DE19626701A1 - New pyrrolidone, imidazolone, furanone or thiophenone derivatives - Google Patents

Abstract

5-Membered azacyclic derivatives (I) and their salts are new. W = C(R<16>)-D-B-A-R<1> (a), C=C(R<16>)-D-B-A-R<1> (b) or a group of formula (c) or (d); the ring of formula (e) is saturated or partly or fully unsaturated, and optionally contains 1 or 2 N, O and/or S atoms and is optionally mono-, di- or trisubstituted by R<16> or mono- or disubstituted by =Q; Y = CQ or CH2; Z = N(R<0>), Q or CH2; A = bond, 1-8C alkanediyl, CR<2>=NNR<2>, NR<2>CQNR<2>, QCQ'NR<2>, NR<2>S(O)nNR<2>, OS(O)nNR<2>, S(O)nNR<2>, 3-12 cycloalkanediyl, C?=C, NR<2>CO, CONR<2>, NR<2>CO-5-14C arylene, O, S(O)n, 5-14C arylene, CO, CO-5-14C arylene, NR<2>, NR<2>SO2, OCO, COO, N=CR<2> CR<2>=N, CR<2>=CR<3> or S(O)n-5-14C arylene (all optionally substituted by NR<2> and/or by 1 or 2 1-8C alkanediyl); Q, Q' = O or S; B = bond, 1-8C alkanediyl, 5-10C arylene, 3-8C cycloalkanediyl, C?=C, NR<2>, CO, CONR<2>, NR<2>CO, NR<2>-CQ-NR<2>, OCO, COO, SO, SO2, SONR<2>, SO2NR<2>, NR<2>SO, NR<2>SO2, Q or CR<2>=CR<3> (all optionally mono- or disubstitute d by 1-6C alkanediyl) or a divalent residue of a 5-6 membered saturated or unsaturated ring containing 1 or 2 N atoms (optionally mono- or disubstituted substituted by 1-6C alkyl or =Q); D, F = bond, 1-8C alkanediyl, 5-10C arylene, Q, NR<2>, CONR<2>, NR<2>CO, NR<2>CQNR<2>, OCO, COO, CQ, SO, SO2, SO2NR<2>, NR<2>SO, NR<2>SO2, CR<2>=CR<3>, C?=C, CR<2>=NNR<2>, N=CR<2>, CR<2>=N or CHOH (all optionally mono- or disubstituted by 1-8C alkanediyl, CR<2>=CR<3> or 5-6C arylene); E = bond, 1-6C alkanediyl, 2-6C alkenediyl, 2-6C alkynediyl, phenylene, phenylene-1-3C alkanediyl or 1-3C alkanediyl-phenylene; G = CR<4>R<5>(CR<6>R<7>)p(CH2)qR<10>; L = C(R<16>) or N; R<0> = H, 1-8C alkyl (optionally substituted by 3-12C cycloalkyl or 5-14C aryl), 1-8C alkylcarbonyl, 3-12C cycloalkyl-carbonyl, (3-12C cycloalkyl- or 5-14C aryl-substituted) 1-6C alkylcarbonyl, 5-14C aryl-carbonyl, 3-12C cycloalkyl or 5-14C aryl (where all alkyl are optionally substituted by 1 or more F); R<1> = NR<2>CR<2>(=NR<2>), C(=NR<2>)NR<2>R<3>, NR<2>C(=NR<2>)NR<2>R<3>, or a 4-14 membered mono- or polycyclic optionally aromatic ring (optionally containing 1-4 N, O and/or S and optionally substituted by R<12>-R<15>); R<2>, R<3> = H. 1-10C alkyl (optionally substituted by 1 or more F), 3-12C cycloalkyl, 3-12C cycloalkyl-1-8C alkyl, 5-14C aryl, 5-14C aryl-1-8C alkyl, NH2; NR<9>OR<8>, R<9>OR<8>, R<9>COOR<8>, R<9>-5-14C aryl-R<8>, R<9>N(R<8>)2, R<9>-NR<8>-(1-8C hydroxyalkyl), R<9>CON(R<8>)2, R<9>NR<8>COR<8>, R<9>COR8, C(=NR<8>)N(R<8>)2; NR<8>C(=NR<8>)N(R<8>)2 or (1-18C alkyl)-COO-1-6C alkoxycarbonyl; R<4>-R<7> = H, F, OH, 1-8C alkyl, 3-12C cycloalkyl, 3-12C cycloalkyl-1-8C alkyl, R<9>QR<8>, R<9>OCOR<8>, R<9>COOR<8>, R<9>-5-14C aryl-R<8>, R<9>N(R<2>)R<8>, R<9>N(R<8>)2, R<9>OCONR<8>R<2>, R<9>N(R<2>)S(O)nR<8>, R<9>NR<2>COQR<8>, R<9>NR<2>COR<8>, R<9>N(R<2>)CON(R<2>)R<8>, R<9>N(R<2>)S(O)nNR<2>R<8>, R<9>S(O)nR<8>, R<9>NR<2>COSR<8>, R<9>COR<8>, R<9>CONR<2>R<8> or R<9>S(O)nNR<2>R<8>; R<8> = H, 1-8C alkyl (optionally substituted by 3-12C cycloalkyl or 5-14C aryl), 3-12C cycloalkyl or 5-14C aryl (where all alkyl are optionally substituted by 1 or more F); R<9> = bond or 1-8C alkanediyl; R<10> = CQR<11>, S(O)nR<11>, P(O)nR<11> or a 4-8 membered saturated or unsaturated heterocycle containing 1-4 N, O and/or S atoms; R<11> = OH, 1-8C alkoxy, 5-14C aryl-1-8C alkoxy, 5-14C aryloxy, 1-8C alkylcarbonyloxy-1-4C alkoxy, 5-14C aryl-1-8C alkylcarbonyloxy-1-4C alkoxy, NH2, mono- or di-1-8C alkylamino, 5-14C aryl-1-8C alkylamino, 1-8C dialkylaminocarbonylmethoxy, 5-14C aryl-1-8C dialkylaminocarbonylmethoxy, 5-14C arylamino or a D- or L-amino acid; R<12>-R<15> = H, 1-10C alkyl (optionally substituted by one or more F), 3-12C cycloalkyl, 3-12C cycloalkyl-1-8C alkyl, 5-14C aryl, 5-14C aryl-1-8C alkyl, NH2, R<9>OR<8>, R<9>COOR<8>, R<9>N(R<8>)2, R<9>-5-14C aryl-R<8>; R<9>-NR<2> (1-8C hydroxyalkyl), R<9>CON(R<2>)R<8>, R<9>N(R<2>)COR<8>, R<9>COR<8>, NR<2>C(=NR<3>)-NR<2>R<3>, C(=NR<2>)NR<2>R<3> or Q; or 2 of R<12>-R<15> which are adjacent form -OCH2O-, -OCH2CH2O- or -OC(CH3)2O-; R<16> = H, 1-10C alkyl optionally substituted by 1 o

Description

The present invention relates to compounds of the formula I and their physiologically tolerable salts and those containing such compounds pharmaceutical preparations, their preparation and use as Remedies, especially as inhibitors of bone resorption Osteoclasts, as inhibitors of tumor growth and tumor metastasis, as an anti-inflammatory, for the treatment or prophylaxis of cardiovascular Diseases such as arteriosclerosis or restenosis, for treatment or Prophylaxis of nephropathies and retinopathies, such as B. diabetic Retinopathy, as well as vitronectin receptor antagonists for treatment and Prevention of diseases based on the interaction between Vitronectin receptors and their ligands in cell-cell or cell matrix Interaction processes are based. The invention further relates to the use of Compounds of formula I and their physiologically tolerable salts and pharmaceutical preparations containing such compounds as medicinal products to alleviate or cure diseases at least in part by a undesirable level of bone resorption, angiogenesis, or proliferation of Cells of the smooth vascular muscles are caused.

Human bones are subject to constant dynamic Remodeling process that includes bone resorption and bone building. This Processes are controlled by specialized cell types. Bone structure relies on the deposition of bone matrix by osteoblasts, Bone resorption is based on the breakdown of bone matrix Osteoclasts. The majority of bone diseases are based on one disturbed balance between bone formation and bone resorption.  

Osteoporosis is characterized by a loss of bone matrix. Activated osteoclasts are much nuclei with a diameter up to 400 µm, remove the bone matrix. Activated osteoclasts attach themselves to the Surface of the bone matrix and secrete proteolytic enzymes and Acids in the so-called "sealing zone", the area between their Cell membrane and the bone matrix. The acidic environment and the proteases cause the bone to degrade.

The compounds of formula I according to the invention inhibit the Bone resorption by osteoclasts. Bone Diseases Against which Compounds according to the invention can be used above all Osteoporosis, hypercalcaemia, osteopenia, e.g. B. caused by metastases, Dental diseases, hyperparathyroidism, periarticular erosions rheumatoid arthritis and Paget's disease.

Furthermore, the compounds of formula I for relief, avoidance or Therapy of bone diseases caused by a glucocorticoid, steroid or Corticosteroid therapy or due to a lack of sex hormone (s) are caused, used. All of these diseases are through Bone loss characterized on the imbalance between Bone build-up and bone loss based.

Studies have shown that the attachment of osteoclasts to the bones controlled by integrin receptors on the cell surface of osteoclasts becomes.

Integrins are a super family of receptors which include the fibrinogen receptor α _IIb β₃ on platelets and the vitronectin receptor α _v β₃. The vitronectin receptor α _v β₃ is a membrane-bound glycoprotein, which is expressed on the cell surface of a number of cells such as endothelial cells, cells of the smooth vascular muscles, osteoclasts and tumor cells. The vitronectin receptor α _v β₃, which is expressed on the osteoclast membrane, controls the process of attachment to the bone and bone resorption and thus contributes to osteoporosis.

α _v β₃ binds to bone matrix proteins such as osteopontin, bone sialoprotein and thrombospontin, which contain the tripeptide motif Arg-Gly-Asp (or RGD).

Horton and co-workers describe RGD peptides and an anti Vitronectin Receptor Antibodies (23C6) that reduce tooth decay by osteoclasts and inhibit osteoclast migration (Horton et al., Exp. Cell. Res. 1991, 195, 368). Sato et al. describe in J. Cell Biol. 1990, 111, 1713 Echistatin, an RGD peptide from snake venom, as a potent inhibitor of Bone resorption in a tissue culture and as an inhibitor of osteoclasts Attachment to the bones. Fischer et al. (Endocrinology, 1993, 132, 1411) were able to show in the rat that echistatin also supports bone resorption in vivo inhibits.

The vitronectin receptor α _v β₃ on human cells of the smooth vascular muscles of the aorta stimulates the migration of these cells into the neointima, which ultimately leads to arteriosclerosis and restenosis after angioplasty (Brown et al., Cardiovascular Res. 1994, 28, 1815).

Brooks et al. (Cell 1994, 79, 1157) showed that antibodies against α _v β₃ or α _v β₃ antagonists can cause tumor shrinkage by inducing apoptosis of blood vessel cells during angiogenesis. Chersh et al. (Science 1995, 270, 1500) describe anti α _v β₃ antibodies or α _v β₃ antagonists which inhibit bFGF-induced angiogenesis processes in the rat eye, which could be therapeutically useful in the treatment of retinopathies.

In EP-A 449 079, EP-A 530 505, EP-A 566 919, WO 93/18057 are hydantoin derivatives, 5-ring heterocycles substituted in WO 95/14008 described that have antiplatelet effects.

In patent application WO 94/12181 substituted aromatic or non-aromatic ring systems, heterocycles substituted in WO 94/08577 as Fibrinogen receptor antagonists and platelet aggregation inhibitors described. From EP-A-052 856 and EP-A-052 857 are aminoalkyl or Heterocyclyl-substituted phenylalanine derivatives, from WO 95/32710 aryl derivatives known as inhibitors of bone resorption by osteoclasts. In WO 95/28426 RGD peptides are used as inhibitors of bone resorption, Angiogenesis and restenosis are described. WO 96/00574 describes Benzodiazepines, WO 96/00730 fibrinogen receptor antagonist template, especially benzodiazepines, which are linked to a nitrogen-bearing 5-ring are called vitronectin receptor antagonists.

The present invention relates to 5-ring heterocycles general formula I,

in which mean:

W R¹-A-B-D-C (R¹⁶), R¹-A-B-D-C (R¹⁶) = C,

or

being the ring systems

Can contain 1 or 2 heteroatoms from the series N, O, S, can be saturated or mono- or polyunsaturated and can be substituted with 1-3 substituents from R¹⁶ or mono- or disubstituted with double-bonded O or S;
YC = O, C = S or -CH₂-;
ZN (RO), O, S or -CH₂-;
A is a direct bond, (C₁-C₈) alkyl, -NR² N = CR²-, -NR²-C (O) -NR²-, -NR²-C (O) O-, -NR²-C (O) S- , -NR²-C (S) -NR²-, -NR²-C (S) -O-, -NR²-C (S) -S-, -NR²-S (O) _n -NR²-, -NR²-S (O) _n -O-, -NR²-S (O) _n -, (C₃-C₁ ₂) cycloalkyl, -C≡C-, -NR²-C (O) -, -C (O) -NR²- , - (C₅-C₁₄) aryl-C (O) -NR²-, -O-, -S (O) _n -, - (C₅-C₁₄) - aryl-, -CO-, (C₅-C₁₄) - Aryl-CO-, -NR²-, -SO₂-NR², -CO₂-, -N = CR², -R²C-N-, -CR² = CR³-, - (C₅-C₁₄) -aryl-S (O) _n - , each of which can be substituted by NR² and / or mono- or disubstituted by (C₁-C₈) alkyl, such as. B. - (C₁-C₈) alkyl-CO-NR²- (C₁-C₈) alkyl, - (C₁-C₈) alkyl-CO-NR²- or -CO-NR²- (C₁-C₈) alkyl;
B is a direct bond, (C₁-C₈) -alkyl, -CR² = CR³- or -C≡C-, optionally substituted once or twice by (C₁-C₈) -alkyl, or a divalent radical of a 5- or 6- membered saturated or unsaturated ring containing 1 or 2 nitrogen atoms and can be mono- or disubstituted by (C₁-C₆) alkyl or doubly bound oxygen or sulfur;
D is a direct bond, (C₁-C₈) alkyl or -O-, -NR²-, -CO-NR²-, -NR²-CO-, -NR²-C (O) -NR²-, -NR²-C (S ) -NR²-, -OC (O) -, -C (O) O-, -CO-, -CS-, -S (O) -, -S (O) ₂-, -S (O) ₂- NR²-, -NR²-S (O) -, -NR²-S (O) ₂-, -S-, -CR² = CR³-, -C≡C-, -NR²-N = CR²-, -N = CR² , R²C-N- or -CH (OH) -, which can each be mono- or disubstituted by (C₁-C₈) alkyl;
E is a direct bond, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, phenyl, phenyl- (C₁-C₃) alkyl, (C₁-C₃) alkylphenyl ;
F is defined as D;

LC (R¹⁶) or N;
R ° H, (C₁-C₈) alkyl, which is optionally mono- or polysubstituted, (C₃-C₁₂) cycloalkyl, (C₃-C₁₂) cycloalkyl- (C₁-C₈) alkyl, (C₅- C₁₄) aryl, (C₅-C₁₄) aryl- (C₁-C₈) alkyl or (C₁-C₈) alkyl-C (O) -, (C₃-C₁₂) -cycloalkyl-C (O), (C₃ -C₁₂) -cycloalkyl- (C₁-C₆) -alkyl-C (O), (C C-C₁₄) -aryl-C (O) -, (C₅-C₁₄) -aryl- (C₁-C₆) -alkyl-C (O), where the alkyl radicals can be substituted one or more times by F;
R¹ R²-C (= NR²) NR²-, R²R³N-C (= NR²) -, R²R³N-C (= NR²) -NR², or a 4- 10-membered mono- or polycyclic aromatic or non-aromatic ring system, which optionally 1-4 Can contain heteroatoms from the series N, O and S and can optionally be mono- or polysubstituted by substituents from the series R¹², R¹³, R¹⁴ and R¹⁵;
R², R³ independently of one another H, (C₁-C₁₀) alkyl which is optionally mono- or polysubstituted by F, (C₃-C₁₂) cycloalkyl, (C₃-C₁₂) - cycloalkyl- (C₁-C₈) alkyl, (C₅-C₁₄) aryl, (C₅-C₁₄) aryl (C₁-C₈) alkyl, H₂N, R⁸ONR⁹, R⁸OR⁹, R⁸OC (O) R⁹, R⁸- (C₅-C₁₄) aryl-R⁹, R⁸R⁸NR⁹, HO- (C₁- C₈) alkyl-NR⁸R⁹, R⁸R⁸NC (O) R⁹, R⁸C (O) NR⁸R⁹, R⁸C (O) R⁹, R⁸R⁸N- C (= NR⁸) -, R⁸R⁸N C (= NR⁸) -NR⁸- or (C₁ -C₁₈) alkylcarbonyloxy- (C₁-C₆) alkoxycarbonyl;
R⁴, R⁵, R⁶, R⁷ independently of one another H, F, OH, (C₁-C₈) alkyl, (C₃-C₁₂) cycloalkyl, (C₃-C₁₂) cycloalkyl- (C₁-C₈) alkyl, or R⁸OR⁹, R⁸SR⁹, R⁸CO₂R⁹, R⁸OC (O) R⁹, R⁸- (C₅-C₁₄) aryl-R⁹, R⁸N (R²) R⁹, R⁸R⁸NR⁹, R⁸N (R²) C (O) OR⁹, R⁸S (O) _n N (R²) R⁹ , R⁸OC (O) N (R²) R⁹, R⁸C (O) N (R²) R⁹, R⁸N (R²) C (O) N (R²) R⁹, R⁸N (R²) S (O) _n N (R²) R⁹, R⁸S (O) _n R⁹, R⁸SC (O) N (R²) R⁹, R⁸C (O) R⁹, R⁸N (R²) C (O) R⁹, R⁸N (R²) S (O) _n R⁹;
R⁸ H, (C₁-C₈) alkyl, (C₃-C₁₂) cycloalkyl, (C₃-C₁₂) cycloalkyl- (C₁-C₈) alkyl, (C₅-C₁₄) aryl, (C₅-C₁₄) aryl - (C₁-C₈) alkyl, where the alkyl radicals can be substituted one or more times by F;
R⁹ is a direct bond or (C₁-C₈) alkyl;
R¹⁰ C (O) R¹¹, C (S) R¹¹, S (O) _n NR¹¹, P (O) _n R¹¹ or a four to eight membered, saturated or unsaturated heterocycle, of 1, 2, 3 or 4 heteroatoms from the series N, O, S contains such. B. tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiadiazolyl;
R¹¹ OH, (C₁-C₈) alkoxy, (C₅-C₁₄) aryl- (C₁-C₈) alkoxy, (C₅-C₁₄) aryloxy, (C₁- C₈) alkylcarbonyloxy- (C₁-C₄) alkoxy , (C₅-C₁₄) aryl- (C₁-C₈) - alkylcarbonyloxy- (C₁-C₆) alkoxy, NH₂, mono- or di- (C₁-C₈-alkyl) - amino, (C₅-C₁₄) aryl- (C₁-C₈) alkylamino, (C₁-C₈) dialkylaminocarbonylmethyloxy, (C₅-C₁₄) aryl- (C₁-C₈) dialkylaminocarbonylmethyloxy or (C₅-C₁₄) arylamino or an L- or D-amino acid;
R¹², R¹³, R¹⁴, R¹⁵ independently of one another H, (C₁-C₁₀) alkyl, which is optionally mono- or polysubstituted, (C₃-C₁₂) cycloalkyl, (C₃-C₁₂) cycloalkyl- (C₁-C₈ ) alkyl, (C₅-C₁₄) aryl, (C₅-C₁₄) aryl- (C₁-C-) alkyl, H₂N, R⁸ONR⁹, R⁸OR⁹, R⁸OC (O) R⁹, R⁸R⁸NR⁹, R⁸- (C₅- C₁₄) - Aryl-R⁹, HO- (C₁-C₈) -alkyl-N (R²) R⁹, R⁸N (R²) C (O) R⁹, R⁸C (O) N (R²) R⁹, R⁸C (O) R⁹, R²R³N-C ( = NR²) -NR²-, R²R³N-C (= NR²), = O, = S;
R¹⁶ H, (C₁-C₁₀) alkyl, which is optionally mono- or polysubstituted, (C₃-C₁₂) cycloalkyl, (C₃-C₁₂) cycloalkyl- (C₁-C₈) alkyl, (C₅-C₁₄ ) Aryl, (C₅-C₁₄) aryl- (C₁-C₈) alkyl, (C₂-C₂₀) alkenyl, (C₂-C₁₀) alkynyl;
m 1, 2, 3,4, 5 or 6;
n 1 or 2;
p, q independently of one another 0 or 1;
and their physiologically tolerable salts,
with the exception of compounds in which R¹-ABDC (R¹⁶) or R¹-ABDC (R¹⁶) -C are equal to R¹-KC (R¹⁶) or R¹-K-CH = C (R¹⁶ = H), where
here
R¹ is X-NH-C (= NH) - (CH₂) _p , X¹-NH- (CH₂) _p or 4-imidazolyl-CH₂-,
where p can be an integer from 0 to 3,
X is hydrogen, (C₁-C₆) alkyl, (C₁-C₆) alkylcarbonyl, (C₁-C₆) alkoxycarbonyl, (C₁-C₁₈) alkylcarbonyloxy- (C₁-C₆) alkoxycarbonyl, (C₆- C₁₄) arylcarbonyl , (C₆-C₁₄) aryloxycarbonyl, (C₆-C₁₄) aryl- (C₁-C₆) - alkoxycarbonyl, hydroxy, (C₁-C₆) alkoxy, (C₆-C₁₄) aryl- (C₁-C₆) alkoxy , or amino, where the aryl groups in X represent pure, optionally mono- or polysubstituted carbocycles.

X¹ (C₄-C₁₀) arylcarbonyl, (C₄-C₁₀) aryloxycarbonyl, (C₄-C₁₀) aryl- (C₁-C₆) - alkoxycarbonyl, (C₄-C₁₀) aryl- (C₁-C₆) alkoxy or R′-NH-C (= N-R ′ ′) means, where R 'and R' 'independently of one another the meanings of X have and the aryl groups in X₁ pure, optionally one or represent multiply substituted carbocycles.

K (C₁-C₆) alkyl, (C₃-C₇) cycloalkyl, phenyl, phenyl- (C₁-C₆) alkyl, (C₁-C₆) - Alkyl-phenyl, phenyl- (C₂-C₆) alkenyl or a divalent radical of a 5- or 6-membered saturated or unsaturated ring, the 1 or 2 Contain nitrogen atoms and once or twice by (C₁-C₆) alkyl or substituted double bonded oxygen or sulfur can.

The alkyl radicals occurring in the substituents can be straight-chain or be branched, saturated or mono- or polyunsaturated. The same applies to residues derived therefrom, such as. B. alkoxy. Cycloalkyl radicals can be mono-, bi- or tricyclic.

Monocyclic cycloalkyl radicals are in particular cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, but also by for example, (C₁-C₄) alkyl may be substituted. As examples of substituted cycloalkyl radicals are 4-methylcyclohexyl and 2,3-Dimethylcyclopentyl called.

Bicyclic and tricyclic cycloalkyl radicals can be unsubstituted or in any suitable positions by one or more oxo groups and / or one or more identical or different (C₁-C₄) alkyl groups, e.g. B. methyl or Isopropyl groups, preferably methyl groups, may be substituted. The free Binding of the bicyclic or tricyclic radical can be in any position of the molecule, so the rest can have a bridgehead atom or a Atom bound in a bridge. The free bond can also be in a  any stereochemical position, for example in an exo or an endo position.

Examples of basic bodies of bicyclic ring systems are norbornane (= Bicyclo [2.2.1] heptane), the bicyclo [2.2.2] octane and the bicyclo [3.2.1] octane. An example of a system substituted by an oxo group is the camphor (= 1,7,7-trimethyl-2-oxobicyclo [2.2.1] heptane).

Examples of basic bodies of tricyclic systems are twistan (= tricyclo [4.4.0.0 ^3.8 ] decane, adamantane (= tricyclo [3.3.1.1 ^3.7 ] decane), noradamantane (= tricyclo [3.3.1.0 ^3.7 ] -nonane), tricyclo [2.2.1.0 ^2.6 ] heptane, tricyclo [5.3.2.0 ^4.9 ] dodecane, tricyclo [5.4.0.0 ^2.9 ] undecane or tricyclo [5.5.1.0 ^3.11 ] tridecan.

Aryl are, for example, phenyl, naphthyl, biphenylyl, anthryl or fluorenyl, with 1-naphthyl, 2-naphthyl and especially phenyl being preferred. Aryl radicals, in particular phenyl radicals, can be preferred one or more times one, two or three times, by identical or different residues from the series (C₁-C₈) alkyl, especially (C₁-C₄) alkyl, (C₁-C₈) alkoxy, especially (C₁-C₄) alkoxy, halogen, such as fluorine, chlorine and bromine, nitro, amino, Trifluoromethyl, hydroxy, methylenedioxy, cyano, hydroxycarbonyl, Aminocarbonyl, (C₁-C₄) alkoxycarbonyl, phenyl, phenoxy, benzyloxy, (R¹⁷O) ₂P (O), (R¹⁷O) ₂P (O) -O-, with R¹⁷ = H, (C₁-C₁₀) alkyl, (C₆-C₁₄) aryl or (C₆-C₁₄) aryl (C₁-C₈) alkyl or tetrazolyl may be substituted.

In monosubstituted phenyl radicals, the substituent in 2-, 3- or the 4-position, with the 3- and the 4-position being preferred. Is Phenyl substituted twice, the substituents in 1,2-, 1,3- or 1.4 position to each other. Preferred are doubly substituted Phenyl residues the two substituents in the 3- and the 4-position, based on the link, arranged.  

Aryl groups can also be mono- or polycyclic aromatic ring systems represent, wherein 1 to 5 carbon atoms are replaced by 1 to 5 heteroatoms can, such as B. 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, furyl, thienyl, Imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, tetrazolyl, Pyridyl, pyrazinyl, pyrimidinyl, indolyl, isoindolyl, indazolyl, phthalazinyl, Quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, β-carbolinyl, or a benz-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivative these leftovers. These heterocycles can have the same substituents as those above mentioned carbocyclic aryl systems.

In the series of these aryl groups are preferably mono- or bicyclic aromatic ring systems with 1-3 heteroatoms from the series N, O, S, with 1-3 substituents from the series (C₁-C₆) alkyl, (C₁-C₆) alkoxy, F, Cl, NO₂, NH₂, CF₃, OH, (C₁-C₄) alkoxycarbonyl, phenyl, phenoxy, benzyloxy or Benzyl can be substituted.

Mono- or bicyclic aromatic 5-10 are particularly preferred link ring systems with 1-3 heteroatoms from the series N, O, S, with 1 - 2 substituents from the series (C₁-C₄) alkyl, (C₁-C₄) alkoxy, phenyl, phenoxy, Benzyl or benzyloxy can be substituted.

Preference is also given to compounds of the formula I which have a lipophilic radical R⁴, R⁵, R⁶ or R⁷ such as. B. benzyloxycarbonylamino, Wear cyclohexylmethylcarbonylamino etc.

L or D amino acids can be natural or unnatural amino acids. Α-Amino acids are preferred. Examples include (see Houben-Weyl, Methods of Organic Chemistry, Volumes XV / 1 and 2, Georg Thieme Verlag, Stuttgart, 1974):
Aad, Abu, γAbu, ABz, 2ABz, εAca, Ach, Acp, Adpd, Ahb, Aib, βAib, Ala, βAla, ΔAla, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Cit, Cys, (Cys) ₂, Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Fel, Gln, Glu, Gly, Guv , hAla, hArg, hCys, hGln, hGlu, His, hIle, hLeu, hLys, hMet, hPhe, hPro, hSer, hThr, hTrp, hTyr, Hyl, Hyp, 3Hyp, Ile, Ise, Iva, Kyn, Lant, Lcn , Leu, Lsg, Lys, βLys, ΔLys, Met, Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, ΔPro, Pse, Pya, Pyr, Pza , Qin, Ros, Sar, Sec, Sem, Ser, Thi, βThi, Thr, Thy, Thx, Tia, Tle, Tly, Trp, Trta, Tyr, Val, tert. Butylglycine (Tbg), neopentylglycine (Npg), cyclohexylglycine (Chg), cyclohexylalanine (Cha), 2-thienylalanine (Thia), 2,2-diphenylaminoacetic acid, 2- (p-tolyl) -2-phenylaminoacetic acid, 2- (p- Chlorphenyl) amino acetic acid.
further:
Pyrrolidine-2-carboxylic acid; Piperidine-2-carboxylic acid; 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; Decahydroisoquinoline-3-carboxylic acid; Octahydroindole-2-carboxylic acid; Decahydroquinoline-2-carboxylic acid; Octahydrocyclopenta [b] pyrrole-2-carboxylic acid; 2-azabicyclo [2.2.2] octane-3-carboxylic acid; 2-azabicyclo [2.2.1] heptane-3-carboxylic acid; 2-azabicyclo [3.1.0] hexane-3-carboxylic acid; 2-azaspiro [4.4] nonane-3-carboxylic acid; 2-azaspiro [4.5] decane-3-carboxylic acid; Spiro (bicyclo [2.2.1] heptane) -2,3-pyrrolidine-5-carboxylic acid; Spiro (bicyclo [2.2.2] octane) -2,3-pyrrolidine-5-carboxylic acid; 2-azatricyclo [4.3.0.1 ^6,9 ] decane-3-carboxylic acid; Decahydrocyclohepta [b] pyrrole-2-carboxylic acid; Decahydrocycloocta [c] pyrrole-2-carboxylic acid; Octahydrocyclopenta [cipyrrole-2-carboxylic acid; Octahydroisoindole-1-carboxylic acid; 2,3,3a, 4,6a-hexahydrocyclopenta [b] pyrrole-2-carboxylic acid; 2,3,3a, 4,5,7a-hexahydroindole-2-carboxylic acid; Tetahydrothiazole-4-carboxylic acid; Isoxazolidine-3-carboxylic acid; Pyrazolidine-3-carboxylic acid, hydroxypyrrolidine-2-carboxylic acid, all of which can optionally be substituted (see the following formulas):

The heterocycles on which the above radicals are based are, for example known from US-A-4,344,949; US-A 4,374,847; US-A 4,350,704; EP-A 29,488; EP-A 31,741; EP-A 46,953; EP-A 49,605; EP-A 49,658; EP-A 50,800; EP-A 51,020; EP-A 52,870; EP-A 79,022; EP-A 84,164; EP-A 89,637; EP-A 90,341; EP-A 90,362; EP-A 105,102; EP-A 109,020; EP-A 111,873; EP-A 271,865 and EP-A 344,682.

Furthermore, the amino acids can also be present as esters or amides, such as. B. Methyl ester, ethyl ester, isopropyl ester, isobutyl ester, tert-butyl ester, Benzyl ester, ethyl amide, semicarbazide or (ω) -amino- (C₂-C₈) alkyl amide.

Functional groups of the amino acids can be protected. Suitable Protecting groups such as B. urethane protecting groups, carboxyl protecting groups and Side chain protection groups are available from Hubbuch, contacts (Merck) 1979, No. 3, Pages 14 to 23 and at Büllesbach, contacts (Merck) 1980, No. 1, pages 23 to 35 described. The following may be mentioned in particular: Aloc, Pyoc, Fmoc, Tcboc, Z, Boc, Ddz, Bpoc, Adoc, Msc, Moc, Z (NO₂), Z (Haln), Bobz, Iboc, Adpoc, Mboc, Acm, tert.-butyl, OBzl, ONbzl, OMbzl, Bzl, Mob, Pic, Trt.

Physiologically acceptable salts of the compounds of general formula I are in particular pharmaceutically usable or non-toxic salts. Such salts are used, for example, by compounds of the general Formula I, which acidic groups, e.g. As carboxy, contain, with alkali or Alkaline earth metals formed such. B. Na, K, Mg and Ca, and with physiological compatible organic amines, such as. B. triethylamine, ethanolamine or Tris- (2-hydroxy-ethyl) amine.

Compounds of general formula I, which basic groups, for. Legs Form amino group, an amidino group or a guanidino group with inorganic acids, such as. B. hydrochloric acid, sulfuric acid or Phosphoric acid, and with organic carboxylic or sulfonic acids, such as. B.  Acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, Methanesulfonic acid or p-toluenesulfonic acid salts.

The compounds of general formula I according to the invention can be optical active carbon atoms, which are independently R or S configurations may have contained and thus in the form of pure enantiomers or pure Diastereomers or in the form of mixtures of enantiomers or Mixtures of diastereomers are present. Both pure enantiomers and Mixtures of enantiomers and diastereomers and mixtures of diastereomers are the subject of the present invention.

The compounds of general formula I according to the invention can be used also contain mobile hydrogen atoms, i.e. in different tautomeric forms exist. These tautomers are also the subject of present invention.

The compounds of formula I according to the invention, if A, D or F independently of one another -CR² = CR³, NR² N = CR²-, -N = CR² or -R²C = N- and / or B is CR² = CR³-, and / or W is R¹-A-B-D-C (R¹⁶) -C, as E / Z- Mixtures of isomers are present. The present invention relates to both pure E or Z isomers and E / Z isomer mixtures. Diastereomers, including E / Z isomers can be chromatographed into the individual isomers be separated. Racemates can be determined either by chromatography chiral phases or by resolution into the two enantiomers be separated.

Compounds of the formula I are preferred in which:
W R¹-ABDR (R¹⁶), R¹-ABD (R¹⁶) = C,

being the ring systems

Contain 1 or 2 heteroatoms from the series N, O, can be saturated or monounsaturated and can be substituted with 1 or 2 substituents from R¹⁶;
YC = O, C = S or -CH₂-;
ZN (R °), O or -CH₂-;
A is a direct bond, (C₁-C₆) alkyl, -NR² N = CR²-, -NR²-C (O) -NR²-, -NR²-C (O) O-, -NR²-C (O) S- , -NR²-C (S) -NR²-, -NR²-C (S) -O-, -NR²-C (S) -S-, NR²-S (O) _n -NR²-, -NR²-S ( O) _n -O-, -NR²-S (O) _n - or (C₃-C₈) -cycloalkyl, -C≡C-, -NR²-C (O) -, -C (O) -NR²-, - (C₅-C₁₂) aryl-C (O) -NR²-, -O-, -S (O) _n -, - (C₅-C₁₂) aryl-, -CO-, - (C₅-C₁₂) aryl -CO-, -NR²-, -SO₂-NR², -CO₂-, -N = CR²-, -R²C = N-, -CR² = CR³-, - (C₅-C₁₂) -aryl-S (O) _n - , each of which can be substituted by NR² and / or mono- or disubstituted by (C₁-C₈) alkyl;
B is a direct bond, (C₁-C₈) alkyl, -CR² = CR³- or -C≡C-, optionally substituted once or twice by (C₁-C₈) alkyl;
D is a direct bond, (C₁-C₈) alkyl or -O-, -NR²-, -CO-NR²-, -NR²-CO-, -NR²-C (O) -NR²-, -NR²-C (S ) -NR²-, -OC (O) -, -C (O) O-, -CO-, -CS-, -S (O) -, -S (O) 2-, -S (O) ₂- NR²-, -NR²-S (O) -, -NR²-S (O) ₂-, -S, CR² = CR³-, -C≡C-, -NR²-N = CR², -N = CR² - or - R²C-N, which can each be mono- or disubstituted by (C₁-C₆) alkyl;
E is a direct bond, (C₁-C₄) alkyl, (C₂-C₄) alkenyl, (C₂-C₄) alkynyl, phenyl, phenyl- (C₁-C₂) alkyl, (C₁-C₂) alkylphenyl ;
F is defined as D;

LC (R¹⁶) or N;
R ° H, (C₁-C₆) alkyl, (C₃-C₈) cycloalkyl, (C₃-C₈) cycloalkyl- (C₁-C₆) alkyl, (C₅-C₁₂) aryl, (C₅-C₁₂) - Aryl- (C₁-C₆) -alkyl, (C₁-C₈) -alkyl-C (O), (C₃-C₈) -cycloalkyl-C (O), (C₃-C₈) -cycloalkyl- (C₁-C₄) - Alkyl-C (O), (C₅-C₁₂) - aryl-C (O), (C₅-C₁₂) aryl- (C₁-C₄) -alkyl-C (O), the alkyl radicals by F one or more times can be substituted;
R¹ R²-C (= NR²) NR³-, R²R³N-C (= NR²) -, R²R³N-C (= NR²) -NR², or a 4-10 membered mono- or polycyclic aromatic or non-aromatic ring system, which optionally 1- Can contain 4 heteroatoms from the series N, O and S and can optionally be mono- or polysubstituted with substituents from the series R¹², R¹³, R¹⁴ and R¹⁵;
R², R³ independently of one another are H, (C₁-C₈) -alkyl, which is optionally mono- or polysubstituted by F, (C₃-C₈) -cycloalkyl, (C₃-C₈) -cycloalkyl- (C₁-C₆) -alkyl, (C₅-C₁₂) aryl, (C₅-C₁₂) aryl- (C₁-C₆) alkyl, H₂N, R⁸ONR⁹, R⁸OR⁹, R⁸OC (O) R⁹, R⁸- (C₅-C₁₂) aryl-R⁹, R⁸R⁸NR⁹, HO- (C₁-C₈) alkyl- NR⁸R⁹, R⁸R⁸NC (O) R⁹, R⁸C (O) NR⁸R⁹, R⁸C (O) R⁹, R⁸R⁸N-C (= NR⁸) -, R⁸R⁸N-C (= NR⁸) -NR⁸- or (C₁-C₁₀) alkylcarbonyloxy- (C₁-C₄) alkoxycarbonyl;
R⁴, R⁵, R⁶, R⁷ independently of one another H, F, OH, (C₁-C₈) alkyl, (C₃-C₈) cycloalkyl, (C₃-C₈) cycloalkyl- (C₁-C₈) alkyl, or R⁸OR⁹, R⁸SR⁹, R⁸CO₂R⁹, R⁸OC (O) R⁹, R⁸- (C₅-C₁₂) aryl-R⁹, R⁸N (R²) R⁹, R⁸R⁸NR⁹, R⁸N (R²) C (O) OR⁹, R⁸S (O) _n N (R²) R⁹ , R⁸OC (O) N (R²) R⁹, R⁸C (O) N (R²) R⁹, R⁸N (R²) C (O) N (R²) R⁹, R⁸N (R²) S (O) _n N (R²) R⁹, R⁸S (O) _n R⁹, R⁸SC (O) N (R²) R⁹, R⁸C (O) R⁹, R⁸N (R²) C (O) R⁹, R⁸N (R²) S (O) _n R⁹;
R⁸ H, (C₁-C₆) alkyl, (C₃-C₈) cycloalkyl, (C₃-C₈) cycloalkyl- (C₁-C₆) alkyl, (C₅-C₁₂) aryl, (C₅-C₁₂) aryl - (C₁-C₆) alkyl, where the alkyl radicals can be substituted one or more times by F;
R⁹ is a direct bond or (C₁-C₆) alkyl;
R¹⁰ C (O) R¹¹, C (S) R¹¹, S (O) _n NR¹¹, P (O) _n R¹¹ or a four to eight membered, saturated or unsaturated heterocycle, of 1, 2, 3 or 4 heteroatoms from the series Contains N, O, S;
R¹¹ OH, (C₁-C₆) alkoxy, (C₅-C₁₂) aryl- (C₁-C₆) alkoxy, (C₅-C₁₂) aryloxy, (C₁- C₆) alkylcarbonyloxy- (C₁-C₄) alkoxy , (C₅-C₁₂) aryl- (C₁-C₆) - alkylcarbonyloxy- (C₁-C₆) alkoxy, NH₂, mono- or di- (C₁-C₆-alkyl) - amino, (C₅-C₁₂) aryl- (C₁-C₆) alkylamino, (C₁-C₆) dialkylaminocarbonylmethyloxy;
R¹², R¹³, R¹⁴, R¹⁵ independently of one another H, (C₁-C₈) alkyl, which is optionally mono- or polysubstituted, (C₃-C₈) - cycloalkyl, (C₃-C₈) -cycloalkyl- (C₁-C₆ ) Alkyl, (C₅-C₁₂) aryl, (C₅-C₁₂) aryl- (C₁-C₆) alkyl, H₂N, R⁸ONR⁹, R⁸OR⁹, R⁸OC (O) R⁹, R⁸- (C₅-C₁₂) aryl- R⁹, R⁸R⁸NR⁹, HO- (C₁-C₈) alkyl-N (R²) R⁹, R⁸N (R²) C (O) R⁹, R⁸C (O) N (R²) R⁹, R⁸C (O) R⁹, R²R³N-C (= NR²) -, R²R³N-C (= NR³) -NR², = O, = S;
R¹⁶ H, (C₁-C₈) alkyl which is optionally mono- or polysubstituted, (C₃-C₈) cycloalkyl, (C₃-C₈) cycloalkyl- (C₁-C₆) alkyl, (C₅- C₁₂ ) Aryl, (C₅-C₁₂) aryl- (C₁-C₆) alkyl, (C₂-C₈) alkenyl, (C₂-C₈) alkynyl;
m 3, 4 or 5;
n 1 or 2; and
p, q independently of one another 0 or 1.

Compounds of the formula I are particularly preferred in which:
W R¹-ABDC (R¹⁶), R¹-ABDC (R¹⁶) = C or

YC = O or -CH₂-;
ZN (R °) or -CH₂-;
A is a direct bond, (C₁-C₆) alkyl, -NR² N = CR²-, -NR²-C (O) -NR²-, -NR²-C (O) O-, -NR²-C (O) S- , NR²-S (O) _n -NR²-, NR²-S (O) _n or (C₃-C₆) - cycloalkyl, -C≡C-, -NR²-C (O) -, -C (O) -NR² -, - (C₅-C₁₀) -aryl-C (O) -NR²-, -O-, - (C₅-C₁₀) -aryl-, -CO-, - (C₅-C₁₀) -aryl-CO-, - NR²-, -CO₂-, -N = CR²-, -R²C = N-, -CR² = CR³, each of which can be substituted by NR² and / or mono- or disubstituted by (C₁-C₆) alkyl;
B is a direct bond, (C₁-C₆) alkyl, -CR² = CR³, optionally mono- or disubstituted by (C₁-C₆) alkyl;
D is a direct bond, (C₁-C₆) alkyl or -O-, -NR²-, NR²-CO-, -NR²-C (O) -NR²-, -NR²-C (S) -NR²-, -OC (O) -, -C (O) -, -S (O) ₂-NR²-, -NR²-S (O) -, -NR²-S (O) ₂-, -N = CR²- or -R²C- N, which can each be mono- or disubstituted by (C₁-C₆) alkyl;
E is a direct bond, (C₁-C₄) alkyl, (C₂-C₄) alkenyl;
F is a direct bond, (C₁-C₆) alkyl, or -O-, -CO-NR², -NR²-CO-, -NR²-C (O) -NR²-, -OC (O) -, -C ( O) O-, -CO-, -S (O) 2-, -S (O) ₂-NR², -NR²-S (O) ₂-, -CR² = CR³-, -C≡C-, -N = CR²-, -R²C = N-, which can each be mono- or disubstituted by (C₁-C₆) alkyl;

LC (R¹⁶) or N;
R ° H, (C₁-C₆) alkyl, (C₃-C₆) cycloalkyl, (C₃-C₆) cycloalkyl- (C₁-C₄) alkyl, (C₅-C₁₀) aryl, (C₅-C₁₀) - Aryl- (C₁-C₄) alkyl, (C₁-C₆) alkyl-C (O) -, (C₅-C₆) - cycloalkyl-methyl-C (O) -, phenyl-C (O), benzyl-C (O), where the alkyl radicals can be substituted with 1-6 F atoms;
R¹ R² C (= NR²) NR²-, R²R³N-C (= NR²) -,

R², R³ independently of one another are H, (C₁-C₆) alkyl which is optionally mono- or polysubstituted by F, preferably 1-6-fold, (C₃-C₆) cycloalkyl, (C₃-C₆) cycloalkyl- (C₁- C₄) alkyl, (C₅-C₁₀) aryl, (C₅-C₁₀) aryl- (C₁-C₄) alkyl, H₂N, R⁸OR⁹, R⁸- (C₅-C₁₀) aryl-R⁹, R⁸NHR⁹, R⁸R⁸NR⁹, R⁸NHC (O) R⁹, H₂N-C (= NH), H₂N-C (= NH) -NH-;
R⁴, R⁵, R⁶, R⁷ independently of one another H, F, OH, (C₁-C₆) alkyl, (C₃-C₆) cycloalkyl, (C₃-C₆) cycloalkyl- (C₁-C₆) alkyl, or R⁸OR⁹, R⁸CO₂R⁹, R⁸OC (O) R⁹, R⁸- (C₅-C₁₀) aryl-R⁹, R⁸NHR⁹, R⁸R⁸NR⁹, R⁸NHC (O) OR⁹, R⁸S (O) _n NHR⁹, R⁸OC (O) NHR⁹, R⁸C (O) NHR⁹, R⁸C (O) R⁹, R⁸NHC (O) NHR⁹, R⁸NHS (O) _n NHR⁹, R⁸NHC (O) R⁹, R⁸NHS (O) _n R⁹;
R⁸ H, (C₁-C₆) alkyl, (C₃-C₆) cycloalkyl, (C₃-C₆) cycloalkyl- (C₁-C₄) alkyl, (C₅-C₁₀) aryl, (C₅-C₁₀) aryl - (C₁-C₄) alkyl, where the alkyl radicals can be substituted with 1-6 F atoms;
R⁹ is a direct bond or (C₁-C₆) alkyl;
R¹⁰ C (O) R¹¹, S (O) _n NR¹¹, P (O) _n R¹¹;
R¹¹ OH, (C₁-C₆) alkoxy, (C₅-C₁₀) aryl- (C₁-C₆) alkoxy, (C₅-C₁₀) aryloxy, (C₁- C₆) alkylcarbonyloxy- (C₁-C₄) alkoxy , (C₅-C₁₀) aryl- (C₁-C₄) alkylcarbonyloxy- (C₁-C₄) alkoxy, NH₂, mono- or di- (C₁-C₆-alkyl) - amino;
R¹² H, (C₁-C₆) alkyl, which is optionally mono- or polysubstituted, (C₃-C₆) cycloalkyl, (C₃-C₆) cycloalkyl- (C₁-C₄) alkyl, (C₅- C₁₀ ) -Aryl, (C₅-C₁₀) -aryl- (C₁-C₄) -alkyl, H₂N, R⁸OR⁹, R⁸OC (O) R⁹, R⁸- (C₅- C₁₀) -aryl-R⁹, R⁸R⁸NR⁹, R⁸NHC (O) R⁹, R⁸C (O) NHR⁹, H₂N-C (= NH) -, H₂N- C (= NH) -NH-, = O;
R¹⁶ H, (C₁-C₆) alkyl, which can be substituted 1-6 times with F, (C₃-C₆) cycloalkyl, (C₃-C₆) cycloalkyl- (C₁-C₄) alkyl, phenyl, phenyl- ( C₁-C₄) alkyl, (C₂-C₆) alkenyl;
m 3, 4 or 5;
n 1 or 2; and
p, q independently of one another 0 or 1.

Compounds of the formula I are very particularly preferred in which:
W R¹-ABDC (R¹⁶);
YC = O;
ZN (R °);
A is a direct bond, (C₁-C₄) alkyl, -NR² N = CR²-, -NR²-C (O) -NR²-, -NR²-C (O) O-, -NR²-S (O) _n - , -NR²-S (O) _n -NR² or -NR²-CO-, -NR²-, -N = CR², each of which can be substituted by NH and / or mono- or disubstituted by (C₁- C₄) alkyl;
B is a direct bond, (C₁-C₄) alkyl, optionally substituted once or twice by (C₁-C₄) alkyl;
D is a direct bond, (C₁-C₄) alkyl or -O-, -NR²-, -NR²-CO-, -NR²-C (O) -NR²-, -R²N-S (O) ₂-NR²-, -NR²-S (O) ₂-, -NR²-S (O) - or -N = CR²-, R²C-N-, which can each be mono- or disubstituted by (C₁-C₄) alkyl;
E is a direct bond or (C₁-C₄) alkyl;
F is a direct bond, (C₁-C₆) alkyl, or -O-, -CO-NR²-, -NR²-CO-, -NR²-C (O) -NR²-, -S (O) ₂-NR²- , -NR²-S (O) ₂, CR² = CR³-, -C≡C-, -N = CR²
or -R²C-N, which can each be mono- or disubstituted by (C₁-C₄) alkyl;

R⁰ H, (C₁-C₆) alkyl, CF₃, C₂F₅, (C₅-C₆) cycloalkyl, (C₅-C₆) cycloalkyl- (C₁- C₂) alkyl, optionally substituted phenyl or optionally substituted benzyl on the phenyl radical;
R¹ R²R³N-C (= NR²),

R², R³ independently of one another H, (C₁-C₆) alkyl, CF₃, CF₂CF₃, (C₅-C₆) - cycloalkyl, (C₅-C₆) cycloalkyl- (C₁-C₂) alkyl, phenyl, benzyl, H₂N, R⁸OR⁹ , R⁸- (C₅-C₁₀) arylR⁹, R⁸NHR⁹, R⁸R⁸NR⁹, R⁸NHC (O) R⁹, H₂N-C (= NH), H₂N-C (= NH) -NH-;
R⁴, R⁵, R⁶, R⁷ independently of one another H, F, OH, (C₁-C₆) alkyl, (C₅-C₆) cycloalkyl, (C₅-C₆) cycloalkyl- (C₁-C₆) alkyl, or R⁸OR⁹, R⁸- (C₅-C₁₀) arylR⁹, R⁸R⁸NR⁹, R⁸NHC (O) OR⁹, R⁸S (O) _n NHR⁹, R⁸OC (O) NHR⁹, R⁸C (O) NHR⁹;
R⁸ H, (C₁-C₆) alkyl, (C₅-C₆) cycloalkyl, (C₅-C₆) cycloalkyl- (C₁-C₂) alkyl, (C₅-C₁₀) aryl, (C₅-C₁₀) aryl - (C₁-C₂) alkyl;
R⁹ is a direct bond or (C₁-C₆) alkyl;
R¹⁰ C (O) R¹¹;
R¹¹ OH, (C₁-C₆) alkoxy, phenoxy, benzyloxy, (C₁-C₄) alkylcarbonyloxy- (C₁-C₄) alkoxy, NH₂, mono- or di- (C₁-C₆-alkyl) amino;
R¹⁶ H, (C₁-C₄) alkyl, CF₃, CF₂CF₃, (C₅-C₆) cycloalkyl, (C₅-C₆) cycloalkyl- (C₁-C₂) alkyl, phenyl, benzyl;
n 1 or 2; and
p, q independently of one another 0 or 1.

Used abbreviations:

Boc: t-butoxycarbonyl
DCCl: dicyclohexylcarbodiimide
DMF: dimethylformamide
HOOBt: 3-hydroxy-4-oxo-3,4-dihydro-1.2.3-benzotriazine
THF: tetrahydrofuran
RT: room temperature
Z: benzyloxycarbonyl

Compounds of the formula I can generally, for example in the course of a convergent synthesis, by linking two or more fragments, which can be derived retrosynthetically from the general formula I, getting produced. In the preparation of the compounds of formula I it can generally necessary in the course of the synthesis, functional groups that are in the respective synthesis step to undesired reactions or side reactions could lead by a adapted to the synthesis problem Blocking the protective group strategy temporarily, which is known to the person skilled in the art is. The method of fragment linking is not based on the following Examples limited, but generally for syntheses of the compounds of Formula I applicable.

For example, compounds of formula I of the type

with F = C (O) NR² by condensation of a compound of formula II

where M for hydroxycarbonyl, (C₁-C₆) alkoxycarbonyl, activated Carboxylic acid derivatives such as acid chlorides, active esters or mixed anhydrides stands, are manufactured with HNR²-G.  

To condense two fragments to form an amide bond one advantageously uses the coupling methods known per se peptide chemistry (see e.g. Houben-Weyl, Methods of Organic Chemistry, Volume 15/1 and 15/2, Georg Thieme Verlag, Stuttgart, 1974). It is in the As a rule, it is necessary that existing, unreactive amino groups are reversible Protecting groups are protected during the condensation. The same applies to carboxyl groups not involved in the reaction, preferably as (C₁-C₆) - Alkyl, benzyl or tert-butyl esters can be used. An amino group Protection is unnecessary if the amino groups to be generated are still as nitro or Cyano groups are present and only after coupling by hydrogenation be formed. After coupling, the existing protective groups in appropriately split off. For example, NO₂ groups (Guanidino protection), benzyloxycarbonyl groups and benzyl esters will. The protective groups of the tert-butyl type are split off acidically, while the 9-fluorenylmethyloxycarbonyl residue was removed by secondary amines becomes.

Compounds of formula I in which

represents a dioxo or thioxo-oxo substituted imidazolidine ring in which W is R¹-ABDC (R¹⁶) can be obtained, for example:
by reaction of α-amino acids or N-substituted α-amino acids or preferably their esters, e.g. B. the methyl, ethyl, tert-butyl or benzyl ester, for example a compound of general formula III

with an isocyanate or isothiocyanate, for example the general formula U - E - F - G with U equal to isocyanato, isothiocyanato or Trichloromethylcarbonylamino, whereby one takes urea or thiourea derivatives of the general formula IV,

in which V means oxygen or sulfur, which is caused by heating with acid Saponification of the ester function to give compounds of the formula I of the type

be cyclized.

Another method for the preparation of compounds of the general formula I in which Y is C = O or C = S and W R¹-A-B-D-C (R¹⁶) is, for example the implementation of compounds of formula V

with phosphene, thiophosgene or equivalent (analogous to S. Goldschmidt and M. Wick, Liebigs Ann. Chem. 575 (1952), 217-231 and C. Tropp, Chem. Ber. 61 (1928), 1431-1439).  

Compounds of formula I in which

a heterocycle of the type

represents in which Y is C = O or C = S and W R¹-A-B-D-C (R¹⁶) = C, are produced, for example, according to the following scheme 1:

Scheme 1

U represents -NCO or -NCS; V means O, S.

The conversion of compounds of the formula VI to compounds of the formula VII and compounds of formula VII to compounds of formula VIII can for example analogue S. Chung-gi et al., Tetrahedron Lett 1987, 28 (33), 3827 or U. Schmidt et al. Appl. Chemistry 1984, 53 are carried out.

Another possibility for the preparation of compounds of formula VIII consists, for example, of first taking compounds of the formula VII Influence of acid on compounds of formula XII

to cyclize and then compounds of the formula XII in a Horner Emmons reaction with

to convert to compounds of formula VIII.  

Compounds of formula I in which

a heterocycle of the type

in which W

is, for example, according to the following Scheme 2 are made:

Scheme 2

Q means a nucleophilically substitutable leaving group such as. B. halogen, Mesylate, tosylate etc.

The conversion of compounds of formula IX to compounds of formula X can, for example, analogously to E. Marinez et al., Helv. Chim. Acta 1983, 66 (1), 338 or E.W. Logusch et al., J. Org. Chem. 1988, 53 (17), 4069 be performed.

Compounds of formula I in which

a heterocycle of the type

in which Y represents C = O or C = S and W

means in the following scheme 3 shown:

Scheme 3

U represents -NCO or -NCS; V means O, S.

Another possibility for the preparation of compounds of formula XIII consists, for example, of compounds of formula VII under the influence of Cyclize acid to compounds of formula XII and then Compounds of formula XII in a Horner-Emmons reaction with

to convert to compounds of formula XIII.

However, in the course of a convergent synthesis, it can be advantageous depending on the meaning of the individual substituents R¹, A, B, D etc. heterocyclic ring system that carries only some of the substituents, build up and then the remaining substituents, for example in Introduce a fragment link. The synthesis is an example mentioned in example 1:  

Scheme 4

However, this general principle is not limited to this one example, but generally applicable.

Compounds of the formula I in which R¹-A,

or cyclic aminoguanidinylimines of the type

mean, for example, by condensation of

with ketones or aldehydes of the type O = C (R²) - or corresponding acetals or ketals according to common literature procedures, for example analogous to N. Desideri et al., Arch. Pharm. 325 (1992) 773-777 or A. Alves et al., Eur. J. Med. Chem. Chim. Ther. 21 (1986) 297-304.

The above aminoguanidinylimines can optionally be used as E / Z isomer mixtures incurred, which are separated according to common chromatography procedures can.  

Compounds of formula I in which R¹-A R²-C (= NR²) NR² N-C (R²) - or a a mono- or polycycle-containing system of the type

represents can be obtained analogously.

Compounds of the formula I with R¹⁰ = SO₂R¹¹ are prepared, for example, in which compounds of the formula I with R¹⁰ = SH according to the literature Process (see Houben-Weyl, Methods of Organic Chemistry, Vol. El 2/2, Georg Thieme Verlag, Stuttgart 1985, pp. 1058ff) on compounds of the formula I. oxidized with R¹⁰-SO₃H, from which then directly or via appropriate Sulfonic acid halides by esterifying or forming an amide bond Compounds of formula I with R¹⁰-SO₂R¹¹ (R¹¹ ≠ OH) are prepared. Oxidation sensitive groups in the molecule, such as. B. amino, amidino or Guanidino groups are, if necessary, before performing the oxidation protected by suitable protective groups.

Compounds of the formula I with R¹⁰-S (O) R¹¹ are prepared, for example, by converting compounds of the formula I with R¹⁰ = SH into the corresponding sulfide (R¹⁰ = S⊖) and then with meta-chloroperbenzoic acid to give the sulfinic acids (R¹⁰- SO₂H) oxidized (cf. Houben-Weyl, Methods of Organic Chemistry, Vol. E11 / 1, Georg Thieme Verlag, Stuttgart 1985, p. 5618f), from which the corresponding sulfinic acid esters or amides R¹⁰-S (O) are obtained using methods known from the literature. R¹¹ (R¹¹ ≠ OH) can be prepared. In general, other methods known from the literature for the preparation of compounds of the formula I with R¹⁰ = S (O) _n R¹¹ (n = 1.2) can also be used (cf. Houben-Weyl, Methods of Organic Chemistry, Vol. E11 / 1, Georg Thieme Verlag, Stuttgart 1985, p. 618ff or vol.E11 / 2, Stuttgart 1985, p. 1055ff).

Compounds of formula I with R¹⁰ = P (O) Rn¹¹ (n = 1.2) are after processes known from the literature (cf. Houben-Weyl, Methods of Organic Chemistry, Vol. E1 and E2, Georg Thieme Verlag, Stuttgart 1982) from suitable Precursors built, the chosen synthesis method the target molecule is to be adjusted.

Compounds of formula I with R¹⁰ = C (S) R¹¹ can by literature methods be produced (cf. Houben-Weyl, Methods of Organic Chemistry, Vol. E5 / 1 and E5 / 2, Georg Thieme Verlag, Stuttgart 1985).

Compounds of formula I with R¹⁰ = S (O) _n R¹¹ (n = 1.2), P (O) R¹¹n (n = 1.2) or C (S) R¹¹ can of course also be prepared by fragment linking, as described above become, which is advisable, for example, if in EFG of the formula I z. B. an (commercially available) aminosulfonic acid, aminosulfinic acid, aminophosphonic acid or aminophosphinic acid or derivatives derived therefrom, such as esters or amides, are contained.

Compounds of formula I in which R¹-A

or cyclic acylguanidines of the type

means can be made for example by using a compound of formula I in which W Q (O) C-B-D-C (R¹⁶) - or Q (O) C-B-D-C (R¹⁶) = C or

and Q is an easily nucleophilically substitutable leaving group, with the corresponding guanidine (derivative) of the type

or cyclic guanidine (derivative)

implements.

The above activated Q (O) C acid derivatives, wherein Q is a Alkoxy, preferably a methoxy group, a phenoxy group, phenylthio, Methylthio, 2-pyridylthio group, a nitrogen heterocycle, preferably 1-imidazolyl means, is advantageously obtained in a manner known per se the underlying carboxylic acid chlorides Q = Cl, which in turn again in a manner known per se from the underlying carboxylic acids Q = OH can be produced, for example, with thionyl chloride.

In addition to the carboxylic acid chlorides (Q = Cl), other activated ones can also be used Acid derivatives of the type Q (O) C- in a manner known per se directly from the underlying carboxylic acids (Q = OH), such as Methyl ester (Q = OCH₃) by treatment with gaseous HCl in methanol, the Imidazolides (Q = 1-imidazolyl) by treatment with carbonyldiimidazole [cf. Staab, Angew. Chem. Int. Ed. Engl. 1, 351-367 (1962)], the mixed Anhydrides (Q = C₂H₅OC (O) O or TosO with Cl-COOC₂H₅ or tosyl chloride in Presence of triethylamine in an inert solvent. The activation of the Carboxylic acids can also be treated with dicyclohexylcarbodiimide (DCCl) or with O- [(Cyano (ethoxycarbonyl) methylene) amino] -1,1,3,3-tetramethyluronium  tetrafluoroborate ("TOTU") [Weiss and Krommer, Chemiker Zeitung 98, 817 (1974)] and other activation methods commonly used in peptide chemistry Reagents are done. A number of suitable methods for producing activated carboxylic acid derivatives of the formula II are given by Source literature in J. March, Advanced Organic Chemistry, Third Edition (John Wiley & Sons, 1985), p. 350.

The reaction of an activated carboxylic acid derivative of the type Q (O) C- with the respective guanidine (derivative) takes place in a manner known per se in one protic or aprotic polar but inert organic solvents, The implementation of the methyl esters (Q = OMe) with the respective guanidines methanol, isopropanol or THF from 20 ° C to The boiling point of these solvents has been proven. With most implementations of compounds of the type Q (O) C- with salt-free guanidines is advantageous in aprotic inert solvents such as THF, dimethoxyethane, dioxane worked. But water can also be used using a base (like for example NaOH) as a solvent in the reaction of Q (O) C- Guanidines can be used.

If Q = Cl, one works advantageously with the addition of an acid scavenger, e.g. B. in the form of excess guanidine (derivative) for setting the Hydrohalic acid.

Compounds of formula I in which R¹-A

or a one Mono- or polycyclic system of the type

represents can be obtained analogously.

Compounds of the formula I in which R¹-A is a sulfonyl or sulfoxylguanidine of the type R²R³N-C (= NR²) -NR²-S (O) _n (n = 1,2) or

represents are after processes known from the literature by reaction of R²R³N-C (= NR³) NR²H or

with sulfinic or sulfonic acid derivatives of the formula I with W equal to QS (O) _n -BDC (R¹⁶) - or QS (O) _n -BDC (R¹⁶) = C or

and O z. B. equal to Cl or NH₂ analog S. Birtwell et al., J. Chem. Soc. (1946) 491 or Houben-Weyl, Methods of Organic Chemistry, Vol. E4, Georg Thieme Verlag, Stuttgart 1983; P. 620 ff.

Compounds of formula I in which R¹A R²-C (= NR²) NR²-S (O) _n (n = 1,2) or a system of the type containing a mono- or polycycle

(n = 1.2) means can be obtained analogously.

Compounds of the formula I in which A -NR²-C (O) -NR²-, -NR²-C (O) O-, -NR²-C (O) S- and R¹ R²R³N-C (= NR²), R² C (= NR²) or a 4-10-membered mono- or polycyclic, aromatic or non-aromatic ring system, which is specified as described on page 6 and as described there may be substituted means, for. B. made by one  Compound of the formula I in which W Q-B-D-C (R¹⁶) - or Q-B-D-C (R¹⁶) = C or

and Q is HNR²-, HO- or HS- with an appropriate one Carbonic acid derivative, preferably phosgene, diphosgene (Trichloromethyl chloroformate), triphosgene (carbonic acid bis- trichloromethyl ester), chloroformic acid ethyl ester, chloroformic acid-i- butyl ester, bis (1-hydroxy-1-H-benzotriazolyl) carbonate or N, N'- Carbonyldiimidazole, in an inert to the reagents used Solvent, preferably DMF, THF or toluene, at a temperature between -20 ° C and the boiling point of the solvent, preferably between 0 ° C and 60 ° C, first to a substituted carbonic acid derivative of the formula I, in to which W

R -NR²-, -O- or -S- and Q ′ depending on the carbonic acid derivative used chlorine, Ethoxy, isobutoxy, benzotriazol-1-oxy or 1-imidazolyl mean, implemented.

The reaction of these derivatives with R²R³N-C (= NR²) -NR²H or R²-C (= NR²) NR²H or with those containing a mono- or polycycle Systems of the type

takes place as above in the production of acylguanidine (derivatives) described.

Compounds of formula I in which F is R²N-C (O) -NR² or R²N-C (S) -NR², are made, for example, by using a connection of the type

with an isocyanate OCN-G or isothiocyanate SCN-G implemented according to methods known from the literature.

Compounds of the formula I in which F is C (O) NR², -SO₂NR²- or -C (O) O- can e.g. B. by implementing

(Q is an easily nucleophilically substitutable leaving group, such as OH, Cl, OMe etc.) with HR²N-G or HO-G can be obtained according to literature procedures.

Compounds of formula I in which R¹-A is a mono- or polycycle of Type

includes, for example, can be manufactured  by using a compound of formula I in the W HR²N-B-D-C (R¹⁶) - or HR²N-B-D-C (R¹⁶) -C or

means with a mono- or polycycle of the type

in the X a nucleophilically substitutable leaving group such as e.g. B. halogen or SH, SCH₃, SOCH₃, SO₂CH₃ or HN-NO₂, after methods known from the literature (see, for example, A.F. McKay et al., J. Med. Chem. 6 (1963) 587, M.N. Buchman et al., J. Am. Chem. Soc. 71 (1949), 766, F. Jung et al., J. Med. Chem. 34 (1991) 1110 or G. Sorba et al., Eur. J. Med. Chem. 21 (1986), 391).

Compounds of formula I in which R¹A is a mono- or polycycle of Type

can be produced, for example, by one a compound of formula I in the W HR²N-B-D-C (R¹⁶) - or HR²N-B-D-C (R¹⁶) = C or

means with a connection of the type

in the X a leaving group, such as B. -SCH₃, after methods known from the literature (see, for example, T. Hiroki et al., Synthesis (1984) 703 or M. Purkayastha et al., Indian J. Chem. Sect. B 30 (1991) 646).

Compounds of the formula I in which R¹A is a bis-aminotriazole or a bis- Amino-oxadiazole residue, for example according to P.J. Garrett et al., Tetrahedron 49 (1993) 165 or R. Lee Webb et al., J. Heterocyclic Chem. 24 (1987) 275 can be prepared according to the following reaction sequence:

Scheme 5

Known manufacturing processes are e.g. B. in J. March, Advanced Organic Chemistry, Third Edition (John Wiley & Sons, 1985).

The compounds of general formula I and their physiologically tolerable Salts can be found in animals, preferably in mammals, and especially in humans as a remedy on its own, in mixtures with each other or in the form of pharmaceutical preparations are administered, which enteral or allow parenteral use and which are effective as an active ingredient Dose of at least one compound of general formula I or a salt of which, in addition to the usual pharmaceutically perfect carriers and additives contain. The preparations normally contain about 0.5 to 90% by weight the therapeutically active compound.

The remedies can be administered orally, e.g. B. in the form of pills, tablets, coated tablets, Coated tablets, granules, hard and soft gelatin capsules, solutions, syrups, Emulsions, suspensions or aerosol mixtures can be administered. The Administration can also be rectal, e.g. B. in the form of suppositories, or parenterally, e.g. B. in the form of solutions for injection or infusion, microcapsules or Rods, percutaneously, e.g. B. in the form of ointments or tinctures, or nasally, e.g. B. in Form of nasal sprays.

The pharmaceutical preparations are produced in a manner known per se Way, being pharmaceutically inert inorganic or organic carriers be used. For the production of pills, tablets, coated tablets and Hard gelatin capsules can e.g. B. lactose, corn starch or derivatives thereof, Use talc, stearic acid or its salts etc. Carriers for Soft gelatin capsules and suppositories are e.g. B. fats, waxes, semi-solid and liquid polyols, natural or hardened oils etc. As carriers for the Production of solutions and syrups are suitable for. B. water, sucrose,  Invert sugar, glucose, polyols etc. As carriers for the production of Injection solutions are water, alcohols, glycerin, polyols, vegetable Oils etc. are suitable as carriers for microcapsules, implants or rods Copolymers of glycolic acid and lactic acid.

In addition to the active substances and carriers, the pharmaceutical preparations can additives such as B. fillers, stretching, explosive, binding, sliding, mesh, Stabilizing, emulsifying, preserving, sweet, coloring, flavoring or Flavorings, thickeners, diluents, buffer substances, furthermore Solvents or solubilizers or agents to achieve a Depot effect, as well as salts to change the osmotic pressure, Contain coating agents or antioxidants. You can also choose two or several compounds of general formula I or their physiological contain acceptable salts; furthermore in addition to at least one connection of the Formula I one or more other therapeutically active substances.

The dose can vary within wide limits and is in each individual case adapt to individual circumstances.

With oral administration, the daily dose can be between 0.01 to 50 mg / kg, preferably 0.1 to 5 mg / kg, preferably 0.3 to 0.5 mg / kg body weight to achieve effective results, with intravenous administration the daily dose is generally about 0.01 to 100 mg / kg, preferably 0.05 to 10 mg / kg body weight. The daily dose can, especially in the Application of larger quantities, in several, e.g. B. 2, 3 or 4 sub-administrations be divided. If necessary, depending on individual behavior, be required from the specified daily dose upwards or downwards deviate below.

Examples

The products were identified by mass spectra and / or NMR spectra.

example 1 (2S) - [((4S) -4- (3- (imidazolin-2-yl-amino)) propyl-2,5-dioxoimidazolidi-n-1-yl) - acetylamino] -2-benzyloxycarbonylamino-propionic acid (1.8)

The synthesis was carried out according to the following reaction sequence:

1a) (2S) -2-Amino-5-benzyloxycarbonylamino-pentanoic acid methyl ester hydrochloride (1.2)

240 ml of thionyl chloride are added dropwise with ice cooling in an argon atmosphere 300 ml abs. Methanol and then add 40 g (150 mmol) (2S) -2-amino-5- benzyloxycarbonylamino-pentanoic acid (1.1) and leaves for 3 h at room temperature and react overnight at 4 ° C. The solution is in methyl tert-butyl ether poured, the solvent is decanted off and the residue with Triturated diethyl ether. After suction, 29.14 g (61%) of (1.2) are obtained as colorless solid.

1b) (2S) -Ethyloxycarbonylmethyl-aminocarbonyl-amino-5- methyl benzyloxycarbonylamino-pentanoate (1.3)

It is added dropwise at 0 ° C. to a solution of 9.41 g (29.7 mmol) of the compound (1.2) in 150 ml dichloromethane / tetrahydrofuran (2: 1) with stirring at 0 ° C 3.83 g (29.7 mmol) of ethyl isocyanato acetate and then 3 g (29.7 mmol)  Triethylamine. After 30 min at 0 ° C the ice bath is removed and the Reaction mixture stirred for 1.5 h at room temperature. After removing the Solvent in vac. the residue with ethyl acetate over silica gel chromatographed. The product fractions are concentrated and the residue triturated with ether and suction filtered. 11.02 g (83%) of (1.3) are obtained as colorless solid.

1c) 2 - [(⁴S) - (4- (3-aminopropyl)) - 2,5-dioxoimidazolidine] acetic acid hydrochloride (1.4)

10.4 g (42.9 mmol) of (1.3) are mixed with 100 ml of 6N hydrochloric acid for 45 min. to the Reflux heated. The solution is concentrated, the residue is mixed with H₂O and freeze-dried. 7.1 g (66%) of (1.4) are obtained as a colorless solid.

1d) 2 - [(⁴S) -4- (3- (imidazolin-2-yl-amino) propyl) -2,5-dioxoimidazolidine] acetic acid hydrochloride (1.5)

400 mg (1.59 mmol) of (1.4) and 388 mg (1.59 mmol) 2- (methylmercapto) -2- imidazoline hydroiodide are dissolved in 5 ml of H₂O. The mixture is made up with 1N NaOH to pH 9 and heated to 60 ° C for 2.5 h, taking the pH of the solution is kept at 9 by adding 1N NaOH (total consumption of IN NaOH: 3.4 ml). The reaction mixture is left for 3 days at room temperature stand, adjust to 1 with IN HCl, remove the solvent in vacuo and chromatograph the residue with MeOH / H₂O = 9/1 over silica gel. The Product fractions are concentrated and freeze-dried. 230 mg are obtained (45%) of (1.5) as a colorless powder.  

1e) (2S) -3-amino-2-benzyloxycarbonylaminopropionic acid tert-butyl ester (1.6)

10 g (42 mmol) of (2S) -3-amino-2-benzyloxycarbonylamino-propionic acid in a mixture of 100 ml of dioxane, 100 ml of isobutylene and 8 ml of conc. H₂SO₄ 3 days at 20 atm. N₂ pressure shaken in an autoclave. Excess Isobutylene is blown off and 150 ml of the remaining solution Diethyl ether and 150 ml of saturated NaHCO₃ solution. The phases are separated and the aqueous phase is 2 times with 100 ml of diethyl ether extracted. The combined organic phases are with 2 × 100 ml of H₂O washed and dried over Na₂SO₄. After removing the solvent i. Vac. 9.58 (78%) of (1.6) are obtained as a pale yellow oil.

1f) (2S) -3 - [((4S) - (3- (imidazolin-2-yl-amino)) propyl-2,5-dioxoimidazolidi-n-1-yl) - acetylamino] -2-benzyloxycarbonylamino-propionic acid tert-butyl ester (1.7)

200 mg (0.7 mmol) of (1.5) and 114 mg (0.7 mmol) HOOBt are added in 5 ml Suspended DMF and mixed with 154 mg (0.7 mmol) DCCl at 0 ° C. You stir 1 h at 0 ° C and 1 h at RT and then add 206 mg (0.7 mmol) (1.6), Stir at RT for 2 h and let stand at RT overnight. The solvent will i.Vac. removed and the residue with dichloromethane / methanol / glacial acetic acid / water = 8/2 / 0.2 / 0.2 chromatographed on silica gel. After constriction and Freeze-drying gives 105 mg (27%) of (1.7) as a colorless solid.

1g) (2S) -3 - [((4S) - (3- (imidazolin-2-yl-amino)) propyl-2,5-dioxoimidazolidi-n-1- yl) acetylamino] -2-benzyloxycarbonylamino-propionic acid (1.8)

105 mg (0.188 mmol) of (1.7) are mixed in a homogeneous solution from 2 ml of 90%  Trifluoroacetic acid and 0.2 ml of 1,2-dimercaptoethane dissolved and 1 h at RT ditched. After narrowing i. Vac. the gap between Distributed diethyl ether / water and the aqueous phase freeze-dried. After Chromatography over ®Sephadex LH 20 with H₂O / n-butanol / HOAc 43 / 4.3 / 3.5 and subsequent freeze drying, 45 mg (48%) are obtained (1.8) as a colorless solid.

Example 2 (2S) -3 - [((4S) -4- (3- (3-Amino-1,2,4-triazol-5-yl-amino)) propyl-2,5-dio-xo imidazolidin-1-yl) ace-iamino] -2-benzyloxycarbonylamino-propionic acid (2.5)

The synthesis was carried out according to the following reaction sequence:

For the synthesis of (1.4) and (1.6) see Example 1.  

2a) 2 - [(4S) -4- (3-tert.butoxycabonylaminopropyl) -2,5-dioxoimidazolidine] - acetic acid (2.1)

6 g (23.84 mmol) of (1.4) are dissolved in 350 ml THF / H₂O = 2/1. One poses at 0 ° C with IN NaOH pH 10.5, gives 6.24 g (28.61 mmol) di-tert.- butyl dicarbonate and maintains the pH of the solution by adding IN NaOH between 9-10.5. The mixture is stirred at 0 ° C. for 1 hour and left at 4 ° C. overnight stand. The pH is adjusted to 4 using phosphate buffer and the solvent is removed i.Vac. . The residue is triturated in methanol, filtered and the filtrate constricted. After chromatography on silica gel with dichloromethane / MeOH / Glacial acetic acid / water = 7/3 / 0.3 / 0.3 gives 5.65 g (75%) of a viscous syrup (2.1).

2b) (2S) -3 - [((4S) -4- (3-tert-butoxycarbonylaminopropyl) -2,5- dioxoimidazolidin-1-yl) acetylamino] -2-benzyloxycarbonylamino tert-butyl propionate (2.2)

2.8 g (8.9 mmol) of (2.1) and 1.45 g (8.9 mmol) HOOBt are dissolved in 50 ml DMF dissolved and mixed with 1.95 g (8.9 mmol) of DCCl at 0 ° C. After 1h at 0 ° C and 1 h at RT, 2.6 g (8.9 mmol) of (1.6) are added, the mixture is stirred at RT for 2 h and the reaction mixture was left to stand at RT overnight. After filtration the filtrate was concentrated, the residue between H₂O and ethyl acetate ver 07987 00070 552 001000280000000200012000285910787600040 0002019626701 00004 07868, the organic phase dried over Na₂SO₄, the solvent i.Vak. away and the residue over silica gel with ethyl acetate / heptane 9/1 to 6/4 chromatographed. 2.98 g (57%) of (2.2) are obtained.  

2c) (2S) -3 - [((4S) -4- (3-aminopropyl) -2,5-dioxoimidazolidin-1-yl) acetylamino-no] -2- benzyloxycarbonylamino-propionic acid trifluoroacetate (2.3)

2.9 g (4.9 mmol) of (2.2) are mixed in a mixture of 20 ml dichloromethane, 9.8 ml of trifluoroacetic acid and 2.35 ml of triethylsilane dissolved. After 3.5 h at RT the mixture is concentrated and then freeze-dried. The residue is triturated in diethyl ether, dried, crystallized in a little methanol and triturated with ether. 1.34 g (50%) of (2.3) are obtained as a colorless solid.

2d) (2S) -3 - [((4S) -4- (3- (phenoxy-N-cyano-iminocarbonylamino) propyl) -2,5- dioxo-imidazolidin-1-yl) acetylamino] -2-benzyloxycarbonylamino propionic acid (2.4)

400 mg (0.73 mmol) of (2.3) are dissolved in 10 ml DMF. 0.14 ml is added Triethylamine and then 190.7 mg (0.8 mmol) of cyanocarbamic acid di phenyl ester in 2 ml of DMF. After stirring at RT for 2 h, the solvent i.Vac. removed, the residue dissolved in 50 ml of 5% acetic acid solution and freeze-dried. After chromatography on silica gel with methanol 260 mg (61%) of (2.4).

2e) (2S) -3 - [((4S) -4- (3- (3-Amino-1,2,4-triazol-5-yl-amino)) propyl-2,5- dioxoimidazolidin-1-yl) acetylamino] -2-benzyloxycarbonylamino propionic acid (2.5)

260 mg (0.45 mmol) of (2.4) are suspended in 10 ml of isopropanol and mixed with 62.4 ul (0.45 mmol) of triethylamine were added. 28.5 µl (0.585 mmol) are added Hydrazine and heated to reflux for 10h. You let it stand at RT overnight, sucks off the precipitate and washes with butanol, THF and ether. After Chromatography over ®Sephadex LH 20 with H₂O / n-butanol / HOAc  43 / 4.3 / 3.5 and subsequent freeze drying, 80 mg (34%) are obtained (2.5) as a colorless solid.

The inhibition of bone resorption by the compounds according to the invention can be determined, for example, using an osteoclast resorption test ("PIT ASSAY"), for example analogously to WO 95/32710. The test methods by which the antagonistic action of the compounds according to the invention on the vitronectin receptor α _v β₃ can be determined are described below.

Test method 1 Inhibition of the binding of human vitronectin (Vn) to human vitronectin receptor (VnR) α _v β₃: ELISA test (Test method 1 is used to list the test results with Vn / VnR abbreviated) 1. Purification of human vitronectin

Human vitronectin is isolated from human plasma and by Affinity chromatography according to the method of Yatohyo et al., Cell Structure and Function, 1988, 23, 281-292.

2. Purification of human vitronectin receptor α _v β₃

Human vitronectin receptor is made from the human placenta by the method of Pytela et al., Methods Enzymol. 1987, 144, 475 won. Human vitronectin receptor α _v β₃ can also be obtained from some cell lines (e.g. from 293 cells, a human embryonic kidney cell line), which are transfected with DNA sequences for both subunits α _v and β₃ of the vitronectin receptor. The subunits are extracted with octylglycoside and then chromatographed on concanavalin A, heparin-Sepharose and S-300.

3. Monoclonal antibodies

Murine monoclonal antibodies specific for the β₃ subunit of Vitronectin receptor, are according to the method of Newman et al., Blood, 1985, 227-232, or by a similar process. The rabbit Fab 2 anti-mouse Fc conjugate to horseradish peroxidase (anti-mouse Fc HRP) was from Pel Freeze (Catalog No. 715 305-1) based.

4. ELISA test

Nunc Maxisorp 96 well microtiter plates are coated with a solution of human vitronectin (0.002 mg / ml, 0.05 ml / well) in PBS (phosphate buffered saline) overnight at 4 ° C. The plates are washed twice with PBS / 0.05% Tween 20 and incubated (60 min) with bovine serum albumin (BSA, 0.5%, RIA grade or better) in Tris-HCl (50 mM), NaCl (100 mM ), MgCl₂ (1 mM), CaCl₂ (1 mM), MnCl₂ (1 mM), pH 7, blocked. Solutions of known inhibitors and of the test substances are prepared in a concentration of 2 × 10 ^-12 - 2 × 10 ^-6 mol / l in assay buffer [BSA (0.5 RIA grade or better) in Tris-HCl (50 mM / l), NaCl (100 mM), MgCl₂ (1 mM), CaCl₂ (1 mM), MnCl₂ (1 mM), pH 7]. The blocked plates are emptied and 0.025 ml of this solution, which contains a defined concentration (2 × 10 ^-12 to 2 × 10 ^-6 ) either on a known inhibitor or on a test substance, is added to each well. 0.025 ml of a solution of the vitronectin receptor in the test buffer (0.03 mg / ml) is pipetted into each well of the plate and the plate is incubated on a shaker for 60-180 min at room temperature. In the meantime, a solution (6 ml / plate) of a murine monoclonal antibody specific for the β₃ subunit of the vitronectin receptor is prepared in the assay buffer (0.001 5 mg / ml). A second rabbit antibody (0.001 ml stock solution / 6 ml of the murine monoclonal anti-β₃ antibody solution), which is an anti-mouse Fc HRP antibody conjugate, and this mixture of murine anti-β₃ antibody and rabbit anti are added to this solution -Mouse Fc HRP antibody conjugate is allowed to incubate during the time of the receptor inhibitor incubation.

The test plates are 4 times with PBS solution containing 0.05% Tween-20 contains, washed and pipetted 0.05 ml / well each Antibody mixture in each well of the plate and incubated for 60-180 min. The Plate is washed 4 times with PBS / 0.05% Tween-20 and then with 0.05 ml / well of a PBS solution containing 0.67 mg / ml o-phenylenediamine and Contains 0.012% H₂O₂, developed. Alternatively, o-phenylenediamine be used in a buffer (pH 5), the Na₃PO₄ (50 mM) and Contains citric acid (0.22 mM). The color development is done with IN H₂SO₄ (0.05 ml / well) stopped. The absorption of each well is at 492-405 nm measured and the data are evaluated according to standard methods.

Test method 2 Inhibition of the binding of kistrin to human vitronectin receptor (VnR) α _v β₃: ELISA test (test method 2 is abbreviated Kistrin / VnR when listing the test results) 1. Purification of Kistrin

Kistrin is made using the methods of Dennis et al., As described in Proc. Natl. Acad. Sci. USA 1989, 87, 2471-2475 and PROTEINS: Structure, Function and Genetics 1993, 15, 312-321.

2. Purification of human vitronectin receptor (α _v β₃)

see test method 1.

3. Monoclonal antibodies

see test method 1.  

4. ELISA test

The ability of substances to bind Kistrin to the Inhibiting the vitronectin receptor can be determined using an ELISA test will. For this purpose, Nunc 96 well microtiter plates with a Solution of kistrin (0.002 mg / ml) by the method of Dennis et al., Such as in PROTEINS: Structure, Function and Genetics 1993, 15, 312-321, described, documented. The further experimental implementation of the ELISA The test is carried out as described in test method 1, point 4.

Test results

Claims (8)

1. Compounds of the formula I in which mean:
w R¹-ABDC (R¹⁶), R¹-ABDC (R¹⁶) = C, or being the ring systems Can contain 1 or 2 heteroatoms from the series N, O, S, can be saturated or mono- or polyunsaturated and can be substituted with 1-3 substituents from R¹⁶ or mono- or disubstituted with double-bonded O or S;
YC = O, C = S or -CH₂-;
ZN (R °), O, S or -CH₂-;
A is a direct bond, (C₁-C₈) alkyl, -NR²-N = CR², -NR²-C (O) -NR²-, -NR²-C (O) O-, -NR²-C (O) S- , -NR²-C (S) -NR²-, -NR²-C (S) -O-, -NR²-C (S) -S-, NR²-S (O) _n -NR²-, -NR²-S ( O) _n -O-, NR²-S (O) _n - or (C₃-C₁₂) cycloalkyl, -C≡C-, -NR²-C (O) -, -C (O) -NR²-, - ( C₅-C₁₄) -aryl-C (O) -NR²-, -O-, -S (O) _n -, - (C₅- C₁₄) -aryl-, -CO-, (C₅-C₁₄) -aryl-CO -, -NR²-, -SO₂-NR², -CO₂-, -N = CR²-, - R²C = N, CR² = CR³-, - (C₅-C₁₄) -aryl-S (O) _n -, each by NR² and / or can be substituted once or twice by (C₁-C₈) alkyl;
B is a direct bond, (C₁-C₈) alkyl, CR² = CR³- or -C≡C-, optionally substituted once or twice by (C₁-C₈) alkyl, or a divalent radical of a 5- or 6-membered saturated or unsaturated ring which contains 1 or 2 nitrogen atoms and can be mono- or disubstituted by (C₁-C₆) alkyl or double-bonded oxygen or sulfur;
D is a direct bond, (C₁-C₈) alkyl or -O-, -NR²-, -CO-NR²-, -NR²-CO-, -NR²-C (O) -NR²-, -NR²-C (S ) -NR²-, -OC (O) -, -C (O) O-, -CO-, -CS-, -S (O) -, -S (O) ₂-, -S (O) ₂- NR²-, -NR²-S (O) -, -NR²-S (O) ₂-, -S-, CR² = CR³-, -C≡C-, -NR² N = CR²-, -N = CR², R²C -N or -CH (OH) -, which can each be mono- or disubstituted by (C₁-C-) alkyl;
E is a direct bond, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, phenyl, phenyl- (C₁-C₃) alkyl, (C₁-C₃) alkylphenyl ;
F is defined as D; LC (R¹⁶) or N;
R⁰ H, (C₁-C₈) alkyl, which is optionally mono- or polysubstituted, (C₃-C₁₂) cycloalkyl, (C₃-C₁₂) cycloalkyl- (C₁-C₈) alkyl, (C₅- C₁₄ ) Aryl, (C₅-C₁₄) aryl- (C₁-C₈) alkyl or (C₁-C₈) alkyl-C (O) -, (C₃-C₁₂) - cycloalkyl-C (O), (C₃- C₁₂) -cycloalkyl- (C₁-C₆) -alkyl-C (O), (C₅-C₁₄) -aryl-C (O) - (C₅-C₁₄) -aryl- (C₁-C₆) -alkyl-C (O ), where the alkyl radicals can be substituted one or more times by F;
R¹ R² C (= NR²) NR²-, R²R³N-C (= NR²) -, R²R³N-C - (= NR²) -NR², or a 4-10 membered mono- or polycyclic aromatic or non-aromatic ring system, which may 1- Can contain 4 heteroatoms from the series N, O and S and can optionally be mono- or polysubstituted with substituents from the series R¹², R¹³, R¹⁴ and R¹⁵;
R², R³ independently of one another H, (C₁-C₁₀) alkyl which is optionally mono- or polysubstituted by F, (C₃-C₁₂) cycloalkyl, (C₃-C₁₂) cycloalkyl- (C₁-C₈) alkyl, (C₅-C₁₄) aryl, (C₅-C₁₄) aryl (C₁-C₈) alkyl, H₂N, R⁸ONR⁹, R⁸OR⁹, R⁸OC (O) R⁹, R⁸- (C₅-C₁₄) aryl-R⁹, R⁸R⁸NR⁹, HO- (C₁-C₈) alkyl-NR⁸R⁹, R⁸R⁸NC (O) R⁹, R⁸C (O) NR⁸R⁹, R⁸C (O) R⁹, R⁸R⁸N-C (= NR⁸) -, R⁸R⁸N-C (= NR⁸) - NR⁸- or ( C₁-C₁₈) alkylcarbonyloxy- (C₁-C₆) alkoxycarbonyl;
R⁴, R⁵, R⁶, R⁷ independently of one another H, F, OH, (C₁-C₈) alkyl, (C₃-C₁₂) cycloalkyl, (C₃-C₁₂) cycloalkyl- (C₁-C₆) alkyl, or R⁸OR⁹, R⁸SR⁹, R⁸CO₂R⁹, R⁸OC (O) R⁹, R⁸- (C₅-C₁₄) aryl-R⁹, R⁸N (R²) R⁹, R⁸R⁸NR⁹, R⁸N (R²) C (O) OR⁹, R⁸S (O) _n N (R²) R⁹ , R⁸OC (O) N (R²) R⁹, R⁸C (O) N (R²) R⁹, R⁸N (R²) C (O) N (R²) R⁹, R⁸N (R²) S (O) _n N (R²) R⁹, R⁸S (O) _n R⁹, R⁸SC (O) N (R²) R⁹, R⁸C (O) R⁹, R⁶N (R²) C (O) R⁹, R⁸N (R²) S (O) _n R⁹;
R⁸ H, (C₁-C₈) alkyl, (C₃-C₁₂) cycloalkyl, (C₃-C₁₂) cycloalkyl- (C₁-C₈) alkyl, (C₅-C₁₄) aryl, (C₅-C₁₄) aryl - (C₁-C₈) alkyl, where the alkyl radicals can be substituted one or more times by F;
R⁹ is a direct bond or (C₁-C₈) alkyl;
R¹⁰ C (O) R¹¹, C (S) R¹¹, S (O) _n NR¹¹, P (O) _n R¹¹ or a four to eight membered, saturated or unsaturated heterocycle, of 1, 2, 3 or 4 heteroatoms from the series Contains N, O, S;
R¹¹ OH, (C₁-C₈) alkoxy, (C₅-C₁₄) aryl- (C₁-C₈) alkoxy, (C₅-C₁₄) aryloxy, (C₁- C₈) alkylcarbonyloxy- (C₁-C₄) alkoxy , (C₅-C₁₄) aryl- (C₁-C₆) - alkylcarbonyloxy- (C₁-C₆) alkoxy, NH₂, mono- or di- (C₁-C₈-alkyl) -amino, (C₅-C₁₄) aryl- (C₁-C₈) alkylamino, (C₁-C₈) dialkylaminocarbonylmethyloxy, (C₅-C₁₄) aryl- (C₁ C₈) dialkylaminocarbonylmethyloxy or (C₅-C₁ 4) arylamino or an L- or D-amino acid;
R¹², R¹³, R¹⁴, R¹⁵ independently of one another H, (C₁-C₁₀) alkyl, which is optionally mono- or polysubstituted, (C₃-C₁₂) cycloalkyl, (C₃-C₁₂) cycloalkyl- (C₁-C₈ ) alkyl, (C₅-C₁₄) aryl, (C₅-C₁₄) aryl- (C₁-C₈) alkyl, H₂N, R⁸ONR⁹, R⁸OR⁹, R⁸OC (O) R⁹, R⁸R⁸NR⁹, R⁸- (C₅-C₁₄) - Aryl-R⁹, HO- (C₁-C₈) -alkyl-N (R²) R⁹, R⁸N (R²) C (O) R⁹, R⁸C (O) N (R²) R⁹, R⁸C (O) R⁹, R²R³N-C ( = NR²) -NR²-, R²R³N-C (= NR²), = O, = S;
R¹⁶ H, (C₁-C₁₀) alkyl, which is optionally mono- or polysubstituted, (C₃-C₁₂) cycloalkyl, (C₃-C₁₂) cycloalkyl- (C₁-C₈) alkyl, (C₅- C₁₄ ) Aryl, (C₅-C₁₄) aryl- (C₁-C₈) alkyl, (C₂-C₂₀) alkenyl, (C₂-C₁₀) alkynyl;
m 1, 2, 3, 4, 5 or 6;
n 1 or 2;
p, q independently of one another 0 or 1;
and their physiologically tolerable salts,
with the exception of compounds in which R¹-ABDC (R¹⁶) or R¹-ABDC (R¹⁶) = C are R¹-KC (R¹⁶) or R¹-K-CH = C (R¹⁶ = H), where here
R¹ is X-NH-C (= NH) - (CH₂) p, X¹-NH- (CH₂) p or 4-imidazolyl-CH₂-,
where p can be an integer from 0 to 3,
X is hydrogen, (C₁-C₆) alkyl, (C₁-C₆) alkylcarbonyl, (C₁-C₆) alkoxycarbonyl, (C₁-C₁₈) alkylcarbonyloxy- (C₁-C₆) alkoxycarbonyl, (C₆- C₁₄) arylcarbonyl , (C₆-C₁₄) aryloxycarbonyl, (C₆-C₁₄) aryl- (C₁-C₆) - alkoxycarbonyl, hydroxy, (C₁-C₆) alkoxy, (C₆-C₁₄) aryl- (C₁-C₆) alkoxy , or amino, where the aryl groups in X are pure, optionally mono- or polysubstituted carbocycles,
X¹ (C₄-C₁₀) arylcarbonyl, (C₄-C₁₀) aryloxycarbonyl, (C₄-C₁₀) aryl- (C₁-C₆) alkoxycarbonyl, (C₄-C₁₀) aryl- (C₁-C₆) alkoxy or R. '-NH-C (= NR "), where R' and R '' independently of one another have the meanings of X and the aryl groups in X₁ represent pure, optionally mono- or polysubstituted carbocycles,
K (C₁-C₆) alkyl, (C₃-C₇) cycloalkyl, phenyl, phenyl- (C₁-C₆) alkyl, (C₁-C₆) alkylphenyl, phenyl- (C₂-C₆) alkenyl or a divalent radical of a 5- or 6-membered saturated or unsaturated ring which contains 1 or 2 nitrogen atoms and can be mono- or disubstituted by (C₁-C₆) alkyl or double-bonded oxygen or sulfur. 2. Compounds of formula I according to claim 1, in which:
W R¹-ABDC (R¹⁶), R¹-ABDC (R¹⁶) = C, or being the ring systems Contain 1 or 2 heteroatoms from the series N, O, can be saturated or monounsaturated and can be substituted with 1 or 2 substituents from R¹⁶;
YC = O, C = S or -CH₂-;
ZN (R °), O or -CH₂-;
A is a direct bond, (C₁-C₆) alkyl, -NR²-N = CR², -NR²-C (O) -NR²-, -NR²-C (O) O-, -NR²-C (O) S- , -NR²-C (S) -NR²-, -NR²-C (S) -O-, -NR²-C (S) -S-, -NR²-S (O) _n -NR²-, -NR²-S (O) _n -O-, -NR²-S (O) _n - or (C₃-C₈) -cycloalkyl, -C≡C-, -NR²-C (O) -, -C (O) -NR²-, - (C₅-C₁₂) -aryl-C (O) -NR²-, -O-, -S (O) _n -, - (C₅- C₁₂) -aryl-, -CO-, - (C₅-C₁₂) - Aryl-CO-, -NR²-, -SO₂-NR², -CO₂-, -N = CR²-, R²C-N, CR² = CR³-, - (C₅-C₁₂) aryl-S (O) _n -, the can each be substituted by NR² and / or mono- or disubstituted by (C₁-C₈) alkyl;
B is a direct bond, (C₁-C₈) -alkyl, CR² = CR³- or -C≡C-, optionally substituted once or twice by (C₁-C₆) -alkyl;
D is a direct bond, (C₁-C₈) alkyl or -O-, -NR²-, -CO-NR²-, -NR²-CO-, -NR²-C (O) -NR²-, -NR²-C (S ) -NR²-, -OC (O) -, -C (O) O-, -CO-, -CS-, -S (O) -, -S (O) 2-, -S (O) ₂- NR²-, -NR²-S (O) -, -NR²-S (O) ₂-, -S-, CR² = CR³, C≡C-, NR² N = CR²-, -N = CR² or -R²C = N -, which can each be mono- or disubstituted by (C₁-C₆) alkyl;
E is a direct bond, (C₁-C₄) alkyl, (C₂-C₄) alkenyl, (C₂-C₄) alkynyl, phenyl, phenyl- (C₁-C₂) alkyl, (C₁-C₂) alkylphenyl ;
F is defined as D; LC (R¹⁶) or N;
R⁰ H, (C₁-C₆) alkyl, (C₃-C₈) cycloalkyl, (C₃-C₈) cycloalkyl- (C₁-C₆) alkyl, (C₅-C₁₂) aryl, (C₅-C₁₂) aryl - (C₁-C₆) alkyl, (C₁-C₈) alkyl-C (O), (C₃-C₈) cycloalkyl-C (O), (C₃-C₈) cycloalkyl- (C₁-C₄) alkyl -C (O), (C₅-C₁₂) - aryl-C (O), (C₅-C₁₂) -aryl- (C₁-C-) -alkyl-C (O), the alkyl radicals being substituted one or more times by F. could be;
R¹ R² C (= NR²) NR³-, R²R³N-C (= NR²) -, R²R³N-C (= NR²) -NR², or a 4-10 membered mono- or polycyclic aromatic or non-aromatic ring system, which optionally 1-4 Can contain heteroatoms from the series N, O and S and can optionally be mono- or polysubstituted by substituents from the series R¹², R¹³, R¹⁴ and R¹⁵;
R², R³ independently of one another H, (C₁-C₈) -alkyl, which is optionally mono- or polysubstituted by F, (C₃-C₈) -cycloalkyl, (C₃-C₈) -cycloalkyl- (C₁-C₆) -alkyl, (C₅-C₁₂) aryl, (C₅-C₁₂) aryl- (C₁-C₆) alkyl, H₂N, R⁸ONR⁹, R⁸OR⁹, R⁸OC (O) R⁹, R⁸- (C₅-C₁₂) aryl-R⁹, R⁸R⁸NR⁹, HO- (C₁-C₈) -alkyl- NR⁸R⁹, R⁸R⁸NC (O) R⁹, R⁸C (O) NR⁸R⁹, R⁸C (O) R⁹, R⁸R⁸N-C (= NR⁸) -, R⁸R⁸N-C (= NR⁸) NR⁸- or ( C₁-C₁₀) alkylcarbonyloxy- (C₁-C₄) alkoxycarbonyl;
R⁴, R⁵, R⁶, R⁷ independently of one another H, F, OH, (C₁-C₈) alkyl, (C₃-C₈) cycloalkyl, (C₃-C₆) cycloalkyl- (C₁-C₈) alkyl, or R⁸OR⁹, R⁸SR⁹, R⁸CO₂R⁹, R⁸OC (O) R⁹, R⁸- (C₅-C₁₂) aryl-R⁹, R⁸N (R²) R⁹, R⁸R⁸NR⁹, R⁸N (R²) C (O) OR⁹, R⁸S (O) _n N (R²) R⁹ , R⁸OC (O) N (R²) R⁹, R⁶C (O) N (R²) R⁹, R⁸N (R²) C (O) N (R²) R⁹, R⁸N (R²) S (O) _n N (R²) R⁹, R⁸S (O) _n R⁹, R⁸SC (O) N (R²) R⁹, R⁸C (O) R⁹, R⁸N (R²) C (O) R⁹, R⁸N (R²) S (O) _n R⁹;
R⁸ H, (C₁-C₆) alkyl, (C₃-C₈) cycloalkyl, (C₃-C₈) cycloalkyl- (C₁-C₆) alkyl, (C₅- C₁₂) aryl, (C₅-C₁₂) aryl - (C₁-C₆) alkyl, where the alkyl radicals can be substituted one or more times by F;
R⁹ is a direct bond or (C₁-C₆) alkyl;
R¹⁰ C (O) R¹¹, C (S) R¹¹, -S (O) _n NR¹¹, P (O) _n R¹¹ or a four to eight membered, saturated or unsaturated heterocycle which is 1, 2, 3 or 4 heteroatoms from the Row N, O, S contains;
R¹¹ OH, (C₁-C₆) alkoxy, (C₅-C₁₂) aryl- (C₁-C₆) alkoxy, (C₅-C₁₂) aryloxy, (C₁- C₆) alkylcarbonyloxy- (C₁-C₄) alkoxy , (C₅-C₁₂) aryl- (C₁-C₆) alkylcarbonyloxy- (C₁-C₆) alkoxy, NH₂, mono- or di- (C₁-C₆-alkyl) -amino, (C₅-C₁₂) aryl- (C₁-C₆) alkylamino, (C₁-C₆) dialkylaminocarbonylmethyloxy;
R¹², R¹³, R¹⁴, R¹⁵ independently of one another H, (C₁-C₈) alkyl, which is optionally mono- or polysubstituted, (C₃-C₈) - cycloalkyl, (C₃-C₈) -cycloalkyl- (C₁-C₆ ) Alkyl, (C₅-C₁₂) aryl, (C₅-C₁₂) aryl- (C₁-C₆) alkyl, H₂N, R⁸ONR⁹, R⁸OR⁹, R⁸OC (O) R⁹, R⁸- (C₅-C₁₂) aryl- R⁹, R⁸R⁸NR⁹, HO- (C₁-C₈) alkyl-N (R²) R⁹, R⁸N (R²) C (O) R⁹, R⁸C (O) N (R²) R⁹, R⁸C (O) R⁹, R²R³N-C (= NR²) -, R²R³N-C (= NR³) -NR²-, = O, = S;
R¹⁶ H, (C₁-C₈) -alkyl, which is optionally mono- or polysubstituted, (C₃-C₈) -cycloalkyl, (C₃-C₈) -cycloalkyl- (C₁-C₆-alkyl, (C₅- C₁₂) Aryl, (C₅-C₁₂) aryl- (C₁-C₆) alkyl, (C₂-C₈) alkenyl, (C₂-C₈) alkynyl;
m 3, 4 or 5;
n 1 or 2; and
p, q independently of one another 0 or 1. 3. Compounds of formula I according to claim 1 or 2, in which:
W R¹-ABDC (R¹⁶), R¹-ABDC (R¹⁶) = C or YC = O or -CH₂-;
ZN (R °) or -CH₂-;
A is a direct bond, (C₁-C₆) alkyl, -NR²-N = CR², -NR²-C (O) -NR²-, -NR²-C (O) O-, -NR²-C (O) S- , -NR²-S (O) _n -NR²-, -NR²-S (O) _n - or (C₃-C₆) - cycloalkyl, -C≡C-, -NR²-C (O) -, -C (O ) -NR²-, - (C₅-C₁₀) -aryl-C (O) -NR²-, -O-, - (C₅-C₁₀) -aryl-, -CO-, - (C₅-C₁₀) -aryl-CO -, -NR²-, -CO₂-, -N = CR²-, -R²C-N-, CR² = CR³-, which can each be substituted by NR² and / or mono- or disubstituted by (C₁- C₆) alkyl;
B is a direct bond, (C₁-C₆) alkyl, CR² = CR³-, optionally substituted once or twice by (C₁-C₁) alkyl;
D is a direct bond, (C₁-C₆) alkyl or -O-, -NR²-, NR²-CO-, -NR²-C (O) -NR²-, -NR²-C (S) -NR²-, -OC (O) -, -C (O) -, -S (O) ₂-NR²-, -NR²-S (O) -, -NR²-S (O) ₂-, -N = CR²- or -R²C = N-, which can each be mono- or disubstituted by (C₁-C₆) alkyl;
E is a direct bond, (C₁-C₄) alkyl, (C₂-C₄) alkenyl;
F is a direct bond, (C₁-C₆) alkyl, or -O-, -CO-NR², -NR²-CO-, -NR²-C (O) -NR²-, -OC (O) -, -C ( O) O-, -CO-, -S (O) ₂-, -S (O) ₂-NR², -NR²-S (O) ₂-, - CR² = CR³-, -C≡C-, -N = CR²-, -R²C = N-, which can each be mono- or disubstituted by (C₁-C₆) alkyl; LC (R¹⁶) or N;
R ° H, (C₁-C₆) alkyl, (C₃-C₆) cycloalkyl, (C₃-C₆) cycloalkyl- (C₁-C₄) alkyl, (C₅-C₁₀) aryl, (C₅-C₁₀) - Aryl- (C₁-C₄) alkyl, (C₁-C₆) alkyl-C (O) -, (C₅-C₆) - cycloalkyl-methyl-C (O) -, phenyl-C (O), benzyl-C (O), where the alkyl radicals can be substituted with 1-6 F atoms;
R¹ R² C (= NR²) NR²-, R²R³N-C (= NR²) -, R², R³ independently of one another are H, (C₁-C₆) alkyl which is optionally mono- or polysubstituted by F, preferably 1-6-fold, (C₃-C₆) -cycloalkyl, (C₃-C₆) -cycloalkyl- (C₁- C₄) alkyl, (C₅-C₁₀) aryl, (C₅-C₁₀) aryl- (C₁-C₄) alkyl, H₂N, R⁸OR⁹, R⁸- (C₅-C₁₀) aryl-R⁹, R⁸NHR⁹, R⁸R⁸NR⁹, R⁸NHC (O) R⁹, H₂N- C (= NH), H₂N-C (= NH) -NH-;
R⁴, R⁵, R⁶, R⁷ independently of one another H, F, OH, (C₁-C₆) alkyl, (C₃-C₆) cycloalkyl, (C₃-C₆) cycloalkyl- (C₁-C₆) alkyl, or R⁸OR⁹, R⁸CO₂R⁹, R⁸OC (O) R⁹, R⁸- (C₅-C₁₀) aryl-R⁹, R⁸NHR⁹, R⁸R⁸NR⁹, R⁸NHC (O) OR⁹, R⁸S (O) _n NHR⁹, R⁸OC (O) NHR⁹, R⁸C (O) NHR⁹, R⁸C (O) R⁹, R⁸NHC (O) NHR⁹, R⁸NHS (O) _n NHR⁹, R⁸NHC (O) R⁹, R⁸NHS (O) _n R⁹;
R⁸ H, (C₁-C₆) alkyl, (C₃-C₆) cycloalkyl, (C₃-C₆) cycloalkyl- (C₁-C₄) alkyl, (C₅- C₁₀) aryl, (C₅-C₁₀) aryl - (C₁-C₄) alkyl, where the alkyl radicals can be substituted with 1-6 F atoms;
R⁹ is a direct bond or (C₁-C₆) alkyl;
R¹⁰ C (O) R¹¹, S (O) _n NR¹¹, P (O) _n R¹¹;
R¹¹ OH, (C₁-C₆) alkoxy, (C₅-C₁₀) aryl- (C₁-C₆) alkoxy, (C₅-C₁₀) aryloxy, (C₁- C₆) alkylcarbonyloxy- (C₁-C₄) alkoxy , (C₅-C₁₀) aryl- (C₁-C₄) alkylcarbonyloxy- (C₁-C₄) alkoxy, NH₂, mono- or di- (C₁-C₆-alkyl) amino;
R¹² H, (C₁-C₆) alkyl, which is optionally mono- or polysubstituted, (C₃-C₆) cycloalkyl, (C₃-C₆) cycloalkyl- (C₁-C₄) alkyl, (C₅- C₁₀ ) -Aryl, (C₅-C₁₀) -aryl- (C₁-C₄) -alkyl, H₂N, R⁸OR⁹, R⁸OC (O) R⁹, R⁸- (C₅- C₁₀) -aryl-R⁹, R⁸R⁸NR⁹, R⁸NHC (O) R⁹, R⁸C (O) NHR⁹, H₂N-C (= NH) -, H₂N- C (= NH) -NH-, = O;
R¹⁶ H, (C₁-C₆) alkyl, which can be substituted 1-6 times with F, (C₃-C₆) cycloalkyl, (C₃-C₆) cycloalkyl- (C₁-C₄) alkyl, phenyl, phenyl- ( C₁-C₄) alkyl, (C₂-C₆) alkenyl;
m 3, 4 or 5;
n 1 or 2; and
p, q independently of one another 0 or 1. 4. Compounds of formula I according to claims 1 to 3, in which:
W R¹-ABDC (R¹⁶);
YC = O;
ZN (R °);
A is a direct bond, (C₁-C₄) alkyl, -NR²-N = CR², -NR²-C (O) -NR²-, -NR²-C (O) O-, NR²-S (O) _n -, -NR²-S (O) _n -NR ^2- or -NR²-CO-, -NR²-, -N = CR², each of which can be substituted by NH and / or mono- or disubstituted by (C₁-C₄) alkyl ;
B is a direct bond, (C₁-C₄) alkyl, optionally substituted once or twice by (C₁-C₄) alkyl;
D is a direct bond, (C₁-C₄) alkyl or -O-, -NR²-, -NR²-CO-, -NR²-C (O) -NR²-, -R²N-S (O) ₂-NR²-, -NR²-S (O) ₂-, -NR²-S (O) - or -N = CR²-, -R²C-N, which can each be mono- or disubstituted by (C₁-C₄) alkyl;
E is a direct bond or (C₁-C₄) alkyl;
F is a direct bond, (C₁-C₆) alkyl, or -O-, -CO-NR²-, -NR²-CO-, -NR²-C (O) -NR²-, -S (O) ₂-NR²- , -NR²-S (O) ₂-, -CR² = CR³-, -C = C-, -N = CR²- or -R²C = N-, each substituted once or twice by (C₁-C₄) alkyl could be; R⁰ H, (C₁-C₆) alkyl, CF₃, C₂F₅, (C₅-C₆) cycloalkyl, (C₅-C₆) cycloalkyl- (C₁-C₂) alkyl, optionally substituted phenyl or optionally substituted benzyl on the phenyl radical;
R¹ R²R³N-C (= NR²), R², R³ independently of one another H, (C₁-C₆) alkyl, CF₃, CF₂CF₃, (C₅-C₆) - cycloalkyl, (C₅-C₆) cycloalkyl- (C₁-C₂) alkyl, phenyl, benzyl, H₂N, R⁸OR⁹ , R⁸- (C₅-C₁₀) arylR⁹, R⁸NHR⁹, R⁸R⁸NR⁹, R⁸NHC (O) R⁹, H₂N-C (= NH), H₂N-C (= NH) -NH-;
R⁴, R⁵, R⁶, R⁷ independently of one another H, F, OH, (C₁-C₆) alkyl, (C₅-C₆) cycloalkyl, (C₅-C₆) cycloalkyl- (C₁-C₆) alkyl, or R⁸OR⁹, R⁸- (C₅-C₁₀) arylR⁹, R⁸R⁸NR⁹, R⁸NHC (O) OR⁹, R⁸S (O) _n NHR⁹, R⁸OC (O) NHR⁹, R⁸C (O) NHR⁹;
R⁸ H, (C₁-C₆) alkyl, (C₅-C₆) cycloalkyl, (C₅-C₆) cycloalkyl- (C₁-C₂) alkyl, (C₅- C₁₀) aryl, (C₅-C₁₀) aryl - (C₁-C₂) alkyl;
R⁹ is a direct bond or (C₁-C₆) alkyl;
R¹⁰ C (O) R¹¹;
R¹¹ OH, (C₁-C₆) alkoxy, phenoxy, benzyloxy, (C₁-C₄) alkylcarbonyloxy- (C₁-C₄) alkoxy, NH₂, mono- or di- (C₁-C₆-alkyl) amino;
R¹⁶ H, (C₁-C₄) alkyl, CF₃, CF₂CF₃, (C₅-C₆) cycloalkyl, (C₅-C₆) cycloalkyl- (C₁- C₂) alkyl, phenyl, benzyl;
n 1 or 2; and
p, q independently of one another 0 or 1. 5. A process for the preparation of a compound of formula I according to Claims 1 to 4, characterized in that two or more Fragments that can be derived retrosynthetically from Formula I linked. 6. Use of the compounds of formula I according to claims 1 to 4 as a remedy.   7. Use of the compounds of formula I according to claims 1 to 4 as inhibitors of bone resorption by osteoclasts, as inhibitors of Tumor growth and tumor metastasis, as anti-inflammatory, for Treatment or prophylaxis of cardiovascular diseases, for Treatment or prophylaxis of nephropathies and retinopathies as well as Vitronectin receptor antagonists for the treatment and prophylaxis of Diseases related to the interaction between vitronectin receptors and whose ligands are based on cell-cell or cell-matrix interaction processes. 8. Pharmaceutical preparation containing at least one compound of Formula I according to claims 1 to 4 or their physiologically compatible Salts in addition to pharmaceutically perfect carriers and additives.