphenylphosphine (0.87 mmol, 0.23 g) under argon. The mixture was stirred at RT overnight. Concentration, codistillation with xylene and filtration through silica gel afforded 0.12 g; ESI-MS: [M+K+]=498.1, [M+H+]=460.15, 230.6.
The suspension of methyl (2E,Z)-(5-methyl-3-{3-[(1-oxido-2-pyridinyl)-amino]propoxy)-6-oxo-5,6-dihydro-11H-dibenzo[b,e]-azepin-11-ylidene)ethanoate (16, 0.11 mmol, 50.0 mg), cyclohexene (4.93 mmol, 0.50 ml) and Pd/carbon (50.0 mg) was stirred under reflux for 2 d. Filtration through Celite, chromatography on silica gel (heptane/CH2Cl2 0 to 100%.
CH2Cl2/MeOH 0 to 100%) afforded 31.80 mg; ESI-.MS: [M+K+]=482.1, [M+H+]=444.15, 222.6.
Methyl (2 E,Z)-(5-methyl-6-oxo-3-{3-(2-pyridinylamino)-propoxy]-5,6-dihydro-11H-dibenzo[b,e]azepin-11-ylidene)ethanoate (17, 0.12 mol, 55.0 mg) and Pd/carbon (5 mg) in MeOH (4 ml/ethyl acetate (4 ml) were treated with H2 gas at 50° C., 120 bar for 21 h. Filtration through Celite, concentration and column chromatography afforded 22.0 mg; ESI-MS: [M+K+]=484.1, [M+Na+]=468.0, [M+H+]=446.15, 223.6.
Trifluoromethanesulfonic anhydride (1.15 mmol, 326.2 mg) was added at −78° C. under argon to a solution of [3-hydroxy-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetate (13, 0.58 mmol, 180.0 mg) and 2,6-dimethylpyridine (1.16 mmol, 123.9 mg) in CH2Cl2 (6 ml). The mixture was stirred at −78° C. for 30 min and then at RT overnight. The excess of triflate was removed in a high vacuum. The oily residue was taken up in CH2Cl2, washed with HCl (IN), buffered with aq. NaHCO3 and washed with sat. aq. NaCl. Drying and concentration afforded 250.0 mg of brownish oil, which was reacted further without additional purification.
Carbon monoxide was passed through a suspension of methyl (5-methyl-6-oxo-3-{[(trifluoromethyl)sulfonyl]oxy)-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetate (19, 0.56 mmol, 250.0 mg), potassium acetate (2.26 mmol, 221.3 mg, 1,1′-bis(diphenyl-phosphino)ferrocene (0.11 mmol, 64.8 mg) and palladium acetate (0.03 mmol, 6.4 mg) in DMSO (9 ml). The mixture was then heated at 70° C. for 3 h, a CO-filled balloon guaranteeing a CO atmosphere over the reaction mixture going into solution. For the work-up, the solution was diluted with water (40 ml), brought to pH 8 using aq. NaHC03 and extracted with diethyl ether. The aq. phase was then acidified with HCl (1N) at 0° C. and extracted with CH2Cl2. In order to remove DMSO, the CH2Cl2 phases were washed a number of times with water. Drying and concentration afforded 120.0 mg of yellow oil; ESI-MS: [M+H+]=340.11.
Diisopropylethylamine (0.4 mmol, 51.4 mg) and EDCI*HCl (0.19 mmol, 36.71 mg) were added at 0° C. to a solution of 1′-(2-methoxy-2-oxoethyl)-5-methyl-6-oxo-6,1,1-dihydro-5H-dibenzo-[b,e]azepioe-3-carboxylic acid (20, 0.15 mmol, 50.0 mg) in CH2Cl2 (2 ml)/DMF (1 ml). The mixture was then stirred at 0° C. for 1 h before adding N-[4-(aminomethyl)phenyl]-1H-benzimidazol-2-amine (hydrochloride) (3) (0.16 mmol, 44.5 mg) dissolved in DMF. The mixture was stirred at 0° C. for 1 hour and at RT overnight. Concentration and chromatography (CH2Cl2/MeOH 0 to 100%) afforded 16.0 mg of target product; ESI-MS: [M+H+]=560.15, 280.65.
Diisopropylethylamine (0.2 mmol, 25.3 mg) and EDCI*HCl (0.19 mmol, 36.71 mg) were added at 0° C. to a solution of 11-(2-methoxy-2-oxoethyl)-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo-[b,e]azepin-3-carboxylic acid (20, 0.15 mmol, 50.0 mg) in CH2Cl2 (2 ml)/DMF (1 ml). The mixture was then stirred at 0° C. for 1 h before adding N1-pyridin-2-ylpropane-1,3-diamine (4) (0.15 mol, 22.7 mg) dissolved in DMF. The mixture was stirred at 0° C. for 1 hour and at RT overnight. Concentration and chromatography (CH2Cl2/M OH 0 to 100%) afforded 15.0 mg of target product; ESI-MS: [M+H]=473.15, 237.1.
Trifluoromethanesulfonic anhydride (4.20 mmol, 1.2 g) was added at −78° C. under argon to a solution of methyl (2E,Z)-(3-hydroxy-5-methyl-6-oxo-5,6-dihydro-11H-dibenzo[b,e]azepin-11-ylidene)-ethanoate (10, 3.23 mmol, 1.0 g) and 2,6-dimethylpyridine (6.47 mmol, 0.69 g) in CH2Cl2 (30 ml). The mixture was stirred at −78° C. for 30 min and then at RT overnight. The excess of triflate was removed in a high vacuum. The oily residue was taken up in CH2Cl2, washed with HCl (1N), buffered with aq. NaHCO3 and washed with sat. aq. NaCl. Drying and concentration of the organic phase afforded 1.1 g of brownish oil, which was reacted further without additional purification.
Carbon monoxide was passed through a suspension of methyl (2E,Z)-(5-methyl-6-oxo-3-{[(trifluoromethyl)sulfonyl]oxy}-5,6-dihydro-11H-dibenzo-[b,e]azepin-11-ylidene)ethanoate (23, 2.54 mmol, 1.1 g), potassium acetate (10.15 mmol, 1.0 g), 1,1′-bis(diphenylphosphino)ferrocene (0.51 mmol, 0.29 g), palladium acetate (0.13 mmol, 28.5 mg) in DMSO (40 ml). The mixture was then heated at 70° C. for 3 h, a CO-filled balloon guaranteeing a CO atmosphere over the reaction mixture going into solution. For the work-up, the solution was diluted with water (50 ml), brought to pH 7 to 8 using aq. NaECO3 and extracted with diethyl ether. The aq. phase was then acidified with HCl (IN) at 0° C. and extracted with combined CH2Cl2. In order to remove DMSO, the combined CH2Cl2 phases were washed a number of times with water. Drying and concentration afforded 200.0 mg of yellow oil; ESI-MS: [M+K+]=376.0, [M+H+]=338.05, 102.15.
Preparation was carried out analogously to the synthesis of 3 starting from 7 g of N-Boc-1,5-diaminopentane hydrochloride (29.3 mmol). After reaction analogously to 3a, 10.3 g of N-Boc-5-{[(2-aminoanilino)-carbothioyl]amino}pentan-1-amin were obtained; ESI-MS [M+H+]=353.25. Cyclodesulfurization and subsequent removal of the Boc group using TFA afforded an oily crude product, which was taken up in CH3OH and converted into the corresponding hydrochloride using 250 ml of ethereal HCl (saturated at 0° C.). Stirring the obtained solid with a mixture of CH3OH/methyl tert-butyl ether afforded 1.8 g of a reddish amorphous solid.
1H-NMR (360 MHz, DMSO) d ppm: 9.30 (t, 1H), 8.15 (s broad, 3H), 7.40 and 7.25 (each m, 2H); 3.35 (m, 2H superimposed with H2O 10 peak), 2.80 (m, 2H), 1.65 (m, 4H), 1.45 (m, 2H).
3.32 g of 30% NaOCH3 soln were added to tert-butyl cyanomethylcarbamate (3 g; 19.21 mmol) in 20 ml of CH3OH and the mixture was stirred at room temperature for 1 h. After addition of 3.4 g of 1,2-phenylenediamine bishydrochloride, the reaction mixture was stirred further overnight, then added to 100 ml of H2O, filtered and the solid thus obtained was dried in vacuo. 3.45 g; ESI-MS [M+H+]=248.15
1H-NMR (270 MHz; DMSO-d6) d (ppm) 12.60 (s, 1H), 7.30-7.15 (m 3H). 7.05 (m 2H), 4.15 (d, 2H), 1.29 (s, 9H).
3 g of the Boc compound 26 were suspended in 15 ml of CH2Cl2, 25 m l of TFA were added and the mixture was stirred at RT for 3 h. The mixture was then concentrated and the residue obtained was stirred with n-pentane (5.8 g); ESI-MS [M+H+]=148.05.
TOTU (0.24 mmol, 77.3 mg) was added in portions at 0° C. to a solution of N1-(1H-benzimidazol-2-yl)pentane-1,5-diamine (hydrochloride) (25, 0.24 mmol, 60.1 mg), 11-(2-methoxy-2-oxoethyl)-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepine-3-carboxylic acid (20, 0.24 mmol, 80.0 mg) and N-methylmorpholine (0.49 mmol, 50.1 mg) in DMF (5 ml). The mixture was stirred at 0° C. for 2 h and concentrated in a rotary evaporator. The residue was taken up in ethyl acetate (20 ml), and washed with H2O, a 5% aq. K2CO3 solution and subsequently a 5% aq. NaCl solution. The org. phase was dried over Na2SO4 and concentrated. Chromatography on silica gel (CH2Cl2/MeOH 0 to 100%) afforded 23.0 mg of target product; ESI-MS: [M+H+]=540.42.
Diisopropylethylamine (0.24 mmol, 30.5 mg) and EDCI*HCl (0.28 mmol, 54.1 mg) were added at 0° C. to a solution of 11-(2-methoxy-2-oxoethyl)-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo [b,e]azepine-3-carboxylic acid (20, 0.24 mmol, 80.0 mg) in CH2Cl2 (1.5 ml)/DMF (0.5 ml). The mixture was then stirred at RT for 1 h before adding 1H-benzimidazol-2-ylmethanamine (trifluoroacetate) (27) (0.24 mmol, 88.4 mg) and diisopropylethylamine (0.47 mmol, 60.9 mg) dissolved in DMF. The mixture then was stirred at 0° C. for 1 hour and at RT for 6 h. Concentration and chromatography (CH2Cl2/MeOH 0 to 100%) afforded 37.0 mg of target product; ESI-MS: [M+H+]=469.15.
1H-NMR (270 MHz, CDCl3) δ (ppm): 4.63 (1H, s. br.), 3.68 (3H, s), 3.21-3.05 (3+2H, m), 2.44 (2H, t), 1.76-1.48 (2+2H, m), 1.43 (9H, s).
1H-NMR (360 MHz, CDCl3) δ (ppm): 7.04 (1H, d), 6.29 (1H, d), 4.97 (1H, s. br.), 4.81 (1H, s. br.), 3.37 (2H, m sym.), 3-12 (2H, q br.), 2.65 (2H, t), 2.53 (2H, t), 1.89 (2H, quint.), 1.67 (2H, quint.), 1.51 (2H, quint.), 1.43 (9H, s).
The preparation was carried out similarly to that of compound 3 starting with 10 g of benzyl {4-[(tert-butoxycarbonyl)amino]cyclohexyl)methylcarbamate (EP 669317) by removing the Boc group using 4N HCl in dioxane, .synthesis of the benzimidazole and subsequent hydrogenolysis. 3.6 g of white dihydrochloride were isolated; FAB-MS [M+H+]: 245.
The preparation was carried out similarly to that of compound 3 using 9.87 g of N-Boc-1,4-diaminobutan (52.3 mmol) as starting material. Reaction similarly to that of 3a gave 17.08 g of N-Boc-4-{[(2-aminoanilino)carbothioyl]amino)butane-1-amine; ESI-MS [M+H+]=338.99.
Subsequent cyclodesulfurization and removal of Boc using TFA gave a brown solid which was repeatedly triturated with n-pentane and then recrystallized from a mixture of CH3OH/methyl test-butyl ether; 14.35 g, ESI-MS [M+E+]=205.15.
1H-NMR (360 MHz, DMSO) δ ppm: 9.20 (t, 1H), 7.80 (s broad, 3H), 7.35 and 7.20 (each m, 2H), 3.40 (m, 2H partially obscured by H2O peak), 2.80 (m, 2H), 1.65 (m, 4H).
NaOH (0.01 mmol, 138.7 mg] was added to a solution of methyl {5-methyl-6-oxo-3-{4-(2-pyridinylamino)-butoxy]-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl}acetate (15, 0.01 mmol, 6.7 mg) in water (3 ml/MeOH (3 ml). The mixture was stirred at 60° C. overnight. After concentration, water was added and the solution was extracted with CH2Cl2. The aqueous phase was concentrated in a rotary evaporator. Lyophilization afforded 3.10.mg; ESI-MS: [M+H+]=445.
NaOH (0.01 mmol, 106.4 mg) was added to a solution of {5-methyl-6-oxo-3-[3-(2-pyridinylamino)-propoxy]-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetate (18, 0.01 mmol, 5.0 mg) in water (2 ml)/MeOH (2 ml). The mixture was stirred at 60° C. overnight. After concentration, water was added and the solution was extracted with CH2Cl2. The aqueous phase was concentrated in a rotary evaporator. Lyophilization afforded 3.16 mg; ESI-MS: [M+K+]=470.0, [M+H+]=432.15, 216.6.
Methyl [3-({[4-(1H-benzimidazol-2-ylamino)benzyl]amino)-carbonyl)-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetate (21, 0.03 mol, 15.0 mg) dissolved in water. (6 ml)/MeOH (6 ml) was treated at O° C. with NaOH (0.03 mmol, 254.6 mg) and stirred at RT overnight. After concentrating in a rotary evaporator, the residue was taken up in water/CH2Cl2, and extracted a number of times with CH2Cl2 and diethyl ether. Lyophilization afforded 9.2 mg of white salt; ESI-MS: [M+K+]=584.2, [M+H+]=546.15, 273.65, 118.9.
Methyl (5-methyl-6-oxo-3-({[3-(2-pyridinylamino)propyl]-amino)-carbonyl)-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetate (22, 0.03 mmol, 14.0 mg) dissolved in water (6 ml)/MeOH (6 ml) was treated at 0° C. with NaOH (0.03 mmol, 0.28 ml of 0.1 N aq. soln) and stirred at RT overnight. After concentrating in a rotary evaporator, the residue was taken up in water/CH2Cl2, and extracted a number of times with CHCl3 and diethyl ether. Lyophilization afforded 5.1 mg of -salt; ESI-MS: [M+H+]=459.15, 230.1.
Diisopropylethylamine (0.30 mmol, 38.3 mg) and HATU (0.36 mmol, 51.50 mg) were added at 0° C. to a solution of (11 E, Z)-11-(2-methoxy-2-oxoethylidene)-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo-[b,e]azepine-3-carboxylic acid (24, 0.30 mmol, 0.1 g) in CH2Cl2 (5 ml)/DMF (2 ml). The mixture was then stirred at 0° C. for 1 h before injecting N-[4-(aminomethyl)phenyl]-1H-benzimidazol-2-amine (hydrochloride) (3) (0.33 mmol, 89.6 mg) and diisopropylethylamine (0.30 mmol, 38.3 mg) dissolved in DMF. The mixture was stirred at 0° C. for 30 min and at RT for 5 h. After concentration, the residue was taken up using CH2Cl2/water, washed with aq. NaBC03 and then with a 5% solution of citric acid, buffered with aq. NaEC03 and finally washed with aq. saturated NaCl solution. Concentration and column chromatography (heptane/CH2Cl2 0 to 100% CH2Cl2/MeOH 0 to 100%) afforded 70.0 mg of target product; ESI-MS: [M+K+ J=596.2, [M+H+]=558.25, 279.65.
Aq. LiOH (0.34 mmol, 8.3 mg) was added dropwise at 5° C. to methyl (2 E, Z)-[3-({[4-(1H-benzimidazol-2-ylamino)benzyl]amino)-carbonyl)-5-methyl-6-oxo-5,6-d-hydro-11H-dibenzo[b,e]azepin-11-ylidene]ethanoate (Example V, 0.04 mmol, 20.0 mg) dissolved in water (3 ml)/EtOH (3 ml) and the mixture was stirred at RT overnight. After concentrating in a rotary evaporator, the residue was taken up in water/CH2Cl2, and extracted a number of times with CHCl3 and diethyl ether. The water phase was adjusted to pH 4 to 5 at 0° C. Filtration and drying of the deposited precipitate afforded 15.0 mg of target product; ESI-MS: [M+H+]=544.05, 272.6, 130.1.
Methyl (2 E, Z)-(5-methyl-6-oxo-3-{3-(2-pyridinyl amino)propoxy)-5,6-dihydro-11H-dibenzo[b,e]azepin-11-ylidene)ethanoate (17, 0.03 mmol, 15.0 mg) dissolved in water (6 ml)/MeOH (6 ml) was treated at 5° C. with NaOH (0-03 mmol, 321.1 mgj and the mixture was heated at 60° C. for 6 h. After concentrating in a rotary evaporator, the residue was taken up in water/CH2Cl2 and extracted a number of times with CHCl3 and diethyl ether. Lyophilization of the water phase afforded 5.2 mg of white salt; ESI-MS: [M+K+]=468.1, [M+H+]=430.15; 215.6, 101.1.
Methyl [3-({[5-(1H-benzimidazol-2-ylamino)pentyl]amino}-carbonyl)-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetate (28, 0.04 mmol, 20.0 mg) dissolved in water (7 ml)/MeOH (7 ml) was treated at 5° C. with NaOH (0.03 mmol, 333.9 mg) and the mixture was heated at 40° C. for 4 h. After concentrating in a-rotary evaporator, the residue was taken up in water/CH2Cl2 and extracted a number of times with CHCl3 and diethyl ether. Lyophilization of the water phase afforded 14.6 mg of salt; ESI-MS: [M+H+]=526.25.
Methyl (3-{[(1H-benzimidazol-2-ylmethyl)amino]carbonyl)-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetate (29, 0.08 mmol, 37.0 mg) dissolved in water (10 ml)/MeOH (10 ml) was treated at 5° C. with NaOH (0.07 mmol, 711.0 mg) and the mixture was heated at 40° C. for 6 h. After concentrating in a rotary evaporator, the residue was taken up in water/CH2Cl2 and extracted a number of times with CHCl3 and diethyl ether. Lyophilization of the water phase afforded 28.6 mg of salt; ESI-MS: [M+H+]=455.15.
At 0° C., ethyldiisopropylamine (0.29 mmol, 114.27 mg) and HATU (0.35 mmol, 134.45 mg) were added to a solution of 11-(2-methoxy-2-oxoethyl)-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepine-3-carboxylic acid (20) (0.29 mmol, 100.00 mg) in CH2Cl2 (15 ml), the mixture was then stirred at O° C. for 1 h, and 7-(4-iminobutyl)-1,2,3,4-tetrahydro [1,8] naphthyridin (bistrifluoracetate) (30) (0.41 mmol, 131.75 mg) and ethyldiisopropylamine (0.64 mmol, 251.39 mg) were added. The mixture was stirred at 0° C. for 1 h and at RT overnight and then concentrated. The residue was taken up in ethyl acetate/water, the pH was adjusted to 6.5 using a 5% strength aqueous NH4Cl solution and the mixture was extracted with ethyl acetate. Concentration and silica gel chromatography (CH2Cl2/CH3OH 0-100%) gave 71.80 mg of target product; ESI-MS [M+H+]; 527.25.
The methyl ester (Example X) was hydrolyzed similarly to Example II; 44.00 mg of target product; ESI-MS: [M+H+]=513.25.
Preparation similar to Example X starting with 11-(2-methoxy-2-oxoethyl)-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepine-3-carboxylic acid (20) (0.29 mmol, 100.00 mg) and trans-N-{[4-(aminomethy-)cyclohexyl]methyl}-1H-benzimidazol-2-amine (dihydrochloride) (31) (0.32 mmol, 102.85 mg). 90.90 mg of target product; ESI-MS: [M+H+]=566.25, 283.65.
The methyl ester (Example XII) was hydrolyzed similarly to Example II; 9.50 mg of target product; ESI-MS: [M+H+]=552.35, 276.55.
Preparation similar to Example X starting with 11-(2-methoxy-2-oxoethyl)-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepine-3-carboxylic acid (20) (0.29 mmol, 100.00 mg) and 5-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)-1-pentanaminium chloride (32) (0.41 mmol, 105.54 mg). 102.00 mg of target product; ESI-MS [M+H+]: 541.25.
The methyl ester (Example XIV) was hydrolyzed similarly to Example II; 49.20 pg of target product (about −95% pure according to HPLC); ESI-MS: [M+H+]=527.25, 264.1.
Coupling of 11-(2-methoxy-2-oxoethyl)-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-3-carboxylic acid-(20) (0.29 mmol, 100.00 mg) with N1-(1H-benzimidazol-2-yl)butane-1,4-diamine (trifluoroacetate) (33) (0.32 mmol, 103.18) similarly to 21 and purification by silica gel chromatography (ethyl acetate/CH3OH 0-100%) gave 39.50 mg of target product; ESI-MS [M+H+]: 526.25, 263.6.
The methyl ester (Example XIV) was hydrolyzed similarly to Example II; 18.70 mg of target product; ESI-MS: [M+H+]=512.15.
For the identification and assessment of integrin αvβ3 ligands, a test system was used which was based on competition between the natural integrin αvβ3 ligand vitronectin and the test substance for binding to solid phase-bound integrin αvβ3
Integrin αvβ3: Human placenta is solubilized with Nonidet and integrin αvβ3 affinity-purified on a GRGDSPK matrix (elution with EDTA). Impurities due to integrin αIIbβ3 and human serum albumin, and the detergent and EDTA are removed by anion-exchange chromatography.
Assay buffer: 50 mM tris pH 7.5; 100 mM NaCl; 1 mM CaCl2; 1 mM MgCl2; Peroxidase substrate: mix 0.1 ml of TMB solution (42 mM TMB in DMSO) and 10 ml of substrate buffer (0.1 M sodium acetate pH 4.9), then add 14.7 μl of 3% H2O2.
Various dilutions of the test substances are employed in the assay and the IC50 values are determined (concentration of the ligand at which 50% of the ligand is displaced). The compound from Example I showed the best result here.
The assay is based on competition between the natural integrin αIIbβ3 ligand fibrinogen and the test substance for binding to integrin αIIbβ3.
Peroxidase substrate: mix 0.1 ml of TMB solution (42 mM TMB in DMSO) and 10 ml of substrate buffer (0.1 M Na acetate pH 4.9), then add 14.7 μl of 3% H2O2
Various dilutions of the test substances are employed in the assay and the IC50 values are determined (concentration of the antagonists at which 50% of the ligand is displaced). By comparison of the IC50 values in the integrin αIIbβ3 and integrin αIIbβ3 assay, the selectivity of the substances can be determined.
The CAM (chorioallantoic membrane) assay serves as a generally recognized model for the assessment of the in vivo activity of integrin αvβ3 antagonists. It is based on the inhibition of angiogenesis and neovascularization of tumor tissue (Am. J. Pathol. 1975, 79, 597-618; Cancer Res. 1980, 40, 2300-2309; Nature 1987, 329, 630). The procedure is carried out analogously to the prior art. The growth of the chicken embryo blood vessels and of the transplanted tumor tissue can be readily monitored and assessed.
In this in-vivo model, the inhibition of angiogenesis and neovascularization in the presence of integrin αvβ3 antagonists can be monitored and assessed analogously to Example 3. The model is generally recognized and is based on the growth of rabbit blood vessels starting from the edge in the corn a of the eye (Proc. Natl. Acad. Sci. USA. 1994, 91, 4082-4085; Science 1976, 193, 70-72). The procedure is carried out analogously to the prior art.
| Number | Date | Country | Kind |
|---|---|---|---|
| 100 28 575.9 | Aug 2000 | DE | national |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 10344449 | Sep 2003 | US |
| Child | 12396698 | US |
