Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2001-01-12
2001-12-04
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C546S306000, C562S434000, C562S560000
Reexamination Certificate
active
06326403
ABSTRACT:
The invention relates to compounds of the formula I,
wherein
X is H
2
N—C(═NH)—, H
2
N—C(═NH)—NH—, A—C(═NH)—NH—, Het
1
— or Het
1
—NH—,
Y is
—(CH
2
)
s
—CH(R
4
)—(CH
2
)
t
— or —(CH
2
)
p
—Het
2
—(CH
2
)
q
—,
Z is —(CH
2
)
r
—R
5
,
R
1
, R
2
are each independently of one another H or A,
R
3
is H, F, Cl, Br, A, OA or OCF
3
,
R
4
is phenyl which is unsubstituted or substituted by F, Cl, Br, A, OA or OCF
3
,
R
5
is COOH, COOA, CONH
2
, SO
3
H, PO
3
H
2
or tetrazolyl,
Het
1
is a mono- or bicyclic heterocycle having 1 to 4 nitrogen atoms which may be unsubstituted or mono- or disubstituted by NH
2
,
Het
2
is a 5- or 6-membered aromatic heterocycle having 1 to 4 nitrogen and/or sulfur atoms which may be unsubstituted or mono- or disubstituted by F, Cl, Br, A, OA or OCF
3
,
A is alkyl having 1 to 6 carbon atoms,
n is 0, 1, 2, 3, 4, 5, 6, 7 or 8,
m, o, p,
q, r, s,
t are each independently of one another 0, 1, 2, 3, 4 or 5,
and their salts and solvates.
Partially similar compounds are known, for example, from U.S. Pat. No. 5,741,796.
The invention was based on the object of discovering novel compounds having valuable properties, in particular those which can be used for the preparation of medicaments.
It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties, coupled with a good tolerability. Above all, they act as integrin inhibitors, and in particular inhibit the interactions of the &agr;
v
-, &bgr;
3
- or &bgr;
5
-integrin receptors with ligands, such as, for example, binding of fibrinogen to the &bgr;
3
-integrin receptor. In the case of the integrins &agr;
v
&bgr;
1
, &agr;
v
&bgr;
3
, &agr;
v
&bgr;
5
, &agr;
IIb
&bgr;
3
and &agr;
v
&bgr;
6
and &agr;
v
&bgr;
8
, the compounds display particular activity; in particular, potent selective inhibitors of the vitronectin receptor &agr;
v
&bgr;
3
were found.
This action can be demonstrated, for example, by the method described by J. W. Smith et al. in J. Biol. Chem. 265, 12267-12271 (1990).
The dependence of the development of angiogenesis on the interaction between vascular integrins and extracellular matrix proteins has been described by P. C. Brooks, R. A. Clark and D. A. Cheresh in Science 264, 569-71 (1994).
The possibility of inhibiting this interaction, thus initiating apoptosis (programmed cell death) of angiogenic vascular cells, by a cyclic peptide has been described by 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).
Compounds of the formula I which block the interaction of integrin receptors and ligands, such as, for example, the binding of fibrinogen to the fibrinogen receptor (glycoprotein IIb/IIIa), prevent, as GPIIb/IIIa antagonists, the spreading of tumour cells by metastasis. This is confirmed by the following observations:
The compounds are capable of inhibiting binding of metalloproteinases to integrins, thus preventing the cells from utilizing the enzymatic activity of the proteinase. An example is found in the inhibition of MMP-2 (matrix metalloproteinase-2) binding to the vitronectin receptor &agr;
v
&bgr;
3
by a cyclo-RGD peptide, as described in P. C. Brooks et al., Cell 85, 683-693 (1996).
The spread of tumour cells from a local tumour into the vascular system takes place by the formation of microaggregates (microthrombi) by interaction of the tumour cells with blood platelets. The tumour cells are shielded by the protection in the microaggregate, and are not recognized by the cells of the immune system. The microaggregates can attach themselves to vessel walls, whereby further penetration of tumour cells into tissue is facilitated. Since the formation of the microthrombi is mediated by binding of fibrinogen to the fibrinogen receptors on activated blood platelets, the GPIIa/IIIb antagonists can be regarded as active metastasis inhibitors.
The compounds of the formula I can be employed as medicinally active substances in human and veterinary medicine, in particular for the prophylaxis and/or therapy of thrombosis, myocardial infarction, arteriosclerosis, inflammations, apoplexy, angina pectoris, tumour diseases, osteolytic diseases, such as osteoporosis, pathologically angiogenic diseases, such as, for example, inflammations, opthalmological diseases, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatic arthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis, Crohn's disease, atherosclerosis, psoriasis, restenosis after angioplasty, multiple sclerosis, viral infection, bacterial infection, fungal infection, in cases of acute renal failure and in cases of wound healing to assist the healing processes.
The compounds of the formula I can be employed as antimicrobially acting substances during operations where biomaterials, implants, catheters or cardiac pacemakers are used. Here, they have an antiseptic action. The efficacy of the antimicrobial activity can be demonstrated by the method described by P. Valentin-Weigund et al. in Infection and Immunity, 2851-2855 (1988).
Since the compounds of the formula I are inhibitors of fibrinogen binding and thus ligands of the fibrinogen receptors on blood platelets, they can be used as diagnostics for the detection and localization of thrombi in the vascular system in vivo if they are substituted, for example, by a radioactive or UV-detectable radical.
As inhibitors of fibrinogen binding, the compounds of the formula I can also be employed as effective auxiliaries for the study of the metabolism of blood platelets in different activation stages or of intracellular signal mechanisms of the fibrinogen receptor. The detectable unit of a “label” which has to be incorporated, for example isotope labelling by
3
H, permits the investigation of the abovementioned mechanisms after receptor binding.
The following abbreviations are used below:
Ac acetyl
Asp aspartic acid
Aza-Gly H
2
N-NH-COOH
BOC tert-butoxycarbonyl
CBZ or Z benzyloxycarbonyl
DCCI dicyclohexylcarbodiimide
DCM dichloromethane
DIPEA diisopropylethylamine
DMF dimethylformamide
EDCI N-ethyl-N,N′-(dimethylaminopropyl)-carbodiimide
Et ethyl
Fmoc 9-fluorenylmethoxycarbonyl
Gly glycine
HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetra-methyluronium hexafluorophosphate
HOBt 1-hydroxybenzotriazole
Me methyl
MBHA 4-methylbenzhydrylamine
Mtr 4-methoxy-2,3,6-trimethylphenylsulfonyl
NMP N-methylpyrrolidone
HONSu N-hydroxysuccinimide
OBzl benzyl ester
OtBu tert-butyl ester
Oct octanoyl
OMe methyl ester
OEt ethyl ester
Pbf 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl
POA phenoxyacetyl
Sal salicyloyl
TBTU O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate
TFA trifluoroacetic acid
Trt trityl (triphenylmethyl).
The compounds of the formula I have at least one chiral centre and can therefore be present in a plurality of stereoisomeric forms. All of these forms (for example D and L forms) and their mixtures (for example the DL forms) are embraced by the formula I.
The compounds according to the invention also include so-called prodrug derivatives, i.e. compounds of the formula I which are derivatized with, for example, alkyl or acyl groups, sugars or oligopeptides and which are rapidly cleaved in the organism to the active compounds according to the invention. These also include biodegradable polymer derivatives of the compounds according to the invention, as described, for example, in Int. J. Pharm, 115, 61-67 (1995).
Solvates are addition compounds of the compounds of the formula I with inert solvents. Solvates are, for example, a mono- or dihydrate or an adduct with alcohols, such as, for example, with methanol or ethanol.
The invention furthermore provides a process for preparing compounds of the formula I according to claim
1
and their salts, characterized in that
a) a compound of the formula II,
wherein X, Y, R
1
and R
2
are as defined in claim
1
and wherein free amino groups are protected by a suitable amino protective group, is reacted with a compound of t
Gibson Christoph
Goodman Simon
Holzemann Gunter
Kessler Horst
Schmitt Jörg Simon
Gerstl Robert
Merck Patent Gesellschaft mit
Millen White Zelano & Branigan P.C.
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