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    The present invention relates to acyltryptophanols of the general formula I. The compounds according to the invention are effective FSH antagonists and can be used for example for fertility control in men or in women. In the female mammal, FSH controls the early ripening of ovarian primary follicles and the biosynthesis of sex steroids.

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    The present invention relates to acyltryptophanols of the general formula I. The compounds according to the invention are effective FSH antagonists and can be used for example for fertility control in men or in women. In the female mammal, FSH controls the early ripening of ovarian primary follicles and the biosynthesis of sex steroids.

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    8 visualizzazioni64 pagine

    US20090075987

    Caricato da

    tsha757
    The present invention relates to acyltryptophanols of the general formula I. The compounds according to the invention are effective FSH antagonists and can be used for example for fertility control in men or in women. In the female mammal, FSH controls the early ripening of ovarian primary follicles and the biosynthesis of sex steroids.

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    'US 2009007598741 cz) Patent Application Publication — co) Pub. No.: US 2009/0075987 A1 cu») United States Wortmann et al. (34) ALKYLACETYLENE SUBSTITUTED ACYLTRYPTOPHANOLS (76) Inveators: Lars Wortmann, Beslia (DE) Mareus Koppitz, Berlin (DE), Hans Peter Muha, Bein (DE) Thomas renzel, Berlin (D8) Florian Peter Liesener, Trosibers (DE); Anna Sehrey, Berlin (DE), Ronald Kuehne, Bestia (DE) CComespondence Address ANO & BRANIGAN.P.C, 2200 CLARENDON BLVD., SUITE 1400, ARLINGTON, VA 22201 (US) (21) Appl. No: 278,825 (22) Filed Jul. 23, 2008, Related U, Application Data (60) Provisional application No. 601951,552, fled on J. 24, 2007 G0) Forcign Application Priority Data Jul. 24,2007 07075 641.6 Publication Classification 1) Inc AGIK 31/541 (2006.01) CozD 209/18 (2006.01), AGIK 31/404 (2008.01) GIP 1508, (2006.01) ‘GIP 19/10 (2005.01), Corp 41702 (2006.01), (43) Pub, Date Mar. 19, 2009 (2) US.EL 514/228.2; 548/495; 514/419; 544/62 on ABSTRACT The present invention eates to aeyltrypropbanolsof the gen cra form a in hich RI,R2,R3, Q and X have the meaning as defined in the description, The compounds cording to the invention ae effective FSH. antagonists andcan bused fr example for fertility contol in ‘men or in wonten, of forthe prevention andioe treatment of osteoporosis US 2009/0075987 AI ALKYLACETYLENE SUBSTITUTED "ACYLTRYPTOPHANOLS, 10001) This application claims the benefit of he filing date ‘ofUS. Provisional Application Ser. No. 609S1,$52 fled Jul 24, 2007 0002} ‘The present invention reates to novel alkylacety- Tene substituted acylryptophanols with ”FSH-receptor antagonist activity. The present invention also relates to @ process for their preparation, pharmaceutical compositions ‘comprising the compounds according to the invention, and the use thereof for fertility contol in men or women, for the treatment andlor prevention of ostenporosis, 0003] Folliclestimolsting hormone (FSH) and luteinizing hormone (LH) are together responsible forthe control ofmale nd female ferility and of the production of sex steroids 10003} Tn the female mammal, FSH controls the early rip- ‘ening of ovarian primary follicles and the biosyathesis oF sex steroids. In the advanced stage of differentiation (preantal follicles), the influence of LH becomes inereasingly impor- tant for further development ofthe follicles until ovulation 10005) In male mammals, PSH is primarily responsible for the differentiation andstimulation of Sertoli cells. Their func- tion consist of assisting spermatogenesis on many levels. LT Js primarily responsible fr stimulating the Leydig ells and Uhhs androgen production, FSH, LH and TSH (Uhyrotropic hormone) together form the group of glycoprotein hormones Which are formed inthe pituitary und are secreted from there Whereas the alpha subunit is eommon to the three hormones, their specificity of action is detemnined by the beta chain ‘hich is unique in each case. The molecular weight of FSH ‘including the sugar portion is about 30 KD. 10006] "FSH and the other glycoprotein hormones act spe- cifically via their selectively expressed G protein-coupled receptor (GPCR), FSH stimulates, through binding to its receptor, the association thereof with a stimulating G protein (G,) which is thereby stimulated 10 hydrolyse guanosine triphosphate (GTP) and to activate the membranc-associated adenylate eyelase, Cyclic adenosine monophosphate (cAMP) i accordingly an important snd readily quantifiable second- ‘ary messenger substance of FSH (G. Vassar, L. Pardo, S. ‘Costagliola, Trends Biochem. Sei. 2004, 29, 119-126). [0007] -Theimportance of FSH for male Ferility is the sub- ‘of intensive research, It has been possible to show that St influences several processes of spermatogenesis such as the proliferation of spermatogonia, the antiapoptotic effect on spermatogonia and spermatocytes and the stimulstion of sperm maturation including motility thereof. [0008] The following arguments are also in favour of the FSH receptor as tant for male ferility contol: [0009] 1. The FSH receptor is exclusively expressed on Sertoli cells (high specificity), [0010] 2. Contraceptive vaccination agsinst PSH betachain ‘or the FSH receptor induces infertility in male primates (. R. Mougdal, M, Jeyakumar, 1. N. Krishnamorthy, S Sridhar, H, Krishnamurthy, F Martin, Human Reprodue> tion Update 1997, 3, 335-346). [0011] 3. Naturally occurring mutations in the FSH recep- tororthe FSH beta chain may Jead to suh-o infer snc (1 Huhtaniemi, Journal of Reprehction and Feet 3000. 119. 13-186: LC Layman, PG. MeDonoogh, ‘Molecular and Cellule Endocrinology 2000, 161, 9-17) Mar. 19, 2009 [0012] 4. Neutralizing FSH antiserum has no effect on tes- tis weight and testosterone production (V. Sriramaa, A.J. Roo, Molecular and Cellular Eadocrionology 2004, 224, 73.82), Adverse fects of PSH blockade on androgen pro duction therefore appear unlikely [0013] In line with these arguments, PSH antagonists are ‘expected to be stable for spermatogenesis inhibition (pre- ‘Moreover a suitable FSH antagonist may juste infertility in women, because suppresses follicle ripening and thus also ovulation. On the other han, the skies! person expects advantages from non-peptidersic FSH agonists when used t promote fertility in women (stimulation of follicle ipening). There are no reports of experience on the use of FSH of FSH agonists in mae infer- tility, but specific indications are also conceivable inthis ‘connection. New findings demonstrate that there is also a Girt effect of FSH on cells of bone metabolism, There are ‘so fundamentally cilferent cll types in bones: osteoclasts ‘and osteoblasts, While osteoclasts playa central role in bone resorption (breakdown of bone), osteoblasts simulate bone Sensity (anabolic effet) 0014] | FSH receptors have heen detected in osteoclasts but ‘ot inostooblsts. In vito, FSH stimulates bone resorption by mouse osteoclasts (Li Sua etal. Cell 2006; 125: 247-60). A clinical coreelation berween the serum FSH level and loss bone deasity has been observe in postmenopausal women (Devleta et a J, Bone Miner. Metab, 2004, 22: 360-4), [0015] These findings among others suggest that FSH stimulate loss of bone mas, and consequently FSH antago- nists will display an antiesorptve effect on bone and are therefore stable for the taerapy andor prevention of peri- ‘and postmenopausal loss of bone mass and osteoporosis, [0016] FSHfreceptormodulatorsare compounds that haves rixed profile of both FSH receptor antagonistic snd PSH recepior agonistic properties, FSH receptor modulators of various compound classes of low molecular weight, have ‘een reported on recently, FSH reveptor modulators are di closed in WO 20041056779, WO 2004056780; J. Med. ‘Chem. 2005, 48, 1657 [tetra droquinolines}; WO02/70493, Bioorg. Med. Chem, Lett. 2004, 14, 1713 aad 1717 [dike- topineravines|; WO 01/47875 [sulphonamides} and [EPO7090087.3 [hydroxyethylteyptamines}. [0017] FSH receptor agonists are disclosed in WO (02109706; J. Comb. Chem. 2004, 6,196 [Thiaeoiginones} ‘WO 2003/020726 and WO 03/20727, Chem. Biochem. 2002, 10, 1023 {thieno[2,3-d}pyrimidines)}; WO O1/87287 [pyrae oles]; WO 0008015 [carbazoles|; WO 06/117028, WO (06/117368, WO O6/117370 and WO 06/117371 (hexabydro- quinoline [0018] FSH receptor antagonists are disclosed in WO (034004028 [tetralydroguinolines}, WO.02/09705 [thiazolii- ones), WO 0058277, Bioorg. Med. Chem. 2002, 10, 639 [sulphonic acids}; WO 00/58276, Endocr 2002, 143, 382: Synth, Comm, 2002, 32, 2695 azo compounds}; US 2006) (0199806, US 20060258644, US 200610258645, US 2006/ (0287522 [pyrmolobeazodiazepines), WO 20071017289 (seyl- ypiophaiols), EP05050223.6 _[.2-diarylacetyene CO)-NH—C,-Ceyeloalkyl, | NC -Cealks > S0--C Cally, NCC ealky SO CC eyeloallyl, "N(Cy-Cy-allyD-SO,Neai(C;,C, alky)), N(Co-C pally) $0;—NH (CSC, cycloalkyl, 0032] —C(O)—N¢t)—C,-Cealkylene(C,-Cealky)) amine, —C(O}-N(H)—C,-Csalkylene {d(C -C- alkyD]amine, —C(O)-N(H)"C,-C,-alkylene(C,- (C-eyeloalky amine, alkylene (CC -eyeloalkyl-C, [0033] —S(0,)-N(tH)—C.-Csallylene(C,-C, alkyDamine, —S(0;)—N(H)—Cx-Cealkylene-[(C > CealkyDlamine, —S(0,)N(H)-C,-Cy-alkylene- (€-Cy-cyeloalkybamine, ” —S(0;)-NE)—C,-C alkylene.(C,-C-eyeloalkyl-C,-C,-alkylene}amine, 0034] —0—C,-C-alkylene-C -Cealkyamine, —0-C,-Cralkylene{a(Cy-C, alkylene} amine, 0035] or the radicals I Coceallyl Cost US 2009/0075987 AI -eontinved o 00 OO EeLeatiyt — rCealtye oes Cotes! omy a t 4 s“ Qo a aa +s °. Oo O0 a yh Q Mar. 19, 2009 continued Ngee SESE coca I © omimo Q ‘eCealky CoCeallyl \y Caley IM ect SMe lee lees See I | ewe = Oe Oe th tn ei ee ese “0 Great Ny Ateh OS, Cocoa cee (0036) in which the art orheteoarylgroup may option- ally be substituted with halogen, cyano, SO,Me, C -C- alkyl, C-Cgatkenyl, C-Csalkynyl or C-Cyalkyloxy, ‘where the hydrocarbon chains therein may optionally be substituted one or more times by Horie andor eyanos US 2009/0075987 AI ‘and X is a bond, C,-Cyalkylene, Cy alkynylene: Qisanaryl orbeteroaryl group, [0087] or he group AV Dd -Aisamonoeyelicaryloramonocyelic heteroaryl [oo3s} [039] soup: [0040] V is a cyctoalhylen, eyetoatkenylen, heteroey- cloalkylen or heteraeycloalkenylen group: where [0041] RI substitutes one oF more postions ofthe ary oF Fbteroary rng in the indole reside; 10042] -R2 substitutes one oF more postions of the ary oF Fptoroary ring in the radicals Q, Aor V; 10043] -R3 substitutes oneor more positions ofthe group X. [0044] |The present invention relates to both possible enan- tiomerie forme atthe stereocentre ofthe tryptophanol reside 10045] Theuabranched C,-C, alkyl groups forthe radicals R110 RS may be for example @ methyl ethyl, propyl, buy, pentylorahexyl group: and the branched C,-C alk] proups Jor the radicals RI to R3 may be an isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbatyl, I-methyiba ‘gl, L-thylpropy!, neopentyl, 1.i-dimethylpropyl,4-methyl- pentyl, 3-methylpentyl, 2-methylpentyl, I-methyipentyl 2eethyibutyl, Iethylbuty, 33-dimethylbuty, 2,2-dimethyle butyl, 1.1-dimedhytbutyl, 2-dimedhylbutyl, 13-dimethyl- butyl or a 1.2 S-ethylbut-2-enyl, (Z)--ethylbut-2-enyl, (E}-2- yay, but-3-ynyl,pent-1-ynyl pent-2-ynyl, pentyl pent- -ynyl,hexe1-yyl, hex-2-ynyl ex-3-yy, hexyl ex Syayl L-methylprop-2-yayl, _ 2-methylbut-3-ynyl T-metiytbut-3-ynyl, -I-mediybut-2-ynyl, 3-methyIbut-l- xyayl, T-eshylprop-2-yny], 3-methylpent-4-ynyl, 2-metbyl- ent-4-ynyl, I-methylpent-4-ynyl, 2-methylpent3-yny], [methylpent-8-ynyl,4-methylpent-2-ynyl, I-methylpent-2 -miethy}pent-1-yny, 3sniehylpenI-yny,2-thylbt- thylbut-3-ynyl I-ethylot2-yay, 1-propylpeop Trisopropylprop-2-ynyl, 2.2-dimethyIbut-3-yny, 10070) the radicals R2 to R3 it is possible forthe C,-C,-alkyloxy _aroup,forexampleamethyloxy. cthyloxy: propylony isopro- Pyloxy, butyloxy isobutyloxy, see-butylony, tet-butyloxy, Pentyloxy, isopentyloxy, (2-methylbutyDoxy, (I-methyba ‘yDoxy, (ethylpmopyloxy, neopentyloxy, (1. 1-dimethyl- propyloxy,hexyloxy, (4+methylpentyDoxy, @-methylpen- yDoxy, | Q-methylpentyDoxy, (L-methylpentyl)oxy. (L-ethylbutyoxy, Q-athylbutyToxy, (3.3-dimethylbuty!) ‘oxy, (22-dimedisTbutyDoxy, (,L-dimethsTbutyDoxy, (23+ dimethyibutyDoxy ora (1-2timethylbatyDoxy group, to be locate! at any desired postion ofthe C,-C,-alkynyl group {or example of prop-I-ynyl prop-2m,butI-yny, bul 2eynyl, but--ynyl, peat-L-ynyl, pent-2-ynyl,pent--ynyh pent-4-yny,bex-I-ys hex hex-Syayl, -methylprop-2-yns Ismetylbt-3-ynyl, yayl, ethyiprop-23 pent-tynyl T-methylpent {-methyipent3-ynyl, 4-methyipent ynyl,4mtethylpent-I-yny,3-methylpent-1-yny, 2-ethyb Soynyl, -ethylbut-3-yny, L-ethylbut2-yns, I-prorylprop- 2amyh, T-iopropyiprop-2ayl, 2.2-dimethylbut-3-yn, 1,i-dimethytbut3-ynyl, 1,Lalimethytbut-2-ynyl oF «3. ‘yay group, andto be combined independently US 2009/0075987 AI 10071] In the C,-CeallyloxyphenylC -Cyalkylene troup forthe rica 12 RS its possible forthe C Ce allloxy group tbe selected independently of one anther from mediyoxy, ebloxy, popslon. soproptoxy. uty= Joxy, isobutyloxy, sec-butyl, tert-buslony, peniyoxy, ibopentyioxy, » Q-methytbusloxy. C-methytbuyDoxs, (tty propyl, neopentyoxy (1.-timethyprepsDoxy, hexyloxy. (metiylpentlioxy, | (Gomtylpenty on Gemethyipentyoxy,(I-methypenyioxy, (L-sthybuty ‘ox: (-etnlbuty)ony 3 edimelinlbutsljony(22dimetie dibutsoxs, (Lt-imetylbuyDoxy. @-cimethy buy)- ‘oxy, (L3-dimetiytbutyoxy or a (1,2-dimettybutyoxy. ant by combined independently ofone another with -C,- alllene groups such as, for example, mehyene, ene propylene, butylene, penylene, hexylene 10072] In the. CyCyeyeloalhyl(C,,C-alkyleneamino _r0ups ofthe radicals 2 to R3 itis possible foreach ofthe CoCr -eyeoalkyl arups of the Cy-C;-eyeoalkyl4(Cy Ce allylencamino group, orexample ofa eyelepeopy,eyela- (ph evelopensl,eylohexyl oreyeloepiy group 0 be co bined independcnlyofone anole wih each CC, alkylene troup, for example wih a bond, a methylene, eliTens roe pene, butylene petslen,hexsene group. 0073] In the Cy-Calkylony-C-Cyalkylene groups for the radical R2 to 13. s possible forthe C\-Cralkyloxy group tobe selected independently for example from meth loxy.eliylony. prpyloxy iopropyloxy,buloxy abuly~ Tony, sce-butyioxy,ter-bryloxs, pensions, isopentyoxy, (Chmethybutsoxy, (-medifbutloxy. (-eilylprops!) ‘oxy, neopentylony, (L.-dimethypropyDoxy, hexyloxy, Emethylpentyoxy, Cmethylpenty}-oxy, Comethylpen- ‘yboxy,(lmethypeny pony, (I-ethybutyoxy, (2 bu Dos, G-dimetiybustoxs, (22m lbuyboxy, G.Ldimetis buyoxy, 23-dimeylbu ons, (dine ciylbus)oxy or a (1-2-dimedhslbutexy and io Be eom- bined independently of one another with C,-C,slkylene rus clas, forexample, methylene, ellen, propylene burylene, pontlens, hexslene. 0074] Inthe d(C, -C,-alkyamine-C-Cyatkyene group forthe radial R3 its possible foreach of the two radicals on the nitrogen stom ofthe amino group to be selected indepen- dently for cxample fem meth, etl, propy,isopeop but isobutyl, see-buty, erhalten, pentyl, (2-me- tkyDbuty), (-metitbuty), -thyiprops, ncopenty] L.t- imethyipopy!), hens, (4th pens) G-metiylpens), (C-metiypentt, Isineiytpenty) (etstbus)- Oty bul), G.dimethylbuyd, @2-dimethylbury!), (l- lene group, may be combined independently of one another swith each of the two identically or different Cy-Cealkyl proupson the amino group, for example with a methyl. ey] propyl, isopropyl, butyl, isobutyl, sec-butyl, tent-buty, pen= ‘yl isopentyl, 2-methylbutyl), (1-methylbuty), (1- Ceealkylene) groups of the C(O) -N(H)-Cs-Cealky Jene(Cy-C,-eycloalkyDamine group, for example an ‘ethylene, propylene, butylene, peatylene or hexylene group, ‘may be combined independently of one another with each Mar. 19, 2009 Cy-Creyeloalkyl group on the amine, for example with a cyclopropyl. yelobuyl, cyclopentyl, cyclen oF eyclor ‘hepty! group. {0106} In. the —C(O) NEC palienc(C eyeloayl-C,-Cyalkylene)anine groups ofthe radical R3, each ofthe (C.-C alkylene) groups ofthe —C(O)—N(H)— EC rallglene(C,-CyeeylealKs1-C Caylee rou, for example an etiyiene, propylene, buylene, pty Jeno or hexslene group, may be eombined independently of one another with each Cy-Creycloalky-C,-C,-allylene group onthe amin, foe example with a eeloprepylmethy- re, eyclopropyltiylene,cyelopropylpropylene, eye Pulbutylene, “cyclopropypentylen, eyclopropylhexylene, {jlobntyimethylene,cjelobutyetylene, eylobutlpropy Jene, eyclobuytbutylene,eyelobuslpentyene, yelobuty henglene, eyclopentylmetivens, evelopentyletiyene escopelnatene,elpetibaten, cid tylene eylohexslthyene,cyelohexypropyene, clo. evihopiane, cycoheryipenglene, Serban ene, cloheptyimethylene, yelohepyltylene, cyelootyeo- pene, ecTohepyibuslene,cyeloeptypentyene or eylo~ Fepylbexylene group. {0107} Is the —S,) NED C,-Cealkglene-(C,€, allyDiamine groups of the radical R3, the (Cx-Calkylens) gxoups of the —S,)-NGD—C-Calylene (CC. Allyn group, for example an then, propylene, ty lene, pentylene or hexslene proup, may be combined inde- petienly ofone mather witheach Call group onthe ‘up for example witha met eli props, a= propyl, bush, sour, see-butyl tert-butyl pets pent Gemetitbuiy, (-nettyPouy), (-eliyipropy), aeopen: ‘9h Ua-aimethy propyl, hexyl, $-methylpenyD, Cometh YipenyD), @-methylpenyD, (emethylpenty, (-etylbn- yb. Gathylbayd, ” GS-dimethybuy), 2. dimethytouy), (t-dimethytbuy), (23edimetiybuy), (3-dimetts buy) ora (2m bus group {0108} Ia. the —S(0,) -NO)—C,-Cyalliylene (8, C-allybamine groups othe rica RS, theC-C,-allylene group of the —S(O,}—N(H)—C,-Ce-alkylene-{di(C-Cy- alkyljamine group, for example an ‘ethylene, propylene butylene, pentyleae or hexylene aroup, may he combined indopendenly of one snater with exch of the wo C.< alkyl groups onthe amino group, for exatple witha mel, ety propyl bopropy, uty, sbuty, see-bayl er butyl peuph sopens 2-medis bus), C-metytbut!),(L-ethy Propy) neopentl (i t-dimethylpropy) hexyl methyl penty, G-methsipety), (2-methylpenyl. (Lanehylpen: 5D, (eighty) stylus), Qaeimetytbuyl) 02. dimetiybuy), C.i-dimettylbuty), 2.3.timethylbuty), ((3aimethsIbury) ora (12-metis bas) sroup {0109} In the —S(O,)}—N(H)—C,-Calkylene-(Cy-Cy- celoalkyamine groups of the radical 8 the Cy Cy alk. Jene group of the —S(O,)—N(H)—C,-C-alkylene-(C,-C elo nine group. forename an ethylene propyen bulene, penylene or hexylene group, may be combined indpendenly of one another with each Cy-Cy-cyclally] aroap on the amino group, for example with a eylopron, ‘yclouty,eyelopenil elohexsl ce cyelohepil group. {0110}. In the —S(0,) NOH) —CrC eallglene(C,-C cycloalkyl-C,-C,-alkylene)amine groups of the radical R3, each C_Cratigfene group of the — S(0;) NDCC albslene(€,-C,-eyeloul$-C,-Callslenemine grup, for example an eiylene, propylene, butylene, petylene or hexylene group, may be combined independetly of one US 2009/0075987 AI another with each C,-C,-cyeloalkylC; -Cyalkylene group ‘on the amine, for example with @ eyclopropylmethylene, ‘eyclopropyletiylene, eyclopropylpropylene, cyelopropy bu tylene, — eyclopropylpentylene, —_eyelopropythexylene ‘yclobutylmethylene, eyelobutylethylene, cyelobutylpropy’ Jene, eyclobutylbutylene, eyclobutylpentylene, eyclabutyl- hhexylene, eyclopentylmethylene, —yclopentylethylene ‘eyclopentylpropylene, cyclopentylhexylene, eyclohexylm- ‘ethylene, cyclohexylethylene, eyclohexylpropylene, cyelo= hexylbutylene, eyclohexylpentylene, cyclohexylhexylenc, ‘eycloheptylmethylene,cyelohepiyletiylene, eyeloheptylpro- pylene, eyelohepiylbutylene, eycloheptylpentylen or eyelo- heptylhexylene group. In the -O—C,-Cyalkylene-(Cy-Cy- alkyamine groups of the radical R3, the C,-C,-alkyleae group of the —O—C,-Coalkylene(C,-Cyalkyamine ‘group, for example an ethylene, propylene butylene, ponty ene or hexylene group, may be combined independently of ‘one anther with each C,-C,-alky group onthe amino group, for example a methyl ethyl, propy!, isopropyl, bury) sobu- ‘yl, sec-butyl, tert-butyl, pentyl, isopentyl, 2-methylbuty), (L-methylbuty), (I-ethylpropyl), neopenty (.t-dimethy! propy). hexyl, -methylpeny]}, 3-methypeatyl) (2-mets- ‘ypentyl), CLemethylpentyl, (I-etybty!), Q-ethylouty), (G,3 ethylearhamoyl}-pheny) -hex-5-ynoie acids methylester, [0187] 44 3.46-Hydroxy-hen-l-ynyl)-N—[(R)t-hy- eoxymethyl-2-(1indol-+y1)-cthyl-benzamide [0188] 45” 3.(5-Cycloheryl-pentl-ynyl)-N—[(R)--hy- eoxymethyl-2-(11Findol--y1-sthyl-bencamide [0139] 46 3.(5-Cyano-pent-l-ynyl)-N—[R)-hy- roxymethy1-2-(11-indol3-y)-thy]|-benzamide {0160} 47 _N—{(R)--Hydroxymethyl-241H-indol3-y0- ethyl 3(S-iydroxy-pent--ynyl)-benzamide;, [ot61] 48 34(4Hlydroxy-butet-ynyt)-N—[) ddroxymetiyl-211indol3-y1)-etyll-benzamide US 2009/0075987 AI 4 10162} 49 N—{(R)-L-ttydroxynety-2-(indo-3.3)- ily l}3-[34{(0R28)-2-hydroxy-T-meliylpropsl ee thyL-amio}-prop-L-yayl}-benzamide 10163} $0. N—[(R)-1-Hiydroxymetiy1-2-(11-indol-3y- shy] 3-]3-G-methylurido)prop--ynyl-benramide 0164] "51 9-{3-[(R)-I-Hyroxymethyi-2I1-indol3-y)) cilyl}3-(4medhyearbamoy {0168} $5 N—((R cabsl}3-(S-methyearbas azamide: [0169] 56 $.[3(Benzyl-methyl-amino)-prop-1-ynyl]-2- ‘romo-N-[(R}-1-hyelroxymethyl-2(0F-néa) 3-91) ethyl-benzamide; 10170] $7. 2.Bron0-5.G-dimethylamino-prop-1-ynyl)- N(R} T-hycoxymetty amide; (1H-indol-3-y2-thy]} [0171] $8 2-Rromo-S..3-(13-dimethyl-ureido)-prop-1- yy N—{(R)-2-hydroxy- 1-1 H-indol3-ylmethy)- thyl-benzamide; 10172] | $9 2-Bromo-54S-cyano-pent--yayl)-N—[(R)-1- hnydoxymethy1-2-(1H-indo 10173) xyl)23, [(R)-I-hydroxym= 10180] | 67 6-(94[(R)-1-Hydroxymethyl-2-(1F-indol-3-yD- ethylearbamoyl}-2,3,45-tetraydro-ben7o| bjoxepin-7- yi-hex-5-ynoie [0181] 68 6-{94[(R)-1-Hydroxymethyl-2-(1H-indol-3-yD)- cthylearbamoyl)-23.45-ttrahydr-bon7o[ joxepin-7- yl}-hex-5-ynoie acid methyl ester; [0182] 69 7-(6HHydoxy-hex-I-y benzofbjoxepine-9-carboxylic acid cthy/-2-Feindol-3-y))- 23 §-{3Benzyl-metlylamino)-prop-l-ynyll-N—{(R)l- hydoxyimethyl-2-(1H-indol-3-yP-thyl}-2-isopropoxy-ben- amide: 24 $.G-Dimethylamino-prop-1-yay-N—[(R)-t-by- ‘roxymety-2-Hindol-3y1 ety] 2-isopropoxy-env- ride: 25_$434.3-Dimethyl-uredo}-prop-I-ynyll-N—{(R)-1- hydoxymethy-2-(1H-indol-3-y-thyl}-2-sopropoxy-ben- amide 26 6-{3-(R)+I-Hydroxymethy-2-(IH-indol-3-y)1- hydoxymethy-2-(H-indol-3-yethyl-benzamide; Mar. 19, 2009 59 42 634{(R)l-Hydroxymethy-2-(11indol3-1)-etbyle carbamesi-peasl} -her--yn0i ai 43. 6(3-[(R)L-Hydoxymethyl-2-(111indol-3-)-cthye carbamcy phenyl hers acid methyl excr 44 346-Hydroxy-hex-L-yny])-N_[(®)-Lydeoxym- edty|-2-(Htndol-3-y-etbyl-benzamide; 45 _345-Cyclohenypent-|-ynyl)-N—[(R)I-hydroxym- cily|-2-I1Lindol-yD-etyl-betzamide; 46. 345-Cyano-pentL-yny-N —[(R)-L-hydoxymetty- 2-1 Findol3-y-etyl-benzamide; 47 N—{(@)-1-ydeoxymethy-2-(1TFindot 3-9) -th]- 3S-hydrony-pet- lyn beni 48 344 Hydroxy-but-L-yny)-N—(R}-L-hydoxyn 2-thindol--yetyl-benzamide; 49. N-((R)-1-Hydronymethyl-2(1H-indol 3-4 3-(34((IR2R)-2-hyroxy-l-methy-propyl) metiyl- amino}-prop-1-yny enzamide; 50 _N-{(@)-I-Hydroxymethy-2-(1FLindol-3y)-cth]- 3-[3(G-methyl-arsido)-prop--ynyl-bonvamids SI. V-{34{0R)L-Hydroxymethy-2-IUindol-3-)ctyle carbamoyl} peas} -non--yn0ie aid 92. ¥{44(1.3-Dimethyl-uride)-but-L-yayl]-N—((R) ydroxymetiy2-( indo] ty: eazamide 58 N—{(®)-L-Hydroxymethy-2-(ITFindol3-y)}-ehy]- 3-4-G-meylureido)-utl-yn-bewanide $4 N—{R-1-Hydroxymethy/-2-Findol3-yethyl- 24 emetlearbamoy bu $5 N—{(@)-1-lydroxymethyl-2.(11Findo- 3(S:methyearbamoy!-pent--yny)-benzamide; 56 §-[(Benzsl-metllamino)-prop-Lyuyl-2-brome- -hydoxyateliy2-(TTindl-3-eths amide 7, Process for preparing compounds ofthe fornula I of claim 1 whoreinatrypophanol derivative ofthe forms VI D0 u Jn which the radical RI has the same meaning as defined in claim I, js coupled with a carboxylic ac of the formula VII we in which R2, R3, Qand X have the same meaning as defined inclaim 1, jn ait amide forming reetion comprising ‘) conversion of said carboxylic acids into an imerme- date active ester o earbony! chloride with suitable peplide-coupling reagent, or with thionyl chloride Oxalyl chloride, phosuene or derivatives thereof, ‘where appropriate in the presence ofa base, Mar. 19, 2009 by reacting the aetve intermediate resulting from step) ‘with said tryptophanol 8. Process according to claim 7 for preparing compounds of the forma TL u Ri, wherein a txyptophanol derivative of the formula VI is coupled with a carboxylic acid of the forma VIL V4 in which R2, R3 and X have the same meaning as defined in claim 7, and RI is hydrogen, halogen, cyano, —SO,Me, Cy-Cealkyl, CoCyalkenyl, Cy-Cyalkyayl oF CCylkys loss, Where the hydrocarbon chsns therein may optionally be substituted one or more times by Nuorine andor eyano 9. Process according to claim 7 for preparing compounds of the fora I US 2009/0075987 AI 6L wherein a uyptoplianol derivative of the formula VI is ‘coupled with a eatboxylie aid ofthe formula IX Inwhich R2, R3, X and V have the same me: in claim 7, and RI is hydrogen, halogen, cyano, —SO,Me, C.Gealkyl, CoCyalkenyl, C-Cealkynyl oF C-Cy-alky- Joy. where the hydrocarbon cliins therein may optionally be substituted one or more times by fhiorine andr eyano and V is a cycloalkylen, eycloalkenylen, heteroey- Cloalkylen or heteracycloalkenylen group, 10, Process aeconing to clam 7 for preparing compounds ‘ofthe formula 1V ead wherein a uyploplianol derivative of the formula VI is ‘coupled with a carboxylic acid ofthe formula X jn which R2, R3 and X have the same meaning as defined ia ‘claim 7 and RI is hydrogen, halogen, eyano, —SO.Me, C,Coallyl, C-Conalkenyl, C,-Cyalkynyl oF C.-Cy-alky- loxy. where the hydrocarbon chins therein may optionally be sbstiited one or more times by florine andor eyano, 11, Process aecosng to clans 7 for preparing compounds ‘ofthe formula V Mar. 19, 2009 & al, ‘wherein a typtophanol derivative of the fomnula VI is coupled with a carboxylic acid ofthe formula XI xt Inwhich R2, RS, and X have the same meaning as defined in claim 7 and RI is hydrogen, halogen, cyano, —SO.Me, Cy-Cealkyl, C-Cralkenyl, Cy-Calkyayl or C,-Cynalky- oxy, ‘where the hydrocarbon chains therein may optionally be substituted one or more times by fluorine andor eyano and V is a cycloalkylen, eyelolkenylen, hetemoey-

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