EP1480971A1

EP1480971A1 - Isoquinoline derivatives

Info

Publication number: EP1480971A1
Application number: EP03714735A
Authority: EP
Inventors: Matthias Wiesner; Simon Goodman; Horst Kessler; Georgette Thumshirn; Dirk Weber; Dirk Gottschling
Original assignee: Merck Patent GmbH
Current assignee: Merck Patent GmbH
Priority date: 2002-03-06
Filing date: 2003-02-07
Publication date: 2004-12-01
Also published as: CN1639150A; DE10209692A1; BR0308195A; AU2003218980A1; ZA200408027B; WO2003074512A1; US7060707B2; US20050090525A1; RU2004129734A; CA2478618A1; KR20040089704A; AR038869A1; JP2005525363A; PL371216A1; MXPA04008469A

Abstract

Disclosed are isoquinoline derivatives of general formula (I), in which X, Y, Z, R1, R2, and n have the meanings indicated in claim (1), and the physiologically acceptable salts or solvates thereof, which are integrin inhibitors and can be used for the prevention of thromboses, heart attack, coronary heart diseases, arteriosclerosis, inflammations, tumors, osteoporosis, infections, and post-angioplasty restenosis or in pathological processes that are entertained or propagated by angiogenesis.

Description

isoquinoline

The invention relates to compounds of the general formula

wherein

XH, -C (= NR ³ ) -NHR ⁴ or Het,

Y - (CH ₂ ) m-,

NH or CH ₂ ,

R, R each independently of one another H, A, OH, OA, arylalkyl, shark, -CO-A, CN, N0 ₂ , NHR ³ , COOA, COOH, S0 ₂ A, CF ₃ or OCF ₃ ,

R each independently of one another H or A,

R, R each independently of one another H, A, -CO-A, N0 ₂ or CN,

A alkyl with 1-6 C atoms,

m 0, 1, 2, 3, 4, 5 or 6,

n, p independently of one another are 1, 2 or 3,

as well as their physiologically acceptable derivatives, in particular their salts and solvates. The object of the invention was to find new compounds with valuable properties, in particular those which are used for the production of medicaments.

It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties with good tolerability. Above all, they act as integrin inhibitors, in particular inhibiting the interactions of the αv, β3, β5 or β6 integrin receptors with ligands, such as e.g. the binding of fibrinogen to the integrin receptor.

Integrins belong to the family of heterodimeric class I transmembrane receptors, which play an important role in numerous cell matrix or cell-cell adhesion processes (Tuckwell et al., 1996, Symp. Soc. Exp. Biol. 47) , They can be roughly divided into three classes: the β1 integrins, which are receptors for the extracellular matrix, the β2 integrins, which can be activated on leukocytes and are "triggered" during inflammatory processes, and the αv integrins, which are the cell response in wound healing and other pathological processes (Marshall and Hart, 1996, Semin. Cancer

Biol. 7, 191). The relative affinity and specificity for ligand binding is determined by combining the different α and β subunits.

The compounds according to the invention show particular effectiveness in

Case of the integrins αvßl, αvß3, αvß5, αllbß3 as well as αvßδ and αvßδ, preferably of αvß3, αvß5 and αvßδ, as well as αllbß3.

αvß6 is a relatively rare integrin (Busk et al., J. Biol. Chem. 1992, 267 (9), 5790), which is increasingly formed in repair processes in epithelial tissue and which preferentially binds the natural matrix molecules fibronectin and tenascin (Wang et al. , Am. J. Respir. Cell Mol. Biol. 1996, 75 (5), 664). The physiological and pathological functions of αvß6 are not yet exactly known, but it is suspected that this integrin is associated with physiological processes and diseases (e.g. inflammation,

Wound healing, tumors) involving epithelial cells, one plays an important role. Thus, αvß6 is expressed on keratinocytes in wounds (Haapasalmi et al., J. Invest. Dermatol. 1996, 106 (1), 42). B. Psoriasis, bullous pemphigus, dermatitis and erythema as well as cystic

Fibrous, endometriosis, cirrhosis of the liver or periodontitis can be influenced by agonists or antagonists of said integrin. Furthermore, αvßδ plays a role in the respiratory epithelium (Weinacker et al., Am. J. Respir. Cell Mol. Biol. 1995, 12 (5), 547), so that corresponding agonists / antagonists of this integrin in respiratory diseases such as bronchitis, asthma, Lung fibrosis and respiratory tumors could be used successfully. Ultimately, it is known that αvβδ also plays a role in the intestinal epithelium, so that corresponding integrin agonists / antagonists could be used in the treatment of inflammation, tumors and wounds of the gastrointestinal tract.

It has been found that the compounds of the formula I according to the invention and their salts act as soluble molecules on cells which carry the receptor mentioned, or, if they are bound to surfaces, are artificial ligands for αvβδ-mediated cell attachment. Above all, they act as αvβδ integrin inhibitors, in particular inhibiting the interactions of the receptor with other ligands, e.g. the binding of fibronectin.

The compounds of the invention are particularly potent

Inhibitors of the vitronectin receptor αvß3 and / or potent inhibitors of the αvßδ receptor.

The αvß3 integrin is grown on a number of cells, e.g. Endothelial cells, cells of the smooth vascular muscles, for example of the aorta, cells for

Degradation of bone matrix (osteoclasts) or tumor cells, expressed.

The action of the compounds of the invention can be demonstrated, for example, by the method described by JW Smith et al. in J. Biol. Chem. 1990, 265, 12267-12271. B. Felding-Habermann and DA Cheresh describe in Curr. Opin. Cell. Biol. 1993, - 5, 864 the meanings of integrins as adhesion receptors for a wide variety of phenomena and clinical pictures, especially in relation to the vitronectin receptor αvß3.

The dependence of the development of angiogenesis on the interaction between vascular integrins and extracellular matrix proteins is described by P.C. Brooks, R.A. Clark and D.A. Cheresh in Science 1994, 264, 569-571.

The possibility of inhibiting this interaction and thus inducing apoptosis (programmed cell death) of angiogenic vascular cells by a cyclic peptide has been discussed by P.C. Brooks, A.M. Montgomery, M. Rosenfeld, R.A. Reisfeld, T. Hu, G. Klier and D.A. Cheresh in Cell 1994, 79, 1157-1164. In it e.g. αvß3 antagonists or

Antibodies against αvß3 are described which cause tumor shrinkage by inducing apoptosis.

The experimental proof that the compounds according to the invention also prevent the attachment of living cells to the corresponding matrix proteins and accordingly also prevent the attachment of tumor cells to matrix proteins can be provided in a cell adhesion test, analogously to the method by F. Mitjans et al., J. Cell Science 1995, 108, 2825-2838.

PC Brooks et al. describe in J. Clin. Invest. 1995, 96, 1815-1822 α _v ß ₃ - antagonists for combating cancer and for treating tumor-induced angiogenic diseases.

The compounds can inhibit the binding of metal proteinases to integrins and thus prevent the cells from the enzymatic activity of the

Can use proteinase. An example can be found in the inhibition of the binding of MMP-2- (matrix metallo-proteinase-2) to the vitronectin receptor αvß3 by a cyclo-RGD peptide, as in PC Brooks et al., Cell 1996, 85, 683-693. The compounds of the formula I according to the invention can therefore be used as active pharmaceutical ingredients, in particular for the treatment of tumor diseases, osteoporoses, osteolytic diseases and for suppressing angiogenesis.

Compounds of the formula I which show the interaction of integrin receptors and ligands, e.g. of fibrinogen to the fibrinogen receptor (glycoprotein llb / llla), as GPIIb / llla antagonists, prevent the spread of tumor cells through metastasis. This is evidenced by the following observations:

The spread of tumor cells from a local tumor into the vascular system occurs through the formation of micro-aggregates (microthrombi) through the interaction of the tumor cells with platelets. The tumor cells are shielded by the protection in the micro-aggregate and are not recognized by the cells of the immune system.

The micro-aggregates can attach themselves to the vessel walls, which facilitates further penetration of tumor cells into the tissue. Since the formation of the microthrombi is mediated by fibrinogen binding to the fibrinogen receptors on activated platelets, the GPIIb / llla antagonists can be regarded as effective metastasis inhibitors.

In addition to the binding of fibrinogen, fibronectin and von Willebrand factor to the fibrinogen receptor of the platelets, compounds of the formula I also inhibit the binding of other adhesive proteins, such as

Vitronectin, collagen and laminin, to the appropriate receptors on the surface of different cell types. In particular, they prevent the formation of platelet thrombi and can therefore be used to treat thrombosis, apoplexy, heart attack, inflammation and arteriosclerosis.

The antiplatelet effect can be demonstrated in vitro by the method of Born (Nature 1962, 4832, 927-929).

A measure of the inclusion of a drug ingredient in one

Organism is its bioavailability. If the active pharmaceutical ingredient is added intravenously to the organism in the form of a solution for injection, its absolute bioavailability, ie the proportion of the drug that remains unchanged in the systemic blood, ie in the large circulation, is 100%. When a therapeutic agent is administered orally, the agent is usually present as a solid in the formulation and must therefore first dissolve so that it can overcome the entry barriers, for example the gastrointestinal tract, the oral mucosa, nasal membranes or the skin, in particular the stratum corneum or can be absorbed by the body. Pharmacokinetic data, ie

Bioavailability can be obtained analogously to the method of J. Shaffer et al, J. Pharm. Sciences, 1999, 88, 313-318.

The invention relates to compounds of the formula I as claimed in claim 1 and their physiologically acceptable salts and / or solvates as active therapeutic substances.

The invention accordingly relates to compounds of the formula I as claimed in claim 1 and their physiologically acceptable salts and / or solvates as integrin inhibitors.

The invention relates to compounds of the formula I according to claim 1 and their physiologically acceptable salts and / or solvates for use in combating diseases.

The compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine, in particular for the prophylaxis and / or therapy of diseases of the circulatory system, thrombosis, heart attack, arteriosclerosis, apoplexy, angina pectoris, tumor diseases such as tumor growth or tumor metastasis, osteolytic diseases such as Osteoporosis, pathologically angiogenic diseases such as inflammation, ophthalmological diseases, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis, Crohn's disease, atherosclerosis, erythematosus, psoriasis sores, psoriasem sebioma, psoriasis sebiitis, psoriasem sebioma, psoriasis inflammation, psoriasem sebiitis, psoriasis sebiitis, psoriasis sebiitis, psoriasis sebiitis, psoriasis sebioma cystic Fibrosis, endometriosis, cirrhosis of the liver, periodontitis, restenosis after angioplasty, multiple sclerosis, viral infection, bacterial infection, fungal infection, with acute kidney failure and with wound healing to support the healing process.

The compounds of formula I can be used as antimicrobial substances in operations where biomaterials, implants, catheters or pacemakers are used. They have an antiseptic effect. The effectiveness of the antimicrobial activity can be determined by the P. Valentin-Weigund et al. in Infection and

Immunity, 1988, 2851-2855.

Since the compounds of the formula I are inhibitors of fibrinogen binding and thus ligands of the fibrinogen receptors on platelets, they can be used as diagnostics for the detection and localization of thrombi in the vascular system in vivo, provided that they are substituted, for example, by a radioactive or UV-detectable residue.

The compounds of formula I can act as inhibitors of

Fibrinogen binding can also be used as an effective tool for studying the metabolism of platelets in different stages of activation or intracellular signaling mechanisms of the fibrinogen receptor. The detectable unit of a "label" to be incorporated, for example isotope labeling by ³ H, allows the mechanisms mentioned to be investigated after binding to the receptor.

It means below:

Ac Acetyl

Aza-Gly H ₂ N-NH-COOH

BOC tert-butoxycarbonyl

CBZ or ZBenzyloxycarbonyl

DCCI dicyclohexylcarbodiimide DCM dichloromethane

DIPEA diisopropylethylamine DMF dimethylformamide

DMSO dimethyl sulfoxide

EDCI N-ethyl-N, N '- (dimethylaminopropyl) carbodiimide

Et ethyl

Fmoc 9-fluorenylmethoxycarbonyl

Gly glycine

Gua guanidine

HATU 0- (7-azabenzotriazol-1-yl) -N, N, ^N, N'-tetramethyluronium hexafluorophosphate

HOBt 1 -hydroxybenzotriazole

Me methyl

MBHA 4-methyl-benzhydrylam in

Mtr 4-methoxy-2,3,6-trimethylphenyl sulfonyl

NMP N-methylpyrrolidone

NMR nuclear magnetic resonance

HONSu N-hydroxysuccinimide

OBzl benzyl ester

OtBu tert-butyl ester

Oct octanoyl

OMe methyl ester

OEt ethyl ester

Pbf 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl ß-Phe ß-phenylalanine

POA phenoxyacetyl

Pyr pyridine

R _f retention factor

RP reversed phase

RT retention time

Sal salicyloyl

TBTU O ^ I H-benzotriazol-l-y -N.N.N'.N'- tetramethyluronium tetrafluoroborate

TFA trifluoroacetic acid

Thiqu 1, 2,3,4-tetrahydroisoquinoline

Trt trityl (triphenylmethyl). The compounds of formula I have at least one chiral center and can therefore occur in several stereoisomeric forms. All of these forms (e.g. D and L forms) and their mixtures (e.g. the DL forms) are included in Formula I.

So-called prodrug derivatives are also included in the compounds according to the invention, i.e. with e.g. Alkyl or acyl groups, sugars or oligopeptides modified compounds of formula I, which are quickly cleaved in the organism to the active compounds of the invention.

This also includes biodegradable polymer derivatives of the compounds according to the invention, as described, for. B. in Int. J. Pharm. 1995, 115, 61-67. Derivatives of the compounds of the formula I are also included in the compounds according to the invention, according to the invention

Carboxyl group is converted into a pharmaceutically acceptable metabolically labile ester or an amide thereof. Furthermore, free amino groups or free hydroxyl groups as substituents of compounds of the formula I can be provided with corresponding protective groups.

Solvates of the compounds of the formula I are understood to mean additions of inert solvent molecules to the compounds of the formula I which are formed on account of their mutual attraction. Solvates are e.g. Mono- or dihydrates or

Addition compounds with alcohols, e.g. with methanol or ethanol.

The invention further relates to a process for the preparation of compounds of the formula I according to claim 1 and their salts, characterized in that a) a compound of the formula II, in which Z, R ¹ and n have the meaning given above and W denotes a customary protective group or a solid phase used in peptide chemistry,

with a compound of formula III in which Y has the meanings given above and Q denotes a suitable protective group or Het, in the presence of a condensing agent such as, for example, HATU,

and then removing the protecting groups and / or the solid phase,

and the resulting product, if Q is removed as a protective group, with a suitable guanyl compound, e.g. N, N'- bis-BOC-1-guanylpyrazole reacted and, if appropriate, the remaining protective groups and / or the solid phase are split off or

b) liberates a compound of formula I from one of its functional derivatives by treatment with a solvolysing or hydrogenolysing agent,

and / or that a basic or acidic compound of the formula I is converted into one of its salts by treatment with an acid or base. It applies to the entire invention that all radicals which occur more than once, for example R ^{1, can be the} same or different, ie are independent of one another.

In the above formulas, A means alkyl, is linear or branched, and has 1 to 6, preferably 1, 2, 3, 4, 5 or 6 carbon atoms. A is preferably methyl, furthermore ethyl, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl or tert-butyl, further also n-pentyl, 1-, 2- or 3-methylbutyl, 1, 1- , 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1, 1-, 1, 2-, 1,3-, 2,2- , 2,3- or 3,3-dimethylbutyl, 1- or 2-

Ethyl butyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 1, 2- or 1, 2,2-trimethylpropyl. Methyl is particularly preferred for A.

The term “protective group” preferably means acetyl, propionyl,

Butyryl, phenylacetyl, benzoyl, toluyl, POA, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl, CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, Fmoc, Mtr or benzyl. Fmoc is particularly preferred.

Arylalkyl preferably means benzyl, phenylethyl, phenylpropyl or naphthylmethyl, particularly preferably benzyl.

Shark is preferably F, Cl or Br.

Het means a mono- or bicyclic aromatic or saturated radical with up to three heteroatoms, preferably a saturated, partially or completely unsaturated mono- or bicyclic heterocyclic radical with 5 to 10 ring members, where 1 or 2 N- and / or 1 or 2 S - Or O atoms can be present and the heterocyclic radical can be substituted once or twice by CN, shark, OH, OA, CF ₃ , A, N0 ₂ or OCF ₃ .

Het is preferably substituted or unsubstituted 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, further preferably 1, 2,3-triazol-1-, -4- or -5-yl, 1, 2,4-triazol-1- , -4- or -5-yl, 1- or 5-tetrazolyl, 1, 2,3-oxadiazol-4- or -5-yl 1, 2,4-oxadiazol-3- or -5-yl, 1, 3,4-thiadiazol-2- or -5-yl, 1, 2,4-

Thiadiazol-3- or -5-yl, 1, 2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6- 2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7 - benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-1 H-indolyl, 1 -, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or

7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7- benzthiazolyl, 2-, 4-, 5-, 6- or 7- Benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1, 3-oxadiazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1- , 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5- , 6-, 7-, 8- or 9-acridinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8- quinazolinyl. The heterocyclic radicals can also be partially or completely hydrogenated. Het can also mean 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5-furyl, tetrahydro -2- or -3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl,

1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -3-pyrollyl, tetrahydro-1-, -2- or 4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4-, -5-, -6-, -7-1 H-indolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, Tetrahydro-1-, -3- or -4-pyrazolyl, 1, 4-dihydro-1-, -2-, -3- or -4-pyridyl, 1, 2,3,4-tetrahydro-1-, - 2-, -3-, -4-, -5- or -6-pyridyl, 1, 2,3,6-tetrahydro-1-, -2-, -3, -4-, -5- or -6 - pyridyl, 1-, 2-, 3- or 4-piperidinyl, 1-, 2-, 3- or 4-azepanyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxane 2-, -4- or -5-yl, hexahydro-1 -, -3- or -4-pyridazinyl, hexahydro-1-, -2 -, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1, 2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolinyl, 1, 2,3,4-tetrahydro-1-, -2-, -3-, -4-, -

5-, -6-, -7- or -8-isoquinolinyl.

Het methylpyridyl, in particular 4-methylpyridin-2-yl, pyridin-2-yl, pyrimidin-2-yl, imidazol-2-yl, benzimidazol-2-yl and their hydrogenated derivatives, is particularly preferred. OA preferably means methoxy, ethoxy, propoxy or butoxy, further also pentyloxy or hexyloxy.

R ¹ and R ⁵ independently of one another are preferably H, A, CN, NO ₂ , shark or -COA-, where A has one of the meanings given above; in particular R ¹ and R ⁵ mean H.

R ² is preferably H or A, where A has one of the meanings given above; especially H.

R ³ and R ⁴ independently of one another preferably mean H or -COA-, in particular H.

X preferably denotes H, -C (= NH) -NH ₂ , -C (= NMethyl) -NH ₂ , 4-methylpyridin-2-yl, pyridin-2-yl, pyriminin-2-yl, imidazol-2-yl , Benzimidazol-2-yl and their hydrogenated derivatives.

Y means - (CH ₂ ) m- or in particular - (CH ₂ ) - or

n and p independently of one another are preferably 1 or 2, in particular 1.

m preferably denotes 0, 2 or 4, in particular 0 or 4.

The compounds of the formulas IA and IB are preferred:

wherein X, Y, Z and R ^{2 have} the meaning given above. In the formulas IA and IB, R ² denotes in particular H. Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the abovementioned

Radicals has one of the preferred meanings given above. Some preferred groups of compounds can be expressed by the following sub-formulas 11 to I36:

11

12

13

Iδ 19

110

111

112

113 114

115

116

117

118

119 I20

121

I22

I23

I24

I30 131

I32

I33

I34 I35

I36

The compounds of the formula I and also the starting materials for their preparation are otherwise prepared by methods known per se, as described in the literature (for example in the standard works such as Houben-Weyl, methods of organic chemistry, Georg-Thieme-Verlag, Stuttgart) are described, namely under reaction conditions which are known and suitable for the reactions mentioned. Use can also be made of variants which are known per se and are not mentioned here in detail.

If desired, the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I. Compounds of formula I can preferably be obtained under the conditions of peptide synthesis. The procedure is advantageously carried out according to customary methods of peptide synthesis, as described, for example, in Houben-Weyl, 1.c, volume 15/11, pages 1 to 806 (1974).

The direct precursors of the compounds of formula I can also e.g. according to Merrifield (Angew. Chem. 97, 801-812, 1985) on a solid phase, e.g. a swellable polystyrene resin. In principle, all carriers, e.g. from the

Solid phase peptide chemistry or nucleic acid synthesis are known to be used.

Suitable polymeric carrier materials are polymeric solid phases with preferably hydrophilic properties, for example cross-linked poly sugars such as cellulose, Sepharose or Sephadex ^R , acrylamides,

Polyethylene glycol-based polymer or tentacle polymers ^R.

Preferably, the solid phase is trityl chloride polystyrene resin, 4-

Methoxytritylchloride resin, Merrifield resin. And Wang resin used.

Thus compounds of formula I can be obtained by using a

Reacts compound of formula II with a compound of formula III, and then the protective groups or the solid phase removed.

The compounds of formula I can also be obtained by reacting a compound of formula IV with a compound of formula V and then removing the protecting groups.

The coupling reaction is preferably accomplished in the presence of a dehydrating agent, e.g. a carbodiimide such as DCCI or EDCI, further e.g. Propanephosphonic anhydride (cf. Angew. Chem. 1980, 92,

129), diphenylphosphoryl azide or 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline, in an inert solvent, e.g. a halogenated hydrocarbon such as dichloromethane, an ether such as tetrahydrofuran or dioxane, an amide such as DMF or dimethylacetamide, a nitrile such as acetonitrile, in dimethyl sulfoxide or in the presence of these solvents

Temperatures between about -10 and 40, preferably between 0 and 30 °. In order to promote intramolecular cyclization before intermolecular peptide binding, it is advisable to work in dilute solutions.

The reaction time is between a few minutes and 14 days depending on the conditions used.

Instead of compounds of the formula II and / or IV, derivatives of compounds of the formula II and / or IV, preferably a preactivated carboxylic acid, or a carboxylic acid halide, a symmetrical or mixed anhydride or an active ester can also be used. Such residues for activating the carboxy group in typical acylation reactions are described in the literature (e.g. in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart). Activated esters are conveniently formed in situ, e.g. B. by adding

HOBt or N-hydroxysuccinimide.

The reaction is usually carried out in an inert solvent, when using a carboxylic acid halide in the presence of an acid-binding agent, preferably an organic base such as

Triethylamine, dimethylaniline, pyridine or quinoline. The addition of an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali metal or alkaline earth metal, preferably of potassium, sodium, calcium or cesium, can also be favorable.

The compounds of formula I can also be obtained by liberating them from their functional derivatives by solvolysis, in particular hydrolysis, or by hydrogenolysis.

Preferred starting materials for solvolysis or hydrogenolysis are those which otherwise correspond to the formula I, but instead of one or more free amino and / or hydroxyl groups contain corresponding protected amino and / or hydroxyl groups, in particular those which have a instead of an HN group Carry SG ¹ -N group, wherein

SG ^{1 means} an amino protecting group and / or those which replace the H atoms of a hydroxyl group carry a hydroxyl protective group, for example those which correspond to the formula I, but instead of a group -COOH carry a group -COOSG ² , in which SG ² denotes a hydroxyl protective group.

Several - identical or different - protected amino and / or hydroxy groups can also be present in the molecule of the starting material. If the existing protective groups are different from each other, they can be split off selectively in many cases (see: T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Chemistry, 2nd ed.,

Wiley, New York 1991 or P.J. Kocienski, Protecting Groups, 1st edition, Georg Thieme Verlag, Stuttgart - New-York, 1994, H. Kunz, H. Waldmann in Comprehensive Organic Synthesis, Vol. 6 (ed. BM Trost, I. Fleming, E. Winterfeldt ), Pergamon, Oxford, 1991, pp. 631-701).

The term "amino protecting group" is generally known and refers to groups which are suitable for protecting (blocking) an amino group against chemical reactions. Unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups are particularly typical of such groups. Since the amino protective groups are removed after the desired reaction (or reaction sequence), their type and size is otherwise not critical; however, those with 1-20 C atoms are preferred. The term "acyl group" is to be understood in the broadest sense in connection with the present process. It encompasses acyl groups derived from aliphatic, araliphatic, alicyclic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular alkoxy-carbonyl, alkenyloxycarbonyl, aryloxycarbonyl and especially aralkoxy-carbonyl groups. Examples of such acyl groups are alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluyl;

Aryloxyalkanoyl such as phenoxyacetyl; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, Boc, 2-iodoethoxycarbonyl; Alkenyloxycarbonyl such as allyloxycarbonyl (aloe), aralkyloxycarbonyl such as CBZ (synonymous with Z), 4-methoxybenzyloxycarbonyl (MOZ), 4-nitrobenzyloxycarbonyl or 9-fluorenylmethoxycarbonyl (Fmoc); 2

(Phenylsulfonyl) ethoxycarbonyl; Trimethylsilylethoxycarbonyl (Teoc) or Arylsulfonyl such as 4-methoxy-2,3,6-trimethylphenylsulfonyl (Mtr). Preferred amino protecting groups are Boc, Fmoc and aloe, furthermore Z, benzyl and acetyl.

The term "hydroxyl protecting group" is also generally known and refers to groups which are suitable for protecting a hydroxyl group against chemical reactions. Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl, aroyl or acyl groups, furthermore also alkyl groups, alkyl, aryl or aralkylsilyl groups or 0.0- or 0, S-acetals. The nature and size of the

Hydroxy protective groups are not critical since they are removed again after the desired chemical reaction or reaction sequence; groups with 1-20, in particular 1-10, carbon atoms are preferred. Examples of hydroxy protecting groups include Aralkyl groups such as benzyl, 4-methoxybenzyl or 2,4-dimethoxybenzyl, aroyl groups such as benzoyl or p-nitrobenzoyl, acyl groups such as acetyl or pivaloyl, p-toluenesulfonyl, alkyl groups such as methyl or tert-butyl, but also allyl, alkylsilyl groups such as trimethylsilyl (TMS ), Triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS) or triethylsilyl, trimethylsilylethyl, aralkylsilyl groups such as tert.-butyldiphenylsilyl (TBDPS), cyclic acetals such as isopropylidene,

Cyclopentylidene, cyclohexylidene, benzylidene, p-methoxybenzylidene or o, p-dimethoxybenzylidene acetal, acyclic acetals such as tetrahydropyranyl (Thp), methoxymethyl (MOM), methoxyethoxymethyl (MEM), benzyloxymethyl (BOM) or methylthiomethyl. Particularly preferred hydroxyl protecting groups are benzyl, acetyl, tert-butyl or

TBS.

The liberation of the compounds of the formula I from their functional derivatives is known from the literature for the protective group used in each case (e.g. T.W. Greene, P.G.M. Wuts, Protective Groups in

Organic Chemistry, 2nd ed., Wiley, New York 1991 or PJ Kocienski, Protecting Groups, 1st ed., Georg Thieme Verlag, Stuttgart - New York, 1994). Use can also be made of variants which are known per se and are not mentioned here in detail. A base of the formula I can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation. In particular, acids that provide physiologically acceptable salts are suitable for this implementation. Thus, inorganic acids can be used, for example sulfuric acid, sulfurous acid, dithionic acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or poly-based carbon. , Sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, hexanoic acid, octanoic acid, decanoic acid, hexadecanoic acid, octadecanoic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid,

Lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfonic acid, benzenesulfonic acid, trimethoxybenzoic acid, adamantane carboxylic acid, p-toluenesulfonic acid, glycolic acid, embonic acid, chlorophenoxyacetic acid, aspartic acid, proline acid, glutamic acid

Glyoxylic acid, palmitic acid, parachlorophenoxyisobutyric acid, cyclohexane carboxylic acid, glucose-1-phosphate, naphthalene mono- and disulfonic acids or lauryl sulfuric acid. Salts with physiologically unacceptable acids, e.g. Picrates can be used for the isolation and / or purification of the compounds of the formula I.

On the other hand, compounds of the formula I with bases (for example sodium or potassium hydroxide or carbonate) can be converted into the corresponding metal, in particular alkali metal or alkaline earth metal or into the corresponding ammonium salts. Substituted ammonium salts, for example the dimethyl, diethyl or diisopropylammonium salts, monoethanol, diethanol or diisopropylammonium salts, cyclohexyl, dicyclohexylammonium salts, dibenzylethylenediammonium salts, furthermore, for example, salts with arginine or lysine. The invention further relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production of a pharmaceutical preparation.

The invention further relates to pharmaceutical preparations containing at least one compound of the formula I and / or one of its physiologically acceptable salts or solvates, which are prepared in particular by a non-chemical route. The compounds of the formula I can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more further active compounds.

These preparations can be used as medicinal products in human or veterinary medicine. Suitable carriers are organic or inorganic substances which are suitable for enteral (e.g. oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc,

Vaseline. Tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used for oral use, suppositories for rectal use, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for topical use for parenteral use

Ointments, creams or powder. The new compounds can also be lyophilized and the resulting lyophilisates e.g. can be used for the production of injectables. The specified preparations can be sterilized and / or contain auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, taste and / or several other active substances, e.g. one or more vitamins. For the application as an inhalation spray, sprays can be used which either dissolved or suspended in a propellant or the active ingredient

Propellant mixture (e.g. C0 ₂ or chlorofluorocarbons) contain. The active ingredient is expediently used in micronized form, it being possible for one or more additional physiologically compatible solvents to be present, for example ethanol. Inhalation solutions can be administered using standard inhalers.

The compounds of the formula I and their physiologically acceptable salts can be used as integrin inhibitors in combating diseases, in particular thromboses, heart attacks, coronary heart diseases, arteriosclerosis, tumors, osteoporosis, inflammations and infections.

The compounds of formula I according to claim 1 and / or their physiologically acceptable salts are also used in pathological processes which are maintained or propagated by angiogenesis, in particular in tumors or rheumatoid arthritis.

The substances according to the invention are generally administered in analogy to other known, commercially available peptides, but in particular in analogy to the compounds described in US Pat. No. 4-472,305, preferably in doses between about 0.05 and 500 mg , in particular between 0.5 and 100 mg per dosage unit. The daily dosage is preferably between about 0.01 and 2 mg / kg body weight. However, the specific dose for each patient depends on a wide variety of factors, for example on the effectiveness of the specific ones used

Connection, age, body weight, general state of health, gender, diet, time and route of administration, excretion rate, drug combination and severity of the respective disease to which the therapy applies. Parenteral administration is preferred.

Furthermore, the compounds of the formula I can be used as integrin ligands for the preparation of columns for affinity chromatography for the purification of integrins. The ligand, ie a compound of the formula I, is covalently coupled to a polymeric support via an anchor function, for example the carboxy group of Asp.

The manufacture of materials for affinity chromatography

Integrin purification takes place under conditions which are customary and known per se for the condensation of amino acids.

The compounds of the formula I contain one or more chiral centers and can therefore be present in racemic or in optically active form.

Racemates obtained can be separated mechanically or chemically into the enantiomers by methods known per se. Diastereomers are preferably formed from the racemic mixture by reaction with an optically active release agent. Suitable release agents are e.g. optically active acids, such as the D and L forms of tartaric acid,

Diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as ß-camphorsulfonic acid. Enantiomer separation using a column filled with an optically active separating agent (e.g. dinitrobenzoylphenylglycine) is also advantageous; a suitable solvent is e.g. a mixture

Hexane / isopropanol / acetonitrile, e.g. in the volume ratio 82: 15: 3.

Of course, it is also possible to obtain optically active compounds of the formula I by the methods described above by using starting materials which are already optically active.

All temperatures above and below are given in ° C. In the examples below, "customary work-up" means: if necessary, water is added and, if necessary, the pH is adjusted to between 2 and 10, depending on the constitution of the end product, extracted with

Ethyl acetate or dichloromethane is separated off, the organic phase is dried over sodium sulfate, evaporated and purified by chromatography on silica gel and / or by crystallization.

RT = retention time (minutes) with HPLC in the following systems:

Columns from Omnicrom YMC: 1. 4.6x250 mm, 5 μm, C ₁₈ (analysis);

2. 30x250 mm, 7μm, C ₁₈ (preparation).

Gradients of acetonitrile (B) with 0.1% TFA and water (A) with 0.1% TFA are used as eluents (details in volume percent of acetonitrile). Retention time was at a flow of

1 ml / min. determined. Detection at 220 nm.

The diastereomers are preferably separated under the stated conditions.

Mass spectrometry (MS): ESI (electrospray ionization) (M + H) ⁺

FAB (Fast Atomic Bombardment) (M + H) ⁺ .

1. Material and general working instructions

Solvents for the synthesis were either obtained “technically” and distilled before use, or bought from Fluka (Seelze) or Merck (Darmstadt) in the purity “absolute” or “for synthesis”. NMP

(distilled) was obtained free of charge from BASF (Ludwigshafen). Solvents for column chromatography were obtained "technically" and either distilled before use or used undistilled (hexane). The HPLC solvents acetonitrile (solvent B) and TFA were purchased in "gradient grade" from Merck (Darmstadt),

Water (solvent A) was deionized and treated with a Milli-Q system from Millipore (Molsheim, France).

Fmoc-protected amino acids were purchased from Novabiochem, Advanced ChemTech, MultiSynTech or PepTech Corporation (Cambridge, USA).

PE syringes from Becton-Dickinson (Fraga, Spain) or Braun (Melsungen) with PE frits from Roland Vetter Laborbedarf (Ammerbuch) were used for manual solid-phase synthesis. The syringes were rotated at about 30 rpm to mix the resin suspension. The resin was loaded in glass shaking vessels.

Reactions sensitive to air or moisture were carried out in dry glass vessels and under an argon atmosphere (99.996%).

Hygroscopic and / or absolute solvents were transferred in syringes under argon.

For HPLC purification, the compounds were dissolved in DMSO, acetonitrile or methanol ("gradient grade") and filtered using a syringe filter RC 15 or RC 25 (RC membrane, 0.45 μm) from Sartorius (Göttingen). Analytical, semi-preparative and preparative separations were carried out on two HPLC systems from Amersham Pharmacia Biotech (analytical: Äkta Basic 10F with autosampler A-900; preparative: Äkta Basic 100F with pump system P-900 and detector UV-900) and two systems from Beckman (System Gold with solvent module 125 and detector module 166; pump system 110B, control unit 420 and detector Knauer Uvicord). The following columns were used for analytical separations: ODS-A C-ι ₈ (250 mm x 4.6 mm, 5 μm, flow rate: 1 mL / min) from Omnicrom YMC; for semi-preparative

Separations: ODS-A C-ι ₈ (250 mm x 20 mm, 5 μm or 10 μm, flow rate: 8 mL / min) from Omnicrom YMC; for preparative separations: ODS-A Cι ₈ (250 mm x 30 mm, 10 μm, flow rate: 25 mUmin) from Omnicrom YMC and Nucleosil Cι ₈ (250 mm x 20 mm, 7 μm, flow rate: 25 mUmin) from Macherey-Nagel , The compounds were eluted with linear gradients (30 min) from acetonitrile (solvent B) in water (solvent A) and 0.1% (v / v) TFA. For the analytical determination of the purity of the compounds after semi-preparative or preparative HPLC purification, the peak integral of the analytical HPLC chromatogram was evaluated at a detector wavelength of 220 nm.

Silica Gel 60 (230-400 mesh ASTM, particle size 0.040-0.063 mm) from Merck (Darmstadt) was used for column chromatography. Flash chromatography was carried out at a pressure of 1-1.2 bar. Thin layer chromatography (TLC) and the determination of the R _f values were carried out using TLC aluminum plates coated with Silica Gel 60 F ₂ 54 from Merck (Darmstadt). For detection, the DC plates were viewed under UV light (λ = 254 nm).

Melting points were measured on a Büchi 510 melting point apparatus according to Dr. Tottoli determined and are uncorrected.

All ¹ H-NMR and ¹³ C-NMR spectra were recorded on a Bruker AC250 or DMX500 spectrometer at 300 K, the spectra data were recorded on Bruker Aspect 1000 (AC 250) or on Silicon Graphics Indy, 02 and Octane workstations with XWINNMR Software processed. Chemical shifts (δ) are given in parts per million (ppm) relative to tetramethylsilane, coupling constants are given in Hertz (Hz). The internal standard was tetramethylsilane or

Solvent peak used: DMSO-d ₆ : 2.49 ppm ( ¹ H-NMR) and 39.5 ppm ( ¹³ C-NMR); CDCI ₃ : 7.24 ppm ( ¹ H-NMR) and 77.0 ppm ( ¹³ C-NMR). ¹³ C-NMR spectra were recorded with ¹ H broadband decoupling. In most cases, the signals were assigned using HMQC and COZY experiments.

Mass spectra were recorded using electron impact (El) and chemical ionization (Cl) technology on a Finnigan MAT 8200 instrument. Electrospray ionization (ESI) mass spectra were recorded on a Finnigan LCQ mass spectrometer in combination with a

Hewlett Packard 1100 HPLC system with an ODS-A Cι ₈ (125 mm x 2 mm, 3 μm, flow rate: 0.2 mL / min) column from Omnicrom YMC. The compounds were eluted with a linear gradient (15 min) of acetonitrile (solvent B) in water (solvent A) and 0.1% (v / v) formic acid. Mass spectra are in the form "X

(Y) [M + Zf, where "X" is the detected mass, "Y" the observed intensity of the mass peak, "M" the molecule under investigation and "Z" the attached cation. High resolution mass spectra (HRMS) were developed by Koka Jajasimhulu, Ph.D. (University of Cincinnati, USA) using the electrospray ionization-time of flight (ESI-TOF) technique.

Lyophilization was carried out using the Alpha 2-4 device from Christ

(Osterode) performed. AAV 1: loading of TCP resin

The corresponding Fmoc-protected amino acid (1.56 mmol, 1.5eq) and DIPEA (177 μL, 1.03 mmol) are added to pre-swollen TCP resin (1.16 g, maximum loading: 0.9 mmol / g) in dry CH2CI2 (6 mL, 10 min.) ) added. After 5 min. further DIPEA (91 μL, 0.52 mmol) is added and the resin is shaken. After 2 hours, methanol (1.16 ml) is added to cap the unreacted trityl groups and the resin is stirred for a further 15 min. shaken. Then the resin is mixed with dry CH ₂ CI ₂ (5 x 20 mL, 3 min. Each), NMP (5 x 20 mL, 3 min. Each) and again with dry CH2CI ₂ (5 x 20 mL, 3 min. ) finally washed with a mixture of methanol / CH ₂ Cl ₂ (1: 1, 20 ml) and methanol (20 ml). The resin is dried in a high vacuum, the load can be determined using the following equation:

(m2 - mi) ^χ l000 ~ (MW - 36.45) ^χ m ₂

I loading of the resin with building block [mmol / g] rτiι weight of the resin before the coupling [g] m ₂ weight of the dried resin after the coupling [g]

MW molecular weight of the Fmoc-protected

Amino acid / carboxylic acid building block [g / mol]

The error caused by the different masses of Cl- and MeO- can be neglected.

AAV 2: The Fmoc protecting group is split off

The resin (100 mg) is pre-swollen in NMP (5 mL, 10 min.). The Fmoc protective group is removed by treatment with a freshly prepared 20% piperidine solution (v / v) in NMP (5 mL) for 15 min. cleaved. Then the resin is washed with NMP (5 x 5 mL, 3 min. Each) and again with a 20 % Piperidine solution (v / v) in NMP (5 mL, 15 min.) Added. Finally the resin is washed with NMP (5 5 mL, 3 min each).

AAV 3: Coupling of 5- (9H-fluoren-9-ylmethoxy) -3H- [1, 3,4] oxadiazol-2-one (142) to resin-bound, free amines according to Gibson

To deprotect the resin bound amine, 20% piperidine (v / v) in NMP (2 x 5 mL, 15 min each) is added to the TCP resin (100 mg, 0.354 mmol / g, 0.035 mmol). The resin is then washed with NMP (5 × 5 mL, 3 min. Each) dry CH ₂ CI ₂ (5 5 mL, 3 min. Each) and then swollen in dry CH ₂ CI ₂ (5 mL) for half an hour , Then the resin is mixed with a solution of 5- (9H-fluoren-9-ylmethoxy) -3H- [1, 3,4] oxadiazol-2-one (142) (30.5 mg, 0.108 mmol, 3.1 eq) in dry CH ₂ CI ₂ (1 mL) added and for 90 min. shaken. The reaction is stopped by washing with CH ₂ CI (5 x 5 mL, 3 min. Each) and NMP (5 x 5 mL, 3 min. Each).

AAV 4: coupling with HATU / HOAt

The resin-bound, free amine or hydrazine (0.389 mmol) is washed with NMP (5 x 5 mL, 3 min each). Then the resin is mixed with a solution of the appropriate Fmoc-protected amino acid or a carboxylic acid building block (0.779 mmol, 2eq), HATU (296 mg, 0.779 mmol,

2eq) and HOAt (106 mg, 0.779 mmol, 2eq) in NMP (5 mL). Finally, sym.-collidine (1027 μL, 7.79 mmol, 20eq) is added and the resin is shaken overnight. Then it is washed with NMP (5 5 mL, 3 min each) and the coupling step is repeated with the same reagents, amounts and reaction time. Then the resin with

NMP (5 x 5 mL, 3 min each) washed.

AAV 5: separation from the TCP resin

The connection from the TCP resin is split off according to the following flow diagram:

Step reagents operation number time [min]

1 CH2CI2 wash 3 10

2 TFA / TIPS / H ₂ O cleavage / deprotection 3 30 (18: 1: 1) s

3 CH2CI2 wash 3 3 2 mL cleavage solution was usually used for 100 mg resin. The combined filtrates from steps 2 and 3 were concentrated.

2. Examples

Example 1a)

N - [(9H-Fluoren-9-ylmethoxy) carbonyl] hydrazine (141) Boc hydrazine (10.0 g, 75.6 mmol) and DIPEA (12.95 mL, 75.6 mmol) were dissolved in dry CH ₂ CI ₂ (200 mL) and cooled to 0 ° C. Then FmocCI (19.6 g, 75.8 mmol), dissolved in dry CH ₂ CI ₂ (100 mL), was dissolved within 30 min. added and the mixture was stirred at room temperature overnight. The organic phase was extracted with water (200 mL) and concentrated to a volume of about 100 mL. Then trifluoroacetic acid (100 mL) was carefully added at 0 ° C and the mixture was stirred for 1.5 hours. The product was precipitated by careful addition of saturated Na ₂ CO ₃ solution (300 mL). After drying, a colorless solid was obtained (18.02 g, 70.8 mmol, 94%).

Mp 150-153 ° C; ¹ H-NMR (250 MHz, DMSO-d ₆ , 300 K) δ = 10.10 (bs, 1 H, NH), 9.60 (bs, 1 H, NH), 7.89 (d, J = 7.6 Hz, 2H, aromatic ), 7.70 (d, J = 7.3 Hz, 2H, aroma), 7.30-7.45 (m, 4H, aroma), 4.48 (d, J = 6.6 Hz, 2H, CO-CH ₂ ), 4.27 (t, J = 6.7 Hz, 1H, CO-CH ₂ -CH); ¹³ C-NMR (62.9 MHz, DMSO-d ₆ , 300 K) δ = 156.26, 143.59, 140.98, 127.96, 127.34, 125.33, 120.39, 67.00, 46.60; HRMS (ESI-TOF) for C ₁₅ H ₁₅ N ₂ θ2 [M + H] ⁺ : 255.1134 (calc. 255.1 119); Analytical HPLC (5-90% in 30 min) t _R = 16.47 min.

Example 1b)

5- (9H-Fluoren-9-ylmethoxy) -3H- [1, 3,4] oxadiazol-2-one (142) A suspension of N - [(9H-fluoren-9-ylmethoxy) carbonyl] hydrazine (141 ) (1.49 g, 5.78 mmol), CH ₂ CI ₂ (60 mL) and saturated NaHC0 ₃ solution (60 mL) was 5 min. long stirred vigorously at 0 ° C, then the solution was left

5 min. long without stirring. Then phosgene (1.89 M in toluene, 7.95 mL, 15.0 mmol) was carefully added to the lower, organic phase with a syringe and the reaction mixture started to stir again immediately after the addition. After 10 min. the reaction mixture was mixed with water (20 mL) and CH ₂ CI ₂ (20 mL). The phases were then quickly separated, the aqueous phase with

CH ₂ CI ₂ (50 mL) extracted and the combined organic phases dried over Na ₂ S0 ₄ . Removal of the solvent in vacuo and drying gave a colorless solid (1.35 g, 4.82 mmol, 83%).

Mp 125 ° C; ¹ H NMR (250 MHz, CDCI ₃ , 300 K) δ = 8.72 (bs, 1H, NH),

7.77 (d, J = 7.5 Hz, 2H, aroma), 7.59 (d, J = 7.4 Hz, 2H, aroma), 7.28-7.45 (m, 4H, aroma), 4.49 (d, J = 7.8 Hz, 2H, CH ₂ -CH), 4:32 to 4:41 (m, 1H, CH ₂ - CH).

Example 2a)

N-phenylethylformamide (146)

A mixture of phenylethylamine (20.0 g, 0.165 mol) and formic acid (49.4 ml, 1.309 mol) was slowly heated to 200 ° C. Excess water and formic acid were distilled off. The mixture was then kept at 200 ° C. for 1 hour. After vacuum distillation of the product, a colorless oil was obtained (22.0 g, 0.147 mol, 89%).

¹ H NMR (250 MHz, DMSO-d ₆ , 300 K) δ = 8.06 (bs, 1 H, CHO), 7.16-7.32 (m, 5H, aroma), 3.32-3.42 (m, 2H, NH-CH ₂ ), 2.77 (t, J = 7.2 Hz, 2H, NH-CH ₂ -CH ₂ ); Analytical HPLC (5-90% in 30 min) t _R = 15.04 min.

Example 2b)

3,4-dihydro-isoquinoline (147)

Polyphosphoric acid (25 g) and phosphorus pentaoxide (5.4 g, 38.0 mmol) were heated to 180 ° C. in an oil bath under an argon atmosphere within one hour. Then N-phenylethylformamide (146) (4.3 g, 28.8 mmol) added at 160 ° C and stirred at a constant temperature for 1.5 hours. Then the mixture was allowed to cool to room temperature and water (40 mL) was added. The mixture was then brought to pH 10 by carefully adding saturated aqueous NaOH solution. The mixture was then extracted with ether (500 mL), the organic

Phase was separated and dried with NaOH. After concentration, a brown oil was obtained (2.81 g, 21.4 mmol, 74%).

¹ H-NMR (250 MHz, DMSO-d ₆ , 300 K) δ = 8.32 (t, J = 2.3 Hz, 1 H, N-CH), 7.16-7.40 (m, 4H, aroma), 3.59-3.66 ( m, 2H, N-CH ₂ ), 2.66 (t, J = 7.3 Hz, 2H,

N-CH ₂ -CH ₂ ); Analytical HPLC (5-90% in 30 min) t _R = 8.29 min.

Example 2c)

2- (1, 2,3,4-Tetrahydro-1-isoquinolinyl) acetic acid (148) 3,4-dihydro-isoquinoline (147) (2.2 g, 16.77 mmol) and malonic acid (1.94 g, 16.77 mmol) were at room temperature mixed and heated in an oil bath at 120 ° C for 1 hour. Then the mixture was left on

Cool to room temperature and recrystallize from methanol (150 mL). After drying, a colorless solid was obtained (1.52 g, 7.99 mmol, 48%).

Mp 230 ° C decomp; ¹ H-NMR (250 MHz, D ₂ 0, 300 K) δ = 7.13-7.23 (m,

4H, aromatic), 4.65 (t, J = 6.9 Hz, 1 H, CH-NH ₂ ), 3.44-3.54 (m, 1 H, NH-CH ₂ ), 3.24-3.34 (m, 1 H, NH-CH ₂ ), 2.95-3.03 (m, 2H, NH-CH ₂ -CH ₂ ), 2.79 (d, J = 6.1 Hz, 2H, CH ₂ -COOH); HRMS (ESI-TOF) for CnH ₁₄ N0 ₂ [M + H] ⁺ : 192.1047 (calc. 192.1025); Analytical HPLC (5-90% in 30 min) t _R = 10.15 min. 1-carboxymethyl-3,4-dihydro-1 H-isoquinoline-2-carboxylic acid-9H-fluorene-9-yl methyl ester (149)

A suspension of 2- (1, 2,3,4-tetrahydro-1-isoquinolinyl) acetic acid (148) (0.9 g, 4.73 mmol), saturated NaHC0 ₃ solution (15 mL) and dioxane (5 mL) was made up to 0 ° C cooled. Then FmocCI (1.35 g, 5.2 mmol), dissolved in dioxane (5 mL), was added dropwise within 30 min. added and the mixture stirred overnight. Then it was shaken with ether (30 mL) and the aqueous phase with pH 1 with conc. HCI. The product was then extracted with ethyl acetate (50 ml), the organic phase was dried over MgSO 4 and concentrated. The

The crude product was then purified by column chromatography (ethyl acetate / hexane / acetic acid, 1: 1: 1%). After drying, a colorless foam was obtained (1.54 g, 3.73 mmol, 79%).

Mp 61-63 ° C; TLC R _f (ethyl acetate / hexane / acetic acid, 1: 1: 1%) =

0:54; ¹ H-NMR (250 MHz, DMSO-d ₆ , 300 K) δ = 7.79-7.91 (m, 2H, aroma), 7.63-7.66 (m, 2H, aroma), 7.05-7.39 (m, 8H, aroma) , 5.40-5.52 (m, 1 H, NH-CH), 4.37-4.42 (m, 1 H, COO-CH ₂ -CH), 4.25-4.32 (m, 2H, COO-CH ₂ ), 3.62- 4.02 ( m, 1 H, N-CH ₂ ), 3.27-3.38 (m, 1 H, N-CH ₂ ), 2.52-2.76 (m, 4H, N-CH-CH ₂ and N-CH ₂ -CH ₂ ); MS (ESI) m / z 179.1 (30), 414.0 (20) [M + Hf, 436.2

(25) [M + Na] ⁺ , 492.8 (15), 826.7 (5) [2M + H] ⁺ , 849.1 (45) [2M + Na] ⁺ , 865.1 (100) [2M + K] ⁺ ; HRMS (ESI-TOF) for C ₂₆ H ₂₄ N0 ₄ [M + H] ⁺ : 414.1721 (calc. 414.1705); Analytical HPLC (5-90% in 30 min) t _R = 27.53 min.

Example 3a)

5- [N- (4-Methylpyridin-2-yl) amino] - pentanoic acid ethyl ester 5-bromopentanoic acid ethyl ester (33.03 g, 25 mL, 158 mmol) and 2-amino-4-methylpyridine (32.9 g, 304 mmol) were added overnight heated at reflux at 130 ° C (oil bath temperature). After cooling to room temperature, saturated NaHC0 ₃ solution (100 mL) was added

Given reaction mixture, and extracted with ether (5 x 100 mL). The combined organic phases were dried over MgSO 4 and the solvent was removed. The crude product was purified by flash chromatography (ethyl acetate / hexane, 1: 1, 2 L; 3: 2, 1 L; 7: 3, 1 L; 4: 1, 1 L); after drying, a colorless solid was obtained (July 16 g, 70.7 mmol, 45%).

Mp 41-43 ° C; TLC R _f (ethyl acetate / hexane, 1: 1) = 0.26; ¹ H-NMR (250 MHz, DMSO-de, 300 K) δ = 7.90 (d, J = 5.3 Hz, 1 H, N-CH-CH), 6.38 (d, J = 5.2 Hz, 1 H, NC- CH), 6.17 (s, 1 H, N-CH-CH), 4.51 (bs, 1 H, NH), 4.1 1 (q, J = 7.2 Hz, 2H, 0-CH ₂ -CH ₃ ), 3.25 ( q, J = 6.3 Hz, 2H, NH-CH ₂ ),

2.33 (t, J = 7.0 Hz, 2H, CH ₂ -CO), 2.21 (s, 3H, C-CH ₃ ), 1.60-1 .80 (m, 4H, NH-CH2-CH2-CH2), 1.23 ( t, J = 7.0 Hz, 2H, 0-CH ₂ -CH ₃ ); Analytical HPLC (5-90% in 30 min) t _R = 13.58 min.

Example 3b)

5- [N- (4-Methylpyridin-2-yl) amino] pentanoic acid 5- [N- (4-Methylpyridin-2-yl) amino] pentanoic acid ethyl ester (16.7 g, 70.7 mmol, obtainable according to Example 3a) ) was dissolved in methanol (20 mL), 2N aqueous NaOH (71 mL, 141 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was then removed and the solid obtained extracted thoroughly with CHCI ₃ (500 ml) and excess DIPEA. The filtrate was concentrated, and after drying a colorless solid was obtained (3.92 g, 18.8 mmol, 27%).

M.p. 138-140 ° C; ¹ H-NMR (250 MHz, DMSO-d ₆ , 300 K) δ = 7.79 (d, J = 5.2 Hz, 1 H, NH), 6.26-6.30 (m, 2H, aromatic C ⁵ -H and C ⁶ -H), 6.22 (s, 1 H, aromatic C ³ -H), 3.17 (dt, J = 5.8 Hz, 2H, NH-CH ₂ ), 2.21 (t, J = 7.0 Hz, 2H, CH ₂ - CH ₂ -

CO), 2.1 1 (s, 3H, C ^quart -CH ₃ ), 1.41-1.58 (m, 4H, CH2-CH ₂ -CH ₂ -CH ₂ ); ¹³ C NMR (67.5 MHz, DMSO-d ₆ , 300 K) δ = 174.6 (COOH), 159.3, 147.3, 146.8, 113.1, 107.9, 40.5, 33.7, 28.8, 22.4, 20.8; HRMS (ESI-TOF) for CιιH ₁₇ N ₂ θ2 [M + Hf: 209.1293 (calc. 209.1290); Analytical HPLC (5-90% in 30 min) t _R = 9.83 min. example 4

TCP resin was charged with 1-carboxymethyl-3,4-dihydro-1 H-isoquinoline-2-carboxylic acid 9H-fluoren-9-ylmethyl ester (149 from Example 2d)) (0.48 g, 1.16 mmol) according to AAV 1 ( ITH = 0.84 g, m ₂ = 1.0 g, I = 0.426 mmol / g). Fmoc deprotection and coupling of the freshly prepared 5- (9H-fluoren-9-ylmethoxy) -3H- [1, 3,4] oxadiazol-2-one (142 from Example 1b)) (385 mg, 1.32 mmol) were carried out in accordance with AAV 2 and 3, coupling of 5- [N- (4-methylpyridin-2-yl) amino] pentanoic acid (177 mg, 0.852 mmol) according to AAV 4, cleavage from the resin was carried out according to AAV 5. After HPLC purification (10-80% in 30 min) and lyophilization, a colorless powder was obtained (3.0 mg, 0.00542 mmol, 1.3%).

M.p. 103-109 ° C; ¹ H NMR (500 MHz, DMSO-d ₆ , 300 K) δ = 8.81 (bs, 1 H, NH-NH), 8.44 (bs, 1H, NH-NH), 8.25 (d, J = 6.5 Hz, 1 H, N-CH-CH), 7.74-7.77 (m, 4H, aroma), 7.34 (s, 1 H, NC-CH), 7.21 (d, J = 6.4 Hz, 1 H, N-CH - CH), 6.06-6.07 (m, 1 H, N-CH), 4.46-4.52 (m, 1 H, CH-CH ₂ ), 3.82-3.93 (m, 3H, NH-CH ₂ and CH-CH ₂ ), 3.47-3.57 (m, 2H, NCH ₂ CH ₂ ), 3.30-3.40 (m, 2H, NCH ₂ CH ₂ ), 2.94 (s, 3H, C-CH ₃ ), 2.79-2.84 (m, 2H, CH ₂ -CO), 2.23-2.35 (m, 4H, NH-CH ₂ -CH ₂ -CH ₂ ); MS (ESI) m / z 191.2 (8), 249.1 (100), 440.1 (30) [M + Hf, 462.1 (8) [M + Na] ⁺ , 478.1 (10) [M + K] \ 901.0 (2nd ) [2M + Na] ⁺ , 917.1 (3) [2M + K] ⁺ , 939.1 (4) [2M-H + Na + K] ⁺ , 945.1 (4); HRMS for C ₂₃ H ₃ or ₅ 0 ₄ [M + H] ⁺ 440.2273 (calc. 440.2298); Analytical HPLC (5-90% in 30 min) t _R = 14.69 min (92.7% purity at 220 nm)

Example 5a) A Resin-bound Fmoc-1, 2,3,4-tetrahydroisoquinolin-3 (S) -yl-acetic acid

200 mg trityl chloride polystyrene resin (0.18 mmol theoretical loading) is washed in 1.5 ml abs DCM. The resin is then cross-linked with a solution of 0.24 mmol Fmoc-1, 2,3,4-tetrahydroisoquinolin-3 (S) -yl-acetic acid and 0.6 mmol DIPEA in 1.5 ml abs DCM, shaken for 1.5 hours at room temperature and then 0.2 ml Methanol added. It is washed with DCM (5 x 1.5 ml) and methanol (3 x 1.5 ml) and dried.

Example 5b)

B Resin-bound Fmoc-Gly-1, 2,3,4-tetrahydroisoquinolin-3-yl-acetic acid 0.072 mmol A are washed with DMF (1 x 2 ml). Then deprotected twice with 20% piperidine in DMF (2 x 2 ml), first for 5 min and then for 15 min and washed with DMF (6 x 2 ml). The resin-bound free amine is mixed with an approx. 0.1 M solution from 2.5 equiv. (based on resin occupancy, 0.18 mmol) Fmoc-Glycine, 2.4 equiv. (0.17 mmol) HATU and 30 equiv. (2.16 mmol) sym-collidine in dry DMF and shaken for 90 min at room temperature. The reaction is terminated by washing in DMF (6 x 2 ml).

Example 5c) 3-Guanidinobenzoyl-glycyl-1, 2,3,4-tetrahydroisoquinolin-3-yl-acetic acid 0.036 mmol B are washed with DMF (1 x 1 ml). Then deprotected twice with 20% piperidine in DMF (2 x 1 ml), first for 5 min and then for 15 min and washed with DMF (6 x 1 ml). The resin-bound free

Amine is mixed with an approx. 0.1 M solution from 2.5 equiv. (based on resin coverage, 0.09 mmol) Fmoc-3-aminobenzoic acid, 2.4 equiv. (0.086) HATU and 30 equiv. (1.08) sym-collidine added in dry DMF and shaken for 90 min at room temperature. It is washed with DMF (6 x 1 ml) and deprotected as described.

The resin is then washed with anhydrous chloroform (3 × 1 ml) and mixed with a solution of 0.36 mmol of N, N'-bis-BOC-1-guanylpyrazole in 0.4 ml of anhydrous chloroform and reacted at 50 ° C. in a heated shaker. After 20 hours the resin is washed with DCM (6 x 1 ml).

To split off the resin with simultaneous BOC release, the resin is shaken with a 4.75: 4.75: 0.5 mixture of DCM, TFA and TIPS (3 × 1 ml) once for 1.5 hours, once for 30 minutes and once for 3 minutes and filtered off. The combined filtrates are concentrated and the residue is lyophilized from tert-butanol / water. Purification with preparative HPLC gives 3-guanidinobenzoyl-glycyl-1, 2,3,4-tetrahydroisoquinolin-3-yl-acetic acid, trifluoroacetate. RT = 12.3 (10 → 90% ACN, 30 min) MS (ESI): m / z = 410.2 ([M + H] ⁺ ). 1H-NMR (1.3: 1 ratio of the rotational isomers, ^* smaller

Rotational isomer signals, 500 MHz, DMSO-d ₆ ) δ = 12.39 (br. S, 1 H, COOH), 9.95 (s, 1 H, NH- ^Ar C), 8.67 (t, J = 5.4 Hz, 1 H , NH- ^Gly CH ₂ ), 8.63 * (t, J = 5.4 Hz, 1 H, NH- ^Gly CH ₂ ), 7.78 (d, J = 7.8 Hz, 1 H, ^Ar C ⁶ -H), 7.72 (see , 1 H, ^Ar C ² -H), 7.58 (s, 4H, ^Gua N ₂ H ₄ ), 7.53 (t, J = 7.8 Hz, 1 H, ^Ar C ⁵ -H), 7.39 (d, J = 7.8 Hz, 1 H, ^Ar C ⁴ -H), 7.17-7.25 (m, 4H, ™ ^q u _C ^5,6,7,8 _ _{H)) 5 (d} _ j _{= π g Hz}

-IH, ^Thiqu C ¹ -H ₂ ), 5.01-5.02 * (m, 1 H, ^Thic < ^u C ³ -H), 4.82 ^* (d, J = 16.2 Hz, 1 H, ^τhiqu C ¹ -H ₂ ) , 4.73-4.75 (m, 1H, ^{Thi u} C ³ -H), 4.55 ^* (d, J = 16.2 Hz, 1H, ^Thiqu C ¹ - H ₂ ), 4.44 (dd, J = 16.4 Hz, J = 5.4 Hz , 1 H, ^Gly CH ₂ ), 4.19-4.29 (m, 3H, ^{G, y} CH ₂ ), 4.10 (d, J = 17.9 Hz, 1 H, ^Thiqu C ¹ -H ₂ ), 3.15 (dd, J = 16.4 Hz, J = 5.0 Hz, 1 H CH ₂ C0 ₂ H), 2.98 * (dd, J = 15.8 Hz, J = 5.2 Hz, 1 H, CH ₂ C0 ₂ H), 2.74-2.79 (m, 2H, CH ₂ C0 ₂ H), 2.41-2.51, 2.33-2.37, 2.16-2.21 (m, 4H,

Th, qu, _c 4_ _H2)

Example 6

5- (4-Methylpyridin-2-ylamino) pentanoyl-glycyl-1, 2,3,4-tetrahydroisoquinolin-3-yl-acetic acid

0.036 mmol B (obtainable according to Example 5b)) are washed with DMF (1 x 1 ml). Then deprotected twice with 20% piperidine in DMF (2 x 1 ml), first for 5 min and then for 15 min and washed with DMF (6 x 1 ml). The resin-bound free amine is mixed with an approx. 0.1 M solution from 2.5 equiv. (0.09 mmol) 5- (N- (4-Methylpyridin-2-yl) -aminopentanoic acid, 2.4 equiv. (0.086 mmol) HATU and 30 equiv. (1.08 mmol) collidine in absolute DMF, shaken overnight at room temperature Washes with DMF and DCM To split off from the solid phase, the washed resin is shaken with 1 ml of a mixture of DCM / trifluoroethanol / acetic acid (31/1) first for 90 min, then 30 min and finally for 1 min, removing the solvent and cleaning with preparative HPLC gives 5- (4-methylpyridin-2-ylamino) -pentanoyl-glycyl-1, 2,3,4-tetrahydroisoquinolin-3-yl-acetic acid, trifluoroacetate. RT = 13.3 (10 → 90% ACN, 30 min) MS (ESI): m / z = 439.3 ([M + H] ⁺ ).

¹ H-NMR (1.3: 1 ratio of the rotation isomers, ^* smaller rotation isomer signals, 500 MHz, DMSO-d ₆ ) δ = 12.35 (br. S, 1H, COOH), 8.46 (br. S, 1 H, NH- CH ₂ ), 7.93-7.97 (m, 1 H, NH- ^Gly CH ₂ ), 7.78 (d, J = 6.5 Hz, 1H, ^Pyr C ⁶ -H), 7.14-7.22 (m, 4H, ^Thic > ^u c ^5l6 ' ⁷ ' ⁸ -H), 6.81 (s, 1 H, ^Pyr C ³ - H), 6.69 (d, J = 6.5 Hz, 1 H, ^Pyr C ⁵ -H), 5.08 (d, J = 17.9 Hz , 1H, ^Thιqu C ¹ -H ₂ ), 4.97-5.01 * (m, 1 H, ^Thiqu C ³ -H), 4.71 * (d, J = 16.2 Hz, 1 H, ^Thiqu C ¹ -H ₂ ), 4.59 - 4.63 (m, 1 H, ^Thιqu C ³ -H), 4.47 * (d, J = 16.2 Hz, 1H, ^Thιqu C ¹ -H ₂ ), 4.21 (dd, J = 16.7 Hz, J = 5.5 Hz, 1 H, ^Gly CH ₂ ), 4.04-4.08 (m, 3H, ^Gly CH ₂ , ^Thiqu C ¹ -H ₂ ), 3.97 ^* (dd, J = 16.9 Hz, J = 5.4 Hz , 1 H, ^Gly CH ₂ ), 3.27 (m, 2H, NH-CH ₂ ), 3.11 (dd, J = 16.2 Hz, J = 5.3 Hz, 1 H, CH ₂ C0 ₂ H), 2.95 * (dd, J = 15.7 Hz, J = 5.4 Hz, 1 H, CH ₂ C0 ₂ H), 2.62-2.77 (m, 2H, CH ₂ C0 ₂ H), 2.34-2.44 (m, 3H, ™ ^qui C ⁴ -H ₂ ) 2.31 (s, 3H, CH ₃ ), 2.12-2.21 (m, 3H, ^Thiqui C ⁴ -H ₄ , CH ₂ -CH ₂ -CO),

1:58 (s, 4H, (CH ₂₎ ₂ -CH ₂ -CO).

The other compounds of the formula I, in particular the compounds of the formulas 11 to I36, can be obtained analogously using the corresponding precursors.

The following examples relate to pharmaceutical preparations:

Example A: Injection glasses

A solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Each injection glass contains 5 mg of active ingredient.

Example B: Suppositories

A mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.

Example C: solution

A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g

NaH2P04 • 2 H2O, 28.48 g Na2HP04 • 12 H2O and 0.1 g benzalkonium chloride in 940 ml double-distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D: ointment 500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.

Example E: tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient.

Example F: coated tablets

Analogously to Example E, tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.

Example G: capsules

2 kg of active ingredient of the formula I are filled into hard gelatin capsules in a conventional manner, so that each capsule contains 20 mg of the active ingredient.

Example H: ampoules

A solution of 1 kg of active ingredient of formula I in 60 I double distilled

Water is filtered sterile, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.

Example I: Inhalation spray

14 g of active ingredient of the formula I are dissolved in 10 I of isotonic NaCl solution and the solution is filled into commercially available spray vessels with a pump mechanism. The solution can be sprayed into the mouth or nose. One spray (approximately 0.1 ml) corresponds to a dose of approximately 0.14 mg.

Claims

claims

Compounds of formula I.

NH or CH ₂ ,

R) 1, R each independently of one another H, A, OH, OA, arylalkyl, shark, -CO-A, CN, N0 ₂ , NHR ³ , COOA, COOH, S0 ₂ A, CF ₃ or OCF ₃ ,

R> 2 each independently of one another H or A,

R ^J , R each independently of one another H, A, -CO-A, N0 ₂ or CN,

Alkyl with 1-6 C atoms,

m 0, 1, 2, 3, 4, 5 or 6,

n, p independently of one another are 1, 2 or 3,

as well as their physiologically acceptable derivatives, in particular their salts and solvates. Compounds of formula I according to claim 1, wherein A is methyl, furthermore ethyl, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

Compounds of formula I according to one or more of claims 1 or 2, wherein Het 4-methylpyridin-2-yl, pyridin-2-yl, pyriminin-2-yl, imidazol-2-yl, benzimidazol-2-yl and their hydrogenated Derivatives means.

Compounds of formula I according to one or more of claims 1 to 3, characterized in that R ¹ and R ⁵ independently of one another are preferably H, A, CN, N0 ₂ , shark or - COA-.

Compounds of formula I according to one or more of claims 1 to 3, characterized in that R ^{2 is} preferably H or A.

Compounds of formula I according to one or more of claims 1 to 3, characterized in that R ³ and R ⁴ independently of one another are preferably H or -COA-.

Compounds of formula I according to one or more of claims 1 to 3, characterized in that XH, -C (= NH) -NH ₂ , -C (= NMethyl) -NH ₂ , 4-methylpyridin-2-yl, pyridine- 2-yl, pyrimidin-2-yl, imidazol-2-yl, benzimidazol-2-yl and their hydrogenated derivatives.

Compounds of formula I according to one or more of claims 1 to 3, characterized in that Y - (CH ₂ ) _m - or means. Compounds of formula I according to one or more of claims 1 to 3, characterized in that n and p are independently 1 or 2.

Compounds of formula I according to one or more of claims 1 to 3, characterized in that m is 0, 2 or 4.

Compounds of formula 11 to I36:

11

12

13

14

15

16

17

18

19

110 111

112

113

114

115 116

117

118

119

I20

131 I32

I33

I34

I35 I36

Process for the preparation of compounds of the formula I according to one or more of claims 1 to 11 and their salts, characterized in that a) a compound of the formula II, in which Z, R ¹ and n have the meaning given above and W denotes a customary protective group or a solid phase used in peptide chemistry,

and then removing the protecting groups and / or the solid phase,

and the product obtained, if necessary, if Q is split off as a protective group, with a suitable one

Guanyl compound, e.g. N, N'-bis-BOC-1-guanylpyrazole reacted and, if appropriate, the remaining protective groups and / or the solid phase are eliminated

or

and / or converting a basic or acidic compound of the formula I into one of its salts by treatment with an acid or base.

13. Compounds of formula I according to one or more of the

Claims 1 to 11 and their physiologically acceptable salts or solvates as therapeutic agents.

14. Compounds of formula I according to one or more of claims 1 to 11 and their physiologically acceptable salts or solvates as integrin inhibitors.

15. Compounds of formula I according to one or more of claims 1 to 11 and their physiologically acceptable salts or solvates for use in combating diseases. Pharmaceutical preparation characterized by a content of at least one compound of the formula I according to one or more of claims 1 to 11 and / or one of its physiologically acceptable salts or solvates.

Use of compounds of the formula I according to one or more of claims 1 to 11 and / or their physiologically acceptable salts or solvates for the production of a pharmaceutical preparation.

Use of compounds of the formula I according to one or more of claims 1 to 11 and / or their physiologically acceptable salts or solvates for the production of a pharmaceutical preparation for combating thromboses, heart attacks, coronary heart diseases, arteriosclerosis,

Inflammation, tumors, osteoporosis, infections and restenosis after angioplasty.

Use of compounds of the formula I according to one or more of claims 1 to 11 and / or their physiologically acceptable salts or solvates in pathological processes which are maintained or propagated by angiogenesis.