MXPA98010586A - Phenylalanin derivatives as laintegr inhibitors - Google Patents
Phenylalanin derivatives as laintegr inhibitorsInfo
- Publication number
- MXPA98010586A MXPA98010586A MXPA/A/1998/010586A MX9810586A MXPA98010586A MX PA98010586 A MXPA98010586 A MX PA98010586A MX 9810586 A MX9810586 A MX 9810586A MX PA98010586 A MXPA98010586 A MX PA98010586A
- Authority
- MX
- Mexico
- Prior art keywords
- phenyl
- oxo
- formula
- compounds
- guanidino
- Prior art date
Links
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 18
- 239000003112 inhibitor Substances 0.000 title claims abstract description 11
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical class OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 100
- 239000011780 sodium chloride Substances 0.000 claims abstract description 31
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 201000010099 disease Diseases 0.000 claims abstract description 15
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- 208000001132 Osteoporosis Diseases 0.000 claims abstract description 8
- 208000007536 Thrombosis Diseases 0.000 claims abstract description 8
- 230000001575 pathological Effects 0.000 claims abstract description 8
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 6
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- 230000033115 angiogenesis Effects 0.000 claims abstract description 4
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 4
- 230000000069 prophylaxis Effects 0.000 claims abstract description 3
- -1 COOA Chemical group 0.000 claims description 126
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 38
- 239000002253 acid Substances 0.000 claims description 32
- 150000002148 esters Chemical class 0.000 claims description 21
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 17
- 125000002947 alkylene group Chemical group 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- 125000006239 protecting group Chemical group 0.000 claims description 12
- 125000002252 acyl group Chemical group 0.000 claims description 10
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 230000002491 angiogenic Effects 0.000 claims description 8
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 8
- 206010061218 Inflammation Diseases 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
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- 125000000217 alkyl group Chemical group 0.000 claims description 6
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- 125000004433 nitrogen atoms Chemical group N* 0.000 claims description 5
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- 125000004430 oxygen atoms Chemical group O* 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- BMMSHDHMJYZEAB-HNNXBMFYSA-N (2S)-2-(butylsulfonylamino)-3-[4-[4-(diaminomethylideneamino)-4-oxobutoxy]phenyl]propanoic acid Chemical compound CCCCS(=O)(=O)N[C@H](C(O)=O)CC1=CC=C(OCCCC(=O)N=C(N)N)C=C1 BMMSHDHMJYZEAB-HNNXBMFYSA-N 0.000 claims description 3
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- 125000004429 atoms Chemical group 0.000 claims description 3
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 3
- 125000006588 heterocycloalkylene group Chemical group 0.000 claims description 3
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 3
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- ZFVKDHLGHXITCL-INIZCTEOSA-N C(CCC)S(=O)(=O)N[C@H](C(=O)O)CC1=CC=C(C=C1)OCCCCC(=O)NC(=N)N Chemical compound C(CCC)S(=O)(=O)N[C@H](C(=O)O)CC1=CC=C(C=C1)OCCCCC(=O)NC(=N)N ZFVKDHLGHXITCL-INIZCTEOSA-N 0.000 claims 1
- 238000010265 fast atom bombardment Methods 0.000 description 61
- 238000006243 chemical reaction Methods 0.000 description 36
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 36
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 35
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- 239000000126 substance Substances 0.000 description 32
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- NIDZRKDDYDJZBP-UHFFFAOYSA-N 4-bromobutanoyl cyanide Chemical compound BrCCCC(=O)C#N NIDZRKDDYDJZBP-UHFFFAOYSA-N 0.000 description 23
- 239000000203 mixture Substances 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- 238000003776 cleavage reaction Methods 0.000 description 16
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 12
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 8
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 210000004027 cells Anatomy 0.000 description 7
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- VLTRZXGMWDSKGL-UHFFFAOYSA-N Perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 6
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- 125000003277 amino group Chemical group 0.000 description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 4
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
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- 230000003993 interaction Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 4
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- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
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Abstract
The invention relates to the compounds of the formula I wherein X, Y, Z, R1, R2, R3 and R4 have the meanings indicated in claim 1, with the proviso that at least one element selected from the group consisting of X , Y, Z must be CH2, and its salts acceptable from the physiological point of view. The invention also relates to a process for preparing these compounds, to pharmaceutical preparations containing them and to the use thereof as integrin inhibitors, in particular for the prophylaxis and treatment of diseases of the circulatory system, thrombosis, myocardial infarction, coronorary diseases, arteriosclerosis, osteoporosis, pathological processes that are maintained or spread by angiogenesis and in tumor therapy
Description
DERIVATIVES OF PHENYLALANIN AS INHIBITORS OF THE INTEGRINE
Field of Invention
The invention relates to the compounds of formula I
where
X is absent or represents alkylene, arylene, cycloalkylene of 4 to 8 carbon atoms or heterocycloalkylene with 1 to 3 atoms of N, 0 and / or S which may be unsubstituted or mono, di or trisustuido with A, oxo and / or or R4
And, Z independently of one another, are absent or represent alkylene, 0, S,
REF .: 28903 NH, C (= 0), CONH, NHCO, C (= S), S02NH, NHS02,
CA = CA 'or -C = C-,
RJ represents H2N-C (= NH) or H2N- (C = NH) -NH, wherein the primary amino groups can also be protected with conventional amino protecting groups or can be substituted one, two or three times with A, Ar or R5, NH-CH2-R6, NH-R6, NH-C (= NH) -NH-R6 or R6,
R 'represents A, Ar or aralkylene,
R 'represents H or A,
R represents H, Hal, OA, NHA, NAA ', -NH-acyl, -O-acyl, CN, N02, SA, SOA, S02A, S02Ar, or S03H,
R- represents alkanoyl or cycloalkanoyl of 1 to 18 carbon atoms, in which one, two or three methylene groups may be replaced by N, O and / or S, Ar-CO- or Ar-alkylene-CO-, A A 'independently represent H, either alkyl or cycloalkyl of 1 to 15 unsubstituted C atoms or mono, di or trisus stained with R4 and wherein one, two or three methylene groups can be replaced by N, 0 and / or S,
Ar represents an aromatic ring system of one or two nuclei and with 0, 1, 2, 3 or 4 N, O and / or S atoms, which may be unsubstituted or mono, di or trisubstituted with A and / or R4,
Rc represents a heterocycle of one or two nuclei and with 1 to 4 N, O and / or S atoms, which may be unsubstituted or mono, di or trisubstituted with Hal, A, acyl, OH, CN, COOH, COOA, CONH2, N02, = NH or = 0,
Hal represents F, Cl, Br or I
with the proviso that at least one element chosen from the group consisting of X, Y, Z must be and its salts acceptable from the physiological point of view.
Background of the Invention
Similar compounds are disclosed, for example in European patents No. 478,363 and
478. 328 and in the world patents n ° 94/12181 and 95/32710.
Description of the invention
The aim of the invention was to develop new compounds with valuable properties, in particular compounds that can be used in the manufacture of medicines.
It was found that the compounds of formula I and their salts possess very valuable pharmacological properties and are well tolerated. First of all, they act as integrin inhibitors, in particular by inhibiting the interactions of the integrin av receptors with the ligands. These compounds have a particular effect in the case of the avß3 and avß5 injects. They are particularly effective as adhesion receptor antagonists in the case of the avr3 vitronectin receptor. This effect can be checked, for example, according to the method described by J.W. Smith et al. In J. Biol. Chem. 265, pages 11008 to 11013 and 12267 to 12271 (1990).
The inhibition of vitronectin binding to the receptors was tested experimentally with some representative compounds of formula I.
The data from pharmacological trials are summarized in Tables I and II.
B. Felding-Habermann and D.A. Cheresh describes in Curr. Opin. Cell. Biol. 5_, page 864 (1993) the meanings that the integrins have as adhesion receptors for the most diverse phenomena and clinical pictures, in particular with reference to the vitronectin avß3 receptor -
P.C. Brooks, R.A. Clark and D.A. Cheresh described in Science 264, pages 569-71 (1994), the dependence of the beginning of angiogenesis on the interaction between vascular integrins and extracellular matrix proteins.
The possibility of inhibiting this exchange and thus introducing apoptosis (programmed cell death) of angiogenic vascular cells by a cyclic peptide is described in Cell 79, pages 1157-64 (1994), by P.C. Brooks, A.M. Montgomery, M. Rosenfeld, R.A. Reisfeld, T. -Hu, G. Klier and D.A. Cheresh
The experimental verification that the compounds of the invention also prevent living cells from being fixed on the corresponding matrix proteins and, therefore, also that the tumor cells are fixed on the matrix proteins, was carried out by means of an assay of cell adhesion similar to the method employed by F. Mitjans et al in Cell Science 108 pages 2825 to 2838 (1995).
P.C. Brooks et al. Describe in J. Clin. Invest. 9_6, page 1815 to 1822 (1995) avß3 antagonists used to combat cancer and for the treatment of angiogenic diseases induced by tumors.
Therefore, the compounds of formula I of the invention can be used as active substances of medicaments intended, in particular, for the treatment of tumoral diseases, osteoporosis, osteolytic diseases and also to repress angiogenesis.
The compounds of formula I, which block the interaction of integrin receptors with ligands such as, for example, the binding of fibrinogen to the fibrinogen receptor
(glycoprotein Ilb / IIIa), act as antagonists of GPIIb / IIIa and prevent the proliferation of tumor cells by metastasis. This concept is supported by the following observations: the extension of tumor cells from a local tumor to the vascular system occurs due to the formation of microaggregates (microthrombi) by the interaction of tumor cells with platelets. The tumor cells are protected and camouflaged in the microaggregate and are not recognized by the cells of the immune system.
The microaggregates can be fixed to the walls of the vessels, which facilitates the internalization of the tumor cells in the tissue. Since the formation of microthrombi is facilitated by the binding of fibrinogen to the fibrinogen receptors in activated platelets, the GTPIIa / IIIb antagonists can be considered active inhibitors of metastasis.
The compounds of formula I inhibit both the binding of fibrinogen, fibronectin and illebrand factor to the fibrinogen receptor of the platelets as well as the binding of other adhesive proteins such as vitronectin, collagen and laminin, to the corresponding receptors on the surface of different cell types. In particular, they inhibit the formation of platelet thrombi and, therefore, can be used for the treatment of thromboses, strokes, myocardial infarction, inflammations and arteriosclerosis.
The properties of the compounds can also be checked according to the methods described in the European document Al-0 462 960. The inhibition of the fibrinogen binding to the fibrinogen receptor can be checked according to the method described in the European document Al-0 381 033 .
The experimental test that the compounds of the invention also motivate the inhibition of the binding of fibrinogen to the corresponding receptors has been carried out for some representative compounds of formula I. The data of the pharmacological tests are summarized in Table III.
The inhibitory effect of thrombocyte aggregation can be checked in vitro according to the Born method (Nature 4832, page 927-929, 1962).
Accordingly, the object of the invention is the compounds of formula I according to claim 1, and / or their physiologically acceptable salts which are used to prepare a medicament intended to be used as an integrin inhibitor. A particular object of the invention are the compounds of formula I, according to claim 1, and / or their physiologically acceptable salts, wherein R.sup.2 represents campidoxyl, compounds which are used to prepare a medicament intended to combat pathological angiogenic diseases, tumors, osteoporosis, inflammations and infections.
The compounds of formula I can be used in medicine and veterinary medicine as active substances of drugs used for the prophylaxis and / or therapy of thrombosis, myocardial infarction, arteriosclerosis, inflammations, stroke, angina pectoris, tumor diseases, osteolytic diseases such as osteoporosis, pathological angiogenic diseases such as, for example, inflammations, ophthalmological diseases, diabetic retinopathy, macular degeneration, myopia, hi s topl asmos is ocular, rheumatic arthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis, Crobus morbus, atherosclerosis, psoriasis, restenosis after angioplasty, viral infection, bacterial infection, fungal infection, acute renal insufficiency and in wound healing to help to the healing processes.
The compounds of formula I can be used as substances with an antimicrobial effect in operations in which biological materials, implants, a catheter or a pacemaker are used. In these cases they act as antiseptic substances. The effect of the antimicrobial activity can be checked according to the procedure described by P. Valentin-eigund et al. In "Infection and Immunity", pages 2851 to 2855 (1988).
Another object of the invention is a process for preparing compounds of formula I, according to claim 1, and their salts, characterized in that
a) a compound of formula I is released from one of the functional derivatives by treatment with a solvolysis or hydrogenolysis agent,
or b) a compound of formula II is reacted
wherein R1, R3, R4, X, Y and Z have the meanings indicated in claim 1, with a compound of formula III,
R -SO? -L (III)
where
R has the meaning indicated in claim 1 and L represents Cl, Br, I, OH or an esterified and reactive OH group,
saponify an ester of formula I, d) a residue R1 and / or R3 is transformed into another residue R1 and / or R3,
I
e) a base or an acid of formula I is converted to one of its salts by treatment with an acid or a base.
The compounds of formula I have at least one chiral center and therefore may have different stereoisomeric forms. Formula I encompasses all of these forms (e.g. forms D and L) and their mixtures (e.g., DL forms).
The compounds of the invention also include so-called prodrugs, that is, compounds of formula I that have been derivatized with, for example, alkyl or acyl groups, sugars or oligopeptides, which are rapidly cleaved in the body by releasing thus the active compounds of the invention.
The abbreviations indicated in this text mean the following:
Ac acetyl BOC terbutoxycarbonyl CBZ or Z benzyloxycarbonyl DCCI dicyclohexylcarbodiimide DMF dimethylformamide EDC1 N-ethyl-N, N '- (dimethylaminopropyl) -carbodiimide
Et ethyl Fmoc 9-fluorenylmethoxycarbonyl HOBt 1-hydroxybenzotriazole Methyl 4-methoxy-2,3,6-trimethylphenylsulfonyl HONSu N-hydroxysuccinimide OBn benzoate OBut terbutyl or Oct octanoyl OMe methylate OEt ethylate POA phenoxyacetyl TBTU tetrafluoroborate O- (benzotriazole -1-yl) - N, N, N, N-tetramethyluronium TFA trifluoroacetic acid trityl (triphenylmethyl) tr.
All the remains that are mentioned in the text of the invention and that appear repeatedly as, for example, A and A ', can be the same or different, that is, they are independent of each other.
In the formulas indicated above, alkyl preferably represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tertbutyl, then also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2, 2 -dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2, 3- or 3, 3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1, 2, 2-t-ri et-il-propyl, heptyl, octyl, nonyl or decyl.
Cycloalkyl preferably represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or 3-menthyl. In particular, cycloalkyl represents the remainder of a bicyclic terpene and more preferably the campyl-1-yl moiety.
Alkylene preferably represents methylene, ethylene, propylene, butylene, pentylene, then also hexylene, heptylene, octylene, nonylene or decylene.
Aralkylene preferably represents alkylenephenyl and is, for example, preferably benzyl or phenethyl.
Cycloalkylene preferably represents cyclopropylene, 1,2- or 1,3-cyclobutylene, 1,2- or 1,3-cyclopentylene, 1,2-, 1,3- or 1,4-cyclohexylene, then 1,2-, 1,3- or 1,4-cycloheptylene.
Alkanoyl preferably represents formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, t-ridecanoyl, ededecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl or octadecanoyl.
Acyl preferably represents, for example, formyl, acetyl, propionyl, butyryl, tr.i fluoroacetyl or benzoyl.
Preferred substituents of alkyl, alkylene, cycloalkyl, cycloalkylene, alkanoyl and cycloalkanoyl are, for example, Hal, OA, NHA, NAA ', CN, N02, SA, SOA, S02A, S02Ar and / or S03H, in particular, for example , F, Cl, hydroxy, methoxy, ethoxy, amino, dimethylamino, methylthio, methylsulfinyl, methylsulfonyl or phenylsulfonyl.
Preferred substituents of Ar and arylene are, for example, A and / or Hal, OA, NHA, NAA ', CN, SA, SOA, S02A, S02Ar and / or S03H, in particular, for example, F, Cl, hydroxy , methoxy, ethoxy, amino, dimethylamino, methylthio, methylsulfyl, methylsulfonyl or phenylsulfonyl.
In each of the alkyl, alkylene, cycloalkyl, cycloalkylene, alkanoyl and cycloalkanoyl moieties there may be one, two or three methylene groups that are replaced by N, O and / or S.
Ar-CO is aroyl and preferably represents benzoyl or naphthoyl.
Ar represents unsubstituted phenyl, preferably - as indicated above - monosubstituted phenyl, in particular, preferably phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, or-, m- or p-propyl phenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-cyanophenyl, o-, m- or p-methoxyphenyl, or-, m- or p-ethoxy phenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenium, o-, m- or p-methyl thiophenyl, or- , m- or p-methylsulfinylphenyl, o-, m- or p-methylsulfonylphenyl, o-, m- or p-aminophenyl, o-, m- or p-methylaminophenyl, o-, m- or p-dimethylaminophenyl, or -, m- or p-nitrophenyl, then preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4 -, 2,5-, 2,6-, 3,4 or 3, 5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3, 5 -bibromophenyl, 2-chloro-3-methyl-1-yl, 2-chloro-4-ethyl-, 2-chloro-5-methyl-2, 2-chloro-6-methyl, 2-methyl-3-chloro, 2-methyl-4-chloro-, 2-methyl-5-chloro-, 2-methyl-6-chloro-, 3-chloro-4-methyl-, 3-chloro-5-methyl- or 3-methyl-4-chlorophenyl, 2-bromo-3-met il-, 2-bromo-4-me t il-, 2 -bromo -5-me-butyl-, 2-bromo-6-methyl-, 2-methyl-3-bromo-, 2-met-il-4-bromo-, 2-me t -yl-5-bromo-, 2 -met il-6-bromo-, 3-bromo-4-methyl-, 3-bromo-5-met il- or 3-methyl-4-bromo-phenyl, 2,4- or 2,5-dini-tro-phenyl, 2, 5- or 3,4-dimethoxyphenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6 -triterb-butylphenyl, 2,5-dimethylphenyl, p-iodophenyl, 4-fluoro-3-chlorophenyl, 4-fluoro-3,5-dimethylphenyl, 2-fluoro-4-bromo-phenyl, 2,5-difluoro-4-bromo-phenyl, , 4-dichloro-5-methylphenyl, 3-bromo-6-methoxyphenyl, 2-methoxy-5-methyl phenyl, 2,4,6-triisopropylphenyl, naphthyl, 1,3-benzodioxol-5-yl, 1,4- benzodioxan-6-yl, benzothiadiazol-5-yl or benzoxadiazol-5-yl.
Ar also preferably represents 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-i soxa zolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothione zolyl, 2-, 3-or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, then preferably 1, 2, 3-triazol-1-, -4- or -5-yl, 1,2, 4-triazol-l-, -3- or -5-yl, 1- or 5-tetrazolyl, 1, 2, 3-oxadiazol-4 - or -5-yl, 1,2,4-oxadiazol-3- or 5-yl, 1, 3, 4-liadiazol-2 - or -5-yl, 1, 2, 4-thiadiazol-3- or -5-yl, 1, 2, 3 -1i-adiazole-4 - or - 5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7 -benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzoisoxazolyl, 2-, 4-, 5-, 6- or 7 -be nzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6 or 7-benzo-2, 1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinoline, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinolinyl , 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl.
Arylene has the same meanings as Ar, but with the proviso that the aromatic system is linked to the nearest neighbor by means of yet another union.
Heterocycloalkylene preferably represents 1,2-, 2,3- or 1,3-pyrrolidinyl, 1,2-, 2,4-, 4,5- or 1,5-imidazolidinyl, 1,2-, 2,3-or 1,3-pyrazolidinyl, 2,3-, 3,4-, 4,5- or 2,5-oxazolidinyl, 1,2-, 2,3-, 3,4- or 1,4-isoxazolidinyl, 2 , 3-, 3,4-, 4,5- or 2,5-thiazolidinyl, 2,3-, 3,4-, 4,5- or 2,5-isothiazolidinyl, 1,2-, 2,3- , 3,4- or 1,4-piperidinyl, 1,4- or 1,2-piperazinyl, then preferably 1,2,3-tetrahydro-triazol-1,2- or 1,4-yl, 1, 2, 4-tetrahydro-triazole-1, 2- or 3,5-yl, 1,2- or 2,5-tetrahydrotetrazolyl, 1,2,3-tetrahydrooxadiazol-2, 3-, -3,4-, -4, 5- or -1,5-yl, 1, 2,4-t-tetrahydrooxadiazol-2, 3-, -3,4- or -4,5-yl, 1, 3, 4 -te thrahydro-thiadiazole- 2, 3 -, -3,4-, -4,5- or -1,5-yl, 1, 2, 4-t-tetrahydro-thiadiazole-2, 3-, -3,4-, -4,5 - or -1,5-yl, 1, 2, 3-thiadiazol-2, 3-, -3,4-, -4,5- or -1,5-yl, 2,3- or 3, 4- morpholinyl, 2,3-, 3,4- or 2,4-t -omorphonylinyl.
R represents preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or
-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or
-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pi rimidinyl, then preferably 1, 2, 3 -1ria zol-1 -, -4- or -5-yl,
1, 2, 4-t-riazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4- oxadiazol-3-y-5-yl, 1, 3, 4-tiadiazol-2-y-5-yl, 1, 2,4-thiadiazol-3-y-5-yl, 1,2,3-thiadiazole -4- or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-H-thiopyranyl, 3- or 4-pyridazyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5- , 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzoisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benzo-2, 1, 3-oxadia z oli lo, 2-, 3-, 4-, 5-, 6-, 7- or 8 -quinoline, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8 -cynolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl.
The heterocyclic moieties may also be partially or totally hydrogenated.
Thus, R can also represent, for example, 2, 3-dihydro-2 -, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or - 5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tert-rahydro-2-o -3-thienyl, 2,3-dihydro-1 -, -2-, - 3-, - 4 - or -5-pyrrolyl, 2,5-dihydro-l-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro- 1-, -2- or -4-imidazolyl, 2,3-dihydro-l-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4 -pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1, 2, 3, 4 -tet rahydro-1-, -2-, -3-, -4- , 5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or -morpholinyl, tet rahydro-2-, -3- or -4-pyranyl, 1,4- dioxanyl, 1,3-dioxan-2-, 4- or 5-yl, hexahydro-1 -, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1, 2, 3, 4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8- quinoline, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinoline.
An amino-protecting group is preferably understood to be acetyl, propionyl, butyryl, phenylacetyl, benzoyl, toluyl, POA, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl, CBZ, (carbobenzoxy), 4 - I am toxibenzyloxycarbonyl, FMOC, Mtr or benzyl.
Therefore, a particular object of the invention are those compounds of formula I in which at least one of the mentioned moieties has one of the preferred meanings indicated above. Some preferred groups of compounds can be represented by the partial formulas ai I which are indicated below which correspond to formula I and in which the radicals which are not explicitly stated have the meanings indicated for formula I, namely:
in the) R1 represents H2N-C (= NH), X represents alkylene of 1 to 6 carbon atoms, Y represents O, R2 represents A, represents H; in Ib) represents H2N- (C = NH) -NH, represents alkylene of 1 to 6 C atoms, Y represents O, R2 represents A, R3, R4 represent H; in le) X represents alkylene of 1 to 6 carbon atoms, Y is absent, R3, R4 represent H and represents aryl;
in Id) R1 represents H2N- (C = NH) -NH, X represents alkylene of 1 to 6 carbon atoms, Y represents CONH, R3, R4 represent H and represents A; in le) represents alkylene of 1 to 6 atoms Y represents O or CO-NH, Z is absent, R2 represents canfo-10-yl, R3 represents H or A and R4 represents H; in If) R1 represents H2N-C (= NH) or H2N- (C = NH) -NH, X is absent, Y represents alkylene of 1 to 6 C atoms, represents O, represents A, represents H; in Ig) R1 represents H2N-C (= NH) or H2N- (C = NH) -NH, X is absent, Y represents alkylene of 1 to 6 C atoms, represents O, represents canfo-10-yl, R * represent H; in Ih) R1 represents NH-CH2-R6, NH-R6 or R6, X is absent, Y represents alkylene of 1 to 6 carbon atoms, represents O, R? represents canfo-10-yl, R? represent H; in Ii) R1 represents H2N-C (= NH) or H2N- (C = NH) -NH, wherein the primary amino groups may also be protected with conventional amino protecting groups or may be substituted one, two or three times with A, Ar or R5, NH-CH2-R6, NH-R6 or R6, X is absent, represents alkylene of 1 to 6 C atoms, represents O, is canfo-10-yl, RJ represents H or A, R4 is H, R5 represents acetyl or benzyloxycarbon and R6 represents a heterocycle of one or two nuclei and with 1 to 4 N, O and / or S atoms, which may be unsubstituted or substituted one, two or three times with Hal, A, acyl, OH, = NH u = 0.
In general, both the compounds of formula I and the starting materials for their preparation are prepared according to known methods, as described in the literature (for example, in certain works such as Houben-Weyl, "Methoden der organischen Chemie "(Methods of Organic Chemistry), Geor fg-Thieme-Verlag, Stuttgart) and under reaction conditions that are known and suitable for the reactions mentioned. You can also make use of known variants of these methods that are not detailed in this text.
If desired, the starting materials can be prepared in situ, but in such a way that instead of isolating them from the reaction mixture they are directly reacted to form the compounds of formula I.
To obtain the compounds of formula I they can be released from one of their functional derivatives by treatment with a solvolysis or hydrogenolysis agent.
As starting substances for solvolysis or hydrogenolysis, those which satisfy the formula I are preferred, but instead of one or more free amino groups and / or free hydroxyl groups they contain amino and / or hydroxyl groups correspondingly protected, preferably those which instead of an H atom attached to an N atom carry an amino protecting group, in particular those which instead of a group of NH carry a group of R'-N, where R 'is a group Amino protector, and / or those which, instead of the H atom of a hydroxyl group, carry a hydroxyl protecting group, for example, those which correspond to formula I, but instead of a group of COOH carry a COOR group '', where R "is a hydroxyl protecting group.
There can also be several groups, the same or different, of protected amino and / or hydroxyl in the starting material molecule. If the protective groups present are different from each other, then they can be removed in many cases selectively.
The term "amino protecting group" is known and refers to groups that are adapted to protect (block) an amino group from chemical reactions, but which can be easily removed after having carried out the desired chemical reaction in other places of the molecule. Typical examples of these groups are, in particular, the unsubstituted groups of acyl, aryl, aralkoxymethyl or aralkyl. Since amino-protecting groups are removed after the desired reaction (or sequence of reactions) has elapsed, the type and size of the same is not a critical point; however, those groups from 1 to 20, in particular from 1 to 8, C atoms are preferred. In the context of the process of the present invention, the expression "acyl group" has a very broad interpretation. It encompasses acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic or sulfonic acids such as, in particular, the alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of acyl groups of this type are the alkanoyl groups such as acetyl, propionyl and butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as POA; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroet oxycarbonyl, BOC, 2-iodo-toxicarbonyl; aralkyloxycarbonyl such as the CBZ
("carbobenzoxy"), 4-methoxybenzyloxycarbonyl,
FMOC; aryl sulfonyl such as Mtr. Preferred amino protecting groups are BOC and Mtr, then CBZ, Fmoc, benzyl and acetyl.
The separation of the amino protecting group is carried out - depending on the protecting group used - for example, with strong acids, conveniently with TFA or perchloric acid, but also with other strong inorganic acids such as hydrochloric or sulfuric acid, with carboxylic acids strong organics such as trichloroacetic acid, or with sulfonic acids such as benzenesulfonic or p-toluensulonic. It is possible to carry out the reaction in an additional inert solvent, but the presence thereof is not indispensable in all cases. As inert solvents, organic solvents such as, for example, carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, can be used. also alcohols such as methanol, ethanole or isopropanol, and water. Mixtures of these solvents can also be used. The TFA is preferably used in excess and without the additional addition of another solvent; the perchloric acid is used in the form of a mixture composed of acetic acid and 70% perchloric acid in a ratio of 9: 1. The reaction temperatures for the cleavage are conveniently between about 0 and about 50 ° C, preferably between 15 and 30 ° C (room temperature).
The BOC, Obut and Mtr groups can be cleaved preferably with, for example, TFA in dichloromethane or with about 3N HCl to 5N in dioxane, at a temperature comprised between 15 and 30 ° C; The FMOC group can be cleaved using a 5-50% solution of dimethylamine, diethylamine or piperidine in DMF, at a temperature between 15 and 30 ° C.
Protective groups that are separated by hydrogenolysis (eg, CBZ or benzyl) can be removed, for example, by treatment with hydrogen in the presence of a catalyst (for example, a noble metal catalyst such as palladium, conveniently on a support like coal). Suitable solvents are the same as mentioned above, in particular alcohols such as methanol or ethanol, or amides such as DMF. In general, the hydrogenolysis is carried out at temperatures between approximately 0 and 100 ° C and pressures between approximately 1 and 200 bar, preferably at temperatures between 20 and 30 ° C and pressures comprised between 1 and 10 bar. The hydrogenolysis of the CBZ group proceeds favorably with, for example, 5-10% Pd / C in methanol or with ammonium formate (instead of hydrogen) over Pd / C in methanol / DMF, at temperatures between 20 and 30 ° C.
The compounds of formula I can be prepared preferably by reaction of compounds of formula II with compounds of formula III. In general, the starting compounds of formulas II and III are new. However, they can be prepared according to methods known per se.
In the compounds of formula III L, preferably represents Cl, Br, I or an OH group transformed into a reactive group such as, for example, a group of alkyl sulphonyloxy having from 1 to 6 carbon atoms (preferably me t-sulfonyloxy) or of aryl sulphonyloxy of 6 to 10 C atoms (preferably phenylsul fonyloxy or p-tolylsulfonyloxy).
In general, the reaction of the compounds of formula III is carried out in an inert solvent and in the presence of an acid trapping agent, preferably an organic base such as triethylamine, dimethylaniline, pyridine or quinoline.
The addition of an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or another alkaline or alkaline earth metal salt of a weak acid, preferably of a potassium salt, sodium calcium or cesium may also be suitable.
Depending on the conditions employed, the reaction time may be from a few minutes up to 14 days and the reaction temperatures are between approximately -30 and 140 °, generally between -10 ° and 90 °, in particular between approximately 0 °. and approximately 70 °.
Among the suitable inhertes solvents there may be mentioned, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; esters such as diethyl ether, di-isopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomer, t-ether (methyl glycol) or ethylene glycol monoethyl ether (ethyl glycol), and tileglycoldime thyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); carbon sulfide; carboxylic acids such as formic or acetic acid; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate, water or mixtures of the solvents mentioned.
Another possibility is to saponify an ester of formula I. This reaction is conveniently carried out by solvolysis or hydrogenolysis, as indicated above, for example, with NaOH or KOH in dioxane-water, and at temperatures between 0 and 60 ° C, preferably between 10 and 40 ° C.
It is also possible to transform a radical R1 and / or R3 into another radical R1 and / or R3.
In particular, a carboxylic acid can be converted to a carboxylic acid ester.
The transformation of a cyano group into an amidino group is carried out by reaction with, for example, hydroxylamine and then by reduction of the N-hydroxyamidine with hydrogen in the presence of a catalyst such as, for example, Pd / C.
It is also possible to replace a conventional amino protecting group with hydrogen by cleaving the protecting group by solvolysis or hydrogenolysis, as described above, or by solvolysis or hydrogenolysis to liberate an amino group protected with a conventional protecting group.
A base of formula I can be converted into its salt by the addition of an acid, for example, by reaction of equivalent amounts of the base and the acid in an inert solvent such as ethanol and then by evaporation of the latter. For this reaction, acids that form physiologically acceptable salts are particularly suitable. Therefore, inorganic acids such as, for example, sulfuric acid, nitric acid, hydrocides such as hydrochloric or hydrobromic acid, forphoric acids such as orthophoric acid, sulphamic acid, then also organic acids can be used , in particular the aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulphonic or sulfuric acids such as, for example, formic, acetic, propionic, pivalic, diethylactic, malonic, succinic, pimelic, fumaric acid , maleic, lactic, tartaric, malic, citric, gluconic, ascorbic, nicotinic, isonicotinic, phonic or phthalic acid, ethansulonic, ethanedi sulphonic, 2-hydroxy-ethanesulonic, benzenesulfonic, p-toluenesul phonic, naphthalene monophonic, naphthaleonic phonic and lauryl sul phonic. Salts of physiologically unacceptable acids, for example picrates, can be used to isolate and / or purify the compounds of formula I.
An acid of formula I can also be converted into one of its physiologically acceptable metal or ammonium salts by treatment with a base. Particularly preferred salts are sodium, potassium, magnesium, calcium and ammonium salts, then also substituted ammonium salts, for example, dimethylamine, diethylammonium or diisopropylammonium salts, monoethanolammonium or diethylammonium salts, cyclohexylammonium salts , dici clohexilamonio, dibenci letilendiamoni or, and also, for example, the salts formed with arginine or lysine.
The compounds of formula I have one or several chiral centers, whereby they can be obtained as racemates or in their optically active forms. The obtained racemates can be separated into their enantiomers by known chemical or mechanical methods. From the racemic mixture, the diastereomers are formed preferably by reaction with an optically active separation agent. Examples of suitable separation agents are optically active acids such as the D and L forms of tartaric, diacetyltartaric, dibenzoyl tartaric, mandelic, malic, lactic acids, or the various optically active camphorsulfonic acids such as β-camphorsulfonic acid. It is also convenient to separate the enantiomers through a column filled with an optically active separation agent (for example dinitribenzoyl-phenyl-glycine); As the mobile phase, a hexane / isopropanol / acetonitrile mixture can be used, for example, in a volume ratio of, for example, 82: 15: 3.
Of course it is also possible to obtain optically active compounds of formula I according to the methods described above, by employing optically active starting substances.
The results of the inhibition assay of ctvß3 and avßs caused by some representative compounds of formula I are summarized in Tables I and II below. The IC50 values of the vitronectin binding assay are also indicated, ie the concentrations in nmol / liter that inhibit the binding of vitronectin to the corresponding isolated receptor by 50%.
Table I
IC50 values (concentrations in nmol / liter that inhibit the binding of vitronectin to the isolated receptor by 50%) of representative compounds of formula I, obtained analogously to the method of Smith et al., J. Biol. Chem-265 , page 12267-71 (1990), and the FAB measurements of the substances.
(I)
R * FAB IC 5, 0 I heard .. IC 50 v ^
(1) butyl H propylene 0 471 6.5 55
H butyl H propylene 0 429 1.1 2.1
(2) butyl H propylene 0 563 92 (2) (A) H propylene 0 657 61 136
H (A) H Propylene O 523 0.13 0.16
H (A) ethyl propylene 0 551 16 13 ethyl butyl H propylene 0 457 0.81 (2) (A) H butylene 0 671 252 H 4-tolyl H butylene 0 477 4.6 H butyl H butylene 0 443 6.2 H (A) H butylene 0 537 0.45
(1) = acetyl; (2) = benzyloxycarbonyl; (A) = (S) -confo- 10 - ilo
Table I I
IC50 values (concentrations in nmol / liter that inhibit the binding of vitronectin to the isolated receptor by 50%) of representative co-compounds of formula I, obtained analogously to the method of Smith et al., J. Biol. Chem. 265 , page 12267-71 (1990), and the FAB measurements of the substances
FAB IC 50 < * &
(1) (A) H _ CH2 0 569 6.9
(1) (A) H - propylene 0 597 7.0
(2) (B) H - propylene 0 564 82
(3) (B) H - propylene 0 547 33
(1) (B) H - CH2 0 583 25
(4) (B) H - propylene 0 547 0.5
(5) (B) H - propylene 0 577 970 (avß5)
(6) (B) H - propylene 0 639 61
(4) (B) et.ilo - propylene 0 575 100
(1) (B) et.ylpropylene 0 625 98
(7) (B) H CH2-CH2 CONH-549 45
(4) (B) H - CH2 0 519 55
(A) = (S) -canfo-10-yl (B) = (R) -canfo-10-yl 'The pharmacological data demonstrate the antagonistic activity of the compounds of formula I of the invention for the vitronectin receptors avß3 and avßs.
The results of the inhibition of GPIIb / IIIa for some representative compounds of formula I are summarized in Table III below. The IC50 values are indicated, ie the concentrations in nmol / liter that inhibit by 50% the binding of fibrinogen to the corresponding isolated receptors.
Table III
IC50 values (concentrations in nmol / liter that inhibit the binding of fibrinogen to the isolated receptor by 50%) of representative compounds of formula I, and the measured values of FAB.
R3 RJ FAB IC50 GPIIblIIa
(1) Butyl H propylene O 471 1860
H butyl H propylene O 429 16
(2) Butyl ^ T y propylene O 563 5600
(2) (A) H propylene or 657 167
H (A) H Propylene O 523 1,
H (A) ethyl propylene O 551 78
(1) = acetyl; (2) = benzyloxycarbonyl;
(A) = (S) -ca? Fo-10-ilo
The pharmacological data show the antagonist activity of the compounds of formula I of the invention for the fibrinogen receptor GPIIblIIa.
The invention also relates to the use of the compounds of formula I and / or their physiologically acceptable salts for preparing pharmaceutical preparations, in particular by a non-chemical route. For these purposes, the compounds can be brought into a suitable dosage form, together with at least one solid, liquid and / or semi-liquid auxiliary excipient or auxiliary product and, optionally, in combination with one or more additional active substances.
The invention also relates to pharmaceutical preparations containing at least one compound of formula I and / or one of its physiologically acceptable salts.
These preparations can be used in medicine and veterinary medicine as a medicine. Among the excipients, mention may be made of organic or inorganic substances which are suitable for enteral (for example, oral), parenteral, topical application or for application in the form of an inhaled aerosol solution, and which do not react with the new compounds. Examples of these excipients are water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerin triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petrolatum. For oral administration, in particular, tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used for the rectal application of suppositories, for parenteral application the solutions, preferably the oily solutions or aqueous, and also suspensions, emulsions or implants, and for topical application, ointments, creams or powders. The new compounds can also be lyophilized and the resulting lyophilized products can be used, for example, for the preparation of injectable preparations. The aforementioned preparations can be sterilized and / or contain auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifying agents, salts for influencing the osmotic pressure, pH regulating substances, dyes, taste-correcting substances and / or various additional active substances such as, for example, one or several vitamins.
For the application in the form of aerosol inhaling solution, aerosols may be used which contain the active substance either dissolved or suspended in a carrier gas or in a mixture of gases (for example, C02 or chlorofluorocarbons). The active substance particles usually have a micron size, and it is also possible to add one or more additional solvents that are physiologically acceptable, such as, for example, ethanol. Inhalant solutions can be administered using conventional inhalers.
The compounds of formula I and their physiologically acceptable salts can be used as integrin inhibitors to combat diseases, in particular pathological angiogenic diseases, thrombosis, myocardial infarction, coronary diseases, arteriesclerosis, tumors, inflammations and infections
To combat pathological angiogenic diseases, tumors, osteoporosis, inflammations and infections, the compounds of formula I according to claim 1, and / or physiologically acceptable salts thereof, wherein R2 represents canfo-10, are preferred. -ilo.
The substances of the invention are generally administered analogously to the other known and commercial peptides, in particular, in a manner analogous to that of the compounds described in US Pat. No. 4,472,305, preferably in doses between approximately 0.05 and 500 mg, in particular between 0.5 and 100 mg per dosage unit. The daily dose is preferably between about 0.01 and 2 mg / kg of body weight. However, the particular dose for each patient depends on a wide variety of factors, for example, the effect of the particular compound used, age, body weight, general state of health, sex, diet, of the time and method of administration, the rate of excretion, the combination of drugs and the severity of the particular disease to which the therapy is applied. Parenteral application is preferred.
All temperatures of the present text are given in ° C. In the examples that follow, the expression "is worked (or treated) in the usual way" means the following: if necessary, water is added, if necessary the pH is adjusted between 2 and 10 depending on the constitution of the final product it is extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulphate, concentrated by evaporation and purified by chromatography on silica gel and / or by recrystallization.
Mass spectrometry (MS): The (electronic impact ionization M + FAB (fast atom bombardment) (M + H) + Example 1
A solution of 25 g of benzyloxycarbonyl-L-tyrosine terbutyl ester, 29 ml of ethyl 4-bromobutyrate, 18.7 g of potassium carbonate and 1.8 g of 18-cro n-6 in 300 ml of toluene for 12 hours at 85 °. After working the mixture in the usual manner, 25.3 g of (2S) -2-benzyloxycarboxamido-3- [4- (4-ethoxy-4-oxo-butyloxy) -phenyl] -propylene tertbutyl ester ("A") are obtained. ) to colorless syrup state; FAB 486
To a solution of 10 g of "A" in 70 ml of ethyl acetate, 20 ml of methanol, 10 ml of water and 2 ml of TFA is added 1 g of 10% palladium on activated carbon and hydrogenated with hydrogen for 4 hours. hours at room temperature. After removing the catalyst and working the product in the usual manner, 8.8 g of (2 S) -2-amino-3- [4- (4-ethoxy-4-oxo-butyloxy) -phenyl] -propionate are obtained. of terbutyl, tri f luoroacetate ("B"); FAB 352.
At room temperature, a solution of 8.8 g of "B" in 100 ml of dichloromethane is mixed with 5.5 ml of triethylamine and 3.9 ml of 1-butanesulfonyl chloride and stirred for 5 hours. After working the mixture in the usual manner, 7.9 g of tert-butyl (2S) -2-butylsulfonamido-3- [4- (4-ethoxy-4-oxo-butyloxy) -phenyl] -propionate are obtained; FAB 472.
Analogously, by reaction of "B" with (S) - (+) - canfo-10-sulphonyl chloride, the (2S) -2- [(S) -canfo-10-sulfonamido] -3 is obtained - [4- (4-Ethoxy-4-oxo-butyloxy) -phenyl] -propionate of tert-butyl; FAB 566 with 4-tolylsulfonyl chloride, tert-butyl (2S) -2-tolyl-sulfonamido-3- [4- (4-ethoxy-4-oxo-butyloxy) -phenyl] -propionate; FAB 506
A solution of 7.9 g of (2S) -2-butylsulfonamido-3- [4- (4-ethoxy-4-oxo-butyloxy) -phenyl] -propionate of tertbutyl and 10 ml of 2N sodium hydroxide is stirred in 75 ml of methanol for 12 hours at room temperature. After working the product in the usual manner, (2S) -2-butylsulfonamido-3- [4- (3-carboxy-propyloxy) -phenyl] -propionate of terbutyl is obtained in the state of colorless syrup; FAB 444.
Analogously, it is obtained, by cleavage of the ethyl ester, from (2 S) -2 - [(S) -canfo-l 0 -sulfonamido] -3- [4- (4-ethoxy-4-oxo-butyloxy ) -phenyl] -propionate of terbuti or terbutyl (2S) -2 - [(S) -canfo-10-sulfonamido] -3- [4- (3-carboxy-propyloxy) -phenyl] -propionate; FAB 538 and from (2S) -2-tolylsulfonamido-3- [4 - (4-ethoxy-4-oxo-butyloxy) -phenyl-tert-butyl propionate (2S) -2-tolylsulfonamido-3- [4- ( Terbutyl 3-carboxypropyloxy) -phenyl] -propionate; FAB 478.
To a solution of 1.3 g of (2S) -2-butylsulfonamido-3- [4- (3-carboxy-propyloxy) -phenyl] -propylene tertbutyl in 15 ml of DMF is added 1.1 g of iodide of 2-chloro-1-methylpyridinium, 3.9 ml of e-tildii sopropylamine and 2.8 g of Z-guanidine and then stirred for 12 hours at room temperature. After working the reaction mixture in the usual manner, 1.0 g of (2S) -2-butylsulfonamido-3- [4 - (4-N-benzyloxycarbonyl-guanidino-4-oxo-butyloxy) -phenyl] -propionate is obtained. of terbutyl; FAB 619
Analogously, from (2 S) -2 - [(S) -canfo-l-0-sulfonamido] -3- [4- (3-carboxy-propyloxy) -phenyl] -propionate of tert-butyl, the (2S) -2- [(S) -canfo-l-sulfonamido] -3- [4-N-benzyloxy -carbonyl-guanidino-4-oxo-butyloxy) phenyl] -tertbutylpropionate; FAB 713 and from (2 S) -2-lolyl sulfonamido-3 - [4- (3-carboxy-propyloxy) phenyl] -tripebutylpropionate, (2S) -2-tolylsulfonamido-3- [4- (4- N-benzyloxycarbonyl-guanidino-4-oxo-butyloxy) -phenyl] -propionate of tertbutyl; FAB 653
Example 2
To a solution of 1 g of tert-butyl (2S) -2-butylsulfonamido-3- [4- (4-N-benzyloxycarbonyl-guanidino-4-oxo-butyloxy) phenyl] -propionate in 18 ml of dioxane and 2 ml of 250 mg of palladium (10% on activated charcoal) are added to the water and hydrogenated for 3 hours at room temperature. After removing the catalyst and working the product in the usual manner, 0.78 g of (2S) -2-butylsulfonamido-3- [4- (4-guanidino-4-oxo-butyloxy) -phenyl] -propionate is obtained. of terbutyl; FAB 485
Analogously, it is obtained from (2S) -2 - [(S) -canfo-l 0-sulphonamido] -3- [4- (4-N-benzyloxycarbonyl-guanidino-4-oxo-butyloxy) - Terbutyl phenyl] -propionate, (2S) -2 - [(S) -canfo-l-sulfonamido] -3- [4- (4-guanidino-4-oxo-butyloxy) -phenyl] -tertbutylpropionate; FAB 579 and from (2S) -2- 1-Silyl sulfonamido-3- [4- (4-N-benzyloxycarbonylguanidino-4-oxo-butyloxy) -phenyl] -propionate terbutyl, (2S) -2-tolylsulfonamido - 3- [4- (4-guanidino-4-oxo-butyloxy) -phenyl] -propionate of tertbutyl; FAB 519.
E j us 3
To a solution of 0.78 g of (2S) -butyl-sulfonamido-3- [4- (4-guanidino-4-oxo-butyloxy) phenyl] -propylene tertbutyl in 20 ml of dichloromethane is added 2 ml of TFA and Stir for 12 hours. After working the mixture in the usual manner and freeze drying, 0.87 g of (2 S) -2-butylsulfonamido-3- [4 - (4-guanidino-4-oxo-butyloxy) -phenyl] -propionic acid is obtained, trifluoroacetate, at the state of white amorphous powder; FAB 429
Analogously, • from (2S) -2 - [(S) -canfo-l 0-sulphonamido] -3- [4- (4-guanidino-4-oxo-butyloxy) -phenyl] - terbutyl propionate, (2S) -2- [(S) -canfo-10-sulfonamido] -3- [4- (4-guanidino-4-oxo-butyloxy) -phenyl] -propionic acid, trifluoroacetate; FAB 523 and from (2 S) -2-tolylsulfonamido-3- [4- (4-guanidino-4-oxo-butyloxy) -phenyl] -propionate of tert-butyl, (2S) -2-tolylsulfonamido-3- [4- (4- guanidino-4-oxo-butyloxy) -phenyl] -propionic trifluoroacetate; FAB 463.
Example 4
To a solution of 50 mg of (2S) -2-butylsulfonamido-3- [4- (4-guanidino-4-oxo-butyloxy) -phenyl] -propionic acid, trifluoroacetate, in 5 ml of pyridine are added at 0 to 10 ul acetyl chloride and stir for 2 hours. After working the mixture in the usual manner, 0.027 g of (2S) -2-butylsulfonamido-3- [4 - (-N-acetylguanidino-4-oxo-butyloxy) -phenyl] -propionic acid is obtained; FAB 471
Analogously, it is obtained from the acid (2 S) -2 - [(S) -canfo-l 0 -sulfonamido] -3- [4- (4-guanidino-4-oxo-butyloxy) -phenyl] - propionic, trifluoroacetate, (2S) -2- [(S) -canfo-10-sulfonamido] -3- [4- (4-N-acetylguanidino-4-oxo-butyloxy) -phenyl] -propionic acid, FAB 565 and from (2S) -2-tolyl sulfonamido-3- [- (4-guanidino-4-oxo-butyloxy) -phenyl] -propionic acid, trifluoroacetate, (2S) -2-tolylsulfonamido-3- [4] acid - (4-N-acetyl-guanidino-4-oxo-butyloxy) -phenyl] -propionic, FAB 505.
Example 5
To a solution of 0.05 g of (2S) -2-butylsulfonamido-3- [4- (4-N-benzyloxycarbonyl-guanidino-4-oxo-butyloxy) phenyl] -troterbutylpropionate in 5 ml of dichloromethane is added 1 ml of TFA and stirred for 12 hours at room temperature. After working the mixture in the usual manner, 0.045 g of (2S) -2-butylsulfonamido-3- [4- (4-N-benzyloxycarbonyl-guanidino-4-oxo-butyloxy) phenyl] -propionic acid is obtained; FAB 563
Analogously, it is obtained from (2S) -2 - [(S) -canfo-l 0-sulphonamido] -3- [4- (4-N-benzyloxycarbonyl-guanidino-4-oxo-butyloxy) - Terbutyl phenyl] -propionate, (2S) -2- [(S) -canfo-l 0-sulfonamido] -3- [4- (4-N-benzyloxycarbonyl-guanidino-4-oxo-butyloxy) -phenyl acid ] -propionic, FAB 657 and from (2 S) -2- 1 -sulfonamido-3- [- (4-N-benzyloxycarbonyl-guanidino-4-oxo-butyloxy) -phenyl] -propylene tertbutyl, the acid (2S) -2-tolyl sulfonamido-3- [4- (4-N-benzyloxycarbonyl-guanidino-4-oxo-butyloxy) -phenyl] -propionic, FAB 597.
Example 6
To a solution of 0.1 (2S) -2 - [(S) -canfo-10-sulfonamido] -3- [4- (4-guanidino-4-oxo-butyloxy) -phenyl] -propionic acid, trifluoroacetate, in 10 ml of ethanol 5 mg of p-toluenesulfonic acid are added and the mixture is stirred for 72 hours at room temperature. After working the reaction mixture in a usual manner and lyophilizing, 0.055 mg of (2S) -2 - [(S) -canfo-10-sulfonamido] -3- [4- (4-guanidino-4-oxo- ethyl butyloxy) -phenyl] -propionate; FAB 551
Analogously, it is obtained from (2S) -2-butylsulfonamido-3- [4 - (4-guanidino-4-oxo-bu-yloxy) -phenyl] -propionic acid, trifluoroacetate, (2S) - Ethyl 2-butylsulfonamido-3- [4- (4-guanidino-4-oxo-butyloxy) -phenyl] -propionate, and from (2 S) -2-lolyl sulphonido-3 - [4 - (4 -guanidino-4-oxo-butyloxy) -phenyl] -propionic acid, trifluoroacetate, ethyl (2S) -2-tolyl sulfonamido-3- [4- (4-guanidino-4-oxo-butyloxy) -phenyl] -propionate , FAB 491.
Example 7
In a manner analogous to that of Example 1, the (2S) -2-benzyloxycarboxamido- is obtained by reaction of the terbutyl ester of benzyloxycarbonyl-Lp-amino-phenylalanine and 1-chloro-4-ethoxy-butane-1,4-dione. Terbutyl 3 - [4- (3-ethoxy-3-oxo-propylcarboxamido) -phenyl] -propionate. Removal of the protective group Z yields (2S) -2-amino-3- [4- (3-ethoxy-3-oxo-propylcarboxamido) -phenyl] -propylene tert-butyl ester ("C").
The following is obtained, by reaction of "C" with 1-butanesulfonyl chloride, (2S) -2-butyl sulfonamido-3- [4- (3-ethoxy-3-oxo-propylcarboxamido) -phenyl] -propylene tertbutyl ester with 4-t-olylsulfonyl chloride, tert -butyl (2S) -2-tolylsulfonamido-3- [4- (3-ethoxy-3-oxo-propylcarboxamido) -phenyl] -propionate and with (S) - (+) chloride -canfo-l 0 sulphonyl, the (2S) -2 - [(S) -canfo-l 0-sulfonamido] -3- [4- (3-ethoxy-3-oxo-propyl carboxamido) -phenyl] -propionate of terbutyl.
By cleavage of the ethyl ester, the (2S) -2-butyl sulfonamido-3- [4- (2-carboxy-ethylcarboxamido) -phenyl] -propionate of tert-butyl, the (2S) - is obtained from the mentioned compounds. 2-Tolylsulfonamido-3- [4- (2-carboxy-ethylcarboxamido) -phenyl] -propionate of tertbutyl and (2S) -2- [(S) -canfo-l-sulphonido] -3- [4- Terbutyl (2-carboxy-ylcarboxamido) -phenyl] -propionate.
In a manner analogous to that of Example 1, (2S) -2-butylsulfonamido-3- [4- (3-N-benzyloxycarbonyl-guanidino-3-oxo-propylcarboxamido is obtained by reaction of the latter Z-guanidine compounds. ) -phenyl] -propionate, terbutyl (2S) -2-tolylsulfonamido-3- [4- (3-N-benzyloxycarbonyl-guanidino-3-oxo-propylcarboxamido) -phenyl] -propionate and (2S) -2- [(S) -canfo-10-sulfonamido] -3- [4- (3-N-benzyloxycarbonyl-guanidino-3-oxo-propylcarboxamido) -phenyl] -tertbutylpropionate.
The cleavage of the protective group Z is carried out analogously to that of Example 2 and the following compounds are obtained: (2S) -2-Butylsulfonamido-3- [4- (3-guanidino-3-oxo-propylcarboxamido) - terbutyl phenyl] -propionate, (2S) -2-tolylsulfonamido-3- [4- (3-guanidino-3-oxo-propylcarboxamido) -phenyl] -propylene tertbutyl, and (2S) -2- [(S) -butyl-1-sulphonamido] -3- [4- (3-guanidino-3-oxo-propylcarboxamido) -phenyl] -propionate.
Analogously to Example 3, the terbutyl ester is cleaved with TFA and (2S) -2-Butylsulfonamido-3- [4- (3-guanidino-3-oxo-propyl carboxamido) -phenyl] -propionic acid is obtained. , trifluoroacetate, (2S) -2-tolylsulfonamido-3- [4- (3'-guanidino-3-oxo-propylcarboxamido) -phenyl] -propionic acid, trifluoroacetate and (2S) -2 - [(S) - canfo-l 0-sulfonamido] -3- [4 - (3-guanidino-3-oxo-propyl carboxamido) -phenyl] -propionic, trifluoroacetate.
In a manner analogous to that of Example 4, the following compounds are obtained by reaction of the latter compounds with acetyl chloride: (2S) -2-butylsulfonamido-3- [4- (3-N-acetyl-guanidino-3-oxo) acid -propylcarboxamido) -phenyl] -propionic acid (2S) -2-tolyl sulfonamido-3- [4- (3-N-acetyl-guanidino-3-oxo-propylcarboxamido) -phenyl] -propionic acid and (2S) acid - 2- [(S) -canfo-l 0-sulfonamido] -3- [4- (3-N-acetyl-guanidino-3-oxo-propylcarboxamido) -phenyl] -propionic acid.
In a manner analogous to that of Example 5, by treatment with TFA of (2S) -2-butylsulfonamido-3- [4- (3-N-benzyloxycarbonyl-guanidino-3-oxo-propylcarboxamido) -phenyl] -propionate of terbutyl, (2S) -2-tolyl sulfonamido-3- [4- (3-N-benzyloxycarbonyl-guanidino-3-oxo-propylcarboxamido) -phenyl] -propylene tertbutyl and (2S) -2- [(S) - 3-sulphonamido] -3- [4- (3-N-benzyloxycarbonylguanidino-3-oxo-propylcarboxamido) -phenyl] -propionate] tert-butyl ester, the following compounds: (2S) -2-butyl sulfonamido-3 acid - [4- (3-N-benzyloxycarbonyl-guanidino-3-oxo-propylcarboxamido) -phenyl] -propionic acid (2S) -2-tolylsulfonamido-3- [4- (3-N-benzyloxycarbonyl-guanidino-3-) oxo-propyl carboxamido) -phenyl] -propionic acid and (2S) -2- [(S) -canfo-10-sulfonamido] -3- [4- (3-N-benzyloxycarbonyl-guanidino-3-oxo-propylcarboxamido)] -phenyl] -propionic.
Example
In a manner analogous to that of Example 1, the (2S) -2-benzyloxycarboxamido-3- is obtained by reaction of the terbutyl ester of benzyloxycarbonyl-Lp-aminophenylalanine and 1-chloro-5-ethoxy-pentan-1,5-dione. [4- (4-ethoxy-butylcarboxamido) -phenyl] -propylene tertbutyl ester.
Removal of the protecting group Z yields (2 S) -2-amino-3- [4- (4-ethoxy-butylcarboxamido) -phenyl] -propylene tertbutyl ester ("D").
Then, by reaction of "D" with 1-butanesulfonyl chloride, (2S) -2-butyl sulfonamido-3- [4- (4-ethoxy-butylcarboxamido) -phenyl] -propionate of tert-butyl, with tolylsulfonyl chloride, tertbutyl (2S) -2-tolyl sulfonamido-3- [4- (4-ethoxy-butylcarboxamido) -phenyl] -propionate and with (S) - (+) - campho-1-chloride -sulfonyl, the (2S) -2- [(S) -canfo-10-sulfonamido] -3- [4- (4-ethoxy-butylcarboxamido) -phenyl] -propionate of tert-butyl.
These compounds are obtained by cleavage of the ethyl ester, (2S) -2-butylsulfonamido-3- [4- (3-carboxy-propylcarboxamido) -phenyl] -propionate of tert-butyl, (2S) -2- tolylsulfone-3- [4- (3-carboxy-propylcarboxamido) -phenyl] -propyl-tertiarybutylsulfone and (2S) -2- [(S) -canfo-1 O -sulfonamido] -3- [4- (3 - tert-butyl carboxy-propylcarboxamido) -phenyl] -propionate.
In a manner analogous to that of Example 1, (2S) -2-butyl sulfonamido-3- [4- (4-N-benzyloxycarbonyl-guanidino-4-oxo-) is obtained by reaction of the latter compounds with Z-guanidine. butylcarboxamido) -phenyl] -propionate, terbutyl (2S) -2-tolyl sulfonamido-3- [4- (4-N-benzyloxycarbonyl-guanidino-3-oxo-butylcarboxamido) -phenyl] -propionate and ( 2S) -2- [(S) -canfo-10-sulfonamido] -3- [4- (4-N-benzyloxycarbonyl-guanidino-3-oxo-butylcarboxamido) -phenyl] -tertbutylpropionate.
The cleavage of the protective group Z is carried out analogously to that of Example 2 and the following compounds are obtained: (2S) -2-Butylsulfonamido-3- [4-guanidino-oxo-butylcarboxamido) -phenyl] - terbutyl propionate, tertbutyl (2S) -2-tolylsulfonamido-3- [4-guanidino-4-oxo-butylcarcaramido) -phenyl] -propionate and (2S) -2- [(S) -canfo-l 0- sulfonamido] -3- [guanidino-oxo-butylcarboxamido) -phenyl] -propionate of tertbutyl.
Analogously to Example 3, the terbutyl ester was cleaved with TFA and (2S) -2-butylsulfonamido-3- [4-guanidino-4-oxo-butylcarboxamido) -phenyl] -propionic acid, trifluoroacetate, (2 S) -2-tolylsulfonamido-3- [4-guanidino-4-oxo-butylcarboxamido) -phenyl] -propionic acid, trifluoroacetate and (2 S) -2 - [(S) -canfo-10 -sul) acid fonamido] - 3 - [4-guanidino-4-oxo-butylcarboxamido) -phenyl] -propionic, trifluoroacetate.
Analogously to that of Example 4, the following compounds are obtained by reaction of the latter compounds with acetyl chloride: (2S) -2-Butylsulfonamido-3- [4-N-acetyl-guanidino-4-oxo-but-ylcarboxamido] acid ) -phenyl] -propioni co, (2S) -2-tolyl sulfonamido-3- [4-N-acetyl-guanidino-4-oxo-butylcarboxamido) -phenyl] -propionic acid and (2S) -2- [( S) -canfo-10-sulfonamido] -3- [4-N-acetyl-guanidino-4-oxo-butylcarboxamido) -phenyl] -propionic acid.
In a manner analogous to that of Example 5, by treatment with TFA of (2S) -2-butylsulfonamido-3- [4-N-benzylcarbonylguanidino-4-oxo-butylcarboxamido) -phenyl] -propionate of tertbutyl, ( 2S) -2-tolylsulfonamido-3- [4-N-benzylcarbonyl-guanidino-4-oxo-butylcarboxamido) -phenyl] -tertbutylpropionate and (2S) -2 - [(S) -canfo-l-0-sulfonamido] -3- [4-N-Behcylcarbonyl-guanidino-4-oxo-butylcarboxamido) -phenyl] -propylene tertbutyl, the following compounds: (2S) -2-Butylsulfonamido-3- [4-N-benzyloxycarbonyl-guanidino-] -oxo-butylcarboxamido) -phenyl] -propionic acid (2S) -2-tolylsulfonamido-3- [4-N-benzyloxycarbonyl-guanidino-4-oxo-butylcarboxamido) -phenyl] -propionic acid and (2S) -2-acid - [(S) -canfo-10-sulfonamido] -3- [4-N-benzyloxycarbonyl-guanidino-4-oxo-butylcarboxamido) -phenyl] -propionic acid.
E j us 9
In a manner analogous to that of Example 1, the (2S) -2-benzyloxycarboxamido- is obtained by reaction of the terbutyl ester of benzyloxycarbonyl-Lp-amino-phenylalanine and 1-chloro-3-ethoxy-propan-1,3-dione. Terbutyl 3- [4- (2-ethoxy-2-oxo-e-tylcarboxamido) -phenyl] -propionate. Removal of the protective group Z yields (2 S) -2-amino-3- [4- (2-ethoxy-2-oxo-ethylcarboxamido) -phenyl] -propylene tert-butyl ester ("E").
Then, by reaction of "E" with 1-butanesulfonyl chloride, the (2S) -2-butylsulfonamido-3- [4- (2-ethoxy-2-oxo-ethylcarboxamido) -phenyl] -propionate of tert-butyl with 4-tolylsulfonyl chloride, tert-butyl (2S) -2-tolylsulfonamido-3- [4- (2-ethoxy-2-oxo-ethylcarboxamido) -phenyl] -propionate and with (S) - (+ ) -canfo-l 0-sulfonyl, (2S) -2 - [(S) -canfo-l 0-sulfonamido] -3- [4- (2-ethoxy-2-oxo-ethylcarboxamido) -phenyl] -propionate of terbutyl.
From these compounds, (2S) -2-butylsulfonamido-3- [4- (carboxymethylcarboxamido) -phenyl] -propionate of tert-butyl, (2S) -2-tolyl sulfonamido is obtained by cleavage of the ethyl ester. -3- [4- (carboxymethylcarboxamido) -phenyl] -propionate of tert-butyl and (2S) -2- [(S) -canfo-l-sulphonido] -3- [4- (carboxy-methyl-ylcarboxamido]] tert-butyl) propionate.
Analogously to that of Example 1, (2S) -2-butylsulfonamido-3- [4- (2-N-benzyloxycarbonyl-guanidino-2-oxo- terbutyl ethylcarboxamido) -phenyl] -propionate, (2S) -2-tolyl sulfonamido-3- [4- (2-N-benzyloxycarbonyl-guanidino-2-oxo-ethylcarboxamido) -phenyl] -propylene tert-butyl ester and (2 S) -2 - [(S) -canfo-10-sulphonido] -3 - [4 - (2-N-benzyloxycarbonyl-guanidino-2-oxo-ethylcarboxamido) -phenyl] -propionate of tert-butyl.
The cleavage of the protective group Z is carried out analogously to that of example 2 and the following compounds are obtained: (2 S) -2-butylsulfonamido-3- [4- (2-guanidino-2-oxo-ethylcarboxamido) tert-butyl-phenyl] -propionate, (2S) -2-tolylsulfonamido-3- [4- (2-guanidino-2-oxo-ethylcarboxamido) -phenyl] -tertbutylpropionate and (2S) -2- [(S) -butyl-1-sulfonamido] -3- [4- (2-guanidino-2-oxo-ethylcarboxamido) -phenyl] -propionate.
Analogously to Example 3, the terbutyl ester is cleaved with TFA and (2S) -2-Butylsulfonamido-3- [4- (2-guanidino-2-oxo-ethylcarboxamido) -phenyl] -propionic acid is obtained, trifluoroacetate, (2S) -2-tolylsul-fonmido-3- [4- (2-guanidino-2-oxo-e-tylcarboxamido) -phenyl] -propionic acid, trifluoroacetate and (2 S) -2 - [(S ) -canfo-l 0-sulfonamido] -3 - [4 - (2-guanidino-2-oxo-et ilcarboxamido) -phenyl] -propionic, trifluoroacetate.
In a manner analogous to that of Example 4, the following compounds are obtained by reaction of the latter compounds with acetyl chloride: (2S) -2-butylsulfonamido-3- [4- (2-N-acetyl-guanidino-2 -oxo) acid. -ethylcarboxamido) -phenyl] -propionic acid (2S) -2-tolyl sulfonamido-3- [4- (2-N-acetyl-guanidino-2-oxo-ethylcarboxamido) -phenyl] -propionic acid and (2S) - 2- [(S) -canfo-l 0-sulfonamido] -3- [4- (2-N-acetyl-guanidino-2-oxo-ethylcarboxamido) -phenyl] -propionic acid.
Analogously to example 5, they are obtained by treatment with TFA of (2S) -2-butylsulfonamido-3- [4- (2-N-benzyloxycarbonyl-guanidino-2-oxo-ylcarboxamido) -phenyl] -propionate of terbutyl,
(2S) -2-t-butyl sulfonamido-3- [4- (2-N-benzyloxycarbonyl-guanidino-2-oxo-ylcarboxamido) -phenyl] -tertbutylpropionate and (2S) -2- [(S) -canfo -l 0-sulfonamido] -3- [4- (2-N-benzyloxycarbonyl-guanidino-2-oxo-ethylcarboxamido) -phenyl] -propylene tertbutyl, the following compounds: (2S) -2-butylsulfonamido-3 - [4- (2-N-benzyloxycarbonyl-guanidino-2-oxo-ethylcarboxamido) -phenyl] -propionic acid (2S) -2-tolyl-sulfonamido-3- [4- (2-N-benzyloxycarbonyl-guanidino-2) -oxo-ethylcarboxamido) -phenyl] -propionic acid and (2S) -2- [(S) -canfo-l-sulfonamido] -3- [4- (2-N-benzyloxycarbonyl-guanidino-2-oxo-ethylcarboxamido] ) -phenyl] -propionic.
Example 10
In a manner analogous to that of example 1, (2 S) -2-benzyloxycarboxamido-3- [4 - (5-ethoxy-5-benzoxycarboxamido-5-benzoxycarbonyl-3-yl-5-bromoxy-tert-butyl ester) tert-butyl-oxo-pentyloxy) -phenyl] -propionate. Removal of the protective group Z yields (2S) -2-amino-3- [4- (5-ethoxy-5-oxo-pentyloxy) -phenyl] -propylene tertbutyl ester ("F").
Then, by reaction of "F" with 1-butanesulfonyl chloride, the (2S) -2-butylsufonamido-3- [4- (5-ethoxy-5-oxo-pentyloxy) -phenyl] -propionate of terbutyl with 4-tolylsulfonyl chloro, (2S) -2-tolylsufonamido-3- [4- (5-ethoxy-5-oxo-pentyloxy) -phenyl] -propylene tertbutyl and with (S) - ( +) -canfo-l 0-sulfonyl, (2S) -2- [(S) -canfo-10 -sufonamido] -3- [4- (5-ethoxy-5-oxo-pentyloxy) -phenyl] -propionate of terbutyl.
From these compounds, the (2S) -2-butylsufonamido-3- [4- (5-carboxy-butyloxy) -phenyl] -propionate of tert-butyl, the (2S) -2- is obtained by cleavage of the ethyl ester. tolyl-sulfonaraido-3- [4- (5-carboxy-butyloxy) -phenyl] -propionate of terbutyl and the (2 S) -2 - [(S) -canfo-10 -sufonamido] -3 - [4 - ( Terbutyl 5-carboxy-butyloxy) -phenyl] -propionate.
In a manner analogous to that of Example 1, by reaction of the latter compounds with Z-guanidine, (2S) -2-butyl-sufonamido-3- [4- (5-N-benzyloxycarbonyl-guanidino-5-oxo-) is obtained. terbutyl pentyloxy) -phenyl] -propionate, the (2S) -2-tolyl-suleyamido-3- [4- (5-N-benzyloxycarbonyl-guanidino-5-oxo-pentyloxy) -phenyl] -propylene tertbutyl ester and the ( 2S) -2- [(S) -canfo-10-sufonamido] -3- [4- (5-N-benzyloxycarbonyl-guanidino-5-oxo-pentyloxy) -phenyl] -tertbutylpropionate.
The cleavage of the protective group Z is carried out analogously to that of Example 2 and the following compounds are obtained: (2S) -2-butylsufonamido-3- [4- (5-guanidino-5-oxo-pentyloxy) - terbutyl phenyl] -propionate, (2S) -2-tolyl-sulfonamido-3- [4- (5-guanidino-5-oxo-pent-loxi) -phi-1] -tributyl-propionate and (2S) -2- [ (S) -canfo-10-sufonamido] -3- [4- (5-guanidino-5-oxo-pentyloxy) -phenyl] -propionate of tert-butyl.
Analogously to Example 3, the terbutyl ester is cleaved with TFA and (2S) -2-butylsufonamido-3 - [4- (5-guanidino-5-oxo-pentyloxy) -phenyl] -propionic acid is obtained. , trifluoroacetate; FAB 443 (2S) -2-Tolylsufonamido-3- [- (5-guanidino-5-oxo-pentyloxy) -phenyl] -propionic acid, trifluoroacetate; FAB 477 and (2S) -2 - [(S) -canfo-l 0 -sufonamido] -3- [4- (5-guanidino-5-oxo-pentyloxy) -phenyl] -propionic acid, trifluoroacetate; FAB 537.
In a manner analogous to that of Example 4, the following compounds are obtained by reaction of the latter compounds with acetyl chloride: (2S) -2-butylsufonamido-3- [4- (5-N-acetyl-guanidino-5-oxo) acid. -pentyloxy) -phenyl] -propionic acid (2S) -2-tolyl-sulfonamido-3- [4- (5-N-acetyl-guanidino-5-oxo-pentyloxy) -phenyl] -propionic acid and (2S) - 2 - [(S) -canfo-l 0 -sufonamido] -3- [4 - (5-N-acetyl-guanidino-5-oxo-pentyloxy) -phenyl] -propionic acid.
In a manner analogous to that of the example, by treatment with TFA of (2S) -2-butylsufonamido-3- [4- (5-N-benzyloxycarbonyl-guanidino-5-oxo-pentyloxy) phenyl] -tertbutylpropionate, (2S) -2-tolyl-sufonamido-3- [4- (5-N-benzyloxycarbonyl-guanidino-5-oxo-pentyloxy) -phenyl] -propylene tertbutyl and (2S) -2 - [(S) -canfo- [0-sufonamido] -3- [4- (5-N-benzyloxycarbonyl-guanidino-5-oxo-pentyloxy) -phenyl] -propionate of tertbutyl, the following compounds: (2S) -2-butylsufonamido-3- [ 4- (5-N-benzyloxycarbonyl-guanidino-5-oxo-pentyloxy) -phenyl] -propionic; FAB 577 (2S) -2-tolyl-sufonamido-3- [4- (5-N-benzyloxycarbonyl-guanidino-5-oxo-penti-loxi) -phenyl] -propionic acid and (2S) -2- [(S ) -canfo-10-sufonamido] -3- [4- (5-N-benzyloxycarbonyl-guanidino-5-oxo-pentyloxy) -phenyl] -propionic acid; FAB 671.
E jmplo 11
In a manner analogous to that of Example 1, it is obtained, by reaction of the terbutyl ester of benzyloxycarbonyl-Lt-irosine with 5-bromo-2-oxo-valeronitrile, (2S) -2-benzyloxy-carboxamido-3- [4- Terbutyl (4-cyano-4-oxo-butyloxy) -phenyl] -propionate.
Removal of the protective group Z yields (2S) -2-amino-3- [4- (4-cyano-4-oxo-butyloxy) -phenyl] -propionate of tertbutyl ("G").
By reaction of "G" with 1-butanesulfonyl chloride, tert -butyl (2S) -2-butylsulfonamido-3- [4- (4-cyano-4-oxo-butyloxy) -phenyl] -propionate ("H") is obtained. ).
A solution of "H" and equimolar amounts of hydroxylamine hydrochloride and sodium bicarbonate in i sopropanol / water 6: 1 are refluxed for 12 hours. After working the reaction mixture in a usual manner, the (2S) -2-butylsulfonamido-3- [4- (5-amino-5-N-hydroxylimino-4-oxo-pentyloxy) -phenyl] -tertbutylpropionate is obtained ("J").
A solution of "J" in acetic acid is hydrogenated with a palladium catalyst (10% on activated carbon) for 12 hours at room temperature and normal pressure. After separating the catalyst and working the product in a usual manner, the (2S) -2-butyl sul-fonamido-3- [4- (4-amidino-4-oxo-butyloxy) -phenyl] -propionic acid is obtained.
E gin 12
In a manner analogous to that of Example 1, it is obtained by reaction of N-benzyloxycarbonyl-Ne-tylguanidine with (2S) -2-butylsulfonamido-3- [4- (3-carboxy-propyloxy) -phenyl] -propylene tert-butyl ester , tert-butyl (2S) -2-butylsulfonamido-3- [4- (4-N-benzyloxycarbonyl-N-ethyl-guanidino-4-oxo-butyloxy) -phenyl] -propionate; FAB 647 with (2S) -2 - [(S) -canfo-10-sulfonamido] -3- [4- (3-carboxy-propyloxy) -phenyl] -propionate of tertbutyl, (2S) -2 - [( S) -canfo-l 0-sulfonamido] -3- [4- (3-benzyloxycarboni-tert-butyl-1-N-ethyl-guanidino-4-oxo-butyloxy) -phenyl] -propionate; FAB 741 and with (2S) -2-tolylsulfonamido-3- [4- (3-carboxy-propyloxy) -phenyl] -propionate of tertbutyl, (2S) -2-tolylsulfonamido-3- [4- (4-N - tert-butyl benzyloxycarbonyl-N-ethyl-guanidino-4-oxo-butyloxy) -phenyl] -propionate; FAB 681.
The protective group Z is separated analogously to that described in example 2 and the following compounds are obtained: (2S) -2-butylsulfonamido-3- [4- (4-N-ethyl-guanidino-4-oxo-butyloxy ) -phenyl] -tertbutylpropionate; FAB 513 (2S) -2- [(S) -canfo-l 0-sulfonamido] -3- [4- (4-N-ethyl-guanidino-4-oxo-butyloxy) -phenyl] -propionate of tertbutyl; FAB 607 and (2S) -2-tolylsulfonamido-3- [4- (4-N-ethyl-guanidino-4-oxo-butyloxy) -phenyl] -propionate of tert-butyl; FAB 547
Analogously to that of Example 3, the terbutyl ester is cleaved with TFA and the acid (2S) -2-butyl sulphonido-3- [4- (4-N-ethyl-guanidino-4-oxo-butyloxy) is obtained) -phenyl] -propionic, trifluoroacetate; FAB 457 (2S) -2- [(S) -canfo-l 0-sulfonamido] -3- [4- (4-N-ethyl-guanidino-4-oxo-butyloxy) -phenyl] -propionic acid, trifluoroacetate; FAB 551 and (2 S) -2-tolylsulfonamido-3- [4 - (4-N-ethyl-guanidino-4-oxo-butyloxy) -phenyl] -propionic acid, trifluoroacetate; FAB 491.
E xemployment 13
A solution of 3.5 g of BOC-L-tyrosine benzylester, 5.5 g of tert-butyl bromoacetate, 2.61 g of potassium carbonate and 250 mg of 18-crown-6 in 100 ml of toluene is stirred. for 12 hours at 85 °. After working the mixture in the usual manner, 4.35 g of benzyl ("s) -2-terbutoxycarboxamido-3- (4- (terbutoxycarbonylmethoxy) -phenyl) -propionate (" K "), FAB 486 are obtained.
A solution of 4.3 g of "K" in 20 ml of dichloromethane and 100 ml of 3N HCl in diethyl ether is stirred for 6 hours at room temperature.
After working the mixture in the usual manner, 2.8 g of benzyl (2 S) -2-amino-3- (4 - (terbutoxycarbonylmethoxy) -phenyl) -propionate ("L"); FAB 386.
To a solution of 2.8 g of "L" in 50 ml of dichloromethane is added 3.7 g of triethylamine and 3.64 g of (R) -canfo-10-sulfonyl chloride and is stirred for 2 hours. After working the mixture in the usual way and purifying by chromatography on silica gel (toluene: acetone 10: 1), 3.8 g of (2S) -2- ((R) -canfor-10-sulfonamido) is obtained. Benzyl 3- (4- (terbutoxycarbonyl-methoxy) -phenyl) -propionate ("M"); FAB 600
Dissolve 2.5 g of "M" in 5 ml of trifluoroacetic acid and stir for 2 hours. The mixture is worked up in the usual manner and 1.9 g of (2S) - ((R) -canfo-10-sulfonamido) -3- (4- (carboxymethoxy) -phenyl) -propionate benzyl ("N" is obtained. ); FAB 544
A solution of 1 g of "N", 270 mg of 2-aminoimidazole sulfate, 770 mg TBTÜ, 85 mg of HOBt and 1.3 g of triethylamine in 30 ml of DMF is stirred at room temperature overnight. After working the mixture in the usual manner, 1 g of (2 S) -2 - ((R) -canfo-l 0 -sulphonido-3- (4- (N- (2-imidazolyl) -carboamoyl-methoxy is obtained. benzyl propionate (phenyl) -propionate ("O"); FAB 609.
Dissolve 1 g of "O" in 45 ml of dioxane and 5 ml of water and hydrogenate in the presence of 0.5 g of palladium (10% on activated charcoal) for 2 hours and at room temperature. After the catalyst is removed, the reaction mixture is blocked in the usual manner, preparative chromatography is carried out by HPLC (RP-18, elution gradient acetonitrile / water + 0.3% TFA 1:99 to 99: 1 in one hour) and lyophilize 180 mg of (2S) -2- ((R) -canfo-l-sulfonamido) -3- (4- (N- (2-imidazolyl) -carboamoylmetoxy) -phenyl) -propionic acid, trifluoroacetate are obtained; FAB 519.
Example 14
Analogous to the preparation of "O" is obtained, by reaction of (2 S) -2- ((R) -canfo-10-sulfonamido) -3- (4- (3-carboxypropoxy) -phenyl) -propionate of terbutyl ("P") with 2-aminobenzimidazole, (2S) -2 - ((R) - can fo-10-sulfonamido) -3- (4- (3- (N- (2-benzimidazolyl) -carbamoyl) ) -propoxy) -phenyl) -propyl tertiary butyl ester.
Cleavage of the ester with TFA gives (2S) -2 - ((R) -canfo-l-sulphonamido) -3- (4- (3- (N- (2-benzimidazolyl) -carbamoyl)) - propoxy) -phenyl) -propionic, trifluoroacetate; FAB 597.
Analogously, by the reaction of "P" with 2-aminoimdazole and subsequent cleavage of the ester, the acid (2S) -2 - ((R) -canfo-10-sulphonamido) -3- (4- (3- (N- (2-imidazolyl) -carbamoyl) -propoxy) -phenyl) -propionic acid, trifluoroacetate; FAB 547; with 5-aminotet razol and subsequent cleavage of the ester the acid (2S) -2- ((R) -canfo-l 0-sulfonamido) -3- (4- (3- (N- (5-tetrazolyl) -carbamoyl) -propoxy) -phenyl) -propionic, trifluoroacetate; FAB 549; with 3-aminoimidazole and subsequent cleavage of the ester, the (2S) -2 - ((R) -canfo-l 0-sulphonamido) -3- (4- (3- (N- (3-imidazolyl) -carbamoyl) acid ) -propoxy) - pheni 1) -propionic acid, trifluoroacetate; FAB 547; with 2-aminot-iazole and subsequent cleavage of the ester, (2S) -2- ((R) -canfo-l-sulfonamido) -3- (4- (3- (N- (2-thiazolyl) -carbamoyl) acid ) -propoxy) -phenyl) -propionic, trifluoroacetate; FAB 564; and with 2-aminomethyl-benzimidazole and subsequent cleavage of the ester, (2S) -2- ((R) -canfo-10-sulfonamido) -3- (4- (3- (N- (benzimidazol-2-ylmethyl) ) -carbamoyl) -propoxy) -phenyl) -propionic, trifluoroacetate; FAB 583
Example 15
A solution of 250 mg of acid is stirred (2S) -2 - ((R) -canfo-l 0-sulphonamido) -3- (4- (3- (N- (2-benzimidazolyl) -carbamoyl) -propoxy) -phenyl) -propionic acid and 25 mg of toluene-4-sulphonic acid in 25 ml of ethanol for 7 days and at room temperature. After working the product in the usual way, 170 mg of (2S) -2 - ((R) -canfo-l-sulphonamido) -3- (4- (3- (N- (2-benzimidazolyl) -carbamoyl) are obtained. ) -propoxy) -phenyl) -propionate; FAB 625.
Analogously, (2S) -2 - ((R) -canfo-l-sulfonamido) -3- (4- (3- (N- (2-imidazolyl) -carbamoyl) -propoxy) -phenyl is obtained) ethyl-propionate; FAB 575
The following examples relate to pharmaceutical preparations.
Example A: injection bottles
The pH of a solution of 100 g of an active substance of formula I and 5 g of disodium hydrogen phosphate in 3 1 of bidistilled water is adjusted to 6.5 with 2 N hydrochloric acid, then filtered under sterile conditions, this is introduced solution inside the bottles, it is lyophilized and finally the bottles are closed under sterile conditions. Each bottle for injection contains 5 mg of the active substance.
Example B: suppositories
A mixture composed of 20 g of an active substance of formula I, 100 g of soy lecithin and 1400 g of cocoa butter is melted, the melt is poured into the molds and allowed to cool. Each suppository contains 20 mg of active substance.
Example C: solution
A solution is prepared with 1 g of active substance of formula I, 9.38 g of NaH2P04 x 2 H20, 28.48 g of Na2HP04 x 12 H20, 0.1 g of benzalkonium chloride and 940 ml of bidistilled water. The pH is adjusted to 6.8, brought to a volume of 1 1 and sterilized by irradiation. This solution can be used in the form of eye drops.
Example D: ointment
Under aseptic conditions 500 mg of an active substance of formula I are mixed with 99.5 g of Vaseline.
Example ?: tablets
A mixture composed of 1 kg of an active substance of formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets, such that each tablet contains 10 mg of the active substance.
Example F: dragees
The tablets are formed analogously to that described in Example E and then they are coated in the usual manner with a bath of sucrose, potato starch, talc, tragacanth and dye.
Example G: capsules
With 2 kg of an active substance of formula I, hard gelatin capsules are filled in such a way that each capsule contains 20 mg of the active substance.
Example H: ampoules
A solution of 1 kg of an active substance of formula I in 60 1 of bidistilled water is filtered under sterile conditions. The ampules are filled with this solution and then lyophilized and closed under sterile conditions. Each vial contains 10 mg of the active substance.
Example I: aerosol inhalant solution
14 g of an active substance of formula I are dissolved in 10 L of isotonic NaCl solution. With this solution, commercial vessels filled with a vaporizing mechanism are filled. The solution can be inhaled through the mouth or nose. Each spray (approximately 0.1 ml) corresponds to a dose of approximately 0.14 mg.
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Having described the invention as above, the content of the following is claimed as property.
Claims (11)
1. Compounds characterized because they respond to formula I where X is absent or represents alkylene, arylene, cycloalkylene of 4 to 8 C atoms or heterocycloalkylene with 1 to 3 N, 0 and / or S atoms which may be unsubstituted or mono, di or trisuced with A, "oxo and / or R4 And, independently of one another, they are absent or represent alkylene, 0, S, NH, C (= 0), CONH, NHCO, C (= S), S02NH, NHS02, CA = CA 'or -C = C-, RJ represents H2N-C (= NH) or H2N- (C = NH) -NH, wherein the primary amino groups can also be protected with conventional amino protecting groups or can be substituted one, two or three times with A, Ar or R5, NH-CH2-R6, NH-R6, NH-C (= NH) -NH-R6 or R6, R 'represents A, Ar or aralkylene, R 'represents H or A, R 'represents H, Hal, OA, NHA, NAA', -NH-acyl, -O-acyl, CN, N02, SA, SOA, S02A, S02Ar, or S03H, R- represents alkanoyl or cycloalkanoyl of 1 to 18 carbon atoms, in which one, two or three methylene groups can be replaced by N, O and / or S, Ar-CO- or Alkylene-CO-, A, A 'independently represent H, or alkyl or cycloalkyl of 1 to 15 C atoms unsubstituted or mono, di or trisubstituted with R and wherein one, two or three methylene groups may be replaced by N, O and / or S, Ar represents an aromatic ring system of one or two nuclei and with 0, 1, 2, 3 or 4 atoms of N, 0 and / or S, which may be unsubstituted or mono, di or trisubstituted with A and / or R4, R 'represents a heterocycle of one or two nuclei and with 1 to 4 N, O and / or S atoms, which may be unsubstituted or mono, di or trisubstituted with Hal, A, acyl, OH, CN, COOH , COOA, CONH2, N02, = NH or = 0, Hal represents F, Cl, Br or I with the proviso that at least one element chosen from the group consisting of X, Y, Z must be CH2, and its salts acceptable from the physiological point of view.
2. Compounds according to claim 1, characterized in that they are enantiomers or diastereomers of the compounds of formula I.
3. Compounds of formula I, according to claim 1, characterized in that they have the following designations: a) (2S) -2-Butylsulfonamido-3- [4- (4-N-acetyl-guanidino-4-oxo-butyloxy) -phenyl] -propionic acid; b) (2S) -2-Butylsulfonamido-3- [4- (4-guanidino-4-oxo-butyloxy) -phenyl] -propionic acid; c) (2S) -2- (canfo- 10 -sulfonamido) -3- [4- (4-N-ethylguanidino-4-oxo-butyloxy) -phenyl] -propionic acid; d) (2S) -2- (campho-10-sulfonamido) -3- [4- (4-N-benzyloxycarbonyl-guanidino-4-oxo-butyloxy) -phenyl] -propionic acid; e) (2S) -2- (canfo- 10 -sulfonamido) -3- [4- (4-guanidino-4-oxo-butyloxy) -phenyl] -propionic acid, -f) (2S) -2- (canfo-10 -sulfonamido) -3- [4- (4-guanidino-4-oxo-butyloxy) -phenyl] -propionate ethyl; g) (2S) -2-Butylsulfonamido-3- [4- (4-N-ethylguanidino-4-oxo-butyloxy) -phenyl] -propionic acid; h) (2S) -2-Butylsulfonamido-3- [4- (5-guanidino-5-oxo-pentyloxy) -phenyl] -propionic acid; i) (2S) -2- (campho-10-sulfonamido) -3- [4- (5-guanidino-5-oxo-pentyloxy) -phenyl] -propionic acid; j) (2S) -2- (canfo-10-sulfonamido) -3- [4- (3- (1H-imidazol-2-ylcarbamoyl) -propoxy) -phenyl] -propionic acid; k) (2S) -2- (canfo-10-sulfonamido) -3- [4- (3- (lH-benzimidazol-2-ylcarbamoyl) -propoxy) -phenyl] -propionic acid; and its salts acceptable from the physiological point of view.
4. Process for preparing the compounds of formula I, according to claim 1, and their salts, characterized in that a) a compound of formula I is released from one of its functional derivatives by treatment with a solvolysis or hydrogenolysis agent, b) a compound of formula II is reacted (II), wherein R1, R3, R4, X, Y and Z have the meanings indicated in claim 1, with a compound of formula III, R -S02-L (III) wherein R2 has the meaning indicated in claim 1 and L represents Cl, Br, I, OH or an esterified and reactive OH group, or c) an ester of formula I, or d) is converted to a R1 residue and / or R3 in another residue R1 and / or R3, and / or e) se. transforms a base or an acid of formula I into one of its salts by treatment with an acid or a base.
5. Process for obtaining a pharmaceutical preparation based on the compounds of claim 1, characterized in that a compound of formula I and / or one of its physiologically acceptable salts is brought into a suitable dosage form, together with at least one an excipient or solid, liquid or semi-liquid auxiliary product.
6. Pharmaceutical preparation based on the compounds of claim 1, characterized in that it contains at least one compound of formula I and / or one of its salts acceptable from the physiological point of view.
7. Compound of formula I, according to claim 1, and its physiologically acceptable salts, characterized in that it is an antagonist of GPIIb / IIIa and combat thrombosis, myocardial infarction, coronary diseases and arteriesclerosis.
8. Compounds of formula I, according to claim 1, and their physiologically acceptable salts, characterized in that they act as inhibitors of the integrin av and combat pathological angiogenic diseases, thrombosis, myocardial infarction, coronary diseases, arteriesclerosis, tumors, osteoporosis , inflammations and infections.
9. Compounds of formula I, according to claim 1, and their physiologically acceptable salts, characterized in that R 2 represents canfo-10-yl and because they act as inhibitors of av integrin and combat pathological angiogenic diseases, thrombosis, myocardial infarction , coronary diseases, arteriosclerosis, tumors, osteoporosis, inflammations and infections.
10. Use of the compounds of formula I, according to claim 1, and / or their physiologically acceptable salts, said compounds are used to prepare a medicament.
11. Compounds of formula I, according to claim 1, and / or their physiologically acceptable salts, characterized in that they are used in the preparation of a medicament which in turn is used as an integrin inhibitor. the invention The invention relates to the compounds of formula I wherein X, Y, Z, R1, R2, R3 and R4 have the meanings indicated in claim 1, with the proviso that at least one element chosen from the group consisting of X, Y, Z must be CH2, and its salts acceptable from the physiological point of view. The invention also relates to a process for preparing these compounds, to the pharmaceutical preparations containing them and to the use thereof as integrin inhibitors, in particular for the prophylaxis and treatment of diseases of the circulatory system, thrombosis, myocardial infarction, coronary diseases, arteriesclerosis, osteoporosis, pathological processes that are maintained or spread by angiogenesis and in the therapy of tumors.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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DE19625929.0 | 1996-06-28 | ||
DE19654483.1 | 1996-12-27 |
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MXPA98010586A true MXPA98010586A (en) | 1999-09-01 |
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