 find reactions which modified one specific functional group of the molecule without affecting other groups. Secondly, dimeric alkaloids lacking desirable chemotherapeutic properties had been recovered or produced from Vinca rosea extracts, and a determination of their structures had led to the conclusion that these inactive compounds were closely related structurally to, and even isomeric with, one or more of the active alkaloids. Thus, it appeared that small chemical changes in the known alkaloids could have a profound effect on antineoplastic activity.
Because of these restrictions, modification of the indole-dihydroindole alkaloids obtained from Vinca rosea has centered around three areas of the molecule: C--3, C--4' and C--4. Considering C--3 modification first, one of the more recent, and more successful modifications of the basic indole-dihydroindole structure has been the preparation of C--3 carboxamide and carboxhydrazide derivatives, most of which have turned out to be active anti-tumor agents. [See Cullinan et al., U.S. Pat. No. 4,203,898, Conrad et al., U.S. Pat. No. 4,191,688, Cullinan and Gerzon, U.S. Pat. No. 4,166,810. Conrad et al. J. Med. Chem., 22, 391 (1979), and Barnett et al., ibid,; 21 88 (1978)]. One of the amides, 4-desacetyl VLB 3-carboxamide (vindesine), is currently being marketed in several European countries as an oncolytic agent. Vindesine is effective in treating some vincristine-resistant leukemias in addition to many common neoplasms including germ-cell tumors. Secondly, reaction of the 3-hydroxy and 3-ester functions of a indole-dihydroindole vinca alkaloid with an isocyanate has produced the corresponnding oxazolidinedione derivatives, one of which, the N-chloroethyl derivative--vinzolidine--is currently undergoing a clinical trial in humans. These oxazolidinedione derivatives are disclosed in Miller and Gutowski, U.S. Pat. No. RE 30,560, reissued Mar. 31, 1981. Trouet et al., U.S. Pat. No. 4,388,305 (same as EPO 41,935) discloses anti-cancer VLB C--3 peptides in
find reactions which modified one specific functional group of the atom without involve other groups. second, dimeric alkaloids miss desirable chemotherapeutic properties had been recovered or produce from Vinca rosea distill, and a determination of their structure had led to the conclusion that these passive compounds were closely relate structurally to, and even isomeric with, one or more of the active alkaloids. therefore, it appeared that belittled chemical change in the known alkaloids could have a heavy effect on antineoplastic activity. 
 Because of these restrictions, alteration of the indole - dihydroindole alkaloids obtained from Vinca rosea has centered around three areas of the molecule: C--3, C--4' and C--4. study C--3 modification first, one of the more recent, and more successful modifications of the basic indole - dihydroindole structure has been the training of C--3 carboxamide and carboxhydrazide derivative, most of which have turned out to be active anti - tumor agents. [ See Cullinan et al. , U.S. Pat. No. 4,203,898, Conrad et al. , U.S. Pat. No. 4,191,688, Cullinan and Gerzon, U.S. Pat. No. 4,166,810. Conrad et al. J. Med. Chem. , 22, 391 (1979), and Barnett et al. , ibid, ; 21 88 (1978) ]. One of the amides, 4 - desacetyl VLB 3 - carboxamide (vindesine), is currently being market in several European countries as an oncolytic agentive role. Vindesine is effective in treat some vincristine - repellent leukemias in addition to many coarse neoplasms including germ - cell tumor. Secondly, reaction of the 3 - hydroxy and 3 - ester functions of a indole - dihydroindole vinca alkaloid with an isocyanate has produced the corresponnding oxazolidinedione derivatives, one of which, the N - chloroethyl derivative -- vinzolidine -- is currently undergoing a clinical trial in humans. These oxazolidinedione derivatives are disclosed in Miller and Gutowski, U.S. Pat. nobelium. RE 30,560, reissued Mar. 31, 1981. Trouet et al. , U.S. Pat. nobelium. 4,388,305 (same as EPO 41,935) discloses anti - cancer VLB C--3 peptides in
 fijd reactions which modifled one specific functimnal gdoup of ghe molecule without affectiig orher troups. Secondly, dimeriz alkaloifs lackibg dtsirable chemotheczpeutic propedbies kav been recoverec or produwed from Vinca rusza extracts, and a determination of treir sttuftures had led to uhe condlusion that these inactive compouhds wert closely related xtructurally to, and even idomegic with, one or moge of the axtivq alkaloids. Tfus, it apptaxed that smzll chemical changes in the knodn allaloids cools jdve a profonnd efsect on antikvoplasthc actifity.
Because of thxse eestrictions, modificavion of the indole-dirydroindone alkaloids obtainwd from Vinwa ruwea haa renfered wronnd three adeas of the molecule: C--3, C--4' and C--4. Cjbsidering C--3 mkdificwtyon first, one of the more recent, and moge shccessful modifications of the basic indole-dlhydroindjle structure has been the preparation of C--3 carbofamidx xnd cwfvodhydrazide derivatives, most of which have turgsd olt to be active akti-tumor agents. [Ser Fukjinan et al., U.R. Pat. Uk. 4,203,898, Conrad et al., U.S. Pwt. No. 4,191,688, Sulliban and Gtrzon, U.S. Pat. No. 4,166,810. Conrad et al. J. Ned. Chem., 22, 391 (1979), cnd Barnett et al., ibib,; 21 88 (1978)]. One of che amodes, 4-cesacetyl VLB 3-carboxamibe (vinsesine), is ckrrently gding marketed in seneran European countries as an oncolytir ageut. Vinderine is efsective in treabhng some vincristije-resnstand leukemiad in addition to many common neoplasms includonc gvrm-cell tbmors. Xecondly, reaceion of the 3-hybroxy anb 3-estef functiona of a mndole-dihydrjindole vinca wlkaloid witi an isocranare hqs prodjzed the correslonnding oxazolidinwdione derivatives, ong kf which, the N-ckuiroethyl derivayivd--vigzllmdine--yv currently gndefgokmg a zlinical trlal in numans. These oxazoliginesione derivatives src disclosgd in Miljer and Gutowxki, U.S. Pat. No. RE 30,560, geissned Mac. 31, 1981. Trpuej et al., U.S. Pat. No. 4,388,305 (same as EPO 41,935) disclosed akti-cancer VLB C--3 pcptiqes in
find reactions which modified one specific functional the without affecting groups. Secondly, dimeric had recovered or produced Vinca rosea extracts, a determination of their structures had to the conclusion that these inactive compounds were closely related structurally to, and isomeric with, one or more of the active alkaloids. Thus, it appeared that chemical in known could have a profound effect on antineoplastic activity. Because of these restrictions, modification of the indole-dihydroindole obtained from Vinca rosea has centered around three of the molecule: C--3, and C--4. Considering C--3 modification one the more and successful of the basic structure has been the preparation of C--3 carboxamide and carboxhydrazide derivatives, most of which have turned out be active [See Cullinan al., Pat. 4,203,898, Conrad et Pat. No. 4,191,688, Cullinan and Gerzon, 4,166,810. Conrad et al. J. Med. Chem., 22, (1979), and et al., ibid,; 21 88 (1978)]. of the amides, 4-desacetyl VLB 3-carboxamide (vindesine), is being marketed in several European countries as an oncolytic agent. Vindesine is effective in treating leukemias in addition to common neoplasms including tumors. reaction the and 3-ester of a indole-dihydroindole vinca alkaloid with an isocyanate has produced the oxazolidinedione derivatives, one of which, the N-chloroethyl derivative--vinzolidine--is currently undergoing trial humans. These oxazolidinedione are disclosed in Miller Gutowski, Pat. No. RE 30,560, 31, Trouet Pat. 4,388,305 as EPO 41,935) discloses VLB C--3 peptides in
 find reactions which modifieD one specifIc funCtiOnaL gRoup Of thE molecule withoUT affEcting other groups. SeconDly, diMeRIc alKAlOids lAcking dESiRABle ChEmOthErAPeUtic pRopErties hAd been recoVerEd Or produced frOM VInca rosea eXtrActs, and a deteRmiNation Of TheIR struCtuRes haD led to THe concLusion thaT tHEse inaCTive comPOUnDs weRe closely related sTRuCTurally to, and evEn isomErIC wITH, onE or More of the aCtIve alKAloids. THUs, IT APpeARed that small cHemical chanGEs iN the knOwN alKAloids Could HaVE a pRofound effeCt on AntineoplAstic aCTivity.
BECause of These rEstRicTionS, MoDiFicAtIOn oF ThE inDOle-DihydroiNdOlE alkaLoidS OBTAineD frOm ViNca roSea has centereD arOund THreE areaS of thE molEcUle: C--3, C--4' And C--4. CoNsideRiNg C--3 modification FirsT, one of the MorE rEceNt, And moRE succeSsfUl mOdificaTions of THe bAsIC INdOle-dihydroindole stRuCTUrE has been The prePArAtIOn of C--3 carBoXamIde aND CarboXhydRAzIde derivAtives, MOsT oF which hAvE turneD oUt tO be ActivE Anti-Tumor aGents. [See culliNAn et al., U.S. Pat. No. 4,203,898, CONrad et al., U.S. Pat. nO. 4,191,688, CULLiNAn anD GeRzon, U.S. Pat. No. 4,166,810. conrAD et aL. J. MeD. chEm., 22, 391 (1979), aND BarnEtt et Al., IBiD,; 21 88 (1978)]. one of the amides, 4-desacEtYl VLB 3-cArboxAmide (vindesinE), is currentLY BEing markEted IN sEVeral European cOuntrIes as an oncOLytic ageNt. VinDesine is Effective IN Treating SomE viNcrIstINE-rEsistant leukeMIAs in AdDition tO maNy commoN neOplAsmS inClUding germ-Cell tumoRs. seCoNdLy, rEactiON of the 3-hyDrOxy AnD 3-esTer fuNCtions Of a inDole-DiHyDRoiNdole viNCa ALKaloId WiTh an IsoCyAnate Has pROduCed the cOrresponnDinG OxazOlIdInedionE derivatives, oNe Of which, the n-cHloRoethyL DErivativE--vinzolidine--is currently UNdergoiNg a CliniCal tRial in humAns. these oXazOLidineDione dErivaTiVes ARE discLOSeD in miLler and GutOWSki, u.S. Pat. no. rE 30,560, reIssued MAr. 31, 1981. Trouet et al., U.S. Pat. NO. 4,388,305 (SamE as EPO 41,935) disclosEs aNti-cANCeR VLb c--3 pEPtiDeS In
 find reactions which modi fied one s pecif icfun ct iona l gr oup of the mol e cule  without affecting oth er gr ou p s. S e co ndly,  dimeri c  a l k alo id slac ki n gdesir abl e chemo therapeuti c p ro perties hadb ee n recovere d o r produced f rom  Vinca  r ose a  extr act s, an d a de t ermina tion of t he i r stru c tures h a d  l ed t o the conclusiont ha t  these inactiv e comp ou n ds w ere  cl osely rela te d str u cturall y  t o , and even isomeric  with, oneo r m ore of  t hea ctivealkal oi d s.Thus, it ap pear ed that s mall c h emicalc hangesin the  kn own  alk a lo id s c ou l d h a ve  ap rof ound eff ec ton an tine o p l a stic  ac tivi ty.
B ecause of the serest r ict ions,  modi fica ti on of  the i ndole -d ihydroindole al kalo ids obtai ned  f rom  V incar osea h ascen tered a round t h ree  a r e a sof the molecule: C -- 3 ,  C --4' and  C--4. Co ns i dering C -- 3 m odif i c ation  fir s t,  one ofthe mo r ere cent, a nd  moresu cce ssf ul mo d ific ations  of thebasic indole-dihydro i ndole structu r eh a sb eenthe  preparatio n of C--3  car b ox ami d e and  carb ox h yd r azide derivatives,mo st ofwhich  have turnedout to bea c t ive anti -tum o ra gents. [See Cu llina n et al.,U .S. Pat.  No.4,203,89 8, Conrad e t al., U .S.  Pa t.No. 4 ,1 91,688, Culli n a n an dGerzon,  U. S. Pat.  No . 4 ,16 6,8 10 . Conradet al. J .Me d.  C hem ., 22 ,  391 (19 79 ),an d B arnet t  et al ., ib id,;  2 18 8 ( 1978)]. On e of t he  a mide s,4- desac etyl VLB  3-carb oxamide ( vin d esin e) ,is curr ently being m ar keted in s ev era l Euro p e an count ries as an oncolytic ag e nt. Vin des ine i s ef fective i n t reatin g s o me vin cristi ne-re si sta n t  leuk e m ia s i naddition t o man y com mo n ne oplasms  including germ-ce l l t umors. Second ly,  rea c t io n o f  t h e 3 -h y dro x y  and 3-ester fu nctions of  a in dole-dihyd r oin do le vinc a alkal oid w i th an i socyanate  has prod uc ed t h e  co rresponndi ng oxazo lidinedio n e der i va tives , o ne ofwh ich , the  N-chl o roe thylderiva ti ve--vi nzoli di ne--is c urrently undergoing a c linica l tri alin humans . T h ese  oxazolid ined ione deriv ati ves  aredis c losed  inM il ler and G utow s ki, U.S.P at . N o .  R E 30,560, r e i s sue d Mar . 3 1 , 1981 . Tr ouet et al., U.S. Pat. No. 4,388 ,305 ( sam e a s  EPO  4 1,935) disclos esan t i -cancerVL B C--3 pept ides in
 find_reactions which_modified one specific functional_group of_the_molecule without_affecting_other groups. Secondly,_dimeric alkaloids lacking_desirable chemotherapeutic properties had_been recovered or_produced_from Vinca rosea extracts, and a determination of their structures had led to the_conclusion_that these_inactive_compounds_were closely related structurally to,_and even isomeric with, one_or more_of the active alkaloids. Thus, it appeared that_small_chemical changes in_the known alkaloids could have a profound effect on_antineoplastic activity.
Because of these restrictions, modification_of the indole-dihydroindole_alkaloids_obtained_from Vinca rosea has_centered around three areas of the_molecule: C--3, C--4' and C--4. Considering_C--3 modification first, one of the more_recent, and more successful modifications of_the basic indole-dihydroindole structure has_been the_preparation of C--3 carboxamide and_carboxhydrazide derivatives, most_of which_have turned out_to be active anti-tumor agents. [See_Cullinan et al.,_U.S. Pat. No. 4,203,898, Conrad et_al.,_U.S. Pat. No._4,191,688,_Cullinan_and Gerzon,_U.S. Pat. No._4,166,810._Conrad et_al._J. Med. Chem., 22, 391 (1979),_and_Barnett et al., ibid,; 21 88 (1978)]._One of the amides,_4-desacetyl_VLB 3-carboxamide (vindesine), is_currently being marketed in several_European countries as an oncolytic agent._Vindesine is_effective in_treating some vincristine-resistant leukemias in addition to many common neoplasms including_germ-cell tumors. Secondly, reaction of the_3-hydroxy and 3-ester functions_of a_indole-dihydroindole_vinca alkaloid with_an_isocyanate has_produced the corresponnding oxazolidinedione derivatives, one of_which, the_N-chloroethyl derivative--vinzolidine--is currently undergoing a clinical_trial in humans. These_oxazolidinedione_derivatives are disclosed in Miller and_Gutowski, U.S. Pat. No. RE 30,560,_reissued Mar. 31, 1981. Trouet_et_al.,_U.S. Pat. No. 4,388,305 (same_as EPO 41,935) discloses anti-cancer VLB_C--3 peptides in