NO965608L - Vitronectin receptor antagonists - Google Patents

Vitronectin receptor antagonists

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Publication number
NO965608L
NO965608L NO965608A NO965608A NO965608L NO 965608 L NO965608 L NO 965608L NO 965608 A NO965608 A NO 965608A NO 965608 A NO965608 A NO 965608A NO 965608 L NO965608 L NO 965608L
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methyl
tetrahydro
oxo
benzodiazepine
acetic acid
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NO965608A
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Norwegian (no)
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NO965608D0 (en
Inventor
Fadia Ali
William Edward Bondinell
William Francis Huffmann
M Amparo Lago
Richard Mcculloch Keenan
Chet Kwon
William Henry Miller
Thomas Nguyen
Dennis T Takata
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Smithkline Beecham Corp
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Publication of NO965608D0 publication Critical patent/NO965608D0/en
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Description

Denne oppfinnelse vedrører farmasøytisk aktive forbindelser som inhiberer vitronectin-reseptorer og er nyttige ved behandlingen av inflammasjon, kreft og kardiovaskulære forstyrrelser, så som aterosklerose og restenose, og sykdommer hvor benresorpsjon er en faktor, så som osteoporose. This invention relates to pharmaceutically active compounds that inhibit vitronectin receptors and are useful in the treatment of inflammation, cancer and cardiovascular disorders, such as atherosclerosis and restenosis, and diseases where bone resorption is a factor, such as osteoporosis.

BAKGRUNN FOR OPPFINNELSENBACKGROUND OF THE INVENTION

Integriner er en superfamilie av celleadhesjons-reseptorer som er transmembrane glykoproteiner som uttrykkes i en rekke celler. Disse celleoverflate adhesjons-reseptorer inkluderer gpllb/llla, fibrinogenreseptoren, og avp3, vitronectin-reseptoren. Fibrinogen-reseptoren gpllb/llla uttrykkes på blodplateoverflaten og medierer blodplateaggregasjon og dannelsen av en hemostatisk koagel på det blødende sted. Philips et al., Blood., 1988, 71, 831. Vitronectin-reseptoren avp3uttrykkes i en rekke celler, inklusivt endotel, glatt muskulatur, osteoklaster og tumorceller og har således mange forskjellige funksjoner. avp3-reseptorer uttrykt på membranen til osteoklastceller, medierer benresorpsjonsprosessen og bidrar til utviklingen av osteoporose. Ross, et al., J. Biol. Chem., 1987, 262, 7703. avp3-reseptorer uttrykt på humane glatte aorta muskelceller stimulerer deres migrering inn i neointima, som fører til dannelse av aterosklerose og restenose etter angioplastikk. Brown, et al., Cardiovascular Res., 1994, 28, 1815. En nylig undersøkelse har dessuten vist at en avp3-antagonist er i stand til å fremme tumor-regresjon ved å indusere apoptose i angiogene blodkar. Brooks, et al., Cell, 1994, 79, 1157. Midler som kan blokkere vitronectin-reseptorer kan således være egnet ved behandling av sydkommer mediert av denne reseptor, så som osteoporose, aterosklerose, restenose og kreft. Integrins are a superfamily of cell adhesion receptors that are transmembrane glycoproteins expressed in a variety of cells. These cell surface adhesion receptors include gp11b/lla, the fibrinogen receptor, and avp3, the vitronectin receptor. The fibrinogen receptor gpllb/llla is expressed on the platelet surface and mediates platelet aggregation and the formation of a hemostatic clot at the bleeding site. Philips et al., Blood., 1988, 71, 831. The vitronectin receptor is expressed in a variety of cells, including endothelium, smooth muscle, osteoclasts and tumor cells and thus has many different functions. avp3 receptors expressed on the membrane of osteoclast cells mediate the bone resorption process and contribute to the development of osteoporosis. Ross, et al., J. Biol. Chem., 1987, 262, 7703. avp3 receptors expressed on human aortic smooth muscle cells stimulate their migration into the neointima, leading to the formation of atherosclerosis and restenosis after angioplasty. Brown, et al., Cardiovascular Res., 1994, 28, 1815. Furthermore, a recent study has shown that an αvβ3 antagonist is able to promote tumor regression by inducing apoptosis in angiogenic blood vessels. Brooks, et al., Cell, 1994, 79, 1157. Agents that can block vitronectin receptors may thus be suitable in the treatment of diseases mediated by this receptor, such as osteoporosis, atherosclerosis, restenosis and cancer.

Vitronectin-reseptoren er kjent for å binde benmatriks-proteiner, som f.eks. osteopontin, ben-sialoprotein og trombospondin, som inneholder tripeptidet Arg-Gly-Asp- (eller RGD) motivet. Horton, et al., Exp. Cell Res., 1991, 195, 368, beskriver at RGD-holdige peptider og et anti-vitronectin-reseptor-antistoff (23C6) inhiberer dentinresorpsjon og cellespredning via osteoklaster. Dessuten beskriver Sato, et al., J. Cell Biol., 1990, 111, 1713 at echistatin, et slangegiftpeptid som inneholder RGD-sekvensen, er en sterk inhibitor av benresorpsjon i vevskultur og inhiberer festingen av osteoklaster til ben. Fisher, et al., Endocrinology, 1993, 132, 1411, har dessuten vist at echistatin inhiberer benresorpsjon in vivo i rotte. Bertolini, et al., J. Bone Min. Res., 6, Sup. 1, s. 146, 252, har vist at cyklo-S,S-Na<->acetyl-cysteinyl-N°-metyl-argininyl-glycyl-aspartyl-penicillamin inhiberer osteoklast-festing til ben. The vitronectin receptor is known to bind bone matrix proteins, such as e.g. osteopontin, benzyl sialoprotein and thrombospondin, which contain the tripeptide Arg-Gly-Asp (or RGD) motif. Horton, et al., Exp. Cell Res., 1991, 195, 368, describe that RGD-containing peptides and an anti-vitronectin receptor antibody (23C6) inhibit dentin resorption and cell spreading via osteoclasts. Moreover, Sato, et al., J. Cell Biol., 1990, 111, 1713 describe that echistatin, a snake venom peptide containing the RGD sequence, is a strong inhibitor of bone resorption in tissue culture and inhibits the attachment of osteoclasts to bone. Fisher, et al., Endocrinology, 1993, 132, 1411, have also shown that echistatin inhibits bone resorption in vivo in the rat. Bertolini, et al., J. Bone Min. Res., 6, Sup. 1, pp. 146, 252, have shown that cyclo-S,S-Na<->acetyl-cysteinyl-N°-methyl-argininyl-glycyl-aspartyl-penicillamine inhibits osteoclast attachment to bone.

EP 528 587 og 528 586 omtaler substituerte fenylderivater som inhiberer osteoklast-mediert benresorpsjon. EP 528 587 and 528 586 mention substituted phenyl derivatives which inhibit osteoclast-mediated bone resorption.

Alig, et al., EP 0 381 033, Hartman, et al., EP 0 540.334, Blackburn, et al., WO 93/08174, Bondinell, et al., WO 93/00095, Blackburn, et al., WO 95/04057, Egbertson, et al., EP 0 478 328, Sugihara, et al., EP 529.858, Porter, et al., Alig, et al., EP 0 381 033, Hartman, et al., EP 0 540,334, Blackburn, et al., WO 93/08174, Bondinell, et al., WO 93/00095, Blackburn, et al., WO 95/04057, Egbertson, et al., EP 0,478,328, Sugihara, et al., EP 529,858, Porter, et al.,

EP 0 542 363 og Fischer, et al., EP 0 635 492 beskriver visse forbindelser som er egnet for inhibering av fibrinogen-reseptorer. Det er nå oppdaget at visse passende substituerte forbindelser er potente inhibitorer av vitronectin-reseptorer. Det er særlig oppdaget at slike forbindelser er mer potente inhibitorer av vitronectin-reseptorer enn fibrinogen-reseptoren og slike forbindelser inneholder en fibrinogen-reseptorantagonist-templat. EP 0 542 363 and Fischer, et al., EP 0 635 492 describe certain compounds which are suitable for inhibiting fibrinogen receptors. It has now been discovered that certain suitably substituted compounds are potent inhibitors of vitronectin receptors. In particular, it has been discovered that such compounds are more potent inhibitors of vitronectin receptors than the fibrinogen receptor and such compounds contain a fibrinogen receptor antagonist template.

SAMMENFATNING AV OPPFINNELSENSUMMARY OF THE INVENTION

Oppfinnelsen vedrører forbindelser med formel (l)-(V) som beskrevet nedenfor.som har farmakologisk inhiberende virkning på vitronectin-reseptorer og er egnet ved behandling av inflammasjon, kreft og kardiovaskulære forstyrrelser, så som aterosklerose og restenose, og sykdommer hvor benresorpsjon er en faktor, så som osteoporose. The invention relates to compounds of formula (l)-(V) as described below, which have a pharmacological inhibitory effect on vitronectin receptors and are suitable in the treatment of inflammation, cancer and cardiovascular disorders, such as atherosclerosis and restenosis, and diseases where bone resorption is a factor, such as osteoporosis.

Oppfinnelsen vedrører også en farmasøytisk blanding som omfatter en forbindelse ifølge formel (l)-(V) og en farmasøytisk bærer. The invention also relates to a pharmaceutical mixture comprising a compound according to formula (1)-(V) and a pharmaceutical carrier.

Oppfinnelsen vedrører også en fremgangsmåte for behandling av sykdommer som medieres av vitronectin-reseptorer. I henhold til et særlig aspekt, er forbindelsene ifølge oppfinnelsen egnet for behandling av aterosklerose, restenose, inflammasjon, kreft og sykdommer hvor benresorpsjon er en faktor, så som osteoporose. The invention also relates to a method for treating diseases mediated by vitronectin receptors. According to a particular aspect, the compounds according to the invention are suitable for the treatment of atherosclerosis, restenosis, inflammation, cancer and diseases where bone resorption is a factor, such as osteoporosis.

DETALJERT BESKRIVELSEDETAILED DESCRIPTION

Foreliggende oppfinnelse omfatter nye forbindelser som er mere potente inhibitorer av vitronectin-reseptorer enn fibrinogenreseptorer. Forbindelsene ifølge oppfinnelsen omfatter en fibrinogen-reseptorantagonist-templat som er bundet til en nitrogenholdig fem-leddet ring, som eventuelt er kondensert til en aromatisk seks-leddet ring. Fibrinogen-reseptorantagonist-templaten er substituert med en alifatisk substituent som inneholder en sur del. Det er å foretrekke at ca. 14 intervenerende kovalente bindinger via den intramolekylært korteste vei, vil forekomme mellom syregruppen i fibrinogen-reseptorantagonist-templaten og nitrogenet i den eventuelt kondenserte fem-leddede ring. The present invention comprises new compounds which are more potent inhibitors of vitronectin receptors than fibrinogen receptors. The compounds according to the invention comprise a fibrinogen receptor antagonist template which is bound to a nitrogen-containing five-membered ring, which is optionally condensed to an aromatic six-membered ring. The fibrinogen receptor antagonist template is substituted with an aliphatic substituent containing an acidic moiety. It is preferable that approx. 14 intervening covalent bonds via the intramolecularly shortest path will occur between the acid group in the fibrinogen receptor antagonist template and the nitrogen in the possibly condensed five-membered ring.

I denne sammenheng betyr betegnelsen "fibrinogen-reseptorantagonist-templat" kjernestrukturen for en fibrinogen-reseptorantagonist hvor kjernen er substituert med en syregruppe og kjernen er bundet til en organisk gruppe substituert med en basisk nitrogendel. En fibrinogen-reseptorantagonist er et middel som inhiberer bindingen av fibrinogen til den blodplate-bundne fibrinogen-reseptor GPIIb-llla. Det er et formål med foreliggende oppfinnelse at en fibrinogen-reseptorantagonist omdannes til en vitronectin-reseptorantagonist ved å erstatte den organiske gruppe som er substituert med en basisk nitrogendel i en fibrinogen-reseptorantagonist, med en eventuelt kondensert nitrogenholdig fem-leddet ring, fortrinnsvis en imidazolring og helst en benzimidazolring. In this context, the term "fibrinogen receptor antagonist template" means the core structure of a fibrinogen receptor antagonist where the core is substituted with an acid group and the core is bound to an organic group substituted with a basic nitrogen moiety. A fibrinogen receptor antagonist is an agent that inhibits the binding of fibrinogen to the platelet-bound fibrinogen receptor GPIIb-IIIa. It is an object of the present invention that a fibrinogen receptor antagonist is converted into a vitronectin receptor antagonist by replacing the organic group which is substituted with a basic nitrogen part in a fibrinogen receptor antagonist, with an optionally condensed nitrogen-containing five-membered ring, preferably an imidazole ring and preferably a benzimidazole ring.

Foreliggende oppfinnelse omfatter forbindelser med formel (l)-(V):The present invention comprises compounds of formula (l)-(V):

hvor: where:

W er CHRVU-CHRVV eller W is CHRVU-CHRVV or

A er en fibrinogen-reseptorantagonist-templat; A is a fibrinogen receptor antagonist template;

U og V mangler eller er CO, CR<9>2, C(=CR<B>2), S(0)k, 0, NR°, CR<9>OR<fl>, U and V are missing or are CO, CR<9>2, C(=CR<B>2), S(0)k, 0, NR°, CR<9>OR<fl>,

CR<9>(OR<k>)CR<9>2, CR<g>2CR9(OR<k>), C(0)CR<fl>2, CR<9>2C(0), CONR<1>, NR'CO, 0C(0), C(0)0, C(S)0, OC(S), C(S)NR<9>, NR<9>C(S), S(0)2NR<fl>, NR<9>S(0)2, CR<9>(OR<k>)CR<9>2, CR<g>2CR9(OR<k>), C(0)CR<fl>2, CR<9>2C(0), CONR<1 >, NR'CO, 0C(0), C(0)0, C(S)0, OC(S), C(S)NR<9>, NR<9>C(S), S(0) 2NR<fl>, NR<9>S(0)2,

N=N,NR9NR<9>, NR<g>CR<9>2, NR9CR<9>2, CR<9>20, OCRfl2l C=C eller CR<B>=CR<B>;G er NR<e>, S eller 0; N=N,NR9NR<9>, NR<g>CR<9>2, NR9CR<9>2, CR<9>20, OCRfl2l C=C or CR<B>=CR<B>;G is NR< e>, S or 0;

R<9>er H, Ci.6-alkyl, Het-C0-6-alkyl, C3.7-cykloalkyl-Co-6-alkyl eller Ar-Cws-alkyl;R<k>erR<9>, -C(0)R<9>eller -C(0)OR<f>; R<9> is H, C1-6-alkyl, Het-C0-6-alkyl, C3-7-cycloalkyl-C0-6-alkyl or Ar-C8-alkyl; R<k> is R<9>, -C (O)R<9>or -C(O)OR<f>;

R' er H, Ci-e-alkyl, Het-Co-e-alkyl, C3.7-cykloalkyl-C0-6-alkyl, Ar-Co-e-alkyl eller Ci-e-alkyl substituert med én til tre grupper valgt fra halogen, CN, NR°2, R' is H, C1-e-alkyl, Het-C0-e-alkyl, C3.7-cycloalkyl-C0-6-alkyl, Ar-C0-e-alkyl or C1-e-alkyl substituted with one to three groups selected from halogen, CN, NR°2,

OR9, SR<9>, C02R<9>og CON(R<9>)2; OR9, SR<9>, CO2R<9> and CON(R<9>)2;

R<f>er H, Ci.6-alkyl eller Ar-Ci.6-alkyl; R<f>is H, C 1-6 alkyl or Ar-C 1-6 alkyl;

Re er H,^Ci.6-alkyl, Ar-Ci.6-alkyl, Het-Ci.6-alkyl, Cs-y-cykloalkyl-Ci-e-alkyl eller (CH2)kC02R<9>; Re is H1-C1-6 alkyl, Ar-C1-6 alkyl, Het-C1-6 alkyl, C5-y cycloalkyl-C1-6 alkyl or (CH2)kCO2R<9>;

k er 0, 1 eller 2; k is 0, 1 or 2;

q er 1 eller 2; q is 1 or 2;

a erO, 1 eller 2; a is 0, 1 or 2;

b erO, 1 eller 2; b is 0, 1 or 2;

R<b>og R<c>er uavhengig av hverandre valgt fra H, Ci-6-alkyl, Ar-Co^-alkyl, R and R are independently selected from H, C 1-6 alkyl, Ar-C 6 alkyl,

Het-Co-e-alkyl eller C3-6-cykloalkyl-Co-6-alkyl, halogen, CF3)0Rf, S(0)kR<f>, COR<f>, N02l. N(R<f>)2, C0(NR<f>)2, CH2N(R<f>)2eller Rb og R<c>er forenet under dannelse av en fem- eller seks-leddet aromatisk eller ikke-aromatisk karbocyklisk eller heterocyklisk ring, som eventuelt er substituert med opp til tre substituenter valgt fra halogen, CF3, d^-alkyl, 0Rf, S(0)kR', COR<f>, C02R<f>, Het-Co-e-alkyl or C3-6-cycloalkyl-Co-6-alkyl, halogen, CF3)0Rf, S(0)kR<f>, COR<f>, NO2l. N(R<f>)2, C0(NR<f>)2, CH2N(R<f>)2 or Rb and R<c> are joined to form a five- or six-membered aromatic or non-aromatic carbocyclic or heterocyclic ring, which is optionally substituted with up to three substituents selected from halogen, CF3, d-alkyl, ORf, S(O)kR', COR<f>, CO2R<f>,

OH, N02, N(R')2, CO(NR<f>)2og CH2N(R<f>)2; eller metylendioksy:OH, NO 2 , N(R') 2 , CO(NR<f>) 2 and CH 2 N(R<f>) 2 ; or methylenedioxy:

eller et farmasøytisk akseptabelt salt derav,or a pharmaceutically acceptable salt thereof,

med det forbehold at:with the proviso that:

(i) når A er 1,2,4,5-tetrahydro-3-okso-4-(2-fenyletyl)-1 H-1,4-benzodiazepin-2-eddiksyre, da er W ikke -(CH2)2.3NHCO-bundet til imidazolringens 1-stilling; og (ii) når A er 1,2,4,5-tetrahydro-3-okso-4-(2-fenyletyl)-1 H-1,4-benzodiazepin-2-eddiksyre, da er W ikke -(CH2)2NHCO-bundet til imidazolringens 4(5)-stilling . (i) when A is 1,2,4,5-tetrahydro-3-oxo-4-(2-phenylethyl)-1H-1,4-benzodiazepine-2-acetic acid, then W is not -(CH2)2.3 NHCO bonded to the 1-position of the imidazole ring; and (ii) when A is 1,2,4,5-tetrahydro-3-oxo-4-(2-phenylethyl)-1H-1,4-benzodiazepine-2-acetic acid, then W is not -(CH2) 2NHCO-bonded to the 4(5) position of the imidazole ring.

Oppfinnelsen innbefatter også farmasøytisk akseptable addisjonssalter, komplekser eller prodrugs av forbindelsene ifølge foreliggende oppfinnelse. Med prodrugs skal forstås en hvilken som helst kovalent bundet bærer som frigjør virkestoffet ifølge formel (I) in vivo. I de tilfeller hvor forbindelsene ifølge foreliggende oppfinnelse kan ha ett eller flere chirale sentra, innbefatter foreliggende oppfinnelse, med mindre annet er angitt, enhver egen ikke-racemisk forbindelse som kan syntetiseres og spaltes via konvensjonell teknikk. I de tilfeller hvor forbindelsene har umettede karbon-karbon dobbeltbindinger, faller både cis (Z) og trans (E) isomerer inn under rammen for oppfinnelsen. I de tilfeller hvor forbindelsene kan eksistere i tautomere former, så som keto-enol tautomerer som f.eks. The invention also includes pharmaceutically acceptable addition salts, complexes or prodrugs of the compounds according to the present invention. By prodrugs should be understood any covalently bound carrier that releases the active substance according to formula (I) in vivo. In those cases where the compounds according to the present invention may have one or more chiral centers, the present invention includes, unless otherwise indicated, any non-racemic compound of its own which can be synthesized and resolved via conventional techniques. In those cases where the compounds have unsaturated carbon-carbon double bonds, both cis (Z) and trans (E) isomers fall within the scope of the invention. In those cases where the compounds may exist in tautomeric forms, such as keto-enol tautomers such as e.g.

ansees begge tautomere former å være inkludert i oppfinnelsen enten de foreligger i likevekt eller ér låst i én form ved passende substitusjon med R'. both tautomeric forms are considered to be included in the invention whether they exist in equilibrium or are locked in one form by suitable substitution with R'.

Forbindelsene med formel (l)-(V) inhiberer bindingen av vitronectin og andre RGD-holdige peptider til vitronectin (avP3) reseptoren. Inhibering av vitronectin-reseptorer på osteoklaster inhiberer osteoklastisk benresorpsjon og er egnet for behandling av sykdommer hvor benresorpsjon er assosiert med sykdom, så som osteoporose. Siden forbindelsene ifølge foreliggende oppfinnelse inhiberer vitronectin-reseptorer på en rekke ulike celletyper, vil forbindelsene dessuten være anvendelige ved behandlingen av inflammasjon og kardiovaskulære sykdommer som f.eks. aterosklerose og restenose, samt egnet som antimetastase- og anti-tumor-midler. The compounds of formula (1)-(V) inhibit the binding of vitronectin and other RGD-containing peptides to the vitronectin (avP3) receptor. Inhibition of vitronectin receptors on osteoclasts inhibits osteoclastic bone resorption and is suitable for the treatment of diseases where bone resorption is associated with disease, such as osteoporosis. Since the compounds according to the present invention inhibit vitronectin receptors on a number of different cell types, the compounds will also be useful in the treatment of inflammation and cardiovascular diseases such as e.g. atherosclerosis and restenosis, as well as being suitable as anti-metastasis and anti-tumor agents.

I henhold til en særlig utførelsesform har forbindelsene ifølge oppfinnelsen formelen (II), hvor Rb og R° er forbundet til en aromatisk ring som inneholder opp til 2 nitrogenatomer. I en foretrukket utførelsesform er R<b>og R<c>forbundet til en eventuelt substituert fenylring i henhold til formel (Ila): According to a particular embodiment, the compounds according to the invention have the formula (II), where Rb and R° are connected to form an aromatic ring containing up to 2 nitrogen atoms. In a preferred embodiment, R<b>and R<c> are connected to an optionally substituted phenyl ring according to formula (Ila):

hvor G er N-R°, S, CH eller 0. Hensiktsmessig står W for -(CHR<fl>)aNR'CO- eller where G is N-R°, S, CH or 0. Conveniently, W stands for -(CHR<fl>)aNR'CO- or

eller, når or, when

G er CH, står W for -CH2CH2NR'CO- hvor R<1>er en metylengruppe forbundet med G. G is CH, W stands for -CH2CH2NR'CO- where R<1>is a methylene group connected to G.

Fortrinnsvis står W for -CHR<9>NR'CO-.Preferably, W stands for -CHR<9>NR'CO-.

Hensiktsmessig står R' for H, Ci-e-alkyl, C3-7-cykloalkyl, Ar eller Ci-e-alkyl substituert med én til tre grupper valgt fra halogen, CN, NR<9>2, OR<9>, SR<9>, C02R<9>og CON(R<9>)2, Ar, Het eller C3-7-cykloalkyl. Særlig står R1 for H, metyl, butyl, cyanometyl, karboksymetyl, fenyletyl eller benzimidazolylmetyl. Conveniently, R' stands for H, C1-e-alkyl, C3-7-cycloalkyl, Ar or C1-e-alkyl substituted with one to three groups selected from halogen, CN, NR<9>2, OR<9>, SR <9>, CO2R<9> and CON(R<9>)2, Ar, Het or C3-7 cycloalkyl. R1 in particular stands for H, methyl, butyl, cyanomethyl, carboxymethyl, phenylethyl or benzimidazolylmethyl.

Hensiktsmessig er Rx, Ry og R<z>uavhengig av hverandre valgt fra Ci-e-alkyl, metoksy, nitro, trifluormetyl, fluor, klor, amino eller er Rx og Ry nabostillet til hverandre og forbundet under dannelse av en metylendioksygruppe. Conveniently, Rx, Ry and R<z> are independently selected from C 1-6 alkyl, methoxy, nitro, trifluoromethyl, fluorine, chlorine, amino or Rx and Ry are adjacent to each other and connected to form a methylenedioxy group.

Fortrinnsvis står G for NR<e>.Preferably, G stands for NR<e>.

Hensiktsmessig står Re for H, d-4-alkyl, Ar, Het eller Ci.4-alkyl substituert med Ar eller Het. Mer hensiktsmessig står Re for H, metyl eller benzimidazolylmetyl. Conveniently, Re stands for H, d-4-alkyl, Ar, Het or C1-4-alkyl substituted with Ar or Het. More conveniently, Re stands for H, methyl or benzimidazolylmethyl.

I henhold til en annen bestemt utførelsesform danner Rb og R<c>en seks-leddet aromatisk ring som inneholder ett eller to nitrogenatomer i henhold til formel (llb-d): According to another particular embodiment, Rb and R<c> form a six-membered aromatic ring containing one or two nitrogen atoms according to formula (llb-d):

hvor G, Rx og Ry er som ovenfor angitt for formel (Ila). where G, Rx and Ry are as stated above for formula (Ila).

I henhold til et annet aspekt vedrører oppfinnelsen en mellomforbindelse med formel XXX: According to another aspect, the invention relates to an intermediate compound of formula XXX:

hvor Pr<1>er en nitrogen-beskyttede gruppe, R'står for H, Ci-e-alkyl eller ArCi-e-alkyl, a' er 1-3, og R", Ry og R<z>uavhengig av hverandre valgt fra H, halogen, SR<f>, OR<f>, CF3, N(R<f>)2, N02og Ci-e-alkyl. Foretrukne nitrogen-beskyttende grupper er alkyl- og aryl-karboksylsyregrupper og alkyloksykarbonyl- eller arylmetyloksykarbonylgrupper, så som acetyl-, BOC- og Cbz-gruppen. En typisk R<B->gruppe er H eller metyl. where Pr<1>is a nitrogen-protected group, R' stands for H, C1-e-alkyl or ArCi-e-alkyl, a' is 1-3, and R", Ry and R<z> are independent of each other selected from H, halogen, SR<f>, OR<f>, CF3, N(R<f>)2, N02 and C1-e alkyl Preferred nitrogen protecting groups are alkyl and aryl carboxylic acid groups and alkyloxycarbonyl or arylmethyloxycarbonyl groups such as the acetyl, BOC and Cbz group A typical R<B> group is H or methyl.

Nærmere bestemt utgjøres forbindelsen ifølge foreliggende oppfinnelse av en nitrogenholdig eventuelt kondensert fem-leddet ring, en sammenbindende gruppe W og en fibrinogen-reseptorantagonist-templat. Spesielt er fibrinogen-reseptorantagonist-templaten A som definert i Bondinell, et al., WO 93/00095, publisert 7. januar, 1993, med under-formelen (VI): More specifically, the compound according to the present invention consists of a nitrogen-containing, possibly condensed, five-membered ring, a linking group W and a fibrinogen receptor antagonist template. In particular, the fibrinogen receptor antagonist template A as defined in Bondinell, et al., WO 93/00095, published January 7, 1993, is of the sub-formula (VI):

A<1>til A<5>danner en tilgjengelig substituert syv-leddet ring som kan være mettet eller umettet, og som eventuelt inneholder opp til to heteroatomer valgt fra gruppen 0, S og N, hvor S og N eventuelt kan være oksydert; A<1> to A<5> form an accessible substituted seven-membered ring which may be saturated or unsaturated, and which optionally contains up to two heteroatoms selected from the group 0, S and N, where S and N may optionally be oxidized;

D<1>til D<4>danner en tilgjengelig substituert seks-leddet ring som eventuelt inneholder opp til to nitrogenatomer; D<1> to D<4> form an accessible substituted six-membered ring optionally containing up to two nitrogen atoms;

R er minst én substituent valgt fra gruppen R7 eller Q-Ci-4-alkyl, Q-C^alkenyl, Q-C2.4-alkynyl, eventuelt substituert med én eller flere =0, R<11>eller R<7>; R is at least one substituent selected from the group R7 or Q-C1-4-alkyl, Q-C1-4-alkenyl, Q-C2-4-alkynyl, optionally substituted with one or more =0, R<11> or R<7>;

R<*>er H, Q-Ci.6-alkyl, Q-Ci.6-oksoalkyl, Q-C2.6-alkenyl, Q-CtM-oksoalkenyl, Q-C3.4-oksoalkynyl, Q-C2.4-alkynyl, C3.6-cykloalkyl, Ar eller Het, eventuelt substituert med én eller flere R<11>; R<*>is H, Q-Ci.6-alkyl, Q-Ci.6-oxoalkyl, Q-C2.6-alkenyl, Q-CtM-oxoalkenyl, Q-C3.4-oxoalkynyl, Q-C2.4 -alkynyl, C3.6-cycloalkyl, Ar or Het, optionally substituted with one or more R<11>;

Q er H, C3-6-cykloalkyl, Het eller Ar; Q is H, C3-6 cycloalkyl, Het or Ar;

R7 er -COR<8>, -COCR'2R<9>, -C(S)R<8>, -S(0)mOR\ -S(0)mNR'R", -PO(OR'), R7 is -COR<8>, -COCR'2R<9>, -C(S)R<8>, -S(0)mOR\ -S(0)mNR'R", -PO(OR'),

-PO(OR')2, -B(OR')2, -N02og Tet; R<8>er -OR', -NR'R", -NR'S02R\ -NR'OR', -OCR'2C(0)OR', -OCR'2OC(0)-R', -OCR'2C(0)NR'2, CF3eller AA<1>; R<9>er -OR', -CN, -S(0)rR', S(0)mNR'2, -C(0)R'C(0)NR'2eller -C02R';R1<1>er H, halogen, -OR<12>, -CN, -NR'R<12>, -N02, -CF3lCF3S(0)r, -C02R', -CONR'2, Q-Co-6-alkyl-, Q-C^-oksoalkyl, Q-C2-6-alkenyl-, Q-C2^-alkynyl-, Q-Cm-alkyloksy-, Q-Co-e-alkylamino- eller Q-Co-6-alkylS(0)r-; -PO(OR') 2 , -B(OR') 2 , -NO 2 and Tet; R<8>is -OR', -NR'R", -NR'S02R\ -NR'OR', -OCR'2C(0)OR', -OCR'2OC(0)-R', -OCR' 2C(0)NR'2, CF3 or AA<1>; R<9> is -OR', -CN, -S(0)rR', S(0)mNR'2, -C(0)R'C (0)NR'2or -CO2R';R1<1>is H, halogen, -OR<12>, -CN, -NR'R<12>, -NO2, -CF3lCF3S(0)r, -CO2R', -CONR' 2 , Q-C 6 -alkyl-, Q-C 6 -oxoalkyl, Q-C 2-6 -alkenyl-, Q-C 2-6 -alkynyl-, Q-C 6 -alkyloxy-, Q-Co-e-alkylamino - or Q-C0-6-alkylS(O)r-;

R<12>er R', -C(0)R', -C(0)NR'2, -C(0)OR<15>, -S(0)mR' eller S(0)mNR'2; R<12> is R', -C(0)R', -C(0)NR'2, -C(0)OR<15>, -S(0)mR' or S(0)mNR'2 ;

R<13>er R', -CF3, -SR" eller -OR'; R<13> is R', -CF3, -SR" or -OR';

R<14>er R', C(0)R', CN, N02lS02R' eller C(0)OR15;R<14> is R', C(O)R', CN, NO 2 1 SO 2 R' or C(O)OR 15 ;

R1<5>er H, Ci.6-alkyl eller Ar-C0-4-alkyl; R 1<5> is H, C 1-6 alkyl or Ar-C 0-4 alkyl;

R' er H, d-e-alkyl, C3.7-cykloalkyl-Co.4-alkyl eller Ar-C0-4-alkyl; R' is H, C 1-6 alkyl, C 3-7 cycloalkyl-C 0-4 alkyl or Ar-C 0-4 alkyl;

R" er R', -C(0)R" eller -C(0)OR<15>; R" is R', -C(O)R" or -C(O)OR<15>;

R'" er R" eller AA2; R'" is R" or AA2;

AA1 er en aminosyre bundet gjennom aminogruppen og hvor karboksylgruppen eventuelt er beskyttet, og AA2 er en aminosyre bundet via karboksylgruppen og hvor aminogruppen eventuelt er beskyttet; AA1 is an amino acid bound through the amino group and where the carboxyl group is optionally protected, and AA2 is an amino acid bound via the carboxyl group and where the amino group is optionally protected;

m er 1 eller 2; m is 1 or 2;

n er 0 til 3; n is 0 to 3;

p er 0 eller 1; ogp is 0 or 1; and

terOtil 2; ellerterOtil 2; or

farmasøytisk akseptable salter derav, med det forbehold:pharmaceutically acceptable salts thereof, with the proviso:

(i) når A er 1,2,4,5-tetrahydro-3-okso-4-(2-fenyletyl)-1 H-1,4-benzodiazepin-2-eddiksyre, da er W ikke -(CH2)2.3NHCO- som i 1-stillingen er bundet til en imidazolring, og (ii) når A er 1,2,4,5-tetrahydro-3-okso-4-(2-fenyletyl)-1 H-1,4-benzodiazepin-2-eddiksyre, da er W ikke -(CH2)2NHCO- som i 4(5)-stillingen er bundet til en imidazolring. (i) when A is 1,2,4,5-tetrahydro-3-oxo-4-(2-phenylethyl)-1H-1,4-benzodiazepine-2-acetic acid, then W is not -(CH2)2.3 NHCO- which in the 1-position is bound to an imidazole ring, and (ii) when A is 1,2,4,5-tetrahydro-3-oxo-4-(2-phenylethyl)-1H-1,4-benzodiazepine -2-acetic acid, then W is not -(CH2)2NHCO- which in the 4(5) position is bound to an imidazole ring.

Med referanse til formel (VI) står hensiktsmessigWith reference to formula (VI) is appropriate

A<1>forCR<1>R<1>', CR<1>,NR<1>, N, 0 eller S(0)x; A<1>forCR<1>R<1>', CR<1>,NR<1>, N, 0 or S(0)x;

A<2>for CR<2>R<2>',CR<2>,NR<2>;A<2>for CR<2>R<2>',CR<2>,NR<2>;

A3 for CR<3>R<3>', CR<3>, NR<3>, N, 0 eller S(0)x; A3 for CR<3>R<3>', CR<3>, NR<3>, N, 0 or S(0)x;

A<4>for CR4R4', CR4, NR<4>, eller N; A<4> for CR4R4', CR4, NR<4>, or N;

A5 for CR<5>R<5>', CR<5>, NR<5>, N, 0 eller S(0)x; A5 for CR<5>R<5>', CR<5>, NR<5>, N, 0 or S(0)x;

D1-D4 erCR11, CR<6>eller N; D1-D4 are CR11, CR<6> or N;

R<1>ogR<1>' er R<*>eller R eller utgjør sammen = 0; R<1>andR<1>' are R<*>or R or together constitute = 0;

R2 og R<2>' er R<*>, R eller =0; R2 and R<2>' are R<*>, R or =O;

R3 og R3' er R<*>, R eller =0; R3 and R3' are R<*>, R or =O;

R4 og R4' er R<*>, R eller =0; R4 and R4' are R<*>, R or =O;

R<5>ogR<5>er R<*>, R eller =0; ogR<5> and R<5> are R<*>, R or =0; and

x er 0 til 2.x is 0 to 2.

Mer hensiktsmessig stårA<1>for CR<1>R<1>', CR<1>, NR<1>, N, 0 eller S; A<2>for CR<2>R<2>', NR2 eller CR<2>; A3 forCR<3>R<3>'; A4 for CR<4>R<4>', CR<4>, NR4 eller N; A<5>for CR<5>R<5>', CR<5>,NR<5>, N, 0; More conveniently, A<1> stands for CR<1>R<1>', CR<1>, NR<1>, N, 0 or S; A<2>for CR<2>R<2>', NR2 or CR<2>; A3 forCR<3>R<3>'; A4 for CR<4>R<4>', CR<4>, NR4 or N; A<5>for CR<5>R<5>', CR<5>,NR<5>, N, 0;

D<1->D<4>er CH; R<2>eller R4 er R;R3,R<3>' og R5,R5' er =0 eller R<*>, H.D<1->D<4> is CH; R<2>or R4 is R;R3,R<3>' and R5,R5' is =O or R<*>,H.

Fortrinnsvis står A<1>for CHR<1>, CR<1>, NR", N eller S; A2 for CR<2>eller CR<2>R<2>'; A<3>for CR<3>R<3>'; A4 for CR4R4' eller NR<4>; A<5>for CR<5>R<5>', og D<1->D<4>er CH. Preferably, A<1> stands for CHR<1>, CR<1>, NR", N or S; A2 for CR<2>or CR<2>R<2>'; A<3> for CR<3> R<3>'; A4 for CR4R4' or NR<4>; A<5> for CR<5>R<5>', and D<1->D<4> is CH.

I en utførelsesform står A<1>for CR<1>;A2for CR<2>; A3 for C=0; A4 for NR4 og A<5>for CHR5 In one embodiment, A<1> stands for CR<1>; A2 stands for CR<2>; A3 for C=0; A4 for NR4 and A<5> for CHR5

I nok en utførelsesform står A<1>for NR<1>, A<2>for CHCR<2>, A<3>for CR3R3', A<4>for<NR4,>og A<5>for C=0. In yet another embodiment, A<1> stands for NR<1>, A<2> for CHCR<2>, A<3> for CR3R3', A<4> for <NR4,> and A<5> for C= 0.

I enda en utførelsesform stårA<1>og A<4>for C=0, A<2>for NR<2>, A3 for CHR<3>' og A<5>for NR5 In yet another embodiment, A<1> and A<4> stand for C=0, A<2> for NR<2>, A3 for CHR<3>' and A<5> for NR5

I en foretrukket utførelsesform står A<1>for NR<1>, A2 for CHR2,A<3>for C=0, A4 for NR'og A<5>for CHR<5.>In a preferred embodiment, A<1> stands for NR<1>, A2 for CHR2, A<3> for C=0, A4 for NR' and A<5> for CHR<5.>

Representative underformler av (VI) er angittt nedenfor med formlene (Vla)-(Vli): Representative subformulas of (VI) are indicated below by the formulas (Vla)-(Vli):

Bestemte utførelsesformer av oppfinnelsen hvor fibrinogen-reseptorantagonist-templaten A har underformelen (VI) er angitt i Eksempel 1-75. Certain embodiments of the invention where the fibrinogen receptor antagonist template A has the subformula (VI) are set forth in Example 1-75.

Foretrukne forbindelser ifølge oppfinnelsen er: (2S)-7-[[[N-(2-benzimidazolyl)metyl-N-metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; 7-[[[2-(4-aza-5-metylbenzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (±)-7-[[[2-(4-azabenzimidazoIyl)metyl]metylamino]karbonyl]-4-(2-metoksyetyl)-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (±)-7-tt[2-(benzimidazolyl)metyl]metylamino]karbonyl]-4-(2-metoksyetyl)-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; 7-[[[2-(4-azabenzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre, (2S)-7-[[[N-butyl-N-benzimidazol-2-yl)metyl]amino]karbonyl]-3-okso-4-metyl-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; 7-[[[(2-benzimidazolyl)metyl]metylamino]karbonyl]-3-okso-4-(2-fenyletyl)-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; -7[[[N-(2-benzimidazolyl)metyl]-N-(2-fenyletyl)]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre, Preferred compounds according to the invention are: (2S)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro -1 H-1,4-benzodiazepine-2-acetic acid; 7-[[[2-(4-aza-5-methylbenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine- 2-acetic acid; (±)-7-[[[2-(4-azabenzimidazoyl)methyl]methylamino]carbonyl]-4-(2-methoxyethyl)-3-oxo-2,3,4,5-tetrahydro-1 H-1, 4-benzodiazepine-2-acetic acid; (±)-7-tt[2-(benzimidazolyl)methyl]methylamino]carbonyl]-4-(2-methoxyethyl)-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine -2-acetic acid; 7-[[[2-(4-azabenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid, (2S)-7-[[[N-butyl-N-benzimidazol-2-yl)methyl]amino]carbonyl]-3-oxo-4-methyl-2,3,4,5-tetrahydro-1 H-1 ,4-benzodiazepine-2-acetic acid; 7-[[[(2-benzimidazolyl)methyl]methylamino]carbonyl]-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2- acetic acid; -7[[[N-(2-benzimidazolyl)methyl]-N-(2-phenylethyl)]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1 ,4-benzodiazepine-2-acetic acid,

(±)-7-[[[2-(ben2imidazolyl)metyl]amino]karbonyl-4-[2-(3,4-metylendioksyfenyl)etyl]-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre; og (±)-7-[[[2-(ben2imidazolyl)methyl]amino]carbonyl-4-[2-(3,4-methylenedioxyphenyl)ethyl]-3-oxo-2,3,4,5-tetrahydro-1H -1,4-benzodiazepine-2-acetic acid; and

(±)-7-[[[N-(2-benzimidazolyl)metyl-N-metyl]amino]karbonyl]-3-okso-4-(2-fenyletyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre. (±)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1H -1,4-benzodiazepine-2-acetic acid.

Den mest foretrukne fibrinogen-reseptorantagonist-templat har underformelen (Via), hvor CR<2>R2'står for CHCH2C02H, CR<3>R<3>' for C=0, og CR<5>R<5>' for CH2. Vitronectin-fibrinogen-reseptorantagonismen er særlig uttalt når A-W-substituenten er bundet til 7-stillingen i 3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-ringsystemet. (±)-8-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre har en Ki på mer enn 50 mikromolar ifølge den nedenfor beskrevne in vitro vitronectin-bindingsbestemmelse. I formelen nedenfor, er definisjonene for substituentene som definert i formel (l)-(IV) om intet annet er angitt. The most preferred fibrinogen receptor antagonist template has the subformula (Via), where CR<2>R2' stands for CHCH2CO2H, CR<3>R<3>' for C=0, and CR<5>R<5>' for CH2. The vitronectin-fibrinogen receptor antagonism is particularly pronounced when the A-W substituent is attached to the 7-position of the 3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine ring system. (±)-8-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid has a Ki of greater than 50 micromolar according to the in vitro vitronectin binding assay described below. In the formula below, the definitions for the substituents are as defined in formula (l)-(IV) unless otherwise stated.

I en annen utførelsesform av en foretrukket fibrinogen-reseptor-templat er A representert gjennom 1,4-benzodiazepin-2,5-dionet med underformel (VII): In another embodiment of a preferred fibrinogen receptor template, A is represented by the 1,4-benzodiazepine-2,5-dione of subformula (VII):

hvor: where:

Y er H, Ci.4-alkyl, Ci.4-alkoksy, C^-alkoksykarbonyl, F, Cl, Br, I, CF3, OR<r>, S(0)kR', COR<f>, N02, N(R<f>)2, CO(NR<f>)2, CH2N(R<f>)2, metylendioksy, CN, C02R<f>, OC(0)Rf eller NHC(0)R<f>; og Y is H, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, F, Cl, Br, I, CF 3 , OR<r>, S(O)kR', COR<f>, NO 2 , N(R<f>)2, CO(NR<f>)2, CH2N(R<f>)2, methylenedioxy, CN, CO2R<f>, OC(0)Rf or NHC(0)R<f> ; and

Rh er (CH2)qC02R<f.>Rh is (CH 2 ) qCO 2 R<f>

Fremstillingen og anvendelsen av denne substruktur ved fremstilling av fibrinogen-reseptorantagonister av denne underformel er omtalt i detalj i Bondinell, et al. WO 93/00095, publisert 7. januar, 1993 og Blackburn et al., WO 93/08174, publisert 29. april, 1993. The preparation and use of this substructure in the preparation of fibrinogen receptor antagonists of this subformula is discussed in detail in Bondinell, et al. WO 93/00095, published January 7, 1993 and Blackburn et al., WO 93/08174, published April 29, 1993.

Tabell I nedenfor sammenfatter andre foretrukne fibrinogen-reseptortemplater som faller innenfor rammen for foreliggende oppfinnelse. Slike templater er: Table I below summarizes other preferred fibrinogen receptor templates that fall within the scope of the present invention. Such templates are:

hvor: where:

R<2>1ogR2<2>uavhengig av hverandre er H eller -Z-C02Rf eller Z-CON(Rf)2 med det forbehold at R<2>1 and R2<2> are independently H or -Z-CO2Rf or Z-CON(Rf)2 with the proviso that

én av A<1>eller A2 er -Z-C02Rf eller Z-CON(R')2; one of A<1> or A2 is -Z-CO2 Rf or Z-CON(R')2;

Z er -CH2-, -0(CH2)q-, -NR<f>(CH2)q-, -S(CH2)q, -CH2CH2-, -CH(CH3)CH2-, Z is -CH2-, -O(CH2)q-, -NR<f>(CH2)q-, -S(CH2)q, -CH2CH2-, -CH(CH3)CH2-,

-(CH2)'3-, -CH=CH-, -C(CH3)=CH-, CH2-CH=CH- eller CH=CHCH2; og-(CH2)'3-, -CH=CH-, -C(CH3)=CH-, CH2-CH=CH- or CH=CHCH2; and

Y er H, C^-alkyl, d-4-alkoksy, Ci.4-alkoksykarbonyl, F, Cl, Br, I, CF3, OR<f>, S(0)kR<f>, COR<f>, N02, N(R')2, CO(NR')2, CH2N(R<f>)2, metylendioksy eller Z-CO-R', i Alig. et al., EP 0 381 033, publisert 8. august, 1990. Y is H, C 1-4 alkyl, C 1-4 -alkyloxy, C 1-4 -alkoxycarbonyl, F, Cl, Br, I, CF 3 , OR<f>, S(0)kR<f>, COR<f>, N02, N(R')2, CO(NR')2, CH2N(R<f>)2, methylenedioxy or Z-CO-R', in Alig. et al., EP 0 381 033, published August 8, 1990.

Den foretrukne fibrinogen-reseptor-templat A i formel (VIII) er The preferred fibrinogen receptor template A of formula (VIII) is

Spesifikke utførelsesformer i henhold til dette aspekt ved oppfinnelsen er: 4-[2-[[[1-[(benzimidazol-2-yl)metyl]benzimidazol-2-yl]metyl]metyl-amino]acetyl]fenoksyeddiksyre; (±)-4-[[2-[(benzimidazol-2-yl)-metyl]metylamino]-1-hydroksyetyl]-1,2-fenylen-dioksydieddiksyre; 4-[2-[[(benzimidazol-2-yl)metyl]metylamino]acetyl]-1,2-fenylen-dioksydieddiksyre; eller 3-[[4-[[[(benzimidazbl-2-yl)-metyl]amino]karbonyl]fenyl]amino]propionsyre. Specific embodiments according to this aspect of the invention are: 4-[2-[[[1-[(benzimidazol-2-yl)methyl]benzimidazol-2-yl]methyl]methyl-amino]acetyl]phenoxyacetic acid; (±)-4-[[2-[(benzimidazol-2-yl)-methyl]methylamino]-1-hydroxyethyl]-1,2-phenylene-dioxydiacetic acid; 4-[2-[[(benzimidazol-2-yl)methyl]methylamino]acetyl]-1,2-phenylene dioxydiacetic acid; or 3-[[4-[[[(benzimidazbl-2-yl)-methyl]amino]carbonyl]phenyl]amino]propionic acid.

hvor: where:

R<6>er aryl, Ci.io-alkyl, C3-6-cykloalkyl, C^io-aralkyl, Ci.i0-alkoksyalkyl, Cmo-alkaryl, Ci.10-alkyltioalkyl, Ci.i0-alkoksytioalkyl, Ci.i0-alkylamino, C-Mo-aralkylamino, Ci-10-alkanoylamino, C4-i0-aralkanoylamino, Ci.io-alkanoyl, C^io-aralkanoyl eller C1-10-karboksyalkyl; og R<6> is aryl, C1-10-alkyl, C3-6-cycloalkyl, C1-10-aralkyl, C1-10-alkoxyalkyl, C10-alkaryl, C1-10-alkylthioalkyl, C1-10-alkoxythioalkyl, C1-10 -alkylamino, C1-10-aralkylamino, C1-10-alkanoylamino, C4-10-aralkanoylamino, C1-10-alkanoyl, C1-10-aralkanoyl or C1-10-carboxyalkyl; and

Y er H, Ci.4-alkyl, Ci.4-alkoksy, C^-alkoksykarbonyl, F, Cl, Br, I, CF3, OR<f>, S(0)kR<f>,<*>COR<f>, N02, N(R')2, CO(NR<f>)2, CH2N(R<f>)2, metylendioksy, CN, C02R<f>, OC(0)Rf eller NHC(0)R<f>, Y is H, C 1-4 -alkyl, C 1-4 -alkoxy, C 1-4 -alkylcarbonyl, F, Cl, Br, I, CF 3 , OR<f>, S(0)kR<f>,<*>COR< f>, N02, N(R')2, CO(NR<f>)2, CH2N(R<f>)2, methylenedioxy, CN, C02R<f>, OC(0)Rf or NHC(0)R <f>,

i Egbertson, et al., EP 0 478 328, publisert 1. april, 1992.in Egbertson, et al., EP 0 478 328, published April 1, 1992.

De foretrukne forbindelser med formel (IX) er slike hvor R<6>er aryl, Ci.io-alkyl, C3.6-cykloalkyl eller C4.i0-aralkyl. En bestemt utførelsesform av dette aspekt ved oppfinnelsen er (S)-(2-butylsulfonylamino)-3-[4-(3-benzimidazo-2-yl)propyloksy)]fenylpropionsyre. The preferred compounds of formula (IX) are those where R<6> is aryl, C1-10-alkyl, C3-6-cycloalkyl or C4-10-aralkyl. A specific embodiment of this aspect of the invention is (S)-(2-butylsulfonylamino)-3-[4-(3-benzimidazo-2-yl)propyloxy)]phenylpropionic acid.

hvor: where:

M<1>erCH eller N; M<1> is CH or N;

M<2>er CH eller N, med det forbehold at når M<1>er CH, da er M<2>N; ogM<2>is CH or N, with the proviso that when M<1>is CH, then M<2>is N; and

G<1>er N eller NØR",G<1>is N or NØR",

i Eldred, et al., EP 0 542 363, publisert 19. mai, 1993.in Eldred, et al., EP 0 542 363, published May 19, 1993.

Foretrukne utførelsesformer av de vitronectin-reseptorantagonister som inneholder substrukturen av formel (X) er de hvor G' er N og M<1>er N. En forbindelse som inneholder denne substruktur, nemlig 4-[4-[1-(2-metylbenzimidazolyl)-piperidinyl]]-piperidin-eddiksyre har en Ki-verdi på mer enn 50 mikromolar i den nedenfor beskrevne in vitro vitronectin-bindingsbestemmelse. Preferred embodiments of the vitronectin receptor antagonists containing the substructure of formula (X) are those wherein G' is N and M<1> is N. A compound containing this substructure, namely 4-[4-[1-(2-methylbenzimidazolyl )-piperidinyl]]-piperidineacetic acid has a Ki value of greater than 50 micromolar in the in vitro vitronectin binding assay described below.

hvor: where:

Mj er CH eller N; ogMj is CH or N; and

M<2>er CH eller N, med det forbehold at når M<1>er CH, da er M<2>N, i Porter, et al", EP 0 537 980, publisert 21. april, 1993. M<2> is CH or N, with the proviso that when M<1> is CH, then M<2> is N, in Porter, et al", EP 0 537 980, published April 21, 1993.

hvor: where:

M1 er CH eller N,M1 is CH or N,

Y er H, Ci.4-alkyl, Ci.4-alkoksy, Ci^-alkoksykarbonyl, F, Cl, Br, I, CF3, OR<1>, S(0)kR<f>, COR<f>, N02, N(R<f>)2, CO(NR<f>)2. CH2N(R')2, metylendioksy, CN, C02R<f>, OC(0)Rf eller NHC(0)R<f>; Y is H, C 1-4 -alkyl, C 1-4 -alkyloxy, C 1-4 -alkoxycarbonyl, F, Cl, Br, I, CF 3 , OR<1>, S(0)kR<f>, COR<f>, NO2, N(R<f>)2, CO(NR<f>)2. CH2N(R')2, methylenedioxy, CN, CO2R<f>, OC(O)Rf or NHC(O)R<f>;

D<3>er CH2eller C=0; ogD<3> is CH2 or C=0; and

Rh er (CH2)qC02R,1Rh is (CH2)qCO2R,1

i Klinnick, et al., EP 0635,492, publisert 25. januar, 1995. in Klinnick, et al., EP 0635,492, published January 25, 1995.

hvor: where:

Y er H, Cn-alkyl, C^-alkoksy, C^-alkoksykarbonyl, F, Cl, Br, I, CF3, OR<f>, S(0)kR', COR<f>, N02, N(R<f>)2, CO(NR<f>)2, CH2N(R<f>)2, metylendioksy, CN, C02R<f>, OC(0)Rf eller NHC(0)R'; Y is H, C 1 -alkyl, C 1 -alkoxy, C 1 -alkoxycarbonyl, F, Cl, Br, I, CF 3 , OR<f>, S(0)kR', COR<f>, NO 2 , N(R <f>)2, CO(NR<f>)2, CH2N(R<f>)2, methylenedioxy, CN, CO2R<f>, OC(0)Rf or NHC(0)R';

Rh er (CH2)nC02R<f>; ogRh is (CH 2 ) n CO 2 R<f>; and

i Blackburn, et al., WO 95/04057, publisert 9. februar, 1995. in Blackburn, et al., WO 95/04057, published February 9, 1995.

hvor: where:

L<*>er -C(0)NR<9->(CH2)-, -C(0)-(CH2)q-, NR°-(CH2)q-, -0-(CH2)q-, eller S(0)k-(CH2)q- L<*>is -C(0)NR<9->(CH2)-, -C(0)-(CH2)q-, NR°-(CH2)q-, -0-(CH2)q-, or S(0)k-(CH2)q-

i Hartman, et al., EP 0 540 331, publisert 5. mai, 1993.in Hartman, et al., EP 0 540 331, published May 5, 1993.

i Sugihara, et al., EP 0 529,858, publisert 3. mars, 1993. in Sugihara, et al., EP 0 529,858, published March 3, 1993.

hvor: where:

Y er H, Ci.4-alkyl, Ci-4-alkoksy, Ci-4-alkoksykarbonyl, F, Cl, Br, I, CF3, OR', S(0)kR<f>, COR'<1>, N02, N(R')2, CO(NR<f>)2, CH2N(R<f>)2, metylendioksy, CN, C02R<f>, OC(0)R<f>eller NHC(0)R<f>, Y is H, C1-4 alkyl, C1-4 alkoxy, C1-4 alkoxycarbonyl, F, Cl, Br, I, CF3, OR', S(0)kR<f>, COR'<1>, N02, N(R')2, CO(NR<f>)2, CH2N(R<f>)2, methylenedioxy, CN, C02R<f>, OC(0)R<f>or NHC(0)R <f>,

i Himmeisbach, et al., EP 0 483 667, publisert 6. mai, 1992.in Himmeisbach, et al., EP 0 483 667, published May 6, 1992.

i Linz, et al., EP 0 567 968, publisert 3. november, 1993. in Linz, et al., EP 0 567 968, published November 3, 1993.

hvor: where:

Rd er. Het-Co-e-alkyl; og Rd is. Het-C0-6-alkyl; and

Z", Z'" uavhengig av hverandre, er hydrogen, Ci.4-alkyl, halogen, OR<f>, CN, S(0)kRf, C02Rf eller OH, Z", Z'" independently of each other, are hydrogen, C1-4 alkyl, halogen, OR<f>, CN, S(0)kRf, CO2Rf or OH,

i Bovy, et al., EP 0 539 343, publisert 28. april, 1993.in Bovy, et al., EP 0 539 343, published April 28, 1993.

Ovennevnte beskrivelser av fibrinogen-reseptortemplater for anvendelse ved foreliggende oppfinnelse ble tatt fra publiserte verserende patentsøknader. Det henvises til disse patentsøknadenes fulle beskrivelse, inklusivt fremgangsmåtene for fremstilling av templatene og bestemte forbindelser som gjør bruk av templatene, idet patentsøknadene herved med hele sitt innhold inkorporeres i foreliggende beskrivelse. The above descriptions of fibrinogen receptor templates for use in the present invention were taken from published pending patent applications. Reference is made to the full description of these patent applications, including the methods for producing the templates and specific compounds that make use of the templates, as the patent applications are hereby incorporated in their entirety into the present description.

Tabell II, nedenfor, beskriver andre fibrinogen-reseptorantagonister, hvis kjernestrukturer ville kunne benyttes ved utførelse av foreliggende oppfinnelse. Det henvises til disse patentsøknadene og andre publikasjoners fulle beskrivelse, inklusivt fremgangsmåtene for fremstilling av templatene og bestemte forbindelser som gjør bruk av templatene, idet patentsøknadene og andre publikasjoner herved med hele sitt innhold inkorporeres i foreliggende beskrivelse. Siden det antas at en hvilken som helst fibrinogen-reseptorantagonist som er bundet til en eventuelt kondensert nitrogenholdig fem-leddet ring vil være i besittelse av den her beskrevne nye anvendelsesmulighet, begrenser ikke den nedenfor angitte liste rammen for foreliggende oppfinnelse. Table II, below, describes other fibrinogen receptor antagonists, the core structures of which could be used in carrying out the present invention. Reference is made to these patent applications and other publications' full description, including the methods for producing the templates and certain compounds that make use of the templates, as the patent applications and other publications are hereby incorporated with their entire content into the present description. Since it is believed that any fibrinogen receptor antagonist which is bound to an optionally condensed nitrogen-containing five-membered ring will be in possession of the new possibility of application described here, the list given below does not limit the scope of the present invention.

Tabell IITable II

Adir et CompagnieAdir et Compagnie

FR 928004, 30. juni, 1992, Fauchere, J.L. et al.FR 928004, June 30, 1992, Fauchere, J.L. et al.

EP 0578535, 29. juni, 1993, Fauchere, J.L. et al.: beskriver X-RGDW-OH-analoger, EP 0578535, June 29, 1993, Fauchere, J.L. et al.: describe X-RGDW-OH analogs,

hvor X inneholder et kationisk amin.where X contains a cationic amine.

CA 2128560, 24. januar, 1995, Godfroid, J.J. et al., substituerte piperaziner.CA 2128560, Jan. 24, 1995, Godfroid, J.J. et al., substituted piperazines.

Asahi Breweries, Ltd.Asahi Breweries, Ltd.

JP 05239030, 17. september, 1993, aminometyltetrahydroisokinoliner.JP 05239030, September 17, 1993, Aminomethyltetrahydroisoquinolines.

Asahi GlassAsahi Glass

WO 90/02751, Ohba, M. et al., 8. september, 1989: beskriver cykliske WO 90/02751, Ohba, M. et al., September 8, 1989: describes cyclic

RGD-holdige peptider.RGD-containing peptides.

WO 90/115950, 22. mars, 1990, Ohba, M et al.,WO 90/115950, Mar. 22, 1990, Ohba, M et al.,

EP 0406428, 1/9/91: beskriver cykliske RGD-holdige peptider WO 92/09627, Isoai, A. et al.,: 29. november, 1991: beskriver cykliske EP 0406428, 1/9/91: describes cyclic RGD-containing peptides WO 92/09627, Isoai, A. et al.,: November 29, 1991: describes cyclic

RGD-holdige peptider.RGD-containing peptides.

Casella AGCasella AG

DE 4207254, (Der 93-289298/37) 7. mars, 1992, Zoller, G. et al.: beskriver DE 4207254, (Der 93-289298/37) March 7, 1992, Zoller, G. et al.: describes

guanidinopropyl-4-okso-2-tioimidazolidin-3-yl-Asp-X-analogerguanidinopropyl-4-oxo-2-thioimidazolidin-3-yl-Asp-X analogs

EP 93904010, 24. februar, 1993, Zoller, G., 4-okso-2-tioksoimidazolidin-derivater. EP 0565896, 18. mars, 1993, Klinger, 0. et al.: beskriver guanidino-etylfenyloksyacetyl-Asp-X-analoger. EP 93904010, February 24, 1993, Zoller, G., 4-oxo-2-thioxoimidazolidine derivatives. EP 0565896, March 18, 1993, Klinger, 0. et al.: describes guanidino-ethylphenyloxyacetyl-Asp-X analogs.

EP 0566919, (Der 93-338002/43) 3. april, 1993, Zoller, G., et al.: beskriver EP 0566919, (Der 93-338002/43) Apr. 3, 1993, Zoller, G., et al.: describes

guanidinopropyl-4-okso-2-tioimidazolidin-3-yl-Asp-X-analoger.guanidinopropyl-4-oxo-2-thioimidazolidin-3-yl-Asp-X analogs.

EP 580008, (Der 94-027663/04) 6. juli, 1993, Zoller, G. et al.: beskriver 5-m-guanidinofenyl-2,4-dioksoimidazolidin-3-yl)acetyl-Asp-Phg. EP 580008, (Der 94-027663/04) July 6, 1993, Zoller, G. et al.: discloses 5-m-guanidinophenyl-2,4-dioxoimidazolidin-3-yl)acetyl-Asp-Phg.

DE 224414, 6. juli, 1993, Zoller, G. et al.: beskriver 5-m-guanidinofenyl-2,4-dioksoimidazolidin-3-yl)acetyl-Asp-Phg. DE 224414, July 6, 1993, Zoller, G. et al.: discloses 5-m-guanidinophenyl-2,4-dioxoimidazolidin-3-yl)acetyl-Asp-Phg.

EP 584694, (Der 94-067259/09, 2. april, 1994, Zoller, G. et al.: beskriver 5-m-guanidinofenyl-2,4-dioksoimidazolidin-3-yl)acetyl-Asp-Phg. EP 584694, (Der 94-067259/09, April 2, 1994, Zoller, G. et al.: discloses 5-m-guanidinophenyl-2,4-dioxoimidazolidin-3-yl)acetyl-Asp-Phg.

DE 4301747, (Der 94-235891/29) 28. juli, 1994, Zoller, G. et al.: beskriver 5-m-guanidinofenyl-2,4-dioksoimidazolidin-3-yl)acetyl-Asp-Phg-analoger. DE 4301747, (Der 94-235891/29) July 28, 1994, Zoller, G. et al.: describes 5-m-guanidinophenyl-2,4-dioxoimidazolidin-3-yl)acetyl-Asp-Phg analogs.

DE 4308034, (Der 94-286666/36) 15. september, 1994, Klinger, 0. et al.: beskriver DE 4308034, (Der 94-286666/36) Sep. 15, 1994, Klinger, 0. et al.: describes

5-m-guanidinofenyl-2,4-dioksoimidazolidin-3-yl)-acetyl-Asp-Phg-analoger. DE 4309867, 29. september, 1994, Klingler, 0. et al.: beskriver 5-m-guanidinofenyl-2,4-dioksoimidazolidin-3-yl)acetyl-Asp-Phg. 5-m-guanidinophenyl-2,4-dioxoimidazolidin-3-yl)-acetyl-Asp-Phg analogs. DE 4309867, September 29, 1994, Klingler, 0. et al.: describes 5-m-guanidinophenyl-2,4-dioxoimidazolidin-3-yl)acetyl-Asp-Phg.

ChironChiron

WO 93/07169, (Der 93-134382/16), 15. mars, 1993, Devlin, J.J., et al.: beskriver RGD-peptider. WO 93/07169, (Der 93-134382/16), March 15, 1993, Devlin, J.J., et al.: describes RGD peptides.

Ciba GeigyCiba Geigy

EP 0452210, (Der 91-305246/42), 5. april, 1990, beskriver aminoalkanoyl-GDF-analoger. EP 0452210, (Der 91-305246/42), April 5, 1990, discloses aminoalkanoyl GDF analogs.

EP 0452257, 26. mars, 1991, Allen, M.C. et al.: beskriver aminoalkanoyl-Asp-Phe-analoger. EP 0452257, March 26, 1991, Allen, M.C. et al.: describe aminoalkanoyl-Asp-Phe analogs.

COR TherapeuticsCOR Therapeutics

WO 90/15620, 15. juni, 1990: beskriver cykliske RGD-holdige peptider.WO 90/15620, June 15, 1990: describes cyclic RGD-containing peptides.

EP 0477295, 1. april, 1992: Scarborough, R.M. et al.EP 0477295, Apr. 1, 1992: Scarborough, R.M. et al.

WO 92/08472, 29. mai, 1992, Scarborough, R.M. et al.WO 92/08472, May 29, 1992, Scarborough, R.M. et al.

WO 93/223356, 27.april, 1993, Swift, R.L. et al.: beskriver cykliske RGD-holdige peptider. WO 93/223356, Apr. 27, 1993, Swift, R.L. et al.: describe cyclic RGD-containing peptides.

EP 0557442, 1. september, 1993, Scarborough, R.M. et al.EP 0557442, September 1, 1993, Scarborough, R.M. et al.

Scarborough, R.M.; Rose, J.W.; Hsu, MA: Phillips, D.R.; Fried, V.A.; Scarborough, R. M.; Rose, J. W.; Hsu, MA: Phillips, D.R.; Fried, V. A.;

Campbell, A.M.; Nunnizzi, L; Charo, I.F., Barbourin, A GPIIb-llla-Specific Integrin Antagonist from the Venom of Sistrurus M. Barbouri, Campbell, A. M.; Nunnizzi, L; Charo, I.F., Barbourin, A GPIIb-llla-Specific Integrin Antagonist from the Venom of Sistrurus M. Barbouri,

J. Biol. Chem., 266, 9359, 1991. J. Biol. Chem., 266, 9359, 1991.

Daiichi Pharm Co Ltd.Daiichi Pharm Co Ltd

JP 05078344-A, (Der 93-140339/17) 30. mars, 1993: beskriver JP 05078344-A, (Der 93-140339/17) Mar. 30, 1993: describes

bisamidinoheterocykler, f.eks. benzofuraner.bisamidinoheterocycles, e.g. benzofurans.

DuPont MerckDuPont Merck

WO 93/07170, 15. april, 1993: beskriver cykliske RGD-holdige peptider.WO 93/07170, April 15, 1993: describes cyclic RGD-containing peptides.

WO 94/11398, 26. mai, 1994: Wells, G.J. et al. beskriver cykliske RGD-holdige peptider. WO 94/11398, May 26, 1994: Wells, G.J. et al. describes cyclic RGD-containing peptides.

IL 109237, 31. juli, 1994. IL 109237, July 31, 1994.

WO 94/22909, (Der 94-333113/41) 13. oktober, 1994,: DeGrado, W.F. et al. WO 94/22910, (Der 94-333114/41) 13. oktober, 1994; DeGrado, W.F. et al. WO 94/22909, (Der 94-333113/41) Oct. 13, 1994,: DeGrado, W.F. et al. WO 94/22910, (Der 94-333114/41) October 13, 1994; DeGrado, W.F. et al.

Prodrugs.Prodrugs.

WO 94/22494, (Der 94-332838/41) 13. oktober, 1994; DeGrado, W.F. et al. WO 94/22494, (Der 94-332838/41) October 13, 1994; DeGrado, W.F. et al.

cykliske peptidercyclic peptides

EP 625164, 23. november, 1994; DeGrado, W.F. et al., cykliske peptider. Mousa, S.A.: Bozarth, J.M.; Forsythe, M.S.; Jackson, S.M.: Leamy, A.; EP 625164, November 23, 1994; DeGrado, W.F. et al., Cyclic Peptides. Mousa, S.A.: Bozarth, J.M.; Forsythe, M. S.; Jackson, S.M.: Leamy, A.;

Diemer, M.M.; Kapil, R.P.; Knabb, R.M.; Mayo, M.C.; Diemer, M.M.; Kapil, R.P.; Knabb, R.M.; Mayo, M. C.;

Pierce, S.K. et alPierce, S.K. et al

Antiplatelet and Antithrombotic Efficacy of DMP 728, a NovelAntiplatelet and Antithrombotic Efficacy of DMP 728, a Novel

Platelet GPIIb/llla Receptor Antagonist, Clrculation, 89 3, 1994. Jackson, S.; DeGrado, W.; Dwivedi, A.; Parthasarathy, A.; Higley, A.; Platelet GPIIb/llla Receptor Antagonist, Clrculation, 89 3, 1994. Jackson, S.; DeGrado, W.; Dwivedi, A.; Parthasarathy, A.; Higley, A.;

Krywko, J.; Rockwell, A.; Markwalder, J.; Wells, G.; Wexler, R.; Krywko, J.; Rockwell, A.; Markwalder, J.; Wells, G.; Wexler, R.;

Mousa, S.; Harlow, R., Template-Constrained Cyclic Peptides:Mousa, S.; Harlow, R., Template-Constrained Cyclic Peptides:

Design of High-Affinity Ligands for GPIIb/llla, J. Amer. Chem. Soc. 116, 3220, 1994. Design of High-Affinity Ligands for GPIIb/lla, J. Amer. Chem. Soc. 116, 3220, 1994.

Ellem Ind Farma SpaEllem Ind Farma Spa

GB 2207922, 3. august, 1988, beskriver lineære RGD-analoger.GB 2207922, 3 August 1988, describes linear RGD analogues.

Farmitalia Erba SRL CarloFarmitalia Erba SRL Carlo

EP 611765 (Der 94-265375/33), 24. august, 1994: Cozzi, P. et al. beskriver 5-(2-pyrazinylmetyl-2-imidazol-1-yl)-1-cykloheksyletyliden)amin-oksypentansyre. EP 611765 (Der 94-265375/33), August 24, 1994: Cozzi, P. et al. describes 5-(2-pyrazinylmethyl-2-imidazol-1-yl)-1-cyclohexylethylidene)amine-oxypentanoic acid.

Fuji Photo FilmFuji Photo Film

JP 04208296-A (Der. 92-303598/38), 30. november, 1990, beskriver RGD-peptider. JP 04208296-A (Der. 92-303598/38), November 30, 1990, discloses RGD peptides.

JP 04213311-A (Der. 92-305482/38), 27. november, 1990, beskriver multimere JP 04213311-A (Der. 92-305482/38), Nov. 27, 1990, describes multimer

RGD-peptider.RGD peptides.

JP 04217693-A, (Der 92-312284/38), 23. oktober, 1990, beskriver multimere JP 04217693-A, (Der 92-312284/38), October 23, 1990, describes multimer

RGD-peptider.RGD peptides.

JP 04221394-A (Der. 92-313678/38), 26. oktober, 1990, beskriver multimere JP 04221394-A (Der. 92-313678/38), October 26, 1990, describes multimer

RGD-peptider.RGD peptides.

JP 04221395-A (Der. 92-313679/38), 26. oktober, 1990, beskriver multimere RGD-peptider. JP 04221395-A (Der. 92-313679/38), October 26, 1990, discloses multimeric RGD peptides.

JP 04221396-A (Der. 92-313680/38), 26. oktober, 1990, beskriver multimere JP 04221396-A (Der. 92-313680/38), Oct. 26, 1990, describes multimer

RGD-peptiderRGD peptides

JP 04221397-A (Der. 92-313681/38), 20. desember, 1990, beskriver multimere JP 04221397-A (Der. 92-313681/38), Dec. 20, 1990, describes multimer

RGD-peptider.RGD peptides.

EP 0482649 A2, 29. april, 1992, Kojima, M. et al: beskriver RGD-peptider.EP 0482649 A2, Apr. 29, 1992, Kojima, M. et al: describes RGD peptides.

EP 0488258A2, 3. juni, 1992, Komazawa, H., et al.: beskriver RGD-peptider.EP 0488258A2, June 3, 1992, Komazawa, H., et al.: describes RGD peptides.

EP 503301-A2, 14. februar, 1991, Kitaguchi, H. et al.: beskriver RGD-peptider.EP 503301-A2, Feb. 14, 1991, Kitaguchi, H. et al.: describes RGD peptides.

JP 05222092, 21. mai, 1993, Nishikawa, N. et al.: beskriver lineær X-RGDS.JP 05222092, May 21, 1993, Nishikawa, N. et al.: describes linear X-RGDS.

JP 06239885, (Der 94-313705/39), 30.august, 1993, Nishikawa, N. et al.,: beskriver JP 06239885, (Der 94-313705/39), August 30, 1993, Nishikawa, N. et al.,: describes

multimere RGD-peptider.multimeric RGD peptides.

WO 9324448, (Der 93-405663/50), 9. desember, 1993, Nishikawa, N. et al: WO 9324448, (Der 93-405663/50), December 9, 1993, Nishikawa, N. et al:

beskriver multimere retro-inverse RGD-peptider.describes multimeric retro-inverse RGD peptides.

JP 06228189, (Der 94-299801/37), 16. august, 1994: beskriver RGD-peptider.JP 06228189, (Der 94-299801/37), August 16, 1994: describes RGD peptides.

EP 619118, (Der 94-311647/39), 12. oktober, 1994, Nishikawa, N. et al: beskriver EP 619118, (Der 94-311647/39), October 12, 1994, Nishikawa, N. et al: describes

lineære RGD-peptider.linear RGD peptides.

FujisawaFujisawa

EP 0513675, 8. mai, 1992, N. Umekita, et al: beskriver amidino-fenyloksyalkanoyl-Asp-Val-OH-analoger. EP 0513675, May 8, 1992, N. Umekita, et al: describes amidino-phenyloxyalkanoyl-Asp-Val-OH analogs.

WO 9409030-A1, 28. april, 1994, Takasugi, H. et al.: beskriver amidino-fenoksybutanoyl-Asp-Val-OH-analoger. WO 9409030-A1, April 28, 1994, Takasugi, H. et al.: describes amidino-phenoxybutanoyl-Asp-Val-OH analogs.

EP 0513675, (Der 92-383589/47): beskriver amidinofenyloksybutyryl-Asp-Val-analoger. EP 0513675, (Der 92-383589/47): describes amidinophenyloxybutyryl-Asp-Val analogues.

WO 9500502, 5. januar, 1995, Oku, T. et al.: beskriver "aminopiperazin-derivater." WO 9500502, Jan. 5, 1995, Oku, T. et al.: describes "aminopiperazine derivatives."

FR 144633: Thromb. Haem. 69, 706, 1993. FR 144633: Thromb. Ahem. 69, 706, 1993.

Cox, D.; Aoki, T.; Seki, J.; Motoyama, Y.; Yoshida, K., Pentamidine: A Specific Nonpeptide GPIIb/llla Antagonist, Thromb. Haem. 69, 707, 1993. Cox, D.; Aoki, T.; Seki, J.; Motoyama, Y.; Yoshida, K., Pentamidine: A Specific Nonpeptide GPIIb/lla Antagonist, Thromb. Ahem. 69, 707, 1993.

GenentechGenentech

WO 90/15072 (Der 91007159); beskriver RGD-holdige peptider:WO 90/15072 (Der 91007159); describes RGD-containing peptides:

WO 91/01331 (Der 91058116), 5. juli, 1990, P.L Barker, et al.: beskriver WO 91/01331 (Der 91058116), July 5, 1990, P.L Barker, et al.: describes

cykliske RGD-holdige peptider.cyclic RGD-containing peptides.

WO 91/04247, 24. september, 1990, T.R. Webb: beskriver (guanidinoalkyl)-Pro-GD-analoger. WO 91/04247, Sep. 24, 1990, T.R. Webb: describes (guanidinoalkyl)-Pro-GD analogs.

WO 91/11458 (Der 91252610), 28. januar, 1991, P.L. Barker, et al: beskriver WO 91/11458 (Der 91252610), Jan. 28, 1991, P.L. Barker, et al: describe

cykliske RGD-holdige peptidercyclic RGD-containing peptides

WO 92/07870, 24. oktober, 1991, J.P. Burnier, et al.: beskriver cykliske WO 92/07870, October 24, 1991, J.P. Burnier, et al.: describes cyclic

RGD-holdige peptider.RGD-containing peptides.

WO 92/17492, 15. oktober, 1992, Burnier, J.P. et al: beskriver cykliske WO 92/17492, October 15, 1992, Burnier, J.P. et al: describes cyclic

RGD-holdige peptiderRGD-containing peptides

CA 2106314, 6. oktober, 1992, Burnier, J.P. et al.CA 2106314, Oct. 6, 1992, Burnier, J.P. et al.

WO 93/08174, 15. oktober, 1991, B.K. Blackburn, et al: beskriver 2,5-diokso-1,4-benzodiazepiner. WO 93/08174, October 15, 1991, B.K. Blackburn, et al: describe 2,5-dioxo-1,4-benzodiazepines.

CA 2106314, 6. oktober, 1992, Burnier, J.P. et al.CA 2106314, Oct. 6, 1992, Burnier, J.P. et al.

EP 0555328, 18. august, 1993, J.P. Burnier, et al.EP 0555328, August 18, 1993, J.P. Burnier et al.

WO 95/04057, 9. februar, 1995, Blackburn, B.K. et al: beskriver 1,4-benzodiazepiner inneholdende en heterocyklus i 1,2-stillingene. Scarborough, R.M., Naughton, M.A., Teng, W., Rose, J.W., Philllips, D.R. WO 95/04057, February 9, 1995, Blackburn, B.K. et al: describe 1,4-benzodiazepines containing a heterocycle in the 1,2-positions. Scarborough, R.M., Naughton, M.A., Teng, W., Rose, J.W., Phillips, D.R.

Nannizzi, L, Arfsten, A., Campbell, A.M., og Charo, I.F. J. Biol. Chem. Nannizzi, L, Arfsten, A., Campbell, A.M., and Charo, I.F. J. Biol. Chem.

268, 1066, 1993. 268, 1066, 1993.

Dennis, M.S.; Henzel, W. J.; Pitti, R.M.; T.L.M.; Napier, M.A.; Deisher, T.A.; Bunting, S.; Lazarus, R. Platelet Glycoprotein llb-llla Protein Antagonists from snake Venoms; Evidence for a Family of Platelet-Aggregation Dennis, M. S.; Henzel, W.J.; Pitti, R.M.; T.L.M.; Napier, M.A.; Deisher, T. A.; Bunting, S.; Lazarus, R. Platelet Glycoprotein llb-llla Protein Antagonists from snake Venoms; Evidence for a Family of Platelet Aggregation

Inhibitors, Proe. Nati. Acad. Sel. USA, 87, 2471, 1989.Inhibitors, Proe. Nati. Acad. Seal. USA, 87, 2471, 1989.

Barker, P.L.; Bullens, S.; Bunting. S.M.; Burdick, D.J.; Chan, K.S.; Barker, P. L.; Bullens, S.; Bunting. S. M.; Burdick, D. J.; Chan, K.S.;

Deisher, T.; Eigenbrot, C; Gadek, T.R.; Gantzos, R.; Lipari, M.T.; Deisher, T.; Eigenbrot, C; Gadek, T.R.; Gantzos, R.; Lipari, M.T.;

Muir, OD. Napier, M.A. Pitti, R.M.; Padua, A.; Quan, O; Stanley, M.; Muir, OD. Napier, M.A. Pitti, R.M.; Padua, A.; Quan, O; Stanley, M.;

Struble, M.; Tom, J.Y.K.; Burnier, J.P.; Cyclic RGD Peptide Analogues Struble, M.; Tom, J. Y. K.; Burnier, J.P.; Cyclic RGD Peptide Analogues

as Antiplatelet Antithrombotics, J. Med. Chem. 35, 2040, 1992. McDowell, R.S.; Gadek, T.R. Structural Studies of Potent Constrained RGD as Antiplatelet Antithrombotics, J. Med. Chem. 35, 2040, 1992. McDowell, R.S.; Gadek, T.R. Structural Studies of Potently Constrained RGD

Peptides, J. Amer. Chem. Soc. 114, 9245, 1992.Peptides, J. Amer. Chem. Soc. 114, 9245, 1992.

GlaxoGlaxo

EP 537980, 13. oktober, 1992, B. Porter, et al: beskriver seks cis-4-[4-(4-amidinofenyl)-1-piperazinyl]-1-hydroksycykloheksan-eddiksyreanaloger. EO 0542363, 10. november, .1992, Porter, B. et al: beskriver 4-[4-amidino-fenylpiperazinyl]piperidin-1-eddiksyreanaloger. EP 537980, Oct. 13, 1992, B. Porter, et al: describes six cis-4-[4-(4-amidinophenyl)-1-piperazinyl]-1-hydroxycyclohexane-acetic acid analogs. EO 0542363, November 10, 1992, Porter, B. et al: describes 4-[4-amidino-phenylpiperazinyl]piperidine-1-acetic acid analogs.

WO 93/22303, 11. januar, 1993, Middlemiss, D. et al: beskriver amidino-fenylarylpiperazin-eddiksyreanaloger. WO 93/22303, Jan. 11, 1993, Middlemiss, D. et al: describes amidino-phenylarylpiperazine-acetic acid analogs.

WO 93/14077, 15. januar, 1993, B. Porter, et al: beskriver amidinofenyl-piperizinyl-piperidin-eddiksyreanaloger. WO 93/14077, Jan. 15, 1993, B. Porter, et al: describes amidinophenyl-piperizinyl-piperidine-acetic acid analogs.

EP 609282 A1, 10. august, 1994, Porter, B. et al: beskriver cykloheksan-eddiksyre-derivater. EP 609282 A1, August 10, 1994, Porter, B. et al: describes cyclohexane-acetic acid derivatives.

EP 612313, 31. august, 1994, Porter, B. et al: beskriver alfa-alkylpiperidin-eddiksyre-derivater. EP 612313, August 31, 1994, Porter, B. et al: discloses alpha-alkylpiperidine acetic acid derivatives.

EP 93911769, 20. april, 1994, Middlemiss, D, et al.EP 93911769, April 20, 1994, Middlemiss, D, et al.

EP 637304 A1, 8. februar, 1995, Middlemiss, D, et al.; Piperazine Acetic Acid Dervatives EP 637304 A1, February 8, 1995, Middlemiss, D, et al.; Piperazine Acetic Acid Derivatives

Hann, M.M.; Carter, B.; Kitchin, J.; Ward, P.; Pipe, A.; Broomhead, J.; Hann, M.M.; Carter, B.; Kitchin, J.; Ward, P.; Pipe, A.; Broomhead, J.;

Hornby, E.; Forster, M.; Perry, C. An Investigation of the Bioactive Conformation of ARG-GLY-ASP Containing Cyclic Peptides and Snake Venom Peptides Which Inhibit Human Platelet Aggregation, Hornby, E.; Forster, M.; Perry, C. An Investigation of the Bioactive Conformation of ARG-GLY-ASP Containing Cyclic Peptides and Snake Venom Peptides Which Inhibit Human Platelet Aggregation,

In Molecular Recognition: Chemical and Biochemical Problems II", In Molecular Recognition: Chemical and Biochemical Problems II",

S.M. Roberts, Ed. The Royal Society of Chemistry, Cambridge, 1992. Ross, B.C. Nonpeptide Fibrinogen Receptor Antagonists", (SAR leading to the discovery of GR 144053), In Seventh RSC-SCI Medicinal Chemistry Symposium, The Royal Society of Chemistry, Fine Chemicals and Medicinals Group and SCI Fine Chemicals Group, Churchill College, S.M. Roberts, Ed. The Royal Society of Chemistry, Cambridge, 1992. Ross, B.C. Nonpeptide Fibrinogen Receptor Antagonists", (SAR leading to the discovery of GR 144053), In Seventh RSC-SCI Medicinal Chemistry Symposium, The Royal Society of Chemistry, Fine Chemicals and Medicinals Group and SCI Fine Chemicals Group, Churchill College,

Cambridge, 1993, L20.Cambridge, 1993, L20.

Pike, N.B.; Foster, M.R.; Hornby, E.J.; Lumley, P., Effect of the Fibrinogen Receptor Antagonist GR 144053 Upon Platelet Aggregation Ex vivo Following Intravenous and Oral Administration to the Marmoset and Pike, N.B.; Foster, M.R.; Hornby, E.J.; Lumley, P., Effect of the Fibrinogen Receptor Antagonist GR 144053 Upon Platelet Aggregation Ex vivo Following Intravenous and Oral Administration to the Marmoset and

Cynomologous Monkey, Thromb. Haem., 69, 1071, 1993.Cynomologous Monkey, Thromb. Haem., 69, 1071, 1993.

HoechstHoechst

DE 40049506, 24. mars, 1990, Konig, W. et al: beskriver hydantoin-(Arg-Gly)-Asp-X-anaolger. DE 40049506, March 24, 1990, Konig, W. et al: describes hydantoin-(Arg-Gly)-Asp-X analogs.

Hoffmann-la RocheHoffmann-la Roche

AU 9344935, (Der 94-118783/15), 10. mars, 1994,: beskriver cykliske AU 9344935, (Der 94-118783/15), March 10, 1994,: describes cyclic

RGD-analoger.RGD analogues.

EP 0592791, 20. april, 1994, Bannwarth, W. et al.: beskriver cykliske EP 0592791, Apr. 20, 1994, Bannwarth, W. et al.: describes cyclic

RGD-analoger.RGD analogues.

Kogyo GijutsuinKogyo Gijutsuin

JP 06179696, 28. juni, 1994, Maruyama, S. et al: beskriver Gly-Pro-Arg-Pro-Pro JP 06179696, June 28, 1994, Maruyama, S. et al: describes Gly-Pro-Arg-Pro-Pro

og analoger.and analogues.

Kyowa Hakko Kogyo KKKyowa Hakko Kogyo KK

JP 05078244-A, 30. mars, 1993; beskriver dibenzo(b,e)oksepin-derivater. JP 05078244-A, March 30, 1993; describes dibenzo(b,e)oxepine derivatives.

Laboratorie ChauvinLaboratory Chauvin

WO 9401456, 20, januar, 1994, Regnouf, D.V.J, et al.: beskriver WO 9401456, 20, January, 1994, Regnouf, D.V.J, et al.: describes

Ac-Arg-Gly-Asp-NHBn-analoger.Ac-Arg-Gly-Asp-NHBn analogs.

La Jolla Cancer Res. FndnLa Jolla Cancer Res. Found

WO 9500544, 5. januar, 1994, Pierschbacher, M.D. et al.WO 9500544, January 5, 1994, Pierschbacher, M.D. et al.

US 079441, 5. januar, 1994, Pierschbacher, M.D. et al: beskriver RGD-peptider. US 079441, Jan. 5, 1994, Pierschbacher, M.D. et al: describe RGD peptides.

Lilly/CORLilly/COR

EP 0635492, 25. januar, 1995, Fisher, M.J., Happ, A.M., Jakubowski, J.A., EP 0635492, January 25, 1995, Fisher, M.J., Happ, A.M., Jakubowski, J.A.,

Kinnick, M.D., Kline, A.D., Morin, Jr., J.M., Sali. M.A., Vasileff, R.T., beskriver forbindelser med 6,6-templater. Kinnick, M.D., Kline, A.D., Morin, Jr., J.M., Sali. M.A., Vasileff, R.T., describe compounds with 6,6-templates.

Medical University of South CarolinaMedical University of South Carolina

EP 587770, 23. mars, 1994, Hallushka, P.V., Spicer, K.M.EP 587770, March 23, 1994, Hallushka, P.V., Spicer, K.M.

MerckMerck

EP 0368486 (Der 90-149427/20), 10, november, 1988; beskriver EP 0368486 (Der 90-149427/20), 10, November, 1988; describes

X-R-Tyr-D-Y-analoger.X-R-Tyr-D-Y analogs.

EP 0382451 (Der 90248531): beskriver RGD-holdige slangegift-inhibitorer. EP 0382451 (Der 90248531): describes RGD-containing snake venom inhibitors.

EP 0382538 (Der 90248420): beskriver RGD-holdige slangegift-inhibitorer. EP 0382538 (Der 90248420): describes RGD-containing snake venom inhibitors.

EP 0410537, 23. juli, 1990, R.F. Nutt, et al: beskriver cykliske EP 0410537, July 23, 1990, R.F. Nutt, et al: describes cyclic

RGD-holdige peptider.RGD-containing peptides.

EP 0410539, 25. juli, 1990, R.F. Nutt, et al: beskriver cykliske EP 0410539, July 25, 1990, R.F. Nutt, et al: describes cyclic

RGD-holdige peptider.RGD-containing peptides.

EP 0410540, 25. juli, 1990, R.F. Nutt, et al: beskriver cykliske EP 0410540, July 25, 1990, R.F. Nutt, et al: describes cyclic

RGD-holdige peptider.RGD-containing peptides.

EP 0410541, 25. juli, 1990, R.F. Nutt, et al: beskriver cykliske EP 0410541, July 25, 1990, R.F. Nutt, et al: describes cyclic

RGD-holdige peptider.RGD-containing peptides.

EP 0410767, 26. juli, 1990, R.F. Nutt, et al: beskriver cykliske EP 0410767, July 26, 1990, R.F. Nutt, et al: describes cyclic

RGD-holdige peptider.RGD-containing peptides.

EP 0411833, 26. juli, 1990, R.F. Nutt, et al: beskriver cykliske EP 0411833, July 26, 1990, R.F. Nutt, et al: describes cyclic

RGD-holdige peptider.RGD-containing peptides.

EP 0422937, 11. oktober, 1990, R.F. Nutt, et al: beskriver cykliske EP 0422937, October 11, 1990, R.F. Nutt, et al: describes cyclic

RGD-holdige peptider.RGD-containing peptides.

EP 0422938, 11. oktober, 1990, R.F. Nutt, et al: beskriver cykliske EP 0422938, October 11, 1990, R.F. Nutt, et al: describes cyclic

RGD-holdige peptider.RGD-containing peptides.

EP 0487238, 13. oktober, 1991, T.M. Connolly, et al.: beskriver lineære EP 0487238, October 13, 1991, T.M. Connolly, et al.: describes linear

RGD-holdige.RGD-containing.

EP 0437367 (Der 91209968), M. Sato, et al: beskriver cykliske RGD-holdige peptider som inhibitorer av osteoklast-mediert benresorpsjon. EP 0437367 (Der 91209968), M. Sato, et al: describes cyclic RGD-containing peptides as inhibitors of osteoclast-mediated bone resorption.

EP 576898, 5. januar, 1994, Jonczyk, A. et al: beskriver lineære RGD-peptid-analoger for bruk ved inhibering av celleadhesjon. EP 576898, Jan. 5, 1994, Jonczyk, A. et al: describes linear RGD peptide analogs for use in inhibiting cell adhesion.

WO 9409029, 28. april, 1994, Nutt, R.F. & Veber, D.F., beskriver WO 9409029, Apr. 28, 1994, Nutt, R.F. & Veber, D.F., describe

piperidinyletylpyrrolidinylacetyl-Asp-Trp (tetrazoler).piperidinylethylpyrrolidinylacetyl-Asp-Trp (tetrazoles).

EP 618225, (Der 94-304404/38) 5. oktober, 1994, beskriver RGD-EP 618225, (Der 94-304404/38) October 5, 1994, describes RGD-

peptidanaloger som antimetastase-forbindelser.peptide analogs as antimetastasis compounds.

DE 4310643, (Der 94-311172/39), 6.oktober, 1994, Jonczyk, A. et al: beskriver DE 4310643, (Der 94-311172/39), October 6, 1994, Jonczyk, A. et al: describes

cykliske RGD-analoger som antimetastase-midler.cyclic RGD analogues as antimetastasis agents.

NO 9404093, 27. oktober, 1994, Jonczyk, A. et al.NO 9404093, October 27, 1994, Jonczyk, A. et al.

EP 0632053, 4. januar, 1995, Jonczyk, A. et al: beskriver cykliske RGD-analoger EP 0632053, Jan. 4, 1995, Jonczyk, A. et al: describes cyclic RGD analogs

som antimetastase-midler.as antimetastasis agents.

EP 0479481, 25.september, 1991, M.E. Duggan et al: beskriverEP 0479481, September 25, 1991, M.E. Duggan et al: describe

X-GlyAsp-Y lineære semipeptider.X-GlyAsp-Y linear semipeptides.

EP 0478328, 26. september, 1991, M.S. Egbertson, et al: beskriver tyrosin-derivater. EP 0478362, 27. september, 1991, M.E. Duggan et al: beskriver X-Gly(3-fenetyl)(3Ala-analoger. EP 0478328, September 26, 1991, M.S. Egbertson, et al: describes tyrosine derivatives. EP 0478362, September 27, 1991, M.E. Duggan et al: describe X-Gly(3-phenethyl)(3Ala) analogs.

EP 04780363, 27. september, 1991, W.L. Laswell, et al: beskriver tyrosin-sulfonamider. EP 04780363, September 27, 1991, W.L. Laswell, et al: describe tyrosine sulfonamides.

EP 0512829, 7. mai, 1992, Duggan, M.E. et al: beskriver chirale 3-hydroksy-6-(4-piperidinyl)heptanoyl-P-X-(3-Ala-OH-analoger, med variasjoner EP 0512829, May 7, 1992, Duggan, M.E. et al: describe chiral 3-hydroxy-6-(4-piperidinyl)heptanoyl-P-X-(3-Ala-OH) analogs, with variations

på X og den sentrale alkanoylkjede.on X and the central alkanoyl chain.

EP 0512831, 7. mai, 1992, Duggan, M.E. et al: beskriver chirale 2-okso-3-(piperidinyletyl)piperidinylacetyl-p-X-p-Ala-OH-analoger, EP 0512831, May 7, 1992, Duggan, M.E. et al: describe chiral 2-oxo-3-(piperidinylethyl)piperidinylacetyl-p-X-p-Ala-OH analogs,

med variasjoner på X og den sentrale piperidinylring.with variations on X and the central piperidinyl ring.

EP 0528586, 5. august, 1992, M.S. Egbertson, et al: beskriver tyrosin-sulfonamider som inhibitorer av osteoklast-mediert benresorpsjon. EP 0528586, August 5, 1992, M.S. Egbertson, et al: describes tyrosine sulfonamides as inhibitors of osteoclast-mediated bone resorption.

EP 0528587, 5. august, 1992, M.S. Egbertson, et al: beskriver tyrosin-sulfonamider som inhibitorer av osteoklast-mediert benresorpsjon. EP 0528587, August 5, 1992, M.S. Egbertson, et al: describes tyrosine sulfonamides as inhibitors of osteoclast-mediated bone resorption.

EP 0540334, 29. oktober, 1992, G.D. Hartman, et al: beskriver benz-EP 0540334, October 29, 1992, G.D. Hartman, et al: describe benz-

imidazoler.imidazoles.

US 5227490, 21. februar, 1992, G.D. Hartman, et al.: beskriver tyrosin-sulfonamider. US 5,227,490, Feb. 21, 1992, G.D. Hartman, et al.: describe tyrosine sulfonamides.

CA 2088518, 10. februar, 1993, Egbertson, M.S. et al. aminoalkylfenyl-derivater som benresorpsjons-inhibitorer. CA 2088518, February 10, 1993, Egbertson, M.S. et al. aminoalkylphenyl derivatives as bone resorption inhibitors.

US 5206373-A, (Der 93-151790/18) 27. april, 1993, Chung, J.Y.L. et al.: US 5206373-A, (Der 93-151790/18) Apr. 27, 1993, Chung, J.Y.L. et al.:

beskriver MK-383-type forbindelser.describes MK-383-type compounds.

WO 9316994, (Der 93-288324/36), 2. september, 1993, Chung, J.Y.L. et al: WO 9316994, (Der 93-288324/36), Sep. 2, 1993, Chung, J.Y.L. et al:

beskriver pyridinylbutyl-L-Tyr-butylsulfonamid.describes pyridinylbutyl-L-Tyr-butylsulfonamide.

US 5264420-A, 23. november, 1993, beskriver piperidinylalkyl-Gly-betaAla-analoger. US 5,264,420-A, Nov. 23, 1993, describes piperidinyl alkyl Gly-betaAla analogs.

US 5272158, 21. desember, 1993, Hartman, G.D. et al: beskriver US 5272158, December 21, 1993, Hartman, G.D. et al: describe

piperidinyletylisoindol-analoger.piperidinylethylisoindole analogs.

US 5281585, 25. januar, 1994, Ihle, N. et al: beskriver 3-(piperidinyletyl)-piperidinon-analoger. US 5281585, Jan. 25, 1994, Ihle, N. et al: discloses 3-(piperidinylethyl)-piperidinone analogs.

GB 945317 A, 17. mars, 1994 (Prioritet US 34042A, 22. mars, 1993).GB 945317 A, March 17, 1994 (Priority US 34042A, March 22, 1993).

GB 2271567 A, 20, april, 1994, Hartman, G.D. et al: beskriver forbindelser GB 2271567 A, 20, April, 1994, Hartman, G.D. et al: describe compounds

som erstatter Tyr med beta-fenylsuccinat.which replaces Tyr with beta-phenylsuccinate.

US 5294616, (Der 94-091561/11), 15. mars, 1994, Egbertson, M.S. et al. US 5292756, (Der 94-082364) 8. april, 1994, Hartman, G.D. et al. US 5294616, (Der 94-091561/11), Mar. 15, 1994, Egbertson, M.S. et al. US 5292756, (Der 94-082364) Apr. 8, 1994, Hartman, G.D. et al.

WO 9408577, 28. april, 1994, Hartman, G.D. et al.WO 9408577, Apr. 28, 1994, Hartman, G.D. et al.

WO 9408962, 28. april, 1994, Hartman, G.D. et al.WO 9408962, Apr. 28, 1994, Hartman, G.D. et al.

WO 9409029, (Der 94-151241/18), 28. april, 1994, Hartman, G.D. et al. WO 9409029, (Der 94-151241/18), Apr. 28, 1994, Hartman, G.D. et al.

beskriver piperidinylpyrrolinylacetyl-Asp-Trp-tetrazoler.describes piperidinylpyrrolinylacetyl-Asp-Trp tetrazoles.

US 5312923, 17. mai, 1994, Chung, J.Y.L. et al.US 5312923, May 17, 1994, Chung, J.Y.L. et al.

HU 9400249, 30. mai, 1994, Gante, J. et al: beskriver piperazinanaloger. WO 9412181, (Der 94-199942/24), 9. juni, 1994, Egbertson, M.S. et al.: HU 9400249, May 30, 1994, Gante, J. et al: describes piperazine analogs. WO 9412181, (Der 94-199942/24), June 9, 1994, Egbertson, M.S. et al.:

beskriver piperidinyletyloksyfenyl-eddiksyreanaloger.describes piperidinylethyloxyphenylacetic acid analogs.

US 5321034, 14. juni, 1994, Duggan, M.E. et al.: beskriver piperidinyl-alkyl-beta-aminosyrer. US 5321034, June 14, 1994, Duggan, M.E. et al.: describe piperidinyl-alkyl-beta-amino acids.

US 5334596, 2. august, 1994, Hartman, G.D. et al.US 5334596, August 2, 1994, Hartman, G.D. et al.

EP 0608759 A, 3. august, 1994, Gante, J.P. et al.: beskriver amidino-piperazinyl-forbindelser. EP 0608759 A, August 3, 1994, Gante, J.P. et al.: describe amidino-piperazinyl compounds.

WO 9418981 (Der 94-293975/36), 1. september, 1994, Claremon, D. A. et al: WO 9418981 (Der 94-293975/36), September 1, 1994, Claremon, D. A. et al:

beskriver mange forskjellige amin-surrogater.describes many different amine surrogates.

GB 2276384, (Der 94-287743/36), 28. september, 1994, Claremon, D.A., GB 2276384, (Der 94-287743/36), September 28, 1994, Claremon, D.A.,

Liverton, N.: beskriver piperidinyletylkinazolinanaloger.Liverton, N.: describes piperidinylethylquinazoline analogues.

WO 9422825 13. oktober, 1994, Claremon, D.A., Liverton, N.J.: beskriver WO 9422825 October 13, 1994, Claremon, D.A., Liverton, N.J.: describes

piperidinyletyl-retro-benzodiazepin-analoger.piperidinylethyl retro-benzodiazepine analogues.

EP 0623615A, 9. november, 1994, Raddatz, P. et al.: beskriver amidino-fenyloksazolidinylmetyl-piperidin-4-karboksylsyre og analoger. EP 0623615A, November 9, 1994, Raddatz, P. et al.: discloses amidino-phenyloxazolidinylmethyl-piperidine-4-carboxylic acid and analogs.

WO 9504531, 16. februar, 1995, Hartman, G.D et al.: beskriver piperidinylalkyl-heterocykler. WO 9504531, February 16, 1995, Hartman, G.D et al.: describes piperidinylalkyl heterocycles.

Nutt, R.F.; Brady, S.F.,Colton, C.D.; Sisko, J.T.; Ciccarone, T.M.; Levy, M.R.; Duggan, M.E.; Imagire, I.S.; Gould, R.J.; Anderson, P.S.; Veber, D.F.; Nutt, R.F.; Brady, S.F., Colton, C.D.; Sisko, J.T.; Ciccarone, T. M.; Levy, M.R.; Duggan, M.E.; Imagire, I.S.; Gould, R. J.; Anderson, P. S.; Veber, D.F.;

Development of Novel, Highly Selective Fibrinogen Receptor Antagonists as Potentially Useful Antithrombotic Agents, i Peptides, Chemistry and Biology, Proe. 12th Amer. Peptide Symp., J.A. Smith & J.E. Rivier, red. Development of Novel, Highly Selective Fibrinogen Receptor Antagonists as Potentially Useful Antithrombotic Agents, in Peptides, Chemistry and Biology, Proe. 12th Amer. Peptide Symp., J.A. Smith & J.E. Rivier, ed.

ESCOM, Leiden, 1992; 914.ESCOM, Leiden, 1992; 914.

Hartman, G.D.; Egbertson, M.S.; Halszenko, W.; Laswell, W.L.; Duggan, M.E.; Hartman, G.D.; Egbertson, M. S.; Halszenko, W.; Laswell, W. L.; Duggan, M.E.;

Smith, R.L.; Naylor, A.M.; Manno, P.D.; Lynch, R.J.; Zhang, G.; Smith, R.L.; Naylor, A. M.; Manno, P.D.; Lynch, R. J.; Zhang, G.;

Chang, C.T.C.; Gould, R.J.; Non-peptide Fibrinogen Receptor Antagonists. 1. Discovery and Design of Exosite Inhibitors, J. Med. Chang, C. T. C.; Gould, R. J.; Non-peptide Fibrinogen Receptor Antagonists. 1. Discovery and Design of Exosite Inhibitors, J. Med.

Chem. 35, 4640, 1992. Chem. 35, 4640, 1992.

Gould, R.J.; Barrett, S.; Ellis, J.D.; Holahan, MA; Stranieri, M.T.; Gould, R. J.; Barrett, S.; Ellis, J.D.; Holahan, MA; Stranieri, M.T.;

Theoharides, A.D.; Lynch, J.J.; Friedman, PA.; Duggan, M.E.; Theoharides, A.D.; Lynch, J. J.; Friedman, PA.; Duggan, M.E.;

Ihle, N.C.; Anderson, P.S.; Hartman, G.D., Characterization of L-703.014, A Novel Fibrinogen Receptor Antagonist, Following Oral Administration to Dogs, Thromb. Haem., 69, 539, 1993. Ihle, N. C.; Anderson, P. S.; Hartman, G.D., Characterization of L-703,014, A Novel Fibrinogen Receptor Antagonist, Following Oral Administration to Dogs, Thromb. Haem., 69, 539, 1993.

Merrell DowMerrell Dow

WO 93/24520, 14. mai, 1993, Harbeson, S.L. et al: beskriver cykliske WO 93/24520, May 14, 1993, Harbeson, S.L. et al: describes cyclic

RGD-peptider.RGD peptides.

WO 9324520, 9. desember, 1993, Harbeson, Bitonti, JA: beskriver cykliske WO 9324520, Dec. 9, 1993, Harbeson, Bitonti, JA: describes cyclic

RGD-analoger som antimetastase-midler.RGD analogs as antimetastasis agents.

WO 9429349, 22. desember, 1994, Harbeson, Bitonti, JA.: beskriver cykliske RGD-analoger som antimetastase-midler. WO 9429349, Dec. 22, 1994, Harbeson, Bitonti, JA.: discloses cyclic RGD analogs as antimetastatic agents.

Nippon Steel Corp.Nippon Steel Corp.

WO 9405696, 17. mars, 1993, Sato, Y. et al.WO 9405696, March 17, 1993, Sato, Y. et al.

EP 628571, 14. desember, 1994, Sato, Y. et al.EP 628571, Dec. 14, 1994, Sato, Y. et al.

WO 9501371, 12. januar, 1995, Sato, Y, et al.: beskriver RWSRGDW-WO 9501371, Jan. 12, 1995, Sato, Y, et al.: describes RWSRGDW-

analoger.analogues.

ONO PharmaceuticalsONO Pharmaceuticals

JP 05286922 (Der 93-383035/48) beskriver guanidinofenol-alkylbenzosyre-estere. JP 05286922 (Der 93-383035/48) describes guanidinophenol alkylbenzoic acid esters.

RocheRoche

EP 038.362, 19. februar, 1990, Muller et al: beskriver X-NHCHYCO-Gly-Asp-NHCHZC02H-analoger. EP 038,362, Feb. 19, 1990, Muller et al: describes X-NHCHYCO-Gly-Asp-NHCHZC02H analogs.

EP 0372486, 13. juni, 1990, Allig, L. et al.EP 0372486, June 13, 1990, Allig, L. et al.

EP 0381033, 8. juli, 1990, Allig, L. et al.:EP 0381033, July 8, 1990, Allig, L. et al.:

EP 0384362, 29. august, 1990, Allig, L. et al.: beskriver amidinofenyl-koblede EP 0384362, August 29, 1990, Allig, L. et al.: discloses amidinophenyl-linked

Gly-Asp-X semipeptider.Gly-Asp-X semipeptides.

EP 0445796, 11. september, 1991, Allig, L. et al: beskriver amidinofenyl-koblede Gly-Asp-X semipeptider. EP 0445796, September 11, 1991, Allig, L. et al: describes amidinophenyl-linked Gly-Asp-X semipeptides.

EP 0505868, 30. september, 1992, Allig, L. et al: beskriver N-acyl-alfa-aminosyre-derivater, dvs. analogerfra EP0381003 med variasjoner i fenyloksy-eddiksyregruppen. EP 0505868, September 30, 1992, Allig, L. et al: describes N-acyl-alpha-amino acid derivatives, ie analogs of EP0381003 with variations in the phenyloxy-acetic acid group.

US 5273982-A, (Der 94-006713/01), 28. desember, 1993: beskriver amidinofenyl-koblede Gly-Asp-X semipeptider. US 5273982-A, (Der 94-006713/01), December 28, 1993: describes amidinophenyl-linked Gly-Asp-X semipeptides.

Alig, L; Edenhofer, A.; Hadvary, P.; Hurzeler, M.; Knopp, D.; Muller, M.; Alig, L; Edenhofer, A.; Hadvary, P.; Hurzeler, M.; Knopp, D.; Muller, M.;

Steiner, B.; Trzeciak, A.; Weller, T.; Low Molecular Weight, Non-Steiner, B.; Trzeciak, A.; Weller, T.; Low Molecular Weight, Non-

peptide Fibrinogen Receptor Antagonists, J. Med. Chem., 35,peptide Fibrinogen Receptor Antagonists, J. Med. Chem., 35,

4393, 1992. 4393, 1992.

Rhone-Poulence RorerRhone-Poulence Rudders

US 4952562, 29. september, 1989, S.l. Klein, et al: beskriver X-Gly-Asp-Val-OH-analoger. US 4952562, September 29, 1989, S.l. Klein, et al: describe X-Gly-Asp-Val-OH analogs.

US 5064814, (Der 91-353169/48), 5. april, 1990: beskriver piperidinyl-azetidinyl-Asp-X-analoger. US 5064814, (Der 91-353169/48), Apr. 5, 1990: describes piperidinyl-azetidinyl-Asp-X analogs.

WO 9104746, 25. september, 1990, S.I.KIein, et al: beskriver X-Asp-Val-OH-analoger. WO 9104746, September 25, 1990, S.I.Kiein, et al: describes X-Asp-Val-OH analogs.

WO 91/05562, 10. oktober, 1989, S.l Klein et al: beskriver X-Gly-Asp-Val-OH-analoger. WO 91/05562, October 10, 1989, S.l Klein et al: describes X-Gly-Asp-Val-OH analogs.

WO 91/07976, (Der 91-192965), 28. november, 1990, S.l. Klein et al: beskriver WO 91/07976, (Der 91-192965), Nov. 28, 1990, S.l. Klein et al: describe

X-cykloAA-Asp-Val-OH-analoger.X-cycloAA-Asp-Val-OH analogs.

WO 91/04746, S.l. Klein et al: beskriver des-amino-arginin RGD-analoger.WO 91/04746, S.l. Klein et al: describe des-amino-arginine RGD analogues.

WO 92/18117, 11. april, 1991, S.l. Klein, et al: beskriver X-Asp-Val-OH-analoger. US 5086069, (Der 92-064426/08), 2. april, 1992, beskriver X-Gly-Asp-Val-OH-analoger. WO 92/18117, Apr. 11, 1991, S.l. Klein, et al: describe X-Asp-Val-OH analogs. US 5086069, (Der 92-064426/08), April 2, 1992, describes X-Gly-Asp-Val-OH analogs.

WO 92/17196, 30. mars, 1992, S.l. Klein et al: beskriver X-Gly-Asp-Val-OH-analoger. WO 92/17196, Mar. 30, 1992, S.l. Klein et al: describe X-Gly-Asp-Val-OH analogs.

US 5328900, (Der 94-221950/27), 12. juli, 1992: beskriver X-azetidinyl-Asp-Val-OH-analoger. US 5328900, (Der 94-221950/27), July 12, 1992: describes X-azetidinyl-Asp-Val-OH analogs.

US 5332726, (Der 94-241043/29), 26. juli, 1994; beskriver guanidinoalkanoyl-(N-alkyl)-Gly-Asp-Val-OH-analoger. US 5332726, (Der 94-241043/29), July 26, 1994; describes guanidinoalkanoyl-(N-alkyl)-Gly-Asp-Val-OH analogs.

WO 93/11759, 7. desember, 1992, S.l. Klein et al: beskriver bis-guanidinoalkan-Syreanaloger. WO 93/11759, Dec. 7, 1992, S.l. Klein et al: describe bis-guanidinoalkane acid analogues.

EP 0577775, 12. januar, 1994, Klein, S.l et al.EP 0577775, January 12, 1994, Klein, S.l et al.

CA 2107088, 29. september, 1992, Klein, S.l. et al.CA 2107088, Sep. 29, 1992, Klein, S.l. et al.

SandozSandoz

EP 0560730, 8. mars, 1993, G. Kottirisch & R. Metternich: beskriver EP 0560730, March 8, 1993, G. Kottirisch & R. Metternich: describes

amidinofenylalkanamid-S-a-eddiksyreanaloger.amidinophenylalkanamide-S-α-acetic acid analogs.

G. Kottirisch, et al. Biorg. Med. Chem. Lett 3, 1675-1680, 1993, beskriver G. Kottirisch, et al. Bioorg. With. Chem. Lett 3, 1675-1680, 1993, describes

amidinofenylacetyl-(Gly-Asp-y-laktam-mimetika)-analoger.amidinophenylacetyl-(Gly-Asp-γ-lactam mimetics) analogs.

Schering AGSchering AG

E 530937, lO.mars, 1993, Noeski-Jungblut, C. et al. "Collagen InducedE 530937, March 10, 1993, Noeski-Jungblut, C. et al. "Collagen Induced

Platelet Aggregation Inhibitor." Platelet Aggregation Inhibitor."

Searle/MonsantoSearle/Monsanto

EP 0319506, (Der 89-3195506) 2. desember, 1988, S.P. Adams, et al: EP 0319506, (Der 89-3195506) Dec. 2, 1988, S.P. Adams, et al:

beskriver RGD-X-analoger.describes RGD-X analogs.

EP 0462,960, 19. juni, 1991, Tjoeng, F.S. et al: beskriver guanidino-o.ktanoyl-Asp-Phe-analoger. EP 0462,960, June 19, 1991, Tjoeng, F.S. et al: describe guanidino-o.ctanoyl-Asp-Phe analogs.

US 4857508, S.P. Adams,.et al: beskriver RGD-analoger.US 4857508, S.P. Adams,.et al: describes RGD analogs.

EP 0502536, (Der 92-301855) 3. mars, 1991, R.B. Garland, et al:EP 0502536, (Der 92-301855) Mar. 3, 1991, R.B. Garland, et al:

beskriver amidinofenylalkanoyl-Asp-Phe-analoger.describes amidinophenylalkanoyl-Asp-Phe analogs.

EP 0319506. 2. desember, 1988, S.P.Adams, et al.: beskriver RGDX-analoger. US 4992463, 18. august, 1989: beskriver guanidinoalkanoyl-Asp-X-analoger. US 5037808, 23. april, 1990: beskriver guanidinoalkanoyl-Asp-X-analoger. EP 0454651 A2, 30. oktober, 1991, Tjoeng, F.S. et al.: beskriver amidino-alkanoyl-Asp-X-analoger. EP 0319506. Dec. 2, 1988, S.P. Adams, et al.: Describes RGDX analogs. US 4992463, August 18, 1989: describes guanidinoalkanoyl Asp-X analogs. US 5037808, April 23, 1990: describes guanidinoalkanoyl Asp-X analogs. EP 0454651 A2, October 30, 1991, Tjoeng, F.S. et al.: describe amidino-alkanoyl-Asp-X analogs.

US 4879313, 20. juli, 1988: beskriver guanidinoalkanoyl-Asp-X-analoger. WO 93/12074, 19. november, 1991, N. Abood, et al.: beskriver amidinofenylalkanoyl-p-X-AlaOH-analoger. US 4879313, July 20, 1988: describes guanidinoalkanoyl Asp-X analogs. WO 93/12074, Nov. 19, 1991, N. Abood, et al.: describes amidinophenylalkanoyl-p-X-AlaOH analogs.

WO 93/12103, 11. desember, 1991, P.R. Bovy, et al.: beskriver amidinofenylalkanoyl-(3-X-lakton-analoger. WO 93/12103, Dec. 11, 1991, P.R. Bovy, et al.: describe amidinophenylalkanoyl-(3-X-lactone analogs).

US 5091396, 25. februar, 1992, Tjoeng, F.S. et al.: beskriver amidinoalkanoyl-Asp-X-analoger. US 5091396, February 25, 1992, Tjoeng, F.S. et al.: describe amidinoalkanoyl-Asp-X analogs.

WO 92/15607, 5. mars, 1992, Garland, R.B. et al.: beskriver amidinofenylalkanoyl-Asp-X-analoger. WO 92/15607, Mar. 5, 1992, Garland, R.B. et al.: describe amidinophenylalkanoyl-Asp-X analogs.

WO 93/07867, 29. april, 1993, P.R. Bovy, et al.: beskriver amidinofenyl-amidopropionyl-p-X-AlaOH-analoger. WO 93/07867, Apr. 29, 1993, P.R. Bovy, et al.: describe amidinophenyl-amidopropionyl-p-X-AlaOH analogs.

US 888686, 22. mai, 1992, Bovy, P.R. et al.US 888686, May 22, 1992, Bovy, P.R. et al.

CA 2099994, 7. september, 1992, Garland, R.B. et al.CA 2099994, September 7, 1992, Garland, R.B. et al.

US 5254573, 6. oktober, 1992, Bovy, P.R. et al.: beskriver amidino-fenylamidopropionyl-p-X-p-Ala-OH. US 5254573, October 6, 1992, Bovy, P.R. et al.: describe amidino-phenylamidopropionyl-p-X-p-Ala-OH.

(PF54C06), EP 0539343, 14. oktober, 1992, P.R. Bovy et al.: beskriver amidinofenylamidopropinyl-p-X-p-Ala-OH. (PF54C06), EP 0539343, October 14, 1992, P.R. Bovy et al.: describe amidinophenylamidopropynyl-p-X-p-Ala-OH.

WO 93/12074, 27. november, 1992, N.A. Abood, et al.: beskriver amidinofenylalkylamido-(R)-Asp-(dvs. retro-Asp)-alkyl og -arylamider og WO 93/12074, Nov. 27, 1992, N.A. Abood, et al.: describe amidinophenylalkylamido-(R)-Asp-(ie, retro-Asp)-alkyl and -aryl amides and

sulfonamider.sulfonamides.

WO 93/12103, 11. desember, 1992, P.R. Bovy, et al.: beskriver amidinofenylalkanoyl-Asp-X-laktoner. WO 93/12103, Dec. 11, 1992, P.R. Bovy, et al.: describe amidinophenylalkanoyl-Asp-X-lactones.

EP 0539343, 28.april, 1993, Bovy, P.R. et al.EP 0539343, Apr. 28, 1993, Bovy, P.R. et al.

EP 0542708, 19, mai, 1993, Bovy, P.R. et al.EP 0542708, May 19, 1993, Bovy, P.R. et al.

WO 94/00424, 23. juni, 1993, Abood, N.A. et al.: beskriver amidino-fenylalkansyrelaktoner beslektet med tidligere forbindelser. WO 94/00424, June 23, 1993, Abood, N.A. et al.: describe amidino-phenylalkanoic acid lactones related to previous compounds.

WO 93/16038, 16. august, 1993, Miyano. M., et al.: beskriver WO 93/16038, Aug. 16, 1993, Miyano. M., et al.: describe

amidinofenylpentanoyl-p-arylsulfonamidometyl-fj-Ala-OH-analoger. WO 93US7975, 17. august, 1993, Zablocki, J.A., Tjoeng, F.S. amidinophenylpentanoyl-p-arylsulfonamidomethyl-fj-Ala-OH analogs. WO 93US7975, August 17, 1993, Zablocki, J.A., Tjoeng, F.S.

WO 93/18058, 16. september, 1993, Bovy, P.R. et al.: beskriver amidinofenyl-amidopropionyl-Asp-X-OH-analoger. WO 93/18058, Sep. 16, 1993, Bovy, P.R. et al.: describe amidinophenyl-amidopropionyl-Asp-X-OH analogs.

US 5254573, 19. oktober, 1993, Bovy, P.R. et al.: beskriver amidinofenyl-propionylaminosyrederivater. US 5254573, October 19, 1993, Bovy, P.R. et al.: describe amidinophenyl-propionyl amino acid derivatives.

US 5272162, 21. desember, 1993, Tjoeng, F.S. et al: beskriver amidinofenyl-X-NHCO-p-Y-p-Ala-OH-analoger. US 5272162, December 21, 1993, Tjoeng, F.S. et al: describe amidinophenyl-X-NHCO-p-Y-p-Ala-OH analogs.

EP 0574545, 22. desember, 1993, Garland, R.B. et al.: amidinofenyl-X-Asp-ånaloger. EP 0574545, Dec. 22, 1993, Garland, R.B. et al.: amidinophenyl-X-Asp analogs.

WO 9401396, 20. januar, 1994, Tjoeng, F.S. et al.: beskriver amidinofenylalkylamido-aminosyre-derivater. WO 9401396, January 20, 1994, Tjoeng, F.S. et al.: describe amidinophenylalkylamido-amino acid derivatives.

WO 9405694, (Der 94-101119/12), 17. mars, 1994, Zablocki, et al: beskriver WO 9405694, (Der 94-101119/12), March 17, 1994, Zablocki, et al: describes

amidinofenylalkylamido-aminosyre-derivater.amidinophenylalkylamido-amino acid derivs.

US 5314902, 24. mai, 1994, Adams, S.P. et al.: beskriver amidinofenyl-amidoalkanoyl-derivater. US 5314902, May 24, 1994, Adams, S.P. et al.: describe amidinophenyl-amidoalkanoyl derivatives.

WO 9418162, 18. august, 1994, Adams, S.P. et al.: beskriver amidinofenylalkanoyl-aminosyre-derivater. WO 9418162, August 18, 1994, Adams, S.P. et al.: describe amidinophenylalkanoyl amino acid derivatives.

WO 9419341, 1. september, 1994, Tjoeng, F.S. et al.: beskriver amidino-fenylnipekotinsyre-derivater. WO 9419341, September 1, 1994, Tjoeng, F.S. et al.: describe amidino-phenylnipecotic acid derivatives.

US 5344837, (Der 94-285503/35), 6. september, 1994, Zablocki, J.A. et al. EP 614360, 14. september, 1994, Bovy, P.R. et al. US 5344837, (Der 94-285503/35), Sep. 6, 1994, Zablocki, J.A. et al. EP 614360, September 14, 1994, Bovy, P.R. et al.

WO 9420457, (Der 94-302907/37), 15. september, 1994, Tjoeng, F.S. et al. WO 9420457, (Der 94-302907/37), September 15, 1994, Tjoeng, F.S. et al.

amidinofenyl-forbindelser med sentral ring.amidinophenyl compounds with a central ring.

WO 9421602, (Der 94-316876/39), 29. september, 1994, Tjoeng, F.S. et al.: WO 9421602, (Der 94-316876/39), September 29, 1994, Tjoeng, F.S. et al.:

beskriver guanidinoalkylaminokarbonylaminosyre-derivater.describes guanidinoalkylaminocarbonylamino acid derivatives.

WO 9422820, 13. oktober, 1994, Abood, N.A. et al.: beskriver amidino-fenylpyrrolidinonyl-p-Ala-derivater. WO 9422820, October 13, 1994, Abood, N.A. et al.: describe amidino-phenylpyrrolidinonyl-p-Ala derivatives.

EP 630366, 28. desember, 1994, Bovy, P.R. et al.EP 630366, Dec. 28, 1994, Bovy, P.R. et al.

US 5378727, 3. januar, 1995, Bovy, P.R. et al.US 5378727, January 3, 1995, Bovy, P.R. et al.

K.F.Fok, et al. Int. J. Peptide Prot. Res., 38, 124-130, 1991, SAR av RGDY-analoger. K.F. Fok, et al. Int. J. Peptide Prot. Res., 38, 124-130, 1991, SAR of RGDY analogs.

J.A. Zablocki, et al. J. Med. Chem. 35, 4914-4917, 1992, SAR-sammenfatning YES. Zablocki et al. J. Med. Chem. 35, 4914-4917, 1992, SAR Summary

av guanidinoalkanoyl-Asp-Phe-analoger.of guanidinoalkanoyl-Asp-Phe analogs.

Tjoeng, F.S.; Fok, K.F.; Zupec, M.E.; Garland, R.B.; Miyano, M.; Panzer-Knodle, Tjoeng, F.S.; Fok, K.F.; Zupec, M.E.; Garland, R.B.; Miyano, M.; Panzer-Knodle,

S.; King, L.W.; Taite, B.B.; Nicholson, N.S.; Feigen, LP.; Adams, S.P.; S.; King, L. W.; Taite, B.B.; Nicholson, N. S.; Feigen, LP.; Adams, S. P.;

Peptide Mimetics of the RGD Sequence, In Peptides, Chem. andPeptide Mimetics of the RGD Sequence, In Peptides, Chem. duck

Biol. Proe. 12th Amer. Peptide Symp., J.A. Smith & J.E. Rivier, red. Biol. Pro. 12th Amer. Peptide Symp., J.A. Smith & J.E. Rivier, ed.

ESCOM, Leiden, 1992, 752.ESCOM, Leiden, 1992, 752.

Nicholson, N.; Taite, B.; Panzer-Knodle, S.; Salyers, A.; Haas, N.; Szalony, J.; Nicholson, N.; Taite, B.; Panzer-Knodle, S.; Salyers, A.; Haas, N.; Szalony, J.;

Zablocki, J.; Feigen, L.; Glenn, K.; Keller, B.; Broschat, K.; Herin, M.; Zablocki, J.; Feigen, L.; Glenn, K.; Keller, B.; Broschat, K.; Herin, M.;

Jacqmin, P.; Lesne, M.; An Orally Active Glycoprotein Hb/Illa Antagonist-SC-54684, Thromb. Haem., 69, 975, 1993. Jacquemin, P.; Lesne, M.; An Orally Active Glycoprotein Hb/Illa Antagonist-SC-54684, Thromb. Haem., 69, 975, 1993.

Sumitomo Pharm. Co Ltd.Sumitomo Pharm. Co. Ltd.

WO 9501336, 6. juni, 1994, Ikeda, Y. et al.: beskriver piperidinyloksy-acetyl-Tyr-piperidinyloksyeddiksyre-derivater. WO 9501336, June 6, 1994, Ikeda, Y. et al.: describes piperidinyloxy-acetyl-Tyr-piperidinyloxyacetic acid derivatives.

Sumitomo Seiyaku KKSumitomo Seiyaku KK

JP 0602590, (Der 94-077374/10), 1. februar, 1994, beskriver multimerJP 0602590, (Der 94-077374/10), February 1, 1994, describes multimer

RGDT.RGDT.

Taisho Pharm. (Teijin, Ltd.)Taisho Pharm. (Teijin, Ltd.)

JP 05230009, (Der 93-317431/40), 24. februar, 1992: beskriver amidino-Cbz-meta-aminofenylpropionat. JP 05230009, (Der 93-317431/40), February 24, 1992: discloses amidino-Cbz-meta-aminophenylpropionate.

JP 9235479, 24. februar, 1992: beskriver amidinofenylkarbamater.JP 9235479, February 24, 1992: discloses amidinophenyl carbamates.

(PFD4C06), WO 94/17804, 18. august, 1994, Mizushima, Y. Pharm. Comp(PFD4C06), WO 94/17804, Aug. 18, 1994, Mizushima, Y. Pharm. Comp

for Treating Cerebral Thrombosis.for Treating Cerebral Thrombosis.

(EP 634171), 18. januar, 1995, Nizushima, M. Pharm. Comp for Treating (EP 634171), Jan. 18, 1995, Nizushima, M. Pharm. Comp for Treating

Cerebral Thrombosis, ProstaglandinsCerebral Thrombosis, Prostaglandins

TakedaTakeda

EP 0529858, 3. april, 1993, H. Sugihara, et al: beskriver amidinobenzoyl-Gly-piperazinon-analoger. EP 0529858, Apr. 3, 1993, H. Sugihara, et al: describes amidinobenzoyl-Gly-piperazinone analogs.

EP 606881, 20. juli, 1994, Cyclic peptides with beta- and gamma turns.EP 606881, July 20, 1994, Cyclic peptides with beta- and gamma turns.

EP 614664, 14. september, 1994, Miyake, A. et al: Quinolone carboxylicEP 614664, September 14, 1994, Miyake, A. et al: Quinolone carboxylic

acids as Cell Adhesion Inhibitorsacids as Cell Adhesion Inhibitors

TanabeTanabe

WO 89/07609, T.J. Lobl, et al: beskriver RGD-analoger.WO 89/07609, T.J. Lobl, et al: describe RGD analogs.

WO 92/00995, 9. juli, 1991, T.J. Lobl, et al: beskriver cykliske RGD-analoger. WO 93708823, 6. november, 1991, T.C. McKenzie: beskriver guanidinoalkanoyl-Gly-Asp-X-analoger. WO 92/00995, July 9, 1991, T.J. Lobl, et al: describe cyclic RGD analogs. WO 93708823, November 6, 1991, T.C. McKenzie: describes guanidinoalkanoyl-Gly-Asp-X analogs.

CA 2087021, 10. januar, 1991, Lobl, T.J. et al.: beskriver cykliske RGD-analoger. WO 92/08464, 15. november, 1991, T.C. McKenzie, et al: beskriver. CA 2087021, Jan. 10, 1991, Lobl, T.J. et al.: describe cyclic RGD analogs. WO 92/08464, Nov. 15, 1991, T.C. McKenzie, et al: describes.

Telios/La Jolla Cancer ResearchTelios/La Jolla Cancer Research

US 4578079, 22. november, 1983, E. Ruoslathi og M. Pierschbacher: beskriver US 4578079, November 22, 1983, E. Ruoslathi and M. Pierschbacher: describes

X-RGD-Y-analoger.X-RGD-Y analogs.

US 4614517, 17. juni, 1985, E. Ruoslahti, og M. Pierschbacher: beskriver US 4614517, June 17, 1985, E. Ruoslahti, and M. Pierschbacher: describes

X-RGD-Y-analoger.X-RGD-Y analogs.

US 4792,525, 17. juni, 1985, E. Ruoslahti, og M. Pierschbacher: beskriver US 4792,525, June 17, 1985, E. Ruoslahti, and M. Pierschbacher: describes

X-RGD-Y-analoger.X-RGD-Y analogs.

US 4879237, (Der 90-154405/20), 24. mai, 1985, beskriver X-RGD-Y-analoger. US 4879237, (Der 90-154405/20), May 24, 1985, describes X-RGD-Y analogs.

WO 91/15515, (Der 91-325173/44), 6. april, 1990: beskriver cykliske WO 91/15515, (Der 91-325173/44), April 6, 1990: describes cyclic

RGD-analoger.RGD analogues.

US 5041380, 1991, E. Ruoslahti, og M. Pierschbacher: beskriver RGD-X-analoger. US 5041380, 1991, E. Ruoslahti, and M. Pierschbacher: describes RGD-X analogs.

WO 95/00544, 5. januar, 1995, Craig, W.S. et al.WO 95/00544, Jan. 5, 1995, Craig, W.S. et al.

Cheng. S.; Craig, W.S.: Mullen, D.; Tschopp, J.F.; Dixon, D.; Cheng. S.; Craig, W.S.: Mullen, D.; Tschopp, J.F.; Dixon, D.;

Pierschbacher, M.F.; Design and Synthesis of Novel Cyclic RGD-Containing Peptides as Highly Potent and Selective Integrin aiib(33 Antagonists, J. Medicin. Chem., 37, 1, 1994. Pierschbacher, M.F.; Design and Synthesis of Novel Cyclic RGD-Containing Peptides as Highly Potent and Selective Integrin aiib(33 Antagonists, J. Medicin. Chem., 37, 1, 1994.

Coilen, D.; Lu, H.R.; Stassen, J.M.; Vreys, I.; Yasuda, T.; Bunting, S.; Coilen, D.; Lu, H.R.; Stassen, J.M.; Vreys, I.; Yasuda, T.; Bunting, S.;

Gold, H.K.; Antithrombotic Effects and Bleeding Time Prolongation with Synthetic Platelet GPIIb/llla Inhibitors in Animal Models of Platelet-Mediated Thrombosis, Thrombosis and Haemostasis, 71, 95, 1994. Gold, H.K.; Antithrombotic Effects and Bleeding Time Prolongation with Synthetic Platelet GPIIb/llla Inhibitors in Animal Models of Platelet-Mediated Thrombosis, Thrombosis and Haemostasis, 71, 95, 1994.

Temple U.Temple U.

WO 9409036, (Der 94-151248/18), 28. april, 1994, beskriver disintegrin-peptider. WO 9409036, (Der 94-151248/18), April 28, 1994, describes disintegrin peptides.

Terumo KKTerumo KK

JP 6279389, 4. oktober, 1994, Obama, H. et al.: beskriver 3-(4-amidino-fenyloksymetyl)fenylamidopropionsyreanaloger (ala Roche I-35) JP 6279389, October 4, 1994, Obama, H. et al.: discloses 3-(4-amidino-phenyloxymethyl)phenylamidopropionic acid analogs (ala Roche I-35)

Karl Thomae/Boehringer IngelheimKarl Thomae/Boehringer Ingelheim

EP 0483667, 6. mai, 1992, Himmelsbach, F. et al.: beskriver amidino-bifenyloksymetyl-2-pyrrolidinon-eddiksyre. EP 0483667, May 6, 1992, Himmelsbach, F. et al.: discloses amidino-biphenyloxymethyl-2-pyrrolidinone-acetic acid.

EP 0496378, 22. januar, 1992, Himmelsbach, F. et al: beskriver amidino-bifenylaminokarbonylcykloheksylkarboksylsyre-analoger. EP 0496378, Jan. 22, 1992, Himmelsbach, F. et al: describes amidino-biphenylaminocarbonylcyclohexylcarboxylic acid analogs.

EP 0503548, 16. september, 1992, Himmelsbach, F. et al.: beskriver amidino-fenylpyrrolidinon-fenylpropionsyre-analoger. EP 0503548, September 16, 1992, Himmelsbach, F. et al.: discloses amidino-phenylpyrrolidinone-phenylpropionic acid analogs.

AU A-86926/91, 7. mai, 1992, Himmelsbach, F. et al: beskriver amidinofenyl-forbindelser. AU A-86926/91, May 7, 1992, Himmelsbach, F. et al: discloses amidinophenyl compounds.

EP 0528369, 24. februar, 1993, Austel, V. et al.: beskriver amidinobifenyl-oksymetyl-2-pyrrolidinon-eddiksyre. EP 0528369, February 24, 1993, Austel, V. et al.: discloses amidinobiphenyl-oxymethyl-2-pyrrolidinone-acetic acid.

EP 0537696, 21. april, 1993, Linz, G. et al: beskriver amidinofenyl-pyridazin-analoger. EP 0537696, Apr. 21, 1993, Linz, G. et al: describes amidinophenyl-pyridazine analogs.

DE 4124942, 28. januar, 1993, Himmelsbach, F. et al: beskriver amidino-triarylpropionsyre-analoger. DE 4124942, Jan. 28, 1993, Himmelsbach, F. et al: describes amidino-triarylpropionic acid analogs.

DE 4129603, 11. mars, 1993, Pieper, H. et al: beskriver amidinobifenyl-benzimidazol. DE 4129603, March 11, 1993, Pieper, H. et al: discloses amidinobiphenyl-benzimidazole.

EP 0547517 A1, (Der 93-198544), 23. juni, 1993, Soyka, R. et al.: beskriver EP 0547517 A1, (Der 93-198544), June 23, 1993, Soyka, R. et al.: describes

pyridyl-forbindelser.pyridyl compounds.

EP 0567966, 3. november, 1993, Himmelsbach, F. et al: beskriver amidino-bifenyloksymetyl-2-pyrrolidinon-eddiksyre. EP 0567966, November 3, 1993, Himmelsbach, F. et al: discloses amidino-biphenyloxymethyl-2-pyrrolidinone-acetic acid.

EP 0567967, 3. november, 1993, Weisenberger, J. et al: beskriver amidino-bifenyloksymetyl-2-pyrrolidinon-eddiksyre. EP 0567967, November 3, 1993, Weisenberger, J. et al: discloses amidino-biphenyloxymethyl-2-pyrrolidinone-acetic acid.

EP 0567968, 3. november, 1993, Linz, G. et al.: beskriver amidinobifenyl-laktam-eddiksyre- og amidinofenyl-laktamfenylpropionsyre-analoger. EP 0574808, 11. juni, 1993, Pieper, H. et al: beskriver amidinobifenyl-X-eddiksyreester-analoger. EP 0567968, Nov. 3, 1993, Linz, G. et al.: describes amidinobiphenyl-lactam-acetic acid and amidinophenyl-lactam-phenylpropionic acid analogs. EP 0574808, June 11, 1993, Pieper, H. et al: describes amidinobiphenyl-X-acetic acid ester analogs.

Der 93-406657/51, Austel, V. et al.: beskriver amidinobifenyl-analoger.Der 93-406657/51, Austel, V. et al.: describes amidinobiphenyl analogues.

EP 58/134, (Der 94-085077/11), 16. mars, 1994, Himmerlsbach, F.D.D et al.: EP 58/134, (Der 94-085077/11), March 16, 1994, Himmerlsbach, F.D.D et al.:

beskriver amidinofenyltriazolon-analoger.describes amidinophenyltriazolone analogs.

EP 589874, 6. april, 1994, Grell, W. et al.EP 589874, April 6, 1994, Grell, W. et al.

(P534005), DE 4234295, 14. april, 1994, Pieper, H. et al. beskriver hetero-arylazacykloheksylkarboksylsyre-analoger. (P534005), DE 4234295, April 14, 1994, Pieper, H. et al. describes hetero-arylazacyclohexylcarboxylic acid analogs.

EP 0592949, 20. april, 1994, Pieper, H.D. et al., beskriver amidinofenyl-4-piperidinamido-4-cykloheksylkarboksylsyre-analoger. EP 0592949, Apr. 20, 1994, Pieper, H.D. et al., describe amidinophenyl-4-piperidinamido-4-cyclohexylcarboxylic acid analogs.

EP 596326, 11. mai, 1994, Maier, R. et al.EP 596326, May 11, 1994, Maier, R. et al.

DE 4241632, 15. juni, 1994, Himmelsbach, F. et al. beskriver piperidino-fenylamido-fenylpropionyl-analoger. DE 4241632, June 15, 1994, Himmelsbach, F. et al. describes piperidino-phenylamido-phenylpropionyl analogs.

EP 0604800 A, 6. juli, 1994, Himmelsbach, F. et al. beskriver piperidino-fenylamido-fenylalanin-derivater. EP 0604800 A, July 6, 1994, Himmelsbach, F. et al. describes piperidino-phenylamido-phenylalanine derivatives.

DE 4302051, (Der 94-235999/29), 28. juli, 1994, beskriver forbindelser som DE 4302051, (Der 94-235999/29), July 28, 1994, describes compounds which

inneholder 2H-pyrazol-5-on.contains 2H-pyrazol-5-one.

EP 0608858 A, 3. august, 1994, Linz, G.D. et al.: beskriver amidino-bifenyl-forbindelser. EP 0608858 A, August 3, 1994, Linz, G.D. et al.: describe amidino-biphenyl compounds.

DE 4304650, (Der 94-256165/32), 18. august, 1994, Austel, V. et al.: beskriver DE 4304650, (Der 94-256165/32), August 18, 1994, Austel, V. et al.: describes

forbindelser med en 5,6-templat.compounds with a 5,6 template plate.

EP 611660, 24. august, 1994, Austel, V. et al. beskriver tricyklisk templat.EP 611660, August 24, 1994, Austel, V. et al. describes tricyclic template.

DE 4305388, (Der 94-264904/33), 25. august, 1994, Himmelsbach, F. et al. DE 4305388, (Der 94-264904/33), August 25, 1994, Himmelsbach, F. et al.

beskriver 6,6- og 7,6-templater.describes 6,6 and 7,6 templates.

(P5D4005), EP 612741, (Der 94-265886/33), 31. august, 1994, Himmelsbach, F. (P5D4005), EP 612741, (Der 94-265886/33), August 31, 1994, Himmelsbach, F.

et al., beskriver 6,6- og 7,6-templater.et al., describe 6,6- and 7,6-templates.

EP 0639575 A, 22. februar, 1995, Linz, G. et al: beskriver tetrahydrotiazolo-[5,4-c]pyridin-kation erstatninger. EP 0639575 A, February 22, 1995, Linz, G. et al: describes tetrahydrothiazolo-[5,4-c]pyridine cation substitutes.

DE 4324580, 26. januar, 1995, Linz, G et al.DE 4324580, January 26, 1995, Linz, G et al.

EP 0638553, 15. februar, 1995, Himmelsbach, F. et al.EP 0638553, February 15, 1995, Himmelsbach, F. et al.

F, Himmelsbach, V. Austel, G. Kruger, H. Pieper, H. Weisenberger, T.H. Muller, F, Himmelsbach, V. Austel, G. Kruger, H. Pieper, H. Weisenberger, T.H. Muller,

og W.G. Eisert, i Xllth Int. Symp. on Med. Chem. Basel, Book of Abstracts, 47, 1992. V. Austel, W. Eisert, F. Himmelsbach, G. Kruger, G. Linz, T. Muller, H. Pieper og J. Weisenberger, Nati., Mtg. Amer. Chem. Soc. Book of Abstracts, and W.G. Claimed, in Xllth Int. Symp. on Med. Chem. Basel, Book of Abstracts, 47, 1992. V. Austel, W. Eisert, F. Himmelsbach, G. Kruger, G. Linz, T. Muller, H. Pieper and J. Weisenberger, Nati., Mtg. Amer. Chem. Soc. Book of Abstracts,

Denver, Div. Med. Chem. 1993.Denver, Div. Med. Chem. 1993.

Muller, T.H.; Schurer, H.; Waldmann, L.; Bauer, E.; Himmelsbach, F.; Muller, T.H.; Schurer, H.; Waldmann, L.; Bauer, E.; Himmelsbach, F.;

Binder, K.; Orally Activity of BIBU 104, a Prodrug of the Non-peptide Fibrinogen Receptor Antagonist BIBU 52, in Mice and Monkeys, Thromb. Haem., 69, 975, 1993. Binder, K.; Orally Activity of BIBU 104, a Prodrug of the Non-peptide Fibrinogen Receptor Antagonist BIBU 52, in Mice and Monkeys, Thromb. Haem., 69, 975, 1993.

Univ. CaliforniaUniv. of California

WO 94/14848, 7. juli, 1994, Zanetti, M. RGD-peptider fra CDR.WO 94/14848, July 7, 1994, Zanetti, M. RGD peptides from CDR.

Univ. New YorkNew York Univ

WO 94/00144, 29. juni, 1993, Ojima, I. et al. beskriver RGD-peptid multimerer. WO 94/00144, June 29, 1993, Ojima, I. et al. describes RGD peptide multimers.

Yeda Res. and Dev. Co.Yeda Res. and Dev. Co.

WO 93/09795, (Der 93-182236/22), Lido, 0. et al: beskriver guanidino-pentansyre-analoger. WO 93/09795, (Der 93-182236/22), Lido, 0. et al: describes guanidino-pentanoic acid analogues.

ZenecaZeneca

WO 9422834, 13. oktober, 1994, Wayne, M.G. et al. beskriver pyridino-piperazino-fenylkarbonyl-aminosyrer. WO 9422834, October 13, 1994, Wayne, M.G. et al. describes pyridino-piperazino-phenylcarbonyl-amino acids.

WO 9422835, 13. oktober, 1994, Wayne, M.G. et al: beskriver pyridino-piperidinoamidofenyleddiksyrer. WO 9422835, October 13, 1994, Wayne, M.G. et al: describes pyridino-piperidinoamidophenylacetic acids.

EP 632016, 4. januar, 1995, Brewster, A.G. et al. beskriver pyridino-propionylhydrazinylbenzoyl-analoger. EP 632016, January 4, 1995, Brewster, A.G. et al. describes pyridino-propionylhydrazinylbenzoyl analogs.

EO 632019, 4. januar, 1995, Brown, G., Shute, R.E.EO 632019, January 4, 1995, Brown, G., Shute, R.E.

EO 632020, 4. januar, 1995, Brown, G., Shute, R.E.EO 632020, January 4, 1995, Brown, G., Shute, R.E.

I de tilfeller forbindelsene ifølge oppfinnelsen har ett eller flere chirale sentra, inkluderer oppfinnelsen, med mindre annet er angitt, enhver ikke-racemisk forbindelse som kan syntetiseres og spaltes ved konvensjonell teknikk. I tilfelle forbindelsene har umettede karbon-karbon dobbeltbindinger faller både cis (Z) og trans (E) isomerer innenfor oppfinnelsens ramme. Betydningen av en substituent ved en hvilken som helst forekomst, er uavhengig av dens betydning, eller en hvilken som helst annen substituents betydning, ved en hvilken som helst annen forekomst. In those cases where the compounds of the invention have one or more chiral centers, the invention includes, unless otherwise indicated, any non-racemic compound which can be synthesized and resolved by conventional techniques. If the compounds have unsaturated carbon-carbon double bonds, both cis (Z) and trans (E) isomers fall within the scope of the invention. The meaning of a substituent at any one occurrence is independent of its meaning, or the meaning of any other substituent, at any other occurrence.

Forkortelser og symboler som vanligvis benyttes innen peptidkjemien og andre kjemiske områder, er her benyttet for å beskrive forbindelsene ifølge oppfinnelsen. I alminnelighet er de aminosyreforkortelser som følger IUPAC-IUB Joint Commission on Biochemical Nomenclature, slik den beskrevet i Eur. J. Biochem., 158, 9(1984). Abbreviations and symbols that are usually used in peptide chemistry and other chemical areas are used here to describe the compounds according to the invention. In general, they are amino acid abbreviations that follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature, as described in Eur. J. Biochem., 158, 9(1984).

Ci-4-alkyl betyr i denne sammenheng en eventuelt substituert alkylgruppe med 1 til 4 karbonatomer og inkluderer metyl, etyl, n-propyl, isopropyl, n-butyl, isobutyl og t-butyl. Ci-e-alkyl inkluderer dessuten pentyl, n-pentyl, isopentyl, neopentyl og heksyl og de enkle alifatiske isomerer derav. Co-4-alkyl og Co-e-alkyl indikerer dessuten at det ikke behøver forekomme noen alkylgruppe (f.eks. at det foreligger en kovalent binding). C1-4-alkyl in this context means an optionally substituted alkyl group with 1 to 4 carbon atoms and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl. C 1-6 alkyl also includes pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof. Co-4-alkyl and Co-e-alkyl also indicate that no alkyl group needs to be present (e.g. that a covalent bond exists).

Enhver Ci.4-alkyl- eller Ci-e-alkyl-, C2-e-alkenyl-, C2-e-alkynyl- eller Ci^-oksoalkylgruppe kan eventuelt være substituert med gruppen Rx på et hvilket som helst karbonatom som resulterer i en stabil struktur og som er tilgjengelig via konvensjonell synteseteknikk. Egnede grupper for Rx er Ci-4-alkyl, OR<1>, SR<1>, Cm-alkyl, Ci-4-alkylsulfonyl, C^-alkylsulfoksyl, -CN, N(R<1>)2, CH2N(R<1>)2, -N02, -CF3, -C02R'<3>, -CON(R<1>)2, -COR<1>, -NR<1>C(0)R<1>, OH, F, Cl, Br, I eller CF3S(0)r-, hvor r er 0 til 2. Any C1-4 alkyl or C1-e alkyl, C2-e alkenyl, C2-e alkynyl or C1-4 oxoalkyl group may be optionally substituted with the group Rx on any carbon atom resulting in a stable structure and which is accessible via conventional synthesis techniques. Suitable groups for Rx are C1-4-alkyl, OR<1>, SR<1>, Cm-alkyl, C1-4-alkylsulfonyl, C1-4-alkylsulfoxyl, -CN, N(R<1>)2, CH2N( R<1>)2, -N02, -CF3, -C02R'<3>, -CON(R<1>)2, -COR<1>, -NR<1>C(0)R<1>, OH, F, Cl, Br, I or CF3S(0)r-, where r is 0 to 2.

Ar, eller aryl, betyr her fenyl eller naftyl, eller fenyl eller naftyl substituert med én til tre substituenter, så som de som ovenfor er definert for alkyl, spesielt Ci^-alkyl, d-4-alkoksy, Ci.4-alkyltio, trifluoralkyl, OH, F, Cl, Br eller I. Ar, or aryl, here means phenyl or naphthyl, or phenyl or naphthyl substituted with one to three substituents, such as those defined above for alkyl, especially C 1-4 -alkyl, C 1-4 -alkyl, C 1-4 -alkylthio, trifluoroalkyl, OH, F, Cl, Br or I.

Het, eller heterocyklus, angir en eventuelt substituert fem- eller seks-leddet monocyklisk ring, eller en ni- eller ti-leddet bicyklisk ring som inneholder ett til tre heteroatomer valgt fra gruppen nitrogen, oksygen og svovel, og som er stabile og tilgjengelige via konvensjonell kjemisk syntese. Eksempler på heterocykler er benzfuryl, benzimidazol, benzopyran, benzotiofen, furan, imidazol, indolin, morfolin, piperidin, piperazin, pyrrol, pyrrolidin, tetrahydropyridin, pyridin, tiazol, tiofen, kinolin, isokinolin, og tetra- og perhydrokinolin og isokinolin. En hvilken som helst tilgjengelig kombinasjon av opp til tre substituenter på Het-ringen, som de som ovenfor er definert for alkyl og som er tilgjengelige gjennom kjemisk syntese og er stabile, ligger innenfor oppfinnelsens ramme. Het, or heterocycle, denotes an optionally substituted five- or six-membered monocyclic ring, or a nine- or ten-membered bicyclic ring containing one to three heteroatoms selected from the group of nitrogen, oxygen and sulphur, and which are stable and accessible via conventional chemical synthesis. Examples of heterocycles are benzfuryl, benzimidazole, benzopyran, benzothiophene, furan, imidazole, indoline, morpholine, piperidine, piperazine, pyrrole, pyrrolidine, tetrahydropyridine, pyridine, thiazole, thiophene, quinoline, isoquinoline, and tetra- and perhydroquinoline and isoquinoline. Any available combination of up to three substituents on the Het ring, such as those defined above for alkyl and which are accessible through chemical synthesis and are stable, is within the scope of the invention.

C3.7-cykloalkyl refererer seg til et eventuelt substituert karbocyklisk system med tre til syv karbonatomer som kan inneholde opp til to umettede karbon-karbon-bindinger. Typiske C3.7-cykloalkylgrupper er cyklopropyl, cyklobutyl, cyklopentyl, cyklopentenyl, cykloheksyl, cykloheksenyl og cykloheptyl. En hvilken som helst kombinasjon av opp til tre substituenter, som f.eks. de som ovenfor er definert for alkyl, på cykloalkylringen og som er tilgjengelig gjennom konvensjonell kjemisk syntese og er stabile, ligger innenfor oppfinnelsens ramme. C3.7-cycloalkyl refers to an optionally substituted carbocyclic system with three to seven carbon atoms which may contain up to two unsaturated carbon-carbon bonds. Typical C3.7 cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and cycloheptyl. Any combination of up to three substituents, such as those defined above for alkyl, on the cycloalkyl ring and which are available through conventional chemical synthesis and are stable, are within the scope of the invention.

Når Rb og R<c>er koblet sammen under dannelse av en fem- eller seks-leddet aromatisk eller ikke-aromatisk karbocyklisk eller heterocyklisk ring kondensert til ringen som Rb og R<c>er knyttet til, vil den resulterende ring i alminnelighet være en fem- eller seks-leddet heterocyklus valgt blant dem som ovenfor er angitt for Het, eller utgjøre en fenyl-, cykloheksyl- eller cyklopentyl-ring. Fortrinnsvis vil Rb og R<c>være -D1=D2-D3=D4, hvor D1 - D4 uavhengig av hverandre er CH, N eller C-Rx med det forbehold at ikke mer enn to av D1 - D4 er N. Helst danner R<b>og R<c>ved sammenkobling gruppen CH=CH-CH=CH- When Rb and R<c>are linked together to form a five- or six-membered aromatic or non-aromatic carbocyclic or heterocyclic ring fused to the ring to which Rb and R<c>are attached, the resulting ring will generally be a five- or six-membered heterocycle selected from those indicated above for Het, or form a phenyl, cyclohexyl or cyclopentyl ring. Preferably Rb and R<c> will be -D1=D2-D3=D4, where D1 - D4 independently of each other are CH, N or C-Rx with the proviso that no more than two of D1 - D4 are N. Preferably form R<b>and R<c>when connecting the group CH=CH-CH=CH-

Enkelte radikalgrupper er her forkortet. t-Bu refererer seg til det tertiære butylradikal, Boe refererer seg til t-butyloksykarbonylradikalet, Fmoc refererer seg til fluorenylmetoksykarbonylradikalet, pH refererer seg til fenylradikalet, Cbz refererer seg til benzyloksykarbonylradikalet, BrZ refererer seg til o-brombenzyloksy-karbonylradikalet, CIZ refererer seg til o-klorbenzyloksykarbonylradikalet, Bzl refererer seg til benzylradikalet, 4-MBzl refererer seg til 4-metyl-benzylradikalet, Me refererer seg til metyl, Et refererer seg til etyl, Ac refererer seg til acetyl, Alk refererer seg til Ci-4-alkyl, Nph refererer seg til 1- eller 2-naftyl og cHex refererer seg til cykloheksyl. Tet refererer seg til 5-tetrazolyl. Certain radical groups are abbreviated here. t-Bu refers to the tertiary butyl radical, Boe refers to the t-butyloxycarbonyl radical, Fmoc refers to the fluorenylmethoxycarbonyl radical, pH refers to the phenyl radical, Cbz refers to the benzyloxycarbonyl radical, BrZ refers to the o-bromobenzyloxycarbonyl radical, CIZ refers to the o-chlorobenzyloxycarbonyl radical, Bzl refers to the benzyl radical, 4-MBzl refers to the 4-methyl-benzyl radical, Me refers to methyl, Et refers to ethyl, Ac refers to acetyl, Alk refers to C 1-4 alkyl, Nph refers to 1- or 2-naphthyl and cHex refers to cyclohexyl. Tet refers to 5-tetrazolyl.

Enkelte reagenser er her forkortet. DCC refererer seg til dicykloheksylkarbodiimid, DMAP refererer seg til dimetylaminopyridin, DIEA refererer seg til diisopropyletylamin, EDC refererer seg til 1-(3-dimetylaminopropyl)-3-etylkarbodiimid-hydroklorid, HOBt refererer seg til 1-hydroksybenzotriazol, THF refererer seg til tetrahydrofuran, DIEA refererer seg til diisopropyletylamin, DME refererer seg til dimetoksyetan, DMF refererer seg til dimetylformamid, NBS refererer seg til N-bromsuccinimid, Pd/C refererer seg til palladium på kull katalysator, PPA refererer seg til 1-propanfosfonsyre-cyklisk anhydrid, DPPA refererer seg til difenylfosforylazid, BOP refererer seg til benzotriazol-1-yloksytris(dimetylamino)fosfonium-heksafluorfosfat, HF refererer seg til hydrogenfluoridsyre, TEA refererer seg til trietylamin, TFA refererer seg til trifluroeddiksyre, PCC refererer seg til pyridinium-klorkromat. Certain reagents are abbreviated here. DCC refers to dicyclohexylcarbodiimide, DMAP refers to dimethylaminopyridine, DIEA refers to diisopropylethylamine, EDC refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, HOBt refers to 1-hydroxybenzotriazole, THF refers to tetrahydrofuran, DIEA refers to diisopropylethylamine, DME refers to dimethoxyethane, DMF refers to dimethylformamide, NBS refers to N-bromosuccinimide, Pd/C refers to palladium on carbon catalyst, PPA refers to 1-propanephosphonic acid cyclic anhydride, DPPA refers to refers to diphenylphosphoryl azide, BOP refers to benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, HF refers to hydrofluoric acid, TEA refers to triethylamine, TFA refers to trifluoroacetic acid, PCC refers to pyridinium chlorochromate.

Forbindelser med formel (l)-(V) fremstilles for eksempel ved å omsette en forbindelse med formel (XIX) med en forbindelse med formel (XX), hvor L<1>og L2 er grupper som kan reagere under dannelse av en kovalent binding i delen W, ved hjelp av alminnelig kjente metoder. Compounds of formula (l)-(V) are prepared, for example, by reacting a compound of formula (XIX) with a compound of formula (XX), where L<1> and L2 are groups that can react to form a covalent bond in part W, using commonly known methods.

Typiske metoder inkluderer kobling under dannelse av amid-bindinger, nukleofile substitusjonsreaksjoner og palladium katalyserte koblinger. Når W for eksempel inneholder en eter- eller amin-binding, kan bindingen dannes ved en fortrengningsreaksjon, idet den ene av L<1>og L<2>vil inneholde en amino- eller hydoksygruppe og den andre vil inneholde en gruppe som kan fortrenges, så som en klor-, brom- eller jodgruppe. Når W inneholder en amid-binding, vil L<1>og L<2>, f.eks. inneholde en aminogruppe, og den andre inneholde en karboksylsyregruppe. I en annen sammenheng kan L<1>være et aryl- eller heteroaryl-bromid, -jodid eller trifluormetylsulfonylsoksyderivat, og L<2>kan inneholde en aminogruppe og amid-bindingen dannes ved palladium katalysert aminokarbonylering med karbon-monooksyd i et egnet løsningsmiddel, som f.eks. dimetylformamid eller toluen. Typical methods include coupling to form amide bonds, nucleophilic substitution reactions, and palladium-catalyzed couplings. When W, for example, contains an ether or amine bond, the bond can be formed by a displacement reaction, as one of L<1> and L<2> will contain an amino or hydroxy group and the other will contain a group that can be displaced , such as a chlorine, bromine or iodine group. When W contains an amide bond, L<1> and L<2>, e.g. contain an amino group, and the other contain a carboxylic acid group. In another context, L<1> can be an aryl or heteroaryl bromide, iodide or trifluoromethylsulfonyloxy derivative, and L<2> can contain an amino group and the amide bond is formed by palladium-catalyzed aminocarbonylation with carbon monoxide in a suitable solvent, like for example. dimethylformamide or toluene.

Den nøyaktige identitet av L<1>og L<2>vil selvsagt avhenge av hvilket sted bindingen dannes. Generelle metoder for fremstilling av bindingen (CHR")r-U-(CHR")s-V- er beskrevet, for eksempel i EP-A 0 372 486 og EP-A 0 381 033 og EP-A 0 478 363, som herved med hele sitt innhold inkorporeres i foreliggende beskrivelse. The exact identity of L<1> and L<2> will of course depend on where the bond is formed. General methods for the preparation of the bond (CHR")r-U-(CHR")s-V- are described, for example in EP-A 0 372 486 and EP-A 0 381 033 and EP-A 0 478 363, which hereby in their entirety content is incorporated into the present description.

Dersom for eksempel V er CONH, kan L<1>være -NH2, L2 være OH (som i en syre) eller Cl (som i et syreklorid), og R<6>" kan være For example, if V is CONH, L<1> can be -NH2, L2 can be OH (as in an acid) or Cl (as in an acid chloride), and R<6>" can be

W-(CR'2)q-Z-(CR'R<10>)rU-(CR'2)s-C(O), hvor funksjonelle grupper eventuelt er beskyttet. For eksempel kan R<6>" være (benzyloksykarbonyl-amidino)benzoyl- eller (Na<->Boc,N<9uan->Tos)arginyl-. Når L2 er OH, benyttes et koblingsmiddel. W-(CR'2)q-Z-(CR'R<10>)rU-(CR'2)s-C(O), where functional groups are optionally protected. For example, R<6>" can be (benzyloxycarbonyl-amidino)benzoyl- or (Na<->Boc,N<9uan->Tos)arginyl-. When L2 is OH, a coupling agent is used.

Dersom V er NHCO, kan L<1>være -C02H eller CO-CI, L2 kan være -NH2og R<6>" kan være W-(CR,2)q-Z-(CR,R<10>)r-U-(CR'2)s-. For eksempel kan R6" være (benzyloksykarbonyl-amidino)fenyl, (benzyloksykarbonylamino)metylbenzyl- eller 6-(benzyloksykarbonylamino)heksyl-. If V is NHCO, L<1> can be -CO2H or CO-CI, L2 can be -NH2 and R<6>" can be W-(CR,2)q-Z-(CR,R<10>)r-U-( CR'2)s-. For example, R6" can be (benzyloxycarbonylamidino)phenyl, (benzyloxycarbonylamino)methylbenzyl- or 6-(benzyloxycarbonylamino)hexyl-.

Når W er NHS02) kan L<1>være S02CI, L<2>kan være -NH2og R<6>" kan være som ovenfor. Når V er S02NH, kan være L<1>være -NH2og L2 være S02CI. Fremstillingsmetoder for slike sulfonylklorider er omtalt for eksempel i J. Org. Chem. 23, 1257 (1958). When W is NHS02) L<1> can be SO2Cl, L<2> can be -NH2 and R<6>" can be as above. When V is SO2NH, L<1> can be -NH2 and L2 can be SO2CI. Methods of Preparation for such sulfonyl chlorides is discussed, for example, in J. Org. Chem. 23, 1257 (1958).

Om V er CH=CH, kan L<1>være -CHO, L2 kan være CH=P-Ph3og R<6>" kan være W-(CR'2)q-Z-(CR,R<10>)r-U-(CR,2)s. Alternativt kan L<1>være CH=P-Ph3, L<2>være f.eks. CHO, R<6>" være W-(CR'2)q-Z-(CR,R<10>)r-U-(CR,2)s-rCHO. If V is CH=CH, L<1> can be -CHO, L2 can be CH=P-Ph3 and R<6>" can be W-(CR'2)q-Z-(CR,R<10>)r-U- (CR,2)p. Alternatively, L<1> can be CH=P-Ph3, L<2> can be e.g. CHO, R<6>" can be W-(CR'2)q-Z-(CR,R <10>)r-U-(CR,2)s-rCHO.

Dersom V er CH2CH2kan gruppen oppnås ved reduksjon av en passende beskyttet forbindelse hvor V er CH=CH. If V is CH2CH2, the group can be obtained by reduction of a suitable protected compound where V is CH=CH.

Dersom V er CH20, CH2N eller C=C, kan L<1>være henholdsvis -OH, -NH eller -ChCH; L<2>kan være -Br og R<6>' kan være W-(CR,2)q-Z-(CR'R10)r-U-(CR,2)8-. For eksempel kan R6" være (benzyloksykarbonylamino)metylbenzyl- eller 2-(N-benzyl-4-piperidinyl)-etyl. Dersom U eller V er OCH2lNR'CH2eller C=C, kan L<1>være -CH2Br og L<2>være henholdsvis -OH, -NH eller -C=CH. Alternativt når U eller V er C=C, kan L<1>være Br, I eller CF3S03, L2 være C=CH og koblingen katalyseres med palladium og en base. If V is CH2O, CH2N or C=C, L<1> can be -OH, -NH or -ChCH respectively; L<2> can be -Br and R<6>' can be W-(CR,2)q-Z-(CR'R10)r-U-(CR,2)8-. For example, R6" can be (benzyloxycarbonylamino)methylbenzyl- or 2-(N-benzyl-4-piperidinyl)-ethyl. If U or V is OCH21NR'CH2 or C=C, L<1> can be -CH2Br and L<2 >be respectively -OH, -NH or -C=CH Alternatively when U or V is C=C, L<1>can be Br, I or CF 3 SO 3 , L 2 is C=CH and the coupling is catalysed with palladium and a base.

Forbindelser hvor V er CHOHCH2kan fremstilles fra en passende beskyttet forbindelse hvor V er CH=CHetter fremgangsmåten omtalt i J. Org. Chem. 54,1354 Compounds where V is CHOHCH 2 can be prepared from a suitably protected compound where V is CH=CH following the procedure described in J. Org. Chem. 54.1354

(1989). (1989).

Forbindelser hvor V er CH2CHOH kan oppnås fra en passende beskyttet forbindelse hvor V er CH=CH, ved hydroborering og basisk oksydasjon som omtalt i Tet. Lett, 31, 231 (1990). Compounds where V is CH2CHOH can be obtained from a suitably protected compound where V is CH=CH, by hydroboration and basic oxidation as discussed in Tet. Lett, 31, 231 (1990).

Forbindelser med formel (l)-(V), hvor fibrinogen-reseptorantagonist-templaten har formel (VI), fremstilles etter de generelle metoder beskrevet i Reaksjonsskjema l-lll. Compounds of formula (l)-(V), where the fibrinogen receptor antagonist template has formula (VI), are prepared according to the general methods described in Reaction Schemes 1-lll.

a) EDC, HOBT, (i-Pr)2NEt, DM F, 2-aminometylbenzimidazol: a) EDC, HOBT, (i-Pr)2NEt, DM F, 2-aminomethylbenzimidazole:

b) SOCI2, tilbakeløpsbehandling; c) 2-aminobenzimidazol, pyridin, CH2CI2; d) 1,0 N LiOH, vandig THF; e) surgjøring. b) SOCI2, reflux treatment; c) 2-aminobenzimidazole, pyridine, CH2Cl2; d) 1.0 N LiOH, aqueous THF; e) acidification.

Metyl(±)-7-karboksy-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (1-1), fremstillet som beskrevet av Bondinell, et al. (WO 93/00095), omdannes til en aktivert form av karboksylsyren ved for eksempel å benytte EDC og HOBT eller SOCI2, hvorpå den aktiverte form omsettes med et passende amin for å gi det tilsvarende amid I-2. Det er dessuten kjent mange andre metoder for å omdanne en karboksylsyre til et amid, og slike er beskrevet i standard oppslagsverker som f.eks. "Compendium of Organic Synthetic Methods", Bd. I-VI Methyl(±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (1-1), prepared as described by Bondinell, et al. (WO 93/00095), is converted to an activated form of the carboxylic acid by, for example, using EDC and HOBT or SOCI2, whereupon the activated form is reacted with a suitable amine to give the corresponding amide I-2. Many other methods are also known for converting a carboxylic acid into an amide, and such are described in standard reference works such as e.g. "Compendium of Organic Synthetic Methods", Vols I-VI

(publisert av Wiley-lnterscience). Metylesteren av 1-2 hydrolyseres ved å benytte en vandig base, som for eksempel vandig LiOH i THF eller vandig NaOH i metanol og det intermediære karboksylatsalt surgjøres med en passende syre, for eksempel TFA eller HCI, for å gi karboksylsyren 1-3. Om ønskes kan det intermediære karboksylatsalt alternativt isoleres. (published by Wiley-lnterscience). The methyl ester of 1-2 is hydrolyzed using an aqueous base, such as aqueous LiOH in THF or aqueous NaOH in methanol, and the intermediate carboxylate salt is acidified with an appropriate acid, such as TFA or HCl, to give the carboxylic acid 1-3. If desired, the intermediate carboxylate salt can alternatively be isolated.

a) (BOC)20, DMAP, CH3CN; b) SOCI2, toluen, 70°C; c) H2, 10% Pd/C, 2,6-lutidin, THF; d) 2-(aminometyl)benzimidazol, NaBH3CN, MeOH; e) formaldehyd, NaBH3CN, AcOH, CH3CN; f) LiOH, THF, H20; a) (BOC) 2 O, DMAP, CH 3 CN; b) SOCI 2 , toluene, 70°C; c) H 2 , 10% Pd/C, 2,6-lutidine, THF; d) 2-(aminomethyl)benzimidazole, NaBH3CN, MeOH; e) formaldehyde, NaBH3CN, AcOH, CH3CN; f) LiOH, THF, H 2 O;

g) surgjøring.g) acidification.

Omdannelse av karboksylsyredelen av l-Reaksjonsskjema II til et aldehyd Conversion of the carboxylic acid part of l-Reaction scheme II to an aldehyde

kan oppnås ved standard metodikk som beskrevet i "Compendium of Organic Synthetic Methods", (publisert av Wiley-lnterscience). Etter beskyttelse av anilin-nitrogenet som dets tert-butylkarbamat, omdannes for eksempel karboksylsyren til det tilsvarende syreklorid med et passende reagens, så som tionylklorid. Tert-butylkarbamatet går under disse betingelsene tapt. Det resulterende syreklorid reduseres deretter til aldehyd 3-Reaksjonsskjema II ved hydrogenering over en passende katalysator som for eksempel palladium på kull, i nærvær av 2,6-lutidin. Aldehydet 3-Reaksjonsskjema II omdannes deretter til aminet 4-Reaksjonsskjema II ved omsetning med 2-(aminometyl)benzimidazol i nærvær av et passende reduksjonsmiddel, som f.eks. natriumcyanoborhydrid. Alternative metoder for å omdanne et aldehyd til et amin er beskrevet i "Compendium of Organic Synthetic Methods", (publisert av Wiley-lnterscience). Det basiske nitrogenatom i 4- Reaksjonsskjema II metyleres under modifiserte Eschweiler-Clarke-betingelser (SondeTigam. B.L. et al. Tetrahedron Letters 1973, 261; Borsch, R.F.; Hassid, A.l. J. Org. Chem. 1972, 37, 1673). Omsetningen av 4-Reaksjonsskjema II med formaldehyd i nærvær av et passende reduksjonsmiddel som f.eks. cyanoborhydrid gir deretter 5-Reaksjonsskjema II. Forsåpning av metylesteren av 5- Reaksjonsskjema II etter tidligere beskrevne metoder gir 6-Reaksjonsskjema II. Metylesteren av 4-Reaksjonsskjema II kan spaltes på lignende måte. can be obtained by standard methodology as described in "Compendium of Organic Synthetic Methods", (published by Wiley-lnterscience). For example, after protection of the aniline nitrogen as its tert-butylcarbamate, the carboxylic acid is converted to the corresponding acid chloride with a suitable reagent, such as thionyl chloride. The tert-butyl carbamate is lost under these conditions. The resulting acid chloride is then reduced to the aldehyde 3-Reaction scheme II by hydrogenation over a suitable catalyst such as palladium on charcoal, in the presence of 2,6-lutidine. The aldehyde 3-Reaction scheme II is then converted to the amine 4-Reaction scheme II by reaction with 2-(aminomethyl)benzimidazole in the presence of a suitable reducing agent, such as e.g. sodium cyanoborohydride. Alternative methods for converting an aldehyde to an amine are described in "Compendium of Organic Synthetic Methods", (published by Wiley-lnterscience). The basic nitrogen atom in 4- Reaction scheme II is methylated under modified Eschweiler-Clarke conditions (SondeTigam. B.L. et al. Tetrahedron Letters 1973, 261; Borsch, R.F.; Hassid, A.l. J. Org. Chem. 1972, 37, 1673). The reaction of 4-Reaction scheme II with formaldehyde in the presence of a suitable reducing agent such as e.g. cyanoborohydride then gives 5-Reaction scheme II. Saponification of the methyl ester of 5-Reaction scheme II according to previously described methods gives 6-Reaction scheme II. The methyl ester of 4-Scheme II can be cleaved in a similar manner.

a) NCS, DMF, 80°C; . a) NCS, DMF, 80°C; .

b) Se Reaksjonsskjema 1.b) See Reaction form 1.

Halogenering av den aromatiske delen av 1-Reaksjonsskjema III kan oppnås Halogenation of the aromatic part of 1-Reaction scheme III can be achieved

med et passende elektrofilt halogeneringsreagens, så som N-klorsuccinimid. Det resulterende klorerte derivat, 2-Reaksjonsskjema III, omdannes deretter til 3-Reaksjonsskjema III etter de metoder som er beskrevet i Reaksjonsskjema I. with a suitable electrophilic halogenating reagent, such as N-chlorosuccinimide. The resulting chlorinated derivative, 2-Reaction scheme III, is then converted to 3-Reaction scheme III according to the methods described in Reaction scheme I.

Den 6-7-kondenserte ringsystem-kjerne fremstilles av forbindelse (VI) etter velkjente metoder, f.eks. Hynes, et al., J. Het. Chem. 1988, 25, 1173; Muller, et al., Heiv. Chim. Acta., 1982, 65,2118; Mori, et al. Heterocycles, 1981, 16,1491. Likeledes er fremgangsmåter for fremstilling av benzazepiner, 1,4-benzotiazepiner, 1,4-benzoksazepiner og 1,4-benzodiazepiner kjent og omtalt for eksempel av Bondinell, et al. International Patent Application WO 93/00095. The 6-7-fused ring system core is prepared from compound (VI) by well-known methods, e.g. Hynes, et al., J. Het. Chem. 1988, 25, 1173; Muller, et al., Heiv. Chim. Acta., 1982, 65, 2118; Mori et al. Heterocycles, 1981, 16, 1491. Likewise, methods for the production of benzazepines, 1,4-benzothiazepines, 1,4-benzoxazepines and 1,4-benzodiazepines are known and discussed, for example, by Bondinell, et al. International Patent Application WO 93/00095.

En representativ metode for fremstilling av benzodiazepin-kjemene er angitt i Reaksjonsskjema IV og V. En representativ metode for fremstilling av en benzazepin-kjerne er angitt i Reaksjonsskjema VI. En representativ metode for fremstilling av et benzotiazepin er angitt i Reaksjonsskjema VII. En benzoksazepin-kjeme kan fremstilles på samme måte som i Reaksjonsskjema VII bortsett fra at en benzylalkohol benyttes i stedet for et benzyltiol. A representative method for the preparation of the benzodiazepine nuclei is given in Reaction Schemes IV and V. A representative method for the preparation of a benzazepine nucleus is given in Reaction Scheme VI. A representative method for the preparation of a benzothiazepine is indicated in Reaction Scheme VII. A benzoxazepine ring can be prepared in the same way as in Reaction Scheme VII except that a benzyl alcohol is used instead of a benzyl thiol.

De enkle tri-substituerte benzen-utgangsmaterialene er kommersielt tilgjengelige eller fremstilles etter velkjente rutinemetoder. The simple tri-substituted benzene starting materials are commercially available or prepared by well-known routine methods.

Reaksjonsskjema VIII-XI illustrerer fremgangsmåter for fremstilling av visse forbindelser ifølge foreliggende oppfinnelse. I Reaksjonsskjema VIII-X fremstilles en kovalent binding av gruppen W ved en nukleofil fortrengningsreaksjon. Reaction schemes VIII-XI illustrate methods for the preparation of certain compounds according to the present invention. In Reaction scheme VIII-X, a covalent bond of the group W is produced by a nucleophilic displacement reaction.

I Reaksjonsskjema VIII N-beskyttes 4-[2-(metylamino)acetyl]fenol-hydroklorid (Reel. Trav. Chim. Pays-Bas 1949, 68, 960) med en passende nitrogen-beskyttende gruppe, så som en tert-butoksykarbonyl(BOC)-gruppe for å gi det N-beskyttede derivatet 2-Reaksjonsskjema VIII. In Reaction Scheme VIII, 4-[2-(methylamino)acetyl]phenol hydrochloride (Reel. Trav. Chim. Pays-Bas 1949, 68, 960) is N-protected with a suitable nitrogen-protecting group, such as a tert-butoxycarbonyl ( BOC) group to give the N-protected derivative 2-Reaction Scheme VIII.

a) (BOC)20, NaOH, 1,4-dioksan, H20; b) BrCH2C02Bn, K2C03, aceton; c) 4M HCI i 1,4-dioksan; d) 2-(klormetyl)benzimidazol, Et3N, CH3CN, CH2CI2; a) (BOC) 2 O, NaOH, 1,4-dioxane, H 2 O; b) BrCH2CO2Bn, K2CO3, acetone; c) 4M HCl in 1,4-dioxane; d) 2-(chloromethyl)benzimidazole, Et3N, CH3CN, CH2Cl2;

e) H2, 5% Pd/C, MeOHe) H 2 , 5% Pd/C, MeOH

Det kan velges andre vanlige nitrogen-beskyttende grupper, som f.eks. beskrevet i Greene "Protective Groups in Organic Synthesis", slik at den anvendte beskyttelsesgruppe passer for den påfølgende kjemiske omsetning og kan fjernes selektivt under betingelser som ikke griper inn i molekylets øvrige funksjoner. Alkylering av fenyldelen av forbindelse 2-Reaksjonsskjema VIII for å oppnå aryloksy-eddiksyre-derivatet 3-Reaksjonsskjema VIII kan oppnås ved omsetning med en halogen-eddiksyreester, for eksempel benzylbromacetat, under basiske betingelser i et nøytralt løsningsmiddel. Generelt gir K2C03i kokende aceton eller 2-butanon, akseptable resultater, men andre baser som Li2C03eller Cs2C03, og andre løsningsmidler som DMF, THF eller DME, kan også benyttes. Den nitrogen-beskyttende gruppe i 3-Reaksjonsskjema VIII fjernes under betingelser som egner seg for selektiv avbeskyttelse av den bestemte beskyttelsesgruppe som er benyttet. For eksempel kan BOC-gruppen i 3-Reaksjonsskjema VIII fjernes under sure betingelser, så som 4 M HCI i 1,4-dioksan eller TFA i CH2CI2, for å oppnå amin-4- Reaksjonsskjema VIII som det tilsvarende ammoniumsalt. Omdannelse av forbindelse 4-Reaksjonsskjema VIII til bis-benzimidazol-derivatet 5- Reaksjonskjema VIII kan oppnås ved alkylering med 2-(klormetyl)benzimidazol i en løsningsmiddelblanding av CH3CN og CH2CI2i nærvær av Et3N. Etterfølgende fjerning av estergruppen fra forbindelse 5-Reaksjonsskjema VIII under passende betingelser, gir forbindelse 6-Reaksjonsskjema VIII. Betingelsene som velges for fjerning av esteren må passe for de bestemte esterne som foreligger, så vel som være forenelige med molekylets øvrige funksjoner. Eksempelvis kan benzylesteren i 5-Reaksjonsskjema VIII fjernes ved hydrogenolyse i nærvær en av passende katalysator, som f.eks. Pd på kull, i et inert løsningsmiddel, i alminnelighet MeOH, EtOH, eller eddiksyre, for å oppnå 6-Reaksjonsskjema VIII. Other common nitrogen-protecting groups can be chosen, such as e.g. described in Greene "Protective Groups in Organic Synthesis", so that the protective group used is suitable for the subsequent chemical reaction and can be removed selectively under conditions that do not interfere with the molecule's other functions. Alkylation of the phenyl part of compound 2-Scheme VIII to obtain the aryloxy-acetic acid derivative 3-Scheme VIII can be achieved by reaction with a haloacetic acid ester, for example benzyl bromoacetate, under basic conditions in a neutral solvent. Generally, K 2 CO 3 in boiling acetone or 2-butanone gives acceptable results, but other bases such as Li 2 CO 3 or Cs 2 CO 3 , and other solvents such as DMF, THF or DME, can also be used. The nitrogen protecting group in 3-Reaction Scheme VIII is removed under conditions suitable for selective deprotection of the particular protecting group used. For example, the BOC group in 3-Scheme VIII can be removed under acidic conditions, such as 4 M HCl in 1,4-dioxane or TFA in CH 2 Cl 2 , to obtain the amine-4-Scheme VIII as the corresponding ammonium salt. Conversion of compound 4-Reaction scheme VIII to the bis-benzimidazole derivative 5- Reaction scheme VIII can be achieved by alkylation with 2-(chloromethyl)benzimidazole in a solvent mixture of CH3CN and CH2CI2 in the presence of Et3N. Subsequent removal of the ester group from compound 5-Scheme VIII under appropriate conditions yields compound 6-Scheme VIII. The conditions chosen for removal of the ester must be suitable for the specific esters present, as well as being compatible with the other functions of the molecule. For example, the benzyl ester in 5-Reaction scheme VIII can be removed by hydrogenolysis in the presence of a suitable catalyst, such as e.g. Pd on charcoal, in an inert solvent, generally MeOH, EtOH, or acetic acid, to obtain 6-Reaction Scheme VIII.

I Reaksjonsskjema IX N-beskyttes kommersielt tilgjengelig adrenolon-hydroklorid (1-Reaksjonsskjema 2) som omtalt i Reaksjonsskjema I for å oppnå Cbz-derivatet 2-Reaksjonskjema II. In Reaction scheme IX, commercially available adrenolone hydrochloride (1-Reaction scheme 2) is N-protected as discussed in Reaction scheme I to obtain the Cbz derivative 2-Reaction scheme II.

a) CbzCI, NaOH, toluen, H20; b) BrCH2C02CH3, K2C03, aceton; c) H2, 10% Pd/C, EtOAc, MeOH; d) 2-(klormetyl)benzimidazol, Et3N, CH3CN, CH2CI2; a) CbzCl, NaOH, toluene, H 2 O; b) BrCH2CO2CH3, K2CO3, acetone; c) H 2 , 10% Pd/C, EtOAc, MeOH; d) 2-(chloromethyl)benzimidazole, Et3N, CH3CN, CH2Cl2;

e) 1,0 N LiOH, THF, H20.e) 1.0 N LiOH, THF, H 2 O.

Dialkylering av 2-Reaksjonsskjema IX ved reaksjon med en halogen-eddiksyreester, for eksempel metylbromacetatet, gir under basiske betingelser i et nøytralt løsningsmiddel, 1,2-fenylendioksy-dieddiksyrederivatet 3-Reaksjonsskjema IX. K2C03i tilbakeløpskokende aceton gir i alminnelighet akseptable resultater, men andre baser og løsningsmidler, så som de som er omtalt under Reaksjonsskjema VIII, kan også benyttes. Fjerning av den nitrogen-beskyttende gruppe fra 3-Reaksjonsskjema IX ved hydrogenolyse over en Pd/C katalysator i en løsningsmiddelblanding av EtOAc og MeOH, ledsages av en samtidig reduksjon av ketonet til aminoalkoholen 4-Reaksjonsskjema IX. N-alkylering av forbindelse 4-Reaksjonsskjema IX med 2-(klormetyl)benzimidazol i en løsningsmiddelblanding av CH3CN og CH2CI2 i nærvær av Et3N, gir mono-benzylimidazol-derivatet 5-Reaksjonsskjema IX. Påfølgende fjerning av estergruppen av 5-Reaksjonsskjema IX under passende betingelser, omtalt i Reaksjonsskjema VIII, gir forbindelsen 6-Reaksjonsskjema IX. Generelt fjernes en metylester, som den i 5-Reaksjonsskjema IX, ved hydrolyse i nærvær av et alkalimetallhydroksyd, så som LiOH, NaOH eller KOH, i et vandig løsningsmiddel, som MeOH, EtOH eller THF. Dialkylation of 2-Reaction scheme IX by reaction with a haloacetic acid ester, for example methyl bromoacetate, gives under basic conditions in a neutral solvent, the 1,2-phenylenedioxy-diacetic acid derivative 3-Reaction scheme IX. K 2 CO 3 in refluxing acetone generally gives acceptable results, but other bases and solvents, such as those discussed under Reaction Scheme VIII, may also be used. Removal of the nitrogen-protecting group from 3-Reaction scheme IX by hydrogenolysis over a Pd/C catalyst in a solvent mixture of EtOAc and MeOH, accompanied by a simultaneous reduction of the ketone to the amino alcohol 4-Reaction scheme IX. N-Alkylation of compound 4-Scheme IX with 2-(chloromethyl)benzimidazole in a solvent mixture of CH3CN and CH2CI2 in the presence of Et3N gives the mono-benzylimidazole derivative 5-Scheme IX. Subsequent removal of the ester group of 5-Scheme IX under appropriate conditions, discussed in Scheme VIII, gives the compound 6-Scheme IX. In general, a methyl ester, such as that in 5-Reaction Scheme IX, is removed by hydrolysis in the presence of an alkali metal hydroxide, such as LiOH, NaOH, or KOH, in an aqueous solvent, such as MeOH, EtOH, or THF.

I Reaksjonsskjema X, N-beskyttes kommersielt tilgjengelig adrenolon-hydroklorid (1-Reaksjonsskjema X) som beskrevet i Reaksjonsskjema VIII, for å gi BOC-derivatet 2-Reaksjonsskjema X. In Scheme X, commercially available adrenolone hydrochloride (1-Scheme X) is N-protected as described in Scheme VIII to give the BOC derivative 2-Scheme X.

a) (BOC)20, NaOH, 1,4-dioksan, H20; b) BrCH2C02CH3, K2C03, aceton; c) 4MHCM1,4-dioksan; d) 1-(BOC)-2-(bro.mmetyl)benzimidazol, Et3N, THF, CH2CI2; e) TFA, CH2CI2; a) (BOC) 2 O, NaOH, 1,4-dioxane, H 2 O; b) BrCH2CO2CH3, K2CO3, acetone; c) 4MHCM1,4-dioxane; d) 1-(BOC)-2-(bromomethyl)benzimidazole, Et 3 N, THF, CH 2 Cl 2 ; e) TFA, CH 2 Cl 2 ;

f) 1.0N LiOH, THF, H20f) 1.0N LiOH, THF, H 2 O

Dialkylering av 2-Reaksjonsskjema X som diskutert i Reaksjonsskjema IX, Dialkylation of 2-Reaction Scheme X as discussed in Reaction Scheme IX,

fører til 3-Reaksjonsskjema X. Nitrogen-beskyttelsesgruppen i 3-Reaksjonsskjema X fjernes som diskutert i Reaksjonsskjema VIII, for å gi aminet 4-Reaksjonsskjema X som det tilsvarende ammoniumsalt. Alkylering 4-Reaksjonsskjema X med 1-BOC-2-(brommetyl)benzimidazol i en løsningsmiddelblanding av THF og CH2CI2i nærvær leads to 3-Scheme X. The nitrogen protecting group in 3-Scheme X is removed as discussed in Scheme VIII, to give the amine 4-Scheme X as the corresponding ammonium salt. Alkylation 4-Reaction scheme X with 1-BOC-2-(bromomethyl)benzimidazole in a solvent mixture of THF and CH2Cl2 in the presence

av Et3N, gir mono-benzimidazol-derivatet 5-Reaksjonsskjema X. Påfølgende fjerning av BOC-gruppen fra 5-Reaksjonsskjema X som omtalt under Reaksjonsskjema VIII, fører til 6-Reaksjonsskjema X. Fjerning av estergruppen fra 6-Reaksjonsskjema X som omtalt i Reaksjonsskjema I og 2, gir 7-Reaksjonsskjema IX. Alternativt kan estergruppen i 5-Reaksjonsskjema X fjernes først før fjerning av Boc-gruppen. of Et3N, gives the mono-benzimidazole derivative 5-Reaction Scheme X. Subsequent removal of the BOC group from 5-Reaction Scheme X as discussed under Reaction Scheme VIII leads to 6-Reaction Scheme X. Removal of the ester group from 6-Reaction Scheme X as discussed in Reaction Scheme I and 2, gives 7-Reaction scheme IX. Alternatively, the ester group in 5-Reaction scheme X can be removed first before removing the Boc group.

I Reaksjonsskjema XI fremstilles delen W ved en amid-koblingsreaksjon. In Reaction Scheme XI, part W is prepared by an amide coupling reaction.

a) etylakrylat, HOAc, a) ethyl acrylate, HOAc,

b) SOCI2; c) 2-(aminometyl)benzimidazol, DIEA, CH2CI2; b) SOCI2; c) 2-(aminomethyl)benzimidazole, DIEA, CH2Cl2;

d) NaOH, H20, MeOH.d) NaOH, H 2 O, MeOH.

Til å begynne med fremstilles etyl-3-[4-(karboksy)fenyl]amino]propionsyre (2-Reaksjonsskjema XI) ved en Michael-addisjon av 4-(karboksy)anilin (1- To begin with, ethyl 3-[4-(carboxy)phenyl]amino]propionic acid (2-Reaction Scheme XI) is prepared by a Michael addition of 4-(carboxy)aniline (1-

Reaksjonsskjema XI) til etyl-akrylat i eddiksyre som beskrevet i Chem. Ber. 91, 2239, 1958. Karboksylgruppen i forbindelse 2-Reaksjonsskjema XI omdannes til syrekloridet med tionylklorid og syrekloridet kondenseres med 2-(aminometyl)benzimidazol-dihydroklorid-hydrat med diisopropyletylamin i diklormetan for å danne forbindelse 3-Reaksjonsskjema XI. Etylesteren 3-Reaksjonsskjema XI forsåpes med natriumhydroksyd i vandig metanol for å gi forbindelse 4-Reaksjonsskjema XI. Alternativt kan esteren omdannes til karboksylsyren med andre metallhydroksyder eller karbonater i et egnet løsningsmiddel. Reaction scheme XI) to ethyl acrylate in acetic acid as described in Chem. Pray. 91, 2239, 1958. The carboxyl group in compound 2-Reaction Scheme XI is converted to the acid chloride with thionyl chloride and the acid chloride is condensed with 2-(aminomethyl)benzimidazole dihydrochloride hydrate with diisopropylethylamine in dichloromethane to form compound 3-Reaction Scheme XI. The ethyl ester 3-Reaction scheme XI is saponified with sodium hydroxide in aqueous methanol to give compound 4-Reaction scheme XI. Alternatively, the ester can be converted to the carboxylic acid with other metal hydroxides or carbonates in a suitable solvent.

Utgangsmaterialet for formel 1 g-Reaksjonsskjema XII forbindelser fremstilles ved å følge fremgangsmåtene til Egbertson, et al. J. Med. Chem. 1994, 37, 2537-3551 som omtaler generelle fremgangsmåter for alkylering av fenolen i et N-beskyttet tyrosin-derivat, fjerne N-beskyttelsesgruppen og sulfonylere aminet. Ved å benytte benzyl-4-brom-butyrat som alkyleringsmiddel, ble mellomproduktet 1d-Reaksjonsskjema XII, fremstillet. Fjerning av benzylesteren og omsetning med ortofenylendiamin under standardbetingelser førte til benzimidazolet 1f- Reaksjonsskjema XII. Til slutt ga forsåpning av metylesteren den ønskede forbindelse 1g-Reaksjonsskjema XII. The starting material for formula 1 g-Reaction scheme XII compounds is prepared by following the methods of Egbertson, et al. J. Med. Chem. 1994, 37, 2537-3551 which discusses general procedures for alkylating the phenol in an N-protected tyrosine derivative, removing the N-protecting group and sulfonylating the amine. By using benzyl-4-bromo-butyrate as an alkylating agent, the intermediate 1d-Reaction scheme XII was prepared. Removal of the benzyl ester and reaction with orthophenylenediamine under standard conditions led to the benzimidazole 1f- Reaction scheme XII. Finally, saponification of the methyl ester gave the desired compound 1g-Reaction Scheme XII.

Mellomforbindelser med formel (XXX) kan fremstilles fra passende beskyttede aminosyrer og fenyl-1,2-diaminer eller 2-nitroaniliner som er kommersielt tilgjengelige eller som fagmannen kan fremstille i henhold til Reaksjonsskjema XIII og XIV. a) isobutyl-Worformiat, THF, NEt3; Intermediates of formula (XXX) can be prepared from suitably protected amino acids and phenyl-1,2-diamines or 2-nitroanilines which are commercially available or which the person skilled in the art can prepare according to Reaction Schemes XIII and XIV. a) isobutyl Worformate, THF, NEt3;

b) A, AcOH.b) A, AcOH.

a) tionylklorid; a) thionyl chloride;

b) Fe, AcOH, Ab) Fe, AcOH, A

Amid-koblingsreagenser som her er benyttet er reagenser som kan benyttes Amide coupling reagents used here are reagents that can be used

for å danne peptidbindinger. Typiske koblingsmetoder gjør bruk av karbodiimider, aktiverte anhydrider og estere og acylhalogenider. Typiske reagenser er EDC, DCC, DPPA, PPA, BOP-reagens, HOBt, N-hydroksysuccinimid og oksalylklorid. to form peptide bonds. Typical coupling methods make use of carbodiimides, activated anhydrides and esters and acyl halides. Typical reagents are EDC, DCC, DPPA, PPA, BOP reagent, HOBt, N-hydroxysuccinimide and oxalyl chloride.

Koblingsmetoder for å danne peptidbindinger er generelt velkjent på området. Fremgangsmåter for peptidsynteser som generelt beskrevet av Bodansky et al., THE PRACTICE OF PEPTIDE SYNTHESIS, Springer-Verlag, Berlin, 1984, Ali et al. i J. Med. Chem. 29, 984 (1986) og J. Med. Chem. 30, 2291 (1987) er generelt illustrerende for teknikken og inkorporeres herved med hele sitt innhold i foreliggende beskrivelse. Coupling methods for forming peptide bonds are generally well known in the art. Procedures for peptide syntheses as generally described by Bodansky et al., THE PRACTICE OF PEPTIDE SYNTHESIS, Springer-Verlag, Berlin, 1984, Ali et al. in J. Med. Chem. 29, 984 (1986) and J. Med. Chem. 30, 2291 (1987) is generally illustrative of the technique and is hereby incorporated in its entirety in the present description.

Aminet eller anilinet kobles via dets frie aminogruppe til et passende karboksylsyre-substrat ved å benytte et egnet karbodiimid-koblingsmiddel, så som N,N'-dicykloheksylkarbodiimid (DCC), eventuelt i nærvær av en katalysator som f.eks. 1-hydroksybenzotriazol (HOBt) og dimetylamino-pyridin (DMAP). Andre metoder, som f.eks. dannelsen av aktiverte estere, anhydrider eller syrehalogenider, av den frie karboksylgruppe i et passende beskyttet syresubstrat, og påfølgende omsetning med det frie amin i et passende beskyttet amin, eventuelt i nærvær av en base, er også egnet. For eksempel behandles en beskyttet BOC-aminosyre eller Cbz-amidino-benzoesyre i et vannfritt løsningsmiddel, som f.eks. metylenklorid eller tetrahydrofuran (THF), i nærvær av en base, så som N-metylmorfolin, DMAP eller trialkylamin, med isobutyl-klorformiat for å danne det "aktiverte anhydrid" som deretter omsettes med det frie amin i en annen beskyttet aminosyre eller anilin. The amine or aniline is coupled via its free amino group to a suitable carboxylic acid substrate by using a suitable carbodiimide coupling agent, such as N,N'-dicyclohexylcarbodiimide (DCC), optionally in the presence of a catalyst such as e.g. 1-hydroxybenzotriazole (HOBt) and dimethylamino-pyridine (DMAP). Other methods, such as the formation of activated esters, anhydrides or acid halides, of the free carboxyl group in a suitable protected acid substrate, and subsequent reaction with the free amine in a suitable protected amine, optionally in the presence of a base, is also suitable. For example, a protected BOC amino acid or Cbz-amidino-benzoic acid is treated in an anhydrous solvent, such as e.g. methylene chloride or tetrahydrofuran (THF), in the presence of a base, such as N-methylmorpholine, DMAP or trialkylamine, with isobutyl chloroformate to form the "activated anhydride" which is then reacted with the free amine of another protected amino acid or aniline.

Forbindelsene med formel (XIX) og (XX) er kommersielt tilgjengelige eller lar seg fremstille etter kjente fremgangsmåter som for eksempel omtalt i standard referanser som COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Bd. I-VI The compounds of formula (XIX) and (XX) are commercially available or can be prepared according to known methods which are for example described in standard references such as COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-VI

(Wiley-lnterscience). En generelt brukbar vei til benzimidazoler er beskrevet i Nestor et al., J. Med. Chem. 1984, 27, 320. Representative fremgangsmåter for fremstilling av forbindelser med formel (XX) er også vanlige på området og finnes for eksempel i EP-A 0 381 033. (Wiley-lnterscience). A generally useful route to benzimidazoles is described in Nestor et al., J. Med. Chem. 1984, 27, 320. Representative methods for the preparation of compounds of formula (XX) are also common in the field and can be found, for example, in EP-A 0 381 033.

Syreaddisjonssalter av forbindelsene fremstilles på vanlig måte i et egnet løsningsmiddel ved å gå ut fra opphavsforbindelsen og et overskudd av en syre som f.eks. saltsyre, hydrogenbromidsyre, hydrogenfluoridsyre, svovelsyre, fosforsyre, eddiksyre, trifluoreddiksyre, maleinsyre, ravsyre eller metansulfonsyre Enkelte av forbindelsene danner innvendige salter eller zwitter-ioner som også kan være akseptable. Kationiske salter fremstilles ved å behandle opphavsforbindelsen med et Acid addition salts of the compounds are prepared in the usual way in a suitable solvent by starting from the parent compound and an excess of an acid such as e.g. hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid or methanesulfonic acid Some of the compounds form internal salts or zwitter ions which may also be acceptable. Cationic salts are prepared by treating the parent compound with a

overskudd av et alkalireagens, så som et hydroksyd, karbonat eller alkoksyd, som inneholder det passende kation; eller med et passende organisk amin. Kationer som Li<+>, Na<+>, K\ Ca<++>, Mg<++>og NH4<+>er eksempler på kationer som forekommer i farmasøytisk akseptable salter. excess of an alkali reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation; or with a suitable organic amine. Cations such as Li<+>, Na<+>, K\ Ca<++>, Mg<++>and NH4<+> are examples of cations occurring in pharmaceutically acceptable salts.

Oppfinnelsen tilveiebringer også en farmasøytisk blanding som omfatter en forbindelse ifølge formel (l)-(V) og en farmasøytisk akseptabel bærer. Forbindelsene med formel (l)-(V) kan således benyttes for fremstillingen av et medikament. Farmasøytiske blandinger av forbindelser med formel (l)-(V), fremstillet som foran beskrevet, kan formuleres som løsninger eller lyofiliserte pulvere for parenteral administrering. Pulvere kan før bruk rekonstitueres ved tilsetning av et passende The invention also provides a pharmaceutical composition comprising a compound of formula (I)-(V) and a pharmaceutically acceptable carrier. The compounds of formula (l)-(V) can thus be used for the production of a drug. Pharmaceutical mixtures of compounds of formula (I)-(V), prepared as described above, can be formulated as solutions or lyophilized powders for parenteral administration. Powders can be reconstituted before use by adding a suitable

fortynningsmiddel eller en annen farmasøytisk akseptabel bærer. Den flytendediluent or other pharmaceutically acceptable carrier. The liquid

i formuleringen kan være en buffret, isoton, vandig løsning. Eksempler på egnede fortynningsmidler er normal isotonisk saltløsning, standard 5% dekstrose i vann eller buffret natrium- eller ammoniumacetatløsning. Slike formuleringer er spesielt egnet in the formulation may be a buffered, isotonic, aqueous solution. Examples of suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution. Such formulations are particularly suitable

for parenteral administrering, men kan også benyttes for peroral administrering eller inngå i en avmålt dose for en inhalator eller nebulisator for innblåsning. Det kan være ønskelig å tilsette hjelpestoffer som polyvinylpyrrolidon, gelatin, hydroksycellulose, akasie, polyetylenglykol, mannitol, natriumklorid eller natriumcitrat. for parenteral administration, but can also be used for oral administration or included in a measured dose for an inhaler or nebulizer for inhalation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.

Alternativt kan disse forbindelsene innkapsles, tabletteres eller fremstilles som en emulsjon eller sirup for peroral administrering. Farmasøytisk akseptable faste eller flytende bærere kan tilsettes for å forbedre eller stabilisere blandingen eller for å lette fremstillingen av blandingen. Faste bærere inkluderer stivelse, laktose, kalsiumsulfat-dihydrat, terra alba, magnesiumstearat eller stearinsyre, talk, pektin, akasie, agar eller gelatin. Flytende bærere inkluderer sirup, jordnøttolje, olivenolje, saltvann og vann. Bæreren kan også inkludere et materiale som gir forlenget frigjøring, så som glyceryl-monostearat eller glyceryl-diastearat, alene eller sammen med en voks. Mengden av fast bærer varierer, men vil fortrinnsvis være mellom ca. 20 mg og ca. 1 g per doseringsenhet. De farmasøytiske preparatene fremstilles ifølge konvensjonell farmasøytisk teknikk som kan innebære oppmaling, blanding, granulering og komprimering for tablettformer; eller oppmaling, blanding og påfylling for hårde gelatinkapsler. Når det benyttes en flytende bærer, vil preparatet ha form av en sirup, mikstur, emulsjon eller en vandig eller ikke-vandig suspensjon. En slik flytende formulering kan administreres direkte p.o. eller fylles over på en myk gelatinkapsel. Alternatively, these compounds can be encapsulated, tableted or prepared as an emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition or to facilitate preparation of the composition. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. Liquid carriers include syrup, peanut oil, olive oil, saline and water. The carrier may also include a sustained release material, such as glyceryl monostearate or glyceryl diastearate, alone or together with a wax. The amount of solid carrier varies, but will preferably be between approx. 20 mg and approx. 1 g per dosage unit. The pharmaceutical preparations are prepared according to conventional pharmaceutical techniques which may involve grinding, mixing, granulation and compression for tablet forms; or grinding, mixing and filling for hard gelatin capsules. When a liquid carrier is used, the preparation will take the form of a syrup, mixture, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation can be administered directly p.o. or filled onto a soft gelatin capsule.

For rektal administrering kan forbindelsene ifølge oppfinnelsen også kombineres med hjelpestoffer som kakaosmør, glycerol, gelatin eller polyetylenglykoler og støpes til en stikkpille. For rectal administration, the compounds according to the invention can also be combined with excipients such as cocoa butter, glycerol, gelatin or polyethylene glycols and molded into a suppository.

Forbindelsene som her er beskrevet er antagonister av vitronectin-reseptorer og er anvendelige ved behandling av sykdommer hvor den underliggende patologi kan tilskrives ligander eller celler som virker på vitronectin-reseptorer. Disse forbindelsene er for eksempel egnet for behandling av sykdommer hvor tap av benmatriks fører til sykdom. Foreliggende forbindelser er således egnet for behandling av osteoporose, hyperparathyroidisme, Pagefs sykdom, hyperkalsemi-sykdom, osteolyttiske lesjoner dannet ved benmetastase, bentap som følge av immobilisering eller kjønnshormon-underskudd. Forbindelsene ifølge oppfinnelsen antas også å kunne benyttes som anti-tumor, anti-angiogene, antiinflammatoriske og anti-metastatiske midler og er nyttige ved behandling av aterosklerose og restenose. The compounds described here are antagonists of vitronectin receptors and are useful in the treatment of diseases where the underlying pathology can be attributed to ligands or cells that act on vitronectin receptors. These compounds are, for example, suitable for the treatment of diseases where loss of bone matrix leads to disease. The present compounds are thus suitable for the treatment of osteoporosis, hyperparathyroidism, Pagef's disease, hypercalcemia disease, osteolytic lesions formed by bone metastasis, bone loss as a result of immobilization or sex hormone deficiency. The compounds according to the invention are also believed to be able to be used as anti-tumor, anti-angiogenic, anti-inflammatory and anti-metastatic agents and are useful in the treatment of atherosclerosis and restenosis.

Forbindelsen administreres pasienten peroralt eller parenteralt på en slik måte at medikamentkonsentrasjonen er tilstrekkelig til å inhibere benresorpsjon eller5annen tilsvarende indikasjon. Den farmasøytiske blanding som innnholder peptidet, administreres i en peroral dose på mellom 0,1 til ca. 50 mg/kg på en måte som tar hensyn til pasientens tilstand. Fortrinnsvis utgjør den perorale dose 0,5 til ca. The compound is administered to the patient orally or parenterally in such a way that the drug concentration is sufficient to inhibit bone resorption or another corresponding indication. The pharmaceutical mixture containing the peptide is administered in an oral dose of between 0.1 to approx. 50 mg/kg in a manner that takes the patient's condition into account. Preferably, the oral dose amounts to 0.5 to approx.

20 mg/kg. For akutt terapi foretrekkes parenteral administrering. En intravenøs 20 mg/kg. For acute therapy, parenteral administration is preferred. An intravenous

infusjon av peptidet i 5% dekstrose i vann eller normal saltløsning, eller en lignende ) formulering med passende hjelpestoffer, er mest effektiv, men en intramuskulær bolusinjeksjon er også egnet. Den typiske parenterale dose vil være fra ca.0,01 til ca. 100 mg/kg; fortrinnsvis mellom 0,1 og 20 mg/kg. Forbindelsen administreres én til fire ganger daglig i en nivå som bevirker at det oppnås en total døgndose på ca. infusion of the peptide in 5% dextrose in water or normal saline, or a similar formulation with appropriate excipients, is most effective, but an intramuscular bolus injection is also suitable. The typical parenteral dose will be from about 0.01 to about 100 mg/kg; preferably between 0.1 and 20 mg/kg. The compound is administered one to four times a day at a level which results in a total daily dose of approx.

0,4 til ca. 400 mg/kg/dag. Det nøyaktige nivå og hvilken metode som benyttes for0.4 to approx. 400 mg/kg/day. The exact level and which method is used for

i administreringen avgjøres lett av fagmannen ved å sammenligne nivået av midlet i blodet med den konsentrasjon som fordres for å ha en terapeutisk effekt. in administration is easily determined by the person skilled in the art by comparing the level of the agent in the blood with the concentration required to have a therapeutic effect.

Forbindelsene kan undersøkes etter én av flere biologiske metoder for å bestemme den konsentrasjon av forbindelsen som fordres for å ha en gitt The compounds can be examined by one of several biological methods to determine the concentration of the compound required to have a given

farmakologisk effekt.pharmacological effect.

i in

Inhibering av vitronectin-bindingInhibition of vitronectin binding

Fastfase [<3>H]-SK&F-107260 binding til avp3:Solid phase [<3>H]-SK&F-107260 binding to avp3:

Human placenta eller humane blodplater avp3(0,1-0,3 mg/mL) i buffer T (inneholdende 2 mM CaCI2 og 1 % oktylglukosid) ble fortynnet med buffer T inneholdende 1 mM CaCI2, 1 mM MnCI2, 1 mM MgCI2(buffer A) og 0,05% NaN3 og deretter umiddelbart tilsatt til 96 brønns ELISA-plater (Corning, New York, NY) med 0,1 mL per brønn. 0,1-0,2 \ ig av avp3 ble tilsatt per brønn. Platene ble inkubert over natten ved 4°C. På forsøkstidspunktet ble brønnene vasket én gang med buffer A og inkubert med 0,1 mL 3,5% bovint serumalbumin i den samme buffer i 1 time ved romtemperatur. Etter inkubering ble brønnene avsuget fullstendig og vasket to ganger med 0,2 mL buffer A. Forbindelser ble løst i 100% DMSO for å gi en 2 mM stam-løsning som senere ble fortynnet med bindingsbuffer (15 mM TrisHCI (pH 7,4), 100 mM NaCI, 1 mM CaCI2, 1 mM MnCI2, 1 mM MgCI2) til en sluttkonsentrasjon av forbindelsen på 100U.M. Denne løsningen fortynnes til den nødvendige sluttkonsentrasjon. Forskjellige konsentrasjoner av umerkede antagonister (0,001-100 \ iM) ble tilsatt til brønnene i tre paralleller, og deretter tilsatt 5,0 nM [<3>H]-SK&F-107260 (65- Human placenta or human platelets of p3 (0.1-0.3 mg/mL) in buffer T (containing 2 mM CaCl2 and 1% octylglucoside) were diluted with buffer T containing 1 mM CaCl2, 1 mM MnCl2, 1 mM MgCl2 (buffer A) and 0.05% NaN3 and then immediately added to 96-well ELISA plates (Corning, New York, NY) at 0.1 mL per well. 0.1-0.2 µg of avp3 was added per well. The plates were incubated overnight at 4°C. At the time of the experiment, the wells were washed once with buffer A and incubated with 0.1 mL of 3.5% bovine serum albumin in the same buffer for 1 hour at room temperature. After incubation, the wells were aspirated completely and washed twice with 0.2 mL buffer A. Compounds were dissolved in 100% DMSO to give a 2 mM stock solution which was later diluted with binding buffer (15 mM TrisHCl (pH 7.4) , 100 mM NaCl, 1 mM CaCl 2 , 1 mM MnCl 2 , 1 mM MgCl 2 ) to a final compound concentration of 100 U.M. This solution is diluted to the required final concentration. Different concentrations of unlabeled antagonists (0.001-100 µM) were added to the wells in triplicate, and then 5.0 nM [<3>H]-SK&F-107260 (65-

86 Ci/mmol).86 Ci/mmol).

Platene ble inkubert i 1 time ved romtemperatur. Etter inkubering ble brønnene avsuget fullltendig og vasket én gang med 0,2 mL iskald buffer A brønn-til-brønn. Reseptorene ble solubilisert med 0,1 mL 1% SDS og det bundne [<3>H]-SK&F-107260 bestemt ved væskescintillasjonstelling ved tilsetning av 3 mL Ready Safe i en Beckman LS væskescintillasjonsteller, med 40% effektivitet. Uspesifikk binding av [<3>H]-SK&F-107260 ble bestemt i nærvær av 2 |iM SK&F-107260 og var konsekvent mindre enn 1% av den totale utgangsmengde av radioligand. IC5o(den antagonistkonsentrasjon som inhiberer 50% binding av [<3>H]-SK&F-107260 ble bestemt ved en ikke-lineær, minste kvadraters kurvetilpasning som var en modifikasjon av LUNDON-2 programmet. Kr (dissosiasjonskonstanten av antagonisten) ble beregnet etter ligningen: Kj = ICso/O + L/Kd), hvor L og Kdhenholdsvis er konsentrasjonen og dissosiasjonskonstanten av [<3>H]-SK&F-107260. The plates were incubated for 1 hour at room temperature. After incubation, the wells were aspirated completely and washed once with 0.2 mL of ice-cold buffer A well-to-well. The receptors were solubilized with 0.1 mL of 1% SDS and the bound [<3>H]-SK&F-107260 determined by liquid scintillation counting by adding 3 mL of Ready Safe in a Beckman LS liquid scintillation counter, with 40% efficiency. Nonspecific binding of [<3>H]-SK&F-107260 was determined in the presence of 2 µM SK&F-107260 and was consistently less than 1% of the total starting amount of radioligand. IC50 (the antagonist concentration that inhibits 50% binding of [<3>H]-SK&F-107260) was determined by a non-linear, least-squares curve fitting which was a modification of the LUNDON-2 program. Kr (the dissociation constant of the antagonist) was calculated by the equation: Kj = ICso/O + L/Kd), where L and K are respectively the concentration and the dissociation constant of [<3>H]-SK&F-107260.

Forbindelser ifølge foreliggende oppfinnelse inhiberer vitronectin-binding til SK&F-107260 i konsentrasjonsområdet fra ca. 0,001 til 50 mikromolar. Compounds according to the present invention inhibit vitronectin binding to SK&F-107260 in the concentration range from approx. 0.001 to 50 micromolar.

Forbindelser ifølge oppfinnelsen ble også undersøkt med henblikk på in vitro og in vivo benresorpsjon ved hjelp av standardbestemmelser for evaluering av bendannelsesinhibering, så som den grop-dannelsesanalyse (pit formation) som er omtalt i EP 528 587, som også kan utføres under bruk av humane osteoklaster i stedet for rotte-osteoklaster, og den ooforektomerte rottemodell beskrevet av Wronski et al. Cells and Materials 1991, Sup. 1, 69-74. Compounds according to the invention were also investigated for in vitro and in vivo bone resorption using standard assays for the evaluation of bone formation inhibition, such as the pit formation assay described in EP 528 587, which can also be performed using human osteoclasts rather than rat osteoclasts, and the oophorectomized rat model described by Wronski et al. Cells and Materials 1991, Suppl. 1, 69-74.

Migreringsbestemmelse i vaskulære glatte muskelcellerMigration determination in vascular smooth muscle cells

Det ble benyttet glatte muskelceller fra rotte- eller human aorta. Cellemigreringen ble overvåket i et Transwell cellekultur-kammer ved å benytte en polykarbonatmembran med porer på 8 (iM (Costar). Den nedre overflate av filteret ble dekket med vitronectin. Cellene ble suspendert i DMEM supplert med 0,2% bovint serumalbumin i en konsentrasjon på 2,5-5,0 x 10<6>celler/mL og ble forbehandlet med testforbindelsen i ulike konsentrasjoner i 20 minutter ved 20°C. Løsningsmidlet som sådant ble benyttet som kontroll. 0,2 mL av cellesuspensjonen ble anbragt i kammerets øvre rom. Det nedre rom inneholdt 0,6 mL DMEM supplert med 0,2% bovint serumalbumin. Inkuberingen ble foretatt ved 37°C i en atmosfære av 95% luft/5% C02i 24 timer. Etter inkubering ble de ikke-migrerte cellene på den øvre filterflate fjernet ved forsiktig skraping. Filteret ble deretter fiksert i metanol og farvet med 10% Giemsafarve. Migreringen ble målt enten ved a) å telle antallet av celler som hadde migrert til den nedre filteroverflate eller ved b) å ekstrahere de farvede cellene med 10% eddiksyre og deretter bestemme absorbansen ved 600 nm. Smooth muscle cells from rat or human aorta were used. The cell migration was monitored in a Transwell cell culture chamber using a polycarbonate membrane with pores of 8 µM (Costar). The lower surface of the filter was covered with vitronectin. The cells were suspended in DMEM supplemented with 0.2% bovine serum albumin at a concentration of 2.5-5.0 x 10<6>cells/mL and were pretreated with the test compound in various concentrations for 20 minutes at 20°C. The solvent as such was used as a control. 0.2 mL of the cell suspension was placed in the chamber's upper chamber. The lower chamber contained 0.6 mL of DMEM supplemented with 0.2% bovine serum albumin. The incubation was carried out at 37°C in an atmosphere of 95% air/5% CO 2 for 24 hours. After incubation, the non-migrated cells were on the upper filter surface removed by gentle scraping. The filter was then fixed in methanol and stained with 10% Giemsa stain. Migration was measured either by a) counting the number of cells that had migrated to the lower filter surface or by b) extracting the stained cells by 10% acetic acid and then determine the absorbance at 600 nm.

PARATHYROIDEKTOMERT ROTTEMODELLPARATHYROIDECTOMATED RAT MODEL

Hver forsøksgruppe besto av 5-6 Sprague-Dawley hannrotter. Rottene ble parathyroidektomert (av forhandleren, Taconic Farms) 7 dager før bruk. 24 timer før bruk ble sirkulerende ionisert kalsiumnivå målt i helblod umiddelbart etter at prøven var tatt fra halen ved venepunktering over i hepariniserte rør. Rottene ble inkludert dersom ionisert Ca-nivå (målt med en Ciba-Corning modell 634 calcium pH analyzer) var 1,2 mM/L. Rottene ble deretter satt på en diett av kalsiumfritt tørrfor (Chow) og deionisert vann. Ved forsøksstad veide rottene ca. 100 g. Basislinje Ca-nivået ble målt og rottene administrert kontroll-bærer (saltvann) eller forbindelse (løst i saltvann) som en enkelt intravenøs bolusinjeksjon (halevene), umiddelbart etterfulgt av en enkelt subkutan injeksjon av enten human parathyroidhormon-1-34-peptid (hPTH1-34, dose 0,2 mg/kg i saltvann/0,1% bovint serumalbumin, Bachem, Ca) eller PTH-bæreren. Kalsemi-responsen på PTH (og eventuell effekt av forbindelsen på denne respons) måles 2 timer etter administrering av forbindelse/PTH. Each experimental group consisted of 5-6 male Sprague-Dawley rats. The rats were parathyroidectomized (by the supplier, Taconic Farms) 7 days before use. 24 hours before use, circulating ionized calcium level was measured in whole blood immediately after the sample had been taken from the tail by venipuncture into heparinized tubes. The rats were included if the ionized Ca level (measured with a Ciba-Corning model 634 calcium pH analyzer) was 1.2 mM/L. The rats were then put on a diet of calcium-free dry food (chow) and deionized water. At the experimental site, the rats weighed approx. 100 g. The baseline Ca level was measured and the rats administered control vehicle (saline) or compound (dissolved in saline) as a single intravenous bolus injection (tail vein), immediately followed by a single subcutaneous injection of either human parathyroid hormone-1-34- peptide (hPTH1-34, dose 0.2 mg/kg in saline/0.1% bovine serum albumin, Bachem, Ca) or the PTH carrier. The calcemia response to PTH (and any effect of the compound on this response) is measured 2 hours after administration of the compound/PTH.

ROTTE ULNA DRIFT MODELLRAT ULNA OPERATION MODEL

Hver forsøksgruppe besto av 8-10 Sprague-Dawley eller Wistar hannrotter med en kroppsvekt på ca. 30-40 g ved forsøksstad. Testforbindelsen administreres på passende måte som enkle eller avdelte døgndoser over et tidsrom på 7 dager. Før administrering av den første dose, gis rottene en enkelt dose av en fluorescerende markør (tetracyklin 25 mg/kg eller calcein 10 mg/kg) som markerer posisjonen av bendannende overflater på dette tidspunkt. Etter at doseringen av testforbindelsen er fullført, avlives rottene, hvorpå begge forlemmene skilles fra ved albuen, føttene fjernes ved ankelen og huden tas av. Prøven fryses og monteres loddrett på en mikroton-chuck. Snitt, på tvers av midtskaftregionen av ulna snittes i kryostaten. Graden av benresorpsjon måles morfometrisk i den medialt dorsale del av det kortikale ben. Målingen foretas som følger: mengden av ben resorbert i den periosteale overflate er lik den distanse som den periosteale overflate har forskjøvet seg mot den fluorescerende markør som var inkorporert på den endosteale bendannende overflate på dag null. Denne distanse beregnes ved å subtrahere bredden av ben mellom markøren og den periosteale overflate på dag 7 fra bredden på dag null. Resorpsjonshastigheten i mikron per dag beregnes ved å dividere resultatet med 7. Each experimental group consisted of 8-10 male Sprague-Dawley or Wistar rats with a body weight of approx. 30-40 g at the experimental site. The test compound is conveniently administered as single or divided daily doses over a period of 7 days. Before administration of the first dose, the rats are given a single dose of a fluorescent marker (tetracycline 25 mg/kg or calcein 10 mg/kg) that marks the position of bone-forming surfaces at this time. After dosing of the test compound is completed, the rats are euthanized, whereupon both forelimbs are severed at the elbow, the feet are removed at the ankle, and the skin is removed. The sample is frozen and mounted vertically on a microton chuck. Section, across the midshaft region of the ulna is sectioned in the cryostat. The degree of bone resorption is measured morphometrically in the medially dorsal part of the cortical bone. The measurement is made as follows: the amount of bone resorbed in the periosteal surface is equal to the distance that the periosteal surface has moved towards the fluorescent marker that was incorporated on the endosteal bone-forming surface on day zero. This distance is calculated by subtracting the width of bone between the marker and the periosteal surface on day 7 from the width on day zero. The resorption rate in microns per day is calculated by dividing the result by 7.

BESTEMMELSE AV HUMAN OSTEOKLAST-RESORPSJON ("PIT ASSAY")DETERMINATION OF HUMAN OSTEOCLAST RESORPTION ("PIT ASSAY")

<*>Alikvoter av cellesuspensjoner som skriver seg fra osteoklastomer tas ut fra oppbevaringen i flytende nitrogen, oppvarmes hurtig til 37°C og vaskes én gang i RPMI-1640 medium ved sentrifugering (1000 rpm., 5 minutter ved 4°C).<*>Avsug mediet og erstatt det med murint anti-HLA-DR-antistoff fortynnet 1:3 i RPMI-1640 medium. Inkuber i 30 minutter på is og bland cellesuspensjonen hyppig.<*>Cellene vaskes to ganger med kald PRPMI-1640 ved sentrifugering (1000 rpm., 5 minutter ved 4°C) hvoretter cellene overføres til et sterilt 15 mL sentrifugerør. Antallet mononukleære celler telles i et forbedret Neubauer tellekammer.<*>Tilstrekkelig antall magnetiske kuler (5/mononukleære celle), dekket med geit-anti-mus-IgG, uttas fra forrådsflasken og anbringes i 5 mL friskt medium (dette <*>Aliquots of cell suspensions derived from osteoclastomas are removed from storage in liquid nitrogen, quickly warmed to 37°C and washed once in RPMI-1640 medium by centrifugation (1000 rpm., 5 minutes at 4°C).< *>Aspirate the medium and replace it with murine anti-HLA-DR antibody diluted 1:3 in RPMI-1640 medium. Incubate for 30 minutes on ice and mix the cell suspension frequently.<*>The cells are washed twice with cold PRPMI-1640 by centrifugation (1000 rpm., 5 minutes at 4°C) after which the cells are transferred to a sterile 15 mL centrifuge tube. The number of mononuclear cells is counted in an improved Neubauer counting chamber.<*>A sufficient number of magnetic beads (5/mononuclear cell), coated with goat anti-mouse IgG, is taken from the stock bottle and placed in 5 mL of fresh medium (this

vasker bort det toksiske azid-konserveringsmiddel). Mediet fjernes ved å immobilisere kulene på en magnet og erstatte med friskt medium. washes away the toxic azide preservative). The medium is removed by immobilizing the beads on a magnet and replacing with fresh medium.

Kulene blandes med cellene og suspensjonen inkuberes på is i 30 minutter. The beads are mixed with the cells and the suspension is incubated on ice for 30 minutes.

Suspensjonen blandes hyppig.The suspension is mixed frequently.

5 * De kuleovertrukne cellene immobiliseres på en magnet og de øvrige celler (osteoklast-rike fraksjon) dekanteres over i et sterilt 50 mL sentrifugerør. 5 * The bead-coated cells are immobilized on a magnet and the other cells (osteoclast-rich fraction) are decanted into a sterile 50 mL centrifuge tube.

Friskt medium tilsettes til de kuledekkende cellene for å løsne eventuelt innfangede osteoklaster. Denne prosess gjentas 10x. De kuledekkede cellene Fresh medium is added to the sphere-covering cells to loosen any trapped osteoclasts. This process is repeated 10x. The globular cells

kasseres.be discarded.

o * Osteoklastene telles i et tellekammer ved å benytte en en-gangs plast-pasteur pipette med vid åpning for å fylle kammeret med prøven. o * The osteoclasts are counted in a counting chamber by using a single-use plastic Pasteur pipette with a wide opening to fill the chamber with the sample.

Cellene pelleteres ved sentrifugering og tettheten av osteoklaster justeres til 1,5 x 10<4>/mL i EMEM-medium supplert med 10% føtalt kalveserum og 1,7 g/L The cells are pelleted by centrifugation and the density of osteoclasts is adjusted to 1.5 x 10<4>/mL in EMEM medium supplemented with 10% fetal calf serum and 1.7 g/L

natriumbikarbonat.sodium bicarbonate.

5 * 3 mL alikvoter av cellesuspensjonen (per behandling) dekanteres over i5 * 3 mL aliquots of the cell suspension (per treatment) are decanted over i

15 mL sentrifugerør. Cellene pelleteres ved sentrifugering.15 mL centrifuge tube. The cells are pelleted by centrifugation.

Til hvert rør tilsettes 3 mL av den passende behandling (fortynnet til 50 |iM i EMEM-medium). Det inkluderes dessuten passende bærer-kontroller, en positiv To each tube, add 3 mL of the appropriate treatment (diluted to 50 µM in EMEM medium). Also included are appropriate carrier controls, a positive

kontroll (87 MEM1 fortynnet til 100 jig/mL) og en isotype-kontroll (lgG2a fortynnet til d 100 ug/mL). Inkuber ved 37°C i 30 minutter. control (87 MEM1 diluted to 100 µg/mL) and an isotype control (lgG2a diluted to d 100 µg/mL). Incubate at 37°C for 30 minutes.

0,5 mL alikvoter av cellene sås ut på sterile dentin-skiver i en 48 brønns plate og inkuberes ved 37°C i 2 timer. Hver behandling underkastes screening i fire paralleller. 0.5 mL aliquots of the cells are seeded onto sterile dentin discs in a 48-well plate and incubated at 37°C for 2 hours. Each treatment is subjected to screening in four parallels.

Skivene vaskes ved seks gangers utveksling av varm PBS (10 ml_/brønn) i en56 brønns plate) og anbringes deretter i frisk behandling- eller kontrollprøve. Inkuber ved 37° i 48 timer. The slices are washed by six exchanges of warm PBS (10 ml_/well) in a 56-well plate) and then placed in fresh treatment or control sample. Incubate at 37° for 48 hours.

Tartrat-resistent syrefosfatase (TRAP) prosedyre (farver selektivt celler av Tartrate-resistant acid phosphatase (TRAP) procedure (selectively stains cells off

osteoklastlinjen)the osteoclast lineage)

d * Skivene vaskes i fosfatbuffret saltløsning og fikseres i 2% glutaraldehyd (i 0,2 M natriumkakodylat) i 5 minutter. d * The slices are washed in phosphate-buffered saline and fixed in 2% glutaraldehyde (in 0.2 M sodium cacodylate) for 5 minutes.

De vaskes i vann og inkuberes i TRAP-buffer i 5 minutter ved 37°C.They are washed in water and incubated in TRAP buffer for 5 minutes at 37°C.

Etter vask i kaldt vann inkuberes de i kald acetatbufferffast red garnet" i 5 minutter ved 4°C. After washing in cold water, they are incubated in cold acetate buffer solid red yarn" for 5 minutes at 4°C.

Bufferoverskuddet suges av og skivene tørkes etter vask i vann.The excess buffer is sucked off and the slices are dried after washing in water.

De TRAP-positive osteoklastene telles ved mikroskopi i opplyst felt og fjernes deretter fra dentin-overflaten ved ultralydbehandling. The TRAP-positive osteoclasts are counted by light-field microscopy and then removed from the dentin surface by ultrasound treatment.

<*>Pit-volumer bestemmes ved å benytte en Nikon/Lasertec ILM21W konfokalt mikroskop. <*>Pit volumes are determined using a Nikon/Lasertec ILM21W confocal microscope.

Inhibering av RGD-mediert GPIIb-llla-bindingInhibition of RGD-mediated GPIIb-IIIa binding

Rensing av GPIIb-lllaPurification of GPIIb-lla

Ti enheter dato-utgåtte vaskede humane blodplater (fra Røde Kors) ble lysert ved forsiktig omrøring i 3% oktylglykosid, 20 mM Tris-HCI, pH 7,4, 140 mM NaCI, 2 mM CaCI2ved 4°C i 2 timer. Lysatet ble sentrifugert ved 100.000 g i 1 time. Den oppnådde supematant ble anbragt på en 5 mL bønnelektin-sepharose 4B kolonne (E.Y. Labs) preekvilibrert med 20 mM Tris-HCI, pH 7,4, 100 mM NaCI, 2 mM CaCI2, Ten units of expired washed human platelets (from the Red Cross) were lysed by gentle agitation in 3% octyl glycoside, 20 mM Tris-HCl, pH 7.4, 140 mM NaCl, 2 mM CaCl 2 at 4°C for 2 hours. The lysate was centrifuged at 100,000 g for 1 hour. The resulting supernatant was applied to a 5 mL bean lectin-Sepharose 4B column (E.Y. Labs) pre-equilibrated with 20 mM Tris-HCl, pH 7.4, 100 mM NaCl, 2 mM CaCl2,

1 % oktylglykosid (buffer A). Etter inkubering i 2 timer ble kolonnen vasket med1% octyl glycoside (buffer A). After incubation for 2 hours, the column was washed with

50 mL kald buffer A. GPIIb-llla holdt tilbake på lektin, ble eluert med buffer A inneholdende 10% dekstrose. Alle prosedyrer ble foretatt ved 4°C. Det oppnådde GPIIb-llla var ifølge SDS polyakrylamid-gelelektroforese >95%rent. 50 mL cold buffer A. GPIIb-lla retained on lectin, was eluted with buffer A containing 10% dextrose. All procedures were carried out at 4°C. The obtained GPIIb-lla was >95% pure according to SDS polyacrylamide gel electrophoresis.

Inkorporering av GPIIb-llla i liposomerIncorporation of GPIIb-lla into liposomes

En blanding av fosfatidylserin (70%) og fosfatidylcholin (30%) (Avanti Polar Lipids) fikk tørke seg til veggene i et glassrør under en nitrogenstrøm. Renset GPIIb-llla ble fortynnet til en sluttkonsentrasjon på 0,5mg/mL og blandet med fosfolipidene i et protein:fosfolipid-forhold på 1:3 (vektdeler). Blandingen ble resuspendert og ultralydbehandlet i et ultralydbad i 5 minutter. Blandingen ble deretter dialysert over natten ved å benytte et dialyserør med en 12.000-14.000 molekylvekt cutoff mot et 1000 gangers overskudd av 50 mM Tris-HCI, pH 7,4, 100 mM NaCI, 2 mM CaCI2(med to utskiftninger). De GPIIb-llla-holdige liposomene ble sentrifugert ved 12.000 g i 15 minutter og resuspendert i dialysebufferen til en endelig proteinkonsentrasjon på ca.1 mg/mL. Liposomene ble oppbevart ved -70°C inntil bruk. A mixture of phosphatidylserine (70%) and phosphatidylcholine (30%) (Avanti Polar Lipids) was allowed to dry to the walls of a glass tube under a stream of nitrogen. Purified GPIIb-lla was diluted to a final concentration of 0.5mg/mL and mixed with the phospholipids in a protein:phospholipid ratio of 1:3 (parts by weight). The mixture was resuspended and sonicated in an ultrasonic bath for 5 minutes. The mixture was then dialyzed overnight using a dialysis tube with a 12,000-14,000 molecular weight cutoff against a 1000-fold excess of 50 mM Tris-HCl, pH 7.4, 100 mM NaCl, 2 mM CaCl2 (with two exchanges). The GPIIb-IIIa-containing liposomes were centrifuged at 12,000 g for 15 minutes and resuspended in the dialysis buffer to a final protein concentration of approximately 1 mg/mL. The liposomes were stored at -70°C until use.

Konkurrerende binding til GPIIb-lllaCompetitive binding to GPIIb-lla

Bindingen til fibrinogen-reseptoren (GPIIb-llla) ble bestemt ved en indirekte konkurrerende bindingsmetode ved å benytte [<3>H]-SK&F-107260 som en RGD-type ligand. Bindingsbestemmelsen ble foretatt på et 96 brønns filtreringsplate-sett (Millipore Corporation, Bedford, MA) ved å benytte 0,22 u.m hydrofile Durapore-membraner. Veggene ble på forhånd dekket med 0,2 mL 10 u.g/mL polylysin (Sigma Chemical, Co. St. Louis, MO) ved romtemperatur i 1 time for å blokkere uspesifikk binding. Forskjellige konsentrasjoner av umerkede benzadiazepiner ble tilsatt til brønner i fire paralleller. [<3>H]-SK&F-107260 ble påført hver brønn i en sluttkonsentrasjon på 4,5 nM, etterfulgt av tilsetning av 1 ug av de rensede blodplate-GPIIb-llla-holdige liposomene. Blandingen ble inkubert i 1 time ved romtemperatur. GPIIb-llla-bundet [<3>H]-SK&F-107260 ble separert fra ubundet ved filtrering under bruk av en Millipore filtrerings-manifold, med påfølgende vask med iskald buffer (to ganger å 0,2 mL). Gjenværende bundet radioaktivitet på filterne ble tellet i 1,5 mL Ready Solve (Beckman Instruments, Fullerton, CA) i en Beckman væskescintillasjonsteller (Modell LS6800) med 40% effektivitet. Uspesifikk binding ble bestemt i nærvær av 2 jiM umerket SK&F-107260 og var konsekvent mindre enn 0,14% av den totale radioaktivitet tilsatt til prøvene. Alle datapunkter er gjennomsnitt av de fire parallellbestemmelsene. The binding to the fibrinogen receptor (GPIIb-llla) was determined by an indirect competitive binding method using [<3>H]-SK&F-107260 as an RGD-type ligand. The binding assay was performed on a 96-well filter plate kit (Millipore Corporation, Bedford, MA) using 0.22 µm hydrophilic Durapore membranes. The walls were precoated with 0.2 mL of 10 µg/mL polylysine (Sigma Chemical, Co. St. Louis, MO) at room temperature for 1 hour to block nonspecific binding. Different concentrations of unlabeled benzadiazepines were added to wells in four parallels. [<3>H]-SK&F-107260 was applied to each well at a final concentration of 4.5 nM, followed by the addition of 1 µg of the purified platelet GPIIb-IIIa-containing liposomes. The mixture was incubated for 1 hour at room temperature. GPIIb-IIIa-bound [<3>H]-SK&F-107260 was separated from unbound by filtration using a Millipore filtration manifold, followed by washing with ice-cold buffer (twice to 0.2 mL). Remaining bound radioactivity on the filters was counted in 1.5 mL of Ready Solve (Beckman Instruments, Fullerton, CA) in a Beckman liquid scintillation counter (Model LS6800) with 40% efficiency. Nonspecific binding was determined in the presence of 2 µM unlabeled SK&F-107260 and was consistently less than 0.14% of the total radioactivity added to the samples. All data points are averages of the four parallel determinations.

Kompetitive bindingsdata ble anlysert ved hjelp av en ikke-lineær minste kvadraters kurvetilpasningsprosedyre. Denne metode gir antagonistenes ICso-verdi (den antagonistkonsentrasjon som inhiberer spesifikk binding av [<3>H]-SK&F-107260 med 50% ved likevekt). IC50-verdien er relatert til likevekts-dissosiasjonskonstanten (Ki) av antagonisten på basis av Cheng og Prusoff-ligningen: Ki = IC50/(1+L/Kd), hvor L er konsentrasjonen av [<3>H]-SK&F-107260 benyttet i den kompetitive bindingsbestemmelse (4,5 nM) og Kd er dissosiasjonskonstanten av [<3>H]-SK&F-107260 som ifølge Scatchard-analyse er 4,5 nM. Competitive binding data were analyzed using a non-linear least squares curve fitting procedure. This method gives the antagonists' IC 50 value (the antagonist concentration that inhibits specific binding of [<3>H]-SK&F-107260 by 50% at equilibrium). The IC50 value is related to the equilibrium dissociation constant (Ki) of the antagonist based on the Cheng and Prusoff equation: Ki = IC50/(1+L/Kd), where L is the concentration of [<3>H]-SK&F-107260 used in the competitive binding determination (4.5 nM) and Kd is the dissociation constant of [<3>H]-SK&F-107260 which according to Scatchard analysis is 4.5 nM.

Forbindelser ifølge foreliggende oppfinnelse inhiberer vitronectin-binding til SK&F-107260 med en Ki på vitronectin-reseptoren som er ca. ti ganger større enn den for fibrinogen-reseptoren. Foretrukne forbindelser har en Ki-verdi på vitronectin-reseptoren som er tredve ganger høyere enn den for fibrinogen-reseptoren. De mest foretrukne forbindelsene har en Ki-verdi på vitronectin-reseptoren som er hundre ganger høyere enn fibrinogen-reseptoren. Compounds according to the present invention inhibit vitronectin binding to SK&F-107260 with a Ki on the vitronectin receptor that is approx. ten times greater than that of the fibrinogen receptor. Preferred compounds have a Ki value on the vitronectin receptor that is thirty times higher than that of the fibrinogen receptor. The most preferred compounds have a Ki value on the vitronectin receptor that is one hundred times higher than the fibrinogen receptor.

De etterfølgende eksempler er ikke på noen måte ment å begrense rammen for oppfinnelsen, men er tatt med for å illustrere hvorledes forbindelsene ifølge oppfinnelsen kan fremstilles og benyttes. Fagmannen vil lett se muligheten for mange andre utførelsesformer. The following examples are in no way intended to limit the scope of the invention, but are included to illustrate how the compounds according to the invention can be prepared and used. The person skilled in the art will readily see the possibility of many other embodiments.

EksemplerExamples

GenereltGenerally

Kjernemagnetiske resonansspektra ble tatt opp ved 250 eller ved 400 MHz ved å benytte henholdsvis et Bruker AM250 eller Bruker AC 400 spektrometer. CDCI3 er deuteriokloroform, DMSO-d6er heksadeuteriodimetylsulfoksyd og CD3OD er tetradeuteriometanol. Kjemiske skift er angitt i parts per million (5) mot lavere felt fra den interne standard tetrametylsilan. Forkortelser av NMR-data er som følger: s=singlet, d=dublett, t=triplet, q=kvartet, m=multiplet, dd= dublett av dubletter, dt= dublett av tripletter, app=tilsynelatende, br= bred. J angir NMR-koblingskonstanten målt i Hertz. Kontinuerlige infrarødt (IR) spektra ble tatt opp på et Perkin Eimer 683 infrarødt spektrometer og Fourier transformasjons infrarødt (FTIR) spektra ble tatt opp på et Nicolet Impact 400 D infrarødt spektrometer. IR- og FTIR-spektra ble tatt opp i transmisjonsmodus, og bånd-posisjoner er angitt i inverse bølgetall (cm'<1>). Massespektra ble tatt opp enten på VG 70 FE, PE Syx API III eller VG ZAB HF instrumenter, ved å benytte FAB (fast atom bombardment) eller ES (elektrospray ioniseringsteknikk). Elementanalyser ble foretatt ved å benytte en Perkin Eimer 240C elemental analyzer. Smeltepunkter ble bestemt i et Thomas-Hoover smeltepunktapparat og er ukorrigerte. Alle temperaturer er angitt i °C. Nuclear magnetic resonance spectra were recorded at 250 or at 400 MHz using a Bruker AM250 or Bruker AC 400 spectrometer, respectively. CDCI3 is deuteriochloroform, DMSO-d6 is hexadeuteriodimethylsulfoxide and CD3OD is tetradeuterium methanol. Chemical shifts are indicated in parts per million (5) against lower fields from the internal standard tetramethylsilane. Abbreviations of NMR data are as follows: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, dd=doublet of doublets, dt=doublet of triplets, app=apparent, br=broad. J denotes the NMR coupling constant measured in Hertz. Continuous infrared (IR) spectra were recorded on a Perkin Eimer 683 infrared spectrometer and Fourier transform infrared (FTIR) spectra were recorded on a Nicolet Impact 400 D infrared spectrometer. IR and FTIR spectra were recorded in transmission mode, and band positions are given in inverse wavenumber (cm'<1>). Mass spectra were recorded either on VG 70 FE, PE Syx API III or VG ZAB HF instruments, using FAB (solid atom bombardment) or ES (electrospray ionization technique). Elemental analyzes were carried out using a Perkin Eimer 240C elemental analyzer. Melting points were determined in a Thomas-Hoover melting point apparatus and are uncorrected. All temperatures are given in °C.

Analtech Silica Gel GF og E. Merck Silica Gel 60 F-254 tynnskiktplater ble benyttet for tynnskiktkromatografi. Både hurtigkromatografi (flash chromatography) og gravitasjonskromatografi ble foretatt på E. Merck, Kieselgel 60 (230-400 mesh) silikagel. Analytisk og preparativ HPLC ble foretatt på Rainin eller Beckman kromatografer. ODS refererer seg til en oktadecylsilyl-derivatisert silikagel kromatografisk bærer. 5 [ x Apex-ODS angir en oktadecylsilyl-derivatisert silikagel kromatografisk bærer som har en nominell partikkelstørrelse på 5 u. og som produseres av Jones Chromatography, Littleton, Colorado. YMC ODS-AQ® er en ODS kromatografisk bærer og er et registrert varemerke tilhørende YMC Co. Ltd. Kyoto, Japan. PRP-1® er en polymer (styren-divinylbenzen) kromatografisk bærer og er et registrert varemerke tilhørende Hamilton Co. Reno, Nevada). Celite® er filterhjelp bestående av syrevasket kiselgur og er et registrert varemerke tilhørende Manville Corp. Denver, Colorado. Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin-layer plates were used for thin-layer chromatography. Both flash chromatography and gravity chromatography were performed on E. Merck, Kieselgel 60 (230-400 mesh) silica gel. Analytical and preparative HPLC were performed on Rainin or Beckman chromatographs. ODS refers to an octadecylsilyl derivatized silica gel chromatographic support. 5 [ x Apex-ODS denotes an octadecylsilyl derivatized silica gel chromatographic support having a nominal particle size of 5 µm and manufactured by Jones Chromatography, Littleton, Colorado. YMC ODS-AQ® is an ODS chromatographic support and is a registered trademark of YMC Co. Ltd. Kyoto, Japan. PRP-1® is a polymeric (styrene-divinylbenzene) chromatographic support and is a registered trademark of Hamilton Co. Reno, Nevada). Celite® is a filter aid consisting of acid-washed diatomaceous earth and is a registered trademark of Manville Corp. Denver, Colorado.

Metyl-(±)-7-karboksy-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat, metyl-(2S)-7-karboksy-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat, metyl-(2R)-7-karboksy-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat, metyl-(±)-7-karboksy-4-isopropyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat, metyl-(±)-7-karboksy-3-okso-2-(2-fenyletyl)-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat og metyl-(±)-8-karboksy-2-metyl-3-okso-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetat ble fremstillet ifølge metoden til Bondinell, et al. WO 93/00095. 2-(aminometyl)imidazol ble fremstillet etter fremgangsmåten i Annalen 1968, 718, 249. Methyl-(±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate, methyl-(2S)-7-carboxy- 4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate, methyl-(2R)-7-carboxy-4-methyl-3-oxo-2 ,3,4,5-tetrahydro-1 H -1,4-benzodiazepine-2-acetate, methyl-(±)-7-carboxy-4-isopropyl-3-oxo-2,3,4,5-tetrahydro- 1 H-1,4-benzodiazepine-2-acetate, methyl-(±)-7-carboxy-3-oxo-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1 H-1, 4-benzodiazepine-2-acetate and methyl-(±)-8-carboxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate were prepared according to the method of Bondinell, et al. WO 93/00095. 2-(Aminomethyl)imidazole was prepared according to the procedure in Annalen 1968, 718, 249.

Fremstilling 1Production 1

Fremstilling av metyl-(±)-7-karboksy-4-(2-metoksyetyl)-3-okso-2,3,4,5-tetrahydro-l H-1,4-benzodiazepin-2-acetat Preparation of methyl-(±)-7-carboxy-4-(2-methoxyethyl)-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate

a) tert-butyl-3-[(2-metoksyetyl)amino]metyl-4-nitrobenzoata) tert-butyl-3-[(2-methoxyethyl)amino]methyl-4-nitrobenzoate

En blanding av tert-butyl-3-metyl-4-nitrobenzoat (WO 93/00095; 14,96 g, A mixture of tert-butyl-3-methyl-4-nitrobenzoate (WO 93/00095; 14.96 g,

63,05 mmol), NBS(16,83 g, 94,58 mmol), benzoylperoksyd (1,53 g, 6,31 mmol) og CCU (315 mL) ble kokt under tilbakeløpskjøling. Etter 18,5 timer ble reaksjonsblandingen grundig avkjølt i is og filtrert for å fjerne det utfelte succinimid. Filtratet ble konsentrert og etterlot en gul olje. 63.05 mmol), NBS (16.83 g, 94.58 mmol), benzoyl peroxide (1.53 g, 6.31 mmol) and CCU (315 mL) were boiled under reflux. After 18.5 hours, the reaction mixture was thoroughly cooled in ice and filtered to remove the precipitated succinimide. The filtrate was concentrated to leave a yellow oil.

Denne gule oljen ble løst i tørr THF (315 mL) og i én porsjon tilsatt 2-metoksyetylamin (16,4 mL, 189,2 mmol). Den orange-gule løsningen ble omrørt ved romtemperatur i 40 minutter og deretter konsentrert for å fjerne THF. Residuet ble fortynnet med Et20 (630 mL) og vasket suksessivt med 1,0 N NaOH (125 mL) og H20 (125 mL). De kombinerte vandige lagene ble ekstrahert med Et20 (300 mL) og de kombinerte organiske lagene vasket med saltvann (125 mL) og tørket (MgS04). Konsentrering og silikagelkromatografi (3:2 EtOAc/heksaner) ga tittelforbindelsen (10,30 g, 53%) som en gul olje: TLC Rf (1:1, EtOAC/heksaner) 0,43; This yellow oil was dissolved in dry THF (315 mL) and 2-methoxyethylamine (16.4 mL, 189.2 mmol) was added in one portion. The orange-yellow solution was stirred at room temperature for 40 minutes and then concentrated to remove THF. The residue was diluted with Et 2 O (630 mL) and washed successively with 1.0 N NaOH (125 mL) and H 2 O (125 mL). The combined aqueous layers were extracted with Et 2 O (300 mL) and the combined organic layers were washed with brine (125 mL) and dried (MgSO 4 ). Concentration and silica gel chromatography (3:2 EtOAc/hexanes) afforded the title compound (10.30 g, 53%) as a yellow oil: TLC Rf (1:1, EtOAC/hexanes) 0.43;

<1>H NMR (250 MHz, CDCI3) 6 8,22 (d, J=1,7Hz, 1H); 7,99 (dd, J=8,4, 1,7Hz, 1H); 7,92 (d, J=8,4Hz, 1H); 4,08 (s, 2H); 3,51 (t, J=5,1Hz, 1H); 3,36 (s, 3H); 2,82 (t, J=5,1Hz, 2H); 1,61 (s, 9H); FTIR(CCU) 1723, 1530, 1369, 1302, 1162, 1116, 842 cm"<1>; <1>H NMR (250 MHz, CDCl 3 ) δ 8.22 (d, J=1.7Hz, 1H); 7.99 (dd, J=8.4, 1.7Hz, 1H); 7.92 (d, J=8.4Hz, 1H); 4.08 (s, 2H); 3.51 (t, J=5.1Hz, 1H); 3.36 (s, 3H); 2.82 (t, J=5.1Hz, 2H); 1.61 (s, 9H); FTIR(CCU) 1723, 1530, 1369, 1302, 1162, 1116, 842 cm"<1>;

MS (ES) m/e 311 (M+H)<*>, 255 (M+H - C4H8)<+>.MS (ES) m/e 311 (M+H)<*>, 255 (M+H - C 4 H 8 )<+>.

b) tert-butyl-3-[[N-(2-metoksyetyl)-N-(tert-butoksykarbonyl)]amino]metyl-4-nitrobenzoat b) tert-butyl-3-[[N-(2-methoxyethyl)-N-(tert-butoxycarbonyl)]amino]methyl-4-nitrobenzoate

Di-tert-butyl-dikarbonat (7,97g, 36,51 mmol) ble i én porsjon tilsatt til en løsning av tert-butyl-3-[(2-metoksyetyl)amino]metyl-4-nitrobenzoat (10,30 g, Di-tert-butyl dicarbonate (7.97 g, 36.51 mmol) was added in one portion to a solution of tert-butyl 3-[(2-methoxyethyl)amino]methyl-4-nitrobenzoate (10.30 g ,

33,19 mmol) i CHCI3(165 mL) ved romtemperatur. Etter 16 timer ble reaksjonsblandingen konsentrert og konsentrert på nytt fra heksaner (for å fjerne CHCI3). Silikagelkromatografi (20% EtOAc/heksaner) ga tittelforbindelsen (13,21 g, 97%) som en gul olje: TLC Rf (20% EtOAc/heksaner) 0,49; 33.19 mmol) in CHCl3 (165 mL) at room temperature. After 16 hours, the reaction mixture was concentrated and re-concentrated from hexanes (to remove CHCl 3 ). Silica gel chromatography (20% EtOAc/hexanes) gave the title compound (13.21 g, 97%) as a yellow oil: TLC Rf (20% EtOAc/hexanes) 0.49;

<1>H NMR (250 MHz, CDCI3) 5 7,85-8,15 (m, 3H); 4,75-4,95 (m, 2H); 3,35-3,65 (m, 4H), 3,25 (bs s, 3H); 1,60 (s, 9H); 1,15-1,80 (m, 9H); FTIR (CCI4) 1723, 1701, 1531, 1368, 1304, 1161, 1119 cm"1; <1>H NMR (250 MHz, CDCl 3 ) δ 7.85-8.15 (m, 3H); 4.75-4.95 (m, 2H); 3.35-3.65 (m, 4H), 3.25 (bs s, 3H); 1.60 (s, 9H); 1.15-1.80 (m, 9H); FTIR (CCI 4 ) 1723, 1701, 1531, 1368, 1304, 1161, 1119 cm"1;

MS (ES) m/e 428,2 (M+NH4)<+>, 411,2 (M+H)<+>, 355,2 (M+H - C4H8)<+>, 311,2 (M+H -*C4H8-C02)+. MS (ES) m/e 428.2 (M+NH4)<+>, 411.2 (M+H)<+>, 355.2 (M+H - C4H8)<+>, 311.2 (M +H -*C4H8-C02)+.

c) tert-butyl-4-amino-3-[[N-(2-metoksyetyl)-N-(tert-butoksykarbonyl)]-aminojmetylbenzoat c) tert-butyl-4-amino-3-[[N-(2-methoxyethyl)-N-(tert-butoxycarbonyl)]-aminojmethylbenzoate

10% Pd/C (3,42 g, 3,22 mmol) ble tilsatt til en løsning av tert-butyl-3-[[N-(2-metoksyetyl)-N-(tert-butoksykarbonyl)]amino]metyl-4-nitrobenzoat (13,21 g, 10% Pd/C (3.42 g, 3.22 mmol) was added to a solution of tert-butyl-3-[[N-(2-methoxyethyl)-N-(tert-butoxycarbonyl)]amino]methyl- 4-nitrobenzoate (13.21 g,

32,18 mmol) i EtOAc (320 mL) og blandingen ristet på et Parr-apparat ved romtemperatur under H2(3,9 kg/cm<2>). Etter 4 timer ble reaksjonsblandingen filtrert gjennom Celite® og filtratet konsentrert for å gi tittelforbindelsen (12,16 g, 99%) som et farveløst skum: TLC Rf (20% EtOAc/heksaner) 0,34; 32.18 mmol) in EtOAc (320 mL) and the mixture shaken on a Parr apparatus at room temperature under H2 (3.9 kg/cm<2>). After 4 h, the reaction mixture was filtered through Celite® and the filtrate concentrated to give the title compound (12.16 g, 99%) as a colorless foam: TLC Rf (20% EtOAc/hexanes) 0.34;

<1>H NMR (250 MHz, CDCI3) 8 7,68-7,77 (m, 2H); 6,56 (d, J=8,9Hz, 1H); 5,00 (br s, 2H); 4,46 (s, 2H); 3,38-3,52 (m, 2H); 3,32 (s, 3H); 3,20-3,35 (m, 2H); 1,57 (s, 9H), <1>H NMR (250 MHz, CDCl 3 ) δ 7.68-7.77 (m, 2H); 6.56 (d, J=8.9Hz, 1H); 5.00 (br s, 2H); 4.46 (s, 2H); 3.38-3.52 (m, 2H); 3.32 (s, 3H); 3.20-3.35 (m, 2H); 1.57 (p, 9H),

1,48 (s, 9H); FTIR (CCI4) 3490, 3340, 3230, 1703, 1673, 1642, 1367, 1284, 1149, 1170 cm'1; 1.48 (s, 9H); FTIR (CCl 4 ) 3490, 3340, 3230, 1703, 1673, 1642, 1367, 1284, 1149, 1170 cm -1 ;

MS (ES) m/e 403,2 (M+Na)<+>, 381,2 (M+H)\ 325,2 (M+H - C4H8f, 281 MS (ES) m/e 403.2 (M+Na)<+>, 381.2 (M+H)\ 325.2 (M+H - C4H8f, 281

(M<+>H - C4H8- C02)\ 269,0 (M<+>H- 2 x C4H8f, 225,0 (M<+>H - 2 x C4H8- C02f. (M<+>H - C4H8- C02)\ 269.0 (M<+>H- 2 x C4H8f, 225.0 (M<+>H - 2 x C4H8- C02f.

i in

d) t-butyl-(±)-4-[2-(1,4-dimetoksy-1,4-dioksobutyl)amino]-3-[[N-(2-metoksyetyl)-N-(tert-butoksykarbonyl)]amino]metylbenzoat d) t-butyl-(±)-4-[2-(1,4-dimethoxy-1,4-dioxobutyl)amino]-3-[[N-(2-methoxyethyl)-N-(tert-butoxycarbonyl) ]amino]methylbenzoate

En løsning av tert-butyl-4-amino-3-[[N-(2-metoksyetyl)-N-(tert-butoksykarbonyl)]amino]metylbenzoat (12,16 g, 31,96 mmol) og dimetylacetylen- A solution of tert-butyl-4-amino-3-[[N-(2-methoxyethyl)-N-(tert-butoxycarbonyl)]amino]methylbenzoate (12.16 g, 31.96 mmol) and dimethylacetylene-

) dikarboksylat (4,3 mL, 35,2 mmol) i MeOH (65 mL) ble kokt under tilbakeløpskjøling i 45 minutter og deretter avkjølt til RT. Den resulterende løsning ble kombinert med ) dicarboxylate (4.3 mL, 35.2 mmol) in MeOH (65 mL) was refluxed for 45 min and then cooled to RT. The resulting solution was combined with

MeOH (260 mL) og 10% Pd/C (6,80 g, 6,4 mmol) og blandingen ristet på et Parr-apparat ved RT under H2(3,5 kg/cm2). Etter 6,5 timer ble reaksjonsblandingen MeOH (260 mL) and 10% Pd/C (6.80 g, 6.4 mmol) and the mixture shaken on a Parr apparatus at RT under H 2 (3.5 kg/cm 2 ). After 6.5 hours, the reaction mixture was

filtrert gjennom Celite® og filtratet konsentrert på en rotasjonsfordamper. Residuetfiltered through Celite® and the filtrate concentrated on a rotary evaporator. The residue

> ble konsentrert på nytt fra CHCI3(for å fjerne MeOH) og ble deretter kromatografert på silikagel (30% EtOAc/heksaner). Tittelforbindelsen (15,03 g, 90%) ble oppnådd som en blekgul olje: TLC Rf (30% EtOAc/heksaner) 0,39; > was re-concentrated from CHCl3 (to remove MeOH) and then chromatographed on silica gel (30% EtOAc/hexanes). The title compound (15.03 g, 90%) was obtained as a pale yellow oil: TLC Rf (30% EtOAc/hexanes) 0.39;

<1>H NMR (250 MHz, CDCI3) 5 7,82 (dd, J=8,6, 2,0Hz, 1H); 7,72 (d, J=2,0Hz, 1H); 6,63 <1>H NMR (250 MHz, CDCl 3 ) δ 7.82 (dd, J=8.6, 2.0Hz, 1H); 7.72 (d, J=2.0Hz, 1H); 6.63

(d, J=8,6Hz, 1H); 6,35-6,55 (m, 1H); 4,55-4,70 (m, 1H); 4,52 (1/2 AB, J=15,1Hz, 1H); ) 4,40(1/2 AB, J=15,1Hz, 1H); 3,71 (s, 3H); 3,69 (s, 3H); 3,35-3,50 (m, 2H); 3,31 (s, (d, J=8.6Hz, 1H); 6.35-6.55 (m, 1H); 4.55-4.70 (m, 1H); 4.52 (1/2 AB, J=15.1Hz, 1H); ) 4.40(1/2 AB, J=15.1Hz, 1H); 3.71 (s, 3H); 3.69 (s, 3H); 3.35-3.50 (m, 2H); 3.31 (s,

3H); 3,20-3,30 (m, 2H); 2,98 (dd, J=16,2, 6,7Hz, 1H); 2,84 (dd, J=16,2, 6,8Hz, 1H); 3H); 3.20-3.30 (m, 2H); 2.98 (dd, J=16.2, 6.7Hz, 1H); 2.84 (dd, J=16.2, 6.8Hz, 1H);

1,56 (s, 9H), 1,48 (s, 1H); FTIR (CCI4) 3312, 1748, 1704, 1670, 1610, 1367, 1297, 1142, 1172 cm'1; 1.56 (s, 9H), 1.48 (s, 1H); FTIR (CCl 4 ) 3312, 1748, 1704, 1670, 1610, 1367, 1297, 1142, 1172 cm -1 ;

Me (ES) m/e 547,2 (M+Na)<+>, 525,2 (M+H)<+>, 469,2 (M+H - C4H8r, 425, 2 Me (ES) m/e 547.2 (M+Na)<+>, 525.2 (M+H)<+>, 469.2 (M+H - C4H8r, 425, 2

; (M+H -C4H8- C02)<+.>; (M+H -C4H8- CO2)<+.>

e) Metyl-(±)-7-karboksy-4-(2-metoksyetyl)-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre e) Methyl-(±)-7-carboxy-4-(2-methoxyethyl)-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid

TFA (140 mL) ble i én porsjon tilsatt til en løsning av t-butyl-(±)-4-[2-(1,4-TFA (140 mL) was added in one portion to a solution of t-butyl-(±)-4-[2-(1,4-

) dimetoksy-1,4-dioksobutyl)amino]-34[N-(2-metoksyetyl)-N-(tert-butoksykarbonyl)]amino]metylbenzoat (15,03 g, 28,65 mmol) i vannfritt CH2CI2) dimethoxy-1,4-dioxobutyl)amino]-34[N-(2-methoxyethyl)-N-(tert-butoxycarbonyl)]amino]methylbenzoate (15.03 g, 28.65 mmol) in anhydrous CH 2 Cl 2

(140 mL) ved 0°C, hvorpå den blekgule løsningen ble oppvarmet til RT. Etter 2 timer (140 mL) at 0°C, whereupon the pale yellow solution was warmed to RT. After 2 hours

ble løsningen konsentrert på en rotasjonsfordamper og residuet rekonsentrert fra toluen (for å fjerne gjenværende TFA). Den resulterende olje ble kombinert med toluen (280 mL) og Et3N (20 mL, 143 mmol) og blandingen kokt under tilbakeløpskjøling. Det ble dannet en lysegul homogen løsning. Etter 23,5 timer ble reaksjonsblandingen konsentrert på rotasjonsfordamperen for å etterlate et fast residuum. Dette ble løst i et minimum kokende MeOH (ca. 720 mL), fortynnet med H20 (720 mL) og surgjort med iseddik (8 mL). Løsningen ble avkjølt til RT og deretter avkjølt i kjøleskap! Etter flere timer ble mer iseddik (24 mL) tilsatt. Blandingen ble holdt i kjøleskap over natten og deretter filtrert. Faststoffet ble vasket suksessivt med MeOH og Et20, deretter tørket i høy vakuum for å gi tittelforbindelsen (6,40 g, 66%) som et nesten farveløst pulver: smp. 228-230°C; TLC R, (10% MeOH/CHCI3) 0,51; the solution was concentrated on a rotary evaporator and the residue reconcentrated from toluene (to remove residual TFA). The resulting oil was combined with toluene (280 mL) and Et 3 N (20 mL, 143 mmol) and the mixture boiled under reflux. A pale yellow homogeneous solution was formed. After 23.5 hours, the reaction mixture was concentrated on the rotary evaporator to leave a solid residue. This was dissolved in a minimum of boiling MeOH (ca. 720 mL), diluted with H 2 O (720 mL) and acidified with glacial acetic acid (8 mL). The solution was cooled to RT and then cooled in a refrigerator! After several hours, more glacial acetic acid (24 mL) was added. The mixture was refrigerated overnight and then filtered. The solid was washed successively with MeOH and Et 2 O, then dried under high vacuum to give the title compound (6.40 g, 66%) as an almost colorless powder: m.p. 228-230°C; TLC R, (10% MeOH/CHCl 3 ) 0.51;

<1>H NMR (250 MHz, DMSO-d6) 5 7,59 (d, J=1,9Hz, 1H); 7,54 (dd, J=8,5, 1,9Hz, 1H); 6,50-6,60 (m, 2H); 5,43 (d, J=16,6Hz, 1H); 5,12-5,22 (m, 1H); 4,04 (d, J=16,6Hz, 1H); 3,60 (s, 3H); 3,20-3,70 (m, 4H); 3,08 (s, 3H); 2,83 (dd, J=16,7, 8,8Hz, 1H); 2,65 (dd, J=16,7, 5,3Hz, 1H); <1>H NMR (250 MHz, DMSO-d6) δ 7.59 (d, J=1.9Hz, 1H); 7.54 (dd, J=8.5, 1.9Hz, 1H); 6.50-6.60 (m, 2H); 5.43 (d, J=16.6Hz, 1H); 5.12-5.22 (m, 1H); 4.04 (d, J=16.6Hz, 1H); 3.60 (s, 3H); 3.20-3.70 (m, 4H); 3.08 (s, 3H); 2.83 (dd, J=16.7, 8.8Hz, 1H); 2.65 (dd, J=16.7, 5.3Hz, 1H);

MS (ES) m/e 359,0 (M+Na)<+>, 337,0 (M+H)<+>. Moderluten ble konsentrert på rotasjonsfordamper til ca. 500 mL, avkjølt og filtrert for å gi mer av tittelforbindelsen (1,51 g, totalt=7,91g, 82%) som et lysegult faststoff: smp. 226-229,5°C. MS (ES) m/e 359.0 (M+Na)<+>, 337.0 (M+H)<+>. The mother liquor was concentrated on a rotary evaporator to approx. 500 mL, cooled and filtered to give more of the title compound (1.51 g, total=7.91 g, 82%) as a pale yellow solid: m.p. 226-229.5°C.

Fremstilling 2Manufacturing 2

Ved bruk av fremgangsmåtene under Fremstilling 1, men med 3,4-metylendioksyfenetylamin i stedet for 2-metoksyetylamin, ble følgende forbindelse fremstillet: a) Metyl-(±)-7-karboksy-4-[2-(3,4-metylendioksyfenyl)etyl]-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat. Using the methods under Preparation 1, but with 3,4-methylenedioxyphenethylamine instead of 2-methoxyethylamine, the following compound was prepared: a) Methyl-(±)-7-carboxy-4-[2-(3,4-methylenedioxyphenyl) )ethyl]-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate.

<1>H NMR (DMSO-d6) 5 7,51 (dd, J=8,6, 2Hz, 1H); 7,45 (s, 1H); 6,57 (m, 2H); 6,49 (m, 2H); 5,87 (s, 2H); 5,32 (d, J=16,5Hz, 1H), 5,07 (m, 1H); 3,78 (d, J=16,5Hz, 1H); 3,62 (s, 3H); 3,56 (m, 2H); 2,88 (dd, J=16,7, 8,8Hz, 1H); 2,60 (m, 3H). <1>H NMR (DMSO-d6) δ 7.51 (dd, J=8.6, 2Hz, 1H); 7.45 (s, 1H); 6.57 (m, 2H); 6.49 (m, 2H); 5.87 (s, 2H); 5.32 (d, J=16.5Hz, 1H), 5.07 (m, 1H); 3.78 (d, J=16.5Hz, 1H); 3.62 (s, 3H); 3.56 (m, 2H); 2.88 (dd, J=16.7, 8.8Hz, 1H); 2.60 (m, 3H).

Fremstilling 3Manufacturing 3

Fremstilling av metyl-(±)-7-karboksy-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat Preparation of methyl-(±)-7-carboxy-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate

a) tert-butyl-3-[[bis-(t-butoksykarbonyl)]amino]metyl-4-nitrobenzoat a) tert-butyl-3-[[bis-(t-butoxycarbonyl)]amino]methyl-4-nitrobenzoate

Di-tert-butyliminodikarboksylat (4,35 g, 20,0 mmol) ble tilsatt til en suspensjon Di-tert-butyliminodicarboxylate (4.35 g, 20.0 mmol) was added to a suspension

av natriumhydrid (0,48 g, 20,0 mmol) i vannfritt DMF (30 mL) ved RT. Etter 30 minutter ble en løsning av t-butyl-3-brommetyl-4-nitrobenzoat (6,3 g, 20 mmol) i DMF (15 mL) hurtig tilsatt dråpevis. Etter 16 timer ble løsningsmidlet fordampet og residuet fordelt mellom EtOAc (200 mL) og vann (40 mL). Det organiske lag ble ekstrahert med vann (3 x 50 mL) og saltvann (40 mL) og tilslutt tørket over Na2S04. Fjerning av løsningsmidlet ga råproduktet som ble renset ved hurtigkromatografi (15:85; EtOAc:heksan) for å gi tittelforbindelsen (81,5%): MS (ES) m/e 453 (M+H)<+>; of sodium hydride (0.48 g, 20.0 mmol) in anhydrous DMF (30 mL) at RT. After 30 minutes, a solution of t-butyl-3-bromomethyl-4-nitrobenzoate (6.3 g, 20 mmol) in DMF (15 mL) was quickly added dropwise. After 16 h, the solvent was evaporated and the residue partitioned between EtOAc (200 mL) and water (40 mL). The organic layer was extracted with water (3 x 50 mL) and brine (40 mL) and finally dried over Na 2 SO 4 . Removal of the solvent gave the crude product which was purified by flash chromatography (15:85; EtOAc:hexane) to give the title compound (81.5%): MS (ES) m/e 453 (M+H)<+>;

<1>H NMR (400 MHz, CDCI3) 5 7,97-8,10 (m, 3H); 5,16 (s, 2H); 1,62 (s, 9H),1,49 (s, 18H). <1>H NMR (400 MHz, CDCl 3 ) δ 7.97-8.10 (m, 3H); 5.16 (s, 2H); 1.62 (p, 9H), 1.49 (p, 18H).

b) tert-butyl-4-amino-3-[[bis-(t-butoksykarbonyl)]amino]metylbenzoatb) tert-butyl-4-amino-3-[[bis-(t-butoxycarbonyl)]amino]methylbenzoate

En løsning av tert-butyl-3-[[bis-(t-butoksykarbonyl)]amino]metyl-4-nitrobenzoat A solution of tert-butyl-3-[[bis-(t-butoxycarbonyl)]amino]methyl-4-nitrobenzoate

(4,2 g, 9,3 mmol) i etanol (150 mL) ble hydrogenert ved 2,8 kg/cm<2>i nærvær av 10% Pd på C (0,40 g). Etter 30 minutter ble katalysatoren frafiltrert og løsningsmidlet fjernet for å gi tittelforbindelsen i tilnærmet i kvantitativt utbytte: MS (ES) m/e 423 (M+H)<+>; (4.2 g, 9.3 mmol) in ethanol (150 mL) was hydrogenated at 2.8 kg/cm<2> in the presence of 10% Pd on C (0.40 g). After 30 minutes, the catalyst was filtered off and the solvent removed to give the title compound in approximately quantitative yield: MS (ES) m/e 423 (M+H)<+>;

<1>H NMR (400 MHz, CDCI3) 5 7,82 (s, 1H); 7,71 (d, J=8,4Hz, 1H); 6,56 (d, J=8,4Hz, 1H); 4,92 (br s, 2H); 4,68 (s, 2H); 1,62 (s, 9H); 1,49 (s, 18H). <1>H NMR (400 MHz, CDCl 3 ) δ 7.82 (s, 1H); 7.71 (d, J=8.4Hz, 1H); 6.56 (d, J=8.4Hz, 1H); 4.92 (br s, 2H); 4.68 (s, 2H); 1.62 (s, 9H); 1.49 (p, 18H).

c) (E/Z)-tert-butyl-4-[2-(1,4-dimetoksy-1,4-diokso-2-butenyl)amino]-3-[[bis-(t-butoksykarbonyl)]amino]metylbenzoat c) (E/Z)-tert-butyl-4-[2-(1,4-dimethoxy-1,4-dioxo-2-butenyl)amino]-3-[[bis-(t-butoxycarbonyl)]amino ]methyl benzoate

En løsning av tert-butyl-4-amino-3-[[bis-(t-butoksykarbonyl)]amino]-metylbenzoat (3,9 g, 9,2 mmol) og dimetylacetylen-dikarboksylat (1,34 g, 9,4 mmol) ble kokt under tilbakeløpskjøling i 1 time og inndampet til tørrhet for å gi tittelforbindelsen: MS (ES) m/e 565,2 (M+H)<+>; A solution of tert-butyl-4-amino-3-[[bis-(t-butoxycarbonyl)]amino]-methylbenzoate (3.9 g, 9.2 mmol) and dimethyl acetylene dicarboxylate (1.34 g, 9, 4 mmol) was refluxed for 1 hour and evaporated to dryness to give the title compound: MS (ES) m/e 565.2 (M+H)<+>;

<1>H NMR (400 MHz, CDCI3) 5 9,69 (s, 1H); 7,91 (s, 1H); 7,77 (m, 1H); 6,75 (d, J=7,3Hz, 1H); 5,56 (s, 1H); 4,92 (s, 2H); 3,77 (s, 3H); 3,59 (s, 3H); 1,62 (s, 9H); 1,49 (s, 18H). <1>H NMR (400 MHz, CDCl 3 ) δ 9.69 (s, 1H); 7.91 (s, 1H); 7.77 (m, 1H); 6.75 (d, J=7.3Hz, 1H); 5.56 (s, 1H); 4.92 (s, 2H); 3.77 (s, 3H); 3.59 (s, 3H); 1.62 (s, 9H); 1.49 (p, 18H).

d) tert-buty l-(±)-4-[2-( 1,4-dimetoksy-1,4-dioksobutyl)amino]-3-[[bis-(t-butoksykarbonyl)]amino]metylbenzoat d) tert-butyl l-(±)-4-[2-(1,4-dimethoxy-1,4-dioxobutyl)amino]-3-[[bis-(t-butoxycarbonyl)]amino]methylbenzoate

En løsning av (E/Z)-tert-butyl-4-[2-(1,4-dimetoksy-1,4-diokso-2-butenyl)amino]-3-[[bis-(t-butoksykarbonyl)]amino]metylbenzoat (5,2 g, 9,2 mmol) i metanol (150 mL) ble hydrogenert ved 2,8 kg/cm<2>i nærvær av 10% Pd/C (0,75 g). Etter 2 timer ble katalysatoren frafiltrert og løsningsmidlet fjernet for å gi råproduktet. Rensing ved hurtigkromatografi ga tittelforbindelsen (80%). A solution of (E/Z)-tert-butyl-4-[2-(1,4-dimethoxy-1,4-dioxo-2-butenyl)amino]-3-[[bis-(t-butoxycarbonyl)] amino]methylbenzoate (5.2 g, 9.2 mmol) in methanol (150 mL) was hydrogenated at 2.8 kg/cm<2> in the presence of 10% Pd/C (0.75 g). After 2 hours, the catalyst was filtered off and the solvent removed to give the crude product. Purification by flash chromatography gave the title compound (80%).

MS (ES) m/e 567,2 (M+H)<+>; MS (ES) m/e 567.2 (M+H)<+>;

<1>H NMR (400 MHz, CDCI3) 5 7,82 (s, 1H); 6,66 (d, J=8,5Hz, 1H); 6,39 (d, J=8,5Hz, 1H), 4,70 (d, J=4,5Hz, 2H); 4,61 (m, 1H); 3,72 (s, 6H); 2,82-2,99 (m, 2H); 1,62 (s, 9H); 1,49 (s, 18H). <1>H NMR (400 MHz, CDCl 3 ) δ 7.82 (s, 1H); 6.66 (d, J=8.5Hz, 1H); 6.39 (d, J=8.5Hz, 1H), 4.70 (d, J=4.5Hz, 2H); 4.61 (m, 1H); 3.72 (s, 6H); 2.82-2.99 (m, 2H); 1.62 (s, 9H); 1.49 (p, 18H).

e) (±)-4-[2-(1,4-dimetoksy-1,4-dioksobutyl)amino]-3-(aminometyl)benzoesyre-bis(trifluoracetat) e) (±)-4-[2-(1,4-dimethoxy-1,4-dioxobutyl)amino]-3-(aminomethyl)benzoic acid-bis(trifluoroacetate)

En løsning av tert-butyl-4-[2-(1,4-dimetoksy-1,4-dioksobutyl)amino]-3-[[bis-(t-butoksykarbonyl)]amino]metylbenzoat (4,0 g, 7,1 mmol) i en blanding av metylenklorid (100 mL) og trifluoreddiksyre (25 mL) ble holdt i 16 timer ved RT. Løsningsmidlene ble fordampet og residuet utgnidd med eter for å gi tittelforbindelsen i tilnærmet kvantitativt utbytte: MS (ES) m/e 310,2 (M+H)<+>; A solution of tert-butyl-4-[2-(1,4-dimethoxy-1,4-dioxobutyl)amino]-3-[[bis-(t-butoxycarbonyl)]amino]methylbenzoate (4.0 g, 7 .1 mmol) in a mixture of methylene chloride (100 mL) and trifluoroacetic acid (25 mL) was kept for 16 h at RT. The solvents were evaporated and the residue triturated with ether to give the title compound in approximately quantitative yield: MS (ES) m/e 310.2 (M+H)<+>;

<1>H NMR (400 MHz, DMSO-d6) 5 8,25 (br s, 3H); 7,89 (s, 1H); 7,79 (d, J=8,4Hz, 1H); 6,75 (d, J=8,4Hz, 1H); 6,25 (d, J=8,4Hz, 1H); 4,65 (m, 1H); 4,05 (s, 2H); 3,69 (s, 3H); 3,65 (s, 3H); 2,89-3,07 (m, 2H). <1>H NMR (400 MHz, DMSO-d6) δ 8.25 (br s, 3H); 7.89 (s, 1H); 7.79 (d, J=8.4Hz, 1H); 6.75 (d, J=8.4Hz, 1H); 6.25 (d, J=8.4Hz, 1H); 4.65 (m, 1H); 4.05 (s, 2H); 3.69 (s, 3H); 3.65 (s, 3H); 2.89-3.07 (m, 2H).

f) Metyl-(±)-7-karboksy-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat f) Methyl-(±)-7-carboxy-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate

En løsning av natriummetoksyd i metanol (25 vekt%, 6,7 mL, 30 mmol) ble tilsatt til en løsning av 4-[2-(1,4-dimetoksy-1,4-dioksobutyl)amino]-3-(aminometyl)benzoesyre-bis(trifluoracetat) (4,0 g, 7,0 mmol) ved -10°C under argon. Etter 30 minutter ble reaksjonen avbrutt med eddiksyre (1,5 mL). Reaksjonsblandingen ble holdt i 1 time ved -20°C og filtrert. Filterkaken ble oppslemmet i vann (30 mL) og filtrert for å gi tittelforbindelsen (65%); A solution of sodium methoxide in methanol (25% by weight, 6.7 mL, 30 mmol) was added to a solution of 4-[2-(1,4-dimethoxy-1,4-dioxobutyl)amino]-3-(aminomethyl )benzoic acid bis(trifluoroacetate) (4.0 g, 7.0 mmol) at -10 °C under argon. After 30 minutes, the reaction was quenched with acetic acid (1.5 mL). The reaction mixture was kept for 1 hour at -20°C and filtered. The filter cake was slurried in water (30 mL) and filtered to give the title compound (65%);

MS (ES) m/e 279,0 (M+H)<+>; MS (ES) m/e 279.0 (M+H)<+>;

<1>H NMR (400 MHz, DMSO-d6) 8 8,21 (t, J=5,4Hz, 1H); 7,55 (m, 2H); 6,55 (d, J=8,4Hz, 1H); 6,45 (s, 1H); 5,05 (m, 2H); 3,76 (dd, J=15,8, 7,5Hz, 1H); 2,82 (dd, 16,8, 9,8Hz, 1H); 2,65 (dd, J=16,8, 4,5Hz, 1H). <1>H NMR (400 MHz, DMSO-d6) δ 8.21 (t, J=5.4Hz, 1H); 7.55 (m, 2H); 6.55 (d, J=8.4Hz, 1H); 6.45 (s, 1H); 5.05 (m, 2H); 3.76 (dd, J=15.8, 7.5Hz, 1H); 2.82 (dd, 16.8, 9.8Hz, 1H); 2.65 (dd, J=16.8, 4.5Hz, 1H).

Fremstilling 4Manufacturing 4

Fremstilling av 2-(metylaminometyl)benzimidazol-dihydrokloridPreparation of 2-(methylaminomethyl)benzimidazole dihydrochloride

a) 2-[(tert-butoksykarbonyl)sarkosyl]aminoanilina) 2-[(tert-butoxycarbonyl)sarcosyl]aminoaniline

En løsning av fenylendiamin (100 g, 0,924 mol) og Boc-sarkosin (175 g, A solution of phenylenediamine (100 g, 0.924 mol) and Boc-sarcosine (175 g,

0,924 mol) i DMF (1750 mL) ble avkjølt til -10°C under argon, og deretter i en langsom strøm tilsatt en løsning av DCC (190,8 g, 0,924 mol) i CH2CI2(1750 mL) i løpet av 1 time. Temperaturen steg til 0°C under tilsetningen. Reaksjonsblandingen ble omrørt over natten mens temperaturen fikk stige til RT. Det hvite bunnfallet ble fjernet ved filtrering og filtratet fortynnet med H20 (3,5 L) og med mettet saltvann (1 L). CH2CI2-laget ble fraskilt og den vandige fase ekstrahert med EtOAc (2 x 1 L). De kombinerte organiske lagene ble vasket med H20 (1 L) og saltvann (0,5 L), deretter konsentrert til et gult residuum (341 g). Dette ble utgnidd med EtOAc for å gi tittelforbindelsen (179,4 g, 70%); smp. 134-136°C. . . The temperature rose to 0°C during the addition. The reaction mixture was stirred overnight while the temperature was allowed to rise to RT. The white precipitate was removed by filtration and the filtrate diluted with H 2 O (3.5 L) and with saturated saline (1 L). The CH 2 Cl 2 layer was separated and the aqueous phase extracted with EtOAc (2 x 1 L). The combined organic layers were washed with H 2 O (1 L) and brine (0.5 L), then concentrated to a yellow residue (341 g). This was triturated with EtOAc to give the title compound (179.4 g, 70%); m.p. 134-136°C.

b) 2-[(N-tert-butoksykarbonyl-N-metyl)aminometyl]benzimidazolb) 2-[(N-tert-butoxycarbonyl-N-methyl)aminomethyl]benzimidazole

En løsning av 2-[(tert-butoksykarbonyl)sarkosyl]aminoanilin (178,4 g,A solution of 2-[(tert-butoxycarbonyl)sarcosyl]aminoaniline (178.4 g,

0,639 mol) i THF (900 mL) og AcOH (900 mL) ble kokt under tilbakeløpskjøling under argon i 1 time, hvoretter reaksjonsblandingen forsiktig ble satt under vakuum og det meste av THF fjernet ved destillasjon. Den gjenværende løsning ble helt over 0.639 mol) in THF (900 mL) and AcOH (900 mL) was refluxed under argon for 1 h, after which the reaction mixture was carefully placed under vacuum and most of the THF removed by distillation. The remaining solution was completely over

i isvann og tilsatt kons. NH4OH (1150 mL) for å justere pH til 10. Det ble dannet en olje som krystalliserte ved omrøring over natten. Faststoffet ble frafiltrert og tørket ved 50°C ved atmosfæretrykk i to dager for å etterlate et gulhvitt faststoff (167 g, 100%): smp. 140-150°C. Ytterligere tørking ved RT og atmosfæretrykk ga den rå tittelforbindelse (162 g, 97%). in ice water and added conc. NH 4 OH (1150 mL) to adjust the pH to 10. An oil formed which crystallized upon stirring overnight. The solid was filtered off and dried at 50°C at atmospheric pressure for two days to leave an off-white solid (167 g, 100%): m.p. 140-150°C. Further drying at RT and atmospheric pressure afforded the crude title compound (162 g, 97%).

c) 2-(metylaminometyl)benzimidazol-dihydrokloridc) 2-(methylaminomethyl)benzimidazole dihydrochloride

En løsning av 4 M HCI/dioksan (616 mL, 2,46 mol) og anisol (134 mL,A solution of 4 M HCl/dioxane (616 mL, 2.46 mol) and anisole (134 mL,

1,23 mol) ble avkjølt til 0°C under argon og i en langsom strøm tilsatt en løsning av 2-[(N-tert-butoksykarbonyl-N-metyl)aminometyl]benzimidazol (161 g, 0,616 mol) i CH2CI2(800 mL) i løpet av 30 minutter. Temperaturen steg til 8°C i løpet av tilsetningen og et hvitt bunnfall begynte å dannes før fullført tilsetning. Reaksjonsblandingen ble omrørt i 20 minutter og tittelforbindelsen (66,6 g, 46%) deretter oppsamlet ved filtrering: smp. 250-255°C (dekomp.). 1.23 mol) was cooled to 0°C under argon and in a slow stream added a solution of 2-[(N-tert-butoxycarbonyl-N-methyl)aminomethyl]benzimidazole (161 g, 0.616 mol) in CH 2 Cl 2 (800 mL) within 30 minutes. The temperature rose to 8°C during the addition and a white precipitate began to form before the addition was complete. The reaction mixture was stirred for 20 min and the title compound (66.6 g, 46%) was then collected by filtration: m.p. 250-255°C (decomp.).

Analyse beregnet for C9HnN3-2HCI:Analysis calculated for C9HnN3-2HCI:

C, 46,17; H, 5,60; N, 17,95. C, 46.17; H, 5.60; N, 17.95.

Funnet: C, 46,33; H, 5,68; N, 17,55. Found: C, 46.33; H, 5.68; N, 17.55.

Filtratet ble fortynnet med Et20 og blandingen fikk stå over natten. Filtrering ga ytterligere tittelforbindelse (62 g, totalutbytte 128,6 g, 89%) som et rosa faststoff: smp. 248-253°C (dekomp.). The filtrate was diluted with Et 2 O and the mixture was allowed to stand overnight. Filtration gave additional title compound (62 g, total yield 128.6 g, 89%) as a pink solid: m.p. 248-253°C (decomp.).

Eksempel 1Example 1

Fremstilling av (±)-7-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre Preparation of (±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine- 2-acetic acid

a) Metyl-(±)-7-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat a) Methyl-(±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1,4- benzodiazepine-2-acetate

En blanding av metyl-(±)-7-karboksy-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (0,57 g, 1,82 mmol) og tionylklorid (15 mL) ble kokt under tilbakeløpskjøling i 1 time. Den resulterende orange løsningen ble konsentrert til tørrhet for å etterlate et gulorange skum. Dette ble løst i CH2CI2(10 mL) og dråpevis tilsatt til en løsning inneholdende 2-(aminometyl)benzimidazol-dihydroklorid (1,2 g, 5,46 mmol), pyridin (0,72 g, 9,1 mmol) og trietylamin (0,55 g, 5,46 mmol) i CH2CI2(15 mL) ved 0°C under argon. Reaksjonsblandingen ble deretter omrørt ved RT under argon. Etter 25,5 timer ble CH2CI2(200 mL) og 5% NaHC03(50 mL) tilsatt til reaksjonsblandingen for å gi et lysegult bunnfall som ble filtrert og lufttørket for å gi tittelforbindelsen (0,11 g, 14%). Filtratet ble fraskilt og det organiske lag vasket med 5% NaHC03(50 mL) og deretter med H20 (50 mL) og deretter konsentrert på rotasjonsfordamper. Etter utgnidning med CH2CI2og lufttørking, ble det oppsamlet et gulaktig bunnfall som ga mer tittelforbindelse (0,35 g, 45%); A mixture of methyl-(±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (0.57 g, 1, 82 mmol) and thionyl chloride (15 mL) were boiled under reflux for 1 hour. The resulting orange solution was concentrated to dryness to leave a yellow-orange foam. This was dissolved in CH 2 Cl 2 (10 mL) and added dropwise to a solution containing 2-(aminomethyl)benzimidazole dihydrochloride (1.2 g, 5.46 mmol), pyridine (0.72 g, 9.1 mmol) and triethylamine (0.55 g, 5.46 mmol) in CH 2 Cl 2 (15 mL) at 0 °C under argon. The reaction mixture was then stirred at RT under argon. After 25.5 h, CH 2 Cl 2 (200 mL) and 5% NaHCO 3 (50 mL) were added to the reaction mixture to give a pale yellow precipitate which was filtered and air dried to give the title compound (0.11 g, 14%). The filtrate was separated and the organic layer washed with 5% NaHCO 3 (50 mL) and then with H 2 O (50 mL) and then concentrated on a rotary evaporator. After trituration with CH 2 Cl 2 and air drying, a yellowish precipitate was collected which gave more of the title compound (0.35 g, 45%);

<1>H NMR (250 MHz, CDCIs/DMSO-de) 5 6,30-8,70 (m, 9H); 5,52 (d, J=16Hz, 1H); 5,14 (m, 1H); 4,67 (d, J=5Hz, 2H); 3,80 (d, J=17Hz, 1H); 3,63 (s, 3H), 2,97 (s, 3H); 2,85 (dd, J=16,9Hz, 1H); 2,64 (dd, J=17,5Hz, 1H); <1>H NMR (250 MHz, CDCl/DMSO-de) δ 6.30-8.70 (m, 9H); 5.52 (d, J=16Hz, 1H); 5.14 (m, 1H); 4.67 (d, J=5Hz, 2H); 3.80 (d, J=17Hz, 1H); 3.63 (s, 3H), 2.97 (s, 3H); 2.85 (dd, J=16.9Hz, 1H); 2.64 (dd, J=17.5Hz, 1H);

MS (ES) m/e 422,2 (M+H)<+>.MS (ES) m/e 422.2 (M+H)<+>.

b) (±)-7-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre b) (±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine- 2-acetic acid

1,0 N LiOH (0,57 mL, 0,57 mmol) ble ved RT dråpevis tilsatt til en blanding av metyl-(±)-7-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (0,11 g, 0,26 mmol) i THF (4 mL) og H20 (5 mL). Den resulterende lyst brungule løsning ble omrørt i 21,5 timer og deretter konsentrert på rotasjonsfordamper. Det resulterende residuum ble lyofilisert for å gi råproduktet (0,11 g, 100%) som et gulaktig pulver. Preparativ HPLC (PRP-1® kolonne, trinnvis gradient, 10-20% CH3CN/H2O-0,1% TFA) førte til tittelforbindelsen:<1>H NMR (250 MHz, DMSO-d6) 6 6,45-9,06 (m, 9H); 5,53 (d, J=16Hz, 1H); 5,13 (m, 1H); 4,86 (d, J=5Hz, 2H); 3,87 (d, J=17Hz, 1H); 2,95 (s, 3H); 2,80 (dd, J=17,9Hz, 1H); 2,57 (dd, J=17,5Hz, 1H); 1.0 N LiOH (0.57 mL, 0.57 mmol) was added dropwise at RT to a mixture of methyl-(±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-4- methyl 3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (0.11 g, 0.26 mmol) in THF (4 mL) and H 2 O (5 mL) . The resulting pale tan solution was stirred for 21.5 hours and then concentrated on a rotary evaporator. The resulting residue was lyophilized to give the crude product (0.11 g, 100%) as a yellowish powder. Preparative HPLC (PRP-1® column, stepwise gradient, 10-20% CH3CN/H2O-0.1% TFA) led to the title compound: <1>H NMR (250 MHz, DMSO-d6) 6 6.45-9, 06 (m, 9H); 5.53 (d, J=16Hz, 1H); 5.13 (m, 1H); 4.86 (d, J=5Hz, 2H); 3.87 (d, J=17Hz, 1H); 2.95 (s, 3H); 2.80 (dd, J=17.9Hz, 1H); 2.57 (dd, J=17.5Hz, 1H);

MS (ES) m/e 408,2 (M+H)<+>.MS (ES) m/e 408.2 (M+H)<+>.

Analyse beregnet for C2iH2iN504 • 4/3 CF3C02H • H20:Analysis calculated for C2iH2iN504 • 4/3 CF3C02H • H20:

C, 49,22; H, 4,25; N, 12,13. C, 49.22; H, 4.25; N, 12,13.

Funnet: C, 49,24; H, 4,22; N, 12,11. Found: C, 49.24; H, 4.22; N, 12,11.

Eksempel 2Example 2

Fremstilling av (±)-7-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-3-okso-4-(2-fenyletyl^S^S-tetrahydro-IH-l^-benzodiazepin^-eddiksyre Preparation of (±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-3-oxo-4-(2-phenylethyl^S^S-tetrahydro-1H-1^-benzodiazepine^-acetic acid

a) Metyl-(±)-7-[[[(2-benzimidazolyl)-metyl]amino]karbonyl]-3-okso-4-(2-fenyletyl)-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat a) Methyl-(±)-7-[[[(2-benzimidazolyl)-methyl]amino]carbonyl]-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1 H -1,4-benzodiazepine-2-acetate

EDC (230 mg, 1,2 mmol) ble tilsatt til en omrørt løsning av metyl-(±)-7-karboksy-3-okso-4-(2-fenyletyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (382,4 mg, 1,0 mmol), 2-(aminometyl)benzimidazol-dihydroklorid (264 mg, EDC (230 mg, 1.2 mmol) was added to a stirred solution of methyl-(±)-7-carboxy-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1H -1,4-benzodiazepine-2-acetate (382.4 mg, 1.0 mmol), 2-(aminomethyl)benzimidazole dihydrochloride (264 mg,

1,2 mmol), HOBT-H20 (162 mg, 1,2 mmol) og diisopropyletylamin (0,70 mL,1.2 mmol), HOBT-H 2 O (162 mg, 1.2 mmol) and diisopropylethylamine (0.70 mL,

4,0 mmol) i vannfritt DMF (5 mL) ved RT. Etter 19 timer ble reaksjonsblandingen konsentrert på rotasjonsfordamper (høyvakuum) og residuet fordelt mellom H20 4.0 mmol) in anhydrous DMF (5 mL) at RT. After 19 hours, the reaction mixture was concentrated on a rotary evaporator (high vacuum) and the residue partitioned between H20

(5 mL) og EtOAc (20 mL). Lagene ble separert og det organiske lag vasket med H20 (5 mL). Tørking (MgS04), konsentrering og silikagelkromatografi (pakket med 5% MeOH/CHCI3; gradient: 5% MeOH i 1:1 EtOAc/CHCI3(300 mL) deretter 10% MeOH/EtOAc (400 mL) deretter 10% MeOH/CHCI3) ga tittelforbindelsen (414,9 mg, 81%) som et hvitaktig faststoff: TLC (10% MeOH/EtOAc) Rf 0,62; (5 mL) and EtOAc (20 mL). The layers were separated and the organic layer washed with H 2 O (5 mL). Drying (MgSO 4 ), concentration and silica gel chromatography (packed with 5% MeOH/CHCl 3 ; gradient: 5% MeOH in 1:1 EtOAc/CHCl 3 (300 mL) then 10% MeOH/EtOAc (400 mL) then 10% MeOH/CHCl 3 ) gave the title compound (414.9 mg, 81%) as an off-white solid: TLC (10% MeOH/EtOAc) Rf 0.62;

<1>H NMR (250 MHz, DMSO-d6) 5 8,72 (br t, J=5,6Hz, 1H); 7,35-7,75 (m, 4H); 7,00-7,35 (m, 7H); 6,56 (d, J=8,4Hz, 1H); 6,37 (brd, J=3,5Hz, 1H); 5,42 (d, J=16,6Hz, 1H); 5,08-5,20 (m, 1H); 4,52-4,75 (m, 2H); 3,93 (d, J=16,6Hz, 1H); 3,45-3,72 (m, 2H); 3,61 (s, 3H); 2,83 (dd, J=16,7, 8,9Hz, 1H); 2,60-2,75 (m, 3H); <1>H NMR (250 MHz, DMSO-d6) δ 8.72 (br t, J=5.6Hz, 1H); 7.35-7.75 (m, 4H); 7.00-7.35 (m, 7H); 6.56 (d, J=8.4Hz, 1H); 6.37 (brd, J=3.5Hz, 1H); 5.42 (d, J=16.6Hz, 1H); 5.08-5.20 (m, 1H); 4.52-4.75 (m, 2H); 3.93 (d, J=16.6Hz, 1H); 3.45-3.72 (m, 2H); 3.61 (s, 3H); 2.83 (dd, J=16.7, 8.9Hz, 1H); 2.60-2.75 (m, 3H);

MS (ES) 512,2 (M+H)<+>.MS (ES) 512.2 (M+H)<+>.

b) (±)-7-[[[(2-benzimidazolyl)-metyl]amino]karbonyl]-3-okso-4-(2-fenyletyl)-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre b) (±)-7-[[[(2-benzimidazolyl)-methyl]amino]carbonyl]-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1 H-1 ,4-benzodiazepine-2-acetic acid

En blanding av metyl-(±)-7-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-3-okso-4-(2-fenyletyl)-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat (413,1 mg, A mixture of methyl-(±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1 H -1,4-benzodiazepine-2-acetate (413.1 mg,

0,81 mmol), 1,0 N LiOH (0,97 mL, 0,97 mmol), THF (4 mL) og H20 (3 mL) ble omrørt ved 40-45°C i 20 minutter og den resulterende løsning omrørt ved RT i 17 timer. Surgjøring med TFA (0,19 mL, 2,4 mmol) og konsentrering etterlot et hvitaktig faststoff. Omkrystallisasjon fra CH3CN/H20 ga tittelforbindelsen (343,2 mg, 69%) som etfarveløst pulver: HPLC (PRP-1®, 30% CH3CN/H2O-0,1% TFA) K'=1,5; 0.81 mmol), 1.0 N LiOH (0.97 mL, 0.97 mmol), THF (4 mL) and H 2 O (3 mL) were stirred at 40-45 °C for 20 min and the resulting solution stirred at RT for 17 h. Acidification with TFA (0.19 mL, 2.4 mmol) and concentration left an off-white solid. Recrystallization from CH 3 CN/H 2 O gave the title compound (343.2 mg, 69%) as a colorless powder: HPLC (PRP-1®, 30% CH 3 CN/H 2 O-0.1% TFA) K'=1.5;

<1>H NMR (400 MHz, CD3OD) 5 7,68-7,75 (m, 2H); 7,60 (dd, J=8,6, 2,2Hz, 1H); 7,51-7,58 (m, 2H); 7,49 (d, J=2,2Hz, 1H); 7,07-7,22 (m, 5H); 6,61 (d, J=8,6Hz, 1H); 5,46 (d, J=16,8Hz, 1H); 5,18 (dd, J=9,0, 5,1Hz, 1H); 4,95 (s, 2H); 3,81 (d, J=16,8Hz, 1H); 3,61-3,78 (m, 2H), 2,94 (dd, J=16,8, 9,0Hz, 1H); 2,71-2,83 (m, 2H); 2,65 (dd, J=16,8, 5,1 Hz, 1H): <1>H NMR (400 MHz, CD 3 OD) δ 7.68-7.75 (m, 2H); 7.60 (dd, J=8.6, 2.2Hz, 1H); 7.51-7.58 (m, 2H); 7.49 (d, J=2.2Hz, 1H); 7.07-7.22 (m, 5H); 6.61 (d, J=8.6Hz, 1H); 5.46 (d, J=16.8Hz, 1H); 5.18 (dd, J=9.0, 5.1Hz, 1H); 4.95 (s, 2H); 3.81 (d, J=16.8Hz, 1H); 3.61-3.78 (m, 2H), 2.94 (dd, J=16.8, 9.0Hz, 1H); 2.71-2.83 (m, 2H); 2.65 (dd, J=16.8, 5.1 Hz, 1H):

MS (ES) m/e 498,4 (M+H)<+>.MS (ES) m/e 498.4 (M+H)<+>.

Analyse beregnet for C28H27N5O4• CF3C02H • 0,25 H20:Analysis calculated for C28H27N5O4• CF3C02H • 0.25 H20:

C, 58,49; H, 4,66; N, 11,37. C, 58.49; H, 4.66; N, 11.37.

Funnet: C, 58,52; H, 4,47; N, 11,04. Found: C, 58.52; H, 4.47; N, 11.04.

Eksempel 3Example 3

Fremstilling av (±)-4-isopropyl-7-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre Preparation of (±)-4-isopropyl-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine- 2-acetic acid

a) Metyl-(±)-4-isopropyl-7-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat a) Methyl-(±)-4-isopropyl-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-3-oxo-2,3,4,5-tetrahydro-1 H-1,4- benzodiazepine-2-acetate

EDC (173 mg, 0,90 mmol) ble tilsatt til en omrørt løsning av metyl-(±)-7-karboksyl-4-isopropyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (240,3 mg, 0,75 mmol), 2-(aminometyl)benzimidazol-dihydroklorid (198 mg, EDC (173 mg, 0.90 mmol) was added to a stirred solution of methyl-(±)-7-carboxyl-4-isopropyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4 -benzodiazepine-2-acetate (240.3 mg, 0.75 mmol), 2-(aminomethyl)benzimidazole dihydrochloride (198 mg,

0,90 mmol), HOBT H20 (122 mg, 0,90 mmol) og diisopropyletylamin (0,52 mL,0.90 mmol), HOBT H 2 O (122 mg, 0.90 mmol) and diisopropylethylamine (0.52 mL,

3,0 mmol) i vannfritt DMF (4 mL) ved RT. Etter 20 timer ble reaksjonsblandingen konsentrert på en rotasjonsfordamper (høyvakuum) og residuet fortynnet med H20 (5 mL) for å gi et gummiaktig bunnfall. EtOAc (3 mL) ble tilsatt og blandingen kraftig omrørt. Bunnfallet forble gummiaktig men endret form slik at det var suspendert som en masse i løsningsmidlene. Løsningsmidlene ble suget av med en pipette og residuet suspendert i MeOH (3 mL) og EtOAc (6 mL). Blandingen ble kraftig omrørt ved RT i flere minutter og deretter avkjølt på is og filtrert. Filterkaken ble vasket med EtOAc og tørket i høyvakuum for å etterlate tittelforbindelsen (275,1 mg, 82%) som et hvitaktig pulver:<1>H NMR (250 MHz, 20%CD3OD/CDCL3) 6 7,45-7,70 (m, 4H); 7,15-7,35 (m, 2H); 6,56 (d, J=9,1Hz, 1H); 5,22 (d, J=16,9Hz, 1H); 5,13 (tilsynelatende t, 1H); 4,72-4,92 (m, 1H); 4,72 (s, 2H); 4,03 (d, J=16,9Hz, 1H); 3,74 (s, 3H); 3,00 (d, J=16,4, 7,7Hz, 1H); 2,67 (dd, J=16,4, 6,0Hz, 1H); 1,21 (d, J=6,7Hz, 3H); 1,03 (d, J=6,8Hz, 3H); 3.0 mmol) in anhydrous DMF (4 mL) at RT. After 20 h, the reaction mixture was concentrated on a rotary evaporator (high vacuum) and the residue diluted with H 2 O (5 mL) to give a gummy precipitate. EtOAc (3 mL) was added and the mixture stirred vigorously. The precipitate remained gummy but changed form so that it was suspended as a mass in the solvents. The solvents were pipetted off and the residue suspended in MeOH (3 mL) and EtOAc (6 mL). The mixture was vigorously stirred at RT for several minutes and then cooled on ice and filtered. The filter cake was washed with EtOAc and dried under high vacuum to leave the title compound (275.1 mg, 82%) as an off-white powder: <1>H NMR (250 MHz, 20%CD3OD/CDCL3) 6 7.45-7.70 (m, 4H); 7.15-7.35 (m, 2H); 6.56 (d, J=9.1Hz, 1H); 5.22 (d, J=16.9Hz, 1H); 5.13 (apparent t, 1H); 4.72-4.92 (m, 1H); 4.72 (s, 2H); 4.03 (d, J=16.9Hz, 1H); 3.74 (s, 3H); 3.00 (d, J=16.4, 7.7Hz, 1H); 2.67 (dd, J=16.4, 6.0Hz, 1H); 1.21 (d, J=6.7Hz, 3H); 1.03 (d, J=6.8Hz, 3H);

MS (ES) 450,2 (M+H)<+>.MS (ES) 450.2 (M+H)<+>.

b) (+)-4-isopropyl-7-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-3-okso-2,3,4,5-tetrahydrc-1 H-1,4-benzodiazepin-2-eddiksyre b) (+)-4-isopropyl-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-3-oxo-2,3,4,5-tetrahydrc-1H-1,4-benzodiazepine- 2-acetic acid

En blanding av metyl-(+)-4-isopropyl-7-[[[(2-benzimidazolyl)metyl]-amino]karbonyl]-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (275,1 mg, 0,61 mmol), 1,0 N LiOH (0,73 mL, 0,73 mmol), THF (3 mL) og H20 A mixture of methyl-(+)-4-isopropyl-7-[[[(2-benzimidazolyl)methyl]-amino]carbonyl]-3-oxo-2,3,4,5-tetrahydro-1H-1,4 -benzodiazepine-2-acetate (275.1 mg, 0.61 mmol), 1.0 N LiOH (0.73 mL, 0.73 mmol), THF (3 mL), and H 2 O

(2,3 mL) ble omrørt ved 35°C i 45 minutter og den resulterende løsning omrørt ved RT. Etter 17,5 timer ble løsningen filtrert og filtratet nøytralisert med 1,0 N HCI (0,73 mL). Siden produktet ikke utfeltes, ble løsningen surgjort med TFA (0,2 mL) og konsentrert. Det resulterende faststoff ble utgnidd med H20 for å etterlate et nesten farveløst faststoff, som ble oppløst under oppvarming i 1:1 CH3CN/H20. Løsningen ble avkjølt til RT og fortynnet med flere volumer H2O/0,1% TFA. ODS-kromatografi (20% CH3CN/H2O-0,1% TFA), konsentrering og lyofilisering ga tittelforbindelsen (293,4 mg, 80%) som et farveløst pulver: HPLC (PRP-1®, 20% CH3CN/H2O-0,1% TFA) K'=2,5; (2.3 mL) was stirred at 35°C for 45 min and the resulting solution stirred at RT. After 17.5 hours, the solution was filtered and the filtrate neutralized with 1.0 N HCl (0.73 mL). Since the product did not precipitate, the solution was acidified with TFA (0.2 mL) and concentrated. The resulting solid was triturated with H 2 O to leave an almost colorless solid, which was dissolved under heating in 1:1 CH 3 CN/H 2 O. The solution was cooled to RT and diluted with several volumes of H2O/0.1% TFA. ODS chromatography (20% CH3CN/H2O-0.1% TFA), concentration and lyophilization afforded the title compound (293.4 mg, 80%) as a colorless powder: HPLC (PRP-1®, 20% CH3CN/H2O-0 .1% TFA) K'=2.5;

<1>H NMR (400 MHz, CD3OD) 5 7,70-7,76 (m, 2H); 7,65 (d, J=2,2Hz, 1H); 7,61 (dd, J=8,5, 2,2Hz, 1H), 7,53-7,60 (m, 2H); 6,62 (d, J=8,5Hz, 1H); 5,33 (d, J=16,9Hz, 1H); 5,21 (dd, J=8,9, 5,2Hz, 1H); 4,97 (d, J=1,9Hz, 2H); 4,72-4,85 (m, 1H); 4,10 (d, J=16,9Hz, 1H); 2,96 (dd, J=16,8, 8,9Hz, 1H), 2,65 (dd, J=16,8, 5,2Hz, 1H); 1,21 (d, J=6,7Hz, 3H); 1,03 (d, J=6,8Hz, 3H); <1>H NMR (400 MHz, CD 3 OD) δ 7.70-7.76 (m, 2H); 7.65 (d, J=2.2Hz, 1H); 7.61 (dd, J=8.5, 2.2Hz, 1H), 7.53-7.60 (m, 2H); 6.62 (d, J=8.5Hz, 1H); 5.33 (d, J=16.9Hz, 1H); 5.21 (dd, J=8.9, 5.2Hz, 1H); 4.97 (d, J=1.9Hz, 2H); 4.72-4.85 (m, 1H); 4.10 (d, J=16.9Hz, 1H); 2.96 (dd, J=16.8, 8.9Hz, 1H), 2.65 (dd, J=16.8, 5.2Hz, 1H); 1.21 (d, J=6.7Hz, 3H); 1.03 (d, J=6.8Hz, 3H);

MS (ES) m/e 436,2 (M+H)<+>.MS (ES) m/e 436.2 (M+H)<+>.

Analyse beregnet for C23H25N504• 1,25 CF3C02H • 1,25 H20:Analysis calculated for C23H25N504• 1.25 CF3C02H • 1.25 H20:

C, 51,00; H, 4,83; N, 11,66. C, 51.00; H, 4.83; N, 11.66.

Funnet: C, 51,12; H, 4,91; N, 11,37. Found: C, 51.12; H, 4.91; N, 11.37.

Eksempel 4Example 4

Fremstilling av (±)-7-[[[N-(2-benzotiazolyl)metyl-N-metyl]amino]karbonyl]-4-metyl-S-okso^SAS-tetrahydro-IH-M-benzodiazepin^-eddiksyre Preparation of (±)-7-[[[N-(2-benzothiazolyl)methyl-N-methyl]amino]carbonyl]-4-methyl-S-oxo^SAS-tetrahydro-1H-M-benzodiazepine^-acetic acid

a) 2-brommetylbenzotiazola) 2-bromomethylbenzothiazole

En blanding av 2-metylbenzotiazol (2,0 g, 13,40 mmol), N-bromsuccinimid A mixture of 2-methylbenzothiazole (2.0 g, 13.40 mmol), N-bromosuccinimide

(2,39 g, 13,40 mmol) og AIBN (0,5 g, 3,04 mmol) i CCI4(40 mL) ble kokt under tilbakeløpskjøling i 12 timer og blandingen deretter avkjølt og filtrert. Filtratet ble konsentrert og renset ved silikagelkromatografi (5% EtOAc/heksan) for å gi tittelforbindelsen (2,19 g, 72%) som en gul olje:<1>H NMR (250 MHz, DMSO-d6) 8 5,12 (s, 2H); 7,5 (m, 2H); 8,01 (dd, J=7,9, 1,8Hz, 1H); 8,15 (dd, J=7,9, 1,8Hz, 1H). (2.39 g, 13.40 mmol) and AIBN (0.5 g, 3.04 mmol) in CCl 4 (40 mL) were refluxed for 12 h and the mixture then cooled and filtered. The filtrate was concentrated and purified by silica gel chromatography (5% EtOAc/hexane) to give the title compound (2.19 g, 72%) as a yellow oil: <1>H NMR (250 MHz, DMSO-d6) δ 5.12 ( s, 2H); 7.5 (m, 2H); 8.01 (dd, J=7.9, 1.8Hz, 1H); 8.15 (dd, J=7.9, 1.8Hz, 1H).

b) 2-[(metylamino)metyl]benzotiazolb) 2-[(methylamino)methyl]benzothiazole

Til en omrørt løsning av 2-brommetylbenzotiazol (0,4 g, 1,75 mmol) i THFTo a stirred solution of 2-bromomethylbenzothiazole (0.4 g, 1.75 mmol) in THF

(4 mL) ble det tilsatt 40% vandig metylamin (0,30 g, 8,77 mmol). Omrøring ble fortsatt over natten, hvorpå blandingen ble konsentrert. Residuet ble tatt opp i H20, nøytralisert med 2,5 N NaOH og ekstrahert med CH2CI2. De organiske ekstraktene ble tørket (MgS04) og konsentrert for å gi tittelforbindelsen (0,36 g, 80%) som en brun olje: (4 mL) was added 40% aqueous methylamine (0.30 g, 8.77 mmol). Stirring was continued overnight, after which the mixture was concentrated. The residue was taken up in H 2 O, neutralized with 2.5 N NaOH and extracted with CH 2 Cl 2 . The organic extracts were dried (MgSO 4 ) and concentrated to give the title compound (0.36 g, 80%) as a brown oil:

<1>H NMR (250 MHz, DMSO-d6) 5 2,70 (s, 3H); 4,71 (s, 2H); 7,55 (m, 2H); 8,0 (d, J=7,9Hz, 1H); 8,17 (d, J=7,9Hz, 1H). c) Metyl-(±)-7-[[[N-(2-benzotiazolyl)metyl-N-metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat En blanding av metyl-(±)-7-karboksy-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (0,25 g, 0,855 mmol), 2-[(metylamino)metyl]benzotiazol (0,228 g, 1,283 mmol), EDC (0,31 g, 1,0026 mmol), HOBT • H20 (0,14 g, 1,026 mmol) og diisopropyletylamin (0,30 mL, 1,711 mmol) i tørr DMF (5 mL) ble omrørt ved RT i 20 timer. Reaksjonsblandingen ble konsentrert og residuet tatt opp i H20 og ekstrahert med CH2CI2. De kombinerte organiske ekstraktene ble tørket (MgS04) og konsentrert. Silikagelkromatografi (5% MeOH/CH2CI2) ga tittelforbindelsen (0,289 g, 75%) som en gul olje:<1>H NMR (400 MHz, DMSO-d6) 5 2,65 (dd, J=16,8, 5,0Hz, 1H); 2,82 (dd, J=16,8, 8,9Hz, 1H); 2,90 (s, 3H); 3,15 (s, 3H); 3,62 (s, 3H); 3,90 (d, J=16,1Hz, 1H); 4,90 (s, 2H); 5,13 (m, 1H); 5,45 (d, J=16,1Hz, 1H); 6,29 (d, J=3,6Hz, 1H); 6,57 (d, J=8,3Hz, 1H); 7,19 (d, J=8,3Hz, 1H); 7,21 (s, 1H); 7,45 (t, J=7,4Hz, 1H); 7,52 (t, J=7,4Hz, 1H); 8,00 (d, J=7,9Hz, 1H); 8,10 (d, J=7,9Hz, 1H). d) (±)-7-[[[N-(2-benzotiazolyl)metyl-N-m^ 2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre 2,5 N NaOH (3,0 mL) ble tilsatt til en omrørt løsning av metyl-(±)-7-[[[N-(2-benzotiazolyl)metyl-N-metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (0,289 g, 0,639 mmol) i MeOH (3 mL) ved RT. Etter 3 timer ble blandingen konsentrert og residuet surgjort til pH 4. Det farveløse faststoff ble oppsamlet og utgnidd i Et20 for å gi tittelforbindelsen (0,250 g, 89%) som et farveløst faststoff:<1>H NMR (400 MHz, DMSO-d6) 5 2,55 (dd, J=16,8, 5,0Hz, 1H); 2,75 (dd, J=16,8, 8,9Hz, 1H); 2,91 (s, 3H); 3,1 (s, 3H); 3,9 (d, J=16,1Hz, 1H); 4,9 (d, J=5,7Hz, 2H); 5,10 (m, 1H); 5,45 (d, J=16,1Hz, 1H); 6,29 (d, J=3,6Hz, 1H); 6,57 (d, J=8,3Hz, 1H); 7,19 (d, J=8,3Hz, 1H); 7,21 (s, 1H); 7,45 (t, J=7,4Hz, 1H); 7,52 (t, J=7,4Hz, 1H); 8,00 (d, J=7,9Hz, 1H); 8,10 (d, J=7,9Hz, 1H); IR (KBr) 3500, 3286, 3100, 3000, 1735, 1719, 1662, 1652, 1614, 1595, 1482, 1392, 827, 765 cm'<1>; <1>H NMR (250 MHz, DMSO-d6) δ 2.70 (s, 3H); 4.71 (s, 2H); 7.55 (m, 2H); 8.0 (d, J=7.9Hz, 1H); 8.17 (d, J=7.9Hz, 1H). c) Methyl-(±)-7-[[[N-(2-benzothiazolyl)methyl-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepine-2-acetate A mixture of methyl-(±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine- 2-acetate (0.25 g, 0.855 mmol), 2-[(methylamino)methyl]benzothiazole (0.228 g, 1.283 mmol), EDC (0.31 g, 1.0026 mmol), HOBT • H2O (0.14 g, 1.026 mmol) and diisopropylethylamine (0.30 mL, 1.711 mmol) in dry DMF (5 mL) was stirred at RT for 20 h. The reaction mixture was concentrated and the residue taken up in H 2 O and extracted with CH 2 Cl 2 . The combined organic extracts were dried (MgSO 4 ) and concentrated. Silica gel chromatography (5% MeOH/CH 2 Cl 2 ) afforded the title compound (0.289 g, 75%) as a yellow oil:<1>H NMR (400 MHz, DMSO-d6) δ 2.65 (dd, J=16.8, 5, 0Hz, 1H); 2.82 (dd, J=16.8, 8.9Hz, 1H); 2.90 (s, 3H); 3.15 (s, 3H); 3.62 (s, 3H); 3.90 (d, J=16.1Hz, 1H); 4.90 (s, 2H); 5.13 (m, 1H); 5.45 (d, J=16.1Hz, 1H); 6.29 (d, J=3.6Hz, 1H); 6.57 (d, J=8.3Hz, 1H); 7.19 (d, J=8.3Hz, 1H); 7.21 (s, 1H); 7.45 (t, J=7.4Hz, 1H); 7.52 (t, J=7.4Hz, 1H); 8.00 (d, J=7.9Hz, 1H); 8.10 (d, J=7.9Hz, 1H). d) (±)-7-[[[N-(2-benzothiazolyl)methyl-N-m^ 2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid 2.5 N NaOH ( 3.0 mL) was added to a stirred solution of methyl-(±)-7-[[[N-(2-benzothiazolyl)methyl-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2 ,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (0.289 g, 0.639 mmol) in MeOH (3 mL) at RT. After 3 h the mixture was concentrated and the residue acidified to pH 4. The colorless solid was collected and triturated in Et 2 O to give the title compound (0.250 g, 89%) as a colorless solid:<1>H NMR (400 MHz, DMSO-d6 ) δ 2.55 (dd, J=16.8, 5.0Hz, 1H); 2.75 (dd, J=16.8, 8.9Hz, 1H); 2.91 (s, 3H); 3.1 (s, 3H); 3.9 (d, J=16.1Hz, 1H); 4.9 (d, J=5.7Hz, 2H); 5.10 (m, 1H); 5.45 (d, J=16.1Hz, 1H); 6.29 (d, J=3.6Hz, 1H); 6.57 (d, J=8.3Hz, 1H); 7.19 (d, J=8.3Hz, 1H); 7.21 (s, 1H); 7.45 (t, J=7.4Hz, 1H); 7.52 (t, J=7.4Hz, 1H); 8.00 (d, J=7.9Hz, 1H); 8.10 (d, J=7.9Hz, 1H); IR (KBr) 3500, 3286, 3100, 3000, 1735, 1719, 1662, 1652, 1614, 1595, 1482, 1392, 827, 765 cm'<1>;

MS (ES) m/e 439,2 (M+H)<+>.MS (ES) m/e 439.2 (M+H)<+>.

Analyse beregnet for C22H22N404S • 1,5 H20:Analysis calculated for C22H22N404S • 1.5 H20:

C, 56,76; H, 5,41; N, 12,03. C, 56.76; H, 5.41; N, 12.03.

Funnet: C, 56,37; H, 5,23; N, 11,86. Found: C, 56.37; H, 5.23; N, 11.86.

Eksempel 5Example 5

Fremstilling av (±)-7-[[[N-(2-benzoksazolyl)metyl-N-metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre Preparation of (±)-7-[[[N-(2-benzoxazolyl)methyl-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1 ,4-benzodiazepine-2-acetic acid

a) 2-brommetylbenzoksazola) 2-bromomethylbenzoxazole

Ved å følge fremgangsmåten i Eksempel 4(a) men med 2-metylbenzoksazol i By following the procedure in Example 4(a) but with 2-methylbenzoxazole i

stedet for 2^-metylbenzotiazol, ble tittelforbindelsen fremstillet (2,22 g, 70%) som en gul olje:<1>H NMR (250 MHz, DMSO>de) 5 5,17 (s, 2H); 7,55 (m, 2H); 8,01 (d, J=7,9, 1,8Hz, 1H); 8,20 (dd, J=7,9, 1,8Hz, 1H). in place of 2^-methylbenzothiazole, the title compound was prepared (2.22 g, 70%) as a yellow oil:<1>H NMR (250 MHz, DMSO>de) δ 5.17 (s, 2H); 7.55 (m, 2H); 8.01 (d, J=7.9, 1.8Hz, 1H); 8.20 (dd, J=7.9, 1.8Hz, 1H).

b) 2-[(metylamino)metyl]benzoksazolb) 2-[(methylamino)methyl]benzoxazole

Ved å følge fremgangsmåten i Eksempel 4(b) men med 2-brommetylbenzoksazol i stedet for 2-brommetylbenzotiazol, ble tittelforbindelsen (0,250 g, 71%) fremstillet som en brun olje:<1>H NMR (400 MHz, DMSO-d6) 6 2,75 (s, 3H); 4,71 (s, 2H); 7,60 (m, 2H); 8,01 (d, J=7,9Hz, 1H); 8,17 (d, J=7,9Hz, 1H). Following the procedure of Example 4(b) but with 2-bromomethylbenzoxazole in place of 2-bromomethylbenzothiazole, the title compound (0.250 g, 71%) was prepared as a brown oil:<1>H NMR (400 MHz, DMSO-d6) 6 2.75 (s, 3H); 4.71 (s, 2H); 7.60 (m, 2H); 8.01 (d, J=7.9Hz, 1H); 8.17 (d, J=7.9Hz, 1H).

c) Metyl-(+)-7-[[[N-(2-benzoksazolyl)metyl-N-metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat c) Methyl-(+)-7-[[[N-(2-benzoxazolyl)methyl-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepine-2-acetate

Ved å følge fremgangsmåten i Eksempel 4(c), men med 2-[(metylamino)metyljbenzoksazol i stedet for 2-[(metylamino)metyl]benzotiazol, ble tittelforbindelsen (0,342 g, 91%) fremstillet som en brun olje:<1>H NMR (DMSO-d6) 6 2,65 (dd, J=16,8, 5,0Hz, 1H); 2,82 (dd, J=16,8, 8,9Hz, 1H); 2,91 (s, 3H); 3,15 (s, 3H); 3,61 (s, 3H); 3,90 (d, J=16,1Hz, 1H); 4,91 (s, 2H); 5,15 (m, 1H); 5,47 (d, J=16,1Hz, 1H); 6,30 (d, J=3,6Hz, 1H); 6,57 (d, J=8,3Hz, 1H); 7,20 (m, 2H); 7,40 (m, 2H); 7,72 (t, J=7,4Hz, 2H); 7,95 (s, 1H). Following the procedure of Example 4(c), but with 2-[(methylamino)methyl]benzoxazole instead of 2-[(methylamino)methyl]benzothiazole, the title compound (0.342 g, 91%) was prepared as a brown oil: <1 >H NMR (DMSO-d 6 ) δ 2.65 (dd, J=16.8, 5.0Hz, 1H); 2.82 (dd, J=16.8, 8.9Hz, 1H); 2.91 (s, 3H); 3.15 (s, 3H); 3.61 (s, 3H); 3.90 (d, J=16.1Hz, 1H); 4.91 (s, 2H); 5.15 (m, 1H); 5.47 (d, J=16.1Hz, 1H); 6.30 (d, J=3.6Hz, 1H); 6.57 (d, J=8.3Hz, 1H); 7.20 (m, 2H); 7.40 (m, 2H); 7.72 (t, J=7.4Hz, 2H); 7.95 (pp, 1H).

d) (±)-7-[[[N-(2-benzoksazolyl)metyl-n-metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre d) (±)-7-[[[N-(2-benzoxazolyl)methyl-n-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H- 1,4-benzodiazepine-2-acetic acid

Metyl-(+)-7-[[[N-(2-benzoksazolyl)metyl-N-metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat ble forsåpet ved å følge fremgangsmåten i Eksempel 4(d). Rensing ved silikagelkromatografi (2:8:1 MeOH/CH2CI2/Et3N) ga tittelforbindelsen (0,231 g, 70%) som et hvitaktig faststoff:<1>H NMR (400 MHz, DMSO-d6) 6 2,45 (dd, J=16,8, 5,0Hz, 1H); 2,70 (dd, J=16,8, 8,9Hz, 1H); 2,90 (s, 3H); 3,15 (s, 3H); 3,91 (d, J=16,1Hz, 1H); 4,90 (d, J=5,7Hz, 2H); 5,07 (m, 1H); 5,45 (d, J=16,1Hz, 1H); 6,30 (d, J=3,6Hz, 1H); 6,58 (d, J=8,3Hz, 1H); 7,20 (m, 2H); 7,40 (m, 2H); 7,70 (m, 2H); IR (KBr) 3370, 3100, 3000, 1728, 1653, 1612, 1575, 1485, 1455, 1397, 831, 765 cm'<1>; Methyl-(+)-7-[[[N-(2-benzoxazolyl)methyl-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H- 1,4-benzodiazepine-2-acetate was saponified by following the procedure in Example 4(d). Purification by silica gel chromatography (2:8:1 MeOH/CH2Cl2/Et3N) afforded the title compound (0.231 g, 70%) as an off-white solid: <1>H NMR (400 MHz, DMSO-d6) 6 2.45 (dd, J =16.8, 5.0Hz, 1H); 2.70 (dd, J=16.8, 8.9Hz, 1H); 2.90 (s, 3H); 3.15 (s, 3H); 3.91 (d, J=16.1Hz, 1H); 4.90 (d, J=5.7Hz, 2H); 5.07 (m, 1H); 5.45 (d, J=16.1Hz, 1H); 6.30 (d, J=3.6Hz, 1H); 6.58 (d, J=8.3Hz, 1H); 7.20 (m, 2H); 7.40 (m, 2H); 7.70 (m, 2H); IR (KBr) 3370, 3100, 3000, 1728, 1653, 1612, 1575, 1485, 1455, 1397, 831, 765 cm'<1>;

MS (ES) m/e 421 (M-H)'.MS (ES) m/e 421 (M-H)'.

Analyse beregnet for C22H22N405• 1,25 H20:Analysis calculated for C22H22N405• 1.25 H20:

C, 59,39; H, 5,45; N, 12,50. C, 59.39; H, 5.45; N, 12.50.

Funnet: C, 59,43; H, 5,23; N, 12,14. Found: C, 59.43; H, 5.23; N, 12,14.

Eksempel 6Example 6

Fremstilling av (±)-7-[[[N-[2-(5(6)-klorbenzimidazolyl)metyl]-N-metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre Preparation of (±)-7-[[[N-[2-(5(6)-chlorobenzimidazolyl)methyl]-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4, 5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid

a) 2-[[(N-tert-butoksykarbonyl-N-metyl)amino]metyl]-5(6)-klorbenzimidazola) 2-[[(N-tert-butoxycarbonyl-N-methyl)amino]methyl]-5(6)-chlorobenzimidazole

Til en omrørt og avkjølt (0°C) blanding av Boc-sarkosin (2,0 g, 10,571 mmol) To a stirred and cooled (0 °C) mixture of Boc-sarcosine (2.0 g, 10.571 mmol)

og Et3N (1,12 g, 11,01 mmol) i vannfritt THF (25 mL) ble det tilsatt isobutylklorformiat (1,51 g, 11,01 mmol). Etter 1 time ble 4-klor-1,2-fenylendiamin (1,43 g, and Et 3 N (1.12 g, 11.01 mmol) in anhydrous THF (25 mL) was added isobutyl chloroformate (1.51 g, 11.01 mmol). After 1 hour, 4-chloro-1,2-phenylenediamine (1.43 g,

10,571 mmol) tilsatt. Omrøring ble fortsatt i 2 timer, hvorpå eddiksyre (10 mL) ble tilsatt og reaksjonsblandingen kokt under tilbakeløpskjøling. Etter 4 timer ble blandingen avkjølt, konsentrert, nøytralisert med 2,5 N NaOH og ekstrahert med CH2CI2. Tørking (MgS04), konsentrering og silikagelkromatografi (1% MeOH/CH2CI2) ga tittelforbindelsen (2,10 g, 67%) som et brunt skum:<1>H NMR (250 MHz, DMSO-d6) 8 1,45 (s, 9H); 2,95 (s, 3H); 4,60 (s, 2H); 7,10 (d, J=9,3Hz, 1H); 7,50 (d, J=9,3Hz, 1H); 7,60 (s, 1H). 10.571 mmol) added. Stirring was continued for 2 hours, whereupon acetic acid (10 mL) was added and the reaction mixture boiled under reflux. After 4 hours, the mixture was cooled, concentrated, neutralized with 2.5 N NaOH and extracted with CH 2 Cl 2 . Drying (MgSO 4 ), concentration and silica gel chromatography (1% MeOH/CH 2 Cl 2 ) afforded the title compound (2.10 g, 67%) as a brown foam:<1>H NMR (250 MHz, DMSO-d6) 8 1.45 (s , 9H); 2.95 (s, 3H); 4.60 (s, 2H); 7.10 (d, J=9.3Hz, 1H); 7.50 (d, J=9.3Hz, 1H); 7.60 (p, 1H).

b) 5(6)-klor-2-[(metylamino)metyl]benzimidazolb) 5(6)-chloro-2-[(methylamino)methyl]benzimidazole

Til en omrørt løsning av 2-[[(N-tert-butoksykarbonyl-N-metyl)amino]metyl]-5(6)-klorbenzimidazol (2,10 g, 7,101 mmol) i vannfritt CH2CI2(20 mL) ble det tilsatt TFA (2,2 mL, 28,404 mmol). Etter omrøring over natten ble blandingen konsentrert, nøytralisert med 2,5 N NaOH og ekstrahert med CH2CI2. De kombinerte organiske ekstraktene ble vasket med saltvann, tørket (MgS04) og konsentrert for å gi tittelforbindelsen (1,25 g, 90%) som en brun olje. To a stirred solution of 2-[[(N-tert-butoxycarbonyl-N-methyl)amino]methyl]-5(6)-chlorobenzimidazole (2.10 g, 7.101 mmol) in anhydrous CH 2 Cl 2 (20 mL) was added TFA (2.2 mL, 28.404 mmol). After stirring overnight, the mixture was concentrated, neutralized with 2.5 N NaOH and extracted with CH 2 Cl 2 . The combined organic extracts were washed with brine, dried (MgSO 4 ) and concentrated to give the title compound (1.25 g, 90%) as a brown oil.

<1>H NMR (250 MHz, DMSO-d6) 8 2,35 (s, 3H); 3,88 (s, 2H); 7,17 (d, J=9,3Hz, 1H); 7,50 (d, J=9,3Hz, 1H); 7,55 (s, 1H). <1>H NMR (250 MHz, DMSO-d6) δ 2.35 (s, 3H); 3.88 (s, 2H); 7.17 (d, J=9.3Hz, 1H); 7.50 (d, J=9.3Hz, 1H); 7.55 (p, 1H).

c) Metyl-(±)-7-[[[N-[2-(5(6)-klorbenzimidazolyl)metyl]-N-metyl]amino]karbony^ metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat c) Methyl-(±)-7-[[[N-[2-(5(6)-chlorobenzimidazolyl)methyl]-N-methyl]amino]carbonyl^methyl-3-oxo-2,3,4,5 -tetrahydro-1H-1,4-benzodiazepine-2-acetate

Ved å følge fremgangsmåten i Eksempel 4(c), men med 5(6)-klor-2-[(metylamino)-metyl]benzimidazol i stedet for 2-[(metylamino)metyl]benzotiazol ble tittelforbindelsen (0,262 g, 59%) oppnådd som et hvitaktig faststoff etter silikagelkromatografi (5% MeOH/CH2CI2):<1>H NMR (250 MHz, DMSO-d6) 5 2,65 (dd, J=16,8, 5,0Hz, 1H); 2,82 (dd, J=16,8, 8,9Hz, 1H); 2,91 (s, 3H); 3,15 (s, 3H); 3,61 (s, 3H); 3,91 (d, J=16,1Hz, 1H); 4,80 (d, J=5,7Hz, 2H); 5,15 (m, 1H); 5,47 (d, J=16,1Hz, 1H); 6,25 (d, J=3,6Hz, 1H), 6,55 (d, J=8,3Hz, 1H); 7,20 (m, 2H); 7,60 (m, 2H). Following the procedure in Example 4(c), but with 5(6)-chloro-2-[(methylamino)methyl]benzimidazole instead of 2-[(methylamino)methyl]benzothiazole, the title compound (0.262 g, 59% ) obtained as a whitish solid after silica gel chromatography (5% MeOH/CH 2 Cl 2 ):<1>H NMR (250 MHz, DMSO-d6) δ 2.65 (dd, J=16.8, 5.0Hz, 1H); 2.82 (dd, J=16.8, 8.9Hz, 1H); 2.91 (s, 3H); 3.15 (s, 3H); 3.61 (s, 3H); 3.91 (d, J=16.1Hz, 1H); 4.80 (d, J=5.7Hz, 2H); 5.15 (m, 1H); 5.47 (d, J=16.1Hz, 1H); 6.25 (d, J=3.6Hz, 1H), 6.55 (d, J=8.3Hz, 1H); 7.20 (m, 2H); 7.60 (m, 2H).

d) (±)-7-[[[N-[2-(5(6)-klorbenzimidazolyl)metyl]-N-metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre d) (±)-7-[[[N-[2-(5(6)-chlorobenzimidazolyl)methyl]-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4, 5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid

Metyl-(±)-7-[[[N-[2-(5(6)-klorbenzimidazolyl)metyl]-N-metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat ble forsåpet ved å følge fremgangsmåten i Eksempel 4(d). Utgnidning med EtOH/Et20 ga tittelforbindelsen (0,100 g, 69%) som et farveløst faststoff:<1>H NMR (400 MHz, DMSO-d6) 8 2,55 (dd, J=16,8, 5,0Hz, 1H); 2,75 (dd, J=16,8, 8,9Hz, 1H); 2,91 (s, 3H); 3,10 (s, 3H); 3,90 (d, J=16,1Hz, 1H), 4,9 (s, 2H); 5,10 (m, 1H); 5,45 (d, J=16,1Hz, 1H); 6,25 (s, 1H); 6,57 (d, J=8,3Hz, 1H); 7,20 (m, 3H); 7,50 (d, J=9,3Hz, 1H); 7,60 (s, 1H); 12,3 (br s, 1H); 12,5 (br s, 1H): Methyl-(±)-7-[[[N-[2-(5(6)-chlorobenzimidazolyl)methyl]-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4, 5-tetrahydro-1H-1,4-benzodiazepine-2-acetate was saponified by following the procedure in Example 4(d). Trituration with EtOH/Et 2 O gave the title compound (0.100 g, 69%) as a colorless solid:<1>H NMR (400 MHz, DMSO-d6) δ 2.55 (dd, J=16.8, 5.0Hz, 1H ); 2.75 (dd, J=16.8, 8.9Hz, 1H); 2.91 (s, 3H); 3.10 (s, 3H); 3.90 (d, J=16.1Hz, 1H), 4.9 (s, 2H); 5.10 (m, 1H); 5.45 (d, J=16.1Hz, 1H); 6.25 (s, 1H); 6.57 (d, J=8.3Hz, 1H); 7.20 (m, 3H); 7.50 (d, J=9.3Hz, 1H); 7.60 (s, 1H); 12.3 (br s, 1H); 12.5 (br s, 1H):

MS (ES) m/e 456,0 (M+H)<+>.MS (ES) m/e 456.0 (M+H)<+>.

Analyse beregnet for C22H22CIN50v.Analysis calculated for C22H22CIN50v.

C, 56,30; H, 5,50; N, 14,92. C, 56.30; H, 5.50; N, 14.92.

Funnet: C, 56,27; H, 5,30; N, 15,14. Found: C, 56.27; H, 5.30; N, 15,14.

Eksempel 7Example 7

Fremstilling av (±)-7-[[[(2-indolyl)metyl]amino]karbonyI]-4-metyl-3-okso-2l3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre Preparation of (±)-7-[[[(2-indolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2l3,4,5-tetrahydro-1H-1,4-benzodiazepine-2- acetic acid

i a) lndol-2-karboksamidi a) indole-2-carboxamide

En blanding av etylindol-2-karboksylat (5 g, 26,5 mmol) og ammoniumhydroksyd (30 ml_)ble oppvarmet til 80°C i en forseglet glassbeholder over natten. Reaksjonsblandingen ble avkjølt og tittelforbindelsen (3,06 g, 73%) ble oppsamlet ved filtrering som et farveløst faststoff:<1>H NMR (400 MHz, DMSO-d6) 5 7,95 (br, 1H); 7,61 (d, 1H); 7,41 (d, 1H); 7,36 (br, 1H); 7,12 (t, 1H); 7,01 (t, 1H). A mixture of ethylene indole-2-carboxylate (5 g, 26.5 mmol) and ammonium hydroxide (30 mL) was heated to 80°C in a sealed glass container overnight. The reaction mixture was cooled and the title compound (3.06 g, 73%) was collected by filtration as a colorless solid: <1>H NMR (400 MHz, DMSO-d6) δ 7.95 (br, 1H); 7.61 (d, 1H); 7.41 (d, 1H); 7.36 (br, 1H); 7.12 (t, 1H); 7.01 (t, 1H).

b) 2-cyanindolb) 2-cyanindole

En løsning av indol-2-karboksamid (3,02 g, 18,8 mmol) i diklorfenyl-fosfinoksyd (20 mL) ble oppvarmet til 80°C over natten. Den avkjølte blandingen ble deretter helt over i 100 mL is og pH justert til 11 med 50% vandig natriumhydroksyd. Ekstraksjon med etylacetat og deretter konsentrering i vakuum ga et hvitaktig faststoff som ble renset ved silikagelkromatografi (1% MeOH/CH2CI2) for å gi tittelforbindelsen (2,41 g, 90%):<1>H NMR (400 MHz, DMSOd6) 5 7,68 (d, 1H); 7,46 (d, 1H); 7,36 (s, 1H); 7,34 (t, 1H); 7,14 (t,1H). A solution of indole-2-carboxamide (3.02 g, 18.8 mmol) in dichlorophenylphosphine oxide (20 mL) was heated to 80°C overnight. The cooled mixture was then poured into 100 mL of ice and the pH adjusted to 11 with 50% aqueous sodium hydroxide. Extraction with ethyl acetate and then concentration in vacuo gave an off-white solid which was purified by silica gel chromatography (1% MeOH/CH 2 Cl 2 ) to give the title compound (2.41 g, 90%):<1>H NMR (400 MHz, DMSOd6) 5 7.68 (d, 1H); 7.46 (d, 1H); 7.36 (s, 1H); 7.34 (t, 1H); 7.14 (t.1H).

c) 2-aminometylindolc) 2-aminomethylindole

LAH (42 mL, 1M løsning i THF) ble via en sprøyte dråpevis tilsatt til en LAH (42 mL, 1M solution in THF) was added dropwise via a syringe to a

løsning av 2-cyanindol (2,0 g, 14,1 mmol) i vannfritt THF (20 mL) undre avkjøling, hvorpå den resulterende løsning ble omrørt ved RT under argon i 5 timer. H20 ble dråpevis tilsatt under avkjøling for å ødelegge overskudd av LAH og det farveløse bunnfall fjernet ved filtrering og vasket med THF. Filtratet ble tørket (K2C03) og konsentrert for å gi tittelforbindelsen (2,11 g, kvantitativt) som et gult faststoff:<1>H NMR (400 MHz, DMSO-d6) 5 7,41 (d, 1H); 7,29 (d, 1H); 6,97 (t, 1H); 6,91 (t, 1H); 6,20 (s, 1H);3,82 (s, 2H); 2,18 (br, 1H). solution of 2-cyanindole (2.0 g, 14.1 mmol) in anhydrous THF (20 mL) under cooling, whereupon the resulting solution was stirred at RT under argon for 5 h. H 2 O was added dropwise with cooling to destroy excess LAH and the colorless precipitate removed by filtration and washed with THF. The filtrate was dried (K 2 CO 3 ) and concentrated to give the title compound (2.11 g, quantitative) as a yellow solid: 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.41 (d, 1H); 7.29 (d, 1H); 6.97 (t, 1H); 6.91 (t, 1H); 6.20 (s, 1H); 3.82 (s, 2H); 2.18 (br, 1H).

d) Metyl-(±)-7-[[[(2-indolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat d) Methyl-(±)-7-[[[(2-indolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1,4- benzodiazepine-2-acetate

EDC (1,53 g, 7,99 mmol) ble tilsatt til en løsning av metyl-(+)-7-karboksy-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (2,13 g, 7,26 mmol), 2-aminometylindol (1,06 g, 7,26 mmol), HOBT • H20 (1,08 g, 7,99 mmol) og diisopropyletylamin (1,53 mL, 8,71 mmol) i vannfritt DMF (10 mL) ved RT. Etter 20 timer ble reaksjonsblandingen konsentrert på en rotasjonsfordamper (høyvakuum). Residuet ble tatt opp i EtOAc og vasket med H20 og deretter med 10% Na2C03(2 x 30 mL), Tørking (MgS04), konsentrering og silikagelkromatografi (2% MeOH/CH2CI2) ga tittelforbindelsen (1,8 g, 60%); EDC (1.53 g, 7.99 mmol) was added to a solution of methyl-(+)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1, 4-benzodiazepine-2-acetate (2.13 g, 7.26 mmol), 2-aminomethylindole (1.06 g, 7.26 mmol), HOBT • H2O (1.08 g, 7.99 mmol) and diisopropylethylamine (1.53 mL, 8.71 mmol) in anhydrous DMF (10 mL) at RT. After 20 hours, the reaction mixture was concentrated on a rotary evaporator (high vacuum). The residue was taken up in EtOAc and washed with H 2 O and then with 10% Na 2 CO 3 (2 x 30 mL), drying (MgSO 4 ), concentration and silica gel chromatography (2% MeOH/CH 2 Cl 2 ) gave the title compound (1.8 g, 60%);

<1>H NMR (400 MHz, DMSO-d6) 5 8,56 (t, 1H); 7,95 (s, 1H); 7,59 (s, 1H); 7,56 (d, 1H); 7,43 (d, 1H); 7,33 (d, 1H); 7,01 (t, 1H); 6,93 (t, 1H); 6,55 (d, 1H); 6,33 (br, 1H); 6,25 (s, 1H); 5,49 (d, 1H); 5,14 (t, 1H); 4,56 (d, 2H); 3,82 (d, 1H); 3,61 (s, 3H); 2,92 (s, 3H); 2,75 (dd, 1H); 2,53 (d, 1H); <1>H NMR (400 MHz, DMSO-d6) δ 8.56 (t, 1H); 7.95 (s, 1H); 7.59 (s, 1H); 7.56 (d, 1H); 7.43 (d, 1H); 7.33 (d, 1H); 7.01 (t, 1H); 6.93 (t, 1H); 6.55 (d, 1H); 6.33 (br, 1H); 6.25 (s, 1H); 5.49 (d, 1H); 5.14 (t, 1H); 4.56 (d, 2H); 3.82 (d, 1H); 3.61 (s, 3H); 2.92 (s, 3H); 2.75 (dd, 1H); 2.53 (d, 1H);

MS (ES) m/e 421,2 (M+H)<+>.MS (ES) m/e 421.2 (M+H)<+>.

e) (±)-7-[[[(2-indolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre e) (±)-7-[[[(2-indolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2 -acetic acid

1,0 N NaOH (1 mL, 1,0 mmol) ble dråpevis tilsatt til en løsning av metyl-(±)-7-[[[(2-indolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (0,35 g, 0,83 mmol) i THF (5 mL) og MeOH (2 mL) ved RT. Den resulterende blanding ble omrørt i 20 timer og deretter konsentrert. Residuet ble løst i H20 (20 mL) og surgjort med TFA. ODS-kromatografi (27% CH3CN/H2O-0,1% TFA), konsentrering og lyofilisering ga tittelforbindelsen (100 mg, 30%) som et hvitaktig faststoff: HPLC (ODS, 5-60% CH3CN/H2O-0,1% TFA gradienteluering i løpet av 20 minutter) K'=10,2; 1.0 N NaOH (1 mL, 1.0 mmol) was added dropwise to a solution of methyl-(±)-7-[[[(2-indolyl)methyl]amino]carbonyl]-4-methyl-3- oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (0.35 g, 0.83 mmol) in THF (5 mL) and MeOH (2 mL) at RT. The resulting mixture was stirred for 20 hours and then concentrated. The residue was dissolved in H 2 O (20 mL) and acidified with TFA. ODS chromatography (27% CH3CN/H2O-0.1% TFA), concentration and lyophilization afforded the title compound (100 mg, 30%) as an off-white solid: HPLC (ODS, 5-60% CH3CN/H2O-0.1% TFA gradient elution over 20 minutes) K'=10.2;

<1>H NMR (400 MHz, DMSO-d6) 5 8,55 (t, 1H); 7,57 (s, 1H); 7,56 (d, 1H); 7,43 (d, 1H); 7,33 (d, 1H); 7,01 (t, 1H); 6,93 (t, 1H); 6,55 (d, 1H); 6,33 (br, 1H); 6,25 (s, 1H); 5,49 (d, 1H); 5,08 (t, 1H); 4,55 (d, 2H); 3,82 (d, 1H); 2,92 (s, 3H); 2,75 (dd, 1); 2,53 (d, 1H): <1>H NMR (400 MHz, DMSO-d6) δ 8.55 (t, 1H); 7.57 (s, 1H); 7.56 (d, 1H); 7.43 (d, 1H); 7.33 (d, 1H); 7.01 (t, 1H); 6.93 (t, 1H); 6.55 (d, 1H); 6.33 (br, 1H); 6.25 (s, 1H); 5.49 (d, 1H); 5.08 (t, 1H); 4.55 (d, 2H); 3.82 (d, 1H); 2.92 (s, 3H); 2.75 (dd, 1); 2.53 (d, 1H):

MS (ES) m/e 407,2 (M+H)<+>.MS (ES) m/e 407.2 (M+H)<+>.

Analyse beregnet for C22H22N404 • H20:Analysis calculated for C22H22N404 • H20:

C, 62,25; H, 5.70; N, 13,20. C, 62.25; H, 5.70; N, 13.20.

Funnet: C, 62,66; H, 5,64; N, 12,99. Found: C, 62.66; H, 5.64; N, 12.99.

Eksempel 8Example 8

Fremstilling av (2S)-7-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre Preparation of (2S)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2 -acetic acid

a) Metyl-(2S)-7-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat a) Methyl-(2S)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4- benzodiazepine-2-acetate

EDC (1,15 g, 6,02 mmol) ble tilsatt til en løsning av metyl-(2S)-7-karboksy-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (2,11 g, 5,02 mmol), 2-aminometylbenzimidazol-dihydroklorid (1,15 g, 6,02 mmol), HOBTH20 (811 mg, 6,02 mmol) og diisopropyletylamin (1,76 mL, 10 mmol) i vannfritt DMF (25 mL) ved RT. Etter 21 timer ble reaksjonsblandingen konsentrert på rotasjonsfordamper (høyvakuum) og residuet tatt opp i CH2CI2(240 mL) og vasket med H20. Det organiske lag ble tørket (Na2S04), løst i xylener og konsentrert på nytt for å fjerne gjenværende DMF. Råproduktet ble kromatografert på silikagel (MeOH/CHCI3) for å gi tittelforbindelsen (1,1 g, 52%). EDC (1.15 g, 6.02 mmol) was added to a solution of methyl-(2S)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1, 4-benzodiazepine-2-acetate (2.11 g, 5.02 mmol), 2-aminomethylbenzimidazole dihydrochloride (1.15 g, 6.02 mmol), HOBTH20 (811 mg, 6.02 mmol) and diisopropylethylamine (1 .76 mL, 10 mmol) in anhydrous DMF (25 mL) at RT. After 21 hours, the reaction mixture was concentrated on a rotary evaporator (high vacuum) and the residue was taken up in CH 2 Cl 2 (240 mL) and washed with H 2 O. The organic layer was dried (Na 2 SO 4 ), dissolved in xylenes and re-concentrated to remove residual DMF. The crude product was chromatographed on silica gel (MeOH/CHCl 3 ) to give the title compound (1.1 g, 52%).

b) (2S)-7-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre b) (2S)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine- 2-acetic acid

1 N NaOH (4,75 mL, 4,75 mmol) ble tilsatt til en kald løsning av metyl-(2S)-7-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat (1,0 g, 2,38 mmol), MeOH (10 mL) og H20 (5 mL). Løsningen ble omrørt ved romtemperatur i 18 timer og konsentrert. ODS-kromatografi (CH3CN/H2O-0,1% TFA) ga tittelforbindelsen (0,91 g, 94%): HPLC (5 Altex Ultrasphere ODS, 4,5 mm x 25 cm, 5%-60% CH3CN/H2O-0,1% TFA gradient i løpet av 20 minutter) K-5,7; 1 N NaOH (4.75 mL, 4.75 mmol) was added to a cold solution of methyl-(2S)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-4-methyl-3- oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (1.0 g, 2.38 mmol), MeOH (10 mL) and H 2 O (5 mL). The solution was stirred at room temperature for 18 hours and concentrated. ODS chromatography (CH3CN/H2O-0.1% TFA) gave the title compound (0.91 g, 94%): HPLC (5 Altex Ultrasphere ODS, 4.5 mm x 25 cm, 5%-60% CH3CN/H2O- 0.1% TFA gradient over 20 minutes) K-5.7;

<1>H NMR (400 MHz, DMSO-d6) 5 8,7-8,9 (t, 1H); 6,3-7,6 (m, 8H); 5,4-5,6 (d, 1H); 5,0-5,1 (q, 1H); 4,5-4,7 (d, 2H); 3,8-3,9 (d, 1H); 2,9-3,0 (s, 3H); 2,7-2,9 (dd, 2H); <1>H NMR (400 MHz, DMSO-d6) δ 8.7-8.9 (t, 1H); 6.3-7.6 (m, 8H); 5.4-5.6 (d, 1H); 5.0-5.1 (q, 1H); 4.5-4.7 (d, 2H); 3.8-3.9 (d, 1H); 2.9-3.0 (s, 3H); 2.7-2.9 (dd, 2H);

MS (ES) m/e 408,2 (M+H)<+>.MS (ES) m/e 408.2 (M+H)<+>.

Analyse beregnet for C2iH2iN504 • 3,5 H20:Analysis calculated for C2iH2iN504 • 3.5 H20:

C, 53,61; H, 6,00; N, 14,89. C, 53.61; H, 6.00; N, 14.89.

Funnet: C. 53,38; H, 6,00; N, 14,55. [<x]D -237° (c 0,1). Found: C. 53.38; H, 6.00; N, 14.55. [<x]D -237° (c 0.1).

Eksempel 9Example 9

Fremstilling av (2R)-7-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre Preparation of (2R)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine- 2-acetic acid

a) Metyl-(2R)-7-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-2,3,4,5-tetrahydro-4-metyl-3-okso-1 H-1,4-benzodiazepin-2-acetat a) Methyl-(2R)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1 H-1,4- benzodiazepine-2-acetate

Ved å følge fremgangsmåten i Eksempel 8(a), men med metyl-(2R)-7-karboksy-4-metyl-3-okso-2,3,4,5-1H-1,4-benzodiazepin-2-acetat i stedet for (2S)-isomeren, ble tittelforbindelsen (0,37 g, 86%) fremstillet. By following the procedure in Example 8(a), but with methyl-(2R)-7-carboxy-4-methyl-3-oxo-2,3,4,5-1H-1,4-benzodiazepine-2-acetate instead of the (2S) isomer, the title compound (0.37 g, 86%) was prepared.

b) (2R)-7-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre b) (2R)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine- 2-acetic acid

Ved å følge fremgangsmåten i Eksempel 8(b), ble forbindelsen fra Eksempel 9(a) forsåpet for å gi tittelforbindelsen (0,20 g, 57%). HPLC (5 Altex Ultrasphere ODS, 4,5 mm x 25 cm, 12% CH3CN/H2O/0,1% TFA) K'=4,7; Following the procedure of Example 8(b), the compound from Example 9(a) was saponified to give the title compound (0.20 g, 57%). HPLC (5 Altex Ultrasphere ODS, 4.5 mm x 25 cm, 12% CH 3 CN/H 2 O/0.1% TFA) K'=4.7;

<1>H NMR (400 MHz, DMSO-d6) 8 8,7-8,9 (t, 1H); 6,3-7,6 (m, 8H); 5,4-5,6 (d, 1H); 5,0-5,1 (q, 1H); 4,5-4,7 (d, 2H); 3,8-3,9 (d, 1H); 2,9-3,0 (s, 3H); 2,7-2,9 (dd, 2H); <1>H NMR (400 MHz, DMSO-d6) δ 8.7-8.9 (t, 1H); 6.3-7.6 (m, 8H); 5.4-5.6 (d, 1H); 5.0-5.1 (q, 1H); 4.5-4.7 (d, 2H); 3.8-3.9 (d, 1H); 2.9-3.0 (s, 3H); 2.7-2.9 (dd, 2H);

MS (ES) m/e 408,2 (M+H)<+>.MS (ES) m/e 408.2 (M+H)<+>.

Analyse beregnet for C21H21N5O4 ■ 3,75 H20:Analysis calculated for C21H21N5O4 ■ 3.75 H20:

C, 53,10; H, 6,05; N, 14,74. C, 53.10; H, 6.05; N, 14.74.

Funnet: C, 52,86; H, 6,03; N, 14,39. [a]<D>= +205° (c 0,1) Found: C, 52.86; H, 6.03; N, 14.39. [a]<D>= +205° (c 0.1)

Eksempel 10Example 10

Fremstilling av (±)-7-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-9-klor-4-metyl-S-okso^.SAS-tetrahydro-l H-1,4-benzodiazepin-2-eddiksyre Preparation of (±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-9-chloro-4-methyl-S-oxo^.SAS-tetrahydro-1H-1,4-benzodiazepine-2 -acetic acid

a) Metyl-(+)-7-karboksy-9-klor-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat a) Methyl-(+)-7-carboxy-9-chloro-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate

En løsning av (±)-7-karboksy-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (1,0 g, 3,4 mmol), NCS (0,683 g, 4,0 mmol) i DMF (15 mL) ble oppvarmet til 50°C i 18 timer. Vann (150 mL) ble tilsatt og det heterogene system filtrert. Faststoffet ble utgnidd med CH2CI2/MeOH (9:1, 20 mL) i 1 time. Filtrering og tørking i vakuum ga tittelforbindelsen (0,61 g, 55%):<1>H NMR (400 MHz, DMSO-d6) 5 7,6-7,8 (m, 2H); 4,0-5,8 (m, 4H); 3,6-3,7 (s, 3H); 2,8-3,0 (m, 5H); A solution of (±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (1.0 g, 3.4 mmol ), NCS (0.683 g, 4.0 mmol) in DMF (15 mL) was heated to 50 °C for 18 h. Water (150 mL) was added and the heterogeneous system was filtered. The solid was triturated with CH 2 Cl 2 /MeOH (9:1, 20 mL) for 1 hour. Filtration and drying in vacuo gave the title compound (0.61 g, 55%):<1>H NMR (400 MHz, DMSO-d 6 ) δ 7.6-7.8 (m, 2H); 4.0-5.8 (m, 4H); 3.6-3.7 (s, 3H); 2.8-3.0 (m, 5H);

MS (ES) m/e 327,0 (M+H)<+>.MS (ES) m/e 327.0 (M+H)<+>.

b) Metyl-(±)-7-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-9-klor-4-metyl-3-okso-2,3,4,5-tetrahydro-l H-1,4-benzodiazepin-2-acetat b) Methyl-(±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-9-chloro-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H- 1,4-benzodiazepine-2-acetate

Ved å følge fremgangsmåten i Eksempel 8(a), men med metyl-(±)-7-karboksy-9-klor-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat i stedet for metyl-(2S)-7-karboksy-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat og benytte 2-aminometylbenzimidazol-dihydroklorid i stedet for 4-(1-piperidinyl)piperidin, ble tittelforbindelsen (0,68 g, 81%) fremstillet. By following the procedure in Example 8(a), but with methyl-(±)-7-carboxy-9-chloro-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4 -benzodiazepine-2-acetate instead of methyl-(2S)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate and use 2-aminomethylbenzimidazole dihydrochloride in place of 4-(1-piperidinyl)piperidine, the title compound (0.68 g, 81%) was prepared.

c) (±)-7-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-9-klor-4-metyl-3-okso 2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre c) (±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-9-chloro-4-methyl-3-oxo 2,3,4,5-tetrahydro-1 H-1,4 -benzodiazepine-2-acetic acid

Ved å følge fremgangsmåten i Eksempel 8(b), ble metyl-(±)-7-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-9-klor-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat forsåpet og renset for å gi tittelforbindelsen (0,53 g, 84%); HPLC (5 Altex Ultrasphere ODS, 4,5 mm x 25 cm, 5%-60% CH3CN/H2O-0,1% TFA gradient i løpet av 20 minutter) K-6,5; By following the procedure in Example 8(b), methyl-(±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-9-chloro-4-methyl-3-oxo-2,3 ,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate saponified and purified to give the title compound (0.53 g, 84%); HPLC (5 Altex Ultrasphere ODS, 4.5 mm x 25 cm, 5%-60% CH3CN/H2O-0.1% TFA gradient over 20 minutes) K-6.5;

<1>H NMR (400 MHz, DMSO-d6) 8 8,8-9,0 (t, 1H); 7,0-8,0 (m, 8H); 3,9-5,7 (m, 6H); 2,9-3,0 (s, 3H); 2,7-2,9 (m, 2H) <1>H NMR (400 MHz, DMSO-d6) δ 8.8-9.0 (t, 1H); 7.0-8.0 (m, 8H); 3.9-5.7 (m, 6H); 2.9-3.0 (s, 3H); 2.7-2.9 (m, 2H)

MS (ES) m/e 442,2 (M+H)<+>.MS (ES) m/e 442.2 (M+H)<+>.

Analyse beregnet for C21H20CIN5O41,25 H20:Analysis calculated for C21H20CIN5O41.25 H20:

C, 54,31; H, 4,88; N, 15,08. C, 54.31; H, 4.88; N, 15.08.

Funnet: C, 54,77; H, 4,73; N, 14,68. Found: C, 54.77; H, 4.73; N, 14.68.

Eksempel 11Example 11

Fremstilling av (±)-8-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-2-metyl-3-okso^.S.^S-tetrahydro-IH^-benzazepin^-eddiksyre Preparation of (±)-8-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-2-methyl-3-oxo^.S.^S-tetrahydro-1H^-benzazepine^-acetic acid

a) Metyl-(±)-8-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-2-metyl-3-okso-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetat a) Methyl-(±)-8-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4 -acetate

Til en løsning omrørt under argon ved romtemperatur av metyl-(±)-8-karboksy-2-metyl-3-okso-2,3,4,5-tetrahydro-1 H-2-benzazepin-4-acetat (0,30 g, To a solution stirred under argon at room temperature of methyl-(±)-8-carboxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (0, 30 g,

1 mmol), 2-aminometylbenzimidazol-dihydroklorid (0,27 g, 1,2 mmol), HOBTH20 (0,17 g, 1,2 mmol), diisopropyletylamin (0,53 g, 4 mmol) og DMF (5 mL) ble det tilsatt EDC (0,24 g, 1,2 mmol). Den resulterende blanding ble omrørt i 18 timer og deretter konsentrert til tørrhet, hvorpå residuet ble fordelt mellom EtOAc og H20. Den organiske fase ble vasket to ganger med H20 og én gang med saltvann, tørket (MgS04) og konsentrert. Residuet ble omkrystallisert fra kokende EtOAc for å gi tittelforbindelsen (0,16 g, 37%) som et farveløst faststoff:<1>H NMR (CDCIa) 5 9,95 (m, 1H); 7,86 (d, J=8Hz, 1H); 7,79 (s, 1H); 7,52 (m, 2H); 7,28 (m, 2H); 7,07 (d, J=8,1Hz, 1H); 5,16 (d, J=16,4Hz, 1H); 4,82 (m, 2H); 3,78 (m, 1H); 3,69 (s, 3H); 3,65 (d, J=16,6Hz, 1H); 3,10-2,90 (m, 3H); 2,87 (s, 3H); 2,40 (dd, J=16,9, 5,4Hz, 1H). 1 mmol), 2-aminomethylbenzimidazole dihydrochloride (0.27 g, 1.2 mmol), HOBTH20 (0.17 g, 1.2 mmol), diisopropylethylamine (0.53 g, 4 mmol) and DMF (5 mL) EDC (0.24 g, 1.2 mmol) was added. The resulting mixture was stirred for 18 h and then concentrated to dryness, after which the residue was partitioned between EtOAc and H 2 O. The organic phase was washed twice with H 2 O and once with brine, dried (MgSO 4 ) and concentrated. The residue was recrystallized from boiling EtOAc to give the title compound (0.16 g, 37%) as a colorless solid: <1>H NMR (CDCl 1a ) δ 9.95 (m, 1H); 7.86 (d, J=8Hz, 1H); 7.79 (s, 1H); 7.52 (m, 2H); 7.28 (m, 2H); 7.07 (d, J=8.1Hz, 1H); 5.16 (d, J=16.4Hz, 1H); 4.82 (m, 2H); 3.78 (m, 1H); 3.69 (s, 3H); 3.65 (d, J=16.6Hz, 1H); 3.10-2.90 (m, 3H); 2.87 (s, 3H); 2.40 (dd, J=16.9, 5.4Hz, 1H).

b) t±)-8-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-2-metyl-3-okso-2,3,4,5-tetrahydro-1H-2-benzazepin-4-eddiksyre b) t±)-8-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid

En løsning av metyl-(±)-8-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-2-metyl-3-okso-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetat (0,10 g, 0,24 mmol), LiOHH20 (0,013 g, 0,31 mmol), THF (2 mL) og H20 (2 mL) ble omrørt ved RT i 18 timer og deretter konsentrert til tørrhet. Residuet ble løst i H20 og løsningen bragt til pH 4-5 med 3N HCI. Det resulterende bunnfall ble oppsamlet ved filtrering og tørket. Omkrystallisasjon fra kokende isopropanol ga tittelforbindelsen (0,035 g, 36%) som et farveløst faststoff:<1>H NMR (DMSO-d6) 6 9,13 (t, J=5,7Hz, 1H); 7,79 (m, 1H); 7,48 (m, 2H); 7,23 (d, J=7,9Hz, 1H); 7,14 (m, 2H); 5,32 (d, J=16,9Hz, 1H); 4,69 (d, J=5,7Hz, 2H); 4,03 (d, J=16,7Hz, 1H); 3,79 (m, 1H); 3,14 (dd, J=18, 2Hz, 1H); 2,90 (s, 3H); 2,70 (m, 2H); 2,38 (dd, J=11,4, 3Hz, 1H); A solution of methyl-(±)-8-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine- 4-acetate (0.10 g, 0.24 mmol), LiOHH 2 O (0.013 g, 0.31 mmol), THF (2 mL) and H 2 O (2 mL) were stirred at RT for 18 h and then concentrated to dryness. The residue was dissolved in H2O and the solution brought to pH 4-5 with 3N HCI. The resulting precipitate was collected by filtration and dried. Recrystallization from boiling isopropanol gave the title compound (0.035 g, 36%) as a colorless solid:<1>H NMR (DMSO-d6) δ 9.13 (t, J=5.7Hz, 1H); 7.79 (m, 1H); 7.48 (m, 2H); 7.23 (d, J=7.9Hz, 1H); 7.14 (m, 2H); 5.32 (d, J=16.9Hz, 1H); 4.69 (d, J=5.7Hz, 2H); 4.03 (d, J=16.7Hz, 1H); 3.79 (m, 1H); 3.14 (dd, J=18, 2Hz, 1H); 2.90 (s, 3H); 2.70 (m, 2H); 2.38 (dd, J=11.4, 3Hz, 1H);

MS (ES) m/e 407 (M+H)<+>.MS (ES) m/e 407 (M+H)<+>.

Analyse beregnet for C22H22N404• 1,5 H20 • 0,5 C3H80:Analysis calculated for C22H22N404• 1.5 H20 • 0.5 C3H80:

C, 60,90; H, 6,31; N, 12,09 C, 60.90; H, 6.31; N, 12.09

Funnet: C, 60,68; H, 6,05; N, 12,05. Found: C, 60.68; H, 6.05; N, 12.05.

Eksempel 12Example 12

Fremstilling av (±)-8-[[[N-(2-benzimidazolyl)metyl-N-metyl]amino]karbonyl]-2-metyl-3-okso-2,3,4,5-tetrahydro-1H-2-benzazepin-4-eddiksyre Preparation of (±)-8-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2 -benzazepine-4-acetic acid

a) Metyl-(+)-8-[[[N-(2-benzimidazolyl)metyl-N-metyl]amino]karbonyl]-2-metyl-3-okso-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetat a) Methyl-(+)-8-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H -2-benzazepine-4-acetate

Ved å følge fremgangsmåten i Eksempel 11(a) ble metyl-(±)-8-karboksy-2-metyl-3-okso-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetat koblet med 2-(metylamino)metylbenzimidazol. Kromatografi på silikagel (5% MeOH/CH2CI2) ga tittelforbindelsen (67%) som et farveløst skum:<1>H NMR (CDCL3) 5 7,62 (m, 2H); 7,30 (m, 4H); 7,16 (d, J=8,3Hz, 1H); 5,31 (d, J=16,4Hz, 1H); 4,92 (d, J=14,5Hz, 1H); 4,87 (d, J=14,5Hz, 1H); 3,88 (m, 2H); 3,71 (s, 3H); 3,02 (s, 3H); 3,16 (s, 3H); 3,15-2,90 (m, 3H); 2,43 (dd, J=16,9, 5,3Hz, 1H). Following the procedure in Example 11(a), methyl-(±)-8-carboxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate was coupled with 2-(Methylamino)methylbenzimidazole. Chromatography on silica gel (5% MeOH/CH 2 Cl 2 ) afforded the title compound (67%) as a colorless foam: <1>H NMR (CDCL3 ) δ 7.62 (m, 2H); 7.30 (m, 4H); 7.16 (d, J=8.3Hz, 1H); 5.31 (d, J=16.4Hz, 1H); 4.92 (d, J=14.5Hz, 1H); 4.87 (d, J=14.5Hz, 1H); 3.88 (m, 2H); 3.71 (s, 3H); 3.02 (s, 3H); 3.16 (s, 3H); 3.15-2.90 (m, 3H); 2.43 (dd, J=16.9, 5.3Hz, 1H).

b) (±)-8-[[[N-(2-benzimidazolyl)metyl-N-metyl]amino]karbonyl]-2-metyl-3-okso-2,3,4,5-tetrahydro-1H-2-benzazepin-4-eddiksyre b) (±)-8-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2 -benzazepine-4-acetic acid

Ved å følge fremgangsmåten i Eksempel 11 (b), ble metyl-(±)-8-[[[N-(2-benzimidazolyl)metyl-N-metyl]amino]karbonyl]-2-metyl-3-okso-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetat forsåpet. Ekstraksjon med CH2CI2, konsentrering og tørking ga tittelforbindelsen (52%) som et farveløst faststoff:<1>H NMR (DMSO-de) 8 7,59 (m, 1H); 7,47 (d, J=8Hz, 1H); 7,35 (m, 2H); 7,15 (m, 3H); 5,25 (d, J=16Hz, 1H); 4,87 (d, J=14Hz, 1H); 4,08 (d, J=16Hz, 1H); 3,78 (m, 1H); 3,10 (m, 1H); 3,35 (s, 3H); 3,03 (s, 3H); 2,85-2,65 (m, 2H); 2,35 (dd, J=16, 5Hz, 1H); By following the procedure in Example 11 (b), methyl-(±)-8-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]-2-methyl-3-oxo-2 ,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate saponified. Extraction with CH 2 Cl 2 , concentration and drying gave the title compound (52%) as a colorless solid:<1>H NMR (DMSO-de) δ 7.59 (m, 1H); 7.47 (d, J=8Hz, 1H); 7.35 (m, 2H); 7.15 (m, 3H); 5.25 (d, J=16Hz, 1H); 4.87 (d, J=14Hz, 1H); 4.08 (d, J=16Hz, 1H); 3.78 (m, 1H); 3.10 (m, 1H); 3.35 (s, 3H); 3.03 (s, 3H); 2.85-2.65 (m, 2H); 2.35 (dd, J=16, 5Hz, 1H);

MS (ES) m/e 421,2 (M+H)<+>.MS (ES) m/e 421.2 (M+H)<+>.

Analyse beregnet for C23H24N404 • HCI • 1,2 CH2CI2- H20:Analysis calculated for C23H24N404 • HCI • 1.2 CH2CI2- H20:

C, 50,82; H, 5,18; N, 9,79. C, 50.82; H, 5.18; N, 9.79.

Funnet: C, 50,96; H, 5,48; N, 9,55. Found: C, 50.96; H, 5.48; N, 9.55.

Eksempel 13Example 13

Fremstilling av (+)-7-[[[N-(2-benzimidazolyl)metyl-N-metyl]amino]karbonyl]--3-okso-4-(2-fenyletyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre Preparation of (+)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]-3-oxo-4-(2-phenylethyl)-2,3,4,5- tetrahydro-1H-1,4-benzodiazepine-2-acetic acid

a) Metyl-(+)-7-[[[N-(2-benzimidazolyl)metyl-N-metyl]amino]karbonyl]-3-okso-4-(2-fenyletyl)-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat a) Methyl-(+)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]-3-oxo-4-(2-phenylethyl)-2,3,4,5 -tetrahydro-1H-1,4-benzodiazepine-2-acetate

Ved å følge fremgangsmåten i Eksempel 11 (a), ble metyl-(±)-7-karboksy-3-okso-4-(2-fenyletyl)-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepinacetat og 2-(metylamino)metylbenzimidazol koblet. Kromatografi på silikagel (1%-5% MeOH/CH2CI2) ga tittelforbindelsen (57%) som et farveløst faststoff:<1>H NMR (CDCIs) 8 7,62 (m, 2H); 7,35-7,00 (m, 9H); 6,46 (d, J=8Hz, 1H); 5,24 (d, J=16,6Hz, 1H); 5,03 (m, 1H); 4,95 (d, J=14,6Hz, 1H); 4,82 (d, J=14,6Hz, 1H); 4,51 (d, J=5Hz, 1H); 3,82 (m, 1H); 3,74 (s, 3H); 3,58 (m, 2H); 3,17 (s, 3H); 2,99 (dd, J=16, 6,8Hz, 1H); 2,81 (m, 2H); 2,67 (dd, J=16, 6,3Hz, 1H). By following the procedure in Example 11 (a), methyl-(±)-7-carboxy-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4 -benzodiazepine acetate and 2-(methylamino)methylbenzimidazole linked. Chromatography on silica gel (1%-5% MeOH/CH 2 Cl 2 ) afforded the title compound (57%) as a colorless solid: <1>H NMR (CDCIs) δ 7.62 (m, 2H); 7.35-7.00 (m, 9H); 6.46 (d, J=8Hz, 1H); 5.24 (d, J=16.6Hz, 1H); 5.03 (m, 1H); 4.95 (d, J=14.6Hz, 1H); 4.82 (d, J=14.6Hz, 1H); 4.51 (d, J=5Hz, 1H); 3.82 (m, 1H); 3.74 (s, 3H); 3.58 (m, 2H); 3.17 (s, 3H); 2.99 (dd, J=16, 6.8Hz, 1H); 2.81 (m, 2H); 2.67 (dd, J=16, 6.3Hz, 1H).

b) Metyl-(+)-7-[[[N-(2-benzimidazolyl)metyl-N-metyl]amino]karbonyl]-3-okso-4-(2-fenyletyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre b) Methyl-(+)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]-3-oxo-4-(2-phenylethyl)-2,3,4,5 -tetrahydro-1H-1,4-benzodiazepine-2-acetic acid

Metyl-(+)-7-[[[N-(2-benzimidazolyl)metyl-N-metyl]amino]karbonyl]-3-okso-4-(2-fenyletyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat ble forsåpet ifølge fremgangsmåten i Eksempel 11 (b). Omkrystallisasjon fra kokende isopropanol ga tittelforbindelsen (57%) som et farveløst faststoff:<1>H NMR (DMSO-d6) 8 7,58 (m, 1H); 7,47 (m, 1H); 7,35-7,10 (m, 8H); 6,55 (d, J=8Hz, 1H); 6,23 (m, 1H); 5,37 (d, J=16Hz, 1H); 5,05 (m, 1H); 4,77 (s, 2H); 3,95 (m, 1H); 3,58 (m, 2H); 3,05 (s, 3H); 2,65 (m, 2H); 2,58 (m, 1H); Methyl-(+)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro -1H-1,4-benzodiazepine-2-acetate was saponified according to the procedure in Example 11 (b). Recrystallization from boiling isopropanol gave the title compound (57%) as a colorless solid: <1>H NMR (DMSO-d6) δ 7.58 (m, 1H); 7.47 (m, 1H); 7.35-7.10 (m, 8H); 6.55 (d, J=8Hz, 1H); 6.23 (m, 1H); 5.37 (d, J=16Hz, 1H); 5.05 (m, 1H); 4.77 (s, 2H); 3.95 (m, 1H); 3.58 (m, 2H); 3.05 (s, 3H); 2.65 (m, 2H); 2.58 (m, 1H);

MS (ES) m/e 512,2 (M+H)<+>MS (ES) m/e 512.2 (M+H)<+>

Analyse beregnet for C29H29N504 • 2 H20:Analysis calculated for C29H29N504 • 2 H20:

C, 63,61; H, 6,07; N, 12,79 C, 63.61; H, 6.07; N, 12.79

Funnet: C, 63,33; H, 6,18; N, 12,58. Found: C, 63.33; H, 6.18; N, 12.58.

Eksempel 14Example 14

Fremstilling av (±)-7-[[[N-(2-benzimidazolyl)metyl-N-metyl]amino]metyl]-1,4-dimetyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre Preparation of (±)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]methyl]-1,4-dimethyl-3-oxo-2,3,4,5-tetrahydro-1H -1,4-benzodiazepine-2-acetic acid

a) Metyl-(±)-1-(tert-butoksykarbonyl)-7-karboksy-4-metyl-3-okso-2,3)4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat a) Methyl-(±)-1-(tert-butoxycarbonyl)-7-carboxy-4-methyl-3-oxo-2,3)4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate

En blanding av metyl-(±)-7-karboksy-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (1 g, 3,42 mmol), di-tert-butyldikarbonat (1,48 g, A mixture of methyl-(±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (1 g, 3.42 mmol ), di-tert-butyl dicarbonate (1.48 g,

6,8 mmol) og 4-dimetylaminopyridin (42 mg, 0,3 mmol) i vannfritt CH3CN (30 mL) ble omrørt ved RT i 3 timer. Mer di-tert-butyl-dikarbonat (0,65 g, 3 mmol) ble deretter tilsatt til den klare gule løsningen og reaksjonsblandingen omrørt ved RT i ytterligere 1 time. Reaksjonen ble avbrutt med vann, CH3CN fjernet i vakuum og residuet ekstrahert med EtOAc. De organiske lagene ble vasket suksessivt med mettet NH4CI og med H20 og deretter tørket (MgS04) og konsentrert i vakuum. Silikagelkromatografi (7/3 heksan/EtOAc-1 % AcOH) ga tittelforbindelsen (1,05 g, 78%) som et hvitt faststoff. 6.8 mmol) and 4-dimethylaminopyridine (42 mg, 0.3 mmol) in anhydrous CH 3 CN (30 mL) was stirred at RT for 3 h. More di-tert-butyl dicarbonate (0.65 g, 3 mmol) was then added to the clear yellow solution and the reaction mixture stirred at RT for an additional 1 h. The reaction was quenched with water, CH 3 CN removed in vacuo and the residue extracted with EtOAc. The organic layers were washed successively with saturated NH 4 Cl and with H 2 O and then dried (MgSO 4 ) and concentrated in vacuo. Silica gel chromatography (7/3 hexane/EtOAc-1% AcOH) afforded the title compound (1.05 g, 78%) as a white solid.

1H NMR (CDCI3. 400 MHz) 5 1,55 (s, 9H); 2,69 (dd, J=16, 5Hz, 1H); 2,98 (dd, J=16, 5Hz, 1H); 3,10 (s, 3H); 3,65-3,68 (m, 1H); 3,72 (s, 3H); 5,16 (dd, J=5, 5Hz, 1H); 5,45 (d, J=16,4Hz, 1H); 6,52 (d, J=8,4Hz, 1H); 7,59 (d, J=1,4Hz, 1H); 7,78 (dd, J=8,4, 1,4Hz, JH). 1 H NMR (CDCl 3 , 400 MHz) δ 1.55 (s, 9H); 2.69 (dd, J=16, 5Hz, 1H); 2.98 (dd, J=16, 5Hz, 1H); 3.10 (s, 3H); 3.65-3.68 (m, 1H); 3.72 (s, 3H); 5.16 (dd, J=5, 5Hz, 1H); 5.45 (d, J=16.4Hz, 1H); 6.52 (d, J=8.4Hz, 1H); 7.59 (d, J=1.4Hz, 1H); 7.78 (dd, J=8.4, 1.4Hz, JH).

b) Metyl-(±)-7-formyl-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat b) Methyl-(±)-7-formyl-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate

Metyl-(±)-1 -(tert-butoksykarbonyl)-7-karboksy-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (400 mg, 1,02 mmol) ble suspendert i Methyl-(±)-1-(tert-butoxycarbonyl)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (400 mg , 1.02 mmol) was suspended in

toluen og tilsatt SOCI2(3 mL). Reaksjonsblandingen ble oppvarmet til 80°C i 3 timer. Den resulterende løsning ble konsentrert til tørrhet for å etterlate et blekgult faststoff. Det således oppnådde syreklorid ble deretter suspendert i THF (2 mL) og tilsatt 2,6-lutidin (109 mg, 1,02 mmol), etterfulgt av 10% Pd/C (40 mg). Den resulterende suspensjon ble omrørt under H2-atmosfære over natten og deretter filtrert gjennom et tynt lag av Celite®. Filtratet ble fortynnet med EtOAc og løsningen vasket med 5% HCI og deretter med H20. Tørking (MgS04) og konsentrering ga tittelforbindelsen toluene and added SOCI2 (3 mL). The reaction mixture was heated to 80°C for 3 hours. The resulting solution was concentrated to dryness to leave a pale yellow solid. The acid chloride thus obtained was then suspended in THF (2 mL) and 2,6-lutidine (109 mg, 1.02 mmol) was added, followed by 10% Pd/C (40 mg). The resulting suspension was stirred under H 2 atmosphere overnight and then filtered through a thin layer of Celite®. The filtrate was diluted with EtOAc and the solution washed with 5% HCl and then with H 2 O. Drying (MgSO 4 ) and concentration gave the title compound

(139 mg, 60%) som et blekgult faststoff som ble benyttet i det neste trinn uten videre rensing. (139 mg, 60%) as a pale yellow solid which was used in the next step without further purification.

<1>H NMR (CDCI3, 400 MHz) 5 2,70 (dd, J=15,6, 6,8Hz, 1H); 3,01 (dd, J=15,6, 6,4Hz, 1H); 3,08 (s, 3H); 3,75-3,82 (m, 1H); 3,76 (s, 3H); 5,17 (dd, J=6,8, 6,4Hz, 1H); 5,47 (d, J=16,4Hz, 1H); 6,59 (d, J=8,4Hz, 1H); 7,50 (s, 1H); 7,58 (d, J=8,4Hz, 1H). <1>H NMR (CDCl3 , 400 MHz) δ 2.70 (dd, J=15.6, 6.8Hz, 1H); 3.01 (dd, J=15.6, 6.4Hz, 1H); 3.08 (s, 3H); 3.75-3.82 (m, 1H); 3.76 (s, 3H); 5.17 (dd, J=6.8, 6.4Hz, 1H); 5.47 (d, J=16.4Hz, 1H); 6.59 (d, J=8.4Hz, 1H); 7.50 (s, 1H); 7.58 (d, J=8.4Hz, 1H).

c) Metyl-(±)-7-[[[N-(2-benzimidazolyl)-metyl-N-metyl]amino]metyl]-1,4-dimetyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat c) Methyl-(±)-7-[[[N-(2-benzimidazolyl)-methyl-N-methyl]amino]methyl]-1,4-dimethyl-3-oxo-2,3,4,5- tetrahydro-1H-1,4-benzodiazepine-2-acetate

Metyl-(±)-7-formyl-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (125 mg, 0,45 mmol) ble suspendert i vannfritt MeOH og deretter tilsatt natriumacetat (111 mg, 1,35 mmol), 2-(aminometyl)benzimidazol-dihydroklorid (100 mg, 0,45 mmol) og 4Å molekylsikt. Etter 30 minutter ble natriumcyanoborhydrid (32 mg, 0,49 mmol) tilsatt i to porsjoner i løpet av 30 minutter. Reaksjonsblandingen ble omrørt ved RT over natten og MeOH deretter fjernet i vakuum. Formaldehyd (37 vekt% i H20, 3 mL) ble tilsatt og deretter CH3CN (3 mL), AcOH og natriumcyanoborhydrid (34 mg, 0,49 mmol). Etter 40 minutter ble reaksjonsblandingen konsentrert under redusert trykk. Residuet ble fortynnet med CH2CI2og løsningen vasket med mettet NaHC03. Tørking (MgS04), konsentrering og silikagelkromatografi (55% CH2CI2/20% EtOAc/20% heksan/5% MeOH) ga tittelforbindelsen (55 mg, 29%):<1>H NMR (CDCI3, 400 MHz) 5 2,33 (s, 3H); 2,63 (dd, J=16,0, 5,0Hz, 1H); 2,74 (s, 3H); 3,03 (dd, J=16,0, 8,8Hz, 1H); 3,07 (s, 3H); 3,57 (br s, 2H); 3,68 (s, 3H); 3,87 (br s, 2H); 3,87 (d, J=16,4Hz, 1H); 4,71 (dd, J=8,8Hz, 5,0, 1H); 5,20 (d, J=16,4Hz, 1H); 6,94-6,97 (m, 2H); 7,20-7,26 (m, 5H); 7,57 (bs, 1H); MS (ES) m/e 436 (M+H)<+>d) (±)-7-[[[N-(2-benzimidazolyl)metyl-N-metyl]amino]metyl]-1,4-dimetyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre Methyl-(±)-7-formyl-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (125 mg, 0.45 mmol) was suspended in anhydrous MeOH and then added sodium acetate (111 mg, 1.35 mmol), 2-(aminomethyl)benzimidazole dihydrochloride (100 mg, 0.45 mmol) and 4Å molecular sieve. After 30 min, sodium cyanoborohydride (32 mg, 0.49 mmol) was added in two portions over 30 min. The reaction mixture was stirred at RT overnight and the MeOH was then removed in vacuo. Formaldehyde (37 wt% in H 2 O, 3 mL) was added followed by CH 3 CN (3 mL), AcOH and sodium cyanoborohydride (34 mg, 0.49 mmol). After 40 minutes, the reaction mixture was concentrated under reduced pressure. The residue was diluted with CH 2 Cl 2 and the solution washed with saturated NaHCO 3 . Drying (MgSO 4 ), concentration and silica gel chromatography (55% CH 2 Cl 2 /20% EtOAc/20% hexane/5% MeOH) afforded the title compound (55 mg, 29%):<1>H NMR (CDCl 3 , 400 MHz) 5 2.33 (p, 3H); 2.63 (dd, J=16.0, 5.0Hz, 1H); 2.74 (s, 3H); 3.03 (dd, J=16.0, 8.8Hz, 1H); 3.07 (s, 3H); 3.57 (br s, 2H); 3.68 (s, 3H); 3.87 (br s, 2H); 3.87 (d, J=16.4Hz, 1H); 4.71 (dd, J=8.8Hz, 5.0, 1H); 5.20 (d, J=16.4Hz, 1H); 6.94-6.97 (m, 2H); 7.20-7.26 (m, 5H); 7.57 (bs, 1H); MS (ES) m/e 436 (M+H)<+>d) (±)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]methyl]-1,4-dimethyl -3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid

LiOH (5,8 mg, 0,17 mmol) ble ved RT tilsatt til en løsning av metyl-(±)-7-[[[N-(2-benzimidazolyl)metyl-N-metyl]amino]metyl]-1,4-dimetyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (50 mg, 0,115 mmol) i THF (2 mL) og H20 (3 mL). Reaksjonsblandingen ble oppvarmet til 50°C i 30 minutter og deretter konsentrert i vakuum. Det resulterende residuum ble lyofilisert for å gi et blekgult faststoff som ble renset ved preparativ HPLC (11% CH3CN/H2O-0,1% TFA) for å gi tittelforbindelsen (30 mg, 31%):<1>H NMR (CD30D, 400 MHz) 5 2,57 (m, 1H); 2,58 (s, 3H); 2,76 (s, 3H); 2,95 (dd, J=16, 8Hz, 1H); 3,04 (s, 3H); 3,93 (d, J=16,3Hz, 1H); 4,07 (br s, 2H); 4,38 (br s, 2H); 4,67 (dd, J=8,4, 7,0Hz, 1H); 5,18 (d, J=16,3Hz, 1H); 6,91 (d, J=8,4Hz, 1H); 7,12 (s, 1H); 7,26 (d, J=8,4Hz, 1H); 7,42 (m, 2H); 7,64 (m, 2H): LiOH (5.8 mg, 0.17 mmol) was added at RT to a solution of methyl-(±)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]methyl]-1 ,4-dimethyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (50 mg, 0.115 mmol) in THF (2 mL) and H 2 O (3 mL). The reaction mixture was heated to 50°C for 30 minutes and then concentrated in vacuo. The resulting residue was lyophilized to give a pale yellow solid which was purified by preparative HPLC (11% CH3CN/H2O-0.1% TFA) to give the title compound (30 mg, 31%):<1>H NMR (CD30D, 400 MHz) δ 2.57 (m, 1H); 2.58 (s, 3H); 2.76 (s, 3H); 2.95 (dd, J=16, 8Hz, 1H); 3.04 (s, 3H); 3.93 (d, J=16.3Hz, 1H); 4.07 (br s, 2H); 4.38 (br s, 2H); 4.67 (dd, J=8.4, 7.0Hz, 1H); 5.18 (d, J=16.3Hz, 1H); 6.91 (d, J=8.4Hz, 1H); 7.12 (s, 1H); 7.26 (d, J=8.4Hz, 1H); 7.42 (m, 2H); 7.64 (m, 2H):

MS (ES) m/e 422 (M+H)<+>MS (ES) m/e 422 (M+H)<+>

Analyse beregnet for C25H27N503 • 3,5 CF3C02H:Analysis calculated for C25H27N503 • 3.5 CF3C02H:

C, 42,51; H, 3,98; N, 8,26 C, 42.51; H, 3.98; N, 8.26

Funnet: C, 42,58; H, 4,27; N, 7,89. Found: C, 42.58; H, 4.27; N, 7.89.

Eksempel 15Example 15

Fremstilling av (±)-7-[[[N-(2-benzimidazolyl)metyl-N-metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre Preparation of (±)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1 ,4-benzodiazepine-2-acetic acid

a) 2-(metylaminometyl)benzimidazol-dihydroklorida) 2-(methylaminomethyl)benzimidazole dihydrochloride

Metylamin (5,0 g, 0,16 mol) ble løst i en løsning av Et20 (100 mL) og EtOH Methylamine (5.0 g, 0.16 mol) was dissolved in a solution of Et 2 O (100 mL) and EtOH

(5 mL) ved 0°C, og i små porsjoner tilsatt 2-klormetylbenzimidazol (13,4 g, 0,08 mol). Reaksjonsblandingen ble omrørt ved RT i 3 timer og fikk deretter stå ved RT over natten.^Mer Et20 (200 mL) ble tilsatt og reaksjonsblandingen avkjølt i et isbad i 3 timer før frafiltrering av bunnfallet. Filtratet ble mettet med HCI og filtrert og filtratet konsentrert. Silikagelkromatografi (trinnvis gradient, 10-25% MeOH/CH2CI2) førte til tittelforbindelsen (2,5 g, 13%): (5 mL) at 0°C, and in small portions added 2-chloromethylbenzimidazole (13.4 g, 0.08 mol). The reaction mixture was stirred at RT for 3 hours and then allowed to stand at RT overnight. More Et 2 O (200 mL) was added and the reaction mixture was cooled in an ice bath for 3 hours before filtering off the precipitate. The filtrate was saturated with HCl and filtered and the filtrate concentrated. Silica gel chromatography (stepwise gradient, 10-25% MeOH/CH2Cl2) afforded the title compound (2.5 g, 13%):

<1>H NMR (250 MHz, 5:1 DMSO-ds/CDCb) 5 7,13-7,54 (m, 4H); 4,11 (s, 2H); 2,50 (s, 3H); MS (ES) m/e 162,0 (M+H)<+>b) Metyl-(±)-7-[[[N-(2-benzimidazolyl)metyl-N-metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat <1>H NMR (250 MHz, 5:1 DMSO-ds/CDCb) δ 7.13-7.54 (m, 4H); 4.11 (s, 2H); 2.50 (s, 3H); MS (ES) m/e 162.0 (M+H)<+>b) Methyl-(±)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]-4 -methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate

Ved å følge fremgangsmåten i Eksempel 1(a), men med 2-(metylaminometyl)benzimidazol-dihydroklorid (1,2 g, 5,13 mmol) i stedet for 2-(aminometyl)benzimidazol-dihydroklorid, ble den rå tittelforbindelsen fremstillet. Silikagekromatografi (10% MeOH/CH2CI2) førte til tittelforbindelsen (0,29 g, 39%) som et hvitaktig faststoff:<1>H NMR (250 MHz, CDCI3) 5 6,44-7,62 (m, 9H); 5,41 (d, J=16,2Hz, 1H); 5,07 (m, 1H); 4,81 (m, 2H); 4,52 (d, J=5,2Hz, 2H); 3,73 (s, 3H); 3,68 (d, J=16,6Hz, 1H); 3,04 (s, 3H); 2,96 (s, 3H); 2,93 (dd, J=17,1, 6,5Hz, 1H); 2,67 (dd, J=17,1, 6,3Hz, 1H); By following the procedure of Example 1(a), but with 2-(methylaminomethyl)benzimidazole dihydrochloride (1.2 g, 5.13 mmol) instead of 2-(aminomethyl)benzimidazole dihydrochloride, the crude title compound was prepared. Silica chromatography (10% MeOH/CH 2 Cl 2 ) afforded the title compound (0.29 g, 39%) as an off-white solid: 1 H NMR (250 MHz, CDCl 3 ) δ 6.44-7.62 (m, 9H); 5.41 (d, J=16.2Hz, 1H); 5.07 (m, 1H); 4.81 (m, 2H); 4.52 (d, J=5.2Hz, 2H); 3.73 (s, 3H); 3.68 (d, J=16.6Hz, 1H); 3.04 (s, 3H); 2.96 (s, 3H); 2.93 (dd, J=17.1, 6.5Hz, 1H); 2.67 (dd, J=17.1, 6.3Hz, 1H);

MS (ES) m/e 436,2 (M+H)<+>MS (ES) m/e 436.2 (M+H)<+>

c) (±)-7-[[[N-(2-benzimidazolyl)metyl-N-metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre c) (±)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H- 1,4-benzodiazepine-2-acetic acid

Ved å følge fremgangsmåten i Eksempel 1(b), ble forbindelsen i Eksempel 15(b) forsåpet og renset for å gi tittelforbindelsen (0,21 g, 80%); Following the procedure of Example 1(b), the compound of Example 15(b) was saponified and purified to give the title compound (0.21 g, 80%);

i MS (ES) m/e 422,2 (M+H)<+>.in MS (ES) m/e 422.2 (M+H)<+>.

Analyse beregnet for C22H23N504 • 4/3 CF3C02H H20:Analysis calculated for C22H23N504 • 4/3 CF3C02H H20:

C, 47,93; H, 4,22; N, 10,96. C, 47.93; H, 4.22; N, 10.96.

Funnet: C, 47,88; H, 4,35; N, 10,96. Found: C, 47.88; H, 4.35; N, 10.96.

Eksempel 16Example 16

Fremstilling av (±)-7-[[[2-(2-benzimidazolyl)etyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre Preparation of (±)-7-[[[2-(2-benzimidazolyl)ethyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4- benzodiazepine-2-acetic acid

a) 2-aminoetylbenzimidazol-diacetata) 2-aminoethyl benzimidazole diacetate

En blanding av 2-cyanometylbenzimidazol (2,0 g, 12,7 mmol), 10% Pd/C A mixture of 2-cyanomethylbenzimidazole (2.0 g, 12.7 mmol), 10% Pd/C

(1,0 g) og AcOH (40 mL) ble hydrogenert ved 2,9 kg/cm<2>i 6 timer i et Parr-apparat. Reaksjonsblandingen ble filtrert gjennom et lag av Celite® og konsentrert for å gi tittelforbindelsen (3,4 g, 95%):<1>H NMR (250 MHz, CDCI3) 5 7,04-8,13 (m, 7H); 3,17-3,39 (m, 4H); (1.0 g) and AcOH (40 mL) were hydrogenated at 2.9 kg/cm<2> for 6 h in a Parr apparatus. The reaction mixture was filtered through a pad of Celite® and concentrated to give the title compound (3.4 g, 95%):<1>H NMR (250 MHz, CDCl 3 ) δ 7.04-8.13 (m, 7H); 3.17-3.39 (m, 4H);

MS (ES) m/e 162,0 (M+H)<+>.MS (ES) m/e 162.0 (M+H)<+>.

b) Metyl-(±)-7-[[[2-(2-benzimidazolyl)etyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat b) Methyl-(±)-7-[[[2-(2-benzimidazolyl)ethyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1, 4-benzodiazepine-2-acetate

Ved å følge fremgangsmåten i Eksempel 1(a), men med 2-aminoetylbenzimidazol-diacetat (1,44 g, 5,13 mmol) i stedet for 2-(aminometyl)benzimidazol-dihydroklorid, ble den rå tittelforbindelsen fremstillet. Silikagelkromatografi (9% MeOH/CH2CI2) førte til tittelforbindelsen (0,64 g, 86%) som et hvitaktig faststoff:<1>H NMR (250 MHz, CDCI3) 5 6,20-8,23 (m, 9H); 5,50 (d, J=16,2Hz, 1H); 5,11 (m, 1H); 3,70-3,81 (m, 3H); 3,64 (s, 3H); 3,11 (t, J=7,2Hz, 2H); 2,98 (s, 3H); 2,86 (dd, J=16,8, 8,0Hz, 1H); 2,63 (dd, J=16,8, 5,0Hz, 1H); By following the procedure of Example 1(a), but with 2-aminoethylbenzimidazole diacetate (1.44 g, 5.13 mmol) instead of 2-(aminomethyl)benzimidazole dihydrochloride, the crude title compound was prepared. Silica gel chromatography (9% MeOH/CH 2 Cl 2 ) afforded the title compound (0.64 g, 86%) as an off-white solid: 1 H NMR (250 MHz, CDCl 3 ) δ 6.20-8.23 (m, 9H); 5.50 (d, J=16.2Hz, 1H); 5.11 (m, 1H); 3.70-3.81 (m, 3H); 3.64 (s, 3H); 3.11 (t, J=7.2Hz, 2H); 2.98 (s, 3H); 2.86 (dd, J=16.8, 8.0Hz, 1H); 2.63 (dd, J=16.8, 5.0Hz, 1H);

MS (ES) m/e 436,2 (M+H)<+>.MS (ES) m/e 436.2 (M+H)<+>.

c) (±)-7-[[[2-(2-benzimidazolyl)etyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre c) (±)-7-[[[2-(2-benzimidazolyl)ethyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1,4- benzodiazepine-2-acetic acid

Ved å følge fremgangsmåten i Eksempel 1(b) ble tittelforbindelsen fra Eksempel16(b) forsåpet og renset for å gi tittelforbindelsen (7,8 mg, 10%); Following the procedure of Example 1(b), the title compound from Example 16(b) was saponified and purified to give the title compound (7.8 mg, 10%);

MS (ES) m/e 422,0 (M+H)<+>.MS (ES) m/e 422.0 (M+H)<+>.

Analyse beregnet for C22H23N5O4 • 2,5 H20:Analysis calculated for C22H23N5O4 • 2.5 H20:

C, 44,96; H, 4,35; N, 10,08 C, 44.96; H, 4.35; N, 10.08

Funnet: C, 44,79; H, 4,21; N, 10,08. Found: C, 44.79; H, 4.21; N, 10.08.

Eksempel 17Example 17

Fremstilling av (±)-7-[[(2-benzimidazolyl)amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-l H-1,4-benzodiazepin-2-eddiksyre Preparation of (±)-7-[[(2-benzimidazolyl)amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid

a) Metyl-(±)-7-[[(2-benzimidazolyl)amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat a) Methyl-(±)-7-[[(2-benzimidazolyl)amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2 -acetate

Ved å følge fremgangsmåten i Eksempel 1(a) men med 2-amino-benzimidazol (0,68 g, 5,13 mmol) i stedet for 2-(aminometyl)benzimidazol-dihydroklorid, ble den rå tittelforbindelsen fremstillet. Silikagelkromatografi (7% MeOH/CH2CI2) førte til tittelforbindelsen (0,48 g, 69%) som et hvitaktig faststoff:<1>H NMR (250 MHz, CDCI3) 8 6,50-8,16 (m, 9H); 5,47 (d, J=16,3Hz, 1H); 5,24 (m, 1H); 3,82 (d, J=4,5Hz, 1H); 3,65 (s, 3H); 2,60-3,01 (m, 6H); Following the procedure of Example 1(a) but with 2-amino-benzimidazole (0.68 g, 5.13 mmol) instead of 2-(aminomethyl)benzimidazole dihydrochloride, the crude title compound was prepared. Silica gel chromatography (7% MeOH/CH 2 Cl 2 ) afforded the title compound (0.48 g, 69%) as an off-white solid: 1 H NMR (250 MHz, CDCl 3 ) δ 6.50-8.16 (m, 9H); 5.47 (d, J=16.3Hz, 1H); 5.24 (m, 1H); 3.82 (d, J=4.5Hz, 1H); 3.65 (s, 3H); 2.60-3.01 (m, 6H);

MS (ES) m/e 408,2 (M+H)<+>.MS (ES) m/e 408.2 (M+H)<+>.

b) (±)-7-[[(2-benzimidazolyl)amino]karbonyl]-4-metyl-3-okso-2>3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre b) (±)-7-[[(2-benzimidazolyl)amino]carbonyl]-4-methyl-3-oxo-2>3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid

Ved å følge fremgangsmåten i Eksempel 1(b) ble forbindelsen i Eksempel 32(a) forsåpet og renset for å gi tittelforbindelsen (50 mg, 55%); Following the procedure of Example 1(b), the compound of Example 32(a) was saponified and purified to give the title compound (50 mg, 55%);

MS (ES) m/e 394,2 (M+H)<+>.MS (ES) m/e 394.2 (M+H)<+>.

Analyse beregnet for C20H19N5O4 • 4/3 CF3C02H:Analysis calculated for C20H19N5O4 • 4/3 CF3C02H:

C, 49,91; H, 3,76; N, 12,84. C, 49.91; H, 3.76; N, 12.84.

Funnet: C, 49,92; H, 3,83; N, 12,93. Found: C, 49.92; H, 3.83; N, 12.93.

Eksempel 18Example 18

Fremstilling av (2S)-7-[[[N-(2-benzimidazolyl)metyl-N-metyl]amino]karbonyl]-4-metyl-3-okso-2,3A5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre Preparation of (2S)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3A5-tetrahydro-1H-1,4-benzodiazepine -2-acetic acid

a) Metyl-(2S)-7-[[[N-(2-benzimidazolyl)metyl-N-metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat a) Methyl-(2S)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepine-2-acetate

Diisopropyletylamin (0,29 g, 2,25 mmol) ble i én porsjon tilsatt til en omrørt blanding av 2-(metylaminometyl)benzimidazol-bis(trifluoracetat) (1,8 mmol), metyl-(2S)-7-karboksy-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (0,44 g, 1,50 mmol), EDC (0,34 g, 1,8 mmol) og HOBTH20 (0,24 g, 1,8 mmol) i DMF (8 mL) ved RT under argon. Etter 24 timer ble løsningen helt over i en blanding av is-vann (90 g) og 5% NaHC03(10 mL). Det resulterende bunnfall ble frafiltrert og lufttørket. Hurtigkromatografi (silikagel, MeOH/CH2CI2) førte til tittelforbindelsen (79%); Diisopropylethylamine (0.29 g, 2.25 mmol) was added in one portion to a stirred mixture of 2-(methylaminomethyl)benzimidazole-bis(trifluoroacetate) (1.8 mmol), methyl-(2S)-7-carboxy- 4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (0.44 g, 1.50 mmol), EDC (0.34 g, 1, 8 mmol) and HOBTH20 (0.24 g, 1.8 mmol) in DMF (8 mL) at RT under argon. After 24 hours, the solution was poured into a mixture of ice-water (90 g) and 5% NaHCO 3 (10 mL). The resulting precipitate was filtered off and air dried. Flash chromatography (silica gel, MeOH/CH 2 Cl 2 ) afforded the title compound (79%);

<1>H NMR (400 MHz, CDCI3) 5 6,51-7,60 (m, 9H); 5,41 (d, J=16,4Hz, 1H); 5,07 (m, 1H); 4,82 (t, J=15,0Hz, 2H); 4,50 (d, J=4,8Hz, 1H); 3,74 (s, 3H); 3,68 (d, J=16,6Hz, 1H); 3,15 (s, 3H); 2,96 (s, 3H); 2,93 (dd, J=17,1, 6,5Hz, 1H); 2,67 (dd, J=16,1, 6,5Hz, 1H); MS (ES) m/e 436,2 (M+H)<+>b) (2S)-7-[[[N-(2-benzimidazolyl)metyl-N-metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre <1>H NMR (400 MHz, CDCl 3 ) δ 6.51-7.60 (m, 9H); 5.41 (d, J=16.4Hz, 1H); 5.07 (m, 1H); 4.82 (t, J=15.0Hz, 2H); 4.50 (d, J=4.8Hz, 1H); 3.74 (s, 3H); 3.68 (d, J=16.6Hz, 1H); 3.15 (s, 3H); 2.96 (s, 3H); 2.93 (dd, J=17.1, 6.5Hz, 1H); 2.67 (dd, J=16.1, 6.5Hz, 1H); MS (ES) m/e 436.2 (M+H)<+>b) (2S)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]-4-methyl -3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid

Ved å følge fremgangsmåten i Eksempel 1(b), ble forbindelsen fra Eksempel 18(a) forsåpet og renset for å gi tittelforbindelsen (0,11 g, 91 %); Following the procedure of Example 1(b), the compound from Example 18(a) was saponified and purified to give the title compound (0.11 g, 91%);

MS (ESMS) m/e 422,2 (M+H)<+>MS (ESMS) m/e 422.2 (M+H)<+>

Analyse beregnet for C22H23N504 • 3 H20:Analysis calculated for C22H23N504 • 3 H20:

C, 55,57; H, 6,15; N, 14,73 C, 55.57; H, 6.15; N, 14.73

Funnet: C, 55,30; H, 6,13; N, 14,39. Found: C, 55.30; H, 6.13; N, 14.39.

Eksempel 19Example 19

Fremstilling av (±)-4-metyl-7-[[[N-(2-(1 -metyl)benzimidazolyl)metyl-N-metyl]amino]karbonyl]-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre Preparation of (±)-4-methyl-7-[[[N-(2-(1-methyl)benzimidazolyl)methyl-N-methyl]amino]carbonyl]-3-oxo-2,3,4,5- tetrahydro-1H-1,4-benzodiazepine-2-acetic acid

a) 2-[[N-(tert-butoksykarbonyl)-N-metyl]aminometyl]benzimidazol a) 2-[[N-(tert-butoxycarbonyl)-N-methyl]aminomethyl]benzimidazole

Di-tert-butyl-dikarbonat (1,12 g, 5,13 mmol) ble ved 0°C dråpevis tilsatt til en Di-tert-butyl dicarbonate (1.12 g, 5.13 mmol) was added dropwise at 0°C to a

blanding inneholdende 2-(metylaminometyl)benzimidazol-dihydroklorid (1,0 g,mixture containing 2-(methylaminomethyl)benzimidazole dihydrochloride (1.0 g,

4,27 mmol), dioksan (25 mL), H20 (25 mL) og 1N NaOH (12,8 mL, 12,8 mmol). Etter 2 timer ble reaksjonsblandingen oppvarmet til RT og omrørt i 21 timer. Løsningsmidlet ble fordampet på rotasjonsfordamper og pH justert til 5 ved bruk av 4.27 mmol), dioxane (25 mL), H 2 O (25 mL) and 1N NaOH (12.8 mL, 12.8 mmol). After 2 h, the reaction mixture was warmed to RT and stirred for 21 h. The solvent was evaporated on a rotary evaporator and the pH adjusted to 5 using

1 M NaHS04. Blandingen ble ekstrahert med CH2CI2(2 x 80 mL), og de kombinerte organiske lagene ble vasket med saltvann (30 mL) og tørket (MgS04). Konsentrering ga tittelproduktet (0,7 g, 64%):<1>H NMR (400 MHz, CDCI3) 5 7,59 (b, 2H); 7,26 (m, 3H); 4,57 (s, 2H); 2,98 (s, 3H); 1,50 (s, 9H); MS (ES) m/e 262,0 (M+H)<+>. 1 M NaHSO 4 . The mixture was extracted with CH 2 Cl 2 (2 x 80 mL), and the combined organic layers were washed with brine (30 mL) and dried (MgSO 4 ). Concentration gave the title product (0.7 g, 64%):<1>H NMR (400 MHz, CDCl 3 ) δ 7.59 (b, 2H); 7.26 (m, 3H); 4.57 (s, 2H); 2.98 (s, 3H); 1.50 (s, 9H); MS (ES) m/e 262.0 (M+H)<+>.

b) 1-metyl-2-[[N-(tert-butoksykarbonyl)-N-metyl]aminometyl]benzimidazolb) 1-methyl-2-[[N-(tert-butoxycarbonyl)-N-methyl]aminomethyl]benzimidazole

En blanding av 2-[[N-(tert-butoksykarbonyl)-N-metyl]aminometyl]benzimidazol A mixture of 2-[[N-(tert-butoxycarbonyl)-N-methyl]aminomethyl]benzimidazole

(0,51 g, 1,95 mmol), NaH (0,12 g, 5,0 mmol), DMF (5 mL) og THF (20 mL) ble omrørt ved RT under argon i 5 minutter og deretter tilsatt metyljodid (0,83 g, 5,86 mmol). Reaksjonsblandingen ble omrørt ved RT i 170 minutter og deretter konsentrert på rotasjonsfordamper. Residuet ble fortynnet med CH2CI2(100 mL) og blandingen vasket suksessivt med H20 (30 mL), 5% NaHC03(30 mL) og saltvann (30 mL). Tørking (Na2S04) og konsentrering ga tittelforbindelsen (0,51 g, 94%); (0.51 g, 1.95 mmol), NaH (0.12 g, 5.0 mmol), DMF (5 mL) and THF (20 mL) were stirred at RT under argon for 5 min and then methyl iodide ( 0.83 g, 5.86 mmol). The reaction mixture was stirred at RT for 170 min and then concentrated on a rotary evaporator. The residue was diluted with CH 2 Cl 2 (100 mL) and the mixture washed successively with H 2 O (30 mL), 5% NaHCO 3 (30 mL) and brine (30 mL). Drying (Na 2 SO 4 ) and concentration gave the title compound (0.51 g, 94%);

<1>H NMR (250 MHz, CDCI3) 5 7,23-7,77 (m, 4H); 4,79 (s, 2H); 3,82 (s, 3H); 2,86 (s, 3H); 1,50 (s, 9H); MS (ES) m/e 276,2 (M+H)<+>. <1>H NMR (250 MHz, CDCl 3 ) δ 7.23-7.77 (m, 4H); 4.79 (s, 2H); 3.82 (s, 3H); 2.86 (s, 3H); 1.50 (s, 9H); MS (ES) m/e 276.2 (M+H)<+>.

c) 1 -metyl-2-(metylarninometyl)benzimidazol-bis(trifluoracetat)c) 1-methyl-2-(methylarninomethyl)benzimidazole-bis(trifluoroacetate)

En blanding av 1-metyl-2-[[N-(tert-butoksykarbonyl)-N-metyl]aminometyl]-benzimidazol (0,51 g, 1,85 mmol) i 25% TFA/CH2CI2(20 mL) ble omrørt ved RT under argon i 20 minutter. Løsningsmidlet ble fjernet på rotasjonsfordamper og residuet omkrystallisert fra Et20/CH2CI2for å gi tittelforbindelsen (0,69 g, 92%); A mixture of 1-methyl-2-[[N-(tert-butoxycarbonyl)-N-methyl]aminomethyl]-benzimidazole (0.51 g, 1.85 mmol) in 25% TFA/CH 2 Cl 2 (20 mL) was stirred at RT under argon for 20 min. The solvent was removed on a rotary evaporator and the residue recrystallized from Et 2 O/CH 2 Cl 2 to give the title compound (0.69 g, 92%);

<1>H NMR (250 MHz, 5:1 CDCI3:DMSO-d6) 5 7,24-7,68 (m, 4H); 4,56 (s, 2H); 3,84 (s, 3H); 2,84 (s, 3H); MS (ES) m/e 176,0 (M+H)<+>d) Metyl-(+)-4-metyl-7-[[[N-(2-(1-metyl)benzimidazolyl)metyl-N-metyl]amino]karbonyl]-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat <1>H NMR (250 MHz, 5:1 CDCl3:DMSO-d6) δ 7.24-7.68 (m, 4H); 4.56 (s, 2H); 3.84 (s, 3H); 2.84 (s, 3H); MS (ES) m/e 176.0 (M+H)<+>d) Methyl-(+)-4-methyl-7-[[[N-(2-(1-methyl)benzimidazolyl)methyl-N -methyl]amino]carbonyl]-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate

Ved å følge fremgangsmåten i Eksempel 18(a) men med 1-metyl-2-(metylaminometyl)benzimdiazol-bis(trifluoracetat) i stedet for 2,6-diaminopyridin, ble tittelforbindelsen (0,53 g, 77%) fremstillet:<1>H NMR (250 MHz, CDCI3) 5 6,50-7,80 (m, 9H); 5,43 (d, J=16,4Hz, 1H); 5,03-5,10 (m, 3H); 4,42 (d, J=4,7Hz, 1H); 3,88 (s, 3H); 3,74 (s, 3H); 3,68 (d, J=16,6Hz, 1H); 3,13 (s, 3H); 3,06 (s, 3H); 2,99 (dd, J=16,2, 6,7Hz, 1H); 2,66 (dd, J=16,2, 6,5Hz, 1H); MS (ES) m/e 450,2 (M+H)<+>e) (+)-4-metyl-7-[[[N-(2-(1-metyl)benzimidazolyl)metyl-N-metyl]amino]karbonyl]-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre By following the procedure of Example 18(a) but with 1-methyl-2-(methylaminomethyl)benzimdiazole-bis(trifluoroacetate) instead of 2,6-diaminopyridine, the title compound (0.53 g, 77%) was prepared:< 1>H NMR (250 MHz, CDCl 3 ) δ 6.50-7.80 (m, 9H); 5.43 (d, J=16.4Hz, 1H); 5.03-5.10 (m, 3H); 4.42 (d, J=4.7Hz, 1H); 3.88 (s, 3H); 3.74 (s, 3H); 3.68 (d, J=16.6Hz, 1H); 3.13 (s, 3H); 3.06 (s, 3H); 2.99 (dd, J=16.2, 6.7Hz, 1H); 2.66 (dd, J=16.2, 6.5Hz, 1H); MS (ES) m/e 450.2 (M+H)<+>e) (+)-4-methyl-7-[[[N-(2-(1-methyl)benzimidazolyl)methyl-N-methyl ]amino]carbonyl]-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid

Ved å følge fremgangsmåten i Eksempel 1(b) ble forbindelsen fra Eksempel 19(d) forsåpet og renset for å gi tittelforbindelsen (0,13 g, 60%): Following the procedure of Example 1(b), the compound from Example 19(d) was saponified and purified to give the title compound (0.13 g, 60%):

MS (ES) m/e 436,2 (M+H)<+>MS (ES) m/e 436.2 (M+H)<+>

Analyse beregnet for C23H25N504• 1,5 H20:Analysis calculated for C23H25N504• 1.5 H20:

C, 59,73; H, 6,10; N, 15,14 C, 59.73; H, 6.10; N, 15,14

Funnet: C, 59,39; H, 6,05; N, 14,96. Found: C, 59.39; H, 6.05; N, 14.96.

Eksempel 20Example 20

Fremstilling av (±)-7-[[[(2-(5(6)-metoksy)benzimidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2)3J4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre Preparation of (±)-7-[[[(2-(5(6)-methoxy)benzimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2)3J4,5-tetrahydro-1H-1 ,4-benzodiazepine-2-acetic acid

a) N-[N-(benzyloksykarbonyl)glycyl]-4-metoksy-2-nitroanilin a) N-[N-(benzyloxycarbonyl)glycyl]-4-methoxy-2-nitroaniline

N-(benzyloksykarbonyl)glycin (2,72 g, 13,13 mmol) ble løst i CH2CI2og et N-(benzyloxycarbonyl)glycine (2.72 g, 13.13 mmol) was dissolved in CH 2 Cl 2 and a

overskudd av tionylklorid ved romtemperatur. Etter 2 timer ble reaksjonsblandingen inndampet i vakuum og residuet inndampet med toluen to ganger og tørket under vakuum. Det hvite faststoff ble tatt opp i CH2CI2og 4-metoksy-2-nitroanilin (2,1819 g, 12,98 mmol) tilsatt som et faststoff, etterfulgt av trietylamin (2,0 mL, 1,455 g, excess of thionyl chloride at room temperature. After 2 hours, the reaction mixture was evaporated in vacuo and the residue evaporated with toluene twice and dried under vacuum. The white solid was taken up in CH 2 Cl 2 and 4-methoxy-2-nitroaniline (2.1819 g, 12.98 mmol) added as a solid, followed by triethylamine (2.0 mL, 1.455 g,

14,38 mmol). Reaksjonsblandingen ble omrørt ved RT i 24 timer og deretter inndampet under vakuum. Residuet ble løst i EtOAc og vasket med vandig 1N NaHC03. EtOAc-laget ble tørket (MgS04) og konsentrert under vakuum. Tynnskiktkromatografisk analyse (1:1:1 heksaner/Et20/CH2CI2) viste god omdannelse til det acylerte materiale. Råmaterialet ble først løst i 2:1:1 heksaner/Et20/CH2CI2med tilstrekkelig Et20/CH2CI2og ultralydbehandling/- oppvarming for å løse alt fast materiale. Silikagelkromatografi (2:1:1 heksaner/Et20/CH2CI2(2 L) deretter .1:1:1 heksaner/Et20/CH2CI2(1,5 L), deretter Et20/CH2CI2) ga tittelforbindelsen (3,3387 g, 72%); 14.38 mmol). The reaction mixture was stirred at RT for 24 h and then evaporated under vacuum. The residue was dissolved in EtOAc and washed with aqueous 1N NaHCO 3 . The EtOAc layer was dried (MgSO 4 ) and concentrated in vacuo. Thin layer chromatographic analysis (1:1:1 hexanes/Et 2 O/CH 2 Cl 2 ) showed good conversion to the acylated material. The crude material was first dissolved in 2:1:1 hexanes/Et20/CH2Cl2 with sufficient Et20/CH2Cl2 and ultrasonication/heating to dissolve all solid material. Silica gel chromatography (2:1:1 hexanes/Et 2 O/CH 2 Cl 2 (2 L) then .1:1:1 hexanes/Et 2 O/CH 2 Cl 2 (1.5 L), then Et 2 O/CH 2 Cl 2 ) gave the title compound (3.3387 g, 72% );

<1>H NMR (250 MHz, CDCI3) 6 3,85 (s, 3H); 4,06 (d, 2H); 5,18 (s, 2H); 5,61 (t, 1H), 7,2-7,4(m,*6H); 7,65 (d, 1H); 8,63 (d, 1H) <1>H NMR (250 MHz, CDCl 3 ) δ 3.85 (s, 3H); 4.06 (d, 2H); 5.18 (s, 2H); 5.61 (t, 1H), 7.2-7.4 (m,*6H); 7.65 (d, 1H); 8.63 (d, 1H)

b) 2-[N-[(benzyloksykarbonyl)amino]metyl]-5(6)-metoksybenzimidazol b) 2-[N-[(benzyloxycarbonyl)amino]methyl]-5(6)-methoxybenzimidazole

N-[N-(benzyloksykarbonyl)glycyl]-4-metoksy-2-nitroanilin (1,0 g, 2,87 mmol) N-[N-(benzyloxycarbonyl)glycyl]-4-methoxy-2-nitroaniline (1.0 g, 2.87 mmol)

ble løst i iseddik og tilsatt jernpulver. Blandingen ble oppvarmet i et oljebad ved ca. 65°C under omrøring. Etter 24 timer ble reaksjonsblandingen inndampet under vakuum. Residuet ble inndampet med toluen, tørket under vakuum og adsorbert på silikagel. Kromatografi på en tørr silikagelkolonne (1:1 Et20/CH2CI2(1,5 L) og deretter 5% MeOH/CH2CI2) ga tittelforbindelsen (1,0063 g, 94%): was dissolved in glacial acetic acid and iron powder added. The mixture was heated in an oil bath at approx. 65°C with stirring. After 24 hours, the reaction mixture was evaporated under vacuum. The residue was evaporated with toluene, dried under vacuum and adsorbed on silica gel. Chromatography on a dry silica gel column (1:1 Et 2 O/CH 2 Cl 2 (1.5 L) then 5% MeOH/CH 2 Cl 2 ) afforded the title compound (1.0063 g, 94%):

<1>H NMR (250 MHz, CDCI3) 5 3,78 (s, 3H); 4,57 (s, 2H); 5,05 (s, 2H); 6,8-7,5 (m, 8H), 10,85 (br s, 1H): MS (ES) m/e 312,0 (M+H)<+>c) 2-(aminometyl)-5(6)-metoksybenzimidazol 2-[N-[(benzyloksykarbonyl)amino]metyl]-5(6)-metoksybenzimidazol (1,0063 g, 3,23 mmol) ble løst i MeOH og tilsatt 10% Pd/C. Reaksjonsblandingen ble omrørt ved RT under H2(ballongtrykk) i 17 timer og deretter filtrert gjennom et lag av Celite®. Filtratet ble inndampet under vakuum for å gi tittelforbindelsen (411,7 mg, 72%) som en olje:<1>H NMR (250 MHz, CDCI3) 8 3,75 (s, 3H); 4,05 (s, 2H); 5,59 (br s, 2H); 6,82 (dd, 1H); 6,97 (d, 1H); 7,40 (d, 1H) d) Metyl-(±)-7-[[[(2-(5(6)-metoksy)benzimidazol)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat Metyl-(±)-7-karboksy-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (245,4 mg, 0,84 mmo) ble løst i DMF. En løsning av EDC (169,3 mg, 0,88 mmol) i DMF ble tilsatt og deretter HOBTH20 (112,1 mg, 0,83 mmol). En løsning av 2-(aminometyl)-5(6)-metoksybenzimidazol (1,434 mg, 0,81 mmol) i DMF ble tilsatt og deretter diisopropyletylamin (0,2 mL, 1,44 mmol). Reaksjosnblandingen ble omrørt ved RT i 5 dager, deretter konsentrert under vakuum. Residuet ble inndampet én gang med toluen. Råmaterialet ble fordelt mellom H20 og EtOAc. Den vandige fase ble ekstrahert tilbake med EtOAc og de kombinerte organiske lagene tørket (MgSO,») og konsentrert. TLC (10% MeOH/CHCI3) viste to hovedprodukter. Silikagelkromatografi (CHCI3(0,25 L), deretter 3% MeOH/CHCI3) ga tre fraksjoner; fraksjon 3 ga tittelforbindelsen (112,9 mg, 31%):<1>H NMR (250 MHz, CD3OD) 5 3,06 (s, 3H); 3,70 (s, 3H); 3,80 (s, 3H); 4,74 (s, 2H); 5,28 (t, 1H); 5,51 (d, 1H); 6,58 (d, 1H); 6,85 (d, 1H); 7,00 (s, 1H); 7,48 (d, 1H); 7,5-7,65 (m, 2H); MS (ES) m/e 452,2 (M+H)<+>e) (±)-7[[[(2-(5(6)-metoksy)benzimidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre <1>H NMR (250 MHz, CDCl 3 ) δ 3.78 (s, 3H); 4.57 (s, 2H); 5.05 (s, 2H); 6.8-7.5 (m, 8H), 10.85 (br s, 1H): MS (ES) m/e 312.0 (M+H)<+>c) 2-(aminomethyl)-5 (6)-Methoxybenzimidazole 2-[N-[(benzyloxycarbonyl)amino]methyl]-5(6)-methoxybenzimidazole (1.0063 g, 3.23 mmol) was dissolved in MeOH and added 10% Pd/C. The reaction mixture was stirred at RT under H 2 (balloon pressure) for 17 hours and then filtered through a pad of Celite®. The filtrate was evaporated in vacuo to give the title compound (411.7 mg, 72%) as an oil: <1>H NMR (250 MHz, CDCl3 ) δ 3.75 (s, 3H); 4.05 (s, 2H); 5.59 (br s, 2H); 6.82 (dd, 1H); 6.97 (d, 1H); 7.40 (d, 1H) d) Methyl-(±)-7-[[[(2-(5(6)-methoxy)benzimidazole)methyl]amino]carbonyl]-4-methyl-3-oxo-2 ,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate Methyl-(±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H -1,4-benzodiazepine-2-acetate (245.4 mg, 0.84 mmol) was dissolved in DMF. A solution of EDC (169.3 mg, 0.88 mmol) in DMF was added followed by HOBTH20 (112.1 mg, 0.83 mmol). A solution of 2-(aminomethyl)-5(6)-methoxybenzimidazole (1.434 mg, 0.81 mmol) in DMF was added followed by diisopropylethylamine (0.2 mL, 1.44 mmol). The reaction mixture was stirred at RT for 5 days, then concentrated under vacuum. The residue was evaporated once with toluene. The crude material was partitioned between H 2 O and EtOAc. The aqueous phase was back extracted with EtOAc and the combined organic layers dried (MgSO 4 ) and concentrated. TLC (10% MeOH/CHCl 3 ) showed two major products. Silica gel chromatography (CHCl 3 (0.25 L), then 3% MeOH/CHCl 3 ) gave three fractions; fraction 3 gave the title compound (112.9 mg, 31%): 1 H NMR (250 MHz, CD 3 OD) δ 3.06 (s, 3H); 3.70 (s, 3H); 3.80 (s, 3H); 4.74 (s, 2H); 5.28 (t, 1H); 5.51 (d, 1H); 6.58 (d, 1H); 6.85 (d, 1H); 7.00 (p, 1H); 7.48 (d, 1H); 7.5-7.65 (m, 2H); MS (ES) m/e 452.2 (M+H)<+>e) (±)-7[[[(2-(5(6)-methoxy)benzimidazolyl)methyl]amino]carbonyl]-4- methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid

Metyl-(±)-7-[[[(2-(5(6)-metoksy)benzimidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (112,9 mg, 0,25 mmol) ble løst i MeOH og vandig 1N natriumhydroksyd (0,5 mL, 0,5 mmol) tilsatt. Reaksjonsblandingen ble omrørt ved RT i to dager, deretter oppvarmet i en oljebad til ca. 65°C. Løsningen ble konsentrert og residuet oppløst på nytt i vandig MeOH. Løsningen ble nøytralisert med vandig 1N saltsyre (0,5 mL, 0,5 mmol) og blandingen inndampet under vakuum for å fjerne det meste av MeOH. Bunnfallet som oppsto ble oppsamlet på en sinterglass-trakt og tørket under høyvakuum for å gi tittelforbindelsen (103,1 mg, 94%): TLC (3:1:1 n-BuOH/AcOH/H20) Rf=0,62; Methyl-(±)-7-[[[(2-(5(6)-methoxy)benzimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H -1,4-benzodiazepine-2-acetate (112.9 mg, 0.25 mmol) was dissolved in MeOH and aqueous 1N sodium hydroxide (0.5 mL, 0.5 mmol) added. The reaction mixture was stirred at RT for two days, then heated in an oil bath to approx. 65°C. The solution was concentrated and the residue redissolved in aqueous MeOH. The solution was neutralized with aqueous 1N hydrochloric acid (0.5 mL, 0.5 mmol) and the mixture evaporated under vacuum to remove most of the MeOH. The resulting precipitate was collected on a sintered glass funnel and dried under high vacuum to give the title compound (103.1 mg, 94%): TLC (3:1:1 n-BuOH/AcOH/H 2 O) Rf=0.62;

MS (ES) m/e 438,2 (M+H)<+>.MS (ES) m/e 438.2 (M+H)<+>.

Analyse beregnet for C22H23N5O5 • 2 H20:Analysis calculated for C22H23N5O5 • 2 H20:

C, 55,81; H, 5,75; N, 14,70. C, 55.81; H, 5.75; N, 14.70.

Funnet: C, 55,69; H, 5,59; N, 14,41. Found: C, 55.69; H, 5.59; N, 14.41.

Eksempel 21Example 21

Fremstilling av (±)-7-[[[N-[2-(4-azabenzimidazolyl)metyl-N-metyllaminojkarbonyll^-metyl-S-okso^.S^.S-tetrahydro-IH-l^-benzodiazepin-2-eddiksyre Preparation of (±)-7-[[[N-[2-(4-azabenzimidazolyl)methyl-N-methylaminojcarbonyl^-methyl-S-oxo^.S^.S-tetrahydro-1H-1^-benzodiazepine-2 -acetic acid

a) 2-amino-3-[[N-(benzyloksykarbonyl)sarkosyl]amino]pyridin a) 2-amino-3-[[N-(benzyloxycarbonyl)sarcosyl]amino]pyridine

N-(benzyloksykarbonyl)sarkosin (4,1 g, 18,5 mmol) ble løst i tørr THF og N-(benzyloxycarbonyl)sarcosine (4.1 g, 18.5 mmol) was dissolved in dry THF and

tilsatt trietylamin (3 mL, 21,6 mmol) og deretter isobutylklorformiat (2,5 mL,added triethylamine (3 mL, 21.6 mmol) and then isobutyl chloroformate (2.5 mL,

19,27 mmol). Løsningen ble avkjølt til ca. -20°C i 15 minutter hvorpå en løsning av 2,3-diaminopyridin (2,0767 g, 19,03 mmol) i tørr THF langsomt ble tilsatt. Reaksjonsblandingen ble omrørt ved -10°C til -20°C i 15 minutter og fikk deretter oppvarmes til RT. Etter 3 dager ble reaksjonsblandingen inndampet under vakuum og residuet fordelt mellom EtOAc og 1N NaHC03. EtOAc-fasen ble tørket (MgS04) og inndampet under vakuum. Residuet ble løst i iseddik og omrørt i et oljebad ved 70°C. Etter 24 timer ble reaksjonsblandingen fjernet fra oljebadet og fikk avkjøles til RT og ble konsentrert under vakuum. Residuet ble inndampet med toluen og deretter kromatografert på silikagel (CHCI3, deretter 3% MeOH/CHCI3, deretter 5% MeOH/CHCI3) for å gi tittelforbindelsen (1,13 g, 19%): 19.27 mmol). The solution was cooled to approx. -20°C for 15 minutes whereupon a solution of 2,3-diaminopyridine (2.0767 g, 19.03 mmol) in dry THF was slowly added. The reaction mixture was stirred at -10°C to -20°C for 15 min and then allowed to warm to RT. After 3 days, the reaction mixture was evaporated under vacuum and the residue partitioned between EtOAc and 1N NaHCO 3 . The EtOAc phase was dried (MgSO 4 ) and evaporated in vacuo. The residue was dissolved in glacial acetic acid and stirred in an oil bath at 70°C. After 24 hours, the reaction mixture was removed from the oil bath and allowed to cool to RT and was concentrated under vacuum. The residue was evaporated with toluene and then chromatographed on silica gel (CHCl 3 , then 3% MeOH/CHCl 3 , then 5% MeOH/CHCl 3 ) to give the title compound (1.13 g, 19%):

<1>H NMR (250 MHz, CDCI3) 5 3,05 (s, 3H); 3,99 (s, 2H); 4,82 (br s, 1H); 6,5-6,65 (m, 1H); 7,32 (s, 5H); 7,87 (d, 1H); 8,84 (br s, 1H); MS (ES) m/e 315,4 (M+H)<+>b) 2-[[N-(benzyloksykarbonyl)-N-metylamino]metyl]-4-azabenzimidazol 2-amino-3-[[N-(benzyloksykarbonyl)sarkosyl]amino]pyridin (513 mg, 1,63 mmol) ble tatt opp i iseddik (25 mL) og reaksjonsblandingen oppvarmet i et oljebad innstillet på 100-105°C. Etter 24 timer ble reaksjonsblandingen inndampet under vakuum og residuet konsentrert fra toluen. Silikagelkromatografi (CHCI3, deretter 2% MeOH/CHCI3, deretter 4% MeOH/CHCI3) ga tittelforbindelsen (385 mg, 80%):<1>H NMR (250 MHz, CDCI3) 5 3,07 (s, 3H); 4,83 (s, 2H); 5,17 (s, 2H); 7,1-7,4 (m, 6H); 8,03 (d, 1H); 8,46 (d, 1H); MS (ES) m/e 297,2 (M+H)<+>c) 2-(metylamino)metyl-4-azabenzimidazol <1>H NMR (250 MHz, CDCl 3 ) δ 3.05 (s, 3H); 3.99 (p, 2H); 4.82 (br s, 1H); 6.5-6.65 (m, 1H); 7.32 (s, 5H); 7.87 (d, 1H); 8.84 (br s, 1H); MS (ES) m/e 315.4 (M+H)<+>b) 2-[[N-(benzyloxycarbonyl)-N-methylamino]methyl]-4-azabenzimidazole 2-amino-3-[[N- (benzyloxycarbonyl)sarcosyl]amino]pyridine (513 mg, 1.63 mmol) was taken up in glacial acetic acid (25 mL) and the reaction mixture heated in an oil bath set at 100-105°C. After 24 hours, the reaction mixture was evaporated under vacuum and the residue concentrated from toluene. Silica gel chromatography (CHCl 3 , then 2% MeOH/CHCl 3 , then 4% MeOH/CHCl 3 ) afforded the title compound (385 mg, 80%):<1>H NMR (250 MHz, CDCl 3 ) δ 3.07 (s, 3H); 4.83 (s, 2H); 5.17 (s, 2H); 7.1-7.4 (m, 6H); 8.03 (d, 1H); 8.46 (d, 1H); MS (ES) m/e 297.2 (M+H)<+>c) 2-(methylamino)methyl-4-azabenzimidazole

2-[[N-(benzyloksykarbonyl)-N-metylamino]metyl]-4-azabenzimidazol2-[[N-(benzyloxycarbonyl)-N-methylamino]methyl]-4-azabenzimidazole

(385,5 mg, 1,30 mmol) ble løst i MeOH og tilsatt 10% Pd/C. Blandingen ble omrørt ved RT under H2(ballongtrykk) i 4 timer, hvorpå katalysatoren ble fjernet ved filtrering gjennom et lag av Celite®. Det klare farveløse filtratet ble inndampet under vakuum for å gi tittelforbindelsen (237,0 mg, 100%): (385.5 mg, 1.30 mmol) was dissolved in MeOH and added 10% Pd/C. The mixture was stirred at RT under H2 (balloon pressure) for 4 hours, after which the catalyst was removed by filtration through a pad of Celite®. The clear colorless filtrate was evaporated in vacuo to give the title compound (237.0 mg, 100%):

<1>H NMR (250 MHz, CDCIa/CDaOD) 5 2,48 (s, 3H); 4,06 (s, 2H); 5,38 (br s, 1H); 7,15-8,35 (m, 4H). d) metyl-(±)-7-[[[N-[2-(4-azabenzimidazolyl)]metyl-N-metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat EDC (263,1 mg, 1,37 mmol) ble tilsatt til en suspensjon av metyl-(±)-7-karboksy-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (392,2 mg, 1,34 mmol) og HOBTH20 (195,5 mg, 1,45 mmol) i DMF i en tørr 100 mL rundkolbe. Den hvite suspensjonen oppløstes langsomt til en klar, farveløs løsning. En løsning av 2-(metylamino)metyl-4-azabenzimidazol (237,0 mg, 1,3 mmol) i DMF ble tilsatt etterfulgt av diisopropyletylamin (0,3 mL, 1,72 mmol). Reaksjonsblandingen ble omrørt ved RT i 4 dager, deretter inndampet under høyvakuum. Residuet ble konsentrert fra toluen og kromatografert på silikagel (CHCI3, deretter 5% MeOH/CHCI3, deretter 10% MeOH/CHCI3) for å gi tittelforbindelsen (183,3 mg, 32%):<1>H NMR (250 MHz, CDCI3/CD3OD) 8 3,04 (s, 3H); 3,17 (s, 3H); 3,72 (s, 3H); 4,13 (s, 2H); 5,13 (dd, 1H); 5,49 (d, 1H); 6,54 (d, 1H); 7,2-7,5 (m, 5H); 8,37 (brs, 1H): <1>H NMR (250 MHz, CDCIa/CDaOD) δ 2.48 (s, 3H); 4.06 (s, 2H); 5.38 (br s, 1H); 7.15-8.35 (m, 4H). d) methyl-(±)-7-[[[N-[2-(4-azabenzimidazolyl)]methyl-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5 -tetrahydro-1 H -1,4-benzodiazepine-2-acetate EDC (263.1 mg, 1.37 mmol) was added to a suspension of methyl-(±)-7-carboxy-4-methyl-3-oxo -2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (392.2 mg, 1.34 mmol) and HOBTH20 (195.5 mg, 1.45 mmol) in DMF in a dry 100 mL round flask. The white suspension slowly dissolved into a clear, colorless solution. A solution of 2-(methylamino)methyl-4-azabenzimidazole (237.0 mg, 1.3 mmol) in DMF was added followed by diisopropylethylamine (0.3 mL, 1.72 mmol). The reaction mixture was stirred at RT for 4 days, then evaporated under high vacuum. The residue was concentrated from toluene and chromatographed on silica gel (CHCl 3 , then 5% MeOH/CHCl 3 , then 10% MeOH/CHCl 3 ) to give the title compound (183.3 mg, 32%):<1>H NMR (250 MHz, CDCl 3 /CD 3 OD) δ 3.04 (s, 3H); 3.17 (s, 3H); 3.72 (s, 3H); 4.13 (s, 2H); 5.13 (dd, 1H); 5.49 (d, 1H); 6.54 (d, 1H); 7.2-7.5 (m, 5H); 8.37 (brs, 1H):

MS (ES) m/e 437,2 (M+H)<+>MS (ES) m/e 437.2 (M+H)<+>

e) (±)-7-[[[N-[2-(4-azabenzimidazolyl)metyl-N-metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre e) (±)-7-[[[N-[2-(4-azabenzimidazolyl)methyl-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro- 1 H-1,4-benzodiazepine-2-acetic acid

Metyl-(±)-7-[[[N-[2-(4-azabenzimidazolyl)]metyl-N-metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (183 g, 0,42 mmol) ble løst i MeOH og tilsatt 1N natriumhydroksyd (1,5 mL, 1,5 mmol). Reaksjonsblandingen ble omrørt ved RT inntil den ifølge TLC var fullstendig, hvorpå den ble nøytralisert med 1N HCI (1,5 mL, 1,5 mmol). Reaksjonsblandingen ble inndampet under vakuum og residuet delvis løst i MeOH og utfelt med H20. Blandingen ble inndampet under vakuum for å fjerne det meste av MeOH og den resulterende vandige suspensjon fikk stå ved RT i ca. 1 time før den ble filtrert på en sinterglasstrakt. Det isolerte materialet ble tørket i en vakuum-eksikkator under høyvakuum for å gi tittelforbindelsen (154,5 mg): MS (ES) m/e 423,2 (M+H)<+>Analyse beregnet for C21H22N6O4• 2,75 H20: C, 53,44; H, 5,87; N, 17,81. Methyl-(±)-7-[[[N-[2-(4-azabenzimidazolyl)]methyl-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro -1H-1,4-benzodiazepine-2-acetate (183 g, 0.42 mmol) was dissolved in MeOH and 1N sodium hydroxide (1.5 mL, 1.5 mmol) was added. The reaction mixture was stirred at RT until complete by TLC, whereupon it was neutralized with 1N HCl (1.5 mL, 1.5 mmol). The reaction mixture was evaporated under vacuum and the residue partially dissolved in MeOH and precipitated with H 2 O. The mixture was evaporated under vacuum to remove most of the MeOH and the resulting aqueous suspension was allowed to stand at RT for ca. 1 hour before it was filtered on a sintered glass funnel. The isolated material was dried in a vacuum desiccator under high vacuum to give the title compound (154.5 mg): MS (ES) m/e 423.2 (M+H)<+>Analysis calcd for C21H22N6O4• 2.75 H20 : C, 53.44; H, 5.87; N, 17.81.

Funnet: C, 53,52; H, 5,62; N, 17,23. Found: C, 53.52; H, 5.62; N, 17.23.

Eksempel 22Example 22

Fremstilling av (±)-7-[[[N-[2-(5(6)-azabenzimidazolyl)]metyl-N-metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre Preparation of (±)-7-[[[N-[2-(5(6)-azabenzimidazolyl)]methyl-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4, 5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid

a) 2-[[N-(benzyloksykarbonyl)-N-metylamino]metyl]-5(6)-azabenzimidazol a) 2-[[N-(benzyloxycarbonyl)-N-methylamino]methyl]-5(6)-azabenzimidazole

N-(benzyloksykarbonyl)sarkosin (4,07 g, 18,24 mmol) ble løst i tørr THF og N-(benzyloxycarbonyl)sarcosine (4.07 g, 18.24 mmol) was dissolved in dry THF and

tilsatt trietylamin (3,0 mL, 21,57 mmol) og deretter isobutylklorformiat (2,5 mL, 19,27 mmol). Den hvite blandingen ble avkjølt i et aceton/tørris-bad til ca. -20°C. Etter 20 minutter ble en løsning av 3,4-diaminopyridin (2,0319 g, 18,62 mmol) i THF tilsatt. Den gule løsningen ble holdt under omrøring ved -10 til -20°C i 15 minutter og fikk deretter oppvarmes langsomt til RT. Etter 3 dager ble reaksjonsblandingen inndampet under vakuum og residuet fordelt mellom EtOAc og 1,0N NaHC03. De added triethylamine (3.0 mL, 21.57 mmol) and then isobutyl chloroformate (2.5 mL, 19.27 mmol). The white mixture was cooled in an acetone/dry ice bath to approx. -20°C. After 20 minutes, a solution of 3,4-diaminopyridine (2.0319 g, 18.62 mmol) in THF was added. The yellow solution was kept under stirring at -10 to -20°C for 15 minutes and then allowed to warm slowly to RT. After 3 days, the reaction mixture was evaporated under vacuum and the residue partitioned between EtOAc and 1.0N NaHCO 3 . The

kombinerte EtOAc-lagene ble tørket (MgS04) og konsentrert. Det klare, svakt lysebrune residuet ble løst i iseddik og løsningen omrørt i et oljebad ved 70°C. Etter 24 timer fikk reaksjonsblandingen avkjøles til RT og ble konsentrert. Residuet ble konsentrert fra toluen og deretter kromatografert på silikagel (CHCI3, deretter 2% MeOH/CHCb, deretter 4% MeOH/CHCI3). To fraksjoner ble oppsamlet. Fraksjon 1 (530 mg, 5,5%) syntes å være det diacylerte materiale (MS (ES) m/e 520,2 (M+H)<+>. Fraksjon 2 inneholdt tittelforbindelsen (761 mg, 14%); the combined EtOAc layers were dried (MgSO 4 ) and concentrated. The clear, slightly light brown residue was dissolved in glacial acetic acid and the solution stirred in an oil bath at 70°C. After 24 h, the reaction mixture was allowed to cool to RT and was concentrated. The residue was concentrated from toluene and then chromatographed on silica gel (CHCl 3 , then 2% MeOH/CHCl 3 , then 4% MeOH/CHCl 3 ). Two factions were collected. Fraction 1 (530 mg, 5.5%) appeared to be the diacylated material (MS (ES) m/e 520.2 (M+H)<+>. Fraction 2 contained the title compound (761 mg, 14%);

<1>H NMR (250 MHz, CDCI3) 5 3,07 (s, 3H); 4,77 (s, 2H); 5,07 (s, 2H); 7,2-7,3 (m, 5H); 7,44 (d, 1H); 8,34 (d, 1H); 8,95 (s, 1H); MS (ES) m/e 297,2 (M+H)<*>b) 2-(metylamino)metyl-5-(6)-azabenzimidazol <1>H NMR (250 MHz, CDCl 3 ) δ 3.07 (s, 3H); 4.77 (s, 2H); 5.07 (s, 2H); 7.2-7.3 (m, 5H); 7.44 (d, 1H); 8.34 (d, 1H); 8.95 (s, 1H); MS (ES) m/e 297.2 (M+H)<*>b) 2-(methylamino)methyl-5-(6)-azabenzimidazole

2-[[N-(benzyloksykarbonyl)-N-metylamino]metyl]-5(6)-azabenzimidazol 2-[[N-(benzyloxycarbonyl)-N-methylamino]methyl]-5(6)-azabenzimidazole

(685,5 mg, 2,31 mmol) ble løst i MeOH og tilsatt 10% Pd/C. Blandingen ble kraftig omrørt ved RT under H2(ballongtrykk) i 4 timer og deretter filtrert gjennom Celite® for å fjerne katalysatoren. Et klart, farveløst filtrat ble inndampet under vakuum for å etterlate tittelproduktet (381 mg, 100%). (685.5 mg, 2.31 mmol) was dissolved in MeOH and added 10% Pd/C. The mixture was vigorously stirred at RT under H 2 (balloon pressure) for 4 hours and then filtered through Celite® to remove the catalyst. A clear, colorless filtrate was evaporated in vacuo to leave the title product (381 mg, 100%).

c) Metyl-(±)-7-[[[N-[2-(5(6)-azabenzimidazolyl)]metyl-N-metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat c) Methyl-(±)-7-[[[N-[2-(5(6)-azabenzimidazolyl)]methyl-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3, 4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate

EDC (263,1 mg, 1,37 mmol) ble tilsatt til en suspensjon av metyl-(±)-7-karboksy-4-metyl-3-okso-2,3,4,5-tefrahydro-1H-1,4-benzodiazepin-2-acetat (697,3 mg, 2,39 mmol) og HOBT-H20 (345,5 mg, 2,56 mmol) i DMF i en tørket 100 mL rundkolbe. Den hvite suspensjonen begynte å oppløses. Etter ca. 15 minutter ble en løsning av 2-(metylamino)metyl-5(6)-azabenzimidazol (380,6 mg, 2.35 mmol) i DMF tilsatt. Reaksjonsblandingen ble omrørt ved RT i 20 timer og deretter konsentrert under vakuum. Silikagelkromatografi (CHCI3|deretter 5% MeOH/CHCI3, deretter 10% MeOH/CHCI3) ga tittelforbindelsen (679 mg, 66%): 'H NMR (250 MHz, CDCI3) 5 3,00 (s, 3H); 3,12 (s, 3H), 3,48 (s, 3H), 3,66 (s, 3H), 5,07 (m, 1H); 5,40 (d, 1H), 6,35 (br s, 1H); 7,05 (br s, 1H); 7,12 (s, 1H); 7,47 (d, 1H); 8.36 (d, 1H); 8,94 (s, 1H) EDC (263.1 mg, 1.37 mmol) was added to a suspension of methyl-(±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1, 4-benzodiazepine-2-acetate (697.3 mg, 2.39 mmol) and HOBT-H 2 O (345.5 mg, 2.56 mmol) in DMF in a dried 100 mL round bottom flask. The white suspension began to dissolve. After approx. After 15 minutes, a solution of 2-(methylamino)methyl-5(6)-azabenzimidazole (380.6 mg, 2.35 mmol) in DMF was added. The reaction mixture was stirred at RT for 20 h and then concentrated under vacuum. Silica gel chromatography (CHCl 3 |then 5% MeOH/CHCl 3 , then 10% MeOH/CHCl 3 ) afforded the title compound (679 mg, 66%): 1 H NMR (250 MHz, CDCl 3 ) δ 3.00 (s, 3H); 3.12 (s, 3H), 3.48 (s, 3H), 3.66 (s, 3H), 5.07 (m, 1H); 5.40 (d, 1H), 6.35 (br s, 1H); 7.05 (br s, 1H); 7.12 (s, 1H); 7.47 (d, 1H); 8.36 (d, 1H); 8.94 (pp, 1H)

d) (±)-7-[[[N-[2-(5(6)-azabenzimidazolyl)]metyl-N-metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre d) (±)-7-[[[N-[2-(5(6)-azabenzimidazolyl)]methyl-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4, 5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid

Metyl-(±)-7-[[[N-[2-(5(6)-azabenzimidazolyl)]metyl-N-metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat (679,0 mg, Methyl-(±)-7-[[[N-[2-(5(6)-azabenzimidazolyl)]methyl-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4, 5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (679.0 mg,

1,56 mmol) ble løst i MeOH og tilsatt 1M NaOH (3,0 mL, 3,0 mmol). Det oppsto nesten umiddelbart en klar, gul løsning. Reaksjonsblandingen ble omrørt ved RT i 24 timer og deretter nøytralisert med 1N vandig HCI (3,0 mL, 3,0 mmol). Reaksjonsblandingen ble konsentrert og residuet suspendert i H20. Blandingen ble ultralydbehandlet og det farveløse bunnfall ble oppsamlet og tørket i en vakuum-eksikkator for å etterlate tittelforbindelsen (471 mg, 71%): 1.56 mmol) was dissolved in MeOH and 1M NaOH (3.0 mL, 3.0 mmol) was added. A clear, yellow solution formed almost immediately. The reaction mixture was stirred at RT for 24 h and then neutralized with 1N aqueous HCl (3.0 mL, 3.0 mmol). The reaction mixture was concentrated and the residue suspended in H 2 O. The mixture was sonicated and the colorless precipitate was collected and dried in a vacuum desiccator to leave the title compound (471 mg, 71%):

MS (ES) m/e 423,2 (M+H)<+>MS (ES) m/e 423.2 (M+H)<+>

Analyse beregnet for C2iH22N604• 2,25 H20:Analysis calculated for C2iH22N604• 2.25 H20:

C, 54,48; H, 5,77; N, 18,15. C, 54.48; H, 5.77; Sun, 18.15.

Funnet: C, 54,67; H, 5,58; N, 17,64. Found: C, 54.67; H, 5.58; N, 17.64.

Eksempel 23Example 23

Fremstilling av (±)-7-[[[(2-imidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-l H-1,4-benzodiazepin-2-acetat Preparation of (±)-7-[[[(2-imidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine- 2-acetate

a) Metyl- (±)-7-[[[(2-imidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat a) Methyl-(±)-7-[[[(2-imidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1,4- benzodiazepine-2-acetate

En blanding av metyl-(±)-7-karboksy-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (584 mg, 2,0 mmol), 2-(aminometyl)imidazol (2,2 mmol, fremstillet ifølge Annalen 1968, 718, 249), HOBTH20 (270 mg, 2 mmol), trietylamin (1,0 mL, 7,2 mmol) og EDC (383 mg, 2 mmol) i vannfritt DMF (40 mL) ble omrørt ved RT over natten. Reaksjonsblandingen ble konsentrert i vakuum og det resulterende residuet fortynnet med 5% K2C03. CH2CI2-ekstraksjon, tørking (MgS04) og konsentrering ga tittelforbindelsen (0,76 g, 86%): MS (ES) m/e 372 (M+H)<*>b) (±)-7-[[[(2-imidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre A mixture of methyl-(±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (584 mg, 2.0 mmol ), 2-(aminomethyl)imidazole (2.2 mmol, prepared according to Annalen 1968, 718, 249), HOBTH20 (270 mg, 2 mmol), triethylamine (1.0 mL, 7.2 mmol) and EDC (383 mg , 2 mmol) in anhydrous DMF (40 mL) was stirred at RT overnight. The reaction mixture was concentrated in vacuo and the resulting residue diluted with 5% K 2 CO 3 . CH 2 Cl 2 extraction, drying (MgSO 4 ) and concentration gave the title compound (0.76 g, 86%): MS (ES) m/e 372 (M+H)<*>b) (±)-7-[[[( 2-imidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid

Forbindelsen fra Eksempel 23(a) (0,7 g, 1,6 mmol) ble suspendert i MeOH (10 mL) og tilsatt THF (5 mL) og 1.0N NaOH (6 mL). Reaksjonsblandingen ble omrørt ved RT i 2 dager og deretter konsentrert i vakuum. Residuet ble fortynnet med H20 og pH justert til 5-6 med 1,5N HCI. Lyofilisering ga tittelforbindelsen: The compound from Example 23(a) (0.7 g, 1.6 mmol) was suspended in MeOH (10 mL) and added THF (5 mL) and 1.0N NaOH (6 mL). The reaction mixture was stirred at RT for 2 days and then concentrated in vacuo. The residue was diluted with H 2 O and pH adjusted to 5-6 with 1.5N HCl. Lyophilization gave the title compound:

MS (ES) m/e 358 (M+H)<+>MS (ES) m/e 358 (M+H)<+>

Analyse beregnet for Ci7Hi9N504• 1,75 CF3C02H:Analysis calculated for Ci7Hi9N504• 1.75 CF3C02H:

C, 44,21; H, 3,75; N, 12,57. C, 44.21; H, 3.75; N, 12.57.

Funnet: C, 44,21; H, 3,96; N, 12,54 Found: C, 44.21; H, 3.96; N, 12.54

Eksempel 24Example 24

Fremstilling av (±)-7-[[[2-(benzimidazolyl)metyl]metylamino]karbonyl]-4-(2-metoksyetyl)-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre Preparation of (±)-7-[[[2-(benzimidazolyl)methyl]methylamino]carbonyl]-4-(2-methoxyethyl)-3-oxo-2,3,4,5-tetrahydro-1 H-1, 4-benzodiazepine-2-acetic acid

a) Metyl-(±)-7-[[[2-(benzimidazolyl)metyl]metylamino]karbonyl]-4-(2-metoksyetyl)-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat a) Methyl-(±)-7-[[[2-(benzimidazolyl)methyl]methylamino]carbonyl]-4-(2-methoxyethyl)-3-oxo-2,3,4,5-tetrahydro-1 H- 1,4-benzodiazepine-2-acetate

EDC (138 mg, 0,72 mmol) ble tilsatt til en løsning av metyl-(±)-7-karboksy-4-(2-metoksyetyl)-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat (202 mg, 0,6 mmol), 2-(metylaminometyl)benzimidazol-dihydroklorid (0,72 mmol), HOBTH20 (97 mg, 0,72 mmol) og diisopropyletylamin (0,42 mL, 2,4 mmol) i vannfritt DMF EDC (138 mg, 0.72 mmol) was added to a solution of methyl-(±)-7-carboxy-4-(2-methoxyethyl)-3-oxo-2,3,4,5-tetrahydro-1 H -1,4-benzodiazepine-2-acetate (202 mg, 0.6 mmol), 2-(methylaminomethyl)benzimidazole dihydrochloride (0.72 mmol), HOBTH20 (97 mg, 0.72 mmol) and diisopropylethylamine (0, 42 mL, 2.4 mmol) in anhydrous DMF

(3 mL) ved RT. Reaksjonsblandingen ble omrørt ved RT i 22,5 timer og deretter konsentrert på rotasjonsfordamper. Residuet ble konsentrert på nytt fra xylener (for å fjerne DMF) og deretter fortynnet med H20 (2 mL). CHCI3-ekstraksjon, tørking (MgS04), konsentering og kromatografi på silikagel (5% MeOH/CHCI3) ga tittelforbindelsen (265,7 mg, 92%) som et hvitaktig faststoff: TLC Rf (5% MeOH/CHCI3) 0,39; (3 mL) at RT. The reaction mixture was stirred at RT for 22.5 h and then concentrated on a rotary evaporator. The residue was re-concentrated from xylenes (to remove DMF) and then diluted with H 2 O (2 mL). CHCl 3 extraction, drying (MgSO 4 ), concentration and chromatography on silica gel (5% MeOH/CHCl 3 ) afforded the title compound (265.7 mg, 92%) as an off-white solid: TLC Rf (5% MeOH/CHCl 3 ) 0.39;

<1>H NMR (400 MHz, CDCI3) 8 7,68-7,82 (m, 1H); 7,37-7,51 (m, 1H); 7,15-7,35 (m, 4H); 6,45-6,57 (m, 1H); 5,38 (d, J=16,5Hz, 1H); 5,04-5,14 (m, 1H); 4,82 (1/2 AB, J=14,6Hz, 1H); 4,74 (1/2 AB, J=14,6Hz, 1H); 4,53 (d, J=5,0Hz, 1H); 3,99 (d, J=16,5Hz, 1H); 3,74 (s, 3H); 3,65-3,83 (m, 1H); 3,37-3,61 (m, 3H); 3,22 (s, 3H); 3,15 (s, 3H); 2,98 (dd, J=16,0, 6,2Hz, 1H); 2,68 (dd, J=16,0, 6,7Hz, 1H); <1>H NMR (400 MHz, CDCl 3 ) δ 7.68-7.82 (m, 1H); 7.37-7.51 (m, 1H); 7.15-7.35 (m, 4H); 6.45-6.57 (m, 1H); 5.38 (d, J=16.5Hz, 1H); 5.04-5.14 (m, 1H); 4.82 (1/2 AB, J=14.6Hz, 1H); 4.74 (1/2 AB, J=14.6Hz, 1H); 4.53 (d, J=5.0Hz, 1H); 3.99 (d, J=16.5Hz, 1H); 3.74 (s, 3H); 3.65-3.83 (m, 1H); 3.37-3.61 (m, 3H); 3.22 (s, 3H); 3.15 (s, 3H); 2.98 (dd, J=16.0, 6.2Hz, 1H); 2.68 (dd, J=16.0, 6.7Hz, 1H);

MS (ES) m/e 480,2 (M+H)<+>, 319,0 (M+H -161)<+>b) (±)-7-[[[2-(benzimidazolyl)metyl]metylamino]karbonyl]-4-(2-metoksyetyl)-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre MS (ES) m/e 480.2 (M+H)<+>, 319.0 (M+H -161)<+>b) (±)-7-[[[2-(benzimidazolyl)methyl] methylamino]carbonyl]-4-(2-methoxyethyl)-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid

1,0 N LiOH (0,66 mL, 0,66 mmol) ble tilsatt til en løsning av metyl-(±)-7-[[[2-(benzimidazolyl)metyl]metylamino]karbonyl]-4-(2-metoksyetyl)-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (265,7 mg, 0,55 mmol) i THF (2,8 mL) og H20 (2,1 mL) ved RT. Den lysegule løsningen ble omrørt ved RT i 17 timer og deretter konsentrert til tørrhet på rotasjonsfordamper. Residuet ble løst i H20 (2 mL) og løsningen nøytralisert med 1,0N HCI (0,66 mL). Det faste bunnfall ble oppsamlet ved sugfiltrering og omkrystallisert fra H20/CH3CN for å gi tittelforbindelsen (147,0 mg, 55%): HPLC (PRP-1®, 15% CH3CN/H2O-0,1% TFA) K'=4,3; 1.0 N LiOH (0.66 mL, 0.66 mmol) was added to a solution of methyl-(±)-7-[[[2-(benzimidazolyl)methyl]methylamino]carbonyl]-4-(2- methoxyethyl)-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (265.7 mg, 0.55 mmol) in THF (2.8 mL) and H 2 O ( 2.1 mL) at RT. The pale yellow solution was stirred at RT for 17 h and then concentrated to dryness on a rotary evaporator. The residue was dissolved in H 2 O (2 mL) and the solution neutralized with 1.0 N HCl (0.66 mL). The solid precipitate was collected by suction filtration and recrystallized from H2O/CH3CN to give the title compound (147.0 mg, 55%): HPLC (PRP-1®, 15% CH3CN/H2O-0.1% TFA) K'=4 ,3;

<1>H NMR (400 MHz, DMSO-d6) 5 7,59 (d, J=7,6Hz, 1H); 7,47 (d, J=7,1Hz, 1H); 7,08-7,25 (m, 4H); 6,53 (d, J=8,2Hz, 1H); 6,13-6,26 (m, 1H); 5,42 (d, J=16,3Hz, 1H); 5,00-5,12 (m, 1H); 4,70-4,86 (m, 2H); 3,88-4,03 (m, 1H); 3,44-3,60 (m, 2H); 3,22-3,40 (m, 2H); 3,33 (s, 3H); 3,08 (s, 3H); 2,76 (dd, J=16,7, 8,8Hz, 1H), 2,53 (dd, J=16,7, 5,1Hz, 1H, delvis skjult av signal fra gjenværende løsningsmiddel); <1>H NMR (400 MHz, DMSO-d6) δ 7.59 (d, J=7.6Hz, 1H); 7.47 (d, J=7.1Hz, 1H); 7.08-7.25 (m, 4H); 6.53 (d, J=8.2Hz, 1H); 6.13-6.26 (m, 1H); 5.42 (d, J=16.3Hz, 1H); 5.00-5.12 (m, 1H); 4.70-4.86 (m, 2H); 3.88-4.03 (m, 1H); 3.44-3.60 (m, 2H); 3.22-3.40 (m, 2H); 3.33 (s, 3H); 3.08 (s, 3H); 2.76 (dd, J=16.7, 8.8Hz, 1H), 2.53 (dd, J=16.7, 5.1Hz, 1H, partially obscured by signal from residual solvent);

MS (ES) 466,2 (M+H)<+>, 305,0 (M+H -161)<+>. MS (ES) 466.2 (M+H)<+>, 305.0 (M+H -161)<+>.

Analyse beregnet for C^H^NsOs • H20:Analysis calculated for C^H^NsOs • H20:

C, 59,62; H, 6,04; N, 14,48 C, 59.62; H, 6.04; N, 14.48

Funnet: C. 59,62; H, 6,18; N, 14,46. Found: C. 59.62; H, 6.18; N, 14.46.

Eksempel 25Example 25

Fremstilling av (±)-7-[[[2-(4-azabenzimidazolyl)metyI]metylamino]karbonyl]-4-(2-metoksyetyl)-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre Preparation of (±)-7-[[[2-(4-azabenzimidazolyl)methyl]methylamino]carbonyl]-4-(2-methoxyethyl)-3-oxo-2,3,4,5-tetrahydro-1H-1 ,4-benzodiazepine-2-acetic acid

a) Metyl-(±)-7-[[[2-(4-azabenzimidazolyl)metyl]metylamino]karbonyl]-4-(2-metoksyetyl)-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat a) Methyl-(±)-7-[[[2-(4-azabenzimidazolyl)methyl]methylamino]carbonyl]-4-(2-methoxyethyl)-3-oxo-2,3,4,5-tetrahydro-1H -1,4-benzodiazepine-2-acetate

EDC (115 mg, 0,60 mmol) ble tilsatt til en løsning av metyl-(±)-7-karboksy-4-(2-metoksyetyl)-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat (168,2 mg, 0,50 mmol), 4-aza-2-(metylaminometyl)benzimidazol (0,62 mmol), HOBTH20 EDC (115 mg, 0.60 mmol) was added to a solution of methyl-(±)-7-carboxy-4-(2-methoxyethyl)-3-oxo-2,3,4,5-tetrahydro-1 H -1,4-benzodiazepine-2-acetate (168.2 mg, 0.50 mmol), 4-aza-2-(methylaminomethyl)benzimidazole (0.62 mmol), HOBTH20

(81 mg, 0,60 mmol) og diisopropyletylamin (0,17 mL, 1,0 mmol) i vannfritt DMF(81 mg, 0.60 mmol) and diisopropylethylamine (0.17 mL, 1.0 mmol) in anhydrous DMF

(2,5 mL) ved RT. Reaksjonsblandingen ble omrørt ved RT i 20 timer og deretter konsentrert på rotasjonsfordamper og residuet fortynnet med H20 (2 mL). CHCI3-ekstraksjon (3x5 mL), tørking (MgS04), konsentrering og ny konsentrering fra (2.5 mL) at RT. The reaction mixture was stirred at RT for 20 h and then concentrated on a rotary evaporator and the residue diluted with H 2 O (2 mL). CHCl3 extraction (3x5 mL), drying (MgSO4), concentration and reconcentration from

xylener (for å fjerne DMF) etterlot en lysegul olje. Kromatografi på silikagel (10% MeOH/CHCI3) ga tittelforbindelsen (225,4 mg, 94%) som et farveløst skum: TLC Rf (10% MeOH/CHCI3) 0,39; xylenes (to remove DMF) left a pale yellow oil. Chromatography on silica gel (10% MeOH/CHCl 3 ) afforded the title compound (225.4 mg, 94%) as a colorless foam: TLC Rf (10% MeOH/CHCl 3 ) 0.39;

<1>H NMR (400 MHz, CDCI3) to komponenter; kun data for hovedkomponenten. 5 8,37-i 8,47 (m, 1H); 7,98-8,06 (m, 1H); 7,17-7,37 (m, 3H); 6,43-6,57 (m, 1H); 5,38 (d, <1>H NMR (400 MHz, CDCl3) two components; data for the main component only. δ 8.37-in 8.47 (m, 1H); 7.98-8.06 (m, 1H); 7.17-7.37 (m, 3H); 6.43-6.57 (m, 1H); 5.38 (d,

J=16,6Hz, 1H); 5,04-5,13 (m, 1H); 4,85(1/2 AB, J=14,7Hz, 1H); 4,78(1/2 AB, J=14,7Hz, 1H); 4,53 (d, J=4,9Hz, 1H); 4,00 (d, J=16,6Hz, 1H); 3,74 (s, 3H); 3,65-3,81 (m, 1H); 3,35-3,61 (m, 3H); 3,23 (s, 3H); 3,16 (s, 3H); 2,98 (dd, J=15,9, 6,2Hz, J=16.6Hz, 1H); 5.04-5.13 (m, 1H); 4.85(1/2 AB, J=14.7Hz, 1H); 4.78(1/2 AB, J=14.7Hz, 1H); 4.53 (d, J=4.9Hz, 1H); 4.00 (d, J=16.6Hz, 1H); 3.74 (s, 3H); 3.65-3.81 (m, 1H); 3.35-3.61 (m, 3H); 3.23 (s, 3H); 3.16 (s, 3H); 2.98 (dd, J=15.9, 6.2Hz,

1H); 2,68 (dd, J=15,9, 6,7Hz, 1H); MS (ES) m/e 503,2 (M+Na)<+>, 481,2 (M+H)<*>, 319,0 ) (M+H-162)<*>. 1H); 2.68 (dd, J=15.9, 6.7Hz, 1H); MS (ES) m/e 503.2 (M+Na)<+>, 481.2 (M+H)<*>, 319.0 ) (M+H-162)<*>.

b) (±)-7-[[[2-(4-azabenzimidazolyl)metyl]metylamino]karbonyl]-4-(2-metoksyetyl)-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre b) (±)-7-[[[2-(4-azabenzimidazolyl)methyl]methylamino]carbonyl]-4-(2-methoxyethyl)-3-oxo-2,3,4,5-tetrahydro-1 H- 1,4-benzodiazepine-2-acetic acid

1,0 N LiOH (0,56 mL, 0,56 mmol) ble tilsatt til en løsning av metyl-(±)-7-[[[2-(4-i azabenzimidazolyl)metyl]metylamino]karbonyl]-4-(2-metoksyetyl)-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (225,4 mg, 0,47 mmol) i THF (2,4 mL) og H20 (1,8 mL) ved RT. Løsningen ble omrørt ved RT i 16,5 timer og deretter surgjort med TFA (0,11 mL) og konsentrert til tørrhet på rotasjonsfordamper. ODS-kromatografi (trinnvis gradient: 12% CH3CN/H2O-0,1% TFA, deretter 20% 1.0 N LiOH (0.56 mL, 0.56 mmol) was added to a solution of methyl-(±)-7-[[[2-(4-i azabenzimidazolyl)methyl]methylamino]carbonyl]-4- (2-Methoxyethyl)-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (225.4 mg, 0.47 mmol) in THF (2.4 mL) and H 2 O (1.8 mL) at RT. The solution was stirred at RT for 16.5 h and then acidified with TFA (0.11 mL) and concentrated to dryness on a rotary evaporator. ODS chromatography (stepwise gradient: 12% CH3CN/H2O-0.1% TFA, then 20%

i CH3CN/H2O-0,1% TFA), konsentrering til et lite volum og lyofilisering ga tittelforbindelsen (167,2 mg, 55%) som et lysegult pulver: HPLC (PRP-1®, 12% CH3CN/H2O-0,1% TFA) K'=2,7; in CH3CN/H2O-0.1% TFA), concentration to a small volume and lyophilization gave the title compound (167.2 mg, 55%) as a pale yellow powder: HPLC (PRP-1®, 12% CH3CN/H2O-0, 1% TFA) K'=2.7;

<1>H NMR (400 MHz, DMSO-d6) 8 8,48 (d, J=4,9Hz, 1H); 8,22 (d, J=8,0Hz, 1H); 7,38-7,50 (m, 1H); 7,15-7,30 (m, 2H); 6,54 (d, J=8,1Hz, 1H); 6,10-6,45 (m, 1H); 5,43 (d, J=16,5Hz, 1H); 5,02-5,14 (m, 1H); 4,82-4,99 (m, 2H); 3,95 (brd, J=16,5Hz, 1H); <1>H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J=4.9Hz, 1H); 8.22 (d, J=8.0Hz, 1H); 7.38-7.50 (m, 1H); 7.15-7.30 (m, 2H); 6.54 (d, J=8.1Hz, 1H); 6.10-6.45 (m, 1H); 5.43 (d, J=16.5Hz, 1H); 5.02-5.14 (m, 1H); 4.82-4.99 (m, 2H); 3.95 (brd, J=16.5Hz, 1H);

3,44-3,63 (m, 2H); 3,23-3,40 (m, 2H); 3,13 (br s, 3H); 3,08 (s, 3H); 2,76 (dd, J=16,7, 8,8Hz, 1H); 2,53 (dd, J=16,7, 5,0Hz, 1H delvis skjult av signal fra gjenværende løsningsmiddel); MS (ES) m/e 467,2 (M+H)<+>, 305,0 (M+H -162)<*>. 3.44-3.63 (m, 2H); 3.23-3.40 (m, 2H); 3.13 (br s, 3H); 3.08 (s, 3H); 2.76 (dd, J=16.7, 8.8Hz, 1H); 2.53 (dd, J=16.7, 5.0Hz, 1H partially obscured by signal from residual solvent); MS (ES) m/e 467.2 (M+H)<+>, 305.0 (M+H -162)<*>.

Analyse beregnet for C23H26N605 -1,5 CF3C02H • 0,5 H20:Analysis calculated for C23H26N605 -1.5 CF3C02H • 0.5 H20:

C, 48,30; H, 4,44; N, 13,00 C, 48.30; H, 4.44; N, 13.00

Funnet: C, 48,09; H, 4,38; N, 12,95. Found: C, 48.09; H, 4.38; N, 12.95.

Eksempel 26Example 26

Fremstilling av (±)-7-[[[2-(1 -metylindolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre Preparation of (±)-7-[[[2-(1-methylindolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine -2-acetic acid

a) Etyl-1 -metylindol-2-karboksylata) Ethyl 1-methylindole-2-carboxylate

Jodmetan (4,98 mL, 80 mmol) ble dråpevis tilsatt til en blanding inneholdende Iodomethane (4.98 mL, 80 mmol) was added dropwise to a mixture containing

etylindol-2-karboksylat (1,89 g, 10 mmol) og natriumhydrid (1,2 g, 60% dispersjon, på forhånd vasket med heksan) i vannfritt THF (60 mL) i en flammetørket kolbe under argon ved 0°C. Etter 4 timer ved RT ble reaksjonsblandingen konsentrert på rotasjonsfordamper. Residuet ble tatt opp i EtOAc og vasket med H20 og deretter med mettet NaCI. Tørking (MgS04) og konsentrering ga tittelforbindelsen (1,01 g, 50%) som et blekgult faststoff. ethylene indole-2-carboxylate (1.89 g, 10 mmol) and sodium hydride (1.2 g, 60% dispersion, pre-washed with hexane) in anhydrous THF (60 mL) in a flame-dried flask under argon at 0 °C. After 4 h at RT, the reaction mixture was concentrated on a rotary evaporator. The residue was taken up in EtOAc and washed with H 2 O and then with saturated NaCl. Drying (MgSO 4 ) and concentration gave the title compound (1.01 g, 50%) as a pale yellow solid.

b) 1 -metyl-2-(metylaminokarbonyl)indolb) 1-methyl-2-(methylaminocarbonyl)indole

En blanding av etyl-1 -metylindol-2-karboksylat (4,06 g, 20 mmol) og A mixture of ethyl 1-methylindole-2-carboxylate (4.06 g, 20 mmol) and

metylamin (50 mL) ble oppvarmet til 80°C i en forseglet glassbeholder over natten. Reaksjonsblandingen ble avkjølt og tittelforbindelsen (2,4 g, 64%) oppsamlet ved filtrering som et farveløst faststoff. MS (ES) m/e 189,0 (M+H)<+>methylamine (50 mL) was heated to 80°C in a sealed glass container overnight. The reaction mixture was cooled and the title compound (2.4 g, 64%) collected by filtration as a colorless solid. MS (ES) m/e 189.0 (M+H)<+>

c) 1 -metyl-2-(metylamino)metylindolc) 1-methyl-2-(methylamino)methylindole

LAH (50 mL, 1M løsning i THF) ble via en sprøyte dråpevis tilsatt til en LAH (50 mL, 1M solution in THF) was added dropwise via a syringe to a

løsning av 1-metyl-2-(metylaminokarbonyl)indol (2,33 g, 12,4 mmol) i vannfritt THF (10 mL) under avkjøling og den resulterende løsning omrørt ved RT under argon over natten. H20 ble dråpevis tilsatt under avkjøling for å ødelegge overskudd av LAH, hvorpå det farveløse bunnfall ble fjernet ved filtrering og vasket med THF. Filtratet ble tørket (K2C03), konsentrert og renset ved silikagel hurtigkromatografi for å gi tittelforbindelsen (430 mg, 20% utbytte) som et gult faststoff. MS (ES) m/e 175 (M+H)+ d) Metyl-(+)-7-[[[2-(1-metylindolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat solution of 1-methyl-2-(methylaminocarbonyl)indole (2.33 g, 12.4 mmol) in anhydrous THF (10 mL) under cooling and the resulting solution stirred at RT under argon overnight. H 2 O was added dropwise with cooling to destroy excess LAH, after which the colorless precipitate was removed by filtration and washed with THF. The filtrate was dried (K 2 CO 3 ), concentrated and purified by silica gel flash chromatography to give the title compound (430 mg, 20% yield) as a yellow solid. MS (ES) m/e 175 (M+H)+ d) Methyl-(+)-7-[[[2-(1-methylindolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2 ,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate

EDC (508 mg, 2,65 mmol) ble tilsatt til en løsning av metyl-(±)-7-karboksy-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat (774 mg, 2,65 mmol), 1-metyl-2-(metylamino)metylindol (420 mg, 2,41 mmol), HOBTH20 (358 mg, 2,65 mmol) og diisopropyletylamin (0,54 mL, 2,89 mmol) i vannfritt DMF (10 mL) ved RT. Etter 20 timer ble reaksjonsblandingen konsentrert på EDC (508 mg, 2.65 mmol) was added to a solution of methyl-(±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4 -benzodiazepine-2-acetate (774 mg, 2.65 mmol), 1-methyl-2-(methylamino)methylindole (420 mg, 2.41 mmol), HOBTH20 (358 mg, 2.65 mmol) and diisopropylethylamine (0 .54 mL, 2.89 mmol) in anhydrous DMF (10 mL) at RT. After 20 hours, the reaction mixture was concentrated

rotasjonsfordamper (høyvakuum), residuet ble tatt opp i EtOAc og vasket med H20 (3 x 30 mL) og deretter med 10% Na2C03(2 x 30 mL). Tørking (MgS04), rotary evaporator (high vacuum), the residue was taken up in EtOAc and washed with H 2 O (3 x 30 mL) and then with 10% Na 2 CO 3 (2 x 30 mL). Drying (MgSO4),

konsentrering og silikagelkromatografi (1% MeOH/CH2CI2) ga tittelforbidelsen (809 mg, 75%) som et hvitt faststoff. MS (ES) m/e 449,2 (M+H)<+>e) (±)-7-[[[2-(1-metylindolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre concentration and silica gel chromatography (1% MeOH/CH 2 Cl 2 ) afforded the title compound (809 mg, 75%) as a white solid. MS (ES) m/e 449.2 (M+H)<+>e) (±)-7-[[[2-(1-methylindolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo -2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid

1,0 N NaOH (2 mL, 2 mmol) ble dråpevis tilsatt til en løsning av metyl-(±)-7-[[[2-(1-metylindolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (600 mg, 1,34 mmol) i MeOH (10 mL) ved RT. Den 1.0 N NaOH (2 mL, 2 mmol) was added dropwise to a solution of methyl-(±)-7-[[[2-(1-methylindolyl)methyl]methylamino]carbonyl]-4-methyl-3- oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (600 mg, 1.34 mmol) in MeOH (10 mL) at RT. It

resulterende blanding ble omrørt i 2.0 timer og deretter konsentrert. Residuet ble løst i i H20 (10 mL) og surgjort med 1,0 N HCI under avkjøling. Det faste bunnfall ble the resulting mixture was stirred for 2.0 h and then concentrated. The residue was dissolved in H 2 O (10 mL) and acidified with 1.0 N HCl under cooling. The solid precipitate was

oppsamlet ved filtrering for å gi tittelforbindelsen (400 mg, 69%) som et hvitt faststoff. MS (ES) m/e 435,2 (M+H)<+>collected by filtration to give the title compound (400 mg, 69%) as a white solid. MS (ES) m/e 435.2 (M+H)<+>

Analyse beregnet for C24H26N404■ 0,75 H20:Analysis calculated for C24H26N404■ 0.75 H20:

C, 64,34; H, 6,19; N, 12,51. C, 64.34; H, 6.19; N, 12.51.

i Funnef: C, 64,16; H, 6,13; N, 12,50. in Funnef: C, 64.16; H, 6.13; N, 12.50.

Eksempel 27Example 27

Fremstilling av (±)-7-[[[2-(1 -metylindolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre Preparation of (±)-7-[[[2-(1-methylindolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4- benzodiazepine-2-acetic acid

a) 1-metylindol-2-karboksamida) 1-methylindole-2-carboxamide

En blanding av etyl-1 -metylindol-2-karboksylat (5,9 g, 29 mmol) og A mixture of ethyl 1-methylindole-2-carboxylate (5.9 g, 29 mmol) and

ammoniumhydroksyd (50 mL) ble oppvarmet til 80°C i en forseglet glassbeholder over natten. Reaksjonsblandingen ble avkjølt og tittelforbindelsen (2,2 g, 44%) ble oppsamlet ved filtrering som et farveløst faststoff. MS (ES) m/e 175,0 (M+H)<+>ammonium hydroxide (50 mL) was heated to 80°C in a sealed glass container overnight. The reaction mixture was cooled and the title compound (2.2 g, 44%) was collected by filtration as a colorless solid. MS (ES) m/e 175.0 (M+H)<+>

b) 1-metyl-2-(aminometyl)indolb) 1-methyl-2-(aminomethyl)indole

Ved å følge fremgangsmåten i Eksempel 26(c) med med 1-metylindol-2-karboksamid i stedet for 1-metyl-2-(metylaminokarbonyl)indol, ble tittelforbindelsen (86%) oppnådd som et gulbrunt faststoff. MS (ES) m/e 161,0 (M+H)<+>By following the procedure in Example 26(c) with 1-methylindole-2-carboxamide instead of 1-methyl-2-(methylaminocarbonyl)indole, the title compound (86%) was obtained as a tan solid. MS (ES) m/e 161.0 (M+H)<+>

c) Metyl-(±)-7-[[[2-(1-metylindolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat Ved å følge fremgangsmåten i Eksempel 26(d) men med 1-metyl-2-(aminometyl)indol i stedet for 1-metyl-2-(metylamino)metylindol ble tittelforbindelsen (50%) fremstillet: MS (ES) m/e 435,2 (M+H)<+>d) (±)-7-[[[2-(1-metylindolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre c) Methyl-(±)-7-[[[2-(1-methylindolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1, 4-benzodiazepine-2-acetate By following the procedure in Example 26(d) but with 1-methyl-2-(aminomethyl)indole instead of 1-methyl-2-(methylamino)methylindole, the title compound (50%) was prepared: MS (ES) m/e 435.2 (M+H)<+>d) (±)-7-[[[2-(1-methylindolyl)methyl]amino]carbonyl]-4-methyl-3-oxo -2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid

Ved å følge fremgangsmåten i Eksempel 26(e) ble metyl-(±)-7-[[[2-(1-metylindolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat forsåpet for å gi tittelforbindelsen som et farveløst faststoff: MS (ES) m/e 358 (M+H)<+>By following the procedure in Example 26(e), methyl-(±)-7-[[[2-(1-methylindolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4, 5-tetrahydro-1H-1,4-benzodiazepine-2-acetate saponified to give the title compound as a colorless solid: MS (ES) m/e 358 (M+H)<+>

Analyse beregnet for C23H24N404 • 3 HCI • 0,875 H20:Analysis calculated for C23H24N404 • 3 HCI • 0.875 H20:

C, 50,63; H, 5,31; N, 10,26 C, 50.63; H, 5.31; N, 10.26

Funnet: C, 51,00; H, 5,02; N, 9,89. Found: C, 51.00; H, 5.02; N, 9.89.

Eksempel 28Example 28

Fremstilling av 7-[[[(2RS-indolinyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2S-eddiksyre Preparation of 7-[[[(2RS-indolinyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2S-acetic acid

a) Metyl-(±)-indolin-2-karboksylata) Methyl-(±)-indoline-2-carboxylate

Tinonylklorid (2,86 mL, 39 mmol) ble tilsatt til en løsning av (±)-indolin-2-karboksylsyre (4,26 g, 26 mmol) i metanol (30 mL) ved 0°C. Den resulterende blanding ble omrørt ved RT i 18 timer. Løsningsmidlet ble fjernet i vakuum og residuet tatt opp i CH2CI2og vasket med H20 og deretter med mettet NaCI. Tørking (MgS04) og konsentrering ga tittelforbindelsen (4,31 g, 94%) som en blekgul olje. Tinonyl chloride (2.86 mL, 39 mmol) was added to a solution of (±)-indoline-2-carboxylic acid (4.26 g, 26 mmol) in methanol (30 mL) at 0 °C. The resulting mixture was stirred at RT for 18 h. The solvent was removed in vacuo and the residue taken up in CH 2 Cl 2 and washed with H 2 O and then with saturated NaCl. Drying (MgSO 4 ) and concentration gave the title compound (4.31 g, 94%) as a pale yellow oil.

b) (+)-indolin-2-karboksamidb) (+)-indoline-2-carboxamide

NH3-gass ble boblet inn i en løsning av metyl-(±)-indolin-2-karboksylat (4,3 g, NH 3 gas was bubbled into a solution of methyl-(±)-indoline-2-carboxylate (4.3 g,

24,2 mmol) i metanol (50 mL) ved RT i 30 minutter. Reaksjonsblandingen ble omrørt i 18 timer og deretter filtrert for å gi tittelforbindelsen (3,35 g, 85%) som et farveløst faststoff: MS (ES) m/e 163,0 (M+H)<+>24.2 mmol) in methanol (50 mL) at RT for 30 min. The reaction mixture was stirred for 18 h and then filtered to give the title compound (3.35 g, 85%) as a colorless solid: MS (ES) m/e 163.0 (M+H)<+>

c) (+)-2-(aminometyl)-indolinc) (+)-2-(aminomethyl)-indoline

LAH (20 mL, 1M løsnnig i THF) ble dråpevis via en sprøyte tilsatt til en LAH (20 mL, 1 M solution in THF) was added dropwise via a syringe to a

løsning av (±)-indolin-2-karboksamid (2,2 g, 13,6 mmol) i vannfritt THF (20 mL) under avkjøling og den resulterende løsning kokt under tilbakeløpskjøling under argon i 5 timer. Mer LAH (20 mL) ble tilsatt og tilbakeløpsbehandlingen fortsatt i ytterligere 6 timer. 10% vandig THF ble dråpevis tilsatt under avkjøling for å ødelegge overskudd av LAH, hvorpå Et20 ble tilsatt. Etter omrøring i 10 minutter ble det farveløse bunnfall fjernet ved filtrering og vasket med THF. Filtratet ble tørket (K2CO3), konsentrert og renset ved silikagel-hurtigkromatografi (90:10:0,2 CH2CI2/MeOH/Et3N). Tittelforbindelsen (1,02 g, 51%) ble oppnådd som en ravfarvet olje: MS (ES) m/e 149,0 (M+H)<+>d) Metyl-7-[[[(2RS-indolinyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2S-acetat solution of (±)-indoline-2-carboxamide (2.2 g, 13.6 mmol) in anhydrous THF (20 mL) under cooling and the resulting solution refluxed under argon for 5 h. More LAH (20 mL) was added and reflux continued for an additional 6 hours. 10% aqueous THF was added dropwise with cooling to destroy excess LAH, after which Et 2 O was added. After stirring for 10 minutes, the colorless precipitate was removed by filtration and washed with THF. The filtrate was dried (K 2 CO 3 ), concentrated and purified by silica gel flash chromatography (90:10:0.2 CH 2 Cl 2 /MeOH/Et 3 N). The title compound (1.02 g, 51%) was obtained as an amber oil: MS (ES) m/e 149.0 (M+H)<+>d) Methyl-7-[[[(2RS-indolinyl)methyl ]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2S-acetate

Ved å følge fremgangsmåten i Eksempel 26(d) men med (±)-2-(aminometyl)indolin i stedet for 1-metyl-2-(metylamino)-metylindol ble tittelforbindelsen (44%) fremstillet: MS (ES) m/e 423,0 (M+H)<+>By following the procedure in Example 26(d) but with (±)-2-(aminomethyl)indoline instead of 1-methyl-2-(methylamino)methylindole, the title compound (44%) was prepared: MS (ES) w/ e 423.0 (M+H)<+>

e) 7-[[[(2RS)-indolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3l4,5-tetrahydro-e) 7-[[[(2RS)-indolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3l4,5-tetrahydro-

1 H-1,4-benzodiazepin-2S-eddiksyre1 H-1,4-benzodiazepine-2S-acetic acid

Ved å følge fremgangsmåten i Eksempel 26(e) ble metyl-7-[[[(2RS-indolinyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2S-acetat forsåpet for å gi tittelforbindelsen som et farveløst faststoff. MS (ES) m/e 409,2 (M+H)<+>By following the procedure in Example 26(e), methyl-7-[[[(2RS-indolinyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H- 1,4-benzodiazepine-2S-acetate saponified to give the title compound as a colorless solid. MS (ES) m/e 409.2 (M+H)<+>

Analyse beregnet for C22H24N4O4 • 1 HCI • 0,5 H20:Analysis calculated for C22H24N4O4 • 1 HCI • 0.5 H20:

C, 58,21; H, 5,77; N, 12,34. C, 58.21; H, 5.77; N, 12.34.

Funnet: C, 58,36; H, 5,56; N, 12,26 Found: C, 58.36; H, 5.56; N, 12.26

Eksempel 29Example 29

Fremstilling av (±)-7-[[[(2-imidazolyl)metyl]amino]karbonyl]-3-okso-4-(2-fenyletylJ^.SAS-tetrahydro-IH-M-benzodiazepin^-eddiksyre Preparation of (±)-7-[[[(2-imidazolyl)methyl]amino]carbonyl]-3-oxo-4-(2-phenylethylJ^.SAS-tetrahydro-1H-M-benzodiazepine^-acetic acid

a) Metyl-(+)-7-[[[(2-imidazolyl)metyl]amino]karbonyl]-4-(2-fenyletyl)-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat a) Methyl-(+)-7-[[[(2-imidazolyl)methyl]amino]carbonyl]-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1 H-1,4- benzodiazepine-2-acetate

Metyl-(±)-7-karboksy-3-okso-2-(2-fenyletyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (400 mg, 1,04 mmol) ble suspendert i vannfri toluen (5 mL) hvorpå tionylklorid (3 mL) ble tilsatt og reaksjonsblandingen kokt under tilbakeløpskjøling i 1,5 timer. Løsningsmidlet ble deretter fjernet og mer toluen tilsatt (2x5 mL) som så ble avdestillert. Det således oppnådde syreklorid ble løst i tørr DMF (8 mL) og tilsatt diisopropyletylamin (506 mg, 3,9 mmol), DM AP (12,2, Methyl-(±)-7-carboxy-3-oxo-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (400 mg, 1.04 mmol) was suspended in anhydrous toluene (5 mL) whereupon thionyl chloride (3 mL) was added and the reaction mixture boiled under reflux for 1.5 hours. The solvent was then removed and more toluene added (2x5 mL) which was then distilled off. The acid chloride thus obtained was dissolved in dry DMF (8 mL) and diisopropylethylamine (506 mg, 3.9 mmol), DM AP (12.2,

0,1 mmol) og 2-(aminometyl)imidazol-dihydroklorid (222 mg, 1,3 mmol). Reaksjonsblandingen fikk omrøres ved RT over natten, hvorpå løsningsmidlet ble fjernet under vakuum. Residuet ble renset på en silikagel hurtigkromatografikolonne (95% CH2CI2/5% metanol) .for å gi tittelforbindelsen (120 mg, 26%). 0.1 mmol) and 2-(aminomethyl)imidazole dihydrochloride (222 mg, 1.3 mmol). The reaction mixture was allowed to stir at RT overnight, after which the solvent was removed under vacuum. The residue was purified on a silica gel flash chromatography column (95% CH 2 Cl 2 /5% methanol) to give the title compound (120 mg, 26%).

<1>H NMR (CDCI3, 400 MHz) 5 2,62 (dd, J=16,2, 6,2Hz, 1H); 2,76 (m, 2H); 2,94 (dd, J=16,2, 7,4Hz, 1H); 3,6-3,71 (m, 3H); 3,70 (s, 3H); 4,45 (s, 2H); 5,02 (dd, J=7,2, 6,4Hz, 1H); 5,27 (d, J=16,6Hz, 1H); 6,47 (d, J=8,5, 1H); 6,89 (s, 2H); 7,06-7,16 (m, 5H); 7,31 (br s, 1H); 7,49 (d, J=8,5Hz, 1H). <1>H NMR (CDCl3 , 400 MHz) δ 2.62 (dd, J=16.2, 6.2Hz, 1H); 2.76 (m, 2H); 2.94 (dd, J=16.2, 7.4Hz, 1H); 3.6-3.71 (m, 3H); 3.70 (s, 3H); 4.45 (s, 2H); 5.02 (dd, J=7.2, 6.4Hz, 1H); 5.27 (d, J=16.6Hz, 1H); 6.47 (d, J=8.5, 1H); 6.89 (s, 2H); 7.06-7.16 (m, 5H); 7.31 (br s, 1H); 7.49 (d, J=8.5Hz, 1H).

b) (±)-7-[[[(2-imidazolyl)metyl]amino]karbonyl]-3-okso-4-(2-fenyletyl)-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre b) (±)-7-[[[(2-imidazolyl)methyl]amino]carbonyl]-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1 H-1, 4-benzodiazepine-2-acetic acid

LiOH (16 mg, 0,38 mmol) ble ved RT tilsatt til en løsning av metyl-(+)-7-[[[(2-imidazolyl)metyl]amino]karbonyl]-3-okso-4-(2-fenyletyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (98 mg, 0,21 mmol) i dioksan (3 mL) og H20 (3 mL). Reaksjonsblandingen ble oppvarmet til 65°C i 3 timer, hvorpå det organiske løsningsmidlet ble fjernet i vakuum. Det vandige residuet ble surgjort med 1M HCI-løsning (0,38 mL) for å oppnå et hvitt faststoff som ble frafiltrert, løst i varm metanol og utfelt med eter. Det således oppnådde hvite faststoff ble oppsamlet for å gi tittelforbindelsen (72 mg, 78%). LiOH (16 mg, 0.38 mmol) was added at RT to a solution of methyl-(+)-7-[[[(2-imidazolyl)methyl]amino]carbonyl]-3-oxo-4-(2- phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (98 mg, 0.21 mmol) in dioxane (3 mL) and H 2 O (3 mL). The reaction mixture was heated to 65°C for 3 hours, after which the organic solvent was removed in vacuo. The aqueous residue was acidified with 1M HCl solution (0.38 mL) to obtain a white solid which was filtered off, dissolved in hot methanol and precipitated with ether. The white solid thus obtained was collected to give the title compound (72 mg, 78%).

<1>H NMR (DMSO-de, 400 MHz) 8 2,59 (dd, J=16,2, 5,0Hz, 1H); 2,77 (dd, J=7,7, 6,8Hz, 2H); 2,92 (dd, J=16,5, 8,8Hz, 1H); 3,63-3,75 (m, 2H); 3,79 (d, J=16,5Hz, 1H); 4,61 (s, 2H); 5,13 (dd, J=8,8, 5,0Hz, 1H); 5,45 (d, J=16,5Hz, 1H); 6,57 (d, J=8,6Hz, 1H); 7,07 (s, 2H); 7,10-7,19 (m, 5H); 7,41 (s, 1H); 7,54 (d, J=8,4Hz, 1H). <1>H NMR (DMSO-de, 400 MHz) δ 2.59 (dd, J=16.2, 5.0Hz, 1H); 2.77 (dd, J=7.7, 6.8Hz, 2H); 2.92 (dd, J=16.5, 8.8Hz, 1H); 3.63-3.75 (m, 2H); 3.79 (d, J=16.5Hz, 1H); 4.61 (s, 2H); 5.13 (dd, J=8.8, 5.0Hz, 1H); 5.45 (d, J=16.5Hz, 1H); 6.57 (d, J=8.6Hz, 1H); 7.07 (s, 2H); 7.10-7.19 (m, 5H); 7.41 (s, 1H); 7.54 (d, J=8.4Hz, 1H).

MS (ES) m/e 448 (M+H)<+>MS (ES) m/e 448 (M+H)<+>

Analyse beregnet for C24H25N5O4 • H20:Analysis calculated for C24H25N5O4 • H20:

C, 61,92; H, 5,85; N, 15,04 C, 61.92; H, 5.85; N, 15.04

Funnet: C, 61,69; H, 5,60; N, 14,86. Found: C, 61.69; H, 5.60; N, 14.86.

Eksempel 30Example 30

Fremstilling av (±)-7-[[[(2-benzimidazolyl)metyl]amino]metyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre Preparation of (±)-7-[[[(2-benzimidazolyl)methyl]amino]methyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine- 2-acetic acid

a) Metyl-(±)-7-[[[(2-benzimidazolyl)metyl]amino]metyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat a) Methyl-(±)-7-[[[(2-benzimidazolyl)methyl]amino]methyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1,4- benzodiazepine-2-acetate

Metyl-(±)-7-formyl-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (180 mg, 0,65 mmol) (fremstillet som i Eksempel 14(b)) ble suspendert i vannfrLmetanol og deretter tilsatt natriumacetat (160 mg, 1,95 mmol), 2-(aminometyl)-benzimidazol-dihydroklorid (143 mg, 0,65 mmol) og 4Å molekylsikt. Etter 30 minutter ble natriumcyanoborhydrid (45 mg, 0,71 mmol) tilsatt i to porsjoner i løpet av 30 minutter. Reaksjonsblandingen fikk omrøres ved RT over natten, hvorpå metanolen ble fjernet under vakuum. Residuet ble fortynnet med CH2CI2og løsningen vasket med mettet NaHC03. Tørking (MgS04), konsentrering og silikagelkromatografi (90% CH2CI2/9% metanol/1% NEt3) ga tittelforbindelsen (133 mg, 49%). Methyl-(±)-7-formyl-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (180 mg, 0.65 mmol) (prepared as in Example 14(b)) was suspended in aqueous methanol and then sodium acetate (160 mg, 1.95 mmol), 2-(aminomethyl)-benzimidazole dihydrochloride (143 mg, 0.65 mmol) and 4Å molecular sieve were added. After 30 min, sodium cyanoborohydride (45 mg, 0.71 mmol) was added in two portions over 30 min. The reaction mixture was allowed to stir at RT overnight, after which the methanol was removed under vacuum. The residue was diluted with CH 2 Cl 2 and the solution washed with saturated NaHCO 3 . Drying (MgSO 4 ), concentration and silica gel chromatography (90% CH 2 Cl 2 /9% methanol/1% NEt 3 ) afforded the title compound (133 mg, 49%).

<1>H NMR (CDCI3, 400 MHz) 8 2,67 (dd, J=16,1, 6,1Hz, 1H); 2,96 (dd, J=16,1, 6,8Hz, 1H); 3,05 (s, 3H); 3,68 (d, J=16,4Hz); 3,72 (br s, 2H); 3,75 (s, 3H); 4,11 (br s, 2H); 4,97 (dd, J=6,8Hz, 6,1, 1H); 5,35 (d, J=16,4Hz, 1H); 6,54 (d, J=8,1Hz, 1H); 6,87 (s, 1H); 7,05 (d, J=8,2Hz, 1H); 7,20-7,26 (m, 2H); 7,57 (m, 2H); <1>H NMR (CDCl3 , 400 MHz) δ 2.67 (dd, J=16.1, 6.1Hz, 1H); 2.96 (dd, J=16.1, 6.8Hz, 1H); 3.05 (s, 3H); 3.68 (d, J=16.4Hz); 3.72 (br s, 2H); 3.75 (s, 3H); 4.11 (br s, 2H); 4.97 (dd, J=6.8Hz, 6.1, 1H); 5.35 (d, J=16.4Hz, 1H); 6.54 (d, J=8.1Hz, 1H); 6.87 (s, 1H); 7.05 (d, J=8.2Hz, 1H); 7.20-7.26 (m, 2H); 7.57 (m, 2H);

MS (ES) m/e 408 (M+H)<+>MS (ES) m/e 408 (M+H)<+>

b) (±)-7-[[[(2-benzimidazolyl)metyl]amino]metyl]-4-metyl-3-okso-2,314,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre b) (±)-7-[[[(2-benzimidazolyl)methyl]amino]methyl]-4-methyl-3-oxo-2,314,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid

LiOH (14,6 mg, 0,34 mmol) ble ved RT tilsatt til en løsning av metyl-(±)-7-[[[(2-benzimidazolyl)metyl]amino]metyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (133 mg, 0,31 mmol) i dioksan (3 mL) og H20 (1 mL). Reaksjonsblandingen ble omrørt ved RT over natten, hvorpå det organiske løsningsmiddel ble fjernet på rotasjonsfordamper. Det vandige residuet ble surgjort med 1M HCI-løsning (0,38 mL) for å oppnå et hvitt faststoff som ble renset ved ODS-kromatografi (10% acetonitril/H2O-0,1% TFA) for å gi tittelforbindelsen (65 mg, 51%):<1>H NMR (DMSO-d6, 400 MHz) 5 2,51 (m, 1H); 2,73 (m, 1H); 2,91 (s, 3H); 3,69 (bs, 2H); 3,76 (d, J=16,6Hz, 1H); 3,97 (br s, 2H); 4,97 (m, 1H); 4,45 (d, J=16,6Hz, 1H); 5,77 (m, 1H); 6,52 (d, J=8,1Hz, 1H); 6,97 (s, 1H); 7,02 (d, J=8,1Hz, 1H); 7,20 (m, 2H); 7,52 (m, 2H); MS (ES) m/e 394 (M+H)<+>LiOH (14.6 mg, 0.34 mmol) was added at RT to a solution of methyl-(±)-7-[[[(2-benzimidazolyl)methyl]amino]methyl]-4-methyl-3-oxo -2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (133 mg, 0.31 mmol) in dioxane (3 mL) and H 2 O (1 mL). The reaction mixture was stirred at RT overnight, after which the organic solvent was removed on a rotary evaporator. The aqueous residue was acidified with 1M HCl solution (0.38 mL) to obtain a white solid which was purified by ODS chromatography (10% acetonitrile/H2O-0.1% TFA) to give the title compound (65 mg, 51%):<1>H NMR (DMSO-d 6 , 400 MHz) δ 2.51 (m, 1H); 2.73 (m, 1H); 2.91 (s, 3H); 3.69 (bs, 2H); 3.76 (d, J=16.6Hz, 1H); 3.97 (br s, 2H); 4.97 (m, 1H); 4.45 (d, J=16.6Hz, 1H); 5.77 (m, 1H); 6.52 (d, J=8.1Hz, 1H); 6.97 (s, 1H); 7.02 (d, J=8.1Hz, 1H); 7.20 (m, 2H); 7.52 (m, 2H); MS (ES) m/e 394 (M+H)<+>

Analyse beregnet for C2iH23N503 • 2 CF3C02H • H20:Analysis calculated for C2iH23N503 • 2 CF3C02H • H20:

C, 46,95; H, 4,26; N, 10,95. C, 46.95; H, 4.26; N, 10.95.

Funnet: C, 46,81; H, 4,00; N, 10,84 Found: C, 46.81; H, 4.00; N, 10.84

Eksempel 31Example 31

Fremstilling av (±)-7-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-1,4-dimetyl-3-okso^^^.S-tetrahydro-l H-1,4-benzodiazepin-2-eddiksyre Preparation of (±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-1,4-dimethyl-3-oxo^^^.S-tetrahydro-1H-1,4-benzodiazepine-2 -acetic acid

a) Metyl-(±)-7-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-1,4-dimetyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat a) Methyl-(±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-1,4-dimethyl-3-oxo-2,3,4,5-tetrahydro-1 H-1, 4-benzodiazepine-2-acetate

Ved å følge fremgangsmåten i Eksempel 2(a) med med metyl-(±)-7-karboksy-1,4-dimetyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat i stedet for metyl-(±)-7-karboksy-3-okso-4-(2-fenyletyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat, ble tittelforbindelsen fremstillet (60%): By following the procedure in Example 2(a) with methyl-(±)-7-carboxy-1,4-dimethyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine- 2-acetate instead of methyl-(±)-7-carboxy-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate, the title compound was prepared (60%):

MS (ES) m/e 435 (M+H)<+>MS (ES) m/e 435 (M+H)<+>

<1>H NMR (CDCI3, 250 MHz) 5 9,82 (m, 1H); 7,81 (d, J=7,9Hz, 1H); 7,62 (s, 1H); 7,5 (m, 2H); 7,22 (m, 2H); 6,79 (d, J=7,9Hz, 1H); 5,09 (d, J=16,6Hz, 1H); 4,76-5,01 (m, 3H); 3,61 (s, 3H); 3,59 (d, J=16,6Hz, 1H); 3,1 (m, 1H); 2,90 (s, 3H); 2,81 (s, 3H); 2,65 (m, 1H) <1>H NMR (CDCl3 , 250 MHz) δ 9.82 (m, 1H); 7.81 (d, J=7.9Hz, 1H); 7.62 (s, 1H); 7.5 (m, 2H); 7.22 (m, 2H); 6.79 (d, J=7.9Hz, 1H); 5.09 (d, J=16.6Hz, 1H); 4.76-5.01 (m, 3H); 3.61 (s, 3H); 3.59 (d, J=16.6Hz, 1H); 3.1 (m, 1H); 2.90 (s, 3H); 2.81 (s, 3H); 2.65 (m, 1H)

b) (±)-7-[[[(2-benzimidazolyI)metyl]amino]karbonyl]-1,4-dimetyl-3-okso-2,3,4l5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre b) (±)-7-[[[(2-benzimidazolyI)methyl]amino]carbonyl]-1,4-dimethyl-3-oxo-2,3,4l5-tetrahydro-1H-1,4-benzodiazepine- 2-acetic acid

En løsning av metyl-(±)-7-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-1,4-dimetyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat (0,080 g, A solution of methyl-(±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-1,4-dimethyl-3-oxo-2,3,4,5-tetrahydro-1 H-1 ,4-benzodiazepine-2-acetate (0.080 g,

0,18 mmol) i en blanding av metanol (10 mL), vann (1,0 mL) og 1,0 M NaOH0.18 mmol) in a mixture of methanol (10 mL), water (1.0 mL) and 1.0 M NaOH

(0,75 mL) ble oppvarmet til 50°C i 2 timer, avkjølt til RT og inndampet til tørrhet. Residuet ble løst i vann (5,0 mL) og løsningen surgjort til pH 5 med 0,25 N HCI for å utfelle tittelforbindelsen (55%): MS (ES) m/e 422 (M+H)<+>(0.75 mL) was heated to 50 °C for 2 h, cooled to RT and evaporated to dryness. The residue was dissolved in water (5.0 mL) and the solution acidified to pH 5 with 0.25 N HCl to precipitate the title compound (55%): MS (ES) m/e 422 (M+H)<+>

Analyse beregnet for C22H23N5O4 • 2,3 H20:Analysis calculated for C22H23N5O4 • 2.3 H20:

C, 57,09; H, 6,01; N, 15,13 C, 57.09; H, 6.01; N, 15,13

Funnet: C, 57,29; H, 5,79; N, 14,82. Found: C, 57.29; H, 5.79; N, 14.82.

<1>H NMR ( 400 MHz, DMSO-d6) 5 8,93 (br t, J=5,6Hz, 1H); 7,78 (d, J=8,4Hz, 1H); 7,73 (s, 1H); 7,49 (m, 2H); 7,12 (m, 2H); 6,98 (d, J=8,4Hz, 1H); 5,30 (d, J=16,6Hz, 1H); 4,85 (m, 1H); 4,68 (d, J=5,4Hz, 2H); 4,10 (d, J=16,6Hz, 1H); 2,98 (s, 3H); 2,92 (m, 1H); 2,80 (s, 3H); 2,60 (dd, J=16,7, 8,9Hz, 1H) <1>H NMR (400 MHz, DMSO-d6) δ 8.93 (br t, J=5.6Hz, 1H); 7.78 (d, J=8.4Hz, 1H); 7.73 (s, 1H); 7.49 (m, 2H); 7.12 (m, 2H); 6.98 (d, J=8.4Hz, 1H); 5.30 (d, J=16.6Hz, 1H); 4.85 (m, 1H); 4.68 (d, J=5.4Hz, 2H); 4.10 (d, J=16.6Hz, 1H); 2.98 (s, 3H); 2.92 (m, 1H); 2.80 (s, 3H); 2.60 (dd, J=16.7, 8.9Hz, 1H)

Eksempel 32Example 32

Fremstilling av (±)-7-[[[(2-benzimidazolyl)metyl]metylamino]karbonyl]-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre Preparation of (±)-7-[[[(2-benzimidazolyl)methyl]methylamino]carbonyl]-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid

a) Metyl-(+)-7-[[[(2-benzimidazolyl)metyl]metylamino]karbonyl]-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat a) Methyl-(+)-7-[[[(2-benzimidazolyl)methyl]methylamino]carbonyl]-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2- acetate

Ved å følge fremgangsmåten i Eksempel 15(b) med med metyl-7-karboksy-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat i stedet for metyl-(±)-7-karboksy-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat, ble den rå tittelforbindelsen fremstillet. Kromatografi (silikagel, 7% MeOH/CH2CI2) førte til tittelforbindelsen (35%): MS (ES) m/e 422,2 (M+H)<+>By following the procedure in Example 15(b) with methyl-7-carboxy-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate instead of methyl-(± )-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate, the crude title compound was prepared. Chromatography (silica gel, 7% MeOH/CH2Cl2) afforded the title compound (35%): MS (ES) m/e 422.2 (M+H)<+>

<1>H NMR (CDCI3, 400 MHz) 5 7,45 (m, 1H); 7,38 (m, 4H); 7,15 (d, J=8,4Hz, 1H); 6,90 (s, 1H); 6,50 (d, J=8,4Hz, 1H); 5,35 (s, 3H); 4,95 (m, 1H); 4,65 (m, 1H); 3,71 (s, 3H); 3,65 (m, 1H); 3,48 (s, 3H); 3,07 (m, 1H); 2,75 (dd, J=16,4, 8,4Hz, 1H). <1>H NMR (CDCl3 , 400 MHz) δ 7.45 (m, 1H); 7.38 (m, 4H); 7.15 (d, J=8.4Hz, 1H); 6.90 (s, 1H); 6.50 (d, J=8.4Hz, 1H); 5.35 (s, 3H); 4.95 (m, 1H); 4.65 (m, 1H); 3.71 (s, 3H); 3.65 (m, 1H); 3.48 (s, 3H); 3.07 (m, 1H); 2.75 (dd, J=16.4, 8.4Hz, 1H).

b) (±)-7-[[[(2-benzimidazolyl)metyl]metylarnino]karbonyl]-3-okso-2l3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre b) (±)-7-[[[(2-benzimidazolyl)methyl]methylarino]carbonyl]-3-oxo-2l3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid

En løsning av metyl-(±)-7-[[[(2-benzimidazolyl)metyl]metylmino]karbonyl]-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (0,040 g, 0,09 mmol) i en blanding av metanol (7,0 mL), vann (0,7 mL) og 1,0 M NaOH (0,7 mL) ble holdt i 16 timer ved RT. Trifluoreddiksyre (0,5 mL) ble tilsatt og løsningsmidlene fjernet for å gi råproduktet. Rensing ved halv-preparativ HPLC (YMC ODS-AQ, 15:85; acetonitril:vann, 0,1% TFA) ga tittelforbindelsen: MS (ES) m/e 408,2 (M+H)<+>A solution of methyl-(±)-7-[[[(2-benzimidazolyl)methyl]methylmino]carbonyl]-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2- acetate (0.040 g, 0.09 mmol) in a mixture of methanol (7.0 mL), water (0.7 mL) and 1.0 M NaOH (0.7 mL) was kept for 16 h at RT. Trifluoroacetic acid (0.5 mL) was added and the solvents removed to give the crude product. Purification by semi-preparative HPLC (YMC ODS-AQ, 15:85; acetonitrile:water, 0.1% TFA) gave the title compound: MS (ES) m/e 408.2 (M+H)<+>

<1>H NMR (DMSO-d6, 250 MHz) 5 8,19 (br t, J=4,5Hz, 1H); 7,72 (m, 2H); 7,38 (rn, 2H), 7,28 (d, J=8,4Hz, 1H); 7,15 (s, 1H); 6,62 (d, J=8,4Hz, 1H); 6,22 (brs, 1H); 5,05 (m, 1H); 4,95 (s, 2H); 3,74 (dd, J=15,8, 7,4Hz, 1H); 3,15 (s, 3H); 2,75 (dd, J=16,4, 8,5Hz, 1H); 2,50 (m, 1H) <1>H NMR (DMSO-d6, 250 MHz) δ 8.19 (br t, J=4.5Hz, 1H); 7.72 (m, 2H); 7.38 (rn, 2H), 7.28 (d, J=8.4Hz, 1H); 7.15 (s, 1H); 6.62 (d, J=8.4Hz, 1H); 6.22 (brs, 1H); 5.05 (m, 1H); 4.95 (s, 2H); 3.74 (dd, J=15.8, 7.4Hz, 1H); 3.15 (s, 3H); 2.75 (dd, J=16.4, 8.5Hz, 1H); 2.50 (m, 1H)

Eksempel 33Example 33

Fremstilling av (2S)-7-[[[N-butyl-N-benzimidazol-2-yl)metyl]amino]karbonyl]-3-okso-4-metyl-2,3A5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre Preparation of (2S)-7-[[[N-butyl-N-benzimidazol-2-yl)methyl]amino]carbonyl]-3-oxo-4-methyl-2,3A5-tetrahydro-1H-1,4- benzodiazepine-2-acetic acid

a) N-BOC-2-metylbenzimidazola) N-BOC-2-methylbenzimidazole

Til en omrørt blanding av 2-metylbenzimidazol (15 g, 113,5 mmol), trietylamin To a stirred mixture of 2-methylbenzimidazole (15 g, 113.5 mmol), triethylamine

(12 g, 119,2 mmol) og DMAP (kat.) i tørr CH2CI2(150 mL) ble det tilsatt (Boc)20. Etter 24 timer ble blandingen konsentrert. Residuet ble tatt opp i H20, omrørt og filtrert for å gi et hvitt faststoff (26,3 g, 100%): smp. 71-72°C; (12 g, 119.2 mmol) and DMAP (cat.) in dry CH 2 Cl 2 (150 mL) was added (Boc) 2 O. After 24 hours the mixture was concentrated. The residue was taken up in H 2 O, stirred and filtered to give a white solid (26.3 g, 100%): m.p. 71-72°C;

<1>H NMR (CDCI3, 250 MHz) 8 1,71 (s, 9H); 2,83 (s, 3H); 7,29 (m, 2H); 7,65 (m, 1H); 7,91 (m, 1H) <1>H NMR (CDCl3 , 250 MHz) δ 1.71 (s, 9H); 2.83 (s, 3H); 7.29 (m, 2H); 7.65 (m, 1H); 7.91 (m, 1H)

b) 1-BOC-2-brommetylbenzimidazolb) 1-BOC-2-bromomethylbenzimidazole

Ved å følge fremgangsmåten i Eksempel 4(a) men med N-BOC-2-metylbenzimidazol i stedet for 2-metylbenzotiazol, ble tittelforbindelsen fremstillet som en gul olje (12,88 g, 77%):<1>H NMR (250 MHz, CDCI3) 8 1,79 (s, 9H); 4,95 (s, 2H); 7,40 (m, 2H); 7,75 (m, 1H); 8,01 (m, 1H) Following the procedure of Example 4(a) but with N-BOC-2-methylbenzimidazole in place of 2-methylbenzothiazole, the title compound was prepared as a yellow oil (12.88 g, 77%):<1>H NMR (250 MHz, CDCl 3 ) δ 1.79 (s, 9H); 4.95 (s, 2H); 7.40 (m, 2H); 7.75 (m, 1H); 8.01 (m, 1H)

c) 2-(1 -butylamino)metylbenzimidazolc) 2-(1-butylamino)methylbenzimidazole

Til en omrørt løsning av 1-BOC-2-brommetylbenzimidazol (2,00 g, 6,4 mmol) i To a stirred solution of 1-BOC-2-bromomethylbenzimidazole (2.00 g, 6.4 mmol) in

tørr THF (20 mL) ble det tilsatt n-butylamin (1,2 g, 15,4 mmol). Etter omrøring ved RT over natten ble blandingen konsentrert. Residuet ble tatt opp i H20 og ekstrahert med CH2CI2. De organiske ekstraktene ble tørket over MgS04og konsentrert for å gi et brunt residuum som ble løst i CH2CI2(15 mL) og behandlet med TFA (5 mL). Den resulterende blanding ble omrørt ved RT over natten og deretter konsentrert. dry THF (20 mL) was added n-butylamine (1.2 g, 15.4 mmol). After stirring at RT overnight, the mixture was concentrated. The residue was taken up in H 2 O and extracted with CH 2 Cl 2 . The organic extracts were dried over MgSO 4 and concentrated to give a brown residue which was dissolved in CH 2 Cl 2 (15 mL) and treated with TFA (5 mL). The resulting mixture was stirred at RT overnight and then concentrated.

Residuet ble tatt opp i H20 og løsningen nøytralisert med 2,5N NaOH. CH2CI2-ekstraksjon, tørking (MgS04), konsentrering og silikagelkromatografi (2% The residue was taken up in H2O and the solution neutralized with 2.5N NaOH. CH2CI2 extraction, drying (MgSO4), concentration and silica gel chromatography (2%

i MeOH/CH2CI2) ga tittelforbindelsen som en gul olje (0,91 g, 70%)in MeOH/CH2Cl2) gave the title compound as a yellow oil (0.91 g, 70%)

<1>H NMR (250 MHz, CDCI3) 5 0,79 (t, J=7,2Hz, 3H); 1,23 (m, 2H); 1,54 (m, 2H); 3,35 (t, J=7,2Hz, 2H); 4,55 (s, 2H); 7,25 (m, 2H); 7,48 (m, 1H); 7,75 (m, 1H). <1>H NMR (250 MHz, CDCl 3 ) δ 0.79 (t, J=7.2Hz, 3H); 1.23 (m, 2H); 1.54 (m, 2H); 3.35 (t, J=7.2Hz, 2H); 4.55 (s, 2H); 7.25 (m, 2H); 7.48 (m, 1H); 7.75 (m, 1H).

d) Metyl-(S)-7-[[[N-(2-benzimidazolyl)metyl-N-(n-butyl)]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat d) Methyl-(S)-7-[[[N-(2-benzimidazolyl)methyl-N-(n-butyl)]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5 -tetrahydro-1H-1,4-benzodiazepine-2-acetate

Til en omrørt blanding av 2-(1-butylamino)metylbenzimidazol (0,14 g, 0,6671 mmol), metyl-(S)-7-karboksy-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat (0,15 g, 0,5132 mmol), HOBT-H20 (0,083 g, 0,6158 mmol) To a stirred mixture of 2-(1-butylamino)methylbenzimidazole (0.14 g, 0.6671 mmol), methyl-(S)-7-carboxy-4-methyl-3-oxo-2,3,4,5 -tetrahydro-1 H -1,4-benzodiazepine-2-acetate (0.15 g, 0.5132 mmol), HOBT-H 2 O (0.083 g, 0.6158 mmol)

og (i-Pr)2NEt (0,133 g, 1,0263 mmol) i tørr MeCN (5 mL) ble det tilsatt EDC (0,183 g, 0,6158 mmol). Etter omrøring ved RT over natten ble blandingen konsentrert. and (i-Pr) 2 NEt (0.133 g, 1.0263 mmol) in dry MeCN (5 mL) was added EDC (0.183 g, 0.6158 mmol). After stirring at RT overnight, the mixture was concentrated.

Residuet ble tatt opp i H20 og ekstrahert med CH2CI2. De kombinerte organiskeThe residue was taken up in H 2 O and extracted with CH 2 Cl 2 . They combined organic

. lagene ble vasket suksessivt med mettet NaHC03og saltvann og deretter tørket (MgS04) og konsentrert for å gi tittelforbindelsen som et gult skum (0,232 g, 95%):<1>H NMR (250 MHz, CDCI3) 5 0,79 (t, J=7,2Hz, 3H); 1,23 (m, 2H); 1,54 (m, 2H); 2,54 (dd, J=16,8Hz, 5,0Hz, 1H); 2,75 (dd, J=16,8Hz, 8,9Hz, 1H); 2,86 (s, 3H); 3,32 (t, J=7,2Hz, 2H); 3,60 (s, 3H); 3,72 (d, J=16,1Hz, 1H); 4,75 (s, 2H); 5,05 (m, 1H); 5,48 (d, J=16,1Hz, 1H); 6,20 (d, J=3,6Hz, 1H); 6,55 (d, J=8,9Hz, 1H); 7,16 (m, 4H); 7,53 . the layers were washed successively with saturated NaHCO 3 and brine then dried (MgSO 4 ) and concentrated to give the title compound as a yellow foam (0.232 g, 95%): <1>H NMR (250 MHz, CDCl 3 ) δ 0.79 (h, J=7.2Hz, 3H); 1.23 (m, 2H); 1.54 (m, 2H); 2.54 (dd, J=16.8Hz, 5.0Hz, 1H); 2.75 (dd, J=16.8Hz, 8.9Hz, 1H); 2.86 (s, 3H); 3.32 (t, J=7.2Hz, 2H); 3.60 (s, 3H); 3.72 (d, J=16.1Hz, 1H); 4.75 (s, 2H); 5.05 (m, 1H); 5.48 (d, J=16.1Hz, 1H); 6.20 (d, J=3.6Hz, 1H); 6.55 (d, J=8.9Hz, 1H); 7.16 (m, 4H); 7.53

(m, 2H)(m, 2H)

i in

e) (S)-7-[[[N-(2-benzimidazolyl)metyl-N-(n-butyl)]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre e) (S)-7-[[[N-(2-benzimidazolyl)methyl-N-(n-butyl)]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro -1 H-1,4-benzodiazepine-2-acetic acid

Ved å følge fremgangsmåten i Eksempel 11(b) ble metyl-(S)-7-[[[N-(2-benzimidazolyl)metyl-N-(n-butyl)]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat forsåpet for å gi et hvitaktig faststoff. Utgnidning i varm EtOH ga tittelforbindelsen som et hvitt faststoff (0,15 g, 60%): smp. 160-162°C By following the procedure in Example 11(b), methyl-(S)-7-[[[N-(2-benzimidazolyl)methyl-N-(n-butyl)]amino]carbonyl]-4-methyl-3- oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate saponified to give an off-white solid. Trituration in hot EtOH gave the title compound as a white solid (0.15 g, 60%): m.p. 160-162°C

(dekomp.)(decomp.)

<1>H NMR (400 MHz, DMSO-d6) 5 0,79 (t, J=7,2Hz, 3H); 1,23 (m, 2H); 1,54 (m, 2H); 2,54 (dd, J=16,8Hz, 5,0Hz, 1H); 2,75 (dd, J=16,8Hz, 8,9Hz, 1H); 2,86 (s, 3H); 3,32 (t, J=7,2Hz, 2H); 3,72 (d, J=16,1Hz, 1H); 4,75 (s, 2H); 5,05 (m, 1H); 5,48 (d, J=16,1Hz, 1H); 6,20 (d, J=3,6Hz, 1H); 6,55 (d, J=8,9Hz, 1H); 7,16 (m, 4H); 7,53 (m, 2H); <1>H NMR (400 MHz, DMSO-d6) δ 0.79 (t, J=7.2Hz, 3H); 1.23 (m, 2H); 1.54 (m, 2H); 2.54 (dd, J=16.8Hz, 5.0Hz, 1H); 2.75 (dd, J=16.8Hz, 8.9Hz, 1H); 2.86 (s, 3H); 3.32 (t, J=7.2Hz, 2H); 3.72 (d, J=16.1Hz, 1H); 4.75 (s, 2H); 5.05 (m, 1H); 5.48 (d, J=16.1Hz, 1H); 6.20 (d, J=3.6Hz, 1H); 6.55 (d, J=8.9Hz, 1H); 7.16 (m, 4H); 7.53 (m, 2H);

MS (ES) m/e 464 (M+H)<+>; IR (KBr) 3400, 3000-3100, 2800-3100, 1712, 1671, 1655, 1630, 1611, 1271, 828 cm"<1>MS (ES) m/e 464 (M+H)<+>; IR (KBr) 3400, 3000-3100, 2800-3100, 1712, 1671, 1655, 1630, 1611, 1271, 828 cm"<1>

Analyse beregnet for C25H29N5O4 • 0,75 H20:Analysis calculated for C25H29N5O4 • 0.75 H20:

C, 62,95; H, 6,44; N, 14,68 C, 62.95; H, 6.44; N, 14.68

Funnet: C, 62,75; H, 6,40; N, 14,41 Found: C, 62.75; H, 6.40; N, 14.41

Eksempel 34Example 34

Fremstilling av (S)-7-[[[N-(2-benzimidazolyl)metyl-N-(2-fenyletyl)]amino]-karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre Preparation of (S)-7-[[[N-(2-benzimidazolyl)methyl-N-(2-phenylethyl)]amino]-carbonyl]-4-methyl-3-oxo-2,3,4,5- tetrahydro-1H-1,4-benzodiazepine-2-acetic acid

a) 2-(2-fenyletylamino)metylbenzimidazola) 2-(2-phenylethylamino)methylbenzimidazole

Ved å følge fremgangsmåten i Eksempel 33(c) men med 2-fenyletylamin i By following the procedure in Example 33(c) but with 2-phenylethylamine i

stedet for n-butylamin, ble tittelforbindelsen (0,100 g, 31%) fremstillet som en brun olje etter silikagel hurtigkromatografi (5% MeOH/CH2CI2):<1>H NMR (250 MHz, CDCI3) 5 2,82 (t, J=7,5Hz, 2H); 2,97 (t, J=7,5Hz, 2H); 4,10 (s, 2H); 7,21 (m, 5H); 7,35 (m, 2H); 7,52 (m, 2H) instead of n-butylamine, the title compound (0.100 g, 31%) was prepared as a brown oil after silica gel flash chromatography (5% MeOH/CH 2 Cl 2 ):<1>H NMR (250 MHz, CDCl 3 ) δ 2.82 (t, J =7.5Hz, 2H); 2.97 (t, J=7.5Hz, 2H); 4.10 (s, 2H); 7.21 (m, 5H); 7.35 (m, 2H); 7.52 (m, 2H)

b) Metyl-(S)-7-[[[N-(2-benzimidazolyl)metyl-N-(2-fenyletyl)]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat b) Methyl-(S)-7-[[[N-(2-benzimidazolyl)methyl-N-(2-phenylethyl)]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5 -tetrahydro-1H-1,4-benzodiazepine-2-acetate

Ved å følge fremgangsmåten i Eksempel 33(d) men med 2-(2-fenyletylamino)metylbenzimidazol i stedet for 2-(1-butylamino)metyl-benzimidazol ble tittelforbindelsen (0,195 g, 97%) fremstillet som et hvitaktig skum, etter sillikagel hurtigkromatografi (2-5% MeOH/CH2CI2):<1>H NMR (250 MHz, DMSO-d6) 5 2,54 (dd, J=16,5, 5,0Hz, 1H); 2,75 (dd, J=16,5, 8,9Hz, 1H); 2,85 (s, 3H); 2,90 (t, J=7,5Hz, 2H); 3,60 (t, J=7,5Hz, 2H), 3,65 (s, 3H); 3,78 (d, J=16,3Hz, 1H); 4,78 (s, 2H); 5,05 (m, 1H); 5,42 (d, J=16,3Hz, 1H); 6,18 (d, J=3,5Hz, 1H); 6,54 (d, J=8,9Hz, 1H); 7,10 (m, 7H); 7,26 (m, 2H); 7,48 (m, 1H); 7,60 (m, 1H); 12,30 (s, 1H) By following the procedure in Example 33(d) but with 2-(2-phenylethylamino)methylbenzimidazole instead of 2-(1-butylamino)methylbenzimidazole, the title compound (0.195 g, 97%) was prepared as a whitish foam, after silica gel flash chromatography (2-5% MeOH/CH 2 Cl 2 ):<1>H NMR (250 MHz, DMSO-d 6 ) δ 2.54 (dd, J=16.5, 5.0Hz, 1H); 2.75 (dd, J=16.5, 8.9Hz, 1H); 2.85 (s, 3H); 2.90 (t, J=7.5Hz, 2H); 3.60 (t, J=7.5Hz, 2H), 3.65 (s, 3H); 3.78 (d, J=16.3Hz, 1H); 4.78 (s, 2H); 5.05 (m, 1H); 5.42 (d, J=16.3Hz, 1H); 6.18 (d, J=3.5Hz, 1H); 6.54 (d, J=8.9Hz, 1H); 7.10 (m, 7H); 7.26 (m, 2H); 7.48 (m, 1H); 7.60 (m, 1H); 12.30 (s, 1H)

c) (S)-7-[[[N-(2-benzimidazolyl)metyl-N-(2-fenyletyl)]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre c) (S)-7-[[[N-(2-benzimidazolyl)methyl-N-(2-phenylethyl)]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro -1 H-1,4-benzodiazepine-2-acetic acid

Ved å følge fremgangsmåten i Eksempel 11(b) ble metyl-(S)-7-[[[N-(2-benzimidazolyl)metyl-N-(2-fenyletyl)]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat forsåpet. Omkrystallisasjon fra EtOH ga tittelforbindelsen (0,070 g, 40%) som et hvitaktig faststoff: MS (ES) m/e 512 (M+H)<+>; IR (KBr) 3300-3500, 3000-3100, 2800-300, 1631, 1647, 1652, 1618, 1405, 698 cm"<1>. Analyse beregnet for C29H29N504 • 2,5 H20: C, 62,58; H, 6,16; N, 12,58 By following the procedure in Example 11(b), methyl-(S)-7-[[[N-(2-benzimidazolyl)methyl-N-(2-phenylethyl)]amino]carbonyl]-4-methyl-3- oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate saponified. Recrystallization from EtOH gave the title compound (0.070 g, 40%) as an off-white solid: MS (ES) m/e 512 (M+H)<+>; IR (KBr) 3300-3500, 3000-3100, 2800-300, 1631, 1647, 1652, 1618, 1405, 698 cm"<1>. Analysis calculated for C29H29N504 • 2.5 H20: C, 62.58; H , 6.16; N, 12.58

Funnet: C, 62,92; H, 6,02; N, 12,28 Found: C, 62.92; H, 6.02; N, 12.28

Eksempel 35Example 35

Fremstilling av (S)-7-[[[N-(2-benzimidazolyl)metyl-N-karboksymetyl]-amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre Preparation of (S)-7-[[[N-(2-benzimidazolyl)methyl-N-carboxymethyl]-amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H- 1,4-benzodiazepine-2-acetic acid

a) N-[(2-benzimidazolyl)metyl]glycin-benzylestera) N-[(2-benzimidazolyl)methyl]glycine benzyl ester

Ved å følge fremgangsmåten i Eksempel 33(c) men med glycin-By following the procedure in Example 33(c) but with glycine-

benzylester HCI i stedet for n-butylamin, ble tittelforbindelsen (1,00 g, 60%) fremstillet som et hvitaktig faststoff:<1>H NMR (250 MHz, CDCI3) 5 3,86 (s, 2H); 4,31 (s, 2H); 5,23 (s, 2H); 7,23 (m, 5H); 7,35 (m, 2H); 7,55 (m, 2H) benzyl ester HCl in place of n-butylamine, the title compound (1.00 g, 60%) was prepared as an off-white solid: <1>H NMR (250 MHz, CDCl3 ) δ 3.86 (s, 2H); 4.31 (s, 2H); 5.23 (s, 2H); 7.23 (m, 5H); 7.35 (m, 2H); 7.55 (m, 2H)

b) Metyl-(S)-7-[[[N-(2-benzimidazolyl)metyl-N-(benzyloksykarbonyl)-metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat b) Methyl-(S)-7-[[[N-(2-benzimidazolyl)methyl-N-(benzyloxycarbonyl)-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5 -tetrahydro-1H-1,4-benzodiazepine-2-acetate

Ved å følge fremgangsmåten i Eksempel 33(d) men med N-[(2-benzimidazolyl)metyl]glycin-benzylester i stedet for 2-(1-butylamino)metylbenzimidazol, ble tittelforbindelsen (0,95 g 81%) fremstillet som et gult skum:<1>H NMR (250 MHz, CDCI3) 5 2,54 (dd, J=16,5, 3,5Hz, 1H); 2,75 (dd, J=16,5, 8,9Hz, 1H); 2,87 (s, 3H); 3,65 (s, 3H), 3,78 (d, J=16,3Hz, 1H), 4,30 (s, 2H); 4,86 (s, 2H); 5,05 (m, 1H); 5,23 (s, 2H); 5,45 (d, J=16,3Hz, 1H); 6,55 (d, J=8,9Hz, 1H); 7,10 (m, 2H); 7,23 (m, 5H); 7,55 (m, 2H); 7,81 (m, 2H) By following the procedure in Example 33(d) but with N-[(2-benzimidazolyl)methyl]glycine benzyl ester instead of 2-(1-butylamino)methylbenzimidazole, the title compound (0.95 g 81%) was prepared as a yellow foam:<1>H NMR (250 MHz, CDCl 3 ) δ 2.54 (dd, J=16.5, 3.5Hz, 1H); 2.75 (dd, J=16.5, 8.9Hz, 1H); 2.87 (s, 3H); 3.65 (s, 3H), 3.78 (d, J=16.3Hz, 1H), 4.30 (s, 2H); 4.86 (s, 2H); 5.05 (m, 1H); 5.23 (s, 2H); 5.45 (d, J=16.3Hz, 1H); 6.55 (d, J=8.9Hz, 1H); 7.10 (m, 2H); 7.23 (m, 5H); 7.55 (m, 2H); 7.81 (m, 2H)

c) Metyl-(S)-7-[[[N-(2-benzimidazolyl)metyl-N-karboksymetyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat c) Methyl-(S)-7-[[[N-(2-benzimidazolyl)methyl-N-carboxymethyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepine-2-acetate

En løsning av metyl-(S)-7-[[[N-(2-benzimidazolyl)metyl-N-(benzyloksy-karbonyl)-metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (0,185 g, 0,333 mmol) i metanol (5 mL) ble hydrogenert over 10% Pd/C ved RT over natten. Katalysatoren ble fjernet ved filtrering gjennom Celite® og filtratet konsentrert for å gi et gult skum. Utgnidning med aceton ga tittelforbindelsen (0,140 g, 90%) som et hvitaktig faststoff. A solution of methyl-(S)-7-[[[N-(2-benzimidazolyl)methyl-N-(benzyloxy-carbonyl)-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3, 4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (0.185 g, 0.333 mmol) in methanol (5 mL) was hydrogenated over 10% Pd/C at RT overnight. The catalyst was removed by filtration through Celite® and the filtrate concentrated to give a yellow foam. Trituration with acetone gave the title compound (0.140 g, 90%) as an off-white solid.

<1>H NMR (250 MHz, CDCI3) 5 2,54 (dd, J=16,5, 3,5Hz, 1H); 2,75 (dd, J=16,5, 8,9Hz, 1H); 2,87 (s, 3H); 3,65 (s, 3H); 3,78 (d, J=16,3Hz, 1H); 4,86 (s, 2H); 5,05 (m, 1H); 5,23 (s, 2H); 5,45 (d, J=16,3Hz, 1H); 6,55 (d, J=8,9Hz, 1H), 7,10 (m, 2H); 7,55 (m, 2H); 7,81 (m, 2H) <1>H NMR (250 MHz, CDCl 3 ) δ 2.54 (dd, J=16.5, 3.5Hz, 1H); 2.75 (dd, J=16.5, 8.9Hz, 1H); 2.87 (s, 3H); 3.65 (s, 3H); 3.78 (d, J=16.3Hz, 1H); 4.86 (s, 2H); 5.05 (m, 1H); 5.23 (s, 2H); 5.45 (d, J=16.3Hz, 1H); 6.55 (d, J=8.9Hz, 1H), 7.10 (m, 2H); 7.55 (m, 2H); 7.81 (m, 2H)

d) (S)-7-[[[N-(2-benzimidazolyl)metyl-N-karboksymetyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre d) (S)-7-[[[N-(2-benzimidazolyl)methyl-N-carboxymethyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H- 1,4-benzodiazepine-2-acetic acid

En løsning av Eksempel 35(b) i metanol (5 mL) ble hydrogenert ved RT i 10% Pd/C over natten. Katalysatoren ble frafiltrert gjennom Celite. Filtratet ble konsentrert for å gi et gult skum som ble utgnidd i aceton for å gi tittelforbindelsen som et hvitaktig faststoff (0,140 g, 90%): MS (ES) m/e 465 (M+H)<+>A solution of Example 35(b) in methanol (5 mL) was hydrogenated at RT in 10% Pd/C overnight. The catalyst was filtered off through Celite. The filtrate was concentrated to give a yellow foam which was triturated in acetone to give the title compound as an off-white solid (0.140 g, 90%): MS (ES) m/e 465 (M+H)<+>

Analyse beregnet for C23H23N5O6 • 1,2 H20:Analysis calculated for C23H23N5O6 • 1.2 H20:

C, 56,92; H, 5,26; N, 14,38 C, 56.92; H, 5.26; N, 14.38

Funnet: C, 57,09; H, 5,33; N, 14,00 Found: C, 57.09; H, 5.33; Thu, 14.00

Eksempel 36Example 36

Fremstilling av (S)-7-[[[N-(2-benzimidazolyl)metyl-N-cykloheksyl]-amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre Preparation of (S)-7-[[[N-(2-benzimidazolyl)methyl-N-cyclohexyl]-amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H- 1,4-benzodiazepine-2-acetic acid

a) 2-(cykloheksylamino)metylbenzimidazola) 2-(cyclohexylamino)methylbenzimidazole

Ved å følge fremgangsmåten i Eksempel 33(c) men med cykloheksylamin i By following the procedure in Example 33(c) but with cyclohexylamine i

stedet for n-butylamin, ble tittelforbindelsen (0,191 g, 52%) fremstillet som en brun olje:<1>H NMR (250 MHz, CDCI3) 8 1,35 (m, 4H); 1,75 (m, 4H); 2,21 (m, 2H); 2,78 (m, 1H); 4,31 (s, 2H); 7,21 (m, 2H); 7,51 (m, 2H) in place of n-butylamine, the title compound (0.191 g, 52%) was prepared as a brown oil: <1>H NMR (250 MHz, CDCl3 ) δ 1.35 (m, 4H); 1.75 (m, 4H); 2.21 (m, 2H); 2.78 (m, 1H); 4.31 (s, 2H); 7.21 (m, 2H); 7.51 (m, 2H)

b) Metyl-(S)-7-[[[N-(2-benzimidzazolyl)metyl-N-cykloheksyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat b) Methyl-(S)-7-[[[N-(2-benzimidazolyl)methyl-N-cyclohexyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepine-2-acetate

Ved å følge fremgangsmåten i Eksempel 33(d) men med 2-(cykloheksylamino)metylbenzimidazol i stedet for 2-(1-butylamino)metylbenzimidazol, ble tittelforbindelsen (0,174 g, 50%) fremstillet som et gult skum:<1>H NMR (250 MHz, CDCI3) 8 1,15 (m, 4H); 1,60 (m, 4H); 1,85 (m, 2H); 2,65 (dd, J=16,5, 3,5Hz, 1H); 2,98 (dd, J=16,5, 8,9Hz, 1H); 3,07 (s, 3H); 3,71 (d, J=16,3Hz, 1H); 4,48 (d, J=3,5Hz, 1H); 4,67 (s, 2H); 5,10 (m, 1H); 5,47 (d, J=16,3Hz, 1H), 6,51 (d, J=8,9Hz, 1H); 7,15 (m, 3H); 7,22 (m, 2H); 7,31 (m, 1H); 7,65 (m, 1H) By following the procedure of Example 33(d) but with 2-(cyclohexylamino)methylbenzimidazole instead of 2-(1-butylamino)methylbenzimidazole, the title compound (0.174 g, 50%) was prepared as a yellow foam:<1>H NMR (250 MHz, CDCl 3 ) δ 1.15 (m, 4H); 1.60 (m, 4H); 1.85 (m, 2H); 2.65 (dd, J=16.5, 3.5Hz, 1H); 2.98 (dd, J=16.5, 8.9Hz, 1H); 3.07 (s, 3H); 3.71 (d, J=16.3Hz, 1H); 4.48 (d, J=3.5Hz, 1H); 4.67 (s, 2H); 5.10 (m, 1H); 5.47 (d, J=16.3Hz, 1H), 6.51 (d, J=8.9Hz, 1H); 7.15 (m, 3H); 7.22 (m, 2H); 7.31 (m, 1H); 7.65 (m, 1H)

c) (S)-7-[[[N-(2-benzimidazolyl)metyl-N-cykloheksyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre c) (S)-7-[[[N-(2-benzimidazolyl)methyl-N-cyclohexyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H- 1,4-benzodiazepine-2-acetic acid

Ved å følge fremgangsmåten i Eksempel 4(d) ble metyl-(S)-7-[[[N-(2-benzimidazolyl)metyl-N-cykloheksyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat forsåpet. Tittelforbindelsen (0,100 g, 60%) ble oppnådd som et hvitaktig faststoff:<1>H NMR (400 MHz, DMSO-d6) 5 1,15 (m, 4H); 1,55 (m, 4H), 1,93 (m, 2H); 2,54 (dd, J=16,5, 3,5Hz, 1H); 2,78 (dd, J=16,5, 8,9Hz, 1H); 2,91 (s, 3H); 3,83 (d, J=16,3Hz, 1H); 3,85 (m, 1H); 4,97 (s, 2H); 5,07 (m, 1H); 5,48 (d, J=16,3Hz, 1H); 6,56 (d, J=8,9Hz, 1H); 7,20 (s, 1H); 7,25 (d, J=8,9Hz, 1H); 7,50 (m, 2H); 7,82 (m, 2H); By following the procedure in Example 4(d), methyl-(S)-7-[[[N-(2-benzimidazolyl)methyl-N-cyclohexyl]amino]carbonyl]-4-methyl-3-oxo-2, 3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate saponified. The title compound (0.100 g, 60%) was obtained as an off-white solid: <1>H NMR (400 MHz, DMSO-d6) δ 1.15 (m, 4H); 1.55 (m, 4H), 1.93 (m, 2H); 2.54 (dd, J=16.5, 3.5Hz, 1H); 2.78 (dd, J=16.5, 8.9Hz, 1H); 2.91 (s, 3H); 3.83 (d, J=16.3Hz, 1H); 3.85 (m, 1H); 4.97 (s, 2H); 5.07 (m, 1H); 5.48 (d, J=16.3Hz, 1H); 6.56 (d, J=8.9Hz, 1H); 7.20 (s, 1H); 7.25 (d, J=8.9Hz, 1H); 7.50 (m, 2H); 7.82 (m, 2H);

MS (ES) m/e 489 (M+H)<+>MS (ES) m/e 489 (M+H)<+>

Analyse beregnet for C27H31N5O4■ H2O:Analysis calculated for C27H31N5O4■ H2O:

C, 63,90; H, 6,55; N, 13,80 C, 63.90; H, 6.55; N, 13.80

Funnet: C, 63,91; H, 6,27; N, 13,60 Found: C, 63.91; H, 6.27; N, 13.60

Eksempel 37Example 37

Fremstilling av (±)-7-[[[2-(5-nitrobenzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre Preparation of (±)-7-[[[2-(5-nitrobenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine -2-acetic acid

a) 2-[[N-(tert-butoksykarbonyl)-N-metyl]aminometyl]-5-nitrobenzimidazol a) 2-[[N-(tert-butoxycarbonyl)-N-methyl]aminomethyl]-5-nitrobenzimidazole

BOC-sarkosin (2,555 g, 13,51 mmol) ble veid inn i en tørr 250 mL rundkolbe BOC-sarcosine (2.555 g, 13.51 mmol) was weighed into a dry 250 mL round bottom flask

spylt med argon. Materialet ble løst i tørr THF (20 mL). Et3N (3 mL, 21,6 mmol) ble tilsatt og deretter isobutylklorformiat (1,8 mL, 13,88 mmol). Reaksjonsblandingen ble omrørt ved RT under argon i 30 minutter og deretter avkjølt til -20°C og tilsatt 4-nitrofenylendiamin (2,0423 g, 13,34 mmol) som et faststoff. Etter fullført tilsetning ble kjølebadet fjernet og blandingen fikk oppvarmes til RT. Etter 20 timer ble reaksjonsblandingen konsentrert under vakuum. Materialet ble løst i EtOAc og ekstrahert med 1,0 N NaHC03. Den organiske fase ble tørket (MgS04), filtrert og konsentrert under vakuum. Residuet ble løst i iseddik og oppvarmet til 75°C i et oljebad. Etter 24 timer ble reaksjonsblandingen konsentrert under vakuum. Residuet ble konsentrert på nytt fra toluen. Materialet ble hurtigkromatografert (silikagel, 1:2 CH2CI2/Et20, 1:1 CH2CI2/Et20, 5% MeOH/CH2CI2) for å gi tittelforbindelsen (2,05 g, 51%). Begge fraksjoner hadde identiske massespektra: MS (ES) m/e 307,0 (M+H)<+><1>H NMR (250 MHz, CDCI3) 5 8,61-7,46 (m, 5H); 4,65 (s, 2H); 3,04 (s, 3H); 1,50 (s, 9H) purged with argon. The material was dissolved in dry THF (20 mL). Et 3 N (3 mL, 21.6 mmol) was added followed by isobutyl chloroformate (1.8 mL, 13.88 mmol). The reaction mixture was stirred at RT under argon for 30 min and then cooled to -20°C and 4-nitrophenylenediamine (2.0423 g, 13.34 mmol) was added as a solid. After the addition was complete, the cooling bath was removed and the mixture was allowed to warm to RT. After 20 hours, the reaction mixture was concentrated under vacuum. The material was dissolved in EtOAc and extracted with 1.0 N NaHCO 3 . The organic phase was dried (MgSO 4 ), filtered and concentrated under vacuum. The residue was dissolved in glacial acetic acid and heated to 75°C in an oil bath. After 24 hours, the reaction mixture was concentrated under vacuum. The residue was re-concentrated from toluene. The material was flash chromatographed (silica gel, 1:2 CH2Cl2/Et2O, 1:1 CH2Cl2/Et2O, 5% MeOH/CH2Cl2) to give the title compound (2.05 g, 51%). Both fractions had identical mass spectra: MS (ES) m/e 307.0 (M+H)<+><1>H NMR (250 MHz, CDCl 3 ) δ 8.61-7.46 (m, 5H); 4.65 (s, 2H); 3.04 (s, 3H); 1.50 (pp, 9H)

b) 2-(metylamino)metyl-5-nitrobenzimidazol b) 2-(methylamino)methyl-5-nitrobenzimidazole

2-[N-(tert-butoksykarbonyl)-N-metyl]aminometyl-5-nitrobenzimidazol2-[N-(tert-butoxycarbonyl)-N-methyl]aminomethyl-5-nitrobenzimidazole

(904,8 mg, 2,96 mmol) ble behandlet med 4 N HCI i dioksan. Reaksjonsblandingen (904.8 mg, 2.96 mmol) was treated with 4 N HCl in dioxane. The reaction mixture

ble omrørt ved RT i 1 time og deretter konsentrert under vakuum. Den gule oppslemmingen ble konsentrert på nytt fra toluen. Residuet ble tørket under høyvakuum, hvilket etterlot tittelforbindelsen (830,5 mg) som et lysegult faststoff. Dette materialet ble benyttet uten videre rensing. was stirred at RT for 1 h and then concentrated under vacuum. The yellow slurry was re-concentrated from toluene. The residue was dried under high vacuum, leaving the title compound (830.5 mg) as a pale yellow solid. This material was used without further purification.

c) Metyl-(±)-7-[[[2-(5-nitrobenzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat c) Methyl-(±)-7-[[[2-(5-nitrobenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1, 4-benzodiazepine-2-acetate

Metyl-(±)-7-karboksy-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (511,8 mg, 1,75 mmol) ble veid inn i en tørr 200 mL rundkolbe. Tørr DMF ble tilsatt og deretter HOBtH20 (258,1 mg, 1,91 mmol) og EDC (351,5 mg, 1,83 mmol). Blandingen ble omrørt ved RT inntil alt faststoff var oppløst, hvoretter en løsning av 2-(metylamino)metyl-5-nitrobenzimidazol (492,5 mg, Methyl-(±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (511.8 mg, 1.75 mmol) was weighed into a dry 200 mL round bottom flask. Dry DMF was added followed by HOBtH 2 O (258.1 mg, 1.91 mmol) and EDC (351.5 mg, 1.83 mmol). The mixture was stirred at RT until all the solid had dissolved, after which a solution of 2-(methylamino)methyl-5-nitrobenzimidazole (492.5 mg,

1,76 mmol) og diisopropyletylamin (1,0 mL, 5,74 mmol) i DMF ble tilsatt ved RT. Reaksjonsblandingen ble omrørt ved RT i 24 timer og deretter konsentrert under vakuum. Residuet ble rekonsentrert fra toluen og deretter kromatografert på silikagel (CHCI3(0,25 L) deretter 3% MeOH/CHCI3(1 L) deretter 5% MeOH/CHCI3(1 L) for å gi tittelforbindelsen (847,5 mg, kvantitativt): MS (ES) m/e 481,0 (M+H)<+>d) (±)-7-[[[2-(5-nitrobenzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre 1.76 mmol) and diisopropylethylamine (1.0 mL, 5.74 mmol) in DMF were added at RT. The reaction mixture was stirred at RT for 24 h and then concentrated under vacuum. The residue was reconcentrated from toluene and then chromatographed on silica gel (CHCl 3 (0.25 L) then 3% MeOH/CHCl 3 (1 L) then 5% MeOH/CHCl 3 (1 L) to give the title compound (847.5 mg, quantitative) : MS (ES) m/e 481.0 (M+H)<+>d) (±)-7-[[[2-(5-nitrobenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3- oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid

Metyl-(±)-7-[[[2-(5-nitrobenzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (386,3 mg, 0,080 mmol) ble suspendert i MeOH og tilsatt 1,0 N NaOH (2,5 mL, 2,5 mmol). Reaksjonsblandingen ble omrørt ved RT i 18 timer og deretter oppvarmet i et oljebad innstillet på 70°C. Etter 4 timer ble reaksjonsblandingen avkjølt til RT og nøytralisert med 1,0 N HCI (2,5 mL). Løsningen ble konsentrert under vakuum. Etter at det meste av MeOH var fordampet ble det dannet et gult bunnfall. Bunnfallet ble oppsamlet på en sinterglass-trakt og tørket i en eksikkator under vakuum for å gi tittelforbindelsen (317,3 g, 85%); Methyl-(±)-7-[[[2-(5-nitrobenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine -2-acetate (386.3 mg, 0.080 mmol) was suspended in MeOH and 1.0 N NaOH (2.5 mL, 2.5 mmol) was added. The reaction mixture was stirred at RT for 18 hours and then heated in an oil bath set at 70°C. After 4 h, the reaction mixture was cooled to RT and neutralized with 1.0 N HCl (2.5 mL). The solution was concentrated under vacuum. After most of the MeOH had evaporated, a yellow precipitate formed. The precipitate was collected on a sintered glass funnel and dried in a desiccator under vacuum to give the title compound (317.3 g, 85%);

<1>H NMR (250 MHz, CDCI3) 5 8,55-6,60 (m, 6H); 5,50 (d, 1H); 5,15 (dd, 1H); 4,91 (s, 2H); 3,20 (s, 3H); 3,09 (s, 3H); MS (ES) m/e 467,2 (M+H)<+><1>H NMR (250 MHz, CDCl 3 ) δ 8.55-6.60 (m, 6H); 5.50 (d, 1H); 5.15 (dd, 1H); 4.91 (s, 2H); 3.20 (s, 3H); 3.09 (s, 3H); MS (ES) m/e 467.2 (M+H)<+>

Analyse beregnet for C22H22N606 • HCI:Analysis calculated for C22H22N606 • HCI:

C, 52,54; H, 4,61; N, 16,71 C, 52.54; H, 4.61; N, 16.71

Funnet: C, 52,63; H, 4,83; N, 16,53. Found: C, 52.63; H, 4.83; N, 16.53.

Eksempel 38Example 38

Fremstilling av (±)-7-[[[2-(5-aminobenzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1>4-benzodiazepin-2-eddiksyre Preparation of (±)-7-[[[2-(5-aminobenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1>4-benzodiazepine -2-acetic acid

a) (±)-7-[[[2-(5-aminobenzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre a) (±)-7-[[[2-(5-aminobenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1,4- benzodiazepine-2-acetic acid

Metyl-(±)-7-[[[2-(5-nitrobenzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (367,4 mg, 0,76 mmol) ble suspendert i MeOH og tilsatt 10% Pd/C katalysator. Blandingen ble kraftig omrørt ved RT under H2(ballong). Etter 4,5 timer ble katalysatoren fjernet ved filtrering gjennom Celite®. Filtratet ble konsentrert under vakuum og residuet løst i MeOH. 1,0 N NaOH (2,5 mL, 2,5 mmol) og H20 (10 mL) ble tilsatt. Reaksjonsblandingen ble omrørt ved RT i24 timer og deretter nøytralisert med 1,0 N HCI (2,5 mL). Konsentrering i vakuum etterlot et mørkt residuum som ble løst i MeOH. Aktivkull (Norit®) ble tilsatt og blandingen kokt under tilbakeløpskjøling på et dampbad. Aktivkujlet ble fjernet ved filtrering gjennom Celite® og filtratet konsentrert til ca. 50 mL. Bunnfallet ble oppsamlet på en sinterglass-trakt og tørket i en vakuum-eksikkator for å gi tittelforbindelsen (158,0 mg) som et rødt pulver: HPLC (PRP-1®. 10% CH3CN/H2O-0,1% TFA) tR=4,64; MS (ES) m/e 437,2 (M+H)<*>; Methyl-(±)-7-[[[2-(5-nitrobenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine -2-acetate (367.4 mg, 0.76 mmol) was suspended in MeOH and 10% Pd/C catalyst was added. The mixture was vigorously stirred at RT under H2 (balloon). After 4.5 hours, the catalyst was removed by filtration through Celite®. The filtrate was concentrated under vacuum and the residue dissolved in MeOH. 1.0 N NaOH (2.5 mL, 2.5 mmol) and H 2 O (10 mL) were added. The reaction mixture was stirred at RT for 24 h and then neutralized with 1.0 N HCl (2.5 mL). Concentration in vacuo left a dark residue which was dissolved in MeOH. Activated charcoal (Norit®) was added and the mixture boiled under reflux cooling on a steam bath. The active bead was removed by filtration through Celite® and the filtrate concentrated to approx. 50 mL. The precipitate was collected on a sintered glass funnel and dried in a vacuum desiccator to give the title compound (158.0 mg) as a red powder: HPLC (PRP-1®. 10% CH3CN/H2O-0.1% TFA) tR =4.64; MS (ES) m/e 437.2 (M+H)<*>;

<1>H NMR (250 MHz, CD3OD) 5 7,42-6,56 (m, 6H), 5,54 (d, 1H); 5,15 (dd, 1H); 4,80 (s, 2H), 3,13 (s, 3H); 3,05 (s, 3H) <1>H NMR (250 MHz, CD 3 OD) δ 7.42-6.56 (m, 6H), 5.54 (d, 1H); 5.15 (dd, 1H); 4.80 (s, 2H), 3.13 (s, 3H); 3.05 (s, 3H)

Analyse beregnet for C22H24N604 • 0,75 HCI • 1,75 H20:Analysis calculated for C22H24N604 • 0.75 HCI • 1.75 H20:

C, 53,35; H, 5,75; N, 16,97 C, 53.35; H, 5.75; N, 16.97

Funnet: C, 53,91; H, 6,00; N, 16,36 Found: C, 53.91; H, 6.00; N, 16.36

Eksempel 39Example 39

Fremstilling av (±)-7-[2-(1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indolyl)karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-ben2odiazepin-2-eddiksyre Preparation of (±)-7-[2-(1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indolyl)carbonyl]-4-methyl-3-oxo-2,3,4 ,5-tetrahydro-1H-1,4-ben2odiazepine-2-acetic acid

a) Metyl-(±)-7-[2-(1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indolyl)karbonyl]-4-metyl-3-5okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat a) Methyl-(±)-7-[2-(1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indolyl)carbonyl]-4-methyl-3-5oxo-2,3 ,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate

Metyl-(±)-7-karboksy-4-metyl-3-okso-2,3,4l5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (308,5 mg, 1,06 mmol) ble veid inn i en 250 mL rundkolbe. Tørr DMF ble tilsatt og deretter HOBtH20 (159,1 mg, 1,18 mmol) og EDC (248,3 mg, Methyl-(±)-7-carboxy-4-methyl-3-oxo-2,3,415-tetrahydro-1H-1,4-benzodiazepine-2-acetate (308.5 mg, 1.06 mmol) was weighed into a 250 mL round bottom flask. Dry DMF was added followed by HOBtH 2 O (159.1 mg, 1.18 mmol) and EDC (248.3 mg,

1,30 mmol). Diisopropyletylamin (0,20 mL, 1,15 mmol) ble tilsatt og deretter en1.30 mmol). Diisopropylethylamine (0.20 mL, 1.15 mmol) was added and then a

) løsning av 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol (187,6 mg, 1,09 mmol) i DMF. ) solution of 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (187.6 mg, 1.09 mmol) in DMF.

Reaksjonsblandingen ble omrørt ved RT i 24 timer og deretter konsentrert under vakuum. Kromatografi (silikagel, trinnvis gradient, 2% MeOH/CHCI3, 3% MeOH/CHCI3) ga tittelforbindelsen som en klar, farveløs olje (484,7 mg):<1>H NMR (250 MHz, CDCI3) 5 9,09 (br s, 1H); 7,47-7,04 (m, 7H); 6,49 (d, 1H); 5,37 (d, 1H); 5,05 (dd, 1H), 4,77 (s, 2H), 3,69 (s, 3H); 2,99 (s, 3H); The reaction mixture was stirred at RT for 24 h and then concentrated under vacuum. Chromatography (silica gel, stepwise gradient, 2% MeOH/CHCl 3 , 3% MeOH/CHCl 3 ) afforded the title compound as a clear, colorless oil (484.7 mg):<1>H NMR (250 MHz, CDCl 3 ) δ 9.09 ( br s, 1H); 7.47-7.04 (m, 7H); 6.49 (d, 1H); 5.37 (d, 1H); 5.05 (dd, 1H), 4.77 (s, 2H), 3.69 (s, 3H); 2.99 (p, 3H);

MS (ES) m/e 447,2 (M+H)<+>MS (ES) m/e 447.2 (M+H)<+>

b) (±)-7-[2-(1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indolyl)karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre b) (±)-7-[2-(1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indolyl)carbonyl]-4-methyl-3-oxo-2,3,4 ,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid

) Metyl-(+)-7-[2-(1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indolyl)karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (484,7 mg, 1,09 mmol) ble løst i MeOH og tilsatt 1,0 N NaOH (2,0 mL, 2,0 mmol). Reaksjonsblandingen ble omrørt ved RT i 24 timer og deretter oppvarmet i et oljebad innstillet på 75°C. Etter 4 ) Methyl-(+)-7-[2-(1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indolyl)carbonyl]-4-methyl-3-oxo-2,3, 4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (484.7 mg, 1.09 mmol) was dissolved in MeOH and added 1.0 N NaOH (2.0 mL, 2.0 mmol) . The reaction mixture was stirred at RT for 24 hours and then heated in an oil bath set at 75°C. After 4

timer ble blandingen nøytralisert med 1,0 N HCI og konsentrert under vakuum. Dethours, the mixture was neutralized with 1.0 N HCl and concentrated under vacuum. The

i resulterende bunnfall ble oppsamlet og utfelt på nytt fra metanol/vann for å gi tittelforbindelsen (380 mg, 80%) som et farveløst pulver: MS (ES) m/e 433,2 (M+H)<+>Analyse beregnet for C24H24N404• 1,5 H20. in resulting precipitate was collected and reprecipitated from methanol/water to give the title compound (380 mg, 80%) as a colorless powder: MS (ES) m/e 433.2 (M+H)<+>Analysis calculated for C 24 H 24 N 4 O 4 • 1.5 H 2 O.

C, 62,73; H, 5,92; N, 12,19 C, 62.73; H, 5.92; N, 12,19

Funnet: C, 62,56; H, 5,55; N, 11,91. Found: C, 62.56; H, 5.55; N, 11.91.

) )

Eksempel 40Example 40

Fremstilling av (S)-7-[[[2-(5,6-metylendioksybenzimidazolyl)-metyllmetylaminolkarbonylJ^-metyl-S-okso^.S^.S-tetrahydro-IH-IA benzodiazepin-2-eddiksyre Preparation of (S)-7-[[[2-(5,6-methylenedioxybenzimidazolyl)-methylmethylaminolcarbonylJ^-methyl-S-oxo^.S^.S-tetrahydro-IH-IA benzodiazepine-2-acetic acid

a) 2-[[N-(benzyloksykarbonyl)-N-metyl]aminometyl]-5,6-metylendioksybenzimidazol a) 2-[[N-(benzyloxycarbonyl)-N-methyl]aminomethyl]-5,6-methylenedioxybenzimidazole

Cbz-sarkosin (310,0 mg, 1,39 mmol) ble løst i tørr THF (10 mL) i en 250 mL rundkolbe under argon. Isobutylklorformiat (0,2 mL, 1,54 mmol) ble tilsatt etterfulgt av Et3N (0,25 mL, 1,80 mmol). Reaksjonsblandingen ble omrørt ved RT under argon i 30 minutter og deretter avkjølt til -10°C til -20°C. En løsning av 1,2-diamino-4,5-metylendioksybenzen (0,2 g, 1,314 mmol) i tørr THF ble tilsatt og reaksjonsblandingen oppvarmet tii RT. Etter 18 timer ble reaksjonsblandingen konsentrert under vakuum. Det hvite faste residuet ble løst i EtOAc og løsningen vasket med 1,0 N NaHC03. Det organiske lag ble tørket (MgS04), filtert og konsentrert under vakuum. Residuet ble løst i iseddik og oppvarmet i et oljebad innstillet på 70°C. Etter 24 timer ble reaksjonsblandingen konsentrert under vakuum. Residuet ble konsentrert på nytt fra toluen og deretter kromatografert på silikagel (1:1 CH2CI2/Et20). Materialet oppnådd på denne måte (to komponenter eluert sammen) ble oppløst på nytt i iseddik og oppvarmet til 100°C. TLC av reaksjonsblandingen etter 24 timer viste to produkter. Konsentrering og kromatografi (silikagel, 1:1 CHCIs/Et20) ga tittelforbindelsen (145,0 mg, 32,7%): MS (ES) m/e 340,0 (M+H)<+>;Cbz-sarcosine (310.0 mg, 1.39 mmol) was dissolved in dry THF (10 mL) in a 250 mL round bottom flask under argon. Isobutyl chloroformate (0.2 mL, 1.54 mmol) was added followed by Et 3 N (0.25 mL, 1.80 mmol). The reaction mixture was stirred at RT under argon for 30 min and then cooled to -10°C to -20°C. A solution of 1,2-diamino-4,5-methylenedioxybenzene (0.2 g, 1.314 mmol) in dry THF was added and the reaction mixture warmed to RT. After 18 hours, the reaction mixture was concentrated under vacuum. The white solid residue was dissolved in EtOAc and the solution washed with 1.0 N NaHCO 3 . The organic layer was dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was dissolved in glacial acetic acid and heated in an oil bath set at 70°C. After 24 hours, the reaction mixture was concentrated under vacuum. The residue was re-concentrated from toluene and then chromatographed on silica gel (1:1 CH 2 Cl 2 /Et 2 O). The material obtained in this way (two components eluted together) was redissolved in glacial acetic acid and heated to 100°C. TLC of the reaction mixture after 24 hours showed two products. Concentration and chromatography (silica gel, 1:1 CHCl 3 /Et 2 O) gave the title compound (145.0 mg, 32.7%): MS (ES) m/e 340.0 (M+H)<+>;

<1>H NMR (250 MHz, CDCI3) 6 7,32 (s, 5H); 7,27 (s, 1H); 7,11 (s, 1H); 5,94 (s, 2H); 5,13 (s, 2H); 4,58 (s, 2H); 3,03 (s, 3H) <1>H NMR (250 MHz, CDCl 3 ) δ 7.32 (s, 5H); 7.27 (s, 1H); 7.11 (p, 1H); 5.94 (s, 2H); 5.13 (s, 2H); 4.58 (s, 2H); 3.03 (s, 3H)

b) 2-(metylamino)metyl-5,6-metylendioksybenzimidazol b) 2-(methylamino)methyl-5,6-methylenedioxybenzimidazole

2-[[N-(benzyloksykarbonyl)-N-metyl]aminometyl]-5,6-metylendioksybenzimidazol (145,0 mg, 0,43 mmol) ble løst i MeOH og tilsatt 10% Pd/C. Blandingen ble kraftig omrørt ved RT under H2(ballong). Etter 4 timer ble reaksjonsblandingen filtrert gjennom Celite® og filtratet konsentrert under vakuum for å gi tittelforbindelsen (70,8 mg, 80,2%). 2-[[N-(benzyloxycarbonyl)-N-methyl]aminomethyl]-5,6-methylenedioxybenzimidazole (145.0 mg, 0.43 mmol) was dissolved in MeOH and added 10% Pd/C. The mixture was vigorously stirred at RT under H2 (balloon). After 4 h, the reaction mixture was filtered through Celite® and the filtrate concentrated under vacuum to give the title compound (70.8 mg, 80.2%).

c) Metyl-(S)-7-[[[2-(5,6-metylendioksybenzimidazolyl)-metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat c) Methyl-(S)-7-[[[2-(5,6-methylenedioxybenzimidazolyl)-methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H- 1,4-benzodiazepine-2-acetate

EDC (76,2 mg, 0,40 mmol) ble tilsatt til en løsning av metyl-(2S)-7-karboksy-EDC (76.2 mg, 0.40 mmol) was added to a solution of methyl-(2S)-7-carboxy-

i 4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat (0,35 mmol) og HOBtH20 (57,9 mg, 0,43 mmol) i tørr DMF og reaksjonsblandingen omrørt ved RT. Diisopropyletylamin (0,150 mL, 0,86 mmol) ble tilsatt og deretter en løsning av 2-(metylamino)metyl-5,6-metylendioksybenzimidazol (70,8 mg, 0,35 mmol) i tørr DMF. in 4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (0.35 mmol) and HOBtH 2 O (57.9 mg, 0.43 mmol) in dry DMF and the reaction mixture stirred at RT. Diisopropylethylamine (0.150 mL, 0.86 mmol) was added followed by a solution of 2-(methylamino)methyl-5,6-methylenedioxybenzimidazole (70.8 mg, 0.35 mmol) in dry DMF.

Reaksjonsblandingen ble omrørt ved RT i 24 timer og deretter konsentrert under vakuum. Kromatografi (silikagel, trinnsvis gradient, CHCI3, 1:1 MeOH/CHCI3), hvorpå The reaction mixture was stirred at RT for 24 h and then concentrated under vacuum. Chromatography (silica gel, stepwise gradient, CHCl3, 1:1 MeOH/CHCl3), then

rekromatografi (2% MeOH/CHCI3, 10% MeOH/CHCI3) ga tittelforbindelsen (102,5 mg, 61,1%); rechromatography (2% MeOH/CHCl 3 , 10% MeOH/CHCl 3 ) afforded the title compound (102.5 mg, 61.1%);

<1>H NMR (250 MHz, CDCI3) 5 7,18-7,13 (m, 3H); 6,82 (s, 1H); 6,49 (s, 1H); 5,97 (s, 2H); 5,40 (d, 1H); 5,05 (dd, 1H); 4,74-4,56 (m, 2H); 3,73 (s, 3H); 3,13 (s, 3H); 3,01 <1>H NMR (250 MHz, CDCl 3 ) δ 7.18-7.13 (m, 3H); 6.82 (s, 1H); 6.49 (s, 1H); 5.97 (s, 2H); 5.40 (d, 1H); 5.05 (dd, 1H); 4.74-4.56 (m, 2H); 3.73 (s, 3H); 3.13 (s, 3H); 3.01

(s. 3H)(p. 3H)

d) (S)-7-[[[2-(5,6-metylendioksybenzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre d) (S)-7-[[[2-(5,6-methylenedioxybenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4 -benzodiazepine-2-acetic acid

Metyl-(S)-7-[[[2-(5,6-metylendioksybenzimidazolyl)-metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (102,5 mg, 0,21 mmol) ble løst i MeOH og tilsatt 1,on NaOH (0,5 mL, 0,5 mmol). Reaksjonsblandingen ble omrørt ved RT i 48 timer og deretter nøytralisert med 1,0 N HCI. Konsentrering under vakuum etterlot et residuum som ble fortynnet med vann og fikk stå ved RT over natten. Det resulterende bunnfall ble oppsamlet ved filtrering og tørket under høyvakuum for å gi tittelforbindelsen (29,0 mg, 30%); HPLC tR=11,67; (PRP-1 ®, gradienteluering i løpet av 20 minutter, 5-5-50% CH3CN/H2O-0,1% TFA) MS (ES) m/e 466,2 (M+H)<+>Methyl-(S)-7-[[[2-(5,6-methylenedioxybenzimidazolyl)-methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1, 4-Benzodiazepine-2-acetate (102.5 mg, 0.21 mmol) was dissolved in MeOH and 1,one NaOH (0.5 mL, 0.5 mmol) was added. The reaction mixture was stirred at RT for 48 h and then neutralized with 1.0 N HCl. Concentration under vacuum left a residue which was diluted with water and allowed to stand at RT overnight. The resulting precipitate was collected by filtration and dried under high vacuum to give the title compound (29.0 mg, 30%); HPLC tR=11.67; (PRP-1 ® , gradient elution over 20 minutes, 5-5-50% CH3CN/H2O-0.1% TFA) MS (ES) m/e 466.2 (M+H)<+>

Eksempel 41Example 41

Fremstilling av (S)-7-[[[2-(4,6-dlazabenzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre Preparation of (S)-7-[[[2-(4,6-dlazabenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4 -benzodiazepine-2-acetic acid

a) 2-[[N-(tert-butoksykarbonyl)-N-metyl]aminometyl]-4,6-diazabenzimidazol a) 2-[[N-(tert-butoxycarbonyl)-N-methyl]aminomethyl]-4,6-diazabenzimidazole

Boc-sarkosin (3,6 g, 19,1 mmol) ble løst i tørr THF i en flammetørket 250 mL Boc-sarcosine (3.6 g, 19.1 mmol) was dissolved in dry THF in a flame-dried 250 mL

rundkolbe og tilsatt Et3N (6 mL, 43,14 mmol). Løsningen ble avkjølt til 0°C til -5°C og tilsatt isobutylklorformiat (2,5 mL, 1,93 mmol). Den hvite blandingen ble omrørt ved round flask and added Et3N (6 mL, 43.14 mmol). The solution was cooled to 0°C to -5°C and isobutyl chloroformate (2.5 mL, 1.93 mmol) was added. The white mixture was stirred at

-5°C i 15 minutter og deretter avkjølt til -20°C til -30°C, hvorpå 4,5-diaminopyrimidin (2,1 g, 19,15 mmol) ble tilsatt som faststoff. Kjølebadet ble fjernet og reaksjonsblandingen fikk oppvarmes til RT. Etter 24 timer ble reaksjonsblandingen konsentrer under vakuum. Residuet ble løst i EtOAc og vasket med 1,0 N NaHC03. Det organiske lag ble tørket (MgS04), filtrert og konsentrert under vakuum. Residuet ble oppløst på nytt i iseddik og oppvarmet i et oljebad innstillet på 70°C. Etter 24 timer ble reaksjonsblandingen avkjølt til RT, konsentrert under vakuum og rekonsentrert fra toluen. Hurtigkromatografikolonne (silikagel, trinnsvis gradient, 5% MeOH/CHCI3, 10% MeOH/CHCIa) ga tittelforbindelsen (1,66 g,33%):<1>H NMR (250 MHz, CDCI3) 5 9,11 (s, 1H); 9,09 (s, 1H), 3,92 (s, 2H); 2,90-2,95 (m, 3H); 1,40-1,45 (m, 9H): MS (ES) m/e 264 (M+H)<+>b) 2-(metylamino)metyl-4,6-diazabenzimidazol 2-[[N-(tert-butoksykarbonyl)-N-metyl]aminometyl]-4,6-diazabenzimidazol (1,13 g, 4,29 mmol) ble behandlet med 4 N HCI i dioksan. Det ble dannet en suspensjon og mer 4 N HCI ble tilsatt. Den heterogene blanding ble omrørt ved RT i 2 timer og deretter konsentrert under vakuum. Residuet ble løst i MeOH og produktet utfelt med Et20. Bunnfallet ble oppsamlet på en sinterglass-trakt og tørket i en vakuum-eksikkator for å gi tittelforbindelsen (328,5 mg, 46,9%) som et hvitt pulver. TLC Rf 0,36 (3:1:1 n-BuOH/HOAc/H20);<1>H NMR (250 MHz, CD3OD) 8 9,56 (s, 1H); 9,33 (s, 1H); 4,81 (s, 2H); 2,99 (s, 3H), MS (ES) m/e 164,0 (M+H)<+>c) Metyl-(S)-7-[[[2-(4,6-diazabenzimidazo 3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat Metyl-(S)-7-karboksy-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (262,6 mg, 0,55 mmol) ble suspendert i CH3CN (10 mL) og tilsatt HOBtH20 (86,7 mg, 0,64 mmol) og deretter EDC (115,5 mg, 0,60 mmol). Diisopropyletylamin (150 mL, 0,86 mmol) ble tilsatt, hvilket førte til en homogen løsning. En løsning av 2-(metylamino)metyl-4,6-diazabenzimidazol (99,0 mg, 0,61 mmol) og diisopropyletylamin (150 mL, 0,86 mmol) ble tilsatt og reaksjonsblandingen omrørt ved RT. Etter 3 dager ble løsningsmidlet fordampet under vakuum og residuet rekonsentrert fra toluen. Kromatografi (silikagel, trinnsvis gradient, 5% MeOH/CHCI3, 10% MeOH/CHCI3) førte til tittelforbindelsen (190 mg, 79%): MS (ES) m/e 438,2 (M+H)<+>;<1>H NMR (250 MHz, CDCI3) 8 9,06 (s, 1H); 9,03 (s, 1H); 7,90-7,15 (m, 3H); 6,45 (d, 1H); 5,40 (d, 1H); 4,93 (dd, 1H); 3,71 (s, 3H); 3,16 (s, 3H); 2,98 (s, 3H) d) (S)-7-[[[2-(4,6-diazabenzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre 1,0 N NaOH (1,5 mL, 1,5 mmol) ble tilsatt til en løsning av metyl-(S)-7-[[[2-(4,6-diazabenzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (190,3 mg, 0,44 mmol) i MeOH (5 mL) og H20 (5 mL). Reaksjonsblandingen ble omrørt ved RT i 24 timer og deretter nøytralisert med 1,0 N HCI (1,5 mL). Reaksjonsblandingen ble konsentrert til tørrhet under vakuum og residuet renset ved kromatografi (ODS, trinnvis gradient, 5% CH3CN/H2O-0,1% TFA, 10% CH3CN/H2O-0,1% TFA, 20% CH3CN/H2O-0,1% TFA). En fraksjon ble oppsamlet og konsentrert under vakuum. Residuet ble rekonsentrert fra toluen og tørket under vakuum og deretter løst i MeOH og utfelt med Et3N. Det hvite bunnfallet ble oppsamlet på en sinterglass-trakt og tørket i en vakuum-eksikkator for å gi tittelforbindelsen som et hvitt pulver (126,5 mg, 67,9%): HPLC tR0,41; (ODS, gradienteluering i løpet av 20 minutter, 5-50% CH3CN/H20-0,1% TFA); MS (ES) m/e 424,2 (M+H)<+>-5°C for 15 minutes and then cooled to -20°C to -30°C, whereupon 4,5-diaminopyrimidine (2.1 g, 19.15 mmol) was added as a solid. The cooling bath was removed and the reaction mixture was allowed to warm to RT. After 24 hours, the reaction mixture was concentrated under vacuum. The residue was dissolved in EtOAc and washed with 1.0 N NaHCO 3 . The organic layer was dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was redissolved in glacial acetic acid and heated in an oil bath set at 70°C. After 24 h, the reaction mixture was cooled to RT, concentrated under vacuum and reconcentrated from toluene. Flash chromatography column (silica gel, stepwise gradient, 5% MeOH/CHCl 3 , 10% MeOH/CHCl 3 ) afforded the title compound (1.66 g, 33%):<1>H NMR (250 MHz, CDCl 3 ) δ 9.11 (s, 1H ); 9.09 (s, 1H), 3.92 (s, 2H); 2.90-2.95 (m, 3H); 1.40-1.45 (m, 9H): MS (ES) m/e 264 (M+H)<+>b) 2-(methylamino)methyl-4,6-diazabenzimidazole 2-[[N-(tert-butoxycarbonyl)-N-methyl]aminomethyl]-4,6-diazabenzimidazole (1.13 g, 4.29 mmol) was treated with 4N HCl in dioxane. A suspension was formed and more 4N HCl was added. The heterogeneous mixture was stirred at RT for 2 h and then concentrated under vacuum. The residue was dissolved in MeOH and the product precipitated with Et2O. The precipitate was collected on a sintered glass funnel and dried in a vacuum desiccator to give the title compound (328.5 mg, 46.9%) as a white powder. TLC Rf 0.36 (3:1:1 n-BuOH/HOAc/H 2 O);<1>H NMR (250 MHz, CD 3 OD) δ 9.56 (s, 1H); 9.33 (s, 1H); 4.81 (s, 2H); 2.99 (s, 3H), MS (ES) m/e 164.0 (M+H)<+>c) Methyl-(S)-7-[[[2-(4,6-diazabenzimidazo 3- oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate Methyl-(S)-7-carboxy-4-methyl-3-oxo-2,3,4,5- tetrahydro-1H-1,4-benzodiazepine-2-acetate (262.6 mg, 0.55 mmol) was suspended in CH 3 CN (10 mL) and added HOBtH 2 O (86.7 mg, 0.64 mmol) and then EDC ( 115.5 mg, 0.60 mmol). Diisopropylethylamine (150 mL, 0.86 mmol) was added, resulting in a homogeneous solution. A solution of 2-(methylamino)methyl-4,6-diazabenzimidazole (99.0 mg, 0.61 mmol) and diisopropylethylamine (150 mL, 0.86 mmol) were added and the reaction mixture was stirred at RT. After 3 days, the solvent was evaporated under vacuum and the residue reconcentrated from toluene. Chromatography (silica gel, stepwise gradient, 5% MeOH /CHCl 3 , 10% MeOH/CHCl 3 ) led to the title compound (190 mg, 79%): MS (ES) m/e 438.2 (M+H)<+>;<1>H NMR (250 MHz, CDCl 3 ) 8 9.06 (s, 1H); 9.03 (s, 1H); 7.90-7.15 (m, 3H); 6.45 (d, 1H); 5.40 (d, 1H); 4.93 (dd, 1H); 3.71 (s, 3H); 3.16 (s, 3 H); 2.98 (s, 3H) d) (S)-7-[[[2-(4,6-diazabenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5 -tetrahydro-1 H -1,4-benzodiazepine-2-acetic acid 1.0 N NaOH (1.5 mL, 1.5 mmol) was added to a solution of methyl-(S)-7-[[[2- (4,6-diazabenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (190.3 mg, 0 .44 mmol) in MeOH (5 mL) and H 2 O (5 mL). The reaction mixture was stirred at RT for 24 h and then neutralized with 1.0 N HCl (1.5 mL). The reaction mixture was concentrated to dryness under vacuum and the residue purified by chromatography (ODS, stepwise gradient, 5% CH3CN/H2O-0.1% TFA, 10% CH3CN/H2O-0.1% TFA, 20% CH3CN/H2O-0, 1% TFA). A fraction was collected and concentrated under vacuum. The residue was reconcentrated from toluene and dried under vacuum and then dissolved in MeOH and precipitated with Et 3 N. The white precipitate was collected on a sintered glass funnel and dried in a vacuum desiccator to give the title compound as a white powder (126.5 mg, 67.9%): HPLC tR0.41; (ODS, gradient elution over 20 minutes, 5-50% CH 3 CN/H 2 O-0.1% TFA); MS (ES) m/e 424.2 (M+H)<+>

Analyse beregnet for C20H21N7O4 ■ 0,5 CF3C02H:Analysis calculated for C20H21N7O4 ■ 0.5 CF3C02H:

C, 52,50; H, 4,51; N, 20,41 C, 52.50; H, 4.51; N, 20,41

Funnet: C, 52,62; H, 4,88; N, 20,01. Found: C, 52.62; H, 4.88; N, 20.01.

Eksempel 42Example 42

Fremstilling av (S)-7-[[[2-(4-azabenzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-S-okso^.S.^S-tetrahydro-IH-l^-benzodiazepin^-eddiksyre Preparation of (S)-7-[[[2-(4-azabenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-S-oxo^.S.^S-tetrahydro-1H-1^-benzodiazepine^-acetic acid

a) 2-[[N-(benzyloksykarbonyl)-N-metyl]aminometyl]-4-azabenzimidazola) 2-[[N-(benzyloxycarbonyl)-N-methyl]aminomethyl]-4-azabenzimidazole

En løsning av Cbz-sarkosin (5 g, 22,4 mmol) og Et3N (4 mL, 28,76 mmol) i tørr A solution of Cbz-sarcosine (5 g, 22.4 mmol) and Et3N (4 mL, 28.76 mmol) in dry

THF ble avkjølt til 0°C i et isbad og deretter tilsatt isobutylklorformiat (3,0 mL,THF was cooled to 0°C in an ice bath and then isobutyl chloroformate (3.0 mL,

23,13 mmol). Reaksjonsblandingen ble omrørt ved RT i 15 minutter og deretter tilsatt til en løsning av 2,3-diaminopyridin (2,5 g, 22,7 mmol) i tørr THF ved -25°C. Reaksjonsblandingen ble omrørt ved -20°C i 30 minutter og fikk deretter oppvarmes til RT. Etter 24 timer ble reaksjonsblandingen konsentrert under vakuum. Residuet ble tatt opp i EtOAc og vasket med 1,0 N NaHC03. Det organiske lag ble tørket (MgS04), filtrert og konsentrert under vakuum. Residuet ble løst i iseddik (200 mL) og oppvarmet i et oljebad innstillet på 109°C. Etter 20 timer ble reaksjonsblandingen konsentrert under vakuum og residuet rekonsentrert fra toluen. Kromatografi (silikagel trinnsvis gradient, CHCI3, 3% MeOH/CHCI3, 5% MeOH/CHCI3) ga tittelforbindelsen (2,2 g, 33%) som ble omkrystallisert fra Et20: 23.13 mmol). The reaction mixture was stirred at RT for 15 min and then added to a solution of 2,3-diaminopyridine (2.5 g, 22.7 mmol) in dry THF at -25 °C. The reaction mixture was stirred at -20°C for 30 minutes and then allowed to warm to RT. After 24 hours, the reaction mixture was concentrated under vacuum. The residue was taken up in EtOAc and washed with 1.0 N NaHCO 3 . The organic layer was dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was dissolved in glacial acetic acid (200 mL) and heated in an oil bath set at 109°C. After 20 hours, the reaction mixture was concentrated under vacuum and the residue reconcentrated from toluene. Chromatography (silica gel stepwise gradient, CHCl 3 , 3% MeOH/CHCl 3 , 5% MeOH/CHCl 3 ) afforded the title compound (2.2 g, 33%) which was recrystallized from Et 2 O:

MS (ES) m/e 296,2 (M+H)<+>MS (ES) m/e 296.2 (M+H)<+>

b) 2-(metylamino)metyl-4-azabenzimidazol b) 2-(methylamino)methyl-4-azabenzimidazole

2-[[N-(benzyloksykarbonyl)-N-metyl]aminometyl]-4-azabenzimidazol2-[[N-(benzyloxycarbonyl)-N-methyl]aminomethyl]-4-azabenzimidazole

(551,3 mg, 1,86 mmol) ble løst i MeOH og tilsatt 10% Pd/C. Blandingen ble kraftig omrørt ved RT under H2(ballong). Etter 4 timer ble reaksjonsblandingen filtrert gjennom Celite® og filtratet konsentrert under vakuum for å gi tittelforbindelsen (420,1 mg, kvantitativt):<1>H NMR (250 MHz, CDCI3) 5 8,34-8,32 (m, 1H); 7,98-7,14 (m, 4H); 5,18-5,12 (m, 1H); 4,87 (s, 2H); 3,32 (s, 3H) (551.3 mg, 1.86 mmol) was dissolved in MeOH and added 10% Pd/C. The mixture was vigorously stirred at RT under H2 (balloon). After 4 h, the reaction mixture was filtered through Celite® and the filtrate concentrated under vacuum to give the title compound (420.1 mg, quantitative):<1>H NMR (250 MHz, CDCl3 ) δ 8.34-8.32 (m, 1H ); 7.98-7.14 (m, 4H); 5.18-5.12 (m, 1H); 4.87 (s, 2H); 3.32 (s, 3H)

c) Metyl-(S)-7-[[[2-(4-azabenzimidazoty okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat c) Methyl-(S)-7-[[[2-(4-azabenzimidazoty oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate

EDC (309,1 mg, 1,61 mmol) ble tilsatt til en løsning av metyl-(S)-7-karboksy-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat (504,6 mg, EDC (309.1 mg, 1.61 mmol) was added to a solution of methyl-(S)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1 ,4-benzodiazepine-2-acetate (504.6 mg,

1,54 mmol), diisopropyletylamin (0,30 mL, 1,78 mmol) og HOBtH20 (228,2 mg, 1,69 mmol) i tørr DMF ved RT. Etter 10 minutter ble 2-(metylamino)metyl-4-azabenzimidazol (3,08 mmol), nøytralisert med diisopropyletylamin (0,600 mL), tilsatt og reaksjonsblandingen omrørt ved RT. Etter 20 timer ble løsningsmidlene fordampet under vakuum og residuet rekonsentrert fra toluen. Kromatografi (silikagel, trinnvis gradient, CHCI3, 5% MeOH/CHCI3, 10% MeOH/CHCI3) ga tittelforbindelsen (326,8 mg, 48,6%): MS (ES) m/e 437,2 (M+H)<+>; 1.54 mmol), diisopropylethylamine (0.30 mL, 1.78 mmol) and HOBtH 2 O (228.2 mg, 1.69 mmol) in dry DMF at RT. After 10 minutes, 2-(methylamino)methyl-4-azabenzimidazole (3.08 mmol), neutralized with diisopropylethylamine (0.600 mL), was added and the reaction mixture stirred at RT. After 20 hours, the solvents were evaporated under vacuum and the residue reconcentrated from toluene. Chromatography (silica gel, stepwise gradient, CHCl 3 , 5% MeOH/CHCl 3 , 10% MeOH/CHCl 3 ) gave the title compound (326.8 mg, 48.6%): MS (ES) m/e 437.2 (M+H) <+>;

<1>H NMR (250 MHz, CDCI3) 5 8,39 (d, 1H); 8,00-7,20 (m, 5H); 5,50 (d, 1H); 5,15-4,80 (m, 3H); 3,70 (s, 3H); 3,10 (s, 3H); 2,93 (s, 3H) <1>H NMR (250 MHz, CDCl 3 ) δ 8.39 (d, 1H); 8.00-7.20 (m, 5H); 5.50 (d, 1H); 5.15-4.80 (m, 3H); 3.70 (s, 3H); 3.10 (s, 3H); 2.93 (p, 3H)

d) (S)-7-[[[2-(4-azabenzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat d) (S)-7-[[[2-(4-azabenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4- benzodiazepine-2-acetate

1,0 N NaOH (2,0 mL, 2,0 mmol) ble tilsatt til en løsning av metyl-(S)-7-[[[2-(4-azabenzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (326,8 mg, 0,75 mmol) i MeOH (10 mL) og H20 1.0 N NaOH (2.0 mL, 2.0 mmol) was added to a solution of methyl-(S)-7-[[[2-(4-azabenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl -3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (326.8 mg, 0.75 mmol) in MeOH (10 mL) and H 2 O

(10 mL) ved RT. Etter 26 timer ble reaksjonsblandingen nøytralisert med 1,0 N HCI (2,0 mL, 2,0 mmol) og konsentrert under vakuum. Residuet ble tatt opp i H20 og det resulterende hvite bunnfall oppsamlet på en sinterglass-trakt, vasket med H20 og tørket under vakuum for å gi tittelforbindelsen (218,1 mg, 69%) som et hvitt pulver: MS (ES) m/e 423,4 (M+H)<+>(10 mL) at RT. After 26 h, the reaction mixture was neutralized with 1.0 N HCl (2.0 mL, 2.0 mmol) and concentrated in vacuo. The residue was taken up in H 2 O and the resulting white precipitate collected on a sintered glass funnel, washed with H 2 O and dried under vacuum to give the title compound (218.1 mg, 69%) as a white powder: MS (ES) m/e 423.4 (M+H)<+>

Analyse beregnet for C2iH22N604 • 2 H20:Analysis calculated for C2iH22N604 • 2 H20:

C, 55,02; H, 5,72; N, 18,33. C, 55.02; H, 5.72; N, 18.33.

Funnet: C, 55,07; H, 5,55; N, 17,81 Found: C, 55.07; H, 5.55; N, 17.81

Eksempel 43Example 43

Fremstilling av 7-[1 -[2R-(2-benzimidazolyl)pyrrolidinyl]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2S-eddiksyre Preparation of 7-[1-[2R-(2-benzimidazolyl)pyrrolidinyl]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2S-acetic acid

a) 1 -tert-butoksykarbonyl-2R-(2-benzimidazolyl)pyrrolidina) 1-tert-butoxycarbonyl-2R-(2-benzimidazolyl)pyrrolidine

En løsning av BOC-D-prolin (3,0 g, 14 mmol) og Et3N (2,5 mL, 18 mmol) i tørr A solution of BOC-D-proline (3.0 g, 14 mmol) and Et3N (2.5 mL, 18 mmol) in dry

THF ble avkjølt til 0°C i et isbad og tilsatt isobutylklorformiat (2,0 mL, 15 mmol). Reaksjonsblandingen ble omrørt ved 0°C i 20 minutter og deretter tatt ut fra kjølebadet, hvorpå den fikk oppvarmes til RT i løpet av 10 minutter. Den hvite oppslemmingen ble tilsatt til en løsning av o-fenylendiamin (1,55 g, 4,3 mmol) i THF ved -20°C til -30°C. Etter fullført tilsetning ble reaksjonsblandingen fjernet fra kjølebadet og fikk anta RT. Etter 20 timer ble reaksjonsblandingen konsentrert under vakuum. Residuet ble tatt opp i EtOAc og vasket med 1,0 N NaHC03. Det organiske lag ble tørket (MgSO-0, filtrert og konsentrert under vakuum. Residuet ble løst i iseddik og oppvarmet i et oljebad innstillet på 70-75°C. Etter 24 timer ble AcOH fordampet under vakuum og residuet rekonsentrert fra toluen. Omkrystallisasjon fra EtOAc ga tittelforbindelsen (1,1 g). Moderluten ble konsentrert og residuet tatt opp i Et20 for å gi ytterligere tittelforbindelse (1,47 g). THF was cooled to 0°C in an ice bath and isobutyl chloroformate (2.0 mL, 15 mmol) was added. The reaction mixture was stirred at 0°C for 20 minutes and then removed from the cooling bath, after which it was allowed to warm to RT over 10 minutes. The white slurry was added to a solution of o-phenylenediamine (1.55 g, 4.3 mmol) in THF at -20°C to -30°C. After the addition was complete, the reaction mixture was removed from the cooling bath and allowed to warm to RT. After 20 hours, the reaction mixture was concentrated under vacuum. The residue was taken up in EtOAc and washed with 1.0 N NaHCO 3 . The organic layer was dried (MgSO-0), filtered and concentrated under vacuum. The residue was dissolved in glacial acetic acid and heated in an oil bath set at 70-75°C. After 24 hours the AcOH was evaporated under vacuum and the residue reconcentrated from toluene. Recrystallization from EtOAc gave the title compound (1.1 g).The mother liquor was concentrated and the residue taken up in Et 2 O to give additional title compound (1.47 g).

b) 2R-(2-benzimidazolyl)pyrrolidin b) 2R-(2-benzimidazolyl)pyrrolidine

1-tert-butoksykarbonyl-2R-(2-benzimidazolyl)pyrrolidin (1,0702 g, 3,72 mmol) 1-tert-butoxycarbonyl-2R-(2-benzimidazolyl)pyrrolidine (1.0702 g, 3.72 mmol)

ble behandlet med 4 N HCI/dioksan. Etter 2 timer ved RT ble reaksjonsblandingen konsentrert under vakuum og residuet behandlet med Et20. Det hvite bunnfall ble oppsamlet og tørket under vakuum for å gi tittelforbindelsen (958,1 mg, 99,1%); was treated with 4 N HCl/dioxane. After 2 h at RT, the reaction mixture was concentrated under vacuum and the residue treated with Et 2 O. The white precipitate was collected and dried under vacuum to give the title compound (958.1 mg, 99.1%);

<1>H NMR (250 MHz, CDCI3) 5 7,89-7,85 (m, 2H); 7,68-7,65 (m, 2H); 5,38-5,31 (m, 1H); 3,67-3,61 (m, 2H); 3,33-3,31 (m, 1H); 2,88-2,21 (m, 4H); <1>H NMR (250 MHz, CDCl 3 ) δ 7.89-7.85 (m, 2H); 7.68-7.65 (m, 2H); 5.38-5.31 (m, 1H); 3.67-3.61 (m, 2H); 3.33-3.31 (m, 1H); 2.88-2.21 (m, 4H);

[<x]D-4,9(c°1,0, H20) [<x]D-4.9(c°1.0, H2O)

c) Metyl-7-[1-[2R-(2-benzimidazolyl)pyrrolidinyl]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2S-acetat c) Methyl-7-[1-[2R-(2-benzimidazolyl)pyrrolidinyl]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2S -acetate

EDC (74,4 mg, 0,39 mmol) ble tilsatt til en løsning av metyl-(S)-7-karboksy-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat (104,2 mg, EDC (74.4 mg, 0.39 mmol) was added to a solution of methyl-(S)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1 ,4-benzodiazepine-2-acetate (104.2 mg,

0,32 mmol), diisopropyletylamin (0,06 mL, 0,34 mmol) og HOBtH20 (56,6 mg,0.32 mmol), diisopropylethylamine (0.06 mL, 0.34 mmol) and HOBtH 2 O (56.6 mg,

0,42 mmol) i tørr DMF ved RT. Reaksjonsblandingen ble omrørt ved RT og tilsatt en løsning av 2R-(2-benzimidazolyl)pyrrolidin (89,7 mg, 0,35 mmol) og diisopropyletylamin (0,120 mL, 0,69 mmol) i DMF. Etter 20 timer ble reaksjonsblandingen konsentrert under vakuum og residuet rekonsentrert fra toluen. Kromatografi (silikagel, trinnvis gradient, CHCI3l3% MeOH/CHCI3, 5% MeOH/CHCI3) ga tittelforbindelsen (136,9 mg, 92,5%):<1>H NMR (250 MHz, CDCI3) 5 7,77 (d, 1H); 7,63 (d, 1H), 7,34-7,22 (m, 4H); 7,06-7,05 (m, 1H); 6,37 (d, 1H); 5,55-5,49 (m, 1H); 5,30 (d, 1H); 5,08-5,00 (m, 1H); 3,68 (s, 3H); 2,92 (s, 3H); 2,55-1,70 (m, 4H), 1,22 (t' 3H); MS (ES) m/e 462,2 (M+H)<+>d) 7-[1-[2R-(2-benzimidazolyl)pyrrolidinyl]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2S-eddiksyre 0.42 mmol) in dry DMF at RT. The reaction mixture was stirred at RT and a solution of 2R-(2-benzimidazolyl)pyrrolidine (89.7 mg, 0.35 mmol) and diisopropylethylamine (0.120 mL, 0.69 mmol) in DMF was added. After 20 hours, the reaction mixture was concentrated under vacuum and the residue reconcentrated from toluene. Chromatography (silica gel, stepwise gradient, CHCl 3 13% MeOH/CHCl 3 , 5% MeOH/CHCl 3 ) afforded the title compound (136.9 mg, 92.5%):<1>H NMR (250 MHz, CDCl 3 ) δ 7.77 (d , 1H); 7.63 (d, 1H), 7.34-7.22 (m, 4H); 7.06-7.05 (m, 1H); 6.37 (d, 1H); 5.55-5.49 (m, 1H); 5.30 (d, 1H); 5.08-5.00 (m, 1H); 3.68 (s, 3H); 2.92 (s, 3H); 2.55-1.70 (m, 4H), 1.22 (t' 3H); MS (ES) m/e 462.2 (M+H)<+>d) 7-[1-[2R-(2-benzimidazolyl)pyrrolidinyl]carbonyl]-4-methyl-3-oxo-2,3, 4,5-tetrahydro-1H-1,4-benzodiazepine-2S-acetic acid

1,0 N NaOH (0,75 mL, 0,75 mmol) ble tilsatt til en løsning av metyl-7-[1 -[2R-(2-benzimidazolyl)pyrrolidinyl]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2S-acetat (136,9 mg, 0,30 mmol) i MeOH (5 mL) og H20 (5 mL) ved RT. Etter 24 timer ble 1,0 N HCI (0,75 mL, 0,75 mmol) tilsatt og reaksjonsblandingen konsentrert under vakuum. Kromatografi (ODS, trinnvis gradient, 0,1% TFA/H2O, 20% CH3CN/H2O-0,1 % TFA), konsentrering og rekonsentrering fra toluen etterlot et residuum som ble løst opp igjen i H20. Lyofilisering ga tittelforbindelsen (92 mg): HPLC fR=10,68 (ODS, gradienteluering i løpet av 20 minutter, 5-50% CH3CN/H20-0,1 % TFA); MS (ES) m/e 448,2 (M+H)<+>1.0 N NaOH (0.75 mL, 0.75 mmol) was added to a solution of methyl 7-[1-[2R-(2-benzimidazolyl)pyrrolidinyl]carbonyl]-4-methyl-3-oxo- 2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2S-acetate (136.9 mg, 0.30 mmol) in MeOH (5 mL) and H 2 O (5 mL) at RT. After 24 h, 1.0 N HCl (0.75 mL, 0.75 mmol) was added and the reaction mixture was concentrated under vacuum. Chromatography (ODS, stepwise gradient, 0.1% TFA/H2O, 20% CH3CN/H2O-0.1% TFA), concentration and reconcentration from toluene left a residue which was redissolved in H2O. Lyophilization gave the title compound (92 mg): HPLC fR=10.68 (ODS, gradient elution over 20 min, 5-50% CH 3 CN/H 2 O-0.1% TFA); MS (ES) m/e 448.2 (M+H)<+>

Eksempel 44Example 44

Fremstilling av 7-[1 -[2S-(2-benzimidazolyl)pyrrolidinyl]karbonyl]-4-metyl-3-okso^.SAS-tetrahydro-l H-1,4-benzodiazepin-2S-eddiksyre Preparation of 7-[1-[2S-(2-benzimidazolyl)pyrrolidinyl]carbonyl]-4-methyl-3-oxo^.SAS-tetrahydro-1H-1,4-benzodiazepine-2S-acetic acid

a) 1 -tert-butoksykarbonyl-2S-(2-benzimidazolyl)pyrrolidina) 1-tert-butoxycarbonyl-2S-(2-benzimidazolyl)pyrrolidine

Ved å følge fremgangsmåten i Eksempel 43(a) men med BOC-L-prolin i By following the procedure of Example 43(a) but with BOC-L-proline i

stedet for BOC-D-prolin, ble tittelforbindelsen (3,2 g, 74%) fremstillet.instead of BOC-D-proline, the title compound (3.2 g, 74%) was prepared.

<1>H NMR (250 MHz, CDCI3) 5 7,53 (br s, 1H); 7,19-7,16 (m, 4H); 5,14 (d, 1H); 3,50 (s, 2H); 2,87 (brs, 1H); 2,19-1,97 (m, 3H); 1,49 (s, 9H); 1,25 (brs, 2H); <1>H NMR (250 MHz, CDCl 3 ) δ 7.53 (br s, 1H); 7.19-7.16 (m, 4H); 5.14 (d, 1H); 3.50 (s, 2H); 2.87 (brs, 1H); 2.19-1.97 (m, 3H); 1.49 (p, 9H); 1.25 (brs, 2H);

MS (ES) m/e 288,2 (M+H)<+>MS (ES) m/e 288.2 (M+H)<+>

b) 2S-(2-benzimidazolyl)pyrrolidinb) 2S-(2-benzimidazolyl)pyrrolidine

Ved å følge fremgangsmåten i Eksempel 43(b) men med -tert-butoksykarbonyl-2S-(2-benzimidazolyl)pyrrolidin i stedet for 1-tert-butoksykarbonyl-2R-(2-benzimidazolyl)pyrrolidin, ble tittelforbindelsen fremstillet (1,7988 g, 98,4%):<1>H NMR (250 MHz, CDCI3l) 5 7,89-7,86 (m, 2H); 7,69-7,65 (m, 2H); 5,30-5,40 (m, 1H), 3,68-3,63 (m, 2H), 3,33-3,32 (m, 1H), 2,20-2,89 (m, 4H); By following the procedure of Example 43(b) but with -tert-butoxycarbonyl-2S-(2-benzimidazolyl)pyrrolidine instead of 1-tert-butoxycarbonyl-2R-(2-benzimidazolyl)pyrrolidine, the title compound was prepared (1.7988 g, 98.4%): <1>H NMR (250 MHz, CDCl31) δ 7.89-7.86 (m, 2H); 7.69-7.65 (m, 2H); 5.30-5.40 (m, 1H), 3.68-3.63 (m, 2H), 3.33-3.32 (m, 1H), 2.20-2.89 (m, 4H );

[a] +3,9-(c° 1,0, H20)[a] +3.9-(c° 1.0, H2O)

c) Metyl-7-[1-[2S-(2-benzimidazolyl)pyrrolidinyl]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2S-acetat c) Methyl-7-[1-[2S-(2-benzimidazolyl)pyrrolidinyl]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2S -acetate

Ved å følge fremgangsmåten i Eksempel 43(c) men med 2S-(2-benzimidazolyl)pyrrolidin i stedet for 2R-(2-benzimidazolyl)pyrrolidin, ble tittelforbindelsen (90,4 mg, 61%) fremstillet: MS (ES) m/e 462,4 (M+H)<+>d) 7-[1-[2S-(2-benzimidazolyl)pyrrolidinyl]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2S-eddiksyre Following the procedure of Example 43(c) but with 2S-(2-benzimidazolyl)pyrrolidine instead of 2R-(2-benzimidazolyl)pyrrolidine, the title compound (90.4 mg, 61%) was prepared: MS (ES) m /e 462.4 (M+H)<+>d) 7-[1-[2S-(2-benzimidazolyl)pyrrolidinyl]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro -1 H-1,4-benzodiazepine-2S-acetic acid

Ved å følge fremgangsmåten i Eksempel 43(d) men med metyl-7-[1-[2S-(2-benzimidazolyl)pyrrolidinyl]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2S-acetat i stedet for metyl-7-[1-[2R-(2-benzimidazolyl)-pyrrolidinyl]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2S-acetat, ble tittelforbindelsen (65,8 mg, 75%) fremstillet: HPLC tR=10,63 (ODS, gradienteluering i løpet av 20 minutter, 5-50% CH3CN/H20-0,1% TFA); MS (ES) m/e 448,2 (M+H)<+>By following the procedure in Example 43(d) but with methyl-7-[1-[2S-(2-benzimidazolyl)pyrrolidinyl]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro- 1H-1,4-benzodiazepine-2S-acetate instead of methyl-7-[1-[2R-(2-benzimidazolyl)-pyrrolidinyl]carbonyl]-4-methyl-3-oxo-2,3,4,5 -tetrahydro-1H-1,4-benzodiazepine-2S-acetate, the title compound (65.8 mg, 75%) was prepared: HPLC tR=10.63 (ODS, gradient elution over 20 min, 5-50% CH3CN/ H2O-0.1% TFA); MS (ES) m/e 448.2 (M+H)<+>

Eksempel 45Example 45

Fremstilling av (±)-7-[[[2-(4-azabenzimidazolyl)metyl]metylamino]karbonyl]-4-isopropyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre Preparation of (±)-7-[[[2-(4-azabenzimidazolyl)methyl]methylamino]carbonyl]-4-isopropyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine -2-acetic acid

a) metyl-(±)-7-[[[2-(4-azabenzimidazolyl)metyl]metylamino]karbonyl]-4-isopropyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat a) methyl-(±)-7-[[[2-(4-azabenzimidazolyl)methyl]methylamino]carbonyl]-4-isopropyl-3-oxo-2,3,4,5-tetrahydro-1 H-1, 4-benzodiazepine-2-acetate

Ved å følge fremgangsmåten i Eksempel 42(c) men med metyl-(±)-7-karboksy-4-isopropyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat i stedet for metyl-(S)-7-karboksy-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat, ble tittelforbindelsen (226 mg, 96%) fremstillet: TLC Rf (5% MeOH/CHCI3) 0,28; By following the procedure in Example 42(c) but with methyl-(±)-7-carboxy-4-isopropyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2 -acetate instead of methyl-(S)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate, the title compound (226 mg, 96%) prepared: TLC Rf (5% MeOH/CHCl 3 ) 0.28;

<1>H NMR (250 MHz, CDCI3) 5 8,45 (d, 1H); 7,96-7,10 (m, 5H); 6,40 (br s, 1H); 5,09-4,88 (m, 5H); 3,70 (s, 3H); 3,47 (s, 3H), 3,09 (s, 3H), 1,23 (t, 1H); 1,09 (d, 1H); 0,86 <1>H NMR (250 MHz, CDCl 3 ) δ 8.45 (d, 1H); 7.96-7.10 (m, 5H); 6.40 (br s, 1H); 5.09-4.88 (m, 5H); 3.70 (s, 3H); 3.47 (s, 3H), 3.09 (s, 3H), 1.23 (t, 1H); 1.09 (d, 1H); 0.86

(brs, 1H)(brs, 1H)

b) (+)-7-[[[2-(4-azabenzimidazolyl)metyl]metylamino]karbonyl]-4-isopropyl-3-okso-2,,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre b) (+)-7-[[[2-(4-azabenzimidazolyl)methyl]methylamino]carbonyl]-4-isopropyl-3-oxo-2,,3,4,5-tetrahydro-1 H-1,4 -benzodiazepine-2-acetic acid

1,0 N NaOH (1,5 mL, 1,5 mmol) ble tilsatt til en løsning av metyl-(±)-7-[[[2-(4-azabenzimidazolyl)metyl]metylamino]karbonyl]-4-isopropyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (226,2 mg, 0,49 mmol) i MeOH (5 mL) og H20 (5 mL) ved RT. Etter 24 timer ble reaksjonsblandingen nøytralisert med 1,on HCI og løsningsmidlene fordampet under vakuum. ODS-kromatografi (0,1 % TFA/H20, deretter 20% CH3CN/H2O-0,1% TFA), konsentrering og rekonsentrering fra toluen etterlot et residuum som ble løst på nytt i H20. Lyofilisering ga uren tittelforbindelse (181,9 mg) som et hvitt pulver, som ble renset ved ODS-kromatografi (10% CH3CN/H2O-0,1% TFA og deretter 20% CH3CN/H2O-0,1% TFA). Konsentrering og rekonsentrering fra toluen etterlot et residuum som ble løst i MeOH og utfelt med Et20. Bunnfallet ble oppsamlet på en sinterglass-trakt og tørket i en vakuum-eksikkator for å gi tittelforbindelsen (65,5 mg): HPLC (ODS, gradienteluering i løpet av 20 minutter, 5-50% CH3CN/H2O-0,1% TFA) tR=12,32; MS (ES) m/e 451,2 (M+H)<+>1.0 N NaOH (1.5 mL, 1.5 mmol) was added to a solution of methyl-(±)-7-[[[2-(4-azabenzimidazolyl)methyl]methylamino]carbonyl]-4-isopropyl -3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (226.2 mg, 0.49 mmol) in MeOH (5 mL) and H 2 O (5 mL) at RT. After 24 hours, the reaction mixture was neutralized with 1.N HCl and the solvents evaporated under vacuum. ODS chromatography (0.1% TFA/H 2 O, then 20% CH 3 CN/H 2 O-0.1% TFA), concentration and reconcentration from toluene left a residue which was redissolved in H 2 O. Lyophilization gave the crude title compound (181.9 mg) as a white powder, which was purified by ODS chromatography (10% CH 3 CN/H 2 O-0.1% TFA and then 20% CH 3 CN/H 2 O-0.1% TFA). Concentration and reconcentration from toluene left a residue which was dissolved in MeOH and precipitated with Et 2 O. The precipitate was collected on a sintered glass funnel and dried in a vacuum desiccator to give the title compound (65.5 mg): HPLC (ODS, gradient elution over 20 min, 5-50% CH3CN/H2O-0.1% TFA ) tR=12.32; MS (ES) m/e 451.2 (M+H)<+>

Analyse beregnet for C23H26N6O4 • 0,5 CF3C02H • 0,75 H20:Analysis calculated for C23H26N6O4 • 0.5 CF3C02H • 0.75 H20:

C, 55,33; H, 5,42; N, 16,13. C, 55.33; H, 5.42; N, 16,13.

Funnet: C, 55,43; H, 5,60; N, 16,01 Found: C, 55.43; H, 5.60; N, 16.01

Eksempel 46Example 46

Fremstilling av (S)-7-[[[2-(4-aza-5-metylbenzimidazoyl)metyl]-metylaminojkarbonylJ^-metyl-S-okso^.S^.S-tetrahydro-IH-l^-benzodiazepin-2-eddiksyre Preparation of (S)-7-[[[2-(4-aza-5-methylbenzimidazolyl)methyl]-methylaminojcarbonylJ^-methyl-S-oxo^.S^.S-tetrahydro-1H-1^-benzodiazepine-2 -acetic acid

a) 2-amino-6-metyl-3-nitropyridina) 2-amino-6-methyl-3-nitropyridine

2-amino-6-pikolin (5,1 g, 47,1 mmol) ble veid inn i en 500 mL rundkolbe og 2-amino-6-picoline (5.1 g, 47.1 mmol) was weighed into a 500 mL round bottom flask and

kolben avkjølt til -30°C. Konsentrert H2S04(20 mL) ble tilsatt, hvilket forårsaket en viss røkning. Konsentrert HN03 (10 mL, 160 mmol) ble deretter langsomt og dråpevis tilsatt. Reaksjonsblandingen fikk oppvarmes til RT i løpet av 30 minutter og ble deretter oppvarmet i et oljebad innstillet på 80°C. Etter 90 minutter ble reaksjonsblandingen fjernet fra varmebadet og tilsatt is. 6,25 N NaOH (150 mL, 937,5 mmol) ble langsomt tilsatt og det resulterende gule bunnfall oppsamlet på en sinterglass-trakt. Tørking i en vakuum-eksikkator ga tittelforbindelsen (1,7 g, 24%); TLC Rf (5% MeOH/CHCI3) 0,77; flask cooled to -30°C. Concentrated H 2 SO 4 (20 mL) was added, causing some smoking. Concentrated HNO 3 (10 mL, 160 mmol) was then slowly and dropwise added. The reaction mixture was allowed to warm to RT over 30 minutes and was then heated in an oil bath set at 80°C. After 90 minutes, the reaction mixture was removed from the heat bath and ice was added. 6.25 N NaOH (150 mL, 937.5 mmol) was slowly added and the resulting yellow precipitate collected on a sintered glass funnel. Drying in a vacuum desiccator gave the title compound (1.7 g, 24%); TLC R f (5% MeOH/CHCl 3 ) 0.77;

<1>H NMR (250 MHz, CDCI3|) 6 8,31 (d, 1H); 6,32 (d, 1H); 2,46 (s, 3H); <1>H NMR (250 MHz, CDCl 3 |) δ 8.31 (d, 1H); 6.32 (d, 1H); 2.46 (s, 3H);

MS (ES) m/e 154,0 (M+H)<+>MS (ES) m/e 154.0 (M+H)<+>

b) 2,3-diamino-6-metylpyridinb) 2,3-diamino-6-methylpyridine

2-amino-6-metyl-3-nitropyridin (754 mg, 4,92 mmol) ble suspendert i MeOH 2-Amino-6-methyl-3-nitropyridine (754 mg, 4.92 mmol) was suspended in MeOH

og tilsatt 10% Pd/C. Blandingen ble kraftig omrørt ved RT under H2(ballong). Etter 4 timer ble reaksjonsblandingen filtrert gjennom Celite® og filtratet konsentrert under vakuum for å gi tittelforbindelsen (677 mg, kvantitativt):<1>H NMR (250 MHz, CD3OD) 5 6,82 (d, 1H), 6,36 (d, 1H), 2,25 (s, 3H) and added 10% Pd/C. The mixture was vigorously stirred at RT under H2 (balloon). After 4 h, the reaction mixture was filtered through Celite® and the filtrate concentrated under vacuum to give the title compound (677 mg, quantitative): <1>H NMR (250 MHz, CD3OD) δ 6.82 (d, 1H), 6.36 ( d, 1H), 2.25 (s, 3H)

c) 2-[[N-(benzyloksykarbonyl)-N-metyl]aminometyl]-5-metyl-4-azabenzimidazol c) 2-[[N-(benzyloxycarbonyl)-N-methyl]aminomethyl]-5-methyl-4-azabenzimidazole

En løsning av Cbz-sarkosin (1,8 g, 7,85 mmol) i tørr THF ble ved RT A solution of Cbz-sarcosine (1.8 g, 7.85 mmol) in dry THF was at RT

behandlet med isobutylklorformiat (i,25 mL, 9,64 mmol) og deretter med Et3Ntreated with isobutyl chloroformate (i.25 mL, 9.64 mmol) and then with Et 3 N

(3,0 mL, 21,57 mmol). Etter 30 minutter ble en løsning av 2,3-diamino-6-metylpyridin (882 mg, 7,16 mmol) i tørr THF tilsatt og reaksjonsblandingen omrørt ved RT. Etter 3 dager ble reaksjonsblandingen konsentrert under vakuum. Residuet ble tatt opp i EtOAc og vasket med 1,0 N NaHC03. Det organiske lag ble tørket (MgS04), filtrert, konsentrert under vakuum og rekonsentrert fra toluen. Residuet ble løst i iseddik (100 mL) og oppvarmet i et oljebad innstillet på 110°C. Etter 24 timer ble reaksjonsblandingen konsentrert under vakuum og residuet rekonsentrert fra toluen. Kromatografi (silikagel, trinnvis gradient, CHCI3, 2% MeOH/CHCI3, 3% MeOH/CHCI3) ga tittelforbindelsen (1,0 g, 46,6%):<1>H NMR (250 MHz, CDCI3) 5 7,29 (s, 5H); 7,17 (s, 1H); 7,03 (d, 1H), 5,09 (s, 2H), 4,74 (s, 2H); 3,05 (s, 3H), 2,61 (s, 3H); MS (ES) m/e 311,0 (M+H)<+>d) 2-(metylamino)metyl-5-metyl-4-azabenzimidazol (3.0 mL, 21.57 mmol). After 30 min, a solution of 2,3-diamino-6-methylpyridine (882 mg, 7.16 mmol) in dry THF was added and the reaction mixture was stirred at RT. After 3 days, the reaction mixture was concentrated under vacuum. The residue was taken up in EtOAc and washed with 1.0 N NaHCO 3 . The organic layer was dried (MgSO 4 ), filtered, concentrated in vacuo and reconcentrated from toluene. The residue was dissolved in glacial acetic acid (100 mL) and heated in an oil bath set at 110°C. After 24 hours, the reaction mixture was concentrated under vacuum and the residue reconcentrated from toluene. Chromatography (silica gel, stepwise gradient, CHCl 3 , 2% MeOH/CHCl 3 , 3% MeOH/CHCl 3 ) gave the title compound (1.0 g, 46.6%):<1>H NMR (250 MHz, CDCl 3 ) 5 7.29 (p, 5H); 7.17 (s, 1H); 7.03 (d, 1H), 5.09 (s, 2H), 4.74 (s, 2H); 3.05 (s, 3H), 2.61 (s, 3H); MS (ES) m/e 311.0 (M+H)<+>d) 2-(methylamino)methyl-5-methyl-4-azabenzimidazole

2-[[N-(benzyloksykarbonyl)-N-metyl]aminometyl]-5-metyl-4-azabenzimidazol 2-[[N-(benzyloxycarbonyl)-N-methyl]aminomethyl]-5-methyl-4-azabenzimidazole

(1,0347 g, 0,33 mmol) ble løst i MeOH og tilsatt 10% Pd/C. Blandingen ble kraftig omrørt ved RT under H2(ballong). Etter 20 timer ble reaksjonsblandingen filtrert gjennom Celite® og det lysegule filtratet konsentrert under vakuum for å gi tittelforbindelsen (678,9 mg, kvantitativt) som et rødaktig materiale. (1.0347 g, 0.33 mmol) was dissolved in MeOH and added 10% Pd/C. The mixture was vigorously stirred at RT under H2 (balloon). After 20 h, the reaction mixture was filtered through Celite® and the light yellow filtrate concentrated under vacuum to give the title compound (678.9 mg, quantitative) as a reddish material.

e) Metyl-(S)-7-[[[2-(4-aza-5-metylbenzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat e) Methyl-(S)-7-[[[2-(4-aza-5-methylbenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepine-2-acetate

EDC (212,7 mg, 1,11 mmol) ble tilsatt til en løsning av metyl-(S)-7-karboksy-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat (293,5 mg, EDC (212.7 mg, 1.11 mmol) was added to a solution of methyl-(S)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1 ,4-benzodiazepine-2-acetate (293.5 mg,

0,93 mmol), diisopropyletylamin (0,30 mL, 1,72 mmol) og HOBtH20 (143,5 mg,0.93 mmol), diisopropylethylamine (0.30 mL, 1.72 mmol) and HOBtH 2 O (143.5 mg,

1,06 mmol) i tørr DMF ved RT. Etter 30 minutter ble en løsnnig av 2-(metylamino)metyl-5-metyl-4-azabenzimidazol (190,7 mg, 1,08 mmol) i tørr DMF tilsatt. Reaksjonsblandingen ble omrørt ved RT i 24 timer og deretter konsentrert under vakuum, hvorpå residuet ble rekonsentrert fra toluen. Kromatografi (silikagel, trinnvis gradient, CHCI3, 3% MeOH/CHCI3, 5% MeOH/CHCI3) ga tittelforbindelsen (265 mg, 63%): 1.06 mmol) in dry DMF at RT. After 30 minutes, a solution of 2-(methylamino)methyl-5-methyl-4-azabenzimidazole (190.7 mg, 1.08 mmol) in dry DMF was added. The reaction mixture was stirred at RT for 24 h and then concentrated under vacuum, after which the residue was reconcentrated from toluene. Chromatography (silica gel, stepwise gradient, CHCl 3 , 3% MeOH/CHCl 3 , 5% MeOH/CHCl 3 ) afforded the title compound (265 mg, 63%):

<1>H NMR (250 MHz, CDCI3) 5 8,51 (br s, 1H); 7,86-7,05 (m, 5H); 5,34 (d, 1H); 5,06 (t, 1H); 3,69 (s, 3H); 3,08 (s, 3H); 2,62 (s, 3H); MS (ES) m/e 451,2 (M+H)<+>f) (S)-7-[[[2-(4-aza-5-metylbenzimidazolyl)metyl]metylamino]karbonyl]-4-mety okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre 1,0 N NaOH (2,0 mL, 2,0 mmol) ble tilsatt til en løsning av metyl-(S)-7-[[[2-(4-aza-5-metylbenzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (264,7 mg, 0,59 mmol) i MeOH (10 mL) og H20 (10 mL) ved RT. Etter 20 timer ble reaksjonsblandingen nøytralisert med 1,0 N HCI (2,0 mL) og løsningsmidlet fordampet under vakuum. Råmaterialet ble utfelt fra vann for å gi tittelforbindelsen (49,8 mg): TLC Rf 0,51 (3:1:1 n-BuOH/HOAc/H20); HPLC tR=8,35 min(PRP-1®, gradienteluering i løpet av 20 minutter, 5-50% CH3CN/H2O-0,1% TFA); <1>H NMR (250 MHz, CDCl 3 ) δ 8.51 (br s, 1H); 7.86-7.05 (m, 5H); 5.34 (d, 1H); 5.06 (t, 1H); 3.69 (s, 3H); 3.08 (s, 3H); 2.62 (s, 3H); MS (ES) m/e 451.2 (M+H)<+>f) (S)-7-[[[2-(4-aza-5-methylbenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl oxo-2,3,4,5-tetrahydro-1 H -1,4-benzodiazepine-2-acetic acid 1.0 N NaOH (2.0 mL, 2.0 mmol) was added to a solution of methyl-(S )-7-[[[2-(4-aza-5-methylbenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine -2-acetate (264.7 mg, 0.59 mmol) in MeOH (10 mL) and H 2 O (10 mL) at RT. After 20 h, the reaction mixture was neutralized with 1.0 N HCl (2.0 mL) and the solvent evaporated under vacuum. The crude material was precipitated from water to give the title compound (49.8 mg): TLC Rf 0.51 (3:1:1 n-BuOH/HOAc/H 2 O); HPLC tR=8.35 min (PRP-1®, gradient elution over 20 min, 5-50% CH3CN/H2O-0.1% TFA);

MS (ES) m/e 437,2 (M+H)<+>MS (ES) m/e 437.2 (M+H)<+>

Analyse beregnet for C22H24N604 • 0,75H2O • 1,2 HCI:Analysis calculated for C22H24N604 • 0.75H2O • 1.2 HCI:

C, 42,56; H, 3,53; N, 11,03 C, 42.56; H, 3.53; N, 11.03

Funnet: C, 42,20; H, 3,02; N, 11,36. Found: C, 42.20; H, 3.02; N, 11.36.

Eksempel 47Example 47

Fremstilling av (S)-7-[[[2(5,6-dimetoksybenzimidazolyl)metyl]-metylaminoJkarbonyll^-metyl-S-okso^.S^.S-tetrahydro-IH-l^-benzodiazepin-2-eddiksyre Preparation of (S)-7-[[[2(5,6-dimethoxybenzimidazolyl)methyl]-methylaminoJcarbonyl^-methyl-S-oxo^.S^.S-tetrahydro-1H-1^-benzodiazepine-2-acetic acid

a) 2-[[N-(benzyloksykarbonyl)-N-metyl]aminometyl]-5,6-dimetoksybenzimidazol a) 2-[[N-(benzyloxycarbonyl)-N-methyl]aminomethyl]-5,6-dimethoxybenzimidazole

Cbz-sarkosin (1,4 g, 6,1 mmol) ble løst i tørr THF i en 100 mL rundkolbe og Cbz-sarcosine (1.4 g, 6.1 mmol) was dissolved in dry THF in a 100 mL round bottom flask and

tilsatt Et3N (1,5 mL, 10,8 mmol) og deretter isobutylklorformiat (0,80 mL, 6,17 mmol). Reaksjonsblandingen ble omrørt ved RT og deretter tilsatt til en løsning av 4,5-dimetoksyfenylendiamin (6,06 mmol) i tørr THF ved -25°C. Cbz-sarkosin, blandet anhydrid-løsningen, ble tilsatt til den avkjølte fenylendiamin-løsningen. Reaksjonsblandingen ble omrørt ved -25°C i 10 minutter og fikk deretter oppvarmes til RT. Etter 20 timer ble reaksjonsblandingen konsentrert under vakuum. Residuet ble tatt opp i EtOAc og vasket med 1,0 N NaHC03. Det organiske lag ble tørket (MgS04), filtrert, konsentrert under vakuum og rekonsentrert fra toluen. Residuet ble løst i iseddik (100 mL) og oppvarmet i et oljebad innstillet på 110°C. Etter 24 timer ble reaksjonsblandingen konsentrert under vakuum. Hurtigkromatografi (silikagel, added Et 3 N (1.5 mL, 10.8 mmol) and then isobutyl chloroformate (0.80 mL, 6.17 mmol). The reaction mixture was stirred at RT and then added to a solution of 4,5-dimethoxyphenylenediamine (6.06 mmol) in dry THF at -25°C. Cbz-sarcosine, the mixed anhydride solution, was added to the cooled phenylenediamine solution. The reaction mixture was stirred at -25°C for 10 minutes and then allowed to warm to RT. After 20 hours, the reaction mixture was concentrated under vacuum. The residue was taken up in EtOAc and washed with 1.0 N NaHCO 3 . The organic layer was dried (MgSO 4 ), filtered, concentrated in vacuo and reconcentrated from toluene. The residue was dissolved in glacial acetic acid (100 mL) and heated in an oil bath set at 110°C. After 24 hours, the reaction mixture was concentrated under vacuum. Flash chromatography (silica gel,

trinnvis gradient, 2% MeOH/CHCI3, 5% MeOH/CHCI3) ga tittelforbindelsen (1,7g, 81%); stepwise gradient, 2% MeOH/CHCl 3 , 5% MeOH/CHCl 3 ) afforded the title compound (1.7g, 81%);

<1>H NMR (250 MHz, CDCI3,) 5 7,33 (s, 5H); 7,05 (s, 2H), 5,15 (s, 2H); 4,64 (s, 2H); <1>H NMR (250 MHz, CDCl 3 , ) δ 7.33 (s, 5H); 7.05 (s, 2H), 5.15 (s, 2H); 4.64 (s, 2H);

3,88 (s, 6H), 3,04 (s, 3H), MS (ES) m/e 356,2 (M+H)<+>3.88 (s, 6H), 3.04 (s, 3H), MS (ES) m/e 356.2 (M+H)<+>

b) 2-(metylamino)metyl-5,6-dimetoksybenzimidazol b) 2-(methylamino)methyl-5,6-dimethoxybenzimidazole

2-[[N-(benzyloksykarbonyl)-N-metyl]aminometyl]-5,6-dimetoksybenzimidazol 2-[[N-(benzyloxycarbonyl)-N-methyl]aminomethyl]-5,6-dimethoxybenzimidazole

(1,7454 g, 4,91 mmol) ble løst i MeOH og tilsatt 10% Pd/C. Blandingen ble kraftig (1.7454 g, 4.91 mmol) was dissolved in MeOH and added 10% Pd/C. The mixture became powerful

omrørt ved RT under H2(ballong). Etter 4 timer ble reaksjonsblandingen filtrertstirred at RT under H2(balloon). After 4 hours, the reaction mixture was filtered

i gjennom Celite® og filtratet konsentrert under vakuum for å gi tittelforbindelsen.in through Celite® and the filtrate concentrated under vacuum to give the title compound.

c) Metyl-(S)-7-[[[2-(5,6-dimetoksybenzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat c) Methyl-(S)-7-[[[2-(5,6-dimethoxybenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H- 1,4-benzodiazepine-2-acetate

EDC (139,9 mg, 0,73 mmol) ble tilsatt til en suspensjon av metyl-(S)-7-karboksy-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat (198,5 mg, 0,68 mmol) og HOBt-H20) (98,8 mg, 0,73 mmol) i CH3CN ved RT. Etter 15 minutter ble diisopropyletylamin (0,200 mL, 1,15 mmol) tilsatt og deretter en EDC (139.9 mg, 0.73 mmol) was added to a suspension of methyl-(S)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1 ,4-benzodiazepine-2-acetate (198.5 mg, 0.68 mmol) and HOBt-H 2 O) (98.8 mg, 0.73 mmol) in CH 3 CN at RT. After 15 min, diisopropylethylamine (0.200 mL, 1.15 mmol) was added and then a

løsning av 2-(metylamino)metyl-5,6-dimetoksybenzimidazol (147,3 mg, 0,67 mmol) i solution of 2-(methylamino)methyl-5,6-dimethoxybenzimidazole (147.3 mg, 0.67 mmol) in

CH3CN. Reaksjonsblandingen ble omrørt ved RT i 24 timer og løsningsmidlene deretter fordampet under vakuum. Residuet ble rekonsentrert fra toluen og deretter kromatografert (silikagel, trinnvis gradient, CHCI3, 3% MeOH/CHCI3, 5% MeOH/CHCI3) for å gi tittelforbindelsen (227 mg, 68%); CH3CN. The reaction mixture was stirred at RT for 24 h and the solvents then evaporated under vacuum. The residue was reconcentrated from toluene and then chromatographed (silica gel, stepwise gradient, CHCl 3 , 3% MeOH/CHCl 3 , 5% MeOH/CHCl 3 ) to give the title compound (227 mg, 68%);

<1>H NMR (250 MHz, CDCI3l) 5 7,29-7,16 (m, 5H); 5,37 (d, 1H); 5,09-5,03 (m, 1H); <1>H NMR (250 MHz, CDCl31) δ 7.29-7.16 (m, 5H); 5.37 (d, 1H); 5.09-5.03 (m, 1H);

4,86-4,72 (m, 3H); 3,90 (s, 6H); 3,71 (s, 3H); 3,12 (s, 3H). 4.86-4.72 (m, 3H); 3.90 (s, 6H); 3.71 (s, 3H); 3.12 (p, 3H).

MS (ES) m/e 496 (M+H)<+>MS (ES) m/e 496 (M+H)<+>

d) (S)-7-[[[2-(5,6-dimetoksybenzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre d) (S)-7-[[[2-(5,6-dimethoxybenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1, 4-benzodiazepine-2-acetic acid

1,0 N NaOH (1,5 mL, 1,5 mmol) ble tilsatt til en løsning av metyl-(S)-7-[[[2-(5,6-dimetoksybenzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (227,1 mg, 0,46 mmol) i MeOH (10 mL) og H20 (10 mL) ved RT. Etter 24 timer ble reaksjonsblandingen nøytralisert med 1.0 N NaOH (1.5 mL, 1.5 mmol) was added to a solution of methyl-(S)-7-[[[2-(5,6-dimethoxybenzimidazolyl)methyl]methylamino]carbonyl]-4 -methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (227.1 mg, 0.46 mmol) in MeOH (10 mL) and H 2 O (10 mL ) at RT. After 24 hours, the reaction mixture was neutralized with

1,0 N HCI (1,5 mL, 1,5 mmol). Etter 30 minutter ble det dannet et hvitt bunnfall som ble oppsamlet på en sinterglass-trakt og vasket med vann. Materialet ble tørket i en vakuum-eksikkator for å gi tittelforbindelsen (144,3 mg, 65%): 1.0 N HCl (1.5 mL, 1.5 mmol). After 30 minutes a white precipitate formed which was collected on a sintered glass funnel and washed with water. The material was dried in a vacuum desiccator to give the title compound (144.3 mg, 65%):

MS (ES) m/e 482,2 (M+H)<+>MS (ES) m/e 482.2 (M+H)<+>

Analyse beregnet for C24H27N5O6• 1,75 H20 • 0,4 HCI:Analysis calculated for C24H27N5O6• 1.75 H20 • 0.4 HCI:

C, 54,64; H, 5,90; N, 13,27 C, 54.64; H, 5.90; N, 13.27

Funnet: C, 54,69; H, 5,92; N, 12,67 Found: C, 54.69; H, 5.92; N, 12.67

Eksempel 48Example 48

Fremstilling av (±)-8-[[2-(2-benzimidazolyl)acetyl]amino]-2-metyl-3-okso-2>3,4,5-tetrahydro-1H-2-benzazepin-4-eddiksyre Preparation of (±)-8-[[2-(2-benzimidazolyl)acetyl]amino]-2-methyl-3-oxo-2>3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid

a) Metyl-(±)-8-[[2-(2-benzimidazolyl)acetyl]amino]-2-metyl-3-okso-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetat a) Methyl-(±)-8-[[2-(2-benzimidazolyl)acetyl]amino]-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4- acetate

Metyl-(+)-8-amino-2-metyl-3-okso-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetat ble koblet med 2-benzimidazolyleddiksyre ifølge fremgangsmåten i Eksempel 11 (a). Rensing ved kromatografi (silikagel 2%-5% CH3OH/CH2CI2) ga tittelforbindelsen som et farveløst skum (31%):<1>H NMR (CDCI3l) 7,55 (m, 1H); 7,44 (d, J=2Hz, 1H), 7,38 (dd, J=8,3Hz, J=2Hz, 1H); 7,30 (m, 2H); 5,18 (d, J=16,3Hz, 1H); 4,24 (s, 2H), 3,71 (m, 1H); 3,68 (s, 3H); 3,65 (d, J=16,3Hz, 1H), 3,03 (m, 1H); 2,95 (s, 3H); 2,85 (m, 1H); 2,40 (dd, J=16,9, 6,3Hz, 1H) Methyl-(+)-8-amino-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate was coupled with 2-benzimidazolyacetic acid according to the procedure in Example 11 (a ). Purification by chromatography (silica gel 2%-5% CH 3 OH/CH 2 Cl 2 ) gave the title compound as a colorless foam (31%): 1 H NMR (CDCl 3 1 ) 7.55 (m, 1H); 7.44 (d, J=2Hz, 1H), 7.38 (dd, J=8.3Hz, J=2Hz, 1H); 7.30 (m, 2H); 5.18 (d, J=16.3Hz, 1H); 4.24 (s, 2H), 3.71 (m, 1H); 3.68 (s, 3H); 3.65 (d, J=16.3Hz, 1H), 3.03 (m, 1H); 2.95 (s, 3H); 2.85 (m, 1H); 2.40 (dd, J=16.9, 6.3Hz, 1H)

b) (±)-8-[[2-(2-benzimidazolyl)acetyl]amino]-2-metyl-3-okso-2,3,4,5-tetrahydro-b) (±)-8-[[2-(2-benzimidazolyl)acetyl]amino]-2-methyl-3-oxo-2,3,4,5-tetrahydro-

1 H-2-benzazepin-4-eddiksyre 1 H-2-benzazepine-4-acetic acid

Metyl-(±)-8-[[2-(2-benzimidazolyl)acetyl]-2-metyl-3-okso-2,3,4,5-tetrahydro-Methyl-(±)-8-[[2-(2-benzimidazolyl)acetyl]-2-methyl-3-oxo-2,3,4,5-tetrahydro-

1 H-2-benzazepin-4-acetat ble forsåpet ifølge fremgangsmåten i Eksempel 24(b) for å gi tittelforbindelsen som et hvitt faststoff (47%):<1>H NMR (DMSO-d6l) 5 10,38 (s, 1H); 7,49 (m, 3H); 7,42 (d, J=8,4Hz, 1H), 7,15 (m, 2H); 7,06 (d, J=8,4Hz, 1H), 5,24 (d, J=16,5Hz, 1H), 3,96 (s, 2H), 2,35 (m, 1H); 1H-2-benzazepine-4-acetate was saponified according to the procedure of Example 24(b) to give the title compound as a white solid (47%): <1>H NMR (DMSO-d6l) δ 10.38 (s, 1H); 7.49 (m, 3H); 7.42 (d, J=8.4Hz, 1H), 7.15 (m, 2H); 7.06 (d, J=8.4Hz, 1H), 5.24 (d, J=16.5Hz, 1H), 3.96 (s, 2H), 2.35 (m, 1H);

MS (ES) m/e 407,2 (M+H)<+>MS (ES) m/e 407.2 (M+H)<+>

Analyse beregnet for C22H22N4O4 -1,75 H20:Analysis calculated for C22H22N4O4 -1.75 H20:

C, 60,33; H, 5,87; N, 12,79. C, 60.33; H, 5.87; N, 12.79.

Funnet: C, 60,57; H, 5,49; N, 12,41. Found: C, 60.57; H, 5.49; N, 12.41.

Eksempel 49Example 49

Fremstilling av (±)-8-[[[(2-benzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-2-benzazepin-4-eddiksyre Preparation of (±)-8-[[[(2-benzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid

a) Metyl-(±)-8-[[[(2-benzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetat a) Methyl-(±)-8-[[[(2-benzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4 -acetate

Metyl-(±)-8-karboksy-3-okso-2,3,4,5-tetrahydro-1 H-2-benzazepin-4-acetat ble koblet med 2-(metylamino)metylbenzimidazol ifølge fremgangsmåten i Eksempel 2(a). Rensing ved kromatografi (silikagel, 1%-6% CH3OH/CH2CI2) ga tittelforbindelsen som et hvitt skum (76%):<1>H NMR (CDCI3,) 5 7,62 (m, 2H); 7,43 (m, 1H); 7,30 (m, 2H); 7,13 (m, 2H), 5,06 (d, J=14,6Hz, 1H); 4,86 (d, J=14,6Hz, 1H); 4,77 (dd, J=16,6Hz, J=4Hz); 3,91 (dd, J=16,6, 6Hz, 1H); 3,72 (s, 3H); 3,08 (s, 3H), 3,05 (m, 2H); 2,52 (dd, J=16,9, 5,7Hz, 1H) Methyl-(±)-8-carboxy-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate was coupled with 2-(methylamino)methylbenzimidazole according to the procedure in Example 2 (a ). Purification by chromatography (silica gel, 1%-6% CH 3 OH/CH 2 Cl 2 ) afforded the title compound as a white foam (76%): 1 H NMR (CDCl 3 ) δ 7.62 (m, 2H); 7.43 (m, 1H); 7.30 (m, 2H); 7.13 (m, 2H), 5.06 (d, J=14.6Hz, 1H); 4.86 (d, J=14.6Hz, 1H); 4.77 (dd, J=16.6Hz, J=4Hz); 3.91 (dd, J=16.6, 6Hz, 1H); 3.72 (s, 3H); 3.08 (s, 3H), 3.05 (m, 2H); 2.52 (dd, J=16.9, 5.7Hz, 1H)

b) (+)-8-[[[(2-benzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-2-benzazepin-4-eddiksyre b) (+)-8-[[[(2-benzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid

Metyl-(±)-8-[[[(2-benzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetat ble forsåpet ifølge fremgangsmåten i Eksempel 11 (b) for å gi tittelforbindelsen som et hvitt faststoff (90%):<1>H NMR (DMSO-d6) 5 7,88 (m, 1H); 7,54 (m, 2H); 7,34 (d, J=7,9Hz, 1H); 7,30 (s, 1H); 7,16 (m, 2H); 6,98 (m, 1H); 4,87 (m, 1H); 4,67 (m, 2H); 4,00 (m, 1H); 3,87 (m, 1H); 3,10 (m, 1H), 3,02 (s, 3H), 2,76 (m, 1H), 2,43 (m, 1H); 1,97 (m, 1H); Methyl-(±)-8-[[[(2-benzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate was saponified according to the procedure of Example 11 (b) to give the title compound as a white solid (90%): <1>H NMR (DMSO-d6) δ 7.88 (m, 1H); 7.54 (m, 2H); 7.34 (d, J=7.9Hz, 1H); 7.30 (s, 1H); 7.16 (m, 2H); 6.98 (m, 1H); 4.87 (m, 1H); 4.67 (m, 2H); 4.00 (m, 1H); 3.87 (m, 1H); 3.10 (m, 1H), 3.02 (s, 3H), 2.76 (m, 1H), 2.43 (m, 1H); 1.97 (m, 1H);

MS (ES) m/e 407 (M+H)<+>MS (ES) m/e 407 (M+H)<+>

Analyse beregnet for C22H21N4O4L1-2,375 H20:Analysis calculated for C22H21N4O4L1-2.375 H20:

C, 58,05; H, 5,70; N, 12,31. C, 58.05; H, 5.70; N, 12.31.

Funnet: C, 57,85; H, 5,41; N, 12,66. Found: C, 57.85; H, 5.41; N, 12.66.

Eksempel 50Example 50

Fremstilling av (S)-7-[[[(2-benzimidazolyl)metyl]metylamino]karbonyl]-3-okso-4-(2-fenyletyl)-2,3,4I5-tetrahydro-1H-1I4-benzodiazepin-2-eddiksyre Preparation of (S)-7-[[[(2-benzimidazolyl)methyl]methylamino]carbonyl]-3-oxo-4-(2-phenylethyl)-2,3,4I5-tetrahydro-1H-1I4-benzodiazepine-2 -acetic acid

a) Metyl-(S)-7-karboksy-3-okso-4-(2-fenyletyl)-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat a) Methyl-(S)-7-carboxy-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate

Til en løsning omrørt under argon ved RT av metyl-(±)-7-karboksy-3-okso-4-(2-fenyletyl)-2,3,4l5-tetrahydro-1H-1,4-benzodiazepin-2-acetat (9,0 g, 23 mmol) i CH3CN (100 mL) ble det tilsatt diazabicykloundecen (4,6 g, 30 mmol) og deretter benzylbromid (20 g, 116 mmol). Den resulterende løsning ble omrørt i 1 time og deretter konsentrert. Residuet ble fordelt mellom 1,0 N HCI og EtOAc og lagene separert. Det organiske lag ble vasket med saltvann, tørket (MgS04) og konsentrert. Residuet ble renset ved kromatografi (silikagel, CH2CI2) for å gi en blekgul olje (7 g). Preparativ HPLC (Whelk 0-1, 50:50:1 heksan:CHCI3:CH3OH) ga en olje som var 97% av den ønskede (S)-enantiomer. Fjerning av racematet ved krystallisasjon (EtOAc) ga en farveløs olje (3,2 g, 98%) ee). Dette materialet ble anbragt i en 500 mL Parr-hydrogeneringskolbe med CH3OH (30 mL) og 10% Pd/C (0,45 g) og blandingen ristet under H2(3,5 kg/cm<2>) i 6 timer. Reaksjonsblandingen ble deretter filtrert og filtratet konsentrert for å gi tittelforbindelsen som et farveløst skum (2,1 g, 47%):<1>H NMR (CDCI3) 8 7,78 (dd, J=8,5, 1,9Hz, 1H); 7,55 (d, J=1,9Hz, 1H); 7,30-7,10 (m, 5H); 6,51 (d, J=8,5Hz, 1H); 5,30 (d, J=16,6Hz, 1H); 5,10 (t, J=6,5Hz; 1H), 3,77 (s, 3H); 3,74 (m, 3H); 3,67 (d, J=16,6Hz, 1H); 3,02 (dd, J=16, 6,8Hz, 1H); 2,83 (t, J=7,1Hz, 2H); 2,69 (dd, J=16, 6,5Hz, 1H). To a solution stirred under argon at RT of methyl-(±)-7-carboxy-3-oxo-4-(2-phenylethyl)-2,3,4l5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (9.0 g, 23 mmol) in CH 3 CN (100 mL) was added diazabicycloundecene (4.6 g, 30 mmol) followed by benzyl bromide (20 g, 116 mmol). The resulting solution was stirred for 1 hour and then concentrated. The residue was partitioned between 1.0 N HCl and EtOAc and the layers separated. The organic layer was washed with brine, dried (MgSO 4 ) and concentrated. The residue was purified by chromatography (silica gel, CH 2 Cl 2 ) to give a pale yellow oil (7 g). Preparative HPLC (Whelk 0-1, 50:50:1 hexane:CHCl3:CH3OH) gave an oil which was 97% of the desired (S)-enantiomer. Removal of the racemate by crystallization (EtOAc) gave a colorless oil (3.2 g, 98%) ee). This material was placed in a 500 mL Parr hydrogenation flask with CH 3 OH (30 mL) and 10% Pd/C (0.45 g) and the mixture shaken under H 2 (3.5 kg/cm<2>) for 6 hours. The reaction mixture was then filtered and the filtrate concentrated to give the title compound as a colorless foam (2.1 g, 47%):<1>H NMR (CDCl3) δ 7.78 (dd, J=8.5, 1.9Hz, 1H); 7.55 (d, J=1.9Hz, 1H); 7.30-7.10 (m, 5H); 6.51 (d, J=8.5Hz, 1H); 5.30 (d, J=16.6Hz, 1H); 5.10 (t, J=6.5Hz; 1H), 3.77 (s, 3H); 3.74 (m, 3H); 3.67 (d, J=16.6Hz, 1H); 3.02 (dd, J=16, 6.8Hz, 1H); 2.83 (t, J=7.1Hz, 2H); 2.69 (dd, J=16, 6.5Hz, 1H).

b) Metyl-(S)-7-[[[(2-benzimidazolyl)metyl]metylamino]karbonyl]-3-okso-4-(2-fenyletyl)-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat b) Methyl-(S)-7-[[[(2-benzimidazolyl)methyl]methylamino]carbonyl]-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1 H- 1,4-benzodiazepine-2-acetate

Metyl-(S)-7-karboksy-3-okso-4-(2-fenyletyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat ble koblet med 2-(metylamino)metylbenzimidazol ifølge fremgangsmåten i Eksempel 2(a). Rensing ved kromatografi på silikagel (1%-5% CH3OH/CH2CI2) ga tittelforbindelsen (2,85 g, 99%) som et farveløst skum:<1>H NMR (CDCI3) 5 7,63 (m, 2H), 7,33 (m, 2H), 7,25-7,10 (m, 7H); 6,59 (d, J=8,3Hz, 1H); 5,24 (d, J=16,7Hz, 1H); 5,03 (m, 1H); 4,94 (d, J=14,6Hz, 1H); 4,85 (d, J=14,6Hz, 1H); 4,50 (d, J=4,7Hz, 1H); 3,77 (m, 1H); 3,76 (s, 3H); 3,59 (d, J=16,7Hz, 1H); 3,57 (m, 1H); 3,19 (s, 3H); 2,99 (dd, J=16, 6,5Hz, 1H); 2,81 (m, 2H); 2,67 (dd, J=16, 6,4Hz, 1H) Methyl-(S)-7-carboxy-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate was coupled with 2-(methylamino )methylbenzimidazole according to the procedure in Example 2(a). Purification by chromatography on silica gel (1%-5% CH3OH/CH2Cl2) afforded the title compound (2.85 g, 99%) as a colorless foam: <1>H NMR (CDCl3) δ 7.63 (m, 2H), 7 .33 (m, 2H), 7.25-7.10 (m, 7H); 6.59 (d, J=8.3Hz, 1H); 5.24 (d, J=16.7Hz, 1H); 5.03 (m, 1H); 4.94 (d, J=14.6Hz, 1H); 4.85 (d, J=14.6Hz, 1H); 4.50 (d, J=4.7Hz, 1H); 3.77 (m, 1H); 3.76 (s, 3H); 3.59 (d, J=16.7Hz, 1H); 3.57 (m, 1H); 3.19 (s, 3H); 2.99 (dd, J=16, 6.5Hz, 1H); 2.81 (m, 2H); 2.67 (dd, J=16, 6.4Hz, 1H)

c) (S)-7-[[[(2-benzimidazolyl)metyl]metylamino]karbonyl]-3-okso-4-(2-fenylety 2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre c) (S)-7-[[[(2-benzimidazolyl)methyl]methylamino]carbonyl]-3-oxo-4-(2-phenylethyl 2,3,4,5-tetrahydro-1H-1,4- benzodiazepine-2-acetic acid

Metyl-(S)-7-[[[(2-benzimidazolyl)metyl]metylamino]karbonyl]-3-okso-4-(2-fenyletyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat ble forsåpet ifølge fremgangsmåten i Eksempel 11 (b) for å gi tittelforbindelsen (1,8 g, 66%) som et hvitt faststoff:<1>H NMR (DMSO-d6) 5 7,54 (m, 2H); 7,30-7,10 (m, 9H); 6,54 (d, J=8,3Hz, 1H); 6,30 (br s, 1H); 5,37 (d, J=16,2Hz, 1H); 5,05 (m, 1H); 4,77 (s, 2H); 3,97 (br s, 1H); 3,51 (m, 3H), 3,05 (s, 3H); 2,65 (m, 3H); 2,49 (m, 1H) Methyl-(S)-7-[[[(2-benzimidazolyl)methyl]methylamino]carbonyl]-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4 -benzodiazepine-2-acetate was saponified according to the procedure of Example 11 (b) to give the title compound (1.8 g, 66%) as a white solid:<1>H NMR (DMSO-d6) δ 7.54 (m , 2H); 7.30-7.10 (m, 9H); 6.54 (d, J=8.3Hz, 1H); 6.30 (br s, 1H); 5.37 (d, J=16.2Hz, 1H); 5.05 (m, 1H); 4.77 (s, 2H); 3.97 (br s, 1H); 3.51 (m, 3H), 3.05 (s, 3H); 2.65 (m, 3H); 2.49 (m, 1H)

Analyse beregnet for C29H29N5O4 • H20:Analysis calculated for C29H29N5O4 • H20:

C, 65,77; H, 5,90; N, 13,22 C, 65.77; H, 5.90; N, 13,22

Funnet: C, 65,51; H, 5,84; N, 13,19 Found: C, 65.51; H, 5.84; N, 13,19

Eksempel 51Example 51

Fremstilling av (±)-7-[[[2-(benzimidazolyl)metyl]amino]karbonyl-4-[2-(3,4-metylendioksyfenyOetylj-S-okso^.S^.S-tetrahydro-IH-l^-benzodiazepin^-eddiksyre Preparation of (±)-7-[[[2-(benzimidazolyl)methyl]amino]carbonyl-4-[2-(3,4-methylenedioxyphenylOethylj-S-oxo^,S^,S-tetrahydro-1H-1^ -benzodiazepine^-acetic acid

a) metyl-(+)-7-[[[2-(benzimidazolyl)metyl]amino]karbonyl-4-[2-(3,4-metylendioksyfenyl)etyl]-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat a) methyl-(+)-7-[[[2-(benzimidazolyl)methyl]amino]carbonyl-4-[2-(3,4-methylenedioxyphenyl)ethyl]-3-oxo-2,3,4,5 -tetrahydro-1H-1,4-benzodiazepine-2-acetate

Metyl-(±)-7-karboksy-4-[2-(3,4-metylendioksyfenyl)etyl]-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat ble koblet med 2-(aminometyl)-benzimidazol-dihydrokloridhydrat ifølge fremgangsmåten i Eksempel 2(a). Rensing ved kromatografi (silikagel, 1%-5% CH3OH/CH2CI2) etterfulgt av omkrystallisasjon (CH3OH/EtOAc) ga tittelforbindelsen som et lysebrunt faststoff (59%):<1>H NMR (DMSO-d6) 5 8,72 (t, J=5Hz, 1H); 7,61 (s, 1H); 7,56 (m, 2H); 7,43 (m, 1H); 7,13 (m, 2H); 6,76 (m, 2H); 6,57 (m, 2H); 6,37 (d, J=3,6Hz, 1H); 5,95 (s, 2H); 5,42 (d, J=16,5Hz, 1H); 5,13 (m, 1H); 4,64 (m, 2H); 3,92 (d, J=16,5Hz, 1H); 3,61 (s, 3H); 3,58 (m, 2H); 2,83 (dd, J=16,6, 7,6Hz, 1H); 2,65 (m, 3H) Methyl-(±)-7-carboxy-4-[2-(3,4-methylenedioxyphenyl)ethyl]-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate was coupled with 2-(aminomethyl)-benzimidazole dihydrochloride hydrate according to the procedure in Example 2(a). Purification by chromatography (silica gel, 1%-5% CH3OH/CH2Cl2) followed by recrystallization (CH3OH/EtOAc) gave the title compound as a light brown solid (59%): <1>H NMR (DMSO-d6) δ 8.72 (t , J=5Hz, 1H); 7.61 (s, 1H); 7.56 (m, 2H); 7.43 (m, 1H); 7.13 (m, 2H); 6.76 (m, 2H); 6.57 (m, 2H); 6.37 (d, J=3.6Hz, 1H); 5.95 (s, 2H); 5.42 (d, J=16.5Hz, 1H); 5.13 (m, 1H); 4.64 (m, 2H); 3.92 (d, J=16.5Hz, 1H); 3.61 (s, 3H); 3.58 (m, 2H); 2.83 (dd, J=16.6, 7.6Hz, 1H); 2.65 (m, 3H)

b) (±)-7-[[[2-(benzimidazolyl)metyl]amino]karbonyl-4-[2-(314-metylendioksyfenyl)etyl]-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre b) (±)-7-[[[2-(benzimidazolyl)methyl]amino]carbonyl-4-[2-(314-methylenedioxyphenyl)ethyl]-3-oxo-2,3,4,5-tetrahydro-1H -1,4-benzodiazepine-2-acetic acid

Metyl-(±)-7-[[[2-(benzimidazolyl)metyl]amino]karbonyl-4-[2-(3,4-metylendioksyfenyl)etyl]-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat ble forsåpet ifølge fremgangsmåten i Eksempel 11 (b) for å gi tittelforbindelsen (84%) som et hvitt faststoff:<1>H NMR (DMSO-de) 5 8,76 (t, J=5Hz, 1H); 7,58 (m, 2H); 7,48 (m, 2H); 7,13 (m, 2H); 6,76 (m, 2H); 6,58 (m, 2H); 5,94 (s, 2H); 5,40 (d, J=16,5Hz, 1H); 5,06 (m, 1H); 4,64 (m, 2H); 3,91 (d, J=16,5Hz, 1H); 3,54 (m, 2H); 2,72 (m, 1H); 2,60 (t, J=8Hz, 2H); 2,50 (m, 1H); MS (ES) m/e 542 (M+H)<+>Methyl-(±)-7-[[[2-(benzimidazolyl)methyl]amino]carbonyl-4-[2-(3,4-methylenedioxyphenyl)ethyl]-3-oxo-2,3,4,5-tetrahydro -1H-1,4-benzodiazepine-2-acetate was saponified according to the procedure of Example 11 (b) to give the title compound (84%) as a white solid: <1>H NMR (DMSO-de) δ 8.76 ( t, J=5Hz, 1H); 7.58 (m, 2H); 7.48 (m, 2H); 7.13 (m, 2H); 6.76 (m, 2H); 6.58 (m, 2H); 5.94 (s, 2H); 5.40 (d, J=16.5Hz, 1H); 5.06 (m, 1H); 4.64 (m, 2H); 3.91 (d, J=16.5Hz, 1H); 3.54 (m, 2H); 2.72 (m, 1H); 2.60 (t, J=8Hz, 2H); 2.50 (m, 1H); MS (ES) m/e 542 (M+H)<+>

Analyse beregnet for C29H27N5O6 • 1,5 H20:Analysis calculated for C29H27N5O6 • 1.5 H20:

C, 61,26; H, 5,32; N, 12,32 C, 61.26; H, 5.32; N, 12.32

Funnet: C, 61,42; H, 5,22; N, 12,25. Found: C, 61.42; H, 5.22; N, 12.25.

Eksempel 52Example 52

Fremstilling av (±)-7-[[[(4(5)-imidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre Preparation of (±)-7-[[[(4(5)-imidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4 -benzodiazepine-2-acetic acid

a) Metyl-(+)-7-[[[(4(5)-imidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat a) Methyl-(+)-7-[[[(4(5)-imidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1 ,4-benzodiazepine-2-acetate

Ved å følge fremgangsmåten i Eksempel 23(a) men med 4(5)-(aminometyl)imidazol (fremstillet ifølge J. Pharm. Sei., 1973, 403) i stedet for 2-(aminometyl)imidazol, og oppvarming av reaksjonsblandingen til 90-100°C i 24 timer, ble tittelforbindelsen (21%) fremstillet: MS (ES) m/e 372 (M+H)<+>b) (±)-7-[[[(4(5)-imidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre By following the procedure in Example 23(a) but with 4(5)-(aminomethyl)imidazole (prepared according to J. Pharm. Sei., 1973, 403) instead of 2-(aminomethyl)imidazole, and heating the reaction mixture to 90-100°C for 24 h, the title compound (21%) was prepared: MS (ES) m/e 372 (M+H)<+>b) (±)-7-[[[(4(5)- imidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid

Ved å følge fremgangsmåten i Eksempel 23(b) ble metyl-(±)-7-[[[(4(5)-imidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat forsåpet for å gi tittelforbindelsen: By following the procedure in Example 23(b), methyl-(±)-7-[[[(4(5)-imidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4 ,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate saponified to give the title compound:

MS (ES) m/e 358 (M+H)<+>MS (ES) m/e 358 (M+H)<+>

Analyse beregnet for Ci7H19N504 • 1,15 CF3C02H • 0,05 H20:Analysis calculated for Ci7H19N504 • 1.15 CF3C02H • 0.05 H20:

C, 47,37; H, 4,17; N, 14,31 C, 47.37; H, 4.17; N, 14.31

Funnet: C, 47,70; H, 3,91; N, 13,92 Found: C, 47.70; H, 3.91; N, 13.92

Eksempel 53Example 53

Fremstilling av (±)-[[[4-(2-fenylimidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre Preparation of (±)-[[[4-(2-phenylimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine- 2-acetic acid

a) 4-aminometyl-2-fenylimidazol-dihydroklorida) 4-aminomethyl-2-phenylimidazole dihydrochloride

Hydroksylamin-hydroklorid (229 mg, 3,3 mmol) ble tilsatt til en suspensjon av Hydroxylamine hydrochloride (229 mg, 3.3 mmol) was added to a suspension of

2-fenylimidazol-4-karboksaldehyd (516 mg, 3 mmol; fremstillet ifølge J. Chem. Soc. Perkin Trans 11974, 1527) og natriumacetat (541 mg, 6,6 mmol) i absolutt EtOH 2-Phenylimidazole-4-carboxaldehyde (516 mg, 3 mmol; prepared according to J. Chem. Soc. Perkin Trans 11974, 1527) and sodium acetate (541 mg, 6.6 mmol) in absolute EtOH

(5 mL) og H20 (5 mL) ved RT. Det oppsto en gul, homogen løsning. Etter 15 minutter ble reaksjonsblandingen konsentrert på rotasjonsfordamper for å fjerne EtOH og den oljaktige, vandige blanding ekstrahert med 20% MeOH/CHCI3 (10 mL) og deretter med CHCI3 (10 mL). De kombinerte organiske lagene ble tørket (MgS04) og konsentrert for å etterlate et gult skum. (5 mL) and H 2 O (5 mL) at RT. A yellow, homogeneous solution was formed. After 15 min, the reaction mixture was concentrated on a rotary evaporator to remove EtOH and the oily, aqueous mixture was extracted with 20% MeOH/CHCl 3 (10 mL) and then with CHCl 3 (10 mL). The combined organic layers were dried (MgSO 4 ) and concentrated to leave a yellow foam.

Det gule skummet ble løst i absolutt EtOH (9 mL) og tilsatt 1,0 N HCI (6 mL, 6 mmol) og 10% Pd/C (0,32 g, 0,3 mmol). Blandingen ble ristet på et Parr-apparat ved RT under H2(3,5 kg/cm<2>) i 4 timer og deretter filtrert gjennom Celite®. Filtratet ble konsentrert på rotasjonsfordamper for å etterlate et lysegult faststoff. Omkrystallisasjon fra absolutt EtOH/H20 ga tittelforbindelsen som et lyst, rosa faststoff (465 mg, 63%): smp. 273-275°C (dekomp.); The yellow foam was dissolved in absolute EtOH (9 mL) and 1.0 N HCl (6 mL, 6 mmol) and 10% Pd/C (0.32 g, 0.3 mmol) were added. The mixture was shaken on a Parr apparatus at RT under H2 (3.5 kg/cm<2>) for 4 hours and then filtered through Celite®. The filtrate was concentrated on a rotary evaporator to leave a pale yellow solid. Recrystallization from absolute EtOH/H 2 O afforded the title compound as a pale pink solid (465 mg, 63%): m.p. 273-275°C (decomp.);

<1>H NMR (250 MHz, CD3OD) 5 7,93-8,12 (m, 2H); 7,80 (s, 1H); 7,50-7,76 (m, 3H); 4,40 (s, 2H); MS (ES) m/e 347,2 (2M+H)<+>, 174,0 (M+H)<+>, 157,0 (M+H-NH3)<+>b) Metyl-(±)-[[[4-(2-fenylimidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat <1>H NMR (250 MHz, CD 3 OD) δ 7.93-8.12 (m, 2H); 7.80 (s, 1H); 7.50-7.76 (m, 3H); 4.40 (s, 2H); MS (ES) m/e 347.2 (2M+H)<+>, 174.0 (M+H)<+>, 157.0 (M+H-NH3)<+>b) Methyl-(± )-[[[4-(2-phenylimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate

EDC (138 mg, 0,72 mmol) ble tilsatt til en løsning av metyl-(±)-7-karboksy-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat (175,4 mg, EDC (138 mg, 0.72 mmol) was added to a solution of methyl-(±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4 -benzodiazepine-2-acetate (175.4 mg,

0,6 mmol), 4-aminometyl-2-fenylimidazol-dihydroklorid (177,2 mg, 0,72 mmol), HOBT H20 (97,3 mg, 0,72 mmol) og diisopropyletylamin (0,52 mL, 3,0 mmol) i vannfritt DMF (3 mL) ved RT. Etter 22 timer ble reaksjonsblandingen konsentrert på 0.6 mmol), 4-aminomethyl-2-phenylimidazole dihydrochloride (177.2 mg, 0.72 mmol), HOBT H 2 O (97.3 mg, 0.72 mmol) and diisopropylethylamine (0.52 mL, 3, 0 mmol) in anhydrous DMF (3 mL) at RT. After 22 hours, the reaction mixture was concentrated

rotasjonsfordamper (høyvakuum) og residuet fordelt mellom H20 og EtOAc. Lagene ble separert og det vandige lag ekstrahert med CHCI3. De organiske lagene ble kombinert, hvilket bevirket at det utskiltes en olje. Denne ble løst ved tilsetning av MeOH. Tørking (MgS04), konsentrering og rekonsentrering fra xylener (for å fjerne DMF) etterlot en gult halvfast residuum. Kromatografi (silikagel, 10% MeOH/CHCI3) ga tittelforbindelsen (230 mg, 86%) som et oljeaktig skum som størknet til et hvitaktig faststoff ved behandling med EtOAc: TLC Rf 0,42 (10% MeOH/CHCI3); rotary evaporator (high vacuum) and the residue partitioned between H 2 O and EtOAc. The layers were separated and the aqueous layer extracted with CHCl 3 . The organic layers were combined, causing an oil to separate. This was resolved by adding MeOH. Drying (MgSO 4 ), concentration and reconcentration from xylenes (to remove DMF) left a yellow semi-solid residue. Chromatography (silica gel, 10% MeOH/CHCl 3 ) gave the title compound (230 mg, 86%) as an oily foam which solidified to an off-white solid on treatment with EtOAc: TLC Rf 0.42 (10% MeOH/CHCl 3 );

<1>H NMR (400 MHz, 10% CD3OD/CDCI3) 8 7,82 (d, J=7,3Hz, 2H); 7,28-7,57 (m, 5H); 7,03 (s, 1H); 6,54 (d, J=8,5Hz, 1H);5,48 (d, J=16,6Hz, 1H); 5,12 (t, J=6,8Hz, 1H); 4,52 (s, 2H); 3,79 (d, J=16,6Hz, 1H); 3,73 (s, 3H); 3,06 (s, 3H); 2,98 (dd, J=16,2, 7,6Hz, 1H); 2,66 (dd, J=16,2, 6,0Hz, 1H); <1>H NMR (400 MHz, 10% CD3OD/CDCl3) δ 7.82 (d, J=7.3Hz, 2H); 7.28-7.57 (m, 5H); 7.03 (s, 1H); 6.54 (d, J=8.5Hz, 1H); 5.48 (d, J=16.6Hz, 1H); 5.12 (t, J=6.8Hz, 1H); 4.52 (s, 2H); 3.79 (d, J=16.6Hz, 1H); 3.73 (s, 3H); 3.06 (s, 3H); 2.98 (dd, J=16.2, 7.6Hz, 1H); 2.66 (dd, J=16.2, 6.0Hz, 1H);

MS (ES) m/e 470,2 (M+Na)<+>, 448,2 (M+H)<+>MS (ES) m/e 470.2 (M+Na)<+>, 448.2 (M+H)<+>

c) (±)-[[[4-(2-fenylimidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre c) (±)-[[[4-(2-phenylimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine- 2-acetic acid

En suspensjon av metyl-(±)-[[[4-(2-fenylimidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat (229,6 mg, A suspension of methyl-(±)-[[[4-(2-phenylimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4 -benzodiazepine-2-acetate (229.6 mg,

0,51 mmol), 10 N LiOH (0,61 mL, 0,61 mmol), THF (2,6 mL) og H20 (2 mL) ble omrørt ved RT. Innen 15 minutter ble det dannet en homogen løsning. Etter 2,5 timer ble reaksjonsblandingen konsentrert til ca. 1 mL og filtrert. En ekstra porsjon H20 0.51 mmol), 10 N LiOH (0.61 mL, 0.61 mmol), THF (2.6 mL) and H 2 O (2 mL) were stirred at RT. Within 15 minutes a homogeneous solution was formed. After 2.5 hours, the reaction mixture was concentrated to approx. 1 mL and filtered. An extra portion of H20

(2 mL) ble benyttet ved filtreringen. Filtratet ble nøytralisert med 1,0 N HCI (0,61 mL) og faststoffet oppsamlet og vasket med H20. Det resulterende faststoff ble utgnidd med varm 1:1 CH3CN/H20, filtrert og vasket suksessivt med CH3CN og H20. Tørking under høyvakuum ga tittelforbindelsen (187,4 mg, 82%) som et farveløst pulver: HPLC k' 1,6 (PRP-1®, 20% CH3CN/H2O-0,1% TFA); (2 mL) was used in the filtration. The filtrate was neutralized with 1.0 N HCl (0.61 mL) and the solid collected and washed with H 2 O. The resulting solid was triturated with hot 1:1 CH 3 CN/H 2 O, filtered and washed successively with CH 3 CN and H 2 O. Drying under high vacuum afforded the title compound (187.4 mg, 82%) as a colorless powder: HPLC k' 1.6 (PRP-1®, 20% CH 3 CN/H 2 O-0.1% TFA);

<1>H NMR (400 MHz, DMSO-d6) 8 8,32-8,47 (m, 1H); 7,90 (d, J=7,5Hz, 2H); 7,51-7,61 (m, 2H); 7,38-7,48 (m, 2H); 7,26-7,36 (m, 1H); 7,01 (br s, 1H); 6,54 (d, J=8,3Hz, 1H); 6,30 (s, 1H); 5,48 (d, J=16,5Hz, 1H); 5,02-5,12 (m, 1H); 4,38 (brs, 2H); 3,81 (d, J=16,5Hz, 1H); 2,91 (s, 3H); 2,76 (dd, J=16,7, 9,1Hz, 1H); 2,54 (dd, J=16,7, 4,9Hz, 1H, delvis skjult av signal fra gjenværende løsningsmiddel); <1>H NMR (400 MHz, DMSO-d6) δ 8.32-8.47 (m, 1H); 7.90 (d, J=7.5Hz, 2H); 7.51-7.61 (m, 2H); 7.38-7.48 (m, 2H); 7.26-7.36 (m, 1H); 7.01 (br s, 1H); 6.54 (d, J=8.3Hz, 1H); 6.30 (s, 1H); 5.48 (d, J=16.5Hz, 1H); 5.02-5.12 (m, 1H); 4.38 (brs, 2H); 3.81 (d, J=16.5Hz, 1H); 2.91 (s, 3H); 2.76 (dd, J=16.7, 9.1Hz, 1H); 2.54 (dd, J=16.7, 4.9Hz, 1H, partially obscured by signal from residual solvent);

MS (ES) m/e 434,2 (M+H)<+>MS (ES) m/e 434.2 (M+H)<+>

Analyse beregnet for C23H23N504• 0,75 H20:Analysis calculated for C23H23N504• 0.75 H20:

C, 61,81; H, 5,52; N, 15,67 C, 61.81; H, 5.52; N, 15.67

Funnet: C, 62,05; H, 5,44; N, 15,59 Found: C, 62.05; H, 5.44; N, 15.59

5Eksempel 545Example 54

Fremstilling av (+)-7-[[[2-(3-indolyl)etyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre Preparation of (+)-7-[[[2-(3-indolyl)ethyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4- benzodiazepine-2-acetic acid

a) Metyl-(±)-7-[[[2-(3-indolyl)etyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat3Ved å følge fremgangsmåten i Eksempel 26(d) men med 3-(2-aminoetyl)indol i stedet for 1-metyl-2-(metylamino)metylindol, ble tittelforbindelsen fremstillet (50%); a) Methyl-(±)-7-[[[2-(3-indolyl)ethyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1, 4-benzodiazepine-2-acetate3 Following the procedure of Example 26(d) but with 3-(2-aminoethyl)indole instead of 1-methyl-2-(methylamino)methylindole, the title compound was prepared (50%);

MS (ES) m/e 435,2 (M+H)<+>MS (ES) m/e 435.2 (M+H)<+>

b) (±)-7-[[[2-(3-indolyl)etyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-b) (±)-7-[[[2-(3-indolyl)ethyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-

51 H-1,4-benzodiazepin-2-eddiksyre51 H-1,4-benzodiazepine-2-acetic acid

Ved å følge fremgangsmåten i Eksempel 26(e) ble metyl-(±)-7-[[[2-(3-indolyl)etyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat forsåpet for å gi tittelforbindelsen som et farveløst faststoff: By following the procedure in Example 26(e), methyl-(±)-7-[[[2-(3-indolyl)ethyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4, 5-tetrahydro-1H-1,4-benzodiazepine-2-acetate saponified to give the title compound as a colorless solid:

MS (ES) m/e 421,0 (M+H)<+>MS (ES) m/e 421.0 (M+H)<+>

) Analyse beregnet for C23H24N404• 1,3 H20:) Analysis calculated for C23H24N404• 1.3 H20:

C, 62,24; H, 6,04; N, 12,24 C, 62.24; H, 6.04; N, 12,24

Funnet: C, 62,31; H, 5,61; N, 12,04 Found: C, 62.31; H, 5.61; N, 12.04

Eksempel 55Example 55

> Fremstilling av (S)-7-[[[2-(4-fenylimidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre > Preparation of (S)-7-[[[2-(4-phenylimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4- benzodiazepine-2-acetic acid

a) Metyl-(S)-7-[[[2-(4-fenylimidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat a) Methyl-(S)-7-[[[2-(4-phenylimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1, 4-benzodiazepine-2-acetate

Ved å følge fremgangsmåten i Eksempel 23(a) men med 2-(aminometyl)-4-By following the procedure in Example 23(a) but with 2-(aminomethyl)-4-

) fenylimidazol (Aust. J. Chem. 1971, 24, 2389) i stedet for 2-(aminometyl)imidazol, ) phenylimidazole (Aust. J. Chem. 1971, 24, 2389) instead of 2-(aminomethyl)imidazole,

ble tittelforbindelsen fremstillet: MS (ES) m/e 448 (M+H)<+>the title compound was prepared: MS (ES) m/e 448 (M+H)<+>

b) (S)-7-[[[2-(4-fenylimidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre b) (S)-7-[[[2-(4-phenylimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4- benzodiazepine-2-acetic acid

Ved å følge fremgangsmåten i Eksempel 23(b) ble metyl-(S)-7-[[[2-(4-fenylimidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-acetat forsåpet for å gi tittelforbindelsen: By following the procedure in Example 23(b), methyl-(S)-7-[[[2-(4-phenylimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4, 5-tetrahydro-1H-1,4-benzodiazepine-2-acetate saponified to give the title compound:

MS (ES) m/e 434 (M+H)<+>MS (ES) m/e 434 (M+H)<+>

Analyse beregnet for C23H23N504• 0,5 CF3C02H • 0,5 HCI • 1,75 H20:Analysis calculated for C23H23N504• 0.5 CF3C02H • 0.5 HCI • 1.75 H20:

C, 47,01; H, 4,80; N, 11,42 C, 47.01; H, 4.80; N, 11.42

Funnet: C, 47,14; H, 4,17; N, 11,51 Found: C, 47.14; H, 4.17; N, 11.51

Eksemplene 56-75Examples 56-75

Ved å følge de generelle fremgangsmåter i Eksempel 1-55, ble følgende forbindelser fremstillet. 56. (+/-)-2,3,4,5-tetrahydro-7-[[[benzimidazol-2-yl)metyl]metylamino]karbonyl]-4-(3,3-dimetylbutyl)-3-okso-1 H-1,4-benzodiazepin-2-eddiksyre; 57. (-)-7-[[[6-trifluormetylbenzimidazolyl-2-ylmetyl]aminometyl]karbonyl)-2,3,4,5-tetrahydro-4-metyl-3-okso-benzodiazepin-2-eddiksyre, 58. (-)-7-[[[4,7-dimetoksybenzimidazolyl-2-ylmetyl]aminometyl]karbonyl]-2,3,4,5-tetrahydro-4-metyl-3-okso-benzodiazepin-2-eddiksyre; 59. (+/-)-2,3,4,5-tetrahydro-7-[[[(benzimidazol-2-yl)metylamino]karbonyl]-4-3,3-dimetylbutyl-3-okso-1 H-1,4-benzodiazepin-2-eddiksyre; 60. (-)-7-[[[7-metylbenzimidazol-2-ylmetyl]metylamino]karbonyl]-2,3,4,5-tetrahydro-4-metyl-3-okso-1,4-benzodiazepin-2-eddiksyre; 61. (2S)-[[[N-aminobutyl-N-(benzimidazol-2-yl)metyl]amino]karbonyl]-3-okso-4-metyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre-bis(trifluoracetat)salt; 62. (2S)-[[[N-cyanometyl-N-(benzimidazol-2-yl)metyl]amino]karbonyl]-3-okso-4-metyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre-dihydroklorid-salt; 63. (S)-2,3,4,5-tetrahydro-7-[[[(benzimidazol-2-yl)metyl]amino]karbonyl]-4-(4-ftalimidobutyl)-3-okso-1,4-benzodiazepin-2-eddiksyre; 64. (-)-7-[[[imidazo[4,5-b]-4,6-dimetylpyridyl-2-ylmetyl]aminometyl]karbonyl]-2,3,4,5-tetrahydro-4-metyl-3-okso-benzodiazepin-2-eddiksyre-trifluoracetatsalt; 65. (+/-)-7-[[(2-benzimidazol-2-ylmetyl)-N-metylamino]karbonyl]-2,3,4,5-tetrahydro-3-okso-4-[2-(3'l4'-metylendioksyfenyl)etyl]-1H-1,4-benzodiazepin-2-eddiksyre; 66. (+/-)-2,3,4,5-tetrahydro-7-[[[(benzimidazol-2-yl)metyl]amino]karbonyl]-4-(2-metoksyetyl)-3-okso-1 H-1,4-benzodiazepin-2-eddiksyre; 67. (S)-7-[[2-[1-metylbenzimidazolyl]benzimidazolylmetylamino]karbonyl]-2,3,4,5-tetrahydro-4-metyl-3-okso-1 H-1,4-benzodiazepin-2-eddiksyre; 68. (S)-7-[[[N-cykloheksyl-N-(benzimidazol-2-yl)metyl]amino]karbonyl]-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; 69. (S)-7-[[[2-bis-(benzimidazolylmetyl)aminokarbonyl]-2,3,4,5-tetrahydro-4-metyl-3-okso-1 H-1,4-benzodiazepin-2-eddiksyre; 70. (+/-)-2,3,4,5-tetrahydro-7-[[[imidazo[4,5-b]pyrid-2-yl]metyl]metylamino]-karbonyl]-4-(3,3-dimetylbutyl)-3-okso-1H-1,4-benzodiazepin-2-eddiksyre; 71. (+/-)-7-[[(2-benzimidazol-2-ylmetyl)-N-metylamino]karbonyl-2,3,4,5-tetrahydro-3- okso-4-(2',2',2'-trifluoretyl)-1H-1,4-benzodiazepin-2-eddiksyre; 72. (+/-)-7-[[(2-benzimidazolyl)acetyl]amino]-5-okso-4-(2-fenyletyl)-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; 73. (+/-)-7-[[(2-benzimidazol-2-ylmetyl)amino]karbonyl]-2,3,415-tetrahydro-3-okso-4- (2',2',2,-trifluoretyl)-1 H-1,4-benzodiazepin-2-eddiksyre; 74. (-)-7-[[[5,6-difluorbenzimidazolyl-2-ylmetyl]aminometyl]karbonyl]-2,3,4,5-tetrahydro-4-metyl-3-okso-1,4-benzodiazepin-2-eddiksyre; og 75. (+/-)-7-[[bis-(benzimidazol-2-ylmetyl)amino]karbonyl]-2,3,4,5-tetrahydro-4-fenyletyl-3-okso-1H-1,4-benzodiazepin-2-eddiksyre-tris(trifluoracetat)salt. By following the general procedures of Examples 1-55, the following compounds were prepared. 56. (+/-)-2,3,4,5-tetrahydro-7-[[[benzimidazol-2-yl)methyl]methylamino]carbonyl]-4-(3,3-dimethylbutyl)-3-oxo- 1 H-1,4-benzodiazepine-2-acetic acid; 57. (-)-7-[[[6-trifluoromethylbenzimidazolyl-2-ylmethyl]aminomethyl]carbonyl)-2,3,4,5-tetrahydro-4-methyl-3-oxo-benzodiazepine-2-acetic acid, 58. (-)-7-[[[4,7-dimethoxybenzimidazolyl-2-ylmethyl]aminomethyl]carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-benzodiazepine-2-acetic acid; 59. (+/-)-2,3,4,5-tetrahydro-7-[[[(benzimidazol-2-yl)methylamino]carbonyl]-4-3,3-dimethylbutyl-3-oxo-1 H- 1,4-benzodiazepine-2-acetic acid; 60. (-)-7-[[[7-methylbenzimidazol-2-ylmethyl]methylamino]carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1,4-benzodiazepine-2- acetic acid; 61. (2S)-[[[N-aminobutyl-N-(benzimidazol-2-yl)methyl]amino]carbonyl]-3-oxo-4-methyl-2,3,4,5-tetrahydro-1H-1 ,4-benzodiazepine-2-acetic acid bis(trifluoroacetate) salt; 62. (2S)-[[[N-cyanomethyl-N-(benzimidazol-2-yl)methyl]amino]carbonyl]-3-oxo-4-methyl-2,3,4,5-tetrahydro-1H-1 ,4-benzodiazepine-2-acetic acid dihydrochloride salt; 63. (S)-2,3,4,5-tetrahydro-7-[[[(benzimidazol-2-yl)methyl]amino]carbonyl]-4-(4-phthalimidobutyl)-3-oxo-1,4 -benzodiazepine-2-acetic acid; 64. (-)-7-[[[imidazo[4,5-b]-4,6-dimethylpyridyl-2-ylmethyl]aminomethyl]carbonyl]-2,3,4,5-tetrahydro-4-methyl-3 -oxo-benzodiazepine-2-acetic acid trifluoroacetate salt; 65. (+/-)-7-[[(2-benzimidazol-2-ylmethyl)-N-methylamino]carbonyl]-2,3,4,5-tetrahydro-3-oxo-4-[2-(3 '14'-methylenedioxyphenyl)ethyl]-1H-1,4-benzodiazepine-2-acetic acid; 66. (+/-)-2,3,4,5-tetrahydro-7-[[[(benzimidazol-2-yl)methyl]amino]carbonyl]-4-(2-methoxyethyl)-3-oxo-1 H-1,4-benzodiazepine-2-acetic acid; 67. (S)-7-[[2-[1-methylbenzimidazolyl]benzimidazolylmethylamino]carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2 -acetic acid; 68. (S)-7-[[[N-cyclohexyl-N-(benzimidazol-2-yl)methyl]amino]carbonyl]-3-oxo-2,3,4,5-tetrahydro-1 H-1, 4-benzodiazepine-2-acetic acid; 69. (S)-7-[[[2-bis-(benzimidazolylmethyl)aminocarbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2- acetic acid; 70. (+/-)-2,3,4,5-tetrahydro-7-[[[imidazo[4,5-b]pyrid-2-yl]methyl]methylamino]-carbonyl]-4-(3, 3-dimethylbutyl)-3-oxo-1H-1,4-benzodiazepine-2-acetic acid; 71. (+/-)-7-[[(2-benzimidazol-2-ylmethyl)-N-methylamino]carbonyl-2,3,4,5-tetrahydro-3-oxo-4-(2',2' ,2'-trifluoroethyl)-1H-1,4-benzodiazepine-2-acetic acid; 72. (+/-)-7-[[(2-benzimidazolyl)acetyl]amino]-5-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4 -benzodiazepine-2-acetic acid; 73. (+/-)-7-[[(2-benzimidazol-2-ylmethyl)amino]carbonyl]-2,3,415-tetrahydro-3-oxo-4-(2',2',2,-trifluoroethyl) -1 H-1,4-benzodiazepine-2-acetic acid; 74. (-)-7-[[[5,6-difluorobenzimidazolyl-2-ylmethyl]aminomethyl]carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1,4-benzodiazepine- 2-acetic acid; and 75. (+/-)-7-[[bis-(benzimidazol-2-ylmethyl)amino]carbonyl]-2,3,4,5-tetrahydro-4-phenylethyl-3-oxo-1H-1,4 -benzodiazepine-2-acetic acid-tris(trifluoroacetate) salt.

Eksempel 76 «Example 76 «

Fremstilling av 4-[2-[[[1 -[(benzimidazol-2-yl)metyl]benzimidazol-2-yl]metyl]metylamino]acetyl]fenoksy-eddiksyre Preparation of 4-[2-[[[1 -[(benzimidazol-2-yl)methyl]benzimidazol-2-yl]methyl]methylamino]acetyl]phenoxy-acetic acid

a) 4-[2-(BOC-metylamino)acetyl]fenola) 4-[2-(BOC-methylamino)acetyl]phenol

En løsning av di-tert-butyldikarbonat (5,96 g, 27,3 mmol) i 1,4-dioksanA solution of di-tert-butyl dicarbonate (5.96 g, 27.3 mmol) in 1,4-dioxane

(25 mL) ble ved 0°C dråpevis tilsatt til en blanding av 4-[2-(metylamino)acetyl]fenol-hydroklorid (5,0 g, 24,8 mmol), 1,4-dioksan (30 mL), H20 (25 mL) og 1,0 N NaOH (25 mL, 25 mmol). Etter 24 timer ble reaksjonsblandingen oppvarmet til RT og (25 mL) was added dropwise at 0°C to a mixture of 4-[2-(methylamino)acetyl]phenol hydrochloride (5.0 g, 24.8 mmol), 1,4-dioxane (30 mL), H 2 O (25 mL) and 1.0 N NaOH (25 mL, 25 mmol). After 24 h, the reaction mixture was warmed to RT and

omrørt i 1,5 timer til. Mer 1,0 N NaOH (25 mL, 25 mmol) ble tilsatt og reaksjonsblandingen omrørt i ytterligere 0,5 timer ved RT, hvorpå den ble inndampet på rotasjonsfordamper. Residuet ble fortynnet med EtOAc (80 mL) og blandingen surgjort til pH 2 ved bruk av 1,0 M NaHS04. Den resulterende blanding ble ekstrahert med EtOAc og de kombinerte organiske lagene vasket med H20 og tørket (Na2S04). Filtrering og konsentrering ga tittelforbindelsen (6,49 g, 99%):<1>H NMR (250 MHz, CDCI3) 5 6,70-8,05 (m, 4H); 4,53 (s, 2H); 2,98 (s, 3H); 1,50 (s, 9H). stirred for another 1.5 hours. More 1.0 N NaOH (25 mL, 25 mmol) was added and the reaction mixture was stirred for an additional 0.5 h at RT, after which it was evaporated on a rotary evaporator. The residue was diluted with EtOAc (80 mL) and the mixture acidified to pH 2 using 1.0 M NaHSO 4 . The resulting mixture was extracted with EtOAc and the combined organic layers washed with H 2 O and dried (Na 2 SO 4 ). Filtration and concentration gave the title compound (6.49 g, 99%):<1>H NMR (250 MHz, CDCl 3 ) δ 6.70-8.05 (m, 4H); 4.53 (s, 2H); 2.98 (s, 3H); 1.50 (p, 9H).

b) Benzyl-4-[2-(BOC-metylamino)acetyl]fenoksyacetatb) Benzyl 4-[2-(BOC-methylamino)acetyl]phenoxyacetate

En blanding av 4-[2-(BOC-metylamino)acetyl]fenol (5,04 g, 19,0 mmol) og A mixture of 4-[2-(BOC-methylamino)acetyl]phenol (5.04 g, 19.0 mmol) and

K2C03(2,63 g, 19,0 mmol) i aceton (100 mL) ble omrørt under tilbakeløpskjøling under argon i 1 time. Blandingen ble avkjølt til RT og tilsatt benzylbromacetat (5,23 g, 22,8 mmol). Reaksjonsblandingen ble kokt under tilbakeløpskjøling i 18 timer og deretter avkjølt og filtrert. Filterkaken ble vasket med aceton og filtratet konsentrert på rotasjonsfordamper. Residuet ble løst i CH2CI2(300 mL) og vasket med H20 (50 mL) og deretter med saltvann (50 mL). Tørking (Na2S04), konsentrering og hurtigkromatografi (silikagel, 1:3 EtOAc/heksaner) førte til tittelforbindelsen (7,28 g, 93%); K 2 CO 3 (2.63 g, 19.0 mmol) in acetone (100 mL) was stirred under reflux under argon for 1 h. The mixture was cooled to RT and benzyl bromoacetate (5.23 g, 22.8 mmol) was added. The reaction mixture was refluxed for 18 hours and then cooled and filtered. The filter cake was washed with acetone and the filtrate concentrated on a rotary evaporator. The residue was dissolved in CH 2 Cl 2 (300 mL) and washed with H 2 O (50 mL) and then with brine (50 mL). Drying (Na 2 SO 4 ), concentration and flash chromatography (silica gel, 1:3 EtOAc/hexanes) afforded the title compound (7.28 g, 93%);

<1>H NMR (250 MHz, CDCI3) 5 6,85-7,95 (m, 9H); 5,23 (s, 2H); 4,71 (s, 2H); 4,55 (d, 2H); 2,95 (d, 3H); 1,45 (d, 9H) <1>H NMR (250 MHz, CDCl 3 ) δ 6.85-7.95 (m, 9H); 5.23 (s, 2H); 4.71 (s, 2H); 4.55 (d, 2H); 2.95 (d, 3H); 1.45 (d, 9H)

c) Benzyl-4-[2-(metylamino)acetyl]fenoksyacetat-hydrokloridc) Benzyl 4-[2-(methylamino)acetyl]phenoxyacetate hydrochloride

En blanding av benzyl-4-[2-(BOC-metylamino)acetyl]fenoksyacetat (7,26 g, A mixture of benzyl 4-[2-(BOC-methylamino)acetyl]phenoxyacetate (7.26 g,

17,57 mmol) og 4 M HCI i 1,4-dioksan (150 mL) ble omrørt i 1 time ved RT. Inndampning på rotasjonsfordamper og utgnidning med Et20 førte til tittelforbindelsen som et hvitt pulver (5,93 g, 97%); 17.57 mmol) and 4 M HCl in 1,4-dioxane (150 mL) were stirred for 1 h at RT. Evaporation on a rotary evaporator and trituration with Et 2 O gave the title compound as a white powder (5.93 g, 97%);

<1>H NMR (250 MHz, CD3OD) 5 7,05-8,00 (m, 9H); 5,23 (s, 2H); 4,88 (s, 2H); 4,65 (s, 2H); 2,80 (s, 3H) <1>H NMR (250 MHz, CD 3 OD) δ 7.05-8.00 (m, 9H); 5.23 (s, 2H); 4.88 (s, 2H); 4.65 (s, 2H); 2.80 (s, 3H)

d) Benzyl-4-[2-[[[1 -[(benzimidazol-2-yl)metyl]benzimidazol-2-yl]metyl]metylamino]-acetyl]fenoksyacetat d) Benzyl-4-[2-[[[1-[(benzimidazol-2-yl)methyl]benzimidazol-2-yl]methyl]methylamino]acetyl]phenoxyacetate

Et3N (0,28 g, 2,78 mmol) ble langsomt tilsatt til en blanding av benzyl-4-[2-(metylamino)acetyl]fenoksyacetat-hydroklorid (0,39 g, 1,11 mmol), 2-(klormetyl)benzimidazol (0,24 g, 1,45 mmol), CH3CN (20 mL) og CH2CI2(5 mL) ved RT under argon. Etter 5 timer ble reaksjonsblandingen konsentrert på rotasjonsfordamper. Residuet ble løst i CH2CI2og vasket med 5% NaHC03og deretter med saltvann. Tørking (MgS04), konsentrering og hurtigkromatografi (silikagel, trinnvis gradient, 7-15% MeOH/CH2CI2) førte til tittelforbindelsen som et hvitaktig pulver (0,08 g, 12%): MS (ES) m/e 574,2 [M+H]<+>e) 4-[2-[[[1-[(benzimidazol-2-yl)metyl]benzimidazol-2-yl]metyl]metylamino]-acetyljfenoksy-eddiksyre Et3N (0.28 g, 2.78 mmol) was slowly added to a mixture of benzyl 4-[2-(methylamino)acetyl]phenoxyacetate hydrochloride (0.39 g, 1.11 mmol), 2-(chloromethyl )benzimidazole (0.24 g, 1.45 mmol), CH 3 CN (20 mL) and CH 2 Cl 2 (5 mL) at RT under argon. After 5 hours, the reaction mixture was concentrated on a rotary evaporator. The residue was dissolved in CH 2 Cl 2 and washed with 5% NaHCO 3 and then with brine. Drying (MgSO 4 ), concentration and flash chromatography (silica gel, stepwise gradient, 7-15% MeOH/CH 2 Cl 2 ) afforded the title compound as an off-white powder (0.08 g, 12%): MS (ES) m/e 574.2 [ M+H]<+>e) 4-[2-[[[1-[(benzimidazol-2-yl)methyl]benzimidazol-2-yl]methyl]methylamino]-acetyljphenoxy-acetic acid

En blanding av benzyl-4-[2-[[[1-[(benzimidazol-2-yl)metyl]benzimidazol-2-yl]metyl]metylamino]acetyl]fenoksyacetat (0,08 g, 0,18 mmol) og 5% Pd/C (0,11 g) i MeOH (15 mL) ble ristet på et Parr-apparat under H2(2,9 kg/cm<2>) i 1 time. Blandingen ble filtrert gjennom et lag av Celite® og filterlaget vasket med iseddik og MeOH. Filtratet ble konsentrert for å gi råproduktet (0,07 g). Preparativ HPLC (Hamilton PRP-1® kolonne, trinnvis gradient, 10-30% CH3CN/H2O-0,1% TFA) førte til tittelforbindelsen: MS (ES) m/e 484,2 [M+H]<+>A mixture of benzyl 4-[2-[[[1-[(benzimidazol-2-yl)methyl]benzimidazol-2-yl]methyl]methylamino]acetyl]phenoxyacetate (0.08 g, 0.18 mmol) and 5% Pd/C (0.11 g) in MeOH (15 mL) was shaken on a Parr apparatus under H2 (2.9 kg/cm<2>) for 1 hour. The mixture was filtered through a layer of Celite® and the filter layer washed with glacial acetic acid and MeOH. The filtrate was concentrated to give the crude product (0.07 g). Preparative HPLC (Hamilton PRP-1® column, stepwise gradient, 10-30% CH3CN/H2O-0.1% TFA) led to the title compound: MS (ES) m/e 484.2 [M+H]<+>

Analyse beregnet for C27H25N504 • 3 C2HF302:Analysis calculated for C27H25N504 • 3 C2HF302:

C, 48,01; H, 3,42; N, 8,48 C, 48.01; H, 3.42; N, 8.48

Funnet: C, 48,40; H, 3,72; N, 8,77 Found: C, 48.40; H, 3.72; N, 8.77

Eksempel 77 Example 77

(±)-4-[[2-[(benzimidazol-2-yl)metyl]metylamino]-1-hydroksyetyl]-1,2-fenylendioksy-dieddiksyre (±)-4-[[2-[(benzimidazol-2-yl)methyl]methylamino]-1-hydroxyethyl]-1,2-phenylenedioxydiacetic acid

a) N-Cbz-adrenalona) N-Cbz-adrenalone

Adrenalon-hydroklorid (28,6 g, 0,121 mol) ble tilsatt til 2,0 N NaOH (200 mL, Adrenalone hydrochloride (28.6 g, 0.121 mol) was added to 2.0 N NaOH (200 mL,

0,2 mol) som først var avkjølt til 5°C i et isbad. 2,0 N NaOH (60 mL, 0,06 mol) i en dråpetrakt og en løsning av benzylklorformiat (17,3 mL, 0,121 mol) i toluen (18 mL) i en annen dråpetrakt, ble tilsatt med en slik hastighet at reaksjonstemperaturen holdt 0.2 mol) which had first been cooled to 5°C in an ice bath. 2.0 N NaOH (60 mL, 0.06 mol) in a dropping funnel and a solution of benzyl chloroformate (17.3 mL, 0.121 mol) in toluene (18 mL) in another dropping funnel were added at such a rate that the reaction temperature held

seg ved 5-10°C og slik at begge tilsetningene ble fullført samtidig. Den resulterende brune løsningen ble omrørt ved 5°C i 75 minutter og ble deretter fortynnet med H20 (230 mL) og surgjort med 1,0 N HCI (536 mL). Det ble første dannet et gummiaktig bunnfall som gikk over i fast tilstand ved utgniding med en glasstav etterfulgt av omrøring i 30 minutter. Det blekgrønne faststoff ble frafiltert, kort omrørt med H20, filtrert, kort omrørt med EtOH og filtrert. Det resulterende faststoff ble malt i en morter med mer EtOH og deretter filtrert og tørket i vakuum for å gi tittelforbindelsen (28,6 g, 75%), smp., 183-186°C themselves at 5-10°C and so that both additions were completed simultaneously. The resulting brown solution was stirred at 5°C for 75 min and was then diluted with H 2 O (230 mL) and acidified with 1.0 N HCl (536 mL). A gummy precipitate first formed which solidified by rubbing with a glass rod followed by stirring for 30 minutes. The pale green solid was filtered off, briefly stirred with H 2 O, filtered, briefly stirred with EtOH and filtered. The resulting solid was ground in a mortar with more EtOH and then filtered and dried in vacuo to give the title compound (28.6 g, 75%), mp 183-186°C

b) Dimetyl-4-[2-(Cbz-metylamino)acetyl]-1,2-fenylendioksyacetatb) Dimethyl-4-[2-(Cbz-methylamino)acetyl]-1,2-phenylenedioxyacetate

En blanding av N-Cbz-adrenalon (23,6g, 74,8 mmol), aceton (340 mL) og A mixture of N-Cbz-adrenalone (23.6g, 74.8 mmol), acetone (340 mL) and

vannfritt K2C03(21,0 g, 152 mmol) ble kokt under tilbakeløpskjøling under argon. Etter 70 minutter ble den beige suspensjonen avkjølt til RT og tilsatt metylbromacetat (17,9 ml, 189 mmol). Den resulterende suspensjon ble omrørt ved RT under argon i 16 timer, deretter oppvarmet til 50°C. Etter 6 timer ble blandingen avkjølt til RT og filtrert og filtratet konsentrert til tørrhet. Residuet ble løst i CH2CI2og vasket med H20 og deretter med 5% K2C03. Tørking (Na2S04) og konsentrering ga tittelforbindelsen som en olje som størknet ved henstand (26,35 g, 82%); smp. 56-59°C. anhydrous K 2 CO 3 (21.0 g, 152 mmol) was refluxed under argon. After 70 minutes, the beige suspension was cooled to RT and methyl bromoacetate (17.9 mL, 189 mmol) was added. The resulting suspension was stirred at RT under argon for 16 h, then heated to 50°C. After 6 h the mixture was cooled to RT and filtered and the filtrate concentrated to dryness. The residue was dissolved in CH 2 Cl 2 and washed with H 2 O and then with 5% K 2 CO 3 . Drying (Na 2 SO 4 ) and concentration gave the title compound as an oil which solidified on standing (26.35 g, 82%); m.p. 56-59°C.

c) Dimetyl-4-[2-(metylamino)-1 -hydroksyetyl]-1,2-fenylendioksydiacetatc) Dimethyl-4-[2-(methylamino)-1-hydroxyethyl]-1,2-phenylenedioxydiacetate

Ved å følge fremgangsmåten i Eksempel 76(e) men med dimetyl-4-[2-(Cbz-metylamino)acetyl]-1,2-fenylendioksydiacetat (2,1 g, 4,57 mmol) i stedet for benzyl-4-[2-[[[1-[(benzimidazol-2-yl)metyl]benzimidazol-2-yl]metyl]metylamino]-acetyljfenoksyacetat og benytte EtOAc (50 mL) og MeOH (20 mL) som løsningsmidler, ble tittelforbindelsen (1,34 g, 90%) fremstillet: By following the procedure of Example 76(e) but with dimethyl-4-[2-(Cbz-methylamino)acetyl]-1,2-phenylenedioxydiacetate (2.1 g, 4.57 mmol) instead of benzyl-4- [2-[[[1-[(benzimidazol-2-yl)methyl]benzimidazol-2-yl]methyl]methylamino]-acetylphenoxyacetate and using EtOAc (50 mL) and MeOH (20 mL) as solvents, the title compound (1 .34 g, 90%) produced:

MS (ES) m/e 328,0 [M+H]<+>MS (ES) m/e 328.0 [M+H]<+>

d) Dimetyl-(±)-4-[[2-[(benzimidazol-2-yl)metyl]metylamino]-1 -hydroksyetyl]-1,2-fenylendioksydiacetat d) Dimethyl-(±)-4-[[2-[(benzimidazol-2-yl)methyl]methylamino]-1-hydroxyethyl]-1,2-phenylenedioxydiacetate

Ved å følge fremgangsmåten i Eksempel 76(d) men med dimetyl-4-[2-(metylamino)-1-hydroksyetyl]-1,2-fenylendioksydiacetat (1,37 g, 4,20 mmol) i stedet for benzyl-4-[2-(metylamino)acetyl]fenoksyacetat-hydroklorid, ble tittelforbindelsen fremstillet (0,25 g, 13%): MS (ES) m/e 458,2 [M+H]<+>e) (±)-4-[[2-[(benzimidazol-2-yl)metyl]metylamino]-1 -hydroksyetyl]-1,2-fenylendioksydieddiksyre By following the procedure of Example 76(d) but with dimethyl-4-[2-(methylamino)-1-hydroxyethyl]-1,2-phenylenedioxydiacetate (1.37 g, 4.20 mmol) instead of benzyl-4 -[2-(methylamino)acetyl]phenoxyacetate hydrochloride, the title compound was prepared (0.25 g, 13%): MS (ES) m/e 458.2 [M+H]<+>e) (±)- 4-[[2-[(benzimidazol-2-yl)methyl]methylamino]-1-hydroxyethyl]-1,2-phenylenedioxydiacetic acid

En blanding av dimetyl-(±)-4-[[2-[(benzimidazol-2-yl)metyl]metylamino]-1-hydroksyetyl]-1,2-fenylendioksydiacetat (0,23 g, 0,5 mmol), THF (10 mL), H20 A mixture of dimethyl-(±)-4-[[2-[(benzimidazol-2-yl)methyl]methylamino]-1-hydroxyethyl]-1,2-phenylenedioxydiacetate (0.23 g, 0.5 mmol), THF (10 mL), H 2 O

(10 mL) og 1,0 N LiOH (2,0 mL, 2,0 mmol) ble omrørt ved RT i 26 timer. Reaksjonsblandingen ble konsentrert på rotasjonsfordamper og det vandige residuum surgjort med 1,0 N AcOH (2 mL) under avkjøling i et isbad. Den resulterende blanding ble lyofilisert for å gi råproduktet (0,32 g). Preparativ HPLC (Hamilton PRP-1® kolonne, 10% CH3CN/H2O-0,1% TFA) førte til tittelforbindelsen: MS (ES) m/e 430,2 [M+H]<+>(10 mL) and 1.0 N LiOH (2.0 mL, 2.0 mmol) were stirred at RT for 26 h. The reaction mixture was concentrated on a rotary evaporator and the aqueous residue acidified with 1.0 N AcOH (2 mL) while cooling in an ice bath. The resulting mixture was lyophilized to give the crude product (0.32 g). Preparative HPLC (Hamilton PRP-1® column, 10% CH3CN/H2O-0.1% TFA) led to the title compound: MS (ES) m/e 430.2 [M+H]<+>

Analyse beregnet for C2iH23N307 • 7/2 C2HF302:Analysis calculated for C2iH23N307 • 7/2 C2HF302:

C, 39,73; H, 3,39; N, 4,97 C, 39.73; H, 3.39; N, 4.97

Funnet: C, 39,47; H, 3,38; N, 4,86 Found: C, 39.47; H, 3.38; N, 4.86

Eksempel 78 Example 78

4-[2-[[(benzimidazol-2-yl)metyl]metylamino]acetyl]-1,2-fenylendioksy-dieddiksyre 4-[2-[[(benzimidazol-2-yl)methyl]methylamino]acetyl]-1,2-phenylenedioxydiacetic acid

a) 1-BOC-2-metylbenzimidazola) 1-BOC-2-methylbenzimidazole

En blanding av 2-metylbenzimidazol (1,5 g, 11,35 mmol), Et3N (1,66 mL, A mixture of 2-methylbenzimidazole (1.5 g, 11.35 mmol), Et3N (1.66 mL,

11,92 mmol), DMAP (0,20 g, 1,6 mmol) og (BOC)20 (2,60 g, 11,92 mmol) i vannfritt CH2CI2(15 mL) ble omrørt ved RT i 24 timer og deretter konsentrert. Residuet ble tatt opp i H20, omrørt og filtrert for å gi tittelforbindelsen som et farveløst faststoff (2,63 g, 100%): smp. 71-72°C. 11.92 mmol), DMAP (0.20 g, 1.6 mmol) and (BOC) 2 O (2.60 g, 11.92 mmol) in anhydrous CH 2 Cl 2 (15 mL) were stirred at RT for 24 h and then concentrated. The residue was taken up in H 2 O, stirred and filtered to give the title compound as a colorless solid (2.63 g, 100%): m.p. 71-72°C.

b) 1 -BOC-2-(brommetyl)benzimidazolb) 1-BOC-2-(bromomethyl)benzimidazole

NBS (8,43 g, 47,4 mmol) og AIBN (2,1 g, 12,8 mmol) ble tilsatt til en løsning NBS (8.43 g, 47.4 mmol) and AIBN (2.1 g, 12.8 mmol) were added to a solution

av 1-BOC-2-metylbenzimidazol (10,0 g, 43,1 mmol) i CCI4(120 mL) under tilbakeløpskjøling. Etter 21 timer ble reaksjonsblandingen avkjølt og filtrert. Filtratet of 1-BOC-2-methylbenzimidazole (10.0 g, 43.1 mmol) in CCI 4 (120 mL) under reflux. After 21 hours, the reaction mixture was cooled and filtered. The filtrate

ble konsentrert og den resulterende brune olje kromatografert (silikagel, 15% EtOAc/heksaner) for å gi tittelforbindelsen:<1>H NMR (400 MHz, CDCI3) 5 7,94-8,01 (m, 1H); 7,70-7,75 (m, 1H); 7,31-7,44 (m, 2H); 4,96 (s,2H); 1,75 (s,9H) was concentrated and the resulting brown oil chromatographed (silica gel, 15% EtOAc/hexanes) to give the title compound:<1>H NMR (400 MHz, CDCl 3 ) δ 7.94-8.01 (m, 1H); 7.70-7.75 (m, 1H); 7.31-7.44 (m, 2H); 4.96 (s, 2H); 1.75 (p.9H)

c) 4-[2-(BOC-metylamino)acetyl]-1,2-dihydroksybenzenc) 4-[2-(BOC-methylamino)acetyl]-1,2-dihydroxybenzene

Ved å følge fremgangsmåten i Eksempel 76(a) men med adrenalon-hydroklorid (5,0 g, 23,0 mmol) i stedet for 4-[2-(metylamino)acetyl]fenol-hydroklorid, ble tittelforbindelsen (1,2 g, 19%) oppnådd etter hurtigkromatografi (silikagel, 1:1 EtOAc/heksaner): MS (ES) m/e 282,2 [M+Hf By following the procedure of Example 76(a) but with adrenalone hydrochloride (5.0 g, 23.0 mmol) instead of 4-[2-(methylamino)acetyl]phenol hydrochloride, the title compound (1.2 g , 19%) obtained after flash chromatography (silica gel, 1:1 EtOAc/hexanes): MS (ES) m/e 282.2 [M+Hf

d) Dimetyl-4-[2-(BOC-metylamino)acetyl]-1,2-fenylendioksydiacetatd) Dimethyl-4-[2-(BOC-methylamino)acetyl]-1,2-phenylenedioxydiacetate

Ved å følge fremgangsmåten i Eksempel 76(b) men med 4-[2-(BOC-metylamino)acetyl]-1,2-dihydroksybenzen (0,9 g, 3,2 mmol) i stedet for 4-[2-(BOC-metylamino)acetyl]fenol og metylbromacetat (1,23 g, 8,0 mmol) i stedet for benzylbromacetat, ble tittelforbindelsen (1,11 g, 81%) fremstillet: By following the procedure of Example 76(b) but with 4-[2-(BOC-methylamino)acetyl]-1,2-dihydroxybenzene (0.9 g, 3.2 mmol) instead of 4-[2-( BOC-methylamino)acetyl]phenol and methyl bromoacetate (1.23 g, 8.0 mmol) in place of benzyl bromoacetate, the title compound (1.11 g, 81%) was prepared:

MS (ES) m/e 426,2 [M+H]<+>MS (ES) m/e 426.2 [M+H]<+>

e) Dimetyl-4-[2-(metylamino)acetyl]-1,2-fenylendioksydiacetat-hydrokloride) Dimethyl-4-[2-(methylamino)acetyl]-1,2-phenylenedioxydiacetate hydrochloride

Ved å følge fremgangsmåten i Eksempel 76(c) men med dimetyl-4-[2-(BOC-metylamino)acetyl]-1,2-fenylendioksydiacetat (1,11 g, 2,6 mmol) i stedet for benzyl-4-[2-(BOC-metylamino)acetyl]fenoksyacetat, ble tittelforbindelsen fremstillet (1,1 g, kvantitativt): MS (ES) m/e 326,0 [M+H]<+>f) Dimetyl-4-[2-[[(1 -BOC-benzimidazol-2-yl)metyl]metylamino]acetyl9-1,2-fenylendioksydiacetat By following the procedure of Example 76(c) but with dimethyl-4-[2-(BOC-methylamino)acetyl]-1,2-phenylenedioxydiacetate (1.11 g, 2.6 mmol) instead of benzyl-4- [2-(BOC-methylamino)acetyl]phenoxyacetate, the title compound was prepared (1.1 g, quantitative): MS (ES) m/e 326.0 [M+H]<+>f) Dimethyl-4-[2 -[[(1-BOC-benzimidazol-2-yl)methyl]methylamino]acetyl9-1,2-phenylenedioxydiacetate

Ved å følge fremgangsmåten i Eksempel 76(d) men med dimetyl-4-[2-(metylamino)acetyl]-1,2-fenylendioksydiacetat-hydroklorid (0,24 g, 0,66 mmol) i stedet for benzyl-4-[2-(metylamino)acetyl]fenoksyacetat-hydroklorid, 1-BOC-2-(brommetyl)benzimidazol (0,31 g, 0,99 mmol) i stedet for 2-(klormetyl)benzimidazol og benytte THF (5 mL) og CH2CI2(5 mL) som løsningsmidler, ble tittelforbindelsen fremstillet (0,14 g, 38%): MS (ES) m/e 556,2 [M+Hf By following the procedure of Example 76(d) but with dimethyl-4-[2-(methylamino)acetyl]-1,2-phenylenedioxydiacetate hydrochloride (0.24 g, 0.66 mmol) instead of benzyl-4- [2-(methylamino)acetyl]phenoxyacetate hydrochloride, 1-BOC-2-(bromomethyl)benzimidazole (0.31 g, 0.99 mmol) in place of 2-(chloromethyl)benzimidazole and using THF (5 mL) and CH 2 Cl 2 (5 mL) as solvents, the title compound was prepared (0.14 g, 38%): MS (ES) m/e 556.2 [M+Hf

g) Dimetyl-4-[2-[[(benzimidazol-2-yl)metyl]metylamino]acetyl]-1,2-fenylendioksydiacetat-bis(trifluoracetat) g) Dimethyl-4-[2-[[(benzimidazol-2-yl)methyl]methylamino]acetyl]-1,2-phenylenedioxydiacetate-bis(trifluoroacetate)

En blanding av dimetyl-4-[2-[[(1-BOC-benzimidazol-2-yl)metyl]metylamino]-acetyl]-1,2-fenylendioksydiacetat (0,13 , 0,23 mmol) i TFA (4 mL) og CH2CI2(12 mL) ble omrørt ved RT under argon i 20 minutter. Fjerning av løsningsmidlene på rotasjonsfordamper ga tittelforbindelsen (0,18 g, kvantitativt): A mixture of dimethyl-4-[2-[[(1-BOC-benzimidazol-2-yl)methyl]methylamino]-acetyl]-1,2-phenylenedioxydiacetate (0.13, 0.23 mmol) in TFA (4 mL) and CH 2 Cl 2 (12 mL) were stirred at RT under argon for 20 min. Removal of the solvents on a rotary evaporator gave the title compound (0.18 g, quantitative):

MS (ES) m/e 456,2 [M+H]<+>MS (ES) m/e 456.2 [M+H]<+>

h) 4-[2-[[(benzimidazol-2-yl)metyljmetylamino]acetyl]-1,2-fenylendioksy-dieddiksyre h) 4-[2-[[(benzimidazol-2-yl)methyljmethylamino]acetyl]-1,2-phenylenedioxydiacetic acid

Ved å følge fremgangsmåten i Eksempel 77(e) men med dimetyl-4-[2-[[(benzimidazol-2-yl)metyl]metylamino]acetyl]-1,2-fenylendioksydiacetat-bis(trifluoracetat) (0,16 g, 0,23 mmol) i stedet for dimetyl-(+)-4-[[2-[(benzimidazol-2-yl)metyl]metylamino]-1 -hydroksyetyl]-1,2-fenylendioksydiacetat, ble tittelforbindelsen fremstillet (0,08 g, 80%): MS (ES) m/e 428,2 [M+H]<+>By following the procedure in Example 77(e) but with dimethyl-4-[2-[[(benzimidazol-2-yl)methyl]methylamino]acetyl]-1,2-phenylenedioxydiacetate-bis(trifluoroacetate) (0.16 g , 0.23 mmol) instead of dimethyl-(+)-4-[[2-[(benzimidazol-2-yl)methyl]methylamino]-1-hydroxyethyl]-1,2-phenylenedioxydiacetate, the title compound was prepared (0 .08 g, 80%): MS (ES) m/e 428.2 [M+H]<+>

Analyse beregnet for C2iH2iN307■ 11/5 C2HF302 • 9/5 H20:Analysis calculated for C2iH2iN307■ 11/5 C2HF302 • 9/5 H20:

C, 42,93; H, 3,80; N, 5,91 C, 42.93; H, 3.80; N, 5.91

Funnet: C, 42,62; H. 3,52; N, 6,30 Found: C, 42.62; H. 3.52; N, 6.30

Eksempel 79Example 79

Fremstilling av 3-[[4-[[[(benzimidazol-2-yl)metyl]amino]karbonyl]-fenyl]amino]propionsyre Preparation of 3-[[4-[[[(benzimidazol-2-yl)methyl]amino]carbonyl]-phenyl]amino]propionic acid

a) etyl-3-[4-(karboksy)fenylamino]propionata) ethyl 3-[4-(carboxy)phenylamino]propionate

En løsning av 4-aminobenzoesyre (6,85 g, 0,05 mol) og etylakrylat (15 g, A solution of 4-aminobenzoic acid (6.85 g, 0.05 mol) and ethyl acrylate (15 g,

0,15 mol) i eddiksyre (40 mL) ble oppvarmet til 100°C i 15 timer. Faststoffet som ble dannet ble frafiltrert, vasket med heksan og tørket for å gi tittelforbindelsen (7,5 g, 63%). 0.15 mol) in acetic acid (40 mL) was heated to 100°C for 15 hours. The solid that formed was filtered off, washed with hexane and dried to give the title compound (7.5 g, 63%).

b) etyl-3-[[4-[[[(benzimidazol-2-yl)metyl]amino]karbonyl]fenyl]amino]propionsyre b) ethyl 3-[[4-[[[(benzimidazol-2-yl)methyl]amino]carbonyl]phenyl]amino]propionic acid

Forbindelsen fra Eksempel 79(a) (0,3 g, 1,26 mmol) i tionylklorid (10 mL) ble The compound from Example 79(a) (0.3 g, 1.26 mmol) in thionyl chloride (10 mL) was

kokt under tilbakeløpskjøling i 10 minutter, avkjølt, konsentrert i vakuum og det gjenværende tionylklorid fjernet ved tilsetning av metylenklorid og deretter boiled under reflux for 10 minutes, cooled, concentrated in vacuo and the remaining thionyl chloride removed by addition of methylene chloride and then

konsentret i vakuum. Den gjenværende olje ble løst i metylenklorid og behandlet med 2-(aminometyl)benzimidazol-dihydrokloridhydrat (0,33 g, 1,5 mmol) og diisopropyletylamin (0,56 g, 4,3 mmol). Den resulterende blanding ble omrørt over natten, vasket med vann og den organiske fase tørket (natriumsulfat) og konsentrert i vakuum. Det resulterende blekgule faststoff ble kromatografert (silikagel, metanol-diklormetan 3:97) og produktholdige fraksjoner slått sammen og konsentrert i vakuum for å gi tittelforbindelsen: MS (ES) m/e 367 [M+Hf concentrated in vacuo. The remaining oil was dissolved in methylene chloride and treated with 2-(aminomethyl)benzimidazole dihydrochloride hydrate (0.33 g, 1.5 mmol) and diisopropylethylamine (0.56 g, 4.3 mmol). The resulting mixture was stirred overnight, washed with water and the organic phase dried (sodium sulfate) and concentrated in vacuo. The resulting pale yellow solid was chromatographed (silica gel, methanol-dichloromethane 3:97) and product-containing fractions combined and concentrated in vacuo to give the title compound: MS (ES) m/e 367 [M+Hf

c) 3-[[4-[[[(benzimidazol-2-yl)metyl]amino]karbonyl]fenyl]amino]propionsyrec) 3-[[4-[[[(benzimidazol-2-yl)methyl]amino]carbonyl]phenyl]amino]propionic acid

En løsning av forbindelsen fra Eksempel 79(b) (0,4 g, 1,1 mmol) i metanol A solution of the compound from Example 79(b) (0.4 g, 1.1 mmol) in methanol

(20 mL), vann (2 mL) og 0,95N vandig natriumhydroksyd (2,5 mL) ble omrørt og oppvarmet til 50°C i 2 timer.Blandingen ble behandlet med trifluoreddiksyre (1 mL), konsentrert i vakuum og residuet utgnidd med diklormetan (4 x 100 mL). Det resulterende hvite faststoff ble omkrystallisert fra 20% acetonitril/vann-0,1% trifluoreddiksyre for å gi tittelforbindelsen: MS (ES) m/e 339 [M+Hf (20 mL), water (2 mL) and 0.95N aqueous sodium hydroxide (2.5 mL) were stirred and heated to 50 °C for 2 h. The mixture was treated with trifluoroacetic acid (1 mL), concentrated in vacuo and the residue triturated with dichloromethane (4 x 100 mL). The resulting white solid was recrystallized from 20% acetonitrile/water-0.1% trifluoroacetic acid to give the title compound: MS (ES) m/e 339 [M+Hf

Eksempel 80Example 80

Fremstilling av 4-[4-[1 -(2-metylbenzimidazolyl)piperidinyl]]-piperidin-eddiksyre-natriumsalt Preparation of 4-[4-[1-(2-methylbenzimidazolyl)piperidinyl]]-piperidine-acetic acid sodium salt

a) metyl-4-[4-[1-(t-butyloksykarbonyl)piperidinyl]]piperidinacetata) methyl 4-[4-[1-(t-butyloxycarbonyl)piperidinyl]]piperidine acetate

En blanding av t-butyl-1-(4,4'-bipiperidin)karboksylat (3,1 g, 10 mmol), A mixture of t-butyl 1-(4,4'-bipiperidine)carboxylate (3.1 g, 10 mmol),

fremstillet som beskrevet av Bondinell, et al.(WO 93/00095), metylbromacetat (1,7 g, 11 mmol) og trietylamin (2,3 g, 22 mmol) i DMF (15 mL) ble oppvarmet til 85°C i 4 timer. Reaksjonsblandingen ble fortynnet med EtOAc (50 mL), fordelt mellom NaHC03(5% løsning, 100 mL) og ekstrahert med EtOAc (2 x 50 mL). De kombinerte organiske ekstraktene ble vasket med H20, mettet NaCI-løsning, tørket over MgS04 og inndampet for å gi tittelforbindelsen (3,37 g, 99%). prepared as described by Bondinell, et al. (WO 93/00095), methyl bromoacetate (1.7 g, 11 mmol) and triethylamine (2.3 g, 22 mmol) in DMF (15 mL) were heated to 85°C in 4 hours. The reaction mixture was diluted with EtOAc (50 mL), partitioned between NaHCO 3 (5% solution, 100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with H 2 O, saturated NaCl solution, dried over MgSO 4 and evaporated to give the title compound (3.37 g, 99%).

MS (ES) m/e 341,2 [M+HfMS (ES) m/e 341.2 [M+Hf

b) Metyl-4-[4-(1 -piperidinyl)piperidinacetatb) Methyl 4-[4-(1-piperidinyl)piperidine acetate

En blanding av forbindelsen i Eksempel 1(a) (3,37 g, 10 mmol) og 4 M HCI i A mixture of the compound of Example 1(a) (3.37 g, 10 mmol) and 4 M HCl in

dioksan (20 mL) i CH2CI2(25 mL) ble omrørt ved RT i 18 timer. Den resulterende hvite suspensjon ble filtrert for å gi tittelforbindelsen som dihydrokloridet (3,1 g, 99%) dioxane (20 mL) in CH 2 Cl 2 (25 mL) was stirred at RT for 18 h. The resulting white suspension was filtered to give the title compound as the dihydrochloride (3.1 g, 99%)

c) Metyl-4-[4-[1-(2-metylbenzimidazolyl)piperidinyl]]-piperidinacetatc) Methyl 4-[4-[1-(2-methylbenzimidazolyl)piperidinyl]]-piperidine acetate

En omrørt løsning av forbindelsen fra Eksempel 1(b) (2 g, 6,4 mmol) og A stirred solution of the compound from Example 1(b) (2 g, 6.4 mmol) and

trietylamin (3,6 mL, 25,6 mmol) i CH2CI2(50 mL) ble porsjonsvis tilsatt en suspensjon av 2-klormetylbenzimidazol (1,1 g, 6,6 mmol) i CH2CI2(25 mL) ved RT. Etter omrøring i 4 timer ble reaksjonsblandingen fortynnet med CH2CI2(50 mL), fordelt mellom NaHC03(5% løsning, 100 mL) og ekstrahert med CH2CI2(2 x 50 mL). De kombinerte organiske ekstraktene ble vasket med H20, en mettet NaCI-løsning, tørket over MgS04og inndampet. Tittelforbindelsen ble renset ved hurtigkromatografi (Si02/6% MeOH/CH2CI2) for å gi tittelforbindelsen (0,36 g, 16%).<1>H NMR (400 MHz, CDCI3) 5 1,07 (m, 2H); 1,35 (m, 4H); 1,65 (t, J=9,1, 4H); 2,09 (q, J=10,9, 4H); 2,93 (m, 4H); 3,20 (s, 2H); 3,71 (s, 3H); 3,79 (s, 2H); 7,22 (m, 2H); 7,56 (bs, 2H): Triethylamine (3.6 mL, 25.6 mmol) in CH 2 Cl 2 (50 mL) was added portionwise to a suspension of 2-chloromethylbenzimidazole (1.1 g, 6.6 mmol) in CH 2 Cl 2 (25 mL) at RT. After stirring for 4 h, the reaction mixture was diluted with CH 2 Cl 2 (50 mL), partitioned between NaHCO 3 (5% solution, 100 mL) and extracted with CH 2 Cl 2 (2 x 50 mL). The combined organic extracts were washed with H 2 O, a saturated NaCl solution, dried over MgSO 4 and evaporated. The title compound was purified by flash chromatography (SiO 2 /6% MeOH/CH 2 Cl 2 ) to give the title compound (0.36 g, 16%).<1>H NMR (400 MHz, CDCl 3 ) δ 1.07 (m, 2H); 1.35 (m, 4H); 1.65 (t, J=9.1, 4H); 2.09 (q, J=10.9, 4H); 2.93 (m, 4H); 3.20 (s, 2H); 3.71 (s, 3H); 3.79 (s, 2H); 7.22 (m, 2H); 7.56 (bs, 2H):

MS (ES) m/e 471,2 [M+H]<+>MS (ES) m/e 471.2 [M+H]<+>

d) 4-[4-[1-(2-metylbenzimidazolyl)piperidinyl]]-piperidineddiksyre-natriumsaltd) 4-[4-[1-(2-methylbenzimidazolyl)piperidinyl]]-piperidineacetic acid sodium salt

Til en omrørt løsning av forbindelsen i Eksempel 1(c) (0,45 g, 1,2 mmol) i To a stirred solution of the compound of Example 1(c) (0.45 g, 1.2 mmol) in

MeOH (15 mL) ble det tilsatt 1N NaOH-løsning (8,5 mL, 8,5 mmol) ved RT. Etter 18 timer ble den hvite suspensjonen filtrert og et hvitt faststoff (0,2 g, smp.>250°C, 43%) oppnådd som tittelforbindelsen. MS (ES) m/e 357,2 [M+Hf<1>H NMR (400 MHz, CD3OD) 5 1,10 (bm, 2H); 1,34 (bm, 4H); 1,73 (bm, 4H); 2,11 (bm, 4H); 3,05 (m, 6H); 3,77 (s, 2H); 7,21 (bm, 2H); 7,52 (bm , 2H) To MeOH (15 mL) was added 1N NaOH solution (8.5 mL, 8.5 mmol) at RT. After 18 hours, the white suspension was filtered and a white solid (0.2 g, mp>250°C, 43%) was obtained as the title compound. MS (ES) m/e 357.2 [M+Hf<1>H NMR (400 MHz, CD3OD) δ 1.10 (bm, 2H); 1.34 (bm, 4H); 1.73 (bm, 4H); 2.11 (bm, 4H); 3.05 (m, 6H); 3.77 (s, 2H); 7.21 (bm, 2H); 7.52 (bm , 2H)

Analyse beregnet for C2oH27N402Na • 0,375 H20:Analysis calculated for C2oH27N402Na • 0.375 H20:

C, 62,36; H, 7,26; N, 14,54. C, 62.36; H, 7.26; N, 14.54.

Funnet: C, 62,38; H, 7,20; N, 14,32 Found: C, 62.38; H, 7.20; N, 14.32

Eksempel 81Example 81

1a) Benzyl-4-brombutyrat:1a) Benzyl-4-bromobutyrate:

Til en omrørt, avkjølt (0°C) blanding av benzylalkohol (1,0 g, 5,392 mmol) og pyridin (0,47 g, 5,9312 mmol) i vannfritt metylenklorid (10 mL) ble det tilsatt 4-brombutyrylklorid (0,58 g, 5,9312 mmol). Etter omrøring i 1 time ved romtemperatur ble blandingen konsentrert, tatt opp i H20, ekstrahert med EtOAc, vasket med saltvann, tørket over MgS04, filtrert og konsentrert for å gi en farveløs olje (1,38 g, 100%). To a stirred, cooled (0°C) mixture of benzyl alcohol (1.0 g, 5.392 mmol) and pyridine (0.47 g, 5.9312 mmol) in anhydrous methylene chloride (10 mL) was added 4-bromobutyryl chloride (0 .58 g, 5.9312 mmol). After stirring for 1 h at room temperature, the mixture was concentrated, taken up in H 2 O, extracted with EtOAc, washed with brine, dried over MgSO 4 , filtered and concentrated to give a colorless oil (1.38 g, 100%).

<1>H NMR (300 MHz, CDCI3) 5 2,24 (m, 2H); 2,59 (t, J=5,7Hz, 2H); 3,48 (t, J=5,7Hz, 2H); 5,14 (s, 2H); 7,38 (m, 5H) <1>H NMR (300 MHz, CDCl 3 ) δ 2.24 (m, 2H); 2.59 (t, J=5.7Hz, 2H); 3.48 (t, J=5.7Hz, 2H); 5.14 (s, 2H); 7.38 (m, 5H)

1 b) (S)-benzyl-4-(N-t-Boc-tyrosin-metylester)butyrat:1 b) (S)-benzyl-4-(N-t-Boc-tyrosine methyl ester) butyrate:

En blanding av forbindelsen i Eksempel 1a (1,57 g, 6,1177 mmol), N-t-Boc-tyrosin-metylester (1,80 g, 6,1177 mmol) og CsC03i tørr DMF (10 mL) ble omrørt ved RT i 20 timer. Blandingen ble konsentrert, tatt opp i H20 og ekstrahert med EtOAc. De organiske ekstraktene ble vasket med saltvann, tørket over MgS04, filtrert og konsentrert for å gi 2,30 g brun olje av tittelforbindelsen (79%). A mixture of the compound of Example 1a (1.57 g, 6.1177 mmol), N-t-Boc-tyrosine methyl ester (1.80 g, 6.1177 mmol) and CsCO 3 in dry DMF (10 mL) was stirred at RT in 20 hours. The mixture was concentrated, taken up in H 2 O and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO 4 , filtered and concentrated to give 2.30 g of the title compound as a brown oil (79%).

<1>H NMR (300 MHz, CDCI3) 5 1,47 (s, 9H); 2,15 (m, 2H); 2,59 (t, J=5,7Hz, 2H); 3,03 (m, 2H); 3,70 (s, 3H); 3,97 (t, J=5,7Hz, 2H); 4,55 (m, 1H), 4,97 (d, 5,8Hz, 1H); 5,12 (s, 2H); 6,78 (d, J=8,3Hz, 2H); 7,05 (d, J=8,3Hz, 2H); 7,41 (m, 5H) <1>H NMR (300 MHz, CDCl 3 ) δ 1.47 (s, 9H); 2.15 (m, 2H); 2.59 (t, J=5.7Hz, 2H); 3.03 (m, 2H); 3.70 (s, 3H); 3.97 (t, J=5.7Hz, 2H); 4.55 (m, 1H), 4.97 (d, 5.8Hz, 1H); 5.12 (s, 2H); 6.78 (d, J=8.3Hz, 2H); 7.05 (d, J=8.3Hz, 2H); 7.41 (m, 5H)

1 c) (S)-benzyl-4-(tyrosin-metylester)butyrat:1 c) (S)-benzyl-4-(tyrosine methyl ester) butyrate:

Til en omrørt løsning av forbindelsen fra Eksempel 1b (2,30 g, 4,8778 mmol) i tørr CH2CI2(10 mL) ble det tilsatt 12 mL TFA. Etter omrøring ved RT i 3 timer ble To a stirred solution of the compound from Example 1b (2.30 g, 4.8778 mmol) in dry CH 2 Cl 2 (10 mL) was added 12 mL of TFA. After stirring at RT for 3 hours, the

blandingen konsentrert, tatt opp i H20, nøytralisert med 2,5 N NaOH, ekstrahert med CH2CI2, tørket over MgS04, filtrert og konsentrert for å gi en brun olje (1,60 g, 88%).<1>H NMR (300 MHz, CDCI3) 5 2,15 (m, 2H); 2,55 (t, J=5,7Hz, 2H); 2,95 (dd, J=13,8Hz, 7,3Hz, 1H); 3,13 (dd, J=13,8Hz, 7,3Hz, 1H); 3,70 (s, 3H); 3,97 (t, J=5,7Hz, 1H); 4,95 (d, J=7,3Hz, 1H);.5,15 (s, 2H); 6,80 (d, J=8,3Hz, 2H); 7,10 (d, J=8,3Hz, 2H); 7,35 (m, 5H) the mixture was concentrated, taken up in H 2 O, neutralized with 2.5 N NaOH, extracted with CH 2 Cl 2 , dried over MgSO 4 , filtered and concentrated to give a brown oil (1.60 g, 88%).<1>H NMR (300 MHz, CDCl 3 ) δ 2.15 (m, 2H); 2.55 (t, J=5.7Hz, 2H); 2.95 (dd, J=13.8Hz, 7.3Hz, 1H); 3.13 (dd, J=13.8Hz, 7.3Hz, 1H); 3.70 (s, 3H); 3.97 (t, J=5.7Hz, 1H); 4.95 (d, J=7.3Hz, 1H); .5.15 (s, 2H); 6.80 (d, J=8.3Hz, 2H); 7.10 (d, J=8.3Hz, 2H); 7.35 (m, 5H)

1 d) (S)-benzyl-4-[(N-butylsulfonyl)tyrosin-metylester]butyrat:1 d) (S)-benzyl-4-[(N-butylsulfonyl)tyrosine methyl ester]butyrate:

Til en omrørt blanding av forbindelsen fra Eksempel 1c (1,60 g, 4,3079 mmol) og pyridin (0,41 g, 5,1695 mmol) i tørr CH2CI2(15 mL) ble det tilsatt n-butylsulfonylklorid (0,81 g, 5,1695 mmol). Etter omrørinmg ved RT i 2 timer, ble blandingen konsentrert, tatt opp i H20 og ekstrahert med EtOAc. De organiske ekstraktene ble vasket med 2N HCI, mettet NaHC03, saltvann, tørket over MgS04, filtrert og konsentrert for å gi en brun olje (2,01 g, 95%). To a stirred mixture of the compound from Example 1c (1.60 g, 4.3079 mmol) and pyridine (0.41 g, 5.1695 mmol) in dry CH 2 Cl 2 (15 mL) was added n-butylsulfonyl chloride (0.81 g, 5.1695 mmol). After stirring at RT for 2 h, the mixture was concentrated, taken up in H 2 O and extracted with EtOAc. The organic extracts were washed with 2N HCl, saturated NaHCO 3 , brine, dried over MgSO 4 , filtered and concentrated to give a brown oil (2.01 g, 95%).

<1>H NMR (300 MHz, CDCI3) 5 0,89 (t, J=7,3Hz, 3H); 1,37 (m, 2H); 1,65 (m, 2H); 2,20 (m, 2H); 2,60 (t, J=5,7Hz, 2H); 2,72 (t, J=7,3Hz, 2H); 2,95 (dd, J=13,8Hz, 7,3Hz, 1H); 3,10 (dd, J=13,8Hz, 7,3Hz, 1H); 3,77 (s, 3H); 3,93 (t, J=5,7Hz, 2H); 4,30 (m, 1H); 4,70 (d, J=7,3Hz, 1H); 5,12 (s, 2H); 6,80 (d, J=8,3Hz, 2H); 7,03 (d, J=8,3Hz, 2H); 7,35 (m, 5H). <1>H NMR (300 MHz, CDCl 3 ) δ 0.89 (t, J=7.3Hz, 3H); 1.37 (m, 2H); 1.65 (m, 2H); 2.20 (m, 2H); 2.60 (t, J=5.7Hz, 2H); 2.72 (t, J=7.3Hz, 2H); 2.95 (dd, J=13.8Hz, 7.3Hz, 1H); 3.10 (dd, J=13.8Hz, 7.3Hz, 1H); 3.77 (s, 3H); 3.93 (t, J=5.7Hz, 2H); 4.30 (m, 1H); 4.70 (d, J=7.3Hz, 1H); 5.12 (s, 2H); 6.80 (d, J=8.3Hz, 2H); 7.03 (d, J=8.3Hz, 2H); 7.35 (m, 5H).

1 e) (S)-4[(N-butylsulfonyl)tyrosin-metylester]smørsyre:1 e) (S)-4[(N-butylsulfonyl)tyrosine methyl ester]butyric acid:

En løsning av forbindelsen fra Eksempel 1d (0,781 g, 1,589 mmol) i MeOH (10 mL) ble hydrogenert ved 3,5 kg/cm<2>i 10% Pd/C (0,50 g) i 3 timer. Katalysatoren ble frafiltrert gjennom Celite. Filtratet ble konsentrert for å gi et hvitt faststoff (0,59 g, 93%) A solution of the compound from Example 1d (0.781 g, 1.589 mmol) in MeOH (10 mL) was hydrogenated at 3.5 kg/cm<2> in 10% Pd/C (0.50 g) for 3 hours. The catalyst was filtered off through Celite. The filtrate was concentrated to give a white solid (0.59 g, 93%)

<1>H NMR (300 MHz, CDCI3) 5 0,89 (t, J=7,3Hz, 3H); 1,35 (m, 2H); 1,65 (m, 2H); 2,10 (m, 2H); 2,55 (t, J=5,7Hz, 2H); 2,75 (t, J=7,3Hz, 2H); 2,95 (dd, J=13,8Hz, 7,3Hz, 1H); 3,05 (dd, J=13,8Hz, 7,3Hz, 1H); 3,48 (s, 3H); 3,97 (t, J=5,7Hz, 2H); 4,30 (m, 1H); 4,90 (d, J=7,3Hz, 1H); 6,90 (d, J=8,3Hz, 2H); 7,10 (d, J=8,3Hz, 2H) <1>H NMR (300 MHz, CDCl 3 ) δ 0.89 (t, J=7.3Hz, 3H); 1.35 (m, 2H); 1.65 (m, 2H); 2.10 (m, 2H); 2.55 (t, J=5.7Hz, 2H); 2.75 (t, J=7.3Hz, 2H); 2.95 (dd, J=13.8Hz, 7.3Hz, 1H); 3.05 (dd, J=13.8Hz, 7.3Hz, 1H); 3.48 (s, 3H); 3.97 (t, J=5.7Hz, 2H); 4.30 (m, 1H); 4.90 (d, J=7.3Hz, 1H); 6.90 (d, J=8.3Hz, 2H); 7.10 (d, J=8.3Hz, 2H)

1f) (S)-N-butylsulfonyl-4-(3-(benzimidazol-2-yl)propyl)tyrosin-metylester:1f) (S)-N-butylsulfonyl-4-(3-(benzimidazol-2-yl)propyl)tyrosine methyl ester:

Til en omrørt, avkjølt (0°C) blanding av forbindelsen fra Eksempel 1eTo a stirred, cooled (0°C) mixture of the compound from Example 1e

(0,595 g, 1,4823 mmol) og Et3N (0,16 g, 1,5565 mmol) i tørr THF (7 mL) ble det tilsatt isobutylklorformiat (0,212 g, 1,5565 mmol). Etter omrøring ved 0°C i 1 time ble o-fenylendiamin (0,16 g, 14823 mmol) og 1 mL HOAc tilsatt. Reaksjonsblandingen ble kokt under tilbakeløpskjøling over natten. Blandingen ble avkjølt, fortynnet med EtOAc, vasket med H20, mettet NaHC03 og saltvann, tørket over MgS04, konsentrert og renset ved hurtigkromatografi (5% MeOH/CH2CI2) for å gi et hvitt skum (0,487 g, 69%). (0.595 g, 1.4823 mmol) and Et 3 N (0.16 g, 1.5565 mmol) in dry THF (7 mL) was added isobutyl chloroformate (0.212 g, 1.5565 mmol). After stirring at 0°C for 1 hour, o-phenylenediamine (0.16 g, 14823 mmol) and 1 mL of HOAc were added. The reaction mixture was refluxed overnight. The mixture was cooled, diluted with EtOAc, washed with H 2 O, saturated NaHCO 3 and brine, dried over MgSO 4 , concentrated and purified by flash chromatography (5% MeOH/CH 2 Cl 2 ) to give a white foam (0.487 g, 69%).

<1>H NMR (300 MHz, CDCI3) 5 0,89 (t, J=7,3Hz, 3H); 1,35 (m, 2H); 1,65 (m, 2H); 2,30 (m, 2H); 2,80 (t, J=5,7Hz, 2H); 2,95 (dd, J=13,8Hz, 7,3Hz, 1H); 3,10 (m, 3H); 3,0 (s, 3H); 3,98 (t, J=5,7Hz, 2H); 4,35 (m, 1H); 4,90 (d, 7,3Hz, 1H); 6,77 (d, J=8,3Hz, 2H); 7,03 (d, J=8,3Hz, 2H); 7,26 (m, 2H); 7,58 (m, 2H) <1>H NMR (300 MHz, CDCl 3 ) δ 0.89 (t, J=7.3Hz, 3H); 1.35 (m, 2H); 1.65 (m, 2H); 2.30 (m, 2H); 2.80 (t, J=5.7Hz, 2H); 2.95 (dd, J=13.8Hz, 7.3Hz, 1H); 3.10 (m, 3H); 3.0 (s, 3H); 3.98 (t, J=5.7Hz, 2H); 4.35 (m, 1H); 4.90 (d, 7.3Hz, 1H); 6.77 (d, J=8.3Hz, 2H); 7.03 (d, J=8.3Hz, 2H); 7.26 (m, 2H); 7.58 (m, 2H)

1g) (S)-N-butylsulfonyl-p-[3-(2-benzimidazolyl)propyl]tyrosin:1g) (S)-N-butylsulfonyl-p-[3-(2-benzimidazolyl)propyl]tyrosine:

Til en omrørt løsning av forbindelsen fra Eksempel 1 f (0,487 g, 1,0285 mmol) i MeOH (5 mL) ble det tilsatt LiOHH20 (0,09 g, 2,0571 mmol) i løpet av 24 timer. Blandingen ble konsentrert, fortynnet i H20 og nøytralisert med 2,0 N HCI. Det hvite faststoffet ble frafiltrert og utgnidd i varm EtOH for å gi tittelforbindelsen som et hvitt faststoff (0,377 g, 80%), Smp.: >230°C). To a stirred solution of the compound from Example 1 f (0.487 g, 1.0285 mmol) in MeOH (5 mL) was added LiOHH 2 O (0.09 g, 2.0571 mmol) over 24 hours. The mixture was concentrated, diluted in H 2 O and neutralized with 2.0 N HCl. The white solid was filtered off and triturated in hot EtOH to give the title compound as a white solid (0.377 g, 80%), mp: >230°C).

<1>H NMR (300 MHz, DMSO-d6) 5 0,75 (t, 7,3Hz, 3H); 1,15 (m, 2H); 1,30 (m, 2H); 2,20 (m, 2H); 2,52 (m, 2H); 2,75 (dd, J=13,8Hz, 7,3Hz, 1H); 2,97 (dd, J=13,8Hz, 7,3Hz, 1H); 3,00 (t, J=5,7Hz, 2H); 3,90 (m, 1H); 4,10 (t, J=5,7Hz, 2H); 6,85 (d, 8,3Hz, 2H); 7,10 (m, 2H); 7,20 (d, J=8,3Hz, 2H); 7,50 (m, 2H); 7,61 (d, J=7,3Hz, 1H). <1>H NMR (300 MHz, DMSO-d6) δ 0.75 (t, 7.3Hz, 3H); 1.15 (m, 2H); 1.30 (m, 2H); 2.20 (m, 2H); 2.52 (m, 2H); 2.75 (dd, J=13.8Hz, 7.3Hz, 1H); 2.97 (dd, J=13.8Hz, 7.3Hz, 1H); 3.00 (t, J=5.7Hz, 2H); 3.90 (m, 1H); 4.10 (t, J=5.7Hz, 2H); 6.85 (d, 8.3Hz, 2H); 7.10 (m, 2H); 7.20 (d, J=8.3Hz, 2H); 7.50 (m, 2H); 7.61 (d, J=7.3Hz, 1H).

IR (cm"<1>, KBr) 3300-3400, 3244, 3000-3100, 2800-300, 1634, 1612, 1512, 1466, 1384, 1245, 1148, 1110. MS (ESI, M+H) 460,2 IR (cm"<1>, KBr) 3300-3400, 3244, 3000-3100, 2800-300, 1634, 1612, 1512, 1466, 1384, 1245, 1148, 1110. MS (ESI, M+H) 460, 2

Analyse beregnet for C23H29N305S:Analysis calculated for C23H29N305S:

C, 60,11; H, 6,36; N, 9,14 C, 60.11; H, 6.36; N, 9,14

Funnet<*>C, 60,01; H, 6,34; N, 9,01 Found<*>C, 60.01; H, 6.34; N, 9.01

Eksempel 82Example 82

Fremstilling av 4-[2-[[[1 -[(benzimidazol-2-yl)metyl]benzimidazol-2-yl]metyl]metylamino]acetyl]fenoksyeddiksyre Preparation of 4-[2-[[[1 -[(benzimidazol-2-yl)methyl]benzimidazol-2-yl]methyl]methylamino]acetyl]phenoxyacetic acid

a) 4-[2-(BOC-metylamino)acetyl]fenola) 4-[2-(BOC-methylamino)acetyl]phenol

En løsning av di-tert-butyl-dikarbonat (5,96 g, 27,3 mmol) i 1,4-dioksanA solution of di-tert-butyl dicarbonate (5.96 g, 27.3 mmol) in 1,4-dioxane

(25 mL) ble ved 0°C dråpevis tilsatt til en blanding av 4-[2-(metylamino)acetyl]fenol-hydroklorid (5,0 g, 24,8 mmol), 1,4-dioksan (30 mL), H20 (25 mL) og 1,0 N NaOH (25 mL, 25 mmol)..Etter 24 timer ble reaksjonsblandingen oppvarmet til RT og omrørt i 1,5 timer til. Mer 1,0 N NaOH (25 mL, 25 mmol) ble tilsatt og blandingen omrørt i ytterligere 0,5 timer ved RT og deretter inndampet på rotasjonsfordamper. Residuet ble fortynnet med EtOAc (80 mL) og blandingen surgjort til pH 2 ved bruk (25 mL) was added dropwise at 0°C to a mixture of 4-[2-(methylamino)acetyl]phenol hydrochloride (5.0 g, 24.8 mmol), 1,4-dioxane (30 mL), H 2 O (25 mL) and 1.0 N NaOH (25 mL, 25 mmol)..After 24 h, the reaction mixture was warmed to RT and stirred for another 1.5 h. More 1.0 N NaOH (25 mL, 25 mmol) was added and the mixture stirred for an additional 0.5 h at RT and then evaporated on a rotary evaporator. The residue was diluted with EtOAc (80 mL) and the mixture acidified to pH 2 in use

av 1,0 M NaHSCv Den resulterende blanding ble ekstrahert med EtOAc (2 x 50 mL) og de kombinerte organiske lagene vasket med H20 (30 mL) og tørket (Na2S04). Filtrering og konsentrering ga tittelforbindelsen (6,49 g, 99%):<1>H NMR (250 MHz, CDCI3) 5 6,70-8,05 (m, 4H); 4,53 (s, 2H); 2,98 (s, 3H); 1,50 (s, i 9H). of 1.0 M NaHSCv The resulting mixture was extracted with EtOAc (2 x 50 mL) and the combined organic layers washed with H 2 O (30 mL) and dried (Na 2 SO 4 ). Filtration and concentration gave the title compound (6.49 g, 99%):<1>H NMR (250 MHz, CDCl 3 ) δ 6.70-8.05 (m, 4H); 4.53 (s, 2H); 2.98 (s, 3H); 1.50 (p, in 9H).

b) Benzyl-4-[2-(BOC-metylamino)acetyl]fenoksyacetatb) Benzyl 4-[2-(BOC-methylamino)acetyl]phenoxyacetate

En blanding av 4-[2-(BOC-metylamino)acetyl]fenol (5,04 g, 19,0 mmol) og A mixture of 4-[2-(BOC-methylamino)acetyl]phenol (5.04 g, 19.0 mmol) and

K2C03(2,63 g, 19,0 mmol) i aceton (100 mL) ble omrørt under tilbakeløpskjøling i under argon i 1 time. Blandingen ble avkjølt til RT og tilsatt benzylbromacetat (5,23 g, 22,8 mmol). Reaksjonsblandingen ble kokt under tilbakeløpskjøling i 18 timer og deretter avkjølt og filtrert. Filterkaken ble vasket med aceton og filtratet konsentrert på rotasjonsfordamper. Residuet ble løst i CH2CI2(300 mL) og vasket K 2 CO 3 (2.63 g, 19.0 mmol) in acetone (100 mL) was stirred under reflux under argon for 1 h. The mixture was cooled to RT and benzyl bromoacetate (5.23 g, 22.8 mmol) was added. The reaction mixture was refluxed for 18 hours and then cooled and filtered. The filter cake was washed with acetone and the filtrate concentrated on a rotary evaporator. The residue was dissolved in CH 2 Cl 2 (300 mL) and washed

med H20 (50 mL) og deretter med saltvann (50 mL). Tørking Na2S04), konsentrering i og silikagel-hurtigkromatografi (1:3 EtOAc/heksaner) førte til tittelforbindelsen with H 2 O (50 mL) and then with brine (50 mL). Drying Na 2 SO 4 ), concentration in and silica gel flash chromatography (1:3 EtOAc/hexanes) afforded the title compound

(7,28 g, 93%):<1>H NMR (250 MHz, CDCI3) 5 6,85-7,95 (m, 9H); 5,23 (s, 2H); 4,71 (s, 2H); 4,55 (d, 2H);2,95 (d, 3H); 1,45 (d, 9H) (7.28 g, 93%):<1>H NMR (250 MHz, CDCl 3 ) δ 6.85-7.95 (m, 9H); 5.23 (s, 2H); 4.71 (s, 2H); 4.55 (d, 2H); 2.95 (d, 3H); 1.45 (d, 9H)

c) Benzyl-4-[2-(metylamino)acetyl]fenoksyacetat-hydrokloridc) Benzyl 4-[2-(methylamino)acetyl]phenoxyacetate hydrochloride

En blanding av benzyl-4-[2-(BOC-metylamino)acetyl]fenoksyacetat (7,26 g, A mixture of benzyl 4-[2-(BOC-methylamino)acetyl]phenoxyacetate (7.26 g,

17,57 mmol) og 4 M HCI i 1,4-dioksan (150 mL) ble omrørt ved RT i 1 time. Inndampning på rotasjonsfordamper og utgnidning med Et20 førte til tittelforbindelsen (5,93 g, 97%) som et hvitt pulver:<1>H NMR (250 MHz, CD3OD) 5 7,05-8,00 (m, 9H); 5,23 (s, 2H); 4,88 (s, 2H); 4,65 (s, 2H); 2,80 (s, 3H) 17.57 mmol) and 4 M HCl in 1,4-dioxane (150 mL) was stirred at RT for 1 h. Evaporation on a rotary evaporator and trituration with Et 2 O gave the title compound (5.93 g, 97%) as a white powder: 1 H NMR (250 MHz, CD 3 OD) δ 7.05-8.00 (m, 9H); 5.23 (s, 2H); 4.88 (s, 2H); 4.65 (s, 2H); 2.80 (s, 3H)

d) Benzyl-4-[2-[[[1 -[(benzimidazol2-yl)metyl]benzimidazol-2-yl]metyl]metylamino]acetyl]fenoksyacetat d) Benzyl-4-[2-[[[1 -[(benzimidazol-2-yl)methyl]benzimidazol-2-yl]methyl]methylamino]acetyl]phenoxyacetate

Et3N (0,28 g, 2,78 mmol) ble langsomt tilsatt til en blanding av benzyl-4-[2-(metylamino)acetyl]fenoksyacetat-hydroklorid (0,39 g, 1,11 mmol), 2-(klormetyl)benzimidazol (0,24 g, 1,45 mmol), CH3CN (20 mL) og CH2CI2(5 mL) ved RT under argon. Etter 5 timer ble reaksjonsblandingen konsentrert på rotasjonsfordamper. Residuet ble løst i CH2CI2(100 mL) og vasket med 5% NaHC03(2 x 20 mL) og deretter med saltvann (20 mL). Tørking (MgSO,»), konsentrering og silikagel-hurtigkromatografi (trinnvis gradient, 7-15% MeOH/CH2CI2) førte til tittelforbindelsen (0,08 g, 12%) som et hvitaktig pulver Et3N (0.28 g, 2.78 mmol) was slowly added to a mixture of benzyl 4-[2-(methylamino)acetyl]phenoxyacetate hydrochloride (0.39 g, 1.11 mmol), 2-(chloromethyl )benzimidazole (0.24 g, 1.45 mmol), CH 3 CN (20 mL) and CH 2 Cl 2 (5 mL) at RT under argon. After 5 hours, the reaction mixture was concentrated on a rotary evaporator. The residue was dissolved in CH 2 Cl 2 (100 mL) and washed with 5% NaHCO 3 (2 x 20 mL) and then with brine (20 mL). Drying (MgSO, ), concentration and silica gel flash chromatography (step gradient, 7-15% MeOH/CH 2 Cl 2 ) afforded the title compound (0.08 g, 12%) as an off-white powder

MS (ES) m/e 574,2 [M+HfMS (ES) m/e 574.2 [M+Hf

e) 4-[2-[[[1-[(benzimidazol-2-yl)metyl]benzimidazol-2-yl]metyl]-metylamino]acetyljfenoksyeddiksyre e) 4-[2-[[[1-[(benzimidazol-2-yl)methyl]benzimidazol-2-yl]methyl]-methylamino]acetylphenoxyacetic acid

En blanding av benzyl-4-[2-[[[1-[(benzimidazol-2-yl)metyl]benzimidazol-2-yl]metyl]metylamino]acetyl]fenoksyacetat (0,08 g, 0,18 mmol), og 5% Pd/C (0,11 g) i MeOH (15 mL) ble ristet i et Parr-apparat under H2(2,9 kg/cm<2>) i 1 time. Blandingen ble filtrert gjennom et lag av Celite® og filterlaget vasket med iseddik og MeOH. Filtratet ble konsentrert for å gi råproduktet (0,07 g). Preparativ HPLC (Hamilton PRP-1® kolonne, trinnvis gradient, 10-30% CH3CN/H20 inneholdende 0,1% TFA) førte til tittelforbindelsen: MS (ES) m/e 484,2 [M+Hf A mixture of benzyl 4-[2-[[[1-[(benzimidazol-2-yl)methyl]benzimidazol-2-yl]methyl]methylamino]acetyl]phenoxyacetate (0.08 g, 0.18 mmol), and 5% Pd/C (0.11 g) in MeOH (15 mL) was shaken in a Parr apparatus under H 2 (2.9 kg/cm<2>) for 1 h. The mixture was filtered through a layer of Celite® and the filter layer washed with glacial acetic acid and MeOH. The filtrate was concentrated to give the crude product (0.07 g). Preparative HPLC (Hamilton PRP-1® column, stepwise gradient, 10-30% CH 3 CN/H 2 O containing 0.1% TFA) led to the title compound: MS (ES) m/e 484.2 [M+Hf

Analyse beregnet for C27H25N504 • 3 C2HF302:Analysis calculated for C27H25N504 • 3 C2HF302:

C, 48,01; H, 3,42; N, 8,48 C, 48.01; H, 3.42; N, 8.48

Funnet: C, 48,40; H, 3,72; N, 8,77 Found: C, 48.40; H, 3.72; N, 8.77

Eksempel 83 Example 83

(±)-4-[[2-[(benzimidazol-2-yl)metyl]metylamino]-1-hydroksyetyl]-1,2-fenylendioksydieddiksyre (±)-4-[[2-[(benzimidazol-2-yl)methyl]methylamino]-1-hydroxyethyl]-1,2-phenylenedioxydiacetic acid

a) N-Cbz-adrenalona) N-Cbz-adrenalone

Adrenalon-hydroklorid (28,6 g, 0,121 mol) ble tilsatt til 2,0 N NaOH (200 mL, Adrenalone hydrochloride (28.6 g, 0.121 mol) was added to 2.0 N NaOH (200 mL,

0,2 mol) som først var avkjølt til 5°C i et isbad. 2,0 N NaOH (60 mL, 0,06 mol) i en dråpetrakt og en løsning av benzylklorformiat (17,3 mL, 0,121 mol) i toluen (18 mL) i en annen dråpetrakt ble tilsatt med en hastighet som holdt reaksjonstemperaturen mellom 5 og 10°C og slik at tilsetningen av begge løsningene ble fullført samtidig. Den resulterende brune løsningen ble omrørt ved 5°C i 75 minutter og deretter fortynnet med H20 (230 mL) og surgjort med 1,0 N HCI (536 mL). Det oppsto først et gummiaktig bunnfall som gikk over i fast form ved utgnidning med en glasstav 0.2 mol) which had first been cooled to 5°C in an ice bath. 2.0 N NaOH (60 mL, 0.06 mol) in a dropping funnel and a solution of benzyl chloroformate (17.3 mL, 0.121 mol) in toluene (18 mL) in another dropping funnel were added at a rate that kept the reaction temperature between 5 and 10°C and so that the addition of both solutions was completed simultaneously. The resulting brown solution was stirred at 5°C for 75 min and then diluted with H 2 O (230 mL) and acidified with 1.0 N HCl (536 mL). A rubbery precipitate first formed, which changed to a solid form when rubbed with a glass rod

etterfulgt av omrøring i 30 minutter. Det blekgrønne faststoff ble frafiltrert, kort omrørt med H20 (180 mL), filtrert/kort omrørt med EtOH (135 mL) og filtrert. Det resulterende faststoff ble malt i en morter med mer EtOH (135 mL) og deretter filtrert followed by stirring for 30 minutes. The pale green solid was filtered off, stirred briefly with H 2 O (180 mL), filtered/stirred briefly with EtOH (135 mL) and filtered. The resulting solid was ground in a mortar with more EtOH (135 mL) and then filtered

og tørket i vakuum for å gi tittelforbindelsen (28,6 g, 75%): smp. 183-186°C.and dried in vacuo to give the title compound (28.6 g, 75%): m.p. 183-186°C.

i in

b) Dimetyl-4-[2-(Cbz-metylamino)acetyl]-1,2-fenylendioksydiacetatb) Dimethyl-4-[2-(Cbz-methylamino)acetyl]-1,2-phenylenedioxydiacetate

En blanding av N-Cbz-adrenalon (23,6 g, 74,8 mmol), aceton (340 mL) og A mixture of N-Cbz-adrenalone (23.6 g, 74.8 mmol), acetone (340 mL) and

vannfritt K2C03(21,0 g, 152 mmol) ble kokt under tilbakeløpskjøling under argon. anhydrous K 2 CO 3 (21.0 g, 152 mmol) was refluxed under argon.

Etter 70 minutter ble den beige suspensjonen avkjølt til RT og tilsatt metyl-After 70 minutes, the beige suspension was cooled to RT and methyl-

) bromacetat (17,9 mL, 189 mmol). Den resulterende suspensjon ble omrørt ved RT ) bromoacetate (17.9 mL, 189 mmol). The resulting suspension was stirred at RT

under argon i 16 timer og deretter oppvarmet til 50°C. Etter 6 timer ble blandingen avkjølt til RT og filtrert og filtratet konsentrert til tørrhet. Residuet ble løst i CH2CI2(800 mL) og vasket suksessivt med H20 (160 mL) og 5% K2C03(2 x 100 mL). under argon for 16 hours and then heated to 50°C. After 6 h the mixture was cooled to RT and filtered and the filtrate concentrated to dryness. The residue was dissolved in CH 2 Cl 2 (800 mL) and washed successively with H 2 O (160 mL) and 5% K 2 CO 3 (2 x 100 mL).

Tørking (Na2S04) og konsentrering ga tittelforbindelsen (26,35 g, 82%) som en olje i som størknet ved henstand: smp.: 56-59°C. Drying (Na 2 SO 4 ) and concentration gave the title compound (26.35 g, 82%) as an oil which solidified on standing: mp: 56-59°C.

c) Dimetyl-4-[2-(metylamino)-1 -hydroksyetyl]-1,2-fenylendioksydiacetatc) Dimethyl-4-[2-(methylamino)-1-hydroxyethyl]-1,2-phenylenedioxydiacetate

Ved å følge fremgangsmåten i Eksempel 82(e) men med dimetyl-4-[2-(Cbz-metylamino)acetyl]-1,2-fenylendioksydiacetat (2,1 g, 4,57 mmol) i stedet for benzyl-i 4-[2-[[[i-[(benzimidazol-2-yl)metyl]benzimidazol-2-yl]metyl]metylamino]acetyl]-fenoksyacetat og med EtOAc (50 mL) og MeOH (20 mL) som løsningsmidler, ble tittelforbindelsen (1,34 g, 90%) fremstillet: MS (ES) m/e 328,0 [M+Hf By following the procedure of Example 82(e) but with dimethyl-4-[2-(Cbz-methylamino)acetyl]-1,2-phenylenedioxydiacetate (2.1 g, 4.57 mmol) instead of benzyl-i 4 -[2-[[[i-[(benzimidazol-2-yl)methyl]benzimidazol-2-yl]methyl]methylamino]acetyl]-phenoxyacetate and with EtOAc (50 mL) and MeOH (20 mL) as solvents, was the title compound (1.34 g, 90%) prepared: MS (ES) m/e 328.0 [M+Hf

d) Dimetyl-(±)-4-[[2-[(benzimidazol-2-yl)metyl]metylamino]-1 -hydroksyetyl]-1,2-fenylendioksydiacetat d) Dimethyl-(±)-4-[[2-[(benzimidazol-2-yl)methyl]methylamino]-1-hydroxyethyl]-1,2-phenylenedioxydiacetate

Ved å følge fremgangsmåten i Eksempel 82(d) men med dimetyl-4-[2-(metylamino)-1-hydroksyetyl]-1,2-fenylendioksydiacetat (1,37 g, 4,20 mmol) i stedet for benzyl-4-[2-(metylamino)acetyl]fenoksyacetat-hydroklorid, ble tittelforbindelsen (0,25 g, 13%) fremstillet:MS (ES) m/e 458,2 [M+Hf By following the procedure of Example 82(d) but with dimethyl-4-[2-(methylamino)-1-hydroxyethyl]-1,2-phenylenedioxydiacetate (1.37 g, 4.20 mmol) instead of benzyl-4 -[2-(methylamino)acetyl]phenoxyacetate hydrochloride, the title compound (0.25 g, 13%) was prepared: MS (ES) m/e 458.2 [M+Hf

e) (±)-4-[[2-[(benzimidazol-2-yl)metyl]metylamino]-1 -hydroksyetyl]-1,2-fenylendioksydieddiksyre e) (±)-4-[[2-[(benzimidazol-2-yl)methyl]methylamino]-1-hydroxyethyl]-1,2-phenylenedioxydiacetic acid

En blanding av dimetyl-(±)-4-[[2-[(benzimidazol-2-yl)metyl]metylarnino]-1-hydroksyetyl]-1,2-fenylendioksydiacetat (0,23 g, 0,5 mmol), THF (10 mL), H20 A mixture of dimethyl-(±)-4-[[2-[(benzimidazol-2-yl)methyl]methylarnino]-1-hydroxyethyl]-1,2-phenylenedioxydiacetate (0.23 g, 0.5 mmol), THF (10 mL), H 2 O

(10 mL) og 1,0 N LiOH (2,0 mL, 2,0 mmol) ble omrørt ved RT i 26 timer. Reaksjonsblandingen ble konsentrert på rotasjonsfordamper og det vandige residuet surgjort med 1,0 N AcOH (2 mL) under avkjøling i et isbad. Den resulterende blanding ble lyofilisert for å gi råproduktet (0,32 g). Preparativ HPLC (Hamilton PRP-1® kolonne, 10% CH3CN/H20 inneholdende 0,1% TFA) førte til tittelforbindelsen: MS (ES) m/e 430,2 [M+H]<+>(10 mL) and 1.0 N LiOH (2.0 mL, 2.0 mmol) were stirred at RT for 26 h. The reaction mixture was concentrated on a rotary evaporator and the aqueous residue acidified with 1.0 N AcOH (2 mL) while cooling in an ice bath. The resulting mixture was lyophilized to give the crude product (0.32 g). Preparative HPLC (Hamilton PRP-1® column, 10% CH3CN/H2O containing 0.1% TFA) led to the title compound: MS (ES) m/e 430.2 [M+H]<+>

Analyse beregnet for C2iH23N307• 7/2 C2HF302:Analysis calculated for C2iH23N307• 7/2 C2HF302:

C, 39,73; H, 3,39; N, 4,97 C, 39.73; H, 3.39; N, 4.97

Funnet: C, 39,47; H, 3,38; N, 4,86. Found: C, 39.47; H, 3.38; N, 4.86.

Eksempel 84 Example 84

4-[2-[[(benzimidazol-2-yl)metyl]metylamino]acetyl]-1,2-fenylendioksy-dieddiksyre 4-[2-[[(benzimidazol-2-yl)methyl]methylamino]acetyl]-1,2-phenylenedioxydiacetic acid

a) 1-BOC-2-metylbenzimidazola) 1-BOC-2-methylbenzimidazole

En blanding av 2-metylbenzimidazol (1,5 g, 11,35 mmol), Et3N (1,66 mL, A mixture of 2-methylbenzimidazole (1.5 g, 11.35 mmol), Et3N (1.66 mL,

11,92 mmol), DMAP (0,20 g, 1,6 mmol) og (BOC)20 (2,60 g, 11,92 mmol) i vannfritt CH2CI2(15 mL) ble omrørt ved RT i 24 timer og deretter konsentrert. Residuet ble tatt opp i H20, omrørt og filtrert for å gi tittelforbindelsen (2,63 g, 100%) som et farveløst faststoff: smp. 71-72°C. 11.92 mmol), DMAP (0.20 g, 1.6 mmol) and (BOC) 2 O (2.60 g, 11.92 mmol) in anhydrous CH 2 Cl 2 (15 mL) were stirred at RT for 24 h and then concentrated. The residue was taken up in H 2 O, stirred and filtered to give the title compound (2.63 g, 100%) as a colorless solid: m.p. 71-72°C.

b) 1 -BOC-2-(brommetyl)benzimidazolb) 1-BOC-2-(bromomethyl)benzimidazole

NBS (8,43 g, 47,4 mmol) og AIBN (2,1 g, 12,8 mmol) ble tilsatt til en løsning NBS (8.43 g, 47.4 mmol) and AIBN (2.1 g, 12.8 mmol) were added to a solution

av 1-BOC-2-metylbenzimidazol (10,0 g, 43,1 mmol) i CCU (120 mL) under tilbakeløpskjøling. Etter 21 timer ble reaksjonsblandingen avkjølt og filtrert. Filtratet ble konsentrert og den resulterende brune olje kromatografert på silikagel (15% EtOAc/heksaner) for å gi tittelproduktet:<1>H NMR (400 MHz, CDCI3) 5 7,94-8,01 (m, 1H); 7,70-7,75 (m, 1H); 7,31-7,44 (m, 2H); 4,96 (s, 2H); 1,75 (s,9H) of 1-BOC-2-methylbenzimidazole (10.0 g, 43.1 mmol) in CCU (120 mL) under reflux. After 21 hours, the reaction mixture was cooled and filtered. The filtrate was concentrated and the resulting brown oil chromatographed on silica gel (15% EtOAc/hexanes) to give the title product: <1>H NMR (400 MHz, CDCl3 ) δ 7.94-8.01 (m, 1H); 7.70-7.75 (m, 1H); 7.31-7.44 (m, 2H); 4.96 (s, 2H); 1.75 (p.9H)

c) 4-[2-(BOC-metylamino)acetyl]-1,2-dihydroksybenzenc) 4-[2-(BOC-methylamino)acetyl]-1,2-dihydroxybenzene

Ved å følge fremgangsmåten i Eksempel 82(a) men med adrenalon-hydroklorid (5,0 g, 23,0 mmol) i stedet for 4-[2-(metylamino)acetyl]fenol-hydroklorid, ble tittelforbindelsen (1,2 g, 19%) fremstillet ved hurtigkromatografi på silikagel (1:1 EtOAc/heksaner): MS (ES) m/e 282,2 [M+H]<+>Following the procedure of Example 82(a) but with adrenalone hydrochloride (5.0 g, 23.0 mmol) instead of 4-[2-(methylamino)acetyl]phenol hydrochloride, the title compound (1.2 g , 19%) prepared by flash chromatography on silica gel (1:1 EtOAc/hexanes): MS (ES) m/e 282.2 [M+H]<+>

d) Dimetyl-4-[2-(BOC-metylamino)acetyl]-1,2-fenylendioksydiacetatd) Dimethyl-4-[2-(BOC-methylamino)acetyl]-1,2-phenylenedioxydiacetate

Ved å følge fremgangsmåten i Eksempel 82(b), men med 4-[2-(BOC-metylamino)acetyl]-1,2-dihydroksybenzen (0,9 g, 3,2 mmol) i stedet for 4-[2-(BOC-metylamino)acetyl]fenol og metylbromacetat (1,23 g, 8,0 mmol) i stedet for benzylbromacetat, ble tittelforbindelsen (1,11 g, 81%) fremstillet: By following the procedure of Example 82(b), but with 4-[2-(BOC-methylamino)acetyl]-1,2-dihydroxybenzene (0.9 g, 3.2 mmol) instead of 4-[2- (BOC-methylamino)acetyl]phenol and methyl bromoacetate (1.23 g, 8.0 mmol) in place of benzyl bromoacetate, the title compound (1.11 g, 81%) was prepared:

MS (ES) m/e 426,2 [M+H]<+>MS (ES) m/e 426.2 [M+H]<+>

e) Dimetyl-4-[2-(metylamino)acetyl]-1,2-fenylendioksydiacetat-hydrokloride) Dimethyl-4-[2-(methylamino)acetyl]-1,2-phenylenedioxydiacetate hydrochloride

Ved å følge fremgangsmåten i Eksempel 82(c), men med dimetyl-4-[2-(BOC-metylamino)acetyl]-1,2-fenylendioksydiacetat (1,11 g, 2,6 mmol) i stedet for benzyl-4-[2-(BOC-metylamino)acetyl]fenoksyacetat, ble tittelforbindelsen (1,1 g, kvantitativt) fremstillet: MS (ES) m/e 326,0 [M+H]<+>f) Dimetyl-4-[2-[[(1 -BOC-benzimidazol-2-yl)metyl]metylamino]acetyl]-1,2-fenylendioksydiacetat By following the procedure of Example 82(c), but with dimethyl-4-[2-(BOC-methylamino)acetyl]-1,2-phenylenedioxydiacetate (1.11 g, 2.6 mmol) instead of benzyl-4 -[2-(BOC-methylamino)acetyl]phenoxyacetate, the title compound (1.1 g, quantitative) was prepared: MS (ES) m/e 326.0 [M+H]<+>f) Dimethyl-4-[ 2-[[(1-BOC-benzimidazol-2-yl)methyl]methylamino]acetyl]-1,2-phenylenedioxydiacetate

Ved å følge fremgangsmåten i Eksempel 82(d), men med dimetyl-4-[2-(metylamino)acetyl]-1,2-fenylendioksydiacetat-hydroklorid (0,24 g, 0,66 mmol) i stedet for benzyl-4-[2-(metylamino)acetyl]fenoksyacetat-hydroklorid, 1-BOC-2-(brommetyl)benzimidazol (0,31 g, 0,99 mmol) i stedet for 2-(klormetyl)benzimidazol og med THF (5 mL) og CH2CI2som løsningsmidler, ble tittelforbindelsen (0,14 g, 38%) fremstillet: MS (ES) m/e 556,2 [M+H]<+>g) Dimetyl-4-[2-[[(benzimidazol-2-yl)metyl]-metylamino]acetyl]-1,2-fenylendioksydiacetat-bis(trifluoracetat) By following the procedure of Example 82(d), but with dimethyl-4-[2-(methylamino)acetyl]-1,2-phenylenedioxydiacetate hydrochloride (0.24 g, 0.66 mmol) in place of benzyl-4 -[2-(methylamino)acetyl]phenoxyacetate hydrochloride, 1-BOC-2-(bromomethyl)benzimidazole (0.31 g, 0.99 mmol) in place of 2-(chloromethyl)benzimidazole and with THF (5 mL) and CH2Cl2 as solvents, the title compound (0.14 g, 38%) was prepared: MS (ES) m/e 556.2 [M+H]<+>g) Dimethyl-4-[2-[[(benzimidazol-2 -yl)methyl]-methylamino]acetyl]-1,2-phenylenedioxydiacetate-bis(trifluoroacetate)

En blanding av dimetyl-4-[2-[[(1-BOC-benzimidazol-2-yl)metyl]metylamino]-acetyl]-1,2-fenylendioksydiacetat (0,13 g, 0,23 mmol) i TFA (4 mL) og CH2CI2A mixture of dimethyl-4-[2-[[(1-BOC-benzimidazol-2-yl)methyl]methylamino]-acetyl]-1,2-phenylenedioxydiacetate (0.13 g, 0.23 mmol) in TFA ( 4 mL) and CH 2 Cl 2

(12 mL) ble omrørt ved RT under argon i 20 minutter. Fjerning av løsningsmidlene på rotasjonsfordamper ga tittelforbindelsen (0,18 g, kvantitativt): (12 mL) was stirred at RT under argon for 20 min. Removal of the solvents on a rotary evaporator gave the title compound (0.18 g, quantitative):

MS (ES) m/e 456,2 [M+H]<+>MS (ES) m/e 456.2 [M+H]<+>

h) 4-[2-[[(benzimidazol-2-yl)metyl]metylamino]acetyl]-1,2-fenylen-dioksydieddiksyre h) 4-[2-[[(benzimidazol-2-yl)methyl]methylamino]acetyl]-1,2-phenylene-dioxydiacetic acid

Ved å følge fremgangsmåten i Eksempel 82(e), men med dimetyl-4-[2-[[(benzimidazol-2-yl)-metyl]metylamino]acetyl]-1,2-fenylendioksydiacetat-bis(trifluoracetat) (0,16 g, 0,23 mmol) i stedet for dimetyl-(±)-4-[[2-[(benzimidazol-2-yl)metyl]metylamino]-1 -hydroksyetyl]-1,2-fenylendioksydiacetat, ble tittelforbindelsen (0,08 g, 80%) fremstillet: MS (ES) m/e 428,2 [M+H]<+>By following the procedure of Example 82(e), but with dimethyl-4-[2-[[(benzimidazol-2-yl)-methyl]methylamino]acetyl]-1,2-phenylenedioxydiacetate-bis(trifluoroacetate) (0, 16 g, 0.23 mmol) instead of dimethyl-(±)-4-[[2-[(benzimidazol-2-yl)methyl]methylamino]-1-hydroxyethyl]-1,2-phenylenedioxydiacetate, the title compound ( 0.08 g, 80%) prepared: MS (ES) m/e 428.2 [M+H]<+>

Analyse beregnet for C2iH21N307 -11/5 C2HF302• 9/5 H20:Analysis calculated for C2iH21N307 -11/5 C2HF302• 9/5 H20:

C, 42,93; H, 3,80; N, 5,91 C, 42.93; H, 3.80; N, 5.91

Funnet: C, 42,62; H, 3,52; N, 6,30 Found: C, 42.62; H, 3.52; N, 6.30

Eksempel 85Example 85

Fremstilling av 3-[[4-[[[(benzimidazol-2-yl)metyl]amino]karbonyl]-fenyl]amino]propionsyre Preparation of 3-[[4-[[[(benzimidazol-2-yl)methyl]amino]carbonyl]-phenyl]amino]propionic acid

a) etyl-3-[4-(karboksy)fenylamino]propionata) ethyl 3-[4-(carboxy)phenylamino]propionate

En løsning av 4-aminobenzoesyre (6,85 g, 0,05 mol) og etylakrylat (15 g, A solution of 4-aminobenzoic acid (6.85 g, 0.05 mol) and ethyl acrylate (15 g,

0,15 mol) i eddiksyre (40 mL) ble oppvarmet til 100°C i 15 timer. Det dannede faststoff ble frafiltrert, vasket med heksan og tørket for å gi tittelforbindelsen (7,5 g, 63%). 0.15 mol) in acetic acid (40 mL) was heated to 100°C for 15 hours. The solid formed was filtered off, washed with hexane and dried to give the title compound (7.5 g, 63%).

b) etyl-3-[[4-[[[(benzimidazol-2-yl)metyl]amino]karbonyl]fenyl]amino]propionsyre b) ethyl 3-[[4-[[[(benzimidazol-2-yl)methyl]amino]carbonyl]phenyl]amino]propionic acid

Forbindelsen fra Eksempel 85(a) (0,3 g, 1,26 mmol) i tionylklorid (10 mL) ble The compound from Example 85(a) (0.3 g, 1.26 mmol) in thionyl chloride (10 mL) was

kokt under tilbakeløpskjøling i 10 minutter, avkjølt, konsentrert i vakuum og gjenværende tionylklorid fjernet ved tilsetning av metylenklorid og deretter boiled under reflux for 10 minutes, cooled, concentrated in vacuo and residual thionyl chloride removed by addition of methylene chloride and then

konsentrert i vakuum. Den gjenværende olje ble løst i metylenklorid og behandlet med 2-(aminometyl)benzimidazol-dihydrokloridhydrat (0,33 g, 1,5 mmol) og diisopropyletylamin (0,56 g, 4,3 mmol). Den resulterende blanding ble omrørt over natten, vasket med vann og den organiske fase tørket (natriumsulfat) og konsentrert i vakuum. Det resulterende blekgule faststoff ble kromatografert (silikagel, metanol-diklormetan 3:97) og produktholdige fraksjoner slått sammen og konsentrert i vakuum for å gi tittelforbindelsen. MS (ES) m/e 367 [M+H]<+>concentrated in vacuum. The remaining oil was dissolved in methylene chloride and treated with 2-(aminomethyl)benzimidazole dihydrochloride hydrate (0.33 g, 1.5 mmol) and diisopropylethylamine (0.56 g, 4.3 mmol). The resulting mixture was stirred overnight, washed with water and the organic phase dried (sodium sulfate) and concentrated in vacuo. The resulting pale yellow solid was chromatographed (silica gel, methanol-dichloromethane 3:97) and product-containing fractions combined and concentrated in vacuo to give the title compound. MS (ES) m/e 367 [M+H]<+>

c) 3-[[4-[[[(benzimidazol-2-yl)metyl]amino]karbonyl]fenyl]amino]propionsyrec) 3-[[4-[[[(benzimidazol-2-yl)methyl]amino]carbonyl]phenyl]amino]propionic acid

En løsning av forbindelsen fra Eksempel 85(b) (0,4 g, 1,1 mmol) i metanol A solution of the compound from Example 85(b) (0.4 g, 1.1 mmol) in methanol

(20 mL), vann (2 mL) og 0,95 N vandig natriumhydroksyd (2,5 mL) ble omrørt og oppvarmet til 50°C i 2 timer. Blandingen ble behandlet med trifluoreddiksyre (1 mL), konsentrert i vakuum og residuet utgnidd med diklormetan (4 x 100 mL). Det resulterende hvite faststoff ble omkrystallisert fra 20% acetonitril/vann-0,1% trifluoreddiksyre for å gi tittelforbindelsen. MS (ES) m/e 339 [M+H]<+>(20 mL), water (2 mL) and 0.95 N aqueous sodium hydroxide (2.5 mL) were stirred and heated to 50°C for 2 h. The mixture was treated with trifluoroacetic acid (1 mL), concentrated in vacuo and the residue triturated with dichloromethane (4 x 100 mL). The resulting white solid was recrystallized from 20% acetonitrile/water-0.1% trifluoroacetic acid to give the title compound. MS (ES) m/e 339 [M+H]<+>

Eksempel 86-92Example 86-92

Ved å følge de generelle fremgangsmåter i Eksempel 1-55, ble følgende forbindelser fremstillet: By following the general procedures of Examples 1-55, the following compounds were prepared:

Eksempel Example

Beskrivelsen ovenfor omtaler fullstendig hvorledes forbindelsene ifølge oppfinnelsen fremstilles og benyttes. Oppfinnelsen er imidlertid ikke begrenset til de ovenfor beskrevne bestemte utførelsesformer, men innbefatter samtlige modifikasjoner av disse innenfor rammen av de etterfølgende patentkrav. De forskjellige referanser til tidsskrifter, patenter og andre publikasjoner som her er sitert, viser teknikkens stand, og disse inkorporeres herved med hele sitt innhold i foreliggende beskrivelse. The description above describes completely how the compounds according to the invention are produced and used. However, the invention is not limited to the specific embodiments described above, but includes all modifications thereof within the scope of the subsequent patent claims. The various references to journals, patents and other publications cited here show the state of the art, and these are hereby incorporated with their entire contents into the present description.

Eksempel 93Example 93

Enhetsblanding for parenteral doseringUnit mixture for parenteral dosing

En blanding som inneholder 20 mg av forbindelsen fra Eksempel 1 som tørt, sterilt pulver fremstilles som følger: 20 mg av forbindelsen løses i 15 mL destillert vann. Løsningen filtreres under sterile betingelser over i 25 mL hetteglass og lyofiliseres. Pulveret rekonstitueres ved tilsetning av 20 mL 5% dekstrose i vann (D5W) for intravenøs eller intramuskulær injeksjon. Doseringen bestemmes derved ut fra injeksjonsvolumet. Påfølgende fortynning kan skje ved tilsetning av et avmålt volum av denne doseringsenhet til et annet volum av D5Wfor injeksjon, eller kan en avmålt dose tilsettes til en annen mekanisme for administrering av medikamentet, som f.eks. til en flaske eller pose for i.v. dråpeinfusjon eller et annet system for injeksjon-infusjon. A mixture containing 20 mg of the compound from Example 1 as dry, sterile powder is prepared as follows: 20 mg of the compound is dissolved in 15 mL of distilled water. The solution is filtered under sterile conditions into a 25 mL vial and lyophilized. The powder is reconstituted by adding 20 mL of 5% dextrose in water (D5W) for intravenous or intramuscular injection. The dosage is thereby determined based on the injection volume. Subsequent dilution can be done by adding a measured volume of this dosage unit to another volume of D5W for injection, or a measured dose can be added to another mechanism for administering the drug, such as to a bottle or bag for i.v. drip infusion or another system of injection-infusion.

Eksempel 94Example 94

Enhetsblanding for peroral doseringUnit mixture for oral dosing

En kapsel for peroral administrering fremstilles ved å blande og male 50 mg av forbindelsen fra Eksempel 1 med 75 mg laktose og 5 mg magnesiumstearat. Det resulterende pulver siktes og fylles over i en hård-gelatinkapsel. A capsule for oral administration is prepared by mixing and grinding 50 mg of the compound from Example 1 with 75 mg of lactose and 5 mg of magnesium stearate. The resulting powder is sieved and filled into a hard gelatin capsule.

Eksempel 95Example 95

Enhetsblanding for peroral doseringUnit mixture for oral dosing

En tablett for peroral administrering fremstilles ved å blande og granulereA tablet for oral administration is prepared by mixing and granulating

20 mg sukrose, 150 mg kalsiumsulfatdihydrat og 50 mg av forbindelsen fra Eksempel 1 med 10% gelatinløsning. De fuktige granulene siktes, tørkes, blandes med 10 mg stivelse, 5 mg talk og 3 mg stearinsyre, og presses til en tablett. 20 mg sucrose, 150 mg calcium sulfate dihydrate and 50 mg of the compound from Example 1 with 10% gelatin solution. The moist granules are sieved, dried, mixed with 10 mg of starch, 5 mg of talc and 3 mg of stearic acid, and pressed into a tablet.

Claims (45)

1. Forbindelse med formel (I) eller (II) eller (III) eller (IV) eller (V): 1. Compound of formula (I) or (II) or (III) or (IV) or (V): W er CHRVU-CHRVV eller W is CHRVU-CHRVV or A er en fibrinogen-reseptorantagonist-templat; U og V mangler eller er CO, CR <9>2 , C(=CR92 ), S(0)k , O, NR <9> , CR <9> OR <9> , CR9 (OR k) CR <9>2 , CR <9>2 CR <9> (OR <k> ), C(0)CR <9>2 , CR <9>2 C(0), CONR', NR^O, OC(O), C(0)0, C(S)0, OC(S), C(S)NR <9> , NR <9> C(S), S(0)2 NR <9> , NR <9> S(0)2 , N=N, NR <9> NR <9> , NR <9> CR <9>2 , NR <9> CR <9>2 , CR <9>2 0, OCR <9>2 , C=C eller CR <9> =C R <9> ; G er NR <e> , S eller O; R <9> er H, C^ -alkyl, Het-C0 .6 -alkyl, C3 .7 -cykloalkyl-C0 .6 -alkyl eller Ar-C0 .6 -alkyl; R <k> er R <9> , -C(0)R <9> eller -C(0)OR <f> ; R' er H, C^-a^yl, Het-C0 .6 -alkyl, C3 .7 -cykloalkyl-C0 .6 -alkyl, Ar-C0 .6 -alkyl eller C^ -alkyl substituert med én til tre grupper valgt fra halogen, CN, NR <9>2 , OR9, SR9, C02 R <9> og CON(R <9> )2 ; R'er H, C^ -alkyl eller Ar-C^ -alkyl; Re er H, C^ -alkyl, Ar-C^-a^yl, Het-CLe-alkyl, C3 .7 -cykloalkyl-Cv6 -alkyl eller (CH2 )k C02 R <9> ; kerO, 1 eller 2; q er 1 eller 2; a erO, 1 eller2; b erO, 1 eller2; R <b> og R <c> er uavhengig av hverandre valgt fra H, C^e -alkyl, Ar-C0 .6 -alkyl, Het-C0 .6 -alkyl eller C3.6-cykloalkyl-C0.6-alkyl, halogen, CF3 , OR <f> , S(0)k R <f> , COR', N02 , N(R <f> )2 , CO(NR <f> )2 , CH2N(R')2 eller R <b> og R <c> er forenet under dannelse av en fem- eller seks-leddet aromatisk eller ikke-aromatisk karbocyklisk eller heterocyklisk ring, som eventuelt er substituert med opp til tre substituenter valgt fra halogen, CF3 , C^ -alkyl, OR', S(0)k R', COR <f> , C02 R <f> , OH, N02 , N(R')2 , CO(NR')2 og CH2N(R')2; eller metylendioksy. eller et farmasøytisk akseptabelt salt derav, med det forbehold at: (i) når A er 1,2,4,5-tetrahydro-3-okso-4-(2-fenyletyl)-1 H-1,4-benzodiazepin-2-eddiksyre, da er W ikke -(CH2 )2 .3 NHCO-bundet til imidazolringens 1-stilling; og (ii) når A er 1,2,4,5-tetrahydro-3-okso-4-(2-fenyletyl)-1 H-1,4-benzodiazepin-2-eddiksyre, da er W ikke -(CH2 )2 NHCO-bundet til imidazolringens 4(5)-stilling .A is a fibrinogen receptor antagonist template; U and V are missing or are CO, CR <9>2 , C(=CR92 ), S(0)k , O, NR <9> , CR <9> OR <9> , CR9 (OR k) CR <9 >2 , CR <9>2 CR <9> (OR <k> ), C(0)CR <9>2 , CR <9>2 C(0), CONR', NR^O, OC(O) , C(0)0, C(S)0, OC(S), C(S)NR <9> , NR <9> C(S), S(0)2 NR <9> , NR <9> S(0)2 , N=N, NR <9> NR <9> , NR <9> CR <9>2 , NR <9> CR <9>2 , CR <9>2 0, OCR <9> 2 , C=C or CR <9> =C R <9> ; G is NR <e> , S or O; R<9> is H, C 1 -alkyl, Het-C 0.6 -alkyl, C 3.7 -cycloalkyl-C 0.6 -alkyl or Ar-C 0.6 -alkyl; R <k> is R <9> , -C(0)R <9> or -C(0)OR <f> ; R' is H, C 1 -a 6 -yl, Het -C 0 .6 -alkyl, C 3 .7 -cycloalkyl-C 0 .6 -alkyl, Ar -C 0 .6 -alkyl or C 1 -alkyl substituted with one to three groups selected from halogen, CN, NR <9>2 , OR9, SR9, CO2 R <9> and CON(R <9> )2 ; R' is H, C 1 -alkyl or Ar -C 1 -alkyl; Re is H, C 1 -alkyl, Ar-C 1 -alkyl, Het-C 1 -alkyl, C 3 -7 -cycloalkyl-C 6 -alkyl or (CH 2 )k CO 2 R<9> ; kerO, 1 or 2; q is 1 or 2; a is 0, 1 or 2; b is 0, 1 or 2; R <b> and R <c> are independently selected from H, C 6 -alkyl, Ar-C 0.6 -alkyl, Het-C 0.6 -alkyl or C 3.6 -cycloalkyl-C 0.6 -alkyl , halogen, CF3 , OR <f> , S(0)k R <f> , COR', N02 , N(R <f> )2 , CO(NR <f> )2 , CH2N(R')2 or R <b> and R <c> are united to form a five- or six-membered aromatic or non-aromatic carbocyclic or heterocyclic ring, which is optionally substituted with up to three substituents selected from halogen, CF 3 , C 3 -alkyl , OR', S(0)k R', COR <f> , CO 2 R <f> , OH, NO 2 , N(R') 2 , CO(NR') 2 and CH 2 N(R') 2 ; or methylenedioxy. or a pharmaceutically acceptable salt thereof, with the proviso that: (i) when A is 1,2,4,5-tetrahydro-3-oxo-4-(2-phenylethyl)-1H-1,4-benzodiazepine-2-acetic acid, then W is not -(CH2 )2 .3 NHCO-bonded to the 1-position of the imidazole ring; and (ii) when A is 1,2,4,5-tetrahydro-3-oxo-4-(2-phenylethyl)-1H-1,4-benzodiazepine-2-acetic acid, then W is not -(CH2 )2 NHCO-bonded to the 4(5) position of the imidazole ring. 2. Forbindelse ifølge krav 1, hvor fibrinogen reseptorantagonist-templat A er 2. A compound according to claim 1, wherein fibrinogen receptor antagonist template A is hvor: A <1> til A <5> danner en tilgjengelig substituert syv-leddet ring som kan være mettet eller umettet, og som eventuelt inneholder opp til to heteroatomer valgt fra gruppen O, S og N, hvor S og N eventuelt kan være oksydert; D <1> til D <4> danner en tilgjengelig substituert seks-leddet ring som eventuelt inneholder opp til to nitrogenatomer; R er minst én substituent valgt fra R <7-> gruppen eller Q-C^ -alkyl, Q-C^ alkenyl, Q-C2 .4 -alkynyl, eventuelt substituert med én eller flere =0 , R <11> eller R <7> ; R <*> er H, Q-C^ -alkyl, Q-CLg-oksoalkyl, Q-C2 .6 -alkenyl, Q-C3 .4 -oksoalkenyl, Q-C3 .4 -oksoalkynyl, Q-C2 .4 -alkynyl, C3 .6 -cykloalkyl, Ar eller Het, eventuelt substituert med én eller flere R11; Q er H, C3 .6 -cykloalkyl, Het eller Ar; R7 er -COR <8> , -COCR'2 R <9> , -C(S)R <8> , -S(0)m OR', -S(0)m NR'R", -PO(OR'), -PO(OR')2 , -B(OR')2 , -N02 og Tet; R <8> er-OR', -NR'R", -NR'S02 R', -NR'OR', -OCR'2 C(0)OR', -OCR'2 OC(0)-R', -OCR'2 C(0)NR'2 , CF3 eller AA; R9 er -OR', -CN, -S(0)r R', S(0)m NR'2 , -C(0)R'C(0)NR'2 eller -C02 R'; R11 er H, halogen, -OR <12> , -CN, -NR'R <12> , -N02> -CF3 , CF3 S(0)r , -C02 R', -CONR'2l Q-C0 .6 -alkyl-, Q-C^ -oksoalkyl-, Q-C2 .s- <a> lkenyl-, Q-C2 .6 -alkynyl-, Q-C0 .6 -alkyloksy-, Q-C0 .6 -alkylamino- eller Q-C0 .6 -alkylS(O)r -; R <12> er R', -C(0)R\ -C(0)NR'2 , -C(0)OR <15> , -S(0)mR' eller S(0)mNR2; R <13> er R', -CF3 , -SR' eller-OR'; R <14> er R', C(0)R', CN, N02, S02R' eller C(0)OR <15> ; R <15> er H, C,.6 -alkyl eller Ar-C0 .4 -alkyl; R' er H, C^ -alkyl, C3 .7 -cykloalkyl-C0 .4 -alkyl eller Ar-C0^ ,-alkyl; R" er R', -C(0)R' eller -C(0)OR <15> ; R'" er R" eller AA2; AA1 er en aminosyre bundet gjennom aminogruppen og hvor karboksylgruppen eventuelt er beskyttet, og AA2 er en aminosyre bundet via karboksylgruppen og hvor aminogruppen eventuelt er beskyttet; m er 1 eller 2; n er 0 til 3; p er 0 eller 1; og t er 0 til 2; eller farmasøytisk akseptable salter derav, med det forbehold: (i) når A er 1,2,4,5-tetrahydro-3-okso-4-(2-fenyletyl)-1 H-1,4-benzodiazepin-2-eddiksyre, da er W. ikke -(CH2 )2 .3 NHCO- som i 1-stillingen er bundet til en imidazolring, og (ii) når A er 1,2,4,5-tetrahydro-3-okso-4-(2-fenyletyl)-1 H-1,4-benzodiazepin-2-eddiksyre, da er W ikke -(CH2 )2 NHCO- som i 4(5)-stillingen er bundet til en imidazolring.where: A <1> to A <5> form an available substituted seven-membered ring which may be saturated or unsaturated, and which optionally contains up to two heteroatoms selected from the group O, S and N, where S and N may optionally be oxidized; D <1> to D <4> form an accessible substituted six-membered ring optionally containing up to two nitrogen atoms; R is at least one substituent selected from the R <7-> group or Q-C 4 -alkyl, Q-C 4 alkenyl, Q-C 2 , 4 -alkynyl, optionally substituted with one or more =0 , R <11> or R <7> ; R <*> is H, Q-C 1 -alkyl, Q-C 6 -oxoalkyl, Q-C 2 .6 -alkenyl, Q-C 3 .4 -oxoalkenyl, Q-C 3 .4 -oxoalkynyl, Q-C 2 .4 -alkynyl, C3.6 -cycloalkyl, Ar or Het, optionally substituted with one or more R11; Q is H, C3.6 -cycloalkyl, Het or Ar; R7 is -COR <8> , -COCR'2 R <9> , -C(S)R <8> , -S(0)m OR', -S(0)m NR'R", -PO( OR'), -PO(OR') 2 , -B(OR') 2 , -NO 2 and Tet; R <8> is -OR', -NR'R", -NR'SO2 R', -NR'OR', -OCR'2 C(0)OR', -OCR'2 OC(0)-R' , -OCR'2 C(0)NR'2 , CF3 or AA; R 9 is -OR', -CN, -S(O)r R', S(O)m NR' 2 , -C(O)R'C(O)NR' 2 or -CO 2 R'; R11 is H, halogen, -OR <12> , -CN, -NR'R <12> , -N02> -CF3 , CF3 S(0)r , -CO2 R', -CONR'2l Q-C0 .6 -alkyl-, Q-C^ -oxoalkyl-, Q-C2 .s- <a>lkenyl-, Q-C2 .6 -alkynyl-, Q-C0 .6 -alkyloxy-, Q -C0.6 -alkylamino- or C -C0.6 -alkylS(O)r -; R <12> is R', -C(0)R\ -C(0)NR'2 , -C(0)OR <15> , -S(0)mR' or S(0)mNR2 ; R<13> is R', -CF3, -SR' or -OR'; R<14> is R', C(0)R', CN, NO2, SO2R' or C(0)OR<15>; R<15> is H, C1-6 alkyl or Ar-C0-4 alkyl; R' is H, C 1 -alkyl, C 3-7 -cycloalkyl-C 0-4 -alkyl or Ar-C 0-4 -alkyl; R" is R', -C(0)R' or -C(0)OR <15> ; R'" is R" or AA2; AA1 is an amino acid bound through the amino group and where the carboxyl group is optionally protected, and AA2 is an amino acid bound via the carboxyl group and where the amino group is optionally protected; m is 1 or 2; n is 0 to 3; p is 0 or 1; and t is 0 to 2; or pharmaceutically acceptable salts thereof, with the proviso: (i) when A is 1,2,4,5-tetrahydro-3-oxo-4-(2-phenylethyl)-1H-1,4-benzodiazepine-2-acetic acid, then W is not -(CH2 ) 2 .3 NHCO- which in the 1-position is bound to an imidazole ring, and (ii) when A is 1,2,4,5-tetrahydro-3-oxo-4-(2-phenylethyl)-1H-1,4-benzodiazepine-2-acetic acid, then W is not -(CH2 )2 NHCO- which in the 4(5) position is bound to an imidazole ring. 3. Forbindelse ifølge krav 2, hvor: A<1> er CR1R1', CR <1> ,NR<1> , N, O eller S(0)x ; A2 er CR2R2', CR2, NR2; A3 er CR<3>R<3> ',CR<3> , NR <3> , N, O eller S(0)x ; A <4> er CR <4> R <4> , CR <4> , NR <4> , eller N; A5 er CR <5>R<5> ',CR<5> ,NR<5> , N, O eller S(0)x ; D <1->D<4> er CH eller N; R <1> og R <1> ' er R <*> eller R eller utgjør sammen =0; R2 og R2' er R <*> , R eller =0; R3 og R <3> er R <*> , R eller =0; R<4> og R <4> ' er R <*> , R eller =0; R5 og R5' er R <*> , R eller =0; og xerO, 1, eller 2.3. Connection according to claim 2, where: A<1> is CR1R1', CR<1>, NR<1>, N, O or S(0)x; A 2 is CR 2 R 2', CR 2 , NR 2 ; A3 is CR<3>R<3> ',CR<3> , NR <3> , N, O or S(0)x ; A <4> is CR <4> R <4> , CR <4> , NR <4> , or N; A5 is CR <5>R<5> ',CR<5> ,NR<5> , N, O or S(0)x ; D<1->D<4> is CH or N; R <1> and R <1> ' are R <*> or R or together constitute =0; R2 and R2' are R <*> , R or =O; R3 and R<3> are R<*> , R or =O; R<4> and R<4>' are R<*> , R or =0; R5 and R5' are R <*> , R or =O; and xerO, 1, or 2. 4. Forbindelse ifølge krav 2, hvor A<1> står for CR <1> R <1> , CR <1> ,N R <1> , N, 0 eller S; A <2> for CR <2>R<2> ', NR2 eller CR <2>;A<3> for CR 3R3';A<4> for CR<4>R<4> , CR <4> , NR <4> eller N; A <5> for CR<5> R <5> ', CR <5> ,NR<5> , N, 0; D<1> og D4 er CH; D <2> eller D <3> er CH <6> ; R2 eller R <4> er R;R<3> ,R<3> ' og R5,R5 er <=> 0 eller R <*> ,H.4. Compound according to claim 2, wherein A<1> stands for CR <1> R <1> , CR <1> ,N R <1> , N, 0 or S; A <2> for CR <2>R<2> ', NR2 or CR <2>;A<3> for CR 3R3';A<4> for CR<4>R<4> , CR <4> , NR <4> or N; A <5> for CR<5> R <5> ', CR <5> ,NR<5> , N, 0; D<1> and D4 are CH; D <2> or D <3> is CH <6> ; R2 or R <4> is R;R<3> ,R<3> ' and R5,R5 is <=> 0 or R <*> ,H. 5. Forbindelse ifølge krav 2,.hvor A<1> står for CHR1 , CR <1> , NR", N eller S; A2 for CR <2> eller CR<2>R<2>; A3 for CR <3>R<3> ';A<4> for CR4R4' eller NR4;A 5 for CR<5> R <5> ', og D <1->D<4> er CH.5. Compound according to claim 2, where A<1> stands for CHR1 , CR <1> , NR", N or S; A2 for CR <2> or CR<2>R<2>; A3 for CR <3>R<3> ';A< 4> for CR4R4' or NR4; A 5 for CR<5> R <5> ', and D <1->D<4> is CH. 6. Forbindelse ifølge krav 2, hvor A <1> står for CR <1> , A <2> for CR <2> ,A<3> for C=0, A <4> for NR<4> ogA<5> for CHR <5> .6. Compound according to claim 2, wherein A <1> stands for CR <1> , A <2> for CR <2> , A<3> for C=0, A <4> for NR<4> and A<5> for CHR <5> . 7. Forbindelse ifølge krav 2, hvor A <1> står for NR1 , A2 for CHCR<2> ,A<3> for CR <3>R<3> ,A4 for NR <4> og A <5> for C=0.7. Compound according to claim 2, wherein A <1> stands for NR1, A2 for CHCR<2>, A<3> for CR <3>R<3>, A4 for NR <4> and A <5> for C=0. 8. Forbindelse ifølge krav 2, hvor A <1> ogA4 står for C=0 , A2 for NR <2> , A <3> for CHR <3> ogA<5> for NR<5> .8. Compound according to claim 2, wherein A <1> and A4 stand for C=0, A2 for NR <2>, A <3> for CHR <3> and A<5> for NR<5>. 9. Forbindelse ifølge krav 2, hvor A <1> står for NR<1> , A2 for CHR <2> ,A<3> for C=0, A <4> for NR' og A <5> for CHR <5> .9. Compound according to claim 2, wherein A <1> stands for NR<1>, A2 for CHR <2>, A<3> for C=0, A <4> for NR' and A <5> for CHR <5>. 10. Forbindelse ifølge krav 2, hvor: 10. Compound according to claim 2, where: 11. Forbindelse ifølge krav 2, hvor: 11. Compound according to claim 2, where: 12. Forbindelse ifølge krav 11, karakterisert ved at: R <1> er H eller C^ -alkyl; R2, R2 er H, -CH2 C02 H; ogR<5> ,R<5> ' er H,H. 12. Compound according to claim 11, characterized in that: R<1> is H or C 1 -alkyl; R 2 , R 2 is H, -CH 2 CO 2 H; and R<5> , R<5> ' are H,H. 13. Forbindelse ifølge krav 2, karakterisert ved at den er: (2S)-7-[[[N-(2-benzimidazolyl)metyl-N-metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; 7-[[[2-(4-aza-5-metylbenzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (±)-7-[[[2-(4-azabenzimidazolyl)metyl]metylamino]karbonyl]-4-(2-metoksyetyl)-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (±)-7-[[[2-(benzimidazolyl)metyl]metylamino]karbonyl]-4-(2-metoksyetyl)-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; 7-[[[2-(4-azabenzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (2S)-7-[[[N-butyl-N-benzimidazol-2-yl)metyl]amino]karbonyl]-3-okso-4-metyl-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; 7-[[[(2-benzimidazolyl)metyl]metylamino]karbonyl]-3-okso-4-(2-fenyl® tyl)-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; 7-[[[N-(2-benzimidazolyl)metyl-N-(2-fenyletyl)]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (±)-7-[[[2-(benzimidazolyl)metyl]amino]karbonyl-4-[2-(3,4-metylendioksyfenyl)etyl]-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre; og (±)-7-[[[N-(2-benzimidazolyl)metyl-N-metyl]amino]karbonyl]-3-okso-4-(2-fenyletyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre; (±)-7-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (±)-7-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-3-okso-4-(2-fenyletyl)-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (±)-4-isopropyl-7-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (±)-7-[[[N-(2-benzotiazolyl)metyl-N^ 2,3,4,5-tetrahydro-l H-1,4-benzodiazepin-2-eddiksyre; (+)-7-[[[N-(2-benzoksazolyl)metyl-N-metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (±)-7-[[[N-[2-(5(6)-klorbenzimidazolyl)metyl]-N-metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (±)-7-[[[2-indolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre; (2S)-7-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (2R)-7-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (±)-7-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-9-klor-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (±)-8-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-2-metyl-3-okso-2,3,4,5-tetrahydro-1 H-2-benzazepin-4-eddiksyre; (±)-8-[[[N-(2-benzimidazolyl)metyl-N-rr^ tyl]amino]karbonyl]-2-metyl-3-okso-2,3,4,5-tetrahydro-1H-2-benzazepin-4-eddiksyre; (+)-7-[[[N-(2-benzimidazolyl)metyl-N-metyl]amino]karbonyl]- 3-okso-4-(2-fenyletyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre; (+)-7-[[[N-(2-benzimidazolyl)metyl-N-metyl]amino]metyl]-1,4-dimetyl-3-okso-2,3,4,S-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (±)-7-[[[N-(2-benzimidazolyl)metyl-N-metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (±)-7-[[[2-(2-benzimidazolyl)etyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (±)-7-[[(2-benzimidazolyl)amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (2S)-7-[[[N-(2-benzimidazolyl)metyl-N-metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (+)-4-metyl-7-[[[N-(2-(1-metyl)benzimidazolyl)metyl-N-metyl]amino]karbonyl]-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (±)-7-[[[(2-(5(6)-metoksy)benzim^ okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (±)-7-[[[N-[2-(4-azabenzimidazolyl)]metyl-N-metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (±)-7-[[[N-[2-(5(6)-azabenzimidazolyl)metyl-N-metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (±)-7-[[[(2-imidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-acetat; (±)-7-[[[2-(benzimidazolyl)metyl]metylamino]karbonyl]-4-(2-metoksyetyl)- 3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (+)-7-[[[2-(4-azabenzimidazolyl)metyl]metylamino]karbonyl]-4-(2-metoksyetyl)-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (±)-7-[[[2-(1-metylindolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (±)-7-[[[2-(1-metylindolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; [[[(2RS-indolinyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2S-eddiksyre; (±)-7-[[[(2-imidazolyl)metyl]amino]karbonyl]- 3-okso-4-(2-fenyletyl)-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (±)-7-[[[(2-benzimidazolyl)metyl]amino]metyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (±)-7-[[[(2-benzimidazolyl)metyl]amino]karbonyl]-1,4-dimetyl-3-okso-2^ tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (±)-7-[[[(2-benzimidazolyl)metyl]metylamino]karbonyl]- 3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (2S)-7-[[[N-butyl-N-benzimidazol-2-yl)mer7 l]amino]karbonyl]-3-okso-4-metyl-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; 7-[[[N-(2-behzimidazolyl)metyl-N-(2-fenyletyl)amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; 7-[[[N-(2-benzimidazolyl)metyl-N-karboksymetyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; 7-[[[N-(2-benzimidazolyl)-metyl-N-cykloheksyl]amino]karbonyl]-4-metyl-3 2,3,4,5-tetrahydro-l H-1,4-benzodiazepin-2-eddiksyre; (±)-7-[[[2-(5-nitrobenzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-l H-1,4-benzodiazepin-2-eddiksyre; (±)-7-[[[2-(5-aminobenzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-oks 2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (±)-7-[2-(1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indolyl)karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; 7-[[[2-(5,6-metylendioksybenzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; 7-[[[2-(4,6-diazabenzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; 7-[[[2-(4-azabenzimidazolyl)metyl]metylamtno]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; [1-[2R-(2-benzimidazolyl)pyrrolidinyl]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2S-eddiksyre; [1-[2S-(2-benzimidazolyl)pyrrolidinyl]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2S-eddiksyre; (±)-7-[[[2-(4-azabenzimidazolyl)metyl]metylamino]karbonyl]-4-isopropyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; 7-[[[2-(4-aza-5-metylbenzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; 7-[[[2-(5,6-dimetoksybenzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (±)-8-[[2-(2-benzimidazolyl)acetyl]amino]-2-metyl-3-okso-2,3,4,5-tetrahydro-1 H-2-benzazepin-4-eddiksyre; (±)-8-[[[(2-benzimidazolyl)metyl]metylamino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-2-benzazepin-4-eddiksyre; 7-[[[(2-benzimidazolyl)metyl]metylamino]karbonyl]- 3-okso-4-(2-fenyletyl)-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (±)-7-[[[2-(benzimidazolyl)metyl]amino]karbonyl-4-[2-(3,4-metylendioksyfenyl)etyl]-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre; (±)-7-[[[(4(5)-imidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (+)-[[[4-(2-fenylimidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (±)-[[[4-(2-fenylimidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; ) (±)-7-[[[2-(3-indolyl)etyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre; 7-[[[2-(4-fenylimidazolyl)metyl]amino]karbonyl]-4-metyl-3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; (+/-)-2,3,4,5-tetrahydro-7-[[[benzimidazol-2-yl)metyl]metylamino]karbonyl]-4- > (3,3-dimetylbutyl)- 3-okso-1 H-1,4-benzodiazepin-2-eddiksyre; (-)-7-[[[6-trifluormetylbenzimidazoyl-2-ylmetyl]aminometyl]karbonyl]-2,3,4,5-tetrahydro-4-metyl-3-okso-benzodiazepin-2-eddiksyre; (-)-7-[[[4,7-dimetoksybenzimidazoyl-2-ylmetyl]aminometyl]karbonyl]-2,3,4,5-tetrahydro-4-metyl-3-okso-benzodiazepin-2-eddiksyre; ) (+/-)-2,3,4 ,5-tetrahydro-7-[[[(benzimidazol-2-yl)metylamino]karbonyl]-4-(3,3-dimetylbutyl)- 3-okso-1H-1,4-benzodiazepin-2-eddiksyre; (-)-7-[[[7-metylbenzimidazol-2-ylmetyl]metylamino]karbonyl]-2,3,4,5-tetrahydro^ 4-metyl-3-okso-1,4-benzodiazepin-2-eddiksyre; (2S)-[[[N-aminobutyl-N-(benzimidazol-2-yl)metyl]amino]karbonyl]-3-okso-4-5 metyl-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre-bis(trifluoracetat)salt; (2S)-[[[N-cyanometyl-N-(benzimidazol-2-yl)metyl]amino]karbonyl]-3-okso-4-metyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-eddiksyre-dihydrokloridsalt; 2,3,4,5-tetrahydro-7-[[[(benzimidazol-2-yl)metyl]amino]karbonyl]-4-(4-ftalimidobutyl)- 3-okso-1,4-benzodiazepin-2-eddiksyre; (-)-7-[[[imidazo[4,5-b]-4,6-dimetylpyridyl-2-ylmetyl]aminometyl]karbonyl]-2,3,4,5-tetrahydro-4-metyl-3-okso-benzodiazepin-2-eddiksyre-trifluoracetatsalt; (+/-)-7-[[(2-benzimidazol-2-ylmety^^ 3-okso-4-[2-(3'> 4'-metylendoksyfenyl)etyl]-1H-1,4-benzodiazepin-2-eddiksyre; (+/-)-2,3,4,5-tetrahydro-7-[[[(benzimidazol-2-yl)metyl]amino]karbonyl]-4-(2-metoksyetyl)- 3-okso-1 H-1,4-benzodiazepin-2-eddiksyre; 7-[[2-[1-metylbenzimidazolyl]benzimidazolylmetylamino]karbonyl]-2,3,4,5-tetrahydro-4-metyl-3-okso-1 H-1,4-benzodiazepin-2-eddiksyre; 7-[[[N-cykloheksyl-N-(benzimidazol-2-yl)metyl]amino]karbonyl]- 3-okso-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre; 7-[[[2-bis(benzimidazolylmetyl)aminokarbonyl]-2,3,4,5-tetrahydro-4-metyl-3-okso-1 H-1,4-benzodiazepin-2-eddiksyre; (+/-)-2,3,4,5-tetrahydro-7-[[[imidazo[4,5-b]pyrid-2-yl]metyl]metylamino]-karbonyl]-4-(3,3-dimetylbutyl)- 3-okso-1 H-1,4-benzodiazepin-2-eddiksyre; (+/-)-7-[[(2-benzimidazol-2-ylmetyl)-N-metylamino]karbonyl-2,3,4,5-tetrahydro-3- okso-4-(2',2,,2'-trifluoretyl)-1H-1,4-benzodiazepin-2-eddiksyre; (+/-)-7-[[(2-benzimidazolyl)acetyl]amino]-5-okso-4-(2-fenyletyl)-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepin-2-eddiksyre, (+/-)-7-[[(2-benzimidazol-2-ylmetyl)amino]karbonyl]-2,3,4,5-tetrahydro-3-okso-4- (2',2',2'-trifluoretyl)-1 H-1,4-benzodiazepin-2-eddiksyre; (-)-7-[[[5,6-difluorbenzimidazolyl-2-ylmetyl]aminometyl]karbonyl]-2,3,4,5-tetrahydro-4-metyl-3-okso-1,4-benzodiazepin-2-eddiksyre; og (+/-)-7-[[bis-(benzimidazol-2-ylmetyl)amino]karbonyl]-2,3,4,5-tetrahydro-4-fenyletyl-3-okso-1H-1,4-benzodiazepin-2-eddiksyre-tris(trifluoracetat)salt.13. Compound according to claim 2, characterized in that it is: (2S)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1, 4-benzodiazepine-2-acetic acid; 7-[[[2-(4-aza-5-methylbenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine- 2-acetic acid; (±)-7-[[[2-(4-azabenzimidazolyl)methyl]methylamino]carbonyl]-4-(2-methoxyethyl)-3-oxo-2,3,4,5-tetrahydro-1 H-1, 4-benzodiazepine-2-acetic acid; (±)-7-[[[2-(benzimidazolyl)methyl]methylamino]carbonyl]-4-(2-methoxyethyl)-3-oxo-2,3,4,5-tetrahydro-1 H-1,4- benzodiazepine-2-acetic acid; 7-[[[2-(4-azabenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid; (2S)-7-[[[N-butyl-N-benzimidazol-2-yl)methyl]amino]carbonyl]-3-oxo-4-methyl-2,3,4,5-tetrahydro-1 H-1 ,4-benzodiazepine-2-acetic acid; 7-[[[(2-benzimidazolyl)methyl]methylamino]carbonyl]-3-oxo-4-(2-phenyl® ethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine- 2-acetic acid; 7-[[[N-(2-benzimidazolyl)methyl-N-(2-phenylethyl)]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1, 4-benzodiazepine-2-acetic acid; (±)-7-[[[2-(benzimidazolyl)methyl]amino]carbonyl-4-[2-(3,4-methylenedioxyphenyl)ethyl]-3-oxo-2,3,4,5-tetrahydro-1H -1,4-benzodiazepine-2-acetic acid; and (±)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1H -1,4-benzodiazepine-2-acetic acid; (±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2- acetic acid; (±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1 H-1,4- benzodiazepine-2-acetic acid; (±)-4-isopropyl-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2- acetic acid; (±)-7-[[[N-(2-benzothiazolyl)methyl-N, 2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid; (+)-7-[[[N-(2-benzoxazolyl)methyl-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1, 4-benzodiazepine-2-acetic acid; (±)-7-[[[N-[2-(5(6)-chlorobenzimidazolyl)methyl]-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5- tetrahydro-1H-1,4-benzodiazepine-2-acetic acid; (±)-7-[[[2-indolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid; (2S)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2- acetic acid; (2R)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2- acetic acid; (±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-9-chloro-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1,4- benzodiazepine-2-acetic acid; (±)-8-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid; (±)-8-[[[N-(2-benzimidazolyl)methyl-N-aryl]amino]carbonyl]-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2 -benzazepine-4-acetic acid; (+)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]- 3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1H -1,4-benzodiazepine-2-acetic acid; (+)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]methyl]-1,4-dimethyl-3-oxo-2,3,4,S-tetrahydro-1 H- 1,4-benzodiazepine-2-acetic acid; (±)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1, 4-benzodiazepine-2-acetic acid; (±)-7-[[[2-(2-benzimidazolyl)ethyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine- 2-acetic acid; (±)-7-[[(2-benzimidazolyl)amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid; (2S)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1, 4-benzodiazepine-2-acetic acid; (+)-4-methyl-7-[[[N-(2-(1-methyl)benzimidazolyl)methyl-N-methyl]amino]carbonyl]-3-oxo-2,3,4,5-tetrahydro- 1 H-1,4-benzodiazepine-2-acetic acid; (±)-7-[[[(2-(5(6)-methoxy)benzim^oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid; (±)-7-[[[N-[2-(4-azabenzimidazolyl)]methyl-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1,4-benzodiazepine-2-acetic acid; (±)-7-[[[N-[2-(5(6)-azabenzimidazolyl)methyl-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro -1 H-1,4-benzodiazepine-2-acetic acid; (±)-7-[[[(2-imidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2- acetate; (±)-7-[[[2-(benzimidazolyl)methyl]methylamino]carbonyl]-4-(2-methoxyethyl)- 3-oxo-2,3,4,5-tetrahydro-1H-1,4- benzodiazepine-2-acetic acid; (+)-7-[[[2-(4-azabenzimidazolyl)methyl]methylamino]carbonyl]-4-(2-methoxyethyl)-3-oxo-2,3,4,5-tetrahydro-1 H-1, 4-benzodiazepine-2-acetic acid; (±)-7-[[[2-(1-methylindolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine- 2-acetic acid; (±)-7-[[[2-(1-methylindolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine- 2-acetic acid; [[[(2RS-indolinyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2S-acetic acid; (±)-7-[[[(2-imidazolyl)methyl]amino]carbonyl]- 3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1 H-1,4- benzodiazepine-2-acetic acid; (±)-7-[[[(2-benzimidazolyl)methyl]amino]methyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2- acetic acid; (±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-1,4-dimethyl-3-oxo-2, tetrahydro-1H-1,4-benzodiazepine-2-acetic acid; (±)-7-[[[(2-benzimidazolyl)methyl]methylamino]carbonyl]-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid; (2S)-7-[[[N-butyl-N-benzimidazol-2-yl)mer7 l]amino]carbonyl]-3-oxo-4-methyl-2,3,4,5-tetrahydro-1 H- 1,4-benzodiazepine-2-acetic acid; 7-[[[N-(2-behzimidazolyl)methyl-N-(2-phenylethyl)amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-1,4 -benzodiazepine-2-acetic acid; 7-[[[N-(2-benzimidazolyl)methyl-N-carboxymethyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine- 2-acetic acid; 7-[[[N-(2-benzimidazolyl)-methyl-N-cyclohexyl]amino]carbonyl]-4-methyl-3 2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2- acetic acid; (±)-7-[[[2-(5-nitrobenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine- 2-acetic acid; (±)-7-[[[2-(5-aminobenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-ox 2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2 -acetic acid; (±)-7-[2-(1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indolyl)carbonyl]-4-methyl-3-oxo-2,3,4,5 -tetrahydro-1H-1,4-benzodiazepine-2-acetic acid; 7-[[[2-(5,6-methylenedioxybenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2- acetic acid; 7-[[[2-(4,6-diazabenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2- acetic acid; 7-[[[2-(4-azabenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid; [1-[2R-(2-benzimidazolyl)pyrrolidinyl]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2S-acetic acid; [1-[2S-(2-benzimidazolyl)pyrrolidinyl]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2S-acetic acid; (±)-7-[[[2-(4-azabenzimidazolyl)methyl]methylamino]carbonyl]-4-isopropyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine- 2-acetic acid; 7-[[[2-(4-aza-5-methylbenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine- 2-acetic acid; 7-[[[2-(5,6-Dimethoxybenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2- acetic acid; (±)-8-[[2-(2-benzimidazolyl)acetyl]amino]-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid; (±)-8-[[[(2-benzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid; 7-[[[(2-benzimidazolyl)methyl]methylamino]carbonyl]- 3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2- acetic acid; (±)-7-[[[2-(benzimidazolyl)methyl]amino]carbonyl-4-[2-(3,4-methylenedioxyphenyl)ethyl]-3-oxo-2,3,4,5-tetrahydro-1H -1,4-benzodiazepine-2-acetic acid; (±)-7-[[[(4(5)-imidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine -2-acetic acid; (+)-[[[4-(2-phenylimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2- acetic acid; (±)-[[[4-(2-phenylimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2- acetic acid; ) (±)-7-[[[2-(3-indolyl)ethyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine- 2-acetic acid; 7-[[[2-(4-phenylimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid; (+/-)-2,3,4,5-tetrahydro-7-[[[benzimidazol-2-yl)methyl]methylamino]carbonyl]-4- > (3,3-dimethylbutyl)-3-oxo-1H-1,4-benzodiazepine-2-acetic acid; (-)-7-[[[6-trifluoromethylbenzimidazol-2-ylmethyl]aminomethyl]carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-benzodiazepine-2-acetic acid; (-)-7-[[[4,7-Dimethoxybenzimidazol-2-ylmethyl]aminomethyl]carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-benzodiazepine-2-acetic acid; ) (+/-)-2,3,4,5-tetrahydro-7-[[[(benzimidazol-2-yl)methylamino]carbonyl]-4-(3,3-dimethylbutyl)-3-oxo-1H- 1,4-benzodiazepine-2-acetic acid; (-)-7-[[[7-methylbenzimidazol-2-ylmethyl]methylamino]carbonyl]-2,3,4,5-tetrahydro 4-methyl-3-oxo-1,4-benzodiazepine-2-acetic acid; (2S)-[[[N-aminobutyl-N-(benzimidazol-2-yl)methyl]amino]carbonyl]-3-oxo-4-5 methyl-2,3,4,5-tetrahydro-1 H-1 ,4-benzodiazepine-2-acetic acid bis(trifluoroacetate) salt; (2S)-[[[N-cyanomethyl-N-(benzimidazol-2-yl)methyl]amino]carbonyl]-3-oxo-4-methyl-2,3,4,5-tetrahydro-1H-1,4 -benzodiazepine-2-acetic acid dihydrochloride salt; 2,3,4,5-tetrahydro-7-[[[(benzimidazol-2-yl)methyl]amino]carbonyl]-4-(4-phthalimidobutyl)- 3-oxo-1,4-benzodiazepine-2-acetic acid ; (-)-7-[[[imidazo[4,5-b]-4,6-dimethylpyridyl-2-ylmethyl]aminomethyl]carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo -benzodiazepine-2-acetic acid trifluoroacetate salt; (+/-)-7-[[(2-benzimidazol-2-ylmethyl^^ 3-oxo-4-[2-(3'> 4'-methyleneendoxyphenyl)ethyl]-1H-1,4-benzodiazepine-2 -acetic acid; (+/-)-2,3,4,5-tetrahydro-7-[[[(benzimidazol-2-yl)methyl]amino]carbonyl]-4-(2-methoxyethyl)- 3-oxo-1 H- 1,4-benzodiazepine-2-acetic acid; 7-[[2-[1-methylbenzimidazolyl]benzimidazolylmethylamino]carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid; 7-[[[N-cyclohexyl-N-(benzimidazol-2-yl)methyl]amino]carbonyl]- 3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2- acetic acid; 7-[[[2-bis(benzimidazolylmethyl)aminocarbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid; (+/-)-2,3,4,5-tetrahydro-7-[[[imidazo[4,5-b]pyrid-2-yl]methyl]methylamino]-carbonyl]-4-(3,3- dimethylbutyl)-3-oxo-1H-1,4-benzodiazepine-2-acetic acid; (+/-)-7-[[(2-benzimidazol-2-ylmethyl)-N-methylamino]carbonyl-2,3,4,5-tetrahydro-3-oxo-4-(2',2,,2 ('-trifluoroethyl)-1H-1,4-benzodiazepine-2-acetic acid; (+/-)-7-[[(2-benzimidazolyl)acetyl]amino]-5-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine -2-acetic acid, (+/-)-7-[[(2-benzimidazol-2-ylmethyl)amino]carbonyl]-2,3,4,5-tetrahydro-3-oxo-4-(2',2',2'- trifluoroethyl)-1H-1,4-benzodiazepine-2-acetic acid; (-)-7-[[[5,6-difluorobenzimidazolyl-2-ylmethyl]aminomethyl]carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1,4-benzodiazepine-2- acetic acid; and (+/-)-7-[[bis-(benzimidazol-2-ylmethyl)amino]carbonyl]-2,3,4,5-tetrahydro-4-phenylethyl-3-oxo-1H-1,4-benzodiazepine -2-acetic acid tris(trifluoroacetate) salt. 14. Forbindelse ifølge krav 1, hvor fibrinogen-reseptorantagonist-templat A er 14. A compound according to claim 1, wherein fibrinogen receptor antagonist template A is hvor: R <21> og R <22> uavhengig av hverandre er H eller -Z-C02R' eller Z-CON(Rf)2 med det forbehold at én av A1 eller A2 er -Z-C02R' eller Z-CON(R <f> )2 ; Zer -CH2-, -0(CH2 )q-, -NR <f> (CH2 )q-, -S(CH2 )q, -CH2 CH2 -, -CH(CH3 )CH2 -, -(CH2 )3 -, -CH=CH-, -C(CH3 )=CH-, CH2 -CH=CH- eller CH=CHCH2 ; og YerH, C^ -alkyl, C^ -alkoksy, CM-alkoksykarbonyl, F, Cl. Br, I, CF3 , OR', S(0)k R <f> , COR <f> , N02 , N(R <f> )2 , CO(NR <f> )2 , CH2 N(R')2 , metylendioksy eller Z-CO-R'.where: R <21> and R <22> are independently H or -Z-CO2R' or Z-CON(Rf)2 with the proviso that one of A1 or A2 is -Z-CO2R' or Z-CON(R <f> )2 ; Zer -CH2-, -0(CH2 )q-, -NR <f> (CH2 )q-, -S(CH2 )q, -CH2 CH2 -, -CH(CH3 )CH2 -, -(CH2 )3 -, -CH=CH-, -C(CH3 )=CH-, CH2 -CH=CH- or CH=CHCH2 ; and YerH, C 1 -alkyl, C 1 -alkyl, C 1 -C 6 -alkyl, F, Cl. Br, I, CF3 , OR', S(0)k R <f> , COR <f> , N02 , N(R <f> )2 , CO(NR <f> )2 , CH2 N(R') 2 , methylenedioxy or Z-CO-R'. 15. Forbindelse ifølge krav 14, hvor A er 15. Compound according to claim 14, where A is 16. Forbindelse ifølge krav 15, som er: 4-[2-[[[1-[(benzimidazol-2-yl)metyl]benzimidazol-2- yl]metyl]metylamino]acetyl]fenoksyeddiksyre; (±)-4-[[2-[(benzimidazol-2-yl)metyl]metylamino]-1-hydroksyetyl]-1,2-fenylendioksydieddiksyre; 4-[2-[[(benzimidazol-2-yl)metyl]metylamino]acetyl]-1,2-fenylendioksydieddiksyre; eller 3-[[4-[[[(benzimidazol-2-yl)metyl]amino]karbonyl]fenyl]amino]propionsyre. 16. Compound according to claim 15, which is: 4-[2-[[[1-[(benzimidazol-2-yl)methyl]benzimidazol-2- yl]methyl]methylamino]acetyl]phenoxyacetic acid; (±)-4-[[2-[(benzimidazol-2-yl)methyl]methylamino]-1-hydroxyethyl]-1,2-phenylenedioxydiacetic acid; 4-[2-[[(benzimidazol-2-yl)methyl]methylamino]acetyl]-1,2-phenylenedioxydiacetic acid; or 3-[[4-[[[(benzimidazol-2-yl)methyl]amino]carbonyl]phenyl]amino]propionic acid. 17. Forbindelse ifølge krav 1, hvor fibrinogen-reseptorantagonist-templat A er 17. A compound according to claim 1, wherein fibrinogen receptor antagonist template A is hvor: R<6> er aryl, C^ -alkyl, C3 .6 -cykloalkyl, C4 .10 -aralkyl, C^o -alkoksyalkyl, C^ 0-alkaryl, C^^ -alkyltioalkyl, C^o -alkoksytioalkyl, C^o -alkylamino, C4 .10 -aralkylamino, CL^ -alkanoylamino, C4 .10 -aralkanoylamino, C^ -alkanoyl, C4 .10 -aralkanoyl eller C^ 0-karboksyalkyl; og Y er H, C^ -alkyl, C^ -alkoksy, C^ -alkoksykarbonyl, F, Cl, Br, I, CF3, OR', S(0)k R <f> , COR <f> , N02 , N(R')2 , CO(NR <f> )2 , CH2 N(R <f> )2 , metylendioksy, CN, C02 R <f> , OC(0)R'eller NHC(0)R <f.>where: R<6 > is aryl, C 1 -alkyl, C 3 .6 -cycloalkyl, C 4 .10 -aralkyl, C 3 - 0 -alkoxyalkyl, C 3 -0 -alkaryl, C 3 -alkylthioalkyl, C 3 -alkoxythioalkyl, C 3 o -alkylamino, C 4 .10 -aralkylamino, C 1 -alkanoylamino, C 4 .10 -aralkanoylamino, C 1 -alkanoyl, C 4 .10 -aralkanoyl or C 1 0 -carboxyalkyl; and Y is H, C₁ -alkyl, C₁ -alkyl, C₁ -alkoxycarbonyl, F, Cl, Br, I, CF₃, OR', S(0)k R <f> , COR <f> , NO 2 , N (R')2 , CO(NR <f> )2 , CH2 N(R <f> )2 , methylenedioxy, CN, C02 R <f> , OC(0)R'or NHC(0)R <f. > 18. Forbindelse ifølge krav 17, hvor R <6> er aryl, C^ -alkyl, C3 .6 -cykloalkyl eller C4.10-aralkyl.18. Compound according to claim 17, where R <6> is aryl, C 1 -alkyl, C 3.6 -cycloalkyl or C 4.10 -aralkyl. 19. Forbindelse ifølge krav 18, som er (S)-(2-butylsulfonyl-amino)-3-[4-(3-benzimidazo-2-yl)propyloksy)]fenylpropionsyre eller et farmasøytisk akseptabelt salt derav.19. A compound according to claim 18, which is (S)-(2-butylsulfonyl-amino)-3-[4-(3-benzimidazo-2-yl)propyloxy)]phenylpropionic acid or a pharmaceutically acceptable salt thereof. 20. Forbindelse ifølge krav 1, hvor fibrinogen-reseptorantagonist-templat A er 20. A compound according to claim 1, wherein fibrinogen receptor antagonist template A is hvor: M <1> erCH eller N; M <2> er CH eller N, med det forbehold at når M <1> er CH, da er M <2> N; og G' er N ellerN<æ>R" .where: M<1> is CH or N; M <2> is CH or N, with the proviso that when M <1> is CH, then M <2> is N; and G' is N or N<æ>R". 21. Forbindelse ifølge krav 20, hvor G er N og D' er N.21. Compound according to claim 20, where G is N and D' is N. 22. Forbindelse ifølge krav 21, hvor fibrinogen-reseptorantagonist-templat A er 22. A compound according to claim 21, wherein fibrinogen receptor antagonist template A is hvor: M<1> erCH eller N, og M <2> er CH eller N, med det forbehold at når M <1> er CH, da er M <2> N.where: M<1> is CH or N, and M <2> is CH or N, with the proviso that when M <1> is CH, then M <2> is N. 23. Forbindelse ifølge krav 1, hvor fibrinogen-reseptorantagonist-templat A er 23. A compound according to claim 1, wherein fibrinogen receptor antagonist template A is hvor: M<1> erCH eller N; Y er H, Ci .4 -alkyl, d.4 -alkoksy, Ci .4 -alkoksykarbonyl, F, Cl, Br, I, CF3 , OR <f> , S(0)kR <f> , COR <f> , N02 , N(R')2 , CO(NR <f> )2 , CH2 N(R <f> )2 , metylendioksy, CN, C02 R <f> , OC(0)Rf eller NHC(0)R <f> ; D<3> erCH2 eller C=0; og Rh er (CH2 )qC02 R <f.>where: M<1> is CH or N; Y is H, C 1 4 -alkyl, C 1 4 -alkyl, C 1 4 -alkylcarbonyl, F, Cl, Br, I, CF 3 , OR <f> , S(0)kR <f> , COR <f> , N02 , N(R')2 , CO(NR <f> )2 , CH2 N(R <f> )2 , methylenedioxy, CN, C02 R <f> , OC(0)Rf or NHC(0)R <f> ; D<3> is CH2 or C=O; and Rh is (CH2 )qCO2 R <f.> 24. Fremgangsmåte ifølge krav 1, hvor fibrinogen-reseptorantagonist-templat A er 24. Method according to claim 1, wherein fibrinogen receptor antagonist template A is hvor: Y er H, Ci .4 -alkyl, Ci .4 -alkoksy, Ci .4 -alkoksykarbonyl, F, Cl, Br, I, CF3 , OR <f> , S(0)k R <f> , COR', N02 , N(R <f> )2 , CO(NR <f> )2 , CH2 N(R')2 , metylendioksy, CN, C02 R <f> , OC(0)R <f> eller NHC(0)R <f> ; og Rh er (CH2 )qC02 R <f.>where: Y is H, C 1 .4 -alkyl, C 1 .4 -alkoxy, C 1 .4 -alkoxycarbonyl, F, Cl, Br, I, CF 3 , OR <f> , S(0)k R <f> , COR', N02 , N(R <f> )2 , CO(NR <f> )2 , CH2 N(R')2 , methylenedioxy, CN, C02 R <f> , OC(0)R <f> or NHC(0 )R <f> ; and Rh is (CH2 )qCO2 R <f.> 25. Forbindelse ifølge krav 1, hvor fibrinogen-reseptorantagonist-templat A er 25. A compound according to claim 1, wherein fibrinogen receptor antagonist template A is hvor: Y er H, d-4 -alkyl, C^ -alkoksy, Ci .4 -alkoksykarbonyl, F, Cl, Br, I, CF3 , OR <f> , S(0)k R <f> , CO R', N02 , N(R')2 , CO(NR')2 , CH2 N(R <f> )2 , metylendioksy, CN, C02 R <f> , OC(0)Rf eller NHC(0)R <f> ; . Rh er (CH2 )nC02 R <f> ; og where: Y is H, d-4 -alkyl, C 1 -alkyl, C 1 -4 -alkylcarbonyl, F, Cl, Br, I, CF 3 , OR <f> , S(0)k R <f> , CO R', N02 , N(R')2 , CO(NR')2 , CH2 N(R <f> )2 , methylenedioxy, CN, C02 R <f> , OC(0)Rf or NHC(0)R <f> ; . Rh is (CH 2 )nCO 2 R <f> ; and 26. Forbindelse ifølge krav 1, hvor fibrinogen-reseptorantagonist-templat A er 26. A compound according to claim 1, wherein fibrinogen receptor antagonist template A is hvor: L <*> er -C(0)NR <9-> (CH2 )-, -C(0)-(CH2 )q-, NR <8-> (CH2 )q-, -0-(CH2 )q- eller S(0)k -(CH2 )q-.where: L <*> is -C(0)NR <9-> (CH2 )-, -C(0)-(CH2 )q-, NR <8-> (CH2 )q-, -0-(CH2 )q - or S(O)k -(CH2 )q-. 27. Forbindelse ifølge krav 1, hvor fibrinogen-reseptorantagonist-templat A er 27. A compound according to claim 1, wherein fibrinogen receptor antagonist template A is 28. Forbindelse ifølge krav 1, hvor fibrinogen-reseptorantagonist-templat A er 28. A compound according to claim 1, wherein fibrinogen receptor antagonist template A is hvor: Y er H, C^ -alkyl, Ci .4 -alkoksy, C^ -alkoksykarbonyl, F, Cl, Br, I, CF3 , OR <f> , S(0)k R', COR <f1> , N02 , N(R <f> )2 , CO(NR <f> )2l CH2 N(R <f> )2 , metylendioksy, CN, C02R <f> , OC(0)Rf eller NHC(0)R <f> .where: Y is H, C 1 -alkyl, C 1 -4 -alkyloxy, C 1 -4 -alkoxycarbonyl, F, Cl, Br, I, CF 3 , OR <f> , S(0)k R', COR <f1> , NO 2 , N(R <f> )2 , CO(NR <f> )2l CH2 N(R <f> )2 , methylenedioxy, CN, C02R <f> , OC(0)Rf or NHC(0)R <f> . 29. Forbindelse ifølge krav 1, hvor fibrinogen-reseptor-templat A er 29. A compound according to claim 1, wherein the fibrinogen receptor template A is hvor: Rd er Het-Ci.o-alkyl; og Z", Z" uavhengig av hverandre, er hydrogen, Ci -4 -alkyl, halogen, OR <f> , CN, S(0)kRf, C02Rf eller OH.where: R d is Het -C 1-0 alkyl; and Z", Z" independently of each other, are hydrogen, C1-4 alkyl, halogen, OR<f> , CN, S(O)kRf, CO2Rf or OH. 30. Forbindelse ifølge krav 1, hvor fibrinogen-reseptorantagonist-templat A er 30. A compound according to claim 1, wherein fibrinogen receptor antagonist template A is 31. Forbindelse ifølge krav 1, som er: 31. Compound according to claim 1, which is: hvor: Rx, Ry og R <z> uavhengig av hverandre er Ci -e-alkyl, metoksy, nitro, trifluormetyl, fluor, klor eller amino; eller Rx og Ry er nabostillet til hverandre og er forenet under dannelse av en metylendioksygruppe.where: Rx, Ry and R<z> independently of each other are C1-6-alkyl, methoxy, nitro, trifluoromethyl, fluoro, chloro or amino; or Rx and Ry are adjacent to each other and are united to form a methylenedioxy group. 32. Forbindelse ifølge krav 1, som er: 32. Compound according to claim 1, which is: hvor: Rx og Ry uavhengig av hverandre er Ci-e-alkyl, metoksy, nitro, trifluormetyl, fluor, klor eller amino; eller Rx og Ry er nabostillet til hverandre og forenet under dannelse av en metylendioksygruppe.where: Rx and Ry are independently C 1-6 alkyl, methoxy, nitro, trifluoromethyl, fluoro, chloro or amino; or Rx and Ry are adjacent to each other and united to form a methylenedioxy group. 33. Farmasøytisk blanding som har vitronectin-reseptor-inhiberende virkning, og som omfatter en farmasøytisk akseptabel bærer og en forbindelse med formel (I) eller (II) eller (III) eller (IV) eller (V).33. Pharmaceutical composition which has vitronectin receptor-inhibiting action, and which comprises a pharmaceutically acceptable carrier and a compound of formula (I) or (II) or (III) or (IV) or (V). 34. Fremgangsmåte for inhibering av en vitronectin-reseptor i et pattedyr, og som omfatter administrering av en effektiv mengde av en forbindelse ifølge formel (I) eller (II) eller (III) eller (IV) eller (V): 34. Method for inhibiting a vitronectin receptor in a mammal, and comprising administering an effective amount of a compound according to formula (I) or (II) or (III) or (IV) or (V): hvor:W er CHRVU-CHRVV eller where:W is CHRVU-CHRVV or A er en fibrinogen-reseptorantagonist-templat; U og V mangler eller er CO, CR <9>2 , C(=CR <9>2 ), S(0)k , 0, NR <9> , CR <8> OR <B> , CR <9> (OR <k> )CR <9>2 , CR <9>2 CR <9> (OR <K> ), C(0)CR <9>2l CR <9>2 C(0), CONR <1> , NR'CO, 0C(0), C(0)0, C(S)0, OC(S), C(S)NR <9> , NR <9> C(S), S(0)2 NR°, NR <fl> S(0)2 , N=N, NR <9> NR <9> ,NR<S> CR <9>2 , NR9 CR <9>2l CR <9>2 0, OCR <9>2 , C=C eller CR <9> =C R <9> ; G er NR°, S eller 0; R <9> er H, d-e-alkyl, Het-Co-e-alkyl, C3 .7 -cykloalkyl-Co-6 -alkyl eller Ar-Co-e-alkyl; Rk er R <9> , -C(0)R <9> eller -C(0)OR <f> ; R1 er H, Ci -e-alkyl, Het-Co-e-alkyl, d-r cykloalkyl-Co-e-alkyl, Ar-Co-e-alkyl eller Ci .6 -alkyl substituert med én til tre grupper valgt fra halogen, CN, NR <B>2 , OR9 , SR <9> , C02 R <9> og CON(R <9> )2 ; Rf er H, Ci -e-alkyl eller Ar-Ci .6 -alkyl; Re er H, Ci -e-alkyl, Ar-Ci -6 -alkyl, Het-Ci -e-alkyl, C3 .7 -cykloalkyl-Ci .e -alkyl eller (CH2 )k C02 R <9> ; k er 0, 1 eller 2; q er 1 eller 2; a erO, 1 eller 2; b er 0, 1 eller 2; R <b> og R <c> er uavhengig av hverandre valgt fra H, Ci -e-alkyl, Ar-Ccwralkyl, Het-Co-e-alkyl eller C3 .6 -cykloalkyl-C0 .6 -alkyl, halogen, CF3 , OR <f> , S(0)k R <f> , COR <f> , N02 , N(R <f> )2 , CO(NR <f> )2 , CH2 N(R <f> )2 eller Rb og R <c> er forenet under dannelse av en fem- eller seks-leddet aromatisk eller ikke-aromatisk karbocyklisk eller heterocyklisk ring, som eventuelt er substituert med opp til tre substituenter valgt fra halogen, CF3 , C^ -alkyl, OR <f> , S(0)k R <f> , COR', C02 R', OH, N02 , N(R')2 , CO(NR <f> )2 og CH2 N(R <f> )2 ; eller metylendioksy: eller et farmasøytisk akseptabelt salt derav.A is a fibrinogen receptor antagonist template; U and V are missing or are CO, CR <9>2 , C(=CR <9>2 ), S(0)k , 0, NR <9> , CR <8> OR <B> , CR <9> (OR <k> )CR <9>2 , CR <9>2 CR <9> (OR <K> ), C(0)CR <9>2l CR <9>2 C(0), CONR <1 > , NR'CO, 0C(0), C(0)0, C(S)0, OC(S), C(S)NR <9> , NR <9> C(S), S(0) 2 NR°, NR <fl> S(0)2 , N=N, NR <9> NR <9> ,NR<S> CR <9>2 , NR9 CR <9>2l CR <9>2 0, OCR <9>2 , C=C or CR <9> =C R <9> ; G is NR°, S or 0; R<9> is H, d-e-alkyl, Het-Co-e-alkyl, C 3-7 -cycloalkyl-Co-6-alkyl or Ar-Co-e-alkyl; Rk is R <9> , -C(0)R <9> or -C(0)OR <f> ; R1 is H, Ci -e-alkyl, Het-Co-e-alkyl, d-r cycloalkyl-Co-e-alkyl, Ar-Co-e-alkyl or Ci .6 -alkyl substituted with one to three groups selected from halogen, CN, NR <B>2 , OR9 , SR <9> , CO2 R <9> and CON(R <9> )2 ; Rf is H, C1-6 alkyl or Ar-C1-6 alkyl; Re is H, C 1 -6 -alkyl, Ar -C 1 -6 -alkyl, Het -C 1 -6 -alkyl, C 3 .7 -cycloalkyl-C 1 -6 -alkyl or (CH 2 )k CO 2 R <9> ; k is 0, 1 or 2; q is 1 or 2; a is 0, 1 or 2; b is 0, 1 or 2; R<b> and R<c> are independently selected from H, C1-e-alkyl, Ar-Ccwralkyl, Het-Co-e-alkyl or C3 .6 -cycloalkyl-C0 .6 -alkyl, halogen, CF3 , OR <f> , S(0)k R <f> , COR <f> , N02 , N(R < f> )2 , CO(NR <f> )2 , CH2 N(R <f> )2 or Rb and R <c> are united to form a five- or six-membered aromatic or non-aromatic carbocyclic or heterocyclic ring, which is optionally substituted with up to three substituents selected from halogen, CF 3 , C 2 -alkyl, OR <f> , S(0)k R <f> , COR', CO 2 R', OH, NO 2 , N( R')2 , CO(NR <f> )2 and CH2 N(R <f> )2 ; or methylenedioxy: or a pharmaceutically acceptable salt thereof. 35. Fremgangsmåte ifølge krav 34, hvor forbindelsen inhiberer vitronectin-reseptoren i en konsentrasjon på mindre enn 50 mikromolar.35. Method according to claim 34, wherein the compound inhibits the vitronectin receptor in a concentration of less than 50 micromolar. 36. Fremgangsmåte ifølge krav 34, hvor forbindelsen inhiberer vitronectin-reseptoren i en konsentrasjon på mindre enn 1 mikromolar.36. Method according to claim 34, wherein the compound inhibits the vitronectin receptor in a concentration of less than 1 micromolar. 37. Fremgangsmåte ifølge krav 34, hvor forbindelsen inhiberer vitronectin-reseptoren med en Ki for vitronectin-reseptoren som er ti ganger høyere enn fibrinogen-reseptorens Ki for nevnte forbindelse.37. Method according to claim 34, where the compound inhibits the vitronectin receptor with a Ki for the vitronectin receptor that is ten times higher than the fibrinogen receptor's Ki for said compound. 38. "Fremgangsmåte ifølge krav 34, hvor forbindelsen inhiberer vitronectin-reseptoren med en Ki for vitronectin-reseptoren som er tredve ganger høyere enn fibrinogen-reseptorens Ki for nevnte forbindelse.38. "The method according to claim 34, wherein the compound inhibits the vitronectin receptor with a Ki for the vitronectin receptor that is thirty times higher than the fibrinogen receptor's Ki for said compound. 39. Fremgangsmåte ifølge krav 34, hvor forbindelsen inhiberer vitronectin-reseptoren med en Ki for vitronectin-reseptoren som er hundre ganger høyere enn fibrinogen-reseptorens Ki for nevnte forbindelse.39. Method according to claim 34, wherein the compound inhibits the vitronectin receptor with a Ki for the vitronectin receptor that is one hundred times higher than the fibrinogen receptor's Ki for said compound. 40. Fremgangsmåte ifølge krav 34, for behandling av sykdommer hvor benresorpsjon er en faktor.40. Method according to claim 34, for the treatment of diseases where bone resorption is a factor. 41. Fremgangsmåte ifølge krav 34, for behandling av osteoporose.41. Method according to claim 34, for the treatment of osteoporosis. 42. Fremgangsmåte ifølge krav 34, for behandling av inflammasjon.42. Method according to claim 34, for treating inflammation. 43. Fremgangsmåte ifølge krav 34, for behandling av restenose.43. Method according to claim 34, for treating restenosis. 44. Fremgangsmåte ifølge krav 34, for behandling av aterosklerose.44. Method according to claim 34, for the treatment of atherosclerosis. 45. Forbindelse med formel (XXX): 45. Compound of formula (XXX): hvor Pr <1> er en nitrogen-beskyttende gruppe; Rf er H, Ci .6 -alkyl eller ArCi^-alkyl, a' er 1-3 og R", Ry og R <z> er uavhengig av hverandre, H, halogen, SR', OR <f> , CF3 , N(R')2 , N02 og Ci-e-alkyl.where Pr<1> is a nitrogen-protecting group; Rf is H, C1-6 alkyl or ArC1-6 alkyl, a' is 1-3 and R", Ry and R <z> are independent of each other, H, halogen, SR', OR <f> , CF3 , N(R') 2 , NO 2 and C 1-6 alkyl.
NO965608A 1994-06-29 1996-12-27 Vitronectin receptor antagonists NO965608L (en)

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