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Pharmaceuticals Containing Other Organic And Inorganic Compounds
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Claims (16)
PATENTNI ZAHTEVKI 1. Derivati N-acil-a-aminokisline s formulo Ο R- R- Ι II \ / C-N—C-C-0 I II R’ O v kateri L označuje skupino s formuloClaims 1. N-acyl-α-amino acid derivatives of the formula Ο R- R- Ι II \ / C-N — C-C-0 I II R ’O in which L denotes a group of the formulaX = Y ali R°-NH(CH2)t L2 R označuje amidino ali gvanidino, eden izmed X in Y označuje CH in drugi označuje CH ali N, R° označuje vodik ali amidino, t označuje celo število od 2 do 6, R’ R” in R”’ označujejo vodik ali N-substituente oz. stranske verige, običajne pri z- α-aminokarboksilnih kislinah, pri čemer so pri R’ R” in R’” prisotne hidroksi oz. karboksi skupine lahko zaetrene ali zaestrene ali amidirane, in so v R’ R” in R”’ prisotne amino skupine lahko Ci.6-alkanoilirane ali aroilirane·, Q označuje skupino s formulo ,(CH2)n — NX = Y or R ° -NH (CH2) t L2 R denotes amidino or guanidino, one of X and Y denotes CH and the other denotes CH or N, R ° denotes hydrogen or amidino, t denotes an integer from 2 to 6, R "R" and "R" denote hydrogen or N-substituents or side chains common to z-α-aminocarboxylic acids, with hydroxy or R 'R' and R '' being present. carboxy groups may be esterified or esterified or amidated, and the amino groups present in R 'R "and R"' may be C1-6-alkanoylated or aroylated ·, Q denotes a group of formula, (CH2) n - NO COO-T\/ Q’About COO-T \ / Q ’Q2Q2Q 3Q 33 ali -N(V’)(CH2)v-C(V’\ V”’)CH2OCH2COO-T Q8 ali, v kolikor R’ in R” skupaj z N-atomom in C-atomom, s katerima sta vezana, tvorita obroč, prav tako lahko označujejo skupino s formulo R2 R3 -C V-O COO-T \_/ vr-^A. Q 9 n v ΊΝηΊΠ VdO V’” U in U’ Ar R2 do R5 R2 in R3 predstavlja število 0 ali 1, je celo število od 0 do 3, označujeta vodik ali nižji alkil ali fenil-nižji alkil, ki se da odcepiti pod fiziološkimi pogoji, označujejo vodik ali nižji alkil, označujeta vodik, Ci^-alkanoil ali aroil, označuje aril, in označujejo vodik, nižji alkil, nižji alkoksi, halogen ali skupino -OCH2COO-T’, ali skupaj s fenilno skupino, na katero sta vezana, označujeta 1-naftilno skupino, pri čemer »nižji« označuje skupine z 1-6 C atomi, kot tudi njihovi hidrati ali solvati in fiziološko uporabne soli.3 or -N (V ') (CH2) vC (V' \ V "') CH2OCH2COO-T Q8 or, in so far as R' and R" together with the N-atom and C-atom to which they are attached form a ring , may also denote a group of formula R2 R3 -C VO COO-T \ _ / vr- ^ A. Q 9 nv ΊΝηΊΠ VdO V '”U and U' Ar R2 to R5 R2 and R3 represent the number 0 or 1, an integer from 0 to 3, denote hydrogen or lower alkyl or phenyl-lower alkyl which can be cleaved below physiological conditions denoting hydrogen or lower alkyl, denoting hydrogen, C1-4alkanoyl or aroyl, denoting aryl, and denoting hydrogen, lower alkyl, lower alkoxy, halogen or the group -OCH2COO-T ', or together with the phenyl group to which they are attached , denote a 1-naphthyl group, the "lower" denoting groups having 1-6 C atoms, as well as their hydrates or solvates and physiologically useful salts.2. Spojine po zahtevku 1, označene s tem, da L označuje skupino L1, R’, R” in R’” označujejo vodik ali N-substituente oz. stranske verige, ki so običajni pri ct-amino-karboksilnih kislinah, pri čemer so prisotne hidroksi ali karboksi skupine lahko zaetrene ali zaestrene ali amidirane, in T v skupini Q označuje vodik ali nižji alkil, ki ga lahko odcepimo pod fiziološkimi pogoji.Compounds according to Claim 1, characterized in that L represents a group L1, R ', R "and R'" denote hydrogen or N-substituents or side chains common to ct-amino-carboxylic acids, wherein the hydroxy or carboxy groups present may be esterified or esterified or amidated, and T in the Q group denotes hydrogen or lower alkyl which can be cleaved under physiological conditions.3. Spojine po zahtevku 1 ali 2, označene s tem, da L označuje skupino L1, R označuje l 2 4 5 amidino, X označuje CH, Y označuje CH ali N, in Q označuje skupino Q , Q , Q , Q ali Q9Compounds according to Claim 1 or 2, characterized in that L denotes the group L1, R denotes l 2 4 5 amidino, X denotes CH, Y denotes CH or N, and Q denotes the group Q, Q, Q, Q or Q94. Spojine po zahtevku 1, 2 ali 3, označene s tem, da Q označuje skupino Q*, kjer je n = 1 in T označuje vodik ali metil in -N(R’)C(R”,R”’)CO- označuje enega od ostankov Gly, Ala, D-Ala, Val, Leu, Sar, Om, Lys, Phg, 2-metil-Pro, Phe, Tyr, 3-jodo-Tyr, 3,5-dijodo-Tyr, Ser(Ac), Ser, Asp, Glu, Pro, 4-benziloksi-pro, 4-hidroksi-Pro, 2-piperidilenkarbonil, NHCH(CH2CH2NH2)CO, Trp, Tyr(Me), Tyr(heksil) in 0,N(Me)2-Tyr.Compounds according to Claim 1, 2 or 3, characterized in that Q denotes a group Q *, wherein n = 1 and T denotes hydrogen or methyl and -N (R ') C (R ", R"') CO - indicates one of the residues of Gly, Ala, D-Ala, Val, Leu, Sar, Om, Lys, Phg, 2-methyl-Pro, Phe, Tyr, 3-iodo-Tyr, 3,5-diiodo-Tyr, Ser (Ac), Ser, Asp, Glu, Pro, 4-benzyloxy-pro, 4-hydroxy-Pro, 2-piperidylenecarbonyl, NHCH (CH2CH2NH2) CO, Trp, Tyr (Me), Tyr (hexyl) and 0, N ( Me) 2-Tyr.5. Spojine po zahtevku 1,2 ali 3, označene s tem, da Q označuje skupino Q , zlasti kjer je n = 1, T označuje vodik in -N(R’)C(R”,R”’)CO- označuje ostanek Ala.Compounds according to Claims 1, 2 or 3, characterized in that Q denotes a group Q, in particular where n = 1, T denotes hydrogen and -N (R ') C (R ", R"') CO- denotes the rest of Ala.6. Spojine po zahtevku 1,2 ali 3, označene s tem, da Q označuje skupino Q , zlasti kjer je n = 1, T označuje vodik, U in U’sta vodik ali Ac in -N(R’)C(R”,R”’)CO- označuje ostanek Ala.Compounds according to Claim 1, 2 or 3, characterized in that Q denotes a group Q, in particular where n = 1, T denotes hydrogen, U and U'sta hydrogen or Ac and -N (R ') C (R ”, R” ') CO- denotes the residue Ala.7. Spojine po zahtevku 1,2 ali 3, označene s tem, da Q označuje skupino Q5, zlasti kjer je n = 1, T označuje vodik, Arje α,α,α-trifluoro-m-tolil in -N(R’)C(R”,R’”)CO- označuje ostanek Ala. gCompounds according to Claim 1, 2 or 3, characterized in that Q denotes a group Q5, in particular where n = 1, T denotes hydrogen, Ar is α, α, α-trifluoro-m-tolyl and -N (R ' ) C (R ”, R '”) CO- denotes the residue Ala. g8. Spojine po zahtevku 1,2 ali 3, označene s tem, da Q označuje skupino Q , zlasti kjer so R2 do R5 vodik ali je R2 skupina -OCH2COO(H ali metil), T je vodik ali metil in -N(R’)C(R”,R’”)CO- označuje ostanek Pro. 5"Compounds according to Claim 1, 2 or 3, characterized in that Q represents a group Q, in particular where R 2 to R 5 are hydrogen or R 2 is a group -OCH 2 COO (H or methyl), T is hydrogen or methyl and -N ') C (R ”, R'”) CO- denotes the residue Pro. 5 "9. Spojine po zahtevku 1 ali 3 iz skupine: [[l-[N-(p-amidinobenzoil)-L-alanil]-4-piperidinil]oksi]ocetna kislina, [[l-[N-[(5-amidino-2-piridil)karbonil]-L-alanil]-4-piperidinil]oksi]ocetna kislina, [[l-[N-(p-amidinobenzoil)-3-(4-hidroksi-3-jodofenil)-L-alanil]-4-piperidinil]-oksijocetna kislina, [[l-[3-acetoksi-N-(p-amidinobenzoil)-L-alanil]-4-piperidinil]oksi]ocetna kislina, [p-[[ 1 -(p-amidinobenzoil)-2-pirolidinil]karbonil]fenoksi]ocetna kislina, [[ 1 -[N-[(5-amidino-2-piridil)karbonil]-L-tirozil]-4-piperidinil]oksi]ocetna kislina, in zlasti [[ 1 -[N-(p-amidinobenzoil)-L-tirozil]-4-piperidinil]oksi]ocetna kislina.Compounds according to claim 1 or 3 of the group: [[1- [N- (p-amidinobenzoyl) -L-alanyl] -4-piperidinyl] oxy] acetic acid, [[1- [N - [(5-amidino -2-pyridyl) carbonyl] -L-alanyl] -4-piperidinyl] oxy] acetic acid, [[1- [N- (p-amidinobenzoyl) -3- (4-hydroxy-3-iodophenyl) -L-alanyl ] -4-piperidinyl] -oxyacetic acid, [[1- [3-acetoxy-N- (p-amidinobenzoyl) -L-alanyl] -4-piperidinyl] oxy] acetic acid, [p - [[1 - (p -amidinobenzoyl) -2-pyrrolidinyl] carbonyl] phenoxy] acetic acid, [[1 - [N - [(5-amidino-2-pyridyl) carbonyl] -L-tyrosyl] -4-piperidinyl] oxy] acetic acid, and in particular [1- [N- (p-amidinobenzoyl) -L-tyrosyl] -4-piperidinyl] oxy] acetic acid.10. Spojine po zahtevku 1, označene s tem, daje Q skupina Q3, zlasti kjer je n = 0 in je T 7 vodik, ali skupma Q , zlasti kjer je T vodik. gCompounds according to Claim 1, characterized in that Q is a group Q3, in particular where n = 0 and T 7 is hydrogen, or a group Q, in particular where T is hydrogen. g11. Spojine po zahtevku 1, označene s tem, daje Q skupina Q , zlasti kjer je v = 1, T je vodik ali butil in so V’ do V’” vodik.Compounds according to Claim 1, characterized in that Q is a group Q, in particular where v = 1, T is hydrogen or butyl and V 'to V' is hydrogen.12. Spojine po zahtevku 1, označene s tem, da je -N(R’)C(R”,R’”)CO- ostanek N(metoksietil)Gly.Compounds according to Claim 1, characterized in that -N (R ') C (R ", R'") CO- is a residue of N (methoxyethyl) Gly.13. Spojine po zahtevku 1 iz skupine: (S)-l-[2-(5-amidinopiridin-2-ilkarbonilamino)-3-(4-metoksifenil)propionil]piperidin-4-iloksiocetna kislina, etil (S)-l-[2-(4-amidinobenzamido)-3-(4-metoksifenil)propionil]piperidin-4-iloksiacetat, (S)-l-[2-(4-amidinobenzamido)-3-(4-metoksifenil)propionil]piperidin-4-iloksiocetna kislina, [ 1 -[N-(4-amidinobenzoil)-4’-heksiloksi-L-fenilalanil ]piperidin-4-iloksi]-ocetna kislina.Compounds according to claim 1 of the group: (S) -1- [2- (5-amidinopyridin-2-ylcarbonylamino) -3- (4-methoxyphenyl) propionyl] piperidin-4-yloxyacetic acid, ethyl (S) -1 - [2- (4-amidinobenzamido) -3- (4-methoxyphenyl) propionyl] piperidin-4-yloxyacetate, (S) -1- [2- (4-amidinobenzamido) -3- (4-methoxyphenyl) propionyl] piperidine -4-yloxyacetic acid, [1- [N- (4-amidinobenzoyl) -4'-hexyloxy-L-phenylalanyl] piperidin-4-yloxy] -acetic acid.14. Spojine s formulo ali N=C L o O II C-N I E' E” Ε ν / -C-C-G IIO It X = Y O R- R~ II N / C—N—C—C—Q I IIR· O III v kateri označujejo L° skupino s formulo A-^- L°’ X = Y ali R01-(CH2)t L02 v kateri A označuje v danem primeru zaščiteno amidino- ali gvanidino- · skupino, rOI označuje v danem primeru zaščitenij amino ali,gvanidino skupino, E’, E”, E’” in G imajo isti pomen kot R’, R” , R’” oz. Q v formuli I, pri čemer v primeru, kadar R01 označuje amino ali gvanidino, ali kadar A označuje amidino ali gvanidino, najmanj eden od E’, E”, E”’ in G vsebuje najmanj eno estrsko skupino karboksilne kisline in /ali estrsko skupino in/ali zaščiteno amino skupino. 7214. Compounds of formula or N = CL o O II CN IE 'E ”Ε ν / -CCG IIO It X = YO R- R ~ II N / C — N — C — C — QI IIR · O III in which they denote L ° is a group of formula A - ^ - L ° 'X = Y or R01- (CH2) t L02 in which A optionally represents a protected amidino- or guanidino- group, rOI denotes optionally a protected amino or, guanidine group , E ', E ”, E'” and G have the same meaning as R ', R ”, R'” or Q in formula I, wherein in the case where R01 denotes amino or guanidino, or when A denotes amidino or guanidino, at least one of E ', E ", E"' and G contains at least one ester group of carboxylic acid and / or ester group and / or protected amino group. 7215. Postopek za pripravo spojin po enem od zahtevkov 1-13, označen s tem, da a) v spojini s formulo O g- E'" o 11 x / L — C-N—C—C-G I II E' O v kateri L° označuje skupino s formuloProcess for the preparation of compounds according to one of Claims 1 to 13, characterized in that a) in the compound of formula O g-E '" o 11 x / L - C-N — C — C-G I II E 'O in which L ° denotes a group of formulav katerih je A v danem primeru zaščitena amidino ali gvanidino skupina, Ro1 označuje v danem primeru zaščiteno amino ali gvanidino skupino, <? E’, E”, E’” in G imajo isti pomen kot R\ R” , R”’ oz. Q v formuli I, pri čemer v primeru, da R01 označuje amino, ali kjer A označuje amidino ali gvanidino, najmanj eden od E’, E”, E’” in G vsebuje najmanj eno skupino estra karboksilne kisline in /ali estrsko skupino in/ali zaščiteno amino skupino, odcepimo etrsko skupino oz. zaščiteno amino, amidino oz. gvanidino skupino oz. estrsko skupino karboksilne kisline, ali b) v nitrilu s formulo N = C X = Y o Fr R- ii n / _C —N —C —C —Q (II I u R’ O prevedemo ciano skupino v amidino skupino, ali c) amin s formulo R’-NHC(R”,R’”)CO-Q IV pretvorimo s kislino s formulo Ll-COOH ali reaktivnim derivatom te kisline in d) po želji funkcionalno pretvorimo reaktivno skupino, ki se nahaja v spojini s formulo I, in e) po želji spojino s formulo I prevedemo v fiziološko prenesljivo sol, ali sol spojine s formulo I prevedemo v prosto kislino ali bazo. 9in which A is optionally a protected amidino or guanidino group, Ro1 denotes optionally a protected amino or guanidino group, <? E ’, E”, E ’” and G have the same meaning as R \ R ”, R” ’or Q in formula I, wherein in case R01 denotes amino, or wherein A denotes amidino or guanidino, at least one of E ', E ", E'" and G contains at least one carboxylic acid ester group and / or ester group and / or a protected amino group, the ether group or protected amino, amidino or guanidine group or an ester group of a carboxylic acid, or b) in nitrile of formula N = CX = Y o Fr R- ii n / _C —N —C —C —Q (II I u R 'O convert the cyano group to an amide group, or c) an amine of formula R'-NHC (R ", R '") CO-Q IV is converted to an acid of formula L1-COOH or a reactive derivative of this acid and d) optionally a functional conversion of a reactive group present in a compound of formula I , and e) optionally converting the compound of formula I into a physiologically tolerable salt, or converting a salt of the compound of formula I into a free acid or base. 916. Farmacevtski pripravki, zlasti za zdravljenje ali profilakso bolezni, ki jih povzroča vezava adhezivnih proteinov na krvne ploščice in agregacija krvnih ploščic ter adhezija celice na celico, označeni s tem, da vsebujejo spojino po kateremkoli izmed zahtevkov 1-13 kot^učinkovino.Pharmaceutical preparations, in particular for the treatment or prophylaxis of diseases caused by the binding of adhesive proteins to platelets and platelet aggregation and cell-to-cell adhesion, characterized in that they contain a compound according to any one of claims 1-13 as an active ingredient.