SI9300328A - 1,5-Benzodiazepine Derivates - Google Patents

Abstract

Spojine s splošno formulo (I) Sl 9300328 A i premoščeno cikloalkilno ali Ci ^alkilno skupino, alkilna skupina pa je lahko substituirana s hidroksi, fenilno, Ci-6alkoksi-karbonilno, C3-7Cikloalkilno ali C7.11 premoščeno cikloalkilno skupino; R2 predstavlja substituirano ali nesubstituirano fenilno skupino (kjer so lahko substituenti 1 ali 2 izmed halo, Ci-4alkila, nitro, ciano trifluorometila, trifluorometoksi, Ci-4alkiltio ali (CH2)nR4 hidroksi, Ci-4alkoksi, CO2R5 ali NR6R7 R3 je fenil, v danem primeru substituiran z enim ali dvema atomoma halogena; R5 predstavlja vodik ali Ci-4alkilno skupino; R6 in R7 neodvisno predstavljata vodik ali CMalkilno skupino; R8 predstavlja atom vodika ali halogena; m je 0, 1 ali 2; n je 0 ali 1; so antagonisti gastrinskih in CCK-B receptorjev.Compounds of General Formula (I) Sl 9300328 A i bridged cycloalkyl or C 1-6 alkyl group, alkyl and the group may be substituted by hydroxy, phenyl, C 1-6 alkoxy-carbonyl, C 3-7 cycloalkyl or C 7-11 bridged a cycloalkyl group; R2 represents substituted or an unsubstituted phenyl group (where may be substituents 1 or 2 of halo, C 1-4 alkyl, nitro, cyano trifluoromethyl, trifluoromethoxy, C 1-4 alkylthio or (CH2) nR4 hydroxy, C1-4alkoxy, CO2R5 or NR6R7 R3 is phenyl optionally substituted by one or two halogen atoms; R 5 represents hydrogen or C 1-4 alkyl a group; R 6 and R 7 independently represent hydrogen or a C 1-4 alkyl group; R8 represents a hydrogen atom or halogens; m is 0, 1 or 2; n is 0 or 1; they are antagonists gastrin and CCK-B receptors.

Description

Predloženi izum se nanaša na nove derivate 1,5-benzodiazepina, na postopke za njihovo pripravo, na farmacevtske sestavke, ki jih vsebujejo, in na njihovo uporabo v medicini.The present invention relates to novel 1,5-benzodiazepine derivatives, to processes for their preparation, to pharmaceutical compositions containing them, and to their use in medicine.

Zlasti se izum nanaša na spojine, ki so močni in specifični antagonisti gastrina in/ali holecistokinina (CCK).In particular, the invention relates to compounds that are potent and specific gastrin and / or cholecystokinin (CCK) antagonists.

(I)(I)

2' kjer2 'where

R¹ predstavlja fenilno, C_{3 7}cikloalkilno, C_{? n} premoščeno cikloalkilno ali C^alkilno skupino, alkilna skupina pa je lahko substituirana s hidroksi, fenilno, C^alkoksikarbonilno, C_{3 7}cikloalkilno ali C_{7 n} premoščeno cikloalkilno skupino;R ¹ represents phenyl, C _3-7 cycloalkyl, C _{? n is a} bridged cycloalkyl or C 1-6 alkyl group, and the alkyl group may be substituted by hydroxy, phenyl, C 1-4 alkoxycarbonyl, C _3-7 cycloalkyl or C _{7 n} bridged cycloalkyl group;

R² predstavlja substituirano ali nesubstituirano fenilno skupino (kjer so lahko substituenti 1 ali 2 izmed halo, C_Malkila, nitro, ciano trifluorometila, trifluorometoksi, ₄alkiltio ali (CH₂)_nR⁴, kjer je R⁴ hidroksi, C^alkoksi, CO₂R⁵ ali NR⁶R⁷;R ² represents a substituted or unsubstituted phenyl group (wherein the substituents may be 1 or 2 of halo, C _M alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, ₄ alkylthio, or (CH _{2) n} R ^4, wherein R ⁴ is hydroxy, C ^ alkoxy , CO ₂ R ⁵ or NR ⁶ R ⁷ ;

R³ je fenil, v danem primeru substituiran z enim ali dvema atomoma halogena;R ³ is phenyl optionally substituted by one or two halogen atoms;

R⁵ predstavlja vodik ali C₁₄alkilno skupino;R ⁵ represents hydrogen or a C ₁₄ alkyl group;

R⁶ in R⁷ neodvisno predstavljata vodik ali C₁₄alkilno skupino;R ⁶ and R ⁷ independently represent hydrogen or a C ₁₄ alkyl group;

R⁸ predstavlja atom vodika ali halogena; m je 0,1 ali 2;R ⁸ represents a hydrogen or halogen atom; m is 0.1 or 2;

n je 0 ali 1; ter njihove farmacevtsko sprejemljive soli in solvate.n is 0 or 1; and pharmaceutically acceptable salts and solvates thereof.

Treba je upoštevati, da imajo spojine s formulo (I) vsaj ena simetričen atom ogljika (namreč atom ogljika, ki zavzema lego 3 diazepinskega obroča) in spojine v smislu izuma tako zajemajo vse stereizomere in njihove zmesi, vključno racemate.It is to be appreciated that the compounds of formula (I) have at least one symmetric carbon atom (namely the carbon atom occupying the position of the 3 diazepine ring) and the compounds of the invention thus cover all stereisomers and mixtures thereof, including racemates.

V spojinah s formulo (I) pomeni alkil, kadar se uporablja kot substituent ali del substituentne skupine, da je skupina lahko ravna ali razvejena. Tako je C₁₆alkil metil, etil, n-propil, izopropil, n-butil, izobutil ali terc.butil, n-pentil, izopentil, neopentil, n-heksil, izoheksil, 1,3-dimetilbutil, 3,3-dimetilbutil, 2,3-dimetilbutil.In the compounds of formula (I), alkyl, when used as a substituent or part of a substituent group, means that the group may be straight or branched. Thus, C _{16 is} alkyl methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 1,3-dimethylbutyl, 3,3-dimethylbutyl , 2,3-dimethylbutyl.

Za skupino R¹ se izraz C_{3 7}cikloalkil kot skupina ali del skupine nanaša na monociklično alkilno skupino, kot ciklopropil, ciklobutil, ciklopentil, cikloheksil ali cikloheptil. Izraz C_{7 n} premoščen cikloalkil se nanaša na skupine, kot adamantil, norbornanil ali norbornenil.For the R ¹ group, the term C _3-7 cycloalkyl as a group or part of a group refers to a monocyclic alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. The term C _{7 n} bridged cycloalkyl refers to groups such as adamantyl, norbornanyl or norbornenyl.

Za skupine R⁵, R⁶ in R⁷ izraz C_{4 4} alkil zajema 3-4-cikloalkil (npr. ciklopropil ali ciklobutil) kot tudi ravne ali razvejene alkilne skupine, kot je definirano zgoraj.For the groups R ⁵ , R ⁶ and R ^{7, the} term C _{4 4} alkyl includes 3-4-cycloalkyl (eg cyclopropyl or cyclobutyl) as well as straight or branched alkyl groups as defined above.

Halogen pri definiciji spojin s formulo (I) lahko predstavlja fluoro, kloro, bromo ali jodo substituent.Halogen in the definition of compounds of formula (I) may be a fluoro, chloro, bromo or iodo substituent.

Kadar je R² fenilna skupina, substituirana z enim samim substituentom, je lahko ta v orto, para ali bolj prednostno v meta legi.When R ^{2 is a} phenyl group substituted by a single substituent, it may be in ortho, para or more preferably in the meta position.

Kadar je R⁸ halogen, je prednostno klor ali fluor.When R ^{8 is} halogen, it is preferably chlorine or fluorine.

Kadar je m 1 ali 2, je atom halogena (atomi halogena) npr. klor ali fluor, prednostno v legi 7 in/ali 8.When m is 1 or 2, the halogen atom (halogen atoms) is e.g. chlorine or fluorine, preferably in position 7 and / or 8.

Spojine s formulo (I) imajo vsaj en asimetričen atom ogljika (namreč atom ogljika, ki zavzema lego 3 diazepinskega obroča) in posebno prednostne spojine v smislu izuma so tiste z relativno stereokemijo, prikazano na formuli (la)The compounds of formula (I) have at least one asymmetric carbon atom (namely, the carbon atom occupying the position of the 3 diazepine ring) and the particularly preferred compounds of the invention are those with relative stereochemistry shown in formula (Ia)

kjer vez s polnim klinom nakazuje, daje skupina nad ravnino diazepinskega obroča, in prekinjena vez nakazuje, daje skupina pod ravnino diazepinskega obroča.wherein the full-wedge bond indicates that the group is above the plane of the diazepine ring, and the broken bond indicates that the group is below the plane of the diazepine ring.

Kadar R¹ predstavlja alkilno skupino, substituirano s hidroksilno skupino, je ta prednostno C_{3 6}alkilna skupina, substituirana s hidroksi. Primeri takih skupin so 2- hidroksipropil, 2-hidroksi-3-metilbutil in 2-hidroksi-3,3-dimetiIbutil, od katerih sta posebno prednostna 2-hidroksi-3-metilbutil in 2-hidroksi-3,3-dimetilbutil.When R ¹ represents an alkyl group substituted by a hydroxyl group, it is preferably a C _3-6 alkyl group substituted by hydroxy. Examples of such groups are 2- hydroxypropyl, 2-hydroxy-3-methylbutyl and 2-hydroxy-3,3-dimethylbutyl, of which 2-hydroxy-3-methylbutyl and 2-hydroxy-3,3-dimethylbutyl are particularly preferred.

Kadar R¹ predstavlja alkilno skupino, substituirano s C_{3 7}cikloalkilno skupino, je ta prednostno C_{2 3}alkilna skupina, kot etil ali 1-metiletil, substituiran s C_{3 7}cikloalkilno skupino, kot je ciklopentil.When R ¹ represents an alkyl group substituted with a C _3-7 cycloalkyl group, it is preferably a C _2-3 alkyl group such as ethyl or 1-methylethyl substituted with a C _3-7 cycloalkyl group such as cyclopentyl.

Kadar je R¹ premoščena C_{? n}cikloalkilna skupina, je lahko npr. adamantilna skupina, kot 1-adamantilna ali 2-adamantilna skupina ali 2-norbomanilna skupina.When R ^{1 is} bridged C _{? n is a} cycloalkyl group, e.g. an adamantyl group such as a 1-adamantyl or 2-adamantyl group or a 2-norbomanyl group.

Kadar je R¹ alkilna skupina, substituirana s premoščeno C_{? n}cikloalkilno skupino, je to prednostno etilna skupina ali še posebej metilna skupina, substituirana s premoščeno C_{? n}cikloalkilno skupino. Primeri ustreznih premoščenih cikloalkilnih skupin so adamantil, kot 1-adamantil ali 2-adamantil, 2-norbornanil ali 5-norbornenil Najbolj prednostno R¹ predstavlja 1-adamantilmetil.When R ^{1 is an} alkyl group substituted by a bridged C _{? n is a} cycloalkyl group, is it preferably an ethyl group or, in particular, a methyl group substituted by a bridged C _{? n is a} cycloalkyl group. Examples of suitable bridged cycloalkyl groups are adamantyl, such as 1-adamantyl or 2-adamantyl, 2-norbornanyl or 5-norbornenyl. Most preferably, R ¹ represents 1-adamantylmethyl.

Kadar je R¹ alkil, substituiran s fenilom, je ta lahko npr. benzil ali fenetil.When R ^{1 is} alkyl substituted by phenyl, this may be e.g. benzyl or phenethyl.

Kadar je R¹ alkil, substituiran z alkoksikarbonilom, je to prednostno metil, substituiran z alkoksikarbonilom, kot je metoksikarbonil ali t-butoksikarbonil.When R ^{1 is} alkyl substituted with alkoxycarbonyl, it is preferably methyl substituted with alkoxycarbonyl such as methoxycarbonyl or t-butoxycarbonyl.

Prednosten razred spojin s formulo (I) je tisti, kjer R¹ predstavlja fenil, adamantil, norbornanil, fenetil, C₄₆alkil, npr. n-butil, 3-metilbutil, 3,3-dimetilbutil, 1,3dimetilbutil, 2,3-dimetilbutil, C₃^hidroksialkil, npr. 2-hidroksipropil, 2-hidroksi-3metilbutil, 2-hidroksi-3,3-dimetilbutil, C_{7 2}alkil, substituiran s premoščeno C_{? 1Q}cikloalkilno skupino, npr. kot je 2-norbornanilmetil, 5-norbornenilmetil,A preferred class of compounds of formula (I) is one where R ¹ represents phenyl, adamantyl, norbornanyl, phenethyl, C _1-4 alkyl, e.g. n-butyl, 3-methylbutyl, 3,3-dimethylbutyl, 1,3dimethylbutyl, 2,3-dimethylbutyl, C _3-4 hydroxyalkyl, e.g. 2-hydroxypropyl, 2-hydroxy-3methylbutyl, 2-hydroxy-3,3-dimethylbutyl, C _{7 2} alkyl substituted with bridged C _{? A 1Q} cycloalkyl group, e.g. such as 2-norbornanylmethyl, 5-norbornenylmethyl,

2-adamantilmetil, 2-adamantiletil, 2-(l-adamantil)etil, 1-adamantilmetil, alkoksikarbonilalkil, npr. metoksikarbonilmetil ali t-butoksikarbonilmetil, ali 2-ciklopentiletil.2-adamantylmethyl, 2-adamantylethyl, 2- (1-adamantyl) ethyl, 1-adamantylmethyl, alkoxycarbonylalkyl, e.g. methoxycarbonylmethyl or t-butoxycarbonylmethyl, or 2-cyclopentylethyl.

Posebno prednostni razred spojin s formulo (I) je tisti, kjer je R¹ 3-metilbutil, 3,3dimetilbutil, 2-hidroksi-3-metilbutil, 2-hidroksi-3,3-dimetilbutil, 2-ciklopentiletil,A particularly preferred class of compounds of formula (I) is that wherein R ^{1 is} 3-methylbutyl, 3,3 dimethylbutyl, 2-hydroxy-3-methylbutyl, 2-hydroxy-3,3-dimethylbutyl, 2-cyclopentylethyl,

5-norbornenilmetil ali 1-adamantilmetil.5-norbornenylmethyl or 1-adamantylmethyl.

Nadaljnji prednostni razred spojin s formulo (I) je tisti, kjer R² predstavlja fenil, v danem primeru substituiran z bromom, klorom, fluorom, metilom, metoksi, metiltio, trifluorometoksi, ciano, dimetilamino ali (CH2)nCO2R⁵, kjer je R⁵ vodik ali etil. Najbolj prednostno R² predstavlja fenil, v danem primeru substituiran z metoksi, dimetilamino, ciano, metiltio, CO2H ali CO₂C₂H₅.A further preferred class of compounds of formula (I) is one where R ² represents phenyl optionally substituted by bromine, chlorine, fluorine, methyl, methoxy, methylthio, trifluoromethoxy, cyano, dimethylamino or (CH 2) nCO ² R ⁵ , where R ⁵ is hydrogen or ethyl. Most preferably R ² represents phenyl optionally substituted by methoxy, dimethylamino, cyano, methylthio, CO2H or CO ₂ C ₂ H ₅ .

Nadaljnji prednostni razred spojin s formulo (I) je tisti, kjer R³ predstavlja fenil ali fenil, mono- ali di-substituiran s fluorom, prednostno v legi orto in/ali para. Prednostno R³ predstavlja nesubstituiran fenil ali ortofluorofenil.A further preferred class of compounds of formula (I) is one where R ³ represents phenyl or phenyl mono- or di-substituted with fluorine, preferably in the ortho and / or para position. Preferably R ³ represents unsubstituted phenyl or orthofluorophenyl.

Prednostne skupine spojin s formulo (I) so tiste, kjer R¹ predstavlja C^alkil, kotPreferred groups of compounds of formula (I) are those wherein R ¹ represents C 1-6 alkyl, such as

3-metilbutil, 3,3-dimetilbutil, 2-hidroksi-3-metilbutil, 2-hidroksi-3,3-dimetilbutil,3-methylbutyl, 3,3-dimethylbutyl, 2-hydroxy-3-methylbutyl, 2-hydroxy-3,3-dimethylbutyl,

2-ciklopentiletil, 5-norbomenilmetil ali 1-adamantilmetil; R² predstavlja fenil ali fenil, substituiran z metoksi, ciano, nitro, karboksilom, etoksikarbonilom, metiltio ali dimetilamino ter je prednostno substituent v meta legi 1;2-cyclopentylethyl, 5-norbomenylmethyl or 1-adamantylmethyl; R ² represents phenyl or phenyl substituted with methoxy, cyano, nitro, carboxyl, ethoxycarbonyl, methylthio or dimethylamino and is preferably a substituent in meta position 1;

R³ predstavlja fenil ali orto trifluorofenil; R⁸ predstavlja vodik, klor ali fluor; ter njihovi enantiomeri in soli.R ³ represents phenyl or ortho trifluorophenyl; R ⁸ represents hydrogen, chlorine or fluorine; and their enantiomers and salts.

Posebno prednostna skupina spojin s formulo (I) so tiste, kjer je R¹ 3-metilbutil; R² je fenil, v danem primeru substituiran v legi meta z metiltio ali dimetilamino skupino; R³ je fenil ali orto fluorofenil; R⁸ je vodik ali klor ali fluor in je m 0,1 ali 2.A particularly preferred group of compounds of formula (I) are those wherein R ^{1 is} 3-methylbutyl; R ² is phenyl optionally substituted in the meta position by a methylthio or dimethylamino group; R ³ is phenyl or ortho fluorophenyl; R ⁸ is hydrogen or chlorine or fluorine and m is 0,1 or 2.

Nadaljnja posebno prednostna skupina spojin s formulo (I) so tiste, kjer R¹ predstavlja l-adamantilmetil, R² je fenil, v danem primeru substituian v legi meta z metilno, metoksi, metiltio, nitro, dimetilamino, etoksikarbonilno ali karboksilno skupino; R³ je fenil in R⁸ je vodik. V tej skupini so posebno prednostne spojine tiste, kjer je R² fenil, v danem primeru substituiran z dimetilamino, etoksikarbonilno ali karboksilno skupino.A further particularly preferred group of compounds of formula (I) are those wherein R ¹ represents l-adamantylmethyl, R ² is phenyl optionally substituted in the methyl position with a methyl, methoxy, methylthio, nitro, dimethylamino, ethoxycarbonyl or carboxyl group; R ³ is phenyl and R ⁸ is hydrogen. Particularly preferred compounds in this group are those wherein R ^{2 is} phenyl optionally substituted by a dimethylamino, ethoxycarbonyl or carboxyl group.

Prednostne spojine v smislu izuma so;Preferred compounds of the invention are;

N-fenil-N’-[2,3,4,5-tetrahidro-2,4-diokso-l-(3-metilbutil)-5-fenil-lH-l,5benzodiazepin-3-il]sečnina;N-phenyl-N '- [2,3,4,5-tetrahydro-2,4-dioxo-1- (3-methylbutyl) -5-phenyl-1H-1,5-benzodiazepin-3-yl] urea;

N-[l-(3,3-dimetil-2-hidroksibut-l-il)-2,4-diokso-5-(2-fluorofenil)-3,4,5-tetrahidrolH-l,5-benzodiazepin-3-il]-N’-fenilsečnina;N- [1- (3,3-dimethyl-2-hydroxybut-1-yl) -2,4-dioxo-5- (2-fluorophenyl) -3,4,5-tetrahydrol-1,5,5-benzodiazepine-3 -yl] -N'-phenylurea;

N-fenil-N’-[2,3,4,5-tetrahidro-2,4-diokso-l-(3,3-dimetilbutil)-5-fenil-lH-l,5benzodiazepin-3-il]sečnina;N-phenyl-N '- [2,3,4,5-tetrahydro-2,4-dioxo-1- (3,3-dimethylbutyl) -5-phenyl-1H-1,5-benzodiazepin-3-yl] urea;

N-fenil-N’-[2,3,4,5-tetrahidro-2,4-diokso-l-(l-adamantilmetil)-5-fenil-lH-l,5benzodiazepin-3-il]sečnina;N-phenyl-N '- [2,3,4,5-tetrahydro-2,4-dioxo-1- (1-adamantylmethyl) -5-phenyl-1H-1,5-benzodiazepin-3-yl] urea;

N-[2,4-diokso-l-(2-hidroksi-3-metilbutil)-5-fenil-2,3,4,5-tetrahidro-lH-l,5benzodiazepin-3-il]N’-fenilsečnina;N- [2,4-dioxo-1- (2-hydroxy-3-methylbutyl) -5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl] N'-phenylurea;

N-(3-dimetilaminofenil)-N’-[2,3,4,5-tetrahidro-2,4-diokso-l-(3-metilbutil)-5(2-fluorofenil)-lH-l,5-benzodiazepin-3-il]sečnina;N- (3-dimethylaminophenyl) -N '- [2,3,4,5-tetrahydro-2,4-dioxo-1- (3-methylbutyl) -5 (2-fluorophenyl) -1H-1,5-benzodiazepine -3-yl] urea;

N-[l-(l-adamantilmetil)-2,4-diokso-5-fenil-2,3,4,5-tetrahidro-lH-l,5-benzodiazepin-3-il]-N’-(3-etoksikarbonilfenil)sečnina;N- [1- (1-adamantylmethyl) -2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl] -N '- (3- ethoxycarbonylphenyl) urea;

N-[l-(l-adamantilmetil)-2,4-diokso-5-fenil-2,3,4,5-tetrahidro-lH-l,5-benzodiazepin-3-il]-N’-[(3-(N,N-dimetilamino)fenil]sečnina;N- [1- (1-adamantylmethyl) -2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl] -N '- [(3 - (N, N-dimethylamino) phenyl] urea;

N-[l-(l-adamantilmetil)-2,4-diokso-5-fenil-2,3,4,5-tetrahidro-lH-l,5-benzodiazepin-3-il]-N’-(3-karboksifenil)sečnina;N- [1- (1-adamantylmethyl) -2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl] -N '- (3- carboxyphenyl) urea;

N-[l-(adamantan-l-metil)-2,4-diokso-7-fluoro-5-(4-fluorofenil)-2,3,4,5-tetrahidrolH-l,5-benzodiazepin-3-il]-N’-(3-dimetilamino)fenilsečnina ter njihovi (+) enantiomeri in soli.N- [1- (adamantan-1-methyl) -2,4-dioxo-7-fluoro-5- (4-fluorophenyl) -2,3,4,5-tetrahydrol-1,5-benzodiazepin-3-yl ] -N '- (3-dimethylamino) phenylurea and their (+) enantiomers and salts.

Posebno prednostne spojine v smislu izuma so: N-fenil-N’-[2,3,4,5tetrahidro-2,4-diokso-l-(l-adamantilmetil)-5-fenil-lH-l,5-benzodiazepin-3-il]sečnina;Particularly preferred compounds of the invention are: N-phenyl-N '- [2,3,4,5tetrahydro-2,4-dioxo-1- (1-adamantylmethyl) -5-phenyl-1H-1,5-benzodiazepine- 3-yl] urea;

N-[l-(l-adamantilmetil)2,4-diokso-5-fenil-2,3,4,5-tetrahidro-lH-l,5-benzodiazepin3-il]-N’-(3-karboksifenil)sečnina;N- [1- (1-adamantylmethyl) 2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl] -N '- (3-carboxyphenyl) urea ;

N-fenil-N’-[2,3,4,5-tetrahidro-2,4-diokso-l-(3-metilbutil)-5-fenil-lH-l,5benzodiazepin-3-il]sečnina;N-phenyl-N '- [2,3,4,5-tetrahydro-2,4-dioxo-1- (3-methylbutyl) -5-phenyl-1H-1,5-benzodiazepin-3-yl] urea;

N-(3-dimetilaminofenil)-N’-[2,3,4,5-tetrahidro-2,4-diokso-l-(3-metilbutil)-5-(2fIuorofeniI)-lH-l,5-benzodidazepin-3-il]sečnina ter njihovi (+) enantiomeri in soli.N- (3-dimethylaminophenyl) -N '- [2,3,4,5-tetrahydro-2,4-dioxo-1- (3-methylbutyl) -5- (2fluorophenyl) -1H-1,5-benzodidazepine- 3-yl] urea and their (+) enantiomers and salts.

Farmacevtsko sprejemljive soli spojin s formulo (I) so običajne soli, nastale npr. iz farmacevtsko sprejemljivih anorganskih ali organskih kislin, kot tudi kvarterne amonijeve kislinske adicijske soli. Primeri ustreznih soli so soh klorovodikove, bromovodikove, žveplove, fosforjeve, dušikove, perklorove, fumarjeve, ocetne, propionske, jantarne, glikolne, mravljinčne, mlečne, maleinske, vinske, citronske, pamojske, malonske, hidroksimaleinske, fenilocetne, glutaminske, benzojske, salicilne, fumarne, toluensulfonske, metansulfonske, naftalen-2-sulfonske, benzensulfonske kisline ipd. Druge kisline, kot oksalna kislina, ki same niso farmacevtsko sprejemljive, so lahko koristne pri pripravi soli, uporabnih kot intermediati pri pridobivanju spojin v smislu izuma in njihovih farmacevtsko sprejemljivih soli.Pharmaceutically acceptable salts of the compounds of formula (I) are conventional salts formed e.g. from pharmaceutically acceptable inorganic or organic acids, as well as quaternary ammonium acid addition salts. Examples of suitable salts are hydrochloric acid, hydrobromic, sulfuric, phosphoric, nitrogen, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, milky, maleic, wine, citric, cotton, malonic, hydroxymalein, phenylamino, benzylacetyl, benzyl , fumaric, toluenesulfonic, methanesulfonic, naphthalene-2-sulfonic, benzenesulfonic acids and the like. Other acids, such as oxalic acid, which are not themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in the preparation of the compounds of the invention and their pharmaceutically acceptable salts.

Spojine s formulo (I), kjer R⁵ predstavlja vodik, lahko tvorijo farmacevtsko sprejemljive soli s primernimi kationi. Primerni farmacevtsko sprejemljivi kationi so alkalijski (npr. natrijevi ali kalijevi) in zemeljsko alkalijski (npr. kalcijevi ali magnezijevi) kationi.Compounds of formula (I) wherein R ⁵ represents hydrogen may form pharmaceutically acceptable salts with suitable cations. Suitable pharmaceutically acceptable cations are alkali (eg sodium or potassium) and earth alkali (eg calcium or magnesium) cations.

V nadaljevanju zajemajo sklicevanja na spojino v smislu izuma tako spojine s formulo (I) kot tudi njihove farmacevtsko sprejemljive soli in solvate.The following will include references to a compound of the invention of both the compounds of formula (I) and their pharmaceutically acceptable salts and solvates.

Spojine v smislu izuma so močni in specifični antagonisti gastrina in/ali CCK. Pokazalo se je, da so spojine v smislu izuma antagonisti CCK, zlasti pri CCK-B receptorjih, kot je prikazano npr. s sposobnostjo spojine, da inhibira kontraktilne učinke CCK-4 v prisotnosti CCK-A antagonista pri vzdolžni mišici izoliranega ileuma morskega prašička - mienteričnem pleksusu.The compounds of the invention are potent and specific gastrin and / or CCK antagonists. The compounds of the invention have been shown to be CCK antagonists, especially at CCK-B receptors, as shown e.g. with the ability of the compound to inhibit the contractile effects of CCK-4 in the presence of a CCK-A antagonist in the longitudinal muscle of an isolated guinea pig ileum - the myenteric plexus.

Za spojine v smislu izuma se je tudi pokazalo, da so antagonisti gastrina, kot je prikazano z njihovo sposobnostjo za inhibiranje s pentagastrinom stimuliranega kislinskega izločanja iz izolirane želodčne sluznice podgane ob uporabi postopka, opisanega v J.J. Reves and R. Stables v Br. J. Pharmac., 1985, 86, str. 677-684.The compounds of the invention have also been shown to be gastrin antagonists, as shown by their ability to inhibit pentagastrin-stimulated acid secretion from the isolated gastric mucosa of the rat using the procedure described in J.J. Reves and R. Stables in Br. J. Pharmac., 1985, 86, p. 677-684.

Ugotovili smo tudi, da imajo spojine v smislu izuma znatno šibkejšo aktivnost pri CCK-A receptorjih v primerjavi z njihovo aktivnostjo pri gastrinu in/ali CCK-B receptorjih, kot pokažemo z njihovo sposobnostjo, da inhibirajo kontraktilno aktivnost CCK-8 pri izolirani vzdolžni mišici ileuma morskega prašička - mienteričnem pleksusu.We have also found that the compounds of the invention have significantly lower activity at CCK-A receptors compared to their activity at gastrin and / or CCK-B receptors, as demonstrated by their ability to inhibit CCK-8 contractile activity in isolated longitudinal muscle guinea pig ileum - myenteric plexus.

Pripravo in uporabo izolirane vzdolžne mišice ileuma morskega prašička mienteričnega pleksusa so opisali K-H Buchheit et al. v Nauyn-Schmeidebergovi Arch. Pharmacol, (1985), 329, s.36-41, in V.L. Lucaites et al (1991) v J. Pharmacol. Exp. Ther., 256, 695-703.The preparation and use of an isolated longitudinal guinea pig ileum muscle of the myenteric plexus was described by K-H Buchheit et al. in Nauyn-Schmeideberg Arch. Pharmacol, (1985), 329, s.36-41, and V.L. Lucaites et al (1991) in J. Pharmacol. Exp. Ther., 256, 695–703.

Večjo afiniteto spojin v smislu izuma za CCK-B receptor v primerjavi s CCK-A receptorjem smo tudi ugotovili ob uporabi CCK receptorskega vezivnega testa, ki je opisan v G Dal Fornos et al., J. Pharmacol. Exp & Ther. 261,1056-1063,1992.The higher affinity of the compounds of the invention for the CCK-B receptor compared to the CCK-A receptor was also found using the CCK receptor binding assay described in G Dal Fornos et al., J. Pharmacol. Exp & Ther. 261,1056-1063,1992.

Spojine v smislu izuma so zato koristne za zdravljenje in/ali preprečevanje motenj pri sesalcih, zlasti človeku, kjer je modifikacija učinkov gastrina ali CCK terapevtsko ugodna. Tako so spojine v smislu izuma koristne za zdravljenje motenj centralnega živčnega sistema, kjer sta vpletena CCK in/ali gastrin, kot so npr. motnje zaskrbljenosti (vključno panična motnja, agorafobija, socialna fobija, enostavna fobija, obsesivne kompulzivne motnje, postratravmatska stresna motnja in splošna zaskrbljenostna motnja), tardivna diskinezija, depresija, Parkinsonova bolezen ali psihoza. Spojine v smislu izuma so tudi koristne pri zdravljenju gastrointestinalnih motenj, zlasti tistih, kjer je koristno znižanje želodčne kislosti. Take motnje so peptična ulceracija, refluksni ezofagitis in Zolinger Elisonov sindrom. So lahko tudi koristne pri zdravljenju gastrointestinalnih motenj, kot sindroma razdražljivega črevesa, prekomernega pankreatskega izločanja, akutnega pankreatitisa, motilnostnih motenj, antralne G celične hiperplazije, fundusne mukozne hiperplazije ali gastointestinalnih neoplazem. So lahko tudi koristne za zdravljenje odvisnosti od zdravil ali drugih snovi, ki povzročajo odvisnost, Gilles de la Tourette-jevega sindroma ali disfunkcije regulacijskih sistemov za apetit; kot tudi za zdravljenje določenih tumorjev nižjega ezofagusa, želodca, tankega črevesa in debelega črevesa. Spojine v smislu izuma so tudi koristne za direktno induciranje analgezije ali za povečanje z opiati ali ne-opiati posredovane analgezije kot tudi anestezije ali izgube občutka za bolečino.The compounds of the invention are therefore useful for treating and / or preventing disorders in mammals, especially in humans, where modification of the effects of gastrin or CCK is therapeutically advantageous. Thus, the compounds of the invention are useful for treating disorders of the central nervous system where CCK and / or gastrin, such as e.g. anxiety disorders (including panic disorder, agoraphobia, social phobia, simple phobia, obsessive compulsive disorders, post-traumatic stress disorder and general anxiety disorder), tardive dyskinesia, depression, Parkinson's disease or psychosis. The compounds of the invention are also useful in the treatment of gastrointestinal disorders, especially those where a reduction in gastric acidity is advantageous. Such disorders are peptic ulceration, reflux esophagitis and Zolinger Ellison syndrome. They may also be useful in the treatment of gastrointestinal disorders, such as irritable bowel syndrome, excessive pancreatic secretion, acute pancreatitis, motility disorders, antral G cell hyperplasia, fundus mucosal hyperplasia, or gastointestinal neoplasms. They may also be useful for the treatment of addiction to drugs or other addictive substances, Gilles de la Tourette's syndrome or dysfunction of appetite regulatory systems; as well as for the treatment of certain tumors of the lower esophagus, stomach, small intestine and colon. The compounds of the invention are also useful for directly inducing analgesia or for increasing opiate or non-opiate mediated analgesia as well as anesthesia or loss of pain.

Za spojine v smislu izuma smo tudi ugotovili, da imajo anksiolitično aktivnost v običajnih farmakoloških testih, npr. pri miših v testu črno-bele škatle in v podganjem socialnem interakcijskem modelu.The compounds of the invention have also been found to have anxiolytic activity in conventional pharmacological tests, e.g. in mice in a black-and-white box test and in a rat social interaction model.

Pri izumu gre zato za spojino s formulo (I) ali njeno farmacevtsko sprejemljivo sol ali solvat za uporabo v terapiji, zlasti v humani medicini.The invention therefore provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy, in particular in human medicine.

V skladu z drugim vidikom gre pri izumu za uporabo spojine s formulo (I) ali njene farmacevtsko sprejemljive soli ali solvata za izdelavo zdravila za zdravljenje stanj, kjer je terapevtsko ugodna modifikacija učinkov gastrina in/ali CCK.According to another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of conditions wherein the modification of the effects of gastrin and / or CCK is therapeutically advantageous.

V skladu z nadaljnjim vidikom izuma gre za postopek za zdravljenje sesalca, vključno človeka, zlasti pri zdravljenju stanj, kjer je terapevtsko koristna modifikacija učinkov gastrina in/ali CCK, postopek pa obsega dajanje učinkovite količine spojine s formulo (I) ali njene farmacevtsko sprejemljive soli ali solvata pacientu.According to a further aspect of the invention, there is provided a method of treating a mammal, including a human, especially in the treatment of conditions where modification of the effects of gastrin and / or CCK is therapeutically useful, comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof but solvates the patient.

Strokovnjaki bodo upoštevali, da se sklicevanje tukaj na zdravljenje razteza tako na profilakso kot tudi na zdravljenje znanih bolezni ali simptomov.It will be appreciated by those skilled in the art that the reference herein to treatment extends to both prophylaxis and treatment of known diseases or symptoms.

Nadalje je treba upoštevati, da bo količina spojine v smislu izuma, potrebna za uporabo pri zdravljenju, variirala od narave stanja, ki ga zdravimo, ter starosti in stanja pacienta in bo končno v diskreciji lečečega zdravnika ali veterinarja. Na splošno pa bodo doze, uporabljene za zdravljenje odraslega človeka, tipično v območju od 0,01 do 2000 mg dnevno, npr. 0,01 do 500 mg na dan.It should further be appreciated that the amount of the compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and condition of the patient and will ultimately be at the discretion of the treating physician or veterinarian. In general, however, the dosages used to treat an adult will typically be in the range of 0.01 to 2000 mg per day, e.g. 0.01 to 500 mg per day.

Želeno dozo lahko s pridom dajemo kot eno samo dozo ali kot porazdeljene doze, dajane v primernih presledkih, npr. kot 2,3,4 ali več pod-doz dnevno.The desired dose can conveniently be given as a single dose or as divided doses administered at appropriate intervals, e.g. as 2,3,4 or more sub-doses daily.

Ker spojine v smislu izuma antagonizirajo funkcijo CCK pri živalih, jih lahko tudi uporabimo kot dodatke hrani, da povečajo navzem hrane pri živalih pri dnevnih dozah okoli 1 mg/kg do 10 mg/kg.Because the compounds of the invention antagonize CCK function in animals, they can also be used as food additives to increase animal food intake at daily doses of about 1 mg / kg to 10 mg / kg.

Za uporabo v terapiji je možno, da spojino v smislu izuma lahko dajemo kot surovo kemikalijo, vendar je prednostno, da predložimo aktivno sestavino kot farmacevtski pripravek.For use in therapy, it is possible that the compound of the invention may be administered as a crude chemical, but it is preferable to present the active ingredient as a pharmaceutical preparation.

Pri izumu gre tako nadalje za farmacevatski pripravek, ki obsega spojino s formulo (I) ali njeno farmacevtsko sprejemljivo sol skupaj z enim ali več farmacevtsko sprejemljivi nosilci zanjo ter v danem primeru druge terapevtske in/ali profilaktiČne sestavine. Nosilec (nosilci) mora biti sprejemljiv v tem smislu, da je kompatibilen z drugimi sestavinami pripravka in ne škoduje jemalcu.The invention further provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers therefor, and optionally other therapeutic and / or prophylactic ingredients. The carrier (s) must be acceptable in that it is compatible with the other constituents of the preparation and does not cause harm to the recipient.

Sestavki v smislu izuma obsegajo tiste v obliki, posebno formulirani za oralno, bukalno, parenteralno, vsaditveno ali rektalno dajanje. Prednostno je oralno dajanje.The compositions of the invention include those in a formulation specifically formulated for oral, buccal, parenteral, implantation or rectal administration. Oral administration is preferred.

Tablete in kapsule za oralno dajanje lahko vsebujejo običajne nosilce, kot veziva, npr. sirup, akacijo, želatino, sorbitol, tragakant, hidroksipropilcelulozo, sluz škroba ali polivinilpirolidon; polnila, npr. laktozo, sladkor, mikrokristalno celulozo, koruzni škrob, kalcijev fosfat ali sorbitol; maziva, npr. hidrogenirana rastlinska olja, magnezijev stearat, stearinsko kislino, smukec, polietilenglikol ali silicijev dioksid; razpadna sredstva, npr. krompiijev škrob ali natrijev škrobni glikolat, ali omočilna sredstva, kot natrijev lavrilsulfat. Tablete lahko preslojimo po znanih postopkih. Oralni tekoči pripravki so lahko v obliki npr. vodnih ali oljnatih suspenzij, raztopin, emulzij, sirupov ali eliksirjev ali so lahko predloženi kot suh produkt za konstituiranje z vodo ali drugim primernim vehiklom pred uporabo. Taki tekoči pripravki lahko vsebujejo običajne aditive, kot suspendirna sredstva, npr. sorbitol sirup, metilcelulozo, sirup glukoze/sladkorja, želatino, hidroksietilcelulozo, karboksimetilcelulozo, aluminijev stearatni gel ali hidrogenirane užitne maščobe; emulgirna sredstva, npr. lecitin, sorbitan monooleat ali akacijo; nevodne vehikle (ki lahko zajemajo užitna olja), npr. mandljevo olje, frakcionirano kokosovo olje, oljnate estre, propilenglikol ali etilalkohol; in konzervirna sredstva, npr. metil- ali propil-p10 hidroksi-benzoate ali sorbinsko kislino. Sestavke lahko tudi formuliramo kot supozitorije, npr. ki vsebujejo običajne supozitorijske baze, kot kakavovo maslo ali druge gliceride.Tablets and capsules for oral administration may contain conventional carriers such as binders, e.g. syrup, acacia, gelatin, sorbitol, tragacanth, hydroxypropylcellulose, starch mucilage or polyvinylpyrrolidone; fillers, e.g. lactose, sugar, microcrystalline cellulose, corn starch, calcium phosphate or sorbitol; lubricants, e.g. hydrogenated vegetable oils, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrating agents, e.g. potato starch or sodium starch glycolate, or wetting agents such as sodium lauryl sulfate. The tablets may be coated according to known methods. Oral liquid preparations may take the form of e.g. aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable solvent before use. Such liquid preparations may contain conventional additives such as suspending agents, e.g. sorbitol syrup, methylcellulose, glucose / sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents, e.g. lecithin, sorbitan monooleate or acacia; non-aqueous solvents (which may contain edible oils), e.g. almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives, e.g. methyl or propyl-p10 hydroxy-benzoates or sorbic acid. The compositions can also be formulated as suppositories, e.g. containing conventional suppository bases, such as cocoa butter or other glycerides.

Za bukalno dajanje lahko sestavek zavzame obliko tablet ali pastil, formuliranih na običajen način.For buccal administration, the composition may take the form of tablets or lozenges formulated in a conventional manner.

Sestavek v smislu izuma lahko formuliramo za parenteralno dajanje z injekcijo ali kontinuirno infuzijo. Pripravki za injekcije so lahko predloženi v enotski dozirni obliki v predhodno napolnjenih brizgah, fiolah in ampulah ali pa v posodah z več dozami z dodanim konzervimim sredstvom. Sestavki lahko zavzamejo take oblike, kot so suspenzije, raztopine ali emulzije v oljnatih ali vodnih vehiklih, in lahko vsebujejo formulirna sredstva, kot suspendirna, stabilizirna in/ali dispergirna sredstva. Po drugi strani je lahko aktivna sestavina v praškasti obliki, ki jo lahko dobimo z liofiliziranjem za konstituiranje s primernim vehiklom, npr. sterilno vodo brez pirogenov, pred uporabo.The composition of the invention can be formulated for parenteral administration by injection or continuous infusion. Injectable preparations may be presented in unit dosage form in pre-filled syringes, vials and ampoules or in multi-dose containers with the addition of a preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous solvents and may contain formulating agents such as suspending, stabilizing and / or dispersing agents. On the other hand, the active ingredient may be in powder form, which can be obtained by lyophilization for constitution with a suitable solvent, e.g. sterile pyrogen-free water before use.

Sestavke v smislu izuma lahko tudi formuliramo kot depojski pripravek. Take pripravke z dolgim delovanjem lahko dajemo z vsaditvijo (npr. subkutano ali intramuskulamo) ali z intramuskulamo injekcijo. Tako npr. spojine v smislu izuma formuliramo s polimernimi ali hidrofobnimi materiali (npr. kot emulzijo v sprejemljivem olju) ali ionskimi izmenjevalnimi smolami ali pa kot komajda topne derivate, npr. kot komajda topno sol.The compositions of the invention can also be formulated as a depot preparation. Such long acting preparations may be administered by implantation (eg subcutaneously or intramuscularly) or by intramuscular injection. So e.g. the compounds of the invention are formulated with polymeric or hydrophobic materials (e.g., as an emulsion in acceptable oil) or ion exchange resins, or as hardly soluble derivatives, e.g. as hardly soluble salt.

Sestavki v smislu izuma lahko vsebujejo med 0,1 do 99 % aktivne sestavine, ugodno od 30 do 95 % za tablete in kapsule ter 3 do 50 % za tekoče pripravke.The compositions of the invention may contain from 0.1 to 99% of the active ingredient, preferably from 30 to 95% for tablets and capsules and from 3 to 50% for liquid preparations.

Spojine s splošno formulo (I) in njihove soli lahko pripravimo po splošnih metodah, navedenih spodaj. V sledečem opisu so skupine R^R⁸, kot je definirano za spojine s formulo (I), če ni navedeno drugače.Compounds of general formula (I) and their salts can be prepared by the general methods given below. In the following description, the groups R 1 and R ⁸ are as defined for the compounds of formula (I), unless otherwise indicated.

Po prvem splošnem postopku (A) lahko spojine s formulo (I) pripravimo z reakcijo spojine s formulo (II), kjer X predstavlja skupino -N=C=O ali NHCOR⁹, kjer je R⁹ v danem primeru substituirana fenoksi skupina ali 1-imidazolna skupinaAccording to the first general procedure (A), compounds of formula (I) can be prepared by reaction of a compound of formula (II), wherein X represents a group -N = C = O or NHCOR ⁹ , where R ⁹ is optionally substituted phenoxy group or 1 -imidazole group

z aminom s formulo (III)with an amine of formula (III)

H₂NR² (III) v danem primeru v prisotnosti baze, kot terciarnega amina (npr. trietilamina). Reakcija s pridom poteka v primernem topilu, kot halogeniranem ogljikovodiku (npr. diklorometanu) ali etru (npr. tetrahidrofuranu) ali amidu, npr. Ν,Ν-dimetilformamidu, v danem primeru pri temperaturi v območju od sobne temperature do temperature refluksa topila.H ₂ NR ² (III) optionally in the presence of a base such as a tertiary amine (e.g. triethylamine). The reaction is advantageously carried out in a suitable solvent, such as a halogenated hydrocarbon (e.g. dichloromethane) or ether (e.g. tetrahydrofuran) or an amide, e.g. N, N-dimethylformamide, optionally at a temperature in the range from room temperature to the reflux temperature of the solvent.

Pri posebnem vidiku postopka (A), kjer je X skupina NHCOR⁹ in je R⁹1-imidazolna skupina, lahko imidazolid (II) tvorimo in situ, v tem primeru pa bomo amin s formulo (III) pomešali s spojino s formulo (IV)In a particular aspect of process (A), where X is NHCOR group ⁹ and R ^{9 is a} 1-imidazole group, imidazolid (II) may be formed in situ, in which case the amine of formula (III) will be mixed with a compound of formula (IV )

v prisotnosti karbonildiimidazola ob prej omenjenih pogojih. Za postopek (A), kjer je X skupina NHCOR⁹ in je R⁹ v danem primeru substituirana fenoksi skupina, izvedemo reakcijo s primarnim aminom (III) prednostno v prisotnosti baze, kot terciarnega amina, npr. trietilamina.in the presence of carbonyldiimidazole under the aforementioned conditions. For process (A), where X is NHCOR group ⁹ and R ⁹ is optionally substituted phenoxy group, the reaction with the primary amine (III) is carried out preferably in the presence of a base, such as a tertiary amine, e.g. of triethylamine.

Za postopek A, kjer je X izocianatna skupina -N=C=O, izvedemo reakcijo s primarnim aminom (III), prednostno v aprotičnem topilu, kot haloogljikovodiku, npr.For process A, where X is an isocyanate group -N = C = O, a reaction with a primary amine (III) is carried out, preferably in an aprotic solvent, such as a halocarbon, e.g.

metilenkloridu. S pridom tvorimo izocianat in situ pred dodatkom primarnega amina (III).methylene chloride. It is advantageous to form isocyanate in situ before the addition of primary amine (III).

Spojine s formulo (II), kjer je R⁹ v danem primeru substituirana fenoksi skupina, lahko pripravimo iz primarnega amina (TV) z reakcijo z ustreznim, v danem primeru substituiranim fenilkloroformatom v prisotnosti baze, kot piridina. Reakcijo lahko izvedemo v topilu, kot haloogljikovodiku, npr. diklorometanu, in pri temperaturi od 0 do 50°C.Compounds of formula (II), wherein R ⁹ is optionally substituted phenoxy, can be prepared from the primary amine (TV) by reaction with the corresponding, optionally substituted phenylchloroformate in the presence of a base such as pyridine. The reaction may be carried out in a solvent such as a halocarbon, e.g. dichloromethane, and at a temperature of 0 to 50 ° C.

Spojine s formulo (II), kjer je R⁹ 1-imidazolna skupina, lahko pripravimo z reakcijo spojine s formulo (IV) s karbonildiimidazolom v prisotnosti primernega topila, kot halogeniranega ogljikovodika (npr. diklorometana) ali etra (npr. tetrahidrofurana), pri temperaturi v območju od 0° do 80°C (ugodno pri sobni temperaturi).Compounds of formula (II) wherein R ^{9 is a} 1-imidazole group can be prepared by reacting a compound of formula (IV) with carbonyldiimidazole in the presence of a suitable solvent, such as a halogenated hydrocarbon (e.g. dichloromethane) or ether (e.g. tetrahydrofuran), at temperature in the range of 0 ° to 80 ° C (favorable at room temperature).

Spojine s formulo (II), kjer je X izocianatna grupacija -N=C=O, lahko pripravimo iz primarnega amina (IV) z reakcijo s fosgenom (COC1₂) v primernem topilu, kot metilenkloridu.Compounds of formula (II) wherein X is an isocyanate group of -N = C = O can be prepared from the primary amine (IV) by reaction with phosgene (COC1 ₂ ) in a suitable solvent such as methylene chloride.

Po nadaljnjem splošnem postopku (B) lahko pripravimo spojine s formulo (I) z reakcijo spojine s formulo (IV) z izocianatom s formulo (V)According to a further general procedure (B), compounds of formula (I) can be prepared by reacting a compound of formula (IV) with an isocyanate of formula (V)

O=C=N=R² (V) ali karbamoilkloridom s formulo (VI)O = C = N = R ² (V) or carbamoyl chloride of formula (VI)

C1C(O)NHR² (VI).C1C (O) NHR ² (VI).

Reakcija s pridom poteka v prisotnosti primernega topila, kot haloogljikovodika (npr. diklorometana), etra (npr. tetrahidrofuma) ali nitrila (npr. acetonitrila) ali njihove zmesi pri temperaturi v območju od 0°C do 80°C.The reaction is advantageously carried out in the presence of a suitable solvent such as a halocarbon (eg dichloromethane), ether (eg tetrahydrofum) or nitrile (eg acetonitrile) or mixtures thereof at a temperature in the range of 0 ° C to 80 ° C.

Spojine s formulo (IV) lahko pripravimo z redukcijo spojin s formulo (VII)Compounds of formula (IV) can be prepared by reducing compounds of formula (VII)

(VII) kjer je W CH-N₃ ali C=N-NHPh.(VII) where W is CH-N ₃ or C = N-NHPh.

Spojine s formulo (VII), kjer je W CH-N₃, lahko reduciramo v spojino s formulo (IV) s hidrogeniranjem v prisotnosti primernega katalizatorja, kot paladija, na nosilcu, kot oglju ali kalcijevem karbonatu, ali platinovega (IV) oksida. Reakcija s pridom poteka v prisotnosti topila, kot alkanola (npr. etanola), estra (npr. etilacetata) ali ocetne kisline.Compounds of formula (VII) wherein W is CH-N ₃ can be reduced to a compound of formula (IV) by hydrogenation in the presence of a suitable catalyst, such as palladium, on a carrier such as carbon or calcium carbonate, or platinum (IV) oxide. The reaction is advantageously carried out in the presence of a solvent such as alkanol (eg ethanol), ester (eg ethyl acetate) or acetic acid.

Spojine s formulo (VII), kjer je W C=N-NHPh, lahko reduciramo v spojino s formulo (IV) z reakcijo s cinkom in ocetno kislino. To reakcijo lahko izvedemo pri temperaturi v območju od 0 do 50°C.Compounds of formula (VII) wherein W is C = N-NHPh can be reduced to a compound of formula (IV) by reaction with zinc and acetic acid. This reaction can be carried out at a temperature in the range of 0 to 50 ° C.

Spojine s formulo (VII), kjer je W CHN₃, lahko pripravimo iz spojine s formulo (VII), kjer je W CH₂, z obdelavo z močno bazo, kot natrijevim hidridom ali kalijevim terc.butoksidom, nato pa s triizopropilbenzensulfonilazidom. Reakcija s pridom poteka v topilu, kot etru (npr. tetrahidrofuranu), pri temperaturi v območju od -78° do 20°C.Compounds of formula (VII) wherein W is CHN ₃ can be prepared from a compound of formula (VII) wherein W is CH ₂ by treatment with a strong base such as sodium hydride or potassium tert.butoxide and then with triisopropylbenzenesulfonyl azide. The reaction is advantageously carried out in a solvent such as ether (eg tetrahydrofuran) at a temperature in the range of -78 ° to 20 ° C.

Spojine s formulo (VII), v kateri je W C=NNHPh, lahko pripravimo z reakcijo ortofenilendiamina (VIII) z dikislinskim kloridom (IX) v primernem topilu, kot etru, npr. tetrahidrofuranuCompounds of formula (VII) wherein W is C = NNHPh can be prepared by reaction of orthophenylenediamine (VIII) with diacid chloride (IX) in a suitable solvent, such as ether, e.g. tetrahydrofuran

RR

aocaoc

Spojina s formulo (VII) kjer je W CH^ pripravimo z reakcijo ustrezne spojine (X)A compound of formula (VII) wherein W is CH2 is prepared by the reaction of the corresponding compound (X)

(X) s spojino IVV, kjer je Y halogen (npr. atom klora ali broma) ali mezilatna skupina, ob močno bazičnih pogojih. Tako lahko reakcijo s pridom izvedemo s predhodno obdelavo spojine s formulo (X) z močno bazo, kot natrijevim hidridom, v primernem aprotičnem topilu, kot amidu (npr. Ν,Ν-dimetilformamidu) pri temperaturi v območju od 0°C do refluksa. V zgoraj opisani reakcijski shemi, kadar skupina R¹ vsebuje hidroksilno skupino, je lahko ta prisotna v zaščiteni obliki, npr. kot eter, kot arilmetileter, npr. benzileter.(X) with compound IVV wherein Y is halogen (e.g., chlorine or bromine atom) or mesylate group under strongly basic conditions. Thus, the reaction can advantageously be carried out by pre-treating the compound of formula (X) with a strong base, such as sodium hydride, in a suitable aprotic solvent such as an amide (e.g., Ν, et-dimethylformamide) at a temperature in the range of 0 ° C to reflux. In the reaction scheme described above, when the R ¹ group contains a hydroxyl group, it may be present in a protected form, e.g. as ether, as arylmethylether, e.g. benzyl ether.

Spojine s formulo (VIII) so bodisi znane spojine ali jih lahko pripravimo z analognimi metodami. Tako lahko npr. spojino s formulo (VIII) pripravimo z alkiliranjem amina (xi)The compounds of formula (VIII) are either known compounds or can be prepared by analogous methods. Thus, e.g. a compound of formula (VIII) is prepared by alkylation of an amine (xi)

(xi)(xi)

Tako lahko amin (XI) lahko presnovimo s spojino R¹Y, kjer je Y klor ali brom, v danem primeru v prisotnosti natrijevega jodida v topilu, kot Ν,Ν-dimetilformamidu.Thus, the amine (XI) can be reacted with the compound R ¹ Y, where Y is chlorine or bromine, optionally in the presence of sodium iodide in a solvent, such as Ν, dim-dimethylformamide.

Spojine s formulo (VIII), kjer R¹ predstavlja skupino -CH2-CH(OH)R¹a, kjer je R^xa C₁₄alkilna skupina, lahko pripravimo z reakcijo spojine (XI) z epoksidom (XII) v topilu, kot alkanolu, npr. etanolu, in v prisotnosti kislinskega katalizatorja, kot p-toluensulfonske kislineCompounds of formula (VIII) wherein R ¹ represents the group -CH 2 -CH (OH) R ¹ a, where R ^{x is} a C ₁₄ alkyl group, can be prepared by reaction of compound (XI) with epoxide (XII) in a solvent such as alkanol, e.g. ethanol, and in the presence of an acid catalyst such as p-toluenesulfonic acid

CHj_CH__R‘_a (XII)CHj_CH_ _R ' _a (XII)

Spojine s formulo (VIII), kjer je R¹ v danem primeru substituirana alkilna skupina, lahko tudi pripravimo iz spojine (XI) z reakcijo s primernim aldehidom ali ketonom z istočasno ali sledečo redukcijo reakcijskega produkta. Tako lahko npr. spojino s formulo (VIII), kjer je R¹ 1,3-dimetilbutil, pripravimo iz spojine (XII) z reakcijo z metilizobutilketonom, nato pa z reakcijo z natrijevim borohidridom.Compounds of formula (VIII) wherein R ¹ is optionally substituted alkyl may also be prepared from compound (XI) by reaction with a suitable aldehyde or ketone with simultaneous or subsequent reduction of the reaction product. Thus, e.g. a compound of formula (VIII) wherein R ^{1 is} 1,3-dimethylbutyl is prepared from compound (XII) by reaction with methylisobutyl ketone followed by reaction with sodium borohydride.

Na splošno so spojine s formulo (III), (V) in (VI) bodisi znane spojine ali jih lahko pripravimo po postopkih, uporabljenih za pripravo znanih spojin.In general, the compounds of formula (III), (V) and (VI) are either known compounds or can be prepared by the procedures used to prepare known compounds.

Po nadaljnjem postopku (C) lahko spojino s formulo (I) pretvorimo v drugo spojino s formulo (I) ob uporabi običajnih tehnik.According to a further process (C), a compound of formula (I) can be converted to another compound of formula (I) using conventional techniques.

Tako lahko spojine s formulo (I), kjer je R² fenilna skupina, substituirana s karboksilno skupino, pripravimo s hidrolizo ustrezne spojine s formulo (I), kjer je R² fenilna skupina, substituirana z alkoksikarbonilno skupino.Thus, compounds of formula (I) wherein R ^{2 is a} phenyl group substituted by a carboxyl group can be prepared by hydrolysis of the corresponding compound of formula (I) wherein R ^{2 is a} phenyl group substituted by an alkoxycarbonyl group.

Pri zgoraj opisanih postopkih sta lahko skupini R¹ in R² v intermediatih II, III, V in VI skupina, kot je definirano v formuli (I), ali skupina, ki je vanjo prevedljiva.In the methods described above, the groups R ¹ and R ² in the intermediates II, III, V and VI may be a group as defined in formula (I) or a group which is translatable thereto.

Gornja vrsta reakcij zajema številne alternativne poti, ki se lahko začnejo z 1,5benzodiazepinom s formulo (X), kot je definirano zgoraj. Tako lahko po nadaljnjem splošnem postopku (D) pripravimo spojino s formulo (I) z reakcijo spojine s formulo (X) v eni ali več stopnjah z reagenti, ki služijo zato, da uvedemo skupine R¹ in NHCONHR².The above type of reaction encompasses a number of alternative routes that can be initiated with 1,5benzodiazepine of formula (X) as defined above. Thus, according to a further general procedure (D), a compound of formula (I) can be prepared by reacting a compound of formula (X) in one or more steps with reagents that serve to introduce the R ¹ and NHCONHR ² groups.

Spojine s formulo (I) vsebujejo vsaj en asimetričen atom ogljika, namreč atom ogljika diazepinskega obroča, na katerega je vezana substituirana sečninska grupacija. Specifične enantiomere spojin s formulo (I) lahko dobimo z ločenjem racemne spojine ob uporabi običajnih postopkov, kot je kiralna HPLC. Alternativno lahko zahtevan enatiomer pripravimo z ustreznim enantiomernim aminom s formulo (IV) ob uporabi kateregakoli od postopkov, opisanih zgoraj za pripravo spojin s formulo (I) iz amina (IV). Enantiomere amina (IV) lahko pripravimo iz racemnega amina (IV) ob uporabi običajni postopkov, kot je tvorba soli s primerno optično aktivno kislino, kot je R- kafrasulfonska kislina.The compounds of formula (I) comprise at least one asymmetric carbon atom, namely the carbon atom of the diazepine ring to which the substituted urea group is attached. Specific enantiomers of compounds of formula (I) can be obtained by separating the racemic compound using conventional methods such as chiral HPLC. Alternatively, the required enantiomer may be prepared with the corresponding enantiomeric amine of formula (IV) using any of the methods described above for the preparation of compounds of formula (I) from amine (IV). The enantiomers of amine (IV) can be prepared from racemic amine (IV) using conventional methods such as the formation of salts with a suitable optically active acid such as R-camphrasulfonic acid.

Naslednji primeri, ki so neomejevalni, ilustrirajo izum.The following non-limiting examples illustrate the invention.

V pripravkih in primerih, če ni drugače navedeno, smo določili tališča na Buchi tal. aparatu in niso korigirana. Vse temperature se nanašajo na °C. IR spektre smo merili v kloroformskih-dj raztopinah na FT-IR instrumentu. Protonske in magnetne resonančne (1H-NMR) spektre smo registrirali pri 300 MHz kot raztopine v kloroformu-d . Kemični premiki so navedeni v ppm navzdol (d) od Me4Si kot notranji standard in so označeni kot singleti (s), dubleti (d), dubleti dubletov (dd) ali multipleti (m). Kolonsko kromatografijo smo izvedli preko silikagela (Merck AG Darmstadt, Nemčija). Raztopine smo sušili preko brezvodnega natrijevega sulfata. Petrol se nanaša na petroleter, vrel. 40-60°C. Diklorometan smo predestilirali preko kalicijevega hidrida; tetrahidrofuran smo predestilirani nad natrijem; etileter smo predestilirali nad natrijem in etilacetat posušili nad aktiviranimi molekulskimi siti. V tekstu so uporabljene naslednje okrajšave. EA = etilacetat, CH = cikloheksan, P = petroleter 40-60°C, THF = tetrahidrofuran, DCM = diklorometan, EE = etileter, DMF = Ν,Ν-dimetilformamid. Tlc se nanaša na tenkoslojno kromatografijo na ploščah iz silicijevega dioksida. Za vse spojine je mišljeno, da so racemne zmesi, če ni drugače navedeno.In preparations and cases, unless otherwise stated, we determined the melting points at Buchi tal. and not corrected. All temperatures refer to ° C. IR spectra were measured in chloroform-dj solutions on a FT-IR instrument. The proton and magnetic resonance (1H-NMR) spectra were recorded at 300 MHz as solutions in chloroform-d. Chemical shifts are listed in ppm down (d) from Me4Si as an internal standard and are referred to as singlets (s), doublets (d), doublets doublets (dd) or multiplets (m). Column chromatography was performed over silica gel (Merck AG Darmstadt, Germany). The solutions were dried over anhydrous sodium sulfate. Petrol refers to light petroleum, boiling point. 40-60 ° C. Dichloromethane was pre-distilled over calcium hydride; tetrahydrofuran was pre-distilled over sodium; ethyl ether was pre-distilled over sodium and ethyl acetate dried over activated molecular sieves. The following abbreviations are used throughout the text. EA = ethyl acetate, CH = cyclohexane, P = petroleum ether 40-60 ° C, THF = tetrahydrofuran, DCM = dichloromethane, EE = ethyl ether, DMF = Ν, dim-dimethylformamide. Tlc refers to thin layer chromatography on silica plates. All compounds are intended to be racemic mixtures unless otherwise indicated.

Intermediat 1Intermediate 1

2- fluoro-2’-(3-metilbut-l-il)amino-difenilamin l-bromo-3-metilbutan (4,33 ml) dodamo k raztopini 2-amino-2’-fluorodifenilamina (7,0 g) in natrijevega jodida (5,24 g) v dimetilformamidu (250 ml) v atmosferi dušika. Raztopino mešamo pri 120° 8 ur, nato ohladimo na sobno temperaturo, razredčimo z vodo (300 ml) in ekstrahiramo z dietiletrom (2 x 250 ml). Združene organske ekstrakte izperemo s slanico (300 ml), posušimo in koncentriramo v vakuumu v olje, ki ga čistimo s flash kromatografijo (ob eluiranju s CH-EA 95:5), da dobimo naslovno spojino kot rumeno olje (6,3 g) T.l.c. CH-EA (9:1), Rf 0,75.2-Fluoro-2 '- (3-methylbut-1-yl) amino-diphenylamine 1-bromo-3-methylbutane (4.33 ml) was added to a solution of 2-amino-2'-fluorodiphenylamine (7.0 g) and of sodium iodide (5.24 g) in dimethylformamide (250 ml) under a nitrogen atmosphere. The solution was stirred at 120 ° for 8 hours, then cooled to room temperature, diluted with water (300 ml) and extracted with diethyl ether (2 x 250 ml). The combined organic extracts were washed with brine (300 ml), dried and concentrated in vacuo to an oil which was purified by flash chromatography (eluting with CH-EA 95: 5) to give the title compound as a yellow oil (6.3 g) Tlc CH-EA (9: 1), Rf 0.75.

Intermediat 2Intermediate 2

2,4-diokso-5-(2-fluorofenil)-l-(3-metilbut-l-il)-3-fenilhidrazono-2,3A5-tetrahidrolH-l,5-benzodiazepin2,4-dioxo-5- (2-fluorophenyl) -1- (3-methylbut-1-yl) -3-phenylhydrazono-2,3A5-tetrahydroH-1,5-benzodiazepine

Vsakega od intermediata 1 (6,3 g) in 2-fenilhidrazonomalonildiklorida (6,8 g) prevzamemo v THF (150 ml) in nakapljamo v bučo, ki vsebuje THF (200 ml), vzdrževano pri -5° pri atmosferi dušika. Po končanem dodajanju raztopino pustimo segreti na sobno temperaturo in nato segrevamo 2 uri na 50°C. Raztopino koncentriramo v vakuumu do olja, ki ga čistimo s flash kromatografijo (ob eluiranju s CH-EA 8:2), da dobimo naslovno spojino kot rumeno trdno snov (5,8 g). Tal. 104-105° T.l.c. CH-EA (7:3), Rf 0,59.Each of intermediate 1 (6.3 g) and 2-phenylhydrazonomalonyl dichloride (6.8 g) was taken up in THF (150 ml) and added to a flask containing THF (200 ml) maintained at -5 ° C under a nitrogen atmosphere. After complete addition, the solution was allowed to warm to room temperature and then heated to 50 ° C for 2 hours. The solution was concentrated in vacuo to an oil which was purified by flash chromatography (eluting with CH-EA 8: 2) to give the title compound as a yellow solid (5.8 g). Tal. 104-105 ° T.l.c. CH-EA (7: 3), Rf 0.59.

Intermediat 3Intermediate 3

3- amino-2,4-diokso-5-(2-fluorofenil)-l-(3-metiIbut-l-il)-2,3.4,5-tetrahidrolH-l,5-benzodiazepin3-amino-2,4-dioxo-5- (2-fluorophenyl) -1- (3-methylbut-1-yl) -2,3,4,5-tetrahydrol-1,5-benzodiazepine

Raztopino intermediata 2 (5,8 g) v ledoctu (50 ml) dodamo po kapljicah k suspenziji cinkovega prahu (6,37 g) v ledoctu (20 ml), ohlajeni na 0°. Zmes mešamo 3 ure pri 23° nato razredčimo z vodo (200 ml) in dekantiramo od cinka. Dodajamo trden natrijev karbonat do pH 9 in zmes ekstrahiramo z etilacetatom (2 x 300 ml). Združene organske ekstrakte izperemo s slanico (300 ml), posušimo in koncentriramo v vakuumu do olja, ki ga čistimo s flash kromatografijo (ob eluiranju v gradientu od CH-EA 2:1 do EA), da dobimo naslovno spojino kot belo peno (2,8 g). Tal. 125-126°. T.l.c. DCM-metanol (30:1), Rf 0,38.A solution of intermediate 2 (5.8 g) in ice (50 ml) was added dropwise to a suspension of zinc powder (6.37 g) in ice (20 ml) cooled to 0 °. The mixture was stirred for 3 hours at 23 ° then diluted with water (200 ml) and decanted from zinc. Solid sodium carbonate was added to pH 9 and the mixture was extracted with ethyl acetate (2 x 300 ml). The combined organic extracts were washed with brine (300 ml), dried and concentrated in vacuo to an oil which was purified by flash chromatography (eluting in a gradient from CH-EA 2: 1 to EA) to give the title compound as a white foam (2 , 8 g). Tal. 125-126 °. T.l.c. DCM-methanol (30: 1), Rf 0.38.

Intermediat 4Intermediate 4

2- (3,3-dimetilbut-l-il)amino-2’-fluoro-difenilamin2- (3,3-dimethylbut-1-yl) amino-2'-fluoro-diphenylamine

Natrijev borohidrid (22,7 g) dodamo po deležih k zmesi 2-amino-2’-fluorodifenilamina (8,0 g), natrijevega acetat trihidrata (16,33 g) in 3,3-dimetilbutiraldehida (5 ml) v ocetni kislini (12,8 ml), vodi (50 ml) in etanolu (40 ml), ohlajeni na 0°. Raztopino mešamo 30 minut pri 23°, nato razredčimo z etilacetatom (300 ml). Organski sloj izperemo z 10 %-no raztopino natrijevega hidroksida (3 x 200 ml) in slanico (200 ml), posušimo in koncentriramo v vakuumu do olja, ki ga čistimo s flash kromatografijo (ob eluiranju s CH-EA 9:1), da dobimo naslovno spojino kot rumeno olje (7,44 g). T.l.c. CH-EA (9:1), Rf 0,85.Sodium borohydride (22.7 g) was added portionwise to a mixture of 2-amino-2'-fluorodiphenylamine (8.0 g), sodium acetate trihydrate (16.33 g) and 3,3-dimethylbutyraldehyde (5 ml) in acetic acid (12.8 ml), water (50 ml) and ethanol (40 ml) cooled to 0 °. The solution was stirred for 30 minutes at 23 °, then diluted with ethyl acetate (300 ml). The organic layer was washed with 10% sodium hydroxide solution (3 x 200 ml) and brine (200 ml), dried and concentrated in vacuo to an oil which was purified by flash chromatography (eluting with CH-EA 9: 1). to give the title compound as a yellow oil (7.44 g). T.l.c. CH-EA (9: 1), Rf 0.85.

Intermediat 5 l-(3,3-dimetilbut-l-il)-2,4-diokso-5-(2-fluorofenil)-3-fenilhidrazono-2,3,4,5tetrahidro-lH-l,5-benzodiazepinIntermediate 5 1- (3,3-dimethylbut-1-yl) -2,4-dioxo-5- (2-fluorophenyl) -3-phenylhydrazono-2,3,4,5tetrahydro-1H-1,5-benzodiazepine

Vsakega od intermediata 4 (7,73 g) in 2-fenilhidrazonomalonildiklorida (7,97 g) prevzamemo v THF (100 ml) in nakapljamo v bučo, ki vsebuje THF (300 ml), vzdrževano pri -5° v atmosferi dušika. Po končanem dodajanju raztopino pustimo segreti na sobno temperaturo in nato segrevamo 3 ure na 50°. Raztopino koncentriramo v vakuumu do olja, ki ga čistimo s flash kromatografijo (ob eluiranju s CH-EA 8:2), da dobimo naslovno spojino kot rumeno trdno snov (10,8 g). Tal. 112-114°. T.l.c. CHEA (8:2), Rf0,40.Each of intermediate 4 (7.73 g) and 2-phenylhydrazonomalonyl dichloride (7.97 g) was taken up in THF (100 ml) and added to a flask containing THF (300 ml) maintained at -5 ° C under a nitrogen atmosphere. After the addition is complete, the solution is allowed to warm to room temperature and then heated to 50 ° C for 3 hours. The solution was concentrated in vacuo to an oil which was purified by flash chromatography (eluting with CH-EA 8: 2) to give the title compound as a yellow solid (10.8 g). Tal. 112-114 °. T.l.c. CHEA (8: 2), Rf0,40.

Intermediat 6Intermediate 6

3- amino-l-(3,3-dimetilbut-l-il)-2,4-diokso-5-(2-fluorofenil)-2,3,4,5-tetrahidrolH-l,5-benzodiazepin3- amino-1- (3,3-dimethylbut-1-yl) -2,4-dioxo-5- (2-fluorophenyl) -2,3,4,5-tetrahydrol-1,5,5-benzodiazepine

Raztopino intermediata 5 (10,1 g) v ledoctu (80 ml) dodamo po kapljicah k suspenziji cinkovega prahu (10,8 g) v ledoctu (20 ml), ohlajeni na 0°. Zmes mešamo 2 uri pri 23°, nato razredčimo z vodo (200 ml) in dekantiramo od cinka. Dodajamo trden natrijev karbonat do pH 9 in raztopino nato ekstrahiramo z etilacetatom (3 x 250 ml). Združene organske ekstrakte izperemo s slanico (400 ml), posušimo in koncentriramo v vakuumu do olja, ki ga očistimo s flash kromatografijo (ob eluiranju v gradientu od CH-EA 2:1 do etilacetata), da dobimo naslovno spojino kot belo peno (5,4 g). Tal. 98-100°. T.l.c. DCM-metanol (20:0,5), Rf 0,3.A solution of intermediate 5 (10.1 g) in ice (80 ml) was added dropwise to a suspension of zinc powder (10.8 g) in ice (20 ml) cooled to 0 °. The mixture was stirred at 23 ° for 2 hours, then diluted with water (200 ml) and decanted from zinc. Solid sodium carbonate was added to pH 9 and the solution was then extracted with ethyl acetate (3 x 250 ml). The combined organic extracts were washed with brine (400 ml), dried and concentrated in vacuo to an oil which was purified by flash chromatography (eluting in a gradient from CH-EA 2: 1 to ethyl acetate) to give the title compound as a white foam (5 , 4 g). Tal. 98-100 °. T.l.c. DCM-methanol (20: 0.5), Rf 0.3.

Intermediat 7Intermediate 7

2.4- diokso-5-(2-fluorofenil)-3-izocianat-l-(3-metilbut-f-il)-2,3,4,5-tetrahidrolH-l,5-benzodiazepin2,4-dioxo-5- (2-fluorophenyl) -3-isocyanate-1- (3-methylbut-f-yl) -2,3,4,5-tetrahydrol-1,5,5-benzodiazepine

Fosgen v toluenu (1,93 M raztopina; 7 ml) dodamo k raztopini intermediata 3 (0,2 g) v diklorometanu (3 ml). Dobljeno raztopino mešamo 5 ur pri 23°, nato koncentriramo 3 ure v vakuumu pri 50°, da dobimo naslovno spojino kot belo trdno snov (0,21 g). Tal. 167-8°.Phosgene in toluene (1.93 M solution; 7 ml) was added to a solution of intermediate 3 (0.2 g) in dichloromethane (3 ml). The resulting solution was stirred for 5 hours at 23 °, then concentrated in vacuo at 50 ° for 3 hours to give the title compound as a white solid (0.21 g). Tal. 167-8 °.

Intermediat 8Intermediate 8

2.4- diokso-5-(2-fluorofenil)-l-(3-metilbut-l-il)-3-(feniloksikarbonilamino)2,3,4,5-tetrahidro-lH-l,5-benzodiazepin2,4-dioxo-5- (2-fluorophenyl) -1- (3-methylbut-1-yl) -3- (phenyloxycarbonylamino) 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Piridin (0,137 ml) in fenilkloroformat (0,21 ml) dodamo k raztopini intermediata 3 (0,3 g) v diklorometanu (15 ml) v atmosferi dušika. Dobljeno raztopino mešamo 30 minut pri 23°, nato izperemo z 1 %-no raztopino klorovodikove kisline (15 ml), 5 %-no raztopino natrijevega hidrogenkarbonata (15 ml) in slanico (20 ml). Organski sloj posušimo in koncentriramo v vakuumu do trdne snovi, ki jo trituriramo z etilacetatom, da dobimo naslovno spojino kot belo trdno snov (0,3 g). Tal. 226-227°. T.l.c. CH-EA (1:1), Rf0,75.Pyridine (0.137 ml) and phenylchloroformate (0.21 ml) were added to a solution of intermediate 3 (0.3 g) in dichloromethane (15 ml) under a nitrogen atmosphere. The resulting solution was stirred for 30 minutes at 23 °, then washed with 1% hydrochloric acid solution (15 ml), 5% sodium hydrogen carbonate solution (15 ml) and brine (20 ml). The organic layer was dried and concentrated in vacuo to a solid, which was triturated with ethyl acetate to give the title compound as a white solid (0.3 g). Tal. 226-227 °. T.l.c. CH-EA (1: 1), Rf 0.75.

Intermediat 9 l-(3,3-dimetilbut-l-il)-2,4-diokso-5-(2-fluorofeniI)-3-(feniloksikarbonilamino)2,3,4,5-tetrahidro-lH-l,5-benzodiazepinIntermediate 9 1- (3,3-dimethylbut-1-yl) -2,4-dioxo-5- (2-fluorophenyl) -3- (phenyloxycarbonylamino) 2,3,4,5-tetrahydro-1H-1,5 -benzodiazepine

Piridin (0,64 ml) in fenilkloroformat (1,0 ml) dodamo k raztopini intermediata 6 (1,5Pyridine (0.64 ml) and phenylchloroformate (1.0 ml) were added to a solution of intermediate 6 (1.5

g) v diklorometanu (100 ml) v atmosferi dušika. Dobljeno raztopino mešamo 30 minut pri 23°, nato jo izperemo z 1 %-no raztopino klorovodikove kisline (2 x 70 ml), 5 %-no raztopino natrijevega hidrogenkarbonata (2 x 70 ml) in slanico (100 ml). Organski sloj posušimo in koncentriramo v vakuumu do trdne snovi, ki jo trituriramo z dietiletrom, da dobimo naslovno spojino kot belo trdno snov (1,4 g). Tal. 199-200°. T.l.c. CH-EA (1:1), Rf0,82.g) in dichloromethane (100 ml) under a nitrogen atmosphere. The resulting solution was stirred for 30 minutes at 23 °, then washed with 1% hydrochloric acid solution (2 x 70 ml), 5% sodium hydrogen carbonate solution (2 x 70 ml) and brine (100 ml). The organic layer was dried and concentrated in vacuo to a solid, which was triturated with diethyl ether to give the title compound as a white solid (1.4 g). Tal. 199-200 °. T.l.c. CH-EA (1: 1), Rf 0.82.

Intermediat 10Intermediate 10

2-(3,3-dimetil-2-hidroksibut-l-il)amino-2^,-fIuorodifenilamin l,2-epoksi-3,3-dimetilbutan (7 ml) dodamo po deležih k zmesi 2-amino-2’fluorodifenilamina (7,46 g) in p-toluensulfonske kisline (0,6 g) v etanolu (30 ml), segreti na 80°C. Zmes mešamo 19 ur pri 80°, nato koncentriramo v vakuumu in porazdelimo med vodo (100 ml) in etilacetat (150 ml). Organski sloj izperemo s 5 %-no raztopino natrijevega hidrogenkarbonata (2 x 100 ml), slanico (150 ml), posušimo in koncentriramo v vakuumu do olja, ki ga čistimo s flash kromatografijo (ob eluiranju s CH-EA 80:20), da dobimo naslovno spojino kot rumeno olje (3,21 g). T.l.c. CH-DCM (1:1), Rf 0,25.2- (3,3-dimethyl-2-hydroxybut-1-yl) amino-2 ^, -fluorodiphenylamine 1,2-epoxy-3,3-dimethylbutane (7 ml) was added portionwise to a mixture of 2-amino-2'fluorodiphenylamine (7.46 g) and p-toluenesulfonic acid (0.6 g) in ethanol (30 ml) heated to 80 ° C. The mixture was stirred at 80 ° for 19 hours, then concentrated in vacuo and partitioned between water (100 ml) and ethyl acetate (150 ml). The organic layer was washed with 5% sodium hydrogen carbonate solution (2 x 100 ml), brine (150 ml), dried and concentrated in vacuo to an oil which was purified by flash chromatography (eluting with CH-EA 80:20). to give the title compound as a yellow oil (3.21 g). Tlc CH-DCM (1: 1), Rf 0.25.

Intermediat 11 l-(3,3-dimetil-2-hidroksibut-l-il)-2,4-diokso-5-(2-fluorofenil)-3-fenilhidrazono2,3,4,5-tetrahidro-lH-l,5-benzodiazepinIntermediate 11 1- (3,3-dimethyl-2-hydroxybut-1-yl) -2,4-dioxo-5- (2-fluorophenyl) -3-phenylhydrazono2,3,4,5-tetrahydro-1H-1. 5-benzodiazepine

Vsakega od intermediata 10 (1,8 g) in 2-fenilhidrazonomalonildiklorida (1,76 g) prevzamemo v THF (35 ml) in nakapljamo v bučo, ki vsebuje THF (30 ml), vzdrževano pri -15° v atmosferi dušika. Po končanem dodajanju raztopino pustimo segreti na sobno temperaturo in nato segrevamo 3 ure na 50°. Raztopino koncentriramo v vakuumu do olja, ki ga čistimo s flash kromatografijo (ob eluiranju s CH-EA 8:2), da dobimo naslovno spojino kot rumeno trdno snov (2,1 g). Tal. 217-218°. T.l.c. CH-EA (2:1), Rf0,71.Each of intermediate 10 (1.8 g) and 2-phenylhydrazonomalonyl dichloride (1.76 g) was taken up in THF (35 ml) and added to a flask containing THF (30 ml) maintained at -15 ° C under a nitrogen atmosphere. After the addition is complete, the solution is allowed to warm to room temperature and then heated to 50 ° C for 3 hours. The solution was concentrated in vacuo to an oil which was purified by flash chromatography (eluting with CH-EA 8: 2) to give the title compound as a yellow solid (2.1 g). Tal. 217-218 °. T.l.c. CH-EA (2: 1), Rf 0.71.

Intermediat 12Intermediate 12

3-amino-l-(3,3-dimetil-2-hidroksibut-l-il)-2,4-diokso-5-(2-fluorofenil)-2,3A5tetrahidro-lH-l,5-benzodiazepin3-amino-1- (3,3-dimethyl-2-hydroxybut-1-yl) -2,4-dioxo-5- (2-fluorophenyl) -2,3A5tetrahydro-1H-1,5-benzodiazepine

Cink v prahu (2,17 g) dodamo po deležih k raztopini intermediata 11 (2,1 g) v ledoctu (30 ml), predhodno ohlajeni na 0°. Zmes mešamo 20 ur pri 23°, nato razredčimo z vodo (100 ml) in dekantiramo od cinka. Trden natrijev karbonat dodajamo do pH 9 in zmes ekstrahiramo z etilacetatom (3 x 100 ml). Združene organske ekstrakte izperemo s slanico (200 ml), sušimo in koncentriramo v vakuumu do olja, ki ga čistimo s flash kromatografijo (ob eluiranju z EA), da dobimo naslovno spojino kot belo peno (1,09 g). Tal. 104-105°. T.l.c. EA-metanoI (20:2), Rf 0,66 in 0,61.Zinc powder (2.17 g) was added portionwise to a solution of intermediate 11 (2.1 g) in ice (30 ml), pre-cooled to 0 °. The mixture was stirred at 23 ° for 20 hours, then diluted with water (100 ml) and decanted from zinc. Solid sodium carbonate was added to pH 9 and the mixture was extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were washed with brine (200 ml), dried and concentrated in vacuo to an oil which was purified by flash chromatography (eluting with EA) to give the title compound as a white foam (1.09 g). Tal. 104-105 °. T.l.c. EA-methanoI (20: 2), Rf 0.66 and 0.61.

Intermediat 13Intermediate 13

3-amino-l-(3,3-dimetil-2-hidroksibut-l-il)-2,4-diokso-5-(2-fluorofeniI)-2,3,4,5tetrahidro-lH-l,5-benzodiazepin (diastereomer 1:13a in diastereomer II: 13b)3-amino-1- (3,3-dimethyl-2-hydroxybut-1-yl) -2,4-dioxo-5- (2-fluorophenyl) -2,3,4,5tetrahydro-1H-1,5 benzodiazepine (diastereomer 1: 13a and diastereomer II: 13b)

Diastereomemo zmes, intermediat 12, ločimo s preparativno HPLC (Column Spherisorb 5uCN 25 x 0,46 cm) ob eluiranju s heksanom/etanolom/izopropanolom 85:10:5 in izopropilaminom 0,05 % (flux 2 ml/min), detekcija UV pri 235 nm), da dobimo naslovno spojino 13a (retencijski čas 8,9 min) kot belo trdno snov (0,3 g), tal. 164-165°, T.l.c. EA-metanol (20:2), Rf 0,66, in naslovno spojino 13b (retencijski čas 6 min) kot belo peno (0,35 g). T.l.c. EA-metanol (20:2), Rf 0,61.The diastereomic mixture, intermediate 12, was separated by preparative HPLC (Column Spherisorb 5uCN 25 x 0.46 cm) eluting with hexane / ethanol / isopropanol 85: 10: 5 and isopropylamine 0.05% (flux 2 ml / min), UV detection. at 235 nm) to give the title compound 13a (retention time 8.9 min) as a white solid (0.3 g), m.p. 164-165 °, T.l.c. EA-methanol (20: 2), Rf 0.66, and the title compound 13b (retention time 6 min) as white foam (0.35 g). T.l.c. EA-methanol (20: 2), Rf 0.61.

Intermediat 14Intermediate 14

2-(l,3-dimetilbut-l-il)amino-difenilamin2- (1,3-dimethylbut-1-yl) amino-diphenylamine

Natrijev borohidrid (0,4 g) dodamo po deležih k zmesi 2-amino-difenilamina (0,5 g), natrijevega acetat-trihidrata (0,5 g) in 4-metil-2-oksopentana (0,25 ml) v ocetni kislini (1,7 ml), vodi (5 ml) in etanolu (4 ml), ohlajeni pri 0°. Dodamo nadaljnjo količino natrijevega borohidrida (2,0 g) in 4-metil-2-okso-pentana (3 ml) ter raztopino mešamo 30 minut pri 23°, nato razredčimo z etilacetatom (100 ml) in vodo (100 ml). Organski sloj izperemo z 10 %-no raztopino natrijevega hidroksida (50 ml) in slanico (50 ml), posušimo in koncentriramo v vakuumu, da dobimo olje, ki ga čistimo s flash kromatografijo (ob eluiranju s CH-EA 90:10), da dobimo naslovno spojino kot rumeno olje (0,42 g). T.l.c. CH-EA (90:10), Rf 0,79. IR:3420 (NH), 1599, 1514 in 1497 (C=C) cm-1.Sodium borohydride (0.4 g) was added portionwise to a mixture of 2-amino-diphenylamine (0.5 g), sodium acetate trihydrate (0.5 g) and 4-methyl-2-oxopentane (0.25 ml) in acetic acid (1.7 ml), water (5 ml) and ethanol (4 ml) cooled to 0 °. A further amount of sodium borohydride (2.0 g) and 4-methyl-2-oxo-pentane (3 ml) was added and the solution stirred for 30 minutes at 23 °, then diluted with ethyl acetate (100 ml) and water (100 ml). The organic layer was washed with 10% sodium hydroxide solution (50 ml) and brine (50 ml), dried and concentrated in vacuo to give an oil which was purified by flash chromatography (eluting with CH-EA 90:10). to give the title compound as a yellow oil (0.42 g). T.l.c. CH-EA (90:10), Rf 0.79. IR: 3420 (NH), 1599, 1514 and 1497 (C = C) cm-1.

Intermediat 15 l-(L3-dimetilbut-l-il)-2,4-diokso-5-fenil-3-fenilhidrazono-2,3,4,5tetrahidro-lH-l,5-benzodiazepinIntermediate 15 1- (L3-dimethylbut-1-yl) -2,4-dioxo-5-phenyl-3-phenylhydrazono-2,3,4,5tetrahydro-1H-1,5-benzodiazepine

Vsakega od intermediata 14 (0,42 g) in 2-fenilhidrazonomalonildiklorida (0,46 g) prevzamemo v THF (20 ml) in nakapljamo v bučo, ki vsebuje THF (10 ml), vzdrževano pri 0°C pri atmosferi dušika. Po končanem dodajanju pustimo raztopino segreti na 23° in mešamo 20 ur. Dodamo nadaljnjo količino 2-fenilhidrazonomalonildiklorida (0,13 g) in mešamo 1 uro pri 23°, nato pa 90 minut pri 50°. Reakcijsko zmes razredčimo z etilacetatom (200 ml); organski sloj izperemo z 10 %-no raztopino natrijevega hidroksida (60 ml) in slanico (2 x 70 ml), posušimo in koncentriramo v vakuumu, da dobimo olje, ki ga čistimo s flash kromatografijo (ob eluiranju s CH-EA 95:5, ob povečanju polarnosti na 90:10), da dobimo naslovno spojino kot rumeno trdno snov (0,43 g). T.l.c. CH-EA (70:30), Rf 0,73. IR:1668, 1653 (C-O); 1591 (C-C) cm-1.Each of intermediate 14 (0.42 g) and 2-phenylhydrazonomalonyl dichloride (0.46 g) was taken up in THF (20 ml) and added to a flask containing THF (10 ml) maintained at 0 ° C under a nitrogen atmosphere. After the addition is complete, the solution is allowed to warm to 23 ° and stirred for 20 hours. A further amount of 2-phenylhydrazonomalonyl dichloride (0.13 g) was added and stirred at 23 ° for 1 hour and then at 50 ° for 90 minutes. The reaction mixture was diluted with ethyl acetate (200 ml); The organic layer was washed with 10% sodium hydroxide solution (60 ml) and brine (2 x 70 ml), dried and concentrated in vacuo to give an oil which was purified by flash chromatography (eluting with CH-EA 95: 5 , increasing the polarity to 90:10) to give the title compound as a yellow solid (0.43 g). T.l.c. CH-EA (70:30), Rf 0.73. IR: 1668, 1653 (C-O); 1591 (C-C) cm-1.

Intermediat 16Intermediate 16

3-amino-l-(l,3-dimeti1but-l-il)-2,4-diokso-5-fenil-2,3,4,5-tetrahidro-lH-l,5benzodiazepin3-amino-1- (1,3-dimethylbut-1-yl) -2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Cink v prahu (0,55 g) dodamo po deležih raztopini intermediata 15 (0,42 g) v ledoctu (10 ml) ohlajeni pri 0°. Zmes mešamo 8 ur pri 23°, nato dekantiramo od cinka, razredčimo z etilacetatom (50 ml), izperemo z 10 %-no raztopino natrijevega hidroksida (60 ml), slanico (2 x 60 ml), posušimo in koncentriramo v vakuumu, da dobimo olje, ki ga čistimo s flash kromatografijo (ob eluiranju v gradientu od CH-EA 1:1 do DCM-metanola 90:10), da dobimo naslovno spojino kot belo peno (0,22 g). T.l.c. DCM-metanol (90:10), Rf 0,53. IR: 3500-3000 (NH2), 1703 in 1672 (C-O), 1593 (C-C) cm-1.Zinc powder (0.55 g) was added portionwise to a solution of intermediate 15 (0.42 g) in ice (10 ml) cooled to 0 °. The mixture was stirred for 8 hours at 23 °, then decanted from zinc, diluted with ethyl acetate (50 ml), washed with 10% sodium hydroxide solution (60 ml), brine (2 x 60 ml), dried and concentrated in vacuo to The oil was purified by flash chromatography (eluting in a gradient from CH-EA 1: 1 to DCM-methanol 90:10) to give the title compound as a white foam (0.22 g). T.l.c. DCM-methanol (90:10), Rf 0.53. IR: 3500-3000 (NH2), 1703 and 1672 (C-O), 1593 (C-C) cm-1.

Intermediat 17Intermediate 17

2-amino-5-kloro-difenilamin2-amino-5-chloro-diphenylamine

Kalijev karbonat (29 g) in natrijev hidrosulfid (25,3 g) dodajamo 1 uro po deležih k suspenziji 5-kloro-2-nitrodifenilamina (8 g) v 95 %-nem etanolu (250 ml) in vodi (250 ml). Zmes mešamo pri 23° 20 ur, nato dodamo nadaljno količino natrijevega hidrosulfita (1 g) in mešamo 1 uro. Reakcijsko zmes nakisamo na pH 4 s koncentrirano klorovodikovo kislino in nato dodajamo 10 %-no raztopino natrijevega hidroksida, dokler pH ni 10. Raztopino koncentriramo v vakuumu in ekstrahiramo z etiletrom (2 x 250 ml). Združene organske ekstrakte izperemo s slanico (2 x 250 ml), posušimo in koncentriramo v vakuumu, da dobimo surovo spojino kot rumeno trdno snov (7,8 g), ki jo čistimo s flash kromatografijo (ob eluiranju s P-EE 1:1), da dobimo naslovno spojino kot rumeno peno (4,4 g). T.l.c. CH-EA (1:1), Rf 0,50. IR: 3412 in 3320 (NH), 1592-1589 (C-C) cm-1.Potassium carbonate (29 g) and sodium hydrosulfide (25.3 g) were added 1 hour in portions to a suspension of 5-chloro-2-nitrodiphenylamine (8 g) in 95% ethanol (250 ml) and water (250 ml). The mixture was stirred at 23 ° for 20 hours, then a further amount of sodium hydrosulfite (1 g) was added and stirred for 1 hour. The reaction mixture was acidified to pH 4 with concentrated hydrochloric acid and then a 10% solution of sodium hydroxide was added until the pH was 10. The solution was concentrated in vacuo and extracted with ethyl ether (2 x 250 ml). The combined organic extracts were washed with brine (2 x 250 ml), dried and concentrated in vacuo to give the crude compound as a yellow solid (7.8 g), which was purified by flash chromatography (eluting with P-EE 1: 1 ) to give the title compound as a yellow foam (4.4 g). T.l.c. CH-EA (1: 1), Rf 0.50. IR: 3412 and 3320 (NH), 1592-1589 (C-C) cm-1.

Intermediat 18Intermediate 18

5-kloro-2-(3-metilbut-l-il)amino-difenilamin5-chloro-2- (3-methylbut-1-yl) amino-diphenylamine

Natrijev borohidrid (2 g) dodamo po deležih k zmesi intermediata 17 (2 g), natrijevega acetata trihidrata (2,28 g) in 3-metilbutiraldehida (2 ml) v ocetni kislini (8 ml), vodi (15 ml) in etanolu (35 ml), ohlajeni na 0°. Raztopino mešamo pri 23° 30 minut, nato razredčimo z etilacetatom (200 ml). Organski sloj izperemo z 10 %-no raztopino kalijevega karbonata (100 ml) in slanico (100 ml), posušimo in koncentriramo v vakuumu, da dobimo olje, ki ga čistimo s flash kromatografijo (ob eluiranju s CH-EA 95:5), da dobimo naslovno spojino kot rumeno olje (0,8 g). T.l.c. CH-EA (1:1), Rf 0,72.Sodium borohydride (2 g) was added portionwise to a mixture of intermediate 17 (2 g), sodium acetate trihydrate (2.28 g) and 3-methylbutyraldehyde (2 ml) in acetic acid (8 ml), water (15 ml) and ethanol (35 ml), cooled to 0 °. The solution was stirred at 23 ° for 30 minutes, then diluted with ethyl acetate (200 ml). The organic layer was washed with 10% potassium carbonate solution (100 ml) and brine (100 ml), dried and concentrated in vacuo to give an oil which was purified by flash chromatography (eluting with CH-EA 95: 5). to give the title compound as a yellow oil (0.8 g). T.l.c. CH-EA (1: 1), Rf 0.72.

Intermediat 19Intermediate 19

7-kloro-2,4-diokso-l-(3-metilbut-l-il)-5-fenil-3-fenilhidrazono-2,3A5tetrahidro-lH-l,5-benzodiazepin7-chloro-2,4-dioxo-1- (3-methylbut-1-yl) -5-phenyl-3-phenylhydrazono-2,3A5tetrahydro-1H-1,5-benzodiazepine

Vsakega izmed intermediata 18 (1,15 g) in 2-feniIhidrazonomalonildiklorida (1,17 g) prevzamemo v THF (30 ml) in dodamo po kapljicah v bučo, ki vsebuje THF (10 ml), vzdrževano pri 0°C v atmosferi dušika. Po končanem dodajanju pustimo raztopino segreti na 23°, mešamo 30 minut, nato segrevamo 2 uri pri 60°. Raztopino razredčimo z etilacetatom (150 ml), jo speremo s slanico (2 x 100 ml), posušimo ter koncentriramo v vakuumu, da dobimo olje, ki ga čistimo s flash kromatografijo (ob eluiranju s CH-EA 95:5, ob naraščanju polarnosti do 70:30), da dobimo naslovno spojino kot rumeno trdno snov (1,12 g). T.l.c. CH-EA (1:1), Rf 0,61. IR: 3452 (NH), 1664 (C=O) cm-1.Each of intermediate 18 (1.15 g) and 2-phenylhydrazonomalonyl dichloride (1.17 g) was taken up in THF (30 ml) and added dropwise to a flask containing THF (10 ml) maintained at 0 ° C under a nitrogen atmosphere. . After the addition is complete, the solution is allowed to warm to 23 °, stirred for 30 minutes, then heated at 60 ° for 2 hours. The solution was diluted with ethyl acetate (150 ml), washed with brine (2 x 100 ml), dried and concentrated in vacuo to give an oil which was purified by flash chromatography (eluting with CH-EA 95: 5, increasing in polarity to 70:30) to give the title compound as a yellow solid (1.12 g). T.l.c. CH-EA (1: 1), Rf 0.61. IR: 3452 (NH), 1664 (C = O) cm -1.

Intermediat 20Intermediate 20

3-amino-2,4-diokso-7-kloro-5-fenil-l-(3-metilbut-l-iI)-2,3A5-tetrahidro-lH1,5-benzodiazepin3-amino-2,4-dioxo-7-chloro-5-phenyl-1- (3-methylbut-1-yl) -2,3A5-tetrahydro-1H1,5-benzodiazepine

Raztopino intermediata 19 (0,6 g) v ledoctu (14 ml) dodamo po kapljicah k suspenziji cinka v prahu (0,76 g) v ledoctu (14 ml), ohlajeni na 0°. Zmes mešamo 3 ure pri 23°, nato dekantiramo od cinka, izperemo z etilacetatom (80 ml) ter nato z 10 %-nim natrijevim hidroksidom (100 ml) in slanico (70 ml). Združene organske ekstrakte posušimo in koncentriramo v vakuumu, da dobimo olje, ki ga čistimo s flash kromatografijo (ob eluiranju v gradientu od CH-EA 1:1 do EA-metanola 27:3), da dobimo naslovno spojino (0,3 g). T.l.c. DCM-metanol (27:3), Rf 0,5.A solution of intermediate 19 (0.6 g) in ice (14 ml) was added dropwise to a suspension of zinc powder (0.76 g) in ice (14 ml) cooled to 0 °. The mixture was stirred for 3 hours at 23 °, then decanted from zinc, washed with ethyl acetate (80 ml) and then with 10% sodium hydroxide (100 ml) and brine (70 ml). The combined organic extracts were dried and concentrated in vacuo to give an oil which was purified by flash chromatography (eluting in a gradient from CH-EA 1: 1 to EA-methanol 27: 3) to give the title compound (0.3 g) . T.l.c. DCM-methanol (27: 3), Rf 0.5.

Intermediat 21Intermediate 21

4-kloro-2-nitrodifenilamin4-chloro-2-nitrodiphenylamine

Zmes 4-kloro-2-nitroanilina (5,5 g), bromobenzena (20 ml), kalijevega karbonata (1,63 g) in bakrovega(I) jodida (0,68 g) segrevamo 36 ur na 180°. Reakcijsko zmes ohladimo na sobno temperaturo, nato dodamo etilacetat (200 ml) in vodo (300 ml); organske ekstrakte izperemo s slanico (2 x 150 ml), posušimo in koncentriramo v vakuumu, da dobimo surovo spojino, ki jo čistimo s flash kromatografijo (ob eluiranju s CH-EA 95:5), da dobimo naslovno spojino (3,67 g). T.l.c. CH-EA (1:1), Rf0,71.A mixture of 4-chloro-2-nitroaniline (5.5 g), bromobenzene (20 ml), potassium carbonate (1.63 g) and copper (I) iodide (0.68 g) was heated for 180 hours at 180 °. The reaction mixture was cooled to room temperature, then ethyl acetate (200 ml) and water (300 ml) were added; The organic extracts were washed with brine (2 x 150 ml), dried and concentrated in vacuo to give the crude compound, which was purified by flash chromatography (eluting with CH-EA 95: 5) to give the title compound (3.67 g ). T.l.c. CH-EA (1: 1), Rf 0.71.

Intermediat 22Intermediate 22

2-amino-4-klorodifenilamin2-amino-4-chlorodiphenylamine

Kalijev karbonat (13 g) in natrijev hidrosulfit (11,4 g) dodajamo po deležih 3 ure k suspenziji 4-kloro-2-nitrodifenilamina (3,6 g) v 95 %-nem etanolu (100 ml) in vodi (100 ml). Zmes mešamo 20 ur pri 23°. Reakcijsko zmes nato nakisamo do pH 4 s koncentrirano klorovodikovo kislino (20 ml); nato dodajamo 10 %-no raztopino natrijevega hidroksida (80 ml) do pH 10 in raztopino ekstrahiramo z etilacetatom (2 x 150 ml). Združene organske ekstrakte izperemo s slanico (2 x 150 ml), sušimo in koncentriramo v vakuumu, da dobimo surovo spojino kot rumeno trdno snov (7,8 g), ki jo čistimo s flash kromatografijo (ob eluiranju s CH-EA 90:10, nato 70:30), da dobimo naslovno spojino kot rumeno peno (2,37 g). T.l.c. CH-EA (1:1), Rf 0,66.Potassium carbonate (13 g) and sodium hydrosulphite (11.4 g) were added in 3 hours increments to a suspension of 4-chloro-2-nitrodiphenylamine (3.6 g) in 95% ethanol (100 ml) and water (100 ml) ). The mixture was stirred at 23 ° for 20 hours. The reaction mixture was then acidified to pH 4 with concentrated hydrochloric acid (20 ml); then a 10% solution of sodium hydroxide (80 ml) was added to pH 10 and the solution was extracted with ethyl acetate (2 x 150 ml). The combined organic extracts were washed with brine (2 x 150 ml), dried and concentrated in vacuo to give the crude compound as a yellow solid (7.8 g), which was purified by flash chromatography (eluting with CH-EA 90:10 , then 70:30) to give the title compound as a yellow foam (2.37 g). T.l.c. CH-EA (1: 1), Rf 0.66.

Intermediat 23Intermediate 23

4-kloro-2-(3-metilbut-l-il)amino-difenilamin4-Chloro-2- (3-methylbut-1-yl) amino-diphenylamine

Bromo-3-metilbutan (0,62 ml) dodamo k raztopini intermediata 22 (1,00 g) in natrijevega jodida (0,7 g) v dimetilformamidu (40 ml) v atmosferi dušika. Raztopino mešamo 12 ur pri 120°, nato ohladimo pri 23°, razredčimo z etilacetatom (150 ml) in izperemo s slanico (3 x 100 ml). Združene organske ekstrakte posušimo in koncentriramo v vakuumu, da dobimo olje, ki ga čistimo s flash kromatografijo (ob eluiranju s CH-EA 95:5), da dobimo naslovno spojino kot rumeno olje (0,74 g). T.l.c. CH-EA (1:1), Rf0,76.Bromo-3-methylbutane (0.62 ml) was added to a solution of intermediate 22 (1.00 g) and sodium iodide (0.7 g) in dimethylformamide (40 ml) under a nitrogen atmosphere. The solution was stirred for 12 hours at 120 °, then cooled to 23 °, diluted with ethyl acetate (150 ml) and washed with brine (3 x 100 ml). The combined organic extracts were dried and concentrated in vacuo to give an oil which was purified by flash chromatography (eluting with CH-EA 95: 5) to give the title compound as a yellow oil (0.74 g). T.l.c. CH-EA (1: 1), Rf 0.76.

Intermediat 24Intermediate 24

8-kloro-2,4-diokso-l-(3-metilbut-l-il)-5-fenil-3-fenilhidrazono-2,3.4,5tetrahidro-lH-1.5-benzodiazepin8-chloro-2,4-dioxo-1- (3-methylbut-1-yl) -5-phenyl-3-phenylhydrazono-2,3,4,5tetrahydro-1H-1,5-benzodiazepine

Vsakega izmed intermediata 23 (0,74 g) in 2-fenilhidrazonomalonildiklorida (0,75 g) prevzamemo v THF (15 ml) in nakapljamo v bučo, ki vsebuje THF (20 ml), vzdrževano pri 0° v atmosferi dušika. Po končanem dodajanju raztopino pustimo segreti na 23°, mešamo 30 minut, nato segrevamo 2 uri pri 60°. Raztopino razredčimo z etilacetatom (120 ml), izperemo s slanico (2 x 100 ml), posušimo in koncentriramo v vakuumu, da dobimo olje, ki ga čistimo s flash kromatografijo (ob eluiranju s CHEA 95:5, ob naraščanju polarnosti do 70:30), da dobimo naslovno spojino kot rumeno trdno snov (0,91 g). T.l.c. CH-EA (1:1), Rf 0,68.Each of intermediate 23 (0.74 g) and 2-phenylhydrazonomalonyl dichloride (0.75 g) was taken up in THF (15 ml) and added to a flask containing THF (20 ml) maintained at 0 ° under a nitrogen atmosphere. After the addition is complete, the solution is allowed to warm to 23 °, stirred for 30 minutes, then heated at 60 ° for 2 hours. The solution was diluted with ethyl acetate (120 ml), washed with brine (2 x 100 ml), dried and concentrated in vacuo to give an oil which was purified by flash chromatography (eluting with CHEA 95: 5, increasing the polarity to 70: 30) to give the title compound as a yellow solid (0.91 g). T.l.c. CH-EA (1: 1), Rf 0.68.

Intermediat 25Intermediate 25

3-amino-8“kloro-2,4-diokso-l-(3-metilbut-l-il)-5-fenil-2,3,4,5-tetrahidrolH-l,5-benzodiazepin3-amino-8-chloro-2,4-dioxo-1- (3-methylbut-1-yl) -5-phenyl-2,3,4,5-tetrahydrol-1,5-benzodiazepine

K raztopini intermediata 24 (0,9 g) v ledoctu (20 ml) pri 0° dodamo po deležih cink v prahu (1,14 g). Zmes mešamo 1 uro pri 23°, nato dekantiramo od cinka, izperemo z etilacetatom (150 ml) in nato z 10 %-nim natrijevim hidroksidom (150 ml) in slanico (100 ml). Združene organske ekstrakte posušimo in koncentriramo v vakuumu do olja, ki ga čistimo s flash kromatografijo (ob eluiranju v gradientu od CH-EA 1:1 do EA-metanola 27:3), da dobimo naslovno spojino (0,53 g). T.l.c. EA-metanol (27:3), Rf0,6.To a solution of intermediate 24 (0.9 g) in ice (20 ml) at 0 ° was added the proportions of zinc powder (1.14 g). The mixture was stirred at 23 ° for 1 hour, then decanted from zinc, washed with ethyl acetate (150 ml) and then with 10% sodium hydroxide (150 ml) and brine (100 ml). The combined organic extracts were dried and concentrated in vacuo to an oil which was purified by flash chromatography (eluting in a gradient from CH-EA 1: 1 to EA-methanol 27: 3) to give the title compound (0.53 g). T.l.c. EA-methanol (27: 3), Rf0.6.

Intermediat 26Intermediate 26

4,5-dikloro-2-nitrodifenilamin4,5-dichloro-2-nitrodiphenylamine

Zmes 4,5-dikloro-2-nitroanilina (5,0 g), bromobenzena (16 ml), kalijevega karbonata (1,17 g) in bakrovega(I) jodida (0,46 g) segrevamo 36 ur na 150°. Reakcijsko zmes koncentriramo v vakuumu, da dobimo surovo spojino, ki jo čistimo s flash kromatografijo (ob eluiranju s CH-EA (90:10), da dobimo naslovno spojino (4,34 g). T.l.c. CH-EA (1:1), Rf 0,7.A mixture of 4,5-dichloro-2-nitroaniline (5.0 g), bromobenzene (16 ml), potassium carbonate (1.17 g) and copper (I) iodide (0.46 g) was heated at 150 ° for 36 hours. The reaction mixture was concentrated in vacuo to give the crude compound, which was purified by flash chromatography (eluting with CH-EA (90:10) to give the title compound (4.34 g). Tlc CH-EA (1: 1) , Rf 0.7.

Intermediat 27Intermediate 27

2-amino-4,5-dikloro-difenilamin2-amino-4,5-dichloro-diphenylamine

Kalijev karbonat (13,8 g) in natrijev hidrosulfit (12,1 g) dodajamo po deležih 3 ure suspenziji 4,5-dikloro-2-nitrodifenilamina (4,34 g) v 95 %-nem etanolu (100 ml) in vodi (100 ml). Zmes mešamo 20 ur pri 23°. Reakcijsko zmes nato nakisamo na pH 4 s koncentrirano klorovodikovo kislino (20 ml), nato dodajamo 10 %-no raztopino natrijevega hidroksida (80 ml) do pH 10 in raztopino ekstrahiramo z etilacetatom (2 x 120 ml). Združene organske ekstrakte izperemo s slanico (2 x 100 ml), posušimo in koncentriramo v vakuumu, da dobimo surovo spojino, ki jo čistimo s flash kromatografijo (ob eluiranju s CH-EA (90:10, nato 80:20), da dobimo naslovno spojino kot rumeno peno (2,15 g). T.l.c. CH-EA (1:1), Rf 0,54.Potassium carbonate (13.8 g) and sodium hydrosulfite (12.1 g) were added portionwise for 3 hours to a suspension of 4,5-dichloro-2-nitrodiphenylamine (4.34 g) in 95% ethanol (100 ml) and water (100 ml). The mixture was stirred at 23 ° for 20 hours. The reaction mixture was then acidified to pH 4 with concentrated hydrochloric acid (20 ml), then a 10% solution of sodium hydroxide (80 ml) was added to pH 10 and the solution was extracted with ethyl acetate (2 x 120 ml). The combined organic extracts were washed with brine (2 x 100 ml), dried and concentrated in vacuo to give the crude compound, which was purified by flash chromatography (eluting with CH-EA (90:10 then 80:20) to give the title compound as a yellow foam (2.15 g), Tlc CH-EA (1: 1), Rf 0.54.

Intermediat 28Intermediate 28

4,5-dikloro-2-(3-metilbut-l-il)amino-difenilamin l-bromo-3-metilbutan (1,2 ml) dodamo k raztopini intermediata 27 (2,15 g) in natrijevega jodida (1,3 g) v dimetilformamidu (70 ml) v atmosferi dušika. Raztopino mešamo 9 ur pri 120° in 20 ur pri 23°. Nato dodamo nadaljnjo količino bromo-3metilbutana (0,5 ml) in mešamo 8 ur pri 120°. Reakcijsko zmes razredčimo z etilacetatom (300 ml) in izperemo s slanico (150 ml). Združene organske ekstrakte posušimo in koncentriramo v vakuumu, da dobimo olje, ki ga čistimo s flash kromatografijo (ob eluiranju s CH-EA (95:5), da dobimo naslovno spojino kot rumeno olje (1,72 g). T.l.c. CH-EA (1:1), Rf 0,70.4,5-Dichloro-2- (3-methylbut-1-yl) amino-diphenylamine 1-bromo-3-methylbutane (1.2 ml) was added to a solution of intermediate 27 (2.15 g) and sodium iodide (1, 3 g) in dimethylformamide (70 ml) under a nitrogen atmosphere. The solution was stirred for 9 hours at 120 ° and 20 hours at 23 °. A further amount of bromo-3methylbutane (0.5 ml) was then added and stirred at 120 ° for 8 hours. The reaction mixture was diluted with ethyl acetate (300 ml) and washed with brine (150 ml). The combined organic extracts were dried and concentrated in vacuo to give an oil which was purified by flash chromatography (eluting with CH-EA (95: 5) to give the title compound as a yellow oil (1.72 g). Tlc CH-EA (1: 1), Rf 0.70.

Intermediat 29Intermediate 29

7-8-dikloro-2,4-diokso-l-(3-metilbut-l-il)-5-fenil-3-fenilhidrazono-2,3,4,5tetrahidro-lH-l,5-benzodiazepin7-8-dichloro-2,4-dioxo-1- (3-methylbut-1-yl) -5-phenyl-3-phenylhydrazono-2,3,4,5tetrahydro-1H-1,5-benzodiazepine

Vsakega izmed intermediata 28 (1,72 g) in 2-fenilhidrazonomalonildiklorida (1,53 g) prevzamemo v THF (15 ml) in nakapljamo v bučo, ki vsebuje THF (40 ml), vzdrževano pri 0° v atmosferi dušika. Po končanem dodajanju raztopino pustimo segreti na 23°, mešamo 45 minut, nato 1,5 ure segrevamo pri 60°. Raztopino razredčimo z etilacetatom (150 ml), izperemo s slanico (2 x 100 ml), posušimo in koncentriramo v vakuumu, da dobimo olje, ki ga čistimo s flash kromatografijo (ob eluiranju s CH-EA 95:5, naraščajoča polarnost do 80:20), da dobimo naslovno spojino kot rumeno trdno snov (1,85 g). T.l.c. CH-EA (1:1), Rf 0,66.Each of intermediate 28 (1.72 g) and 2-phenylhydrazonomalonyl dichloride (1.53 g) was taken up in THF (15 ml) and added to a flask containing THF (40 ml) maintained at 0 ° under a nitrogen atmosphere. After complete addition, the solution was allowed to warm to 23 °, stirred for 45 minutes, then heated to 60 ° C for 1.5 hours. The solution was diluted with ethyl acetate (150 ml), washed with brine (2 x 100 ml), dried and concentrated in vacuo to give an oil which was purified by flash chromatography (eluting with CH-EA 95: 5, increasing polarity to 80 : 20) to give the title compound as a yellow solid (1.85 g). T.l.c. CH-EA (1: 1), Rf 0.66.

Intermediat 30Intermediate 30

3-amino-7-8-dikloro-2,4-diokso-l-(3-metilbut-l-il)-5-fenil-2,3,4.5-tetrahidro26 lH-l,5-benzodiazepin3-amino-7-8-dichloro-2,4-dioxo-1- (3-methylbut-1-yl) -5-phenyl-2,3,4,5-tetrahydro26 1 H -1,5-benzodiazepine

K raztopini intermediata 29 (1,0 g) v ledoctu (15 ml) pri 0° dodamo po deležih cinkov prah (0,65 g). Zmes mešamo 6 ur pri 23°, nato dekantiramo od cinka, izperemo z etilacetatom (150 ml) in nato z 10 %-nim natrijevim hidroksidom (150 ml) in slanico (100 ml). Združene organske ekstrakte posušimo in koncentriramo v vakuumu, da dobimo olje, ki ga čistimo s flash kromatografijo (ob eluiranju v gradientu od CH-EA 1:1 do EA-metanola 80:20), da dobimo naslovno spojino (0,44 g). T.l.c. EA-metanol (27:3), Rf0,59.To a solution of Intermediate 29 (1.0 g) in glacial (15 ml) at 0 ° was added a portion of zinc powder (0.65 g). The mixture was stirred for 6 hours at 23 °, then decanted from zinc, washed with ethyl acetate (150 ml) and then with 10% sodium hydroxide (150 ml) and brine (100 ml). The combined organic extracts were dried and concentrated in vacuo to give an oil which was purified by flash chromatography (eluting in a gradient from CH-EA 1: 1 to EA-methanol 80:20) to give the title compound (0.44 g) . T.l.c. EA-methanol (27: 3), Rf 0.59.

Intermediat 31Intermediate 31

4-fluoro-2-nitrodifenilamin4-Fluoro-2-nitrodiphenylamine

Zmes 4-fluoro-2-nitroanilina (5,0 g), bromobenzena (20 ml), kalijevega karbonata (1,54 g) in bakrovega(I) jodida (0,61 g) segrevamo 30 ur na 150°. Reakcijsko zmes ohladimo pri 23°, nato dodamo etilacetat (200 ml); organske ekstrakte izperemo s slanico (100 ml), posušimo in uparimo v vakuumu, da dobimo surovo spojino, ki jo čistimo s flash kromatografijo (ob eluiranju s CH-EA 95:5), da dobimo naslovno spojino (2,4 g). T.l.c. CH-EA (1:1), Rf 0,68.A mixture of 4-fluoro-2-nitroaniline (5.0 g), bromobenzene (20 ml), potassium carbonate (1.54 g) and copper (I) iodide (0.61 g) was heated at 150 ° C for 30 hours. The reaction mixture was cooled to 23 °, then ethyl acetate (200 ml) was added; The organic extracts were washed with brine (100 ml), dried and evaporated in vacuo to give the crude compound, which was purified by flash chromatography (eluting with CH-EA 95: 5) to give the title compound (2.4 g). T.l.c. CH-EA (1: 1), Rf 0.68.

Intermediat 32Intermediate 32

2-amino-4-fluoro-difenilamin2-amino-4-fluoro-diphenylamine

Kalijev karbonat (9,3 g) in natrijev hidrosulfit (8,2 g) dodajamo 3 ure po deležih k suspenziji 4-fluoro-2-nitrodifenilamina (2,4 g) v 95 %-nem etanolu (70 ml) in vodi (70 ml). Zmes mešamo 20 ur pri 23°. Reakcijsko zmes nato nakisamo na pH 4 s koncentrirano klorovodikovo kislino (15 ml), nato dodajamo 10 %-no raztopino natrijevega hidroksida (50 ml) do pH 10 in koncentrirano raztopino ekstrahiramo z etilacetatom (2 x 100 ml). Združene organske ekstrakte izperemo s slanico (2 x 80 ml), posušimo in koncentriramo v vakuumu, da dobimo surovo spojino, ki jo čistimo s flash kromatografijo (ob eluiranju s CH-EA 90:10, nato 80:20), da dobimo naslovno spojino kot rumeno peno (1,44 g). T.l.c. CH-EA (1:1), Rf 0,72.Potassium carbonate (9.3 g) and sodium hydrosulfite (8.2 g) were added 3 hours in portions to a suspension of 4-fluoro-2-nitrodiphenylamine (2.4 g) in 95% ethanol (70 ml) and water ( 70 ml). The mixture was stirred at 23 ° for 20 hours. The reaction mixture was then acidified to pH 4 with concentrated hydrochloric acid (15 ml), then a 10% solution of sodium hydroxide (50 ml) was added to pH 10 and the concentrated solution was extracted with ethyl acetate (2 x 100 ml). The combined organic extracts were washed with brine (2 x 80 ml), dried and concentrated in vacuo to give the crude compound, which was purified by flash chromatography (eluting with CH-EA 90:10 then 80:20) to give the title compound as a yellow foam (1.44 g). T.l.c. CH-EA (1: 1), Rf 0.72.

Intermediat 33Intermediate 33

4-fluoro-2-(3-metilbut-l-il)amino-difenilamin l-bromo-3-metilbutan (1,0 ml) dodamo k raztopini intermediati 32 (1,44 g) in natrijevega jodida (1,1 g) v dimetilformamidu (60 ml) v atmosferi dušika. Raztopino mešamo 9 ur pri 120°; reakcijsko zmes razredčimo z etilacetatom (300 ml) in jo speremo s slanico (3 x 150 ml). Združene organske ekstrakte posušimo in koncentriramo v vakuumu, da dobimo olje, ki ga čistimo s flash kromatografijo (ob eluiranju s CH-EA 95:5), da dobimo naslovno spojino kot rumeno olje (0,96 g). T.l.c. CH-EA (1:1), Rf 0,74.4-Fluoro-2- (3-methylbut-1-yl) amino-diphenylamine 1-bromo-3-methylbutane (1.0 ml) was added to solution 32 (1.44 g) and sodium iodide (1.1 g) ) in dimethylformamide (60 ml) under a nitrogen atmosphere. The solution was stirred for 9 hours at 120 °; The reaction mixture was diluted with ethyl acetate (300 ml) and washed with brine (3 x 150 ml). The combined organic extracts were dried and concentrated in vacuo to give an oil which was purified by flash chromatography (eluting with CH-EA 95: 5) to give the title compound as a yellow oil (0.96 g). T.l.c. CH-EA (1: 1), Rf 0.74.

Intermediat 34Intermediate 34

2.4-diokso-8-fluoro-l-(3-metiIbut-l-il)-5-fenil-3-fenilhidrazono-2,3A5tetrahidro-lH-l,5-benzodiazepin2,4-dioxo-8-fluoro-1- (3-methylbut-1-yl) -5-phenyl-3-phenylhydrazono-2,3A5tetrahydro-1H-1,5-benzodiazepine

Vsakega izmed intermediata 33 (0,96 g) in 2-fenilhidrazonomalonildiklorida (1,01 g) prevzamemo v THF (15 ml) in nakapljamo v bučo, ki vsebuje THF (40 ml), vzdrževano pri 0° v atmosferi dušika. Po končanem dodajanju raztopino pustimo segreti pri 23°, mešamo 30 minut, nato segrevamo 2 uri pri 60°. Raztopino razredčimo z etilacetatom (120 ml), izperemo s slanico (2 x 100 ml), posušimo in koncentriramo v vakuumu, da dobimo olje, ki ga čistimo s flash kromatografijo (ob eluiranju s CH-EA 95:5, ob naraščanju polarnosti do 80:20), da dobimo naslovno spojino kot rumeno trdno snov (1,3 g). T.l.c. CH-EA (1:1), Rf 0,74.Each of intermediate 33 (0.96 g) and 2-phenylhydrazonomalonyl dichloride (1.01 g) was taken up in THF (15 ml) and added to a flask containing THF (40 ml) maintained at 0 ° under a nitrogen atmosphere. After complete addition, the solution was allowed to warm to 23 °, stirred for 30 minutes, then heated to 60 ° for 2 hours. The solution was diluted with ethyl acetate (120 ml), washed with brine (2 x 100 ml), dried and concentrated in vacuo to give an oil which was purified by flash chromatography (eluting with CH-EA 95: 5, increasing in polarity to 80:20) to give the title compound as a yellow solid (1.3 g). T.l.c. CH-EA (1: 1), Rf 0.74.

Intermediat 35Intermediate 35

3-amino-2,4-diokso-8-fluoro-l-(3-metilbut-l-il)-5-fenil-2,3,4,5-tetrahidrolH-l,5-benzodiazepin3-amino-2,4-dioxo-8-fluoro-1- (3-methylbut-1-yl) -5-phenyl-2,3,4,5-tetrahydrol-1,5-benzodiazepine

K raztopini intermediata 34 (1,3 g) v ledoctu (20 ml) pri 0° dodamo po deležih cinkov prah (1,2 g). Zmes mešamo 1 uro pri 23°, nato dekantiramo od cinka, izperemo z etilacetatom (150 ml), nato z 10 %-nim natrijevim hidroksidom (150 ml) in slanico (100 ml). Združene organske ekstrakte posušimo in koncentiramo v vakuumu, da dobimo olje, ki ga čistimo s flash kromatografijo (ob eluiranju v gradientu od CH-EA 1:1 do EA-metanola 80:20), da dobimo naslovno spojino (0,72 g). T.l.c. EA-metanol (27:3), Rf0,47.To a solution of Intermediate 34 (1.3 g) in ice (20 ml) at 0 ° was added a portion of zinc powder (1.2 g). The mixture was stirred at 23 ° for 1 hour, then decanted from zinc, washed with ethyl acetate (150 ml), then with 10% sodium hydroxide (150 ml) and brine (100 ml). The combined organic extracts were dried and concentrated in vacuo to give an oil which was purified by flash chromatography (eluting in a gradient from CH-EA 1: 1 to EA-methanol 80:20) to give the title compound (0.72 g) . T.l.c. EA-methanol (27: 3), Rf 0.47.

Intermediat 36Intermediate 36

2,4-diokso-5-fenil-l-(2-feniletil)-2,3,4,5-tetrahidro-lH-l,5-benzodiazepin2,4-dioxo-5-phenyl-1- (2-phenylethyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Natrijev hidrid (80 %-na disperzija v olju; 0,13 g) dodamo po deležih k raztopini 2,428 diokso-5-feniI-2,3,4,5-tetrahidro-lH-l,5-benzodiazepina (spojina a) (1 g) v DMF (18 ml), predhodno ohlajeni na 0°. Reakcijsko zmes mešamo 20 minut pri 0°, nato po kapljicah dodamo raztopino 2-feniletilbromida (0,85 ml) v DMF (2 ml), zmes mešamo 15 ur pri 23 °, nato razredčimo z EA (80 ml) in izperemo s slanico (3 x 100 ml), posušimo in koncentriramo v vakuumu. Surov produkt čistimo s flash kromatografijo (ob eluiranju s CH-EA 1:1), da dobimo naslovno spojino kot bel prah (0,85 g). T.l.c. CH-EA (1:1), Rf 0,27.Sodium hydride (80% dispersion in oil; 0.13 g) was added portionwise to a solution of 2,428 dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (compound a) ( 1 g) in DMF (18 ml), pre-cooled to 0 °. The reaction mixture was stirred at 0 ° for 20 minutes, then a solution of 2-phenylethyl bromide (0.85 ml) in DMF (2 ml) was added dropwise, the mixture was stirred at 23 ° for 15 hours, then diluted with EA (80 ml) and washed with brine. (3 x 100 ml), dried and concentrated in vacuo. The crude product was purified by flash chromatography (eluting with CH-EA 1: 1) to give the title compound as a white powder (0.85 g). T.l.c. CH-EA (1: 1), Rf 0.27.

Intermediat 37Intermediate 37

3-azido-2,4-diokso-5-fenil-l-(2-feniletil)-2,3,4,5-tetrahidro-lH-l,5-benzodiazepin3-Azido-2,4-dioxo-5-phenyl-1- (2-phenylethyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Raztopino intermediata 36 (0,85 g) v THF (20 ml), ohlajeno na -70°, dodamo po kapljicah raztopini kalijevega terc.butoksida (0,3 g) v THF (10 ml), ohlajeni na -70° v atmosferi dušika. Zmes mešamo 20 minut pri -70°, nato dodamo raztopino 2,4,6triizopropilbenzensulfonilazida (0,96 g) v THF (15 ml), predhodno ohlajeno na -70°, in ocetno kislino (0,14 ml). Reakcijsko zmes pustimo stati pri 23° in mešamo 1,5 ure, nato dodamo še ocetno kislino (0,14 ml) in zmes mešamo 2 uri. Dodamo etilacetat (150 ml) in raztopino izperemo z nasičeno raztopino natrijevega hidrogenkarbonata (100 ml) in slanico (3 x 100 ml), posušimo in koncentriramo v vakuumu. Surovi produkt čistimo s flash kromatografijo (ob eluiranju s CH-EA 90:10), da dobimo naslovno spojino kot belo peno (0,38 g). T.l.c. CH-EA (1:1), Rf 0,57.A solution of intermediate 36 (0.85 g) in THF (20 ml) cooled to -70 ° was added dropwise to a solution of potassium tert.butoxide (0.3 g) in THF (10 ml) cooled to -70 ° in the atmosphere nitrogen. The mixture was stirred at -70 ° for 20 minutes, then a solution of 2,4,6triisopropylbenzenesulfonylazide (0.96 g) in THF (15 ml), pre-cooled to -70 ° and acetic acid (0.14 ml) was added. The reaction mixture was allowed to stand at 23 ° and stirred for 1.5 hours, then acetic acid (0.14 ml) was added and the mixture stirred for 2 hours. Ethyl acetate (150 ml) was added and the solution was washed with saturated sodium bicarbonate solution (100 ml) and brine (3 x 100 ml), dried and concentrated in vacuo. The crude product was purified by flash chromatography (eluting with CH-EA 90:10) to give the title compound as a white foam (0.38 g). T.l.c. CH-EA (1: 1), Rf 0.57.

Intermediat 38Intermediate 38

3-amino-2,4-diokso-5-feni1-l-(2-feniletil)-2,3A5-tetrahidro-lH-l,5-benzodiazepin3-amino-2,4-dioxo-5-phenyl-1- (2-phenylethyl) -2,3A5-tetrahydro-1H-1,5-benzodiazepine

Raztopino intermediata 37 (0,38 g) v etanolu (15 ml) in etilacetatu (15 ml) mešamo pri 1 baru pod vodikom v prisotnosti 5 %-nega Pd/CACO₃ (0,25 g) 3 ure pri 23°. Katalizator odfiltriramo na blazinici celita, izperemo z diklorometanom (25 ml) in etanolom (25 ml) ter organski sloj koncentriramo v vakuumu. Surov produkt čistimo s flash kromatografijo (ob eluiranju s DCM-etanolom 90:10), da dobimo naslovno spojino kot belo peno (0,3 g). T.l.c. DCM-etanol (90:10), Rf 0,1.A solution of intermediate 37 (0.38 g) in ethanol (15 ml) and ethyl acetate (15 ml) was stirred at 1 bar under hydrogen in the presence of 5% Pd / CACO ₃ (0.25 g) for 3 hours at 23 °. The catalyst was filtered off on a pad of celite, washed with dichloromethane (25 ml) and ethanol (25 ml), and the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography (eluting with DCM-ethanol 90:10) to give the title compound as a white foam (0.3 g). Mp DCM-ethanol (90:10), Rf 0.1.

Intermediat 39 l-(l-adamantil)metil-2,4-diokso-5-fenil-2,3A5-tetrahidro-lH,l,5-benzodiazepmIntermediate 39 1- (1-adamantyl) methyl-2,4-dioxo-5-phenyl-2,3A5-tetrahydro-1H, 1,5-benzodiazepine

Natrijev hidrid (80 %-na disperzija v olju; 0,07 g) dodamo po deležih k raztopini spojine (a) (0,5 g) v DMF (50 ml). Reakcijsko zmes mešamo 30 minut, nato dodamo raztopino 1-adamantilmetilmetansulfonata (0,537 g) v DMF (3 ml). Reakcijsko zmes mešamo 7 ur pri 120° in 15 ur pri 23°, nato koncentriramo. Ostanek razredčimo z etilacetatom (100 ml), izperemo s slanico (2 x 30 ml) in vodo (50 ml), posušimo in koncentriramo v vakuumu. Surovi produkt čistimo s flash kromatografijo (ob eluiranju s CH-EA 1:1), da dobimo naslovno spojino kot belo peno (0,15 g). T.l.c. CH-EA (1:1), Rf 0,42.Sodium hydride (80% dispersion in oil; 0.07 g) was added portionwise to a solution of compound (a) (0.5 g) in DMF (50 ml). The reaction mixture was stirred for 30 minutes, then a solution of 1-adamantylmethylmethanesulfonate (0.537 g) in DMF (3 ml) was added. The reaction mixture was stirred for 7 hours at 120 ° and for 15 hours at 23 ° then concentrated. The residue was diluted with ethyl acetate (100 ml), washed with brine (2 x 30 ml) and water (50 ml), dried and concentrated in vacuo. The crude product was purified by flash chromatography (eluting with CH-EA 1: 1) to give the title compound as a white foam (0.15 g). T.l.c. CH-EA (1: 1), Rf 0.42.

Intermediat 40 l-(l-adamantiI)metil-l-(2-feniletil)-3-azido-2,4-diokso-5-fenil-2,3A5-tetrahidrolH-l,5-benzodiazepinIntermediate 40 1- (1-adamantyl) methyl-1- (2-phenylethyl) -3-azido-2,4-dioxo-5-phenyl-2,3A5-tetrahydrol-1,5-benzodiazepine

Raztopino kalijevega terc.butoksida (0,146 g) v THF (7 ml) dodamo po kapljicah k raztopini intermediata 39 (0,4 g) v THF (15 ml), ohlajeni na -70° v atmosferi dušika. Zmes mešamo 20 minut pri -70°C, nato dodamo raztopino 2,4,6-triizopropil- benzensulfonilazida (0,53 g) v THF (7 ml), predhodno ohlajeno na -70°, in ocetno kislino (0,14 ml). Reakcijsko zmes pustimo stati pri 23° in mešamo 15 ur, nato dodamo etilacetat (70 ml) in raztopino izperemo z vodo (2 x 50 ml) in slanico (2 x 30 ml), sušimo in koncentriramo v vakuumu. Surov produkt čistimo s flash kromatografijo (ob eluiranju s CH-EA 70:30), da dobimo naslovno spojino kot belo peno (0,338 g). T.l.c. CH-EA (1:1), Rf0,73.A solution of potassium tert-butoxide (0.146 g) in THF (7 ml) was added dropwise to a solution of intermediate 39 (0.4 g) in THF (15 ml) cooled to -70 ° under a nitrogen atmosphere. The mixture was stirred for 20 minutes at -70 ° C, then a solution of 2,4,6-triisopropyl-benzenesulfonyl azide (0.53 g) in THF (7 ml), pre-cooled to -70 ° and acetic acid (0.14 ml) was added. ). The reaction mixture was allowed to stand at 23 ° and stirred for 15 hours, then ethyl acetate (70 ml) was added and the solution was washed with water (2 x 50 ml) and brine (2 x 30 ml), dried and concentrated in vacuo. The crude product was purified by flash chromatography (eluting with CH-EA 70:30) to give the title compound as a white foam (0.338 g). T.l.c. CH-EA (1: 1), Rf 0.73.

Intermediat 41 l-(l-adamantil)metil-3-amino-2,4-diokso-5-fenil-2,3,4,5-tetrahidro-lH-l,5benzodiazepinIntermediate 41 1- (1-adamantyl) methyl-3-amino-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Raztopino intermediata 40 (0,18 g) v etanolu (10 ml) in etilacetata (5 ml) mešamo pri 1 baru pod vodikom v prisotnosti 5 %-nega Pd/CaCO₃ (0,2 g) 3 ure pri 23°, nato katalizator odfiltriramo na blazinici celita in organski sloj koncentriramo v vakuumu. Surov produkt čistimo s flash kromatografijo (ob eluiranju z DCM-metanolom 90:1)), da dobimo naslovno spojino kot belo peno (0,15 g). T.l.c. DCM-metanol (90:10), Rf 0,51.A solution of intermediate 40 (0.18 g) in ethanol (10 ml) and ethyl acetate (5 ml) was stirred at 1 bar under hydrogen in the presence of 5% Pd / CaCO ₃ (0.2 g) for 3 hours at 23 °, then the catalyst was filtered off on a pad of celite and the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography (eluting with DCM-methanol 90: 1) to give the title compound as a white foam (0.15 g). Tlc DCM-methanol (90:10), Rf 0.51.

Intermediat 42 l-(2,2-dimetiletoksikarbonilmetil)-2,4-diokso-5-fenil-2,3,4,5-tetrahidro-lH1,5-benzodiazepinIntermediate 42 1- (2,2-dimethylethoxycarbonylmethyl) -2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H1,5-benzodiazepine

Natrijev hidrid (80 %-na disperzija v olju; 0,155 g) dodamo po deležih k raztopini spojine (a) (1,022 g) v DMF (30 ml), predhodno ohlajeni na 0°. Reakcijsko zmes mešamo 15 minut pri 23°, nato dodamo t-butilbromoacetat (0,7 ml). Raztopino mešamo 1 uro pri 23°, nato dodamo slanico (100 ml), zmes ekstrahiramo z etilacetatom (3 x 30 ml), posušimo in koncentriramo v vakuumu. Surov produkt čistimo s flash kromatografijo (ob eluiranju s CH-EA 60:40), da dobimo naslovno spojino kot bel prah (1,31 g). T.l.c. CH-EA (60:40), Rf 0,4.Sodium hydride (80% dispersion in oil; 0.155 g) was added portionwise to a solution of compound (a) (1.022 g) in DMF (30 ml), pre-cooled to 0 °. The reaction mixture was stirred at 23 ° for 15 minutes, then t-butyl bromoacetate (0.7 ml) was added. The solution was stirred at 23 ° for 1 hour, then brine (100 ml) was added, the mixture was extracted with ethyl acetate (3 x 30 ml), dried and concentrated in vacuo. The crude product was purified by flash chromatography (eluting with CH-EA 60:40) to give the title compound as a white powder (1.31 g). T.l.c. CH-EA (60:40), Rf 0.4.

Intermediat 43Intermediate 43

3-azido-l-(2,2-dimetiletoksikarbonilmetil)-2,4-diokso-5-fenil-2,3A5-tetrahidrolH-l,5-benzodiazepin3-Azido-1- (2,2-dimethylethoxycarbonylmethyl) -2,4-dioxo-5-phenyl-2,3A5-tetrahydrol-1,5,5-benzodiazepine

Raztopino intermediata 42 (0,5 g) v THF (6 ml), ohlajeno na -70°, dodamo po kapljicah k raztopini kalijevega terc.butoksida (0,168 g) v THF (6 ml), ohlajeni na -70° v atmosferi dušika. Reakcijsko zmes mešamo 30 minut pri -70°, nato dodamo raztopino 2,4,6-triizopropilbenzensulfonilazida (0,556 g) v THF (6 ml), predhodno ohlajeno na -70°, in ocetno kislino (0,078 ml). Reakcijsko zmes pustimo stati pri 23° in mešamo 18 ur, dodamo etilacetat (30 ml) in raztopino izperemo s slanico (3 x 100 ml), nasičeno raztopino natrijevega hidrogenkarbonata (20 ml), slanico (20 ml), posušimo in koncentriramo v vakuumu. Surov produkt čistimo s flash kromatografijo (ob eluiranju s CH-EA 70:30), da dobimo naslovno spojino kot belo peno (0,5 g). T.l.c. CH-EA (1:1), Rf0,36.A solution of intermediate 42 (0.5 g) in THF (6 ml) cooled to -70 ° was added dropwise to a solution of potassium tert.butoxide (0.168 g) in THF (6 ml) cooled to -70 ° under a nitrogen atmosphere . The reaction mixture was stirred for 30 minutes at -70 °, then a solution of 2,4,6-triisopropylbenzenesulfonylazide (0.556 g) in THF (6 ml), pre-cooled to -70 ° and acetic acid (0.078 ml) was added. The reaction mixture was allowed to stand at 23 ° and stirred for 18 hours, ethyl acetate (30 ml) was added and the solution was washed with brine (3 x 100 ml), saturated sodium hydrogen carbonate solution (20 ml), brine (20 ml), dried and concentrated in vacuo . The crude product was purified by flash chromatography (eluting with CH-EA 70:30) to give the title compound as a white foam (0.5 g). T.l.c. CH-EA (1: 1), Rf 0.36.

Intermediat 44Intermediate 44

3-amino-l-(2,2-dimetiletoksikarbonilmetil)-2,4-diokso-5-fenil-2,3,4,5-tetrahidrolH-l,5-benzodiazepin3-amino-1- (2,2-dimethylethoxycarbonylmethyl) -2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrol-1,5,5-benzodiazepine

Raztopino intermediata 43 (0,354 g) v zmesi etanola (10 ml) in etilacetata (2 ml) mešamo pod vodikom pri 1 baru v prisotnosti 5 %-nega Pd/CaCO₃ (0,183 g) pri 23° 3 ure, nato dodamo še 5 %-ni Pd/CaCO₃ (0,183 g) in reakcijsko zmes mešamo 15 ur. Katalizator odfiltriramo na blazinici celita, izperemo z diklorometanom (9 ml), metanolom (5 ml) in organski sloj koncentriramo v vakuumu. Surov produkt čistimo s flash kromatografijo (ob eluiranju z DCM-metanolom 96:4), da dobimo naslovno spojino kot belo peno (0,33 g). T.l.c. DCM-metanol (95:5), Rf 0,5.A solution of intermediate 43 (0.354 g) in a mixture of ethanol (10 ml) and ethyl acetate (2 ml) was stirred under hydrogen at 1 bar in the presence of 5% Pd / CaCO ₃ (0.183 g) at 23 ° for 3 hours, then 5 more were added. % Pd / CaCO ₃ (0.183 g) and the reaction mixture was stirred for 15 hours. The catalyst was filtered off on a pad of celite, washed with dichloromethane (9 ml), methanol (5 ml) and the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography (eluting with DCM-methanol 96: 4) to give the title compound as a white foam (0.33 g). Mp DCM-methanol (95: 5), Rf 0.5.

Intermediat 45 l-(3,3-dimetilbutil)-2,4-diokso-5-fenil-2,3A5-tetrahidro-lH-l,5-benzodiazepinIntermediate 45 1- (3,3-dimethylbutyl) -2,4-dioxo-5-phenyl-2,3A5-tetrahydro-1H-1,5-benzodiazepine

Natrijev hidrid (80 %-na disperzija v olju; 0,100 g) dodamo po deležih k raztopini spojine (a) (0,7 g) v DMF (60 ml). Reakcijsko zmes mešamo 30 minut, nato dodamo raztopino 3,3-dimetilbutilmetansulfonata (0,575 g) v DMF (3 ml). Reakcijo zmes mešamo 50 minut pri 90°, 15 ur pri 23°, 2 uri pri 90° in 45 minut pri 140°, nato koncentriramo. Ostanek razredčimo z vodo (30 ml) in slanico (20 ml) ter ekstrahiramo z etilacetatom (150 ml); organski sloj izperemo z vodo (2 x 50 ml) in slanico (50 ml), posušimo in koncentriramo v vakuumu. Surov produkt čistimo s flash kromatografijo (ob eluiranju s CH-EA 1:1), da dobimo naslovno spojino kot belo peno (0,4 g). T.l.c. CH-EA (1:1), Rf 0,39.Sodium hydride (80% dispersion in oil; 0.100 g) was added portionwise to a solution of compound (a) (0.7 g) in DMF (60 ml). The reaction mixture was stirred for 30 minutes, then a solution of 3,3-dimethylbutylmethanesulfonate (0.575 g) in DMF (3 ml) was added. The reaction mixture was stirred for 50 minutes at 90 °, 15 hours at 23 °, 2 hours at 90 ° and 45 minutes at 140 °, then concentrated. The residue was diluted with water (30 ml) and brine (20 ml) and extracted with ethyl acetate (150 ml); The organic layer was washed with water (2 x 50 ml) and brine (50 ml), dried and concentrated in vacuo. The crude product was purified by flash chromatography (eluting with CH-EA 1: 1) to give the title compound as a white foam (0.4 g). T.l.c. CH-EA (1: 1), Rf 0.39.

Intermediat 46Intermediate 46

3-azido-l-(3,3-dimetilbutil)-2,4-diokso-5-fenil-2,3,4,5-tetrahidro-lH-l,5benzodiazepin3-Azido-1- (3,3-dimethylbutyl) -2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Raztopino kalijevega terc.butoksida (0,146 g) v THF (7 ml), ohlajeno na na -70°, dodamo po kapljicah k raztopini intermediata 45 (0,4 g) v THF (15 ml), ohlajeni na -70° v atmosferi dušika. Raztopino mešamo 20 minut pri -70°, nato dodamo raztopino 2,4,6-triizopropilbenzensulfonilazida (0,530 g) v THF (7 ml), predhodno ohlajeno na -70°, in ocetno kislino (0,139 ml). Reakcijsko zmes pustimo stati pri 23° in mešamo 18 ur, nato dodamo etilacetat (75 ml) ter raztopino izperemo z vodo (2 x 50 ml) in slanico (2 x 30 ml), posušimo in koncentriramo v vakuumu. Surov produkt čistimo s flash kromatografijo (ob eluiranju s CH-EA 30:70), da dobimo naslovno spojino kot belo peno (0,338 g). T.l.c. CH-EA (1:1), Rf 0,73.A solution of potassium tert-butoxide (0.146 g) in THF (7 ml) cooled to -70 ° was added dropwise to a solution of intermediate 45 (0.4 g) in THF (15 ml) cooled to -70 ° in the atmosphere nitrogen. The solution was stirred at -70 ° for 20 minutes, then a solution of 2,4,6-triisopropylbenzenesulfonyl azide (0.530 g) in THF (7 ml), pre-cooled to -70 ° and acetic acid (0.139 ml) was added. The reaction mixture was allowed to stand at 23 ° and stirred for 18 hours, then ethyl acetate (75 ml) was added and the solution was washed with water (2 x 50 ml) and brine (2 x 30 ml), dried and concentrated in vacuo. The crude product was purified by flash chromatography (eluting with CH-EA 30:70) to give the title compound as a white foam (0.338 g). T.l.c. CH-EA (1: 1), Rf 0.73.

Intermediat 47Intermediate 47

3-amino-l-(3,3-dimetilbutil)-2,4-diokso-5-fenil-2,3,4,5-tetrahidro-lH-l,5benzodiazepin3-amino-1- (3,3-dimethylbutyl) -2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Raztopino intermediata 46 (0,298 g) v zmesi etanola (18 ml) in etilacetata (7 ml) mešamo pod vodikom pri 1 baru v prisotnosti 5 %-nega Pd/CaCO₃ (0,186 g) 1,5 ure pri 23°, nato dodamo še 5 %-ni Pd/CaCO₃ (0,180 g) in reakcijsko zmes mešamo 1 uro. Katalizator odfiltriramo na blazinici celita, izperemo z etanolom (20 ml) in organski sloj koncentriramo v vakuumu. Surov produkt čistimo s flash kromatografijo (ob eluiranju z DCM-metanolom 90:10), da dobimo naslovno spojino kot belo peno (0,205 g). T.l.c. DCM-metanol (90:10), Rf 0,46.A solution of intermediate 46 (0.298 g) in a mixture of ethanol (18 ml) and ethyl acetate (7 ml) was stirred under hydrogen at 1 bar in the presence of 5% Pd / CaCO ₃ (0.186 g) for 1.5 hours at 23 °, then added another 5% Pd / CaCO ₃ (0.180 g) and the reaction mixture was stirred for 1 hour. The catalyst was filtered off on a pad of celite, washed with ethanol (20 ml) and the organic layer concentrated in vacuo. The crude product was purified by flash chromatography (eluting with DCM-methanol 90:10) to give the title compound as a white foam (0.205 g). Tlc DCM-methanol (90:10), Rf 0.46.

Intermediat 48Intermediate 48

1-(3,3-dimetilbutil)-2,4-diokso-3-izocianato-5-fenil-2,3,4,5-tetrahidro-lH1,5-benzodiazepin1- (3,3-dimethylbutyl) -2,4-dioxo-3-isocyanato-5-phenyl-2,3,4,5-tetrahydro-1H, 1,5-benzodiazepine

K raztopini intermediata 47 (0,3 g) v diklorometanu (20 ml) dodamo 1,93 M raztopino COC1₂ v toluenu (10 ml). Reakcijsko zmes mešamo 5 ur pri 23°, nato koncentriramo v vakuumu 3 ure pri 50°, da dobimo naslovno spojino kot belo peno (0,370 g). IR: 2218 (N=C=O); 1693,1668 (C=O), (C=C) cm-1.To a solution of intermediate 47 (0.3 g) in dichloromethane (20 ml) was added a 1.93 M solution of COC1 ₂ in toluene (10 ml). The reaction mixture was stirred for 5 hours at 23 °, then concentrated in vacuo for 3 hours at 50 ° to give the title compound as a white foam (0.370 g). IR: 2218 (N = C = O); 1693.1668 (C = O), (C = C) cm -1.

Intermediat 49 l-(3,3-dimetilbutil)-2,4-diokso-5-fenil-3-feniloksikarbonilamino-2,3,4,5-tetrahidrolH-l,5-benzodiazepinIntermediate 49 1- (3,3-dimethylbutyl) -2,4-dioxo-5-phenyl-3-phenyloxycarbonylamino-2,3,4,5-tetrahydrolH-1,5-benzodiazepine

K raztopini intermediata 47 (1 g) v diklorometanu (50 ml) dodamo piridin (0,46 ml) in fenilkloroformat (0,7 ml). Reakcijsko zmes mešamo 30 minut pri 23°, nato izperemo z 1 %-no raztopino klorovodikove kisline (20 ml), 5 %-no raztopino natrijevega hidrogenkarbonata (20 ml), vodo (20 ml), slanico (20 ml), posušimo in koncentriramo v vakuumu. Surov produkt trituriramo z acetonitrilom (10 ml), da dobimo naslovno spojino kot bel prašek (1,2 g). T.l.c. CH-EA (1:1), Rf 0,8.To a solution of intermediate 47 (1 g) in dichloromethane (50 ml) was added pyridine (0.46 ml) and phenylchloroformate (0.7 ml). The reaction mixture was stirred for 30 minutes at 23 °, then washed with 1% hydrochloric acid solution (20 ml), 5% sodium hydrogen carbonate solution (20 ml), water (20 ml), brine (20 ml), dried and concentrated in vacuo. The crude product was triturated with acetonitrile (10 ml) to give the title compound as a white powder (1.2 g). T.l.c. CH-EA (1: 1), Rf 0.8.

Intermediat 50 l-[2-(l-adamantil)etill-2,4-diokso-5-fenil-3-feniloksikarbonilamino-2,3,4,5tetrahidro-lH-l,5-benzodiazepinIntermediate 50 1- [2- (1-adamantyl) ethyl-2,4-dioxo-5-phenyl-3-phenyloxycarbonylamino-2,3,4,5tetrahydro-1H-1,5-benzodiazepine

K raztopini intermediata 53 (0,1 g) v diklorometanu (10 ml) dodamo piridin (0,03 ml) in fenilkloroformat (0,01 ml). Reakcijsko zmes mešamo 2 uri pri 23°, nato razredčimo z diklorometanom (30 ml), izperemo z nasičeno raztopino amonijevega klorida (30 ml) in slanico (40 ml), posušimo in koncentriramo v vakuumu. Surov produkt trituriramo z acetonitrilom (10 ml), da dobimo naslovno spojino kot bel prah (0,05 g). T.l.c. CH-EA (1:1), Rf 0,77.To a solution of intermediate 53 (0.1 g) in dichloromethane (10 ml) was added pyridine (0.03 ml) and phenylchloroformate (0.01 ml). The reaction mixture was stirred for 2 hours at 23 °, then diluted with dichloromethane (30 ml), washed with saturated ammonium chloride solution (30 ml) and brine (40 ml), dried and concentrated in vacuo. The crude product was triturated with acetonitrile (10 ml) to give the title compound as a white powder (0.05 g). T.l.c. CH-EA (1: 1), Rf 0.77.

Intermediat 51 l-12-(l-adamantil)etil1-2,4-diokso-5-fenil-2,3,4,5-tetrahidro-lH-1.5benzodiazepinIntermediate 51 1- 12- (1-adamantyl) ethyl1-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1.5benzodiazepine

Natrijev hidrid (80 %-na disperzija v olju; 0,15 g) dodamo po deležih k raztopini spojine (a) (0,8 g) v DMF (20 ml), predhodno ohlajeni na 0°. Reakcijsko zmes mešamo 15 minut pri 0°, po kapljicah dodamo raztopino 2-(l-adamantil)etilbromida (0,8 g) v DMF (10 ml), zmes mešamo 8 ur pri 23°, nato razredčimo z DMF (20 ml), segrevamo 1 uro pri 80° in pustimo stati 2 dni pri 23°. Dodamo etilacetat (200 ml) in raztopino izperemo s slanico (3 x 100 ml), posušimo in koncentriramo v vakuumu. Surov produkt čistimo s flash kromatografijo (ob eluiranju s CH-EA 70:30), da dobimo naslovno spojino kot belo peno (0,45 g). T.l.c. CH-EA (1:1), Rf 0,42.Sodium hydride (80% dispersion in oil; 0.15 g) was added portionwise to a solution of compound (a) (0.8 g) in DMF (20 ml), pre-cooled to 0 °. The reaction mixture was stirred at 0 ° for 15 minutes, a solution of 2- (1-adamantyl) ethyl bromide (0.8 g) in DMF (10 ml) was added dropwise, the mixture was stirred at 23 ° for 8 hours, then diluted with DMF (20 ml). , heated at 80 ° for 1 hour and allowed to stand at 23 ° for 2 days. Ethyl acetate (200 ml) was added and the solution was washed with brine (3 x 100 ml), dried and concentrated in vacuo. The crude product was purified by flash chromatography (eluting with CH-EA 70:30) to give the title compound as a white foam (0.45 g). T.l.c. CH-EA (1: 1), Rf 0.42.

Intermediat 52 l-[2-(l-adamantil)etil]-3-azido-2,4-diokso-5-fenil-2,3A5-tetrahidro-lH-l,5benzodiazepinIntermediate 52 1- [2- (1-adamantyl) ethyl] -3-azido-2,4-dioxo-5-phenyl-2,3A5-tetrahydro-1H-1,5-benzodiazepine

Raztopino kalijevega terc.butoksida (0,2 g) v THF (10 ml) dodamo po kapljicah k raztopini intermediata 51 (0,67 g) v THF (20 ml), ohlajeni na -70°, v atmosferi dušika. Zmes mešamo 20 minut pri -70°, nato dodamo raztopino 2,4,6-triizopropilbenzensulfonilazida (0,65 g) v THF (10 ml), predhodno ohlajeno na -70°, in ocetno kislino (0,18 ml). Reakcijsko zmes pustimo stati pri 23° in mešamo 15 ur, nato dodamo EA (150 ml) ter raztopino izperemo s 5 %-no raztopino natrijevega hidrogenkarbonata (80 ml) in slanico (100 ml), posušimo in koncentriramo v vakuumu. Surov produkt čistimo s flash kromatografijo (ob eluiranju s CH-EA 90:10), da dobimo naslovno spojino kot belo peno (0,71 g). T.l.c CH-EA (1:1), Rf 0,68.A solution of potassium tert-butoxide (0.2 g) in THF (10 ml) was added dropwise to a solution of intermediate 51 (0.67 g) in THF (20 ml) cooled to -70 ° under a nitrogen atmosphere. The mixture was stirred at -70 ° for 20 minutes, then a solution of 2,4,6-triisopropylbenzenesulfonylazide (0.65 g) in THF (10 ml), pre-cooled to -70 ° and acetic acid (0.18 ml) was added. The reaction mixture was allowed to stand at 23 ° and stirred for 15 hours, then EA (150 ml) was added and the solution was washed with 5% sodium hydrogen carbonate solution (80 ml) and brine (100 ml), dried and concentrated in vacuo. The crude product was purified by flash chromatography (eluting with CH-EA 90:10) to give the title compound as a white foam (0.71 g). Mp CH-EA (1: 1), Rf 0.68.

Intermediat 53 l-[2-(l-adamantil)etil]-3-amino-2,4-diokso-5-fenil-2,3.4.5-tetrahidro-lH-1.5benzodiazepinIntermediate 53 1- [2- (1-adamantyl) ethyl] -3-amino-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1.5benzodiazepine

Raztopino intermediata 52 (0,71 g) v etanolu (30 ml) in etilacetatu (15 ml) mešamo pri 1 baru pod vodikom v prisotnosti 5 %-nega Pd/CaCO₃ (0,7 g) 3 ure pri 23°. Katalizator odfiltriramo na blazinici celita, izperemo z metanolom (50 ml) in organski sloj koncentriramo v vakuumu. Surov produkt čistimo s flash kromatografijo (ob eluiranju z DCM-metanolom 90:10), da dobimo naslovno spojino kot belo peno (0,5 g). T.l.c. DCM-metanol (90:10), Rf 0,62.A solution of intermediate 52 (0.71 g) in ethanol (30 ml) and ethyl acetate (15 ml) was stirred at 1 bar under hydrogen in the presence of 5% Pd / CaCO ₃ (0.7 g) for 3 hours at 23 °. The catalyst was filtered off on a pad of celite, washed with methanol (50 ml) and the organic layer concentrated in vacuo. The crude product was purified by flash chromatography (eluting with DCM-methanol 90:10) to give the title compound as a white foam (0.5 g). Mp DCM-methanol (90:10), Rf 0.62.

Intermediat 54 l-(2,3-dimetil)butil-2,4-diokso-5-fenil-2,3A5-tetrahidro-lH-l,5-benzodiazepinIntermediate 54 1- (2,3-dimethyl) butyl-2,4-dioxo-5-phenyl-2,3A5-tetrahydro-1H-1,5-benzodiazepine

Natrijev hidrid (80 %-na disperzija v olju; 0,06 g) dodamo po deležih k raztopini spojine (a) (0,38 g) v DMF (10 ml). Reakcijsko zmes mešamo 1 uro pri 23°, nato dodamo 2,3-dimetilbutilmetansulfonat (0,32 g). Zmes mešamo 15 ur pri 23°, nato dodamo vodo (70 ml), raztopino ekstrahiramo z etilacetatom (2 x 50 ml) ter združeni organski sloj izperemo s slanico (2 x 50 ml), posušimo in koncentriramo v vakuumu. Surovi produkt čistimo s flash kromatografijo (ob eluiranju s CH-EA 80:20), da dobimo naslovno spojino kot belo peno (0,23 g). T.l.c. CH-EA (1:1), Rf 0,4.Sodium hydride (80% dispersion in oil; 0.06 g) was added portionwise to a solution of compound (a) (0.38 g) in DMF (10 ml). The reaction mixture was stirred for 1 hour at 23 °, then 2,3-dimethylbutylmethanesulfonate (0.32 g) was added. The mixture was stirred at 23 ° C for 15 hours, then water (70 ml) was added, the solution was extracted with ethyl acetate (2 x 50 ml) and the combined organic layer was washed with brine (2 x 50 ml), dried and concentrated in vacuo. The crude product was purified by flash chromatography (eluting with CH-EA 80:20) to give the title compound as a white foam (0.23 g). T.l.c. CH-EA (1: 1), Rf 0.4.

Intermediat 55Intermediate 55

3-azido-l-(2,3-dimetilbutil)-2,4-diokso-5-fenil-2.3.4,5-tetrahidro-lH-l,5benzodiazepin3-Azido-1- (2,3-dimethylbutyl) -2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Raztopino kalijevega terc.butoksida (0,121 g) v THF (10 ml) dodamo k raztopni intermediata 54 (0,33 g) v THF (20 ml), ohlajeni na -70°, v atmosferi dušika. Zmes mešamo 30 minut pri -70°, nato dodamo raztopino 2,4,6-triizopropilbenzensulfonilazida (0,349 g) v THF (10 ml), predhodno ohlajeno na -70°, in po 20 minutah ocetno kislino (0,06 ml). Reakcijsko zmes pustimo stati pri 23° in mešamo 24 ur, dodamo etilacetat (50 ml) in raztopino izperemo s 5 %-no raztopino natrijevega hidrogenkarbonata (2 x 50 ml) in slanico (2 x 50 ml), posušimo in koncentriramo v vakuumu. Surov produkt čistimo s flash kromatografijo (ob eluiranju s CH-EA 80:20), da dobimo naslovno spojino kot belo peno (0,1 g). T.l.c. CH-EA (1:1), Rf 0,53.A solution of potassium tert-butoxide (0.121 g) in THF (10 ml) was added to a solution of intermediate 54 (0.33 g) in THF (20 ml) cooled to -70 ° under a nitrogen atmosphere. The mixture was stirred for 30 minutes at -70 °, then a solution of 2,4,6-triisopropylbenzenesulfonyl azide (0.349 g) in THF (10 ml), pre-cooled to -70 °, and acetic acid (0.06 ml) were added after 20 minutes. The reaction mixture was allowed to stand at 23 ° and stirred for 24 hours, ethyl acetate (50 ml) was added and the solution was washed with 5% sodium hydrogen carbonate solution (2 x 50 ml) and brine (2 x 50 ml), dried and concentrated in vacuo. The crude product was purified by flash chromatography (eluting with CH-EA 80:20) to give the title compound as a white foam (0.1 g). T.l.c. CH-EA (1: 1), Rf 0.53.

Intermediat 56Intermediate 56

3-amino-l-(2,3-dimetilbutil)-2,4-diokso-5-fenil-2.3,4,5-tetrahidro-lH-l,5benzodiazepin3-amino-1- (2,3-dimethylbutyl) -2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Raztopino intermediata 55 (0,19 g) v etanolu (15 ml) in etilacetatu (3 ml) mešamo pod dušikom pri 1 baru v prisotnosti 5 %-nega Pd/CaCO₃ (0,18 g) 4 ure pri 23°. Katalizator odfiltriramo na blazinici celita, izperemo z etilacetatom in organski sloj koncentriramo v vakuumu. Surov produkt čistimo s flash kromatografijo (ob eluiranju z EA-metanolom 90:10), da dobimo naslovno spojino kot belo peno (0,95 g). T.l.c. EA-metanol (90:10), Rf 0,55.A solution of intermediate 55 (0.19 g) in ethanol (15 ml) and ethyl acetate (3 ml) was stirred under nitrogen at 1 bar in the presence of 5% Pd / CaCO ₃ (0.18 g) for 23 hours at 23 °. The catalyst was filtered off on a pad of celite, washed with ethyl acetate, and the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography (eluting with EA-methanol 90:10) to give the title compound as a white foam (0.95 g). Tlc EA-methanol (90:10), Rf 0.55.

Intermediat 57 l-butil-2,4-diokso-5-fenil-2,3,4,5-tetrahidro-lH-l,5-benzodiazepinIntermediate 57 1-Butyl-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Natrijev hidrid (80 %-na disperzija v olju; 0,031 g) dodamo po deležih k raztopini spojine (a) (0,3 g) v DMF (18 ml) pri 0° v atmosferi dušika. Reakcijsko zmes pustimo stati 30 minut pri 23°, nato po kapljicah dodamo raztopino 1-bromobutana (0,154 ml) v DMF (3 ml). Zmes mešamo 2 uri pri 23°, nato dodamo vodo (30 ml) in raztopino ekstrahiramo z etilacetatom (2 x 60 ml), združeni organski sloj posušimo in koncentriramo v vakuumu. Surov produkt čistimo s flash kromatografijo (ob eluiranju s CH-EA 60:40), da dobimo naslovno spojino kot belo peno (0,057 g). T.l.c. CH-EA (70:30), Rf0,53.Sodium hydride (80% dispersion in oil; 0.031 g) was added portionwise to a solution of compound (a) (0.3 g) in DMF (18 ml) at 0 ° under a nitrogen atmosphere. The reaction mixture was allowed to stand at 23 ° for 30 minutes, then a solution of 1-bromobutane (0.154 ml) in DMF (3 ml) was added dropwise. The mixture was stirred at 23 ° for 2 hours, then water (30 ml) was added and the solution was extracted with ethyl acetate (2 x 60 ml), the combined organic layer was dried and concentrated in vacuo. The crude product was purified by flash chromatography (eluting with CH-EA 60:40) to give the title compound as a white foam (0.057 g). T.l.c. CH-EA (70:30), Rf0.53.

Intermediat 58Intermediate 58

3-azido-l-butil-2,4-diokso-5-fenil-2,3,4,5-tetrahidro-lH-l,5-benzodiazepin3-Azido-1-butyl-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Raztopino kalijevega terc.butoksida (0,0418 g) v THF (2 ml) dodamo k raztopini intermediata 57 (0,104 g) v THF (2 ml), ohlajeni na -70°, v atmosferi dušika. Zmes mešamo 30 minut pri -70°, nato dodamo raztopino 2,4,6-triizopropilbenzensulfonilazida (0,136 g) v THF (10 ml), predhodno ohlajeno na -70°, in ocetno kislino (0,019 ml). Reakcijsko zmes pustimo stati pri 23° in mešamo 24 ur, dodamo etilacetat (50 ml) ter raztopino izperemo s 5 %-no raztopino natrijevega hidrogenkarbonata (10 ml), slanico (10 ml), posušimo in koncentriramo v vakuumu. Surovi produkt čistimo s flash kromatografijo (ob eluiranju s CH-EA 80:20), da dobimo naslovno spojino kot belo peno (0,043 g). T.l.c. CH-EA (60:40), Rf 0,67.A solution of potassium tert-butoxide (0.0418 g) in THF (2 ml) was added to a solution of intermediate 57 (0.104 g) in THF (2 ml) cooled to -70 ° under a nitrogen atmosphere. The mixture was stirred for 30 minutes at -70 °, then a solution of 2,4,6-triisopropylbenzenesulfonyl azide (0.136 g) in THF (10 ml), pre-cooled to -70 ° and acetic acid (0.019 ml) was added. The reaction mixture was allowed to stand at 23 ° and stirred for 24 hours, ethyl acetate (50 ml) was added and the solution was washed with 5% sodium hydrogen carbonate solution (10 ml), brine (10 ml), dried and concentrated in vacuo. The crude product was purified by flash chromatography (eluting with CH-EA 80:20) to give the title compound as a white foam (0.043 g). T.l.c. CH-EA (60:40), Rf 0.67.

Intermediat 59Intermediate 59

3-amino-l-butil-2,4-diokso-5-fenil-2.3.4,5-tetrahidro-lH-l,5-benzodiazepin3-amino-1-butyl-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Raztopino intermediata 58 (0,217 g) v etanolu (4 ml) in etilacetatu (10 ml) mešamo pri 1 baru pod vodikom v prisotnosti 5 %-nega Pd/CaCO₃ (0,18 g) 10 ur pri 23°. Katalizator odfiltriramo na blazinici celita, izperemo z etilacetatom (3x5 ml) in etanolom (3x5 ml) ter organski sloj koncentriramo v vakuumu. Surov produkt čistimo s flash kromatografijo (ob eluiranju z EA-metanolom 90:10), da dobimo naslovno spojino kot belo peno (0,094 g). T.l.c. EA-metanol (95:5), Rf 0,25.A solution of intermediate 58 (0.217 g) in ethanol (4 ml) and ethyl acetate (10 ml) was stirred at 1 bar under hydrogen in the presence of 5% Pd / CaCO ₃ (0.18 g) for 10 hours at 23 °. The catalyst was filtered off on a pad of celite, washed with ethyl acetate (3x5 ml) and ethanol (3x5 ml) and the organic layer concentrated in vacuo. The crude product was purified by flash chromatography (eluting with EA-methanol 90:10) to give the title compound as a white foam (0.094 g). Tlc EA-methanol (95: 5), Rf 0.25.

Intermediat 60Intermediate 60

2.4-diokso-5-fenil-l-(3-metil-2-okso)butil-2,3,4,5-tetrahidro-lH-l,5benzodiazepin2,4-dioxo-5-phenyl-1- (3-methyl-2-oxo) butyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Natrijev hidrid (80 %-na disperzija v olju; 0,4 g) dodamo po deležih k raztopini spojine (a) (2 g) v DMF (50 ml), predhodno ohlajeni na 0°. Reakcijsko zmes mešamo minut pri 0°, nato po kapljicah dodamo raztopino l-bromo-3-metil-2-oksobutana (2,6 g) v DMF (10 ml), zmes mešamo pri 0° 45 minut, dodamo etilacetat (450 ml), raztopino izperemo s slanico (4 x 100 ml), posušimo in koncentriramo v vakuumu. Surov produkt čistimo s flash kromatografijo (ob eluiranju s CH-EA 1:1), da dobimo naslovno spojino kot belo peno (2,3 g). T.l.c. CH-EA (1:1), Rf 0,19.Sodium hydride (80% dispersion in oil; 0.4 g) was added portionwise to a solution of compound (a) (2 g) in DMF (50 ml), pre-cooled to 0 °. The reaction mixture was stirred for minute at 0 °, then a solution of 1-bromo-3-methyl-2-oxobutane (2.6 g) in DMF (10 ml) was added dropwise, the mixture was stirred at 0 ° for 45 minutes, ethyl acetate (450 ml was added). ), the solution was washed with brine (4 x 100 ml), dried and concentrated in vacuo. The crude product was purified by flash chromatography (eluting with CH-EA 1: 1) to give the title compound as a white foam (2.3 g). T.l.c. CH-EA (1: 1), Rf 0.19.

Intermediat 61Intermediate 61

3-azido-2,4-diokso-l-(3-metil-2-okso)butil-5-fenil-2,3A5-tetrahidro-lH-l,5benzodiazepin3-Azido-2,4-dioxo-1- (3-methyl-2-oxo) butyl-5-phenyl-2,3A5-tetrahydro-1H-1,5-benzodiazepine

Raztopino kalijevega terc.butoksida (0,185 g) v THF (10 ml) dodamo po kapljicah k raztopini intermediata 60 (0,5 g) v THF (20 ml), ohlajeni na -70°, v atmosferi dušika. Zmes mešamo 20 minut pri -70°, nato dodamo raztopino 2,4,6-triizopropilbenzensulfonilazida (0,688 g) v THF (10 ml), predhodno ohlajeno na -70°, in ocetno kislino (0,2 ml). Rakcijsko zmes pustimo stati pri 23° in mešamo 15 ur, dodamo etilacetat (400 ml) ter raztopino izperemo s slanico (3 x 100 ml), posušimo in koncentriramo v vakuumu. Surov produkt čistimo s flash kromatografijo (ob eluiranju s CH-EA 1:1), da dobimo naslovno spojino kot peno. T.l.c. CH-EA (1:1), Rf 0,51.A solution of potassium tert-butoxide (0.185 g) in THF (10 ml) was added dropwise to a solution of intermediate 60 (0.5 g) in THF (20 ml) cooled to -70 ° under a nitrogen atmosphere. The mixture was stirred at -70 ° for 20 minutes, then a solution of 2,4,6-triisopropylbenzenesulfonylazide (0.688 g) in THF (10 ml), pre-cooled to -70 ° and acetic acid (0.2 ml) was added. The reaction mixture was allowed to stand at 23 ° and stirred for 15 hours, ethyl acetate (400 ml) was added and the solution was washed with brine (3 x 100 ml), dried and concentrated in vacuo. The crude product was purified by flash chromatography (eluting with CH-EA 1: 1) to give the title compound as a foam. T.l.c. CH-EA (1: 1), Rf 0.51.

Intermediat 62Intermediate 62

3-amino-2Adiokso-l-(3-metil-2-okso)butil-5-fenil-2,3A5-tetrahidro-lH-l,5benzodiazepin3-amino-2Adioxo-1- (3-methyl-2-oxo) butyl-5-phenyl-2,3A5-tetrahydro-1H-1,5-benzodiazepine

Raztopino intermediata 61 (0,85 g) v etanolu (35 ml) mešamo pod vodikom pri 1 baru v prisotnosti 5 %-nega Pd/CaCO₃ (1 g) 2 uri pri 23°. Katalizator odfiltriramo na blazinici celita, izperemo z etanolom (30 ml) in organski sloj koncentriramo v vakuumu. Surovi produkt čistimo s flash kromatografijo (ob eluiranju z DCMmetanolom 90:10), da dobimo naslovno spojino kot belo peno (0,5 g). T.l.c. DCMetanol (95:5), Rf0,56.A solution of intermediate 61 (0.85 g) in ethanol (35 ml) was stirred under hydrogen at 1 bar in the presence of 5% Pd / CaCO ₃ (1 g) for 2 hours at 23 °. The catalyst was filtered off on a pad of celite, washed with ethanol (30 ml) and the organic layer concentrated in vacuo. The crude product was purified by flash chromatography (eluting with DCMmethanol 90:10) to give the title compound as a white foam (0.5 g). Tlc DCMethanol (95: 5), Rf0.56.

Intermediat 63Intermediate 63

N-[2Adiokso-l-(3-metil-2-okso)butil-5-fenil-2,3A5-tetrahidro-lH-l,5benzodiazepin-S-ilj-FP-fenilsečninaN- [2Adioxo-1- (3-methyl-2-oxo) butyl-5-phenyl-2,3A5-tetrahydro-1H-1,5-benzodiazepine-S-yl-FP-phenylurea

Fenilizocianat (0,2 ml) dodamo k raztopini intermediata 62 (0,43 g) v suhem acetonitrilu (15 ml) v atmosferi dušika. Zmes mešamo 1 uro pri 23° in nastalo oborino filtiramo in izperemo z acetonitrilom (30 ml), da dobimo naslovno spojino kot belo trdno snov (0,37 g). T.l.c. CH-EA (1:1), Rf 0,27.Phenylisocyanate (0.2 ml) was added to a solution of Intermediate 62 (0.43 g) in dry acetonitrile (15 ml) under a nitrogen atmosphere. The mixture was stirred for 1 hour at 23 ° and the resulting precipitate was filtered and washed with acetonitrile (30 ml) to give the title compound as a white solid (0.37 g). T.l.c. CH-EA (1: 1), Rf 0.27.

Intermediat 64Intermediate 64

2,4-diokso-l-(3-metilbut-l-il)-5-fenil-2,3,4,5-tetrahidro-lH-l,5-benzodiazepin2,4-dioxo-1- (3-methylbut-1-yl) -5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

NaH (80 %-na disperzija v olju; 0,057 g) dodamo k raztopini 2,4-diokso-5-fenil2,3,4,5-tetrahidro-lH-l,5-benzodiazepina (0,40 g) v suhem DMF (15 ml). Reakcijsko zmes ohladimo na 0° in mešamo 15 minut, dodamo l-bromo-3-metil-butan (0,23 ml) v suhem DMF (4 ml) in mešamo Še 2 uri. Reakcijsko zmes nato razredčimo z vodo (100 ml), ekstrahiramo z etilacetatom (3 x 100 ml), izperemo s slanico (2 x 50 ml), posušimo in koncentriramo v vakuumu, da dobimo olje (0,75 g), ki ga čistimo s flash kromatografijo (ob eluiranju s CH-EA 60:40), da dobimo naslovno spojino kot belo trdno snov (0,44 g). T.l.c. CH-EA (1:1), Rf 0,36.NaH (80% dispersion in oil; 0.057 g) was added to a solution of 2,4-dioxo-5-phenyl2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (0.40 g) in dry DMF (15 ml). The reaction mixture was cooled to 0 ° and stirred for 15 minutes, 1-bromo-3-methyl-butane (0.23 ml) was added in dry DMF (4 ml) and stirred for another 2 hours. The reaction mixture was then diluted with water (100 ml), extracted with ethyl acetate (3 x 100 ml), washed with brine (2 x 50 ml), dried and concentrated in vacuo to give an oil (0.75 g), which was purified flash chromatography (eluting with CH-EA 60:40) to give the title compound as a white solid (0.44 g). T.l.c. CH-EA (1: 1), Rf 0.36.

Intermediat 65Intermediate 65

3-azido-2,4-diokso-l-(3-metilbut-l-il)-5-fenil-2,3,4.5-tetrahidro-lH-l,5benzodiazepin3-Azido-2,4-dioxo-1- (3-methylbut-1-yl) -5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Raztopino intermediata 64 (0,397 g) v suhem THF (7 ml) dodamo h kalijevemu terc.butoksidu (0,154 g) v suhem THF (6 ml), ohlajenemu na 78°. Reakcijsko zmes mešamo 30 minut, nato dodamo ohlajeno (-78°) raztopino 2,4,6-triizopropilbenzensulfonilazida (0,49 g) v suhem THF (7 ml). Po 5 minutah dodamo ledocet (0,07 ml), raztopino pustimo segreti na 23° in mešamo 24 ur. Rekacijsko zmes razredčimo z etilacetatom (40 ml) in izperemo z vodo (20 ml), nasičeno raztopino natrijevega hidrogenkarbonata (20 ml) in slanico (20 ml). Združene organske ekstrakte posušimo in koncentriramo v vakuumu, da dobimo olje (0,7 g). S čiščenjem s flash kromatografijo (ob eluiranju s CH-EA 60:40) dobimo naslovno spojino kot belo trdno snov (0,25 g). T.l.c. CH-EA (60:40), Rf 0,3.A solution of intermediate 64 (0.397 g) in dry THF (7 ml) was added to potassium tert-butoxide (0.154 g) in dry THF (6 ml) cooled to 78 °. The reaction mixture was stirred for 30 minutes, then a cooled (-78 °) solution of 2,4,6-triisopropylbenzenesulfonylazide (0.49 g) in dry THF (7 ml) was added. After 5 minutes, glacial acetic acid (0.07 ml) was added, the solution allowed to warm to 23 ° and stirred for 24 hours. The reaction mixture was diluted with ethyl acetate (40 ml) and washed with water (20 ml), saturated sodium bicarbonate solution (20 ml) and brine (20 ml). The combined organic extracts were dried and concentrated in vacuo to give an oil (0.7 g). Purification by flash chromatography (eluting with CH-EA 60:40) gave the title compound as a white solid (0.25 g). T.l.c. CH-EA (60:40), Rf 0.3.

Intermediat 66Intermediate 66

3-amino-2,4-diokso-l-(3-metiIbut-l-il)-5-fenil-2,3,4,5-tetrahidro-lH-l,5benzodiazepin %-en Pd/CaCO₃ (0,61 g) dodamo k raztopini intermediata 65 (1,21 g) v etilacetatu (60 ml) in etanolu (60 ml) ter reakcijsko zmes hidrogeniramo pri 1 baru 3,5 ure.3-amino-2,4-dioxo-1- (3-methylbut-1-yl) -5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine% Pd / CaCO ₃ (0 , 61 g) was added to a solution of intermediate 65 (1.21 g) in ethyl acetate (60 ml) and ethanol (60 ml) and the reaction mixture was hydrogenated at 1 bar for 3.5 hours.

Katalizator odfiltriramo in topilo uparimo v vakuumu, da dobimo naslovno spojino kot bledo rumeno peno (1,14 g). T.l.c. DCM-metanol (95:5), Rf 0,55.The catalyst was filtered off and the solvent was evaporated in vacuo to give the title compound as a pale yellow foam (1.14 g). T.l.c. DCM-methanol (95: 5), Rf 0.55.

Intermediat 67Intermediate 67

3-amino-2,4-diokso-l-(3-metilbut-l-il_-5-fenil-2,3.4,5-tetrahidro-lH-1.5benzodiazepin (lS)-(+)-10-kafrasulfonska sol3-amino-2,4-dioxo-1- (3-methylbut-1-yl-5-phenyl-2,3,4,5-tetrahydro-1H-1.5benzodiazepine (1S) - (+) - 10-carbasulfone salt

K intermediatu 66 (2,05 g), raztopljenemu v vročem etilacetatu (35 ml), dodamo (lS)-(+)-10-kafrasulfonsko kislino. Dobljeno sol (5b) izkristaliziramo iz hladne raztopine z dodajanjem cikloheksana po kapljicah; oborino odfiltriramo in izperemo s hladnim cikloheksanom, da dobimo (+)/(-) 3/97 zmes diastereomerne soli (1,11 g) in matične lužnice. S prekristalizacijo (dvakrat) iz 2-propanola dobimo čisto naslovno spojino (0,49 g). IR: 2750-2600 (NH3), 1736,1713,1700 (C=O) cm-1; ^-NMR: 9,07,4 (m); 7,5 (d); 7,45-7,2 (m); 7,18 (t); 6,97 (d); 5,05 (s); 4,58 (m); 3,68 (m); 3,20 (m);To intermediate 66 (2.05 g) dissolved in hot ethyl acetate (35 ml) was added (1S) - (+) - 10-camphrasulfonic acid. The resulting salt (5b) was crystallized from cold solution by the addition of cyclohexane dropwise; The precipitate was filtered off and washed with cold cyclohexane to give (+) / (-) 3/97 a mixture of diastereomeric salt (1.11 g) and mother liquor. Recrystallization (twice) from 2-propanol gave the pure title compound (0.49 g). IR: 2750-2600 (NH3), 1736.1713.1700 (C = O) cm-1; 1 H-NMR: 9.07.4 (m); 7.5 (d); 7.45-7.2 (m); 7.18 (t); 6.97 (d); 5.05 (s); 4.58 (m); 3.68 (m); 3.20 (m);

2,72 (m); 2,42 (m); 2,22 (m); 2,0 (m); 1,2 (m); 1,0-0,7 (m).2.72 (m); 2.42 (m); 2.22 (m); 2.0 (m); 1.2 (m); 1.0-0.7 (m).

Intermediat 68 (-)-3-amino-2.4-diokso-l-(3-metilbut-l-il)-5-fenil-2,3,4,5-tetrahidro-lH-l,5benzodiazepinIntermediate 68 (-) - 3-amino-2,4-dioxo-1- (3-methylbut-1-yl) -5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Intermediat 67 (0,47 g) suspendiramo v etilacetatu ter izperemo s 5 %-no raztopino amoniaka (2 x 20 ml) in slanico (2 x 20 ml). Organski sloj posušimo in koncentriramo v vakuumu, da dobimo naslovno spojino kot belo peno (0,27 g). T.l.c DCM-metanol (95:5), Rf 0,55. [alfa]_D= -114. IR: 3377 (NH2), 1705-1670 (C=C), 1593 cm-1; ΉNMR: 7,5-7,1 (m); 6,95 (dd); 4,55 (m); 4,23 (s); 3,7 (m); 1,8 (m); 1,64-1,4 (m); 0,92 . (d); 0,89 (d).Intermediate 67 (0.47 g) was suspended in ethyl acetate and washed with 5% ammonia solution (2 x 20 ml) and brine (2 x 20 ml). The organic layer was dried and concentrated in vacuo to give the title compound as a white foam (0.27 g). Mp DCM-methanol (95: 5), Rf 0.55. [alpha] _D = -114. IR: 3377 (NH2), 1705-1670 (C = C), 1593 cm -1; ΉNMR: 7.5-7.1 (m); 6.95 (dd); 4.55 (m); 4.23 (s); 3.7 (m); 1.8 (m); 1.64-1.4 (m); 0.92. (d); 0.89 (d).

Intermediat 69Intermediate 69

3-amino-2,4-diokso-l-(3-metilbut-l-il)-5-fenil-2,3,4,5-tetrahidro-lH-l,5benzodiazepin (lR)-(-)-10-kafrasulfonska sol3-amino-2,4-dioxo-1- (3-methylbut-1-yl) -5-phenyl-2,3,4,5-tetrahydro-1H-1,5benzodiazepine (1R) - (-) - 10 -Cafrasulfone salt

Matične lužnice, dobljene po začetnem obarjanju intermediata 67, uparimo do suhega, da dobimo trdno snov (2,19 g). Ostanek prevzamemo v etilacetatu (30 ml), ekstrahiramo s 5 %-no raztopino amoniaka (20 ml) in izperemo s slanico (20 ml), organski sloj posušimo in uparimo v vakuumu, da dobimo ostanek (1,0 g). (lR)-(-)-10kafrasulfonsko kislino v etilacetatu (6 ml) dodamo k raztopini ostanka (1 g) v etilacetatu (5 ml) in dobljeno raztopino mešamo 2 uri pri 0°. Dobljeno oborino odfiltriramo, izperemo z etilacetatom (20 ml) in posušimo, da dobimo naslovno spojino (0,97 g). Ή-NMR: 9,0-7,2 (m); 7,5 (d); 7,45-7,2 (m); 7,18 (t); 6,97 (d); 5,04 (s); 4,6 (m); 3,68 (m); 3,20 (m); 2,70 (m); 2,42 (m); 2,22 (m); 2,0-1,8 (m); 1,7-1,2 (m); 1,0-0,7 (m).The mother liquors obtained after initial precipitation of intermediate 67 were evaporated to dryness to give a solid (2.19 g). The residue was taken up in ethyl acetate (30 ml), extracted with 5% ammonia solution (20 ml) and washed with brine (20 ml), the organic layer was dried and evaporated in vacuo to give a residue (1.0 g). (lR) - (-) - 10cafrasulfonic acid in ethyl acetate (6 ml) was added to a solution of the residue (1 g) in ethyl acetate (5 ml) and the resulting solution was stirred for 2 hours at 0 °. The resulting precipitate was filtered off, washed with ethyl acetate (20 ml) and dried to give the title compound (0.97 g). Ή-NMR: 9.0-7.2 (m); 7.5 (d); 7.45-7.2 (m); 7.18 (t); 6.97 (d); 5.04 (s); 4.6 (m); 3.68 (m); 3.20 (m); 2.70 (m); 2.42 (m); 2.22 (m); 2.0-1.8 (m); 1.7-1.2 (m); 1.0-0.7 (m).

Intermediat 70 (+)-3-amino-2,4-diokso-l-(3-metilbut-l-il)-5-fenil-2,3A5-tetrahidro-lH1,5-benzodiazepinIntermediate 70 (+) - 3-amino-2,4-dioxo-1- (3-methylbut-1-yl) -5-phenyl-2,3A5-tetrahydro-1H1,5-benzodiazepine

Intermediat 69 (0,95 g) suspendiramo v etilacetatu (130 ml), izperemo s 5 %-no raztopino amoniaka (70 ml) in mešamo 10 minut pri 23°. Organski sloj ločimo, izperemo s slanico (3 x 70 ml), posušimo in koncentriramo v vakuumu, da dobimo surovo spojino. S čiščenjem s flash kromatografijo (ob eluiranju z acetonom-metanolom 9:1) dobimo naslovno spojino kot belo peno (0,51 g). [alfa]_D; IR: 3375 (NH₂), 1715-1661 (C=C), 1591 cm-1; 1H-NMR: 7,5-7,1 (m); 6,95 (dd); 4,6-4,5 (m); 4,24 (s); 3,8-3.65 (m); 1,8 (m); 1,62-1,4 (m); 0,92 (d); 0,89 (d).Intermediate 69 (0.95 g) was suspended in ethyl acetate (130 ml), washed with 5% ammonia solution (70 ml) and stirred for 10 minutes at 23 °. The organic layer was separated, washed with brine (3 x 70 ml), dried and concentrated in vacuo to give the crude compound. Purification by flash chromatography (eluting with acetone-methanol 9: 1) gave the title compound as a white foam (0.51 g). [alpha] _D ; IR: 3375 (NH ₂ ), 1715-1661 (C = C), 1591 cm -1; 1H-NMR: 7.5-7.1 (m); 6.95 (dd); 4.6-4.5 (m); 4.24 (s); 3.8-3.65 (m); 1.8 (m); 1.62-1.4 (m); 0.92 (d); 0.89 (d).

Intermediat 71Intermediate 71

3-amino-2,4-diokso-5-(2-fluorofenil)-l-(3-metilbut-l-il)-2,3A5-tetrahidro-lH1,5-benzodiazepin, (lR)-(-)-10-kafrasulfonat3-amino-2,4-dioxo-5- (2-fluorophenyl) -1- (3-methylbut-1-yl) -2,3A5-tetrahydro-1H, 1,5-benzodiazepine, (1R) - (-) - 10-camphrasulfonate

Vročo raztopino (lR)-(-)-10-kafrasulfonske kisline (1,685 g) v etilacetatu (15 ml) dodajamo 30 minut po kapljicah k raztopini intermediata 3 (3,0 g) v etilacetatu (7 ml), predhodno segreti na 90°, v atmosferi dušika. Dobljeno raztopino segrevamo na 90° 10 minut, nato koncentriramo v vakuumu. Ostanek, trituriran z EE-petroletrom, da (+)/(-) 50/50 zmes diastereomerne soli (4,65 g). S prekristalizacijo iz 2-propanola dobimo naslovno spojino (0,9 g). Tal. 216-217 [alfa]_D = +67,8.A hot solution of (1R) - (-) - 10-camphrasulfonic acid (1,685 g) in ethyl acetate (15 ml) was added dropwise 30 minutes dropwise to a solution of intermediate 3 (3.0 g) in ethyl acetate (7 ml), pre-heated to 90 °, under nitrogen atmosphere. The resulting solution was heated to 90 ° for 10 minutes, then concentrated in vacuo. The residue triturated with EE-petroleum ether to give a (+) / (-) 50/50 mixture of diastereomeric salt (4.65 g). Recrystallization from 2-propanol gave the title compound (0.9 g). Tal. 216-217 [alpha] _D = +67.8.

Intermediat 72Intermediate 72

3-(+)-amino-2Adiokso-5-(2-fluorofenil)-l-(3-metilbut-l-il)-2,3,4,5-tetrahidrolH-l,5-benzodiazepin3- (+) - amino-2-adioxo-5- (2-fluorophenyl) -1- (3-methylbut-1-yl) -2,3,4,5-tetrahydrol-1,5-benzodiazepine

Intermediat 70 (0,85 g) raztopimo v 5 %-ni raztopini amoniaka (50 ml) in ekstrahiramo z etilacetatom (2 x 40 ml). Združene organske ekstrakte izperemo s slanico (60 ml), posušimo in koncentriramo v vakuumu, da dobimo naslovno spojino kot belo peno (0,5 g). Tal. 125-126°.Intermediate 70 (0.85 g) was dissolved in 5% ammonia solution (50 ml) and extracted with ethyl acetate (2 x 40 ml). The combined organic extracts were washed with brine (60 ml), dried and concentrated in vacuo to give the title compound as a white foam (0.5 g). Tal. 125-126 °.

T.l.c. DCM-metanol (30:1), Rf 0,38. [alfa]_D = +115,2.Mp DCM-methanol (30: 1), Rf 0.38. [alpha] _D = +115.2.

Intermediat 73Intermediate 73

2-(adamant-2-il)amino-difenilamin2- (adamant-2-yl) amino-diphenylamine

Natrijev borohidrid (1,873 g) dodamo po deležih k zmesi 2-aminodifenilamina 1 (0,61 g), natrijevega acetata-trihidrata (1,36 g) in 2-adamantanona (0,5 g) v ocetni kislini (2,1 ml), vodi (8 ml) in etanolu (6,5 ml), ohlajeni na 0°. Reakcijsko zmes mešamo 1 uro pri 23°, nato razredčimo z etilacetatom (100 ml). Organski sloj izperemo z vodo (30 ml), 10 %-no raztopino natrijevega hidroksida (2 x 25 ml), vodo (30 ml) in slanico (20 ml), posušimo in koncentriramo v vakuumu, da dobimo ostanek, ki ga prevzamemo v DCM, ter nepresnovljeni trdni 2-adamantanon odstranimo s filtracijo. Filtrat koncentriramo v vakuumu in čistimo s flash kromatografijo (ob eluiranju s CH-EA 95:5), da dobimo naslovno spojino kot rumeno trdno snov (0,185 g).Sodium borohydride (1.873 g) was added portionwise to a mixture of 2-aminodiphenylamine 1 (0.61 g), sodium acetate trihydrate (1.36 g) and 2-adamantanone (0.5 g) in acetic acid (2.1 ml) ), water (8 ml) and ethanol (6.5 ml) cooled to 0 °. The reaction mixture was stirred for 1 hour at 23 °, then diluted with ethyl acetate (100 ml). The organic layer was washed with water (30 ml), 10% sodium hydroxide solution (2 x 25 ml), water (30 ml) and brine (20 ml), dried and concentrated in vacuo to give a residue which was taken up in DCM, and unprocessed solid 2-adamantanone were removed by filtration. The filtrate was concentrated in vacuo and purified by flash chromatography (eluting with CH-EA 95: 5) to give the title compound as a yellow solid (0.185 g).

T.l.c. CH-EA (90:10), Rf 0,73.T.l.c. CH-EA (90:10), Rf 0.73.

Intermediat 74 l-(adamant-2-iI)-2,4-diokso-5-fenil-3-fenilhidrazono-2,3A5-tetrahidro-lH1,5-benzodiazepinIntermediate 74 1- (adamant-2-yl) -2,4-dioxo-5-phenyl-3-phenylhydrazono-2,3A5-tetrahydro-1H1,5-benzodiazepine

Vsakega izmed intermediata 73 (0,96 g) in 2-fenilhidrazonomalonildiklorida (0,89 g) prevzamemo v THF (10 ml) in nakapljamo v bučo, ki vsebuje THF (50 ml), vzdrževano pri 0° v atmosferi dušika. Po končanem dodajanju pustimo raztopino segreti na sobno temperaturo, nato segrevamo 3 ure na 50°. Reakcijsko zmes koncentriramo v vakuumu, da dobimo olje, ki ga čistimo s flash kromatografijo (ob eluiranju s CH-EA 90:10), da dobimo naslovno spojino kot rumeno trdno snov (0,758 g). T.l.c. CH-EA (80:20), Rf 0,60.Each of intermediate 73 (0.96 g) and 2-phenylhydrazonomalonyl dichloride (0.89 g) was taken up in THF (10 ml) and added to a flask containing THF (50 ml) maintained at 0 ° under a nitrogen atmosphere. After the addition is complete, the solution is allowed to warm to room temperature, then heated to 50 ° C for 3 hours. The reaction mixture was concentrated in vacuo to give an oil which was purified by flash chromatography (eluting with CH-EA 90:10) to give the title compound as a yellow solid (0.758 g). T.l.c. CH-EA (80:20), Rf 0.60.

Intermediat 75 l-(adamant-2-il)-3-amino-2,4-diokso-5-fenil-2,3,4,5-tetrahidro-lH-l,5-benzodiazepinIntermediate 75 1- (adamant-2-yl) -3-amino-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Suspenzijo intermediata 74 (0,745 g) v ledoctu (10 ml) dodamo k zmesi cinka v prahu (0,956 g) v ledoctu (5 ml), ohlajeni na 0°. Zmes mešamo 3 ure pri 23°, nato razredčimo z vodo (100 ml) in dekantiramo od cinka. Trdni natrijev karbonat dodajamo do pH 9 in zmes ekstrahiramo z etilacetatom (3 x 100 ml). Združene organske ekstrakte posušimo in koncentriramo v vakuumu. Ostanek trituriramo z etilacetatom, da dobimo naslovno spojino kot belo trdno snov (0,51 g). Tal. 231-233° (razp.). T.l.c. DCM-metanol (90:10), Rf 0,61.A suspension of intermediate 74 (0.745 g) in ice (10 ml) was added to a mixture of zinc powder (0.956 g) in ice (5 ml) cooled to 0 °. The mixture was stirred for 3 hours at 23 °, then diluted with water (100 ml) and decanted from zinc. Solid sodium carbonate was added to pH 9 and the mixture was extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were dried and concentrated in vacuo. The residue was triturated with ethyl acetate to give the title compound as a white solid (0.51 g). Tal. 231-233 ° (dec.). T.l.c. DCM-methanol (90:10), Rf 0.61.

Intermediat 76Intermediate 76

1- (adamant-2-il)-2,4-diokso-3-izocianat-5-fenil-2,3,4.5-tetrahidro-lH-l,5benzodiazepin1- (adamant-2-yl) -2,4-dioxo-3-isocyanate-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Fosgen v toluenu (1,93 M raztopine, 10 ml) dodamo k raztopini intermediata 75 (0,285 g) v diklorometanu (10 ml); dobljeno raztopino mešamo 4 ure pri 23°, nato koncentriramo v vakuumu pri 50° 2,5 ure, da dobimo naslovno spojino kot belo peno (0,29 g).Phosgene in toluene (1.93 M solution, 10 ml) was added to a solution of intermediate 75 (0.285 g) in dichloromethane (10 ml); the resulting solution was stirred for 4 hours at 23 °, then concentrated in vacuo at 50 ° for 2.5 hours to give the title compound as a white foam (0.29 g).

IR: 2220 (N=C), 1697 in 1676 (C=O) cm-1;IR: 2220 (N = C), 1697 and 1676 (C = O) cm-1;

'H-NMR: 7,50-7,15 (m); 7,05-6,95 (m); 4,7 (s); 4,55 (m); 3,05 (m); 2,35 (m); 1,95-1,1 (m).≪ 1 > H-NMR: 7.50-7.15 (m); 7.05-6.95 (m); 4.7 (s); 4.55 (m); 3.05 (m); 2.35 (m); 1.95-1.1 (m).

Intermediat 77Intermediate 77

2- (2-ciklopentil-etil)-amino-2^,-fluoro-difenilamin2- (2-cyclopentyl-ethyl) -amino-2 ^, -fluoro-diphenylamine

Natrijev borohidrid (17,86 g) dodamo po deležih k zmesi 2-amino-2’-fluorodifenilamina (6,47 g), natrijevega acetata trihidrata (4,24 g) in ciklopentilacetaldehida (3,58 g) v ocetni kislini (19,6 ml), vodi (76 ml) in etanolu (60 ml), ohlajeni na 0°. Reakcijsko zmes mešamo 1,5 ure pri 23°C nato razredčimo z etilacetatom (200 ml). Organski sloj speremo z vodo (70 ml), 10 %-no raztopino natrijevega hidroksida (70 ml) in slanico (50 ml), posušimo in koncentriramo v vakuumu, da dobimo ostanek, ki ga čistimo s flash kromatografijo (ob eluiranju s CH-EA 9:1), da dobimo naslovno spojino kot rumeno olje (3,35 g). T.l.c. CH-EA (9:1), Rf 0,78.Sodium borohydride (17.86 g) was added portionwise to a mixture of 2-amino-2'-fluorodiphenylamine (6.47 g), sodium acetate trihydrate (4.24 g) and cyclopentylacetaldehyde (3.58 g) in acetic acid (19 , 6 ml), water (76 ml) and ethanol (60 ml) cooled to 0 °. The reaction mixture was stirred for 1.5 hours at 23 ° C and then diluted with ethyl acetate (200 ml). The organic layer was washed with water (70 ml), 10% sodium hydroxide solution (70 ml) and brine (50 ml), dried and concentrated in vacuo to give a residue which was purified by flash chromatography (eluting with CH- EA 9: 1) to give the title compound as a yellow oil (3.35 g). T.l.c. CH-EA (9: 1), Rf 0.78.

Intermediat 78 l-(2-ciklopentil-etil)-2,4-diokso-5-(2-fluorofenil)-3-fenilhidrazono-2,3,4,5tetrahidro-lH-l,5-benzodiazepinIntermediate 78 1- (2-cyclopentyl-ethyl) -2,4-dioxo-5- (2-fluorophenyl) -3-phenylhydrazono-2,3,4,5tetrahydro-1H-1,5-benzodiazepine

Vsakega izmed intermediata 77 (3,30 g) in 2-fenilhidrazonomalonildiklorida (3,25 g) prevzamemo v THF (25 ml) in nakapljamo v bučo, ki vsebuje THF (150 ml), vzdrževano pri 0° v atmosferi dušika. Po končanem dodajanju pustimo raztopino segreti na 23°; reakcijsko zmes nato segrevamo na. 55° 3 ure in koncentriramo v vakuumu. Ostanek prevzamemo v cikloheksanu/EA 7/3 (40 ml); oborino odfiltriramo in izperemo s cikloheksanom, da dobimo naslovno spojino kot rumeno trdno snov (3>75 g).Each of intermediate 77 (3.30 g) and 2-phenylhydrazonomalonyl dichloride (3.25 g) was taken up in THF (25 ml) and added to a flask containing THF (150 ml) maintained at 0 ° under a nitrogen atmosphere. After the addition is complete, allow the solution to warm to 23 °; the reaction mixture is then heated to. 55 ° for 3 hours and concentrated in vacuo. The residue was taken up in cyclohexane / EA 7/3 (40 ml); The precipitate was filtered off and washed with cyclohexane to give the title compound as a yellow solid (3> 75 g).

T.l.c. CH-EA (1:1), Rf0,71.T.l.c. CH-EA (1: 1), Rf 0.71.

Intermediat 79Intermediate 79

3-amino-l-(2-ciklopentil-etil)-2,4-diokso-5-(2-fluoro)fenil-2.3.4.5-tetrahidrolH-l,5-benzodiazepin3-amino-1- (2-cyclopentyl-ethyl) -2,4-dioxo-5- (2-fluoro) phenyl-2.3.4.5-tetrahydrol-1,5,5-benzodiazepine

K suspenziji cinka v prahu (4,70 g), ohlajeni na 0°, dodamo intermediat 78 (3,70 g) v ledoctu (50 ml). Zmes mešamo 5 ur pri 23°, nato razredčimo z vodo (250 ml) in dekantiramo od cinka. Trden natrijev karbonat dodajamo do pH 9, nato dodamo EA (300 ml), organske ekstrakte posušimo in koncentriramo v vakuumu, da dobimo ostanek, ki ga čistimo s flash kromatografijo (ob eluiranju s CH-EA 1:1), nato z DCM/metanolom 9:1, da dobimo naslovno spojino (2,55 g) kot belo peno.To a suspension of zinc powder (4.70 g) cooled to 0 ° was added intermediate 78 (3.70 g) in ice (50 ml). The mixture was stirred for 5 hours at 23 °, then diluted with water (250 ml) and decanted from zinc. Solid sodium carbonate was added to pH 9, then EA (300 ml) was added, the organic extracts were dried and concentrated in vacuo to give a residue which was purified by flash chromatography (eluting with CH-EA 1: 1) then DCM / methanol 9: 1 to give the title compound (2.55 g) as a white foam.

T.l.c. DCM-metanol (90:10), Rf 0,63.T.l.c. DCM-methanol (90:10), Rf 0.63.

Intermediat 80Intermediate 80

1- (2-ciklopentil-etil)-2,4-diokso-5-(2-fluorofenil)-3-izocianat-2,3,4,5-tetrahidrolH-l,5-benzodiazepin1- (2-cyclopentyl-ethyl) -2,4-dioxo-5- (2-fluorophenyl) -3-isocyanate-2,3,4,5-tetrahydrol-1,5,5-benzodiazepine

Fosgen v toluenu (1,93 M raztopina, 25 ml) dodamo k raztopini intermediata 79 (0,734 g) v suhem diklorometanu (60 m); dobljeno raztopino mešamo 5 ur pri 23°, nato koncentriramo 3 ure v vakuumu pri 50°, da dobimo naslovno spojino kot belo trdno snov. T.l.c. DCM-metanol (90:10), Rf 0,63Phosgene in toluene (1.93 M solution, 25 ml) was added to a solution of intermediate 79 (0.734 g) in dry dichloromethane (60 m); the resulting solution was stirred for 5 hours at 23 °, then concentrated for 3 hours in vacuo at 50 ° to give the title compound as a white solid. T.l.c. DCM-methanol (90:10), Rf 0.63

Intermediat 81Intermediate 81

2- (biciklo[2.2.1]-5-hepten-2-il-metil)-amino-difenilamin2- (bicyclo [2.2.1] -5-hepten-2-yl-methyl) -amino-diphenylamine

K raztopini 2-aminodifenilamina (3,06 g) v toluenu (100 ml) dodamo 5-norbornen-2karboksaldehid (2 ml) ter zmes refluktiramo v atmosferi dušika v prisotnosti molekulskih sit 4A 6 ur.To a solution of 2-aminodiphenylamine (3.06 g) in toluene (100 ml) was added 5-norbornene-2carboxaldehyde (2 ml) and the mixture was refluxed under nitrogen in the presence of 4A molecular sieves for 6 hours.

Raztopino dekantiramo od sit in topilo uparimo. Ostanek raztopimo v metanolu (100 ml) in po deležih dodamo natrijev borohidrid (5,70 g). Zmes mešamo 12 ur pri 23°, razredčimo z etilacetatom (100 ml), izperemo z 10 %-no raztopino kalijevega karbonata (2 x 100 ml) in slanico (100 ml), nato posušimo in koncentriramo v vakuumu. Surovi material čistimo s flash kromatografijo (ob eluiranju s CH-EA 95:5), da dobimo naslovno spojino (0,92 g) kot rumeno steklo. T.l.c. CH-EA (95:5), Rf 0,56.The solution was decanted from the sieves and the solvent was evaporated. The residue was dissolved in methanol (100 ml) and sodium borohydride (5.70 g) was added portionwise. The mixture was stirred for 12 hours at 23 °, diluted with ethyl acetate (100 ml), washed with 10% potassium carbonate solution (2 x 100 ml) and brine (100 ml), then dried and concentrated in vacuo. The crude material was purified by flash chromatography (eluting with CH-EA 95: 5) to give the title compound (0.92 g) as a yellow glass. T.l.c. CH-EA (95: 5), Rf 0.56.

Intermediat 82 l-(bicikloi2.2.1]-5-hepten-2-ilmetil)-2.4-diokso-5-fenil-3-fenilhidrazono2,3,4,5-tetrahidro-lH-l,5-benzodiazepinIntermediate 82 1- (bicyclo [2.2.1] -5-hepten-2-ylmethyl) -2,4-dioxo-5-phenyl-3-phenylhydrazono2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Vsakega izmed intermediata 81 (0,85 g) in 2-fenilhidrazonomalonildiklorida (0,87 g) prevzamemo v suhem THF (40 ml) in nakapljamo v bučo, ki vsebuje THF (10 ml). Zmes refluktiramo v dušiku 2 uri, nato jo razredčimo z etilacetatom (50 ml) in izperemo s 5 %-no raztopino natrijevega bikarbonata (50 ml) in slanico (50 ml). Organski sloj posušimo, koncentriramo v vakuumu in čistimo s flash kromatografijo (ob eluiranju s CH:EA 9:1), da dobimo naslovno spojino (1,27 g) kot rumeno peno. Tal. 149-151°. T.l.c. (CH-EA 8:2), Rf 0,34.Each of intermediate 81 (0.85 g) and 2-phenylhydrazonomalonyl dichloride (0.87 g) was taken up in dry THF (40 ml) and added to a flask containing THF (10 ml). The mixture was refluxed for 2 hours, then diluted with ethyl acetate (50 ml) and washed with 5% sodium bicarbonate solution (50 ml) and brine (50 ml). The organic layer was dried, concentrated in vacuo and purified by flash chromatography (eluting with CH: EA 9: 1) to give the title compound (1.27 g) as a yellow foam. Tal. 149-151 °. T.l.c. (CH-EA 8: 2), Rf 0.34.

Intermediat 83Intermediate 83

3-amino-l-(biciklo[2.2.1.]-5-hepten-2-il-metil)-2,4-diokso-5-fenil-2,3,4,5tetrahidro-lH-l,5-benzodiazepin3-amino-1- (bicyclo [2.2.1.] -5-hepten-2-yl-methyl) -2,4-dioxo-5-phenyl-2,3,4,5tetrahydro-1H-1,5- benzodiazepine

Zink v prahu (1,5 g) dodamo k raztopini intermediata 82 (0,49 g) v ledoctu (20 ml). Zmes mešamo 12 ur pri 23° nato jo filtriramo skozi blazinico celita. Filtrat koncentriramo v vakuumu. Ostanek prevzamemo v etilacetatu (70 ml) ter izperemo z 10 %-no raztopino natrijevega hidroksida (2 x 50 ml) in slanico (2 x 50 ml), nato posušimo in koncentriramo v vakuumu. S čiščenjem s flash kromatografijo (ob eluiranju z EA-MeOH 9:1) dobimo naslovno spojino (0,26 g) kot svetlo rumeno peno. T.l.c. (EA-MeOH 9:1), Rf 0,37.Zinc powder (1.5 g) was added to a solution of intermediate 82 (0.49 g) in ice (20 ml). The mixture was stirred for 12 hours at 23 ° then filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate (70 ml) and washed with 10% sodium hydroxide solution (2 x 50 ml) and brine (2 x 50 ml), then dried and concentrated in vacuo. Purification by flash chromatography (eluting with EA-MeOH 9: 1) gave the title compound (0.26 g) as a pale yellow foam. T.l.c. (EA-MeOH 9: 1), Rf 0.37.

Intermediat 84Intermediate 84

3-amino-l-(biciklo[2.2.1.1-2-heptilmetil)-2,4-diokso-5-fenil-2,3,4,5-tetrahidrolH-l,5-benzodiazepin3-amino-1- (bicyclo [2.2.1.1-2-heptylmethyl) -2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrol-1,5,5-benzodiazepine

Intermediat 82 (0,506 g), suspendiran v metanolu (20 ml), hidrogeniramo pri 1 baru v prisotnosti 5 %-nega Pd/C (0,271 g) in koncentrirane klorovodikove kisline (1,6 ml) 7 ur. Nato zmes filtriramo skozi blazinico celita in topilo uparimo. Ostanek prevzamemo v etilacetatu (100 ml) ter izperemo s 5 %-no raztopino natrijevega hidroksida (2 x 100 ml) in slanico (100 ml); organski sloj posušimo, koncentriramo v vakuumu in čistimo s flash kromatografijo (ob eluiranju z EA-MeOH 9:1), da dobimo naslovno spojino (0,31 g) kot belo peno. T.l.c. (EA-MeOH 9:1), Rf 0,55.Intermediate 82 (0.506 g), suspended in methanol (20 ml), was hydrogenated at 1 bar in the presence of 5% Pd / C (0.271 g) and concentrated hydrochloric acid (1.6 ml) for 7 hours. The mixture was then filtered through a pad of celite and the solvent was evaporated. The residue was taken up in ethyl acetate (100 ml) and washed with 5% sodium hydroxide solution (2 x 100 ml) and brine (100 ml); the organic layer was dried, concentrated in vacuo and purified by flash chromatography (eluting with EA-MeOH 9: 1) to give the title compound (0.31 g) as a white foam. T.l.c. (EA-MeOH 9: 1), Rf 0.55.

Intermediat 85Intermediate 85

2-(biciklo[2.2.1]-2-heptil)amino-difenilamin2- (bicyclo [2.2.1] -2-heptyl) amino-diphenylamine

Zmes 2-aminodifenilamina (5,0 g), 2-norbomanona (3,0 g) in molekulskih sit v suhem toluenu (200 ml) segrevamo 6 ur na 120°. Zmes pustimo ohladiti na sobno temperaturo, filtriramo in raztopino koncentriramo v vakuumu. Ostanek raztopimo v etanolu (200 ml), nato po deležih dodamo natrijev borohidrid (3,0 g). Dobljeno zmes mešamo 30 minut pri 23°, razredčimo z vodo (150 ml) in ekstrahiramo z etilacetatom (300 ml). Organski sloj izperemo s slanico (2 x 200 ml), posušimo in koncentriramo v vakuumu do olja, ki ga čistimo s flash kromatografijo (ob eluiranju s CH-EA 9:1), da dobimo naslovno spojino kot rumeno olje (3,5 g). T.l.c. CH-EA (9:1), Rf 0,74.A mixture of 2-aminodiphenylamine (5.0 g), 2-norbomanon (3.0 g) and molecular sieves in dry toluene (200 ml) was heated at 120 ° for 6 hours. The mixture was allowed to cool to room temperature, filtered and the solution was concentrated in vacuo. The residue was dissolved in ethanol (200 ml), then sodium borohydride (3.0 g) was added portionwise. The resulting mixture was stirred for 30 minutes at 23 °, diluted with water (150 ml) and extracted with ethyl acetate (300 ml). The organic layer was washed with brine (2 x 200 ml), dried and concentrated in vacuo to an oil which was purified by flash chromatography (eluting with CH-EA 9: 1) to give the title compound as a yellow oil (3.5 g ). T.l.c. CH-EA (9: 1), Rf 0.74.

Intermediat 86 l-ibicikioi2.2.11-2-heptil)-2,4-diokso-5-fenil-3-fenilhidrazono-2.3.4.5-tetrahidrolH-l,5-benzodiazepinIntermediate 86 1-Ibicyclo [2.2.11-2-heptyl) -2,4-dioxo-5-phenyl-3-phenylhydrazono-2.3.4.5-tetrahydrol-1,5,5-benzodiazepine

Vsakega izmed intermediata 85 (3,77 g) in 2-fenilhidrazonomalonildiklorida (3,98 g) prevzamemo v THF (70 ml) in nakapljamo v bučo, ki vsebuje THF (60 ml) v atmosferi dušika. Po končanem dodajanju raztopino segrevamo 1 uro na 50°. Raztopino koncentriramo v vakuumu do olja, ki ga čistimo s flash kromatografijo (ob eluiranju s CH-EA 8:2), da dobimo naslovno spojino kot rumeno trdno snov (6,0 g). Tal. 110111°. T.l.c. CH-EA (7:3), Rf 0,72 in 0,66.Each of intermediate 85 (3.77 g) and 2-phenylhydrazonomalonyl dichloride (3.98 g) was taken up in THF (70 ml) and added to a flask containing THF (60 ml) under a nitrogen atmosphere. After the addition is complete, the solution is heated to 50 ° for 1 hour. The solution was concentrated in vacuo to an oil which was purified by flash chromatography (eluting with CH-EA 8: 2) to give the title compound as a yellow solid (6.0 g). Tal. 110111 °. T.l.c. CH-EA (7: 3), Rf 0.72 and 0.66.

Intermediat 87Intermediate 87

3-amino-l-(biciklo[2.2.1]-2-heptil)-2,4-diokso-5-fenil-2,3,4,5-tetrahidro-lH-l,5benzodiazepin3-amino-1- (bicyclo [2.2.1] -2-heptyl) -2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Cink v prahu (3,26 g) dodamo k raztopini intermediata 86 (3,0 g) v ledoctu (30 ml). Zmes mešamo 4 ure pri 23°, nato dekantiramo od cinka. Raztopino naalkalimo do pH 9 ob uporabi 10 %-ne raztopine natrijevega hidroksida in ekstrahiramo z etilacetatom (2 x 100 ml). Združene organske ekstrakte izperemo s slanico (150 ml), posušimo in koncentriramo v vakuumu do ostanka, ki ga trituriramo z dietiletrom, da dobimo naslovno spojino kot belo trdno snov (1,34 g); tal. 172-173°. T.l.c EA-MeOH (95:5), Rf0,3.Powdered zinc (3.26 g) was added to a solution of intermediate 86 (3.0 g) in glacial (30 ml). The mixture was stirred for 4 hours at 23 °, then decanted from zinc. The solution was basified to pH 9 using 10% sodium hydroxide solution and extracted with ethyl acetate (2 x 100 ml). The combined organic extracts were washed with brine (150 ml), dried and concentrated in vacuo to a residue triturated with diethyl ether to give the title compound as a white solid (1.34 g); m.p. 172-173 °. T.l.c EA-MeOH (95: 5), Rf0.3.

Intermediat 88Intermediate 88

2-(2-adamantilmetil)amino-difenilamin2- (2-adamantylmethyl) amino-diphenylamine

Raztopino natrijevega acetata-trihidrata (6,45 g) in ocetne kisline (5 ml) v vodi dodamo k zmesi 2-adamantankarboksaldehida (2,6 g) in 2-aminodifenilamina 1 (2,84 g) v etanolu (130 ml). Nato po deležih dodamo natrijev borohidrid (5,97 g). Dobljeno zmes mešamo 6 ur pri 23°, nato razredčimo z vodo (80 ml) in ekstrahiramo z etilacetatom (2 x 150 ml). Združene organske ekstrakte izperemo s slanico (150 ml), posušimo in koncentriramo v vakuumu do ostanka, ki ga čistimo s flash kromatografijo, da dobimo naslovno spojino kot rumeno olje (2,15 g). T.l.c CH-EA 8:2), Rf0,86.A solution of sodium acetate trihydrate (6.45 g) and acetic acid (5 ml) in water was added to a mixture of 2-adamantanecarboxaldehyde (2.6 g) and 2-aminodiphenylamine 1 (2.84 g) in ethanol (130 ml). Sodium borohydride (5.97 g) was then added portionwise. The resulting mixture was stirred for 6 hours at 23 °, then diluted with water (80 ml) and extracted with ethyl acetate (2 x 150 ml). The combined organic extracts were washed with brine (150 ml), dried and concentrated in vacuo to a residue which was purified by flash chromatography to give the title compound as a yellow oil (2.15 g). T.l.c. CH-EA 8: 2), Rf0.86.

Intermediat 89 l-(2-adamantilmetil)-2Adiokso-5-fenil-3-fenilhidrazono-2,3A5-tetrahidrolH-l,5-benzodiazepinIntermediate 89 1- (2-adamantylmethyl) -2Adioxo-5-phenyl-3-phenylhydrazono-2,3A5-tetrahydrol-1,5-benzodiazepine

Raztopino 2-fenilhidrazonomalonildiklorida (1,78 g) v THF (50 ml) dodamo k raztopini intermediata 88 (2,0 g) v THF (50 ml) v atmosferi dušika. Dobljeno raztopino segrevamo 1 uro na 50°, nato koncentriramo v vakuumu do ostanka, ki ga čistimo s flash kromatografijo (ob eluiranju s CH-EA 9:1), da dobimo naslovno spojino kot rumeno trdno snov (1,95 g); tal. 135-136°(razp.). T.l.c. CH-EA (8:2), Rf 0,48.A solution of 2-phenylhydrazonomalonyl dichloride (1.78 g) in THF (50 ml) was added to a solution of intermediate 88 (2.0 g) in THF (50 ml) under a nitrogen atmosphere. The resulting solution was heated to 50 ° C for 1 hour, then concentrated in vacuo to a residue which was purified by flash chromatography (eluting with CH-EA 9: 1) to give the title compound as a yellow solid (1.95 g); m.p. 135-136 ° (dec.). T.l.c. CH-EA (8: 2), Rf 0.48.

Intermediat 90 l-(2-adamantilmetil)-3-amino-2Adiokso-5-fenil-2,3A5-tetrahidiro-lH-l,5benzodiazepinIntermediate 90 1- (2-adamantylmethyl) -3-amino-2Adioxo-5-phenyl-2,3A5-tetrahydiro-1H-1,5-benzodiazepine

Cink v prahu (1,84 g) dodamo k raztopini intermediata 89 (1,9 g) v ledoctu (20 ml). Zmes mešamo 2 uri pri 23°, nato dekantiramo od cinka. Raztopino naalkalimo do pH 9 ob uporabi 10 %-ne raztopine natrijevega hidroksida in ekstrahiramo z etilacetatom (2 x 80 ml). Združene organske ekstrakte izperemo s slanico (100 ml), posušimo in koncentriramo v vakuumu do ostanka, ki ga čistimo s flash kromatografijo (ob eluiranju v gradientu od CH-EA 1:1) do EA), da dobimo naslovno spojino kot rumeno trdno snov (0,95 g); tal. 209-210°. T.l.c. EA-MeOH (20:1), Rf0,38.Powdered zinc (1.84 g) was added to a solution of intermediate 89 (1.9 g) in ice (20 ml). The mixture was stirred for 2 hours at 23 °, then decanted from zinc. The solution was basified to pH 9 using 10% sodium hydroxide solution and extracted with ethyl acetate (2 x 80 ml). The combined organic extracts were washed with brine (100 ml), dried and concentrated in vacuo to a residue which was purified by flash chromatography (eluting in a gradient from CH-EA 1: 1) to EA) to give the title compound as a yellow solid. (0.95 g); m.p. 209-210 °. T.l.c. EA-MeOH (20: 1), Rf 0.38.

Intermediat 91Intermediate 91

5-fluoro-N-(4-fluorofenil)-2-nitroanilin5-Fluoro-N- (4-fluorophenyl) -2-nitroaniline

Zmes 2,4-difluoronitrobenzena (5,5 ml), 4-fluroanilina (14,2 ml) in natrijevega kar46 bonata (5,3 g) segrevamo 3 ure pri 180°. Reakcijsko zmes ohladimo na sobno temperaturo, nato razredčimo z DCM, izperemo z vodo (50 ml), slanico (2 x 50 ml), posušimo in uparimo v vakuumu, da dobimo surovo spojino (22,6 g), ki jo čistimo s flash kromatografijo s CH-EA 4/1, da dobimo naslovno spojino kot oranžno trdno snov (12,35 g); tal. 115-116°. T.l.c. CH-EA (10:1), Rf 0,52.A mixture of 2,4-difluoronitrobenzene (5.5 ml), 4-fluroaniline (14.2 ml) and sodium carbamate (5.3 g) was heated at 180 ° for 3 hours. The reaction mixture was cooled to room temperature, then diluted with DCM, washed with water (50 ml), brine (2 x 50 ml), dried and evaporated in vacuo to give the crude compound (22.6 g), which was flash-purified chromatography with CH-EA 4/1 to give the title compound as an orange solid (12.35 g); m.p. 115-116 °. T.l.c. CH-EA (10: 1), Rf 0.52.

Intermediat 92Intermediate 92

4-fluoro-N^,-[4-fluorofenilI-l,2-benzendiamin4-fluoro-N ^, - [4-fluorophenyl] -1,2-benzenediamine

Raztopino kalijevega karbonata (8,292 g) in natrijevega hidrosulfita (6,964 g) v vodi (200 ml) dodamo k suspenziji intermediata 91 (2,502 g) v 95 %-nem etanolu (350 ml). Zmes mešamo 1 uro pri 23°, reakcijsko zmes nakisamo na pH 3,5 s koncentrirano klorovodikovo kislino in koncentriramo v vakuumu do polovičnega volumna. Dodajamo 10 %-no raztopino natrijevega hidroksida do pH 10 in raztopino ekstrahiramo z etilacetatom (200 ml). Združene organske ekstrakte izperemo s slanico (200 ml), posušimo in koncentriramo v vakuumu, da dobimo surovo spojino (2,93 g), ki jo čistimo s flash kromatografijo ob uporabi CH-EA 3/2 kot eluenta, da dobimo naslovno spojino kot rjavo olje (1,64 g); tal. 83-84°. T.l.c. CH-EA (2:1), Rf 0,35.A solution of potassium carbonate (8.292 g) and sodium hydrosulfite (6.964 g) in water (200 ml) was added to a suspension of intermediate 91 (2.502 g) in 95% ethanol (350 ml). The mixture was stirred for 1 hour at 23 °, the reaction mixture was acidified to pH 3.5 with concentrated hydrochloric acid and concentrated in vacuo to half volume. A 10% solution of sodium hydroxide was added to pH 10 and the solution was extracted with ethyl acetate (200 ml). The combined organic extracts were washed with brine (200 ml), dried and concentrated in vacuo to give the crude compound (2.93 g), which was purified by flash chromatography using CH-EA 3/2 as eluent to give the title compound as brown oil (1.64 g); m.p. 83-84 °. T.l.c. CH-EA (2: 1), Rf 0.35.

Intermediat 93Intermediate 93

N’-(adamantan-l-metil)-4-fluoro-N-(4-fluorofenil)-1.2-benzendiaminN '- (adamantan-1-methyl) -4-fluoro-N- (4-fluorophenyl) -1,2-benzenediamine

K raztopini 1-adamantankarboksaldehida (1,223 g) in intermediata 92 (1,64 g) v etanolu (50 ml) dodamo pufer, pripravljen z natrijevim acetatom trihidratom (3,04 g) in ledoctom (00,4 ml) v vodi (25 ml) ter zmes mešamo pri 23°.To a solution of 1-adamantanecarboxaldehyde (1.223 g) and intermediate 92 (1.64 g) in ethanol (50 ml) was added a buffer prepared with sodium acetate trihydrate (3.04 g) and glacial (00.4 ml) in water (25 ml) and the mixture was stirred at 23 °.

Dodamo nadaljnjo količino etanola (15 ml), da dobimo bistro raztopino, ter po deležih dodamo natrijev borohidrid (2,8 g). Zmes mešamo 20 ur pri 23° in nato razredčimo z etilacetatom (30 ml). Združene organske ekstrakte izperemo s kalijevim karbonatom (30 ml), s slanico (30 ml), posušimo in koncentriramo v vakuumu, da dobimo rdeče olje (3,102 g), ki ga čistimo s flash kromatografijo (ob eluiranju s CH-EA 15:1), da dobimo naslovno spojino kot oranžno olje (0,854 g). T.l.c. CH-EA (9:1), Rf0,59.A further amount of ethanol (15 ml) was added to give a clear solution, and sodium borohydride (2.8 g) was added portionwise. The mixture was stirred at 23 ° for 20 hours and then diluted with ethyl acetate (30 ml). The combined organic extracts were washed with potassium carbonate (30 ml), brine (30 ml), dried and concentrated in vacuo to give a red oil (3.102 g), which was purified by flash chromatography (eluting with CH-EA 15: 1 ) to give the title compound as an orange oil (0.854 g). T.l.c. CH-EA (9: 1), Rf 0.59.

Intermediat 94 l-(adamantan-l-metil)-2,4-diokso-7-fluoro-5-(4-fluorofenil)-3-fenilhidrazono47Intermediate 94 1- (adamantan-1-methyl) -2,4-dioxo-7-fluoro-5- (4-fluorophenyl) -3-phenylhydrazono47

2,3A5-tetrahidro-lH-l,5-benzodiazepin2,3A5-tetrahydro-1H-1,5-benzodiazepine

Vsakega izmed intermediata 93 (0,850 g) in fenilhidrazonomalonildiklorida (0,565 g) prevzamemo THF (30 ml) in nakapljamo v bučo, ki vsebuje THF (30 ml), vzdrževano v atmosferi dušika. Po končanem dodajanju raztopino segrevamo 3 ure na 70°. Raztopino razredčimo z EA (100 ml), izperemo s 5 %-no raztopino natrijevega hidrogenkarbonata (100 ml) in slanico (100 ml), posušimo in koncentriramo v vakuumu do rdeče pene (1,268 g), ki jo čistimo s flash kromatografijo (ob eluiranju s CH-EA 3:1), da dobimo naslovno spojino kot rumeno peno (0,562 g). T.l.c. CH-EA (3:1), Rf 0,46.Each of intermediate 93 (0.850 g) and phenylhydrazonomalonyl dichloride (0.565 g) was taken up in THF (30 ml) and added to a flask containing THF (30 ml) maintained under a nitrogen atmosphere. After the addition is complete, the solution is heated to 70 ° for 3 hours. The solution was diluted with EA (100 ml), washed with 5% sodium hydrogen carbonate solution (100 ml) and brine (100 ml), dried and concentrated in vacuo to a red foam (1.268 g), which was purified by flash chromatography (ob eluting with CH-EA 3: 1) to give the title compound as a yellow foam (0.562 g). T.l.c. CH-EA (3: 1), Rf 0.46.

Intermediat 95 l-(adamantan-l-metil)-3-amino-2,4-diokso-7-fIuoro-5-(4-fluorofeniI)-2,3A5tetrahidro-lH-l,5-benzodiazepinIntermediate 95 1- (adamantan-1-methyl) -3-amino-2,4-dioxo-7-fluoro-5- (4-fluorophenyl) -2,3A5tetrahydro-1H-1,5-benzodiazepine

Cink v prahu (0,673 g) dodamo k raztopini intermediata 94 (0,557 g) v ledoctu (20 ml). Zmes mešamo 6 ur pri 23°, filtriramo in uparimo do suhega; ostanek raztopimo v vodi (80 ml), raztopino naalkalimo s trdnim natrijevim hidroksidom do pH 9, ekstrahiramo s EA (100 ml). Združene organske ekstrakte izperemo s slanico (2 x 30 ml). Posušimo in koncentriramo v vakuumu, da dobimo rumeno peno (0,547 g), ki jo čistimo s flash kromatografijo (ob eluiranju z EA-metanolom 9/1, da dobimo naslovno spojino kot belo trdno snov (0,322 g); tal. 232-233°. T.l.c. EA-metanol (9:1), Rf 0,56.Powdered zinc (0.673 g) was added to a solution of intermediate 94 (0.557 g) in glacial (20 ml). The mixture was stirred for 6 hours at 23 °, filtered and evaporated to dryness; the residue was dissolved in water (80 ml), the solution basified with solid sodium hydroxide to pH 9, extracted with EA (100 ml). The combined organic extracts were washed with brine (2 x 30 ml). Dry and concentrate in vacuo to give a yellow foam (0.547 g), which was purified by flash chromatography (eluting with EA-methanol 9/1 to give the title compound as a white solid (0.322 g); mp 232-233 ° Tlc EA-methanol (9: 1), Rf 0.56.

Intermediat 96Intermediate 96

N-l-(adamantan-l-metil)-3-amino-5-fenil-2,3,4,5-tetrahidro-lH-l,5-benzodiazepin, (IR)-(-)-10-kafrasulfonatN-1- (adamantan-1-methyl) -3-amino-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine, (IR) - (-) - 10-carbasulfonate

Raztopino (IR)-(-)-10-kafrasulfonske kisline (13,2 g) v acetonitrilu (1035 ml) dodamo po kapljicah k raztopini intermediata 41 (33 g) v acetonitrilu (1089 ml) in mešano zmes pustimo preko noči pri sobni temperaturi. Oborino filtriramo in izperemo z acetonitrilom (80 ml), etilacetatom (50 ml) in petroletrom (50 ml), da dobimo po sušenju v vakuumu naslovno spojino (16,17 g) kot belo trdno snov; tal. 270-272°.A solution of (IR) - (-) - 10-camphrasulfonic acid (13.2 g) in acetonitrile (1035 ml) was added dropwise to a solution of intermediate 41 (33 g) in acetonitrile (1089 ml) and the stirred mixture was left overnight at room temperature. temperature. The precipitate was filtered and washed with acetonitrile (80 ml), ethyl acetate (50 ml) and petroleum ether (50 ml) to give the title compound (16.17 g) as a white solid after vacuum drying; m.p. 270-272 °.

Intermediat 97 (+)-N-l-(adamantan-l-metil)-3-amino-2Adiokso-5-fenil-2,3A5-tetrahidro-lH48Intermediate 97 (+) - N-1- (adamantan-1-methyl) -3-amino-2Adioxo-5-phenyl-2,3A5-tetrahydro-1H48

1,5-benzodiazepin1,5-benzodiazepine

Suspenzijo intermediata 96 (6,05 g) v etilacetatu (395 ml) mešamo s 5 %-nim vodnim amoniakom (395 ml) 5 minut in organski sloj ločimo. Vodni sloj izperemo z etilacetatom (395 ml) in nato etilacetatno fazo ločimo. Združene organske ekstrakte posušimo in topilo uparimo, da dobimo naslovno spojino kot belo peno (4,1 g). T.l.c. EA-metanol (95:5), Rf 0,33 [alfa]_D = +31.A suspension of intermediate 96 (6.05 g) in ethyl acetate (395 ml) was stirred with 5% aqueous ammonia (395 ml) for 5 minutes and the organic layer was separated. The aqueous layer was washed with ethyl acetate (395 ml) and then the ethyl acetate phase was separated. The combined organic extracts were dried and the solvent was evaporated to give the title compound as a white foam (4.1 g). Tlc EA-methanol (95: 5), Rf 0.33 [alpha] _D = +31.

Intermediat 98Intermediate 98

4-fluoro-N’-(3-metilbut-l-il)-N-fenil-1.2-benzendiamin4-Fluoro-N '- (3-methylbut-1-yl) -N-phenyl-1,2-benzenediamine

Bromo-3-metilbutan (0,38 ml) dodamo k raztopini 5-fluoro-N’-fenil-l,2-benzendiamina (0,645 g) in natrijevega jodida (0,476 g) v dimetilformamidu (25 ml) v atmosferi dušika. Raztopino mešamo 10 ur pri 120°, nato ohladimo na sobno temperaturo, razredčimo z vodo (30 ml) in ekstrahiramo z etiletrom (2 x 25 ml). Združene organske ekstrakte izperemo s slanico (30 ml), posušimo in koncentriramo v vakuumu, da dobimo rdeče olje, ki ga čistimo s flash kromatografijo (ob eluiranju s CH-EA 9:1), da dobimo naslovno spojino kot rjavo olje (0,467 g). T.l.c. CH-EA (2:1), Rf 0,78.Bromo-3-methylbutane (0.38 ml) was added to a solution of 5-fluoro-N'-phenyl-1,2-benzenediamine (0.645 g) and sodium iodide (0.476 g) in dimethylformamide (25 ml) under a nitrogen atmosphere. The solution was stirred at 120 ° for 10 hours, then cooled to room temperature, diluted with water (30 ml) and extracted with ethyl ether (2 x 25 ml). The combined organic extracts were washed with brine (30 ml), dried and concentrated in vacuo to give a red oil, which was purified by flash chromatography (eluting with CH-EA 9: 1) to give the title compound as a brown oil (0.467 g ). T.l.c. CH-EA (2: 1), Rf 0.78.

Intermediat 99Intermediate 99

2,4-diokso-7-fluoro-l-(3-metilbut-l-il)-5-fenil-3-fenilohidrazono-2,3,4,5tetrahidro-lH-l,5-benzodiazepin2,4-dioxo-7-fluoro-1- (3-methylbut-1-yl) -5-phenyl-3-phenylohydrazono-2,3,4,5tetrahydro-1H-1,5-benzodiazepine

Vsakega izmed intermediata 98 (0,454 g) in fenilhidrazonomalonildiklorida (0,49 g) prevzamemo v THF (15 ml) in nakapljamo v bučo, ki vsebuje THF (15 ml), vzdrževano v atmosferi dušika. Po končanem dodajanju raztopino segrevamo 1 uro na 70°. Raztopino razredčimo z EA (20 ml), izperemo s 5 %-no raztopino natrijevega hidrogenkarbonata (20 ml) in slanico (20 ml), posušimo in koncentriramo v vakuumu do olja, ki ga čistimo s flash kromatografijo (ob eluiranju s CH-EA 8:2), da dobimo naslovno spojino kot rumeno peno (0,565 g). T.l.c. CH-EA (4:1), Rf 0,33.Each of intermediate 98 (0.454 g) and phenylhydrazonomalonyl dichloride (0.49 g) was taken up in THF (15 ml) and added to a flask containing THF (15 ml) maintained under a nitrogen atmosphere. After the addition is complete, the solution is heated to 70 ° for 1 hour. The solution was diluted with EA (20 ml), washed with 5% sodium hydrogen carbonate solution (20 ml) and brine (20 ml), dried and concentrated in vacuo to an oil which was purified by flash chromatography (eluting with CH-EA 8: 2) to give the title compound as a yellow foam (0.565 g). T.l.c. CH-EA (4: 1), Rf 0.33.

Intermediat 100Intermediate 100

3-amino-2,4-diokso-7-fluoro-l-(3-metilbut-l-il)-5-feniI-2,3,4,5-tetrahidrolH-l,5-benzodiazepin3-amino-2,4-dioxo-7-fluoro-1- (3-methylbut-1-yl) -5-phenyl-2,3,4,5-tetrahydrol-1,5-benzodiazepine

Cinkov prah (0,822 g) dodamo k raztopini intermediata 99 (0,559 g) v ledoctu (20 ml). Zmes mešamo 2 uri pri 23°, nato jo razredčujemo z 10 %-no raztopino natrijevega hidroksida do pH 9 in zmes ekstrahiramo z etilacetatom (2 x 30 ml). Združene organske ekstrakte izperemo s slanico (30 ml), posušimo in koncentriramo v vakuumu, da dobimo ijavo olje (0,529 g), ki ga čistimo s flash kromatografijo (ob eluiranju s CH-metanolom 19/1), da dobimo naslovno spojino kot rumeno peno (0,323 g); tal. 125-126°. T.l.c. EA-metanol (19:1), Rf 0,45.Zinc powder (0.822 g) was added to a solution of intermediate 99 (0.559 g) in ice (20 ml). The mixture was stirred at 23 ° for 2 hours, then diluted with 10% sodium hydroxide solution to pH 9 and extracted with ethyl acetate (2 x 30 ml). The combined organic extracts were washed with brine (30 ml), dried and concentrated in vacuo to give an oil (0.529 g) which was purified by flash chromatography (eluting with CH-methanol 19/1) to give the title compound as a yellow foam (0.323 g); m.p. 125-126 °. T.l.c. EA-methanol (19: 1), Rf 0.45.

PRIMER 1EXAMPLE 1

N-i2Adiokso-5-(2-fluorofenil)-l-(3-metilbut-l-il)-2,3A5-tetrahidro-lHl,5-benzodiazepin-3-il1-N’-fenilsečninaN-Adoxo-5- (2-fluorophenyl) -1- (3-methylbut-1-yl) -2,3A5-tetrahydro-1H1, 5-benzodiazepin-3-yl1-N'-phenylurea

Fenilizocianat (0,136) g dodamo k raztopini intermediata 3 (0,4 g) v suhem acetonitrilu (10 ml) v atmosferi dušika. Zmes mešamo 1 uro pri 23°, filtriramo in trdno snov izperemo z dietiletrom, da dobimo naslovno spojino, kot belo trdno snov (0,45 g); tal. 254-255°. T.l.c. CH-EA (1:1), Rf 0,65. IR: 3450 (NH), 1707 in 1670 (C=O), 1601 in 1533 (C=C) cm-1; Ή-NMR: 7,459 (dd); 7,4-7,1 (m); 7,03 (m); 6,989 (dd); 6,933 (bs); 6,353 (d); 5,366 (d); 4,457 (m); 3,70 (m); 1,6-1,4 (m); 0,902 (d); 0,888 (d)·Phenylisocyanate (0.136) g was added to a solution of Intermediate 3 (0.4 g) in dry acetonitrile (10 ml) under a nitrogen atmosphere. The mixture was stirred for 1 hour at 23 °, filtered and the solid was washed with diethyl ether to give the title compound as a white solid (0.45 g); m.p. 254-255 °. T.l.c. CH-EA (1: 1), Rf 0.65. IR: 3450 (NH), 1707 and 1670 (C = O), 1601 and 1533 (C = C) cm-1; Ή-NMR: 7.459 (dd); 7.4-7.1 (m); 7.03 (m); 6,989 (dd); 6,933 (bs); 6,353 (d); 5,366 (d); 4,457 (m); 3.70 (m); 1.6-1.4 (m); 0.902 (d); 0.888 (d) ·

PRIMER 2EXAMPLE 2

N-[l-(3,3-dimetilbut-l-il)-2Adiokso-5-(2-fluorofenil)-2,3A5-tetrahidro-lH-l,5benzodiazepin-S-ill-N^fenilsečninaN- [1- (3,3-dimethylbut-1-yl) -2adioxo-5- (2-fluorophenyl) -2,3A5-tetrahydro-1H-1,5benzodiazepin-S-yl-N ^ phenylurea

Fenilizocianat (0,106 ml) dodamo k raztopini intermediata 6 (0,3 g) v suhem acetonitrilu (5 ml) v atmosferi dušika. Zmes mešamo 1 uro pri 23°, filtriramo in trdno snov izperemo z dietiletrom, da dobimo naslovno spojino kot belo trdno snov (0,27 g). Tal. 271-272°. T.l.c. CH-EA (7:3), Rf 0,32. IR: 3310 (NH), 1718, 1668 in 1639 (C=O), 1601 in 1556 (C=C) cm-1; Ή-NMR: 7,45 (dd); 7,4-7,10 (m); 7,06-6,97 (m); 6,414 (d); 5,362 (d); 4,476-4,373 (m); 3,757-3,656 (m); 1,503 (m); 0,924 (s).Phenylisocyanate (0.106 ml) was added to a solution of Intermediate 6 (0.3 g) in dry acetonitrile (5 ml) under a nitrogen atmosphere. The mixture was stirred for 1 hour at 23 °, filtered and the solid was washed with diethyl ether to give the title compound as a white solid (0.27 g). Tal. 271-272 °. T.l.c. CH-EA (7: 3), Rf 0.32. IR: 3310 (NH), 1718, 1668 and 1639 (C = O), 1601 and 1556 (C = C) cm-1; Ή-NMR: 7.45 (dd); 7.4-7.10 (m); 7.06-6.97 (m); 6,414 (d); 5,362 (d); 4,476-4,373 (m); 3,757-3,656 (m); 1,503 (m); 0.924 (s).

PRIMER 3EXAMPLE 3

N-f2,4-diokso-5-(2-fluorofenil-l-(3-metilbut-l-il)-2A4,5-tetrahidro-lH-l,5benzodiazepin-S-ill-NVS-metilmerkaptojfenilsečninaN-f2,4-dioxo-5- (2-fluorophenyl-1- (3-methylbut-1-yl) -2A4,5-tetrahydro-1H-1,5-benzodiazepin-S-yl-NVS-methylmercaptoylphenylurea

3-metilmerkaptoanilin (0,065 ml) dodamo k raztopini intermediata 7 (0,2 g) v diklorometanu (10 ml) v atmosferi dušika. Raztopino mešamo 3 ure pri 23°, nato koncentriramo v vakuumu in trituriramo z acetonitrilom, da dobimo naslovno spojino kot belo trdno snov (0,132 g). Tal. 246-247°. T.l.c. CH-EA (1:1), Rf 0,58. IR: 1711, 1691, 1680, in 1670 (C=O), 1595 (C=C) cm-1; Ή-NMR: 7,46 (dd); 7,4-7,3 (m); 7,26-7,10 (m); 7,04-6,9 (m); 6,82-6,76 (bm); 6,257 (d); 5,333 (d); 4,46 (m); 3,700 (m); 2,436 (s); 1,6-1,4 (m); 0,906 (d); 0,886 (d).3-Methylmercaptoaniline (0.065 ml) was added to a solution of intermediate 7 (0.2 g) in dichloromethane (10 ml) under a nitrogen atmosphere. The solution was stirred for 3 hours at 23 °, then concentrated in vacuo and triturated with acetonitrile to give the title compound as a white solid (0.132 g). Tal. 246-247 °. T.l.c. CH-EA (1: 1), Rf 0.58. IR: 1711, 1691, 1680, and 1670 (C = O), 1595 (C = C) cm -1; Ή-NMR: 7.46 (dd); 7.4-7.3 (m); 7.26-7.10 (m); 7.04-6.9 (m); 6.82-6.76 (bm); 6,257 (d); 5,333 (d); 4.46 (m); 3,700 (m); 2,436 (s); 1.6-1.4 (m); 0.906 (d); 0.886 (d).

PRIMER 4EXAMPLE 4

N-r2,4-diokso-5-(2-fluorofenil-l-(3-metilbut-l-il)-2,3A5-tetrahidro-lH-l,551 benzodiazepin-3-il-N’-(3-dimetilamino)fenilsečninaN-1,2,4-dioxo-5- (2-fluorophenyl-1- (3-methylbut-1-yl) -2,3A5-tetrahydro-1H-1,551 benzodiazepin-3-yl-N '- (3- dimethylamino) phenylurea

Trietilamin (0,32 ml) in 3-dimetilaminoanilin-dihidroklorid (0,24 g) dodamo k suspenziji intermediata 8 (0,22 g) v suhem dimetilformamidu (5 ml) v atmosferi dušika. Dobljeno zmes segrevamo 2 uri na 160°, nato ohladimo na sobno temperaturo, razredčimo z vodo (20 ml) in ekstrahiramo z etilacetatom (2 x 20 ml). Združene organske ekstrakte posušimo, koncentriramo v vakuumu in trituriramo z acetonitrilom, da dobimo naslovno spojino kot belo trdno snov (0,12 g). Tal. 252253°. T.l.c. CH-EA (1:1), Rf 0,5. IR: 3312 (NH), 1707, 1676, in 1639 (C=O), 1593 in 1558 (C=C) cm-1; Ή-NMR: 7,45 (dd); 7,41-7,28 (m); 7,25-7,1 (m); 7,134 (t); 6,981(dd); 6,818 (t); 6,634 (bs); 6,599 (dd); 6,455 (dd); 6,365 (d); 5,359 (d); 4,509-4,409 (m); 3,741-3,645 (m); 2,918 (s); 1,6-1,42 (m); 0,908 (d); 0,896 (d).Triethylamine (0.32 ml) and 3-dimethylaminoaniline dihydrochloride (0.24 g) were added to a suspension of intermediate 8 (0.22 g) in dry dimethylformamide (5 ml) under a nitrogen atmosphere. The resulting mixture was heated to 160 ° for 2 hours, then cooled to room temperature, diluted with water (20 ml) and extracted with ethyl acetate (2 x 20 ml). The combined organic extracts were dried, concentrated in vacuo and triturated with acetonitrile to give the title compound as a white solid (0.12 g). Tal. 252253 °. T.l.c. CH-EA (1: 1), Rf 0.5. IR: 3312 (NH), 1707, 1676, and 1639 (C = O), 1593 and 1558 (C = C) cm-1; Ή-NMR: 7.45 (dd); 7.41-7.28 (m); 7.25-7.1 (m); 7,134 (t); 6,981 (dd); 6,818 (t); 6,634 (bs); 6,599 (dd); 6,455 (dd); 6,365 (d); 5,359 (d); 4,509-4,409 (m); 3,741-3,645 (m); 2,918 (s); 1.6-1.42 (m); 0.908 (d); 0.896 (d).

PRIMER 5EXAMPLE 5

N-[l-(3,3-dimetilbut-l-il)-2,4-diokso-5-(2-fluorofenil)-2,3,4,5-tetrahidro-lH-l,5benzodiazepin-3-ill-N^,-(3-metilmerkapto)fenilsečninaN- [1- (3,3-dimethylbut-1-yl) -2,4-dioxo-5- (2-fluorophenyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl -N ^, - (3-methylmercapto) phenylurea

3-metilmerkaptoanilin (0,19 ml) dodamo k raztopini intermediata 9 (0,3 g) v suhem dimetilformamidu (5 ml) v atmosferi dušika. Raztopino segrevamo 5 ur na 160°, nato ohladimo na sobno temperaturo, razredčimo z vodo in ekstrahiramo z etilacetatom (2 x 20 ml). Združene organske ekstrakte posušimo, koncentriramo v vakuumu in trituriramo z acetonitrilom, da dobimo naslovno spojino kot belo trdno snov (0,08 g). Tal. 249-250°. T.l.c. CH-EA (7:3), Rf 0,33. IR: 3308 (NH), 1707, 1676, in 1643 (C=O), 1607 (C=C) cm-1; Ή-NMR: 7,48-7,30 (m); 7,28-7,10 (m); 7,04-6,90 (m); 6,83-(bs); 6,29 (d); 5,34 (d); 4,41 (m); 3,71 (m); 2,44 (s); 1,50 (m); 0,93 (s).3-Methylmercaptoaniline (0.19 ml) was added to a solution of Intermediate 9 (0.3 g) in dry dimethylformamide (5 ml) under a nitrogen atmosphere. The solution was heated to 160 ° C for 5 hours, then cooled to room temperature, diluted with water and extracted with ethyl acetate (2 x 20 ml). The combined organic extracts were dried, concentrated in vacuo and triturated with acetonitrile to give the title compound as a white solid (0.08 g). Tal. 249-250 °. T.l.c. CH-EA (7: 3), Rf 0.33. IR: 3308 (NH), 1707, 1676, and 1643 (C = O), 1607 (C = C) cm -1; Ή-NMR: 7.48-7.30 (m); 7.28-7.10 (m); 7.04-6.90 (m); 6.83- (bs); 6.29 (d); 5.34 (d); 4.41 (m); 3.71 (m); 2.44 (s); 1.50 (m); 0.93 (s).

PRIMER 6EXAMPLE 6

N-[l-(3,3-dimetiIbut-l-il)-2,4-diokso-5-(2-fluorofenil)-2,3A5-tetrahidro-lHl,5-benzodiazepin-3-il1-N^>-(3-dimetilamino)fenilsečninaN- [1- (3,3-dimethylbut-1-yl) -2,4-dioxo-5- (2-fluorophenyl) -2,3A5-tetrahydro-1H, 5-benzodiazepin-3-yl1-N ^> - (3-dimethylamino) phenylurea

Trietilamin (0,43 ml) in 3-dimetilaminoanilin-dihidroklorid (0,324 g) dodamo k raztopini intermediata 9 (0,3 g) v suhem dimetilformamidu (5 ml) v atmosferi dušika. Rztopino segrevamo 2 uri na 160°, nato ohladimo na sobno temperaturo, razredčimo z vodo in ekstrahiramo z etilacetatom (2 x 20 ml). Združene organske ekstrakte posušimo, koncentriramo v vakuumu in trituriramo z acetonitrilom, da dobimo naslovno spojino kot belo trdno snov (0,16 g). Tal. 255-256°. T.l.c. CH-EA (6:4), Rf 0,28. IR: 3308 (NH), 1717 (C=O), 1637 (C=C) cm-1; Ή-NMR: 7,48-7,10 (m); 6,98 (dd);Triethylamine (0.43 ml) and 3-dimethylaminoaniline dihydrochloride (0.324 g) were added to a solution of Intermediate 9 (0.3 g) in dry dimethylformamide (5 ml) under a nitrogen atmosphere. The solution was heated to 160 ° for 2 hours, then cooled to room temperature, diluted with water and extracted with ethyl acetate (2 x 20 ml). The combined organic extracts were dried, concentrated in vacuo and triturated with acetonitrile to give the title compound as a white solid (0.16 g). Tal. 255-256 °. T.l.c. CH-EA (6: 4), Rf 0.28. IR: 3308 (NH), 1717 (C = O), 1637 (C = C) cm -1; Ή-NMR: 7.48-7.10 (m); 6.98 (dd);

6,81 (t); 6,66-6,56 (m); 6,46 (dd); 6,34 (d); 5,36 (d); 4,41 (m); 3,70 (m).6.81 (t); 6.66-6.56 (m); 6.46 (dd); 6.34 (d); 5.36 (d); 4.41 (m); 3.70 (m).

PRIMER 7AEXAMPLE 7A

N-[l-(3,3-dimetil-2-hidroksibut-l-il)-2Adiokso-5-(2-fluorofenil)-2,3A5-tetrahidrolH-l,5-benzodiazepin-3-il]-N’-fenilsečninaN- [1- (3,3-dimethyl-2-hydroxybut-1-yl) -2Adioxo-5- (2-fluorophenyl) -2,3A5-tetrahydrol-1,5-benzodiazepin-3-yl] -N ' -Phenylurea

Fenilizocianat (0,068 ml) dodamo k raztopini intermediata 12 (0,2 g) v suhem acetonitrilu (5 ml) v atmosferi dušika. Zmes mešamo 20 ur pri 23°, koncentriramo v vakuumu in ostanek trituriramo z dietiletrom, da dobimo naslovno spojino kot belo trdno snov (0,2 g). Tal. 248-249°. T.l.c. CH-EA (1:1), Rf 0,60 in 0,58. IR: 3308 (NH), 1709, in 1670 (C=O), 1639 in 1601 (C=C) cm-1; ^-NMR: 7,66 (d); 7,46-7,06 (m); 7,02-6,9 (m); 6,8-6,7 (bs); 6,62 (d); 5,412 (d); in 5,402 (d); 4,492 (bd); 4,303 (bm); 3,936 (d); 3,95-3,85 (m); 3,613 (bt); 3,48 (bs); 2,634 (bs); 2,504 (bs); 0,918 (s).Phenylisocyanate (0.068 ml) was added to a solution of Intermediate 12 (0.2 g) in dry acetonitrile (5 ml) under a nitrogen atmosphere. The mixture was stirred for 20 hours at 23 °, concentrated in vacuo, and the residue triturated with diethyl ether to afford the title compound as a white solid (0.2 g). Tal. 248-249 °. T.l.c. CH-EA (1: 1), Rf 0.60 and 0.58. IR: 3308 (NH), 1709, and 1670 (C = O), 1639 and 1601 (C = C) cm-1; 1 H-NMR: 7.66 (d); 7.46-7.06 (m); 7.02-6.9 (m); 6.8-6.7 (bs); 6.62 (d); 5,412 (d); and 5,402 (d); 4,492 (bd); 4,303 (bm); 3,936 (d); 3.95-3.85 (m); 3,613 (bt); 3.48 (bs); 2,634 (bs); 2,504 (bs); 0.918 (s).

PRIMER 7BEXAMPLE 7B

N-[l-(3,3-dimetil-2-hidroksibut-l-il)-2,4-diokso-5-(2-fluorofenil)-2,3,4,5tetrahidro-lH-l,5-benzodiazepin-3-il]-N’-fenilsečnina (diastereomer I)N- [1- (3,3-dimethyl-2-hydroxybut-1-yl) -2,4-dioxo-5- (2-fluorophenyl) -2,3,4,5tetrahydro-1H-1,5-benzodiazepine -3-yl] -N'-phenylurea (diastereomer I)

Fenilizocianat (0,0984 ml) dodamo k suspenziji intermediata 13a (0,29 g) v suhem acetonitrilu (5 ml) v atmosferi dušika. Zmes mešamo 20 ur pri 23°, koncentriramo v vakuumu in ostanek trituriramo z dietiletrom, da dobimo naslovno spojino kot belo trdno snov (0,29 g). Tal. 255-256°(razp.). T.l.c. CH-EA (1:1), Rf 0,6. IR: 3352,3282 in 3253 (NH in OH), 1705 in 1680 (C=O), 1630 in 1599 (C=C) cm-1; VH-NMR: 7,905 (dd); 7,38-7,24 (m); 7,24-7,1 (m); 7,05 (bs); 6,98-6,85 (m); 6,80 (bs); 5,395 (d); 4,513 (bd); 3,936 (bs); 3,598 (bt); 2,521 (bs); 0,924 (s).Phenylisocyanate (0.0984 ml) was added to a suspension of intermediate 13a (0.29 g) in dry acetonitrile (5 ml) under a nitrogen atmosphere. The mixture was stirred for 20 hours at 23 °, concentrated in vacuo, and the residue triturated with diethyl ether to give the title compound as a white solid (0.29 g). Tal. 255-256 ° (dec.). T.l.c. CH-EA (1: 1), Rf 0.6. IR: 3352,3282 and 3253 (NH and OH), 1705 and 1680 (C = O), 1630 and 1599 (C = C) cm-1; VH-NMR: 7,905 (dd); 7.38-7.24 (m); 7.24-7.1 (m); 7.05 (bs); 6.98-6.85 (m); 6.80 (bs); 5,395 (d); 4,513 (bd); 3,936 (bs); 3,598 (bt); 2,521 (bs); 0.924 (s).

PRIMER 7CEXAMPLE 7C

N-[l-(3,3-dimetil-2-hidroksibut-l-il)-2,4-diokso-5-(2-fluorofenil)-2,3,4,5tetrahidro-lH-l,5-benzodiazepin-3-il1-N’-fenilsečnina (diastereomer II)N- [1- (3,3-dimethyl-2-hydroxybut-1-yl) -2,4-dioxo-5- (2-fluorophenyl) -2,3,4,5tetrahydro-1H-1,5-benzodiazepine -3-yl1-N'-phenylurea (diastereomer II)

Fenilizocianat (0,12 ml) dodamo k suspenziji intermediata 13b (0,33 g) v suhem acetonitrilu (5 ml) v atmosferi dušika. Zmes mešamo 3 ure pri 23°, filtriramo in trdno snov izperemo z dietiletrom, da dobimo naslovno spojino kot belo trdno snov (0,27 g). Tal. 204-205°. T.l.c. CH-EA (1:1), Rf 0,58. IR: 3308 (NH in OH), 1718 in 1670 (C=O), 1601 (C=C), cm-1; ^-NMR: 7,86 (d); 7,4-7,12 (m); 7,02-6,94 (m); 6,577 (d); 5,414 (d); 4,312 (t); 3,931 (d); 3,454 (bs); 2,560 (bs); 0,919 (s).Phenylisocyanate (0.12 ml) was added to a suspension of intermediate 13b (0.33 g) in dry acetonitrile (5 ml) under a nitrogen atmosphere. The mixture was stirred for 3 hours at 23 °, filtered and the solid was washed with diethyl ether to give the title compound as a white solid (0.27 g). Tal. 204-205 °. T.l.c. CH-EA (1: 1), Rf 0.58. IR: 3308 (NH and OH), 1718 and 1670 (C = O), 1601 (C = C), cm-1; 1 H-NMR: 7.86 (d); 7.4-7.12 (m); 7.02-6.94 (m); 6,577 (d); 5,414 (d); 4,312 (t); 3,931 (d); 3,454 (bs); 2,560 (bs); 0.919 (s).

PRIMER 8EXAMPLE 8

N-fl-(l,3-dimetilbut-l-il)-2,4-diokso-5-fenil-2,3,4,5-tetrahidro-lH-l,5benzodiazepin-3-ill-N^>-fenilsečninaN-Fl- (l, 3-dimethylbutyl-l-yl) -2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-lH-l, ^{5benzodiazepin-3-yl-N>} -fenilsečnina

Fenilizocianat (0,1 ml) dodamo k raztopini intermediata 16 (0,22 g) v suhem acetonitrilu (10 ml) v atmosferi dušika. Zmes mešamo 1 uro pri 23°, koncentriramo v vakuumu, da dobimo olje, ki ga čistimo s flash kromatografijo (ob eluiranju s CH-EA 80:20, da dobimo surov vzorec, ki ga trituriramo z 1:1 z zmesjo petroletra/etiletra (30 ml), da dobimo naslovno spojino (0,12 g). T.l.c. CH-EA (1:1), Rf 0,53. IR: 3370 (NH), 1701 in 1670 (C=O), 1651 in 1601 (C=C), cm-1; Ή-NMR: 7,44-7,35 (m); 7,34-7,24 (m); 7,24-7,15 (m); 6,982 (m); 6,538 (d); 6,529 (d); 5,328 (d); 5,321 (d); 4,576 (m); 4,438 (q); 2,11 (m); 1,74-1,64 (m); 1,64-1,44 (m); 1,542 (d); 1,435 (d); 0,886 (d); 0,882 (d); 0,873 (d); 0,827 (d).Phenylisocyanate (0.1 ml) was added to a solution of Intermediate 16 (0.22 g) in dry acetonitrile (10 ml) under a nitrogen atmosphere. The mixture was stirred at 23 ° for 1 hour, concentrated in vacuo to give an oil which was purified by flash chromatography (eluting with CH-EA 80:20 to give a crude sample, triturated with 1: 1 with a petroleum ether / ethyl ether mixture (30 ml) to give the title compound (0.12 g). Tlc CH-EA (1: 1), Rf 0.53. IR: 3370 (NH), 1701 and 1670 (C = O), 1651 and 1601 (C = C), cm-1; Ή-NMR: 7.44-7.35 (m); 7.34-7.24 (m); 7.24-7.15 (m); 6.982 (m ); 6.538 (d); 6.529 (d); 5.328 (d); 5.321 (d); 4.576 (m); 4.438 (q); 2.11 (m); 1.74-1.64 (m); 1.64-1.44 (m); 1.542 (d); 1.435 (d); 0.886 (d); 0.882 (d); 0.873 (d); 0.827 (d).

PRIMER 9EXAMPLE 9

N-i7-kloro-2,4-diokso-l-(3-metiIbut-l-il)-5-fenil-2,3A5-tetrahidro-lH-l,5benzodiazepin-3-il]-N^,-fenilsečninaN-7-chloro-2,4-dioxo-1- (3-methylbut-1-yl) -5-phenyl-2,3A5-tetrahydro-1H-1,5-benzodiazepin-3-yl] -N ^, -phenylurea

Fenilizocianat (0,1 ml) dodamo k raztopini intermediata 20 (0,2 g) v suhem acetonitrilu (9 ml) v atmosferi dušika. Zmes mešamo 2 uri pri 0°, filtriramo in trdno snov trituriramo s petroletrom/etiletrom (2/2 ml) pri 0°, odfiltriramo, izperemo z 1/1 zmesjo petroletra/etiletra (10 ml), da dobimo naslovno spojino kot belo trdno snov (0,17 g). T.l.c. CH-EA (1:1), Rf 0,59. IR: 3312 (NH), 1713 in 1684 (C=O), 1639 in 1605 (C=C), cm-1; Ή-NMR: 7,45-7,00 (m); 7,10 (m); 6,989 (dd); 6,97 (d); 6,42 (d);Phenylisocyanate (0.1 ml) was added to a solution of Intermediate 20 (0.2 g) in dry acetonitrile (9 ml) under a nitrogen atmosphere. The mixture was stirred at 0 ° for 2 hours, filtered and the solid triturated with petroleum ether / ethyl ether (2/2 ml) at 0 °, filtered off, washed with 1/1 petroleum ether / ethyl ether (10 ml) to give the title compound as a white solid substance (0.17 g). T.l.c. CH-EA (1: 1), Rf 0.59. IR: 3312 (NH), 1713 and 1684 (C = O), 1639 and 1605 (C = C), cm-1; Ή-NMR: 7.45-7.00 (m); 7.10 (m); 6,989 (dd); 6.97 (d); 6.42 (d);

5,31 (d); 4,51 (m); 3,59 (m); 1,58-1,46 (m); 1,46-1,38 (m); 0,87 (d); 0,85 (d).5.31 (d); 4.51 (m); 3.59 (m); 1.58-1.46 (m); 1.46-1.38 (m); 0.87 (d); 0.85 (d).

PRIMER 10EXAMPLE 10

N-[8-kloro-2,4-diokso-l-(3-metilbut-l-il)-5-fenil-2,3A5-tetrahidro-lH-l,5benzodiazeDin-3-ill-N’-fenilsečninaN- [8-chloro-2,4-dioxo-1- (3-methylbut-1-yl) -5-phenyl-2,3A5-tetrahydro-1H-1,5-benzodiazepin-3-yl-N'-phenylurea

Fenilizocianat (0,1 ml) dodamo k raztopini intermediata 25 (0,2 g) v suhem acetonitrilu (4 ml) v atmosferi dušika, zmes mešamo 30 minut pri 0°, nato dodamo petroleter in mešamo še 1 uro. Trdno snov odfiltriramo, izperemo s 3/1 zmesjo petroletra/etiletra (15 ml), da dobimo naslovno spojino kot belo trdno snov (0,22 g). T.l.c. CH-EA (1:1), Rf 0,63. IR: 3310 (NH), 1717, 1668 in 1641 (C=O), cm-1; ΉNMR: 7,44-7,35 (m); 7,32 (t); 7,25-7,16 (m); 7,14 (m); 7,03 (m); 6,92 (d); 6,41 (d);Phenylisocyanate (0.1 ml) was added to a solution of Intermediate 25 (0.2 g) in dry acetonitrile (4 ml) under a nitrogen atmosphere, the mixture was stirred for 30 minutes at 0 °, then petroleum ether was added and stirred for another 1 hour. The solid was filtered off, washed with a 3/1 petroleum ether / ethyl ether mixture (15 ml) to give the title compound as a white solid (0.22 g). T.l.c. CH-EA (1: 1), Rf 0.63. IR: 3310 (NH), 1717, 1668 and 1641 (C = O), cm-1; ΉNMR: 7.44-7.35 (m); 7.32 (t); 7.25-7.16 (m); 7.14 (m); 7.03 (m); 6.92 (d); 6.41 (d);

5,31 (d); 4,52 (m); 3,62 (m); 1,60-1,40 (m); 0,89 (d); 0,87 (d).5.31 (d); 4.52 (m); 3.62 (m); 1.60-1.40 (m); 0.89 (d); 0.87 (d).

PRIMER 11EXAMPLE 11

N-i7,8-dikloro-2,4-diokso-l-(3-metilbut-l-il)-5-fenil-2,3,4,5-tetrahidro-lHl^-benzodiazepin-S-ilj-NMenilsečninaN-7,8-Dichloro-2,4-dioxo-1- (3-methylbut-1-yl) -5-phenyl-2,3,4,5-tetrahydro-1 H -benzodiazepine-S-yl-N-urea urea

Fenilizocianat (0,09 ml) dodamo k raztopini intermediata 30 (0,19 g) v suhem acetonitrilu (2,5 ml) v atmosferi dušika. Zmes mešamo 20 minut pri 0°, nato uparimo do suhega in dobljeno trdno snov trituriramo z 1/1 zmesjo petroletra/etiletra (10 ml) 1 uro pri 0°, odfiltriramo, izperemo z 1/1 zmesjo petroletra/etiletra (15 ml), da dobimo naslovno spojino kot belo trdno snov (0,15 g). T.l.c. CH-EA (1:1), Rf 0,6. IR: 3375 (NH), 1711, 1684 in 1655 (C=O), 1599, 1547 9C=C) cm-1; Ή-NMR: 7,51 (s); 7,46-7,32 (m); 7,28-7,14 (m); 7,05 (s); 7,06-7,00 (m); 6,40 (d); 5,31 (d); 4,50 (m); 3,56 (m); 1,60-1,40 (m); 0,89 (d); 0,86 (d).Phenylisocyanate (0.09 ml) was added to a solution of Intermediate 30 (0.19 g) in dry acetonitrile (2.5 ml) under a nitrogen atmosphere. The mixture was stirred at 0 ° for 20 minutes, then evaporated to dryness and the resulting solid triturated with 1/1 petroleum ether / ethyl ether (10 ml) for 1 hour at 0 °, filtered off, washed with 1/1 petroleum ether / ethyl ether (15 ml). to give the title compound as a white solid (0.15 g). T.l.c. CH-EA (1: 1), Rf 0.6. IR: 3375 (NH), 1711, 1684 and 1655 (C = O), 1599, 1547 9C = C) cm-1; Ή-NMR: 7.51 (s); 7.46-7.32 (m); 7.28-7.14 (m); 7.05 (s); 7.06-7.00 (m); 6.40 (d); 5.31 (d); 4.50 (m); 3.56 (m); 1.60-1.40 (m); 0.89 (d); 0.86 (d).

PRIMER 12EXAMPLE 12

N-[2,4-diokso-8-fluro-l-(3-metilbut-l-il)-5-fenil-2,3,4,5-tetrahidro-lH-l,5benzodiazepin-3-il]-N’-fenilsečninaN- [2,4-dioxo-8-fluoro-1- (3-methylbut-1-yl) -5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl] - N'-phenylurea

Fenilizocianat (0,1 ml) dodamo k raztopini intermediata 35 (0,2 g) v suhem acetonitrilu (2,5 ml) v atmosferi dušika. Zmes mešamo 30 minut pri 0°, nato dodamo dietleter (5 ml) in mešamo še 1 uro. Dobljeno trdno snov odfiltriramo, izperemo z 1/1 zmesjo petroletra/etiletra (10 ml), da dobimo naslovno spojino kot belo trdno snov (0,25 g). T.l.c. CH-EA (1:1), Rf 0,53. IR: 3312 (NH), 1718, 1670 (C=O), 1639, 1605 (C=C) cm-1; Ή-NMR: 7,44-7,36 (m); 7,32 (t); 7,30-7,10 (m); 7,06-6,9 (m); 6,35 (d); 5,33 (d); 4,52 (m); 3,62 (m); 1,60-1,40 (m); 0,90 (d); 0,87 (d).Phenylisocyanate (0.1 ml) was added to a solution of Intermediate 35 (0.2 g) in dry acetonitrile (2.5 ml) under a nitrogen atmosphere. The mixture was stirred for 30 minutes at 0 °, then diethyl ether (5 ml) was added and stirred for another 1 hour. The resulting solid was filtered off, washed with 1/1 petroleum ether / ethyl ether mixture (10 ml) to give the title compound as a white solid (0.25 g). T.l.c. CH-EA (1: 1), Rf 0.53. IR: 3312 (NH), 1718, 1670 (C = O), 1639, 1605 (C = C) cm -1; Ή-NMR: 7.44-7.36 (m); 7.32 (t); 7.30-7.10 (m); 7.06-6.9 (m); 6.35 (d); 5.33 (d); 4.52 (m); 3.62 (m); 1.60-1.40 (m); 0.90 (d); 0.87 (d).

PRIMER 13EXAMPLE 13

N-[2,4-diokso-5-fenil-l-(2-feniletil)-2,3,4,5-tetrahidro-lH-l,5-benzodiazepin3-ilj-N’-fenilsečninaN- [2,4-dioxo-5-phenyl-1- (2-phenylethyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-yl-N'-phenylurea

Fenilizocianat (0,1 ml) dodamo k raztopini intermediata 38 (0,3 g) v suhem acetonitrilu (15 ml) v atmosferi dušika. Zmes mešamo 1 uro pri 23°, dodamo EE (30 ml) in dobljeno oborino mešamo 45 minut pri 0°. Oborino filtriramo, izperemo z dietiletrom (25 ml), da dobimo naslovno spojino kot belo trdno snov (0,27 g). T.l.c. CH-EA (1:1), Rf 0,45. IR: 3310 (NH), 1707, 1678 (C=O), 1643, 1603, 1556 (C=C) cm-1; Ή-NMR: 7,428 (dd); 7,36-7,27 (m); 7,27-7,12 (m); 7,07-6,94 (m); 6,484 (d); 5,361 (d); 4,78-4,66 (m); 3,98-3,86 (m); 2,927 (m).Phenylisocyanate (0.1 ml) was added to a solution of Intermediate 38 (0.3 g) in dry acetonitrile (15 ml) under a nitrogen atmosphere. The mixture was stirred at 23 ° for 1 hour, EE (30 ml) was added and the resulting precipitate was stirred at 0 ° for 45 minutes. The precipitate was filtered, washed with diethyl ether (25 ml) to give the title compound as a white solid (0.27 g). T.l.c. CH-EA (1: 1), Rf 0.45. IR: 3310 (NH), 1707, 1678 (C = O), 1643, 1603, 1556 (C = C) cm -1; Ή-NMR: 7.428 (dd); 7.36-7.27 (m); 7.27-7.12 (m); 7.07-6.94 (m); 6,484 (d); 5,361 (d); 4.78-4.66 (m); 3.98-3.86 (m); 2,927 (m).

PRIMER 14EXAMPLE 14

N-[l-(l-adamantil)metil-2,4-diokso-5-fenil-2.3,4.5-tetrahidro-lH-l,5benzodiazepin-3-il]-N’-fenilsečninaN- [1- (1-adamantyl) methyl-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl] -N'-phenylurea

Fenilizocianat (0,039 ml) dodamo k raztopini intermediata 41 (0,13 g) v suhem acetonitrilu (7 ml) v atmosferi dušika. Zmes mešamo 1,5 ure in dobljeno oborino odfiltriramo ob izpiranju z acetonitrilom (3 ml), da dobimo naslovno spojino kot belo trdno snov (0,085 g). T.l.c. CH-EA (1:1), Rf 0,23. IR: 3294 (NH), 1717, 1705, 1680 (C=O), 1643, (C=C) cm-1; Ή-NMR: 7,5-6,96 (m); 7,08 (bs); 6,50 (d); 5,31 (d); 4,49 (d); 3,37 (d); 1,84 (m); 1,6-1,3 (m).Phenylisocyanate (0.039 ml) was added to a solution of Intermediate 41 (0.13 g) in dry acetonitrile (7 ml) under a nitrogen atmosphere. The mixture was stirred for 1.5 hours and the resulting precipitate was filtered off by washing with acetonitrile (3 ml) to give the title compound as a white solid (0.085 g). T.l.c. CH-EA (1: 1), Rf 0.23. IR: 3294 (NH), 1717, 1705, 1680 (C = O), 1643, (C = C) cm -1; Ή-NMR: 7.5-6.96 (m); 7.08 (bs); 6.50 (d); 5.31 (d); 4.49 (d); 3.37 (d); 1.84 (m); 1.6-1.3 (m).

PRIMER 15EXAMPLE 15

N-[l-(2,2-dimetiletoksikarbonilmetil)-2,4-diokso-5-fenil-2,3,4,5-tetrahidrolH-l.S-benzodiazepin-S-ilj-N^fenilsečninaN- [1- (2,2-dimethylethoxycarbonylmethyl) -2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrolH-1S-benzodiazepine-S-yl-N ^ phenylurea

Fenilizocianat (0,091 ml) dodamo k raztopini intermediata 44 (0,244 g) v suhem acetonitrilu (16 ml) v atmosferi dušika. Zmes mešamo 2 uri pri 23°, dodamo diklorometan (30 ml) in organski sloj izperemo s slanico (2 x 10 ml), posušimo in koncentriramo v vakuumu. Surov produkt čistimo s flash kromatografijo (ob eluiranju z DCM-metanolom 98:2), da dobimo naslovno spojino kot belo trdno snov (0,232 g). T.l.c. DCM-metanol (95:5), Rf 0,8. IR: 3431, 3395 (NH), 1745, 1684 (C=O) cm-1; Ή-NMR: 7,4-6,95 (m); 7,1 (bs); 6,5 (d); 5,45 (d); 4,61 (dd); 1,40 (s).Phenylisocyanate (0.091 ml) was added to a solution of Intermediate 44 (0.244 g) in dry acetonitrile (16 ml) under a nitrogen atmosphere. The mixture was stirred at 23 ° for 2 hours, dichloromethane (30 ml) was added and the organic layer was washed with brine (2 x 10 ml), dried and concentrated in vacuo. The crude product was purified by flash chromatography (eluting with DCM-methanol 98: 2) to give the title compound as a white solid (0.232 g). T.l.c. DCM-methanol (95: 5), Rf 0.8. IR: 3431, 3395 (NH), 1745, 1684 (C = O) cm -1; Ή-NMR: 7.4-6.95 (m); 7.1 (bs); 6.5 (d); 5.45 (d); 4.61 (dd); 1.40 (s).

PRIMER 16EXAMPLE 16

N-il-(3,3-dimetilbutil)-2,4-diokso-5-fenil-2,3,4,5-tetrahidro-lH-l,5-benzodiazepin3-ill-N’-fenilsečninaN-yl- (3,3-dimethylbutyl) -2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine 3-ill-N'-phenylurea

Fenilizocianat (0,067) ml dodamo k raztopini intermediata 47 (0,190 g) v suhem acetonitrilu (10 ml) v atmosferi dušika. Zmes mešamo 1 uro pri 23° in nastalo oborino filtriramo ob izpiranju z acetonitrilom (3 ml), da dobimo naslovno spojino kot belo trdno snov (0,198 g). T.l.c. CH-EA (1:1), Rf 0,57. IR: 3431, 3350 (NH), 1745, 1668, (C=O), 1599 (C=C) cm-1; Ή-NMR: 7,48-7,26 (m); 7,26-7,14 (m); 7,04-6,96 (m); 6,523 (d); 5,352 (d); 4,511-4,409 (m); 1,467 (t); 0,915 (s).Phenylisocyanate (0.067) ml was added to a solution of Intermediate 47 (0.190 g) in dry acetonitrile (10 ml) under a nitrogen atmosphere. The mixture was stirred at 23 ° for 1 hour and the resulting precipitate was filtered off by washing with acetonitrile (3 ml) to give the title compound as a white solid (0.198 g). T.l.c. CH-EA (1: 1), Rf 0.57. IR: 3431, 3350 (NH), 1745, 1668, (C = O), 1599 (C = C) cm -1; Ή-NMR: 7.48-7.26 (m); 7.26-7.14 (m); 7.04-6.96 (m); 6,523 (d); 5,352 (d); 4,511-4,409 (m); 1,467 (t); 0.915 (s).

PRIMER 17EXAMPLE 17

N-i2,4-diokso-l-f2-hidroksi'-3-metilbutil)-5-fenil-2,3,4,5-tetrahidro-lH-l,556 benzodiazepin-3-ill-N’-fenilsečninaN-1,2,4-dioxo-1-f2-hydroxy'-3-methylbutyl) -5-phenyl-2,3,4,5-tetrahydro-1H-1, 556 benzodiazepin-3-yl-N'-phenylurea

K raztopini intermediata 63 (0,12 g) v metanolu (20 ml) in vodi (3 ml) dodamo po deležih pri 0° natrijev borohidrid (1,5 g), pri čemer vzdržujemo pH pri 7 do 7,5 z dodatkom 1 M raztopine klorovodikove kisline. Med reakcijo dodamo najdaljnji metanol. Reakcijsko zmes mešamo 1 uro, nato koncentriramo, razredčimo z etilacetatom (100 ml) in izperemo s slanico (3 x 70 ml), posušimo in koncentriramo v vakuumu. Surov produkt raztopimo v dietiletru (5 ml) in oborimo s petroletrom (10 ml), da dobimo naslovno spojino kot belo trdno snov (0,07 g). T.l.c. CH-EA (1:1), Rf 0,36. IR: 3337 (NH, OH), 1701, 1647, (C=O), 1597, 1553 (C=C) cm-1; Ή-NMR:To a solution of intermediate 63 (0.12 g) in methanol (20 ml) and water (3 ml) was added portionwise at 0 ° sodium borohydride (1.5 g), maintaining the pH at 7 to 7.5 with the addition of 1 M hydrochloric acid solution. The longest methanol is added during the reaction. The reaction mixture was stirred for 1 hour, then concentrated, diluted with ethyl acetate (100 ml) and washed with brine (3 x 70 ml), dried and concentrated in vacuo. The crude product was dissolved in diethyl ether (5 ml) and precipitated with light petroleum (10 ml) to give the title compound as a white solid (0.07 g). T.l.c. CH-EA (1: 1), Rf 0.36. IR: 3337 (NH, OH), 1701, 1647, (C = O), 1597, 1553 (C = C) cm -1; Ή-NMR:

7,6-6,65 (m); 5,37 (d); 5,35 (d); 3,92 (bm); 3,48 (bm); 4,50 (dd); 3,80 (dd); 4,34 (dd); 3,57 (dd); 2,50 (bm); 1,58 (m); 0,93-0,87 (m).7.6-6.65 (m); 5.37 (d); 5.35 (d); 3.92 (bm); 3.48 (bm); 4.50 (dd); 3.80 (dd); 4.34 (dd); 3.57 (dd); 2.50 (bm); 1.58 (m); 0.93-0.87 (m).

PRIMER 18EXAMPLE 18

N-[l-(3,3-dimetilbutil)-2.4-diokso-5-fenil-2,3.4,5-tetrahidro-lH-l,5-benzodiazepin3-il1-N^,-(3-trifluorometoksifenil)sečninaN- [1- (3,3-dimethylbutyl) -2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl-N ^, - (3-trifluoromethoxyphenyl) urea

Raztopino 3-trifluorometoksifenilamina (0,047 g) in intermediata 48 (0,100 g) v diklorometanu (5 ml) mešamo 20 ur pri 23° v atmosferi dušika, nato koncentriramo v vakuumu. Surov produkt trituriramo z acetonitrilom (2 ml), da dobimo naslovno spojino kot belo trdno snov (0,067 g). T.l.c. CH-EA (60:40), Rf 0,57. IR: 3317 (NH), 1717,1650, (C=O), 1609,1558 (C=C) cm-1; Ή-NMR: 7,53 (bs); 7,46 (dd); 7,45-7,30 (m); 7,30-7,18 (m); 7,10 (t); 7,00 (dd); 6,88 (m); 6,77 (m); 6,66 (d); 5,35 (d); 4,44 (m);A solution of 3-trifluoromethoxyphenylamine (0.047 g) and intermediate 48 (0.100 g) in dichloromethane (5 ml) was stirred for 20 hours at 23 ° under a nitrogen atmosphere, then concentrated in vacuo. The crude product was triturated with acetonitrile (2 ml) to give the title compound as a white solid (0.067 g). T.l.c. CH-EA (60:40), Rf 0.57. IR: 3317 (NH), 1717.1650, (C = O), 1609.1558 (C = C) cm-1; Ή-NMR: 7.53 (bs); 7.46 (dd); 7.45-7.30 (m); 7.30-7.18 (m); 7.10 (t); 7.00 (dd); 6.88 (m); 6.77 (m); 6.66 (d); 5.35 (d); 4.44 (m);

3,70 (m); 1,54-1,42 (m); 0,91 (s).3.70 (m); 1.54-1.42 (m); 0.91 (s).

PRIMER 19EXAMPLE 19

N-[l-(3,3-dimetilbutil)-2,4-diokso-5-fenil-2,3,4,5-tetrahidro-lH-l,5-benzodiazepin3-ill-N^>-(3-cianofenil)sečninaN- [1- (3,3-dimethylbutyl) -2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl-N ^> - (3-cyanophenyl) ) urea

Raztopino 3-cianofenilamina (0,118 g) in intermediata 48 (0,339 g) v diklorometanu (10 ml) mešamo 5 ur pri 23° v atmosferi dušika, nato koncentriramo v vakuumu. Surov produkt trituriramo z acetonitrilom (8 ml), filtriramo in izperemo z acetonitrilom (3 ml), da dobimo naslovno spojino kot belo trdno snov (0,216 g). T.l.c. CH-EA (1:1), Rf 0,55. IR: 3319 (NH), 2230 (C=N), 1711, 1647 (C=O) cm-1; ΉNMR: 7,91 (bs); 7,52-7,30 (m); 7,30-7,12 (m); 7,01 (dd); 6,88 (d); 5,34 (d); 4,52-4,38 (m); 3,80-3,68 (m); 1,51 (m); 0,91 (s).A solution of 3-cyanophenylamine (0.118 g) and intermediate 48 (0.339 g) in dichloromethane (10 ml) was stirred for 5 hours at 23 ° under a nitrogen atmosphere, then concentrated in vacuo. The crude product was triturated with acetonitrile (8 ml), filtered and washed with acetonitrile (3 ml) to give the title compound as a white solid (0.216 g). T.l.c. CH-EA (1: 1), Rf 0.55. IR: 3319 (NH), 2230 (C = N), 1711, 1647 (C = O) cm -1; ΉNMR: 7.91 (bs); 7.52-7.30 (m); 7.30-7.12 (m); 7.01 (dd); 6.88 (d); 5.34 (d); 4.52-4.38 (m); 3.80-3.68 (m); 1.51 (m); 0.91 (s).

PRIMER 20EXAMPLE 20

N-il-(3,3-dimetilbutil)-2,4-diokso-5-fenil-2,3A5-tetrahidro-lH-l,5-benzodiazepin3-ill-N’-f3-metiltiofenil)sečninaN-yl- (3,3-dimethylbutyl) -2,4-dioxo-5-phenyl-2,3A5-tetrahydro-1H-1,5-benzodiazepin-3-yl-N'-f3-methylthiophenyl) urea

K raztopini intermediata 49 (0,20 g) v suhem DMF (5 ml) dodamo 3-metiltiofenilamin (0,218 ml) in reakcijsko zmes mešamo 4 ure pri 120° v atmosferi dušika. Dodamo etilacetat (50 ml) ter raztopino izperemo z vodo (2 x 25 ml) in slanico (25 ml), posušimo in koncentriramo v vakuumu. Surov produkt trituriramo z acetonitrilom (4 ml), da dobimo naslovno spojino kot belo trdno snov (0,115 g). T.l.c. CHEA (1:1), Rf 0,62. IR: 3300 (NH), 1705, 1674,1641 (C=O), 1607 (C=C) cm-1; ^ΧΗNMR: 7,48-7,10 (m); 7,02-6,90 (m); 6,82 (s); 6,30 (d); 5,30 (d); 4,46 (m); 3,70 (m); 2,44 (s); 1,48 (t); 0,93 (s).To a solution of intermediate 49 (0.20 g) in dry DMF (5 ml) was added 3-methylthiophenylamine (0.218 ml) and the reaction mixture was stirred for 4 hours at 120 ° under a nitrogen atmosphere. Ethyl acetate (50 ml) was added and the solution was washed with water (2 x 25 ml) and brine (25 ml), dried and concentrated in vacuo. The crude product was triturated with acetonitrile (4 ml) to give the title compound as a white solid (0.115 g). Tlc CHEA (1: 1), Rf 0.62. IR: 3300 (NH), 1705, 1674, 1641 (C = O), 1607 (C = C) cm -1; ^Χ Η NMR: 7.48-7.10 (m); 7.02-6.90 (m); 6.82 (s); 6.30 (d); 5.30 (d); 4.46 (m); 3.70 (m); 2.44 (s); 1.48 (t); 0.93 (s).

PRIMER 21EXAMPLE 21

N-il-(3,3-dimetilbutil)-2,4-diokso-5-fenil-2,3,4,5-tetrahidro-lH-l,5-benzodiazepin3-il]-N’-f3-N,N-dimetilaminofenil)sečninaN-yl- (3,3-dimethylbutyl) -2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin3-yl] -N'-f3-N, N-dimethylaminophenyl) urea

K raztopini intermediata 49 (0,20 g) v suhem DMF (8 ml) dodamo 3-N,N-dimetilaminofenil-hidroklorid (0,177 g) in trietilamin (0,118 ml) ter reakcijsko zmes mešamo 4 ure pri 120° v atmosferi dušika. Dodamo etilacetat (50 ml), raztopino izperemo z vodo (2 x 25 ml) in slanico (25 ml), posušimo in koncentriramo v vakuumu. Surov produkt čistimo s flash kromatografijo (ob eluiranju s CH-EA 60:40), nato trituriramo z zmesjo etilacetata in petroletra, da dobimo naslovno spojino kot belo trdno snov (0,076 g). T.l.c. CH-EA (1:1), Rf 0,31. IR: 3500 (NH), 1794, 1707, 1666, (C=O), 1607 (C=C) cm-1; ^-NMR: 7,46-7,10 (m); 6,99 (dd); 6,82 (t); 6,60 (m); 6,46 (m); 6,53 (bs); 6,31 (d); 5,31 (d); 4,47 (m); 3,69 (m); 2,94 (s); 2,93 (s); 1,47 (m);To a solution of intermediate 49 (0.20 g) in dry DMF (8 ml) was added 3-N, N-dimethylaminophenyl hydrochloride (0.177 g) and triethylamine (0.118 ml) and the reaction mixture was stirred for 4 hours at 120 ° under a nitrogen atmosphere. Ethyl acetate (50 ml) was added, the solution was washed with water (2 x 25 ml) and brine (25 ml), dried and concentrated in vacuo. The crude product was purified by flash chromatography (eluting with CH-EA 60:40), then triturated with a mixture of ethyl acetate and light petroleum to give the title compound as a white solid (0.076 g). T.l.c. CH-EA (1: 1), Rf 0.31. IR: 3500 (NH), 1794, 1707, 1666, (C = O), 1607 (C = C) cm -1; 1 H-NMR: 7.46-7.10 (m); 6.99 (dd); 6.82 (t); 6.60 (m); 6.46 (m); 6.53 (bs); 6.31 (d); 5.31 (d); 4.47 (m); 3.69 (m); 2.94 (s); 2.93 (s); 1.47 (m);

0,94 (s).0.94 (s).

PRIMER 22EXAMPLE 22

N-ll-f2-(l-adamantil)etil]-2,4-diokso-5-fenil-2,3,4,5-tetrahidro-lH-l,5benzodiazepin-S-ill-NVS.N.N-dimetilaminofeniDsečninaN-1,1-2- (1-adamantyl) ethyl] -2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-S-ill-NVS.N.N-dimethylaminophenes urea

K raztopini intermediata 50 (0,12 g) v suhem DMF (2 ml) dodamo 3-N,Ndimetilaminofenilamin-dihidroklorid (0,084 g) in trietilamin (0,1 ml) ter reakcijsko zmes mešamo 9 ur pri 120° v atmosferi dušika. Dodamo etilacetat (50 ml) ter raztopino izperemo z nasičeno raztopino amonijevega klorida (50 ml) in slanico (3 x 50 ml), posušimo in koncentriramo v vakuumu. Surov produkt trituriramo z acetonitrilom (10 ml), da dobimo naslovno spojino kot belo trdno snov (0,030 g). T.l.c. CH-EA (1:1), Rf 0,37. IR: 3373 (NH), 1707, 1682, 1660, (C=O), 1595, 1580 (C=C) cm-1; ^-NMR: 7,45-6,35 (m); 7,34-7,26 (m); 7,22-7,15 (m); 7,116 (t); 6,978 (dd); 6,740 (bs); 6,563 (dd); 6,44 (dd); 6,418 (d); 5,314 (d); 4,523-4,420 (m); 3,7213,621 (m); 2,911 (s); 1,936 (bs); 1,672 (bq); 1,500 (d); 1,332 (t).To a solution of intermediate 50 (0.12 g) in dry DMF (2 ml) was added 3-N, N-dimethylaminophenylamine dihydrochloride (0.084 g) and triethylamine (0.1 ml), and the reaction mixture was stirred for 9 hours at 120 ° under a nitrogen atmosphere. Ethyl acetate (50 ml) was added and the solution was washed with saturated ammonium chloride solution (50 ml) and brine (3 x 50 ml), dried and concentrated in vacuo. The crude product was triturated with acetonitrile (10 ml) to give the title compound as a white solid (0.030 g). T.l.c. CH-EA (1: 1), Rf 0.37. IR: 3373 (NH), 1707, 1682, 1660, (C = O), 1595, 1580 (C = C) cm -1; N-NMR: 7.45-6.35 (m); 7.34-7.26 (m); 7.22-7.15 (m); 7.116 (t); 6,978 (dd); 6,740 (bs); 6,563 (dd); 6.44 (dd); 6,418 (d); 5,314 (d); 4,523-4,420 (m); 3,7213,621 (m); 2,911 (s); 1,936 (bs); 1,672 (bq); 1,500 (d); 1,332 (t).

PRIMER 23EXAMPLE 23

N-fl-(2,3-dimetil)butil-2,4-diokso-5-fenil-2.3A5-tetrahidro-lH-l,5-benzodiazepin3-il1-N’-fenilsečninaN-flu- (2,3-dimethyl) butyl-2,4-dioxo-5-phenyl-2,3A5-tetrahydro-1H-1,5-benzodiazepin-3-yl 1-N'-phenylurea

Fenilizocianat (0,03 ml) dodamo k raztopini intermediata 56 (0,087 g) v suhem acetonitrilu (3 ml) pri 0° v atmosferi dušika. Zmes pustimo stati pri 23° in mešamo 1 uro, nato dodamo petroleter in dobljeno oborino mešamo 4 ure, filtriramo in izperemo s petroletrom. Oborino trituriramo z zmesjo petroletra/dietiletra (1:1; 10 ml) 1 uro in filtriramo, da dobimo naslovno spojino kot belo trdno snov (0,08 g). T.l.c. CH-EA (1:1), Rf 0,49. IR: 3300 (NH), 1707, 1641 (C=O), 1558, 1541 (C=C) cm-1; 'H-NMR: 7,46-7,10 (m); 6,9 (m); 6,4 (m); 5,32 (d); 5,29 (d); 4,61 (dd); 4,48 (dd); 3,60 (dd); 3,42 (dd); 1,8 (m); 1,4 (m); 0,86 (d); 0,80 (d); 0,77 (d); 0,75 (d); 0,73 (d); 0,70 (d)·Phenylisocyanate (0.03 ml) was added to a solution of Intermediate 56 (0.087 g) in dry acetonitrile (3 ml) at 0 ° under a nitrogen atmosphere. The mixture was allowed to stand at 23 ° and stirred for 1 hour, then petroleum ether was added and the resulting precipitate was stirred for 4 hours, filtered and washed with petroleum ether. The precipitate was triturated with a petroleum ether / diethyl ether mixture (1: 1; 10 ml) for 1 hour and filtered to give the title compound as a white solid (0.08 g). T.l.c. CH-EA (1: 1), Rf 0.49. IR: 3300 (NH), 1707, 1641 (C = O), 1558, 1541 (C = C) cm -1; ≪ 1 > H-NMR: 7.46-7.10 (m); 6.9 (m); 6.4 (m); 5.32 (d); 5.29 (d); 4.61 (dd); 4.48 (dd); 3.60 (dd); 3.42 (dd); 1.8 (m); 1.4 (m); 0.86 (d); 0.80 (d); 0.77 (d); 0.75 (d); 0.73 (d); 0.70 (d) ·

PRIMER 24EXAMPLE 24

N-[l-butil-2.4-diokso-5-fenil-2.3.4.5-tetrahidro-lH-1.5-benzodiazepin-3-il]N’-fenilsečninaN- [1-Butyl-2.4-dioxo-5-phenyl-2.3.4.5-tetrahydro-1H-1.5-benzodiazepin-3-yl] N'-phenylurea

Fenilizocianat (0,04 ml) dodamo k raztopini intermediata 59 (0,09 g) v suhem acetonitrilu (10 ml) pri 23° v atmosferi dušika. Zmes mešamo 3 ure, dodamo diklorometan (30 ml) ter raztopino izperemo z vodo (50 ml), čistimo s filtriranjem na blazinici silicijevega dioksida (ob eluiranju z DCM), da dobimo naslovno spojino kot belo trdno snov (0,1 g). T.l.c. DCM-metanol (95:5), Rf 0,65. IR: 3431 (NH), 1707, 1670 (C=O), 1599 (C=C) cm-1; ^-NMR: 7,4-7,00 (m); 6,66 (bs); 6,22 (d); 5,3 (d);Phenylisocyanate (0.04 ml) was added to a solution of Intermediate 59 (0.09 g) in dry acetonitrile (10 ml) at 23 ° under a nitrogen atmosphere. The mixture was stirred for 3 hours, dichloromethane (30 ml) was added and the solution was washed with water (50 ml), purified by filtration on a silica pad (eluting with DCM) to give the title compound as a white solid (0.1 g). T.l.c. DCM-methanol (95: 5), Rf 0.65. IR: 3431 (NH), 1707, 1670 (C = O), 1599 (C = C) cm -1; N-NMR: 7.4-7.00 (m); 6.66 (bs); 6.22 (d); 5.3 (d);

4,55 (m); 3,7 (m); 1,53 (m); 1,3 (m); 0,88 (t).4.55 (m); 3.7 (m); 1.53 (m); 1.3 (m); 0.88 (t).

PRIMER 25EXAMPLE 25

N-12,4-diokso-5-fenil-l-(3-metilbut-l-il)-2,3,4,5-tetrahidro-lH-l,5-benzodiazepin3-ill-N’-fenilsečnina 'N-12,4-dioxo-5-phenyl-1- (3-methylbut-1-yl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-ill-N'-phenylurea '

Fenilizocianat (0,08 ml) dodamo k raztopini intermediata 66 (0,206 g) v suhem acetonitrilu (12 ml) v atmosferi dušika. Zmes mešamo 1 uro pri 23°C, nato dodajamo diklorometan do popolnega raztapljanja oborine. Organski sloj ločimo, izperemo s slanico (3 x 20 ml), posušimo in koncentriramo v vakuumu, da dobimo surovo spojino (0,3 g), ki jo čistimo s flash kromatografijo (ob eluiranju z DCM-metanolom 98:2), da dobimo naslovno spojino kot belo trdno snov (0,06 g). T.l.c. DCM-metanol (95:5), Rf 0,87. IR: 3440-3350 (NH), 1701 in 1680 (C=O), 1616 in 1599 (C=C) cm-1; Ή-NMR: 7,44-7,16 (m); 7,00 (m); 6,4 (m); 5,33 (d); 4,53 (m); 3,68 (m); 1,6-1,4 (m); 0,89 (d); 0,86 (d).Phenylisocyanate (0.08 ml) was added to a solution of Intermediate 66 (0.206 g) in dry acetonitrile (12 ml) under a nitrogen atmosphere. The mixture was stirred at 23 ° C for 1 hour, then DCM was added until complete precipitation of the precipitate. The organic layer was separated, washed with brine (3 x 20 ml), dried and concentrated in vacuo to give the crude compound (0.3 g), which was purified by flash chromatography (eluting with DCM-methanol 98: 2) to give the title compound was obtained as a white solid (0.06 g). T.l.c. DCM-methanol (95: 5), Rf 0.87. IR: 3440-3350 (NH), 1701 and 1680 (C = O), 1616 and 1599 (C = C) cm-1; Ή-NMR: 7.44-7.16 (m); 7.00 (m); 6.4 (m); 5.33 (d); 4.53 (m); 3.68 (m); 1.6-1.4 (m); 0.89 (d); 0.86 (d).

PRIMER 26 (+)-N-[2,4-diokso-5-fenil-l-(3-metilbut-l-il)-2,3.4.5-tetrahidro-lH-L5benzodiazepin-3-il]-N’-fenilsečninaEXAMPLE 26 (+) - N- [2,4-dioxo-5-phenyl-1- (3-methylbut-1-yl) -2,3,4,5-tetrahydro-1H-L5benzodiazepin-3-yl] -N ' -Phenylurea

Fenilizocianat (0,15 ml) dodamo k raztopini intermediata 70 (0,42 g) v suhem acetonitrilu (20 ml) v atmosferi dušika. Zmes mešamo 1 uro pri 23°, nato oborino odfiltriramo in izperemo z acetonitrilom (10 ml) ter posušimo, da dobimo naslovno spojino kot belo trdno snov (0,52 g). [alfa]_D = +116. T.l.c. DCM-metanol (95:5), Rf 0,87. IR: 3308 (NH), 1703-1674 (C=O), 1645 in 1601 (C=C) cm-1; Ή-NMR: 7,5-7,1 (m); 6,98 (m); 6,58 (d); 5,34 (d); 4,53 (m); 3,68 (m); 1,58-1,4 (m); 0,87 (d); 0,84 (d).Phenylisocyanate (0.15 ml) was added to a solution of Intermediate 70 (0.42 g) in dry acetonitrile (20 ml) under a nitrogen atmosphere. The mixture was stirred at 23 ° for 1 hour, then the precipitate was filtered off and washed with acetonitrile (10 ml) and dried to give the title compound as a white solid (0.52 g). [alpha] _D = +116. Mp DCM-methanol (95: 5), Rf 0.87. IR: 3308 (NH), 1703-1674 (C = O), 1645 and 1601 (C = C) cm-1; Ή-NMR: 7.5-7.1 (m); 6.98 (m); 6.58 (d); 5.34 (d); 4.53 (m); 3.68 (m); 1.58-1.4 (m); 0.87 (d); 0.84 (d).

PRIMER 27 (+)-N-[2,4-diokso-5-(2-fluorofenil)-l-(3-metilbut-l-il)-2,3,4,5-tetrahidro-lHI,5-benzodiazepin-3-ill-N^,-[3-(N,N-dimetilamino)fenil1sečninaEXAMPLE 27 (+) - N- [2,4-dioxo-5- (2-fluorophenyl) -1- (3-methylbut-1-yl) -2,3,4,5-tetrahydro-1HI, 5-benzodiazepine -3-ill-N ^, - [3- (N, N-dimethylamino) phenyl] urea

3-(N,N-dimetilamino)fenilizocianat (0,257 g) dodamo k raztopini intermediata 72 (0,47 g) v suhem acetonitrilu (10 ml) v atmosferi dušika. Reakcijsko zmes mešamo 1 uro pri 23° in nastalo oborino filtriramo, da dobimo naslovno spojino kot belo trdno snov (0,58 g) v enantiomernem razmerju (+)/(-) = 93/7. Vzorec čistimo s HPLC, da dobimo čisto naslovno spojino. Tal. 252-253°. T.l.c. CH-EA (1:1), Rf 0,50. [alfa]_D = + 109,6. IR (nujol): 3420 (NH), 1717,1701,1690 in 1649 (C=O), 1616 in 1560 (C=C) cm-1; Ή-NMR: 7,45 (dd); 7,42-7,28 (m); 7,25-7,1 (m); 6,98 (dd); 6,82 (t); 6,60 (m); 6,45 (dd); 6,356 (d); 5,36 (d); 4,52-4,38 (m); 3,80-3,60 (m); 2,92 (s); 1,66-1,4 (m); 0,90 (d); 0,89 (d).3- (N, N-dimethylamino) phenylisocyanate (0.257 g) was added to a solution of intermediate 72 (0.47 g) in dry acetonitrile (10 ml) under a nitrogen atmosphere. The reaction mixture was stirred for 1 hour at 23 ° and the resulting precipitate was filtered to give the title compound as a white solid (0.58 g) in enantiomeric ratio (+) / (-) = 93/7. The sample was purified by HPLC to give the pure title compound. Tal. 252-253 °. Tlc CH-EA (1: 1), Rf 0.50. [alpha] _D = + 109.6. IR (nujol): 3420 (NH), 1717,1701,1690 and 1649 (C = O), 1616 and 1560 (C = C) cm-1; Ή-NMR: 7.45 (dd); 7.42-7.28 (m); 7.25-7.1 (m); 6.98 (dd); 6.82 (t); 6.60 (m); 6.45 (dd); 6,356 (d); 5.36 (d); 4.52-4.38 (m); 3.80-3.60 (m); 2.92 (s); 1.66-1.4 (m); 0.90 (d); 0.89 (d).

PRIMER 28EXAMPLE 28

N-[l-(adamant-2-il)-2,4-diokso-5-fenil-2,3,4,5-tetrahidro-lH-l,5-benzodiazepinS-ill-N^D-fN.N-dimetilarninofeniljlsečninaN- [1- (adamant-2-yl) -2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinS-yl-N-D-fN.N -Dimethylarnino-phenylurea

Trietilamin (0,065 ml) in 3-dimetilaminoanilin-dihidroklorid (0,049 g) dodamo k raztopini intermediata 76 (0,1 g) v diklorometanu (5 ml) v atmosferi dušika. Raztopino mešamo 3 ure pri 23°, nato koncentriramo v vakuumu in čistimo s flash kromatografijo (ob eluiranju s CH-EA 1:1), da dobimo naslovno spojino (0,052 g) kot belo trdno snov. T.l.c. DCM-metanol (95:0,5), Rf 0,72. ER: 3300 (NH), 1713 in 1676 (C=O), 1637 in 1610 (C=C) cm-1; Ή-NMR: 7,4-7,1 (m); 6,99 (m); 6,80 (t); 6,62 (m); 6,56 (dd); 6,45 (dd); 6,31 (d); 5,31 (d); 4,52 (m); 2,91 (m); 2,32 (m); 2,0-1,1 (m).Triethylamine (0.065 ml) and 3-dimethylaminoaniline dihydrochloride (0.049 g) were added to a solution of intermediate 76 (0.1 g) in dichloromethane (5 ml) under a nitrogen atmosphere. The solution was stirred for 3 hours at 23 °, then concentrated in vacuo and purified by flash chromatography (eluting with CH-EA 1: 1) to give the title compound (0.052 g) as a white solid. T.l.c. DCM-methanol (95: 0.5), Rf 0.72. ER: 3300 (NH), 1713 and 1676 (C = O), 1637 and 1610 (C = C) cm-1; Ή-NMR: 7.4-7.1 (m); 6.99 (m); 6.80 (t); 6.62 (m); 6.56 (dd); 6.45 (dd); 6.31 (d); 5.31 (d); 4.52 (m); 2.91 (m); 2.32 (m); 2.0-1.1 (m).

PRIMER 29EXAMPLE 29

N-[f2-ciklopentil-etil)-2,4-diokso-5-(2-fluorofenil)-2,3,4.5-tetrahidro-lH-1.5benzodiazepin-3-il]-N’-fenilsečninaN- [f2-cyclopentyl-ethyl) -2,4-dioxo-5- (2-fluorophenyl) -2,3,4,5-tetrahydro-1H-1,5benzodiazepin-3-yl] -N'-phenylurea

Fenilizocianat (0,044 ml) dodamo k raztopini intermediata 79 (0,154 g) v acetonitrilu (5 ml) v atmosferi dušika. Zmes mešamo 1 uro pri 23°; dobljeno trdno snov filtriramo in izperemo z acetonitrilom (2 ml), da dobimo naslovno spojino (0,163 g) kot belo trdno snov. Tal. 255-257°. T.l.c. CH-EA (1:1), Rf 0,58. IR: 3400 (NH), 1718 in 1650 (C=O), 1600 (C=C) cm-1; Ή-NMR: 7,46 (dd); 7,4-7,1 (m); 7,0 (t); 6,98 (d); 6,52 (d);Phenylisocyanate (0.044 ml) was added to a solution of Intermediate 79 (0.154 g) in acetonitrile (5 ml) under a nitrogen atmosphere. The mixture was stirred for 1 hour at 23 °; The resulting solid was filtered and washed with acetonitrile (2 ml) to give the title compound (0.163 g) as a white solid. Tal. 255-257 °. T.l.c. CH-EA (1: 1), Rf 0.58. IR: 3400 (NH), 1718 and 1650 (C = O), 1600 (C = C) cm -1; Ή-NMR: 7.46 (dd); 7.4-7.1 (m); 7.0 (t); 6.98 (d); 6.52 (d);

5,38 (d); 4,44 (m); 3,66 (m); 1,84-1,40 (m); 1,20-1,00 (m).5.38 (d); 4.44 (m); 3.66 (m); 1.84-1.40 (m); 1.20-1.00 (m).

PRIMER 30EXAMPLE 30

N-[l-(2-ciklopentil-etil)-2,4-diokso-5-(2-fluorofenil)-2,3,4,5-tetrahidro-lH-l,5benzodiazepin-3-ill-N’-[4-(climetilamino)fenil]sečninaN- [1- (2-cyclopentyl-ethyl) -2,4-dioxo-5- (2-fluorophenyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl-N'- [4- (Climethylamino) phenyl] urea

Trietilamin (0,184 ml) in 4-(dimetilamino)anilin (0,138 g) dodamo k raztopini intermediata 80 (0,270 g) v suhem diklorometanu (50 ml) v atmosferi dušika. Raztopino mešamo 4 ure pri 23°, nato razredčimo z diklorometanom (20 ml) in izperemo z vodo (20 ml), 5 %-no raztopino HC1 (20 ml), vodo (20 ml) in slanico (15 ml). Organski sloj sušimo, koncentriramo v vakuumu in ostanek čistimo s flash kromatografijo (ob eluiranju z DCM-metanolom 95:5), da dobimo naslovno spojino (0,077 g) kot belo trdno snov. T.l.c. DCM-metanol (9:1), Rf 0,81. IR: 3304 (NH), 1718-1641 (C=O), 1605-1549 (C=C) cm-1; ¹ H-NMR: 7,46 (dd); 7,40-7,10 (m); 6,98 (dd); 6,68 (d); 6,28 (bs); 6,07 (d); 5,32 (d); 4,41 (m); 3,66 (m); 2,91 (s); 1,84-1,00 (m).Triethylamine (0.184 ml) and 4- (dimethylamino) aniline (0.138 g) were added to a solution of intermediate 80 (0.270 g) in dry dichloromethane (50 ml) under a nitrogen atmosphere. The solution was stirred for 4 hours at 23 °, then diluted with dichloromethane (20 ml) and washed with water (20 ml), 5% HCl solution (20 ml), water (20 ml) and brine (15 ml). The organic layer was dried, concentrated in vacuo and the residue purified by flash chromatography (eluting with DCM-methanol 95: 5) to give the title compound (0.077 g) as a white solid. Mp DCM-methanol (9: 1), Rf 0.81. IR: 3304 (NH), 1718-1641 (C = O), 1605-1549 (C = C) cm -1; ¹ H-NMR: 7.46 (dd); 7.40-7.10 (m); 6.98 (dd); 6.68 (d); 6.28 (bs); 6.07 (d); 5.32 (d); 4.41 (m); 3.66 (m); 2.91 (s); 1.84-1.00 (m).

PRIMER 31EXAMPLE 31

N-fl-(biciklof2.2.1]-5-hepten-2-ilmetifi-2,4-diokso-5-fenil-2,3,4,5-tetrahidro61 lH-l,5-benzodiazepin-3-il]-N’-fenilsečninaN-flu- (bicyclof2.2.1] -5-hepten-2-ylmethyl-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro61H-1,5-benzodiazepin-3-yl] - N'-phenylurea

Fenilizocianat (0,026 ml) dodamo k raztopini intermediata 83 (0,074 g) v suhem acetonitrilu (5 ml) in zmes mešamo pri 23° v dušiku 1 uro. Dodajamo diklorometan (50 ml) do dokončnega raztapljanja oborine, nato raztopino izperemo s slanico (20 ml), posušimo in koncentriramo v vakuumu. Ostanek trituriramo z dietiletrorn, da dobimo naslovno spojino (0,0521 g) kot umazano belo trdno snov. Tal. 184-186°.Phenylisocyanate (0.026 ml) was added to a solution of intermediate 83 (0.074 g) in dry acetonitrile (5 ml) and the mixture was stirred at 23 ° in nitrogen for 1 hour. Dichloromethane (50 ml) was added until complete precipitation of the precipitate, then the solution was washed with brine (20 ml), dried and concentrated in vacuo. The residue was triturated with diethyl ether to give the title compound (0.0521 g) as a dirty white solid. Tal. 184-186 °.

T.l.c. CH-EA (7:3), Rf 0,32. IR: 3308 (NH), 1715-1670 (C=O), 1639-1599 (9C=C); Ή-NMR: 7,5-7,0 (m); 6,84 (bs); 6,80 (bs); 6,33 (d); 6,31 (d); 6,18-6,10 (m); 6,12-5,96 (m); 5,90-5,84 (m); 5,64-5,60 (m); 5,32 (d); 5,29 (d); 4,64 (m); 4,4-4,2 (m); 3,8 (m); 3,45-3,30 (m); 2,80 (bs); 2,74 (bs); 2,6-0,60 (m).T.l.c. CH-EA (7: 3), Rf 0.32. IR: 3308 (NH), 1715-1670 (C = O), 1639-1599 (9C = C); Ή-NMR: 7.5-7.0 (m); 6.84 (bs); 6.80 (bs); 6.33 (d); 6.31 (d); 6.18-6.10 (m); 6.12-5.96 (m); 5.90-5.84 (m); 5.64-5.60 (m); 5.32 (d); 5.29 (d); 4.64 (m); 4.4-4.2 (m); 3.8 (m); 3.45-3.30 (m); 2.80 (bs); 2.74 (bs); 2.6-0.60 (m).

PRIMER 32EXAMPLE 32

N-[l-biciklo[2.2.1]-5-hepten-2-ilmetil)-2.4-diokso-5-fenil-2,3,4,5-tetrahidrolH-l,5-benzodiazepin-3-il]-N^,-(3-nitrofenil)sečninaN- [1-bicyclo [2.2.1] -5-hepten-2-ylmethyl) -2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrol-1,5-benzodiazepin-3-yl] - N ^, - (3-nitrophenyl) urea

K raztopini intermediata 83 (0,072 g) v suhem acetonitrilu (10 ml) dodamo 3-nitrofenilizocianat (0,048 g) in zmes mešamo pri 23° 1 uro v dušiku. Dobljeno oborino filtriramo, izperemo z dietiletrorn in posušimo, da dobimo naslovno spojino (0,0712 g). Tal. 195-197°. T.l.c. CH-EA (7:3), Rf 0,24. IR: 3300 (NH); 1713 (C=O); 1651 (C=O); 1556 (C=C) cm-1. Ή-NMR: 8,26-6,92 (m); 6,13-5,58 (m); 5,34-5,25 (m); 4,70-3,83 (m); 2,80-0,45 (m).To a solution of intermediate 83 (0.072 g) in dry acetonitrile (10 ml) was added 3-nitrophenylisocyanate (0.048 g) and the mixture was stirred at 23 ° for 1 hour in nitrogen. The resulting precipitate was filtered, washed with diethyl ether and dried to give the title compound (0.0712 g). Tal. 195-197 °. T.l.c. CH-EA (7: 3), Rf 0.24. IR: 3300 (NH); 1713 (C = O); 1651 (C = O); 1556 (C = C) cm -1. Ή-NMR: 8.26-6.92 (m); 6.13-5.58 (m); 5.34-5.25 (m); 4.70-3.83 (m); 2.80-0.45 (m).

PRIMER 33EXAMPLE 33

N-[l-(bicik]o[2.2.11-2-heptilmetil)-2,4-diokso-5-fenil-2,3,4,5-tetrahidro-lH-l,5benzodi3zepin-3-il]-N’-fenilsečninaN- [1- (bicyclo] o [2.2.11-2-heptylmethyl) -2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl] - N'-phenylurea

Fenilizocianat (0,03 ml) dodamo k raztopini intermediata 84 (0,088 g) v suhem acetonitrilu (10 ml) in zmes mešamo pri 23° v atmosferi dušika 1 uro. Dobljeno oborino filtriramo, izperemo z dietiletrorn in posušimo, da dobimo naslovno spojino (0,0858 g) kot belo trdno snov. Tal. 255-256°. T.l.c. CH-EA (7:3), Rf 0,29. IR: 34003200 (NH), 1711 in 1705 (C=C); Ή-NMR: 7,50-7,10 (m); 7,02 (m); 6,38 (m); 6,91 (bs); 6,42-6,34 (m); 5,35-5,27 (m); 4,71-4,61 (dd); 4,48 (dd); 4,38 (dd); 3,65 (dd); 3,59 (dd); 3,37 (dd); 3,55 (dd); 2,3-0,50 (m).Phenylisocyanate (0.03 ml) was added to a solution of Intermediate 84 (0.088 g) in dry acetonitrile (10 ml) and the mixture was stirred at 23 ° under a nitrogen atmosphere for 1 hour. The resulting precipitate was filtered, washed with diethyl ether and dried to give the title compound (0.0858 g) as a white solid. Tal. 255-256 °. T.l.c. CH-EA (7: 3), Rf 0.29. IR: 34003200 (NH), 1711 and 1705 (C = C); Ή-NMR: 7.50-7.10 (m); 7.02 (m); 6.38 (m); 6.91 (bs); 6.42-6.34 (m); 5.35-5.27 (m); 4.71-4.61 (dd); 4.48 (dd); 4.38 (dd); 3.65 (dd); 3.59 (dd); 3.37 (dd); 3.55 (dd); 2.3-0.50 (m).

PRIMER 34EXAMPLE 34

N-[l-(biciklof2.2.11-2-heptilmetil-2,4-diokso-5-fenil-2.3,4.5-tetrahidro-lH-l,562 benzodiazepin^-ill-NVS-metoksifeniljsečninaN- [1- (bicyclof2.2.11-2-heptylmethyl-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1, 562 benzodiazepine-4-yl-NVS-methoxyphenylurea)

K raztopini intermediata 84 (0,0883 g) v suhem acetonitrilu (10 ml) in zmes mešamo 1 uro pri 23° v dušiku. Dobljeno oborino filtriramo, izperemo z dietiletrom in posušimo, da dobimo naslovno spojino (0,0858 g) kot belo trdno snov. Tal. 255-256°. T.l.c. CH-EA (7:3), Rf 0,29. IR: 3400-3200 (NH), 1711 in 1705 (C=C); Ή-NMR:To a solution of intermediate 84 (0.0883 g) in dry acetonitrile (10 ml) and the mixture was stirred for 1 hour at 23 ° in nitrogen. The resulting precipitate was filtered, washed with diethyl ether and dried to give the title compound (0.0858 g) as a white solid. Tal. 255-256 °. T.l.c. CH-EA (7: 3), Rf 0.29. IR: 3400-3200 (NH), 1711 and 1705 (C = C); Ή-NMR:

7,5-6,9 (m); 6,75-6,69 (m); 6,60-6,55 (m); 6,44 (m); 5,31 (m); 4,71-4,62 (m); 4,49 (dd);7.5-6.9 (m); 6.75-6.69 (m); 6.60- 6.55 (m); 6.44 (m); 5.31 (m); 4.71-4.62 (m); 4.49 (dd);

4,38 (dd); 3,75 (s); 3,65 (dd); 3,59 (dd); 3,56 (dd); 3,38 (dd); 2,25-0,6 (m).4.38 (dd); 3.75 (s); 3.65 (dd); 3.59 (dd); 3.56 (dd); 3.38 (dd); 2.25-0.6 (m).

PRIMER 35EXAMPLE 35

N-il-biciklo[2.2.n-2-heptil]-2,4-diokso-5-fenil-2,3A5-tetrahidro-lH-1.5benzodiazepin-3-il]l-N’-fenilsečninaN-yl-bicyclo [2.2.n-2-heptyl] -2,4-dioxo-5-phenyl-2,3A5-tetrahydro-1H-1.5benzodiazepin-3-yl] 1-N'-phenylurea

Fenilizocianat (0,056 ml) dodamo raztopini intermediata 87 (0,15 g) v suhem acetonitrilu (5 ml) v atmosferi dušika. Zmes mešamo 1 uro pri 23°, nato filtriramo. Dobljeno trdno snov izperemo z dietiletrom in posušimo v vakuumu, da dobimo naslovno spojino kot belo trdno snov (0,12 g). Tal. 267-268°. T.l.c. CH-EA (1:1), Rf 0,62. IR: 3300 (NH), 1705, 1678 in 1645 (C=O), 1599 in 1556 (C=C) cm-1; Ή-NMR: 7,46-7,12 (m); 7,026-6,94 (m); 6,423 (d); 6,436 (d); 5,328 (d); 5,321 (d); 4,5-4,4 (m); 3,459 (s); 2,637 (s); 2,396 (m); 2,180 (m); 1,958 (m); 1,6 (m); 1,54-1,38 (m); 1,38-1,1 (m); 0,99 (m); 0,864 (m).Phenylisocyanate (0.056 ml) was added to a solution of Intermediate 87 (0.15 g) in dry acetonitrile (5 ml) under a nitrogen atmosphere. The mixture was stirred for 1 hour at 23 ° then filtered. The resulting solid was washed with diethyl ether and dried in vacuo to give the title compound as a white solid (0.12 g). Tal. 267-268 °. T.l.c. CH-EA (1: 1), Rf 0.62. IR: 3300 (NH), 1705, 1678 and 1645 (C = O), 1599 and 1556 (C = C) cm-1; Ή-NMR: 7.46-7.12 (m); 7,026-6.94 (m); 6,423 (d); 6,436 (d); 5,328 (d); 5,321 (d); 4.5-4.4 (m); 3,459 (s); 2,637 (s); 2,396 (m); 2,180 (m); 1,958 (m); 1.6 (m); 1.54-1.38 (m); 1.38-1.1 (m); 0.99 (m); 0.864 (m).

PRIMER 36EXAMPLE 36

N-[l-(2-adamantilmetil)-2,4-diokso-5-fenil-2.3,4.5-tetrahidro-lH-1.5-benzodiazepin3-il1-N’-fenilsečninaN- [1- (2-adamantylmethyl) -2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin3-yl1-N'-phenylurea

Fenilizocianat (0,063 ml) dodamo k raztopini intermediata 90 (0,2 g) v suhem acetonitrilu (5 ml) v atmosferi dušika. Zmes mešamo pri 23° 1 uro, nato filtriramo. Dobljeno trdno snov izperemo z dietiletrom in posušimo v vakuumu, da dobimo naslovno spojino kot belo trdno snov (0,22 g). Tal. 192-193°. T.l.c. CH-EA (1:1), Rf 0,73. IR: 3306 (NH), 1717 in 1701 (C=O), 1643 in 1620 (C=C) cm-1; Ή-NMR: 7,5-7,14 (m); 7,00 (m); 7,049 (m); 6,47 (d); 5,33 (d); 5,05 (m); 3,59 (m); 2,02 (m); 1,84-1,36 (m).Phenylisocyanate (0.063 ml) was added to a solution of Intermediate 90 (0.2 g) in dry acetonitrile (5 ml) under a nitrogen atmosphere. The mixture was stirred at 23 ° for 1 hour, then filtered. The resulting solid was washed with diethyl ether and dried in vacuo to give the title compound as a white solid (0.22 g). Tal. 192-193 °. T.l.c. CH-EA (1: 1), Rf 0.73. IR: 3306 (NH), 1717 and 1701 (C = O), 1643 and 1620 (C = C) cm-1; Ή-NMR: 7.5-7.14 (m); 7.00 (m); 7,049 (m); 6.47 (d); 5.33 (d); 5.05 (m); 3.59 (m); 2.02 (m); 1.84-1.36 (m).

PRIMER 37EXAMPLE 37

N-[l-(l-adamantilmetiI)-2,4-diokso-5-fenil-2,3A5-tetrahidro-lH-l,5-benzodiazepin3-il1-N’-(3-metoksifenil)sečninaN- [1- (1-adamantylmethyl) -2,4-dioxo-5-phenyl-2,3A5-tetrahydro-1H-1,5-benzodiazepin3-yl1-N '- (3-methoxyphenyl) urea

3-metoksifenilizocianat (0,066 ml) dodamo k raztopini intermediata 41 (0,2 g) v suhem acetonitrilu (10 ml) v atmosferi dušika. Zmes mešamo 16 ur pri 23°, nato razredčimo z diklorometanom (15 ml) in izperemo s slanico (15 ml). Organsko raztopino posušimo, koncentriramo v vakuumu in ostanek čistimo s flash kromatografijo (ob eluiranju s CH-EA 2:1); dobljeno trdno snov nadalje čistimo s trituriranjem z dietiletrom, da dobimo naslovno spojino kot belo trdno snov (0,2 g). Tal. 267-268°. T.l.c. CH-EA (2:1), Rf 0,2. IR: 3302 (NH), 1713,1674 in 1641 (C=O), 1612 in 1558 (C=C) cm-1; ^-NMR: 7,492 (dd); 7,45-7,35 (m); 7,35-7,25 (m); 7,162 (m); 7,120 (t); 7,041 (t); 6,992 (dd); 6,904 (s); 6,738 (m); 6,578 (m); 6,413 (m); 5,292 (d); 4,496 (d); 3,744 (s); 3,382 (d); 1,857 (s); 1,66-1,32 (m).3-Methoxyphenylisocyanate (0.066 ml) was added to a solution of Intermediate 41 (0.2 g) in dry acetonitrile (10 ml) under a nitrogen atmosphere. The mixture was stirred at 23 ° C for 16 hours, then diluted with dichloromethane (15 ml) and washed with brine (15 ml). The organic solution was dried, concentrated in vacuo and the residue purified by flash chromatography (eluting with CH-EA 2: 1); the resulting solid was further purified by trituration with diethyl ether to give the title compound as a white solid (0.2 g). Tal. 267-268 °. T.l.c. CH-EA (2: 1), Rf 0.2. IR: 3302 (NH), 1713,1674 and 1641 (C = O), 1612 and 1558 (C = C) cm-1; N-NMR: 7,492 (dd); 7.45-7.35 (m); 7.35-7.25 (m); 7,162 (m); 7,120 (t); 7,041 (t); 6,992 (dd); 6,904 (s); 6,738 (m); 6,578 (m); 6,413 (m); 5,292 (d); 4,496 (d); 3,744 (s); 3,382 (d); 1,857 (s); 1.66-1.32 (m).

PRIMER 38EXAMPLE 38

N-[l-(l-adamantilmetil)2,4-diokso-5-fenil-2,3,4,5-tetrahidro-lH,l,5benzodiazepin-3-ill-N^>-(3-metilfenil)sečninaN- [1- (1-adamantylmethyl) 2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H, 1,5-benzodiazepin-3-yl-N ^> - (3-methylphenyl) urea

3-metilfenilizocianat (0,064 ml) dodamo k raztopini intermediata 41 (0,2 g) v suhem acetonitrilu (10 ml) v atmosferi dušika. Zmes mešamo 1 uro pri 23°, nato razredčimo z diklorometanom (15 ml) in izperemo s slanico (15 ml). Organsko raztopino posušimo, koncentriramo v vakuumu in ostanek trituriramo z dietiletrom, da dobimo naslovno spojino kot belo trdno snov (0,2 g). Tal. 244-246°. T.l.c. CH-EA (2:1), Rf 0,32. IR: 3300 (NH), 1715 in 1672 (C=O), 1645 in 1616 (C=C) cm-1; ‘H-NMR: 7,493 (dd); 7,45-7,35 (m); 7,35-7,25 (m); 7,21-7,15 (m); 7,135 (t); 7,034 (m); 6,992 (dd); 6,854 (m); 6,751 (s); 6,318 (d); 5,293 (d); 4,498 (d); 3,384 (d); 2,287 (s); 1,865 (s); 1,68-1,3 (m).3-methylphenylisocyanate (0.064 ml) was added to a solution of Intermediate 41 (0.2 g) in dry acetonitrile (10 ml) under a nitrogen atmosphere. The mixture was stirred at 23 ° for 1 hour, then diluted with dichloromethane (15 ml) and washed with brine (15 ml). The organic solution was dried, concentrated in vacuo and the residue triturated with diethyl ether to give the title compound as a white solid (0.2 g). Tal. 244-246 °. T.l.c. CH-EA (2: 1), Rf 0.32. IR: 3300 (NH), 1715 and 1672 (C = O), 1645 and 1616 (C = C) cm-1; ≪ 1 > H-NMR: 7.493 (dd); 7.45-7.35 (m); 7.35-7.25 (m); 7.21-7.15 (m); 7,135 (t); 7,034 (m); 6,992 (dd); 6,854 (m); 6,751 (s); 6,318 (d); 5,293 (d); 4,498 (d); 3,384 (d); 2,287 (s); 1,865 (s); 1.68-1.3 (m).

PRIMER 39EXAMPLE 39

N-ri-(l-adamantiImetil)-2,4-diokso-5-fenil-2,3A5-tetrahidro-lH-l,5benzodiazepin-3-il]-N^,-(3-nitrofenil)sečninaN-R- (1-adamantylmethyl) -2,4-dioxo-5-phenyl-2,3A5-tetrahydro-1H-1,5-benzodiazepin-3-yl] -N ^, - (3-nitrophenyl) urea

Raztopino 3-nitrofenilizocianata (0,082 g) v suhem acetonitrilu (8 ml) dodamo k raztopini intermediata 41 (0,2 g) v suhem acetonitrilu (10 ml) v atmosferi dušika. Zmes mešamo 2 uri pri 23°, nato razredčimo z diklorometanom (15 ml) in izperemo s slanico (15 ml). Organsko raztopino posušimo, koncentriramo v vakuumu in ostanek trituriramo z dietiletrom, da dobimo naslovno spojino kot belo trdno snov (0,229 g). Tal. 213-215°. T.l.c. CH-EA (2:1), Rf 0,33. IR: 3296 (NH), 1713 in 1645 (C=O), 1597 (C=C) cm-1; ^-NMR: 8,25 (s); 8,15 (t); 7,64 (m); 7,52 (dd); 7,45 (m); 7,36-7,29 (m);A solution of 3-nitrophenylisocyanate (0.082 g) in dry acetonitrile (8 ml) was added to a solution of intermediate 41 (0.2 g) in dry acetonitrile (10 ml) under a nitrogen atmosphere. The mixture was stirred at 23 ° for 2 hours, then diluted with dichloromethane (15 ml) and washed with brine (15 ml). The organic solution was dried, concentrated in vacuo and the residue triturated with diethyl ether to give the title compound as a white solid (0.229 g). Tal. 213-215 °. T.l.c. CH-EA (2: 1), Rf 0.33. IR: 3296 (NH), 1713 and 1645 (C = O), 1597 (C = C) cm -1; N-NMR: 8.25 (s); 8.15 (t); 7.64 (m); 7.52 (dd); 7.45 (m); 7.36-7.29 (m);

7,24-7,17 (m); 7,13 (t); 7,06 (d); 7,02 (dd); 5,27 (d); 4,51 (d); 3,40 (d); 1,86 (s); 1,661,34 (m).7.24-7.17 (m); 7.13 (t); 7.06 (d); 7.02 (dd); 5.27 (d); 4.51 (d); 3.40 (d); 1.86 (s); 1,661.34 (m).

PRIMER 40EXAMPLE 40

N-fl-(l-adamantilmetil)-2,4-diokso-5-feniI-2,3,4,5-tetrahidro-lH-l,5-benzodiazepin3-il1-N’-f3-bromofenil)sečninaN-flu- (1-adamantylmethyl) -2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl1-N'-f3-bromophenyl) urea

3-bromofenilizocianat (0,063 ml) dodamo k raztopini intermediata 41 (0,2 g) v suhem acetonitrilu (10 ml) v atmosferi dušika. Zmes mešamo 1 uro pri 23°, nato filtriramo. Dobljeno trdno snov izperemo z dietiletrom, da dobimo naslovno spojino kot belo trdno snov (0,25 g). Tal. 254-256°. T.l.c. CH-EA (2:1), Rf 0,53. IR: 3290 (NH), 1717 in 1672 (C=O) cm-1; H-NMR: 7,56-7,15 (m); 7,03-6,88 (m); 6,99 (dd); 6,93 (dd);3-Bromophenylisocyanate (0.063 ml) was added to a solution of Intermediate 41 (0.2 g) in dry acetonitrile (10 ml) under a nitrogen atmosphere. The mixture was stirred for 1 hour at 23 ° then filtered. The resulting solid was washed with diethyl ether to give the title compound as a white solid (0.25 g). Tal. 254-256 °. T.l.c. CH-EA (2: 1), Rf 0.53. IR: 3290 (NH), 1717 and 1672 (C = O) cm-1; H-NMR: 7.56-7.15 (m); 7.03-6.88 (m); 6.99 (dd); 6.93 (dd);

6,73 (d); 5,29 (d); 4,49-3,38 (m); 1,83 (m); 1,64-1,30 (m).6.73 (d); 5.29 (d); 4.49-3.38 (m); 1.83 (m); 1.64-1.30 (m).

PRIMER 41EXAMPLE 41

N-ri-(l-adamantilmetil)-2,4-diokso-5-fenil-2,3,4,5-tetrahidro-lH-l,5benzodiazepin-3-il1-N’-f3-etoksikarbonilfeniDsečninaN-ri- (1-adamantylmethyl) -2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl1-N'-f3-ethoxycarbonylphenylurea

3-nitrofenilizocianat (0,1 g) dodamo k raztopini intermediata 41 (0,415 g) v suhem acetonitrilu (13 ml) v atmosferi dušika. Zmes mešamo 1 uro pri 23°, nato razredčimo z diklorometanom (20 ml) in izperemo s slanico (20 ml). Organsko raztopino sušimo, koncentriramo v vakuumu in ostanek trituriramo z dietiletrom, da dobimo naslovno spojino kot belo trdno snov (0,407 g). Tal. 246-248°. T.l.c. CH-EA (2:1), Rf 0,37. IR: 1709,1690 in 1670 (C=O) cm-1; H-NMR: 7,93 (t); 7,64-7,50 (m); 7,44-7,39 (m); 7,38 (s); 7,35-7,27 (m); 7,24-7,14 (m); 6,89 (dd); 6,58 (d); 5,31 (d); 4,50 (d); 4,34 (m); 3,38 (d); 1,85 (m); 1,61-1,51 (m); 1,45-1,37 (m); 1,35 (t).3-Nitrophenylisocyanate (0.1 g) was added to a solution of Intermediate 41 (0.415 g) in dry acetonitrile (13 ml) under a nitrogen atmosphere. The mixture was stirred at 23 ° for 1 hour, then diluted with dichloromethane (20 ml) and washed with brine (20 ml). The organic solution was dried, concentrated in vacuo and the residue triturated with diethyl ether to give the title compound as a white solid (0.407 g). Tal. 246-248 °. T.l.c. CH-EA (2: 1), Rf 0.37. IR: 1709, 1690 and 1670 (C = O) cm-1; H-NMR: 7.93 (t); 7.64-7.50 (m); 7.44-7.39 (m); 7.38 (s); 7.35-7.27 (m); 7.24-7.14 (m); 6.89 (dd); 6.58 (d); 5.31 (d); 4.50 (d); 4.34 (m); 3.38 (d); 1.85 (m); 1.61-1.51 (m); 1.45-1.37 (m); 1.35 (t).

PRIMER 42EXAMPLE 42

N-[l-(l-adamantilmetil)-2,4-diokso-5-fenil-2,3,4,5-tetrahidro-lH-l,5benzodiazepin-3-ill-N^,-13-(N,N-dimetilamino)fenillsečninaN- [1- (1-adamantylmethyl) -2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl-N ^, -13- (N, N -dimethylamino) phenylurea

Raztopino 3-(N,N-dimetilamino)fenilizocianata (0,122 g) v suhem acetonitrilu (7 ml) dodamo k raztopini intermediata 41 (0,2 g) v suhem acetonitrilu (7 ml) v atmosferi dušika. Zmes mešamo 30 minut pri 23°, nato razredčimo z diklorometanom (20 ml) in izperemo s slanico (20 ml). Organsko raztopino posušimo, koncentriramo v vakuumu in ostanek trituriramo z dietiletrom, da dobimo naslovno spojino kot belo trdno snov (0,221 g). Tal. 263-265°. T.l.c. CH-EA (1:1), Rf 0,52. IR: 3300 (NH), 1717 in 1674 (C=O) cm-1; Ή-NMR: 7,48 (dd); 7,45-7,24 (m); 7,19-7,10 (m); 6,98 (dd); 6,93 (dd); 6,61 (s); 6,58-6,45 (m); 6,38 (d); 5,29 (d); 4,49-3,37 (m); 2,92 (s); 1,87 (m); 1,63-1,53 (m); 1,44-1,34 (m).A solution of 3- (N, N-dimethylamino) phenylisocyanate (0.122 g) in dry acetonitrile (7 ml) was added to a solution of intermediate 41 (0.2 g) in dry acetonitrile (7 ml) under a nitrogen atmosphere. The mixture was stirred at 23 ° for 30 minutes, then diluted with dichloromethane (20 ml) and washed with brine (20 ml). The organic solution was dried, concentrated in vacuo and the residue triturated with diethyl ether to give the title compound as a white solid (0.221 g). Tal. 263-265 °. T.l.c. CH-EA (1: 1), Rf 0.52. IR: 3300 (NH), 1717 and 1674 (C = O) cm-1; Ή-NMR: 7.48 (dd); 7.45-7.24 (m); 7.19-7.10 (m); 6.98 (dd); 6.93 (dd); 6.61 (s); 6.58-6.45 (m); 6.38 (d); 5.29 (d); 4.49-3.37 (m); 2.92 (s); 1.87 (m); 1.63-1.53 (m); 1.44-1.34 (m).

PRIMER 43EXAMPLE 43

N-fl-(l-adamantilmetil)-2,4-diokso-5-feniI-2,3,4,5-tetrahidro-lH-1.5benzodiazepin-3-il1-N’-(3-karboksifenil)sečninaN-flu- (1-adamantylmethyl) -2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5benzodiazepin-3-yl1-N '- (3-carboxyphenyl) urea

Vodno 0,1 M raztopino litijevega hidroksida (6,6 ml) dodamo k raztopini primera 41 (0,2 g) v THF (15 ml), predhodno ohlajeni na 0°. Raztopino mešamo 16 ur pri 23°, nato segrevamo 1 uro na 60° in 13 ur na 80°. Raztopino ohladimo na 23°, nevtraliziramo z ocetno kislino, koncentriramo v vakuumu in ostanek čistimo s flash kromatografijo (ob eluiranju v gradientu od CH-EA 3:1 do DCM in končno do DCM-MeOH 10:1), da dobimo naslovno spojino kot belo trdno snov (0,183 g), ki še vsebuje sledi anorganskih soli. Vzorec nadalje čistimo z raztapljanjem v DCM in izpiranjem z 10 %-no klorovodikovo kislino; organski sloj posušimo, koncentriramo v vakuumu in ostanek trituriramo z dietiletrom, da dobimo čisto naslovno spojino. Tal. 260-270° (razp.). T.l.c. EA, Rf 0,64. IR: 3354 (NH in OH), m 1701 in 1684 (C=O) cm-1; Ή-NMR: 9,21 (s); 7,9-7,8 (m); 7,6-7,16 (m); 7,0-6,9 (m); 4,99 (d); 4,30 (d); 3,60 (d); 1,83 (s); 1,65-1,2 (m).An aqueous 0.1 M solution of lithium hydroxide (6.6 ml) was added to the solution of Example 41 (0.2 g) in THF (15 ml), pre-cooled to 0 °. The solution was stirred for 16 hours at 23 °, then heated for 1 hour to 60 ° and 13 hours to 80 °. The solution was cooled to 23 °, neutralized with acetic acid, concentrated in vacuo and the residue purified by flash chromatography (eluting in a gradient from CH-EA 3: 1 to DCM and finally to DCM-MeOH 10: 1) to give the title compound as white solid (0,183 g) containing traces of inorganic salts. The sample was further purified by dissolving in DCM and washing with 10% hydrochloric acid; the organic layer was dried, concentrated in vacuo and the residue triturated with diethyl ether to give the pure title compound. Tal. 260-270 ° (dec.). T.l.c. EA, Rf 0.64. IR: 3354 (NH and OH), m 1701 and 1684 (C = O) cm-1; Ή-NMR: 9.21 (s); 7.9-7.8 (m); 7.6-7.16 (m); 7.0-6.9 (m); 4.99 (d); 4.30 (d); 3.60 (d); 1.83 (s); 1.65-1.2 (m).

PRIMER 44EXAMPLE 44

N-il-(adamantanmetil)-2,4-diokso-7-fluoro-5-(4-fluorofenil)-2,3A5-tetrahidro-lHl,5-benzodiazepin-3-il1-N’-(3-dimetilamino)fenilsečnmaN-yl- (adamantanmethyl) -2,4-dioxo-7-fluoro-5- (4-fluorophenyl) -2,3A5-tetrahydro-1H, 5-benzodiazepin-3-yl1-N '- (3-dimethylamino) phenylurea

Raztopino 3-dimetilaminofenilizocianata (0,043 g) v suhem acetonitrilu (3 ml) dodamo k raztopim intermediata 95 (0,079 g) v suhem acetonitrilu (5 ml) v dušiku, raztopino zmesi mešamo 1 uro pri 23°, razredčimo z DCM, izperemo s slanico (30 ml), uparimo in dobimo surovo spojino (0,145 g), ki jo trituriramo z etiletrom, da dobimo naslovno spojino kot belo trdno snov (0,046 g). Tal. > 270°. T.l.c. CH-EA (1:1), Rf 0,61. IR: 3439, 3333 (NH), 1715 (C=O), 1610 in 1590 (C=C) cm-1; ΉNMR: 7,46 (dd); 7,38-7,3 (m); 7,20-7,10 (m); 7,06-7,00 (m); 6,78 (t); 6,69-6,58 (m);A solution of 3-dimethylaminophenylisocyanate (0.043 g) in dry acetonitrile (3 ml) was added to solutions of intermediate 95 (0.079 g) in dry acetonitrile (5 ml) in nitrogen, the solution was stirred for 1 hour at 23 °, diluted with DCM, washed with brine (30 ml) was evaporated to give the crude compound (0.145 g), which was triturated with ethyl ether to give the title compound as a white solid (0.046 g). Tal. > 270 °. T.l.c. CH-EA (1: 1), Rf 0.61. IR: 3439, 3333 (NH), 1715 (C = O), 1610 and 1590 (C = C) cm-1; Ή NMR: 7.46 (dd); 7.38-7.3 (m); 7.20-7.10 (m); 7.06-7.00 (m); 6.78 (t); 6.69-6.58 (m);

6,49 (dd); 6,27 (d); 5,26 (d); 4,49 (d); 3,28 (d); 2,93 (s); 1,88 (bs); 1,67-1,30 (m).6.49 (dd); 6.27 (d); 5.26 (d); 4.49 (d); 3.28 (d); 2.93 (s); 1.88 (bs); 1.67-1.30 (m).

PRIMER 45 (+)-N-[l-(adamantanmetil)2,4-diokso-5-fenil-2,3,4,5-tetrahidro-lH-l,5benzodiazepin-3-in-N’-fenilsečninaEXAMPLE 45 (+) - N- [1- (adamanthanmethyl) 2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5benzodiazepin-3-and-N'-phenylurea

Fenilizocianat (0,033 ml) dodamo raztopini intermediata 97 (0,096 g) v suhem acetonitrilu (9 ml). Zmes mešamo pri 23° v atmosferi dušika 1 uro, nato jo razredčimo z diklorometanom (40 ml) in izperemo s slanico (2 x20 ml). Organski sloj posušimo in koncentriramo v vakuumu. S kristalizacijo surovega materiala iz etilacetata dobimo naslovno spojino (0,075 g) kot bele igle. Tal. 264-265°. T.l.c. CHEA (50:50), Rf 0,77 [alfa]_D = +38,4. IR (nujol); 3400 (NH); 1707 in 1653 (C=O), 1597 in 1551 (C=C) cm-1; Ή-NMR: 7,48 (d); 7,46-7,20 (m); 7,16 (m); 7,04-6,94 (m); 6,92 (s); 6,37 (d); 5,29 (d); 4,48 (d); 3,38 (d); 1,85 (m); 1,64-1,30 (m).Phenylisocyanate (0.033 ml) was added to a solution of intermediate 97 (0.096 g) in dry acetonitrile (9 ml). The mixture was stirred at 23 ° C under a nitrogen atmosphere for 1 hour, then diluted with dichloromethane (40 ml) and washed with brine (2 x 20 ml). The organic layer was dried and concentrated in vacuo. Crystallization of the crude material from ethyl acetate gave the title compound (0.075 g) as white needles. Tal. 264-265 °. Tlc CHEA (50:50), Rf 0.77 [alpha] _D = +38.4. IR (nujol); 3400 (NH); 1707 and 1653 (C = O), 1597 and 1551 (C = C) cm-1; Ή-NMR: 7.48 (d); 7.46-7.20 (m); 7.16 (m); 7.04-6.94 (m); 6.92 (s); 6.37 (d); 5.29 (d); 4.48 (d); 3.38 (d); 1.85 (m); 1.64-1.30 (m).

PRIMER 46 (+)-N-[l-(adamantilmetil)-2,4-diokso-5-fenil-2,3A5-tetrahidro-lH-l,5benzodiazepin-3-il1-N’-f3-etoksikarbonilfenir)sečninaEXAMPLE 46 (+) - N- [1- (adamantylmethyl) -2,4-dioxo-5-phenyl-2,3A5-tetrahydro-1H-1,5-benzodiazepin-3-yl1-N'-3-ethoxycarbonylphenyl) urea

3-etoksikarbonilfenilizocianat (0,152 ml) dodamo raztopini intermediata 97 (0,490 g) v suhem acetonitrilu (20 ml) v atmosferi dušika. Zmes mešamo 1 uro pri 23°, nato razredčimo z diklorometanom (20 ml), koncentriramo v vakuumu in ostanek trituriramo z dietiletrom, da dobimo naslovno spojino kot belo trdno snov (0,543 g). Tal. 220-221°. [alfa]_D = +60,8, (CHC1₃, c = 1,020). T.l.c. CH-EA (2:1), Rf 0,35 IR: 1709,1670 in 1690 (C=O) cm-1; Ή-NMR: 7,93 (t); 7,64 (m); 7,44-7,39 (m); 7,35-7,27 (m); 7,24-7,14 (m); 7,38 (bs); 6,89 (dd); 6,58 (d); 5,31 (d); 4,50 (d); 4,34 (q); 3,38 (d); 1,85 (m); 1,61 (m); 1,51 (m); 1,45 (m); 1,37 (m); 1,35 (t).3-Ethoxycarbonylphenylisocyanate (0.152 ml) was added to a solution of Intermediate 97 (0.490 g) in dry acetonitrile (20 ml) under a nitrogen atmosphere. The mixture was stirred at 23 ° for 1 hour, then diluted with dichloromethane (20 ml), concentrated in vacuo and the residue triturated with diethyl ether to give the title compound as a white solid (0.543 g). Tal. 220-221 °. [alpha] _D = +60.8, (CHCl ₃ , c = 1.020). Tlc CH-EA (2: 1), Rf 0.35 IR: 1709.1670 and 1690 (C = O) cm-1; Ή-NMR: 7.93 (t); 7.64 (m); 7.44-7.39 (m); 7.35-7.27 (m); 7.24-7.14 (m); 7.38 (bs); 6.89 (dd); 6.58 (d); 5.31 (d); 4.50 (d); 4.34 (q); 3.38 (d); 1.85 (m); 1.61 (m); 1.51 (m); 1.45 (m); 1.37 (m); 1.35 (t).

PRIMER 47 (+)-N-[l-(l-adamantilmetil)-2,4-diokso-5-fenil-2,3,4,5-tetrahidro-lH-l,5benzodiazepin-3-ill-N^,-(3-karboksifenil)sečninaEXAMPLE 47 (+) - N- [1- (1-adamantylmethyl) -2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl-N ^, - (3-carboxyphenyl) urea

Aluminijev jodid (0,137 g) dodamo k suspenziji primera 46 (0,10 g) v suhem acetonitrilu (10 ml). Reakcijsko zmes mešamo 6 ur pri 80°, nato ohladimo na 23°, razredčimo z diklorometanom (30 ml) in vlijemo na led (10 g). Vodni sloj nakisamo z 10 %-no raztopino klorovodikove kisline (1 ml), izperemo s 5 %-no raztopino natrijevega tiosulfata (20 ml) in ekstrahiramo z diklorometanom (2 x 25 ml). Zbrane organske faze speremo s vodo (30 ml) in slanico (10 ml), posušimo in uparimo, da dobimo belo trdno snov (0,118 g). Ta material čistimo na silikagelu, eluiramo s CH/EA 1/1 in nato EA/metanolom 1/1, da dobimo naslovno spojino (41 mg). T.l.c. EA, Rf 0,64 IR: 3354 (NH in OH), 1701 in 1684 (C=O) cm-1; Ή-NMR: 9,21 (s); 7,9-7,8 (m); 7,6-7,16 (m); 7,0-6,9 (m); 4,99 (d); 4,30 (d); 3,60 (d); 1,83 (s); 1,65-1,2 (m).Aluminum iodide (0.137 g) was added to the suspension of Example 46 (0.10 g) in dry acetonitrile (10 ml). The reaction mixture was stirred for 6 hours at 80 ° C, then cooled to 23 °, diluted with dichloromethane (30 ml) and poured onto ice (10 g). The aqueous layer was acidified with 10% hydrochloric acid solution (1 ml), washed with 5% sodium thiosulphate solution (20 ml) and extracted with dichloromethane (2 x 25 ml). The combined organic phases were washed with water (30 ml) and brine (10 ml), dried and evaporated to give a white solid (0.118 g). This material was purified on silica gel, eluting with CH / EA 1/1 and then EA / methanol 1/1 to give the title compound (41 mg). T.l.c. EA, Rf 0.64 IR: 3354 (NH and OH), 1701 and 1684 (C = O) cm-1; Ή-NMR: 9.21 (s); 7.9-7.8 (m); 7.6-7.16 (m); 7.0-6.9 (m); 4.99 (d); 4.30 (d); 3.60 (d); 1.83 (s); 1.65-1.2 (m).

PRIMER 48EXAMPLE 48

N-r2,4-diokso-7-fluoro-l-(3-metilbut-l-il)-5-fenil-2.3.4,5-tetrahidro-lH-l,5benzodiazepin-S-ill-NVS-dimetilaminolfenilsečninaN-1,2,4-dioxo-7-fluoro-1- (3-methylbut-1-yl) -5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-S-yl-NVS-dimethylaminolphenylurea

3-dimetilaminofenilizocianat (0,055 g) dodamo k raztopini intermediata 100 (0,08 g) v suhem acetonitrilu (5 ml) v atmosferi dušika. Zmes mešamo 30 minut pri 23°; dobljeno oborino fitriramo in izperemo z etiletrom, da dobimo naslovno spojino kot belo trdno snov (0,086 g). Tal. 249-251°. T.l.c. CH-EA (1:1), Rf 0,5 IR: 1705,1672 in 1636 (C=O), 1607 (C=C) cm-1; ^I-NMR: 7,0-7,50 (m); 6,81(bt); 6,68 (dd); 6,63-6,46 (dd); 6,51 (bs); 6,28 (d); 5,31 (d); 4,54-3,60 (m); 2,92 (s); 1,6-1,40 (m); 0,95-0,85 (d).3-dimethylaminophenylisocyanate (0.055 g) was added to a solution of intermediate 100 (0.08 g) in dry acetonitrile (5 ml) under a nitrogen atmosphere. The mixture was stirred for 30 minutes at 23 °; The resulting precipitate was filtered and washed with ethyl ether to give the title compound as a white solid (0.086 g). Tal. 249-251 °. T.l.c. CH-EA (1: 1), Rf 0.5 IR: 1705.1672 and 1636 (C = O), 1607 (C = C) cm-1; 1 H-NMR: 7.0-7.50 (m); 6.81 (bt); 6.68 (dd); 6.63-6.46 (dd); 6.51 (bs); 6.28 (d); 5.31 (d); 4.54-3.60 (m); 2.92 (s); 1.6-1.40 (m); 0.95-0.85 (d).

Farmacevtski primerA pharmaceutical example

Kapsule ali tablete mg/dozimo obliko aktivna sestavina polietilenglikol laktoza škrob magnezijev stearat silicijev dioksid natrijev lavrilsulfatCapsules or tablets mg / dosage form active ingredient polyethylene glycol lactose starch magnesium stearate silica sodium lauryl sulfate

0,10.1

15,015.0

52,452,4

30,030.0

0,50.5

1,01.0

1,01.0

100,0100,0

Aktivno sestavino dispergiramo v primernem topilu (npr. etanolu) skupaj s polietilenglikolom. Topilo odstranimo. Tako dobljen prašek pomešamo z drugimi ekscipienti. Mešanico lahko uporabimo za polnjenje želatinskih kapsul ali stisnemo ob uporabi primernih pehal. Tablete lahko preslojimo ob uporabi običajnih tehnik in preslojevanj.The active ingredient is dispersed in a suitable solvent (eg ethanol) together with polyethylene glycol. The solvent is removed. The powder thus obtained is mixed with other excipients. The mixture can be used to fill gelatin capsules or squeezed using suitable cups. The tablets can be coated using conventional techniques and coatings.

Aktivna sestavina 0,1 povidon 15,4 laktoza 74,0 hidrogenirana rastlinska olja 3,0Active ingredient 0.1 povidone 15.4 lactose 74.0 hydrogenated vegetable oils 3.0

68 68 silicijev dioksid silica 1,0 1.0 natrijev lavrilsulfat sodium lauryl sulfate 1,5 1.5 krospovidon crospovidone 5,0 5.0 100,0 100,0 Aktivno sestavino dispergiramo The active ingredient is dispersed v primernem topilu (npr. etanolu) skupaj s in a suitable solvent (eg ethanol) together with povidonom. Raztopino napršimo na laktozo in topilo odstranimo. Dobljen prašek pomešamo z drugimi ekscipienti. Mešanico uporabimo za polnjenje želatinskih kapsul ali stisnemo ob uporabi primernih pehal. Tableto lahko preslojimo ob uporabi povidone. The solution was sprayed onto lactose and the solvent removed. The resulting powder is mixed with other excipients. The mixture is used to fill the gelatin capsules or squeezed using suitable cups. The tablet can be coated when used običajnih tehnik in preslojevanj. conventional techniques and layering. Oralna tekočina Oral fluid Aktivna sestavina Active ingredient 70-100/zg/dozo 70-100 / zg / dose etanol ethanol 5-15 % 5-15% natrijev saharinat saccharinate sodium 0,1-1 % 0.1-1% propilenglikol q.b. propylene glycol q.b. 100% 100% Injekcijski pripravek Injectable preparation Aktivna sestavina Active ingredient 0,1-100/zg 0,1-100 / zg natrijev fosfat sodium phosphate 1,50 mg/ml 1.50 mg / ml NaOH q.s NaOH q.s želeni pH (območje 3-9) desired pH (range 3-9) glicerol glycerol 10-500 mg/ml 10-500 mg / ml voda za injekcije q.s.do water for injections q.s.do 0,5-10 ml 0,5-10 ml Pakirati v steklene posode (ampule) z gumijastim zamaškom (fiole, brizge) in plastično/kovinskim tesnilom (le fiole). V mrtev prostor posode lahko uvedemo atmosfero inertnega plina (npr. dušika). Pack in glass containers (ampoules) with rubber stopper (vials, syringes) and plastic / metal seal (vials only). An inert gas (eg nitrogen) atmosphere can be introduced into the dead space of the container. CCK - Antagonistična aktivnost CCK - Antagonistic activity

CCK-A antagonistične in CCK-B antagonistične aktivnosti spojin v smislu izuma določimo ob uporabi pripravka izolirane vzdolžne mišice ileuma morskega prašička mienteričnega pleksusa. Spojine testiramo ob uporabi postopka G Dal Forno et al.,The CCK-A antagonist and CCK-B antagonist activities of the compounds of the invention are determined using the preparation of an isolated longitudinal guinea pig ileum muscle of the myenteric plexus. The compounds are tested using the procedure of G Dal Forno et al.,

J. Pharmacol. Exp & Ther. 261 -1056-1063,1992, in določimo vrednost pKb za vsako spojino.J. Pharmacol. Exp & Ther. 261 -1056-1063,1992, and determine the pKb value for each compound.

Rezultati, dobljeni z reprezentativnimi spojinami v smislu izuma, so, kot sledi:The results obtained with the representative compounds of the invention are as follows:

Spojine primera št. pKbThe compounds of Example no. pKb

CCK-A CCK-A CCK-B CCK-B 4 4 5,5 5.5 10,1 10.1 14 14 6,8 6,8 8,5 8.5 25 25 <6,0 <6.0 9,1 9.1 26 26 < 5,5 <5.5 8,7 8.7 45 45 5,9 5.9 8,9 8.9

CCK - Recepetorska vezavaCCK - Receptor attachment

Vezivno afiniteto spojin v smislu izuma za CCK-A receptor (pankreasni test) in CCK-B receptor (test korteksa morskega prašička) določimo ob uporabi postopka G Dal Forno et al. J. Pharmacol. Exp & Ther. 261 -1056-1063. Vrednosti pKi, določene z reprezentativnimi spojinami v smislu izuma, so naslednje:The binding affinity of the compounds of the invention for CCK-A receptor (pancreatic test) and CCK-B receptor (guinea pig cortex test) was determined using the procedure of G Dal Forno et al. J. Pharmacol. Exp & Ther. 261 -1056-1063. The pKi values determined by the representative compounds of the invention are as follows:

Spojina primera št. pKiThe compound of Example no. pKi

4 4 CCK-A 6,9 CCK-A 6,9 CCK-B 9,6 CCK-B 9.6 7A 7A 6,33 6.33 8,71 8.71 9 9 6,02 6.02 8,31 8.31 11 11 5,80 5.80 8,01 8.01 14 14 6,15 6.15 8,64 8.64 16 16 6,95 6.95 9,17 9.17 25 25 6,49 6.49 8,81 8.81 26 26 6,30 6.30 8,81 8.81 27 27 6,83 6.83 9,54 9.54 30 30 7,00 7,00 9,14 9.14 31 31 6,76 6.76 8,82 8.82 39 39 6,52 6.52 8,72 8.72 41 41 6,09 6.09 8,53 8.53 45 45 5,95 5.95 9,02 9.02

Spojine v smislu izuma so v bistvu netoksične v terapevtsko koristnih dozah. Tako npr. ne opazimo škodljivih učinkov, kadar dajemo spojino primera 45 oralno mišim in podganam pri dozah, pri katerih ima spojina anksiolitično aktivnost.The compounds of the invention are substantially non-toxic at therapeutically useful doses. So e.g. no adverse effects were observed when the compound of Example 45 was administered orally to mice and rats at doses at which the compound had anxiolytic activity.

Claims (14)

PATENTNI ZAHTEVKIPATENT APPLICATIONS 1. Spojine s splošno formulo (I) kjerCompounds of general formula (I) wherein R¹ predstavlja fenilno, C_{3 7}cikloalkilno, C_{? n} premoščeno cikloalkilno ali C₁₆alkilno skupino, alkilna skupina pa je lahko substituirana s hidroksi, fenilno, C₁₆alkoksikarbonilno, C_{3 7}cikloalkilno ali C_{? n} premoščeno cikloalkilno skupino;R ¹ represents phenyl, C _3-7 cycloalkyl, C _{? n a} bridged cycloalkyl or C ₁₆ alkyl group, and the alkyl group may be substituted by hydroxy, phenyl, C ₁₆ alkoxycarbonyl, C _{3 7} cycloalkyl or C _{? n a} bridged cycloalkyl group; R² predstavlja substituirano ali nesubstituirano fenilno skupino (kjer so lahko substituenti 1 ali 2 izmed halo, C^alkila, nitro, ciano trifluorometila, trifluorometoksi, C14alkiltio ali (CH2)nR⁴, kjer je R⁴ hidroksi, C^alkoksi, CO2R⁵ ali NR⁶R⁷ R³ je fenil, v danem primeru substituiran z enim ali dvema atomoma halogena;R ² represents a substituted or unsubstituted phenyl group (wherein the substituents may be 1 or 2 of halo, C ^ alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, C14alkiltio or (CH 2) n R ^4, wherein R ⁴ is hydroxy, C ^ alkoxy, CO 2 R ⁵ or NR ⁶ R ⁷ R ³ is phenyl optionally substituted by one or two halogen atoms; R⁵ predstavlja vodik ali C₁₄alkilno skupino;R ⁵ represents hydrogen or a C ₁₄ alkyl group; R⁶ in R⁷ neodvisno predstavljata vodik ali C^alkilno skupino;R ⁶ and R ⁷ independently represent hydrogen or a C 1-6 alkyl group; R⁸ predstavlja atom vodika ali halogena; m je 0,1 ali 2;R ⁸ represents a hydrogen or halogen atom; m is 0.1 or 2; n je 0 ali 1; ter njihove farmacevtsko sprejemljive soli in solvati.n is 0 or 1; and pharmaceutically acceptable salts and solvates thereof. 2. Spojine po zahtevku 1, označene s tem, da R¹ predstavlja fenil, fenetil, premoščen C₇₁₀cikloalkil, C^alkil, C₃Jhidroksialkil, C_{4 2}alkil, substituiran s premoščenim G? ₁₀cikloalkilom, alkoksikarbonilmetilom, ali C₂ alkil, substituiran s C_{3 7}cikloalkilom.2. Compounds according to claim 1, characterized in that R ¹ represents phenyl, phenethyl, bridged C ₇₁₀ cycloalkyl, C ^ alkyl, C ₃ Jhidroksialkil, C _{2 4} alkyl substituted by bridged G? ₁₀ cycloalkyl, alkoxycarbonylmethyl, or C ₂ alkyl substituted with C _3-7 cycloalkyl. 3. Spojine po zahtevku 1 ali 2, označene s tem, da R¹ predstavlja 3-metilbutil,Compounds according to claim 1 or 2, characterized in that R ¹ represents 3-methylbutyl, 3,3-dimetilbutil, 2-hidroksi-3-metilbutil, 2-hidroksi-3,3-dimetilbutil, 2-ciklopentiletil,3,3-dimethylbutyl, 2-hydroxy-3-methylbutyl, 2-hydroxy-3,3-dimethylbutyl, 2-cyclopentylethyl, 5-norbornenilmetil ali 1-adamantilmetil.5-norbornenylmethyl or 1-adamantylmethyl. 4. Spojine po kateremkoli od zahtevkov 1 do 3, označene s tem, da R² predstavlja fenil, v danem primeru substituiran z bromom, klorom, fluorom, metilom, metoksi, metiltio, triflurometoksi, ciano, dimetilamino ali (CH₂)_nCO₂R⁵, kjer je R⁵ vodik ali C^alkil.Compounds according to any one of claims 1 to 3, characterized in that R ² represents phenyl optionally substituted by bromine, chlorine, fluorine, methyl, methoxy, methylthio, trifluoromethoxy, cyano, dimethylamino or (CH ₂ ) _n CO ₂ R ⁵ wherein R ^{5 is} hydrogen or C 1-6 alkyl. 5. Spojine po kateremkoli od zahtevkov 1 do 4, označene s tem, da je R² predstavlja fenil, v danem primeru substituiran z metoksi, ciano, nitro, metiltio, dimetilamino, etoksikarbonilom ali karboksilom.Compounds according to any one of claims 1 to 4, characterized in that R ² represents phenyl optionally substituted by methoxy, cyano, nitro, methylthio, dimethylamino, ethoxycarbonyl or carboxyl. 6. Spojine po kateremkoli od zahtevkov 1 do 5, označene s tem, da R³ predstavlja fenil, v danem primeru substituiran s fluorom v orto ali para položaju.Compounds according to any one of claims 1 to 5, characterized in that R ³ represents phenyl optionally substituted by fluorine in the ortho or para position. 7. Spojine po kateremkoli od zahtevkov 1 do 6, označene s tem, da R⁸ predstavlja vodik, klor ali fluor.Compounds according to any one of claims 1 to 6, characterized in that R ⁸ represents hydrogen, chlorine or fluorine. 8. Spojine po kateremkoli od zahtevkov 1 do 7, označene s tem, da imajo konfiguracijoCompounds according to any one of claims 1 to 7, characterized in that they have a configuration 9. N-fenil-N’-[2,3,4,5-tetrahidro-2,4-diokso-l-(l-adamantilmetil)-5-fenil-lH-l,5benzodiazepin3-il]sečnina, njen (+) enantiomer in njene soli.9. N-phenyl-N '- [2,3,4,5-tetrahydro-2,4-dioxo-1- (1-adamantylmethyl) -5-phenyl-1H-1,5-benzodiazepin3-yl] urea, its ( +) the enantiomer and its salts. 10. N-[l-(l-adamantilmetil)-2,4-diokso-5-fenil-2,3,4,5-tetrahidro-lH-l,5-benzodiazepin-3-il]-N’-(3-karboksifenil)sečnina;10. N- [1- (1-adamantylmethyl) -2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl] -N '- ( 3-carboxyphenyl) urea; N-fenil-N’-[2,3,4,5-teatrahidro-2,4-diokso-l-(3-metilbutil)-5-fenil-lH-l,5benzodiazepin-3-il]sečnina;N-phenyl-N '- [2,3,4,5-tetrahydro-2,4-dioxo-1- (3-methylbutyl) -5-phenyl-1H-1,5-benzodiazepin-3-yl] urea; N-(3-dimetilaminofenil)-N’-[2,3,4,5-tetrahidro-2,4-diokso-l-(3-metilbutil)-5-(2fluorofenil)-lH-l,5-benzodiazepin-3-il]sečnina;N- (3-dimethylaminophenyl) -N '- [2,3,4,5-tetrahydro-2,4-dioxo-1- (3-methylbutyl) -5- (2fluorophenyl) -1H-1,5-benzodiazepine- 3-yl] urea; njihovi (+) enantiomeri in njihove soli.their (+) enantiomers and their salts. 11. Spojine po kateremkoli od zahtevkov 1 do 10 za uporabo v terapiji.Compounds according to any one of claims 1 to 10 for use in therapy. 12. Uporaba spojine po kateremkoli od zahtevkov 1 do 10, za izdelavo zdravila za zdravljenje stanj, kjer je terapevtsko ugodna modifiakcija učinkov gastrina in/ali CCK.Use of a compound according to any one of claims 1 to 10 for the manufacture of a medicament for the treatment of conditions wherein the modification of the effects of gastrin and / or CCK is therapeutically advantageous. 13. Farmacevtski sestavki, označeni s tem, da obsegajo spojino po kateremkoli od zahtevkov 1 do 10 v mešanici z enim ali več fiziološko sprejemljivimi nosilci ali ekscipienti.Pharmaceutical compositions comprising a compound according to any one of claims 1 to 10 in admixture with one or more physiologically acceptable carriers or excipients. 14. Postopek za pripravo spojin po zahtevku 1, označen s tem, da (a) spojino s formulo (II), kjer so R¹, R³ R⁸ in m, kot je definirano v formuli (I) in X predstavlja skupino -N=C=O ali NHCOR⁹, kjer je R⁹ v danem primeru substituirana fenoksi skupina ali 1-imidazolna skupina presnovimo z aminom s formulo (III)A process for the preparation of compounds according to claim 1, characterized in that (a) a compound of formula (II), wherein R ¹ , R ^{3 are} R ⁸ and m as defined in formula (I) and X represents a group - N = C = O or NHCOR ⁹ , wherein R ⁹ is optionally substituted phenoxy or 1-imidazole group with an amine of formula (III) NH₂R² (III) kjer ima R² pomen, definiran v formuli (I), ali je skupina, ki se da vanj pretvoriti;NH ₂ R ² (III) wherein R ^{2 has the} meaning defined in formula (I) or is a group convertible thereto; (b) aciliramo amin s formulo (IV) z reakcijo z izocianatom s formulo (V) ali karbamoilkloridom s formulo (VI)(b) acylating an amine of formula (IV) by reaction with an isocyanate of formula (V) or carbamoyl chloride of formula (VI) O=C=NR² (V) C1C(O)NHR² (VI) (c) hidroliziramo spojino s formulo (I), v kateri je R² fenilna skupina, substituirana z alkoksikarbonilno skupino, da dobimo spojino s formulo (I), v kateri je R² fenilna skupina, substituirana s karboksilom;O = C = NR ² (V) C1C (O) NHR ² (VI) (c) hydrolyse a compound of formula (I) in which R ^{2 is a} phenyl group substituted by an alkoxycarbonyl group to give a compound of formula (I) wherein R ^{2 is} a carboxyl substituted phenyl group; in nato po potrebi ali želji pretvorimo dobljeno spojino, bodisi pred ali po katerikoli ločbi v njene stereokemične izomere v drugo spojino v smislu izuma.and then converting the resulting compound, if necessary or desired, either before or after any separation into its stereochemical isomers, into another compound of the invention.