WO1998018764A1

WO1998018764A1 - Dihydrobenzoanthracenone, -pyrimidinone or dihydronaphtoquinolinone

Info

Publication number: WO1998018764A1
Application number: PCT/EP1997/005592
Authority: WO
Inventors: Horst Juraszyk; Joachim Gante; Hanns Wurziger; Peter Raddatz; Sabine Bernotat-Danielowski; Guido Melzer
Original assignee: Merck Patent Gmbh
Priority date: 1996-10-28
Filing date: 1997-10-10
Publication date: 1998-05-07
Also published as: AU4946697A

Abstract

Novel compounds having formula (I) wherein X,Y,R?1,R2,R3,R4 and R5¿ have the meaning cited in claim 1, their salts and their solvates. Said compounds inhibit the binding of fibrinogens on the corresponding receptor and can for instance be used in the treatment of thromboses, osteoporoses, tumour diseases, apoplexia, heart attacks, ischemias, inflammations, arteriosclerosis and osteolytic diseases.

Description

Dihydrobenzoanthracenones, pyrimidinones or dihydronaphthoquinolinones

The invention relates to compounds of the formula I.

wherein

X CH, CR ⁶ or N,

Y CH, CR ⁷ or N,

R ¹ H, A, shark, OH, OA, NH ₂ , NHA, NA _2l NHR ⁸ , CN, N0 ₂ , CF _3l H ₂ NC (= NH) -, H ₂ NC (= NH) -NH-, H ₂ NC (= NOH) -NH-,

H ₂ NC (= NOH) -, where NHA, NH ₂ , -C (= NH) -NH ₂ , H ₂ NC (= NOH) -, H ₂ NC (= NOH) -NH and H ₂ NC (= NH ) -NH- can also be simply substituted by A-CO, Ar-alk-CO, AO-CO, Ar-alk-O-CO or by a conventional amino protecting group,

R, R ³ , R ⁴ and R ⁵ each independently of one another H, A, Hai, OH, OA, NH _2l NHA, NA ₂ , NHR ⁹ , CN, N0 ₂ , CF ₃ , H ₂ NC (= NH) -, H ₂ NC (= NH) -NH-, H ₂ NC (= NOH) -NH-, H ₂ NC (= NOH) -, where NHA, NH ₂ , -C (= NH) - NH ₂ , H ₂ NC (= NOH) -, H ₂ NC (= NOH) -NH and H ₂ NC (= NH) -NH- also simply by A-CO, Ar-alk-CO, AO-CO, Ar-alk-O-CO or can be substituted by a conventional amino protecting group,

R ⁶ CN, COOH, COOA, CONH ₂ , CONHA or CONA ₂ , R ⁷ CN, CF ₃ , shark, OH, OA, Het or S-Het,

R ⁸ A, Ar, A-CO, Ar-alk-CO, AO-CO or Ar-alk-O-CO,

R ⁹ C _n H _2n -Z, C _n H _2n -0-COOA, C _n H _2n -0-COOH or C _n H _2n -0-COOAr,

R ² and R ⁶ together also -CH ₂ -CH ₂ -, -CH ₂ -CO-, -CHA-CO-, -CA ₂ -CO- or -CO-C = CH-CH = CR ¹⁰ ,

R ¹⁰ (H, H), (H, A), (A, A), (H.Hal), (A, Hal) or

R ³ and R ¹⁰ together also form a bond, the free valence of the R ^10- bearing C atom being saturated by H,

R ⁴ and R ⁷

R ¹ H, A, shark, OH, OA, NH ₂ , NHA, NA ₂ , CN, N0 ₂ , or CF _3l

A alkyl with 1-6 C atoms,

Ar unsubstituted or single, double or triple by A, OH, OA,

Shark, CN, N0 ₂ , CF ₃ , NH ₂ , NHA or NA ₂ substituted phenyl, unsubstituted or appropriately substituted benzyl or unsubstituted or appropriately substituted naphthyl,

Z shark, OH, OA, COOH, CN, COOA, CONH ₂ , CONHA or

CONA ₂ ,

Shark F, Cl, Br or I,

alk unbranched or branched alkylene with 1-6 C atoms,

Het 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 0- Atoms can be present and the heterocyclic radical can be substituted once or twice by CN, shark, OH, OA, CF ₃ , A, NH _{2 1} NHA, NA ₂ or N0 ₂

n 1, 2, 3 or 4,

mean,

and their physiologically acceptable salts and solvates.

Similar compounds, but in the form of pigments and dyes, are known from DE 38 64 063 and U.S. 5,476,544.

The invention was based on the task of finding new compounds with valuable properties, in particular those which can be used for the production of medicaments.

It has been found that the compounds of the formula I and their salts and solvates have very valuable pharmacological properties with good tolerability. Above all, they act as integrin inhibitors, in particular inhibiting the interactions of the αv integrin receptors with ligands. The compounds are particularly effective in the case of the integrins α _v ß ₃ and ßs- The compounds are particularly effective as adhesion receptor antagonists for the vitronectin receptor α _v ß ₃ .

This effect can e.g. B. detected by the method described by J.W. Smith et al. in J. Biol. Chem. 265, 11008-11013 and 12267-12271 (1990).

B. Felding-Habermann and DA Cheresh describe in Curr. Opin. Cell. Biol. 5, 864 (993) the meanings of integrins as adhesion receptors for a wide variety of phenomena and clinical pictures, especially in relation to the vitronectin receptor _v ß ₃ . The dependence of the development of angiogenesis on the interaction between vascular integrins and extracellular matrix proteins is described by PC Brooks, RA Clark and DA Cheresh in Science 264, 569-71 (1994).

The possibility of inhibiting this interaction and thus the initiation of apoptosis (programmed cell death) of angiogenic vascular cells by a cyclic peptide is from P.C. Brooks, A.M. Montgomery, M. Rosenfeld, R.A. Reisfeld, T.-Hu, G. Klier and D.A. Cheresh in Cell 79, 1157-64 (1994).

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

PC Brooks et al. describe in J. Ciin. Invest. 96, 1815-1822 (1995) α β ₃ antagonists for combating cancer and for treating tumor-induced angiogenic diseases.

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 in the pathological environment of the organism.

Compounds of formula I, the interaction of integrin receptors and ligands, such as. B. from fibrinogen to the fibrinogen receptor (glycoprotein llb / llla) prevent GPIIb / llla antagonists from spreading 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 (microthroma ben) by 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 walls of the vessels, 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 GPIIa / IIIb antagonists can be regarded as effective metastasis inhibitors.

In addition to the binding of fibrinogen, fibronectin and the Willebrand factor to the fibrinogen receptor of the platelets, compounds of the formula I also inhibit the binding of other adhesive proteins, such as vitonectin, collagen and laminin, to the corresponding receptors on the surface of various 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 properties of the compounds can also be demonstrated by methods which are described in EP-A1-0462 960. The

Inhibition of fibrinogen binding to the fibrinogen receptor can be detected using the method specified in EP-A1-0 381 033. The antiplatelet effect can be demonstrated in vitro by the method of Born (Nature 4832, 927-929, 1962).

The invention accordingly relates to compounds of the formula I according to claim 1 and / or their physiologically acceptable salts for the preparation of a medicament for use as integrin inhibitors.

The compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine. They act as adhesion receptor antagonists and are suitable for the prophylaxis and / or therapy of thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, tumor diseases, osteolytic diseases such as osteoporosis, pathologically angiogenic diseases such as eg inflammation, ophthalmological diseases, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis, Crohn's disease, atherosclerosis, psoriasis, restenosis after angioplasty, infection, viral infection, angioplasty, viral acute kidney failure and in wound healing to support the healing processes. Furthermore, they can be used to coat artificial surfaces and can thus be used for the therapeutic purposes mentioned.

The compounds of the formula I, in particular in the form of coating materials, can be used as antimicrobial substances in operations where biomaterials, implants, catheters or pacemakers are used. They also have an antiseptic effect. The effectiveness of the antimicrobial activity can be demonstrated by the method described by P.Valentin-Weigund et al., In Infection and Immunity, 2851-2855 (1988).

The invention relates to the compounds of the formula I and their salts and to a process for the preparation of these compounds and their salts, characterized in that

(a) liberating a compound of the formula I from one of its functional derivatives by treatment with a solvolysing or hydrogenolysing agent,

or,

(b) that a compound of formula

live R ¹ , R ² , R ³ , R ⁴ and R ⁵ and Y have the meanings given in claim 1 and

HC = 0, -CH ₂ -NH ₂ or -CHz-NHR ⁶ ,

means

cyclized,

or,

(b) that a compound of formula III

wherein R, R, R, R and R and X and Y have the meanings given in claim 1 and

Q COOH, COOA, COCI, COBr or another reactive radical which is derived from an acid group,

means

cyclized,

or.

(c) that a compound of formula IV

in which R ² , R ³ , R ⁴ and R ^{5 have} the meanings given in claim 1,

with a compound of formula V

wherein R ¹ and shark have the meanings given in claim 1.

implements

or

(d) that binaphthyl derivative of the formula VI

wherein R ¹ , R ² , R ³ and R ^{4 have} the meanings given in claim 1 and

means

cyclized,

(e) converting an amino group into a guanidino group by reaction with an amidinizing agent,

or,

(f) that a radical R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X and / or Y into another radical R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X and / or Y is converted by e.g. B.

- reduced a nitro group, - etherified an OH group or an OA group

Subjugates ether,

alkylated a primary or secondary amino group,

partially or completely hydrolyzed a CN group,

- cleaves an ester group or esterifies a carboxylic acid residue, - or carries out a nucleophilic or electrophilic substitution,

and or

(g) converting a base or acid of the formula I into one of its salts or solvates in a manner known per se.

For all residues or parameters that occur several times, such as B. A, applies that their meanings are independent of one another and can be different. Compounds of the formula I which, because of their radicals R ¹ , R ² , R ³ , R or R ^{5, have} one or more centers of chirality can occur in various enantiomeric forms. All of these forms (eg R and S forms) and their mixtures (eg the RS forms) are included in the formula I.

The abbreviations used have the following meanings:

BOC tert-butoxycarbonyl

CBZ benzyloxycarbonyl

DCCI dicyclohexylcarbodiimide

DMF dimethylformamide

Et ethyl

Me methyl

OBut tert-butyl ester

OMe methyl ester

OEt ethyl ester

TFA trifluoroacetic acid.

Furthermore, free amino groups can be provided as substituents of compounds of the formula I with corresponding protective groups known per se.

In the above formulas, A is alkyl and has 1 to 6, preferably 1, 2, 3 or 4, carbon atoms. Alkyl is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1, 1 -, 1, 2- or 2,2-dimethylpropyl, 1 - ethylpropyl, hexyl, 1 -, 2-, 3- or 4-methylpentyl, 1, 1 -, 1, 2-, 1, 3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 1, 2- or 1, 2,2-trimethylpropyl.

Alkyl also means cyclobutyl, methylene cyclobutyl, cyclopentyl, methylene cyclopentyl, cyclohexyl or methylene cyclohexyl, methylene cyclopropyl or cyclopropyl. The remainder alk denotes alkylene and is preferably methylene, ethylene, propylene, but also butylene, pentylene or hexylene.

Alkanoyl preferably means formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, furthermore nonanoyl or

Decanoyl.

Ar is preferably phenyl, preferably - as indicated - monosubstituted phenyl, in particular preferably phenyl, o-, m- or p-methylphenyl, o-, m- or p-ethylphenyl, o-, m- or p- Propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-aminophenyl, o-, m- or p-aminocarbonylphenyl, o-, m- or p- nitrophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p- chlorophenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- or p-

Ethoxycarbonylphenyl, more preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2-chlorine -3-methyl, 2-chloro-4-methyl, 2-chloro-5-methyl, 2-chloro-6-methyl, 2-methyl-3-chloro, 2-methyl-4-chloro , 2-methyl-5-chloro, 2-methyl-6-chloro, 3-chloro-4-methyl, 3-chloro-5-methyl or 3-methyl-4-chlorophenyl, 2-bromo-3 methyl, 2-bromo-4-methyl, 2-bromo-5-methyl, 2-bromo-6-methyl, 2-methyl-3-bromo, 2-methyl-4-bromo, 2 -Methyl-5-bromo-, 2-methyl-6-bromo-, 3-bromo-4-methyl-, 3-bromo-5-methyl- or 3-methyl-4-bromophenyl, 2,5- or 3, 4-dimethoxyphenyl. However, unsubstituted benzyl or naphthyl is also preferred.

Aralkanoyl preferably means benzoyl, unsubstituted, preferably - as indicated - monosubstituted phenyl, in particular preferably phenylacetyl, o-, m- or p-methoxyphenyl acetyl, o-, o-, m- or p-ethoxyphenylacetyl, o-, m - or p-fluorophenylacetyl, o-, m- or p-bromophenylacetyl, o-, m- or p-chlorophenylacetyl, o-, m- or p-methylphenylacetyl, o-, m- or p-ethylphenylacetyl, o- , m- or p-aminophenyl acetyl, o-, m- or p-nitrophenylacetyl, o-, m- or p-aminocarbonylphenylacetyl, o-, m- or p-methoxycarbonylphenylacetyl, further preferably 3-phenylpropionyl, 4-phenylbutyryl, 5-phenylpentanoyl or 6-phenylhexanoyl. Alkoxycarbonyl preferably means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, and also isopropoxycarbonyl, tert. -Butoxycarbonyl or hexyloxycarbonyl.

Het is preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 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- , -3- 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-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-benzothiazolyl, 2-, 4-, 5-, 6- or 7-B enzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1, 3-oxadiazolyl, 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 thus also mean, for example, 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 -4-imidazolyl, 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 , 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4- pyranyl, 1, 4-dioxanyl, 1, 3-dioxan-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-l-, -2-, -3-, -4-, -5-, -6- , -7- or -8- quinolinyl, 1,2,3,4-tetrahydro-l-, -2-, -3-, -4-, -5-, -6-, -7- or 8-iso - quinolinyl.

R ¹ is preferably A, Cl, Br, NHR ⁸ , -C (= NH) -NH ₂ or H ₂ N- C (= NH) -NH-.

R ² , R ³ , R ⁴ and R ⁵ are preferably different from one another, but two to three of the radicals can also have the same meaning. Preferably one or two radicals mean H, while the others have different meanings. The radicals mentioned preferably each mean independently of one another F, Cl, Br, NH ₂ , -C (= NH) - NH ₂ , H ₂ NC (= NH) -NH-, NHA, NHR ⁹ , A, OH, OMe, OEt , -C (= NOH) -NH _2l or H ₂ NC (= NOH) -NH-.

R ⁶ preferably denotes COOH or COOA, in particular COOMe or COOEt.

R ⁷ preferably denotes Het or S-Het, where Het in particular denotes pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl or morphlidinyl in substituted or unsubstituted form. In S-Het, Het is also preferably benzimidazolyl, benzodioxanyl, indolyl, quinolinyl or isoquinolinyl.

Amino protecting group preferably means acetyl, propionyl, butyryl, phenylacetyl, benzoyl, toluyl, POA, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl, CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl or benzyl and will be explained in more detail later.

Shark is preferably F, Cl or Br.

The preferred meanings of X are N or CR 6, those of Y are N or CR ⁷ . In addition to the preferred meanings mentioned for the individual radicals, preference is also given in particular to those compounds of the formula I in which R ² and R ⁶ , R ³ and R ¹⁰ and / or R ⁴ and R ⁷ together have one of the meanings mentioned and thus change the ring structure one or more rings is expanded. In particular, the following ring systems are intended to be included by the present invention through these definitions:

7a, 11 a-dihydro-benzo [de] anthracen-7-one; 7a, 11 a-dihydro-7H-benzo [e] perimidine;

7a, 11 a-dihydro-7H-naphtho [1, 2,3-de] quinolin-7-one;

7a, 11 a-dihydro-7H-naphtho [1, 2,3-de] quinoline;

7a, 11 a-dihydro-7H-benzo [e] perimidin-7-one;

1 H-benzo [cd] pyrene-2,6-dione; Dibenzo [def, mno] chrysen-6,12-dione;

3,4-dihydro-dibenzo [b, def] chrysene-7, 14-dione.

Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above.

Some preferred groups of compounds can be expressed by the following sub-formulas Ia to Ih, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in ia

in la X nitrogen,

Y CH or CR ⁷ ,

in lb X CH or CR ⁶ ,

Y nitrogen,

in Ic X and Y each nitrogen, in ld X and Y each CH or CR ⁶ or CR ⁷ ,

and

R ¹ shark, CN, OA, NHR ⁸ , with R ⁸ preferably phenyl,

NH ₂ , NHA or NA ₂ ;

in le X and Y each CH or CR ⁶ or CR ⁷ , at least one

Rest is different from CH

and

R ² and R ⁶ together -CH ₂ -CH ₂ -, -CH ₂ -CO-, -CHA-CO-, -CA ₂ -CO- or -CO-C = CH-CH = CR ^ ¹ 10

or

R ⁴ and R ⁷ together -CO-CH ₂ -CH ₂ -, -CO-CH ₂ -CHA-,

-CO-CH ₂ -CA ₂ -, -CO-CHA-CHA, -CO-CHA-CH ₂ - or -CO- @ 4 ¹¹ ,

in If X and Y each CH or CR ⁶ or CR ⁷ , at least one

Rest is different from CH

and

R ² and R ⁶ together -CH ₂ -CH ₂ -, -CH ₂ -CO-, -CHA-CO-, -CA ₂ -CO- or -CO-C = CH-CH = CR ¹⁰ ,

and

R ³ and R ¹⁰ together form a bond, the free valence of the R ^10- bearing C atom being saturated by H,

in Ig X nitrogen, CH or CR ⁷ , and

R ² , R ³ and R ^{5 are} hydrogen;

in Ih X CH or CR ⁶ ,

Y nitrogen, and

R ² , R ³ and R ^{5 are} hydrogen.

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.

The compounds of the formula I can 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, preferably those which instead of an H atom, which is connected to an N atom carry an amino protective group, in particular those which carry an R'-N group instead of an Hn group, in which R 'represents an amino protective group, and / or those which have one instead of the H atom Hydroxy group carry a hydroxyl protective group, for example those which correspond to the formula I, but instead of a group -COOH carry a group -COOR "in which R" 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 one another, they can in many cases be split off selectively.

The term "amino protecting group" is generally known and refers to groups which are suitable for protecting (blocking) an amino group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at other locations in the molecule. Unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups are particularly typical of such groups. Since the amino protective groups are removed after the desired reaction (or reaction sequence), their type and size is otherwise not critical; however, preference is given to those having 1-20, in particular 1-8, carbon atoms. 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, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl 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 POA; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl such as Mtr. Preferred amino protecting groups are BOC, furthermore CBZ, Fmoc, 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, but which are easily removable after the desired chemical reaction has been carried out elsewhere in the molecule. They are typical of such groups - 1 o -

The unsubstituted or substituted aryl, aralkyl or acyl groups mentioned above, and also alkyl groups. The nature and size of the hydroxyl protective groups is not critical since they are removed again after the desired chemical reaction or reaction sequence; groups with 1-20, in particular 1-10, carbon atoms are preferred. Examples of hydroxy protecting groups include Benzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, with benzyl and tert-butyl being particularly preferred.

The liberation ^'-Sit of the compounds of the formula I from their functional derivatives-depending tional achieved by the protective group used - eg. B. with strong acids, suitably with TFA or perchloric acid, but also with other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol, and water. Mixtures of the abovementioned solvents are also suitable. TFA is preferably used in excess without the addition of another solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9: 1. The reaction temperatures for the cleavage are advantageously between about = and about 50 °, preferably between 15 and 30 ° (room temperature).

The groups BOC and OBut can e.g. B. preferably with TFA in dichloromethane or with about 3 to 5N HCl in dioxane at 15-30 °, the FMOC group with an about 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30 °.

Hydrogenolytically removable protective groups (e.g. CBZ or benzyl) can e.g. B. by treatment with hydrogen in the presence of a catalyst (z. B. a noble metal catalyst such as palladium, conveniently on a support such as coal). As a solvent are the above, especially z. B. alcohols such as methanol or ethanol or amides such as DMF. The hydrogenolysis is generally carried out at temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably at 20-30 ° and 1-10 bar. Hydrogenolysis of the CBZ group succeeds e.g. B. good at 5 to 10

% Pd / C in methanol or with ammonium formate (instead of hydrogen) on Pd / C in methanol / DMF at 20-30 °.

Compounds of formula I can also preferably be obtained by cyclizing compounds of formula II or formula III. The starting compounds of the formula II are generally known and are commercially available. However, the unknown compounds can be prepared by methods known per se.

The compounds of formula II are anthraquinone derivatives. They can be prepared in a conventional manner from anthraquinone or suitable derivatives by appropriate substitutions on the aromatic system. It is also possible to convert appropriately substituted anthracenes into the anthraquinones by oxidation.

The compounds of the formula III are quinazoline derivatives, which are also generally commercially available. Furthermore, these compounds can be prepared by reacting o-acylanilines with acid amides.

The cyclizations are usually carried out in an inert solvent, preferably in the presence of an acid. Depending on the conditions used, the reaction time is between a few minutes and several days, the reaction temperature is between approximately 0 ° and 150 °, normally between 20 ° and 130 °. The reactions can e.g. B. in analogy to those in U.S. 2, 15,445 specified methods are carried out.

Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulfide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of the solvents mentioned.

The compounds of the formula IV are derived from the anthrone and can be prepared from appropriately substituted anthraquinones by reduction with tin and hydrochloric acid in glacial acetic acid under conditions known per se. Furthermore, the substituents R ² to R ^{5 can} also be introduced by substitutions on the aromatic. In many cases, however, it is advisable to introduce these substituents before the reduction.

The halides of the formula V are generally known and their preparation is familiar to the person skilled in the art, so that a description of the

Syntheses are not necessary here.

The reaction of the compounds of formula IV with compounds of formula V is preferably carried out in an inert solvent

Add a base and at temperatures and reaction times as previously indicated. Suitable acid-binding agents are preferably alkali or alkaline earth metal hydroxides, carbonates or bicarbonates or other salts of a weak acid of the alkali or alkaline earth metals, preferably potassium, sodium, calcium or cesium. The addition of an organic base such as triethylamine, dimethylaniline, pyridine or quinoline can also be favorable. Derivatives with a free primary or an additional secondary amino group are expediently used in protected form. The aforementioned groups can be used as protective groups.

The compounds of formula VI are derived from binaphthyl and are known per se or can be prepared by synthetic methods known per se. The substituents R ² to R ⁵ can preferably be introduced by substitution on the aromatic.

The cyclization of the binaphthyls is generally known to the person skilled in the art and their preparation is prior art, so that a description of the syntheses is unnecessary here.

The cyclization of the compounds of formula VI is preferably carried out in an inert solvent. The addition of a base can be advantageous. The preferred reaction temperatures and reaction times are given above. Suitable base additives are preferably alkali or alkaline earth metal hydroxides, carbonates or bicarbonates, and the others mentioned above. The reactions can preferably be carried out in analogy to those in J. Amer. Chem. Soc. 53, 3104-3108 (1931).

To prepare compounds of the formula I in which R ² , R ³ , R ⁴ and / or R ^{5 is} H ₂ NC (= NH) -NH-, a corresponding amino-substituted compound can be treated with an amidinating agent. 1-Amidino-3,5-dimethylpyrazole (DPFN), which is used in particular in the form of its nitrate, is preferred as the amidizing agent. It is advantageous to work with the addition of a base such as triethylamine or ethyldiisopropylamine in an inert solvent or solvent mixture, for example water / dioxane, at temperatures between 0 and 120 ° C., preferably between 60 and 120 ° C.

For the esterification, an acid of the formula I (for example R ⁶ = -COOH) can be treated with an excess of an alcohol, advantageously in the presence of a strong acid such as hydrochloric acid or sulfuric acid at temperatures between 0 and 100 ° C, preferably between 20 and 50 ° C. Conversely, an ester of the formula I (R ⁶ = -COOA) can be converted into the corresponding acid of the formula I, advantageously by solvolysis using one of the methods given above, for example using NaOH or KOH in water dioxane at temperatures between 0 and 40 ° C, preferably between

10 and 30 ° C.

To prepare an amidine of the formula I (R ² , R ³ , R ⁴ and / or R ⁵ -C (= NH) -NH ₂ ), a nitrile of the formula I (R ² , R ³ , R ⁴ and / or R ⁵ = CN) add ammonia. The addition is preferably carried out in several stages by, in a manner known per se, a) converting the nitrile with H ₂ S into a thioamide, which is converted into the corresponding S-alkylimidothioester using an alkylating agent, for example CH ₃ I, which in turn contains NH ₃ reacts to the amidine, b) the nitrile is converted to the corresponding imidoester with an alcohol, for example ethanol in the presence of HCl, and treated with ammonia, or c) the nitrile is reacted with lithium bis (trimethylsilyl) amide and the product then hydrolyzed.

Furthermore, free amino groups can be acylated in the usual way with an acid chloride or anhydride or alkylated with an unsubstituted or substituted alkyl halide, advantageously in an inert solvent such as dichloromethane or THF and / or in the presence of a base such as triethylamine or pyridine at temperatures between -60 and + 30 °.

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, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, and also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carbon, sulfone - or sulfuric acids, e.g. Formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane acid or ethanesulfonic acid, ethanesulfonic acid , Benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, lauryl-sulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used for the isolation and / or purification of the compounds of the formula I.

On the other hand, compounds of formula I with bases (e.g. 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.

All of the synthesis methods given here and all other suitable processes for the preparation of compounds of the formula I can also be achieved by the new methods of combinatorial chemistry, i.e. H. carried out by computer-assisted syntheses and subjected to mass screening.

The invention furthermore relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular by a non-chemical route. They 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 ingredients.

The invention further relates to pharmaceutical preparations containing at least one compound of the formula I and / or one of its physiologically acceptable salts.

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

Dragees, capsules, powders, granules, syrups, juices or drops, for rectal use suppositories, for parenteral use solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, for topical 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, flavoring and / or several other active substances, e.g. one or more vitamins.

The compounds of formula I and their physiologically acceptable salts and solvates act as adhesion receptor antagonists and can be used in the control of diseases, in particular for the treatment of thromboses, tumor diseases, arteriosclerosis, apoplexy, inflammation, ischemia, osteoporosis and heart failure.

The substances according to the invention are generally preferably administered in doses between about 1 and 500 mg, in particular between 5 and 100 mg, per dosage unit. The daily dosage is preferably between about 0.02 and 10 mg / kg body weight. However, the specific dose for each patient depends on a variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of elimination, combination of drugs and severity the respective disease to which the therapy applies. Oral application is preferred. All temperatures above and below are given in ° C. In the examples below, "customary work-up" means: if necessary, water is added, if necessary, depending on the constitution of the end product, the pH is adjusted to between 2 and 10, extracted with ethyl acetate or dichloromethane, separated, dried organic phase over sodium sulfate, evaporates and purifies by chromatography on silica gel, the isomers described below also being separated and / or by crystallization.

example 1

A suspension of 4.37 g of 4- (2- (4-methyl-piperazino) propenal-3-yl) anthraquinone in 180 ml of THF is prepared under the conditions of the McMurray reaction (Accounts Chem. Res. 16, 405 (1983 )), ie cyclized in the presence of potassium and TiCl ₃ by refluxing for 12 hours. After 12

The reaction mixture is allowed to cool for hours, the solvent is removed in vacuo and the mixture is worked up in the customary manner. 2- (4-Methylpiperazino) -7a, 11a-dihydro-benzo [de] anthracen-7-one is obtained.

The cyclization of the corresponding anthraquinones is analogous

from 4- (2-piperidino-propenal-3-yl) anthraquinone

2- (piperidino) -7a, 11 a-dihydro-benzo [de] anthracen-7-one;

from 4- (2- (1-hexyl-benzimidazol-2-yl-sulfanyl) -propenal-3-yl) -anthraquinone

2- (1-hexyl-benzimidazol-2-yl-sulfanyl) -7a, 11 a-dihydro-benzo [de] anthracen-7-one;

from 4- (2- (1-methyl-benzimidazol-2-yl) -propenal-3-yl) -anthraquinone the 2- (1-methyl-benzimidazol-2-yl) -7a, 11 a-dihydro-benzo [ de] anthracen- 7-one;

from 4- (2-bromo-propenal-3-yl) anthraquinone

2-bromo-7a, 11 a-dihydro-benzo [de] anthracen-7-one; from 4- (2- (1-methyl-benzimidazol-2-yl-sulfanyl) -propenal-3-yl) -anthraquinone that

2- (1-methyl-benzimidazol-2-yl-sulfanyl) -7a, 11a-dihydro-benzo [de] anthracen-7-one;

from 4- (2-morpholin-4-yl) anthraquinone

2- (morpholin-4-yl) -7a, 11 a-dihydro-benzo [de] anthracen-7-one;

from 4- (2-pyrrolidin-1-yl-propenal-3-yl) -anthraquinone the 2- (pyrrolidin-1-yl) -7a, 11a-dihydro-benzo [de] anthracen-7-one;

from 4- (3- (4-methyl-piperazino) propenal-3-yl) anthraquinone

3- (4-methyl-piperazino) -7a, 11 a-dihydro-benzo [de] anthracen-7-one;

from 4- (3-piperidino-propenal-3-yl) anthraquinone

3- (piperidino) -7a, 11 a-dihydro-benzo [de] anthracen-7-one;

from 4- (3- (1-hexyl-benzimidazol-2-yl-sulfanyl) -propenal-3-yl) -anthraquinone the 3- (1-hexyl-benzimidazol-2-yl-sulfanyl) -7a, 11 a- dihydrobenzo [de] anthracen-7-one;

from 4- (3- (1-methyl-benzimidazol-2-yl) -propenal-3-yl) -anthraquinone the 3- (1-methyl-benzimidazol-2-yl) -7a, 11 a-dihydro-benzo [ de] anthracen- 7-one;

from 4- (3-bromo-propenal-3-yl) anthraquinone

3-bromo-7a, 11 a-dihydro-benzo [de] anthracen-7-one;

from 4- (3- (1-methyl-benzimidazol-2-yl-sulfanyl) -propenal-3-yl) -anthraquinone that

3- (1-methyl-benzimidazol-2-yl-sulfanyl) -7a, 11 a-dihydro-benzo [de] anthracen-7-one;

from 4- (3-morpholin-4-yl) anthraquinone

3- (morpholin-4-yl) -7a, 11 a-dihydro-benzo [de] anthracen-7-one; from 4- (3-pyrrolidin-1-yl-propenaI-3-yl) -anthraquinone

3- (pyrrolidin-1-yl) -7a, 11a-dihydro-benzo [de] anthracen-7-one;

from 4- (3-ethoxy-propenal-3-yl) -anthraquinone the 3-ethoxy-7a, 11 a-dihydro-benzo [de] anthracen-7-one;

from 4- (2-methoxy-propenal-3-yl) anthraquinone

4-methoxy-7a, 11 a-dihydro-benzo [de] anthracen-7-one;

from 4- (2-phenylamino-propenal-3-yl) anthraquinone

4-phenylamino-7a, 11 a-dihydro-benzo [de] anthracen-7-one;

from 1, 6,8-trihydroxy-3-methyl-4- (1-methoxycarbonyl-2,2-dimethyl-3-oxo-5-methoxy-pent-4-en-5-yl) -anthraquinone 1 - (1st -Ethoxycarbonyl-prop-2-yl) -3-methoxy-4-methyl-6,8, 10-trihydroxy-7a, 11 a-dihydrobenzo [de] anthracen-7-one.

Example 2

Starting from 2.11 g of 1-N- (aminomethyl) imino-2-N- (2- (phenoxycarbonyloxy) ethyl) amino-anthraquinone in 180 ml of dimethyl sulfoxide (DMSO), the reflux is carried out in the customary manner for 10 hours Work up the 4-N- (2- (phenoxycarbonyloxy) ethyl) amino-7-oxo-7a, 11 a-dihydro-7H-benzo [e] - perimidine.

The same is obtained by cyclization

of 1 -N- (aminomethyl) imino-2-N- (2- (phenoxycarbonyloxy) ethyl) amino 6-amidino-anthraquinone the 4-N- (2- (phenoxycarbonyloxy) ethyl) amino-7 -oxo-9-amidino-7a, 11a- dihydro-7H-benzo [e] -perimidine;

of 1 -N- (aminomethyl) imino-4-cyclohexylamino-anthraquinone the 6-cyclohexylamino-7a, 11 a-dihydro-benzo [e] perimidin-7-one; of 1-N- (aminomethyl) imino-4-cyclohexyl-amino-6-amidinoanthraquinone

6-cyclohexylamino-9-amidino-7a, 11 a-dihydro-benzo [e] perimidin-7-one;

of 1-N- (aminomethyl) -imino-2-N- (2- (phenoxycarbonyloxy) -ethyl) -amino-6-guanidino-anthraquinone

4-N- (2- (phenoxycarbonyloxy) ethyl) amino-7-oxo-9-guanidino-

7a, 11a-dihydro-7H-benzo [e] -perimidine;

of 1-N- (aminomethyl) imino-4-cyclohexyl-amino ~ 8-guanidinoanthraquinone that

6-cyclohexylamino-11-guanidino-7a, 11 a-dihydro-benzo [e] perimidine-

7-one;

of 1 -N- (aminomethyl) imino-4-cyclohexyl-amino-6-guanidinoanthraquinone that

6-Cyclohexylamino-9-guanidino-7a, 11 a-dihydro-benzo [e] perimidin-7- one.

Example 3

A suspension of 1.2 g of 1-amino-4-cyan-7-amidino-anthraquinone in 120 ml of THF is mixed with 2 equivalents of formamide and refluxed for 6 hours. The mixture is allowed to cool and, after customary working up, 6-cyan-10-amidino-7a, 11-a-dihydro-benzo [e] peπ ^' midin-7-one is obtained.

One obtains analogously by conversion of formamide

with 1-amino-4-nitro-8-amidino-anthraquinone

6-nitro-11-amidino-7a, 11 a-dihydro-benzo [e] perimidin-7-one;

with 1-amino-3-methoxy-8-amidino-anthraquinone

5-methoxy-1 1 -aminino-7a, 11 a-dihydro-benzo [e] perimidin-7-one; with 1-amino-3-methoxy-6-methoxy-anthraquinone

5-methoxy-9-methoxy-7a, 11 a-dihydro-benzo [e] perimidin-7-one.

Example 4

A suspension of 2.1 g of 2-N-phenylamino-4-phenyl-5-chlorocarbonyl-quinoline in 100 ml of dichloromethane under addition of 0.9 g of AlCl ₃ was refluxed for 3 hours. The reaction mixture is then allowed to cool, poured onto ice water and the organic phase is separated off. You work up as usual and then evaporate to dryness. The 2-phenylamino-7a, 11a-dihydronaphtho [1, 2,3-de] -quinolin-7-one is obtained.

Analogously one obtains by ring closure under Friedel-Crafts conditions

from 2-chloro-3-ethoxycarbonyl-4-phenyl-5-chlorocarbonyl-quinoline

2-chloro-1-ethoxycarbonyl-7a, 11a-dihydro-7H-naphtho [1, 2,3-de] - quinolin-7-one;

from 2-chloro-3-ethoxycarbonyl-4-phenyl-5-chlorocarbonyl-6-amino-8-bromoquinoline

1-ethoxycarbonyl-2-chloro-4-bromo-6-amino-7a, 11 a-dihydro-7H-naphtho [1, 2,3-de] -quinolin-7-one;

from 2-chloro-3-ethoxycarbonyl-4- (4-amidino-phenyl) -5-chlorocarbonyl-quinoline

2-chloro-1-ethoxycarbony! -9-amidino-7a, 11 a-dihydro-7H-naphtho [1, 2,3-de] -quinolin-7-one;

from 2-fluoro-3-ethoxycarbonyl-4- (5-amidino-phenyl) -5-chlorocarbonyl-quinoline

2-fluoro-1-ethoxycarbonyl-10-amidino-7a, 11 a-dihydro-7H-naphtho [1, 2,3-de] -quinolin-7-one; from 2-nitro-3-ethoxycarbonyl-4- (4-amidino-phenyl) -5-chlorocarbonyl-quinoline

2-nitro-1-ethoxycarbonyl-9-amidino-7a, 11a-dihydro-7H-naphtho [1, 2,3-de] -quinolin-7-one.

Example 5

Analogously to Example 4, starting from 1- (1-chlorocarbonylprop-2-yl) -3-methoxy-4-methyl-6,8,10-trihydroxy-7a, 11a-dihydrobenzo [de] anthracen-7-one [obtainable according to Example 1 by subsequent conversion of the ester into the acid chloride] by cyclization under Friedel-Crafts conditions 3,5,7-trihydroxy-10-methoxy-1, 1, 9-trimethyl-1 H-benzo [cd] pyrene-2,6-dione.

The same is obtained by cyclization

of 1 - (1-chlorocarbonylprop-2-yl) -3-methoxy-4-amidino-8, 10-dicyan- 7a, 11 a-dihydrobenzo [de] anthracen-7-one the 5,7-dicyan-10- methoxy-9-amidino-1 H-benzo [cd] pyrene-2,6-dione;

of 1 - (1-chlorocarbonylprop-2-yl) -3-amino-4-amidino-7a, 11 a-dihydrobenzo [de] anthracen-7-one that

10-amino-9-amidino-1 H-benzo [cd] pyrene-2,6-dione.

Example 6

A solution of 3.21 g of 1, 5-di- (3-bromobenzoyl) naphthalene in 170 ml of toluene with the addition of 1, 4 g refluxed AICI _3, 2 g NaCl, 2 equivalents dinitrobenzene and introducing oxygen 8 hours . The reaction mixture is then allowed to cool, poured onto ice water and the organic phase is separated off. It is usually worked up and then evaporated to dryness. 2,9-Dibromo-3,4-dihydro-dibenzo [b, def] -chrysene-7, 14-dione is obtained. You get analog

2,9-dibromo-5-amidino-3,4-dihydro-dibenzo [b, def] -chrysene-7,14-dione;

2 _I 9-Dibromo-6-amidino-3 _l 4-dihydro-dibenzo [b, def] -chrysene-7,14-dione;

2-bromo-9-methoxy-5-guanidino-3,4-dihydro-dibenzo [b, def] -chrysene-7,14-dione;

3-chloro-6-amidino-3,4-dihydro-dibenzo [b, def] -chrysene-7,14-dione;

9-methoxy-5-guanidino-3,4-dihydro-dibenzo [b, def] -chrysene-7,14-dione;

9-methoxy-6-amidino-3,4-dihydro-dibenzo [b, def] -chrysene-7,14-dione.

Example 7

A solution of 1, 2 g of 1,8-di-nitro-3-methoxy-10-cyanodibenzo [def, mno] - chrysene in 170 ml of toluene is treated with the addition of 30 ml of glacial acetic acid at 60 ° with one equivalent of triacetyl manganese trichloride . After 4 hours, the reaction mixture is allowed to cool, poured onto ice water and the organic phase is separated off. The mixture is worked up in the customary manner and then evaporated to dryness, giving 1,8-di-nitro-3-methoxy-10-cyanodibenzo [def, mno] -chrysen-6,12-dione.

You get analog

from 1,8-di-methoxy-10-trifluoromethyl-dibenzo [def, mno] -chrysen das

1,8-di-methoxy-10-trifluoromethyl-dibenzo [def, mno] -chrysen-6, 12-dione

from 1,8-di-bromo-7-methoxy-10-cyanodibenzo [def, mno] -chrysen das

1,8-di-bromo-7-methoxy-10-cyanodibenzo [def, mno] -chrysen-6,12-dione

from 2,7-di-methoxy-10-bromo-dibenzo [def, mno] -chrysen the 2,7-di-methoxy-10-bromo-dibenzo [def, mno] -chrysen-6,12-dione. 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 jar contains 5 mg of active ingredient.

Example B: Suppositories

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

Example C: solution

A solution of 1 g of an active ingredient is prepared of the formula I, 9.38 g of NaH ₂ P0 ₄ • 2 H ₂ 0, 28.48 g Na ₂ HP0 ₄ ^• 12 H ₂ 0 and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D: ointment

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

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 the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.

Claims

claims

1. Compounds of formula I.

wherein

X CH, CR ⁶ or N,

Y CH, CR ⁷ or N,

R ¹ H, A, shark, OH, OA, NH ₂ , NHA, NA ₂ , NHR ⁸ , CN, N0 ₂ , CF ₃ , H ₂ NC (= NH) -, H ₂ NC (= NH) -NH- , H ₂ NC (= NOH) -NH-,

R ² , R ³ , R ⁴ and R ⁼ each independently of one another H, A, Hai, OH, OA, NH ₂ , NHA, NA ₂ , NHR ⁹ , CN, N0 ₂ , CF ₃ , H ₂ NC (= NH) -, H ₂ NC (= NH) -NH-, H ₂ NC (= NOH) -NH-, H ₂ NC (= NOH) -, where NHA, NH ₂ , -C (= NH) - NH ₂ , H ₂ NC (= NOH) -, H ₂ NC (= NOH) -NH and H ₂ NC (= NH) -NH- also simply by A-CO, Ar-alk-CO, AO-CO, Ar-alk-O -CO or can be substituted by a conventional amino protecting group,

R ⁸ A, Ar, A-CO, Ar-alk-CO, AO-CO or Ar-alk-O-CO,

R ¹⁰ (H, H), (H, A), (A, A), (H.Hal), (A.Hal) or

R ⁴ and R ⁷ together also -CO-CH ₂ -CH ₂ -, -CO-CH ₂ -CHA-, -CO-CH ₂ -CA ₂ -, -CO-CHA-CHA, -CO-CHA-CH ₂ - or -CO- -R ¹¹ ,

R ¹¹ H, A, shark, OH, OA, NH ₂ , NHA, NA ₂ , CN, N0 ₂ , or CF ₃ ,

A alkyl with 1 -6 carbon atoms,

Ar unsubstituted or single, double or triple by A, OH, OA,

Z shark, OH, OA, COOH, CN, COOA, CONH ₂ , CONHA or

CONA ₂ ,

Shark F, Cl, Br or I,

alk unbranched or branched alkylene with 1 -6 C atoms,

Het 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 once or twice by CN, shark, OH, OA, CF ₃ , A, NH ₂ , NHA, NA ₂ or N0 ₂ may be substituted

n 1, 2, 3 or 4,

mean,

and their physiologically acceptable salts and solvates.

2. Compounds of formula I according to claim 1

a) 2-bromo-7a, 11 a-dihydro-benzo [de] anthracen-7-one;

b) 4-N- (2- (phenoxycarbonyloxy) ethyl) amino-7-oxo-7a, 11 a-dihydro-7H-benzo [e] -perimidine;

c) 3- (4-methyl-piperazin-1-yl) -7a, 11 a-dihydro-benzo [de] anthracen-7-one;

d) 3-morpholin-4-yl-7a, 11 a-dihydro-benzo [de] anthracen-7-one;

e) 4, 10-dibromo-dibenzo [def, mno] chrysen-6, 12-dione;

f) 2,9-dibromo-3,4-dihydro-dibenzo [b, def] chrysene-7, 14-dione;

g) 2-chloro-7-oxo-7a, 11 a-dihydro-7H-naphtho [1, 2,3-de] quinoline-1-carboxylic acid ethyl ester;

and their physiologically acceptable salts and solvates.

3. A process for the preparation of compounds of the formula I as claimed in claim 1 and their salts, characterized in that

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

or.

(b) that a compound of formula II

L

wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ and Y have the meanings given in claim 1 and

L HC = 0, -CH ₂ -NH ₂ or -CH ₂ -NHR ⁶ ,

means

cyclized, or,

(b) that a compound of formula III

wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ and X and Y have the meanings given in claim 1 and

means

cyclized,

or,

(c) that a compound of formula IV

in which R ² , R ³ , R ⁴ and R ^{5 have} the meanings given in claim 1,

with a compound of formula V

wherein R ¹ and shark have the meanings given in claim 1,

implements or

(d) that binaphthyl derivatives of the formula VI

wherein R ¹ , R ² , R ³ and R ^{4 have} the meanings given in claim 1 and

means

cyclized,

or,

(f) that one radical R ¹ , R ² and / or R ^{3 is converted} into another radical R ¹ , R ² and / or R ³ by z. B.

- reduced a nitro group,

etherifies an OH group or subjects an OA group to ether cleavage,

alkylated a primary or secondary amino group, partially or completely hydrolyzed a CN group,

- cleaves an ester group or esterifies a carboxylic acid residue,

- or carries out a nucleophilic or electrophilic substitution,

and or

4. A process for the preparation of pharmaceutical preparations, characterized in that a compound of the formula I according to Claim 1 and / or one of its physiologically acceptable salts is brought into a suitable dosage form together with at least one solid, liquid or semi-liquid carrier or auxiliary.

5. Pharmaceutical preparation, characterized in that it contains at least one compound of the formula I as claimed in claim 1 and / or one of its physiologically acceptable salts.

6. Compounds of formula I according to claim 1 and their physiologically acceptable salts as GPIIb / llla antagonists for combating thrombosis, heart attack, coronary heart disease and arteriosclerosis.

7. Compounds of formula I according to claim 1 and their physiologically acceptable salts as α _v -integrin inhibitors for combating pathologically angiogenic diseases, tumors, osteoporosis, inflammation and infections.

8. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts for the manufacture of a medicament.

9. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts in the Combating thrombosis, heart attack, coronary heart disease, arteriosclerosis, apoplexy, tumors, osteoporosis, inflammation and infections.