DK2104497T3 - Sulfamidderivater som inhibitorer af tafia - Google Patents

Sulfamidderivater som inhibitorer af tafia Download PDF

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DK2104497T3
DK2104497T3 DK07856207.1T DK07856207T DK2104497T3 DK 2104497 T3 DK2104497 T3 DK 2104497T3 DK 07856207 T DK07856207 T DK 07856207T DK 2104497 T3 DK2104497 T3 DK 2104497T3
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alkylene
alkyl
phenyl
unsubstituted
amino
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DK07856207.1T
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English (en)
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Christopher Kallus
Mark Broenstrup
Werngard Czechtizky
Andreas Evers
Nis Halland
Herman Schreuder
Markus Follmann
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Sanofi Sa
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
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    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
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    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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Claims (8)

1. Forbindelse med formel I
(l) og/eller en stereoisomer form af forbindelsen med formel I og/eller blandinger af disse former i ethvert forhold og/eller et fysiologisk forligeligt salt af forbindelsen med formel I, idet X står for -S02-, Ri står for 1) hydrogenatom, 2) - (Ci-C6)-alkyl, 3) - (C0-C4)-alkylen-(C3-C12)-cycloalkyl eller 4) - (C1-C6) -alkylen- (C6-C14) -aryl, R2 står for gruppen med formel II -(Al)m-A2 (II) hvor m betegner det hele tal nul eller 1, Al står for 1) -(CH2)n-, hvor n betegner det hele tal nul, 1, 2 eller 3,
2. Forbindelse med formel I ifølge krav 1, idet Ri står for 1) hydrogenatom eller 2) - (C1-C4) -alkyl, R2 står for 1) - (Ci-C6) -alkylen-NH2, 2) - (C0-C4) -alkylen-pyridyl-NH2, 3) - (C0-C4) -alkylen-piperidinyl-NH2, 4) - (C0-C4) -alkylen-thiazolyl-NH2, 5) - (Ci-C6) -alkylen-NH-C (=NH) -NH2, 6) - (C0-C4) -alkylen- (C3-C8) -cycloalkyl-NH2, 7) - (Ci-C6) -alkylen-NH-C (=NH) - (C1-C4) -alkyl, 8) - (C0-C4) -alkylen-O-NH-C (=NH) -NH2, 9) - (C1-C6)-alkylen-NH-C (0)-0-(C1-C4)-alkylen-aryl, idet aryl er usubstitueret eller er substitueret med -NH2 eller er substitueret med -NH2 og en, to eller tre gange med R15, 10) - (C0-C4) -alkylen-NH-C (0) - (C1-C4) -alkyl, 11) - (C0-C4)-alkylen-(C6-Ci4)-aryl, idet aryl er usubstitueret eller er substitueret med -NH2 eller er substitueret med -NH2 og en, to eller tre gange med R15, eller 12) - (C1-C4)-alkylen-SOx-(C1-C4)-alkylen-NH2, idet x betegner det hele tal nul, 1 eller 2, R3 står for 1) - (C1-C4)-alkyl, 2) - (C0-C4) -alkylen- (C3-C8) -cycloalkyl, 3) - (Ci-Cé) -alkylen-aryl, idet aryl uafhængigt af hinanden er substitueret en, to eller tre gange med R15, 4) - (C1-C6)-alkylen-NH-C (0)-0-(C1-C4)-alkylen-aryl, idet aryl uafhængigt af hinanden er substitueret en, to eller tre gange med RI5, 5) - (Ci-C6) -alkylen-NH-PG, 6) - (Ci-C6) -alkylen-O-PG, 7) - (Ci-C6) -alkyl, eller 8) hydrogenatom, idet PG står for t-butyl-, t-butyloxycarbonyl eller benzyloxycarbonyl, R4 står for -N(R6)2, idet R6 er ens eller forskellige og uafhængigt af hinanden står for 1) hydrogenatom, 2) - (Ci-C6)-alkyl, 3) - (C0-C4)-alkylen-(C3-C12)-cycloalkyl, idet cycloalkyl er usubstitueret eller uafhængigt af hinanden er substitueret en, to, tre eller fire gange med Ril, halogen, -C(0)-O-Ril, - (Ci-C4)-alkyl-O-Rll eller -0-(C1-C4)-alkyl 4) - (C0-C4)-alkylen-C (Ril) (R12) - (C3-C12)-cycloalkyl, idet cycloalkyl er usubstitueret eller uafhængigt af hinanden er substitueret en, to eller tre gange med Ril, halogen, -C(0)-0-Rll, - (C1-C4)-alkyl-O-Rll eller -0-(C1-C4)-alkyl, 5) -(C0-C4)-alkylen-Het, idet der ved Het forstås et 4- til 15-leddet heterocyklisk ringsystem med 4 til 15 ringatomer, som foreligger i et, to eller tre med hinanden forbundne ringsystemer, og som indeholder et, to, tre eller fire ens eller forskellige heteroatomer fra rækken oxygen, nitrogen eller svovl, idet Het eller alkylen er usubstitueret eller uafhængigt af hinanden er substitueret en, to eller tre gange med Ril, halogen, -C(0)-0-Rll, - (C1-C4) -alkyl-O-Rll eller -0- (C1-C4) -alkyl, 6) - (C0-C6) -alkylen-aryl, idet aryl eller alkylen er usubstitueret eller uafhængigt af hinanden er substitueret en, to eller tre gange med Ril, halogen, -C(0)-0-Rll, -(C0-C4)- alkyl-O-Rll eller -0-(C1-C4)-alkyl, 7) - (C0-C4) -alkylen-C(Ril) (R12)-aryl, idet aryl eller alkylen er usubstitueret eller uafhængigt af hinanden er substitueret en, to eller tre gange med Ril, halogen, -C(0)-0-Rll, -(C0-C4)-alkyl-O-Rll eller -0-(C1-C4)-alkyl, 8) 1,2,3,4-tetrahydro-naphthalenyl, 9) - (C0-C4) -alkylen-CH (Ril) -C (0) -NH2, 10) - (C0-C4) -alkylen-CH (Ril) -C (0) -NH- (C1-C4) -alkyl, 11) - (C0-C4) -alkylen-CH(Ril)-C(0)-NH-CH(R12)-R13, 12) - (C0-C6) -alkylen-C(0)-O-Ril, idet alkylen er usubstitueret eller uafhængigt af hinanden er substitueret en eller to gange med Ril, halogen, -C(0)-0-Rll, - (C1-C4) -alkyl-O-Rll eller -0- (C1-C4) -alkyl, 13) - (C0-C4)-alkylen-C(Ril) (R12)-C(0)-O-Ril, eller 14) - (C1-C3)-fluoralkyl, eller de to grupper R6 sammen med det N-atom, som de er bundet til, danner en mono- eller bicyklisk ring med 4 til 9 ringatomer, som er mættet, delvist mættet eller aromatisk, idet ringen er usubstitueret eller er substitueret en eller to gange med - (C1-C4)-alkyl, -C(0)-0-Rll, halogen, - (C1-C4)-alkyl-O-Rll eller phenyl, R7 står for hydrogenatom eller -(C1-C4)-alkyl, R9 står for hydrogenatom eller -(C1-C4)-alkyl, Ril og R12 er ens eller forskellige og uafhængigt af hinanden står for 1) hydrogenatom, 2) - (C1-C4)-alkyl, 3) -(C0-C4)-alkylen-phenyl, idet phenyl er usubstitueret eller uafhængigt af hinanden er substitueret en, to eller tre gange med halogen, -OH eller -0-(C1-C4)-alkyl, 4) - (C0-C4)-alkylen-(C3-C12)-cycloalkyl, idet cycloalkyl er usubstitueret eller uafhængigt af hinanden er substitueret en, to, tre eller fire gange med R13, halogen, -C(0)-0-R13, - (Ci- C4) -alkyl-0-R13, -0-(C1-C4)-alkyl eller - (C0-C4) -alkylen-phenyl, 5) - (C0-C4)-alkylen-C (0)-N (R13) 2 eller 6) - (C0-C4) -alkylen-indolyl, R13 står for 1) hydrogenatom, 2) - (C1-C4)-alkyl, 3) - (C0-C4)-alkylen-C(0)-0-R14, 4) - (C0-C4)-alkylen-C(0)-R14 eller 5) - (C0-C4) -alkylen-0-Rl4, R14 står for hydrogenatom, - (C1-C4)-alkyl, -NH2 eller -OH, og R15 står for hydrogenatom, - (C1-C4)-alkyl, -0-CF3, -NH2, -OH, - CF3 eller halogen.
2) -NH-(CH2)n-, hvor n betegner det hele tal nul, 1, 2 eller 3,
3. Forbindelse med formel I ifølge krav 1 eller 2, idet Ri står for 1) hydrogenatom eller 2) - (C1-C4) -alkyl, R2 står for 1) - (C1-C6) -alkylen-NH2, 2) - (C1-C4) -alkylen-pyridyl-NH2, 3) - (C1-C4) -alkylen-piperidinyl-NH2, 4) - (Ci-C6) -alkylen-NH-C (=NH) -NH2, 5) - (C0-C4) -alkylen- (C3-C6) -cycloalkyl-NH2, 6) - (Ci-C6) -alkylen-NH-C (=NH) - (C1-C4) -alkyl, 7) - (Ci-C4) -alkylen-O-NH-C (=NH) -NH2, 8) - (Ci-C6)-alkylen-NH-C (0)-0-(C1-C4)-alkylen-phenyl, idet phenyl er usubstitueret eller er substitueret med -NH2 eller er substitueret med -NH2 og en, to eller tre gange med R15, 9) - (C1-C4) -alkylen-NH-C (0) - (Ci-C6) -alkyl, 10) -(C1-C4)-alkylen-phenyl, idet phenyl er usubstitueret eller er substitueret med -NH2 eller er substitueret med -NH2 og en, to eller tre gange med R15, 11) - (C1-C4)-alkylen-S02-(C1-C4)-alkylen-NH2 eller 12) - (C1-C4) -alkylen-S- (C1-C4) -alkylen-NH2, R3 står for 1) - (C1-C4) -alkyl, 2) - (C1-C4) -alkylen- (C3-C6) -cycloalkyl, 3) -(C1-C4)-alkylen-phenyl, idet phenyl uafhængigt af hinanden er substitueret en, to eller tre gange med R15, 4) - (Ci-C6)-alkylen-NH-C (0)-0-(C1-C4)-alkylen-phenyl, idet phenyl uafhængigt af hinanden er substitueret en, to eller tre gange med R15, 5) hydrogenatom, R4 står for -N(R6)2, idet R6 er ens eller forskellige og uafhængigt af hinanden står for 1) hydrogenatom, 2) - (C1-C4) -alkyl, 3) - (C0-C4)-alkylen-(C3-C12)-cycloalkyl, idet cycloalkyl er udvalgt af gruppen cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl, 1,7,7-trimethyl- bicyclo[3.1.1]heptanyl, decahydro-naphthalenyl, tetrahydronaphthalenyl, octahydro-4,7-methano-indenyl eller bicyclo[2.2.1]heptanyl, og hvor cycloalkyl er usubstitueret eller uafhængigt af hinanden er substitueret en, to, tre eller fire gange med - (C1-C4)-alkyl, -C(0)-0-Rll eller -(C1-C4)- alkylen-phenyl, idet phenyl er usubstitueret eller er substitueret med halogen, 4) - (C0-C4)-alkylen-C (Ril) (R12) - (C3-C12)-cycloalkyl, idet cycloalkyl er udvalgt af gruppen cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl, 1,7,7-trimethyl-bicyclo[3.1.1]heptanyl, decahydronaphthalen, tetrahydronaphthalenyl, octahydro-4,7-methano-indenyl eller bicyclo[2.2.1]heptanyl, og hvor cycloalkyl er usubstitueret eller uafhængigt af hinanden er substitueret en, to, tre eller fire gange med - (C1-C4)-alkyl, -C(0)-0-Rll eller - (C1-C4)- alkylen-phenyl, idet phenyl er usubstitueret eller er substitueret med halogen, 5) -(C0-C4)-alkylen-Het, idet Het er udvalgt fra gruppen acridinyl, azepinyl, azetidinyl, aziridinyl, benzimidazalinyl, benzimidazolyl, benzo[1,3]dioxolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, deca-hydroquinolinyl, dibenzofuranyl, dibenzothiophenyl, dihydrofuran[2,3 —b]-tetrahydrofuranyl, dihydrofuranyl, dioxolyl, dioxanyl, 2H, 6H-1,5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolidinyl, 2-isothiazolinyl, isothiazolyl, isoxazolyl, isoxazolidinyl, 2-isoxazolinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, oxothiolanyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxatiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pryidooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyridinyl, 6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienoimidazolyl, thienooxazolyl, thienopyridin, thienothiazolyl, thiomorpholinyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl og xanthenyl, idet Het eller alkylen er usubstitueret eller uafhængigt af hinanden er substitueret en eller to gange med -(C1-C4)-alkyl, 6) -(Ci-C6)-alkylen-phenyl, idet phenyl eller alkylen er usubstitueret eller uafhængigt af hinanden er substitueret en eller to gange med halogen, phenyl, -C(0)-O-Rll, -(C1-C4)-alkyl-O-Rll, -0- (C1-C4) -alkyl eller - (C1-C4) -alkyl, 7) - (C0-C4)-alkylen-C(Ril) (R12)-phenyl, idet phenyl er usubstitueret eller uafhængigt af hinanden er substitueret en, to eller tre gange med phenyl eller fluor, 8) 1,2,3,4-tetrahydro-naphthalenyl, 9) - (C0—C4) -alkylen-CH(Ril)-C(O)-NH2, 10) - (C0-C4) -alkylen-CH(Ril)-C(0)-NH-(C1-C4)-alkyl, 11) - (C0-C4) -alkylen-CH(Ril)-C(0)-NH-CH(R12)-R13, 12) - (C1-C6)-alkylen-C(0)-O-Rll, idet alkylen er usubstitueret eller uafhængigt af hinanden er substitueret en eller to gange med halogen, phenyl, -C(0)-0-Rll, -(C1-C4)-alkyl-O-Rll, -0-(Ci — C4) -alkyl eller- (C1-C4) -alkyl, 13) - (C0-C4)-alkylen-C(Ril) (R12)-C(0)-O-Rll eller 14) - (C1-C3)-fluoralkyl, eller de to grupper R6 sammen med det N-atom, som de er bundet til, danner en mono- eller bicyklisk ring udvalgt af gruppen pyrrolidin, piperidin, 2-aza-bicyclo[3.2.2]nonan og 7-aza- bicyclo[2.2.1]heptan, idet ringen er usubstitueret eller er substitueret en eller to gange med -(C1-C4)-alkyl, -C(0)-0-Rll, -(C1-C4)-alkyl-O-Rll eller phenyl, R7 står for hydrogenatom eller -(C1-C4)-alkyl, R9 står for hydrogenatom eller -(C1-C4)-alkyl, Ril og R12 er ens eller forskellige og uafhængigt af hinanden står for 1) hydrogenatom, 2) - (C1-C4) -alkyl, 3) -(C0-C4)-alkylen-phenyl, idet phenyl er usubstitueret eller uafhængigt af hinanden er substitueret en, to eller tre gange med -OH, halogen eller -0-(C1-C4)-alkyl, 4) - (C0-C4)-alkylen-(C3-C12)-cycloalkyl, idet cycloalkyl er udvalgt af gruppen cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl, 1,7,7-trimethyl- bicyclo[3.1.1]heptanyl, decahydro-naphthalenyl, tetrahydronaphthalenyl, octahydro-4,7-methano-indenyl eller bicyclo[2.2.1]heptanyl, og hvor cycloalkyl er usubstitueret eller uafhængigt af hinanden er substitueret en, to, tre eller fire gange med -(C1-C4)-alkyl, -C(0)-0-R13 eller phenyl, eller 5) -(C0-C4)-alkylen-indolyl, R13 står for 1) hydrogenatom, 2) - (C1-C4) -alkyl, 3) - (C0-C4)-alkylen-C(0)-0-R14, 4) - (C0-C4)-alkylen-C(0)-R14 eller 5) - (C0-C4)-alkylen-0-R14, og R14 står for hydrogenatom, - (C1-C4) -alkyl, -NH2 eller -OH, og R15 står for hydrogenatom, - (C1-C4) -alkyl, -O-CF3, -NH2, -OH, - CF3 eller halogen.
3) -NH (C1-C6) -alkyl) - (CH2) , hvor n betegner det hele tal nul, 1, 2 eller 3,
4. Forbindelse med formel I ifølge krav 1 til 3, idet RI står for 1) hydrogenatom eller 2) - (C1-C4)-alkyl, R2 står for 1) - (Οι-Οε) -alkylen-NH2, 2) - (C1-C4) -alkylen-pyridyl-NH2, 3) - (C1-C4) -alkylen-piperidinyl-NH2, 4) - (C1-C4) -alkylen-NH-C (=NH) -NH2, 5) - (Ci-C6) -alkylen-NH-C (=NH) - (C1-C4) -alkyl, 6) - (C1-C4) -alkylen- (C3-C6) -cycloalkyl-NH2, 7) - (C1-C4) -alkylen-O-NH-C (=NH) -NH2, 8) - (Ci-C6) -alkylen-NH-C (0) -0- (C1-C4) -alkylen-phenyl, 9) - (C1-C4) -alkylen-NH-C (0) - (Ci-C6) -alkyl, 10) - (C1-C4) -alkylen-phenyl-NH2, 11) - (C1-C4)-alkylen-S02-(C1-C4)-alkylen-NH2 eller 12) - (C1-C4) -alkylen-S- (C1-C4) -alkylen-NH2, R3 står for 1) - (C1-C4) -alkyl, 2) - (C1-C4) -alkylen- (C3-C6) -cycloalkyl, 3) -(C1-C4)-alkylen-phenyl, idet phenyl er usubstitueret eller er substitueret med -OH, 4) - (C1-C6) -alkylen-NH-C (0) -0- (C1-C4) -alkylen-phenyl, 5) hydrogenatom, R4 står for -N(R6)2, idet R6 er ens eller forskellige og uafhængigt af hinanden står for 1) hydrogenatom, 2) - (Ci-C6) -alkyl, 3) - (C0-C4) -alkylen- (C3-Cs) -cycloalkyl, idet cycloalkyl er udvalgt af gruppen cyclohexyl, cyclopentyl, cyclopropyl, adamantanyl, 1,7,7-trimethyl-bicyclo[3.1.1]heptanyl, decahydro-naphthalen, octahydro-4,7-methano-indenyl eller bicyclo[2.2.1]heptanyl, og hvor cycloalkyl er usubstitueret eller uafhængigt af hinanden er substitueret en, to eller tre gange med -(C1-C4)-alkyl eller phenyl, 4) -C(Ril)(R12)-adamantanyl,
4) -NH ( (C3-C6) -cycloalkyl) - (CH2) n~, hvor n betegner det hele tal nul, 1, 2 eller 3, 5) -0-(CH2)n-, hvor n betegner det hele tal nul, 1, 2 eller 3, eller 6) - (CH2) n-S0x-, hvor n betegner det hele tal nul, 1, 2 eller 3, og x betegner det hele tal nul, 1 eller 2, A2 står for 1) Het, idet der ved Het forstås et 4- til 15-leddet heterocyklisk ringsystem med 4 til 15 ringatomer, som foreligger i et, to eller tre med hinanden forbundne ringsystemer, og som indeholder en, to, tre eller fire ens eller forskellige heteroatomer fra rækken oxygen, nitrogen eller svovl og er usubstitueret eller uafhængigt af hinanden er substitueret en, to eller tre gange med et - (C1-C3)-alkyl, halogen, -NH2, -CF3 eller -0-CF3, 2) - (C0-C6) -alkylen-NH2, 3) - (Ci-C6) -alkylen-NH-C (=NH) -NH2, 4) - (Ci-C6) -alkylen-NH-C (=NH) - (C1-C4) -alkyl, 5) - (C0-C4) -alkylen-O-NH-C (=NH) -NH2, 6) - (C0-C4) -alkylen-NH-C (0) - (Ci-C6) -alkyl, 7) - (C1-C6)-alkylen-NH-C (0)-0-(C1-C4)-alkylen-aryl, idet aryl er usubstitueret eller er substitueret med -NH2 eller er substitueret med -NH2 og en, to eller tre gange med R15, 8) - (C3-C8) -cycloalkyl-NH2 eller 9) - (C0-C4)-alkylen-(C6-C14)-aryl, idet aryl er usubstitueret eller er substitueret med -NH2 eller er substitueret med -NH2 og en, to eller tre gange med R15, R3 står for 1) - (Ci-C6)-alkyl, 2) - (C0-C4) -alkylen- (C3~Ci2) -cycloalkyl, 3) - (Ci-C6)-alkylen-(C6-C14)-aryl, idet aryl uafhængigt af hinanden er substitueret en, to eller tre gange med R15, 4) - (C0-C8)-alkylen-N (R5)-PG, 5) - (C1-C6)-alkylen-NH-C (0)-0-(C1-C4)-alkylen-aryl, idet aryl uafhængigt af hinanden er substitueret en, to eller tre gange med RI5, 6) - (C0-C4) -alkylen- (C6-Ci4) -aryl- (C0-C4) -alkylen-N (R5) -PG, 7) - (C0-C8)-alkylen-O-PG, 8) - (C0-C4) -alkylen- (C6-Ci4) -aryl- (C0-C4) -alkylen-O-PG, 9) - (C0-C8) -alkylen-C (0) -0-PG, 10) - (C0-C4) -alkylen- (C6-Ci4) -aryl- (C0-C4) -alkylen-C (0) -0-PG eller 11) hydrogenatom, R4 står for -N(R6)2, idet R6 er ens eller forskellige og uafhængigt af hinanden står for 1) hydrogenatom, 2) - (Ci-C6)-alkyl, 3) - (C0-C4)-alkylen-(C3-C12)-cycloalkyl, idet cycloalkyl er usubstitueret eller uafhængigt af hinanden er substitueret en, to, tre eller fire gange med Ril, halogen, -C(0)-0-Rll, —(Ci— C4)-alkyl-O-Rll eller -O-(C1-C4)-alkyl, 4) - (C0-C6)-alkylen-(C6-C14)-aryl, idet aryl og alkylen er usubstitueret eller uafhængigt af hinanden er substitueret en, to, tre eller fire gange med Ril, halogen, -C(0)-0-Rll, - (C4- C4) -alkyl-O-Rll, -C(0)-N(R8)2 eller -0-(C1-C4)-alkyl, 5) - (Co-Cø) -alkylen-N (R5)-PG, 6) - (C0-C4) -alkylen- (C6-C14) -aryl- (C0-C4) -alkyl-N (R5) -PG, 7) - (C0-C8)-alkylen-O-PG, 8) - (C0-C4) -alkylen- (C6-C14) -aryl- (C0-C4) -alkyl-O-PG, 9) - (C0-C8)-alkylen-C (O)-O-Rll, 10) - (C0-C4) -alkylen- (C6-C14) -aryl- (C0-C4) -alkyl-C (0) -0-PG, 11) - (C0-C4)-alkylen-Het, idet der ved Het forstås et 4- til 15-leddet heterocyklisk ringsystem med 4 til 15 ringatomer, som foreligger i et, to eller tre med hinanden forbundne ringsystemer, og som indeholder et, to, tre eller fire ens eller forskellige heteroatomer fra rækken oxygen, nitrogen eller svovl, idet Het eller alkylen er usubstitueret eller uafhængigt af hinanden er substitueret en, to eller tre gange med Ril, halogen, -C(0)-0-Rll, - (C1-C4)-alkyl-O-Rll eller -0-(C1-C4)-alkyl, 12) - (C1-C3)-fluoralkyl, 13) - (C0-C4) -alkylen-CH (Ril) -C (0) -NH2, 14) - (C0-C4)-alkylen-CH (Ril)-C (0)-NH-(C1-C4)-alkyl eller 15) - (C0-C4) -alkylen-CH(Ril)-C(0)-NH-CH(R12)-RI3, eller de to grupper R6 sammen med det N-atom, som de er bundet til, danner en mono- eller bicyklisk ring med 4 til 9 ringatomer, som er mættet, delvist mættet eller aromatisk, idet ringen er usubstitueret eller er substitueret en eller to gange med - (C1-C4) -alkyl, -C(0)-0-Rll, halogen, - (C1-C4)-alkyl- O-Rll eller phenyl, R5 står for hydrogenatom eller -(Ci-C6)-alkyl, PG står for en beskyttelsesgruppe for amino-, carboxyl- eller for hydroxyfunktionen, R7 står for hydrogenatom eller -(Ci-C6)-alkyl, R8 står for hydrogenatom eller -(Ci-C6)-alkyl, R9 står for hydrogenatom eller -(Ci-C6)-alkyl, Ril og R12 er ens eller forskellige og uafhængigt af hinanden står for 1) hydrogenatom, 2) - (Ci-C6) -alkyl, 3) -(Co-C4)-alkylen-phenyl, idet phenyl er usubstitueret eller uafhængigt af hinanden er substitueret en, to eller tre gange med halogen, -OH eller -0-(C1-C4)-alkyl, 4) - (C0-C4)-alkylen-(C3-C12)-cycloalkyl, idet cycloalkyl er usubstitueret eller uafhængigt af hinanden er substitueret en, to, tre eller fire gange med R13, halogen, -C(0)-0-R13, -(Ci- C4) -alkyl-0-R13, -0-(C1-C4)-alkyl eller - (C0-C4)-alkylen-phenyl, 5) - (C0-C4)-alkylen-C (0)-N (R13) 2 eller 6) - (C0-C4)-alkylen-indolyl, R13 står for 1) hydrogenatom, 2) - (C1-C4) -alkyl, 3) - (C0-C4)-alkylen-C(0)-0-R14, 4) - (C0-C4)-alkylen-C(0)-R14 eller 5) - (C0-C4) -alkylen-0-R14, R14står for hydrogenatom, - (C1-C4)-alkyl, -NH2 eller -OH, og R15 står for hydrogenatom, - (C1-C4)-alkyl, -0-CF3, -NH2, -OH, - CF3 eller halogen.
5. Forbindelse med formel I ifølge et eller flere af kravene 1 til 4, kendetegnet ved, at det er forbindelsen med formel I (S)-6-amino-2-(3 —{ (S)-1-[ (S)-1-((S)-l-methoxycarbonyl-2-methyl-propylcarbamoyl)-2-methyl-propylcarbamoyl]-2-phenyl-ethyl}-sulfamidyl)-hexansyre, (S)-6-amino-2-{3-[ (R)-1- (bicyclo[2.2.1]hept-2-ylcarbamoyl)-2-cyclohexyl-ethyl]-sulamidyl}-hexansyre, (S)-6-amino-2-[3-( (S)-1- cyclohexylcarbamoyl-2-phenyl-ethyl)-sulfamidyl]-hexansyre, (S)-6-acetimidoylamino-2-{[(S)-2-cyclohexyl-l-((1R,2S,4R)- 1,7,7-trimethyl-bicyclo[2.2.1]hept-2-ylcarbamoyl)-ethylsulfamidyl] }-hexansyre, 3-(6-amino-pyridin-3-yl)-2-[ (S)- 2-cyclohexyl-l-((1R,2S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]hept-2-ylcarbamoyl)-ethylsulfamid-yl]-propionsyreethylester, (S)-6- amino-2-{[(S)—1—((1R,2S,4R)-1,7,7-trimethyl- bicyclo[2.2.1]hept-2-ylcarbamoyl)-propylsulfamidyl] -} -hexansyre, (S) -2-{[(S)-2-cyclohexyl-l-((IR,2S,4R)-1,7,7- trimethyl-bicyclo[2.2.1]hept-2-ylcarbamoyl)-ethylsulfamidyl]-}-5-guanidino-pentansyre, (S) -6-amino-2-{[(S)-2-cyclobutyl-l-((1R,2S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]hept-2-ylcarbamoyl)-ethylsulf-amidyl]}-hexansyre, (S)-5-amino-2-({2-cyclohexyl-l- [(R)-(1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl]-ethylsulfamidyl})-pentanyre, (S)-2-{[(S)-2-cyclohexyl-l- ((IR, 2S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]hept-2-ylcarbamoyl)-ethylsulfamidyl]}-6-hexanoylamino-hexansyre-ethylester, (S)— 6 — amino-2-{[(S)—1—((IR,2S,4R)-1,7,7-trimethyl- bicyclo [2.2.1]hept-2-ylcarbamoyl)-butylsulfamidyl]}-hexansyre, (S)-6-amino-2-{[(S)-3-cyclohexyl-l-((1R,2S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]hept-2-ylcarbamoyl)-propy1sulf-amidyl]-methyl}-hexansyre, (S) -6-amino-2-{[(S)-2-cyclohexyl-l-(decahydro-naphthalen-2-ylcarbamoyl)-ethylsulfamidyl]}-hexansyre, (S) -2-{[(S)-1-(adamantan-l-ylcarbamoyl)-2- cyclohexyl-ethylsulfamidyl]}-6-amino-hexansyre, (S)— 2 —[(S)—2 — cyclohexyl-1-((1R,2S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]-hept-2-ylcarbamoyl)-ethylsulfamidyl]-3-pyridin-3-yl-propionsyre, (S)-2-[(S)-2-cyclohexyl-l-((1R,2S,4R)-1,7,7-trimethyl-bicyclo [2.2.1]hept-2-ylcarbamoyl)-ethylsulfamidyl]-3-pyridin-4-yl-propionsyre, (S)-6-amino-2-{[(S)-2-cyclohexyl-l- ((lS,2S,3S,5R)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-ylcarbamoyl)-ethylsulfamidyl]}-hexansyre, (S)-6-amino-2-{[(S)-2-cyclohexyl-l-(3,3,5-trimethyl-cyclohexylcarbamoyl)-ethylsulfamidyl][-hexansyre, (S)-6-amino-2-{[(S)-1-(4-tert- butyl-cyclohexylcarbamoyl)-2-cyclohexyl-ethylsulfamidyl]}-hexansyre, (S) -6-amino-2-{[(S)-2-cyclohexyl-l-(3-methyl- cyclohexylcarbamoyl)-ethylsulfamidyl][-hexansyre, (S)-6-amino- 2- {[(S)-2-cyclohexyl-l-((1R,2S,4R)-1,7,7-trimethyl- bicyclo [2.2.1]hept-2-ylcarbamoyl)-ethylsulfamidyl]}-hexansyre, 3- (6-amino-pyridin-3-ylmethyl)-2-[(S)-2-cyclohexyl-l-((IR,2S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl-carbamoyl)-ethylsulfamidyl]-propionsyre, 2-[(S)-2-cyclohexyl- 1-((IR,2S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]hept-2-ylcarbamoyl)-ethylsulfamidyl]-3-piperidin-4-yl-propionsyre, (S)-3-(4-amino-phenyl)-2-[(S)-2-cyclohexyl-l-((IR,2S,4R)- 1.7.7- trimethyl-bicyclo[2.2.1]hept-2-ylcarbamoyl)- ethylsulfamidyl]-propionsyre, (S)-6-amino-2-[((S)-1- cyclohexylmethyl-2-oxo-2-piperidin-l-yl-ethylsulfamidyl)]-hexansyre, (S) -5-amino-2-{[(S)-2-cyclohexyl-1-((1R,2S,4R)- 1.7.7- trimethyl-bicyclo[2.2.1]hept-2-ylcarbamoyl)- ethylsulfamidyl]}-pentansyre, (S)-6-amino-2-{[(S) —2 — cyclohexyl-1-((S)-l-isobutylcarbamoyl-2-methyl- propylcarbamoyl)-ethylsulfamidyl]}-hexansyre (S)-6-amino-2- {[(S)-1-((S)-l-isobutylcarbamoyl-2-methyl-propylcarbamoyl)-2-phenyl-ethylsulfamidyl]}-hexansyre, (S)-6-amino-2-[((S)-2- cyclohexyl-l-isobutylcarbamoyl-ethylsulfamidyl)]-hexansyre, (S) - 6-amino-2-{ [ (S) —1— ((lR,2R,4S)-bicyclo[2.2.1]hept-2-ylcarbamoyl)-2-cyclohexyl-ethylsulfamidyl]}-hexansyre, (S) -6-amino-2-{[(S)-2-cyclohexyl-l-((1R,2S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]hept-2-ylcarbamoyl)-ethylsulfamidyl]}-hexansyre, (S)- 6-amino-2-{[(S)—1—((1S,4R)-bicyclo[2.2.1]hept-2-ylcarbamoyl)-2-cyclohexyl-ethylsulf-amidyl]}-hexansyre, (S) — 6— amino-2-{[(S)-2-cyclohexyl-l-(octahydro-4,7-methano-inden-5-ylcarbamoyl)-ethylsulfamidyl] }-hexansyre, (S)-6-amino-2-[ ( (S)- 1- tert-butylcarbamoyl-2-cyclohexyl-ethylsulfamidyl)]- hexansyre, (S) — 2 —{ [(S)-1-(adamantan-1-ylcarbamoyl)-2-phenyΙέ thy lsu If amidyl ] }- 6-amino-hexansyre, (S) - 6-amino-2-{[(S) —1 — ((lS,4R)-bicyclo[2.2.1]hept-2-ylcarbamoyl) -2-phenyΙέ thy lsu If amidyl ] }-hexansyre, (S) — 2 —{ [(S)-1-(adamantan-1- ylcarbamoyl)-2-(4-hydroxy-phenyl)-ethylsulfamidyl]}-6-amino-hexansyre, (S)-6-amino-2-{[(S)-2-phenyl-1-((1R,2S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]hept-2-ylcarbamoyl)-ethylsulfamidyl]}-hexansyre, (S) -6-amino-2-({[(S)-cyclohexyl-(1,7,7-trimethyl-bicyclo [2.2.1]hept-2-ylcarbamoyl)-methyl]-sulfamidyl}) -hexansyre, (S) - 6-amino-2-{[(S)-2-cyclohexyl-l-((1R, 2R, 4R) - 1.7.7- trimethyl-bicyclo[2.2.1]hept-2-ylcarbamoyl)- ethylsulfamidyl][-hexansyre, (S)-6-amino-2-{[(S) — 2 — cyclopropyl-1-((1R,2R,4R)-1,7,7-trimethyl-bicyclo[2.2.1]hept- 2- ylcarbamoyl)-ethylsulfamidyl][-hexansyre, (S)-6-amino-2- {[(S)-2-cyclohexyl-l-(3,5-dimethyl-adamantan-l-ylcarbamoyl)-ethylsulf-amidyl]}-hexansyre, (S)-6-amino-2-{[(S) —2 — cyclohexyl-1-(3-isopropyl-adamantan-l-ylcarbamoyl)-ethylsulfamidyl][-hexansyre, (S) -6-amino-2-{[(S)-2-cyclohexyl- 1 -((1R,2R,4R)-1,7,7-trimethyl-bicyclo[2.2.1]hept-2- ylcarbamoyl)-ethylsulfamidyl]}-hexansyre-tert-butylester eller (S)-2-{[(S)-1-(adamantan-l-ylcarbamoyl)-3-methylbutylsulfamidyl]}-6-amino-hexansyre.
5) -CH(Ril)-C(0)-NH-CH(R12)-R13, 6) - (C0-C4) -alkylen-Het, idet Het er udvalgt af gruppen benzimidazolyl, isoxazolyl, piperidin, pyridin, pyrrolidinyl, thiophenyl og benzo[1,3]dioxol, 7) 1,2,3,4-tetrahydro-naphthalenyl, 8) - (C0-C4)-alkylen-C (Ril) (R12)-phenyl, idet phenyl er usubstitueret eller uafhængigt af hinanden er substitueret en, to eller tre gange med phenyl eller fluor,
9) -CH(Rll)-C (0)-NH2,
10) -CH(Ril)-C(0)-NH-CH(R12)-CH2-0H, 11) -(C1-C6)-alkylen-phenyl, idet phenyl eller alkylen er usubstitueret eller uafhængigt af hinanden er substitueret en eller to gange med chlor, fluor, -C(0)-0-Rll, - (C1-C4)-alkyl-0-Rll, -0-(C1-C4)-alkyl, phenyl eller - (C1-C4)-alkyl,
12) -CH (Ril) -C (0) -NH- (C1-C4) -alkyl, 13) -(C0-C4)-alkylen-C(Ril) (R12)-bicyclo[3.1.1]heptanyl, idet bicyclo[3.1.1]heptanyl er usubstitueret eller er substitueret en til fire gange med -(C1-C4)-alkyl, 14) -(Ci-C6)-alkylen-C(0)-0-R11, idet alkylen er usubstitueret eller uafhængigt af hinanden er substitueret en eller to gange med chlor, fluor, -C(0)-0-Rll, - (C1-C4) -alkyl-0-Rll, -0-(Ci-C4)-alkyl, phenyl eller -(C1-C4)-alkyl, 15) - (C0-C4)-alkylen-C(Ril) (R12)-C(0)-0-R11 eller
16) -CH2-CF2-CF3, eller de to grupper R6 sammen med det N-atom, som de er bundet til, danner en mono- eller bicyklisk ring udvalgt af gruppen pyrrolidin, 2-aza-bicyclo[3.2.2]nonan og 7-aza- bicyclo[2.2.1]heptan, idet ringen er usubstitueret eller er substitueret en eller to gange med - (C1-C4) -alkyl, -C(0)-0-Rll, - (C1-C4)-alkyl-0-Rll eller phenyl, R7 står for hydrogenatom eller -(C1-C4)-alkyl, R9 står for hydrogenatom eller -(C1-C4)-alkyl, Ril og R12 er ens eller forskellige og uafhængigt af hinanden står for 1) hydrogenatom, 2) - (C1-C4) -alkyl, 3) -(C0-C4)-alkylen-phenyl, idet phenyl er usubstitueret eller uafhængigt af hinanden er substitueret en, to eller tre gange med -OH, halogen eller -0-(C1-C4)-alkyl, 4) - (C0-C4)-alkylen-(C3-C12)-cycloalkyl, idet cycloalkyl er udvalgt af gruppen cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl, 1,7,7-trimethyl- bicyclo[3.1.1]heptanyl, decahydro-naphthalenyl, octahydro-4,7-methano-indenyl eller bicyclo[2.2.1]heptanyl, og hvor cycloalkyl er usubstitueret eller uafhængigt af hinanden er substitueret en, to, tre eller fire gange med -(C1-C4)-alkyl, -C (0)-0-R13 eller phenyl, eller 5) -(C0-C4)-alkylen-indolyl, R13 står for 1) hydrogenatom, 2) - (C1-C4) -alkyl, 3) - (C0-C4) -alkylen-C(0)-0-R14, 4) - (C0-C4)-alkylen-C(0)-R14 eller 5) - (C0-C4)-alkylen-0-R14, R14 står for hydrogenatom, - (C1-C4)-alkyl, -NH2 eller -OH, og R15 står for hydrogenatom, - (C1-C4)-alkyl, -0-CF3, -NH2, -OH, - CF3 eller halogen.
6. Fremgangsmåde til fremstilling af forbindelsen med formel I ifølge et eller flere af kravene 1 til 5, kendetegnet ved, at man omsætter a) en forbindelse med formel II
(II) idet R2 og PG har de i forbindelsen med formel I nævnte betegnelser, med en forbindelse med formel IX, °R7 R4"UNj—NH2 (Ιχ) R3 idet R3, R4, R7 og PG har de i forbindelsen med formel I nævnte betegnelser, til en forbindelse med formel X,
(X) idet R2, R3, R4, R7, R9 og PG har de i forbindelsen med formel I nævnte betegnelser, og så omdanner den til en forbindelse med formel I, eller fraskiller b) en ifølge fremgangsmåde a) fremstillet forbindelse med formel I, eller et egnet forstadie med formel I, som på grund af dens kemiske struktur optræder i enantiomere former, ved hjælp af saltdannelse med enantiomerrene syrer eller baser, kromatografi på chirale stationærfaser eller derivatisering ved hjælp af chirale enantiomerrene forbindelser såsom aminosyrer, separation af de således opnåede diastereomerer og fraspaltning af de chirale hjælpegrupper til de rene enantiomerer, eller isolerer c) den ifølge fremgangsmåde a) eller b) fremstillede forbindelse med formel I enten i fri form, eller i det tilfælde at der foreligger sure eller basiske grupper, omdanner den til fysiologisk forligelige salte.
7. Lægemiddel, kendetegnet ved et virksomt indhold af i det mindste en forbindelse med formel I ifølge et eller flere af kravene 1 til 5 sammen med et farmaceutisk egnet og fysiologisk forligeligt bærestof, tilsætningsstof og/eller andre aktiv- og hjælpestoffer.
8. Anvendelse af forbindelsen med formel I
0) og/eller en stereoisomer form af forbindelsen med formel I og/eller blandinger af disse former i ethvert forhold og/eller et fysiologisk forligeligt salt af forbindelsen med formel I ifølge krav 1 til 5 til fremstilling at et lægemiddel til profylakse, sekundærprævention og terapi af en eller flere sygdomme, som er forbundet med tromboser, embolier, hyperkoagulabilitet eller fibrotiske forandringer, udvalgt af rækken myokardinfarkt, angina pectoris og andre former for akut koronarsyndrom, slagtilfælde, de perifært vaskulære sygdomme, dyb venetrombose, lungeemboli, emboliske eller trombotiske hændelser betinget af kardiale arytmier, kardiovaskulære hændelser såsom restenose efter revaskularisering og angioplastik og lignende indgreb såsom stentimplantationer og bypass-operationer eller reduktion af tromboserisikoen efter kirurgiske indgreb som ved knæ- og hofteledsoperationer eller dissemineret intravaskulær koagulation, sepsis og andre intravaskulære hændelser, som er forbundet med en betændelse, aterosklerose, diabetes og det metaboliske syndrom og følgerne heraf, tumorvækst og tumormetastasering, betændelses- og degenerative ledsygdomme såsom reumatoid arthritis og arthrose, forstyrrelser i det hæmostatiske system såsom fibrinaflejringer, fibrotiske forandringer i lungerne såsom kronisk obstruktiv lungesygdom, adult respiratory distress syndromet eller fibrinaflejringer i øjet efter øjenoperationer eller hindring af eller behandling af ardannelse.
DK07856207.1T 2006-12-06 2007-11-22 Sulfamidderivater som inhibitorer af tafia DK2104497T3 (da)

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CA2726554C (en) 2008-06-06 2015-02-24 Sanofi-Aventis Macrocyclic urea and sulfamide derivatives as inhibitors of tafia
EA018502B1 (ru) 2008-06-23 2013-08-30 Астразенека Аб Новые гетероциклические карбоксамиды и фармацевтические композиции, содержащие их
US8354444B2 (en) 2008-09-18 2013-01-15 Hoffmann-La Roche Inc. Substituted pyrrolidine-2-carboxamides
WO2010050525A1 (ja) 2008-10-29 2010-05-06 大正製薬株式会社 ＴＡＦＩａ阻害活性を有する化合物
BR112015029667A2 (pt) * 2013-06-10 2017-07-25 Sanofi Sa derivados de ureia macrocíclica como inibidores de tafia, sua preparação e seus usos como produtos farmacêuticos
CN104529859B (zh) * 2015-01-13 2016-08-17 佛山市赛维斯医药科技有限公司 含苯胺和二烯氟代金刚烷结构的化合物、其制备方法和用途
RU2687254C1 (ru) * 2018-10-03 2019-05-08 Федеральное государственное бюджетное учреждение науки Новосибирский институт органической химии им. Н.Н. Ворожцова Сибирского отделения Российской академии наук (НИОХ СО РАН) N-гетероциклические производные борниламина в качестве ингибиторов ортопоксвирусов

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CO6180422A2 (es) 2010-07-19
NZ577312A (en) 2012-02-24
WO2008067909A3 (de) 2009-04-09
BRPI0720241A2 (pt) 2013-12-31
KR20090087044A (ko) 2009-08-14
TWI399203B (zh) 2013-06-21
ZA200903040B (en) 2010-02-24
PL2104497T3 (pl) 2015-07-31
AR064119A1 (es) 2009-03-11
CL2007003494A1 (es) 2008-06-13
CN101553219B (zh) 2013-04-24
NO20092246L (no) 2009-07-01
CN101553219A (zh) 2009-10-07
AU2007327959A1 (en) 2008-06-12
SI2104497T1 (sl) 2015-06-30
EP2104497B1 (de) 2015-02-25
CA2671861A1 (en) 2008-06-12
WO2008067909A2 (de) 2008-06-12
RU2009125534A (ru) 2011-01-20
MA30968B1 (fr) 2009-12-01
PE20081349A1 (es) 2008-10-24
JP5396279B2 (ja) 2014-01-22
US8389764B2 (en) 2013-03-05
CA2671861C (en) 2015-12-29
MX2009005516A (es) 2009-06-04
CY1116384T1 (el) 2017-02-08
JP2010511641A (ja) 2010-04-15
RU2459619C2 (ru) 2012-08-27
ES2537093T3 (es) 2015-06-02
US20100035930A1 (en) 2010-02-11
HRP20150514T1 (hr) 2015-09-11
EP2104497A2 (de) 2009-09-30
HK1137928A1 (en) 2010-08-13
TW200838498A (en) 2008-10-01
AU2007327959B2 (en) 2013-08-01
PT2104497E (pt) 2015-06-09

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